Application of AKT inhibitor in preparation of medicine for preventing or treating breast cancer

Abstract

The invention discloses application of an AKT inhibitor in preparation of a medicine for preventing or treating breast cancer. In particular, the invention provides application of an AKT inhibitor combined with fulvestrant in preparation of medicines for preventing or treating breast cancer. The AKT inhibitor and fulvestrant are combined to effectively inhibit the growth of breast tumor cells and cell clone formation, the combined effect is obviously superior to that of single medication, the additive or synergistic effect is achieved, meanwhile, the toxic and side effects on normal cells are low, the safety is high, a more effective method is provided for treating breast cancer, and the important clinical value is achieved.

Description

Use of AKT inhibitors in the preparation of drugs for preventing or treating breast cancer

[0001] This application claims priority to Chinese patent application No. 2023107072372, filed on June 14, 2023, and cites the full text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention belongs to the field of biomedicine, and specifically relates to the use of AKT inhibitors in preparing drugs for preventing or treating breast cancer. Background Art

[0003] Cancer is a disease with a high mortality rate, second only to cardiovascular disease. The number of cancer patients and deaths is increasing worldwide. Among them, breast cancer is the most common malignant tumor in the world, with an increasing incidence rate year by year. It is the "number one killer" that endangers women's lives. According to the driver genes of breast cancer, breast cancer can be divided 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. Studies have found that the PI3K-Akt signaling pathway plays an important role in 60% of breast cancers. Due to the high activation rate and important role of PI3K / Akt, a number of PI3K / Akt inhibitors have been approved for breast cancer indications or are undergoing clinical trials in multiple types of breast cancer.

[0004] Targeted therapy specifically targets the changed genes or proteins in tumor cells. It has the advantages of strong specificity, significant efficacy, and few toxic and side effects. It has become a new treatment method besides the three traditional treatments of surgery, radiotherapy, and chemotherapy, bringing benefits to the majority of breast cancer patients.

[0005] AKT is a serine / threonine kinase that influences cell survival, growth, metabolism, proliferation, migration, and differentiation through numerous downstream effectors. Over 50% of human tumors exhibit AKT overactivation. AKT overactivation can lead to tumorigenesis, metastasis, and drug resistance. AKT has three isoforms: AKT1, AKT2, and AKT3. As typical protein kinases, each isoform consists of an amino-terminal PH domain (Pleckstrin homology domain), a central ATP-binding kinase domain, and a carboxyl-terminal regulatory domain. The three isoforms share approximately 80% amino acid sequence homology, with significant variations only in the linker region between the PH domain and the kinase domain. Therefore, inhibiting AKT activity can avoid both the severe side effects of upstream PI3K inhibition and the negative feedback mechanisms that can affect drug efficacy caused by downstream mTOR inhibition. Molecular targeted therapy targeting AKT is gaining increasing attention and is currently a key area of ​​research and development for targeted cancer drugs.

[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]hept-2-yl)-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one, and its chemical molecular formula is shown in the following formula (A):

[0007] The compound represented by formula (A) is an AKT protein kinase inhibitor that can effectively inhibit AKT kinase activity and is used to treat locally advanced or metastatic solid tumors. However, there are currently no reports of the compound represented by formula (A) combined with fulvestrant in the preparation of a drug for the prevention or treatment of breast cancer.

[0008] Summary of the Invention

[0009] The purpose of the present invention is to overcome the above-mentioned defects and deficiencies in the prior art and to provide a use of an AKT inhibitor in the preparation of a drug for preventing or treating breast cancer, in particular to provide a use of an AKT inhibitor in combination with fulvestrant in the preparation of a drug for preventing or treating breast cancer.

[0010] To achieve the above objectives, the present invention provides the following technical solutions:

[0011] A use of an AKT inhibitor in the preparation of a drug for preventing or treating breast cancer, wherein the AKT inhibitor is a compound represented by formula (I) (hereinafter collectively referred to as the compound of formula (I)) or a pharmaceutically acceptable salt or hydrate thereof.

[0012] In some embodiments, the compound of formula (I) is a compound of formula (A) or a compound of formula (B):

[0013] The present invention also provides a use of an AKT inhibitor in the preparation of a drug for preventing or treating breast cancer, wherein the AKT inhibitor is a compound represented by formula (A) (hereinafter collectively referred to as the compound of formula (A)) or a pharmaceutically acceptable salt or hydrate thereof.

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

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

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

[0017] In a preferred embodiment of the present invention, the breast cancer is hormone receptor-positive breast cancer that is ER-positive, PR-positive and HER-2-negative.

[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.

[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 with or without PI3K / Akt / PTEN pathway alterations.

[0020] In a preferred embodiment of the present invention, the breast cancer is HR-positive and HER-2-negative breast cancer with PI3K / Akt / PTEN pathway alterations that has failed standard treatment, and is locally advanced or metastatic.

[0021] 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 without PI3K / Akt / PTEN pathway changes.

[0022] In a preferred embodiment of the present invention, the compound of formula (A) is used in combination with fulvestrant.

[0023] In one embodiment of the present invention, the administration of the combined use is selected from simultaneous, concurrent, independent or sequential application.

[0024] In one embodiment of the present invention, the combined administration route is selected from oral, parenteral, rectal, pulmonary or local administration, and the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, and intramuscular injection.

[0025] In one embodiment of the present invention, the dosage of the compound of formula (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 g, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 2 00mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 350mg, 400mg, 450m, 500mg, 550mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg or 1000 mg and values ​​between any two of the above values ​​(although not listed one by one, but deemed to be clearly indicated); preferably 20-500 mg; more preferably 100, 200, 300, 400 or 500 mg; further preferably 300, 400 or 500 mg.

[0026] In one embodiment of the present invention, the administration frequency of the compound of formula (A) can be once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, once a month, 21+7 (28 days as a cycle, once a day or twice a day for the first 21 days, rest for 7 days), 4+3 (7 days as a cycle, once a day or twice a day for the first 4 days, rest for 3 days) or 5+2 (7 days as a cycle, once a day or twice a day for the first 5 days, rest for 2 days); preferably once a day, twice a day, 21+7 (28 days as a cycle, once a day or twice a day for the first 21 days, rest for 7 days), 4+3 (7 days as a cycle, once a day or twice a day for the first 4 days, rest for 3 days) or 5+2 (7 days as a cycle, once a day or twice a day for the first 5 days, rest for 2 days).

[0027] In one embodiment of the present invention, the compound of formula (A) is administered 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; preferably once a day or twice a day.

[0028] In one embodiment of the present invention, the compound of formula (A) is administered once a day, twice a day, or three times a day for 21 consecutive days, followed by an interval of 1 to 2 weeks without administration of the compound; or administered for 5 or 4 consecutive days, followed by an interval of 1 to 3 days without administration of the compound.

[0029] In one embodiment of the present invention, the compound of formula (A) is administered once a day or twice a day for 21 consecutive days, followed by a 1-week interval without administration of the compound; or administered for 5 consecutive days, followed by a 2-day interval without administration of the compound; or administered for 4 consecutive days, followed by a 3-day interval without administration of the compound.

[0030] In one embodiment of the present invention, the dosage 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, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 310 mg, 320 mg, 330 mg, 330 mg, 340 mg, 350 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg 40mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 350mg, 400mg, 450m, 500mg, 600mg, 700mg, 750mg or 800mg and values ​​between any two of the above values ​​(although not listed one by one, but deemed to be clearly indicated), the preferred dosage is 20-500mg; more preferably 100, 200, 300mg, 400mg or 500mg, and even more preferably 300, 400 or 500mg.

[0031] In one embodiment of the present invention, the administration frequency 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; preferably once every two weeks or once every four weeks.

[0032] In one embodiment of the present invention, the administration frequency of the compound of formula (A) is 21+7 (28 days as a cycle, once a day or twice a day for the first 21 days, and rest for 7 days); the administration frequency of fulvestrant is 28 days as a cycle, and it is administered once two weeks after the first administration of the first cycle, and then once on the first day of each cycle.

[0033] In one embodiment of the present invention, a cycle is 28 days; the administration frequency of the compound of formula (A) is 21 consecutive days, followed by a 1-week interval between each administration cycle; the administration frequency of fulvestrant is once two weeks after the first administration of the first cycle, and then once on the first day of each cycle.

[0034] In one embodiment of the present invention, the dosage ratio of the compound of formula (A) to fulvestrant is selected from 0.001-500:1, 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 values ​​between any two of the above values ​​(although not listed one by one, but deemed to be clearly indicated); preferably 0.001-100:1.

[0035] 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 treatment methods for cancer treatment, such as other chemotherapy, hormones, antibodies, targeted drugs and other therapeutic agents, as well as surgery and / or radiotherapy.

[0036] In one embodiment of the present invention, the compound of formula (A) can be administered to the patient in the form of a free base, or in the form of a pharmaceutically acceptable salt, hydrate, and prodrug (which will be converted into a free base form in vivo), such as a fumarate salt. The compound of formula (A) or a salt thereof can be prepared with reference to the preparation method disclosed in WO2022017448A1.

[0037] In one embodiment of the present invention, the pharmaceutically acceptable salt of the compound of formula (A) is a fumarate salt.

[0038] In one embodiment of the present invention, the pharmaceutically acceptable salt of the compound of formula (A) is a fumarate dihydrate, chemically named (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]pyrimidin-7(6H)-one fumarate dihydrate, and the chemical formula is shown in the following formula (IA):

[0039] The present invention also provides a pharmaceutical combination or pharmaceutical composition, which contains a compound of formula (I) or a pharmaceutically acceptable salt thereof and fulvestrant, and one or more pharmaceutically acceptable carriers;

[0040] In some embodiments, the compound of formula (I) is a compound of formula (A) or a compound of formula (B):

[0041] The present invention also provides a pharmaceutical combination comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof and fulvestrant, and one or more pharmaceutically acceptable carriers.

[0042] In the pharmaceutical combination or pharmaceutical composition, the administration method, dosage, frequency and ratio of the compound of formula (A) and / or fulvestrant are consistent with those of the aforementioned combined use.

[0043] The present invention also provides a pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof and fulvestrant, and one or more pharmaceutically acceptable carriers.

[0044] The compound of formula (A) and fulvestrant pharmaceutical composition of the present invention can be prepared into any pharmaceutically acceptable dosage form, for example, tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injection, and concentrated solutions for injection), suppositories, inhalants, or sprays.

[0045] The compound of formula (A) and fulvestrant pharmaceutical composition of the present invention can also be administered to patients or subjects in need of such treatment by any suitable route of administration, such as oral, parenteral, rectal, pulmonary, or topical administration. When used for oral administration, the pharmaceutical composition can be prepared into an oral preparation, such as an oral solid preparation, such as a tablet, capsule, pill, granule, or the like; or an oral liquid preparation, such as an oral solution, oral suspension, syrup, or the like. When prepared into an oral preparation, the pharmaceutical preparation may further contain a suitable filler, binder, disintegrant, lubricant, or the like.

[0046] The compound of formula (A) and the fulvestrant pharmaceutical composition of the present invention can be administered alone, or can also be used in combination with other therapeutic agents or treatment methods for treating breast cancer other than fulvestrant, for example, combined treatment with other therapeutic agents such as chemotherapy, hormones, antibodies, targeted drugs, and surgery and / or radiotherapy.

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

[0048] The present invention also provides a method for preventing and / or treating breast cancer, comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition of the compound of formula (A) and fulvestrant. Beneficial effects:

[0049] The present invention provides a use of an AKT inhibitor in combination with fulvestrant in the preparation of a drug for preventing or treating breast cancer. The combination can effectively inhibit the growth and cell clone formation of breast tumor cells. The combined effect is significantly better than that of using either drug alone, and has an additive or synergistic effect. At the same time, the toxic side effects on normal cells are low, the safety is high, and it provides a more effective method for treating breast cancer, which has important clinical value.

[0050] Related definitions

[0051] Unless otherwise specified, the following terms used in the specification and claims have the following meanings:

[0052] The "combination" described herein is a mode of administration, which includes various situations in which two drugs are administered sequentially or simultaneously, and refers to the administration of at least one dose of the compound of formula (A) and at least one dose of fulvestrant in any manner within a certain time period. The time period can be within a dosing cycle, and the compound of formula (A) inhibitor and fulvestrant can be administered simultaneously or sequentially, and any of the methods described includes administering the compound of formula (A) and fulvestrant through the same administration route or different administration routes. For example, in one embodiment, one or more doses of the compound of formula (A) are administered simultaneously or separately with one or more doses of fulvestrant; in one embodiment, multiple doses of the compound of formula (A) are administered simultaneously or separately with multiple doses of fulvestrant; in one embodiment, multiple doses of the compound of formula (A) are administered simultaneously or separately with one dose of fulvestrant; in one embodiment, one dose of the compound of formula (A) is administered simultaneously or separately with multiple doses of fulvestrant; in one embodiment, one dose of the compound of formula (A) is administered simultaneously or separately with one 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 the administration of two or more drugs to a patient at the same time or very close in time. The term "concurrent administration" refers to the administration of two or more drugs within the same time period, such as on the same day, but not necessarily at the same time. The term "independent administration" refers to the independent administration of one drug over a period of time, such as the independent administration of one drug over the course of several days or a week, followed by the independent administration of other drugs over a subsequent period of time. The term "sequential administration" refers to the administration of drugs to a patient in a specific order, with each drug administered after the previous drug, forming an ordered sequence.

[0053] The term "oral administration" as used herein refers to the ingestion of drugs into the body through oral administration. The drugs are absorbed into the blood circulation through the gastrointestinal tract and then distributed throughout the body or act on specific organs.

[0054] The term "parenteral administration" as used herein refers to administration methods that do not pass through the gastrointestinal tract, including subcutaneous injection, intramuscular injection, intravenous injection, and the like.

[0055] The term "rectal administration" as used herein refers to a method in which the drug is delivered into the rectum through the anus, and the drug is absorbed into the blood circulation through the rectal mucosa.

[0056] The term "pulmonary administration" as used herein refers to delivering the drug directly into the lungs by inhalation, where the drug is absorbed into the bloodstream through the alveoli.

[0057] As used herein, "topical administration" refers to administration of a drug by coating or applying the drug directly to the epidermal tissue, including the skin or mucous membranes of the mouth or vagina.

[0058] As used herein, "used in combination" or "used in combination with" is not intended to imply that the therapies or therapeutic agents must be physically mixed or administered simultaneously and / or formulated for delivery together, although such methods of delivery are within the scope described herein. The therapeutic agents in these combinations can be administered simultaneously with, before, or after one or more other additional therapies or therapeutic agents. The therapeutic agents can be administered in any order. In general, each therapeutic agent will be administered at a dose and / or time schedule determined for that therapeutic agent. It will also be understood that the additional therapeutic agents used in the combination can be administered together in a single composition or separately in different compositions. In general, it is contemplated that the additional therapeutic agents used in the combination will be used at levels no greater than when they are used alone. In one embodiment, the levels used in the combination will be lower than the levels used in the single agent therapy.

[0059] The "combination use" and "combination use" described herein refer to the use of a compound of formula (A) or a pharmaceutically acceptable salt thereof and fulvestrant together. Depending on the intended dosage and frequency of administration, the two compounds can be administered together or separately. The dosage and frequency of administration may vary depending on the compound used and the specific condition to be treated. Generally, it is preferred to use the minimum dose sufficient to provide effective treatment, and it can be determined by the following criteria, such as the patient's age, weight and sex; the extent and severity of the cancer to be treated; and the judgment of the treating physician. The patient's therapeutic effect can usually be monitored using an assay suitable for the condition being treated, or the optimal dose can be determined using conventional tests and procedures well known in the art. For example, as indicated by the urgency of the treatment situation, a single bolus can be given, several divided doses can be given over time, or the dose can be proportionally reduced or increased. These assays are well known to those of ordinary skill in the art. In addition, it should also be understood that the therapeutic agents of the combination of the present invention can be administered by any suitable route, and the route of administration can vary according to, for example, the health status of the recipient of the combination and the cancer to be treated.

[0060] The "pharmaceutical composition" described herein refers to a mixture containing at least one therapeutic agent and at least one pharmaceutically acceptable carrier, and the "pharmaceutically acceptable carrier" includes but is not limited to a diluent, a binder, a disintegrant, and a lubricant.

[0061] As used herein, the amount of the "administered dose" refers to the amount of the therapeutic agent. For example, when a 2 mg dose of the compound of formula (A) is administered and the compound of formula (A) is administered as a tablet containing a fumarate salt of the compound of formula (A), the tablet will contain an amount of the fumarate salt of the compound of formula (A) equivalent to 2 mg of the compound of formula (A).

[0062] The "salt" described herein may exist alone or in a mixture with a free compound of the present invention, and is preferably a pharmaceutically acceptable salt. The "pharmaceutically acceptable salt" refers to an organic acid salt or an inorganic acid salt commonly used in pharmacy, wherein the organic acid salt 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 gentisate, and the inorganic acid salt includes but is not limited to hydrochloride, sulfate or phosphate. In one embodiment, the "pharmaceutically acceptable salt" is a fumarate; preferably a monofumarate; more preferably a fumarate hydrate; and further preferably a fumarate dihydrate.

[0063] The term "HR-positive (Hormone Receptor) breast cancer" as used herein refers to hormone receptors, including estrogen receptors (ER) and progesterone receptors (PR).

[0064] The "HER-2 negative breast cancer" mentioned herein refers to breast cancer that is negative for human epidermal growth factor receptor 2 (HER2).

[0065] For the purposes of this article, "failure of standard therapy" refers to patients who have previously received endocrine therapy and: (a) have radiographic evidence of breast cancer recurrence or progression during or within 12 months after the completion of (neo)adjuvant endocrine therapy, or (b) have radiographic evidence of progression during or after endocrine therapy for locally advanced or metastatic breast cancer.

[0066] " locally advanced " described herein refers to that tumor is confined to primary organ or adjacent tissue organ, but may onset time is longer, tumor body is larger, yet metastasis of distant organ does not occur.According to NCCN (National Comprehensive Cancer Network of the U.S.) guide, locally advanced breast cancer is stage III breast cancer, and locally advanced breast cancer is divided into operable locally advanced breast cancer (cT3N1M0) and inoperable locally advanced breast cancer (c any TN2M0, and IIIB stage, IIIC stage).In one embodiment, locally advanced breast cancer is inoperable locally advanced breast cancer (c any TN2M0, and IIIB stage, IIIC stage).

[0067] As used herein, a "therapeutically effective amount" includes an amount sufficient to improve or prevent the symptoms or symptoms of a disorder. In the case of cancer, a therapeutically effective dose of a drug can reduce the number of cancer cells; reduce the size of the tumor; inhibit (i.e., slow down to a certain extent and preferably prevent) the infiltration of cancer cells into surrounding organs; inhibit (i.e., slow down to a certain extent and preferably prevent) tumor metastasis; inhibit tumor growth to a certain extent; and / or alleviate one or more symptoms associated with the disorder to a certain extent. Depending on the extent to which the drug can prevent the growth of existing cancer cells and / or kill existing cancer cells, it can be cytostatic and / or cytotoxic. For cancer treatment, in vivo efficacy can be measured by assessing duration of survival, progression-free survival (PFS) duration, response rate (RR), duration of response, and / or quality of life.

[0068] The "MTD" referred to herein is the maximum tolerated dose.

[0069] The “DLT” mentioned in this article is defined as the following toxic reactions related to the study drug (including definitely related, probably related, or possibly related) that occur in subjects in each dose group from the start of drug administration to the end of the first course of treatment (a total of 28 days): (1) Hematological toxicity: Grade 4 neutropenia lasting for more than 3 days; Grade 3 febrile neutropenia; Grade 4 thrombocytopenia; Grade 3 thrombocytopenia with bleeding; Grade 4 anemia; (2) Non-hematological toxicity: Grade 4 non-hematological toxicity; Grade 3 non-hematological toxicity, which occurs after 3 days of treatment Grade 4 hyperglycemia: blood glucose >27.8mmol / L or 500mg / dL; Grade 3 hyperglycemia: blood glucose >13.9mmol / L or 250mg / dL, which persists for ≥7 days after treatment; (3) Other toxic reactions that require permanent discontinuation of the study drug or result in the total dose of the study drug received during the DLT observation period being less than 75% of the planned dose as determined by the investigator.

[0070] The "RP2D" mentioned in this article means the recommended dose for Phase II clinical trials.

[0071] The "objective response rate (ORR)" mentioned in this article is defined as the proportion of subjects whose tumors achieved complete remission (CR) and partial remission (PR) after treatment.

[0072] The "disease control rate (DCR)" mentioned in this article is defined as the proportion of subjects whose tumors achieved complete remission (CR), partial remission (PR) and stable disease (SD) after treatment.

[0073] Duration of response (DOR) is defined as the time from the start of objective response to the first occurrence of tumor progression or death due to any cause.

[0074] The "progression-free survival (PFS)" mentioned in this article is defined as the time from the start of treatment to tumor progression or death due to any cause.

[0075] The “OS” mentioned in this article, overall survival, is defined as the time from randomization to the death of the patient due to various causes.

[0076] The "ECOG performance status score" mentioned in this article refers to the Eastern Cooperative Oncology Group (ECOG) performance status score (Zubrod-ECOG-WHO, ZPS, 5-point method). It is an important indicator for assessing the general condition of cancer patients. It can help predict the patient's prognosis and estimate the patient's tolerance to various treatments. It is an important parameter in various prognostic evaluation systems.

[0077] The "AE incidence rate" mentioned in this article refers to adverse events in the medical field, which are adverse medical events that occur after patients or clinical trial subjects receive a drug.

[0078] The "synergistic effect" herein refers to a phenomenon in which the combined effects of two drugs are more effective than their individual effects, as opposed to antagonistic effects.

[0079] The compound of formula (I) or formula (A) disclosed herein is an effective AKT inhibitor, and its preparation method is disclosed in international application WO2020156437A1. The "compound" described 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 indicated, all stereoisomers are included, such as enantiomers and diastereomers. Compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved 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 "fulvestrant" herein includes stereoisomers, solvates or pharmaceutically acceptable salts thereof.

[0082] Herein, unless otherwise specified, when referring to the dosage of the compound of formula (A) or fulvestrant, it refers to the dosage of the active compound (free base). It will be understood that when the compound is in the form of a pharmaceutically acceptable salt or hydrate, the dosage or the ratio between the two can still be calculated based on the active compound. DETAILED DESCRIPTION

[0083] The following typical examples illustrate the present invention and demonstrate the beneficial activities or technical effects of the compositions of the present invention. However, it should be understood that the following experimental protocols are merely illustrative of the present invention and are not intended to limit the scope of the present invention. Simple substitutions or modifications made by those skilled in the art to the present invention are considered to be within the technical solutions protected by the present invention.

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

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

[0086] 2. Experimental Methods

[0087] 2.1 Cell culture

[0088] a) BT-474 cells were cultured in Hybri-Care medium, supplemented with 1% double-antibody and 10% FBS, at 37°C and 5% CO2; b) MCF-7 cells were cultured in EMEM medium, supplemented with 1% double-antibody, 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, supplemented with 1% double-antibody and 10% FBS, at 37°C and 5% CO2; d) T47D cells were cultured in RPMI-1640 medium, supplemented with 1% double-antibody, 0.2 U / mL insulin, and 10% FBS, at 37°C and 5% CO2; e) CAMA-1 cells were cultured in EMEM medium, supplemented with 1% double-antibody and 10% FBS, at 37°C and 5% CO2.

[0089] 2.2 Cell plating

[0090] a) Culture cells routinely until cell saturation reaches 80%-90%. When the cell number reaches the required level, harvest the cells. b) Resuspend the cells in the appropriate culture medium, count the cells, and prepare a cell suspension of appropriate density. c) Add the cell suspension to a 384-well plate, 40 μL per well.

[0091] Table 1. Plating density of different cell lines

[0092] d) The cells were cultured in a 37°C, 5% CO2 incubator overnight.

[0093] 2.3 Preparation of compounds

[0094] a) The compound of formula (A) was diluted 3-fold from the original solution of 60 mM to 10 concentrations (using the monofumarate dihydrate of the compound of formula (A), the concentration was calculated based on the free base of the compound of formula (A); the compound of formula (A) or its salt was prepared by the preparation method disclosed in WO2022017448A1); b) Fulvestrant was diluted from 10 mM to 2 mM with DMSO, and then 3-fold dilution was started for 10 concentrations; c) Fulvestrant was diluted from 2 mM to 0.2 mM with DMSO, and then d) Dilute fulvestrant with DMSO from 0.2 mM to 2 μM; e) Dilute fulvestrant with DMSO from 2 μM to 0.8 μM; f) Dilute fulvestrant with DMSO from 2 μM to 0.3 μM; g) Dilute fulvestrant with DMSO from 0.8 μM to 0.08 μM; h) The final concentration of DMSO is 0.1%; i) Cells plus DMSO serve as high-reading control wells; j) Cell-free culture medium serves as low-reading control wells.

[0095] 2.4 Compound treatment of cells

[0096] a) Use alone:

[0097] 24 hours after BT474 and ZR-75-1 cells were plated, the compound was treated alone. For the compound of formula (A), 20 nL of the compound prepared in step 2.3a) plus 20 nL of DMSO was added. For the compound of formula (fulvestrant), 20 nL of the compound prepared in step 2.3b) plus 20 nL of DMSO was added.

[0098] 24 hours after plating MCF-7, T47D, and CAMA-1 cells, the compound was treated alone. For the compound of formula (A), 20 nL of the compound prepared in step 2.3a) plus 20 nL of DMSO was added. For the compound fulvestrant, 20 nL of the compound prepared in step 2.3c) plus 20 nL of DMSO was added.

[0099] b) Combination therapy:

[0100] 24 hours after BT474 and ZR-75-1 cells were plated, the compound of formula (A) was combined with fulvestrant: 20 nL of the compound prepared in step 2.3a) + 20 nL of the compound prepared in step 2.3b) and 2.3d).

[0101] 24 hours after MCF-7 cells were plated, the compound of formula (A) was combined with fulvestrant: 20 nL of the compound prepared in step 2.3a) + 20 nL of the compound prepared in step 2.3c), e), f).

[0102] 24 hours after T47D cells were plated, the compound of formula (A) was combined with fulvestrant: 20 nL of the compound prepared in step 2.3a) + 20 nL of the compound prepared in step 2.3c), e), g).

[0103] 24 hours after CAMA-1 cells were plated, the compound of formula (A) was combined with fulvestrant: 20 nL of the compound prepared in step 2.3a) + 20 nL of the compound prepared in step 2.3c).

[0104] c) Final concentration of test compound:

[0105] 1) BT474, ZR-75-1 cells:

[0106] Gradient concentration of compound (A) (nM): 30000, 10000, 3333, 1111, 370, 123, 41.2, 13.7, 4.57, 1.52 nM

[0107] Point-to-point combination of fulvestrant (nM): 1000, 333, 111, 37, 12.3, 4.1, 1.37, 0.46, 0.15, 0.05, respectively, with gradient concentrations of the compound of formula (A);

[0108] Fulvestrant was used in combination with a single concentration (nM): 1000, 1, respectively, in combination with gradient concentrations of the compound of formula (A).

[0109] 2) MCF-7 cells:

[0110] Compounds of formula (A) (nM): 30000, 10000, 3333, 1111, 370, 123, 41.2, 13.7, 4.57, 1.52;

[0111] Point-to-point combination of fulvestrant (nM): 100, 33.3, 11.1, 3.7, 1.23, 0.41, 0.14, 0.046, 0.015, 0.005, respectively, with gradient concentrations of the compound of formula (A);

[0112] Fulvestrant was used in combination with a single concentration (nM): 0.4, 0.15, respectively, in combination with gradient concentrations of the compound of formula (A).

[0113] 3) T47D cells:

[0114] Compounds of formula (A) (nM): 30000, 10000, 3333, 1111, 370, 123, 41.2, 13.7, 4.57, 1.52;

[0115] Point-to-point combination of fulvestrant (nM): 100, 33.3, 11.1, 3.7, 1.23, 0.41, 0.14, 0.046, 0.015, 0.005, respectively, with gradient concentrations of the compound of formula (A);

[0116] Fulvestrant was used in combination with a single concentration (nM): 0.4, 0.04, respectively, in combination with gradient concentrations of the compound of formula (A).

[0117] 4) CAMA-1 cells:

[0118] Compounds of formula (A) (nM): 30000, 10000, 3333, 1111, 370, 123, 41.2, 13.7, 4.57, 1.52;

[0119] Point-to-point combination of fulvestrant (nM): 100, 33.3, 11.1, 3.7, 1.23, 0.41, 0.14, 0.046, 0.015, 0.005, respectively, with gradient concentrations of the compound of formula (A);

[0120] Fulvestrant was used in combination at a single concentration (nM): 1.2, 0.14, respectively, in combination with a gradient concentration of the compound of formula (A).

[0121] d) The cell culture plate was centrifuged at 1000 rpm for 1 min and placed in a 37° C., 5% CO 2 incubator for 7 days.

[0122] 2.5CTG method detection

[0123] a) Add 40 μL of CTG reagent (CelltiterGlo kit) to each well, shake on a fast shaker for 2 minutes, centrifuge at 1000 rpm for 1 minute, and place at room temperature in the dark for 30 minutes; b) Read the chemiluminescence signal value using an Envision instrument.

[0124] 2.6 Data Analysis

[0125] The inhibition rate data obtained from single drug or single concentration combination in Section 2.4 were used to calculate IC using GraphPad Prism 8 software. 50 , the IC of the compound is obtained using the following nonlinear fitting formula 50 (half inhibitory concentration): Y = minimum value + (maximum value - minimum value) / (1 + 10^((LogIC 50 -X)*slope))

[0126] X: log value of compound concentration, Y: inhibition rate (%inhibition)

[0127] Inhibition rate (% inhibition) = 100-(compound well reading-low reading control reading) / (high reading control reading-low reading control reading)*100

[0128] 2.7 Cell proliferation activity IC 50

[0129] Cell proliferation activity IC 50 The measurement results are shown in Tables 2 to 5 below.

[0130] Table 2. Study results of the inhibitory effect of the compound of formula (A) combined with fulvestrant on the proliferation of BT-474 and ZR-75-1 cells Note: *The maximum inhibition rate was calculated using GraphPad Prism 8 software. 50 The maximum value obtained by automatic fitting.

[0131] Table 3. Study results of the inhibitory effect of the compound of formula (A) combined with fulvestrant on the proliferation of MCF-7 cells Note: *The maximum inhibition rate was calculated using GraphPad Prism 8 software.50 The maximum value obtained by automatic fitting at

[0132] Table 4. Research results on the inhibitory effect of the compound of formula (A) combined with fulvestrant on the proliferation of T47D cells Note: *The maximum inhibition rate is the maximum value obtained by automatic fitting when calculating IC using GraphPad Prism 8 software 50 The maximum value obtained by automatic fitting at

[0133] Table 5. Research results on the inhibitory effect of the compound of formula (A) combined with fulvestrant on the proliferation of CAMA-1 cells Note: *The maximum inhibition rate is the maximum value obtained by automatic fitting when calculating IC using GraphPad Prism 8 software 50 The maximum value obtained by automatic fitting at

[0134] Conclusion: The compound of formula (A) alone and in combination with fulvestrant respectively has good in vitro anti-cell proliferation effects on 5 cell lines (BT-474, MCF-7, ZR-75-1, T47D, CAMA-).

[0135] 2.8 Evaluation index of compound combination (Synergy.score)

[0136] Detection method: Import the inhibition rate data measured by point-to-point combination in part 2.4 into the specific calculation template of the SynergyFinder website (https: / / tangsoftwarelab.shinyapps.io / synergyfinder / #! / dashboard.) and upload it for analysis of the combination index.

[0137] Evaluation criteria: Synergy.score < -10, the interaction between the two compounds is antagonistic;

[0138] -10 < Synergy.score < 10, the interaction between the two compounds is additive;

[0139] Synergy.score > 10, the interaction between the two compounds is synergistic.

[0140] The evaluation index of specific compound combination is shown in the following table:

[0141] Table 6. Combination index of compounds in different cell lines

[0142] Conclusion: The compound of formula (A) combined with fulvestrant has a synergistic effect in inhibiting the proliferation of breast cancer cells such as MCF-7, ZR-75-1, T47D, and CAMA-1.

[0143] Example 2: Study on the tumor inhibition rate of the compound of formula (A) combined with fulvestrant in the treatment of MCF-7 human breast cancer subcutaneous xenograft model

[0144] 1. Experimental purpose: The purpose of this study is to evaluate the efficacy of the compound of formula (A) combined with fulvestrant in the MCF-7 human breast cancer subcutaneous xenograft model in female BALB / c nude mice.

[0145] 2. Experimental materials and equipment

[0146] 2.1 Experimental animals: BALB / c nude mice, 6-8 weeks old, female, weighing 18-20 g, were purchased from Beijing Ankai Yibo Biotechnology Co., Ltd. and housed in an SPF-grade environment with a temperature of (23±3)°C and a humidity of 40-70%.

[0147] 2.2 Test sample

[0148] 2.2.1 Solvent selection:

[0149] Formula (A) compound solvent: 1,2-propylene glycol (PG): 50% Solutol HS-15: 0.5% Hydroxypropyl methylcellulose (HPMC) = 2:1:7

[0150] 2.2.3 The preparation method is shown in the table below:

[0151] Table 7. Compound preparation method

[0152] 3. Experimental methods and steps

[0153] 3.1 Cell culture

[0154] MCF-7 tumor cells were cultured in DMEM medium containing inactivated 15% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin at 37°C in a 5% CO 2 incubator. Tumor cells in the logarithmic growth phase were used for inoculation of tumors in vivo.

[0155] 3.2 Tumor cell inoculation and grouping

[0156] One day before inoculation of MCF-7 tumor cells, mice were required to have an estrogen tablet (0.5 mg, release period 90 days) implanted subcutaneously on the left side of the mouse. MCF-7 tumor cells resuspended in serum-free DMEM were cultured at a concentration of 1.5×10 7(0.2mL + Matrigel) was inoculated subcutaneously on the right flank of the experimental animals. A total of 72 animals were inoculated. The tumor grew to 204mm. 3 48 animals with relatively uniform tumor volumes were selected and divided into 4 groups for drug administration according to the drug administration schedule.

[0157] Table 8. Compound Dosage Regimen Note: po means oral administration; sc means subcutaneous injection; QD x 4 weeks means administration once a day for four consecutive weeks; QW x 4 weeks means administration once a week for four consecutive weeks.

[0158] 3.3 Detection indicators

[0159] 3.3.1 Tumor volume: Tumor volume was measured twice a week using a vernier caliper. The long and short diameters of the tumor were measured. The volume was calculated using the formula: volume = 0.5 × long diameter × short diameter 2 .

[0160] 3.3.2 Animal Responses After Dosing: While measuring tumor volume, weigh the mice. Record changes in weight relative to dosing time. Observe the survival and health of the mice, including general activity and feeding status, during dosing.

[0161] 3.4 Drug evaluation indicators

[0162] 3.4.1 Relative tumor volume increase ratio T / C (%)

[0163] T / C (%) = mean relative tumor volume of the treatment group / mean relative tumor volume of the control group × 100

[0164] 3.4.2 Tumor growth inhibition rate (TGI,%)

[0165] Tumor growth inhibition rate (TGI,%) = (1-T / C) × 100

[0166] 3.5 Statistical analysis

[0167] 3.5.1 Data collection: Measure and observe as required by the experimental plan, and record them manually or directly in a computer database.

[0168] 3.5.2 Statistical analysis: SPSS 16.0 statistical software and One-Way ANOVA test were used to perform statistical analysis of tumor volume between groups. A p < 0.05 was considered to be a significant difference.

[0169] 4. Experimental Results

[0170] Table 9. Efficacy data of the compound of formula (A) combined with fulvestrant in the MCF-7 human breast cancer subcutaneous xenograft model

[0171] Note: a Mean ± standard error; b Compared with the control group; c One-way ANOVA combined with LSD test, P < 0.05 indicates significant difference

[0172] 5. Experimental Conclusions: The 25 mg / kg compound of formula (A) monotherapy group, the 5 mg / mouse fulvestrant monotherapy group, and the combination therapy group all showed significant inhibition of tumor growth. Compared with the monotherapy groups, the combination therapy group showed a greater inhibitory effect on tumor growth.

[0173] Example 3: Pharmacodynamic study of the compound of formula (A) combined with fulvestrant in the treatment of MCF-7 human breast cancer subcutaneous xenograft model

[0174] 1. Purpose of the experiment

[0175] The purpose of this study was to evaluate the efficacy of the compound of formula (A) combined with fulvestrant in the MCF-7 human breast cancer subcutaneous xenograft model in female BALB / c nude mice.

[0176] 2. Experimental plan:

[0177] In Experiment 2, plasma samples were collected from mice on day 28 of treatment for PK testing, totaling 112 plasma samples and 16 tumor samples. The detailed sampling plan is shown in the table below:

[0178] Table 10. PK sample sampling plan

[0179] 3. Experimental Results

[0180] Table 11. Pharmacokinetic parameters of the compound of formula (A) in plasma

[0181] Table 12. Pharmacokinetic parameters of Fulvestrant in plasma

[0182] The 25 mg / kg monotherapy group of the compound of formula (A), the 5 mg / mouse fulvestrant monotherapy group, and the combination therapy group all showed significant inhibition of tumor growth. Compared with each monotherapy group, the combination therapy group showed a certain enhanced effect in inhibiting tumor growth. The results of the accompanying PK study showed that after the combination therapy of the compound of formula (A) and fulvestrant in the MCF-7 human breast cancer subcutaneous xenograft model, the compound of formula (A) and fulvestrant had no significant effect on their respective plasma pharmacokinetic parameters, suggesting that the compound of formula (A) and fulvestrant did not have a significant plasma pharmacokinetic interaction in this model.

[0183] Example 4: Safety, tolerability, pharmacokinetic properties and preliminary efficacy evaluation of the compound of formula (A) tablets in patients with advanced malignant solid tumors

[0184] The entire contents of the trial protocol and its results, registered with the China Drug Clinical Trial Registration and Information Disclosure Platform with number CTR20211999, are incorporated into this article by reference.

[0185] Study objectives: To evaluate the safety and tolerability of the compound of formula (A) in the treatment of patients with advanced malignant solid tumors (including breast cancer and ovarian cancer) who have failed standard treatment, and to explore the maximum tolerated dose (MTD) of the compound of formula (A) and determine the recommended dose (RP2D) for Phase II clinical trials: to evaluate the pharmacokinetic (PK) characteristics of the compound of formula (A) after single administration and continuous administration for 21 days in patients with advanced solid tumors; to evaluate the preliminary efficacy of the compound of formula (A) in the treatment of advanced solid tumors.

[0186] Trial Design: This study is an open-label, single-arm, non-randomized clinical trial of safety, efficacy, and pharmacokinetic efficacy. The first part is the dose-finding phase, and the second part is the dose-expansion phase.

[0187] Part I, Dose-Finding Phase: 20 mg was selected as the starting dose of the compound of formula (A), and ascending dose groups of 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, and 400 mg were established. Once daily, single dosing (with a 7-day washout period) and multiple dosing (21 consecutive days, 28 days per cycle), were used until intolerance, disease progression, or subject withdrawal.

[0188] The second part is the dose expansion phase. Following the dose-finding phase, the dose expansion phase begins. Based on the results of the dose escalation phase, the dose for the dose expansion group is determined. The drug is administered orally once daily for 21 consecutive days, with each cycle consisting of 28 days, until intolerance, disease progression, or subject withdrawal.

[0189] Endpoint indicators: 1) Safety and tolerability: maximum tolerated dose (MTD) and dose-limiting toxicity (DLT);

[0190] 2) PK indicators, see Tables 13 and 14 below;

[0191] 3) Effectiveness indicators: objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS).

[0192] Table 13. PK indicators of the compound of formula (A) in the single-dose exploratory phase

[0193] Table 14. PK indicators of the compound of formula (A) in the single-dose expansion phase

[0194] Example 5: Safety, tolerability, pharmacokinetic properties and preliminary efficacy evaluation of the compound of formula (A) tablets combined with fulvestrant in patients with locally advanced or metastatic HR-positive and HER-2-negative breast cancer who have failed standard treatment

[0195] Study objective: To evaluate the safety and tolerability of the compound of formula (A) combined with fulvestrant in patients with locally advanced or metastatic HR-positive / HER-2-negative breast cancer, and to determine the recommended dose for subsequent clinical trials and the preliminary efficacy of the combination.

[0196] Study Design: The study was divided into two phases, the first part was the dose-finding phase and the second part was the dose-expansion phase.

[0197] In the dose exploration phase, 400 mg was selected as the starting dose of the compound of formula (A) combined with fulvestrant. Based on the safety and tolerability results of the 400 mg dose group, the dose escalation of the 500 mg dose group was continued. The dosing regimen of the compound of formula (A) is once a day for 21 consecutive days, followed by a 7-day rest, with a dosing cycle of 28 days. The combined drug fulvestrant was administered according to standard treatment, intramuscularly, once on the first day of each cycle, 500 mg each time (administered in two intramuscular injections, 250 mg once in each buttock), and another 500 mg dose was administered two weeks after the first dose, with a dosing cycle of 28 days. In the dose exploration phase, the subjects were observed for dose-limiting toxicity (DLT), and the DLT observation period was from the start of administration to the end of the first cycle.

[0198] The second part is the dose expansion phase. After the safety of the 400mg and 500mg dose levels in the dose exploration phase is preliminarily confirmed, the dose expansion phase will be entered to further evaluate the safety and tolerability of the combination of the compound of formula (A) and fulvestrant, as well as to preliminarily evaluate the anti-tumor efficacy. The dosing regimen for the subjects is the same as in the dose exploration phase, with 400mg or 500mg of the compound of formula (A) taken orally daily for 21 consecutive days, followed by a 7-day rest, and a dosing cycle of 28 days. The combined drug fulvestrant is injected intramuscularly once on the first day of each cycle, 500mg each time (administered in two intramuscular injections, 250mg once in each buttock), and another 500mg dose is given two weeks after the first dose, with a dosing cycle of 28 days. All subjects can continue to receive the drug until the disease progresses, or intolerable toxicity occurs, or the subject voluntarily withdraws, or the subject dies, or is lost to follow-up (whichever occurs first).

[0199] Research results: In the dose-finding phase, all 6 subjects receiving combination therapy completed dose-limiting toxicity (DLT) observation, and no DLT events occurred.

[0200] (1) Safety data of combination therapy: A safety analysis was conducted on the subjects who had received the drug, which showed that the overall safety of the combination therapy was good and controllable, and the types of adverse events were similar to those of drugs with the same target. The incidence of adverse events related to drug treatment (TRAE) was 100%, most of which were grade 1-2 adverse events, and there were no reports of grade 3 or higher adverse events or serious adverse events. Common TRAEs were mainly diarrhea (100%), vomiting (75.0%), hypercholesterolemia (62.5%), hyperglycemia (50.0%), nausea (50.0%), increased glycated hemoglobin (37.5%), increased AST / ALT (37.5%), proteinuria (37.5%), increased lipase (37.5%), hypoalbuminemia (25.0%), etc.

[0201] (2) Preliminary efficacy of combined therapy: Tumors were evaluated after treatment in 5 subjects in the dose expansion phase. Among them, 1 subject had no measurable target lesions and the overall efficacy was assessed as stable disease (SD); 1 subject had a confirmed partial response (PR), with the tumor lesion shrinking from 32.9 mm at baseline to 16 mm; 3 subjects had SD, of which 1 had a tumor lesion shrinking 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 withdrawals.

[0202] (3) Pharmacokinetic (PK) Data: During the dose-finding and dose-expansion phases, blood samples were collected after dosing to measure the corresponding parameters. PK data for a total of 6 subjects in the 400 mg group have been collected. Comparison of available data reveals the pharmacokinetic data for the compound of formula (A) in the 400 mg dose group, both as a single agent and in combination with fulvestrant. Detailed PK data are summarized in Tables 15 and 16 below.

[0203] Table 15. PK indicators of the combination of the compound of formula (A) and fulvestrant in the dose-finding phase

[0204] Table 16. PK indicators of the combination of the compound of formula (A) and fulvestrant in the dose expansion phase

[0205] Example 6: Study on the efficacy and safety of the compound of formula (A) tablets combined with fulvestrant in patients with locally advanced or metastatic HR-positive and HER-2-negative breast cancer who have failed standard treatment

[0206] Study objective: To evaluate the anti-tumor efficacy and safety of the compound of formula (A) combined with fulvestrant versus placebo combined with fulvestrant in the treatment of patients with locally advanced or metastatic HR-positive and HER-2-negative breast cancer in the overall population and the subgroup population with PIK3CA / AKT1 / PTEN alterations.

[0207] Study Design: This study is a randomized, controlled, double-blind, multicenter study designed for patients with recurrent locally advanced or metastatic HR-positive and HER-2-negative breast cancer who have previously received first- to second-line systemic therapy (at least one line of endocrine therapy). Enrolled subjects will be randomly assigned in a 1:1 ratio to either the (A) compound plus fulvestrant group or the placebo plus fulvestrant group. The proposed dosing regimen for the compound of formula (A) is 400 mg or 500 mg once daily for 21 consecutive days, followed by a 7-day rest period, with a dosing cycle of 28 days. The actual dose and frequency of administration may be adjusted based on the results of the exploratory study and quantitative pharmacological model analysis.

[0208] The combination drug Fulvestrant was administered according to standard treatment, intramuscularly, once on the first day of each cycle, 500 mg each time (administered as two intramuscular injections, 250 mg once in each buttock), and another 500 mg dose was given two weeks after the first dose. One dosing cycle was 28 days.

[0209] Endpoints: The primary endpoint was progression-free survival (PFS) for the overall population and the PIK3CA / AKT1 / PTEN alteration subgroup, as assessed by investigators according to RECIST 1.1. The key secondary endpoint was overall survival (OS) for the overall population and the PIK3CA / AKT1 / PTEN alteration subgroup. All subjects received continuous dosing until disease progression, unacceptable toxicity, voluntary withdrawal, death, or loss to follow-up (whichever occurred first).

Claims

1. Use of a compound represented by formula (I) or a pharmaceutically acceptable salt or a hydrate thereof in the preparation of a drug for preventing or treating breast cancer, wherein: The breast cancer is hormone receptor positive breast cancer, 2. The use according to claim 1, wherein The compound of formula (I) is a compound of formula (A) or a compound of formula (B):

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

4. The use according to any one of claims 1 to 3, characterized in that: The breast cancer is HR-positive breast cancer; Preferably, it is HR-positive and HER-2-negative breast cancer; more preferably, it is ER-positive, PR-positive and HER2-negative hormone receptor-positive breast cancer; further preferably, it is HR-positive and HER-2-negative breast cancer that has failed standard treatment, is locally advanced or metastatic; further preferably, it is HR-positive and HER-2-negative breast cancer that has failed standard treatment, is locally advanced or metastatic, with or without PI3K / Akt / PTEN pathway changes.

5. The use according to claim 3 or 4, wherein The combined administration method is selected from simultaneous, concurrent, independent or sequential application; the combined administration route is selected from oral, parenteral, rectal, pulmonary or local administration.

6. The use according to any one of claims 3 to 5, wherein The dosage of the compound of formula (A) is 0.1 to 1000 mg; preferably 20 to 500 mg; more preferably 100, 200, 300, 400 or 500 mg; further preferably 300, 400 or 500 mg; 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; preferably once a day or twice a day; Preferably, the compound of formula (A) is administered once a day, twice a day or three times a day for 21 consecutive days, followed by an interval of 1 to 2 weeks without administration of the compound; or administered for 5 or 4 consecutive days, followed by an interval of 1 to 3 days without administration of the compound; Further preferably, the administration frequency of the compound of formula (A) is once a day or twice a day, for 21 consecutive days, followed by a 1-week interval without administration of the compound; or for 5 consecutive days, followed by a 2-day interval without administration of the compound; or for 4 consecutive days, followed by a 3-day interval without administration of the compound.

7. The use according to any one of claims 3 to 6, wherein The dosage of Fulvestrant is 0.1 to 800 mg; preferably 20 to 500 mg; more preferably 100, 200, 300, 400 or 500 mg; further preferably 300, 400 or 500 mg; the administration frequency 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. The use according to any one of claims 3 to 7, wherein One cycle is 28 days; the administration frequency of the compound of formula (A) is 21 consecutive days, followed by a 1-week interval between each administration cycle; the administration frequency of Fulvestrant is one administration two weeks after the first administration of the first cycle, and then one administration on the first day of each cycle.

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

1.

10. The use according to any one of claims 1 to 9, wherein The pharmaceutically acceptable salt of the compound of formula (A) is an organic acid salt or an inorganic acid salt; wherein the organic acid salt includes one or more of fumarate, methanesulfonate, hydroxyethanesulfonate, α-naphthalenesulfonate, p-toluenesulfonate, 1,2-ethanedisulfonate, oxalate, maleate, citrate, succinate, L-(+)-tartrate, hippurate, L-ascorbate, L-malate, benzoate or gentisate; the inorganic acid salt includes one or more of hydrochloride, sulfate or phosphate; preferably fumarate; more preferably monofumarate; further preferably monofumarate dihydrate.

11. A pharmaceutical composition or drug combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and fulvestrant, and one or more pharmaceutically acceptable carriers; Preferably, the compound of formula (I) is a compound of formula (A) or a compound of formula (B): Preferably, the pharmaceutically acceptable salt of the compound of formula (A) is an organic acid salt or an inorganic acid salt; wherein, The organic acid salt includes one or more of fumarate, methanesulfonate, hydroxyethanesulfonate, α-naphthalenesulfonate, p-toluenesulfonate, 1,2-ethanedisulfonate, oxalate, maleate, citrate, succinate, L-(+)-tartrate, hippurate, L-ascorbate, L-malate, benzoate or gentisate; the inorganic acid salt includes one or more of hydrochloride, sulfate or phosphate; preferably fumarate; more preferably monofumarate; further preferably monofumarate dihydrate.