Use of combination therapy for treatment of cancer

Abstract

Disclosed herein are combination therapies for the treatment of cancer, the combination therapies comprising a WEE1 inhibitor compound A, also known as ZN-C3 or azeosertib, and any one of a CDK4 / 6 inhibitor (e.g., palbociclib)) or a HER-2 inhibitor (e.g., trastuzumab). In particular, the combination of the invention is intended for the treatment of breast cancer, such as triple negative breast cancer, ER + breast cancer, HER2 + breast cancer, and low HER2 breast cancer.

Description

[0001] Incorporation by reference into any priority application

[0002] Any and all applications identifying foreign or domestic priority claims, such as in an application data sheet or request filed with this application, are hereby incorporated by reference in accordance with 37 CFR 1.57 and Rules 4.18 and 20.6, including U.S. Provisional Application No. 63 / 265,441 filed on December 15, 2021, the entirety of which is incorporated by reference. Technical Field

[0003] The present application relates to the fields of chemistry, biochemistry and medicine.More specifically, disclosed herein are combination therapies, and methods of using the combination therapies described herein to treat diseases and / or conditions. Background Art

[0004] Cancer is a family of diseases involving abnormal cell growth that may invade or spread to other parts of the body. Current cancer treatments include surgery, hormone therapy, radiation therapy, chemotherapy, immunotherapy, targeted therapy, and combinations thereof. Survival rates vary depending on the type of cancer and the stage of cancer at diagnosis. Therefore, there remains a need for effective cancer treatments. Summary of the invention

[0005] Some embodiments described herein, among others, provide a combination therapy comprising a WEE1 inhibitor (e.g., Compound A) and a CDK4 / 6 inhibitor or a HER-2 inhibitor for treating a disease or condition (e.g., cancer). In some embodiments, the HER-2 inhibitor is selected from a HER-2 small molecule inhibitor, a HER-2 antibody, a HER-2 antibody drug conjugate, and a HER2 bispecific antibody, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the HER-2 inhibitor is selected from a HER-2 antibody, a HER-2 antibody drug conjugate, and a HER2 bispecific antibody, or a pharmaceutically acceptable salt of any of the foregoing.

[0006] In one aspect, some embodiments provide a method of treating cancer, comprising administering to a subject an effective amount of compound (A) and an effective amount of compound (B), or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0007] Compound (A) is or a pharmaceutically acceptable salt thereof; and compound (B) is selected from the group consisting of a CDK4 / 6 inhibitor, a HER-2 small molecule inhibitor, a HER-2 antibody, a HER-2 antibody drug conjugate, and a HER2 bispecific antibody, or a pharmaceutically acceptable salt of any one of the foregoing.

[0008] In one aspect, some embodiments provide a method of treating cancer, comprising administering to a subject an effective amount of compound (A) and an effective amount of compound (B), or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0009] Compound (A) is or a pharmaceutically acceptable salt thereof; and compound (B) is selected from the group consisting of: a HER-2 small molecule inhibitor, a HER-2 antibody, a HER-2 antibody drug conjugate, and a HER2 bispecific antibody, or a pharmaceutically acceptable salt of any one of the foregoing.

[0010] In some embodiments, compound (B) is a HER-2 small molecule inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, compound (B) is a HER-2 antibody. In some embodiments, compound (B) is a HER-2 antibody drug conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, compound (B) is a HER-2 bispecific antibody, or a pharmaceutically acceptable salt thereof.

[0011] In one aspect, some embodiments provide a method of treating cancer, comprising administering to a subject an effective amount of compound (A) and an effective amount of compound (B), or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0012] Compound (A) is or a pharmaceutically acceptable salt thereof; and compound (B) is a CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof.

[0013] In one aspect, some embodiments provide a method of treating triple-negative breast cancer, the method comprising administering to a subject an effective amount of compound (A) and an effective amount of compound (B), or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0014] Compound (A) is or a pharmaceutically acceptable salt thereof; and

[0015] Compound (B) is fam-trastuzumab-deruxtecan-nxki (DS8201a).

[0016] Some embodiments described herein relate to combinations of compounds, which may include an effective amount of compound (A), or a pharmaceutically acceptable salt thereof, and an effective amount of compound (B), or a pharmaceutically acceptable salt of any of the foregoing.

[0017] Some embodiments described herein relate to the use of a combination of compounds for treating a disease or condition, wherein the combination comprises an effective amount of compound (A) or a pharmaceutically acceptable salt thereof, and an effective amount of compound (B) or a pharmaceutically acceptable salt of any of the foregoing. Other embodiments described herein relate to the use of a combination of compounds for the manufacture of a medicament for treating a disease or condition, wherein the combination comprises an effective amount of compound (A) or a pharmaceutically acceptable salt thereof, and an effective amount of compound (B) or a pharmaceutically acceptable salt of any of the foregoing.

[0018] In some embodiments, the disease or condition may be a cancer described herein.

[0019] In one aspect, some embodiments provide for use of a combination of compounds for treating a disease or condition, wherein the combination comprises an effective amount of compound (A) and an effective amount of compound (B), or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0020] Compound (A) is or a pharmaceutically acceptable salt thereof; and

[0021] Compound (B) is selected from the group consisting of a CDK4 / 6 inhibitor, a HER-2 small molecule inhibitor, a HER-2 antibody, a HER-2 antibody drug conjugate, and a HER2 bispecific antibody, or a pharmaceutically acceptable salt of any one of the foregoing;

[0022] wherein the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, trilaciclib (G1T28), lerociclib (G1T38), SHR6390, FCN-437, AMG 925, BPI-1178, BPI-16350, Birociclib, BEBT-209, TY-302, TQB-3616, HS-10342, PF-06842874, CS-3002, and MM-D37K, or a pharmaceutically acceptable salt of any one of the foregoing;

[0023] wherein the HER-2 antibody is selected from the group consisting of trastuzumab, trastuzumab-dkst, pertuzumab, and ZW25, or a pharmaceutically acceptable salt of any one of the foregoing;

[0024] The HER-2 antibody drug conjugate is selected from the group consisting of: Ado-trastuzumab emtansine (T-DM1), ARX788, ALT-P7, (dexitumomab, DSDS8201a), MEDI4276, MM302, PF-06804103, SYD985, XMT-1522, ZW49, MRG002, GQ1001, A166, RC48-ADC, BDC-1001, and FS-1502, or a pharmaceutically acceptable salt of any one of the foregoing; and

[0025] The HER2 bispecific antibody is selected from the group consisting of margetuximab, ertumaxomab, HER2Bi-aATC, MM-111, MCLA-128, BTRC4017A, GBR-1302, and PRS-343, or a pharmaceutically acceptable salt of any one of the foregoing.

[0026] Exemplary HER-2 antibody drug conjugates are described in Ferraro et al., Implementing antibody-drug conjugates (ADCs) in HER2-positive breast cancer: state of the art and future directions. Breast Cancer Res (2021) 23(1): 84. (https: / / doi.org / 10.1186 / s13058-021-01459-y), which is incorporated herein by reference in its entirety.

[0027] In some embodiments, compound (B) is a HER-2 small molecule inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, compound (B) is a HER-2 small molecule inhibitor selected from tucatinib, lapatinib, and neratinib, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, compound (B) is tacatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, compound (B) is lapatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, compound (B) is neratinib, or a pharmaceutically acceptable salt thereof. In some embodiments, HER-2 small molecule inhibitors are administered in combination with HER-2 antibodies (e.g., trastuzumab).

[0028] In some embodiments, compound (B) is a CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, compound (B) is selected from Figure 1 A CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the CDK4 / 6 inhibitor is palbociclib.

[0030] In some embodiments, the CDK4 / 6 inhibitor is abemaciclib.

[0031] In some embodiments, the CDK4 / 6 inhibitor is ribociclib.

[0032] In some embodiments, the CDK4 / 6 inhibitor is tracinib.

[0033] In some embodiments, compound (B) is a HER-2 antibody, or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the HER-2 antibody is trastuzumab.

[0035] In some embodiments, compound (B) is a HER-2 antibody drug conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, compound (B) is a trastuzumab antibody drug conjugate, or a pharmaceutically acceptable salt thereof. In some embodiments, compound (B) is dextran trastuzumab (DS8201a).

[0036] In some embodiments, compound (B) is a HER2 bispecific antibody, or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, compound (B) is selected from Figure 2 .

[0038] In some embodiments, compound (B) is a HER-2 small molecule inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, compound (B) is a HER-2 small molecule inhibitor selected from tucatinib, lapatinib, and neratinib, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the HER-2 small molecule inhibitor is administered in combination with a HER-2 antibody (e.g., trastuzumab), or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the disease or condition is breast cancer.

[0040] In some embodiments, the disease or condition is selected from the group consisting of triple negative breast cancer (TNBC), and estrogen receptor positive (ER+) breast cancer. In some embodiments, breast cancer is ER positive (ER+) breast cancer. In some embodiments, breast cancer is ER positive, HER2 negative (ER+ / HER2-) breast cancer. In some embodiments, breast cancer is triple negative breast cancer (TNBC).

[0041] In some embodiments, breast cancer is classified by HER2 status. In some embodiments, breast cancer is HER2 positive (HER2+) breast cancer. In some embodiments, breast cancer is low HER2 breast cancer. In some embodiments, breast cancer is classified as HER2 negative (HER2-) breast cancer.

[0042] In some embodiments, the disease or condition is lung cancer, gastric cancer, or esophagogastric junction adenocarcinoma.

[0043] In one aspect, some embodiments provide a use of an effective amount of compound (A), or a pharmaceutically acceptable salt of any of the foregoing, for preparing or manufacturing a medicament for treating ER+ breast cancer, wherein compound (A) is or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the breast cancer does not comprise any ER point mutations.

[0045] In some embodiments, the breast cancer has at least one point mutation in the estrogen receptor 1 gene (ESR1), which encodes estrogen receptor alpha (ERα), wherein the mutation is selected from the group consisting of: K303R, D538G, Y537S, E380Q, Y537C, Y537N, A283V, A546D, A546T, A58T, A593D, A65V, C530L, D411H, E279V, E471D, E471V, E523Q, E542G, F461V, F97L, G145D, G160D, G274R, G344D, G420D, G442R, G557R, H524L, K252N , K481N, K531E, L370F, L453F, L466Q, L497R, L536H, L536P, L536Q, L536R, L540Q, L549P, M388L, M396V, M421V, M437I, M522I, N156T, N532K, N69K, P14 7Q, P222S, P535H, R233G, R477Q, R503W, R555H, S282C, S329Y, S338G, S432L, S463P, S47T, S576L, V392I, V418E, V478L, V533M, V534E, Y537D, and Y537H.

[0046] In some embodiments, the breast cancer is ER-positive breast cancer.

[0047] In some embodiments, the breast cancer is ER-positive / HER2-negative breast cancer.

[0048] In some embodiments, the breast cancer is localized breast cancer.

[0049] In some embodiments, the breast cancer is metastatic breast cancer.

[0050] In some embodiments, the breast cancer is recurrent breast cancer.

[0051] In some embodiments, breast cancer has previously been treated with endocrine therapy. In some embodiments, treatment uses a selective ER regulator (SERM). In some embodiments, a selective ER regulator is selected from the group consisting of: tamoxifen, raloxifene, ospemifene, bazedoxifene, toremifene, and lasofoxifene, or a pharmaceutically acceptable salt of any one of the foregoing.

[0052] In some embodiments, the prior treatment uses a selective ER degrader (SERD). In some embodiments, the selective ER degrader is selected from the group consisting of fulvestrant, (E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid (AZD9496), (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (elacestrant, RAD1901), (E)-3-(4-((E) (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (LSZ102), (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)ethyl)amino)butyl -2-enamide (H3B-6545), (E)-3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thien-3-yl)oxy)phenyl)acrylic acid (rintodestrant, G1T48), D-0502, SHR9549, ARV-471, 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol (giredes trant), GDC-9545), (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (SAR439859), N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (AZD9833), OP-1250, and LY3484356, or a pharmaceutically acceptable salt of any one of the foregoing.

[0053] In some embodiments, the prior treatment was with an aromatase inhibitor. In some embodiments, the aromatase inhibitor is a steroidal aromatase inhibitor.

[0054] In some embodiments, the steroidal aromatase inhibitor is selected from the group consisting of exemestane and testolactone, or a pharmaceutically acceptable salt of any of the foregoing.

[0055] In some embodiments, the aromatase inhibitor is a non-steroidal aromatase inhibitor. In some embodiments, the non-steroidal aromatase inhibitor is selected from the group consisting of anastazole and letrazole, or a pharmaceutically acceptable salt of any of the foregoing.

[0056] In some embodiments, the breast cancer has not been previously treated.

[0057] In some embodiments, breast cancer is present in women. In some embodiments, women are premenopausal women. In some embodiments, women are perimenopausal women. In some embodiments, women are menopausal women. In some embodiments, breast cancer is present in postmenopausal women.

[0058] In some embodiments, the breast cancer is present in a male.

[0059] In some embodiments, the breast cancer is present in a human subject.In some embodiments, the breast cancer is present in a subject having serum estradiol levels in the range of >15 pg / mL to 350 pg / mL.

[0060] In some embodiments, breast cancer is present in patients with >15 pg / mL to 300 pg / mL, >20 pg / mL to 350 pg / mL, >25 pg / mL to 350 pg / mL, >30 pg / mL to 350 pg / mL, >35 pg / mL to 350 pg / mL, >40 pg / mL to 350 pg / mL, >45 pg / mL to 350 pg / mL, >50 pg / mL to 350 pg / mL, >55 pg / mL to 350 pg / mL, >60 pg / mL to 350 pg / mL, >65 pg / mL to 350 pg / mL, >70 pg / mL to 350 pg / mL, >75 pg / mL to 350 pg / mL, >80 pg / mL to 350 pg / mL, >85 pg / mL to 350 pg / mL, >90 pg / mL to 350 pg / mL, >95 pg / mL to 350 pg / mL, >100 pg / mL to 350 pg / mL, >110 pg / mL to 350 pg / mL, >120 pg / mL to 350 pg / mL, >130 pg / mL to 350 pg / mL, >140 pg / mL to 350 pg / mL, >150 pg / mL to 350 pg / mL, >160 pg / mL to 350 pg / mL, >170 pg / mL to 350 pg / mL, >180 pg / mL to 350 pg / mL pg / mL, >75-350 pg / mL, >80-350 pg / mL, >85-350 pg / mL, >90-350 pg / mL, >95-350 pg / mL, >100-350 pg / mL, >125-350 pg / mL, >150-350 pg / mL, >200-350 pg / mL, >250-350 pg / mL, or >300-350 pg / mL.

[0061] In some embodiments, the breast cancer is present in a subject with a serum estradiol level of ≤ 15 pg / mL. In some embodiments, the breast cancer is present in a subject with a serum estradiol level of ≤ 10 pg / mL.

[0062] In some embodiments, the breast cancer is present in a subject having a serum estradiol level of ≤20 pg / mL, ≤19 pg / mL, ≤18 pg / mL, ≤17 pg / mL, ≤16 pg / mL, ≤15 pg / mL, ≤14 pg / mL, ≤13 pg / mL, ≤12 pg / mL, ≤11 pg / mL, or ≤10 pg / mL.

[0063] In one aspect, some embodiments provide a method of treating cancer, comprising administering to a subject an effective amount of compound (A) and an effective amount of compound (B), or a pharmaceutically acceptable salt of any of the foregoing, wherein:

[0064] Compound (A) is or a pharmaceutically acceptable salt thereof; and

[0065] Compound (B) is selected from the group consisting of a CDK4 / 6 inhibitor, a HER-2 small molecule inhibitor, a HER-2 antibody, a HER-2 antibody drug conjugate, and a HER2 bispecific antibody, or a pharmaceutically acceptable salt of any one of the foregoing;

[0066] wherein the CDK4 / 6 inhibitor is selected from the group consisting of: palbociclib, abemaciclib, ribociclib, triclasiclib (G1T28), lerociclib (G1T38), SHR6390, FCN-437, AMG 925, BPI-1178, BPI-16350, bilociclib, BEBT-209, TY-302, TQB-3616, HS-10342, PF-06842874, CS-3002, and MM-D37K, or a pharmaceutically acceptable salt of any one of the foregoing;

[0067] wherein the HER-2 antibody is selected from the group consisting of trastuzumab, trastuzumab-dkst, pertuzumab, and ZW25, or a pharmaceutically acceptable salt of any one of the foregoing;

[0068] wherein the HER-2 antibody drug conjugate is selected from the group consisting of: ado-trastuzumab emtacin (T-DM1), ARX788, ALT-P7, DS8201a, MEDI4276, MM302, PF-06804103, SYD985, XMT-1522, ZW49, MRG002, GQ1001, A166, RC48-ADC, BDC-1001, and FS-1502, or a pharmaceutically acceptable salt of any one of the foregoing; and

[0069] The HER2 bispecific antibody is selected from the group consisting of margetuximab, ertumaxomab, HER2Bi-aATC, MM-111, MCLA-128, BTRC4017A, GBR-1302, and PRS-343, or a pharmaceutically acceptable salt of any one of the foregoing.

[0070] In some embodiments, compound (B) is a HER-2 small molecule inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, compound (B) is a HER-2 small molecule inhibitor selected from tucatinib, lapatinib, and neratinib, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the HER-2 small molecule inhibitor is administered in combination with a HER-2 antibody (e.g., trastuzumab), or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] Figure 1 Examples of CDK4 / 6 inhibitors are provided.

[0072] Figure 2 Examples of HER-2 antibodies, HER-2 antibody drug conjugates, and HER2 bispecific antibodies are provided.

[0073] Figure 3 Shown are the results of in vivo studies of Compound (A), or a pharmaceutically acceptable salt thereof, in the MCF-7 xenograft model.

[0074] Figure 4 Shown are the results of in vivo studies of Compound (A), or a pharmaceutically acceptable salt thereof, or tamoxifen in the ZR-75-1 tamoxifen-resistant tumor model.

[0075] Figure 5 Shown are the results of in vivo studies of Compound (A), or a pharmaceutically acceptable salt thereof, in human HCC1428 breast cancer xenograft tumors.

[0076] Figure 6 Shown are the results of in vivo studies of compound (A), or a pharmaceutically acceptable salt thereof, as monotherapy or in combination with the CDK4 / 6 inhibitor, palbociclib, in the MCF-7 xenograft model.

[0077] Figure 7 Shown are the results of in vivo studies of compound (A), or a pharmaceutically acceptable salt thereof, as monotherapy or in combination with the CDK4 / 6 inhibitor, palbociclib, in the MCF-7 xenograft model.

[0078] Figure 8 The changes in tumor volume for treatment with vehicle, Compound (A), trastuzumab, or a combination of Compound (A) and trastuzumab are provided.

[0079] Fig. 9 The changes in tumor volume for treatment with vehicle, Compound (A), trastuzumab, or a combination of Compound (A) and trastuzumab are provided.

[0080] Fig. 10A and Fig. 10B Tumor volume and body weight changes in palbociclib-resistant breast cancer patient-derived xenograft (PDX) model (CTG-1207) mice treated with vehicle, Compound (A), palbociclib, or a combination of Compound (A) and palbociclib are provided, respectively. DETAILED DESCRIPTION

[0081] definition

[0082] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as understood by those of ordinary skill in the art. Unless otherwise noted, the full text of all patents, applications, open applications, and other publications cited herein are incorporated herein by reference. If a term in this article has multiple definitions, unless otherwise noted, the definition in this section is dominant.

[0083] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant stimulation to the organism to which it is applied and does not invalidate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting the compound with an inorganic acid, such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid (e.g., 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting the compound with an organic acid, such as an aliphatic or aromatic carboxylic acid or sulfonic acid, such as formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, benzoic acid, salicylic acid, 2-side oxoglutaric acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, such as an amine salt, an alkali metal salt (e.g., a sodium salt, a potassium salt, or a lithium salt), an alkaline earth metal salt (e.g., a calcium or magnesium salt), a carbonate, a bicarbonate, a salt with an organic base (e.g., dicyclohexylamine, N-methyl-D-reduced glucosamine, phenyl(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine), and a salt with an amino acid (e.g., arginine and lysine). With respect to compounds (A) and (B), those skilled in the art understand that when a salt is formed by protonation of a nitrogen-based group (e.g., NH2), the nitrogen-based group may be associated with a positive charge (e.g., NH2 may become NH3 + ), and the positive charge can be replaced by a negatively charged counter ion (e.g. Cl - )balance.

[0084] It should be understood that in any compound described herein with one or more chiral centers, if the absolute stereochemistry is not explicitly indicated, each center can independently have the R-configuration, or the S-configuration, or a mixture thereof. Therefore, the compounds provided herein can be enantiomerically pure, enantiomerically enriched racemic mixtures, diastereomerically pure, diastereomerically enriched, or stereoisomeric mixtures. In addition, it should be understood that in any compound described herein with one or more double bonds that produce geometric isomers (which can be defined as E or Z), each double bond can independently be E or Z or a mixture thereof. Similarly, it should be understood that in any of the described compounds, all tautomeric forms are also intended to be included.

[0085] It is understood that where compounds disclosed herein have unfilled valences, then the valences should be filled with hydrogen or an isotope thereof, for example hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0086] It should be understood that the compounds described herein may be isotopically labeled. Substitution with isotopes such as deuterium may provide certain therapeutic advantages resulting from higher metabolic stability, such as increased half-life in vivo or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of the element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of a compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, the compounds referred to herein encompass all potential isotopic forms unless the context clearly indicates otherwise.

[0087] It should be understood that the methods and combinations described herein include crystalline forms (also referred to as polymorphs, which include different crystal packing arrangements of compounds composed of the same elements), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in a solvated form with a pharmaceutically acceptable solvent (e.g., water, ethanol, etc.). In other embodiments, the compounds described herein exist in a non-solvated form. Solvates contain stoichiometric or non-stoichiometric amounts of solvents and can be formed with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.) during a crystallization procedure. When the solvent is water, a hydrate is formed, and when the solvent is alcohol, an alcoholate is formed. In addition, the compounds provided herein may exist in a non-solvated form as well as a solvated form. In general, for the purposes of the compounds and methods provided herein, the solvated form is considered to be equivalent to the non-solvated form.

[0088] When a range of values ​​is provided, it is understood that the upper and lower limits of the range and every intervening value between the upper and lower limits are encompassed within the embodiments.

[0089]

[0043] Unless expressly stated otherwise, terms, and phrases used in this application, and variations thereof (especially in the following claims) should be construed as open ended as opposed to limiting. As an example of the foregoing, the term "including" should be interpreted as meaning "including but not limited to" and the like; as used herein, the term "comprising" is synonymous with "including, containing, or "characterized by", and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term "having" should be interpreted as "having at least"; the term "include" should be interpreted as "includes but is not limited to"; the term "example" is used to provide an illustrative example of the items discussed rather than an exhaustive or limiting list thereof; and the use of terms such as "preferably", "preferred", or "desired / desirable", and similarly meaning texts should not be construed to imply that certain features are critical, necessary, or even essential to structure or function, but are merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. Furthermore, the term "comprising" should be used in conjunction with the phrase "having at least" to provide an illustrative example of the items discussed, rather than an exhaustive or limiting list thereof. When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

[0090] With respect to the use of substantially any plural and / or singular terms herein, one of ordinary skill in the art may convert from the plural to the singular and / or from the singular to the plural as appropriate to the context and / or application. Various singular / plural permutations and combinations may be expressly set forth herein for clarity. The indefinite article "a" does not exclude a plurality. The mere fact that certain measures are listed in mutually different appendices does not indicate that a combination of these measures cannot be used to advantage. Any element signs in the claims should not be construed as limiting the scope.

[0091] Compound

[0092] Some embodiments disclosed herein relate to the use of a combination of compounds for treating a disease or condition, wherein the combination may comprise an effective amount of compound (A) or a pharmaceutically acceptable salt thereof, and an effective amount of compound (B) or a pharmaceutically acceptable salt of any of the foregoing, wherein compound (A) may be a WEE1 inhibitor, or a pharmaceutically acceptable salt thereof; and compound (B) may be selected from CDK4 / 6 inhibitors, HER-2 antibodies, HER-2 antibody drug conjugates, and HER2 bispecific antibodies (including pharmaceutically acceptable salts of any of the foregoing).

[0093] Compound (A) (including pharmaceutically acceptable salts thereof) may be (including pharmaceutically acceptable salts thereof). In some embodiments, compound (B) (including pharmaceutically acceptable salts thereof) may be a CDK4 / 6 inhibitor selected from palbociclib, abemaciclib, ribociclib, traceranib (G1T28), lerociclib (G1T38), SHR6390, FCN-437, AMG 925, BPI-1178, BPI-16350, pyroximate, BEBT-209, TY-302, TQB-3616, HS-10342, PF-06842874, CS-3002, and MM-D37K (together with pharmaceutically acceptable salts of any of the foregoing). In other embodiments, compound (B) (including pharmaceutically acceptable salts thereof) may be a HER-2 small molecule inhibitor selected from tacatinib, lapatinib, and neratinib, or a pharmaceutically acceptable salt of any of the foregoing. In yet other embodiments, compound (B) (including its pharmaceutically acceptable salt) can be a HER-2 antibody selected from trastuzumab, trastuzumab-dkst, pertuzumab, and ZW25 (together with a pharmaceutically acceptable salt of any of the foregoing). In yet other embodiments, compound (B) (including its pharmaceutically acceptable salt) can be a HER-2 antibody drug conjugate selected from adotrastuzumab emtasin (T-DM1), ARX788, ALT-P7, DS8201a, MEDI4276, MM302, PF-06804103, SYD985, XMT-1522, ZW49, MRG002, GQ1001, A166, RC48-ADC, BDC-1001, FS-1502 (together with a pharmaceutically acceptable salt of any of the foregoing). In some embodiments, compound (B) (including pharmaceutically acceptable salts thereof) may be a HER2 bispecific antibody selected from makituximab, ertuinomab, HER2Bi-aATC, MM-111, MCLA-128, BTRC4017A, GBR-1302, and PRS-343 (together with pharmaceutically acceptable salts of any of the foregoing).

[0094] Embodiments of the combination of compound (A) and compound (B) (including pharmaceutically acceptable salts of any of the foregoing) are provided in Table 1. In Table 1, "A" means compound (A) (including pharmaceutically acceptable salts thereof), and numbers 1A to 18A represent Figure 1 The compounds provided, and numbers 1B to 28B represent Figure 2 The provided compounds include pharmaceutically acceptable salts thereof. For example, in Table 1, the combination represented by 1A:A corresponds to palbociclib and (including a pharmaceutically acceptable salt of any one of the foregoing).

[0095] Table 1

[0096]

[0097] The order of administration of the compounds in the combinations described herein may vary. In some embodiments, compound (A) (including its pharmaceutically acceptable salt) may be administered before all compounds (B) (or its pharmaceutically acceptable salt). In other embodiments, compound (A) (including its pharmaceutically acceptable salt) may be administered before at least one compound (B) (or its pharmaceutically acceptable salt). In still other embodiments, compound (A) (including its pharmaceutically acceptable salt) may be administered together with compound (B) (or its pharmaceutically acceptable salt). In still other embodiments, compound (A) (including its pharmaceutically acceptable salt) may be administered after at least one compound (B) (or its pharmaceutically acceptable salt) is administered. In some embodiments, compound (A) (including its pharmaceutically acceptable salt) may be administered after all compounds (B) (or its pharmaceutically acceptable salt) are administered.

[0098] There may be several benefits to using a combination of compounds described herein. For example, combining compounds that attack several pathways simultaneously may be more effective in treating cancers such as those described herein than when the combined compounds are used as monotherapy.

[0099] In some embodiments, the combination of compound (A) (including pharmaceutically acceptable salts thereof) and compound (B) (or a pharmaceutically acceptable salt thereof) as described herein can reduce the number and / or severity of side effects attributable to the compounds described herein (e.g., compound (B) or a pharmaceutically acceptable salt thereof).

[0100] The use of the combination of compounds described herein may produce additive, synergistic, or strongly synergistic effects. The combination of compounds as described herein may produce non-antagonistic effects.

[0101] In some embodiments, the combination of compound (A) (including its pharmaceutically acceptable salt) and compound (B) (or its pharmaceutically acceptable salt) as described herein may produce an additive effect. In some embodiments, the combination of compound (A) (including its pharmaceutically acceptable salt) and compound (B) (or its pharmaceutically acceptable salt) as described herein may produce a synergistic effect. In some embodiments, the combination of compound (A) (including its pharmaceutically acceptable salt) and compound (B) (or its pharmaceutically acceptable salt) as described herein may produce a strong synergistic effect. In some embodiments, the combination of compound (A) (including its pharmaceutically acceptable salt) and compound (B) (or its pharmaceutically acceptable salt) as described herein is non-antagonistic.

[0102] As used herein, the term "antagonism" means that the activity of a combination of compounds is lower than the sum of the activities of the compounds in the combination (when the activity of each compound is determined individually, i.e., as a single compound). As used herein, the term "synergistic effect" means that the activity of a combination of compounds is higher than the sum of the individual activities of the compounds in the combination (when the activity of each compound is determined individually). As used herein, the term "additive effect" means that the activity of a combination of compounds is approximately equal to the sum of the individual activities of the compounds in the combination (when the activity of each compound is determined individually).

[0103] One possible benefit of using a combination as described herein may be that the amount of compound required to be effective for treating the conditions disclosed herein is reduced compared to when each compound is administered as a monotherapy. For example, the amount of compound (B) (or a pharmaceutically acceptable salt thereof) used in the combination described herein may be lower than the amount of compound (B) (or a pharmaceutically acceptable salt thereof) required to achieve a reduction in the same disease marker (e.g., tumor size) when compound (B) (or a pharmaceutically acceptable salt thereof) is administered as a monotherapy. Another possible benefit of using the combination described herein is that the use of two or more compounds with different mechanisms of action may create a higher barrier to the emergence of resistance compared to when the compounds are administered as monotherapy. Additional advantages of utilizing a combination as described herein may include little cross-resistance between the compounds of the combination described herein; different pathways for eliminating the compounds of the combination described herein; and / or little overlapping toxicity between the compounds of the combination described herein.

[0104] Pharmaceutical composition

[0105] Compound (A) (including its pharmaceutically acceptable salt) can be provided in the form of a pharmaceutical composition. Similarly, compound (B) (including its pharmaceutically acceptable salt) can be provided in the form of a pharmaceutical composition.

[0106] The term "pharmaceutical composition" refers to a mixture of one or more compounds and / or salts disclosed herein with other chemical components (e.g., diluents, carriers, and / or excipients). Pharmaceutical compositions facilitate administration of compounds to organisms. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid). Pharmaceutical compositions are typically designed for specific intended routes of administration.

[0107] As used herein, "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, but not limited to, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0108] As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that lacks significant pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent can be used to increase the volume of an effective drug that is too small to be used for manufacturing and / or administration. A diluent can also be a liquid used to dissolve a drug to be administered by injection, ingestion, or inhalation. A common form of diluent in the art is a buffered aqueous solution, such as, but not limited to, phosphate-buffered saline that simulates the pH and isotonicity of human blood.

[0109] As used herein, "excipient" refers to a substantially inert substance that is added to a pharmaceutical composition to provide, but is not limited to, bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. to the composition. For example, stabilizers such as antioxidants and metal chelators are excipients. In one embodiment, the pharmaceutical composition comprises an antioxidant and / or a metal chelator. A "diluent" is a type of excipient.

[0110] In some embodiments, compound (B) (together with its pharmaceutically acceptable salt) can be provided in the form of a pharmaceutical composition comprising compound (A) (including its pharmaceutically acceptable salt). In other embodiments, compound (B) (together with its pharmaceutically acceptable salt) can be administered in the form of a pharmaceutical composition separate from a pharmaceutical composition comprising compound (A) (including its pharmaceutically acceptable salt).

[0111] The pharmaceutical compositions described herein can be administered to human patients by themselves, or can be administered to human patients in admixture with other active ingredients (such as in combination therapy), or carriers, diluents, excipients, or combinations thereof. The appropriate formulation depends on the route of administration selected. The formulation and administration techniques for the compounds described herein are known to those skilled in the art.

[0112] The pharmaceutical compositions disclosed herein can be manufactured in a manner known per se, such as by conventional mixing, dissolving, granulating, dragee manufacturing, grinding, emulsifying, encapsulating, encapsulating, or tableting procedures. In addition, the amount of active ingredient contained can effectively achieve its intended purpose. Many compounds used in the pharmaceutical combinations disclosed herein can be provided as salts containing pharmaceutically compatible counterions.

[0113] There are a variety of techniques for administering compounds, salts, and / or compositions in the art, including but not limited to oral, rectal, pulmonary, topical, aerosol, injection, infusion, and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injection. In some embodiments, compound (A) (including its pharmaceutically acceptable salt) can be administered orally. In some embodiments, compound (A) (including its pharmaceutically acceptable salt) can be provided to a subject by the same route of administration as compound (B) (together with its pharmaceutically acceptable salt). In other embodiments, compound (A) (including its pharmaceutically acceptable salt) can be provided to a subject by a route of administration different from compound (B) (together with its pharmaceutically acceptable salt).

[0114] Compounds, salts, and / or compositions may also be administered in a local rather than systemic manner, for example by direct injection or implantation of the compound, typically in a depot or sustained release formulation, into the infected area. Additionally, compounds may be administered using targeted drug delivery systems (e.g., liposomes coated with tissue-specific antibodies). Liposomes will target organs and be selectively taken up by them. For example, intranasal or pulmonary delivery may be desired to target respiratory diseases or conditions.

[0115] When necessary, the composition may be presented in a package or dispensing device that may contain one or more unit dosage forms (containing active ingredients). The package may, for example, include metal or plastic foil, such as a blister pack. The package or dispenser device may be accompanied by instructions for use. The package or dispenser may also be accompanied by a notice associated with the container to regulate the manufacture, use, or sale of the drug, the form of which is specified by a government agency, which reflects the agency's approval of the drug form for human or veterinary administration. For example, the notice may be a label or product leaflet approved by the U.S. Food and Drug Administration for prescription drugs. Compositions of compounds and / or salts described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of the indicated condition.

[0116] Therapeutic uses and methods

[0117] As provided herein, in some embodiments, a combination of compounds comprising an effective amount of Compound (A) (including a pharmaceutically acceptable salt thereof) and an effective amount of Compound (B) (or a pharmaceutically acceptable salt of any of the foregoing) can be used to treat a disease or condition.

[0118] As used herein, "subject" refers to an animal that is the target of treatment, observation, or experiment. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, crustaceans, reptiles, and particularly mammals. "Mammals" include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cattle, horses, primates, such as monkeys, chimpanzees, and apes, and particularly humans. In some embodiments, the subject can be a human. In some embodiments, the subject can be a child and / or an infant, such as a child or infant with a fever. In other embodiments, the subject can be an adult.

[0119] As used herein, the terms "treat" and "therapy" do not necessarily mean a complete cure or elimination of a disease or condition. Any alleviation to any degree of any undesirable signs or symptoms of a disease or condition may be considered treatment and / or therapy. In addition, treatment may include procedures that may worsen a subject's overall sense of well-being or appearance.

[0120] The term "effective amount" is used to indicate the amount of an active compound or pharmaceutical preparation that triggers an indicated biological or pharmaceutical response. For example, the effective amount of a compound, salt, or composition can be the amount required to prevent, alleviate, or improve the symptoms of a disease or condition, or to prolong the survival of the treated subject. This reaction can occur in a tissue, system, animal, or human, and includes alleviating the signs or symptoms of the treated disease or condition. In view of the disclosure provided herein, the determination of the effective amount is completely within the capabilities of those skilled in the art. The effective amount of the compound disclosed herein required as a dosage will depend on the route of administration, the type of animal (including humans) being treated, and the physical characteristics of the particular animal being considered. The dosage can be adjusted to achieve the desired effect, but depends on factors such as body weight, diet, and concomitant medications, and other factors that will be recognized by those skilled in the art of medicine.

[0121] For example, an effective amount of a compound or radiation is an amount that causes (a) reduction, alleviation, or disappearance of one or more symptoms caused by cancer, (b) reduction in tumor size, (c) tumor elimination, and / or (d) long-term disease stabilization (growth arrest) of a tumor.

[0122] In some embodiments, the disease or condition can be selected from lung cancer, gastric cancer, and esophagogastric junction adenocarcinoma. In some embodiments, the disease or condition can be breast cancer. Various types of breast cancer are known. In some embodiments, breast cancer can be ER positive (ER+) breast cancer. In some embodiments, breast cancer can be ER positive, HER2 negative (ER+ / HER2-) breast cancer.

[0123] In some embodiments, breast cancer is classified by HER2 status. In some embodiments, breast cancer is HER2 positive (HER2+) breast cancer. In some embodiments, breast cancer is low HER2 breast cancer.

[0124] In some embodiments, breast cancer can be localized breast cancer (as used herein, "localized" breast cancer means that the cancer has not spread to other areas of the body). In other embodiments, breast cancer can be metastatic breast cancer. In yet other embodiments, breast cancer can be triple-negative breast cancer.

[0125] The subject may have breast cancer that has not been previously treated.

[0126] In some cases, after treatment of breast cancer, the subject may relapse or breast cancer relapses. As used herein, the terms "relapse" and "relapse" are used with their normal meaning as understood by those skilled in the art. Therefore, breast cancer can be recurrent breast cancer. In some embodiments, the subject has relapsed after the previous treatment for breast cancer. For example, the subject has relapsed after receiving one or more treatments using SERM, SERD, and / or aromatase inhibitors (such as those described herein).

[0127] In ESR1, several amino acid mutations have been identified. It has been proposed that mutations in ESR1 play a role in resistance. There are several therapies for inhibiting estrogen receptors, including selective ER modulators (SERMs), selective ER degraders (SERDs), and aromatase inhibitors. One problem that can be caused by the aforementioned cancer therapies is the development of resistance to cancer therapies. Acquired resistance to cancer therapies (e.g., endocrine therapies) has been noted in nearly one-third of women treated with tamoxifen and other endocrine therapies. See Alluri et al., "Estrogen receptor mutations and their role in breast cancer progression" Breast Cancer Research (2014) 16: 494. Researchers have suspected that mutations in estrogen receptors are one of the causes of acquired resistance to cancer therapies (e.g., endocrine therapies). Therefore, there is a need for compounds that can treat breast cancer (wherein the cancer has one or more mutations in ESR1).

[0128] Some embodiments disclosed herein relate to the use of a combination of compounds described herein (e.g., compound (A) and compound (B), together with a pharmaceutically acceptable salt of any of the foregoing) for the manufacture of a medicament for treating breast cancer in a subject in need thereof, wherein the breast cancer has at least one point mutation (e.g., 1, 2, 3, 4, or more than 4 point mutations) within estrogen receptor 1 (ESR1) encoding estrogen receptor α (ERα). Other related embodiments herein relate to the use of a combination of compounds described herein for treating breast cancer in a subject in need thereof, the combination of compounds comprising an effective amount of compound (A) (including a pharmaceutically acceptable salt thereof), and an effective amount of compound (B) (or a pharmaceutically acceptable salt thereof) (together with a pharmaceutically acceptable salt thereof), wherein the breast cancer has at least one point mutation within estrogen receptor 1 (ESR1) encoding estrogen receptor α (ERα). Still other embodiments disclosed herein relate to a method of treating breast cancer in a subject in need thereof using a combination of the compounds described herein (e.g., Compound (A) and Compound (B), together with a pharmaceutically acceptable salt of any of the foregoing), wherein the breast cancer has at least one point mutation (e.g., 1, 2, 3, 4, or more than 4 point mutations) within estrogen receptor 1 (ESR1) encoding estrogen receptor alpha (ERα).

[0129] In some embodiments, the mutation may be in the ligand binding domain (LBD) of ESR1. In some embodiments, one or more mutations may be at an amino acid selected from the group consisting of: A593, S576, G557, R555, L549, A546, E542, L540, D538, Y537, L536, P535, V534, V533, N532, K531, C530, H524, E523, M522, R503, L497, K481, V478, R477, E471, S463, F461, S 432, G420, V418, D411, L466, S463, L453, G442, M437, M421, M396, V392, M388, E380, G344, S338, L370, S329, K303, A283, S282, E279, G274, K252, R233, P222, G160, N156, P147, G145, F97, N69, A65, A58, and S47. In some embodiments, the one or more mutations may be at an amino acid selected from the group consisting of: D538, Y537, L536, P535, V534, S463, V392, and E380. In some embodiments, the one or more mutations may be at an amino acid selected from the group consisting of: D538 and Y537.

[0130] In some embodiments, the one or more mutations may be selected from the group consisting of: K303R, D538G, Y537S, E380Q, Y537C, Y537N, A283V, A546D, A546T, A58T, A593D, A65V, C530L, D411H, E279V, E471D, E471V, E523Q, E542G, F461V, F97L, G145D, G160D, G274R, G344D, G420D, G442R, G557R, H524L, K252N, K481N, K531E, L370F, L453F, L466Q, L497R, L536H, L536P, L536Q, L536R, L540Q, L549P, M388L, M396V, M421V, M437I, M522I, N156T, N532K, N69K, P147Q, P222S, P535H, R233G, R477Q, R503W, R555H, S282C, S329Y, S338G, S432L, S463P, S47T, S576L, V392I, V418E, V478L, V533M, V534E, Y537D, and Y537H.

[0131] Some embodiments disclosed herein relate to the use of a combination of compounds for the manufacture of a medicament for treating breast cancer in a subject in need thereof, the combination of compounds comprising an effective amount of compound (A) (including a pharmaceutically acceptable salt thereof) and an effective amount of one or more compounds (B) (or a pharmaceutically acceptable salt thereof), wherein the breast cancer does not comprise at least one point mutation (e.g., a point mutation within estrogen receptor 1 (ESR1) encoding estrogen receptor alpha (ERα)). Other related embodiments herein relate to the use of a combination of compounds for the treatment of breast cancer in a subject in need thereof, the combination of compounds comprising an effective amount of compound (A) and an effective amount of one or more compounds (B), together with a pharmaceutically acceptable salt of any of the foregoing, wherein the breast cancer does not comprise a subject having at least one point mutation, such as a point mutation within estrogen receptor 1 (ESR1) encoding estrogen receptor alpha (ERα). Still other embodiments disclosed herein relate to a method of treating breast cancer in a subject in need thereof using a combination of compounds described herein (e.g., a combination of Compound (A) and Compound (B), or a pharmaceutically acceptable salt of any of the foregoing), wherein the breast cancer does not comprise at least one point mutation within estrogen receptor 1 (ESR1) encoding estrogen receptor alpha (ERα) (e.g., a point mutation within estrogen receptor 1 (ESR1) encoding estrogen receptor alpha (ERα)).

[0132] As provided herein, several studies have shown that the potential cause of resistance in ER-positive breast cancer is due to acquired mutations in ESR1 caused by endocrine therapy. In some embodiments, the subject has previously been treated with one or more selective ER regulators. For example, the subject has previously been treated with one or more selected from the following selected ER regulators: tamoxifen, raloxifene, ospemifene, bazedoxifene, toremifene and lasofoxifene or a pharmaceutically acceptable salt of any one of the foregoing.In some embodiments, the subject has been previously treated with one or more selective ER degraders, such as fulvestrant, (E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid (AZD9496), (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (elastostat, RAD1901), (E)-3-(4 -((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (Brindestran, ARN-810, GDC-0810), (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thien-3-yl)oxy)phenyl)acrylic acid (LSZ102), (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)ethyl)amino 1-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (lindodestran, G1T48), D-0502, SHR9549, ARV-471, 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol (gileaddestran, GDC-95 45), (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (SAR439859), N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (AZD9833), OP-1250, and LY3484356, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the subject has previously been treated with one or more aromatase inhibitors. The aromatase inhibitor can be a steroidal aromatase inhibitor or a non-steroidal aromatase inhibitor.For example, the one or more aromatase inhibitors can be selected from exemestane (steroidal aromatase inhibitor), testolactone (steroidal aromatase inhibitor); anastrozole (non-steroidal aromatase inhibitor), and letrozole (non-steroidal aromatase inhibitor), including pharmaceutically acceptable salts of any of the foregoing.

[0133] In some embodiments, breast cancer may be present in a subject, wherein the subject may be a woman. As women approach middle age, women may enter menopause. In some embodiments, the subject may be a woman before menopause. In other embodiments, the subject may be a woman in perimenopause. In yet other embodiments, the subject may be a woman in menopause. In yet other embodiments, the subject may be a woman after menopause. In other embodiments, breast cancer may be present in a subject, wherein the subject may be a man. The serum estradiol level of the subject may vary. In some embodiments, the serum estradiol level (E2) of the subject may be in the range of >15pg / mL to 350pg / mL. In other embodiments, the serum estradiol level (E2) of the subject may be ≤15pg / mL. In other embodiments, the serum estradiol level (E2) of the subject may be ≤10pg / mL.

[0134] The amount of the compound, salt, and / or composition required for treatment will vary not only with the specific compound or salt selected, but also with the route of administration, the nature and / or symptoms of the disease or condition being treated, and the age and condition of the patient, and will ultimately be determined by the attending physician or clinician. In the case of administering a pharmaceutically acceptable salt, the dosage can be calculated as the free base. It will be appreciated by those skilled in the art that in some cases, it may be necessary to administer the compounds disclosed herein in an amount exceeding or even far exceeding the dosage range described herein to effectively and actively treat particularly aggressive diseases or conditions.

[0135] As will be apparent to those skilled in the art, useful in vivo doses to be administered and specific modes of administration will vary depending on the age, body weight, severity of affliction and species of mammal being treated, the specific compounds employed and the specific uses for which these compounds are employed. Determination of effective dose levels (i.e., dose levels required to achieve the desired effect) can be achieved by those skilled in the art using conventional methods, such as human clinical trials, in vivo studies, and in vitro studies. For example, useful doses of compounds (A) and / or (B), or pharmaceutically acceptable salts of any of the foregoing, can be determined by comparing their in vitro activity and in vivo activity in animal models. Such comparisons can be made by comparison with established drugs (e.g., cisplatin and / or gemcitabine).

[0136] Dosage and time interval can be adjusted individually to provide a plasma level or minimum effective concentration (MEC) of the active part sufficient to maintain the regulatory effect. The MEC of each compound will be different, but can be estimated by in vivo and / or in vitro data. The dosage required to achieve MEC will depend on individual characteristics and route of administration. However, HPLC assay or bioassay can be used to determine plasma concentration. The dose time interval can also be determined using the MEC value. The composition should be administered using a regimen that maintains plasma levels above the MEC for 10% to 90% of the time, preferably between 30% and 90% of the time, and most preferably between 50% and 90% of the time. In the case of local administration or selective absorption, the local effective concentration of the drug may be independent of the plasma concentration.

[0137] It should be noted that the attending physician will understand how and when to terminate, interrupt or adjust the administration due to toxicity or organ dysfunction. Conversely, the attending physician will also know that if the clinical response is insufficient (excluding toxicity), the treatment will be adjusted to a higher level. The magnitude of the administered dose when managing the condition of interest will vary with the severity of the disease or condition being treated and the route of administration. The severity of the disease or condition can be assessed, for example, in part based on standard prognostic assessment methods. In addition, the dosage and possible dosing frequency will also vary according to the age, weight and response of the individual patient. Plans similar to the plans discussed above can be used in veterinary medicine.

[0138] The compounds, salts, and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound or a subgroup of compounds sharing certain chemical moieties can be established by determining in vitro toxicity to a cell line (e.g., a mammal and preferably a human cell line). The results of this study can generally predict toxicity in animals (e.g., mammals) or more specifically in humans. Alternatively, known methods can be used to determine the toxicity of a particular compound in an animal model (e.g., mouse, rat, rabbit, dog, or monkey). The efficacy of a particular compound can be established using several recognized methods (e.g., in vitro methods, animal models, or human clinical trials). When selecting a model to determine the efficacy, a person skilled in the art can be guided by the state of the art to select an appropriate model, dosage, route of administration, and / or regimen.

[0139] Example

[0140] Additional embodiments are disclosed in further detail in the following examples, which are not intended in any way to limit the scope of the claims.

[0141] Efficacy Study Procedure

[0142] The antitumor activity of compound (A) was evaluated using the MCF-7 xenograft model. 1.5×10 50 cells / mL in 200 μL of serum-free DMEM Matrigel mixture (1:1 ratio) were subcutaneously inoculated in the second right mammary fat pad of each mouse. 7 MCF-7 tumor cells were used for tumor development. In addition, estradiol benzoate injections (40 μg / 20 μL, twice a week) were delivered subcutaneously. When the average tumor size reached 204 mm 3 At 14:00, animals were randomly assigned to 2 groups (10 animals / group) and treatment was started. Compound (A) or vehicle control group was administered once daily by oral gavage and continued for 28 days. The study endpoints included daily body weight, clinical observations, and tumor volume. Figure 3 Compound (A) at a dose level of 80 mg / kg was shown to produce robust tumor growth inhibition (132.6%) and tumor regression as a single agent. Figure 3 In the graph, the top line is vehicle, and the bottom line is compound (A) (80 mg / kg qd×22 p.o). There were no adverse clinical observations in any dose group, and there was no significant effect on mean body weight.

[0143] The efficacy of compound (A) as a single agent was evaluated in the ZR-75-1 tamoxifen-resistant tumor model. Tamoxifen-resistant ZR-75-1 tumor cells (ZR-75-1R) were maintained in vitro as monolayers in RPMI1640 medium supplemented with 10% fetal bovine serum and 10 μM tamoxifen in an incubator at 37°C in a 5% CO2 atmosphere. 1×10 cells were then subcutaneously inoculated in 100 μL of serum-free RPMI-1640 Matrigel mixture (1:1 ratio) on the right flank of each mouse. 7 ZR-75-1R tumor cells were used for tumor development. In addition, estradiol benzoate injection (40 μg / 20 μL, twice a week) was delivered subcutaneously. When the average tumor size reached 191 mm 3 The mice were then randomly assigned to three groups and treatment was initiated. Tamoxifen was administered at 100 mg / kg for 5 days per week for three weeks, and compound (A) was orally administered at 80 mg / kg daily for 28 days. The study endpoints included daily body weight, clinical observations, and tumor volume. Figure 4 In the figure, the top line is Tamoxifen (100 mg / kg), the middle line is vehicle, and the bottom line is Compound (A) (80 mg / kg). Figure 4As shown, after 28 days of treatment, tamoxifen caused -47.9% tumor growth inhibition, and it was shown that this is a tamoxifen-resistant breast cancer model. 80 mg / kg of compound (A) produced a strong anti-tumor activity with 69.9% tumor growth inhibition (TGI). During the treatment period, no other major clinical abnormalities were observed, and animal body loss was controlled by giving animals a dosing holiday.

[0144] The activity of compound (A) was evaluated in mice bearing human HCC1428 breast cancer xenograft tumors. HCC1428 tumor cells (1×10 40 50 50 60 70 90 10 0 4 ... 7 ) for tumor development, the mice were subcutaneously implanted with 17β-estradiol tablets (0.18 mg, 90-day release) two days before cell implantation. When the average tumor size reached approximately 185 mm 3 After that, treatment was started on day 21 after tumor inoculation. Animals were divided into two groups using excel-based randomization software based on tumor volume. Each group consisted of 10 tumor-bearing mice. 80 mg / kg of vehicle control group or compound (A) was administered orally by gastric tube to mice once daily for 28 days. Figure 5 In the figure, the top line is the vehicle, and the bottom line is compound (A). Figure 5 As shown, treatment with compound (A) as a single agent produced significant inhibition of HCC1428 tumor growth relative to the vehicle group, with 96.2% tumor growth inhibition (TGI) observed at 80 mg / kg of compound (A). There were no adverse clinical observations, and no significant weight loss was observed in animals treated with compound (A).

[0145] The antitumor activity of compound (A) in combination with a CDK4 / 6 inhibitor (palbociclib) was evaluated in the MCF-7 xenograft model. MCF-7 tumor cells (1.5×10 7 ) for tumor development. In addition, estradiol benzoate injections (40 μg / 20 μL, twice a week) were delivered subcutaneously. When the average tumor size reached 202 mm 3At 14:00, mice were randomly assigned to 5 groups (10 animals / group) and treatment was started. Animals were dosed with the following: vehicle, 80 / 60 mg / kg compound (A) alone, 50 mg / kg palbociclib alone, 80 mg / kg compound (A) in combination with 50 mg / kg palbociclib (via a sequential dosing schedule (alternating every two weeks)), or 80 / 60 mg / kg compound (A) in combination with 50 mg / kg palbociclib. The treatment cycle was 28 days. Figure 6 In the figure, the top line (represented by a circle) is the vehicle. Figure 6 As shown, 80 / 60 mg / kg of compound (A) or 50 mg / kg of palbociclib alone resulted in TGIs of approximately 116% and 119%, respectively. Sequential treatment with compound (A) and palbociclib resulted in a TGI of 127%; therefore, this data shows better anti-tumor activity compared to monotherapy with compound (A) or palbociclib, respectively. Co-treatment of 80 / 60 mg / kg of compound (A) with 50 mg / kg of palbociclib also resulted in greater anti-tumor activity, with a TGI of 126.2%. In addition, the combination of compound (A) and palbociclib resulted in approximately 55% tumor regression. By comparison, treatment with compound (A) or palbociclib alone only resulted in 32.7% and 39.1% tumor regression, respectively. Overall, compound (A) combined with palbociclib significantly improved efficacy.

[0146] The antitumor activity of compound (A) in combination with a CDK4 / 6 inhibitor (low-dose palbociclib) was evaluated in an MCF-7 xenograft model. 1.5×10 50-well cells in 200 μL of serum-free DMEM Matrigel mixture (1:1 ratio) were subcutaneously inoculated in the second right mammary fat pad of each mouse. 7 MCF-7 cells were used for tumor development. In addition, estradiol benzoate injections (40 μg / 20 μL, twice a week) were delivered subcutaneously. When the average tumor size reached 203 mm 3 Treatment was started at 14:00 pm. Mice were randomly assigned to 4 groups (8 mice per group) and treated with vehicle control group, 60 mg / kg compound (A) alone, 25 mg / kg palbociclib alone, and 60 mg / kg compound (A) in combination with 25 mg / kg palbociclib. Study endpoints included daily body weight, clinical observations, and tumor volume. Figure 7As shown, 60 mg / kg of compound (A) alone (second bar from the bottom line), and 25 mg / kg of palbociclib alone (second bar from the top line, represented by triangles) caused 48.6% TGI and 14.2% TGI, respectively, and 60 mg / kg of compound (A) combined with 25 mg / kg of palbociclib (bottom line, represented by triangles) caused 82.7% TGI. Therefore, the combination of compound (A) and palbociclib significantly improved efficacy. All animals tolerated the treatment well.

[0147] The anti-tumor activity of compound (A) in combination with palbociclib was further evaluated in a palbociclib-resistant breast cancer PDX model (CTG-1207). Mice were subcutaneously inoculated with palbociclib-resistant breast cancer cells in a DMEM Matrigel mixture without serum (1:1 ratio) for tumor development. Once the tumor size reached approximately 200 mm 3 Mice were randomly assigned to 4 groups (8 mice per group) and treated with vehicle control group, 80 mg / kg compound (A) alone, 50 mg / kg palbociclib alone, and 80 mg / kg compound (A) in combination with 50 mg / kg palbociclib. Study endpoints included daily body weight, clinical observations, and tumor volume. Fig. 10A As shown, 80 mg / kg of compound (A) alone (second from the bottom line, represented by triangles) reduced tumor growth, while 50 mg / kg of palbociclib alone (second from the top line, represented by diamonds) showed a lower TGI. 80 mg / kg of compound (A) combined with 50 mg / kg of palbociclib (bottom line, represented by triangles) caused enhanced TGI in the palbociclib-resistant PDX breast cancer model. Therefore, the combination of compound (A) and palbociclib significantly improved efficacy. All animals tolerated the treatment well, as shown in Figure 2. Fig. 10B Proven.

[0148] Study 1 - Part 1

[0149] The HER2+ JIMT-1 breast cancer cell line was used for tumor xenograft inoculation and subsequent treatment. The JIMT-1 breast cancer cell line has been described in the literature as being relatively resistant to HER2-targeted therapy (the JIMT-1 cell line was established from a pleural metastasis of a 62-year-old breast cancer patient who was clinically resistant to trastuzumab (see Tanner et al., Mol Cancer Ther (2004) 3(12):1585–1592)), which includes weekly administration of trastuzumab. To test whether compound (A) can improve the anti-tumor effect of HER2-targeted therapy, 95% viable tumor cells (5×10 6) in 100 μL of DMEM Matrigel mixture (1:1 ratio) for tumor development. When the average tumor size reached 204 mm 3 The treatment was started at 4 pm. The mice were then randomly assigned into 5 groups, and the treatment was administered to the tumor-bearing mice according to the study design in Table 2.

[0150] Table 2

[0151]

[0152] Treatment with Compound (A) alone (60 mg / kg), or trastuzumab alone (10 mg / kg), produced tumor growth inhibition (TGI) values ​​of 68% and 59%, respectively, on day 29, compared to the respective vehicle controls (whether administered po or ip, respectively). Figure 8 In the figure, the top line (represented by circles) is vehicle A, and the third line from the bottom line (represented by circles) is trastuzumab alone (10 mg / kg). On day 29, the combination of compound (A) and trastuzumab caused a 94% TGI compared to the vehicle control group of either. The tumor growth curves are summarized in Figure 8 The data were summarized in Table 3. These data show that the combination of Compound (A) and trastuzumab has a superior anti-tumor effect compared to either treatment as a monotherapy. All treatments were well tolerated, including Compound (A) alone, trastuzumab alone, or the combination of Compound (A) and trastuzumab. Table 3 summarizes Figure 8 Results of the experiments described in . a TGI = tumor growth inhibition, calculated as TGI = (1-(T d –T0) / (C d –C0))×100%,T d and C d is the mean tumor volume of treated and control animals, and T0 and C0 are the mean tumor volumes of treated and control animals at the start of the experiment; b Calculations performed with the Dunnett's T3 test are relative to vehicle control values.

[0153] Table 3

[0154]

[0155]

[0156] Study 1 - Part 2

[0157] Next, mice in the two vehicle groups were randomized on day 29 for treatment with vehicle, compound (A) alone, trastuzumab alone, or a combination of compound (A) and trastuzumab according to Table 4. At this time, tumors had reached approximately 1000 mm 3 , and therefore, treatment of these mice occurred at a high initial tumor burden.

[0158] Table 4

[0159]

[0160] Study 2

[0161] On day 14 of the second part of the experiment, treatment with compound (A) alone (60 mg / kg), or trastuzumab alone (10 mg / kg) produced TGI values ​​of 68.2% and 68.0%, respectively, compared to the vehicle control group. The combination of compound (A) and trastuzumab produced a TGI of 97% ( Fig. 9 and Table 5). Table 5 summarizes Fig. 9 Results of the experiments described (tumor growth inhibition). a TGI = tumor growth inhibition at day 14. On day 35 of the second part of the experiment, the combination of compound (A) and trastuzumab had produced 30.6% tumor regression ( Fig. 9 and Table 6). Table 6 summarizes Fig. 9 Results of the experiments described (tumor regression). a Tumor regression = (1-(T d / T0))×100%.

[0162] Table 5

[0163]

[0164]

[0165] Table 6

[0166] treat <![CDATA[Tumor regression on day 35 a (%)]]> Compound (A) - Trastuzumab - Compound (A) + trastuzumab 30.6

[0167] These data show that when mice were treated at high initial tumor burden, the combination of Compound (A) and trastuzumab showed significantly better anti-tumor effects than either as a monotherapy. In addition, all treatment regimens were well tolerated.

[0168] In addition, although the foregoing has been described in some detail by way of illustration and example for the purpose of clarity and understanding, those skilled in the art will appreciate that various modifications may be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are only for illustration and are not intended to limit the scope of the present disclosure, but also cover all modifications and alternatives that come with the true scope and spirit of the present disclosure.

Claims

1. Use of a combination of compounds for treating a disease or condition, wherein the combination comprises an effective amount of compound (A) and an effective amount of compound (B), or a pharmaceutically acceptable salt of any of the foregoing, in: Compound (A) is or a pharmaceutically acceptable salt thereof; and Compound (B) is selected from the group consisting of a CDK4 / 6 inhibitor, a HER-2 small molecule inhibitor, a HER-2 antibody, a HER-2 antibody drug conjugate, and a HER2 bispecific antibody, or a pharmaceutically acceptable salt of any one of the foregoing; wherein the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, trilaciclib (G1T28), lerociclib (G1T38), SHR6390, FCN-437, AMG 925, BPI-1178, BPI-16350, Birociclib, BEBT-209, TY-302, TQB-3616, HS-10342, PF-06842874, CS-3002, and MM-D37K, or a pharmaceutically acceptable salt of any one of the foregoing; wherein the HER-2 antibody is selected from the group consisting of trastuzumab, trastuzumab-dkst, pertuzumab and ZW25, or a pharmaceutically acceptable salt of any one of the foregoing; wherein the HER-2 antibody drug conjugate is selected from the group consisting of: Ado-trastuzumab emtansine (T-DM1), ARX788, ALT-P7, DS8201a, MEDI4276, MM302, PF-06804103, SYD985, XMT-1522, ZW49, MRG002, GQ1001, A166, RC48-ADC, BDC-1001, and FS-1502, or a pharmaceutically acceptable salt of any one of the foregoing; wherein the HER2 bispecific antibody is selected from the group consisting of margetuximab, ertumaxomab, HER2Bi-aATC, MM-111, MCLA-128, BTRC4017A, GBR-1302, and PRS-343, or a pharmaceutically acceptable salt of any one of the foregoing; and The HER-2 small molecule inhibitor is selected from the group consisting of tucatinib, lapatinib, and neratinib, or a pharmaceutically acceptable salt of any one of the foregoing.

2. The use according to claim 1, wherein compound (B) is a CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof.

3. The use according to claim 2, wherein the CDK4 / 6 inhibitor is palbociclib.

4. The use according to claim 2, wherein the CDK4 / 6 inhibitor is abemaciclib.

5. The use according to claim 2, wherein the CDK4 / 6 inhibitor is ribociclib.

6. The use according to claim 2, wherein the CDK4 / 6 inhibitor is tricasisib.

7. The use according to claim 1, wherein compound (B) is a HER-2 antibody, or a pharmaceutically acceptable salt thereof.

8. The use according to claim 7, wherein the HER-2 antibody is trastuzumab.

9. The use according to claim 1, wherein compound (B) is a HER-2 antibody-drug conjugate, or a pharmaceutically acceptable salt thereof.

10. The use according to claim 1, wherein compound (B) is a HER2 bispecific antibody, or a pharmaceutically acceptable salt thereof.

11. The use according to any one of claims 1 to 10, wherein the disease or condition is a cancer selected from the group consisting of lung cancer, gastric cancer, esophagogastric junction adenocarcinoma, and breast cancer.

12. The use according to claim 11, wherein the breast cancer is selected from the group consisting of triple-negative breast cancer, ER+ breast cancer, HER2-positive (HER2+) breast cancer, and low HER2 breast cancer.

13. Use of an effective amount of compound (A), or a pharmaceutically acceptable salt of any of the foregoing, for preparing a medicament for treating ER+ breast cancer, wherein compound (A) is or a pharmaceutically acceptable salt thereof.

14. The use according to any one of claims 11 to 13, wherein the breast cancer does not contain any point mutation ER mutation.

15. The method of any one of claims 11 to 13, wherein the breast cancer has at least one point mutation in estrogen receptor 1 (ESR1) encoding estrogen receptor alpha (ERα), wherein the mutation is selected from the group consisting of: K303R, D538G, Y537S, E380Q, Y537C, Y537N, A283V, A546D, A546T, A58T, A593D, A65V, C530L, D411H, E279V, E471D, E471V, E523Q, E542G, F461V, F97L, G145D, G160D, G274R, G344D, G420D, G442R, G557R, H5264, 4L, K252N, K481N, K531E, L370F, L453F, L466Q, L497R, L536H, L536P, L536Q, L536R, L540Q, L549P, M388L, M396V, M421V, M437I, M522I, N156T, N532K, N69K , P147Q, P222S, P535H, R233G, R477Q, R503W, R555H, S282C, S329Y, S338G, S432L, S463P, S47T, S576L, V392I, V418E, V478L, V533M, V534E, Y537D, and Y537H.

16. The use according to any one of claims 11 to 13, wherein the cancer is ER-positive breast cancer.

17. The use according to any one of claims 11 to 13, wherein the cancer is ER-positive / HER2-negative breast cancer.

18. Use according to any one of claims 11 to 13, wherein the cancer is localized breast cancer.

19. The use according to any one of claims 11 to 13, wherein the cancer is metastatic breast cancer.

20. The use according to any one of claims 11 to 13, wherein the cancer is recurrent breast cancer.

21. The use according to any one of claims 11 to 20, wherein the cancer is breast cancer that has been previously treated with endocrine therapy.

22. The use according to claim 21, wherein the treatment uses a selective ER modulator (SERM).

23. The use according to claim 22, wherein the selective ER modulator is selected from the group consisting of tamoxifen, raloxifene, ospemifene, bazedoxifene, toremifene, and lasofoxifene, or a pharmaceutically acceptable salt of any one of the foregoing.

24. The use according to claim 21, wherein the treatment uses a selective ER degrader (SERD).

25. The use according to claim 24, wherein the selective ER degrader is selected from the group consisting of: fulvestrant, (E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid (AZD9496), (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (elacestrant, RAD1901), (E)- 3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (brilanestrant, ARN-810, GDC-0810), (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (LSZ102), (E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)ethyl 1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol (gileadestrant destrant), GDC-9545), (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (SAR439859), N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (AZD9833), OP-1250, and LY3484356, or a pharmaceutically acceptable salt of any of the foregoing.

26. The use according to claim 21, wherein the treatment is with an aromatase inhibitor.

27. The use according to claim 26, wherein the aromatase inhibitor is a steroidal aromatase inhibitor.

28. The use according to claim 27, wherein the steroidal aromatase inhibitor is selected from the group consisting of exemestane and testolactone, or a pharmaceutically acceptable salt of any of the foregoing.

29. The use according to claim 26, wherein the aromatase inhibitor is a non-steroidal aromatase inhibitor.

30. The use according to claim 29, wherein the non-steroidal aromatase inhibitor is selected from the group consisting of anastazole and letrazole, or a pharmaceutically acceptable salt of any of the foregoing.

31. The use according to any one of claims 11 to 20, wherein the breast cancer has not been previously treated.

32. The use according to any one of claims 11 to 31, wherein the breast cancer is present in a female.

33. The use according to claim 32, wherein the female is a premenopausal female.

34. The use according to claim 32, wherein the female is a perimenopausal female.

35. The use according to claim 32, wherein the female is a menopausal female.

36. The use according to claim 32, wherein the breast cancer is present in a postmenopausal woman.

37. The use according to any one of claims 11 to 31, wherein the breast cancer is present in a male.

38. Use according to any one of claims 11 to 37, wherein the breast cancer is present in a subject having serum estradiol levels in the range of >15 pg / mL to 350 pg / mL.

39. The use of any one of claims 11 to 37, wherein the breast cancer is present in a subject having a serum estradiol level of ≤ 15 pg / mL.

40. The use of any one of claims 11 to 37, wherein the breast cancer is present in a subject having a serum estradiol level of ≤ 10 pg / mL.

41. A method for treating cancer, comprising administering to a subject an effective amount of compound (A) and an effective amount of compound (B), or a pharmaceutically acceptable salt of any of the foregoing, in: Compound (A) is or a pharmaceutically acceptable salt thereof; and Compound (B) is selected from the group consisting of a CDK4 / 6 inhibitor, a HER-2 small molecule inhibitor, a HER-2 antibody, a HER-2 antibody drug conjugate, and a HER2 bispecific antibody, or a pharmaceutically acceptable salt of any one of the foregoing; wherein the CDK4 / 6 inhibitor is selected from the group consisting of: palbociclib, abemaciclib, ribociclib, triclasiclib (G1T28), lerociclib (G1T38), SHR6390, FCN-437, AMG 925, BPI-1178, BPI-16350, bilociclib, BEBT-209, TY-302, TQB-3616, HS-10342, PF-06842874, CS-3002, and MM-D37K, or a pharmaceutically acceptable salt of any one of the foregoing; wherein the HER-2 antibody is selected from the group consisting of trastuzumab, trastuzumab-dkst, pertuzumab, and ZW25, or a pharmaceutically acceptable salt of any one of the foregoing; wherein the HER-2 antibody drug conjugate is selected from the group consisting of: ado-trastuzumab emtacin (T-DM1), ARX788, ALT-P7, DS8201a, MEDI4276, MM302, PF-06804103, SYD985, XMT-1522, ZW49, MRG002, GQ1001, A166, RC48-ADC, BDC-1001, and FS-1502, or a pharmaceutically acceptable salt of any one of the foregoing; wherein the HER2 bispecific antibody is selected from the group consisting of magituximab, ertuinomab, HER2Bi-aATC, MM-111, MCLA-128, BTRC4017A, GBR-1302, and PRS-343, or a pharmaceutically acceptable salt of any one of the foregoing; and The HER-2 small molecule inhibitor is selected from the group consisting of tacatinib, lapatinib, and neratinib, or a pharmaceutically acceptable salt of any one of the foregoing.

42. The method of claim 41, wherein compound (B) is a CDK4 / 6 inhibitor, or a pharmaceutically acceptable salt thereof.

43. The method of claim 42, wherein the CDK4 / 6 inhibitor is palbociclib.

44. The method of claim 42, wherein the CDK4 / 6 inhibitor is abemaciclib.

45. The method of claim 42, wherein the CDK4 / 6 inhibitor is ribociclib.

46. ​​The method of claim 42, wherein the CDK4 / 6 inhibitor is tricasisib.

47. The method of claim 42, wherein compound (B) is a HER-2 antibody, or a pharmaceutically acceptable salt thereof.

48. The method of claim 42, wherein the HER-2 antibody is trastuzumab.

49. The method of claim 42, wherein compound (B) is a HER-2 antibody drug conjugate, or a pharmaceutically acceptable salt thereof.

50. The method of claim 42, wherein compound (B) is a HER-2 antibody drug conjugate, or a pharmaceutically acceptable salt thereof, wherein the HER-2 antibody is trastuzumab.

51. The method of claim 42, wherein compound (B) is fam-trastuzumab-deruxtecan-nxki (DS8201a).

52. The method of claim 42, wherein compound (B) is a HER2 bispecific antibody, or a pharmaceutically acceptable salt thereof.

53. The method of any one of claims 41 to 52, wherein the cancer is selected from the group consisting of lung cancer, gastric cancer, esophagogastric junction adenocarcinoma, and breast cancer.

54. The method of claim 53, wherein the cancer is breast cancer selected from the group consisting of triple-negative breast cancer, ER+ breast cancer, HER2-positive (HER2+) breast cancer, and low HER2 breast cancer.

55. A method for treating triple-negative breast cancer, the method comprising administering to a subject an effective amount of compound (A) and an effective amount of compound (B), or a pharmaceutically acceptable salt of any of the foregoing, in: Compound (A) is or a pharmaceutically acceptable salt thereof; and Compound (B) is dextran trastuzumab (DS8201a).

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