CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to, and the benefit of, U.S. Provisional Application No. 63/125,371, filed Dec. 14, 2020, the contents of which are incorporated herein by reference in their entirety.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Dec. 8, 2021, is named “ARVN-015-001US_ST25.txt” and is about 6 KB in size.

BACKGROUND OF THE DISCLOSURE

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 breast cancer in 2018. While breast cancer is less common in men, men account for approximately 1% of all newly diagnosed cases, and almost 500 men are projected to die from their disease in 2018 (Seigel R. L. et al. Cancer Statistics, CA Cancer J Clin. 2018, 68(1); 7-30.).

It is estimated that as of January 2017, approximately 155,000 women with metastatic breast cancer (mBC) were living in the US. It was also reported that the number of women living with mBC is increasing primarily because of improvements in treatment and the aging of the US population. The estimated number of women living with mBC increased by 17% from 2000 to 2010 and is projected to increase by 31% from 2010 to 2020 (Mariotto A. B. et 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.).

Treatment options for advanced breast cancer or mBC depend on many different factors, including whether the tumors express hormone receptors, i.e., estrogen receptor (ER) and/or progesterone receptor, or human epidermal growth factor receptor 2 (HER2). The standard of care for women with mBC is endocrine therapy, chemotherapy and/or targeted therapy alone or in combination. Patients with ER positive (ER+) and HER2 negative (HER2−) mBC are treated with endocrine therapy, sometimes in combination with targeted drugs such as CDK4/6 inhibitors (CDKi). In patients with aggressive disease or whose disease continues to progress on endocrine therapy, chemotherapy may be prescribed.

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

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

SUMMARY OF THE DISCLOSURE

In one aspect, this application pertains to a method of treating breast cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I),

[Image Omitted]

or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein:

each R¹and each R²is independently selected from the group consisting of halo, OR⁵, N(R⁵)(R⁶), NO₂, CN, SO₂(R⁵), C₁-C₆alkyl and C₃-C₆cycloalkyl; R³and R⁴are either both hydrogen or, taken together with the carbon to which they are attached, form a carbonyl;

each R⁵and each R⁶is independently selected from the group consisting of hydrogen, C₁-C₆alkyl and C₃-C₆cycloalkyl;

m is 0, 1, 2, 3, 4, or 5; and

n is 0, 1, 2, 3, or 4,

wherein the therapeutically effective amount of the compound of Formula (I) is about 10 mg to about 1000 mg.

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

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

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

In one aspect, this application pertains to a compound of Formula (I) for use in a method of treating breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation. In some embodiments, the breast cancer comprises at least one somatic ER tumor mutation selected from the group consisting of Y537X, D538X, E380X, L379X, V422X, S463X, and L536X, wherein “X” refers to any amino acid residue, 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.

In some embodiments, the breast cancer is ER+, HER2−. In some embodiments, the breast cancer is metastatic or locally advanced.

In some embodiments, the compound of Formula (I) is:

[Image Omitted]

or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof.

In some embodiments, wherein the compound of Formula (I) is a compound of Formula (I-a). In some embodiments, the compound of Formula (I) is a compound of Formula (I-c). In some embodiments, the compound of Formula (I) is a compound of Formula (I-j).

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

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

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

In some embodiments, the additional anti-cancer agent is selected from the group consisting of FLT-3 inhibitor, VEGFR inhibitor, EGFR TK inhibitor, aurora kinase inhibitor, PIK-1 modulator, Bcl-2 inhibitor, HDAC inhibitor, c-Met inhibitor, PARP inhibitor, CDK 4/6 inhibitor, anti-HGF antibody, PI3 kinase inhibitor, AKT inhibitor, mTORC1/2 inhibitor, JAK/STAT inhibitor, checkpoint 1 inhibitor, checkpoint 2 inhibitor, PD-1 inhibitor, PD-L1 inhibitor, B7-H3 inhibitor, CTLA4 inhibitor, LAG-3 inhibitor, OX40 agonist, focal adhesion kinase inhibitor, Map kinase kinase inhibitor, and VEGF trap antibody. In some embodiments, the additional anti-cancer agent is a CDK 4/6 inhibitor.

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

In one aspect, this application pertains to method of treating breast cancer in a subject in need thereof, comprising once a day, oral administration of a therapeutically effective amount of the compound of Formula (I), wherein the compound of Formula (I) is:

[Image Omitted]

or a pharmaceutically 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 mutation.

In one aspect, this application pertains to method of treating breast cancer in a subject in need thereof, comprising once a day, oral administration of a therapeutically effective amount of the compound of Formula (I), wherein the compound of Formula (I) is (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), or (I-j), or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation.

In one aspect, this application pertains to a method of treating breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation, the method comprising:

- (i) once a day, oral administration of a therapeutically effective amount of a compound of Formula (I-a) or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, and
- (ii) once a day, oral administration of palbociclib.

In one aspect, this application pertains to a method of treating breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation, the method comprising:

- (i) once a day, oral administration of a therapeutically effective amount of a compound of Formula (I-c) or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, and
- (ii) once a day, oral administration of palbociclib.

In one aspect, this application pertains to a method of treating breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation, the method comprising:

- (i) once a day, oral administration of a therapeutically effective amount of a compound of Formula (I-j), or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, and
- (ii) once a day, oral administration of palbociclib.

In one aspect, this application pertains to a method of treating breast cancer in a subpopulation of breast cancer subjects, comprising:

- selecting a breast cancer subject for treatment based on the subject's somatic ER tumor biomarker status; and
- administering a therapeutically effective amount of a compound of Formula (I),

[Image Omitted]

- or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein:
- each R¹and each R²is independently selected from the group consisting of halo, OR⁵, N(R⁵)(R⁶), NO₂, CN, SO₂(R⁵), C₁-C₆alkyl and C₃-C₆cycloalkyl;
- R³and R⁴are either both hydrogen or, taken together with the carbon to which they are attached, form a carbonyl;
- each R⁵and each R⁶is independently selected from the group consisting of hydrogen, C₁-C₆alkyl and C₃-C₆cycloalkyl;
- m is 0, 1, 2, 3, 4, or 5; and
- n is 0, 1, 2, 3, or 4, and
  
  wherein the therapeutically effective amount of the compound of Formula (I) is about 10 mg to about 1000 mg.

In one aspect, this application pertains to a method of treating breast cancer in a subpopulation of breast cancer subjects, comprising:

- selecting a breast cancer subject for treatment based on the subject's somatic ER tumor biomarker status; and
- administering a therapeutically effective amount of a compound of Formula (I),

[Image Omitted]

- or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein:
- each R¹and each R²is independently selected from the group consisting of halo, OR⁵, N(R⁵)(R⁶), NO₂, CN, SO₂(R⁵), C₁-C₆alkyl and C₃-C₆cycloalkyl;
- R³and R⁴are either both hydrogen or, taken together with the carbon to which they are attached, form a carbonyl;
- each R⁵and each R⁶is independently selected from the group consisting of hydrogen, C₁-C₆alkyl and C₃-C₆cycloalkyl;
- m is 0, 1, 2, 3, 4, or 5; and
- n is 0, 1, 2, 3, or 4, and
- wherein the therapeutically effective amount of the compound of Formula (I) is about 10 mg to about 1000 mg.

In some embodiments, the method further comprises the administration of at least one additional anti-cancer agent. In some embodiments, the additional anti-cancer agent is selected from the group consisting of FLT-3 inhibitor, VEGFR inhibitor, EGFR TK inhibitor, aurora kinase inhibitor, PIK-1 modulator, Bcl-2 inhibitor, HDAC inhibitor, c-Met inhibitor, PARP inhibitor, CDK 4/6 inhibitor, anti-HGF antibody, PI3 kinase inhibitor, AKT inhibitor, mTORC1/2 inhibitor, JAK/STAT inhibitor, checkpoint 1 inhibitor, checkpoint 2 inhibitor, PD-1 inhibitor, PD-L1 inhibitor, B7-H3 inhibitor, CTLA4 inhibitor, LAG-3 inhibitor, OX40 agonist, focal adhesion kinase inhibitor, Map kinase kinase inhibitor, and VEGF trap antibody. In some embodiments, the additional anti-cancer agent is a CDK 4/6 inhibitor. the additional anti-cancer agent is SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, venetoclax, inavolisib, pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, epithilone B, fulvestrant, acolbifene, lasofoxifene, idoxifene, topotecan, pemetrexed, erlotinib, ticilimumab, ipilimumab, vorinostat, etoposide, gemcitabine, doxorubicin, 5′-deoxy-5-fluorouridine, vincristine, temozolomide, capecitabine, camptothecin, PD0325901, irinotecan, tamoxifen, toremifene, anastrazole, letrozole, bevacizumab, goserelin acetate, raloxifene, alpelisib, trastuzumab, trastuzumab emtansine, pertuzumab, fam-trastuzumab deruxtecan-nxki (Enhertu), or eribulin (halaven). In some embodiments, the additional anti-cancer agent is palbociclib,

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

In one aspect, this application pertains to a compound of Formula (I),

[Image Omitted]

or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein:

each R¹and each R²is independently selected from the group consisting of halo, OR⁵, N(R⁵)(R⁶), NO₂, CN, SO₂(R⁵), C₁-C₆alkyl and C₃-C₆cycloalkyl;

R³and R⁴are either both hydrogen or, taken together with the carbon to which they are attached, form a carbonyl;

each R⁵and each R⁶is independently selected from the group consisting of hydrogen, C₁-C₆alkyl and C₃-C₆cycloalkyl;

m is 0, 1, 2, 3, 4, or 5; and

n is 0, 1, 2, 3, or 4,

for use in the treatment of breast cancer in a subject in need thereof, wherein the subject comprises at least one somatic ER tumor mutation; and

wherein the therapeutically effective amount of the compound of Formula (I) is about 10 mg to about 1000 mg. In some embodiments, the breast cancer comprises at least one somatic ER mutation.

In one aspect, this application pertains to a compound of Formula (I),

[Image Omitted]

or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein:

each R¹and each R²is independently selected from the group consisting of halo, OR⁵, N(R⁵)(R⁶), NO₂, CN, SO₂(R⁵), C₁-C₆alkyl and C₃-C₆cycloalkyl;

R³and R⁴are either both hydrogen or, taken together with the carbon to which they are attached, form a carbonyl;

each R⁵and each R⁶is independently selected from the group consisting of hydrogen, C₁-C₆alkyl and C₃-C₆cycloalkyl;

m is 0, 1, 2, 3, 4, or 5; and

n is 0, 1, 2, 3, or 4,

for use in the treatment of breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation; and

wherein the therapeutically effective amount of the compound of Formula (I) is about 10 mg to about 1000 mg.

In one aspect, this application pertains to a compound of Formula (I):

[Image Omitted]

or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, for use in the treatment of breast cancer in a subject in need thereof, wherein the subject comprises at least one somatic ER tumor mutation. In some embodiments, the breast cancer comprises at least one somatic ER tumor mutation.

In one aspect, this application pertains to a compound of Formula (I):

[Image Omitted]

or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, for use in the treatment of breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation.

In one aspect, this application pertains to a combination for use in the treatment of breast cancer in a subject in need thereof, comprising a compound of Formula (I) as disclosed herein further comprising at least one additional anti-cancer agent.

In one aspect, this application pertains to a combination comprising (i) a compound of Formula (I-a), 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 comprises at least one somatic ER tumor mutation.

In one aspect, this application pertains to a combination comprising (i) a compound of Formula (I-c), 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 comprises at least one somatic ER tumor mutation.

In one aspect, this application pertains to a combination comprising (i) a compound of Formula (I-j), 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 comprises at least one somatic ER tumor mutation.

In one aspect, this application pertains to a compound of Formula (I), or a pharmaceutically 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 wherein the therapeutically effective amount of the compound of Formula (I) is about 10 mg to about 1000 mg.

In one aspect, this application pertains to a compound of Formula (I):

[Image Omitted]

or a pharmaceutically 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 subject comprises at least one somatic ER tumor mutation; and wherein the therapeutically effective amount of the compound of Formula (I) is about 10 mg to about 1000 mg. In some embodiment, the breast cancer comprises at least one somatic ER tumor mutation.

In one aspect, this application pertains to a compound of Formula (I):

[Image Omitted]

or a pharmaceutically 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 wherein the therapeutically effective amount of the compound of Formula (I) is about 10 mg to about 1000 mg.

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

In one aspect, this application pertains to a combination comprising (i) a compound of Formula (I-a), 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.

In one aspect, this application pertains to a combination comprising (i) a compound of Formula (I-c), 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.

In one aspect, this application pertains to a combination comprising (i) a compound of Formula (I-j), 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.

In one aspect, this application pertains to a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, for use in the manufacture of a medicament for 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 wherein the therapeutically effective amount of the compound of Formula (I) is about 10 mg to about 1000 mg.

BRIEF DESCRIPTION OF THE FIGURES

The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

FIG. 1 shows the results of tumor growth inhibition experiments (mean tumor volume (mm³) vs. time) associated with oral, once daily administration of Compound (I-c) 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 (I-c), tumor growth inhibition (TGI) of 85%, 98%, and 124%, respectively, was observed compared to a control group in a MCF7 xenograft model.

FIG. 2 is a Western Blot experiment that shows the reduction of ER in MCF7 xenograft tumors in response to dosing of Compound (I-c) of 3 mg/kg, 10 mg/kg, and 30 mg/kg (oral, once daily).

FIG. 3 is a pair of line graphs which show the mean concentration of the compound of Formula (I-c) (ng/mL) over the course of 24 hours post-dosing on both day 1 and day 15 in a Phase I clinical trial.

FIG. 4 is a line graph that provides a representation of mean trough concentrations of Compound (I-c) (ng/mL) throughout the course of a Phase I clinical trial.

FIG. 5 is a graph and a Western Blot experiment that shows the ERα degradation activity of Compound (I-c) after 3 daily oral administrations at 10 mg/kg.

FIG. 6 shows the results of tumor growth inhibition experiments (mean tumor volume (mm³) vs. time) associated with oral, once daily administration of Compound (I-c) for 28 days 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 (I-c), tumor growth inhibition (TGI) of 85%, 98%, and 124%, respectively, was observed compared to a control group in a MCF7 xenograft model.

FIG. 7 are graphs that show that daily oral doses of 3 mg/kg, 10 mg/kg, and 30 mg/kg of Compound (I-c) for 28 days reduce ERα levels by >94% compared to mice administered vehicle only.

FIG. 8 shows the results of tumor growth inhibition experiments (mean tumor volume (mm³) vs. time) associated with oral, once daily administration of Compound (I-c) at a dose of 30 mg/kg for 28 days, Compound (I-c) (30 mg/kg, oral, once daily for 28 days) plus palbociclib (oral, once daily administration at 60 mg/kg for 28 days), fulvestrant (200 mg/kg, subcutaneous twice/week for 2 weeks), and fulvestrant (200 mg/kg, subcutaneous twice/week for 2 weeks) plus palbociclib (oral, once daily administration at 60 mg/kg for 28 days) compared to vehicle. When compared to single-agent Compound (I-c) activity in this model (105% TGI), combination of Compound (I-c) and palbociclib provided significant tumor regressions (131% TGI). In contrast, single-agent fulvestrant, which was dosed subcutaneously, resulted in only modest tumor growth inhibition (46% TGI), while the combination of fulvestrant and palbociclib resulted in improved inhibition of tumor growth (108% TGI), but not to the levels of that achieved with Compound (I-c) and palbociclib.

FIG. 9 shows the results of tamoxifen-resistant MCF7 xenograft growth inhibition experiments (mean tumor volume (mm³) vs. time) associated with oral, once daily administration of Compound (I-c) at a dose of 30 mg/kg for 28 days compared to palbociclib (60 mg/kg, oral, once daily for 28 days), Compound (I-c) (30 mg/kg, oral, once daily for 28 days) plus palbociclib (60 mg/kg, oral, once daily for 28 days), and vehicle. When Compound (I-c) was combined with 60 mg/kg/day palbociclib, the combination regimen caused greater tumor growth inhibition (113% TGI) when compared to the single-agent arm of palbociclib (91% TGI).

FIG. 10, FIG. 11, and FIG. 12 are graphs that show the effects of doses of Compound (I-c) (30 mg/kg, oral, once daily for 28 days, FIG. 10), palbociclib (60 mg/kg, oral, once daily for 28 days, FIG. 12), and Compound (I-c) (30 mg/kg, oral, once daily for 28 days) plus palbociclib (60 mg/kg, oral, once daily for 28 days) (FIG. 11) on in vivo ERα levels in tamoxifen-resistant MCF7 xenografts experiments.

FIG. 13 provides the results of several Western Blot experiments that compares the in vitro ERα degradation activity of fulvestrant and Compound (I-c) at various concentrations in several ER-positive breast cancer cell lines.

FIG. 14 is a graph that shows that the half-maximal degradation concentration (DC₅₀) of Compound (I-c) is 0.9 nM in MCF7 cells.

FIG. 15 provides the results of several Western Blot experiments that compare the in vitro ERα degradation activity of fulvestrant and Compound (I-c) at various concentrations in clinically-relevant ESR1 cell line variants Y537S and D538G.

FIG. 16 is a graph showing the relative expression of GREB1 and PR in experiments with fulvestrant and Compound (I-c) compared to vehicle (DMSO).

FIG. 17 is a graph showing the effect on uterine weight of fulvestrant (100 mg/kg once per day, subcutaneous administration) and Compound (I-c) (30 mg/kg once a day, oral administration) compared to vehicle.

FIG. 18 is a Western Blot comparing the in vivo ERα degradation activity of Compound (I-c) (oral administration at 10 mg/kg for 3 days) to vehicle in a MCF7/E2 xenograft model.

FIG. 19 shows the results of tumor growth inhibition experiments (mean tumor volume (mm³) vs. time) associated with oral, once daily administration of Compound (I-c) at doses of 3 mg/kg, 10 mg/kg, and 30 mg/kg for 28 days compared to vehicle. At doses of 3 mg/kg, 10 mg/kg, and 30 mg/kg of Compound (I-c), tumor growth inhibition (TGI) of 85%, 98%, and 124%, respectively, was observed compared to a control group in a MCF7/estradiol xenograft model.

FIG. 20 shows the results of tumor growth inhibition (mean tumor volume (mm³) vs. time) experiments in a MCF7/estradiol model associated with administration of Compound (I-c) at an oral, once daily dose of 30 mg/kg for 28 days, fulvestrant (200 mg/kg, subcutaneous twice/week for 2 weeks), Compound (I-c) (oral, once daily dose of 30 mg/kg for 28 days) plus palbociclib (oral, once daily dose of 60 mg/kg for 28 days), and fulvestrant (200 mg/kg, subcutaneous twice/week, for 2 weeks) plus palbociclib (oral, once daily dose of 60 mg/kg for 28 days) compared to vehicle. When compared to single-agent Compound (I-c) activity in this model (105% TGI), the combination of Compound (I-c) and palbociclib provided significant tumor regressions (131% TGI). In contrast, single-agent fulvestrant, which was dosed subcutaneously, resulted in only modest tumor growth inhibition (46% TGI), while the combination of fulvestrant and palbociclib resulted in improved inhibition of tumor growth (108% TGI) but not to the levels of that achieved with Compound (I-c) and palbociclib (131% TGI).

FIG. 21 shows the results of tumor growth inhibition (mean tumor volume (mm³) vs. time) experiments in a tamoxifen-resistant MCF7 model associated with administration of Compound (I-c) at an oral, once daily dose of 30 mg/kg for 28 days, palbociclib (oral, once daily dose of 60 mg/kg for 28 days), and Compound (I-c) (oral, once daily dose of 30 mg/kg for 28 days) plus palbociclib (oral, once daily dose of 60 mg/kg for 28 days) compared to vehicle. While Compound (I-c) alone reduced tumor growth, the combination of Compound (I-c) and palbociclib resulted in an improved inhibition of tumor growth compared to Compound (I-c) alone (113% vs. 65%).

FIG. 22 shows the results of tumor growth inhibition (mean tumor volume (mm³) vs. time) experiments in a ESR1 (Y537S) PDX model associated with administration of Compound (I-c) at an oral, once daily dose of 10 mg/kg or 30 mg/kg for 28 days, or fulvestrant (200 mg/kg, subcutaneous twice/week, for 2 weeks). At either the 10 mg/kg or 30 mg/kg dose, Compound (I-c) reduced tumor ERα levels in greater amounts compared to fulvestrant (79/88% vs. 63%) and resulted in an improved inhibition of tumor growth compared to fulvestrant (99/106% vs. 62%).

FIGS. 23A-23F show the growth inhibitory effects observed by combining the CDK4/6 inhibitor abemaciclib with Compound (I-c) in a luminescence-based MCF7 cell proliferation assay. FIG. 23A shows dose-response analysis of the effects of Compound (I-c) on cell proliferation relative to vehicle control (DMSO)-treated cells (% change); FIG. 23B shows dose-response analysis of the effects of abemaciclib on cell proliferation relative to vehicle control (DMSO)-treated cells (% change); FIG. 23C shows Compound (I-c) dose-response shift with the addition of abemaciclib; FIG. 23D shows drug combination efficacy analysis using the Bliss independence model; FIG. 23E shows drug combination efficacy analysis using the Loewe additivity model; FIG. 23F shows drug combination efficacy analysis using the Highest Single Agent model.

FIGS. 24A and 24B show live-cell imaging analysis demonstrating the enhanced growth inhibitory effects of the combination of Compound (I-c) and abemaciclib on MCF7 cells relative to either single agent alone. FIG. 24A) Change in cell growth of drug-treated cells relative to control cells over 120 hours; FIG. 24B) Change in cell growth of drug-treated cells relative to control cells at the 120-hour time point.

FIGS. 25A-25F show the growth inhibitory effects observed by combining the mTOR inhibitor everolimus with Compound (I-c) in a luminescence-based MCF7 cell proliferation assay. FIG. 25A shows dose-response analysis of the effects of Compound (I-c) on cell proliferation relative to vehicle control (DMSO)-treated cells (% change); FIG. 25B shows dose-response analysis of the effects of everolimus on cell proliferation relative to vehicle control (DMSO)-treated cells (% change); FIG. 25C shows Compound (I-c) dose-response shift with the addition of everolimus; FIG. 25D shows drug combination efficacy analysis using the Bliss independence model; FIG. 25E shows drug combination efficacy analysis using the Loewe additivity model; FIG. 25F shows drug combination efficacy analysis using the Highest Single Agent model.

FIGS. 26A-26D show live-cell imaging analysis demonstrating the enhanced growth inhibitory effects of the combination of Compound (I-c) and everolimus on MCF7 (FIG. 26A, FIG. 26B) or T47D cells (FIG. 26C, FIG. 26D) relative to cells treated with either drug alone. FIG. 26A shows change in cell growth of drug-treated MCF7 cells relative to control cells over time;

FIG. 26B shows change in cell growth of drug-treated MCF7 cells relative to control cells. FIG. 26C shows change in cell growth of drug-treated T47D cells relative to control cells over time; FIG. 26D shows change in cell growth of drug-treated T47D cells relative to control cells.

FIGS. 27A-27D show live-cell imaging analysis demonstrating the enhanced growth inhibitory effects of the combination of Compound (I-c) and everolimus on T47D cells harboring the ESR1 Y537S (FIG. 27A, FIG. 27B) or D538G (FIG. 27C, FIG. 27D) mutations relative to cells treated with either drug alone. FIG. 27A shows Change in cell growth of drug-treated MCF7 cells relative to control cells over time; FIG. 27B shows Change in cell growth of drug-treated MCF7 cells relative to control cells. FIG. 27C shows Change in cell growth of drug-treated T47D cells relative to control cells over time; FIG. 27D shows Change in cell growth of drug-treated T47D cells relative to control cells.

FIG. 28 shows the results of tumor growth inhibition (TGI) experiments (mean tumor volume (mm³) vs. time) associated with oral, once daily administration of Compound (I-c), everolimus, and Compound (I-c) plus everolimus compared to vehicle.

FIGS. 29A-29F demonstrate the enhanced growth inhibitory effects observed by combining the PI3 kinase inhibitor alpelisib with Compound (I-c) in a luminescence-based MCF7 cell proliferation. FIG. 29A shows Dose-response analysis of the effects of Compound (I-c) on cell proliferation relative to vehicle control (DMSO)-treated cells (% change); FIG. 29B shows dose-response analysis of the effects of alpelisib on cell proliferation relative to vehicle control (DMSO)-treated cells (% change); FIG. 29C shows Compound (I-c) dose-response shift with the addition of alpelisib; FIG. 29D shows drug combination efficacy analysis using the Bliss independence model; FIG. 29E shows drug combination efficacy analysis using the Loewe additivity model; FIG. 29F shows drug combination efficacy analysis using the Highest Single Agent model.

FIGS. 30A-30D show live-cell imaging analysis demonstrating the enhanced growth inhibitory effects of the combination of Compound (I-c) and alpelisib on MCF7 (FIG. 30A, FIG. 30B) or T47D cells (FIG. 30C, FIG. 30D) relative to cells treated with either drug alone. FIG. 30A shows Change in cell growth of drug-treated MCF7 cells relative to control cells over time; FIG. 30B shows Change in cell growth of drug-treated MCF7 cells relative to control cells at the 120-hour time point. FIG. 30C shows Change in cell growth of drug-treated T47D cells relative to control cells over time; FIG. 30D shows Change in cell growth of drug-treated T47D cells relative to control cells at the 120-hour time point.

FIG. 31 shows the results of tumor growth inhibition (TGI) associated with administration of Compound (I-c), alpelisib, and Compound (I-c) plus compared to vehicle.

FIGS. 32A-32F demonstrate the enhanced growth inhibitory effects observed by combining the PI3 kinase inhibitor inavolisib (GDC-0077) with Compound (I-c) in a luminescence-based MCF7 cell proliferation assay. FIG. 32A shows Dose-response analysis of the effects of Compound (I-c) on cell proliferation relative to vehicle control (DMSO)-treated cells (% change); FIG. 32B shows dose-response analysis of the effects of GDC-0077 on cell proliferation relative to vehicle control (DMSO)-treated cells (% change); FIG. 32C shows Compound (I-c) dose-response shift with the addition of GDC-0077; FIG. 32D shows drug combination efficacy analysis using the Bliss independence model; FIG. 32E shows drug combination efficacy analysis using the Loewe additivity model; FIG. 32F shows drug combination efficacy analysis using the Highest Single Agent model.

FIG. 33A-33D show live-cell imaging analysis demonstrating the enhanced growth inhibitory effects of the combination of Compound (I-c) and GDC-0077 on MCF7 (FIG. 33A, FIG. 33B) or T47D cells (FIG. 33C, FIG. 33D) relative to cells treated with either drug alone. FIG. 33A shows Change in cell growth of drug-treated MCF7 cells relative to control cells over time; FIG. 33B shows Change in cell growth of drug-treated MCF7 cells relative to control cells. FIG. 33C shows Change in cell growth of drug-treated T47D cells relative to control cells over time; FIG. 33D shows Change in cell growth of drug-treated T47D cells relative to control cells.

FIG. 34A-34F demonstrate the enhanced growth inhibitory effects observed by combining the BCL2 inhibitor venetoclax with Compound (I-c) in a luminescence-based MCF7 cell proliferation assay. FIG. 34A shows Dose-response analysis of the effects of Compound (I-c) on cell proliferation relative to vehicle control (DMSO)-treated cells (% change); FIG. 34B shows dose-response analysis of the effects of venetoclax on cell proliferation relative to vehicle control (DMSO)-treated cells (% change); FIG. 34C shows Compound (I-c) dose-response shift with the addition of venetoclax; FIG. 34D shows drug combination efficacy analysis using the Bliss independence model; FIG. 34E shows drug combination efficacy analysis using the Loewe additivity model; FIG. 34F shows drug combination efficacy analysis using the Highest Single Agent model.

FIGS. 35A and 35B show live-cell imaging analysis demonstrating the enhanced growth inhibitory effects of Compound (I-c), venetoclax and the combination on cell growth relative to DMSO-treated (Control) cells over 120 hours (5 days). FIG. 35A shows change in cell growth of drug-treated cells relative to control cells over time; FIG. 35B shows change in cell growth of drug-treated cells relative to control cells.

SEQUENCE LISTING

All references to amino acid mutations in the Estrogen Receptor are numbered relative to SEQ ID NO: 1, which is provided below:

10 20 30 40

MTMTLHTKAS GMALLHQIQG NELEPLNRPQ LKIPLERPLG

50 60 70 80

EVYLDSSKPA VYNYPEGAAY EFNAAAAANA QVYGQTGLPY

90 100 110 120

GPGSEAAAFG SNGLGGFPPL NSVSPSPLML LHPPPQLSPF

130 140 150 160

LQPHGQQVPY YLENEPSGYT VREAGPPAFY RPNSDNRRQG

170 180 190 200

GRERLASTND KGSMAMESAK ETRYCAVCND YASGYHYGVW

210 220 230 240

SCEGCKAFFK RSIQGHNDYM CPATNQCTID KNRRKSCQAC

250 260 270 280

RLRKCYEVGM MKGGIRKDRR GGRMLKHKRQ RDDGEGRGEV

290 300 310 320

GSAGDMRAAN LWPSPLMIKR SKKNSLALSL TADQMVSALL

330 340 350 360

DAEPPILYSE YDPTRPFSEA SMMGLLTNLA DRELVHMINW

270 380 390 400

AKRVPGFVDL TLHDQVHLLE CAWLEILMIG LVWRSMEHPG

410 420 430 440

KLLFAPNLLL DRNQGKCVEG MVEIFDMLLA TSSRFRMMNL

450 460 470 480

QGEEFVCLKS IILLNSGVYT FLSSTLKSLE EKDHIHRVLD

490 500 510 520

KITDTLIHLM AKAGLTLQQQ HQRLAQLLLI LSHIRHMSNK

530 540 550 560

GMEHLYSMKC KNVVPLYDLL LEMLDAHRLH APTSRGGASV

570 580 590

EETDQSHLAT AGSTSSHSLQ KYYITGEAEG FPATV

DETAILED DESCRIPTION

In one aspect, this application pertains to a method of treating breast cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I),

[Image Omitted]

or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein:

- each R¹and each R²is independently selected from the group consisting of halo, OR⁵, N(R⁵)(R⁶), NO₂, CN, SO₂(R⁵), C₁-C₆alkyl and C₃-C₆cycloalkyl;
- R³and R⁴are either both hydrogen or, taken together with the carbon to which they are attached, form a carbonyl;
- each R⁵and each R⁶is independently selected from the group consisting of hydrogen, C₁-C₆alkyl and C₃-C₆cycloalkyl;
- m is 0, 1, 2, 3, 4, or 5; and
- n is 0, 1, 2, 3, or 4.

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

[Image Omitted]

or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein:

- each R¹and each R²is independently selected from the group consisting of halo, OR⁵, N(R⁵)(R⁶), NO₂, CN, SO₂(R⁵), C₁-C₆alkyl and C₃-C₆cycloalkyl;
- R³and R⁴are either both hydrogen or, taken together with the carbon to which they are attached, form a carbonyl;
- each R⁵and each R⁶is independently selected from the group consisting of hydrogen, C₁-C₆alkyl and C₃-C₆cycloalkyl;
- m is 0, 1, 2, 3, 4, or 5; and
- n is 0, 1, 2, 3, or 4. In some embodiments, the breast cancer comprises at least one somatic ER mutation.

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

[Image Omitted]

or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein:

- each R¹and each R²is independently selected from the group consisting of halo, OR⁵, N(R⁵)(R⁶), NO₂, CN, SO₂(R⁵), C₁-C₆alkyl and C₃-C₆cycloalkyl;
- R³and R⁴are either both hydrogen or, taken together with the carbon to which they are attached, form a carbonyl;
- each R⁵and each R⁶is independently selected from the group consisting of hydrogen, C₁-C₆alkyl and C₃-C₆cycloalkyl;
- m is 0, 1, 2, 3, 4, or 5; and
- n is 0, 1, 2, 3, or 4.

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

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

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

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

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.

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

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

In some embodiments, each R¹and each R²is independently selected from the group consisting of halo and OR⁵.

In some embodiments, R³and R⁴are both hydrogen.

In some embodiments, R³and R⁴, taken together with the carbon to which they are attached, form a carbonyl.

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 another embodiment, m is 0 and n is 1.

In some embodiments, the compound of Formula (I) is:

[Image Omitted]

or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof.

In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isotopic derivative thereof.

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

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

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

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

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

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

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

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

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

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

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

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

In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 3,500 ng*hr/mL, about 3,600 ng*hr/mL, about 3,700 ng*hr/mL, about 3,800 ng*hr/mL, about 3,900 ng*hr/mL, about 4,000 ng*hr/mL, about 4,100 ng*hr/mL, about 4,200 ng*hr/mL, about 4,300 ng*hr/mL, 4,400 ng*hr/mL, about 4,500 ng*hr/mL, about 4,600 ng*hr/mL, about 4,700 ng*hr/mL, about 4,800 ng*hr/mL, about 4,900 ng*hr/mL, or about 5,000 ng*hr/mL.

In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 3,500 ng*hr/mL and less than about 4,000 ng*hr/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 3,600 ng*hr/mL and less than about 4,100 ng*hr/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 3,700 ng*hr/mL and less than about 4,200 ng*hr/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 3,800 ng*hr/mL and less than about 4,300 ng*hr/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 3,900 ng*hr/mL and less than about 4,400 ng*hr/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 4,000 ng*hr/mL and less than about 4,500 ng*hr/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 4,100 ng*hr/mL and less than about 4,600 ng*hr/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 4,200 ng*hr/mL and less than about 4,700 ng*hr/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 4,300 ng*hr/mL and less than about 4,800 ng*hr/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 4,400 ng*hr/mL and less than about 4,900 ng*hr/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 4,500 ng*hr/mL and less than about 5,000 ng*hr/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 4,600 ng*hr/mL and less than about 5,100 ng*hr/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 4,700 ng*hr/mL and less than about 5,200 ng*hr/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 4,800 ng*hr/mL and less than about 5,300 ng*hr/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 4,900 ng*hr/mL and less than about 5,400 ng*hr/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 5,000 ng*hr/mL and less than about 5,500 ng*hr/mL.

In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 4,000 ng*hr/mL and less than about 4,200 ng*hr/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 3,900 ng*hr/mL and less than about 4,300 ng*hr/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 3,800 ng*hr/mL and less than about 4,400 ng*hr/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 3,700 ng*hr/mL and less than about 4,500 ng*hr/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 AUC_TAUof greater than about 3,600 ng*hr/mL and less than about 4,600 ng*hr/mL.

In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 C_maxof 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.

In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 C_maxof greater than about 200 ng/mL and less than about 220 ng/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 C_maxof greater than about 205 ng/mL and less than about 225 ng/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 C_maxof greater than about 210 ng/mL and less than about 230 ng/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 C_maxof greater than about 215 ng/mL and less than about 235 ng/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 C_maxof greater than about 220 ng/mL and less than about 240 ng/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 C_maxof greater than about 225 ng/mL and less than about 245 ng/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 C_maxof greater than about 230 ng/mL and less than about 250 ng/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 C_maxof greater than about 235 ng/mL and less than about 255 ng/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 C_maxof greater than about 240 ng/mL and less than about 260 ng/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 C_maxof greater than about 245 ng/mL and less than about 265 ng/mL. In some embodiments, the therapeutically effective amount of the compound of Formula (I) results in a mean day 15 C_maxof greater than about 250 ng/mL and less than about 270 ng/mL.

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

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

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

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

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

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

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

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

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

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

In some embodiments, the at least one additional anti-cancer agent is SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, or palbociclib.

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.

In some embodiments, the administration of the additional anti-cancer agent occurs before the administration of the compound of Formula (I).

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

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

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

In some embodiments, for the 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) and further comprising the administration of a therapeutically effective amount of palbociclib, the 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, the palbociclib is administered once daily for up to 21 consecutive days, followed by up to 7 consecutive days off treatment, wherein the cycle of treatment with palbociclib followed by off treatment is repeated one, two, three, four, five, or more times. In some embodiments, the compound of formula (I) is administered once daily for 21 up to consecutive days, followed by up to 7 consecutive days off treatment, wherein the cycle of treatment with the compound of formula (I) followed by off treatment is repeated one, two, three, four, five, or more times. In some embodiments, the administration of the compound of Formula (I) and palbociclib to the subject in need thereof occurs when the subject is in a fed state. In some embodiments, the administration of the compound of Formula (I) and palbociclib to the subject in need thereof occurs when the subject is in a fasted state.

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

[Image Omitted]

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

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

[Image Omitted]

In one aspect, this application pertains to a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, for use in a method of treating breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation; the method comprising once a day, oral administration of a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein the compound of Formula (I), is selected from the group consisting of (I-a), (I-b), (I-c), (I-d), (I-e), (I-g), (I-h), and (I-i).

In one aspect, this application pertains to a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, for use in the treatment of breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation; the treatment comprising once a day, oral administration of a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein the compound of Formula (I), is selected from the group consisting of (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), and (I-i).

In some embodiments, the compound of Formula (I), is the compound of Formula (I-c).

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.

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

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

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

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

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

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

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

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

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

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

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

In some embodiments, the at least one additional anti-cancer agent is SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, everolimus, venetoclax, inavolisib (GDC-0077), or palbociclib.

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.

In some embodiments, the administration of the additional anti-cancer agent occurs before the administration of the compound of Formula (I).

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

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

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

In one aspect, the application pertains to a method of treating breast cancer in a subject in need thereof, wherein the subject comprises at least one somatic ER tumor mutation, the method comprising:

(i) once a day, oral administration of a therapeutically effective amount of a compound of Formula (I-c),

[Image Omitted]

or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, and

(ii) once a day, oral administration of palbociclib. In some embodiments, the breast cancer comprises at least one somatic ER tumor mutation.

In one aspect, the application pertains to a method of treating breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation, the method comprising:

(i) once a day, oral administration of a therapeutically effective amount of a compound of Formula (I-c),

[Image Omitted]

or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, and

(ii) once a day, oral administration of palbociclib.

In one aspect, the application pertains to a compound of Formula (I-c) 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 a day, oral administration of a therapeutically effective amount of a compound of Formula (I-c), or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, and

(ii) once a day, oral administration of palbociclib.

In one aspect, the application pertains to a compound of Formula (I-c) for use the treatment of breast cancer in a subject in need thereof, wherein the breast cancer comprises at least one somatic ER tumor mutation, the treatment comprising:

(i) once a day, oral administration of a therapeutically effective amount of a compound of Formula (I-c), or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, and

(ii) once a day, oral administration of palbociclib.

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.

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

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

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

In some embodiments, the therapeutically effective amount of palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg. In some embodiments, the palbociclib is administered once daily for up to 21 consecutive days, followed by up to 7 consecutive days off treatment, wherein the cycle of treatment with palbociclib followed by off treatment is repeated one, two, three, four, five, or more times.

In some embodiments, the compound of Formula (I-c) is administered once daily for up to 21 consecutive days, followed by up to 7 consecutive days off treatment, wherein the cycle of treatment with the compound of Formula (I-c) followed by off treatment is repeated one, two, three, four, five, or more times.

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

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

In some embodiments, the administration of palbociclib occurs before the administration of the compound of Formula (I-c).

In some embodiments, the administration of palbociclib occurs at least 30 minutes before the administration of the compound of Formula (I-c).

In some embodiments, the administration of palbociclib occurs after the administration of the compound of Formula (I-c).

In some embodiments, the administration of palbociclib occurs at least 30 minutes after the administration of the compound of Formula (I-c).

In one aspect, this application pertains to a method of treating breast cancer in a subpopulation of breast cancer subjects, comprising:

- selecting a breast cancer subject for treatment based on the subject's somatic ER tumor biomarker status; and
- administering a therapeutically effective amount of a compound of Formula (I),

[Image Omitted]

- or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein:
- each R¹and each R²is independently selected from the group consisting of halo, OR⁵, N(R⁵)(R⁶), NO₂, CN, SO₂(R⁵), C₁-C₆alkyl and C₃-C₆cycloalkyl;
- R³and R⁴are either both hydrogen or, taken together with the carbon to which they are attached, form a carbonyl;
- each R⁵and each R⁶is independently selected from the group consisting of hydrogen, C₁-C₆alkyl and C₃-C₆cycloalkyl;
- m is 0, 1, 2, 3, 4, or 5; and
- n is 0, 1, 2, 3, or 4, and
- wherein the therapeutically effective amount of the compound of Formula (I) is about 10 mg to about 1000 mg.

In one aspect, this application pertains to a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein:

- each R¹and each R²is independently selected from the group consisting of halo, OR⁵, N(R⁵)(R⁶), NO₂, CN, SO₂(R⁵), C₁-C₆alkyl and C₃-C₆cycloalkyl;
- R³and R⁴are either both hydrogen or, taken together with the carbon to which they are attached, form a carbonyl;
- each R⁵and each R⁶is independently selected from the group consisting of hydrogen, C₁-C₆alkyl and C₃-C₆cycloalkyl;
- m is 0, 1, 2, 3, 4, or 5; and
- n is 0, 1, 2, 3, or 4,
  
  for use in a method of treating breast cancer in a subpopulation of breast cancer subjects, the method comprising:
- selecting a breast cancer subject for treatment based on the subject's somatic ER tumor biomarker status; and
- administering a therapeutically effective amount of a compound of Formula (I),

wherein the therapeutically effective amount of the compound of Formula (I) is about 10 mg to about 1000 mg.

In one aspect, this application pertains to a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein:

- each R¹and each R²is independently selected from the group consisting of halo, OR⁵, N(R⁵)(R⁶), NO₂, CN, SO₂(R⁵), C₁-C₆alkyl and C₃-C₆cycloalkyl;
- R³and R⁴are either both hydrogen or, taken together with the carbon to which they are attached, form a carbonyl;
- each R⁵and each R⁶is independently selected from the group consisting of hydrogen, C₁-C₆alkyl and C₃-C₆cycloalkyl;
- m is 0, 1, 2, 3, 4, or 5; and
- n is 0, 1, 2, 3, or 4,
  
  for use the treatment of breast cancer in a subpopulation of breast cancer subjects, the treatment comprising:
- selecting a breast cancer subject for treatment based on the subject's somatic ER tumor biomarker status; and
- administering a therapeutically effective amount of a compound of Formula (I),

wherein the therapeutically effective amount of the compound of Formula (I) is about 10 mg to about 1000 mg.

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.

In some embodiments, the ER biomarker status of the subject is determined by ctDNA analysis, fluorescent in situ hybridization, immunohistochemistry, PCR analysis, or sequencing.

In some embodiments, the ER biomarker status of the subject is determined in a blood sample derived from the subject.

In some embodiments, the ER biomarker status of the subject is determined in a solid biopsy derived from the tumor of the subject.

In some embodiments, the compound of Formula (I) is selected from the group consisting of:

[Image Omitted]

or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof

In some embodiments, the compound of Formula (I) is

[Image Omitted]

or a pharmaceutically acceptable salt, solvate, polymorph, isotopic derivative, or prodrug thereof.

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

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

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

In some embodiments, the additional anti-cancer agent is selected from the group consisting of FLT-3 inhibitor, VEGFR inhibitor, EGFR TK inhibitor, aurora kinase inhibitor, PIK-1 modulator, Bcl-2 inhibitor, HDAC inhibitor, c-Met inhibitor, PARP inhibitor, CDK 4/6 inhibitor, anti-HGF antibody, PI3 kinase inhibitor, AKT inhibitor, mTORC1/2 inhibitor, JAK/STAT inhibitor, checkpoint 1 inhibitor, checkpoint 2 inhibitor, focal adhesion kinase inhibitor, Map kinase kinase inhibitor, and VEGF trap antibody.

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

In some embodiments, the additional anti-cancer agent is SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, pazopanib, venetoclax, inavolisib (GDC-0077), carboplatin, cisplatin, oxaliplatin, paclitaxel, epithilone B, fulvestrant, acolbifene, lasofoxifene, idoxifene, topotecan, pemetrexed, erlotinib, ticilimumab, ipilimumab, vorinostat, etoposide, gemcitabine, doxorubicin, 5′-deoxy-5-fluorouridine, vincristine, temozolomide, capecitabine, camptothecin, PD0325901, irinotecan, tamoxifen, toremifene, anastrazole, letrozole, bevacizumab, goserelin acetate, raloxifene, alpelisib, trastuzumab, trastuzumab emtansine, pertuzumab, fam-trastuzumab deruxtecan-nxki (Enhertu), or eribulin (halaven).

In some embodiments, the at least one additional anti-cancer agent is SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, alpelisib, everolimus, venetoclax, inavolisib (GDC-0077), or palbociclib.

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.

In some embodiments, the administration of the additional anti-cancer agent occurs before the administration of the compound of Formula (I).

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

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

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

Definitions

“H” refers to hydrogen.

Halogen or “halo” refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

“C₁-C₆alkyl” refers to a straight or branched chain saturated hydrocarbon containing 1-6 carbon atoms. Examples of a (C₁-C₆) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

“C₃-C₆cycloalkyl” means monocyclic saturated carbon rings containing 3-6 carbon atoms., i.e., a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl moiety.

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

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

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

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

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

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

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

“Prodrug”, as used herein means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to afford any compound delineated by the formulae of the instant invention. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). “Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 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 Prodrug Metabolism: Chemistry, Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

This invention also encompasses pharmaceutical compositions containing, and methods of treating disorders through administering, pharmaceutically acceptable prodrugs of compounds of the invention. For example, compounds of the invention having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the invention. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxy carbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 1 15. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are 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.

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

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

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

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

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

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

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

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

In some embodiments, the anti-cancer agent is selected from any of the following: FLT-3 inhibitor, VEGFR inhibitor, EGFR TK inhibitor, aurora kinase inhibitor, PIK-1 modulator, Bcl-2 inhibitor, HDAC inhibitor, c-Met inhibitor, PARP inhibitor, CDK 4/6 inhibitor, anti-HGF antibody, PI3 kinase inhibitor, AKT inhibitor, mTORC1/2 inhibitor, JAK/STAT inhibitor, checkpoint 1 inhibitor, checkpoint 2 inhibitor, PD-1 inhibitor, PD-L1 inhibitor, B7-H3 inhibitor, CTLA4 inhibitor, LAG-3 inhibitor, OX40 agonist, focal adhesion kinase inhibitor, Map kinase kinase inhibitor, and VEGF trap antibody.

In some embodiments, the anti-cancer agent is selected from any of the following: SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, venetoclax, inavolisib (GDC-0077), pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel, epithilone B, fulvestrant, acolbifene, lasofoxifene, idoxifene, topotecan, pemetrexed, erlotinib, ticilimumab, ipilimumab, vorinostat, etoposide, gemcitabine, doxorubicin, 5′-deoxy-5-fluorouridine, vincristine, temozolomide, capecitabine, camptothecin, PD0325901, irinotecan, tamoxifen, toremifene, anastrazole, letrozole, bevacizumab, goserelin acetate, raloxifene, alpelisib, trastuzumab, trastuzumab emtansine, pertuzumab, fam-trastuzumab deruxtecan-nxki (Enhertu), 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.

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

“C_max”, as used herein, refers to the observed maximum (peak) plasma concentration of a specified compound in the subject after administration of a dose of that compound to the subject.

“AUC”, as used herein, 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*hr/mL (ng×hr/mL).

“AUC_tau”, as used herein, refers to the AUC from 0 hours to the end of a dosing interval.

“Controlled release” or “CR” as used herein with respect to an oral dosage form of the disclosure means that a compound of Formula (I) is released from the dosage form according to a pre-determined profile that may include when and where release occurs after oral administration and/or a specified rate of release over a specified time period. Controlled release may be contrasted with uncontrolled or immediate release.

“Controlled release agent” as used herein with respect to an oral dosage form of the disclosure refers to one or more substances or materials that modulate release of a compound of Formula (I) from the dosage form. Controlled release agents may be materials which are organic or inorganic, naturally occurring or synthetic, such as polymeric materials, triglycerides, derivatives of triglycerides, fatty acids and salts of fatty acids, talc, boric acid and colloidal silica.

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

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

The term “about” as part of a quantitative expression such as “about X”, includes any value that is 10% higher or lower than X, and also includes any numerical value that falls between X−10% and X+10%. Thus, for example, a weight of about 40 g includes a weight of between 36 to 44 g. When used herein to denote amino acid residues in the ER, the term “about” means any amino acid residue that is within 5 amino acid residues of what is specified. For example, when referring to a contiguous stretch of amino acid residues extending from about amino acid residue 181 to about amino acid residue 263 of the ER, this refers to a contiguous stretch of amino acid residues extending 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” means any amino acid residue that is within 3 amino acid residues of what is specified. In some embodiments, the term “about” means any amino acid residue that is within 1 amino acid residue of what is specified.

As used herein, the term “del” denotes an in-frame deletion of the amino acid residue(s) relative to wild type. For example, “V422del” indicates that a mutant in which the valine at position 422 in the wild-type ER protein has been deleted.

As used herein, an underscore between the notation of two amino acids indicates that the sequence of residues, inclusive of both endpoints, has been altered. For example “L536_D538>P” indicates a mutant arising from an in-frame deletion resulting in the amino acid residues beginning with lysine at position 536 and ending at aspartic acid at position 538 having been replaced by a single proline.

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

“Fasted condition” or “fasted state” as used to describe a subject means the subject has not eaten for at least 4 hours before a time point of interest, such as the time of administering a compound of Formula (I). In an embodiment, a subject in the fasted state has not eaten for at least any of 6, 8, 10 or 12 hours prior to administration of a compound of Formula (I).

“Fed condition” or “fed state” as used to describe a subject herein means the subject has eaten less than 4 hours before a time point of interest, such as the time of administering a compound of Formula (I). In an embodiment, a subject in the fed state has not eaten for at most any of 4, 3, 2, 1 or 0.5 hours prior to administration of a compound of Formula (I).

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)derivs., (Z)-.

As used herein, “low molecular weight polyethylene glycol” or “low molecular weight PEG” generally refers to polyethylene glycol (PEG) polymers 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.

As used herein, the term “CDK4/6 inhibitor” refers to a compound that inhibits the enzymes in humans referred to as cyclin-dependent kinases (CDK) 4 and 6. Examples of a CDK4/6 inhibitor include, without limitation, SHR6390, trilaciclib, lerociclib, 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.

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

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

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

In some embodiments, the subject is a human.

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

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

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

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

Compounds of Formula (I)

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

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

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

As referred to herein, a compound of Formula (I) refers to a compound with the following structure:

[Image Omitted]

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein:

each R¹and each R²is independently selected from the group consisting of halo, OR⁵, N(R⁵)(R⁶), NO₂, CN, SO₂(R⁵), C₁-C₆alkyl, and C₃-C₆cycloalkyl;

R³and R⁴are either both hydrogen or, taken together with the carbon to which they are attached, form a carbonyl;

each R⁵and each R⁶is independently selected from the group consisting of hydrogen, C₁-C₆alkyl, and C₃-C₆cycloalkyl;

- m is 0, 1, 2, 3, 4, or 5; and
- n is 0, 1, 2, 3, or 4.

In some embodiments, each R¹and each R²is independently selected from the group consisting of halo, OR⁵, and C₁-C₆alkyl.

In some embodiments, R¹is hydrogen, halo, OR⁵, N(R⁵)(R⁶), or C₁-C₆alkyl. In some embodiments, R¹is hydrogen. In some embodiments, R¹is halo. In some embodiments, R¹is OR⁵. In some embodiments, R¹is N(R⁵)(R⁶). In some embodiments, R¹is C₁-C₆alkyl.

In some embodiments, R²is hydrogen, halo, OR⁵, N(R⁵)(R⁶), or C₁-C₆alkyl. In some embodiments, R²is hydrogen. In some embodiments, R²is halo. In some embodiments, R²is OR⁵. In some embodiments, R²is N(R⁵)(R⁶). In some embodiments, R²is C₁-C₆alkyl.

In some embodiments, R³and R⁴are both hydrogen.

In some embodiments, R³and R⁴, taken together with the carbon to which they are attached, form a carbonyl.

In some embodiments, each R⁵and each R⁶is independently selected from the group consisting of hydrogen and C₁-C₆alkyl. In some embodiments, R⁵and R⁶are each hydrogen.

In some embodiments, m is 0.

In some embodiments, m is 1.

In some embodiments, m is 2.

In some embodiments, m is 3.

In some embodiments, m is 4.

In some embodiments, m is 5.

In some embodiments, n is 0.

In some embodiments, n is 1.

In some embodiments, n is 2.

In some embodiments, n is 3.

In some embodiments, n is 4.

In some embodiments, m and n are each 0.

In some embodiments, m is 0 and n is 1.

In some embodiments, m is 1 and n is 0.

In some embodiments, m is 1 and n is 1.

In some embodiments, the compound of Formula (I) is selected from the group consisting of:

[Image Omitted]