Use of AKT inhibitor in preparation of drug for preventing or treating ovarian cancer

Abstract

Use of an AKT inhibitor in the preparation of a drug for preventing or treating ovarian cancer, and use of an AKT inhibitor in combination with other drugs for treating ovarian cancer comprising one or more of a PARP inhibitor, a plant-based chemotherapy drug, an antibiotic chemotherapy drug, a platinum drug and an alkylating agent in the preparation of a drug for preventing or treating ovarian cancer. The combined administration can effectively inhibit the growth of ovarian tumor cells and cell colony formation, and is significantly superior to the administration of a single drug. In addition, the combined administration has an additive or synergistic effect, has few toxic side effects on normal cells and has a high safety, provides a more effective method for treating ovarian cancer, and has an important clinical value.

Description

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

[0001] This application claims priority to Chinese patent application No. 202310707215.6, filed on June 14, 2023, and Chinese patent application No. 202311223529.5, filed on September 21, 2023. This application cites the full text of the above-mentioned Chinese patent applications. Technical Field

[0002] The present invention belongs to the field of biomedicine. Specifically, the present application relates to the use of an AKT inhibitor in the preparation of a drug for preventing or treating ovarian cancer. Background Art

[0003] Cancer is second only to cardiovascular disease in terms of mortality, with both the number of cancer patients and deaths increasing globally. Ovarian cancer is a common malignancy in women, with the highest mortality rate among all cancers in women. Due to the lack of obvious symptoms in its early stages, the disease is insidious, making it prone to misdiagnosis. Most ovarian cancer patients have already developed metastases by the time they are diagnosed, making surgery alone ineffective in completely eliminating the tumor and leading to a high risk of recurrence. Over 70% of patients are diagnosed in the advanced stage, and approximately 70% experience recurrence within two years of surgery.

[0004] Drug therapy is an adjunct to surgical treatment of ovarian cancer, and commonly used therapeutic drugs are platinum compounds. Platinum compounds (such as cisplatin and carboplatin) can activate the DNA damage response, causing DNA damage, thereby inducing cell apoptosis and exerting significant anti-cancer activity. Although tumor cells are initially sensitive to platinum treatment, ovarian cancer patients are prone to drug resistance. Resistance to platinum may be attributed to upregulation of the ABCB1 gene, reversal of BRCA1 and BRCA2 germline alleles, or impaired apoptosis pathways. Therefore, there is an urgent need to develop a reliable drug to treat drug-resistant ovarian cancer.

[0005] Currently, the anti-ovarian cancer drugs under development are primarily targeted drugs. Targeted therapies specifically target altered genes or proteins in tumor cells. They offer advantages such as high specificity, significant efficacy, and minimal toxicity and side effects, making them a novel treatment option alongside the three traditional treatments of surgery, radiotherapy, and chemotherapy.

[0006] Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors are new molecular targeted anti-tumor drugs developed and marketed in recent years. They are clinically indicated for patients with advanced ovarian cancer who have or do not have mutations in the tumor suppressor gene BRCA. PARP-1 inhibitors work through a "synergistic lethal effect," meaning that in the presence of DNA homologous recombination defects caused by BRCA mutations, the simultaneous action of PARP-1 inhibitors and BRCA gene mutations can further aggravate DNA damage, preventing DNA repair in ovarian cancer cells with BRCA mutations and leading to their death. Currently, several PARP-1 inhibitors, including olaparib, rucaparib, niraparib, talazoparib, and fluzoparib, have been approved for marketing or are in clinical trials.

[0007] AKT is a type of serine / threonine kinase that affects cell survival, growth, metabolism, proliferation, migration and differentiation through numerous downstream effectors. More than 50% of human tumors have overactivation of AKT. Overactivation of AKT can lead to tumorigenesis, metastasis and drug resistance. AKT has three subtypes: AKT1, AKT2 and AKT3. As a typical protein kinase, each subtype consists of an amino-terminal PH domain (Pleckstrin homology domain), a central ATP-binding kinase domain and a carboxyl-terminal regulatory domain. The three subtypes share approximately 80% amino acid sequence homology, with only significant differences in the linker region between the PH domain and the kinase domain. Therefore, molecular targeted therapy targeting AKT is also an important direction in the current development of tumor targeted drugs.

[0008] 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):

[0009] 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) being used in combination with other ovarian cancer therapeutics to prepare drugs for the prevention or treatment of ovarian cancer.

[0010] Summary of the Invention

[0011] 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 ovarian cancer, and in particular to provide a use of an AKT inhibitor in combination with other ovarian cancer therapeutic drugs in the preparation of a drug for preventing or treating ovarian cancer.

[0012] To achieve the above objectives, the present invention provides the following technical solutions:

[0013] A use of an AKT inhibitor in the preparation of a drug for preventing or treating ovarian 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,

[0014] In some embodiments, the compound of formula (I) is a compound of formula (A) or a compound of formula (B):

[0015] The present invention also provides a use of an AKT inhibitor in the preparation of a drug for preventing or treating ovarian 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.

[0016] In one embodiment of the present invention, the ovarian cancer is platinum-resistant ovarian cancer.

[0017] In one embodiment of the present invention, the ovarian cancer is platinum-resistant high-grade serous carcinoma, platinum-resistant ovarian adenocarcinoma, platinum-resistant epithelial serous carcinoma, platinum-resistant clear cell carcinoma, platinum-resistant endometrioid ovarian cancer, platinum-resistant fallopian tube cancer or platinum-resistant primary peritoneal cancer.

[0018] In one embodiment of the present invention, the ovarian cancer is platinum-resistant high-grade serous carcinoma or platinum-resistant ovarian adenocarcinoma.

[0019] In one embodiment of the present invention, the ovarian cancer is locally advanced or metastatic ovarian cancer.

[0020] In one embodiment of the present invention, the ovarian cancer is locally advanced or metastatic ovarian cancer that has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

[0021] In one embodiment of the present invention, the ovarian cancer is platinum-resistant locally advanced or metastatic ovarian cancer.

[0022] In one embodiment of the present invention, the ovarian cancer is platinum-resistant locally advanced or metastatic ovarian cancer that has failed standard treatment, has no standard treatment options, or is not currently suitable for standard treatment.

[0023] In one embodiment of the present invention, the compound of formula (A) is used in combination with other drugs for treating ovarian cancer.

[0024] In one embodiment of the present invention, the administration of the combined use is selected from simultaneous, concurrent, independent or sequential application.

[0025] 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.

[0026] In one embodiment of the present invention, the other ovarian cancer treatment drugs include one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs, platinum drugs or alkylating agents; preferably one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs or platinum drugs.

[0027] In one embodiment of the present invention, the compound of formula (A) is used in combination with a PARP inhibitor.

[0028] In one embodiment of the present invention, the PARP inhibitor includes one or more of niraparib, olaparib, rucaparib, talazoparib or fluzoparib; preferably niraparib or olaparib.

[0029] In a preferred embodiment of the present invention, the PARP inhibitor is niraparib.

[0030] In a preferred embodiment of the present invention, the PARP inhibitor is olaparib.

[0031] 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, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg , 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 700mg, 750mg, 800mg, 900mg or 1000mg and values ​​between any two of the above values ​​(although not listed one by one, but deemed to be clearly indicated); preferably 20-500mg; more preferably 200-400mg; more preferably 100, 200, 300, 400 or 500mg; further preferably 300, 400 or 500mg.

[0032] 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).

[0033] 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.

[0034] 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.

[0035] 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.

[0036] In one embodiment of the present invention, the dosage of the PARP inhibitor is 100 to 1000 mg, specifically 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, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg 0mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg or 1000mg and values ​​between any two of the above values ​​(although not listed one by one, but deemed to be clearly indicated); preferably 100-600mg; more preferably 200mg, 400mg, 300mg or 600mg.

[0037] In one embodiment of the present invention, the PARP inhibitor can be 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, twice a day, or three times a day.

[0038] In one embodiment of the present invention, a cycle is 28 days; the administration frequency of the compound of formula (A) is 21+7, and the dosage is 200-400 mg / time; the administration frequency of the PARP inhibitor is once a day, and the dosage is 300 mg / time.

[0039] 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 without administration of the compound, and the dosage is 200-400 mg / time; the administration frequency of the PARP inhibitor is once a day, and the dosage is 300 mg / time.

[0040] 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 without administration of the compound, and the dosage is 200-400 mg / time; the administration frequency of niraparib is once a day, and the dosage is 300 mg / time.

[0041] 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 without administration of the compound, and the dosage is 200-400 mg / time; the administration frequency of olaparib is once a day, and the dosage is 300 mg / time.

[0042] In one embodiment of the present invention, the dosage ratio of the compound of formula (A) to the PARP inhibitor is selected from 1:0.1-300, preferably 1:0.1, 1:0.2, 1:0.5, 1:1, 1:2.5, 1:1.5, 1:2, 1:3, 1:5, 1:6.5, 1:8, 1:10, 1:15, 1:20, 1:30, 1:45, 1:50, 1:60, 1:75, 1:85, 1:90, 1:100, 1:120, 1:150, 1:200, 1:250 or 1:300, and values ​​between any two of the above values ​​(although not listed one by one, but deemed to be clearly indicated).

[0043] In one embodiment of the present invention, the dosage ratio of the compound of formula (A) to niraparib is selected from 1:0.01-300, preferably 1:0.01, 1:0.1, 1:0.2, 1:0.5, 1:0.75, 1:1, 1:2.5, 1:1.5, 1:2, 1:3, 1:5, 1:6.5, 1:8, 1:10, 1:15, 1:20, 1:30, 1:45, 1:50, 1:60, 1:75, 1:85, 1:90, 1:100, 1:120, 1:150, 1:200, 1:25 0 or 1:300 and values ​​between any two of the above values ​​(although not listed one by one, but deemed to be clearly indicated); preferably 1:0.75, 1:1, 1:1.3, 1:1.5, 1:2.7, 1:3.1, 1:4.6, 1:6.3, 1:6.6, 1:7, 1:8, 1:10, 1:13, 1:20, 1:21, 1:25, 1:30, 1:33, 1:40, 1:50 or 1:60 and values ​​between any two of the above values ​​(although not listed one by one, but deemed to be clearly indicated); more preferably 1:0.75, 1:1 or 1:0.5.

[0044] In one embodiment of the present invention, the dosage ratio of the compound of formula (A) to olaparib is selected from 1:0.01-300, preferably 1:0.01, 1:0.1, 1:0.2, 1:0.5, 1:0.75, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, 1:5, 1:6, 1:7:1:8, 1:10, 1:15, 1:20, 1:30, 1:40, 1:50, 1:60, 1:75, 1:85, 1:90, 1:100, 1:120, 1:130, 1:140, 1:150, 1:160, 1:175, 1:185, 1:190, 1:100, 1:110, 1:120, 1:130, 1:140, 1:150, 1:160, 1:175, 1:185, 1:190, 1:100, 1:111 :150, 1:200, 1:250 or 1:300 and values ​​between any two of the above values ​​(although not listed one by one, but deemed to be clearly indicated); preferably 1:0.75, 1:1, 1:1.6, 1:2.5, 1:3.1, 1:4, 1:5, 1:6, 1:6.3, 1:6.6, 1:7, 1:8, 1:25, 1:39, 1:40, 1:50 or 1:100 and values ​​between any two of the above values ​​(although not listed one by one, but deemed to be clearly indicated); more preferably 1:0.75, 1:1 or 1:1.5.

[0045] In one embodiment of the present invention, the dosage ratio of the compound of formula (A) to olaparib is selected from 1:5 or 1:6.3 by mass ratio.

[0046] In one embodiment of the present invention, the dosage ratio of the compound of formula (A) to olaparib is selected from 1:1.25 by mass ratio.

[0047] In one embodiment of the present invention, the compound of formula (A) is used in combination with a platinum drug.

[0048] In one embodiment of the present invention, the platinum drug includes one or more of cisplatin, carboplatin, lobaplatin or nedaplatin; preferably carboplatin.

[0049] In one embodiment of the present invention, the dosage of carboplatin is 50 to 1000 mg, specifically 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 The present invention relates to an oral dosage of 400mg, 500mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg or 1000mg, and values ​​between any two of the above values ​​(although not listed one by one, but deemed to be clearly indicated); preferably 400-800mg; more preferably 400mg, 500mg, 600mg, 700mg or 800mg.

[0050] In one embodiment of the present invention, the administration frequency of carboplatin can be once a day, once a week, once every two weeks, once every three weeks, once a month, once every two months, once every three weeks, once every four weeks, once every three weeks (administered once over 5 days), and once every four weeks (administered once over 5 days).

[0051] 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 without administration of the compound; the administration frequency of carboplatin can be once a week for 3 consecutive weeks.

[0052] In one embodiment of the present invention, the dosage ratio of the compound of formula (A) to carboplatin, calculated by mass ratio, is selected from 1:0.1-300; preferably 1:0.1, 1:0.2, 1:0.5, 1:1, 1:2.5, 1:1.5, 1:2, 1:3, 1:5, 1:6.5, 1:8, 1:10, 1:15, 1:20, 1:30, 1:45, 1:50, 1:60, 1:75, 1:85, 1:90, 1:100, 1:120, 1:150, 1:200, 1:250 or 1:300, and values ​​between any two of the above values ​​(although not listed one by one, but deemed to be clearly indicated); preferably 1:0.2, 1:0.5, 1:1, 1:2.5, 1:1.5, 1:2 or 1:3; more preferably 1:1, 1:1.5 or 1:2.

[0053] In one embodiment of the present invention, the dosage ratio of the compound of formula (A) to carboplatin is selected from 1:1 by mass ratio.

[0054] In one embodiment of the present invention, the compound of formula (A) is used in combination with a phytochemical chemotherapeutic agent.

[0055] In one embodiment of the present invention, the plant-based chemotherapy drug includes one or more of vincristine, vinblastine, etoposide or paclitaxel; preferably paclitaxel; more preferably paclitaxel injection.

[0056] In one embodiment of the present invention, the dosage of paclitaxel is 1 to 300 mg / m 2 , can be selected from 10mg / m 2 , 30mg / m 2 , 50mg / m 2 , 55mg / m 2 , 60mg / m 2 , 65mg / m 2 , 70mg / m 2 , 75mg / m 2 , 80mg / m 2 , 85mg / m 2 , 90mg / m 2 , 95mg / m 2 , 100mg / m 2 , 105mg / m 2 , 110mg / m 2 , 115mg / m 2 , 120mg / m 2 , 125mg / m 2 , 130mg / m 2 , 135mg / m 2 , 140mg / m 2 , 145mg / m 2 , 150mg / m 2 , 155mg / m 2 , 160mg / m 2 , 165mg / m 2 , 170mg / m 2 , 175mg / m 2 , 180mg / m 2 , 185mg / m 2 , 190mg / m 2 , 195mg / m 2 , 200mg / m 2 , 205mg / m 2 , 210mg / m 2 , 215mg / m 2 , 220mg / m 2 , 225mg / m 2, 230mg / m 2 , 235mg / m 2 , 240mg / m 2 , 245mg / m 2 , 250mg / m 2 , 255mg / m 2 , 260mg / m 2 , 265mg / m 2 , 270mg / m 2 , 275mg / m 2 , 280mg / m 2 , 285mg / m 2 , 290mg / m 2 , 295mg / m 2 or 300 mg / m 2 and values ​​between any two of the above values ​​(although not listed one by one, but deemed to be clearly indicated); preferably 10 to 150 mg / m 2 More preferably 40 to 100 mg / m 2 ; More preferably 60mg / m 2 , 70mg / m 2 , 80mg / m 2 , 90mg / m 2 or 100 mg / m 2 ; further preferably 80mg / m 2 .

[0057] In one embodiment of the present invention, the administration frequency of paclitaxel can be once a day, once a week, once every two weeks, once every three weeks, once a month, once every two months, once a week (once for 2 weeks and rest for 1 week), once a week (once for 3 weeks and rest for 1 week), once a week (once for 6 weeks and rest for 2 weeks), once every 3 weeks or once every 4 weeks; preferably, once a week (once for 3 weeks and rest for 1 week).

[0058] In one embodiment of the present invention, a cycle is 28 days; the frequency of administration of the compound of formula (A) is 21+7, and the dosage is 200-400 mg / time; the frequency of administration of paclitaxel is once a week (on for 3 weeks and off for 1 week, administered on days 1, 8, and 15 of each cycle), and the dosage is 80 mg / m 2 / Second-rate.

[0059] In one embodiment of the present invention, a cycle of 28 days is used; the compound of formula (A) is administered for 21 consecutive days, followed by a one-week interval without administration of the compound, at a dose of 200 to 400 mg / time; paclitaxel is administered on days 1, 8, and 15 of each cycle, at a dose of 80 mg / m 2 / Second-rate.

[0060] In one embodiment of the present invention, the dosage ratio of the compound of formula (A) to paclitaxel is selected from 0.01-300:1, preferably 0.01:1, 0.1:1, 0.2:1, 0.5:1, 1:1, 1.5:1, 2:1, 3:1, 4:1, 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. 1, 200:1, 220:1, 250:1 or 300:1 and values ​​between any two of the above values ​​(although not listed one by one, but deemed to be clearly indicated); preferably 1:1, 1.5:1, 2:1, 3:1, 4:1, 5:1, 8:1, 10:1, 12:1, 15:1, 18:1 or 20:1 and values ​​between any two of the above values ​​(although not listed one by one, but deemed to be clearly indicated); more preferably 1:1, 1.5:1, 2:1, 3:1 or 4:1.

[0061] In one embodiment of the present invention, the dosage ratio of the compound of formula (A) to paclitaxel is selected from 4:1 by mass ratio.

[0062] In a preferred embodiment of the present invention, the compound of formula (A) is used in combination with an antibiotic chemotherapy drug.

[0063] In one embodiment of the present invention, the antibiotic chemotherapy drug includes one or more of actinomycin D, mitomycin, doxorubicin, doxorubicin, epirubicin or daunorubicin; preferably doxorubicin; more preferably liposome doxorubicin.

[0064] In one embodiment of the present invention, the dosage of doxorubicin is 0.1 to 300 mg / m 2 , 1mg / m 2 , 2.5mg / m 2 , 5mg / m 2 , 7.5mg / m 2 , 10mg / m 2 , 12.5mg / m 2 , 15mg / m 2 , 17.5mg / m 2 , 20mg / m 2 , 22.5mg / m 2 , 25mg / m 2 , 30mg / m 2 , 32.5mg / m 2 , 35mg / m 2 , 37.5mg / m 2 , 40mg / m 2 , 50mg / m 2 , 52.5mg / m2 , 55mg / m 2 , 60mg / m 2 , 65mg / m 2 , 70mg / m 2 , 75mg / m 2 , 80mg / m 2 , 85mg / m 2 , 90mg / m 2 , 95mg / m 2 , 100mg / m 2 , 105mg / m 2 , 110mg / m 2 , 120mg / m 2 , 130mg / m 2 , 140mg / m 2 , 150mg / m 2 , 160mg / m 2 , 170mg / m 2 , 180mg / m 2 , 190mg / m 2 , 200mg / m 2 , 210mg / m 2 , 220mg / m 2 , 230mg / m 2 , 240mg / m 2 , 250mg / m 2 , 260mg / m 2 , 270mg / m 2 , 280mg / m 2 , 290mg / m 2 or 300 mg / m 2 and values ​​between any two of the above values ​​(although not listed one by one, but deemed to be clearly indicated); preferably 1 to 100 mg / m 2 More preferably, 10 to 60 mg / m 2 ; More preferably 10mg / m 2 , 20mg / m 2 , 30mg / m 2 , 40mg / m 2 or 50 mg / m 2 ; further preferably 40mg / m 2 .

[0065] In one embodiment of the present invention, the administration frequency of doxorubicin can 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, once every three weeks, or once every four weeks; more preferably once every four weeks; and further preferably once every four weeks (administered on the first day of each cycle).

[0066] In one embodiment of the present invention, a cycle of 28 days is used; the frequency of administration of the compound of formula (A) is 21+7, and the dosage is 200-400 mg / time; the frequency of administration of doxorubicin is once every four weeks (administered on the first day of each cycle), and the dosage is 40 mg / m 2 / Second-rate.

[0067] In one embodiment of the present invention, a cycle is 28 days; the frequency of administration of the compound of formula (A) is 21 consecutive days, followed by a 1-week interval without administration of the compound, and the dosage is 200-400 mg / time; the frequency of administration of doxorubicin is 80 mg / m2 on the first day of each cycle. 2 / Second-rate.

[0068] In one embodiment of the present invention, the dosage ratio of the compound of formula (A) to doxorubicin is selected from 0.01-300:1, 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, 10 0:1, 130:1, 150:1, 180:1, 200:1, 220:1, 250:1 or 300:1 and values ​​between any two of the above values ​​(although not listed one by one, but deemed to be clearly indicated); preferably 3:1, 5:1, 8:1, 10:1, 12:1, 15:1, 18:1 or 20:1 and values ​​between any two of the above values ​​(although not listed one by one, but deemed to be clearly indicated).

[0069] In one embodiment of the present invention, the compound of formula (A) is used in combination with one or more of a PARP inhibitor, a botanical chemotherapeutic drug or an antibiotic chemotherapeutic drug.

[0070] In one embodiment of the present invention, the compound of formula (A) is used in combination with one or more of niraparib, paclitaxel or doxorubicin.

[0071] In one embodiment of the present invention, the compound of formula (A) is used in combination with niraparib, paclitaxel or doxorubicin.

[0072] In one embodiment of the present invention, the above-mentioned combined use can be further used in combination with other treatment methods in addition to PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs or platinum drugs, for example, further combined with other chemotherapy, hormones, antibody reagents, targeted drugs and surgery and / or radiotherapy.

[0073] 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 or prodrug (which will be converted into the free base form in vivo), such as a fumarate salt, preferably a monofumarate salt.

[0074] In one embodiment of the present invention, the pharmaceutically acceptable salt of the compound of formula (A) is a fumarate dihydrate, the chemical name of which 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 fumarate dihydrate, and the chemical formula is shown in the following formula (I-1):

[0075] In one embodiment of the present invention, other ovarian cancer therapeutic drugs can be administered to patients in the form of free bases, or in the form of pharmaceutically acceptable salts, hydrates or prodrugs (which will be converted to free base forms in vivo), such as salts of PARP inhibitors.

[0076] The present invention also provides a pharmaceutical combination or pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and other ovarian cancer therapeutic drugs, and one or more pharmaceutically acceptable carriers; the other ovarian cancer therapeutic drugs include one or more of PARP inhibitors, botanical chemotherapy drugs, antibiotic chemotherapy drugs, platinum drugs, or alkylating agents; preferably one or more of PARP inhibitors, botanical chemotherapy drugs, antibiotic chemotherapy drugs, or platinum drugs;

[0077] In some embodiments, the compound of formula (I) is a compound of formula (A) or a compound of formula (B):

[0078] The present invention also provides a pharmaceutical combination or pharmaceutical composition containing a compound of formula (A) and other ovarian cancer therapeutic drugs, and one or more pharmaceutically acceptable carriers; the other ovarian cancer therapeutic drugs include one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs, platinum drugs or alkylating agents; preferably one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs or platinum drugs.

[0079] In the drug combination or pharmaceutical composition of the present invention, the PARP inhibitor includes one or more of niraparib, olaparib, rucaparib, talazoparib or fluzoparib, preferably niraparib or olaparib; the plant-based chemotherapy drugs include one or more of vincristine, vinblastine, etoposide or paclitaxel; preferably paclitaxel; the platinum drugs include one or more of cisplatin, carboplatin, lobaplatin or nedaplatin; preferably carboplatin; the antibiotic chemotherapy drugs include one or more of actinomycin D, mitomycin, doxorubicin, doxorubicin, epirubicin or daunorubicin; preferably doxorubicin.

[0080] In the pharmaceutical combination or pharmaceutical composition of the present invention, the mass ratio of the compound of formula (A) to other ovarian cancer therapeutic drugs is as described above.

[0081] In the pharmaceutical combination or pharmaceutical composition of the present invention, the administration method, dosage, and frequency of administration of the compound of formula (A) and other ovarian cancer therapeutic drugs are as described above.

[0082] The pharmaceutical composition of the present invention can be prepared into any pharmaceutically acceptable dosage form. For example, it can be formulated into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection, and concentrated solutions for injection), liposomes, suppositories, inhalants, or sprays.

[0083] The pharmaceutical compositions 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 administered orally, the pharmaceutical compositions can be formulated into oral preparations, such as oral solid preparations, such as tablets, capsules, pills, granules, or the like; or oral liquid preparations, such as oral solutions, oral suspensions, and syrups. When formulated into oral preparations, the pharmaceutical preparations can further contain suitable fillers, binders, disintegrants, lubricants, and the like.

[0084] The pharmaceutical composition of the present invention can be administered alone, or can be further used in combination with other treatment methods other than PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs or platinum drugs, for example, combined treatment with other chemotherapy, hormones, antibodies, targeted drugs and other therapeutic agents as well as surgery and / or radiotherapy.

[0085] The present invention also provides a method for preventing and / or treating ovarian cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (A) and other ovarian cancer therapeutic drugs, wherein the other ovarian cancer therapeutic drugs include one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs, platinum drugs or alkylating agents; preferably one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs or platinum drugs.

[0086] The present invention also provides a method for preventing and / or treating ovarian cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (A) and other ovarian cancer therapeutic drugs, wherein the other ovarian cancer therapeutic drugs include one or more of niraparib, olaparib, paclitaxel, doxorubicin or carboplatin.

[0087] The present invention also provides a method for preventing and / or treating ovarian cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (A) and other ovarian cancer therapeutic drugs, wherein the other ovarian cancer therapeutic drugs include niraparib, olaparib, paclitaxel, doxorubicin or carboplatin.

[0088] The present invention also provides a method for preventing and / or treating ovarian cancer, comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition of a compound of formula (A) and other ovarian cancer therapeutic drugs, wherein the other ovarian cancer therapeutic drugs include one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs, platinum drugs or alkylating agents; preferably one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs or platinum drugs.

[0089] The present invention also provides a method for preventing and / or treating ovarian cancer, comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition of a compound of formula (A) and other ovarian cancer therapeutic drugs, wherein the other ovarian cancer therapeutic drugs include one or more of niraparib, olaparib, paclitaxel, doxorubicin or carboplatin.

[0090] The present invention also provides a method for preventing and / or treating ovarian cancer, comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition of a compound of formula (A) and other ovarian cancer therapeutic drugs, wherein the other ovarian cancer therapeutic drugs include niraparib, olaparib, paclitaxel, doxorubicin or carboplatin. Beneficial effects:

[0091] The present invention provides a use of an AKT inhibitor alone or in combination with other ovarian cancer therapeutic drugs in the preparation of a drug for preventing or treating ovarian cancer. The AKT inhibitor can effectively inhibit the growth and cell clone formation of ovarian tumor cells. The combined effect is significantly better than that of a single drug, with additive or synergistic effects. At the same time, it has low toxic side effects on normal cells and high safety. It provides a more effective method for treating ovarian cancer and has important clinical value.

[0092] Related definitions

[0093] Unless otherwise specified, the following terms used in the specification and claims have the following meanings:

[0094] The term "combination" as used herein refers to 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 a compound of formula (A) and at least one dose of another ovarian cancer therapeutic drug (such as a PARP inhibitor) 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 the other ovarian cancer therapeutic drug can be administered simultaneously or sequentially. Any of the above methods include administering the compound of formula (A) and the other ovarian cancer therapeutic drug via the same route of administration or different routes of administration. 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 the other ovarian cancer therapeutic drug; in one embodiment, multiple doses of the compound of formula (A) are administered simultaneously or separately with multiple doses of the other ovarian cancer therapeutic drug; in one embodiment, multiple doses of the compound of formula (A) are administered simultaneously or separately with one dose of the other ovarian cancer therapeutic drug; in one embodiment, one dose of the compound of formula (A) is administered simultaneously or separately with multiple doses of the other ovarian cancer therapeutic drug; in one embodiment, one dose of the compound of formula (A) is administered simultaneously or separately with one dose of the other ovarian cancer therapeutic drug; in all embodiments, the compound of formula (A) may be administered first, or the other ovarian cancer therapeutic drug 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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 other ovarian cancer therapeutic drugs 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. Usually, an assay suitable for the condition being treated can be used to monitor the patient's therapeutic effect, or conventional tests and procedures well known in the art can be used to determine the optimal dose. 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.

[0102] 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.

[0103] 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).

[0104] 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.

[0105] The term "standard treatment" used in this article refers to a pre-treatment assessment of the patient's condition, followed by the selection of an appropriate treatment plan. During treatment, the doctor will adjust the treatment plan based on changes in the patient's condition. The treatment model for ovarian cancer is surgery / neoadjuvant chemotherapy followed by surgery, post-operative adjuvant chemotherapy, maintenance therapy, and multiple lines of treatment for recurrence after initial treatment.

[0106] "Standard treatment failure" as described in this article refers to tumor progression or the appearance of new tumors after receiving standard treatment.

[0107] In this article, according to the Chinese Anti-Cancer Association, Guidelines for the Diagnosis and Treatment of Ovarian Tumors (Fifth Edition), 6.1 Classification of Recurrent Ovarian Cancer: Referring to the criteria of the American Gynecologic Oncology Group (GOG): "Platinum resistance" refers to a response to initial chemotherapy but progression or recurrence within 6 months after completion of chemotherapy.

[0108] Herein, the term "locally advanced" refers to a tumor that is confined to the primary organ or adjacent tissues and organs, but may have been onset for a long time and the tumor is relatively large, but has not yet metastasized to distant organs.

[0109] 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.

[0110] 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.

[0111] The "objective response rate (ORR)" mentioned in this article is defined as the proportion of subjects with complete remission (CR) and partial remission (PR) of their tumors after treatment.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] The "CA-125" mentioned in this article refers to tumor antigen 125, which is currently recognized as the most valuable observation indicator for preoperative diagnosis of ovarian cancer, observation of postoperative recurrence and prognosis evaluation.

[0116] As used herein, "GCIG" stands for Gynecologic Cancer Institute.

[0117] The "RP2D" mentioned in this article means the recommended dose for Phase II clinical trials.

[0118] The term "synergistic effect" as used herein refers to the phenomenon that the combined effects of two drugs are more effective than their individual effects, as opposed to antagonism. The compound of formula (I) or formula (A) disclosed herein is a potent AKT inhibitor, the preparation method of which is disclosed in international application WO2020156437A1. The "compound" described herein includes all stereoisomers and tautomers.

[0119] 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.

[0120] Unless otherwise specified herein, when referring to the dosage of the compound of formula (A) or fulvestrant, it refers to the dosage of the active compound. It is understood that when the compound is in the form of a pharmaceutically acceptable salt or hydrate, the dosage or the ratio of the two can still be calculated based on the active compound.

[0121] PG: Propylene glycol.

[0122] Solutol HS-15: Polyethylene glycol-15-hydroxystearic acid.

[0123] HPMC: Hydroxypropyl methylcellulose.

[0124] DMSO: dimethyl sulfoxide.

[0125] HP-β-CD: Hydroxypropyl-β-cyclodextrin.

[0126] PBS: phosphate buffered saline.

[0127] FBS: fetal bovine serum.

[0128] MW: molecular weight.

[0129] COLO-704: a high-grade serous carcinoma cell line.

[0130] SK-OV-3: epithelial serous carcinoma cell line.

[0131] OVCAR-3: a high-grade serous carcinoma cell line, platinum-resistant.

[0132] TOV-21G: clear cell carcinoma cell line.

[0133] A2780: Ovarian adenocarcinoma cell line, platinum-resistant.

[0134] ES-2: clear cell carcinoma cell line. DETAILED DESCRIPTION

[0135] The following typical examples are used to illustrate the present invention. Simple replacements or improvements made to the present invention by those skilled in the art are all technical solutions protected by the present invention.

[0136] Example 1 Experiment on the effect of the compound of formula (A) alone or in combination on the proliferation of ovarian cancer cells (COLO-704 and SK-OV-3) 1. Experimental purpose: The effect of the compound of formula (A) in combination with niraparib / olaparib on the proliferation of COLO-704 and SK-OV-3 cell lines.

[0137] 2. Experimental Methods

[0138] 2.1 Cell culture

[0139] a) COLO-704 cells were cultured in RPMI-1640 medium supplemented with 1% double-antibody and 10% FBS at 37°C and 5% CO2.

[0140] b) SK-OV-3 cells were cultured in McCoy's 5A medium supplemented with 1% double antibody and 10% FBS at 37°C and 5% CO2.

[0141] 2.2 Cell plating

[0142] a) Culture cells conventionally until the confluence reaches 80%-90%. When the required number of cells is reached, harvest the cells; b) Resuspend the cells in the corresponding culture medium, count the cells, and prepare a cell suspension of appropriate density; c) Add the COLO-704 and SK-OV-3 cell suspensions to a 384-well plate and culture in an incubator overnight.

[0143] 2.3 Preparation of compounds

[0144] a) The compound of formula (A) (using the monofumarate dihydrate of the compound of formula (A), with the concentration calculated as the compound of formula (A); refer to the preparation method disclosed in WO2022017448A1 to prepare the compound of formula (A) or a salt thereof) was diluted 3-fold from the 100 mM stock solution to 10 concentrations. b) The compound of formula (A) was diluted with DMSO from 100 mM to 12 mM, and then 3-fold diluted to 10 concentrations. c) Niraparib was diluted with DMSO from 100 mM to 32 mM, and then 2-fold diluted to 10 concentrations. d) Olaparib was diluted with DMSO from 100 mM to 80 mM and 75 mM, and then 2-fold diluted to 10 concentrations, starting from 80 mM. e) Niraparib was diluted with DMSO from 32 mM to 24 mM. f) The final DMSO concentration was 0.5%. g) Cells plus DMSO served as a high-reading control well. h) Cell-free culture medium served as a low-reading control well.

[0145] 2.4 Compound treatment of cells

[0146] a) Use alone:

[0147] 24 hours after COLO-704 and SK-OV-3 cells were plated, the compound was used alone. Compounds of formula (A), niraparib, and olaparib: 75 nL of the compound prepared in steps 2.3b)-d) plus 75 nL of DMSO were added.

[0148] b) Combination medication:

[0149] 24 hours after plating COLO-704 and SK-OV-3 cells, the compound of formula (A) was combined with niraparib: 75 nL of the compound prepared in step 2.3b) + 75 nL of the compound prepared in steps 2.3c) and e). The compound of formula (A) was combined with olaparib: 75 nL of the compound prepared in step 2.3b) + 75 nL of the compound prepared in step 2.3d).

[0150] c) Final concentration of test compound:

[0151] COLO-704, SK-OV-3 cells:

[0152] Compound of formula (A): 30000, 10000, 3333, 1111, 370, 123, 41.2, 13.7, 4.57, 1.52 nM;

[0153] Niraparib: 80,000, 40,000, 20,000, 10,000, 5,000, 2,500, 1,250, 625, 312.5, 156.25 nM;

[0154] Niraparib: 20,000, 40,000, 60,000 nM, respectively, in combination with gradient concentrations of the compound of formula (A);

[0155] Olaparib: 200,000, 150,000, 100,000, 50,000, 25,000, 12,500, 6,250, 3,125, 1,562.5, 781.25 nM;

[0156] Olaparib: 25000, 50000, 100000 nM, respectively, used in combination with gradient concentrations of the compound of formula (A).

[0157] e) The cell culture plate was centrifuged at 1000 rpm for 1 min and placed in a 37° C., 5% CO 2 incubator for 72 hours.

[0158] 2.5 CTG method detection

[0159] a) Add 30 μL of CTG reagent (CelltiterGlo kit) to each well, shake on a high-speed shaker for 2 minutes, centrifuge at 100 rpm for 1 minute, and store at room temperature in the dark for 30 minutes.

[0160] b) Read the chemiluminescent signal using an Envision instrument.

[0161] 2.6 Data Analysis

[0162] a) Compound IC 50 Calculation:

[0163] IC was calculated using GraphPadPrism 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))

[0164] X: log value of compound concentration, Y: inhibition rate (%inhibition)

[0165] Inhibition rate (% inhibition) = 100-(compound well reading-low reading control reading) / (high reading control reading-low reading control reading)*100

[0166] b) Compound combination evaluation index (Synergy.score)

[0167] The calculated cell viability inhibition rate was imported into the SynergyFinder website for the analysis of the combination index. Website: https: / / tangsoftwarelab.shinyapps.io / synergyfinder / #! / dashboard.

[0168] Evaluation index: 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.

[0169] 3. Experimental results

[0170] 3.1 IC of cell proliferation activity 50

[0171] The experiment was carried out according to the above steps, and the inhibition rate was calculated from the readings obtained.

[0172] Table 1. Study on the inhibitory effect of the compound of formula (A) combined with PARP inhibitor on the proliferation of ovarian cancer cells

[0173] 4. Experimental conclusions

[0174] As shown in Table 1, the compound of formula (A) alone or in combination with niraparib / olaparib showed good in vitro anti-cell proliferation effects on the above-mentioned tumor cells.

[0175] [[ID=...]]

[0176]

[0176] 1. Experimental purpose: To investigate the effect of the compound of formula (A) alone or in combination with niraparib / olaparib on the proliferation of three cell lines (OVCAR-3, TOV-21G, A2780).

[0177] 2. Experimental methods

[0178] 2.1 Cell culture

[0179] a) OVCAR-3 cells were cultured in RPMI 1640 medium containing 20% FBS and incubated at 37°C and 5% CO2. b) TOV-21G cells were cultured in RPMI 1640 medium containing 15% FBS and incubated at 37°C and 5% CO2. c) A2780 cells were cultured in RPMI 1640 medium containing 10% FBS and incubated at 37°C and 5% CO2.

[0180] 2.2 Cell plating

[0181] a) Culture cells routinely until confluence reaches 80%-90%. Harvest cells when the required number is reached. b) Resuspend cells in the appropriate culture medium, count, and prepare a cell suspension of appropriate density. c) Inoculate the OVCAR-3, TOV-21G, and A2780 cell suspensions into a 96-well plate at 150 μL / well and culture in an incubator overnight.

[0182] 2.3 Preparation of compounds

[0183] Table 2. Compound information

[0184] a) Drugs were added 24 hours after cell plating.

[0185] b) Compound test concentration:

[0186] 1) OVCAR-3 cells:

[0187] Compound of formula (A): 30, 15, 7.5, 3.75, 1.88, 0.94, 0.47, 0.23, 0.12, 0.06 μM;

[0188] Olaparib: 200, 100, 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39 μM;

[0189] Olaparib: 100, 50, 25 μM, respectively, in combination with gradient concentrations of the compound of formula (A);

[0190] Niraparib: 80, 70, 60, 50, 40, 30, 20, 10, 5, 2.5 μM;

[0191] Niraparib: 40, 30, 20 μM, respectively, used in combination with gradient concentrations of the compound of formula (A).

[0192] 2) TOV-21G cells:

[0193] Compound of formula (A): 5, 2.5, 1.25, 0.63, 0.31, 0.16, 0.08, 0.04, 0.02, 0.01 μM;

[0194] Olaparib: 200, 100, 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39 μM;

[0195] Olaparib: 6.25, 3.13, 1.56 μM, respectively, in combination with gradient concentrations of the compound of formula (A);

[0196] Niraparib: 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39, 0.20, 0.10 μM;

[0197] Niraparib: 3.13, 1.56, 0.78 μM, respectively, used in combination with gradient concentrations of the compound of formula (A).

[0198] 3) A2780 cells:

[0199] Compound of formula (A): 30, 15, 7.5, 3.75, 1.88, 0.94, 0.47, 0.23, 0.12, 0.06 μM;

[0200] Olaparib: 200, 100, 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39 μM.

[0201] c) Cells plus DMSO were used as high-reading control wells, and cell-free culture medium was used as low-reading control wells. The final concentration of DMSO in each well was 0.5%.

[0202] d) After drug addition, the cell culture plate was placed in a 37° C., 5% CO 2 incubator for 72 h.

[0203] 2.4 Detection

[0204] a) After drug incubation, remove the cell culture plate and equilibrate at room temperature for 30 minutes. Add 50 μL of pre-thawed and room temperature CellCounting-Lite solution to each well. Shake the plate at 450 rpm for 5 minutes on a microplate shaker and allow to stand at room temperature for 10 minutes. b) Read the chemiluminescent signal using a multi-function microplate reader.

[0205] 2.5 Data Analysis

[0206] a) IC was calculated 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))

[0207] X: log value of compound concentration, Y: inhibition rate (%inhibition)

[0208] Inhibition rate (% inhibition) = 100-(compound well reading-low reading control reading) / (high reading control reading-low reading control reading)*100

[0209] b) The Combination Index (CI value) was calculated using CompuSyn software.

[0210] Evaluation criteria: CI < 1, the interaction between the two compounds is synergistic; CI = 1, the interaction between the two compounds is additive; CI > 1, the interaction between the two compounds is antagonistic.

[0211] 3. Experimental Results

[0212] Table 3. Study on the inhibitory effect of compound of formula (A) combined with PARP inhibitor on ovarian cancer cell proliferation (OVCAR-3, TOV-21G)

[0213] Table 4. Study on the inhibitory effect of compound of formula (A) combined with PARP inhibitor on ovarian cancer cell proliferation (A2780)

[0214] Table 5. Combination evaluation index (OVCAR-3) of compound of formula (A) combined with PARP inhibitor in ovarian cancer cells

[0215] Table 6. Evaluation index of the combination of the compound of formula (A) and PARP inhibitor in ovarian cancer cells (TOV-21G)

[0216] Table 7. Evaluation index (A2780) of the combination of the compound of formula (A) and PARP inhibitor in ovarian cancer cells

[0217] 4. Experimental conclusions:

[0218] As shown in the table above, compound (A) exhibited synergistic efficacy when used in combination with the PARP inhibitors olaparib and niraparib on the above ovarian cancer cells. The above experiments were performed twice in parallel, and the results were consistent.

[0219] Example 3 Pharmacodynamic study of the compound of formula (A) alone or in combination with olaparib in the treatment of SK-OV-3 human ovarian cancer xenograft model

[0220] 1. Experimental purpose: The purpose of this study is to evaluate the efficacy of the compound of formula (A) combined with olaparib in the female NOD SCID mouse SK-OV-3 human ovarian cancer xenograft model.

[0221] 2. Experimental animals: NOD SCID female mice, 6-8 weeks old, 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%.

[0222] 3. Test sample

[0223] 3.1 Solvent selection:

[0224] Solvent of compound of formula (A): PG: 50% HS-15: 0.5% HPMC=2:1:7

[0225] Olaparib vehicle: 10% DMSO + 90% (10% HP-β-CD in PBS pH 7.4)

[0226] 3.2 Preparation method: The preparation and storage conditions of the drug are shown in Table 8 below:

[0227] Table 8 Drug preparation information

[0228] 4. Experimental methods and steps

[0229] 4.1 Cell culture

[0230] SK-OV-3 tumor cells were cultured in McCoy's 5a medium containing inactivated 10% 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.

[0231] 4.2 Tumor cell inoculation and grouping

[0232] SK-OV-3 tumor cells were resuspended in serum-free McCoy's 5a medium at a concentration of 1×10 7 (0.1mL + Matrigel) was inoculated subcutaneously on the right flank of the experimental animals. A total of 48 animals were inoculated. The tumor grew to 239mm 3 Thirty-two animals with relatively uniform tumor volumes were selected and divided into four groups for drug administration, with eight animals in each group. The specific drug administration schedule is shown in the table below:

[0233] Table 9 Compound Dosage Regimen

[0234] Note: po means oral administration; QD x 28 days means administration once a day for 28 consecutive days; in the group receiving combination of compound of formula (A) and olaparib, compound of formula (A) was administered first, followed by olaparib after an interval of 1 hour; the dose of olaparib from day 1 to day 17 after grouping was 100 mg / kg; after day 17: the dose of olaparib was adjusted to 125 mg / kg.

[0235] 4.3 Detection indicators

[0236] 4.3.1 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 .

[0237] 4.3.2 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.

[0238] 4.4 Drug Evaluation Indicators

[0239] 4.4.1 Relative tumor volume increase ratio T / C (%)

[0240] T / C (%) = mean relative tumor volume of the treatment group / mean relative tumor volume of the control group × 100

[0241] 4.4.2 Tumor Growth Inhibition Rate (TGI, %)

[0242] Tumor growth inhibition rate (TGI,%) = (1-T / C) × 100

[0243] 4.5 Statistical analysis

[0244] 4.5.1 Data collection: Measure and observe as required by the experimental plan, and record them manually or directly in a computer database.

[0245] 4.5.2 Statistical analysis: SPSS 16.0 statistical software and One-Way ANOVA test were used to perform statistical analysis of tumor volumes among the groups. A p < 0.05 was considered to indicate a significant difference.

[0246] 5 Experimental results

[0247] Table 10. Pharmacodynamic data of the compound of formula (A) alone or in combination with olaparib in the treatment of SK-OV-3 human ovarian cancer

[0248] Note: a Mean ± standard error; b Compared with the control group; c One-way ANOVA combined with LSD test, P < 0.05 indicates a significant difference, P < 0.001 indicates an extremely significant difference 6. Experimental Conclusion

[0249] During the experiment, the animals in the experimental group were in good condition in terms of activity and eating, and no abnormalities were observed in the animals. On the 19th day after SK-OV-3 tumor cell inoculation, the animals were divided into groups and given medication. The average tumor volume in each group was 239 mm 3On day 28 after grouping, the mean tumor volume in the solvent control group was 1,962 mm 3 The tumor volume of the 20 mg / kg compound of formula (A) monotherapy group was 933 mm 3 (T / C = 46.0%, TGI = 54.0%, P < 0.001 compared with the solvent control group); the tumor volume in the 100 mg / kg / 125 mg / kg olaparib monotherapy group was 1,597 mm 3 (T / C = 81.5%, TGI = 18.5%, P = 0.029 compared with the solvent control group); the tumor volume of the 20 mg / kg compound of formula (A) and 100 mg / kg / 125 mg / kg olaparib combination treatment group was 759 mm 3 (T / C=36.9%, TGI=63.1%, compared with the solvent control group, P<0.001).

[0250] Compared with the solvent control group and each single treatment group, the anti-tumor effect of the combination treatment group of the compound of formula (A) and olaparib was stronger.

[0251] Example 4 Pharmacodynamic Study of Compounds Alone or in Combination with Paclitaxel in the Treatment of TOV-21G Human Ovarian Cancer Xenograft Model

[0252] 1. Study objective: To test the inhibitory effect of compounds on tumor growth in the TOV-21G human ovarian cancer xenograft model.

[0253] 2. Experimental animals: NOD SCID female mice, 6-8 weeks old, 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%.

[0254] 3. Preparation of test samples

[0255] 3.1 Solvent selection:

[0256] Solvent of compound of formula (A): PG: 50% HS-15: 0.5% HPMC=2:1:7

[0257] Paclitaxel solvent: normal saline

[0258] 3.2 Preparation method: The preparation and storage conditions of the drug are shown in the table below:

[0259] Table 11. Drug preparation information

[0260] Note: The compound is calculated and corrected according to the conversion factor and purity.

[0261] 4 Experimental plan

[0262] 4.1 Cell culture

[0263] TOV-21G tumor cells were cultured in a 1:1 mixture of MCDB 105 medium (1.5 g / L sodium bicarbonate) and 199 medium (2.2 g / L sodium bicarbonate) containing inactivated 15% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin at 37°C in a 5% CO2 incubator. Tumor cells in the logarithmic growth phase were used for in vivo tumor inoculation.

[0264] 4.2 Tumor cell inoculation and grouping

[0265] TOV-21G tumor cells were resuspended in a mixed medium (1:1) of serum-free MCDB 105 culture medium (1.5 g / L sodium bicarbonate) and 199 culture medium (2.2 g / L sodium bicarbonate) at a concentration of 1×10 7 0.1mL + Matrigel (1:1) was inoculated subcutaneously on the right flank of the experimental animals. A total of 60 animals were inoculated. The tumor grew to 150mm. 3 40 animals with relatively uniform tumor volumes were selected and divided into 4 groups for drug administration. The specific dosing regimen is shown in the table below:

[0266] Table 12. Compound Dosage Regimen

[0267] Note: po means oral administration; iv means intravenous injection; QD x 21 days means administration once a day for 21 consecutive days; QWx3 weeks means administration once a week for 3 consecutive weeks.

[0268] On treatment day 21, plasma was collected and stored continuously at designated time points, totaling 100 plasma samples and 16 tumor samples. Detailed sampling protocols are shown in the table below.

[0269] Table 13. Sample collection plan

[0270] 4.3 Detection indicators

[0271] 4.3.1 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 .

[0272] 4.3.2 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.

[0273] 4.4 Drug Evaluation Indicators

[0274] 4.4.1 Relative tumor volume increase ratio T / C (%)

[0275] T / C (%) = mean relative tumor volume of the treatment group / mean relative tumor volume of the control group × 100

[0276] 4.4.2 Tumor Growth Inhibition Rate (TGI, %)

[0277] Tumor growth inhibition rate (TGI,%) = (1-T / C) × 100

[0278] 4.4.3 Collection of animal plasma and PK analysis

[0279] 4.5 Statistical analysis

[0280] 4.5.1 Data collection: Measure and observe as required by the experimental plan, and record them manually or directly in a computer database.

[0281] 4.5.2 Statistical analysis: SPSS 16.0 statistical software and One-Way ANOVA test were used to perform statistical analysis of tumor volumes among the groups. A p < 0.05 was considered to indicate a significant difference.

[0282] 5 Experimental results

[0283] Table 14. Tumor inhibition data of the compound of formula (A) combined with paclitaxel in the TOV-21G human ovarian cancer subcutaneous xenograft model

[0284] Note: a Mean ± standard error; b Compared with the control group; c One-way ANOVA combined with Dunnett T3 test, P < 0.05 indicates a significant difference

[0285] Table 15. Pharmacodynamic data of the compound of formula (A) combined with paclitaxel in the TOV-21G human ovarian cancer subcutaneous xenograft model

[0286] Compared with the monotherapy group of the compound of formula (A), the combination therapy group of the two showed a significant inhibitory effect on tumor growth (P=0.016); compared with the monotherapy group of paclitaxel, the combination therapy group of the two showed a significant inhibitory effect on tumor growth (P=0.001). The results of the accompanying PK study showed that after the compound of formula (A) was combined with paclitaxel in the TOV-21G human ovarian cancer subcutaneous xenograft model, the main PK parameters of paclitaxel were not affected by each other. During the experiment, the general state of animals in all experimental groups, such as activity and eating, was good, and the animals had no abnormalities. Example 5 Combination experiment of compound alone or in combination with paclitaxel or doxorubicin in ovarian cancer cells

[0287] 1. Study Objective: To evaluate the effects of the compound of formula (A) alone or in combination with paclitaxel or doxorubicin on the proliferation of ovarian cancer cell lines (TOV-21G, SK-OV-3, OVCAR-3)

[0288] 2. Experimental Methods

[0289] 2.1 Cell culture

[0290] a) TOV-21G cells were cultured in RPMI1640 medium containing 15% FBS at 37°C and 5% CO2. b) SK-OV-3 cells were cultured in McCoy's 5a medium containing 10% FBS at 37°C and 5% CO2.

[0291] c) OVCAR-3 cells were cultured in RPMI1640 medium containing 20% ​​FBS at 37° C. and 5% CO 2 .

[0292] 2.2 Cell plating

[0293] a) Cells were routinely cultured until the confluence reached 80%-90%. When the number of cells reached the required level, the cells were harvested. b) Cells were resuspended in the corresponding culture medium, counted, and prepared into a cell suspension of appropriate density. c) TOV-21G cells were cultured in complete culture medium at a concentration of 2×10 4 150 μL / well of cells were inoculated into 96-well plates; SK-OV-3 cells were cultured in complete medium at a density of 2×10 3 OVCAR-3 cells were seeded into 96-well plates at a density of 5000 cells / well and 150 μL / well using complete medium.

[0294] 2.3.1 Preparation of compounds

[0295] Table 16. Compound information

[0296] Note: The compound of formula (A) or its salt is prepared by using the monofumarate dihydrate of the compound of formula (A) and referring to the preparation method disclosed in WO2022017448A1.

[0297] 2.3.2 Compound treatment of cells

[0298] 1) Use alone:

[0299] a) 24 hours after plating, the compound was treated alone and the sample was added using a compound titrator.

[0300] b) Compound test concentration:

[0301] TOV-21G cells:

[0302] Compound of formula (A): 30000, 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52 nM;

[0303] SK-OV-3 cells, OVCAR-3 cells:

[0304] Compound of formula (A): 100000, 33333.33, 11111.11, 3703.70, 1234.57, 411.52, 137.17, 45.72, 15.24, 5.08 nM; Paclitaxel (consistent in the three cell lines):

[0305] 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05nM;

[0306] Doxorubicin (consistent in all three cell lines):

[0307] 30000, 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52nM.

[0308] c) Set up medium + DMSO wells and cell + DMSO wells simultaneously. Set the DMSO concentration in each well to 0.3% for TOV-21G cells and OVCAR-3 cell lines, and 0.5% for SK-OV-3 cell lines. Set up three parallel plates for each compound, and measure cell viability after 48, 72, and 96 hours of drug exposure.

[0309] 2) Matrix:

[0310] a) 24 hours after plating, the cells were treated with the compound of formula (A) and paclitaxel or doxorubicin simultaneously, and the samples were added using a compound titrator.

[0311] b) Compound test concentration:

[0312] TOV-21G cells:

[0313] Compound of formula (A): 30000, 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52 nM.

[0314] Paclitaxel: 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05 nM.

[0315] Doxorubicin: 30000, 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52 nM.

[0316] SK-OV-3 cells:

[0317] Compound of formula (A): 100000, 33333.33, 11111.11, 3703.70, 1234.57, 411.52, 137.17, 45.72, 15.24, 5.08 nM.

[0318] Paclitaxel: 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05 nM.

[0319] Doxorubicin: 30000, 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52 nM.

[0320] OVCAR-3 cells:

[0321] Compound of formula (A): 100000, 33333.33, 11111.11, 3703.70, 1234.57, 411.52, 137.17, 45.72, 15.24, 5.08 nM.

[0322] Paclitaxel: 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37 nM.

[0323] Doxorubicin: 30000, 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15 nM.

[0324] c) Set up medium + DMSO wells and cell + DMSO wells simultaneously. Set the DMSO concentration in each well to 0.5% in duplicate. Measure cell viability 96 hours after drug inoculation. Repeat the experiment three times.

[0325] 3) Combination therapy (paclitaxel or doxorubicin fixed concentration):

[0326] a) 24 hours after cell plating, the cells were treated simultaneously with the compound of formula (A) and paclitaxel or doxorubicin. The concentration of paclitaxel or doxorubicin was fixed, and samples were added using a compound titrator.

[0327] b) TOV-21G cells:

[0328] Compound of formula (A): 30000, 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52 nM.

[0329] Paclitaxel: 3 nM, 4 nM, 5 nM, respectively, was used in combination with gradient concentrations of the compound of formula (A).

[0330] Doxorubicin: 20 nM, 40 nM, 80 nM, respectively, used in combination with gradient concentrations of the compound of formula (A).

[0331] SK-OV-3 cells:

[0332] Paclitaxel: 4 nM, 8 nM, 12 nM, respectively, was used in combination with gradient concentrations of the compound of formula (A).

[0333] Compound of formula (A): 100000, 33333.33, 11111.11, 3703.70, 1234.57, 411.52, 137.17, 45.72, 15.24, 5.08 nM;

[0334] Doxorubicin: 40 nM, 80 nM, 120 nM, respectively, used in combination with gradient concentrations of the compound of formula (A).

[0335] OVCAR-3 cells:

[0336] The final concentrations of the compound of formula (A) are: 100000, 33333.33, 11111.11, 3703.70, 1234.57, 411.52, 137.17, 45.72, and 15.24 nM.

[0337] Paclitaxel: 1 nM, 2 nM, 3 nM, respectively, was used in combination with gradient concentrations of the compound of formula (A).

[0338] Doxorubicin: 50 nM, 100 nM, 200 nM, respectively, used in combination with gradient concentrations of the compound of formula (A).

[0339] c) Set up medium + DMSO wells and cell + DMSO wells simultaneously. Set the DMSO concentration in each well to 0.5% in duplicate. Measure cell viability 96 hours after drug inoculation. Repeat the experiment three times.

[0340] 2.4 Cell viability assay

[0341] a) About 2 hours before the test, remove an appropriate amount of CellCounting-Lite 2.0 Luminescent Cell Viability Assay Reagent (hereinafter referred to as the assay reagent) and return the solution to room temperature.

[0342] b) After the drug and cell incubation is complete, remove the cell culture plate and equilibrate at room temperature for 30 minutes;

[0343] c) Add 50 μL of detection reagent to each well of the cell culture plate in the dark, shake on a fast shaker for 3 minutes, and then let it stand at room temperature for 10 minutes;

[0344] d) Read the chemiluminescent signal using an Envision instrument.

[0345] 2.5 Data Analysis

[0346] a) Compound IC 50 Calculation:

[0347] IC was calculated using GraphPadPrism 8 software. 50 , the IC of the compound is obtained using the following nonlinear fitting formula 50 (50% inhibitory concentration):

[0348] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)).

[0349] X: log value of compound concentration, Y: inhibition rate (% inhibition).

[0350] Inhibition rate (% inhibition) = 100 - (compound well reading - low read control reading) / (high read control reading - low read control reading) * 100.

[0351] b) Compound combination evaluation index (Synergy.score)

[0352] Apply the calculated cell viability inhibition rate and import it into the SynergyFinder website for the analysis of the combination index. Website: https: / / tangsoftwarelab.shinyapps.io / synergyfinder / #! / dashboard. Synergy.score < -10 indicates an antagonistic interaction between the two compounds; -10 < Synergy.score < 10 indicates an additive interaction between the two compounds; Synergy.score > 10 indicates a synergistic interaction between the two compounds.

[0353] 3. Experimental Results

[0354] Combined drug use (fixed concentration of paclitaxel or doxorubicin)

[0355] Table 17. Inhibitory activities of the compound of formula (A) combined with paclitaxel or doxorubicin on ovarian cancer cells

[0356] Experimental conclusion: The compound of formula (A) combined with paclitaxel or doxorubicin shows good cell inhibitory activities in the above-mentioned ovarian cancer cells.

[0357] Example 6. Experiment on the proliferation effect of the compound of formula (A) combined with carboplatin on ovarian cancer cells (ES-2)

[0358] 1. Experimental purpose: To study the effect of the compound of formula (A) combined with carboplatin on the proliferation of ovarian cancer cell line (ES-2).

[0359] 2. Experimental method:

[0360] 2.1 Cell culture: ES-2 cells (purchased from the Cell Bank of the Chinese Academy of Sciences): a human ovarian clear cell carcinoma cell line, cultured in McCoy's 5A medium containing 10% FBS.

[0361] 2.2 Cell seeding: On the 0th day of the experiment, adjust the density of viable cells in the logarithmic growth phase to 10,000 cells / mL, and inoculate 100 μL / well into a 96-well plate. Place the inoculated cell plate in an incubator at 37 °C and 5% CO2 for overnight culture.

[0362] 2.3 Drug incubation

[0363] 24 hours after cell seeding, take out the overnight-cultured cell plate, and add 50 μL of McCoy's 5A medium containing 10% FBS and the drug to each well. Set the cell control group as the high-reading control well and the cell-free medium as the low-reading control well. After adding the drugs, place the cell culture plate in an incubator at 37 °C and 5% CO2 for 72 hours. The final drug concentrations are as follows:

[0364] Option 1:

[0365] Compound of formula (A): 40.0, 29.3, 25.0, 20.0, 15.0, 7.5, 3.8, 1.9, 0.9 μM;

[0366] Carboplatin: 25.0, 20.0, 17.5, 15.0, 10.0, 7.5, 5.0, 2.5, 1.3 μM.

[0367] Option 2:

[0368] Compound of formula (A): 50.0, 29.3, 20.0, 15.0, 7.5, 3.8, 1.9, 0.9 μM;

[0369] Carboplatin: 10, 15, 20 μM, respectively, was used in combination with gradient concentrations of the compound of formula (A).

[0370] After the drug incubation is complete, remove the cell culture plate and equilibrate at room temperature for 30 minutes. Add 50 μL of pre-thawed and room temperature CellCounting-Lite solution to each well. Shake the plate at 450 rpm for 5 minutes and let it stand at room temperature for 10 minutes. Read the chemiluminescent signal using a multi-function microplate reader.

[0371] 2.4 Data Analysis

[0372] GraphPad Prism 5 software was used to fit the dose-effect curve, and the IC value of the compound on cell proliferation inhibition was obtained using the following nonlinear fitting formula. 50 (50% inhibitory concentration):

[0373] Y=minimum value+(maximum value-minimum value) / (1+10^((LogIC 50 -X)*slope))

[0374] X: log value of compound concentration, Y: inhibition rate (%inhibition)

[0375] Inhibition rate (% inhibition) = 100-(compound well reading-low reading control reading) / (high reading control reading-low reading control reading)*100

[0376] The Q value is the combination index, and the Q value is calculated using the following formula:

[0377] Q value = EA + B / (EA + EB - EA × EB), where EA + B is the inhibition rate of combined drug use, and EA and EB are the inhibition rates of drug A and drug B, respectively.

[0378] Evaluation criteria for the combination index: Q value > 1.15, the interaction between the two compounds is synergistic; 0.85 ≤ Q value ≤ 1.15, the interaction between the two compounds is additive; Q value < 0.85, the interaction between the two compounds is antagonistic.

[0379] 3 Experimental results

[0380] 3.1 IC 50 value

[0381] Table 18. Study on the inhibitory effect of compound of formula (A) combined with carboplatin on the proliferation of ovarian cancer (ES-2) cells

[0382] 3.2 Compound Combination Index

[0383] Table 19. Evaluation index of the combination of compound of formula (A) and carboplatin in ES-2 ovarian cancer cells

[0384] Example 7 Pharmacodynamic study of the compound of formula (A) in combination with olaparib and carboplatin in the treatment of OVCAR-3 human ovarian cancer xenograft model

[0385] 1. Study objective: To test the inhibitory effect of the compound of formula (A) in combination with olaparib and carboplatin on tumor growth in the OVCAR-3 human ovarian cancer xenograft model.

[0386] 2. Experimental animals: NOD SCID female mice, 6-8 weeks old, 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%.

[0387] 3. Preparation of test samples

[0388] 3.1 Solvent selection:

[0389] Solvent of compound of formula (A): PG: 50% HS-15: 0.5% HPMC=2:1:7

[0390] Olaparib vehicle: 10% DMSO + 90% (10% HP-β-CD in PBS pH 7.4)

[0391] Carboplatin solvent: normal saline

[0392] 3.2 Preparation method: The preparation and storage conditions of the drug are shown in the table below:

[0393] Table 20. Drug preparation information

[0394] 4. Experimental Methods and Procedures

[0395] 4.1 Cell culture

[0396] OVCAR-3 tumor cells were cultured in RPMI1640 medium containing 20% ​​inactivated 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.

[0397] 4.2 Tumor cell inoculation and grouping

[0398] OVCAR-3 tumor cells resuspended in serum-free RPMI1640 culture medium were cultured at a concentration of 2×10 7 (0.2mL + Matrigel) was inoculated subcutaneously on the right flank of the experimental animals. A total of 60 animals were inoculated. The tumor grew to 222mm. 3 36 animals with relatively uniform tumor volumes were selected and divided into 6 groups for drug administration.

[0399] Table 21. Compound Dosage Regimen

[0400] Note: po indicates oral administration; ip indicates intraperitoneal injection; QD x 21 days indicates daily administration for 21 consecutive days; QW x 3 weeks indicates weekly administration for 3 consecutive weeks. In the group treated with the compound of formula (A) combined with olaparib and carboplatin, the compound of formula (A) was administered first, followed by olaparib and carboplatin, respectively, 1 hour apart.

[0401] 4.3 Detection indicators

[0402] 4.3.1 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 .

[0403] 4.3.2 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.

[0404] 4.4 Drug Evaluation Indicators

[0405] 4.4.1 Relative tumor volume increase ratio T / C (%)

[0406] T / C (%) = mean relative tumor volume of the treatment group / mean relative tumor volume of the control group × 100

[0407] 4.4.2 Tumor Growth Inhibition Rate (TGI, %)

[0408] Tumor growth inhibition rate (TGI,%) = (1-T / C) × 100

[0409] 4.5 Statistical analysis

[0410] 4.5.1 Data collection: Measure and observe as required by the experimental plan, and record them manually or directly in a computer database.

[0411] 4.5.2 Statistical analysis: SPSS 16.0 statistical software and One-Way ANOVA test were used to perform statistical analysis of tumor volumes among the groups. A p < 0.05 was considered to indicate a significant difference.

[0412] 5. Results

[0413] Table 22. Tumor inhibition data of compound of formula (A) in combination with olaparib and carboplatin on OVCAR-3 ovarian cancer transplanted mice

[0414] Note: a Mean ± standard error; b Compared with the control group; c One-way ANOVA combined with Dunnett T3 test, P < 0.05 indicates a significant difference

[0415] Table 23. Pharmacodynamic data of the compound of formula (A) in combination with olaparib and carboplatin on OVCAR-3 ovarian cancer transplanted mice

[0416] 6. Experimental Conclusion

[0417] OVCAR-3 tumor cells were inoculated and the patients were divided into groups and given medication 21 days later. The mean tumor volume of each group was 222 mm 3 After 21 days of administration, the mean tumor volume in the solvent control group was 2,370 mm 3 The mean tumor volume of the group treated with 40 mg / kg of compound of formula (A) alone was 1,370 mm 3 (T / C = 56.1%, TGI 43.9%, p = 0.124 compared with the solvent control group); the mean tumor volume in the olaparib 50 mg / kg monotherapy group was 1,982 mm 3 (T / C = 77.5%, TGI 22.5%, p = 0.978 compared with the solvent control group); the mean tumor volume of the group receiving a combination of 40 mg / kg of the compound of formula (A) and 50 mg / kg of olaparib was 1,156 mm 3 (T / C = 46.1%, TGI 53.9%, p = 0.057 compared with the solvent control group); the mean tumor volume in the carboplatin 40 mg / kg monotherapy group was 896 mm 3(T / C=36.0%, TGI was 64.0%, compared with the solvent control group p=0.028); the mean tumor volume of the group administered with 40 mg / kg of the compound of formula (A) and 40 mg / kg of carboplatin was 512 mm 3 (T / C=20.3%, TGI 79.7%, compared with the solvent control group p=0.013).

[0418] Both the 40 mg / kg carboplatin monotherapy group and the 40 mg / kg carboplatin combined therapy group with the compound of formula (A) showed significant tumor growth inhibition, with the combined group exhibiting a stronger tumor inhibition effect than either monotherapy group.

[0419] Example 8 Safety, tolerability, pharmacokinetic properties, and preliminary efficacy evaluation of a tablet of the compound of formula (A) combined with niraparib tosylate capsules / paclitaxel injection / doxorubicin hydrochloride liposome injection in patients with locally advanced or metastatic ovarian cancer who have failed standard treatment. Study population:

[0420] Cohort A: Patients with locally advanced / metastatic ovarian cancer confirmed by cytology or histology who have failed standard treatment, have no standard treatment options, or are not currently suitable for standard treatment.

[0421] Cohorts B and C: Patients with platinum-resistant locally advanced / metastatic ovarian cancer confirmed by cytological or histological examination who have failed standard treatment, have no standard treatment options, or are not currently suitable for standard treatment.

[0422] Experimental design: This study was an open, single-arm, non-randomized trial.

[0423] Table 24. Dosage regimen

[0424] Final indicator:

[0425] ORR, DCR, DOR, PFS, CA-125 response rate (GCIG standard), and pharmacokinetic parameters.

[0426] Example 9: An open, randomized, positive-controlled, phase II clinical study on the efficacy and safety of formula (A) compound tablets combined with niraparib tosylate capsules / paclitaxel injection / doxorubicin hydrochloride liposome injection in the treatment of platinum-resistant ovarian cancer

[0427] Study objectives: To evaluate the clinical efficacy of the compound of formula (A) combined with niraparib tosylate capsules / paclitaxel injection / doxorubicin hydrochloride liposome injection compared with niraparib tosylate capsules / paclitaxel injection / doxorubicin hydrochloride liposome injection in the treatment of platinum-resistant ovarian cancer subjects; to further evaluate the clinical efficacy of the compound of formula (A) combined with niraparib tosylate capsules / paclitaxel injection / doxorubicin hydrochloride liposome injection in the treatment of platinum-resistant ovarian cancer subjects; to investigate the clinical efficacy of the compound of formula (A) combined with niraparib tosylate capsules / paclitaxel injection / doxorubicin hydrochloride liposome injection in the treatment of platinum-resistant ovarian cancer subjects at steady state; explore the potential effect of the combined use of formula (A) compound and niraparib tosylate capsules / paclitaxel injection / doxorubicin hydrochloride liposome injection on the PK of niraparib / paclitaxel / doxorubicin at steady state, with each group of single-drug treatment as a control; evaluate the safety and tolerability of the compound of formula (A) combined with niraparib tosylate capsules / paclitaxel injection / doxorubicin hydrochloride liposome injection in the treatment of platinum-resistant ovarian cancer subjects.

[0428] Experimental design: This study is an open, parallel, randomized, phase II multicenter clinical trial of safety and efficacy.

[0429] Trial groups:

[0430] This study included 6 cohorts:

[0431] Cohort 1: Formula (A) compound tablets combined with niraparib tosylate capsules;

[0432] Cohort 2: Formula (A) compound tablets combined with paclitaxel injection;

[0433] Cohort 3: Formula (A) compound tablets combined with doxorubicin hydrochloride liposome injection;

[0434] Cohort 4: niraparib tosylate capsule monotherapy;

[0435] Cohort 5: paclitaxel injection monotherapy;

[0436] Cohort 6: Doxorubicin hydrochloride liposome injection monotherapy.

[0437] Dosage regimen for specific drugs:

[0438] Tablets of the compound of formula (A): Specification: 100 mg, oral, once daily, dosage: 200 mg / time to 400 mg / time; continuous administration for 21 days, rest for 7 days, 28 days as a dosing cycle, treatment until intolerance or disease progression or subject withdrawal.

[0439] Niraparib tosylate capsules: Specifications: 100 mg, dosage: 300 mg / time, oral, once a day, with a dosing cycle of 28 days, treatment until intolerance or disease progression or subject withdrawal.

[0440] Paclitaxel injection: Specification: 30mg (5mL) / bottle, dosage: 80mg / m 2 / time, intravenous infusion, administered on days 1, 8, and 15 of each cycle, with a dosing cycle of 28 days. Treatment continues until intolerance, disease progression, or subject withdrawal.

[0441] Doxorubicin hydrochloride liposome injection: Specifications: 10mL: 20mg, 40mg / m 2 / time, intravenous infusion, administered on the first day of each cycle, with a dosing cycle of 28 days, and treatment continued until intolerance, disease progression, or subject withdrawal.

[0442] Final indicator:

[0443] ORR, DCR, DOR, PFS, CA-125 response rate (GCIG criteria), pharmacokinetic parameters, adverse events, vital signs, electrocardiogram (ECG), physical examination, and laboratory tests.

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 ovarian cancer, wherein: The ovarian cancer is platinum-resistant ovarian cancer, Preferably, the ovarian cancer is platinum-resistant high-grade serous carcinoma, platinum-resistant ovarian adenocarcinoma, platinum-resistant epithelial serous carcinoma, platinum-resistant clear cell carcinoma, platinum-resistant endometrioid ovarian cancer, platinum-resistant fallopian tube cancer or platinum-resistant primary peritoneal cancer; More preferably, the ovarian cancer is platinum-resistant high-grade serous carcinoma or platinum-resistant ovarian adenocarcinoma.

2. 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 ovarian cancer, wherein: The ovarian cancer is locally advanced or metastatic ovarian cancer, Preferably, the ovarian cancer is locally advanced or metastatic ovarian cancer that has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment; Preferably, the ovarian cancer is locally advanced or metastatic ovarian cancer that is platinum-resistant; More preferably, the ovarian cancer is locally advanced or metastatic ovarian cancer that is platinum-resistant and has failed standard treatment, or has no standard treatment options, or is not currently suitable for standard treatment.

3. The use according to claim 1 or 2, wherein The compound of formula (I) is a compound of formula (A) or a compound of formula (B):

4. The use according to any one of claims 1 to 3, wherein The compound of formula (A) is used in combination with other ovarian cancer therapeutic drugs; the other ovarian cancer therapeutic drugs include one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs, platinum drugs or alkylating agents; preferably one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs or platinum drugs.

5. The use according to claim 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 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 fumarate, methanesulfonate, isethionate, 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 hydrochloride, sulfate or phosphate; preferably fumarate; more preferably monofumarate; further preferably monofumarate dihydrate; Preferably, the dosage of the compound of formula (A) is 0.1 to 1000 mg; preferably 20 to 500 mg; more preferably 200 to 400 mg; more preferably 100, 200, 300, 400 or 500 mg; further preferably 300, 400 or 500 mg; Preferably, the frequency of administration 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 claim 4, characterized in that The compound of formula (A) is used in combination with a PARP inhibitor; the PARP inhibitor includes one or more of niraparib, olaparib, rucaparib, talazoparib or fluzoparib; preferably, the PARP inhibitor is niraparib or olaparib; more preferably, the PARP inhibitor is niraparib; more preferably, the PARP inhibitor is olaparib; Preferably, the PARP inhibitor is administered at a dosage of 100 to 1000 mg; preferably 100 to 600 mg; more preferably 200 mg, 400 mg, 300 mg or 600 mg; Preferably, the PARP inhibitor 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, twice a day, or three times a day; Preferably, the dosage ratio of the compound of formula (A) to the PARP inhibitor is selected from 1:0.1-300 by mass ratio; more preferably, the dosage ratio of the compound of formula (A) to niraparib is selected from 1:0.01-300 by mass ratio; more preferably 1:0.75, 1:1 or 1:0.5; more preferably, the dosage ratio of the compound of formula (A) to olaparib is selected from 1:0.01-300 by mass ratio; more preferably 1:0.75, 1:1 or 1:1.5; Preferably, the administration of the combination therapy is 28 days as a cycle; the administration frequency of the compound of formula (A) is 21 consecutive days, followed by a 1-week interval without administration of the compound, and the dosage is 200-400 mg / time; the administration frequency of the PARP inhibitor is once a day, and the dosage is 300 mg / time; More preferably, the combination is administered for a period of 28 days; the compound of formula (A) is administered for 21 consecutive days, followed by a one-week interval without administration of the compound, and the dosage is 200-400 mg / time; the niraparib is administered once a day, and the dosage is 300 mg / time; More preferably, the combination is administered in a cycle of 28 days; the compound of formula (A) is administered continuously for 21 days, followed by a 1-week interval without administration of the compound, and the dosage is 200-400 mg / time; the frequency of olaparib is once a day, and the dosage is 300 mg / time.

8. The use according to claim 4, characterized in that The compound of formula (A) is used in combination with a platinum drug; the platinum drug includes one or more of cisplatin, carboplatin, lobaplatin or nedaplatin; preferably carboplatin; Preferably, the dosage of carboplatin is 50 to 1000 mg; preferably 400 to 800 mg; more preferably 400 mg, 500 mg, 600 mg, 700 mg or 800 mg; Preferably, the administration frequency of carboplatin is once a day, once a week, once every two weeks, once every three weeks, once a month, once every two months, once every three weeks, once every four weeks, once every three weeks, divided into 5 days, or once every four weeks, divided into 5 days; More preferably, the administration of the combination therapy is 28 days as a cycle; the administration frequency of the compound of formula (A) is 21 consecutive days, followed by a 1-week interval without administration of the compound; the administration frequency of carboplatin may be once a week for 3 consecutive weeks; Preferably, in terms of mass ratio, the dosage ratio of the compound of formula (A) to carboplatin is selected from 1:0.1-300; more preferably 1:1, 1:1.5 or 1:2; further preferably 1:

1.

9. The use according to claim 4, characterized in that: The compound of formula (A) is used in combination with a plant-based chemotherapeutic drug; the plant-based chemotherapeutic drug includes one or more of vincristine, vinblastine, etoposide or paclitaxel; preferably paclitaxel; more preferably paclitaxel injection; Preferably, the dosage of paclitaxel is 1 to 300 mg / m 2 ; preferably 10-150 mg / m 2 More preferably 40 to 100 mg / m 2 ; More preferably 60mg / m 2 , 70mg / m 2 , 80mg / m 2 , 90mg / m 2 or 100 mg / m 2 ; further preferably 80mg / m 2 ; Preferably, the administration frequency of paclitaxel is once a day, once a week, once every two weeks, once every three weeks, once a month, once every two months, once a week, use for 2 weeks and rest for 1 week, once a week, use for 3 weeks and rest for 1 week, once a week, use for 6 weeks and rest for 2 weeks, once every 3 weeks or once every 4 weeks; preferably once a week, use for 3 weeks and rest for 1 week; Preferably, the administration of the combination therapy is 28 days as a cycle; the administration frequency of the compound of formula (A) is 21 consecutive days, followed by a 1-week interval without administration of the compound, and the dosage is 200-400 mg / time; the administration frequency of paclitaxel is 1, 8, and 15 days of each cycle, and the dosage is 80 mg / m 2 / Second-rate; Preferably, in terms of mass ratio, the dosage ratio of the compound of formula (A) to paclitaxel is selected from 0.01-300:1; more preferably 1:1, 1.5:1, 2:1, 3:1 or 4:1; further preferably 4:

1.

10. The use according to claim 4, characterized in that The compound of formula (A) is used in combination with an antibiotic chemotherapeutic drug; the antibiotic chemotherapeutic drug includes one or more of actinomycin D, mitomycin, adriamycin, doxorubicin, epirubicin or daunorubicin; preferably doxorubicin; more preferably doxorubicin liposomes; Preferably, the dosage of doxorubicin is 0.1 to 300 mg / m 2 ; preferably 1 to 100 mg / m 2 More preferably 10 to 60 mg / m 2 ; More preferably 10mg / m 2 , 20mg / m 2 , 30mg / m 2 , 40mg / m 2 or 50 mg / m 2 ; further preferably 40mg / m 2 ; Preferably, the administration frequency of doxorubicin can be once a day, once a week, once every two weeks, once every three weeks, once every four weeks, once every month, or once every two months; preferably once every two weeks, once every three weeks, or once every four weeks; more preferably once every four weeks; further preferably once every four weeks, on the first day of each cycle; Preferably, the administration of the combination therapy is 28 days as a cycle; the administration frequency of the compound of formula (A) is 21 consecutive days, followed by a 1-week interval without administration of the compound, and the dosage is 200-400 mg / time; the administration frequency of doxorubicin is 80 mg / m on the first day of each cycle. 2 / Second-rate; Preferably, the dosage ratio of the compound of formula (A) to doxorubicin is selected from 0.01-300:1 by mass ratio; preferably 3:1, 5:1, 8:1, 10:1, 12:1, 15:1, 18:1 or 20:

1.

11. A pharmaceutical composition or a pharmaceutical combination, characterized in that: Containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and other ovarian cancer therapeutic drugs, and one or more pharmaceutically acceptable carriers; the other ovarian cancer therapeutic drugs include one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs, platinum drugs or alkylating agents; preferably one or more of PARP inhibitors, plant-based chemotherapy drugs, antibiotic chemotherapy drugs or platinum drugs; 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.

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