Combined use of KAT6 inhibitor

Abstract

Provided in the present disclosure is the combined use of a KAT6 inhibitor. Specifically, the present invention relates to the use of a compound as represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating breast cancer in combination with the following: a) a cyclin-dependent kinase 4 (CDK4) inhibitor; b) an antiestrogen drug; or c) a CDK4 inhibitor and an antiestrogen drug.

Description

Combination use of a KAT6 inhibitor Technical Field

[0001] This disclosure relates to the combined use of a KAT6 inhibitor and belongs to the pharmaceutical field. Background Technology

[0002] Lysine acetyltransferases (KATs) are a class of enzymes that catalyze the transfer of acetyl groups from acetyl-CoA to the ε-amino group of lysine residues in protein substrates. Lysine acetylation affects protein function, playing a crucial regulatory role in chromosome structure, gene transcription regulation, DNA binding capacity, enzyme activity and stability, protein-protein interactions, and intracellular localization. KATs are divided into several subfamilies, with MYST (MOZ, YBF2 / SAS3, SAS2, TIP60) being the largest, including KAT5 (TIP60), KAT6A (MOZ; MYST3), KAT6B (MORF; MYST4), KAT7 (HBO; MYST2), and KAT8 (MOF; MYST1). KAT6A / B, as key members of the MYST family, play a vital role in development, the maintenance of stem cells in hematopoiesis and the immune system, tumorigenesis and drug resistance.

[0003] TCGA database analysis revealed that KAT6A and KAT6B are amplified in various tumors. KAT6A, located in the 8p11-p12 amplicon region of chromosome 8, amplifies in 10-15% of breast cancers, and its copy number is positively correlated with mRNA expression and associated with poor prognosis. Both KAT6A and KAT6B are significantly overexpressed in breast cancer. Further subtype analysis showed a correlation between high KAT6A / B expression and ERα expression levels, suggesting that KAT6A / B may be a precursor to ERα expression. + / HER2 - Potential targets for breast cancer.

[0004] Literature reports that knocking down KAT6A in SUM-52 luminal breast cancer cells, which amplifies KAT6A, significantly inhibits colony formation compared to non-tumor-forming MCF10A cells. RNA-seq analysis showed that KAT6A knockdown resulted in the downregulation of several genes, including ESR1 and genes related to the hormonal stress pathway. Further research indicated that KAT6A-highly expressed ER... +In breast cancer cell lines T47D and CAMA1, KAT6A knockdown inhibits colony formation, but this effect is not observed in the low-expression cell lines MCF7 and SKBR3. KAT6A knockdown in T47D and CAMA1 downregulates ERα expression, while overexpression of wild-type KAT6A in MCF7 and LY2 upregulates ERα. Mutants with lost KAT activity do not exhibit this effect, revealing the importance of KAT function. Overexpression of ERα in T47D reverses the inhibitory effect of KAT6A knockdown on colony formation, suggesting that KAT6A function may be mediated through the regulation of ERα expression. Consistent with this, KAT6A enrichment was found in the promoter region of the ESR1 gene. In vivo pharmacodynamic experiments in the T47D model also demonstrated the tumor-suppressive effect of KAT6A knockdown and the downregulation of ERα. In T47D, knockdown of both KAT6A and KAT6B can downregulate ERα expression and inhibit colony formation, with KAT6A having a greater effect than KAT6B. If both are knocked down simultaneously, the effect is more pronounced, showing an additive effect.

[0005] WO2023016484A discloses a new class of KAT6 inhibitors. Summary of the Invention

[0006] This disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with the following groups in the preparation of a medicament for treating breast cancer:

[0007] a) Cyclin-dependent kinase 4 (CDK4) inhibitors; or

[0008] b) Anti-estrogenic drugs; or

[0009] c) CDK4 inhibitors and anti-estrogenic drugs;

[0010] In some implementations, the breast cancer is ER-positive breast cancer.

[0011] In some implementations, the breast cancer is HER2-negative breast cancer.

[0012] In some implementations, the breast cancer referred to is ER-positive / HER2-negative breast cancer.

[0013] In some implementations, the breast cancer referred to is advanced, unresectable, or metastatic breast cancer.

[0014] In some implementations, the breast cancer referred to is ER-positive / HER2-negative advanced unresectable or metastatic breast cancer.

[0015] In some implementations, the breast cancer referred to is advanced-stage breast cancer that has failed CDK4 / 6 inhibitor and / or endocrine therapy.

[0016] In some implementations, the breast cancer referred to is ER-positive / HER2-negative breast cancer in an advanced stage that has failed CDK4 / 6 inhibitor and / or endocrine therapy.

[0017] In some implementations, the breast cancer is ER-positive / HER2-negative advanced unresectable or metastatic breast cancer that has failed CDK4 / 6 inhibitor and / or endocrine therapy.

[0018] In some implementations, the breast cancer is ER-positive / HER2-negative advanced unresectable or metastatic breast cancer that has failed CDK4 / 6 inhibitor and / or endocrine therapy at an advanced stage.

[0019] In some implementation schemes, the breast cancer referred to is breast cancer that has undergone systemic anti-tumor therapy (including but not limited to chemotherapy, endocrine therapy, targeted therapy, immunotherapy, and other anti-tumor drug treatments) during the recurrence and metastasis stage.

[0020] In some implementations, the breast cancer referred to is ER-positive / HER2-negative breast cancer that has undergone systemic anti-tumor therapy (including but not limited to chemotherapy, endocrine therapy, targeted therapy, immunotherapy, and other anti-tumor drug treatments) during the recurrence and metastasis stage.

[0021] In some implementations, the breast cancer referred to is ER-positive / HER2-negative advanced unresectable or metastatic breast cancer that has undergone systemic anti-tumor therapy (including but not limited to chemotherapy, endocrine therapy, targeted therapy, immunotherapy, and other anti-tumor drug treatments) during the recurrence and metastasis stage.

[0022] In some implementation schemes, the breast cancer referred to is breast cancer in the recurrent or metastatic stage that has not received systemic anti-tumor treatment (including but not limited to chemotherapy, endocrine therapy, targeted therapy, immunotherapy, and other anti-tumor drug treatments).

[0023] In some implementations, the breast cancer referred to is ER-positive / HER2-negative breast cancer that has not received systemic anti-tumor treatment (including but not limited to chemotherapy, endocrine therapy, targeted therapy, immunotherapy, and other anti-tumor drug treatments) during the recurrent and metastatic stage.

[0024] In some implementations, the breast cancer referred to is ER-positive / HER2-negative advanced unresectable or metastatic breast cancer that has not received systemic anti-tumor therapy (including but not limited to chemotherapy, endocrine therapy, targeted therapy, immunotherapy, and other anti-tumor drug treatments) during the recurrent and metastatic stage.

[0025] In some embodiments, the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 0.1-100 mg (calculated as free base) (e.g., 0.1 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg and any value between the two), and the dosing frequency is selected from once daily, twice daily and three times daily.

[0026] In some embodiments, the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 0.1-50 mg, and the frequency of administration is selected from once daily, twice daily, and three times daily.

[0027] In some embodiments, the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 1-50 mg, and the frequency of administration is selected from once daily, twice daily, and three times daily.

[0028] In some embodiments, the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 1-20 mg, and the frequency of administration is selected from once daily, twice daily, and three times daily.

[0029] In some embodiments, the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 2.5-10 mg, and the frequency of administration is selected from once daily, twice daily, and three times daily.

[0030] In some embodiments, the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 0.1 mg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, and any value between two values, and the dosing frequency is selected from once a day, twice a day, and three times a day.

[0031] In some embodiments, the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, and any value between two values, and the dosing frequency is selected from once a day, twice a day, and three times a day.

[0032] In some embodiments, the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg and 20 mg, and the frequency of administration is once daily.

[0033] In some embodiments, the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 2.5 mg, 5 mg, 7.5 mg and 10 mg, and the frequency of administration is once daily.

[0034] In some embodiments, the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 5 mg and 10 mg, and the frequency of administration is once daily.

[0035] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are selected from any combination of the following:

[0036] (a-1) The dosage is 2.5 mg, and the frequency of administration is once a day;

[0037] (a-2) The dosage is 5 mg, and the frequency of administration is once a day;

[0038] (a-3) The dosage is 7.5 mg, and the frequency of administration is once a day;

[0039] (a-4) The dosage is 10 mg, and the frequency of administration is once a day.

[0040] In some embodiments, the dosage of the CDK4 inhibitor is selected from 1-1000 mg (calculated as free base) (e.g., 1 mg, 5 mg, 10 mg, 15 mg, 25 mg, 30 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg). The dosage ranges are 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, or any value between two of these values. The dosing frequency is selected from once a day, twice a day, and three times a day.

[0041] In some embodiments, the dosage of the CDK4 inhibitor is selected from 1-500 mg, and the dosing frequency is selected from once a day, twice a day, and three times a day.

[0042] In some embodiments, the dosage of the CDK4 inhibitor is selected from 1-200 mg, and the dosing frequency is selected from once a day, twice a day, and three times a day.

[0043] In some embodiments, the dosage of the CDK4 inhibitor is selected from 20-200 mg, and the dosing frequency is selected from once a day, twice a day, and three times a day.

[0044] In some embodiments, the dosage of the CDK4 inhibitor is selected from 30-100 mg, and the dosing frequency is selected from once a day, twice a day, and three times a day.

[0045] In some embodiments, the dosage of the CDK4 inhibitor is selected from 1 mg, 5 mg, 10 mg, 15 mg, 25 mg, 30 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, and any value between two values, and the dosing frequency is selected from once a day, twice a day, and three times a day.

[0046] In some embodiments, the CDK4 inhibitor is administered at a dose selected from 1 mg, 5 mg, 10 mg, 15 mg, 25 mg, 30 mg, 50 mg, 65 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, and 200 mg, and is administered twice daily.

[0047] In some embodiments, the CDK4 inhibitor is administered at a dose selected from 30 mg, 50 mg, 65 mg, 75 mg, and 100 mg, and is administered twice daily.

[0048] In some embodiments, the dosage of the CDK4 inhibitor is selected from 50 mg and 75 mg, and the dosing frequency is twice a day.

[0049] In some embodiments, the dosage and frequency of administration of the CDK4 inhibitor are selected from any combination of the following:

[0050] (b-1) The dosage is 30 mg, and the frequency of administration is twice a day;

[0051] (b-2) The dosage is 50 mg, and the frequency of administration is twice a day;

[0052] (b-3) The dosage is 65 mg, administered twice daily;

[0053] (b-4) The dosage is 75 mg, administered twice daily;

[0054] (b-5) The dosage is 100 mg, and the frequency of administration is twice a day.

[0055] In some implementations, the CDK4 inhibitor is a CDK4 selective inhibitor or a CDK4 / 6 inhibitor.

[0056] In some implementations, the CDK4 inhibitor is a selective CDK4 inhibitor.

[0057] In some implementations, the CDK4 selective inhibitor is PF-07220060.

[0058] In some embodiments, the CDK4 selective inhibitor is a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the CDK4 inhibitor is a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 1-1000 mg (calculated as free base) (e.g., 1 mg, 5 mg, 10 mg, 15 mg, 25 mg, 30 mg, 50 mg, 65 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, ... 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg (or any value between two values), with the dosing frequency selected from once a day, twice a day, and three times a day.

[0061] In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 1-500 mg, and the frequency of administration is selected from once daily, twice daily, and three times daily.

[0062] In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 1-200 mg, and the frequency of administration is selected from once daily, twice daily, and three times daily.

[0063] In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 20-200 mg, and the frequency of administration is selected from once daily, twice daily, and three times daily.

[0064] In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 30-100 mg, and the frequency of administration is selected from once daily, twice daily, and three times daily.

[0065] In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 1 mg, 5 mg, 10 mg, 15 mg, 25 mg, 30 mg, 50 mg, 65 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg and any value between the two values, and the dosing frequency is selected from once a day, twice a day and three times a day.

[0066] In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 1 mg, 5 mg, 10 mg, 15 mg, 25 mg, 30 mg, 50 mg, 65 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg and 200 mg, and the frequency of administration is twice a day.

[0067] In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 30 mg, 50 mg, 65 mg, 75 mg and 100 mg, and the dosage is twice daily.

[0068] In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 50 mg and 75 mg, and is administered twice daily.

[0069] In some embodiments, the dosage and frequency of administration of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof are selected from any combination of the following:

[0070] (b1-1) The dosage is 30 mg, and the frequency of administration is twice a day;

[0071] (b1-2) The dosage is 50 mg, and the frequency of administration is twice a day;

[0072] (b1-3) The dosage is 65 mg, and the frequency of administration is twice a day;

[0073] (b1-4) The dosage is 75 mg, and the frequency of administration is twice a day;

[0074] (b1-5) The dosage is 100 mg, and the frequency of administration is twice a day.

[0075] In some implementations, the CDK4 inhibitor is a CDK4 / 6 inhibitor.

[0076] In some embodiments, the CDK4 / 6 inhibitor is selected from at least one of abeciclib, ribociclib, and palbociclib, or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the dosage of the anti-estrogenic drug is selected from 1-1000 mg (calculated as free base) (e.g., 1 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg). The dosage ranges are 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg or any value between two of these. The dosing frequency is selected from once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, and once every four weeks.

[0078] In some embodiments, the dosage of the anti-estrogenic drug is selected from 1-800 mg, and the frequency of administration is selected from once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, and once every four weeks.

[0079] In some embodiments, the dosage of the anti-estrogenic drug is selected from 200-700 mg, and the dosing frequency is selected from once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, and once every four weeks.

[0080] In some embodiments, the dosage of the anti-estrogenic drug is selected from 300-600 mg, and the dosing frequency is selected from once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, and once every four weeks.

[0081] In some embodiments, the dosage of the anti-estrogenic drug is selected from 1 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, and any value between two values, and the dosing frequency is selected from once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, and once every four weeks.

[0082] In some embodiments, the dosage of the anti-estrogenic drug is selected from 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg and 700 mg, and the dosing frequency is selected from once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks and once every four weeks.

[0083] In some embodiments, the dosage of the anti-estrogenic drug is selected from 300 mg, 350 mg, 500 mg and 600 mg, and the dosing frequency is selected from once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks and once every four weeks.

[0084] In some embodiments, the anti-estrogenic drug is selected from at least one of aromatase inhibitors, selective estrogen receptor degraders (SERDs), selective estrogen receptor modulators (SERMs), and estrogen receptor-targeting protein degradation chimeras (ER PROTACs). In some embodiments, the anti-estrogenic drug is a SERD and / or an ER PROTAC. In some embodiments, the anti-estrogenic drug is a SERD. In some embodiments, the anti-estrogenic drug is an ER PROTAC.

[0085] In some implementations, the anti-estrogenic drug is fulvestrant.

[0086] In some implementations, the SERD is fulvestrant.

[0087] In some embodiments, the dosage of fulvestrant is selected from 1-1000 mg (calculated as free base) (e.g., 1 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg). The dosage can be 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg or any value between two of these values. The dosing frequency can be selected from once a week, once every two weeks, once every three weeks, or once every four weeks.

[0088] In some embodiments, the dosage of fulvestrant is selected from 1-800 mg, and the dosing frequency is selected from once a week, once every two weeks, once every three weeks, and once every four weeks.

[0089] In some embodiments, the dosage of fulvestrant is selected from 200-700 mg, and the dosing frequency is selected from once a week, once every two weeks, once every three weeks, and once every four weeks.

[0090] In some embodiments, the dosage of fulvestrant is selected from 300-600 mg, and the dosing frequency is selected from once a week, once every two weeks, once every three weeks, and once every four weeks.

[0091] In some embodiments, the dosage of fulvestrant is selected from 1 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, and any value between two values, and the dosing frequency is selected from once a week, once every two weeks, once every three weeks, and once every four weeks.

[0092] In some embodiments, the dosage of fulvestrant is selected from 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg and 700 mg, and the dosing frequency is selected from once a week, once every two weeks, once every three weeks and once every four weeks.

[0093] In some embodiments, the dosage of fulvestrant is selected from 300 mg, 400 mg, 500 mg and 600 mg, and the dosing frequency is selected from once every two weeks and once every four weeks.

[0094] In some embodiments, the dosage and frequency of administration of the fulvestrant are selected from the following:

[0095] (c1-1) The dosage is 500 mg, and the frequency of administration is once every two weeks;

[0096] (c1-2) The dosage is 500 mg, and the frequency of administration is once every four weeks.

[0097] In some embodiments, the anti-estrogenic drug is a compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the anti-estrogenic drug is a compound of formula (III-1) or a pharmaceutically acceptable salt thereof, or a compound of formula (III-2) or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, the anti-estrogenic drug is a compound of formula (III-1) or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, the ER PROTAC is a compound of formula (III) or a pharmaceutically acceptable salt thereof. In some embodiments, the ER PROTAC is a compound of formula (III-1) or a pharmaceutically acceptable salt thereof, or a compound of formula (III-2) or a pharmaceutically acceptable salt thereof. In some embodiments, the ER PROTAC is a compound of formula (III-1) or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, the dosage of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof is selected from 1-1000 mg (calculated as free base) (e.g., 1 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg). The dosage range is 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg or any value between two values), and the dosing frequency is selected from once a day, twice a day or three times a day.

[0102] In some embodiments, the dosage of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof is selected from 1-800 mg, and the frequency of administration is selected from once daily, twice daily, and three times daily.

[0103] In some embodiments, the dosage of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof is selected from 200-700 mg, and the frequency of administration is selected from once daily, twice daily, and three times daily.

[0104] In some embodiments, the dosage of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof is selected from 300-600 mg, and the frequency of administration is selected from once daily, twice daily, and three times daily.

[0105] In some embodiments, the dosage of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof is selected from 1 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg and any value between the two values, and the dosing frequency is selected from once a day, twice a day and three times a day.

[0106] In some embodiments, the dosage of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof is selected from 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg and 700 mg, and the frequency of administration is selected from once a day, twice a day and three times a day.

[0107] In some embodiments, the dosage of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof is selected from 300 mg, 350 mg, 400 mg, 500 mg and 600 mg, and the frequency of administration is selected from once daily.

[0108] In some embodiments, the dosage and frequency of administration of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof are selected from the following:

[0109] (c2-1) The dosage is 350 mg, and the frequency of administration is once a day;

[0110] (c2-2) The dosage is 500 mg, and the frequency of administration is once a day.

[0111] In some implementations, the anti-estrogenic drug is SERD.

[0112] In some embodiments, the anti-estrogenic drug is a compound of formula (IV) or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the SERD is a compound of formula (IV) or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments, the dosage of the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof is selected from 1-1000 mg (calculated as free base) (e.g., 1 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, ... 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg or any value between two of these values), with the dosing frequency selected from once a day, twice a day, or three times a day.

[0115] In some embodiments, the dosage of the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof is selected from 1-800 mg, and the frequency of administration is selected from once daily, twice daily, and three times daily.

[0116] In some embodiments, the dosage of the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof is selected from 200-700 mg, and the frequency of administration is selected from once daily, twice daily, and three times daily.

[0117] In some embodiments, the dosage of the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof is selected from 300-600 mg, and the frequency of administration is selected from once daily, twice daily, and three times daily.

[0118] In some embodiments, the dosage of the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof is selected from 1 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg and any value between the two values, and the dosing frequency is selected from once a day, twice a day and three times a day.

[0119] In some embodiments, the dosage of the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof is selected from 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg and 700 mg, and the frequency of administration is selected from once a day, twice a day and three times a day.

[0120] In some embodiments, the dosage of the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof is selected from 300 mg, 350 mg, 400 mg, 500 mg and 600 mg, and the frequency of administration is selected from once a day and twice a day.

[0121] In some embodiments, the dosage and frequency of administration of the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof are selected from the following:

[0122] (c3-1) The dosage is 600 mg, and the frequency of administration is once a day;

[0123] (c3-2) The dosage is 300 mg, and the frequency of administration is twice a day.

[0124] In some embodiments, the anti-estrogenic drug is selected from fulvestrant, the compound of formula (III-1) or a pharmaceutically acceptable salt thereof, and the compound of formula (IV) or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is combined with the CDK4 inhibitor.

[0126] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are selected from any one of (a-1) to (a-4), and the dosage and frequency of administration of the CDK4 inhibitor are selected from any one of (b-1) to (b-5).

[0127] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-2), and the dosage and frequency of administration of the CDK4 inhibitor are (b-2).

[0128] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-2), and the dosage and frequency of administration of the CDK4 inhibitor are (b-4).

[0129] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-4), and the dosage and frequency of administration of the CDK4 inhibitor are (b-2).

[0130] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-4), and the dosage and frequency of administration of the CDK4 inhibitor are (b-4).

[0131] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with a CDK4 inhibitor, which is the compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are selected from any one of (a-1) to (a-4), and the dosage and frequency of administration of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof are selected from any one of (b1-1) to (b1-5).

[0133] In some embodiments, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof are (a-2), and the dosage and frequency of administration of the compound of formula (II) or a pharmaceutically acceptable salt thereof are (b1-2).

[0134] In some embodiments, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof are (a-2), and the dosage and frequency of administration of the compound of formula (II) or a pharmaceutically acceptable salt thereof are (b1-4).

[0135] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-4), and the dosage and frequency of administration of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof are (b1-2).

[0136] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-4), and the dosage and frequency of administration of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof are (b1-4).

[0137] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is combined with an anti-estrogenic drug.

[0138] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are selected from any one of (a-1) to (a-4), and the dosage and frequency of administration of the anti-estrogenic drug are as described in any of the preceding embodiments.

[0139] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is combined with an anti-estrogenic drug, wherein the anti-estrogenic drug is fulvestrant.

[0140] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are selected from any one of (a-1) to (a-4), and the dosage and frequency of administration of the fulvestrant are selected from (c1-1) and (c1-2).

[0141] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-2), and the dosage and frequency of administration of the fulvestrant are (c1-1).

[0142] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-2), and the dosage and frequency of administration of fulvestrant are (c1-2). In some embodiments, fulvestrant 500 mg is administered again two weeks after the initial administration.

[0143] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-4), and the dosage and frequency of administration of the fulvestrant are (c1-1).

[0144] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-4), and the dosage and frequency of administration of fulvestrant are (c1-2). In some embodiments, fulvestrant 500 mg is administered again two weeks after the initial administration.

[0145] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with an anti-estrogenic drug, said anti-estrogenic drug being the compound of formula (III-1) or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are selected from any one of (a-1) to (a-4), and the dosage and frequency of administration of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof are selected from (c2-1) and (c2-2).

[0147] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-2), and the dosage and frequency of administration of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof are (c2-1).

[0148] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-2), and the dosage and frequency of administration of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof are (c2-2).

[0149] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-4), and the dosage and frequency of administration of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof are (c2-1).

[0150] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-4), and the dosage and frequency of administration of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof are (c2-2).

[0151] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with an anti-estrogenic drug, said anti-estrogenic drug being the compound of formula (IV) or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are selected from any one of (a-1) to (a-4), and the dosage and frequency of administration of the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof are selected from (c3-1) and (c3-2).

[0153] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-2), and the dosage and frequency of administration of the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof are (c3-1).

[0154] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-2), and the dosage and frequency of administration of the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof are (c3-2).

[0155] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-4), and the dosage and frequency of administration of the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof are (c3-1).

[0156] In some embodiments, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof are (a-4), and the dosage and frequency of administration of the compound of formula (IV) or a pharmaceutically acceptable salt thereof are (c3-2).

[0157] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is combined with a CDK4 inhibitor and an anti-estrogenic drug.

[0158] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are selected from any one of (a-1) to (a-4), the dosage and frequency of administration of the CDK4 inhibitor are selected from any one of (b-1) to (b-5), and the dosage and frequency of administration of the anti-estrogenic drug are as described in any of the preceding embodiments.

[0159] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with a CDK4 inhibitor and an anti-estrogenic drug, wherein the CDK4 inhibitor is the compound of formula (II) or a pharmaceutically acceptable salt thereof, and the anti-estrogenic drug is fulvestrant.

[0160] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are selected from any one of (a-1) to (a-4), the dosage and frequency of administration of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof are selected from any one of (b1-1) to (b1-5), and the dosage and frequency of administration of the fulvestrant are selected from (c1-1) and (c1-2).

[0161] In some embodiments, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof are (a-2), the dosage and frequency of administration of the compound of formula (II) or a pharmaceutically acceptable salt thereof are (b1-2), and the dosage and frequency of administration of the fulvestrant are (c1-1).

[0162] In some embodiments, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof are (a-2), the dosage and frequency of administration of the compound of formula (II) or a pharmaceutically acceptable salt thereof are (b1-2), and the dosage and frequency of administration of fulvestrant are (c1-2). In some embodiments, 500 mg of fulvestrant is administered again two weeks after the initial administration.

[0163] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-2), the dosage and frequency of administration of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof are (b1-4), and the dosage and frequency of administration of the fulvestrant are (c1-1).

[0164] In some embodiments, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof are (a-2), the dosage and frequency of administration of the compound of formula (II) or a pharmaceutically acceptable salt thereof are (b1-4), and the dosage and frequency of administration of fulvestrant are (c1-2). In some embodiments, 500 mg of fulvestrant is administered again two weeks after the initial administration.

[0165] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-4), the dosage and frequency of administration of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof are (b1-2), and the dosage and frequency of administration of the fulvestrant are (c1-1).

[0166] In some embodiments, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof are (a-4), the dosage and frequency of administration of the compound of formula (II) or a pharmaceutically acceptable salt thereof are (b1-2), and the dosage and frequency of administration of fulvestrant are (c1-2). In some embodiments, 500 mg of fulvestrant is administered again two weeks after the initial administration of fulvestrant.

[0167] In some embodiments, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof are (a-4), the dosage and frequency of administration of the compound of formula (II) or a pharmaceutically acceptable salt thereof are (b1-4), and the dosage and frequency of administration of the fulvestrant are (c1-1).

[0168] In some embodiments, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof are (a-4), the dosage and frequency of administration of the compound of formula (II) or a pharmaceutically acceptable salt thereof are (b1-4), and the dosage and frequency of administration of fulvestrant are (c1-2). In some embodiments, 500 mg of fulvestrant is administered again two weeks after the initial administration of fulvestrant.

[0169] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with a CDK4 inhibitor and an anti-estrogenic drug, wherein the CDK4 inhibitor is the compound of formula (II) or a pharmaceutically acceptable salt thereof, and the anti-estrogenic drug is the compound of formula (III-1) or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are selected from any one of (a-1) to (a-4), the dosage and frequency of administration of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof are selected from any one of (b1-1) to (b1-5), and the dosage and frequency of administration of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof are selected from (c2-1) and (c2-2).

[0171] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-2), the dosage and frequency of administration of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof are selected from (b1-2), and the dosage and frequency of administration of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof are (c2-1).

[0172] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-2), the dosage and frequency of administration of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof are selected from (b1-2), and the dosage and frequency of administration of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof are (c2-2).

[0173] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-2), the dosage and frequency of administration of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof are selected from (b1-4), and the dosage and frequency of administration of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof are (c2-1).

[0174] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-2), the dosage and frequency of administration of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof are selected from (b1-4), and the dosage and frequency of administration of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof are (c2-2).

[0175] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-4), the dosage and frequency of administration of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof are selected from (b1-2), and the dosage and frequency of administration of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof are (c2-1).

[0176] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-4), the dosage and frequency of administration of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof are selected from (b1-2), and the dosage and frequency of administration of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof are (c2-2).

[0177] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-4), the dosage and frequency of administration of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof are selected from (b1-4), and the dosage and frequency of administration of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof are (c2-1).

[0178] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-4), the dosage and frequency of administration of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof are selected from (b1-4), and the dosage and frequency of administration of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof are (c2-2).

[0179] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with a CDK4 inhibitor and an anti-estrogenic drug, wherein the CDK4 inhibitor is the compound of formula (II) or a pharmaceutically acceptable salt thereof, and the anti-estrogenic drug is the compound of formula (IV) or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are selected from any one of (a-1) to (a-4), the dosage and frequency of administration of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof are selected from any one of (b1-1) to (b1-5), and the dosage and frequency of administration of the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof are selected from (c3-1) and (c3-2).

[0181] In some embodiments, the dosage and frequency of administration of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are (a-2), the dosage and frequency of administration of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof are selected from (b1-2), and the dosage and frequency of administration of the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof are (c3-1).

[0182] In some embodiments, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof are (a-2), the dosage and frequency of administration of the compound of formula (II) or a pharmaceutically acceptable salt thereof are selected from (b1-2), and the dosage and frequency of administration of the compound of formula (IV) or a pharmaceutically acceptable salt thereof are (c3-2).

[0183] In some embodiments, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof are (a-2), the dosage and frequency of administration of the compound of formula (II) or a pharmaceutically acceptable salt thereof are selected from (b1-4), and the dosage and frequency of administration of the compound of formula (IV) or a pharmaceutically acceptable salt thereof are (c3-1).

[0184] In some embodiments, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof are (a-2), the dosage and frequency of administration of the compound of formula (II) or a pharmaceutically acceptable salt thereof are selected from (b1-4), and the dosage and frequency of administration of the compound of formula (IV) or a pharmaceutically acceptable salt thereof are (c3-2).

[0185] In some embodiments, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof are (a-4), the dosage and frequency of administration of the compound of formula (II) or a pharmaceutically acceptable salt thereof are selected from (b1-2), and the dosage and frequency of administration of the compound of formula (IV) or a pharmaceutically acceptable salt thereof are (c3-1).

[0186] In some embodiments, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof are (a-4), the dosage and frequency of administration of the compound of formula (II) or a pharmaceutically acceptable salt thereof are selected from (b1-2), and the dosage and frequency of administration of the compound of formula (IV) or a pharmaceutically acceptable salt thereof are (c3-2).

[0187] In some embodiments, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof are (a-4), the dosage and frequency of administration of the compound of formula (II) or a pharmaceutically acceptable salt thereof are selected from (b1-4), and the dosage and frequency of administration of the compound of formula (IV) or a pharmaceutically acceptable salt thereof are (c3-1).

[0188] In some embodiments, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof are (a-4), the dosage and frequency of administration of the compound of formula (II) or a pharmaceutically acceptable salt thereof are selected from (b1-4), and the dosage and frequency of administration of the compound of formula (IV) or a pharmaceutically acceptable salt thereof are (c3-2).

[0189] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered over a period of 4 weeks.

[0190] In some implementations, the CDK4 inhibitor is administered over a period of 4 weeks.

[0191] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered over a period of 4 weeks.

[0192] In some implementations, the administration period of the anti-estrogenic drug is 4 weeks.

[0193] In some implementations, the fulvestrant is administered over a period of 4 weeks.

[0194] In some embodiments, the compound of formula (III-1) or a pharmaceutically acceptable salt thereof is administered over a period of 4 weeks.

[0195] In some embodiments, the compound of formula (IV) or a pharmaceutically acceptable salt thereof is administered over a period of 4 weeks.

[0196] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, CDK inhibitor, compound of formula (II) or a pharmaceutically acceptable salt thereof, anti-estrogenic drug, compound of formula (III-1) or a pharmaceutically acceptable salt thereof, and compound of formula (IV) or a pharmaceutically acceptable salt thereof may be present in any pharmaceutically acceptable formulation, for example, tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection, and concentrated solutions for injection), suppositories, inhalers, or sprays.

[0197] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is present in tablet form.

[0198] In some implementations, the CDK inhibitor is present in capsule form.

[0199] In some embodiments, the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is present in capsule form.

[0200] In some embodiments, the anti-estrogenic drug is present in the form of an injection, tablet, or solid dispersion.

[0201] In some implementations, the fulvestrant is available in injectable form.

[0202] In some embodiments, the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof is present in tablet form.

[0203] In some embodiments, the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof is present in the form of a solid dispersion.

[0204] In some embodiments, the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof is present in tablet form.

[0205] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered orally.

[0206] In some implementations, the CDK4 inhibitor is administered orally.

[0207] In some embodiments, the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is administered orally.

[0208] In some implementations, the anti-estrogenic drug is administered by injection or oral administration.

[0209] In some embodiments, the fulvestrant is administered by injection. In some embodiments, the fulvestrant is administered by intramuscular injection.

[0210] In some embodiments, the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof is administered orally.

[0211] In some embodiments, the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof is administered orally.

[0212] This disclosure provides a method for treating breast cancer, comprising administering to a subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and

[0213] a) CDK4 inhibitors; or

[0214] b) Anti-estrogenic drugs; or

[0215] c) CDK4 inhibitors and anti-estrogenic drugs.

[0216] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a CDK4 inhibitor, and an anti-estrogenic drug are used as defined in any of the foregoing uses.

[0217] In some implementations, the breast cancer is defined as in any of the foregoing uses.

[0218] This disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating breast cancer, in combination with the following groups:

[0219] a) CDK4 inhibitors; or

[0220] b) Anti-estrogenic drugs; or

[0221] c) CDK4 inhibitors and anti-estrogenic drugs.

[0222] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a CDK4 inhibitor, and an anti-estrogenic drug are used as defined in any of the foregoing uses.

[0223] In some implementations, the breast cancer is defined as in any of the foregoing uses.

[0224] This disclosure provides a CDK4 inhibitor for the treatment of breast cancer, which is combined with the following groups:

[0225] a) The compound of formula (I) or a pharmaceutically acceptable salt thereof; or

[0226] b) Anti-estrogenic drugs; or

[0227] c) The compound represented by formula (I) or its pharmaceutically acceptable salt and anti-estrogenic drug.

[0228] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a CDK4 inhibitor, and an anti-estrogenic drug are used as defined in any of the foregoing uses.

[0229] In some implementations, the breast cancer is defined as in any of the foregoing uses.

[0230] This disclosure provides an anti-estrogenic drug for treating breast cancer, which is combined with the following groups:

[0231] a) The compound of formula (I) or a pharmaceutically acceptable salt thereof; or

[0232] b) CDK4 inhibitors; or

[0233] c) The compound represented by formula (I) or its pharmaceutically acceptable salt and CDK4 inhibitor.

[0234] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a CDK4 inhibitor, and an anti-estrogenic drug are used as defined in any of the foregoing uses.

[0235] In some implementations, the breast cancer is defined as in any of the foregoing uses.

[0236] This disclosure provides a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and

[0237] a) CDK4 inhibitors; or

[0238] b) Anti-estrogenic drugs; or

[0239] c) CDK4 inhibitors and anti-estrogenic drugs.

[0240] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a CDK4 inhibitor, and an anti-estrogenic drug are used as defined in any of the foregoing uses.

[0241] This disclosure provides a kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and

[0242] a) CDK4 inhibitors; or

[0243] b) Anti-estrogenic drugs; or

[0244] c) CDK4 inhibitors and anti-estrogenic drugs.

[0245] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a CDK4 inhibitor, and an anti-estrogenic drug are used as defined in any of the foregoing uses.

[0246] This disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and

[0247] a) CDK4 inhibitors; or

[0248] b) Anti-estrogenic drugs; or

[0249] c) CDK4 inhibitors and anti-estrogenic drugs;

[0250] and one or more pharmaceutically acceptable carriers.

[0251] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a CDK4 inhibitor, and an anti-estrogenic drug are used as defined in any of the foregoing uses.

[0252] In some embodiments, the pharmaceutical composition can be formulated into any pharmaceutically acceptable dosage form. For example, it can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection, and concentrated solutions for injection), suppositories, inhalers, or sprays.

[0253] This disclosure also provides a medicine box containing the above-described composition or the above-described pharmaceutical composition.

[0254] In some implementations, the subjects described in this disclosure are humans or non-human mammals.

[0255] In some implementations, the subjects described in this disclosure are humans.

[0256] In some implementations, the subjects described in this disclosure are breast cancer patients.

[0257] In some embodiments, the compound of formula (I) in this disclosure, or a pharmaceutically acceptable salt thereof, is specifically the compound of formula (I).

[0258] In some embodiments, the compound of formula (II) in this disclosure, or a pharmaceutically acceptable salt thereof, is specifically the compound of formula (II).

[0259] In some embodiments, the compound represented by formula (III-1) in this disclosure or a pharmaceutically acceptable salt thereof, specifically the hydrochloride salt of the compound represented by formula (III-1).

[0260] In some embodiments, the compound represented by formula (IV) in this disclosure, or a pharmaceutically acceptable salt thereof, specifically a triphosphate of the compound represented by formula (IV).

[0261] The combined administration methods described in this disclosure are selected from simultaneous administration, independently prepared and co-administered, or independently prepared and sequentially administered.

[0262] The combined routes of administration described in this disclosure are selected from oral administration, parenteral administration, and transdermal administration, wherein parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection.

[0263] In the scheme described in this disclosure, the combination may optionally also include other components, including but not limited to other anti-tumor drugs.

[0264] In this disclosure, the components to be combined (e.g., compounds of formula (I) or their pharmaceutically acceptable salts, CDK4 inhibitors, anti-estrogenic drugs, and optionally any other component drugs) may be administered simultaneously or sequentially separately. Furthermore, the components to be combined may also be administered in combination in the same formulation or in separate, different formulations.

[0265] In this disclosure, the dosage may be a unit dose.

[0266] Terminology Definition

[0267] The "anti-estrogenic drugs" described in this disclosure refer to a class of drugs that prevent the biological effects of estrogens such as estradiol from being mediated by the body. Anti-estrogenic drugs work by blocking estrogen receptors (ER) and / or inhibiting or suppressing estrogen production.

[0268] The term "combination" as used in this disclosure refers to a route of administration in which at least one dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one dose of a CDK4 inhibitor are administered over a specified time period, wherein both drugs exhibit pharmacological effects. The time period can be within a dosing cycle, preferably within 4 weeks, 3 weeks, 2 weeks, 1 week, or within 24 hours, more preferably within 12 hours. The compound of formula (I) or a pharmaceutically acceptable salt thereof, and the CDK4 inhibitor may be administered simultaneously or sequentially. This period includes treatments in which the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the CDK4 inhibitor are administered via the same or different routes of administration. The routes of administration for the combination described in this disclosure are selected from simultaneous administration, independently formulated and co-administered administration, or independently formulated and sequentially administered administration.

[0269] "Optional" or "optionally" means that the event or situation described below may, but does not have to, occur, and the description includes the circumstances under which the event or situation may or may not occur.

[0270] The term "effective amount" or "therapeutic effective amount" as used in this disclosure includes an amount sufficient to improve or prevent symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity.

[0271] The term “pharmaceutically acceptable carrier” as used in this disclosure includes, but is not limited to, any adjuvant, flow aid, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration (FDA) for use in humans or livestock.

[0272] The values ​​in this disclosure are instrument measurements and are subject to a certain degree of error. Generally, ±10% is within the reasonable error range. Of course, the context in which the value is used must be considered. For example, in the case of particle size of the active ingredient, where the measurement error variation does not exceed ±10%, the value can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0273] Objective response rate (ORR): The percentage of subjects who achieve CR or PR.

[0274] Disease control rate (DCR): The percentage of cases that achieve remission (CR+PR) and stable disease (SD) after treatment.

[0275] Clinical benefit rate (CBR): The percentage of cases that achieve remission (CR+PR) and stable disease (SD) for at least 6 months after treatment.

[0276] Duration of Response (DoR): The duration from the first recorded objective tumor response (CR or PR) to the first recorded disease progression or death from any cause (whichever occurs first).

[0277] Progression-free survival (PFS): The duration from the date of first administration to the recorded progression of disease or death from any cause (whichever occurs first).

[0278] Overall survival (OS): defined as the time from the date of first administration to the subject's death from any cause.

[0279] QD: Once a day; BID: Twice a day; BIW: Twice a week; 4wks: Four weeks.

[0280] po: oral administration; sc: subcutaneous injection. Attached Figure Description

[0281] Figure 1 shows the changes in tumor volume in each group of animals in Example 1.

[0282] Figure 2 shows the percentage change in tumor volume in each group of animals in Example 1. Detailed Implementation Plan

[0283] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0284] Example 1: Pharmacodynamic study of a subcutaneous animal model of ZR-75-1 human breast cancer cells

[0285] 1. Experimental Design

[0286] Laboratory animals: BALB / c nude mice (purchased from Beijing Ankai Yibo Biotechnology Co., Ltd.), 6-8 weeks old, female, 20-25g

[0287] Compounds:

[0288] The compound shown in formula (I) (hereinafter referred to as compound I) can be prepared by referring to the method in WO2023016484A;

[0289] The compound shown in formula (II) (hereinafter referred to as compound II) can be prepared by referring to the method in WO2022166799A;

[0290] The compound shown in formula (III-1) (hereinafter referred to as compound III-1) can be prepared by referring to the method in WO2022206737A;

[0291] Fluvestrant was purchased from Kanglong Chemical.

[0292] 2. Experimental Methods

[0293] 2.1 Cell Culture

[0294] ZR-75-1 tumor cells were cultured in vitro in an incubator at 37°C and 5% CO2 using medium containing 10% fetal bovine serum and RPMI 1640. The medium was changed every 2 days, and the number of passages was not exceeded 4-5. Tumor cells in the logarithmic growth phase were used for in vivo tumor seeding.

[0295] 2.2 Inoculation and Grouping of Tumor Cells

[0296] ZR-75-1 tumor cells resuspended in RPMI 1640 medium were inoculated at 1×10⁻⁶ 7 +0.1 mL of gel was injected subcutaneously on the right side of the experimental animals, with a total of 110 animals inoculated. Starting one day before cell inoculation, estrogen was administered subcutaneously twice a week at a dose of 40 μg / 20 μl per animal until the average tumor size reached 178 mm. 3 Sixty-four animals with relatively uniform tumor volume were selected and divided into eight groups of eight. The specific dosing regimens are shown in Table 1.

[0297] Table 1 Dosing Regimen Note: 1. BID interval is 6 hours; 2. In the combination drug group, the drugs are administered simultaneously (the second drug is administered after the first drug is administered). The drug preparation is shown in Table 2.

[0298] Table 2. Preparation of Drugs Note: The drug preparation information in the table are theoretical values. The actual amount of drug prepared each time shall be based on the data recorded in the experimental record book.

[0299] Table 3. Reagent and Consumable Information

[0300] 2.3 Detection Indicators

[0301] Routine monitoring includes not only monitoring tumor growth but also monitoring behavioral changes in the animal, such as movement, food and water consumption (observed from the cage side only), weight changes, luster of the eyes / coat, and any other abnormal effects. Any clinical signs such as death and / or abnormalities should be recorded.

[0302] 2.3.1 Weight

[0303] During the experiment, all animals were weighed twice a week. The percentage change in body weight (BW change, %) was calculated using the following formula: BW change% = (BW change, %) / (BW change, %) Day X / BW Day 0 )×100%, of which BW Day X BW represents the animal's body weight on the day of administration. Day 0 The animal's weight on the day of grouping.

[0304] 2.3.2 Tumor volume measurement

[0305] The tumor's major and minor diameters were measured using vernier calipers, and its volume was calculated using the formula: Volume = 0.5 × Major Diameter × Minor Diameter 2 During the experiment, tumor volume was measured twice a week. Tumor volume was used to calculate the tumor growth inhibition rate (TGI) (an indicator of antitumor activity): TGI = (1-T / C) × 100%, where T and C are the mean relative tumor volumes (mean percentage of tumor proliferation) of the treatment group and the control group, respectively.

[0306] 2.4 Statistical Analysis

[0307] 2.4.1 Data Acquisition: Measure and observe according to the requirements of the experimental protocol, and record manually or directly in the computer database.

[0308] 2.4.2 Statistical Analysis: SPSS 16.0 statistical software was used to perform statistical analysis between groups, and the mean and standard error were calculated based on all measurement parameters in the experimental design. The significance level was set at 0.05 or P < 0.05.

[0309] 3. Experimental Results

[0310] The mean tumor volume during the experiment is shown in Table 4, and the corresponding tumor volume curves are shown in Figures 1 and 2. During the administration period, the animals in each treatment group tolerated the medication well, and no other abnormal clinical symptoms were observed. All treatment groups showed significant antitumor activity.

[0311] Table 4. Mean tumor volume of each group of animals Note: a Mean ± Standard Error

[0312] The mean tumor volume of each group on day 45 after tumor cell inoculation is shown in Table 5.

[0313] Table 5. Tumor suppression effect of the treatment group 45 days after tumor inoculation Note: a . Mean ± standard error; b One-way ANOVA LSD test was used to compare the results with the solvent control group.

[0314] Example 2: An open-label, multicenter Phase Ib / II clinical study of the safety, tolerability, pharmacokinetics, and preliminary efficacy of drug a in combination with fulvestrant ± drug b, or in combination with drug c ± compound b, or in combination with drug b + drug d in patients with ER-positive / HER2-negative advanced unresectable or metastatic breast cancer.

[0315] 1. Drug Information:

[0316] Drug A is manufactured by Shandong Shengdi Pharmaceutical Co., Ltd., in tablet form, with strengths of 0.5 mg, 2.5 mg and 10 mg, and its active ingredient is the compound shown in formula (I).

[0317] Drug B is produced by Jiangsu Hengrui Medicine Co., Ltd., in capsule form, with specifications of 10mg, 15mg, 25mg, and 50mg. The active ingredient is the compound shown in formula (II).

[0318] Drug C is produced by Shandong Shengdi Pharmaceutical Co., Ltd., in tablet form, with specifications of 75mg and 150mg. The active ingredient is the triphosphate of the compound shown in formula (IV), which can be prepared by referring to the method in WO2021139756A.

[0319] Drug d is produced by Shandong Shengdi Pharmaceutical Co., Ltd., in tablet form, with specifications of 50mg and 250mg, and the active ingredient is the hydrochloride salt of the compound shown in formula (III-1);

[0320] Fulvestrant is an injection solution (Pulehe) produced by Jiangsu Hansoh Pharmaceutical Group Co., Ltd., with a specification of 5ml:0.25g.

[0321] 2. Study population: Patients with ER-positive / HER2-negative advanced unresectable or metastatic breast cancer confirmed by histological or cytological pathology.

[0322] 3. Research Design:

[0323] Drug A combined with fulvestrant (Group A):

[0324] The initial dose of drug A is 5 mg once daily orally, for a period of 4 weeks. The dose of fulvestrant is fixed at 500 mg intramuscularly, for a period of 4 weeks, with an additional 500 mg dose two weeks after the first dose (C1D15). Drug A has a pre-set dose up-regulation level of 10 mg once daily and a dose down-regulation level of 2.5 mg once daily.

[0325] The dosage combination of drug A and fulvestrant is as follows:

[0326] Based on the safety, efficacy, and pharmacokinetic (PK) data from the initial escalation phase, SMC can adjust the dosage of drug a by increasing it, such as to 7.5 mg QD. Similarly, after exploring the 10 mg dosage, an intermediate dose can be added, such as 7.5 mg QD.

[0327] Drug A combined with drug C (Group B):

[0328] The initial dose of drug A is 5 mg QD, once daily, orally, for a period of 4 weeks. The dose of drug C is 600 mg QD, once daily, orally, for a period of 4 weeks (28 days). Drug A is pre-programmed with one up-regulation level of 10 mg QD and one down-regulation level of 2.5 mg QD.

[0329] The dosage combination of drug A and drug C is as follows:

[0330] Based on the safety, efficacy, and pharmacokinetic (PK) data from earlier studies, SMC can adjust the dosage of drug a by increasing the dose, such as to 7.5 mg QD. Similarly, after exploring the 10 mg dose, an intermediate dose can be added, such as 7.5 mg QD. With the consent of SMC, the starting dose of drug c can be adjusted based on other earlier studies, such as 300 mg BID.

[0331] Drug a in combination with drug b and fulvestrant (Group C):

[0332] The initial dose of drug A is 5 mg QD, once daily, orally, for a period of 4 weeks. The initial dose of drug B is 50 mg BID, twice daily, orally, for a period of 4 weeks. The dose of fulvestrant is fixed at 500 mg, intramuscularly, for a period of 4 weeks, with a booster dose of 500 mg two weeks after the first dose.

[0333] The initial dose is designated as dose group ①. The combination of drug a, drug b, and fulvestrant is as follows:

[0334] Drug A is pre-set with an up-regulation level of 10 mg QD and a down-regulation level of 2.5 mg QD. The SMC can adjust the up-regulation dose of drug A, such as to 7.5 mg QD, based on the safety, efficacy, and pharmacokinetic data from the initial escalation. Similarly, after exploring the 10 mg dose, an intermediate dose can be added, such as 7.5 mg QD. If there are expansion data from other studies of drug B in combination with fulvestrant, with the SMC's consent, prior data supporting the dose selection of drug B in combination with fulvestrant can be accepted, such as adjusting the initial dose of drug B to 30 mg BID, 65 mg BID, 75 mg BID, or 100 mg BID, etc.

[0335] Drug a combined with drugs b and c (Group D):

[0336] The initial dose of drug a is 5 mg QD, once daily, orally, for a period of 4 weeks. The initial dose of drug b is 50 mg BID, twice daily, orally, for a period of 4 weeks. The dose of drug c is 600 mg QD, once daily, orally, for a period of 4 weeks (28 days). The dosage combination of drug a, drug b, and drug c is as follows:

[0337] Drug A is pre-set with an up-regulation level of 10 mg QD and a down-regulation level of 2.5 mg QD. The SMC can adjust the up-regulation dose of drug A, such as to 7.5 mg QD, based on the safety, efficacy, and pharmacokinetic data from the initial escalation. Similarly, after exploring the 10 mg dose, an intermediate dose can be added, such as 7.5 mg QD. If there is expansion data from other studies involving drug B in combination with drug C, with the SMC's consent, prior data supporting the dose selection of drug B (30 mg BID, 65 mg BID, 75 mg BID, or 100 mg BID) in combination with drug C (600 mg QD or 300 mg BID) may be accepted.

[0338] Drug a combined with drugs b and d (Group E):

[0339] The initial dose of drug a is 5 mg QD, once daily, orally, for a period of 4 weeks. The initial dose of drug b is 50 mg BID, twice daily, orally, for a period of 4 weeks. The initial dose of drug d is 350 mg QD, once daily, orally, for a period of 4 weeks (28 days). The dosage combination of drug a, drug b, and drug d is as follows:

[0340] Drug A is pre-set with an upregulation level of 10 mg QD and a downregulation level of 2.5 mg QD. The SMC can adjust the upregulation dose of drug A, such as to 7.5 mg QD, based on the safety, efficacy, and pharmacokinetic (PK) data from the initial escalation. Similarly, after exploring the 10 mg dose, an intermediate dose can be added, such as 7.5 mg QD. If there is expansion data from other studies involving drug B in combination with drug D, with the SMC's consent, prior data supporting the dose selection for drug B in combination with drug D can be accepted. For example, the initial dose of drug B can be adjusted to 30 mg BID, 65 mg BID, 75 mg BID, 100 mg BID, etc., and the initial dose of drug D can be adjusted to 500 mg.

[0341] 4. Inclusion criteria

[0342] 1) Advanced unresectable or metastatic breast cancer confirmed by histopathology or cytopathology. Histopathological examination is required to confirm ER positivity and HER2 negativity.

[0343] 2) Previous treatment:

[0344] Dosage exploration phase (Group A / Group B / Group C / Group D / Group E): Late stage CDK4 / 6 inhibitor therapy and endocrine therapy failed.

[0345] Therapeutic efficacy expansion phase:

[0346] Groups A, B, C, D1, and E1: Late-stage patients who failed CDK4 / 6 inhibitor therapy and endocrine therapy.

[0347] Groups D2 and E2: Required to have not received any systemic anti-tumor treatment during the recurrence and metastasis stage.

[0348] 5. Results:

[0349] In evaluable cases of ER-positive HER2-negative breast cancer that have failed CDK4 / 6 inhibitor therapy and endocrine therapy in advanced stages, the objective response rate (ORR) of drug a 5 mg QD combined with fulvestrant 500 mg was 28.6% (6 / 21), and the disease control rate (DCR) was 76.2% (16 / 21).

[0350] The objective response rate (ORR) of drug a 5mg QD combined with drug c 300mg BID was 50% (3 / 6) and the disease control rate (DCR) was 66.7% (4 / 6), demonstrating good clinical efficacy.

[0351] The objective response rate (ORR) was 100% (1 / 1) in the combination of drug a 5 mg QD, drug b 75 mg BID, and drug c 300 mg BID. The disease control rate (DCR) was 100% (1 / 1).

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with each of the following groups for the manufacture of a medicament for the treatment of breast cancer: a) a cyclin-dependent kinase 4 (CDK4) inhibitor; or b) an anti-estrogen; or c) a CDK4 inhibitor and an anti-estrogen drug; 2. The use according to claim 1, wherein the breast cancer is ER-positive breast cancer, preferably ER-positive / HER2-negative breast cancer.

3. The use according to claim 1 or 2, wherein the breast cancer is advanced unresectable or metastatic breast cancer, preferably ER-positive / HER2-negative advanced unresectable or metastatic breast cancer.

4. The use according to any one of claims 1 to 3, wherein the breast cancer is advanced stage CDK4 / 6 inhibitor and / or endocrine therapy-failed breast cancer, preferably ER-positive / HER2-negative advanced stage CDK4 / 6 inhibitor and / or endocrine therapy-failed breast cancer, more preferably ER-positive / HER2-negative advanced stage CDK4 / 6 inhibitor and / or endocrine therapy-failed advanced unresectable or metastatic breast cancer.

5. The use according to any one of claims 1 to 3, wherein the breast cancer is relapse metastatic stage systemically antitumor treatment-naive breast cancer, preferably ER-positive / HER2-negative relapse metastatic stage systemically antitumor treatment-naive breast cancer, more preferably ER-positive / HER2-negative relapse metastatic stage systemically antitumor treatment-naive advanced unresectable or metastatic breast cancer.

6. The use according to any one of claims 1 to 5, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose selected from the group consisting of 0.1 to 100 mg (as free base) at a frequency selected from the group consisting of once a day, twice a day and three times a day; preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose selected from the group consisting of 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg and 20 mg at a frequency of once a day.

7. The use according to claim 6, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose selected from the group consisting of: (a-1) 2.5 mg at a frequency of once a day; (a-2) 5 mg at a frequency of once a day; (a-3) 7.5 mg at a frequency of once a day; (a-4) 10 mg at a frequency of once a day.

8. The use according to any one of claims 1-7, wherein the dosage of the CDK4 inhibitor is selected from 1-1000 mg (calculated as free base), and the frequency of administration is selected from once a day, twice a day, and three times a day; preferably, the dosage of the CDK4 inhibitor is selected from 1 mg, 5 mg, 10 mg, 15 mg, 25 mg, 30 mg, 50 mg, 65 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, and 200 mg, and the frequency of administration is twice a day.

9. The use according to any one of claims 1-8, wherein the CDK4 inhibitor is a CDK4 selective inhibitor or a CDK4 / 6 inhibitor, preferably a CDK4 selective inhibitor.

10. The use of claim 9, wherein the CDK4 selective inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof, Preferably, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 1-1000 mg (calculated as free base), and the dosing frequency is selected from once daily, twice daily, and three times daily; preferably, the dosage of the CDK4 inhibitor is selected from 1 mg, 5 mg, 10 mg, 15 mg, 25 mg, 30 mg, 50 mg, 65 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, and 200 mg, and the dosing frequency is twice daily.

11. The use according to claim 10, wherein the dosage and frequency of administration of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof are selected from the following: (b1-1) The dosage is 30 mg, and the frequency of administration is twice a day; (b1-2) The dosage is 50 mg, and the frequency of administration is twice a day; (b1-3) The dosage is 65 mg, and the frequency of administration is twice a day; (b1-4) The dosage is 75 mg, and the frequency of administration is twice a day; (b1-5) The dosage is 100 mg, and the frequency of administration is twice a day.

12. The use according to any one of claims 1-11, wherein the dosage of the anti-estrogenic drug is selected from 1-1000 mg (calculated as free base), and the frequency of administration is selected from once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, and once every four weeks; preferably, the dosage of the anti-estrogenic drug is selected from 1 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, and 800 mg, and the frequency of administration is selected from once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, and once every four weeks.

13. The use according to any one of claims 1-12, wherein the anti-estrogenic drug is an aromatase inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM).

14. The use according to any one of claims 1-13, wherein the anti-estrogenic drug is fulvestrant; Preferably, the dosage of fulvestrant is selected from 1-1000 mg, and the dosing frequency is selected from once a week, once every two weeks, once every three weeks, and once every four weeks; more preferably, the dosage of fulvestrant is selected from 1 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, and 800 mg, and the dosing frequency is selected from once a week, once every two weeks, once every three weeks, and once every four weeks.

15. The use according to claim 14, wherein the dosage and frequency of administration of fulvestrant are selected from the following: (c1-1) The dosage is 500 mg, and the frequency of administration is once every two weeks; (c1-2) The dosage is 500 mg, and the frequency of administration is once every four weeks.

16. The use according to any one of claims 1-13, wherein the anti-estrogen drug is a compound of formula (III) or a pharmaceutically acceptable salt thereof, Preferably, the compound of formula (III-1) or a pharmaceutically acceptable salt thereof, or the compound of formula (III-2) or a pharmaceutically acceptable salt thereof, More preferably, the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof.

17. The use according to claim 16, wherein the anti-estrogenic drug is a compound of formula (III-1) or a pharmaceutically acceptable salt thereof, the dosage of the compound of formula (III-1) or a pharmaceutically acceptable salt thereof is selected from 1-1000 mg (calculated as free base), and the frequency of administration is selected from once daily, twice daily, and three times daily; preferably, the dosage of the compound of formula (III-1) or a pharmaceutically acceptable salt thereof is selected from 1 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, and 800 mg, and the frequency of administration is selected from once daily, twice daily, and three times daily.

18. The use according to claim 17, wherein the dosage and frequency of administration of the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof are selected from the following: (c2-1) The dosage is 350 mg, and the frequency of administration is once a day; (c2-2) The dosage is 500 mg, and the frequency of administration is once a day.

19. The use according to any one of claims 1-13, wherein the anti-estrogen drug is a compound of formula (IV) or a pharmaceutically acceptable salt thereof, Preferably, the dosage of the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof is selected from 1-1000 mg (calculated as free base), and the frequency of administration is selected from once daily, twice daily, and three times daily; more preferably, the dosage of the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof is selected from 1 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, and 800 mg, and the frequency of administration is selected from once daily, twice daily, and three times daily.

20. The use according to claim 19, wherein the dosage and frequency of administration of the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof are selected from the following: (c3-1) The dosage is 600 mg, and the frequency of administration is once a day; (c3-2) The dosage is 300 mg, and the frequency of administration is twice a day.

21. The use according to claim 10 or 11, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with a CDK4 inhibitor, wherein the CDK4 inhibitor is the compound of formula (II) or a pharmaceutically acceptable salt thereof; Preferably, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from any of the groups (a-1) to (a-4) and the dosage and frequency of administration of the compound of formula (II) or a pharmaceutically acceptable salt thereof is selected from any of the groups (b1-1) to (b1-5), wherein, The dosage and frequency of administration for (a-1) to (a-4) are as defined in claim 7, and the dosage and frequency of administration for (b1-1) to (b1-5) are as defined in claim 11.

22. The use according to claim 14 or 15, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is combined with an anti-estrogenic drug, wherein the anti-estrogenic drug is fulvestrant; Preferably, the dosage and frequency of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is selected from any one of (a-1) to (a-4), and the dosage and frequency of administration of the fulvestrant is selected from (c1-1) and (c1-2), wherein, The dosage and frequency of administration for (a-1) to (a-4) are as defined in claim 7, and the dosage and frequency of administration for (c1-1) or (c1-2) are as defined in claim 15.

23. The use according to any one of claims 16-18, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with an anti-estrogenic drug, said anti-estrogenic drug being the compound of formula (III-1) or a pharmaceutically acceptable salt thereof; Preferably, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from any one of (a-1) to (a-4) and the dosage and frequency of administration of the compound of formula (III-1) or a pharmaceutically acceptable salt thereof is selected from (c2-1) and (c2-2), wherein, The dosage and frequency of administration for (a-1) to (a-4) are as defined in claim 7, and the dosage and frequency of administration for (c2-1) or (c2-2) are as defined in claim 18.

24. The use according to claim 19 or 20, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with an anti-estrogenic drug, wherein the anti-estrogenic drug is the compound of formula (IV) or a pharmaceutically acceptable salt thereof; Preferably, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from any one of (a-1) to (a-4) and the dosage and frequency of administration of the compound of formula (IV) or a pharmaceutically acceptable salt thereof is selected from (c3-1) and (c3-2), wherein, The dosage and frequency of administration for (a-1) to (a-4) are as defined in claim 7, and the dosage and frequency of administration for (c3-1) or (c3-2) are as defined in claim 20.

25. The use according to claim 14 or 15, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with a CDK4 inhibitor and an anti-estrogenic drug, wherein the CDK4 inhibitor is the compound of formula (II) or a pharmaceutically acceptable salt thereof, and the anti-estrogenic drug is fulvestrant; Preferably, the dosage and frequency of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is selected from any one of (a-1) to (a-4), the dosage and frequency of administration of the compound of Formula (II) or a pharmaceutically acceptable salt thereof is selected from any one of (b1-1) to (b1-5), and the dosage and frequency of administration of fulvestrant is selected from (c1-1) and (c1-2), wherein, The dosage and frequency of administration for (a-1) to (a-4) are as defined in claim 7, the dosage and frequency of administration for (b1-1) to (b1-5) are as defined in claim 11, and the dosage and frequency of administration for (c1-1) or (c1-2) are as defined in claim 15.

26. The use according to any one of claims 16-18, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with a CDK4 inhibitor and an anti-estrogenic drug, wherein the CDK4 inhibitor is the compound of formula (II) or a pharmaceutically acceptable salt thereof, and the anti-estrogenic drug is the compound of formula (III-1) or a pharmaceutically acceptable salt thereof; Preferably, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from any one of (a-1) to (a-4), the dosage and frequency of administration of the compound of formula (II) or a pharmaceutically acceptable salt thereof is selected from any one of (b1-1) to (b1-5), and the dosage and frequency of administration of the compound of formula (III-1) or a pharmaceutically acceptable salt thereof is selected from (c2-1) and (c2-2), wherein, The dosage and frequency of administration for (a-1) to (a-4) are as defined in claim 7, the dosage and frequency of administration for (b1-1) to (b1-5) are as defined in claim 11, and the dosage and frequency of administration for (c2-1) or (c2-2) are as defined in claim 18.

27. The use according to claim 19 or 20, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with a CDK4 inhibitor and an anti-estrogenic drug, wherein the CDK4 inhibitor is the compound of formula (II) or a pharmaceutically acceptable salt thereof, and the anti-estrogenic drug is the compound of formula (IV) or a pharmaceutically acceptable salt thereof. Preferably, the dosage and frequency of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from any one of (a-1) to (a-4), the dosage and frequency of administration of the compound of formula (II) or a pharmaceutically acceptable salt thereof is selected from any one of (b1-1) to (b1-5), and the dosage and frequency of administration of the compound of formula (IV) or a pharmaceutically acceptable salt thereof is selected from (c3-1) and (c3-2), wherein, The dosage and frequency of administration for (a-1) to (a-4) are as defined in claim 7, the dosage and frequency of administration for (b1-1) to (b1-5) are as defined in claim 11, and the dosage and frequency of administration for (c3-1) or (c3-2) are as defined in claim 20.

28. The use according to any one of claims 1-27, wherein the administration period of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 4 weeks; And / or, the CDK4 inhibitor is administered over a period of 4 weeks; And / or, the administration cycle of the anti-estrogenic drug is 4 weeks.

29. A composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a) CDK4 inhibitors; or b) Anti-estrogenic drugs; or c) CDK4 inhibitors and anti-estrogenic drugs; The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a CDK4 inhibitor, and an anti-estrogenic drug are defined as any one of claims 1-28.

30. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a) CDK4 inhibitors; or b) Anti-estrogenic drugs; or c) CDK4 inhibitors and anti-estrogenic drugs; And one or more pharmaceutically acceptable carriers; The compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a CDK4 inhibitor, and an anti-estrogenic drug are defined as any one of claims 1-28.

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