Pharmaceutical composition for treating tumors, pharmaceutical composition and application of pharmaceutical composition

Abstract

A pharmaceutical combination comprising a selective estrogen receptor down-modulator (SERD) and a mammalian target of rapamycin (mTOR) inhibitor, a combination product or pharmaceutical composition comprising said pharmaceutical combination, and the use of said pharmaceutical combination, combination product or pharmaceutical composition for the preparation of a medicament for the treatment of tumors such as breast cancer, wherein the SERD is selected from a compound of formula (K) or a pharmaceutically acceptable salt thereof. # imgabs0 #

Description

Drug combination for treating tumors, pharmaceutical composition and use thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This disclosure claims priority to and the benefit of Chinese patent application No. 202211331159.2, filed with the State Intellectual Property Office of China on October 28, 2022, entitled “Drug Combinations, Pharmaceutical Compositions, and Uses Thereof for Treating Tumors.” The entire text of the aforementioned prior application is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure belongs to the field of medicine and relates to a drug combination comprising a selective estrogen receptor downregulator (SERD) and a mammalian target of rapamycin (mTOR) inhibitor, a combination product or a pharmaceutical composition comprising the drug combination, and the use of the drug combination, the combination product or the pharmaceutical composition for treating tumors. Background Art

[0004] Estrogen and estrogen receptor α (ERα) are important drivers of breast cancer development and progression. ER transcription factors are expressed in more than two-thirds of breast cancer patients, and in most ER-positive patients, ER remains a key driver, even in tumors that progress after early endocrine therapy. Therefore, ER is a major target for breast cancer treatment (Pharmacology & Therapeutics 186(2018)1–24). Endocrine therapy aims to reduce ER activity. There are three main types of endocrine therapy: selective estrogen receptor modulators (SERMs), such as tamoxifen, which are allosteric modulators of ER that inhibit its transcriptional activity upon binding to ER; aromatase inhibitors (AIs), which reduce estrogen levels in the body by inhibiting the conversion of androgens to estrogens; and selective estrogen receptor downregulators, such as fulvestrant, which not only act as ER antagonists to inhibit its activity but also induce ER protein degradation. Although endocrine therapy is the first choice for patients with estrogen receptor-positive breast cancer, approximately 30% of patients will relapse after treatment, and almost all patients with metastatic breast cancer will develop drug resistance and progress.

[0005] Clinically, approximately 70-80% of breast cancers test positive for estrogen receptors (ER). These breast cancer cells are heavily dependent on ER for growth, and 50% of breast cancer deaths occur in this subtype. Early-stage ER-positive breast cancer has a good prognosis, with a 5-year survival rate exceeding 90%. Approximately 30% of patients who receive postoperative endocrine therapy (TAM or AI drugs) experience recurrence within 10 years, but standard endocrine therapy is still acceptable.

[0006] Fulvestrant is the first and only SERD drug clinically approved for the treatment of postmenopausal patients with ER-positive, metastatic breast cancer after progression on tamoxifen or aromatase inhibitors. Multiple studies have shown that ER degradation is not fully achieved in patients treated with fulvestrant. Furthermore, intramuscular injections can cause significant reactions such as pain, swelling, and redness at the injection site. Furthermore, slow absorption and limited in vivo exposure limit its clinical application. Therefore, new treatment options are urgently needed for patients with ER-positive breast cancer.

[0007] The mammalian target of rapamycin (mTOR) is a key serine-threonine kinase whose activity is upregulated in some human tumors. Everolimus (chemical name: (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxo-4-aza-tricyclo[30.3.1.04,9]-triacontahedral-16,24,26,28-tetraene-2,3,10,14,20-pentanone) ) as a selective inhibitor of mTOR and can be used to treat cancer patients.

[0008] Summary of the Invention

[0009] In one aspect, the present disclosure provides a pharmaceutical combination comprising at least one selective estrogen receptor downregulator (SERD) and at least one mTOR inhibitor, wherein the SERD is selected from a compound of formula (K) or a pharmaceutically acceptable salt thereof:

[0010] in,

[0011] R 1 、R 2 、R 3 、R 4 Independently selected from H, F, Cl, Br, I, CN, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl;

[0012] X1, X2, X3, and X4 are independently selected from CR 6 or N;

[0013] R 6 Selected from H, F, Cl, Br, I, OH, CN, C1-C 10Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C1-C 10 Alkoxy, C3-C 10 Cycloalkyloxy or 3-10 membered heterocyclyloxy;

[0014] R 5 is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally replaced by R a replace;

[0015] R a is selected from F, Cl, Br, I, OH, CN, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl.

[0016] In some embodiments, R in the compound of formula (K) 1 、R 2 、R 3 、R 4 Independently selected from H, F, Cl, Br, I, CN or C1-C6 alkyl.

[0017] In some embodiments, R in the compound of formula (K) 1 、R 2 、R 3 、R 4 are independently selected from H, F or methyl.

[0018] In some embodiments, R in the compound of formula (K) 1 、R 2 are independently selected from H, F or methyl.

[0019] In some embodiments, R in the compound of formula (K) 3 、R 4 are independently selected from H or methyl.

[0020] In some embodiments, R in the compound of formula (K) 3 、R 4 Independently selected from H.

[0021] In some embodiments, the structural unit in the compound of formula (K) Selected from

[0022] In some embodiments, R in the compound of formula (K) 6 Selected from H or F.

[0023] In some embodiments, the structural unit in the compound of formula (K) Selected from

[0024] In some embodiments, R in the compound of formula (K) 5 Selected from CH2CF3.

[0025] In some embodiments, the compound of formula (K) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (K-1) or a pharmaceutically acceptable salt thereof:

[0026] Among them, R 1 、R 2 、R 3 、R 4 、R 5 , X1, X2, X3, X4 are as defined above.

[0027] In some embodiments, the compound of formula (K) or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0028] In some embodiments, the compound of formula (K) or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0029] In some embodiments, the compound of formula (K) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0030] In some embodiments, the mTOR inhibitor is selected from Sirolimus, Temsirolimus, Everolimus, Zotarolimus, Umirolimus, Novolimus, Dactolisib, Onatasertib, or Bimiralisib.

[0031] In some embodiments, the mTOR inhibitor is selected from Everolimus.

[0032] In some embodiments, the present disclosure provides a pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and Everolimus.

[0033] In some embodiments, the pharmaceutical combination is a fixed combination. In some embodiments, the fixed combination is in the form of a solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition is selected from a tablet or a capsule.

[0034] In some embodiments, the pharmaceutical combination is a non-fixed combination. In some embodiments, the compound of formula (K) or a pharmaceutically acceptable salt thereof (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) and the mTOR inhibitor (such as Everolimus) in the non-fixed combination are each in the form of a solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition is selected from a tablet or a capsule.

[0035] On the other hand, the present disclosure also provides a pharmaceutical composition, comprising any one of the above-mentioned drug combinations and at least one pharmaceutically acceptable excipient.

[0036] In some embodiments, the pharmaceutical composition comprises:

[0037] 1) a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0038] 2) Everolimus; and,

[0039] 3) at least one pharmaceutically acceptable excipient.

[0040] On the other hand, the present disclosure provides a combination product comprising a first pharmaceutical composition and a second pharmaceutical composition, wherein the first pharmaceutical composition comprises at least one compound of formula (K) above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and the second pharmaceutical composition comprises at least one mTOR inhibitor above and a pharmaceutically acceptable excipient.

[0041] The present disclosure also provides a medicine box comprising:

[0042] 1) a first container comprising the first pharmaceutical composition as described above; and

[0043] 2) A second container, comprising the pharmaceutical composition II as described above.

[0044] In one embodiment of the present disclosure, the compound of formula (K) or a pharmaceutically acceptable salt thereof in the first pharmaceutical composition is selected from the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0045] In one embodiment of the present disclosure, the mTOR inhibitor in the pharmaceutical composition II is selected from Everolimus.

[0046] In some embodiments, the present disclosure provides a pharmaceutical kit comprising 1) a first container comprising a pharmaceutical composition I comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient; and 2) a second container comprising a pharmaceutical composition II comprising everolimus and a pharmaceutically acceptable excipient.

[0047] In another aspect, the present disclosure relates to use of any of the above-mentioned drug combinations, pharmaceutical compositions, combination products or drug kits in the preparation of anti-tumor drugs.

[0048] In another aspect, the present disclosure relates to use of any of the above-mentioned drug combinations, pharmaceutical compositions, combination products or drug kits in anti-tumor treatment.

[0049] In another aspect, the present disclosure relates to any one of the above-mentioned pharmaceutical combinations, pharmaceutical compositions, combination products or pharmaceutical kits for anti-tumor use.

[0050] In another aspect, the present disclosure relates to an anti-tumor method, which comprises administering a therapeutically effective amount of any one of the above-mentioned pharmaceutical combinations, pharmaceutical compositions, combination products or kits to a patient in need thereof.

[0051] On the other hand, the present disclosure also relates to the use of a compound of formula (K) or a pharmaceutically acceptable salt thereof in combination with at least one mTOR inhibitor in the preparation of an anti-tumor drug.

[0052] Furthermore, the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with at least one mTOR inhibitor in the preparation of an anti-tumor drug.

[0053] In one embodiment of the present disclosure, the mTOR inhibitor is Everolimus.

[0054] In one embodiment of the present disclosure, the tumor is breast cancer.

[0055] In one embodiment of the present disclosure, the tumor is ER-positive breast cancer.

[0056] In one embodiment of the present disclosure, the tumor is ER-positive breast cancer with brain metastasis.

[0057] In one embodiment of the present disclosure, the tumor is ER-positive, HER-2-negative locally advanced or metastatic breast cancer.

[0058] In some embodiments, the compound of formula (K) or the compound of formula (I) in the pharmaceutical combination, use or treatment method can be administered at a frequency of 3 times a day (tid), 2 times a day (bid) or once a day (qd); the daily dosage is 0.01 to 100 mg / kg body weight, or 0.05 to 50 mg / kg body weight, or 0.1 to 30 mg / kg body weight.

[0059] In some embodiments, the mTOR inhibitor or Everolimus in the pharmaceutical combination, use or treatment method can be administered at a frequency of 3 times a day (tid), 2 times a day (bid), once a day (qd), once a week (q1w), once every 2 weeks (q2w), once every 3 weeks (q3w) or once every 4 weeks (q4w); the daily dosage is 0.01 to 100 mg / kg body weight, or 0.05 to 50 mg / kg body weight, or 0.1 to 30 mg / kg body weight.

[0060] Technical Effects

[0061] Compared with the administration of any drug in the combination alone, the combination of the SERD compound disclosed herein and an mTOR inhibitor (such as Everolimus) produces better therapeutic effects in reducing tumor growth or even eliminating tumors, showing an excellent anti-tumor synergistic effect.

[0062] Definitions and Explanations of Terms

[0063] Unless otherwise indicated, the definitions of groups and terms in this disclosure and claims, including definitions provided as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The resulting group definitions and compound structures shall fall within the scope of this disclosure.

[0064] In this article Indicates the attachment site.

[0065] The diagrammatic representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the solid and imaginary bonds are wedge-shaped. To express the absolute configuration of a stereocenter, use direct real bonds and direct virtual bonds. Indicates the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).

[0066] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom in a molecule between two positions. The compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present disclosure encompasses all tautomeric forms of the compounds.

[0067] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0068] The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so that the compounds of the present invention may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and mixtures thereof. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of which are within the definition of the compounds of the present invention and mixtures thereof. Compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.

[0069] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence of the particular atom is normal and the compound after the substitution is stable.

[0070] The term "optional" or "optionally" refers to that the event or situation described subsequently may or may not occur, and the description includes that the event or situation occurs and that the event or situation does not occur. For example, an ethyl group is "optionally" substituted with halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, any sterically impossible and / or incomposable replacement or substitution pattern will not be introduced.

[0071] When any variable (such as R a 、R b ) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is represented by two R b is replaced, then each R b There are independent options.

[0072] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0073] The term "alkyl" refers to a group of the formula C n H 2n+1 The term "C1-C 10 The term "alkyl" is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl radical include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2- dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C1-C6 alkyl" can be understood to mean an alkyl group having 1 to 6 carbon atoms, and specific examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C3 alkyl" can be understood to mean a straight-chain or branched saturated alkyl group having 1 to 3 carbon atoms. The "C1-C 10 The term "alkyl" may include "C1-C6 alkyl" or "C1-C3 alkyl" and the like, and the "C1-C6 alkyl" may further include "C1-C3 alkyl".

[0074] The term "alkoxy" refers to a group generated by the loss of a hydrogen atom from a hydroxyl group of a straight-chain or branched alcohol, and can be understood as "alkyloxy" or "alkyl-O-". The term "C1-C 10 "Alkoxy" can be understood as "C1-C 10 Alkyloxy" or "C1-C 10 Alkyl-O-"; the term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-". The "C1-C 10 The term "alkoxy" may include "C1-C6 alkoxy" and "C1-C3 alkoxy", and the "C1-C6 alkoxy" may further include "C1-C3 alkoxy".

[0075] The term "cycloalkyl" refers to a fully saturated carbocyclic group that exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered ring. The term "C3-C 10"Cycloalkyl" is understood to mean a saturated monocyclic, bicyclic, spirocyclic or bridged ring group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, and the like. The term "C3-C 10 "Cycloalkyl" may include "C3-C6 cycloalkyl". The term "C3-C6 cycloalkyl" may be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms. Specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0076] The term "C3-C 10 "Cycloalkyloxy" can be understood as "C3-C 10 Cycloalkyl-O-", preferably, "C3-C 10 The “cycloalkyloxy” may include a “C3-C6 cycloalkyloxy”.

[0077] The term "heterocyclyl" refers to a fully saturated or partially saturated (heteroaromatic as a whole that is not aromatic) monocyclic, fused, spiro or bridged ring group, which contains 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups (i.e., heteroatom-containing groups) in its ring atoms, wherein the "heteroatoms or heteroatomic groups" include, but are not limited to, nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O)2-, -S(=O)-, -P(=O)2-, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-. The term "3-10 membered heterocyclyl" refers to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned heteroatoms or heteroatomic groups in its ring atoms. In particular, the heterocyclic group may include but is not limited to: specific examples of 4-membered heterocyclic groups include but are not limited to azetidinyl or oxetanyl; specific examples of 5-membered heterocyclic groups include but are not limited to tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6-membered heterocyclic groups include but are not limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membered heterocyclic groups include but are not limited to diazepanyl. The heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Although some bicyclic heterocyclic groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclic group as a whole is still non-aromatic.

[0078] The term "3-10 membered heterocyclyloxy" refers to "3-10 membered heterocyclyl-O-".

[0079] The term "drug combination" refers to a combination of two or more active ingredients or pharmaceutically acceptable salts thereof. In some embodiments of the present disclosure, the active ingredients or pharmaceutically acceptable salts thereof in the drug combination may be administered simultaneously. In some embodiments of the present disclosure, the active ingredients or pharmaceutically acceptable salts thereof in the drug combination may also be administered separately or sequentially.

[0080] The term "pharmaceutically acceptable salts" refers to salts of pharmaceutically acceptable acids or bases, including salts of inorganic acids and bases, organic acids and bases, such as succinate.

[0081] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present disclosure and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure or a pharmaceutical combination thereof to a subject.

[0082] The term "treating" means administering a compound or formulation of the present disclosure to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0083] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0084] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0085] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition, or disorder as described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0086] As used herein, the terms "subject" or "patient" are used interchangeably. In some embodiments, the term "subject" or "patient" is a mammal. In some embodiments, the subject or patient is a mouse. In some embodiments, the subject or patient is a human.

[0087] The term "administering" means physically introducing a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration of SERD and mTOR inhibitors include, but are not limited to, oral, parenteral, intravenous, transdermal, sublingual, intramuscular, and subcutaneous administration. In some specific embodiments, the SERD and mTOR inhibitors are administered orally.

[0088] The term "fixed combination" means that the active ingredients (e.g., a SERD or mTOR inhibitor) are administered to a subject simultaneously in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or formulation. In other words, the active ingredients are present in the same pharmaceutical formulation, for example, in the same tablet, capsule or sachet, in some embodiments.

[0089] The term "non-fixed combination" refers to two or more active ingredients that are administered to a subject as independent entities (e.g., pharmaceutical compositions, pharmaceutical preparations) simultaneously, concurrently or sequentially and without specific time limits, wherein the active ingredients are administered to the subject at a therapeutically effective level. In a non-fixed combination, the individual active ingredients can be packaged, sold or administered as completely independent pharmaceutical compositions. The "non-fixed combination" also includes the combined use of "fixed combinations" with each other or with any one or more independent entities of the active ingredients.

[0090] In the pharmaceutical combination or pharmaceutical composition of the present disclosure, the SERD and mTOR inhibitor may be in separate or single formulations. When the SERD and mTOR inhibitor are in separate formulations, the SERD and mTOR inhibitor may be administered simultaneously, separately or sequentially.

[0091] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0092] The words “comprise,” “comprise,” or “comprises,” and variations thereof such as comprises or comprising, should be construed in an open, non-exclusive sense, ie, “including but not limited to.”

[0093] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments disclosed in WO2021228210A1, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art.

[0094] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P.32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0095] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0096] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

[0097] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0098] Typical routes of administration of the disclosed compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0099] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0100] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0101] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0102] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0103] BRIEF DESCRIPTION OF THE DRAWINGS

[0104] FIG1 is a graph showing the in vitro synergistic anti-proliferative effect of the compound of formula (I) in combination with Everolimus on human breast cancer MCF-7 cells.

[0105] FIG2 is a graph showing the anti-tumor growth effect of the compound of formula (I) in combination with Everolimus in a human breast cancer MCF-7 subcutaneous xenograft mouse model. Example

[0106] The present disclosure is described in detail below by way of examples, but is not intended to limit the present disclosure in any way. While the present disclosure has been described in detail herein, including specific examples thereof, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific examples without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

[0107] Example 1: Preparation of succinate salt of compound of formula (I)

[0108] 5.0 g of the free form compound of formula (I) (prepared as described in Example 3 of WO2021228210A1) and 100 ml of isopropyl ether were placed in a 250 ml single-necked flask and stirred at room temperature until the solid was completely dissolved. 1.21 g of succinic acid was added, and the mixture was stirred at room temperature overnight. The mixture was filtered and dried under vacuum at room temperature for 3 h to obtain 5.4 g of the succinate salt of the compound of formula (I) as a solid.

[0109] Test Example 1 Inhibitory effect of compound of formula (I) combined with everolimus on proliferation of human breast cancer MCF-7 cells

[0110] Cell and compound information: Human breast cancer MCF-7 cells were purchased from ATCC and cultured in DMEM (Gibco) + 10% FBS (Gibco) + 0.01 mg / ml human insulin (Shanghai Yisheng) + 1% non-essential amino acids (Gibco). Everolimus was purchased from MCE (HY-10218).

[0111] Experimental Methods: Human breast cancer MCF-7 cells were cultured. When the cell confluence reached 70% or higher, the cells were digested and seeded at a density of 500 / 20 μL / well in a 384-well cell culture plate (Corning) overnight. Using an Echo650 (Beckman), 120 nL of a two-fold serial dilution of the compound of formula (I) (succinate salt) was transferred to the cell plate. Simultaneously, 60 nL of a two-fold serial dilution of everolimus was transferred to the cell plate. 40 μL of culture medium was added. After 7 days of compound treatment, cell viability was measured using CellTiter-Glo (Promega). The cell wells served as 100% viability controls, and the culture wells served as 0% viability controls. Combenefit analysis was performed for combined use (values ​​greater than 10 indicate a strong synergistic effect).

[0112] Results: The compound of formula (I) (0.5-512 nM) combined with everolimus (2-2048 nM) had a synergistic effect on the proliferation inhibition of human breast cancer MCF-7 cells, wherein a strong synergistic effect was exhibited in the combined use range of 2-16 nM compound of formula (I) combined with 16-64 nM everolimus. The results are shown in Figure 1.

[0113] Test Example 2: Combined pharmacodynamic study of human breast cancer MCF-7 subcutaneous xenograft mouse model

[0114] Experimental Materials:

[0115] Human breast cancer MCF-7 cells: ATCC HTB-22

[0116] 17β-estradiol tablets: Innovative Research of America, Cat No.: SE-121, 60-day release, 0.72mg / pellet

[0117] EMEM culture medium: ATCC, Cat No.: 30-2003

[0118] Fetal bovine serum: Gibco; Cat No.: 10091-148

[0119] Bispecific antibody: Gibco, Cat No.: 15140-122

[0120] 0.25% Trypsin-EDTA: Gibco, Cat No.: 25200-072

[0121] PBS:Hyclone Cytiva,Cat.No.:SH30256.01

[0122] Matrigel: Corning, Cat. No.: 356234

[0123] Everolimus: MCE, Cat No.: 159351-69-6

[0124] Experimental methods:

[0125] Animal information: NPG mice, female, 6-8 weeks old, weighing approximately 18-22 g, were purchased from Beijing Weitongda Biotechnology Co., Ltd. The mice were housed in an SPF-grade environment with separate ventilation in each cage. All animals had free access to standard certified commercial laboratory diet and free drinking water.

[0126] Cell Culture: Human breast cancer MCF-7 cells were cultured in vitro in EMEM (cell culture medium) supplemented with 10% fetal bovine serum, 1% double-antibody, and 10 μg / ml recombinant human insulin at 37°C in a 5% CO2 incubator. Cells were routinely digested and passaged once or twice weekly using 0.25% trypsin-EDTA. Cells were harvested and counted when confluence reached 80%-90% and the required number of cells was reached.

[0127] Cell inoculation: 17β-estradiol patch was subcutaneously inoculated one day before cell inoculation. On the day of cell inoculation, 0.1 ml / (containing 1×10 7 MCF-7 cell suspension (PBS: Matrigel, volume ratio of 1:1) was subcutaneously inoculated on the right back of each mouse. On the 23rd day after cell inoculation, the average tumor volume reached approximately 166 mm 3 The drugs were randomly divided into groups according to the tumor volume, and the day of grouping was designated as Day 0.

[0128] Dosing: The compound of formula (I) (succinate salt form, dosed as free base) was administered at a dose of 1 mg / kg, orally (PO), once daily (QD), for a total of 33 doses (to Day 32). The single-drug group received everolimus at a dose of 2.5 mg / kg, orally (PO), once daily (QD), for a total of 28 doses (to Day 27). There were 8 mice per group. Similarly, the compound of formula (I) in the combination group was administered 33 times (to Day 32), and everolimus was administered 28 times (to Day 27).

[0129] Tumor measurements and experimental parameters:

[0130] Tumor diameter was measured twice a week using a vernier caliper. Tumor volume was calculated using the formula: V = 0.5a × b 2 , a and b represent the long diameter and short diameter of the tumor, respectively. The body weight of mice was measured twice a week.

[0131] The anti-tumor efficacy of the compound was evaluated by tumor growth inhibition rate (TGI) (%). TGI (%) = [(1 - (average tumor volume of a treatment group at the end of drug administration - average tumor volume of the treatment group at the start of drug administration) / (average tumor volume of the solvent control group at the end of treatment - average tumor volume of the solvent control group at the start of treatment)] × 100%. Relative tumor volume (RTV) = V t / V0, where V0 is the tumor volume measured at the time of group administration (i.e., Day 0), V t The RTV value is used for statistical analysis of tumor size in each group.

[0132] Experimental results:

[0133] See Table 1 and Figure 2. One mouse in the solvent group died on day 35 after estrogen patch inoculation (11 days after group administration) due to side effects of the estrogen patch. One mouse in the everolimus (2.5 mg / kg) group lost more than 20% of its body weight, which then recovered on its own. The body weights of the compound of formula (I) (1 mg / kg) monotherapy group and the group treated with everolimus (2.5 mg / kg) remained relatively stable during the experiment.

[0134] The test results showed that on Day 32 after the start of administration, the single-drug groups (2.5 mg / kg of Everolimus was administered orally (PO) once a day to tumor-bearing mice until Day 27, and 1 mg / kg of the compound of Formula (I) was administered orally once a day to tumor-bearing mice until Day 32) both showed significant inhibition of tumor growth (P<0.0001); the combination group (2.5 mg / kg of Everolimus and 1 mg / kg of the compound of Formula (I)) showed significantly enhanced tumor inhibition compared to the vehicle control group and the single-drug group (P<0.0001).

[0135] The Jin Zhengjun method, also known as the probability addition method, was used to determine whether two drugs exhibited synergistic effects. The specific formula is: q = Eab / (Ea + Eb - Ea × Eb), where Ea and Eb represent the individual drug effects, and Eab represents the combined effect. A q value between 0.85 and 1.15 indicates a purely additive effect; a q value greater than 1.15 indicates synergism; and a q value less than 0.85 indicates antagonism. Substituting the TGI (%) as the efficacy value into the Jin Zhengjun formula yielded q = 1.43, indicating synergism in the combination.

[0136] Table 1 Tumor volume of MCF-7 subcutaneous tumor model

Claims

1. A pharmaceutical combination comprising at least one selective estrogen receptor downregulator (SERD) and at least one mTOR inhibitor, wherein the SERD is selected from a compound of formula (K) or a pharmaceutically acceptable salt thereof: in, R 1 、R 2 、R 3 、R 4 Independently selected from H, F, Cl, Br, I, CN, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl; X1, X2, X3, X4 are independently selected from CR 6 or N; R 6 Selected from H, F, Cl, Br, I, OH, CN, C1-C 10 Alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic group, C1-C 10 Alkoxy, C3-C 10 Cycloalkyloxy or 3-10 membered heterocyclyloxy; R 5 is selected from C1-C6 alkyl, wherein the C1-C6 alkyl is optionally replaced by R a replace; R a is selected from F, Cl, Br, I, OH, CN, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl.

2. The pharmaceutical combination according to claim 1, wherein the compound of formula (K) or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

3. The pharmaceutical combination according to claim 1 or 2, wherein the mTOR inhibitor is selected from Sirolimus, Temsirolimus, Everolimus, Zotarolimus, Umirolimus, Novolimus, Dactolisib, Onatasertib or Bimiralisib.

4. The pharmaceutical combination according to any one of claims 1 to 3, wherein the compound of formula (K) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (I) or a pharmaceutically acceptable salt thereof:

5. The pharmaceutical combination according to any one of claims 1 to 4, wherein the mTOR inhibitor is selected from Everolimus.

6. A combination product comprising a pharmaceutical composition I and a pharmaceutical composition II, wherein the pharmaceutical composition I comprises a compound of formula (K) or a pharmaceutically acceptable salt thereof as described in any one of claims 1, 2 and 4 and a pharmaceutically acceptable excipient, and the pharmaceutical composition II comprises at least one mTOR inhibitor and a pharmaceutically acceptable excipient.

7. The combination product according to claim 6, wherein the mTOR inhibitor is selected from Sirolimus, Temsirolimus, Everolimus, Zotarolimus, Umirolimus, Novolimus, Dactolisib, Onatasertib or Bimiralisib.

8. The combination product according to claim 6, wherein the mTOR inhibitor is selected from Everolimus.

9. A pharmaceutical composition comprising the drug combination according to any one of claims 1 to 5, and pharmaceutically acceptable excipients.

10. Use of the pharmaceutical combination according to any one of claims 1 to 5, the combination product according to any one of claims 6 to 8, or the pharmaceutical composition according to claim 9 in the preparation of an anti-tumor drug.

11. An anti-tumor method, comprising administering a therapeutically effective amount of the pharmaceutical combination according to any one of claims 1 to 5, the combination product according to any one of claims 6 to 8, or the pharmaceutical composition according to claim 9 to a patient in need thereof.

12. The pharmaceutical combination according to any one of claims 1 to 5, the combination product according to any one of claims 6 to 8 or the pharmaceutical composition according to claim 9 for treating tumors.

13. The use of claim 10, the method of claim 11, or the pharmaceutical combination, combination product or pharmaceutical composition of claim 12, wherein the tumor is breast cancer; or, the tumor is ER-positive breast cancer; or, the tumor is ER-positive breast cancer with brain metastasis; or, the tumor is ER-positive, HER-2-negative locally advanced or metastatic breast cancer.

14. The pharmaceutical combination of any one of claims 1 to 5, the method of claim 11 or 13, or the pharmaceutical combination, combination product or pharmaceutical composition of claim 12 or 13, wherein the compound of formula (K) is administered at a frequency of 3 times a day (tid), 2 times a day (bid) or once a day (qd), and / or the daily dose is 0.01 to 100 mg / kg body weight, or 0.05 to 50 mg / kg body weight, or 0.1 to 30 mg / kg body weight; and The mTOR inhibitor is administered at a frequency of three times a day (tid), twice a day (bid), once a day (qd), once a week (q1w), once every two weeks (q2w), once every three weeks (q3w) or once every four weeks (q4w), and / or at a daily dose of 0.01 to 100 mg / kg body weight, or 0.05 to 50 mg / kg body weight, or 0.1 to 30 mg / kg body weight.

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