Methods for treating breast cancer using tetrahydronaphthalene derivatives as estrogen receptor degraders

Abstract

The present application relates to the treatment and / or prevention of breast cancer, including locally advanced or metastatic ER+, HER2- breast cancer, in a subject in need thereof, comprising administering to a subject a compound of formula (I): TIFF2022546471000081.tif55128 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein R 1 , R 2 , R3, R4, m, and n are defined herein. TIFF2022546471000082.tif121138

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Patent Application No. 63 / 023,067, filed May 11, 2020, U.S. Patent Application No. 62 / 942,663, filed December 2, 2019, U.S. Patent Application No. 62 / 924,653, filed October 22, 2019, and U.S. Patent Application No. 62 / 891,648, filed August 26, 2019, each of which is incorporated by reference in its entirety.

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

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

[0004] As of January 2017, it is estimated that approximately 155,000 women with metastatic breast cancer (mBC) were living in the United States. It has also been reported that the number of women living with mBC is increasing, mainly due to improved treatment and the aging of the US population. The estimated number of women living with mBC increased by 17% from 2000 to 2010 and is projected to increase by 31% from 2010 to 2020 (Marioto AB 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, i.e., estrogen receptor (ER) and / or progesterone receptor, or human epidermal growth factor receptor 2 (HER2). The standard of care for women with mBC is endocrine therapy, chemotherapy, and / or targeted therapy, alone or in combination. Patients with ER-positive (ER+) and HER2-negative (HER2-) mBC are treated with endocrine therapy, sometimes in combination with targeted agents such as CDK4 / 6 inhibitors (CDKi). In patients with aggressive disease, or whose disease continues to progress on endocrine therapy, chemotherapy may be prescribed.

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

[0007] Fulvestrant is considered a fundamental component of ER-targeted endocrine regimens in advanced disease settings, acting via an indirect mechanism of proteolysis, resulting in ER destabilization. Single-agent fulvestrant is administered intramuscularly at 500 mg on days 1, 15, and 29, and once 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 antiestrogen or progestin for breast cancer in the adjuvant or advanced disease setting. In both studies, eligible patients with measurable and / or evaluable disease were randomized to receive either fulvestrant 250 mg intramuscularly once a month (28 days + 3 days) or anastrozole 1 mg orally once a day. The results of the studies excluded the inferiority of fulvestrant to anastrozole after a minimum follow-up of 14.6 months. There was no statistically significant difference in overall survival (OS) between the two treatment arms after more than 2 years of follow-up. The third study compared a dose of fulvestrant 500 mg with a dose of fulvestrant 250 mg. The results of this study after a minimum follow-up of 18 months showed a statistically significant superior progression-free survival (PFS) with fulvestrant 500 mg versus fulvestrant 250 mg (6.5 vs. 5.4 months, respectively). There was no statistically significant difference in OS between the two treatment groups (25.1 months with fulvestrant 500 mg and 22.8 months with fulvestrant 250 mg). 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 Document 1] Seigel RLet al.Cancer Statistics,CA Cancer J Clin.2018,68(1);7-30. [Non-Patent Document 2] Mariotto ABet al. “Estimation of the Number of Women Living with Metastatic Breast Cancer in the United States” Cancer Epidemiol. Biomarkers Prev. 2017, 26(6):809-815. [Non-Patent Document 3] Astra Zeneca Faslodex Full Prescribing Information, Revised March 2019 Summary of the Invention

[0009] Summary of the Disclosure In one aspect, the present application relates to a method of treating breast cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of formula (I): administering to a subject TIFF0007656589000001.tif55128 or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof; During the ceremony, 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.

[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 is independently selected from the group consisting of halo and OR5.

[0013] In one embodiment, R3 and R4 are both 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 TIFF0007656589000002.tif139128TIFF0007656589000003.tif176128TIFF0007656589000004.tif94128 or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug of any of the foregoing.

[0017] In one embodiment, the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically 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 a compound of formula (I) is administered to a subject once a day, twice a day, three times a day, or four times a day. In one embodiment, a therapeutically effective amount of a compound of formula (I) is administered to a subject once a day. In one embodiment, a therapeutically effective amount of a compound of formula (I) is administered to a subject all at once, or in two, three, or four portions.

[0020] In one embodiment, the therapeutically effective amount of a 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, the therapeutically effective amount of the compound of formula (I) is from about 10 mg to about 1000 mg.

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

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

[0024] In one embodiment, the 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 230 to about 240 mg, about 250 to about 260 mg, about 270 to about 280 mg, about 290 to about 300 mg, about 310 to about 320 mg, about 330 to about 340 mg, about 350 to about 360 mg, about 370 to about 380 mg, about 390 to about 400 mg, about 410 to about 420 mg, about 430 to about 440 mg, about 450 to about 460 mg, about 470 to about 480 mg, about 490 to about 500 mg, about 510 to about 520 mg, about 530 to about 540 mg, about 550 to about 560 mg, about 570 to about 580 mg, about 590 to about 600 mg, about 600 to about 610 mg, about 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, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC of more than about 3,500 ng·hr / mL, about 3,600 ng·hr / mL, about 3,700 ng·hr / mL, about 3,800 ng·hr / mL, about 3,900 ng·hr / mL, about 4,000 ng·hr / mL, about 4,100 ng·hr / mL, about 4,200 ng·hr / mL, about 4,300 ng·hr / mL, 4,400 ng·hr / mL, about 4,500 ng·hr / mL, about 4,600 ng·hr / mL, about 4,700 ng·hr / mL, about 4,800 ng·hr / mL, about 4,900 ng·hr / mL, or about 5,000 ng·hr / mL. TAU results.

[0027] In one embodiment, a therapeutically effective amount of a compound of Formula (I) has a day 15 mean AUC of greater than about 3,500 ng·hr / mL and less than about 4,000 ng·hr / mL. TAU In one embodiment, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAUIn one embodiment, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In one embodiment, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In one embodiment, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In one embodiment, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In one embodiment, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In one embodiment, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In one embodiment, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In one embodiment, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In one embodiment, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In one embodiment, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In one embodiment, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAUIn one embodiment, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In one embodiment, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In one embodiment, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU results.

[0028] In one embodiment, a therapeutically effective amount of a compound of Formula (I) has a day 15 mean AUC of greater than about 4,000 ng·hr / mL and less than about 4,200 ng·hr / mL. TAU In one embodiment, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In one embodiment, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In one embodiment, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU In one embodiment, a therapeutically effective amount of a compound of Formula (I) provides a day 15 mean AUC TAU results.

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

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

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

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

[0033] In one embodiment, the compound of formula (I) is formulated as a tablet. In one embodiment, the tablet comprises a compound of formula (I) and, optionally, one or more of the following: an emulsifier, a surfactant, a binder, a disintegrant, a flow agent, 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 flow agent 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 fasted state.

[0034] In one aspect, the present application relates to 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) 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, relociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, or palbociclib. In one embodiment, the CDK4 / 6 inhibitor is palbociclib.

[0035] In one embodiment, a method for treating breast cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I) to the subject and further comprising administering a therapeutically effective amount of palbociclib, wherein a 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 up to 7 consecutive days off treatment, wherein the cycle of palbociclib treatment followed by off treatment is repeated once, twice, three times, four times, five times, or more times. In one embodiment, the compound of formula (I) is administered once a day for up to 21 consecutive days, followed by up to 7 consecutive days off treatment, wherein the cycle of palbociclib treatment followed by off treatment is repeated once, twice, three times, four times, five times, 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 fasted state.

[0036] In one aspect, the present application relates to 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), or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein the compound of formula (I) is TIFF0007656589000005.tif139128TIFF0007656589000006.tif176128TIFF0007656589000007.tif94128.

[0037] In one embodiment, a therapeutically effective amount of a compound of formula (I) is administered to a subject all at once or in 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 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 230 to about 240 mg, about 250 to about 260 mg, about 270 to about 280 mg, about 290 to about 300 mg, about 310 to about 320 mg, about 330 to about 340 mg, about 350 to about 360 mg, about 370 to about 380 mg, about 390 to about 400 mg, about 410 to about 420 mg, about 430 to about 440 mg, about 450 to about 460 mg, about 470 to about 480 mg, about 490 to about 500 mg, about 510 to about 520 mg, about 530 to about 540 mg, about 550 to about 560 mg, about 570 to about 580 mg, about 590 to about 600 mg, about 600 to about 610 mg, about 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.

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

[0041] In one aspect, the present application relates to 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 (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ii), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, and 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, relociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, or palbociclib. In one embodiment, the CDK4 / 6 inhibitor is palbociclib.

[0042] In one embodiment, for a method of treating breast cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), or Formula (Ii) to the subject and further comprising administration of a therapeutically effective amount of palbociclib, the therapeutically effective amount of palbociclib is administered simultaneously with the administration of the compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), or Formula (Ii). In one embodiment, for a method of treating breast cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), or Formula (Ii) to the subject and further comprising administration of a therapeutically effective amount of palbociclib, the therapeutically effective amount of palbociclib is administered prior to administration of the compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), or Formula (Ii). In one embodiment, for a method of treating breast cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), or Formula (Ii) to the subject and further comprising administration of a therapeutically effective amount of palbociclib, the therapeutically effective amount of palbociclib is administered following administration of the compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), or Formula (Ii).In some embodiments, for a method of treating breast cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), or Formula (Ii) to the subject and further comprising administration of a therapeutically effective amount of palbociclib, the administration of the compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), or Formula (Ii) and the administration of palbociclib are separated in time such that the two compounds and their respective excipients (if present) do not mix in the subject's stomach.

[0043] In one embodiment, for a method of treating breast cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), or Formula (Ii) to the subject and further comprising administration of a therapeutically effective amount of palbociclib, 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 prior to administration of the compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), or Formula (Ii). In one embodiment, for a method of treating breast cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), or Formula (Ii) to the subject and further comprising administration of a therapeutically effective amount of palbociclib, the therapeutically effective amount of palbociclib is administered at least 30 minutes prior to administration of the compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), or Formula (Ii). In one embodiment, for a method of treating breast cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) to the subject and further comprising administration of a therapeutically effective amount of palbociclib, the therapeutically effective amount of palbociclib is administered between 30 and 60 minutes prior to administration of the compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii).

[0044] In one embodiment, for a method of treating breast cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), or Formula (Ii) to the subject and further comprising administration of a therapeutically effective amount of palbociclib, 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 (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), or Formula (Ii). In one embodiment, for a method of treating breast cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), or Formula (Ii) to the subject and further comprising administration of a therapeutically effective amount of palbociclib, the therapeutically effective amount of palbociclib is administered at least 30 minutes after administration of the compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), or Formula (Ii). In one embodiment, for a method of treating breast cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) to the subject and further comprising administration of a therapeutically effective amount of palbociclib, the therapeutically effective amount of palbociclib is administered between 30 and 60 minutes after administration of the compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii).

[0045] In one embodiment, for 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 (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), or Formula (Ii), and further comprising 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 up to 7 consecutive days of rest, where the cycle of treatment with palbociclib followed by rest is repeated once, twice, three times, four times, five times, or more times. In one embodiment, a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) is administered once daily for up to 21 consecutive days, followed by up to 7 consecutive days of rest from treatment, wherein the cycle of treatment with a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) followed by rest from treatment is repeated one, two, three, four, five, or more times. In one embodiment, the compound of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), or formula (Ii) and palbociclib are administered to a subject in need thereof when the subject is in a fed state. In one embodiment, the compound of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), or formula (Ii) and palbociclib are administered to a subject in need thereof when the subject is in a fasted state.

[0046] In one aspect, the present application provides a method of treating breast cancer in a subject in need thereof, comprising: (i) administering to a subject a therapeutically effective amount of a compound of formula (Ic): or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, and (ii) a 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) a once-daily oral administration of a therapeutically effective amount of a compound of formula (Ic), and (ii) a once-daily oral administration of palbociclib. In one embodiment, the therapeutically effective amount of the compound of formula (Ic) is 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 a day for up to 21 consecutive days, followed by up to 7 consecutive days of rest, where the cycle of treatment with palbociclib followed by rest is repeated once, twice, three times, four times, five times, or more. In one embodiment, the compound of formula (Ic) is administered once a day for up to 21 consecutive days, followed by up to 7 consecutive days of rest, where the cycle of treatment with the compound of formula (Ic) followed by rest is repeated once, twice, three times, four times, five times, or more. In one embodiment, the compound of formula (Ic) and palbociclib are administered to a subject in need thereof when the subject is in a fed state. In one embodiment, the compound of formula (Ic) and palbociclib are administered to a subject in need thereof when the subject is in a fasted state.

[0047] In one embodiment, for a method of treating breast cancer in a subject in need thereof, comprising a therapeutically effective amount of a compound of formula (Ic) administered orally once a day and further comprising a daily oral administration of palbociclib, the administration of the compound of formula (Ic) and the administration of palbociclib are separated in time such that the two compounds and their respective excipients (if present) are not mixed in the stomach of the subject. In one embodiment, for a method of treating breast cancer in a subject in need thereof, comprising a therapeutically effective amount of a compound of formula (Ic) administered orally once a day and further comprising a daily oral administration of palbociclib, palbociclib is administered before the administration of the compound of formula (Ic). In one embodiment, for a method of treating breast cancer in a subject in need thereof, comprising a therapeutically effective amount of a compound of formula (Ic) administered orally once a day and further comprising a 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 before the administration of the compound of formula (Ic). In one embodiment, for a method of treating breast cancer in a subject in need thereof, comprising once daily oral administration of a therapeutically effective amount of a compound of formula (Ic) and further comprising once daily oral administration of palbociclib, palbociclib is administered at least 30 minutes prior to administration of the compound of formula (Ic). In one embodiment, for a method of treating breast cancer in a subject in need thereof, comprising once daily oral administration of a therapeutically effective amount of a compound of formula (Ic) and further comprising once daily oral administration of palbociclib, palbociclib is administered between 30 and 60 minutes prior to administration of the compound of formula (Ic).

[0048] In one embodiment, for a method of treating breast cancer in a subject in need thereof, comprising a therapeutically effective amount of a compound of formula (Ic) administered orally once a day and further comprising a daily oral administration of palbociclib, palbociclib is administered after administration of the compound of formula (Ic). In one embodiment, for a method of treating breast cancer in a subject in need thereof, comprising a therapeutically effective amount of a compound of formula (Ic) administered orally once a day and further comprising a 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 administration of the compound of formula (Ic). In one embodiment, for a method of treating breast cancer in a subject in need thereof, comprising a therapeutically effective amount of a compound of formula (Ic) administered orally once a day and further comprising a daily oral administration of palbociclib, palbociclib is administered at least 30 minutes after administration of the compound of formula (Ic). In one embodiment, for a method of treating breast cancer in a subject in need thereof comprising once daily oral administration of a therapeutically effective amount of a compound of Formula (Ic), and further comprising once daily oral administration of palbociclib, wherein palbociclib is administered between 30 and 60 minutes after administration of the compound of Formula (Ic).

[0049] In one aspect, the present application provides a method for selective estrogen receptor degradation in a patient, comprising: (i) administering to a patient a therapeutically effective amount of a compound of formula (Ic): once daily oral administration of TIFF0007656589000009.tif45128 or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof; and (ii) A method comprising once-daily oral administration of palbociclib.

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

[0051] In one aspect, the present application relates to a compound of formula (Ic): TIFF0007656589000011.tif45128, relating to the kit, including palbociclib, and instructions for use.

[0052] In one aspect, the present application relates to a surfactant, a solvent, and a compound of formula (Ic): TIFF0007656589000012.tif45128. In some embodiments, the surfactant is a sorbitan derivative. In some embodiments, the surfactant is Tween 80. In some embodiments, the solvent is a 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 surfactant, a solvent, and a compound of formula (Ic): The present invention relates to a method of making a liquid composition comprising TIFF0007656589000013.tif45128, comprising adding a solvent to a pre-aliquoted amount of a surfactant. In some embodiments, the method further comprises adding a compound of formula (Ic) to the 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 a low molecular weight polyethylene glycol (PEG). In some embodiments, the solvent is polyethylene glycol (PEG)-400. [The present invention 1001] A method of treating breast cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I): TIFF0007656589000014.tif55128 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 , CN, SO 2 (R 5 )、C 1 ~C 6 Alkyl, and C 3 ~C 6 cycloalkyl; R 3 and R 4 are either both hydrogen or together with the carbon to which they are attached form a carbonyl, Each R 5 and 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 method, wherein the therapeutically effective amount of the compound of formula (I) is from about 10 mg to about 1000 mg. [The present invention 1002] The method of claim 1001, wherein said breast cancer is ER+, HER2-. [The present invention 1003] The method of any one of claims 1001 to 1002, wherein said breast cancer is metastatic or locally advanced. [The present invention 1004] R 1 and R 2 each independently represents halo and OR 5 Any of the methods according to claims 1001 to 1003, selected from the group consisting of: [The present invention 1005] R 3 and R 4 The method according to any one of 1001 to 1004, wherein both are hydrogen. [The present invention 1006] R 3 and R 4 are combined with the carbon to which they are attached to form a carbonyl. [The present invention 1007] The method of any one of 1001 to 1003, 1005, or 1006, wherein m and n are each 0. [The present invention 1008] The method of any one of 1001 to 1006, wherein m and n are each 1. [The present invention 1009] The method according to any one of claims 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) TIFF0007656589000015.tif91128TIFF0007656589000016.tif184128TIFF0007656589000017.tif134128 Or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug of any of the foregoing. [The present invention 1011] The compound of formula (I) is a compound of formula (Ic): TIFF0007656589000018.tif44128 The method according to any one of claims 1001 to 1003, [The present invention 1012] The method according to any one of claims 1001 to 1011, wherein said compound of formula (I) is orally administered to said subject. [The present invention 1013] The method of any of claims 1001 to 1012, wherein said therapeutically effective amount of a compound of formula (I) is administered to said subject once a day, twice a day, three times a day, or four times a day. [The present invention 1014] The method of any of claims 1001 to 1013, wherein said therapeutically effective amount of a compound of formula (I) is administered to said subject once a day. [The present invention 1015] The method of any one of claims 1001 to 1012, wherein said therapeutically effective amount of the compound of formula (I) is administered to said subject at once or in two, three or four portions. [The present invention 1016] The method of any one of claims 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] The method according to any one of claims 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] The method according to any one of claims 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] The method according to any one of claims 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] 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 Any of the methods of the present invention 1001 to 1019, which results in [The present invention 1021] The therapeutically effective amount of a compound of formula (I) has a day 15 mean AUC of greater than about 4,000 ng·hr / mL and less than about 4,500 ng·hr / mL. TAU Any of the methods of the present invention 1001 to 1019, which results in [The present invention 1022] 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 Any of the methods of the present invention 1001 to 1021, which results in [The present invention 1023] 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 Any of the methods of the present invention 1001 to 1021, which results in [The present invention 1024] The method according to any one of claims 1001 to 1023, wherein said compound of formula (I) is formulated as a tablet. [The present invention 1025] The method of claim 1024, wherein said 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. [The present invention 1026] The method of claim 10, wherein the emulsifier is hypromellose. [The present invention 1027] The method of claim 1025, wherein the surfactant is vitamin E polyethylene glycol succinate. [The present invention 1028] The method of claim 1025, wherein the binder is microcrystalline cellulose or lactose monohydrate. [The present invention 1029] The method of claim 1025, wherein the disintegrant is croscarmellose sodium. [The present invention 1030] The method of claim 1025, wherein the flow agent is silicon dioxide. [The present invention 1031] The method of claim 1025, wherein the lubricant is sodium stearyl fumarate. [The present invention 1032] The method of any of claims 1001 to 1031, further comprising administering a therapeutically effective amount of a CDK4 / 6 inhibitor to said subject in need thereof. [The present invention 1033] The method of claim 1032, wherein the CDK4 / 6 inhibitor is SHR6390, trilaciclib, relociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, or palbociclib. [The present invention 1034] The method of claim 1032, wherein the CDK4 / 6 inhibitor is palbociclib. [The present invention 1035] The method of claim 1034, wherein said therapeutically effective amount of palbociclib is administered to said subject once a day. [The present invention 1036] The method of any one of claims 1034 to 1035, wherein the therapeutically effective amount of palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg. [The present invention 1037] Any of the methods of claims 1033 to 1036, wherein the palbociclib is administered once daily for up to 21 consecutive days followed by a treatment break of up to 7 consecutive days, and the cycle of palbociclib treatment followed by a treatment break is repeated one, two, three, four, five or more times. [The present invention 1038] Any of the methods of claims 1001 to 1037, 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. [The present invention 1039] The method according to any one of claims 1001 to 1038, wherein the subject is in a fed state. [The present invention 1040] Any of the methods according to claims 1001 to 1038, wherein the subject is in a fasting state. [The present invention 1041] 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 TIFF0007656589000019.tif139128TIFF0007656589000020.tif176128TIFF0007656589000021.tif94128 or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug of any of the foregoing. [The present invention 1042] The compound of formula (I) is a compound of formula (Ic): TIFF0007656589000022.tif44128 The method of the present invention 1041. [The present invention 1043] The method of any one of claims 1041 to 1042, wherein said therapeutically effective amount of a compound of formula (I) is administered to said subject at once or in two, three or four portions. [The present invention 1044] The method according to any one of claims 1041 to 1043, wherein the therapeutically effective amount of the compound of formula (I) is from about 30 mg to about 1000 mg. [The present invention 1045] The method according to any one of claims 1041 to 1044, wherein said compound of formula (I) is formulated as a tablet. [The present invention 1046] The method of any of claims 1041 to 1045, further comprising administering to said subject in need thereof a therapeutically effective amount of a CDK4 / 6 inhibitor. [The present invention 1047] The method of claim 1046, wherein said CDK4 / 6 inhibitor is SHR6390, trilaciclib, relociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, or palbociclib. [The present invention 1048] The method of claim 1046, wherein said CDK4 / 6 inhibitor is palbociclib. [The present invention 1049] The method of claim 1048, wherein the therapeutically effective amount of palbociclib is administered to the subject once a day. [The present invention 1050] The method of any one of claims 1048 to 1049, wherein the therapeutically effective amount of palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg. [The present invention 1051] Any of the methods of claims 1048 to 1050, wherein the palbociclib is administered once daily for up to 21 consecutive days followed by a treatment break for up to 7 consecutive days, and the cycle of palbociclib treatment followed by a treatment break is repeated one, two, three, four, five or more times. [The present invention 1052] Any of the methods of claims 1041 to 1051, wherein the compound of formula (I) is administered once daily for up to 21 consecutive days followed by a period of up to 7 consecutive days off treatment, and the cycle of treatment with the compound of formula (I) followed by a period of off treatment is repeated one, two, three, four, five or more times. [The present invention 1053] The method according to any one of claims 1041 to 1052, wherein the subject is in a fed state. [The present invention 1054] Any of the methods of claims 1041 to 1052, wherein the subject is in a fasting state. [The present invention 1055] The method according to any one of claims 1046 to 1054, wherein the administration of said CDK4 / 6 inhibitor is performed prior to the administration of said compound of formula (I). [The present invention 1056] The method of claim 1055, wherein the administration of said CDK4 / 6 inhibitor occurs at least 30 minutes prior to the administration of said compound of formula (I). [The present invention 1057] The method according to any one of claims 1046 to 1054, wherein the administration of said CDK4 / 6 inhibitor is performed after the administration of said compound of formula (I). [The present invention 1058] 1057. The method of claim 1057, wherein the administration of said CDK4 / 6 inhibitor occurs at least 30 minutes after the administration of said compound of formula (I). [The present invention 1059] 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 (Ic): TIFF0007656589000023.tif45128 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: [The present invention 1060] 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 (Ic): TIFF0007656589000024.tif45128 once daily by oral administration, and (ii) Palbociclib administered orally once daily A method comprising: [The present invention 1061] The method of claim 1059 or 1060, wherein the therapeutically effective amount of the compound of formula (Ic) is about 30 mg to about 1000 mg. [The present invention 1062] The method of any of claims 1059 to 1061, wherein the therapeutically effective amount of palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg. [The present invention 1063] Any of the methods of claims 1059 to 1062, wherein the palbociclib is administered once daily for up to 21 consecutive days, followed by a treatment break for up to 7 consecutive days, and the cycle of palbociclib treatment followed by treatment break is repeated one, two, three, four, five or more times. [The present invention 1064] Any of the methods of claims 1059 to 1062, wherein the compound of formula (Ic) is administered once daily for up to 21 consecutive days followed by a period of up to 7 consecutive days off treatment, and the cycle of treatment with the compound of formula (Ic) followed by a period of off treatment is repeated one, two, three, four, five or more times. [The present invention 1065] Any of the methods of claims 1059 to 1064, wherein the subject is in a fed state. [The present invention 1066] Any of the methods of claims 1059 to 1064, wherein the subject is in a fasting state. [The present invention 1067] The method according to any one of claims 1059 to 1066, wherein the administration of palbociclib is performed prior to the administration of the compound of formula (Ic). [The present invention 1068] The method of claim 1067, wherein said administration of palbociclib occurs at least 30 minutes prior to said administration of the compound of formula (Ic). [The present invention 1069] The method according to any one of claims 1059 to 1066, wherein the administration of palbociclib is performed after the administration of the compound of formula (Ic). [The present invention 1070] The method of claim 1069, wherein said administration of palbociclib occurs at least 30 minutes after said administration of the compound of formula (Ic). [The present invention 1071] 1. A method for selective estrogen receptor degradation in a patient, comprising: (i) a therapeutically effective amount of a compound of formula (Ic): TIFF0007656589000025.tif45128 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: [The present invention 1072] 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 (Ic): TIFF0007656589000026.tif45128 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: [The present invention 1073] (i) A compound of formula (Ic): TIFF0007656589000027.tif45128 (ii) palbociclib, and (iii) Instructions for use Including the kit. [The present invention 1074] A surfactant, a solvent, and a compound of formula (Ic): TIFF0007656589000028.tif45128 A liquid composition comprising: [The present invention 1075] The liquid composition of the present invention 1074, wherein the surfactant is Tween 80. [The present invention 1076] The liquid composition of claim 1074 or 1075, wherein the solvent is PEG-400. [The present invention 1077] A surfactant, a solvent, and a compound of formula (Ic): TIFF0007656589000029.tif45128 1. A method of making a liquid composition comprising the step of adding said solvent to a pre-aliquoted amount of said surfactant. [The present invention 1078] The method of claim 1077, wherein the surfactant is Tween 80. [The present invention 1079] The method of any one of claims 1077 to 1078, wherein the solvent is PEG-400. [Brief description of the drawings]

[0054] [Figure 1]Figure 1 shows the results of tumor growth inhibition experiments (mean tumor volume (mm3) vs. time) associated with once-daily oral administration of compound (Ic) at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg compared to vehicle. In the MCF7 xenograft model, tumor growth inhibition (TGI) of 85%, 98%, and 124% was observed with compound (Ic) at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg, respectively, compared to the control group.

[0055] [Diagram 2] FIG. 2 is a Western blot experiment showing the reduction of ER in MCF7 xenograft tumors in response to administration of 3 mg / kg, 10 mg / kg, and 30 mg / kg of compound (Ic) (orally, once daily).

[0056] [Diagram 3] FIG. 3 is a pair of line graphs showing the mean concentration (ng / mL) of the compound of formula (Ic) over a 24 hour period following dosing on both days 1 and 15 of a Phase I clinical trial.

[0057] [Figure 4] FIG. 4 is a line graph depicting the mean trough concentrations (ng / mL) of compound (Ic) throughout the course of the Phase I clinical trial.

[0058] [Diagram 5] FIG. 5 is a graph and Western blot experiment showing the ERα degradation activity of compound (Ic) following three daily oral doses at 10 mg / kg.

[0059] [Figure 6]Figure 6 shows the results of a tumor growth inhibition study (mean tumor volume (mm3) vs. time) associated with once-daily oral administration of compound (Ic) at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg for 28 days compared to vehicle. In the MCF7 xenograft model, tumor growth inhibition (TGI) of 85%, 98%, and 124% was observed with compound (Ic) at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg, respectively, compared to the control group.

[0060] [Figure 7] FIG. 7 is a graph showing that daily oral administration of 3 mg / kg, 10 mg / kg, and 30 mg / kg of Compound (Ic) for 28 days reduced ERα levels by more than 94% compared to mice receiving vehicle only.

[0061] [Figure 8] Figure 8 shows the results of tumor growth inhibition experiments (mean tumor volume (mm3) vs. time) involving oral administration of compound (Ic) at a dose of 30 mg / kg once a day for 28 days, compound (Ic) (30 mg / kg, oral, once a day, for 28 days) + palbociclib (oral, once a day, 60 mg / kg for 28 days), fulvestrant (200 mg / kg, subcutaneous, twice a week for 2 weeks), and fulvestrant (200 mg / kg, subcutaneous, twice a week for 2 weeks) + palbociclib (oral, once a day, 60 mg / kg for 28 days) compared to vehicle. The combination of compound (Ic) and palbociclib resulted in significant tumor regression (131% TGI) compared to the activity of compound (Ic) as a single agent in this model (105% TGI). In contrast, fulvestrant administered subcutaneously as a single agent resulted in only modest tumor growth inhibition (46% TGI), while the combination of fulvestrant with palbociclib resulted in improved tumor growth inhibition (108% TGI), but not to the level achieved with compound (Ic) and palbociclib.

[0062] [Figure 9]Figure 9 shows the results of a tamoxifen-resistant MCF7 xenograft growth inhibition study (mean tumor volume (mm3) versus time) associated with oral administration of compound (Ic) at a dose of 30 mg / kg once daily for 28 days compared to palbociclib (60 mg / kg, orally, once daily, for 28 days), compound (Ic) (30 mg / kg, orally, once daily, for 28 days) plus palbociclib (60 mg / kg, orally, once daily, for 28 days), and vehicle. When compound (Ic) was combined with 60 mg / kg / day palbociclib, the combination regimen resulted in greater tumor growth inhibition (113% TGI) compared to the palbociclib monotherapy group (91% TGI).

[0063] [Figure 10] Figures 10, 11, and 12 are graphs showing the effect of administration of compound (Ic) (30 mg / kg, orally, once daily for 28 days; Figure 10), the effect of administration of palbociclib (60 mg / kg, orally, once daily for 28 days; Figure 12), and the effect of administration of compound (Ic) (30 mg / kg, orally, once daily for 28 days) plus palbociclib (60 mg / kg, orally, once daily for 28 days) (Figure 11) on in vivo ERα levels in a tamoxifen-resistant MCF7 xenograft experiment. [Figure 11] Same as above. [Figure 12] Same as above.

[0064] [Figure 13] FIG. 13 provides the results of several Western blot experiments comparing the in vitro ERα degradation activity of various concentrations of Fulvestrant and Compound (Ic) in several ER-positive breast cancer cell lines.

[0065] [Figure 14] FIG. 14 is a graph showing that the median maximal degradation concentration (DC50) of compound (Ic) in MCF7 cells is 0.9 nM.

[0066] [Figure 15]FIG. 15 provides the results of several Western blot experiments comparing the in vitro ERα degradation activity of various concentrations of Fulvestrant and Compound (Ic) in the clinically relevant ESR1 cell line variants Y537S and D538G.

[0067] [Figure 16] FIG. 16 is a graph showing the relative expression of GREB1 and PR in experiments with fulvestrant and compound (Ic) compared to vehicle (DMSO).

[0068] [Figure 17] FIG. 17 is a graph showing the effect of Fulvestrant (100 mg / kg, once daily, subcutaneously) and Compound (Ic) (30 mg / kg, once daily, orally) compared to vehicle on uterine weight.

[0069] [Figure 18] FIG. 18 is a Western blot comparing the in vivo ERα degradation activity of compound (Ic) (10 mg / kg orally for 3 days) to vehicle in a MCF7 / E2 xenograft model.

[0070] [Figure 19] Figure 19 shows the results of tumor growth inhibition experiments (mean tumor volume (mm3) vs. time) associated with oral administration of compound (Ic) at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg once a day for 28 days compared to vehicle. In the MCF7 / estradiol xenograft model, 85%, 98%, and 124% tumor growth inhibition (TGI) was observed for compound (Ic) at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg, respectively, compared to the control group.

[0071] [Figure 20]Figure 20 shows the results of tumor growth inhibition (mean tumor volume (mm3) vs. time) experiments in the MCF7 / estradiol model involving oral administration of compound (Ic) at a dose of 30 mg / kg once a day for 28 days, fulvestrant (200 mg / kg, subcutaneous, twice a week for 2 weeks), compound (Ic) (oral, 30 mg / kg once a day for 28 days) + palbociclib (oral, 60 mg / kg once a day for 28 days), and fulvestrant (200 mg / kg, subcutaneous, twice a week for 2 weeks) + palbociclib (oral, 60 mg / kg once a day for 28 days) compared to vehicle. Compared to the activity of compound (Ic) as a single agent in this model (105% TGI), the combination of compound (Ic) and palbociclib resulted in significant tumor regression (131% TGI). In contrast, fulvestrant administered subcutaneously as a single agent resulted in only modest tumor growth inhibition (46% TGI), while the combination of fulvestrant with palbociclib resulted in improved tumor growth inhibition (108% TGI), but not to the level achieved with compound (Ic) and palbociclib (131% TGI).

[0072] [Figure 21] Figure 21 shows the results of tumor growth inhibition (mean tumor volume (mm3) vs. time) experiments in tamoxifen-resistant MCF7 models involving oral administration of compound (Ic) at a dose of 30 mg / kg once a day for 28 days, palbociclib (oral, at a dose of 60 mg / kg once a day for 28 days), and compound (Ic) (oral, at a dose of 30 mg / kg once a day for 28 days) + palbociclib (oral, at a dose of 60 mg / kg once a day for 28 days) compared to vehicle. Compound (Ic) alone reduced tumor growth, but the combination of compound (Ic) and palbociclib resulted in improved inhibition of tumor growth compared to compound (Ic) alone (113% vs. 65%).

[0073] [Figure 22]Figure 22 shows the results of a tumor growth inhibition (mean tumor volume (mm3) vs. time) experiment in the ESR1(Y537S) PDX model associated with oral administration of compound (Ic) at a dose of 10 mg / kg or 30 mg / kg once daily for 28 days, or administration of fulvestrant (200 mg / kg, subcutaneous, twice weekly, for 2 weeks). At either a dose of 10 mg / kg or 30 mg / kg, compound (Ic) reduced tumor ERα levels to a greater extent compared to fulvestrant (79 / 88% vs. 63%) and resulted in improved inhibition of tumor growth compared to fulvestrant (99 / 106% vs. 62%). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0074] Detailed Description definition "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 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 carbocyclic ring containing from 3 to 6 carbon atoms, i.e., a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl moiety.

[0078] As used herein with respect to compounds of formula (I), "pharmaceutically acceptable salts" refers to salt forms of compounds of formula (I), as well as hydrate forms of salts in which one or more water molecules are present. Such salts and hydrate forms retain the biological activity of the compounds of formula (I) and are not biologically or otherwise undesirable, i.e., exhibit minimal, if any, toxicological effects. Representative "pharmaceutically acceptable salts" include, for example, acetate, anthonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, and 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-methane-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, theoclate, tosylate, triethiodide, and valerate salts.

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

[0080] Compounds of formula (I) may exist in unsolvated as well as solvated forms, such as, for example, hydrated forms.

[0081] "Solvate" means a solvent addition form that contains either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate, and if the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more water molecules with one of the substances in which water retains its molecular state as H2O, and such a combination can form one or more hydrates. In a hydrate, the water molecules are bonded through subvalence by intermolecular forces, in particular hydrogen bridges. A solid hydrate contains water in a stoichiometric ratio as the so-called water of crystallization, and the water molecules do not necessarily have to be equivalent in terms of their bonding state. Examples of hydrates include sesquihydrates, monohydrates, dihydrates, or trihydrates. Hydrates of salts of the compounds of the invention are also suitable.

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

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

[0084] The term "pharmaceutically acceptable prodrug" as used herein refers to a prodrug of a compound of formula (I) that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals having excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and is effective for its intended use, and preferably is a zwitterionic form of the compound of this 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 invention. Various forms of prodrugs are known in the art and are described, for example, in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). “Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 1 13-191 (1991); Bundgaard, et al., Journal of Drug Delivery Reviews, 8:1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, “Hydrolysis In Drug and Prodrug Metabolism: Chemistry, Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

[0086] The present invention also includes pharmaceutical compositions containing pharma- ceutically acceptable prodrugs of the compounds of the present invention, and methods of treating disorders by administering pharma- ceutically acceptable prodrugs of the compounds of the present invention. For example, compounds of the present invention having free amino, amide, hydroxy, or carboxylic acid groups can be converted into prodrugs. Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues is covalently linked to a free amino, hydroxy, or carboxylic acid group of a compound of the present invention by an amide or ester bond. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids commonly designated by three letter symbols, and also include 4-hydroxyproline, hydroxylysine, decomosine, isodecomosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Additional types of prodrugs are also included. For example, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups may be derivatized using groups including, but not limited to, hemisuccinate, phosphate ester, dimethylaminoacetate, and phosphoryloxymethyloxycarbonyl, as reviewed in Advanced Drug Delivery Reviews, 1996, 19, 1 15. Carbamate prodrugs of hydroxy and amino groups also include sulfonate and sulfate esters of hydroxy groups, as carbonate prodrugs. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers is also included, where the acyl group can be an alkyl ester, which may be substituted with groups including, but not limited to, ether, amine, and carboxylic acid functional groups, or the acyl group is an amino acid ester as described above. This type of prodrug is described in J.Med.Chem.1996, 39, 10. Free amines may also be derivatized as amides, sulfonamides, or phosphonamides.All of these prodrug moieties may incorporate groups including, but not limited to, ether, amine, and carboxylic acid functionalities. Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds.

[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 bones, liver, lungs, or brain. (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 tumor in the breast in the absence of distant metastases, where the tumor is greater than 5 cm in size with regional lymphadenopathy, any size tumor (including ulcers or satellite nodes) with direct extension to the chest wall or skin, or both, regardless of regional lymphadenopathy, and the presence of regional lymphadenopathy (either clinically fixed or matted axillary nodes, or subclavian, supraclavicular, or medial mammary lymphadenopathy), regardless of tumor stage. (Garg et al. Curr Oncol. 2015 Oct;22(5):e409-e410; National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology:Breast Cancer. Fort Washington, PA:NCCN;2015.Ver.2.2015.)

[0089] ER+, estrogen receptor positive, as used herein, refers to breast cancer cells that have a receptor protein that binds to the hormone estrogen. Cancer cells that are ER+ may require estrogen to grow and may stop growing or die when treated with substances that block the binding and action of estrogen. (https: / / www.cancer.gov / publications / dictionaries / cancer-terms / def / 44404.)

[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 slower 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, including the reduction or alleviation of symptoms or complications, or elimination of the disease, condition, or disorder.

[0092] As used herein, "prevent" refers to arresting the onset of a symptom or complication of a disease, condition, or disorder.

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

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

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

[0096] As used herein, "AUC" refers to the total area under the plasma concentration-time curve, which is a measure of exposure to a compound of interest and is the integral of the concentration-time curve after a single dose or at steady state. AUC is expressed in units of ng·hour / mL (ng × hour / mL).

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

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

[0099] "Controlled release agent," as used herein with respect to oral dosage forms of the present disclosure, refers to one or more substances or materials that modulate the release of the compound of formula (I) from the dosage form. Controlled release agents can be organic or inorganic, of natural origin or synthetic, such as polymeric materials, triglycerides, derivatives of triglycerides, fatty acids and salts of fatty acids, talc, boric acid, and colloidal silica.

[0100] As used herein, "oral dosage form" refers to a pharmaceutical product containing a specific amount (dose) of a compound of formula (I), or a pharma- ceutically acceptable salt and / or solvate thereof, as an active ingredient, and inactive ingredients (excipients), and formulated into a specific con?guration suitable for oral administration and drug delivery, such as a tablet, capsule, or liquid oral formulation. In one embodiment, the composition is in the form of a tablet that can be scored.

[0101] The term "carrier" as used in this disclosure encompasses carriers, excipients, and diluents, and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent 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 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 from 36 to 44 g.

[0103] "Comprising" or "comprises" as applied to a particular dosage form, composition, use, method, or process described or claimed herein means that the dosage form, composition, use, method, or process includes all of the elements recited in the particular statement or claim, but does not exclude other elements. "Consists essentially of" and "consisting essentially of" mean that the composition, dosage form, method, use, or process described or claimed does not exclude other materials or steps that do not substantially affect the recited physical, pharmacological, pharmacokinetic properties, or therapeutic efficacy of the composition, dosage form, method, use, or process. "Consists of" and "consisting of" refer to the exclusion of trace elements of other ingredients, and more than substantial method or process steps.

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

[0105] "Fed condition" or "fed state" as used herein to describe a subject means that the subject has consumed a meal for at least 4 hours prior to the time of interest, such as the time of administration of a compound of formula (I). In one embodiment, a subject in a fed state has not consumed a meal for 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 polysorbate 80, also known as polyoxyethylene (20) sorbitan monooleate, and sorbitan, mono-9-octadecenoate, poly(oxy-1,2-ethanediyl) derivative, (Z)-.

[0107] As used herein, "low molecular weight polyethylene glycol" or "low molecular weight PEG" generally refers to a polyethylene glycol (PEG) polymer having a molecular weight of less than 1500, 1400, 1300, 1200, 1100, 1000, 900, 800, 700, 600, 500, 400, or 300 Daltons. Examples of low molecular weight PEGs include PEG-200, PEG-400, and PEG-600.

[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, relociclib, 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 to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[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 a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey.

[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] Compounds of formula (I) 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 compound of formula (I).

[0118] In one aspect, the present application relates to the use of compounds 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: TIFF0007656589000030.tif55128, or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, During the ceremony, 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 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.

[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, OR, N(R)(R), or C-C alkyl. 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, OR, N(R)(R), or C-C alkyl. 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 is 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 TIFF0007656589000031.tif43128TIFF0007656589000032.tif187128TIFF0007656589000033.tif179128 or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0143] In one embodiment, the compound of formula (I) is a compound of formula (Ia): TIFF0007656589000034.tif43128 or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0144] In one embodiment, the compound of formula (I) is a compound of formula (Ib): TIFF0007656589000035.tif46128 or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0145] In one embodiment, the compound of formula (I) is a compound of formula (Ic), i.e., compound (Ic) or Cmp(Ic): TIFF0007656589000036.tif46128 or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0146] In one embodiment, the compound of formula (I) is a compound of formula (Ic), i.e., compound (Ic) or Cmp(Ic): The file is TIFF0007656589000037.tif46128.

[0147] In one embodiment, the compound of formula (I) is a compound of formula (Id): TIFF0007656589000038.tif46128 or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0148] In one embodiment, the compound of formula (I) is a compound of formula (Ie): TIFF0007656589000039.tif43128 or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0149] In one embodiment, the compound of formula (I) is a compound of formula (If): TIFF0007656589000040.tif43128 or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0150] In one embodiment, the compound of formula (I) is a compound of formula (Ig): TIFF0007656589000041.tif38133 or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0151] In one embodiment, the compound of formula (I) is a compound of formula (Ih): TIFF0007656589000042.tif46128 or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0152] In one embodiment, the compound of formula (I) is a compound of formula (Ii): TIFF0007656589000043.tif46128 or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0153] Compounds of formula (I) may be synthesized using standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations, including the use of protecting groups, as may be obtained from the relevant scientific literature or standard reference textbooks in the field, within the scope of this disclosure. Recognized reference textbooks on organic synthesis, without being limited to any one or several sources, include Smith, MB; March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, 1999, pp. 111-115, 2002; th ed.; John Wiley & Sons: New York, 2001; and Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 3 rd John Wiley & Sons: New York, 1999. Methods for preparing compounds of formula (I) are described in U.S. Patent Application Publication No. 2018 / 0155322, issued as U.S. Patent No. 10,647,698, the contents of which are incorporated herein in their entirety.

[0154] For example, compounds (Ib) and (Ic) 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 (Ib)): Step 1: Preparation of 6-tert-butoxytetralin-1-one TIFF0007656589000044.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. An additional amount of 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) was added and the reaction mixture was stirred at 10 °C for 15 h. This process was repeated three times. Thin-layer chromatography (petroleum ether:ethyl acetate=3:1, R f =0.8) indicated that most of the reactants were still remaining, and the reaction mixture was stirred at 10°C for 72 h. The reaction mixture was quenched by adding sodium bicarbonate solution (1500 mL) at 15°C, then extracted with dichloromethane (300 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 100:1 to 50:1) to give 6-tert-butoxytetralin-1-one (21 g, 96.20 mmol, 31% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ7.97(d,J=8.8Hz,1H),6.91(dd,J=2.4,8.8Hz,1H),6.82(d,J=2.0Hz, 1H), 2.93-3.90(t,J=6.0Hz,2H),2.63-2.60(m,t,J=6.0Hz,2H),2.13(m,2H),1.43(s,9H).

[0157] Step 2: (6-tert-butoxy-3,4-dihydronaphthalen-1-yl) Preparation of trifluoromethanesulfonate salt TIFF0007656589000045.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, then a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (72.01 g, 201.56 mmol, 1.1 equiv) in tetrahydrofuran (200 mL) was added dropwise to the mixture. The reaction mixture was stirred at 20 °C for 2 h. Thin layer chromatography (petroleum ether: ethyl acetate = 5:1) showed the reaction was complete. Saturated ammonium chloride (300 mL) was added to the mixture and the organic layer was separated. Ethyl acetate (500 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 to 50:1) to give (6-tert-butoxy-3,4-dihydronaphthalen-1-yl)trifluoromethanesulfonate (52 g, 144.64 mmol, 78% yield, 97% purity) as a yellow oil. LC-MS(ESI)m / z:294.9[M+1-56] + . 1 H-NMR (400MHz, CDCl3)δ:7.30(d,J=6.4Hz,1H),6.91(d,J=8.4Hz,1H),6.84(s,1H),5.95(s,1H),2.93-2.78(m,2H),2.59-2.46(m,2H),1.42(s,9H).

[0159] Step 3: Preparation of 4-(6-tert-butoxy-3,4-dihydronaphthalen-1-yl)phenol TIFF0007656589000046.tif19128

[0160] To a solution of (6-tert-butoxy-3,4-dihydronaphthalen-1-yl)trifluoromethanesulfonate (52 g, 148.42 mmol, 1 equiv.), (4-hydroxyphenyl)boronic acid (24.57 g, 178.11 mmol, 1.2 equiv.) in dioxane (800 mL) and water (150 mL), potassium carbonate (41.03 g, 296.84 mmol, 2 equiv.) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (10.86 g, 14.84 mmol, 0.1 equiv.) were added under nitrogen. The reaction mixture was stirred at 100 °C for 10 h. Thin layer chromatography (petroleum ether:ethyl acetate = 5:1) showed the reaction was complete. The residue was diluted with water (500 mL) and extracted with ethyl acetate (500 mL 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 to 20:1) to give 4-(6-tert-butoxy-3,4-dihydronaphthalen-1-yl)phenol (43 g, 131.46 mmol, 88% yield, 90% purity) as a yellow oil. LCMS (ESI) m / z: 239.1 [M+1-56] + ; 1 H-NMR(400MHz,CDCl3)δ7.23(d,J=7.6Hz,2H),6.91(d,J=8.0Hz,1H),6.87-6.79(m,3H),6.73(d, J=8.4Hz,1H),5.95(s,1H),4.83-4.75(m,1H),2.87-2.73(m,2H),2.44-2.31(m,2H),1.37(s,9H).

[0161] Step 4: Preparation of 4-(2-bromo-6-tert-butoxy-3,4-dihydronaphthalen-1-yl)phenol TIFF0007656589000047.tif27128

[0162] To a solution of 4-(6-tert-butoxy-3,4-dihydronaphthalen-1-yl)phenol (1 g, 3.06 mmol, 1 equiv.) in acetonitrile (20 mL) was added N-bromosuccinimide (489 mg, 2.75 mmol, 0.9 equiv.) in three portions. The reaction mixture was stirred at 20° C. for 1.5 h. LC-MS showed the reaction was complete. The residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×2). The combined organic layer was washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:0-20:1) to give 4-(2-bromo-6-tert-butoxy-3,4-dihydronaphthalen-1-yl)phenol (1 g, 2.46 mmol, 80% yield, 91% purity) as a yellow oil. LC-MS (ESI) m / z: 316.9 [M+1-56] + ; 1 H-NMR(400MHz,CDCl3)δ7.12(d,J=8.4Hz,2H),6.90(d,J=8.0Hz,2H),6.77(s,1H ),6.69-6.62(m,1H),6.60-6.53(m,1H),4.86(s,1H),2.96(s,4H),1.35(s,9H).

[0163] Step 5: Preparation of 4-(6-tert-butoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenol TIFF0007656589000048.tif24128

[0164] To a solution of 4-(2-bromo-6-tert-butoxy-3,4-dihydronaphthalen-1-yl)phenol (1g, 2.46mmol, 1eq), phenylboronic acid (314mg, 2.58mmol, 1.05eq) in dioxane (10mL) and water (2mL) was added potassium carbonate (678mg, 4.91mmol, 2eq) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (179mg, 0.24mmol, 0.1eq) under nitrogen. The reaction mixture was stirred at 100°C for 12 hours. LC-MS showed the reaction was complete. The residue was diluted with water (20mL) and extracted with ethyl acetate (20mLx2). The combined organic layer was washed with brine (20mLx3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:0-10:1) to give 4-(6-tert-butoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenol (930 mg, 2.35 mmol, 95% yield, 93% purity) as an orange oil. LCMS (ESI) m / z: 314.1 [M+1-56] + ; 1 H-NMR(400MHz,CDCl3)δ7.16-7.09(m,2H),7.08-6.99(m,3H),6.97-6.89(m,2H),6.86-6.82 (m,1H),6.74-6.66(m,4H),4.70(s,1H),2.99-2.89(m,2H),2.84-2.75(m,2H),1.37(s,9H).

[0165] Step 6: Preparation of 4-(6-tert-butoxy-2-phenyl-tetralin-1-yl)phenol TIFF0007656589000049.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 activated carbon catalyst (100 mg, 10% purity) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred under hydrogen (50 psi) at 30° C. for 36 h. LC-MS showed the reaction was complete. The reaction mixture was filtered and the solution was concentrated. The resulting material was used directly in the next step without further purification to give cis-4-(6-tert-butoxy-2-phenyl-tetralin-1-yl)phenol (870 mg, 2.14 mmol, 91% yield, 91% purity) as a white solid. LC-MS (ESI) m / z: 317.0 [M+1-56] + ; 1 H-NMR(400MHz,CDCl3)δ7.22-7.12(m,3H),6.89-6.78(m,4H),6.74(dd,J=2.0,8.4Hz,1H),6.45(d,J=8.4Hz,2H),6.27(d,J=8.4Hz,2H), 4.51(s,1H),4.25(d,J=4.8Hz,1H),3.38(dd,J=3.2,12.8Hz,1H),3.08-2.99(m,2H),2.27-2.08(m,1H),1.87-1.76(m,1H),1.37(s,9H).

[0167] Step 7: Preparation of 4-[(1S,2R)-6-tert-butoxy-2-phenyl-tetralin-1-yl]phenol TIFF0007656589000050.tif24128

[0168] 4-(6-tert-butoxy-2-phenyl-tetralin-1-yl)phenol (870 mg, 2.13 mmol, 1 equiv.) was subjected to supercritical fluid chromatography for chiral separation (column: AD, 250 mm × 30 mm, 5 um; mobile phase: 0.1% ammonium hydroxide in methanol, 20% to 20%, 4.2 min for each run) to obtain 4-[(1S,2R)-6-tert-butoxy-2-phenyl-tetralin-1-yl]phenol (420 mg, 1.04 mmol, 97% yield, 92% purity) as the first fraction, and 4-[(1R,2S)-6-tert-butoxy-2-phenyl-tetralin-1-yl]phenol (420 mg, 1.04 mmol, 97% yield, 92% purity) as the second fraction. Fraction 1: [α] D =+336.9(C=0.50g / 100mL in ethyl acetate, 25℃), LC-MS(ESI) m / z:395.1[M+23] + ; 1 H NMR(400MHz,DMSO-d6)δ9.02(s,1H),7.20-7.07(m,3H),6.87-6.79(m,3H),6.79-6.72(m,1H),6.71-6.64(m,1H),6.36(d,J=8.4Hz,2H) ,6.15(d,J=8.4Hz,2H),4.19(d,J=4.8Hz,1H),3.31-3.26(m,1H),3.09-2.89(m,2H),2.17-2.04(m,1H),1.79-1.65(m,1H),1.29(s,9H). Fraction 2: [α] D =-334.1 (C=0.50g / 100mL in ethyl acetate, 25℃), LC-MS(ESI) m / z:395.2[M+23] + ; 1 H-NMR(400MHz,DMSO-d6)δ:9.02(s,1H),7.21-7.06(m,3H),6.88-6.78(m,3H),6.78-6.72(m,1H),6.71-6.64(m,1H),6.36(d,J=8.4Hz,2H ),6.15(d,J=8.4Hz,2H),4.19(d,J=4.8Hz,1H),3.30-3.27(m,1H),3.08-2.90(m,2H),2.16-2.04(m,1H),1.79-1.65(m,1H),1.29(s,9H).

[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 TIFF0007656589000051.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) showed that the starting material was completely consumed and one new spot was formed. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:0 to 50:1). The desired 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(400MHz,CDCl3)δ7.21-7.11(m,3H),6.94-6.86(m,3H),6.84-6.73(m,4H),6.46(d,J=8.8Hz,2H),4.33 (d,J=5.2Hz,1H),3.50-3.40(m,1H),3.16-2.95(m,2H),2.20-2.02(m,1H),1.91-1.79(m,1H),1.38(s,9H).

[0171] Step 9: Preparation of 1-[4-(6-benzyloxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenyl]-4-(dimethoxymethyl)piperidine TIFF0007656589000052.tif32128

[0172] A mixture of [4-[(1R,2S)-6-tert-butoxy-2-phenyl-tetralin-1-yl]phenyl]1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (1.6 g, 2.44 mmol, 1 equiv), 4-(dimethoxymethyl)piperidine (584 mg, 3.67 mmol, 1.5 equiv), sodium tert-butoxide (705 mg, 7.33 mmol, 3 equiv), palladium acetate (82 mg, 0.37 mmol, 0.15 equiv), and dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (233 mg, 0.49 mmol, 0.2 equiv) in toluene (30 mL) was degassed and purged with nitrogen three times, then the mixture was stirred at 90 °C under nitrogen atmosphere for 16 h. LC-MS showed that one main peak with the desired MS was detected. TLC (petroleum ether:ethyl acetate=10:1) showed that the starting material was completely consumed and one new spot was formed. The mixture was cooled, diluted with ethyl acetate (50 mL), filtered over a plug of diatomaceous earth, and the filter cake was washed with ethyl acetate (30 mL). The filtrate was concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=100:1 to 10:1). The desired 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] + ; 1H NMR(400MHz,CDCl3)δ7.21-7.11(m,3H),6.88-6.78(m,4H),6.73(dd,J=2.4,8.0 Hz,1H),6.57(d,J=8.4Hz,2H),6.27(d,J=8.8Hz,2H),4.23(d,J=4.8Hz,1H),4.06 (d,J=7.2Hz,1H),3.63-3.52(m,2H),3.41-3.30(m,7H),3.13-2.96(m,2H),2.54( d,J=2.0,12.0Hz,2H),2.28-2.10(m,1H),1.85-1.63(m,4H),1.49-1.31(m,11H).

[0173] Step 10: Preparation of 1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]piperidine-4-carbaldehyde TIFF0007656589000053.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 h. LC (petroleum ether:ethyl acetate=3:1) showed that the starting material was completely consumed and one new spot was formed. The reaction mixture was quenched to pH=about 7-8 by adding saturated sodium bicarbonate solution and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used in the next step without further purification. The desired 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] Step 11: Preparation of 3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (compound (Ib)) TIFF0007656589000054.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 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, after which the mixture was added with 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 showed that the starting material was completely consumed and one main peak with the desired MW was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (Phenomenex luna C18 column, 250x50mm, 10um; mobile phase: [water (0.05% HCl)-acetonitrile]; B%: acetonitrile 10%-40%, 30min). 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 (288.4mg, 0.37mmol, 51% yield) was obtained as a white solid of hydrochloride salt. LC-MS(ESI)m / z:724.4[M+1] + ; 1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),10.83(s,0.9H,HCl),7.60(d,J=8.5Hz,1H),7.40(br s,2H),7.22-7.11(m,5H),6.83(d,J=6.0Hz,2H),6.69-6.63(m,2H),6.58-6.47(m,3H),5.07(dd,J=5.2,13.2Hz,1H ),4.41-4.30(m,2H),4.28-4.21(m,1H),4.00(d,J=12.7Hz,2H),3.61(d,J=11.0Hz,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 (Ic))

[0178] Step 1: Preparation of (4S)-tert-butyl 5-amino-4-(benzyloxycarbonylamino)-5-oxo-pentanoate TIFF0007656589000055.tif21128A mixture of (2S)-2-(benzyloxycarbonylamino)-5-tert-butoxy-5-oxo-pentanoic acid (20 g, 59.28 mmol, 1.00 equiv.), di-tert-butyl dicarboxylate (94.85 mmol, 21,79 mL, 1.60 equiv.) and pyridine (9.38 g, 118.57 mmol, 9.57 mL, 2.00 equiv.) in 1,4-dioxane (200 mL) was degassed at 0° C. and purged with nitrogen three times, after which the mixture was stirred under nitrogen atmosphere at 0° C. for 0.5 h. Ammonium bicarbonate (14.06 g, 177.85 mmol, 14.65 mL, 3.00 equiv.) was added at 0° C. The mixture was stirred at 25° C. for 16 hours. LC-MS showed the desired mass. The volatiles were removed under reduced pressure. The residue was diluted with water (300 mL) and extracted with ethyl acetate (300 mL×1). The combined organic phase was washed with aqueous hydrochloric acid (0.5 M, 200 mL×2), saturated sodium bicarbonate (300 mL×3), and brine (500 mL×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 (4S)-tert-butyl 5-amino-4-(benzyloxycarbonylamino)-5-oxo-pentanoate (19 g, 56.08 mmol, 94% yield, 99% purity) as a white solid. LC-MS(ESI)m / z:359.0[M+23] + . 1 H-NMR(400 MHz, CDCl3)δ7.39-7.29(m,5H),6.38(s,1H),5.74(d,J=7.2Hz,1H),5.58(s,1H),5.11(s,2H),4.25(d, J=5.6Hz,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 (4S)-tert-butyl 4,5-diamino-5-oxo-pentanoate TIFF0007656589000056.tif21128

[0180] To a solution of (4S)-tert-butyl 5-amino-4-(benzyloxycarbonylamino)-5-oxo-pentanoate (19 g, 56.48 mmol, 1.00 equiv) in methanol (200 mL) was added palladium on carbon (2 g, 10%) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred under H2 (50 psi) at 25°C for 16 h. Thin layer chromatography (petroleum ether:ethyl acetate=1:2) showed the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated. The compound (4S)-tert-butyl 4,5-diamino-5-oxo-pentanoate (11 g, 54.39 mmol, 96% yield) was obtained as a light green oil. 1 H NMR(400MHz,CDCl3)δ7.03(br s,1H),5.55(br s,1H),3.44(br s, 1H), 2.49-2.31 (m, 2H), 2.11 (dd, J=6.0, 12.8Hz, 1H), 1.92-1.76 (m, 1H), 1.66 (s, 2H), 1.45 (s, 9H).

[0181] Step 3: Preparation of tert-butyl 4-[2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate TIFF0007656589000057.tif341364-To a solution of tert-butyl [3-(bromomethyl)-4-methoxycarbonyl-phenyl]piperazine-1-carboxylate (1.5 g, 3.63 mmol, 1 eq., prepared in step 15 of exemplary compound 62 of US Patent Application Publication No. 2018 / 0155322) in acetonitrile (30 mL), tert-butyl (4S)-4,5-diamino-5-oxo-pentanoate (1.10 g, 5.44 mmol, 1.5 eq.) and diisopropylethylamine (1.41 g, 10.89 mmol, 1.90 mL, 3 eq.) were added. The mixture was stirred at 80° C. for 12 hours. LC-MS showed the reaction was complete. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (column: Phenomenex Synergi Max-RP 250x50 mm, 10 microns; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: acetonitrile 40% to acetonitrile 70%, 30 min) to give tert-butyl 4-[2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (1.6 g, 2.94 mmol, 81.05% yield, 92% purity) as an off-white solid. LC-MS (ESI) m / z: 503.2 [M+1] + .

[0182] Step 4: Preparation of (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione TIFF0007656589000058.tif241304-To a solution of tert-butyl [2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-butyl]-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (700 mg, 1.39 mmol, 1 equiv.) in acetonitrile (15 mL) was added benzenesulfonic acid (440 mg, 2.79 mmol, 2 equiv.). The mixture was stirred at 85° C. for 12 h. LC-MS indicated 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 grey solid. LC-MS (ESI) m / z: 329.1 [M+1] + ; 100% ee by chiral SFC analysis.

[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 (Ic)) TIFF0007656589000059.tif43143 To a mixture of (3S)-3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (1.30 g, 3.47 mmol, 1 equiv., benzenesulfonate) in dichloromethane (8 mL) and methanol (32 mL) was added sodium acetate (854 mg, 10.41 mmol, 3 equiv.) in one portion at 20° C. The mixture was stirred for 10 min at 20° C. Then 1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]piperidine-4-carbaldehyde (1 g, 2.43 mmol, 0.7 equiv., prepared as described above in the synthesis of compound (Ib)) was added. The mixture was stirred at 20° C. for 10 min. Then, acetic acid (0.2 mL) and sodium cyanoborohydride (436 mg, 6.94 mmol, 2 equiv.) were added in one portion. The mixture was stirred at 20° C. for 40 min. The mixture was concentrated in vacuo and 50 mL of tetrahydrofuran and 20 mL of water were added. The mixture was stirred for 20 min. Saturated aqueous sodium bicarbonate 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×3). The combined organic phase was washed with brine (60 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative reversed-phase HPLC (column: Phenomenex luna C18 250x50mm, 10 microns; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 20%-50%, 30 min). The product, (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (964 mg, 1.23 mmol, 35% yield, 98% purity, formate salt), was obtained as a white solid of formate salt after lyophilization. Chiral purity was analyzed by chiral SFC (Chiralcel OJ-3 50 × 4.6 mm, 3 microns; mobile phase: 50% ethanol (0.05% DEA) in CO2; flow rate: 3 mL / min, wavelength: 220 nm) and t p=2.89 points, 95% of the total score. [α D =-267.5 (in DMF, c=0.2, 25℃). LC-MS(ESI)m / z:724.2[M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.94 (s, 1H), 8.16 (s, 1H, acid hydroxide), 7.51 (d, J=8.8H z,1H),7.21-6.98(m,5H),6.83(d,J=6.4Hz,2H),6.68-6.57(m,2H),6.56 -6.44(m,3H),6.20(d,J=8.8Hz,2H),5.04(dd,J=5.2,13.2Hz,1H),4.32(d,J=16.8Hz,1H),4.19(d,J=17.2Hz,1H),4.12(d,J=4.8Hz,1H),3.51(br d,J=10.0Hz,4H),3.27(br s,8H),3.03-2.82(m,3H),2.63-2.54(m,1H),2.43-2.28(m,2H),2.19(d,J=6.8Hz ,2H),2.15-2.02(m,1H),2.01-1.89(m,1H),1.83-1.51(m,4H),1.28-1.04(m,2H).

[0184] Free non-transformation form 1H-NMR:(400MHz,DMSO-d6)δ10.93(s,1H),9.09(s,1H),7.51(d,J=8.8Hz,1H),7.18-7.09(m,3H),7.08-7.02(m,2H),6.83(d,J=6.4Hz,2H),6 .64(d,J=8.4Hz,1H),6.60(d,J=2.0Hz,1H),6.53(d,J=8.8Hz,2H),6.48(dd,J=2.4,8.4Hz,1H),6.20(d,J=8.8Hz,2H),5.04(dd,J=5.2,13.2 Hz,1H),4.39-4.27(m,1H),4.24-4.15(m,1H),4.12(d,J=4.8Hz,1H),3.51(d,J=9.6Hz,2H),3.29-3.24(m,5H),3.03-2.83(m,3H),2.62-2.5 4(m,4H),2.52(s,3H),2.41-2.36(m,1H),2.19(d,J=7.2Hz,2H),2.15- 2.08 (m, 1H), 2.00-1.89 (m, 1H), 1.81-1.58 (m, 4H), 1.22-1.06 (m, 2H).

[0185] Palbociclib Palbociclib, also known as 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, has the following structural formula: has TIFF0007656589000060.tif50128.

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

[0187] Human bone marrow mononuclear cells treated in vitro with palbociclib in the presence or absence of antiestrogen did not undergo senescence and resumed proliferation after palbociclib was discontinued.

[0188] In one embodiment, the 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 pharma- ceutically acceptable salt thereof and a therapeutically effective amount of a CDK4 / 6 inhibitor or a pharma- ceutically acceptable salt thereof, or comprises co-administering to a subject in need thereof a therapeutically effective amount of a combination of a compound of formula (Ic) or a pharma- ceutically acceptable salt thereof and a CDK4 / 6 inhibitor or a pharma- ceutically acceptable salt thereof. In one embodiment, the compound of formula (Ic) is a free base or a pharma- ceutically acceptable salt thereof. In one embodiment, the CDK4 / 6 inhibitor is a free base or a pharma- ceutically acceptable salt thereof. In one embodiment, the CDK4 / 6 inhibitor is palbociclib or a pharma- ceutically acceptable salt thereof. In one embodiment, the CDK4 / 6 inhibitor is palbociclib dihydrochloride. The dihydrochloride salt of palbociclib can be prepared, for example, by reaction of palbociclib free base in an ethereal solution of hydrogen chloride. Palbociclib is a marketed drug for the treatment of breast cancer, developed by Pfizer and sold under the brand name Ibrance®.

[0189] How to ubiquitinate and degrade target proteins in cells The present invention provides a method for ubiquitinating / degrading a target protein (e.g., an intracellular target protein) in a cell. The method includes administering a bifunctional compound including an E3 ubiquitin ligase binding moiety and a protein targeting moiety, preferably linked via a linker moiety, where the E3 ubiquitin ligase binding moiety recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, preferably an E3 ubiquitin ligase), and the protein targeting moiety recognizes a target protein (e.g., an intracellular target protein), such that when the target protein is placed in close proximity to the E3 ubiquitin ligase, ubiquitination of the target protein occurs, resulting in degradation of the target protein via the proteasome pathway, leading to control (e.g., reduction) of the target protein 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 bond or chemical group that 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 a pyrrolidine, imidazolidine, piperidine, or piperazine. In one embodiment, the E3 ubiquitin ligase is cereblon. In certain embodiments, the cereblon binding moiety is thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, or derivatives thereof. The control (e.g., reduction) of protein levels provided by the present invention provides treatment of a disease state or condition that is regulated via a target protein by lowering the levels of that protein in the patient's cells.

[0190] In one embodiment, the invention is directed to a method of treating a patient in need thereof for a disease state or condition causally associated with a protein, where degradation of the protein produces a therapeutic effect in the patient, the method comprising administering to a patient in need thereof an effective amount of a compound of the invention, optionally in combination with another bioactive agent. The disease state or condition may be a disease state or condition causally related to expression or overexpression of the 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 pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

[0192] The methods of treating cancer described herein include reducing tumor size. Alternatively, or additionally, the cancer is a metastatic cancer and the methods of treatment include inhibiting metastatic cancer cell invasion.

[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 metastatic ER+, HER2- breast cancer that is also locally advanced.

[0199] In one aspect, the present application relates to treating breast cancer with a compound of formula (I), which has the following structure: TIFF0007656589000061.tif58128, or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, In the formula, 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), TIFF0007656589000062.tif91128TIFF0007656589000063.tif184128TIFF0007656589000064.tif134128 or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof. In one embodiment, the compound of formula (I) is a compound of formula (Ic). 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 embodiment, 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, the tumor size is reduced by 20% or more, more preferably, the tumor size is reduced by 30% or more, more preferably, the tumor size is reduced by 40% or more, even more preferably, the tumor size is reduced by 50% or more, and most preferably, the tumor size is reduced by more than 75%. The tumor size may be measured by any reproducible measurement means. In a preferred embodiment, the tumor size may be measured as the diameter of the tumor.

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

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

[0204] In another embodiment, the treatment of cancer leads to a reduction 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 5% or more compared to the number before treatment, more preferably, the number of metastatic lesions is reduced by 10% or more, more preferably, the number of metastatic lesions is reduced by 20% or more, more preferably, the number of metastatic lesions is reduced by 30% or more, more preferably, the number of metastatic lesions is reduced by 40% or more, even more preferably, the number of metastatic lesions is reduced by 50% or more, and most preferably, the number of metastatic lesions is reduced by more than 75%. The number of metastatic lesions may be measured by any reproducible measuring means. In a preferred embodiment, the number of metastatic lesions may be measured by counting the metastatic lesions that can be seen with the naked eye or at a specified magnification. In a preferred embodiment, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

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

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

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

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

[0209] The dosage of the compounds of formula (I) for any of the methods and uses described herein will vary according to the agent, the age, weight, and clinical condition of the recipient subject, as well as the experience and judgment of the clinician or practitioner administering the therapy, among other factors which will influence the selected dosage.

[0210] A therapeutically effective amount of a compound of formula (I) may be administered 1, 2, 3, 4, 5 or more times per day for a period of 5, 10, 15, 30, 60, 90, 120, 150, 180 days or more, 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 or more days without administration of the compound of formula (I). This type of treatment schedule, i.e., administration of a compound of formula (I) on consecutive days, followed by non-administration of a compound of formula (I) on consecutive days, may be referred to as a treatment cycle.

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

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

[0214] In one embodiment, the therapeutically effective amount of a compound of Formula (I) 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, 30 consecutive days, or for a period of 2, 3, 4, 5, 6, or more months, administered in single or divided doses. 2, 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, 3 95, 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, 55 0, 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, the therapeutically effective amount of a compound of Formula (I) 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, or about 460 mg, administered once, twice, three times, four or more times daily in single or divided doses. about 450 mg, about 480 mg, about 510 mg, about 540 mg, about 570 mg, about 600 mg, about 630 mg, about 660 mg, about 690 mg, about 720 mg, about 750 mg, about 780 mg, about 810 mg, about 840 mg, about 870 mg, about 900 mg, about 930 mg, about 960 mg, or about 990 mg (this dose is determined based on the patient's weight (kg), body surface area (m 2 ), and may be adjusted for age (in years).

[0216] In one embodiment, the therapeutically effective amount of a compound of Formula (I) is from about 30 mg to about 1000 mg (based on the patient's body weight (kg), body surface area (m2), administered once, twice, three times, four times, or more per day in single or divided doses. 2 ), and may be adjusted for age (in years).

[0217] In one embodiment, a therapeutically effective amount of a compound of Formula (I) is about 10 to about 40 mg, about 20 to about 50 mg, about 30 to about 60 mg, about 40 to about 70 mg, about 50 to about 80 mg, about 60 to about 90 mg, about 70 to about 100 mg, about 80 to about 110 mg, about 90 to about 120 mg, about 100 to about 130 mg, about 110 to about 140 mg, about 120 to about 150 mg, about 130 to about 160 mg, about 140 to about 170 mg, about 150 to about 180 mg, about 160 to about 190 mg, about 170 to about 200mg, about 180 to about 210mg, about 190 to about 220mg, about 200 to about 230mg, about 210 to about 240mg, about 220 to about 250mg, about 230 to about 260mg, about 240 to about 270mg, about 250 to about 280mg, about 260 to about 290mg, about 270 to about 300mg , 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 ~ 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 90~620mg, 600~630mg, 610~640mg, 620~650mg, 630~660mg, 640~670mg, 650~680mg, 660~690mg, 670~700mg, 680~710mg, 690~7 20mg, about 700 to about 730mg, about 710 to about 740mg, about 720 to about 750mg, about 730 to about 760mg, about 740 to about 770mg, about 750 to about 780mg, about 760 to about 790mg, about 770 to about 800mg, about 780 to about 810mg, about 790 to about 820mg,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 dose is determined based on the patient's body weight (kg), body surface area (m, 2) , and may be adjusted for age (in years).

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

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

[0223] In one embodiment, a therapeutically effective amount of a compound of formula (I) is about 3,500 ng·hr / mL, about 3,550 ng·hr / mL, about 3,600 ng·hr / mL, about 3,650 ng·hr / mL, about 3,700 ng·hr / mL, about 3,750 ng·hr / mL, about 3,800 ng·hr / mL, about 3,850 ng·hr / mL, about 3,900 ng·hr / mL, about 3,950 ng·hr / mL, about 4,000 ng·hr / mL, about 4,050 ng·hr / mL, about 4,100 ng·hr / mL, about 4,150 ng·hr / mL, about 4,200 ng·hr / mL, about 4,250 ng·hr / mL, about 4,300 ng·hr / mL, about 4,400 ng·hr / mL, about 4,500 ng·hr / mL, about 4,600 ng·hr / mL, about 4,700 ng·hr / mL, about 4,850 ng·hr / mL, about 4,900 ng·hr / mL, about 4,950 ng·hr / mL, about 5,000 ng·hr / mL, about 5,100 ng·hr / mL, about 5,150 ng·hr / mL, about 5,200 ng·hr / mL, about 5,300 ng·hr / mL, about 5,400 ng·hr / mL, about 5,500 ng·hr / mL, about 5,600 ng·hr / mL, about 5,750 ng·hr / mL, about 5,800 ng·hr / mL, about 5,900 ng·hr / mL, about 5 Day 15 mean AUC greater than 50 ng·hr / mL, about 4,300 ng·hr / mL, about 4,350 ng·hr / mL, 4,400 ng·hr / mL, about 4,450 ng·hr / mL, about 4,500 ng·hr / mL, about 4,550 ng·hr / mL, about 4,600 ng·hr / mL, about 4,650 ng·hr / mL, about 4,700 ng·hr / mL, about 4,750 ng·hr / mL, about 4,800 ng·hr / mL, about 4,850 ng·hr / mL, about 4,900 ng·hr / mL, about 4,950 ng·hr / mL, or about 5,000 ng·hr / mL TAU results.

[0224] In one embodiment, a therapeutically effective amount of a compound of formula (I) is 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 a day 15 mean C greater than 250ng / mL, about 255ng / mL, about 260ng / mL, about 265ng / mL, about 270ng / mL, about 275ng / mL, about 280ng / mL, about 285ng / mL, about 290ng / mL, about 295ng / mL, about 300ng / mL, about 305ng / mL, about 310ng / mL, about 315ng / mL, about 320ng / mL, about 325ng / mL, about 330ng / mL, about 335ng / mL, about 340ng / mL, about 345ng / mL, or about 350ng / mL max results.

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

[0226] Dosage and administration are adjusted to provide sufficient levels of the compound of formula (I) or to maintain the desired effect.Factors that may be considered include the severity of the condition, the subject's general health, the subject's age, weight, and sex, diet, time and frequency of administration, drug combinations, reaction sensitivities, and tolerance / response to therapy.Long-acting pharmaceutical compositions may be administered every 3-4 days, every week, or every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0227] Methods of treatment comprising administering a compound of formula (I) and a CDK4 / 6 inhibitor In one aspect, the application relates to a method of treating and / or preventing breast cancer in a subject in need thereof, comprising co-administering a therapeutically effective amount of a compound of formula (I) and a therapeutically effective amount of a CDK4 / 6 inhibitor to the subject. These methods include reducing tumor size. Alternatively, or additionally, the breast cancer is metastatic breast cancer and the treatment method includes inhibiting 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 a compound of formula (I) and a therapeutically effective amount of a CDK4 / 6 inhibitor are administered simultaneously (either in the same formulation or in separate formulations).

[0229] 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 sequentially, i.e., the compound of formula (I) is administered first, followed by the CDK4 / 6 inhibitor, or the CDK4 / 6 inhibitor is administered first, followed by the compound of formula (I). In one embodiment, the CDK4 / 6 inhibitor is administered first, followed by the compound of formula (I) one 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 close temporal proximity.

[0231] In some embodiments, "temporal proximity" refers to administering a compound of formula (I) within a period of time before or after 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" refers to administering a compound of formula (I) within a period of time before or after 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" may vary depending on a variety of factors, including, but not limited to, the age, sex, weight, genetic background, medical condition, medical history, and treatment history of the subject to whom the therapeutic agent is administered; the disease or condition to be treated or improved; the therapeutic outcome to be achieved; the dose, frequency, and duration of administration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route by which the therapeutic agent is administered. In some embodiments, "temporal proximity" means within 15 minutes, within 30 minutes, within 1 hour, within 2 hours, within 4 hours, within 6 hours, within 8 hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 1 week, within 2 weeks, within 3 weeks, within 4 weeks, within 6 weeks, or within 8 weeks. In some embodiments, multiple administrations of one therapeutic agent may be administered in temporal proximity to a single administration of another therapeutic agent. In some embodiments, temporal proximity may vary during a treatment cycle or within a dosing regimen.

[0233] In one aspect, the present application relates to a method of treating and / or preventing breast cancer in a subject in need thereof, 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: TIFF0007656589000065.tif56128, or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, wherein R 1 , R 2 , R3, R4, m, and n are defined herein, and the CDK4 / 6 inhibitor or a pharma- ceutically acceptable salt thereof is a compound that inhibits the human enzymes called cyclin-dependent kinases (CDK) 4 and 6. In one embodiment, the CDK4 / 6 inhibitor is palbociclib, palbociclib dihydrochloride, or any other pharma- ceutically 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, 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 TIFF0007656589000066.tif42128TIFF0007656589000067.tif189128TIFF0007656589000068.tif182128 or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof, and the CDK4 / 6 inhibitor is SHR6390, trilaciclib, relociclib, 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 (Ic). 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 (Ic) 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 (Ic) as defined herein and a palbociclib inhibitor as defined herein for simultaneous, separate or sequential use in the treatment and / or prevention of breast cancer. In 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 embodiment, 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, the tumor size is reduced by 20% or more, more preferably, the tumor size is reduced by 30% or more, more preferably, the tumor size is reduced by 40% or more, even more preferably, the tumor size is reduced by 50% or more, and most preferably, the tumor size is reduced by more than 75%. The tumor size may be measured by any reproducible measurement means. In a preferred embodiment, the tumor size may be measured as the diameter of the tumor.

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

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

[0242] In another embodiment, treating cancer with a compound of formula (I) and a CDK4 / 6 inhibitor results in a reduction 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 5% or more compared to the number before treatment, more preferably, the number of metastatic lesions is reduced by 10% or more, more preferably, the number of metastatic lesions is reduced by 20% or more, more preferably, the number of metastatic lesions is reduced by 30% or more, more preferably, the number of metastatic lesions is reduced by 40% or more, even more preferably, the number of metastatic lesions is reduced by 50% or more, and most preferably, the number of metastatic lesions is reduced by more than 75%. The number of metastatic lesions may be measured by any reproducible measuring means. In a preferred embodiment, the number of metastatic lesions may be measured by counting the metastatic lesions that can be seen with the naked eye or at a specified magnification. In a preferred embodiment, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

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

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

[0245] In another embodiment, using the compound of formula (I) and CDK4 / 6 inhibitor to treat cancer results in the reduction of tumor growth rate.After treatment, tumor growth rate is preferably reduced by at least 5% compared to the number before treatment, more preferably, tumor growth rate is reduced by at least 10%, more preferably, reduced by at least 20%, more preferably, reduced by at least 30%, more preferably, reduced by at least 40%, more preferably, reduced by at least 50%, even more preferably, reduced by at least 50%, and most preferably, reduced by at least 75%.Tumor growth rate may be measured by any reproducible measuring means.In a preferred embodiment, tumor growth rate is measured according to the change in tumor diameter per unit time.

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

[0247] The dosage of the compounds of formula (I) and CDK4 / 6 inhibitors for any of the methods and uses described herein will vary according to the agent, the age, weight, and clinical condition of the recipient subject, as well as the experience and judgment of the clinician or practitioner administering the therapy, among other factors that will influence the selected dosage.

[0248] A therapeutically effective amount of a CDK4 / 6 inhibitor may be administered 1, 2, 3, 4, 5 or more times per day for 5, 10, 15, 30, 60, 90, 120, 150, 180 days or more, 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 or more days 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 daily for up to 5, 10, 15, 20, 25, or 30 days, which may be followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days without administration of the CDK4 / 6 inhibitor.

[0250] In one embodiment, a therapeutically effective amount of a CDK4 / 6 inhibitor is administered once daily for up to 5, 10, 15, 20, 25, or 30 days, which may be followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days without administration of the CDK4 / 6 inhibitor.

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

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

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

[0254] The therapeutically effective amount of the compound of formula (I) and the CDK4 / 6 inhibitor may be administered one or more times a day for up to 30 days or more, followed by one or more days without administration of the compound of formula (I) and / or the CDK4 / 6 inhibitor. 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 cycle. In one embodiment, the treatment cycle may be repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times. In one embodiment, the treatment cycle of the CDK4 / 6 inhibitor may be repeated as many times as necessary to achieve the intended effect.

[0255] In one embodiment, for the methods disclosed herein comprising administering a compound of Formula (I) and a CDK4 / 6 inhibitor, the therapeutically effective amount of the compound of Formula (I) 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, 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, or more months, administered in single or divided doses. ,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, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 108, 109, 101, 102, 103, 104, 105, 106 7, 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, 1 75, 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, 33 0, 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, 8 30, 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 comprising administering a compound of Formula (I) and a CDK4 / 6 inhibitor, a therapeutically effective amount of a compound of Formula (I) 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, or about 400 mg, administered once, twice, three times, four or more times daily in single or divided doses. about 390 mg, about 420 mg, about 450 mg, about 480 mg, about 510 mg, about 540 mg, about 570 mg, about 600 mg, about 630 mg, about 660 mg, about 690 mg, about 720 mg, about 750 mg, about 780 mg, about 810 mg, about 840 mg, about 870 mg, about 900 mg, about 930 mg, about 960 mg, or about 990 mg (this dose is determined based on the patient's weight (kg), body surface area (m 2 ), and may be adjusted for age (in years).

[0257] 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 30 mg to about 1000 mg, administered in single or divided doses, one, two, three, four or more times daily (based on the patient's body weight (kg), body surface area (m 2) , and may be adjusted for age (in years).

[0258] 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 a compound of Formula (I) is about 10 to about 40 mg, about 20 to about 50 mg, about 30 to about 60 mg, about 40 to about 70 mg, about 50 to about 80 mg, about 60 to about 90 mg, about 70 to about 100 mg, about 80 to about 110 mg, about 90 to about 120 mg, about 100 to about 130 mg, about 110 to about 140 mg, about 120 to about 150 mg, about 130 to about 160 mg, about 170 to about 180 mg, about 190 to about 200 mg, about 210 to about 220 mg, about 220 to about 230 mg, about 230 to about 240 mg, about 240 to about 250 mg, about 250 to about 260 mg, about 260 to about 270 mg, about 270 to about 280 mg, about 280 to about 300 mg, about 290 to about 310 mg, about 320 to about 330 mg, about 330 to about 340 mg, about 340 to about 350 mg, about 350 to about 360 mg, about 370 to about 380 mg, about 390 to about 400 mg, about 400 to about 400 mg, about 400 to about 410 mg, about 410 to about 420 mg, about 420 to about 430 mg, about 430 to about 440 mg, about 440 to about 450 mg, about 450 to about 460 mg, 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 ~ about 370 mg, about 350 to about 380 mg, about 360 to about 390 mg, about 370 to about 400 mg, about 380 to about 410 mg, about 390 to about 420 mg, about 400 to about 430 mg, about 410 to about 440 mg, about 420 to about 450 mg, about 430 to about 460 mg, about 440 to about 470 mg, about 450 to about 480 mg, about 460 to about 490 mg, about 470 to about 500 mg, about 480 to about 510 mg, about 490 to about 520 mg, about 500 to about 530 mg, about 510 to about 540 mg, about 520 to about 550 mg, about 530 to about 560 mg, about 540 to about 570 mg, about 50 to 580 mg, 560 to 590 mg, 570 to 600 mg, 580 to 610 mg, 590 to 620 mg, 600 to 630 mg, 610 to 640 mg, 620 to 650 mg, 630 to 660 mg, 640 to 670 mg, 650 to 6 80 mg, about 660 to about 690 mg, about 670 to about 700 mg, about 680 to about 710 mg, about 690 to about 720 mg, about 700 to about 730 mg, about 710 to about 740 mg, about 720 to about 750 mg, about 730 to about 760 mg, about 740 to about 770 mg, about 750 to about 780 mg,About 760 to about 790 mg, about 770 to about 800 mg, about 780 to about 810 mg, about 790 to about 820 mg, about 800 to about 830 mg, about 810 to about 840 mg, about 820 to about 850 mg, about 830 to about 860 mg, about 840 to about 870 mg, about 850 to about 880 mg, about 860 to about 890 mg, about 870 to about 900 mg, about 88 The dose is about 0 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 dose depends on the patient's body weight (kg), body surface area (m, 2 ), and may be adjusted for age (in years).

[0259] In one embodiment, for 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) may also be in the range of about 0.01 mg / kg per day to about 100 mg / kg per day, about 0.05 mg / kg per day to about 10 mg / kg per day, about 0.075 mg / kg per day to about 5 mg / kg per day, about 0.10 mg / kg per day to about 1 mg / kg per day, or about 0.20 mg / kg per day to about 0.70 mg / kg per day.

[0260] In one embodiment, for the methods disclosed herein comprising 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 0.50 mg / kg per day, about 0.60 mg / kg per day, about 0.70 mg / kg per day, about 0.80 mg / kg per day, about 0.90 mg / kg per day, ...90 mg / kg per day, about 0.10 mg / kg per day, about 0.10 mg / kg per day, about 0.15 mg / kg per day, about 0.20 mg / kg per day, about 0.15 mg / kg per day, about 0.20 mg / kg per day, about 0.25 mg / kg per day, about 0.30 mg / kg per day, about 0.35 mg / kg per day, about 0.40 mg / kg per day, about 0.50 mg / kg per day, about 0.50 mg / kg per day, about 0.60 mg / kg per day, about 0.70 mg / kg per day, about 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 comprising 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 1.50 mg / kg per day, about 1.60 mg / kg per day, about 1.70 mg / kg per day, about 1.80 mg / kg per day, about 1.90 mg / kg per day, about 1.15 mg / kg per day, about 1.20 mg / kg per day, about 1.35 mg / kg per day, about 1.40 mg / kg per day, about 1.50 mg / kg per day, about 1.60 mg / kg per day, about 1.70 mg / kg per day, about 1.80 mg / kg per day, about 1.90 mg / kg per day, about 1.90 mg / kg per day, about 1.15 mg / kg per day, about 1.15 mg / kg per day, about 1.20 mg / kg per day, about 1.25 mg / kg per day, about 1.30 mg / kg per day, about 1.35 mg / kg per day, about 1.40 mg / kg per day, about 1.50 mg / kg per day, about 1.60 mg / kg per day, about 1.70 mg / kg per day, about 1.80 mg / kg per day, about 1.90 mg / kg per day, about 1.90 mg / kg per day, about 1.90 mg / kg per day, about 1.15 mg / kg per day, about 1.15 mg / kg per day, about , 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 comprising 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 comprising administering a compound of Formula (I) and a CDK4 / 6 inhibitor, a therapeutically effective amount of the CDK4 / 6 inhibitor is administered in single or divided doses of 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 10, 11, 12, 13, 14, 15, 30 consecutive days, or once, twice, three, four or more times per day, or for a period of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 30 consecutive days, or once, twice, three, four or more times per day, or for a period of 2, 3, 4, 5, 6, or more months. .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 7, 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, 2 95, 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, 45 0, 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 compound of formula (I) and palbociclib are administered simultaneously. In some embodiments, the compound of formula (I) and palbociclib are administered sequentially.

[0265] In one embodiment, palbociclib is administered prior to administration of the compound of formula (I), so that the two compounds and their respective excipients do not mix in the subject's stomach. In one embodiment, the maximum time between administration of palbociclib and administration of the compound of formula (I) is such that the benefits of the combination are achieved. In 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 administration of the compound of formula (I). 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 administration of the compound of formula (I). 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 administration of the compound of formula (I), such that the two compounds and their respective excipients (if present) do not mix in the subject's stomach. In one embodiment, the maximum time between administration of palbociclib and administration of the compound of formula (I) is such that the benefits of the combination are achieved. In 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 administration of the compound of formula (I). 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 administration of the compound of formula (I). 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 comprising 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 in 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 7 days of treatment rest. In one embodiment, the CDK4 / 6 inhibitor is palbociclib.

[0268] Twenty-one consecutive days of treatment with the CDK4 / 6 inhibitor followed by seven days of rest from treatment are referred to herein 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 or more times. 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 comprising administering a compound of Formula (I) and a CDK4 / 6 inhibitor, a 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, about 0.6 mg / kg per day, about 0.7 mg / kg per day, about 0.8 mg / kg per day, about 0.9 mg / kg per day, about 1 mg / kg per day, about 1.1 mg / kg per day, about 1.2 mg / kg per day, about 1.3 mg / kg per day, about 1.4 mg / kg per day, about 1.5 mg / kg per day, about 1.6 mg / kg per day, about 1.7 mg / kg per day, about 1.8 mg / kg per day, about 1.9 mg / kg per day, about 2.0 mg / kg per day, about 2.1 mg / kg per day, about 2.2 mg / kg per day, about 2.3 mg / kg per day, about 2.4 mg / kg per day, about 2.5 mg / kg per day, about 2.6 mg / kg per day, about 2.7 mg / kg per day, about 2.8 mg / kg per day, about 2.9 mg / kg per day, about 3.0 mg / kg per day, about 3.1 mg / kg per day, about 3.2 mg / kg per day, about 3.3 mg / kg per day, about 3.4 mg / kg per day, about 3.5 mg / kg per day, about 3.6 mg / kg per day, about 3.7 mg / kg per day, about 3.8 mg / kg per day, about 3.9 mg / kg per day, about 3.1 mg / kg per day, about 3.2 mg / kg per day, about 3.3 mg / kg per day, about 3.4 mg / kg per 0.6mg / kg per day, about 1.7mg / kg per day, about 1.8mg / kg per day, about 1.9mg / kg per day, about 2mg / kg per day, about 2.5mg / kg per day, about 3mg / kg per day, about 3.5mg / kg per day, about 4mg / kg per day, about 4.5mg / kg per day, about 5mg / kg per day, about 5.5mg / kg per day, about 6mg / kg per day, about 6.5mg / kg per day, about 7mg / kg per day, about 7.5mg / kg per day, about 8.0mg / kg per day, about 8.5mg / kg per day, about 9.0mg / kg per day, about 9.5mg / kg per day, or about 10mg / kg per day. In one embodiment, the CDK4 / 6 inhibitor is palbociclib.

[0270] In one embodiment, for the methods disclosed herein comprising 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 comprising administering a compound of formula (I) and a CDK4 / 6 inhibitor, a therapeutically effective amount of a compound of formula (I) is administered to a subject once a day. In one embodiment, the daily dose of a compound of formula (I) is administered to a subject all at once. In one embodiment, the daily dose of a compound of formula (I) is administered to a subject in two portions (split doses). In one embodiment, the daily dose of a compound of formula (I) is administered to a subject in three portions. In one embodiment, the daily dose of a compound of formula (I) is administered to a subject in four portions. In one embodiment, the daily dose of a compound of formula (I) is administered to a subject in five or more portions. In one embodiment, the portions are administered to a subject at regular intervals throughout the day, such as, 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 comprising 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 a day. In one embodiment, the daily dose of the CDK4 / 6 inhibitor is administered to the subject all at once. In one embodiment, the daily dose of the CDK4 / 6 inhibitor is administered to the subject in two portions (split doses). In one embodiment, the daily dose of the CDK4 / 6 inhibitor is administered to the subject in three portions. In one embodiment, the daily dose of the CDK4 / 6 inhibitor is administered to the subject in four portions. In one embodiment, the daily dose of the CDK4 / 6 inhibitor is administered to the subject in five or more portions. In one embodiment, the portions are administered to the subject at regular intervals throughout the day, such as, 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 compounds of formula (I) and CDK4 / 6 inhibitors can be estimated initially either in cell culture assays or animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (therapeutic effective dose in 50% of the population) and LD 50 (the dose that is lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, LD 50 / ED 50 It may be expressed as a ratio. Pharmaceutical compositions which exhibit large therapeutic indices are preferred. The dosage may vary within this range depending on the dosage form employed, sensitivity of the patient, and the route of administration.

[0274] Dosage and administration are adjusted to provide sufficient levels of the compound of formula (I) and / or CDK4 / 6 inhibitor or to maintain the desired effect. Factors that may be considered include the severity of the condition, the subject's general health, the subject's age, weight, and sex, diet, time and frequency of administration, drug combinations, reaction sensitivities, and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered every 3-4 days, every week, or every two weeks, depending on the half-life and clearance rate of the particular formulation.

[0275] Pharmaceutical Compositions Compounds of formula (I) and CDK4 / 6 inhibitors can be administered in accordance with the present invention by any suitable route, including oral, parenteral (subcutaneous, intramuscular, intravenous (bolus or infusion), depot, intraperitoneal), intrathecal, intranasal, intravaginal, sublingual, buccal, ocular, 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, ocular, 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, which may be suitable for administration by any suitable route, including, for example, oral, parenteral (subcutaneous, intramuscular, intravenous, depot), intrathecal, intranasal, intravaginal, sublingual, buccal, ocular, or rectal.

[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, relociclib, 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, relociclib, 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 for oral administration, either separately or together.For example, in one embodiment, the compound of formula (I) and the CDK4 / 6 inhibitor are both formulated as a tablet, either separately or together, containing zero, one, two or more of each of emulsifiers, surfactants, binders, disintegrants, glidants, and lubricants, or alternatively, the compound of formula (I) and the CDK4 / 6 inhibitor can be formulated separately or together in a capsule, or as oral liquid, or 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, a flow agent refers to a substance used to promote powder flow by reducing interparticle cohesion. In one embodiment, in the dosage form of the present disclosure, the flow agent is selected from the group consisting of silicon dioxide, anhydrous silica colloid, starch, and talc.

[0286] In one embodiment, a lubricant refers to a substance that prevents ingredients from sticking and / or clumping in machinery used to prepare the dosage form of the present disclosure. In one embodiment, in the dosage form 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 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 disclosure provides a liquid composition comprising a compound of formula (Ic). In some embodiments, the liquid composition comprises a compound of formula (Ic) and a surfactant. In some embodiments, the liquid composition comprises a compound of formula (Ic) and a solvent. In some embodiments, the composition comprises a therapeutically effective amount of a compound of formula (Ic), a surfactant, and a solvent. In some embodiments, the ratio of surfactant to solvent in the composition is between 0.001-0.035 g surfactant to 1 mL solvent. In some embodiments, the ratio of surfactant to solvent in the composition is between 0.005-0.035 g surfactant to 1 mL solvent. In some embodiments, the ratio of surfactant to solvent in the composition is between 0.01-0.03 g surfactant to 1 mL solvent. In some embodiments, the ratio of surfactant to solvent in the composition is between 0.015-0.025 g surfactant to 1 mL solvent. In some embodiments, the ratio of surfactant to solvent in the composition is between 0.016-0.024 g surfactant to 1 mL solvent. In some embodiments, the ratio of surfactant to solvent in the composition is between 0.017-0.023 g surfactant per mL of solvent. In some embodiments, the ratio of surfactant to solvent in the composition is between 0.018-0.022 g surfactant per mL of solvent. In some embodiments, the ratio of surfactant to solvent in the composition is between 0.019-0.021 g surfactant per mL of solvent. In some embodiments, the ratio of surfactant to solvent in the composition is about 0.02 g surfactant per about 1 mL of solvent. In some embodiments, the ratio of surfactant to solvent in the composition is 0.02 g surfactant per 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 a low molecular weight polyethylene glycol (PEG). In some embodiments, the solvent is polyethylene glycol (PEG)-400.

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

[0290] In some embodiments, the present disclosure provides a method of making a liquid composition comprising a surfactant, a solvent, and a compound of formula (Ic), comprising adding the solvent to a pre-aliquot amount of the surfactant. In some embodiments, the method further comprises adding the compound of formula (Ic) to a mixture of the solvent and the surfactant. In some embodiments, the present disclosure provides a method of making a liquid composition comprising (i) adding the solvent to a pre-aliquot amount of the surfactant, and (ii) adding the compound of formula (Ic) 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 a 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 comprising a surfactant, a solvent, and a compound of formula (Ic) prepared by a method comprising adding a solvent to a pre-aliquot amount of the surfactant comprising the surfactant, a solvent, and a compound of formula (Ic). In some embodiments, the method further comprises adding a compound of formula (Ic) 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 (Ic) prepared by a method comprising (i) adding a solvent to a pre-aliquot amount of the surfactant, and (ii) adding a compound of formula (Ic) 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 a low molecular weight polyethylene glycol (PEG). In some embodiments, the solvent is polyethylene glycol (PEG)-400.

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

[0293] Pharmaceutical compositions containing the compound of formula (I) and the CDK4 / 6 inhibitor (either separately or together) suitable for injection include sterile aqueous solutions (if water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents in the composition, such as sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, such as aluminum monostearate and gelatin.

[0294] Sterile injectable solution can be prepared by incorporating the compound of formula (I) and / or CDK4 / 6 inhibitor in the required amount in a suitable solvent with one or a combination of the above-listed components, and then sterilizing by filtration as required.In general, dispersion is prepared by incorporating the active agent or compound into a sterile vehicle containing a basic dispersion medium and other components required from the above-listed ones.In the case of sterile powder for preparing sterile injectable solution, the preparation method is vacuum drying and freeze-drying, which produces a powder of active ingredient and any additional desired ingredients from its solution that has been previously sterilized and filtered.

[0295] Oral compositions generally contain an inert diluent or an edible pharma- ceutically acceptable carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the compound of formula (I) and / or CDK4 / 6 inhibitors may be combined with excipients and used in the form of tablets, troches, or capsules. Oral compositions may also be prepared using a fluid carrier for use as a mouthwash, where the agent or compound in the fluid carrier is orally applied, swished, expectorated, or swallowed. Pharmaceutically compatible binding agents and / or adjuvant materials may be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a flow agent such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0296] For administration by inhalation, the compounds of Formula (I) and / or CDK4 / 6 inhibitors are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

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

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

[0299] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate the oral or parenteral compositions of the compound of formula (I) and / or CDK4 / 6 inhibitor into unit dosage form.As used herein, unit dosage form refers to a physically discrete unit suitable as a unitary dosage for the subject to be treated; each unit contains a predetermined amount of active agent or compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.The specification of the unit dosage form of this application is determined and directly depends on the inherent properties of the compound of formula (I) and the specific therapeutic effect to be achieved.

[0300] The pharmaceutical compositions of a compound of Formula (I) and / or a CDK4 / 6 inhibitor can be included in a container, pack, or dispenser together with instructions for administration.

[0301] Exemplary administration modes of the compound of formula (I) and / or the CDK4 / 6 inhibitor include systemic administration or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical administration modes. In one embodiment, the compound of formula (I) or its pharma- ceutically acceptable salt or hydrate 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 a salt of a compound of Formula (I) and / or a CDK4 / 6 inhibitor and, for example, a) a diluent, for example, purified water, triglyceride oil, for example, hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, for example EPA or DHA or esters or triglycerides thereof or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, for example, silica, talcum, stearic acid, magnesium or calcium salts thereof, sodium oleate, sodium stearate, magnesium stearate, sodium ... for tablets, 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, flavors and sweeteners; f) Tween and / or g) an emulsifier or dispersing agent, such as, for example, cyclodextrin, hydroxypropyl-cyclodextrin, PEG 400, and / or PEG 200, or other acceptable emulsifier; and / or g) an agent that enhances the absorption of the salt, such as, for example, cyclodextrin, hydroxypropyl-cyclodextrin, PEG 400, and / or PEG 200.

[0303] For preparing pharmaceutical compositions from the compounds of formula (I) and / or CDK4 / 6 inhibitors, or any salts or hydrates thereof, inert, pharma- ceutically acceptable carriers may be either solid or liquid. Solid form preparations 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, e.g., magnesium carbonate, magnesium stearate, talc, sugar, or lactose. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharma- ceutically acceptable carriers and manufacturing methods for various compositions can be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.

[0304] Liquid form preparations of the compound of formula (I) and / or CDK4 / 6 inhibitor include solution, suspension, elixir, tincture, emulsion, syrup, suspension and emulsion.For example, water or water-propylene glycol solution for parenteral injection, or the addition of sweeteners and opacifiers for oral solution, suspension and emulsion.Liquid form preparations can also include solution for intranasal administration.

[0305] Liquid, particularly injectable, compositions, compounds of formula (I) and / or CDK4 / 6 inhibitors can be prepared, for example, by dissolving, dispersing, etc. For example, the disclosed salts are dissolved or mixed with a pharma- ceutically acceptable solvent, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc., to form an injectable isotonic solution or suspension. 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, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.

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

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

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

[0310] All amounts of any component of an oral dosage form, e.g., a tablet, described herein, given on a % w / w basis refer to the total weight of the oral dosage form, unless otherwise indicated. EXAMPLES

[0311] The present disclosure is further illustrated by the following examples, which should not be interpreted as limiting the present disclosure in the scope or spirit of the specific procedures described herein.It should be understood that the examples are provided to illustrate certain embodiments, and no limitation to the scope of the present disclosure is intended thereby.It should be further understood that without departing from the spirit of the present disclosure and / or the scope of the appended claims, various other embodiments, modifications, and equivalents thereof that may suggest themselves to those skilled in the art may have means.

[0312] Example 1 - Compound (Ic) - ER Degrader for Subjects with Locally Advanced or Metastatic Breast Cancer Breast cancer is the second most common cancer in women. Approximately 268,000 women are expected to be diagnosed with invasive breast cancer in the United States in 2019. (American Cancer Society) Metastatic breast cancer accounts for approximately 6% of newly diagnosed cases. (Malmgren, JA, Breast Cancer Res Treat (2018) 167: 579-590.) 80% of newly diagnosed breast cancers are estrogen receptor (ER) positive. (National Cancer Institute, Hormone Therapy for Breast Cancer.)

[0313] Fulvestrant has been implicated in ER degradation in breast cancer.

[0314] After 6 months of fulvestrant treatment, up to 50% of ER baseline levels remain (Gutteridge et al., Breast Cancer Res Treat 2004;88 suppl 1:S177).

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

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

[0317] Figure 1 shows the tumor growth inhibition experiments (mean tumor volume (mm) at the doses tested). 3 ) versus time are shown.

[0318] FIG. 2 shows the reduction of ER in MCF7 xenograft tumors in response to administration of 3 mg / kg, 10 mg / kg, and 30 mg / kg of compound (Ic) (orally, once daily). (Table 1) TIFF0007656589000069.tif37128 a Single dose Values ​​indicate total drug concentrations

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

[0320] Example 4 - Phase I Clinical Trial Study Design with Compound (Ic) A Phase I clinical trial with compound (Ic) was conducted. A conventional 3+3 dose escalation design was implemented. The starting dose of compound (Ic) was 30 mg orally once daily with food. Dose escalation was dependent on toxicity.

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

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

[0323] Example 5 - Phase I Pharmacokinetic Data - Oral Administration of Compound (Ic) In a Phase I clinical trial, compound (Ic) was administered orally at a dose of 30 mg / day. It was observed that treatment with 30 mg / day of compound (Ic) fell within the preclinical efficacy range associated with tumor growth inhibition.

[0324] Initial pharmacokinetic results are shown in Table 2 below and in Figures 3 and 4. Figure 3 represents the concentrations of compound (Ic) over 24 hours after dosing on both Days 1 and 15. Figure 4 represents the mean trough concentrations of compound (Ic) throughout the course of the clinical trial. (Table 2) TIFF0007656589000070.tif29161 a AUC on day 15 calculated using imputed 24-h values

[0325] Example 6 - Phase I dose escalation study with compound (Ic) Compound (Ic) was orally administered to subjects at 30 mg / day or 60 mg / day (n=3 for both dose groups). No dose-limiting toxicity was observed in the 30 mg / day cohort. No treatment-related adverse events were observed in the 30 mg / day cohort.

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

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

[0328] MCF7 tumor-bearing NOD / SCID mice were dosed once daily with vehicle or compound (Ic) (10 mg / kg, po) for three consecutive days. Approximately 18 hours after the last dose, mice were sacrificed and MCF7 xenografts were harvested, lysed, and ER levels were determined by immunoblotting. Compound (Ic) reduced ER levels by up to 95% compared to vehicle (as shown by three samples from each group in Figure 5). β-actin served as a loading control for immunoblots. Diet was supplemented with peanut butter to help maintain body weight.

[0329] Animal Testing Details:

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

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

[0332] Dose: Oral (gavage), once daily (QD) for three days (QDx3). Vehicle: 2% Tween 80 / PEG 400 ("PEG / Tween").

[0333] Table 3: Treatment groups TIFF0007656589000071.tif24161

[0334] Sampling: Terminal sacrifice was approximately 18 hours after the last dose, and tumors were harvested, divided, 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 -80°C storage and placed on dry ice. RIPA lysis buffer and Halt protease inhibitors were used at 400 μl per tumor sample. Steel balls (5 mm) were placed on each sample for tissue disruption. Samples were lysed in a TissueLyzer for 4 min at 24 Hz. Homogenization was stopped midway through the process and the block was turned over for the duration of the process. The steel beads were pulled out of the tubes and the lysates were centrifuged at 21,000×g for 15 min at 4°C. The lysates were then measured for total protein concentration by BCA (following the manufacturer's protocol).

[0337] Protein detection by immunoblot: Lysates were mixed with sample buffer and reducing agent (following the manufacturer's protocol). Samples were denatured at 95°C for 5 min in a thermal cycler. Before loading on the gel, samples were cooled and centrifuged (5000 x g, 1 min). Gels were loaded with 10 µg of total protein per lane. Samples were loaded on 4-15% standard Tris / glycine gels and run for 25 min at 250 constant volts in 1X Tris / glycine / SDS buffer. Proteins were transferred from the gel to nitrocellulose using a Bio-Rad Turbo with default settings. All blots were washed with distilled water and blocked for 1 h at room temperature in 5% BSA in TBS-T (TBS with 0.1% Tween) on a rocker. Blots were cut to allow beta-actin and ERα to be detected from the same lane / sample.

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

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

[0340] Part 2: Antitumor efficacy in MCF7 xenograft models.

[0341] The antitumor activity and prolonged ERα degradation activity of compound (Ic) was evaluated in an MCF7 orthotopic xenograft model.

[0342] In this MCF7-xenograft model, compound (Ic) demonstrated dose-dependent efficacy (Figure 6), with doses of 3 and 10 mg / kg / day showing 85% and 98% tumor growth inhibition (TGI) versus vehicle, respectively, and 30 mg / kg / day resulting in tumor regression (124% TGI) (Table 4).

[0343] In an experimental dose-dependent inhibition of tumor growth by compound (Ic) in an orthotopic MCF7 mouse xenograft model, MCF7 cells were implanted into the mammary fat pad of female NOD / SCID mice and tumors grew to 200 mm 3 Compound (Ic) dosing (QDx28; po) was initiated when tumor volume was reached. Tumor volumes were assessed twice weekly for 28 days. Compound (Ic) at 3, 10, or 30 mg / kg inhibited the growth of estradiol-stimulated MCF7 xenografts (TGI of 85%, 98%, and 124%, respectively).

[0344] Table 4. Tumor growth inhibition (TGI) TIFF0007656589000072.tif50144*Tumor volumes are mean ± SD.

[0345] Sampling: Tumors were measured twice weekly. Terminal sacrifice was approximately 18 hours after the last dose, and tumors were harvested, divided, and snap frozen. ERα levels were determined by immunoblotting.

[0346] Tumor volume calculation: Tumor volume = (width x width x length) / 2, all measurements in the formula are in mm, tumor volume is mm 3 It is expressed as:

[0347] Tumor Growth Inhibition (TGI) Calculation: TGI (%) TIFF0007656589000073.tif13155

[0348] At the end of the study, tumors were removed from the mice and ERα levels were determined by immunoblotting tumor homogenates. As seen in Figure 7, all doses of compound (Ic) significantly (>94%) reduced ERα levels when compared to mice receiving vehicle only. Taken together, these data show the potent antitumor activity of compound (Ic) against a well-established in vivo ER-positive breast cancer model, concomitant with robust degradation of ERα in tumors.

[0349] Table 5: Treatment groups TIFF0007656589000074.tif26156

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

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

[0352] NOD / SCID female mice (Charles River, 6–7 weeks old on arrival) were inoculated with 5 × 10 mice per mouse into the axial mammary fat pad. 6 MCF7 cells / 200 μL were implanted (a 90-day pellet of 0.36 mg 17β-estradiol implanted the day before). 3 Compound dosing was initiated when weight was reached. Diet was supplemented with peanut butter to help maintain weight.

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

[0354] Table 6. Tumor Growth Inhibition (TGI) Test TIFF0007656589000075.tif49167*Tumor volumes are mean ± SD.

[0355] dosage: Compound (Ic) and palbociclib: Oral (gavage), once daily for 28 days (QDx28) Palbociclib is administered 30-60 minutes before Compound (Ic). Without intending to be bound by theory, this is to prevent mixing of palbociclib and Compound (Ic), as well as their respective excipients, in 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 (Ic): 2% Tween 80 / PEG-400 ("PEG / Tween"). The ratio of Tween 80 to PEG-400 is 0.02 g Tween 80 to 1 ml PEG-400. PEG-400 is added to a pre-aliquoted amount of Tween 80. For Fulvestrant: 10% w / v ethanol, 10% w / v benzyl alcohol, and 15% w / v benzyl benzoate as co-solvents, together with castor oil ("EBB / Castor Oil") make up 100% w / v. For palbociclib: 50 mM sodium lactate, pH 4.0 ("sodium lactate")

[0357] Table 7. Treatment groups TIFF0007656589000076.tif74161

[0358] Sampling: Tumors were measured twice weekly. Terminal sacrifice was approximately 18 hours after the last dose, and tumors were harvested, divided, and snap frozen. ERα levels were determined by immunoblotting.

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

[0360] Data Overview

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

[0362] Tumors were removed from the mice at the end of the study, and ERα levels were determined by immunoblotting tumor homogenates. As seen in Figure 10, compound (Ic) at 30 mg / kg reduced ERα levels by 73% compared to vehicle, and the combination with palbociclib at 60 mg / kg similarly reduced ERα levels by 72% (Figure 11). However, palbociclib alone (60 mg / kg) did not reduce ERα levels (Figure 12). ERα levels from the various compound treatment groups were compared to vehicle-treated animals by analyzing tumor lysates on separate immunoblots (graphs in Figures 10, 11, and 12 show data from individual immunoblots), and the average ERα levels with standard deviations are shown.

[0363] Table 8. Tumor growth inhibition (TGI) TIFF0007656589000077.tif46156*Tumor volumes are mean ± SD.

[0364] Animal Testing Details:

[0365] Species: ovariectomized Nu / Nu female mice. Animal handling: Axial mammary fat pad implantation (from passage E45) of tamoxifen-resistant tumor fragments, SC per mouse. Tamoxifen pellets (5 mg, 60 day release) were performed under the same anesthesia as the tumor fragments (pellets - dorsal, tumor - abdominal).

[0366] Dose: Oral (gavage), once daily for 28 days (QDx28)

[0367] Vehicle: for Compound (Ic): 2% Tween 80 / PEG400 ("PEG / Tween"); for Palbociclib: 50 mM sodium lactate, pH 4 ("sodium lactate")

[0368] Table 9: Treatment groups TIFF0007656589000078.tif54161

[0369] Sampling: Tumors were measured twice weekly. Final sacrifice was approximately 18 hours after the last dose, and tumors were harvested, divided, and flash frozen. ERα levels were determined by immunoblotting (see Appendix 1 for details).

[0370] Detailed procedure for ERα degradation assay:

[0371] cell lysis

[0372] Snap-frozen tumors were removed from -80°C storage and placed on dry ice. RIPA lysis buffer and Halt protease inhibitors were used at 400 μl per tumor sample. Steel balls (5 mm) were placed on each sample for tissue disruption. Samples were lysed in a TissueLyzer for 4 min at 24 Hz. Homogenization was stopped midway through the process and the block was turned over for the duration of the process. The steel beads were pulled out of the tubes and the lysates were centrifuged at 21,000×g for 15 min at 4°C. The lysates were then measured for total protein concentration by BCA (following the manufacturer's protocol).

[0373] Protein detection by immunoblotting.

[0374] Lysates were mixed with sample buffer and reducing agent (following the manufacturer's protocol). Samples were denatured in a thermal cycler for 5 min at 95 °C. Before loading on the gel, samples were cooled and centrifuged (5000 x g, 1 min). Gels were loaded with 10 µg of total protein per lane. Samples were loaded on a 4-15% standard Tris / Glycine gel and run for 25 min at 250 constant volts in 1X Tris / Glycine / SDS buffer.

[0375] Proteins were transferred from the gels to nitrocellulose using a 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) on a rocker. Blots were cut to allow beta-actin and ERα to be detected from the same lane / sample. Blots were incubated with primary antibodies overnight in 5% BSA in TBST (0.1%) on a rocker at 4°C. ERα (1:2000) from Bethyl labs · Beta-actin from CST (1:3000)

[0376] Blots were washed three times in TBST (0.1%) for 5 min on a rocker at room temperature. Secondary antibody was added and blots were incubated for 1 h at room temperature on a rocker (anti-rabbit-HRP 1:18,000 in TBS-T). Blots were washed three times in TBST (0.1%) for 5 min at room temperature on a rocker. Signal was developed using Pierce West Femto maximum sensitivity substrate for 5 min and blots were imaged on a BioRad ChemiDoc.

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

[0378] Compound (Ic) was administered at a DC concentration of approximately 1 nM. 50), which potently degrades ER in ER-positive breast cancer cell lines (Figures 13 and 14). ER degradation mediated by compound (Ic) reduces the expression of classically regulated ER target genes MCF7 and T47D (Figures 13-16) and inhibits cell proliferation in ER-dependent cell lines. Furthermore, compound (Ic) degrades the clinically relevant ESR1 variants Y537S and D538G (Figure 15) and inhibits proliferation of cell lines expressing those variants. In an immature rat uterine trophoblastic model, compound (Ic) degrades rat uterine ER and shows no agonist activity (Figure 17). Daily oral administration of single agent compound (Ic) (3, 10, and 30 mg / kg) results in significant antitumor activity in estradiol-dependent MCF7 xenografts and, concomitantly, >90% tumor ER protein reduction at the end of the study (Figures 1, 5, and 7). Furthermore, when CDK4 / 6 inhibitors are combined with compound (Ic) in the MCF7 model, even more significant tumor growth inhibition is observed (131% TGI) (Figure 8). Compound (Ic) caused 65% growth inhibition in tamoxifen-resistant MCF7 xenografts, and when compound (Ic) was combined with palbociclib, it resulted in even greater tumor growth inhibition (113% TGI) compared to the palbociclib monotherapy group (91% TGI) (Table 8 and Figure 9). In a hormone-independent patient-derived xenograft model, a clinically relevant ESR1 Y537S mutant model, 10 mg / kg compound (Ic) completely inhibited growth and also significantly reduced mutant ER protein levels (Figure 22). Taken together, the preclinical data for compound (Ic) supports its continued advancement as an orally available ER proteolytic agent.

[0379] Table 10: Summary of in vivo studies using compound (Ic) TIFF0007656589000079.tif59163nd:Not determined

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

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

[0382] Equivalent Those skilled 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 which equivalents are intended to be encompassed by the following claims.

[0383] The methods of the present disclosure have been described herein by reference to certain preferred embodiments, however, certain variations thereon will be apparent to those of ordinary skill in the art, and therefore the disclosure is not to be considered limited thereto, based on the disclosure set forth herein.

[0384] Unless otherwise defined, 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 claims, the singular forms include the plural forms unless the context clearly dictates otherwise.

[0385] It will be appreciated that at least some of the descriptions of the present disclosure have been simplified to focus on elements relevant to a clear understanding of the present disclosure, but for clarity, to the exclusion of other elements understood by those skilled in the art that may form part of the present disclosure. However, because such elements are well known in the art and do not necessarily facilitate a better understanding of the present disclosure, descriptions of such elements are not provided herein.

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

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

Claims

1. An effective amount of a compound of formula (I-c): or a pharma- ceutical acceptable salt thereof, The effective amount of the compound of formula (I-c) or a pharma- ceutically acceptable salt thereof is 10 mg to 1000 mg; A pharmaceutical composition administered to the subject in combination with an effective amount of palbociclib.

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

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

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition comprising the compound of formula (Ic), or a pharma- ceutically acceptable salt thereof, is orally administered to the subject.

5. A pharmaceutical composition comprising the compound of formula (I-c), or a pharma- ceutically acceptable salt thereof, is administered to the subject once a day, twice a day, three times a day, or four times a day; or The pharmaceutical composition comprising the compound of formula (I-c), or a pharma- ceutically acceptable salt thereof, is administered to the subject at once or in two, three, or four portions; The pharmaceutical composition according to any one of claims 1 to 4.

6. the effective amount of the compound of formula (I-c), or a pharma- ceutically acceptable salt thereof, is 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg; or the effective amount of the compound of formula (Ic), or a pharma- ceutically acceptable salt thereof, is 20 mg to 750 mg; or the effective amount of the compound of formula (Ic), or a pharma- ceutically acceptable salt thereof, is 30 mg to 500 mg; or The effective amount of the compound of formula (I-c) or a pharma- ceutically acceptable salt thereof is 30 mg to 120 mg. The pharmaceutical composition according to any one of claims 1 to 4.

7. and wherein said effective amount of a compound of formula (I-c), or a pharma- ceutically acceptable salt thereof, is administered to a subject in need of an effective amount of said compound of formula (I-c), or a pharma- ceutically acceptable salt thereof, to achieve a day 15 mean AUC of greater than 3,500 ng.hr / mL, greater than 3,600 ng.hr / mL, greater than 3,700 ng.hr / mL, greater than 3,800 ng.hr / mL, greater than 3,900 ng.hr / mL, greater than 4,000 ng.hr / mL, greater than 4,100 ng.hr / mL, greater than 4,200 ng.hr / mL, greater than 4,300 ng.hr / mL, greater than 4,400 ng.hr / mL, greater than 4,500 ng.hr / mL, greater than 4,600 ng.hr / mL, greater than 4,700 ng.hr / mL, greater than 4,800 ng.hr / mL, greater than 4,900 ng.hr / mL, or greater than 5,000 ng.hr / mL. ＴＡＵ and / or The effective amount of the compound of formula (I-c), or a pharma- ceutical acceptable salt thereof, is ＴＡＵ Bring about, The pharmaceutical composition according to any one of claims 1 to 6.

8. The effective amount of the compound of formula (I-c), or a pharma- ceutically acceptable salt thereof, provides a day 15 mean C of greater than 200 ng / mL, greater than 205 ng / mL, greater than 210 ng / mL, greater than 215 ng / mL, greater than 220 ng / mL, greater than 225 ng / mL, greater than 230 ng / mL, greater than 235 ng / mL, greater than 240 ng / mL, greater than 245 ng / mL, or greater than 250 ng / mL. ｍａｘ and / or The effective amount of the compound of formula (I-c), or a pharma- ceutical acceptable salt thereof, provides a 15-day mean C of greater than 215 ng / mL and less than 235 ng / mL. ｍａｘ Bring about, The pharmaceutical composition according to any one of claims 1 to 7.

9. The pharmaceutical composition according to any one of claims 1 to 8, which is formulated as a tablet.

10. 10. The pharmaceutical composition of claim 9, wherein the tablet further comprises one or more of an emulsifier, a surfactant, a binder, a disintegrant, a glidant, and a lubricant.

11. the emulsifier is hypromellose, and / or the surfactant is vitamin E polyethylene glycol succinate; and / or the binder is microcrystalline cellulose or lactose monohydrate, and / or the disintegrant is croscarmellose sodium, and / or the flow agent is silicon dioxide; and / or The lubricant is sodium stearyl fumarate. The pharmaceutical composition according to claim 10.

12. 12. The pharmaceutical composition of claim 11, wherein the palbociclib is administered to the subject once daily.

13. 13. The pharmaceutical composition of any one of claims 1 to 12, wherein the effective amount of palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg.

14. 14. The pharmaceutical composition of any one of claims 1-13, wherein the palbociclib is administered to the subject 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.

15. 15. The pharmaceutical composition of any one of claims 1 to 14, wherein a pharmaceutical composition comprising the compound of formula (I-c), or a pharma- ceutically acceptable salt thereof, is administered to the subject once daily for up to 21 consecutive days, followed by up to 7 consecutive days of rest from treatment, and wherein the cycle of treatment with the compound of formula (I-c), or a pharma- ceutically acceptable salt thereof, followed by rest from treatment, is repeated one, two, three, four, five or more times.

16. An effective amount of a compound of formula (I-c):

1. A pharmaceutical composition for treating metastatic breast cancer in a subject, comprising: A pharmaceutical composition orally administered to said subject in combination with palbociclib, which is orally administered to said subject.

17. The pharmaceutical composition according to claim 16, wherein the effective amount of the compound of formula (Ic) is from 30 mg to 1000 mg.

18. 18. The pharmaceutical composition of claim 16 or 17, wherein the effective amount of palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg.

19. 19. The pharmaceutical composition of any one of claims 16-18, wherein the palbociclib is administered to the subject 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.

20. The pharmaceutical composition of any one of claims 16 to 19, wherein the pharmaceutical composition comprising the compound of formula (I-c) is administered to the subject 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-c) followed by rest from treatment is repeated one, two, three, four, five or more times.

21. The pharmaceutical composition according to any one of claims 16 to 20, wherein the administration of palbociclib occurs prior to the administration of the pharmaceutical composition comprising the compound of formula (Ic).

22. The pharmaceutical composition of claim 21, wherein the administration of palbociclib occurs at least 30 minutes prior to the administration of the pharmaceutical composition comprising the compound of formula (I-c).

23. The pharmaceutical composition according to any one of claims 16 to 22, wherein the administration of palbociclib occurs after the administration of a pharmaceutical composition comprising the compound of formula (Ic).

24. The pharmaceutical composition of claim 23, wherein the administration of palbociclib occurs at least 30 minutes after the administration of the pharmaceutical composition comprising the compound of formula (I-c).

25. An effective amount of a compound of formula (I-c): or a pharma- ceutical acceptable salt thereof, A pharmaceutical composition orally administered to a subject in combination with palbociclib, which is orally administered to the subject.

26. (i) A compound of formula (I-c): or a pharma- ceutically acceptable salt thereof; (ii) palbociclib, and (iii) Instructions for use Including the kit.

27. ​​An effective amount of a compound of formula (I-c):

1. A pharmaceutical composition for treating breast cancer in a subject, comprising: The effective amount of the compound of formula (I-c) is 10 mg to 1000 mg; A pharmaceutical composition administered to the subject in combination with an effective amount of palbociclib.

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