WO2018233620A1 - Use of serd with cdk4/6 inhibitor and pi3k/mtor pathway inhibitor - Google Patents

Abstract

Provided is a use of SERD with a CDK4/6 inhibitor and a PI3K/mTOR pathway inhibitor. In particular, provided is a use of a selective estrogen receptor downregulator (SERD) in combination with one or more selected from a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamyein (mTOR) pathway inhibitor in preparation of a medicament for treating breast tumors.

Description

Use of SERD and CDK4/6 inhibitors, PI3K/mTOR pathway inhibitors Technical field

The invention belongs to the field of medicine and relates to the use of a SERD in combination with one or more selected from the group consisting of a CDK4/6 inhibitor and a PI3K/mTOR pathway inhibitor in the preparation of a medicament for treating breast tumors.

Background technique

Breast cancer is a malignant tumor that occurs in the epithelial tissues of the breast gland. The classification of breast cancer is complex. According to pathological classification, it can be divided into non-invasive breast cancer, early invasive breast cancer, invasive special breast cancer, invasive non-specific breast. Cancer, other rare and special types of breast cancer. According to molecular typing, it can be divided into lumen type A (Luminal A), lumen type B (Luminal B), epidermal growth factor receptor 2 (HER2) overexpression, basal cell type, normal breast type. According to epidemiological statistics, Luminal A and Luminal B breast cancer accounted for 71.6% of all breast cancers. Although both Luminal A and Luminal B breast cancers express hormone receptors (HR), both types have larger difference. Luminal type A is generally well pathologically differentiated; Luminal type B is generally poorly pathologically differentiated. Endocrine therapy for HR is one of the important methods for the treatment of breast cancer. Open research shows that there is a significant correlation between endocrine therapy and breast cancer prognosis.

Although endocrine therapy for breast cancer is a very effective treatment for the highest proportion of HR-positive breast cancer, some patients gradually develop resistance to endocrine therapy during the course of medication, and some metastatic patients will develop into complete Endocrine therapy is resistant, so for these patients, new medical tools must be sought to overcome the resistance of endocrine therapy and improve the effectiveness of its treatment. It has been found that a variety of drugs not only regulate tumor cell proliferation signaling pathways, but also improve the effectiveness of endocrine therapy for HR-positive breast cancer. A large number of studies have found that tumors are associated with abnormal cell cycle. Most tumors have a large number of mitotic signaling proteins/anti-mitotic signaling protein defects, genomic instability (GIN) and genomic instability (CIN). Basic cell cycle defects are directly or indirectly caused by the loss of control of cyclin-dependent kinase (CDK). CDK works by binding to its regulatory subunit cyclin (Cyclin), while the four major classes of cyclins (A-, B-, D-, E-type cyclins) exert different roles at different stages of the cell cycle. Cyclin B/CDK1, Cyclin A/CDK2, Cyclin E/CDK2, Cyclin D/CDK4, Cyclin D/CDK6 and other heterodimers (including CDK3 and CDK7) are important regulators of cell cycle progression, Cyclin/ Additional functions of CDK heterodimers also include regulation of transcription, DNA repair, differentiation, and programmed cell death. Current studies have found that Cyclin, CDK, and retinoblastoma protein (Rb) constitute important cellular proliferation regulatory pathways. Pathological studies have shown that the interaction of Cyclin D1-CDK4/6/Rb in breast cancer samples is out of control, often manifested as Cyclin D1. Overexpression or amplification. In estrogen receptor-positive breast cancer patients, steroid-mediated activation of Cyclin D1-CDK4/6 by ER is accompanied by hyperphosphorylation of pRb and transition to G1/S phase, whereas ER-positive breast cancer cells gradually develop endocrine therapy Drug resistance is associated with sustained expression of Cyclin D1 and phosphorylation of Rb, thereby increasing antagonism with estrogen receptors or blocking Cyclin D1-CDK4/6/Rb signaling pathways to inhibit hyperplasia of breast tumor cells more efficiently . W02014183520 provides a novel CDK4/6 inhibitor that exhibits better antitumor activity compared to marketed CDK inhibitors, and the structure is as follows:

WO2016124067 discloses the above-mentioned novel isethionates of CDK4/6 inhibitors.

In addition, studies have shown that the PI3K/Akt/mTOR signaling pathway plays an important role in the development of breast cancer. Activation of the PI3K/Akt/mTOR signaling pathway can inhibit a variety of stimulation-induced apoptosis and promote cell cycle progression. Survival and proliferation, while participating in tumor formation, invasion, and metastasis. Activated mTOR is capable of activating many downstream signaling pathways. For example, 40S ribosomal protein S6 kinase and eukaryotic initiation factor 4EBP-1, these proteins play an important role in ribosome synthesis and protein translation, and inhibition of mTOR phosphorylation can block the activation of these proteins, thereby enabling The transcription level of mRNA is decreased, and these mRNAs are usually involved in the editing of tumor growth factors, oncoproteins and Cyclin. Therefore, hyperphosphorylation of mTOR is bound to exacerbate the overactivity of the Cyclin D1-CDK4/6/Rb pathway and induce downstream apoptosis pathways. Loss of control, so blocking or inhibiting PI3K/Akt/mTOR and Cyclin D1-CDK4/6/Rb signaling pathways will be one of the options for inhibiting tumor proliferation. The marketed PI3K/Akt/mTOR pathway inhibitor is everolimus. Sirolimus, temsirolimus, etc.

The drugs that have been marketed or are under investigation and target Estrogen receptor (ER) are mainly classified into SERM, SERD, and aromatase inhibitors. The study found that SERMs currently on the market have serious side effects. Long-term use of tamoxifen and toremifene can cause endometrial hyperplasia, polyps and endometrial cancer, while common side effects of raloxifene include hot flashes. , leg pain, breast tenderness and venous embolism; in addition, with the prolongation of endocrine therapy, many HR-positive patients gradually resist SERM and aromatase inhibitors, and SERD is different from SERM and aromatase inhibitors due to its mechanism of action. Still effective for this type of patient, SERD is based on the endocrine treatment dilemma of SERM resistance. The only SERD drug currently on the market is fulvestrant (Astrazeneca, AstraZeneca), but there are still some adverse reactions such as fatigue, hot flashes, joint pain, rash and loss of appetite. The researched SERD has AZD-9496 ( Astrazeneca, AstraZeneca, RAD1901 (Eisai, Eisai), ZB-716 (Louisiana University, University of Louisiana). The present invention provides a novel SERD which exhibits good activity in inhibiting binding of E to ER, ER degradation and proliferation of MCF7 cells, in particular, in terms of _Emax value of ER degradation, compared with AZD-9496 compound. In terms of aspects, it has a more prominent advantage, and its structure is as follows:

The patent application WO2014183520, US2016090377A, US2016367526A, US2016184311A, WO2014203129, US2016175289A disclose CDK4/6 inhibitors in combination with SERD, PI3K/mTOR pathway inhibitors for the treatment of breast cancer, and patent application WO2016176666, WO2016146591, WO2015149045, WO2015135061 disclose CDK4/6 inhibition In combination with SERD for the treatment of breast cancer, the present invention provides the use of a novel structure of SERD in combination with a CDK4/6 inhibitor, a PI3K/mTOR pathway inhibitor, for the preparation of a medicament for the treatment of breast tumors, And showed a good anti-tumor effect.

Summary of the invention

The technical problem to be solved by the present invention is to provide a use of a SERD in combination with one or more selected from the group consisting of a CDK4/6 inhibitor and a PI3K/mTOR pathway inhibitor in the preparation of a medicament for treating breast tumors.

The SERD is a compound of the formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or A pharmaceutically acceptable salt wherein the compound of the formula (I) has the following structure:

among them:

Ring A is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

Ring B is an aryl or heteroaryl group;

R ^{1 is} each the same or different and is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, an amino group, a cycloalkyl group, a halogen, a cyano group, a carboxyl group, an aldehyde group, a hydroxyl group, and a nitro group. And an aryl group and a heteroaryl group; wherein the alkyl group, cycloalkyl group, aryl group and heteroaryl group are optionally selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkane Substituted by one or more substituents of an oxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R ^{2 is} each the same or different and is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, an amino group, a cycloalkyl group, a halogen group, a cyano group, a carboxyl group, an aldehyde group, a hydroxyl group, and a nitro group. And an aryl group and a heteroaryl group; wherein the alkyl group, cycloalkyl group, aryl group and heteroaryl group are optionally selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkane Substituted by one or more substituents of an oxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R ^{3 is} each the same or different and is each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, an amino group, a cycloalkyl group, a halogen group, a cyano group, a carboxyl group, an aldehyde group, a hydroxyl group, a nitro group. And an aryl group and a heteroaryl group; wherein the alkyl group, cycloalkyl group, aryl group and heteroaryl group are optionally selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkane Substituted by one or more substituents of an oxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R ⁴ each being the same or different and each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, an amino group, a cycloalkyl group, a halogen, a cyano group, a carboxyl group, or an aldehyde group. a hydroxyl group, a nitro group, an aryl group and a heteroaryl group; wherein the alkyl group, cycloalkyl group, aryl group and heteroaryl group are optionally selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, Substituted by one or more substituents of a hydroxyalkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R ^{5 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are optionally selected. Substituted from one or more substituents of alkyl, halo, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^{6 is} selected from the group consisting of a hydrogen atom, an alkyl group, a hydroxyl group, a halogen, a cyano group, an amino group, a nitro group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkoxy group The group, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from the group consisting of alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocycle Substituted by one or more substituents in the aryl, aryl and heteroaryl;

m is 0, 1, 2 or 3;

n is 0, 1, 2, 3 or 4;

x is 0, 1, 2 or 3;

y is 0, 1, 2, 3, 4 or 5.

Preferably, the SERD is a compound represented by the formula (I-A):

Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

Ring B, R ¹ to R ⁶ , m, n and y are as defined in the general formula (I).

Further preferably, the SERD is a compound represented by the formula (I-B):

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

R ¹ to R ⁶ , m, n and y are as defined in the formula (I).

Further preferably, the SERD is a compound represented by the formula (I-C):

Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

R ¹ to R ⁶ , m, n and y are as defined in the formula (I).

Further preferably, the SERD is selected from the group consisting of the following compounds or pharmaceutically acceptable salts thereof:

with

More preferred

In the above scheme, the pharmaceutically acceptable salt of the SERD is selected from the group consisting of a lysine salt, a 2-aminoethanol salt, a diethanolamine salt, a sodium salt, a hydrochloride salt or a N-methyl-D-glucosamine salt, preferably Alkaloids.

In the above aspect, the second component is selected from the group consisting of a CDK4/6 inhibitor selected from the group consisting of a compound represented by the formula (II), or a tautomer thereof, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

among them,

For single or double keys;

A ¹ or A ² are each independently selected from -CR' or N;

R' is selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group or an alkoxy group;

Y is selected from S or O;

R ^{1 is} selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group or a cycloalkyl group;

R ^{2 is} selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR ⁷ , -C(O)R ⁷ , —C(O)OR ⁷ , or —OC(O)R ⁷ , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently Optionally further one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl Substituted by a substituent of a heteroaryl group, a carboxyl group or a carboxylate group;

R ^{3 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group are each independently Optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, Substituted with a substituent of an aryl, heteroaryl, carboxy or carboxylate group;

R ^{4 is} selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR ⁷ , -C(O)R ⁷ or -C(O)OR. ⁷ wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano and nitro Substituted by a substituent of an amino group, a hydroxyl group, an oxo group, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group ;

R ⁵ or R ⁶ are each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an oxo group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR ⁷ , -C(O)R ⁷ , -C(O)OR ⁷ or -OC(O)R ⁷ , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, The aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyclo Substituted by a substituent of an alkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

R ^{7 is} selected from a hydrogen atom, an alkyl group, a hydroxyl group, a halogen, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the hetero group The cycloalkyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkane. Substituents of an oxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group are substituted.

Preferably, the CDK4/6 inhibitor or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

or

More preferred

In the above scheme, the pharmaceutically acceptable salt of the CDK4/6 inhibitor is selected from the group consisting of isethionates.

In the present invention, there is provided a method of treating a breast tumor comprising administering to a patient a combination of the above SERD and one or more selected from the group consisting of a CDK4/6 inhibitor, a PI3K/mTOR pathway inhibitor.

In another preferred embodiment of the present invention, the CDK4/6 inhibitor is selected from the group consisting of abemaciclib, ribociclib, palbociclib, alvocidib, trilaciclib, voruciclib, AT-7519, G1T-38, FLX-925, INOC-005, G1T28-1 , BPI-1178, gossypin, G1T30-1, GZ-38-1, P-276-00, staurosporine, R-547, PAN-1215, PD-0183812, AG-024322, NSC-625987, CGP-82996, PD -171851, preferably abemaciclib, ribociclib, palbociclib, alvocidib.

In the above aspect, the combination comprises a third component selected from the group consisting of PI3K/mTOR pathway inhibitors, wherein the PI3K/mTOR pathway inhibitor is selected from the group consisting of everolimus, sirolimus, and Sirolimus, zotarolimus, Ridaforolimus, neratinib, idlelisib, dactolisib, alpelisib, taselisib, buparlisib, sonolisib, gedatolisib, ipatasertib, apitolisib, pictilisib, INK128, INK1117, OSI-027, CC-223, AZD8055 , SAR245408, SAR245409, PF04691502.PQR-6XX, PQR-530, PQR-514, ME-344, SRX-2523, CC-115, LY-3023414, IM-156, BN-107, IBL-301, FP-208 , TAM-01, VS-5584, OB-318, HNC-VP-L, CIJ-906, FIM-X13, KD-06, peptide H3, Y-31, X-480, PBI-05204, CT-365, SKLB-JR02, BGT226, EC-0371, WYE125132, GSK2126458, GSK-2636771, BAY806946, PF05212384, SF1126, PX866, AMG319, ZSTK474, CiJDC-907.

Preferably, the PI3K/mTOR pathway inhibitor is selected from the group consisting of everolimus, sirolimus, temsirolimus, and Ridaforolimus.

In the above scheme, the combination is selected from the group consisting of a combination of a SERD and a CDK4/6 inhibitor and a PI3K/mTOR pathway inhibitor, preferably a combination of compound 14 and compound 59 with everolimus.

In the above scheme, the combination is selected from the group consisting of a combination of SERD and a CDK4/6 inhibitor, preferably a combination of compound 14 and compound 59.

In the above scheme, the synergistic effect of the SERD combined with one or more drugs of a CDK inhibitor, a PI3K/mTOR pathway inhibitor; preferably, the synergistic effect of the SERD and CDK4/6 inhibition The SERD and the CDK4/6 inhibitor have synergistic effects with the PI3K/mTOR pathway inhibitor; more preferably, the compound of the formula 14 or a pharmaceutically acceptable salt thereof and the compound of the formula 59 or The pharmaceutically acceptable salt thereof has a synergistic effect, and the compound of the formula 14 or a pharmaceutically acceptable salt thereof and the compound of the formula 59 or a pharmaceutically acceptable salt thereof have synergistic effect with everolimus .

In the use of the invention, the breast tumor is selected from the group consisting of an estrogen receptor-positive breast tumor, and the estrogen receptor-positive breast tumor is selected from the group consisting of a papillary tumor, a male breast tumor, a breast malignant lymphoma, and a fibroepithelial tumor. , epithelial-muscle epithelial tumor, intraductal carcinoma, lobular carcinoma in situ, papillary eczema-like breast cancer, early invasive ductal carcinoma, early invasive lobular carcinoma, papillary carcinoma, medullary carcinoma, tubular carcinoma, adenoid cystic Cancer, mucinous adenocarcinoma, apocrine adenoid carcinoma, squamous cell carcinoma, invasive lobular carcinoma, invasive ductal carcinoma, hard cancer.

In the use of the present invention, the breast tumor is selected from the group consisting of a tube type A breast cancer and a lumen type B breast cancer.

In the use according to the present invention, preferably, the estrogen receptor-positive breast tumor is a postmenopausal estrogen receptor-positive breast tumor.

In the above preferred embodiment, the estrogen receptor-positive breast tumor is resistant to endocrine therapy, and the endocrine therapy is selected from the group consisting of a selective estrogen receptor modulator (SERM), an aromatase inhibitor, Fulvestrant.

More preferably, the SERM is selected from the group consisting of tamoxifen, raloxifene, lasofoxifene, toremifene, bazedoxifene, droloxifene, dextrozine, and ipoxifen. Opemifene, mprexifen, enclomid, acolbolifene, arzoxifene, pipidoxifene, Fispemifene, Clomiphene, Zuclomiphene, Sivifene, LY335563, GW-5638, SR16234, GW 7603, BL3040, SRI 16158, SR 16157, SRI 16137 , SR 16137, EM-652, EM-800, LY2066948, LY2120310, the aromatase inhibitor is selected from the group consisting of aminoglutethimide, roastamide, lantalol, letrozole, liazodazole, and fluconazole ,Frhizozole, anastrozole, fenoxazole, exemestane, atamestane, minnamer, osilodrostat, pentrozole, BGS-649, TMD-322, SEF-19, NKS-01, FCE- 28718, MR-20492, TZA-2237, YM-511, MEN-11623, TAN-931, MPV-1837-AVB, FCE-27993, CGP-45688, D-3967, SNA-60-367, GW-114, YM-553, RU-56152, Org-33201, RU-54115, MFT-279.

For the use according to the invention, the weight ratio of the SERD to the CDK4/6 inhibitor is selected from the group consisting of 0.1-150, preferably 1:0.1, 1:0.125, 1:0.14, 1:0.15, 1:0.175, 1:0.1875 , 1:0.2, 1:0.25, 1:0.28, 1:0.3, 1:0.35, 1:0.4, 1:0.5, 1:0.7, 1:0.75, 1:1, 1:1.25, 1:1.75, 1 : 2, 1:2.5, 1:3.5, 1:4, 1:5, 1:8, 1:10, 1:15, 2:15, 1:20, 1:25, 3:1, 3:2 , 6:1, 6:5, 6:7, 8:5, 8:7, 12:1, 15:7, 16:3, 16:5, 16:7, 16:15, 16:25, 16 : 35, 24:5, 24:7, 60:7, more preferably 1:4, 1:5, 1:8, 1:10, 1:15, 2:15, 1:20, 1:25, 16 :25, 16:35; the weight ratio of the SERD to CDK4/6 inhibitor to the PI3K/mTOR pathway inhibitor is selected from 0.1-200: 1-500: 0.1-100, preferably 3: 30: 5, 2: 15:3, 8:10:1, 16:20:1, 10:5:1, 20:10:1, 10:7:1, 20:14:1, 10:10:1, 20:20: 1, 20:25:2, 20:25:1, 15:5:1, 30:10:1, 30:15:2, 30:15:1,15:10:1,30:20:1 30:25:2, 30:25:1, 25:5:1, 50:10:1, 25:10:1, 50:20:1,40:5:1,80:50:1,40: 10:1, 80:20:1, more preferably 3:30:5, 2:15:3, 8:10:1, 16:20:1, 20:25:2, 20:25:1.

The use according to the invention, wherein the SERD dosage range is selected from the group consisting of 1-1000 mg, preferably from 5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70mg, 75mg, 80mg, 90mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 600mg, 700mg, 750mg, 800mg, 900mg, 1000mg.

The use according to the present invention, wherein, preferably, the SERD is selected from the compound of the formula 14 or a pharmaceutically acceptable salt thereof, and the dosage range is selected from the group consisting of 20-600 mg, preferably from 20 mg, 25 mg, 40 mg, 50 mg, 60 mg, 70, 75, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600 mg.

The use according to the invention, wherein the dose of the CDK4/6 inhibitor is selected from the group consisting of 1-1000 mg, preferably from 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, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg, 1000 mg.

The use according to the present invention, wherein, preferably, the CDK4/6 inhibitor is selected from the compound of the formula 59 or a pharmaceutically acceptable salt thereof, and the dosage range is selected from the group consisting of 20-600 mg, preferably from 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, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg.

The use according to the invention, wherein the PI3K/mTOR pathway inhibitor dose range is selected from the group consisting of 1-500 mg, preferably from 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5mg, 6mg, 7mg, 7.5mg, 8mg, 9mg, 10mg, 12mg, 12.5mg, 14mg, 15mg, 16mg, 17.5mg, 18mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 75mg, 100mg, 125mg 150mg, 160mg, 175mg, 180mg, 200mg, 250mg, 500mg.

The use according to the present invention, wherein, preferably, the PI3K/mTOR pathway inhibitor is selected from the group consisting of everolimus, sirolimus, temsirolimus, Ridaforolimus, and the dose range is selected from 1-100 mg, preferably from 0.5mg, 1mg, 1.5mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 6mg, 7mg, 7.5mg, 8mg, 9mg, 10mg, 12mg, 12.5mg, 14mg, 15mg, 16mg, 17.5 Mg, 18 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg.

The present invention provides a pharmaceutical composition comprising the above-mentioned SERD and one or more selected from the group consisting of a CDK4/6 inhibitor, a PI3K/mTOR pathway inhibitor, and one or more pharmaceutically acceptable excipients, diluted Agent or carrier.

The present invention provides a combination of the above-described SERD and one or more selected from the group consisting of a CDK4/6 inhibitor and a PI3K/mTOR pathway inhibitor as a medicament for treating a breast tumor.

The combined modes of administration of the present invention are selected from the group consisting of simultaneous administration, independent formulation and co-administration or independent formulation and sequential administration.

The invention further relates to the use of a SERD in combination with a CDK4/6 inhibitor for the preparation of a medicament for treating breast tumors, wherein the frequency of administration of the SERD is once a day, twice a day, once a week, once every two weeks, three weeks, three weeks Once and once a month, the frequency of administration of CDK4/6 inhibitors was once a day, twice a day.

The invention further relates to a use of a SETD and a CDK4/6 inhibitor and a PI3K/mTOR pathway inhibitor for the treatment of a breast tumor drug, wherein the frequency of administration of the SERD inhibitor is once a day, twice a day, once a week, Once every two weeks, once every three weeks, once a month, the frequency of administration of CDK4/6 was once a day, twice a day, and the frequency of administration of PI3K/mTOR pathway inhibitors was once a day, twice a day.

Significantly, the SERD of the present invention has synergistic pharmacological effects in combination with a CDK4/6 inhibitor, and the SERD inhibitor of the present invention has a synergistic effect with a CDK4/6 inhibitor in combination with a PI3K/mTOR pathway inhibitor.

The invention also relates to a pharmaceutical composition of a SERD and a CDK4/6 inhibitor, a pharmaceutical composition of a SERD and CDK4/6 inhibitor and a PI3K/mTOR pathway inhibitor, comprising optionally one or more pharmaceuticals Carrier, excipient and/or diluent. The pharmaceutical composition can be formulated into any of the pharmaceutically acceptable dosage forms. For example, a pharmaceutical preparation comprising an active ingredient is a SERD, a CDK4/6 inhibitor, and a pharmaceutical preparation comprising an active ingredient of a SERD, a CDK4/6 inhibitor, and a PI3K/mTOR pathway inhibitor, which can be formulated into tablets, capsules, pills, Granules, solutions, suspensions, syrups, injections (including injections, sterile powder for injection and concentrated solutions for injection), suppositories, inhalants or sprays.

Furthermore, the pharmaceutical composition of the present invention can also be administered to a patient or subject in need of such treatment by any suitable mode of administration, such as oral, parenteral, rectal, pulmonary or topical administration. When used for oral administration, the pharmaceutical composition can be formulated into an oral preparation, such as an oral solid preparation such as a tablet, a capsule, a pill, a granule, or the like; or an oral liquid preparation such as an oral solution or an oral mixture. Suspension, syrup, and the like. When formulated into an oral preparation, the pharmaceutical preparation may further contain a suitable filler, binder, disintegrant, lubricant, and the like.

The pharmaceutical composition of the SERD and CDK4/6 inhibitor of the present invention, the pharmaceutical composition of the SERD and CDK4/6 inhibitor and the PI3K/mTOR pathway inhibitor, may be administered alone or in combination with one or more therapeutic agents use.

The components to be combined (for example, SERD and CDK4/6 inhibitors, SERD and CDK4/6 inhibitors and PI3K/mTOR pathway inhibitors) can be administered simultaneously or sequentially. Furthermore, the ingredients to be combined may also be administered in combination in the form of the same formulation or in separate separate formulations.

In the present invention, the term "combination or combination" is a mode of administration comprising two or more drugs sequentially or simultaneously, and the term "simultaneously" means the same administration. Periodically administering SERD and CDK4/6 inhibitors, or SERD and CDK4/6 inhibitors with PI3K/mTOR pathway inhibitors, for example, within 1 day, or within 2 days, or within 3 days, or within 14 days, or within 21 days, or within 28 days Give two or more drugs. The so-called "sequential or sequential" administration includes the administration of SERD and CDK4/6 inhibitors, or SERD and CDK4/6 inhibitors and PI3K/mTOR pathway inhibitors, respectively, in different administration cycles. These modes of administration all belong to the combination administration described in the present invention.

An "effective amount" as used herein includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate the diagnosis. An effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the overall health of the patient, the route and dosage of the method of administration, and the severity of the side effects. An effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

Detailed description of the invention

In the description and claims of the present application, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art, unless otherwise indicated. However, for a better understanding of the present invention, definitions and explanations of some related terms are provided below. In addition, when the definitions and explanations of the terms provided by the present application are inconsistent with the meanings generally understood by those skilled in the art, the definitions and explanations of the terms provided by the present application shall prevail.

The "halogen or halogen atom" as used in the present invention means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like.

The "cyano group" as used in the present invention means a group such as -CN.

The "hydroxy group" in the present invention means a group such as -OH.

The "amino group" in the present invention means a group such as -NH.

The "carboxy group" in the present invention means a group such as -COOH.

The "carbonyl group" as used in the present invention means a group such as -CO-.

The "nitro group" as used in the present invention means a group such as -NO ₂ .

The "alkyl group" in the present invention means a linear or branched alkyl group having 1 to 20 carbon atoms, and includes, for example, "C _1-6 alkyl group", "C _1-4 alkyl group", etc., specific examples Including but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, Neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2, 2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2- Ethyl butyl, 1,2-dimethylpropyl and the like.

The "alkynyl group" as used in the present invention means a linear or branched alkynyl group having at least one triple bond and having 2 to 20 carbon atoms, and includes, for example, "C _2-6 alkynyl group, C _2-4 alkynyl group". Wait. Examples thereof include, but are not limited to, ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3 - hexynyl, 5-methyl-2-hexynyl and the like.

As used herein, "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which includes from 3 to 14 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably cycloalkyl. The ring contains from 3 to 8 carbon atoms, and most preferably the cycloalkyl ring contains from 5 to 6 carbon atoms, most preferably a cyclopropyl group. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene The alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group. Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.

The "fused ring group" as used in the present invention refers to a cyclic structure having 4 to 15 carbon atoms formed by two or more ring structures sharing two adjacent atoms with each other, including, for example, "6" a -11 membered fused ring group, a "5-9 membered fused ring group", a "7-10 membered fused ring group", a "9-10 membered fused ring group", etc., optionally, a carbon atom in the cyclic structure Can be oxidized. Examples include, but are not limited to:

Wait.

The "spirocyclic group" as used in the present invention means a cyclic structure having 5 to 15 ring carbon atoms formed by sharing two carbon atoms with each other in two or more cyclic structures. Optionally, the carbon atoms in the cyclic structure can be oxidized. Examples include "6-11 element spiro group", "5-10 member spiro group", "7-8 member spiro group", "9-10 member spiro group", and the like. Specific examples include, but are not limited to:

Wait.

The "bridged ring group" as used in the present invention means a cyclic structure having 5 to 15 ring carbon atoms formed by two or more ring structures sharing two non-adjacent carbon atoms with each other. Optionally, the carbon atoms in the cyclic structure can be replaced by oxo. Examples include "6-11 yuan bridged ring base", "7-10 yuan bridged ring base", "9-10 yuan bridged ring base", and the like. Specific examples include, but are not limited to:

Wait.

As used herein, "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which includes from 3 to 14 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S. (O) a hetero atom of _m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms, more preferably the heterocyclyl ring contains from 3 to 8 ring atoms, more preferably the heterocyclyl ring contains from 5 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

The "fused heterocyclic group" as used in the present invention refers to a group of 4 to 15 ring atoms formed by two or more ring structures sharing two adjacent atoms with each other (at least one of the ring atoms is hetero A cyclic structure of an atom such as a nitrogen atom, an oxygen atom or a sulfur atom. Optionally, a ring atom (eg, a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure can be oxidized. Including, for example, "4-12 membered fused heterocyclic group", "5-9 membered fused heterocyclic group", "6-11 membered fused heterocyclic group", "7-9 membered fused heterocyclic group", "9-10" Yuan fused heterocyclic group" and the like. Specific examples include, but are not limited to, pyrrolidino-cyclopropyl, cyclopentyl-azacyclopropyl, pyrrolidinocyclobutyl, pyrrolidinopyrrolidinyl, pyrrolidinopiperidinyl, pyrrole Alkylpiperazinyl, pyrrolidinomorpholinyl, piperidinylmorpholinyl, benzopyrrolidinyl, tetrahydroimidazo[4,5-c]pyridyl, 3,4-dihydroquinoline Oxazolinyl, 1,2-dihydroquinoxalinyl, benzo[d][1,3]dioxolyl, 1,3-dihydroisobenzofuranyl, 2H-chromogen Base, 2H-chromogen-2-one, 4H-chromenyl, 4H-chromen-4-one, chromanyl, 4H-1,3-benzoxazinyl, 4,6-di Hydrogen-1H-furo[3,4-d]imidazolyl, 3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazolyl, 4,6-dihydro-1H- Thieno[3,4-d]imidazolyl, 4,6-dihydro-1H-pyrrolo[3,4-d]imidazolyl, benzimidazolylalkyl, octahydro-benzo[d]imidazolyl, Decalhydroquinolyl, hexahydrothienoimidazolyl, hexahydrofurfurimidazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, octahydrocyclopentene[c] Pyrrolyl, indanyl, dihydroisoindolyl, benzoxazolidinyl, benzothiazolidinyl, 1,2,3,4 - tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, 4H-1,3-benzoxazinyl and the like.

The "spiroheterocyclic group" as used in the present invention means a ring atom formed by sharing two ring atoms with two or more ring structures, wherein at least one ring atom is a hetero atom, for example, A cyclic structure of a nitrogen atom, an oxygen atom or a sulfur atom, optionally, a ring atom (for example, a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxidized. Examples include, for example, "5-11 membered spiroheterocyclyl", "6-11 membered spiroheterocyclyl", "6-9 membered spiroheterocyclyl", "9-10 membered spiroheterocyclyl", and the like. Specific examples include, but are not limited to:

Wait.

The "bridge heterocyclic group" as used in the present invention refers to a group of 5 to 15 ring atoms (including at least one ring atom) formed by two or more ring structures sharing two non-adjacent ring atoms with each other. A cyclic structure which is a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom, optionally, a ring atom (for example, a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxidized. Examples include, for example, "5-10 membered bridged heterocyclic group", "6-11 membered bridged heterocyclic group", "6-9 membered bridged heterocyclic group", "7-9 membered bridged heterocyclic group", and the like. Specific examples include, but are not limited to:

Wait.

The term "haloalkyl" as used in the present invention refers to a group derived by substituting one or more "halogen atoms" for one or more hydrogen atoms on an "alkyl group" as described above. Defined.

As used herein, "hydroxyalkyl" refers to a radical derived from one or more "hydroxy" groups substituted by one or more hydrogen atoms on an "alkyl group" as defined above.

The "alkoxy group, haloalkoxy group, alkylcarbonyl group, alkoxycarbonyl group, alkylcarbonylamino group, alkylaminocarbonyl group, dialkylaminocarbonyl group, alkylaminocarboxy group, haloalkylcarbonyl group, cycloalkyl group" according to the invention. Alkyl, cycloalkylcarbonyl, heterocyclylcarbonyl, alkylamino, alkylaminoalkyl or dialkylamino" means alkyl-O-, haloalkyl-O-, alkyl-C(O) -, alkyl-OC(O)-, alkyl-C(O)-NH-, alkyl-NH-C(O)-, (alkyl) ₂ -NH-C(O)-, alkyl- C(O)-O-, haloalkyl-C(O)-, cycloalkyl-alkyl-, cycloalkyl-C(O)-, heterocyclyl-C(O)-, alkyl-NH- An alkyl-NH-alkyl-, (alkyl) ₂ -N-linked group wherein "alkyl, haloalkyl, cycloalkyl, heterocyclyl" is as defined above.

The "aryl group" as used in the present invention means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (that is, a ring sharing a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably 6 to 8 The aryl group is more preferably a phenyl group, a fluorenyl group or a phenanthryl group, and most preferably a phenyl group. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:

The "heteroaryl" as used in the present invention refers to a 5- to 15-membered all-carbon monocyclic or fused polycyclic group having a conjugated π-electron system, further comprising from 1 to 4 heteroatoms, wherein the hetero atom is selected from One or more of oxygen, sulfur or nitrogen. It is preferably a 5- to 8-membered heteroaryl group, more preferably a 5- to 6-membered heteroaryl group, and specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl , oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadi Azyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridinone, 4-pyridone , pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetraazinyl, azepanene A group, a 1,3-diazaheptatrienyl group, azacyclooctyltetraenyl group, or the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples comprising:

The "carbon atom, nitrogen atom or sulfur atom to be oxo" as used in the present invention means a structure in which C=O, N=O, S=O or SO ₂ is formed.

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

The term "synergistic effect" includes, but is not limited to, additive effects, potentiating effects, potentiating effects, and "synergistic effects" of the present invention include, but are not limited to, reduction of SERD, CDK4/6 inhibition alone. Tolerance in the agent, PI3K/mTOR pathway inhibitor, reduce the dose of SETD, CDK4/6 inhibitor, PI3K/mTOR pathway inhibitor alone, reduce SERD, CDK4/6 inhibitor, PI3K/mTOR pathway inhibitor The adverse effects when used alone, enhance the effect of treating breast tumors compared to the same dose of SERD, CDK4/6 inhibitor, PI3K/mTOR pathway inhibitor alone.

The term "catheter type A breast cancer" refers to a breast cancer whose gene type is selected from ER and/or PR (progesterone receptor) positive, HER2 negative, and Ki67 (nuclear proliferation index) is low expression; "catheter type B breast cancer" Refers to a gene type selected from ER and / or PR positive, HER2 negative, Ki67 high expression of breast cancer or ER and / or PR positive, HER2 overexpression or proliferation, Ki67 any level of breast cancer.

Advantageous effects of the invention

Compared with the prior art, the technical solution of the present invention has the following advantages:

The combination of the SERD of the present invention and the CDK4/6 inhibitor has a significant inhibitory effect on the human breast cancer MCF7/TamR1 nude mice expressing the estrogen receptor, and has a synergistic effect; the SERD and the CDK4/6 inhibitor of the present invention The combination of PI3K/mTOR pathway inhibitors has a significant and synergistic effect on the subcutaneous xenograft of human breast cancer MCF7/TamR1 nude mice expressing estrogen receptor.

The combination of the SERD and the CDK4/6 inhibitor of the invention has a significant inhibitory effect on the human breast cancer MCF7/TamR1 nude mouse subcutaneous xenografts which are resistant to estrogen receptor and endocrine therapy drugs, and has a synergistic effect; the SERD of the present invention The combination of CDK4/6 inhibitor and PI3K/mTOR pathway inhibitor has a significant and synergistic effect on the expression of estrogen receptor and endocrine therapy drug-resistant human breast cancer MCF7/TamR1 nude mice.

DRAWINGS

Figure 1 is a combination of a SERD (Compound 14) of the present invention in combination with a CDK4/6 inhibitor (Compound 59), and a combination of SERD (Compound 14) and a CDK4/6 inhibitor (Compound 59) with everolimus and each individual component Comparison of the therapeutic effects of (Compound 14, Compound 59, Everolimus) on human estrogen receptor-positive, tamoxifen-resistant human breast cancer MCF-7/TamR1 nude mice subcutaneous xenografts;

Figure 2 is a combination of a SERD (compound 14) of the present invention in combination with a CDK4/6 inhibitor (compound 59), and a combination of SERD (compound 14) and a CDK4/6 inhibitor (compound 59) with everolimus and each individual component. Comparison of the effects of (Compound 14, Compound 59, Everolimus) on the body weight of human breast cancer MCF-7/TamR1 nude mice with positive estrogen receptor expression and tamoxifen resistance.

Detailed ways

Exemplary experimental protocols for the use of the compositions of the present invention in anti-mammary tumor applications are provided below to demonstrate the beneficial or beneficial technical effects of the compositions of the present invention. However, it should be understood that the following experimental schemes are merely illustrative of the present invention and are not intended to limit the scope of the invention. A person skilled in the art can make appropriate modifications or changes to the technical solutions of the present invention without departing from the spirit and scope of the present invention.

Preparation of Compounds of Example 1, Formula 14

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in units of 10-6 (ppm). The NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane ( TMS).

The measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

Chiral HPLC analysis using LC-10A vp (Shimadzu) or SFC-analytical (Berger Instruments Inc.);

Chiral preparative column chromatography using Prep Star SD-1 (Varian Instruments Inc.) or SFC-multigram (Berger Instruments Inc.)

The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Companies such as chemicals.

Unless otherwise specified in the examples, the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.

An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

The pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.

The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.

The microwave reaction used a CEM Discover-S Model 908860 microwave reactor.

Unless otherwise stated in the examples, the solution means an aqueous solution.

There is no particular description in the examples, and the reaction temperature is room temperature and is 20 ° C to 30 ° C.

The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound. Purification compounds using column chromatography eluent systems and thin layer chromatography developer systems include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: dichloromethane and acetone In the system, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid may be added for adjustment.

(E)-3-(4-((1R,3R)-2-(4-cyclopropylphenyl)-6-(1-ethyl-1H-pyrazol-4-yl)-3-methyl -1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)acrylic acid

first step

3-(2-nitropropyl-1-en-1-yl)phenol 4b

m-Hydroxybenzaldehyde 4a (10 g, 81.9 mmol), nitroethane (60 g, 819 mmol) and ammonium acetate (1.54 g, 20 mmol) were added to the reaction flask, heated to 80 ° C, and methylamine (1 g, 32.2 mmol) was added. ), after the addition, the reaction was stirred for 2 hours. Water (50 mL) was added to the reaction mixture, and the mixture was evaporated. The resulting residue was purified with EtOAc EtOAcjjjjjj

Second step

1-(3-hydroxyphenyl)propan-2-one 4c

Add 4b (9.5g, 53mmol) to a mixed solution of methanol and water (V: V = 10:1, 110mL), add Raney nickel (10%, 9.5g) and acetic acid (3.2g, 53mmol), add After completion, the hydrogen was replaced three times, and the reaction was stirred for 16 hours. Filtration, the filtrate was evaporated to dryness eluted with EtOAc EtOAc (EtOAc) The obtained residue was purified to ethylamine.

third step

3-(2-((4-cyclopropylphenyl)amino)propyl)phenol 4e

4-Cyclopropylaniline hydrochloride 4d (390 mg, 2.30 mmol, Pharmaceutical) was dissolved in dichloroethane (10 mL), triethylamine (233 mg, 2.30 mmol) was added, stirred for 5 minutes, and 4c ( 345 mg, 2.30 mmol) and sodium triacetoxyborohydride (730 mg, 3.45 mmol) were stirred for 12 hours. The reaction mixture was poured with water (10 mL), EtOAc (EtOAc m. The obtained residue was purified to ethylamine (yield: ield:

the fourth step

(E)-3-(4-(2-(4-cyclopropylphenyl)-6-hydroxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzene Methyl acrylate 10a

4e (540 mg, 2.02 mmol), 1e (576 mg, 3.03 mmol) and triisopropylchlorosilane (1.95 g, 10.10 mmol) were added to N,N-dimethylformamide (10 mL). The reaction was stirred for 3 hours at 120 °C. The reaction mixture was cooled to room temperature, and then evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The obtained residue was purified to crystalljjjjjjjjj

the fifth step

(E)-3-(4-((1R,3R/1S,3S)-2-(4-cyclopropylphenyl)-3-methyl-6-(((trifluoromethyl)sulfonyl)) Methyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)acrylate 10b

10a (490 mg, 1.11 mmol) was dissolved in dichloromethane (10 mL), and then 2,6-dimethylpyridine (180 mg, 1.67 mmol), trifluoromethanesulfonic anhydride (409 mg, 1.45 mmol), After the addition, the ice bath was removed, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (10 mL), EtOAc (EtOAc)EtOAc. The residue gave the title product 10b (230 mg, m.

Step 6

(E)-3-(4-((1R,3R/1S,3S)-2-(4-cyclopropylphenyl)-6-(1-ethyl-1H-pyrazol-4-yl)- Methyl 3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)acrylate 13a

10b (485mg, 0.85mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridyl Azole (283 mg, 1.275 mmol), 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (63 mg, 0.085 mmol) dissolved in 1,4-dioxane and water (V: 2M sodium carbonate solution (0.85 mL, 1.7 mmol) was added to the mixed solution of V = 7:1, 8 mL), and the mixture was subjected to microwave reaction at 120 ° C for 1 hour. After cooling to room temperature, water (20 mL), EtOAc (EtOAc)EtOAc. The resulting residue was purified to purified crystal crystal crystal crystal crystal crystal crystal

MS m/z (ESI): 518.5 [M+1]

Seventh step

(E)-3-(4-((1R,3R/1S,3S)-2-(4-cyclopropylphenyl)-6-(1-ethyl-1H-pyrazol-4-yl)- 3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)acrylic acid 13

13a (350 mg, 0.676 mmol) was dissolved in a mixed solvent of methanol and tetrahydrofuran (V: V = 1:1, 28 mL), and a 2M sodium hydroxide solution (1.7 mL, 3.38 mmol) was added thereto, and the reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. Water (10 mL) was evaporated, and then evaporated, and then the mixture was stirred, and 2N hydrochloric acid was added dropwise to pH 2 to 3, and extracted with ethyl acetate (50 mL×3). The residue was dried over EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

MS m/z (ESI): 504.5 [M+1]

Eighth step

(E)-3-(4-((1R,3R)-2-(4-cyclopropylphenyl)-6-(1-ethyl-1H-pyrazol-4-yl)-3-methyl -1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)acrylic acid 14

Chiral preparation of 13 (250 mg, 0.497 mmol) (separation conditions: chiral column Superchiral S-AD (Chiralway), 2 cm ID*25 cm, 5 μm, mobile phase: carbon dioxide: ethanol = 60:40, flow rate: 50 g/min The corresponding fractions were collected and concentrated under reduced pressure to give the title product 14 (105 mg, yellow solid)

Chiral HPLC analysis: retention time 9.317 minutes, chiral purity: 100%. (Column column: Superchiral S-AD (Chiralway), 0.46 cm I.D.*15 cm, 5 μm; mobile phase: carbon dioxide: ethanol = 60:40).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.95 (s, 1H), 7.79 (s, 1H), 7.54-7.58 (d, 1H), 7.32-7.42 (m, 7H), 6.86-6. d, 2H), 6.75-6.77 (d, 2H), 6.34-6.38 (d, 1H), 5.72 (s, 1H), 4.72 (m, 1H), 4.16-4.22 (m, 2H), 3.36-3.41 ( m, 1H), 2.75-2.79 (d, 1H), 1.73-1.77 (m, 1H), 1.45-1.49 (m, 3H), 1.00-1.02 (d, 3H), 0.78-0.80 (m, 2H), 0.50-0.51 (m, 2H).

Example 2. Combination of SERD of the present invention with a CDK4/6 inhibitor or a combination of a SETD and a CDK4/6 inhibitor with a PI3K/mTOR pathway inhibitor for human breast cancer expressing estrogen receptor-positive, tamoxifen-resistant Therapeutic effect of subcutaneous transplantation of MCF-7/TamR1 nude mice

Test product: a compound of the formula 14 (using a lysine salt of the compound 14, a compound obtained by the method described in Example 1 to form a salt with lysine), a compound of the formula 59 (using a hydroxyethyl group of the compound 59) Sulfonate, prepared according to the method of patent application WO2016124067), everolimus and tamoxifen (provided by Jiangsu Hengrui Pharmaceutical Co., Ltd.), estrogen sustained release tablets (0.72 mg / tablet, 60 days release) , purchased from Innovative Research of America).

Test animals: BALB/cA-nude nude mice, 6-7 weeks, female, purchased from Shanghai Slack Laboratory Animals Co., Ltd. Feeding environment: SPF level.

Cell line: tamoxifen-resistant, ER-positive human breast cancer MCF7/TamR1 cells were provided by Kunming Institute of Zoology, Chinese Academy of Sciences; MCF7/TamR1 cells were formed by long-term induction of tamoxifen-sensitive MCF7 cells with tamoxifen. It was significantly resistant to tamoxifen in vitro, and the drug resistance multiple was more than 50 times. The cells were cultured in a 10 cm culture dish under the conditions of Dulbecco's Modified Eagle Medium (DMEM) medium plus 10% fetal bovine serum and cyan. Streptomycin, containing 10 μM tamoxifen, was cultured in an incubator containing 5% CO ₂ air at 37 °C. Passage twice a week; when the cells are exponentially growing, trypsinize, collect cells, count, and inoculate.

Preparation of test solution:

Compound 14 and tamoxifen were formulated with 0.5% CMC-Na solution and diluted to the corresponding concentrations;

Compound 59 was prepared with 0.1% Tween-80 distilled water;

Everolimus was diluted with anhydrous ethanol to help dissolve the physiological saline to the corresponding concentration.

experimental method:

The nude mice were implanted with estrogen sustained-release tablets subcutaneously, and the next day, 1×10 ⁷ human breast cancer MCF7/TamR1 cells were inoculated. After the tumors were grown to 100-150 mm ³ , the animals were randomly divided into a solvent group and a treatment group (compounds). Group 14, compound 59, everolimus, compound 14 + compound 59, compound 14 + compound 59 + everolimus, tamoxifen). The number of mice at the start of the experiment was n=10 for the solvent group and n=6 for each group. The administration time was 21 days, the tumor volume was measured 2-3 times per week, the rats were weighed, the data were recorded, and the final tumor inhibition rate was tested on the 21st day.

data analysis:

The following is the formula for calculating the tumor volume (V):

V=1/2×a×b ²

Where a and b represent length and width, respectively.

T/C(%)=(TT ₀ )/(CC ₀ )×100

D21 inhibition rate (%) = [(TT ₀ ) - (CC ₀ )] / (TT ₀ ) × 100

T is the solvent group, C is the tumor volume at the end of the treatment group; T ₀ is the solvent group, C ₀ is the tumor volume at the beginning of each group of treatment, T/C value (percent), D21 inhibition rate ( Percentage) as an indication of anti-tumor efficacy.

Experimental results:

Table 1. Efficacy of compound 14 combined with compound 59, everolimus against estrogen receptor-positive, tamoxifen-resistant human breast cancer MCF7/TamR1 nude mice

D0: first administration time; P value means compared with solvent; PO: intragastric administration; QD: once a day; ^*** P < 0.001, vs vehicle control; ^## P<0.01, ^### P<0.001, vs compound 14 (1 mg/kg); ^$ P<0.05, vs compound 14 (1 mg/kg) + compound 59 (7.5 mg/kg); dose of each compound in the combination group and single-agent dose the same.

Experimental results:

From the data in Table 1 and Figure 1, tamoxifen (30 mg/kg) had no significant inhibitory effect on the growth of subcutaneous xenografts in MCF7/TamR1 nude mice, and the tumor inhibition rate was 19.3%, indicating that the model was tamoxifen. Subcutaneous xenograft model of fens-resistant human breast cancer nude mice; compound 14 (1 mg/kg), compound 59 (7.5 mg/kg) and everolimus (1.5 mg/kg) alone for MCF7/TamR1 nude mice Subcutaneous xenografts had a certain inhibitory effect, and the tumor inhibition rates were 39.4%, 21.7%, and 55.0%, respectively. Compound 14 (1 mg/kg) and compound 59 (7.5 mg/kg) combined significantly inhibited MCF7/TamR1 nude mice. The growth rate of subcutaneous xenografts was 70.7%, and the curative effect was significantly stronger than that of compound 14 or compound 59 alone (P<0.01); compound 14 (1 mg/kg) and compound 59 (7.5 mg/kg) and The combination of everolimus (1.5mg/kg) also significantly inhibited the growth of subcutaneous xenografts in MCF7/TamR1 nude mice. The tumor inhibition rate was 80.6%, and the drug efficacy was significantly stronger than that of compound 14 (1mg/kg) and compound 59. (7.5 mg/kg) combination of two drugs (P<0.05). The weight of all tumor-bearing mice, including the vehicle control group, decreased to some extent during the experiment, which was presumed to be related to the subcutaneous implantation of estrogen sustained-release tablets in mice (Fig. 2). In summary, the combination of SERD and CDK4/6 has obvious pharmacodynamic coordination; SERD and CDK4/6 combined with everolimus have obvious pharmacodynamic coordination.

Claims (21)

1. A selective estrogen receptor down-regulator (SERD) and a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, phosphatidylinositol 3-kinase (PI3K)/rapamycin target protein Use of one or more of (mTOR) pathway inhibitors in the preparation of a medicament for treating breast tumors, characterized in that the SERD is a compound of the formula (I), or a tautomer thereof, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

   

   among them:

   Ring A is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

   Ring B is an aryl or heteroaryl group;

   R ^{1 is} each the same or different and is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, an amino group, a cycloalkyl group, a halogen, a cyano group, a carboxyl group, an aldehyde group, a hydroxyl group, and a nitro group. And an aryl group and a heteroaryl group; wherein the alkyl group, cycloalkyl group, aryl group and heteroaryl group are optionally selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkane Substituted by one or more substituents of an oxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

   R ^{2 is} each the same or different and is each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, an amino group, a cycloalkyl group, a halogen group, a cyano group, a carboxyl group, an aldehyde group, a hydroxyl group, and a nitro group. And an aryl group and a heteroaryl group; wherein the alkyl group, cycloalkyl group, aryl group and heteroaryl group are optionally selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkane Substituted by one or more substituents of an oxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

   R ^{3 is} each the same or different and is each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, an amino group, a cycloalkyl group, a halogen group, a cyano group, a carboxyl group, an aldehyde group, a hydroxyl group, a nitro group. And an aryl group and a heteroaryl group; wherein the alkyl group, cycloalkyl group, aryl group and heteroaryl group are optionally selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkane Substituted by one or more substituents of an oxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

   R ⁴ each being the same or different and each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, an amino group, a cycloalkyl group, a halogen, a cyano group, a carboxyl group, or an aldehyde group. a hydroxyl group, a nitro group, an aryl group and a heteroaryl group; wherein the alkyl group, cycloalkyl group, aryl group and heteroaryl group are optionally selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, Substituted by one or more substituents of a hydroxyalkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

   R ^{5 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are optionally selected. Substituted from one or more substituents of alkyl, halo, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

   R ^{6 is} selected from the group consisting of a hydrogen atom, an alkyl group, a hydroxyl group, a halogen, a cyano group, an amino group, a nitro group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkoxy group The group, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from the group consisting of alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocycle Substituted by one or more substituents in the aryl, aryl and heteroaryl;

   m is 0, 1, 2 or 3;

   n is 0, 1, 2, 3 or 4;

   x is 0, 1, 2 or 3;

   y is 0, 1, 2, 3, 4 or 5.
2. The use according to claim 1, wherein the SERD is a compound represented by the formula (I-A):

   

   Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

   among them:

   Ring B, R ¹ to R ⁶ , m, n and y are as defined in claim 1.
3. The use according to claim 2, wherein the SERD is a compound represented by the formula (I-B):

   

   Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

   among them:

   R ¹ to R ⁶ , m, n and y are as defined in claim 1.
4. The use according to claim 3, wherein the SERD is a compound represented by the formula (I-C):

   

   Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

   among them:

   R ¹ to R ⁶ , m, n and y are as defined in claim 1.
5. The use according to any one of claims 1 to 4, wherein the SERD or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

   

   

   

   

   Optimal

   
6. The use according to any one of claims 1 to 5, wherein the pharmaceutically acceptable salt of the SERD is selected from the group consisting of a lysine salt, a 2-aminoethanol salt, a diethanolamine salt, a sodium salt, a hydrochloride salt or N-methyl-D-glucosamine salt, preferably lysine salt.
7. The use according to any one of claims 1 to 6, wherein the CDK4/6 inhibitor is selected from the group consisting of a compound represented by the formula (II), or a tautomer thereof, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

   

   among them,

   

   For single or double keys;

   A ¹ or A ² are each independently selected from -CR' or N;

   R' is selected from a hydrogen atom, a halogen, a cyano group, a nitro group, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group or an alkoxy group;

   Y is selected from S or O;

   R ^{1 is} selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group or a cycloalkyl group;

   R ^{2 is} selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR ⁷ , -C(O)R ⁷ , —C(O)OR ⁷ , or —OC(O)R ⁷ , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently Optionally further one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl Substituted by a substituent of a heteroaryl group, a carboxyl group or a carboxylate group;

   R ^{3 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group are each independently Optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, Substituted with a substituent of an aryl, heteroaryl, carboxy or carboxylate group;

   R ^{4 is} selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR ⁷ , -C(O)R ⁷ or -C(O)OR. ⁷ wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano and nitro Substituted by a substituent of an amino group, a hydroxyl group, an oxo group, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group ;

   R ⁵ or R ⁶ are each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an oxo group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR ⁷ , -C(O)R ⁷ , -C(O)OR ⁷ or -OC(O)R ⁷ , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, The aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cyclo Substituted by a substituent of an alkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

   R ^{7 is} selected from a hydrogen atom, an alkyl group, a hydroxyl group, a halogen, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the hetero group The cycloalkyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkane. Substituents of an oxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group are substituted.
8. The use according to claim 7, wherein the CDK4/6 inhibitor or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

   

   

   

   Optimal

   
9. The use according to any one of claims 7-8, wherein the pharmaceutically acceptable salt of the CDK4/6 inhibitor is selected from the group consisting of isethionates.
10. The use according to any one of claims 1 to 6, wherein the CDK4/6 inhibitor is selected from the group consisting of abemaciclib, ribociclib, palbociclib, alvocidib, trilaciclib, voruciclib, AT-7519, G1T-38, FLX-925. , INOC-005, G1T28-1, BPI-1178, gossypin, G1T30-1, GZ-38-1, P-276-00, staurosporine, R-547, PAN-1215, PD-0183812, AG-024322, NSC -625987, CGP-82996, PD-171851, preferably abemaciclib, ribociclib, palbociclib, alvocidib.
11. The use according to any one of claims 1 to 10, wherein the PI3K/mTOR pathway inhibitor is selected from the group consisting of everolimus, sirolimus, temsirolimus, zotarolimus, Ridaforolimus, neratinib, idlelisib, dactolisib, alpelisib, taselisib, buparlisib, sonolisib, gedatolisib, ipatasertib, apitolisib, pictilisib, INK128, INK1117, OSI-027, CC-223, AZD8055, SAR245408, SAR245409, PF04691502, PQR-6XX , PQR-530, PQR-514, ME-344, SRX-2523, CC-115, LY-3023414, IM-156, BN-107, IBL-301, FP-208, TAM-01, VS-5584, OB -318, HNC-VP-L, CIJ-906, FIM-X13, KD-06, peptide H3, Y-31, X-480, PBI-05204, CT-365, SKLB-JR02, BGT226, EC-0371, WYE125132, GSK2126458, GSK-2636771, BAY806946, PF05212384, SF1126, PX866, AMG319, ZSTK474, CiJDC-907, preferably from everolimus, sirolimus, temsirolimus, Ridaforolimus.
12. The use according to claims 1-11, characterized in that the combination is selected from the group consisting of a combination of SERD and a CDK4/6 inhibitor with a PI3K/mTOR pathway inhibitor, preferably a combination of compound 14 and compound 59 with everolimus. ,

    
13. The use according to claims 1-11, characterized in that the combination is selected from the group consisting of a combination of SERD and a CDK4/6 inhibitor, preferably a combination of compound 14 and compound 59,

    
14. The use according to claims 1 to 13, characterized in that the weight ratio of the SERD to the CDK4/6 inhibitor is selected from the group consisting of 0.1 to 150, preferably 1:0.1, 1:0.125, 1:0.14, 1:0.15. 1, 1:75, 1:0.1875, 1:0.2, 1:0.25, 1:0.28, 1:0.3, 1:0.35, 1:0.4, 1:0.5, 1:0.7, 1:0.75, 1:1,1 : 1.25, 1:1.75, 1:2, 1:2.5, 1:3.5, 1:4, 1:5, 1:8, 1:10, 1:15, 2:15, 1:20, 1:25 , 3:1, 3:2, 6:1, 6:5, 6:7, 8:5, 8:7, 12:1, 15:7, 16:3, 16:5, 16:7, 16 : 15, 16:25, 16:35, 24:5, 24:7, 60:7, more preferably 1:4, 1:5, 1:8, 1:10, 1:15, 2:15, 1 : 20, 1:25, 16:25, 16:35; the weight ratio of the SERD and CDK4/6 inhibitor to the PI3K/mTOR pathway inhibitor is selected from 0.1-200: 1-500: 0.1-100, preferably 3:30:5, 2:15:3, 8:10:1, 16:20:1, 10:5:1,20:10:1,10:7:1,20:14:1,10: 10:1, 20:20:1, 20:25:2, 20:25:1, 15:5:1, 30:10:1, 30:15:2, 30:15:1,15:10: 1, 30:20:1, 30:25:2, 30:25:1, 25:5:1, 50:10:1, 25:10:1, 50:20:1,40:5:1 80:50:1, 40:10:1, 80:20:1, more preferably 3:30:5, 2:15:3, 8:10:1, 16:20:1, 20:25:2 20:25:1 .
15. The use according to claim 1 wherein said breast tumor is selected from the group consisting of estrogen receptor positive breast tumors.
16. The use according to claim 15, wherein the estrogen receptor-positive breast tumor is a postmenopausal estrogen receptor-positive breast tumor.
17. The use according to claim 1, wherein the breast tumor is selected from the group consisting of a lumen type A breast cancer and a lumen type B breast cancer.
18. The use according to any of claims 15-17, wherein said breast tumor is resistant to endocrine therapy, said endocrine therapy being selected from the group consisting of a selective estrogen receptor modulator (SERM), an aromatase Inhibitor, fulvestrant.
19. The use according to claim 18, wherein said SERM is selected from the group consisting of tamoxifen, raloxifene, lasofoxifene, toremifene, bazedoxifene, droloxifene, and left beauty. Loxixene, idoxifene, omepromide, mprexifen, enclomid, acolbolifene, arzoxifene, pipidoxifene, Fispemifene, Clomiphene, Zuclomiphene, Sivifene, LY335563, GW-5638, SR16234, GW 7603, BL3040 , SRI 16158, SR 16157, SRI 16137, SR 16137, EM-652, EM-800, LY2066948, LY2120310, the aromatase inhibitor is selected from the group consisting of ammonia, latamide, lantalazine, and lysine Oxazole, liazodazole, fluconazole, fartrozole, anastrozole, fenoxazole, exemestane, atamestane, minnamer, osilodrostat, pentrozole, BGS-649, TMD-322, SEF -19, NKS-01, FCE-28718, MR-20492, TZA-2237, YM-511, MEN-11623, TAN-931, MPV-1837-AVB, FCE-27993, CGP-45688, D-3967, SNA -60-367, GW-114, YM-553, RU-56152, Org-33201, RU-54115, MFT-279.
20. The use according to any one of claims 1 to 19, wherein the selective estrogen receptor down-regulator (SERD) is selected from a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, phosphatidyl One or more of the inhibitors of the inositol 3-kinase (PI3K)/rapamycin target protein (mTOR) pathway are administered during the same dosing period, preferably within 1 day, or within 2 days, or within 3 days .
21. A pharmaceutical composition comprising the SERD according to any one of claims 1 to 14 and one or more selected from the group consisting of a CDK4/6 inhibitor, a PI3K/mTOR pathway inhibitor, and one or more pharmaceutically acceptable An excipient, diluent or carrier.

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