Methods of treating breast cancer with tetrahydronaphthalene derivatives as estrogen receptor degraders

Abstract

To provide methods and compounds for use in treating and / or preventing breast cancer, including locally advanced or metastatic, ER+, HER2- breast cancer, in a subject in need of treatment.SOLUTION: Treating and / or preventing methods are provided which comprise administering a compound of Formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.SELECTED DRAWING: Figure 8

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit and priority of U.S. Patent Application No. 63 / 023,067, filed May 11, 2020; U.S. Patent Application No. 62 / 942,663, filed Dec. 2, 2019; U.S. Patent Application No. 62 / 924,653, filed Oct. 22, 2019; and U.S. Patent Application No. 62 / 891,648, filed Aug. 26, 2019, the entire contents of each of which are incorporated herein by reference.

[0002] Field of the Disclosure This application relates to the treatment of breast cancer, including locally advanced or metastatic ER +, HER2 - breast cancer, comprising administering a compound of formula (I) to a subject in need thereof.

Background Art

[0003] Background of the Disclosure In the United States (US), in 2018, breast cancer was the second leading cause of cancer - related death in women, with an estimated 41,000 women dying from it. Breast cancer is less common in men, but men account for about 1% of all newly diagnosed cases and an estimated 500 men are predicted to die in 2018 (Seigel R.L. et al. Cancer Statistics, CA Cancer J Clin. 2018, 68(1); 7 - 30. (Non - Patent Document 1))

[0004] As of January 2017, it was estimated that approximately 155,000 women with metastatic breast cancer (mBC) lived in the United States. It was also reported that the number of women living with mBC was increasing, mainly due to improved treatment and the aging of the US population. The estimated number of women living with mBC was predicted to increase by 17% from 2000 to 2010 and 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. (Non-Patent Document 2))

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

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

[0007] Fulvestrant is considered a basic component of ER-targeted endocrine regimens in advanced disease settings and acts via an indirect mechanism of proteolysis, leading to destabilization of ER. Single-agent fulvestrant is administered intramuscularly at 500 mg on days 1, 15, and 29, and then monthly thereafter. The efficacy of fulvestrant was established by comparison with the selective aromatase inhibitor anastrozole in two randomized controlled clinical trials in postmenopausal women with locally advanced or mBC (Astra Zeneca Faslodex Full Prescribing Information, revised March 2019 (Non-Patent Document 3)). All patients had progressed after previous treatment with anti-estrogen or progestin agents for breast cancer in an adjuvant or advanced disease setting. In both trials, eligible patients with measurable and / or evaluable disease were randomized to receive either fulvestrant 250 mg intramuscularly once monthly (28 days + 3 days) or anastrozole 1 mg orally once daily. The results of the trials excluded inferiority of fulvestrant to anastrozole after a minimum follow-up period of 14.6 months. There was no statistically significant difference in overall survival (OS) between the two treatment groups after a follow-up period of more than 2 years. In a third study, the 500 mg dose of fulvestrant was compared with the 250 mg dose of fulvestrant. The results of this study after a minimum follow-up period of 18 months showed that progression-free survival (PFS) was statistically significantly superior for fulvestrant 500 mg vs fulvestrant 250 mg (6.5 months vs 5.4 months, respectively). There was no statistically significant difference in OS between the two treatment groups (25.1 months for fulvestrant 500 mg and 22.8 months for fulvestrant 250 mg). The overall response rates were similar, with a response rate of 13.8% for the 500 mg dose (95% confidence interval [CI] 9.7 - 18.8%) and 14.6% for the 250 mg dose (CI 10.5 - 19.4%) (Astra Zeneca Faslodex Full Prescribing Information, revised March 2019 (Non-Patent Document 3)).

Prior Art Documents

Non-Patent Literature

[0008]

Non-Patent Literature 1

Non-Patent Literature 2

Non-Patent Literature 3

Summary of the Invention

[0009] Summary of the Present Disclosure In one aspect, the present application relates to a method for 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): TIFF2025094174000002.tif55128 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, wherein, each R 1 and each R 2 is independently selected from the group consisting of halo, OR5, N(R5)(R6), NO2, CN, SO2(R5), C1-C6 alkyl, and C3-C6 cycloalkyl, R3 and R4 are both hydrogen or together with the carbon to which they are attached form a carbonyl, Each R5 and each R6 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl, m is 0, 1, 2, 3, 4, or 5, and n is 0, 1, 2, 3, or 4.

[0010] In one embodiment, the breast cancer is ER+, HER2-.

[0011] In one embodiment, the breast cancer is metastatic or locally advanced.

[0012] In one embodiment, each R 1 and each R 2 are independently selected from the group consisting of halo and OR5.

[0013] In one embodiment, both R3 and R4 are hydrogen.

[0014] In one embodiment, R3 and R4, together with the carbon to which they are attached, form a carbonyl.

[0015] In one embodiment, m and n are each 0. In one embodiment, m and n are each 1. In one embodiment, one of m and n is 0 and the other is 1. For example, in one embodiment, m is 0 and n is 1. In another embodiment, m is 0 and n is 1.

[0016] In one embodiment, the compound of formula (I) is TIFF2025094174000003.tif139128TIFF2025094174000004.tif176128TIFF2025094174000005.tif94128 or any pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0017] In one embodiment, the method comprises administering to a subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or isotopic derivative thereof.

[0018] In one embodiment, the compound of formula (I) is administered orally to the subject.

[0019] In one embodiment, a 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 one embodiment, a therapeutically effective amount of the compound of formula (I) is administered to the subject once a day. In one embodiment, a therapeutically effective amount of the compound of formula (I) is administered to the subject either in its entirety at once or divided into two, three, or four portions.

[0020] In one embodiment, a therapeutically effective amount of the compound of formula (I) is about 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg.

[0021] In one embodiment, a therapeutically effective amount of the compound of formula (I) is from about 10 mg to about 1000 mg.

[0022] In one embodiment, a therapeutically effective amount of the compound of formula (I) is from about 20 mg to about 700 mg.

[0023] In one embodiment, a therapeutically effective amount of the compound of formula (I) is from about 30 mg to about 500 mg.

[0024] In one embodiment, a therapeutically effective amount of the compound of formula (I) is from about 30 mg to about 120 mg.

[0025] In one embodiment, 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.

[0026] In one embodiment, the therapeutically effective amount of the compound of formula (I) results in a 15-day mean AUC of greater than about 3,500 ng·hour / mL, about 3,600 ng·hour / mL, about 3,700 ng·hour / mL, about 3,800 ng·hour / mL, about 3,900 ng·hour / mL, about 4,000 ng·hour / mL, about 4,100 ng·hour / mL, about 4,200 ng·hour / mL, about 4,300 ng·hour / mL, 4,400 ng·hour / mL, about 4,500 ng·hour / mL, about 4,600 ng·hour / mL, about 4,700 ng·hour / mL, about 4,800 ng·hour / mL, about 4,900 ng·hour / mL, or greater than about 5,000 ng·hour / mL. TAU results in.

[0027] In one embodiment, the therapeutically effective amount of the compound of formula (I) results in a 15-day mean AUC of greater than about 3,500 ng·hour / mL and less than about 4,000 ng·hour / mL. TAU results in. In one embodiment, the therapeutically effective amount of the compound of formula (I) results in a 15-day mean AUC of greater than about 3,600 ng·hour / mL and less than about 4,100 ng·hour / mL. TAUresults in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a 15-day average AUC of greater than about 3,700 ng·hour / mL and less than about 4,200 ng·hour / mL TAU results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a 15-day average AUC of greater than about 3,800 ng·hour / mL and less than about 4,300 ng·hour / mL TAU results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a 15-day average AUC of greater than about 3,900 ng·hour / mL and less than about 4,400 ng·hour / mL TAU results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a 15-day average AUC of greater than about 4,000 ng·hour / mL and less than about 4,500 ng·hour / mL TAU results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a 15-day average AUC of greater than about 4,100 ng·hour / mL and less than about 4,600 ng·hour / mL TAU results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a 15-day average AUC of greater than about 4,200 ng·hour / mL and less than about 4,700 ng·hour / mL TAU results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a 15-day average AUC of greater than about 4,300 ng·hour / mL and less than about 4,800 ng·hour / mL TAU results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a 15-day average AUC of greater than about 4,400 ng·hour / mL and less than about 4,900 ng·hour / mL TAU results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a 15-day average AUC of greater than about 4,500 ng·hour / mL and less than about 5,000 ng·hour / mL TAU results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a 15-day average AUC of greater than about 4,600 ng·hour / mL and less than about 5,100 ng·hour / mL TAU results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a 15-day average AUC of greater than about 4,700 ng·hour / mL and less than about 5,200 ng·hour / mL TAUresults in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a 15-day average AUC that is greater than about 4,800 ng·hour / mL and less than about 5,300 ng·hour / mL TAU results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a 15-day average AUC that is greater than about 4,900 ng·hour / mL and less than about 5,400 ng·hour / mL TAU results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a 15-day average AUC that is greater than about 5,000 ng·hour / mL and less than about 5,500 ng·hour / mL TAU results in.

[0028] In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a 15-day average AUC that is greater than about 4,000 ng·hour / mL and less than about 4,200 ng·hour / mL TAU results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a 15-day average AUC that is greater than about 3,900 ng·hour / mL and less than about 4,300 ng·hour / mL TAU results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a 15-day average AUC that is greater than about 3,800 ng·hour / mL and less than about 4,400 ng·hour / mL TAU results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a 15-day average AUC that is greater than about 3,700 ng·hour / mL and less than about 4,500 ng·hour / mL TAU results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a 15-day average AUC that is greater than about 3,600 ng·hour / mL and less than about 4,600 ng·hour / mL TAU results in.

[0029] In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a 15-day average C that is greater than about 200 ng / mL, about 205 ng / mL, about 210 ng / mL, about 215 ng / mL, about 220 ng / mL, about 225 ng / mL, about 230 ng / mL, about 235 ng / mL, about 240 ng / mL, about 245 ng / mL, or about 250 ng / mL max results in.

[0030] In one embodiment, a therapeutically effective amount of the compound of formula (I) results in a mean C on day 15 that is greater than about 200 ng / mL and less than about 220 ng / mL max In one embodiment, a therapeutically effective amount of the compound of formula (I) results in a mean C on day 15 that is greater than about 205 ng / mL and less than about 225 ng / mL max In one embodiment, a therapeutically effective amount of the compound of formula (I) results in a mean C on day 15 that is greater than about 210 ng / mL and less than about 230 ng / mL max In one embodiment, a therapeutically effective amount of the compound of formula (I) results in a mean C on day 15 that is greater than about 215 ng / mL and less than about 235 ng / mL max In one embodiment, a therapeutically effective amount of the compound of formula (I) results in a mean C on day 15 that is greater than about 220 ng / mL and less than about 240 ng / mL max In one embodiment, a therapeutically effective amount of the compound of formula (I) results in a mean C on day 15 that is greater than about 225 ng / mL and less than about 245 ng / mL max In one embodiment, a therapeutically effective amount of the compound of formula (I) results in a mean C on day 15 that is greater than about 230 ng / mL and less than about 250 ng / mL max In one embodiment, a therapeutically effective amount of the compound of formula (I) results in a mean C on day 15 that is greater than about 235 ng / mL and less than about 255 ng / mL max In one embodiment, a therapeutically effective amount of the compound of formula (I) results in a mean C on day 15 that is greater than about 240 ng / mL and less than about 260 ng / mL max In one embodiment, a therapeutically effective amount of the compound of formula (I) results in a mean C on day 15 that is greater than about 245 ng / mL and less than about 265 ng / mL max In one embodiment, a therapeutically effective amount of the compound of formula (I) results in a mean C on day 15 that is greater than about 250 ng / mL and less than about 270 ng / mL max results in

[0031] In one embodiment, a therapeutically effective amount of the compound of formula (I) results in a mean C on day 15 that is greater than about 214 ng / mL and less than about 236 ng / mL max In one embodiment, a therapeutically effective amount of the compound of formula (I) results in a mean C on day 15 that is greater than about 213 ng / mL and less than about 237 ng / mL maxresults in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a mean C on day 15 that is greater than about 212 ng / mL and less than about 238 ng / mL max results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a mean C on day 15 that is greater than about 211 ng / mL and less than about 239 ng / mL max results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a mean C on day 15 that is greater than about 210 ng / mL and less than about 240 ng / mL max results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a mean C on day 15 that is greater than about 205 ng / mL and less than about 245 ng / mL max results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a mean C on day 15 that is greater than about 200 ng / mL and less than about 250 ng / mL max results in.

[0032] In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a mean C on day 15 that is greater than about 223 ng / mL and less than about 225 ng / mL max results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a mean C on day 15 that is greater than about 222 ng / mL and less than about 226 ng / mL max results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a mean C on day 15 that is greater than about 221 ng / mL and less than about 227 ng / mL max results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a mean C on day 15 that is greater than about 220 ng / mL and less than about 228 ng / mL max results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a mean C on day 15 that is greater than about 219 ng / mL and less than about 229 ng / mL max results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a mean C on day 15 that is greater than about 218 ng / mL and less than about 230 ng / mL max results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a mean C on day 15 that is greater than about 217 ng / mL and less than about 231 ng / mL max results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) provides a mean C on day 15 that is greater than about 216 ng / mL and less than about 232 ng / mL maxresults in. In one embodiment, a therapeutically effective amount of the compound of formula (I) results in a mean C on day 15 that is greater than about 215 ng / mL and less than about 233 ng / mL max results in. In one embodiment, a therapeutically effective amount of the compound of formula (I) results in a mean C on day 15 that is greater than about 214 ng / mL and less than about 234 ng / mL max results in.

[0033] In one embodiment, the compound of formula (I) is formulated as a tablet. In one embodiment, the tablet comprises the compound of formula (I) and optionally one or more of the following: an emulsifier, a surfactant, a binder, a disintegrant, a glidant, and a lubricant. In one embodiment, the emulsifier is hypromellose. In one embodiment, the surfactant is vitamin E polyethylene glycol succinate. In one embodiment, the binder is microcrystalline cellulose or lactose monohydrate. In one embodiment, the disintegrant is croscarmellose sodium. In one embodiment, the glidant is silicon dioxide. In one embodiment, the lubricant is sodium stearyl fumarate. In one embodiment, the subject in need of treatment is in a fed state. In one embodiment, the subject in need of treatment is in a fasting state.

[0034] In one aspect, the present application relates to a method of treating breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as defined herein, and further comprising administering to the subject in need thereof a therapeutically effective amount of a CDK4 / 6 inhibitor. In one embodiment, the CDK4 / 6 inhibitor is SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, or palbociclib. In one embodiment, the CDK4 / 6 inhibitor is palbociclib.

[0035] In one embodiment, there is provided a method for 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 administering a therapeutically effective amount of palbociclib, wherein the therapeutically effective amount of palbociclib is administered to the subject once a day. In one embodiment, the therapeutically effective amount of palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg. In one embodiment, palbociclib is administered once a day for up to 21 consecutive days, followed by an off-treatment period of up to 7 consecutive days, wherein the cycle of treatment with palbociclib and the subsequent off-treatment period is repeated one, two, three, four, five, or more times. In one embodiment, the compound of formula (I) is administered once a day for up to 21 consecutive days, followed by an off-treatment period of up to 7 consecutive days, wherein the cycle of treatment with the compound of formula (I) and the subsequent off-treatment period is repeated one, two, three, four, five, or more times. In one embodiment, administering the compound of formula (I) and palbociclib to a subject in need thereof is performed when the subject is in a fed state. In one embodiment, administering the compound of formula (I) and palbociclib to a subject in need thereof is performed when the subject is in a fasting state.

[0036] In one aspect, the present application relates to a method for treating metastatic breast cancer in a subject in need thereof, comprising once-daily oral administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, wherein the compound of formula (I) is selected from the group consisting of TIFF2025094174000006.tif139128TIFF2025094174000007.tif176128TIFF2025094174000008.tif94128.

[0037] In one embodiment, the therapeutically effective amount of the compound of formula (I) is administered to the subject either as a single total dose at one time or divided into two, three, or four portions.

[0038] In one embodiment, the therapeutically effective amount of the compound of formula (I) is from about 30 mg to about 1000 mg.

[0039] In one embodiment, the therapeutically effective amount of the compound of formula (I) is from about 10 to about 40 mg, from about 20 to about 50 mg, from about 30 to about 60 mg, from about 40 to about 70 mg, from about 50 to about 80 mg, from about 60 to about 90 mg, from about 70 to about 100 mg, from about 80 to about 110 mg, from about 90 to about 120 mg, from about 100 to about 130 mg, from about 110 to about 140 mg, from about 120 to about 150 mg, from about 130 to about 160 mg, from about 140 to about 170 mg, from about 150 to about 180 mg, from about 160 to about 190 mg, from about 170 to about 200 mg, from about 180 to about 210 mg, from about 190 to about 220 mg, from about 200 to about 230 mg, from about 210 to about 240 mg, from about 220 to about 250 mg, from about 230 to about 260 mg, from about 240 to about 270 mg, from about 250 to about 280 mg, from about 260 to about 290 mg, from about 270 to about 300 mg, from about 280 to about 310 mg, from about 290 to about 320 mg, from about 300 to about 330 mg, from about 310 to about 340 mg, from about 320 to about 350 mg, from about 330 to about 360 mg, from about 340 to about 370 mg, from about 350 to about 380 mg, from about 360 to about 390 mg, or from about 370 to about 400 mg.

[0040] In one embodiment, the compound of formula (I) is formulated as a tablet.

[0041] In one aspect, the present application is a method for 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, isotope derivative, or prodrug thereof, and further comprising administering to the subject in need thereof a therapeutically effective amount of a CDK4 / 6 inhibitor. In one embodiment, the CDK4 / 6 inhibitor is SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, or palbociclib. In one embodiment, the CDK4 / 6 inhibitor is palbociclib.

[0042] In one embodiment, a method for treating breast cancer in a subject in need thereof is provided, which includes administering to the subject a therapeutically effective amount of 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), or formula (I-i), and further includes administering a therapeutically effective amount of palbociclib, wherein the therapeutically effective amount of palbociclib is administered simultaneously with the administration of the 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), or formula (I-i). In one embodiment, a method for treating breast cancer in a subject in need thereof is provided, which includes administering to the subject a therapeutically effective amount of 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), or formula (I-i), and further includes administering a therapeutically effective amount of palbociclib, wherein the therapeutically effective amount of palbociclib is administered before the administration of the 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), or formula (I-i). In one embodiment, a method for treating breast cancer in a subject in need thereof is provided, which includes administering to the subject a therapeutically effective amount of 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), or formula (I-i), and further includes administering a therapeutically effective amount of palbociclib, wherein the therapeutically effective amount of palbociclib is administered after the administration of the 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), or formula (I-i).In some embodiments, 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-a), formula (I-b), formula (I-c), formula (I-d), formula (I-e), formula (I-f), formula (I-g), formula (I-h), or formula (I-i), and further comprising administering a therapeutically effective amount of palbociclib, wherein the administration of the 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), or formula (I-i), and the administration of palbociclib are carried out at separate times such that the two compounds and their respective excipients, if any, do not mix in the subject's stomach.

[0043] In one embodiment, 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-a), formula (I-b), formula (I-c), formula (I-d), formula (I-e), formula (I-f), formula (I-g), formula (I-h), or formula (I-i), and further comprising administering a therapeutically effective amount of palbociclib, wherein the therapeutically effective amount of palbociclib is administered at least 5, at least 10, at least 15, at least 20, at least 25, or at least 30 minutes before the administration of the 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), or formula (I-i). In one embodiment, 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-a), formula (I-b), formula (I-c), formula (I-d), formula (I-e), formula (I-f), formula (I-g), formula (I-h), or formula (I-i), and further comprising administering a therapeutically effective amount of palbociclib, wherein the therapeutically effective amount of palbociclib is administered at least 30 minutes before the administration of the 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), or formula (I-i). In one embodiment, 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-a), formula (I-b), formula (I-c), formula (I-d), formula (I-e), formula (I-f), formula (I-g), formula (I-h), or formula (I-i), and further comprising administering a therapeutically effective amount of palbociclib, wherein the therapeutically effective amount of palbociclib is administered between 30 and 60 minutes before the administration of the 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), or formula (I-i).

[0044] In one embodiment, a method of treating breast cancer in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of 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), or formula (I-i), and further comprising administering a therapeutically effective amount of palbociclib, wherein the therapeutically effective amount of palbociclib is administered at least 5, at least 10, at least 15, at least 20, at least 25, or at least 30 minutes after administration of the 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), or formula (I-i). In one embodiment, a method of treating breast cancer in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of 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), or formula (I-i), and further comprising administering a therapeutically effective amount of palbociclib, wherein the therapeutically effective amount of palbociclib is administered at least 30 minutes after administration of the 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), or formula (I-i). In one embodiment, a method of treating breast cancer in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of 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), or formula (I-i), and further comprising administering a therapeutically effective amount of palbociclib, wherein the therapeutically effective amount of palbociclib is administered between 30 and 60 minutes after administration of the 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), or formula (I-i).

[0045] In one embodiment, a method for treating breast cancer in a subject in need thereof is provided, which includes administering to the subject a therapeutically effective amount of 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), or formula (I-i), and further includes administering a therapeutically effective amount of palbociclib. The therapeutically effective amount of palbociclib is administered to the subject once a day. In one embodiment, the therapeutically effective amount of palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg. In one embodiment, palbociclib is administered once a day for up to 21 consecutive days, followed by a treatment break for up to 7 consecutive days. Here, the cycle of treatment with palbociclib and the subsequent treatment break is repeated one, two, three, four, five, or more times. In one embodiment, the 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), or formula (I-i) is administered once a day for up to 21 consecutive days, followed by a treatment break for up to 7 consecutive days. Here, the cycle of treatment with the 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), or formula (I-i) and the subsequent treatment break is repeated one, two, three, four, five, or more times. In one embodiment, the administration of the 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), or formula (I-i) and palbociclib to a subject in need thereof is carried out when the subject is in a fed state. In one embodiment, the administration of the 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), or formula (I-i) and palbociclib to a subject in need thereof is carried out when the subject is in a fasting state.

[0046] In one aspect, the present application provides a method for treating breast cancer in a subject in need thereof, comprising: (i) a therapeutically effective amount of a compound of formula (I-c): The once-daily oral administration of TIFF2025094174000009.tif45128 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, and (ii) the once-daily oral administration of palbociclib. In one aspect, the present application relates to a method of treating breast cancer in a subject in need thereof, comprising (i) the once-daily oral administration of a therapeutically effective amount of a compound of formula (I-c), and (ii) the once-daily oral administration of palbociclib. In one embodiment, the therapeutically effective amount of the compound of formula (I-c) is from about 30 mg to about 1000 mg. In one embodiment, the therapeutically effective amount of palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg. In one embodiment, palbociclib is administered once daily for up to 21 consecutive days, followed by a treatment break for up to 7 consecutive days, where the cycle of treatment with palbociclib and the subsequent treatment break is repeated one, two, three, four, five, or more times. In one embodiment, the compound of formula (I-c) is administered once daily for up to 21 consecutive days, followed by a treatment break for up to 7 consecutive days, where the cycle of treatment with the compound of formula (I-c) and the subsequent treatment break is repeated one, two, three, four, five, or more times. In one embodiment, the administration of the compound of formula (I-c) and palbociclib to a subject in need thereof is carried out when the subject is in a fed state. In one embodiment, the administration of the compound of formula (I-c) and palbociclib to a subject in need thereof is carried out when the subject is in a fasting state.

[0047] In one embodiment, a method for treating breast cancer in a subject in need thereof, comprising once-daily oral administration of a therapeutically effective amount of a compound of formula (I-c) and further comprising once-daily oral administration of palbociclib, wherein the administration of the compound of formula (I-c) and the administration of palbociclib are carried out at separate times such that the two compounds and their respective excipients (if any) do not mix in the subject's stomach. In one embodiment, for a method for treating breast cancer in a subject in need thereof, comprising once-daily oral administration of a therapeutically effective amount of a compound of formula (I-c) and further comprising once-daily oral administration of palbociclib, palbociclib is administered prior to the administration of the compound of formula (I-c). In one embodiment, for a method for treating breast cancer in a subject in need thereof, comprising once-daily oral administration of a therapeutically effective amount of a compound of formula (I-c) and further comprising once-daily oral administration of palbociclib, palbociclib is administered at least 5, at least 10, at least 15, at least 20, at least 25, or at least 30 minutes prior to the administration of the compound of formula (I-c). In one embodiment, for a method for treating breast cancer in a subject in need thereof, comprising once-daily oral administration of a therapeutically effective amount of a compound of formula (I-c) and further comprising once-daily oral administration of palbociclib, palbociclib is administered at least 30 minutes prior to the administration of the compound of formula (I-c). In one embodiment, for a method for treating breast cancer in a subject in need thereof, comprising once-daily oral administration of a therapeutically effective amount of a compound of formula (I-c) and further comprising once-daily oral administration of palbociclib, palbociclib is administered between 30 and 60 minutes prior to the administration of the compound of formula (I-c).

[0048] In one embodiment, a method for treating breast cancer in a subject in need thereof is provided, which includes once-daily oral administration of a therapeutically effective amount of a compound of formula (I-c) and further includes once-daily oral administration of palbociclib. In this method, palbociclib is administered after the administration of the compound of formula (I-c). In one embodiment, for a method for treating breast cancer in a subject in need thereof, which includes once-daily oral administration of a therapeutically effective amount of a compound of formula (I-c) and further includes once-daily oral administration of palbociclib, palbociclib is administered at least 5, at least 10, at least 15, at least 20, at least 25, or at least 30 minutes after the administration of the compound of formula (I-c). In one embodiment, for a method for treating breast cancer in a subject in need thereof, which includes once-daily oral administration of a therapeutically effective amount of a compound of formula (I-c) and further includes once-daily oral administration of palbociclib, palbociclib is administered at least 30 minutes after the administration of the compound of formula (I-c). In one embodiment, for a method for treating breast cancer in a subject in need thereof, which includes once-daily oral administration of a therapeutically effective amount of a compound of formula (I-c) and further includes once-daily oral administration of palbociclib, palbociclib is administered between 30 and 60 minutes after the administration of the compound of formula (I-c).

[0049] In one aspect, the present application relates to a method for selective estrogen receptor degradation in a patient, comprising: (i) once-daily oral administration of a therapeutically effective amount of a compound of formula (I-c): TIFF2025094174000010.tif45128 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, and (ii) once-daily oral administration of palbociclib.

[0050] In one aspect, the present application relates to a method for cyclin-dependent kinase inhibition in a subject in need thereof, comprising: (i) once-daily oral administration of a therapeutically effective amount of a compound of formula (I-c): Relates to a method comprising (i) once-daily oral administration of TIFF2025094174000011.tif45128 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, and (ii) once-daily oral administration of palbociclib.

[0051] In one aspect, the present application relates to a compound of formula (I-c): Relates to a kit comprising TIFF2025094174000012.tif45128, palbociclib, and instructions for use.

[0052] In one aspect, the present application relates to a liquid composition comprising a surfactant, a solvent, and a compound of formula (I-c): TIFF2025094174000013.tif45128. In some embodiments, the surfactant is a sorbitan derivative. In some embodiments, the surfactant is Tween80. In some embodiments, the solvent is low molecular weight polyethylene glycol (PEG). In some embodiments, the solvent is polyethylene glycol (PEG)-400.

[0053] In one aspect, the present application relates to a method for preparing a liquid composition comprising a surfactant, a solvent, and a compound of formula (I-c): TIFF2025094174000014.tif45128, the method comprising the step of adding a solvent to a pre-aliquoted amount of the surfactant. In some embodiments, the method further comprises the step of adding a compound of formula (I-c) to a mixture of the solvent and the surfactant. In some embodiments, the surfactant is a sorbitan derivative. In some embodiments, the surfactant is Tween80. In some embodiments, the solvent is low molecular weight polyethylene glycol (PEG). In some embodiments, the solvent is polyethylene glycol (PEG)-400. [The present invention 1001] A method for treating breast cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I): Administering to the subject TIFF2025094174000015.tif55128 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, wherein, each R 1 and each R 2 is independently selected from the group consisting of halo, OR5, N(R5)(R6), NO2, CN, SO2(R5), C1-C6 alkyl, and C3-C6 cycloalkyl, R3 and R4 are either both hydrogen or together with the carbon to which they are attached form a carbonyl, each R5 and each R6 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl, m is 0, 1, 2, 3, 4, or 5, and n is 0, 1, 2, 3, or 4, A method wherein the therapeutically effective amount of the compound of formula (I) is from about 10 mg to about 1000 mg. [Inventive Concept 1002] The method of Inventive Concept 1001, wherein the breast cancer is ER+, HER2-. [Inventive Concept 1003] The method of Inventive Concept 1001 or 1002, wherein the breast cancer is metastatic or locally advanced. [Inventive Concept 1004] R 1 and R 2 are each independently selected from the group consisting of halo and OR5, according to any one of Inventive Concepts 1001 to 1003. [Inventive Concept 1005] The method according to any one of Inventive Concepts 1001 to 1004, wherein R3 and R4 are both hydrogen. [Inventive Concept 1006] The method according to any one of Inventive Concepts 1001 to 1004, wherein R3 and R4 together with the carbon to which they are attached form a carbonyl. [Inventive Concept 1007] The method according to any one of the present inventions 1001 to 1003, 1005, or 1006, wherein m and n are each 0. [The present invention 1008] The method according to any one of the present inventions 1001 to 1006, wherein m and n are each 1. [The present invention 1009] The method according to any one of the present inventions 1001 to 1003, 1005, or 1006, wherein one of m and n is 0 and the other is 1. [The present invention 1010] The compound of formula (I) is TIFF2025094174000016.tif91128TIFF2025094174000017.tif184128TIFF2025094174000018.tif134128 or any of the aforementioned pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotope derivatives, or prodrugs. The method according to any one of the present inventions 1001 to 1003. [The present invention 1011] The compound of formula (I) is a compound of formula (I-c): TIFF2025094174000019.tif44128. The method according to any one of the present inventions 1001 to 1003. [The present invention 1012] The compound of formula (I) is orally administered to the subject. The method according to any one of the present inventions 1001 to 1011. [The present invention 1013] 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. The method according to any one of the present inventions 1001 to 1012. [The present invention 1014] The therapeutically effective amount of the compound of formula (I) is administered to the subject once a day. The method according to any one of the present inventions 1001 to 1013. [The present invention 1015] The therapeutically effective amount of the compound of formula (I) is administered to the subject either once or divided into two, three, or four portions. The method according to the present inventions 1001 to 1012. [The present invention 1016] Any method of the present invention from 1001 to 1015, wherein the therapeutically effective amount of the compound of formula (I) is about 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg. [The present invention 1017] Any method of the present invention from 1001 to 1015, wherein the therapeutically effective amount of the compound of formula (I) is from about 20 mg to about 750 mg. [The present invention 1018] Any method of the present invention from 1001 to 1015, wherein the therapeutically effective amount of the compound of formula (I) is from about 30 mg to about 500 mg. [The present invention 1019] Any method of the present invention from 1001 to 1015, wherein the therapeutically effective amount of the compound of formula (I) is from about 30 mg to about 120 mg. [The present invention 1020] Any method of the present invention from 1001 to 1019, wherein the therapeutically effective amount of the compound of formula (I) results in a mean AUC on day 15 of greater than about 3,500 ng·h / mL, greater than about 3,600 ng·h / mL, greater than about 3,700 ng·h / mL, greater than about 3,800 ng·h / mL, greater than about 3,900 ng·h / mL, greater than about 4,000 ng·h / mL, greater than about 4,100 ng·h / mL, greater than about 4,200 ng·h / mL, greater than about 4,300 ng·h / mL, greater than about 4,400 ng·h / mL, greater than about 4,500 ng·h / mL, greater than about 4,600 ng·h / mL, greater than about 4,700 ng·h / mL, greater than about 4,800 ng·h / mL, greater than about 4,900 ng·h / mL, or greater than about 5,000 ng·h / mL TAU Any method of the present invention from 1001 to 1019. [The present invention 1021] Any method of the present invention from 1001 to 1019, wherein the therapeutically effective amount of the compound of formula (I) results in a mean AUC on day 15 of greater than about 4,000 ng·h / mL and less than about 4,500 ng·h / mL TAU Any method of the present invention from 1001 to 1019. [The present invention 1022] The method according to any one of 1001 to 1021 of the present invention, wherein the therapeutically effective amount of the compound of formula (I) results in a mean C on day 15 that is greater than about 200 ng / mL, greater than about 205 ng / mL, greater than about 210 ng / mL, greater than about 215 ng / mL, greater than about 220 ng / mL, greater than about 225 ng / mL, greater than about 230 ng / mL, greater than about 235 ng / mL, greater than about 240 ng / mL, greater than about 245 ng / mL, or greater than about 250 ng / mL. max The method according to any one of 1001 to 1021 of the present invention. [1023 of the present invention] The method according to any one of 1001 to 1021 of the present invention, wherein the therapeutically effective amount of the compound of formula (I) results in a mean C on day 15 that is greater than about 215 ng / mL and less than about 235 ng / mL. max The method according to any one of 1001 to 1021 of the present invention. [1024 of the present invention] The method according to any one of 1001 to 1023 of the present invention, wherein the compound of formula (I) is formulated as a tablet. [1025 of the present invention] The method according to 1024 of the present invention, wherein the tablet comprises the compound of formula (I) and optionally one or more of an emulsifier, a surfactant, a binder, a disintegrant, a fluidizing agent, and a lubricant. [1026 of the present invention] The method according to 1025 of the present invention, wherein the emulsifier is hypromellose. [1027 of the present invention] The method according to 1025 of the present invention, wherein the surfactant is vitamin E polyethylene glycol succinate. [1028 of the present invention] The method according to 1025 of the present invention, wherein the binder is microcrystalline cellulose or lactose monohydrate. [1029 of the present invention] The method according to 1025 of the present invention, wherein the disintegrant is croscarmellose sodium. [1030 of the present invention] The method according to 1025 of the present invention, wherein the fluidizing agent is silicon dioxide. [1031 of the present invention] The method according to 1025 of the present invention, wherein the lubricant is sodium stearyl fumarate. [1032 of the present invention] The method according to any one of the present inventions 1001 to 1031, further comprising administering to the subject in need thereof a therapeutically effective amount of a CDK4 / 6 inhibitor. [The present invention 1033] The method according to the present invention 1032, wherein the CDK4 / 6 inhibitor is SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, or palbociclib. [The present invention 1034] The method according to the present invention 1032, wherein the CDK4 / 6 inhibitor is palbociclib. [The present invention 1035] The method according to the present invention 1034, wherein the therapeutically effective amount of palbociclib is administered to the subject once a day. [The present invention 1036] The method according to the present invention 1034 or 1035, wherein the therapeutically effective amount of palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg. [The present invention 1037] The method according to any one of the present inventions 1033 to 1036, wherein palbociclib is administered continuously once a day for up to 21 days, followed by a treatment break continuously for up to 7 days, and the cycle of treatment with palbociclib and the subsequent treatment break is repeated once, twice, three times, four times, five times, or more than five times. [The present invention 1038] The method according to any one of the present inventions 1001 to 1037, wherein the compound of formula (I) is administered continuously once a day for up to 21 days, followed by a treatment break continuously for up to 7 days, and the cycle of treatment with the compound of formula (I) and the subsequent treatment break is repeated once, twice, three times, four times, five times, or more than five times. [The present invention 1039] The method according to any one of the present inventions 1001 to 1038, wherein the subject is in a fed state. [The present invention 1040] The method according to any one of the present inventions 1001 to 1038, wherein the subject is in a fasting state. [The present invention 1041] A method of treating metastatic breast cancer in a subject in need thereof, comprising once-daily oral administration of a therapeutically effective amount of a compound of formula (I), wherein the compound of formula (I) is TIFF2025094174000020.tif139128TIFF2025094174000021.tif176128TIFF2025094174000022.tif94128 or any pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof. [Inventive item 1042] The compound of formula (I) is a compound of formula (I-c): TIFF2025094174000023.tif44128 The method of Inventive item 1041. [Inventive item 1043] The method of Inventive item 1041 or 1042, wherein the therapeutically effective amount of the compound of formula (I) is administered to the subject once or divided into two, three, or four portions. [Inventive item 1044] The method according to any one of Inventive items 1041 to 1043, wherein the therapeutically effective amount of the compound of formula (I) is about 30 mg to about 1000 mg. [Inventive item 1045] The method according to any one of Inventive items 1041 to 1044, wherein the compound of formula (I) is formulated as a tablet. [Inventive item 1046] The method according to any one of Inventive items 1041 to 1045, further comprising administration of a therapeutically effective amount of a CDK4 / 6 inhibitor to the subject in need thereof. [Inventive item 1047] The method of Inventive item 1046, wherein the CDK4 / 6 inhibitor is SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, or palbociclib. [Inventive item 1048] The method of Inventive item 1046, wherein the CDK4 / 6 inhibitor is palbociclib. [Inventive item 1049] The method of the present invention 1048, wherein the therapeutically effective amount of palbociclib is administered to the subject once a day. [The present invention 1050] The method of the present invention 1048 or 1049, wherein the therapeutically effective amount of palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg. [The present invention 1051] The method according to any one of the present inventions 1048 to 1050, wherein palbociclib is administered continuously once a day for up to 21 days, followed by a treatment break for up to 7 days continuously, and the cycle of treatment with palbociclib and the subsequent treatment break is repeated once, twice, three times, four times, five times, or more than five times. [The present invention 1052] The method according to any one of the present inventions 1041 to 1051, wherein the compound of formula (I) is administered continuously once a day for up to 21 days, followed by a treatment break for up to 7 days continuously, and the cycle of treatment with the compound of formula (I) and the subsequent treatment break is repeated once, twice, three times, four times, five times, or more than five times. [The present invention 1053] The method according to any one of the present inventions 1041 to 1052, wherein the subject is in a fed state. [The present invention 1054] The method according to any one of the present inventions 1041 to 1052, wherein the subject is in a fasting state. [The present invention 1055] The method according to any one of the present inventions 1046 to 1054, wherein the administration of the CDK4 / 6 inhibitor is performed before the administration of the compound of formula (I). [The present invention 1056] The method of the present invention 1055, wherein the administration of the CDK4 / 6 inhibitor is performed at least 30 minutes before the administration of the compound of formula (I). [The present invention 1057] The method according to any one of the present inventions 1046 to 1054, wherein the administration of the CDK4 / 6 inhibitor is performed after the administration of the compound of formula (I). [The present invention 1058] The method of the present invention 1057, wherein the administration of the CDK4 / 6 inhibitor is performed at least 30 minutes after the administration of the compound of formula (I). [The present invention 1059] A method for treating metastatic breast cancer in a subject in need thereof, (i) A therapeutically effective amount of a compound of formula (I-c): TIFF2025094174000024.tif45128 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, administered orally once a day, and (ii) Oral administration of palbociclib once a day comprising the method. [The present invention 1060] A method for treating metastatic breast cancer in a subject in need thereof, (i) A therapeutically effective amount of a compound of formula (I-c): TIFF2025094174000025.tif45128 administered orally once a day, and (ii) Oral administration of palbociclib once a day comprising the method. [The present invention 1061] The method of the present invention 1059 or the present invention 1060, wherein the therapeutically effective amount of the compound of formula (I-c) is about 30 mg to about 1000 mg. [The present invention 1062] The method according to any one of the present inventions 1059 to 1061, wherein the therapeutically effective amount of the palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg. [The present invention 1063] The method according to any one of the present inventions 1059 to 1062, wherein the palbociclib is administered once a day for up to 21 consecutive days, followed by a treatment break for up to 7 consecutive days, and the cycle of treatment with palbociclib and the subsequent treatment break is repeated once, twice, three times, four times, five times, or more than once. [The present invention 1064] The compound of formula (I-c) is administered once a day for up to 21 consecutive days, followed by a treatment break for up to 7 consecutive days, and the cycle of treatment with the compound of formula (I-c) and the subsequent treatment break is repeated once, twice, three times, four times, five times, or more than five times, according to any one of methods 1059 to 1062 of the present invention. [Inventive concept 1065] According to any one of methods 1059 to 1064 of the present invention, wherein the subject is in a fed state. [Inventive concept 1066] According to any one of methods 1059 to 1064 of the present invention, wherein the subject is in a fasting state. [Inventive concept 1067] According to any one of methods 1059 to 1066 of the present invention, wherein the administration of palbociclib is carried out before the administration of the compound of formula (I-c). [Inventive concept 1068] According to the method of inventive concept 1067, wherein the administration of palbociclib is carried out at least 30 minutes before the administration of the compound of formula (I-c). [Inventive concept 1069] According to any one of methods 1059 to 1066 of the present invention, wherein the administration of palbociclib is carried out after the administration of the compound of formula (I-c). [Inventive concept 1070] According to the method of inventive concept 1069, wherein the administration of palbociclib is carried out at least 30 minutes after the administration of the compound of formula (I-c). [Inventive concept 1071] A method for selective estrogen receptor degrading in a patient, comprising: (i) administering, once a day, a therapeutically effective amount of a compound of formula (I-c): TIFF2025094174000026.tif45128 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, by oral administration once a day, and (ii) administering palbociclib by oral administration once a day A method comprising. [Inventive concept 1072] A method for inhibiting cyclin-dependent kinase in a subject in need thereof, comprising: (i) A therapeutically effective amount of a compound of formula (I-c): Once-daily oral administration of TIFF2025094174000027.tif45128 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, and (ii) Once-daily oral administration of palbociclib A method comprising the same. [Invention 1073] (i) A compound of formula (I-c): TIFF2025094174000028.tif45128 (ii) Palbociclib, and (iii) Instructions for use A kit comprising the same. [Invention 1074] Surfactant, solvent, and a compound of formula (I-c): TIFF2025094174000029.tif45128 A liquid composition comprising the same. [Invention 1075] The liquid composition of Invention 1074, wherein the surfactant is Tween 80. [Invention 1076] The liquid composition of Invention 1074 or 1075, wherein the solvent is PEG-400. [Invention 1077] Surfactant, solvent, and a compound of formula (I-c): TIFF2025094174000030.tif45128 A method for preparing a liquid composition comprising the same, the method comprising the step of adding the solvent to a pre-aliquoted amount of the surfactant. [Invention 1078] The method of Invention 1077, wherein the surfactant is Tween 80. [Invention 1079] The method of Invention 1077 or 1078, wherein the solvent is PEG-400.

Brief Description of the Drawings

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Mode for Carrying Out the Invention

[0074] Detailed Description Definitions "H" refers to hydrogen.

[0075] Halogen or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0076] "C1-C6 alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon containing 1 to 6 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0077] "C3-C6 cycloalkyl" means a monocyclic saturated carbon ring containing 3 to 6 carbon atoms, i.e., a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl moiety.

[0078] As used herein with respect to the compounds of formula (I), "pharmaceutically acceptable salts" means the salt forms of the compounds of formula (I), as well as hydrates of the salt forms in which one or more water molecules are present. Such salt and hydrated forms retain the biological activity of the compounds of formula (I) and are not biologically or otherwise undesirable, i.e., exhibit minimal, if any, toxicological effects. Representative "pharmaceutically acceptable salts" include, for example, acetate, anthranilate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, cancillarate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylic acid salt, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methan-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, basic acetate, succinate, sulfate, sulfosalicylate, slamate, tannate, tartrate, theocurate, tosylate, triethiodide, and valerate, etc., including water-soluble salts and water-insoluble salts.

[0079] The term "isomer" refers to salts and / or compounds that have the same composition and molecular weight but different physical and / or chemical properties. The structural differences can be in the constitution (geometric isomers) or the ability to rotate the plane of polarization (stereoisomers). With respect to stereoisomers, the salts of the compounds of formula (I) may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereomers.

[0080] The compounds of formula (I) can exist in non-solvated and solvated forms, such as hydrates, for example.

[0081] "Solvate" means a solvate addition form containing either a stoichiometric or non-stoichiometric amount of a solvent. Some compounds tend to trap solvent molecules in a fixed molar ratio in the crystalline solid state and thus form solvates. When the solvent is water, the solvate formed is a hydrate, and when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with one of the substances in which the water retains its molecular state as H2O, and such combinations can form more than one hydrate. In hydrates, the water molecules are bonded via secondary valences by intermolecular forces, particularly hydrogen bridges. Solid hydrates contain water in a stoichiometric ratio as so-called water of crystallization, and the water molecules do not have to be equivalent with respect to their bonding state. Examples of hydrates include sesquihydrates, monohydrates, dihydrates, or trihydrates. Hydrates of the salts of the compounds of the present invention are equally suitable.

[0082] When a compound crystallizes from a solution or slurry, it can crystallize in different lattice arrangements in space (this property is called polymorphism) and form crystals with different crystal morphologies, each of which is known as a "polymorph". As used herein, "polymorph" refers to a crystal form of a compound of formula (I), where the molecules are located at lattice sites in three dimensions. Different polymorphs of the compound of formula (I) may differ from one another in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystal form, packing mode, flowability and / or solid state stability.

[0083] As referred to herein, an "isotopically derivative" relates to a compound of formula (I) that is isotopically enriched or labeled by one or more stable isotopes (with respect to one or more atoms of the compound). Thus, in the present application, a compound of formula (I) includes, for example, compounds that are isotopically enriched or labeled with one or more atoms such as deuterium ( 2 H or D) or carbon-13 ( 13 C).

[0084] The term "pharmaceutically acceptable prodrug" as used herein refers to a prodrug of a compound of formula (I) that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals having excessive toxicity, irritation, allergic reaction, etc., commensurate with a reasonable benefit / risk ratio, and effective for its intended use, and is, if possible, the zwitterionic form of the compound of the present invention.

[0085] As used herein, "prodrug" means a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) to yield any compound detailed by the formulas of the present invention. Various forms of prodrugs are known in the art and are discussed, for example, in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985), Krogsgaard-Larsen, et al., (ed). “Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991), Bundgaard, et al., Journal of Drug Delivery Reviews, 8:1-38 (1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988), Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975), and Bernard Testa & Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

[0086] The present invention also encompasses pharmaceutical compositions containing pharmaceutically acceptable prodrugs of the compounds of the present invention, and methods of treating disorders by administering pharmaceutically acceptable prodrugs of the compounds of the present invention. For example, compounds of the present invention having free amino groups, amide groups, hydroxy groups, or carboxylic acid groups can be converted into prodrugs. Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues, is covalently bonded to a free amino group, hydroxy group, or carboxylic acid group of a compound of the present invention by an amide or ester bond. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids commonly designated by three-letter symbols, and also include 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Additional types of prodrugs are also encompassed. For example, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups can be derivatized using groups including, but not limited to, hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as reviewed in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groups also include carbonate prodrugs, sulfonic acid esters, and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers is also encompassed, where the acyl group can be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functional groups, or the acyl group can be an amino acid ester as described above. This type of prodrug is described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides, or phosphonamides.All of these prodrug moieties may incorporate groups containing, but not limited to, ether, amine, and carboxylic acid functional groups. The combinations of substituents and variables contemplated by the present invention are only those that result in the formation of stable compounds.

[0087] Metastatic breast cancer, or metastasis, refers to breast cancer that has spread beyond the breast and nearby lymph nodes to other parts of the body, such as the bone, liver, lung, brain, etc. (https: / / www.cancer.org / cancer / breast-cancer.)

[0088] Locally advanced breast cancer (LABC) is defined by the National Comprehensive Cancer Network as a subset of breast cancer characterized by the most advanced breast tumors in the absence of distant metastasis, where the tumor is larger than 5 cm with associated regional lymph node disease, any size tumor that directly extends to the chest wall and / or skin, with or without associated regional lymph node disease (including ulceration or satellite nodules), regardless of tumor stage, and the presence of regional lymph node disease (clinically fixed or matted axillary lymph nodes, or any of supraclavicular, infraclavicular, or internal mammary lymph node disease). (Garg et al. Curr Oncol. October 2015;22(5):e409-e410; National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Fort Washington, PA: NCCN; 2015. Ver. 2. 2015.)

[0089] 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 require estrogen for growth and may stop growing or die when treated with substances that block the binding and action of estrogen. (https: / / www.cancer.gov / publications / dictionaries / cancer-terms / def / 44404.)

[0090] HER2-, human epidermal growth factor receptor 2, as used herein, refers to breast cancer cells that do not have large amounts of a protein called HER2 on their surface. In normal cells, HER2 helps control cell growth. Cancer cells that are HER2- grow more slowly and are less likely to recur or spread to other parts of the body than cancer cells that have large amounts of HER2 on their surface. (https: / / www.cancer.gov / publications / dictionaries / cancer-terms / def / her2-negative.)

[0091] As used herein, "treating" refers to the management and care of a subject to combat a disease, condition, or disorder and includes the alleviation or reduction of symptoms or complications, or the elimination of the disease, condition, or disorder.

[0092] As used herein, "preventing" refers to stopping the onset of symptoms or complications of a disease, condition, or disorder.

[0093] "Administering" refers to introducing an agent, such as a compound of formula (I), to a subject. The related terms "administer" and "administration of" (and grammatical equivalents) refer to both direct administration, which can be by a healthcare provider or self-administration by the subject, and / or indirect administration, which can be the act of prescribing the agent. For example, a physician who instructs a patient to self-administer an agent and / or provides a prescription for the agent to the patient is administering the agent to the patient.

[0094] As used herein, "therapeutically effective amount" means an amount of the free base of a compound of formula (I) that is sufficient to treat, ameliorate, or prevent a particular disease (e.g., breast cancer), the symptoms of a disease, disorder or condition, or to exert 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 can depend on the subject's weight, size, and health, the nature and extent of the condition, and whether additional therapeutic agents are administered to the subject. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0095] As used herein, "C max " refers to the maximum (peak) plasma concentration of a particular compound observed in a subject after administration of a dose of that compound to the subject.

[0096] As used herein, "AUC" refers to the total area under the plasma concentration-time curve, which is a measure of exposure to the 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·h / mL (ng×h / mL).

[0097] As used herein, "AUC tau " refers to the AUC from 0 hours to the end of the dosing interval.

[0098] As used herein with respect to the oral dosage forms of the present disclosure, "extended release" or "CR" means that the compound of formula (I) is released from the dosage form according to a predetermined profile, which can include when, where release occurs, and / or a specified release rate over a specified period after oral administration. Extended release can be contrasted with unregulated or immediate release.

[0099] As used herein with respect to the oral dosage forms of the present disclosure, "sustained release agent" refers to one or more substances or materials that regulate the release of the compound of formula (I) from the dosage form. The sustained release agent can be an organic or inorganic, natural or synthetic material, such as a polymeric material, triglyceride, derivative of triglyceride, fatty acid and salt of fatty acid, talc, boric acid and colloidal silica.

[0100] As used herein, "oral dosage form" refers to a pharmaceutical product containing a specific amount (dose) of the compound of formula (I) as an active ingredient, or a pharmaceutically acceptable salt and / or solvate thereof, and an inactive ingredient (excipient), formulated into a specific configuration suitable for oral administration and drug delivery, such as tablets, capsules, or liquid oral formulations. In one embodiment, the composition is in the form of a tablet that can be scored.

[0101] The term "carrier" as used in the present disclosure includes carriers, excipients, and diluents, and means a material, composition, or vehicle such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material that is involved in the transport or conveyance of a pharmaceutical from one organ or part of the body of a subject to another organ or part of the body.

[0102] 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 between X - 10% and X + 10%. Thus, for example, a weight of about 40 g includes weights between 36 g and 44 g.

[0103] As used herein to describe a particular dosage form, composition, use, method, or process, "comprising" or "comprises" when applied to such a dosage form, composition, use, method, or process means that the dosage form, composition, use, method, or process includes all of the elements recited in a particular description or claim, but does not exclude other elements. "Consists essentially of" and "consisting essentially of" mean that a described or claimed composition, dosage form, method, use, or process excludes other materials or steps that do not substantially affect the recited physical, pharmacological, pharmacokinetic properties, or therapeutic effects of the composition, dosage form, method, use, or process. "Consists of" and "consisting of" mean the exclusion of trace amounts of other components and anything in excess of substantial method or process steps.

[0104] As used herein to describe a subject, "fasting condition" or "fasting state" means that the subject has not consumed a meal for at least 4 hours prior to the point of interest, such as the time of administration of a compound of formula (I). In one embodiment, a subject in a fasting state has not consumed a meal for at least 6, 8, 10, or 12 hours prior to administration of a compound of formula (I).

[0105] As used herein to describe a subject, "fed condition" or "fed state" means that the subject has consumed a meal less than at least 4 hours prior to the point of interest, such as the time of administration of a compound of formula (I). In one embodiment, a subject in a fed state has consumed a meal at most 4, 3, 2, 1, or 0.5 hours prior to administration of a compound of formula (I).

[0106] As used herein, "Tween 80" refers to polyoxyethylene (20) sorbitan monooleate, and sorbitan, mono-9-octadecenoate, poly(oxy-1,2-ethanediyl) derivatives, also known as polysorbate 80 as (Z).

[0107] 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.

[0108] As used herein, the term "CDK4 / 6 inhibitor" refers to a compound that inhibits human enzymes called cyclin-dependent kinases (CDK) 4 and 6. Examples of CDK4 / 6 inhibitors include, but are not limited to, SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, or any pharmaceutically acceptable salt thereof. In one embodiment, the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof.

[0109] The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., at least one) grammatical object of the article. As an example, "an element" means one element or more than one element.

[0110] The term "and / or" is used in this disclosure to mean either "and" or "or" unless otherwise indicated.

[0111] The terms "patient" and "subject" are used interchangeably herein and refer to a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or macaque.

[0112] In one embodiment, the subject is a human.

[0113] In one embodiment, the subject is a human diagnosed with breast cancer.

[0114] In one embodiment, the subject is a human diagnosed with metastatic breast cancer.

[0115] In one embodiment, the subject is a human diagnosed with ER+, HER2-breast cancer.

[0116] In one embodiment, the subject is a human diagnosed with metastatic ER+, HER2-breast cancer.

[0117] The compound of formula (I) In one aspect, the present application relates to a method of treating and / or preventing cancer comprising administering a compound of formula (I) to a subject in need thereof.

[0118] In one aspect, the present application relates to the use of a compound of formula (I) in the treatment and / or prevention of breast cancer.

[0119] In one aspect, the present application relates to the use of a compound of formula (I) in the manufacture of a medicament for the treatment and / or prevention of breast cancer.

[0120] As referred to herein, the compound of formula (I) has the following structure: A compound having TIFF2025094174000031.tif55128, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, wherein, each R 1 and each R 2is independently selected from the group consisting of halo, OR5, N(R5)(R6), NO2, CN, SO2(R5), C1-C6 alkyl, and C3-C6 cycloalkyl, R3 and R4 are both hydrogen or together with the carbon to which they are attached form a carbonyl, each R5 and each R6 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl, m is 0, 1, 2, 3, 4, or 5, and n is 0, 1, 2, 3, or 4.

[0121] In one embodiment, each R 1 and each R 2 is independently selected from the group consisting of halo, OR5, and C1-C6 alkyl.

[0122] In one embodiment, R 1 is hydrogen, halo, OR5, N(R5)(R6), or C1-C6 alkyl. In one embodiment, R 1 is hydrogen. In one embodiment, R 1 is halo. In one embodiment, R 1 is OR5. In one embodiment, R 1 is N(R5)(R6). In one embodiment, R 1 is C1-C6 alkyl.

[0123] In one embodiment, R 2 is hydrogen, halo, OR5, N(R5)(R6), or C1-C6 alkyl. In one embodiment, R 2 is hydrogen. In one embodiment, R 2 is halo. In one embodiment, R 2 is OR5. In one embodiment, R 2 is N(R5)(R6). In one embodiment, R 2 is C1-C6 alkyl.

[0124] In one embodiment, R3 and R4 are both hydrogen.

[0125] In one embodiment, R3 and R4, together with the carbon to which they are attached, form a carbonyl.

[0126] In one embodiment, each R5 and each R6 are independently selected from the group consisting of hydrogen and C1-C6 alkyl. In one embodiment, R5 and R6 are each hydrogen.

[0127] In one embodiment, m is 0.

[0128] In one embodiment, m is 1.

[0129] In one embodiment, m is 2.

[0130] In one embodiment, m is 3.

[0131] In one embodiment, m is 4.

[0132] In one embodiment, m is 5.

[0133] In one embodiment, n is 0.

[0134] In one embodiment, n is 1.

[0135] In one embodiment, n is 2.

[0136] In one embodiment, n is 3.

[0137] In one embodiment, n is 4.

[0138] In one embodiment, m and n are each 0.

[0139] In one embodiment, m is 0 and n is 1.

[0140] In one embodiment, m is 1 and n is 0.

[0141] In one embodiment, m is 1 and n is 1.

[0142] In one embodiment, the compound of formula (I) is TIFF2025094174000032.tif43128TIFF2025094174000033.tif187128TIFF2025094174000034.tif179128 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0143] In one embodiment, the compound of formula (I) is a compound of formula (I-a): TIFF2025094174000035.tif43128 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0144] In one embodiment, the compound of formula (I) is a compound of formula (I-b): TIFF2025094174000036.tif46128 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0145] In one embodiment, the compound of formula (I) is a compound of formula (I-c), i.e., compound (I-c) or Cmp(I-c): TIFF2025094174000037.tif46128 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0146] In one embodiment, the compound of formula (I) is a compound of formula (I-c), i.e., compound (I-c) or Cmp(I-c): TIFF2025094174000038.tif46128.

[0147] In one embodiment, the compound of formula (I) is a compound of formula (I-d): TIFF2025094174000039.tif46128 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0148] In one embodiment, the compound of formula (I) is a compound of formula (I-e): TIFF2025094174000040.tif43128 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0149] In one embodiment, the compound of formula (I) is a compound of formula (I-f): TIFF2025094174000041.tif43128 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0150] In one embodiment, the compound of formula (I) is a compound of formula (I-g): TIFF2025094174000042.tif38133 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0151] In one embodiment, the compound of formula (I) is a compound of formula (I-h): TIFF2025094174000043.tif46128 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0152] In one embodiment, the compound of formula (I) is a compound of formula (I-i): TIFF2025094174000044.tif46128 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0153] The compounds of formula (I) can be synthesized in the context of the present disclosure using standard synthetic methods and procedures for the preparation of organic molecules, as well as for the conversion and manipulation of functional groups, including the use of protecting groups, as can be obtained from relevant scientific literature or standard reference textbooks in the art. Without being limited to any one or several sources, recognized reference textbooks on organic synthesis include Smith, M.B.; March, J. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th ed.; John Wiley & Sons: New York, 2001; and Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 3 rd ed.; John Wiley & Sons: New York, 1999. Methods for preparing the compounds of formula (I) are described in U.S. Patent Application Publication No. 2018 / 0155322, issued as U.S. Patent No. 10,647,698, the contents of which are hereby incorporated by reference in their entirety.

[0154] For example, compounds (I-b) and (I-c) may be prepared according to the procedures described below.

[0155] Synthesis of 3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (Compound (I-b)): Step 1: Preparation of 6-tert-butoxytetralin-1-one TIFF2025094174000045.tif19128

[0156] To a stirred solution of 6-hydroxytetralin-1-one (50 g, 308.29 mmol, 1 equiv) in anhydrous dichloromethane (2000 mL) at 0 °C was added tert-butyl 2,2,2-trichloroethanimidate (67.36 g, 308.29 mmol, 55 mL, 1 equiv) and pyridinium para-toluenesulfonate (7.75 g, 30.83 mmol, 0.1 equiv). The reaction mixture was stirred at 10 °C for 3 h. Tert-butyl 2,2,2-trichloroethanimidate (67.36 g, 308.29 mmol, 55 mL, 1 equiv) and pyridinium para-toluenesulfonate (7.75 g, 30.83 mmol, 0.1 equiv) were added additionally, and the reaction mixture was stirred at 10 °C for 15 h. This process was repeated three times. Thin layer chromatography (petroleum ether:ethyl acetate = 3:1, R f = 0.8) indicated that most of the reactants still remained, and the reaction mixture was stirred at 10 °C for 72 h. The reaction mixture was quenched by adding sodium bicarbonate solution (1500 mL) at 15 °C, and then extracted with dichloromethane (300 mL × 3). The combined organic layers were washed with brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 100:1 - 50:1) to give 6-tert-butoxytetralin-1-one (21 g, 96.20 mmol, 31% yield) as a yellow oil. 1 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.8 Hz, 1H), 6.91 (dd, J = 2.4, 8.8 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H), 2.93 - 3.90 (t, J = 6.0 Hz, 2H), 2.63 - 2.60 (m, t, J = 6.0 Hz, 2H), 2.13 (m, 2H), 1.43 (s, 9H).

[0157] Step 2: Preparation of (6-tert-butoxy-3,4-dihydronaphthalen-1-yl) trifluoromethanesulfonate TIFF2025094174000046.tif17128

[0158] To a solution of 6-tert-butoxytetralin-1-one (40 g, 183.24 mmol, 1 equiv) in tetrahydrofuran (500 mL) was added lithium diisopropylamide (2 M, 137 mL, 1.5 equiv) at -70 °C. The mixture was stirred at -70 °C for 1 h, and then a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (72.01 g, 201.56 mmol, 1.1 equiv) in tetrahydrofuran (200 mL) was added dropwise to the mixture. The reaction mixture was stirred at 20 °C for 2 h. Thin layer chromatography (petroleum ether:ethyl acetate = 5:1) indicated the completion of the reaction. Saturated ammonium chloride (300 mL) was added to the mixture, and the organic layer was separated. Ethyl acetate (500 mL x 3) was added to the mixture, and the resulting mixture was washed with brine (1000 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:0 - 50:1) to give (6-tert-butoxy-3,4-dihydronaphthalen-1-yl)trifluoromethanesulfonate (52 g, 144.64 mmol, yield 78%, purity 97%) as a yellow oil. LC-MS (ESI) m / z: 294.9 [M+1-56] + 。 1 1H-NMR (400 MHz, CDCl3) δ: 7.30 (d, J = 6.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.84 (s, 1H), 5.95 (s, 1H), 2.93 - 2.78 (m, 2H), 2.59 - 2.46 (m, 2H), 1.42 (s, 9H).

[0159] Step 3: Preparation of 4-(6-tert-butoxy-3,4-dihydronaphthalen-1-yl)phenol TIFF2025094174000047.tif19128

[0160] (6-tert-Butoxy-3,4-dihydronaphthalen-1-yl)trifluoromethanesulfonate (52 g, 148.42 mmol, 1 equiv), (4-hydroxyphenyl)boronic acid (24.57 g, 178.11 mmol, 1.2 equiv) were added to a solution of dioxane (800 mL) and water (150 mL), followed by potassium carbonate (41.03 g, 296.84 mmol, 2 equiv) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (10.86 g, 14.84 mmol, 0.1 equiv) under nitrogen. The reaction mixture was stirred at 100 °C for 10 h. Thin layer chromatography (petroleum ether:ethyl acetate = 5:1) indicated the completion of the reaction. The residue was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 2). The combined organic layers were washed with brine (1000 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:tetrahydrofuran = 50:1 - 20:1) to afford 4-(6-tert-butoxy-3,4-dihydronaphthalen-1-yl)phenol (43 g, 131.46 mmol, 88% yield, 90% purity) as a yellow oil. LCMS (ESI) m / z: 239.1 [M+1-56] + ; 1 1H-NMR (400 MHz, CDCl3) δ 7.23 (d, J = 7.6 Hz, 2H), 6.91 (d, J = 8.0 Hz, 1H), 6.87 - 6.79 (m, 3H), 6.73 (d, J = 8.4 Hz, 1H), 5.95 (s, 1H), 4.83 - 4.75 (m, 1H), 2.87 - 2.73 (m, 2H), 2.44 - 2.31 (m, 2H), 1.37 (s, 9H).

[0161] Step 4: Preparation of 4-(2-bromo-6-tert-butoxy-3,4-dihydronaphthalen-1-yl)phenol TIFF2025094174000048.tif27128

[0162] A solution of 4-(6-tert-butoxy-3,4-dihydronaphthalen-1-yl)phenol (1 g, 3.06 mmol, 1 equiv) in acetonitrile (20 mL) was added N-bromosuccinimide (489 mg, 2.75 mmol, 0.9 equiv) in three portions. The reaction mixture was stirred at 20 °C for 1.5 h. LC-MS indicated that the reaction was complete. The residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:0 - 20:1) to give 4-(2-bromo-6-tert-butoxy-3,4-dihydronaphthalen-1-yl)phenol (1 g, 2.46 mmol, 80% yield, 91% purity) as a yellow oil. LC-MS (ESI) m / z: 316.9 [M+1-56] + ; 1 1H-NMR (400 MHz, CDCl3) δ 7.12 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 6.77 (s, 1H), 6.69 - 6.62 (m, 1H), 6.60 - 6.53 (m, 1H), 4.86 (s, 1H), 2.96 (s, 4H), 1.35 (s, 9H).

[0163] Step 5: Preparation of 4-(6-tert-butoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenol TIFF2025094174000049.tif24128

[0164] 4-(2-Bromo-6-tert-butoxy-3,4-dihydronaphthalen-1-yl)phenol (1 g, 2.46 mmol, 1 equiv), phenylboronic acid (314 mg, 2.58 mmol, 1.05 equiv) were added to a solution of dioxane (10 mL) and water (2 mL), followed by potassium carbonate (678 mg, 4.91 mmol, 2 equiv) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (179 mg, 0.24 mmol, 0.1 equiv) under nitrogen. The reaction mixture was stirred at 100 °C for 12 h. LC-MS indicated the completion of the reaction. The residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:0 - 10:1) to afford 4-(6-tert-butoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenol (930 mg, 2.35 mmol, 95% yield, 93% purity) as an orange oil. LCMS (ESI) m / z: 314.1 [M+1-56] + ; 1 1H-NMR (400 MHz, CDCl3) δ 7.16 - 7.09 (m, 2H), 7.08 - 6.99 (m, 3H), 6.97 - 6.89 (m, 2H), 6.86 - 6.82 (m, 1H), 6.74 - 6.66 (m, 4H), 4.70 (s, 1H), 2.99 - 2.89 (m, 2H), 2.84 - 2.75 (m, 2H), 1.37 (s, 9H).

[0165] Step 6: Preparation of 4-(6-tert-butoxy-2-phenyl-tetralin-1-yl)phenol TIFF2025094174000050.tif24128

[0166] To a solution of 4-(6-tert-butoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenol (930 mg, 2.35 mmol, 1 equiv) in tetrahydrofuran (20 mL) and methanol (4 mL) was added palladium on carbon catalyst (100 mg, 10% purity) under nitrogen. The suspension was degassed under vacuum and purged three times with hydrogen. The mixture was stirred at 30 °C for 36 h under hydrogen (50 psi). LC-MS indicated that the reaction was complete. The reaction mixture was filtered and the solution was concentrated. The resulting material was used directly in the next step without further purification to give cis-4-(6-tert-butoxy-2-phenyl-tetralin-1-yl)phenol (870 mg, 2.14 mmol, 91% yield, 91% purity) as a white solid. LC-MS (ESI) m / z: 317.0 [M+1-56] + ; 1 1H-NMR (400 MHz, CDCl3) δ 7.22 - 7.12 (m, 3H), 6.89 - 6.78 (m, 4H), 6.74 (dd, J = 2.0, 8.4 Hz, 1H), 6.45 (d, J = 8.4 Hz, 2H), 6.27 (d, J = 8.4 Hz, 2H), 4.51 (s, 1H), 4.25 (d, J = 4.8 Hz, 1H), 3.38 (dd, J = 3.2, 12.8 Hz, 1H), 3.08 - 2.99 (m, 2H), 2.27 - 2.08 (m, 1H), 1.87 - 1.76 (m, 1H), 1.37 (s, 9H).

[0167] Step 7: Preparation of 4-[(1S,2R)-6-tert-butoxy-2-phenyl-tetralin-1-yl]phenol TIFF2025094174000051.tif24128

[0168] 4-(6-tert-Butoxy-2-phenyl-tetralin-1-yl)phenol (870 mg, 2.13 mmol, 1 equiv) was subjected to chiral separation by supercritical fluid chromatography (column: AD, 250 mm × 30 mm, 5 μm; mobile phase: methanol solution of 0.1% ammonium hydroxide, 20% - 20%, 4.2 minutes for each run), and 4-[(1S,2R)-6-tert-butoxy-2-phenyl-tetralin-1-yl]phenol (420 mg, 1.04 mmol, yield 97%, purity 92%) was obtained as the first fraction, and 4-[(1R,2S)-6-tert-butoxy-2-phenyl-tetralin-1-yl]phenol (420 mg, 1.04 mmol, yield 97%, purity 92%) was obtained as the second fraction. Fraction 1: [α] D = +336.9 (in ethyl acetate, C = 0.50 g / 100 mL, 25 °C), LC-MS (ESI) m / z: 395.1 [M + 23] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 7.20 - 7.07 (m, 3H), 6.87 - 6.79 (m, 3H), 6.79 - 6.72 (m, 1H), 6.71 - 6.64 (m, 1H), 6.36 (d, J = 8.4 Hz, 2H), 6.15 (d, J = 8.4 Hz, 2H), 4.19 (d, J = 4.8 Hz, 1H), 3.31 - 3.26 (m, 1H), 3.09 - 2.89 (m, 2H), 2.17 - 2.04 (m, 1H), 1.79 - 1.65 (m, 1H), 1.29 (s, 9H). Fraction 2: [α] D = -334.1 (in ethyl acetate, C = 0.50 g / 100 mL, 25 °C), LC-MS (ESI) m / z: 395.2 [M + 23] + ; 1 H-NMR (400 MHz, DMSO-d6) δ: 9.02 (s, 1H), 7.21 - 7.06 (m, 3H), 6.88 - 6.78 (m, 3H), 6.78 - 6.72 (m, 1H), 6.71 - 6.64 (m, 1H), 6.36 (d, J = 8.4 Hz, 2H), 6.15 (d, J = 8.4 Hz, 2H), 4.19 (d, J = 4.8 Hz, 1H), 3.30 - 3.27 (m, 1H), 3.08 - 2.90 (m, 2H), 2.16 - 2.04 (m, 1H), 1.79 - 1.65 (m, 1H), 1.29 (s, 9H).

[0169] Step 8: Preparation of [4-[(6-benzyloxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenyl]1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate TIFF2025094174000052.tif32128

[0170] To a solution of 4-[(1R,2S)-6-tert-butoxy-2-phenyl-tetralin-1-yl]phenol (1 g, 2.68 mmol, 1 equiv) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (811 mg, 2.68 mmol, 1 equiv) in tetrahydrofuran (5 mL) and acetonitrile (5 mL) was added potassium carbonate (557 mg, 4.03 mmol, 1.5 equiv). The reaction mixture was stirred at 25 °C for 16 h. TLC (petroleum ether:ethyl acetate = 10:1) indicated that the starting material was completely consumed and one new spot was formed. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:0 to 50:1). The desired compound, [4-[(1R,2S)-6-tert-butoxy-2-phenyl-tetralin-1-yl]phenyl]1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (1.6 g, 2.44 mmol, 91% yield) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.21 - 7.11 (m, 3H), 6.94 - 6.86 (m, 3H), 6.84 - 6.73 (m, 4H), 6.46 (d, J = 8.8 Hz, 2H), 4.33 (d, J = 5.2 Hz, 1H), 3.50 - 3.40 (m, 1H), 3.16 - 2.95 (m, 2H), 2.20 - 2.02 (m, 1H), 1.91 - 1.79 (m, 1H), 1.38 (s, 9H).

[0171] Step 9: Preparation of 1-[4-(6-benzyloxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenyl]-4-(dimethoxymethyl)piperidine TIFF2025094174000053.tif32128

[0172] [4-[(1R,2S)-6-tert-Butoxy-2-phenyl-tetralin-1-yl]phenyl] 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (1.6 g, 2.44 mmol, 1 equiv), 4-(dimethoxymethyl)piperidine (584 mg, 3.67 mmol, 1.5 equiv), sodium tert-butoxide (705 mg, 7.33 mmol, 3 equiv), palladium acetate (82 mg, 0.37 mmol, 0.15 equiv), and dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl (233 mg, 0.49 mmol, 0.2 equiv) in toluene (30 mL) were degassed and purged three times with nitrogen, and then the mixture was stirred at 90 °C for 16 h under a nitrogen atmosphere. LC-MS showed that one main peak with the desired MS was detected. TLC (petroleum ether:ethyl acetate = 10:1) showed that the starting material was completely consumed and one new spot was formed. The mixture was cooled, diluted with ethyl acetate (50 mL), filtered through a diatomaceous earth plug, and the filter cake was washed with ethyl acetate (30 mL). The filtrate was concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1). The desired compound, 1-[4-[(1R,2S)-6-tert-butoxy-2-phenyl-tetralin-1-yl]phenyl]-4-(dimethoxymethyl)piperidine (1.1 g, 2.14 mmol, 87% yield), was obtained as a white solid. LC-MS (ESI) m / z: 514.3 [M+1] + ; 11H NMR (400 MHz, CDCl3) δ 7.21 - 7.11 (m, 3H), 6.88 - 6.78 (m, 4H), 6.73 (dd, J = 2.4, 8.0 Hz, 1H), 6.57 (d, J = 8.4 Hz, 2H), 6.27 (d, J = 8.8 Hz, 2H), 4.23 (d, J = 4.8 Hz, 1H), 4.06 (d, J = 7.2 Hz, 1H), 3.63 - 3.52 (m, 2H), 3.41 - 3.30 (m, 7H), 3.13 - 2.96 (m, 2H), 2.54 (d, J = 2.0, 12.0 Hz, 2H), 2.28 - 2.10 (m, 1H), 1.85 - 1.63 (m, 4H), 1.49 - 1.31 (m, 11H).

[0173] Step 10: Preparation of 1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]piperidine-4-carbaldehyde TIFF2025094174000054.tif29128

[0174] To a solution of 1-[4-[(1R,2S)-6-tert-butoxy-2-phenyl-tetralin-1-yl]phenyl]-4-(dimethoxymethyl)piperidine (1.1 g, 2.14 mmol, 1 equiv) in tetrahydrofuran (45 mL) was added sulfuric acid (2 M, 43 mL, 40 equiv). The reaction mixture was stirred at 70 °C for 1 hour. LC (petroleum ether:ethyl acetate = 3:1) indicated that the starting material was completely consumed and one new spot was formed. The reaction mixture was quenched to pH = about 7 - 8 by adding saturated sodium bicarbonate solution and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used in the next step without further purification. The desired compound, 1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]piperidine-4-carbaldehyde (900 mg, 2.14 mmol, 99% yield, 97% purity), was obtained as a light yellow solid. LCMS MS (ESI) m / z: 412.1 [M+1] + .

[0175] Preparation of 3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (Compound (I-b)) TIFF2025094174000055.tif30133

[0176] To a solution of 3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione hydrochloride (319 mg, 0.87 mmol, prepared in Step 17 as described for Exemplary Compound 62) in methanol (4 mL) and dichloromethane (4 mL) was added sodium acetate (120 mg, 1.46 mmol, 2 equiv). The mixture was stirred at 20 °C for 0.5 h, and then to the mixture were added 1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]piperidine-4-carbaldehyde (300 mg, 0.73 mmol, 1 equiv) and sodium cyanoborohydride (137 mg, 2.19 mmol, 3 equiv). The mixture was stirred at 20 °C for 12 h. LC-MS indicated that the starting material was completely consumed and one main peak with the desired MW was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (Phenomenex luna C18 column, 250x50 mm, 10um; mobile phase: [water (0.05% HCl)-acetonitrile]; B%: 10% - 40% acetonitrile, 30 min). The desired compound, 3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (288.4 mg, 0.37 mmol, 51% yield) was obtained as a white solid hydrochloride salt. LC-MS (ESI) m / z: 724.4 [M+1] + ; 11H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.83 (s, 0.9H, HCl), 7.60 (d, J = 8.5 Hz, 1H), 7.40 (br s, 2H), 7.22 - 7.11 (m, 5H), 6.83 (d, J = 6.0 Hz, 2H), 6.69 - 6.63 (m, 2H), 6.58 - 6.47 (m, 3H), 5.07 (dd, J = 5.2, 13.2 Hz, 1H), 4.41 - 4.30 (m, 2H), 4.28 - 4.21 (m, 1H), 4.00 (d, J = 12.7 Hz, 2H), 3.61 (d, J = 11.0 Hz, 2H), 3.54 - 3.36 (m, 6H), 3.16 (br s, 4H), 3.06 - 2.84 (m, 3H), 2.76 - 2.53 (m, 1H), 2.43 - 2.33 (m, 1H), 2.27 (br s, 1H), 2.16 - 2.04 (m, 3H), 2.02 - 1.69 (m, 5H).

[0177] Synthesis of (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (Compound (I-c))

[0178] Step 1: Preparation of tert-butyl (4S)-5-amino-4-(benzyloxycarbonylamino)-5-oxo-pentanoate TIFF2025094174000056.tif21128(2S)-2-(Benzyloxycarbonylamino)-5-tert-butoxy-5-oxo-pentanoic acid (20 g, 59.28 mmol, 1.00 eq), di-tert-butyl dicarboxylate (94.85 mmol, 21.79 mL, 1.60 eq) and pyridine (9.38 g, 118.57 mmol, 9.57 mL, 2.00 eq) in 1,4-dioxane (200 mL) were degassed at 0 °C and purged with nitrogen three times. The mixture was then stirred at 0 °C for 0.5 h under a nitrogen atmosphere. Ammonium bicarbonate (14.06 g, 177.85 mmol, 14.65 mL, 3.00 eq) was added at 0 °C. The mixture was stirred at 25 °C for 16 h. LC-MS showed the desired mass. The volatile components were removed under reduced pressure. The residue was diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 1). The combined organic phases were washed with aqueous hydrochloric acid (0.5 M, 200 mL x 2), saturated sodium bicarbonate (300 mL x 3), and brine (500 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was triturated (petroleum ether:ethyl acetate = 10:1, 300 mL) to give tert-butyl (4S)-5-amino-4-(benzyloxycarbonylamino)-5-oxo-pentanoate (19 g, 56.08 mmol, yield 94%, purity 99%) as a white solid. LC-MS (ESI) m / z: 359.0 [M+23] + 。 1 1H-NMR (400 MHz, CDCl3) δ 7.39 - 7.29 (m, 5H), 6.38 (s, 1H), 5.74 (d, J = 7.2 Hz, 1H), 5.58 (s, 1H), 5.11 (s, 2H), 4.25 (d, J = 5.6 Hz, 1H), 2.55 - 2.41 (m, 1H), 2.39 - 2.27 (m, 1H), 2.18 - 2.04 (m, 1H), 2.02 - 1.85 (m, 1H), 1.45 (s, 9H).

[0179] Step 2: Preparation of tert-butyl (4S)-4,5-diamino-5-oxo-pentanoate TIFF2025094174000057.tif21128

[0180] To a solution of tert-butyl (4S)-5-amino-4-(benzyloxycarbonylamino)-5-oxopentanoate (19 g, 56.48 mmol, 1.00 eq) in methanol (200 mL) was added palladium carbon (2 g, 10%) under a nitrogen atmosphere. The suspension was degassed and purged three times with hydrogen. The mixture was stirred at 25 °C for 16 h under H2 (50 psi). Thin layer chromatography (petroleum ether:ethyl acetate = 1:2) indicated the completion of the reaction. The reaction mixture was filtered and the filtrate was concentrated. tert-Butyl (4S)-4,5-diamino-5-oxopentanoate (11 g, 54.39 mmol, 96% yield) of the compound was obtained as a bright green oil. 1 1H NMR (400 MHz, CDCl3) δ 7.03 (br s, 1H), 5.55 (br s, 1H), 3.44 (br s, 1H), 2.49 - 2.31 (m, 2H), 2.11 (dd, J = 6.0, 12.8 Hz, 1H), 1.92 - 1.76 (m, 1H), 1.66 (s, 2H), 1.45 (s, 9H).

[0181] Step 3: Preparation of tert-butyl 4-[2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxobutyl]-1-oxoisoindolin-5-yl]piperazine-1-carboxylate A solution of tert-butyl [3-(bromomethyl)-4-methoxycarbonyl-phenyl]piperazine-1-carboxylate (1.5 g, 3.63 mmol, 1 equiv, exemplified compound 62 of US Patent Application Publication No. 2018 / 0155322, prepared in step 15) in acetonitrile (30 mL) was added with tert-butyl (4S)-4,5-diamino-5-oxo-pentanoate (1.10 g, 5.44 mmol, 1.5 equiv) and diisopropylethylamine (1.41 g, 10.89 mmol, 1.90 mL, 3 equiv). The mixture was stirred at 80 °C for 12 h. LC-MS indicated that the reaction was complete. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative reverse-phase HPLC (column: Phenomenex Synergi Max-RP 250x50 mm, 10 micron; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 40% acetonitrile to 70% acetonitrile, 30 min) to give tert-butyl 4-[2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (1.6 g, 2.94 mmol, yield 81.05%, purity 92%) as an off-white solid. LC-MS (ESI) m / z: 503.2 [M+1] + .

[0182] Step 4: Preparation of (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione TIFF2025094174000059.tif241304 - [2 - [(1S) - 4 - tert - butoxy - 1 - carbamoyl - 4 - oxo - butyl] - 1 - oxo - isoindolin - 5 - yl]piperazine - 1 - carboxylic acid tert - butyl (700 mg, 1.39 mmol, 1 equiv) in acetonitrile (15 mL) was added benzenesulfonic acid (440 mg, 2.79 mmol, 2 equiv). The mixture was stirred at 85 °C for 12 h. LC - MS indicated that the reaction was complete. The mixture was concentrated in vacuo. The residue was triturated with ethyl acetate (30 mL x 3) to give (3S) - 3 - (1 - oxo - 5 - piperazin - 1 - yl - isoindolin - 2 - yl)piperidine - 2,6 - dione (630 mg, crude) as a gray solid. LC - MS (ESI) m / z: 329.1 [M + 1] + ; Chiral SFC analysis showed 100% ee.

[0183] Step 5: Preparation of (3S) - 3 - [5 - [4 - [[1 - [4 - [(1R,2S) - 6 - hydroxy - 2 - phenyl - tetralin - 1 - yl]phenyl] - 4 - piperidyl]methyl]piperazin - 1 - yl] - 1 - oxo - isoindolin - 2 - yl]piperidine - 2,6 - dione (Compound (I - c)) TIFF2025094174000060.tif43143(3S)-3-(1-Oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (1.30 g, 3.47 mmol, 1 equiv, benzenesulfonate) in a mixture of dichloromethane (8 mL) and methanol (32 mL) was added sodium acetate (854 mg, 10.41 mmol, 3 equiv) at 20 °C in one portion. The mixture was stirred at 20 °C for 10 min. Then, 1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]piperidine-4-carbaldehyde (1 g, 2.43 mmol, 0.7 equiv, prepared as described above in the synthesis of compound (I-b)) was added. The mixture was stirred at 20 °C for 10 min. Thereafter, acetic acid (0.2 mL) and sodium cyanoborohydride (436 mg, 6.94 mmol, 2 equiv) were added at once. The mixture was stirred at 20 °C for 40 min. The mixture was concentrated in vacuo, and 50 mL of tetrahydrofuran and 20 mL of water were added. The mixture was stirred for 20 min. Saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8 - 9. The aqueous phase was extracted with ethyl acetate and tetrahydrofuran (v:v = 2:1, 60 mL x 3). The combined organic phases were washed with brine (60 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative reverse-phase HPLC (column: Phenomenex luna C18 250x50 mm, 10 micron; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 20% - 50%, 30 min). The product, (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (964 mg, 1.23 mmol, yield 35%, purity 98%, formate) was obtained as a white solid of the formate after lyophilization. The chiral purity was analyzed by chiral SFC (Chiralcel OJ-3 50×4.6 mm, 3 micron; mobile phase: 50% ethanol (0.05% DEA) in CO2; flow rate: 3 mL / min, wavelength: 220 nm), t p= 2.89 min, observed at over 95%. [α D = -267.5 (in DMF, c = 0.2, 25 °C). LC-MS (ESI) m / z: 724.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.16 (s, 1H, formate), 7.51 (d, J = 8.8 Hz, 1H), 7.21 - 6.98 (m, 5H), 6.83 (d, J = 6.4 Hz, 2H), 6.68 - 6.57 (m, 2H), 6.56 - 6.44 (m, 3H), 6.20 (d, J = 8.8 Hz, 2H), 5.04 (dd, J = 5.2, 13.2 Hz, 1H), 4.32 (d, J = 16.8 Hz, 1H), 4.19 (d, J = 17.2 Hz, 1H), 4.12 (d, J = 4.8 Hz, 1H), 3.51 (br d, J = 10.0 Hz, 4H), 3.27 (br s, 8H), 3.03 - 2.82 (m, 3H), 2.63 - 2.54 (m, 1H), 2.43 - 2.28 (m, 2H), 2.19 (d, J = 6.8 Hz, 2H), 2.15 - 2.02 (m, 1H), 2.01 - 1.89 (m, 1H), 1.83 - 1.51 (m, 4H), 1.28 - 1.04 (m, 2H).

[0184] Free non-salt form of 11H-NMR: (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.09 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.18 - 7.09 (m, 3H), 7.08 - 7.02 (m, 2H), 6.83 (d, J = 6.4 Hz, 2H), 6.64 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 6.53 (d, J = 8.8 Hz, 2H), 6.48 (dd, J = 2.4, 8.4 Hz, 1H), 6.20 (d, J = 8.8 Hz, 2H), 5.04 (dd, J = 5.2, 13.2 Hz, 1H), 4.39 - 4.27 (m, 1H), 4.24 - 4.15 (m, 1H), 4.12 (d, J = 4.8 Hz, 1H), 3.51 (d, J = 9.6 Hz, 2H), 3.29 - 3.24 (m, 5H), 3.03 - 2.83 (m, 3H), 2.62 - 2.54 (m, 4H), 2.52 (s, 3H), 2.41 - 2.36 (m, 1H), 2.19 (d, J = 7.2 Hz, 2H), 2.15 - 2.08 (m, 1H), 2.00 - 1.89 (m, 1H), 1.81 - 1.58 (m, 4H), 1.22 - 1.06 (m, 2H).

[0185] Palbociclib Palbociclib, also known as 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, has the following structural formula: It has TIFF2025094174000061.tif50128.

[0186] Palbociclib is an inhibitor of cyclin-dependent kinases (CDKs) 4 and 6. Cyclin D1 and CDK4 / 6 are downstream of the signaling pathway leading to cell proliferation. In vitro, palbociclib decreased the cell proliferation of estrogen receptor (ER)-positive breast cancer cell lines by blocking the progression of cells from the G1 to the S phase of the cell cycle. Treatment of breast cancer cell lines with the combination of palbociclib and anti-estrogen resulted in a decrease in the phosphorylation of the retinoblastoma (Rb) protein, which in turn led to a decrease in E2F expression and signaling and an increase in growth arrest compared to treatment with each agent alone. Treatment of ER-positive breast cancer cell lines in vitro with the combination of palbociclib and anti-estrogen increased cellular senescence compared to each agent alone, which persisted for up to 6 days after removal of palbociclib and was higher when anti-estrogen treatment was continued. In an in vivo study using a patient-derived ER-positive breast cancer xenograft model, it was demonstrated that the combination of palbociclib and letrozole increased the inhibition of Rb phosphorylation, downstream signaling, and tumor growth compared to each agent alone.

[0187] Human bone marrow mononuclear cells treated with palbociclib in vitro in the presence or absence of anti-estrogen did not senesce and resumed proliferation after discontinuation of palbociclib.

[0188] In one embodiment, the present application relates to any of the methods for treating and / or preventing breast cancer disclosed herein, wherein the method comprises co-administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof, or co-administering to a subject in need thereof a therapeutically effective amount of a combination of a compound of formula (I-c) or a pharmaceutically acceptable salt thereof and a CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of formula (I-c) is a free base or a pharmaceutically acceptable salt thereof. In one embodiment, the CDK4 / 6 inhibitor is a free base or a pharmaceutically acceptable salt thereof. In one embodiment, the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof. In one embodiment, the CDK4 / 6 inhibitor is palbociclib dihydrochloride. Palbociclib dihydrochloride can be prepared, for example, by the reaction of palbociclib free base in an ether solution of hydrogen chloride. Palbociclib is a commercially available agent for the treatment of breast cancer developed by Pfizer and sold under the brand name Ibrance(registered trademark).

[0189] Method for ubiquitinating / degrading a target protein in a cell The present invention provides a method for ubiquitinating / degrading a target protein in a cell (e.g., an intracellular target protein). The method preferably comprises administering a bifunctional compound comprising an E3 ubiquitin ligase binding moiety and a protein targeting moiety linked via a linker moiety, wherein the E3 ubiquitin ligase binding moiety recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, preferably an E3 ubiquitin ligase), and the protein targeting moiety recognizes a target protein (e.g., an intracellular target protein), such that ubiquitination of the target protein occurs when the target protein is placed in proximity to the E3 ubiquitin ligase, resulting in degradation of the target protein via the proteasome pathway and providing control (e.g., reduction) of the target protein level. In one embodiment, the protein targeting moiety binds to a nuclear hormone receptor. In certain embodiments, the protein targeting moiety binds to an estrogen receptor or an estrogen-related receptor. In one embodiment, the intracellular target protein is an estrogen receptor or an estrogen-related receptor. In one embodiment, the linker moiety is a chemical group that binds or covalently attaches the protein targeting moiety to the E3 ubiquitin ligase binding moiety. In certain embodiments, the linker may contain one or more alkanes and one or more heterocyclic moieties. In certain embodiments, the alkane is a C1-C6 alkyl group and the heterocyclic moiety is pyrrolidine, imidazolidine, piperidine, or piperazine. In one embodiment, the E3 ubiquitin ligase is cereblon. In certain embodiments, the cereblon binding moiety is thalidomide, lenalidomide, pomalidomide, an analog thereof, an isostere thereof, or a derivative thereof. The control (e.g., reduction) of the protein level provided by the present invention provides treatment of a disease state or condition, which is mediated via the target protein by reducing the level of that protein in patient cells.

[0190] In one embodiment, the present invention aims at a method of treating a patient in need thereof for a condition or state in which a protein is causally related, where degradation of the protein produces a therapeutic effect in the patient, the method comprising administering to the patient in need thereof an effective amount of a compound of the present invention, optionally in combination with another bioactive agent. The condition or state may be a condition or state causally related to the expression or overexpression of a protein.

[0191] Treatment method In one aspect, the present application relates to a method of treating and / or preventing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof.

[0192] The method of treating cancer described herein includes reducing tumor size. Alternatively or additionally, the cancer is metastatic cancer and the treatment method includes inhibiting metastatic cancer cell infiltration.

[0193] In one embodiment, the cancer is breast cancer.

[0194] In one embodiment, the breast cancer is metastatic breast cancer.

[0195] In one embodiment, the breast cancer is locally advanced breast cancer.

[0196] In one embodiment, the breast cancer is ER+, HER2-breast cancer.

[0197] In one embodiment, the breast cancer is metastatic ER+, HER2-breast cancer.

[0198] In one embodiment, the breast cancer is locally progressing metastatic ER+, HER2-breast cancer.

[0199] In one aspect, the present application relates to treating breast cancer with a compound of formula (I), the compound of formula (I) having the following structure: A compound having TIFF2025094174000062.tif58128, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, wherein R 1 , R 2 , R3, R4, m, and n are defined herein. In one embodiment, the breast cancer is metastatic breast cancer. In one embodiment, the breast cancer is locally advanced breast cancer. In one embodiment, the breast cancer is ER+, HER2-. In one embodiment, the breast cancer is metastatic ER+, HER2- breast cancer. In one embodiment, the breast cancer is locally advanced metastatic ER+, HER2- breast cancer.

[0200] In one aspect, the present application relates to treating breast cancer with a compound of formula (I), the compound of formula (I) being TIFF2025094174000063.tif91128TIFF2025094174000064.tif184128TIFF2025094174000065.tif134128 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, selected from the group consisting of. In one embodiment, the compound of formula (I) is a compound of formula (I-c). In one embodiment, the breast cancer is metastatic breast cancer. In one embodiment, the breast cancer is locally advanced breast cancer. In one embodiment, the breast cancer is ER+, HER2-. In one embodiment, the breast cancer is metastatic ER+, HER2- breast cancer. In one embodiment, the breast cancer is locally advanced metastatic ER+, HER2- breast cancer.

[0201] In one aspect, the treatment of cancer results in a reduction in the size of the tumor. The reduction in the size of the tumor may also be referred to as "tumor regression". After treatment, the tumor size is preferably reduced by 5% or more compared to its size before treatment, more preferably the tumor size is reduced by 10% or more, more preferably 20% or more, more preferably 30% or more, more preferably 40% or more, even more preferably 50% or more, and most preferably reduced by more than 75%. The size of the tumor may be measured by any reproducible measuring means. In a preferred aspect, the size of the tumor may be measured as the diameter of the tumor.

[0202] In another aspect, the treatment of cancer results in a reduction in the tumor volume. After treatment, the tumor volume is preferably reduced by 5% or more compared to its size before treatment, more preferably the tumor volume is reduced by 10% or more, more preferably 20% or more, more preferably 30% or more, more preferably 40% or more, even more preferably 50% or more, and most preferably reduced by more than 75%. The tumor volume may be measured by any reproducible measuring means.

[0203] In another aspect, the treatment of cancer results in a reduction in the number of tumors. After treatment, the number of tumors is preferably reduced by 5% or more compared to its number before treatment, more preferably the number of tumors is reduced by 10% or more, more preferably 20% or more, more preferably 30% or more, more preferably 40% or more, even more preferably 50% or more, and most preferably reduced by more than 75%. The number of tumors may be measured by any reproducible measuring means. In a preferred aspect, the number of tumors can be measured by counting the tumors that can be seen with the naked eye or at a specified magnification. In a preferred aspect, the specified magnification is 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or 50-fold.

[0204] In another aspect, the treatment of cancer results in a decrease in the number of metastatic lesions in other tissues or organs away from the primary tumor site. After treatment, the number of metastatic lesions is preferably reduced by at least 5% compared to the number before treatment, more preferably the number of metastatic lesions is reduced by at least 10%, more preferably by at least 20%, more preferably by at least 30%, more preferably by at least 40%, even more preferably by at least 50%, and most preferably by more than 75%. The number of metastatic lesions may be measured by any reproducible means of measurement. In a preferred embodiment, the number of metastatic lesions can be measured by counting metastatic lesions that are visible to the naked eye or at a specified magnification. In a preferred embodiment, the specified magnification is 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or 50-fold.

[0205] In another aspect, the treatment of cancer results in an increase in the average survival time of the population of treated subjects compared to a population administered the carrier alone. Preferably, the average survival time is extended by more than 30 days, more preferably by more than 60 days, more preferably by more than 90 days, and most preferably by more than 120 days. The increase in the average survival time of the population may be measured by any reproducible means. In a preferred embodiment, the increase in the average survival time of the population may be measured, for example, by calculating the average length of survival after the start of treatment with an active agent or compound for the population. In another preferred embodiment, the increase in the average survival time of the population may be measured, for example, by calculating the average length of survival after the completion of primary treatment with an active agent or compound for the population.

[0206] In another aspect, the treatment of cancer results in an increase in the average survival period of the treated population of subjects as compared to the untreated population of subjects. Preferably, the average survival period is extended by more than 30 days, more preferably by more than 60 days, more preferably by more than 90 days, and most preferably by more than 120 days. The increase in the average survival period of the population may be measured by any reproducible means. In a preferred aspect, the increase in the average survival period of the population may be measured, for example, by calculating the average length of survival after the start of treatment with an active agent or compound for the population. In another preferred aspect, the increase in the average survival period of the population may also be measured, for example, by calculating the average length of survival after the completion of primary treatment with a compound of formula (I) for the population.

[0207] In another aspect, the treatment of cancer results in a decrease in the tumor growth rate. After treatment, the tumor growth rate is preferably decreased by at least 5% compared to the number before treatment, more preferably the tumor growth rate is decreased by at least 10%, more preferably by at least 20%, more preferably by at least 30%, more preferably by at least 40%, more preferably by at least 50%, even more preferably by at least 50%, and most preferably by at least 75%. The tumor growth rate may be measured by any reproducible measuring means. In a preferred aspect, the tumor growth rate is measured according to the change in tumor diameter per unit time.

[0208] In another aspect, the treatment of cancer results in a reduction of tumor regrowth. After treatment, the tumor regrowth is preferably less than 5%, more preferably the tumor regrowth is less than 10%, more preferably less than 20%, more preferably less than 30%, more preferably less than 40%, more preferably less than 50%, even more preferably less than 50%, and most preferably less than 75%. Tumor regrowth may be measured by any reproducible measuring means. In a preferred embodiment, tumor regrowth is measured, for example, by measuring the increase in the diameter of the tumor from the previous post-treatment tumor shrinkage. In another preferred embodiment, the reduction in tumor regrowth is indicated by the failure of the tumor to recur after treatment has stopped.

[0209] The dosage of the compound of formula (I) for any of the methods and uses described herein will vary depending upon, among other things, the drug, the age, weight, and clinical condition of the recipient subject, and other factors that influence the selected dosage, in particular the experience and judgment of the clinician or practitioner administering the therapy.

[0210] A therapeutically effective amount of the compound of formula (I) is administered once, twice, three, four, five, or more times a day for 5, 10, 15, 30, 60, 90, 120, 150, 180 days, or longer, followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 days, or longer without administration of the compound of formula (I). This type of treatment schedule, i.e., administration of the compound of formula (I) on consecutive days followed by non-administration of the compound of formula (I) on consecutive days, may be referred to as a treatment cycle.

[0211] In one embodiment, a therapeutically effective amount of the compound of formula (I) is administered once or twice a day for up to 5, 10, 15, 20, 25, or 30 days, followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days without administration of the compound of formula (I).

[0212] In one embodiment, a therapeutically effective amount of the compound of formula (I) is administered once a day for up to 5, 10, 15, 20, 25, or 30 days, followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days of non - administration of the compound of formula (I).

[0213] In one embodiment, the treatment cycle with the compound of formula (I) can be repeated as many times as necessary to achieve the intended effect.

[0214] In one embodiment, a therapeutically effective amount of the compound of formula (I) is administered once daily, twice, three times, four times, or more than four times, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 30 consecutive days, or for a period of 2, 3, 4, 5, 6 months or more, in a single or divided dose, of 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705,710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1,000 mg.

[0215] In one embodiment, a therapeutically effective amount of the compound of formula (I) is administered once, twice, three times, four times, or more times per day, in single or divided doses, of about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, about 180 mg, about 210 mg, about 240 mg, about 270 mg, about 300 mg, about 330 mg, about 360 mg, about 390 mg, about 420 mg, about 450 mg, about 480 mg, about 510 mg, about 540 mg, about 570 mg, about 600 mg, about 630 mg, about 660 mg, about 690 mg, about 720 mg, about 750 mg, about 780 mg, about 810 mg, about 840 mg, about 870 mg, about 900 mg, about 930 mg, about 960 mg, or about 990 mg (this dose can be adjusted according to the patient's body weight (kg), body surface area (m 2 2), and age (years)).

[0216] In one embodiment, a therapeutically effective amount of the compound of formula (I) is administered once, twice, three times, four times, or more times per day, in single or divided doses, of about 30 mg to about 1000 mg (this dose can be adjusted according to the patient's body weight (kg), body surface area (m 2 2), and age (years)).

[0217] In one embodiment, a therapeutically effective amount of the compound of formula (I) is administered once, twice, three times, four times, or more than four times a day, in a single or divided dose, and 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, about 370 to about 400 mg, about 380 to about 410 mg, about 390 to about 420 mg, about 400 to about 430 mg, about 410 to about 440 mg, about 420 to about 450 mg, about 430 to about 460 mg, about 440 to about 470 mg, about 450 to about 480 mg, about 460 to about 490 mg, about 470 to about 500 mg, about 480 to about 510 mg, about 490 to about 520 mg, about 500 to about 530 mg, about 510 to about 540 mg, about 520 to about 550 mg, about 530 to about 560 mg, about 540 to about 570 mg, about 550 to about 580 mg, about 560 to about 590 mg, about 570 to about 600 mg, about 580 to about 610 mg, about 590 to about 620 mg, about 600 to about 630 mg, about 610 to about 640 mg, about 620 to about 650 mg, about 630 to about 660 mg, about 640 to about 670 mg, about 650 to about 680 mg, about 660 to about 690 mg, about 670 to about 700 mg, about 680 to about 710 mg, about 690 to about 720 mg, about 700 to about 730 mg, about 710 to about 740 mg, about 720 to about 750 mg, about 730 to about 760 mg, about 740 to about 770 mg, about 750 to about 780 mg, about 760 to about 790 mg, about 770 to about 800 mg, about 780 to about 810 mg, about 790 to about 820 mg,About 800 to about 830 mg, about 810 to about 840 mg, about 820 to about 850 mg, about 830 to about 860 mg, about 840 to about 870 mg, about 850 to about 880 mg, about 860 to about 890 mg, about 870 to about 900 mg, about 880 to about 910 mg, about 890 to about 920 mg, about 900 to about 930 mg, about 910 to about 940 mg, about 920 to about 950 mg, about 930 to about 960 mg, about 940 to about 970 mg, about 950 to about 980 mg, about 960 to about 990 mg, or about 970 to about 1,000 mg (this dosage can be adjusted according to the patient's body weight (kg), body surface area (m, 2) , and age (years)).

[0218] The therapeutically effective amount of the compound of formula (I) may also be in the range of about 0.01 mg / kg per day to about 100 mg / kg per day. In one embodiment, the therapeutically effective amount of the compound of formula (I) may be in the range of about 0.05 mg / kg per day to about 10 mg / kg per day. In one embodiment, the therapeutically effective amount of the compound of formula (I) may be in the range of about 0.075 mg / kg per day to about 5 mg / kg per day. In one embodiment, the therapeutically effective amount of the compound of formula (I) may be in the range of about 0.10 mg / kg per day to about 1 mg / kg per day. In one embodiment, the therapeutically effective amount of the compound of formula (I) may be in the range of about 0.20 mg / kg per day to about 0.70 mg / kg per day.

[0219] In one embodiment, the therapeutically effective amount of the compound of formula (I) is about 0.10 mg / kg per day, about 0.15 mg / kg per day, about 0.20 mg / kg per day, about 0.25 mg / kg per day, about 0.30 mg / kg per day, about 0.35 mg / kg per day, about 0.40 mg / kg per day, about 0.45 mg / kg per day, about 0.50 mg / kg per day, about 0.55 mg / kg per day, about 0.60 mg / kg per day, about 0.65 mg / kg per day, about 0.70 mg / kg per day, about 0.75 mg / kg per day, about 0.80 mg / kg per day, about 0.85 mg / kg per day, about 0.90 mg / kg per day, about 0.95 mg / kg per day, or about 1.00 mg / kg per day.

[0220] In one embodiment, the therapeutically effective amount of the compound of formula (I) is about 1.05 mg / kg per day, about 1.10 mg / kg per day, about 1.15 mg / kg per day, about 1.20 mg / kg per day, about 1.25 mg / kg per day, about 1.30 mg / kg per day, about 1.35 mg / kg per day, about 1.40 mg / kg per day, about 1.45 mg / kg per day, about 1.50 mg / kg per day, about 1.55 mg / kg per day, about 1.60 mg / kg per day, about 1.65 mg / kg per day, about 1.70 mg / kg per day, about 1.75 mg / kg per day, about 1.80 mg / kg per day, about 1.85 mg / kg per day, about 1.90 mg / kg per day, about 1.95 mg / kg per day, or about 2.00 mg / kg per day.

[0221] In one embodiment, the therapeutically effective amount of the compound of formula (I) is about 2 mg / kg per day, about 2.5 mg / kg per day, about 3 mg / kg per day, about 3.5 mg / kg per day, about 4 mg / kg per day, about 4.5 mg / kg per day, about 5 mg / kg per day, about 5.5 mg / kg per day, about 6 mg / kg per day, about 6.5 mg / kg per day, about 7 mg / kg per day, about 7.5 mg / kg per day, about 8.0 mg / kg per day, about 8.5 mg / kg per day, about 9.0 mg / kg per day, about 9.5 mg / kg per day, or about 10 mg / kg per day.

[0222] In one embodiment, a therapeutically effective amount of the compound of formula (I) is administered to the subject once a day. In one embodiment, this daily dose of the compound of formula (I) is administered to the subject all at once. In one embodiment, this daily dose of the compound of formula (I) is administered to the subject in two portions (split dose). In one embodiment, this daily dose of the compound of formula (I) is administered to the subject in three portions. In one embodiment, this daily dose of the compound of formula (I) is administered to the subject in four portions. In one embodiment, this daily dose of the compound of formula (I) is administered to the subject in 5 or more portions. In one embodiment, these portions are administered to the subject at regular intervals throughout the day, for example, every 12 hours, every 8 hours, every 6 hours, every 5 hours, every 4 hours, etc.

[0223] In one embodiment, a therapeutically effective amount of the compound of formula (I) results in a 15-day average AUC greater than about 3,500 ng·hour / mL, about 3,550 ng·hour / mL, about 3,600 ng·hour / mL, about 3,650 ng·hour / mL, about 3,700 ng·hour / mL, about 3,750 ng·hour / mL, about 3,800 ng·hour / mL, about 3,850 ng·hour / mL, about 3,900 ng·hour / mL, about 3,950 ng·hour / mL, about 4,000 ng·hour / mL, about 4,050 ng·hour / mL, about 4,100 ng·hour / mL, about 4,150 ng·hour / mL, about 4,200 ng·hour / mL, about 4,250 ng·hour / mL, about 4,300 ng·hour / mL, about 4,350 ng·hour / mL, 4,400 ng·hour / mL, about 4,450 ng·hour / mL, about 4,500 ng·hour / mL, about 4,550 ng·hour / mL, about 4,600 ng·hour / mL, about 4,650 ng·hour / mL, about 4,700 ng·hour / mL, about 4,750 ng·hour / mL, about 4,800 ng·hour / mL, about 4,850 ng·hour / mL, about 4,900 ng·hour / mL, about 4,950 ng·hour / mL, or about 5,000 ng·hour / mL. TAU to result in.

[0224] In one embodiment, a therapeutically effective amount of a compound of formula (I) results in a 15-day average C that is greater than about 150 ng / mL, about 155 ng / mL, about 160 ng / mL, about 165 ng / mL, about 170 ng / mL, about 175 ng / mL, about 180 ng / mL, about 185 ng / mL, about 190 ng / mL, about 195 ng / mL, 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, about 250 ng / mL, about 255 ng / mL, about 260 ng / mL, about 265 ng / mL, about 270 ng / mL, about 275 ng / mL, about 280 ng / mL, about 285 ng / mL, about 290 ng / mL, about 295 ng / mL, about 300 ng / mL, about 305 ng / mL, about 310 ng / mL, about 315 ng / mL, about 320 ng / mL, about 325 ng / mL, about 330 ng / mL, about 335 ng / mL, about 340 ng / mL, about 345 ng / mL, or about 350 ng / mL. max results in.

[0225] A therapeutically effective amount of a compound of formula (I) can first be estimated in either cell culture assays or animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine the appropriate concentration ranges and routes of administration. Such information can then be used to determine useful dosages and routes for administration in humans. Therapeutic / preventive effects, and toxicity, can be determined by standard pharmaceutical procedures in cell culture or experimental animals, e.g., ED 50 (therapeutically effective dose in 50% of the population) and LD 50 (lethal dose for 50% of the population). The dose ratio between toxicity and therapeutic effect is an index of therapy and can be expressed as the LD 50 / ED 50 ratio. Pharmaceutical compositions that exhibit a large therapeutic index are preferred. The dosage can vary within this range depending upon the dosage form employed, the susceptibility of the patient, and the route of administration.

[0226] Dosage and administration are adjusted to provide a sufficient level of the compound of formula (I) or to maintain the desired effect. Factors that may be considered include the severity of the condition, the general health of the subject, the age, weight, and sex of the subject, diet, time and frequency of administration, combination of agents, reaction sensitivity, and tolerance / response to therapy. Extended-release pharmaceutical compositions can be administered every 3-4 days, weekly, or every two weeks depending on the half-life and clearance rate of the particular formulation.

[0227] A method of treatment comprising administering a compound of formula (I) and a CDK4 / 6 inhibitor In one aspect, the present application relates to a method of treating and / or preventing breast cancer in a subject in need thereof, comprising co-administering to the subject a therapeutically effective amount of a compound of formula (I) and a therapeutically effective amount of a CDK4 / 6 inhibitor. These methods include reduction of tumor size. As another method, or additionally, the breast cancer is metastatic breast cancer and the present method of treatment includes inhibition of metastatic cancer cell invasion. In one embodiment, the breast cancer is metastatic breast cancer. In one embodiment, the breast cancer is locally advanced breast cancer. In one embodiment, the breast cancer is ER+, HER2-. In one embodiment, the breast cancer is metastatic ER+, HER2- breast cancer. In one embodiment, the breast cancer is locally advanced metastatic ER+, HER2- breast cancer.

[0228] In one embodiment, a therapeutically effective amount of the compound of formula (I) and a therapeutically effective amount of the CDK4 / 6 inhibitor are administered simultaneously (either in the same formulation or in separate formulations).

[0229] In one embodiment, a therapeutically effective amount of the compound of formula (I) and a therapeutically effective amount of the CDK4 / 6 inhibitor are administered sequentially, i.e., the compound of formula (I) is administered first followed by the CDK4 / 6 inhibitor or the CDK4 / 6 inhibitor first followed by the compound of formula (I). In one embodiment, the CDK4 / 6 inhibitor is administered first and the compound of formula (I) is administered 1 hour later.

[0230] In one embodiment, a therapeutically effective amount of a compound of formula (I) and a therapeutically effective amount of a CDK4 / 6 inhibitor are administered in temporal proximity.

[0231] In some embodiments, "temporal proximity" means that the compound of formula (I) is administered within a period before or after the administration of a CDK inhibitor (e.g., palbociclib) such that the therapeutic effect of the compound of formula (I) overlaps with the therapeutic effect of the CDK inhibitor (e.g., palbociclib). In some embodiments, the therapeutic effect of the compound of formula (I) completely overlaps with the therapeutic effect of the CDK inhibitor (e.g., palbociclib). In some embodiments, "temporal proximity" means that the compound of formula (I) is administered within a period before or after the administration of a CDK inhibitor (e.g., palbociclib) such that there is a synergistic effect between the compound of formula (I) and the CDK inhibitor.

[0232] "Temporal proximity" can vary depending on various factors including, but not limited to, the age, sex, weight, genetic background, medical condition, medical history, and treatment history of the subject to which the therapeutic agent is administered; the disease or condition to be treated or improved; the therapeutic outcome to be achieved; the dosage, frequency of administration, and duration of administration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route by which the therapeutic agent is administered. In some embodiments, "temporal proximity" means within 15 minutes, within 30 minutes, within 1 hour, within 2 hours, within 4 hours, within 6 hours, within 8 hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 1 week, within 2 weeks, within 3 weeks, within 4 weeks, within 6 weeks, or within 8 weeks. In some embodiments, multiple administrations of one therapeutic agent can be performed in temporal proximity to a single administration of another therapeutic agent. In some embodiments, temporal proximity can vary during a treatment cycle or within a dosing regimen.

[0233] In one aspect, the present application relates to a method of treating and / or preventing breast cancer in a subject in need thereof, the method comprising administering to the subject a compound of formula (I) and a CDK4 / 6 inhibitor, wherein the compound of formula (I) has the following structure: Refers to a compound having TIFF2025094174000066.tif56128, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, wherein R 1 , R 2 , R3, R4, m, and n are as defined herein, and the CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof is a compound that inhibits human enzymes called cyclin-dependent kinases (CDK) 4 and 6. In one embodiment, the CDK4 / 6 inhibitor is palbociclib, palbociclib dihydrochloride, or any other pharmaceutically acceptable salt thereof. In one embodiment, the breast cancer is metastatic breast cancer. In one embodiment, the breast cancer is locally advanced breast cancer. In one embodiment, the breast cancer is ER+, HER2-. In one embodiment, the breast cancer is metastatic ER+, HER2- breast cancer. In one embodiment, the breast cancer is locally advanced metastatic ER+, HER2- breast cancer.

[0234] In one aspect, the present application relates to a method of treating and / or preventing 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) and a CDK4 / 6 inhibitor, wherein the compound of formula (I) is TIFF2025094174000067.tif42128TIFF2025094174000068.tif189128TIFF2025094174000069.tif182128or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative, or prodrug thereof, and the CDK4 / 6 inhibitor is selected from the group consisting of SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, or palbociclib, or any pharmaceutically acceptable salt thereof. In one embodiment, the compound of formula (I) is a compound of formula (I-c). In one embodiment, the breast cancer is metastatic breast cancer. In one embodiment, the breast cancer is locally advanced breast cancer. In one embodiment, the breast cancer is ER+, HER2-. In one embodiment, the breast cancer is metastatic ER+, HER2- breast cancer. In one embodiment, the breast cancer is locally advanced metastatic ER+, HER2- breast cancer.

[0235] In one aspect, the present application relates to a combined preparation of a compound of formula (I) as defined herein and a CDK4 / 6 inhibitor as defined herein for simultaneous, separate, or sequential use in the treatment and / or prevention of breast cancer. In one embodiment, the breast cancer is metastatic breast cancer. In one embodiment, the breast cancer is locally advanced breast cancer. In one embodiment, the breast cancer is ER+, HER2-. In one embodiment, the breast cancer is metastatic ER+, HER2- breast cancer. In one embodiment, the breast cancer is locally advanced metastatic ER+, HER2- breast cancer.

[0236] In one aspect, the present application relates to a combined preparation of a compound of formula (I-c) as defined herein and a CDK4 / 6 inhibitor as defined herein for simultaneous, separate, or sequential use in the treatment and / or prevention of breast cancer. In one embodiment, the breast cancer is metastatic breast cancer. In one embodiment, the breast cancer is locally advanced breast cancer. In one embodiment, the breast cancer is ER+, HER2-. In one embodiment, the breast cancer is metastatic ER+, HER2- breast cancer. In one embodiment, the breast cancer is locally advanced metastatic ER+, HER2- breast cancer.

[0237] In one aspect, the present application relates to a combined preparation of a compound of formula (I) as defined herein and a palbociclib inhibitor as defined herein for simultaneous, separate, or sequential use in the treatment and / or prevention of breast cancer. In one embodiment, the breast cancer is metastatic breast cancer. In one embodiment, the breast cancer is locally advanced breast cancer. In one embodiment, the breast cancer is ER+, HER2-. In one embodiment, the breast cancer is metastatic ER+, HER2- breast cancer. In one embodiment, the breast cancer is locally advanced metastatic ER+, HER2- breast cancer.

[0238] In one aspect, the present application relates to a combined preparation of a compound of formula (I-c) as defined herein and a palbociclib inhibitor as defined herein for simultaneous, separate, or sequential use in the treatment and / or prevention of breast cancer. In one embodiment, the breast cancer is metastatic breast cancer. In one embodiment, the breast cancer is locally advanced breast cancer. In one embodiment, the breast cancer is ER+, HER2-. In one embodiment, the breast cancer is metastatic ER+, HER2- breast cancer. In one embodiment, the breast cancer is locally advanced metastatic ER+, HER2- breast cancer.

[0239] In one aspect, treating cancer with a compound of formula (I) and a CDK4 / 6 inhibitor results in a reduction in tumor size. The reduction in tumor size may also be referred to as "tumor regression". After treatment, the tumor size is preferably reduced by 5% or more compared to its size before treatment, more preferably the tumor size is reduced by 10% or more, more preferably 20% or more, more preferably 30% or more, more preferably 40% or more, even more preferably 50% or more, and most preferably reduced by more than 75%. The tumor size may be measured by any reproducible means of measurement. In a preferred aspect, the tumor size may be measured as the diameter of the tumor.

[0240] In another aspect, treating cancer with a compound of formula (I) and a CDK4 / 6 inhibitor results in a decrease in tumor volume. After treatment, the tumor volume is preferably decreased by at least 5% compared to its size before treatment, more preferably the tumor volume is decreased by at least 10%, more preferably by at least 20%, more preferably by at least 30%, more preferably by at least 40%, even more preferably by at least 50%, and most preferably by more than 75%. The tumor volume may be measured by any reproducible measuring means.

[0241] In another aspect, treating cancer with a compound of formula (I) and a CDK4 / 6 inhibitor results in a decrease in the number of tumors. After treatment, the number of tumors is preferably decreased by at least 5% compared to its number before treatment, more preferably the number of tumors is decreased by at least 10%, more preferably by at least 20%, more preferably by at least 30%, more preferably by at least 40%, even more preferably by at least 50%, and most preferably by more than 75%. The number of tumors may be measured by any reproducible measuring means. In a preferred aspect, the number of tumors can be measured by counting tumors visible to the naked eye or at a specified magnification. In a preferred aspect, the specified magnification is 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or 50-fold.

[0242] In another aspect, treating cancer with a compound of formula (I) and a CDK4 / 6 inhibitor results in a decrease in the number of metastatic lesions in other tissues or organs distant from the primary tumor site. After treatment, the number of metastatic lesions is preferably reduced by at least 5% compared to the number before treatment, more preferably the number of metastatic lesions is reduced by at least 10%, more preferably by at least 20%, more preferably by at least 30%, more preferably by at least 40%, even more preferably by at least 50%, and most preferably by more than 75%. The number of metastatic lesions may be measured by any reproducible means of measurement. In a preferred embodiment, the number of metastatic lesions can be measured by counting metastatic lesions that are visible to the naked eye or at a specified magnification. In a preferred embodiment, the specified magnification is 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or 50-fold.

[0243] In another aspect, treating cancer with a compound of formula (I) and a CDK4 / 6 inhibitor results in an increase in the mean survival time of the population of treated subjects compared to a population administered the carrier alone. Preferably, the mean survival time is extended by more than 30 days, more preferably by more than 60 days, more preferably by more than 90 days, and most preferably by more than 120 days. The increase in the mean survival time of the population may be measured by any reproducible means. In a preferred embodiment, the increase in the mean survival time of the population may be measured, for example, by calculating the mean length of survival after the start of treatment with the active agent or compound for the population. In another preferred embodiment, the increase in the mean survival time of the population may be measured, for example, by calculating the mean length of survival after completion of primary treatment with the active agent or compound for the population.

[0244] In another aspect, treating cancer with a compound of formula (I) and a CDK4 / 6 inhibitor results in an increase in the average survival time of the treated population of subjects as compared to an untreated population of subjects. Preferably, the average survival time is extended by more than 30 days, more preferably by more than 60 days, more preferably by more than 90 days, and most preferably by more than 120 days. The increase in the average survival time of the population may be measured by any reproducible means. In a preferred aspect, the increase in the average survival time of the population may be measured, for example, by calculating the average length of survival for the population after initiation of treatment with the active agent or compound. In another preferred aspect, the increase in the average survival time of the population may also be measured, for example, by calculating the average length of survival for the population after completion of primary treatment with a compound of formula (I) and a CDK4 / 6 inhibitor.

[0245] In another aspect, treating cancer with a compound of formula (I) and a CDK4 / 6 inhibitor results in a decrease in the tumor growth rate. After treatment, the tumor growth rate is preferably decreased by at least 5% compared to the pre-treatment figure, more preferably the tumor growth rate is decreased by at least 10%, more preferably by at least 20%, more preferably by at least 30%, more preferably by at least 40%, more preferably by at least 50%, even more preferably by at least 50%, and most preferably by at least 75%. The tumor growth rate may be measured by any reproducible means of measurement. In a preferred aspect, the tumor growth rate is measured according to the change in tumor diameter per unit time.

[0246] In another aspect, treating cancer with a compound of formula (I) and a CDK4 / 6 inhibitor results in a decrease in tumor regrowth. After treatment, the tumor regrowth is preferably less than 5%, more preferably the tumor regrowth is less than 10%, more preferably less than 20%, more preferably less than 30%, more preferably less than 40%, more preferably less than 50%, even more preferably less than 50%, and most preferably less than 75%. Tumor regrowth may be measured by any reproducible means of measurement. In a preferred embodiment, tumor regrowth is measured, for example, by measuring the increase in the diameter or volume of the tumor from the previous tumor shrinkage after treatment. In another preferred embodiment, the decrease in tumor regrowth is indicated by the failure of the tumor to recur after treatment has stopped.

[0247] The dosage of the compound of formula (I) and the CDK4 / 6 inhibitor for any of the methods and uses described herein will vary depending upon, among other things, the agent, the age, weight, and clinical condition of the recipient subject, and other factors that influence the chosen dosage, in particular, the experience and judgment of the clinician or practitioner administering the therapy.

[0248] A therapeutically effective amount of the CDK4 / 6 inhibitor is administered once, twice, three times, four times, five times, or more than five times a day for a period of 5, 10, 15, 30, 60, 90, 120, 150, 180 days or more, followed by a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 days or more without administration of the CDK4 / 6 inhibitor. This type of treatment schedule, i.e., administration of the CDK4 / 6 inhibitor on consecutive days followed by non - administration of the CDK4 / 6 inhibitor on consecutive days, may be referred to as a treatment cycle.

[0249] In one embodiment, a therapeutically effective amount of a CDK4 / 6 inhibitor is administered once or twice a day for up to 5, 10, 15, 20, 25, or 30 days, followed by a non - administration of the CDK4 / 6 inhibitor for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days.

[0250] In one embodiment, a therapeutically effective amount of a CDK4 / 6 inhibitor is administered once a day for up to 5, 10, 15, 20, 25, or 30 days, followed by a non - administration of the CDK4 / 6 inhibitor for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days.

[0251] In one embodiment, the treatment cycle with a CDK4 / 6 inhibitor can be repeated as many times as necessary to achieve the intended effect.

[0252] In one embodiment, the treatment cycle using a CDK4 / 6 inhibitor is the same as the treatment cycle using the compound of formula (I).

[0253] In one embodiment, the treatment cycle using a CDK4 / 6 inhibitor is different from the treatment cycle using the compound of formula (I).

[0254] A therapeutically effective amount of the compound of formula (I) and a CDK4 / 6 inhibitor are administered more than once a day for up to 30 days or more, followed by a non - administration of the compound of formula (I) and / or the CDK4 / 6 inhibitor for one day or more. This type of treatment schedule, i.e., administration of the compound of formula (I) and / or the CDK4 / 6 inhibitor on consecutive days, followed by non - administration of the compound of formula (I) and / or the CDK4 / 6 inhibitor on consecutive days, may be referred to as a treatment cycle, or simply a cycle. In one embodiment, the treatment cycle may be repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 times, or more. In one embodiment, the treatment cycle of the CDK4 / 6 inhibitor can be repeated as many times as necessary to achieve the intended effect.

[0255] In one embodiment, for the methods disclosed herein that involve administering a compound of formula (I) and a CDK4 / 6 inhibitor, the therapeutically effective amount of the compound of formula (I) is administered once, twice, three times, four times, or more than four times a day, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 30 consecutive days, or for a period of 2 months, 3 months, 4 months, 5 months, 6 months, or more than 6 months, either as a single dose or as divided doses, in an amount of 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640,It is 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1,000 mg.

[0256] In one embodiment, for the methods disclosed herein that involve administering a compound of formula (I) and a CDK4 / 6 inhibitor, the therapeutically effective amount of the compound of formula (I) is administered once, twice, three times, four times, or more than four times a day, in a single or divided dose, and is about 30 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, about 180 mg, about 210 mg, about 240 mg, about 270 mg, about 300 mg, about 330 mg, about 360 mg, about 390 mg, about 420 mg, about 450 mg, about 480 mg, about 510 mg, about 540 mg, about 570 mg, about 600 mg, about 630 mg, about 660 mg, about 690 mg, about 720 mg, about 750 mg, about 780 mg, about 810 mg, about 840 mg, about 870 mg, about 900 mg, about 930 mg, about 960 mg, or about 990 mg (this dose can be adjusted according to the patient's weight (kg), body surface area (m 2 ), and age (years)).

[0257] In one embodiment, for the methods disclosed herein that involve administering a compound of formula (I) and a CDK4 / 6 inhibitor, the therapeutically effective amount of the compound of formula (I) is administered once, twice, three times, four times, or more than four times a day, in a single or divided dose, and is about 30 mg to about 1000 mg (this dose can be adjusted according to the patient's weight (kg), body surface area (m 2) ), and age (years)).

[0258] In one embodiment, for the methods disclosed herein that involve administering a compound of formula (I) and a CDK4 / 6 inhibitor, the therapeutically effective amount of the compound of formula (I) is administered once, twice, three times, four times, or more than four times a day, in a single or divided dose, and 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, about 370 to about 400 mg, about 380 to about 410 mg, about 390 to about 420 mg, about 400 to about 430 mg, about 410 to about 440 mg, about 420 to about 450 mg, about 430 to about 460 mg, about 440 to about 470 mg, about 450 to about 480 mg, about 460 to about 490 mg, about 470 to about 500 mg, about 480 to about 510 mg, about 490 to about 520 mg, about 500 to about 530 mg, about 510 to about 540 mg, about 520 to about 550 mg, about 530 to about 560 mg, about 540 to about 570 mg, about 550 to about 580 mg, about 560 to about 590 mg, about 570 to about 600 mg, about 580 to about 610 mg, about 590 to about 620 mg, about 600 to about 630 mg, about 610 to about 640 mg, about 620 to about 650 mg, about 630 to about 660 mg, about 640 to about 670 mg, about 650 to about 680 mg, about 660 to about 690 mg, about 670 to about 700 mg, about 680 to about 710 mg, about 690 to about 720 mg, about 700 to about 730 mg, about 710 to about 740 mg, about 720 to about 750 mg, about 730 to about 760 mg, about 740 to about 770 mg, about 750 to about 780 mg,About 760 to about 790 mg, about 770 to about 800 mg, about 780 to about 810 mg, about 790 to about 820 mg, about 800 to about 830 mg, about 810 to about 840 mg, about 820 to about 850 mg, about 830 to about 860 mg, about 840 to about 870 mg, about 850 to about 880 mg, about 860 to about 890 mg, about 870 to about 900 mg, about 880 to about 910 mg, about 890 to about 920 mg, about 900 to about 930 mg, about 910 to about 940 mg, about 920 to about 950 mg, about 930 to about 960 mg, about 940 to about 970 mg, about 950 to about 980 mg, about 960 to about 990 mg, or about 970 to about 1,000 mg (this dosage can be adjusted according to the patient's body weight (kg), body surface area (m, 2 ), and age (years)).

[0259] In one embodiment, for the methods disclosed herein that involve administering a compound of formula (I) and a CDK4 / 6 inhibitor, the therapeutically effective amount of the compound of formula (I) may also range from about 0.01 mg / kg per day to about 100 mg / kg per day, from about 0.05 mg / kg per day to about 10 mg / kg per day, from about 0.075 mg / kg per day to about 5 mg / kg per day, from about 0.10 mg / kg per day to about 1 mg / kg per day, or from about 0.20 mg / kg per day to about 0.70 mg / kg per day.

[0260] In one embodiment, for the methods disclosed herein that include administering a compound of formula (I) and a CDK4 / 6 inhibitor, the therapeutically effective amount of the compound of formula (I) is about 0.10 mg / kg per day, about 0.15 mg / kg per day, about 0.20 mg / kg per day, about 0.25 mg / kg per day, about 0.30 mg / kg per day, about 0.35 mg / kg per day, about 0.40 mg / kg per day, about 0.45 mg / kg per day, about 0.50 mg / kg per day, about 0.55 mg / kg per day, about 0.60 mg / kg per day, about 0.65 mg / kg per day, about 0.70 mg / kg per day, about 0.75 mg / kg per day, about 0.80 mg / kg per day, about 0.85 mg / kg per day, about 0.90 mg / kg per day, about 0.95 mg / kg per day, or about 1.00 mg / kg per day.

[0261] In one embodiment, for the methods disclosed herein that include administering a compound of formula (I) and a CDK4 / 6 inhibitor, the therapeutically effective amount of the compound of formula (I) is about 1.05 mg / kg per day, about 1.10 mg / kg per day, about 1.15 mg / kg per day, about 1.20 mg / kg per day, about 1.25 mg / kg per day, about 1.30 mg / kg per day, about 1.35 mg / kg per day, about 1.40 mg / kg per day, about 1.45 mg / kg per day, about 1.50 mg / kg per day, about 1.55 mg / kg per day, about 1.60 mg / kg per day, about 1.65 mg / kg per day, about 1.70 mg / kg per day, about 1.75 mg / kg per day, about 1.80 mg / kg per day, about 1.85 mg / kg per day, about 1.90 mg / kg per day, about 1.95 mg / kg per day, or about 2.00 mg / kg per day.

[0262] In one embodiment, for the methods disclosed herein that involve administering a compound of formula (I) and a CDK4 / 6 inhibitor, the therapeutically effective amount of the compound of formula (I) is about 2 mg / kg per day, about 2.5 mg / kg per day, about 3 mg / kg per day, about 3.5 mg / kg per day, about 4 mg / kg per day, about 4.5 mg / kg per day, about 5 mg / kg per day, about 5.5 mg / kg per day, about 6 mg / kg per day, about 6.5 mg / kg per day, about 7 mg / kg per day, about 7.5 mg / kg per day, about 8.0 mg / kg per day, about 8.5 mg / kg per day, about 9.0 mg / kg per day, about 9.5 mg / kg per day, or about 10 mg / kg per day.

[0263] In one embodiment, for the methods disclosed herein that involve administering a compound of formula (I) and a CDK4 / 6 inhibitor, the therapeutically effective amount of the CDK4 / 6 inhibitor is administered once, twice, three times, four times, or more than four times a day, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 30 consecutive days, or once, twice, three times, four times, or more than four times a day, or for a period of 2 months, 3 months, 4 months, 5 months, 6 months, or more than 6 months, in a single or divided dose, and is 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605,610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1,000 mg. In one embodiment, the CDK4 / 6 inhibitor is palbociclib.,

[0264] In one embodiment, the compound of formula (I) and palbociclib may be administered simultaneously. In one embodiment, the compound of formula (I) is administered first and palbociclib is administered second. In one embodiment, palbociclib is administered first and the compound of formula (I) is administered second. For example, in some embodiments, the administration of the compound of formula (I) and the administration of palbociclib are simultaneous. In some embodiments, the administration of the compound of formula (I) and the administration of palbociclib are made sequentially.

[0265] In one embodiment, palbociclib is administered before the administration of the compound of formula (I), such that the two compounds and their respective excipients (if any) do not mix in the subject's stomach. In one embodiment, the maximum time between the administration of palbociclib and the administration of the compound of formula (I) is a time such that the advantages of the combination are achieved. In one embodiment, palbociclib is administered at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, or at least 30 minutes before the compound of formula (I) is administered. In one embodiment, palbociclib is administered 5 to 35 minutes, 10 to 40 minutes, 15 to 25 minutes, 20 to 50 minutes, 25 to 55 minutes, or 30 to 60 minutes before the compound of formula (I) is administered. In one embodiment, palbociclib is administered 30 to 60 minutes, 30 to 70 minutes, 30 to 80 minutes, 30 to 90 minutes, 30 to 120 minutes, 30 to 180 minutes, 30 to 240 minutes, 30 to 300 minutes, 30 to 360 minutes, 30 to 480 minutes, 30 to 600 minutes, or 30 to 720 minutes before the compound of formula (I) is administered.

[0266] In one embodiment, palbociclib is administered after the administration of the compound of formula (I), such that the two compounds and their respective excipients (if any) do not mix in the subject's stomach. In one embodiment, the maximum time between the administration of palbociclib and the administration of the compound of formula (I) is a time such that the advantages of the combination are achieved. In one embodiment, palbociclib is administered at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, or at least 30 minutes after the compound of formula (I) is administered. In one embodiment, palbociclib is administered 5 to 35 minutes, 10 to 40 minutes, 15 to 25 minutes, 20 to 50 minutes, 25 to 55 minutes, or 30 to 60 minutes after the compound of formula (I) is administered. In one embodiment, palbociclib is administered 30 to 60 minutes, 30 to 70 minutes, 30 to 80 minutes, 30 to 90 minutes, 30 to 120 minutes, 30 to 180 minutes, 30 to 240 minutes, 30 to 300 minutes, 30 to 360 minutes, 30 to 480 minutes, 30 to 600 minutes, or 30 to 720 minutes after the compound of formula (I) is administered.

[0267] In one embodiment, for the methods disclosed herein that involve administering a compound of formula (I) and a CDK4 / 6 inhibitor, the therapeutically effective amount of the CDK4 / 6 inhibitor is 60 mg, 75 mg, 100 mg, or 125 mg, administered once daily, as a single or divided dose. In one embodiment, the therapeutically effective amount of the CDK4 / 6 inhibitor is administered once daily for 21 consecutive days, followed by a 7-day treatment hiatus. In one embodiment, the CDK4 / 6 inhibitor is palbociclib.

[0268] The 21 consecutive days of treatment with a CDK4 / 6 inhibitor followed by a 7-day treatment hiatus are herein referred to as a treatment cycle or cycle. In one embodiment, the treatment cycle of the CDK4 / 6 inhibitor may be repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 times, or more. In one embodiment, the treatment cycle of the CDK4 / 6 inhibitor may be repeated as many times as necessary to achieve the intended effect. In one embodiment, the CDK4 / 6 inhibitor is palbociclib.

[0269] In one embodiment, for the methods disclosed herein that involve administering a compound of formula (I) and a CDK4 / 6 inhibitor, the therapeutically effective amount of the CDK4 / 6 inhibitor is about 0.1 mg / kg per day, about 0.2 mg / kg per day, about 0.3 mg / kg per day, about 0.4 mg / kg per day, about 0.5 mg / kg per day, 0.6 mg / kg per day, about 0.7 mg / kg per day, about 0.8 mg / kg per day, about 0.9 mg / kg per day, about 1 mg / kg per day, about 1.1 mg / kg per day, about 1.2 mg / kg per day, about 1.3 mg / kg per day, about 1.4 mg / kg per day, about 1.5 mg / kg per day, 1.6 mg / kg per day, about 1.7 mg / kg per day, about 1.8 mg / kg per day, about 1.9 mg / kg per day, about 2 mg / kg per day, about 2.5 mg / kg per day, about 3 mg / kg per day, about 3.5 mg / kg per day, about 4 mg / kg per day, about 4.5 mg / kg per day, about 5 mg / kg per day, about 5.5 mg / kg per day, about 6 mg / kg per day, about 6.5 mg / kg per day, about 7 mg / kg per day, about 7.5 mg / kg per day, about 8.0 mg / kg per day, about 8.5 mg / kg per day, about 9.0 mg / kg per day, about 9.5 mg / kg per day, or about 10 mg / kg per day. In one embodiment, the CDK4 / 6 inhibitor is palbociclib.

[0270] In one embodiment, for the methods disclosed herein that involve administering a compound of formula (I) and a CDK4 / 6 inhibitor, the therapeutically effective amount of the CDK4 / 6 inhibitor is from about 0.5 mg / kg per day to about 3.0 mg / kg per day.

[0271] In one embodiment, for the methods disclosed herein that include administering a compound of formula (I) and a CDK4 / 6 inhibitor, a therapeutically effective amount of the compound of formula (I) is administered to the subject once daily. In one embodiment, this daily dose of the compound of formula (I) is administered to the subject in one dose. In one embodiment, this daily dose of the compound of formula (I) is administered to the subject in two portions (divided dose). In one embodiment, this daily dose of the compound of formula (I) is administered to the subject in three portions. In one embodiment, this daily dose of the compound of formula (I) is administered to the subject in four portions. In one embodiment, this daily dose of the compound of formula (I) is administered to the subject in five or more portions. In one embodiment, these portions are administered to the subject at regular intervals throughout the day, for example, every 12 hours, every 8 hours, every 6 hours, every 5 hours, every 4 hours, etc.

[0272] In one embodiment, for the methods disclosed herein that include administering a compound of formula (I) and a CDK4 / 6 inhibitor, a therapeutically effective amount of the CDK4 / 6 inhibitor is administered to the subject once daily. In one embodiment, this daily dose of the CDK4 / 6 inhibitor is administered to the subject in one dose. In one embodiment, this daily dose of the CDK4 / 6 inhibitor is administered to the subject in two portions (divided dose). In one embodiment, this daily dose of the CDK4 / 6 inhibitor is administered to the subject in three portions. In one embodiment, this daily dose of the CDK4 / 6 inhibitor is administered to the subject in four portions. In one embodiment, this daily dose of the CDK4 / 6 inhibitor is administered to the subject in five or more portions. In one embodiment, these portions are administered to the subject at regular intervals throughout the day, for example, every 12 hours, every 8 hours, every 6 hours, every 5 hours, every 4 hours, etc.

[0273] The therapeutically effective amount of the compound of formula (I) and the CDK4 / 6 inhibitor can first be estimated in any of cell culture assays or animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine the appropriate concentration range and route of administration. Then, such information can be used to determine useful dosages and routes for administration in humans. The therapeutic / preventive effects, and toxicity can be determined by standard pharmaceutical procedures in cell culture or experimental animals, e.g., ED 50 (the therapeutically effective dose in 50% of the population) and LD 50 (the lethal dose for 50% of the population). The dose ratio between toxicity and therapeutic effect is an index of therapy and can be expressed as the LD 50 / ED 50 ratio. Pharmaceutical compositions showing a large therapeutic index are preferred. The dosage can vary within this range depending on the dosage form employed, the sensitivity of the patient, and the route of administration.

[0274] The dosage and administration are adjusted to provide a sufficient level of the compound of formula (I) and / or the CDK4 / 6 inhibitor or to maintain the desired effect. Factors that may be considered include the severity of the condition, the general health of the subject, the age, weight, and sex of the subject, diet, the time and frequency of administration, the combination of agents, the sensitivity to the reaction, and the tolerance / response to the therapy. Sustained-release pharmaceutical compositions can be administered every 3 - 4 days, weekly, or every two weeks depending on the half-life and clearance rate of the particular formulation.

[0275] Pharmaceutical Compositions The compound of formula (I) and the CDK4 / 6 inhibitor can be administered according to the present invention by any suitable route including oral, parenteral (subcutaneous, intramuscular, intravenous (bolus or infusion), depot, intraperitoneal), intrathecal, intranasal, intravaginal, sublingual, buccal, intraocular, or rectal.

[0276] In one embodiment, the compound of formula (I) and the CDK4 / 6 inhibitor may be formulated into separate dosage forms. These separate dosage forms may be suitable for administration by any suitable route, including, for example, oral, parenteral (subcutaneous, intramuscular, intravenous, depot), intrathecal, intranasal, intravaginal, sublingual, buccal, intraocular, or rectal.

[0277] In one embodiment, the compound of formula (I) and the CDK4 / 6 inhibitor may be combined and formulated into a single dosage form. This single dosage form may be suitable for administration by any suitable route, including, for example, oral, parenteral (subcutaneous, intramuscular, intravenous, depot), intrathecal, intranasal, intravaginal, sublingual, buccal, intraocular, or rectal.

[0278] In one embodiment, the compound of formula (I) and the CDK4 / 6 inhibitor may be formulated into separate dosage forms, each of which is suitable for oral administration. In one embodiment, the CDK4 / 6 inhibitor is SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, or any pharmaceutically acceptable salt thereof. In one embodiment, the CDK4 / 6 inhibitor is palbociclib, palbociclib dihydrochloride, or any other pharmaceutically acceptable salt of palbociclib.

[0279] In one embodiment, the compound of formula (I) and the CDK4 / 6 inhibitor may be formulated into a single dosage form suitable for oral administration. In one embodiment, the CDK4 / 6 inhibitor is SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, or any pharmaceutically acceptable salt thereof. In one embodiment, the CDK4 / 6 inhibitor is palbociclib, palbociclib dihydrochloride, or any other pharmaceutically acceptable salt of palbociclib.

[0280] In one embodiment, the compound of formula (I) and the CDK4 / 6 inhibitor are each formulated, either separately or together, for oral administration. For example, in one embodiment, both the compound of formula (I) and the CDK4 / 6 inhibitor are formulated, either separately or together, as tablets containing zero, one, two or more of each of an emulsifier, a surfactant, a binder, a disintegrant, a fluidizing agent, and a lubricant, or alternatively, the compound of formula (I) and the CDK4 / 6 inhibitor can be formulated separately, or together within a capsule, or as an oral liquid, or in a combination thereof.

[0281] In one embodiment, the emulsifier is hypromellose.

[0282] In one embodiment, the surfactant is vitamin E polyethylene glycol succinate.

[0283] In one embodiment, the binder (also referred to herein as a filler) is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, sucrose, glucose, and sorbitol.

[0284] In one embodiment, the disintegrant is croscarmellose sodium.

[0285] In one embodiment, the fluidizing agent refers to a substance used to promote powder flow by reducing interparticle aggregation. In one embodiment, in the dosage forms of the present disclosure, the fluidizing agent is selected from the group consisting of silicon dioxide, anhydrous silica colloids, starch, and talc.

[0286] In one embodiment, the lubricant refers to a substance that prevents components from sticking and / or aggregating in the machines used in the preparation of the dosage forms of the present disclosure. In one embodiment, in the dosage forms of the present disclosure, the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, and vegetable stearin.

[0287] In some embodiments, the present disclosure provides a liquid composition comprising a compound of formula (I). In some embodiments, the liquid composition comprises a compound of formula (I) and a surfactant. In some embodiments, the liquid composition comprises a compound of formula (I) and a solvent. In some embodiments, the composition comprises a therapeutically effective amount of a compound of formula (I), a surfactant, and a solvent.

[0288] In some embodiments, the present disclosure provides a liquid composition comprising a compound of formula (I-c). In some embodiments, the liquid composition comprises a compound of formula (I-c) and a surfactant. In some embodiments, the liquid composition comprises a compound of formula (I-c) and a solvent. In some embodiments, the composition comprises a therapeutically effective amount of a compound of formula (I-c), a surfactant, and a solvent. In some embodiments, the ratio of the surfactant to the solvent in the composition is between 0.001 and 0.035 g of surfactant to 1 mL of solvent. In some embodiments, the ratio of the surfactant to the solvent in the composition is between 0.005 and 0.035 g of surfactant per 1 mL of solvent. In some embodiments, the ratio of the surfactant to the solvent in the composition is between 0.01 and 0.03 g of surfactant per 1 mL of solvent. In some embodiments, the ratio of the surfactant to the solvent in the composition is between 0.015 and 0.025 g of surfactant per 1 mL of solvent. In some embodiments, the ratio of the surfactant to the solvent in the composition is between 0.016 and 0.024 g of surfactant per 1 mL of solvent. In some embodiments, the ratio of the surfactant to the solvent in the composition is between 0.017 and 0.023 g of surfactant per 1 mL of solvent. In some embodiments, the ratio of the surfactant to the solvent in the composition is between 0.018 and 0.022 g of surfactant per 1 mL of solvent. In some embodiments, the ratio of the surfactant to the solvent in the composition is between 0.019 and 0.021 g of surfactant per 1 mL of solvent. In some embodiments, the ratio of the surfactant to the solvent in the composition is about 0.02 g of surfactant per about 1 mL of solvent. In some embodiments, the ratio of the surfactant to the solvent in the composition is 0.02 g of surfactant per 1 mL of solvent. In some embodiments, the surfactant is a sorbitan derivative. In some embodiments, the surfactant is Tween 80. In some embodiments, the solvent is low molecular weight polyethylene glycol (PEG). In some embodiments, the solvent is polyethylene glycol (PEG)-400.

[0289] In some embodiments, the present disclosure provides a liquid composition comprising a compound of formula (I-c). In some embodiments, the liquid composition comprises a compound of formula (I-c) and Tween 80. In some embodiments, the liquid composition comprises a compound of formula (I-c) and polyethylene glycol (PEG)-400. In some embodiments, the composition comprises a therapeutically effective amount of a compound of formula (I-c), Tween 80, and PEG-400. In some embodiments, the ratio of Tween 80 to PEG-400 in the composition is Tween 80 between 0.001 and 0.035 g per 1 mL of PEG-400. In some embodiments, the ratio of Tween 80 to PEG-400 in the composition is Tween 80 between 0.005 and 0.035 g per 1 mL of PEG-400. In some embodiments, the ratio of Tween 80 to PEG-400 in the composition is Tween 80 between 0.01 and 0.03 g per 1 mL of PEG-400. In some embodiments, the ratio of Tween 80 to PEG-400 in the composition is Tween 80 between 0.015 and 0.025 g per 1 mL of PEG-400. In some embodiments, the ratio of Tween 80 to PEG-400 in the composition is Tween 80 between 0.016 and 0.024 g per 1 mL of PEG-400. In some embodiments, the ratio of Tween 80 to PEG-400 in the composition is Tween 80 between 0.017 and 0.023 g per 1 mL of PEG-400. In some embodiments, the ratio of Tween 80 to PEG-400 in the composition is Tween 80 between 0.018 and 0.022 g per 1 mL of PEG-400. In some embodiments, the ratio of Tween 80 to PEG-400 in the composition is Tween 80 between 0.019 and 0.021 g per 1 mL of PEG-400. In some embodiments, the ratio of Tween 80 to PEG-400 in the composition is about 0.02 g of Tween 80 per about 1 mL of PEG-400. In some embodiments, the ratio of Tween 80 to PEG-400 in the composition is 0.02 g of Tween 80 per 1 mL of PEG-400.

[0290] In some embodiments, the present disclosure provides a method for preparing a liquid composition comprising a surfactant, a solvent, and a compound of formula (I-c), the method comprising the step of adding a solvent to a pre-aliquoted amount of the surfactant. In some embodiments, the method further comprises the step of adding a compound of formula (I-c) to a mixture of the solvent and the surfactant. In some embodiments, the present disclosure provides a method for preparing a liquid composition comprising (i) the step of adding a solvent to a pre-aliquoted amount of the surfactant, and (ii) the step of adding a compound of formula (I-c) to a mixture of the solvent and the surfactant. In some embodiments, the surfactant is a sorbitan derivative. In some embodiments, the surfactant is Tween 80. In some embodiments, the solvent is low molecular weight polyethylene glycol (PEG). In some embodiments, the solvent is polyethylene glycol (PEG)-400.

[0291] In some embodiments, the present disclosure provides a liquid composition adjusted by a method comprising the step of adding a solvent to a pre-aliquoted amount of a surfactant, the liquid composition comprising a surfactant, a solvent, and a compound of formula (I-c). In some embodiments, the method further comprises the step of adding a compound of formula (I-c) to a mixture of the solvent and the surfactant. In some embodiments, the present disclosure provides a liquid composition comprising a surfactant, a solvent, and a compound of formula (I-c) adjusted by a method comprising (i) the step of adding a solvent to a pre-aliquoted amount of the surfactant, and (ii) the step of adding a compound of formula (I-c) to a mixture of the solvent and the surfactant. In some embodiments, the surfactant is a sorbitan derivative. In some embodiments, the surfactant is Tween 80. In some embodiments, the solvent is low molecular weight polyethylene glycol (PEG). In some embodiments, the solvent is polyethylene glycol (PEG)-400.

[0292] A pharmaceutical composition containing a compound of formula (I) and a CDK4 / 6 inhibitor (either separately or together) can be manufactured in a generally known manner, for example, by means of conventional mixing, dissolving, granulating, dragee-making, ligation, emulsifying, encapsulating, enclosing, or freeze-drying processes. The pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, including excipients and / or adjuvants that facilitate processing the compound of formula (I) into a preparation that can be used pharmaceutically. Naturally, the appropriate formulation depends on the selected route of administration.

[0293] A pharmaceutical composition containing a compound of formula (I) suitable for injection and a CDK4 / 6 inhibitor (either separately or together) comprises a sterile aqueous solution (if water-soluble) or dispersion for immediate preparation of a sterile injectable solution or dispersion and sterile powder. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL (trademark) (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent that it is readily injectable. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintenance of the required particle size in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferred to include in the composition isotonic agents such as sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride. Prolongation of the absorption of the injectable composition can be brought about, for example, by including in the composition agents that delay absorption such as aluminum monostearate and gelatin.

[0294] The sterile injectable solution can be prepared by incorporating a compound of formula (I) and / or a CDK4 / 6 inhibitor in a suitable solvent with one or a combination of the ingredients listed above in the required amounts and, if necessary, subsequently filter sterilizing it. Generally, the dispersion is prepared by incorporating the active agent or compound into a sterile vehicle containing a basic dispersion medium and the other ingredients required from those listed above. In the case of a sterile powder for the preparation of a sterile injectable solution, the methods of preparation are vacuum drying and lyophilization, which yield a powder of the active ingredient and any additional desired ingredients from its previously sterile filtered solution.

[0295] Oral compositions generally include an inert diluent or a pharmaceutically acceptable edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the compound of formula (I) and / or a CDK4 / 6 inhibitor can be used in combination with excipients and in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouse wash, where the agent or compound in the fluid carrier is applied orally, swished in the mouth, and spat out or swallowed. Pharmaceutically compatible binding agents and / or adjuvant substances can be included as part of the composition. Tablets, pills, capsules, lozenges, etc. can contain any of the following ingredients, or compounds of similar nature: for example, binding agents such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavor.

[0296] For administration by inhalation, the compound of formula (I) and / or the CDK4 / 6 inhibitor is delivered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant, such as a gas like carbon dioxide, or a nebulizer.

[0297] Systemic administration of the compound of formula (I) and / or the CDK4 / 6 inhibitor may also be by transmucosal or transdermal means. For transmucosal or transdermal administration, a suitable penetrant for the permeated barrier is used in the formulation. Such penetrants are generally known in the art and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be achieved by the use of nasal sprays or suppositories. For transdermal administration, the active agent or compound is formulated into ointments, salves, gels, or creams generally known in the art.

[0298] In one aspect, the compound of formula (I) and / or the CDK4 / 6 inhibitor is prepared with a pharmaceutically acceptable carrier that protects the agent or compound from rapid elimination from the body, such as controlled release formulations including implants and microencapsulation delivery systems. Biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art. Materials can also be obtained commercially from, for example, Alza Corporation and Nova Pharmaceuticals. Liposome suspensions (including liposomes targeted to infected cells having monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, such as those described in U.S. Patent No. 4,522,811.

[0299] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate the oral or parenteral compositions of the compounds of formula (I) and / or CDK4 / 6 inhibitors into unit dosage forms. As used herein, a unit dosage form is a physically discrete unit suitable as a unit dose for the subject to be treated; each unit containing a predetermined quantity of the active agent or compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification of the unit dosage forms of the present application is determined by and directly depends on the unique properties of the compounds of formula (I) and the particular therapeutic effect to be achieved.

[0300] The pharmaceutical compositions of the compounds of formula (I) and / or CDK4 / 6 inhibitors can be contained in a container, pack, or dispenser, together with instructions for administration.

[0301] Exemplary modes of administration of the compounds of formula (I) and / or CDK4 / 6 inhibitors include systemic or topical administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical modes of administration. In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt or hydrate thereof, is administered orally. In one embodiment, the compound of formula (I) is administered as a tablet, capsule, caplet, solution, suspension, syrup, granule, bead, powder, or pellet.

[0302] Exemplary pharmaceutical compositions include salts of the compounds of formula (I) and / or CDK4 / 6 inhibitors and, for example, a) diluents such as purified water, triglyceride oils such as hydrogenated or partially hydrogenated vegetable oils, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil such as EPA or DHA, or esters or triglycerides thereof or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, glucose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) lubricants such as silica, talcum, stearic acid, its magnesium or calcium salts, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and / or polyethylene glycol; for tablets, also c) binders, if desired, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone; d) disintegrants such as starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbents, colorants, flavorants, and sweeteners; f) emulsifiers or dispersants such as Tween 80, Labrasol, HPMC, DOSS, Capryol 909, Labrafac, Labrafil, Peceol, Transcutol, Capmul MCM, Capmul PG-12, Captex 355, Gelsia, Vitamin E TGPS or other acceptable emulsifiers; and / or g) agents that enhance the absorption of salts such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, and / or PEG200, etc., tablets and gelatin capsules containing pharmaceutically acceptable carriers.

[0303] For preparing a pharmaceutical composition from a compound of formula (I) and / or a CDK4 / 6 inhibitor, or any salt or hydrate thereof, the inert and pharmaceutically acceptable carrier may be either solid or liquid. Preparations in solid form include powders, pills, tablets, dispersible granules, capsules (including sustained release capsules), cachets, and suppositories. Powders and tablets may consist of about 5 to about 95% active ingredient. Suitable solid carriers are known in the art and include, for example, magnesium carbonate, magnesium stearate, talc, sugar, or lactose. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions can be found in A. Gennaro (ed.), Remington’s Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.

[0304] Preparations in liquid form of a compound of formula (I) and / or a CDK4 / 6 inhibitor include solutions, suspensions, elixirs, tinctures, emulsions, syrups, suspensions, and emulsions. For example, addition of sweeteners and opacifiers for oral solutions, suspensions, and emulsions, or water or water-propylene glycol solutions for parenteral injection. Liquid form preparations may also include solutions for nasal administration.

[0305] Liquids, especially for injection, compositions, a compound of formula (I) and / or a CDK4 / 6 inhibitor can be prepared, for example, by dissolution, dispersion, etc. For example, the disclosed salts are dissolved in or mixed with pharmaceutically acceptable solvents such as water, physiological saline, aqueous dextrose, glycerol, ethanol, etc., thereby forming an isotonic solution or suspension for injection. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

[0306] Also included are solid form preparations of the compounds of formula (I) and / or CDK4 / 6 inhibitors that are intended to be converted into liquid form preparations for either oral or parenteral administration immediately before use. Such liquid forms include solutions, suspensions, and emulsions.

[0307] Parenteral injectable administration of the compounds of formula (I) and / or CDK4 / 6 inhibitors is commonly used for subcutaneous, intramuscular, or intravenous injection and infusion. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions suitable for dissolution in a liquid before injection or as solid forms.

[0308] Aerosol preparations of the compounds of formula (I) and / or CDK4 / 6 inhibitors suitable for inhalation may include solids in solution and powder form, which may be in combination with a pharmaceutically acceptable carrier such as an inert compressed gas, for example, nitrogen.

[0309] The pharmaceutical compositions of the compounds of formula (I) and / or CDK4 / 6 inhibitors can be prepared according to conventional mixing, granulating, or coating methods, respectively, and the pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% by weight of the compounds of formula (I) and / or CDK4 / 6 inhibitors.

[0310] All amounts of any component of the oral dosage forms described herein, such as tablets, expressed on a % w / w basis, refer to the total weight of the oral dosage form, unless otherwise indicated.

Example

[0311] The present disclosure is further illustrated by the following examples, which should not be construed as limiting the present disclosure in scope or spirit of the specific procedures described herein. Of course, the examples are provided to illustrate a particular embodiment and are not intended to limit the scope of the present disclosure. It should be further understood that one may have means for various other embodiments, modifications, and equivalents thereof that may be suggested to those skilled in the art without departing from the spirit of the present disclosure and / or the appended claims.

[0312] Example 1 - Compound (I-c) - An ER Degrader for Subjects with Locally Advanced or Metastatic Breast Cancer Breast cancer is the second most common cancer in women. In the United States in 2019, it is estimated that about 268,000 women will be diagnosed with invasive breast cancer. (American Cancer Society) Metastatic breast cancer accounts for about 6% of newly diagnosed cases. (Malmgren, J.A., Breast Cancer Res Treat (2018) 167:579 - 590.) 80% of newly diagnosed breast cancers are estrogen receptor (ER) positive. (National Cancer Institute, Hormonal Therapy for Breast Cancer.)

[0313] Fulvestrant has been recognized for its relevance in ER degradation in breast cancer.

[0314] Six months after fulvestrant treatment, a maximum of 50% of the ER baseline level remains (Gutteridge et al., Breast Cancer Res Treat 2004;88 suppl 1:S177).

[0315] Compound (I-c) is a potent degrader of the estrogen receptor (DC 50 = 1.8 nM) and is under development for the treatment of ER+ locally advanced or metastatic breast cancer patients.

[0316] Example 2 - Preclinical Effective Exposure Range for Compound (I-c) In preclinical animal studies, compound (I-c) was administered at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg (oral, once daily). The pharmacokinetic results are shown in Table 1 below. In the MCF7 xenograft model, 85%, 98%, and 124% tumor growth inhibition (TGI) was observed with compound (I-c) at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg, respectively, compared to the control group.

[0317] Figure 1 shows the results of the tumor growth inhibition experiment (mean tumor volume (mm 3 ) vs. time) at the tested doses.

[0318] Figure 2 shows the decrease in ER in MCF7 xenograft tumors in response to administration of compound (I-c) at 3 mg / kg, 10 mg / kg, and 30 mg / kg (oral, once daily). (Table 1) TIFF2025094174000070.tif37128 a Single dose Values represent total drug concentration

[0319] Example 3 - Toxicity study Animals were orally administered compound (I-c) once daily for 28 days, after which the high-dose animals underwent a 28-day recovery period. In dogs, compound (I-c) was orally administered at 15 mg / kg, 45 mg / kg, or 90 mg / kg once daily. In rats, compound (I-c) was orally administered at 3 mg / kg, 10 mg / kg, 30 mg / kg, or 100 mg / kg once daily. These studies showed no clinical signs of toxicity after once-daily oral administration of compound (I-c) at doses up to 100 mg / kg / day in rats and 90 mg / kg / day in dogs. Furthermore, no effects on the overall health or well-being of the animals were observed.

[0320] Example 4 - Phase I clinical trial study design using compound (I-c) A Phase I clinical trial was conducted using compound (I-c). A conventional 3+3 dose escalation design was implemented. The starting dose of compound (I-c) was 30 mg orally, once daily with food. Dose increases were toxicity-dependent.

[0321] The main inclusion criteria for this trial were ER+ / HER2- advanced breast cancer; at least two previous endocrine therapies and CDK4 / 6 inhibitors in any setting; and up to three previous cytotoxic chemotherapy regimens.

[0322] The primary objective of this trial was to obtain the maximum tolerated dose and the recommended Phase II trial dose of compound (I-c). Additional objectives included the overall safety, pharmacokinetics, antitumor activity (e.g., RECIST, CBR) of compound (I-c), and biomarkers including, for example, the ER gene (ESR1) mutation status in ctDNA and / or tumor tissue, and the ER, progesterone receptor, and Ki-67 levels, as evaluated by pre- and post-treatment tumor biopsies in patients with accessible tumor tissue.

[0323] Example 5 - Phase I Pharmacokinetic Data - Oral Administration of Compound (I-c) In the Phase I clinical trial, compound (I-c) was administered orally at a dose of 30 mg / day. Treatment with 30 mg / day of compound (I-c) was observed to fall within the preclinical effective range related to tumor growth inhibition.

[0324] The initial pharmacokinetic results are shown in Table 2 below and Figures 3 and 4. Figure 3 represents the concentration of compound (I-c) over 24 hours after dosing on both Day 1 and Day 15. Figure 4 represents the mean trough concentration of compound (I-c) throughout the clinical trial. (Table 2) TIFF2025094174000071.tif29161 a AUC on Day 15 calculated using the attributed 24-hour values

[0325] Example 6 - Phase I Dose Escalation Study Using Compound (I-c) Compound (I-c) was orally administered to the subjects at 30 mg / day or 60 mg / day. (n = 3 for both dose groups) No dose-limiting toxicity was observed in the 30 mg / day cohort. Also, no treatment-related adverse events were observed in the 30 mg / day cohort group.

[0326] Example 7 - Evaluation of the antitumor and estrogen receptor α degrading activities of compound (I-c) in an ER-positive orthotopic xenograft model MCF7 Part 1: ERα degradation in vivo

[0327] The acute estrogen receptor α (ERα) degrading activity of compound (I-c) was evaluated in the MCF7 orthotopic xenograft model after three daily oral administrations of compound (I-c). To evaluate the compound (I-c)-induced degradation of ERα in vivo, compound (I-c) was administered to MCF7-tumor-bearing NOD / SCID mice at 10 mg / kg by oral gavage, and the change in ERα levels was evaluated after three daily oral administrations. As shown in Figure 5, compound (I-c) reduced the tumor ERα level by up to 95% compared to the ERα level in the tumors of vehicle-treated mice.

[0328] MCF7-tumor-bearing NOD / SCID mice were administered vehicle or compound (I-c) (10 mg / kg, p.o.) once a day for 3 consecutive days. Approximately 18 hours after the final administration, the mice were sacrificed, MCF7 xenografts were harvested, lysed, and ER levels were determined by immunoblotting. Compound (I-c) reduced the ER level by up to 95% compared to the vehicle (as shown by three samples from each group in Figure 5). β-Actin served as a loading control for the immunoblot. Peanut butter was supplemented in the diet to help maintain body weight.

[0329] Details of the animal study:

[0330] Species: NOD / SCID female mice (Charles River, 6 - 7 weeks old at arrival).

[0331] Animal handling: 5×10 MCF7 cells per mouse / 200 μL of axial mammary fat pad transplantation (17β-estradiol 0.36 mg pellet for 90 days transplanted the day before). 6

[0332] Dosage: Oral (gavage), once a day (QD) for 3 days (QDx3). Vehicle: 2% Tween80 / PEG400 (“PEG / Tween”).

[0333] (Table 3) Test treatment group TIFF2025094174000072.tif24161

[0334] Sampling: Final sacrifice was approximately 18 hours after the final dose, and tumors were harvested, dissected, and snap-frozen. ERα levels were determined by immunoblotting.

[0335] Detailed procedure for ERα degradation assay:

[0336] Cell lysis: Snap-frozen tumors were removed from the -80°C freezer and placed on dry ice. RIPA lysis buffer and Halt protease inhibitor were used at 400 μl per tumor sample. Steel balls (5 mm) were placed in each sample for tissue disruption. Samples were lysed in a TissueLyzer at 24 Hz for 4 minutes. Homogenization was stopped midway through the process, and the block was flipped over during the process. Steel beads were removed from the tube, and the lysate was centrifuged at 21,000×g for 15 minutes at 4°C. The total protein concentration of the lysate was then measured by BCA (according to the manufacturer's protocol).

[0337] ​Detection of proteins by immunoblotting: Lysates were mixed with sample buffer and reducing agent (according to the manufacturer's protocol). Samples were denatured at 95 °C for 5 minutes in a thermal cycler. Before loading onto the gel, the samples were cooled and centrifuged (5000×g, 1 minute). 10 μg of total protein per lane was loaded onto the gel. Samples were loaded onto a 4 - 15% standard Tris / Glycine gel and run at 250 constant volts for 25 minutes in 1X Tris / Glycine / SDS buffer. Proteins were transferred from the gel to nitrocellulose using Bio - Rad Turbo with default settings. All blots were washed with distilled water and blocked for 1 hour at room temperature in 5% BSA in TBS - T (TBS with 0.1% Tween). The blots were cut to enable detection of beta - actin and ERα from the same lane / sample.

[0338] Blots were incubated overnight with primary antibodies in 5% BSA in TBST (0.1%) at 4 °C on a rocker: ERα from Bethyl labs (1:2000); Beta - actin from CST (1:3000).

[0339] Blots were washed three times with TBST (0.1%) for 5 minutes each at room temperature on a rocker. Secondary antibody was added and the blots were incubated for 1 hour at room temperature on a rocker (anti - rabbit - HRP at 1:18,000 in TBS - T). Blots were washed three times in TBST (0.1%) for 5 minutes each at room temperature on a rocker. Signals were developed for 5 minutes using Pierce WestFemto maximum sensitivity substrate and the blots were imaged with a BioRad ChemiDoc.

[0340] Part 2: Antitumor effect in the MCF7 xenograft model.

[0341] The antitumor activity and extended ERα degradation activity of compound (I - c) were evaluated in the MCF7 syngeneic xenograft model.

[0342] In this MCF7 xenograft model, compound (I-c) showed dose-dependent efficacy (Figure 6), with tumor growth inhibition (TGI) of 85% and 98% compared to the vehicle at doses of 3 and 10 mg / kg / day, respectively, and a 124% TGI (tumor shrinkage) at 30 mg / kg / day (Table 4).

[0343] Dose-dependent inhibition of tumor growth by compound (I-c) in an orthotopic MCF7 mouse xenograft model in the experiment. MCF7 cells were implanted into the mammary fat pads of female NOD / SCID mice, and compound (I-c) administration (QD x 28; p.o.) was initiated when the tumors reached 200 mm 3 . Tumor volumes were evaluated twice a week for 28 days. Compounds (I-c) at 3, 10, or 30 mg / kg inhibited the growth of estradiol-stimulated MCF7 xenografts (85%, 98%, and 124% TGI, respectively).

[0344] (Table 4) Tumor growth inhibition (TGI) TIFF2025094174000073.tif50144* Tumor volumes are mean ± SD.

[0345] Sampling: Tumors were measured twice a week. Final sacrifice was approximately 18 hours after the final dose, at which time the tumors were harvested, dissected, and snap-frozen. ERα levels were determined by immunoblotting.

[0346] Calculation of tumor volume: Tumor volume = (width × width × length) / 2, where all measurements in the formula are expressed in mm, and tumor volume is expressed in mm 3 .

[0347] Calculation of tumor growth inhibition (TGI): TGI (%) TIFF2025094174000074.tif13155

[0348] At the end of the experiment, tumors were removed from the mice and ERα levels were determined by immunoblotting of tumor homogenates. As seen in Figure 7, all doses of compound (I-c) significantly (more than 94%) decreased ERα levels when compared to mice administered vehicle only. Collectively, these data demonstrate the potent antitumor activity of compound (I-c) against a well-established in vivo ER-positive breast cancer model, concomitant with the definite degradation of ERα in tumors.

[0349] (Table 5) Test treatment groups TIFF2025094174000075.tif26156

[0350] Part 2: Antitumor effect in combination with CDK4 / 6 inhibitors

[0351] To evaluate the antitumor activity of compound (I-c) in combination with a CDK4 / 6 inhibitor in the MCF7 orthotopic xenograft model, the effect of combining compound (I-c) with a CDK4 / 6 inhibitor was evaluated in MCF7-tumor-bearing mice.

[0352] NOD / SCID female mice (Charles River, 6 - 7 weeks old at arrival) were transplanted with 5×10 6 MCF7 cells / 200 μL per mouse into the axial mammary fat pad (17β-estradiol 0.36 mg 90-day pellet transplanted the previous day). Compound administration was initiated when the tumors reached 200 mm 3 . Peanut butter was supplemented in the diet to help maintain body weight.

[0353] Compound (I-c) (30 mg / kg / day) and the CDK4 / 6 inhibitor palbociclib (60 mg / kg / day) were administered for 28 days. When compared to the activity of the single-agent compound (I-c) (105% TGI) in this model, the combination of compound (I-c) and palbociclib resulted in significant tumor regression (131% TGI). In contrast, subcutaneous administration of the single-agent fulvestrant resulted in only slight tumor growth inhibition (46% TGI), while the combination of fulvestrant and palbociclib resulted in improved inhibition of tumor growth (108% TGI), but did not reach the level achieved with compound (I-c) and palbociclib. (Figure 8 and Table 6)

[0354] (Table 6) Tumor Growth Inhibition (TGI) Test TIFF2025094174000076.tif49167*Tumor volume is mean ± SD.

[0355] Dosing: · Compound (I-c) and palbociclib: Oral (gavage), once daily, for 28 days (QDx28) · Palbociclib is administered 30 - 60 minutes before compound (I-c). While not intending to be bound by theory, this is to prevent palbociclib and compound (I-c), and their respective excipients, from mixing within the acidic compartment of the stomach. · Fulvestrant: Subcutaneous (SC), twice weekly (BIW), for 2 weeks (BIWx2), followed by once weekly (QW), for 2 weeks (QWx2)

[0356] Vehicle: · For compound (I-c): 2% Tween 80 / PEG-400 (“PEG / Tween”). The ratio of Tween80 to PEG-400 is 0.02 g of Tween80 per 1 ml of PEG-400. Add PEG-400 to the pre-aliquoted amount of Tween80. · For the full vestrant: 10% w / v ethanol, 10% w / v benzyl alcohol, and 15% w / v benzyl benzoate are used as co-solvents, making up 100% w / v together with castor oil (“EBB / castor oil”). · For palbociclib: 50 mM sodium lactate, pH 4.0 (“sodium lactate”)

[0357] (Table 7) Test treatment groups TIFF2025094174000077.tif74161

[0358] Sampling: Tumors were measured twice a week. The final sacrifice was approximately 18 hours after the final dose, at which time the tumors were harvested, dissected, and snap-frozen. ERα levels were determined by immunoblotting.

[0359] Example 8 - Evaluation of the antitumor activity and estrogen receptor α degrading activity of compound (I-c) in an ER-positive orthotopic xenograft model of tamoxifen-resistant MCF7 cells The antitumor activity of compound (I-c) was evaluated as a single agent and in combination with a CDK4 / 6 inhibitor in a tamoxifen-resistant estrogen receptor-positive (ER+) breast cancer orthotopic xenograft model. Furthermore, the ERα degrading activity of compound (I-c) was evaluated in a tamoxifen-resistant ER+ breast cancer orthotopic xenograft model.

[0360] Data summary

[0361] In Figures 9 and Table 8, after oral administration of 30 mg / kg / day of compound (I-c) once daily for 28 days, the growth of tamoxifen-resistant MCF7 xenografts was inhibited by 65%. When compound (I-c) was combined with 60 mg / kg / day of palbociclib, the combination regimen caused greater tumor growth inhibition (113% TGI) compared to the palbociclib monotherapy group (91% TGI).

[0362] At the end of the experiment, tumors were removed from the mice, and ERα levels were determined by immunoblotting tumor homogenates. As seen in Figure 10, 30 mg / kg of compound (I-c) decreased the ERα level by 73% compared to the vehicle, and the combination with 60 mg / kg of palbociclib also decreased the ERα level by 72% (Figure 11). However, palbociclib alone (60 mg / kg) did not decrease the ERα level (Figure 12). ERα levels from various compound treatment groups were compared to vehicle-treated animals by analyzing tumor lysates on separate immunoblots (the graphs in Figures 10, 11, and 12 show data from individual immunoblots), and mean ERα levels with standard deviation are shown.

[0363] (Table 8) Tumor growth inhibition (TGI) TIFF2025094174000078.tif46156* Tumor volume is mean ± SD.

[0364] Details of animal experiments:

[0365] Species: Ovariectomized Nu / Nu female mice. Animal handling: Axial mammary fat pad transplantation of tamoxifen-resistant tumor fragments (from passage E45. SC per mouse. Tamoxifen pellet (5 mg, 60-day release) was performed under the same anesthesia as the tumor fragment (pellet - back, tumor - abdomen).

[0366] Dosage: Oral (gastrostomy feeding), once a day for 28 days (QD x 28)

[0367] Vehicle: For compound (I-c): 2% Tween 80 / PEG400 (“PEG / Tween”); for palbociclib: 50 mM sodium lactate, pH 4 (“sodium lactate”)

[0368] (Table 9) Test treatment groups TIFF2025094174000079.tif54161

[0369] Sampling: Tumors were measured twice a week. The final sacrifice was approximately 18 hours after the final administration, at which time the tumors were harvested, dissected, and snap-frozen. ERα levels were determined by immunoblotting (see Appendix 1 for details).

[0370] Detailed procedure for ERα degradation assay:

[0371] Cell lysis

[0372] The snap-frozen tumors were removed from the -80°C freezer and placed on dry ice. RIPA lysis buffer and Halt protease inhibitor were used at 400 μl per tumor sample. Steel balls (5 mm) were placed in each sample for tissue disruption. The samples were lysed in a TissueLyzer at 24 Hz for 4 minutes. Homogenization was stopped midway through the process, and the blocks were flipped during the process. The steel beads were removed from the tubes, and the lysates were centrifuged at 21,000×g for 15 minutes at 4°C. The total protein concentration of the lysates was then measured by BCA (according to the manufacturer's protocol).

[0373] Detection of proteins by immunoblotting.

[0374] The lysates were mixed with sample buffer and reducing agent (according to the manufacturer's protocol). The samples were denatured at 95°C for 5 minutes in a thermal cycler. Before loading onto the gel, the samples were cooled and centrifuged (5000×g, 1 minute). 10 μg of total protein per lane was loaded onto the gel. The samples were loaded onto a 4 - 15% standard Tris / glycine gel and run at 250 constant volts for 25 minutes in 1X Tris / glycine / SDS buffer.

[0375] The protein was transferred from the gel to nitrocellulose using Bio-Rad Turbo with default settings. All blots were washed with distilled water and blocked for 1 hour at room temperature in 5% BSA in TBS-T (TBS with 0.1% Tween). The blots were cut to enable detection of beta-actin and ERα from the same lane / sample. The blots were incubated overnight with primary antibodies in 5% BSA in TBST (0.1%) on a rocker at 4°C. · ERα from Bethyl labs (1:2000) · Beta-actin from CST (1:3000)

[0376] The blots were washed three times with TBST (0.1%) for 5 minutes each at room temperature on a rocker. Secondary antibody was added and the blots were incubated for 1 hour at room temperature on a rocker (anti-rabbit-HRP at 1:18,000 in TBS-T). The blots were washed three times in TBST (0.1%) for 5 minutes each at room temperature on a rocker. Signals were developed for 5 minutes using Pierce WestFemto maximum sensitivity substrate and the blots were imaged with a BioRad ChemiDoc.

[0377] Summary of in vivo data for Example 9 - Compound (I-c) The compounds of formula (I) disclosed herein, including compound (I-c), are heterobifunctional molecules that promote the interaction between ERα and the intracellular E3 ligase complex, resulting in ubiquitination and subsequent degradation of the estrogen receptor via the proteasome. Orally administrable compound (I-c) exhibits single-digit nanomolar ERα degradation capacity in wild-type and variant ERα-expressing cell lines.

[0378] Compound (I-c) has a half-degradation concentration (DC of approximately 1 nM 50) and strongly degrades ER in ER-positive breast cancer cell lines (Figures 13 and 14). ER degradation mediated by compound (I-c) decreases the expression of classically regulated ER target genes MCF7 and T47D (Figures 13 - 16) and inhibits the cell proliferation of ER-dependent cell lines. Furthermore, compound (I-c) degrades clinically relevant ESR1 variants Y537S and D538G (Figure 15) and inhibits the proliferation of cell lines expressing these variants. In an immature rat uterine trophic model, compound (I-c) degrades rat uterine ER and does not exhibit agonist activity (Figure 17). Daily oral administration of single-agent compound (I-c) (3, 10, and 30 mg / kg) results in significant antitumor activity of estradiol-dependent MCF7 xenografts at the end of the study and, simultaneously, more than 90% reduction in tumor ER protein (Figures 1, 5, and 7). Furthermore, when a CDK4 / 6 inhibitor is combined with compound (I-c) in the MCF7 model, more significant tumor growth inhibition is observed (131% TGI) (Figure 8). Compound (I-c) causes 65% growth inhibition in tamoxifen-resistant MCF7 xenografts, and when compound (I-c) is combined with palbociclib, it results in greater tumor growth inhibition (113% TGI) compared to the single-agent treatment group of palbociclib (91% TGI) (Table 8 and Figure 9). In a clinically relevant ESR1 Y537S variant model, a hormone-independent patient-derived xenograft model, 10 mg / kg of compound (I-c) completely inhibits proliferation and also significantly reduces mutant ER protein levels (Figure 22). In summary, the preclinical data of compound (I-c) support its continued advancement as an orally administrable ER proteolytic agent.

[0379] (Table 10) Summary of in vivo tests using compound (I-c) TIFF2025094174000080.tif59163nd: Undetermined

[0380] Oral administration of compound (I-c) results in more reliable tumor growth inhibition and ERα degradation compared to fulvestrant in the orthotopic MCF7 / estradiol xenograft model (FIGS. 19 and 20, Table 10). The combination of compound (I-c) and palbociclib results in significant tumor regression and overall superior antitumor activity compared to the combination of fulvestrant and palbociclib (FIGS. 20-22 and Table 10).

[0381] Compound (I-c) inhibits the growth of tamoxifen-resistant tumors and ESR1 (Y537S) tumors while also reducing tumor ERα levels (FIG. 22, Table 10).

[0382] Equivalents One of ordinary skill in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments specifically described herein. Such equivalents are intended to be encompassed by the following claims.

[0383] The methods of the present disclosure are described herein by reference to specific preferred embodiments. However, since certain variations thereof will be apparent to those of ordinary skill in the art, the present disclosure is not considered to be limited thereto based on the disclosure described herein.

[0384] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In this specification and the claims, the singular forms also include the plural unless the context clearly dictates otherwise.

[0385] Of course, while at least some of the description of the present disclosure has been simplified to focus on elements relevant to a clear understanding of the present disclosure, to be clear, other elements understood by those skilled in the art may be excluded and may form part of the present disclosure. However, since such elements are well known in the art and do not necessarily facilitate a better understanding of the present disclosure, an explanation of such elements is not provided herein.

[0386] Furthermore, unless the method depends on a particular order of the steps recited herein, the particular order of the steps recited in the claims should not be construed as a limitation on that claim.

[0387] All patents, patent applications, references, and published documents cited herein are hereby incorporated by reference in their entirety as if fully set forth. Such documents are not admitted to be prior art to the present disclosure.

Claims

1. A method of treating breast cancer in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of a compound of formula (I): or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof to said subject; During the ceremony, Each R １ and each R ２ are independent, halo, OR ５ , N(R ５ ) (R ６ ), NO ２ , C.N., S.O. ２ (R ５ ), C １ ~C ６ Alkyl, and C ３ ~C ６ cycloalkyl; R ３ and R ４ are either both hydrogen or together with the carbon to which they are attached form a carbonyl, Each R ５ and each R ６ are independently hydrogen, C １ ~C ６ Alkyl, and C ３ ~C ６ cycloalkyl; m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, or 4; The therapeutically effective amount of the compound of formula (I) is from about 10 mg to about 1000 mg.

2. The method of claim 1, wherein the breast cancer is ER+, HER2-.

3. 3. The method of claim 1 or 2, wherein the breast cancer is metastatic or locally advanced.

4. R １ and R ２ each independently represents halo and OR ５ The method according to any one of claims 1 to 3, wherein the compound is selected from the group consisting of:

5. R ３ and R ４ The method of any one of claims 1 to 4, wherein both are hydrogen.

6. R ３ and R ４ The method according to any one of claims 1 to 4, wherein, together with the carbon to which they are attached, form a carbonyl.

7. The method of any one of claims 1 to 3, 5, or 6, wherein m and n are each 0.

8. The method of any one of claims 1 to 6, wherein m and n are each 1.

9. The method of any one of claims 1 to 3, 5, or 6, wherein one of m and n is 0 and the other is 1.

10. The compound of formula (I) or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug of any of the foregoing.

11. The compound of formula (I) is a compound of formula (I-c): The method according to any one of claims 1 to 3, wherein

12. The method of any one of claims 1 to 11, wherein the compound of formula (I) is administered orally to the subject.

13. 13. The method of any one of claims 1 to 12, wherein the therapeutically effective amount of a compound of formula (I) is administered to the subject once a day, twice a day, three times a day, or four times a day.

14. The method of any one of claims 1 to 13, wherein the therapeutically effective amount of a compound of formula (I) is administered to the subject once a day.

15. The method according to claims 1 to 12, wherein the therapeutically effective amount of the compound of formula (I) is administered to the subject once or in two, three or four portions.

16. The method of any one of claims 1 to 15, wherein the therapeutically effective amount of the compound of formula (I) is about 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg.

17. The method according to any one of claims 1 to 15, wherein the therapeutically effective amount of the compound of formula (I) is from about 20 mg to about 750 mg.

18. The method according to any one of claims 1 to 15, wherein the therapeutically effective amount of the compound of formula (I) is from about 30 mg to about 500 mg.

19. The method according to any one of claims 1 to 15, wherein the therapeutically effective amount of the compound of formula (I) is from about 30 mg to about 120 mg.

20. and / or greater than about 4,500 ng.hr / mL, greater than about 3,600 ng.hr / mL, greater than about 3,700 ng.hr / mL, greater than about 3,800 ng.hr / mL, greater than about 3,900 ng.hr / mL, greater than about 4,000 ng.hr / mL, greater than about 4,100 ng.hr / mL, greater than about 4,200 ng.hr / mL, greater than about 4,300 ng.hr / mL, greater than about 4,400 ng.hr / mL, greater than about 4,500 ng.hr / mL, greater than about 4,600 ng.hr / mL, greater than about 4,700 ng.hr / mL, greater than about 4,800 ng.hr / mL, greater than about 4,900 ng.hr / mL, or greater than about 5,000 ng.hr / mL. ＴＡＵ The method according to any one of claims 1 to 19, wherein

21. The therapeutically effective amount of a compound of formula (I) provides a day 15 mean AUC of greater than about 4,000 ng-hr / mL and less than about 4,500 ng-hr / mL. ＴＡＵ The method according to any one of claims 1 to 19, wherein

22. The therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 200 ng / mL, greater than about 205 ng / mL, greater than about 210 ng / mL, greater than about 215 ng / mL, greater than about 220 ng / mL, greater than about 225 ng / mL, greater than about 230 ng / mL, greater than about 235 ng / mL, greater than about 240 ng / mL, greater than about 245 ng / mL, or greater than about 250 ng / mL. ｍａｘ The method according to any one of claims 1 to 21, wherein

23. The therapeutically effective amount of a compound of formula (I) provides a day 15 mean C of greater than about 215 ng / mL and less than about 235 ng / mL. ｍａｘ The method according to any one of claims 1 to 21, wherein

24. The method according to any one of claims 1 to 23, wherein the compound of formula (I) is formulated as a tablet.

25. 25. The method of claim 24, wherein the tablet comprises a compound of formula (I) and, optionally, one or more of an emulsifier, a surfactant, a binder, a disintegrant, a glidant, and a lubricant.

26. 26. The method of claim 25, wherein the emulsifier is hypromellose.

27. 26. The method of claim 25, wherein the surfactant is vitamin E polyethylene glycol succinate.

28. 26. The method of claim 25, wherein the binder is microcrystalline cellulose or lactose monohydrate.

29. 26. The method of claim 25, wherein the disintegrant is croscarmellose sodium.

30. 26. The method of claim 25, wherein the flow agent is silicon dioxide.

31. 26. The method of claim 25, wherein the lubricant is sodium stearyl fumarate.

32. The method of any one of claims 1 to 31, further comprising administering to the subject in need thereof a therapeutically effective amount of a CDK4 / 6 inhibitor.

33. 33. The method of claim 32, wherein the CDK4 / 6 inhibitor is SHR6390, trilaciclib, relociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, or palbociclib.

34. 33. The method of claim 32, wherein the CDK4 / 6 inhibitor is palbociclib.

35. 35. The method of claim 34, wherein the therapeutically effective amount of palbociclib is administered to the subject once a day.

36. 36. The method of claim 34 or 35, wherein the therapeutically effective amount of palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg.

37. 37. The method of any one of claims 33-36, wherein the palbociclib is administered once daily for up to 21 consecutive days, followed by up to 7 consecutive days of rest from treatment, and the cycle of palbociclib treatment followed by rest from treatment is repeated one, two, three, four, five or more times.

38. 38. The method of any one of claims 1-37, wherein the compound of formula (I) is administered once daily for up to 21 consecutive days, followed by up to 7 consecutive days off treatment, and the cycle of treatment with the compound of formula (I) followed by off treatment is repeated one, two, three, four, five or more times.

39. The method of any one of claims 1 to 38, wherein the subject is in a fed state.

40. The method of any one of claims 1 to 38, wherein the subject is in a fasted state.

41. 1. A method of treating metastatic breast cancer in a subject in need thereof, comprising once daily oral administration of a therapeutically effective amount of a compound of formula (I), wherein said compound of formula (I) is or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug of any of the foregoing.

42. The compound of formula (I) is a compound of formula (I-c):

42. The method of claim 41 , wherein:

43. 43. The method of claim 41 or 42, wherein the therapeutically effective amount of a compound of formula (I) is administered to the subject at once or in two, three, or four portions.

44. The method according to any one of claims 41 to 43, wherein the therapeutically effective amount of the compound of formula (I) is from about 30 mg to about 1000 mg.

45. The method according to any one of claims 41 to 44, wherein the compound of formula (I) is formulated as a tablet.

46. 46. ​​The method of any one of claims 41 to 45, further comprising administration to the subject in need thereof a therapeutically effective amount of a CDK4 / 6 inhibitor.

47. 47. The method of claim 46, wherein the CDK4 / 6 inhibitor is SHR6390, trilaciclib, relociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, or palbociclib.

48. 47. The method of claim 46, wherein the CDK4 / 6 inhibitor is palbociclib.

49. 49. The method of claim 48, wherein the therapeutically effective amount of palbociclib is administered to the subject once a day.

50. 50. The method of claim 48 or 49, wherein the therapeutically effective amount of palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg.

51. 51. The method of any one of claims 48-50, wherein the palbociclib is administered once daily for up to 21 consecutive days, followed by up to 7 consecutive days of rest from treatment, and wherein the cycle of palbociclib treatment followed by rest from treatment is repeated one, two, three, four, five or more times.

52. 52. The method of any one of claims 41-51, wherein the compound of formula (I) is administered once daily for up to 21 consecutive days, followed by up to 7 consecutive days of rest from treatment, and the cycle of treatment with the compound of formula (I) followed by rest from treatment is repeated one, two, three, four, five or more times.

53. The method of any one of claims 41 to 52, wherein the subject is in a fed state.

54. The method of any one of claims 41 to 52, wherein the subject is in a fasted state.

55. 55. The method of any one of claims 46 to 54, wherein administration of the CDK4 / 6 inhibitor occurs prior to administration of the compound of formula (I).

56. 56. The method of claim 55, wherein administration of the CDK4 / 6 inhibitor occurs at least 30 minutes prior to administration of the compound of formula (I).

57. 55. The method of any one of claims 46 to 54, wherein the administration of the CDK4 / 6 inhibitor occurs after the administration of the compound of formula (I).

58. 58. The method of claim 57, wherein administration of the CDK4 / 6 inhibitor occurs at least 30 minutes after administration of the compound of formula (I).

59. 1. A method of treating metastatic breast cancer in a subject in need thereof, comprising: (i) a therapeutically effective amount of a compound of formula (I-c): or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, and (ii) Palbociclib administered orally once daily. A method comprising:

60. 1. A method of treating metastatic breast cancer in a subject in need thereof, comprising: (i) a therapeutically effective amount of a compound of formula (I-c): once daily by oral administration, and (ii) Palbociclib administered orally once daily. A method comprising:

61. The method according to claim 59 or claim 60, wherein the therapeutically effective amount of the compound of formula (Ic) is from about 30 mg to about 1000 mg.

62. 62. The method of any one of claims 59-61, wherein the therapeutically effective amount of palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg.

63. 63. The method of any one of claims 59-62, wherein the palbociclib is administered once daily for up to 21 consecutive days, followed by up to 7 consecutive days of rest from treatment, and wherein the cycle of palbociclib treatment followed by rest from treatment is repeated one, two, three, four, five or more times.

64. 63. The method of any one of claims 59-62, wherein 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, and 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.

65. The method of any one of claims 59 to 64, wherein the subject is in a fed state.

66. The method of any one of claims 59 to 64, wherein the subject is in a fasted state.

67. The method of any one of claims 59 to 66, wherein the administration of palbociclib occurs prior to the administration of the compound of formula (Ic).

68. 68. The method of claim 67, wherein the administration of palbociclib occurs at least 30 minutes prior to the administration of the compound of formula (I-c).

69. The method of any one of claims 59 to 66, wherein the administration of palbociclib occurs after the administration of the compound of formula (Ic).

70. 70. The method of claim 69, wherein the administration of palbociclib occurs at least 30 minutes after the administration of the compound of formula (I-c).

71. 1. A method for selective estrogen receptor degradation in a patient, comprising: (i) a therapeutically effective amount of a compound of formula (I-c): or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, and (ii) Palbociclib administered orally once daily. A method comprising:

72. 1. A method for inhibiting a cyclin dependent kinase in a subject in need thereof, comprising: (i) a therapeutically effective amount of a compound of formula (I-c): or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, and (ii) Palbociclib administered orally once daily. A method comprising:

73. (i) A compound of formula (I-c): (ii) palbociclib, and (iii) Instructions for use Including the kit.

74. A surfactant, a solvent, and a compound of formula (I-c): A liquid composition comprising:

75. 75. The liquid composition of claim 74, wherein the surfactant is Tween 80.

76. 76. The liquid composition of claim 74 or 75, wherein the solvent is PEG-400.

77. A surfactant, a solvent, and a compound of formula (I-c):

1. A method of making a liquid composition comprising the step of adding said solvent to a pre-aliquoted amount of said surfactant.

78. 78. The method of claim 77, wherein the surfactant is Tween 80.

79. 79. The method of claim 77 or 78, wherein the solvent is PEG-400.

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