Use in treating breast cancer after treatment with CDK4 / 6 inhibitor

Abstract

The present disclosure belongs to the technical field of medicine, and relates to a use in treating breast cancer after treatment with a CDK4 / 6 inhibitor, specifically relating to a use of a compound represented by formula (I) in treating breast cancer treated with a CDK4 / 6 inhibitor.

Description

Use in the treatment of breast cancer following CDK4 / 6 inhibitor therapy Technical Field

[0001] This disclosure pertains to the field of pharmaceutical technology and relates to the use of a compound of formula (I) in treating breast cancer after treatment with a CDK4 / 6 inhibitor. Background Technology

[0002] Cyclins directly act on cell cycle-dependent protein kinases 4 / 6 (CDK4 and CDK6). Therefore, CDK4 and CDK6 are also important molecular targets in HR-positive metastatic breast cancer. Studies show that overexpression of positive regulators of the cell cycle or loss or low expression of negative regulators are involved in endocrine therapy resistance. The G1-S phase transition is the most critical checkpoint in the cell cycle, positively regulated by cyclin and CDK kinases, with Cyclin D1 / CDK4 / 6 being the most important. Retinoblastoma protein (Rb) is phosphorylated and modified by CDK4 / 6. Abnormalities in this pathway lead to persistent cell proliferation and are associated with carcinogenesis. Studies also suggest that Cyclin D-CDK4 can phosphorylate targets such as SMAD2 and FOXM1, directly acting on pathways related to proliferation, metastasis, and DNA damage responses. Furthermore, substantial evidence indicates that Cyclin D1-CDK4 / 6 overexpression also plays an important role in the development and progression of breast cancer. Approximately 15%-25% of breast cancer patients exhibit CDK4 and Cyclin D1 amplification, and about 50% of breast cancers show high Cyclin D1 expression. Furthermore, breast cancers with high Cyclin D1 expression are primarily ER-positive. Therefore, CDK4 / 6 inhibitors (CDK4 / 6i) can inhibit tumor cell proliferation by suppressing CDK4 and CDK6 kinase activity in breast cancer cells and blocking Rb protein phosphorylation, thereby arresting the cell cycle progression from G1 to S phase. Simultaneously, CDK4 / 6 inhibitors can also synergistically enhance endocrine therapy by inhibiting upstream estrogen receptor signaling pathway expression, thus delaying and reversing the development of endocrine resistance.

[0003] However, there remains an unmet clinical need for subsequent treatment of patients who have failed CDK4 / 6 therapy, especially those with primary resistance or rapid progression. Clinical studies exploring treatment strategies after CDK4 / 6 progression are also underway, one type of which involves the reuse of CDK4 / 6i. Summary of the Invention

[0004] On the one hand, this disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for the treatment of CDK4 / 6 inhibitor-resistant breast cancer.

[0005] On the other hand, this disclosure provides a pharmaceutical composition for treating CDK4 / 6 inhibitor-resistant breast cancer, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments of this disclosure, the pharmaceutical composition is packaged in a kit that further includes instructions for using a compound of formula (I) or a pharmaceutically acceptable salt thereof to treat CDK4 / 6 inhibitor-resistant breast cancer.

[0006] On the other hand, this disclosure provides a pharmaceutical combination for treating CDK4 / 6 inhibitor-resistant breast cancer, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and an endocrine therapeutic agent.

[0007] On another front, this disclosure provides a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof with an endocrine therapy for the treatment of CDK4 / 6 inhibitor-resistant breast cancer.

[0008] On the other hand, this disclosure provides a pharmaceutical composition for treating CDK4 / 6 inhibitor-resistant breast cancer, comprising a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of an endocrine therapy drug.

[0009] On another aspect, this disclosure provides a combination of a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating CDK4 / 6 inhibitor-resistant breast cancer and a pharmaceutical composition of an endocrine therapy drug.

[0010] In some embodiments of this disclosure, a pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of an endocrine therapy drug are packaged in a kit, the kit further comprising instructions for the combined use of the compound of formula (I) or a pharmaceutically acceptable salt thereof and an endocrine therapy drug to treat CDK4 / 6 inhibitor-resistant breast cancer. In other embodiments, a pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of an endocrine therapy drug are packaged in the same or different units of the same kit.

[0011] In some embodiments of this disclosure, pharmaceutical compositions of the compound of formula (I) or a pharmaceutically acceptable salt thereof and pharmaceutical compositions of endocrine therapy drugs are packaged in their respective kits, each kit further comprising instructions for the combined use of the compound of formula (I) or a pharmaceutically acceptable salt thereof and an endocrine therapy drug to treat CDK4 / 6 inhibitor-resistant breast cancer.

[0012] In another aspect, this disclosure provides a pharmaceutical product for use in combination with an endocrine therapy for the treatment of CDK4 / 6 inhibitor-resistant breast cancer, wherein the pharmaceutical product comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments of this disclosure, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or combination of pharmaceuticals, the pharmaceutically acceptable salt of the compound of formula (I) is a maleate, such as a monomaleate of the compound of formula (I).

[0014] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or pharmaceutical combination contains 20-240 mg, 40-180 mg, 60-180 mg, 80-180 mg, 100-180 mg, 120-180 mg or 150-180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a whole.

[0015] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or pharmaceutical combination contains 150 to 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a fraction of the compound of formula (I).

[0016] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or pharmaceutical combination contains 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or pharmaceutical combination contains 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or pharmaceutical combination contains 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I).

[0019] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or pharmaceutical combination contains 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a fraction of the compound of formula (I).

[0020] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition or combination of drugs, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is in a single-dose or multiple-dose form. In some embodiments of this disclosure, the pharmaceutical composition wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is in a multiple-dose form.

[0021] In some embodiments of this disclosure, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or combination of pharmaceuticals, is a daily dose.

[0022] In some embodiments of this disclosure, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or combination thereof, is a once-daily dose.

[0023] In some embodiments of this disclosure, the amount of the compound of formula (I) or its pharmaceutically acceptable salt, pharmaceutical composition or combination of pharmaceuticals is a once-daily dose, and each dose is a single dose or multiple doses, usually multiple doses.

[0024] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, the pharmaceutical composition or combination thereof, contains a single dose of 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Alternatively, the pharmaceutical composition is in the form of a single-dose formulation containing 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition, or combination of pharmaceuticals contains a single dose of 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Alternatively, the pharmaceutical composition is in the form of a single-dose formulation containing 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments of this disclosure, each treatment cycle is 28 days.

[0027] In some other embodiments of this disclosure, during each treatment cycle, a subject in need is given once daily the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, once daily. In some other embodiments of this disclosure, during each treatment cycle, a subject in need is given once daily 120 to 180 mg (e.g., 120 mg, 150 mg, or 180 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, once daily.

[0028] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or combination of pharmaceuticals is a formulation suitable for administration over a single treatment cycle (e.g., a 28-day treatment cycle), the formulation comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, in a total dose of 1680 to 5040 mg (e.g., 1680 mg, 3360 mg, 4200 mg, 5040 mg or a range formed by any two of the stated values) based on the compound of formula (I).

[0029] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or combination of pharmaceuticals is a formulation suitable for administration over a single treatment cycle (e.g., a 28-day treatment cycle), the formulation comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 3360 mg, 4200 mg or 5040 mg based on the compound of formula (I).

[0030] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or combination of pharmaceuticals is a formulation suitable for administration over a single treatment cycle (e.g., a 28-day treatment cycle), the formulation comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 5040 mg based on the compound of formula (I).

[0031] In other embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, is in the form of a solid dosage form, such as a capsule, tablet or granule, preferably a capsule.

[0032] In other embodiments of this disclosure, the endocrine therapy drug is in the form of a solid or liquid formulation, such as a powder, injection, or suspension.

[0033] On the other hand, this disclosure also provides a kit for treating CDK4 / 6 inhibitor-resistant breast cancer, comprising a compound of formula (I) as described in this disclosure or a pharmaceutically acceptable salt thereof.

[0034] On the other hand, this disclosure also provides a kit for treating CDK4 / 6 inhibitor-resistant breast cancer, comprising a compound of formula (I) as described in this disclosure or a pharmaceutically acceptable salt thereof and an endocrine therapeutic agent.

[0035] On the other hand, this disclosure also provides a kit for treating CDK4 / 6 inhibitor-resistant breast cancer, comprising the drug combination described in this disclosure.

[0036] On the other hand, this disclosure also provides a kit for a pharmaceutical composition for treating CDK4 / 6 inhibitor-resistant breast cancer, comprising a compound of formula (I) as described in this disclosure or a pharmaceutically acceptable salt thereof.

[0037] On the other hand, this disclosure also provides a kit for a pharmaceutical composition for treating CDK4 / 6 inhibitor-resistant breast cancer, comprising a pharmaceutical composition of a compound of formula (I) as described in this disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of an endocrine therapy drug.

[0038] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or pharmaceutical combination, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared in a unit dosage form containing 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or pharmaceutical combination, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared such that a unit dosage form contains 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0040] On the other hand, this disclosure also provides a method for treating CDK4 / 6 inhibitor-resistant breast cancer, comprising administering to an individual in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, such as administering to an individual in need a pharmaceutical composition or combination thereof of a compound of formula (I) or a pharmaceutically acceptable salt thereof described above in this disclosure in a therapeutically effective amount.

[0041] On the other hand, this disclosure also provides the use of compounds of formula (I) or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating CDK4 / 6 inhibitor-resistant breast cancer, such as the use of pharmaceutical compositions or combinations described in this disclosure in the preparation of medicaments for treating CDK4 / 6 inhibitor-resistant breast cancer.

[0042] On the other hand, this disclosure also provides the use of compounds of formula (I) or pharmaceutically acceptable salts thereof for the treatment of CDK4 / 6 inhibitor-resistant breast cancer, such as the use of pharmaceutical compositions or combinations described in this disclosure for the treatment of CDK4 / 6 inhibitor-resistant breast cancer.

[0043] In some embodiments of this disclosure, in the methods or uses described above, the compound of formula (I) or a pharmaceutically acceptable salt thereof is optionally combined with an endocrine therapy drug.

[0044] In other embodiments of this disclosure, in the methods or uses described above, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and an endocrine therapy drug are administered in combination to a subject in need, for example, simultaneously or separately, together or separately. In other embodiments of this disclosure, in each treatment cycle, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, is administered to a subject in need once daily, and in each treatment cycle (e.g., on day 1 and day 15 of each treatment cycle), one or two doses of the endocrine therapy drug are administered once daily (continuously or intermittently). In other embodiments of this disclosure, during each treatment cycle, a subject in need is given once daily 120 to 180 mg (e.g., 120 mg, 150 mg, or 180 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound, of formula (I), and an endocrine therapy (e.g., fulvestrant at doses of 100 mg to 1000 mg / time, 400 mg to 600 mg / time, or 500 mg / time) is given once daily on days 1 and 15 of the first treatment cycle, and an endocrine therapy (e.g., fulvestrant at doses of 100 mg to 1000 mg / time, 400 mg to 600 mg / time, or 500 mg / time) is given once daily on day 1 of the second treatment cycle and each subsequent treatment cycle.

[0045] On the other hand, this disclosure also provides a method for treating CDK4 / 6 inhibitor-resistant breast cancer, comprising administering to an individual in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an endocrine therapy drug, such as administering to an individual in need a therapeutically effective amount of a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in this disclosure and a pharmaceutical composition of an endocrine therapy drug.

[0046] In other embodiments of this disclosure, a compound of formula (I) or a pharmaceutically acceptable salt thereof and an endocrine therapy are administered simultaneously or separately, together or separately to an individual in need.

[0047] On the other hand, this disclosure also provides a combination therapy for CDK4 / 6 inhibitor-resistant breast cancer, comprising administering to an individual in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an endocrine therapy agent.

[0048] In some embodiments of this disclosure, when administering medication on the same day, the compound of formula (I) or a pharmaceutically acceptable salt thereof is first administered to the individual in need, followed by the administration of an endocrine therapy. In some embodiments of this disclosure, when administering medication on the same day, the endocrine therapy is first administered to the individual in need, followed by the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments of this disclosure, when administering medication on the same day, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the endocrine therapy are administered simultaneously to the individual in need in their respective formulations.

[0049] On the other hand, this disclosure also provides a combination therapy for CDK4 / 6 inhibitor-resistant breast cancer, which includes administering a therapeutically effective amount of the drug combination of this disclosure to an individual in need.

[0050] On the other hand, this disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an endocrine therapy drug in the preparation of a medicament for treating CDK4 / 6 inhibitor-resistant breast cancer.

[0051] In another aspect, this disclosure further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an endocrine therapeutic agent in the preparation of medicaments for the combined treatment of CDK4 / 6 inhibitor-resistant breast cancer.

[0052] On the other hand, this disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an endocrine therapy drug for the treatment of CDK4 / 6 inhibitor-resistant breast cancer, such as the use of a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in this disclosure in combination with a pharmaceutical composition of an endocrine therapy drug for the treatment of CDK4 / 6 inhibitor-resistant breast cancer.

[0053] In another aspect, this disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof and an endocrine therapy agent for combination therapy of CDK4 / 6 inhibitor-resistant breast cancer. Alternatively, this disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an endocrine therapy agent for combination therapy of CDK4 / 6 inhibitor-resistant breast cancer.

[0054] On the other hand, this disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in combination with an endocrine therapy for the treatment of CDK4 / 6 inhibitor-resistant breast cancer.

[0055] On the other hand, this disclosure provides the use of an endocrine therapy drug in the preparation of a medicament for the treatment of CDK4 / 6 inhibitor-resistant breast cancer in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0056] In another aspect, this disclosure provides a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an endocrine therapy agent for adjuvant therapy after surgery in patients with CDK4 / 6 inhibitor-resistant breast cancer. Alternatively, this disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an endocrine therapy agent for adjuvant therapy after surgery in patients with CDK4 / 6 inhibitor-resistant breast cancer. Alternatively, this disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an endocrine therapy agent in the preparation of an adjuvant medicament for adjuvant therapy after surgery in patients with CDK4 / 6 inhibitor-resistant breast cancer. Alternatively, this disclosure provides a method of adjuvant therapy after surgery in patients with CDK4 / 6 inhibitor-resistant breast cancer, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof and an endocrine therapy agent are administered in combination to a subject in need.

[0057] In some embodiments of this disclosure, in the method or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a daily dose, by administering the compound of formula (I) or a pharmaceutically acceptable salt thereof once daily.

[0058] In some embodiments of this disclosure, in the method or use, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a daily dose, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a single-dose or multiple-dose manner, typically in a multiple-dose manner; further, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily in a multiple-dose manner.

[0059] In some embodiments of this disclosure, in the methods or uses described herein, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 120 mg; or, a daily dose of 150 mg; or, a daily dose of 180 mg.

[0060] In some embodiments of this disclosure, in the methods or uses described, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 150 mg; or a daily dose of 180 mg.

[0061] In some embodiments of this disclosure, in the method or use described, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of 180 mg.

[0062] In some embodiments of this disclosure, in the method or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a multiple-dose manner, the multiple doses consisting of a single dose of 50 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments of this disclosure, in the methods or uses described, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a manner that is continuous and daily.

[0064] In some embodiments of this disclosure, in the method or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a multiple-dose manner, the multiple doses consisting of a single dose of 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments of this disclosure, in the methods or uses described, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a manner that is continuous and daily.

[0066] In other embodiments of this disclosure, in the method or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily.

[0067] In some embodiments of this disclosure, in the method or use, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a dose for each treatment cycle, administered by daily application of the compound of formula (I) or a pharmaceutically acceptable salt thereof. The compound of formula (I) or a pharmaceutically acceptable salt thereof is packaged in single or multiple portions (e.g., 2 portions, 4 portions, 7 portions, 14 portions, 28 portions, or more portions).

[0068] In some embodiments of this disclosure, in the method or use, a treatment cycle is 28 days, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily from day 1 to day 28 of each treatment cycle.

[0069] In some specific embodiments of this disclosure, in the method or use, a treatment cycle is 28 days, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily from day 1 to day 28 of each treatment cycle.

[0070] In some embodiments of this disclosure, in the method or use, a treatment cycle is 28 days, with administration once daily for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 1680–5040 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 1680 mg, 3360 mg, 4200 mg, 5040 mg, or any two of these values. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 3360 mg, 4200 mg, or 5040 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 5040 mg.

[0071] In some other embodiments of this disclosure, in the method or use, a treatment cycle is 28 days, and an endocrine therapy drug (e.g., fulvestrant) is administered once or twice daily within each treatment cycle. In still other embodiments of this disclosure, in the method or use, a treatment cycle is 28 days, with the endocrine therapy drug administered once daily on days 1 and 15 of the first treatment cycle, and once daily on day 1 of the second treatment cycle and every subsequent treatment cycle. In other embodiments of this disclosure, in the method or use described, a treatment cycle is 28 days, with the endocrine therapy drug administered once daily on days 1 and 15 of the first treatment cycle at a dose of 100 mg-1000 mg / time, 400 mg-600 mg / time, or 500 mg / time, and on day 1 of the second treatment cycle and each subsequent treatment cycle, an endocrine therapy drug (e.g., fulvestrant) is administered once daily at a dose of 100 mg-1000 mg / time, 400 mg-600 mg / time, or 500 mg / time.

[0072] In some embodiments of this disclosure, the endocrine therapy drug is used as an adjunct to endocrine therapy.

[0073] In some embodiments of this disclosure, the endocrine therapy drug is selected from tamoxifen or aromatase inhibitors.

[0074] In some embodiments of this disclosure, the endocrine therapy drug is selected from aromatase inhibitors.

[0075] In some embodiments of this disclosure, the endocrine therapy drug is selected from one or more of tamoxifen, toremifene, fulvestrant, letrozole, anastrozole, exemestane, goserelin, or leuprorelin.

[0076] In some embodiments of this disclosure, the endocrine therapy drug is tamoxifen, toremifene, fulvestrant, letrozole, anastrozole, exemestane, goserelin, or leuprorelin.

[0077] In some embodiments of this disclosure, the endocrine therapy drug is selected from one or more of fulvestrant, letrozole, or anastrozole.

[0078] In some embodiments of this disclosure, the endocrine therapy drug is fulvestrant, letrozole, or anastrozole.

[0079] In some embodiments of this disclosure, the endocrine therapy drug is fulvestrant.

[0080] In some embodiments of this disclosure, the endocrine therapy drug is fulvestrant injection.

[0081] In some embodiments of this disclosure, the endocrine therapy drug is fulvestrant injection, and the single dose of fulvestrant injection is 5 mL: 0.25 g.

[0082] In some embodiments of this disclosure, the endocrine therapy drug is fulvestrant injection, and the fulvestrant injection is administered at a dose of 500 mg per administration.

[0083] In some embodiments of this disclosure, the endocrine therapy drug refers to fulvestrant injection, wherein 500 mg of fulvestrant is administered intramuscularly, with each treatment cycle lasting 28 days. In the first cycle, the drug is administered on day 1 and day 15, and subsequently on day 1 of each cycle.

[0084] In embodiments of this disclosure, the treatment cycle is repeated as long as the disease remains under control and the dosing regimen is clinically tolerable.

[0085] In some embodiments of this disclosure, the CDK4 / 6 inhibitor in the “CDK4 / 6 inhibitor resistant breast cancer” does not include compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0086] In some embodiments of this disclosure, the CDK4 / 6 inhibitor in the “CDK4 / 6 inhibitor-resistant breast cancer” has lower inhibitory activity against CDK2 kinase than the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments of this disclosure, the CDK4 / 6 inhibitor in the "CDK4 / 6 inhibitor-resistant breast cancer" exhibits a half-maximal inhibitory concentration (IC50) greater than 10 nM for CDK2 kinase in a CDK2 kinase activity assay. 50 ), or has a half-maximal inhibitory concentration (IC50) greater than 100 nM. 50), or has a half-maximal inhibitory concentration (IC50) greater than 1000 nM. 50 ).

[0088] In some embodiments of this disclosure, the "CDK2 kinase activity assay" is performed in an enzymatic reaction system of CDK2 / cyclin A. In some embodiments of this disclosure, the resistance to "CDK4 / 6 inhibitor-resistant breast cancer" includes resistance to CDK4 / 6 inhibitor combined with endocrine therapy.

[0089] In some embodiments of this disclosure, the CDK4 / 6 inhibitor in the “CDK4 / 6 inhibitor-resistant breast cancer” includes, but is not limited to, one or more of palbociclib, ribociclib, abemaciclib, dalpiciclib, lerociclib, birociclib, fuvirselib, and titremciclib.

[0090] In some embodiments of this disclosure, the CDK4 / 6 inhibitor in the “CDK4 / 6 inhibitor resistant breast cancer” includes, but is not limited to, one or more of palbociclib, ribociclib, abemaciclib, and dalpiciclib.

[0091] In some embodiments of this disclosure, the CDK4 / 6 inhibitor in the “CDK4 / 6 inhibitor-resistant breast cancer” includes, but is not limited to, one or more of palbociclib, ribociclib, and dalpiciclib.

[0092] In some embodiments of this disclosure, the CDK4 / 6 inhibitors in the “CDK4 / 6 inhibitor-resistant breast cancer” include, but are not limited to, one or any combination of two of palbociclib, ribociclib, and dalpiciclib.

[0093] In some embodiments of this disclosure, the CDK4 / 6 inhibitor in the “CDK4 / 6 inhibitor resistant breast cancer” includes, but is not limited to, one of palbociclib, ribociclib, and dalpiciclib.

[0094] In some embodiments of this disclosure, the CDK4 / 6 inhibitor-resistant breast cancer refers to breast cancer that has failed previous CDK4 / 6 inhibitor treatment or has relapsed or progressed after previous CDK4 / 6 inhibitor treatment.

[0095] In some other embodiments of this disclosure, the CDK4 / 6 inhibitor-resistant breast cancer refers to recurrent / metastatic breast cancer that has failed previous CDK4 / 6 inhibitor treatment or has relapsed or progressed after previous CDK4 / 6 inhibitor treatment.

[0096] In some embodiments of this disclosure, the CDK4 / 6 inhibitor-resistant breast cancer is selected from CDK4 / 6 inhibitor-resistant HR-positive, HER2-negative breast cancer.

[0097] In some embodiments of this disclosure, the CDK4 / 6 inhibitor-resistant breast cancer is selected from CDK4 / 6 inhibitor-resistant HR-positive, HER2-negative advanced breast cancer.

[0098] In some embodiments of this disclosure, the CDK4 / 6 inhibitor-resistant breast cancer is selected from CDK4 / 6 inhibitor-resistant HR-positive, HER2-negative recurrent / metastatic breast cancer.

[0099] In some embodiments of this disclosure, the CDK4 / 6 inhibitor-resistant breast cancer is selected from HR-positive, HER2-negative recurrent / metastatic breast cancer that has relapsed or progressed after prior CDK4 / 6 inhibitor treatment.

[0100] In some other embodiments of this disclosure, the CDK4 / 6 inhibitor-resistant breast cancer is HR-positive, HER2-negative recurrent / metastatic breast cancer that has progressed after prior CDK4 / 6 inhibitor treatment.

[0101] In some embodiments of this disclosure, CDK4 / 6 inhibitor resistance includes one of the following: (1) relapse or progression during treatment or within one year after completion of adjuvant endocrine therapy with CDK4 / 6 inhibitor combined with endocrine therapy; optionally, no subsequent endocrine therapy was received; (2) relapse or progression more than one year after completion of adjuvant endocrine therapy, and relapse again after receiving CDK4 / 6 inhibitor combined with endocrine therapy as salvage endocrine therapy; (3) disease progression after initial diagnosis of locally advanced or metastatic disease and receiving CDK4 / 6 inhibitor combined with endocrine therapy as salvage endocrine therapy; (4) progression after receiving CDK4 / 6 inhibitor monotherapy in addition to adjuvant endocrine therapy or salvage endocrine monotherapy.

[0102] In some embodiments of this disclosure, the CDK4 / 6 inhibitor combined with endocrine therapy is used as adjunctive endocrine therapy for a period of not less than 2 years.

[0103] In some embodiments of this disclosure, the CDK4 / 6 inhibitor combined with endocrine therapy is used as a rescue endocrine therapy for a period of not less than 6 months.

[0104] In some embodiments of this disclosure, in the prior combination therapy for CDK4 / 6 inhibitor-resistant breast cancer, it is permissible to discontinue the CDK4 / 6 inhibitor early due to intolerance or other non-disease progression reasons and then use endocrine therapy alone.

[0105] In some embodiments of this disclosure, the breast cancer is selected from locally advanced and / or metastatic breast cancer.

[0106] In some embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer.

[0107] In some embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer that is not eligible for radical surgery or radiotherapy.

[0108] In some embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer that is ineligible for radical surgery or radiotherapy and for which chemotherapy is not indicated.

[0109] In other embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative locally recurrent or distant metastatic breast cancer.

[0110] In some embodiments of this disclosure, the breast cancer is selected from postmenopausal or premenopausal / perimenopause breast cancer.

[0111] In other embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative recurrent / metastatic breast cancer in postmenopausal or premenopausal / perimenopause periods.

[0112] In some embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer in postmenopausal or premenopausal / perimenopause patients.

[0113] In some embodiments of this disclosure, the breast cancer is selected from breast cancers from patients who have previously undergone bilateral oophorectomy.

[0114] In some embodiments of this disclosure, the breast cancer patients are selected from breast cancer patients aged ≥60 years; or breast cancer patients aged <60 years who have experienced natural menopause for ≥12 months and whose follicle-stimulating hormone (FSH) and estradiol (E2) levels are within the postmenopausal range; or breast cancer patients who are premenopausal or perimenopausal but receive LHRH agonist therapy during treatment.

[0115] In some other embodiments of this disclosure, the patient with breast cancer is a stage IV breast cancer patient.

[0116] In some embodiments of this disclosure, the breast cancer is selected from postmenopausal or premenopausal / perimenopause breast cancer in patients who have previously undergone bilateral oophorectomy.

[0117] In some embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer in postmenopausal or premenopausal / perimenopause patients who have previously undergone bilateral oophorectomy.

[0118] In some embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer that is not eligible for radical surgery or radiotherapy in postmenopausal or premenopausal / perimenopause patients.

[0119] In some embodiments of this disclosure, HR positivity includes estrogen receptor (ER) positivity and / or progesterone receptor (PR) positivity, defined as: the proportion of positively stained tumor cells ≥10% of all tumor cells.

[0120] In some embodiments of this disclosure, HER2 negative is defined as: immunohistochemical staining (IHC) showing HER2 as 0 / 1+; if the test shows 2+, fluorescence in situ hybridization (FISH) must be performed to confirm that it is negative or FISH test alone is negative.

[0121] In some embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer that has progressed after prior endocrine therapy.

[0122] In some embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer that has previously received no more than one line of chemotherapy.

[0123] In some embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative breast cancer that has recurred or progressed during or within one year after adjuvant endocrine therapy and has not subsequently received endocrine therapy.

[0124] In some embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative breast cancer that has relapsed or progressed more than 1 year after adjuvant endocrine therapy and subsequently progressed again after receiving salvage endocrine therapy; in some embodiments, the salvage endocrine therapy is no more than one line of treatment.

[0125] In some embodiments of this disclosure, the breast cancer is selected from breast cancer that was initially diagnosed as local or metastatic disease and that has progressed after receiving salvage endocrine therapy; in some embodiments, the salvage endocrine therapy is no more than one line of treatment.

[0126] In some embodiments of this disclosure, the duration of adjuvant endocrine therapy is not less than one year.

[0127] In some embodiments of this disclosure, the relapsed or progressive stage subject is permitted to receive no more than one line of rescue chemotherapy or rescue endocrine therapy.

[0128] In other embodiments of this disclosure, the subject with breast cancer is a subject with recurrent or metastatic breast cancer who has failed prior CDK4 / 6 inhibitor therapy or who has relapsed or metastatic breast cancer after prior CDK4 / 6 inhibitor therapy, and the subject with recurrent or metastatic breast cancer is permitted to receive no more than one line of salvage chemotherapy or salvage endocrine therapy.

[0129] In some embodiments of this disclosure, the HR positive is selected from ER positive and PR positive.

[0130] In some embodiments of this disclosure, the HR positive and HER2 negative are ER positive, PR positive, and HER2 negative.

[0131] In some embodiments of this disclosure, the breast cancer is selected from ER-positive, PR-positive, and HER2-negative ductal carcinoma of the breast.

[0132] In some embodiments of this disclosure, the patient with breast cancer is pathologically diagnosed with HR-positive, HER2-negative breast cancer, with evidence of local recurrence or distant metastasis, is not suitable for surgery or radiotherapy for curative purposes, and has no clinical indication for chemotherapy.

[0133] In some embodiments of this disclosure, the patient with breast cancer has at least one measurable lesion according to RECIST 1.1 criteria.

[0134] In some embodiments of this disclosure, the CDK4 / 6 inhibitor resistance is selected from primary resistance to CDK4 / 6 inhibitors or acquired resistance after treatment with CDK4 / 6 inhibitors.

[0135] In some embodiments of this disclosure, the CDK4 / 6 inhibitor resistance is selected from acquired resistance following treatment with a CDK4 / 6 inhibitor.

[0136] In some embodiments of this disclosure, the breast cancer is selected from CDK4 / 6 inhibitor-resistant HR-positive, HER2-negative recurrent / metastatic breast cancer.

[0137] The CDK4 / 6 inhibitors described herein can block the activity of cyclin-dependent kinase 4 / 6 (CDK4 / 6) and inhibit tumor cell proliferation.

[0138] The active components in the pharmaceutical combinations disclosed herein can be formulated into pharmaceutical preparations independently, or in combination, with a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical combinations of this disclosure may also contain additional therapeutic agents. In some embodiments of this disclosure, the additional therapeutic agents may be therapeutic agents known in the art for cancer, preferably therapeutic agents for breast cancer.

[0139] In some embodiments of this disclosure, the additional therapeutic agent may be a therapeutic agent for pancreatic cancer, head and neck cancer, sarcoma, lymphoma, melanoma, or leukemia.

[0140] In some embodiments of this disclosure, the period is 28 days.

[0141] The amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof administered may be determined by a person skilled in the art based on the severity of the disease, the response to the disease, any treatment-related toxicity, the patient’s age, and health status.

[0142] Compounds of formula (I) or pharmaceutically acceptable salts thereof, or endocrine therapeutic agents, may be administered via a variety of routes, including but not limited to: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, local, subcutaneous, intra-fat, intra-articular, intraperitoneal, and intrathecal. In one specific embodiment, compounds of formula (I) or pharmaceutically acceptable salts thereof are administered orally.

[0143] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally on a continuous daily basis.

[0144] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily in multiple doses of an oral solid dosage form.

[0145] Compound of formula (I) or a pharmaceutically acceptable salt thereof

[0146] The compound of formula (I) disclosed herein can be administered in its free base form, or in the form of a pharmaceutically acceptable salt, hydrate, or prodrug, which is converted in vivo into the form of compound (I). For example, a pharmaceutically acceptable salt of compound (I) within the scope of this disclosure can be generated from various organic and inorganic acids according to methods known in the art.

[0147] Regarding pharmaceutically acceptable salts of the compounds of formula (I) described in this disclosure, the molar ratio of the compound of formula (I) to the anion forming the pharmaceutically acceptable salt may be 1:1.

[0148] Pharmaceutically acceptable salts of compounds of formula (I) may be maleates of compounds of formula (I) (e.g., monomaleates of compounds of formula (I)).

[0149] Unless otherwise stated, the dosage of compounds of formula (I) or pharmaceutically acceptable salts thereof mentioned in this disclosure is based on the amount of compound of formula (I).

[0150] In some embodiments of this disclosure, a pharmaceutically acceptable salt of the compound of formula (I) is present in the form of a salt of the compound of formula (I).

[0151] The compounds of formula (I) used in this disclosure or their pharmaceutically acceptable salts can be prepared by methods in the prior art, for example, by referring to the method in WO2016141881.

[0152] Pharmaceutical compositions of compounds of formula (I) or pharmaceutically acceptable salts thereof

[0153] In some embodiments of this disclosure, a single dose of a pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 50 mg or 60 mg, calculated as the compound of formula (I). Alternatively, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared such that a unit dosage form contains 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0154] In some embodiments of this disclosure, a single dose of a pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 60 mg, calculated as compound (I). Alternatively, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared such that a unit dosage form contains 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as compound (I).

[0155] The method of administration can be determined comprehensively based on factors such as the drug's activity, toxicity, and the patient's tolerance.

[0156] In some embodiments of this disclosure, the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof further contains pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, etc. In some embodiments of this disclosure, the pharmaceutical composition includes, but is not limited to, formulations suitable for oral, parenteral, or topical administration. In some embodiments, the pharmaceutical composition is a formulation suitable for oral administration. In some embodiments, the pharmaceutical composition is a solid dosage form suitable for oral administration. In some embodiments, the pharmaceutical composition includes, but is not limited to, tablets and capsules.

[0157] In some embodiments of this disclosure, the pharmaceutical composition is a solid pharmaceutical composition.

[0158] In some embodiments of this disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments of this disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule containing the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0160] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0161] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0162] Technical effect

[0163] The disclosed compounds have demonstrated good therapeutic effects against CDK4 / 6 inhibitor-resistant breast cancer, including but not limited to one or more of the following: high objective response rate (ORR), long progression-free survival (PFS), long duration of response (DOR), high disease control rate (DCR), high clinical benefit rate (CBR), and long overall survival (OS). The disclosed compounds also exhibit good safety and tolerability in the treatment of CDK4 / 6 inhibitor-resistant breast cancer.

[0164] Typically, using the drug combinations disclosed herein will help:

[0165] (1) Compared with any one of the drugs in the combination alone, it produces better efficacy in reducing tumor growth or even eliminating tumors;

[0166] (2) Provides a smaller dosage compared to any one of the drugs in the combination when administered alone;

[0167] (3) Provide treatment that is well tolerated in patients and has fewer adverse reactions and / or complications compared to either drug administered alone;

[0168] (4) Provides better disease control rates among the patients treated;

[0169] (5) Provides longer survival (e.g., median survival, progression-free survival, or overall survival) in the patients treated;

[0170] (6) Provides patients with longer survival (e.g., median survival, progression-free survival, or overall survival) compared to standard chemotherapy;

[0171] (7) Provide a longer duration of disease remission (DOR); and / or

[0172] (8) Compared with any one of the drugs in the combination alone, it has good activity in treating tumors or proliferative diseases and shows a better anti-tumor synergistic effect.

[0173] The compound of formula (I) disclosed herein is "clinically beneficial" in at least one or more of the following aspects: prolonged progression-free survival (PFS), prolonged overall survival (OS), improved objective response rate (ORR), improved disease control rate (DCR), reduced number and / or severity of adverse reactions, and decreased distant metastasis rate and local control rate.

[0174] Definitions and Explanations

[0175] The word “comprise” or “comprise” and its English variants such as comprises or comprising, and their equivalents, should be understood in an open, non-exclusive sense, meaning “including but not limited to”, implying that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be included.

[0176] The term "patient" or "individual / subject" refers to mammals, such as primates (humans, macaques, chimpanzees, etc.), rodents (mice, rats, rabbits, etc.), felines, canines, etc., preferably humans. In some embodiments of this disclosure, the patient and the individual are patients who have failed standard treatment or lack standard treatment.

[0177] The terms “pharmaceutical acceptable” or “medicinal” refer to a carrier, excipient, or excipient used in the preparation of a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and whose use in a human medicine is acceptable.

[0178] The term "therapeutic effective amount" refers to the amount of a compound that, when administered to a person to treat a disease, is sufficient to achieve therapeutic effect on that disease.

[0179] The term “treatment” means administering the compounds or preparations described in this disclosure to improve, alleviate or eliminate a disease or one or more symptoms associated with the disease, and includes: (i) suppressing the disease or disease state, i.e., halting or delaying its development; (ii) alleviating the disease or disease state, even if the disease or disease state subsides.

[0180] As used herein, an “adverse event” (AE) is any unfavorable and generally unintentional or undesirable indication (including abnormal laboratory findings), symptom, or illness associated with the application of a medical treatment. For example, an adverse event may be associated with activation of the immune system in response to treatment or expansion of immune system cells (e.g., T cells). A medical treatment may have one or more associated AEs, and each AE may have the same or different levels of severity. References to methods capable of “modifying adverse events” refer to treatment regimens that reduce the incidence and / or severity of one or more AEs associated with the application of different treatment regimens.

[0181] The use of alternatives (e.g., "or") should be understood to mean any one, two, or any combination of the alternatives. The indefinite articles "a" or "an" as used herein should be understood to mean "one or more / a combination of" any enumerated or listed components.

[0182] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0183] The terms “application” and “administration” refer to the physical introduction of a composition containing a therapeutic agent into an individual using any of a variety of methods and delivery systems known to those skilled in the art. In some embodiments, application is oral administration.

[0184] The term "daily dose" refers to the dose administered to a patient each day.

[0185] The terms "single dose" or "unit dosage form" refer to the smallest packaged unit of a medicine containing a certain amount of active ingredient. For example, if a box of medicine contains seven capsules, then each capsule is a single dose or unit dosage form; if a box of medicine contains seven tablets, then each tablet is a single dose unit dosage form.

[0186] The term "multiple doses" consists of multiple single doses.

[0187] As used herein, “combined use” or “concurrent use” means that two or more active substances may be administered to an individual simultaneously, in parallel, or in any order as individual formulations.

[0188] The term "primary drug resistance," also known as "inherent drug resistance," refers to the fact that an individual is resistant to a drug from the outset, before being given treatment with it.

[0189] The term "secondary drug resistance," also known as "acquired drug resistance," refers to drug resistance that develops after a certain period of drug treatment.

[0190] The term “treatment failure” includes refractory and / or relapse and / or progression and / or intolerance.

[0191] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients or combinations thereof disclosed herein with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate individual administration of the compounds or combinations thereof disclosed herein.

[0192] The terms “drug combination” and “combination drugs” are used interchangeably, referring to the combined use in clinical practice of two or more active pharmaceutical ingredients (including endocrine therapy drugs such as fulvestrant, compounds of formula (I) or pharmaceutically acceptable salts thereof or pharmaceutical compositions containing them) for the combined treatment of patients in need, wherein the two or more active pharmaceutical ingredients may be packaged together or separately (including packaged in different kits or different units of the same kit), and the active pharmaceutical ingredients may each be present as a pharmaceutical composition, and the two or more active pharmaceutical ingredients may be administered simultaneously, at intervals (including regular or irregular intervals), together or separately in clinical practice.

[0193] The terms "optional" and "optionally" indicate whether the object or event they modify exists or does not exist, or whether it occurs or not. For example, "optionally united" means "united or not united".

[0194] When referring to dosing regimens, terms such as "day" or "daily" refer to the time within a calendar day, beginning at midnight and ending at the next midnight.

[0195] In this document, unless the context clearly indicates otherwise, singular terms encompass plural referents, and vice versa. Similarly, unless the context clearly indicates otherwise, the word "or" is intended to include "and," and vice versa.

[0196] Unless otherwise stated, in this document, parameter values ​​representing the amount of an ingredient, its physicochemical properties, or reaction conditions, etc., should be understood to be modified by the term "about" in all cases. When the present disclosure is described using the term "about," the term "about" indicates an existing error value, such as a variation within ±5%, for example ±1%, or ±0.1% of a particular value.

[0197] For purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their publications predate the filing date of this disclosure. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publications are part of the general knowledge in the art. Example

[0198] The specific embodiments described below are intended to enable those skilled in the art to better understand and implement this disclosure. They should not be considered as limiting the scope of this disclosure, but merely as exemplary illustrations and typical representations. Unless otherwise specified, all reagents or materials used in the following embodiments are commercially available.

[0199] Experimental Example 1: In vitro pharmacodynamic evaluation

[0200] 1.1 Cell culture methods and sources

[0201] CDK4 / 6 inhibitor resistant T47D cells (T47D / PalR) were purchased from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd., and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 0.2 U / mL insulin, and 5 μM palbociclib.

[0202] The drug resistance of the above cells was verified by the supplier, and all cells were cultured in a 37°C constant temperature cell culture incubator containing 5% CO2.

[0203] 1.2 Cell Culture Reagents

[0204] MEM medium, phenol red-free 1640 medium, sodium pyruvate, non-essential amino acids, ITS-G, fetal bovine serum, and activated charcoal-treated fetal bovine serum.

[0205] 1.3 Administration

[0206] (1) Determining the drug concentration range: Before the experiment, the concentration range of the drugs (including palbociclib, abecilibiclib, reboxiclib, and compound (I)) was initially determined using the six-well method. Based on the determined drug concentration range, the drug concentration range and the ratio of gradient dilution were set for the experiment. The results were measured 48 hours after drug administration. If the cell growth inhibition curve did not reach the plateau, the drug concentration range and the ratio of gradient dilution were adjusted and the experiment was repeated.

[0207] 1.4 Experimental Methods

[0208] 1.4.1 CCK-8 assay for cell proliferation

[0209] (1) The T47D / PalR cells were digested into single-cell suspensions and seeded into 96-well plates with different cell amounts per well. Each drug concentration group was set up with 6 replicates, and each well had a volume of 100 μL. The edge wells of the culture plate were filled with sterile PBS. Blank control wells (containing no cells) were set up.

[0210] (2) Incubate in a cell culture incubator at 37℃ and 5% CO2 for 24h.

[0211] (3) Different concentrations of the test drug were prepared using the gradient dilution method, and 100 μL of the test drug was added to each well of the 96-well plate.

[0212] (4) After 48 hours, add 20 μL of CCK-8 solution to each well.

[0213] (5) Incubate in a 37℃ incubator for 3 hours.

[0214] (6) After incubation, place the sample on a microplate reader, shake well, and measure the absorbance at a wavelength of 450 nm. Record the results, and zero the colorimeter with a blank.

[0215] 1.4.2 Calculation of the half-maximal inhibitory concentration (IC50) 50

[0216] The inhibitory rate of the drug on cells was analyzed using the following formula:

[0217] Inhibition rate (%) = (1 - OD value of test drug group / OD value of blank control group) × 100%

[0218] After removing the highest and lowest values ​​for each concentration group, the average inhibition rate of the drug on cells was calculated. The growth inhibition curves for each cell type were generated and analyzed using GraphPad Prism 8.0 software. The percentage inhibition of tumor cell growth by the drug was analyzed using nonlinear regression, and the following equation was fitted to obtain the drug's inhibition curve on cell growth: Y=100 / (1+10^((LogIC50-X)*HillSlope))

[0219] 1.5 Experimental Results

[0220] IC50 of palbociclib, abemaciclib, ribociclib, and compounds of formula (I) on the inhibition of T47D / PalR cell proliferation 50 The values ​​are shown in Table 1 below.

[0221] Table 1

[0222] Experimental Example 2: PDX Model TCA In Vitro Drug Sensitivity Detection

[0223] Cell source: Human breast cancer (female, 38 years old)

[0224] Pathological diagnosis: Consistent with invasive breast cancer type 2-3 and nonspecific, PIK3CA mutation.

[0225] Cell type: ER + PR + HER2 + CCNE1 amplification, palbociclib-resistant cells

[0226] Board density: 1×10 4 Cells / pore

[0227] Dosage duration: 6 days

[0228] Test reagent: CTG

[0229] Single-drug concentrations: 20 μM down in a 4-fold gradient, 6 concentrations, 2 replicates.

[0230] Final DMSO concentration: 0.4%

[0231] Calculate the half-maximal inhibitory concentration (IC50) 50 Four-parameter analysis, fitting dose-response curve, and calculation of IC 50

[0232] The results are shown in Table 2:

[0233] Table 2

[0234] Example 3: Evaluation of the efficacy of drugs in a human breast cancer xenograft model

[0235] 3.1 Experimental Materials

[0236] Human breast cancer tumor tissue, passaged to FP3+2, was used in this efficacy study. Basic information is as follows: Human breast cancer (female, 38 years old); Pathological diagnosis: consistent with invasive breast cancer type 2-3 and nonspecific type, PIK3CA mutation; Drug resistance information: primary resistance to palbociclib.

[0237] 3.2 Laboratory Animals

[0238] 3.2.1 Source of experimental animals

[0239] NOD-Scid mice, female, weighing 18-21g. ​​Housing: SPF grade. Animals were allowed at least 3 days of acclimatization before the start of the experiment.

[0240] 3.2.2 Animal husbandry

[0241] All NOD-Scid mice were housed in an SPF-grade animal facility with an IVC (Indoor Temperature and Pressure) system, maintaining a temperature of 20–26°C, humidity of 40–70%, and a 12-hour light-dark cycle. No more than five NOD-Scid mice were housed in each cage, which measured 325mm × 210mm × 180mm. Corn cob bedding was used and changed twice weekly. Throughout the experiment, all mice had free access to food and water. Feed and water were autoclaved and changed twice weekly. Animals were numbered using ear punches.

[0242] 3.3 Experimental Procedures and Methods

[0243] Human breast cancer xenografts were cut into tumor tissues approximately 3mm × 3mm × 3mm in size (approximately 45–60 mg), mixed with 30 μL of L Atrigel, and subcutaneously injected into the right back of NOD-Scid mice. The mice were observed after injection, and tumor growth was monitored. On day 49 after injection, the average tumor volume of the tumor-bearing mice was 127.01 mm². 3 Mice were administered drugs in groups, with one group receiving the same volume of solvent (DMSO:PEG400 = 10:90 (v / v)) as a negative control. The day of drug administration was defined as day 0. Specific grouping information is shown in Table 3 below.

[0244] Table 3 Administration and Treatment Note: N: number of animals; administration volume: adjust the administration volume according to the weight of tumor-bearing mice (0.040 mL / 20 g); PO: gavage administration.

[0245] After the experimental animals were inoculated with tumor tissue, their morbidity and mortality were recorded daily.

[0246] 3.4 Efficacy Evaluation

[0247] 3.4.1 Tumor volume and weight measurement in tumor-bearing mice: Tumors in mice were measured twice a week using vernier calipers. The tumor volume was calculated using the formula V = 0.5 × a × b 2 a and b represent the long and wide diameters of the tumor, respectively;

[0248] 3.4.2 The formula for calculating the relative tumor proliferation rate T / C (%) is as follows: T / C% = T RTV / C RTV ×100% (T) RTV Treatment group RTV; C RTV The negative control group (RTV) was used to calculate the relative tumor volume (RTV) based on tumor measurements. The formula was RTV = V. t / V0, where V0 is the average tumor volume measured at the time of grouped drug administration (i.e., d0), V t T represents the average tumor volume at a subsequent measurement. RTV With C RTV Take data from the same day.

[0249] 3.4.3 Tumor growth inhibition rate TGI (%) = [1-(T i -T0) / (V i -V0)]×100,T i T0 represents the mean tumor volume after administration of the compound group, T0 represents the mean tumor volume at the first administration of the compound group, and V0 represents the mean tumor volume at the first administration of the negative control group. i The mean tumor volume after administration to the negative control group.

[0250] 3.4.4 The body weight of all tumor-bearing mice was measured daily. The relative change in body weight after drug administration was calculated as follows: RCBW (%) = (BW) / (RCBW / (RCBW)) i –BW0) / BW0×100, BW i BW0 is the body weight after administration, and BW0 is the body weight at the time of the first administration.

[0251] 3.4.5 At the end of the experiment, the mice were euthanized and the tumor mass was removed, weighed, and photographed.

[0252] 3.5 Experimental Results

[0253] Compound (I) at different doses effectively inhibited tumor growth in a human breast cancer xenograft model. No significant weight loss was observed in mice after administration to any of the treatment groups, indicating that the tumor-bearing mice tolerated the treatment at the experimental doses well.

[0254] The specific results are shown in Table 4:

[0255] Table 4

[0256] Experimental Example 4: Clinical Trial

[0257] This study is a single-arm, open-label, multicenter trial to evaluate the efficacy and safety of compound (I) in combination with endocrine therapy in patients with HR-positive, HER2-negative recurrent / metastatic breast cancer who have progressed after prior CDK4 / 6 inhibitor therapy (including palbociclib, reboxil, abeciclib, dalcilib, lerocilib, pyrosinib, voveciclib, and tabeciclib).

[0258] 4.1 Selection Criteria

[0259] 1. Participants voluntarily joined this study, signed informed consent forms, and demonstrated good compliance;

[0260] 2. Age: 18-75 years old (at the time of signing the informed consent form); ECOGPS score: 0-1; expected survival period of more than 3 months;

[0261] 3. Postmenopausal or premenopausal / perimenopause female patients;

[0262] 4. Patients with pathologically confirmed HR-positive, HER2-negative breast cancer who have evidence of local recurrence or distant metastasis are not suitable for surgery or radiotherapy aimed at curative treatment and have no clinical indication for chemotherapy (HER2 expression reference ASCO / CAP guidelines).

[0263] 5. Subjects in the relapse / metastatic stage are permitted to receive no more than one-line salvage chemotherapy or salvage endocrine therapy;

[0264] 6. At least one measurable lesion according to RECIST 1.1 criteria (except for cases where only skin and / or brain lesions are measurable lesions);

[0265] 7. Major organs function well;

[0266] 8. Female participants of childbearing age should agree to use contraception (such as intrauterine device, birth control pill or condom) during the study and for 6 months after the study ends; have a negative serum pregnancy test within 7 days prior to study enrollment; and must be a non-lactating participant.

[0267] 4.2 Test Drug

[0268] Formula (I) compound capsules: Specifications: 60mg, 50mg.

[0269] Fulvestrant Injection: 5mL: 0.25g.

[0270] 4.3 Dosing regimen

[0271] Formula (I) compound capsules: Administer orally with or within 2 hours after a meal, in 28-day cycles, once daily. The starting dose level is 180 mg / day. If a dose reduction is required, continue with a reduced dose in subsequent cycles, with a maximum of two dose reductions. Dose level-1 is 150 mg / day, and dose level-2 is 120 mg / day.

[0272] Endocrine therapy regimens are divided into two types based on the subject's menopausal status:

[0273] Premenopausal / perimenopausal subjects: Treatment with LHRH agonists (goserelin, etc.) in combination with fulvestrant. Postmenopausal subjects: Fulvestrant monotherapy.

[0274] Fulvestrant injection: 500mg intramuscular injection, with each treatment cycle lasting 28 days. In the first cycle, the medication is administered on day 1 and day 15, and in subsequent cycles, it is administered on day 1.

[0275] 4.4 Evaluation Criteria

[0276] Efficacy evaluation criteria: The RECIST 1.1 criteria were used to determine the disease status.

[0277] Safety evaluation criteria: The severity of adverse events is determined using the NCI-CTC AE 5.0 standard.

[0278] 4.5 Test Results

[0279] 4.5.1 Security

[0280] Gastrointestinal reactions (diarrhea, vomiting, etc.) are mainly grade 1 to 2, which can be controlled with symptomatic treatment, and the overall safety is good.

[0281] 4.5.2 Validity

[0282] A total of 27 patients were enrolled, including 4 patients with partial remission (PR) and 18 patients with stable disease (SD), resulting in a disease control rate (DCR) of 81.5% (22 / 27). The results showed that the combination drug therapy regimen disclosed in this study has clinical benefit.

[0283] The following table shows the dosing regimens and efficacy evaluation results for representative cases: Note: The dosage of Formula I compound capsules is based on the amount of Formula I compound, and the dosage of fulvestrant injection is based on the amount of fulvestrant.

[0284] Those skilled in the art will recognize that the scope of this disclosure is not limited to the various specific implementations and embodiments described above, but rather that various modifications, substitutions, or recombinations can be made without departing from the spirit and concept of this disclosure, all of which fall within the protection scope of this disclosure.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of CDK4 / 6 inhibitor-resistant breast cancer.

2. A pharmaceutical composition for treating CDK4 / 6 inhibitor-resistant breast cancer, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

3. A combination of drugs for the treatment of CDK4 / 6 inhibitor-resistant breast cancer, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and an endocrine therapy agent.

4. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of CDK4 / 6 inhibitor-resistant breast cancer.

5. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in combination with an endocrine therapy for the treatment of CDK4 / 6 inhibitor-resistant breast cancer.

6. A method for treating CDK4 / 6 inhibitor-resistant breast cancer, comprising administering to an individual in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

7. A method for treating CDK4 / 6 inhibitor-resistant breast cancer, comprising administering to an individual in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an endocrine therapy agent.

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, the pharmaceutical composition according to claim 2, the pharmaceutical composition according to claim 3, the use according to claim 4 or 5, or the method according to claim 6 or 7, comprising 20-240 mg, 40-180 mg, 60-180 mg, 80-180 mg, 100-180 mg, 120-180 mg or 150-180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); preferably comprising 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); more preferably comprising 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I).

9. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, the pharmaceutical composition according to claim 2, the pharmaceutical combination according to claim 3, the use according to claim 4 or 5, or the method according to claim 6 or 7, wherein, The compound of formula (I) or its pharmaceutically acceptable salt is available in single-dose or multi-dose form.

10. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, the pharmaceutical composition according to claim 2, the pharmaceutical combination according to claim 3, the use according to claim 4 or 5, or the method according to claim 6 or 7, wherein, The content of the compound of formula (I) or its pharmaceutically acceptable salt is a daily dose.

11. A formulation suitable for administration over a single treatment cycle, comprising: a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to claim 2, a pharmaceutical combination according to claim 3, the use according to claim 4 or 5, or the method according to claim 6 or 7. A pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, with a total dose of 1680 to 5040 mg based on the compound of formula (I); preferably, the formulation comprises a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, with a total dose of 3360 mg, 4200 mg, or 5040 mg based on the compound of formula (I); more preferably, the formulation comprises a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, with a total dose of 5040 mg based on the compound of formula (I).

12. Use of the compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 2, or the pharmaceutical composition according to claim 3 in the preparation of a medicament for treating CDK4 / 6 inhibitor-resistant breast cancer.

13. The pharmaceutical combination according to claim 3, the use according to claim 5, the method according to claim 7, or the use according to claim 12, wherein, The endocrine therapy drug is selected from one or more of tamoxifen, toremifene, fulvestrant, letrozole, anastrozole, exemestane, goserelin, or leuprorelin.

14. The use according to claim 4 or 5, or the method according to claim 6 or 7, or the use according to claim 12, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose by means of: the compound of formula (I) or a pharmaceutically acceptable salt thereof being administered once daily; or The endocrine therapy drug is fulvestrant injection, with each treatment cycle lasting 28 days. In the first treatment cycle, the drug is administered on day 1 and day 15, and then on day 1 of each subsequent treatment cycle.

15. The use according to claim 4 or 5, or the method according to claim 6 or 7, or the use according to claim 12, wherein, The CDK4 / 6 inhibitor-resistant breast cancer is selected from HR-positive, HER2-negative breast cancer resistant to CDK4 / 6 inhibitors; preferably, HR-positive, HER2-negative recurrent / metastatic breast cancer resistant to CDK4 / 6 inhibitors.

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