Use in treatment of breast cancer treated with CDK4 / 6 inhibitors

Abstract

A compound of formula (I) for treatment of breast cancer resistant to CDK4 / 6 inhibitors or a pharmaceutically acceptable salt thereof and a use thereof in treatment of breast cancer resistant to CDK4 / 6 inhibitors.

Description

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

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefits of Chinese patent application No. 202410171492.4 filed with the State Intellectual Property Office of China on February 4, 2024; Chinese patent application No. 202411606032.6 filed with the State Intellectual Property Office of China on November 11, 2024; and Chinese patent application No. 202510097524.5 filed with the State Intellectual Property Office of China on January 21, 2025, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure belongs to the field of medical technology, and relates to the use of a compound of formula (I) for treating breast cancer that has been treated with a CDK4 / 6 inhibitor. Background Art

[0004] Cyclins directly act on cyclin-dependent protein kinases 4 / 6 (CDK4 and CDK6). Therefore, CDK4 and CDK6 have become important molecular targets in HR+-positive metastatic breast cancer. Studies have shown that overexpression of positive cell cycle regulators, or loss or low expression of negative cell cycle regulators, contributes to endocrine therapy resistance. The G1-to-S phase transition is a critical checkpoint in the cell cycle and is positively regulated by cyclins and CDKs, 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 sustained cell proliferation and are associated with carcinogenesis. Studies have also suggested that cyclin D-CDK4 can also phosphorylate targets such as SMAD2 and FOXM1, directly affecting pathways related to proliferation, metastasis, and the DNA damage response. Furthermore, extensive evidence indicates that overexpression of cyclin D1-CDK4 / 6 plays a crucial role in the development and progression of breast cancer. Approximately 15%-25% of human breast cancers show amplification of CDK4 and CyclinD1, and approximately 50% of breast cancers show overexpression of CyclinD1. This is primarily seen in ER-positive breast cancers. Therefore, CDK4 / 6 inhibitors can inhibit the activity of CDK4 and CDK6 kinases in breast cancer cells, blocking Rb protein phosphorylation and thereby arresting cell cycle progression from G1 to S phase, thereby inhibiting tumor cell proliferation. Furthermore, CDK4 / 6 inhibitors can also synergize with endocrine therapy by inhibiting the expression of the upstream estrogen receptor signaling pathway, thereby delaying and reversing the development of endocrine resistance.

[0005] However, there is still an unmet clinical need for follow-up treatment for 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 in full swing, one of which is the reuse of CDK4 / 6i. Summary of the Invention

[0006] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating breast cancer resistant to CDK4 / 6 inhibitors.

[0007] In another aspect, the present 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 the present disclosure, the pharmaceutical composition is packaged in a kit, which further comprises instructions for using the compound of formula (I) or a pharmaceutically acceptable salt thereof to treat CDK4 / 6 inhibitor-resistant breast cancer.

[0008] In another aspect, the present 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 therapy drug.

[0009] On the other hand, the present disclosure provides a drug combination for treating breast cancer resistant to CDK4 / 6 inhibitors, 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. In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of the endocrine therapy drug are packaged in a kit, and the kit further comprises instructions for combining the compound of formula (I) or a pharmaceutically acceptable salt thereof with an endocrine therapy drug to treat breast cancer resistant to CDK4 / 6 inhibitors. In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of the endocrine therapy drug are respectively packaged in respective kits, and the respective kits further comprise instructions for combining the compound of formula (I) or a pharmaceutically acceptable salt thereof with an endocrine therapy drug to treat breast cancer resistant to CDK4 / 6 inhibitors.

[0010] In some embodiments of the present disclosure, in the compound of formula (I) or its pharmaceutically acceptable salt, pharmaceutical composition or pharmaceutical combination, the pharmaceutically acceptable salt of the compound of formula (I) is a maleate salt, such as a monomaleate salt of the compound of formula (I).

[0011] In some embodiments of the present 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 the compound of formula (I).

[0012] In some embodiments of the present 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 the compound of formula (I).

[0013] In some embodiments of the present 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, calculated as the compound of formula (I).

[0014] In some embodiments of the present 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, calculated as the compound of formula (I).

[0015] In some embodiments of the present 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 the compound of formula (I).

[0016] In some embodiments of the present 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 the compound of formula (I).

[0017] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or pharmaceutical combination is in a single dose or multiple dose form. In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is in a multiple dose form.

[0018] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or pharmaceutical combination, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a daily dose.

[0019] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or pharmaceutical combination is administered once daily.

[0020] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or pharmaceutical combination is administered once daily, and each dose is a single dose or multiple doses, usually multiple doses.

[0021] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or pharmaceutical combination contains a single dose of 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I). 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, calculated as the compound of formula (I).

[0022] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or pharmaceutical combination contains a single dose of 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I). 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, calculated as the compound of formula (I).

[0023] In some embodiments of the present disclosure, every 28 days is one treatment cycle.

[0024] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or drug combination is a preparation suitable for administration within a single treatment cycle (e.g., a treatment cycle of 28 days), and the preparation comprises: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, with 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 values) calculated as the compound of formula (I).

[0025] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or drug combination is a preparation suitable for administration within a single treatment cycle (e.g., a treatment cycle of 28 days), comprising: 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 calculated as the compound of formula (I).

[0026] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or drug combination is a preparation suitable for administration within a single treatment cycle (e.g., a treatment cycle of 28 days), and the preparation comprises: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 5040 mg calculated as the compound of formula (I).

[0027] On the other hand, the present disclosure also provides a kit for treating CDK4 / 6 inhibitor-resistant breast cancer, which contains the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the present disclosure.

[0028] On the other hand, the present disclosure also provides a kit for treating CDK4 / 6 inhibitor-resistant breast cancer, which contains the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the present disclosure and an endocrine therapy drug.

[0029] On the other hand, the present disclosure also provides a kit for treating CDK4 / 6 inhibitor-resistant breast cancer, which contains the drug combination described in the present disclosure.

[0030] In another aspect, the present disclosure further provides a kit for treating CDK4 / 6 inhibitor-resistant breast cancer, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein. In another aspect, the present disclosure further provides a kit for treating CDK4 / 6 inhibitor-resistant breast cancer, comprising a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein and a pharmaceutical composition of an endocrine therapy drug.

[0031] In some embodiments of the present disclosure, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or pharmaceutical combination, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a unit preparation containing 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0032] In some embodiments of the present disclosure, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical composition or pharmaceutical combination, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a unit preparation containing 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0033] On the other hand, the present disclosure also provides a method for treating CDK4 / 6 inhibitor-resistant breast cancer, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual in need thereof, for example, administering a therapeutically effective amount of a pharmaceutical composition or drug combination of the compound of formula (I) or a pharmaceutically acceptable salt thereof as described above to an individual in need thereof. On the other hand, the present disclosure also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating CDK4 / 6 inhibitor-resistant breast cancer, for example, the use of a pharmaceutical composition or drug combination described in the present disclosure in the preparation of a medicament for treating CDK4 / 6 inhibitor-resistant breast cancer.

[0034] On the other hand, the present disclosure also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating CDK4 / 6 inhibitor-resistant breast cancer, for example, the use of the pharmaceutical composition or drug combination described in the present disclosure for treating CDK4 / 6 inhibitor-resistant breast cancer.

[0035] In some embodiments of the present disclosure, in the above methods or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is optionally combined with endocrine drug therapy.

[0036] On the other hand, the present disclosure also provides a method for treating CDK4 / 6 inhibitor-resistant breast cancer, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an endocrine therapy drug to an individual in need thereof, for example, administering a therapeutically effective amount of a pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of an endocrine therapy drug to an individual in need thereof.

[0037] On the other hand, the present disclosure also provides a combined method for treating CDK4 / 6 inhibitor-resistant breast cancer, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an endocrine therapy drug to an individual in need thereof.

[0038] In another aspect, the present disclosure further provides a combined method for treating breast cancer resistant to CDK4 / 6 inhibitors, comprising administering a therapeutically effective amount of the drug combination of the present disclosure to an individual in need thereof.

[0039] In another aspect, the present disclosure provides 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.

[0040] On the other hand, the present 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, for example, the use of a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of an endocrine therapy drug described in the present disclosure for the treatment of CDK4 / 6 inhibitor-resistant breast cancer.

[0041] In another aspect, the present disclosure provides 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 drug to treat CDK4 / 6 inhibitor-resistant breast cancer.

[0042] In another aspect, the present disclosure provides the use of an endocrine therapy drug in the preparation of a medicament for use in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of breast cancer resistant to CDK4 / 6 inhibitors. In some embodiments of the present disclosure, in the method or use, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a daily dose, which is administered as follows: the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily.

[0043] In some embodiments of the present 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 doses, usually in multiple doses; further, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day in multiple doses.

[0044] In some embodiments of the present disclosure, in the method or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 120 mg; or, a daily dose of 150 mg; or, a daily dose of 180 mg.

[0045] In some embodiments of the present disclosure, in the method or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 150 mg; or, a daily dose of 180 mg.

[0046] In some embodiments of the present disclosure, in the method or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 180 mg.

[0047] In some embodiments of the present disclosure, in the methods or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in multiple doses, wherein the multiple doses consist of a single dose of 50 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments of the present disclosure, in the methods or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a continuous daily dosing manner.

[0048] In some embodiments of the present disclosure, in the methods or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in multiple doses, wherein the multiple doses consist of a single dose of 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments of the present disclosure, in the methods or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a continuous daily dosing manner.

[0049] In some embodiments of the present disclosure, in the methods or uses, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a dose per treatment cycle, which is administered as follows: the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily. Wherein, the compound of formula (I) or a pharmaceutically acceptable salt thereof is packaged in a single aliquot or multiple aliquots (e.g., 2 aliquots, 4 aliquots, 7 aliquots, 14 aliquots, 28 aliquots or more).

[0050] In some embodiments of the present disclosure, in the method or use, 28 days is a treatment cycle, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered every day on days 1 to 28 of each treatment cycle.

[0051] In some specific embodiments of the present disclosure, in the method or use, 28 days is a treatment cycle, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1 to 28 of each treatment cycle.

[0052] In some embodiments of the present disclosure, in the method or use, 28 days is a treatment cycle, the drug is administered once a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof in each treatment cycle is 1680 to 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 the range formed by any two 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, 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.

[0053] In some embodiments of the present disclosure, the endocrine therapy drug is used as an adjuvant endocrine therapy drug.

[0054] In some embodiments of the present disclosure, the endocrine therapy drug is selected from tamoxifen or an aromatase inhibitor.

[0055] In some embodiments of the present disclosure, the endocrine therapy drug is selected from aromatase inhibitors.

[0056] In some embodiments of the present disclosure, the endocrine therapy drug is selected from one or more of tamoxifen, toremifene, fulvestrant, letrozole, anastrozole, exemestane, goserelin, or leuprorelin.

[0057] In some embodiments of the present disclosure, the endocrine therapy drug refers to tamoxifen, toremifene, fulvestrant, letrozole, anastrozole, exemestane, goserelin and leuprolide.

[0058] In some embodiments of the present disclosure, the endocrine therapy drug is one or more selected from fulvestrant, letrozole, or anastrozole.

[0059] In some embodiments of the present disclosure, the endocrine therapy drug is fulvestrant, letrozole, or anastrozole.

[0060] In some embodiments of the present disclosure, the endocrine therapy drug is fulvestrant.

[0061] In some embodiments of the present disclosure, the endocrine therapy drug refers to fulvestrant injection treatment, wherein 500 mg of fulvestrant injection is injected intramuscularly, and each 28-day treatment cycle is one cycle, wherein the drug is administered on the 1st and 15th days of the first cycle, and then on the 1st day of each subsequent cycle.

[0062] In embodiments of the present disclosure, the treatment cycles are repeated as long as the disease remains under control and the dosing regimen is clinically tolerated.

[0063] In some embodiments of the present disclosure, the CDK4 / 6 inhibitor in the “CDK4 / 6 inhibitor-resistant breast cancer” does not include the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments of the present disclosure, the inhibitory activity of the CDK4 / 6 inhibitor against CDK2 kinase in the “CDK4 / 6 inhibitor-resistant breast cancer” is lower than that of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments of the present disclosure, the CDK4 / 6 inhibitor in the "CDK4 / 6 inhibitor-resistant breast cancer" has a half-maximal inhibitory concentration (IC50) of greater than 10 nM in a CDK2 kinase activity assay. 50 ), or with a half-maximal inhibitory concentration (IC 50 ), or with a half-maximal inhibitory concentration (IC 50 ).

[0066] In some embodiments of the present disclosure, the "CDK2 kinase activity assay" is performed in an enzyme reaction system of CDK2 / cyclin A. In some embodiments of the present disclosure, the drug resistance of the "CDK4 / 6 inhibitor-resistant breast cancer" includes resistance to CDK4 / 6 inhibitor combined endocrine therapy.

[0067] In some embodiments of the present disclosure, the CDK4 / 6 inhibitors in the "CDK4 / 6 inhibitor-resistant breast cancer" include but are not limited to one or more of Palbociclib, Ribociclib, Abemaciclib, and Dalpiciclib.

[0068] In some embodiments of the present disclosure, the CDK4 / 6 inhibitors in the "CDK4 / 6 inhibitor-resistant breast cancer" include but are not limited to one or more of Palbociclib, Ribociclib, and Dalpiciclib.

[0069] In some embodiments of the present 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.

[0070] In some embodiments of the present 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.

[0071] In some embodiments of the present disclosure, the CDK4 / 6 inhibitor-resistant breast cancer is selected from CDK4 / 6 inhibitor-resistant HR-positive, HER2-negative breast cancer.

[0072] In some embodiments of the present disclosure, the CDK4 / 6 inhibitor-resistant breast cancer is selected from CDK4 / 6 inhibitor-resistant HR-positive, HER2-negative advanced breast cancer.

[0073] In some embodiments of the present disclosure, the CDK4 / 6 inhibitor-resistant breast cancer is selected from CDK4 / 6 inhibitor-resistant HR-positive, HER2-negative recurrent / metastatic breast cancer.

[0074] In some embodiments of the present 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 previous treatment with a CDK4 / 6 inhibitor.

[0075] In some embodiments of the present disclosure, the CDK4 / 6 inhibitor resistance includes one of the following: (1) receiving CDK4 / 6 inhibitor combined with endocrine therapy as adjuvant endocrine therapy, recurrence or progression during treatment or within 1 year after completing adjuvant endocrine therapy; optionally, no subsequent endocrine therapy; (2) recurrence or progression more than 1 year after completing adjuvant endocrine therapy, and further progression after receiving CDK4 / 6 inhibitor combined with endocrine therapy as rescue endocrine therapy; (3) newly diagnosed locally advanced or metastatic disease, and disease progression after receiving CDK4 / 6 inhibitor combined with endocrine therapy as rescue endocrine therapy; (4) progression after receiving CDK4 / 6 inhibitor monotherapy in addition to adjuvant endocrine therapy or rescue endocrine monotherapy.

[0076] In some embodiments of the present disclosure, the CDK4 / 6 inhibitor is combined with endocrine therapy as adjuvant endocrine therapy for no less than 2 years.

[0077] In some embodiments of the present disclosure, the CDK4 / 6 inhibitor is combined with endocrine therapy as rescue endocrine therapy for no less than 6 months.

[0078] In some embodiments of the present disclosure, in the previous combination treatment of CDK4 / 6 inhibitor-resistant breast cancer, early discontinuation of CDK4 / 6 inhibitors due to intolerance or other reasons other than disease progression is allowed, followed by endocrine therapy alone.

[0079] In some embodiments of the present disclosure, the breast cancer is selected from locally advanced and / or metastatic breast cancer.

[0080] In some embodiments of the present disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer.

[0081] In some embodiments of the present disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer that is not amenable to radical surgery or radiotherapy.

[0082] In some embodiments of the present disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer that is not amenable to radical surgery or radiotherapy and has no indication for chemotherapy.

[0083] In some embodiments of the present disclosure, the breast cancer is selected from postmenopausal or premenopausal / perimenopausal breast cancer.

[0084] In some embodiments of the present disclosure, the breast cancer is selected from postmenopausal or premenopausal / perimenopausal HR-positive, HER2-negative locally advanced and / or metastatic breast cancer.

[0085] In some embodiments of the present disclosure, the breast cancer is selected from breast cancer that has undergone previous bilateral oophorectomy.

[0086] In some embodiments of the present disclosure, the breast cancer is selected from breast cancer patients aged ≥60 years; or breast cancer patients aged <60 years, with natural menopause ≥12 months, and follicle-stimulating hormone (FSH) and estradiol (E2) levels within the postmenopausal range; or breast cancer patients who are premenopausal or perimenopausal but receive LHRH agonist treatment during treatment.

[0087] In some embodiments of the present disclosure, the breast cancer is selected from postmenopausal or premenopausal / perimenopausal breast cancer that has previously undergone bilateral oophorectomy.

[0088] In some embodiments of the present disclosure, the breast cancer is selected from postmenopausal or premenopausal / perimenopausal HR-positive, HER2-negative locally advanced and / or metastatic breast cancer that has undergone previous bilateral oophorectomy.

[0089] In some embodiments of the present disclosure, the breast cancer is selected from postmenopausal or premenopausal / perimenopausal HR-positive, HER2-negative locally advanced and / or metastatic breast cancer that is ineligible for radical surgery or radiotherapy.

[0090] In some embodiments of the present disclosure, HR positivity includes estrogen receptor ER positivity and / or progesterone receptor PR positivity, which is defined as: the proportion of positively stained tumor cells in all tumor cells is ≥10%.

[0091] In some embodiments of the present disclosure, HER2 negativity is defined as: immunohistochemistry (IHC) testing 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 only FISH testing is performed to confirm that it is negative.

[0092] In some embodiments of the present disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer that has progressed after previous endocrine therapy.

[0093] In some embodiments of the present disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer that has received no more than one line of chemotherapy.

[0094] In some embodiments of the present disclosure, the breast cancer is selected from HR-positive, HER2-negative breast cancer that relapses or progresses during adjuvant endocrine therapy or within 1 year after completion of adjuvant endocrine therapy and has not subsequently received endocrine therapy.

[0095] In some embodiments of the present disclosure, the breast cancer is selected from HR-positive, HER2-negative breast cancer that relapses or progresses more than one year after completion of adjuvant endocrine therapy and subsequently progresses again after receiving salvage endocrine therapy; in some embodiments, the salvage endocrine therapy is no more than one line of treatment.

[0096] In some embodiments of the present disclosure, the breast cancer is selected from breast cancer that was initially diagnosed as localized or metastatic disease and progressed after receiving salvage endocrine therapy; in some embodiments, the salvage endocrine therapy is no more than 1 line of treatment.

[0097] In some embodiments of the present disclosure, the duration of receiving adjuvant endocrine therapy is no less than 1 year.

[0098] In some embodiments of the present disclosure, the relapsed or progressed subjects are allowed to receive no more than one line of rescue chemotherapy or rescue endocrine therapy.

[0099] In some embodiments of the present disclosure, the HR positive is selected from ER positive and PR positive.

[0100] In some embodiments of the present disclosure, the HR-positive, HER2-negative gene is ER-positive, PR-positive, and HER2-negative.

[0101] In some embodiments of the present disclosure, the breast cancer is selected from ER-positive, PR-positive, HER2-negative breast ductal carcinoma.

[0102] In some embodiments of the present disclosure, the breast cancer patient is pathologically diagnosed with HR-positive, HER2-negative breast cancer, has evidence of local recurrence or distant metastatic disease, is not suitable for surgery or radiotherapy for curative purposes, and has no clinical indication for chemotherapy.

[0103] In some embodiments of the present disclosure, the breast cancer recurrence / metastasis stage patient is allowed to receive no more than first-line salvage chemotherapy or salvage endocrine therapy.

[0104] In some embodiments of the present disclosure, the breast cancer patient has at least one measurable lesion according to RECIST 1.1 criteria.

[0105] In some embodiments of the present disclosure, the CDK4 / 6 inhibitor resistance is selected from primary resistance to CDK4 / 6 inhibitors or acquired resistance after treatment with CDK4 / 6 inhibitors.

[0106] In some embodiments of the present disclosure, the CDK4 / 6 inhibitor resistance is selected from acquired resistance after treatment with a CDK4 / 6 inhibitor.

[0107] In some embodiments of the present disclosure, the breast cancer is selected from HR-positive, HER2-negative recurrent / metastatic breast cancer that is resistant to CDK4 / 6 inhibitors.

[0108] The active ingredients in the pharmaceutical combination of the present disclosure can be formulated independently, or some or all of them together with a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical combination of the present disclosure may also contain an additional therapeutic agent. In some embodiments of the present disclosure, the additional therapeutic agent can be a therapeutic agent for cancer known in the art, preferably a therapeutic agent for breast cancer.

[0109] The active ingredients in the pharmaceutical combination of the present disclosure can be formulated independently, or partly or entirely thereof, with a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical combination of the present disclosure may also contain an additional therapeutic agent. In some embodiments of the present disclosure, the additional therapeutic agent may be a therapeutic agent known in the art for cancer, preferably a therapeutic agent for pancreatic cancer, head and neck cancer, sarcoma, lymphoma, melanoma, or leukemia.

[0110] In some embodiments of the present disclosure, the cycle is 28 days.

[0111] The amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, and the age and health status of the patient.

[0112] The compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered by a variety of routes, including but not limited to the following: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, by inhalation, vaginal, intraocular, topical, subcutaneous, intrafatty, intraarticular, intraperitoneal and intrathecal. In a specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally.

[0113] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a continuous daily oral administration manner.

[0114] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day in the form of a multiple-dose oral solid preparation.

[0115] Compound of formula (I) or a pharmaceutically acceptable salt thereof

[0116] The compounds of formula (I) disclosed herein can be administered in their free base form, or in the form of their pharmaceutically acceptable salts, hydrates, and prodrugs, which are converted into the compound of formula (I) in vivo. For example, pharmaceutically acceptable salts of the compounds of formula (I) are within the scope of the present disclosure and can be produced from various organic and inorganic acids according to methods known in the art.

[0117] Regarding the pharmaceutically acceptable salts of the compounds of formula (I) described in the present disclosure, the molar ratio of the compound of formula (I) to the acid ion forming the pharmaceutically acceptable salt may be 1:1.

[0118] The pharmaceutically acceptable salt of the compound of formula (I) may be a maleate salt of the compound of formula (I) (eg a monomaleate salt of the compound of formula (I)).

[0119] The dosage of the compound of formula (I) or its pharmaceutically acceptable salt referred to in the present disclosure is based on the amount of the compound of formula (I) unless otherwise stated.

[0120] In some embodiments of the present disclosure, the pharmaceutically acceptable salt of the compound of formula (I) exists as a salt of the compound of formula (I).

[0121] The compound of formula (I) or a pharmaceutically acceptable salt thereof used in the present disclosure can be prepared by methods in the prior art, for example, by referring to the method of WO2016141881.

[0122] Pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof

[0123] In some embodiments of the present disclosure, a single dose of the 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 as a unit preparation containing 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof calculated as the compound of formula (I).

[0124] In some embodiments of the present disclosure, a single dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 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 as a unit preparation containing 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof calculated as the compound of formula (I).

[0125] The method of administration can be determined comprehensively based on the activity, toxicity and patient tolerance of the drug.

[0126] In some embodiments of the present disclosure, the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof further contains a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, adhesives, disintegrants, lubricants, etc. In some embodiments of the present disclosure, the pharmaceutical composition includes but is not limited to preparations suitable for oral, parenteral, and topical administration. In some embodiments, the pharmaceutical composition is a preparation suitable for oral administration. In some embodiments, the pharmaceutical composition is a solid preparation suitable for oral administration. In some embodiments, the pharmaceutical composition includes but is not limited to tablets and capsules.

[0127] In some embodiments of the present disclosure, the pharmaceutical composition is a solid pharmaceutical combination.

[0128] In some embodiments of the present 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.

[0129] In some embodiments of the present 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.

[0130] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0131] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0132] Technical Effects

[0133] The compounds disclosed herein exhibit good therapeutic effects on breast cancer resistant to CDK4 / 6 inhibitors, including but not limited to higher objective response rate (ORR), longer progression-free survival (PFS), longer duration of response (DOR), higher disease control rate (DCR), higher clinical benefit rate (CBR), and longer overall survival (OS). The compounds disclosed herein have good safety and tolerability in the treatment of breast cancer resistant to CDK4 / 6 inhibitors.

[0134] In general, use of the pharmaceutical combinations of the present disclosure will help:

[0135] (1) Produce a better therapeutic effect in reducing tumor growth or even eliminating tumors compared to administering either drug alone;

[0136] (2) provide for administration of a smaller amount of the drug than would be possible with either drug alone;

[0137] (3) provide a treatment that is well tolerated by patients and has fewer adverse effects and / or complications than either drug given alone;

[0138] (4) provide better disease control rates among treated patients;

[0139] (5) provide longer survival (e.g., median survival, progression-free survival, or overall survival) in treated patients;

[0140] (6) provide longer survival (e.g., median survival, progression-free survival, or overall survival) for treated patients compared to standard chemotherapy;

[0141] (7) provide a longer duration of disease remission (DOR); and / or

[0142] (8) Compared with the administration of any drug in the combination alone, the combination has good activity in treating tumors or proliferative diseases and exhibits a more excellent anti-tumor synergistic effect.

[0143] The compounds of formula (I) disclosed herein are "clinically beneficial" in at least one or more of the following aspects: prolonged progression-free survival (PFS) of clinical patients, prolonged overall survival (OS), improved objective response rate (ORR), improved disease control rate (DCR), reduced number and / or severity of adverse reactions, decreased distant metastasis rate and local control rate, etc.

[0144] Definition and Description

[0145] The word "comprise" or "comprises" and its English variations such as comprises or comprising and their equivalents should be understood as open and non-exclusive, that is, "including but not limited to", meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included.

[0146] The term "patient" or "individual / subject" refers to a mammal, such as a primate (human, macaque, chimpanzee, etc.), a rodent (mice, rats, rabbits, etc.), a cat, a canine, etc., preferably a human. In some embodiments of the present disclosure, the patient and the individual are patients who have failed standard treatment or lack standard treatment.

[0147] The term "pharmaceutically acceptable" or "pharmaceutically usable" refers to a carrier, excipient or excipient used to prepare a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes that which is acceptable for use in human medicine.

[0148] The term "therapeutically effective amount" means the amount of a compound that, when administered to a human for treating a disease, is sufficient to effect such treatment.

[0149] The term "treating" means administering a compound or formulation of the present disclosure to improve, alleviate, or eliminate a disease or one or more symptoms associated with the disease, and includes: (i) inhibiting a disease or disease state, i.e., curbing or retarding its development; and (ii) relieving a disease or disease state, i.e., causing the disease or disease state to regress.

[0150] As used herein, " adverse event " (AE) is any unfavorable and usually unintentional or undesirable sign (including abnormal laboratory findings), symptom or disease relevant to the application of medical treatment.For example, adverse event can be relevant to the activation of the immune system or the amplification of immune system cells (for example, T cells) in response to treatment.Medical treatment can have one or more related AEs, and each AE can have the same or different levels of severity.Reference to the method that can " modify adverse event " refers to the treatment scheme that reduces the incidence and / or severity of one or more AEs relevant to the application of different treatment schemes.

[0151] The use of alternatives (e.g., "or") should be understood to refer to any one, two, or any combination of the alternatives. The indefinite articles "a" or "an" used herein should be understood to mean "one or more" of any listed or enumerated components.

[0152] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0153] The terms "administering" and "administering" refer to the physical introduction of a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. In certain embodiments, administration is oral administration.

[0154] The term "daily dose" refers to the dose administered to a patient daily.

[0155] The term "single dose" or "unit preparation" refers to the smallest packaging unit of a drug containing a certain amount of active ingredient. For example, if a box of medicine contains seven capsules, each capsule is a single dose or unit preparation; for example, if a box of medicine contains seven tablets, each tablet is a single dose unit preparation.

[0156] The term "multiple doses" consists of a plurality of single doses.

[0157] As used herein, "combination" or "combined use" means that two or more active substances can be administered to an individual simultaneously, concurrently, or sequentially in any order, each as a single formulation.

[0158] The term "primary resistance" is also called "intrinsic resistance", which refers to resistance to a certain drug from the beginning before treatment with a certain drug.

[0159] The term "secondary drug resistance" is also called "acquired drug resistance", which refers to drug resistance that occurs after a certain period of drug treatment.

[0160] The term "treatment failure" includes refractory and / or relapsed and / or progressive and / or intolerant.

[0161] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present disclosure or their pharmaceutical combination and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of the present disclosure or their pharmaceutical combination to an individual.

[0162] When referring to a dosing regimen, the terms "day," "daily," and the like refer to times within a calendar day, starting at midnight and ending at the following midnight.

[0163] In this document, unless the context clearly indicates otherwise, singular terms include plural referents and vice versa. Similarly, unless the context clearly indicates otherwise, the word "or" is intended to include "and" and vice versa.

[0164] Unless otherwise indicated, herein, parameter values ​​representing the amounts of ingredients or physicochemical properties or reaction conditions, etc., should be understood as being modified in all instances by the term "about." When the term "about" is used to describe the present disclosure, the term "about" indicates that there is a deviation, for example, a variation within the range of ±5%, such as ±1%, or ±0.1% of a particular value.

[0165] For the 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 disclosure predates the filing date of the present disclosure. All statements regarding the dates of these documents or representations of the contents of these documents are based on information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any citation of these publications herein does not constitute an admission that such publications are part of the common general knowledge in the art in any country. Example

[0166] The purpose of the following specific embodiments is to enable those skilled in the art to more clearly understand and implement the present disclosure. They should not be considered as limiting the scope of the present disclosure, but are merely exemplary descriptions and typical representatives of the present disclosure.

[0167] Experimental Example 1 In vitro pharmacodynamic evaluation

[0168] 1.1 Cell culture method and source

[0169] CDK4 / 6 inhibitor-resistant T47D cells (T47D / PalR) were purchased from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd. and cultured in RPMI1640 medium containing 10% fetal bovine serum, 0.2 U / mL insulin, and 5 μM palbociclib.

[0170] 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.

[0171] 1.2 Cell culture reagents

[0172] MEM medium, phenol red-free 1640 medium, sodium pyruvate, non-essential amino acids, ITS-G, fetal bovine serum, and charcoal-treated fetal bovine serum.

[0173] 1.3 Administration

[0174] (1) Determine the CCK-8 dosing concentration range: Before the experiment, preliminarily determine the drug concentration range using the six-well assay. Based on the determined drug concentration range, set the dosing concentration range and gradient dilution ratio for the experiment. Test 48 hours after dosing. If the cell growth activity inhibition curve fails to reach a plateau, adjust the dosing concentration range and gradient dilution ratio and repeat the experiment.

[0175] 1.4 Experimental methods

[0176] 1.4.1 CCK-8 cell proliferation assay

[0177] (1) The above cells were digested into a single-cell suspension and inoculated into a 96-well plate at different cell numbers per well. Six replicate wells were set up for each dosing concentration group, with a volume of 100 μL per well. The edge wells of the culture plate were filled with sterile PBS. Blank control wells (containing no cells) were set up.

[0178] (2) Place in a cell culture incubator at 37°C and 5% CO2 for 24 hours.

[0179] (3) Prepare different concentrations of the test drug using the gradient dilution method, and add 100 μL of the test drug to each well of a 96-well plate.

[0180] (4) After 48 h, 20 μL of CCK-8 solution was added to each well.

[0181] (5) Place in a 37°C incubator and incubate for 3 hours.

[0182] (6) After incubation, place the sample on a microplate reader, shake well, and measure the absorbance at 450 nm. Record the results and adjust the colorimetric value to zero using a blank.

[0183] 3.4.2 Calculation of half-maximal inhibitory concentration (IC) 50

[0184] Analysis of drug inhibition rate on cells:

[0185] Calculation formula: Inhibition rate (%) = (1-OD value of drug-treated group / OD value of control group) * 100

[0186] The average inhibition rate of each drug on cells was calculated by removing the highest and lowest values ​​in each concentration group. Growth activity inhibition curves for each cell were generated using GraphPad Prism 8.0 software. Nonlinear regression analysis of the percentage inhibition of tumor cell growth was performed using the following equation to generate the growth activity inhibition curve.

[0187] Y=100 / (1+10^((LogIC50-X)*HillSlope))

[0188] 1.5 Experimental Results

[0189] IC of Palbociclib, Abemaciclib, Ribociclib and the compound of formula (I) on T47D / PalR cells 50 The values ​​are shown in Table 1 below.

[0190] Table 1

[0191] Experimental Example 2: In vitro drug sensitivity test of TCA in PDX model

[0192] Cell source: human breast cancer (female, 38 years old)

[0193] Pathological diagnosis: consistent with invasive breast cancer type 2-3 and unspecialized type, PIK3CA mutation

[0194] Cell type: ER + PR + , HER2 + , CCNE1 amplification, Palbociclib primary resistance cells

[0195] Plating density: 1*10^4 cells / well

[0196] Dosage days: 6 days

[0197] Detection reagent: CTG

[0198] Single drug concentration: 20 μM down 4-fold gradient, 6 concentrations, 2 replicates

[0199] Final DMSO concentration: 0.4%

[0200] Calculate the half-maximal inhibitory concentration (IC)50 :Four-parameter analysis, fitting dose-effect curve, calculating IC 50

[0201] The results are shown in Table 2:

[0202] Table 2

[0203] Experimental Example 3: Evaluation of drug efficacy in a human breast cancer transplant model

[0204] 3.1 Experimental Materials

[0205] Human breast cancer tissue, passaged to FP3+2, was used for this efficacy study. Basic information is as follows: 38-year-old female breast cancer; pathological diagnosis: consistent with invasive breast carcinoma type 2-3 and undifferentiated type, with PIK3CA mutation; drug resistance information: primary resistance to palbociclib.

[0206] 3.2 Experimental animals

[0207] 3.2.1 Source of experimental animals

[0208] Female NOD-Scid mice weighing 18-21 g were housed in an SPF-grade environment. Animals were acclimated for at least 3 days before the experiment began.

[0209] 3.2.2 Animal husbandry

[0210] All NOD-Scid mice were housed in an SPF-grade IVC constant temperature and pressure system at 20–26°C, 40–70% humidity, and a 12-hour light / dark photoperiod. No more than five NOD-Scid mice were housed in each 325 mm × 210 mm × 180 mm cage. Corn cob bedding was changed twice weekly. Throughout the experiment, all mice had free access to food. Autoclaved feed and water were replaced twice weekly. Animals were numbered using a mouse ear punch.

[0211] 3.3 Experimental steps and methods

[0212] Human breast cancer xenografts were cut into approximately 3 mm × 3 mm × 3 mm (approximately 45-60 mg) pieces, mixed with 30 μL of Matrigel, and inoculated subcutaneously on the right back of NOD-Scid mice. The mice were observed and tumor growth was monitored. On day 49 of inoculation, the average tumor volume in the tumor-bearing mice was 127.01 mm. 3 The day of group administration was defined as day 0. The specific group information is shown in Table 3 below:

[0213] Table 3 Drug administration and treatment Note: N: number of animals; Dosage volume: adjusted according to the weight of tumor-bearing mice (0.040 ml / 20 g); PO: intragastric administration.

[0214] After the experimental animals were inoculated with tumor tissue, they were observed every day and their incidence and mortality were recorded.

[0215] 3.4 Efficacy evaluation

[0216] 3.4.1 Tumor volume and weight of tumor-bearing mice were measured twice a week using a vernier caliper. The tumor volume was calculated as V = 0.5a × b 2 , a, b represent the long diameter and wide diameter of the tumor, respectively;

[0217] 3.4.2 Relative tumor growth rate T / C (%): The calculation formula is as follows: T / C% = T RTV / C RTV ×100%(T RTV :RTV in treatment group; C RTV : RTV of negative control group). Relative tumor volume (RTV) was calculated based on the results of tumor measurement. The calculation formula is RTV=V t / V0, where V0 is the average tumor volume measured at the time of group administration (i.e., d0), V t is the average tumor volume at a certain measurement, T RTV with C RTV Get data for the same day.

[0218] 3.4.3 Tumor growth inhibition rate TGI (%) = [1-(T i -T0) / (V i -V0)]×100,T i is the average tumor volume of the compound group after the start of administration, T0 is the average tumor volume of the compound group at the first administration, V0 is the average tumor volume of the vehicle control group at the first administration, and V i The mean tumor volume of the vehicle control group after the start of drug administration.

[0219] 3.4.4 The body weight of all tumor-bearing mice was measured every day. The relative change ratio of the body weight of mice after drug administration was calculated: RCBW (%) = (BW i –BW0) / BW0×100, BW i BW0 is the body weight after the start of drug administration, and BW1 is the body weight at the first drug administration.

[0220] 3.4.5 At the end of the experiment, the tumor pieces were removed, weighed and photographed.

[0221] 3.5 Experimental Results

[0222] The compound of formula (I) showed effective tumor growth inhibition in human breast cancer xenograft models. No significant weight loss was observed in the mice in each administration group after administration, indicating that the tumor-bearing mice tolerated the treatment well at the experimental dose.

[0223] The specific results are shown in Table 4:

[0224] Table 4

[0225] clinical trials

[0226] This study is a single-arm, open-label, multicenter trial to evaluate the efficacy and safety of the compound of formula (I) combined with endocrine therapy in subjects with HR-positive, HER2-negative recurrent / metastatic breast cancer who have progressed after previous treatment with CDK4 / 6 inhibitors.

[0227] 1.1 Inclusion Criteria

[0228] 1. The subjects voluntarily participate in this study, sign the informed consent form, and have good compliance;

[0229] 2. Age: 18-75 years old (at the time of signing the informed consent); ECOGPS score: 0-1; expected survival time: more than 3 months;

[0230] 3. Postmenopausal or premenopausal / perimenopausal female patients;

[0231] 4. Subjects diagnosed with HR-positive, HER2-negative breast cancer by pathological examination, with evidence of local recurrence or distant metastatic disease, who are not suitable for curative surgery or radiotherapy and have no clinical indication for chemotherapy (refer to ASCO / CAP guidelines for HER2 expression);

[0232] 5. Subjects in the recurrence / metastasis stage are allowed to receive no more than first-line rescue chemotherapy or rescue endocrine therapy;

[0233] 6. At least one measurable lesion according to RECIST 1.1 (except for patients with only skin and / or brain lesions as measurable lesions);

[0234] 7. Major organs function well;

[0235] 8. Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, birth control pills or condoms) during the study and within 6 months after the end of the study; the serum pregnancy test must be negative within 7 days before study enrollment, and the subjects must be non-breastfeeding.

[0236] 1.2 Investigational Drugs

[0237] Capsules of compound of formula (I): specifications: 60 mg, 50 mg.

[0238] Fulvestrant injection: Specification: 5ml:0.25g.

[0239] 1.3 Dosage regimen

[0240] The compound of formula (I) capsules are administered orally with or within 2 hours after a meal for a 28-day treatment cycle, once daily. The initial dose is 180 mg / day. If a dose reduction is necessary, the patient will continue with a reduced dose in subsequent cycles. The dose should be reduced no more than twice. Dose level -1 is 150 mg / day, and dose level -2 is 120 mg / day.

[0241] Endocrine therapy regimens are divided into two types according to the menopausal status of the subjects:

[0242] Premenopausal / perimenopausal subjects: LHRH agonists (goserelin, etc.) combined with fulvestrant. Postmenopausal subjects: fulvestrant monotherapy.

[0243] Fulvestrant injection: 500 mg intramuscular injection, every 28 days as a treatment cycle, administered on days 1 and 15 of the first cycle, and on day 1 of each subsequent cycle.

[0244] 1.4 Evaluation Criteria

[0245] Effectiveness evaluation criteria: RECIST 1.1 criteria were used to determine the disease status.

[0246] Safety evaluation criteria: The NCI-CTC AE 5.0 standard was used to judge the severity of adverse events.

[0247] Those skilled in the art will recognize that the scope of the present disclosure is not limited to the various specific implementation modes and examples described above, but that various modifications, replacements, or recombinations can be made without departing from the spirit and concept of the present disclosure, which all fall within the scope of protection of the present disclosure.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating breast cancer resistant to CDK4 / 6 inhibitors, 2. A pharmaceutical composition for treating breast cancer resistant to CDK4 / 6 inhibitors, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, 3. A drug combination for treating breast cancer resistant to CDK4 / 6 inhibitors, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and an endocrine therapy drug, 4. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating breast cancer resistant to CDK4 / 6 inhibitors 5. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for use in combination with an endocrine therapy drug for the treatment of breast cancer resistant to CDK4 / 6 inhibitors 6. A method for treating breast cancer resistant to CDK4 / 6 inhibitors, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof 7. A method for treating breast cancer resistant to CDK4 / 6 inhibitors, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an endocrine therapy drug 8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, a pharmaceutical composition according to claim 2, a pharmaceutical combination according to claim 3, the use according to claim 4 or 5, or a method according to claim 6 or 7, which 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 the compound of formula (I); preferably contains 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); more preferably contains 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, 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 a pharmaceutically acceptable salt thereof is in a single dose or multiple dose form.

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

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

12. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, the pharmaceutical composition according to claim 2, or the pharmaceutical combination 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 content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a daily dose, which is administered as follows: the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day.

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 CDK4 / 6 inhibitor-resistant HR-positive, HER2-negative breast cancer; preferably CDK4 / 6 inhibitor-resistant HR-positive, HER2-negative recurrent / metastatic breast cancer.

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