Use of Combination Therapies to Treat Cancer

Abstract

ZN-C3, also known as azenosertib, for the treatment of cancer Disclosed herein is a combination therapy comprising a WEE1 inhibitor compound A and either a CDK4 / 6 inhibitor (such as palbociclib) or a HER-2 inhibitor (such as trastuzumab). In particular, the combination of the present invention is intended for the treatment of breast cancer, such as triple-negative breast cancer, ER+ breast cancer, HER2+ breast cancer, and HERZ-low breast cancer.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) For example, any and all applications in which a claim of foreign or domestic priority is identified in an Application Data Sheet or claim filed with this application, including U.S. Provisional Application No. 63 / 265,441, filed December 15, 2021, which is incorporated by reference in its entirety, are incorporated by reference herein under 37 CFR 1.57 and Rules 4.18 and 20.6.

[0002] FIELD OF THEINVENTION This application relates to the fields of chemistry, biochemistry, and medicine. More specifically, disclosed herein are combination therapies and methods of treating diseases and / or conditions using the combination therapies described herein. [Background technology]

[0003] Cancer is a group of diseases involving abnormal cell growth that can invade or spread to other parts of the body. Today's cancer treatments include surgery, hormone therapy, radiation, chemotherapy, immunotherapy, targeted therapy, and combinations thereof. Survival rates vary by type of cancer and by the stage at which the cancer is diagnosed. In 2019, approximately 1.8 million people were diagnosed with cancer in the United States, and an estimated 606,880 people died from cancer. Thus, there remains a need for effective cancer treatments. Summary of the Invention [Means for solving the problem]

[0004] Some embodiments described herein provide, inter alia, a combination therapy comprising a WEE1 inhibitor (e.g., Compound A) and a CDK4 / 6 inhibitor or a HER-2 inhibitor for use in 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.

[0005] 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 pharma- ceutically acceptable salt of any of the foregoing; Compound (A) is

[0006] [ka] or a pharma- ceutically acceptable salt thereof, wherein compound (B) is selected from the group consisting of CDK4 / 6 inhibitors, HER-2 small molecule inhibitors, HER-2 antibodies, HER-2 antibody-drug conjugates, and HER-2 antibodies. In another aspect, the present invention provides a method for the treatment of cancer, comprising administering to said patient a therapeutically effective amount of at least one bispecific antibody, said method ...

[0007] 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 pharma- ceutically acceptable salt of any of the foregoing; Compound (A) is

[0008] [ka] or a pharma- ceutically acceptable salt thereof, wherein 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 pharma- ceutically acceptable salt of any of the foregoing.

[0009] In some embodiments, compound (B) is a HER-2 small molecule inhibitor or a pharma- ceutically 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 pharma- ceutically acceptable salt thereof. In some embodiments, compound (B) is a HER-2 bispecific antibody or a pharma- ceutically acceptable salt thereof.

[0010] 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 pharma- ceutically acceptable salt of any of the foregoing; Compound (A) is

[0011] [ka] or a pharma- ceutically acceptable salt thereof, and compound (B) is a CDK4 / 6 inhibitor or a pharma- ceutically acceptable salt thereof.

[0012] In one aspect, some embodiments provide a method of treating triple-negative breast cancer, comprising administering to a subject an effective amount of Compound (A) and an effective amount of Compound (B), or a pharma- ceutical acceptable salt of any of the foregoing; Compound (A) is

[0013] [ka] or a pharma- ceutically acceptable salt thereof; The method includes the step of: providing compound (B) is fam-trastuzumab-deruxtecan-nxki (DS8201a).

[0014] Some embodiments described herein relate to a combination of compounds that may include an effective amount of compound (A), or a pharma- ceutically acceptable salt thereof, and an effective amount of compound (B), or a pharma- ceutically acceptable salt of any of the foregoing.

[0015] Some embodiments described herein relate to the use of a combination of compounds for treating a disease or condition, the combination comprising an effective amount of compound (A), or a pharma- ceutically acceptable salt thereof, and an effective amount of compound (B), or a pharma- ceutically acceptable salt of any of the foregoing. Other embodiments described herein relate to the use of a combination of compounds in the manufacture of a medicament for treating a disease or condition, the combination comprising an effective amount of compound (A), or a pharma- ceutically acceptable salt thereof, and an effective amount of compound (B), or a pharma- ceutically acceptable salt of any of the foregoing.

[0016] In some embodiments, the disease or condition may be a cancer as described herein.

[0017] In one aspect, some embodiments relate to the use of a combination of compounds for treating a disease or condition, the combination comprising an effective amount of Compound (A) and an effective amount of Compound (B), or a pharma- ceutically acceptable salt of any of the foregoing; Compound (A) is

[0018] [ka] or a pharma- ceutically acceptable salt thereof; 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 pharma- ceutically acceptable salt of any of the foregoing; the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, trilaciclib (G1T28), relociclib (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 pharma- ceutically acceptable salt of any of the foregoing; HER-2 antibodies include trastuzumab, trastuzumab-dkst, pertuzumab, and ZW25, or a pharma- ceutically acceptable salt of any of the foregoing; the HER-2 antibody-drug conjugate is selected from the group consisting of Ado-trastuzumab emtansine (T-DM1), ARX788, ALT-P7, Enhertu® (fam-trastuzumab-deruxtecan-nxki, DS8201a), MEDI4276, MM302, PF-06804103, SYD985, XMT-1522, ZW49, MRG002, GQ1001, A166, RC48-ADC, BDC-1001, and FS-1502, or a pharma- ceutically acceptable salt of any of the foregoing; HER2 bispecific antibodies include margetuximab, ertumaxomab, The present invention provides a method for treating cancer, comprising administering to a patient a therapeutically effective amount of a medicament for cancer treatment, the method comprising administering to the ...

[0019] 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 by reference in its entirety.

[0020] In some embodiments, compound (B) is a HER-2 small molecule inhibitor or a pharma- ceutically acceptable salt thereof. In some embodiments, compound (B) is a HER-2 small molecule inhibitor selected from tucatinib, lapatinib, and neratinib, or a pharma- ceutically acceptable salt of any of the foregoing. In some embodiments, compound (B) is tucatinib or a pharma- ceutically acceptable salt thereof. In some embodiments, compound (B) is lapatinib or a pharma- ceutically acceptable salt thereof. In some embodiments, compound (B) is neratinib or a pharma- ceutically acceptable salt thereof. In some embodiments, the HER-2 small molecule inhibitor is administered in combination with a HER-2 antibody (e.g., trastuzumab).

[0021] In some embodiments, compound (B) is a CDK4 / 6 inhibitor or a pharma- ceutically acceptable salt thereof. In some embodiments, compound (B) is a CDK4 / 6 inhibitor selected from Figure 1 or a pharma- ceutically acceptable salt thereof.

[0022] In some embodiments, the CDK4 / 6 inhibitor is palbociclib.

[0023] In some embodiments, the CDK4 / 6 inhibitor is abemaciclib.

[0024] In some embodiments, the CDK4 / 6 inhibitor is ribociclib.

[0025] In some embodiments, the CDK4 / 6 inhibitor is trilaciclib.

[0026] In some embodiments, compound (B) is a HER-2 antibody or a pharma- ceutically acceptable salt thereof.

[0027] In some embodiments, the HER-2 antibody is trastuzumab.

[0028] In some embodiments, compound (B) is a HER-2 antibody-drug conjugate or a pharma- ceutically acceptable salt thereof. In some embodiments, compound (B) is a trastuzumab antibody-drug conjugate or a pharma- ceutically acceptable salt thereof. In one embodiment, compound (B) is fam-trastuzumab-deruxtecan-nxki (DS8201a).

[0029] In some embodiments, compound (B) is a HER2 bispecific antibody or a pharma- ceutically acceptable salt thereof.

[0030] In some embodiments, compound (B) is selected from FIG.

[0031] In some embodiments, compound (B) is a HER-2 small molecule inhibitor or a pharma- ceutically acceptable salt thereof. In some embodiments, compound (B) is a HER-2 small molecule inhibitor selected from tucatinib, lapatinib, and neratinib, or a pharma- ceutically 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 pharma- ceutically acceptable salt thereof.

[0032] In some embodiments, the disease or condition is breast cancer.

[0033] 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, the breast cancer is In some embodiments, the breast cancer is ER positive (ER+) breast cancer. In some embodiments, the breast cancer is ER positive, HER2 negative (ER+ / HER2-) breast cancer. In some embodiments, the breast cancer is triple negative breast cancer (TNBC).

[0034] In some embodiments, the breast cancer is classified by HER2 status. In some embodiments, the breast cancer is a HER2 positive (HER2+) breast cancer. In some embodiments, the breast cancer is a HER2 low breast cancer. In some embodiments, the breast cancer is classified as a HER2 negative (HER2-) breast cancer.

[0035] In some embodiments, the disease or condition is lung cancer, gastric cancer, or gastroesophageal junction adenocarcinoma.

[0036] In one aspect, some embodiments provide for the use of an effective amount of Compound (A), or a pharma- ceutically acceptable salt of any of the foregoing, in the preparation or manufacture of a medicament for treating ER+ breast cancer, wherein Compound (A) is:

[0037] [ka] or a pharma- ceutically acceptable salt thereof.

[0038] In some embodiments, the breast cancer does not contain any ER point mutations.

[0039] In some embodiments, the breast cancer is characterized by a gene encoding estrogen receptor 1 (ESR1), which encodes estrogen receptor alpha (ERα). ), and the mutations are 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.

[0040] In some embodiments, the breast cancer is ER-positive breast cancer.

[0041] In some embodiments, the breast cancer is ER positive / HER2 negative breast cancer.

[0042] In some embodiments, the breast cancer is localized breast cancer.

[0043] In some embodiments, the breast cancer is metastatic breast cancer.

[0044] In some embodiments, the breast cancer is recurrent breast cancer.

[0045] In some embodiments, the breast cancer has been previously treated with endocrine therapy. In some embodiments, the treatment was with a selective ER modulator (SERM). In some embodiments, 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 of the foregoing.

[0046] In some embodiments, the previous treatment is a selective ER degrader. In some embodiments, the selective ER degrader is 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-phenyl But-1-en-1-yl)pyridin-2-yl)oxy)ethyl)amino)but-2-enamide (H3B-6545), (E)-3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (rintodestrant, G1T48), D-0502, SHR9549, ARV-47 1,3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropane) (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]a Nurene-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 pharma- ceutically acceptable salt of any of the foregoing.

[0047] In some embodiments, the previous treatment was with an aromatase inhibitor, hi some embodiments, the aromatase inhibitor is a steroidal aromatase inhibitor.

[0048] In some embodiments, the steroidal aromatase inhibitor is selected from the group consisting of exemestane and testolactone, or a pharma- ceutically acceptable salt of any of the foregoing.

[0049] In some embodiments, the aromatase inhibitor is a non-steroidal aromatase inhibitor. In some embodiments, the non-steroidal aromatase inhibitor is anastazole and letrazole, or any of the pharmaceutical agents listed above. The salt is selected from the group consisting of salts acceptable to the

[0050] In some embodiments, the breast cancer has not been previously treated.

[0051] In some embodiments, the breast cancer is in a woman. In some embodiments, the woman is a premenopausal woman. In some embodiments, the woman is a perimenopausal woman. In some embodiments, the woman is a menopausal woman. In some embodiments, the breast cancer is in a postmenopausal woman.

[0052] In some embodiments, the breast cancer is in a man.

[0053] In some embodiments, the breast cancer is present in a human subject. In some embodiments, the breast cancer is present in a subject with a serum estradiol level in the range of greater than 15 pg / mL to 350 pg / mL.

[0054] In some embodiments, the breast cancer is greater than 15 pg / mL to 300 pg / mL, greater than 20 pg / mL to 350 pg / mL, greater than 25 pg / mL to 350 pg / mL, greater than 30 pg / mL to 350 pg / mL, greater than 35 pg / mL to 350 pg / mL, greater than 40 pg / mL to 350 pg / mL, greater than 45 pg / mL to 350 pg / mL, greater than 50 pg / mL to 350 pg / mL, greater than 55 pg / mL to 350 pg / mL, greater than 60 pg / mL to 350 pg / mL, greater than 65 pg / mL to 350 pg / mL, greater than 70 pg / mL to 350 pg / mL, present in a subject with serum estradiol levels in the range of greater than 75pg / mL to 350pg / mL, greater than 80pg / mL to 350pg / mL, greater than 85pg / mL to 350pg / mL, greater than 90pg / mL to 350pg / mL, greater than 95pg / mL to 350pg / mL, greater than 100pg / mL to 350pg / mL, greater than 125pg / mL to 350pg / mL, greater than 150pg / mL to 350pg / mL, greater than 200pg / mL to 350pg / mL, greater than 250pg / mL to 350pg / mL, or greater than 300pg / mL to 350pg / mL.

[0055] In some embodiments, breast cancer is present in a subject with a serum estradiol level of 15 pg / mL or less. In some embodiments, breast cancer is present in a subject with a serum estradiol level of 10 pg / mL or less.

[0056] In some embodiments, breast cancer is present in a subject with a serum estradiol level of 20 pg / mL or less, 19 pg / mL or less, 18 pg / mL or less, 17 pg / mL or less, 16 pg / mL or less, 15 pg / mL or less, 14 pg / mL or less, 13 pg / mL or less, 12 pg / mL or less, 11 pg / mL or less, or 10 pg / mL or less.

[0057] 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 pharma- ceutically acceptable salt of any of the foregoing; Compound (A) is

[0058] [ka] or a pharma- ceutically acceptable salt thereof; 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 pharma- ceutically acceptable salt of any of the foregoing; the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, trilaciclib (G1T28), relociclib (G1T38), SHR6390, FCN-437, AMG 925, BPI-1178, BPI-16350, vilociclib, BEBT-209, TY-302, TQB-3616, HS-10342, PF-06842874, CS-3002, and MM-D37K, or a pharma- ceutically acceptable salt of any of the foregoing; the HER-2 antibody is selected from the group consisting of trastuzumab, trastuzumab-dkst, pertuzumab, and ZW25, or a pharma- ceutically acceptable salt of any of the foregoing; 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 pharma- ceutically acceptable salt of any of the foregoing; The method provides a method in which 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 pharma- ceutically acceptable salt of any of the foregoing.

[0059] In some embodiments, compound (B) is a HER-2 small molecule inhibitor or a pharma- ceutically acceptable salt thereof. In some embodiments, compound (B) is a HER-2 small molecule inhibitor selected from tucatinib, lapatinib, and neratinib, or a pharma- ceutically acceptable salt of any of the foregoing. In some embodiments, the HER-2 small molecule inhibitor is in combination with a HER-2 antibody (e.g., trastuzumab) or a pharma- ceutically acceptable salt thereof. It is administered. [Brief description of the drawings]

[0060] [Figure 1] Examples of CDK4 / 6 inhibitors are provided. [Diagram 2] Examples of HER-2 antibodies, HER-2 antibody-drug conjugates, and HER2 bispecific antibodies are provided. [Diagram 3] 1 shows the results of an in vivo study of Compound (A) or a pharma- ceutically acceptable salt thereof in an MCF-7 xenograft model. [Figure 4] 1 shows the results of an in vivo study of Compound (A) or a pharma- ceutically acceptable salt thereof, or tamoxifen in the ZR-75-1 tamoxifen-resistant tumor model. [Diagram 5] 1 shows the results of an in vivo study of compound (A) or a pharma- ceutically acceptable salt thereof in human HCC1428 breast cancer xenograft tumors. [Figure 6] 1 shows the results of an in vivo study of Compound (A), or a pharma- ceutically acceptable salt thereof, as monotherapy or in combination with the CDK4 / 6 inhibitor, palbociclib, in an MCF-7 xenograft model. [Figure 7] 1 shows the results of an in vivo study of Compound (A), or a pharma- ceutically acceptable salt thereof, as monotherapy or in combination with the CDK4 / 6 inhibitor, palbociclib, in an MCF-7 xenograft model. [Figure 8] 4 provides the tumor volume change in mice treated with vehicle, Compound (A), trastuzumab, or the combination of Compound (A) and trastuzumab. [Figure 9]4 provides the tumor volume change in mice treated with vehicle, Compound (A), trastuzumab, or the combination of Compound (A) and trastuzumab. [Figure 10A] 1 provides the change in tumor volume and body weight, respectively, in a 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. [Figure 10B] 1 provides the change in tumor volume and body weight, respectively, in a 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. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0061] definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless otherwise specified. In the event that there are a plurality of definitions for a term herein, the definition in this section prevails unless otherwise specified.

[0062] The term "pharmaceutical acceptable salt" refers to a salt of a compound that does not cause significant irritation to the organism to which it is administered and does not abolish 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 a compound with an inorganic acid, such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid (such as 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting a compound with an organic acid, such as an aliphatic or aromatic carboxylic 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-oxopentanedioic acid, or naphthalenesulfonic acid. Pharmaceutical salts also include salts prepared by reacting a compound with a base to form a salt, for example, an ammonium salt, an alkali metal salt, for example, sodium, potassium, or the like. can be obtained by forming salts with lithium salts, alkaline earth metal salts, e.g., calcium or magnesium salts, carbonate salts, bicarbonate salts, organic base salts, e.g., dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, and amino acids such as arginine and lysine. For compounds (A) and / or (B), the skilled artisan will appreciate 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 is converted to NH3 + ), and the positive charge can be a negatively charged counterion (Cl - Understand that balance can be achieved by

[0063] In any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may be independently R or S configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixtures, diastereomerically pure compounds, diastereomerically enriched compounds, or stereoisomeric mixtures. In addition, in any compound described herein having one or more double bonds that generate geometric isomers that can be defined as E or Z, it is understood that each double bond may be independently E or Z, or a mixture thereof. Similarly, it is understood that in any compound described, all tautomeric forms are also intended to be included.

[0064] Where the compounds disclosed herein have unfilled valences, it is understood that the valences are filled with hydrogen or an isotope thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0065] It is understood that the compounds described herein can be isotopically labeled. Substitution with an isotope such as deuterium can provide certain therapeutic advantages due to greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure can include any isotope of that element. For example, in a compound structure, a hydrogen atom can be expressly disclosed or understood as being present in the compound. In any position of a compound where a hydrogen atom can be present, the hydrogen atom can be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference to a compound herein encompasses all possible isotopic forms, unless the context clearly indicates otherwise.

[0066] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, etc. In other embodiments, the compounds described herein exist in nonsolvated forms. Solvates contain either stoichiometric or nonstoichiometric amounts of solvent, and can be formed during the crystallization process with pharma-ceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in nonsolvated as well as solvated forms. In general, solvated forms are considered equivalent to nonsolvated forms for the purposes of the compounds and methods provided herein.

[0067] When a range of values ​​is provided, it is understood that the upper and lower limits, as well as every intervening value between the upper and lower limits of that range, are encompassed within an embodiment.

[0068] The terms and phrases used in this application and variations thereof, particularly in the appended claims, Some should be construed as open-ended rather than limiting unless otherwise specified. As an example above, the term "including" should be construed to mean "including without limitation," "including but not limited to," and the like. As used herein, the term "comprising" is synonymous with "including," "containing," or "featuring," and is inclusive or open-ended and does not exclude additional unrecited elements or method steps. The term "having" should be construed as "having at least." The term "including" should be construed as "including but not limited to." The term "example" is used to provide illustrative examples rather than an exhaustive or exclusive list of the items under discussion. The use of terms such as "preferably," "preferred," "desired," or "desirable," as well as words of similar import, should not be understood as implying that a particular feature is critical, essential, or even important to the structure or function, but rather is merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. In addition, the term "comprising" should be construed as synonymous with the phrases "having at least" or "including at least." 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.

[0069] With respect to the use of substantially any plural and / or singular term herein, those skilled in the art can convert from plural to singular and / or from singular to plural as appropriate depending on the context and / or application. Various singular / plural permutations may be expressly stated herein for clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain means are recited in mutually different dependent claims does not indicate that a combination of these means cannot be used to advantage. Any reference signs in the claims should not be interpreted as limiting the scope thereof.

[0070] compound Some embodiments disclosed herein relate to the use of a combination of compounds for treating a disease or condition, the combination may comprise an effective amount of compound (A), or a pharma- ceutically acceptable salt thereof, and an effective amount of compound (B), or a pharma- ceutically acceptable salt of any of the foregoing, where compound (A) may be a WEE1 inhibitor, or a pharma- ceutically acceptable salt thereof, and compound (B) may be selected from a CDK4 / 6 inhibitor, a HER-2 antibody, a HER-2 antibody-drug conjugate, and a HER2 bispecific antibody (including a pharma- ceutically acceptable salt of any of the foregoing).

[0071] Compound (A), including its pharma- ceutically acceptable salts,

[0072] [ka] In some embodiments, compound (B), including pharma- ceutically acceptable salts thereof, may be palbociclib, abemaciclib, ribociclib, trilaciclib (G1T28), It may be a CDK4 / 6 inhibitor selected from relociclib (G1T38), SHR6390, FCN-437, AMG 925, BPI-1178, BPI-16350, vilociclib, BEBT-209, TY-302, TQB-3616, HS-10342, PF-06842874, CS-3002, and MM-D37K (together with a pharma- ceutically acceptable salt of any of the foregoing). In other embodiments, compound (B), including a pharma- ceutically acceptable salt thereof, may be a HER-2 small molecule inhibitor selected from tucatinib, lapatinib, and neratinib, or a pharma- ceutically acceptable salt of any of the foregoing. In yet other embodiments, compound (B), including pharma- ceutically acceptable salts thereof, can be a HER-2 antibody selected from trastuzumab, trastuzumab-dkst, pertuzumab, and ZW25 (along with a pharma- ceutically acceptable salt of any of the foregoing). In still other embodiments, compound (B), including a pharma- ceutically acceptable salt thereof, can be a HER-2 antibody-drug conjugate selected from Ado-trastuzumab emtansine (T-DM1), ARX788, ALT-P7, DS8201a, MEDI4276, MM302, PF-06804103, SYD985, XMT-1522, ZW49, MRG002, GQ1001, A166, RC48-ADC, BDC-1001, FS-1502 (along with a pharma- ceutically 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 margetuximab, ertumaxomab, HER2Bi-aATC, MM-111, MCLA-128, BTRC4017A, GBR-1302, and PRS-343 (together with pharmaceutically acceptable salts of any of the foregoing).

[0073] Embodiments of combinations of Compound (A) and Compound (B), including any of the foregoing pharma- ceutically acceptable salts, are provided in Table 1. In Table 1, "A" refers to Compound (A), including pharma- ceutically acceptable salts thereof, Numbers 1A-18A represent compounds provided in Figure 1, and Numbers 1B-28B represent compounds provided in Figure 2, including pharma- ceutically acceptable salts thereof. For example, in Table 1, the combination represented by 1A:A is a combination of palbociclib and

[0074] [ka] (including pharma- ceutically acceptable salts of any of the foregoing).

[0075] [Table 1]

[0076] The order of administration of the compounds in the combinations described herein may vary. In some embodiments, compound (A), including its pharma- ceutically acceptable salts, may be administered before all compounds (B) or their pharma- ceutically acceptable salts. In other embodiments, compound (A), including its pharma- ceutically acceptable salts, may be administered before at least one compound (B) or its pharma- ceutically acceptable salts. In still other embodiments, compound (A), including its pharma- ceutically acceptable salts, may be administered simultaneously with compound (B) or its pharma- ceutically acceptable salts. In still yet other embodiments, compound (A), including its pharma- ceutically acceptable salts, may be administered subsequent to administration of at least one compound (B) or its pharma- ceutically acceptable salts. In some embodiments, compound (A), including its pharma- ceutically acceptable salts, may be administered subsequent to administration of all compounds (B) or their pharma- ceutically acceptable salts.

[0077] There may be some advantages to using the combination of compounds described herein.For example, combining compounds that attack multiple pathways simultaneously may be more effective in treating cancers such as those described herein compared to when the combination compounds are used as monotherapy.

[0078] In some embodiments, the combination of compound (A), including pharma- ceutically acceptable salts thereof, described herein with compound (B), or a pharma- ceutically acceptable salt thereof, can reduce the number and / or severity of side effects that can be attributable to a compound described herein, such as compound (B), or a pharma- ceutically acceptable salt thereof.

[0079] The use of the combinations of compounds described herein can result in additive, synergistic, or strongly synergistic effects. The combinations of compounds described herein can result in effects that are not antagonistic.

[0080] In some embodiments, the combination of compound (A), including its pharma- ceutically acceptable salts, as described herein, with compound (B), or a pharma- ceutically acceptable salt thereof, may provide an additive effect. The combination of compound (A), including pharma- ceutically acceptable salts thereof, with compound (B), or a pharma- ceutically acceptable salt thereof, as described herein, may result in a synergistic effect. In some embodiments, the combination of compound (A), including pharma- ceutically acceptable salts thereof, with compound (B), or a pharma- ceutically acceptable salt thereof, as described herein, may result in a strong synergistic effect. In some embodiments, the combination of compound (A), including pharma- ceutical acceptable salts thereof, with compound (B), or a pharma- ceutical acceptable salt thereof, as described herein, is not antagonistic.

[0081] As used herein, the term "antagonistic" means that the activity of the combined compounds is lower than the sum of the activities of each compound in the combination when the activity of each compound is determined individually (i.e., as a single compound). As used herein, the term "synergistic" means that the activity of the combined compounds is higher than the sum of the individual activities of each compound in the combination when the activity of each compound is determined individually. As used herein, the term "additive" means that the activity of the combined compounds is approximately equal to the sum of the individual activities of each compound in the combination when the activity of each compound is determined individually.

[0082] A potential advantage of utilizing the combinations described herein may be that a reduced amount of the compounds is required to be effective in treating a disease condition disclosed herein, compared to when each compound is administered as a monotherapy. For example, the amount of compound (B), or a pharma- ceutically acceptable salt thereof, used in the combinations described herein may be less than the amount of compound (B), or a pharma- ceutically acceptable salt thereof, required to achieve the same reduction in a disease marker (e.g., tumor size) when administered as a monotherapy. Another potential advantage of utilizing the combinations described herein is that the use of two or more compounds with different mechanisms of action may pose a higher barrier to the development of resistance, compared to when the compounds are administered as a monotherapy. Further advantages of utilizing the combinations described herein include little or no cross-resistance between each compound of the combinations described herein, different routes of elimination for each compound of the combinations described herein, and / or there is little overlapping toxicity between each compound in the combinations described herein.

[0083] Pharmaceutical Compositions Compound (A), including its pharma- ceutically acceptable salt, may be provided in a pharmaceutical composition.Similarly, compound (B), including its pharma- ceutically acceptable salt, may be provided in a pharmaceutical composition.

[0084] The term "pharmaceutical composition" refers to a mixture of one or more compounds and / or salts disclosed herein with other chemical components, such as diluents, carriers, and / or excipients. Pharmaceutical compositions facilitate administration of a compound to an organism. Pharmaceutical compositions can also be obtained by reacting a compound with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions are generally tailored to the specific intended route of administration.

[0085] As used herein, "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, and without limitation, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0086] As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that has no apparent pharmacological activity, but may be pharma- ceutical necessary or desirable. For example, a diluent may be used to bulk up a potent drug whose mass is too small for manufacture and / or administration. It may also be a liquid for dissolving 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, without limitation, phosphate buffered saline, which mimics the pH and isotonicity of human blood.

[0087] As used herein, "excipient" refers to an essentially inert substance added to a pharmaceutical composition to provide the composition with, but not limited to, bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. For example, stabilizers such as antioxidants and metal chelators are excipients. In one embodiment, the pharmaceutical composition includes an antioxidant and / or a metal chelator. A "diluent" is a type of excipient.

[0088] In some embodiments, compound (B) may be provided in a pharmaceutical composition comprising compound (A) including its pharma- ceutically acceptable salt, together with its pharma- ceutically acceptable salt. In other embodiments, compound (B) may be administered in a pharmaceutical composition separate from the pharmaceutical composition comprising compound (A) including its pharma- ceutically acceptable salt, together with its pharma- ceutically acceptable salt.

[0089] The pharmaceutical compositions described herein can be administered to human patients by themselves or in pharmaceutical compositions in which they are mixed with other active ingredients, such as in combination therapy, or with carriers, diluents, excipients, or combinations thereof.The appropriate formulation depends on the route of administration selected.Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0090] The pharmaceutical compositions disclosed herein can be prepared in a manner known per se, for example, by conventional mixing, dissolving, granulating, dragee-making, elutriating, emulsifying, encapsulating, entrapping or tabletting processes. In addition, the active ingredient is contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharma-ceutically compatible counterions.

[0091] There are multiple techniques in the art for administering compounds, salts, and / or compositions, 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) and its pharmaceutically acceptable salt. In other embodiments, compound (A), including its pharmaceutically acceptable salt, can be provided to a subject by a different route of administration than compound (B) and its pharmaceutically acceptable salt.

[0092] The compounds, salts, and / or compositions may also be administered in a local rather than systemic manner, for example, by injecting or implanting the compounds directly into the affected area, often as a depot or sustained release formulation. Additionally, the compounds can be administered in targeted drug delivery systems, for example, in liposomes coated with tissue-specific antibodies. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or intrapulmonary delivery may be desired to target respiratory diseases or conditions.

[0093] The composition may be provided in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient, if desired. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container, in a format prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice may include instructions for administration of the drug by the agency in the form of a drug for human or animal administration. The notice may reflect approval. Such notice may be, for example, labeling approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. Compositions that may include the 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 an indicated condition.

[0094] Methods of Use and Treatment As provided herein, in some embodiments, a disease or condition can be treated using a combination of compounds comprising an effective amount of compound (A), including a pharma- ceutically acceptable salt thereof, and an effective amount of compound (B), or a pharma- ceutically acceptable salt of any of the foregoing.

[0095] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animals" include cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, crustaceans, reptiles, and especially mammals. "Mammals" include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and especially humans. In some embodiments, the subject may be a human. In some embodiments, the subject may be a child and / or infant, such as a child or infant with a fever. In other embodiments, the subject may be an adult.

[0096] As used herein, the terms "treat," "treating," "treatment," "therapeutic," and "therapy" do not necessarily mean a complete cure or elimination of a disease or condition. Any alleviation of any undesirable signs or symptoms of a disease or condition, to any degree, may be considered treatment and / or therapy. Additionally, treatment may include actions that may worsen a subject's overall feeling of health or appearance.

[0097] The term "effective amount" is used to indicate the amount of an active compound or drug that induces the indicated biological or pharmaceutical response. For example, an effective amount of a compound, salt or composition may be the amount necessary to prevent, alleviate, or ameliorate the symptoms of a disease or condition, or to prolong the survival of the subject being treated. This response may occur in a tissue, system, animal, or human, and includes alleviating the signs or symptoms of the disease or condition being treated. Determination of an effective amount is well within the capabilities of one of ordinary skill in the art in light of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including humans, being treated, and the physical characteristics of the particular animal under consideration. Dosages may be adjusted to achieve the desired effect, but will depend on factors such as body weight, diet, concurrent medications, and other factors that one of ordinary skill in the medical arts would recognize.

[0098] For example, an effective amount of a compound or radiation is an amount that results in (a) reduction, alleviation, or elimination of one or more symptoms caused by cancer, (b) reduction in tumor size, (c) elimination of the tumor, and / or (d) long-term disease stabilization (growth cessation) of the tumor.

[0099] In some embodiments, the disease or condition may be selected from lung cancer, gastric cancer, and gastroesophageal junction adenocarcinoma. In some embodiments, the disease or condition may be breast cancer. Various types of breast cancer are known. In some embodiments, the breast cancer may be ER positive (ER+) breast cancer. In some embodiments, the breast cancer may be ER positive, HER2 negative (ER+ / HER2-) breast cancer.

[0100] In some embodiments, the breast cancer is classified by HER2 status. In some embodiments, the breast cancer is HER2 positive (HER2+) breast cancer. So, the breast cancer is HER2-low breast cancer.

[0101] In some embodiments, the breast cancer may 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, the breast cancer may be metastatic breast cancer. In yet other embodiments, the breast cancer may be triple-negative breast cancer.

[0102] The subject may have breast cancer that has not been previously treated.

[0103] In some cases, following breast cancer treatment, the subject experiences a relapse or recurrence of breast cancer. The breast cancer may relapse. As used herein, the terms "relapse" and "recurrence" are used in their normal sense as understood by those skilled in the art. Thus, the breast cancer may be recurrent breast cancer. In some embodiments, the subject has relapsed after a previous treatment for breast cancer. For example, the subject has relapsed after one or more treatments with SERMs, SERDs and / or aromatase inhibitors, such as those described herein.

[0104] Within ESR1, several amino acid mutations have been identified. Mutations in ESR1 have been proposed to play a role in resistance. Several therapies exist to inhibit the estrogen receptor, including selective ER modulators (SERMs), selective ER degraders (SERDs), and aromatase inhibitors. One problem that can arise from the aforementioned cancer therapies is the development of resistance to cancer therapies. Acquired resistance to cancer therapies, such as endocrine therapy, has been found in nearly one-third of women treated with tamoxifen and other endocrine therapies. Alluri et al. See, al., "Estrogen receptor mutations and their role in breast cancer progression," Breast Cancer Research (2014) 16:494. Researchers believe that mutations in the estrogen receptor are one of the reasons for acquired resistance to cancer therapies, such as endocrine therapy. Thus, there is a need for compounds that can treat breast cancers that have one or more mutations in ESR1.

[0105] Some embodiments disclosed herein relate to the use of a combination of compounds described herein, such as Compound (A) and Compound (B) (with a pharma- tically acceptable salt of any of the foregoing), in the manufacture of a medicament for treating breast cancer in a subject in need of such treatment, wherein the breast cancer has at least one point mutation (such as 1, 2, 3, 4, or more than 4 point mutations) in estrogen receptor 1 (ESR1), which encodes estrogen receptor alpha (ERα). Other embodiments described herein relate to the use of a combination of compounds described herein, including an effective amount of Compound (A), including a pharma-tically acceptable salt thereof, and an effective amount of Compound (B), or a pharma-tically acceptable salt thereof, in the manufacture of a medicament for treating breast cancer in a subject in need of such treatment, wherein the breast cancer has at least one point mutation ... Yet other embodiments disclosed herein relate to a method of treating breast cancer in a subject in need thereof with a combination of compounds described herein (including pharma- ceutically acceptable salts of any of the foregoing, such as Compound (A) and Compound (B)), where the breast cancer has at least one point mutation (e.g., 1, 2, 3, 4, or more than 4 point mutations) in estrogen receptor 1 (ESR1), which encodes estrogen receptor alpha (ERα).

[0106] In some embodiments, the mutation is in the ligand binding domain of ESR1. In some embodiments, the one or more mutations may be in the 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, S432, G420, V418, D411, L466, S463, L453, G442, M437, The amino acids may be selected from 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 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 D538 and Y537.

[0107] In some embodiments, the one or more mutations are 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, L46 6Q, 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.

[0108] Some embodiments disclosed herein relate to the use of a combination of compounds comprising an effective amount of compound (A), including pharmaceutically acceptable salts thereof, and an effective amount of one or more of compound (B), or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for treating breast cancer in a subject in need of such treatment, wherein the breast cancer does not contain at least one point mutation (e.g., a point mutation in estrogen receptor 1 (ESR1), which encodes estrogen receptor alpha (ERα)). Other embodiments related to the present specification relate to the use of a combination of compounds comprising an effective amount of compound (A), including pharmaceutically acceptable salts thereof, and an effective amount of one or more of compound (B), including pharmaceutically acceptable salts of any of the foregoing, in the manufacture of a medicament for treating breast cancer in a subject in need of such treatment, wherein the breast cancer does not contain at least one point mutation, such as a point mutation in estrogen receptor 1 (ESR1), which encodes estrogen receptor alpha (ERα). Still other embodiments disclosed herein relate to a method for treating breast cancer in a subject in need thereof with a combination of compounds described herein (e.g., a combination of Compound (A) and Compound (B), or a pharma- ceutically acceptable salt of any of the foregoing), wherein the breast cancer does not contain at least one point mutation in estrogen receptor 1 (ESR1), which encodes estrogen receptor alpha (ERα) (e.g., a point mutation in estrogen receptor 1 (ESR1), which encodes estrogen receptor alpha (ERα)).

[0109] As provided herein, some studies have shown that a potential cause of resistance in ER-positive breast cancer is due to acquired mutations in ESR1 by endocrine therapy. In some embodiments, the subject has been previously treated with one or more selective ER modulators. For example, the subject has been previously treated with one or more selected ER modulators selected from tamoxifen, raloxifene, ospemifene, bazedoxifene, toremifene, and lasofoxifene, or a pharma- ceutically acceptable salt of any of the foregoing. In some embodiments, the subject is receiving treatment with 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 (Brillanestrand, 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)amino)but-2-enamide (H3B-6545), (E)-3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (lindestrant, 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 (Giledestrant, 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,The subject has been previously treated with one or more selective ER degraders, such as 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 been previously treated with one or more aromatase inhibitors. The aromatase inhibitor may be a steroidal aromatase inhibitor or a non-steroidal aromatase inhibitor. For example, the one or more aromatase inhibitors may be selected from (exemestane (steroidal aromatase inhibitor), testolactone (steroidal aromatase inhibitor), anastazole (non-steroidal aromatase inhibitor), and letrazole (non-steroidal aromatase inhibitor) (including a pharmaceutically acceptable salt of any of the foregoing).

[0110] In some embodiments, the subject may have breast cancer and may be a woman. As a woman approaches middle age, she may be in the stage of menopause. In some embodiments, the subject may be a pre-menopausal woman. In other embodiments, the subject may be a peri-menopausal woman. In yet other embodiments, the subject may be a menopausal woman. In still yet other embodiments, the subject may be a post-menopausal woman. In other embodiments, the subject may have breast cancer and may be a man. The subject's serum estradiol level may be altered. In some embodiments, the subject's serum estradiol level (E2) may be in the range of greater than 15 pg / mL to 350 pg / mL. In other embodiments, the subject's serum estradiol level (E2) may be 15 pg / mL or less. In other embodiments, the subject's serum estradiol level (E2) may be 10 pg / mL or less.

[0111] The amount of compound, salt, and / or composition required for therapeutic use will depend not only on the particular compound or salt selected, but also on the route of administration, the nature and / or the disease or condition being treated. Also varies according to symptoms and age and condition of the patient, and is ultimately at the discretion of the attending physician or clinician. In the case of administration of a pharmaceutically acceptable salt, the dosage can be calculated as a free base. As will be understood by those skilled in the art, in certain circumstances, it may be necessary to administer the compounds disclosed herein in amounts that exceed or even far exceed the dosage ranges described herein in order to effectively and aggressively treat, particularly, progressive diseases or conditions.

[0112] As will be readily apparent to those skilled in the art, the useful in vivo dosages and the specific administration methods administered will vary depending on the age, weight, severity of the affliction, the mammalian species being treated, the specific compounds used, and the specific applications for which these compounds are used. The determination of effective dosage levels, i.e., the dosage levels required to achieve the desired results, can be accomplished by those skilled in the art using routine methods, such as human clinical trials, in vivo studies, and in vitro studies. For example, useful dosages of compounds (A) and / or (B), or pharma-ceutically acceptable salts of any of the foregoing, can be determined by comparing their in vitro and in vivo activities in animal models. Such comparisons can be made by comparison with established drugs, such as cisplatin and / or gemcitabine).

[0113] Dosage amount and interval are adjusted individually to provide plasma levels of the active moiety sufficient to maintain a modulating effect or minimal effective concentration (MEC). The MEC may be determined by the individual. The MEC varies from compound to compound, but can be estimated from in vivo and / or in vitro data. The dosage required to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using the MEC value. Compositions should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably 30-90% of the time, and most preferably 50-90% of the time. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

[0114] It should be noted that the attending physician would know how and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunction. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response is not adequate (precluding toxicity). The magnitude of the dose administered in the management of the disease of interest will vary with the severity of the disease or condition to be treated and with the route of administration. The severity of the disease or condition can, for example, be assessed, in part, by standard prognostic evaluation methods. Furthermore, the dose and perhaps dose frequency will also vary with the age, weight, and response of the individual patient. Programs comparable to those discussed above can be used in veterinary medicine.

[0115] 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 subset of compounds sharing a certain chemical moiety can be established by determining in vitro toxicity on cell lines, such as mammalian cell lines, preferably human cell lines. The results of such studies often predict toxicity in animals, such as mammals, or especially humans. Alternatively, the toxicity of a particular compound in an animal model, such as mice, rats, rabbits, dogs, or monkeys, can be determined using known methods. The efficacy of a particular compound can be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, a person skilled in the art can be guided by the state of the art in selecting the appropriate model, dose, route of administration, and / or regimen. EXAMPLES

[0116] Further embodiments, which in no way limit the scope of the claims, are described in the following examples. Further details will be disclosed below.

[0117] Efficacy Study Procedures The antitumor activity of compound (A) was evaluated using an MCF-7 xenograft model. Each mouse received 1.5 × 10 cells in 200 μL of serum-free DMEM-Matrigel mixture (1:1 ratio) for tumor development. 7 MCF-7 tumor cells were inoculated subcutaneously onto the second right mammary fat pad. In addition, estradiol benzoate injections were delivered subcutaneously (40ug / 20uL, twice weekly). The mean tumor size was 204mm 3When the schizophrenia score reached 0.01, animals were randomized into two groups (10 animals / group) and treatment was initiated. Compound (A) or vehicle control was administered by oral gavage once daily for 28 days. Study endpoints included daily body weights, clinical observations, and tumor volumes. Figure 3 shows that Compound (A) at a dose level of 80 mg / kg as a single agent caused robust inhibition of tumor growth (132.6%) and tumor regression. In Figure 3, the top line is vehicle and the bottom line is Compound (A) (80 mg / kg qd x 22 p.o). There were no adverse clinical observations in any dose group and no significant effect on mean body weight.

[0118] 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 monolayer cultures in RPMI1640 medium supplemented with 10% fetal bovine serum and 10 μM tamoxifen at 37° C. in an incubator with a 5% CO2 atmosphere. Each mouse was then implanted in the right flank with 1×10 6 cells in 100 μL of serum-free RPMI-1640 Matrigel mixture (1:1 ratio) for tumor development. 7 ZR-75-1R tumor cells were inoculated subcutaneously. In addition, estradiol benzoate injections were delivered subcutaneously (40ug / 20uL, twice weekly). The mean tumor size then increased to 191mm 3 When the tumor reached 100 mg / kg, the mice were randomized into three groups and treatment was initiated. Tamoxifen was administered at 100 mg / kg, 5 days a week for 3 weeks, and Compound (A) was administered orally at 80 mg / kg daily for 28 days. Study endpoints included daily body weight, clinical observations, and tumor volume. In Figure 4, the upper line is Tamoxifen (100 mg / kg), the middle line is vehicle, and the lower line is Compound (A) (80 mg / kg). As shown in Figure 4, Tamoxifen induced -47.9% tumor growth inhibition after 28 days of treatment, indicating that this is a tamoxifen-resistant breast cancer model. Compound (A) at 80 mg / kg showed strong antitumor activity with a TGI (tumor growth inhibition) of 69.9%. No other gross clinical abnormalities were observed during the treatment period, and the weight loss in the animals was manageable by giving the animals a drug holiday.

[0119] Activity of compound (A) evaluated in mice bearing human HCC1428 breast cancer xenograft tumors. HCC1428 tumor cells (1×10) in a 0.2 mL mixture of PBS and matrigel (PBS:matrigel=1:1) for tumor development were subcutaneously implanted with a 17beta-estradiol tablet (0.18 mg, 90-day release) 2 days prior to cell implantation. 7 Each mouse was inoculated subcutaneously into the right flank with a mean tumor size of approximately 185 mm. 3 Treatment was initiated 21 days after tumor inoculation, when tumor volume reached 10. Animals were assigned to two groups using Excel-based randomization software, which performed stratified randomization based on tumor volume. Each group consisted of 10 tumor-bearing mice. Vehicle control or 80 mg / kg of compound (A) was administered to mice by oral gavage once a day for 28 days. In Figure 5, the upper line is vehicle and the lower line is compound (A). As shown in Figure 5, treatment with compound (A) as a single agent resulted in significant inhibition of HCC1428 tumor growth relative to the vehicle group, with a tumor growth inhibition (TGI) of 96.2% 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).

[0120] The antitumor activity of compound (A) in combination with the CDK4 / 6 inhibitor, palbociclib, was evaluated in an MCF-7 xenograft model. The right flank of each mouse was inoculated with MCF-7 tumor cells (1.5 × 10 cells / mL) in 200 μL of serum-free DMEM-Matrigel mixture (1:1 ratio) for tumor development. 7 In addition, estradiol benzoate injections were delivered subcutaneously (40ug / 20uL, twice weekly). The mean tumor size was 202mm 3When the sigma-positive mice reached 10 mg / kg, the mice were randomized into 5 groups (10 animals / group) and treatment was initiated. The animals were dosed with vehicle, 80 / 60 mg / kg compound (A) alone, 50 mg / kg palbociclib alone, 80 mg / kg compound (A) combined with 50 mg / kg palbociclib on a continuous dosing schedule (alternating every 2 weeks), or 80 / 60 mg / kg compound (A) combined with 50 mg / kg palbociclib. The treatment period was 28 days. In FIG. 6, the upper line (shown as a circle) is the vehicle. As shown in FIG. 6, 80 / 60 mg / kg compound (A) or 50 mg / kg palbociclib alone resulted in TGI of about 116% and 119%, respectively. Sequential treatment with compound (A) and palbociclib induced a TGI of 127%, and thus this data shows better antitumor activity than monotherapy with either compound (A) or palbociclib, respectively. Co-treatment with 80 / 60 mg / kg compound (A) and 50 mg / kg palbociclib also induced deeper antitumor activity with a TGI of 126.2%. Furthermore, compound (A) in combination with palbociclib induced tumor regression of about 55%. In comparison, compound (A) or palbociclib treatment alone induced only 32.7% and 39.1% tumor regression, respectively. Overall, compound (A) in combination with palbociclib significantly improved efficacy.

[0121] The antitumor activity of compound (A) in combination with a lower dose of the CDK4 / 6 inhibitor, palbociclib, was evaluated in an MCF-7 xenograft model. Each mouse received 1.5 × 10 cells in 200 μL of serum-free DMEM-Matrigel mixture (1:1 ratio) for tumor development. 7 MCF-7 cells were inoculated subcutaneously onto the second right mammary fat pad. In addition, estradiol benzoate injections were delivered subcutaneously (40ug / 20uL, twice weekly). The average tumor size was 203mm 3Treatment was initiated when the TGI reached 1.5 mg / kg. Mice were randomly divided into 4 groups (8 mice per group) and treated with vehicle control, 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. As shown in FIG. 7, 60 mg / kg compound (A) alone (second from the bottom line) and 25 mg / kg palbociclib alone (second from the top line, indicated by triangles) induced 48.6% TGI and 14.2%, respectively, and 60 mg / kg compound (A) in combination with 25 mg / kg palbociclib (lower line, indicated by triangles) resulted in 82.7% TGI. Thus, compound (A) in combination with palbociclib significantly improved efficacy. All animals tolerated the treatment well.

[0122] The antitumor activity of compound (A) in combination with palbociclib was further evaluated in a palbociclib-resistant breast cancer PDX model (CTG-1207). For tumor development, mice were subcutaneously inoculated with palbociclib-resistant breast cancer cells in a serum-free DMEM-Matrigel mixture (1:1 ratio). Tumors with a size of approximately 200 mm 3 Once the TGI was reached, mice were randomly divided into 4 groups (8 mice per group) and treated with vehicle control, 80 mg / kg compound (A) alone, 50 mg / kg palbociclib alone, or 80 mg / kg compound (A) in combination with 50 mg / kg palbociclib. Study endpoints included daily body weights, clinical observations, and tumor volumes. As shown in FIG. 10A, 80 mg / kg compound (A) alone (indicated by triangles, second from the bottom line) reduced tumor growth, while 50 mg / kg palbociclib alone (indicated by diamonds, second from the top line) showed a lower TGI. Compound (A) at 80 mg / kg in combination with 50 mg / kg palbociclib (indicated by triangles) reduced tumor growth, whereas 50 mg / kg palbociclib alone (indicated by diamonds, second from the top line) showed a lower TGI. Compound (A) in combination with palbociclib significantly improved efficacy. All animals tolerated the treatment well, as shown by Figure 10B.

[0123] Study 1 - Part 1 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 to be relatively resistant to HER2-targeted therapy (the JIMT-1 cell line was established from a pleural metastasis of a 62-year-old patient with breast cancer that 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 antitumor effect of HER2-targeted treatment, NOD / SCID mice were inoculated with 95% viable tumor cells (5×10 ) in 100 μL of DMEM-Matrigel mixture (1:1 ratio) for tumor development in the right flank. 6 A single cell suspension of 1000 cells was inoculated subcutaneously. The average tumor size was 204 mm. 3 Treatment was initiated when tumor-bearing mice reached 0.01 mg / kg / day. Mice were then randomized into 5 groups, and treatment was administered to tumor-bearing mice according to the study design in Table 2.

[0124] [Table 2]

[0125] Treatment with compound (A) (60 mg / kg) alone or trastuzumab (10 mg / kg) alone resulted in tumor growth inhibition (TGI) values ​​of 68% and 59%, respectively, on day 29, compared to their respective vehicle controls (administered either orally or intraperitoneally, respectively). In FIG. 8, the top line (shown in circles) is vehicle A, and the third line from the bottom (shown in circles) is trastuzumab (10 mg / kg) alone. The combination of compound (A) and trastuzumab resulted in a TGI of 94% on day 29, compared to either vehicle control. The tumor growth curves are summarized in FIG. 8 and in Table 3. These data showed that the combination of compound (A) and trastuzumab had superior antitumor efficacy compared to either treatment as monotherapy. All treatments, including Compound (A) alone, trastuzumab alone, or the combination of Compound (A) and trastuzumab, were well tolerated. Table 3 summarizes the results of the experiment shown in FIG. a TGI = tumor growth inhibition, 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. Values ​​calculated by Dunnett's T3 test versus vehicle control.

[0126] [Table 3]

[0127] Study 1 - Part 2 Mice in the two vehicle groups were then randomized on day 29 to be treated with either vehicle, Compound (A) alone, Trastuzumab alone, or the combination of Compound (A) and Trastuzumab according to Table 4. At this time, tumors had grown to approximately 1000 mm 3 and therefore treatment of these mice was performed with a high initial tumor burden.

[0128] [Table 4]

[0129] Research 2 Treatment with Compound (A) (60 mg / kg) alone or Trastuzumab (10 mg / kg) alone on day 14 of the second part of the experiment resulted in TGI values ​​of 68.2% and 68.0%, respectively, compared to vehicle control. The combination of Compound (A) and Trastuzumab resulted in a TGI of 97% compared to vehicle control on day 14 of the second part of the experiment (Figure 9 and Table 5). Table 5 summarizes the results (tumor growth inhibition) of the experiment shown in Figure 9. a TGI = tumor growth inhibition on day 14. On day 35 of the second part of the experiment, the combination of compound (A) and trastuzumab resulted in 30.6% tumor regression (Figure 9 and Table 6). Table 6 summarizes the results (tumor regression) of the experiment shown in Figure 9. a Tumor regression = (1-(T d / T0)) × 100%.

[0130] [Table 5]

[0131] [Table 6]

[0132] These data demonstrated that the combination of Compound (A) and trastuzumab exhibited significantly better antitumor efficacy compared to either treatment as monotherapy when mice were treated with high initial tumor burden. Furthermore, all treatment regimens were well tolerated.

[0133] Moreover, although the above has been described in some detail with reference to the figures and examples for purposes of clarity and understanding, it will be understood by those skilled in the art that numerous and various modifications may be made without departing from the spirit of the present disclosure. It should therefore be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather encompass all modifications and alternative forms consistent with the true scope and spirit of the present invention.

Claims

1. A pharmaceutical for treating a disease or condition comprising a combination of compounds, the combination comprising an effective amount of compound (A), or a pharmaceutically acceptable salt thereof, and an effective amount of compound (B), or a pharmaceutically acceptable salt thereof; Compound (A) is 【Chemistry 1】 or a pharmaceutically acceptable salt thereof; 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 of the foregoing; the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, trilaciclib (G1T28), relociclib (G1T38), SHR6390, FCN-437, AMG 925, BPI-1178, BPI-16350, vilociclib, BEBT-209, TY-302, TQB-3616, HS-10342, PF-06842874, CS-3002, and MM-D37K, or a pharmaceutically acceptable salt of any of the foregoing; the HER-2 antibody is selected from the group consisting of trastuzumab, trastuzumab-dkst, pertuzumab, and ZW25, or a pharmaceutically acceptable salt of any of the foregoing; 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-1 502, or a pharmaceutically acceptable salt of any of the foregoing; 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 of the foregoing; the HER-2 small molecule inhibitor is selected from the group consisting of tucatinib, lapatinib, and neratinib, or a pharmaceutically acceptable salt of any of the foregoing; the disease or condition is a cancer selected from the group consisting of lung cancer, gastric cancer, gastroesophageal junction adenocarcinoma, and breast cancer; A medicament, wherein compound (A), or a pharmaceutically acceptable salt thereof, and compound (B), or a pharmaceutically acceptable salt thereof, are provided in a single pharmaceutical composition or in separate pharmaceutical compositions.

2. The pharmaceutical composition of claim 1, wherein compound (A), or a pharmaceutically acceptable salt thereof, is administered before compound (B), or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition of claim 1, wherein compound (A), or a pharmaceutically acceptable salt thereof, is administered simultaneously with compound (B), or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition of claim 1, wherein compound (A), or a pharmaceutically acceptable salt thereof, is administered subsequent to compound (B), or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical according to any one of claims 1 to 4, wherein compound (B) is a CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical described in claim 5, wherein the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, and trilaciclib, or pharmaceutically acceptable salts thereof.

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

8. The pharmaceutical described in claim 7, wherein the HER-2 antibody is trastuzumab.

9. The use according to any one of claims 1 to 4, wherein compound (B) is a HER-2 antibody-drug conjugate or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition of claim 9, wherein the HER-2 antibody of the HER-2 antibody-drug conjugate is trastuzumab.

11. The pharmaceutical described in claim 9, wherein the HER-2 antibody-drug conjugate is fam-trastuzumab-deruxtecan-nxki (DS8201a).

12. The pharmaceutical composition according to any one of claims 1 to 4, wherein compound (B) is a HER2 bispecific antibody or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical described in any one of claims 1 to 4, wherein the disease or condition is a cancer selected from the group consisting of lung cancer, gastric cancer, and gastroesophageal junction adenocarcinoma.

14. A pharmaceutical described in any one of claims 1 to 4, wherein the disease or condition is breast cancer.

15. The pharmaceutical described in claim 14, wherein the breast cancer is selected from the group consisting of triple-negative breast cancer, ER+ breast cancer, HER2-positive (HER2+) breast cancer and HER2-low breast cancer.

16. The pharmaceutical described in claim 15, wherein the breast cancer is triple-negative breast cancer.

17. The pharmaceutical described in claim 14, wherein the breast cancer is breast cancer that has acquired resistance to cancer treatment.

18. The pharmaceutical described in claim 17, wherein the breast cancer is breast cancer that has acquired resistance to a cancer treatment selected from the group consisting of trastuzumab, palbociclib, and tamoxifen, or pharmaceutically acceptable salts thereof.

19. The pharmaceutical described in claim 17, wherein the breast cancer is HER2-resistant breast cancer.

20. The pharmaceutical described in claim 18, wherein the breast cancer is trastuzumab-resistant breast cancer.

Images