Use of PI3kα-mutant selective inhibitor

Abstract

The present invention relates to use of a PI3Kα-mutant selective inhibitor, specifically, use of compound 1, a racemate, a stereoisomer, or a pharmaceutically acceptable salt thereof, in the preparation of a drug for preventing and / or treating HR-positive / HER2-negative breast cancer, colon cancer, and head and neck cancer. The compound 1 can inhibit the growth of HR-positive / HER2-negative breast cancer cells, colon cancer cells, and head and neck squamous cell carcinoma cells, and can be used in combination with a CDK4 / 6 inhibitor or a selective ER degrading agent, having better therapeutic efficacy and good safety.

Description

Uses of PI3Kα mutation selective inhibitors

[0001] This application requires the applicant to have:

[0002] Priority rights to the earlier application filed with the China National Intellectual Property Administration on October 16, 2024, with patent application number 202411447943.9 and title "PI3Kα inhibitor compound, pharmaceutical composition and application thereof";

[0003] Priority rights to the earlier application filed with the China National Intellectual Property Administration on September 8, 2025, with patent application number 202511276944.6 and entitled "Use of a selective inhibitor of PI3Kα mutation";

[0004] The full text of the two prior applications is incorporated herein by reference. Technical Field

[0005] This invention belongs to the field of pharmaceutical technology, and in particular relates to the use of a selective inhibitor of PI3Kα mutation. Background Technology

[0006] PI3K (phosphatidylinositol 3-kinase) is an important intracellular signal transduction molecule. Mutations in its α isoform (PI3Kα) (such as PIK3CA gene mutations) can lead to abnormal activation of the PI3K-AKT-mTOR pathway, promoting tumor cell proliferation, survival, and drug resistance. PI3Kα mutation-selective inhibitors specifically inhibit mutant PI3Kα, blocking abnormal signal transduction while reducing the impact on wild-type PI3K, thereby reducing toxicity. The development of this class of drugs is based on the dependence of tumor cells on PI3Kα mutations and the need to overcome resistance to existing therapies.

[0007] In the treatment of HR-positive HER2-negative breast cancer, CDK4 / 6 inhibitors combined with endocrine therapy are the first-line treatment for advanced patients. However, approximately 50% of patients develop resistance within 1-2 years. The PIK3CA gene mutation rate is as high as 30%-40% in these patients, and the resulting activation of the PI3K-AKT-mTOR pathway is a significant cause of resistance. Combining PI3Kα inhibitors with CDK4 / 6 inhibitors can create a "dual pathway blockade": the former inhibits compensatory proliferation signals activated after resistance, while the latter blocks cell cycle progression. Combining PI3Kα inhibitors with SERDs can simultaneously target upstream and downstream pathways of the ER signaling pathway; the former blocks ER-independent proliferation signals, while the latter directly degrades ER. Preclinical studies have shown that this combination can enhance ER degradation and inhibit tumor cell survival.

[0008] The PIK3CA mutation rate in colorectal cancer is approximately 15-20%. Mutations lead to abnormal activation of the PI3K / AKT pathway, promoting invasion. This is more common in KRAS wild-type tumors and is associated with resistance to anti-EGFR therapy. These patients lack effective targeted therapies, and PIK3CA-mutated colorectal cancer cells are highly dependent on PI3Kα activity. In head and neck cancer, the PIK3CA gene mutation rate in squamous cell carcinoma of the head and neck is approximately 5%-10%, especially common in HPV-negative, EGFR-overexpressing tumors. Recurrent / metastatic patients often have low objective response rates and short survival rates with standard treatment. Summary of the Invention

[0009] The purpose of this invention is to provide a drug with definite therapeutic effects on HR-positive / HER2-negative breast cancer, colorectal cancer, and head and neck cancer. Specifically, this invention provides a combination of a PI3Kα mutation-selective inhibitor and a CDK4 / 6 inhibitor and / or a selective ER degrader in the treatment of HR-positive / HER2-negative breast cancer, as well as its use alone in the treatment of HR-positive / HER2-negative breast cancer, colorectal cancer, or head and neck cancer.

[0010] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0011] In a first aspect, the present invention provides the use of compound 1 as shown below, its racemic mixture, stereoisomer, or pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention and / or treatment of HR-positive / HER2-negative breast cancer, colon cancer, or head and neck cancer.

[0012] According to embodiments of the present invention, the HR-positive / HER2-negative breast cancer, colon cancer, and head and neck cancer are PI3Kα-mediated diseases or symptoms.

[0013] According to an embodiment of the present invention, the HR-positive / HER2-negative breast cancer is an HR-positive / HER2-negative breast cancer with a PIK3CA mutation.

[0014] According to an embodiment of the present invention, the HR-positive / HER2-negative breast cancer is ER-positive / HER2-negative breast cancer.

[0015] According to an embodiment of the present invention, the HR-positive / HER2-negative breast cancer is an HR-positive / HER2-negative breast cancer that has failed endocrine therapy.

[0016] According to an embodiment of the present invention, the HR-positive / HER2-negative breast cancer is an HR-positive / HER2-negative advanced breast cancer that has failed endocrine therapy.

[0017] According to an embodiment of the present invention, the colon cancer is a PIK3CA-mutated colon cancer.

[0018] According to an embodiment of the present invention, the head and neck cancer is squamous cell carcinoma of the head and neck.

[0019] According to an embodiment of the present invention, the head and neck cancer is a PIK3CA-mutated squamous cell carcinoma of the head and neck.

[0020] According to an embodiment of the present invention, the head and neck cancer is a PIK3CA-mutated squamous cell carcinoma of the tongue.

[0021] According to an embodiment of the present invention, the HR-positive / HER2-negative breast cancer, colon cancer, and head and neck cancer are recurrent and / or metastatic.

[0022] According to an embodiment of the present invention, the medicament is a composition comprising a therapeutically effective amount of the compound 1, its racemic form, stereoisomer, or a pharmaceutically acceptable salt thereof.

[0023] According to an embodiment of the present invention, the medicament is a composition comprising a therapeutically effective amount of the compound 1, its racemate, stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0024] According to embodiments of the present invention, the drug is suitable for preparation into formulations for intravenous infusion, intravenous drip, subcutaneous administration, intradermal administration, intramuscular injection, oral spray, oral administration, and in situ tumor administration.

[0025] According to embodiments of the present invention, the drug is prepared into oral formulations, such as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection, or concentrated solutions for injection), suppositories, inhalers, or sprays.

[0026] According to an embodiment of the present invention, compound 1, its racemate, stereoisomer, or pharmaceutically acceptable salt thereof is prepared into a composition, wherein the composition optionally further comprises a pharmaceutically acceptable carrier or excipient; wherein, in the composition, compound 1, its racemate, stereoisomer, or pharmaceutically acceptable salt thereof is in a therapeutically effective amount.

[0027] The composition is selected from formulations such as intravenous infusion, intravenous drip, subcutaneous administration, intradermal administration, intramuscular injection, oral spray, oral administration, and in situ tumor administration; the composition is an oral formulation, such as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection, or concentrated solutions for injection), suppositories, inhalers, or sprays.

[0028] According to embodiments of the present invention, the composition or formulation is administered in combination with one or more additional therapeutic agents.

[0029] According to an embodiment of the present invention, the daily dose of compound 1, its racemic mixture, stereoisomer, or pharmaceutically acceptable salt thereof is 0.1-1000 mg, and may be 0.1 mg, 0.3 mg, 0.5 mg, 0.7 mg, 0.9 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, etc. 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725 mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg.

[0030] According to an embodiment of the present invention, the amount of compound 1 contained in the pharmaceutical unit formulation, including its racemic form, stereoisomer, or pharmaceutically acceptable salt, is 0.1-1000 mg, and can be 0.1 mg, 0.3 mg, 0.5 mg, 0.7 mg, 0.9 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, etc. mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg , 480mg, 490mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725 mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg.

[0031] In some embodiments, the drug comprises compound 1, its racemate, stereoisomer, or a pharmaceutically acceptable salt thereof as the sole active ingredient; in some embodiments, the drug comprises, in addition to compound 1, its racemate, stereoisomer, or a pharmaceutically acceptable salt thereof, one or more additional therapeutic agents.

[0032] In some embodiments, the drug is administered in combination with one or more additional therapeutic agents, including compound 1, its racemate, stereoisomer, or a pharmaceutically acceptable salt thereof.

[0033] According to an embodiment of the invention, the drug is administered in combination with one or more additional therapeutic agents.

[0034] According to an embodiment of the present invention, the additional therapeutic agent is selected from one or more of CDK4 / 6 inhibitors, selective estrogen receptor (ER) degraders, AKT inhibitors, mTOR inhibitors, and HDAC inhibitors.

[0035] According to an embodiment of the present invention, the CDK4 / 6 inhibitor is selected from palbociclib.

[0036] According to an embodiment of the present invention, the selective estrogen receptor (ER) degrader is selected from Fulvestrant.

[0037] According to an embodiment of the invention, the mass ratio of compound 1, its racemic form, stereoisomer, or pharmaceutically acceptable salt thereof, to an additional therapeutic agent is 1:100 to 100:1, preferably 1:10 to 10:1. Examples include 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, and 10:1.

[0038] According to an embodiment of the present invention, the combined application may be the simultaneous, separate, or time-interval application of the active substances.

[0039] According to an embodiment of the present invention, in the combined administration, the daily dose of compound 1, its racemic mixture, stereoisomer, or pharmaceutically acceptable salt thereof, is 0.1-1000 mg, and can be 0.1 mg, 0.3 mg, 0.5 mg, 0.7 mg, 0.9 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 24 mg, etc. 0mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470m g, 480mg, 490mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 72 5mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg.

[0040] According to an embodiment of the present invention, in the combined administration, the single dose of compound 1, its racemic mixture, stereoisomer, or pharmaceutically acceptable salt thereof is 1-500 mg / kg, preferably 10-200 mg / kg, for example 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200 mg / kg.

[0041] According to an embodiment of the present invention, in the combined administration, the compound 1, its racemic mixture, stereoisomer, or pharmaceutically acceptable salt thereof is administered three times daily, twice daily, once daily, once every two days, once every three days, once every four days, once every five days, once every six days, once weekly, once every two weeks, once every three weeks, or once every four weeks; preferably once daily.

[0042] According to an embodiment of the present invention, in the combined administration, the single dose of the additional therapeutic agent is 1-1000 mg / kg, for example, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700 ,710,720,730,740,750,760,770,780,790,800,810,820,830,840,850,86 0, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000mg / kg.

[0043] According to an embodiment of the present invention, in the combined administration, the additional therapeutic agent is administered 3 times a day, 2 times a day, once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks.

[0044] According to an embodiment of the present invention, in the combined administration, the additional therapeutic agent is selected from CDK4 / 6 inhibitors (e.g., Palbociclib), and its single-dose dose is 1-500 mg / kg, preferably 10-200 mg / kg, for example 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 11 5, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200 mg / kg; dosing frequency is 3 times a day, 2 times a day, once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, preferably once a day.

[0045] According to an embodiment of the present invention, in the combined administration, the additional therapeutic agent is selected from selective estrogen receptor (ER) degraders (e.g., Fulvestrant), with a single dose of 1-1000 mg / kg, preferably 10-500 mg / kg, for example 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 18 5. 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500 mg / kg; Dosage frequency is 3 times a day, 2 times a day, once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, preferably once a week.

[0046] According to an embodiment of the present invention, the compound 1, its racemic form, stereoisomer, or pharmaceutically acceptable salt thereof, is administered simultaneously with an additional therapeutic agent.

[0047] According to an embodiment of the invention, the compound 1, its racemic form, stereoisomer, or pharmaceutically acceptable salt thereof, is administered at time intervals with an additional therapeutic agent.

[0048] According to an embodiment of the present invention, the drug is prepared in the form of a compound preparation.

[0049] According to an embodiment of the present invention, the drug is prepared in the form of a reagent kit.

[0050] A second aspect of the invention also provides a method for preventing and / or treating HR-positive / HER2-negative breast cancer, colon cancer, or head and neck squamous cell carcinoma, the method comprising administering to a subject a therapeutically effective amount of compound 1, its racemate, stereoisomer, or a pharmaceutically acceptable salt thereof, or a composition comprising said therapeutically effective amount of compound 1, its racemate, stereoisomer, or a pharmaceutically acceptable salt thereof, or optionally a pharmaceutically acceptable carrier or excipient.

[0051] According to an embodiment of the present invention, the HR-positive HER2-negative breast cancer, colon cancer, and head and neck cancer are PI3Kα-mediated diseases or symptoms.

[0052] According to an embodiment of the present invention, the HR-positive HER2-negative breast cancer is an HR-positive HER2-negative breast cancer with PIK3CA mutation.

[0053] According to an embodiment of the present invention, the HR-positive / HER2-negative breast cancer is ER-positive / HER2-negative breast cancer.

[0054] According to an embodiment of the present invention, the HR-positive / HER2-negative breast cancer is an HR-positive / HER2-negative breast cancer that has failed endocrine therapy.

[0055] According to an embodiment of the present invention, the HR-positive / HER2-negative breast cancer is an HR-positive / HER2-negative advanced breast cancer that has failed endocrine therapy.

[0056] According to an embodiment of the present invention, the colon cancer is a PIK3CA-mutated colon cancer.

[0057] According to an embodiment of the present invention, the head and neck cancer is squamous cell carcinoma of the head and neck.

[0058] According to an embodiment of the present invention, the head and neck cancer is a PIK3CA-mutated squamous cell carcinoma of the head and neck.

[0059] According to an embodiment of the present invention, the head and neck cancer is a PIK3CA-mutated squamous cell carcinoma of the tongue.

[0060] According to an embodiment of the present invention, the HR-positive / HER2-negative breast cancer, colon cancer, and head and neck cancer are recurrent and / or metastatic.

[0061] According to embodiments of the present invention, compound 1, its racemate, stereoisomer, or pharmaceutically acceptable salt thereof, is administered alone or in combination with one or more additional therapeutic agents.

[0062] According to an embodiment of the present invention, the additional therapeutic agent is selected from one or more of CDK4 / 6 inhibitors, selective estrogen receptor (ER) degraders, AKT inhibitors, mTOR inhibitors, and HDAC inhibitors.

[0063] According to an embodiment of the present invention, the CDK4 / 6 inhibitor is selected from palbociclib.

[0064] According to an embodiment of the present invention, the selective estrogen receptor (ER) degrader is selected from Fulvestrant.

[0065] According to an embodiment of the invention, in the combined administration, the mass ratio of compound 1, its racemic form, stereoisomer, or pharmaceutically acceptable salt thereof, to an additional therapeutic agent is 1:100 to 100:1, preferably 1:10 to 10:1. Examples include 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, and 10:1.

[0066] According to an embodiment of the present invention, the combined application may be the simultaneous, separate, or time-interval application of the active substances.

[0067] According to an embodiment of the present invention, in the combined administration, the daily dose of compound 1, its racemic mixture, stereoisomer, or pharmaceutically acceptable salt thereof, is 0.1-1000 mg, and can be 0.1 mg, 0.3 mg, 0.5 mg, 0.7 mg, 0.9 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 24 mg, etc. 0mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470m g, 480mg, 490mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 72 5mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg.

[0068] According to an embodiment of the present invention, in the combined administration, the single dose of compound 1, its racemic mixture, stereoisomer, or pharmaceutically acceptable salt thereof is 1-500 mg / kg, preferably 10-200 mg / kg, for example 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200 mg / kg.

[0069] According to an embodiment of the present invention, in the combined administration, the compound 1, its racemic mixture, stereoisomer, or pharmaceutically acceptable salt thereof is administered three times daily, twice daily, once daily, once every two days, once every three days, once every four days, once every five days, once every six days, once weekly, once every two weeks, once every three weeks, or once every four weeks; preferably once daily.

[0070] According to an embodiment of the present invention, in the combined administration, the single dose of the additional therapeutic agent is 1-1000 mg / kg, for example, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700 ,710,720,730,740,750,760,770,780,790,800,810,820,830,840,850,86 0, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000mg / kg.

[0071] According to an embodiment of the present invention, in the combined administration, the additional therapeutic agent is administered 3 times a day, 2 times a day, once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks.

[0072] According to an embodiment of the present invention, in the combined administration, the additional therapeutic agent is selected from CDK4 / 6 inhibitors (e.g., Palbociclib), and its single-dose dose is 1-500 mg / kg, preferably 10-200 mg / kg, for example 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 11 5, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200 mg / kg; dosing frequency is 3 times a day, 2 times a day, once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, preferably once a day.

[0073] According to an embodiment of the present invention, in the combined administration, the additional therapeutic agent is selected from selective estrogen receptor (ER) degraders (e.g., Fulvestrant), with a single dose of 1-1000 mg / kg, preferably 10-500 mg / kg, for example 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 18 5. 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500 mg / kg; Dosage frequency is 3 times a day, 2 times a day, once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, preferably once a week.

[0074] According to an embodiment of the present invention, the compound 1, its racemic form, stereoisomer, or pharmaceutically acceptable salt thereof, is administered simultaneously with an additional therapeutic agent.

[0075] According to an embodiment of the invention, the compound 1, its racemic form, stereoisomer, or pharmaceutically acceptable salt thereof, is administered at time intervals with an additional therapeutic agent.

[0076] According to an embodiment of the present invention, the subject is a mammal, preferably a human.

[0077] A third aspect of the invention provides a pharmaceutical composition or combination of pharmaceuticals comprising (a) the compound 1 of the invention, its racemic form, stereoisomer, or a pharmaceutically acceptable salt thereof; and (b) one or more additional therapeutic agents.

[0078] According to embodiments of the present invention, the pharmaceutical composition or combination of drugs further comprises a pharmaceutically acceptable carrier or excipient.

[0079] According to embodiments of the present invention, the pharmaceutical composition is suitable for preparation into formulations for intravenous infusion, intravenous drip, subcutaneous administration, intradermal administration, intramuscular injection, oral spray, oral administration, and in situ tumor administration.

[0080] According to embodiments of the present invention, the pharmaceutical composition is an oral preparation, such as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection, or concentrated solutions for injection), suppositories, inhalers, or sprays.

[0081] According to an embodiment of the invention, the additional therapeutic agent is as previously defined.

[0082] According to an embodiment of the present invention, the pharmaceutical composition is a unit dosage form, wherein the amount of component (a) is 0.1-1000 mg, and can be 0.1 mg, 0.3 mg, 0.5 mg, 0.7 mg, 0.9 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, etc. g, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 48 0mg, 490mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg.

[0083] According to an embodiment of the present invention, the pharmaceutical composition is a unit dosage form, wherein the amount of component (b) is 0.1-1000 mg, and can be 0.1 mg, 0.3 mg, 0.5 mg, 0.7 mg, 0.9 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, etc. g, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 48 0mg, 490mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg.

[0084] According to an embodiment of the present invention, in the pharmaceutical composition or combination of pharmaceuticals, the administration method, dosage, administration ratio, and administration frequency of component (a) or component (b) are adapted to the combined application portion of the aforementioned second aspect.

[0085] A fourth aspect of the invention provides the use of the pharmaceutical composition or combination of the third aspect in the preparation of a medicament for the prevention and / or treatment of HR-positive / HER2-negative breast cancer, colon cancer, or head and neck cancer.

[0086] A fifth aspect of the invention provides a reagent kit or manufactured product comprising the pharmaceutical composition or combination of drugs described in the third aspect of the invention. Beneficial effects

[0087] This invention demonstrates through in vivo animal experiments that compound 1 can inhibit the growth of HR-positive / HER2-negative breast cancer, colon cancer, and head and neck cancer cells. High doses of the compound can induce tumor regression in mice. Compound 1, when used in combination with CDK4 / 6 inhibitors or selective ER degraders, exhibits better therapeutic effects in HR-positive / HER2-negative breast cancer. The combined use is superior to monotherapy, and the safety profile is good. Attached Figure Description

[0088] Figure 1: Line graph showing the effect of T47D xenograft tumor on tumor volume in mice.

[0089] Figure 2: Line graph showing the effect of T47D xenograft on body weight in mice.

[0090] Figure 3: Schematic diagram of tumor weight in T47D xenograft mouse model.

[0091] Figure 4: Line graph showing the effect of Cal33 xenograft tumor model mice on tumor volume.

[0092] Figure 5: Line graph showing the effect of Cal33 xenograft tumor model mice on body weight.

[0093] Figure 6: Schematic diagram of tumor weight in Cal33 xenograft mouse model (**** indicates p<0.0001, data points represent the mean within the group, and error bars represent standard errors (SEM)).

[0094] Figure 7. Line graph showing the effect of tumor volume on the xenograft tumor model in GP2D mice.

[0095] Figure 8: Line graph showing the effect of body weight on the xenograft tumor model in GP2D mice.

[0096] Figure 9: Schematic diagram of tumor weight in GP2D mouse xenograft tumor model (**** indicates p<0.0001, data points represent within-group mean, error bars represent standard error (SEM)).

[0097] Terminology description or definition

[0098] The term "subject" in this article refers to an animal, such as a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cattle, and humans.

[0099] The term "therapeutic effective amount" or "effective amount" herein refers to the amount of a compound disclosed and / or described herein that, when administered to a patient in need of this treatment, is sufficient to achieve the treatment as defined herein. A therapeutically effective amount of a compound may be sufficient to treat HR-positive / HER2-negative breast cancer, colon cancer, or head and neck cancer with a PIK3CA mutation. The therapeutically effective amount will vary depending on factors such as the subject being treated and their disease condition, the subject's weight and age, the severity of the disease condition, the specific compound, the dosing regimen to be followed, the timing of administration, and the method of administration, all of which can be readily determined by one of ordinary skill in the art.

[0100] The term “treatment” in this article includes one or more of the following: suppressing a disease or condition; slowing or halting the development of clinical symptoms of a disease or condition; and / or alleviating a disease or condition (i.e., causing relief or resolution of clinical symptoms), and both complete or partial reduction of clinical symptoms of a disease or condition.

[0101] The term "therapeutic effect" in this article refers to the effect resulting from treatment, which at the cellular level manifests as an inhibition rate of cell growth or a cell death rate, and at the animal level manifests as an alteration, usually a reduction or improvement of the symptoms of a disease or disease condition, or a cure of a disease or disease condition.

[0102] In this article, "positive" can be represented by "+" and "negative" by "-". For example, "HR positive / HER2 negative" can also be represented as "HR+ / HER2-".

[0103] The term "pharmaceutically acceptable salt" in this document means that the compound can exist in various pharmaceutically acceptable salt forms. If the compound has a basic center, it can form an acid addition salt; if the compound has an acidic center, it can form a base addition salt; if the compound contains both an acidic and a basic center, it can also form an inner salt. Preferably, the pharmaceutically acceptable salt is selected from one or more of the following: sodium salt, potassium salt, hydrochloride salt, p-toluenesulfonate, maleate salt, methanesulfonate salt, and ethanesulfonate salt. Detailed Implementation

[0104] The present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0105] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0106] Preparation of Compound 1 in Example 1

[0107] Refer to Example 1 of PCT / CN2025 / 081622 or prepare it by the following method:

[0108] Step 1 (1-(cyanomethyl)-1H-pyrazole-4-yl)carbamate 1-1b

[0109] Under nitrogen protection, phenyl chloroformate (134.81 mg) was added to a 100 mg solution of tetrahydrofuran (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was then evaporated to dryness to give compound 1-1b (160 mg, crude product). The crude product was used directly in the next step. LCMS: (ESI, m / z): 243.1 [M+H] + ;

[0110] Step 2: (R)-1-(1-(cyanomethyl)-1H-pyrazol-4-yl)-3-(1-(5,7-difluoro-3-methylbenzofuran-2-yl)-2,2,2-trifluoroethyl)urea (compound 1)

[0111] Under nitrogen protection, crude compound 1-1b (110.46 mg) and N,N-diisopropylethylamine (147.33 mg) were added to a solution of 1-1c (100 mg) in dimethyl sulfoxide (6 mL) at room temperature, and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, backwashed with saturated brine (3 × 50 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (Waters 2767 / QDA, Column: Xbridge C18 19 × 250 mm, 10 μm; mobile phase A: 0.03% ammonia / water, mobile phase B: acetonitrile; flow rate: 20 mL / min; gradient: 51%–55%) to give compound 1 (42.37 mg).

[0112] LCMS:(ESI,m / z):414.1[M+H] +

[0113] 1 H NMR (400MHz, DMSO-d6) δ8.45(s,1H),7.88(s,1H),7.73(d,1H),7.50(s,1H),7.46-7.37(m,2H),6.09-5.98(m,1H),5.39(s,2H),2.30(s,3H).

[0114] Biological evaluation

[0115] Test Example 1: The purpose of this experiment is to determine the inhibitory effect of compound 1 on PI3Kα and PI3Kα(H1047R) using the ADP-Glo ​​luciferase luminescence detection method.

[0116] Experimental materials and instruments

[0117] A. Reagent Information

[0118] B. Consumables Information

[0119] C. Instrument Information

[0120] Experimental steps

[0121] a. Preparation of reaction buffer

[0122] For example, a 10 ml volume should be prepared and used immediately on the day of the experiment.

[0123] b. Compound preparation

[0124] The test compound was prepared into a 100x concentration stock solution using DMSO. The compound was then serially diluted using a multichannel electric pipette. 50 nL of the test compound was transferred to a 384-well microvolume plate using an automated micropipette system, Echo 550. Only 50 nL of 100% DMSO solution was added to the wells in the negative and positive control areas.

[0125] c. Experimental steps

[0126] PI3Kα and PI3Kα(H1047R) enzyme solutions and substrate mixtures were prepared using reaction buffer. The final concentrations of enzyme and substrate in the reaction solutions are as follows:

[0127] After compound transfer, add 2.5 μL of PI3Ks enzyme solution (compound wells and ZPE wells) or 2.5 μL of reaction buffer (HPE wells) to each well of the 384-well plate as shown in the diagram. Centrifuge at 1000 rpm for 1 minute, then place the 384-well plate in an incubator at 25°C for 10 minutes. After incubation, add 2.5 μL of substrate mixture to each well to start the reaction (total reaction volume 5 μL), and place the 384-well plate in an incubator at 25°C for 60 minutes. After the reaction was complete, 5 μL of ADP-Glo ​​reagent (Promega, #V9102, thawed and equilibrated to room temperature beforehand) was added to stop the reaction. The mixture was incubated at 25°C for 60 minutes. Then, 10 μL of Kinase Detection Substrate (Promega, #V9102, thawed and equilibrated to room temperature beforehand) was added to each well, centrifuged to mix, and then incubated at 25°C for 30 minutes. Fluorescence values ​​were read using an Envision 2104 multi-function plate reader. The reaction signal value read from each well was the raw data, and this raw data was used to analyze the half-maximal inhibitory concentration (WMC) of the compound on PI3K kinase.

[0128] Experimental results

[0129] This experiment used XLfit software, developed by IDBS and integrated into the Microsoft Excel environment, for test data processing and analysis. First, the average reaction signal values ​​of the positive and negative control wells were calculated. Then, the percentage inhibition rate of each compound well was calculated using the formula: "Inhibition rate per well = (Average negative control signal value - Average signal value per well) / (Average negative control signal value - Average positive control signal value) * 100%". Next, the concentration and corresponding inhibition rate data were imported into XLfit software. Using the Dose Response One Site 205 model in the software, a four-parameter method was employed to fit the inhibition rate-concentration curve, and the half-maximum inhibitory concentration (IC50) of the compound was calculated. 50 (Value), the results are shown in Table 1.

[0130] Table 1

[0131] Experimental conclusions

[0132] The data above show that compound 1 has good PI3Kα inhibitory activity.

[0133] Pharmacokinetic study of compound 1 in female BALB / c nude mice (Example 2)

[0134] Experimental methods

[0135] On the day of administration, the test substance was prepared using a solvent formulation of 20% PEG400 + 10% VE-TPGS + 70% HP-β-CD aqueous solution (10% HP-β-CD). The prepared administration solution was then ready for use.

[0136] Animals: Female BALB / c nude mice, 6–8 weeks old, weighing approximately 15–23 grams. A total of 10 mice (6 plus surplus) were provided by Zhejiang Vital River Laboratory Animal Technology Co., Ltd.

[0137] The oral gavage dose of PO is 100 mg / kg, with a concentration of 10 mg / mL. Animals should be fasted overnight, have free access to water, and be fed 4 hours after administration.

[0138] Before administration, weigh the animals and calculate the dosage based on their weight. Administer the medication orally via gavage once on the day of administration. After administration, collect blood via vein at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours. Collect approximately 0.03 mL of blood per time point. Anticoagulate with K2-EDTA in the blood collection tubes. Centrifuge the blood samples within 1 hour of collection to obtain plasma (centrifugation conditions: 6800g, 6 minutes, 2-8℃). Store the samples to be analyzed at -80℃ before analysis.

[0139] Sample preparation for LC-MS / MS assay: 12 μL of plasma sample was precipitated for protein using 240 μL of methanol containing 10 ng / mL internal standard (verapamil). The mixture was vortexed for 1 min and then centrifuged at 4000 rpm for 10 min. 200 μL of the supernatant was transferred to a 96-well plate. 1 μL of the supernatant was analyzed by LC-MS / MS.

[0140] The concentration of the test substance in the plasma of female BALB / c nude mice was determined using a validated LC-MS / MS method.

[0141] Experimental results

[0142] The results are shown in Table 2 below.

[0143] Table 2

[0144] Experimental conclusions

[0145] Compound 1 in BALB / c female nude mice C max The AUC is significantly better than that of the STX-478.

[0146] Test Example 3: Efficacy of Compound 1 in a subcutaneous tumor-bearing model of xxT47D established in female BALB / c nude mice.

[0147] Experimental methods

[0148] Cell culture: Human breast cancer xxT47D cells (ER+ / HER2-) were cultured in vitro under suitable conditions including 10% fetal bovine serum, 100 U / mL penicillin, 100 μg / mL streptomycin, and 1.5 μg / mL blastcin, incubated at 37°C in a 5% CO2 incubator. When cell saturation reached 80%-90%, cells in the logarithmic growth phase were harvested, counted, and seeded.

[0149] Animals: BALB / c female nude mice, 6–8 weeks old, weighing approximately 18–22 grams. A total of 30 mice (18 plus surplus mice) were provided by Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0150] Animal housing: Animals should be housed in the experimental environment for 3-7 days after arrival before experiments can begin. Animals are housed in SPF-grade animal facilities using IVC (Independent Ventilation and Air Conditioning) cages (6 animals per cage). All cages, bedding, and water must be sterilized before use. All personnel handling animals in the animal facility must wear protective clothing and latex gloves. Each cage's animal information card should indicate the number of animals in the cage, sex, strain, date of receipt, drug administration regimen, experiment number, group, and experiment start date. Cages, feed, and water are changed twice a week. The housing environment and lighting conditions are as follows:

[0151] √Temperature: 20~26℃

[0152] √Humidity: 40-70%

[0153] Feed composition: The feed meets the standards for laboratory animal food identification. The maximum level of contaminants is within a controllable range and is routinely tested by the manufacturer. Autoclaved drinking water is used.

[0154] Tumor inoculation: 2-3 days prior to inoculation, all mice were subcutaneously implanted with estrogen tablets (0.36 mg / 60-day release 17β-Estradiol). On the day of inoculation, 0.2 mL (10 × 10⁻⁶) of the estrogen solution was administered. 6 100 Matrigel T47D cells were subcutaneously inoculated into the right posterior dorsal region of mice. Tumors were cultured until the average volume reached 150-200 mm. 3 Animals were grouped and administered medication starting at approximately 10:00 AM. Animals were weighed and tumor volume measured before administration. Animals were randomly assigned to groups based on tumor volume (randomized block design). Experimental groupings and administration protocols are shown in Table 3.

[0155] Table 3. Animal grouping and dosing regimen for in vivo pharmacodynamic experiments of the xxT47D (ER+ / HER2-) subcutaneous tumor-bearing model.

[0156] Note: 1. N: Number of mice in each group; 2. Blank control and compound solvent: 20% PEG400 + 10% VE-TPGS + 70% HP-β-CD aqueous solution (10% HP-β-CD).

[0157] Observation: The use and welfare of laboratory animals will be conducted in accordance with the rules of the International Committee for Evaluation and Accreditation of Laboratory Animals (AAALAC). Animal health and mortality will be monitored daily. Routine checks will include observing the effects of tumor growth and drug treatment on daily behavior, such as activity levels, food and water intake, weight changes (twice weekly), physical appearance, or other abnormalities. The number of deaths and side effects within each group will be recorded based on the number of animals in each group.

[0158] Experimental indicators: The experimental indicators are used to examine whether tumor growth is inhibited, delayed, or cured. Tumor diameter is measured twice weekly using calipers. The formula for calculating tumor volume is: V = 0.5a × b 2 , where a and b represent the long and short diameters of the tumor, respectively.

[0159] The antitumor efficacy of the compound was evaluated using TGI (%) or relative tumor proliferation rate (T / C) (%). TGI (%) reflects the tumor growth inhibition rate. The calculation of TGI (%) is as follows: TGI (%) = [1 - (mean tumor volume at the end of treatment - mean tumor volume at the beginning of treatment) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the beginning of treatment in the solvent control group)] × 100%.

[0160] Tumor tissue was collected from each group 4 hours after drug administration for pharmacokinetic analysis. Plasma was also collected at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, and 24h for pharmacokinetic analysis. The average drug concentration ratio in plasma and tumor tissue at the 4h time point was calculated.

[0161] 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 tumor volume measured at the time of group administration (i.e., d0), V t T represents the tumor volume at a given measurement. RTV With C RTV Take data from the same day.

[0162] Tumor weight was measured and T was calculated after the experiment. weight / C weight Percentage, T weight and C weight The values ​​represent the tumor weight in the drug administration group and the solvent control group, respectively.

[0163] Experiment terminated if the animal's health condition continues to deteriorate, or if the tumor volume exceeds 2,000 mm. 3 If the patient has a serious illness or is in pain, euthanasia may be necessary.

[0164] Data analysis: T-tests were used for comparisons between two groups. One-way ANOVA was used for comparisons between three or more groups. Potential differences between different drug administration groups were analyzed using two-way ANOVA. All data were analyzed using Graphpad Prism. A p-value < 0.05 was considered statistically significant.

[0165] Experimental results

[0166] 1) The results of PK and TGI are shown in Table 4.

[0167] Table 4

[0168] Based on the above results, compound 1 demonstrates a good inhibitory effect on tumor growth in the xxT47D subcutaneous tumor-bearing model established in BALB / c nude mice. Compared to STX-478 (100 mpk), compound 1 showed significantly better tumor inhibition (TGI) at a lower dose (50 mpk) and lower systemic exposure (33149 h*ng / mL vs 46003 h*ng / mL) (1.03 vs 0.85). In conclusion, compound 1 exhibits better in vivo efficacy than STX-478.

[0169] 2) The results of the tumor-to-blood ratio are shown in Table 5.

[0170] Table 5

[0171] Compound 1 showed a significantly better tumor-to-blood ratio than STX-478 (2.66 vs 1.09), indicating that compound 1 had a higher exposure level in tumor tissue.

[0172] Test Example 4

[0173] In vivo pharmacodynamic studies of Palbociclib, Fulvestrant, and compound 1 in a human HR-positive / HER2-negative breast cancer T47D cell subcutaneous xenograft tumor model

[0174] 4.1 Experimental Objective

[0175] The purpose of this experiment was to investigate the in vivo efficacy of the test substances Palbociclib, Fulvestrant, and compound 1 in a subcutaneous xenograft tumor model of human HR-positive / HER2-negative breast cancer cells T47D established in female BALB / c Nude mice.

[0176] 4.2 Experimental Instruments and Materials

[0177] Using instruments

[0178] Use reagents

[0179] 4.3 Preparation method of test drug

[0180] The preparation method of the test drug is shown in Table 6.

[0181] Table 6. Preparation methods of test compounds

[0182] Note: Palbociclib and compound 1 should be prepared every three days, while Fulvestrant should be prepared fresh each time it is needed.

[0183] 4.4 Cell lines

[0184] The human breast cancer cells xxT47D were provided by Nantong WuXi AppTec Pharmaceutical Technology Co., Ltd.

[0185] 4.5 Species of experimental animals: mice; strain: BALB / c Nude mice; age: 6-9 weeks; sex: female; weight: 18-23 grams; quantity: 90 (42 mice remaining after grouping); supplier: Beijing Vital River Laboratory Animal Technology Co., Ltd.; animal qualification certificate number: 110011241102854565.

[0186] Animals were housed in the experimental environment for 3 days after arrival before the experiment began. Animals were housed in SPF-grade animal facilities using IVC (independent ventilation system) cages (6 animals per cage). All cages, bedding, and water were sterilized before use. Cages, feed, and water were changed twice a week. The housing environment and lighting conditions were as follows:

[0187] Temperature: 20-26℃

[0188] Humidity: 40-70%

[0189] Cage: Made of polycarbonate, dimensions 375mm × 215mm × 180mm. Bedding is corn cob, changed twice a week.

[0190] Food: Laboratory animals were allowed free access to food throughout the experimental period (sterilized by irradiation, dry granular food).

[0191] Drinking water: Laboratory animals may drink sterilized water freely.

[0192] Cage labeling: Animal information cards should indicate the number of animals in each cage, their sex, strain, date of receipt, administration regimen, experiment number, group, and start date of the experiment.

[0193] Animal identification: Laboratory animals are identified by ear tags.

[0194] 4.6 Establishment of animal models

[0195] xxT47D tumor cells were cultured in vitro in RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% antibiotic-antifungal agent, and incubated at 37°C in a cell culture incubator containing 5% CO2. Tumor cells were passaged twice weekly as routinely. Cells were washed with PBS. Cells were dispersed into single-cell suspensions using pipettes. Cell counting: 20 μL of cell suspension A was diluted with 980 μL of PBS, and 20 μL of single-cell suspension A was added to 20 μL of trypan blue (1:1). Cells were counted. Cells were resuspended in a mixture of PBS and Matrigel (1:1) at a density of 10 × 10⁻⁶ cells / mL. 6 1 cell / 0.2 mL.

[0196] 0.2 mL of xxT47D tumor cells (containing 10 × 10⁻⁶ cells) were added. 6 Cell suspension (PBS:Matrigel = 1:1) was subcutaneously inoculated into the right nape of each mouse's neck, and 17β-Estradiol tablets (0.36 mg, 60-day sustained release) were implanted 3 days prior to cell inoculation. Mice began requiring urination assistance on day 7 post-17β-Estradiol implantation. On day 7 post-cell inoculation, the average tumor volume reached 150 mmHg. 3 At that time, the mice were divided into groups and administered the drug (see Table 7 for details). Each group consisted of 6 mice.

[0197] Table 7. Animal grouping and dosing regimen for in vivo efficacy studies of xxT47D

[0198] Note: 1. N: Number of mice per group; 2. Dosage: Fulvestrant dosage for groups 3 and 6 was 5 mg / mouse; 3. Dosage volume: Calculated based on body weight (10 μL / g); 4. Dosage was administered on the same day as grouping; 5. Solvents: The solvent for the control group and compound 1 was 20% PEG400 + 10% VE-TPGS + 70% (10% HP-β-CD); the solvent for Palbociclib was 0.5% MC400; the solvent for Fulvestrant was 100% peanut oil; 6. QD: Once daily; QW: Once weekly.

[0199] The observations after drug administration, experimental indicators, the antitumor efficacy of the compound, and data analysis were the same as in test case 3. At the end of the experiment, the tumor weight (g) of the mice after treatment with the test substance was measured.

[0200] 4.7 Experimental Results

[0201] In this pharmacodynamic study, we examined the in vivo efficacy of the test compound, the cyclin-dependent kinase (CDK) 4 / 6 inhibitor Palbociclib, the selective estrogen receptor (ER) degrader Fulvestrant, and compound 1, as well as the combination of compound 1 with Palbociclib and compound 1 with Fulvestrant, in a human T47D subcutaneous xenograft tumor model, and the exposure of test compound 1 in plasma and tumor.

[0202] Figure 2 shows the weight change curves of mice in each group. The mice in each treatment group maintained good weight. Figure 1 shows the tumor volume of each group at different time points. On day 21 after the start of drug administration, the average tumor volume of tumor-bearing mice in the solvent control group reached 665 mmHg. 3 The treatment group of compound 1 showed a significant tumor-suppressing effect compared to the control group, with a statistically significant difference. In different groups, the tumor growth inhibition rate (TGI) after 21 days was 86%, 46%, and 100% when Palbociclib, Fulvestrant, and 50 mg / kg of compound 1 were used alone, respectively. When compound 1 was used in combination with Palbociclib and Fulvestrant, the TGIs were 118% and 117%, respectively. The combination treatment group of Palbociclib, Fulvestrant, and compound 1 showed a stronger tumor-suppressing effect than single-agent treatment, essentially achieving complete inhibition of tumor growth. The tumor weight of mice after treatment with the test substances is shown in Figure 3, demonstrating the efficacy of compound 1 as a single agent and in combination for tumor suppression.

[0203] Test Example 5

[0204] In vivo antitumor efficacy study of compound 1 against human tongue squamous cell carcinoma Cal33 cells in a CB-17SCID mouse xenograft model

[0205] 5.1 Experimental Objective

[0206] The purpose of this experiment was to investigate the antitumor efficacy of compound 1 in human tongue squamous cell carcinoma Cal33 cells in a CB-17SCID mouse xenograft tumor model.

[0207] 5.2 Experimental Instruments and Materials

[0208] Main experimental instruments

[0209] Main reagents

[0210] 5.3 Preparation method of test substance

[0211] Table 8. Preparation methods of test substances

[0212] Note: Prepare the medication twice a week, store at 2-8 degrees Celsius, and gently mix thoroughly before administering to animals.

[0213] 5.4 Cell lines

[0214] Human tongue squamous cell carcinoma Cal33 cells. Maintained and passaged by Shanghai Alamo Pharmaceutical Technology Co., Ltd.

[0215] 5.5 Laboratory Animals

[0216] Species: Mouse

[0217] Strain: CB-17SCID mice

[0218] Age and weight: 6-8 weeks old, weight 17-20 grams

[0219] Sex: Female

[0220] Quantity: 24 (excluding any remaining mice from the group)

[0221] Supplier: Vital River Laboratory Animal Co., Ltd.

[0222] Animal batch: 20240829

[0223] Animal Certificate Number: 20240828Abzz0619000388

[0224] Rearing environment (same as test case 4).

[0225] 5.6 Establishment of Animal Models

[0226] In vitro monolayer culture was performed using a medium containing 10% fetal bovine serum and DMEM at 37°C with 5% CO2. Cells were passaged two to three times per week using trypsin-EDTA at a passage ratio of 1:2 to 1:3. When cell saturation reached 80%-90%, the desired number was achieved, cells were harvested, counted, and seeded. 0.2 mL / 5 × 10⁵ cells were then seeded. 6 Cal33 cells (mixed 1:1 with Matrigel) were subcutaneously inoculated into the right posterior dorsal region of each mouse. Five days after tumor cell inoculation, the average tumor volume reached 137.95 mmHg. 3 Mice were randomly divided into four groups of six each, and were administered the drug on the day of grouping (see Table 9). The day of drug administration is recorded as D1.

[0227] Table 9. Grouping and Dosing Regimens of Animals Experimenting with In Vivo Drug Efficacy in the Cal33 Tumor Model

[0228] Note: 1. N: Number of mice per group; 2. Dosage volume: 10 μL / g based on mouse body weight. If body weight decreases by more than 15%, the dosing regimen should be adjusted accordingly.

[0229] The observations after drug administration, experimental indicators, the antitumor efficacy of the compound, and data analysis were the same as in test case 3. At the end of the experiment, the tumor weight (g) of the mice after treatment with the test substance was measured.

[0230] 5.7 Experimental Results

[0231] In this experiment, we evaluated the in vivo efficacy of the test substance in a human tongue squamous cell carcinoma Cal33 xenograft model. The effect of compound 1 on the body weight of human tongue squamous cell carcinoma Cal33 cells in a CB-17SCID mouse xenograft model is shown in Figure 5. At the end of the experiment, in the 100 mg / kg group of compound 1, on Day 22, 5 out of 6 animals experienced a body weight loss exceeding 10% but not exceeding 15%, falling within the drug-tolerant range.

[0232] Figure 4 shows the tumor volume of each group at different time points in this experiment. On day 22 after the start of drug administration, the average tumor volume of the control group Vehicle reached 2527.13 ± 119.02 mm. 3 .

[0233] In the oral administration group of compound 1, the dosages were 25 mg / kg, 50 mg / kg, and 100 mg / kg, respectively. After 21 consecutive days of administration, the mean tumor volume at the end of the experiment on day 22 was 1126.87 ± 123.7 mm. 3 363.08±67.88mm 3 and 86.87±15.64mm 3 The TGI values ​​were 58.69% (p<0.001 vs vehicle), 90.70% (p<0.001 vs vehicle), and 102.30% (p<0.001 vs vehicle), respectively. Compound 1 exhibited significant antitumor activity, and the antitumor effect showed a dose-dependent relationship.

[0234] The tumor weights of tumor-bearing mice after treatment with the test substance are shown in Figure 6. The mean tumor weight gradually decreased with increasing compound 1 dosage (from 25 mg / kg to 100 mg / kg). The compound 1 (100 mg / kg) group had the lowest mean tumor weight, approaching complete inhibition.

[0235] Test Example 6

[0236] Compound 1 exhibits in vivo antitumor activity against human colon cancer GP2d cells in a CB-17SCID mouse xenograft tumor model.

[0237] 6.1 Experimental Objective

[0238] The purpose of this experiment was to investigate the antitumor efficacy of compound 1 in human colon cancer GP2d cells in a CB-17SCID mouse xenograft tumor model.

[0239] 6.2 Experimental Instruments and Materials

[0240] Same as test case 5.

[0241] 6.3 Main test drugs and reagents

[0242] Same as test case 5.

[0243] 6.4 Cell lines

[0244] Human colon cancer GP2d cells were derived from ECACC (European Certified Cell Culture Collection Center). They were preserved and passaged by Shanghai Alamo Pharmaceutical Technology Co., Ltd.

[0245] 6.5 Laboratory Animals

[0246] Same as test case 5

[0247] 6.6 Establishment of Animal Models

[0248] In vitro monolayer culture was performed in DMEM medium containing 10% fetal bovine serum at 37°C with 5% CO2. Cells were routinely digested with trypsin-EDTA two to three times per week and passaged at a ratio of 1:2 to 1:3. When cell saturation reached 80%-90% and the desired number was achieved, cells were harvested, counted, and seeded. 0.2 mL / 5 × 10⁵ cells were then seeded. 6 GP2d cells (1:1 mixed with Matrigel) were subcutaneously inoculated into the right posterior dorsal region of each mouse. Six days after tumor cell inoculation, the average tumor volume reached 146.04 mm². 3 Mice were randomly divided into four groups of six each, and were administered the drug on the day of grouping (see Table 10). The day of drug administration was recorded as D1.

[0249] Table 10. Grouping and Dosing Regimens of Animals in the In vivo Drug Efficacy Experiment of the GP2D Tumor Model

[0250] Note: 1. N: Number of mice per group; 2. Dosage volume: 10 μL / g based on mouse body weight. If body weight decreases by more than 15%, the dosing regimen should be adjusted accordingly.

[0251] The observations after drug administration, experimental indicators, the antitumor efficacy of the compound, and data analysis were the same as in test case 3. At the end of the experiment, the tumor weight (g) of the mice after treatment with the test substance was measured.

[0252] 6.7 Experimental Results

[0253] In this experiment, we evaluated the in vivo efficacy of the test substance in a human colon cancer GP2d cell subcutaneous xenograft model. The effect of compound 1 on the body weight of human colon cancer GP2d cells in a CB-17SCID mouse xenograft model is shown in Figure 8. All doses of compound 1 were within the tolerable range.

[0254] Figure 7 shows the tumor volume of each group at different time points in this experiment. On day 22 after the start of drug administration, the average tumor volume of the control group Vehicle reached 1168.12 ± 72.36 mm. 3 In the oral administration groups of compound 1, the dosages were 25 mg / kg, 50 mg / kg, and 100 mg / kg, respectively. The low- and medium-dose groups were administered continuously for 22 days until the end of the experiment, and no weight loss was observed. In the high-dose group, prickly hair and weight loss began to appear on day 8 of administration; the treatment period for 6 mice ranged from 16 to 22 days. At the end of the experiment, the average tumor volume in the low, medium, and high-dose groups was 486.81 ± 35.92 mm. 3 354.05±22.14mm 3 and 327.18±29.42mm 3 The TGI values ​​were 66.54% (p<0.001 vs vehicle), 79.60% (p<0.001 vs vehicle), and 82.33% (p<0.001 vs vehicle), respectively. The tumor weights in each group after treatment with the test substance in tumor-bearing mice are shown in Figure 9. The average tumor weights in the three dosage groups of compound 1 (25 mg / kg, 50 mg / kg, and 100 mg / kg) were approximately 0.5 g, 0.3 g, and 0.3 g, respectively. The differences between each experimental group and the solvent group were highly statistically significant (P<0.0001), indicating that compound 1 significantly inhibited tumor weight. Therefore, the conclusion is that compound 1 has a significant antitumor effect, and the antitumor effect exhibits a dose-dependent relationship.

[0255] The above description provides an exemplary account of the implementation methods of the technical solution disclosed herein. It should be understood that the scope of protection of this disclosure is not limited to the above-described embodiments. Any modifications, equivalent substitutions, or improvements made by those skilled in the art within the spirit and principles of this disclosure should be included within the scope of protection of the claims of this application.

Claims

1. Use of Compound 1, its racemate, stereoisomer or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention and / or treatment of HR positive / HER2 negative breast cancer, colon cancer or head and neck cancer, wherein, The compound 1 has the following structure:

2. Use according to claim 1, characterized in that, The HR-positive / HER2-negative breast cancer, colon cancer, and head and neck cancer mentioned are PI3Kα-mediated diseases or symptoms; And / or, the HR-positive / HER2-negative breast cancer is HR-positive / HER2-negative breast cancer with PIK3CA mutation; And / or, the HR-positive / HER2-negative breast cancer is ER-positive / HER2-negative breast cancer; And / or, the HR-positive / HER2-negative breast cancer is HR-positive / HER2-negative breast cancer that has failed endocrine therapy; And / or, the HR-positive / HER2-negative breast cancer is HR-positive / HER2-negative advanced breast cancer that has failed endocrine therapy; And / or, the colon cancer is a PIK3CA-mutated colon cancer; And / or, the head and neck cancer is squamous cell carcinoma of the head and neck; And / or, the head and neck cancer is a PIK3CA-mutated squamous cell carcinoma of the head and neck; And / or, the head and neck cancer is a PIK3CA-mutated squamous cell carcinoma of the tongue.

3. Use according to claim 1, characterized in that, The HR-positive / HER2-negative breast cancer, colon cancer, and head and neck cancer are recurrent and / or metastatic.

4. The use according to any one of claims 1-3, characterized in that, The drug is a composition comprising a therapeutically effective amount of the compound 1, its racemate, stereoisomer, or a pharmaceutically acceptable salt thereof; or, the drug is a composition comprising a therapeutically effective amount of the compound 1, its racemate, stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. And / or, the drug is suitable for preparation into formulations for intravenous infusion, intravenous drip, subcutaneous administration, intradermal administration, intramuscular injection, oral spray, oral administration, or in situ tumor administration; And / or, the drug is prepared as an oral formulation, such as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection, or concentrated solutions for injection), suppositories, inhalers, or sprays; and / or, compound 1, its racemate, stereoisomer, or a pharmaceutically acceptable salt thereof, is prepared as a composition, wherein the composition optionally further comprises a pharmaceutically acceptable carrier or excipient; wherein, in the composition, compound 1, its racemate, stereoisomer, or a pharmaceutically acceptable salt thereof, is in a therapeutically effective amount; And / or, the composition or formulation is administered in combination with one or more additional therapeutic agents. And / or, the daily dose of the racemic mixture, stereoisomer, or pharmaceutically acceptable salt thereof of compound 1 is 0.1-1000 mg; And / or, the amount of compound 1 contained in the pharmaceutical unit formulation is 0.1-1000 mg, its racemic, stereoisomer, or pharmaceutically acceptable salt thereof.

5. The use according to any one of claims 1-4, characterized in that, In the drug, compound 1, its racemate, stereoisomer, or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional therapeutic agents; and / or, the drug is administered in combination with one or more additional therapeutic agents. The additional therapeutic agent is selected from one or more of CDK4 / 6 inhibitors, selective estrogen receptor (ER) degraders, AKT inhibitors, mTOR inhibitors, and HDAC inhibitors. The CDK4 / 6 inhibitor mentioned herein is selected from Palbociclib. The selective estrogen receptor (ER) degrader is selected from Fulvestrant. Wherein, the mass ratio of the racemic mixture, stereoisomer or pharmaceutically acceptable salt thereof of compound 1 to an additional therapeutic agent is 1:100 to 100:1, preferably 1:10 to 10:1; The combined application can be the simultaneous, separate, or time-interval application of the active substances. And / or, in the combined administration, the daily dose of compound 1, its racemic mixture, stereoisomer, or pharmaceutically acceptable salt thereof is 0.1-1000 mg; And / or, in the combined administration, the single dose of compound 1, its racemic mixture, stereoisomer or pharmaceutically acceptable salt thereof is 1-500 mg / kg; And / or, in the combined administration, the frequency of administration of compound 1, its racemic mixture, stereoisomer or pharmaceutically acceptable salt thereof, is as follows: three times daily, twice daily, once daily, once every two days, once every three days, once every four days, once every five days, once every six days, once weekly, once every two weeks, once every three weeks, or once every four weeks. And / or, in the combined administration, the single dose of the additional therapeutic agent is 1-1000 mg / kg; the dosing frequency is 3 times a day, 2 times a day, once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks; And / or, in the combined administration, the additional therapeutic agent is selected from CDK4 / 6 inhibitors (e.g., Palbociclib), with a single dose of 1-500 mg / kg, preferably 10-200 mg / kg; And / or, in the combined administration, the additional therapeutic agent is selected from selective estrogen receptor (ER) degraders (e.g., Fulvestrant), with a single dose of 1-1000 mg / kg.

6. A method for preventing and / or treating HR-positive / HER2-negative breast cancer, colon cancer, or head and neck squamous cell carcinoma, said method comprising administering to a subject a therapeutically effective amount of compound 1, its racemic mixture, stereoisomer, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound 1, its racemic mixture, stereoisomer, or a pharmaceutically acceptable salt thereof, or optionally a pharmaceutically acceptable carrier or excipient, wherein, The compound 1 has the following structure:

7. The method according to claim 6, characterized in that, The HR-positive / HER2-negative breast cancer, colon cancer, and head and neck cancer mentioned are PI3Kα-mediated diseases or symptoms; And / or, the HR-positive / HER2-negative breast cancer is HR-positive / HER2-negative breast cancer with PIK3CA mutation; And / or, the HR-positive / HER2-negative breast cancer is ER-positive / HER2-negative breast cancer; And / or, the HR-positive / HER2-negative breast cancer is HR-positive / HER2-negative breast cancer that has failed endocrine therapy; And / or, the HR-positive / HER2-negative breast cancer is HR-positive / HER2-negative advanced breast cancer that has failed endocrine therapy; And / or, the colon cancer is a PIK3CA-mutated colon cancer; And / or, the head and neck cancer is squamous cell carcinoma of the head and neck; And / or, the head and neck cancer is a PIK3CA-mutated squamous cell carcinoma of the head and neck; And / or, the head and neck cancer is a PIK3CA-mutated squamous cell carcinoma of the tongue; And / or, the HR-positive / HER2-negative breast cancer, colon cancer, and head and neck cancer are recurrent and / or metastatic.

8. The method according to claim 6 or 7, characterized in that, The compound 1, its racemate, stereoisomer, or pharmaceutically acceptable salt thereof, may be administered alone or in combination with one or more additional therapeutic agents. The additional therapeutic agent is selected from one or more of CDK4 / 6 inhibitors, selective estrogen receptor (ER) degraders, AKT inhibitors, mTOR inhibitors, and HDAC inhibitors. The CDK4 / 6 inhibitor mentioned herein is selected from Palbociclib. The selective estrogen receptor (ER) degrader is selected from Fulvestrant. The combined application can be the simultaneous, separate, or time-interval application of the active substances.

9. The method of claim 8, wherein, In the combined administration, the daily dose of compound 1, its racemic mixture, stereoisomer, or pharmaceutically acceptable salt thereof is 0.1-1000 mg; And / or, in the combined administration, the single dose of compound 1, its racemic mixture, stereoisomer or pharmaceutically acceptable salt thereof is 1-500 mg / kg; And / or, in the combined administration, the frequency of administration of compound 1, its racemic mixture, stereoisomer or pharmaceutically acceptable salt thereof, is as follows: three times daily, twice daily, once daily, once every two days, once every three days, once every four days, once every five days, once every six days, once weekly, once every two weeks, once every three weeks, or once every four weeks. And / or, in the combined administration, the single dose of the additional therapeutic agent is 1-1000 mg / kg; the dosing frequency is 3 times a day, 2 times a day, once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks; And / or, in the combined administration, the additional therapeutic agent is selected from CDK4 / 6 inhibitors (e.g., Palbociclib), with a single dose of 1-500 mg / kg, preferably 10-200 mg / kg; And / or, in the combined administration, the additional therapeutic agent is selected from selective estrogen receptor (ER) degraders (e.g., Fulvestrant), with a single dose of 1-1000 mg / kg; and / or, in the combined administration, the mass ratio of compound 1, its racemic form, stereoisomer, or pharmaceutically acceptable salt thereof, to the additional therapeutic agent is 1:100 to 100:1; The subjects are mammals, preferably humans.

10. A pharmaceutical composition or a pharmaceutical combination comprising (a) Compound 1, a racemate, a stereoisomer thereof or a pharmaceutically acceptable salt thereof; wherein, The compound 1 has the following structure: and (b) one or more additional therapeutic agents; The pharmaceutical composition or combination of pharmaceuticals may optionally further comprise a pharmaceutically acceptable carrier or excipient.

11. The pharmaceutical composition or combination of pharmaceuticals according to claim 10, characterized in that, The pharmaceutical composition is prepared into formulations for intravenous infusion, intravenous drip, subcutaneous administration, intradermal administration, intramuscular injection, oral spray, oral administration, and in situ tumor administration. And / or, the pharmaceutical composition is an oral preparation, such as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection, or concentrated solutions for injection), suppositories, inhalers, or sprays. The additional therapeutic agent is selected from one or more of CDK4 / 6 inhibitors, selective estrogen receptor (ER) degraders, AKT inhibitors, mTOR inhibitors, and HDAC inhibitors. The CDK4 / 6 inhibitor mentioned herein is selected from Palbociclib. The selective estrogen receptor (ER) degrader is selected from Fulvestrant. And / or, the pharmaceutical composition is a unit formulation, wherein the amount of component (a) is 0.1-1000 mg, and / or the amount of component (b) is 0.1-1000 mg; And / or, in the pharmaceutical composition or combination of pharmaceuticals, the single dose of compound 1, its racemic mixture, stereoisomer or pharmaceutically acceptable salt thereof, is 1-500 mg / kg; And / or, in the pharmaceutical composition or combination of drugs, the frequency of administration of compound 1, its racemic mixture, stereoisomer, or pharmaceutically acceptable salt thereof is 3 times daily, 2 times daily, 1 time daily, 2 times daily, 3 times daily, 4 times daily, 5 times daily, 6 times daily, once weekly, 2 times daily, 3 times daily, or 4 times daily; the administration lasts from 1 day to 7 weeks; And / or, in the pharmaceutical composition or combination of pharmaceuticals, the single dose of the additional therapeutic agent is 1-1000 mg / kg; the dosing frequency is 3 times a day, 2 times a day, once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks; And / or, in the pharmaceutical composition or combination of pharmaceuticals, the additional therapeutic agent is selected from CDK4 / 6 inhibitors (e.g., Palbociclib), with a single dose of 1-500 mg / kg, preferably 10-200 mg / kg; And / or, in the pharmaceutical composition or combination of pharmaceuticals, the additional therapeutic agent is selected from selective estrogen receptor (ER) degraders (e.g., Fulvestrant), with a single dose of 1-1000 mg / kg; and / or, in the composition, the mass ratio of compound 1, its racemic form, stereoisomer, or pharmaceutically acceptable salt thereof, to the additional therapeutic agent is 1:100 to 100:

1.

12. Use of the pharmaceutical composition or combination of pharmaceuticals according to claim 11 in the preparation of a medicament for the prevention and / or treatment of HR-positive / HER2-negative breast cancer, colon cancer, or head and neck cancer.

13. A kit or article of manufacture comprising the pharmaceutical composition or pharmaceutical combination of claim 12.

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