Methods of using compounds to treat hematological malignancies

Abstract

The present invention relates to methods of treating hematological malignancies using 2-(2,6-dioxopiperidin-3-yl-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione. In particular, provided herein are methods of treating, preventing, or managing hematological malignancies using 2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof.

Description

[0001] This application is a divisional application of PCT application PCT / US2020 / 056408, filed on October 20, 2020, entitled "Method for treating hematologic malignancies using 2-(2,6-dioxadiazin-3-yl-4-((2-fluoro-4-((3-morpholinoazacyclobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione". The PCT application entered the Chinese national phase on June 20, 2022, and the application number is 202080088925.X.

[0002] This application claims priority to U.S. Provisional Application No. 62 / 924,028, filed October 21, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This article provides methods for treating, preventing, or managing hematologic malignancies using 2-(2,6-dioxadiazin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione, or an enantiomer, mixture of enantiomers, tautomers, isotope variants, or pharmaceutically acceptable salts thereof. Background Technology

[0004] The main characteristics of cancer are an increase in the number of abnormal cells originating from a given normal tissue, the invasion of these abnormal cells into adjacent tissues, or the lymphatic or hematogenous spread of malignant cells to local lymph nodes and distant sites. Clinical data and molecular biological studies indicate that cancer is a multi-step process that begins with small pretumoral changes, which may, in some cases, progress to tumor formation. Neoplastic lesions can undergo clonal evolution and develop an increasing capacity for invasion, growth, metastasis, and heterogeneity, especially when the tumor cells evade the host's immune surveillance. Current cancer treatments may include surgery, chemotherapy, hormone therapy, and / or radiation therapy to eradicate tumor cells from the patient's body. Rajkumar et al. discussed recent advances in cancer treatment in Nature Reviews Clinical Oncology 11, 628-630 (2014).

[0005] For patients, all current cancer treatments may have significant drawbacks. For example, surgery may be impossible or unacceptable to the patient due to their health condition. Additionally, surgery may not completely remove tumor tissue. Radiation therapy is only effective when the tumor tissue shows a higher sensitivity to radiation than normal tissue. Radiation therapy can also frequently cause serious side effects. Hormone therapy is rarely used as a single treatment. While hormone therapy can be effective, it is often used to prevent or delay cancer recurrence after other treatments have removed most of the cancer cells.

[0006] Despite the availability of various chemotherapy agents, chemotherapy has many drawbacks. Almost all chemotherapy agents are toxic, and chemotherapy causes significant and often dangerous side effects, including severe nausea, bone marrow suppression, and immunosuppression. Furthermore, even with combination therapy, many tumor cells develop resistance to chemotherapy agents. In fact, these cells that are resistant to a specific chemotherapy agent used in a treatment regimen often prove resistant to other drugs, even if those drugs act through different mechanisms than those used in the specific treatment. This phenomenon is known as multidrug resistance. Due to resistance, many cancers prove or become refractory to standard chemotherapy regimens.

[0007] Hematologic malignancies are forms of cancer that originate in hematopoietic tissues, such as bone marrow or immune system cells. Examples of hematologic malignancies include leukemia, lymphoma, multiple myeloma, and myelodysplastic syndromes (MDS). More specific examples of hematologic malignancies include, but are not limited to, marginal zone lymphoma (MZL) (including splenic marginal zone lymphoma (SMZL)), Burkitt lymphoma (BL), multiple myeloma (MM) (including plasma cell leukemia (PCL)), myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) (including B-cell AML), acute lymphoblastic leukemia (ALL), T-cell lymphoma (TCL) (including anaplastic large cell lymphoma (ALCL) and Cezari syndrome), and Hodgkin lymphoma (HL).

[0008] Any reference cited or identified in this section of this application shall not be construed as an admission that such reference is prior art. Summary of the Invention

[0009] This article provides methods for treating, preventing, or managing hematologic malignancies using 2-(2,6-dioxadiazin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione, or an enantiomer, mixture of enantiomers, tautomers, isotope variants, or pharmaceutically acceptable salts thereof.

[0010] In some embodiments, this document provides a method for treating hematologic malignancies, comprising administering to an individual in need a therapeutically effective amount of a compound of formula 1 or a tautomer thereof, an isotopic variant thereof or a pharmaceutically acceptable salt thereof.

[0011]

[0012] In some embodiments, this document provides a method for treating hematologic malignancies, comprising administering to an individual in need a therapeutically effective amount of a compound of formula 2 or a tautomer thereof, an isotopic variant thereof or a pharmaceutically acceptable salt thereof.

[0013]

[0014] In some embodiments, this document provides a method for treating hematologic malignancies, comprising administering to an individual in need a therapeutically effective amount of a compound of formula 3 or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant thereof or a pharmaceutically acceptable salt thereof.

[0015]

[0016] In some embodiments, this document provides a method for treating hematologic malignancies, wherein the compound is compound 1 of the following formula:

[0017]

[0018] Or its tautomers, isotopic variants or pharmaceutically acceptable salts, wherein the method comprises administering a therapeutically effective amount of compound 1 to an individual in need.

[0019] In some embodiments, this document provides a compound for a method of treating hematologic malignancies, wherein the compound is compound 2 having the following formula:

[0020]

[0021] Or its tautomers, isotopic variants or pharmaceutically acceptable salts, wherein the method comprises administering a therapeutically effective amount of compound 2 to an individual in need.

[0022] In some embodiments, this document provides a compound for a method of treating hematologic malignancies, wherein the compound is compound 3 having the following formula:

[0023]

[0024] Or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts, wherein the method comprises administering a therapeutically effective amount of compound 3 to an individual in need.

[0025] In some embodiments, the hematologic malignancy is marginal zone lymphoma (MZL) (including splenic marginal zone lymphoma (SMZL)), Burkitt lymphoma (BL), multiple myeloma (MM) (including plasma cell leukemia (PCL)), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) (including B-cell AML), acute lymphoblastic leukemia (ALL), T-cell lymphoma (TCL) (including anaplastic large cell lymphoma (ALCL) and Cezari syndrome), or Hodgkin lymphoma (HL).

[0026] In some implementations, the hematologic malignancy is recurrent or refractory.

[0027] A more comprehensive understanding of embodiments of the invention can be obtained by referring to the detailed description and examples intended to illustrate non-limiting implementations.

[0028] Detailed description

[0029] definition

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications are incorporated herein by reference in their entirety. Where a term has multiple definitions in this document, the definition in this section shall prevail unless otherwise stated.

[0031] As used herein, in the specification and appended claims, unless the context clearly indicates otherwise, the indefinite articles “a” and “an” and the definite article “the” include both plural and singular references.

[0032] As used herein, the terms “comprising” and “including” are used interchangeably. The terms “comprising” and “including” should be interpreted as specifying the presence of the mentioned features or components, but do not preclude the presence or addition of one or more features or components or combinations thereof. Furthermore, the terms “comprising” and “including” are intended to encompass examples covered by the term “consisting of”. Therefore, the term “consisting of” may be used in place of the terms “comprising” and “including” to provide more specific embodiments of the invention.

[0033] The term "composed of" means that a subject matter has at least 90%, 95%, 97%, 98%, or 99% of the said features or components thereof. In another embodiment, the term "composed of" excludes any other features or components from the scope of any subsequent description, except those features or components that are essential to the desired technical effect.

[0034] As used herein, the term "or" will be interpreted as inclusive "or," meaning either one or any combination thereof. Therefore, "A, B, or C" refers to any of the following: "A; B; C; A and B; A and C; B and C; A, B, and C." Exceptions to this definition will only occur if the combination of elements, functions, steps, or actions is inherently mutually exclusive in some respect.

[0035] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic acid or base, including inorganic acids and bases as well as organic acids and bases. Suitable pharmaceutically acceptable base addition salts of the compounds described herein include, but are not limited to, metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucosamine), and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, glucuronic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucilage, nitric acid, dihydroxynaphthyl acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, p-aminobenzenesulfonic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Others are known in the art; see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th edition, Mack Publishing, Easton PA (1995).

[0036] As used herein and unless otherwise stated, the terms "stereoisomer" or "stereoisomer-pure" refer to a stereoisomer of a compound that is substantially free of other stereoisomers of the compound. For example, a stereoisomer-pure compound having one chiral center will be substantially free of its opposite enantiomers. A stereoisomer-pure compound having two chiral centers will be substantially free of other diastereomers of the compound. Conventional stereoisomer-pure compounds contain more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound; more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound; more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound; and more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. Compounds may have chiral centers and may exist as racemates, individual enantiomers or diastereomers, or mixtures thereof. All such isomers, including mixtures thereof, are included in the embodiments provided herein.

[0037] The use of stereoisomeric pure forms of such compounds, as well as mixtures of those forms, is included in the embodiments provided herein. For example, mixtures comprising equal or unequal amounts of enantiomers of a particular compound can be used in the methods and compositions provided herein. These isomers can be resolved by asymmetric synthesis or using standard techniques such as chiral columns or chiral resolving agents. See, for example, Jacques, J. et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972): Todd, M., Separation of Enantiomers: Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science&Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0038] It should be understood that the compounds provided herein may contain a chiral center. Such a chiral center may be in (R) or (S) configuration, or a mixture thereof. It should be understood that the chiral center of the compounds provided herein may undergo epimerization in vivo. Therefore, those skilled in the art will recognize that, for compounds undergoing epimerization in vivo, administration of the compound in its (R) form is equivalent to administration of the compound in its (S) form.

[0039] Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography on a chiral stationary phase.

[0040] "Tautomers" refer to the isomers of a compound that are in equilibrium with each other. The concentration of the isomers will depend on the environment in which the compound is found and can vary depending on, for example, whether the compound is a solid or in an organic solution or an aqueous solution. For example, in aqueous solution, pyrazole may exhibit the following isomers, which are referred to as tautomers of each other:

[0041]

[0042] As will be readily understood by those skilled in the art, a variety of functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds are within the scope of the compounds provided herein.

[0043] It should also be noted that the compounds described herein may contain atomic isotopes in non-natural proportions at one or more atoms. For example, the compounds may be radiolabeled with radioactive isotopes, such as tritium ( 3 H), Iodine-125 ( 125 I), sulfur-35( 35 S) or carbon-14 ( 14 C), or it could be isotopically enriched, such as deuterium (C). 2 H), carbon-13 ( 13 C) or nitrogen-15 ( 15(N) enriched. As used herein, an "isotope variant" is an isotope-enriched compound. The term "isotope enrichment" refers to an atom having an isotopic composition different from that of the naturally occurring atom. "Isotope enrichment" can also refer to a compound containing at least one atom having an isotopic composition different from that of the naturally occurring atom. The term "isotopic composition" refers to the amount of each isotope present in a given atom. Radiolabeled and isotope-enriched compounds can be used as therapeutic agents, such as cancer therapeutic agents, research reagents, such as combination assays, and diagnostic agents, such as in vivo imaging agents. All isotope variants of the compound, whether or not radioactive, are intended to be included within the scope of compounds as provided herein. In some embodiments, isotope variants of the compound are provided herein, for example, isotope variants enriched in deuterium, carbon-13 (N), ... 13 C) and / or nitrogen-15 ( 15 Compounds containing N. As used herein, "deuterated" means that at least one hydrogen (H) in which a hydrogen atom (N) has been deuterated (by D or N). 2 H represents a compound that has been substituted with deuterium, meaning that the compound is rich in deuterium at at least one position.

[0044] It should be understood that, regardless of stereoisomerism or isotopic composition, each compound provided herein may be provided in the form of any of the pharmaceutically acceptable salts provided herein. Similarly, it should be understood that the isotopic composition may vary independently of the stereoisomer composition of each compound provided herein. Furthermore, while the isotopic composition is limited by the elements present in the respective compound or its salts, it may also vary independently of the choice of pharmaceutically acceptable salts of the respective compound.

[0045] It should be noted that if there is a difference between the described structure and its name, the described structure should be given greater weight.

[0046] As used herein and unless otherwise specified, the term “treatment” means the relief (in whole or in part) of a symptom, disease, or condition or one or more symptoms associated with the symptom, disease, or condition, or the slowing or halting of the further progression or worsening of those symptoms, or the relief or eradication of the cause of the symptom, disease, or condition itself.

[0047] As used herein and unless otherwise specified, the term “prevention” means delaying and / or preventing the onset, recurrence or spread of a condition, disease or illness (in whole or in part); preventing an individual from contracting a condition, disease or illness; or reducing an individual’s risk of contracting a condition, disease or illness.

[0048] As used herein and unless otherwise specified, the term “management” includes preventing a patient who has previously suffered from a particular disease or condition from recurring the disease or condition, prolonging the time a patient who has previously suffered from the disease or condition remains in remission, reducing patient mortality, and / or maintaining or preventing the occurrence of symptoms associated with the managed disease or condition.

[0049] As used herein and unless otherwise stated, the term “effective amount” in relation to a compound means an amount that is sufficient to treat, prevent, or manage a disease, condition, or its symptoms.

[0050] As used herein and unless otherwise stated, the terms “individual” or “patient” include animals, including but not limited to animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs. In one embodiment, an individual is a mammal, and in another embodiment, a human.

[0051] As used herein and unless otherwise stated, the term "relapse" refers to a condition, disease, or illness that initially responded to treatment (e.g., achieved a complete response) and subsequently progressed. The treatment may include first-line or multiple-line therapy. In one embodiment, the condition, disease, or illness has been previously treated with first-line or multiple-line therapy. In another embodiment, the condition, disease, or illness has been previously treated with first-line, second-line, third-line, or fourth-line therapy. In one embodiment, the condition, disease, or illness is a hematologic malignancy, such as MZL (including SMZL), BL, MM (including PCL), MDS, AML (including B-cell AML), ALL, TCL (including ALCL and Cezari syndrome), or HL.

[0052] As used herein and unless otherwise stated, the term "refractory" refers to a condition, disease, or illness that has not responded to prior treatment, including first-line or multiple lines of therapy. In one embodiment, the condition, disease, or illness has been previously treated with first, second, third, or fourth-line therapy. In one embodiment, the condition, disease, or illness has been previously treated with two or more lines of therapy and has a lower than complete response (CR) to the most recent regimen involving systemic therapy. In one embodiment, the condition, disease, or illness is a hematologic malignancy, such as MZL (including SMZL), BL, MM (including PCL), MDS, AML (including B-cell AML), ALL, TCL (including ALCL and Cezari syndrome), or HL.

[0053] In the case of cancer, such as hematologic malignancies, inhibitory effects can be assessed by: inhibiting disease progression, inhibiting tumor growth, reducing primary tumor size, alleviating tumor-related symptoms, inhibiting tumor-secreting factors, delaying the onset of primary or secondary tumors, slowing the development of primary or secondary tumors, reducing the occurrence of primary or secondary tumors, mitigating or reducing the severity of secondary disease effects, preventing tumor growth and regression, increasing time to progression (TTP), increasing progression-free survival (PFS), and increasing overall survival (OS). OS, as used in this article, refers to the time from the start of treatment to death from any cause. TTP, as used in this article, refers to the time from the start of treatment to tumor progression; TTP does not include death. In one implementation, PFS refers to the time from the start of treatment to tumor progression or death. In one implementation, PFS refers to the time from the first administration of the compound to the first occurrence of disease progression or death from any cause. In one implementation, the PFS rate is calculated by computer using the Kaplan-Mayer estimation method. Event-free survival (EFS) refers to the time from the start of treatment to any treatment failure, including disease progression, interruption of treatment for any cause, or death. In one implementation, the overall response rate (ORR) refers to the percentage of patients who achieve a response. In one implementation, ORR represents the sum of the percentages of patients who achieve a complete response and a partial response. In one implementation, ORR represents the percentage of patients whose best response is ≥ a partial response (PR). In one implementation, the duration of response (DoR) is the time from achieving a response to relapse or disease progression. In one implementation, DoR is the time from achieving a response ≥ a partial response (PR) until relapse or disease progression. In one implementation, DoR is the time from the first recorded response to the first recorded progressive disease or death. In one implementation, DoR is the time from the first recorded response ≥ a partial response (PR) to the first recorded progressive disease or death. In one implementation, the time to response (TTR) refers to the time from the first administration of the compound to the first recorded response. In one implementation, TTR refers to the time from the first administration of the compound to the first recorded response ≥ a partial response (PR). In extreme cases, complete inhibition is referred to herein as prophylaxis or chemoprevention. In this document, the term "prophylaxis" includes both prevention of the onset of clinically apparent cancer and prevention of the onset of cancer at a preclinically apparent stage. This definition also includes prevention of conversion to malignant cells or stopping or reversing the progression of preclinical cells to malignant cells. This includes preventative treatment for people at risk of developing cancer.

[0054] In some implementations, a stable disease or its absence can be determined by methods known in the art, such as assessment of patient symptoms, physical examination, visualization of imaged tumors, for example using FDG-PET (fluorodeoxyglucose positron emission tomography), PET / CT (positron emission tomography / computed tomography) scans, MRI (magnetic resonance imaging) of the brain and spine, CSF (cerebrospinal fluid), ophthalmological examination, vitreous fluid sampling, retinal photography, bone marrow assessment, and other generally accepted assessment methods.

[0055] As used herein and unless otherwise indicated, the terms "co-administered" and "in combination with" include the simultaneous, concurrent, or sequential administration of one or more therapeutic agents (e.g., a compound provided herein and another anticancer agent or supportive care agent) without specific time limitations. In one embodiment, the active agent is simultaneously present in cells or in the patient's body, or exerts its biological or therapeutic effects simultaneously. In one embodiment, the therapeutic agent is in the same composition or unit dosage form. In another embodiment, the therapeutic agent is in a separate composition or unit dosage form.

[0056] The term "supportive care agent" refers to any substance that treats, prevents, or manages adverse reactions resulting from treatment with another therapeutic agent.

[0057] As used herein, unless otherwise stated, the terms “about” and “approximately” when used in conjunction with a dose, amount, or weight percentage of an ingredient in a composition or dosage form mean a dose, amount, or weight percentage that is recognized by those skilled in the art to provide a pharmacological effect equivalent to that obtained from a specified dose, amount, or weight percentage. In one embodiment, the terms “about” and “approximately” as used in the context herein refer to a dose, amount, or weight percentage within 30%, 20%, 15%, 10%, or 5% of a specified dose, amount, or weight percentage.

[0058] compound

[0059] The compound (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione, also referred to as "Compound 1", is provided for use in the methods provided herein:

[0060]

[0061] Or its tautomers, isotopic variants, or pharmaceutically acceptable salts. This article provides for compound 1 used in the treatment methods provided herein.

[0062] Also provided is the compound (R)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione, also referred to as "compound 2", used in the methods provided herein:

[0063]

[0064] Or its tautomers, isotopic variants, or pharmaceutically acceptable salts. This document provides for compound 2 used in the treatments described herein.

[0065] Compound 2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione, also referred to as "compound 3", is provided for use in the methods provided herein:

[0066]

[0067] Or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts. This document provides for compound 3 used in the treatments described herein.

[0068] In one embodiment, compound 1 is used in the method provided herein. In one embodiment, a tautomer of compound 1 is used in the method provided herein. In one embodiment, an isotopic variant of compound 1 is used in the method provided herein. In one embodiment, a pharmaceutically acceptable salt of compound 1 is used in the method provided herein.

[0069] In one embodiment, compound 2 is used in the method provided herein. In one embodiment, a tautomer of compound 2 is used in the method provided herein. In one embodiment, an isotopic variant of compound 2 is used in the method provided herein. In one embodiment, a pharmaceutically acceptable salt of compound 2 is used in the method provided herein.

[0070] In one embodiment, compound 3 is used in the method provided herein. In one embodiment, an enantiomer of compound 3 is used in the method provided herein. In one embodiment, a mixture of enantiomers of compound 3 is used in the method provided herein. In one embodiment, a tautomer of compound 3 is used in the method provided herein. In one embodiment, an isotopic variant of compound 3 is used in the method provided herein. In one embodiment, a pharmaceutically acceptable salt of compound 3 is used in the method provided herein.

[0071] Treatment and prevention methods

[0072] hematologic malignancies

[0073] In one embodiment, this document provides a method for treating, preventing, or managing hematologic malignancies using 2-(2,6-dioxadiazin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0074] In some implementations, the hematologic malignancy is in the form of hematologic malignancies including leukemia, lymphoma, multiple myeloma, and myelodysplastic syndrome (MDS).

[0075] In a more specific implementation, the hematologic malignancy may be marginal zone lymphoma (MZL) (including splenic marginal zone lymphoma (SMZL)), Burkitt lymphoma (BL), multiple myeloma (MM) (including plasma cell leukemia (PCL)), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) (including B-cell AML), acute lymphoblastic leukemia (ALL), T-cell lymphoma (TCL) (including anaplastic large cell lymphoma (ALCL) and Cezari syndrome) or Hodgkin lymphoma (HL).

[0076] In some embodiments, the hematologic malignancy is not non-Hodgkin's lymphoma (NHL). In one embodiment, the hematologic malignancy is not diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), or primary central nervous system lymphoma (PCNSL).

[0077] In some implementations, the hematologic malignancy is not chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL).

[0078] In one embodiment, the hematologic malignancy is MZL. In another embodiment, MZL is SMZL.

[0079] In one implementation, the hematologic malignancy is BL.

[0080] In one embodiment, the hematologic malignancy is MM. In another embodiment, MM is PCL.

[0081] In one implementation, the hematologic malignancy is MDS.

[0082] In one embodiment, the hematologic malignancy is AML. In one embodiment, the AML is B-cell AML.

[0083] In one implementation, the hematologic malignancy is ALL.

[0084] In one embodiment, the hematologic malignancy is TCL. In one embodiment, TCL is ALCL. In one embodiment, TCL is Cezari syndrome.

[0085] In one implementation, the hematologic malignancy is HL.

[0086] In one implementation, this document provides a method for treating hematologic malignancies, comprising administering to an individual in need a therapeutically effective amount of compound 1 of the following formula:

[0087]

[0088] Or its tautomers, isotopic variants or pharmaceutically acceptable salts, wherein the hematologic malignancy is MZL, BL, MM, MDS, AML, ALL, TCL or HL.

[0089] In one implementation, this document provides a method for treating hematologic malignancies, comprising administering to an individual in need a therapeutically effective amount of compound 2 of the following formula:

[0090]

[0091] Or its tautomers, isotopic variants or pharmaceutically acceptable salts, wherein the hematologic malignancy is MZL, BL, MM, MDS, AML, ALL, TCL or HL.

[0092] In one implementation, this document provides a method for treating hematologic malignancies, comprising administering to an individual in need a therapeutically effective amount of compound 3 of the following formula:

[0093]

[0094] Or its enantiomers, mixtures of enantiomers, tautomers, isotope variants or pharmaceutically acceptable salts, wherein the hematologic malignancy is MZL, BL, MM, MDS, AML, ALL, TCL or HL.

[0095] In one embodiment, this document provides a method for preventing hematologic malignancies, the method comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for preventing hematologic malignancies, the method comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for preventing hematologic malignancies, the method comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, enantiomer mixtures, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0096] In one embodiment, this document provides a method for managing hematologic malignancies, the method comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for managing hematologic malignancies, the method comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for managing hematologic malignancies, the method comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, enantiomer mixtures, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0097] In one embodiment, the individual has failed one or more lines of therapy. In one embodiment, the individual has failed at least one prior therapy. In one embodiment, the individual has failed at least two prior therapies.

[0098] In one embodiment, the hematologic malignancy is a newly diagnosed hematologic malignancy. In another embodiment, the hematologic malignancy is a relapsed or refractory hematologic malignancy (R / R hematologic malignancy).

[0099] In one implementation, this document provides a method for treating newly diagnosed hematologic malignancies, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants or pharmaceutically acceptable salts.

[0100] In one implementation, this document provides a method for treating newly diagnosed hematologic malignancies, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0101] In one embodiment, this document provides a method for treating newly diagnosed hematologic malignancies, the method comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts thereof.

[0102] In one embodiment, this document provides a method for preventing newly diagnosed hematologic malignancies, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0103] In another embodiment, this document provides a method for managing newly diagnosed hematologic malignancies, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0104] In one embodiment, this document provides a method for treating relapsed or refractory hematologic malignancies, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants or pharmaceutically acceptable salts.

[0105] In one implementation, this document provides a method for treating relapsed or refractory hematologic malignancies, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants or pharmaceutically acceptable salts.

[0106] In one embodiment, this document provides a method for treating relapsed or refractory hematologic malignancies, comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0107] In one embodiment, this document provides a method for preventing recurrent or refractory hematologic malignancies, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0108] In another embodiment, this document provides a method for managing relapsed or refractory hematologic malignancies, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0109] In another embodiment, this document provides a method for achieving a complete response, partial response, or stable disease, comprising administering to a patient with a hematologic malignancy a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotope variant, or a pharmaceutically acceptable salt thereof. In one embodiment, minimal residual disease (MRD) testing may be performed in an individual undergoing bone marrow evaluation to confirm a complete response (CR). In one embodiment, this document provides a method for achieving a negative MRD in a patient, comprising administering to a patient with a hematologic malignancy a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotope variant, or a pharmaceutically acceptable salt thereof. In one embodiment, MRD negativity is measured in peripheral blood and / or bone marrow. In one embodiment, MRD negativity persists for at least 3 months. In another embodiment, this document provides a method for achieving an increase in overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in a patient, comprising administering to a patient with a hematologic malignancy a therapeutically effective amount of the compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving an increase in overall survival in a patient, comprising administering to a patient with a hematologic malignancy a therapeutically effective amount of the compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving an increase in progression-free survival in a patient, comprising administering to a patient with a hematologic malignancy a therapeutically effective amount of the compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased event-free survival in a patient, comprising administering to a patient with a hematologic malignancy a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased time to progression in a patient, comprising administering to a patient with a hematologic malignancy a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof.In another embodiment, this document provides a method for achieving increased disease-free survival in patients, comprising administering to a patient with a hematologic malignancy a therapeutically effective amount of the compounds described herein, such as compound 1, compound 2 or compound 3 or their enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0110] The methods described herein involve treating patients regardless of their age. In some embodiments, the individual is 18 years of age or older. In other embodiments, the individual is over 18, 25, 35, 40, 45, 50, 55, 60, 65, or 70 years of age. In other embodiments, the individual is under 65 years of age. In other embodiments, the individual is over 65 years of age.

[0111] II. Lymphoma

[0112] Marginal zone lymphoma (MZL)

[0113] In one embodiment, this document provides methods for treating, preventing, or managing MZL using 2-(2,6-dioxadiazin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0114] In one implementation, MZL is SMZL.

[0115] In one implementation, this document provides a method for treating MZL comprising administering a therapeutically effective amount of compound 1 of the following formula to an individual in need:

[0116]

[0117] Or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0118] In one implementation, this document provides a method for treating MZL comprising administering a therapeutically effective amount of compound 2 of the following formula to an individual in need:

[0119]

[0120] Or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0121] In one implementation, this document provides a method for treating MZL comprising administering a therapeutically effective amount of compound 3 of the following formula to an individual in need:

[0122]

[0123] Or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0124] In one embodiment, this document provides a method for preventing MZL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing MZL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing MZL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or an enantiomer, enantiomer mixture, tautomer, isotopic variant, or pharmaceutically acceptable salt thereof.

[0125] In one embodiment, this document provides a method for managing MZL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for managing MZL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for managing MZL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or an enantiomer, enantiomer mixture, tautomer, isotopic variant, or pharmaceutically acceptable salt thereof.

[0126] In one embodiment, the individual has failed first-line or multiple-line therapy. In one embodiment, the individual has failed at least one prior therapy. In one embodiment, the individual has failed at least two prior therapies.

[0127] In one embodiment, MZL is newly diagnosed MZL. In one embodiment, MZL is relapsed or refractory MZL (R / R MZL). In one embodiment, SMZL is newly diagnosed SMZL. In one embodiment, SMZL is relapsed or refractory SMZL (R / R SMZL).

[0128] In one embodiment, this document provides a method for treating newly diagnosed MZL, the method comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants, or pharmaceutically acceptable salts. In one embodiment, this document provides a method for treating newly diagnosed SMZL, the method comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0129] In one embodiment, this document provides a method for treating newly diagnosed MZL, the method comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for treating newly diagnosed SMZL, the method comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0130] In one embodiment, this document provides a method for treating newly diagnosed MZL, the method comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, enantiomer mixtures, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In another embodiment, this document provides a method for treating newly diagnosed SMZL, the method comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, enantiomer mixtures, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0131] In one embodiment, this document provides a method for preventing newly diagnosed MZL, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for preventing newly diagnosed SMZL, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof.

[0132] In another embodiment, this document provides a method for managing newly diagnosed MZL, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for managing newly diagnosed SMZL, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof.

[0133] In one embodiment, this document provides a method for treating relapsed or refractory MZL, the method comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In another embodiment, this document provides a method for treating relapsed or refractory SMZL, the method comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0134] In one embodiment, this document provides a method for treating relapsed or refractory MZL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In another embodiment, this document provides a method for treating relapsed or refractory SMZL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0135] In one embodiment, this document provides a method for treating relapsed or refractory MZL, the method comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, enantiomer mixtures, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In another embodiment, this document provides a method for treating relapsed or refractory SMZL, the method comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, enantiomer mixtures, tautomers, or pharmaceutically acceptable salts thereof.

[0136] In one embodiment, this document provides a method for preventing relapsed or refractory MZL, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotope variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for preventing relapsed or refractory SMZL, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotope variant, or a pharmaceutically acceptable salt thereof.

[0137] In another embodiment, this document provides a method for managing relapsed or refractory MZL, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotope variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for managing relapsed or refractory SMZL, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotope variant, or a pharmaceutically acceptable salt thereof.

[0138] In another embodiment, this document provides a method for achieving a complete response, partial response, or stable disease, comprising administering a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof, to a patient with MZL. In one embodiment, a minimal residual disease (MRD) test may be performed in an individual undergoing bone marrow evaluation to confirm a complete response (CR). In one embodiment, this document provides a method for achieving a negative minimum residual disease (MRD) in a patient, comprising administering a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof, to a patient with MZL. In one embodiment, MRD negativity is measured in peripheral blood and / or bone marrow. In one embodiment, MRD negativity persists for at least 3 months. In another embodiment, this document provides a method for achieving increased overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in a patient, comprising administering to a patient with MZL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving an increase in overall survival in a patient, comprising administering to a patient with MZL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving an increase in progression-free survival in a patient, comprising administering to a patient with MZL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased event-free survival in a patient, comprising administering to a patient with MZL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased progression time in a patient, comprising administering to a patient with MZL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof.In another embodiment, this document provides a method for achieving increased disease-free survival in patients, comprising administering to a patient with MZL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0139] Burkitt lymphoma (BL)

[0140] In one embodiment, this document provides methods for treating, preventing, or managing BL using 2-(2,6-dioxadiazin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0141] In one implementation, this document provides a method for treating BL, comprising administering to an individual in need a therapeutically effective amount of compound 1 of the following formula:

[0142]

[0143] Or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0144] In one implementation, this document provides a method for treating BL, comprising administering to an individual in need a therapeutically effective amount of compound 2 of the following formula:

[0145]

[0146] Or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0147] In one implementation, this document provides a method for treating BL, comprising administering to an individual in need a therapeutically effective amount of compound 3 of the following formula:

[0148]

[0149] Or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0150] In one embodiment, this document provides a method for preventing BL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing BL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing BL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomer, enantiomer mixture, tautomer, isotopic variant, or pharmaceutically acceptable salt thereof.

[0151] In one embodiment, this document provides a method for managing BL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for managing BL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for managing BL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or an enantiomer, enantiomer mixture, tautomer, isotopic variant, or pharmaceutically acceptable salt thereof.

[0152] In one embodiment, the individual has failed first-line or multiple-line therapy. In one embodiment, the individual has failed at least one prior therapy. In one embodiment, the individual has failed at least two prior therapies.

[0153] In one implementation, BL is a newly diagnosed BL. In another implementation, BL is a relapsed or refractory BL (R / R BL).

[0154] In one implementation, this document provides a method for treating newly diagnosed BL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants or pharmaceutically acceptable salts.

[0155] In one implementation, this document provides a method for treating newly diagnosed BL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants or pharmaceutically acceptable salts.

[0156] In one embodiment, this document provides a method for treating newly diagnosed BL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0157] In one implementation, this document provides a method for preventing newly diagnosed BL, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0158] In another embodiment, this document provides a method for managing newly diagnosed BL, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0159] In one implementation, this document provides a method for treating relapsed or refractory BL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants or pharmaceutically acceptable salts.

[0160] In one implementation, this document provides a method for treating relapsed or refractory BL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants or pharmaceutically acceptable salts.

[0161] In one embodiment, this document provides a method for treating relapsed or refractory BL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0162] In one implementation, this document provides a method for preventing relapsed or refractory BL, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0163] In another embodiment, this document provides a method for managing relapsed or refractory BL, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0164] In another embodiment, this document provides a method for achieving a complete response, partial response, or stable disease, comprising administering a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof, to a patient with BL. In one embodiment, a minimal residual disease (MRD) test may be performed in an individual undergoing bone marrow evaluation to confirm a complete response (CR). In one embodiment, this document provides a method for achieving a negative minimum residual disease (MRD) in a patient, comprising administering a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof, to a patient with BL. In one embodiment, MRD negativity is measured in peripheral blood and / or bone marrow. In one embodiment, MRD negativity persists for at least 3 months. In another embodiment, this document provides a method for achieving increased overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in a patient, comprising administering to a patient with BL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased overall survival in a patient, comprising administering to a patient with BL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased progression-free survival in a patient, comprising administering to a patient with BL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving an increase in event-free survival in a patient, comprising administering to a patient with BL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving an increase in progression time in a patient, comprising administering to a patient with BL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof.In another embodiment, this document provides a method for achieving increased disease-free survival in patients, comprising administering to a patient with BL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0165] T-cell lymphoma (TCL)

[0166] In one embodiment, this document provides methods for treating, preventing, or managing TCL using 2-(2,6-dioxadiazin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0167] In some implementations, TCL is ALCL (ALCL). In some implementations, TCL is Cezari syndrome.

[0168] In one implementation, this document provides a method for treating TCL, comprising administering to an individual in need a therapeutically effective amount of compound 1 of the following formula:

[0169]

[0170] Or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0171] In one implementation, this document provides a method for treating TCL, comprising administering a therapeutically effective amount of compound 2 of the following formula to an individual in need:

[0172]

[0173] Or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0174] In one implementation, this document provides a method for treating TCL comprising administering a therapeutically effective amount of compound 3 of the following formula to an individual in need:

[0175]

[0176] Or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0177] In one embodiment, this document provides a method for preventing TCL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing TCL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing TCL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or an enantiomer, enantiomer mixture, tautomer, isotopic variant, or pharmaceutically acceptable salt thereof.

[0178] In one embodiment, this document provides a method for administering TCL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for administering TCL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for administering TCL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or an enantiomer, enantiomer mixture, tautomer, isotopic variant, or pharmaceutically acceptable salt thereof.

[0179] In one embodiment, the individual has failed first-line or multiple-line therapy. In one embodiment, the individual has failed at least one prior therapy. In one embodiment, the individual has failed at least two prior therapies.

[0180] In one embodiment, TCL is newly diagnosed TCL. In one embodiment, TCL is relapsed or refractory TCL (R / R TCL). In one embodiment, ALCL is newly diagnosed ALCL. In one embodiment, ALCL is relapsed or refractory ALCL (R / R ALCL). In one embodiment, Cézari syndrome is newly diagnosed Cézari syndrome. In one embodiment, Cézari syndrome is relapsed or refractory Cézari syndrome (R / R Cézari syndrome).

[0181] In one embodiment, this document provides a method for treating newly diagnosed TCL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for treating newly diagnosed ALCL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for treating newly diagnosed Cezari syndrome, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0182] In one embodiment, this document provides a method for treating newly diagnosed TCL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for treating newly diagnosed ALCL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for treating newly diagnosed Cezari syndrome, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0183] In one embodiment, this document provides a method for treating newly diagnosed TCL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, enantiomer mixtures, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for treating newly diagnosed ALCL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, enantiomer mixtures, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for treating newly diagnosed Cezari syndrome, comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, enantiomer mixtures, tautomers, or pharmaceutically acceptable salts thereof.

[0184] In one embodiment, this document provides a method for preventing newly diagnosed TCL, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing newly diagnosed ALCL, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing newly diagnosed Cezari syndrome, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof.

[0185] In another embodiment, this document provides a method for managing newly diagnosed TCL, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for managing newly diagnosed ALCL, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for managing newly diagnosed Cezari syndrome, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof.

[0186] In one embodiment, this document provides a method for treating relapsed or refractory TCL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for treating relapsed or refractory ALCL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for treating relapsed or refractory Cezari syndrome, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0187] In one embodiment, this document provides a method for treating relapsed or refractory TCL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for treating relapsed or refractory ALCL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for treating relapsed or refractory Cezari syndrome, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0188] In one embodiment, this document provides a method for treating relapsed or refractory TCL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, enantiomer mixtures, tautomers, isotope variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for treating relapsed or refractory ALCL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, enantiomer mixtures, tautomers, isotope variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for treating relapsed or refractory Cezari syndrome, comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, enantiomer mixtures, tautomers, or pharmaceutically acceptable salts thereof.

[0189] In one embodiment, this document provides a method for preventing relapsed or refractory TCL, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing relapsed or refractory ALCL, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing relapsed or refractory Cezari syndrome, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof.

[0190] In another embodiment, this document provides a method for managing relapsed or refractory TCL, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for managing relapsed or refractory ALCL, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for managing relapsed or refractory Cezari syndrome, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof.

[0191] In another embodiment, this document provides a method for achieving a complete response, partial response, or stable disease, comprising administering a therapeutically effective amount of the compound described herein, such as compound 1, compound 2, or compound 3, or its enantiomers, enantiomer mixtures, tautomers, isotope variants, or pharmaceutically acceptable salts, to a patient with TCL. In one embodiment, minimal residual disease (MRD) testing may be performed in an individual undergoing bone marrow evaluation to confirm a complete response (CR). In one embodiment, this document provides a method for achieving a negative minimum residual disease (MRD) in a patient, comprising administering a therapeutically effective amount of the compound described herein, such as compound 1, compound 2, or compound 3, or its enantiomers, enantiomer mixtures, tautomers, isotope variants, or pharmaceutically acceptable salts, to a patient with TCL. In one embodiment, MRD negativity is measured in peripheral blood and / or bone marrow. In one embodiment, MRD negativity persists for at least 3 months. In another embodiment, this document provides a method for achieving increased overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in a patient, comprising administering to a patient with TCL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased overall survival in a patient, comprising administering to a patient with TCL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased progression-free survival in a patient, comprising administering to a patient with TCL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased event-free survival in a patient, comprising administering to a patient with TCL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased time to progression in a patient, comprising administering to a patient with TCL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof.In another embodiment, this document provides a method for achieving increased disease-free survival in patients, comprising administering to a patient with TCL a therapeutically effective amount of the compounds described herein, such as compound 1, compound 2 or compound 3 or their enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0192] Hodgkin's lymphoma (HL)

[0193] In one embodiment, this document provides methods for treating, preventing, or managing HL using 2-(2,6-dioxadiazin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0194] In one implementation, this document provides a method for treating HL, comprising administering to an individual in need a therapeutically effective amount of compound 1 of the following formula:

[0195]

[0196] Or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0197] In one implementation, this document provides a method for treating HL, comprising administering to an individual in need a therapeutically effective amount of compound 2 of the following formula:

[0198]

[0199] Or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0200] In one implementation, this document provides a method for treating HL, comprising administering to an individual in need a therapeutically effective amount of compound 3 of the following formula:

[0201]

[0202] Or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0203] In one embodiment, this document provides a method for preventing HL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing HL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing HL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or an enantiomer, enantiomer mixture, tautomer, isotopic variant, or pharmaceutically acceptable salt thereof.

[0204] In one embodiment, this document provides a method for managing HL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for managing HL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for managing HL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or an enantiomer, enantiomer mixture, tautomer, isotopic variant, or pharmaceutically acceptable salt thereof.

[0205] In one embodiment, the individual has failed first-line or multiple-line therapy. In one embodiment, the individual has failed at least one prior therapy. In one embodiment, the individual has failed at least two prior therapies.

[0206] In one implementation, HL refers to newly diagnosed HL. In another implementation, HL refers to relapsed or refractory HL (R / R HL).

[0207] In one implementation, this document provides a method for treating newly diagnosed HL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants or pharmaceutically acceptable salts.

[0208] In one implementation, this document provides a method for treating newly diagnosed HL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants or pharmaceutically acceptable salts.

[0209] In one implementation, this document provides a method for treating newly diagnosed HL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopic variant, or pharmaceutically acceptable salt thereof.

[0210] In one implementation, this document provides a method for preventing newly diagnosed HL, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0211] In another embodiment, this document provides a method for managing newly diagnosed HL, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0212] In one implementation, this document provides a method for treating relapsed or refractory HL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants or pharmaceutically acceptable salts.

[0213] In one implementation, this document provides a method for treating relapsed or refractory HL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants or pharmaceutically acceptable salts.

[0214] In one implementation, this document provides a method for treating relapsed or refractory HL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0215] In one implementation, this document provides a method for preventing relapsed or refractory HL, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0216] In another embodiment, this document provides a method for managing relapsed or refractory HL, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0217] In another embodiment, this document provides a method for achieving a complete response, partial response, or stable disease, comprising administering a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof, to a patient with HL. In one embodiment, a minimal residual disease (MRD) test may be performed in an individual undergoing bone marrow evaluation to confirm a complete response (CR). In one embodiment, this document provides a method for achieving a negative minimum residual disease (MRD) in a patient, comprising administering a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof, to a patient with HL. In one embodiment, MRD negativity is measured in peripheral blood and / or bone marrow. In one embodiment, MRD negativity persists for at least 3 months. In another embodiment, this document provides a method for achieving increased overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in a patient, comprising administering to a patient with HL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased overall survival in a patient, comprising administering to a patient with HL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased progression-free survival in a patient, comprising administering to a patient with HL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased event-free survival in a patient, comprising administering to a patient with HL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased progression time in a patient, comprising administering to a patient with HL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof.In another embodiment, this document provides a method for achieving increased disease-free survival in patients, comprising administering to a patient with HL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0218] III. Multiple myeloma (MM)

[0219] In one embodiment, this document provides methods for treating, preventing, or managing MM using 2-(2,6-dioxadiazin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0220] In some implementations, MM stands for PCL.

[0221] In one implementation, this document provides a method for treating MM, comprising administering to an individual in need a therapeutically effective amount of compound 1 of the following formula:

[0222]

[0223] Or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0224] In one implementation, this document provides a method for treating MM comprising administering a therapeutically effective amount of compound 2 of the following formula to an individual in need:

[0225]

[0226] Or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0227] In one implementation, this document provides a method for treating MM comprising administering a therapeutically effective amount of compound 3 of the following formula to an individual in need:

[0228]

[0229] Or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0230] In one embodiment, this document provides a method for preventing MM, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing MM, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing MM, comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomer, enantiomer mixture, tautomer, isotopic variant, or pharmaceutically acceptable salt thereof.

[0231] In one embodiment, this document provides a method for managing MM, comprising administering to an individual in need a therapeutically effective amount of compound 1 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for managing MM, comprising administering to an individual in need a therapeutically effective amount of compound 2 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for managing MM, comprising administering to an individual in need a therapeutically effective amount of compound 3 or an enantiomer, enantiomer mixture, tautomer, isotopic variant, or pharmaceutically acceptable salt thereof.

[0232] In one embodiment, the individual has failed first-line or multiple-line therapy. In one embodiment, the individual has failed at least one prior therapy. In one embodiment, the individual has failed at least two prior therapies.

[0233] In one embodiment, MM is newly diagnosed MM. In one embodiment, MM is relapsed or refractory MM (R / R MM). In one embodiment, PCL is newly diagnosed PCL. In one embodiment, PCL is relapsed or refractory PCL (R / R PCL).

[0234] In one embodiment, this document provides a method for treating newly diagnosed MM, the method comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants, or pharmaceutically acceptable salts. In one embodiment, this document provides a method for treating newly diagnosed PCL, the method comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0235] In one embodiment, this document provides a method for treating newly diagnosed MM, the method comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for treating newly diagnosed PCL, the method comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0236] In one embodiment, this document provides a method for treating newly diagnosed MM, the method comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, enantiomer mixtures, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for treating newly diagnosed PCL, the method comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, enantiomer mixtures, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0237] In one embodiment, this document provides a method for preventing newly diagnosed MM, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing newly diagnosed PCL, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof.

[0238] In another embodiment, this document provides a method for managing newly diagnosed MM, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotope variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for managing newly diagnosed PCL, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotope variant, or a pharmaceutically acceptable salt thereof.

[0239] In one embodiment, this document provides a method for treating relapsed or refractory MM, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for treating relapsed or refractory PCL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0240] In one embodiment, this document provides a method for treating relapsed or refractory MM, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In another embodiment, this document provides a method for treating relapsed or refractory PCL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0241] In one embodiment, this document provides a method for treating relapsed or refractory MM, comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, enantiomer mixtures, tautomers, isotope variants, or pharmaceutically acceptable salts thereof. In one embodiment, this document provides a method for treating relapsed or refractory PCL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, enantiomer mixtures, tautomers, isotope variants, or pharmaceutically acceptable salts thereof.

[0242] In one embodiment, this document provides a method for preventing relapsed or refractory MM, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotope variant, or a pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing relapsed or refractory PCL, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotope variant, or a pharmaceutically acceptable salt thereof.

[0243] In another embodiment, this document provides a method for managing relapsed or refractory MM, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotope variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for managing relapsed or refractory PCL, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotope variant, or a pharmaceutically acceptable salt thereof.

[0244] In another embodiment, this document provides a method for achieving a complete response, partial response, or stable disease, comprising administering a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof, to a patient with MM. In one embodiment, a minimal residual disease (MRD) test may be performed in an individual undergoing bone marrow evaluation to confirm a complete response (CR). In one embodiment, this document provides a method for achieving a negative minimum residual disease (MRD) in a patient, comprising administering a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof, to a patient with MM. In one embodiment, MRD negativity is measured in peripheral blood and / or bone marrow. In one embodiment, MRD negativity persists for at least 3 months. In another embodiment, this document provides a method for achieving increased overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in patients, comprising administering to a patient with MM a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased overall survival in patients, comprising administering to a patient with MM a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased progression-free survival in patients, comprising administering to a patient with MM a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased event-free survival in patients, comprising administering to a patient with MM a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased progression time in patients, comprising administering to a patient with MM a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof.In another embodiment, this document provides a method for achieving increased disease-free survival in patients, comprising administering to a patient with MM a therapeutically effective amount of a compound described herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0245] IV. Leukemia

[0246] Acute myeloid leukemia (AML)

[0247] In one embodiment, this document provides methods for treating, preventing, or managing AML using 2-(2,6-dioxadiazin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0248] In some implementations, AML is B-cell AML.

[0249] In one implementation, this document provides a method for treating AML, comprising administering to an individual in need a therapeutically effective amount of compound 1 of the following formula:

[0250]

[0251] Or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0252] In one implementation, this document provides a method for treating AML, comprising administering a therapeutically effective amount of compound 2 of the following formula to an individual in need:

[0253]

[0254] Or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0255] In one implementation, this document provides a method for treating AML comprising administering a therapeutically effective amount of compound 3 of the following formula to an individual in need:

[0256]

[0257] Or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0258] In one embodiment, this document provides a method for preventing AML, comprising administering to an individual in need a therapeutically effective amount of compound 1 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing AML, comprising administering to an individual in need a therapeutically effective amount of compound 2 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing AML, comprising administering to an individual in need a therapeutically effective amount of compound 3 or an enantiomer, enantiomer mixture, tautomer, isotopic variant, or pharmaceutically acceptable salt thereof.

[0259] In one embodiment, this document provides a method for managing AML, comprising administering to an individual in need a therapeutically effective amount of compound 1 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for managing AML, comprising administering to an individual in need a therapeutically effective amount of compound 2 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for managing AML, comprising administering to an individual in need a therapeutically effective amount of compound 3 or an enantiomer, enantiomer mixture, tautomer, isotopic variant, or pharmaceutically acceptable salt thereof.

[0260] In one embodiment, the individual has failed first-line or multiple-line therapy. In one embodiment, the individual has failed at least one prior therapy. In one embodiment, the individual has failed at least two prior therapies.

[0261] In one embodiment, the AML is a newly diagnosed AML. In one embodiment, the AML is relapsed or refractory AML (R / R AML). In one embodiment, the B-cell AML is a newly diagnosed B-cell AML. In one embodiment, the B-cell AML is relapsed or refractory B-cell AML (R / RB cell AML).

[0262] In one embodiment, this document provides a method for treating newly diagnosed AML, the method comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants, or pharmaceutically acceptable salts. In one embodiment, this document provides a method for treating newly diagnosed B-cell AML, the method comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0263] In one embodiment, this document provides a method for treating newly diagnosed AML, the method comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts. In one embodiment, this document provides a method for treating newly diagnosed B-cell AML, the method comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0264] In one embodiment, this document provides a method for treating newly diagnosed AML, the method comprising administering to an individual in need a therapeutically effective amount of compound 3 or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for treating newly diagnosed B-cell AML, the method comprising administering to an individual in need a therapeutically effective amount of compound 3 or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof.

[0265] In one embodiment, this document provides a method for preventing newly diagnosed AML, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for preventing newly diagnosed B-cell AML, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof.

[0266] In another embodiment, this document provides a method for managing newly diagnosed AML, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for managing newly diagnosed B-cell AML, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof.

[0267] In one embodiment, this document provides a method for treating relapsed or refractory AML, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants, or pharmaceutically acceptable salts. In another embodiment, this document provides a method for treating relapsed or refractory B-cell AML, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0268] In one embodiment, this document provides a method for treating relapsed or refractory AML, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof. In another embodiment, this document provides a method for treating relapsed or refractory B-cell AML, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0269] In one embodiment, this document provides a method for treating relapsed or refractory AML, comprising administering to an individual in need a therapeutically effective amount of compound 3 or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for treating relapsed or refractory B-cell AML, comprising administering to an individual in need a therapeutically effective amount of compound 3 or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof.

[0270] In one embodiment, this document provides a method for preventing relapsed or refractory AML, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotope variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for preventing relapsed or refractory B-cell AML, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotope variant, or a pharmaceutically acceptable salt thereof.

[0271] In another embodiment, this document provides a method for managing relapsed or refractory AML, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotope variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for managing relapsed or refractory B-cell AML, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotope variant, or a pharmaceutically acceptable salt thereof.

[0272] In another embodiment, this document provides a method for achieving a complete response, partial response, or stable disease, comprising administering a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof, to a patient with AML. In one embodiment, a minimal residual disease (MRS) test may be performed in an individual undergoing bone marrow evaluation to confirm a complete response (CR). In one embodiment, this document provides a method for achieving a negative minimal residual disease (MRD) in a patient, comprising administering a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof, to a patient with AML. In one embodiment, MRD negativity is measured in peripheral blood and / or bone marrow. In one embodiment, MRD negativity persists for at least 3 months. In another embodiment, this document provides a method for achieving increased overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in a patient, comprising administering to a patient with AML a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased overall survival in a patient, comprising administering to a patient with AML a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased progression-free survival in a patient, comprising administering to a patient with AML a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased event-free survival in patients, comprising administering to a patient with AML a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased progression time in patients, comprising administering to a patient with AML a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof.In another embodiment, this document provides a method for achieving increased disease-free survival in patients, comprising administering to a patient with AML a therapeutically effective amount of a compound described herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0273] Acute lymphoblastic leukemia (ALL)

[0274] In one embodiment, this document provides methods for treating, preventing, or managing ALL using 2-(2,6-dioxadiazin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0275] In one implementation, this document provides a method for treating ALL, comprising administering to an individual in need a therapeutically effective amount of compound 1 of the following formula:

[0276]

[0277] Or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0278] In one implementation, this document provides a method for treating ALL, comprising administering a therapeutically effective amount of compound 2 of the following formula to an individual in need:

[0279]

[0280] Or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0281] In one implementation, this document provides a method for treating ALL comprising administering to an individual in need a therapeutically effective amount of compound 3 of the following formula:

[0282]

[0283] Or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0284] In one embodiment, this document provides a method for preventing ALL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing ALL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing ALL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or an enantiomer, enantiomer mixture, tautomer, isotopic variant, or pharmaceutically acceptable salt thereof.

[0285] In one embodiment, this document provides a method for managing ALL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for managing ALL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for managing ALL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or an enantiomer, enantiomer mixture, tautomer, isotopic variant, or pharmaceutically acceptable salt thereof.

[0286] In one embodiment, the individual has failed first-line or multiple-line therapy. In one embodiment, the individual has failed at least one prior therapy. In one embodiment, the individual has failed at least two prior therapies.

[0287] In one implementation scheme, ALL refers to newly diagnosed ALL. In another implementation scheme, ALL refers to relapsed or refractory ALL (R / R ALL).

[0288] In one implementation, this document provides a method for treating newly diagnosed ALL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants or pharmaceutically acceptable salts.

[0289] In one implementation, this document provides a method for treating newly diagnosed ALL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants or pharmaceutically acceptable salts.

[0290] In one implementation, this document provides a method for treating newly diagnosed ALL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0291] In one implementation, this document provides a method for preventing newly diagnosed ALL, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0292] In another embodiment, this document provides a method for managing newly diagnosed ALL, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0293] In one implementation, this document provides a method for treating relapsed or refractory ALL, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants or pharmaceutically acceptable salts.

[0294] In one implementation, this document provides a method for treating relapsed or refractory ALL, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants or pharmaceutically acceptable salts.

[0295] In one implementation, this document provides a method for treating relapsed or refractory ALL, comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0296] In one implementation, this document provides a method for preventing relapsed or refractory ALL, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0297] In another embodiment, this document provides a method for managing relapsed or refractory ALL, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0298] In another embodiment, this document provides a method for achieving a complete response, partial response, or stable disease, comprising administering a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof, to a patient with ALL. In one embodiment, a minimal residual disease (MRD) test may be performed in an individual undergoing bone marrow evaluation to confirm a complete response (CR). In one embodiment, this document provides a method for achieving a negative minimal residual disease (MRD) in a patient, comprising administering a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotope variants, or a pharmaceutically acceptable salt thereof, to a patient with ALL. In one embodiment, MRD negativity is measured in peripheral blood and / or bone marrow. In one embodiment, MRD negativity persists for at least 3 months. In another embodiment, this document provides a method for achieving increased overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in patients, comprising administering to a patient with ALL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased overall survival in patients, comprising administering to a patient with ALL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased progression-free survival in patients, comprising administering to a patient with ALL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased event-free survival in patients, comprising administering to a patient with ALL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased progression time in patients, comprising administering to a patient with ALL a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof.In another embodiment, this document provides a method for achieving increased disease-free survival in patients, comprising administering to a patient with ALL a therapeutically effective amount of the compounds described herein, such as compound 1, compound 2 or compound 3 or their enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0299] V. Myelodysplastic Syndrome (MDS)

[0300] In one embodiment, this document provides methods for treating, preventing, or managing MDS using 2-(2,6-dioxadiazin-3-yl)-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0301] In one implementation, this document provides a method for treating MDS comprising administering to an individual in need a therapeutically effective amount of compound 1 of the following formula:

[0302]

[0303] Or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0304] In one implementation, this document provides a method for treating MDS comprising administering a therapeutically effective amount of compound 2 of the following formula to an individual in need:

[0305]

[0306] Or its tautomers, isotopic variants, or pharmaceutically acceptable salts.

[0307] In one implementation, this document provides a method for treating MDS comprising administering a therapeutically effective amount of compound 3 of the following formula to an individual in need:

[0308]

[0309] Or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0310] In one embodiment, this document provides a method for preventing MDS, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing MDS, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for preventing MDS, comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomer, enantiomer mixture, tautomer, isotopic variant, or pharmaceutically acceptable salt thereof.

[0311] In one embodiment, this document provides a method for managing MDS, comprising administering to an individual in need a therapeutically effective amount of compound 1 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for managing MDS, comprising administering to an individual in need a therapeutically effective amount of compound 2 or a tautomer, isotopic variant, or pharmaceutically acceptable salt thereof. In one embodiment, this document provides a method for managing MDS, comprising administering to an individual in need a therapeutically effective amount of compound 3 or an enantiomer, enantiomer mixture, tautomer, isotopic variant, or pharmaceutically acceptable salt thereof.

[0312] In one embodiment, the individual has failed first-line or multiple-line therapy. In one embodiment, the individual has failed at least one prior therapy. In one embodiment, the individual has failed at least two prior therapies.

[0313] In one implementation, the MDS is a newly diagnosed MDS. In another implementation, the MDS is a relapsed or refractory MDS (R / R MDS).

[0314] In one implementation, this document provides a method for treating newly diagnosed MDS, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants or pharmaceutically acceptable salts.

[0315] In one implementation, this document provides a method for treating newly diagnosed MDS, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants or pharmaceutically acceptable salts.

[0316] In one embodiment, this document provides a method for treating newly diagnosed MDS, comprising administering to an individual in need a therapeutically effective amount of compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopic variant, or pharmaceutically acceptable salt thereof.

[0317] In one implementation, this document provides a method for preventing newly diagnosed MDS, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0318] In another embodiment, this document provides a method for managing newly diagnosed MDS, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0319] In one embodiment, this document provides a method for treating relapsed or refractory MDS, comprising administering to an individual in need a therapeutically effective amount of compound 1 or its tautomers, isotopic variants or pharmaceutically acceptable salts.

[0320] In one implementation, this document provides a method for treating relapsed or refractory MDS, comprising administering to an individual in need a therapeutically effective amount of compound 2 or its tautomers, isotopic variants or pharmaceutically acceptable salts thereof.

[0321] In one embodiment, this document provides a method for treating relapsed or refractory MDS, comprising administering to an individual in need a therapeutically effective amount of compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof.

[0322] In one embodiment, this document provides a method for preventing relapsed or refractory MDS, the method comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2 or compound 3 or its enantiomers, enantiomer mixtures, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0323] In another embodiment, this document provides a method for managing relapsed or refractory MDS, comprising administering to an individual in need a therapeutically effective amount of a compound provided herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0324] In another embodiment, this document provides a method for achieving a complete response, partial response, or stable disease, comprising administering a therapeutically effective amount of the compound described herein, such as compound 1, compound 2, or compound 3, or its enantiomers, mixtures of enantiomers, tautomers, isotope variants, or pharmaceutically acceptable salts, to a patient with MDS. In one embodiment, minimal residual disease (MRD) testing may be performed in an individual undergoing bone marrow evaluation to confirm a complete response (CR). In one embodiment, this document provides a method for achieving a negative minimum residual disease (MRD) in a patient, comprising administering a therapeutically effective amount of the compound described herein, such as compound 1, compound 2, or compound 3, or its enantiomers, mixtures of enantiomers, tautomers, isotope variants, or pharmaceutically acceptable salts, to a patient with MDS. In one embodiment, MRD negativity is measured in peripheral blood and / or bone marrow. In one embodiment, MRD negativity persists for at least 3 months. In another embodiment, this document provides a method for achieving increased overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in a patient, comprising administering to a patient with MDS a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased overall survival in a patient, comprising administering to a patient with MDS a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased progression-free survival in a patient, comprising administering to a patient with MDS a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, tautomers, isotopic variants, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased event-free survival in a patient, comprising administering to a patient with MDS a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof. In another embodiment, this document provides a method for achieving increased time to progression in a patient, comprising administering to a patient with MDS a therapeutically effective amount of a compound described herein, such as compound 1, compound 2, or compound 3, or an enantiomer thereof, a mixture of enantiomers, a tautomer, an isotopic variant, or a pharmaceutically acceptable salt thereof.In another embodiment, this document provides a method for achieving increased disease-free survival in patients, comprising administering to a patient with MDS a therapeutically effective amount of a compound described herein, such as compound 1, compound 2 or compound 3 or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts.

[0325] Pharmaceutical Compositions and Routes of Administration

[0326] The compounds described herein can be administered orally, topically, or parenterally in conventional formulations, such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. Suitable formulations can be prepared using common methods with conventional, organic, or inorganic additives, such as diluents (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylene pyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), and disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate, or...). The pharmaceutical composition contains calcium citrate, lubricants (e.g., magnesium stearate, light anhydrous silicate, talc, or sodium lauryl sulfate), flavoring agents (e.g., citric acid, menthol, glycine, or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben, or propylparaben), stabilizers (e.g., citric acid, sodium citrate, or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone, or aluminum stearate), dispersants (e.g., hydroxypropyl methylcellulose), water, and base waxes (e.g., cocoa butter, white petrolatum, or polyethylene glycol). The effective amount of the compounds in the pharmaceutical composition may be at a level that will exert the desired effect for oral and parenteral administration.

[0327] The compounds provided herein can be administered orally. In one embodiment, when administered orally, the compounds provided herein are taken with food and water. In another embodiment, the compounds provided herein are dispersed in water or fruit juice (e.g., apple juice or orange juice) and administered orally as a solution or suspension.

[0328] The compounds described herein can also be applied intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, or via inhalation or topical application to the ear, nose, eye, or skin. The method of application is determined by the healthcare practitioner and may depend in part on the site of the medical condition.

[0329] In one embodiment, this document provides a capsule comprising the compound provided herein but without any additional excipients. In another embodiment, this document provides a composition comprising an effective amount of the compound provided herein and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient may comprise a diluent, binder, disintegrant, glidant, lubricant, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.

[0330] The composition may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories, and suspensions. The composition may be formulated into convenient portions containing a daily dose or a daily dose in dosage units, which may be a single tablet or capsule or a convenient volume of liquid. In one embodiment, the solution is prepared from a water-soluble salt. Generally, all compositions are prepared according to methods known in pharmaceutical chemistry. Capsules may be prepared by mixing the compounds provided herein with suitable excipients and filling an appropriate amount of the mixture into capsules. Commonly used excipients include, but are not limited to, inert powdered substances such as many different kinds of starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol, and sucrose, cereal flour, and similar edible powders. Capsule fillers may also be prepared by wet granulation or by dry granulation.

[0331] Lubricants are often essential in capsule formulations to prevent powder from adhering to the shell. Lubricants can be selected from smooth solids such as talc, magnesium stearate and calcium stearate, sodium stearoyl fumarate, stearic acid, and hydrogenated vegetable oils. Disintegrants are substances that swell upon wetting to rupture capsule segments and release compounds. These include starch, clay, cellulose, crospovidone, crospovidone, sodium carboxymethyl cellulose, sodium starch glycolate, alginate, and gums. More specifically, corn and potato starch, methyl cellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resins, alginate, guar gum, citrus pomace, and carboxymethyl cellulose can be used, as well as sodium lauryl sulfate. Gliders, including silica, talc, and calcium silicate, can also be used.

[0332] Tablets can be prepared by direct compression, wet granulation, or dry granulation. Their formulations typically incorporate diluents, binders, lubricants, disintegrants, and compounds. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin, and sugars such as lactose, fructose, and glucose. Natural and synthetic gums are also convenient, including gum arabic, alginate, methylcellulose, polyvinylpyrrolidone, etc. Polyethylene glycol, ethylcellulose, and waxes can also be used as binders.

[0333] Lubricants may be needed in tablet formulations to prevent the tablet and die from sticking to the mold. Lubricants can be selected from slippery solids such as talc, magnesium stearate and calcium stearate, sodium stearoyl fumarate, stearic acid, and hydrogenated vegetable oil. Tablet disintegrants are substances that swell upon wetting to break down the tablet and release compounds. These include starch, clay, cellulose, crospovidone, croscarmellose sodium, sodium hydroxyacetic acid starch, alginate, and gums. More specifically, for example, corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resins, alginate, guar gum, citrus pulp, and carboxymethyl cellulose, as well as sodium lauryl sulfate, can be used. Gliding agents, including silica, talc, and calcium silicate, can also be used. Tablets can be sugar-coated as flavoring agents and sealants, or coated with film-forming protectants to modify their dissolution properties. Compositions can also be formulated into chewable tablets, for example, by using a substance such as mannitol in the formulation.

[0334] When the compounds presented herein are intended for suppository administration, typical bases can be used. Cocoa butter is a conventional suppository base, which can be modified by adding waxes to moderately increase its melting point. In particular, water-miscible suppository bases containing polyethylene glycol of various molecular weights are widely used.

[0335] The effects of the compounds described herein can be delayed or prolonged through appropriate formulation. For example, slow-dissolving pellets of the compounds described herein can be prepared and incorporated into tablets or capsules, or used as sustained-release implantable devices. The technique also includes preparing pellets with several different dissolution rates and filling capsules with a mixture of pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even parenteral formulations can be formulated into long-acting formulations by dissolving or suspending the compounds described herein in an oily or emulsified medium for slow dispersion in serum.

[0336] Depending on the disease state to be treated or the individual's condition, the compounds 1, 2, or 3 described herein, or their enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof, may be administered via oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisional injection or infusion, subcutaneous injection or implantation), inhalation, nasal, vaginal, rectal, sublingual, or local (e.g., transdermal or local) routes of administration. The compounds 1, 2, or 3 described herein, or their enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof, may be formulated alone or with pharmaceutically acceptable excipients, carriers, adjuvants, and mediators in suitable dosage units for their respective routes of administration.

[0337] In one embodiment, the compound 1, compound 2, or compound 3 provided herein, or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof, are administered orally. In another embodiment, the compound 1, compound 2, or compound 3, or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof, are administered parenterally. In yet another embodiment, the compound 1, compound 2, or compound 3, or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof, are administered intravenously.

[0338] Compound 1, Compound 2, or Compound 3, or their enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof, may be delivered as a single dose, such as a single bolus, or orally in capsules, tablets, or pills; or over time, such as by continuous infusion over time, or by fractionated bolus doses over time. If necessary, the compounds described herein may be repeated, for example, until the patient experiences stable disease or remission, or until the patient experiences disease progression or unacceptable toxicity.

[0339] Compound 1, Compound 2, or Compound 3, or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof, may be administered once daily (QD) or divided into multiple doses daily, such as twice daily (BID), three times daily (TID), and four times daily (QID). Furthermore, administration may be continuous (i.e., daily administration for several consecutive days or every day) or intermittent, such as over several cycles (i.e., including rest periods of several days, weeks, or months without drug use). As used herein, the term "daily" will refer to the administration of the therapeutic compound, such as Compound 1, Compound 2, or Compound 3, or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof, once or more daily, for a period of time. The term “continuous” means the daily administration of a therapeutic compound, such as Compound 1, Compound 2, or Compound 3 provided herein, or its enantiomers, enantiomer mixtures, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof, for an uninterrupted period of at least 7 days to 52 weeks. As used herein, the term “intermittent” or “in an intermittent manner” means stopping and starting at regular or irregular intervals. For example, intermittent administration of Compound 1, Compound 2, or Compound 3 provided herein, or its enantiomers, enantiomer mixtures, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof, may be administered 1–6 days per week, administered over several cycles (e.g., daily administration for 2–8 consecutive weeks, followed by a rest period of up to one week), or administered every other day. As used herein, the term “cycled administration” means the daily or continuous administration of a therapeutic compound, such as Compound 1, Compound 2, or Compound 3 provided herein, or its enantiomers, enantiomer mixtures, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof, but with rest periods.

[0340] In some embodiments, the frequency of administration ranges from about a daily dose to about a monthly dose. In one embodiment, administration is once daily, twice daily, three times daily, four times daily, every other day, twice weekly, once weekly, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, compound 1, compound 2, or compound 3 provided herein, or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof, are administered once daily. In another embodiment, compound 1, compound 2, or compound 3 provided herein, or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof, are administered twice daily. In yet another embodiment, compound 1, compound 2, or compound 3 provided herein, or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts thereof, are administered three times daily. In another embodiment, the compound 1, compound 2 or compound 3 provided herein, or their enantiomers, mixtures of enantiomers, tautomers, isotopic variants or pharmaceutically acceptable salts thereof, are administered four times daily.

[0341] In one embodiment, the method provided herein includes administering a therapeutically effective amount of compound 1, compound 2, or compound 3 during one or more 7-day treatment cycles. In another embodiment, the method provided herein includes administering a therapeutically effective amount of compound 1, compound 2, or compound 3 on days 1-5 of a 7-day cycle. In yet another embodiment, the method provided herein includes administering a therapeutically effective amount of compound 1, compound 2, or compound 3 on days 1-3 of a 7-day cycle.

[0342] In one embodiment, the method provided herein includes administering a therapeutically effective amount of compound 1, compound 2, or compound 3 during one or more 14-day treatment cycles. In another embodiment, the method provided herein includes administering a therapeutically effective amount of compound 1, compound 2, or compound 3 on days 1-7 of a 14-day cycle. In yet another embodiment, the method provided herein includes administering a therapeutically effective amount of compound 1, compound 2, or compound 3 on days 1-10 of a 14-day cycle.

[0343] In one embodiment, the method provided herein includes administering a therapeutically effective amount of compound 1, compound 2, or compound 3 over one or more 28-day treatment cycles. In another embodiment, the method provided herein includes administering a therapeutically effective amount of compound 1, compound 2, or compound 3 on days 1-21 of a 28-day cycle. In yet another embodiment, the method provided herein includes administering a therapeutically effective amount of compound 1, compound 2, or compound 3 on days 1-5, 8-12, 15-19, and 22-26 of a 28-day cycle. In yet another embodiment, the method provided herein includes administering a therapeutically effective amount of compound 1, compound 2, or compound 3 on days 1-10 and 15-24 of a 28-day cycle.

[0344] In one embodiment, compound 1, compound 2, or compound 3 is administered once daily for 5 days, followed by a 2-day rest period. In another embodiment, compound 1, compound 2, or compound 3 is administered once daily for 3 days, followed by a 4-day rest period. In yet another embodiment, compound 1, compound 2, or compound 3 is administered once daily for 7 days, followed by a 7-day rest period. In one embodiment, compound 1, compound 2, or compound 3 is administered once daily for 10 days, followed by a 4-day rest period. In yet another embodiment, compound 1, compound 2, or compound 3 is administered once daily for 21 days, followed by a 7-day rest period.

[0345] Any treatment cycle described herein may be repeated for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more cycles. In some cases, the treatment cycle described herein comprises 1 to about 24 cycles, about 2 to about 16 cycles, or about 2 to about 4 cycles. In some embodiments, a therapeutically effective amount of compound 1, compound 2 or compound 3 is administered for 1 to 13 cycles of 28 days (e.g., about 1 year). In some embodiments, a therapeutically effective amount of compound 1, compound 2 or compound 3 is administered for 1 to 24 cycles of 28 days (e.g., about 2 years). In some cases, the cyclical treatment is not limited to the number of cycles, and treatment continues until disease progression. In some cases, the cycle may include variations in the duration of the administration period and / or rest period described herein. Detailed Implementation

[0346] Example

[0347] The following examples are presented in an exemplary and non-limiting manner. Compounds are named using an automatic name generation tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names of chemical structures and supports the Cahn-Ingold-Prelog rule for stereochemistry. Those skilled in the art can modify the methods described in the exemplary embodiments to obtain desired products.

[0348] Abbreviations used:

[0349]

[0350]

[0351] Example 1: Synthesis of (S)-2-(2,6-dioxopiperidin-3-yl-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione (Compound 1)

[0352]

[0353] (S)-2-(2,6-dioxopiperidin-3-yl-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isodihydroindole-1,3-dione: A suspension of (S)-4-amino-2-(2,6-dioxopiperidin-3-ylisodihydroindole-1,3-dione (5.00 g, 18.3 mmol) and 2-fluoro-4-(hydroxymethyl)benzaldehyde (2.82 g, 18.30 mmol) in 2:1 dioxane-MeOH (75 mL) was cooled to 0 °C and added in small batches to B 10 H 14 (4.92 g, 40.3 mmol), time 5 minutes. Equip the reaction flask with a septum and a pinhole (pressure), and stir vigorously for 10 minutes. Allow the mixture to reach ambient temperature and stir for 3 hours. Concentrate the mixture and purify the residue by silica gel chromatography (0-10% MeOH-DCM) to give (S)-2-(2,6-dioxopiperidin-3-yl-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isodihydroindole-1,3-dione, as a yellow solid (4.23 g, 56%). LCMS (ESI) m / z 411.8 [M+H] + .

[0354] (S)-4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-ylisodihydroindole-1,3-dione): A solution of (S)-2-(2,6-dioxopiperidin-3-yl-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isodihydroindole-1,3-dione (0.727 g, 1.77 mmol) in anhydrous NMP (6 mL) was cooled to 0 °C, and methanesulfonyl chloride (0.275 mL, 3.35 mmol) and DIEA (0.617 mL, 3.53 mmol) were added sequentially. The reaction mixture was brought to ambient temperature and stirred for 18 hours. The reaction mixture was then slowly added to 60 mL of H₂O cooled to 0 °C while vigorously mixing. The resulting suspension was filtered, and the collected solid was washed with H₂O and Et₂O. The solid was dissolved in EtOAc, the solution was dried over MgSO₄, filtered, and concentrated to give (S)-4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-ylisodihydroindole-1,3-dione, as a yellow solid (0.600 g, 79%). LCMS (ESI) m / z 430.0 [M+H] + .

[0355] (S)-2-(2,6-dioxopiperidin-3-yl-4-((2-fluoro-4-((3-morpholinoaziridine-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione: Add 4-(aziridine-3-yl)morpholine hydrochloride (125 mL) to a solution of (S)-4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-ylisodihydroindole-1,3-dione (300 mg, 0.698 mmol) in anhydrous DMSO (1.0 mL). mg (0.698 mmol) and DIEA (0.122 mL, 0.698 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and diluted with DMSO (1 mL). The solution was purified by chiral reversed-phase chromatography to give (S)-2-(2,6-dioxadiazin-3-yl-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione (89 mg, 24%, 97% ee). LCMS (ESI) m / z 536.2 [M+H] + .

[0356] Example 2: Synthesis of (R)-2-(2,6-dioxopiperidin-3-yl-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione (compound 2)

[0357]

[0358] The chiral reversed-phase chromatography described in Example 1 also yielded (R)-2-(2,6-dioxopiperidin-3-yl-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione (16 mg, 97% ee). LCMS (ESI) m / z 535.6 [M+H] + .

[0359] Example 3: Synthesis of 2-(2,6-dioxopiperidin-3-yl-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione (compound 3)

[0360]

[0361] (4-Bromo-3-fluoro-phenyl)methanol: A solution of 4-bromo-3-fluorobenzoic acid (15.0 g, 68.5 mmol) in THF (150 mL) was cooled to 0 °C, and a borane-dimethyl sulfide complex (13.7 mL, 137 mmol, 10 M THF solution) was added dropwise under a nitrogen atmosphere. The ice bath was removed, and the mixture was stirred at ambient temperature for 12 hours. The mixture was cooled to 0 °C, quenched with MeOH (50 mL), and poured into water (30 mL). The mixture was concentrated under vacuum, and the residual aqueous mixture was diluted with ethyl acetate (150 mL) and water (150 mL) and stirred for 15 minutes. The organic phase was removed, and the aqueous phase was extracted with ethyl acetate (150 mL x 2). The organic fractions were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (2-10% ethyl acetate in petroleum ether solution) to give (4-bromo-3-fluoro-phenyl)methanol (13.1 g, 93.3% yield) as a colorless liquid. LCMS (ESI) m / z 187.0 [MH-18] + ]. 1 H NMR (400MHz, CDCl3) δppm 7.54-7.45 (m, IH), 7.14 (d, J=9.2Hz, 1H), 7.00 (d, J=7.9Hz, 1H), 4.64 (d, J=4.6Hz, 2H), 2.20 (br s, 1H).

[0362] (4-Bromo-3-fluoro-phenyl)methoxy-tert-butyl-dimethyl-silane: A solution of (4-bromo-3-fluoro-phenyl)methanol (13.1 g, 63.9 mmol) and imidazole (12.2 g, 179 mmol) in DMF (150 mL) was cooled to 0 °C, and tert-butyldimethylchlorosilane (14.4 g, 95.8 mmol) was added. The cooling bath was removed, and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was poured into cooling water (30 mL), diluted with ethyl acetate (100 mL) and water (100 mL), and stirred for 15 minutes. The organic phase was removed, and the aqueous phase was extracted with ethyl acetate (150 mL x 2). The organic fractions were combined, washed with saturated NaCl (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0-10% ethyl acetate in petroleum ether solution) to give (4-bromo-3-fluoro-phenyl)methoxy-tert-butyl-dimethyl-silane (18.6 g, 91.2% yield) as a colorless liquid. 1 H NMR (400MHz, CDCl3) δppm 7.49 (dd, J=7.1, 8.1Hz, 1H), 7.18-7.08 (m, 1H), 7.01-6.92 (m, 1H), 4.69 (s, 2H), 0.96 (s, 9H), 0.12 (s, 6H).

[0363] 4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-fluorobenzaldehyde: Under a nitrogen atmosphere, a solution of (4-bromo-3-fluoro-phenyl)methoxy-tert-butyl-dimethylsilane (18.6 g, 58.3 mmol) in THF (150 mL) was cooled to -78 °C, and n-BuLi (25.6 mL, 64.0 mmol, 2.5 M hexane solution) was added dropwise. The mixture was stirred at -78 °C for 5 min, and DMF (5.83 mL, 75.7 mmol) was added. The mixture was stirred at -78 °C for 2 h and warmed to ambient temperature. The reaction mixture was cooled to 0 °C and quenched with saturated ammonium chloride (60 mL) and water (30 mL). The mixture was extracted with ethyl acetate (2 x 150 mL), and the combined extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (0-2% ethyl acetate in petroleum ether solution) to give 4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-fluorobenzaldehyde (11.5 g, 73.5% yield) as a yellow liquid. MS (ESI) m / z: 269.1 [M+1] + .

[0364] 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluorobenzyl)amino)phthalic acid: A solution of 4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-fluorobenzaldehyde (7.50 g, 27.9 mmol) and 3-aminophthalic acid (5.06 g, 27.9 mmol) in 1:10 acetic acid-MeOH (110 mL) was stirred at 25 °C for 30 min and cooled to 0 °C. A borane-2-methylpyridine complex (4.48 g, 41.9 mmol) was added, and the mixture was brought to ambient temperature. The mixture was stirred at ambient temperature for 16 h, and concentrated under reduced pressure. The residue was diluted with water (25 mL) and ethyl acetate (25 mL) and stirred for 15 min. The organic layer was removed, and the aqueous layer was extracted with ethyl acetate (30 mL x 2). The organic fractions were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (2-5% ethyl acetate in petroleum ether solution) to give 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluorobenzyl)amino)phthalic acid (9.90 g, 81.8% yield) as a white solid. LCMS (ESI) m / z: 434.1 [M+1] + .

[0365] 4-((4-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-ylisodihydroindole-1,3-dione): A solution of 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluorobenzyl)amino)phthalic acid (11.8 g, 27.2 mmol) and 3-aminopiperidin-2,6-dione hydrochloride (6.72 g, 40.8 mmol) in pyridine (150 mL) The mixture was stirred at 120°C under a nitrogen atmosphere for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2-5% ethyl acetate in petroleum ether solution) to give 4-((4-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-ylisodihydroindole-1,3-dione) (9.90 g, 69.2% yield) as a yellow solid. LCMS (ESI) m / z: 526.2 [M+1] + .

[0366] 2-(2,6-dioxopiperidin-3-yl-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isodihydroindole-1,3-dione: Concentrated sulfuric acid (20.0 mL, 368 mmol) was added to a solution of 4-((4-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-ylisodihydroindole-1,3-dione (9.90 g, 18.8 mmol) in THF (100 mL). The mixture was then incubated at ambient temperature. The mixture was stirred at 12°C for 12 hours. The mixture was concentrated under vacuum, and the residue was treated with 1:5 ethyl acetate-petroleum ether (20 mL). The resulting suspension was stirred for 30 minutes and filtered. The collected solid was washed with 1:5 ethyl acetate-petroleum ether and dried under vacuum to give 2-(2,6-dioxopiperidin-3-yl-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isodihydroindole-1,3-dione (6.58 g, 85.2% yield) as a yellow solid. MS (ESI) m / z: 412.0 [M+1] + . 1 HNMR (400MHz, DMSO-d6) δppm 11.12 (s, 1H), 7.54 (dd, J=7.3, 8.4Hz, 1H), 7.33 (t, J=7.8Hz, 1H), 7.16-7.07 (m, 3H), 7.05 (d, J=7.0Hz, 1H), 6.99 (d, J=8.5Hz, 1H), 5.33-5.25 (m, 1H), 5.07 (dd, J=5.3, 12.9Hz, 1H), 4.59 (d, J=6.3Hz, 2H), 4.47 (d, J=5.8Hz, 2H), 2.95-2.84 (m, 1H), 2.65-2.52 (m, 2H), 2.09-2.01 (m, 1H).

[0367] 4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-ylisodihydroindole-1,3-dione): A solution of 2-(2,6-dioxopiperidin-3-yl-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isodihydroindole-1,3-dione (6.58 g, 16.0 mmol) in dichloromethane (200 mL) was cooled to 0 °C, and thionyl chloride (20.0 mL, 276 mmol) was added dropwise. After the addition was complete... The cooling bath was removed, and the reaction mixture was stirred at ambient temperature for 2 hours. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (1.00–1.25% MeOH in dichloromethane solution) to give 4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-ylisodihydroindole-1,3-dione (3.80 g, 55.4% yield) as a yellow solid. LCMS (ESI) m / z: 430.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δppm 11.12 (s, 1H), 7.54 (dd, J=7.3, 8.4Hz, 1H), 7.38 (t, J=7.9 Hz, 1H), 7.32 (dd, J=1.5, 11.0Hz, 1H), 7.24 (dd, J=1.6, 7.8Hz, 1H), 7.16 (t, J=6.3Hz, 1 H), 7.06 (d, J=6.9Hz, IH), 6.98 (d, J=8.5Hz, 1H), 5.08 (dd, J=5.3, 12.9Hz, 1H), 4.74 (s , 2H), 4.63 (d, J=6.3Hz, 2H), 2.95-2.85 (m, 1H), 2.66-2.53 (m, 2H), 2.09-2.02 (m, 1H).

[0368] 2-(2,6-dioxopiperidin-3-yl-4-((2-fluoro-4-((3-morpholinoazacyclobutan-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione: A solution of 4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-ylisodihydroindole-1,3-dione (215 mg, 0.500 mmol) (prepared as described herein) and 4-(azacyclobutan-3-yl)morpholine hydrochloride (107 mg, 0.600 mmol) in anhydrous DMSO (1.7 mL). DIEA (262 μL, 1.50 mmol) was added, and the mixture was stirred at ambient temperature for 48 hours. The reaction mixture was diluted with 2.5 mL of DMSO solution in 20% formic acid and filtered through a membrane injection filter (0.45 μm nylon). The solution was purified using standard methods to give 2-(2,6-dioxadiazin-3-yl-4-((2-fluoro-4-((3-morpholinoazonobutane-1-yl)methyl)benzyl)amino)isodihydroindole-1,3-dione (173 mg, 64.6% yield). LCMS (ESI) m / z 536.2 [M+H] + .

[0369] Example 4: Assay of cell proliferation and viability using blood cell lines

[0370] The following are examples of cell-based assays that can be used to determine the antiproliferative and apoptotic effects of the compounds described herein using exemplary blood cell lines (Table 1). The in vitro growth-inhibiting activity of compound 1 described herein was assessed using 384-well flow cytometry.

[0371] Table 1: Blood Cell Lines

[0372]

[0373] ATCC = American Type Culture Collection; DSMZ = German Microbial and Cell Culture Collection; FBS = Fetal Bovine Serum; IMDM = Iscove Modified Dalbeck Medium; JCRB = Japanese Collection of Research Bioresources Cell Bank; MM = Multiple Myeloma; NEAA = Non-essential Amino Acids; RPMI = RPMI 1640; X = Not provided in this article.

[0374] Cell lines were plated in 384-well flat-bottomed plates under the conditions shown in Table 1 and incubated using either compound 1 or dimethyl sulfoxide (DMSO) controls at incremental concentrations of 0.00015–10 μM. The final concentration of DMSO was 0.1% (v / v). After adding compound 1 or DMSO and incubating for 120 hours, cells were analyzed by flow cytometry using annexin V and the cell-insoluble DNA dye DRAQ7. Thermo Fisher Scientific (TFS) was used to analyze cell number and cell death. In the early stages of apoptosis, phosphatidylserine is translocated from the inner to the outer layer of the cell membrane, and annexin V binds to phosphatidylserine residues exposed on the surface of apoptotic cells. The viability dye DRAQ7 was excluded from use on intact, live cells and was stained only on cells that had died due to apoptosis or necrosis.

[0375] Flow cytometry data were then analyzed using FlowJo_v10 software to determine the number of viable cells (annexin V and DRAQ7 double-negative cells) and the percentage of apoptotic cells (annexin V positive cells) under each condition. Viable cell counts for each concentration were normalized to the DMSO control (considered 100% viable cells) to calculate the percentage of viable cells remaining after treatment, and plotted using GraphPad Prism 7.03. The IC50 was then calculated by fitting a nonlinear regression curve using log(inhibitor) versus normalized response-variable slope analysis with GraphPad Prism 7.03. 50 (50% inhibitory concentration) and E max (Maximum efficacy achieved) value. The area under the curve (AUC) was calculated using GraphPad Prism 7.03. Similarly, for apoptosis analysis, the percentage of apoptosis in cell gates combining “early” (annexin V positive and DRAQ7 negative) and “late” (annexin V and DRAQ7 positive) apoptosis relative to DMSO was plotted using GraphPad Prism 7.03. AUC and EC50 from the apoptosis curves were calculated using log(agonist) versus normalized response-variable slope analysis with GraphPad Prism 7.03, followed by AUC and EC50 fitting with nonlinear regression curves. 50 (Concentration of the compound that produces the half-maximal apoptosis response) and Y max (The maximum percentage of cells that undergo apoptosis) value.

[0376] As shown in Table 2, the dose-response proliferation curves and nonlinear curve fitting regression of the blood cell line group of compound 1 were used to determine the IC50 of viable cells. 50 AUC and E max (Energy) maxThe value varied between 100 at low doses and 0 at high doses (equivalent to the inhibition of all living cells), and the dose-response apoptosis curve of compound 1 was used to determine the percentage of apoptosis in EC50. 50 AUC and Y max (Y-cell apoptosis) max The dosage was varied from a low dose of 0 to a higher dose of 100 (which is equivalent to the death of all cells).

[0377] Compound 1 was found to have antiproliferative activity and / or apoptosis-inducing effects in almost all tested blood cell lines (Table 2).

[0378] Table 2. Antiproliferative activity and apoptosis-inducing effects of compound 1 in blood cell lines

[0379]

[0380]

[0381] AUC = Area under the curve; IC 50 =50% inhibition concentration (μM); E max = The maximum efficacy of eliminating tumor cells, expressed as a percentage of remaining tumor cells; EC 50 = The concentration (μM) of the compound that produces the half-maximal apoptotic response; Y max = The calculated percentage of the control at the highest concentration of compound 1.

[0382] Many references have been cited, and each of them is incorporated into this paper in its entirety through citation.

[0383] The above embodiments are merely exemplary, and those skilled in the art will recognize or be able to determine many equivalent solutions for particular compounds, materials, and methods using experiments no more than those of ordinary kind. All such equivalent solutions are considered to be within the scope of this invention and are covered by the appended claims.

[0384] Implementation plan:

[0385] 1. A method for treating hematologic malignancies, comprising administering to an individual in need a therapeutically effective amount of compound 3 of the following formula:

[0386]

[0387] Or its enantiomers, mixtures of enantiomers, tautomers, isotope variants or pharmaceutically acceptable salts, wherein the hematologic malignancy is marginal zone lymphoma (MZL), Burkitt lymphoma (BL), multiple myeloma (MM), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), T-cell lymphoma (TCL) or Hodgkin lymphoma (HL).

[0388] 2. A method for treating hematologic malignancies, comprising administering to an individual in need a therapeutically effective amount of a chemical of the following formula:

[0389]

[0390] Or its tautomers, isotopic variants or pharmaceutically acceptable salts, wherein the hematologic malignancy is marginal zone lymphoma (MZL), Burkitt lymphoma (BL), multiple myeloma (MM), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), T-cell lymphoma (TCL) or Hodgkin lymphoma (HL).

[0391] 3. A method for treating hematologic malignancies, comprising administering to an individual in need a therapeutically effective amount of compound 2 of the following formula:

[0392]

[0393] Or its tautomers, isotopic variants or pharmaceutically acceptable salts, wherein the hematologic malignancy is marginal zone lymphoma (MZL), Burkitt lymphoma (BL), multiple myeloma (MM), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), T-cell lymphoma (TCL) or Hodgkin lymphoma (HL).

[0394] 4. The method of any one of implementation schemes 1-3, wherein the hematologic malignancy is marginal zone lymphoma.

[0395] 5. The method of implementation plan 4, wherein the marginal zone lymphoma is splenic marginal zone lymphoma.

[0396] 6. The method of any one of implementation schemes 1-3, wherein the hematologic malignancy is Burkitt lymphoma.

[0397] 7. The method of any one of implementation schemes 1-3, wherein the hematologic malignancy is multiple myeloma.

[0398] 8. The method of implementation plan 7, wherein multiple myeloma is plasma cell leukemia.

[0399] 9. The method of any one of implementation schemes 1-3, wherein the hematologic malignancy is myelodysplastic syndrome.

[0400] 10. The method of any one of implementation schemes 1-3, wherein the hematologic malignancy is acute myeloid leukemia.

[0401] 11. The method of implementation plan 10, wherein the acute myeloid leukemia is B-cell acute myeloid leukemia.

[0402] 12. The method of any one of implementation schemes 1-3, wherein the hematologic malignancy is acute lymphoblastic leukemia.

[0403] 13. The method of any one of embodiments 1-3, wherein the hematologic malignancy is a T-cell lymphoma.

[0404] 14. The method of implementation scheme 13, wherein the T-cell lymphoma is anaplastic large cell lymphoma.

[0405] 15. The method of implementation plan 13, wherein the T-cell lymphoma is Cezari syndrome.

[0406] 16. The method of any one of embodiments 1-3, wherein the hematologic malignancy is Hodgkin's lymphoma.

[0407] 17. The method of any one of embodiments 1-16, wherein the hematologic malignancy is recurrent or refractory.

[0408] 18. The method of any one of embodiments 1-16, wherein the hematologic malignancy is newly diagnosed.

[0409] 19. The method of any one of embodiments 1-18, wherein the compound is administered orally.

[0410] 20. A compound for a method of treating hematologic malignancies, wherein the compound is compound 3 having the following formula:

[0411]

[0412] Or its enantiomers, mixtures of enantiomers, tautomers, isotopic variants, or pharmaceutically acceptable salts, wherein the method comprises administering a therapeutically effective amount of the compound to an individual in need, wherein the hematologic malignancy is marginal zone lymphoma (MZL), Burkitt lymphoma (BL), multiple myeloma (MM), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), T-cell lymphoma (TCL), or Hodgkin lymphoma (HL).

[0413] 21. A compound for a method of treating hematologic malignancies, wherein the compound is compound 1 having the following formula:

[0414]

[0415] Or its tautomers, isotopic variants or pharmaceutically acceptable salts, wherein the method comprises administering a therapeutically effective amount of the compound to an individual in need, wherein the hematologic malignancy is marginal zone lymphoma (MZL), Burkitt lymphoma (BL), multiple myeloma (MM), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), T-cell lymphoma (TCL) or Hodgkin lymphoma (HL).

[0416] 22. A compound for a method of treating hematologic malignancies, wherein the compound is compound 2 having the following formula:

[0417]

[0418] Or its tautomers, isotopic variants or pharmaceutically acceptable salts, wherein the method comprises administering a therapeutically effective amount of the compound to an individual in need, wherein the hematologic malignancy is marginal zone lymphoma (MZL), Burkitt lymphoma (BL), multiple myeloma (MM), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), T-cell lymphoma (TCL) or Hodgkin lymphoma (HL).

[0419] 23. A compound for use in any one of embodiments 20-22, wherein the hematologic malignancy is marginal zone lymphoma.

[0420] 24. A compound for use in embodiment 23, wherein the marginal zone lymphoma is a splenic marginal zone lymphoma.

[0421] 25. A compound for use in any one of embodiments 20-22, wherein the hematologic malignancy is Burkitt lymphoma.

[0422] 26. A compound for use in any one of embodiments 20-22, wherein the hematologic malignancy is multiple myeloma.

[0423] 27. A compound used in accordance with embodiment 26, wherein multiple myeloma is plasma cell leukemia.

[0424] 28. A compound for use in any one of embodiments 20-22, wherein the hematologic malignancy is myelodysplastic syndrome.

[0425] 29. A compound for use in any one of embodiments 20-22, wherein the hematologic malignancy is acute myeloid leukemia.

[0426] 30. A compound for use in embodiment 29, wherein the acute myeloid leukemia is B-cell acute myeloid leukemia.

[0427] 31. A compound for use in any one of embodiments 20-22, wherein the hematologic malignancy is acute lymphoblastic leukemia.

[0428] 32. A compound for use in any one of embodiments 20-22, wherein the hematologic malignancy is a T-cell lymphoma.

[0429] 33. A compound for use in embodiment 32, wherein the T-cell lymphoma is anaplastic large cell lymphoma.

[0430] 34. A compound for use in embodiment 32, wherein the T-cell lymphoma is Cezari syndrome.

[0431] 35. A compound for use in any one of embodiments 20-22, wherein the hematologic malignancy is Hodgkin's lymphoma.

[0432] 36. A compound for use in any one of embodiments 20-35, wherein the hematologic malignancy is recurrent or refractory.

[0433] 37. A compound for use in any one of embodiments 20-35, wherein the hematologic malignancy is newly diagnosed.

[0434] 38. A compound for use in any one of embodiments 20-37, wherein the compound is administered orally.

Claims

1. The use of compound 1 of the following formula or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of hematologic malignancies: 1, The hematologic malignancies mentioned therein are marginal zone lymphoma (MZL), Burkitt lymphoma (BL), multiple myeloma (MM), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), T-cell lymphoma (TCL), or Hodgkin lymphoma (HL).

2. The use of claim 1, wherein compound 1 of the following formula is used to prepare a medicament for treating hematologic malignancies: 1， The hematologic malignancies mentioned therein are marginal zone lymphoma (MZL), Burkitt lymphoma (BL), multiple myeloma (MM), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), T-cell lymphoma (TCL), or Hodgkin lymphoma (HL).

3. The use of claim 1, wherein a pharmaceutically acceptable salt of compound 1 of the following formula is used to prepare a medicament for treating hematologic malignancies: 1， The hematologic malignancies mentioned therein are marginal zone lymphoma (MZL), Burkitt lymphoma (BL), multiple myeloma (MM), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), T-cell lymphoma (TCL), or Hodgkin lymphoma (HL).

4. The use according to any one of claims 1-3, wherein the hematologic malignancy is a marginal zone lymphoma.

5. The use of claim 4, wherein the marginal zone lymphoma is a splenic marginal zone lymphoma.

6. The use according to any one of claims 1-3, wherein the hematologic malignancy is Burkitt lymphoma.

7. The use according to any one of claims 1-3, wherein the hematologic malignancy is multiple myeloma.

8. The use of claim 7, wherein multiple myeloma is plasma cell leukemia.

9. The use according to any one of claims 1-3, wherein the hematologic malignancy is myelodysplastic syndrome.

10. The use according to any one of claims 1-3, wherein the hematologic malignancy is acute myeloid leukemia.

11. The use of claim 10, wherein the acute myeloid leukemia is B-cell acute myeloid leukemia.

12. The use according to any one of claims 1-3, wherein the hematologic malignancy is acute lymphoblastic leukemia.

13. The use according to any one of claims 1-3, wherein the hematologic malignancy is a T-cell lymphoma.

14. The use of claim 13, wherein the T-cell lymphoma is anaplastic large cell lymphoma.

15. The use of claim 13, wherein the T-cell lymphoma is Cezari syndrome.

16. The use according to any one of claims 1-3, wherein the hematologic malignancy is Hodgkin's lymphoma.

17. The use according to any one of claims 1-3, wherein the hematologic malignancy is recurrent or refractory.

18. The use according to any one of claims 1-3, wherein the hematologic malignancy is newly diagnosed.

19. The use according to any one of claims 1-3, wherein the medicament is prepared for oral administration.

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