TW202317135A - Use of selective estrogen receptor covalent antagonists in combination with cdk4/6 inhibitors in the preparation of medicaments for the treatment of breast cancer - Google Patents

Abstract

The present disclosure relates to use of selective estrogen receptor covalent antagonists in combination with CDK4/6 inhibitors in preparation of medicaments for the treatment of breast cancer. Specifically, the selective estrogen receptor covalent antagonists are selected from compounds represented by formula (I) or pharmaceutically acceptable salts thereof, and CDK4/6 inhibitors are selected from compounds represented by formula (II) or pharmaceutically acceptable salts thereof.

Description

Use of selective estrogen receptor covalent antagonist combined with CDK4/6 inhibitor in preparation of medicine for treating breast cancer

The disclosure relates to the use of a selective estrogen receptor covalent antagonist combined with a CDK4/6 inhibitor in the preparation of a drug for treating breast cancer, and belongs to the field of pharmacy.

This application claims the priority of Chinese patent application 2021107886085 with a filing date of July 13, 2021. This application cites the full text of the above-mentioned Chinese patent application.

Estrogen receptor-positive (ER+) breast cancer is the most common subtype of breast cancer, and endocrine therapy is the mainstay of treatment for ER+ breast cancer. Although endocrine therapy has greatly reduced breast cancer recurrence and mortality, primary and secondary drug resistance remain major challenges. The SERD drug fulvestrant is the only clinically approved drug molecule that has shown efficacy in the treatment of drug-resistant ER+ breast cancer. The antiestrogenic activity of fulvestrant and its ability to degrade ER protein make it an effective treatment for patients with ER-positive breast cancer, including those who have developed resistance to TAM or aromatase inhibitors. However, due to the poor solubility of fulvestrant and other characteristics, the oral bioavailability is extremely low, and monthly intramuscular injection is required, and it needs to be stored at low temperature (2-8°C). Compared with oral drugs such as tamoxifen and AI Drugs, clinical applications are limited. Based on this, the research and development of a new generation of oral SERDs with higher bioavailability, better pharmacokinetic characteristics and potent anti-estrogen activity in the breast and selective estrogen receptor covalent antagonists (SERCA) is in full swing. Among them, multiple compounds are already in different clinical stages.

The invention provides a use of a selective estrogen receptor covalent antagonist in the preparation of a drug for treating breast cancer.

In some embodiments, the present disclosure provides a use of a selective estrogen receptor covalent antagonist in the preparation of a medicament for treating ER+ or HER2- breast cancer.

In some embodiments, the present disclosure provides a use of a selective estrogen receptor covalent antagonist in the preparation of a medicament for treating ER+, HER2- breast cancer.

。 In some embodiments, the present disclosure provides a use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating breast cancer.

.

In some embodiments, the present disclosure provides a use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating ER+ or HER2- breast cancer.

In some embodiments, the present disclosure provides a use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating ER+, HER2- breast cancer.

Another aspect of the present disclosure provides a combination of a selective estrogen receptor covalent antagonist and a CDK4/6 inhibitor in a drug for treating breast cancer.

In some embodiments, the present disclosure provides the use of a selective estrogen receptor covalent antagonist in combination with a CDK4/6 inhibitor in the treatment of ER+ or HER2- breast cancer.

In some embodiments, the present disclosure provides the use of a selective estrogen receptor covalent antagonist in combination with a CDK4/6 inhibitor in the treatment of ER+, HER2- breast cancer.

In some embodiments, the CDK 4/6 inhibitor described in the present disclosure is selected from palbociclib or a pharmaceutically acceptable salt thereof, bomazenil or a pharmaceutically acceptable salt thereof, ribociclib, 2 '-((5-(4-isopropylpiper-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9 '-pyrrolo[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-6'-one dihydrochloride, G1T-28, AT-7519, FLX-925, A Fuxidi.

The chemical name of palbociclib in this disclosure is: 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperi-1-yl)pyridin-2-yl]amino} Pyrido[2,3-d]pyrimidin-7(8H)-one; Bomazenil compound name: N-(5-((4-ethylpiper-1-yl)methyl)pyridine 2- Base)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine; ribociclib chemical name For: 7-cyclopentyl-2-(5-piper-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide; G1T-28 chemical name: 2'-((5-(4-Methylpiper-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro[ Cyclohexane-1 ,9'-pyrrolo[1',2':1 ,5]pyrrolo[2,3-d]pyrimidin]-6'-one; AT-7519 chemical name: N-( 4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide; FLX-9252 chemical name: 2-hydroxy-1-[2- [[9-(trans-4-methylcyclohexyl)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-yl]amino]-7 ,8-Dihydro-1,6-naphthyridin-6(5H)-yl]ethanone; chemical name of avocidide: 2-(2-chlorophenyl)-5,7-dihydroxy-8- ((3S,4R)-3-Hydroxy-1-methylpiperidin-4-yl)-4H-chromen-4-one.

（II）。 In some embodiments, the present disclosure provides the use of a pharmaceutically acceptable salt of a compound represented by formula (I) in combination with a compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating breast cancer ,

(II).

In some embodiments, the present disclosure provides a combination of a pharmaceutically acceptable salt of a compound represented by formula (I) and a compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the preparation of a drug for the treatment of ER+ or HER2- breast cancer Uses in medicine.

In some embodiments, the present disclosure provides a combination of a pharmaceutically acceptable salt of a compound represented by formula (I) and a compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the preparation of a drug for the treatment of ER+, HER2- breast cancer use in medicine,

In some embodiments, the breast cancer described in the present disclosure is metastatic or locally advanced breast cancer.

In some embodiments, the ER+ or HER2- breast cancer described in the present disclosure is metastatic or locally advanced breast cancer.

In some embodiments, the ER+, HER2- breast cancer described in the present disclosure is metastatic or locally advanced breast cancer.

In some embodiments, the pharmaceutically acceptable salt of the compound represented by formula (I) in the present disclosure is selected from maleate, hydrochloride, oxalate, tartrate, fumarate, citrate, malic acid salt, adipate, methanesulfonate, phosphate, acetate, mandelate, or sulfate.

In some embodiments, the pharmaceutically acceptable salt of the compound represented by formula (I) in the present disclosure is selected from maleate or hydrochloride.

In some embodiments, the pharmaceutically acceptable salt of the compound represented by formula (I) in the present disclosure is selected from maleate.

In some embodiments, the pharmaceutically acceptable salt of the compound represented by formula (I) in the present disclosure is selected from hydrochloride.

In some embodiments, the pharmaceutically acceptable salt of the compound represented by formula (II) in the present disclosure is isethionate.

In some embodiments, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the present co-disclosure is selected from 1-1000 mg, and optional doses are: 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg , 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg , 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 670 mg, 675 mg, 680 mg, 685 mg , 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg, 805 mg, 810 mg, 815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg , 940 mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980 mg, 985 mg, 990 mg, 995 mg, or 1000 mg; dosing frequency is once a day or once a day twice.

In some embodiments, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg , 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg at a frequency of Once a day or twice a day.

In some embodiments, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 25 mg, 75 mg, 150 mg, 300 mg, 450 mg or 600 mg; the administration frequency is once a day or twice a day.

In some embodiments, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 25 mg, and the administration frequency is once a day or twice a day.

In some embodiments, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 75 mg, and the administration frequency is once a day or twice a day.

In some embodiments, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 150 mg; The frequency of administration is once a day or twice a day.

In some embodiments, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 300 mg; the administration frequency is once a day or twice a day.

In some embodiments, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 450 mg; the administration frequency is once a day or twice a day.

In some embodiments, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 600 mg; the administration frequency is once a day or twice a day.

In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 1-500 mg, and the dosage frequency is selected from once a day or twice a day.

In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg , 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg or 500 mg, the dosing frequency is once a day or twice a day.

In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 25 mg, and the dosage frequency is once a day or twice a day.

In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 50 mg, and the dosage is once a day or twice a day.

In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 75 mg, and the dosage frequency is once a day or twice a day.

In some embodiments, the dose of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 100 mg, and the frequency of administration is once a day or twice a day.

In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 125 mg, and the dosage frequency is once a day or twice a day.

In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 150 mg, and the frequency of administration is once a day or twice a day.

In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 175 mg, and the dosage frequency is once a day or twice a day.

In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 200 mg, and the dosage frequency is once a day or twice a day.

In some embodiments, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg , 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg or 600 mg at a frequency of Once a day; the dosage of the compound represented by formula (II) or its pharmaceutically acceptable salt is selected from 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg, given The frequency of the medicine is once a day.

In some embodiments, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 25 mg, 75 mg, 150 mg, 300 mg, 450 mg or 600 mg, and the administration frequency is once a day; (II) The dosage of the indicated compound or its pharmaceutically acceptable salt is selected from 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg, and the frequency of administration is one day once.

In some embodiments, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 25 mg, and the administration frequency is once a day; the dose of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof The dosage is selected from 75 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg, and the frequency of administration is once a day.

In some embodiments, the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 75 mg, and the administration frequency is once a day; the dose of the compound represented by formula (II) or its pharmaceutically acceptable salt The dosage is selected from 75 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg, and the frequency of administration is once a day.

In some embodiments, the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 150 mg, and the administration frequency is once a day; the dose of the compound represented by formula (II) or its pharmaceutically acceptable salt The dosage is selected from 75 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg, and the frequency of administration is once a day.

In some embodiments, the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 300 mg, and the administration frequency is once a day; the dose of the compound represented by formula (II) or its pharmaceutically acceptable salt The dosage is selected from 75 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg, and the frequency of administration is once a day.

In some embodiments, the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 450 mg, and the administration frequency is once a day; the dose of the compound represented by formula (II) or its pharmaceutically acceptable salt The dosage is selected from 75 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg, and the frequency of administration is once a day.

In some embodiments, the dosage of the compound represented by formula (I) or its pharmaceutically acceptable salt is 600 mg, and the administration frequency is once a day; the dosage of the compound represented by formula (II) or its pharmaceutically acceptable salt The dosage is selected from 75 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg, and the frequency of administration is once a day.

In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 50 mg, and the dosage is once a day or twice a day.

In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 75 mg, and the dosage frequency is once a day or twice a day.

In some embodiments, the dose of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 100 mg, and the frequency of administration is once a day or twice a day.

In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 125 mg, and the dosage frequency is once a day or twice a day.

In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 150 mg, and the frequency of administration is once a day or twice a day.

In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 175 mg, and the dosage frequency is once a day or twice a day.

In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 200 mg, and the dosage frequency is once a day or twice a day.

In some embodiments, a cycle of administration of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is 28 days, wherein administration is administered on the first 21 days and administration is stopped on the last 7 days.

Another aspect of the present disclosure provides a method for treating breast cancer patients, giving patients a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a compound represented by formula (II) or a pharmaceutically acceptable salt thereof acceptable salt.

Another aspect of the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof for treating breast cancer, which is used in combination with a compound represented by formula (II) or a pharmaceutically acceptable salt thereof.

Another aspect of the present disclosure provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof for treating breast cancer, which is used in combination with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

Another aspect of the present disclosure provides a pharmaceutical composition, comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable Acceptable excipients include, but are not limited to, fillers, disintegrants, binders or lubricants.

The pharmaceutical compositions described in the present disclosure can be prepared as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections, suppositories, inhalants or sprays and the like.

The administration route of the combination in the present disclosure is selected from oral administration, parenteral administration, and transdermal administration, and said parenteral administration includes but not limited to intravenous injection, subcutaneous injection, and intramuscular injection.

The "combination" mentioned in this disclosure is a mode of administration, which refers to the administration of at least one dose of selective estrogen receptor covalent antagonist (SERCA) or a pharmaceutically acceptable salt thereof and CDK4 within a certain period of time /6 inhibitors, in which both drugs show pharmacological effects. The time period can be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours. A selective estrogen receptor covalent antagonist (SERCA) or a pharmaceutically acceptable salt thereof and a CDK4/6 inhibitor can be administered simultaneously or sequentially. This term includes treatments in which a selective estrogen receptor covalent antagonist (SERCA) or a pharmaceutically acceptable salt thereof and a CDK4/6 inhibitor are administered by the same route of administration or by different routes of administration.

In order to make the above and other objects, features and advantages of the present invention more comprehensible, the following specific embodiments are described in detail in conjunction with the accompanying drawings.

The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

Example 1. Drug A (maleate salt of compound represented by formula (I), refer to WO2020253762A) single drug, fulvestrant single drug and combined drug B (compound isethionate represented by formula (I) , can refer to WO2014183520A) in human breast cancer cell MCF-7 (Y537S, mutant) cell breast cancer animal model of drug effect

1.1 Drug information Fulvestrant, provided by Shanghai Hengrui Medicine Co., Ltd.; Drug A, provided by Jiangsu Hengrui Medicine Co., Ltd.; Drug B was provided by Jiangsu Hengrui Medicine Co., Ltd.

1.2 Experimental animals and cells Scid Beige mice, SPF, 16-19 g, ♀, were purchased from Beijing Weitong Lihua Experimental Animal Co., Ltd. The mutant human breast cancer cell MCF-7 (Y537S) was provided by Shanghai Hengrui Molecular Cell Department.

1.3 Experimental equipment: TESA electronic waterproof caliper IP67, Tesa Measuring Instruments (Shanghai) Co., Ltd.; Electronic balance PL2001-L (0.1 g-2100 g), Mettler-Toledo Instruments Shanghai Co., Ltd.; Electronic balance AL204-IC (0.1 mg-220 g), Mettler-Toledo Instruments Shanghai Co., Ltd.

1.4 Drug preparation Fulvestrant was formulated as a 40 mg/mL (free base) solution in ethanol/olive oil (1:9) and administered at a dose of 200 mg/kg twice a week in a subcutaneous injection volume of 5 mL/kg ; Drug A was formulated with 9% PEG400+0.5% Tween-80+90.5% (0.5% CMC-Na) aqueous solution to make 2, 5 mg/mL (free base) aqueous solution, and the dosage was 20, 50 mg/kg, daily Once, orally gavage with a volume of 10 mL/kg. Drug B was prepared with 9% PEG400+0.5% Tween-80+90.5% (0.5% CMC-Na) aqueous solution to make 2.5 mg/mL (free base) aqueous solution, and the dosage was 25 mg/kg, once a day, orally administered Stomach volume 10 mL/kg. The vehicle is 9% PEG400+0.5% Tween-80+90.5% (0.5% CMC-Na) aqueous solution, once a day, orally administered with a volume of 10 mL/kg.

1.5 Experimental method: 200 μL of MCF-7 (Y537S) cells (1.0×10 ⁷ cells) were inoculated subcutaneously in the right flank of 110 Scid Beige mice. After 20 days of inoculation, the body weight was removed after the tumor volume was ~180 mm ³ 1. If the tumor was too large or too small, the mice were randomly divided into 10 groups according to the tumor volume, with 8 mice in each group, as shown in Table 1. After 21 days of administration, the tumor volume was measured twice a week, the body weight was weighed, and the data was recorded. The grouping and drug administration are shown in Table 1.

See Table 1 for specific dosing regimens. Table 1. Experimental grouping and drug administration group number of animals MCF-7 (Y537S) concentration Dosage (mg/kg) Dosing frequency 1 Vehicle 8 1×10 ⁷ /piece po qd 2 Drug A 8 1×10 ⁷ /piece 20 po qd 3 Drug A 8 1×10 ⁷ /piece 50 po qd 4 Fulvestrant 8 1×10 ⁷ /piece 200 sc biw 5 Drug B 8 1×10 ⁷ /piece 25 po qd 6 Drug A+ Drug B 8 1×10 ⁷ /piece 20+25 po qd 7 Drug A+ Drug B 8 1×10 ⁷ /piece 50+25 po qd 8 Fulvestrant + Drug B 8 1×10 ⁷ /piece 200+25 s.c+po biw+qd

1.6 Data statistics Use Excel statistical software to record data: average value is calculated by avg; SD value is calculated by STDEV; SEM value is calculated by STDEV/SQRT (number of animals in each group); GraphPad Prism software is used for analysis, and Two-way ANOVA or One-way ANOVA is used for analysis. The data were statistically analyzed by way ANOVA. The formula for calculating tumor volume (V) is: V=1/2×L _long ×L _short ² relative tumor proliferation rate T/C (%)=(TT ₀ )/(CC ₀ )×100, where T and C are experimental The tumor volumes of the treatment group and the control group at the end; T ₀ , C ₀ are the tumor volumes at the beginning of the experiment. Tumor inhibition rate TGI (%) = 100- T/C (%).

1.7 Experimental results Table 2 shows the growth inhibitory effect of the administered compounds on MCF-7 (Y537S) tumors. Table 2. The curative effect of administered compounds on transplanted tumors in MCF-7 (Y537S) mice group mean tumor volume D1 Mean tumor volume D22 TGI(%) Pvs blank Pvs administered alone Pvs drug B 1 179.49±10.87 623.59±27.88 2 177.54±9.52 168.91±12.82 102% p<0.001 3 176.07±8.00 140.63±13.49 108% p<0.001 4 175.60±7.99 225.97±10.25 89% p<0.001 5 177.46±8.73 231.42±10.88 88% p<0.001 6 178.61±8.00 84.89±4.74 121% p<0.001 p<0.001 p<0.001 7 175.47±7.70 65.61±3.40 125% p<0.001 p<0.001 p<0.001 8 174.81±8.06 174.14±9.34 100% p<0.001 p<0.001 p<0.001

After 21 days of administration, compared with the Vehicle group, the tumor inhibition rates of drug A at doses of 20 and 50 mg/kg were 102% and 108%, respectively. As the dose increased, the tumor inhibition rate gradually increased, but the two groups There is no significant difference between. The tumor inhibition rate of the reference compound fulvestrant-200 mg/kg was 89%.

The tumor inhibition rate of CDK4/6 inhibitor drug B at 25 mg/kg was 88%. When drug A was administered in combination with drug B-25 mg/kg at doses of 20 and 50 mg/kg, the tumor inhibition rates were 121% and 125%, respectively, which were significantly higher than those of the single-use groups ( p <0.001). Fulvestrant-200 mg/kg combined with drug B-25 mg/kg had a tumor inhibition rate of 100%, which was significantly higher than that of the single-administration group ( p <0.01). The tumor weights of the mice in each group were stripped and weighed. The tumor weight of each drug administration group was significantly smaller than that of the Vehicle group ( p <0.001), and each drug administration group could significantly inhibit the growth of MCF-7 (Y537S) tumors ( p <0.001). The body weight of mice in each group increased slightly, suggesting that there is no obvious toxic effect under the current administration dose.

To sum up, in this experiment, drug A can significantly inhibit the growth of MCF-7 (Y537S) tumors, and its efficacy alone is better than that of the reference compound. Drug A is administered in combination with CDK4/6 inhibitor drug B to further enhance the anti-tumor effect.

Example 2. Drug A (compound maleate represented by formula (I)) alone and in combination with drug B (compound isethionate represented by formula (I)) in ER-positive, HER2-negative metastatic or local Single-arm, open-label, multi-center phase I clinical study of safety, tolerability and pharmacokinetics in patients with advanced breast cancer

Main research purposes: 1) Determine the dose-limiting toxicity (DLT) of drug A alone and in combination with drug B in patients with metastatic or locally advanced breast cancer, and determine the maximum tolerated dose (MTD) and phase II clinical study recommended dose (RP2D); 2) Evaluate the safety of drug A alone and in combination with drug B in patients with metastatic or locally advanced breast cancer. Secondary study objectives included pharmacokinetic (PK) parameters and preliminary efficacy.

Research endpoints: The main research endpoints include MTD and RP2D, as well as safety endpoints (laboratory indicators, electrocardiogram, vital signs, adverse events. The incidence and severity of adverse events/serious adverse events are judged according to NCI-CTCAE V5.0 standards) ; Secondary study endpoints include PK parameters and primary efficacy endpoints.

Primary Efficacy Endpoints: Objective Response Rate (ORR: Complete Response [CR] + Partial Response [PR]), Best Overall Response (BOR), Duration of Response (DoR), Disease Control Rate (DCR: CR + PR + Stable Disease [SD]), Progression-free survival (PFS);

Study population: patients with ER-positive, HER2-negative, metastatic or locally advanced breast cancer who have no standard treatment, have failed standard treatment, or are not suitable for standard treatment.

This trial is a single-arm, open-label, multicenter phase I clinical study of drug A monotherapy and combination drug B dose escalation and dose expansion. In group A, the dose of drug A is increased; Group B is drug A single drug dose expansion; Group C is the combination of drug A and drug B with dose-escalation treatment; Group D is drug A combined with drug B dose expansion.

The single-drug dose escalation of group A drug A is carried out first, and the safety monitoring committee (Safety monitoring committee, SMC) decides when to start the single-drug expansion of group B after obtaining preliminary safety data; after completing the single-drug escalation and After the expansion, the SMC discussed and decided to increase the combined treatment of group C and expand the combined treatment of group D.

Group A: The principle of i3+3 was adopted to carry out single-drug dose escalation. Drug A presets 6 dose groups based on preclinical test data: 25 mg, 75 mg, 150 mg, 300 mg, 450 mg and 600 mg, and subjects can only receive one of the doses.

Group B: Select 2-3 dosage groups for extended research to further clarify the pharmacokinetic characteristics and RP2D of drug A, and expand to 10-12 subjects in each dosage group.

Group C: In this study, the "3+3" principle was adopted for the combined dose escalation test. The drug A preset dose is the previous dose of RP2D (RP2D-1) and the PR2D of drug A, drug B is preset. 100 mg qd and 125 mg qd, the combination of the two drugs was dose-escalated using the "3+3" principle, with a cycle of 28 days. After completing one cycle of combined continuous administration, the subjects will undergo a safety assessment during the DLT observation period, and only after the safety is confirmed can they enter the next dose group trial.

Group D: According to the comprehensive safety and efficacy data of the climbing results of group C, select 1-2 dose groups of drug A and drug B combined for dose expansion, each dose group expanded to 10-12 subjects .

Drug A administration method: oral administration, every morning on an empty stomach, once a day during continuous administration, and continuous administration for 4 weeks as a cycle.

Drug A tablet specification: 25 mg/tablet; 150 mg/tablet.

Single-dose lead-in period: Subjects took drug A orally on an empty stomach and took it with warm water. Do not eat or drink anything (except water) 2 hours before and 1 hour after taking this medicine. After a single dose, PK blood samples were collected, and the next dose was performed after 3 days of washout. This phase applies only to the Drug A monotherapy phase (arms A and B), Combination Drug B does not have a single-dose lead-in phase.

Multiple administrations: After a single administration washes out for 3 days, take drug A tablets orally continuously, once a day, take with warm water on an empty stomach, and fast for food or drink (except water) 2 hours before and 1 hour after taking the medicine. 4 weeks (28 days) is 1 cycle. The drug was taken until disease progression, intolerance, withdrawal of informed consent, or the investigator judged that the subject was no longer suitable for continued treatment.

Drug B administration method: Oral, once a day, every 28 days is a treatment cycle, in which the first 3 weeks (1st to 21st day) of continuous medication, the next 1 week (22nd to 28th day) rest ( without medication).

Drug B tablet specification: 150 mg/tablet, 125 mg/tablet, 50 mg/tablet, 25 mg/tablet.

Inclusion criteria: Women aged 18-75 (both ends included); Patients with metastatic or locally advanced breast cancer confirmed by histology: ER positive and HER2 negative confirmed by histological examination (ER positive standard: Immunohistochemical staining shows that no less than 10% of tumor cell nuclei show different degrees of staining. HER2 Negative standard: Immunohistochemical staining [IHC, staining intensity range 0-3] intensity is 0, 1+; if the intensity is 2+, fluorescent in situ hybridization [FISH] must be carried out to confirm that it is negative).

Menopausal status: a) Previous bilateral oophorectomy, or age ≥60 years; or b) Age <60 years, natural postmenopausal status (defined as spontaneous cessation of regular menstruation for at least 12 consecutive months without other pathological or physiological causes), estradiol and FSH at postmenopausal levels; or c) Premenopausal or perimenopausal patients, but must receive LHRH agonist treatment during the study Previously received at least 1 line of endocrine therapy for advanced stage progression; Previously received ≤ 2 lines of chemotherapy for advanced disease; During or after the last systemic treatment before enrollment, clinically or imaging-confirmed disease progression occurred; Previous treatment: Before the first drug in this study, the interval of receiving nitrosourea or mitomycin was ≥6 weeks; receiving cytotoxic drugs, any other anti-cancer endocrine therapy, immunotherapy, targeted therapy, surgical interval or other clinical studies The last medication ≥ 4 weeks; the interval from the end of radiotherapy ≥ 2 weeks.

Although the present invention has been disclosed above with the embodiments, it is not intended to limit the present invention. Those with ordinary knowledge in the technical field of the present invention can make some changes and modifications without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be defined by the scope of the appended patent application.

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Claims (8)

Use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating breast cancer, the breast cancer is preferably ER+ or HER2- breast cancer, most preferably ER+, HER2- breast cancer,

. According to the use described in Claim 1, the use further includes combining CDK 4/6 inhibitors, and the CDK 4/6 inhibitors are preferably palbociclib or a pharmaceutically acceptable salt thereof, bomazenil or its pharmaceutically acceptable salt, ribociclib, 2'-((5-(4-isopropylpiper-1-yl)pyridin-2-yl)amino)-7',8'-di Hydrogen-6'H-spiro[cyclohexane-1,9'-pyrrolo[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-6'-one dihydrochloride salt, G1T-28, AT-7519, FLX-925, avocidide, or a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,

Most preferred is the compound represented by formula (II) or a pharmaceutically acceptable salt thereof. According to the use described in any one of claims 1-2, the breast cancer is metastatic or locally advanced breast cancer. According to the use described in any one of claim items 1-3, the pharmaceutically acceptable salt of the compound represented by the formula (I) is selected from maleate, hydrochloride, oxalate, tartrate, rich Maleate, citrate, malate, adipate, methanesulfonate, phosphate, acetate, mandelate or sulfate; preferably maleate or hydrochloride, most preferably hydrochloride . According to the use described in any one of claims 2-4, the pharmaceutically acceptable salt of the compound represented by the formula (II) is isethionate. According to the use described in any one of claims 1-5, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 1-1000 mg; the administration frequency is once a day or once a day Twice; preferably, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg, frequency of administration once a day; most preferably, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 25 mg, 75 mg, 150 mg, 300 mg, 450 mg or 600 mg, and the administration frequency is Once a day. According to the use described in claim item 6, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 1-500 mg, and the dosage frequency is selected from once a day or twice a day ; Preferably, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg, given The frequency of the drug is once a day; most preferably, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 75 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg, The dosing frequency is once a day. A pharmaceutical composition, comprising the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and the compound represented by formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims 2-7, and at least one pharmaceutically acceptable excipient.