WO2025199359A1

WO2025199359A1 - Methods of modulating cdk7 and flt3 using fused bicyclic compounds

Info

Publication number: WO2025199359A1
Application number: PCT/US2025/020755
Authority: WO
Inventors: Mohan KAADIGE; Srinivas KASIBHATLA; Trason THODE; Alexis WESTON; Sunil Sharma; Guido Marcucci; Le Xuan TRUONG NGUYEN
Original assignee: Translational Genomics Research Institute TGen; City of Hope
Current assignee: Translational Genomics Research Institute TGen; City of Hope
Priority date: 2024-03-21
Filing date: 2025-03-20
Publication date: 2025-09-25
Anticipated expiration: 2026-09-21

Abstract

The present disclosure generally relates to uses and method of administering compounds (e.g., CDK7 inhibitors, FLT3 inhibitors, venetoclax, and/or hypomethylating agents) as therapeutic agents, for treatment of hematological malignancies.

Description

METHODS OF MODULATING CDK7 AND FLT3 USING FUSED BICYCLIC COMPOUNDS BACKGROUND

Technical Field

Embodiments of the present disclosure are generally directed to uses and methods of administering compounds as therapeutic or prophylactic agents, for example for treatment of hematological malignancies.

Background

Acute Myeloid leukemia (AML) is an aggressive malignancy of the hematopoietic system with poor survival rates. The best responses to treatment are achieved for young and fit patients who can tolerate chemotherapy followed by stem cell transplantation compared to older patients unfit to take intense chemotherapy. Since its approval venetoclax, a BCL2 inhibitor, has been the standard treatment for older patients in combination with a hypomethylating agent (HMA), such as azacitidine or decitabine, with a 76% complete response (CR). Despite this success as a frontline treatment, there is limited response for patients with relapse and refractory (r/r) and development of novel agents is required to improve overall therapeutic response. MYC has been shown to be frequently activated in AML and plays an important role in the induction of leukemogenesis and leukemic progression. While BCL2 inhibition via venetoclax has, in part, been shown to control c-MYC activation, the addition of another inhibitor which controls MYC may prove beneficial. CDK7 plays a dual role in tumor progression by regulating the cell cycle and transcription. CDK7 has also been shown to be associated with the overexpression of oncogenic driver genes such as BCL2 and MYC. The present disclosure shows data supporting the potential benefit of CDK7 inhibition in combination with standard of care therapy for AML.

Accordingly, there is a need to develop inhibitors that can be used for treating hematological malignancies (e.g., leukemia). Embodiments of the present disclosure fulfill this need and provide further related advantages.

Brief Description

In brief, embodiments of the present disclosure provide uses and method for administering compounds, including pharmaceutically acceptable salts, tautomers, stereoisomers, and prodrugs thereof, that are capable of inhibiting CDK7 and/or FLT3. In one embodiment provides a method for treating a hematological malignancy comprising administering an effective amount of a compound having the following structure: or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, to a subject in need thereof, wherein: represents an aromatic ring such that all valences are satisfied;

X¹ is C and X² is N; or X¹ is N and X² is C;

R¹ is a C1-C4 alkyl or C3-C4 cycloalkyl;

R² is 5-7 membered N-heterocyclyl, each of which is optionally substituted with one or more substituents selected from the group consisting of -NH2, -OH;

R³ is phenyl that is optionally substituted with one or more substituents selected from the group consisting of C1-C3 alkyl, cyano, C1-C3 haloalkyl, halo, C1-C3 alkoxy, and C1-C3 haloalkoxy;

L¹ is -O-, -NH-, or -CH2NH-; and

L² is a direct bond or C1-C4 alkylene.

Another embodiment provides a method of modulating cyclin-dependent kinase 7 (CDK7) and FMS-like tyrosine kinase 3 (FLT3) in a hematological malignancy comprising administering an effective amount of a compound having the following Structure (I): or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, to a subject in need thereof, wherein: represents an aromatic ring such that all valences are satisfied;

X¹ is C and X² is N; or X¹ is N and X² is C;

R¹ is a C1-C4 alkyl or C3-C4 cycloalkyl; R² is 5-7 membered N-heterocyclyl, each of which is optionally substituted with one or more substituents selected from the group consisting of -NH2, -OH;

L¹ is -O-, -NH-, or -CH2NH-; and

L² is a direct bond or C1-C4 alkylene.

One embodiment provides a method of modulating cyclin-dependent kinase 7 (CDK7) and FMS-like tyrosine kinase 3 (FLT3) comprising contacting a leukemia cell with an effective amount of a compound having the following Structure (I): or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, to a subject in need thereof, wherein: represents an aromatic ring such that all valences are satisfied;

X¹ is C and X² is N; or X¹ is N and X² is C;

R¹ is a C1-C4 alkyl or C3-C4 cycloalkyl;

L¹ is -O-, -NH-, or -CH2NH-; and

L² is a direct bond or C1-C4 alkylene.

Detailed Description

In the following description, certain specific details are set forth 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. 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."

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. 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.

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 features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

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.

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. "Alkyl" refers to a saturated, straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms (C1-C12 alkyl), one to eight carbon atoms (Ci-Cs alkyl) or one to six carbon atoms (Ci-Ce alkyl), or any value within these ranges, such as C4-C6 alkyl and the like, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, //-propyl, 1 -methylethyl (/.w-propyl), //-butyl, //-pentyl, 1,1 -dimethylethyl (7-butyl), 3 -methylhexyl, 2-methylhexyl and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted.

"Alkoxy" refers to a radical of the formula -ORa where R is an alkyl radical as defined above containing one to twelve carbon atoms (C1-C12 alkoxy), one to eight carbon atoms (Ci-Cs alkoxy) or one to six carbon atoms (Ci-Ce alkoxy), or any value within these ranges. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.

"Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to twelve carbon atoms, e.g., methylene, methylmethylene, ethylene, propylene, //-butylene, ethenylene, propenylene, //-butenylene, propynylene, //-butynylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, alkylene is optionally substituted.

"Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic carbocyclic radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen ring carbon atoms (C3-C15 cycloalkyl), from three to ten ring carbon atoms (C3-C10 cycloalkyl), or from three to eight ring carbon atoms (C3-C8 cycloalkyl), or any value within these ranges such as three to four carbon atoms (C3-C4 cycloalkyl), and which is saturated or partially unsaturated and attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group is optionally substituted. The term "N-heterocyclyl" refers to a 3- to 18-membered, for example 3- to 10-membered or 3- to 8-membered, non-aromatic ring radical having at least one ring nitrogen, one to ten ring carbon atoms (e.g., two to ten) and from one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is partially or fully saturated and is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused, spirocyclic and/or bridged ring systems. Nitrogen, carbon and sulfur atoms in a heterocyclyl radical are optionally oxidized, and nitrogen atoms may be optionally quaternized. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, hexahydro- IH-pyrrolizine, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl group is optionally substituted.

The term "cyano" refers to a -C=N radical.

"Halo" refers to bromo, chloro, fluoro, or iodo.

"Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, tri chloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted.

"Haloalkoxy" refers to a radical of the formula -ORa where Ra is an haloalkyl radical as defined above containing one to twelve carbon atoms (C1-C12 alkoxy), one to eight carbon atoms (Ci-Cs alkoxy) or one to six carbon atoms (Ci-Ce alkoxy), or any value within these ranges. Unless stated otherwise specifically in the specification, a haloalkoxy group is optionally substituted.

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.

The term "co-administration," "administered in combination with," 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 subj ect at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

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

"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- di chloroacetic 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-l,5-disulfonic acid, naphthal ene-2-sulfonic acid, l-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.

"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, or allergic 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.

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

The term "inhibitor" refers to a compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the protein, such as CDK7 and/or FLT3. Accordingly, the term "inhibitor" is defined in the context of the biological role of the target protein. While preferred inhibitors herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity modulated by an inhibitor is associated with the development, growth, or spread of a tumor. "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.

"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.

"Prodrug" is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein (e.g., a compound of Structure (I)). 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 Pergam on 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.

The term "in vivo" refers to an event that takes place in a subject's body.

Embodiments disclosed herein are also meant to encompass all pharmaceutically acceptable forms of compounds of Structure (I).

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, such as 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.

"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

Often crystallizations produce a solvate of the compounds disclosed herein. As used herein, the term "solvate" refers to an aggregate that comprises a compound of Structure (I), venetoclax, and/or a hypomethylating agent with one or more molecules of solvent. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Thus, the compounds of the present disclosure may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. In some embodiments, a compound of Structure (I), venetoclax, and/or a hypomethylating agent are a true solvate, while in other cases, a compound of Structure (I), venetoclax, and/or a hypomethylating agent merely retain adventitious water or is a mixture of water plus some adventitious solvent.

A "pharmaceutical composition" refers to formulations of a compound of Structure (I), venetoclax, and/or a hypomethylating agent and a medium generally accepted in the art for the delivery of a compound of Structure (I), venetoclax, and/or a hypomethylating agent to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients therefor.

"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.

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. The compounds of Structure (I) 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.

Embodiments of the present disclosure include all manner of rotamers and conformationally restricted states of a compound of the disclosure. Atropisomers, which are stereoisomers 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 (e.g., compounds of Structure (I)) may exist as mixtures of atropisomers or purified or enriched for the presence of one atropisomer.

In some embodiments, a compound of Structure (I) refers to a mixture of enantiomers or diastereomers. In other embodiments, a compound of Structure (I) refers to substantially one enantiomer or diastereomer.

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 Profesional 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.

Compounds

The present disclosure is generally directed to the treatment of hematological malignancies using a novel inhibitor of CDK7 and FLT3. More specifically, in some embodiments the small molecule compound is used in combination with venetoclax and/or a hypomethylating agent for treating acute myeloid leukemia.

Without wishing to be bound by theory, it is thought that interference with CDK7 and/or

FLT3 can arrest growth of cancer cells and cancer stem cells by modulation of cell cycle and super-enhancer dependent oncogene expression. The compounds of Structure (I) are best-in- class, potent, selective, reversible inhibitors with robust in vivo efficacy.

Venetoclax (CAS Registry Number 1257044-40-8) has the following structure:

Azacitidine (CAS Registry Number 320-67-2) has the following structure:

Decitabine (CAS Registry Number 2353-33-5) has the following structure: When referring to any one of the foregoing compounds, it is understood that pharmaceutically acceptable salts, stereoisomers, tautomers, and prodrugs are to be included.

The present disclosure shows compounds of Structure (I) have activity at low doses in AML models. In addition, compounds show synergy between compounds of Structure (I) and other agents for AML treatment, including venetoclax, an HMA, and combinations thereof. Western blotting demonstrates significant changes in apoptotic markers. Survival of mice bearing AML is significantly increased with compounds of Structure (I) treatment and combination treatment with venetoclax produce the longest survival.

Targeting CDK7 with compounds of Structure (I) in combination with venetoclax or an HMA is a promising therapeutic approach for treatment of AML.

In some embodiments, R¹ is unsubstituted iso-propyl, unsubstituted cyclopropyl, or unsubstituted cyclobutyl.

In certain embodiments, R² is optionally substituted piperidinyl, unsubstituted azepanyl, morpholino, or cyclohexyl substituted with -NH2. In some embodiments, R² has one of the following structures:

In some embodiments, R²-L'- has one of the following structures:

In certain embodiments, R³ is phenyl substituted with one or two substituents selected from the group consisting of -CH3, -CF3, -CN, -F, -Cl, -OCH3, and -OCF3.

In some embodiments, L² is a direct bond, -CH2-, or -C(CH3)H-. In some embodiments, the compound has one of the structures set forth in Table 1 below or a pharmaceutically acceptable salt or prodrug thereof.

Table 1: Representative compounds of Structure (I) t Also obtained as an HC1 salt

¹ Also obtained as a formic acid salt

Pharmaceutical Compositions

Other embodiments are directed to pharmaceutical compositions. The pharmaceutical composition comprises anyone (or more) of the foregoing compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In still more embodiments, the pharmaceutical compositions comprise a compound as disclosed herein and an additional therapeutic agent (e.g., anticancer agent). Non-limiting examples of such therapeutic agents are described herein below.

In some embodiments, the compounds 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 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 & Wilkinsl999).

Provided herein are pharmaceutical compositions comprising a compound of Structure (I), venetoclax, and/or a hypomethylating agent, and a pharmaceutically acceptable carrier. Provided herein are pharmaceutical compositions comprising a compound of Structure (I), venetoclax, and/or a hypomethylating agent and pharmaceutically acceptable diluent(s), excipient(s), and carrier(s). In certain embodiments, the compounds described are administered as pharmaceutical compositions in which a compound of Structure (I), venetoclax, and/or a hypomethylating agent are mixed with other active ingredients, as in combination therapy. Encompassed herein are all combinations of actives set forth in the combination therapies section below and throughout this disclosure. In specific embodiments, the pharmaceutical compositions include a compound of Structure (I), venetoclax, and/or a hypomethylating agent.

A pharmaceutical composition, as used herein, refers to a mixture of a compound of Structure (I), venetoclax, and/or a hypomethylating 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 the compound to an organism. In some embodiments, therapeutically effective amounts of a compound of Structure (I), venetoclax, and/or a hypomethylating agent provided herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or medical condition to be treated. In specific embodiments, the mammal 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 the compound used and other factors. The compounds described herein are used singly or in combination with one or more therapeutic agents as components of mixtures.

In one embodiment, a compound of Structure (I), venetoclax, and/or a hypomethylating agent are formulated in aqueous solutions. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer. In other embodiments, a compound of Structure (I), venetoclax, and/or a hypomethylating agent are formulated for transmucosal administration. In specific embodiments, transmucosal formulations include penetrants that are appropriate to the barrier to be permeated. In still other embodiments wherein the compounds described herein are formulated for other parenteral injections, appropriate formulations include aqueous or non-aqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and/or excipients.

In another embodiment, compounds described herein 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, the compounds described herein 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.

In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds 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 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.

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.

In certain embodiments, therapeutically effective amounts of at least one of the compounds 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 one or more active compound that is 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.

In still other embodiments, the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations. In still other embodiments, the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles. Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and/or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In additional embodiments, suspensions of a compound of Structure (I), venetoclax, and/or a hypomethylating agent are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent, or excipient, and a compound of Structure (I), venetoclax, and/or a hypomethylating agent, 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 N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass un-solvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented 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.

Methods for the preparation of compositions comprising the compounds 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 contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.

In some embodiments, pharmaceutical compositions comprising a compound of Structure (I), venetoclax, and/or a hypomethylating agent illustratively takes the form of a liquid where the agents are present in solution, in suspension or both. Typically, when the composition is administered as a suspension, a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.

In certain embodiments, aqueous suspensions contain one or more polymers as suspending agents. Polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.

Pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a compound of Structure (I), venetoclax, and/or a hypomethylating agent. The term "solubilizing agent" generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

Furthermore, pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric, and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

Compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

Other pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

Compositions may include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.

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.

In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.

In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, the compounds described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.

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.

In some embodiments, the concentration of a compound of Structure (I), venetoclax, and/or a hypomethylating agent provided 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.

In some embodiments, the concentration of a compound of Structure (I), venetoclax, and/or a hypomethylating agent 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%, approximately 0.05% 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.

In some embodiments, the amount the a compound of Structure (I), venetoclax, and/or a hypomethylating agent 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.

In some embodiments, the amount of the a compound of Structure (I), venetoclax, and/or a hypomethylating agent 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.

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.

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/or devices) desirable from a commercial and user standpoint for use of a compound described herein. Nonlimiting 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 provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

Uses and Methods of Treatment

The present disclosure is generally directed to uses of compositions and method of treating acute myeloid leukemia (AML). It has been unexpectedly discovered that a combination of a CDK7 /FLT3 inhibitor, venetoclax, and/or hypomethylating agent (e.g., decitabine or azacitidine) shows excellent efficacy in treating AML. As a blood and bone marrow cancer, AML generally progresses rapidly and affects a group of white blood cells called myeloid cells. As used herein, the phrase "acute myeloid leukemia" is also known as (and encompasses) acute myeloblastic leukemia, acute granulocytic leukemia, and acute non-lymphocytic leukemia.

As used herein, the term "hematological malignancy" encompasses cancers of the blood and bone marrow.

One embodiment provides a method for treating a hematological malignancy comprising administering an effective amount of a compound having the following structure: or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, to a subject in need thereof, wherein: represents an aromatic ring such that all valences are satisfied;

X¹ is C and X² is N; or X¹ is N and X² is C;

L¹ is -O-, -NH-, or -CH2NH-; and

L² is a direct bond or C1-C4 alkylene.

X¹ is C and X² is N; or X¹ is N and X² is C;

R¹ is a C1-C4 alkyl or C3-C4 cycloalkyl;

L¹ is -O-, -NH-, or -CH2NH-; and

L² is a direct bond or C1-C4 alkylene.

In some embodiments, the method further comprises administering venetoclax. In certain embodiments, the method further comprises administering a hypomethylating agent. In some embodiments, the hypomethylating agent is azacitidine or decitabine.

In certain embodiments, the hematological malignancy is leukemia. In some embodiments, the hematological malignancy is acute myeloid leukemia. In certain embodiments, the hematological malignancy is relapse or refractory acute myeloid leukemia. In some embodiments, the administering of the compound, the venetoclax, the hypomethylating agent, or any combination thereof is via a subcutaneous injection.

X¹ is C and X² is N; or X¹ is N and X² is C;

R¹ is a C1-C4 alkyl or C3-C4 cycloalkyl;

L¹ is -O-, -NH-, or -CH2NH-; and

L² is a direct bond or C1-C4 alkylene.

In some embodiments, the method further comprises contacting the leukemia cell with venetoclax. In certain embodiments, the method further comprises contacting the leukemia cell with a hypomethylating agent. In some embodiments, the hypomethylating agent is azacitidine or decitabine. In certain embodiments, the leukemia cell is acute myeloid leukemia cell. In some embodiments, the leukemia cell is relapse or refractory acute myeloid leukemia. In certain embodiments, the leukemia cell is a MV4-11 cell.

The host 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. Embodiments of the disclosure also relate to the use of a compound of Structure (I), venetoclax, and/or a hypomethylating agent and/or physiologically acceptable salts thereof for the prophylactic or therapeutic treatment and/or monitoring of diseases that are caused, mediated, and/or modulated by CDK7 and/or FLT3 activity. Furthermore, embodiments of the disclosure relate to the use of a compound of Structure (I), venetoclax, and/or a hypomethylating agent and/or physiologically acceptable salts thereof to produce a medicament for the prophylactic or therapeutic treatment and/or monitoring of diseases that are caused, mediated, and/or modulated by CDK7 and/or FLT3. In certain embodiments, the disclosure provides the use of a compound of Structure (I), venetoclax, and/or a hypomethylating agent or physiologically acceptable salts thereof, to produce a medicament for the prophylactic or therapeutic treatment of a CDK7- and/or FLT3-mediated disorder.

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.

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.

In treatment methods according to embodiments of the disclosure, an effective amount of a compound of Structure (I), venetoclax, and/or a hypomethylating 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.

The compounds according to the disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, 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.

In some embodiments, a compound of Structure (I), venetoclax, and/or a hypomethylating agent are administered in a single dose. Typically, such administration will be by injection, e.g., intravenous injection, 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.

In some embodiments, a compound of Structure (I), venetoclax, and/or a hypomethylating agent 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. In another embodiment, a compound of Structure (I), venetoclax, and/or a hypomethylating agent and another agent (e.g., anti-cancer agent) are administered together about once per day to about 6 times per day. In another embodiment the administration of a compound of Structure (I), venetoclax, and/or a hypomethylating agent and an agent 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.

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

In some embodiments, a compound of Structure (I), venetoclax, and/or a hypomethylating agent are administered in individual dosage forms. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy.

Also included herein are methods of treatment in which a compound of Structure (I), venetoclax, and/or a hypomethylating agent is administered in combination with an antiinflammatory or a therapeutic agent. Anti-inflammatory agents include but are not limited to NS AIDs, non-specific and COX-2 specific cyclooxygenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor (TNF) antagonists, immunosuppressants and methotrexate. Examples of NS AIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine.

Examples of NSAIDs also include COX-2 specific inhibitors such as celecoxib, valdecoxib, lumiracoxib dnd/or etoricoxib.

In some embodiments, the anti-inflammatory agent is a salicylate. Salicylates include by are not limited to acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example, the corticosteroid may be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, or prednisone.

In additional embodiments the anti-inflammatory agent is a gold compound such as gold sodium thiomalate or auranofin.

The disclosure also includes embodiments in which the anti-inflammatory agent is a metabolic inhibitor such as a dihydrofolate reductase inhibitor, such as methotrexate or a dihydroorotate dehydrogenase inhibitor, such as leflunomide.

Therapeutic agents can also include agents for pain and inflammation such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine (serotonin), lipid substances that are generated by biotransformation of the products of the selective hydrolysis of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatory agents, analgesic-antipyretic agents, agents that inhibit the synthesis of prostaglandins and thromboxanes, selective inhibitors of the inducible cyclooxygenase, selective inhibitors of the inducible cyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin, cytokines that mediate interactions involved in humoral and cellular immune responses, lipid-derived autacoids, eicosanoids, P-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers and leukotriene inhibitors.

Other embodiments of the disclosure pertain to combinations in which at least one antiinflammatory compound is an anti-monoclonal antibody (such as eculizumab or pexelizumab), a TNF antagonist, such as entanercept, or infliximab, which is an anti-TNF alpha monoclonal antibody.

Therapeutic agents used in combination with the compounds of Structure (I) can also include small molecule compounds that inhibit the activation of NLRP3 inflammasomes, such as MCC950, sulforaphane, iisoliquiritigenin, P-hydroxybutyrate, flufenamic acid, mefenamic acid, 3, 4-m ethylenedi oxy-P-nitrostyrene (MNS), and parthenolide.

Still other embodiments of the disclosure pertain to combinations in which at least one active agent is an immunosuppressant compound such as an immunosuppressant compound chosen from methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, and my cophenolate mofetil.

The disclosed compounds of Structure (I) can be administered in combination with other known therapeutic agents, including anticancer agents. As used here, the term "anticancer agent" relates to any agent which is administered to a patient with cancer for the purposes of treating the cancer.

In some embodiments the anti-cancer agents belong to the following categories - Alkylating agents: such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine, carboquone; apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, TH-3024, VAL-0834;

Platinum Compounds: such as carboplatin, cisplatin, eptaplatin, miriplatine hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin;

DNA altering agents: such as amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine, brostallicin, pixantrone, laromustine 1,3 ;

Topoisomerase Inhibitors: such as etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; amonafide, belotecan, elliptinium acetate, voreloxin;

Microtubule modifiers: such as cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; fosbretabulin, tesetaxel; Antimetabolites: such as asparaginase3, azacitidine, calcium levofolinate, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, elacytarabine, raltitrexed, sapacitabine, tegafur2,3 , trimetrexate;

Anticancer antibiotics: such as bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunurobicin, plicamycin; aclarubicin, peplomycin, pirarubicin;

Hormones/Antagonists: such as abarelix, abiraterone, bicalutamide, buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone, estradiol, fluocortolone fluoxy me sterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane, triptorelin, diethylstilbestrol; acolbifene, danazol, deslorelin, epitiostanol, orteronel, enzalutamide 1,3;

Aromatase inhibitors: such as aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestane;

Small molecule kinase inhibitors: such as crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tipifamib, tivantinib, tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib.

In some embodiments, medicaments which are administered in conjunction with the compounds described herein include any suitable drugs usefully delivered by inhalation for example, analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem; antiallergics, e.g. cromoglycate, ketotifen or nedocromil; anti- infectives, e.g. cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines or pentamidine; antihistamines, e.g. methapyrilene; anti-inflammatories, e.g. beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide or fluticasone; antitussives, e.g. noscapine; bronchodilators, e.g. ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutalin, isoetharine, tulobuterol, orciprenaline or (-)-4-amino-3,5- dichloro-a-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol; diuretics, e.g. , amiloride; anticholinergics, e.g., ipratropium, atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone or prednisolone; xanthines, e.g., aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides, e.g., insulin or glucagon. It will be clear to a person skilled in the art that, where appropriate, the medicaments are used in the form of salts (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimize the activity and/or stability of the medicament.

The agents disclosed herein, or other suitable agents are administered depending on the condition being treated. Hence, in some embodiments the one or more compounds of the disclosure (e.g., compounds of Structure (I)) will be co-administered with other agents as described above. When used in combination therapy, the compounds described herein are administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the disclosure and any of the agents described above can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, a compound of the present disclosure can be administered just followed by and any of the agents described above, or vice versa. In some embodiments of the separate administration protocol, a compound of the disclosure and any of the agents described above are administered a few minutes apart, or a few hours apart, or a few days apart.

In some embodiments, a compound of Structure (I), venetoclax, and/or a hypomethylating agent are administered as a monotherapy.

The methods of embodiments of the disclosure can be performed either in vitro or in vivo. The susceptibility of a particular cell to treatment with a compound of Structure (I), venetoclax, and/or a hypomethylating agent can be particularly determined by in vitro tests, whether during research or clinical application. Typically, a culture of the cell is combined with a compound of Structure (I), venetoclax, and/or a hypomethylating agent at various concentrations for a period which is sufficient to allow the active agents to inhibit a target protein, 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. In some embodiments, the IC50 of a compound of Structure (I), venetoclax, and/or a hypomethylating agent to inhibit CDK7 and/or FLT3 was determined by the concentration of the compound required to inhibit 50% of the activity of the target protein.

The examples and preparations provided below further illustrate and exemplify the compounds of the present disclosure and methods of preparing and testing such compounds. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations. In the following examples, and throughout the specification and claims, molecules with a single stereocenter, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more stereocenters, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.

EXAMPLES

AML lines are co-treated with compounds of Structure (I), venetoclax, and/or an HMA, assessed for viabilities with CellTiter-Glo, and analyzed with the Bliss synergy model. AML CDX or PDX cells are implanted subcutaneously or transplanted via tail vein, respectively, and treated with compounds of Structure (I) and/or venetoclax. Subcutaneous tumors are measured to determine tumor growth inhibition (TGI) and correlating drug accumulation levels are measured in tumors and plasma using mass spectrometry. Leukemic burden and survival are evaluated at the end of treatment for transplanted models. Immunohistochemistry (IHC), Western blotting, and RT-PCR are performed to determine changes in relevant biomarkers in tumors and/or AML cell lines.

Methods of Preparation

Compounds of Structure (I) can be prepared according to methods known in the art and according to methods disclosed herein. In general, starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5^th edition (Wiley, December 2000)). Specifically, synthetic procedures for compounds of Structure (I) can be found in PCT Publication Nos. WO 2020/186196 and/or WO 2022/061155, which are hereby incorporated by reference for the synthetic procedures described therein. It should be noted that various alternative strategies for preparation of a compound of Structure (I) are available to those of ordinary skill in the art. For example, a compound of Structure (I) can be prepared according to analogous methods using the appropriate starting material. It will also be appreciated by those skilled in the art that in the processes for preparing a compound of Structure (I), the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include, but are not limited to, hydroxy, amino, mercapto and carboxylic acid.

Suitable protecting groups for hydroxy include, but are not limited to, trialkylsilyl or diarylalkylsilyl (for example, t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethyl silyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl ("Boc"), benzyloxycarbonyl, and the like. Protecting groups are optionally added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill in the art would appreciate, the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although such protected derivatives of compounds may not possess pharmacological activity as such, they may be administered to a mammal and thereafter metabolized in the body to form a compound of Structure (I) that is pharmacologically active. Such derivatives may therefore be described as "prodrugs." Prodrugs of a compound of Structure (I) are included within the scope of embodiments of the disclosure.

The examples and preparations provided below further illustrate and exemplify a compound of Structure (I) and methods of preparing the same. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations. In the following examples, and throughout the specification and claims, molecules with a single stereocenter, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more stereocenters, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art. BIOLOGICAL EXAMPLE 1

CELL VIABILITY ASSAY

Materials:

• Cell Lines (Treated according to ATCC guidelines) • Cell Titer Gio (Promega Cat# G7572)

• DMSO

• 96-well White Tissue Culture Treated Plates (Perkin Elmer Cat# 60005680)

Cells were seeded in a white 96-well tissue culture treated plate at a density of 1500 cells in 90 pL of media per well and allowed to settle overnight. A ten-point serial dilution of drugs was prepared at 10x concentration in media with the final assay concentrations starting at 30 pM, 10 pM, 3 pM, 1 pM, 0.3 pM. . .0 pM. A dilution of DMSO was included as a control. The assay was set up by adding 10 pL of the corresponding drug to each well in duplicate, followed by a 72-hour incubation at 37°C, 5% CO2. Cell viability was quantified by adding 90 pL of Cell Titer Gio to each well and incubating at room temperature for 10 minutes. The reaction was quantified by measuring luminescence using the Envision Plate Reader. Data was analyzed using Graphpad Prism 7 software.

Table A: List of compounds and IC50 values in J1M for AML cancer cell lines

++++ indicates an IC50 value from 0 up to 0.5 pM

+++ indicates an IC50 value above 0.5 up to 1 pM

++ indicates an IC50 value above 1 up to 5 pM

+ indicates an IC50 value above 5 up to 11.5 pM

BIOLOGICAL EXAMPLE 2

FLT3 INHIBITION

Representative compounds were tested for FLT3 inhibition to determine IC50 values. A biochemical enzymatic assay was used to determine FLT3 inhibition according to the following protocol. FLT3 (h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 50 pM EAIYAAPFAKKK, 10 mM Mg acetate and [gamma-33P]- ATP (specific activity and concentration as required). The reaction is initiated by the addition of the Mg/ ATP mix. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of phosphoric acid to a concentration of 0.5%. An aliquot of the reaction is then spotted onto a filter and washed four times for 4 minutes in 0.425% phosphoric acid and once in methanol prior to drying and scintillation counting. The assay was run as a 10-point curve, in duplicate for each compound and used the ATP Km for FLT3 (h).

Table B: Representative compounds and their IC50 values for FLT3 inhibition

+++ indicates an IC50 value from 0 up to 0.05 pM ++ indicates an IC50 value above 0.05 up to 0.1 pM

+ indicates an IC50 value above 0.1 up to 0.5 pM

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 are incorporated herein by reference, including U.S. Provisional Patent Application No. 63/568,370 filed March 21, 2024, and U.S. Provisional Patent Application No. 63/573,363 filed April 2, 2024, in their entirety to the extent not inconsistent with the present description. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications, and publications to provide yet further embodiments.

From the foregoing it will be appreciated that, although specific embodiments of the disclosure have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the disclosure. Accordingly, the disclosure is not limited except as by the appended claims.

Claims

1. A method for treating a hematological malignancy comprising administering an effective amount of a compound having the following structure: or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, to a subject in need thereof, wherein: represents an aromatic ring such that all valences are satisfied;

X¹ is C and X² is N; or X¹ is N and X² is C;

R¹ is a C1-C4 alkyl or C3-C4 cycloalkyl;

L¹ is -O-, -NH-, or -CH2NH-; and

L² is a direct bond or C1-C4 alkylene.

2. A method of modulating cyclin-dependent kinase 7 (CDK7) and FMS-like tyrosine kinase 3 (FLT3) in a hematological malignancy comprising administering an effective amount of a compound having the following Structure (I): or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, to a subject in need thereof, wherein: represents an aromatic ring such that all valences are satisfied;

X¹ is C and X² is N; or X¹ is N and X² is C;

R¹ is a C1-C4 alkyl or C3-C4 cycloalkyl;

L¹ is -O-, -NH-, or -CH2NH-; and

L² is a direct bond or C1-C4 alkylene.

3. The method of any one of claims 1-2, wherein the method further comprises administering venetoclax.

4. The method of any one of claims 1-3, wherein the method further comprises administering a hypomethylating agent.

5. The method of claim 4, wherein the hypomethylating agent is azacitidine or decitabine.

6. The method of any one of claims 1-5, wherein the hematological malignancy is leukemia.

7. The method of any one of claims 1-6, wherein the hematological malignancy is acute myeloid leukemia.

8. The method of any one of claims 1-7, wherein the hematological malignancy is relapse or refractory acute myeloid leukemia.

9. The method of any one of claims 1-8, wherein the administering of the compound, the venetoclax, the hypomethylating agent, or any combination thereof is via a subcutaneous injection.

10. A method of modulating cyclin-dependent kinase 7 (CDK7) and FMS-like tyrosine kinase 3 (FLT3) comprising contacting a leukemia cell with an effective amount of a compound having the following Structure (I): or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, to a subject in need thereof, wherein: represents an aromatic ring such that all valences are satisfied;

X¹ is C and X² is N; or X¹ is N and X² is C;

R¹ is a C1-C4 alkyl or C3-C4 cycloalkyl;

L¹ is -O-, -NH-, or -CH2NH-; and

L² is a direct bond or C1-C4 alkylene.

11. The method of claim 10, wherein the method further comprises contacting the leukemia cell with venetoclax.

12. The method of any one of claims 10-11, wherein the method further comprises contacting the leukemia cell with a hypomethylating agent.

13. The method of claim 12, wherein the hypomethylating agent is azacitidine or decitabine.

14. The method of any one of claims 10-12, wherein the leukemia cell is acute myeloid leukemia cell.

15. The method of any one of claims 10-14, wherein the leukemia cell is relapse or refractory acute myeloid leukemia.

16. The method of any one of claims 10-15, wherein the leukemia cell is a MV4-11 cell.

17. The method of any one of claims 1-16, wherein R¹ is unsubstituted iso-propyl, unsubstituted cyclopropyl, or unsubstituted cyclobutyl.

18. The method of any one of claims 1-17, wherein R² is optionally substituted piperidinyl, unsubstituted azepanyl, morpholino, or cyclohexyl substituted with -NH2.

19. The method of any one of claims 1-18, wherein R² has one of the following structures:

20. The method of any one of claims 1-19, wherein R²-L'- has one of the following structures:

21. The method of any one of claims 1-20, wherein R³ is phenyl substituted with one or two substituents selected from the group consisting of -CH3, -CF3, -CN, -F, -Cl, -OCH3, and - OCF3.

22. The method of any one of claims 1-21, wherein L² is a direct bond, -CH2-, or -C(CH₃)H-.

23. The method of any one of claims 1-22, wherein the compound of Structure (I) has one of the following structures:

or a pharmaceutically acceptable salt or prodrug thereof.