Substituted 4-aminoisoindoline-1,3-dione compounds and second active agents for combined use

Abstract

Provided herein are methods of using (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with a second active agent to treat, prevent, or manage a hematological malignancy. The second active agent is one or more of an HDAC inhibitor, a BCL2 inhibitor, a BTK inhibitor, an mTOR inhibitor, a PI3K inhibitor, a PKCβ inhibitor, a SYK inhibitor, a JAK2 inhibitor, an Aurora kinase inhibitor, an EZH2 inhibitor, a BET inhibitor, a hypomethylating agent, a DOT1L inhibitor, a HAT inhibitor, a WDR5 inhibitor, a DNMT1 inhibitor, an LSD-1 inhibitor, a G9A inhibitor, a PRMT5 inhibitor, a BRD inhibitor, a SUV420H1 / H2 inhibitor, a CARM1 inhibitor, a PLK1 inhibitor, a NEK2 inhibitor, a MEK inhibitor, a PHF19 inhibitor, a PIM inhibitor, an IGF-1R inhibitor, an XPO1 inhibitor, a BIRC5 inhibitor, or chemotherapy.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Application No. 62 / 923,945, filed October 21, 2019, which is incorporated herein by reference in its entirety.

[0002] Provided herein are methods of using (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with a second active agent to treat, prevent, or manage a hematological malignancy. [Background technology]

[0003] Cancer is primarily characterized by an increase in the number of abnormal cells derived from a given normal tissue, their invasion into surrounding tissues, or the spread of malignant cells from lymphatic or blood to regional lymph nodes and metastasis. Clinical data and molecular biological studies indicate that cancer is a multistep process that begins with subtle preneoplastic changes that, under certain conditions, can progress to neoplasia. Neoplastic lesions may evolve clonally, increasing their capacity for invasion, proliferation, metastasis, and heterogeneity, especially under conditions in which neoplastic cells evade host immune surveillance. Current cancer therapies may involve surgery, chemotherapy, hormonal therapy, and / or radiation therapy to eradicate neoplastic cells in patients. Recent advances in cancer therapeutics are reviewed by Rajkumar et al. in Nature Reviews Clinical Oncology 11, 628-630 (2014).

[0004] All current cancer therapy approaches pose significant disadvantages to patients. For example, surgery may be contraindicated or unacceptable depending on the patient's health. Furthermore, surgery may not completely remove the neoplastic tissue. Radiation therapy is only effective if the neoplastic tissue is more sensitive to radiation than normal tissue. Radiation treatment can also often cause serious side effects. Hormone therapy is rarely administered as a single agent. While hormone therapy can be effective, it is often used to prevent or delay cancer recurrence after other treatments have removed the majority of the cancer cells.

[0005] Despite the availability of a variety of chemotherapy agents, chemotherapy has many drawbacks. Nearly all chemotherapy agents are toxic, and chemotherapy causes significant and often dangerous side effects, such as severe nausea, bone marrow suppression, and immunosuppression. Furthermore, even with the administration of combinations of chemotherapy agents, many tumor cells become resistant or develop resistance to the chemotherapy agents. In fact, cells resistant to a particular chemotherapy agent used in a treatment protocol often prove resistant to other drugs, even when these agents act by a different mechanism than the other drugs used in the particular treatment. This phenomenon is referred to as pleiotropic drug resistance or multidrug resistance. Due to drug resistance, many cancers prove or become refractory to standard chemotherapy treatment protocols.

[0006] Hematological malignancies are cancers that occur in hematopoietic tissues such as bone marrow or cells of the immune system. Examples of hematological malignancies are leukemia, lymphoma, and myeloma. More specific examples of hematological malignancies include, but are not limited to, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), Hodgkin's lymphoma (HL), T-cell lymphoma (TCL), Burkitt's lymphoma (BL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone lymphoma (MZL), and myelodysplastic syndrome (MDS). [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Rajkumar et al., Nature Reviews Clinical Oncology 11, 628-630 (2014) Summary of the Invention

[0008] Described herein is a method of using (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione (Compound 1), or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with a second active agent to treat, prevent, or manage a hematological malignancy, wherein the second active agent is an HDAC inhibitor (e.g., panobinostat, romidepsin, vorinostat, or ribozyme). or citalinostat), BCL2 inhibitors (e.g., venetoclax), BTK inhibitors (e.g., ibrutinib or acalabrutinib), mTOR inhibitors (e.g., everolimus), PI3K inhibitors (e.g., idelalisib), PKCβ inhibitors (e.g., enzastaurin), SYK inhibitors (e.g., fostamatinib), JAK2 inhibitors (e.g., fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, or momelotinib), Aurora kinase inhibitors (e.g., alisertib), EZH2 inhibitors (e.g., For example, tazemetostat, GSK126, CPI-1205, 3-deazaneplanocin A, EPZ005687, EI1, UNC1999, or sinefungin), BET inhibitors (e.g., virabresib or Compound B), hypomethylating agents (e.g., 5-azacytidine or decitabine), DOT1L inhibitors (e.g., pinometostat), HAT inhibitors (e.g., C646), WDR5 inhibitors (e.g., OICR-9429), DNMT1 inhibitors (e.g., GSK3484862), LSD-1 inhibitors (e.g., Compound C or secridemstat), G9 A inhibitors (e.g., UNC0631), PRMT5 inhibitors (e.g., GSK3326595), BRD inhibitors (e.g., LP99), SUV420H1 / H2 inhibitors (e.g., A-196), CARM1 inhibitors (e.g., EZM2302), PLK1 inhibitors (e.g., BI2536), NEK2 inhibitors (e.g., JH295), MEK inhibitors (e.g., trametinib), PHF19 inhibitors, PIM inhibitors (e.g., LGH-447), IGF-1R inhibitors (e.g., linsitinib), XPO1 inhibitors (e.g., selinexor), BIRC5 inhibitors (e.g.,YM155), or chemotherapy (e.g., bendamustine, doxorubicin, etoposide, methotrexate, cytarabine, vincristine, ifosfamide, melphalan, oxaliplatin, or dexamethasone). Compound 1, or an enantiomer, mixture of enantiomers, isotopologue, or pharmaceutically acceptable salt thereof, is also collectively referred to as "Compound A."

[0009] Also provided for use in the methods provided herein are pharmaceutical compositions comprising an effective concentration of a compound provided herein, e.g., Compound A, and optionally at least one pharmaceutical carrier, formulated for administration by a suitable route and means. In one embodiment, the compound provided herein is Compound 1.

[0010] In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for treating a hematological malignancy provided herein. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for preventing a hematological malignancy provided herein. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for ameliorating a hematological malignancy provided herein.

[0011] In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for treating a hematological malignancy provided herein. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for preventing a hematological malignancy provided herein. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for ameliorating a hematological malignancy provided herein.

[0012] In one embodiment, the hematological malignancy is acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), Hodgkin's lymphoma (HL), T-cell lymphoma (TCL), Burkitt's lymphoma (BL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone lymphoma (MZL), or myelodysplastic syndrome (MDS).

[0013] In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for treating AML. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for preventing AML. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for ameliorating AML.

[0014] In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for treating AML. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for preventing AML. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for ameliorating AML.

[0015] In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for treating ALL. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for preventing ALL. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for ameliorating ALL.

[0016] In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for treating ALL. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for preventing ALL. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for ameliorating ALL.

[0017] In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for treating MM. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for preventing MM. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for ameliorating MM.

[0018] In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for treating MM. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for preventing MM. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for ameliorating MM.

[0019] In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for treating NHL. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for preventing NHL. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for ameliorating NHL.

[0020] In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for treating NHL. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for preventing NHL. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for ameliorating NHL.

[0021] In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for treating DLBCL. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for preventing DLBCL. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for ameliorating DLBCL.

[0022] In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for treating DLBCL. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for preventing DLBCL. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for ameliorating DLBCL.

[0023] In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for treating HL. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for preventing HL. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for ameliorating HL.

[0024] In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for treating HL. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for preventing HL. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for ameliorating HL.

[0025] In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for treating TCL. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for preventing TCL. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for ameliorating TCL.

[0026] In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for treating TCL. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for preventing TCL. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for ameliorating TCL.

[0027] In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective to treat BL. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective to prevent BL. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective to ameliorate BL.

[0028] In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for treating BL. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for preventing BL. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for ameliorating BL.

[0029] In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for treating CLL / SLL. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for preventing CLL / SLL. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for ameliorating CLL / SLL.

[0030] In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for the treatment of CLL / SLL. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for the prevention of CLL / SLL. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for the amelioration of CLL / SLL.

[0031] In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for treating MZL. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for preventing MZL. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for ameliorating MZL.

[0032] In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for treating MZL. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for preventing MZL. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for ameliorating MZL.

[0033] In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for treating MDS. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for preventing MDS. In one embodiment, the pharmaceutical composition delivers an amount of Compound A in combination with a second active agent provided herein effective for ameliorating MDS.

[0034] In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for treating MDS. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for preventing MDS. In one embodiment, the pharmaceutical composition delivers an amount of Compound 1 in combination with a second active agent provided herein effective for ameliorating MDS.

[0035] The compounds or compositions provided herein, or pharmaceutically acceptable derivatives thereof, can be administered simultaneously with, prior to, or following the administration of each other and one or more of the above-mentioned therapies.

[0036] These and other aspects of the subject matter described herein will become evident upon reference to the following detailed description. [Brief explanation of the drawings]

[0037] [Figure 1] 1 shows the sensitivity of DLBCL cell line proliferation to Compound 1 treatment as measured by Cell Titer Glo assay. [Figure 2-1] 1 shows a heat map of additive (light grey) and synergistic (dark grey) scoring for combination treatment of hematological malignancy cell lines with Compound 1 and a second active agent. [Figure 2-2] 1 shows a heat map of additive (light grey) and synergistic (dark grey) scoring for combination treatment of hematological malignancy cell lines with Compound 1 and a second active agent. [Figure 3] 1 shows the antitumor activity of Compound 1 alone and in combination with 5-azacytidine in a WSU-DLCL2 (DLBCL) xenograft model. [Figure 4] 1 shows the antitumor activity of Compound 1 alone and in combination with tazemetostat in a WSU-DLCL2 (DLBCL) xenograft model. [Figure 5] 1 shows the antitumor activity of Compound 1 (3, 10, and 30 mg / kg, respectively) alone and in combination with tazemetostat in a DB (DLBCL) xenograft model. [Figure 6] 1 shows a heatmap of the normalized percentage of tumor cells treated with Compound 1 in combination with venetoclax. [Figure 7] 1 shows a heatmap of the normalized percentage of tumor cells treated with Compound 1 in combination with ibrutinib. [Figure 8] 1 shows a heat map of additive and synergistic scoring of combination treatment of DLBCL cell lines with Compound 1 and Compound B. DETAILED DESCRIPTION OF THE INVENTION

[0038] 5.1 Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there are multiple definitions for terms herein, the definitions in this section shall prevail unless otherwise stated.

[0039] As used herein, and in the specification and appended claims, the indefinite articles "a" and "an" and the definite article "the" include plural and singular referents unless the context clearly dictates otherwise.

[0040] As used herein, the terms "comprising" and "including" may be used interchangeably. The terms "comprising" and "including" are interpreted to specify the presence of the specified features or components as referenced, but do not exclude the presence or addition of one or more features or components or groups thereof. Furthermore, the terms "comprising" and "including" are intended to include examples encompassed by the term "consisting of." Thus, the term "consisting of" can be used in place of the terms "comprising" and "including" to provide more specific embodiments of the present invention.

[0041] The term "consisting of" means that the object has at least 90%, 95%, 97%, 98%, or 99% of the specified features or components that make it up. In another embodiment, the term "consisting of" excludes any other features or components from the scope of any subsequent recitation, except those that are not essential to the technical effect to be achieved.

[0042] As used herein, the term "or" should be interpreted as an inclusive "or," meaning any one or any combination. Thus, "A, B, or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B, and C." Exceptions to this definition occur only when combinations of elements, features, steps, or operations are inherently mutually exclusive in some way.

[0043] As used herein, unless otherwise specified, the terms "about" and "approximately," when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, refer to a dose, amount, or weight percent that is recognized by those skilled in the art as providing a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. In certain embodiments, the terms "about" and "approximately," when used in this context, contemplate a dose, amount, or weight percent that is within 30%, 20%, 15%, 10%, or 5% of the specified dose, amount, or weight percent.

[0044] As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, relatively non-toxic acid, including inorganic and organic acids. In certain embodiments, suitable acids include acetic acid, adipic acid, 4-aminosalicylic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphorsulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, carbonic acid, citric acid, cyclamic acid, dihydrogen phosphate, 2,5-dihydroxybenzoic acid (gentisic acid), 1,2-ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isobutyric acid, isethionic acid, and the like. Examples of suitable salts include, but are not limited to, carboxylic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, monohydrogencarbonic acid, monohydrogenphosphoric acid, monohydrogensulfuric acid, mucic acid, 1,5-naphthalenedisulfonic acid, nicotinic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, phthalic acid, propionic acid, pyroglutamic acid, salicylic acid, suberic acid, succinic acid, sulfuric acid, tartaric acid, toluenesulfonic acid, and the like (see, e.g., S.M. Berge et al., J. Pharm. Sci., 66:1-19 (1977); and Handbook of Pharmaceutical Salts: Properties, Selection and Use, P.H. Stahl and C.G. Wermuth, Eds., (2002), Wiley, Weinheim). In certain embodiments, suitable acids are strong acids (e.g., with a pKa of less than about 1), including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, pyridinesulfonic acid, or other substituted sulfonic acids.Also included are salts of other relatively non-toxic compounds with acidic properties, including amino acids such as aspartic acid, and other compounds such as aspirin, ibuprofen, saccharin, etc. Acid addition salts can be obtained by contacting the neutral form of the compound, either neat or in a suitable solvent, with a sufficient amount of the desired acid.

[0045] As used herein, and unless otherwise specified, the term "prodrug" of an active compound refers to a compound that is converted in vivo to produce an active compound or a pharmaceutically acceptable form of the active compound. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood). Prodrugs include compounds in which a hydroxy, amino, or mercapto group is bonded to any group that is cleaved to form a free hydroxy, free amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a subject.

[0046] As used herein, unless otherwise specified, the term "isomer" refers to different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the way their atoms are arranged in space. "Atropisomers" are stereoisomers in which rotation around a single bond is hindered. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in any ratio is sometimes known as a "racemic" mixture. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry can be specified according to the Cahn-Ingold-Prelog RS system. When a compound is an enantiomer, the stereochemistry of each chiral carbon can be specified as either R or S. Resolved compounds of unknown absolute configuration can be specified as (+) or (-) depending on the direction (dextrorotatory or levorotatory) they rotate plane-polarized light at the wavelength of the sodium D line. However, the signs of optical rotation (+) and (-) are unrelated to the absolute configuration R and S of the molecule. Certain compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomers that can be defined as (R)- or (S)-, with respect to the absolute stereochemistry at each asymmetric atom. The present chemical compounds, pharmaceutical compositions, and methods are meant to include all such possible isomers, including racemic mixtures, and may include optically substantially pure forms and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared, for example, using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0047] "Stereoisomer" can also include E and Z isomers, or mixtures thereof, and cis and trans isomers, or mixtures thereof. In certain embodiments, the compounds described herein are isolated as either the E or Z isomer. In certain embodiments, the compounds described herein are a mixture of E or Z isomers.

[0048] "Tautomer" refers to isomeric forms of a compound that are in equilibrium with each other. The concentration of isomeric forms may vary depending on the environment in which the compound is found, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole may exhibit the following isomers, which are referred to as tautomers of each other: [ka]

[0049] It is also noted that the compounds described herein may contain unnatural proportions of atomic isotopes at one or more atoms. For example, the compounds may contain isotopes of, for example, tritium ( 3 H), iodine-125( 125 I), sulfur 35( 35 S), or carbon-14 ( 14 It can be radiolabeled with a radioisotope such as deuterium ( 2 H), carbon-13 ( 13 C), or nitrogen-15( 15 N), and the like, may be isotopically enriched. As used herein, an "isotopologue" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" can also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term "isotopic composition" refers to the amount of each isotope present in a given atom. Radiolabeled isotopically enriched compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, isotopologues of the compounds described herein are provided, e.g., isotopologues that are enriched with deuterium, carbon-13, and / or nitrogen-15. As used herein, "deuterated" refers to a compound in which at least one hydrogen (H) is replaced with deuterium (D or2 H), i.e., the compound is enriched with deuterium at at least one position.

[0050] Note that if there is a discrepancy between a depicted structure and the name of that structure, the depicted structure is given more weight.

[0051] As used herein, unless otherwise specified, the term "treat" means the total or partial alleviation of a disorder, disease or condition, or one or more symptoms associated with a disorder, disease or condition, or the slowing or halting of further progression or worsening of these symptoms, or the alleviation or eradication of the cause of the disorder, disease or condition itself.

[0052] As used herein, unless otherwise specified, the term "prevent" means a method of delaying and / or impeding the onset, recurrence, or spread of a disorder, disease, or condition, in whole or in part; a method of barring a subject from acquiring a disorder, disease, or condition; or a method of reducing a subject's risk of acquiring a disorder, disease, or condition.

[0053] As used herein, unless otherwise specified, the term "managing" encompasses preventing the recurrence of a particular disease or disorder in a patient afflicted with the particular disease or disorder, extending the time a patient afflicted with the disease or disorder remains in remission, reducing patient mortality, and / or maintaining a reduction in the severity or avoidance of symptoms associated with the disease or condition being managed.

[0054] As used herein, unless otherwise specified, the term "effective amount" in reference to a compound means an amount capable of treating, preventing, or managing a disorder, disease, or condition, or a symptom thereof.

[0055] As used herein, unless otherwise specified, the term "subject" or "patient" includes animals, including but not limited to cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, which in one embodiment are mammals, and in another embodiment are humans.

[0056] As used herein, unless otherwise specified, the term "relapse" refers to a disorder, disease, or condition that has responded to treatment (e.g., achieved a complete response) and then progressed. Treatment can include one or more lines of therapy. In one embodiment, the disorder, disease, or condition has previously been treated with one or more lines of therapy. In another embodiment, the disorder, disease, or condition has previously been treated with one, two, three, or four lines of therapy. In some embodiments, the disorder, disease, or condition is a hematological malignancy.

[0057] In one embodiment, "relapsed" DLBCL may refer to DLBCL that has been previously treated with one or more lines of therapy. In one embodiment, relapsed DLBCL is DLBCL that has been previously treated with one, two, three, or four lines of therapy. In one embodiment, relapsed DLBCL is DLBCL that has been previously treated with two or more lines of therapy.

[0058] As used herein, unless otherwise specified, the term "refractory" refers to a disorder, disease, or condition that has not responded to previous treatment, which may include one or more lines of therapy. In one embodiment, the disorder, disease, or condition has been previously treated with one, two, three, or four lines of therapy. In one embodiment, the disorder, disease, or condition has been previously treated with two or more lines of treatment and has experienced less than a complete response (CR) to the most recent systemic therapy, including the regimen. In some embodiments, the disorder, disease, or condition is a hematological malignancy.

[0059] In one embodiment, "relapsed or refractory" CLL / SLL may refer to CLL / SLL that has been previously treated with one or more lines of therapy. In one embodiment, relapsed or refractory CLL / SLL is CLL / SLL that has been previously treated with one, two, three, or four lines of therapy. In one embodiment, relapsed or refractory CLL / SLL is CLL / SLL that has been previously treated with two or more lines of therapy. In one embodiment, relapsed or refractory CLL / SLL is CLL / SLL that has been previously treated with a Bruton's tyrosine kinase (BTK) inhibitor. In one embodiment, relapsed or refractory CLL / SLL is relapsed or refractory to a BTK inhibitor. In one embodiment, the BTK inhibitor is ibrutinib. In one embodiment, the BTK inhibitor is acalabrutinib. In one embodiment, the BTK inhibitor is zanubrutinib. In one embodiment, the BTK inhibitor is tirabrutinib.

[0060] In the context of cancer, e.g., hematological malignancies, inhibition can be assessed by, among other things, inhibition of disease progression, inhibition of tumor growth, shrinkage of the primary tumor, relief of tumor-related symptoms, inhibition of tumor-secreted factors, delay in the appearance of primary or secondary tumors, delay in the onset of primary or secondary tumors, reduction in the onset of primary or secondary tumors, delay or reduction in the severity of secondary disease effects, cessation of tumor growth and tumor regression, increase in time to progression (TTP), increase in progression-free survival (PFS), and increase in overall survival (OS). As used herein, OS refers to the time from the start of treatment to death from any cause. As used herein, TTP refers to the time from the start of treatment to tumor progression; TTP does not include death. In one embodiment, PFS refers to the time from the start of treatment to tumor progression or death. In one embodiment, PFS refers to the time from the first administration of a compound to the first occurrence of disease progression or death from any cause. In one embodiment, the PFS rate is calculated using Kaplan-Meier estimation. Event-free survival (EFS) means the time from initiation of treatment to treatment failure, including disease progression, discontinuation of treatment for any reason, or death. In one embodiment, overall response rate (ORR) means the percentage of patients achieving a response. In one embodiment, ORR means the combined percentage of patients achieving a complete and partial response. In one embodiment, ORR means the percentage of patients whose best response is ≧partial response (PR). In one embodiment, duration of response (DoR) is the time from achieving a response to relapse or disease progression. In one embodiment, DoR is the time from achieving a response ≧ partial response (PR) to relapse or disease progression. In one embodiment, DoR is the time from first documented response to first documented progressive disease or death. In one embodiment, DoR is the time from first documented response ≧ partial response (PR) to first documented progressive disease or death. In one embodiment, time to response (TTR) means the time from first administration of a compound to first documented response. In one embodiment, TTR refers to the time from the first administration of a compound to the first documented response >= partial response (PR). In extreme cases, complete inhibition is referred to herein as prophylaxis or chemoprevention.In this context, the term "prevention" includes either completely preventing the onset of clinically evident cancer or preventing the onset of a preclinically evident stage of cancer. Also intended to be included in this definition is the prevention of transformation to malignant cells or arresting or reversing the progression of premalignant cells to malignant cells. This includes prophylactic treatment of individuals at risk of developing cancer.

[0061] In certain embodiments, treatment of NHL can be evaluated by the International Workshop Criteria for Malignant Lymphoma (see Cheson et al., J. Clin. Oncol. 2014, 32(27):3059-3068) and the Deauville criteria for fluorodeoxyglucose positron emission tomography (FDG-PET) scan interpretation (Itti et al., Eur. J. Nucl. Med. Mol. Imaging, 2013, 40(9):1312-20; Meignan et al., Leuk Lymphoma, 2014, 55(1):31-37) ("Lugano criteria"), using the response and endpoint definitions set forth in Tables 1-3. [Table 1] [Table 2-1] [Table 2-2] [Table 3]

[0062] In one embodiment, treatment response for CLL / SLL can be assessed by the International Workshop on Chronic Lymphocytic Leukemia criteria (see iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood, 131(25), 2745-2760 (2018)) (Table 4). [Table 4]

[0063] In one embodiment, treatment response for CLL / SLL can be assessed by Eastern Cooperative Oncology Group (ECOG) performance status (Table 5). [Table 5]

[0064] In certain embodiments, stable disease or lack thereof can be determined by methods known in the art, such as, for example, assessment of patient symptoms, physical examination, visualization of the tumor on imaging using, for example, FDG-PET (fluorodeoxyglucose positron emission tomography), PET / CT (positron emission tomography / computed tomography) scan, MRI (magnetic resonance imaging) of the brain and spine, CSF (cerebrospinal fluid), ophthalmic examination, vitreous fluid sampling, retinal photography, bone marrow evaluation and other commonly accepted evaluation methods.

[0065] As used herein, unless otherwise specified, the terms "co-administration" and "in combination" include administration of one or more therapeutic agents (e.g., a compound provided herein and another anti-cancer or supportive care agent) either simultaneously, concurrently, or sequentially, without specific time limitations. In one embodiment, the agents are present in a cell or in a patient's body at the same time or exert their biological or therapeutic effects simultaneously. In one embodiment, the therapeutic agents are in the same composition or unit dosage form. In another embodiment, the therapeutic agents are in separate compositions or unit dosage forms.

[0066] The term "supportive care agent" refers to any substance that treats, prevents, or manages adverse effects from treatment with another therapeutic agent.

[0067] 5.2 Compound 1 For use in the methods provided herein, the compound (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione: [ka] (referred to as "Compound 1") or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof is provided. Methods for preparing Compound 1 are described in U.S. Patent Application No. 16 / 390,815, which is incorporated herein by reference in its entirety. Compound 1, or an enantiomer, mixture of enantiomers, isotopologue, or pharmaceutically acceptable salt thereof, is also collectively referred to as "Compound A."

[0068] In one embodiment, Compound 1 free base is used in the methods provided herein. In one embodiment, a pharmaceutically acceptable salt of Compound 1 is used in the methods provided herein. In one embodiment, the hydrochloride salt of Compound 1 is used in the methods provided herein.

[0069] In one embodiment, an enantiomer of Compound 1 (e.g., the R-enantiomer of Compound 1) is used in the methods provided herein. In one embodiment, a mixture of enantiomers of Compound 1 (e.g., a racemate of Compound 1) is used in the methods provided herein.

[0070] In one embodiment, a tautomer of Compound 1 is used in the methods provided herein. In one embodiment, an isotopologue of Compound 1 is used in the methods provided herein.

[0071] 5.3 Second activator In one embodiment, the second active agent used in the methods provided herein is a histone deacetylase (HDAC) inhibitor. In one embodiment, the HDAC inhibitor is panobinostat, romidepsin, vorinostat, or citalinostat, or a stereoisomer, a mixture of stereoisomers, a tautomer, an isotope, or a pharmaceutically acceptable salt thereof.

[0072] In one embodiment, the HDAC inhibitor is panobinostat, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the HDAC inhibitor is panobinostat. In one embodiment, the HDAC inhibitor is a pharmaceutically acceptable salt of panobinostat. In one embodiment, the HDAC inhibitor is panobinostat lactate. In one embodiment, the HDAC inhibitor is panobinostat monolactate. The chemical name of panobinostat is (2E)-N-hydroxy-3-[4-({[2-(2-methyl-1H-indol-3-yl)ethyl]amino}methyl)phenyl]acrylamide, and panobinostat has the following structure: [ka] It has.

[0073] In one embodiment, the HDAC inhibitor is romidepsin, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the HDAC inhibitor is romidepsin. The chemical name of romidepsin is (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1-methylethyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]trichos-16-ene-3,6,9,19,22-pentone, and has the following structure: [ka] It has.

[0074] In one embodiment, the HDAC inhibitor is vorinostat, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the HDAC inhibitor is vorinostat. The chemical name of vorinostat is N-hydroxy-N'-phenyloctanediamide, and vorinostat has the following structure: [ka] It has.

[0075] In one embodiment, the HDAC inhibitor is an HDAC6 inhibitor. In one embodiment, the HDAC6 inhibitor is citalinostat, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the HDAC6 inhibitor is citalinostat. The chemical name of citalinostat (also known as ACY-241) is 2-((2-chlorophenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide, and citalinostat has the following structure: [ka] It has.

[0076] In one embodiment, the second active agent used in the methods provided herein is a B-cell lymphoma 2 (BCL2) inhibitor. In one embodiment, the BCL2 inhibitor is venetoclax, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the BCL2 inhibitor is venetoclax. The chemical name of venetoclax is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide, and venetoclax has the following structure: [ka] It has.

[0077] In one embodiment, the second active agent used in the methods provided herein is a Bruton's tyrosine kinase (BTK) inhibitor. In one embodiment, the BTK inhibitor is ibrutinib or acalabrutinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof.

[0078] In one embodiment, the BTK inhibitor is ibrutinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the BTK inhibitor is ibrutinib. The chemical name of ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one, and ibrutinib has the following structure: [ka] It has.

[0079] In one embodiment, the BTK inhibitor is acalabrutinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the BTK inhibitor is acalabrutinib. The chemical name of acalabrutinib is (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide, and acalabrutinib has the following structure: [ka] It has.

[0080] In one embodiment, the second active agent used in the methods provided herein is a mammalian target of rapamycin (mTOR) inhibitor. In one embodiment, the mTOR inhibitor is rapamycin or an analog thereof (also called a rapalog). In one embodiment, the mTOR inhibitor is everolimus, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the mTOR inhibitor is everolimus. The chemical name of everolimus is 40-O-(2-hydroxyethyl)-rapamycin, and everolimus has the following structure: [ka] It has.

[0081] In one embodiment, the second active agent used in the methods provided herein is a phosphoinositide 3-kinase (PI3K) inhibitor. In one embodiment, the PI3K inhibitor is idelalisib, or a stereoisomer, a mixture of stereoisomers, a tautomer, an isotope, or a pharmaceutically acceptable salt thereof. In one embodiment, the PI3K inhibitor is idelalisib. The chemical name of idelalisib is 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6ylamino)propyl]quinazolin-4(3H)-one, and idelalisib has the following structure: [ka] It has.

[0082] In one embodiment, the second active agent used in the methods provided herein is a protein kinase C beta (PKCβ or PKC-β) inhibitor. In one embodiment, the PKCβ inhibitor is enzastaurin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the PKCβ inhibitor is enzastaurin. In one embodiment, the PKCβ inhibitor is a pharmaceutically acceptable salt of enzastaurin. In one embodiment, the PKCβ inhibitor is the hydrochloride salt of enzastaurin. In one embodiment, the PKCβ inhibitor is the dihydrochloride salt of enzastaurin. The chemical name of enzastaurin is 3-(1-methylindol-3-yl)-4-[1-[1-(pyridin-2-ylmethyl)piperidin-4-yl]indol-3-yl]pyrrole-2,5-dione, and enzastaurin has the following structure: [ka] It has.

[0083] In one embodiment, the second active agent used in the methods provided herein is a spleen tyrosine kinase (SYK) inhibitor. In one embodiment, the SYK inhibitor is fostamatinib, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the SYK inhibitor is fostamatinib. In one embodiment, the SYK inhibitor is a pharmaceutically acceptable salt of fostamatinib. In one embodiment, the SYK inhibitor is fostamatinib disodium hexahydrate. The chemical name of fostamatinib (also known as R788) is (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)methyl dihydrogen phosphate, and fostamatinib has the following structure: [ka] It has.

[0084] In one embodiment, the second active agent used in the methods provided herein is a Janus kinase 2 (JAK2) inhibitor. In one embodiment, the JAK2 inhibitor is fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, or momelotinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof.

[0085] In one embodiment, the JAK2 inhibitor is fedratinib, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the JAK2 inhibitor is fedratinib. The chemical name of fedratinib is N-tert-butyl-3-[(5-methyl-2-{4-[2-(pyrrolidin-1-yl)ethoxy]anilino}pyrimidin-4-yl)amino]benzenesulfonamide, and fedratinib has the following structure: [ka] It has.

[0086] In one embodiment, the JAK2 inhibitor is pacritinib, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the JAK2 inhibitor is pacritinib. Pacritinib has the following structure: [ka] It has.

[0087] In one embodiment, the JAK2 inhibitor is ruxolitinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the JAK2 inhibitor is ruxolitinib. In one embodiment, the JAK2 inhibitor is a pharmaceutically acceptable salt of ruxolitinib. In one embodiment, the JAK2 inhibitor is ruxolitinib phosphate. The chemical name of ruxolitinib is (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile, and ruxolitinib has the following structure: [ka] It has.

[0088] The second active agent is an Aurora kinase inhibitor. In one embodiment, the Aurora kinase inhibitor is an Aurora kinase A inhibitor. In one embodiment, the Aurora kinase inhibitor is an Aurora kinase B inhibitor. In one embodiment, the Aurora kinase inhibitor is a pan-Aurora kinase inhibitor.

[0089] In one embodiment, the Aurora kinase inhibitor is alisertib, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the Aurora kinase inhibitor is alisertib. The chemical name of alisertib is 4-((9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl)amino)-2-methoxybenzoic acid, and alisertib has the following structure: [ka] It has.

[0090] In one embodiment, the Aurora kinase inhibitor is barasertib (also known as AZD1152) or AZD1152-HQPA, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the Aurora kinase inhibitor is barasertib. In one embodiment, the Aurora kinase inhibitor is AZD1152-HQPA. The chemical name of AZD1152-HQPA (also known as AZD2811) is 2-(3-((7-(3-(ethyl(2-hydroxyethyl)amino)propoxy)quinazolin-4-yl)amino)-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide, and AZD1152-HQPA has the following structure: [ka] It has.

[0091] Balasertib is a dihydrogen phosphate prodrug of AZD1152-HQPA and has the following structure: [ka] It has.

[0092] In one embodiment, the Aurora kinase inhibitor is danusertib, or a stereoisomer, a mixture of stereoisomers, a tautomer, an isotope, or a pharmaceutically acceptable salt thereof. In one embodiment, the Aurora kinase inhibitor is danusertib. Danusertib (also known as PHA-739358) has the following structure: [ka] It has.

[0093] In one embodiment, the Aurora kinase inhibitor is AT9283, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the Aurora kinase inhibitor is AT9283. AT9283 has the following structure: [ka] It has.

[0094] In one embodiment, the Aurora kinase inhibitor is PF-03814735, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the Aurora kinase inhibitor is PF-03814735. PF-03814735 has the following structure: [ka] It has.

[0095] In one embodiment, the Aurora kinase inhibitor is AMG900, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the Aurora kinase inhibitor is AMG900. AMG900 has the following structure: [ka] It has.

[0096] In one embodiment, the Aurora kinase inhibitor is tozasertib, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the Aurora kinase inhibitor is tozasertib. Tozasertib (also known as VX-680 or MK-0457) has the following structure: [ka] It has.

[0097] In one embodiment, the Aurora kinase inhibitor is ZM447439, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the Aurora kinase inhibitor is ZM447439. ZM447439 has the following structure: [ka] It has.

[0098] In one embodiment, the Aurora kinase inhibitor is MLN8054, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the Aurora kinase inhibitor is MLN8054. MLN8054 has the following structure: [ka] It has.

[0099] In one embodiment, the Aurora kinase inhibitor is hesperadin, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the Aurora kinase inhibitor is hesperadin. In one embodiment, the Aurora kinase inhibitor is the hydrochloride salt of hesperadin. Hesperadin has the following structure: [ka] It has.

[0100] In one embodiment, the Aurora kinase inhibitor is SNS-314, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the Aurora kinase inhibitor is SNS-314. In one embodiment, the Aurora kinase inhibitor is the mesylate salt of SNS-314. SNS-314 has the following structure: [ka] It has.

[0101] In one embodiment, the Aurora kinase inhibitor is PHA-680632, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the Aurora kinase inhibitor is PHA-680632. PHA-680632 has the following structure: [ka] It has.

[0102] In one embodiment, the Aurora kinase inhibitor is CYC116, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the Aurora kinase inhibitor is CYC116. CYC116 has the following structure: [ka] It has.

[0103] In one embodiment, the Aurora kinase inhibitor is GSK1070916, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the Aurora kinase inhibitor is GSK1070916. GSK1070916 has the following structure: [ka] It has.

[0104] In one embodiment, the Aurora kinase inhibitor is TAK-901, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the Aurora kinase inhibitor is TAK-901. TAK-901 has the following structure: [ka] It has.

[0105] In one embodiment, the Aurora kinase inhibitor is CCT137690, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the Aurora kinase inhibitor is CCT137690. CCT137690 has the following structure: [ka] It has.

[0106] In one embodiment, the second active agent used in the methods provided herein is a potentiator of an eztozolomide 2 (EZH2) inhibitor. In one embodiment, the EZH2 inhibitor is tazemetostat, GSK126, CPI-1205, 3-deazaneplanocin A (DZNep), EPZ005687, EI1, UNC1999, or sinefungin, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof.

[0107] In one embodiment, the EZH2 inhibitor is tazemetostat, or a tautomer, isotope, or pharmaceutically acceptable salt thereof.In one embodiment, the EZH2 inhibitor is tazemetostat.The chemical name of tazemetostat (also known as EPZ-6438) is N-[(1,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-5-[ethyl(tetrahydro-2H-pyran-4-yl)amino]-4-methyl-4'-(4-morpholinylmethyl)-[1,1'-biphenyl]-3-carboxamide, and tazemetostat has the following structure: [ka] It has.

[0108] In one embodiment, the EZH2 inhibitor is GSK126, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the EZH2 inhibitor is GSK126 (also known as GSK-2816126). The chemical name of GSK126 is (S)-1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-6-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indole-4-carboxamide, and GSK126 has the following structure: [ka] It has.

[0109] In one embodiment, the EZH2 inhibitor is CPI-1205, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the EZH2 inhibitor is CPI-1205. The chemical name of CPI-1205 is (R)—N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide, and CPI-1205 has the following structure: [ka] It has.

[0110] In one embodiment, the EZH2 inhibitor is 3-deazaneplanocin A. In one embodiment, the EZH2 inhibitor is EPZ005687. In one embodiment, the EZH2 inhibitor is EI1. In one embodiment, the EZH2 inhibitor is UNC1999. In one embodiment, the EZH2 inhibitor is sinefungin.

[0111] In one embodiment, the second active agent used in the methods provided herein is a bromodomain and extraterminal motif protein (BET) inhibitor. In one embodiment, the BET inhibitor is bilabresib or Compound B, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof.

[0112] In one embodiment, the BET inhibitor is bilabresib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the BET inhibitor is bilabresib. The chemical name of bilabresib (also known as OTX015 or MK-8628) is (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-hydroxyphenyl)acetamide, and bilabresib has the following structure: [ka] It has.

[0113] In one embodiment, the BET inhibitor is Compound B, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. The chemical name of Compound B is 4-[2-(cyclopropylmethoxy)-5-(methanesulfonyl)phenyl]-2-methylisoquinolin-1(2H)-one, and Compound B has the following structure: [ka] It has.

[0114] In one embodiment, the BET inhibitor is BMS-986158, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the BET inhibitor is BMS-986158. BMS-986158 has the following structure: [ka] It has.

[0115] In one embodiment, the BET inhibitor is RO-6870810, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the BET inhibitor is RO-6870810. RO-6870810 has the following structure: [ka] It has.

[0116] In one embodiment, the BET inhibitor is CPI-0610, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the BET inhibitor is CPI-0610. CPI-0610 has the following structure: [ka] It has.

[0117] In one embodiment, the BET inhibitor is molybresive, or a stereoisomer, a mixture of stereoisomers, a tautomer, an isotope, or a pharmaceutically acceptable salt thereof. In one embodiment, the BET inhibitor is molybresive. Molybresive (also known as GSK-525762) has the following structure: [ka] It has.

[0118] In one embodiment, the second active agent used in the methods provided herein is a hypomethylating agent. In one embodiment, the hypomethylating agent is a DNA methyltransferase inhibitor. In one embodiment, the hypomethylating agent is 5-azacytidine or decitabine, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. Unless otherwise specified, the terms "azacytidine" and "azacitidine" are used interchangeably.

[0119] In one embodiment, the hypomethylating agent is 5-azacytidine, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the hypomethylating agent is 5-azacytidine. 5-azacytidine is the chemical name for 4-amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one, which has the following structure: [ka] It has.

[0120] In one embodiment, the hypomethylating agent is decitabine, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the hypomethylating agent is decitabine. Decitabine is the chemical name for 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one, which has the following structure: [ka] It has.

[0121] In one embodiment, the second active agent used in the methods provided herein is a disruptor of telomeric silencing 1-like (DOT1L) inhibitor. In one embodiment, the DOT1L inhibitor is pinometostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the DOT1L inhibitor is pinometostat. Pinometostat (also known as EPZ-5676) is the chemical name for (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran-3,4-diol and has the following structure: [ka] It has.

[0122] In one embodiment, the DOT1L inhibitor is SGC0946, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the DOT1L inhibitor is SGC0946. SGC0946 is the chemical name for 5bromo-7-[5-deoxy-5-[[3-[[[[4-(1,1-dimethylethyl)phenyl]amino]carbonyl]amino]propyl](1-methylethyl)amino]-β-D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine, and SGC0946 has the following structure: [ka] It has.

[0123] In one embodiment, the second active agent used in the methods provided herein is a histone acetyltransferase (HAT) inhibitor. In one embodiment, the HAT inhibitor is C646, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the HAT inhibitor is C646. C646 is the chemical name for 4-(4-((5-(4,5-dimethyl-2-nitrophenyl)furan-2-yl)methylene)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzoic acid, which has the following structure: [ka] It has.

[0124] In one embodiment, the fifth active agent used in the methods provided herein is a WD repeat-containing protein 5 (WDR5) inhibitor. In one embodiment, the WDR5 inhibitor is OICR-9429, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the WDR5 inhibitor is OICR-9429. OICR-9429 is the chemical name for N-(4-(4-methylpiperazin-1-yl)-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide, and has the following structure: [ka] It has.

[0125] In one embodiment, the second active agent used in the methods provided herein is a DNA (cytosine-5)-methyltransferase 1 (DNMT1) inhibitor. In one embodiment, the DNMT1 inhibitor is a DNMT1-selective inhibitor. In one embodiment, the DNMT1-selective inhibitor is GSK3484862, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the DNMT1-selective inhibitor is GSK3484862. GSK3484862 (also known as GSKMI-714) is the chemical name for (R)-2-((3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide, and has the following structure: [ka] It has.

[0126] In one embodiment, the second active agent used in the methods provided herein is a lysine-specific demethylase 1 (LSD-1) inhibitor. In one embodiment, the LSD-1 inhibitor is Compound C or seclidemstat, or a tautomer, isotope, or pharmaceutically acceptable salt thereof.

[0127] In one embodiment, the LSD-1 inhibitor is Compound C, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the LSD-1 inhibitor is Compound C. In one embodiment, the LSD-1 inhibitor is a pharmaceutically acceptable salt of Compound C. In one embodiment, the LSD-1 inhibitor is Compound C besylate. The LSD-1 inhibitor is Compound C monobesylate. Compound C is the chemical name for 4-(2-(4-aminopiperidin-1-yl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-2-fluorobenzonitrile, and has the following structure: [ka] It has.

[0128] In one embodiment, the LSD-1 inhibitor is secridemstat, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the LSD-1 inhibitor is secridemstat. In one embodiment, the LSD-1 inhibitor is a pharmaceutically acceptable salt of secridemstat. In one embodiment, the LSD-1 inhibitor is secridemstat besylate. Secridemstat (also known as SP-2577) is the chemical name for (E)-N'-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-3-((4-methylpiperazin-1-yl)sulfonyl)benzohydrazide and has the following structure: [ka] It has.

[0129] In one embodiment, the second active agent used in the methods provided herein is a G9A (a histone H3 methyltransferase) inhibitor. In one embodiment, the G9A inhibitor is UNC0631, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the G9A inhibitor is UNC0631. UNC0631 is the chemical name for N-(1-(cyclohexylmethyl)piperidin-4-yl)-2-(4-isopropyl-1,4-diazepam-1-yl)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-amine, and has the following structure: [ka] It has.

[0130] In one embodiment, the second active agent used in the methods provided herein is a protein arginine methyltransferase 5 (PRMT5) inhibitor. In one embodiment, the PRMT5 inhibitor is GSK3326595, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the PRMT5 inhibitor is GSK3326595. GSK3326595 (also known as EPZ-015938) is the chemical name for (S)-6-((1-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide, and has the following structure: [ka] It has.

[0131] In one embodiment, the second active agent used in the methods provided herein is a bromodomain (BRD) inhibitor. In one embodiment, the BRD inhibitor is a BRD9 / 7 inhibitor. In one embodiment, the BRD9 / 7 inhibitor is LP99, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the BRD9 / 7 inhibitor is LP99. LP99 is the chemical name for N-((2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxo-1,2-dihydroquinolin-7-yl)-6-oxopiperidin-3-yl)-2-methylpropane-1-sulfonamide, which has the following structure: [ka] It has.

[0132] In one embodiment, the BRD inhibitor is a BRD4 inhibitor. In one embodiment, the BRD4 inhibitor is JQ1, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the BRD4 inhibitor is JQ1. JQ1 is the chemical name for (S)-tert-butyl 2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazole[4,3-a][1,4]diazepin-6-yl)acetate, which has the following structure: [ka] It has.

[0133] In one embodiment, the second active agent used in the methods provided herein is an inhibitor of SUV420H1 / H2 (two homologous enzymes that methylate lysine 20 of histone H4). In one embodiment, the SUV420H1 / H2 inhibitor is A-196, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the SUV420H1 / H2 inhibitor is A-196. A-196 is the chemical name for 6,7-dichloro-N-cyclopentyl-4-(pyridin-4-yl)phthalazin-1-amine, which has the following structure: [ka] It has.

[0134] In one embodiment, the second active agent used in the methods provided herein is a coactivator-associated arginine methyltransferase 1 (CARM1) inhibitor. In one embodiment, the CARM1 inhibitor is EZM2302, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the CARM1 inhibitor is EZM2302. EZM2302 is the chemical name for methyl (R)-2-(2-(2-chloro-5-(2-hydroxy-3-(methylamino)propoxy)phenyl)-6-(3,5-dimethylisoxazol-4-yl)-5-methylpyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate, which has the following structure: [ka] It has.

[0135] In one embodiment, the second active agent used in the methods provided herein is a polo-like kinase 1 (PLK1) inhibitor. In one embodiment, the PLK1 inhibitor is BI2536, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the PLK1 inhibitor is BI2536. BI2536 is the chemical name for (R)-4-((8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide, which has the following structure: [ka] It has.

[0136] In one embodiment, the PLK1 inhibitor is volasertib, or a stereoisomer, a mixture of stereoisomers, a tautomer, an isotope, or a pharmaceutically acceptable salt thereof. In one embodiment, the PLK1 inhibitor is volasertib. Volasertib (also known as BI6727) has the following structure: [ka] It has.

[0137] In one embodiment, the PLK1 inhibitor is CYC140, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof.

[0138] In one embodiment, the PLK1 inhibitor is onvansertib, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the PLK1 inhibitor is onvansertib. Onvansertib (also known as NMS-1286937) has the following structure: [ka] It has.

[0139] In one embodiment, the PLK1 inhibitor is GSK461364, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the PLK1 inhibitor is GSK461364. GSK461364 has the following structure: [ka] It has.

[0140] In one embodiment, the PLK1 inhibitor is TAK960, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the PLK1 inhibitor is TAK960. In one embodiment, the PLK1 inhibitor is the hydrochloride salt of TAK960. TAK960 has the following structure: [ka] It has.

[0141] In one embodiment, the second active agent used in the methods provided herein is a serine / threonine protein kinase (NEK2) inhibitor. In one embodiment, the NEK2 inhibitor is JH295, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the NEK2 inhibitor is JH295. JH295 is the chemical name for (Z)—N-(3-((2-ethyl-4-methyl-1H-imidazol-5-yl)methylene)-2-oxoindolin-5-yl)propiolamid, which has the following structure: [ka] It has.

[0142] In one embodiment, the NEK2 inhibitor is rac-CCT250863, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the NEK2 inhibitor is rac-CCT250863. rac-CCT250863 is the chemical name for 4-[2-amino-5-[4-[(dimethylamino)methyl]-2-thienyl]-3-pyridinyl]-2-[[(2Z)-4,4,4-trifluoro-1-methyl-2-buten-1-yl]oxy]benzamide, which has the following structure: [ka] It has.

[0143] In one embodiment, the second active agent used in the methods provided herein is a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor. In one embodiment, the MEK inhibitor interferes with the function of the RAF / RAS / MEK signaling cascade. In one embodiment, the MEK inhibitor is trametinib, trametinib dimethyl sulfoxide, cobimetinib, binimetinib, or selumetinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the MEK inhibitor is trametinib or trametinib dimethyl sulfoxide, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the MEK inhibitor is trametinib. In one embodiment, the MEK inhibitor is trametinib dimethyl sulfoxide. In one embodiment, the MEK inhibitor is cobimetinib. In one embodiment, the MEK inhibitor is binimetinib. In one embodiment, the MEK inhibitor is selumetinib. The chemical name of trametinib dimethyl sulfoxide is N-[3-[3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]-acetamide, and it is a compound (1:1) with dimethyl sulfoxide. Trametinib dimethyl sulfoxide has the following structure: [ka] It has.

[0144] In one embodiment, the second active agent used in the methods provided herein is a PHD finger protein 19 (PHF19) inhibitor.

[0145] In one embodiment, the second active agent used in the methods provided herein is a proviral integration site of Moloney murine leukemia kinase (PIM) inhibitor. In one embodiment, the PIM inhibitor is a pan-PIM inhibitor. In one embodiment, the PIM inhibitor is LGH-447, AZD1208, SGI-1776, or TP-3654, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the PIM inhibitor is LGH-447, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the PIM inhibitor is LGH-447. In one embodiment, the PIM inhibitor is a pharmaceutically acceptable salt of LGH-447. In one embodiment, the PLK1 inhibitor is the hydrochloride salt of LGH-447. In one embodiment, the hydrochloride salt of LGH-447 is the dihydrochloride salt. In one embodiment, the hydrochloride salt of LGH-447 is the monohydrochloride salt. In one embodiment, the PIM inhibitor is AZD1208. In one embodiment, the PIM inhibitor is SGI-1776. In one embodiment, the PIM inhibitor is TP-3654. LGH-447 is the chemical name for N-[4-[(1R,3S,5S)-3-amino-5-methylcyclohexyl]-3-pyridinyl]-6-(2,6-difluorophenyl)-5-fluoro-2-pyridinecarboxamide, and has the following structure: [ka] It has.

[0146] In one embodiment, the second active agent used in the methods provided herein is an insulin-like growth factor 1 receptor (IGF-1R) inhibitor. In one embodiment, the IGF-1R inhibitor is linsitinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the IGF-1R inhibitor is linsitinib. Linsitinib is the chemical name for cis-3-[8-amino-1-(2-phenyl-7-quinolinyl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutanol, and has the following structure: [ka] It has.

[0147] In one embodiment, the second active agent used in the methods provided herein is an exportin 1 (XPO1) inhibitor. In one embodiment, the XPO1 inhibitor is selinexor, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the XPO1 inhibitor is selinexor. Selinexor is the chemical name for (2Z)-3-{3-[3,5-bis(trifluoromethyl)phenyl]-1H-1,2,4-triazol-1-yl}-N'-(pyrazin-2-yl)prop-2-enehydrazide, which has the following structure: [ka] It has.

[0148] In one embodiment, the second active agent used in the methods provided herein is a survivin (also known as baculoviral inhibitor of apoptosis repeat-containing 5, or BIRC5) inhibitor. In one embodiment, the BIRC5 inhibitor is YM155, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the BIRC5 inhibitor is YM155. YM155 is the chemical name for 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium bromide, which has the following structure: [ka] It has.

[0149] In one embodiment, the second active agent used in the methods provided herein is chemotherapy.In one embodiment, the chemotherapy is bendamustine, doxorubicin, etoposide, methotrexate, cytarabine, vincristine, ifosfamide, melphalan, oxaliplatin, or dexamethasone, or a stereoisomer, a mixture of stereoisomers, a tautomer, an isotope, a prodrug, or a pharmaceutically acceptable salt thereof.

[0150] In one embodiment, the chemotherapy is bendamustine, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the chemotherapy is bendamustine. In one embodiment, the chemotherapy is a pharmaceutically acceptable salt of bendamustine. In one embodiment, the chemotherapy is bendamustine hydrochloride. In one embodiment, the chemotherapy is bendamustine monohydrochloride. Bendamustine is the chemical name for 4-(5-(bis(2-chloroethyl)amino)-1-methyl-1H-benzo[d]imidazol-2-yl)butanoic acid, which has the following structure: [ka] It has.

[0151] In one embodiment, the chemotherapy is doxorubicin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the chemotherapy is doxorubicin. In one embodiment, the chemotherapy is a pharmaceutically acceptable salt of doxorubicin. In one embodiment, the chemotherapy is doxorubicin hydrochloride. In one embodiment, the chemotherapy is doxorubicin monohydrochloride. Doxorubicin has the following structure: [ka] It has.

[0152] In one embodiment, the chemotherapy is etoposide, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, prodrug, or pharmaceutically acceptable salt thereof. In one embodiment, the chemotherapy is etoposide. Etoposide is the chemical name for 4'-demethylepipodophyllotoxin 9-[4,6-O-(R)-ethylidene-β-D-glucopyranoside], which has the following structure: [ka] It has.

[0153] In one embodiment, the chemotherapy is a prodrug of etoposide. In one embodiment, the chemotherapy is an ester prodrug of etoposide. In one embodiment, the chemotherapy is etoposide phosphate. Etoposide phosphate is the chemical name for 4'-demethylepipodophyllotoxin 9-[4,6-O-(R)-ethylidene-β-D-glucopyranoside],4'(dihydrogen phosphate), which has the following structure: [ka] It has.

[0154] In one embodiment, the chemotherapy is methotrexate, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the chemotherapy is methotrexate. In one embodiment, the chemotherapy is a pharmaceutically acceptable salt of methotrexate. In one embodiment, the chemotherapy is methotrexate sodium. Methotrexate is the chemical name for (4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzoyl)-L-glutamic acid and has the following structure: [ka] It has.

[0155] In one embodiment, the chemotherapy is cytarabine, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the chemotherapy is cytarabine. Cytarabine is the chemical name for 4-amino-1-β-D-arabinofuranosyl-2(1H)pyrimidinone, and has the following structure: [ka] It has.

[0156] In one embodiment, the chemotherapy is vincristine, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the chemotherapy is vincristine. In one embodiment, the chemotherapy is a pharmaceutically acceptable salt of vincristine. In one embodiment, the chemotherapy is vincristine sulfate. In one embodiment, the chemotherapy is vincristine monosulfate. Vincristine has the following structure: [ka] It has.

[0157] In one embodiment, the chemotherapy is ifosfamide, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the chemotherapy is ifosfamide. Ifosfamide is the chemical name for 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide, which has the following structure: [ka] It has.

[0158] In one embodiment, the chemotherapy is melphalan, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the chemotherapy is melphalan. In one embodiment, the chemotherapy is a pharmaceutically acceptable salt of melphalan. In one embodiment, the chemotherapy is melphalan hydrochloride. In one embodiment, the chemotherapy is melphalan monohydrochloride. Melphalan is the chemical name for 4-[bis(2-chloroethyl)amino]-L-phenylalanine, which has the following structure: [ka] It has.

[0159] In one embodiment, the chemotherapy is oxaliplatin, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the chemotherapy is oxaliplatin. Oxaliplatin is the chemical name for cis-[(1R,2R)-1,2-cyclohexanediamine-N,N'][oxaliplatin(2-)-O,O']platinum, which has the following structure: [ka] It has.

[0160] In one embodiment, the chemotherapy is dexamethasone, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the chemotherapy is dexamethasone. Dexamethasone is the chemical name for (11b,16a)-9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione, and has the following structure: [ka] It has.

[0161] 5.4 How to use In one embodiment, described herein is a method of treating a hematological malignancy, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is an HDAC inhibitor (e.g., panobinostat, romidepsin, vorinostat, or citalinostat), a BCL2 inhibitor (e.g., venetoclax), a BTK inhibitor (e.g., ibrutinib or acalabrutinib), an mTOR inhibitor (e.g., everolimus), a PI3K inhibitor (e.g., idelalisib), a PKCβ inhibitor (e.g., enzastaurin), a SYK inhibitor (e.g., rituximab), or a combination thereof. (e.g., fostamatinib), JAK2 inhibitors (e.g., fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, or momelotinib), Aurora kinase inhibitors (e.g., alisertib), EZH2 inhibitors (e.g., tazemetostat, GSK126, CPI-1205, 3-deazaneplanocin A, EPZ005687, EI1, UNC1999, or sinefungin), BET inhibitors (e.g., virabresib or compound B), hypomethylating agents (e.g., 5-azacytidine or decitabine), DOT1L inhibitors (e.g., pinometostat), HAT inhibitors (e.g., C646), WDR5 inhibitors (e.g., OICR-9429), DNMT1 inhibitors (e.g., GSK3484862), LSD-1 inhibitors (e.g., Compound C or secridemstat), G9A inhibitors (e.g., UNC0631), PRMT5 inhibitors (e.g., GSK3326595), BRD inhibitors (e.g., LP99), SUV420H1 / H2 inhibitors (e.g., A-196), CARM1 inhibitors (e.g., EZM2302), PLK1 inhibitors (e.g., BI2536 ), a NEK2 inhibitor (e.g., JH295), a MEK inhibitor (e.g., trametinib), a PHF19 inhibitor, a PIM inhibitor (e.g., LGH-447), an IGF-1R inhibitor (e.g., linsitinib), an XPO1 inhibitor (e.g., selinexor), a BIRC5 inhibitor (e.g., YM155), or chemotherapy (e.g., bendamustine, doxorubicin, etoposide, methotrexate, cytarabine, vincristine, ifosfamide, melphalan, oxaliplatin, or dexamethasone).The present specification also provides Compound A for use in a method of treating a hematological malignancy, the method comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent provided herein.

[0162] In one embodiment, described herein is a method of preventing a hematological malignancy, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is an HDAC inhibitor (e.g., panobinostat, romidepsin, vorinostat, or citalinostat), a BCL2 inhibitor (e.g., venetoclax), a BTK inhibitor (e.g., ibrutinib or acalabrutinib), an mTOR inhibitor (e.g., everolimus), a PI3K inhibitor (e.g., idelalisib), a PKCβ inhibitor (e.g., enzastaurin), a SYK inhibitor (e.g., rivaroxaban), or a vasopressin (vasopressin-resistant Sprague-Dawley). (e.g., fostamatinib), JAK2 inhibitors (e.g., fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, or momelotinib), Aurora kinase inhibitors (e.g., alisertib), EZH2 inhibitors (e.g., tazemetostat, GSK126, CPI-1205, 3-deazaneplanocin A, EPZ005687, EI1, UNC1999, or sinefungin), BET inhibitors (e.g., virabresib or compound B), hypomethylating agents (e.g., 5-azacytidine or decitabine), DOT1L inhibitors (e.g., pinometostat), HAT inhibitors (e.g., C646), WDR5 inhibitors (e.g., OICR-9429), DNMT1 inhibitors (e.g., GSK3484862), LSD-1 inhibitors (e.g., Compound C or secridemstat), G9A inhibitors (e.g., UNC0631), PRMT5 inhibitors (e.g., GSK3326595), BRD inhibitors (e.g., LP99), SUV420H1 / H2 inhibitors (e.g., A-196), CARM1 inhibitors (e.g., EZM2302), PLK1 inhibitors (e.g., BI2536 ), a NEK2 inhibitor (e.g., JH295), a MEK inhibitor (e.g., trametinib), a PHF19 inhibitor, a PIM inhibitor (e.g., LGH-447), an IGF-1R inhibitor (e.g., linsitinib), an XPO1 inhibitor (e.g., selinexor), a BIRC5 inhibitor (e.g., YM155), or chemotherapy (e.g., bendamustine, doxorubicin, etoposide, methotrexate, cytarabine, vincristine, ifosfamide, melphalan, oxaliplatin, or dexamethasone).The present specification also provides Compound A for use in a method for preventing a hematological malignancy, the method comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent provided herein.

[0163] In one embodiment, described herein is a method of managing a hematological malignancy, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is an HDAC inhibitor (e.g., panobinostat, romidepsin, vorinostat, or citalinostat), a BCL2 inhibitor (e.g., venetoclax), a BTK inhibitor (e.g., ibrutinib or acalabrutinib), an mTOR inhibitor (e.g., everolimus), a PI3K inhibitor (e.g., idelalisib), a PKCβ inhibitor (e.g., enzastaurin), a SYK inhibitor (e.g., rituximab), or a combination thereof. (e.g., fostamatinib), JAK2 inhibitors (e.g., fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, or momelotinib), Aurora kinase inhibitors (e.g., alisertib), EZH2 inhibitors (e.g., tazemetostat, GSK126, CPI-1205, 3-deazaneplanocin A, EPZ005687, EI1, UNC1999, or sinefungin), BET inhibitors (e.g., virabresib or compound B), hypomethylating agents (e.g., 5-azacytidine or decitabine), DOT1L inhibitors (e.g., pinometostat), HAT inhibitors (e.g., C646), WDR5 inhibitors (e.g., OICR-9429), DNMT1 inhibitors (e.g., GSK3484862), LSD-1 inhibitors (e.g., Compound C or secridemstat), G9A inhibitors (e.g., UNC0631), PRMT5 inhibitors (e.g., GSK3326595), BRD inhibitors (e.g., LP99), SUV420H1 / H2 inhibitors (e.g., A-196), CARM1 inhibitors (e.g., EZM2302), PLK1 inhibitors (e.g., BI2536 ), a NEK2 inhibitor (e.g., JH295), a MEK inhibitor (e.g., trametinib), a PHF19 inhibitor, a PIM inhibitor (e.g., LGH-447), an IGF-1R inhibitor (e.g., linsitinib), an XPO1 inhibitor (e.g., selinexor), a BIRC5 inhibitor (e.g., YM155), or chemotherapy (e.g., bendamustine, doxorubicin, etoposide, methotrexate, cytarabine, vincristine, ifosfamide, melphalan, oxaliplatin, or dexamethasone).The present specification also provides Compound A for use in a method for managing hematological malignancies, the method comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent provided herein.

[0164] In one embodiment, the hematological malignancy is leukemia.

[0165] In one embodiment, the hematological malignancy is acute myeloid leukemia. In one embodiment, the hematological malignancy is B-cell acute myeloid leukemia.

[0166] In one embodiment, the hematological malignancy is acute lymphocytic leukemia.

[0167] In one embodiment, the hematological malignancy is chronic lymphocytic leukemia / small lymphocytic lymphoma.

[0168] In one embodiment, the hematological malignancy is myeloma.

[0169] In one embodiment, the hematological malignancy is multiple myeloma. In one embodiment, the multiple myeloma is plasma cell leukemia (PCL).

[0170] In one embodiment, the hematological malignancy is lymphoma.

[0171] In one embodiment, the hematological malignancy is non-Hodgkin's lymphoma.

[0172] In one embodiment, the hematological malignancy is diffuse large B-cell lymphoma.

[0173] In one embodiment, the hematological malignancy is T-cell lymphoma. In one embodiment, the T-cell lymphoma is anaplastic large cell lymphoma (ALCL). In one embodiment, the T-cell lymphoma is Sézary syndrome.

[0174] In one embodiment, the hematological malignancy is Burkitt's lymphoma.

[0175] In one embodiment, the hematological malignancy is marginal zone lymphoma. In one embodiment, the hematological malignancy is splenic marginal zone lymphoma (SMZL).

[0176] In one embodiment, the hematological malignancy is Hodgkin's lymphoma.

[0177] In one embodiment, the hematological malignancy is myelodysplastic syndrome.

[0178] In one embodiment, the DLBCL is activated B-cell-like DLBCL (ABC-DLBCL). In one embodiment, the DLBCL is germinal center B-cell-like DLBCL (GCB-DLBCL). In one embodiment, the DLBCL is unclassified DLBCL. In one embodiment, the DLBCL is primary mediastinal B-cell DLBCL (PMBL DLBCL). In one embodiment, the DLBCL is double-hit DLBCL (DHIT DLBCL), also referred to as cMyc / Bcl2-mutated DLBCL. In one embodiment, the DLBCL is triple-hit DLBCL (THIT DLBCL), also referred to as cMyc / Bcl2 / Bcl6-translocation DLBCL.

[0179] In one embodiment, the DLBCL is newly diagnosed DLBCL. In one embodiment, the DLBCL is primary DLBCL. In one embodiment, the DLBCL is recurrent DLBCL. In one embodiment, the DLBCL is refractory DLBCL. In one embodiment, the DLBCL is relapsed or refractory DLBCL. In one embodiment, the DLBCL is relapsed / refractory DLBCL. In one embodiment, the DLBCL is refractory to doxorubicin. In one embodiment, the DLBCL is resistant to doxorubicin. In one embodiment, the DLBCL is refractory to one or more of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide, bendamustine, lenalidomide, gemcitabine, dexamethasone, ifosfamide, polatuxumab, or CAR-T.

[0180] In one embodiment, the DLBCL has been treated with two or more prior lines of treatment.

[0181] In one embodiment, the DLBCL is transformed lymphoma. In another embodiment, the DLBCL is not otherwise specified (NOS) DLBCL.

[0182] As used herein, unless otherwise specified, "CLL / SLL" or "CLL and / or SLL" means CLL, or SLL, or CLL and SLL. In one embodiment, the methods provided herein are for treating, preventing, or managing CLL. In one embodiment, the methods provided herein are for treating, preventing, or managing SLL. In one embodiment, the methods provided herein are for treating, preventing, or managing CLL and CLL.

[0183] In one embodiment, the CLL / SLL subject has failed one or more lines of therapy. In one embodiment, the subject has failed at least one prior therapy. In one embodiment, the subject has failed at least two prior therapies. The subject has previously been treated with a Bruton's tyrosine kinase (BTK) inhibitor. In one embodiment, the subject is relapsed or refractory to the BTK inhibitor. In one embodiment, the BTK inhibitor is ibrutinib. In one embodiment, the BTK inhibitor is acalabrutinib. In one embodiment, the BTK inhibitor is zanubrutinib. In one embodiment, the BTK inhibitor is tirabrutinib.

[0184] In one embodiment, the CLL / SLL is newly diagnosed CLL / SLL. In one embodiment, the CLL / SLL is relapsed or refractory CLL / SLL (R / R CLL / SLL).

[0185] In one embodiment, the CLL is characterized by a mutated IGHV (immunoglobulin heavy chain gene). In one embodiment, the CLL is characterized by a non-mutated IGHV.

[0186] In one embodiment, the CLL is characterized by one or more mutations in TP53 (tumor protein 53). In one embodiment, the CLL is characterized by wild-type TP53.

[0187] In one embodiment, the CLL is characterized by one or more cytogenetic abnormalities, such as del(13q), del(11q), del(17p), tri12, t(6;17), del(11q22.3), t(11;14), del(18q), and t(14;19). In one embodiment, the CLL is characterized by del(17p).

[0188] In one embodiment, the CLL is characterized by Richter transformation (also known as Richter syndrome).

[0189] In one embodiment, the hematological malignancy is newly diagnosed. In one embodiment, the hematological malignancy is relapsed or refractory.

[0190] In one embodiment, the AML is newly diagnosed AML. In one embodiment, the AML is relapsed or refractory AML. In one embodiment, the B-cell AML is newly diagnosed B-cell AML. In one embodiment, the B-cell AML is relapsed or refractory B-cell AML.

[0191] In one embodiment, the ALL is newly diagnosed ALL. In one embodiment, the ALL is relapsed or refractory ALL.

[0192] In one embodiment, the MM is newly diagnosed MM. In one embodiment, the MM is relapsed or refractory MM. In one embodiment, the PCL is newly diagnosed PCL. In one embodiment, the PCL is relapsed or refractory PCL.

[0193] In one embodiment, the HL is newly diagnosed HL. In one embodiment, the HL is relapsed or refractory HL.

[0194] In one embodiment, the NHL is newly diagnosed NHL. In one embodiment, the NHL is relapsed or refractory NHL.

[0195] In one embodiment, the TCL is newly diagnosed TCL. In one embodiment, the TCL is relapsed or refractory TCL. In one embodiment, the ALCL is newly diagnosed ALCL. In one embodiment, the ALCL is relapsed or refractory ALCL. In one embodiment, the Sézary syndrome is newly diagnosed Sézary syndrome. In one embodiment, the Sézary syndrome is relapsed or refractory Sézary syndrome.

[0196] In one embodiment, the BL is newly diagnosed BL. In one embodiment, the BL is relapsed or refractory BL.

[0197] In one embodiment, the MZL is newly diagnosed MZL. In one embodiment, the MZL is relapsed or refractory MZL. In one embodiment, the SMZL syndrome is newly diagnosed SMZL syndrome. In one embodiment, the SMZL is relapsed or refractory SMZL.

[0198] In one embodiment, the MDS is newly diagnosed MDS. In one embodiment, the MDS is relapsed or refractory MDS.

[0199] In one embodiment, provided herein is a method for achieving a complete response, partial response, or stable disease in a patient, comprising administering to a patient having a hematological malignancy, as provided herein, a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is selected from the group consisting of an HDAC inhibitor (e.g., panobinostat, romidepsin, vorinostat, or citalinostat), a BCL2 inhibitor (e.g., venetoclax), a BTK inhibitor (e.g., ibrutinib or acalabrutinib), an mTOR inhibitor (e.g., everolimus), a PI3K inhibitor (e.g., cefotaxime), a vasopressin ... e.g., idelalisib), PKCβ inhibitors (e.g., enzastaurin), SYK inhibitors (e.g., fostamatinib), JAK2 inhibitors (e.g., fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, or momelotinib), Aurora kinase inhibitors (e.g., alisertib), EZH2 inhibitors (e.g., tazemetostat, GSK126, CPI-1205, 3-deazaneplanocin A, EPZ005687, EI1, UNC1999, or sinefungin), BET inhibitors (e.g., virabresol or Compound B), hypomethylating agents (e.g., 5-azacytidine or decitabine), DOT1L inhibitors (e.g., pinometostat), HAT inhibitors (e.g., C646), WDR5 inhibitors (e.g., OICR-9429), DNMT1 inhibitors (e.g., GSK3484862), LSD-1 inhibitors (e.g., Compound C or secridemstat), G9A inhibitors (e.g., UNC0631), PRMT5 inhibitors (e.g., GSK3326595), BRD inhibitors (e.g., LP99), SUV420H1 / H2 inhibitors (e.g., A-196), CARM 1 inhibitors (e.g., EZM2302), PLK1 inhibitors (e.g., BI2536), NEK2 inhibitors (e.g., JH295), MEK inhibitors (e.g., trametinib), PHF19 inhibitors, PIM inhibitors (e.g., LGH-447), IGF-1R inhibitors (e.g., linsitinib), XPO1 inhibitors (e.g., selinexor), BIRC5 inhibitors (e.g., YM155), or chemotherapy (e.g., bendamustine, doxorubicin, etoposide, methotrexate, cytarabine, vincristine, ifosfamide, melphalan, oxaliplatin,or dexamethasone). In one embodiment, the hematological malignancy is AML (e.g., B-cell AML). In one embodiment, the hematological malignancy is ALL. In one embodiment, the hematological malignancy is CLL / SLL. In one embodiment, the hematological malignancy is MM. In one embodiment, the hematological malignancy is PCL. In one embodiment, the hematological malignancy is NHL. In one embodiment, the hematological malignancy is DLBCL. In one embodiment, the hematological malignancy is TCL (e.g., ALCL or Sézary syndrome). In one embodiment, the hematological malignancy is Burkitt lymphoma. In one embodiment, the hematological malignancy is HL. In one embodiment, the hematological malignancy is MZL (e.g., SMZL). In one embodiment, the hematological malignancy is MDS.

[0200] In one embodiment, described herein is a method for achieving a complete response, partial response, or stable disease in a patient as determined by Lugano response criteria, comprising administering to the patient having DLBCL a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is selected from the group consisting of an HDAC inhibitor (e.g., panobinostat, romidepsin, vorinostat, or citalinostat), a BCL2 inhibitor (e.g., venetoclax), a BTK inhibitor (e.g., ibrutinib or acalabrutinib), an mTOR inhibitor (e.g., everolimus), a PI3K inhibitor (e.g., rivaroxaban), a vasopressin ... 3K inhibitors (e.g., idelalisib), PKCβ inhibitors (e.g., enzastaurin), SYK inhibitors (e.g., fostamatinib), JAK2 inhibitors (e.g., fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, or momelotinib), Aurora kinase inhibitors (e.g., alisertib), EZH2 inhibitors (e.g., tazemetostat, GSK126, CPI-1205, 3-deazaneplanocin A, EPZ005687, EI1, UNC1999, or sinefungin), BET inhibitors (e.g., bila bresive or Compound B), hypomethylating agents (e.g., 5-azacytidine or decitabine), DOT1L inhibitors (e.g., pinometostat), HAT inhibitors (e.g., C646), WDR5 inhibitors (e.g., OICR-9429), DNMT1 inhibitors (e.g., GSK3484862), LSD-1 inhibitors (e.g., Compound C or secridemstat), G9A inhibitors (e.g., UNC0631), PRMT5 inhibitors (e.g., GSK3326595), BRD inhibitors (e.g., LP99), SUV420H1 / H2 inhibitors (e.g., A-196), CA RM1 inhibitors (e.g., EZM2302), PLK1 inhibitors (e.g., BI2536), NEK2 inhibitors (e.g., JH295), MEK inhibitors (e.g., trametinib), PHF19 inhibitors, PIM inhibitors (e.g., LGH-447), IGF-1R inhibitors (e.g., linsitinib), XPO1 inhibitors (e.g., selinexor), BIRC5 inhibitors (e.g., YM155), or chemotherapy (e.g., bendamustine, doxorubicin, etoposide, methotrexate, cytarabine, vincristine, ifosfamide, melphalan, oxaliplatin,or dexamethasone).

[0201] In one embodiment, described herein is a method for achieving a complete response, partial response, or stable disease in a patient as determined by the International Workshop on Chronic Lymphocytic Leukemia criteria, comprising administering to the patient with CLL / SLL a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is selected from the group consisting of an HDAC inhibitor (e.g., panobinostat, romidepsin, vorinostat, or citalinostat), a BCL2 inhibitor (e.g., venetoclax), a BTK inhibitor (e.g., ibrutinib or acalabrutinib), an mTOR inhibitor (e.g., cefotaxime), or a vasopressin inhibitor (e.g., cefotaxime). e.g., everolimus), PI3K inhibitors (e.g., idelalisib), PKCβ inhibitors (e.g., enzastaurin), SYK inhibitors (e.g., fostamatinib), JAK2 inhibitors (e.g., fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, or momelotinib), Aurora kinase inhibitors (e.g., alisertib), EZH2 inhibitors (e.g., tazemetostat, GSK126, CPI-1205, 3-deazaneplanocin A, EPZ005687, EI1, UNC1999, or sinefungin) , BET inhibitors (e.g., virabresib or Compound B), hypomethylating agents (e.g., 5-azacytidine or decitabine), DOT1L inhibitors (e.g., pinometostat), HAT inhibitors (e.g., C646), WDR5 inhibitors (e.g., OICR-9429), DNMT1 inhibitors (e.g., GSK3484862), LSD-1 inhibitors (e.g., Compound C or secridemstat), G9A inhibitors (e.g., UNC0631), PRMT5 inhibitors (e.g., GSK3326595), BRD inhibitors (e.g., LP99), SUV420H1 / H2 inhibitors agents (e.g., A-196), CARM1 inhibitors (e.g., EZM2302), PLK1 inhibitors (e.g., BI2536), NEK2 inhibitors (e.g., JH295), MEK inhibitors (e.g., trametinib), PHF19 inhibitors, PIM inhibitors (e.g., LGH-447), IGF-1R inhibitors (e.g., linsitinib), XPO1 inhibitors (e.g., selinexor), BIRC5 inhibitors (e.g., YM155), or chemotherapy (e.g., bendamustine, doxorubicin, etoposide, methotrexate, cytarabine, vincristine, ifosfamide,In one embodiment, minimal residual disease (MRD) detection can be performed in subjects undergoing bone marrow evaluation for confirmation of complete response (CR). In one embodiment, described herein is a method for achieving minimal residual disease (MRD) negativity in a patient, comprising administering to a patient with CLL / SLL a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is an HDAC inhibitor (e.g., panobinostat, romidepsin, vorinostat, or citalinostat), a BCL2 inhibitor (e.g., venetoclax), a BTK inhibitor (e.g., ibrutinib or acalabrutinib), an mTOR inhibitor (e.g., evolocumab), or a combination of these. rolimus), PI3K inhibitors (e.g., idelalisib), PKCβ inhibitors (e.g., enzastaurin), SYK inhibitors (e.g., fostamatinib), JAK2 inhibitors (e.g., fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, or momelotinib), Aurora kinase inhibitors (e.g., alisertib), EZH2 inhibitors (e.g., tazemetostat, GSK126, CPI-1205, 3-deazaneplanocin A, EPZ0056 87, EI1, UNC1999, or sinefungin), BET inhibitors (e.g., virabresib or Compound B), hypomethylating agents (e.g., 5-azacytidine or decitabine), DOT1L inhibitors (e.g., pinometostat), HAT inhibitors (e.g., C646), WDR5 inhibitors (e.g., OICR-9429), DNMT1 inhibitors (e.g., GSK3484862), LSD-1 inhibitors (e.g., Compound C or secridemstat), G9A inhibitors (e.g., UNC0631), PRMT5 inhibitors (e.g., GSK3326595), BRD inhibitors (e.g., LP99), SUV420H1 / H2 inhibitors (e.g., A-196), CARM1 inhibitors (e.g., EZM2302), PLK1 inhibitors (e.g., BI2536), NEK2 inhibitors (e.g., JH295), MEK inhibitors (e.g., trametinib), PHF19 inhibitors, PIM inhibitors (e.g., LGH-447), IGF-1R inhibitors (e.g., linsitinib), XPO1 inhibitors (e.g., selinexor),The method further provides a method in which the treatment is one or more of a BIRC5 inhibitor (e.g., YM155), or chemotherapy (e.g., bendamustine, doxorubicin, etoposide, methotrexate, cytarabine, vincristine, ifosfamide, melphalan, oxaliplatin, or dexamethasone). In one embodiment, the MRD negativity is measured in peripheral blood and / or bone marrow. In one embodiment, the MRD negativity persists for at least 3 months.

[0202] In one embodiment, provided herein is a method for achieving increased overall survival, progression-free survival, event-free survival, progression-free survival, or disease-free survival in a patient, comprising administering to a patient having a hematological malignancy as provided herein a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is selected from the group consisting of an HDAC inhibitor (e.g., panobinostat, romidepsin, vorinostat, or citalinostat), a BCL2 inhibitor (e.g., venetoclax), a BTK inhibitor (e.g., ibrutinib or acalabrutinib), an mTOR inhibitor (e.g., cefotaxime), a steroid hormone receptor agonist ... agents (e.g., everolimus), PI3K inhibitors (e.g., idelalisib), PKCβ inhibitors (e.g., enzastaurin), SYK inhibitors (e.g., fostamatinib), JAK2 inhibitors (e.g., fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, or momelotinib), Aurora kinase inhibitors (e.g., alisertib), EZH2 inhibitors (e.g., tazemetostat, GSK126, CPI-1205, 3-deazaneplanocin A, EPZ005687, EI1, UNC1999, or sinefungin lan), BET inhibitors (e.g., virabresib or Compound B), hypomethylating agents (e.g., 5-azacytidine or decitabine), DOT1L inhibitors (e.g., pinometostat), HAT inhibitors (e.g., C646), WDR5 inhibitors (e.g., OICR-9429), DNMT1 inhibitors (e.g., GSK3484862), LSD-1 inhibitors (e.g., Compound C or secridemstat), G9A inhibitors (e.g., UNC0631), PRMT5 inhibitors (e.g., GSK3326595), BRD inhibitors (e.g., LP99), SUV420 H1 / H2 inhibitors In some cases, the treatment may include chemotherapy, chemotherapy alone or in combination with chemotherapy alone, chemotherapy alone or in combination with chemotherapy alone or in combination with chemotherapy alone. In some cases, chemotherapy alone or in combination with ...In one embodiment, the hematological malignancy is one or more of the following: melphalan, oxaliplatin, or dexamethasone. In one embodiment, the hematological malignancy is AML (e.g., B-cell AML). In one embodiment, the hematological malignancy is ALL. In one embodiment, the hematological malignancy is CLL / SLL. In one embodiment, the hematological malignancy is MM. In one embodiment, the hematological malignancy is PCL. In one embodiment, the hematological malignancy is NHL. In one embodiment, the hematological malignancy is DLBCL. In one embodiment, the hematological malignancy is TCL (e.g., ALCL or Sézary syndrome). In one embodiment, the hematological malignancy is Burkitt lymphoma. In one embodiment, the hematological malignancy is HL. In one embodiment, the hematological malignancy is MZL (e.g., SMZL). In one embodiment, the hematological malignancy is MDS.

[0203] In one embodiment, provided herein is a method for achieving increased overall survival in a patient, comprising administering to a patient having a hematological malignancy, as provided herein, a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is selected from the group consisting of an HDAC inhibitor (e.g., panobinostat, romidepsin, vorinostat, or citalinostat), a BCL2 inhibitor (e.g., venetoclax), a BTK inhibitor (e.g., ibrutinib or acalabrutinib), an mTOR inhibitor (e.g., everolimus), a PI3K inhibitor (e.g., idela), and / or a combination of these. lisib), PKCβ inhibitors (e.g., enzastaurin), SYK inhibitors (e.g., fostamatinib), JAK2 inhibitors (e.g., fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, or momelotinib), Aurora kinase inhibitors (e.g., alisertib), EZH2 inhibitors (e.g., tazemetostat, GSK126, CPI-1205, 3-deazaneplanocin A, EPZ005687, EI1, UNC1999, or sinefungin), BET inhibitors (e.g., virabresib or compound Compound B), hypomethylating agents (e.g., 5-azacytidine or decitabine), DOT1L inhibitors (e.g., pinometostat), HAT inhibitors (e.g., C646), WDR5 inhibitors (e.g., OICR-9429), DNMT1 inhibitors (e.g., GSK3484862), LSD-1 inhibitors (e.g., Compound C or secridemstat), G9A inhibitors (e.g., UNC0631), PRMT5 inhibitors (e.g., GSK3326595), BRD inhibitors (e.g., LP99), SUV420H1 / H2 inhibitors (e.g., A-196), CARM1 inhibitors In some cases, the treatment may include chemotherapy (e.g., chemotherapy with anti-cancer drugs ...or dexamethasone). In one embodiment, the hematological malignancy is AML (e.g., B-cell AML). In one embodiment, the hematological malignancy is ALL. In one embodiment, the hematological malignancy is CLL / SLL. In one embodiment, the hematological malignancy is MM. In one embodiment, the hematological malignancy is PCL. In one embodiment, the hematological malignancy is NHL. In one embodiment, the hematological malignancy is DLBCL. In one embodiment, the hematological malignancy is TCL (e.g., ALCL or Sézary syndrome). In one embodiment, the hematological malignancy is Burkitt lymphoma. In one embodiment, the hematological malignancy is HL. In one embodiment, the hematological malignancy is MZL (e.g., SMZL). In one embodiment, the hematological malignancy is MDS.

[0204] In one embodiment, provided herein is a method for achieving increased progression-free survival in a patient, comprising administering to a patient having a hematological malignancy, as provided herein, a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is selected from the group consisting of an HDAC inhibitor (e.g., panobinostat, romidepsin, vorinostat, or citalinostat), a BCL2 inhibitor (e.g., venetoclax), a BTK inhibitor (e.g., ibrutinib or acalabrutinib), an mTOR inhibitor (e.g., everolimus), a PI3K inhibitor (e.g., idempotentiostat), and a vasopressin (vasopressin). ralisib), PKCβ inhibitors (e.g., enzastaurin), SYK inhibitors (e.g., fostamatinib), JAK2 inhibitors (e.g., fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, or momelotinib), Aurora kinase inhibitors (e.g., alisertib), EZH2 inhibitors (e.g., tazemetostat, GSK126, CPI-1205, 3-deazaneplanocin A, EPZ005687, EI1, UNC1999, or sinefungin), BET inhibitors (e.g., virabreceptor or chemoprevention inhibitors), Compound B), hypomethylating agents (e.g., 5-azacytidine or decitabine), DOT1L inhibitors (e.g., pinometostat), HAT inhibitors (e.g., C646), WDR5 inhibitors (e.g., OICR-9429), DNMT1 inhibitors (e.g., GSK3484862), LSD-1 inhibitors (e.g., Compound C or secridemstat), G9A inhibitors (e.g., UNC0631), PRMT5 inhibitors (e.g., GSK3326595), BRD inhibitors (e.g., LP99), SUV420H1 / H2 inhibitors (e.g., A-196), CARM1 inhibitors In some cases, the treatment may include chemotherapy (e.g., chemotherapy with anti-cancer drugs ...or dexamethasone). In one embodiment, the hematological malignancy is AML (e.g., B-cell AML). In one embodiment, the hematological malignancy is ALL. In one embodiment, the hematological malignancy is CLL / SLL. In one embodiment, the hematological malignancy is MM. In one embodiment, the hematological malignancy is PCL. In one embodiment, the hematological malignancy is NHL. In one embodiment, the hematological malignancy is DLBCL. In one embodiment, the hematological malignancy is TCL (e.g., ALCL or Sézary syndrome). In one embodiment, the hematological malignancy is Burkitt lymphoma. In one embodiment, the hematological malignancy is HL. In one embodiment, the hematological malignancy is MZL (e.g., SMZL). In one embodiment, the hematological malignancy is MDS.

[0205] In one embodiment, provided herein is a method for achieving increased event-free survival in a patient, comprising administering to a patient having a hematological malignancy as provided herein a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is selected from the group consisting of an HDAC inhibitor (e.g., panobinostat, romidepsin, vorinostat, or citalinostat), a BCL2 inhibitor (e.g., venetoclax), a BTK inhibitor (e.g., ibrutinib or acalabrutinib), an mTOR inhibitor (e.g., everolimus), a PI3K inhibitor (e.g., idelalisib), PKCβ inhibitors (e.g., enzastaurin), SYK inhibitors (e.g., fostamatinib), JAK2 inhibitors (e.g., fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, or momelotinib), Aurora kinase inhibitors (e.g., alisertib), EZH2 inhibitors (e.g., tazemetostat, GSK126, CPI-1205, 3-deazaneplanocin A, EPZ005687, EI1, UNC1999, or sinefungin), BET inhibitors (e.g., virabrestib or Compound B), hypomethylating agents (e.g., 5-azacytidine or decitabine), DOT1L inhibitors (e.g., pinometostat), HAT inhibitors (e.g., C646), WDR5 inhibitors (e.g., OICR-9429), DNMT1 inhibitors (e.g., GSK3484862), LSD-1 inhibitors (e.g., Compound C or secridemstat), G9A inhibitors (e.g., UNC0631), PRMT5 inhibitors (e.g., GSK3326595), BRD inhibitors (e.g., LP99), SUV420H1 / H2 inhibitors (e.g., A-196), CARM1 inhibitors (e.g., EZM2302), PLK1 inhibitors (e.g., BI2536), NEK2 inhibitors (e.g., JH295), MEK inhibitors (e.g., trametinib), PHF19 inhibitors, PIM inhibitors (e.g., LGH-447), IGF-1R inhibitors (e.g., linsitinib), XPO1 inhibitors (e.g., selinexor), BIRC5 inhibitors (e.g., YM155), or chemotherapy (e.g., bendamustine, doxorubicin, etoposide, methotrexate, cytarabine, vincristine, ifosfamide, melphalan, oxaliplatin,or dexamethasone). In one embodiment, the hematological malignancy is AML (e.g., B-cell AML). In one embodiment, the hematological malignancy is ALL. In one embodiment, the hematological malignancy is CLL / SLL. In one embodiment, the hematological malignancy is MM. In one embodiment, the hematological malignancy is PCL. In one embodiment, the hematological malignancy is NHL. In one embodiment, the hematological malignancy is DLBCL. In one embodiment, the hematological malignancy is TCL (e.g., ALCL or Sézary syndrome). In one embodiment, the hematological malignancy is Burkitt lymphoma. In one embodiment, the hematological malignancy is HL. In one embodiment, the hematological malignancy is MZL (e.g., SMZL). In one embodiment, the hematological malignancy is MDS.

[0206] In one embodiment, provided herein is a method for achieving an increased time to progression in a patient, comprising administering to a patient having a hematological malignancy as provided herein a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is selected from the group consisting of an HDAC inhibitor (e.g., panobinostat, romidepsin, vorinostat, or citalinostat), a BCL2 inhibitor (e.g., venetoclax), a BTK inhibitor (e.g., ibrutinib or acalabrutinib), an mTOR inhibitor (e.g., everolimus), a PI3K inhibitor (e.g., idela), and / or a combination of these. lisib), PKCβ inhibitors (e.g., enzastaurin), SYK inhibitors (e.g., fostamatinib), JAK2 inhibitors (e.g., fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, or momelotinib), Aurora kinase inhibitors (e.g., alisertib), EZH2 inhibitors (e.g., tazemetostat, GSK126, CPI-1205, 3-deazaneplanocin A, EPZ005687, EI1, UNC1999, or sinefungin), BET inhibitors (e.g., virabresib or compound Compound B), hypomethylating agents (e.g., 5-azacytidine or decitabine), DOT1L inhibitors (e.g., pinometostat), HAT inhibitors (e.g., C646), WDR5 inhibitors (e.g., OICR-9429), DNMT1 inhibitors (e.g., GSK3484862), LSD-1 inhibitors (e.g., Compound C or secridemstat), G9A inhibitors (e.g., UNC0631), PRMT5 inhibitors (e.g., GSK3326595), BRD inhibitors (e.g., LP99), SUV420H1 / H2 inhibitors (e.g., A-196), CARM1 inhibitors In some cases, the treatment may include chemotherapy (e.g., chemotherapy with anti-cancer drugs ...or dexamethasone). In one embodiment, the hematological malignancy is AML (e.g., B-cell AML). In one embodiment, the hematological malignancy is ALL. In one embodiment, the hematological malignancy is CLL / SLL. In one embodiment, the hematological malignancy is MM. In one embodiment, the hematological malignancy is PCL. In one embodiment, the hematological malignancy is NHL. In one embodiment, the hematological malignancy is DLBCL. In one embodiment, the hematological malignancy is TCL (e.g., ALCL or Sézary syndrome). In one embodiment, the hematological malignancy is Burkitt lymphoma. In one embodiment, the hematological malignancy is HL. In one embodiment, the hematological malignancy is MZL (e.g., SMZL). In one embodiment, the hematological malignancy is MDS.

[0207] In one embodiment, provided herein is a method for achieving increased disease-free survival in a patient, comprising administering to a patient having a hematological malignancy, as provided herein, a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is selected from the group consisting of an HDAC inhibitor (e.g., panobinostat, romidepsin, vorinostat, or citalinostat), a BCL2 inhibitor (e.g., venetoclax), a BTK inhibitor (e.g., ibrutinib or acalabrutinib), an mTOR inhibitor (e.g., everolimus), a PI3K inhibitor (e.g., idempotentiostat), and a vasopressin (vasopressin). ralisib), PKCβ inhibitors (e.g., enzastaurin), SYK inhibitors (e.g., fostamatinib), JAK2 inhibitors (e.g., fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, or momelotinib), Aurora kinase inhibitors (e.g., alisertib), EZH2 inhibitors (e.g., tazemetostat, GSK126, CPI-1205, 3-deazaneplanocin A, EPZ005687, EI1, UNC1999, or sinefungin), BET inhibitors (e.g., virabreceptor or chemoprevention inhibitors), Compound B), hypomethylating agents (e.g., 5-azacytidine or decitabine), DOT1L inhibitors (e.g., pinometostat), HAT inhibitors (e.g., C646), WDR5 inhibitors (e.g., OICR-9429), DNMT1 inhibitors (e.g., GSK3484862), LSD-1 inhibitors (e.g., Compound C or secridemstat), G9A inhibitors (e.g., UNC0631), PRMT5 inhibitors (e.g., GSK3326595), BRD inhibitors (e.g., LP99), SUV420H1 / H2 inhibitors (e.g., A-196), CARM1 inhibitors In some cases, the treatment may include chemotherapy (e.g., chemotherapy with anti-cancer drugs ...or dexamethasone). In one embodiment, the hematological malignancy is AML (e.g., B-cell AML). In one embodiment, the hematological malignancy is ALL. In one embodiment, the hematological malignancy is CLL / SLL. In one embodiment, the hematological malignancy is MM. In one embodiment, the hematological malignancy is PCL. In one embodiment, the hematological malignancy is NHL. In one embodiment, the hematological malignancy is DLBCL. In one embodiment, the hematological malignancy is TCL (e.g., ALCL or Sézary syndrome). In one embodiment, the hematological malignancy is Burkitt lymphoma. In one embodiment, the hematological malignancy is HL. In one embodiment, the hematological malignancy is MZL (e.g., SMZL). In one embodiment, the hematological malignancy is MDS.

[0208] In one embodiment, the method provided herein further comprises administering to the patient a therapeutically effective amount of obinutuzumab. In one embodiment, the method provided herein provides a method of treating a hematological malignancy provided herein, comprising administering to the patient a therapeutically effective amount of Compound A in combination with a second active agent provided herein (e.g., venetoclax), further in combination with obinutuzumab.

[0209] In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is panobinostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is panobinostat. In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is panobinostat lactate.

[0210] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is romidepsin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is romidepsin.

[0211] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is vorinostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is vorinostat.

[0212] In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is citalinostat, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is citalinostat.

[0213] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, where the second active agent is venetoclax, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, where the second active agent is venetoclax.

[0214] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is ibrutinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is ibrutinib.

[0215] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is everolimus, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is everolimus.

[0216] In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1A in combination with a second active agent, wherein the second active agent is idelalisib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is idelalisib.

[0217] In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is enzastaurin, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is enzastaurin. In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is enzastaurin hydrochloride.

[0218] In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is fostamatinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is fostamatinib. In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is fostamatinib disodium hexahydrate.

[0219] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is fedratinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is fedratinib.

[0220] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is pacritinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is pacritinib.

[0221] In one embodiment, the present disclosure provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is ruxolitinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the present disclosure provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is ruxolitinib. In one embodiment, the present disclosure provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is ruxolitinib.

[0222] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is alisertib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is alisertib.

[0223] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is tazemetostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is tazemetostat.

[0224] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is GSK126, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is GSK126.

[0225] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is CPI-1205, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is CPI-1205.

[0226] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is bilabresib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is bilabresib.

[0227] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, where the second active agent is Compound B, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, where the second active agent is Compound B.

[0228] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is 5-azacytidine, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is 5-azacytidine.

[0229] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is decitabine, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is decitabine.

[0230] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is pinometostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is pinometostat.

[0231] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is C646, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is C646.

[0232] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is OICR-9429, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is OICR-9429.

[0233] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is GSK3484862, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is GSK3484862.

[0234] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is Compound C, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is Compound C. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is Compound C besylate.

[0235] In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is secridemstat, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is secridemstat. In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is secridemstat mesylate.

[0236] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is UNC0631, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is UNC0631.

[0237] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is GSK3326595, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is GSK3326595.

[0238] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is LP99, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is LP99.

[0239] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is A-196, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is A-196.

[0240] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is EZM2302, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is EZM2302.

[0241] In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is bendamustine, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is bendamustine. In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is bendamustine hydrochloride.

[0242] In one embodiment, the present disclosure provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is doxorubicin, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the present disclosure provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is doxorubicin. In one embodiment, the present disclosure provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is doxorubicin hydrochloride.

[0243] In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is etoposide, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, prodrug, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is etoposide. In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is etoposide phosphate.

[0244] In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is methotrexate, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is methotrexate. In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is methotrexate sodium.

[0245] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is cytarabine, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is cytarabine.

[0246] In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is vincristine, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is vincristine. In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is vincristine sulfate.

[0247] In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is ifosfamide, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is ifosfamide.

[0248] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is melphalan, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is melphalan. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is melphalan hydrochloride.

[0249] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is oxaliplatin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is oxaliplatin.

[0250] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is dexamethasone, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is dexamethasone.

[0251] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is BI2536, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is BI2536.

[0252] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is JQ1, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is JQ1.

[0253] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, where the second active agent is Compound B, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, where the second active agent is Compound B.

[0254] In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is rac-CCT250863, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating DLBCL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is rac-CCT250863.

[0255] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is panobinostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is panobinostat. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is panobinostat lactate.

[0256] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is romidepsin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is romidepsin.

[0257] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is vorinostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is vorinostat.

[0258] In one embodiment, the description provides a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is citalinostat, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is citalinostat.

[0259] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, where the second active agent is venetoclax, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, where the second active agent is venetoclax.

[0260] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is ibrutinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is ibrutinib.

[0261] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is everolimus, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is everolimus.

[0262] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is idelalisib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is idelalisib.

[0263] In one embodiment, the description provides a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is enzastaurin, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is enzastaurin. In one embodiment, the description provides a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is enzastaurin hydrochloride.

[0264] In one embodiment, the description provides a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is fostamatinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is fostamatinib. In one embodiment, the description provides a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is fostamatinib disodium hexahydrate.

[0265] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is fedratinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is fedratinib.

[0266] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is pacritinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is pacritinib.

[0267] In one embodiment, the description provides a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is ruxolitinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is ruxolitinib. In one embodiment, the description provides a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is ruxolitinib phosphate.

[0268] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is alisertib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is alisertib.

[0269] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is tazemetostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is tazemetostat.

[0270] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is GSK126, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is GSK126.

[0271] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is CPI-1205, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is CPI-1205.

[0272] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is bilabresib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is bilabresib.

[0273] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, where the second active agent is Compound B, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, where the second active agent is Compound B.

[0274] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is 5-azacytidine, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is 5-azacytidine.

[0275] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is decitabine, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is decitabine.

[0276] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is pinometostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is pinometostat.

[0277] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is C646, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is C646.

[0278] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is OICR-9429, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is OICR-9429.

[0279] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is GSK3484862, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is GSK3484862.

[0280] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is Compound C, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is Compound C. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is Compound C besylate.

[0281] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is secridemstat, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is secridemstat. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is secridemstat mesylate.

[0282] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is UNC0631, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is UNC0631.

[0283] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is GSK3326595, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is GSK3326595.

[0284] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is LP99, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is LP99.

[0285] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is A-196, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is A-196.

[0286] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is EZM2302, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is EZM2302.

[0287] In one embodiment, the description provides a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is bendamustine, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is bendamustine. In one embodiment, the description provides a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is bendamustine hydrochloride.

[0288] In one embodiment, the description provides a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is doxorubicin, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is doxorubicin. In one embodiment, the description provides a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is doxorubicin hydrochloride.

[0289] In one embodiment, the description provides a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is etoposide, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, prodrug, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is etoposide. In one embodiment, the description provides a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is etoposide phosphate.

[0290] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is methotrexate, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is methotrexate. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is methotrexate sodium.

[0291] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is cytarabine, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is cytarabine.

[0292] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is vincristine, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is vincristine. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is vincristine sulfate.

[0293] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is ifosfamide, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is ifosfamide.

[0294] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is melphalan, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is melphalan. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is melphalan hydrochloride.

[0295] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is oxaliplatin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is oxaliplatin.

[0296] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is dexamethasone, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is dexamethasone.

[0297] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is BI2536, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is BI2536.

[0298] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is JQ1, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is JQ1.

[0299] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, where the second active agent is Compound B, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, where the second active agent is Compound B.

[0300] In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is rac-CCT250863, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating CLL / SLL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is rac-CCT250863.

[0301] In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is panobinostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is panobinostat. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is panobinostat lactate. In one embodiment, the AML is B-cell AML.

[0302] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is romidepsin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is romidepsin. In one embodiment, the AML is B-cell AML.

[0303] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is vorinostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is vorinostat. In one embodiment, the AML is B-cell AML.

[0304] In one embodiment, the present disclosure provides a method for treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is citalinostat, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the present disclosure provides a method for treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is citalinostat. In one embodiment, the AML is B-cell AML.

[0305] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is venetoclax, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is venetoclax. In one embodiment, the AML is B-cell AML.

[0306] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is ibrutinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is ibrutinib. In one embodiment, the AML is B-cell AML.

[0307] In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is everolimus, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is everolimus. In one embodiment, the AML is B-cell AML.

[0308] In one embodiment, the present disclosure provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is idelalisib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the present disclosure provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is idelalisib. In one embodiment, the AML is B-cell AML.

[0309] In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is enzastaurin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is enzastaurin. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is enzastaurin hydrochloride. In one embodiment, the AML is B-cell AML.

[0310] In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is fostamatinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is fostamatinib. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is fostamatinib disodium hexahydrate. In one embodiment, the AML is B-cell AML.

[0311] In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is fedratinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is fedratinib. In one embodiment, the AML is B-cell AML.

[0312] In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is pacritinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is pacritinib. In one embodiment, the AML is B-cell AML.

[0313] In one embodiment, the present disclosure provides a method for treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is ruxolitinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the present disclosure provides a method for treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is ruxolitinib. In one embodiment, the present disclosure provides a method for treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is ruxolitinib. In one embodiment, the AML is B-cell AML.

[0314] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is alisertib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is alisertib. In one embodiment, the AML is B-cell AML.

[0315] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is tazemetostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is tazemetostat. In one embodiment, the AML is B-cell AML.

[0316] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is GSK126, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is GSK126. In one embodiment, the AML is B-cell AML.

[0317] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is CPI-1205, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is CPI-1205. In one embodiment, the AML is B-cell AML.

[0318] In one embodiment, the present disclosure provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is bilabresib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the present disclosure provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is bilabresib. In one embodiment, the AML is B-cell AML.

[0319] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, where the second active agent is Compound B, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, where the second active agent is Compound B. In one embodiment, the AML is B-cell AML.

[0320] In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is 5-azacytidine, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is 5-azacytidine. In one embodiment, the AML is B-cell AML.

[0321] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is decitabine, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is decitabine. In one embodiment, the AML is B-cell AML.

[0322] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is pinometostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is pinometostat. In one embodiment, the AML is B-cell AML.

[0323] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is C646, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is C646. In one embodiment, the AML is B-cell AML.

[0324] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is OICR-9429, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is OICR-9429. In one embodiment, the AML is B-cell AML.

[0325] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is GSK3484862, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is GSK3484862. In one embodiment, the AML is B-cell AML.

[0326] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is Compound C, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is Compound C. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is Compound C besylate. In one embodiment, the AML is B-cell AML.

[0327] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is secridemstat, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is secridemstat. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is secridemstat mesylate. In one embodiment, the AML is B-cell AML.

[0328] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is UNC0631, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is UNC0631. In one embodiment, the AML is B-cell AML.

[0329] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is GSK3326595, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is GSK3326595. In one embodiment, the AML is B-cell AML.

[0330] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is LP99, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is LP99. In one embodiment, the AML is B-cell AML.

[0331] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is A-196, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is A-196. In one embodiment, the AML is B-cell AML.

[0332] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is EZM2302, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is EZM2302. In one embodiment, the AML is B-cell AML.

[0333] In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is bendamustine, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is bendamustine. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is bendamustine hydrochloride. In one embodiment, the AML is B-cell AML.

[0334] In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is doxorubicin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is doxorubicin. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is doxorubicin hydrochloride. In one embodiment, the AML is B-cell AML.

[0335] In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is etoposide, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, prodrug, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is etoposide. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is etoposide phosphate. In one embodiment, the AML is B-cell AML.

[0336] In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is methotrexate, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is methotrexate. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is methotrexate sodium. In one embodiment, the AML is B-cell AML.

[0337] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is cytarabine, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is cytarabine. In one embodiment, the AML is B-cell AML.

[0338] In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is vincristine, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is vincristine. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is vincristine sulfate. In one embodiment, the AML is B-cell AML.

[0339] In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is ifosfamide, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is ifosfamide. In one embodiment, the AML is B-cell AML.

[0340] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is melphalan, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is melphalan. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is melphalan hydrochloride. In one embodiment, the AML is B-cell AML.

[0341] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is oxaliplatin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is oxaliplatin. In one embodiment, the AML is B-cell AML.

[0342] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is dexamethasone, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is dexamethasone. In one embodiment, the AML is B-cell AML.

[0343] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is BI2536, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is BI2536. In one embodiment, the AML is B-cell AML.

[0344] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is JQ1, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is JQ1. In one embodiment, the AML is B-cell AML.

[0345] In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, where the second active agent is Compound B, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, where the second active agent is Compound B. In one embodiment, the AML is B-cell AML.

[0346] In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is rac-CCT250863, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating AML, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is rac-CCT250863. In one embodiment, the AML is B-cell AML.

[0347] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is panobinostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is panobinostat. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is panobinostat lactate.

[0348] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is romidepsin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is romidepsin.

[0349] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is vorinostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is vorinostat.

[0350] In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is citalinostat, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is citalinostat.

[0351] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, where the second active agent is venetoclax, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, where the second active agent is venetoclax.

[0352] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is ibrutinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is ibrutinib.

[0353] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is everolimus, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is everolimus.

[0354] In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is idelalisib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is idelalisib.

[0355] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of A in combination with a second active agent, wherein the second active agent is enzastaurin, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is enzastaurin. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is enzastaurin hydrochloride.

[0356] In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is fostamatinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is fostamatinib. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is fostamatinib disodium hexahydrate.

[0357] In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is fedratinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is fedratinib.

[0358] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is pacritinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is pacritinib.

[0359] In one embodiment, the present disclosure provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is ruxolitinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the present disclosure provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is ruxolitinib. In one embodiment, the present disclosure provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is ruxolitinib.

[0360] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is alisertib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is alisertib.

[0361] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is tazemetostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is tazemetostat.

[0362] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is GSK126, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is GSK126.

[0363] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is CPI-1205, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is CPI-1205.

[0364] In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is bilabresib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is bilabresib.

[0365] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, where the second active agent is Compound B, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, where the second active agent is Compound B.

[0366] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is 5-azacytidine, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is 5-azacytidine.

[0367] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is decitabine, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is decitabine.

[0368] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is pinometostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is pinometostat.

[0369] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is C646, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is C646.

[0370] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is OICR-9429, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is OICR-9429.

[0371] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is GSK3484862, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is GSK3484862.

[0372] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is Compound C, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is Compound C. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is Compound C besylate.

[0373] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is secridemstat, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is secridemstat. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is secridemstat mesylate.

[0374] In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is UNC0631, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is UNC0631.

[0375] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is GSK3326595, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is GSK3326595.

[0376] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is LP99, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is LP99.

[0377] In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is A-196, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is A-196.

[0378] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is EZM2302, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is EZM2302.

[0379] In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is bendamustine, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is bendamustine. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is bendamustine hydrochloride.

[0380] In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is doxorubicin, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is doxorubicin. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is doxorubicin hydrochloride.

[0381] In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is etoposide, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, prodrug, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is etoposide. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is etoposide phosphate.

[0382] In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is methotrexate, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is methotrexate. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is methotrexate sodium.

[0383] In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is cytarabine, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is cytarabine.

[0384] In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is vincristine, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is vincristine. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is vincristine sulfate.

[0385] In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is ifosfamide, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is ifosfamide.

[0386] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is melphalan, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is melphalan. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is melphalan hydrochloride.

[0387] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is oxaliplatin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is oxaliplatin.

[0388] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is dexamethasone, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is dexamethasone.

[0389] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is BI2536, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is BI2536.

[0390] In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is JQ1, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is JQ1.

[0391] In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, where the second active agent is Compound B, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, where the second active agent is Compound B.

[0392] In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is rac-CCT250863, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating ALL, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is rac-CCT250863.

[0393] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is panobinostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is panobinostat. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is panobinostat lactate.

[0394] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is romidepsin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is romidepsin.

[0395] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is vorinostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is vorinostat.

[0396] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is citalinostat, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is citalinostat.

[0397] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, where the second active agent is venetoclax, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, where the second active agent is venetoclax.

[0398] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is ibrutinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is ibrutinib.

[0399] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is everolimus, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is everolimus.

[0400] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is idelalisib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is idelalisib.

[0401] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is enzastaurin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is enzastaurin. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is enzastaurin hydrochloride.

[0402] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is fostamatinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is fostamatinib. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is fostamatinib disodium hexahydrate.

[0403] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is fedratinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is fedratinib.

[0404] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is pacritinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is pacritinib.

[0405] In one embodiment, the description provides a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is ruxolitinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, the description provides a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is ruxolitinib. In one embodiment, the description provides a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is ruxolitinib.

[0406] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is alisertib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is alisertib.

[0407] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is tazemetostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is tazemetostat.

[0408] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is GSK126, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is GSK126.

[0409] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is CPI-1205, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is CPI-1205.

[0410] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is bilabresib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is bilabresib.

[0411] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, where the second active agent is Compound B, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, where the second active agent is Compound B.

[0412] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is 5-azacytidine, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is 5-azacytidine.

[0413] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, where the second active agent is decitabine, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, where the second active agent is decitabine.

[0414] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is pinometostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is pinometostat.

[0415] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is C646, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is C646.

[0416] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is OICR-9429, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is OICR-9429.

[0417] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is GSK3484862, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is GSK3484862.

[0418] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is Compound C, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is Compound C. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is Compound C besylate.

[0419] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is secridemstat, or a tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is secridemstat. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is secridemstat mesylate.

[0420] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is UNC0631, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is UNC0631.

[0421] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is GSK3326595, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is GSK3326595.

[0422] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is LP99, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is LP99.

[0423] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is A-196, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is A-196.

[0424] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is EZM2302, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is EZM2302.

[0425] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is bendamustine, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is bendamustine. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is bendamustine hydrochloride.

[0426] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is doxorubicin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is doxorubicin. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is doxorubicin hydrochloride.

[0427] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is etoposide, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, prodrug, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is etoposide. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is etoposide phosphate.

[0428] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is methotrexate, or a stereoisomer, mixture of stereoisomers, tautomer, isotope, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is methotrexate. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is methotrexate sodium.

[0429] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is cytarabine, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is cytarabine.

[0430] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is vincristine, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is vincristine. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is vincristine sulfate.

[0431] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is ifosfamide, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is ifosfamide.

[0432] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is melphalan, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is melphalan. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is melphalan hydrochloride.

[0433] In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound A in combination with a second active agent, wherein the second active agent is oxaliplatin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. In one embodiment, provided herein is a method of treating MM, comprising administering to a patient a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt of Compound 1), in combination with a second active agent, wherein the second active agent is oxaliplatin.

[0434] In one em...

Claims

1. Compound 1: 【Chemistry 1】 or an enantiomer, a mixture of enantiomers, tautomer, isotopologue, or a pharma- ceutical acceptable salt thereof, for treating hematological malignancies, characterized in that the pharmaceutical composition is used such that the compound is administered in combination with a second active agent, the second active agent being an EZH2 inhibitor, an HDAC inhibitor, a BCL2 inhibitor, a BTK inhibitor, an mTOR inhibitor, a PI3K inhibitor, a PKCβ inhibitor, a SYK inhibitor, a JAK2 inhibitor, a CYP ... inhibitor, Aurora kinase inhibitor, BET inhibitor, hypomethylating agent, DOT1L inhibitor, HAT inhibitor, WDR5 inhibitor, DNMT1 inhibitor, LSD-1 inhibitor, G9A inhibitor, PRMT5 inhibitor, BRD inhibitor, SUV420H1 / H2 inhibitor, CARM1 inhibitor, PLK1 inhibitor, NEK2 inhibitor, MEK inhibitor, PHF19 inhibitor, PIM inhibitor, IGF-1R inhibitor, XPO1 inhibitor, or BIRC5 inhibitor.

2. The pharmaceutical composition of claim 1 , wherein the second active agent is an EZH2 inhibitor.

3. 3. The pharmaceutical composition of claim 2, wherein the EZH2 inhibitor is tazemetostat, GSK126, CPI-1205, 3-deazaneplanocin A (DZNep), EPZ005687, EI1, UNC1999, or sinefungin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof.

4. The pharmaceutical composition of claim 3, wherein the EZH2 inhibitor is tazemetostat, GSK126 or CPI-1205.

5. The pharmaceutical composition of claim 4, wherein the EZH2 inhibitor is tazemetostat.

6. 2. The pharmaceutical composition of claim 1, wherein the second active agent is an HDAC inhibitor, and the HDAC inhibitor is panobinostat, romidepsin, vorinostat, or citalinostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof.

7. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a BCL2 inhibitor, and the BCL2 inhibitor is venetoclax, or a tautomer, isotopologue, or a pharma- ceutical acceptable salt thereof.

8. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a BTK inhibitor, and the BTK inhibitor is ibrutinib, or acalabrutinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharma- ceutical acceptable salt thereof.

9. 2. The pharmaceutical composition of claim 1, wherein the second active agent is an mTOR inhibitor, and the mTOR inhibitor is everolimus.

10. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a PI3K inhibitor, and the PI3K inhibitor is idelalisib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof.

11. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a PKCβ inhibitor, and the PKCβ inhibitor is enzastaurin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof.

12. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a SYK inhibitor, and the SYK inhibitor is fostamatinib, or a tautomer, isotopologue, or a pharma- ceutically acceptable salt thereof.

13. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a JAK2 inhibitor, and the JAK2 inhibitor is fedratinib, pacritinib, ruxolitinib, baricitinib, gandotinib, lestaurtinib, or momelotinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof.

14. 2. The pharmaceutical composition of claim 1, wherein the second active agent is an Aurora kinase inhibitor, and the Aurora kinase inhibitor is alisertib, barasertib, AZD1152-HQPA, danusertib, AT9283, PF-03814735, AMG900, tozasertib, ZM447439, MLN8054, hesperidin, SNS-314, PHA-680632, CYC116, GSK1070916, TAK-901, or CCT137690, or a tautomer, isotopologue, or pharma- ceutically acceptable salt thereof.

15. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a BET inhibitor, and the BET inhibitor is virabresib or 4-[2-(cyclopropylmethoxy)-5-(methanesulfonyl)phenyl]-2-methylisoquinolin-1(2H)-one, BMS-986158, RO-6870810, CPI-0610, or molybresib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof.

16. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a hypomethylating agent, and the hypomethylating agent is 5-azacytidine or decitabine, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof.

17. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a DOT1L inhibitor, and the DOT1L inhibitor is SGC0946 or pinometostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof.

18. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a HAT inhibitor, and the HAT inhibitor is C646, or a tautomer, isotopologue, or a pharma- ceutically acceptable salt thereof.

19. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a WDR5 inhibitor, and the WDR5 inhibitor is OICR-9429, or a tautomer, isotopologue, or a pharma- ceutically acceptable salt thereof.

20. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a DNMT1 inhibitor, and the DNMT1 inhibitor is GSK3484862, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof.

21. 2. The pharmaceutical composition of claim 1, wherein the second active agent is an LSD-1 inhibitor, and the LSD-1 inhibitor is 4-(2-(4-aminopiperidin-1-yl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-2-fluorobenzonitrile or secridemstat, or a tautomer, isotopologue, or pharma- ceutically acceptable salt thereof.

22. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a G9A inhibitor, and the G9A inhibitor is UNC0631, or a tautomer, isotopologue, or a pharma- ceutically acceptable salt thereof.

23. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a PRMT5 inhibitor, and the PRMT5 inhibitor is GSK3326595, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof.

24. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a BRD inhibitor, and the BRD inhibitor is LP99 or JQ1, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof.

25. 2. The pharmaceutical composition of claim 1, wherein the second active agent is an SUV420H1 / H2 inhibitor, and the SUV420H1 / H2 inhibitor is A-196, or a tautomer, isotopologue, or pharma- ceutically acceptable salt thereof.

26. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a CARM1 inhibitor, and the CARM1 inhibitor is EZM2302, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof.

27. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a PLK1 inhibitor, and the PLK1 inhibitor is BI2536, volasertib, CYC140, onvansertib, GSK461364, or TAK960, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof.

28. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a NEK2 inhibitor, and the NEK2 inhibitor is JH-295 or rac-CCT250863.

29. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a MEK inhibitor, and the MEK inhibitor is trametinib, trametinib dimethylsulfoxide, cobimetinib, binimetinib, or selumetinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof.

30. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a PIM inhibitor, and the PIM inhibitor is LGH-447, AZD1208, SGI-1776, or TP-3654, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof.

31. 2. The pharmaceutical composition of claim 1, wherein the second active agent is an IGF-1R inhibitor, and the IGF-1R inhibitor is linsitinib.

32. 2. The pharmaceutical composition of claim 1, wherein the second active agent is an XPO1 inhibitor, and the XPO1 inhibitor is selinexor.

33. 2. The pharmaceutical composition of claim 1, wherein the second active agent is a BIRC5 inhibitor, and the BIRC5 inhibitor is YM155.

34. 34. The pharmaceutical composition of any one of claims 1 to 33, wherein the compound is the hydrochloride salt of compound 1.

35. 35. The pharmaceutical composition of any one of claims 1 to 34, wherein the hematological malignancy is acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), Hodgkin's lymphoma (HL), T-cell lymphoma (TCL), Burkitt's lymphoma (BL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone lymphoma (MZL), or myelodysplastic syndrome (MDS).

36. 36. The pharmaceutical composition of claim 35, wherein the hematological malignancy is recurrent or refractory.

37. 36. The pharmaceutical composition of claim 35, wherein the hematological malignancy is newly diagnosed.

Images