WO2023109741A1

WO2023109741A1 - Pharmaceutical composition for treating cancer

Info

Publication number: WO2023109741A1
Application number: PCT/CN2022/138337
Authority: WO
Inventors: 李嘉逵; 史澂空; 徐艳君
Original assignee: 轩竹生物科技股份有限公司
Priority date: 2021-12-13
Filing date: 2022-12-12
Publication date: 2023-06-22
Also published as: CN118119610A

Abstract

A pharmaceutical composition for preventing and/or treating cancer, comprising a combination of a CDK4/6 inhibitor compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a second therapeutic agent or a pharmaceutically acceptable salt thereof in fixed proportions or doses, an application of the foregoing pharmaceutical composition in the preparation of a drug for preventing and/or treating cancer, and a kit containing the pharmaceutical composition.

Description

A kind of pharmaceutical composition for treating cancer

technical field

The present invention belongs to the technical field of medicine, and specifically relates to a pharmaceutical composition for preventing and/or treating cancer, especially containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a second therapeutic agent or a pharmaceutically acceptable salt thereof A pharmaceutical composition of fixed ratio or fixed dose combination of salts, and use of said pharmaceutical composition for treating cancer.

Background technique

Breast cancer is the most common malignant tumor in women, and there are about 2 million new breast cancer patients worldwide every year. Breast cancer is a class of highly heterogeneous tumors at the molecular level, and there are great differences in histomorphology, immunophenotype, biological behavior and treatment response. Breast cancers are classified into three subtypes based on the expression of three receptors: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (Her2). Estrogen receptor positive (ER+) breast cancer is the most common molecular subtype of breast cancer, with an incidence rate of about 65%-70% in the population. The prognosis is the best in breast cancer, and there are more patients in the early stage. Compared with other molecular subtypes of breast cancer, ER+ breast cancer has a better prognosis, but there is still a 5-year recurrence and metastasis rate of about 15-30%. The human epidermal growth factor receptor-2 (HER2) molecule is an independent factor for the poor prognosis of breast cancer. About 20%-30% of Chinese breast cancer patients have HER2 gene amplification/overexpression. HER2 overexpression is typically associated with aggressive, metastatic forms of breast cancer that have high recurrence rates and/or are associated with poor patient prognosis.

The general goal of treatment for all patients with ER/PR-positive metastatic breast cancer is to prolong survival and improve quality of life. This can be achieved with surgical intervention and, where possible, medical therapy. Endocrine (anti-estrogen) drugs are usually used initially and maintained until resistance develops. Their use avoids chemotherapy-based toxicity, but the toxicity and drug resistance of the drug itself still need to be well resolved.

Aromatase (aromatase, AR) (also known as estrogen synthase) is a complex enzyme of microsomal cytochrome P450, which is widely present in ovary, liver, muscle, fat and breast cancer cells, and is a catalyst that catalyzes androgen in vivo. Key and rate-limiting enzyme for the conversion of hormones to estrogens and aromatizes androgens to estrone and estradiol. Aromatase inhibitor (aromatase inhibitor, AI) can specifically lead to the inactivation of aromatase, block the aromatization reaction, inhibit the production of estrogen, and reduce the level of estrogen in the blood so as to achieve the purpose of treating breast cancer. It is mostly used for anti-estrogen Postmenopausal women with advanced breast cancer who have failed hormone (tamoxifen) therapy.

Anastrozole belongs to the third-generation aromatase inhibitor, which is a potent and selective non-steroidal aromatase inhibitor, which can inhibit the conversion of estrenedione to estrone in postmenopausal patients, thereby significantly Reduce the level of estrogen in the body and inhibit the growth of breast tumors. Anastrozole is suitable for advanced breast cancer in postmenopausal women who cannot be controlled by tamoxifen and other anti-estrogen therapy.

Letrozole is also a third-generation aromatase inhibitor, and its in vivo activity is 150-250 times stronger than that of the first-generation aromatase inhibitor aminoglutethimide. Because of its high selectivity, it does not affect the function of glucocorticoids, mineralocorticoids and thyroid gland, and large doses have no inhibitory effect on the secretion of adrenal corticosteroids, so it has a high therapeutic index. It is suitable for postmenopausal advanced breast cancer, and is mostly used for second-line treatment after failure of anti-estrogen therapy.

Exemestane is also a third-generation aromatase inhibitor, which can irreversibly bind to aromatase to inactivate it. Once exemestane binds to aromatase, the enzyme can never produce estrogen again. Thereby preventing the biosynthesis of estrogen. Exemestane is indicated for the adjuvant treatment of early invasive breast cancer in postmenopausal women with estrogen receptor positive after 2-3 years of adjuvant tamoxifen therapy until completion of a total of 5 years of adjuvant endocrine therapy and for advanced breast cancer in postmenopausal women whose disease has progressed despite tamoxifen therapy.

The functional effects of almost all oncogenes and tumor suppressor genes will eventually converge on the cell cycle, and regulating or blocking the cell cycle is one of the ways to treat tumors. At present, many molecules related to cell cycle regulation have been discovered, among which cyclin-dependent kinases (Cyclin-Dependent-Kinases, CDKs) are the core molecules of the cell cycle regulation network. Among the CDK subtypes involved in the cell cycle, CDK4/6 plays an irreplaceable role. CDK4/6-specific activation is closely related to the proliferation of some tumors, and about 80% of human tumors have abnormalities in the cyclin D-CDK4/6-INK4-Rb pathway. CDK4/6 inhibitors currently on the market include PD0332991 (Palbociclib, Ibrance) developed by Pfizer, LY2835219 (Abemaciclib, Verzenio) from Eli Lilly and LEE011 (Ribociclib, Kisqali) from Novartis.

The invention provides a high-efficiency and low-toxicity tumor treatment composition, which mainly relates to the combined use of CDK4/6 inhibitors and aromatase inhibitors for treating cancer.

Contents of the invention

In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent or a pharmaceutically acceptable salt thereof,

The second therapeutic agent is selected from aromatase inhibitors, wherein the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 1 :1-1000:1.

In certain embodiments, the weight ratio of active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 1:1-900:1.

In certain embodiments, the weight ratio of active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 1:1-800:1.

In certain embodiments, the weight ratio of active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 1:1-720:1.

In certain embodiments, the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 28.8:1-720:1.

In certain embodiments, the weight ratio of active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 160:1-720:1.

In certain embodiments, the weight ratio of active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 288:1-720:1.

In certain embodiments, the weight ratio of active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 1:1-700:1.

In certain embodiments, the weight ratio of active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 1:1-600:1.

In certain embodiments, the weight ratio of active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 1:1-500:1.

In certain embodiments, the weight ratio of active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 1:1-400:1.

In certain embodiments, the second therapeutic agent is selected from letrozole, anastrozole, or exemestane.

In certain embodiments, the second therapeutic agent is letrozole, and the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 5:1-400:1.

In certain embodiments, the second therapeutic agent is letrozole, and the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 10:1-400:1.

In certain embodiments, the second therapeutic agent is letrozole, and the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 12.5:1-384:1.

In certain embodiments, the second therapeutic agent is letrozole, and the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 12.5:1-336:1.

In certain embodiments, the second therapeutic agent is letrozole, and the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 12.5:1-300:1.

In certain embodiments, the second therapeutic agent is letrozole, and the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 12.5:1-288:1.

In certain embodiments, the second therapeutic agent is letrozole, and the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 25:1-288:1.

In certain embodiments, the second therapeutic agent is letrozole, and the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 80:1-400:1.

In certain embodiments, the second therapeutic agent is letrozole, and the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 160:1-400:1.

In certain embodiments, the second therapeutic agent is letrozole, and the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 168:1-384:1.

In certain embodiments, the second therapeutic agent is letrozole, and the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to letrozole or a pharmaceutically acceptable salt thereof is 400:1, 390:1, 385:1, 384:1, 383:1, 380:1, 370:1, 360:1, 352:1, 350:1, 344:1, 340:1, 337: 1, 336:1, 335:1, 330:1, 328:1, 320:1, 312:1, 304:1, 300:1, 296:1, 290:1, 289:1, 288:1, 287:1, 285:1, 280:1, 272:1, 270:1, 264:1, 260:1, 256:1, 250:1, 248:1, 241:1, 240:1, 239: 1, 232:1, 230:1, 220:1, 225:1, 224:1, 223:1, 220:1, 216:1, 210:1, 208:1, 200:1, 193:1, 192:1, 191:1, 190:1, 184:1, 180:1, 176:1, 170:1, 169:1, 168:1, 167:1, 160:1, 150:1, 140: 1, 130:1, 120:1, 110:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 35:1, 30:1, 25:1, 20:1, 15:1, 12.5:1, 10:1, 5:1.

In certain embodiments, the second therapeutic agent is anastrozole, and the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to anastrozole or a pharmaceutically acceptable salt thereof is It is 400:1-1000:1, preferably 540:1-960:1, preferably 600:1-960:1, preferably 720:1.

In certain embodiments, the second therapeutic agent is anastrozole, and the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to anastrozole or a pharmaceutically acceptable salt thereof is 400:1, 420:1, 440:1, 460:1, 480:1, 500:1, 520:1, 540:1, 560:1, 580:1, 600:1, 620:1, 640 :1, 660:1, 680:1, 700:1, 720:1, 740:1, 760:1, 780:1, 800:1, 820:1, 840:1, 860:1, 880:1 , 900:1, 960:1.

In certain embodiments, the second therapeutic agent is exemestane.

In certain embodiments, the second therapeutic agent is exemestane, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient of exemestane or a pharmaceutically acceptable salt thereof The weight ratio is 10:1-100:1, preferably 10:1-50:1, preferably 15:1-40:1.

In certain embodiments, the second therapeutic agent is exemestane, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient of exemestane or a pharmaceutically acceptable salt thereof Weight ratios are 16.8:1, 19.2:1, 21.6:1, 22.4:1, 23.2:1, 24:1, 24.8:1, 25.6:1, 26.4:1, 27.2:1, 28:1, 28.8:1 , 29.6:1, 30.4:1, 31.2:1, 32:1, 32.8:1, 33.6:1, 34.4:1, 35.2:1, 36:1, 38.4:1.

In certain embodiments, the second therapeutic agent is exemestane, and the compound of formula (I) or a pharmaceutically acceptable salt thereof and the active ingredient of exemestane or a pharmaceutically acceptable salt thereof The weight ratio is 28.8:1.

In some embodiments, the second therapeutic agent is selected from letrozole or anastrozole, wherein, the compound of formula (I) or its pharmaceutically acceptable salt and letrozole or its pharmaceutically acceptable The active ingredient weight ratio of the salt is 5:1-400:1, preferably 10:1-400:1, preferably 12.5:1-384:1, preferably 12.5:1-336:1, preferably 12.5:1-300:1 , preferably 12.5:1-288:1; the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to Anastrozole or a pharmaceutically acceptable salt thereof is 400:1-1000:1, preferably 540:1-960:1, preferably 600:1-960:1, preferably 720:1.

In some embodiments, the second therapeutic agent is selected from letrozole or anastrozole, wherein, the compound of formula (I) or its pharmaceutically acceptable salt and letrozole or its pharmaceutically acceptable The active ingredient weight ratio of salt is 400:1, 390:1, 385:1, 384:1, 383:1, 380:1, 370:1, 360:1, 352:1, 350:1, 344:1 , 340:1, 337:1, 336:1, 335:1, 330:1, 328:1, 320:1, 312:1, 304:1, 300:1, 296:1, 290:1, 289 :1, 288:1, 287:1, 285:1, 280:1, 272:1, 270:1, 264:1, 260:1, 256:1, 250:1, 248:1, 241:1 , 240:1, 239:1, 232:1, 230:1, 220:1, 225:1, 224:1, 223:1, 220:1, 216:1, 210:1, 208:1, 200 :1, 193:1, 192:1, 191:1, 190:1, 184:1, 180:1, 176:1, 170:1, 169:1, 168:1, 167:1, 160:1 , 150:1, 140:1, 130:1, 120:1, 110:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 35 :1, 30:1, 25:1, 20:1, 15:1, 12.5:1, 10:1, 5:1; Formula (I) compound or its pharmaceutically acceptable salt and Anastrozole or its The active ingredient weight ratio of the pharmaceutically acceptable salt is 400:1, 420:1, 440:1, 460:1, 480:1, 500:1, 520:1, 540:1, 560:1, 580: 1, 600:1, 620:1, 640:1, 660:1, 680:1, 700:1, 720:1, 740:1, 760:1, 780:1, 800:1, 820:1, 840:1, 860:1, 880:1, 900:1, 960:1.

In some embodiments, the second therapeutic agent is selected from letrozole or anastrozole, wherein, the compound of formula (I) or its pharmaceutically acceptable salt and letrozole or its pharmaceutically acceptable The active ingredient weight ratio of the salt is 288:1; the active ingredient weight ratio of the compound of formula (I) or its pharmaceutically acceptable salt to anastrozole or its pharmaceutically acceptable salt is 720:1.

In some embodiments, the second therapeutic agent is selected from letrozole or exemestane, wherein, the compound of formula (I) or its pharmaceutically acceptable salt and letrozole or its pharmaceutically acceptable The active ingredient weight ratio of the salt is 5:1-400:1, preferably 10:1-400:1, preferably 12.5:1-384:1, preferably 12.5:1-336:1, preferably 12.5:1-300: 1, preferably 12.5:1-288:1; the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to exemestane or a pharmaceutically acceptable salt thereof is 10:1-100:1 , preferably 10:1-50:1, preferably 15:1-40:1.

In some embodiments, the second therapeutic agent is selected from letrozole or exemestane, wherein, the compound of formula (I) or its pharmaceutically acceptable salt and letrozole or its pharmaceutically acceptable The active ingredient weight ratio of the salt is 400:1, 390:1, 385:1, 384:1, 383:1, 380:1, 370:1, 360:1, 352:1, 350:1, 344: 1, 340:1, 337:1, 336:1, 335:1, 330:1, 328:1, 320:1, 312:1, 304:1, 300:1, 296:1, 290:1, 289:1, 288:1, 287:1, 285:1, 280:1, 272:1, 270:1, 264:1, 260:1, 256:1, 250:1, 248:1, 241: 1, 240:1, 239:1, 232:1, 230:1, 220:1, 225:1, 224:1, 223:1, 220:1, 216:1, 210:1, 208:1, 200:1, 193:1, 192:1, 191:1, 190:1, 184:1, 180:1, 176:1, 170:1, 169:1, 168:1, 167:1, 160: 1, 150:1, 140:1, 130:1, 120:1, 110:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 35:1, 30:1, 25:1, 20:1, 15:1, 12.5:1, 10:1, 5:1; compound of formula (I) or its pharmaceutically acceptable salt and exemestane The active ingredient weight ratio of its pharmaceutically acceptable salt is 16.8:1, 19.2:1, 21.6:1, 22.4:1, 23.2:1, 24:1, 24.8:1, 25.6:1, 26.4:1, 27.2:1, 28:1, 28.8:1, 29.6:1, 30.4:1, 31.2:1, 32:1, 32.8:1, 33.6:1, 34.4:1, 35.2:1, 36:1, 38.4: 1.

In some embodiments, the second therapeutic agent is selected from letrozole or exemestane, wherein, the compound of formula (I) or its pharmaceutically acceptable salt and letrozole or its pharmaceutically acceptable The active ingredient weight ratio of the salt of the compound is 288:1; the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to exemestane or a pharmaceutically acceptable salt thereof is 28.8:1.

In certain embodiments, the second therapeutic agent is selected from exemestane or anastrozole, wherein, the compound of formula (I) or a pharmaceutically acceptable salt thereof and exemestane or a pharmaceutically acceptable salt thereof The active ingredient weight ratio of the accepted salt is 10:1-100:1, preferably 10:1-50:1, preferably 15:1-40:1; formula (I) compound or its pharmaceutically acceptable salt and A The weight ratio of active ingredients of nastrozole or a pharmaceutically acceptable salt thereof is 400:1-1000:1, preferably 540:1-960:1, preferably 600:1-960:1, preferably 720:1.

In certain embodiments, the second therapeutic agent is selected from exemestane or anastrozole, wherein, the compound of formula (I) or a pharmaceutically acceptable salt thereof and exemestane or a pharmaceutically acceptable salt thereof Accepted salts are active ingredient weight ratios of 16.8:1, 19.2:1, 21.6:1, 22.4:1, 23.2:1, 24:1, 24.8:1, 25.6:1, 26.4:1, 27.2:1, 28 :1, 28.8:1, 29.6:1, 30.4:1, 31.2:1, 32:1, 32.8:1, 33.6:1, 34.4:1, 35.2:1, 36:1, 38.4:1; formula (I ) compound or its pharmaceutically acceptable salt and the active ingredient weight ratio of anastrozole or its pharmaceutically acceptable salt is 400:1, 420:1, 440:1, 460:1, 480:1, 500: 1, 520:1, 540:1, 560:1, 580:1, 600:1, 620:1, 640:1, 660:1, 680:1, 700:1, 720:1, 740:1, 760:1, 780:1, 800:1, 820:1, 840:1, 860:1, 880:1, 900:1, 960:1.

In certain embodiments, the second therapeutic agent is selected from exemestane or anastrozole, wherein, the compound of formula (I) or a pharmaceutically acceptable salt thereof and exemestane or a pharmaceutically acceptable salt thereof The weight ratio of the active ingredients of the accepted salt is 28.8:1; the weight ratio of the active ingredients of the compound of formula (I) or its pharmaceutically acceptable salt to anastrozole or its pharmaceutically acceptable salt is 720:1.

In some embodiments, the second therapeutic agent is selected from letrozole or anastrozole or exemestane, wherein, the compound of formula (I) or a pharmaceutically acceptable salt thereof and letrozole or its The active ingredient weight ratio of the pharmaceutically acceptable salt is 5:1-400:1, preferably 10:1-400:1, preferably 12.5:1-384:1, preferably 12.5:1-336:1, preferably 12.5:1 1-300:1, preferably 12.5:1-288:1; the active ingredient weight ratio of formula (I) compound or its pharmaceutically acceptable salt and Anastrozole or its pharmaceutically acceptable salt is 400:1- 1000:1, preferably 540:1-960:1, preferably 600:1-960:1, preferably 720:1; formula (I) compound or its pharmaceutically acceptable salt and exemestane or its pharmaceutically acceptable The accepted salts have a weight ratio of active ingredients of 10:1-100:1, preferably 10:1-50:1, preferably 15:1-40:1.

In some embodiments, the second therapeutic agent is selected from letrozole or anastrozole or exemestane, wherein, the compound of formula (I) or a pharmaceutically acceptable salt thereof and letrozole or its The active ingredient weight ratio of the pharmaceutically acceptable salt is 400:1, 390:1, 385:1, 384:1, 383:1, 380:1, 370:1, 360:1, 352:1, 350: 1, 344:1, 340:1, 337:1, 336:1, 335:1, 330:1, 328:1, 320:1, 312:1, 304:1, 300:1, 296:1, 290:1, 289:1, 288:1, 287:1, 285:1, 280:1, 272:1, 270:1, 264:1, 260:1, 256:1, 250:1, 248: 1, 241:1, 240:1, 239:1, 232:1, 230:1, 220:1, 225:1, 224:1, 223:1, 220:1, 216:1, 210:1, 208:1, 200:1, 193:1, 192:1, 191:1, 190:1, 184:1, 180:1, 176:1, 170:1, 169:1, 168:1, 167: 1, 160:1, 150:1, 140:1, 130:1, 120:1, 110:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 35:1, 30:1, 25:1, 20:1, 15:1, 12.5:1, 10:1, 5:1; formula (I) compound or its pharmaceutically acceptable salt and The active ingredient weight ratio of anastrozole or its pharmaceutically acceptable salt is 400:1, 420:1, 440:1, 460:1, 480:1, 500:1, 520:1, 540:1, 560 :1, 580:1, 600:1, 620:1, 640:1, 660:1, 680:1, 700:1, 720:1, 740:1, 760:1, 780:1, 800:1 , 820:1, 840:1, 860:1, 880:1, 900:1, 960:1; formula (I) compound or its pharmaceutically acceptable salt and exemestane or its pharmaceutically acceptable The active ingredient weight ratio of salt is 16.8:1, 19.2:1, 21.6:1, 22.4:1, 23.2:1, 24:1, 24.8:1, 25.6:1, 26.4:1, 27.2:1, 28:1 , 28.8:1, 29.6:1, 30.4:1, 31.2:1, 32:1, 32.8:1, 33.6:1, 34.4:1, 35.2:1, 36:1, 38.4:1.

In some embodiments, the second therapeutic agent is selected from letrozole or anastrozole or exemestane, wherein, the compound of formula (I) or a pharmaceutically acceptable salt thereof and letrozole or its The active ingredient weight ratio of the pharmaceutically acceptable salt is 288:1; the active ingredient weight ratio of the compound of formula (I) or its pharmaceutically acceptable salt to Anastrozole or its pharmaceutically acceptable salt is 720:1 ; The active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to exemestane or a pharmaceutically acceptable salt thereof is 28.8:1.

In certain embodiments, the daily dosage of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 200-2000 mg.

In certain embodiments, the daily dosage of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 200-1000 mg.

In certain embodiments, the daily dosage of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 400-1000 mg.

In certain embodiments, the daily dosage of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 960 mg, 840 mg, 720 mg, 600 mg, 560 mg, 480 mg or 420 mg.

In certain embodiments, the daily dosage of the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 900mg, 880mg, 860mg, 820mg, 800mg, 780mg, 760mg, 740mg, 700mg, 680mg, 660mg, 640mg , 620mg, 580mg or 540mg.

In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, or three times a day.

In certain embodiments, the second therapeutic agent, or a pharmaceutically acceptable salt thereof, is administered once a day, twice a day, or three times a day.

In certain embodiments, the active ingredient of the second therapeutic agent or a pharmaceutically acceptable salt thereof is 0.2-400 mg, such as 0.5-200 mg, such as 0.5-100 mg, such as 0.5-50 mg, such as 1- 25 mg, such as 1-10 mg, such as 1-5 mg, such as 25 mg, such as 2.5 mg, such as 1 mg.

In certain embodiments, the active ingredient of the second therapeutic agent or a pharmaceutically acceptable salt thereof is 100 mg, 75 mg, 50 mg, 25 mg, 10 mg, 7.5 mg, 5 mg, 2.5 mg, 1 mg or 0.5 mg per dosage. .

In certain embodiments, the second therapeutic agent is letrozole, and the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is 1-5 mg each time, preferably 2.5 mg, and the administration frequency is one day once.

In certain embodiments, the second therapeutic agent is anastrozole, and the active ingredient of anastrozole or a pharmaceutically acceptable salt thereof is 0.5-2.5 mg each time, preferably 1 mg, and the administration frequency is one day once.

In certain embodiments, the second therapeutic agent is exemestane, and the active ingredient of exemestane or a pharmaceutically acceptable salt thereof is 12.5-50 mg each time, preferably 25 mg, and the administration frequency is one once a day.

In certain embodiments, the second therapeutic agent is letrozole or anastrozole, wherein the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is 2.5 mg each time, and the dosing frequency is one Once a day; the active ingredient of anastrozole or a pharmaceutically acceptable salt thereof is 1 mg each time, and the administration frequency is once a day.

In certain embodiments, the second therapeutic agent is letrozole or exemestane, wherein the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is 2.5 mg each time, and the administration frequency is Once a day; the active ingredient of exemestane or a pharmaceutically acceptable salt thereof is 25 mg each time, and the administration frequency is once a day.

In certain embodiments, the second therapeutic agent is exemestane or anastrozole, wherein the active ingredient of exemestane or a pharmaceutically acceptable salt thereof is 25 mg each time, and the administration frequency is Once a day; the active ingredient of anastrozole or a pharmaceutically acceptable salt thereof is 1 mg each time, and the administration frequency is once a day.

In certain embodiments, the second therapeutic agent is letrozole or exemestane or anastrozole, wherein the active ingredient of letrozole or a pharmaceutically acceptable salt thereof is 2.5 mg each time, The dosing frequency is once a day; the active ingredient of exemestane or its pharmaceutically acceptable salt is 25 mg each time, and the dosing frequency is once a day; the effective dosage of anastrozole or its pharmaceutically acceptable salt The dosage of each component is 1 mg, and the administration frequency is once a day.

In certain embodiments, the compound of formula (I) and the second therapeutic agent are administered simultaneously or sequentially.

In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally.

In certain embodiments, the second therapeutic agent or a pharmaceutically acceptable salt thereof is administered orally.

In another aspect, the present invention also provides a pharmaceutical preparation, comprising the aforementioned pharmaceutical composition, and one or more pharmaceutically acceptable excipients, and the pharmaceutical preparation can be in any pharmaceutically acceptable dosage form. A pharmaceutically acceptable excipient is a substance that is nontoxic, compatible with the active ingredient and otherwise biologically suitable for the organism. The choice of a particular excipient will depend on the mode of administration or the type and state of the disease being used to treat the particular patient.

In certain embodiments, the pharmaceutical formulations described above may be administered orally, parenterally, rectally, or pulmonary to a patient or subject in need of such treatment. When used for oral administration, the pharmaceutical composition can be made into oral preparations, for example, it can be made into conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as Oral solution, oral suspension, syrup, etc. For parenteral administration, the above pharmaceutical preparations can also be made into injections, including injections, sterile powders for injections and concentrated solutions for injections. For rectal administration, the pharmaceutical composition can be made into suppositories and the like. For pulmonary administration, the pharmaceutical composition can be made into inhalation preparations, aerosols, powder mists or sprays and the like.

In another aspect, the present invention also relates to the application of the aforementioned pharmaceutical composition in the preparation of a medicament for the prevention and/or treatment of cancer, the cancer being selected from brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer , ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female reproductive tract cancer , Lymphoma, Neurofibroma, Thyroid Cancer, Bone Cancer, Skin Cancer, Brain Cancer, Colon Cancer, Testicular Cancer, Gastrointestinal Stromal Tumor, Prostate Tumor, Mast Cell Tumor, Multiple Myeloma, Melanoma, Glial Cancer Tumor or sarcoma, preferably breast cancer.

In certain embodiments, the cancer is selected from HR ⁺ , ^HER2- breast cancer.

In certain embodiments, the cancer is selected from postmenopausal HR ⁺ , ^HER2- breast cancer.

In certain embodiments, the cancer is selected from locally advanced or metastatic breast cancer.

In certain embodiments, the cancer is selected from HR ⁺ , ^HER2- advanced or metastatic breast cancer.

In certain embodiments, the cancer is selected from HR ⁺ , ^HER2- advanced or metastatic breast cancer that has progressed after endocrine therapy alone.

In another aspect, the present invention also relates to the combination of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and letrozole or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and/or treating cancer The cancer is selected from brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, Rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female reproductive tract cancer, lymphoma, neurofibroma, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer , gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma or sarcoma, preferably breast cancer.

Further, the present invention also relates to the application of the pharmaceutical preparation containing the aforementioned pharmaceutical composition in the preparation of medicines for preventing and/or treating cancer.

In another aspect, the present invention also provides a kit comprising the aforementioned pharmaceutical composition, and instructions for explaining how to administer the pharmaceutical composition or the compound of formula (I) and the second therapeutic agent contained therein.

In another aspect, the present invention also provides a method for treating cancer, the method comprising administering an effective amount of the aforementioned pharmaceutical composition and a pharmaceutical preparation containing the pharmaceutical composition to a patient in need; the cancer is as described above .

In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a second therapeutic agent or a pharmaceutically acceptable salt thereof according to a specific dosage regimen.

In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered at a dose of 400-1000 mg of active ingredient per day.

In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered at a dose of 960 mg, 840 mg, 720 mg, 600 mg, 560 mg, 480 mg or 420 mg of the active ingredient per day.

In certain embodiments, the second therapeutic agent is letrozole, administered orally at a dose of 1-5 mg active ingredient per day.

In certain embodiments, the second therapeutic agent is letrozole, administered orally at a dose of 2.5 mg of active ingredient per day.

In certain embodiments, the second therapeutic agent is anastrozole, administered orally at a dose of 0.5-2.5 mg of active ingredient per day.

In certain embodiments, the second therapeutic agent is anastrozole, administered orally at a dose of 1 mg of active ingredient per day.

In certain embodiments, the second therapeutic agent is exemestane, administered orally at a dose of 12.5-50 mg active ingredient per day.

In certain embodiments, the second therapeutic agent is exemestane, administered orally at a dose of 25 mg of the active ingredient per day.

In certain embodiments, the second therapeutic agent is letrozole or anastrozole, wherein letrozole is administered orally at a dose of 1-5 mg active ingredient per day or anastrozole is effective at 0.5-2.5 mg per day The dosage of the ingredients is administered orally.

In certain embodiments, the second therapeutic agent is letrozole or anastrozole, wherein letrozole is administered orally at a dose of 2.5 mg active ingredient per day or anastrozole is orally administered at a dose of 1 mg active ingredient per day medication.

In certain embodiments, the second therapeutic agent is letrozole or exemestane, wherein letrozole is administered orally at a dose of 1-5 mg of the active ingredient per day or exemestane at a dose of 12.5-50 mg per day The dosage of the active ingredient is administered orally.

In certain embodiments, the second therapeutic agent is letrozole or exemestane, wherein letrozole is administered orally at a dose of 2.5 mg active ingredient per day or exemestane is administered at a dose of 25 mg active ingredient per day Dosage is administered orally.

In certain embodiments, the second therapeutic agent is exemestane or anastrozole, wherein exemestane is administered orally at a dose of 12.5-50 mg active ingredient per day or anastrozole at a dose of 0.5-2.5 mg per day The dose of active ingredient in mg is administered orally.

In certain embodiments, the second therapeutic agent is exemestane or anastrozole, wherein exemestane is administered orally at a dose of 25 mg active ingredient per day or anastrozole is administered at a dose of 1 mg active ingredient per day Oral administration.

In certain embodiments, the second therapeutic agent is letrozole or anastrozole or exemestane, wherein letrozole is administered orally at a dose of 1-5 mg of the active ingredient per day or anastrozole is administered at a dose of The active ingredient is administered orally at a dose of 0.5-2.5 mg or exemestane is administered orally at a dose of 12.5-50 mg active ingredient per day.

In certain embodiments, the second therapeutic agent is letrozole or anastrozole or exemestane, wherein letrozole is administered orally at a dose of 2.5 mg of the active ingredient per day or anastrozole is administered at a dose of 1 mg per day Dosage of the active ingredient orally or exemestane at a dose of 25 mg of the active ingredient per day.

In the present invention, unless otherwise specified, the scientific and technical terms used herein have the meanings generally understood by those skilled in the art. However, in order to better understand the present invention, definitions of some terms are provided below. When the definitions and explanations of the terms provided in the present invention are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of the terms provided in the present invention shall prevail.

HR positive (HR ⁺ ) in the present invention refers to positive expression of ER (estrogen receptor) and/or positive expression of PR (progesterone receptor), that is, HR ⁺ includes ER ⁺ , PR ⁺ or ER ⁺ /PR ⁺ .

^HER2- in the present invention means that the expression of human epidermal growth factor receptor 2 (HER2) is negative.

The "second therapeutic agent" in the present invention refers to an agent that has a certain preventive and/or therapeutic effect on tumors.

The "effective amount" refers to the dose of the drug that can prevent, alleviate, delay, inhibit or cure the subject's symptoms. The dosage is related to the way of drug administration, the pharmacokinetics of the drug, the severity of the disease, and the individual signs (gender, weight, height, age) of the subject.

The "active ingredient" in the present invention refers to the part of the drug that exerts its medicinal effect. If the compound is a free compound, the active ingredient is the compound; if it is a salt of the compound, the active ingredient is the free compound (excluding the part that forms a salt with it).

The "pharmaceutical composition" in the present invention includes the composition formed by preparing the same compound preparation from the compound of formula (I) and the active ingredients such as the second therapeutic agent, and also includes the active ingredients such as the compound of formula (I) and the second therapeutic agent A composition formed by making a single preparation, respectively.

The "simultaneous administration" of the compound of formula (I) and the second therapeutic agent in the present invention includes administration after the compound of formula (I) and the second therapeutic agent are prepared into the same compound preparation, or the compound of formula (I) and the second therapeutic agent The reagents are prepared into formulations and administered simultaneously.

The "separate administration" of the compound of formula (I) and the second therapeutic agent in the present invention means that after the compound of formula (I) and the second therapeutic agent are respectively prepared into preparations, they are administered separately according to their respective preparation administration methods .

The "pharmaceutically acceptable salt" in the present invention refers to the salt formed by the acidic functional group (such as -COOH, -OH, -SO ₃ H, etc.) present in the compound and an appropriate inorganic or organic cation (base), including Salts formed with alkali metals or alkaline earth metals, ammonium salts, salts formed with nitrogen-containing organic bases; and salts formed by basic functional groups (such as -NH2, etc.) present in compounds with suitable inorganic or organic anions (acids), Salts with inorganic acids or organic acids (eg, carboxylic acids, etc.) are included.

Beneficial Effects of the Invention

1. The pharmaceutical composition of the present invention exhibits excellent synergistic anti-tumor effects in both in vitro cell experiments and in vivo tumor model experiments, especially in breast cancer.

2. The pharmaceutical composition of the present invention has a good clinical synergistic anti-tumor effect.

3. The pharmaceutical composition of the present invention has low or no toxicity and less side effects.

4. The pharmaceutical composition of the present invention can improve the pharmacokinetic properties of the single drug and increase the exposure.

specific implementation plan

Experimental program

Exemplary experimental schemes of some compounds of the present invention are provided below to show the advantageous activities and beneficial technical effects of the compounds of the present invention. However, it should be understood that the following experimental scheme is only an example of the content of the present invention, rather than limiting the scope of the present invention.

Experimental Example 1 The compound of formula (I) of the present invention and letrozole alone and in combination have the effect on human breast cancer xenograft model In vivo efficacy evaluation test

Test product: the compound of formula (I) of the present invention, prepared according to the method of the prior art.

The meanings represented by the abbreviations in the following experiments are as follows:

experimental method:

1. Tumor inoculation and grouping

Patient-derived tumor tissues were inoculated into immunodeficient animals to establish HBCx-34 human breast cancer (ER ⁺ , PR ⁺ , HER2 ^- ) xenograft PDX models. After the tumors of the donor mice grew to a certain volume, they were sacrificed and the tumors were isolated, processed into 20 mm ³ tumor pieces and inoculated subcutaneously in the scapula of the test mice. Tumor-bearing mice were supplemented with β-estradiol (8.5 mg/L) through drinking water during the period from tumor inoculation to grouping, and stopped supplementing estradiol after grouping.

The tumors grew to a volume of ^171.5-405mm and divided into 9 groups: solvent control group, formula (I) compound single use group (50mg/kg, 25mg/kg), letrozole single use group (1.25mg/kg , 2mg/kg) and the combination group, with 8 animals in each group. Both the compound of formula (I) and letrozole were intragastrically administered once a day for 42 days.

When the two are used in combination, the same method of administration is adopted as when they are used alone. The compound of formula (I) was prepared with pH 4.0 buffer (prepared from citric acid monohydrate and disodium hydrogen phosphate dodecahydrate) to the desired concentration, and letrozole was prepared with 0.9% NaCl solution to the desired concentration. The solvent control group was given the vehicle of the compound of formula (I), the above-mentioned pH4.0 buffer solution, and the administration method was intragastric administration once a day for 42 days.

2. Tumor measurement and experimental indicators

The tumor volume was measured twice a week with a vernier caliper, and the long and short diameters of the tumor were measured. The volume calculation formula was: volume=0.5×long diameter×short diameter ² . Calculate the average tumor volume value (T/C) according to the measurement results, T is the average tumor volume of the drug-administered group, and C is the average tumor volume of the solvent control group.

3. Statistical analysis

The Mann-Whitney non-parametric test was used to conduct statistical analysis on the tumor volume between groups, and p<0.05 was considered to have a significant difference.

Experimental results:

Table 1 The compound of the present invention is to the antitumor effect of HBCx-34 human source breast cancer (ER+, HER2-) xenograft model

Note: ^a. mean ± standard error; ^b. compared with the control group; ^c. compared with the single-use group of the corresponding concentration and dosage; ns: no significant difference. Experimental results:

The combination of the compound of formula (I) and letrozole has a significant inhibitory effect on the tumor growth of HBCx-34 (ER ⁺ , PR ⁺ , HER2 ^- ) human breast cancer xenograft PDX model, especially the compound of formula (I) 50mg /kg and letrozole 2mg/kg combination group, and formula (I) compound 50mg/kg and letrozole 1.25mg/kg combination group, its inhibitory effect is significantly better than the formula (I) compound and Letrozole alone group.

Experimental example 2 Clinical trial of the compound of formula (I) of the present invention and letrozole/anastrozole in combination for the treatment of breast cancer patients

testing sample:

The tablet of the compound of formula (I) of the present invention is prepared into a tablet of a certain specification by adding suitable auxiliary materials to the compound of formula (I);

Letrozole and Anastrozole: purchased or prepared according to the methods of the prior art.

Subject inclusion criteria:

1. Age 18-70 years old;

2. Breast cancer patients with hormone receptor positive (HR+) and HER2 negative (HER2-) confirmed by laboratory results have not received systemic anticancer therapy before;

3. The ECOG score is 0-1;

4. The subject's organ function is good at the time of enrollment, and the laboratory test data of blood routine, liver function and kidney function meet the standards;

5. According to the investigator's judgment, the life expectancy of the subject is ≥ 12 weeks;

6. Fertile male or female subjects must agree to use effective contraceptive methods;

7. Before the study starts, the subjects must provide written informed consent.

Evaluation criteria for target lesions

Dosing regimen:

Suitable subjects are screened, and the compound of formula (I) and letrozole/anastrozole are administered to the subjects. in,

The administration method of the compound of formula (I) is: 360mg, orally, twice a day. Every 28 days is a treatment cycle.

The administration method of letrozole is: 2.5mg, orally, once a day. Every 28 days is a treatment cycle.

The administration method of anastrozole is: 1mg, orally, once a day. Every 28 days is a treatment cycle.

A total of 35 subjects were enrolled. As of November 2021, the test results are shown in Table 2.

Table 2 Formula (I) compound and Letrozole/Anastrozole combination therapy to the tumor inhibitory effect of experimenter

a: not evaluated (NE).

b: Disease control rate (DCR), refers to the percentage of the number of subjects in CR, PR and SD in the total number of analyzed data sets.

Test Conclusions:

It can be seen from the data in Table 2 that the compound of formula (I) combined with letrozole/anastrozole has a significant inhibitory effect on tumors, and the disease control rate (DCR) reaches 91.4%. The benefit of the combination therapy is obvious.

Experimental example 3 the clinical trial effect of formula (I) compound of the present invention and letrozole/anastrozole combined medication

testing sample:

Subject inclusion criteria:

1. Age 18-70 years old;

3. The ECOG score is 0-1;

7. Before the study starts, the subjects must provide written informed consent.

Evaluation criteria for target lesions

Dosing regimen:

A total of 35 subjects were enrolled. As of November 2022, the test results are shown in Table 3.

Table 3 Formula (I) compound and Letrozole/Anastrozole combination therapy to the tumor inhibitory effect of experimenter

a: not evaluated (NE).

c: Clinical benefit rate (CBR), refers to the percentage of the number of subjects with CR, PR and SD≥6 months in the total number of analysis data sets.

Test Conclusions:

As can be seen from the data in Table 3, the compound of formula (I) combined with letrozole/anastrozole has a significant inhibitory effect on tumors, the disease control rate (DCR) reached 94.3%, and the clinical benefit rate (CBR) reached 77.2%. The benefit of treatment is obvious.

Experimental example 4 formula (I) compound clinical trial effect of the present invention

testing sample:

The tablet of the compound of formula (I) of the present invention is prepared by adding suitable auxiliary materials to the compound of formula (I) to prepare a tablet of a certain specification.

Subject inclusion criteria:

1. Age ≥ 18 years old.

2. Histologically or cytologically confirmed locally advanced, recurrent or metastatic breast cancer that cannot undergo surgery or radical radiotherapy, and meets the following requirements:

1) HR positive, HER2 negative (based on the latest immunohistochemical results);

2) Previously received at least 2 chemotherapy regimens:

● Recurrent or metastatic stage, receiving 1 to 2 chemotherapy regimens;

●At least one chemotherapy regimen containing taxanes in the previous adjuvant or metastatic phase.

3) Progression after endocrine therapy in recurrence or metastasis stage;

4) Disease progression occurred during or after the last anti-tumor treatment.

3. The ECOG score is 0-1;

7. Before the study starts, the subjects must provide written informed consent.

Evaluation criteria for target lesions

Dosing regimen:

Suitable subjects are screened, and the compound of formula (I) is administered to the subjects. The administration method is: 480mg, orally, twice a day. Every 28 days is a treatment cycle.

Preliminary results: A total of 131 subjects were enrolled, and as of September 2022, the disease control rate (DCR) reached 66.4%.

Claims

A pharmaceutical composition for preventing and/or treating cancer, the pharmaceutical composition contains a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent or a pharmaceutically acceptable of salt,

The second therapeutic agent is selected from aromatase inhibitors, wherein the active ingredient weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second therapeutic agent or a pharmaceutically acceptable salt thereof is 1 :1-1000:1; preferably 1:1-900:1, preferably 1:1-800:1, preferably 1:1-700:1, preferably 1:1-600:1, preferably 1:1-500:1 1, preferably 1:1-400:1.
The pharmaceutical composition of claim 1, wherein said second therapeutic agent is selected from letrozole, anastrozole or exemestane.
The pharmaceutical composition according to claim 1, wherein the second therapeutic agent is letrozole, and the compound of formula (I) or its pharmaceutically acceptable salt and letrozole or its pharmaceutically acceptable The active ingredient weight ratio of the salt is 5:1-400:1, preferably 10:1-400:1, preferably 12.5:1-384:1, preferably 12.5:1-336:1, preferably 12.5:1-300:1 , preferably 12.5:1-288:1.
The pharmaceutical composition according to claim 1, wherein the second therapeutic agent is letrozole, and the compound of formula (I) or its pharmaceutically acceptable salt and letrozole or its pharmaceutically acceptable The active ingredient weight ratio of salt is 400:1, 390:1, 385:1, 384:1, 383:1, 380:1, 370:1, 360:1, 352:1, 350:1, 344:1 , 340:1, 337:1, 336:1, 335:1, 330:1, 328:1, 320:1, 312:1, 304:1, 300:1, 296:1, 290:1, 289 :1, 288:1, 287:1, 285:1, 280:1, 272:1, 270:1, 264:1, 260:1, 256:1, 250:1, 248:1, 241:1 , 240:1, 239:1, 232:1, 230:1, 220:1, 225:1, 224:1, 223:1, 220:1, 216:1, 210:1, 208:1, 200 :1, 193:1, 192:1, 191:1, 190:1, 184:1, 180:1, 176:1, 170:1, 169:1, 168:1, 167:1, 160:1 , 150:1, 140:1, 130:1, 120:1, 110:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 35 :1, 30:1, 25:1, 20:1, 15:1, 12.5:1, 10:1, 5:1.
The pharmaceutical composition according to claim 1, wherein the second therapeutic agent is anastrozole, and the compound of formula (I) or its pharmaceutically acceptable salt and anastrozole or its pharmaceutically acceptable The active ingredient weight ratio of the salt is 400:1-1000:1, preferably 540:1-960:1, preferably 600:1-960:1, preferably 720:1.
The pharmaceutical composition according to claim 1, wherein the second therapeutic agent is exemestane, and the compound of formula (I) or its pharmaceutically acceptable salt and exemestane or its pharmaceutically acceptable The accepted salts have a weight ratio of active ingredients of 10:1-100:1, preferably 10:1-50:1, preferably 15:1-40:1.
The pharmaceutical composition according to any one of claims 1-6, wherein the daily dosage of active ingredients of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 200-2000 mg, preferably 200-1000 mg, preferably 400 mg -1000mg; wherein the daily dosage of the active ingredient of the second therapeutic agent or its pharmaceutically acceptable salt is 0.2-400mg, preferably 0.5-200mg, preferably 0.5-100mg, preferably 0.5-50mg, preferably 1-25mg.
The application of the pharmaceutical composition according to any one of claims 1-7 in the preparation of medicines for preventing and/or treating cancer, wherein said cancer is selected from brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, Gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female reproductive tract Cancer, lymphoma, neurofibroma, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, gum Glioma or sarcoma, preferably breast cancer, preferably HR + , HER2- breast cancer, preferably locally advanced or metastatic breast cancer.
The application of the combination of the compound of formula (I) or its pharmaceutically acceptable salt and letrozole or its pharmaceutically acceptable salt of claim 1 in the preparation of the medicament for preventing and/or treating cancer in therapeutically effective amount, wherein The cancer is selected from brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer , kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female reproductive tract cancer, lymphoma, neurofibroma, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal tract Stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma or sarcoma, preferably breast cancer, preferably HR + , HER2- breast cancer, preferably locally advanced or metastatic breast cancer.
A kit, comprising the pharmaceutical composition according to any one of claims 1-7, and instructions for explaining how to administer the pharmaceutical composition, or the compound of formula (I) and the second therapeutic agent contained therein.