Methods of Treating Breast Cancer Using Tetrahydronaphthalene Derivatives as Estrogen Receptor Degraders - Patent application

Abstract

This application relates to treating and / or preventing breast cancer, including locally advanced or metastatic ER+, HER2- breast cancer, in a subject in need thereof, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, 1 , R 2 , R 3 , R 4 , m, and n are defined herein.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 125,371, filed December 14, 2020, the contents of which are incorporated by reference in their entirety herein.

[0002] Incorporation by reference of sequence listing This application contains a Sequence Listing that was submitted in ASCII format via EFS-Web and is incorporated herein by reference in its entirety. The ASCII copy, created on December 8, 2021, is named "ARVN-015-001WO_ST25.txt" and is approximately 6KB in size. [Background technology]

[0003] In the United States (US), breast cancer is the second leading cause of cancer death in women, with approximately 41,000 women expected to die from it in 2018. Although breast cancer is less common in men, they account for approximately 1% of all newly diagnosed cases, and approximately 500 men are expected to die from their disease in 2018 (Seigel RLet al. Cancer Statistics, CA Cancer J Clin. 2018, 68(1);7-30.).

[0004] As of January 2017, it is estimated that there are approximately 155,000 women living with metastatic breast cancer (mBC) in the United States. It has also been reported that the number of women living with mBC is increasing, mainly due to improved treatment and the aging of the US population. The estimated number of women with mBC increased by 17% from 2000 to 2010 and is projected to increase by 31% from 2010 to 2020 (Marioto ABet al. “Estimation of the Number of Women Living with Metastatic Breast Cancer 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, 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 agents such as CDK4 / 6 inhibitors (CDKi). In patients with aggressive disease, or whose disease continues to progress on endocrine therapy, chemotherapy may be prescribed.

[0006] The current standard of care for women with ER+, HER2-, mBC is endocrine therapy + / - CDKi or mTOR inhibitors. Endocrine therapy includes ovarian ablation or suppression (for premenopausal women), tamoxifen (a selective ER modulator), aromatase inhibitors, and fulvestrant (SERD). Metastatic breast cancer remains incurable, and sequencing endocrine therapy is the recommended approach for treating ER+ breast cancer. Adding targeted agents, including CDKi and mTOR inhibitors, to the endocrine therapy backbone further improves patient outcomes.

[0007] Fulvestrant is considered a cornerstone of ER-targeted endocrine regimens in the advanced disease setting, acting via an indirect mechanism of proteolysis, resulting in ER destabilization. Single-agent fulvestrant is administered 500 mg intramuscularly on days 1, 15, and 29, and then monthly. The efficacy of fulvestrant was established by comparison with the selective aromatase inhibitor anastrozole in two 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 prior treatment with antiestrogen or progestin for breast cancer in the adjuvant or advanced disease setting. In both studies, eligible patients with measurable and / or evaluable disease were randomized to receive either fulvestrant 250 mg intramuscularly once a month (28 days + 3 days) or anastrozole 1 mg orally once daily. The results of the studies after a minimum follow-up of 14.6 months ruled out the inferiority of fulvestrant to anastrozole. There was no statistically significant difference in overall survival (OS) between the two treatment arms after more than 2 years of follow-up. The third study compared a dose of fulvestrant 500 mg with a dose of fulvestrant 250 mg. The results of this study after a minimum follow-up of 18 months showed a statistically significant superior progression-free survival (PFS) with fulvestrant 500 mg versus fulvestrant 250 mg (6.5 vs. 5.4 months, respectively). There was no statistically significant difference in OS between the two treatment groups (25.1 months with fulvestrant 500 mg vs. 22.8 months with fulvestrant 250 mg). Overall response rates were similar, with a response rate of 13.8% (95% confidence interval [CI] 9.7 to 18.8%) for the 500 mg dose and 14.6% (CI 10.5 to 19.4%) for the 250 mg dose (Astra Zeneca Faslodex Full Prescribing Information, revised 03 / 2019). Summary of the Invention

[0008] In one aspect, the present application relates to a method of treating breast cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of formula (I): [ka] or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, to a subject, wherein: Each R 1 and each R 2 are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, SO2(R 5 ), C1-C6 alkyl, and C3-C6 cycloalkyl; R 3 and R 4 are either both hydrogen or together with the carbon to which they are attached form a carbonyl, Each R 5 and each R 6 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, or 4; The therapeutically effective amount of a compound of formula (I) is from about 10 mg to about 1000 mg.

[0009] In one aspect, the application relates to a method of treating breast cancer in a subject in need thereof, the subject comprising at least one somatic ER tumor mutation, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), the therapeutically effective amount of a compound of formula (I) being about 10 mg to about 1000 mg. In some embodiments, the breast cancer comprises at least one somatic ER tumor mutation.

[0010] In one aspect, the application relates 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 a compound of formula (I) is from about 10 mg to about 1000 mg.

[0011] In one aspect, the present application relates 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, and L536X, where "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.

[0012] In one aspect, the present application relates 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 breast cancer comprises at least one somatic ER tumor mutation selected from the group consisting of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to any amino acid residue other than the wild type residue at that position. In some embodiments, the breast cancer 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.

[0013] In some embodiments, the breast cancer is ER+, HER2-. In some embodiments, the breast cancer is metastatic or locally advanced.

[0014] In some embodiments, the compound of formula (I) is [ka] [ka] [ka] or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0015] In some embodiments, the compound of formula (I) is a compound of formula (Ia). In some embodiments, the compound of formula (I) is a compound of formula (Ic). In some embodiments, the compound of formula (I) is a compound of formula (Ij).

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

[0017] In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered to a subject once a day, twice a day, three times a day, or four times a day. In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered to a subject all at once, or in two, three, or four unit doses. In some embodiments, a therapeutically effective amount of a 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 a 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, the application relates 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) and further comprising administering to the subject in need of treatment a therapeutically effective amount of at least one additional anti-cancer agent.

[0019] In some embodiments, the additional anti-cancer agent is selected from the group consisting of FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 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 kinase inhibitors, and VEGF trap antibodies. In some embodiments, the additional anti-cancer agent is a CDK4 / 6 inhibitor.

[0020] In some embodiments, the additional anticancer agent is SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, venetoclax, inavolisib, pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, epithilone B 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, trastuzumab deruxtecan (genetical recombination) (fam-trastuzumab deruxtecan-nxki) (Enhertz), or eribulin (Halaven). In some embodiments, the additional anticancer agent is palbociclib.

[0021] In one aspect, the present application relates to a method of treating breast cancer in a subject in need thereof, comprising once daily oral administration of a therapeutically effective amount of a compound of formula (I), wherein the compound of formula (I) is [ka] [ka] [ka] or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, and the subject comprises at least one somatic ER tumor mutation. In some embodiments, the breast cancer comprises at least one somatic ER mutation.

[0022] In one aspect, the application relates to a method of treating breast cancer in a subject in need thereof comprising once daily oral administration of a therapeutically effective amount of a compound of formula (I), wherein the compound of formula (I) is (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), or (Ij), or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof; and the breast cancer comprises at least one somatic ER tumor mutation.

[0023] In one aspect, the application relates 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: (i) once daily oral administration of a therapeutically effective amount of a compound of formula (Ia) or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof; and (ii) palbociclib, administered orally once daily.

[0024] In one aspect, the application relates 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: (i) once daily oral administration of a therapeutically effective amount of a compound of formula (Ic) or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof; and (ii) palbociclib, administered orally once daily.

[0025] In one aspect, the application relates 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: (i) once daily oral administration of a therapeutically effective amount of a compound of formula (Ij) or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof; and (ii) palbociclib, administered orally once daily.

[0026] In one aspect, the present application provides 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; a therapeutically effective amount of a compound of formula (I), [ka] or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein Each R 1 and each R 2 are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, SO2(R 5 ), C1-C6 alkyl, and C3-C6 cycloalkyl; R 3 and R 4 are either both hydrogen or together with the carbon to which they are attached form a carbonyl, Each R 5 and each R 6 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, or 4; The therapeutically effective amount of the compound of formula (I) is from about 10 mg to about 1000 mg.

[0027] In one aspect, the present application provides 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; a therapeutically effective amount of a compound of formula (I), [ka] or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein Each R 1 and each R 2 are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, SO2(R 5 ), C1-C6 alkyl, and C3-C6 cycloalkyl; R 3 and R 4 are either both hydrogen or together with the carbon to which they are attached form a carbonyl, Each R 5 and each R 6 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, or 4; The therapeutically effective amount of the compound of formula (I) is from about 10 mg to about 1000 mg.

[0028] In some embodiments, the method further comprises administering at least one additional anti-cancer agent. In some embodiments, the additional anti-cancer agent is selected from the group consisting of FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 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 kinase inhibitors, and VEGF trap antibodies. In some embodiments, the additional anti-cancer agent is a CDK4 / 6 inhibitor. Additional anticancer drugs include SHR6390, trilaciclib, relociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, venetoclax, inavolisib, pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, and epithilone B. 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, trastuzumab deruxtecan (genetical recombination) (fam-trastuzumab deruxtecan-nxki) (Enhertz), or eribulin (Halaven). In some embodiments, the additional anticancer agent is palbociclib.

[0029] In some embodiments, administration of the additional anti-cancer agent occurs prior to administration of the compound of Formula (I). In some embodiments, administration of the additional anti-cancer agent occurs at least 30 minutes prior to administration of the compound of Formula (I). In some embodiments, administration of the additional anti-cancer agent occurs after administration of the compound of Formula (I). In some embodiments, administration of the additional anti-cancer agent occurs at least 30 minutes after administration of the compound of Formula (I).

[0030] In one aspect, the present application provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein Each R 1 and each R 2 are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, SO2(R 5 ), C1-C6 alkyl, and C3-C6 cycloalkyl; R 3 and R 4 are either both hydrogen or together with the carbon to which they are attached form a carbonyl, Each R 5 and each R 6 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, or 4; the subject comprises at least one somatic ER tumor mutation; The therapeutically effective amount of a compound of formula (I) is from about 10 mg to about 1000 mg. In some embodiments, the breast cancer contains at least one somatic ER mutation.

[0031] In one aspect, the present application provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein Each R 1 and each R 2 are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, SO2(R 5 ), C1-C6 alkyl, and C3-C6 cycloalkyl; R 3 and R 4 are either both hydrogen or together with the carbon to which they are attached form a carbonyl, Each R 5 and each R 6 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, or 4; the breast cancer contains at least one somatic ER tumor mutation; The therapeutically effective amount of a compound of formula (I) is from about 10 mg to about 1000 mg.

[0032] In one aspect, the present application provides a compound of formula (I): [ka] [ka] [ka] or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic 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 tumor mutation.

[0033] In one aspect, the present application provides a compound of formula (I): [ka] [ka] [ka] or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation.

[0034] In one aspect, the present application relates to a combination comprising a compound of formula (I) as disclosed herein, further comprising at least one additional anti-cancer agent, for use in the treatment of breast cancer in a subject in need thereof.

[0035] In one aspect, the application relates to a combination comprising (i) a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, and (ii) palbociclib, for use in the treatment of breast cancer in a subject in need thereof, wherein the breast cancer contains at least one somatic ER tumor mutation.

[0036] In one aspect, the application relates to a combination comprising (i) a compound of formula (Ic), or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, and (ii) palbociclib, for use in the treatment of breast cancer in a subject in need thereof, wherein the breast cancer contains at least one somatic ER tumor mutation.

[0037] In one aspect, the application relates to a combination comprising (i) a compound of formula (Ij), or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, and (ii) palbociclib, for use in the treatment of breast cancer in a subject in need thereof, wherein the breast cancer contains at least one somatic ER tumor mutation.

[0038] In one aspect, the application relates to a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic 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 the breast cancer comprises at least one somatic ER tumor mutation, and the therapeutically effective amount of the compound of formula (I) is from about 10 mg to about 1000 mg.

[0039] In one aspect, the present application provides a compound of formula (I): [ka] [ka] [ka] or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein the subject comprises at least one somatic ER tumor mutation and the therapeutically effective amount of a 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.

[0040] In one aspect, the present application provides a compound of formula (I): [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein the breast cancer contains at least one somatic ER tumor mutation and the therapeutically effective amount of a compound of formula (I) is from about 10 mg to about 1000 mg.

[0041] In one aspect, the present application relates to a combination comprising a compound of formula (I) as disclosed herein, further comprising at least one additional anti-cancer agent, for use in the manufacture of a medicament for the treatment of breast cancer in a subject in need thereof.

[0042] In one aspect, the application relates to a combination comprising (i) a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, and (ii) palbociclib, for use in the manufacture of a medicament for the treatment of breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation.

[0043] In one aspect, the application relates to a combination comprising (i) a compound of formula (Ic), or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, and (ii) palbociclib, for use in the manufacture of a medicament for the treatment of breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation.

[0044] In one aspect, the application relates to a combination comprising (i) a compound of formula (Ij), or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, and (ii) palbociclib, for use in the manufacture of a medicament for the treatment of breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation.

[0045] In one aspect, the application relates to a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic 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 the breast cancer comprises at least one somatic ER tumor mutation, and the therapeutically effective amount of the compound of formula (I) is from about 10 mg to about 1000 mg. [Brief description of the drawings]

[0046] This patent or application contains at least one drawing executed in color. Copies of this patent or patent application publication including a color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0047] [Figure 1] Figure 1 shows the results of tumor growth inhibition experiments (mean tumor volume (mm3) vs. time) associated with once-daily oral administration of compound (Ic) at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg compared to vehicle. At doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg of compound (Ic), 85%, 98%, and 124% tumor growth inhibition (TGI) was observed, respectively, compared to the control group in the MCF7 xenograft model. [Diagram 2] FIG. 1 is a Western blot experiment showing ER reduction in MCF7 xenograft tumors in response to administration of 3 mg / kg, 10 mg / kg, and 30 mg / kg of Compound (Ic) (orally, once daily). [Diagram 3] 1 is a pair of line graphs showing the mean concentration (ng / mL) of the compound of formula (Ic) over 24 hours post-dose on both Day 1 and Day 15 of a Phase I clinical trial. [Figure 4] 1 is a line graph depicting the mean trough concentrations (ng / mL) of compound (Ic) throughout the course of a Phase I clinical trial. [Diagram 5] 1 is a graph and Western blot experiment showing the ERα degradation activity of compound (Ic) following oral dosing at 10 mg / kg three times daily. [Figure 6] Figure 1 shows the results of a tumor growth inhibition study (mean tumor volume (mm3) vs. time) associated with oral administration of compound (Ic) once a day for 28 days at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg compared to vehicle. At doses of compound (Ic) of 3 mg / kg, 10 mg / kg, and 30 mg / kg, 85%, 98%, and 124% tumor growth inhibition (TGI) was observed, respectively, compared to the control group in the MCF7 xenograft model. [Figure 7] FIG. 1 is a graph showing that daily oral administration of 3 mg / kg, 10 mg / kg, and 30 mg / kg of Compound (Ic) for 28 days reduces ERα levels by >94% compared to mice administered vehicle only. [Figure 8]Figure 1 shows the results of tumor growth inhibition experiments (mean tumor volume (mm3) vs. time) involving oral administration of compound (Ic) at a dose of 30 mg / kg once daily for 28 days, compound (Ic) (30 mg / kg, oral, once daily for 28 days) with palbociclib (oral, once daily at 60 mg / kg for 28 days), fulvestrant (200 mg / kg, subcutaneous, twice weekly for 2 weeks), and fulvestrant (200 mg / kg, subcutaneous, twice weekly for 2 weeks) with palbociclib (oral, once daily at 60 mg / kg for 28 days) compared to vehicle. Compared to single agent compound (Ic) activity in this model (105% TGI), the combination of compound (Ic) with palbociclib resulted in significant tumor regression (131% TGI). In contrast, single-agent fulvestrant administered subcutaneously resulted in only modest tumor growth inhibition (46% TGI), while the combination of fulvestrant with palbociclib resulted in improved tumor growth inhibition (108% TGI), but not near the level achieved with compound (Ic) and palbociclib. [Figure 9] FIG. 1 shows the results of a tamoxifen-resistant MCF7 xenograft growth inhibition study (mean tumor volume (mm3) versus time) associated with oral administration of compound (Ic) at a dose of 30 mg / kg once daily for 28 days compared to palbociclib (60 mg / kg, orally, once daily, for 28 days), compound (Ic) (30 mg / kg, orally, once daily, for 28 days) and palbociclib (60 mg / kg, orally, once daily, for 28 days), and vehicle. When compound (Ic) was combined with 60 mg / kg / day palbociclib, the combination regimen caused greater tumor growth inhibition (113% TGI) compared to the palbociclib monotherapy group (91% TGI). [Figure 10] FIG. 10 is a graph showing the effect of administration of Compound (Ic) (30 mg / kg, orally, once daily for 28 days, FIG. 10) on in vivo ERα levels in a tamoxifen-resistant MCF7 xenograft experiment. [Figure 11]FIG. 11 is a graph showing the effect of administration of Compound (Ic) (30 mg / kg, orally, once daily for 28 days) and Palbociclib (60 mg / kg, orally, once daily for 28 days) on in vivo ERα levels in a tamoxifen-resistant MCF7 xenograft experiment. [Figure 12] FIG. 12 is a graph showing the effect of administration of palbociclib (60 mg / kg, orally, once daily for 28 days; FIG. 12) on in vivo ERα levels in a tamoxifen-resistant MCF7 xenograft experiment. [Figure 13] 1 provides the results of several Western blot experiments comparing the in vitro ERα degrading activity of Fulvestrant and Compound (Ic) at various concentrations in several ER-positive breast cancer cell lines. [Figure 14] FIG. 1 is a graph showing that the half-maximal degradation concentration (DC50) of compound (Ic) in MCF7 cells is 0.9 nM. [Figure 15] 1 provides the results of several Western blot experiments comparing the in vitro ERα degrading activity of Fulvestrant and Compound (Ic) at various concentrations in the clinically relevant ESR1 cell line variants Y537S and D538G. [Figure 16] Graph showing relative expression of GREB1 and PR in experiments with fulvestrant and compound (Ic) compared to vehicle (DMSO). [Figure 17] FIG. 1 is a graph showing the effect of Fulvestrant (100 mg / kg, once daily, subcutaneously) and Compound (Ic) (30 mg / kg, once daily, orally) compared to vehicle on uterine weight. [Figure 18] FIG. 13 is a Western blot comparing the in vivo ERα degradation activity of compound (Ic) (10 mg / kg orally for 3 days) with vehicle in a MCF7 / E2 xenograft model. [Figure 19]Figure 1 shows the results of tumor growth inhibition experiments (mean tumor volume (mm3) vs. time) associated with oral administration of compound (Ic) once a day for 28 days at doses of 3mg / kg, 10mg / kg, and 30mg / kg compared to vehicle. At doses of compound (Ic) of 3mg / kg, 10mg / kg, and 30mg / kg, 85%, 98%, and 124% tumor growth inhibition (TGI) was observed in the MCF7 / estradiol xenograft model, respectively, compared to the control group. [Figure 20] FIG. 1 shows the results of tumor growth inhibition (mean tumor volume (mm3) vs. time) experiments in the MCF7 / estradiol model involving oral administration of compound (Ic) at a dose of 30 mg / kg once daily for 28 days, fulvestrant (200 mg / kg, subcutaneous, twice weekly for 2 weeks), compound (Ic) (oral, 30 mg / kg once daily for 28 days) with palbociclib (oral, 60 mg / kg once daily for 28 days), and fulvestrant (200 mg / kg, subcutaneous, twice weekly for 2 weeks) with palbociclib (oral, 60 mg / kg once daily for 28 days) compared to vehicle. The combination of compound (Ic) with palbociclib resulted in significant tumor regression (131% TGI) compared to single agent compound (Ic) activity in this model (105% TGI). In contrast, single-agent fulvestrant administered subcutaneously resulted in only modest tumor growth inhibition (46% TGI), while the combination of fulvestrant with palbociclib resulted in improved tumor growth inhibition (108% TGI), but not to the level achieved with compound (Ic) and palbociclib (131% TGI). [Figure 21]Figure 1 shows the results of tumor growth inhibition (mean tumor volume (mm3) vs. time) experiments in a tamoxifen-resistant MCF7 model involving oral administration of compound (Ic) at a dose of 30 mg / kg once daily for 28 days, palbociclib (oral, at a dose of 60 mg / kg once daily for 28 days), and compound (Ic) (oral, at a dose of 30 mg / kg once daily for 28 days) and palbociclib (oral, at a dose of 60 mg / kg once daily for 28 days) compared to vehicle. Compound (Ic) alone reduced tumor growth, but the combination of compound (Ic) and palbociclib resulted in improved inhibition of tumor growth compared to compound (Ic) alone (113% vs. 65%). [Figure 22] Figure 1 shows the results of a tumor growth inhibition (mean tumor volume (mm3) vs. time) experiment in the ESR1 (Y537S) PDX model associated with oral administration of compound (Ic) at a dose of 10 mg / kg or 30 mg / kg once daily for 28 days or administration of fulvestrant (200 mg / kg, subcutaneous, twice weekly for 2 weeks). At either a dose of 10 mg / kg or 30 mg / kg, compound (Ic) reduced tumor ERα levels more than fulvestrant (79 / 88% vs. 63%) and resulted in improved inhibition of tumor growth compared to fulvestrant (99 / 106% vs. 62%). [Figure 23A] Figure 23A shows the growth inhibitory effect observed by combining the CDK4 / 6 inhibitor Abemaciclib with compound (Ic) in a luminescence-based MCF7 cell proliferation assay. Figure 23B shows the dose-response analysis (% change) of the effect of compound (Ic) on cell proliferation relative to vehicle control (DMSO) treated cells. [Figure 23B] FIG. 23B shows a dose-response analysis (% change) of the effect of abemaciclib on cell proliferation relative to vehicle control (DMSO) treated cells. [Figure 23C] FIG. 23C shows the dose-response shift of compound (Ic) with the addition of abemaciclib. [Figure 23D] FIG. 23D shows drug combination efficacy analysis using the Bliss independence model. [Figure 23E] FIG. 23E shows drug combination efficacy analysis using the Loewe additivity model. [Figure 23F] FIG. 23F shows drug combination efficacy analysis using the Highest Single Agent model. [Figure 24A] Figure 24 shows live cell imaging analysis demonstrating the enhanced growth inhibitory effect of the combination of compound (Ic) and abemaciclib on MCF7 cells compared to either single agent alone. Figure 24A shows the change in cell growth of drug-treated cells versus control cells over 120 hours. [Figure 24B] FIG. 24B shows the change in cell proliferation of drug-treated cells versus control cells at 120 hours. [Figure 25A] Figure 25 shows the growth inhibitory effect observed by combining compound (Ic) with the mTOR inhibitor everolimus in a luminescence-based MCF7 cell proliferation assay. Figure 25A shows the dose-response analysis (% change) of the effect of compound (Ic) on cell proliferation relative to vehicle control (DMSO) treated cells. [Figure 25B] FIG. 25B shows a dose-response analysis (% change) of the effect of everolimus on cell proliferation relative to vehicle control (DMSO) treated cells. [Figure 25C] FIG. 25C shows the dose-response shift of compound (Ic) upon addition of everolimus. [Figure 25D] FIG. 25D shows drug combination efficacy analysis using the Bliss independence model. [Figure 25E] FIG. 25E shows drug combination efficacy analysis using the Loewe additivity model. [Figure 25F] FIG. 25F shows drug combination efficacy analysis using the best single agent model. [Figure 26A]Live cell imaging analysis shows the enhanced growth inhibitory effect of the combination of compound (Ic) and everolimus in MCF7 (Figure 26A, Figure 26B) or T47D cells (Figure 26C, Figure 26D) compared to cells treated with either drug alone. Figure 26A shows the change in cell growth of drug-treated MCF7 cells compared to control cells over time. [Figure 26B] FIG. 26B shows the change in cell proliferation of drug-treated MCF7 cells versus control cells. [Figure 26C] FIG. 26C shows the change in cell proliferation of drug-treated T47D cells versus control cells over time. [Figure 26D] FIG. 26D shows the change in cell proliferation of drug-treated T47D cells versus control cells. [Figure 27A] Figure 27 shows live cell imaging analysis demonstrating the enhanced growth inhibitory effect of the combination of compound (Ic) and everolimus in T47D cells carrying ESR1 Y537S (Figure 27A, Figure 27B) or D538G (Figure 27C, Figure 27D) relative to cells treated with either drug alone. Figure 27A shows the change in cell growth of drug-treated MCF7 cells relative to control cells over time. [Figure 27B] FIG. 27B shows the change in cell proliferation of drug-treated MCF7 cells versus control cells. [Figure 27C] FIG. 27C shows the change in cell proliferation of drug-treated T47D cells versus control cells over time. [Figure 27D] FIG. 27D shows the change in cell proliferation of drug-treated T47D cells versus control cells. [Figure 28] 1 shows the results of a tumor growth inhibition (TGI) experiment (mean tumor volume (mm3) versus time) associated with once-daily oral administration of compound (Ic), everolimus, and compound (Ic) plus everolimus compared to vehicle. [Figure 29A]Figure 29A shows the enhanced growth inhibitory effect observed by combining the PI3 kinase inhibitor alpelisib with compound (Ic) in luminescence-based MCF7 cell growth. Figure 29B shows a dose-response analysis (% change) of the effect of compound (Ic) on cell growth relative to vehicle control (DMSO) treated cells. [Figure 29B] FIG. 29B shows a dose-response analysis (% change) of the effect of alpelisib on cell proliferation relative to vehicle control (DMSO) treated cells. [Figure 29C] FIG. 29C shows the dose-response shift of compound (Ic) with the addition of alpelisib. [Figure 29D] FIG. 29D shows drug combination efficacy analysis using the Bliss independence model. [Figure 29E] FIG. 29E shows drug combination efficacy analysis using the Loewe additivity model. [Figure 29F] FIG. 29F shows drug combination efficacy analysis using the best single agent model. [Figure 30A] Live cell imaging analysis demonstrates the enhanced growth inhibitory effect of the combination of compound (Ic) and alpelisib in MCF7 (FIG. 30A, FIG. 30B) or T47D cells (FIG. 30C, FIG. 30D) versus cells treated with either drug alone. FIG. 30A shows the change in cell growth of drug-treated MCF7 cells versus control cells over time. [Figure 30B] FIG. 30B shows the change in cell proliferation of drug-treated MCF7 cells versus control cells at 120 hours. [Figure 30C] FIG. 30C shows the change in cell proliferation of drug-treated T47D cells versus control cells over time. [Figure 30D] FIG. 30D shows the change in cell proliferation of drug-treated T47D cells versus control cells at 120 hours. [Diagram 31] 1 shows tumor growth inhibition (TGI) results associated with administration of Compound (Ic), alpelisib, and Compound (Ic) plus compared to vehicle. [Figure 32A]Figure 32A demonstrates the enhanced growth inhibitory effect observed by combining the PI3 kinase inhibitor inavolisib (GDC-0077) with compound (Ic) in a luminescence-based MCF7 cell proliferation assay. Figure 32A shows a dose-response analysis (% change) of the effect of compound (Ic) on cell proliferation relative to vehicle control (DMSO) treated cells. [Figure 32B] FIG. 32B shows a dose-response analysis (% change) of the effect of GDC-0077 on cell proliferation relative to vehicle control (DMSO) treated cells. [Figure 32C] FIG. 32C shows the dose-response shift of compound (Ic) upon addition of GDC-0077. [Fig. 32D] FIG. 32D shows drug combination efficacy analysis using the Bliss independence model. [Figure 32E] FIG. 32E shows drug combination efficacy analysis using the Loewe additivity model. [Fig. 32F] FIG. 32F shows drug combination efficacy analysis using the best single agent model. [Figure 33A] Live cell imaging analysis demonstrates the enhanced growth inhibitory effect of the combination of compound (Ic) and GDC-0077 in MCF7 (Figure 33A, Figure 33B) or T47D cells (Figure 33C, Figure 33D) versus cells treated with either drug alone. Figure 33A shows the change in cell growth of drug-treated MCF7 cells versus control cells over time. [Figure 33B] FIG. 33B shows the change in cell proliferation of drug-treated MCF7 cells versus control cells. [Figure 33C] FIG. 33C shows the change in cell proliferation of drug-treated T47D cells versus control cells over time. [Figure 33D] FIG. 33D shows the change in cell proliferation of drug-treated T47D cells versus control cells. [Figure 34A]34A demonstrates the enhanced growth inhibitory effect observed by combining the BCL2 inhibitor venetoclax with compound (Ic) in a luminescence-based MCF7 cell proliferation assay. Figure 34A shows a dose-response analysis (% change) of the effect of compound (Ic) on cell proliferation relative to vehicle control (DMSO) treated cells. [Figure 34B] Figure 34B shows a dose-response analysis (% change) of the effect of venetoclax on cell proliferation relative to vehicle control (DMSO) treated cells. [Figure 34C] FIG. 34C shows the dose-response shift of compound (Ic) with the addition of venetoclax. [Fig. 34D] FIG. 34D shows drug combination efficacy analysis using the Bliss independence model. [Figure 34E] FIG. 34E shows drug combination efficacy analysis using the Loewe additivity model. [Fig. 34F] FIG. 34F shows drug combination efficacy analysis using the best single agent model. [Figure 35A] Figure 35A shows live cell imaging analysis demonstrating the enhanced growth inhibitory effect of compound (Ic), venetoclax, and the combination on cell proliferation over 120 hours (5 days) versus DMSO-treated (control) cells. Figure 35B shows the change in cell proliferation of drug-treated cells versus control cells over time. [Figure 35B] FIG. 35B shows the change in cell proliferation of drug-treated cells versus control cells.

[0048] Sequence Listing: All references to amino acid mutations in the estrogen receptor are numbered relative to SEQ ID NO:1, provided below. Sequence Listing 1 JPEG2024501471000025.jpg122145 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0049] In one aspect, the present application relates to a method of treating breast cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of formula (I): [ka] or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, to a subject, wherein: Each R 1 and each R 2 are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, SO2(R 5 ), C1-C6 alkyl, and C3-C6 cycloalkyl; R 3 and R 4 are either both hydrogen or together with the carbon to which they are attached form a carbonyl, Each R 5 and each R 6 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, or 4.

[0050] In one aspect, the application relates to a method of treating breast cancer in a subject in need thereof, wherein the subject contains at least one somatic ER tumor mutation, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I): [ka] or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, to a subject, wherein: Each R 1 and each R 2 are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, SO2(R 5), C1-C6 alkyl, and C3-C6 cycloalkyl; R 3 and R 4 are either both hydrogen or together with the carbon to which they are attached form a carbonyl, Each R 5 and each R 6 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, or 4. In some embodiments, the breast cancer comprises at least one somatic ER mutation.

[0051] In one aspect, the application relates to a method of treating breast cancer in a subject in need thereof, the breast cancer comprising at least one somatic ER tumor mutation, the method comprising administering to a subject a therapeutically effective amount of a compound of formula (I): [ka] or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof to a subject, wherein Each R 1 and each R 2 are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, SO2(R 5 ), C1-C6 alkyl, and C3-C6 cycloalkyl; R 3 and R 4 are either both hydrogen or together with the carbon to which they are attached form a carbonyl, Each R 5 and each R 6 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, or 4.

[0052] In one aspect, the application relates 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 a compound of formula (I) is from about 10 mg to about 1000 mg.

[0053] In one aspect, the present application relates 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).

[0054] In one aspect, the application relates to a compound of formula (I) for use in treating breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation.

[0055] In one aspect, the application relates to a compound of formula (I) for use in treating breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation.

[0056] 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, and L536P.

[0057] In some embodiments, the breast cancer is ER+, HER2-.

[0058] In some embodiments, the breast cancer is metastatic or locally advanced.

[0059] In some embodiments, each R 1 and each R 2are independently halo and OR 5 is selected from the group consisting of:

[0060] In some embodiments, R 3 and R 4 are both hydrogen.

[0061] In some embodiments, R 3 and R 4は , together with the carbon to which they are attached to form a carbonyl.

[0062] In some embodiments, m and n are each 0. In some embodiments, m and n are each 1. In some embodiments, one of m and n is 0 and the other is 1. For example, in some embodiments, m is 0 and n is 1. In other embodiments, m is 0 and n is 1.

[0063] In some embodiments, the compound of formula (I) is [ka] [ka] [ka] or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0064] In some embodiments, the methods comprise administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, polymorph, or isotopic derivative thereof.

[0065] In one aspect, the present application relates to a compound of formula (I), or a pharma- ceutically 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 pharma- ceutically acceptable salt, solvate, polymorph, or isotopic derivative thereof. In some embodiments, the compound of formula (I) is orally administered to the subject. In some embodiments, the breast cancer comprises at least one somatic ER mutation.

[0066] In one aspect, the present application relates to a compound of formula (I), or a pharma- ceutically 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 pharma- ceutically acceptable salt, solvate, polymorph, or isotopic derivative thereof. In some embodiments, the compound of formula (I) is orally administered to the subject.

[0067] In one aspect, the present application relates to a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, polymorph, or isotopic derivative thereof, for use in treating breast cancer in a subject in need thereof, the subject comprising at least one somatic ER tumor mutation. In some embodiments, the compound of formula (I) is orally administered to the subject. In some embodiments, the breast cancer comprises at least one somatic ER mutation.

[0068] In one aspect, the present application relates to a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, polymorph, or isotopic derivative thereof, for use in 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 compound of formula (I) is orally administered to the subject.

[0069] In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered to a subject once a day, twice a day, three times a day, or four times a day. In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered to a subject once a day. In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered to a subject all at once, or in two, three, or four unit doses.

[0070] In some embodiments, the therapeutically effective amount of a 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.

[0071] In some embodiments, the therapeutically effective amount of a compound of formula (I) is about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, or about 40 mg.

[0072] In some embodiments, the therapeutically effective amount of a compound of formula (I) is from about 10 mg to about 1000 mg.

[0073] In some embodiments, the therapeutically effective amount of a compound of formula (I) is from about 20 mg to about 700 mg.

[0074] In some embodiments, the therapeutically effective amount of a compound of formula (I) is from about 30 mg to about 500 mg.

[0075] In some embodiments, the therapeutically effective amount of a compound of formula (I) is from about 30 mg to about 120 mg.

[0076] In some embodiments, a therapeutically effective amount of a 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 1 90 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.

[0077] In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a Day 15 mean AUC of greater than about 3,500 ng·hr / mL, greater than about 3,600 ng·hr / mL, greater than about 3,700 ng·hr / mL, greater than about 3,800 ng·hr / mL, greater than about 3,900 ng·hr / mL, greater than about 4,000 ng·hr / mL, greater than about 4,100 ng·hr / mL, greater than about 4,200 ng·hr / mL, greater than about 4,300 ng·hr / mL, greater than about 4,400 ng·hr / mL, greater than about 4,500 ng·hr / mL, greater than about 4,600 ng·hr / mL, greater than about 4,700 ng·hr / mL, greater than about 4,800 ng·hr / mL, greater than about 4,900 ng·hr / mL, or greater than about 5,000 ng·hr / mL. TAU results.

[0078] In some embodiments, a therapeutically effective amount of a compound of Formula (I) has a day 15 mean AUC value of greater than about 3,500 ng·hr / mL and less than about 4,000 ng·hr / mL. TAUIn some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAUIn some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU results.

[0079] In some embodiments, a therapeutically effective amount of a compound of Formula (I) has a day 15 mean AUC value of greater than about 4,000 ng·hr / mL and less than about 4,200 ng·hr / mL. TAU In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU results.

[0080] In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean C of greater than about 200 ng / mL, about 205 ng / mL, about 210 ng / mL, about 215 ng / mL, about 220 ng / mL, about 225 ng / mL, about 230 ng / mL, about 235 ng / mL, about 240 ng / mL, about 245 ng / mL, or about 250 ng / mL. max results.

[0081] In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean C of greater than about 200 ng / mL and less than about 220 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 205 ng / mL and less than about 225 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 210 ng / mL and less than about 230 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 215 ng / mL and less than about 235 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 220 ng / mL and less than about 240 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 225 ng / mL and less than about 245 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 230 ng / mL and less than about 250 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 235 ng / mL and less than about 255 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 240 ng / mL and less than about 260 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 245 ng / mL and less than about 265 ng / mL. maxIn some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 250 ng / mL and less than about 270 ng / mL. max results.

[0082] In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean C of greater than about 214 ng / mL and less than about 236 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 213 ng / mL and less than about 237 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 212 ng / mL and less than about 238 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 211 ng / mL and less than about 239 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 210 ng / mL and less than about 240 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 205 ng / mL and less than about 245 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 200 ng / mL and less than about 250 ng / mL. max results.

[0083] In some embodiments, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean C of greater than about 223 ng / mL and less than about 225 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 222 ng / mL and less than about 226 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 221 ng / mL and less than about 227 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 220 ng / mL and less than about 228 ng / mL.max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 219 ng / mL and less than about 229 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 218 ng / mL and less than about 230 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 217 ng / mL and less than about 231 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 216 ng / mL and less than about 232 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 215 ng / mL and less than about 233 ng / mL. max In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 214 ng / mL and less than about 234 ng / mL. max results.

[0084] In some embodiments, the compound of formula (I) is formulated as a tablet. In some embodiments, the tablet comprises the compound of formula (I) and optionally 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 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.

[0085] In one aspect, the present application relates 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, and further comprising administering to the subject in need of treatment a therapeutically effective amount of at least one additional anti-cancer agent.

[0086] In one aspect, the application relates to a therapeutically effective amount of 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 administering to the subject in need thereof a therapeutically effective amount of at least one additional anti-cancer agent. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I).

[0087] In one aspect, the application relates to a therapeutically effective amount of a compound of formula (I) as defined herein for use in treating breast cancer in a subject in need of such treatment, wherein the treatment further comprises administration to the subject in need of such treatment of a therapeutically effective amount of at least one additional anti-cancer agent.

[0088] In one aspect, the present application relates to a combination comprising a compound of formula (I) as defined herein and at least one additional anti-cancer agent in a therapeutically effective amount for the treatment of breast cancer in a subject in need thereof.

[0089] In some embodiments, the at least one additional anti-cancer 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 CDK4 / 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 kinase inhibitor, or a VEGF trap antibody.

[0090] In some embodiments, the at least one additional anti-cancer agent is a CDK4 / 6 inhibitor.

[0091] In some embodiments, the at least one additional anticancer agent is SHR6390, trilaciclib, relociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, epithilone B 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, trastuzumab deruxtecan (genetical recombination) (fam-trastuzumab deruxtecan-nxki) (Enhertz), or eribulin (Halaven).

[0092] In some embodiments, the at least one additional anticancer agent is selected from SHR6390, trilaciclib, relociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, and palbociclib.

[0093] In some embodiments, the at least one additional anti-cancer agent is palbociclib. In some embodiments, the at least one additional anti-cancer agent is abemaciclib. In some embodiments, the at least one additional anti-cancer agent is everolimus. In some embodiments, the at least one additional anti-cancer agent is alpelisib. In some embodiments, the at least one additional anti-cancer agent is GDC-0077. In some embodiments, the at least one additional anti-cancer agent is venetoclax.

[0094] In some embodiments, administration of the additional anti-cancer agent occurs prior to administration of the compound of Formula (I).

[0095] In some embodiments, the administration of the additional anti-cancer agent occurs at least 30 minutes prior to the administration of the compound of Formula (I).

[0096] In some embodiments, administration of the additional anti-cancer agent occurs after administration of the compound of Formula (I).

[0097] In some embodiments, the administration of the additional anticancer agent occurs at least 30 minutes after the administration of the compound of Formula (I).

[0098] In some embodiments, in a method of treating breast cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I) to the subject and further comprising administering a therapeutically effective amount of palbociclib, a therapeutically effective amount of palbociclib is administered to the subject once a day. In some embodiments, the therapeutically effective amount of palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg. In some embodiments, palbociclib is administered once a day for up to 21 consecutive days, followed by cessation of treatment for up to 7 consecutive days, and the cycle of treatment with palbociclib followed by cessation of treatment is repeated 1, 2, 3, 4, 5, or more times. In some embodiments, the compound of Formula (I) is administered once a day for up to 21 consecutive days, followed by cessation of treatment for up to 7 consecutive days, and the cycle of treatment with the compound of Formula (I) followed by cessation of treatment is repeated 1, 2, 3, 4, 5, or more times. In some embodiments, the administration of the compound of Formula (I) and palbociclib to a subject in need of treatment occurs when the subject is in a fed state. In some embodiments, the administration of the compound of Formula (I) and palbociclib to a subject in need of treatment occurs when the subject is in a fasted state.

[0099] In one aspect, the application relates to a method of treating breast cancer in a subject in need thereof, the subject comprising at least one somatic ER tumor mutation, the method comprising once daily oral administration of a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein the compound of formula (I) is selected from the group consisting of: [ka] [ka] [ka] In some embodiments, the breast cancer comprises at least one somatic ER tumor mutation.

[0100] In one aspect, the application relates to a method of treating metastatic breast cancer in a subject in need thereof, the breast cancer comprising at least one somatic ER tumor mutation, comprising once daily oral administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein the compound of formula (I) is selected from the group consisting of: [ka] [ka] [ka]

[0101] In one aspect, the application relates to a compound of formula (I), or a pharma- ceutically 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, and the method comprises once-daily oral administration of a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein the compound of formula (I) is selected from the group consisting of (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), and (Ii).

[0102] In one aspect, the application relates to a compound of formula (I), or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, for use in treating breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation, and the treatment comprises once-daily oral administration of a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein the compound of formula (I) is selected from the group consisting of (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), and (Ii).

[0103] In some embodiments, the compound of formula (I) is a compound of formula (Ic).

[0104] 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, and L536P.

[0105] In some embodiments, the breast cancer is ER+, HER2-.

[0106] In some embodiments, the breast cancer is metastatic or locally advanced.

[0107] In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered to a subject all at once, or in two, three, or four unit doses.

[0108] In some embodiments, the therapeutically effective amount of a compound of formula (I) is from about 30 mg to about 1000 mg.

[0109] In some embodiments, a therapeutically effective amount of a 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 1 90 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.

[0110] In some embodiments, the compound of formula (I) is formulated as a tablet.

[0111] In one aspect, the application relates 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), wherein the compound of Formula (I) is a compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ii), or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, and the method further comprises administering a therapeutically effective amount of at least one additional anti-cancer agent, wherein the anti-cancer agent is selected from the group consisting of an FLT-3 inhibitor, a VEGFR inhibitor, an EGFR inhibitor, a cytotoxic T-cell inhibitor, a vasopressin ... TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 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 trap antibodies, SHR6390, trilaciclib, relociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, venetoclax, inavolisib (GDC-0077), pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, epithilone B (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, trastuzumab deruxtecan (genetical recombination) (fam-trastuzumab deruxtecan-nxki) (Enhertz), or eribulin (Halaven).

[0112] In one aspect, the application relates to a compound of formula (I) for use in 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), wherein the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ii), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, and the method further comprises administering a therapeutically effective amount of at least one additional anti-cancer agent, wherein the anti-cancer agent is selected from the group consisting of an FLT-3 inhibitor, a VEGFR inhibitor, an EGFR inhibitor, a cytotoxic T-cell inhibitor, a vasopressin ... TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 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 trap antibodies, SHR6390, trilaciclib, relociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, venetoclax, inavolisib (GDC-0077), pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, epithilone B (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, trastuzumab deruxtecan (genetical recombination) (fam-trastuzumab deruxtecan-nxki) (Enhertz), or eribulin (Halaven).

[0113] In one aspect, the application relates to a compound of formula (I) for use in treating breast cancer in a subject in need thereof, the treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (I), wherein the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ii), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, and the treatment further comprises administering a therapeutically effective amount of at least one additional anti-cancer agent, wherein the anti-cancer agent is selected from the group consisting of an FLT-3 inhibitor, a VEGFR inhibitor, an EGFR inhibitor, a cytotoxic T-cell inhibitor, a vasopressin ... TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 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 trap antibodies, SHR6390, trilaciclib, relociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, venetoclax, inavolisib (GDC-0077), pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, epithilone B (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, trastuzumab deruxtecan (genetical recombination) (fam-trastuzumab deruxtecan-nxki) (Enhertz), or eribulin (Halaven).

[0114] In one aspect, the application relates to a combination of a compound of formula (I) and a therapeutically effective amount of at least one additional anti-cancer agent for use in treating breast cancer in a subject in need thereof, wherein the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ii), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, and the at least one additional anti-cancer agent is an FLT-3 inhibitor, a VEGFR inhibitor, an EGFR inhibitor, a cytotoxic T-cell inhibitor, a vasopressin ... TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 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 trap antibodies, SHR6390, trilaciclib, relociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, venetoclax, inavolisib (GDC-0077), pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, epithilone B (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, trastuzumab deruxtecan (genetical recombination) (fam-trastuzumab deruxtecan-nxki) (Enhertz), or eribulin (Halaven).

[0115] In some embodiments, the at least one additional anti-cancer agent is a CDK4 / 6 inhibitor.

[0116] In some embodiments, the at least one additional anticancer agent is SHR6390, trilaciclib, relociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, everolimus, venetoclax, inavolisib (GDC-0077), or palbociclib.

[0117] In some embodiments, the at least one additional anti-cancer agent is palbociclib. In some embodiments, the at least one additional anti-cancer agent is abemaciclib. In some embodiments, the at least one additional anti-cancer agent is alpelisib. In some embodiments, the at least one additional anti-cancer agent is GDC-0077. In some embodiments, the at least one additional anti-cancer agent is everolimus. In some embodiments, the at least one additional anti-cancer agent is venetoclax.

[0118] In some embodiments, administration of the additional anti-cancer agent occurs prior to administration of the compound of Formula (I).

[0119] In some embodiments, the administration of the additional anti-cancer agent occurs at least 30 minutes prior to the administration of the compound of Formula (I).

[0120] In some embodiments, administration of the additional anti-cancer agent occurs after administration of the compound of Formula (I).

[0121] 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).

[0122] In one aspect, the present application relates to a method of treating breast cancer in a subject in need thereof, the subject comprising at least one somatic ER tumor mutation, the method comprising: (i) a therapeutically effective amount of a compound of formula (Ic), [ka] , or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, administered orally once daily; (ii) oral administration of palbociclib once daily. In some embodiments, the breast cancer comprises at least one somatic ER tumor mutation.

[0123] In one aspect, the application relates 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: (i) a therapeutically effective amount of a compound of formula (Ic), [ka] , or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, administered orally once daily; (ii) palbociclib, administered orally once daily.

[0124] In one aspect, the present application relates to a compound of formula (Ic) 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: (i) once daily oral administration of a therapeutically effective amount of a compound of formula (Ic), or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof; (ii) palbociclib, administered orally once daily.

[0125] In one aspect, the present application relates to a compound of formula (Ic) for use in treating breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation, and the treatment comprises: (i) once daily oral administration of a therapeutically effective amount of a compound of formula (Ic), or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof; (ii) palbociclib, administered orally once daily.

[0126] 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, and L536P.

[0127] In some embodiments, the breast cancer is ER+, HER2-.

[0128] In some embodiments, the breast cancer is metastatic or locally advanced.

[0129] In some embodiments, the therapeutically effective amount of a compound of Formula (Ic) is from about 30 mg to about 1000 mg.

[0130] In some embodiments, the therapeutically effective amount of palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg. In some embodiments, palbociclib is administered once daily for up to 21 consecutive days, followed by discontinuation of treatment for up to 7 consecutive days, and the cycle of treatment with palbociclib followed by discontinuation of treatment is repeated 1, 2, 3, 4, 5, or more times.

[0131] In some embodiments, a compound of Formula (Ic) is administered once daily for up to 21 consecutive days followed by cessation of treatment for up to 7 consecutive days, and the cycle of treatment with a compound of Formula (Ic) followed by cessation of treatment is repeated 1, 2, 3, 4, 5, or more times.

[0132] In some embodiments, the subject is in a fed state.

[0133] In some embodiments, the subject is in a fasted state.

[0134] In some embodiments, administration of palbociclib occurs prior to administration of the compound of Formula (Ic).

[0135] In some embodiments, administration of palbociclib occurs at least 30 minutes prior to administration of the compound of Formula (Ic).

[0136] In some embodiments, administration of palbociclib occurs after administration of the compound of Formula (Ic).

[0137] In some embodiments, the administration of palbociclib occurs at least 30 minutes after the administration of the compound of Formula (Ic).

[0138] In one aspect, the present application provides 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; a therapeutically effective amount of a compound of formula (I), [ka] or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein Each R 1 and each R 2 are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, SO2(R 5 ), C1-C6 alkyl, and C3-C6 cycloalkyl; R 3 and R 4 are either both hydrogen or together with the carbon to which they are attached form a carbonyl, Each R 5 and each R 6 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, or 4; The therapeutically effective amount of the compound of formula (I) is from about 10 mg to about 1000 mg.

[0139] In one aspect, the present application relates to a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, for use in a method of treating breast cancer in a subpopulation of breast cancer subjects, wherein: Each R 1 and each R 2 are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, SO2(R 5 ), C1-C6 alkyl, and C3-C6 cycloalkyl; R 3 and R 4 are either both hydrogen or together with the carbon to which they are attached form a carbonyl, Each R 5 and each R 6 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, or 4; The method is: selecting a breast cancer subject for treatment based on the subject's somatic ER tumor biomarker status; administering a therapeutically effective amount of a compound of formula (I), The therapeutically effective amount of a compound of formula (I) is from about 10 mg to about 1000 mg.

[0140] In one aspect, the present application relates to a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, for use in the treatment of breast cancer in a subpopulation of breast cancer subjects, wherein: Each R 1 and each R 2 are independent, halo, OR 5 , N(R5 )(R 6 ), NO2, CN, SO2(R 5 ), C1-C6 alkyl, and C3-C6 cycloalkyl; R 3 and R 4 are either both hydrogen or together with the carbon to which they are attached form a carbonyl, Each R 5 and each R 6 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, or 4; Treatment is selecting a breast cancer subject for treatment based on the subject's somatic ER tumor biomarker status; administering a therapeutically effective amount of a compound of formula (I), The therapeutically effective amount of a compound of formula (I) is from about 10 mg to about 1000 mg.

[0141] In some embodiments, the subject's somatic ER tumor biomarker status comprises at least one somatic ER tumor mutation selected from D538G, E380Q, V422del, and L536P.

[0142] In some embodiments, the subject's ER biomarker status is determined by ctDNA analysis, fluorescent in situ hybridization, immunohistochemistry, PCR analysis, or sequencing.

[0143] In some embodiments, the subject's ER biomarker status is determined in a blood sample from the subject.

[0144] In some embodiments, a subject's ER biomarker status is determined in a solid biopsy derived from the subject's tumor.

[0145] In some embodiments, the compound of formula (I) is [ka] [ka] [ka] or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0146] In some embodiments, the compound of formula (I) is [ka] or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0147] In some embodiments, the breast cancer is ER+, HER2-.

[0148] In some embodiments, the breast cancer is metastatic or locally advanced.

[0149] In some embodiments, the method further comprises administration of at least one additional anti-cancer agent.

[0150] In some embodiments, the additional anti-cancer agent is selected from the group consisting of FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 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, and VEGF trap antibodies.

[0151] In some embodiments, the at least one additional anti-cancer agent is a CDK4 / 6 inhibitor.

[0152] In some embodiments, the additional anticancer agent is SHR6390, trilaciclib, relociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, pazopanib, venetoclax, inavolisib (GDC-0077), carboplatin, cisplatin, oxaliplatin, paclitaxel, epithilone B 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, trastuzumab deruxtecan (genetical recombination) (fam-trastuzumab deruxtecan-nxki) (Enhertz), or eribulin (Halaven).

[0153] In some embodiments, the at least one additional anticancer agent is SHR6390, trilaciclib, relociclib, AT7519M, dinaciclib, ribociclib, alpelisib, abemaciclib, everolimus, venetoclax, inavolisib (GDC-0077), or palbociclib.

[0154] In some embodiments, the at least one additional anti-cancer agent is palbociclib. In some embodiments, the at least one additional anti-cancer agent is abemaciclib. In some embodiments, the at least one additional anti-cancer agent is alpelisib. In some embodiments, the at least one additional anti-cancer agent is GDC-0077. In some embodiments, the at least one additional anti-cancer agent is everolimus. In some embodiments, the at least one additional anti-cancer agent is venetoclax.

[0155] In some embodiments, administration of the additional anti-cancer agent occurs prior to administration of the compound of Formula (I).

[0156] In some embodiments, the administration of the additional anti-cancer agent occurs at least 30 minutes prior to the administration of the compound of Formula (I).

[0157] In some embodiments, administration of the additional anti-cancer agent occurs after 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).

[0158] definition "H" refers to hydrogen.

[0159] Halogen or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0160] "C1-C6 alkyl" refers to a straight or branched chain saturated hydrocarbon containing from 1 to 6 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0161] "C3-C6 cycloalkyl" means a monocyclic saturated carbocyclic ring containing from 3 to 6 carbon atoms, i.e., a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl moiety.

[0162] As used herein with respect to compounds of formula (I), "pharmaceutically acceptable salts" refers to salt forms of compounds of formula (I), as well as hydrate forms of salts in which one or more water molecules are present. Such salts and hydrate forms retain the biological activity of the compounds 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, acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsenilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate ... Included are water soluble and water insoluble salts such as tobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucoate, 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.

[0163] The term "isomers" refers to salts and / or compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. The structural differences can be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, salts of the compounds of formula (I) may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

[0164] The compounds of formula (I) can exist in unsolvated as well as solvated forms such as, for example, hydrated forms.

[0165] "Solvate" means a solvent addition form that contains either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend 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, and if the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more water molecules with one of the substances in which water retains its molecular state as H2O, and such a combination can form one or more hydrates. In a hydrate, the water molecules are bonded through subvalence by intermolecular forces, in particular hydrogen bridges. A solid hydrate contains water in a stoichiometric ratio as the so-called water of crystallization, and the water molecules do not necessarily have to be equivalent in terms of their bonding state. Examples of hydrates include sesquihydrates, monohydrates, dihydrates, or trihydrates. Similarly, hydrates of salts of the compounds of the present invention are also suitable.

[0166] When a compound is crystallized from a solution or slurry, it can crystallize in different arrangements of spatial lattices (this property is called "polymorphism") to form crystals with different crystal forms, each of which is known as a "polymorph." As used herein, "polymorph" refers to a crystalline form of a compound of formula (I) in which the molecules are localized in three-dimensional lattice sites. 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 morphology, storage mode, flowability and / or solid state stability.

[0167] As referred to herein, an "isotopic derivative" refers to a compound of formula (I) that is isotopically enriched or labeled (with respect to one or more atoms of the compound) with one or more stable isotopes. Thus, in the present application, a compound of formula (I) is referred to as a compound having, for example, deuterium ( 2 H or D) or carbon-13 ( 13 C) and other compounds that are isotopically enriched or labeled with one or more atoms.

[0168] The term "pharmaceutically acceptable prodrug" as used herein refers to a prodrug of a compound of formula (I) of the compounds of the present invention that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals having excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and is effective for its intended use, and preferably in zwitterionic form.

[0169] As used herein, "prodrug" means a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) to yield any compound detailed by the formulas of the invention. Various forms of prodrugs are known in the art and are described, for example, 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, 1 13-191 (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 This is discussed in “Prodrug Metabolism: Chemistry, Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

[0170] The present invention also encompasses pharmaceutical compositions containing pharma- ceutically acceptable prodrugs of the compounds of the present invention, and methods of treating disorders by administering pharma- ceutically acceptable prodrugs of the compounds of the present invention. For example, compounds of the present invention having free amino, amide, hydroxy, or carboxylic acid groups can be converted into prodrugs. Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., 2, 3, or 4) amino acid residues is covalently linked to a free amino, hydroxy, or carboxylic acid group of a compound of the present invention by an amide or ester bond. Amino acid residues include the 20 naturally occurring amino acids, commonly designated by three letter symbols, and include, but are not limited to, 4-hydroxyproline, hydroxylysine, decomosine, isodecomosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Additional types of prodrugs are also encompassed. For example, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups can be derivatized using groups including, but not limited to, hemisuccinate, phosphate ester, dimethylaminoacetate and phosphoryloxymethyloxycarbonyl, as reviewed in Advanced Drug Delivery Reviews, 1996, 19, 1 15. Carbamate prodrugs of hydroxy and amino groups also include sulfonate and sulfate esters of hydroxy groups, as carbonate prodrugs. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers is also included, where the acyl group can be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine and carboxylic acid functional groups, or the acyl group is an amino acid ester as described above. This type of prodrug is described in J.Med.Chem., 1996, 39:10. Free amines can also be derivatized as amides, sulfonamides, or phosphonamides.All of these prodrug moieties may incorporate groups including, but not limited to, ether, amine and carboxylic acid functionalities. Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds.

[0171] 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 the bones, liver, lungs, or brain (https: / / www.cancer.org / cancer / breast-cancer.).

[0172] Locally advanced breast cancer (LABC) is defined by the US National Comprehensive Cancer Network as a subset of breast cancer characterized by the most advanced breast tumors in the absence of distant metastases, tumors greater than 5 cm in size with regional lymphadenopathy, tumors of any size with direct extension (including ulcers or satellite nodes) to the chest wall or skin or both, regardless of regional lymphadenopathy, and the presence of regional lymphadenopathy (either clinically fixed or matted axillary nodes, or subclavian, supraclavicular, or internal mammary adenopathy), regardless of tumor stage. (Garg et al. Curr Oncol. 2015 Oct;22(5):e409-e410, National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology:Breast Cancer.Fort Washington,PA:NCCN;2015.Ver.2.2015.)

[0173] ER+, estrogen receptor positive, as used herein, refers to breast cancer cells that have a receptor protein that binds to the hormone estrogen. Cancer cells that are ER+ may require estrogen to grow and may stop growing or die when treated with substances that block the binding and action of estrogen. (https: / / www.cancer.gov / publications / dictionaries / cancer-terms / def / 44404.)

[0174] HER2-, human epidermal growth factor receptor 2, as used herein, refers to breast cancer cells that do not have large amounts of a protein called HER2 on their surface. In normal cells, HER2 helps control cell growth. Cancer cells that are HER2- grow more slowly and are less likely to recur or spread to other parts of the body than cancer cells that have large amounts of HER2 on their surface. (https: / / www.cancer.gov / publications / dictionaries / cancer-terms / def / her2-negative.)

[0175] As used herein, "treating" refers to the management and care of a subject for the purpose of combating a disease, condition, or disorder, including reducing or alleviating symptoms or complications, or eliminating the disease, condition, or disorder.

[0176] As used herein, "prevent" refers to arresting the onset of a symptom or complication of a disease, condition, or disorder.

[0177] "Administering" refers to introducing an agent, such as a compound of Formula (I), into a subject. The related terms "administer" and "administration of" (and grammatical equivalents) refer to both direct administration, which may be administration to a subject by a medical professional or by the subject self-administering, and / or 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 a drug to the patient.

[0178] As used herein, the term "anti-cancer agent" is used to describe an anti-cancer agent, or a therapeutic agent co-administered with an anti-cancer agent (e.g., palonosetron), which may be co-administered and / or co-formulated with a compound of formula (I) to treat cancer and side effects associated with cancer treatment.

[0179] In some embodiments, the anti-cancer agent is selected from any of the following: FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 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 kinase inhibitors, and VEGF trap antibodies.

[0180] In some embodiments, the anticancer agent is selected from any of the following: SHR6390, trilaciclib, relociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, venetoclax, inavolisib (GDC-0077), pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, epithilone B 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, trastuzumab deruxtecan (genetical recombination) (fam-trastuzumab deruxtecan-nxki) (Enhertz), and eribulin (Halaven). In some embodiments, the anti-cancer agent is palbociclib. In some embodiments, the anti-cancer agent is abemaciclib. In some embodiments, the anti-cancer agent is everolimus. In some embodiments, the anti-cancer agent is alpelisib. In some embodiments, the anti-cancer agent is GDC-0077. In some embodiments, the anti-cancer agent is venetoclax.

[0181] As used herein, "therapeutically effective amount" refers to an amount of the free base of the compound of formula (I) that is sufficient to treat, ameliorate, or prevent a particular disease (e.g., breast cancer), disease symptoms, disorders, or conditions, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any analytical method known in the art. The effective amount for a particular subject may depend on the subject's weight, size, and health, the nature and extent of the condition, and whether an additional therapeutic agent is administered to the subject. The therapeutically effective amount for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0182] As used herein, "C max " refers to the maximum (peak) plasma concentration of a particular compound observed in a subject after administration of a dose of that compound to the subject.

[0183] As used herein, "AUC" refers to the total area under the plasma concentration-time curve, which is a measure of exposure to a compound of interest and is the integral of the concentration-time curve after a single dose or at steady state. AUC is expressed in units of ng·hour / mL (ng × hour / mL).

[0184] As used herein, "AUC tau " refers to the AUC from time 0 to the end of the dosing interval.

[0185] As used herein with respect to oral dosage forms of the present disclosure, "controlled release" or "CR" means that the compound of formula (I) is released from the dosage form according to a predetermined profile, which may include when and where the release occurs after oral administration, and / or a specified rate of release over a specified period of time. Controlled release may be contrasted with uncontrolled release or immediate release.

[0186] As used herein with respect to the oral dosage forms of the present disclosure, "controlled release agent" refers to one or more substances or materials that modulate the release of the compound of formula (I) from the dosage form. Controlled release agents can be organic or inorganic, of natural origin or synthetic, such as polymeric materials, triglycerides, derivatives of triglycerides, fatty acids and salts of fatty acids, talc, boric acid, and colloidal silica.

[0187] As used herein, "oral dosage form" refers to a pharmaceutical product containing a specific amount (dose) of a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as an active ingredient, and inactive ingredients (excipients), formulated into a specific con?guration suitable for oral administration and drug delivery, such as a tablet, capsule, or liquid oral formulation. In some embodiments, the composition is in the form of a tablet that can be scored.

[0188] 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, that is involved in the carrying or transport of a pharmaceutical agent from one organ or part of the body of a subject to another organ or part of the body.

[0189] The term "about" as part of a quantitative expression, such as "about X", includes any value 10% higher or lower than X, and also includes any numerical value between X-10% and X+10%. Thus, for example, a weight of about 40 g includes a weight of 36 to 44 g. As used herein, to indicate an amino acid residue in ER, the term "about" refers to any amino acid residue that is within 5 amino acid residues of the specified amino acid residue. For example, when referring to a contiguous stretch of amino acid residues that spans from about amino acid residue 181 to about amino acid residue 263 of ER, this refers to a contiguous stretch of amino acid residues that spans from amino acid residue 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, or 186 to amino acid residue 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, or 268 of the ER of SEQ ID NO:1. In some embodiments, the term "about" refers to any amino acid residue that is within 3 amino acid residues of the specified amino acid residue. In some embodiments, the term "about" refers to any amino acid residue that is within 1 amino acid residue of the specified amino acid residue.

[0190] As used herein, the term "del" refers to an in-frame deletion of an amino acid residue relative to the wild type. For example, "V422del" refers to a mutant in which the valine at position 422 in the wild type ER protein is deleted.

[0191] As used herein, an underline between two amino acid designations indicates that the sequence of residues, including both endpoints, has been altered, e.g., "L536_D538>P" indicates a variant resulting from an in-frame deletion in which the amino acid residues beginning with lysine at position 536 and ending with aspartic acid at position 538 have been replaced with a single proline.

[0192] "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 elements recited in a particular detailed description or claim, but does not exclude other elements. "Consists essentially of" and "consisting essentially of" mean that the composition, dosage form, method, use, or process described or claimed does not exclude other materials or steps that do not substantially affect the recited physical, pharmacological, pharmacokinetic properties, or therapeutic effect of the composition, dosage form, method, use, or process. "Consists of" and "consisting of" refer to the exclusion of trace elements of other ingredients and more than substantial method or process steps.

[0193] "Fasted condition" or "fasted state" as used to describe a subject means that the subject has not eaten for at least 4 hours prior to the time of interest, such as the time of administration of a compound of Formula (I). In one embodiment, a subject in a fasted state has not eaten for at least 6, 8, 10, or 12 hours prior to administration of a compound of Formula (I).

[0194] "Fed condition" or "fed state" as used herein to describe a subject means that the subject has eaten a meal less than 4 hours prior to the time of interest, such as the time of administration of a compound of Formula (I). In one embodiment, a subject in a fed state has not eaten a meal for at most any of 4, 3, 2, 1, or 0.5 hours prior to administration of a compound of Formula (I).

[0195] As used herein, "Tween 80" refers to polysorbate 80, also known as polyoxyethylene (20) sorbitan monooleate and sorbitan, mono-9-octadecenoate, poly(oxy-1,2-ethanediyl) derivative, (Z)-.

[0196] As used herein, "low molecular weight polyethylene glycol" or "low molecular weight PEG" generally refers to a polyethylene glycol (PEG) polymer having a molecular weight of less than 1500, 1400, 1300, 1200, 1100, 1000, 900, 800, 700, 600, 500, 400, or 300 Daltons. Examples of low molecular weight PEGs include PEG-200, PEG-400, and PEG-600.

[0197] As used herein, the term "CDK4 / 6 inhibitor" refers to a compound that inhibits enzymes in humans called cyclin-dependent kinases (CDK) 4 and 6. Examples of CDK4 / 6 inhibitors include, but are not limited to, SHR6390, trilaciclib, relociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, or any pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof.

[0198] The articles "a" and "an" are used in this disclosure to refer to one or to 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.

[0199] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise indicated.

[0200] The terms "patient" and "subject" are used interchangeably herein and refer to a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey.

[0201] In some embodiments, the subject is a human.

[0202] In some embodiments, the subject is a human diagnosed with breast cancer.

[0203] In some embodiments, the subject is a human diagnosed with metastatic breast cancer.

[0204] In some embodiments, the subject is a human diagnosed with ER+, HER2- breast cancer.

[0205] In some embodiments, the subject is a human diagnosed with metastatic, ER+, HER2- breast cancer.

[0206] Compounds of formula (I) In one aspect, the present application relates to a method of treating and / or preventing cancer comprising administering a compound of formula (I) to a subject in need thereof.

[0207] In one aspect, the present application relates to the use of compounds of formula (I) in the treatment and / or prevention of breast cancer.

[0208] In one aspect, the present application relates to the use of a compound of formula (I) in the manufacture of a medicament for the treatment and / or prevention of breast cancer.

[0209] As referred to herein, a compound of formula (I) is a compound having the following structure: [ka] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein: Each R 1 and each R 2 are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, SO2(R 5 ), C1-C6 alkyl, and C3-C6 cycloalkyl; R 3 and R 4 are either both hydrogen or together with the carbon to which they are attached form a carbonyl, Each R 5 and each R 6 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, or 4.

[0210] In some embodiments, each R 1 and each R 2 are independent, halo, OR 5 and C1-C6 alkyl.

[0211] In some embodiments, R 1 is hydrogen, halo, OR 5 , N(R 5 )(R 6 ), or C1-C6 alkyl. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is halo. In some embodiments, R 1 OR 5 In some embodiments, R 1 is N(R 5 )(R 6 In some embodiments, R 1 is C1-C6 alkyl.

[0212] In some embodiments, R 2 is hydrogen, halo, OR 5 , N(R 5)(R 6 ), or C1-C6 alkyl. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is halo. In some embodiments, R 2 OR 5 In some embodiments, R 2 is N(R 5 )(R 6 In some embodiments, R 2 is C1-C6 alkyl.

[0213] In some embodiments, R 3 and R 4 are both hydrogen.

[0214] In some embodiments, R 3 and R 4は , together with the carbon to which they are attached to form a carbonyl.

[0215] In some embodiments, each R 5 and each R 6 is independently selected from the group consisting of hydrogen and C1-C6 alkyl. 5 and R 6 are hydrogen.

[0216] In some embodiments, m is 0.

[0217] In some embodiments, m is 1.

[0218] In some embodiments, m is 2.

[0219] In some embodiments, m is 3.

[0220] In some embodiments, m is 4.

[0221] In some embodiments, m is 5.

[0222] In some embodiments, n is 0.

[0223] In some embodiments, n is 1.

[0224] In some embodiments, n is 2.

[0225] In some embodiments, n is 3.

[0226] In some embodiments, n is 4.

[0227] In some embodiments, m and n are each 0.

[0228] In some embodiments, m is 0 and n is 1.

[0229] In some embodiments, m is 1 and n is 0.

[0230] In some embodiments, m is 1 and n is 1.

[0231] In some embodiments, the compound of formula (I) is [ka] [ka] [ka] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0232] In some embodiments, the compound of formula (I) is [ka] [ka] [ka] is selected from the group consisting of:

[0233] In some embodiments, the compound of formula (I) is a compound of formula (Ia): [ka] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0234] In some embodiments, the compound of formula (I) is a compound of formula (Ia): [ka]

[0235] In some embodiments, the compound of formula (I) is a compound of formula (Ib): [ka] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0236] In some embodiments, the compound of formula (I) is a compound of formula (Ic), i.e., compound (Ic) or Cmp(Ic), [ka] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0237] In some embodiments, the compound of formula (I) is a compound of formula (Ic), i.e., compound (Ic) or Cmp(Ic): [ka]

[0238] In some embodiments, the compound of formula (I) is a compound of formula (Id): [ka] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0239] In some embodiments, the compound of formula (I) is a compound of formula (Ie): [ka] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0240] In some embodiments, the compound of formula (I) is a compound of formula (If): [ka] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0241] In some embodiments, the compound of formula (I) is a compound of formula (Ig): [ka] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0242] In some embodiments, the compound of formula (I) is a compound of formula (Ih): [ka] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0243] In some embodiments, the compound of formula (I) is a compound of formula (Ii): [ka] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0244] In some embodiments, the compound of formula (I) is a compound of formula (Ij): [ka] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0245] In some embodiments, the compound of formula (I) is a compound of formula (Ij): [ka]

[0246] Compounds of formula (I) may be synthesized using standard synthetic methods and procedures for the preparation of organic molecules, functional group transformations and manipulations, including the use of protecting groups, as may be obtained in the field of this disclosure from the relevant scientific literature or from standard reference textbooks in the field. Recognized reference textbooks on organic synthesis, without being limited to any one or several sources, include Smith, MB; March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, 1999; Smith, M.B.; March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, 1999; thed.; John Wiley & Sons: New York, 2001, and Greene, TWWuts, PGMProtective Groups in Organic Synthesis, 3. rd John Wiley & Sons: New York, 1999. Methods for preparing compounds of formula (I) are described in U.S. Patent Application Publication No. 2018 / 0155322, which issued as U.S. Patent No. 10,647,698, the contents of which are incorporated herein in their entirety.

[0247] For example, compounds (Ib) and (Ic) can be prepared according to the procedures described below: Synthesis of 3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (compound (Ib)):

[0248] Step 1: Preparation of 6-tert-butoxytetralin-1-one [ka]

[0249] To a stirred solution of 6-hydroxytetralin-1-one (50 g, 308.29 mmol, 1 equiv) in anhydrous dichloromethane (2000 mL) at 0° C. was added tert-butyl 2,2,2-trichloroethanimidate (67.36 g, 308.29 mmol, 55 mL, 1 equiv) and pyridinium para-toluenesulfonate (7.75 g, 30.83 mmol, 0.1 equiv). The reaction mixture was stirred at 10° C. for 3 h. An additional tert-butyl 2,2,2-trichloroethanimidate (67.36 g, 308.29 mmol, 55 mL, 1 equiv) and pyridinium para-toluenesulfonate (7.75 g, 30.83 mmol, 0.1 equiv) were added and the reaction mixture was stirred at 10° C. for 15 h. This process was repeated three times. Thin layer chromatography (petroleum ether:ethyl acetate=3:1, R f=0.8) indicated that most of the reactants still remained, and the reaction mixture was stirred at 10°C for 72 h. The reaction mixture was quenched by adding sodium bicarbonate solution (1500 mL) at 15°C, then extracted with dichloromethane (300 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 100:1 to 50:1) to give 6-tert-butoxytetralin-1-one (21 g, 96.20 mmol, 31% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ7.97(d,J=8.8Hz,1H),6.91(dd,J=2.4,8.8Hz,1H),6.82(d,J=2.0Hz, 1H), 2.93-3.90(t,J=6.0Hz,2H),2.63-2.60(m,t,J=6.0Hz,2H),2.13(m,2H),1.43(s,9H).

[0250] Step 2: (6-tert-butoxy-3,4-dihydronaphthalen-1-yl) Preparation of trifluoromethanesulfonates [ka]

[0251] To a solution of 6-tert-butoxytetralin-1-one (40 g, 183.24 mmol, 1 equiv.) in tetrahydrofuran (500 mL) was added lithium diisopropylamide (2 M, 137 mL, 1.5 equiv.) at -70°C. The mixture was stirred at -70°C for 1 h, then a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (72.01 g, 201.56 mmol, 1.1 equiv.) in tetrahydrofuran (200 mL) was added dropwise to the mixture. The reaction mixture was stirred at 20°C for 2 h. Thin layer chromatography (petroleum ether:ethyl acetate=5:1) showed the reaction was complete. Saturated ammonium chloride (300 mL) was added to the mixture and the organic layer was separated. Ethyl acetate (500 mLx3) was added to the mixture, and the resulting mixture was washed with brine (1000 mLx2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:0-50:1) to give (6-tert-butoxy-3,4-dihydronaphthalen-1-yl)trifluoromethanesulfonate (52 g, 144.64 mmol, 78% yield, 97% purity) as a yellow oil. LC-MS(ESI)m / z:294.9[M+1-56] + . 1 H-NMR (400MHz, CDCl3)δ:7.30(d,J=6.4Hz,1H),6.91(d,J=8.4Hz,1H),6.84(s,1H),5.95(s,1H),2.93-2.78(m,2H),2.59-2.46(m,2H),1.42(s,9H).

[0252] Step 3: Preparation of 4-(6-tert-butoxy-3,4-dihydronaphthalen-1-yl)phenol [ka]

[0253] To a solution of (6-tert-butoxy-3,4-dihydronaphthalen-1-yl)trifluoromethanesulfonate (52 g, 148.42 mmol, 1 equiv.), (4-hydroxyphenyl)boronic acid (24.57 g, 178.11 mmol, 1.2 equiv.) in dioxane (800 mL) and water (150 mL), potassium carbonate (41.03 g, 296.84 mmol, 2 equiv.) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (10.86 g, 14.84 mmol, 0.1 equiv.) were added under nitrogen. The reaction mixture was stirred at 100° C. for 10 h. Thin layer chromatography (petroleum ether:ethyl acetate=5:1) showed the reaction was complete. The residue was diluted with water (500 mL) and extracted with ethyl acetate (500 mL×2). The combined organic layers were washed with brine (1000 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:tetrahydrofuran = 50:1 to 20:1) to give 4-(6-tert-butoxy-3,4-dihydronaphthalen-1-yl)phenol (43 g, 131.46 mmol, 88% yield, 90% purity) as a yellow oil. LCMS (ESI) m / z: 239.1 [M+1-56] + , 1 H-NMR(400MHz,CDCl3)δ7.23(d,J=7.6Hz,2H),6.91(d,J=8.0Hz,1H),6.87-6.79(m,3H),6.73(d, J=8.4Hz,1H),5.95(s,1H),4.83-4.75(m,1H),2.87-2.73(m,2H),2.44-2.31(m,2H),1.37(s,9H).

[0254] Step 4: Preparation of 4-(2-bromo-6-tert-butoxy-3,4-dihydronaphthalen-1-yl)phenol [ka]

[0255] To a solution of 4-(6-tert-butoxy-3,4-dihydronaphthalen-1-yl)phenol (1 g, 3.06 mmol, 1 equiv.) in acetonitrile (20 mL) was added N-bromosuccinimide (489 mg, 2.75 mmol, 0.9 equiv.) in three portions. The reaction mixture was stirred at 20° C. for 1.5 h. LC-MS showed the reaction was complete. The residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×2). The combined organic layer was washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:0-20:1) to give 4-(2-bromo-6-tert-butoxy-3,4-dihydronaphthalen-1-yl)phenol (1 g, 2.46 mmol, 80% yield, 91% purity) as a yellow oil. LC-MS (ESI) m / z: 316.9 [M+1-56] + , 1 H-NMR(400MHz,CDCl3)δ7.12(d,J=8.4Hz,2H),6.90(d,J=8.0Hz,2H),6.77(s,1H ),6.69-6.62(m,1H),6.60-6.53(m,1H),4.86(s,1H),2.96(s,4H),1.35(s,9H).

[0256] Step 5: Preparation of 4-(6-tert-butoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenol [ka]

[0257] To a solution of 4-(2-bromo-6-tert-butoxy-3,4-dihydronaphthalen-1-yl)phenol (1g, 2.46mmol, 1eq), phenylboronic acid (314mg, 2.58mmol, 1.05eq) in dioxane (10mL) and water (2mL), potassium carbonate (678mg, 4.91mmol, 2eq) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (179mg, 0.24mmol, 0.1eq) were added under nitrogen. The reaction mixture was stirred at 100°C for 12 hours. LC-MS showed the reaction was complete. The residue was diluted with water (20mL) and extracted with ethyl acetate (20mLx2). The combined organic layer was washed with brine (20mLx3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:0-10:1) to give 4-(6-tert-butoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenol (930 mg, 2.35 mmol, 95% yield, 93% purity) as an orange oil. LCMS (ESI) m / z: 314.1 [M+1-56] + , 1 H-NMR(400MHz,CDCl3)δ7.16-7.09(m,2H),7.08-6.99(m,3H),6.97-6.89(m,2H),6.86-6.82 (m,1H),6.74-6.66(m,4H),4.70(s,1H),2.99-2.89(m,2H),2.84-2.75(m,2H),1.37(s,9H).

[0258] Step 6: Preparation of 4-(6-tert-butoxy-2-phenyl-tetralin-1-yl)phenol [ka]

[0259] To a solution of 4-(6-tert-butoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenol (930 mg, 2.35 mmol, 1 equiv.) in tetrahydrofuran (20 mL) and methanol (4 mL) was added palladium on activated carbon catalyst (100 mg, 10% purity) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred under hydrogen (50 psi) at 30° C. for 36 h. LC-MS showed the reaction was complete. The reaction mixture was filtered and the solution was concentrated. The resulting material was used directly in the next step without further purification to give cis-4-(6-tert-butoxy-2-phenyl-tetralin-1-yl)phenol (870 mg, 2.14 mmol, 91% yield, 91% purity) as a white solid. LC-MS (ESI) m / z: 317.0 [M+1-56] + , 1 H-NMR(400MHz,CDCl3)δ7.22-7.12(m,3H),6.89-6.78(m,4H),6.74(dd,J=2.0,8.4Hz,1H),6.45(d,J=8.4Hz,2H),6.27(d,J=8.4Hz,2H), 4.51(s,1H),4.25(d,J=4.8Hz,1H),3.38(dd,J=3.2,12.8Hz,1H),3.08-2.99(m,2H),2.27-2.08(m,1H),1.87-1.76(m,1H),1.37(s,9H).

[0260] Step 7: Preparation of 4-[(1S,2R)-6-tert-butoxy-2-phenyl-tetralin-1-yl]phenol [ka]

[0261] 4-(6-tert-butoxy-2-phenyl-tetralin-1-yl)phenol (870 mg, 2.13 mmol, 1 equiv.) was subjected to supercritical fluid chromatography for chiral separation (column: AD, 250 mm × 30 mm, 5 um; mobile phase: 0.1% ammonium hydroxide in methanol, 20% to 20%, 4.2 min for each run) to give 4-[(1S,2R)-6-tert-butoxy-2-phenyl-tetralin-1-yl]phenol (420 mg, 1.04 mmol, 97% yield, 92% purity) as the first fraction, and 4-[(1R,2S)-6-tert-butoxy-2-phenyl-tetralin-1-yl]phenol (420 mg, 1.04 mmol, 97% yield, 92% purity) as the second fraction. Fraction 1: [α] D =+336.9(C=0.50g / 100mL in ethyl acetate, 25℃), LC-MS(ESI) m / z:395.1[M+23] + , 1 H NMR(400MHz,DMSO-d6)δ9.02(s,1H),7.20-7.07(m,3H),6.87-6.79(m,3H),6.79-6.72(m,1H),6.71-6.64(m,1H),6.36(d,J=8.4Hz,2H) ,6.15(d,J=8.4Hz,2H),4.19(d,J=4.8Hz,1H),3.31-3.26(m,1H),3.09-2.89(m,2H),2.17-2.04(m,1H),1.79-1.65(m,1H),1.29(s,9H). Fraction 2: [α] D =-334.1 (C=0.50g / 100mL in ethyl acetate, 25℃), LC-MS (ESI) m / z:395.2[M+23] + , 1 H-NMR(400MHz,DMSO-d6)δ:9.02(s,1H),7.21-7.06(m,3H),6.88-6.78(m,3H),6.78-6.72(m,1H),6.71-6.64(m,1H),6.36(d,J=8.4Hz,2H ),6.15(d,J=8.4Hz,2H),4.19(d,J=4.8Hz,1H),3.30-3.27(m,1H),3.08-2.90(m,2H),2.16-2.04(m,1H),1.79-1.65(m,1H),1.29(s,9H).

[0262] Step 8: Preparation of 4-(6-benzyloxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenyl]1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate [ka]

[0263] To a solution of 4-[(1R,2S)-6-tert-butoxy-2-phenyl-tetralin-1-yl]phenol (1 g, 2.68 mmol, 1 equiv.) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (811 mg, 2.68 mmol, 1 equiv.) in tetrahydrofuran (5 mL) and acetonitrile (5 mL) was added potassium carbonate (557 mg, 4.03 mmol, 1.5 equiv.). The reaction mixture was stirred at 25 °C for 16 h. TLC (petroleum ether: ethyl acetate = 10:1) showed that the starting material was completely consumed and one new spot was formed. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1:0 to 50:1). The desired product, [4-[(1R,2S)-6-tert-butoxy-2-phenyl-tetralin-1-yl]phenyl]1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (1.6 g, 2.44 mmol, 91% yield) was obtained as a colorless oil. 1 H NMR(400MHz,CDCl3)δ7.21-7.11(m,3H),6.94-6.86(m,3H),6.84-6.73(m,4H),6.46(d,J=8.8Hz,2H),4.33 (d,J=5.2Hz,1H),3.50-3.40(m,1H),3.16-2.95(m,2H),2.20-2.02(m,1H),1.91-1.79(m,1H),1.38(s,9H).

[0264] Step 9: Preparation of 1-[4-(6-benzyloxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenyl]-4-(dimethoxymethyl)piperidine [ka]

[0265] A mixture of [4-[(1R,2S)-6-tert-butoxy-2-phenyl-tetralin-1-yl]phenyl]1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (1.6 g, 2.44 mmol, 1 equiv.), 4-(dimethoxymethyl)piperidine (584 mg, 3.67 mmol, 1.5 equiv.), sodium tert-butoxide (705 mg, 7.33 mmol, 3 equiv.), palladium acetate (82 mg, 0.37 mmol, 0.15 equiv.), and dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (233 mg, 0.49 mmol, 0.2 equiv.) in toluene (30 mL) was degassed and purged with nitrogen three times, then the mixture was stirred at 90° C. under a nitrogen atmosphere for 16 h. LC-MS showed that one main peak with the desired MS was detected. TLC (petroleum ether:ethyl acetate=10:1) showed that the starting material was completely consumed and one new spot was formed. The mixture was cooled, diluted with ethyl acetate (50 mL), filtered through a plug of diatomaceous earth, and the filter cake was washed with ethyl acetate (30 mL). The filtrate was concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=100:1 to 10:1). The desired product 1-[4-[(1R,2S)-6-tert-butoxy-2-phenyl-tetralin-1-yl)phenyl]-4-(dimethoxymethyl)piperidine (1.1 g, 2.14 mmol, 87% yield) was obtained as a white solid. LC-MS(ESI)m / z:514.3[M+1] + , 1 H NMR(400MHz,CDCl3)δ7.21-7.11(m,3H),6.88-6.78(m,4H),6.73(dd,J=2.4,8.0 Hz,1H),6.57(d,J=8.4Hz,2H),6.27(d,J=8.8Hz,2H),4.23(d,J=4.8Hz,1H),4.06 (d,J=7.2Hz,1H),3.63-3.52(m,2H),3.41-3.30(m,7H),3.13-2.96(m,2H),2.54( d,J=2.0,12.0Hz,2H),2.28-2.10(m,1H),1.85-1.63(m,4H),1.49-1.31(m,11H).

[0266] Step 10: Preparation of 1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]piperidine-4-carbaldehyde [ka]

[0267] To a solution of 1-[4-[(1R,2S)-6-tert-butoxy-2-phenyl-tetralin-1-yl]phenyl]-4-(dimethoxymethyl)piperidine (1.1 g, 2.14 mmol, 1 equiv.) in tetrahydrofuran (45 mL) was added sulfuric acid (2 M, 43 mL, 40 equiv.). The reaction mixture was stirred at 70° C. for 1 h. LC (petroleum ether:ethyl acetate=3:1) showed that the starting material was completely consumed and one new spot was formed. The reaction mixture was quenched by adding saturated sodium bicarbonate solution to pH=about 7-8 and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was used in the next step without further purification. The desired product 1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]piperidine-4-carbaldehyde (900 mg, 2.14 mmol, 99% yield, 97% purity) was obtained as a pale yellow solid. LCMS MS(ESI) m / z: 412.1[M+1] +

[0268] Step 11: Preparation of 3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (compound (Ib)) [ka]

[0269] To a solution of 3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione hydrochloride (319 mg, 0.87 mmol, prepared in step 17 described for exemplary compound 62) in methanol (4 mL) and dichloromethane (4 mL) was added sodium acetate (120 mg, 1.46 mmol, 2 eq.). The mixture was stirred at 20° C. for 0.5 h, after which 1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]piperidine-4-carbaldehyde (300 mg, 0.73 mmol, 1 eq.) and sodium cyanoborohydride (137 mg, 2.19 mmol, 3 eq.) were added to the mixture. The mixture was stirred at 20° C. for 12 h. LC-MS showed that the starting material was completely consumed and one main peak with the desired MW was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (Phenomenex luna C18 column, 250x50mm, 10um; mobile phase: [water (0.05% HCl)-acetonitrile]; B%: acetonitrile 10%-40%, 30 min). The desired product 3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (288.4mg, 0.37mmol, 51% yield) was obtained as a white solid of hydrochloride salt. LC-MS(ESI)m / z:724.4 [M+1] + , 11H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.83 (s, 0.9H, HCl), 7.60 (d, J = 8.5 Hz, 1H), 7.40 (br s, 2H), 7.22 - 7.11 (m, 5H), 6.83 (d, J = 6.0 Hz, 2H), 6.69 - 6.63 (m, 2H), 6.58 - 6.47 (m, 3H), 5.07 (dd, J = 5.2, 13.2 Hz, 1H), 4.41 - 4.30 (m, 2H), 4.28 - 4.21 (m, 1H), 4.00 (d, J = 12.7 Hz, 2H), 3.61 (d, J = 11.0 Hz, 2H), 3.54 - 3.36 (m, 6H), 3.16 (br s, 4H), 3.06 - 2.84 (m, 3H), 2.76 - 2.53 (m, 1H), 2.43 - 2.33 (m, 1H), 2.27 (br s, 1H), 2.16 - 2.04 (m, 3H), 2.02 - 1.69 (m, 5H).

[0270] Synthesis of (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (compound (Ic))

[0271] Step 1: Preparation of (4S)-tert-butyl 5-amino-4-(benzyloxycarbonylamino)-5-oxo-pentanoate

Chem.

[0272] Step 2: Preparation of (4S)-tert-butyl 4,5-diamino-5-oxo-pentanoate [ka]

[0273] To a solution of (4S)-tert-butyl 5-amino-4-(benzyloxycarbonylamino)-5-oxo-pentanoate (19 g, 56.48 mmol, 1.00 equiv.) in methanol (200 mL) was added palladium on carbon (2 g, 10%) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred under H2 (50 psi) at 25°C for 16 h. Thin layer chromatography (petroleum ether:ethyl acetate=1:2) showed the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated. The compound (4S)-tert-butyl 4,5-diamino-5-oxo-pentanoate (11 g, 54.39 mmol, 96% yield) was obtained as a pale green oil. 1 H NMR(400MHz,CDCl3)δ7.03(br s,1H),5.55(br s,1H),3.44(br s, 1H), 2.49-2.31 (m, 2H), 2.11 (dd, J=6.0, 12.8Hz, 1H), 1.92-1.76 (m, 1H), 1.66 (s, 2H), 1.45 (s, 9H).

[0274] Step 3: Preparation of tert-butyl 4-[2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-[3-(bromomethyl)-4-methoxycarbonyl-phenyl]piperazine-1-carboxylate (1.5 g, 3.63 mmol, 1 eq., prepared in step 15 of exemplary compound 62 of US Patent Publication No. 2018 / 0155322) in acetonitrile (30 mL), tert-butyl (4S)-4,5-diamino-5-oxo-pentanoate (1.10 g, 5.44 mmol, 1.5 eq.) and diisopropylethylamine (1.41 g, 10.89 mmol, 1.90 mL, 3 eq.) were added. The mixture was stirred at 80° C. for 12 hours. LC-MS showed the reaction was complete. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative reverse-phase HPLC (column: Phenomenex Synergi Max-RP 250x50 mm, 10 micron, mobile phase: [water (0.225% formic acid)-acetonitrile], B%: acetonitrile 40% to acetonitrile 70%, 30 min) to give tert-butyl 4-[2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (1.6 g, 2.94 mmol, 81.05% yield, 92% purity) as an off-white solid. LC-MS (ESI) m / z: 503.2 [M+1] + .

[0275] Step 4: Preparation of (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione [ka] To a solution of tert-butyl 4-[2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (700 mg, 1.39 mmol, 1 equiv.) in acetonitrile (15 mL) was added benzenesulfonic acid (440 mg, 2.79 mmol, 2 equiv.). The mixture was stirred at 85° C. for 12 h. LC-MS showed the reaction was complete. The mixture was concentrated in vacuo. The residue was triturated with ethyl acetate (30 mL×3) to give (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (630 mg, crude) as a grey solid. LC-MS (ESI) m / z: 329.1 [M+1] + ; 100% ee by chiral SFC analysis.

[0276] Step 5: Preparation of (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (compound (Ic)) [ka] To a mixture of (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (1.30 g, 3.47 mmol, 1 eq., benzenesulfonate) in dichloromethane (8 mL) and methanol (32 mL) was added sodium acetate (854 mg, 10.41 mmol, 3 eq.) in one portion at 20° C. The mixture was stirred for 10 minutes at 20° C. Then 1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]piperidine-4-carbaldehyde (1 g, 2.43 mmol, 0.7 eq., prepared as described above in the synthesis of compound (Ib)) was added. The mixture was stirred for 10 minutes at 20° C. Then, acetic acid (0.2 mL) and sodium cyanoborohydride (436 mg, 6.94 mmol, 2 equiv.) were added in one portion. The mixture was stirred at 20° C. for 40 min. The mixture was concentrated in vacuo and 50 mL of tetrahydrofuran and 20 mL of water were added. The mixture was stirred for 20 min. Saturated sodium bicarbonate solution was added and the pH was adjusted to 8-9. The aqueous phase was extracted with ethyl acetate and tetrahydrofuran (v:v=2:1, 60 mLx3). The combined organic phase was washed with brine (60 mLx1), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative reverse phase HPLC (column: Phenomenex luna C18 250x50 mm, 10 micron; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 20%-50%, 30 min). The product, (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (964 mg, 1.23 mmol, 35% yield, 98% purity, formate salt), was obtained as a white solid of the formate salt after lyophilization. Chiral purity was analyzed by chiral SFC (Chiralcel OJ-3 50 × 4.6 mm, 3 microns; mobile phase: 50% ethanol (0.05% DEA) in CO2; flow rate: 3 mL / min, wavelength: 220 nm) and t p = 2.89 min, and over 95% de was observed. D=-267.5(c=0.2 DMF, 25℃). LC-MS(ESI)m / z:724.2[M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.94 (s, 1H), 8.16 (s, 1H, acid salt), 7.51 (d, J = 8.8H z,1H),7.21-6.98(m,5H),6.83(d,J=6.4Hz,2H),6.68-6.57(m,2H),6.56 -6.44(m,3H),6.20(d,J=8.8Hz,2H),5.04(dd,J=5.2,13.2Hz,1H),4.32(d,J=16.8Hz,1H),4.19(d,J=17.2Hz,1H),4.12(d,J=4.8Hz,1H),3.51(br d,J=10.0Hz,4H),3.27(br s,8H),3.03-2.82(m,3H),2.63-2.54(m,1H),2.43-2.28(m,2H),2.19(d,J=6.8Hz ,2H),2.15-2.02(m,1H),2.01-1.89(m,1H),1.83-1.51(m,4H),1.28-1.04(m,2H).

[0277] free non-diabetic 1H-NMR:(400MHz,DMSO-d6)δ10.93(s,1H),9.09(s,1H),7.51(d,J=8.8Hz,1H),7.18-7.09(m,3H),7.08-7.02(m,2H),6.83(d,J=6.4Hz,2H),6 .64(d,J=8.4Hz,1H),6.60(d,J=2.0Hz,1H),6.53(d,J=8.8Hz,2H),6.48(dd,J=2.4,8.4Hz,1H),6.20(d,J=8.8Hz,2H),5.04(dd,J=5.2,13.2 Hz,1H),4.39-4.27(m,1H),4.24-4.15(m,1H),4.12(d,J=4.8Hz,1H),3.51(d,J=9.6Hz,2H),3.29-3.24(m,5H),3.03-2.83(m,3H),2.62-2.5 4(m,4H),2.52(s,3H),2.41-2.36(m,1H),2.19(d,J=7.2Hz,2H),2.15- 2.08 (m, 1H), 2.00-1.89 (m, 1H), 1.81-1.58 (m, 4H), 1.22-1.06 (m, 2H).

[0278] PALBOCICILB Palbociclib, also known as 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, has the following structural formula: [ka] .

[0279] Palbociclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK4 / 6 are downstream of signaling pathways that lead to cell proliferation. In vitro, palbociclib reduced cell proliferation in estrogen receptor (ER)-positive breast cancer cell lines by blocking the progression of cells from the G1 to S phase of the cell cycle. Treatment of breast cancer cell lines with a combination of palbociclib and antiestrogen resulted in decreased phosphorylation of retinoblastoma (Rb) protein, resulting in decreased E2F expression and signaling, and increased growth arrest, compared with treatment with each agent alone. In vitro treatment of ER-positive breast cancer cell lines with a combination of palbociclib and antiestrogen increased cellular senescence compared with each agent alone, which persisted for up to 6 days after removal of palbociclib and was higher if antiestrogen treatment was continued. In vivo studies using patient-derived ER-positive breast cancer xenograft models demonstrated that the combination of palbociclib and letrozole increased Rb phosphorylation, downstream signaling, and inhibition of tumor growth compared with each agent alone.

[0280] Human bone marrow mononuclear cells treated with palbociclib in the presence or absence of antiestrogen in vitro did not undergo senescence and resumed proliferation after cessation of palbociclib.

[0281] In some embodiments, the application relates to any of the methods for treating and / or preventing breast cancer disclosed herein, comprising co-administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof and a therapeutically effective amount of a CDK4 / 6 inhibitor or a pharma- ceutically acceptable salt thereof, or comprising co-administering to a subject in need thereof a therapeutically effective amount of a combination of a compound of formula (Ic) or a pharma- ceutically acceptable salt thereof and a CDK4 / 6 inhibitor or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (Ic) is a free base or a pharma- ceutically acceptable salt thereof. In some embodiments, the CDK4 / 6 inhibitor is a free base or a pharma- ceutically acceptable salt thereof. In some embodiments, the CDK4 / 6 inhibitor is palbociclib or a pharma- ceutically acceptable salt thereof. In some embodiments, the CDK4 / 6 inhibitor is palbociclib dihydrochloride. The dihydrochloride salt of palbociclib can be prepared, for example, by reaction of palbociclib free base in an ethereal solution of hydrogen chloride. Palbociclib is a marketed drug for the treatment of breast cancer, developed by Pfizer and sold under the brand name Ibrance®.

[0282] How to ubiquitinate and degrade target proteins in cells The present invention provides a method for ubiquitinating / degrading a target protein in a cell (e.g., an intracellular target protein). The method includes administering a bifunctional compound including an E3 ubiquitin ligase binding moiety and a protein targeting moiety, preferably linked via a linker moiety, where the E3 ubiquitin ligase binding moiety recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, preferably an E3 ubiquitin ligase) and the protein targeting moiety recognizes a target protein (e.g., an intracellular target protein) such that when the target protein is placed in close proximity to the E3 ubiquitin ligase, ubiquitination of the target protein occurs, resulting in degradation of the target protein via the proteasome pathway, leading to control (e.g., reduction) of the target protein levels. In one embodiment, the protein targeting moiety binds to a nuclear hormone receptor. In certain embodiments, the protein targeting moiety binds to an estrogen receptor or an estrogen-related receptor. In one embodiment, the intracellular target protein is an estrogen receptor or an estrogen-related receptor. In one embodiment, the linker moiety is a bond or chemical group that covalently links the protein targeting moiety to the E3 ubiquitin ligase binding moiety. In certain embodiments, the linker may contain one or more alkanes and one or more heterocyclic moieties. In certain embodiments, the alkane is a C1-C6 alkyl group and the heterocyclic moiety is a pyrrolidine, imidazolidine, piperidine, or piperazine. In one embodiment, the E3 ubiquitin ligase is cereblon. In certain embodiments, the cereblon binding moiety is thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, or derivatives thereof. The control (e.g., reduction) of protein levels provided by the present invention provides treatment of a disease state or condition that is regulated via a target protein by lowering the level of that protein in the patient's cells.

[0283] In one aspect, the present application provides a compound of formula (I), or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, that degrades estrogen receptor (ER) protein. In some embodiments, the ER degraded by the compound of formula (I) is wild-type ER. In some embodiments, the ER degraded by the compound of formula (I) is a mutant form of ER.

[0284] In some embodiments, the mutant form of ER that is degraded by the compounds of formula (I) comprises at least one ER somatic tumor mutation.

[0285] In some embodiments, the at least one somatic ER tumor mutation is selected from Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to any amino acid residue other than the wild-type residue at that position. In some embodiments, the at least one somatic ER tumor mutation is selected from Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to any amino acid residue other than the wild type residue at that position, and is selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E).

[0286] In some embodiments, the mutant form of ER that is degraded by the compounds of formula (I) contains at least the Y537X ER somatic tumor mutation.

[0287] In some embodiments, the mutant form of ER that is degraded by the compounds of formula (I) comprises at least the D538X ER somatic tumor mutation.

[0288] In some embodiments, the mutant form of ER that is degraded by the compounds of formula (I) comprises at least the E380X ER somatic tumor mutation.

[0289] In some embodiments, the mutant form of ER that is degraded by the compounds of formula (I) comprises at least the L379X ER somatic tumor mutation.

[0290] In some embodiments, the mutant form of ER that is degraded by the compounds of formula (I) comprises at least the V422X ER somatic tumor mutation.

[0291] In some embodiments, the mutant form of ER that is degraded by the compounds of formula (I) comprises at least the S463X ER somatic tumor mutation.

[0292] In some embodiments, the mutant form of ER that is degraded by the compounds of formula (I) comprises at least the L536X ER somatic tumor mutation.

[0293] In some embodiments, the at least one somatic ER tumor mutation is selected from Y537S, Y537N, D538G, E380Q, L379I, V422del, S463P, L536P, and L536_D538>P.

[0294] In some embodiments, the mutant form of ER that is degraded by the compounds of formula (I) contains at least the Y537S ER somatic tumor mutation.

[0295] In some embodiments, the mutant form of ER that is degraded by the compounds of formula (I) contains at least the Y537N ER somatic tumor mutation.

[0296] In some embodiments, the mutant form of ER that is degraded by the compounds of formula (I) comprises at least the D538G ER somatic tumor mutation.

[0297] In some embodiments, the mutant form of ER that is degraded by the compounds of formula (I) comprises at least the E380Q ER somatic tumor mutation.

[0298] In some embodiments, the mutant form of ER that is degraded by the compounds of formula (I) comprises at least the L379I ER somatic tumor mutation.

[0299] In some embodiments, the mutant forms of ER that are degraded by compounds of formula (I) include at least the V422del ER somatic tumor mutation.

[0300] In some embodiments, the mutant form of ER that is degraded by the compounds of formula (I) comprises at least the S463P ER somatic tumor mutation.

[0301] In some embodiments, the mutant form of ER that is degraded by the compounds of formula (I) comprises at least the L536P ER somatic tumor mutation.

[0302] In some embodiments, the mutant form of ER that is degraded by the compounds of formula (I) comprises at least the ER somatic tumor mutation L536_D538>P.

[0303] In some embodiments, the disclosure is directed to a method of treating a patient in need of treatment for a disease state or condition causally linked to a protein, where degradation of the protein produces a therapeutic effect in the patient, comprising administering to a patient in need thereof an effective amount of a compound of formula (I), optionally in combination with another bioactive agent, e.g., an anti-cancer agent. The disease state or condition may be a disease state or condition causally linked to expression or overexpression of the protein.

[0304] Treatment method In one aspect, the present application relates to a method of treating and / or preventing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0305] In one aspect, the application relates to a compound of formula (I), or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, for use in a method of treating and / or preventing cancer. In some embodiments, the method comprises administering a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, to a subject in need thereof.

[0306] In one aspect, the present application relates to a method of treating and / or preventing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, in combination with one or more additional anti-cancer agents.

[0307] In one aspect, the present application relates to a compound of formula (I), or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, for use in a method of treating and / or preventing cancer in combination with one or more additional anti-cancer agents. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0308] In one aspect, the application relates to a compound of formula (I) or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, for use in the treatment and / or prevention of cancer, in combination with one or more additional anti-cancer agents.

[0309] The methods of treating cancer described herein include reducing tumor size. Alternatively, or in addition, the cancer is a metastatic cancer and the methods of treatment include inhibiting metastatic cancer cell invasion.

[0310] In some embodiments, the cancer is breast cancer.

[0311] In some embodiments, the breast cancer is metastatic breast cancer.

[0312] In some embodiments, the breast cancer is locally advanced breast cancer.

[0313] In some embodiments, the breast cancer is ER+, HER2- breast cancer.

[0314] In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer.

[0315] In some embodiments, the breast cancer is a metastatic, ER+, HER2- breast cancer that is also locally advanced.

[0316] In some embodiments, subjects afflicted with breast cancer may have different responses to treatment with a compound of formula (I), or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, depending on the subject's ER biomarker status, i.e., whether the subject has one or more somatic tumor mutations to ER.

[0317] In one aspect, the disclosure provides a method of treating breast cancer in a subject having a breast cancer that contains at least one somatic ER tumor mutation.

[0318] As used herein, "ER" refers to human estrogen receptor alpha (ERα) encoded by human ESR1 gene.Somatic ER tumor mutations are observed at increased frequency in patients with breast cancer that has acquired resistance to endocrine therapy (Toy et al (2013) Nature Genetics 45:1439-1445, Merenbakh-Lamin et al (2013) Cancer Research 73:6856-6864, Robinson et al (2013) Nature Genetics 45:1446-1451, Li et al (2013) Cell Reports 4:1116-1130,). Somatic ER mutations frequently occur in the ER ligand-binding domain, a functional domain of human ER that forms a hydrophobic pocket for binding ER hormone ligands (e.g., estrogen) (Hamadeh et al (2018) Cancer Treat Rev 70:47-55; Jeselsohn, et al (2015) Nat Rev Clin Oncol 12:573-583). Furthermore, it has been demonstrated that somatic ER tumor mutations in the ER ligand-binding domain are acquired in response to the selective pressure of endocrine therapy (e.g., aromatase inhibitors) that creates a low estrogen environment (Jeselsohn et al (2014) Clinical Cancer Research 20:1757-1767; Schiavon, et al (2015) Sci Transl Med 7:313ra182). Without wishing to be bound by theory, mutations in the ER ligand-binding domain result in reduced ligand specificity, whereby ER functions independently of estrogen. These ER tumor mutations provide tumor cells with the ability to grow in an estrogen-depleted environment and are therefore selected in response to endocrine therapies that block or reduce estrogen levels.

[0319] As understood by those skilled in the art, ER is a polypeptide that is 525 amino acid residues in length and contains three functional domains: an N-terminal transcriptional regulatory domain, a DNA binding domain, and a ligand binding domain (Kumar, et al. 2011) J. Amino Acids Article ID 812540). The DNA binding domain is linked to the ligand binding domain via a hinge. The reference sequence suitable for ER is described by SEQ ID NO: 1 and is identified as P03372 (ESR1_HUMAN) in the UniProt database.

[0320] As used herein, an "N-terminal transcriptional regulatory domain" refers to a contiguous stretch of amino acid residues that extends from amino acid residue 1 to about amino acid residue 180 of ER (e.g., amino acid residues 1-180 of SEQ ID NO:1). In some embodiments, an "N-terminal transcriptional regulatory domain" refers to a contiguous stretch of amino acid residues that extends from amino acid residue 1 to amino acid residue 180 of ER (e.g., amino acid residues 1-180 of SEQ ID NO:1).

[0321] As used herein, a "DNA binding domain" refers to a contiguous stretch of amino acid residues extending from about amino acid residue 181 to about amino acid residue 263 of ER (e.g., amino acid residues 181-263 of SEQ ID NO:1). In some embodiments, a "DNA binding domain" refers to a contiguous stretch of amino acid residues extending from amino acid residue 181 to amino acid residue 263 of ER (e.g., amino acid residues 181-263 of SEQ ID NO:1).

[0322] As used herein, "hinge" refers to a contiguous stretch of amino acid residues extending from about amino acid residue 264 to about amino acid residue 302 of ER (e.g., amino acid residues 264-302 of SEQ ID NO:1). In some embodiments, "hinge" refers to a contiguous stretch of amino acid residues extending from amino acid residue 264 to amino acid residue 302 of ER (e.g., amino acid residues 264-302 of SEQ ID NO:1).

[0323] As used herein, a "ligand binding domain" refers to a contiguous stretch of amino acid residues extending from about amino acid residue 303 to about amino acid residue 552 (e.g., amino acid residues 303-552 of SEQ ID NO:1). In some embodiments, a "ligand binding domain" refers to a contiguous stretch of amino acid residues extending from amino acid residue 303 to amino acid residue 552 (e.g., amino acid residues 303-552 of SEQ ID NO:1).

[0324] In some embodiments, the subject has a breast cancer that contains at least one somatic ER tumor mutation present in a functional domain of ER.

[0325] In some embodiments, the at least one somatic ER tumor mutation is an insertion, deletion, or substitution of one or more amino acid residues in a functional domain of ER compared to an ER reference sequence (e.g., SEQ ID NO:1).

[0326] In some embodiments, the at least one somatic ER tumor mutation is a substitution of one or more amino acid residues in a functional domain of ER compared to an ER reference sequence (eg, SEQ ID NO:1).

[0327] In some embodiments, the at least one somatic ER tumor mutation is present in the ER ligand binding domain.

[0328] In some embodiments, the at least one somatic ER tumor mutation is an insertion, deletion, or substitution of one or more amino acid residues in the ligand-binding domain of ER compared to an ER reference sequence (e.g., SEQ ID NO:1).

[0329] In some embodiments, the at least one somatic ER tumor mutation is an insertion, deletion, or substitution of one or more amino acid residues selected from amino acid residues 303-552 compared to the ER reference sequence, where the ER reference sequence is described by SEQ ID NO:1.

[0330] In some embodiments, at least one somatic ER tumor mutation in the ER ligand binding domain provides ER with reduced ligand specificity and / or enhanced cofactor recruitment. Without being bound by theory, ER with reduced ligand specificity and / or enhanced cofactor recruitment has an increased ability to trigger the ER signaling pathway, thereby conferring a growth advantage to tumor cells containing the mutated ER.

[0331] In some embodiments, the at least one somatic ER tumor mutation is selected from any one or any combination of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to any amino acid residue other than the wild type residue at that position. In some embodiments, the at least one somatic ER tumor mutation is selected from any one or any combination of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to an amino acid residue other than the wild-type residue at that position and is selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E).

[0332] In some embodiments, the at least one somatic ER tumor mutation is Y537X.

[0333] In some embodiments, the at least one somatic ER tumor mutation is D538X.

[0334] In some embodiments, the at least one somatic ER tumor mutation is E380X.

[0335] In some embodiments, the at least one somatic ER tumor mutation is L379X.

[0336] In some embodiments, the at least one somatic ER tumor mutation is V422X.

[0337] In some embodiments, the at least one somatic ER tumor mutation is S463X.

[0338] In some embodiments, the at least one somatic ER tumor mutation is L536X.

[0339] In some embodiments, the at least one somatic ER tumor mutation comprises any one or any combination of Y537S, Y537N, D538G, E380Q, L379I, V422del, S463P, L536P, and L536_D538>P.

[0340] In some embodiments, the at least one somatic ER tumor mutation is Y537S.

[0341] In some embodiments, the at least one somatic ER tumor mutation is Y537N.

[0342] In some embodiments, the at least one somatic ER tumor mutation is D538G.

[0343] In some embodiments, the at least one somatic ER tumor mutation is E380Q.

[0344] In some embodiments, the at least one somatic ER tumor mutation is L379I.

[0345] In some embodiments, the at least one somatic ER tumor mutation is V422del.

[0346] In some embodiments, the at least one somatic ER tumor mutation is S463P.

[0347] In some embodiments, the at least one somatic ER tumor mutation is L536P.

[0348] In some embodiments, the at least one somatic ER tumor mutation is L536_D538>P.

[0349] In some embodiments, the breast cancer comprises cancer cells characterized by the expression of at least one somatic ER tumor mutation described herein. Methods for identifying cancers characterized by the expression of somatic mutations are known in the art and include, for example, obtaining a biological sample from a subject, harvesting the biological sample to obtain genetic material (e.g., genomic DNA or RNA), and performing sequencing analysis, RNA sequencing analysis, or real-time polymerase chain reaction (RT-PCR). For example, in some embodiments, genomic DNA is first obtained (using any standard technique) from cancer tissue obtained from a subject, cDNA is prepared, amplification is performed (e.g., using polymerase chain reaction) to provide a sufficient amount of cDNA for sequence analysis, and sequencing is performed, for example, using next-generation sequencing. Genomic DNA or RNA is usually extracted from a biological sample, such as tissue removed from a subject, for example, by tissue biopsy. In some embodiments, the biological sample is a tissue biopsy sample (e.g., a breast tumor biopsy sample) and sequence analysis of the genomic DNA or RNA is performed to identify the presence of somatic mutations in the ER (e.g., somatic ER tumor mutations present in the ER ligand binding domain). In some embodiments, a biological sample comprising plasma obtained from a subject is used to detect somatic ER tumor mutations present in circulating tumor DNA, for example, using PCR-based amplification and gene sequencing.

[0350] In one aspect, the present application relates to a method of treating breast cancer in a subpopulation of breast cancer patients, comprising: selecting a breast cancer subject for treatment based on the subject's somatic ER tumor biomarker status; a therapeutically effective amount of a compound of formula (I), [ka] or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein Each R 1 and each R 2 are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, SO2(R 5 ), C1-C6 alkyl, and C3-C6 cycloalkyl; R 3 and R 4 are either both hydrogen or together with the carbon to which they are attached form a carbonyl, Each R 5 and each R 6 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, or 4; The therapeutically effective amount of a compound of formula (I) is from about 10 mg to about 1000 mg.

[0351] In one aspect, the present application relates to a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, for use in a method of treating breast cancer in a subpopulation of breast cancer patients, wherein: Each R 1 and each R 2 are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, SO2(R 5 ), C1-C6 alkyl, and C3-C6 cycloalkyl; R 3 and R 4are either both hydrogen or together with the carbon to which they are attached form a carbonyl, Each R 5 and each R 6 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, or 4; The method is: selecting a breast cancer subject for treatment based on the subject's somatic ER tumor biomarker status; administering a therapeutically effective amount of a compound of formula (I), The therapeutically effective amount of a compound of formula (I) is from about 10 mg to about 1000 mg.

[0352] In one aspect, the present application relates to a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, for use in the treatment of breast cancer in a subpopulation of breast cancer patients, wherein: Each R 1 and each R 2 are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, SO2(R 5 ), C1-C6 alkyl, and C3-C6 cycloalkyl; R 3 and R 4 are either both hydrogen or together with the carbon to which they are attached form a carbonyl, Each R 5 and each R 6 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, or 4; Treatment is selecting a breast cancer subject for treatment based on the subject's somatic ER tumor biomarker status; administering a therapeutically effective amount of a compound of formula (I), The therapeutically effective amount of a compound of formula (I) is from about 10 mg to about 1000 mg.

[0353] In some embodiments, the ER biomarker status of a subject suffering from breast cancer can be determined through analysis of the subject's circulating tumor DNA (ctDNA). Alternative methods for determining the ER biomarker status of a subject suffering from breast cancer include, but are not limited to, fluorescent in situ hybridization, immunohistochemistry, PCR analysis, or sequencing.

[0354] In some embodiments, the subject's ER biomarker status is determined in a blood sample from the subject.

[0355] In some embodiments, the ER biomarker status of a subject afflicted with breast cancer is determined in a solid biopsy derived from the subject's tumor.

[0356] In some embodiments, breast cancer patients are selected for treatment based on the presence of at least one somatic ER tumor mutation.

[0357] In some embodiments, breast cancer patients are selected for treatment based on the presence of at least one somatic ER tumor mutation selected from the group consisting of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to any amino acid residue other than the wild-type residue at that position.

[0358] In some embodiments, breast cancer patients are selected for treatment based on the presence of at least one somatic ER tumor mutation selected from the group consisting of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to an amino acid residue other than the wild-type residue at that position and is selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E).

[0359] In some embodiments, breast cancer patients are selected for treatment based on the presence of 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.

[0360] In some embodiments, breast cancer patients are selected for treatment based on the presence of the Y537S somatic ER tumor mutation.

[0361] In some embodiments, breast cancer patients are selected for treatment based on the presence of the Y537N somatic ER tumor mutation.

[0362] In some embodiments, breast cancer patients are selected for treatment based on the presence of the D538G somatic ER tumor mutation.

[0363] In some embodiments, breast cancer patients are selected for treatment based on the presence of the E380Q somatic ER tumor mutation.

[0364] In some embodiments, breast cancer patients are selected for treatment based on the presence of the L379I somatic ER tumor mutation.

[0365] In some embodiments, breast cancer patients are selected for treatment based on the presence of a V422del somatic ER tumor mutation.

[0366] In some embodiments, breast cancer patients are selected for treatment based on the presence of the S463P somatic ER tumor mutation.

[0367] In some embodiments, breast cancer patients are selected for treatment based on the presence of the L536P somatic ER tumor mutation.

[0368] In some embodiments, breast cancer patients are selected for treatment based on the presence of the L536_D538>P somatic ER tumor mutation.

[0369] In one aspect, the application relates to treating breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), the compound of formula (I) having the following structure: [ka] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4 , m, and n are defined herein. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HER2-. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer that is locally advanced.

[0370] In one aspect, the present application relates to treating breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), wherein the compound of formula (I) is [ka] [ka] [ka] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof. In some embodiments, the compound of formula (I) is a compound of formula (Ia). In some embodiments, the compound of formula (I) is a compound of formula (Ic). In some embodiments, the compound of formula (I) is a compound of formula (Ij). In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HER2-. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer that is locally advanced.

[0371] In one aspect, the present application relates to treating breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), wherein the compound of formula (I) is [ka] is selected from the group consisting of: In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HER2-. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer that is locally advanced.

[0372] In one aspect, the application relates to treating breast cancer in a subject in need thereof, the breast cancer comprising at least one somatic ER tumor mutation, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), the compound of formula (I) being a compound having the following structure: [ka] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4 , m, and n are defined herein. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HER2-. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer that is locally advanced.

[0373] In some embodiments, the at least one somatic ER tumor mutation is selected from any one or any combination of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to any amino acid residue other than the wild type residue at that position. In some embodiments, the at least one somatic ER tumor mutation is selected from any one or any combination of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to an amino acid residue other than the wild-type residue at that position and is selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E).

[0374] In some embodiments, the at least one somatic ER tumor mutation is Y537X.

[0375] In some embodiments, the at least one somatic ER tumor mutation is D538X.

[0376] In some embodiments, the at least one somatic ER tumor mutation is E380X.

[0377] In some embodiments, the at least one somatic ER tumor mutation is L379X.

[0378] In some embodiments, the at least one somatic ER tumor mutation is V422X.

[0379] In some embodiments, the at least one somatic ER tumor mutation is S463X.

[0380] In some embodiments, the at least one somatic ER tumor mutation is L536X.

[0381] In some embodiments, the at least one somatic ER tumor mutation comprises any one or any combination of Y537S, Y537N, D538G, E380Q, L379I, V422del, S463P, L536P, and L536_D538>P.

[0382] In some embodiments, the at least one somatic ER tumor mutation is Y537S.

[0383] In some embodiments, the at least one somatic ER tumor mutation is Y537N.

[0384] In some embodiments, the at least one somatic ER tumor mutation is D538G.

[0385] In some embodiments, the at least one somatic ER tumor mutation is E380Q.

[0386] In some embodiments, the at least one somatic ER tumor mutation is L379I.

[0387] In some embodiments, the at least one somatic ER tumor mutation is V422del.

[0388] In some embodiments, the at least one somatic ER tumor mutation is S463P.

[0389] In some embodiments, the at least one somatic ER tumor mutation is L536P.

[0390] In some embodiments, the at least one somatic ER tumor mutation is L536_D538>P.

[0391] In one aspect, the present application relates to treating breast cancer in a subject in need thereof, the breast cancer comprising at least one somatic ER tumor mutation, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), wherein the compound of formula (I) is [ka] [ka] [ka] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof. In some embodiments, the compound of formula (I) is a compound of formula (Ia). In some embodiments, the compound of formula (I) is a compound of formula (Ic). In some embodiments, the compound of formula (I) is a compound of formula (Ic). In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HER2-. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer that is locally advanced.

[0392] In some embodiments, the at least one somatic ER tumor mutation is selected from any one or any combination of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to any amino acid residue other than the wild type residue at that position. In some embodiments, the at least one somatic ER tumor mutation is selected from any one or any combination of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to an amino acid residue other than the wild-type residue at that position and is selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E).

[0393] In some embodiments, the at least one somatic ER tumor mutation is Y537X.

[0394] In some embodiments, the at least one somatic ER tumor mutation is D538X.

[0395] In some embodiments, the at least one somatic ER tumor mutation is E380X.

[0396] In some embodiments, the at least one somatic ER tumor mutation is L379X.

[0397] In some embodiments, the at least one somatic ER tumor mutation is V422X.

[0398] In some embodiments, the at least one somatic ER tumor mutation is S463X.

[0399] In some embodiments, the at least one somatic ER tumor mutation is L536X.

[0400] In some embodiments, the at least one somatic ER tumor mutation comprises any one or any combination of Y537S, Y537N, D538G, E380Q, L379I, V422del, S463P, L536P, and L536_D538>P.

[0401] In some embodiments, the at least one somatic ER tumor mutation is Y537S.

[0402] In some embodiments, the at least one somatic ER tumor mutation is Y537N.

[0403] In some embodiments, the at least one somatic ER tumor mutation is D538G.

[0404] In some embodiments, the at least one somatic ER tumor mutation is E380Q.

[0405] In some embodiments, the at least one somatic ER tumor mutation is L379I.

[0406] In some embodiments, the at least one somatic ER tumor mutation is V422del.

[0407] In some embodiments, the at least one somatic ER tumor mutation is S463P.

[0408] In some embodiments, the at least one somatic ER tumor mutation is L536P.

[0409] In some embodiments, the at least one somatic ER tumor mutation is L536_D538>P.

[0410] In one aspect, the present application relates to treating breast cancer in a subject in need thereof, the breast cancer comprising at least one somatic ER tumor mutation, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), wherein the compound of formula (I) is [ka] is selected from the group consisting of: In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HER2-. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer that is locally advanced.

[0411] In some embodiments, the at least one somatic ER tumor mutation is selected from any one or any combination of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to any amino acid residue other than the wild type residue at that position. In some embodiments, the at least one somatic ER tumor mutation is selected from any one or any combination of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to an amino acid residue other than the wild-type residue at that position and is selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E).

[0412] In some embodiments, the at least one somatic ER tumor mutation is Y537X.

[0413] In some embodiments, the at least one somatic ER tumor mutation is D538X.

[0414] In some embodiments, the at least one somatic ER tumor mutation is E380X.

[0415] In some embodiments, the at least one somatic ER tumor mutation is L379X.

[0416] In some embodiments, the at least one somatic ER tumor mutation is V422X.

[0417] In some embodiments, the at least one somatic ER tumor mutation is S463X.

[0418] In some embodiments, the at least one somatic ER tumor mutation is L536X.

[0419] In some embodiments, the at least one somatic ER tumor mutation comprises any one or any combination of Y537S, Y537N, D538G, E380Q, L379I, V422del, S463P, L536P, and L536_D538>P.

[0420] In some embodiments, the at least one somatic ER tumor mutation is Y537S.

[0421] In some embodiments, the at least one somatic ER tumor mutation is Y537N.

[0422] In some embodiments, the at least one somatic ER tumor mutation is D538G.

[0423] In some embodiments, the at least one somatic ER tumor mutation is E380Q.

[0424] In some embodiments, the at least one somatic ER tumor mutation is L379I.

[0425] In some embodiments, the at least one somatic ER tumor mutation is V422del.

[0426] In some embodiments, the at least one somatic ER tumor mutation is S463P.

[0427] In some embodiments, the at least one somatic ER tumor mutation is L536P.

[0428] In some embodiments, the at least one somatic ER tumor mutation is L536_D538>P.

[0429] In one embodiment, the treatment of cancer results in a reduction in tumor size. The reduction in tumor size may also be referred to as "tumor regression". Preferably, after treatment, the tumor size is reduced by 5% or more relative to its size before treatment, more preferably, the tumor size is reduced by 10% or more, more preferably, by 20% or more, more preferably, by 30% or more, more preferably, by 40% or more, even more preferably, by 50% or more, and most preferably, by 75% or more. The size of the tumor may be measured by any reproducible means of measurement. In a preferred embodiment, the size of the tumor may be measured as the diameter of the tumor.

[0430] In another embodiment, the treatment of cancer results in a reduction in tumor volume. Preferably, after treatment, the tumor volume is reduced by 5% or more relative to its size before treatment, more preferably, the tumor volume is reduced by 10% or more, more preferably, by 20% or more, more preferably, by 30% or more, more preferably, by 40% or more, even more preferably, by 50% or more, and most preferably, by 75% or more. Tumor volume may be measured by any reproducible means of measurement.

[0431] In another embodiment, the treatment of cancer results in a reduction in the number of tumors. Preferably, after treatment, the number of tumors is reduced by 5% or more relative to its number before treatment, more preferably, the number of tumors is reduced by 10% or more, more preferably, the number of tumors is reduced by 20% or more, more preferably, the number of tumors is reduced by 30% or more, more preferably, the number of tumors is reduced by 40% or more, even more preferably, the number of tumors is reduced by 50% or more, and most preferably, the number of tumors is reduced by 75% or more. The number of tumors may be measured by any reproducible measuring means. In a preferred embodiment, the number of tumors may be measured by counting tumors that can be seen with the naked eye or at a specified magnification. In a preferred embodiment, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0432] In another embodiment, the treatment of cancer results in a reduction in the number of metastatic lesions in other tissues or organs distant from the primary tumor site. Preferably, after treatment, the number of metastatic lesions is reduced by 5% or more relative to the number before treatment, more preferably, the number of metastatic lesions is reduced by 10% or more, more preferably, by 20% or more, more preferably, by 30% or more, more preferably, by 40% or more, even more preferably, by 50% or more, and most preferably, by 75% or more. The number of metastatic lesions may be measured by any reproducible measuring means. In a preferred embodiment, the number of metastatic lesions may be measured by counting metastatic lesions visible to the naked eye or at a specified magnification. In a preferred embodiment, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0433] In another embodiment, treating cancer results in an increase in the average survival time of the population of treated subjects compared to the population administered with carrier alone. Preferably, the average survival time increases by more than 30 days, more preferably by more than 60 days, more preferably by more than 90 days, and most preferably by more than 120 days. The increase in the average survival time of the population may be measured by any reproducible means. In a preferred embodiment, the increase in the average survival time of the population may be measured, for example, by calculating the average length of survival for the population after the start of treatment with an active agent or compound. In another preferred embodiment, the increase in the average survival time of the population may be measured, for example, by calculating the average length of survival for the population after the completion of the first round of treatment with an active agent or compound.

[0434] In another embodiment, treating cancer results in an increase in the average survival time of a population of treated subjects compared to a population of untreated subjects. Preferably, the average survival time is increased by more than 30 days, more preferably more than 60 days, more preferably more than 90 days, and most preferably more than 120 days. The increase in the average survival time of a population may be measured by any reproducible means. In a preferred embodiment, the increase in the average survival time of a population may be measured, for example, by calculating the average length of survival for a population after the start of treatment with an active agent or compound. In another preferred embodiment, the increase in the average survival time of a population may be measured, for example, by calculating the average length of survival for a population after the completion of a first round of treatment with a compound of formula (I).

[0435] In another embodiment, the treatment of cancer leads to a decrease in tumor growth rate.Preferably, after treatment, tumor growth rate is reduced by at least 5% relative to the number before treatment, more preferably, tumor growth rate is reduced by at least 10%, more preferably, by at least 20%, more preferably, by at least 30%, more preferably, by at least 40%, more preferably, by at least 50%, even more preferably, by at least 50%, and most preferably, by at least 75%.Tumor growth rate may be measured by any reproducible measuring means.In a preferred embodiment, tumor growth rate is measured according to the change in tumor diameter per unit time.

[0436] In another embodiment, the treatment of cancer results in a reduction in tumor regrowth. Preferably, after treatment, tumor regrowth is less than 5%, more preferably tumor regrowth is less than 10%, more preferably less than 20%, more preferably less than 30%, more preferably less than 40%, more preferably less than 50%, even more preferably less than 50%, and most preferably less than 75%. Tumor regrowth may be measured by any reproducible means of measurement. In a preferred embodiment, tumor regrowth is measured, for example, by measuring the increase in tumor diameter after tumor shrinkage after treatment. In another preferred embodiment, the reduction in tumor regrowth is indicated by the failure of tumor to recur after treatment is stopped.

[0437] The dosage of the compounds of formula (I) for any of the methods and uses described herein will vary according to the agent, the age, weight, and clinical condition of the recipient subject, as well as the experience and judgment of the clinician or practitioner administering the therapy, among other factors which will influence the selected dosage.

[0438] A therapeutically effective amount of a compound of formula (I) is administered 1, 2, 3, 4, 5 or more times per day for 5, 10, 15, 30, 60, 90, 120, 150, 180 or more days, followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, The compound of formula (I) may be administered for 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 or more days without administration of the compound of formula (I). This type of treatment schedule, i.e., administration of the compound of formula (I) on consecutive days followed by non-administration of the compound of formula (I) on consecutive days, may be referred to as a treatment cycle.

[0439] In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered once or twice daily for up to 5, 10, 15, 20, 25, or 30 days, followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days without administration of the compound of formula (I).

[0440] In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered once daily for up to 5, 10, 15, 20, 25, or 30 days, followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days without administration of a compound of formula (I).

[0441] In some embodiments, treatment cycles with a compound of formula (I) may be repeated as many times as necessary to achieve the intended effect.

[0442] In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered once, twice, three times, four times or more per day for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 30 days consecutively, or for 2 months, 3 months, 4 months, 5 months, 6 months or more, in single or divided doses, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4. 5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82 , 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 1 90, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 34 5, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500 , 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655,660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 83 5, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1,000 mg.

[0443] In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered once, twice, three times, four or more times daily in single or divided doses, about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, about 180 mg, about 210 mg, about 240 mg, about 270 mg, about 300 mg, about 330 mg, about 360 mg The dose is about 390 mg, about 420 mg, about 450 mg, about 480 mg, about 510 mg, about 540 mg, about 570 mg, about 600 mg, about 630 mg, about 660 mg, about 690 mg, about 720 mg, about 750 mg, about 780 mg, about 810 mg, about 840 mg, about 870 mg, about 900 mg, about 930 mg, about 960 mg, or about 990 mg (this dose is determined based on the patient's weight (kg) and body surface area (m 2 ), and may be adjusted for age (years).

[0444] In some embodiments, the therapeutically effective amount of a compound of Formula (I) is about 30 mg to about 1000 mg, administered once, twice, three times, four times, or more per day in single or divided doses (this dose is based on the patient's body weight (kg), body surface area (m 2 ), and may be adjusted for age (years).

[0445] In some embodiments, a therapeutically effective amount of a compound of Formula (I) is administered once, twice, three times, four or more times daily in single or divided doses, 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 170~200mg, 180~210mg, 190~220mg, 200~230mg, 210~240mg, 220~250mg, 230~260mg, 240~270mg, 250~280mg, 260~290mg, 270~ Approximately 300 mg, approximately 280 to approximately 310 mg, approximately 290 to approximately 320 mg, approximately 300 to approximately 330 mg, approximately 310 to approximately 340 mg, approximately 320 to approximately 350 mg, approximately 330 to approximately 360 mg, approximately 340 to approximately 370 mg, approximately 350 to approximately 380 mg, approximately 360 to approximately 390 mg, approximately 370 to approximately 400 mg, about 380 to about 410 mg, about 390 to about 420 mg, about 400 to about 430 mg, about 410 to about 440 mg, about 420 to about 450 mg, about 430 to about 460 mg, about 440 to about 470 mg, about 450 to about 480 mg, about 460 to about 490 mg, about 470 to about 500 mg, About 480 to about 510 mg, about 490 to about 520 mg, about 500 to about 530 mg, about 510 to about 540 mg, about 520 to about 550 mg, about 530 to about 560 mg, about 540 to about 570 mg, about 550 to about 580 mg, about 560 to about 590 mg, about 570 to about 600 mg, about 580 ~610mg, 590~620mg, 600~630mg, 610~640mg, 620~650mg, 630~660mg, 640~670mg, 650~680mg, 660~690mg, 670~700mg, 680~71 0 mg, about 690 to about 720 mg, about 700 to about 730 mg, about 710 to about 740 mg, about 720 to about 750 mg, about 730 to about 760 mg, about 740 to about 770 mg, about 750 to about 780 mg, about 760 to about 790 mg, about 770 to about 800 mg, about 780 to about 810 mg,The dosage is about 790 to about 820 mg, about 800 to about 830 mg, about 810 to about 840 mg, about 820 to about 850 mg, about 830 to about 860 mg, about 840 to about 870 mg, about 850 to about 880 mg, about 860 to about 890 mg, about 870 to about 900 mg, about 880 to about 910 mg, about 890 to about 920 mg, about 900 to about 930 mg, about 910 to about 940 mg, about 920 to about 950 mg, about 930 to about 960 mg, about 940 to about 970 mg, about 950 to about 980 mg, about 960 to about 990 mg, or about 970 to about 1,000 mg (the dosage depends on the patient's body weight (kg), body surface area (m, 2 ) and may be adjusted for age (years).

[0446] The therapeutically effective amount of the compound of formula (I) may also range from about 0.01 mg / kg per day to about 100 mg / kg per day. In one embodiment, the therapeutically effective amount of the compound of formula (I) may range from about 0.05 mg / kg per day to about 10 mg / kg per day. In one embodiment, the therapeutically effective amount of the compound of formula (I) may range from about 0.075 mg / kg per day to about 5 mg / kg per day. In one embodiment, the therapeutically effective amount of the compound of formula (I) may range from about 0.10 mg / kg per day to about 1 mg / kg per day. In one embodiment, the therapeutically effective amount of the compound of formula (I) may range from about 0.20 mg / kg per day to about 0.70 mg / kg per day.

[0447] In some embodiments, the therapeutically effective amount of a compound of formula (I) is about 0.10 mg / kg per day, about 0.15 mg / kg per day, about 0.20 mg / kg per day, about 0.25 mg / kg per day, about 0.30 mg / kg per day, about 0.35 mg / kg per day, about 0.40 mg / kg per day, about 0.45 mg / kg per day, about 0.50 mg / kg per day, about 0.55 mg / kg per day, about 0.60 mg / kg per day, about 0.65 mg / kg per day, about 0.70 mg / kg per day, about 0.75 mg / kg per day, about 0.80 mg / kg per day, about 0.85 mg / kg per day, about 0.90 mg / kg per day, about 0.95 mg / kg per day, or about 1.00 mg / kg per day.

[0448] In some embodiments, the therapeutically effective amount of a compound of formula (I) is about 1.05 mg / kg per day, about 1.10 mg / kg per day, about 1.15 mg / kg per day, about 1.20 mg / kg per day, about 1.25 mg / kg per day, about 1.30 mg / kg per day, about 1.35 mg / kg per day, about 1.40 mg / kg per day, about 1.45 mg / kg per day, about 1.50 mg / kg per day, about 1.55 mg / kg per day, about 1.60 mg / kg per day, about 1.65 mg / kg per day, about 1.70 mg / kg per day, about 1.75 mg / kg per day, about 1.80 mg / kg per day, about 1.85 mg / kg per day, about 1.90 mg / kg per day, about 1.95 ... about 1.50 mg / kg per day, about 1.55 mg / kg per day, about 1.60 mg / kg per day, about 1.65 mg / kg per day, about 1.70 mg / kg per day, about 1.75 mg / kg per day, about 1.80 mg / kg per day, about 1.85 mg / kg per day, about 1.90 mg / kg per day, about 1.95 mg / kg per day, or about 2.00 mg / kg per day.

[0449] In some embodiments, the therapeutically effective amount of a compound of formula (I) is about 2 mg / kg per day, about 2.5 mg / kg per day, about 3 mg / kg per day, about 3.5 mg / kg per day, about 4 mg / kg per day, about 4.5 mg / kg per day, about 5 mg / kg per day, about 5.5 mg / kg per day, about 6 mg / kg per day, about 6.5 mg / kg per day, about 7 mg / kg per day, about 7.5 mg / kg per day, about 8.0 mg / kg per day, about 8.5 mg / kg per day, about 9.0 mg / kg per day, about 9.5 mg / kg per day, or about 10 mg / kg per day.

[0450] In some embodiments, a therapeutically effective amount of a compound of formula (I) is administered to a subject once a day. In some embodiments, the daily dose of a compound of formula (I) is administered to a subject all at once. In some embodiments, the daily dose of a compound of formula (I) is administered to a subject in two unit doses (split doses). In some embodiments, the daily dose of a compound of formula (I) is administered to a subject in three unit doses. In some embodiments, the daily dose of a compound of formula (I) is administered to a subject in four unit doses. In some embodiments, the daily dose of a compound of formula (I) is administered to a subject in five or more unit doses. In some embodiments, these unit doses are administered to a subject at regular intervals throughout the day, for example, every 12 hours, every 8 hours, every 6 hours, every 5 hours, every 4 hours, etc.

[0451] In some embodiments, a therapeutically effective amount of a compound of Formula (I) is greater than about 3,500 ng·hr / mL, greater than about 3,550 ng·hr / mL, greater than about 3,600 ng·hr / mL, greater than about 3,650 ng·hr / mL, greater than about 3,700 ng·hr / mL, greater than about 3,750 ng·hr / mL, greater than about 3,800 ng·hr / mL, greater than about 3,850 ng·hr / mL, greater than about 3,900 ng·hr / mL, greater than about 3,950 ng·hr / mL, greater than about 4,000 ng·hr / mL, greater than about 4,050 ng·hr / mL, greater than about 4,100 ng·hr / mL, greater than about 4,150 ng·hr / mL, or greater than about 4,200 ng·hr / mL , greater than about 4,250 ng·hr / mL, greater than about 4,300 ng·hr / mL, greater than about 4,350 ng·hr / mL, greater than about 4,400 ng·hr / mL, greater than about 4,450 ng·hr / mL, greater than about 4,500 ng·hr / mL, greater than about 4,550 ng·hr / mL, greater than about 4,600 ng·hr / mL, greater than about 4,650 ng·hr / mL, greater than about 4,700 ng·hr / mL, greater than about 4,750 ng·hr / mL, greater than about 4,800 ng·hr / mL, greater than about 4,850 ng·hr / mL, greater than about 4,900 ng·hr / mL, greater than about 4,950 ng·hr / mL, or greater than about 5,000 ng·hr / mL TAU results.

[0452] In some embodiments, a therapeutically effective amount of a compound of formula (I) is greater than about 150 ng / mL, greater than about 155 ng / mL, greater than about 160 ng / mL, greater than about 165 ng / mL, greater than about 170 ng / mL, greater than about 175 ng / mL, greater than about 180 ng / mL, greater than about 185 ng / mL, greater than about 190 ng / mL, greater than about 195 ng / mL, greater than about 200 ng / mL, greater than about 205 ng / mL, greater than about 210 ng / mL, greater than about 215 ng / mL, greater than about 220 ng / mL, greater than about 225 ng / mL, greater than about 230 ng / mL, greater than about 235 ng / mL, greater than about 240 ng / mL, or greater than about 245 ng / mL. More than 250ng / mL, more than about 255ng / mL, more than about 260ng / mL, more than about 265ng / mL, more than about 270ng / mL, more than about 275ng / mL, more than about 280ng / mL, more than about 285ng / mL, more than about 290ng / mL, more than about 295ng / mL, more than about 300ng / mL , 15th day average C of >305ng / mL, >310ng / mL, >315ng / mL, >320ng / mL, >325ng / mL, >330ng / mL, >335ng / mL, >340ng / mL, >345ng / mL, or >350ng / mL. max results.

[0453] Therapeutically effective amounts of compounds of formula (I) can be estimated initially either in cell culture assays or animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models may also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined using standard pharmaceutical procedures in cell cultures or experimental animals, such as ED 50 (therapeutic effective dose in 50% of the population) and LD 50 (the dose at which 50% of the population is lethal). The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 It may be expressed as a ratio. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending on the dosage form employed, sensitivity of the patient, and the route of administration.

[0454] Dosage and administration are adjusted to provide sufficient levels of the compound of formula (I) or to maintain the desired effect. Factors that may be considered include the severity of the condition, the general health of the subject, the age, weight, and sex of the subject, diet, time and frequency of administration, drug combinations, response sensitivity, and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered every 3-4 days, every week, or every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0455] Methods of treatment comprising administering a compound of formula (I) and an additional anti-cancer agent In one aspect, the present application relates to a method of treating and / or preventing breast cancer in a subject in need thereof, comprising co-administering to the subject a therapeutically effective amount of a compound of formula (I) and a therapeutically effective amount of an additional anti-cancer agent.

[0456] In one aspect, the present application relates to a compound of formula (I) for use in a method for treating and / or preventing breast cancer in a subject in need thereof, the method comprising co-administering to the subject a therapeutically effective amount of a compound of formula (I) and a therapeutically effective amount of an additional anti-cancer agent.

[0457] In one aspect, the present application relates to a compound of formula (I) for use in the treatment and / or prevention of breast cancer in a subject in need thereof, the treatment and / or prevention comprising co-administering to the subject a therapeutically effective amount of a compound of formula (I) and a therapeutically effective amount of an additional anti-cancer agent.

[0458] These methods include reducing tumor size. Alternatively, or additionally, the breast cancer is metastatic breast cancer and the method of treatment includes inhibiting metastatic cancer cell invasion. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HER2-. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer that is locally advanced.

[0459] In some embodiments, a therapeutically effective amount of a compound of Formula (I) and a therapeutically effective amount of an additional anti-cancer agent are administered simultaneously (either in the same formulation or in separate formulations).

[0460] In some embodiments, a therapeutically effective amount of a compound of Formula (I) and a therapeutically effective amount of an additional anti-cancer agent are administered sequentially, i.e., the compound of Formula (I) is administered first, followed by the additional anti-cancer agent, or the additional anti-cancer agent is administered first, followed by the compound of Formula (I). In some embodiments, the additional anti-cancer agent is administered first, followed one hour later by the compound of Formula (I).

[0461] In some embodiments, a therapeutically effective amount of a compound of Formula (I) and a therapeutically effective amount of an additional anti-cancer agent are administered in close temporal proximity.

[0462] In some embodiments, "temporal proximity" refers to administration of the compound of formula (I) within a period of time before or after administration of the additional anti-cancer agent, such that the therapeutic effect of the compound of formula (I) overlaps with the therapeutic effect of the additional anti-cancer agent. In some embodiments, the therapeutic effect of the compound of formula (I) completely overlaps with the therapeutic effect of the additional anti-cancer agent. In some embodiments, "temporal proximity" refers to administration of the compound of formula (I) within a period of time before or after administration of the additional anti-cancer agent, such that there is a synergistic effect between the compound of formula (I) and the additional anti-cancer agent.

[0463] "Temporal proximity" may vary depending on a variety of factors, including, but not limited to, the age, sex, weight, genetic background, medical condition, medical and treatment history of the subject to which the therapeutic agent is administered, the disease or condition to be treated or alleviated, the therapeutic outcome to be achieved, the dosage, frequency and duration of administration of the therapeutic agent, the pharmacokinetics and pharmacodynamics of the therapeutic agent, and the route by which the therapeutic agent is administered. In some embodiments, "temporal proximity" means within 15 minutes, within 30 minutes, within 1 hour, within 2 hours, within 4 hours, within 6 hours, within 8 hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 1 week, within 2 weeks, within 3 weeks, within 4 weeks, within 6 weeks, or within 8 weeks. In some embodiments, multiple administrations of one therapeutic agent may be administered in temporal proximity to a single administration of another therapeutic agent. In some embodiments, temporal proximity may vary during a treatment cycle or within a dosing regimen.

[0464] In one aspect, the present application relates to a method of treating and / or preventing breast cancer in a subject in need thereof, the breast cancer comprising at least one somatic ER tumor mutation, comprising administering to the subject a compound of formula (I) and an additional anti-cancer agent, the compound of formula (I) being a compound having the structure: [ka] or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 4 , m, and n are defined herein.

[0465] In one aspect, the application relates to a compound of formula (I), or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, for use in a method of treating and / or preventing 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 compound of formula (I) and an additional anti-cancer agent.

[0466] In one aspect, the application relates to a compound of formula (I), or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, for use in the treatment and / or prevention of breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation, and the treatment and / or prevention comprises administering to the subject a compound of formula (I) and an additional anti-cancer agent.

[0467] In one aspect, the present application relates to a combination comprising a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, and an additional anti-cancer agent, for use in the treatment and / or prevention of breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation.

[0468] In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HER2-. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer that is locally advanced.

[0469] In some embodiments, the at least one somatic ER tumor mutation is selected from any one or any combination of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to any amino acid residue other than the wild type residue at that position. In some embodiments, the at least one somatic ER tumor mutation is selected from any one or any combination of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to an amino acid residue other than the wild-type residue at that position and is selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E).

[0470] In some embodiments, the at least one somatic ER tumor mutation is Y537X.

[0471] In some embodiments, the at least one somatic ER tumor mutation is D538X.

[0472] In some embodiments, the at least one somatic ER tumor mutation is E380X.

[0473] In some embodiments, the at least one somatic ER tumor mutation is L379X.

[0474] In some embodiments, the at least one somatic ER tumor mutation is V422X.

[0475] In some embodiments, the at least one somatic ER tumor mutation is S463X.

[0476] In some embodiments, the at least one somatic ER tumor mutation is L536X.

[0477] In some embodiments, the at least one somatic ER tumor mutation comprises any one or any combination of Y537S, Y537N, D538G, E380Q, L379I, V422del, S463P, L536P, and L536_D538>P.

[0478] In some embodiments, the at least one somatic ER tumor mutation is Y537S.

[0479] In some embodiments, the at least one somatic ER tumor mutation is Y537N.

[0480] In some embodiments, the at least one somatic ER tumor mutation is D538G.

[0481] In some embodiments, the at least one somatic ER tumor mutation is E380Q.

[0482] In some embodiments, the at least one somatic ER tumor mutation is L379I.

[0483] In some embodiments, the at least one somatic ER tumor mutation is V422del.

[0484] In some embodiments, the at least one somatic ER tumor mutation is S463P.

[0485] In some embodiments, the at least one somatic ER tumor mutation is L536P.

[0486] In some embodiments, the at least one somatic ER tumor mutation is L536_D538>P.

[0487] In one aspect, the present application relates to a method of treating and / or preventing 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) and a therapeutically effective amount of an additional anti-cancer agent, wherein the compound of formula (I) is [ka] [ka] [ka] or a pharma- ceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0488] In one aspect, the present application relates to a compound of formula (I) for use in a method for treating and / or preventing 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) and an additional anti-cancer agent, wherein the compound of formula (I) is selected from the group consisting of (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), and (Ij).

[0489] In one aspect, the present application relates to a compound of formula (I) for use in the treatment and / or prevention of breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation, and the treatment and / or prevention comprises administering to the subject a therapeutically effective amount of a compound of formula (I) and an additional anti-cancer agent, wherein the compound of formula (I) is selected from the group consisting of (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), and (Ij).

[0490] In one aspect, the present application relates to a combination comprising a compound of formula (I) and an additional anti-cancer agent for use in the treatment and / or prevention of breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation and the compound of formula (I) is selected from the group consisting of (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), and (Ij).

[0491] In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HER2-. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer that is locally advanced.

[0492] In some embodiments, the at least one somatic ER tumor mutation is selected from any one or any combination of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to any amino acid residue other than the wild type residue at that position. In some embodiments, the at least one somatic ER tumor mutation is selected from any one or any combination of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to an amino acid residue other than the wild-type residue at that position and is selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E).

[0493] In some embodiments, the at least one somatic ER tumor mutation is Y537X.

[0494] In some embodiments, the at least one somatic ER tumor mutation is D538X.

[0495] In some embodiments, the at least one somatic ER tumor mutation is E380X.

[0496] In some embodiments, the at least one somatic ER tumor mutation is L379X.

[0497] In some embodiments, the at least one somatic ER tumor mutation is V422X.

[0498] In some embodiments, the at least one somatic ER tumor mutation is S463X.

[0499] In some embodiments, the at least one somatic ER tumor mutation is L536X.

[0500] In some embodiments, the at least one somatic ER tumor mutation comprises any one or any combination of Y537S, Y537N, D538G, E380Q, L379I, V422del, S463P, L536P, and L536_D538>P.

[0501] In some embodiments, the at least one somatic ER tumor mutation is Y537S.

[0502] In some embodiments, the at least one somatic ER tumor mutation is Y537N.

[0503] In some embodiments, the at least one somatic ER tumor mutation is D538G.

[0504] In some embodiments, the at least one somatic ER tumor mutation is E380Q.

[0505] In some embodiments, the at least one somatic ER tumor mutation is L379I.

[0506] In some embodiments, the at least one somatic ER tumor mutation is V422del.

[0507] In some embodiments, the at least one somatic ER tumor mutation is S463P.

[0508] In some embodiments, the at least one somatic ER tumor mutation is L536P.

[0509] In some embodiments, the at least one somatic ER tumor mutation is L536_D538>P.

[0510] In one aspect, the present application relates to a method of treating and / or preventing 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) and a therapeutically effective amount of an additional anti-cancer agent, wherein the compound of formula (I) is [ka] is selected from the group consisting of:

[0511] In one aspect, the present application relates to a compound of formula (I) for use in a method for treating and / or preventing 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) and an additional anti-cancer agent, wherein the compound of formula (I) is selected from the group consisting of (Ia), (Ic), and (Ij).

[0512] In one aspect, the present application relates to a compound of formula (I) for use in the treatment and / or prevention of breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation, and the treatment and / or prevention comprises administering to the subject a therapeutically effective amount of a compound of formula (I) and an additional anti-cancer agent, wherein the compound of formula (I) is selected from the group consisting of (Ia), (Ic), and (Ij).

[0513] In one aspect, the present application relates to a combination comprising a compound of formula (I) and an additional anti-cancer agent for use in the treatment and / or prevention of breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation and the compound of formula (I) is selected from the group consisting of (Ia), (Ic), and (Ij).

[0514] In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HER2-. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer that is locally advanced.

[0515] In some embodiments, the at least one somatic ER tumor mutation is selected from any one or any combination of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to any amino acid residue other than the wild type residue at that position. In some embodiments, the at least one somatic ER tumor mutation is selected from any one or any combination of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to an amino acid residue other than the wild-type residue at that position and is selected from alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophan (W), proline (P), glycine (G), serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K), arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E).

[0516] In some embodiments, the at least one somatic ER tumor mutation is Y537X.

[0517] In some embodiments, the at least one somatic ER tumor mutation is D538X.

[0518] In some embodiments, the at least one somatic ER tumor mutation is E380X.

[0519] In some embodiments, the at least one somatic ER tumor mutation is L379X.

[0520] In some embodiments, the at least one somatic ER tumor mutation is V422X.

[0521] In some embodiments, the at least one somatic ER tumor mutation is S463X.

[0522] In some embodiments, the at least one somatic ER tumor mutation is L536X.

[0523] In some embodiments, the at least one somatic ER tumor mutation comprises any one or any combination of Y537S, Y537N, D538G, E380Q, L379I, V422del, S463P, L536P, and L536_D538>P.

[0524] In some embodiments, the at least one somatic ER tumor mutation is Y537S.

[0525] In some embodiments, the at least one somatic ER tumor mutation is Y537N.

[0526] In some embodiments, the at least one somatic ER tumor mutation is D538G.

[0527] In some embodiments, the at least one somatic ER tumor mutation is E380Q.

[0528] In some embodiments, the at least one somatic ER tumor mutation is L379I.

[0529] In some embodiments, the at least one somatic ER tumor mutation is V422del.

[0530] In some embodiments, the at least one somatic ER tumor mutation is S463P.

[0531] In some embodiments, the at least one somatic ER tumor mutation is L536P.

[0532] In some embodiments, the at least one somatic ER tumor mutation is L536_D538>P.

[0533] In one aspect, the application relates to a combined preparation of a compound of formula (I) as defined herein with an additional anti-cancer agent as defined herein for simultaneous, separate or sequential use in the treatment and / or prevention of breast cancer. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HER2-. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer that is locally advanced.

[0534] In one aspect, the application relates to a combined preparation of a compound of formula (Ic) as defined herein with an additional anti-cancer agent as defined herein for simultaneous, separate or sequential use in the treatment and / or prevention of breast cancer. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HER2-. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer that is locally advanced.

[0535] In one aspect, the application relates to a combined preparation of a compound of formula (I) as defined herein and a palbociclib inhibitor as defined herein for simultaneous, separate or sequential use in the treatment and / or prevention of breast cancer. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HER2-. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer that is locally advanced.

[0536] In one aspect, the application relates to a combined preparation of a compound of formula (Ic) as defined herein and a palbociclib inhibitor as defined herein for simultaneous, separate or sequential use in the treatment and / or prevention of breast cancer. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HER2-. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer. In some embodiments, the breast cancer is metastatic, ER+, HER2- breast cancer that is locally advanced.

[0537] In one embodiment, treating cancer with a compound of formula (I) and an additional anti-cancer agent results in a reduction in tumor size. The reduction in tumor size may also be referred to as "tumor regression". Preferably, after treatment, the tumor size is reduced by 5% or more relative to its size before treatment, more preferably, the tumor size is reduced by 10% or more, more preferably, by 20% or more, more preferably, by 30% or more, more preferably, by 40% or more, even more preferably, by 50% or more, and most preferably, by 75% or more. The size of the tumor may be measured by any reproducible means of measurement. In a preferred embodiment, the size of the tumor may be measured as the diameter of the tumor.

[0538] In another embodiment, treating cancer with a compound of formula (I) and an additional anticancer agent results in a reduction in tumor volume. Preferably, after treatment, the tumor volume is reduced by 5% or more relative to its size before treatment, more preferably, the tumor volume is reduced by 10% or more, more preferably, by 20% or more, more preferably, by 30% or more, more preferably, by 40% or more, even more preferably, by 50% or more, and most preferably, by 75% or more. Tumor volume may be measured by any reproducible means of measurement.

[0539] In another embodiment, treating cancer with a compound of formula (I) and an additional anticancer agent results in a reduction in the number of tumors. Preferably, after treatment, the number of tumors is reduced by 5% or more relative to its number before treatment, more preferably, the number of tumors is reduced by 10% or more, more preferably, the number of tumors is reduced by 20% or more, more preferably, the number of tumors is reduced by 30% or more, more preferably, the number of tumors is reduced by 40% or more, even more preferably, the number of tumors is reduced by 50% or more, and most preferably, the number of tumors is reduced by 75% or more. The number of tumors may be measured by any reproducible measuring means. In a preferred embodiment, the number of tumors may be measured by counting tumors that can be seen with the naked eye or at a specified magnification. In a preferred embodiment, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0540] In another embodiment, treating cancer with a compound of formula (I) and an additional anticancer agent results in a reduction in the number of metastatic lesions in other tissues or organs distant from the primary tumor site. Preferably, after treatment, the number of metastatic lesions is reduced by 5% or more relative to the number before treatment, more preferably, the number of metastatic lesions is reduced by 10% or more, more preferably, by 20% or more, more preferably, by 30% or more, more preferably, by 40% or more, even more preferably, by 50% or more, and most preferably, by 75% or more. The number of metastatic lesions may be measured by any reproducible measuring means. In a preferred embodiment, the number of metastatic lesions may be measured by counting metastatic lesions visible to the naked eye or at a specified magnification. In a preferred embodiment, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0541] In another embodiment, treating cancer with a compound of formula (I) and an additional anti-cancer agent results in an increase in the average survival time of a population of treated subjects compared to a population administered with the carrier alone. Preferably, the average survival time increases by more than 30 days, more preferably by more than 60 days, more preferably by more than 90 days, and most preferably by more than 120 days. The increase in the average survival time of a population may be measured by any reproducible means. In a preferred embodiment, the increase in the average survival time of a population may be measured, for example, by calculating the average length of survival for a population after the start of treatment with an active agent or compound. In another preferred embodiment, the increase in the average survival time of a population may be measured, for example, by calculating the average length of survival for a population after the completion of a first round of treatment with an active agent or compound.

[0542] In another embodiment, treating cancer with a compound of formula (I) and an additional anti-cancer agent results in an increase in the average survival time of a population of treated subjects compared to a population of untreated subjects. Preferably, the average survival time increases by more than 30 days, more preferably more than 60 days, more preferably more than 90 days, and most preferably more than 120 days. The increase in the average survival time of a population may be measured by any reproducible means. In a preferred embodiment, the increase in the average survival time of a population may be measured, for example, by calculating the average length of survival for the population after the start of treatment with an active agent or compound. In another preferred embodiment, the increase in the average survival time of a population may be measured, for example, by calculating the average length of survival for the population after the completion of a first round of treatment with a compound of formula (I) and an additional anti-cancer agent.

[0543] In another embodiment, treating cancer with a compound of formula (I) and an additional anticancer agent results in a decrease in tumor growth rate.Preferably, after treatment, tumor growth rate is reduced by at least 5% relative to the number before treatment, more preferably, tumor growth rate is reduced by at least 10%, more preferably, by at least 20%, more preferably, by at least 30%, more preferably, by at least 40%, more preferably, by at least 50%, even more preferably, by at least 50%, and most preferably, by at least 75%.Tumor growth rate may be measured by any reproducible measurement means.In a preferred embodiment, tumor growth rate is measured according to the change in tumor diameter per unit time.

[0544] In another embodiment, treating cancer with a compound of formula (I) and an additional anticancer agent results in a reduction in tumor regrowth. Preferably, after treatment, tumor regrowth is less than 5%, more preferably tumor regrowth is less than 10%, more preferably less than 20%, more preferably less than 30%, more preferably less than 40%, more preferably less than 50%, even more preferably less than 50%, and most preferably less than 75%. Tumor regrowth may be measured by any reproducible means of measurement. In a preferred embodiment, tumor regrowth is measured, for example, by measuring the increase in tumor diameter or volume from a previous post-treatment tumor shrinkage. In another preferred embodiment, the reduction in tumor regrowth is indicated by the failure of tumors to recur after treatment is discontinued.

[0545] The dosages of the compounds of formula (I) and the additional anti-cancer agent for any of the methods and uses described herein will vary according to the agents, the age, weight, and clinical condition of the recipient subject, as well as the experience and judgment of the clinician or practitioner administering the therapy, among other factors that will influence the selected dosage.

[0546] A therapeutically effective amount of the additional anticancer agent is administered 1, 2, 3, 4, 5 or more times per day for 5, 10, 15, 30, 60, 90, 120, 150, 180 or more days, followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 1 The additional anticancer agent may be not administered for 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 or more days. This type of treatment schedule, i.e., administration of an additional anticancer agent on consecutive days followed by non-administration of an additional anticancer agent on consecutive days, may be referred to as a treatment cycle.

[0547] In some embodiments, a therapeutically effective amount of an additional anti-cancer agent is administered once or twice daily for up to 5, 10, 15, 20, 25, or 30 days, followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days without administration of the additional anti-cancer agent.

[0548] In some embodiments, a therapeutically effective amount of the additional anti-cancer agent is administered once daily for up to 5, 10, 15, 20, 25, or 30 days, followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days without administration of the additional anti-cancer agent.

[0549] In some embodiments, treatment cycles involving additional anticancer agents may be repeated as many times as necessary to achieve the intended effect.

[0550] In some embodiments, the treatment cycle with the additional anticancer agent is the same as the treatment cycle with the compound of Formula (I).

[0551] In some embodiments, the treatment cycle with the additional anticancer agent is different from the treatment cycle with the compound of Formula (I).

[0552] The therapeutically effective amount of the compound of formula (I) and the additional anti-cancer agent may be administered one or more times per day for up to 30 days or more, followed by one or more days without administration of the compound of formula (I) and / or the additional anti-cancer agent. This type of treatment schedule, i.e., administration of the compound of formula (I) and / or the additional anti-cancer agent on consecutive days, followed by non-administration of the compound of formula (I) and / or the additional anti-cancer agent on consecutive days, may be referred to as a treatment cycle. In some embodiments, the treatment cycle may be repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times. In some embodiments, the treatment cycle of the additional anti-cancer agent may be repeated as many times as necessary to achieve the intended effect.

[0553] In some embodiments, for the methods disclosed herein that include administering a compound of Formula (I) and an additional anti-cancer agent, a therapeutically effective amount of a compound of Formula (I) is administered once, twice, three times, four times or more per day for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 30 days consecutively, or for 2 months, 3 months, 4 months, 5 months, 6 months, or more, in single or divided doses, at a dose of 0.01, 0.05, 0.1, 0.2, 0.3, 0. 4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 2 6, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 1 35, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 29 0, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445 , 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600,605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1,000 mg.

[0554] In some embodiments, for the methods disclosed herein that include administering a compound of Formula (I) and an additional anti-cancer agent, a therapeutically effective amount of a compound of Formula (I) is administered once, twice, three times, four or more times daily in single or divided doses, in the range of about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, about 180 mg, about 210 mg, about 240 mg, about 270 mg, about 300 mg, about 330 mg, about 360 mg, or more. The dose is about 390 mg, about 420 mg, about 450 mg, about 480 mg, about 510 mg, about 540 mg, about 570 mg, about 600 mg, about 630 mg, about 660 mg, about 690 mg, about 720 mg, about 750 mg, about 780 mg, about 810 mg, about 840 mg, about 870 mg, about 900 mg, about 930 mg, about 960 mg, or about 990 mg (this dose is determined based on the patient's weight (kg) and body surface area (m 2 ), and may be adjusted for age (years).

[0555] In some embodiments, for the methods disclosed herein that include administering a compound of Formula (I) and an additional anti-cancer agent, the therapeutically effective amount of a compound of Formula (I) is from about 30 mg to about 1000 mg, administered in single or divided doses, once, twice, three times, four times, or more per day (this dose is based on the patient's body weight (kg), body surface area (m 2 ), and may be adjusted for age (years).

[0556] In some embodiments, for methods disclosed herein that include administering a compound of Formula (I) and an additional anti-cancer agent, a therapeutically effective amount of a compound of Formula (I) is administered once, twice, three times, four or more times daily in single or divided doses, 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 170 to about 180 mg, about 190 to about 200 mg, about 210 to about 220 mg, about 220 to about 230 mg, about 230 to about 240 mg, about 240 to about 250 mg, about 250 to about 260 mg, about 260 to about 270 mg, about 270 to about 280 mg, about 280 to about 300 mg, about 290 to about 310 mg, about 320 to about 330 mg, about 330 to about 340 mg, about 340 to about 350 mg, about 350 to about 360 mg, about 360 to about 370 mg, about 370 to about 380 mg, about 380 to about 390 mg, about 400 to about 400 mg, about 400 to about 400 mg, about 400 to about 450 mg, about 400 to about 460 mg, about 400 to about 4 0 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, Approximately 240~270mg, 250~280mg, 260~290mg, 270~300mg, 280~310mg, 290~320mg, 300~330mg, 310~340mg, 320~350mg, 330~360mg, 340~ about 370 mg, about 350 to about 380 mg, about 360 to about 390 mg, about 370 to about 400 mg, about 380 to about 410 mg, about 390 to about 420 mg, about 400 to about 430 mg, about 410 to about 440 mg, about 420 to about 450 mg, about 430 to about 460 mg, about 440 to about 470 mg, about 450 to about 480 mg, about 460 to about 490 mg, about 470 to about 500 mg, about 480 to about 510 mg, about 490 to about 520 mg, about 500 to about 530 mg, about 510 to about 540 mg, about 520 to about 550 mg, about 530 to about 560 mg, about 540 to about 570 mg, about 50 to 580 mg, 560 to 590 mg, 570 to 600 mg, 580 to 610 mg, 590 to 620 mg, 600 to 630 mg, 610 to 640 mg, 620 to 650 mg, 630 to 660 mg, 640 to 670 mg, 650 to 6 80 mg, about 660 to about 690 mg, about 670 to about 700 mg, about 680 to about 710 mg, about 690 to about 720 mg, about 700 to about 730 mg, about 710 to about 740 mg, about 720 to about 750 mg, about 730 to about 760 mg, about 740 to about 770 mg, about 750 to about 780 mg,About 760 to about 790 mg, about 770 to about 800 mg, about 780 to about 810 mg, about 790 to about 820 mg, about 800 to about 830 mg, about 810 to about 840 mg, about 820 to about 850 mg, about 830 to about 860 mg, about 840 to about 870 mg, about 850 to about 880 mg, about 860 to about 890 mg, about 870 to about 900 mg, about The dose is about 880 to about 910 mg, about 890 to about 920 mg, about 900 to about 930 mg, about 910 to about 940 mg, about 920 to about 950 mg, about 930 to about 960 mg, about 940 to about 970 mg, about 950 to about 980 mg, about 960 to about 990 mg, or about 970 to about 1,000 mg (the dose depends on the patient's body weight (kg), body surface area (m, 2 ) and may be adjusted for age (years).

[0557] In some embodiments, for methods disclosed herein that include administering a compound of Formula (I) and an additional anti-cancer agent, the therapeutically effective amount of the compound of Formula (I) may also be in the range of about 0.01 mg / kg per day to about 100 mg / kg per day, about 0.05 mg / kg per day to about 10 mg / kg per day, about 0.075 mg / kg per day to about 5 mg / kg per day, about 0.10 mg / kg per day to about 1 mg / kg per day, or about 0.20 mg / kg per day to about 0.70 mg / kg per day.

[0558] In some embodiments, for the methods disclosed herein that include administering a compound of Formula (I) and an additional anti-cancer agent, the therapeutically effective amount of the compound of Formula (I) is about 0.10 mg / kg per day, about 0.15 mg / kg per day, about 0.20 mg / kg per day, about 0.25 mg / kg per day, about 0.30 mg / kg per day, about 0.35 mg / kg per day, about 0.40 mg / kg per day, about 0.50 mg / kg per day, about 0.60 mg / kg per day, about 0.70 mg / kg per day, about 0.80 mg / kg per day, about 0.90 mg / kg per day, ...90 mg / kg per day, about 0.10 mg / kg per day, about 0.10 mg / kg per day, about 0.15 mg / kg per day, about 0.20 mg / kg per day, about 0.25 mg / kg per day, about 0.30 mg / kg per day, about 0.35 mg / kg per day, about 0.40 mg / kg per day, about 0.50 mg / kg per day, about 0.50 mg / kg per day, about 0.60 mg / kg per day, about 0.70 mg / kg per day, about 0.80 mg / kg per day, about 0.90 mg / kg per day, 0.45 mg / kg per day, about 0.50 mg / kg per day, about 0.55 mg / kg per day, about 0.60 mg / kg per day, about 0.65 mg / kg per day, about 0.70 mg / kg per day, about 0.75 mg / kg per day, about 0.80 mg / kg per day, about 0.85 mg / kg per day, about 0.90 mg / kg per day, about 0.95 mg / kg per day, or about 1.00 mg / kg per day.

[0559] In some embodiments, for the methods disclosed herein that include administering a compound of Formula (I) and an additional anti-cancer agent, the therapeutically effective amount of the compound of Formula (I) is about 1.05 mg / kg per day, about 1.10 mg / kg per day, about 1.15 mg / kg per day, about 1.20 mg / kg per day, about 1.25 mg / kg per day, about 1.30 mg / kg per day, about 1.35 mg / kg per day, about 1.40 mg / kg per day, about 1.50 mg / kg per day, about 1.60 mg / kg per day, about 1.70 mg / kg per day, about 1.80 mg / kg per day, about 1.90 mg / kg per day, about 1.15 mg / kg per day, about 1.20 mg / kg per day, about 1.30 mg / kg per day, about 1.35 mg / kg per day, about 1.40 mg / kg per day, about 1.50 mg / kg per day, about 1.60 mg / kg per day, about 1.70 mg / kg per day, about 1.80 mg / kg per day, about 1.90 mg / kg per day, about 1.90 mg / kg per day, about 1.10 mg / kg per day, about 1.15 mg / kg per day, about 1.20 mg / kg per day, about 1.25 mg / kg per day, about 1.30 mg / kg per day, about 1.35 mg / kg per day, about 1.40 mg / kg per day, about 1.50 mg / kg per day, about 1.60 mg / kg per day, about 1.70 mg / kg per day, about 1.80 mg / kg per day, about 1.90 mg / kg per day, about 1.90 mg / kg per day, about 1.90 mg / kg per day, about 1.10 mg / kg per day, , about 1.45 mg / kg per day, about 1.50 mg / kg per day, about 1.55 mg / kg per day, about 1.60 mg / kg per day, about 1.65 mg / kg per day, about 1.70 mg / kg per day, about 1.75 mg / kg per day, about 1.80 mg / kg per day, about 1.85 mg / kg per day, about 1.90 mg / kg per day, about 1.95 mg / kg per day, or about 2.00 mg / kg per day.

[0560] In some embodiments, for the methods disclosed herein comprising administering a compound of Formula (I) and an additional anti-cancer agent, the therapeutically effective amount of the compound of Formula (I) is about 2 mg / kg per day, about 2.5 mg / kg per day, about 3 mg / kg per day, about 3.5 mg / kg per day, about 4 mg / kg per day, about 4.5 mg / kg per day, about 5 mg / kg per day, about 5.5 mg / kg per day, about 6 mg / kg per day, about 6.5 mg / kg per day, about 7 mg / kg per day, about 7.5 mg / kg per day, about 8.0 mg / kg per day, about 8.5 mg / kg per day, about 9.0 mg / kg per day, about 9.5 mg / kg per day, or about 10 mg / kg per day.

[0561] In some embodiments, for the methods disclosed herein that include administering a compound of Formula (I) and an additional anti-cancer agent, a therapeutically effective amount of the additional anti-cancer agent is administered once, twice, three times, four times, or more per day for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 30 consecutive days, or once, twice, three, four times, or more per day, or for 2, 3, 4, 5, 6, or more months, in single or divided doses. Administered in amounts of 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 7, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 25 0, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405 , 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560,565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, In some embodiments, the additional anticancer agent is palbociclib.

[0562] In some embodiments, the compound of formula (I) and palbociclib may be administered simultaneously. In some embodiments, the compound of formula (I) is administered first and palbociclib is administered second. In some embodiments, palbociclib is administered first and the compound of formula (I) is administered second. For example, in some embodiments, the compound of formula (I) and palbociclib are administered simultaneously. In some embodiments, the compound of formula (I) and palbociclib are administered sequentially.

[0563] In some embodiments, palbociclib is administered prior to administration of the compound of Formula (I), such that the two compounds and their respective excipients do not mix in the subject's stomach. In some embodiments, the maximum time between administration of palbociclib and administration of the compound of Formula (I) is such that the benefits of the combination are achieved. In some embodiments, palbociclib is administered at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, or at least 30 minutes before the compound of Formula (I) is administered. In some embodiments, palbociclib is administered 5 to 35 minutes, 10 to 40 minutes, 15 to 25 minutes, 20 to 50 minutes, 25 to 55 minutes, or 30 to 60 minutes before the compound of Formula (I) is administered. In some embodiments, palbociclib is administered 30 to 60 minutes, 30 to 70 minutes, 30 to 80 minutes, 30 to 90 minutes, 30 to 120 minutes, 30 to 180 minutes, 30 to 240 minutes, 30 to 300 minutes, 30 to 360 minutes, 30 to 480 minutes, 30 to 600 minutes, or 30 to 720 minutes before the compound of Formula (I) is administered.

[0564] In some embodiments, palbociclib is administered after administration of the compound of Formula (I), such that the two compounds and their respective excipients (if present) do not mix in the subject's stomach. In some embodiments, the maximum time between administration of palbociclib and administration of the compound of Formula (I) is such that the benefit of the combination is achieved. In some embodiments, palbociclib is administered at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, or at least 30 minutes after the compound of Formula (I) is administered. In some embodiments, palbociclib is administered 5 to 35 minutes, 10 to 40 minutes, 15 to 25 minutes, 20 to 50 minutes, 25 to 55 minutes, or 30 to 60 minutes after the compound of Formula (I) is administered. In some embodiments, palbociclib is administered 30 to 60 minutes, 30 to 70 minutes, 30 to 80 minutes, 30 to 90 minutes, 30 to 120 minutes, 30 to 180 minutes, 30 to 240 minutes, 30 to 300 minutes, 30 to 360 minutes, 30 to 480 minutes, 30 to 600 minutes, or 30 to 720 minutes after the compound of formula (I) is administered.

[0565] In some embodiments, for the methods disclosed herein comprising administering a compound of Formula (I) and an additional anti-cancer agent, the therapeutically effective amount of the additional anti-cancer agent is 60 mg, 75 mg, 100 mg, or 125 mg administered once daily in a single or divided dose. In some embodiments, the therapeutically effective amount of the additional anti-cancer agent is administered once daily for 21 consecutive days followed by 7 days of resting treatment. In some embodiments, the additional anti-cancer agent is palbociclib.

[0566] A treatment with an additional anti-cancer agent for 21 consecutive days followed by 7 days off treatment is referred to herein as a treatment cycle or cycle. In some embodiments, the treatment cycle of the additional anti-cancer agent may be repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more times. In some embodiments, the treatment cycle of the additional anti-cancer agent may be repeated as many times as necessary to achieve the intended effect. In some embodiments, the additional anti-cancer agent is palbociclib.

[0567] In some embodiments, for the methods disclosed herein that include administering a compound of Formula (I) and an additional anti-cancer agent, the therapeutically effective amount of the additional anti-cancer agent is about 0.1 mg / kg per day, about 0.2 mg / kg per day, about 0.3 mg / kg per day, about 0.4 mg / kg per day, about 0.5 mg / kg per day, about 0.6 mg / kg per day, about 0.7 mg / kg per day, about 0.8 mg / kg per day, about 0.9 mg / kg per day, about 1 mg / kg per day, about 1.1 mg / kg per day, about 1.2 mg / kg per day, about 1.3 mg / kg per day, about 1.4 mg / kg per day, about 1.5 mg / kg per day, about 1.6 mg / kg per day, about 1.7 mg / kg per day, about 1.8 mg / kg per day, about 1.9 mg / kg per day, about 2.0 mg / kg per day, about 2.1 mg / kg per day, about 2.2 mg / kg per day, about 2.3 mg / kg per day, about 2.4 mg / kg per day, about 2.5 mg / kg per day, about 2.6 mg / kg per day, about 2.7 mg / kg per day, about 2.8 mg / kg per day, about 2.9 mg / kg per day, about 3.0 mg / kg per day, about 3.1 mg / kg per day, about 3.2 mg / kg per day, about 3.3 mg / kg per day, about 3.4 mg / kg per day, about 3.5 mg / kg per day, about 3.6 mg / kg per day, about 3.7 mg / kg per day, about 3.8 mg / kg per day, about 3.9 mg / kg per day, about 3.1 mg / kg per day, about 3.2 mg / kg per day, about 3.3 mg / kg per day, about 3.4 mg / kg 6 mg / kg per day, about 1.7 mg / kg per day, about 1.8 mg / kg per day, about 1.9 mg / kg per day, about 2 mg / kg per day, about 2.5 mg / kg per day, about 3 mg / kg per day, about 3.5 mg / kg per day, about 4 mg / kg per day, about 4.5 mg / kg per day, about 5 mg / kg per day, about 5.5 mg / kg per day, about 6 mg / kg per day, about 6.5 mg / kg per day, about 7 mg / kg per day, about 7.5 mg / kg per day, about 8.0 mg / kg per day, about 8.5 mg / kg per day, about 9.0 mg / kg per day, about 9.5 mg / kg per day, or about 10 mg / kg per day. In some embodiments, the additional anticancer agent is palbociclib.

[0568] In some embodiments, for methods disclosed herein that include administering a compound of Formula (I) and an additional anti-cancer agent, the therapeutically effective amount of the additional anti-cancer agent is from about 0.5 mg / kg per day to about 3.0 mg / kg per day.

[0569] In some embodiments, for the methods disclosed herein that include administering a compound of formula (I) and an additional anti-cancer agent, a therapeutically effective amount of the compound of formula (I) is administered to the subject once a day. In some embodiments, the daily dose of the compound of formula (I) is administered to the subject all at once. In some embodiments, the daily dose of the compound of formula (I) is administered to the subject in two unit doses (split doses). In some embodiments, the daily dose of the compound of formula (I) is administered to the subject in three unit doses. In some embodiments, the daily dose of the compound of formula (I) is administered to the subject in four unit doses. In some embodiments, the daily dose of the compound of formula (I) is administered to the subject in five or more unit doses. In some embodiments, these unit doses are administered to the subject at regular intervals throughout the day, for example, every 12 hours, every 8 hours, every 6 hours, every 5 hours, every 4 hours, etc.

[0570] In some embodiments, for the methods disclosed herein that include administering a compound of Formula (I) and an additional anti-cancer agent, a therapeutically effective amount of the additional anti-cancer agent is administered to the subject once a day. In some embodiments, this daily dose of the additional anti-cancer agent is administered to the subject all at once. In some embodiments, this daily dose of the additional anti-cancer agent is administered to the subject in two unit doses (split doses). In some embodiments, this daily dose of the additional anti-cancer agent is administered to the subject in three unit doses. In some embodiments, this daily dose of the additional anti-cancer agent is administered to the subject in four unit doses. In some embodiments, this daily dose of the additional anti-cancer agent is administered to the subject in five or more unit doses. In some embodiments, these unit doses are administered to the subject at regular intervals throughout the day, for example, every 12 hours, every 8 hours, every 6 hours, every 5 hours, every 4 hours, etc.

[0571] Therapeutically effective amounts of the compounds of formula (I) and additional anticancer agents can be initially estimated in either cell culture assays or animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models may also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity can be assessed using standard pharmaceutical procedures in cell cultures or experimental animals, such as ED 50 (therapeutic effective dose in 50% of the population) and LD 50 (the dose at which 50% of the population is lethal). The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 It may be expressed as a ratio. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending on the dosage form employed, sensitivity of the patient, and the route of administration.

[0572] Dosage and administration are adjusted to provide sufficient levels of the compound of formula (I) and / or additional anticancer agent or to maintain the desired effect. Factors that may be considered include the severity of the condition, the general health of the subject, the age, weight, and sex of the subject, diet, time and frequency of administration, drug combinations, response sensitivity, and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered every 3-4 days, every week, or every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0573] Pharmaceutical Compositions The compound of formula (I) and the additional anti-cancer agent may be administered in accordance with the present invention by any suitable route, including oral, parenteral (subcutaneous, intramuscular, intravenous (bolus or infusion), depot, intraperitoneal), intrathecal, intranasal, intravaginal, sublingual, buccal, intraocular, or rectal.

[0574] In some embodiments, the compound of formula (I) and the additional anticancer agent may be formulated into separate dosage forms that may be suitable for administration by any suitable route, including, for example, oral, parenteral (subcutaneous, intramuscular, intravenous, depot), intrathecal, intranasal, intravaginal, sublingual, buccal, ocular, or rectal.

[0575] In some embodiments, the compound of formula (I) and the additional anti-cancer agent may be combined together and formulated into a single dosage form that may be suitable for administration by any suitable route, including, for example, oral, parenteral (subcutaneous, intramuscular, intravenous, depo), intrathecal, intranasal, intravaginal, sublingual, buccal, ocular, or rectal.

[0576] In some embodiments, the compound of formula (I) and the additional anticancer agent may be formulated into separate dosage forms, each of which is suitable for oral administration. In some embodiments, the additional anticancer agent is SHR6390, trilaciclib, relociclib, AT7519M, dinaciclib, ribociclib, alpelisib, abemaciclib, everolimus, venetoclax, inavolisib (GDC-0077), palbociclib, or a pharmaceutically acceptable salt thereof. In some embodiments, the additional anticancer agent is palbociclib, palbociclib dihydrochloride, or any other pharmaceutically acceptable salt of palbociclib.

[0577] In some embodiments, the compound of formula (I) and the additional anticancer agent may be formulated into a single dosage form suitable for oral administration. In some embodiments, the additional anticancer agent is SHR6390, trilaciclib, relociclib, AT7519M, dinaciclib, ribociclib, alpelisib, abemaciclib, everolimus, venetoclax, inavolisib (GDC-0077), palbociclib, or a pharmaceutically acceptable salt thereof. In some embodiments, the additional anticancer agent is palbociclib, palbociclib dihydrochloride, or any other pharmaceutically acceptable salt of palbociclib.

[0578] In some embodiments, the compound of formula (I) and the additional anticancer drug are each formulated for oral administration, either separately or together.For example, in some embodiments, the compound of formula (I) and the additional anticancer drug are both formulated as a tablet, either separately or together, containing zero, one, two or more of each of the following emulsifiers, surfactants, binders, disintegrants, glidants, and lubricants, or alternatively, the compound of formula (I) and the additional anticancer drug can be formulated separately or together in a capsule, or as an oral liquid, or a combination thereof.

[0579] In some embodiments, the emulsifier is hypromellose.

[0580] In some embodiments, the surfactant is vitamin E polyethylene glycol succinate.

[0581] In some embodiments, the binder (also referred to herein as a filler) is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, sucrose, glucose, and sorbitol.

[0582] In some embodiments, the disintegrant is croscarmellose sodium.

[0583] In some embodiments, glidants refer to substances used to promote powder flow by reducing interparticle cohesion. In some embodiments, in the dosage forms of the present disclosure, the glidant is selected from the group consisting of silicon dioxide, anhydrous silica colloid, starch, and talc.

[0584] In some embodiments, a lubricant refers to a substance that prevents ingredients from sticking and / or clumping in machinery used to prepare the dosage forms of the present disclosure. In some embodiments, in the dosage forms of the present disclosure, the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, and vegetable stearin.

[0585] Pharmaceutical compositions containing the compound of formula (I) and additional anticancer agents (either separately or together) can be prepared in a generally known manner, for example by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, encapsulating, or lyophilizing processes. Pharmaceutical compositions can be formulated in a conventional manner using one or more pharma- ceutically acceptable carriers, including excipients and / or adjuvants, that facilitate the processing of the compound of formula (I) into a pharma- ceutically usable preparation. Of course, the appropriate formulation depends on the selected route of administration.

[0586] Pharmaceutical compositions containing the compound of formula (I) and an additional anticancer agent (either separately or together) suitable for injection include sterile aqueous solutions (if water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL® (BASF, Parsippany, NJ), or phosphate buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, such as aluminum monostearate and gelatin.

[0587] Sterile injectable solutions can be prepared by incorporating the compound of formula (I) and / or additional anticancer drugs in the required amount in a suitable solvent with one or a combination of the above-listed ingredients, and then sterilizing by filtration.In general, dispersions are prepared by incorporating active agents or compounds into a sterile vehicle that contains a basic dispersion medium and other ingredients required from those listed above.In the case of sterile powders for preparing sterile injectable solutions, the preparation method is vacuum drying and freeze-drying, which obtains a powder of active ingredient and any additional desired ingredient from the solution that has been previously sterilized and filtered.

[0588] Oral compositions generally include an inert diluent or an edible pharma- ceutically acceptable carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the compound of formula (I) and / or additional anticancer drugs may be combined with excipients and used in the form of tablets, lozenges or capsules. Oral compositions may also be prepared using a fluid carrier for use as a mouthwash, where the drug or compound in the fluid carrier is applied orally, swished around the mouth, expectorated or swallowed. Pharmaceutically compatible binding agents and / or adjuvant materials may be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring, or compounds of a similar nature.

[0589] For administration by inhalation, the compounds of formula (I) and / or the additional anti-cancer agent are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0590] Systemic administration of the compound of formula (I) and / or additional anticancer agents may also be by transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant appropriate to the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be achieved by using nasal sprays or suppositories. For transdermal administration, the active agent or compound is formulated into ointments, salves, gels, or creams generally known in the art.

[0591] In one embodiment, the compound of formula (I) and / or additional anticancer agent is prepared with a pharma- ceutically acceptable carrier that protects the drug or compound from rapid elimination from the body, such as a controlled release formulation, including, for example, implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as, for example, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such formulations will be clear to those skilled in the art. Materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals. Liposomal suspensions, including liposomes that target infected cells with monoclonal antibodies against viral antigens, can also be used as pharma-ceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0592] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate oral or parenteral compositions of the compound of formula (I) and / or additional anticancer agents into unit dosage forms. As used herein, dosage unit form or "unit dose" refers to physically discrete units suitable as unitary doses for the subject to be treated, each unit containing a predetermined amount of active agent or compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications of dosage unit forms of the present application are determined by and directly depend on the inherent properties of the compound of formula (I) and the particular therapeutic effect to be achieved.

[0593] The pharmaceutical compositions of a compound of Formula (I) and / or additional anti-cancer agent can be included in a container, pack, or dispenser together with instructions for administration.

[0594] Exemplary modes of administration of the compound of formula (I) and / or the additional anticancer agent include systemic administration or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical modes of administration. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt or hydrate thereof, is administered orally. In some embodiments, the compound of formula (I) is administered as a tablet, capsule, caplet, solution, suspension, syrup, granule, bead, powder, or pellet.

[0595] Exemplary pharmaceutical compositions are tablets and gelatin capsules comprising a salt of the compound of formula (I) and / or an additional anticancer agent and a pharma- ceutically acceptable carrier, such as a) a diluent, such as purified water, triglyceride oils such as hydrogenated or partially hydrogenated vegetable oils or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils such as EPA or DHA or esters thereof or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine, b) a lubricant, such as silica, talcum, stearic acid, magnesium or calcium salts thereof, sodium oleate, sodium stearate, stearyl alcohol, sodium oleate, sodium stearate, sodium glycerin ... for tablets also c) binders, for example magnesium aluminium silicate, starch paste, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, if necessary d) disintegrants, for example starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures, e) absorbents, colouring agents, flavourings and sweeteners, f) emulsifiers or dispersing agents, for example Tween 80, Labrasol, HPMC, DOSS, Caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, Vitamin E TGPS or other acceptable emulsifier, and / or g) an agent that enhances absorption of the salt such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, and / or PEG200.

[0596] For preparing pharmaceutical compositions from the compound of formula (I) and / or additional anticancer agents, or any salt or hydrate thereof, inert, pharma- ceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, pills, tablets, dispersible granules, capsules (including time-release capsules), cachets, and suppositories. Powders and tablets may consist of about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar, or lactose. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharma- ceutically acceptable carriers and manufacturing methods for various compositions can be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.

[0597] Liquid form preparations of the compound of formula (I) and / or additional anticancer agents include solutions, suspensions, elixirs, tinctures, emulsions, syrups, suspensions, and emulsions. For example, water or water-propylene glycol solutions for parenteral injection, or the addition of sweeteners and opacifiers for oral solutions, suspensions, and emulsions. Liquid form preparations may also include solutions for intranasal administration.

[0598] Liquid, particularly injectable, compositions of the compound of formula (I) and / or additional anticancer agents can be prepared, for example, by dissolving, dispersing, etc. For example, the disclosed salts are dissolved or mixed in a pharma- ceutically acceptable solvent, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, thereby forming an injectable isotonic solution or suspension. Proteins, such as albumin, chylomicron particles, or serum proteins, can be used to solubilize the disclosed compounds.

[0599] Also included are solid form preparations of the compound of formula (I) and / or additional anticancer agents that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.

[0600] Parenteral injectable administration of the compound of formula (I) and / or additional anticancer agents is generally used for subcutaneous, intramuscular, or intravenous injection and infusion. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolution in liquid prior to injection.

[0601] Aerosol preparations of the compounds of formula (I) and / or additional anti-cancer agents suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharma- ceutically acceptable carrier, such as an inert compressed gas, e.g., nitrogen.

[0602] The pharmaceutical composition of the compound of formula (I) and / or the additional anticancer agent can be prepared according to conventional mixing, granulating or coating methods, respectively, and the pharmaceutical composition can contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% by weight of the compound of formula (I) and / or the additional anticancer agent.

[0603] All amounts of any component of an oral dosage form, e.g., a tablet, described herein given on a w / w % basis refer to the total weight of the oral dosage form unless otherwise indicated. EXAMPLES

[0604] The present disclosure is further illustrated by the following examples, which should not be interpreted as limiting the scope or spirit of the present disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments, and no limitation to the scope of the present disclosure is intended thereby. It should also be understood that it may be necessary to resort to various other embodiments, modifications, and equivalents thereof that may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0605] Example 1 - Compound (Ic) - ER Degrader for Subjects with Locally Advanced or Metastatic Breast Cancer Breast cancer is the second most common cancer in women. Approximately 268,000 women are expected to be diagnosed with invasive breast cancer in the United States in 2019. (American Cancer Society) Metastatic breast cancer accounts for approximately 6% of newly diagnosed cases. (Malmgren, JA, Breast Cancer Res Treat (2018) 167: 579-590.) 80% of newly diagnosed breast cancers are estrogen receptor (ER) positive. (National Cancer Institute, Hormone Therapy for Breast Cancer.)

[0606] Fulvestrant has been implicated in ER degradation in breast cancer.

[0607] After 6 months of fulvestrant treatment, up to 50% of ER baseline levels remain (Gutteridge et al., Breast Cancer Res Treat 2004;88 suppl 1:S177).

[0608] Compound (Ic) is a potent degrader of the estrogen receptor (DC 50 =1.8 nM) and is in development for the treatment of patients with ER+ locally advanced or metastatic breast cancer.

[0609] Example 2 - Preclinical Effective Exposure Range for Compound (Ic) In preclinical animal studies, compound (Ic) was administered at doses of 3mg / kg, 10mg / kg, and 30mg / kg (orally, once daily). Pharmacokinetic results are shown in Table 1 below. At doses of 3mg / kg, 10mg / kg, and 30mg / kg of compound (Ic), 85%, 98%, and 124% tumor growth inhibition (TGI) was observed, respectively, compared to the control group in the MCF7 xenograft model.

[0610] Figure 1 shows the results of the tumor growth inhibition experiments at the doses tested (mean tumor volume (mm 3 ) versus time.

[0611] FIG. 2 shows the reduction of ER in MCF7 xenograft tumors in response to administration of 3 mg / kg, 10 mg / kg, and 30 mg / kg of compound (Ic) (orally, once daily). [Table 1]

[0612] Example 3 - Toxicity Studies Animals were orally dosed with compound (Ic) once daily for 28 days, followed by a 28-day recovery period for high-dose animals. Dogs were given oral doses of 15 mg / kg, 45 mg / kg, or 90 mg / kg of compound (Ic) once daily. Rats were given oral doses of 3 mg / kg, 10 mg / kg, 30 mg / kg, or 100 mg / kg of compound (Ic) once daily. These studies showed no clinical signs of toxicity following oral administration of compound (Ic) once daily at doses up to 100 mg / kg / day in rats and up to 90 mg / kg / day in dogs. Furthermore, no effects on the overall health or well-being of the animals were observed.

[0613] Example 4 - Phase I Clinical Trial Study Design with Compound (Ic) A phase I clinical trial with compound (Ic) was conducted. A conventional 3+3 dose escalation design was implemented. The starting dose of compound (Ic) was 30 mg orally administered once daily with food. Dose escalation was dependent on toxicity.

[0614] The main inclusion criteria for this trial were: ER+ / HER2- advanced breast cancer, at least two prior endocrine therapies in any setting, and a CDK4 / 6 inhibitor, and up to three prior cytotoxic chemotherapy regimens.

[0615] The primary objective of this study was to obtain the maximum tolerated dose and recommended Phase II study dose of compound (Ic). Additional objectives included evaluation of overall safety, pharmacokinetics, antitumor activity (e.g., RECIST, CBR) of compound (Ic), and biomarkers including, for example, ER gene (ESR1) mutation status in ctDNA and / or tumor tissue, as well as ER, progesterone receptor, and Ki-67 levels in pre- and post-treatment tumor biopsies in patients with accessible tumor tissue.

[0616] Example 5 - Phase I Pharmacokinetic Data - Oral Administration of Compound (Ic) In Phase I clinical trials, compound (Ic) was administered orally at a dose of 30 mg / day. It was observed that treatment with 30 mg / day of compound (Ic) fell within the preclinical efficacy range associated with tumor growth inhibition.

[0617] Initial pharmacokinetic results are shown in Table 2 below and in Figures 3 and 4. Figure 3 provides a representation of the concentrations of Compound (Ic) over a 24 hour period post-dose on both Day 1 and Day 15. Figure 4 depicts the mean trough concentrations of Compound (Ic) throughout the course of the clinical trial. [Table 2]

[0618] Example 6 - Phase I dose escalation study with compound (Ic) Compound (Ic) was orally administered to subjects at 30 mg / day or 60 mg / day (n=3 for both dose groups). No dose-limiting toxicity was observed in the 30 mg / day cohort. No treatment-related adverse events were observed in the 30 mg / day cohort.

[0619] Example 7 - Evaluation of the antitumor and estrogen receptor alpha degrading activity of compound (Ic) in the ER positive orthotopic xenograft model MCF7

[0620] Part 1: ERα degradation in vivo The acute estrogen receptor alpha (ERα) degradation activity of compound (Ic) was evaluated in an MCF7 orthotopic xenograft model after three daily oral administrations of compound (Ic). To evaluate compound (Ic)-induced degradation of ERα in vivo, compound (Ic) was administered by oral gavage at 10 mg / kg to MCF7-tumor-bearing NOD / SCID mice, and changes in ERα levels were evaluated after three daily oral administrations. As shown in Figure 5, compound (Ic) reduced tumor ERα levels by up to 95% when compared to ERα levels in tumors of vehicle-treated mice.

[0621] MCF7 tumor-bearing NOD / SCID mice were dosed once daily with vehicle or compound (Ic) (10 mg / kg, orally) for three consecutive days. Approximately 18 hours after the last dose, the mice were sacrificed and MCF7 xenografts were harvested, lysed, and ER levels were determined by immunoblotting. Compound (Ic) reduced ER levels by up to 95% compared to vehicle (as shown by three samples from each group in Figure 5). β-actin served as a loading control for immunoblotting. The diet was supplemented with peanut butter to help maintain body weight.

[0622] Animal Testing Details:

[0623] Species: NOD / SCID female mice (Charles River, 6-7 weeks old on arrival).

[0624] Animal handling: 5 × 10 per mouse 6 MCF7 cells / 200 μL axial mammary fat pad implantation (implanted the day before with a 90-day pellet of 0.36 mg 17β-estradiol).

[0625] Dosing: Oral (gavage), once daily (QD) for three days (QDx3). Vehicle: 2% Tween80 / PEG400 ("PEG / Tween"). [Table 3]

[0626] Sample collection: Terminal sacrifice was approximately 18 hours after the last dose, and tumors were harvested, aliquoted and snap frozen. ERα levels were determined by immunoblotting.

[0627] Detailed procedure for ERα degradation assay:

[0628] Cell lysis: Snap-frozen tumors were removed from -80°C storage and placed on dry ice. RIPA lysis buffer and Halt protease inhibitors were used at 400 μl per tumor sample. For tissue disruption, steel balls (5 mm) were placed on each sample. Samples were lysed using a TissueLyzer at 24 Hz for 4 min. Homogenization was stopped midway through the process and the block was turned over during the process. The steel beads were pulled out of the tubes and the lysates were spun down at 21,000×g for 15 min at 4°C. The lysates were then measured for total protein concentration by BCA (following the manufacturer's protocol).

[0629] Protein detection by immunoblotting: Lysates were mixed with sample buffer and reducing agent (following the manufacturer's protocol). Samples were denatured at 95°C for 5 min in a thermal cycler. Samples were cooled and spun down (5000 x g, 1 min) before loading onto the gel. 10 μg of total protein was loaded onto the gel per lane. Samples were loaded onto 4-15% Criterion Tris / Glycine gels and run for 25 min at 250 constant volts in 1X Tris / Glycine / SDS buffer. Proteins were transferred from the gel to nitrocellulose using a Bio-Rad Turbo with default settings. All blots were rinsed with distilled water and blocked with 5% BSA in TBS-T (TBS with 0.1% Tween) for 1 h at room temperature on a rocker. Blots were cut so that beta-actin and ERα could be detected from the same lane / sample.

[0630] Blots were incubated overnight at 4°C on a rocker with primary antibodies in 5% BSA in TBST (0.1%): ERα (1:2000) from Bethyl labs; beta-actin (1:3000) from CST;

[0631] Blots were washed 3 times in TBST (0.1%) for 5 min on a rocker at room temperature. Secondary antibody was added and blots were incubated for 1 h on a rocker at room temperature (anti-rabbit-HRP 1:18,000 in TBS-T). Blots were washed 3 times in TBST (0.1%) for 5 min on a rocker at room temperature. Signal was developed with Pierce West Femto Maximum Sensitivity Substrate for 5 min and blots were imaged on a BioRad ChemiDoc.

[0632] Part 2: Antitumor efficacy in MCF7 xenograft model.

[0633] The antitumor and sustained ERα degradation activity of compound (Ic) was evaluated in an MCF7 orthotopic xenograft model.

[0634] In this MCF7-xenograft model, compound (Ic) demonstrated dose-dependent efficacy (Figure 6), with doses of 3 and 10 mg / kg / day showing 85% and 98% tumor growth inhibition (TGI) versus vehicle, respectively, and 30 mg / kg / day resulting in tumor regression (124% TGI) (Table 4).

[0635] In an experimental dose-dependent inhibition of tumor growth by compound (Ic) in an orthotopic MCF7 mouse xenograft model, MCF7 cells were implanted into the mammary fat pad of female NOD / SCID mice, and tumors grew to 200 mm 3 Compound (Ic) dosing (QDx28, oral) was initiated when tumor volume was reached. Tumor volumes were assessed twice weekly for 28 days. Compound (Ic) at 3, 10, or 30 mg / kg inhibited the growth of estradiol-stimulated MCF7 xenografts (TGI of 85%, 98%, and 124%, respectively). [Table 4]

[0636] Sampling: Tumors were measured twice weekly. Terminal sacrifice was approximately 18 hours after the last dose, and tumors were harvested, aliquoted, and snap frozen. ERα levels were determined by immunoblotting.

[0637] Tumor volume calculation: Tumor volume = (width x width x length) / 2, where all measurements are in mm and tumor volume is mm 3 It is expressed as:

[0638] Tumor Growth Inhibition (TGI) Calculation: TGI (%)

number

[0639] At the end of the study, tumors were removed from the mice and ERα levels were determined by immunoblotting tumor homogenates. As seen in Figure 7, all doses of compound (Ic) significantly reduced ERα levels (>94%) when compared to mice administered vehicle only. Taken together, these data show strong antitumor activity of compound (Ic) against a well-established in vivo ER-positive breast cancer model, along with potent degradation of ERα in tumors. [Table 5]

[0640] Part 2: Antitumor effects in combination with CDK4 / 6 inhibitors To evaluate the antitumor activity of compound (Ic) in combination with a CDK4 / 6 inhibitor in an MCF7 orthotopic xenograft model, the effect of combining compound (Ic) with a CDK4 / 6 inhibitor was evaluated in MCF7-tumor-bearing mice.

[0641] NOD / SCID female mice (Charles River, 6–7 weeks old on arrival) were implanted with 5 × 10 mice per mouse in the axial mammary fat pad. 6 MCF7 cells / 200 μL were implanted (a 90-day pellet of 0.36 mg 17β-estradiol was implanted the day before). 3 Compound dosing was initiated when weight was reached. Diet was supplemented with peanut butter to help maintain weight.

[0642] Compound (Ic) (30 mg / kg / day) and the CDK4 / 6 inhibitor palbociclib (60 mg / kg / day) were administered for 28 days. When compared to single agent compound (Ic) activity in this model (105% TGI), the combination of compound (Ic) and palbociclib resulted in significant tumor regression (131% TGI). In contrast, single agent fulvestrant administered subcutaneously resulted in only modest tumor growth inhibition (46% TGI), while the combination of fulvestrant and palbociclib resulted in improved tumor growth inhibition (108% TGI), but not to the level achieved with compound (Ic) and palbociclib. (Figure 8 and Table 6) [Table 6]

[0643] dosage: Compound (Ic) and palbociclib: Oral (gavage), once daily for 28 days (QDx28) Palbociclib is administered 30-60 minutes before compound (Ic) is administered. Without intending to be bound by theory, this is to prevent mixing of palbociclib and compound (Ic) and their respective excipients in the acidic compartment of the stomach. Fulvestrant: Subcutaneous (SC), twice weekly (BIW) for 2 weeks (BIWx2), then once weekly (QW) for 2 weeks (QWx2)

[0644] Vehicle: - For compound (Ic): 2% Tween 80 / PEG-400 ("PEG / Tween"). The ratio of Tween 80 to PEG-400 is 0.02 g Tween 80 to 1 ml PEG-400. The PEG-400 is added to a pre-aliquoted volume of Tween 80. For Fulvestrant: 10% w / v ethanol, 10% w / v benzyl alcohol, and 15% w / v benzyl benzoate as co-solvents, made up to 100% w / v with castor oil ("EBB / Castor Oil"). For palbociclib: 50 mM sodium lactate, pH 4.0 ("sodium lactate") [Table 7]

[0645] Sample Collection: Tumors were measured twice weekly. Terminal sacrifice was approximately 18 hours after the last dose, and tumors were harvested, aliquoted, and snap frozen. ERα levels were determined by immunoblotting.

[0646] Example 8 - Evaluation of the antitumor and estrogen receptor alpha degrading activity of compound (Ic) in an ER-positive orthotopic xenograft model of tamoxifen-resistant MCF7 cells The antitumor activity of compound (Ic) was evaluated as a single agent and in combination with a CDK4 / 6 inhibitor in a tamoxifen-resistant estrogen receptor positive (ER+) breast cancer orthotopic xenograft model.Furthermore, the ERα degradation activity of compound (Ic) was evaluated in a tamoxifen-resistant ER+ breast cancer orthotopic xenograft model.

[0647] Data Overview In Figure 9 and Table 8, compound (Ic) at 30 mg / kg / day inhibited the growth of tamoxifen-resistant MCF7 xenografts by 65% ​​after oral administration once daily for 28 days. When compound (Ic) was combined with palbociclib at 60 mg / kg / day, the combination regimen caused greater tumor growth inhibition (113% TGI) compared to the palbociclib monotherapy group (91% TGI).

[0648] At the end of the study, tumors were removed from the mice and ERα levels were determined by immunoblotting tumor homogenates. As seen in Figure 10, compound (Ic) at 30 mg / kg reduced ERα levels by 73% compared to vehicle, and the combination with palbociclib at 60 mg / kg similarly reduced ERα levels by 72% (Figure 11). However, palbociclib alone (60 mg / kg) did not reduce ERα levels (Figure 12). ERα levels from the various compound treatment groups were compared to vehicle-treated animals by analyzing tumor lysates on separate immunoblots (graphs in Figures 10, 11, and 12 show data from individual immunoblots), and the average ERα levels are shown with standard deviations. [Table 8]

[0649] Animal Testing Details:

[0650] Species: ovariectomized Nu / Nu female mice. Animal handling: Axial mammary fat pad implantation of tamoxifen-resistant tumor fragments (from passage E45. SC per mouse. Tamoxifen pellets (5 mg, 60 day release) were implanted under the same anesthesia as the tumor fragments (pellet-dorsal, tumor-ventral).

[0651] Dosage: Oral (gavage), once daily for 28 days (QDx28)

[0652] Vehicle: for Compound (Ic): 2% Tween 80 / PEG 400 ("PEG / Tween"), for Palbociclib: 50 mM sodium lactate, pH 4 ("sodium lactate") [Table 9]

[0653] Sample collection: Tumors were measured twice weekly. Terminal sacrifice was approximately 18 hours after the last dose, and tumors were harvested, aliquoted, and snap frozen. ERα levels were determined by immunoblotting (see Appendix 1 for details).

[0654] Detailed procedure for ERα degradation assay:

[0655] cell lysis

[0656] Snap-frozen tumors were removed from -80°C storage and placed on dry ice. RIPA lysis buffer and Halt protease inhibitors were used at 400 μl per tumor sample. Steel balls (5 mm) were placed on each sample for tissue disruption. Samples were lysed using a TissueLyzer at 24 Hz for 4 min. Homogenization was stopped midway through the process and the block was turned over during the process. The steel beads were pulled out of the tubes and the lysates were spun down at 21,000×g for 15 min at 4°C. The lysates were then measured for total protein concentration by BCA (following the manufacturer's protocol).

[0657] Protein detection by immunoblotting.

[0658] Lysates were mixed with sample buffer and reducing agent (following the manufacturer's protocol). Samples were denatured in a thermal cycler at 95°C for 5 min. Before loading onto the gel, samples were cooled and spun down (5000 x g, 1 min). Gels were loaded with...

Claims

1. A pharmaceutical composition for use in a method of treating a subject, comprising: the breast cancer comprises at least one somatic estrogen receptor (ER) tumor mutation; The pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I), 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, During the ceremony, Each R １ and R2 is independently halo, OR ５ , N(R ５ ) (R ６ ), NO ２ , C.N., S.O. ２ (R ５ ), C １ -C ６ Alkyl and C ３ -C ６ cycloalkyl; R ３ and R ４ are either both hydrogen or together with the carbon to which they are attached form a carbonyl, Each R ５ and R 6 are independently hydrogen, C １ -C ６ Alkyl and C ３ -C ６ cycloalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, or 4; A pharmaceutical composition, wherein said effective amount of said compound of formula (I) is from about 10 mg to about 1000 mg.

2. A pharmaceutical composition for use in a method of treating a subject, comprising: the breast cancer comprises at least one somatic estrogen receptor (ER) tumor mutation; The pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof; The compound of formula (I) 【Chemistry 2-1】 【Chemistry 2-2】 【Chemistry 2-3】 and The method comprises once daily oral administration of a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

3. A pharmaceutical composition for use in a method of treating a subject, comprising: the breast cancer comprises at least one somatic estrogen receptor (ER) tumor mutation; The pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof; The compound of formula (I) is a compound of formula (I-a), 【Chemistry 3】 (Ia) The method further comprising: (i) once daily oral administration of an effective amount of a compound of formula (Ia), or a pharma- ceutically acceptable salt thereof; (ii) palbociclib administered orally once daily; 13. A pharmaceutical composition comprising:

4. A pharmaceutical composition for use in a method of treating a subject, comprising: the breast cancer comprises at least one somatic estrogen receptor (ER) tumor mutation; The pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof; The compound of formula (I) is a compound of formula (I-c), 【Chemistry 4】 (I C) The method further comprising: (i) once daily oral administration of a therapeutically effective amount of a compound of formula (I-c), or a pharma- ceutically acceptable salt thereof; (ii) palbociclib administered orally once daily; 13. A pharmaceutical composition comprising:

5. A pharmaceutical composition for use in a method of treating a subject, comprising: the breast cancer comprises at least one somatic estrogen receptor (ER) tumor mutation; The pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof; The compound of formula (I) is a compound of formula (I-j), 【Chemistry 5】 (Ij) The method further comprising: (i) once daily oral administration of a therapeutically effective amount of a compound of formula (I-j), or a pharma- ceutically acceptable salt thereof; (ii) palbociclib administered orally once daily; 13. A pharmaceutical composition comprising:

6. The pharmaceutical composition according to any one of claims 2 to 5, wherein the therapeutically effective amount of the compound of formula (I) is from about 30 mg to about 1000 mg.

7. The at least one somatic ER tumor mutation is (a) selected from the group consisting of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to any amino acid residue other than the wild type residue at that position; and / or (b) the amino acid sequence selected from the group consisting of Y537S, Y537N, D538G, E380Q, L379I, V422del, S463P, L536P and L536_D538>P,

8. 1. A pharmaceutical composition for use in a method for treating breast cancer in a subpopulation of breast cancer subjects, comprising: The pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I), 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, The method further comprising: selecting a breast cancer subject for treatment based on the subject's somatic estrogen receptor (ER) tumor biomarker status; an effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof; During the ceremony, Each R １ and R ２ are independent, halo, OR ５ , N(R ５ ) (R ６ ), NO ２ , C.N., S.O. ２ (R ５ ), C １ -C ６ Alkyl and C ３ -C ６ cycloalkyl; R ３ and R ４ are either both hydrogen or together with the carbon to which they are attached form a carbonyl, Each R ５ and R ６ are independently hydrogen, C １ -C ６ Alkyl and C ３ -C ６ cycloalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, or 4; A pharmaceutical composition, wherein said therapeutically effective amount of said compound of formula (I) is from about 10 mg to about 1000 mg.

9. The pharmaceutical composition of claim 8, wherein the breast cancer comprises at least one somatic estrogen receptor (ER) tumor mutation.

10. The method of claim 1, wherein the at least one somatic ER tumor mutation is (a) selected from the group consisting of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, where "X" refers to any amino acid residue other than the wild type residue at that position; and / or (b) selected from the group consisting of Y537S, Y537N, D538G, E380Q, L379I, V422del, S463P, L536P, and L536_D538>P; The pharmaceutical composition according to claim 8.

11. the ER biomarker status of the subject is (a) as determined by ctDNA analysis, fluorescent in situ hybridization, immunohistochemistry, PCR analysis, or sequencing; (b) determined in a blood sample from said subject; and / or (c) determined in a solid biopsy from the tumor in the subject; The pharmaceutical composition according to any one of claims 8 to 10.

12. The breast cancer is (a) is estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-); and / or (b) the disease is metastatic or locally advanced; The pharmaceutical composition according to any one of claims 1 to 11.

13. (a) R １ and R ２ each independently represents halo and OR ５ Selected from the group consisting of: (b) R 3 and R 4 are both hydrogen; or R 3 and R 4 together with the carbon to which they are attached form a carbonyl; and / or (c) m and n are each 0; m and n are each 1; or One of m and n is 0 and the other is 1; A pharmaceutical composition according to any one of claims 1 to 12.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the compound of formula (I) is a compound of formula (Ic): 【Chemistry 4】 (I C)

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the compound of formula (I) is administered orally to the subject.

16. said effective amount of said compound of formula (I) (a) is administered to the subject once daily, twice daily, three times daily, or four times daily; (b) administered to the subject once daily; and / or (c) administered to the subject all at once or in two, three, or four unit doses; A pharmaceutical composition according to any one of claims 1 to 15.

17. said effective amount of said compound of formula (I) (a) about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, or about 40 mg; (b) from about 20 mg to about 750 mg; (c) from about 30 mg to about 500 mg; and / or (d) about 30 mg to about 120 mg; A pharmaceutical composition according to any one of claims 1 to 16.

18. said effective amount of said compound of formula (I) (a) a day 15 mean AUC of greater than about 3,500 ng·hr / mL, greater than about 3,600 ng·hr / mL, greater than about 3,700 ng·hr / mL, greater than about 3,800 ng·hr / mL, greater than about 3,900 ng·hr / mL, greater than about 4,000 ng·hr / mL, greater than about 4,100 ng·hr / mL, greater than about 4,200 ng·hr / mL, greater than about 4,300 ng·hr / mL, greater than about 4,400 ng·hr / mL, greater than about 4,500 ng·hr / mL, greater than about 4,600 ng·hr / mL, greater than about 4,700 ng·hr / mL, greater than about 4,800 ng·hr / mL, greater than about 4,900 ng·hr / mL, or greater than about 5,000 ng·hr / mL ＴＡＵ resulting in; (b) resulting in a day 15 mean AUC TAU of greater than about 4,000 ng-hr / mL and less than about 4,500 ng-hr / mL; (c) resulting in a day 15 mean C max of greater than about 200 ng / mL, greater than about 205 ng / mL, greater than about 210 ng / mL, greater than about 215 ng / mL, greater than about 220 ng / mL, greater than about 225 ng / mL, greater than about 230 ng / mL, greater than about 235 ng / mL, greater than about 240 ng / mL, greater than about 245 ng / mL, or greater than about 250 ng / mL; and / or (d) achieving a day 15 mean C max of greater than about 215 ng / mL and less than about 235 ng / mL; A pharmaceutical composition according to any one of claims 1 to 17.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein the compound of formula (I) is formulated as a tablet.

20. 20. The pharmaceutical composition of claim 19, wherein the tablet comprises a compound of formula (I) and one or more excipients selected from the group consisting of emulsifiers, surfactants, binders, disintegrants, glidants, and lubricants.

21. (a) the emulsifier is hypromellose; (b) the surfactant is vitamin E polyethylene glycol succinate; (c) the binder is microcrystalline cellulose or lactose monohydrate; (d) the disintegrant is croscarmellose sodium; (e) the glidant is silicon dioxide; and / or (f) the lubricant is sodium stearyl fumarate; 21. The pharmaceutical composition of claim 20.

22. A pharmaceutical composition described in any one of claims 1 to 21, further comprising administering an effective amount of at least one additional anticancer agent to a subject in need of said treatment.

23. The additional anticancer agent is (a) is selected from the group consisting of FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 6 inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, check point 1 inhibitors, check point 2 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, B7-H3 inhibitors, CTLA4 inhibitors, LAG-3 inhibitors, OX40 agonists, focal adhesion kinase inhibitors, Map kinase kinase inhibitors, and VEGF trap antibodies; and / or (b) SHR6390, trilaciclib, lelociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, venetoclax, inavolisib, pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, epithilone B 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, trastuzumab deruxtecan (genetical recombination) (fam-trastuzumab deruxtecan-nxki) (Enhertz), and eribulin (Halaven); 23. The pharmaceutical composition of claim 22.

24. 24. The pharmaceutical composition of claim 23, wherein the additional anticancer agent is palbociclib.

25. (a) the effective amount of palbociclib is administered to the subject once daily; (b) the effective amount of palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg; (c) the palbociclib is administered once daily for up to 21 consecutive days, followed by discontinuation of treatment for up to 7 consecutive days, and the cycle of palbociclib treatment followed by discontinuation of treatment is repeated 1, 2, 3, 4, 5, or more times; and / or (d) the compound of formula (I) is administered once daily for up to 21 consecutive days, followed by cessation of treatment for up to 7 consecutive days, and the cycle of treatment with the compound of formula (I) followed by cessation of treatment is repeated 1, 2, 3, 4, 5 or more times; A pharmaceutical composition according to any one of claims 1 to 24.

26. The pharmaceutical composition according to any one of claims 1 to 25, wherein the subject is in a fed state.

27. The pharmaceutical composition according to any one of claims 1 to 25, wherein the subject is in a fasting state.

28. (a) The administration of the additional anticancer agent occurs prior to the administration of the compound of formula (I), and optionally, at least 30 minutes prior to said administration of said compound of formula (I); and / or (b) said administration of said additional anti-cancer agent occurs after said administration of said compound of formula (I), and optionally At least 30 minutes after said administration of the compound of formula (I), A pharmaceutical composition according to any one of claims 22 to 27.

29. A pharmaceutical composition for use in a method of treating a subject, comprising: The pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I), 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, The method further comprising: administering an effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof; administering to the subject an effective amount of at least one additional anti-cancer agent; Including, During the ceremony, each R 1 and R 2 is independently selected from the group consisting of halo, OR 5 , N(R 5 )(R 6 ), NO 2 , CN, SO 2 (R 5 ), C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl; R 3 and R 4 are either both hydrogen or together with the carbon to which they are attached form a carbonyl; each R 5 and R 6 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, or 4; A pharmaceutical composition, wherein said effective amount of said compound of formula (I) is from about 10 mg to about 1000 mg.

30. The additional anticancer agent is (a) a Bcl-2 inhibitor, a CDK4 / 6 inhibitor, a PI3 kinase inhibitor, or an mTORC1 / 2 inhibitor; and / or (b) abemaciclib, everolimus, venetoclax, inavolisib, or alpelisib 30. The pharmaceutical composition of claim 29, wherein

31. The pharmaceutical composition according to claim 29 or 30, wherein the compound of formula (I) is a compound of formula (I-c). 【Chemistry 4】 (I C) 32. (a) The administration of the additional anticancer agent occurs prior to the administration of the compound of formula (I), and optionally, at least 30 minutes prior to said administration of said compound of formula (I); and / or (b) said administration of said additional anti-cancer agent occurs after said administration of said compound of formula (I), and optionally At least 30 minutes after said administration of the compound of formula (I), The pharmaceutical composition according to any one of claims 29 to 31.

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