Use of AKT inhibitors in the manufacture of drugs to prevent or treat breast cancer

Abstract

This invention discloses the use of AKT inhibitors in the manufacture of drugs for the prevention or treatment of breast cancer. In particular, it provides the combination of an AKT inhibitor and fulvestrant in the manufacture of drugs for the prevention or treatment of breast cancer. The combination of an AKT inhibitor and fulvestrant can effectively inhibit the proliferation and colonization of breast cancer cells. The combination is clearly more effective than monotherapy, exhibits additive or synergistic effects, has lower toxicity and side effects to normal cells, is safer, and provides a more effective method for treating breast cancer, thus having significant clinical value.

Description

[Technical Field]

[0001] This application claims priority to Chinese Patent Application No. 2023107072372, filed on 14 June 2023, the entire contents of which are incorporated herein by reference.

[0002] This invention belongs to the field of biopharmaceuticals and, more specifically, relates to the use of AKT inhibitors in the manufacture of drugs for the prevention or treatment of breast cancer. [Background technology]

[0003] Cancer is the second leading cause of death after cardiovascular disease, and the number of cancer patients and deaths continues to increase worldwide. Among these, breast cancer is the most common malignant tumor in the world, and its incidence rate is increasing year by year, making it a "top killer" that threatens women's lives. Based on the driver genes of breast cancer, breast cancer is classified into six types: PI3K / Akt / mTOR-driven, growth factor receptor (ERBB2, EGFR, FGFR1)-driven, cell cycle factor (CCND1, CDK4, RB)-driven, ER-driven, and BRCA1 / 2-driven. This study found that the PI3K-Akt signaling pathway plays a crucial role in 60% of breast cancers. Due to the high activation rate and important role of PI3K / Akt, numerous PI3K / Akt inhibitors are approved for the treatment of breast cancer or are undergoing clinical trials for multiple types of breast cancer.

[0004] Targeted therapy specifically targets altered genes or proteins in tumor cells, offering advantages such as high specificity, remarkable efficacy, and low toxicity and side effects. It has become a new treatment option beyond the three traditional main treatments—surgery, radiation therapy, and chemotherapy—and has benefited a wide range of breast cancer patients.

[0005] AKT is a type of serine / threonine kinase that influences cell survival, growth, metabolism, proliferation, migration, and differentiation through numerous downstream effectors. Over 50% of human tumors exhibit AKT hyperactivation. AKT hyperactivation can lead to tumorigenesis, metastasis, and drug tolerance. AKT has three subtypes: AKT1, AKT2, and AKT3. Like typical protein kinases, each subtype consists of an amino-terminal PH domain (Pleckstrin homology domain), an intermediate ATP-binding kinase domain, and a carboxy-terminal regulatory domain. Approximately 80% of the amino acid sequences of the three subtypes are homologous, with only the linkage region between the PH domain and the kinase domain differing significantly. Therefore, inhibiting AKT activity can avoid the serious side effects associated with inhibiting upstream PI3K, and also avoid the negative feedback mechanism affecting drug efficacy caused by inhibiting downstream mTOR. Molecular targeted therapy targeting AKT is increasingly gaining attention and is a key direction in current tumor-targeted drug research and development.

[0006] WO2020156437A1 discloses a compound represented by formula (A), whose chemical name is (R)-4-((1S,6R)-5-((S)-2-(4-chlorophenyl)-3-(isopropylamino)propionyl)-2,5-diazabicyclo[4.1.0]hepta-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidine-7(6H)-one. Its chemical structure is shown in formula (A) below. [ka]

[0007] The compound represented by formula (A) is an AKT protein kinase inhibitor that effectively inhibits AKT kinase activity and is useful in the treatment of locally advanced or metastatic solid tumors. However, there have been no reports of the compound represented by formula (A) being used in combination with fulvestrant in the manufacture of drugs for the prevention or treatment of breast cancer. [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] The object of the present invention is to overcome the above-mentioned drawbacks and deficiencies of the prior art and to provide the use of AKT inhibitors in the manufacture of drugs for the prevention or treatment of breast cancer, and in particular to provide the use of a combination of AKT inhibitors and fulvestrant in the manufacture of drugs for the prevention or treatment of breast cancer. [Means for solving the problem]

[0009] To achieve the above objective, the present invention provides the following technical means.

[0010] The use of AKT inhibitors in the manufacture of drugs for the prevention or treatment of breast cancer, wherein the AKT inhibitor is a compound represented by formula (I) (hereinafter collectively referred to as formula (I) compounds) or a pharmaceutically acceptable salt or hydrate thereof. [ka]

[0011] In some embodiments, the compound of formula (I) is the compound of formula (A) or the compound of formula (B). [ka] [ka]

[0012] Furthermore, the present invention provides the use of AKT inhibitors in the manufacture of drugs for the prevention or treatment of breast cancer, wherein the AKT inhibitor is a compound represented by formula (A) (hereinafter collectively referred to as formula (A) compound) or a pharmaceutically acceptable salt or hydrate thereof.

[0013] In a preferred embodiment of the present invention, the breast cancer is hormone receptor-positive breast cancer.

[0014] In a preferred embodiment of the present invention, the breast cancer is HR-positive breast cancer.

[0015] In a preferred embodiment of the present invention, the breast cancer is HR-positive and HER-2-negative breast cancer.

[0016] In a preferred embodiment of the present invention, the breast cancer is ER-positive, PR-positive and HER-2-negative hormone receptor-positive breast cancer.

[0017] In a preferred embodiment of the present invention, the breast cancer is locally advanced or metastatic HR-positive and HER- negative breast cancer that has failed standard treatment.

[0018] In a preferred embodiment of the present invention, the breast cancer is locally advanced or metastatic HR-positive and HER-2-negative breast cancer that has failed standard treatment, with or without changes in the PI3K / Akt / PTEN pathway.

[0019] In a preferred embodiment of the present invention, the breast cancer is locally advanced or metastatic HR-positive and HER-2-negative breast cancer that has failed standard treatment and has changes in the PI3K / Akt / PTEN pathway.

[0020] In a preferred embodiment of the present invention, the breast cancer is locally advanced or metastatic HR-positive and HER-2-negative breast cancer that has failed standard treatment and has no changes in the PI3K / Akt / PTEN pathway.

[0021] In a preferred embodiment of the present invention, the compound of formula (A) is used in combination with fulvestrant.

[0022] In one embodiment of the present invention, the combined administration method is selected from being applied simultaneously, in parallel, independently, or sequentially.

[0023] In one embodiment of the present invention, the combined route of administration is selected from oral, parenteral, rectal, pulmonary, or topical administration, and the parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection.

[0024] In one embodiment of the present invention, the dosage of compound (A) is 0.1 to 1000 mg, specifically 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg, or 1000 mg, and selected from any two of the above values ​​(deemed to be explicitly stated even if not individually listed), preferably between 20 and 500 mg, more preferably 100, 200, 300, 400, or 500 mg, and even more preferably 300, 400, or 500 mg.

[0025] In one embodiment of the present invention, the administration frequency of the compound of formula (A) is once daily, twice daily, three times daily, once a week, once every two weeks, once every three weeks, once a month, 21+7 (with a 28-day cycle, once or twice daily for the first 21 days, followed by a 7-day rest period), 4+3 (with a 7-day cycle, once or twice daily for the first 4 days, followed by a 3-day rest period), or 5+2 (with a 7-day cycle, for the first 5 days The dosage may be once or twice a day, followed by a 2-day rest period, but it is preferable to have a dosage of once a day, twice a day, 21+7 (with a 28-day cycle, once or twice a day for the first 21 days, followed by a 7-day rest period), 4+3 (with a 7-day cycle, once or twice a day for the first 4 days, followed by a 3-day rest period), or 5+2 (with a 7-day cycle, once or twice a day for the first 5 days, followed by a 2-day rest period).

[0026] In one embodiment of the present invention, the administration frequency of the compound of formula (A) is once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, or once a month, and is preferably once a day or twice a day.

[0027] In one embodiment of the present invention, the compound of formula (A) is administered once, twice, or three times a day for 21 consecutive days, followed by an interval of 1 to 2 weeks during which the compound is not administered, or it is administered for 5 or 4 consecutive days, followed by an interval of 1 to 3 days during which the compound is not administered.

[0028] In one embodiment of the present invention, the administration frequency of the compound of formula (A) is once or twice daily for 21 consecutive days, followed by a 1-week interval between administrations of the compound; or it is administered for 5 consecutive days, followed by a 2-day interval between administrations of the compound; or it is administered for 4 consecutive days, followed by a 3-day interval between administrations of the compound.

[0029] In one embodiment of the present invention, the dose of fulvestrant is 0.1 to 800 mg, specifically 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg The dose is selected from mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 750 mg, or 800 mg, and any two of the above values ​​(even if not individually listed, they are considered to be explicitly stated), and the dose is preferably 20 to 500 mg, more preferably 100, 200, 300 mg, 400 mg, or 500 mg, and even more preferably 300, 400, or 500 mg.

[0030] In one embodiment of the present invention, the frequency of administration of fulvestrant may be once a day, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every two months, and preferably once every two weeks or once every four weeks.

[0031] In one embodiment of the present invention, the administration frequency of compound (A) is 21+7 (with a 28-day cycle, once or twice daily for the first 21 days, followed by a 7-day rest period), and the administration frequency of fulvestrant is once, with a 28-day cycle, administered two weeks after the first dose of the first cycle, and once on the first day of each subsequent cycle.

[0032] In one embodiment of the present invention, one cycle is 28 days, the compound of formula (A) is administered for 21 consecutive days with a one-week interval between each administration cycle, and fulvestrant is administered once two weeks after the first dose of the first cycle, and once on the first day of each subsequent cycle.

[0033] In one embodiment of the present invention, the dose ratio of compound (A) to fulvestrant is selected by mass ratio from 0.001 to 500:1, preferably 0.01:1, 0.1:1, 0.2:1, 0.5:1, 1:1, 1.5:1, 2:1, 3:1, 5:1, 8:1, 10:1, 12:1, 15:1, 18:1, 20:1, 30:1, 40:1, 50:1, 100:1, 130:1, 150:1, 180:1, 200:1, 220:1, 250:1, 300:1, 350:1, 400:1, or 500:1, and any two of the above values ​​(those not individually listed are deemed to be explicitly listed), and is preferably 0.001 to 100:1.

[0034] In one embodiment of the present invention, the compound of formula (A) and fulvestrant can be used alone or in combination with other therapeutic agents or therapies for cancer, such as other chemotherapy, hormones, antibodies, targeted drugs, and combination therapies with surgery and / or radiotherapy.

[0035] In one embodiment of the present invention, the compound of formula (A) may be administered to a patient as a free base or as a prodrug (which is converted to a free base in vivo), such as a pharmaceutically acceptable salt, hydrate, or fumarate. The compound of formula (A) or a salt thereof may be prepared by referring to the manufacturing method disclosed in WO2022017448A1.

[0036] In one embodiment of the present invention, the pharmaceutically acceptable salt of the compound of formula (A) is a monofumarate.

[0037] In one embodiment of the present invention, the pharmaceutically acceptable salt of the compound of formula (A) is a monofumarate dihydrate, which has the chemical name (R)-4-((1S,6R)-5-((S)-2-(4-chlorophenyl)-3-(isopropylamino)propionyl)-2,5-diazabicyclo[4.1.0]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidine-7(6H)-on fumarate dihydrate, and whose chemical structure is represented by formula (IA). [ka]

[0038] Furthermore, the present invention provides a combination of drugs or a drug composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, a fulvestrant, and one or more pharmaceutically acceptable carriers. [ka]

[0039] In some embodiments, the compound of formula (I) is the compound of formula (A) or the compound of formula (B). [ka] [ka]

[0040] Furthermore, the present invention provides a combination of drugs comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, a fulvestrant, and one or more pharmaceutically acceptable carriers.

[0041] In the aforementioned drug combination or drug composition, the method of administration, dosage, frequency of administration, and proportion of compound (A) and / or fulvestrant are selected in accordance with the above-mentioned combination.

[0042] Furthermore, the present invention provides a drug composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, a fulvestrant, and one or more pharmaceutically acceptable carriers.

[0043] A drug composition comprising the compound of formula (A) and fulvestrant as described in the present invention can be formulated into any pharmaceutically acceptable dosage form. For example, it can be formulated as a tablet, capsule, pill, granule, solution, suspension, syrup, injection (including injection solution, sterile powder for injection, and concentrate for injection), suppository, inhalant, or spray.

[0044] A drug composition comprising the compound of formula (A) and fulvestrant of the present invention may also be administered to a patient or subject requiring this treatment by any suitable method of administration, such as orally, parenterally, rectally, pulmonaryly, or topically. When used for oral administration, the drug composition may be formulated into oral solid dosage forms such as tablets, capsules, pills, granules, or oral liquid formulations such as oral liquid formulations, oral suspensions, or syrups. When formulated into oral formulations, the pharmaceutical formulation may contain appropriate fillers, binders, disintegrants, lubricants, etc.

[0045] The drug composition comprising the compound of formula (A) of the present invention and fulvestrant may be administered alone or in combination with other therapeutic agents or treatments for breast cancer other than fulvestrant, such as other chemotherapy, hormones, antibodies, targeted therapies, and combination therapy with surgery and / or radiotherapy.

[0046] The present invention also provides a method for preventing or treating breast cancer, comprising administering a therapeutically effective amount of compound (A) and fulvestrant to a patient.

[0047] The present invention also provides a method for preventing or treating breast cancer, comprising administering to a patient a therapeutically effective amount of a drug composition containing a compound of formula (A) and fulvestrant. [Effects of the Invention]

[0048] The beneficial effects of the invention are as follows:

[0049] This invention provides the use of a combination of an AKT inhibitor and fulvestrant in the manufacture of drugs for the prevention or treatment of breast cancer. This combination can effectively inhibit the proliferation and colonization of breast tumor cells. The combination is significantly more effective than monotherapy, exhibiting additive or synergistic effects, and also has lower toxicity and side effects to normal cells, resulting in higher safety and providing a more effective method for treating breast cancer, thus possessing significant clinical value.

[0050] Related definitions

[0051] Unless otherwise specified, the following terms used in this specification and in the claims shall have the meanings set forth below.

[0052] "Combined use" as used herein refers to a method of administration that includes various situations in which two drugs are administered sequentially or simultaneously. This means administering at least one dose of compound (A) and at least one dose of fulvestrant in any way within a specified period. This period may be within an administration cycle, and compound (A) and fulvestrant may be administered simultaneously or sequentially. The aforementioned any method includes administering compound (A) and fulvestrant via the same or different routes of administration. For example, in one embodiment, one or more doses of compound (A) are administered simultaneously or separately with one or more doses of fulvestrant. In one embodiment, multiple doses of compound (A) are administered simultaneously or separately with multiple doses of fulvestrant. In one embodiment, multiple doses of compound (A) are administered simultaneously or separately with a single dose of fulvestrant. In one embodiment, a single dose of compound (A) is administered simultaneously or separately with multiple doses of fulvestrant. In one embodiment, a single dose of compound (A) is administered simultaneously or separately with a single dose of fulvestrant. In all embodiments, the compound of formula (A) may be administered first, or fulvestrant may be administered first. The term "simultaneous administration" refers to administering two or more drugs to a patient at the same time or in very close succession. The term "concurrent administration" refers to administering two or more drugs within the same period (e.g., on the same day), but not necessarily simultaneously. The term "independent administration" refers to administering one drug independently over a period of time, such as several days or a week, and then administering other drugs independently over a different period. The term "sequential administration" refers to administering drugs to a patient in a specific order, where each drug is administered after the previous drug, forming an ordered sequence.

[0053] The term "oral administration" here refers to taking a drug by oral ingestion. The drug is absorbed from the digestive tract into the bloodstream and then distributed throughout the body or acts on specific organs.

[0054] In this context, "parenteral administration" refers to methods of administration that do not pass through the gastrointestinal tract, such as subcutaneous injection, intramuscular injection, and intravenous injection.

[0055] In this context, the term "rectal administration" refers to a method in which a drug is delivered to the rectum through the anus, and then absorbed into the bloodstream through the rectal mucosa.

[0056] In this context, the term "pulmonary administration" refers to the delivery of a drug directly to the lungs through inhalation, where the drug is absorbed into the bloodstream via the alveoli.

[0057] In this context, the term "local administration" refers to administering a drug by directly applying or coating it to epidermal tissue, including the skin and mucous membranes of the mouth and vagina.

[0058] The terms "to use in combination with..." or "to use in combination with..." as used herein do not mean that the therapies or therapeutic agents must be formulated to be physically mixed or administered simultaneously and / or delivered together, although such delivery methods are within the scope of those described herein. The therapeutic agents in these combinations may be administered before or after one or more other additional therapies or therapeutic agents. The therapeutic agents may be administered in any order. Generally, each therapeutic agent is administered in the dose and / or administration plan determined for that therapeutic agent. It should also be understood that additional therapeutic agents used in combination may be administered together as a single composition or separately as different compositions. Generally, additional therapeutic agents used in combination are intended to be used at levels not exceeding those used when used alone. In one embodiment, the level used in combination is lower than the level used in monotherapy.

[0059] The terms “combined use” or “in combination” as used herein refer to the use of a compound having formula (A) or a pharmaceutically acceptable salt thereof together with fulvestrant. Depending on the intended dosage and frequency of administration, the two compounds may be administered together or separately. The dosage and frequency of administration may vary depending on the compounds used and the specific medical condition being treated. Generally, it is preferable to use the smallest dose sufficient to provide effective treatment, which may be determined by criteria such as the patient’s age, weight, sex, stage and severity of the cancer being treated, and the judgment of the treating physician. Efficacy can generally be monitored by determining the optimal dosage using assays appropriate to the medical condition being treated, or by using standard tests and procedures well known in the art. For example, a single bolus dose may be administered, divided doses may be administered over time, or the dose may be proportionally reduced or increased depending on the emergency situation in the treatment setting. These assays are well known to those skilled in the art. Furthermore, it should be understood that the therapeutic combinations of the present invention can be administered via any appropriate route, and the route of administration may vary, for example, depending on the health status of the recipient of the combination and the cancer being treated.

[0060] The term "drug composition" as used herein refers to a mixture comprising at least one therapeutic agent and at least one pharmaceutically acceptable carrier, the "pharmaceutically acceptable carrier" including, but not limited to, diluents, binders, disintegrants, and lubricants.

[0061] In this context, "dosage" refers to the amount of therapeutic drug. For example, if a 2 mg dose of compound (A) is administered, and the compound (A) is administered in the form of a tablet containing the fumarate of compound (A), then the tablet will contain an amount of compound (A) fumarate equivalent to 2 mg of compound (A).

[0062] The term "salt" as used herein may exist alone or as a mixture with the free compound of the present invention, and preferably refers to a pharmaceutically acceptable salt. The "pharmaceutically acceptable salt" refers to an organic or inorganic salt commonly used in pharmaceuticals, and includes, but is not limited to, fumarate, methanesulfonate, hydroxyethanesulfonate, α-naphthalenesulfonate, p-toluenesulfonate, 1,2-ethanedisulfonate, oxalate, maleate, citrate, succinate, L-(+)-tartrate, hippurate, L-ascorbate, L-malate, benzoate, or gentisinate, and includes, but is not limited to, hydrochloride, sulfate, or phosphate, and is not limited to these, and refers to, but is not limited to these. In one embodiment, the "pharmaceutically acceptable salt" is a fumarate, preferably a monofumarate, more preferably a monofumarate hydrate, and even more preferably a monofumarate dihydrate.

[0063] In the term "HR-positive (Hormone Receptor) breast cancer," "HR" refers to hormone receptors. Hormone receptors include estrogen receptors (ER) and progesterone receptors (PR).

[0064] In this context, "HER-2 negative breast cancer" refers to breast cancer that is negative for Human Epidermal Growth Factor Receptor 2 (HER2).

[0065] "Failure to standard treatment" as used here means having previously received endocrine therapy and having (a) radiological evidence of recurrence or progression of breast cancer during or within 12 months of the completion of (new) adjuvant endocrine therapy, or (b) having received endocrine therapy for locally advanced or metastatic breast cancer and having radiological evidence of progression during or after treatment.

[0066] In this context, "locally advanced" means that the tumor is limited to the primary organ or adjacent tissue organs, but the time to onset is long, the tumor is relatively large, and there has been no metastasis to distant organs. According to the NCCN (National Comprehensive Cancer Network) guidelines, locally advanced breast cancer is stage III breast cancer, and is divided into resectable locally advanced breast cancer (cT3N1M0) and inoperable locally advanced breast cancer (cT3N1M0, and stages IIIB and IIIC). In one embodiment, locally advanced breast cancer is inoperable locally advanced breast cancer (cT3N1M0, and stages IIIB and IIIC).

[0067] The term “therapeutic dose” as used herein refers to an amount sufficient to improve or prevent the symptoms or condition of a disease. In the case of cancer, a therapeutic dose of a drug may reduce the number of cancer cells, shrink the size of the tumor, inhibit (i.e., delay, preferably block) the invasion of cancer cells into surrounding organs, inhibit (i.e., delay, preferably block) tumor metastasis, inhibit tumor growth to some extent, and / or alleviate to some extent one or more symptoms associated with the disease. A drug may be cytoinhibitory and / or cytotoxic to the extent that it can inhibit the growth of existing cancer cells and / or kill existing cancer cells. In cancer treatment, efficacy in vivo can be measured by evaluating survival time, progression-free survival (PFS), response rate (RR), duration of response, and / or quality of life.

[0068] In this context, "MTD" refers to the maximum tolerance level.

[0069] "DLT" as used herein is defined as the following toxic reactions related to the investigational drug (including cases where it is definitely related, very likely related, or potentially related) that occur in subjects in each treatment group from the start of administration to the end of the first course of treatment (a total of 28 days): (1) Hematological toxicity: Grade 4 neutropenia lasting more than 3 days, Grade 3 or higher febrile neutropenia, Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with bleeding, or Grade 4 anemia. (2) Non-hematological toxicity: Grade 4 non-hematological toxicity, Grade 3 non-hematological toxicity that does not improve to Grade 2 or below within 3 days post-treatment (excluding simple laboratory abnormalities that do not require intervention by the principal investigator and do not present with clinical symptoms, excluding hyperglycemia), Grade 4 hyperglycemia with blood glucose > 27.8 mmol / L or 500 mg / dL; Grade 3 hyperglycemia with blood glucose exceeding 13.9 mmol / L or 250 mg / dL and persisting for more than 7 days post-treatment; (3) Other toxic reactions that the principal investigator determines require permanent discontinuation of the investigational drug, or in which the total dose of the investigational drug administered during the DLT observation period is less than 75% of the scheduled dose.

[0070] In this context, "RP2D" refers to the dose recommended in Phase II clinical trials.

[0071] In this context, "objective response rate (ORR)" is defined as the percentage of subjects who achieved complete remission (CR) or partial remission (PR) of their tumor after treatment.

[0072] In this context, "disease control rate (DCR)" is defined as the percentage of subjects who achieved complete remission (CR), partial remission (PR), or stable disease (SD) after treatment.

[0073] In this context, "Duration of Response (DOR)" is defined as the time from the start of recording objective response until the first occurrence of tumor progression or death from any cause.

[0074] In this context, "progression-free survival (PFS)" is defined as the time from the start of treatment until the first occurrence of tumor progression or death from any cause.

[0075] In this context, "OS" refers to overall survival, defined as the time from the start of randomization until the patient dies from any cause.

[0076] The "ECOG Performance Status Score" referred to here is the Eastern Cooperative Oncology Group (ECOG) Performance Status Score (Zubrod-ECOG-WHO, ZPS, 5-point scale), an important indicator for evaluating the overall condition of cancer patients. It is useful for predicting patient prognosis and estimating patient tolerance to various treatments, and is an important parameter in many prognostic evaluation systems.

[0077] In this context, "AE incidence rate" refers to adverse events in the medical field, that is, medical adverse events that occur after a patient or clinical trial subject is administered a drug.

[0078] The term "synergistic effect" used here refers to the phenomenon where the combined effect of two drugs is more effective than the individual effects of the two drugs, in contrast to the antagonistic effect.

[0079] The compounds of formula (I) or formula (A) disclosed herein are effective AKT inhibitors, and methods for producing them are disclosed in international application WO2020156437A1. The term “compound” as used herein includes all stereoisomers and tautomers.

[0080] The compounds of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise specified, this includes all stereoisomers, such as enantiomers and diastereomers. Compounds containing an asymmetric carbon atom of the present invention can be isolated in the form of optically active pures or racemates. Optically active pures can be separated from racemic mixtures or synthesized using chiral starting materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included within the scope of the present invention.

[0081] The term "fulvestrant" as used herein includes its stereoisomers, solvates, or pharmaceutically acceptable salts.

[0082] In this specification, unless otherwise specified, when referring to the amount of compound (A) or fulvestrant, the amount refers to the amount of the active compound (free base). Even when applied in pharmaceutically acceptable forms such as salts or hydrates, it is understood that the amounts or ratios of both can be determined based on the amount of the active compound. [Modes for carrying out the invention]

[0083] The following typical examples illustrate the present invention and are used to demonstrate the advantageous activity or beneficial technical effect of the compositions of the present invention. However, it should be understood that the following test plans are merely illustrative of the content of the present invention and do not limit the scope of the invention. Any simple substitutions or modifications made by those skilled in the art to the present invention are technical solutions protected by the present invention.

[0084] Example 1: Experiment on the inhibition of breast cancer cell proliferation by compound (A) alone or in combination with fulvestrant.

[0085] 1. Experimental Objective: To evaluate the effects of compound (A) alone or in combination with fulvestrant on the proliferation of five cell lines.

[0086] 2. Experimental Method

[0087] 2.1 Cell culture a) BT-474 cells were cultured in Hybri-Care medium containing 1% diabody (penicillin-streptomycin) and 10% FBS at 37°C and 5% CO2. b) MCF-7 cells were cultured in EMEM medium containing 1% penicillin-streptomycin, 0.01 mg / mL insulin, and 10% FBS at 37°C and 5% CO2. c) ZR-75-1 cells were cultured in RPMI-1640 medium containing 1% penicillin-streptomycin and 10% FBS at 37°C and 5% CO2. d) T47D cells were cultured in RPMI-1640 medium containing 1% penicillin-streptomycin, 0.2 U / mL insulin, and 10% FBS at 37°C and 5% CO2. e) CAMA-1 cells were cultured in EMEM medium containing 1% penicillin-streptomycin and 10% FBS at 37°C and 5% CO2.

[0088] 2.2 Cell Plating a) Cells were cultured as usual until cell saturation reached 80%–90% and the required number was reached, and then harvested. b) Cells were resuspended in appropriate culture medium, and the cells were counted to prepare a cell suspension of appropriate density. c) 40 μL of the cell suspension was added to each well of a 384-well plate.

[0089] Table 1: Plating density of different cell systems [Table 1] d) Cells were cultured overnight in a 5% CO2 incubator at 37°C.

[0090] 2.3 Preparation of Compounds a) Compound (A) was diluted threefold to 10 different concentrations, starting from 60 mM (using monofumaric acid dihydrate of compound (A), with concentrations based on the free base of compound (A). Compound (A) or its salts were prepared according to the manufacturing method disclosed in WO2022017448A1). b) Fulvestrant was diluted with DMSO from 10 mM to 2 mM, then threefold to 10 different concentrations. c) Fulvestrant was diluted with DMSO from 2 mM to 0.2 mM, then threefold to 10 different concentrations. d) Fulvestrant was diluted with DMSO from 0.2 mM to 2 μM. e) Fulvestrant was diluted with DMSO from 2 μM to 0.8 μM. f) Fulvestrant was diluted with DMSO from 2 μM to 0.3 μM. g) Fulvestrant was diluted with DMSO from 0.8 μM to 0.08 μM. h) The final concentration of DMSO was 0.1%. i) DMSO was added to cells and used as a high-readability control well. j) Culture medium without cells was used as a low-readability control well.

[0091] 2.4 Compound treatment of cells

[0092] a) Monotherapy: The compounds were used individually 24 hours after plating BT474 cells and ZR-75-1 cells. For compound (A), 20 nL of the compound prepared in step 2.3a) + 20 nL of DMSO was added. For compound fulvestrant, 20 nL of the compound prepared in step 2.3b) + 20 nL of DMSO was added. The compounds were used individually 24 hours after plating MCF-7 cells, T47D cells, and CAMA-1 cells. For compound (A), 20 nL of the compound prepared in step 2.3a) + 20 nL of DMSO was added. For compound fulvestrant, 20 nL of the compound prepared in step 2.3c) + 20 nL of DMSO was added.

[0093] b) Concomitant administration: 24 hours after plating BT474 cells and ZR-75-1 cells, compound (A) was used in combination with fulvestrant: 20 nL of the compound prepared in step 2.3a) + 20 nL of the compounds prepared in steps 2.3b) and d). Twenty-four hours after plating MCF-7 cells, compound (A) was administered in combination with fulvestrant: 20 nL of the compound prepared in step 2.3a) + 20 nL of the compounds prepared in steps 2.3c), e), and f). Twenty-four hours after plating T47D cells, compound (A) was administered in combination with fulvestrant: 20 nL of compound prepared in step 2.3a) + 20 nL of compound prepared in steps 2.3c), e), and g). 24 hours after plating CAMA-1 cells, compound (A) and fulvestrant were used in combination: 20 nL of the compound prepared in step 2.3a) + 20 nL of the compound prepared in step 2.3c).

[0094] c) Detection of the final concentration of the compound:

[0095] 1)BT474, ZR-75-1 cells: Gradient concentration formula (A)(nM): 30000, 10000, 3333, 1111, 370, 123, 41.2, 13.7, 4.57, 1.52 nM Point-to-point combination with fulvestrant (nM): 1000, 333, 111, 37, 12.3, 4.1, 1.37, 0.46, 0.15, 0.05. Each was used in combination with compound (A) of the gradient concentration formula. In combination with fulvestrant at single concentrations (nM): 1000, 1, and each was used in combination with compound (A) of the gradient concentration formula.

[0096] 2)MCF-7 cells: Formula (A) compound (nM): 30000, 10000, 3333, 1111, 370, 123, 41.2, 13.7, 4.57, 1.52 Point-to-point combination with fulvestrant (nM): 100, 33.3, 11.1, 3.7, 1.23, 0.41, 0.14, 0.046, 0.015, 0.005. Each was used in combination with the compound of formula (A) for gradient concentration. The compounds were used in combination with fulvestrant at single concentrations (nM): 0.4 and 0.15, each with a gradient concentration of compound (A).

[0097] 3)T47D cells: Formula (A) compound (nM): 30000, 10000, 3333, 1111, 370, 123, 41.2, 13.7, 4.57, 1.52 Point-to-point combination with fulvestrant (nM): 100, 33.3, 11.1, 3.7, 1.23, 0.41, 0.14, 0.046, 0.015, 0.005. Each was used in combination with the compound of formula (A) for gradient concentration. The compounds were used in combination with fulvestrant at single concentrations (nM): 0.4 and 0.04, each with a gradient concentration formula (A).

[0098] 4) CAMA-1 cells: Formula (A) compound (nM): 30000, 10000, 3333, 1111, 370, 123, 41.2, 13.7, 4.57, 1.52 Point-to-point combination with fulvestrant (nM): 100, 33.3, 11.1, 3.7, 1.23, 0.41, 0.14, 0.046, 0.015, 0.005. Each was used in combination with the compound of formula (A) for gradient concentration. In combination with fulvestrant at single concentrations (nM): 1.2 and 0.14, each was used in combination with the compound of formula (A) for gradient concentration. d) The cell culture plates were centrifuged at 1000 rpm for 1 minute and left in a 37°C, 5% CO2 incubator for 7 days.

[0099] 2.5 Detection by CTG method a) 40 μL of CTG reagent (CelltiterGlo kit) was added to each well, shaken on a high-speed shaker for 2 minutes, centrifuged at 1000 rpm for 1 minute, and left at room temperature in the dark for 30 minutes. b) Chemiluminescence signal values ​​were read using an Envision instrument.

[0100] 2.6 Data Analysis Using the inhibition rate data obtained in section 2.4, measured with single agents or single concentrations in combination, IC was performed using GraphPad Prism 8 software. 50 The IC of the compound was calculated using the following nonlinear fitting equation. 50 The (median inhibitory concentration) was obtained: Y = minimum value + (maximum value - minimum value) / (1 + 10^((LogIC) 50 -X)*slope)) X: Log value of compound concentration, Y: Inhibition rate (% inhibition) Inhibition rate (% inhibition) = 100 - (Reading in compound well - Low reading control reading) / (High reading control reading - Low reading control reading) * 100

[0101] 2.7 Cell proliferation activity IC 50 Cell proliferation activity IC 50 The measurement results are shown in Tables 2-5 below.

[0102] Table 2: Results of studies on the inhibitory effect of compound (A) and fulvestrant on the proliferation of BT-474 and ZR-75-1 cells. [Table 2] Note: *Maximum inhibition rate is measured using GraphPad Prism 8 software for IC 50 This is the maximum value that is automatically fitted when calculating it.

[0103] Table 3: Results of studies on the inhibitory effect of compound (A) and fulvestrant on the proliferation of MCF-7 cells. [Table 3] Note: *The maximum inhibition rate is the maximum value automatically fitted when calculating IC using GraphPad Prism 8 software. 50

[0104] Table 4: Results of the study on the inhibitory effect of the combination of the compound of formula (A) and fulvestrant on the proliferation of T47D cells. [Table 4] Note: *The maximum inhibition rate is the maximum value automatically fitted when calculating IC using GraphPad Prism 8 software. 50

[0105] Table 5: Results of the study on the inhibitory effect of the combination of the compound of formula (A) and fulvestrant on the proliferation of CAMA-1 cells. [Table 5] Note: *The maximum inhibition rate is the maximum value automatically fitted when calculating IC using GraphPad Prism 8 software. 50

[0106] Conclusion: The compound of formula (A) alone and in combination with fulvestrant showed excellent in vitro anti-cell proliferation effects in all five cell lines (BT-474, MCF-7, ZR-75-1, T47D, CAMA-1).

[0107] 2.8 Evaluation Index (Synergy.score) of Compound Combination ​​​Detection method: The inhibition rate data measured by the combined use of point-to-point in Section 2.4 was imported and uploaded to a specific calculation template on the SynergyFinder website (https: / / tangsoftwarelab.shinyapps.io / synergyfinder / #! / dashboard), and the analysis of the combination index was performed.

[0108] Evaluation criteria: Synergy.score < -10: The interaction between the two compounds is antagonistic. -10 < Synergy.score < 10: The interaction between the two compounds is additive. Synergy.score > 10: The interaction between the two compounds is synergistic.

[0109] The evaluation index for the specific combination of compounds is as shown in the following table.

[0110] Table 6: Combination index of compounds in different cell lines

Table 6

[0111] Example 2: Study on the tumor inhibition rate in the treatment of a subcutaneous xenograft model of MCF-7 human breast cancer by the combination of the compound of formula (A) and fulvestrant

[0112] 1. Experimental purpose: The purpose of this study is to evaluate the effectiveness of the combination of the compound of formula (A) and fulvestrant in a subcutaneous xenograft model of MCF-7 human breast cancer in female BALB / c nude mice.

[0113] 2. Experimental materials and equipment

[0114] 2.1 Experimental animals: BALB / c nude mice, 6~8 weeks, female, weight 18~20g, purchased from Beijing Ankai Yibo Biotechnology Co., Ltd., breeding environment: SPF grade, temperature: (23±3)℃, humidity: 40~70%.

[0115] 2.2 Test Samples

[0116] 2.2.1 Selection of Solvent:

[0117] Solvent of compound (A): 1,2-propanediol (PG): 50% Solutol HS-15: 0.5% hydroxypropyl methylcellulose (HPMC) = 2:1:7.

[0118] 2.2.3 The preparation method is as shown in the table below.

[0119] Table 7: Methods for preparing compounds [Table 7]

[0120] 3. Experimental Methods and Procedures

[0121] 3.1 Cell culture MCF-7 tumor cells were cultured in DMEM medium containing inactivated 15% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin in a 37°C, 5% CO2 incubator. Tumor cells in the logarithmic growth phase were used for in vivo tumor inoculation.

[0122] 3.2 Inoculation and grouping of tumor cells One day before inoculation with MCF-7 tumor cells, an estrogen tablet (0.5 mg, release period 90 days) was implanted subcutaneously on the left side of the mice. MCF-7 tumor cells, resuspended in serum-free DMEM medium, were then implanted subcutaneously in 1.5 × 10⁶ units of the right rib region of the experimental animals. 7 (0.2 mL + Matrigel) was administered to a total of 72 animals. The tumor was 204 mm. 3Forty-eight animals with relatively uniform tumor volumes that had grown to a certain extent were selected and divided into four groups for administration. Administration was carried out according to the administration plan.

[0123] Table 8: Compound Dosage Plan [Table 8] Note: po indicates oral administration. sc indicates subcutaneous injection administration. QD×4 weeks indicates administration once daily for 4 consecutive weeks. QW×4 weeks indicates administration once weekly for 4 consecutive weeks.

[0124] 3.3 Detection Indicators

[0125] 3.3.1 Tumor Volume: The tumor volume was measured twice a week using calipers, and the longest and shortest diameters of the tumor were measured. The formula for calculating the volume was: Volume = 0.5 × Longest Diameter × Shortest Diameter 2 .

[0126] 3.3.2 Animal responses after drug administration: The body weight of mice was measured while measuring tumor volume. The relationship between changes in mouse body weight and administration time was recorded. At the same time, the survival and health status of the mice, such as activity level and food intake during administration, was observed.

[0127] 3.4 Drug Evaluation Indicators

[0128] 3.4.1 Relative tumor volume increase rate T / C (%) T / C (%) = Mean relative tumor volume of the treatment group / Mean relative tumor volume of the control group × 100

[0129] 3.4.2 Tumor Growth Inhibition Rate (TGI, %) Tumor growth inhibition rate (TGI, %)=(1-T / C)×100

[0130] 3.5 Statistical analysis

[0131] 3.5.1 Data Collection: Measurements and observations were performed in accordance with the requirements of the experimental protocol and recorded manually or directly into a computer database.

[0132] 3.5.2 Statistical Analysis: Group statistical analysis of tumor volume was performed using the statistical software SPSS 16.0 and the One-Way ANOVA test. A p<0.05 value was considered statistically significant.

[0133] 4. Experimental Results

[0134] Table 9: Drug efficacy data of compound (A) and fulvestrant in a subcutaneous xenograft model of MCF-7 human breast cancer. [Table 9] Note: a: Mean ± standard error, b: Comparison with control group, c: One-way ANOVA and LSD test used, P<0.05: statistically significant difference

[0135] 5. Experimental Conclusion: The 25 mg / kg formula (A) monotherapy group, the 5 mg / animal fulvestrant monotherapy group, and the combination therapy group all showed significant inhibitory effects on tumor growth. Compared to each monotherapy group, the combination therapy group showed superior tumor growth inhibition.

[0136] Example 3: Pharmacodynamic study of the combination of compound (A) and fulvestrant in the treatment of a subcutaneous xenograft model of MCF-7 human breast cancer.

[0137] 1. Experimental Objective The purpose of this study is to evaluate the efficacy of compound (A) in combination with fulvestrant in a subcutaneous xenograft model of MCF-7 human breast cancer in female BALB / c nude mice.

[0138] 2. Experimental protocol: On day 28 of treatment for the mice in Experiment 2, animal plasma was collected sequentially from each sample, and PK measurements were performed, yielding a total of 112 plasma samples and 16 tumor samples. The detailed sample collection protocol is shown in the table below.

[0139] Table 10: PK sample sampling protocol [Table 10]

[0140] 3. Experimental Results

[0141] Table 11: Pharmacokinetic parameters of compound (A) in plasma [Table 11]

[0142] Table 12: Pharmacokinetic parameters of fulvestrant in plasma [Table 12]

[0143] The monotherapy group of compound (A) at 25 mg / kg, the monotherapy group of fulvestrant at 5 mg / animal, and the combination therapy group of both all showed significant inhibitory effects on tumor growth. Compared to each monotherapy group, the combination therapy groups showed a certain enhancement in tumor growth inhibition. Results from the accompanying PK study showed that in a subcutaneous xenograft model of MCF-7 human breast cancer, the combination of compound (A) and fulvestrant did not significantly affect the plasma pharmacokinetic parameters of either compound (A) or fulvestrant, suggesting that no significant plasma pharmacokinetic interaction was observed between compound (A) and fulvestrant in this model.

[0144] Example 4: Evaluation of the safety, tolerability, pharmacokinetic properties, and preliminary efficacy of formula (A) compound tablets in patients with advanced malignant solid tumors.

[0145] All content of the trial plan and results with registration number CTR20211999 in the China Clinical Trials Registry and Information Disclosure Platform is incorporated herein by reference.

[0146] Study Objectives: To evaluate the safety and tolerability of compound (A) in patients with advanced malignant solid tumors (including breast and ovarian cancer) who have failed standard treatment, to explore the maximum tolerated dose (MTD) of compound (A), to determine the recommended dose (RP2D) for Phase II clinical trials, to evaluate the pharmacokinetic (PK) characteristics of compound (A) after a single dose and after 21 days of continuous administration in patients with advanced solid tumors, and to evaluate the preliminary efficacy of compound (A) in the treatment of advanced solid tumors.

[0147] Study Design: This study is an open-label, single-arm, non-randomized clinical trial including safety, efficacy, and pharmacokinetic studies. Part 1 is the dose-exploratory phase, and Part 2 is the dose-elevation phase.

[0148] In the first phase, the dose exploration stage, 20 mg was selected as the starting dose of compound (A), and dose escalations were sequentially established with doses of 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, and 400 mg. The drug was administered once daily as a single dose (with a 7-day washout period) and as multiple doses (administered for 21 consecutive days, with a 28-day cycle, until intolerance occurred, disease progression occurred, or the subject withdrew).

[0149] The second phase, the dose escalation phase: After the completion of the dose exploration phase, the dose escalation phase began. Based on the results of the dose escalation, the dosage for the dose escalation group study was determined and administered orally once daily. (Administered for 21 consecutive days, with a 28-day cycle, until intolerance, disease progression, or withdrawal of the subject).

[0150] Endpoint metrics: 1) Safety and tolerability: Maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) 2) PK index: See Tables 13 and 14 below. 3) Efficacy indicators: Objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS).

[0151] Table 13: Formula (A) PK index in the dose-finding stage of single-agent compounds [Table 13]

[0152] Table 14: Formula (A) PK index in dose escalation phase of single-agent compounds [Table 14]

[0153] Example 5: Evaluation of the safety, tolerability, pharmacokinetics, and preliminary efficacy of combination therapy with compound (A) tablets and fulvestrant in patients with locally advanced or metastatic HR-positive and HER-2-negative breast cancer who have failed standard treatment.

[0154] Study objective: To evaluate the safety and tolerability of compound (A) in combination with fulvestrant in patients with locally advanced or metastatic HR-positive / HER-2-negative breast cancer, and to determine the recommended dosage and preliminary efficacy of the combination in subsequent clinical trials.

[0155] Study Design: This study is divided into two phases: the first phase is the dose exploration phase, and the second phase is the dose escalation phase.

[0156] Dose exploration phase: A dose of 400 mg was selected as the initial dose of compound (A) and fulvestrant. Based on the safety and tolerability results of the 400 mg dose group, dose escalation to 500 mg was continued. The administration plan for compound (A) was once daily for 21 consecutive days, followed by a 7-day rest period, and each administration cycle was 28 days. The concomitant drug, fulvestrant, was administered via intramuscular injection according to standard treatment, with 500 mg (250 mg per buttock, administered intramuscularly twice) once on the first day of each cycle, followed by an additional 500 mg two weeks after the initial dose, with each administration cycle being 28 days. During the dose exploration phase, dose-limiting toxicity (DLT) in subjects was observed from the start of administration to the end of the first cycle.

[0157] The second phase, the dose escalation phase: After first confirming the safety of the 400 mg and 500 mg dose levels from the dose exploration phase, the dose escalation phase was initiated to further evaluate the safety and tolerability of the combination of compound (A) and fulvestrant, and to first assess the antitumor effect. The administration plan for subjects was the same as in the dose exploration phase: compound (A) 400 mg or 500 mg was administered orally once daily for 21 consecutive days, followed by a 7-day rest period, making a 28-day administration cycle. The concomitant drug, fulvestrant, was administered via intramuscular injection, 500 mg (250 mg per buttock, administered intramuscularly twice) once on the first day of each cycle, with an additional 500 mg administered two weeks after the initial dose, making a 28-day administration cycle. All subjects received the medication continuously until disease progression, unacceptable toxicity occurred, the subject voluntarily withdrew, the subject died, or (as it occurred earliest) the subject ceased to visit.

[0158] Study results: All six subjects receiving concomitant medications during the dose-exploratory phase completed dose-limiting toxicity (DLT) observations, and no DLT events occurred.

[0159] (1) Safety data of combination therapy: Safety analysis of subjects who received the drug showed that the overall safety of combination therapy was good and controllable, and the types of adverse events were similar to those of the same target drug. The incidence of drug-related adverse events (TRAEs) was 100%, but the majority were Grade 1-2 adverse events, and there were no reports of Grade 3 or higher adverse events or serious adverse events. Common TRAEs included diarrhea (100%), vomiting (75.0%), hypercholesterolemia (62.5%), hyperglycemia (50.0%), nausea (50.0%), elevated glycated hemoglobin (37.5%), elevated AST / ALT (37.5%), proteinuria (37.5%), elevated lipase (37.5%), and hypoalbuminemia (25.0%).

[0160] (2) Preliminary efficacy of combination therapy: Tumor evaluation was performed in 5 subjects in the dose escalation phase after administration. Of these, 1 had no measurable target lesions and the overall efficacy evaluation was disease stable (SD). 1 had already confirmed a partial response (PR), with the tumor lesion shrinking from 32.9 mm at baseline to 16 mm. 3 were SD, and in one of these cases, the tumor lesion shrank from 100 mm at baseline to 83 mm. The disease control rate (DCR) was 100% (5 / 5), and the objective response rate (ORR) was 20% (1 / 5). Currently, all enrolled subjects are receiving treatment, and there have been no dropouts.

[0161] (3) Pharmacokinetic (PK) data: During the dose exploration and dose escalation phases, blood samples were collected after administration to measure appropriate indicators, and statistical analysis of PK data for a total of 6 subjects in the 400 mg group has now been completed. Comparing with existing data, the pharmacokinetic data for compound (A) after combining the monotherapy drug with fulvestrant in the 400 mg dose group is shown. Detailed PK data are shown in Tables 15 and 16 below.

[0162] Table 15: PK index during dose exploration phase when compound (A) is used in combination with fulvestrant. [Table 15]

[0163] Table 16: PK indicators in the dose escalation phase when compound (A) is used in combination with fulvestrant. [Table 16]

[0164] Example 6: Study on the efficacy and safety of combination therapy with compound (A) tablets and fulvestrant in patients with locally advanced or metastatic HR-positive and HER-2-negative breast cancer who have failed standard treatment.

[0165] Study Objective: To compare and evaluate the antitumor efficacy and safety of the combination of compound (A) with fulvestrant and placebo with fulvestrant in the entire population and subgroups of PIK3CA / AKT1 / PTEN mutations in patients with locally advanced or metastatic HR-positive and HER-2-negative breast cancer.

[0166] Study Design: This study was designed as a randomized, controlled, double-blind, multicenter study. The enrolled population consisted of patients with recurrent, locally advanced, or metastatic HR-positive, HER-2-negative breast cancer who had previously received first-line or second-line systemic therapy (at least first-line being endocrine therapy). Enrolled subjects were randomly assigned in a 1:1 ratio to either compound (A) + fulvestrant or placebo + fulvestrant. The proposed compound (A) dosing regimen consisted of 400 mg or 500 mg once daily for 21 consecutive days, followed by a 7-day rest period, for a total of 28 days per dosing cycle. Actual dosage and frequency may be adjusted based on exploratory study results and quantitative pharmacological model analysis.

[0167] The concomitant medication, fulvestrant, was administered via intramuscular injection according to standard treatment guidelines, with 500 mg (250 mg intramuscularly injected into the buttocks twice) once on the first day of each cycle, followed by an additional 500 mg two weeks after the initial dose, with one administration cycle lasting 28 days.

[0168] Endpoints: The primary endpoint was progression-free survival (PFS) for the entire population and subgroups with PIK3CA / AKT1 / PTEN mutations, as assessed by researchers based on RECIST 1.1 criteria. Secondary endpoints were overall survival (OS) for the entire population and subgroups with PIK3CA / AKT1 / PTEN mutations. All subjects received continuous treatment until disease progression, unacceptable toxicity, voluntary withdrawal, death, or (most likely) non-visitation.

Claims

1. The use of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof or hydrate thereof, in the manufacture of a drug for the prevention or treatment of breast cancer, wherein the breast cancer is hormone receptor-positive breast cancer. 【Chemistry 1】

2. The use according to claim 1, characterized in that the compound of formula (I) is a compound of formula (A) or a compound of formula (B). 【Chemistry 2】 【Transformation 3】

3. The use according to claim 1 or 2, characterized in that the compound of formula (A), or a pharmaceutically acceptable salt thereof, or a hydrate thereof, is used in combination with fulvestrant.

4. The aforementioned breast cancer is HR-positive breast cancer. The use according to any one of claims 1 to 3, preferably HR-positive and HER-2-negative breast cancer, more preferably ER-positive, PR-positive and HER2-negative hormone receptor-positive breast cancer, even more preferably locally advanced or metastatic HR-positive and HER-2-negative breast cancer that has failed standard treatment, and even more preferably locally advanced or metastatic HR-positive and HER-2-negative breast cancer that has failed standard treatment, with or without alteration of the PI3K / Akt / PTEN pathway.

5. The method of administration for concomitant use can be selected from simultaneous, parallel, independent, or sequential application. The use according to claim 3 or 4, characterized in that the route of administration for concomitant use is selected from oral, parenteral, rectal, pulmonary, or local administration.

6. The dosage of compound (A) is 0.1 to 1000 mg, preferably 20 to 500 mg, more preferably 100, 200, 300, 400 or 500 mg, and even more preferably 300, 400 or 500 mg. The administration frequency of compound (A) is once daily, twice daily, three times daily, once a week, once every two weeks, once every three weeks, or once a month, preferably once daily or twice daily. Preferably, the compound of formula (A) is administered once, twice, or three times a day for 21 consecutive days, followed by an interval of 1 to 2 weeks during which the compound is not administered, or it is administered for 5 or 4 consecutive days, followed by an interval of 1 to 3 days during which the compound is not administered. More preferably, the use according to any one of claims 3 to 5, characterized in that the frequency of administration of the compound of formula (A) is once or twice a day for 21 consecutive days, followed by an interval of one week without administration of the compound, or it is administered for 5 consecutive days, followed by an interval of two days without administration of the compound, or it is administered for 4 consecutive days, followed by an interval of three days without administration of the compound.

7. The dosage of fulvestrant is 0.1 to 800 mg, preferably 20 to 500 mg, more preferably 100, 200, 300, 400 or 500 mg, and even more preferably 300, 400 or 500 mg. The use according to any one of claims 3 to 6, characterized in that the frequency of administration of fulvestrant is once a day, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every two months, preferably once every two weeks or once every four weeks.

8. One cycle is 28 days. The compound of formula (A) is administered for 21 consecutive days, with a one-week interval between each administration cycle. The use according to any one of claims 3 to 7, characterized in that the frequency of administration of fulvestrant is once administered two weeks after the first dose of the first cycle, and then once on the first day of each subsequent cycle.

9. The use according to any one of claims 3 to 8, characterized in that the dosage ratio of compound (A) to fulvestrant is selected from 0.001 to 500:1, and preferably 0.001 to 100:

1.

10. The pharmaceutically acceptable salts of the compound of formula (A) are organic or inorganic salts. The aforementioned organic salt comprises one or more of the following: fumarate, methanesulfonate, hydroxyethanesulfonate, α-naphthalenesulfonate, p-toluenesulfonate, 1,2-ethanedisulfonate, oxalate, maleate, citrate, succinate, L-(+)-tartrate, hippurate, L-ascorbate, L-malate, benzoate, or gentisinate. The inorganic salt comprises one or more of hydrochloride, sulfate, or phosphate salts. The use according to any one of claims 1 to 9, characterized in that the pharmaceutically acceptable salt is preferably a fumarate, more preferably a monofumarate, and even more preferably a monofumarate dihydrate.

11. The compound comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, a fulvestrant, and one or more pharmaceutically acceptable carriers. 【Chemistry 4】 Preferably, the compound of formula (I) is the compound of formula (A) or the compound of formula (B), 【Transformation 5】 【Transformation 6】 Preferably, the pharmaceutically acceptable salt of the compound of formula (A) is an organic acid salt or an inorganic acid salt. The aforementioned organic salt comprises one or more of the following: fumarate, methanesulfonate, hydroxyethanesulfonate, α-naphthalenesulfonate, p-toluenesulfonate, 1,2-ethanedisulfonate, oxalate, maleate, citrate, succinate, L-(+)-tartrate, hippurate, L-ascorbate, L-malate, benzoate, or gentisinate. The inorganic salt comprises one or more of hydrochloride, sulfate, or phosphate salts. A drug composition or combination of drugs wherein the pharmaceutically acceptable salt is preferably a fumarate, more preferably a monofumarate, and even more preferably a monofumarate dihydrate.

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