Triple therapy combination of a BCL-2 inhibitor, a WEE-1 inhibitor and another chemotherapy agent

Abstract

Disclosed herein are combinations of Bcl-2 inhibitors, specifically compound (A), with compound (B) (a WEE1 inhibitor) and compound (C) (anticancer agents, such as azacitidine, bendamustine, bortezomib, carfilzomib, ixazomib, busulfan, carboplatin, cytarabine, cyclophosphamide, cladribine, cisplatin, capecitabine, decitabine, dexamethasone, etoposide, fludarabine, gemcitabine, daunorubicin, doxorubicin, ifosfamide, methotrexate, and vincristine), or pharma- ceutically acceptable salts of any of the foregoing, for the treatment of diseases or conditions, including cancer and amyloidosis.

Description

[Technical field]

[0001] (Incorporation by reference of any priority application) For example, any application in which a claim of foreign or domestic priority is identified in an Application Data Sheet or claim filed with this application is incorporated by reference herein under 37 CFR 1.57 and Rules 4.18 and 20.6, including U.S. Provisional Application Nos. 63 / 265,444, filed December 15, 2021, and 63 / 375,510, filed September 13, 2022, which are incorporated by reference in their entireties.

[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 depending on the type of cancer and the stage at which the cancer is diagnosed. In 2019, approximately 1.8 million people in the United States were diagnosed with cancer and an estimated 606,880 people died from cancer. Thus, there remains a need for effective cancer treatments. Summary of the Invention

[0004] Some embodiments described herein relate to a combination of compounds, which may include an effective amount of Compound (A), an effective amount of Compound (B), and an effective amount of Compound (C), or a pharma- ceutically acceptable salt of any of the foregoing.

[0005] 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), an effective amount of compound (B) and an effective amount of compound (C), or a pharmaceutically 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), an effective amount of compound (B) and an effective amount of compound (C), or a pharmaceutically acceptable salt of any of the foregoing. Still other embodiments described herein relate to a combination of an effective amount of compound (A), an effective amount of compound (B) and an effective amount of compound (C), or a pharmaceutically acceptable salt of any of the foregoing, for use in treating a disease or condition. Still further embodiments described herein relate to a method for treating a disease or condition, which may include administering in combination an effective amount of compound (A), an effective amount of compound (B) and an effective amount of compound (C), or a pharmaceutically acceptable salt of any of the foregoing.

[0006] In some embodiments, the disease or condition may be a cancer described herein, such as triple-negative breast cancer, multiple myeloma, acute myeloid leukemia, and / or amyloidosis. [Brief description of the drawings]

[0007] [Figure 1-1] FIG. 1-1 to FIG. 1-2 provide examples of Bcl-2 inhibitors. [Figure 1-2] FIG. 1-1 to FIG. 1-2 provide examples of Bcl-2 inhibitors. [Figure 2-1] Figures 2-1 to 2-6 provide examples of Compound (C) drugs. [Figure 2-2] Figures 2-1 to 2-6 provide examples of Compound (C) drugs. [Figure 2-3] Figures 2-1 to 2-6 provide examples of Compound (C) drugs. [Figure 2-4] Figures 2-1 to 2-6 provide examples of Compound (C) drugs. [Figure 2-5]Figures 2-1 to 2-6 provide examples of Compound (C) drugs. [Figure 2-6] Figures 2-1 to 2-6 provide examples of Compound (C) drugs. [Diagram 3] FIG. 1 shows the effect of compound (1A) or a pharma- ceutically acceptable salt thereof, compound (B) or a pharma- ceutically acceptable salt thereof, and compound (C), used alone or in combination, on cell viability in an OPM-2 cell line based on a CTG assay. [Figure 4] FIG. 1 shows the effect of compound (1A) or a pharma- ceutically acceptable salt thereof, compound (B) or a pharma- ceutically acceptable salt thereof, and compound (C), used alone or in combination, on cell viability in MOLM13 and HL60 cell lines based on a CTG assay. [Diagram 5] FIG. 1 shows the effect of compound (1A) or a pharma- ceutically acceptable salt thereof, compound (B) or a pharma- ceutically acceptable salt thereof, and compound (C), used alone or in combination, on tumor volume in an HL-60 leukemia xenograft model. [Figure 6] FIG. 1 shows the effect of compound (1A) or a pharma- ceutically acceptable salt thereof, compound (B) or a pharma- ceutically acceptable salt thereof, and compound (C), used alone or in combination, on tumor volume in an OPM-2 multiple myeloma model. [Figure 7] FIG. 1 shows the effect of compound (1A) or a pharma- ceutically acceptable salt thereof, compound (B) or a pharma- ceutically acceptable salt thereof, and compound (C), used alone or in combination, on tumor volume in a KMS-12-BM multiple myeloma model. [Figure 8] 1 shows the effect of compound (1A) or a pharma- ceutically acceptable salt thereof, compound (B) or a pharma- ceutically acceptable salt thereof, and compound (C), used alone or in combination, on tumor volume in an MDA-MB-436 triple-negative breast cancer model. [Figure 9]FIG. 1 shows the effect of compound (1A), or a pharma- ceutically acceptable salt thereof, and compound (B), or a pharma- ceutically acceptable salt thereof, used alone or in combination, on tumor volume in an H23 non-small cell lung cancer model. [Figure 10] 1 shows the effect of compound (1A), or a pharma- ceutically acceptable salt thereof, and compound (B), or a pharma- ceutically acceptable salt thereof, used alone or in combination, on tumor volume in a DMS53 small cell lung cancer model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] 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.

[0009] The term "pharmaceutically 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 the compound with inorganic acids, such as hydrohalic acids (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 the compound with organic acids, such as aliphatic or aromatic carboxylic or sulfonic acids, 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 can also be obtained by reacting the compound with a base to form a salt, for example, an ammonium salt, an alkali metal salt, for example, sodium, potassium, or lithium salt, an alkaline earth metal salt, for example, calcium or magnesium salt, a carbonate salt, a bicarbonate salt, a salt with an organic base, for example, a salt with dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and amino acids such as arginine and lysine. With respect to the compounds (A), (B), and (C), those skilled in the art will 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 becomes NH3). + The positive charge is balanced by a negatively charged counterion (Cl - Understand that the following may be taken in various ways:

[0010] 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 in the 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.

[0011] 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).

[0012] 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.

[0013] 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 may 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.

[0014] 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.

[0015] Terms and phrases used in this application, and variations thereof, particularly in the appended claims, should be construed as open-ended and not limiting, unless expressly stated otherwise. As an example above, the word "including" means "including, without limitation." "comprising" should be interpreted to mean "including," "including but not limited to," and the like, and as used herein, the term "comprising" is synonymous with "including," "containing," or "characterized by" and is intended to be inclusive or non-exclusive. is open-ended and does not exclude additional, unrecited elements or method steps, the term "comprising" should be interpreted as "having at least," and the term "include" should be interpreted as "including, but not limited to," The term "example" is used to provide illustrative examples rather than an exhaustive or limiting list of the items under discussion, and the use of terms such as "preferably," "preferred," "desired," or "preferable," 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" is to be interpreted as synonymous with the phrases "having at least" or "comprising 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.

[0016] With respect to the use of substantially any plural and / or singular term herein, those skilled in the art may 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 set forth 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 construed as limiting the scope thereof.

[0017] compound Some embodiments disclosed herein relate to the use of a combination of compounds to treat a disease or condition, where the combination may include an effective amount of compound (A), an effective amount of compound (B) and an effective amount of compound (C), or a pharma- ceutically acceptable salt of any of the foregoing. As provided herein, compound (A) or a pharma- ceutically acceptable salt thereof may be a Bcl-2 inhibitor, compound (B) or a pharma- ceutically acceptable salt thereof may be a WEE1 inhibitor, and compound (C) or a pharma- ceutically acceptable salt thereof may be an agent, such as a chemotherapeutic agent.

[0018] Compound (A) (including pharma- ceutically acceptable salts thereof) is

[0019] [ka] (including pharma- ceutically acceptable salts thereof). Compound (B) may be selected from

[0020] [ka] Compound (C) (including pharmaceutically acceptable salts thereof) can be an agent selected from azacitidine, bendamustine, bortezomib, carfilzomib, ixazomib, busulfan, carboplatin, cytarabine, cyclophosphamide, cladribine, cisplatin, capecitabine, decitabine, dexamethasone, etoposide, fludarabine, gemcitabine, daunorubicin, doxorubicin, ifosfamide, methotrexate, and vincristine, or a pharmaceutically acceptable salt of any of the foregoing.

[0021] Embodiments of combinations of Compound (A), Compound (B), and Compound (C), including pharma- ceutically acceptable salts of any of the foregoing, are provided in Table 1. In Table 1, Numbers 1A-5A correspond to Compound (A) (including pharma- ceutically acceptable salts thereof) provided in Figure 1, "B" indicates Compound (B) (including pharma- ceutically acceptable salts thereof), and Numbers 1-22 correspond to Compound (C) (including pharma- ceutically acceptable salts thereof) provided in Figure 2, including pharma- ceutically acceptable salts thereof.

[0022] [Table 1-1]

[0023] [Table 1-2]

[0024] The order of administration of the compounds in the combinations described herein may vary. In embodiments, compound (A) (including its pharma- ceutically acceptable salts) can be administered before compound (B) or a pharma- ceutically acceptable salt thereof, and before compound (C) (together with its pharma- ceutically acceptable salts). In other embodiments, compound (A) (including its pharma- ceutically acceptable salts) can be administered before compound (B) or a pharma- ceutically acceptable salt thereof, and after administration of compound (C) (together with its pharma- ceutically acceptable salts). In yet other embodiments, compound (A) (including its pharma- ceutically acceptable salts) can be administered before compound (C) or a pharma- ceutically acceptable salt thereof, and after administration of compound (B) or a pharma- ceutically acceptable salt thereof. In yet still other embodiments, compound (A) (including its pharma- ceutically acceptable salts) can be administered after compound (B) or a pharma- ceutically acceptable salt thereof, and after compound (C) or a pharma- ceutically acceptable salt thereof.

[0025] In some embodiments, compound (B) (including its pharma- ceutically acceptable salt) can be administered before compound (A) or a pharma- ceutically acceptable salt thereof, and before compound (C) (together with its pharma- ceutically acceptable salt). In other embodiments, compound (B) (including its pharma- ceutically acceptable salt) can be administered before compound (A) (together with its pharma- ceutically acceptable salt) and after compound (C) or a pharma- ceutically acceptable salt thereof. In yet other embodiments, compound (B) (including its pharma- ceutically acceptable salt) can be administered before compound (C) or a pharma- ceutically acceptable salt thereof, and after compound (A) (including its pharma- ceutically acceptable salt). In still yet other embodiments, compound (B) or its pharma- ceutically acceptable salt can be administered after compound (A) (together with its pharma- ceutically acceptable salt) and after compound (C) or a pharma- ceutically acceptable salt thereof.

[0026] In some embodiments, compound (C) (including its pharma- ceutically acceptable salt) can be administered before compound (A) or a pharma- ceutically acceptable salt thereof, and before compound (B) (together with its pharma- ceutically acceptable salt). In other embodiments, compound (C) (including its pharma- ceutically acceptable salt) can be administered before compound (A) or a pharma- ceutically acceptable salt thereof, and after compound (B) or a pharma- ceutically acceptable salt thereof. In yet other embodiments, compound (C) (including its pharma- ceutically acceptable salt) can be administered before compound (B) (including its pharma- ceutically acceptable salt) and after compound (A) (together with its pharma- ceutically acceptable salt). In still yet other embodiments, compound (C) or its pharma- ceutically acceptable salt can be administered after compound (A) (together with its pharma- ceutically acceptable salt) and after compound (B) or its pharma- ceutically acceptable salt.

[0027] In some embodiments, compound (A) (including a pharma- ceutically acceptable salt thereof) can be administered simultaneously with compound (B), or a pharma- ceutically acceptable salt thereof, and compound (C), or a pharma- ceutically acceptable salt thereof. In other embodiments, compound (B) (including a pharma- ceutically acceptable salt thereof) can be administered simultaneously with compound (A), or a pharma- ceutically acceptable salt thereof, and / or compound (C), or a pharma- ceutically acceptable salt thereof.

[0028] 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.

[0029] In some embodiments, the combinations described herein (e.g., Compound (A), Compound (B) and Compound (C) (with a pharma- ceutically acceptable salt of any of the foregoing) 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. In other embodiments, the combinations described herein (e.g., Compound (A), Compound (B) and Compound (C) (with a pharma- ceutically acceptable salt of any of the foregoing)) 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. The number and / or severity of side effects that can be attributed to a substantially acceptable salt can be reduced.

[0030] 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.

[0031] In some embodiments, the combinations described herein of Compound (A) (including pharma- ceutically acceptable salts thereof), Compound (B) (together with pharma- ceutically acceptable salts thereof), and Compound (C) (including pharma- ceutically acceptable salts thereof) may provide additive effects. In other embodiments, the combinations described herein (such as Compound (A), Compound (B) and Compound (C) (with pharma- ceutically acceptable salts of any of the foregoing)) may provide synergistic effects. In still other embodiments, the combinations described herein (e.g., Compound (A), Compound (B) and Compound (C) (with pharma- ceutically acceptable salts of any of the foregoing)) may provide strong synergistic effects. In still yet other embodiments, the combinations described herein (e.g., Compound (A), Compound (B) and Compound (C) (with pharma- ceutically acceptable salts of any of the foregoing)) are not antagonistic.

[0032] As used herein, the term "antagonistic" means that the activity of the combination of compounds is lower than the sum of the activities of each compound in the combination when the activity of each compound is measured individually (i.e., as a single compound). As used herein, the term "synergistic" means that the activity of the combination of compounds is higher than the sum of the individual activities of each compound in the combination when the activity of each compound is measured individually. As used herein, the term "additive" means that the activity of the combination of compounds is approximately equal to the sum of the individual activities of each compound in the combination when the activity of each compound is measured individually.

[0033] A possible 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 state disclosed herein (such as triple-negative breast cancer, multiple myeloma, acute myeloid leukemia, and / or amyloidosis) 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 combinations described herein may be less compared to the amount of compound (B), or a pharmaceutically acceptable salt thereof, required to achieve the same reduction in a disease marker (e.g., tumor size) when administered as a monotherapy. Another possible advantage of utilizing the combinations described herein is that the use of two or more compounds with different mechanisms of action poses 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, and the elimination of each compound of the combinations described herein. These may include different pathways and / or little overlapping toxicity between the compounds in the combinations described herein.

[0034] Pharmaceutical Compositions Compound (A), including its pharma- ceutically acceptable salts, may be provided in a pharmaceutical composition. Compound (B), including its pharma- ceutically acceptable salts, may be provided in a pharmaceutical composition. Similarly, compound (C), including its pharma- ceutically acceptable salts, may be provided in a pharmaceutical composition. Examples of compound (A), compound (B), and compound (C) are described herein.

[0035] 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. The composition facilitates the administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting the 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 will generally be tailored to the specific intended route of administration.

[0036] 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.

[0037] As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that has no apparent pharmacological activity, but may be pharma- ceutically necessary or desirable. For example, a diluent may be used to bulk 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.

[0038] 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.

[0039] In some embodiments, compound (B) (together with its pharma- ceutically acceptable salt) may be provided in a pharmaceutical composition comprising compound (A) (including its pharma- ceutically acceptable salt), and / or compound (C) (including its pharma- ceutically acceptable salt). In some embodiments, compound (C) (together with its pharma- ceutically acceptable salt) may be provided in a pharmaceutical composition comprising compound (A) (including its pharma- ceutically acceptable salt), and / or compound (B) (including its pharma- ceutically acceptable salt). In other embodiments, compound (B) (together with its pharma- ceutically acceptable salt) may be administered in a pharmaceutical composition that is separate from the pharmaceutical composition comprising compound (A) (including its pharma- ceutically acceptable salt). In yet other embodiments, compound (B) (together with its pharma- ceutically acceptable salt) may be administered in a pharmaceutical composition that is separate from the pharmaceutical composition comprising compound (C) (including its pharma- ceutically acceptable salt). In yet other embodiments, compound (C) or a pharma- ceutically acceptable salt thereof can be administered in a pharmaceutical composition that is separate from a pharmaceutical composition comprising compound (A) (in combination with a pharma- ceutically acceptable salt thereof). In some embodiments, compound (A) or a pharma- ceutically acceptable salt thereof can be administered in a pharmaceutical composition that is separate from a pharmaceutical composition comprising compound (B) or a pharma- ceutically acceptable salt thereof. In other embodiments, compound (A) or a pharma- ceutically acceptable salt thereof can be administered in a pharmaceutical composition that is separate from a pharmaceutical composition comprising compound (B) or a pharma- ceutically acceptable salt thereof, and that is separate from a pharmaceutical composition comprising compound (C) or a pharma- ceutically acceptable salt thereof.

[0040] 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.

[0041] The pharmaceutical compositions disclosed herein can be prepared, for example, by conventional mixing, dissolving, granulating, dragee-making, or other suitable means. It may be prepared in a manner known per se by elutriation, emulsification, encapsulation, entrapment, or tabletting processes. Additionally, 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-ceutical compatible counterions.

[0042] There are multiple techniques in the art for administering compounds, salts, and / or compositions, including, but not limited to, oral, rectal, intrapulmonary, 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 salts) can be administered orally. In some embodiments, compound (B) (including its pharmaceutically acceptable salts) can be administered intravenously, orally, intramuscularly, subcutaneously, and / or topically. In some embodiments, compound (C) (including its pharmaceutically acceptable salts) can be administered orally. In some embodiments, compound (A) (including its pharmaceutically acceptable salts) can be provided to a subject by the same route of administration as compound (B) (together with its pharmaceutically acceptable salts). In other embodiments, compound (A) (including its pharma- ceutically acceptable salts) may be provided to a subject by a different route of administration than compound (B) (along with its pharma- ceutically acceptable salts). In still other embodiments, compound (C) (including its pharma- ceutically acceptable salts) may be provided to a subject by the same route of administration as compound (B) (along with its pharma- ceutically acceptable salts). In still yet other embodiments, compound (C) (including its pharma- ceutically acceptable salts) may be provided to a subject by a different route of administration than compound (B) (along with its pharma- ceutically acceptable salts).

[0043] 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, 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.

[0044] 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 form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the approval by the agency of the form of the drug for human or animal administration. Such notice may, for example, be a label approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. The composition may comprise the compound and / or salt described herein, formulated in a compatible pharmaceutical carrier, and may also be prepared for the treatment of an indicated condition, placed in an appropriate container, and labeled.

[0045] Methods of Use and Treatment As provided herein, in some embodiments, a combination of compounds described herein, such as a combination comprising an effective amount of Compound (A), an effective amount of one or more of Compounds (B), and an effective amount of one or more of Compounds (C), or a pharma- ceutically acceptable salt of any of the foregoing, can be used to treat a disease or condition (including a disease or condition described herein, e.g., triple-negative breast cancer, multiple myeloma, acute myeloid leukemia, and / or amyloidosis) in a subject in need thereof.

[0046] Some embodiments disclosed herein are directed to treating triple-negative breast cancer. For the use of the combination of compounds for the treatment of rheumatoid arthritis, the combination may comprise an effective amount of compound (A), an effective amount of compound (B), or a pharma- ceutically acceptable salt of any of the foregoing, wherein compound (A) is

[0047] [ka] or a pharma- ceutically acceptable salt thereof.

[0048] 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.

[0049] 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.

[0050] The term "effective amount" is used to indicate the amount of an active compound or agent that elicits 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 alleviation of 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 view 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, taking into account body weight, diet, concurrent medications, and medical field. The amount of oxygen that can be absorbed will depend on factors such as the amount of oxygen that can be absorbed, and other factors that one of ordinary skill in the art will recognize.

[0051] For example, an effective amount of a compound or radiation is an amount that results in: (a) a reduction, alleviation, or elimination of one or more symptoms caused by cancer; (b) a reduction in tumor size; (c) elimination of the tumor; and / or (d) long-term disease stabilization (growth cessation) of the tumor.

[0052] In some embodiments, the disease or condition may be triple-negative breast cancer. In some embodiments, the triple-negative breast cancer may be localized triple-negative 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 triple-negative breast cancer may be metastatic triple-negative breast cancer. The subject may have breast cancer that has not been previously treated.

[0053] In some embodiments, the subject may have triple negative 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 yet other embodiments, the subject may be a post-menopausal woman. In other embodiments, the subject may have triple negative breast cancer and may be a man. The subject's serum estradiol concentration may vary. In some embodiments, the subject's serum estradiol concentration (E2) may be in the range of greater than 15 pg / mL to 350 pg / mL. In other embodiments, the subject's serum estradiol concentration (E2) may be 15 pg / mL or less. In other embodiments, the subject's serum estradiol concentration (E2) may be 10 pg / mL or less.

[0054] In some embodiments, the disease or condition can be amyloidosis. Amyloidosis refers to a group of diseases caused by protein misfolding and aggregation into highly ordered amyloid fibrils that deposit in tissues. Some types of amyloidosis include amyloid light-chain (AL) amyloidosis, Amyloidosis includes amyloid type A (AA) amyloidosis, dialysis-related amyloidosis (DRA), familial or hereditary amyloidosis, age-related (senile) systemic amyloidosis, and organ-specific amyloidosis. Left untreated, amyloidosis can lead to progressive organ damage. Current treatments for amyloidosis include chemotherapy, stem cell transplantation therapy, steroid therapy, treatment of the underlying disease, and combinations thereof. In some embodiments, the combination therapy described herein can be used to treat amyloidosis. In some embodiments, the amyloidosis can be selected from amyloid light chain (AL) amyloidosis, amyloid type A (AA) amyloidosis, dialysis-related amyloidosis (DRA), familial or hereditary amyloidosis, age-related (senile) systemic amyloidosis, organ-specific amyloidosis, and combinations thereof. The subject may have amyloidosis that has not been previously treated.

[0055] In some cases, following treatment, the subject may relapse or recur with the disease or condition. As used herein, the terms "relapse" and "recurrence" are used in their normal sense as understood by those of skill in the art. For example, the breast cancer may be recurrent breast cancer. In some embodiments, the subject has relapsed after a previous treatment. By way of example, a subject who has previously been treated for triple-negative breast cancer with an agent described herein may have a recurrence of the triple-negative breast cancer. A non-limiting list of exemplary agents with which a subject diagnosed with recurrent triple-negative breast cancer has previously been treated includes chemotherapeutic agents, PARP inhibitors, and / or PD-L1 inhibitors, such as those described herein. As an additional example, the amyloidosis can be recurrent amyloidosis. In some embodiments, the subject has relapsed after a previous treatment for AL amyloidosis.

[0056] In some embodiments, the disease or condition may be multiple myeloma. In some embodiments, the disease or condition may be acute myeloid leukemia (AML). As with other diseases and conditions described herein, the subject may have previously been treated and subsequently relapsed. For example, a subject diagnosed with multiple myeloma may have previously been treated with an anti-CD38 monoclonal antibody, a proteasome inhibitor, and / or an immunomodulatory agent. In some embodiments, a subject diagnosed with acute myeloid leukemia may have previously been treated with a chemotherapeutic agent.

[0057] The amount of compound, salt, and / or composition required for use in treatment will vary depending on the specific compound or salt selected, 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 at the discretion of the attending physician or clinician.In the case of administration of a pharmaceutically acceptable salt, the dosage amount 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.

[0058] As will be readily apparent to those skilled in the art, the useful in vivo dosages and the specific mode of administration will vary depending on the age, weight, severity of the affliction, the mammalian species being treated, the specific compound being used, and the specific application for which these compounds are being 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), (B) and / or (C), 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).

[0059] Dosage amounts and intervals are adjusted individually to provide plasma concentrations of the active moiety sufficient to maintain a modulating effect or minimal effective concentration (MEC). The MEC may be determined by the concentration of the compound. 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% and most preferably 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

[0060] 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 being 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.

[0061] 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 evaluating in vitro toxicity on cell lines, such as mammalian cell lines, preferably human cell lines. The results of such studies are often predictive of 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

[0062] Further embodiments, which are not intended to limit the scope of the claims in any way, are disclosed in more detail in the following examples.

[0063] Cell proliferation was measured using the CellTiter-Glo® luminescent cell viability assay, which involved the direct addition of a single reagent (CellTiter-Glo® Reagent) to cells cultured in serum-supplemented medium. OPM-2, MOLM-13 and HL-60 cells were cultured according to ATCC recommendations and 10,000 cells were seeded per well.

[0064] Compound (1A), Compound (B) and dexamethasone or azacytidine were prepared as DMSO stock solutions (10 mM). For the OPM-2 cell line, compounds were tested in triplicate using dexamethasone. MOLM-13 and HL-60 cell line compounds were tested in triplicate using azacytidine. The respective concentrations are shown in Figures 3 and 4 and summarized in Tables 2 and 3. Plates were incubated at 37°C, 5% CO2 for 72 hours and then cooled to room temperature. The plates were equilibrated at room temperature (RT) for approximately 30 minutes. An equal volume of CellTiter-Glo® Reagent (100 μL) was added to each well. The plates were mixed on an orbital shaker for 2 minutes to induce cell lysis and then incubated at room temperature for 10 minutes to stabilize the luminescence signal. Luminescence (relative light units (RLU), Relative light units (RLU) were recorded. Percent inhibition was calculated using the following formula: % inhibition = (RLU x 100 / (RLU of cellular background)).

[0065] [Table 2]

[0066] [Table 3]

[0067] Xenograft tumor models Mice were cultured with 95% viable tumor cells (1 × 10 ) in 100 μL of serum-free IMDM-Matrigel mixture (1:1 ratio) for tumor development. 7 HL-60 cells were inoculated subcutaneously into the right flank as a single-cell suspension of 100 μg / ml of HL-60 cells. The average tumor size was approximately 214 mm. 3 (Individual tumor sizes ranged from 185 to 245 mm 3) was reached. Animals were randomly assigned to treatment groups of 10 animals each, and were dosed with vehicle and the indicated compound at the indicated doses and frequencies as shown in Figure 5 and Table 4. In Figure 5, the bottom line is Compound (1A) 25 mg / kg poqd x 21 + Compound (B) 30 mg / kg popd x 21 + Azacitidine 1 mg / kg IP 5 days on 2 days off x 3 cycles, the second line from the bottom is Compound (1A) + Compound (B), the third line from the bottom is Compound (1A) + Azacitidine, the fourth line from the bottom is Compound (1A), the top line is vehicle, the second line from the top is Compound (B), and the remaining two lines are Azacitidine (shown as triangles) and Compound (B) + Azacitidine (shown as diamonds). Tumor volumes were assessed twice weekly to calculate tumor volume over time, and mice were weighed twice weekly as a surrogate for signs of toxicity. Tumor growth inhibition (TGI) was calculated using the following formula: TGI=(1-(Td The tumor volume was calculated using (-T0) / (Cd-C0)×100%. Td and Cd are the mean tumor volumes of treated and control animals, and T0 and C0 are the mean tumor volumes of treated and control animals at the start of the study. Tumor regression was defined as the individual tumor volume (TV) reduction (end TV compared to initial TV). Figure 5 and Table 4 illustrate the single, double and triple treatment of compound (1A) at 25 mg / kg, compound (B) at 30 mg / kg and azacitidine at 1 mg / kg. The combination of compound (1A) (25 mg / kg) + compound (B) (30 mg / kg) with azacitidine exhibited 90% tumor growth inhibition at day 18.

[0068] [Table 4]

[0069] Mice were treated with 100 μL of serum-free IMDM-Matrigel mixture ( 95% viable tumor cells (1 × 10 7OPM-2 cells were inoculated subcutaneously into the right flank as a single cell suspension of 100 μg / ml. The average tumor size was approximately 200 mm. 3 (Individual tumor sizes ranged from 185 to 225 mm 3 ) treatment was initiated. Animals were randomly assigned to treatment groups of 10 animals each and dosed with vehicle and the indicated compound at the indicated doses and frequencies as shown in Figure 6 and Table 5. In Figure 6, the bottom line is Compound (1A) 100 mg / kg poqd x 21 + Compound (B) 60 mg / kg popd x 21 + Bortezomib 0.5 mg / kg IP BIW (twice weekly) x 3, the second line from the bottom is Compound (1A) + Compound (B), the third line from the bottom is Compound (B) + Bortezomib, the fourth line from the bottom is Compound (B), the top line is vehicle, the second line from the top is Bortezomib, the third line from the top (shown as a square) is Compound (1A), and the fourth line from the top is Compound (1A) + Bortezomib. Tumor volumes were assessed twice weekly to calculate tumor volume over time, and mice were weighed twice weekly as a surrogate for signs of toxicity. Tumor growth inhibition (TGI) was calculated using the following formula: TGI=(1-(Td-T0) / (Cd-C0))×100%. Td and Cd are the mean tumor volumes of treated and control animals, and T0 and C0 are the mean tumor volumes of treated and control animals at the start of the study. Tumor regression was defined as the individual tumor volume (TV) reduction (end TV compared to initial TV). Figure 6 and Table 5 illustrate single, double and triple treatments with 100 mg / kg compound (1A), 60 mg / kg compound (B) and 0.5 mg / kg bortezomib. The combination of Compound (1A) (100 mg / kg) + Compound (B) (60 mg / kg) with bortezomib exhibited 87% tumor growth inhibition at day 17. Additionally, the triple combination resulted in tumor retention compared to the single agents and the doublet combination.

[0070] [Table 5]

[0071] Mice were cultured with 95% viable tumor cells (1 × 10 ) in 100 μL of serum-free IMDM-Matrigel mixture (1:1 ratio) for tumor development. 7 ) and inoculated subcutaneously into the right flank with KMS-12-BM cells. The average tumor size was approximately 193 mm 3 (Individual tumor sizes ranged from 185 to 220 mm 3 ) treatment was initiated. Animals were randomly assigned to treatment groups of 10 animals each and dosed with vehicle and the indicated compound at the indicated doses and frequencies as shown in Figure 7 and Table 6. In Figure 7, the bottom line is Compound (1A) 100 mg / kg poqd x 21 + Compound (B) 60 mg / kg popd x 21 + Dexamethasone 1 mg / kg IP 5 days on 2 days off x 3, the second line from the bottom is Compound (1A) + Compound (B), the third line from the bottom is Compound (B) + Dexamethasone, the fourth line from the bottom (shown as triangles) is Compound (B), the top line is vehicle, the second line from the top is Dexamethasone, the third line from the top is Compound (1A), and the remaining lines are Compound (1A) + Dexamethasone. Tumor volumes were assessed twice weekly to calculate tumor volume over time, and mice were weighed twice weekly as a surrogate for signs of toxicity. Tumor growth inhibition (TGI) was calculated using the formula: TGI=(1-(Td-T0) / ( The tumor regression rate was calculated using the formula: (1-(Td / T0))×100%. Td and Cd are the mean tumor volumes of treated and control animals, and T0 and C0 are the mean tumor volumes of treated and control animals at the start of the study. Tumor regression was defined as the individual tumor volume (TV) reduction (end TV compared to initial TV). Tumor regression rate was calculated using the formula: (1-(Td / T0))×100%. Figure 7 and Table 6 illustrate the single, double and triple treatment of 100 mg / kg compound (1A), 60 mg / kg compound (B) and 1 mg / kg dexamethasone. The combination of compound (1A) (100 mg / kg) + compound (B) (60 mg / kg) with dexamethasone exhibited 113% tumor growth inhibition at day 10 and 79% tumor regression at day 21.

[0072] [Table 6]

[0073] Mice were cultured with 95% viable tumor cells (1 × 10 ) in 100 μL of serum-free DMDM-Matrigel mixture (1:1 ratio) for tumor development. 7 ) and MDA-MB-436 cells (a TNBC breast cancer cell line) were inoculated subcutaneously in the right flank. The average tumor size was approximately 210 mm per model. 3 (Individual tumor volumes ranged from 180 to 240 mm 3 ) treatment was initiated. Animals were randomly assigned to treatment groups of 8 animals each and dosed with vehicle and the indicated compound at the indicated doses and frequencies as shown in Figure 8 and Table 7. In Figure 8, the top line (shown as circles) is the vehicle control, the second line from the top (shown as diamonds) is compound (1A) (200 mg / kg 10 mL / kg poqd x 40), and the third line from the top (shown as triangles) is compound (B) (60 mg / kg 10 mL / kg poqd x 40). The bottom line (shown as circles) is compound (1A) (200 mg / kg 10 mL / kg poqd x 40) + compound (B) (60 mg / kg 10 mL / kg poqd x 40). Tumor volumes were assessed twice weekly to calculate tumor volume over time and mice were weighed twice weekly as a surrogate for signs of toxicity. Tumor growth inhibition (TGI) was calculated using the following formula: TGI=(1-(Td-T0) / (Cd-C0))×100%. Td and Cd are the mean tumor volumes of treated and control animals, and T0 and C0 are the mean tumor volumes of treated and control animals at the start of the study. Tumor regression was defined as the individual tumor volume (TV) reduction (end TV compared to initial TV). Figure 8 and Table 7 illustrate that monotherapy with compound (1A) at 200 mg / kg resulted in 60% efficacy, and monotherapy with compound (B) at 60 mg / kg resulted in 55% efficacy. In contrast, the combination of compound (1A) (200 mg / kg) and compound (B) (60 mg / kg) exhibited a significant TGI of 83% at day 40.

[0074] [Table 7]

[0075] Multiple Myeloma Model Multiple myeloma (MM) cell lines containing either a translocation at (11;14) (i.e., KMS-12BM) or not containing a translocation at (11;14) (i.e., OPM-2) are selected. It is understood that compound activity in MM models is predictive of activity in amyloidosis (e.g., AL amyloidosis) models and / or patients.

[0076] The combination effect of compound (A) with dexamethasone is studied in the KMS-12-BM mouse model. Mice are inoculated with 95% viable tumor cells (1×10 6 cells / mL) in 200 μL of serum-free RPMI-1640 Matrigel mixture (1:1 ratio) for tumor development. 7 ) and inoculate KMS-12-BM cells subcutaneously in the right flank. The average tumor size is approximately 200 mm 3 (Individual tumor sizes ranged from 180 to 220 mm 3 ) is reached. Animals are randomly assigned to treatment groups of 10 each, and each group is dosed with vehicle and compound at a given dose and frequency. Tumor volume is assessed twice weekly to calculate tumor volume over time, and mice are weighed twice weekly as a surrogate for signs of toxicity. Tumor growth inhibition (TGI) is calculated using the formula: TGI=(1-(T d -T0) / (C d Calculate using -C0)) x 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.

[0077] The combination effect of compound (A) with bortezomide is studied in the KMS-12-BM mouse model. Mice are inoculated with 95% viable tumor cells (1×10 6 cells / mL) in 200 μL of serum-free RPMI-1640 Matrigel mixture (1:1 ratio) for tumor development. 7) and inoculate KMS-12-BM cells subcutaneously in the right flank. The average tumor size is approximately 200 mm 3 (Individual tumor sizes ranged from 180 to 220 mm 3 ) is reached. Animals are randomly assigned to treatment groups of 10 each, and each group is dosed with vehicle and the indicated compound at the prescribed dose and frequency. Tumor volume is assessed twice weekly to calculate tumor volume over time, and mice are weighed twice weekly as a surrogate for signs of toxicity. Tumor growth inhibition (TGI) is calculated using the following formula: TGI=(1-(T d -T0) / (C d Calculate using -C0)) x 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.

[0078] Lung cancer model The data was generated using the xenograft tumor model provided in WO 2021 / 127044 utilizing a combination of Compound (1A) and Compound (B) using H23 (non-small cell lung) cells or DMS53 (small cell lung) cells instead of HL-60 cells. The data demonstrates that the dual combination of Compound (1A) + Compound (B) has increased efficacy compared to the efficacy when each of the aforementioned compounds is used as a single agent. The results are shown in Figures 9 and 10. As shown in both figures, the efficacy of the dual combination of Compound (1A) and Compound (B) was maintained even using different dosing schedules. In Figure 9 , the top line (shown as a circle, which is the vehicle), the second line from the top (shown as a diamond) is compound (1A), the second line from the bottom (shown as a triangle) is compound (B), and the bottom line (shown as a circle) is compound (1A) + compound (B). In FIG. 10, the top line (shown as a circle, which is the vehicle), the second line from the top (shown as a square) is compound (B), the second line from the bottom (shown as a diamond) is compound (1A), and the bottom line (shown as a diamond) is compound (1A) + compound (B).

[0079] The data in Tables 2-6 and Figures 3-7 demonstrate that the triple combination of compound (A)-Bcl-2 inhibitor, compound (B)-WEE1 inhibitor and anticancer drugs (dexamethasone, bortezomib and azacitidine) is more effective for treating cancers compared to single and double agents such as multiple myeloma (KMS-12-BM and OPM-2) and leukemia (MOLM13 and HL60). In addition, as shown in Table 7 and Figures 9 and 10, the dual combination of compound (A)-Bcl-2 inhibitor and compound (B)-WEE1 inhibitor is effective against cancers such as non-small cell lung cancer and small cell lung cancer.

[0080] Furthermore, although the above has been described in some detail with reference to the figures and examples for 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 disclosure.

Claims

1. 1. Use of a combination of compounds for treating a disease or condition, said combination comprising an effective amount of compound (A), an effective amount of compound (B), and an effective amount of compound (C), or a pharma- ceutically acceptable salt of any of the foregoing; Compound (A) is 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof; Compound (B) is 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof; 13. The use wherein compound (C) is an agent selected from the group consisting of azacitidine, bendamustine, bortezomib, carfilzomib, ixazomib, busulfan, carboplatin, cytarabine, cyclophosphamide, cladribine, cisplatin, capecitabine, decitabine, dexamethasone, etoposide, fludarabine, gemcitabine, daunorubicin, doxorubicin, ifosfamide, methotrexate and vincristine, or a pharma- ceutically acceptable salt of any of the foregoing.

2. The BCL-2 inhibitor is 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

3. The BCL-2 inhibitor is 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof.

4. The BCL-2 inhibitor is 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof.

5. The BCL-2 inhibitor is 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof.

6. The BCL-2 inhibitor is 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof.

7. The use according to any one of claims 1 to 6, wherein compound (C) is azacitidine.

8. The use according to any one of claims 1 to 6, wherein compound (C) is bortezomib.

9. The use according to any one of claims 1 to 6, wherein compound (C) is dexamethasone.

10. The method according to any one of claims 1 to 9, wherein the disease or condition is selected from the group consisting of triple-negative breast cancer, multiple myeloma, acute myeloid leukemia, lung cancer and amyloidosis. Use as described.

11. 11. The use according to claim 10, wherein the disease or condition is triple-negative breast cancer.

12. The use according to claim 11, wherein the triple negative breast cancer is a localized breast cancer.

13. The use of claim 11, wherein the triple negative breast cancer is metastatic breast cancer.

14. The use of claim 11, wherein the triple negative breast cancer is recurrent breast cancer.

15. 15. The use of any one of claims 11 to 14, wherein the triple negative breast cancer has been previously treated with one or more agents selected from the group consisting of chemotherapeutic agents, PARP inhibitors and PD-L1 inhibitors.

16. The use according to any one of claims 11 to 15, wherein the triple negative breast cancer is present in a woman.

17. 17. The use of claim 16, wherein the subject is a premenopausal woman.

18. 17. The use of claim 16, wherein the subject is a peri-menopausal woman.

19. 17. The use according to claim 16, wherein the subject is a menopausal woman.

20. 17. The use of claim 16, wherein the triple negative breast cancer is in a postmenopausal woman.

21. The use according to any one of claims 11 to 15, wherein the triple negative breast cancer is in a male.

22. 22. The use of any one of claims 11 to 21, wherein the triple negative breast cancer is present in a subject with a serum estradiol concentration in the range of greater than 15 pg / mL to 350 pg / mL.

23. The use according to any one of claims 11 to 21, wherein the triple-negative breast cancer is present in a subject with a serum estradiol concentration of 15 pg / mL or less.

24. The use according to any one of claims 11 to 21, wherein the triple-negative breast cancer is present in a subject with a serum estradiol concentration of 10 pg / mL or less.

25. The use according to any one of claims 1 to 10, wherein the disease or condition is amyloidosis.

26. The use according to any one of claims 1 to 10, wherein the disease or condition is multiple myeloma.

27. The use according to any one of claims 1 to 10, wherein the disease or condition is acute myeloid leukemia.

28. The use according to any one of claims 1 to 10, wherein the disease or condition is lung cancer.

29. 29. The use of claim 28, wherein the lung cancer is non-small cell lung cancer.

30. 29. The use of claim 28, wherein the lung cancer is small cell lung cancer.

31. The use according to any one of claims 1 to 13 or 16 to 30, wherein the disease or disorder has not been previously treated.

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