Methods for treating patients with hematological malignancies

Abstract

The present disclosure relates to compounds of Formula 1 and pharmaceutical compositions thereof for use in the treatment of cancer in a subject having a mutant form of NPM1, DNMT3A, RAS, or a combination thereof, or in particular in the treatment of subjects suffering from recurrent or refractory (R / R) acute myelogenous leukemia (AML).

Description

[0001] Cross-referencing related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 431,693, filed December 10, 2022, the disclosure of which is incorporated herein by reference in its entirety for all purposes. Background Technology

[0003] Acute myeloid leukemia (AML) is an aggressive hematologic disorder in which hematopoietic stem cells lose their ability to differentiate normally and continue to proliferate. AML is associated with a poor prognosis and has seen little progress in treatment over the past few decades. Various abnormalities, including FMS-like tyrosine kinase-3 (FLT3), nucleophosphorus protein 1 (NPM1), and rat sarcoma (RAS), have been observed in patients with AML. For example, mutations in the RAS oncogene, NRAS, and KRAS are frequently found in AML, occurring in 11% and 5% of patients, respectively, while FLT3 mutations are found in approximately 30% of adult AML cases. Activating mutations in FLT3, such as internal tandem repeats (ITD) in the proximal domain, account for approximately 25–30% of newly diagnosed AML cases and are associated with poor prognosis (British Journal of Hematology, 2003, 122, 523–538). FLT3 mutations are known to occur in approximately one-third of patients with acute myeloid leukemia (AML). Furthermore, despite the availability of several clinically available FLT3 inhibitors, resistant leukocytes have been observed in AML patients treated with these FLT3 inhibitors, indicating the presence of resistance (Cancer Science, 2020, Vol. 111: 312-322). Additionally, standard chemotherapy for acute myeloid leukemia (AML) does not target AML stem / progenitor cells, frequently leading to disease relapse and thus limiting long-term efficacy (Oncogene, 2010, Vol. 29: 5120-5134). Therefore, there is a need for compounds, compositions, and methods that can effectively treat patients with hematologic malignancies, such as AML carrying mutations like NPM1, DNMT3A, RAS, or combinations thereof. Summary of the Invention

[0004] In the embodiments, this disclosure provides compounds, pharmaceutical compositions, and methods for treating cancers such as acute myeloid leukemia in a subject having one or more mutations (e.g., as defined herein) by using a compound of formula (1) or a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, or a combination thereof.

[0005] In embodiments, this disclosure provides a method for treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, or a combination thereof, wherein the subject has a mutant form of NPM1, DNMT3A, RAS, or a combination thereof:

[0006]

[0007] In equation (1):

[0008] Ea is hydrogen, hydroxyl, or C1-4 alkoxy;

[0009] Eb is hydrogen, halogen, C1-4 alkyl, or C1-4 fluoroalkyl;

[0010] Ec and Ed are each independently hydrogen or hydroxyl groups;

[0011] X' is hydrogen or hydroxyl;

[0012] k is an integer from 1 to 2;

[0013] Each Q is independently a hydroxyl group, a halogen, a C1-4 alkyl group, a hydroxy-C1-4 alkyl group, or a C1-4 alkoxy group;

[0014] Z' is a monovalent functional group represented by equation (2);

[0015]

[0016] in:

[0017] Each A is independently selected from the group consisting of: hydroxyl, C1-4 alkyl, and hydroxyC1-4 alkyl, wherein at least one A is a C1-4 alkyl;

[0018] n is an integer from 1 to 2; and

[0019] L is hydrogen, C1-4 alkyl, hydroxyl, or hydroxyC1-4 alkyl.

[0020] In the embodiments, the compound of formula (1) is a compound of formula (3) or a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, or a combination thereof;

[0021]

[0022] In Equation 3:

[0023] Ef is fluorine, chlorine, bromine, or iodine;

[0024] Qo is hydroxyl, halogen, C1-4 alkyl, hydroxyC1-4 alkyl, or C1-4 alkoxy;

[0025] s is an integer from 1 to 2;

[0026] Ao is selected from the group consisting of: hydroxyl, C1-4 alkyl, and hydroxyC1-4 alkyl; and

[0027] t is an integer from 1 to 2.

[0028] In the embodiments, the compound of formula (1) is compound I.

[0029]

[0030] Or a pharmaceutically acceptable salt thereof, its solvate, its stereoisomer, its tautomer, or a combination thereof.

[0031] In the embodiments, the subjects had mutations in NPM1, DNMT3A, RAS, or combinations thereof, and additionally had a mutation in FLT3.

[0032] In this embodiment, the cancer is a blood cancer, such as leukemia.

[0033] In this embodiment, the leukemia is acute myeloid leukemia (AML). Attached Figure Description

[0034] Figure 1 The clinical responses of each patient treated with compound I are shown.

[0035] Figure 2 The treatment regimen of the combination of compound I and venetoclax is shown.

[0036] Figure 3 Clinical responses of individual patients treated with the combination of compound I and venetoclax are shown. Detailed Implementation

[0037] All publications, patents and patent applications (including any figures and appendices) herein are incorporated herein by reference in their entirety for all purposes, to the extent that each individual publication, patent or patent application, figure or appendice is specifically and individually incorporated herein by reference in its entirety for all purposes.

[0038] definition

[0039] For convenience, certain terms used in the specification, examples, and claims are concentrated herein. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0040] While it is believed that the following terms will be well understood by those skilled in the art, the following definitions are set forth in order to facilitate the interpretation of the subject matter currently disclosed.

[0041] Throughout this specification, the terms “about” and / or “approximately” may be used in conjunction with numerical values ​​and / or ranges. The term “about” should be understood to mean those values ​​close to the listed values. For example, “about 40 [units]” may mean within ±25% of 40 (e.g., 30 to 50), within ±20%, ±15%, ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1%, less than ±1%, or any other value or range of values ​​in or below it. Furthermore, given the definition of the term “about” provided herein, the phrases “less than about [a value]” or “greater than about [a value]” should be understood. The terms “about” and “approximately” are used interchangeably.

[0042] Throughout this specification, a number of numerical ranges are provided. It should be understood that these ranges encompass all subranges within them. Therefore, the range "50 to 80" includes all possible ranges within it (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values ​​within a given range can be endpoints of the ranges they encompass (e.g., the range 50-80 includes ranges with endpoints such as 55-80, 50-70, etc.).

[0043] As used herein, the verb "comprising" as used in this specification, claims, and their derivatives is used in its non-limiting sense to indicate items following the word, but does not exclude items not specifically mentioned. The invention may suitably "comprising," "compose of," or "substantially consist of" the steps, elements, and / or reagents described in the claims.

[0044] It should be further noted that the claims may be drafted to exclude any optional elements. Therefore, this statement is intended to serve as a basis for using exclusive terms such as "solely" or "only" or for using negative limitations in conjunction with the listed claim elements.

[0045] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments. However, those skilled in the art will understand that this disclosure may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context requires otherwise, throughout the following specification and claims, the words “comprise” and its variations, such as “comprises” and “comprising”, shall be interpreted in an open-ended, inclusive sense, meaning “including but not limited to”. Furthermore, the headings provided herein are merely for convenience and do not constitute an explanation of the scope or meaning of the claimed invention.

[0046] Combination therapy with another therapeutically active agent includes sequential, simultaneous, or continuous administration via the same or different routes in the same or different compositions and / or combinations. In some embodiments, the combination therapy optionally includes one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutically active compounds, and / or inert substances.

[0047] The term "combination therapy" refers to a first therapy comprising an active agent, such as compound I, in combination with one or more therapeutic active agents that can be used to treat, stabilize, prevent, and / or delay a disease or symptom. As used herein, the terms "drug combination," "therapeutic combination," or "combination" refer to a single dosage form containing at least two therapeutic active agents, or individual dosage forms containing at least two therapeutic active agents used together or individually in combination therapy. For example, one therapeutic active agent may be formulated into one dosage form or composition, and another therapeutic active agent may be formulated into a single or different dosage form or composition. In a specific example, one therapeutic active agent may be formulated into a solid oral dosage form or composition, while a second therapeutic active agent may be formulated into another oral dosage form or composition, including as a kit or from two kits.

[0048] Unless otherwise stated, the term "halogen" includes fluorine, chlorine, bromine or iodine, and may be, for example, fluorine or chlorine, but is not limited thereto.

[0049] The term "alkyl" refers to a saturated monovalent hydrocarbon group. The term "alkenyl" as used herein refers to a monovalent hydrocarbon group containing at least one carbon-carbon double bond, wherein each double bond may have an E- or Z- spatial configuration. The term "alkynyl" as used herein refers to a monovalent hydrocarbon group containing at least one carbon-carbon triple bond. Such alkyl, alkenyl, and alkynyl groups can be linear, i.e., straight-chained, or side-chained. As defined above, the number of carbon atoms in an alkyl group can be 1, 2, 3, 4, 5, or 6; or 1, 2, 3, or 4. Examples of alkyl groups include methyl, ethyl, propyl (including n-propyl and isopropyl), n-butyl, sec-butyl, butyl (including isobutyl and tert-butyl), pentyl (including n-pentyl, 1-methylbutyl, isopentyl, neopentyl, and tert-pentyl), and hexyl (including n-hexyl, 3,3-dimethylbutyl, and isohexyl). The double bond of the alkenyl group and the triple bond of the alkynyl group can each be in any position. Examples of alkenyl and alkynyl groups are vinyl, propenyl, propenyl (= allyl), butenyl, 2-methylpropenyl, 3-methylbutenyl, hexenyl, hexenyl, propenyl (= propynyl), butenyl, butenyl, hexenyl, and hexenyl (= 5-alkenyl). Where each of these compounds is sufficiently stable and suitable for the desired use, such as pharmaceutical substances, substituted alkyl groups, substituted alkenyl groups, and substituted alkynyl groups can be substituted at any position.

[0050] Unless otherwise stated, the term "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl group, and examples of monocyclic or polycyclic groups are monocyclic or bicyclic aliphatic groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantane-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-yl, or any suitable isomer thereof.

[0051] As used herein, the term "heterocyclic alkyl" means, unless otherwise specified, a substituted or unsubstituted monocyclic or polycyclic alkyl group containing at least one of O, N, and S (e.g., one to four heteroatoms). Examples of monoheterocyclic alkyl groups are piperazinyl, piperidinyl, piperazinyl-1-oxide, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, diazabicycloheptyl, diazabicyclooctane, and diazaspirooctane, as well as similar groups, but not limited thereto.

[0052] Unless otherwise stated, the term "heterobicycloalkyl" as used herein refers to a bicycloalkyl group containing one or more heteroatoms selected from O, N, and S, and includes fused heterobicycloalkyl and bridged heterobicycloalkyl groups. The term "bridged" as used herein refers to a valence bond, single atom, or unbranched chain of atoms connecting two different parts of a molecule. Furthermore, a pair of tertiary or more carbon atoms connected by a bridge is called a "bridgehead." In other words, a carbon atom that participates simultaneously as part of two or more rings is called a bridgehead, and the bond connected to these bridgeheads is called a bridge. The term "bridged compound" as used herein refers to a compound in which two or more rings share one or more carbon atom pairs.

[0053] Examples of fused heterobicycloalkyl groups include, but are not limited to, indole, quinoline, thiazo[4,5-b]-pyridine, quinoline, etc. Examples of bridged heterobicycloalkyl groups include, but are not limited to, 7- to 12-membered heterobicycloalkyl groups, such as diazabicyclo[2.2.1]heptane or diazabicyclo[3.2.1]octane.

[0054] Unless otherwise defined, the term "spiro" as used herein refers to two rings sharing one atom, wherein the two rings are not connected to each other by a bridge. Unless otherwise defined, the term "spirocycloalkyl" as used herein refers to a saturated carbon ring consisting of two rings sharing only one carbon atom as part of the ring. Examples of spirocycloalkyls include, but are not limited to, 7- to 12-membered spirocycloalkyls such as diazaspiro[2.5]octane. Unless otherwise defined, the term "heterospirocycloalkyl" refers to a spirocycloalkyl containing at least one heteroatom selected from O, N, and S. Unless otherwise defined, the expression "spirolinked" as used herein refers to a joint sharing one atom.

[0055] Unless otherwise stated, the term "aryl" as used herein refers to an aromatic group that may be substituted or not substituted, such as phenyl, biphenyl, naphthyl, tolyl, naphthyl, anthracene, or any suitable isomer thereof, but is not limited thereto.

[0056] "Pharmaceutically acceptable carriers, diluents, or excipients" include, but are not limited to, any adjuvant, carrier, excipient, gliding agent, sweetener, diluent, preservative, dye / coloring agent, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the United States Food and Drug Administration for use in humans or livestock as acceptable.

[0057] The term "pharmaceutically acceptable salt" includes both acid addition salts and base addition salts. Pharmaceutically acceptable salts include salts obtained by reacting an active compound acting as a base with an inorganic or organic acid to form a salt, such as salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts can be prepared by reacting a compound with a suitable inorganic or organic acid via any of a variety of known methods.

[0058] As used herein, the term "solvent" is used to describe a molecular complex that can exist as a compound according to the invention and one or more pharmaceutically acceptable solvent molecules. It refers to a molecular complex of a compound of the invention (or a pharmaceutically acceptable salt thereof) with one or more solvent molecules. Such solvent molecules can be those known or commonly used in the pharmaceutical field, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0059] In the embodiments, the therapeutic agent in the pharmaceutical composition may be provided in the form of a "solvent," wherein the solvate includes a hydrate.

[0060] As used in this article, "stereoisomer" refers to compounds that have the same molecular formula and the same atomic arrangement but differ in stereoscopic or optical appearance. In other words, stereoisomers are compounds with the same chemical composition but different three-dimensional arrangements (i.e., different arrangements of atoms or groups). Stereoisomers include geometric isomers, enantiomers, and partial stereoisomers.

[0061] As used herein, the term "geometric isomer" refers to a type of stereoisomer that depends on the orientation of functional groups in the molecule, and may be called a cis-trans isomer. Typically, these isomers contain non-rotatable double bonds, and the substituents in compounds containing double bonds can be in either E or Z form. For example, when a compound contains a 2-substituted cycloalkyl group, the compound can have a cis-trans form. When a compound of Formula 1 contains a bridging ring, the compound can exist as an exogenous or endogenous isomer.

[0062] As used herein, the term "chirality" refers to a molecule having a non-overlapping enantiomeric partner, and the term "chirality" as used herein refers to a molecule having an overlapping enantiomeric partner. The term "enantiomer" as used herein refers to the case where two optically active molecules are mirror-symmetric. That is, an enantiomer indicates an isomer that does not overlap with the original molecule and does not have any symmetry elements including a plane of symmetry and a center of symmetry, but has a stereocenter (chiral center). The term "diastereomer" as used herein refers to the case where a molecule having two or more chiral centers is not an enantiomer but a stereoisomer. Since compounds of Formula 1 according to one aspect of this disclosure may have a chiral center or an asymmetric carbon center (absence of carbon), the compound can exist as an enantiomer (R or S isomer), a racemic mixture, a diastereomer, or a mixture thereof, and all such isomers and mixtures are included within the scope of this disclosure. Optically active (R)- and (S)- isomers can be decomposed using relevant techniques or chiral synthons or chiral reagents.

[0063] As used herein, the term "structural isomer" refers to isomers having the same molecular formula but different atomic sequences, and may include tautomers. The term "tautomer" as used herein refers to structural isomers having different energy structures interchanged through a low-energy barrier. For example, photonic tautomers (also proton tautomers) include interconversions via photon transfer, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions via the rearrangement of some electrons in bound electrons. Compounds of Formula 1 according to one aspect and their stereoisomers or tautomers may exist in solvate form.

[0064] "Pharmaceutical composition" refers to formulations of the compounds disclosed herein and media generally accepted in the art for delivering bioactive compounds to mammals (e.g., humans). Such media include all pharmaceutically acceptable carriers, diluents, or excipients. The pharmaceutical compositions of the present invention can be formulated according to conventional methods, and various oral dosage forms (e.g., tablets, pills, powders, capsules, syrups, emulsions, microemulsions) or parenteral administration (e.g., intramuscular, intravenous, or subcutaneous administration) can be prepared in dosage forms.

[0065] When the pharmaceutical composition is prepared in an oral dosage form, examples of carriers or additives and excipients used include diluents, disintegrants, binders, lubricants, surfactants, suspending agents, or emulsifiers. When the pharmaceutical composition of the present invention is prepared in an injectable form, carriers or additives and excipients include water, saline, aqueous glucose solution, similar sugar solution, alcohol, ethylene glycol, ether (e.g., polyethylene glycol 400), oil, fatty acids and fatty acid esters, glycerides, surfactants, suspensions, or emulsifiers. Such formulation methods are well known to those skilled in the art of pharmaceuticals.

[0066] The term “treatment” means to relieve, reduce, delay, decrease, improve, or manage at least one symptom of a subject’s condition. The term “treatment” may also mean one or more of blocking, delaying onset (i.e., the period prior to the clinical manifestation of the condition), or reducing the risk of the occurrence or exacerbation of the condition.

[0067] "Effective amount" means the amount of the formulation according to the invention that is sufficient to affect such treatment when applied to a patient for the treatment of a state, condition, or symptom. "Effective amount" will vary depending on the active ingredient, the state, condition, or symptom to be treated and its severity, as well as the age, weight, physical condition, and responsiveness of the mammal to be treated.

[0068] The term “therapeuticly effective” when applied to dosage or amount refers to an amount of a compound or pharmaceutical formulation sufficient to produce the desired clinical benefit when administered to a patient in need.

[0069] As used in this article, "subject" can be a human, a non-human primate, a mammal, a rat, a mouse, a cow, a horse, a pig, a sheep, a goat, a dog, a cat, etc.

[0070] "Mammals" include humans, as well as domesticated animals such as laboratory animals (e.g., mice, rats, monkeys, dogs, etc.) and pets such as cats, dogs, pigs, cattle, sheep, goats, horses, rabbits, and non-domesticated animals such as wild animals.

[0071] Therapeutic uses

[0072] In the embodiments, this disclosure provides compounds, pharmaceutical compositions, and methods for treating cancers such as acute myeloid leukemia in a subject having one or more mutations (e.g., as defined herein) by using compounds of the disclosure (e.g., compounds of formula (1), formula (3), compound A, or compound I) or pharmaceutically acceptable salts thereof, solvates thereof, stereoisomers thereof, tautomers thereof, or combinations thereof.

[0073] The compounds, compositions thereof, and uses disclosed herein are described, for example, in U.S. Patent Nos. 10,870,639 and 11,292,786, International Application No. PCT / KR2021 / 015794 (published as WO2022 / 098083) and International Application No. PCT / KR2022 / 016095, the contents of each of which are hereby incorporated herein by reference in their entirety for all purposes.

[0074] In embodiments, this document provides a method for treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, or a combination thereof, wherein the subject has a mutant form of NPM1, DNMT3A, RAS, or a combination thereof:

[0075]

[0076] in:

[0077] R 1 It is hydrogen, halogen, hydroxyl, C 1- C4 alkoxy or -NR a R b ,

[0078] Where R a Rb and C are each independently hydrogen or C. 1- C4 alkyl;

[0079] R 2 It is hydrogen, halogen, cyano, nitro, amino, formamide, formyl, halogenated C 1- C4 alkyl or C 1- C4 alkyl;

[0080] R 3 It is hydrogen, halogen, hydroxyl, halogenated C 1- C4 alkyl, C 1- C4 alkyl, C 2- C4 alkenyl or C 2- C4 acetylenic group;

[0081] Each R 4 Independently, it can be hydrogen, halogen, hydroxyl, cyano, nitro, amino, or -S (=O). l -R c Halogenated C 1- C4 alkyl, C 1- C4 alkoxy, hydroxy C 1- C4 alkyl, C 1- C4 alkyl, C 2- C4 alkenyl, C 2- C4 ynyl group, -NR d R e -CO2R e or -CO-NR d R e ,

[0082] Where R c It is C 1- C4 alkyl or -NR d R e ,

[0083] R d Re and Re are independently hydrogen or C. 1- C4 alkyl,

[0084] I is an integer between 0 and 2; and

[0085] k is an integer from 0 to 4;

[0086] R 5 and R 6 Each of these elements independently is hydrogen, halogen, hydroxyl, nitro, amino, or C. 1- C4 alkoxy or C 1- C4 alkyl;

[0087] R 7 It is a hydroxyl C 1- C4 alkyl, C 1- C4 alkyl, C 2- C4 alkenyl, C 2- C4 ynyl group, C 3- C7 cycloalkyl or C 3- C9 heterocyclic alkyl,

[0088] Where C 3- C7 cycloalkyl or C 3- C9 heterocyclic alkyl groups are not substituted or replaced by halogens, C 1- C4 alkyl or halogenated C 1- C4 alkyl substitution; and

[0089] X is H or OH;

[0090] When X is OH, the compound represented by Formula 1 includes the tautomer structure represented by Formula 2.

[0091] Formula 2

[0092]

[0093] R in Equation 2 3 、R 4 And k is the same as that described in Formula 1;

[0094] Y is -(CH2) m -、-(CH2) m -O-(CH2) n -、-(CH2) m -CO-(CH2) n -、-(CH2) m -NR 8 -(CH2) n -or-(CH2) m -SO2-(CH2) n -,

[0095] Where R 8 Is it hydrogen or C? 1- C4 alkyl,

[0096] m and n are each an independent integer from 0 to 2; and

[0097] Z is represented by Equation 3;

[0098] Formula 3

[0099]

[0100] In Equation 3,

[0101] It is C 3- C 10 cycloalkyl or C 2- C 11 Heterocyclic alkyl groups;

[0102] R 9 It is a halogen, hydroxyl, cyano, nitro, amino, thiol, formyl, or halogenated C. 1- C4 alkyl, C 1- C4 alkoxy, straight-chain or branched hydroxyl group C 1- C4 alkyl, straight-chain or branched C 1- C4 alkyl, C 2- C4 alkenyl, C 2- C4 ynyl group, C 3- C 10 Cycloalkyl, C 2- C9 heterocyclic alkyl, hydroxyl C 2- C9 heterocyclic alkyl, straight-chain or branched hydroxyl group C 1- C4 alkyl carbonyl, -NR 10 R 11 -COR 12 -COOR 12 or -SO2R 13 ,

[0103] q is an integer between 0 and 5.

[0104] Among them when When it is piperazine or piperidine, q is not 0, and

[0105] Two or more R 9 Can be with Connected or fused to form 7- to 12-membered bicycloalkyl, heterobicycloalkyl, spirocycloalkyl, or spiroheterocycloalkyl;

[0106] R 10 and R 11 Each is independently hydrogen, hydroxyl group C 1- C4 alkyl, halogenated C1- C4 alkyl, C 1- C4 alkyl, C 2- C4 alkenyl or C 2- C4 acetylenic group;

[0107] R 12 It is hydrogen, hydroxyl, hydroxyl C 1- C4 alkyl, halogenated C 1- C4 alkyl, C 1- C4 alkyl, C 2- C4 alkenyl, C 2- C4 ynyl group, C 3- C 10 cycloalkyl or C 2- C9 heterocyclic alkyl;

[0108] R 13 It is a hydroxyl group, a halogenated C 1- C4 alkyl, C 1- C4 alkyl, C 2- C4 alkenyl, C 2- C4 ynyl group, C 3- C 10 Cycloalkyl, C 2- C9 heterocyclic alkyl, aryl, or -NR f R g ,and

[0109] R f and R g Each is independently either hydrogen or C. 1- C4 alkyl.

[0110] In embodiments, this document provides a method for treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (14) or a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, or a combination thereof, wherein the subject has a mutant form of NPM1, DNMT3A, RAS, or a combination thereof:

[0111]

[0112] in:

[0113] E a Is it hydrogen, hydroxyl, or C? 1- C4 alkoxy group;

[0114] E b represents hydrogen, halogen, or C. 1- C4 alkyl or C 1- C4 fluoroalkyl;

[0115] E c and E d Each is independently either hydrogen or hydroxyl;

[0116] X' is hydrogen or hydroxyl;

[0117] k is an integer from 0 to 4;

[0118] Each Q is independently a hydroxyl group, halogen, or C. 1- C4 alkyl, hydroxy C 1- C4 alkyl or C 1- C4 alkoxy; and

[0119] Z' is a monovalent functional group represented by Equation 15;

[0120] Formula 15

[0121]

[0122] In Equation 15, n is an integer from 1 to 8;

[0123] Each A is independently selected from hydroxyl, C 1- C4 alkyl and hydroxy C 1- The functional group of a C4 alkyl group, wherein when n is two or more, two of two or more A groups are linked to each other to form an alkylene bridge to form Z', said Z' being a 7- to 12-membered bridged heterocyclic bicyclic alkyl ring, or two A groups being spirolinked to form a 7- to 12-membered spiroheterocyclic alkyl ring; and

[0124] L represents hydrogen, C represents... 1- C4 alkyl, hydroxyl or hydroxyl C 1- C4 alkyl.

[0125] In embodiments, this document provides a method for treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, or a combination thereof, wherein the subject has a mutant form of NPM1, DNMT3A, RAS, or a combination thereof:

[0126]

[0127] In equation (1):

[0128] Ea is hydrogen, hydroxyl, or C1-4 alkoxy;

[0129] Eb is hydrogen, halogen, C1-4 alkyl, or C1-4 fluoroalkyl;

[0130] Ec and Ed are each independently hydrogen or hydroxyl groups;

[0131] X' is hydrogen or hydroxyl;

[0132] k is an integer from 1 to 2;

[0133] Each Q is independently a hydroxyl group, a halogen, a C1-4 alkyl group, a hydroxy-C1-4 alkyl group, or a C1-4 alkoxy group;

[0134] Z' is a monovalent functional group represented by equation (2);

[0135]

[0136] in:

[0137] Each A is independently selected from the group consisting of: hydroxyl, C1-4 alkyl, and hydroxyC1-4 alkyl, wherein at least one A is a C1-4 alkyl;

[0138] n is an integer from 1 to 2; and

[0139] L is hydrogen, C1-4 alkyl, hydroxyl, or hydroxyC1-4 alkyl.

[0140] In the embodiments of the method provided herein, E b It is a halogen, n is 2, and A is a methyl group.

[0141] In the embodiments of the methods provided herein, Z' is 3,5-dimethylpiperazin-1-yl.

[0142] In the embodiments of the method provided herein, E b It is chlorine or fluorine.

[0143] In the embodiments of the methods provided herein, the compound of formula (1) is the compound of formula (3) or a pharmaceutically acceptable salt thereof, its solvate, its stereoisomer, its tautomer, or a combination thereof;

[0144]

[0145] In Equation 3:

[0146] Ef is fluorine, chlorine, bromine, or iodine;

[0147] Qo is hydroxyl, halogen, C1-4 alkyl, hydroxyC1-4 alkyl, or C1-4 alkoxy;

[0148] s is an integer from 1 to 2;

[0149] Ao is selected from the group consisting of: hydroxyl, C1-4 alkyl, and hydroxyC1-4 alkyl; and

[0150] t is an integer from 1 to 2.

[0151] In the embodiments of the method provided herein, the compound of formula (1) is compound A:

[0152]

[0153] Or a pharmaceutically acceptable salt thereof, its solvate, its stereoisomer, its tautomer, or a combination thereof.

[0154] In the embodiments of the method provided herein, the compound of formula (1) is compound I.

[0155]

[0156] Or a pharmaceutically acceptable salt thereof, its solvate, its stereoisomer, its tautomer, or a combination thereof.

[0157] In the embodiments of the methods provided herein, the compounds of formula (1) are selected from the group consisting of:

[0158] 1) 5-Chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-fluoro-1H-indol-3-yl)pyrimidine-2-amine;

[0159] 2) 5-Chloro-4-(6-Chloro-1H-indol-3-yl)-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)pyrimidin-2-amine;

[0160] 3) 2-((2R,6S)-4-(3-((5-chloro-4-(6-fluoro-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl)-2,6-dimethylpiperazin-1-yl)ethanol;

[0161] 4)2-((2R,6S)-4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-

[0162] Cyclopropylbenzyl)-2,6-dimethylpiperazin-1-yl)ethanol;

[0163] 5) 2-((2R,6S)-4-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl)-2,6-dimethylpiperazin-1-yl)ethanol;

[0164] 6)(R)-5-chloro-N-(3-cyclopropyl-5-((3-methylpiperazin-1-yl)methyl)phenyl)-4-(1H-indol-3-yl)pyrimidine-2-amine;

[0165] 7)(R)-5-chloro-N-(3-cyclopropyl-5-((3-methylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidine-2-amine;

[0166] 8) 5-Chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidine-2-amine;

[0167] 9) 5-Chloro-N-(3-cyclopropyl-5-(((3S,5R)-3-ethyl-5-methylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidine-2-amine;

[0168] 10) 5-Chloro-N-(3-cyclopropyl-5-((3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine;

[0169] 11) N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidine-2-amine;

[0170] 12)N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-5-fluoro-4-(6-methyl-1H-indol-3-yl)pyrimidine-2-amine;

[0171] 13)N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(1H-indol-3-yl)-5-methylpyrimidin-2-amine;

[0172] 14) N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-5-methyl-4-(6-methyl-1H-indol-3-yl)pyrimidine-2-amine;

[0173] 15)N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine;

[0174] 16)(3-(5-chloro-2-((3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)amino)pyrimidin-4-yl)-1H-indol-6-yl)methanol;

[0175] 17) 5-Chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(5-methoxy-6-methyl-1H-indol-3-yl)pyrimidine-2-amine;

[0176] 18) 3-(5-chloro-2-((3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)amino)pyrimidin-4-yl)-6-methyl-1H-indole-5-ol;

[0177] 19) 3-(5-chloro-2-((3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)amino)pyrimidin-4-yl)-6-methylindoline-2-one;

[0178] 20) 5-Chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-methoxy-6-(6-methyl-1H-indol-3-yl)pyrimidine-2-amine;

[0179] 21) 5-Chloro-2-((3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)amino)-6-(6-methyl-1H-indol-3-yl)pyrimidin-4-ol;

[0180] 22)3-(5-chloro-2-((3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)amino)pyrimidin-4-yl)-6-methyl-1H-indole-7-ol;

[0181] 23)2-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-cyclopropyl-6-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenol;

[0182] 24) 4-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-cyclopropyl-6-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenol;

[0183] 25)(R)-5-chloro-N-(3-cyclopropyl-5-((3,3,5-trimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidine-2-amine;

[0184] 26)((2R,6R)-4-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl)-6-methylpiperazin-2-yl)methanol;

[0185] 27)(R)-5-chloro-N-(3-cyclopropyl-5-((5-methyl-4,7-diazaspiro[2.5]octane-7-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidine-2-amine;

[0186] 28) 5-Chloro-N-(3-cyclopropyl-5-(((3R,5R)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidine-2-amine;

[0187] 29) 5-Chloro-N-(3-cyclopropyl-5-(((3S,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidine-2-amine;

[0188] 30) 5-Chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,4,5-trimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidine-2-amine;

[0189] 31)(2R,6S)-4-(3-((5-chloro-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-cyclopropylbenzyl)-2,6-dimethylpiperazin-1-ol; and

[0190] 32)(2R,6S)-4-(3-cyclopropyl-5-((4-(6-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)benzyl)-2,6-dimethylpiperazin-1-ol.

[0191] In the embodiments of the methods provided herein, the cancer is a blood cancer.

[0192] In the embodiments of the methods provided herein, the blood cancer is leukemia.

[0193] In the embodiments of the methods provided herein, cancer is leukemia, such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute promyelocytic leukemia (APL), hairy cell leukemia, and chronic neutrophilic leukemia (CNL), etc.

[0194] In the embodiments of the methods provided herein, the leukemia is acute myeloid leukemia, acute lymphoblastic leukemia, or chronic myeloid leukemia.

[0195] In the embodiments of the methods provided herein, the leukemia is acute myeloid leukemia (AML).

[0196] In embodiments of the methods provided herein, acute myeloid leukemia (AML) is acute myeloid leukemia with an FLT3 mutation. In one embodiment, acute myeloid leukemia includes mutated FLT3 polynucleotide-positive myeloid leukemia, ITD-positive acute myeloid leukemia in the FLT3 gene, or acute myeloid leukemia with an FLT3 point mutation.

[0197] In the embodiments of the methods provided herein, AML is relapsed or treatment-refractory (R / R) AML.

[0198] In embodiments of the methods provided herein, AML is relapsed or refractory (R / R) AML with MDS-related changes.

[0199] In embodiments of the methods provided herein, prior treatments performed on the subject with chemotherapy, hematopoietic stem cell transplantation (HSCT) and / or other FLT3 inhibitors have failed.

[0200] In embodiments of the methods provided herein, the subject’s prior treatment with chemotherapy has failed.

[0201] In embodiments of the methods provided herein, prior therapy performed on the subject using hematopoietic stem cell transplantation (HSCT) failed.

[0202] In embodiments of the methods provided herein, the subject’s prior therapy with other FLT3 inhibitors failed.

[0203] In embodiments of the methods provided herein, prior therapy with a DNA demethylating agent (HMA) and other FLT3 inhibitors failed in the subject.

[0204] In embodiments of the methods provided herein, prior therapy performed on the subject using one or more chemotherapeutic agents and other FLT3 inhibitors has failed.

[0205] In embodiments of the methods provided herein, the subject has received one to eight prior cancer (e.g., AML) therapies, including one, two, three, four, five, six, seven, or eight prior therapies. In embodiments, the subject has received at least one prior cancer (e.g., AML) therapy. In embodiments, the subject has received at least two prior cancer (e.g., AML) therapies.

[0206] In embodiments of the methods provided herein, the subject has received prior therapy with a DNA demethylating agent (HMA). In these embodiments, the prior therapy with HMA has failed. Demethylating agents include, for example, azacitidine, decitabine, and combinations thereof. In these embodiments, the prior therapy with azacitidine, decitabine, or combinations thereof has failed.

[0207] In embodiments of the methods provided herein, the subject has received prior therapy with a chemotherapeutic agent. In embodiments, the prior therapy with the chemotherapeutic agent has failed. Chemotherapy agents include cytarabine, daunorubicin, idarubicin, doxorubicin, fludarabine, etc. In embodiments, the chemotherapeutic agent is cytarabine, daunorubicin, fludarabine, or a combination thereof. In embodiments, the chemotherapeutic agent is cytarabine, daunorubicin, or a combination thereof. In embodiments, the chemotherapeutic agent is cytarabine, daunorubicin, or a combination thereof.

[0208] In embodiments of the methods provided herein, the subject had received prior therapy with a Bcl-2 inhibitor (such as venetoclax). In one embodiment, the subject's prior therapy with a Bcl-2 inhibitor failed.

[0209] In embodiments of the methods provided herein, the subject has received prior therapy with an FLT-3 inhibitor (including, but not limited to, midostaurin, gilteritinib, and combinations thereof). In embodiments, the subject's prior therapy with an FLT-3 inhibitor (including, but not limited to, midostaurin, gilteritinib, and combinations thereof) has failed. In embodiments, the patient has received prior therapy with midostaurin. In embodiments, the patient has received prior therapy with gilteritinib. In embodiments, the patient has received prior therapy with both midostaurin and gilteritinib.

[0210] In the embodiments of the methods provided herein, the subjects had already received prior HSCT therapy.

[0211] In embodiments of the methods provided herein, the subject has a mutation in FLT3 and a mutation in NPM1, DNMT3A, RAS, or a combination thereof, or a mutation in RAS.

[0212] In embodiments of the methods provided herein, the subjects have mutations in NPM1, DNMT3A, and / or RAS.

[0213] In embodiments of the methods provided herein, the subjects had mutations in FLT3, NPM1, DNMT3A, and RAS.

[0214] In the embodiments of the methods provided herein, the subjects have a mutated form of NRAS.

[0215] In the embodiments of the methods provided herein, the subjects have a mutated form of KRAS.

[0216] In embodiments of the methods provided herein, the subjects had mutations in FLT3 and NPM1.

[0217] In embodiments of the methods provided herein, the subjects had mutations in FLT3, NPM1, and DNMT3A.

[0218] In embodiments of the methods provided herein, the subject has a mutated form of RAS, such as a mutated form of NRAS or a mutated form of KRAS.

[0219] In the embodiments of the methods provided herein, the subjects had a mutated form of RAS and wild-type FLT3.

[0220] In the embodiments of the methods provided herein, the subjects had mutations in both RAS and FLT3.

[0221] In embodiments of the methods provided herein, the mutated FLT3 comprises an internal tandem repeat (ITD) mutation and / or at least one FLT3 point mutation.

[0222] In embodiments of the methods provided herein, the FLT3 point mutation is performed on one or more residues selected from the group consisting of: D835, F691, K663, Y842, and N841.

[0223] In an embodiment, the FLT3 mutation may be an FLT3 mutation in an internal tandem repeat (ITD) or one or more activation point mutations, such as D835Y, D835V, or I836.

[0224] In the embodiments of the methods provided herein, the FLT3 point mutation is the F691L mutation.

[0225] In the embodiments of the methods provided herein, the FLT3 point mutation is an ITD-F691L double mutation.

[0226] In embodiments of the methods provided herein, the mutated FLT3 comprises at least one mutation in the tyrosine kinase domain of FLT3.

[0227] Mutations in FLT3-TKD can include mutations in one or more amino acids in position regions 823 to 861 of the FLT3 amino acid sequence. Mutations in TKD can include mutations in at least one amino acid selected from the group consisting of numbers 835, 836, and 842 of the FLT3 amino acid sequence. For example, mutations in TKD can include mutations in amino acid 835 of the FLT3 amino acid sequence. For example, a mutation in TKD could be a mutation in which aspartic acid number 835 of the FLT3 amino acid sequence is replaced by valine, tyrosine, histidine, glutamic acid, or asparagine. For example, a mutation in TKD could be a mutation in which isoleucine 836 of the FLT3 amino acid sequence is replaced by leucine or aspartic acid. As another example, a mutation in TKD could be a mutation in which tyrosine 842 of the FLT3 amino acid sequence is replaced by cysteine ​​or histidine. Furthermore, the mutation can be FLT3(D835Y).

[0228] The FLT3-TKD mutation can be a mutation in at least one amino acid selected from the group consisting of amino acid sequences 621, 627, 676, 691, and 697 of the FLT3 amino acid sequence. For example, the TKD mutation can be a mutation in which phenylalanine at position 691 of the FLT3 amino acid sequence is replaced by leucine. For example, the mutation could be FLT3(F691L).

[0229] Mutations in TKD can be further mutations that include internal tandem repeats (ITDs). For example, the mutation could be FLT3 (ITD / D835Y) or FLT3 (ITD / F691L).

[0230] In an embodiment, the FLT3-TKD mutation may include any of the following: FLT3(D835Y), FLT3(F691L), FLT3(F691L / D835Y), FLT3(ITD / D835Y), FLT3(ITD / F691L), and combinations thereof.

[0231] In embodiments of the methods provided herein, the mutated FLT3 contains an internal tandem repeat (ITD) mutation.

[0232] In embodiments of the method provided herein, the mutated FLT3 contains at least one point mutation in the activation loop of FLT3.

[0233] In embodiments of the methods provided herein, the subject contains one or more mutations selected from the group consisting of: NPM1-DNMT3A-FLT3-ITD, NRAS-ITD, KRAS-NPM1-DNMT3A-FLT3-ITD, NRAS-FLT3-ITD, NRAS-FLT3-WT, and NPM1-FLT3-ITD.

[0234] FLT3 is a member of the class III receptor tyrosine kinase (TK) family, normally expressed on the surface of hematopoietic stem cells. FLT3 and its ligands play important roles in the proliferation, survival, and differentiation of pluripotent stem cells. FLT3 is expressed in many AML cases. Furthermore, FLT3 activation in the proximal domain near D835 in the activation loop and in the tyrosine kinase domain (TKD) and surrounding intragenic tandem repeats (ITDs) accounts for 28% to 34% and 11% to 11%, respectively, in AML cases, currently at 14%. These activating mutations in FLT3 are tumorigenic and exhibit transforming activity in cells. In clinical studies, patients with FLT3-ITD mutations have shown poor prognosis and higher relapse rates, shorter duration of remission from initial treatment (6 months, compared to 11.5 months in patients without FLT3-ITD mutations), lower disease-free survival, and reduced overall survival (OS). Relapse rates after hematopoietic stem cell transplantation (HSCT) are also higher in patients with FLT3-ITD mutations. Similar to the prognosis of first-line treatment, patients with relapsed / refractory FLT3-positive AML had lower response rates and shorter remission periods to second-line relapse compared to FLT3-negative patients receiving salvage chemotherapy, resulting in reduced overall survival (OS).

[0235] In the embodiments, the methods of this disclosure demonstrate efficacy in treating acute myeloid leukemia with FMS-like tyrosine kinase 3 (FLT3) mutations that lead to a high risk of relapse, poor prognosis, and reduced overall survival after treatment.

[0236] In some embodiments, the methods of this disclosure even provide clinical benefit in patients with acute myeloid leukemia who are resistant to conventional treatments.

[0237] In the embodiments, the methods provided herein can overcome resistance to treatment for acute myeloid leukemia (AML).

[0238] In embodiments of the methods provided herein, compounds of this disclosure (e.g., compounds of formula (1), (3), (14), compound A, or compound I) are formulated into pharmaceutical formulations that further comprise pharmaceutically acceptable excipients.

[0239] As active ingredients included in pharmaceutical compositions, the compounds disclosed herein (e.g., compounds of formula (1), (3), (14), compound A, or compound I) are provided in an effective amount for the treatment or prevention of an individual or patient, and may be administered orally or parenterously as needed, and when administered orally, the active ingredient is... For parenterial administration, based on the active ingredient, it is administered daily at a dose of, for example, 0.01 mg to 1000 mg, 0.01 mg to 500 mg, 0.1 mg to 300 mg, or 0.1 mg to 100 mg per kg of body weight, as a standard. For example, it may include administration at a dose of 0.01 mg to 100 mg or 0.1 mg to 50 mg per kg, and the composition may be administered in one or more fractional doses. The dose administered to a particular individual or patient should be determined based on several relevant factors, such as the patient's weight, age, sex, health status, diet, time of administration, method of administration, and severity of disease, and may be appropriately adjusted or reduced by an expert. It should be understood that the above doses are not intended to limit the scope of the invention in any way.

[0240] In embodiments of the methods provided herein, the dosage, frequency of administration, or method of administration of the compound used for the treatment may vary depending on the subject being treated, the severity of the disease or symptom, the rate of administration, and the prescribing physician's judgment. Typically, for a person weighing 70 kg, the dosage may be 0.1 mg to 2,000 mg (e.g., 1 mg to 1,000 mg or 10 mg to 2,000 mg) daily. The frequency of administration may be once or several times, for example once or up to four times, or a dosing / stopping schedule may be used, and the method of administration may be oral or parenteral. In some cases, dosages below the foregoing range may be more suitable, higher dosages may be used without producing harmful side effects, and higher dosages may be divided into several smaller doses throughout the day. A physician with ordinary skills in the relevant art may readily determine and prescribe the dosage of the compound to be used as needed. For example, a physician may start with a dosage of the compound of the invention used in the pharmaceutical composition at a level below what is required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0241] The therapeutic drug, depending on the specific case, can be administered at effective treatment intervals. The period or cycle of administration can be 1 week, 28 days, 1 month, 2 months, 3 months, or 4 months, or longer in total. The therapeutic drug can be administered daily throughout the entire duration or only for a portion of the period or cycle.

[0242] In the embodiments, the therapeutic agent (e.g., compound of formula (1), compound of formula (3), compound of formula (14), compound A or compound I) is administered orally once daily over a 28-day period.

[0243] In another embodiment, the dose of the therapeutic agent (e.g., compound of formula (1), compound (3), compound (14), compound A, or compound I) is in the range of about 10 mg to about 300 mg. In another embodiment, the dose is in the range of about 20 mg to about 240 mg. In another embodiment, the dose is in the range of about 40 mg to about 200 mg. In another embodiment, the dose is in the range of about 80 mg to about 160 mg, or any range or subrange thereof.

[0244] In one specific embodiment, the dosage is approximately 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, and 300 mg.

[0245] In one specific embodiment, the dose is administered to the patient once, twice, three times, or four times daily. In one specific embodiment, the dose is administered to the patient once daily. In one specific embodiment, the dose is administered to the patient twice daily. In one specific embodiment, the dose is administered to the patient three times daily. In one specific embodiment, the dose is administered to the patient four times daily.

[0246] In another embodiment, the administration will be carried out in one-week, two-week, three-week, four-week, five-week, six-week, seven-week, or eight-week cycles.

[0247] In the embodiments of the methods provided herein, compound I is administered in amounts from about 10 mg to about 300 mg.

[0248] In the embodiments of the methods provided herein, compound I is administered in amounts of about 40 mg to about 160 mg.

[0249] In the embodiments of the methods provided herein, compound I is administered in amounts of about 80 mg, about 120 mg, and / or about 160 mg.

[0250] In embodiments of the methods provided herein, administration routes include, but are not limited to, oral, intravenous, intra-arterial, intraperitoneal, intradermal, transdermal, intrathecal, intramuscular, intranasal, transmucosal, subcutaneous, and rectal administration.

[0251] In one embodiment, the method may include treating a subject with cancer, the method comprising administering to the subject a therapeutically effective amount of compound A or compound I or a pharmaceutically acceptable salt thereof, its solvate, its stereoisomer, its tautomer, or a combination thereof, wherein the cancer is relapsed or refractory (R / R) acute myeloid leukemia (AML). In one embodiment, the subject has a wild-type or FLT3 mutation. In another embodiment, the FLT3 mutation is an ITD or TKD mutation. In another embodiment, the mutated FLT3 comprises an internal tandem repeat (ITD) mutation and / or at least one FLT3 point mutation. In another embodiment, the at least one point mutation is on one or more residues selected from the group consisting of: D835, F691, K663, Y842, and N841. In another embodiment, the mutated FLT3 comprises at least one mutation in the tyrosine kinase domain of FLT3. In another embodiment, the mutated FLT3 comprises an internal tandem repeat (ITD) mutation. In another embodiment, the mutated FLT3 contains at least one point mutation in the activation loop of FLT3.

[0252] In another embodiment, the subject received prior BCL-2 inhibitor therapy or FLT3 inhibitor therapy. In another embodiment, the BCL-2 inhibitor is venetoclax. In another embodiment, the FLT3 inhibitor is lestaurtinib, sorafenib, midotulin, quizartinib, crenolanib, and / or gitetinib.

[0253] In another embodiment, the dose of compound I or compound A is between about 20 mg and about 250 mg. In one specific embodiment, the dose is administered orally to the subject once daily. In another specific embodiment, the dose of compound I is about 40 mg, about 80 mg, about 120 mg, about 160 mg, or about 200 mg. In another embodiment, the dose is administered once daily for 28 days.

[0254] In one specific embodiment, the 28-day administration period is a cycle in which the subject is repeated more than once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nineteen times, twenty times, or more than twenty times.

[0255] In another specific embodiment, compound A or compound I is administered in combination with a BCL-2 inhibitor. In one specific embodiment, the BCL-2 inhibitor is venetoclax. In one specific embodiment, the combination therapy is administered by the method described above. In another embodiment, the combination therapy schedule is as follows: Figure 2 As described above. In another embodiment, compound I or compound A is administered once daily, and the BCL-2 inhibitor or venetoclax is administered once daily. In another embodiment, compound I is administered at about 80 mg. In another specific embodiment, venetoclax is administered at a daily dose of about 100 mg to about 500 mg. In another specific embodiment, venetoclax is administered at a daily dose of about 400 mg. In another specific embodiment, venetoclax is administered at a lower daily dose on day 1 or day 2 of the treatment plan, wherein the daily dose is increased on day 3, day 4, day 5, day 6, day 7, day 8, day 9, or day 10.

[0256] In the embodiments of the methods provided herein, the formulations for application may be formulated and used in any suitable form according to conventional methods, including oral dosage forms such as tablets, powders, granules, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations such as ointments and creams, injections and suppositories, and sterile injectable solutions, etc.

[0257] In embodiments of the methods provided herein, the compounds disclosed herein (e.g., compounds of formula (1), (3), (14), compound A, or compound I) are administered orally or parenterally.

[0258] Example

[0259] Example 1: Clinical studies of compound I in patients with AML and efficacy evaluation of compound I in AML patients with adverse mutations.

[0260] This study is an open-label, first-in-human, dose-escalation, exploratory, and expansion study of compound I as a single agent in patients with relapsed or refractory (“R / R”) AML. Cycle 1 of dose escalation is defined as 30 days, with all other cycles lasting at least 28 days. Patients will receive compound I orally via a QD (quick dose) except for day 2 of cycle 1 in Part A. Study treatment may continue until the criteria for discontinuation are met.

[0261] The aim of this study is to explore the potential of compound I in treating AML patients with adverse mutations (including but not limited to FLT-3, NPM1, RAS, and DNMT3A).

[0262] Research Design

[0263] The initial dose level of compound I as a single agent was 20 mg daily, and dose escalation to the next dose level was determined based on assessments of safety variables, including moderate toxicity (MT, grade 2 adverse events (excluding hematologic toxicities) as determined by the investigator) or dose-limiting toxicity (DLT). This study consisted of three parts: Part A: Dose escalation; Part B: Dose exploration; and Part C: Dose extension.

[0264] Part A: Dosage escalation:

[0265] Part A includes the initial dose escalation group. The provisional dose escalation scheme for the planned dose of Compound I is as follows: 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg. Patients are treated daily during a 28-day cycle, except for Cycle 1 (30 days). The DLT observation period is during Cycle 1, starting with the first dose on Day 1. Patients in Cycle 1 are PK sampled after receiving a single dose of the study drug on Day 1. This study uses an accelerated titration design. Dose levels are set in increments of approximately 50%. A patient is treated at an initial dose level of 20 mg. If no DLT or MT is identified, the next patient is enrolled at twice the dose level (i.e., dose level 3 (40 mg)). This dose escalation method continues until the first DLT or MT (as determined by the investigator to be a Grade 2 AE (excluding hematologic toxicity) related to the study drug) occurs.

[0266] After identifying a patient for whom DLT is evaluable or after observing MT at each dose level in an accelerated titration design, the data relating to dose escalation decisions are reviewed. Available data will be reviewed, including demographic characteristics, adverse events (AEs), laboratory assessments, dose administration, and any other relevant information related to patient safety. A decision will be made as to whether dose escalation should continue, and if so, at what dose level and schedule. This data review can be performed at any time. Additionally, if a safety assessment is required, a data review can be conducted ad hoc.

[0267] When DLT or MT is observed in patients, the dose escalation plan will discontinue the two-dose-level approach and proceed to the next consecutive dose level using a modified 3+3 design. A modified 3+3 design may also be used to test each consecutive dose level if the safety review meeting (RM) makes recommendations based on a review of available PK data.

[0268] After the dose-escalation design is converted to a 3+3 design, three patients are treated at each dose level. If no DLT is observed in three patients, subsequent patients are treated at the next dose level. If one DLT (observed 1 / 3 DLT) is observed in three patients at a dose level, three more patients are enrolled at that dose level. If no DLT is observed in another three patients (observed ≤1 / 6 DLT), the next dose level is initiated. If two or more DLTs are observed at a dose level (observed ≥2 / 3 or ≥2 / 6 DLT), the dose is considered intolerable, and dose escalation is stopped. The MTD will be determined at the next lower level, or, if appropriate, doses between the highest tolerable and intolerable doses will be further explored to determine the MTD.

[0269] Part B: Dosage Exploration

[0270] Part B is the dose-exploration group. Patients will be treated daily over a 28-day cycle. The DLT observation period is during Cycle 1, starting with the first dose on Day 1. At any dose level, if no DLT is observed in the initial 3 patients in the dose-escalation group (Part A) (0 / 3 DLT observed), the dose level will be expanded to include up to 6 patients (including the initial 3) for DLT assessment. If one or fewer DLTs are observed in 6 patients (≤1 / 6 DLT observed), the dose level will continue to include up to 20 patients. If 2 or more DLTs occur in 6 patients at the dose level (≥2 / 6 DLT observed), further enrollment will be stopped. If one DLT is observed in 6 patients in the dose-escalation group (Part A) (1 / 6 DLT observed), up to 20 patients can be included in the dose-exploration group (Part B) at the dose level. The planned doses of compound I for part B are also as follows: 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg.

[0271] If both Part A and Part B are opened simultaneously, newly enrolled patients will be assigned to Part A first. If multiple dose levels are being explored simultaneously, patients will be enrolled preferentially at the lowest dose of the explored dose levels. Since several complete responses were observed at the 80 mg dose, the 40 mg dose level could be expanded to a total of 20 patients to further explore safety, pharmacokinetics, and activity at this dose level. Part B may occur concurrently with dose expansion in Part C.

[0272] At partial dose levels B, at least half of the patients have AML with an FLT3 mutation (e.g., ITD or activating point mutations such as D835Y, D835V, I836), including partial A patients. If 10 patients without FLT3 mutations are enrolled at a dose level, that level will be stopped to further enroll patients without FLT3 mutations. Patients with or without a history of FLT3 mutations will be enrolled, and samples will be collected at screening visits to confirm or assess FLT3 mutation status. If FLT3 mutation status is unknown at enrollment, the patient will be considered to have an FLT3 mutation status determined by their most recent prior genetic testing. FLT3-ITD or TKD mutations will be determined by FDA-approved testing or empirical assays by a central laboratory.

[0273] Based on the DLT rates observed in patients in both Part A and Part B, the safety of the dose exploration group (Part B) will be monitored using Bayesian logistic regression modeling.

[0274] If at least one patient in Part A achieves a clinical response (CR) at any dose level, including partial hematologic recovery CR (CRh), incomplete platelet recovery CR (CRp), incomplete hematologic recovery CR (CRi), or partial remission (PR), then the dose level may continue to enroll at least 3 patients in Part A or Part B. During accelerated dose escalation, the initial 3 patients will undergo DLT assessment at the exploratory dose level for safety monitoring according to the same protocol as the 3+3 design.

[0275] If no DLT is observed in the initial 3 patients, or if no DLT is observed in subsequent 3 patients after one of the initial 3 patients (0 / 3 or 1 / 6 DLT observed), further patients will be enrolled at the stated dose level. Additionally, if fewer than 2 responses (compound CR [CR+CRh+CRi+CRp](CRc)+PR) are achieved in the 12 patients who have completed 2 treatment cycles, further enrollment will be stopped at the stated dose level. Otherwise, up to 20 evaluable patients will continue to be enrolled at the stated dose level. For patients in Part B, a Bayesian logistic regression model will also be used as a supporting analysis for safety assessment.

[0276] Part C: Dose Extension:

[0277] Part C is a dose-expansion cohort used to determine the safety and tolerability of Compound I as a single agent or in combination with venetoclax. Within each group, approximately half of the patients had an FLT3 mutation, and the other half were FLT3-free. In the Compound I single-agent group, at least 16 (evaluable) patients with FLT3 mutations had received prior therapy with an FLT3 inhibitor. In the Compound I single-agent group, at least 12 (evaluable) patients without FLT3 mutations had a TP53 mutation or a complex karyotype. The initial single-agent dose of Compound I was 120 mg daily, and the starting dose in the Compound I plus venetoclax group was 80 mg daily. In additional dosing studies, the dose of Compound I ranged from 20 mg to 200 mg once daily. Patients were assigned to treatment groups based on the number of available slots. Treatment was administered in 28-day cycles, with patients receiving daily administration of Compound I in all treatment groups. Patients who could not be evaluated for response could be replaced. For the single-drug group, a safety review (SRM) will be conducted after 6 patients have completed Cycle 1 to complete a safety review that includes all subjects in the studies to date. Dosage adjustments can be recommended under the SRM based on the availability of safety information.

[0278] Response assessment will be conducted on day 15 of Cycle 1, and at subsequent time points depending on the response. Events occurring in Part C that also occurred in Part A or Part B will be considered DLT and will be reviewed and assessed at a Safety Review Meeting (SRM). For the combination therapy group, a Safety Review Meeting will be held after 3 patients in each group have completed Cycle 1. The SRM may recommend changes to the dosing schedule for subsequent patients.

[0279] In both Part A and Part B, patients who received less than 80% of the intended dose during Period 1 (e.g., missed 6 daily doses or left the study for reasons other than DLT) will not be able to assess DLT and will be replaced by another patient at the same dose level. Additionally, if any patient is found after enrollment to not meet any inclusion / exclusion criteria that would adversely affect the safety or efficacy assessment of said patient, they may be replaced after discussion between the principal investigator and the medical supervisor. Additional cohorts with potentially modified target patient and investigational drug protocols may be accumulated based on the assessment of the primary objective.

[0280] For some C cases, if a patient is deemed unable to assess their response on day 1 of cycle 3 (due to not having received two cycles of treatment or discontinuing treatment for reasons other than disease progression), the patient may be replaced.

[0281] A provisional dose escalation plan for part of A's planned dose has been proposed. However, this plan may be modified based on recommendations from the group review meeting.

[0282] A DLT assessment will be determined. DLT is defined as any of the following events that occur within cycle 1, starting from the administration of the first dose on day 1 of both Part A and Part B, and are considered relevant to the study drug.

[0283] Any non-hematologic or extramedullary toxicity of grade 3 or higher.

[0284] Note the following exceptions:

[0285] a. Any level of hair loss, loss of appetite, or fatigue.

[0286] b. If hospitalization, TPN, or tube feeding is not required, then it is grade 3 nausea or vomiting or diarrhea.

[0287] c. Grade 3 fever with neutropenia, with or without infection.

[0288] d. Level 3 infection.

[0289] e. Hematologic toxicity is not considered DLT.

[0290] However, in the absence of evidence of active leukemia in the bone marrow or blood, long-term myelosuppression defined as ANC < 500 for more than 21 days after discontinuation of medication will be considered DLT.

[0291] Any Grade 4 organ toxicity falls under the category of DLT.

[0292] Continue overdose toxicity monitoring in the C group. Review all available safety, tolerability, and pharmacokinetic data for patients in the combination therapy group to determine if any dose adjustments to venetoclax and / or compound I are necessary for subsequent patients.

[0293] FLT3 mutation status - bone marrow or peripheral blood

[0294] Central FLT3 mutation testing will be performed for portions A, B, and C. Bone marrow samples will be collected in heparinized tubes and used to determine or confirm FLT3 mutation status. Bone marrow should be collected via aspiration during the screening period. Approximately 1 mL should be collected in a heparinized tube. If a bone marrow sample is unavailable (e.g., dry aspiration), a 3 mL peripheral blood sample should be collected at the screening visit. The presence of FLT3 ITD or TKD mutations in the collected samples will be analyzed using an FDA-approved test or an FDA-validated assay at a central laboratory. Samples collected at the screening visit may be used to develop diagnostic assays.

[0295] Resistance mutation - bone marrow or peripheral blood

[0296] Bone marrow samples will be collected in EDTA tubes. Bone marrow should be aspirated during screening and EOT visits. Approximately 1 mL should be taken into the EDTA tube. If a bone marrow sample is unavailable (e.g., dry aspiration) or the sample volume is insufficient, 3 mL of peripheral blood should be taken into the EDTA tube instead.

[0297] The collected samples will be used to investigate the mutation status of FLT3 and other genes, not limited to NRAS and Kirsten RAS, as mutation status may affect the efficacy of compound I. This analysis will elucidate resistance mutations to compound I treatment. Clinical Laboratory Improvement Amendments (CLIA) certified or validated next-generation sequencing (NGS) assays will be used for the analysis, and these assays are for exploratory purposes only.

[0298] result

[0299] As shown in Tables 1 and 2 below, clinical responses were achieved in patients with adverse mutations. Responses were observed across a range of genetically defined populations with highly adverse mutations. Most responders were bridged to potentially life-saving transplants.

[0300] Table 1. Clinical response in R / R AML patients with adverse mutations after treatment with compound I

[0301]

[0302] Table 2. Efficacy of active / safe doses (40 mg, 80 mg, 120 mg, 160 mg) in assessing response rates in R / R AML patients

[0303]

[0304]

[0305] Example 2: Study and evaluation of the efficacy of compound I in R / R AML patients

[0306] The study was further performed / discontinued using the protocol described in Example 1 above. Specifically, Compound I, or its combination with venetoclax, was tested as a monotherapy in human patients with relapsed or refractory (R / R) AML. Such patients may include, but are not limited to, patients who have not received venetoclax, patients who have previously received venetoclax, patients with FLT-3WT and FLT-3-mutant AML, and patients who have previously received FLT3 inhibitors. Studies have shown that Compound I is well tolerated as a monotherapy and is particularly active in relapsed or refractory AML who have not received VEN. These studies have also shown that Compound I and venetoclax as a combination are well tolerated in a broad R / R AML population, including patients with FLT-3-mutant and FLT-3 wild-type (WT) AML, including those who have previously received FLT3 inhibitors. Table 3 below shows the composite complete response rate in R / R AML patients treated with a single dose of Compound I at a dose of 80–160 mg QD, for example, using the protocol described in Example 1.

[0307] Table 3. Response rate of compound I in R / R AML patients receiving therapeutic doses (80-160 mg QD)

[0308]

[0309] Therefore, the data in Table 3 indicate that compound I is particularly active in venetoclax-naïve R / R AML patients compared to those previously treated with venetoclax. Table 3 also indicates that compound I is active in AML patients with FLT-3WT and FLT-3 mutations. Compound I has actually demonstrated clinical responses as a monotherapy in AML patients as well as in patients with FLT-3WT and FLT-3 mutations (such as ITD or TKD FLT-3 mutations). For example, Figure 1 A broad population of such patients has been shown to respond to doses as low as 80 mg once daily.

[0310] Besides its activity, compound I is well tolerated as a monotherapy. In fact, as shown in Table 3 and Figure 1 Among the indicated treated patients, no treatment-related QT was found in this study. c Prolonged illness, elevated CPK levels, differentiation syndrome, non-hematologic SAE, or death in any patient.

[0311] The study described in Example 1 also showed efficacy in the combination therapy group of compound I plus vernetotox. Figure 2Treatment regimens using such combinations are illustrated. Specifically, the compound I / venetoclax combination is well-tolerated and exhibits good activity in a broad population of relapsed or refractory (R / R) AML. Compound I / venetoclax also offers a unique opportunity due to its activity against AML previously treated with venetoclax, including FLT3 in R / R settings. MUT and FLT3 WT Both AML and venetoclax. Table 4 shows the broad patient populations who responded to the combination therapy with compound I and venetoclax.

[0312] Table 4. Response rates in the combination study of compound I and venetoc in R / R AML patients

[0313]

[0314] The data in Table 4 indicate that the combination of compound I with venetoclax is active against a broad population of relapsed / relapsed AML patients, including those with FLT-3WT and those who have previously received venetoclax. Figure 3 A wide range of such patients were also shown to have a dose response to the combination of 80 mg compound I with 400 mg venetoclax. This included patients with FLT-3WT and FLT-3 mutations (such as ITD or TKD FLT-3 mutations in FLT-3), as well as patients who had previously received venetoclax or had previously received an FLT-3 inhibitor.

[0315] In addition to its activity, the combination of compound I and venetoc was well tolerated. In fact, as shown in Table 4 and... Figure 3 Among the indicated treated patients, the incidence of SAEs was as low as approximately 14% due to combination therapy.

[0316] Therefore, administration of compound I in combination with venetoclax to human patients as indicated therapy was well-tolerated and showed good activity in a broad population of relapsed / relapsed AML patients. In fact, the combination has shown efficacy against FLT3-positive patients. WT AML and FLT3 MUT It is active in AML patients who have previously received FLT3 inhibitors, and is also active in both R / RAML patients who have not received venetoclax and those who have previously received venetoclax (a known and very difficult patient population in need of treatment).

Claims

1. A method of treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, or a combination thereof, wherein the subject has a mutant form of NPM1, DNMT3A, RAS, or a combination thereof: In equation (1): Ea is hydrogen, hydroxyl, or C1-4 alkoxy; Eb is hydrogen, halogen, C1-4 alkyl, or C1-4 fluoroalkyl; Ec and Ed are each independently hydrogen or hydroxyl groups; X' is hydrogen or hydroxyl; k is an integer from 1 to 2; Each Q is independently a hydroxyl group, a halogen, a C1-4 alkyl group, a hydroxy-C1-4 alkyl group, or a C1-4 alkoxy group; Z' is a monovalent functional group represented by equation (2); in: Each A is independently selected from the group consisting of: hydroxyl, C1-4 alkyl, and hydroxyC1-4 alkyl, wherein at least one A is a C1-4 alkyl; n is an integer from 1 to 2; and L is hydrogen, C1-4 alkyl, hydroxyl, or hydroxyC1-4 alkyl.

2. The method according to claim 1, wherein the compound of formula (1) is a compound of formula (3) or a pharmaceutically acceptable salt thereof, a solvate thereof, a stereoisomer thereof, a tautomer thereof, or a combination thereof; In Equation 3: Ef is fluorine, chlorine, bromine, or iodine; Qo is hydroxyl, halogen, C1-4 alkyl, hydroxyC1-4 alkyl, or C1-4 alkoxy; s is an integer from 1 to 2; Ao is selected from the group consisting of: hydroxyl, C1-4 alkyl, and hydroxyC1-4 alkyl; and t is an integer from 1 to 2.

3. The method according to claim 1 or 2, wherein the compound of formula (1) is compound I. Or a pharmaceutically acceptable salt thereof, its solvate, its stereoisomer, its tautomer, or a combination thereof.

4. The method according to any one of claims 1 to 3, wherein the subject further has a mutated form of FLT3.

5. The method of claim 4, wherein the subject has a mutation in FLT3, a mutation in NPM1, a mutation in DNMT3A, and a mutation in RAS.

6. The method according to any one of claims 1 to 5, wherein the subject has a mutated form of NRAS.

7. The method according to any one of claims 1 to 5, wherein the subject has a mutated form of KRAS.

8. The method of claim 4, wherein the subject has a mutant form of FLT3 and a mutant form of NPM1.

9. The method of claim 4, wherein the subject has a mutant form of FLT3, a mutant form of NPM1, and a mutant form of DNMT3A.

10. The method according to any one of claims 1 to 3, wherein the subject has a mutated form of RAS.

11. The method of claim 10, wherein the subject has a mutated form of NRAS.

12. The method of claim 10, wherein the subject has a mutated form of KRAS.

13. The method according to any one of claims 10 to 12, wherein the subject further comprises a mutated form of FLT3.

14. The method according to any one of claims 1 to 10 or 13, wherein the mutated FLT3 comprises an internal tandem repeat (ITD) mutation and / or at least one FLT3 point mutation.

15. The method of claim 14, wherein the at least one point mutation is on one or more residues selected from the group consisting of: D835, F691, K663, Y842, and N841.

16. The method according to any one of claims 1 to 10 or 13, wherein the mutated FLT3 comprises at least one mutation in the tyrosine kinase domain of FLT3.

17. The method according to any one of claims 1 to 10 or 13, wherein the mutated FLT3 comprises an internal tandem repeat (ITD) mutation.

18. The method according to any one of claims 1 to 10 or 13, wherein the mutated FLT3 comprises at least one point mutation in the activation loop of FLT3.

19. The method of any one of claims 1 to 18, wherein the subject comprises one or more mutations selected from the group consisting of: NPM1-DNMT3A-FLT3-ITD, NRAS-ITD, KRAS-NPM1-DNMT3A-FLT3-ITD, NRAS-FLT3-ITD, NRAS-FLT3-WT, NPM1-FLT3-ITD.

20. The method according to any one of claims 1 to 19, wherein the cancer is a hematologic cancer.

21. The method of claim 20, wherein the hematologic cancer is leukemia.

22. The method of claim 21, wherein the leukemia is acute myeloid leukemia (AML).

23. The method of claim 22, wherein the AML is relapsed or refractory (R / R) AML.

24. The method according to any one of claims 1 to 23, wherein prior therapy performed on the subject with chemotherapy, hematopoietic stem cell transplantation (HSCT) and / or with other FLT3 inhibitors has failed.

25. The method according to any one of claims 1 to 24, wherein the compound of formula (1) is formulated into a pharmaceutical formulation further comprising a pharmaceutically acceptable excipient.

26. The method of claim 3, wherein compound I is administered in an amount of about 10 mg to about 300 mg.

27. The method of claim 26, wherein compound I is administered in an amount of about 40 mg to about 160 mg.

28. The method of claim 26, wherein compound I is administered in an amount of about 80 mg, about 120 mg, and / or about 160 mg.

29. The method according to any one of claims 26 to 28, wherein the dose is administered once, twice, three times, or four times daily.

30. The method according to any one of claims 1 to 29, wherein the compound of formula (1) is administered orally or parenterally.

31. A method of treating cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of compound I, Or a pharmaceutically acceptable salt thereof, its solvate, its stereoisomer, its tautomer, or a combination thereof, wherein the cancer is relapsed or refractory (R / R) acute myeloid leukemia (AML).

32. The method of claim 31, wherein the subject has a wild-type or FLT3 mutation.

33. The method of claim 32, wherein the FLT3 mutation is an ITD or TKD mutation.

34. The method of claim 32, wherein the mutated FLT3 comprises an internal tandem repeat (ITD) mutation and / or at least one FLT3 point mutation.

35. The method of claim 32, wherein the at least one point mutation is on one or more residues selected from the group consisting of: D835, F691, K663, Y842 and N841.

36. The method according to any one of claims 32 to 35, wherein the mutated FLT3 comprises at least one mutation in the tyrosine kinase domain of FLT3.

37. The method according to any one of claims 32 to 36, wherein the mutated FLT3 comprises an internal tandem repeat (ITD) mutation.

38. The method according to any one of claims 32 to 37, wherein the mutated FLT3 comprises at least one point mutation in the activation loop of FLT3.

39. The method of any one of claims 31 to 38, wherein the subject has received prior BCL-2 inhibitor therapy or FLT3 inhibitor therapy.

40. The method of claim 39, wherein the BCL-2 inhibitor is venetoclax.

41. The method of claim 39, wherein the FLT3 inhibitor is lestaurtinib, sorafenib, midostaurin, quizartinib, crenolanib, and / or gilteritinib.

42. The method according to any one of claims 31 to 41, wherein the dose of compound I is between about 20 mg and about 250 mg.

43. The method of claim 42, wherein the dose is administered orally to the subject once daily.

44. The method according to claim 42 or 43, wherein the dosage of compound I or a pharmaceutically acceptable salt thereof, its solvate, its stereoisomer, its tautomer or combination thereof is about 40 mg, about 80 mg, about 120 mg, about 160 mg or about 200 mg.

45. The method according to any one of claims 31 to 44, wherein the dose is administered once daily for 28 days.

46. ​​The method of claim 45, wherein the 28-day administration is a cycle of more than one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or more than twenty repetitions for the subject.

47. The method according to any one of claims 31 to 45, wherein compound I or a pharmaceutically acceptable salt thereof, its solvate, its stereoisomer, its tautomer, or a combination thereof is administered in combination with a BCL-2 inhibitor.

48. The method of claim 47, wherein the BCL-2 inhibitor is venetoc.

49. The method of claim 47 or 48, wherein the combined treatment schedule is shown in Figure 2.

50. The method according to claim 47 or 48, wherein compound I or a pharmaceutically acceptable salt thereof, its solvate, its stereoisomer, its tautomer, or a combination thereof is administered once daily, and the BCL-2 inhibitor or venetoclax is administered once daily.

51. The method according to any one of claims 47 to 50, wherein compound I or a pharmaceutically acceptable salt thereof, its solvate, its stereoisomer, its tautomer, or a combination thereof is administered in an amount of about 80 mg.

52. The method according to any one of claims 48 to 51, wherein venetoc is administered at a daily dose of about 100 mg to about 500 mg.

53. The method according to any one of claims 48 to 51, wherein venetoc is administered at a daily dose of about 400 mg.

54. The method according to any one of claims 48 to 51, wherein venetoc is administered at a lower daily dose on day 1 or day 2 of the treatment plan, wherein the daily dose is increased on day 3, day 4, day 5, day 6, day 7, day 8, day 9, or day 10.

55. The method according to any one of claims 1 to 54, wherein the subject is additionally administered a DNA demethylating agent (HMA).

56. The method of claim 55, wherein the HMA is selected from one or more of the group consisting of azacitidine, decitabine, and combinations thereof.

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