SCD1 inhibitors for treating hematolymphoid neoplasms

Abstract

Included herein are methods for treating hematolymphoid neoplasms with an SCD1 inhibitor (e.g., Compound 1) or a pharmaceutical salt, tautomer, stereoisomer, prodrug, or isotopologue thereof. Methods associated with preparation of pharmaceutical compositions comprising such SCD1 inhibitor compounds are also provided.

Description

SCD1 INHIBITORS FOR TREATING HEMATOLYMPHOID NEOPLASMSBACKGROUNDTechnical Field

[0001] Embodiments of the present disclosure are generally directed to use of compounds as therapeutic or prophylactic agents, for example for treatment of hematolymphoid neoplasms (e.g., acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), and multiple myeloma (MM)).Description of the Related Art

[0002] Hematolymphoid neoplasms encompass a diverse group of malignancies affecting the blood, bone marrow, and lymphatic system. Among these, acute myeloid leukemia (AML) represents a significant challenge due to its high morbidity and mortality rates. Despite advances in treatment, negative outcomes and limited therapeutic options remain a concern for patients diagnosed with AML.

[0003] AML is a rapidly progressing cancer characterized by the aberrant proliferation of myeloid precursor cells. Current therapeutic approaches, including chemotherapy and targeted therapy, have demonstrated efficacy in achieving initial remission. However, relapse rates and treatment resistance remain substantial obstacles, leading to poor long-term survival rates. Moreover, conventional treatments often result in severe adverse effects, further compromising patient well-being.

[0004] Accordingly, there is a need to develop compounds and methods of treating hematological malignancies (e.g., AML). Embodiments of the present disclosure fulfill this need and provide further related advantages.BRIEF SUMMARY

[0005] In brief, embodiments of the present disclosure provide compounds, including pharmaceutically acceptable salts, stereoisomers, and prodrugs thereof, which can be used for treating various hematological malignancies (e.g., acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), and multiple myeloma (MM)).

[0006] In some embodiments is provided a method for treating a hematolymphoid neoplasm, the method comprising administering an effective amount of a compound of Structure (I):or a pharmaceutical salt, tautomer, stereoisomer, prodrug, or isotopologue thereof, wherein:X is -(C=O)NR4-;R1is halo; andR2, R3, and R4are each independently hydrogen or an unsubstituted Ci-6 alkyl, to a subject in need thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Figure 1 shows human acute myeloid leukemia cell lines and primary leukemic cells derived from patients in liquid culture. Compound 1 was used in concentration gradient 10 nM - 10 pM for 3 or 7 days. Figure 1 shows a prominent increase in cell death as measured by expression of Annexin V as observed in treated cells both in cell lines and primary samples.

[0008] Figure 2 shows that exposure to Compound 1 in the human AML cell lines at the dose 1 pM for 7 days increased cell death induction in sensitive primary AML samples by 12.63 % on average.

[0009] Figure 3 shows that following 2 weeks of tumor engraftment, NBSGW male and female mice are randomized and Compound 1 treatment is started at dose of 10 mg / kg by oral gavage for 9 days. Figure 3 shows that median animal survival in control group was 34 days versus 42 days in Compound 1 treated group.

[0010] Figure 4 shows a patient-derived xenograft (PDX) model 2-4x106 CD3-depleted mononuclear cells from the bone marrow or peripheral blood of AML patients. Mice are randomized and Compound 1 treatment is started at dose of 10 mg / kg by oral gavage for 14 days after which animals are euthanized and tumor burden is determined by the presence of human myeloid cells (CD45+ / CD33+ / CD19) in the bone marrow as measured by flow cytometry. Figure 4 shows that administration of Compound 1 reduced tumor burden by 54.50% on average.

[0011] Figure 5 shows the murine MLL-AF9 model that has all the hallmarks of acute myeloid leukemia, including presentation in the bone marrow and peripheral blood. Mice are randomized and Compound 1 treatment is started at dose of 10 mg / kg by oral gavage for 7 days with or without the addition of intensive chemotherapeutic protocol. Intensive chemotherapeutic protocol consists of doxorubicin at dose of 1 mg / kg in PBS by IV (tail vein) injections for 3 days and cytarabine at dose of 59 mg / kg in PBS by IV (tail vein) injections for 5 days. Figure 5 shows that median animal survival both in control and Compound 1 treated group was 30 days versus 35 days in chemotherapy treated group and 40 days in the group treated by combination of chemotherapy and Compound 1.DETAILED DESCRIPTION

[0012] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the disclosure. However, one skilled in the art will understand that the disclosure may be practiced without these details.

[0013] Unless the context requires otherwise, throughout the present specification and claims, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense, that is, as "including, but not limited to".

[0014] In the present description, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. As used herein, the terms "about" and "approximately" mean ± 20%, ± 10%, ± 5%, or ± 1% of the indicated range, value, or structure, unless otherwise indicated. It should be understood that the terms "a" and "an" as used herein refer to "one or more" of the enumerated components. The use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives.

[0015] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0016] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. As used in the specification and claims, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise.

[0017] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound described herein that is sufficient to affect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended treatment application (in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and / or cell migration. The specific dose will vary depending on the compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0018] As used herein, "treatment" or "treating" refer to an approach for obtaining beneficial or desired results with respect to a disease, disorder or medical condition including but not limited to a therapeutic effect and / or a prophylactic effect. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

[0019] The terms "co-administration," "administered in combination with," "further comprises administering a [therapeutic agent]," and their grammatical equivalents, as used herein, encompass administration of two or more agents to an animal, including humans, so that both agents and / or their metabolites are present in the subject at the same time. Coadministration includes simultaneous administration in separate compositions, administration atdifferent times in separate compositions, or administration in a composition in which both agents are present.

[0020] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0021] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness of the free bases, which are biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable acid addition salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable acid addition salts which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthal ene- 1,5- disulfonic acid, naphthal ene-2-sulfonic acid, 1 -hydroxy -2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, -toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0022] "Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness of the free acids, which are biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable base addition salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, orallergic response. Pharmaceutically acceptable base addition salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, A-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0023] In some embodiments, pharmaceutically acceptable salts include quaternary ammonium salts such as quaternary amine alkyl halide salts (e.g., methyl bromide).

[0024] The term "inhibitor" refers to a compound having the ability to inhibit a biological function of a target protein (e.g., an enzyme), whether by inhibiting the activity or expression of the protein, such as stearoyl-coenzyme A desaturase-1 (SCD1). Accordingly, the term "inhibitor" are defined in the context of the biological role of the target protein and include competitive inhibition (e.g., rather than downregulating mRNA expression).

[0025] The term "agonist" as used herein refers to a compound having the ability to initiate or enhance a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Accordingly, the term "agonist" is defined in the context of the biological role of the target protein (e.g., a PPAR-gamma agonist).

[0026] "Subject" refers to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is human.

[0027] Mammal" includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.

[0028] "Prodrug" is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some embodiments, a prodrug is inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or thiol group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of a hydroxy functional group, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.

[0029] The term "in vivo" refers to an event that takes place in a subject’s body.

[0030] Embodiments disclosed herein are also meant to encompass all pharmaceutically acceptable compounds, including salts, stereoisomers, tautomers, polymorphs, solvates, hydrates, isotopologues, and prodrugs thereof.

[0031] Certain embodiments are also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, embodiments include compounds produced by a process comprising administering a compound of this disclosure to a mammal for a period sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to an animal, suchas rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.

[0032] A "pharmaceutical composition" refers to formulations of compounds of the disclosure and a medium generally accepted in the art for the delivery of compounds of the disclosure to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients therefor.

[0033] "Pharmaceutically acceptable carrier, diluent, or excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier. In some embodiments, the pharmaceutical excipient is beta-cyclodextrin.

[0034] A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0035] The compounds of the disclosure (e.g., SCD1 inhibitors or PPAR-gamma agonists) or their pharmaceutically acceptable salts may contain one or more centers of geometric asymmetry and may thus give rise to stereoisomers such as enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (5)- or, as (D)- or (L)- for amino acids. Embodiments thus include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (5)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0036] Embodiments of the present disclosure include all manner of rotamers and conformationally restricted states of a compound of the disclosure. Atropisomers, which arestereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers, are also included. As an example, certain compounds of the disclosure may exist as mixtures of atropisomers or purified or enriched for the presence of one atropisomer.

[0037] A "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. Embodiments thus include tautomers of the disclosed compounds.

[0038] The chemical naming protocol and structure diagrams used herein are a modified form of the I.U.P.A.C. nomenclature system, using the ACD / Name Version 9.07 software program and / or ChemDraw Professional Version 17.0.0.206 software naming program (CambridgeSoft). For complex chemical names employed herein, a substituent group is typically named before the group to which it attaches. For example, cyclopropylethyl comprises an ethyl backbone with a cyclopropyl substituent. Except as described below, all bonds are identified in the chemical structure diagrams herein, except for all bonds on some carbon atoms, which are assumed to be bonded to sufficient hydrogen atoms to complete the valency.Compounds

[0039] Compounds of Structure (I) (e.g., Compound 1) disclosed herein is known in the art and can be prepared according to methods known in the art. For example, synthesis of compounds of Structure (I) (e.g., Compound 1) can be found at least in PCT Publication No. WO 2016 / 022955, which is hereby incorporated by references for the details of that synthesis.

[0040] The PPAR-gamma agonists disclosed herein are those that are known in the art. In one embodiment, the PPAR-gamma agonist has the following structure:

[0041] In some embodiments, the foregoing PPAR-gamma agonist is an HC1, CF3COOH, C4H4O4, or (COOH)2 salt. The foregoing PPAR-gamma agonist (and HC1, CF3COOH, C4H4O4, or (COOH)2 salt thereof) can be prepared according to methods known in the art. For example, synthesis of the foregoing PPAR-gamma agonist and HC1, CF3COOH, C4H4O4, or (COOH)2 salt thereof can be found at least in PCT Publication No. WO 2005 / 058827, which is hereby incorporated by references for the details of that synthesis.

[0042] The nucleoside anticancer agents disclosed herein are those that are known in the art and can be prepared according to methods known in the art. For example, synthesis of cytarabine can be found at least in U.S. Patent No. 3,328,388, which is hereby incorporated by reference for the details of that synthesis. Synthesis of gemcitabine can be found at least in U.S. Patent No. 4,526,988, which is hereby incorporated by reference for the details of that synthesis.

[0043] The anthracycline anticancer agents disclosed herein are those that are known in the art and can be prepared according to methods known in the art. For example, synthesis of doxorubicin can be found at least in U.S. Patent No. 3,590,078, which is hereby incorporated by reference for the details of that synthesis. In other embodiments, the anthracycline anticancer therapeutic agent is epirubicin, daunorubicin, idarubicin, aclarubicin, or amrubicin.

[0044] Anticancer therapeutic agents for treating AML are known in the art and can be prepared according to known methods known in the art. In some embodiments, the anticancer therapeutic agent is daunorubicin, cytarabine, azacytidine, enasidenib mesylate, filgrastim, gemtuzumab ozogamicin, gilteritinib, glasdegib, idarubicin hydrochloride, ivosidenib, olutasidenib, rydapt, sargramostim, or venetoclax.

[0045] Anticancer therapeutic agents for treating multiple myeloma are known in the art and can be prepared according to known methods known in the art. In some embodiments, the anticancer therapeutic agent is belantamab, bortexomib, bortezomib, carfilzomib, carmustine, ciltacabtagene autoleucel, cyclophosphamide, daratumumab, denosumab, dexamethasone, diatrizoate, doxorubicin, elotuzumab, idecabtagene vicleucel, isatuximab, ixazomib, lenalidomide, melphalan, pamidronate, panobinostat, plerixafor, pomalidomide, selinexor, teclistamab, thalidomide, thioguanine, zoledronic acid, BMCA antibody bispecific therapy, or a Car-T therapy.Methods

[0046] Embodiments of the present disclosure generally relate to treatment of hematolymphoid neoplasms via the inhibition of SCD1 in a host species. Related embodiments relate to method of treatment of acute myeloid leukemia, the method comprising administering an effective amount of a compound of Structure (I) (e.g., Compound 1) to the subject in need thereof.

[0047] Accordingly, one embodiment provides a method for treating a hematolymphoid neoplasm, the method comprising administering an effective amount of a compound of Structure (I):or a pharmaceutical salt, tautomer, stereoisomer, prodrug, or isotopologue thereof, wherein:X is -(C=O)NR4-;R1is halo; andR2, R3, and R4are each independently hydrogen or an unsubstituted Ci-6 alkyl, to a subject in need thereof.

[0048] In some embodiments, the compound has the following Structure (la):or a pharmaceutical salt, tautomer, stereoisomer, prodrug, or isotopologue thereof.

[0049] In some embodiments, R1is chloro. In certain embodiments, R4is hydrogen. In some embodiments, R2is hydrogen. In certain embodiments, R3is -CH3. In some embodiments, the compound of Structure (I) is Compound 1 having the following structure:Compound 1 or a pharmaceutical salt, tautomer, stereoisomer, prodrug, or isotopologue thereof, to a subject in need thereof.

[0050] In some embodiments, the method treats multiple myeloma.

[0051] In some embodiments, the method treats leukemia. In further embodiments, the leukemia is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), or hairy cell leukemia.

[0052] In certain embodiments, the method treats AML, wherein the AML is independent of any specific genetic abnormality. In certain embodiments, the method treats AML, wherein the AML is: acute promyelocytic leukemia with PML::RARA fusion;AML with RUNXJ::RUNXJT J fusion;AML with CBFB::MYH11 fusion;AML with DEK: :NUP214 fusion;AML with RBM15 ::MRTFA fusion;AML with BCR: : ABU fusion;AML with KMT2A rearrangement;AML with MECOM rearrangement;AML with NUP98 rearrangement;AML with NPM1 mutation;AML with CEBPA mutation; orAML, myelodysplasia-related (AML-MR).In some embodiments, the method treats AML-MR, wherein the AML-MR is characterized by one or more cytogenetics abnormalities comprising: complex karyotype having 3 or more abnormalities;5q deletion or loss of 5q due to unbalanced translocation; monosomy 7, 7q deletion, or loss of 7q due to unbalanced translocation; l lq deletion;12p deletion or loss of 12p due to unbalanced translocation; monosomy 13 or 13q deletion;17p deletion or loss of 17p due to unbalanced translocation; isochromosome 17q; or idic(X)(ql3).In other embodiments, the method treats AML-MR, wherein the AML-MR is characterized by one or more somatic mutations comprising ASXL1, BCOR, EZEE2, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2.

[0053] In some embodiments, the method treats AML, wherein the AML is characterized by differentiation. In some embodiments, the AML is AML with acute myeloid leukemia with minimal differentiation, AML without maturation, AML with maturation, acute basophilicleukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroid leukemia, or acute megakaryoblastic leukemia.

[0054] In some embodiments, the method treats a myeloproliferative neoplasm (MPN). In further embodiments, the myeloproliferative neoplasm is polycythemia vera, essential thrombocythemia, or myelofibrosis.

[0055] In some embodiments, the method treats a myelodysplastic neoplasm (MDS).

[0056] In some embodiments, the method treats a hematolymphoid neoplasm wherein the hematolymphoid neoplasm is a lymphoid proliferation or lymphoma. In further embodiments, the lymphoid proliferation or lymphoma is a precursor B-cell neoplasm, a mature B-cell neoplasm, or a plasma cell neoplasm. In other embodiments, the lymphoid proliferation or lymphoma is Hodgkin’s lymphoma or non-Hodgkin’s lymphoma.

[0057] In certain embodiments, the compound of Structure (I) is administered orally.

[0058] In some embodiments, the compound of Structure (I) is administered once per day. In certain embodiments, the compound of Structure (I) is administered once per day for at least 10 consecutive days. In some embodiments, the compound of Structure (I) is administered once per day for at least 14 consecutive days. In certain embodiments, the compound of Structure (I) is administered once per day for at least 21 consecutive days. In some embodiments, the compound of Structure (I) is administered once per day for at least 28 consecutive days.

[0059] In certain embodiments, mRNA levels of SCD1 are not downregulated. In some embodiments, mRNA levels of PPAR-gamma are upregulated. In some embodiments, the level of PPAR-gamma is increased.

[0060] In certain embodiments, the method further comprises administering a PPAR- gamma agonist. In some embodiments, the compound of Structure (I) is formulated with a pharmaceutical excipient. In certain embodiments, the compound of Structure (I) is formulated with beta-cyclodextrin.

[0061] In some embodiments, the method further comprises performing a clinical eye exam. In some embodiments, the method further comprises administering lipid eye drops. In some embodiments, the compound of Structure (I) and the PPAR-gamma agonist are formulated into a single dosage form comprising the compound of Structure (I) and the PPAR-gamma agonist. In some embodiments, the compound of Structure (I) and the nucleoside anti cancer agent are formulated into a single dosage form comprising the compound of Structure (I) and the nucleoside anticancer agent. In some embodiments, the compound of Structure (I) and the anthracycline anticancer agent are formulated into a single dosage form comprising thecompound of Structure (I) and the anthracycline anticancer agent. In some embodiments, the single dosage form further comprises a pharmaceutical excipient. In certain embodiments, the pharmaceutical excipient is beta-cyclodextrin.

[0062] In some embodiments, the PPAR-gamma agonist has the following structure:or a pharmaceutical salt, tautomer, stereoisomer, or prodrug thereof.

[0063] In some embodiments, the PPAR-gamma agonist is a pharmaceutically acceptable salt of the following structure:

[0064] In some embodiments, the pharmaceutically acceptable salt is an HC1 salt.

[0065] In certain embodiments, the compound of Structure (I) is a deuterated form thereof. In certain embodiments, the compound of Structure (I) has the following structure:or a pharmaceutical salt, tautomer, stereoisomer, or prodrug thereof, wherein:D is deuterium.

[0066] Some embodiments provide a method for treating an hematolymphoid neoplasm, the method comprising contacting the hematopoietic cell or the lymphoid cell with an effective amount of a compound of Structure (I):or a pharmaceutical salt, tautomer, stereoisomer, prodrug, or isotopologue thereof, wherein:X is -(C=O)NR4-;R1is halo; andR2, R3, and R4are each independently hydrogen or an unsubstituted Ci-6 alkyl, to a subject in need thereof.

[0067] In some more specific embodiments, R1is chloro. In some embodiments, R4is hydrogen. In certain embodiments, R2is hydrogen. In certain embodiments, R3is -CH3.

[0068] In some embodiments, the compound of Structure (I) is Compound 1 having the following structure:Compound 1 or a pharmaceutical salt, tautomer, stereoisomer, prodrug, or isotopologue thereof, to a subject in need thereof.

[0069] In certain embodiments, the compound of Structure (I) is a competitive enzyme inhibitor. In some embodiments, mRNA levels of SCD1 are not downregulated in the hematopoietic cell or the lymphoid cell. In certain embodiments, mRNA levels of PPAR-gamma are upregulated in the hematopoietic cell or the lymphoid cell. In some embodiments, mRNA levels for fibrogenic genes are downregulated in the hematopoietic cell or the lymphoid cell. In some embodiments, the level of reactive oxygen species is decreased in the hematopoietic cell or the lymphoid cell. In some embodiments, the level of PPAR-gamma is increased in the hematopoietic cell or the lymphoid cell. In some embodiments, the method further comprises contacting the hematopoietic cell or the lymphoid cell with a PPAR-gamma agonist. In some embodiments, the PPAR-gamma agonist has the following structure:or a pharmaceutical salt, tautomer, stereoisomer, or prodrug thereof.

[0070] In some embodiments, the compound of Structure (I) is a deuterated form thereof.In some embodiments, the compound of Structure (I) has the following structure:or a pharmaceutical salt, tautomer, stereoisomer, or prodrug thereof, whereinD is deuterium.

[0071] The host, subject, or patient can belong to any mammalian species, for example a primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental investigations, providing a model for treatment of human disease.

[0072] Embodiments of the methods of the disclosure can be performed either in vitro or in vivo. The susceptibility of a particular cell or group of cells to treatment with a compound of Structure (I) (e.g., Compound 1) and / or a PPAR-gamma agonist can be particularly determined by in vitro tests, whether in the course of research or clinical application. Typically, a culture of a cell or cells is combined with a compound at various concentrations for a period of time which is sufficient to allow the active agents to inhibit SCD1 activity, usually between about one hour and one week. In vitro treatment can be carried out using cultivated cells from a biopsy sample or cell line.

[0073] Some embodiments described herein refer to "downregulation," "upregulation," "mRNA levels," "level of [biological markers]," or similar. For these embodiments, the increase or decrease in expression is relative to control sample (e.g., other in vivo cells, a separate in vitro culture of cells, etcl) that has not received treatment. In some embodiments, the increase (e.g., upregulation) or decrease (e.g., downregulation) is a statistically significant difference. In some embodiments, the differences in levels or expression are measured for a group or sample of treated cells compacted to a group or sample of untreated cells. In some embodiments, the differences in levels or expression are measured for a group or sample of treated subjects compared to a group or sample of untreated subjects.Pharmaceutical Compositions

[0074] Other embodiments are directed to methods of administering or use of one or more pharmaceutical compositions. The pharmaceutical compositions comprise any one (or more) of a compound of Structure (I) (e.g., Compound 1) and / or a PPAR-gamma agonist and a pharmaceutically acceptable excipient or carrier. The pharmaceutical compositions comprise any one (or more) of a compound of Structure (I) (e.g., Compound 1) and / or an anticancertherapeutic agent and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In still more embodiments, the pharmaceutical compositions comprise a compound of Structure (I) (e.g., Compound 1) and an additional therapeutic agent. Examples of such therapeutic agents include agents that are PPAR-gamma agonists, Type-II diabetes drugs, or anticancer therapeutic agents.

[0075] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0076] In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long-acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the compound is delivered in a targeted drug delivery system, for example, in a liposome coated with and organ-specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended-release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the compound described herein is administered topically.

[0077] In treatment methods according to embodiments of the disclosure, an effective amount of a compound of Structure (I) (e.g., Compound 1) and / or a PPAR-gamma agonist is administered to a subject suffering from or diagnosed as having such a disease, disorder, or medical condition. In treatment methods according to embodiments of the disclosure, an effective amount of a compound of Structure (I) (e.g., Compound 1) and / or an anticancer therapeutic agent is administered to a subject suffering from or diagnosed as having such a disease, disorder, or medical condition. Effective amounts or doses may be ascertained by methods such as modeling, dose escalation studies, or clinical trials, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject’s previous or ongoing therapy, the subject’s health status and response to drugs, and the judgment of the treating physician.

[0078] A compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists according to the disclosure are effective over a wide dosage range. In another embodiment, a compound of Structure (I) (e.g., Compound 1) and / or an anticancer therapeutic agent according to the disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 1 to 5000 mg, dosages from 10 to 5000 mg, from 100 to 5000 mg, from 1000 mg to 4000 mg per day, and from 1000 to 3000 mg per day are examples of dosages that are used in some embodiments. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[0079] In some embodiments, a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists of the disclosure are administered in a single dose. In other embodiments, a compound of Structure (I) (e.g., Compound 1) and / or an anticancer therapeutic agent of the disclosure are administered in a single dose. Administration can be oral or by injection, e.g., intravenous injection, in order to introduce the agent quickly. However, other routes are used as appropriate. A single dose of a compound of the disclosure may also be used for treatment of an acute condition.

[0080] In some embodiments, a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists of the disclosure are administered in multiple doses. In some embodiments, a compound of Structure (I) (e.g., Compound 1) and / or an anticancer therapeutic agent of the disclosure are administered in multiple doses. In some embodiments, dosing is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, dosing is about once a month, once every two weeks, once a week, or once every other day.

[0081] In another embodiment, a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists are administered together about once per day up to and including 6 times per day. In another embodiment, the administration of a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists of the disclosure continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.

[0082] In another embodiment, a compound of Structure (I) (e.g., Compound 1) and / or an anti cancer therapeutic agent are administered together about once per day up to and including 6 times per day. In another embodiment, the administration of a compound of Structure (I) (e.g.,Compound 1) and / or an anticancer therapeutic agent of the disclosure continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.

[0083] Administration of a compound of Structure (I) (e.g., Compound 1) and / or an anticancer therapeutic agent of the disclosure may continue as long as necessary. In some embodiments, a compound of Structure (I) (e.g., Compound 1) and / or an anticancer therapeutic agent of the disclosure are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of Structure (I) (e.g., Compound 1) and / or an anticancer therapeutic agent of the disclosure are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of Structure (I) (e.g., Compound 1) and / or an anticancer therapeutic agent of the disclosure are administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.

[0084] Administration of a compound of Structure (I) (e.g., Compound 1) and / or PPAR- gamma agonists of the disclosure may continue as long as necessary. In some embodiments, a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists of the disclosure are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists of the disclosure are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists of the disclosure are administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.

[0085] Administration of a compound of Structure (I) (e.g., Compound 1) and / or an anticancer therapeutic agent of the disclosure may continue as long as necessary. In some embodiments, a compound of Structure (I) (e.g., Compound 1) and / or an anticancer therapeutic agent of the disclosure are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of Structure (I) (e.g., Compound 1) and / or an anticancer therapeutic agent of the disclosure are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of Structure (I) (e.g., Compound 1) and / or an anticancer therapeutic agent of the disclosure are administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.

[0086] In some embodiments, the compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists of the disclosure are administered in individual dosage forms. It is knownin the art that due to inter-subject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy.

[0087] In some embodiments, the compound of Structure (I) (e.g., Compound 1) and / or an anti cancer therapeutic agent of the disclosure are administered in individual dosage forms. It is known in the art that due to inter-subject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy.

[0088] In some embodiments, a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists described herein are formulated into pharmaceutical compositions. In some embodiments, a compound of Structure (I) (e.g., Compound 1) and / or an anticancer therapeutic agent described herein are formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients (e.g., beta-cyclodextrin) and auxiliaries which facilitate processing of the disclosed compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0089] Provided herein are pharmaceutical compositions comprising a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists and pharmaceutically acceptable diluent(s), excipient(s), and carrier(s).

[0090] Provided herein are pharmaceutical compositions comprising a compound of Structure (I) (e.g., Compound 1) and / or an anticancer therapeutic agent and pharmaceutically acceptable diluent(s), excipient(s), and carrier(s).

[0091] A pharmaceutical composition, as used herein, refers to a mixture of a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of a compound of Structure (I) (e.g., Compound 1) and / or PPAR- gamma agonists to an organism. In some embodiments, therapeutically effective amounts of acompound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists provided herein are administered in a pharmaceutical composition to a subject (e.g., a mammal) having a disease, disorder, or medical condition to be treated. In specific embodiments, the subject is a mammal. In a more specific embodiment, the subject is a human. In certain embodiments, therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists used and other factors. Compounds of Structure (I) (e.g., Compound 1) and / or PPAR- gamma agonists described herein are used singly or in combination with one or more therapeutic agents as components of mixtures.

[0092] A pharmaceutical composition, as used herein, refers to a mixture of a compound of Structure (I) (e.g., Compound 1) and / or an anticancer therapeutic agent with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of a compound of Structure (I) (e.g., Compound 1) and / or an anticancer therapeutic agent to an organism. In some embodiments, therapeutically effective amounts of a compound of Structure (I) (e.g., Compound 1) and / or an anticancer therapeutic agent provided herein are administered in a pharmaceutical composition to a subject (e.g., a mammal) having a disease, disorder, or medical condition to be treated. In specific embodiments, the subject is a mammal. In a more specific embodiment, the subject is a human. In certain embodiments, therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of a compound of Structure (I) (e.g., Compound 1) and / or an anti cancer therapeutic agent used and other factors. Compounds of Structure (I) (e.g., Compound 1) and / or an anticancer therapeutic agent described herein are used singly or in combination with one or more therapeutic agents as components of mixtures.

[0093] In another embodiment, a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists are formulated for oral administration. Compounds described herein are formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients. In various embodiments, a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.

[0094] In another embodiment, a compound of Structure (I) (e.g., Compound 1) and / or an anti cancer therapeutic agent are formulated for oral administration. Compounds describedherein are formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients. In various embodiments, a compound of Structure (I) e.g., Compound 1) and / or an anticancer therapeutic agent are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.

[0095] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with a compound of Structure (I) (e.g., Compound 1) and / or a PPAR-gamma agonist described herein or an anticancer therapeutic agent described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0096] In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coating. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions, optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs and / or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and / or pigments are optionally utilized to characterize different combinations of active compound doses.

[0097] In certain embodiments, therapeutically effective amounts of a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists described herein or anticancer therapeutic agents described herein are formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules, contain a compound of Structure (I)(e.g., Compound 1) and / or PPAR-gamma agonists or anticancer therapeutic agents that are dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[0098] Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent, or excipient, and a compound of Structure (I) (e.g., Compound 1) and / or PPAR- gamma agonists described herein or anticancer therapeutic agents described herein as an active ingredient. The active ingredient is in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of A-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of compounds of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists described herein or anticancer therapeutic agents described herein are included within the scope of the compounds presented herein. Additionally, compounds of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists described herein or anticancer therapeutic agents described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of compounds of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists presented herein or anticancer therapeutic agents described herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0099] Methods for the preparation of compositions comprising a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists described herein or anticancer therapeutic agents described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally containminor amounts of non-toxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.

[0100] Compositions may include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0101] In certain embodiments, the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds, and / or other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[0102] In some embodiments, the concentration of a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists or anticancer therapeutic agents in the pharmaceutical compositions of the present disclosure is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125% , 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v, or v / v.

[0103] In some embodiments, the concentration of a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists or anticancer therapeutic agents provided in the pharmaceutical compositions of the present disclosure is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40 %, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w / w, w / v or v / v.

[0104] In some embodiments, the amount a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists or anticancer therapeutic agents provided in the pharmaceutical compositions of the present disclosure is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

[0105] In some embodiments, the amount of a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists or anticancer therapeutic agents provided in the pharmaceutical compositions of the present disclosure is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

[0106] Packaging materials for use in packaging pharmaceutical compositions described herein include those found in, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, the container(s) includes one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprise a compound with an identifying description or label or instructions relating to its use in the methods described herein.

[0107] For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and / ordevices) desirable from a commercial and user standpoint for use of a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists described herein or anticancer therapeutic agents described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and / or tube labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack for example contains metal or plastic foil, such as a blister pack. Or the pack or dispenser device is accompanied by instructions for administration. Or the pack or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions containing a compound of Structure (I) (e.g., Compound 1) and / or PPAR-gamma agonists provided herein or anticancer therapeutic agents described herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition (e.g., AML).EXPERIMENTAL EXAMPLES

[0108] Efficacy of Compound 1 against hematolymphoid neoplasms can be enhanced by modulating fatty acid biosynthesis and SCD1 inhibition will be more potent in context of a high fat western diet or in patients with high BMI. 4-week-old male and female mice are fed a western diet or normal diet for 3 months for all studies in Examples 1-4 prior to inoculation of tumor cells. SCD1 inhibition may also increase DNA damage and its combination with standard chemotherapy may prolong survival in aggressive murine AML models.EXAMPLE 1IN VIVO MOUSE STUDIES

[0109] (1 xlO6in 100 pL of PBS) I.V. SCID-BIEGE male and female mice (Taconic) by tail vein injection. Following 14 weeks of tumor engraftment mice are randomized and Compound 1 treatment is started at doses of 1 or 2 mg / kg by IP injections for 14 days. Mice are bled weekly to determine tumor volume by detecting circulating light chain in the plasma by ELISA.EXAMPLE 2 5TGM1 MURINE MODEL

[0110] The syngeneic 5TGM1 MM model has all the hallmarks of myeloma, including homing to the bone marrow and bone disease. Specifically, 5TGMl / ErolL deleted and control cells (1 xlO6in 100 pL of PBS) are inoculated intravenously into 6-week-old C57 BL / KaLwRij mice (Harlan Laboratories, The Netherlands) by tail vein injection. After 10 days, drug treatment with Compound 1 is initiated at 1 and 2 mg / kg.EXAMPLE 3 QUANTIFICATION OF TUMOR BURDEN

[0111] Blood is collected by submandibular bleeding, and pathology of these mice is monitored weekly by measuring 5TGM1 secreted IgG2b levels in the serum by ELISA. In addition to ELISA measurements, the detection of 5TGMl-luc tumors is quantified by IVIS workstation. At appropriate time points (mice are imaged once per week) after tumor inoculation, mice are anesthetized with an isoflurane / oxygen mixture delivered within the Xenogen IVIS-200 workstation, and imaged 15 minutes after luciferin injection using the Livingimage software program. Hind limb paralysis and hunching are considered as additional surrogate markers for morbidity. Mice are euthanatized according to IACUC guidelines. Following euthanasia, the spleen, liver, and femur are fixed in formaldehyde (and femurs will be decalcified in EDTA) before embedding in paraffin. Bone marrow or organ replacement by 5TGM1 cells are determined histologically.EXAMPLE 4QUANTIFICATION OF BONE LESIONS

[0112] Bone images of the spine and tibia are obtained using a Siemens Inveon preclinical CT scanner. Quantification of bone lesions is performed in a blinded fashion. After images are generated and subsequently reconstructed, data is analyzed using Inveon research workstation created by Siemens molecular imaging. Bones are visualized using the 3D visualization tool. ROIs of both cortical bone and trabecular bone are obtained for 10 different images spaced 3 partitions apart using the segmentation program provided by the software. Ten bones for each condition are imaged. Additionally, bone volume is determined using histomorphometry. H4C of residual tumors in the bone includes quantification of SCD1.EXAMPLE 5 IN VITRO STUDIES

[0113] To assess efficacy of Compound 1 on human acute myeloid leukemia, human AML cell lines and primary leukemic cells derived from patients were used in liquid culture. Compound 1 was used in concentration gradient 10 nM - 10 pM for 3 or 7 days. Figure 1 shows a prominent increase in cell death as measured by expression of Annexin V was observed in treated cells both in cell lines and primary samples. Figure 2 shows that exposure to Compound 1 at the dose 1 pM for 7 days increased cell death induction in sensitive primary AML samples by 12.63 % on average. Statistical significance was determined using Student t-test and p-value was 0.0002.

[0114] To assess efficacy of Compound 1 in combination with conventional chemotherapy in human acute myeloid leukemia, human AML cell line MV-4-11 (Table 1) and murine MLL-AF9 expressing (iMLL) (Table 2) leukemic cells were used in liquid culture. Compound 1 was used in concentration gradient 10 nM - 10 pM and DNA damaging anthracycline doxorubicin was used in concentration gradient 250 - 2000 nM for 3 days. Cell death was measured using Annexin V and propidium iodide stating and flow cytometry. Both Annexin V negative and propidium iodide negative cells were deemed viable. Synergistic effects were calculated using SynergyFinder 2.0 software and ZIP score of 10 and higher represented synergism. Increased cell cytotoxicity when combination of Compound 1 and doxorubicin was observed in both cell models and synergistic effects were observed on average of doses used in MV-4-11 (Table 3) and in all doses of Compound 1 combined with low doses of doxorubicin in MLL-AF9 expressing cells (Table 4).Table 1MV-4-11 viability decrease (%)0 250 500 1000 2000 doxorubicin (nM)Table 2 iMLL-AF9 viability decrease (%)0 250 500 1000 2000 doxorubicin (nM)Table 3MV-4-11 ZIP Scores (average: 10.225)doxorubicin (nM)Table 4 iMLL-AF9 ZIP Scores(average: 2.342)0 250 500 1000 2000 doxorubicin (nM)EXAMPLE 6 IN VIVO MOUSE STUDIES

[0115] To generate xenograft model 0.1x106 MV-4-11 cells in 100 pL of PBS are inoculated intravenously in 8- to 12-week-old NOD.Cg-KitW-41 J Tyr + Prkdcscid I12rgtmlWjl / ThomJ (NBSGW) male and female mice (Jackson Laboratories, USA) by tail vein injection. Following 2 weeks of tumor engraftment mice are randomized and Compound 1 treatment is started at dose of 10 mg / kg by oral gavage for 9 days. Hind limb paralysis and hunching are considered as additional surrogate markers for morbidity. Mice are euthanatized according to IACUC guidelines. Figure 3 shows that median animal survival in control group was 34 days versus 42 days in Compound 1 treated group. Statistical significance was determined using Mantel-Cox test and p-value was 0.0001.

[0116] To generate patient-derived xenograft (PDX) model 2-4x106 CD3 -depleted mononuclear cells from the bone marrow or peripheral blood of AML patients in 100 pL of PBS are inoculated intravenously in 8- to 12-week-old NOD.Cg-KitW-41 J Tyr + Prkdcscid I12rgtmlWjl / ThomJ (NBSGW) male and female mice (Jackson Laboratories, USA) by tail vein injection. Following 8-10 weeks of tumor engraftment tumor burden is determined by bone marrow sampling and measuring the presence of human CD45-expressing cells. Mice are randomized and Compound 1 treatment is started at dose of 10 mg / kg by oral gavage for 14 days after which animals are euthanized and tumor burden is determined by the presence of human myeloid cells (CD45+ / CD33+ / CD19) in the bone marrow as measured by flow cytometry. Figure 4 shows that administration of Compound 1 reduced tumor burden by 54.50% on average. Statistical significance was determined using Student t-test and p-value was 0.0395.EXAMPLE 7MLL-AF9 MURINE MODEL

[0117] The murine MLL-AF9 model has all the hallmarks of acute myeloid leukemia, including presentation in the bone marrow and peripheral blood. Specifically, MLL-AF9 expressing cells (0.11 xl06 in 100 pL of PBS) are inoculated intravenously into 8- to 12-week- old NOD.Cg-KitW-41 J Tyr + Prkdcscid I12rgtmlWjl / ThomJ (NBSGW) male and female mice (Jackson Laboratories, USA) by tail vein injection. Leukemia burden is followed in peripheral blood starting two weeks after engraftment using the ratio of donor (leukemic) CD45.2 expressing cells and recipient CD45.1 expressing cells as measured by flow cytometry. Treatment is started when tumor burden in peripheral blood reached average 20% , a common clinical criteria for acute myeloid leukemia diagnosis. Mice are randomized and Compound 1 treatment is started at dose of 10 mg / kg by oral gavage for 7 days with or without the addition of intensive chemotherapeutic protocol. Intensive chemotherapeutic protocol consists of doxorubicin at dose of 1 mg / kg in PBS by IV (tail vein) injections for 3 days and cytarabine at dose of 59 mg / kg in PBS by IV (tail vein) injections for 5 days. Hind limb paralysis and hunching are considered as additional surrogate markers for morbidity. Mice are euthanatized according to IACUC guidelines. Figure 5 shows that median animal survival both in control and Compound 1 treated group was 30 days versus 35 days in chemotherapy treated group and 40 days in group treated by combination of chemotherapy and Compound 1. Statistical significance was determined using Mantel-Cox test and p-value was 0.0399

[0118] The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet, including U.S. Provisional Patent Application No. 63 / 513,818, filed July 14, 2023, are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications, and publications to provide yet further embodiments.These and other changes can be made to the embodiments considering the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

CLAIMS1. A method for treating an hematolymphoid neoplasm, the method comprising administering an effective amount of a compound of Structure (I):or a pharmaceutical salt, tautomer, stereoisomer, prodrug, or isotopologue thereof, wherein:X is -(C=O)NR4-;R1is halo; andR2, R3, and R4are each independently hydrogen or an unsubstituted C1-6 alkyl, to a subject in need thereof.

2. The method of claim 1, wherein the compound has the following Structure (la):or a pharmaceutical salt, tautomer, stereoisomer, prodrug, or isotopologue thereof.

3. The method of claim 1 or 2, wherein R1is chloro.

4. The method of any one of claims 1-3, wherein R4is hydrogen.

5. The method of any one of claims 1-4, wherein R2is hydrogen.

6. The method of any one of claims 1-5, wherein R3is -CH3.

7. The method of any one of claims 1-6, wherein the compound having the structure of Formula (I) is Compound 1, having the following structure:Compound 1 or a pharmaceutical salt, tautomer, stereoisomer, prodrug, or isotopologue thereof.

8. The method of any one of claims 1-7, wherein the hematolymphoid neoplasm is multiple myeloma.

9. The method of any one of claims 1-7, wherein the hematolymphoid neoplasm is leukemia.

10. The method of claim 9, wherein the leukemia is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), or hairy cell leukemia.

11. The method of claim 9, wherein the leukemia is acute myeloid leukemia.

12. The method of claim 11, wherein the acute myeloid leukemia is independent of any specific genetic abnormality.

13. The method of claim 11 or 12, wherein the acute myeloid leukemia is: acute promyelocytic leukemia with PML::RARA fusion;AML with RUNXJ::RUNXJT J fusion;AML with CBFB::MYH11 fusion;AML with DEK: :NUP214 fusion;AML with RBM15 ::MRTFA fusion;AML with BCR: : ABU fusion;AML with KMT2A rearrangement;AML with MECOM rearrangement;AML with NUP98 rearrangement;AML with NPM1 mutation;AML with CEBPA mutation; orAML, myelodysplasia-related (AML-MR).

14. The method of claim 13, wherein AML-MR is characterized by one or more cytogenetic abnormalities comprising: complex karyotype having 3 or more abnormalities;5q deletion or loss of 5q due to unbalanced translocation; monosomy 7, 7q deletion, or loss of 7q due to unbalanced translocation; l lq deletion;12p deletion or loss of 12p due to unbalanced translocation; monosomy 13 or 13q deletion;17p deletion or loss of 17p due to unbalanced translocation; isochromosome 17q; or idic(X)(ql3).

15. The method of claim 13, wherein AML-MR is characterized by one or more somatic mutations comprising ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2.

16. The method of claim 11, wherein the acute myeloid leukemia is characterized by differentiation.

17. The method of claim 16, wherein the acute myeloid leukemia is AML with acute myeloid leukemia with minimal differentiation, AML without maturation, AML with maturation, acute basophilic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroid leukemia, or acute megakaryoblastic leukemia.

18. The method of any one of claims 1-7, wherein the hematolymphoid neoplasm is a myeloproliferative neoplasm (MPN).

19. The method of claim 18, wherein the myeloproliferative neoplasm is polycythemia vera, essential thrombocythemia, or myelofibrosis.

20. The method of any one of claims 1-7, wherein the hematolymphoid neoplasm is a myelodysplastic neoplasm (MDS).

21. The method of any one of claims 1-7, wherein the hematolymphoid neoplasm is a lymphoid proliferation or lymphoma.

22. The method of claim 21, wherein the lymphoid proliferation or lymphoma is a precursor B-cell neoplasm, a mature B-cell neoplasm, or a plasma cell neoplasm.

23. The method of claim 21 or 22, wherein the lymphoid proliferation or lymphoma is Hodgkin’s lymphoma or non-Hodgkin’s lymphoma.

24. The method of any one of claims 1-23, wherein the compound of Structure (I) is administered orally.

25. The method of any one of claims 1-24, wherein the compound of Structure (I) is administered once per day.

26. The method of any one of claims 1-25, wherein the compound of Structure (I) is administered once per day for at least 10 consecutive days.

27. The method of any one of claims 1-26, wherein the compound of Structure (I) is administered once per day for at least 14 consecutive days.

28. The method of any one of claims 1-27, wherein the compound of Structure (I) is administered once per day for at least 21 consecutive days.

29. The method of any one of claims 1-28, wherein the compound of Structure (I) is administered once per day for at least 28 consecutive days.

30. The method of any one of claims 1-29, wherein mRNA levels of SCD1 are not downregulated.

31. The method of any one of claims 1-30, wherein mRNA levels of PPAR-gamma are upregulated.

32. The method of any one of claims 1-31, wherein the level of PPAR-gamma is increased.

33. The method of any one of claims 1-32, wherein the method further comprises administering a PPAR-gamma agonist.

34. The method of claim 33, wherein the PPAR-gamma agonist has the following structure:or a pharmaceutical salt, tautomer, stereoisomer, or prodrug thereof.

35. The method of claim 33 or 34, wherein the PPAR-gamma agonist is a pharmaceutically acceptable salt of the following structure:

36. The method of claim 35, wherein the pharmaceutically acceptable salt of the PPAR-gamma agonist is an HC1 salt.

37. The method of any one of claims 1-36, wherein the method further comprises administering an anticancer therapeutic agent.

38. The method of claim 37, wherein the anticancer therapeutic agent treats AML.

39. The method of claim 37 or 38, wherein the anticancer therapeutic agent is a nucleoside therapeutic agent.

40. The method of any one of claims 37-39, wherein the anticancer therapeutic agent is a deoxy cytidine analog therapeutic agent.

41. The method of any one of claims 37-40, wherein the anticancer therapeutic agent is cytarabine or gemcitabine.

42. The method of claim 37 or 38, wherein the anticancer therapeutic agent is an anthracycline therapeutic agent.

43. The method of any one of claims 37, 38, or 42, wherein the anticancer therapeutic agent is doxorubicin, epirubicin, daunorubicin, idarubicin, aclarubicin, or amrubicin.

44. The method of any one of claims 37, 38, 42, or 43, wherein the anticancer therapeutic agent is doxorubicin.

45. The method of claim 37 or 38, wherein the anticancer therapeutic agent is daunorubicin, cytarabine, azacytidine, enasidenib mesylate, filgrastim, gemtuzumab ozogamicin, gilteritinib, glasdegib, idarubicin hydrochloride, ivosidenib, olutasidenib, rydapt, sargramostim, or venetoclax.

46. The method of claim 37, wherein the anticancer therapeutic agent treats multimple myeloma.

47. The method of claim 37 or 46, wherein the anticancer therapeutic agent is belantamab, bortexomib, bortezomib, carfilzomib, carmustine, ciltacabtagene autoleucel, cyclophosphamide, daratumumab, denosumab, dexamethasone, diatrizoate, doxorubicin, elotuzumab, idecabtagene vicleucel, isatuximab, ixazomib, lenalidomide, melphalan, pamidronate, panobinostat, plerixafor, pomalidomide, selinexor, teclistamab, thalidomide, thioguanine, zoledronic acid, BMCA antibody bispecific therapy, or a Car-T therapy.

48. The method of any one of claims 1-47, wherein the compound of Structure (I) is formulated with a pharmaceutical excipient.

49. The method of any one of claims 1-48, wherein the compound of Structure (I) is formulated with beta-cyclodextrin.

50. The method of any one of claims 33-49, wherein the compound of Structure (I) and the PPAR-gamma agonist are formulated into a single dosage form comprising the compound of Structure (I) and the PPAR-gamma agonist.

51. The method of any one of claims 37-50, wherein the compound of Structure (I) and the anticancer therapeutic agent are formulated into a single dosage form comprising the compound of Structure (I) and the anticancer therapeutic agent.

52. The method of claim 50 or 51, wherein the single dosage form further comprises a pharmaceutical excipient.

53. The method of claim 50 or 51, wherein the pharmaceutical excipient is beta- cyclodextrin.

54. The method of any one of claims 33-49, wherein the compound of Structure (I) and the PPAR-gamma agonist are formulated into separate dosage forms and administered to the subject in need thereof at about the same time.

55. The method of any one of claims 37-50, wherein the compound of Structure (I) and the anticancer therapeutic agent are formulated into separate dosage forms and administered to the subject in need thereof at about the same time.

56. The method of any one of claims 1-55, wherein the compound of Structure (I) is a deuterated form thereof.

57. The method of any one of claims 1-56, wherein the compound of Structure (I) has the following structure:or a pharmaceutical salt, tautomer, stereoisomer, or prodrug thereof, wherein:D is deuterium.

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