TREATMENT FOR ACUTE MYELOID LEUKEMIA OR MYELODYSPLASTIC SYNDROME

Abstract

The invention relates to a method of treating a subject with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, non-Hodgkin lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, or myelodysplastic syndrome by administering a Compound (I): (see formula I), or a pharmaceutically acceptable salt thereof.

Description

TREATMENT FOR ACUTE MYELOID LEUKEMIA OR MYELODYSPLASTIC SYNDROME MA / IZ / ZUZZ / U / FOOO CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority over U.S. Provisional Application No. 62 / 944,876, filed on December 6, 2019. The entire content of the above-mentioned application is incorporated herein by reference. FIELD OF INVENTION This document discloses methods for treating a subject with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in patients with (lR,2S)-2-(3-((E)-4(((2S,6R)-2,6-dimethylmorpholino)methyl)steryl)-lH-andazol-6-l)-5'-methoxyspiro[cyclopropan-l,3'indolin]-2'-one (Compound (I)). BACKGROUND OF THE INVENTION The polo-like kinase (PLK) family of serine / threonine kinases comprises at least four known members: PLK1, PLK2 (also known as Snk), PLK3 (also known as Fnk or Prk), and PLK4 (also known as Sak). Agents that inhibit PLK4 have the potential to treat cancer. A number of potent PLK4 inhibitors are described in U.S. Patents Nos. 8,263,596, 8,481,525, and 8,481,533 (the teachings of which are incorporated herein by reference). The structure of one inhibitor disclosed in these patents is shown below as Compound (I). (YO) Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow. This type of cancer usually worsens rapidly if left untreated. It is the most common type of acute leukemia in adults. AML is also called acute myeloid leukemia, acute myeloblastic leukemia, acute granulocytic leukemia, and acute non-lymphocytic leukemia. In acute myeloid leukemia (AML), 10–14% of all AML patients, and up to 23% among older AML patients, have karyotypes with >3 aberrations (complex karyotype). These karyotypes with >3 aberrations are classified as an adverse genetic risk according to the European Leukemia Network (ELN) recommendations. Myelodysplastic syndromes (MDS) are a group of diverse bone marrow disorders in which the bone marrow does not produce enough healthy blood cells. MDS is often referred to as bone marrow failure disorder. MDS is primarily a disease of older people (most patients are over 65 years of age), but it can also affect younger patients. For approximately 30% of patients diagnosed with MDS, this type of bone marrow failure syndrome will progress to acute myeloid leukemia (AML). Chronic myeloid leukemia (CML) is also known as chronic myelogenous leukemia. It is a type of cancer that begins in certain blood cells in the bone marrow. In CML, a genetic change occurs in an early (immature) version of myeloid cells, the cells that produce red blood cells, platelets, and most types of white blood cells (except lymphocytes). This change creates an abnormal gene called BCR-ABL, which transforms the cell into a CML cell. The leukemia cells grow and divide, accumulating in the bone marrow and spreading into the bloodstream. Over time, the cells can also settle in other parts of the body, including the spleen. CML is a fairly slow-growing leukemia, but it can develop into a rapidly growing acute leukemia that is difficult to treat. There is a need to develop new drugs to treat AML, CML, or MDS. BRIEF DESCRIPTION OF THE INVENTION The applicant has now discovered that Compound (I) has potent anticancer activity against acute myeloid leukemia, acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CLL), non-Hodgkin lymphoma (NHL), Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), or myelodysplastic syndrome. Furthermore, Compound (I) has now been discovered to have additive / synergistic activity against multiple karyotype complex (CK) AML cell lines in vitro in combination with the standard treatment agent venetoclax (an inhibitor). IVIA / t / ZUZZ / UZ fOÓO of Bcl2) and 5-Azacitidine (also known as azacitidine). Compound (I) has also been found to positively affect the outcome of a patient with AML CK. Based on these findings, methods of treating AML, CLL, NHL, Burkitt lymphoma, DLBCL, or MDS (including the complex karyotype of each disease) with Compound (I) are disclosed herein. IVIA / t / ZUZZ / UZ fOOO In one aspect, the present disclosure provides a method of treating a subject with acute myeloid leukemia, chronic myeloid leukemia, non-Hodgkin lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, or myelodysplastic syndrome, comprising administering an effective amount of a Compound (I): or a pharmaceutically acceptable salt thereof. In another respect, this disclosure provides for the use of a Compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a drug to treat a subject with acute myeloid leukemia, chronic myeloid leukemia, non-Hodgkin lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, or myelodysplastic syndrome. In another respect, this disclosure provides a Compound (I) or a pharmaceutically acceptable salt thereof for treating a subject with acute myeloid leukemia, chronic myeloid leukemia, non-Hodgkin lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, or myelodysplastic syndrome. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows that treatment of cancer cells with Compound (I) causes aberrant mitosis leading to death or arrest. FIG 2 shows tumor volume (MOLT-4) in SCID mice versus day of treatment. FIG. 3 shows body weight (SCID mice) versus treatment day. FIG 4 shows tumor volume (MV4-11) in SCID mice versus day of treatment. FIG. 5 shows body weight (SCID mice) versus treatment day. DETAILED DESCRIPTION OF THE INVENTION As used herein, Compound (1) refers to a compound having the chemical name (lR,2S)-2-(3-((E)-4-(((2S,6R)-2,6-dimethylmorpholino)methyl)steryl)-lH-indazol-6-yl)-5'-methoxyspiro[cyclopropan-l,3'-indoline]-2,-one, which has the following structure: ML / t / ZUZZ / UZ / 300 (YO)· Compound (I) was developed as a PLK 4 inhibitor and is disclosed in WO2011 / 123946. The preparation of Compound (I) is described in Example A185 of WO2011 / 123946, the teachings of which are incorporated herein by reference. This disclosure includes pharmaceutically acceptable salts of Compound (I). The disclosed compound has basic amine groups and can therefore form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Pharmaceutically acceptable acid addition salts of the compounds of the invention include salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, melic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, and tartaric acid).The compounds of the invention with acid groups, such as carboxylic acids, can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (such as sodium and potassium salts), and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate, and the like.Other examples of such salts include hydrochlorides, hydrobroms, sulfates, methanesulfonates, nitrates, maleates (the molar ratio of Compound (I) to maleic acid is 1:1 or 2:1), acetates, citrates, fumarates (the molar ratio of Compound (I) to fumaric acid is 1:1 or 2:1), tartrates [e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof, including racemic mixtures], succinates, benzoates, and salts with amino acids such as glutamic acid. In some embodiments, this disclosure provides Compound (I) as a fumarate salt. In certain embodiments, the molar ratio of Compound (I) to fumaric acid is 1:1. This disclosure also includes the crystalline forms of Compound (I) or the corresponding pharmaceutically acceptable salt. For example, the crystalline forms and their methods of preparation are disclosed in documents WO2015 / 054793 and WO2020 / 215155, the teachings of which are incorporated herein by reference. The compounds used in the disclosed methods are stereoisomers. Stereoisomers are compounds that differ only in their spatial arrangement. The stereoisomeric purity of the compounds used in the disclosed methods is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. Stereoisomeric purity in this case is determined by dividing the total weight in the mixture of stereoisomers covered by the name or structure by the total weight in the mixture of all stereoisomers. The term an effective amount means an amount, when administered to a subject, that produces beneficial or desired results, including clinical outcomes, such as inhibiting, suppressing, or reducing cancer (e.g., as determined by clinical symptoms or the number of cancer cells) in a subject compared to a control. Specifically, treating a subject with cancer includes achieving, partially or substantially, one or more of the following: stopping the growth or spread of a cancer, reducing the extent of a cancer (e.g., reducing the size of a tumor or reducing the number of affected sites), inhibiting the growth rate of a cancer, and attenuating or improving a symptom or clinical marker associated with a cancer (such as tissue or serum components). In general, an effective amount of a compound of the invention varies depending on several factors, such as the specific drug or compound, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject or host being treated, and the like, but can nevertheless be routinely determined by a person skilled in the art. An effective amount of a compound of the present invention can be readily determined by a person of average knowledge using routine methods known in the ML / t / ZUZZ / UZ / 300 technical. In one embodiment, an effective amount of a compound of the invention ranges from approximately 0.01 to approximately 1000 mg / kg of body weight, alternatively from approximately 0.05 to approximately 500 mg / kg of body weight, alternatively from approximately 0.1 to approximately 100 mg / kg of body weight, alternatively from approximately 0.1 to approximately 15 mg / kg of body weight, alternatively from approximately 1 to approximately 5 mg / kg of body weight, and in another embodiment, from approximately 2 to approximately 3 mg / kg of body weight. A person skilled in the art will appreciate that certain factors may influence the dosage required to effectively treat a subject suffering from cancer, and these factors include, but are not limited to, the severity of the disease or disorder, prior treatments, the subject's general health and / or age, and other present illnesses. As used herein, the terms treat, treats, or treatment, when used in relation to a disorder or condition, include any effect—for example, lessen, reduce, modulate, attenuate, and / or eliminate—that results in improvement of the disorder or condition. Improvement or a decrease in the severity of any symptom of the disorder or condition can be readily assessed in accordance with standard methods and techniques known in the field. As used herein, the term refractory means a cancer that does not respond to treatment. The cancer may be resistant at the beginning of treatment or may become resistant during treatment. As used herein, the term complex karyotype is defined by the presence of >3 chromosomal aberrations (structural and / or numerical) identified by the use of chromosomal banding analysis (CBA). The methods described in this document can be used to treat AML. AML is the most common type of acute leukemia. It occurs when the bone marrow begins to produce blasts, cells that have not yet fully matured. These blasts normally develop into white blood cells. However, in AML, these cells do not develop and are unable to protect against infections. In AML, the bone marrow can also produce abnormal red blood cells and platelets. The number of these abnormal cells increases rapidly, and the abnormal (leukemic) cells begin to crowd out the normal white blood cells, red blood cells, and platelets that the body needs. One of the main things that differentiates AML from the other major forms of leukemia is that it has eight different subtypes, which are based on the cell from which the cancer developed. IVIA / t / ZUZZ / UZ fOÓO leukemia. Types of acute myeloid leukemia include: • Myeloblastic (M0) - in special analyses • Myeloblastic (MI) - without maturation • Myeloblastic (M2) - with maturation • Promyelocytic (M3) • Myelomonocytic (M4) • Monocytic (M5) • Erythroleukemia (M6) • Megakaryocytic (M7) Complex karyotype acute myeloid leukemia (CML) is an acute myeloid leukemia characterized by at least three chromosomal abnormalities. The abnormalities found in CML include the loss of material from chromosome arms 5q, 7q, and / or 17p and are referred to herein as typical CML. The absence of abnormalities in chromosome arms 5q, 7q, and / or 17p is referred to herein as atypical CML. Mutations in TP53, PHF6, FLT3-TKD, MED12, NPM1, DNMT3A, NF1, NRAS, IDH2, RUNX1, NPM1, SRSF2, ZRSR2, ASXL1, and FLT3-ITD are associated with atypical CML. Treatment for both types is addressed using the methods described herein. The methods disclosed also include patients with some or all of the mutations associated with typical and atypical CK. In some cases, the AML being treated is relapsed or refractory. In some cases, the AML being treated is an acute myeloid leukemia with a complex karyotype. In some cases, the myelodysplastic syndrome being treated is relapsing or refractory. In some cases, the myelodysplastic syndrome being treated is a complex karyotype myelodysplastic syndrome. In some cases, the acute lymphoblastic leukemia being treated is relapsed or refractory. In some cases, the ALL being treated is a complex karyotype acute lymphoblastic leukemia. In some modalities, the acute lymphoblastic leukemia that will be treated is T-cell acute lymphoblastic leukemia. In some modalities, the acute lymphoblastic leukemia that will be treated is B-cell acute lymphoblastic leukemia. In some cases, the chronic myeloid leukemia being treated is relapsed or refractory. In some cases, the CML being treated is an acute lymphoblastic leukemia with a complex karyotype. In some cases, the non-Hodgkin lymphoma to be treated is relapsed or refractory. In some cases, the non-Hodgkin lymphoma to be treated is a complex karyotype non-Hodgkin lymphoma. ML / t / ZUZZ / UZ / 300 In some cases, the Burkitt lymphoma to be treated is relapsed or refractory. In some cases, the Burkitt lymphoma to be treated is a complex karyotype Burkitt lymphoma. In some cases, the diffuse large B-cell lymphoma to be treated is relapsed or refractory. In some cases, the diffuse large B-cell lymphoma to be treated is a complex karyotype diffuse large B-cell lymphoma. In some modalities, the diffuse large B-cell lymphoma to be treated is of the germinal center B-cell type. In some modalities, the diffuse large B-cell lymphoma to be treated is of the activated B-cell type. In some modalities, the teachings in this document provide methods for treating a subject with acute myeloid leukemia, chronic myeloid leukemia, non-Hodgkin lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, or myelodysplastic syndrome, comprising administering to the subject an effective amount of Compound (I) in combination with an additional therapeutic agent. In some modalities, the additional therapeutic agent is an anticancer drug. An anticancer drug is a compound that, when administered in an effective amount to a subject with cancer, can partially or substantially achieve one or more of the following: stop growth, reduce the extent of a cancer (e.g., reduce the size of a tumor), inhibit the growth rate of a cancer, and attenuate or improve a symptom or clinical indicator associated with a cancer (such as tissue or serum components) or increase the subject's longevity. The anticancer agent suitable for use in the methods described herein includes any anticancer agents that have been approved for the treatment of cancer. In one modality, the anticancer agent includes, but is not limited to, a targeted antibody, an angiogenesis inhibitor, an alkylating agent, an antimetabolite, a vinca alkaloid, a taxane, a podophyllotoxin, a topoisomerase inhibitor, a hormonal antineoplastic agent, and other antineoplastic agents. In one modality, the anticancer agents that can be used in the methods described herein include, but are not limited to, paclitaxel, docetaxel, 5-fluorouracil, trastuzumab, lapatinib, bevacizumab, letrozole, goserelin, tamoxifen, cetuximab, panitumumab, gemcitabine, capecitabine, irinotecan, oxaliplatin, carboplatin, cisplatin, doxorubicin, epirubicin, cyclophosphamide, methotrexate, vinblastine, vincristine, melphalan, cytarabine, etoposide, daunorubicin, bleomycin, mitomycin, and adriamycin, and a combination thereof. In one formulation, the anticancer drug is Venetoclax. In one formulation, the anticancer drug is 5-Azacitidine. In one formulation, the anticancer drug is decitabine. IVIA / t / ZUZZ / UZ / 300 In the methods disclosed herein, Compound (I) and the additional therapeutic agent are administered simultaneously or sequentially. Compound (I) and / or pharmaceutically acceptable salts thereof described herein are useful as active pharmaceutical ingredients (APIs), as well as materials for preparing pharmaceutical compositions incorporating one or more pharmaceutically acceptable excipients and are suitable for administration to human subjects. In some embodiments, the disclosure provides a pharmaceutical composition comprising a Compound (I) and / or a pharmaceutically acceptable salt thereof and at least one additional pharmaceutically acceptable excipient. The term pharmaceutically acceptable excipient, as used herein, refers to a pharmaceutically acceptable material, composition, and / or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each excipient must be pharmaceutically acceptable in the sense of being compatible with the composition in question and its components and not harmful to the patient.Except to the extent that any conventional pharmaceutically acceptable excipient is incompatible with Compound (I) and / or pharmaceutically acceptable salts thereof, such as by producing any undesirable biological effect or otherwise by interacting deleteriously with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated within the scope of this disclosure. Some non-limiting examples of materials that may serve as pharmaceutically acceptable excipients include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) Esters, such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffering agents, such as magnesium hydroxide and aluminum hydroxide;(15) alginic acid; (16) pyrogen-free water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other compatible non-toxic substances used in pharmaceutical formulations. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. I. Swarbrick and I. C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of which are incorporated herein by reference, also disclose additional, non-limiting examples of IVIA / fOÓO pharmaceutically acceptable excipients, as well as known techniques for preparing and using them. The compounds used in the disclosed methods can be administered to a patient in a variety of ways depending on the selected route of administration, as those skilled in the art will understand. The compounds described herein can be administered, for example, orally, parenterally, buccally, sublingually, nasally, rectally, by patch, by pump, or transdermally, and pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical methods. Parenteral administration may be by continuous infusion over a selected period of time. The compounds used in the disclosed methods can be appropriately formulated into pharmaceutical compositions for administration to a subject. The pharmaceutical compositions described herein may optionally include one or more pharmaceutically acceptable vehicles and / or diluents, such as lactose, starch, cellulose, and dextrose. Other excipients, such as flavoring agents, sweeteners, and preservatives, such as methyl, ethyl, propyl, and butyl parabens, may also be included. More complete lists of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5th ed., Pharmaceutical Press (2005)). A person skilled in the art will know how to prepare formulations suitable for various routes of administration.Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. Vehicles, diluents and / or excipients are acceptable in that they are compatible with the other ingredients of the pharmaceutical composition and are not harmful to the recipient of the formulation. Typically, for oral therapeutic administration, a compound used in the disclosed methods may be incorporated with excipients and used in the form of swallowable tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, and the like. Typically, for parenteral administration, solutions of a compound used in the disclosed methods can generally be prepared in water conveniently mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary storage and use conditions, these preparations contain a preservative to inhibit the growth of microorganisms. Typically, for injectable use, sterile aqueous solutions or dispersions of, and sterile powders of, a compound used in the disclosed methods for the IVIA / t / ZUZZ / UZ / 300 extemporaneous preparation of sterile injectable solutions or dispersions. For nasal administration, the compounds used in the disclosed methods may be formulated as aerosols, drops, gels, and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are generally presented in single-dose or multi-dose quantities in sterile form in a sealed container, which may be a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unit-use dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser provided with a metering valve that is intended to be discarded after use. When the dosage form comprises an aerosol dispenser, it will contain a propellant, which may be a compressed gas, such as compressed air, or an organic propellant, such as a fluorochlorohydrocarbon.Aerosol dosage forms can also take the form of a pump atomizer. For oral or sublingual administration, the compounds used in the disclosed methods can be formulated with a vehicle such as sugar, acacia, tragacanth, or gelatin and glycerin, in the form of tablets, dragees, or lozenges. For rectal administration, the compounds used in the disclosed methods can be formulated in the form of suppositories containing a conventional suppository base such as cocoa butter. EXAMPLES The following examples are intended to be illustrative and are not intended in any way to limit the scope of disclosure. EXAMPLE 1 In Vitro Cytotoxicity Assay (CIso) Cells were seeded in triplicate at 10,000 per 80 µL in 96-well plates 24 hours prior to compound overlay and cultured at 37 °C and 5% CO2. Compound (I) was prepared as a 10 mM strain in 100% DMSO and diluted with RPMI 1640 cell growth medium containing 10% FBS such that the final concentrations ranged from 50 pM to 15 µM. Aliquots (20 µL) of each concentration were overlaid onto 80 µL of pre-seeded cells to achieve final concentrations from 10 pM to 3 µM. After 3 days, cell viability in each well was assessed using the alamarBIue assay according to the manufacturer's instructions. MA / IZ / ZUZZ / U / fOÓO (ThermoFisher Scientific). Absorbance was read at 570 nm using a SpectraPlus microplate reader (Molecular Devices Corporation). AlamarBIue absorbance values ​​were adjusted by subtracting the average of the reference readings from untreated cells evaluated one day after cell seeding. The percentage (%) of relative inhibition of cell viability was calculated by comparing it to cells treated with DMSO. IC50 values ​​were calculated using GraphPad PRISM software (GraphPad Software Inc.). The results are shown in Table 1 below and in Figure 1. IVIA / t / ZUZZ / UZ fOOO TABLE 1 Cell Line Cell Type Response to Compound (I) IC50 of Compound (I) (nM) TP53 Status PTEN Status RAJI NHL, Burkitt B cells death 0.1 R213Q, Y234H WT DAUDI NHL, Burkitt B cells death 0.2 R213*, G266E V175G JURKAT T-ALL death 0.6 multiple mutations multiple mutations KOPN-8 B-ALL death 0.7 R248Q (het) WT THP-1 AMLM5 death 1.4 p.R174fs*3 (het) WT TF-1 AML M6 death 2.2 p.I251fs (het) splice site WT MOLT-4 T-ALL death 4.1 R306* p.K267fs*9 REH B-ALL death 5.1 R181C R173C MV4-11 AML M5 death 5.7 mutation at L344 WT 0CI-LY1O NHL, ABCDLBCL death 6.8 K319* HL-60 splice site AML M2 death 8.4 complete hypermethylation of the SU-DHL-8 promoter NHL, DLBCL death 12 Y234N, R249G WT K-562 CML mitotic defects + arrest p.Q136fs*13 WT 0CI-LY18 NHL, GCBDLBCL mitotic defects + arrest WT WT 0CI-AML4 AMLM4 mitotic defects + arrest WT WT 0CI-LY3 NHL, ABCDLCBL mitotic defects + arrest WT WT NB4 AML M3 mitotic defects + arrest mutations in K319, L344 WT NALM-16 B-ALL mitotic defects + arrest WT WT 0CI-AML2 AML M4 mitotic defects + arrest WT WT RS4;11 B-ALL mitotic defects + arrest I254T (het) WT 0CI-LY8 NHL, GCBDLBCL mitotic defects + arrest WT WT NALM-6 B-ALL mitotic defects + arrest WT WT 0CI-AML3 AML M4 mitotic defects + arrest WT WT. MA / IZ / ZUZZ / U / / 300 EXAMPLE 2 The Fumarate of Compound (1) Inhibits Your Moral Growth in the ALL Model MOLT-4 IVIA / t / ZUZZ / UZ fOOO Drug and test system Drug Name(s) Compound (I) Batch Reference(s) Fumarate Batch 16 Dosage Groups (mg / kg) Compound (I) 7.5 mg / kg once daily Compound (I) 13.5 mg / kg 2 treatment / 5 rest days Vincristine 0.5 mg / kg IP, once weekly Dose Volume 10 ml / kg Formulation Compound (I) will be dissolved / suspended in water prior to dosing. Vehicle Control Group Water (10 ml / kg) Positive Control Group Vincristine diluted in PBS prior to dosing. Route of Administration PO (oral), daily for Compound (I), IP (intraperitoneal injection), weekly for vincristine Tumor Cell Type and Line MOLT-4 Acute Lymphoblastic Leukemia Number of Cells and Volume Injected 1 x 107 cells in a volume of 0.1 ml Tumor Cell Culture: The human acute lymphoblastic leukemia MOLT-4 cell line was acquired from the American Type Culture Collection (Manassas, VA, USA) and cultured in RPMI medium containing 100 units / ml of sodium penicillin G and 100 pg / ml of streptomycin sulfate. The medium was supplemented with 10% heat-inactivated fetal bovine serum, 2 mM L-glutamine, and 0.11% sodium pyruvate. Tumor cells were maintained in a humidified environment of 5% CO2 and 95% air at 37°C. Cells were verified to be free of mouse pathogens by IMPACTIV PCR assay (IDEXX RADIL, Colma, MO, USA) prior to injection. Animals and Tumor Cells: Female SCID mice were purchased from the Ontario Cancer Institute and received and acclimated at the MaRS-TMDT Animal Resource Centre for two weeks prior to the start of the experiment. The mice were fed ad habit with autoclaved water and a laboratory rodent diet (Harian Teklad LM-485) consisting of 19% crude protein, 5% crude fat, and 5% crude fiber. The mice were housed in micro-isolation cages and maintained in an environment with a 12-hour light cycle at a temperature of 20–22°C and a humidity of 40–60%. On the day of implantation, MOLT-4 cells were harvested and resuspended with serum-free DMEM at a concentration of 1 x 108 / ml and each mouse was injected subcutaneously with a volume of 0.1 ml containing 1 x 107 MOLT-4 cells in the right posterior flank. Controls and Dosage: The animals were dosed with Compound (I) via oral gavage at a volume of 10 mL / kg. The animals were dosed using a 2.25 mm x 50 mm curved gavage needle attached to a 1 mL syringe. Vincristine was dosed via intraperitoneal (IP) injection once a week. Observations during life: Toxicity was assessed by body weight measurements and clinical observations. Mice were observed daily for overt signs of any treatment-related adverse side effects and clinical signs of toxicity. Acceptable toxicity was defined as a mean group body weight loss of less than 20% during the study and no more than one treatment-related death in any group. Body weights and tumor growth were monitored, with tumor volumes calculated using the formula: tumor volume = (width² × length) / 2. Results The study evaluated Compound (I) fumarate administered via oral gavage for 21 days, either daily at 7.5 mg / kg or 2 days on / 5 days off at 13.5 mg / kg, compared to the standard agent vincristine, dosed as four weekly intraperitoneal injections of 0.5 mg / kg, in the MOLT-4 acute myeloid leukemia xenograft model in SCID (severe combined immunodeficiency) mice. Xenografts were established by subcutaneous injection of 100 tumor cells into the right flank of female SCID mice. Treatment was initiated 9 days post-implantation when tumor volumes reached a mean volume of approximately 250 mm³. By day 13, the average volume of the control tumors was 1754 mm³, with an average tumor growth of 683%. On day 13, the average tumor growth inhibition in the vincristine-treated arm was 18% (p=0.21). Daily oral dosing of Compound (I) at 7.5 mg / kg resulted in an average tumor regression of 77% (p=2.5 × 10⁻⁶), with regression observed in 7 of 8 tumors, and the 2-day treatment / 5-day rest dosing of 13.5 mg / kg resulted in an average regression of 28% (p=6.5 × 10⁻⁶), with regression observed in 7 of 8 tumors. After 21 days of dosing, tumors continued to recede, with peak antitumor efficacy observed on Day 25, with 8 out of 8 complete regressions in the daily dosing arm and 6 out of 8 complete regressions in the 2 treatment / 5 rest arm (average 96% regression).Over time, the tumor grew back in all animals, with the last animal removed from the study due to excessive tumor burden on Day 68. IVIA / t / ZUZZ / UZ / 300 The results are shown in Figures 2 and 3. Specifically, Figure 2 shows tumor volume (MOLT-4) in SCID mice on the day of treatment. Figure 3 shows body weight (SCID mice) on the day of treatment. Overall, Compound (I) is highly effective and potentially curative in the MOLT-4 acute lymphoblastic leukemia xenograft model. Rooo Protocol Design Group N Trial Article Lot / Supplier Salt Form Ratio Bioequiv. Vehicle Route, Regimen and Dose 1 6 Vehicle N / AN / AN / A water PO once daily + IP once weekly 2 6 Compound (I) 16 fumarate 0.82 water PO, 7.5 mg / kg once daily x21 3 6 Compound (I) 16 fumarate 0.82 water PO, 13.5 mg / kg 2 treatment / 5 rest days x3 (21 days) 4 6 Vincristine Sigma Sulfate 0.89 PBS IP, 0.5 mg / kg once weekly x4 EXAMPLE 3 The Fumarate of Compound fl) Inhibits Tumor Growth in the MV4 AML Model 11 Drug and test system Drug Name(s) Compound (I) Batch Reference(s) Fumarate Batch 16 Dosage Groups (mg / kg) Compound (1)-16 7.5 mg / kg once daily Compound (1)-16 13.5 mg / kg 2 treatment / 5 rest Vincristine 0.5 mg / kg IP, once weekly Dose Volume 10 ml / kg Formulation Compound (I) shall be dissolved / suspended in water prior to dosing. Vehicle Control Group Water (10 ml / kg) Positive Control Group Vincristine diluted in PBS prior to dosing. Route of administration PO (oral), daily for Compound (I), IP (intraperitoneal injection), weekly for vincristine. Tumor cell type and line: Acute myeloid leukemia MV4-11. Number of cells and injected volume: 1 x 107 cells in a volume of 0.1 ml Tumor Cell Culture: The MV4-11 human acute myeloid leukemia cell line was acquired from American The cells were cultured in RPMI medium containing 100 units / ml of sodium penicillin G and 100 pg / ml of streptomycin sulfate. The medium was supplemented with 10% heat-inactivated fetal bovine serum, 2 mM L-glutamine, and 0.11% sodium pyruvate. Tumor cells were maintained in a humidified environment of 5% CO2 and 95% air at 37°C. Cells were verified to be free of mouse pathogens by PCRIMPACT IV assay (IDEXX RADIL, Colma, MO, USA) prior to injection. Animals and Tumor Cells: Female SCID mice were purchased from the Ontario Cancer Institute and received and acclimated at the MaRS-TMDT Animal Resource Centre for two weeks prior to the start of the experiment. The mice were fed ad habit with autoclaved water and a laboratory rodent diet (Harian Teklad LM-485) consisting of 19% crude protein, 5% crude fat, and 5% crude fiber. The mice were housed in micro-isolation cages and maintained in an environment with a 12-hour light cycle at a temperature of 20–22°C and a humidity of 40–60%. On the day of implantation, MV4-11 cells were harvested and resuspended with serum-free DMEM at a concentration of 1 x 108 / ml and each mouse was injected subcutaneously with a volume of 0.1 ml containing 1 x 107 MV4-11 cells in the right posterior flank. Controls and Dosage: The animals were dosed with Compound (I) via oral gavage at a volume of 10 ml / kg. The animals were dosed using a 2.25 mm x 50 mm curved gavage needle attached to a 1 ml syringe. Vincristine was dosed via intraperitoneal (IP) injection once a week. Observations during life: Toxicity was assessed by body weight measurements and clinical observations. Mice were observed daily for overt signs of any treatment-related adverse side effects and clinical signs of toxicity. Acceptable toxicity was defined as a mean group body weight loss of less than 20% during the study and no more than one treatment-related death in any group. Body weights and tumor growth were monitored, with tumor volumes calculated using the formula: (tumor volume - width² × length) / 2. Results The study evaluated Compound (I) fumarate administered via oral gavage, either daily at 7.5 mg / kg or on a 2-day / 5-day rest basis at 13.5 mg / kg, compared to the standard agent vincristine, dosed as four weekly intraperitoneal injections of 0.5 mg / kg, in the MV4-11 acute myeloid leukemia xenograft model in SCID (severe combined immunodeficiency) mice. Xenografts were established by subcutaneous injection of 100 tumor cells into the right flank of female SCID mice. Treatment was initiated 14 days post-implantation when tumor volumes reached a certain level. The mean tumor volume (IVIA / t / ZUZZ / UZ fOÓO) was approximately 90 mm3. Daily oral dosing of Compound (I) at 7.5 mg / kg was discontinued after 14 days due to excessive body weight loss. Animals were dosed on a 2-day treatment / 5-day rest regimen for 21 days. Dosing of Compound (I) on either regimen resulted in complete tumor regress by day 10; at that time, the mean control tumor volume was 589 mm3. By day 13, the mean control tumor volume was 878 mm3, with an average of 1666% tumor growth reduction over the 13 days. On day 13, the mean tumor growth inhibition in the vincristine-treated arm was 85% (p=0.14). The animals remained tumor-free until Day 24 in the 2-day treatment / 5-day rest arm, and until Day 74 in the daily dosing arm. Four of six animals in the daily dosing arm remained tumor-free until the last measurement time point (Day 128). The results are shown in Figures 4 and 5. Specifically, Figure 4 shows tumor volume (MV4-11) in SCID mice versus day of treatment. Figure 5 shows body weight (SCID mice) versus day of treatment. Overall, Compound (I) is highly effective and potentially curative in the MV4-11 acute myeloid leukemia xenograft model. Protocol Design IVIA / t / ZUZZ / UZ / 300 Group N Trial Article Lot / Supplier Salt Form Ratio Bioequiv. Vehicle Route, Regimen and Dose 1 6 Vehicle N / AN / AN / A water PO once daily + IP once weekly 2 6 Compound (I) 16 fumarate 0.82 water PO, 7.5 mg / kg once daily xl3 3 6 Compound (I) 16 fumarate 0.82 water PO, 13.5 mg / kg 2 treatment / 5 rest x3 (21 days) 4 6 Vincristine Sigma Sulfate 0.89 PBS IP, 0.5 mg / kg once weekly x4 EXAMPLE 4 Phase 1 Study of Compound fll Fumarate in Patients with Relapsing or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome This study (NCT number: NCT03187288) is a multicenter, phase 1, dose-escalation trial designed to evaluate the safety, tolerability, pharmacokinetics, and clinical benefit of treatment with orally administered Compound (I) fumarate across a dose range in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who are relapsed or refractory to current treatment or for whom there is no curative therapy. Results: Nine patients with relapsed or refractory AML were treated with escalating doses of Compound (I) (64 mg to 128 mg) administered orally once daily. Of these, three patients received the 64 mg dose, four patients received the 96 mg dose, and two patients received the 128 mg dose. More detailed patient information is provided in the table below. Of the six patients evaluable for response, two (33%) achieved complete remission (CR), and three patients (50%) had stable disease (with one patient experiencing a 78% reduction in bone marrow blast count). The dose-limiting toxicity (DLT) was identified as colitis at the 128 mg dose level. The 96 mg dose level was suggested for further exploration. However, only four patients were enrolled at the 96 mg dose level before study enrollment was discontinued and the study was modified. Conclusion: Compound (I) as a single agent has activity in patients with low-risk AML. EXAMPLE 5 Phase 111 / 2 Study of Compound Fumarate (fl) as a Single Agent or in Combination with Azacitidine or Decitabine in Patients with Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Chronic Myelomonocytic Leukemia Part 1A Optimization of Single Agent Dose The primary objectives of this study are (i) to evaluate the safety and tolerability, and identify the maximum tolerated dose (MTD) of Compound (I) administered orally in patients with acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML); and (ii) to determine the Phase 2 Recommended Dose of Compound (I) in patients with AML, myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML). The secondary objectives of this study are (i) to determine the PK of Compound (I) administered orally in patients with AML, myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML); (ii) to determine the Composite Complete Remission Rate, CRc (complete remission + complete remission with incomplete blood count recovery + complete remission with incomplete platelet count recovery [CR + CRi + CRp]) of Compound (I) in patients with AML; and (iii) to determine the Overall Response Rate (ORR, defined as Complete Remission + Bone Marrow CR + Partial Remission + Hematologic Improvement (CR + mCR-i-PR + HI) in MDS or CMML. Study Design and Methodology In Part 1A, patients will receive Compound (I) orally daily, in the morning and on an empty stomach, i.e., without eating for 2 hours before or 1 hour after taking their dose, for 21 days followed by 7 days off (28-day cycles), except for Day 1 and Day 2. IVIA / t / ZUZZ / UZ / 300 of Cycle 1, in which Compound (I) will be administered after an overnight fast. Ad libitum water intake is permitted 1 hour after administration of the dose following the overnight fast; food intake is not permitted for at least 4 hours after the dose. The initial dose of Compound (I) is 32 mg and is based on preliminary clinical data. Patients who complete the initial cycle of therapy without evidence of significant toxicity or clinical evidence of disease progression may receive additional 28-day cycles of treatment at the same dose level for up to 6 cycles. If a PR or improvement is not achieved, the Investigator should withdraw the patient from the study after discussion with the Medical Monitor. Safety will be assessed through serial physical examinations, vital signs, hematology and chemistry laboratory tests, and adverse events (AEs). The NCI CTCAE v5 will be used to report AEs and laboratory data. Blood samples will be collected to determine the pharmacokinetics (PK) of Compound (I). Whole blood, serum, plasma, and bone marrow and / or peripheral blood blasts will be collected for analysis of the effects of the plasma concentration (PD) of Compound (I) when appropriate. Bone marrow assessment will be performed after cycle 1, and after each cycle until a response occurs (e.g., CR, CRi, CRp), and as clinically indicated. Patients who achieve a CR will require bone marrow examination every 3 months (approximately 12 weeks) for 1 year, and thereafter as clinically indicated. When treatment-related toxicities are observed, treatment with Compound (I) may be delayed until recovery from the observed treatment-related toxicities and to consider whether dose reductions are appropriate for continuing therapy with Compound (I). A delay of up to 14 days is permitted for patients to return to baseline or Grade 1 for any treatment-related adverse event. The investigator, after discussion with the medical monitor, may allow a patient to continue in the study after a treatment delay of more than 14 days if the patient is benefiting from the treatment and the treatment-related toxicities have returned to baseline or Grade 1. The maximum tolerated dose and dose-limiting toxicities are defined below for the escalation portions of the study. Dose adjustments for toxicities that occur during the study will be discussed in the protocol and will generally involve dose withholding, dose reduction, and possibly discontinuation of study drug therapy, depending on the severity. Single-agent dose optimization entry dose levels are defined below: IVIA / t / ZUZZ / UZ fOOO Dose Level Dose (mg) of Compound (I) Once daily x 21 days of treatment / 7 days off (28-day cycles) -1 16 1 32 2 48 3 64 4+ See below IVIA / t / ZUZZ / UZ / 300 Part IB: Effect of Food The primary objectives of this study are (i) to further evaluate the safety and tolerability, and identify the maximum tolerated dose (MTD) of Compound (I) administered orally in patients with acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML); and (ii) to evaluate the effect of food on the pharmacokinetics of Compound (I) through oral administration of Compound (I) with / without a high-fat meal in patients with AML, MDS, or CMML. The secondary objectives of this study are (i) to determine the Composite Complete Remission Rate, CRc (complete remission + complete remission with incomplete blood count recovery + complete remission with incomplete platelet count recovery [CR + CRi + CRp]) of Composite (I) in patients with AML; and (ii) to determine the Overall Response Rate (ORR, defined as Complete Remission + Bone Marrow CR + Partial Remission + Hematologic Improvement (CR + mCR + PR + HI) in MDS or CMML. Study Design and Methodology In Part IB, patients will be administered Compound (I) orally daily at the proposed dose determined in Part 1A for one week (study days 1–7), taking the drug in the morning on an empty stomach, i.e., without eating for 2 hours before or 1 hour after taking their dose, for 21 days followed by 7 days of rest (28-day cycles), except for Day 1 and Day 21 of Cycle 1, when Compound (I) will be administered after an overnight fast. On Day 8 of the study, after an overnight fast (approximately 8 hours), patients will withhold their dose of Compound (I) and arrive at the clinic. After a pre-dose PK sample is taken, patients will be given Compound (I) with 240 ml of water, and a post-dose PK sample will be taken. Ad libitum water consumption is permitted for one hour after dose administration. Food intake is not allowed for at least 4 hours after the dose.On Day 9 of the study, after an overnight fast (approximately 8 hours), patients will withhold their dose of Compound (I) and arrive at the clinic. Following a pre-dose PK sample, patients will receive a high-fat meal 30 minutes before Compound (I) administration with approximately 240 ml of water; the meal should be consumed within 30 minutes. After Compound (I) administration, patients will undergo a post-dose PK sample. Ad libitum water consumption is permitted one hour after dose administration; food intake is not permitted for at least 4 hours post-dose. After Day 9, patients will continue taking Compound (I) daily for the remainder of Cycle 1, taking their dose in the morning on an empty stomach. Safety will be assessed through serial physical examinations, vital signs, hematology and chemistry laboratory tests, and AEs. The NCI CTCAE v5 will be used to report AEs and laboratory data. Blood samples will be collected to determine the pharmacokinetics of Compound (I). Whole blood, serum, plasma, and bone marrow and / or peripheral blood blasts will be collected for analysis of the PD effects of Compound (I). Bone marrow assessment will be performed after cycle 1, and after each cycle until a response occurs (e.g., CR, CRi, CRp), and as clinically indicated. Patients who achieve a CR will require bone marrow examination every 3 months (approximately 12 weeks) for 1 year, and thereafter as clinically indicated. Dose adjustments for toxicities that occur during the study will be discussed in the protocol and will generally involve dose withholding, reduction, and possibly discontinuation of study drug therapy, depending on the severity, and are discussed in Section 3.5 and Section 6. After the PK results for Part IB are analyzed, patients will be advised whether they can take Compound (I) with food or if they should continue taking the drug. Part 2: Dose Escalation for Combination Therapy Part 2A Combination of Compound (I) and Azacitidine Part 2B Combination of Compound (I) and Decitabine. The primary objectives of this study are (i) to evaluate the safety and tolerability, and identify the maximum tolerated dose (MTD) of Compound (I) administered orally in combination with azacitidine or decitabine in patients with AML or CMML; and (ii) to determine the Phase 2 Recommended Dose for Combination Therapy (RP2D) of Compound (I) and azacitidine or of Compound (I) and decitabine in patients with AML or MDS or CMML. The secondary objectives of this study are (i) to determine the PK of Compound (I) administered orally in combination with azacitidine or decitabine in patients with AML or CMML; to determine the Composite Complete Remission Rate, CRc (complete remission + complete remission with incomplete blood count recovery + complete remission with incomplete platelet count recovery [CR + CRi + CRp]) of Compound (I) in patients with AML; and (ii) to determine the Overall Response Rate (ORR, defined as complete remission + bone marrow CR + remission Partial IVIA / t / ZUZZ / UZ / 300 + Hematological Improvement (CR + mCR-ι- PR + HI) in MDS or CMML. During the dose escalation phase of Part 2A or Part 2B, patients will receive Compound (I) orally daily, in the morning, on an empty stomach, i.e., without eating for 2 hours before or 1 hour after taking their dose, for 21 days followed by 7 days off (28-day cycles) (unless otherwise specified), except for Day 1 and Day 21 of Cycle 1, when Compound (I) will be administered after an overnight fast. Ad libitum water intake is permitted 1 hour after administration of the dose following the overnight fast; food intake is not permitted for at least 4 hours after the dose.Patients will receive Compound (I) orally at an initial dose of 32 mg or two dose levels below the Part 1A Maximum Daily Allowance (MTD), whichever is lower, administered daily for 28-day cycles, in addition to azacitidine administered at a dose of 75 mg / m² IV or SC on days 1–7 of the 28-day cycle or decitabine administered at a dose of 20 mg / m² IV on days 1–5 of a 28-day cycle. Administration of azacitidine or decitabine should begin within 5 minutes of dosing Compound (I). Patients who complete the initial course of therapy without evidence of significant toxicity or clinical evidence of disease progression may receive additional 28-day courses of treatment at the same dose level. If the initial dose of Compound (I) is not tolerated, the dose of Compound (I) will be reduced to dose level -1 (24 mg). If this is not tolerated, Part 2 will be closed. Safety will be assessed through serial physical examinations, vital signs, hematology and chemistry laboratory tests, and AEs. The NCI CTCAE v5 will be used to report AEs and laboratory data. Blood samples will be collected to determine the pharmacokinetics of Compound (I). Whole blood, serum, plasma, and bone marrow and / or peripheral blood blast samples will be collected for analysis of the drug-predominant effects of Compound (I) and azacitidine or decitabine, if appropriate. Bone marrow assessment will be performed after cycle 1, and after each cycle until a response occurs (e.g., CR, CRi, CRp), and as clinically indicated. Patients who achieve a CR will require bone marrow examination every 3 months (approximately 12 weeks) for 1 year, and thereafter as clinically indicated. Dose adjustments for toxicities that occur during the study will be discussed in the protocol and will generally involve dose withholding, dose reduction, and possibly discontinuation of study drug therapy, depending on the severity. Dose escalation in Parts 2A and 2B will proceed independently as illustrated below: MA / t / ZUZZ / U / fOOO Dose Level Compound (I) Dose (mg) Once daily x 21 days of treatment / 7 days off (28-day cycles) Azacitidine* Dose (mg / m2, IV / SC, days 1-7) -2 16 75 -1 24 75 1 32 75 2 40 75 3+ 48** 75 *The dose of azacitidine should be administered according to the local SOC: SC or IV, and typically on day 17, or day 1-5 (with the weekend off) and then the following 2 days of the week. **After 48 mg, if the dose needs to be increased, the dose increases should not exceed 33%. Dose Level Compound (I) Dose (mg) Once daily x 21 days of treatment / 7 days off (28-day cycles) Decitabine* Dose (mg / m2, IV / SC, days 1-5) -2 16 20 -1 24 20 1 32 20 2 40 20 3+ 48** 20 **After 48 mg, if the dose needs to be increased, the dose increases should not exceed 33%.

Claims

1. A method of treating a subject with acute myeloid leukemia or myelodysplastic syndrome, comprising administering an effective amount of a Compound (I): or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, further characterized in that compound (I) is a fumarate salt.

3. The method according to claim 2, further characterized in that the molar ratio between Compound (I) and fumaric acid is 1:

1.

4. The method in accordance with any of claims 1 to 3, further characterized in that the subject has acute myeloid leukemia.

5. The method according to claim 4, further characterized in that the acute myeloid leukemia is relapsed or refractory.

6. The method according to any of claims 1 to 5, further characterized in that the acute myeloid leukemia is an acute myeloid leukemia of complex karyotype.

7. The method according to any of claims 1 to 6, further characterized in that it additionally comprises co-administering an additional therapeutic agent.

8. The method according to claim 7, further characterized in that the additional therapeutic agent is an anticancer drug.

9. The method according to claim 8, further characterized in that the anticancer drug is Venetoclax.

10. The method according to claim 8, further characterized in that the anticancer drug is 5-Azacitidine.

11. The method according to any of claims 7 to 10, further characterized in that Compound (I) and the additional therapeutic agent are administered simultaneously. IVIA / t / ZUZZ / UZ fOÓO 12. The method according to any of claims 7 to 10, further characterized in that the Compound (I) and the additional therapeutic agent are administered sequentially.

13. The method according to claim 8, further characterized in that the anticancer drug is decitabine.

14. A method of treating a subject with acute lymphoblastic leukemia, chronic myeloid leukemia, non-Hodgkin lymphoma, Burkitt lymphoma, or diffuse large B-cell lymphoma, comprising administering an effective amount of a Compound (I): (I), or a pharmaceutically acceptable salt thereof.

15. The method according to claim 14, further characterized in that Compound (I) is a fumarate salt.

16. The method according to claim 15, further characterized in that the molar ratio between Compound (I) and fumaric acid is 1:

1.

17. The method in accordance with any of claims 14 to 16, further characterized in that the subject has acute lymphoblastic leukemia.

18. The method according to claim 17, further characterized in that the acute lymphoblastic leukemia is either T-cell acute lymphoblastic leukemia or B-cell acute lymphoblastic leukemia.

19. The method according to any of claims 14 to 16, further characterized in that the subject has chronic myeloid leukemia.

20. The method in accordance with any of claims 14 to 16, further characterized in that the subject has non-Hodgkin lymphoma.

21. The method according to any of claims 14 to 16, further characterized in that the subject has Burkitt lymphoma.

22. The method according to any of claims 14 to 16, further characterized in that the subject has diffuse large B-cell lymphoma.

23. The method according to claim 22, further characterized in that the diffuse large B-cell lymphoma is of the germinal center B-cell type or of the activated B-cell type.

24. The method according to any of claims 14 to 23, further characterized in that the acute lymphoblastic leukemia, chronic myeloid leukemia, non-Hodgkin lymphoma, Burkitt lymphoma, or diffuse large B-cell lymphoma are relapsed or refractory.

25. The method according to any of claims 14 to 24, further characterized in that acute lymphoblastic leukemia, chronic myeloid leukemia, non-Hodgkin lymphoma, Burkitt lymphoma, or diffuse large B-cell lymphoma has a complex karyotype.

26. The method according to any of claims 14 to 25, further characterized in that it additionally comprises co-administering an additional therapeutic agent.

27. The method according to claim 26, further characterized in that the additional therapeutic agent is an anticancer drug.

28. The method according to claim 27, further characterized in that the anticancer drug is Venetoclax, 5-Azacitidine or decitabine.

29. The method according to any of claims 26 to 28, further characterized in that the Compound (I) and the additional therapeutic agent are administered simultaneously or sequentially.