Use of a compound to treat acute myeloid leukemia or myelodysplastic syndrome

Abstract

The present invention relates to methods of treating hematological disorders, such as acute myeloid leukemia, using substituted heterocyclic compounds and pharmaceutically acceptable salts thereof. The compounds inhibit the kinases irak4 and flt-3.

Description

1 / 93 “USE OF A COMPOUND TO TREAT ACUTE MYELOID LEUKEMIA OR MYELODYSPLASTIC SYNDROME” CROSS-REFERENCE TO RELATED REQUEST

[001] This application claims the benefit of priority to Indian Provisional Patent Application serial number 201741011785, filed on March 31, 2017, which is incorporated herein by reference in its entirety. BACKGROUND

[002] Acute myeloid leukemia (hereinafter also referred to as AML) is a hematological malignancy with a poor prognosis that frequently occurs in adults, and the 5-year survival rate is predicted to be 20%. Currently, it is possible to temporarily reduce the number of AML cells to a level below the detection limit through AML treatment. This condition is referred to as complete remission. However, AML usually recurs after achieving complete remission, and for many patients, recurrent AML results in death. In particular, a very low survival rate in cases of recurrence has been a serious matter of concern. Therefore, there is a need for new treatments for AML. SUMMARY

[003] This document provides a method for treating or preventing acute myeloid leukemia in an individual, comprising administering a compound of Formula (I): (i) or a pharmaceutically acceptable salt thereof; wherein The Zi ring is an optionally substituted heteroaryl; Petition 870250061458, dated 07 / 17 / 2025, page 11 / 223 2 / 93 The Z2 ring is an optionally substituted heterocycloalkyl group, an optionally substituted heteroaryl group, or a direct linkage; Ri is alkyl, cyano, -NRaRb, or optionally substituted groups selected from cycloalkyl, aryl, or heterocyclyl; wherein the substituent, in each occurrence, is independently alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, -OCO-CH2O-alkyl, -OP(O)(O-alkyl)2, or -CH2-OP(O)(O-alkyl)2; R2, in each occurrence, is independently an optionally substituted group selected from alkyl or cycloalkyl; wherein the substituent, in each occurrence, is independently halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl or haloalkoxy; R3, in each occurrence, is independently hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, -NRaRb, hydroxyl, or hydroxyalkyl; Ra is hydrogen or alkyl; Rb is hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl or optionally substituted cycloalkyl; 'm' and 'n' are independently 1 or 2.

[004] This document provides a method for treating or preventing acute myeloid leukemia in an individual, comprising administering a compound of Formula (II): (II) or a pharmaceutically acceptable salt thereof; wherein Xi and X3 are independently CH or N; X2 is CR2 or N; provided that one Petition 870250061458, dated 07 / 17 / 2025, page 12 / 223 3 / 93 and no more than one of Xi, X2 or X3 is N; A is O or S; Y is -CH2- or O; The Z ring is aryl or heterocyclyl; Ri, in each occurrence, is independently a halo or optionally substituted heterocycline; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl, or -NRaRb; R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or -NRaRb; wherein the substituent is alkyl, amino, halo or hydroxyl; R3, in each occurrence, is either alkyl or hydroxyl; Ra and Rb are independently hydrogen, alkyl, acyl, or heterocyclyl; 'm' and 'n' are independently 0, 1, or 2; 'p' is 0 or 1.

[005] This document provides a method for treating or preventing acute myeloid leukemia in an individual, comprising administering a compound of Formula (III): (III) or a pharmaceutically acceptable salt thereof; in what Z1 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or is absent; Z2 represents optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclyl; Petition 870250061458, dated 07 / 17 / 2025, page 13 / 223 4 / 93 Ri is hydrogen, optionally substituted alkyl, amino, halo, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl; R2, in each occurrence, is amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted heterocyclylalkyl; R3, in each occurrence, is hydroxyl, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, or -NRaRb; Ra and Rb, independently for each occurrence, are hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted heterocyclylalkyl; m, in each occurrence, is 0, 1, or 2; en, in each occurrence, is 0, 1, or 2.

[006] In some embodiments, a use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for the treatment and prevention of AML is disclosed in this document.

[007] In some embodiments, a use of the compound disclosed herein or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, including mixtures thereof in all proportions, is disclosed in this document as a medicament for the treatment of AML. BRIEF DESCRIPTION OF THE FIGURES

[008] FIG. 1 represents the Kd linkage of Compound A with various kinases, Petition 870250061458, dated 07 / 17 / 2025, p. 14 / 223 5 / 93 including wild-type FLT-3 and its mutations.

[009] FIG. 2A represents the % inhibition of proliferation in MV411 cells by Compound A. FIG. 2B represents the % inhibition of proliferation in MV4-11 cells by Compound B.

[0010] FIG. 3 represents the increase in tumor growth inhibition with increasing doses of Compound A 12.5, 25 and 50 mpk.

[0011] FIG. 4 represents the static body weight of animals in an in vivo xenograft model MV4-11.

[0012] FIG. 5A represents the percentage of tumor growth inhibition (% TGI) in mice with a MOLM-14 FLT3-ITD subcutaneous tumor. FIG. 5B represents the percentage of tumor growth inhibition (% TGI) in mice with a MOLM-14 FLT3-ITD / F691L tumor. FIG. 5C represents the percentage of tumor growth inhibition (% TGI) in mice with a MOLM-14 FLT3-ITD / D835Y tumor. DETAILED DESCRIPTION

[0013] Unless defined otherwise, all technical and scientific terms used in this document have the same meaning as that commonly understood by a person skilled in the art to which this claimed subject matter pertains. As used in the specification and appended claims, unless otherwise specified, the following terms have the meaning indicated in order to facilitate understanding of the present invention.

[0014] The singular forms um, uma and a / o include plural references, unless the context clearly dictates otherwise.

[0015] As used in this document, the term optional or optionally means that the event or circumstance described below may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, alquila Petition 870250061458, dated 07 / 17 / 2025, p. 15 / 223 6 / 93 optionally substituted refers to the alkyl group that can be substituted, as well as the event or circumstance in which the alkyl group is not substituted.

[0016] It is understood that the substituents and substitution patterns in the compounds of the present invention can be selected by one skilled in the art to result in chemically stable compounds that can be readily synthesized by techniques known in the art, as well as the methods set forth below, from readily available raw materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, provided that it results in a stable structure.

[0017] As used in this document, the optionally substituted term refers to the substitution of one to six hydrogen radicals on the same carbon or on different carbons in a given structure with the radical of a specified substituent, including but not limited to: hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, halogen, alkyl, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, cycloalkyl, cycloalkoxy, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, amino, aminoalkyl, alkylamino, dialkylamino, acyl, -C(O)2H, O(acyl), -NH(acyl), -N(alkyl)(acyl), cyano, phosphinate, phosphonate, sulfonate, sulfonamido, sulfate, haloalkyl or haloalkoxy. Preferably, optionally substituted refers to the substitution of one to four hydrogen radicals in a given structure with the aforementioned substituents.More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent may be subsequently replaced.

[0018] The term substituted refers to parts with substituents that replace a hydrogen atom on one or more carbon atoms in the main structure. It will be understood that substitution or substituted by includes the implicit condition that Petition 870250061458, dated 07 / 17 / 2025, p. 16 / 223 7 / 93 such substitution conforms to the permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, for example, one that does not undergo spontaneous transformation, such as by rearrangement, cyclization, elimination, etc. As used in this document, the term substituted is contemplated to include all permissible substituents of organic compounds. In a broad sense, permissible substituents include cyclic and acyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Permissible substituents may be one or more and the same or different, in the case of organic compounds. For the purposes of this invention, heteroatoms, such as nitrogen, may have hydrogen substituents and / or any permissible substituents of organic compounds described in this document that satisfy the valences of the heteroatoms.Substituents may include any substituents described in this document, for example, a halogen, a hydroxyl group, a carbonyl group (such as a carboxyl, an alkoxycarbonyl, a formyl or an acyl), a thiocarbonyl group (such as a thioester, a thioacetate or a thioformate), a peroxyl group, a phosphoryl group, a phosphate group, a phosphonate group, a phosphinate group, an amino group, an amido group, an amidine group, an imine group, a cyano group, a nitro group, an azido group, a sulfhydryl group, an alkylthio group, a sulfate group, a sulfonate group, a sulfamoyl group, a sulfonamido group, a sulfonyl group, a heterocyclyl group, an aralkyl group or a part of an aromatic or heteroaromatic group. It will be understood by those skilled in the art that substituents may themselves be substituted, if appropriate. Unless specifically indicated as unsubstituted, references to chemical fractions are understood in this document as including substituted variants. For example, a reference to an aryl group or moiety implicitly includes both substituted and unsubstituted variants.

[0019] As used herein, the term alkyl refers to saturated aliphatic groups, including, but not limited to, alkyl groups of Petition 870250061458, dated 07 / 17 / 2025, p. 17 / 223 8 / 93 linear C1-C10 chain or C1-C10 branched chain alkyl groups. Preferably, the alkyl group refers to linear C1-C6 chain alkyl groups or C1-C6 branched chain alkyl groups. More preferably, the alkyl group refers to linear C1-C4 chain alkyl groups or C1-C4 branched chain alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl or 4-octyl and the like. An alkyl group may be optionally substituted.

[0020] The term acyl refers to an R-CO- group where R is an optionally substituted alkyl group defined above. Examples of acyl groups are, but are not limited to, CH3CO-, CH3CH2CO-, CH3CH2CH2CO-, or (CH3)2CHCO-.

[0021] As used in this document, the term alkoxy refers to a linear or branched saturated aliphatic C1-C10 hydrocarbon radical attached to an oxygen atom that is bonded to a central structure. Preferably, alkoxy groups have from one to six carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 3-methylbutoxy, and the like.

[0022] As used in this document, the term haloalkyl refers to an alkyl group (as defined above) that is substituted with one or more halogens. A mono-haloalkyl radical, for example, may have a chlorine, bromine, iodine, or fluorine atom. Di-halo and poly-haloalkyl radicals may have two or more of the same or different halogen atoms, respectively. Examples of haloalkyl include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, and the like. Petition 870250061458, dated 07 / 17 / 2025, page 18 / 223 9 / 93

[0023] As used in this document, the term haloalkoxy refers to radicals in which one or more of the hydrogen atoms of the alkoxy group are replaced with one or more halogens. Representative examples of haloalkoxy groups include, but are not limited to, difluoromethoxy (-OCHF2), trifluoromethoxy (-OCF3), or trifluoroethoxy (-OCH2CF3).

[0024] As used in this document, the term aryl alone or in combination with other term(s) means a carbocyclic aromatic system with 6 to 10 members, containing one or two rings in which such rings may be fused. The term fused means that the second ring is linked or formed by having two adjacent atoms in common with the first ring. The term merged is equivalent to the term condensed. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, or indanyl. Unless otherwise specified, all aryl groups described in this document may be optionally substituted.

[0025] The terms amine and amino are recognized in the art and refer to substituted and unsubstituted amines and salts, for example, a moiety that can be represented by where each R10 independently represents a hydrogen atom or a hydrocarbyl group, or two R10s are taken together with the N atom to which they are attached to complete a heterocycle that has 4 to 8 atoms in the ring structure.

[0026] As used in this document, aminoalkyl refers to an amino group, as defined above, in which one or two hydrogen atoms are replaced by the alkyl group.

[0027] As used in this document, nitro refers to a -NO2 group.

[0028] As used herein, alkylamino and cycloalkylamino Petition 870250061458, dated 07 / 17 / 2025, p. 19 / 223 10 / 93 refers to an -N- group, in which a nitrogen atom of said group is bonded to the alkyl or cycloalkyl group, respectively. Representative examples of alkylamino and cycloalkylamino groups include, among others, -NHCH3 and -NHcyclopropyl. An amino group may optionally be replaced by one or more of the appropriate groups.

[0029] As used in this document, the term cycloalkyl alone or in combination with other term(s) means a saturated C3-C10 cyclic hydrocarbon ring. A cycloalkyl may be a single ring, which typically contains 3 to 7 carbon atoms in the ring. Examples of single-ring cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. A cycloalkyl may alternatively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyl include bridged, fused, and spirocyclic carbocyclyl.

[0030] As used in this document, the term cyan refers to the -CN group.

[0031] As used in this document, the term hydroxyl refers to an -OH group.

[0032] As used in this document, the term hydroxyalkyl or hydroxyalkyl refers to alkyl substituted with one or more hydroxyl groups, wherein the alkyl groups are defined above. Examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, propan-2-ol and the like.

[0033] As used in this document, the term halo or halogen alone or in combination with other term(s) refers to fluorine, chlorine, bromine or iodine.

[0034] As used in this document, the term heterocyclyl includes the definitions of heterocycloalkyl and heteroaryl.

[0035] As used in this document, the term heterocycloalkyl is Petition 870250061458, dated 07 / 17 / 2025, page 20 / 223 11 / 93 refers to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system of 3 to 15 members with at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2, NH or C(O), the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur. Examples of heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, 2-azabicyclo[2.2.2]octanyl, azocinyl, cromanyl, xanthenyl and N-oxides thereof.The attachment of a heterocycloalkyl substituent can occur through a carbon atom or a heteroatom. A heterocycloalkyl group can optionally be substituted by one or more of the aforementioned groups. Preferably, heterocycloalkyl refers to a 5- to 6-membered ring selected from azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl and N-oxides thereof. More preferably, heterocycloalkyl includes azetidinyl, pyrrolidinyl, morpholinyl and piperidinyl. Every heterocycloalkyl is optionally substituted by one or more of the aforementioned groups.

[0036] As used in this document, the term heteroaryl refers to an aromatic heterocyclic ring system containing 5 to 20 ring atoms, suitably 5 to 10 ring atoms, which may be a single ring (monocyclic) or multiple rings (bicyclic, tricyclic, or polycyclic) fused together or covalently linked. Preferably, heteroaryl is a 5- to 6-membered ring. The rings may contain 1 to 4 heteroatoms selected from N, O, and Petition 870250061458, dated 07 / 17 / 2025, p. 21 / 223 12 / 93 S, where the N or S atom is optionally oxidized or the N atom is optionally quaternized. Any suitable ring position of the heteroaryl moiety can be covalently linked to the defined chemical structure.

[0037] Exemplos de heteroarila incluem, mas não estão limitados a: furanila, tienila, pirrolila, pirazolila, imidazolila, oxazolila, cinolinila, isoxazolila, tiazolila, isotiazolila, 1H-tetrazolila, oxadiazolila, triazolila, piridila, pirimidinila, pirazinila, piridazinila, benzoxazolila, benzisoxazolila, benzotiazolila, benzofuranila, benzotienila, benzotriazinila, ftalazinila, tiantreno, dibenzofuranila, dibenzotienila, benzimidazolila, indolila, isoindolila, indazolila, quinolinila, isoquinolinila, quinazolinila, quinoxalinila, purinila, pteridinila, 9H-carbazolila, α-carbolina, indolizinila, benzoisotiazolila, benzoxazolila, pirrolopiridila, pirazolopirimidila, furopiridinila, purinila, benzotiadiazolila, benzooxadiazolila, benzotriazolila, benzotriadiazolila, carbazolila, dibenzotienila, acridinila e similares.Preferably, heteroaryl refers to a 5- to 6-membered ring selected from the group consisting of furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl. More preferably, pyrazolyl, pyridyl, oxazolyl, and furanyl. All heteroaryl groups are optionally replaced by one or more of the aforementioned groups.

[0038] As used in this document, the term compound(s) includes the compounds disclosed in the present invention.

[0039] As used in this document, the term includes or comprising is generally used in the sense of including, that is, allowing the presence of one or more resources or components.

[0040] As used in this document, the term or means and / or unless otherwise indicated.

[0041] As used in this document, the term including, as well as Petition 870250061458, dated 07 / 17 / 2025, page 22 / 223 13 / 93 other forms, such as include, includes and included, are not limiting.

[0042] The term pharmaceutically acceptable refers to compounds or compositions that are physiologically tolerable and that normally do not produce an allergic or similar adverse reaction, including, but not limited to, gastric upset or dizziness, when administered to mammals.

[0043] The term pharmaceutically acceptable salt refers to a product obtained by reacting the compound of the present invention with a suitable acid or base. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic bases such as salts of Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn. Examples of pharmaceutically acceptable and non-toxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate or ptoluenesulfonate and the like.Certain compounds of the invention can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine, or metformin. Suitable base salts include, among others, aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc salts.

[0044] As used in this document, the term stereoisomer is a term used for all isomers of individual compounds of the compound of formula (I) that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror-image isomers (enantiomers) of compounds of the present invention, mixtures of mirror-image isomers (racemes, racemic mixtures) of compounds of the present invention, geometric isomers (cis / trans or E / Z, R / S) of compounds of the present invention and isomers of Petition 870250061458, dated 07 / 17 / 2025, page 23 / 223 14 / 93 compounds of the present invention having more than one chiral center that are not mirror images of each other (diastereomers).

[0045] In certain embodiments, the compounds of the present invention may also contain unnatural proportions of atomic isotopes in one or more of the atoms constituting those compounds. For example, the present invention also encompasses isotopically labeled variants of the present invention that are identical to those reported herein, except that one or more atoms of the compound are replaced by an atom with an atomic mass or mass number different from the predominant atomic mass or mass number normally found in nature for the atom. All isotopes of any particular atom or element, as specified, are contemplated within the scope of the compounds of the invention and their uses. Exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H (D), 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I, and 125I.The isotopically labeled compounds of the present invention can generally be prepared following procedures well known in the art, such as replacing an isotopically unlabeled reagent with an isotopically labeled reagent.

[0046] As used in this document, the term pharmaceutically acceptable vehicle refers to any of the standard pharmaceutical vehicles, such as phosphate-buffered saline solution, water, emulsions (e.g., oil-in-water or water-in-oil emulsions), and various types of wetting agents. Compositions may also include stabilizers and preservatives. Examples of vehicles, stabilizers, and adjuvants are mentioned in the literature, such as Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0047] The term treatment / to treat means any treatment of a Petition 870250061458, dated 07 / 17 / 2025, page 24 / 223 15 / 93 disease in a mammal, including: (a) Inhibiting the disease, that is, delaying or stopping the development of clinical symptoms; and / or (b) Relieving the disease, that is, causing the regression of clinical symptoms and / or (c) Attenuating or eliminating a disease and / or its concomitant symptoms.

[0048] As used in this document, the terms prevent, preventing, and prevention refer to a method of preventing the onset of a disease and / or its concomitant symptoms or that prevents an individual from acquiring a disease. As used in this document, prevent, preventing, and prevention also include delaying the onset of a disease and / or its concomitant symptoms and reducing an individual's risk of acquiring a disease.

[0049] As used in this document, the term individual refers to an animal, preferably a mammal and, most preferably, a human.

[0050] As used in this document, the term therapeutically effective amount refers to an amount of a compound of the present invention or a pharmaceutically acceptable salt or a stereoisomer thereof; or a composition comprising the compound of the present invention or a pharmaceutically acceptable salt or a stereoisomer thereof, effective in producing the desired therapeutic response in a particular patient suffering from AML. In particular, the term therapeutically effective amount includes the amount of the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, when administered, that induces a positive modification in the disease or disorder being treated or is sufficient to prevent the development or attenuate, to some extent, one or more symptoms of the disease or disorder being treated in an individual.With regard to the therapeutic amount of the compound, the amount of the compound used to treat an individual is low enough to avoid inappropriate or serious side effects, within the scope of sound medical criteria. A. Petition 870250061458, dated 07 / 17 / 2025, page 25 / 223 16 / 93 The therapeutically effective amount of the compound or composition will vary with the particular condition being treated, with the severity of the condition being treated or prevented, with the duration of treatment, with the nature of concomitant therapy, with the age and physical condition of the end user, with the specific compound or composition used, and with the particular pharmaceutically acceptable vehicle used.

[0051] In certain embodiments, the compounds of the invention may be used alone or administered in combination with another type of therapeutic agent. As used in this document, the phrase "combined administration" refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still in effect in the body (e.g., the two compounds are simultaneously in effect in the patient, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds may be administered in the same formulation or in a separate formulation, simultaneously or sequentially. In certain embodiments, the different therapeutic compounds may be administered within one hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or one week of each other.In some modalities, the additional therapeutic compound is administered within approximately 5 minutes to approximately 168 hours before or after the administration of compound formula I, compound formula II, or compound formula III. Thus, an individual receiving this treatment may benefit from a combined effect of different therapeutic compounds.

[0052] In certain embodiments, the combined administration of compounds of the invention with one or more additional therapeutic agents (for example, one or more additional chemotherapeutic agents) provides enhanced efficacy compared to each individual administration of the compound of the invention or of one or more agent(s). Petition 870250061458, dated 07 / 17 / 2025, p. 26 / 223 17 / 93 additional therapeutic agent(s). In some of these embodiments, co-administration provides an additive effect, where an additive effect refers to the sum of each of the effects of the individual administration of the compound of the invention and one or more additional therapeutic agents.

[0053] A method of treating or preventing acute myeloid leukemia in an individual is provided in this document, comprising administering a compound of Formula (I) (I) or a pharmaceutically acceptable salt thereof; in what The Zi ring is an optionally substituted heteroaryl; The Z2 ring is an optionally substituted heterocycloalkyl group, an optionally substituted heteroaryl group, or a direct linkage; Ri is alkyl, cyano, -NRaRb, or optionally substituted groups selected from cycloalkyl, aryl, or heterocyclyl; wherein the substituent, in each occurrence, is independently alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, -OCO-CH2O-alkyl, -OP(O)(O-alkyl)2, or -CH2-OP(O)(O-alkyl)2; R2, in each occurrence, is independently an optionally substituted group selected from alkyl or cycloalkyl; wherein the substituent, in each occurrence, is independently halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl or haloalkoxy; R3, in each occurrence, is independently hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, -NRaRb, hydroxyl, or hydroxyalkyl; Petition 870250061458, dated 07 / 17 / 2025, page 27 / 223 18 / 93 Ra is hydrogen or alkyl; Rb is hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl or optionally substituted cycloalkyl; 'm' and 'n' are independently 1 or 2.

[0054] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein the Zi Ring is an optionally substituted heteroaryl with 5 or 6 members.

[0055] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein Ring Zi is an optionally substituted heteroaryl; wherein the optional substituent is alkyl.

[0056] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the Zi Ring is selected from tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidil, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl and pyrazolyl.

[0057] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the Zi ring is selected from pyridyl, oxazolyl and furanyl; wherein the pyridyl group is optionally substituted with alkyl; in particular, the alkyl is methyl.

[0058] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring Z2 is a 5- or 6-membered heteroaryl selected from tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidil, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl or pyrazolyl.

[0059] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Petition 870250061458, dated 07 / 17 / 2025, page 28 / 223 19 / 93 The Z2 ring is a 5- or 6-membered heterocycloalkyl group selected from azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl or 1,4-dioxanyl.

[0060] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring Z2 is pyridyl, pyrazolyl or pyrrolidinyl.

[0061] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring Z2 is a direct link.

[0062] In some embodiments, the present methods include a compound of formula (I) that is a compound of formula (IA) or a pharmaceutically acceptable salt thereof; where Z2, R1, R2, R3, 'm' and 'n' are as defined in the compound of formula (I).

[0063] In some embodiments, the present methods include a compound of formula (I) that is a compound of formula (IB) or a pharmaceutically acceptable salt thereof; Petition 870250061458, dated 07 / 17 / 2025, p. 29 / 223 20 / 93 where Z2, Ri, R2, R3, 'm' and 'n' are as defined in the compound of formula (I).

[0064] In some embodiments, the present methods include a compound of formula (I) that is a compound of formula (IC) or a pharmaceutically acceptable salt thereof; where Z2, Ri, R2, R3, 'm' and 'n' are as defined in the compound of formula (I).

[0065] In some embodiments, the present methods include a where Ri, R2 and 'm' are as defined in the compound of formula (I).

[0066] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring Z2 is pyridyl.

[0067] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring Z2 is pyrazolyl. Petition 870250061458, dated 07 / 17 / 2025, p. 30 / 223 21 / 93

[0068] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring Z2 is pyrrolidinyl.

[0069] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ri is an optionally substituted heterocycline; wherein the substituent is halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2 or -CH2-OP(O)(O-alkyl)2.

[0070] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ri is optionally substituted azetidinyl, piperidinyl, morpholinyl, pyrrolidinyl or azepanyl; wherein the substituent is amino, halogen, hydroxyl, hydroxyalkyl, aminoalkyl, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2 or -CH2-OP(O)(O-alkyl)2.

[0071] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein Ri is an optionally substituted piperidinyl; wherein the optional substituent is hydroxyl.

[0072] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein Ri is an optionally substituted phenyl; wherein the optional substituent is a halogen.

[0073] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ri is cycloalkyl.

[0074] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ri is cyclopropyl or cyclohexyl. Petition 870250061458, dated 07 / 17 / 2025, p. 31 / 223 22 / 93

[0075] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ri is -NRaRb; Ra is hydrogen; Rb is optionally substituted cycloalkyl; wherein the substituent is hydroxyl.

[0076] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, where R1 is cyan.

[0077] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein R2 is an optionally substituted alkyl; wherein the optional substituent is alkoxy.

[0078] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 is cycloalkyl.

[0079] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen, halogen, alkyl, alkoxy, -NRaRb, hydroxyl or hydroxyalkyl; Ra is hydrogen or alkyl; and Rbé is hydrogen, alkyl, acyl, hydroxyalkyl or -SO2-alkyl.

[0080] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring Z1 is optionally substituted pyridyl; Ring Z2 is pyridyl, pyrazolyl, pyrrolidinyl or directly linked; R1 is an optionally substituted group selected from cyclopropyl, piperidinyl, morpholinyl or pyrrolidinyl; R2 is optionally substituted alkyl or cycloalkyl; R3 is hydrogen, halogen, alkyl, alkoxy, -NRaRb, hydroxyl or hydroxyalkyl; Ra is hydrogen or alkyl; and Rb is hydrogen or hydroxyalkyl.

[0081] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Petition 870250061458, dated 07 / 17 / 2025, page 32 / 223 23 / 93 Ring Z1 is oxazolyl; Ring Z2 is pyridyl, pyrazolyl or pyrrolidinyl; R1 is cyano, -NRaRb or an optionally substituted group selected from cyclopropyl, cyclohexyl, phenyl, azetidinyl, piperidinyl, morpholinyl or pyrrolidinyl; R2 is optionally substituted alkyl or cycloalkyl; R3 is hydrogen, halogen, alkyl, alkoxy, -NRaRb, hydroxyl or hydroxyalkyl; R1 is hydrogen or alkyl; and Rb is hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl or optionally substituted cycloalkyl.

[0082] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R3 is -NRaRb; Ra is hydrogen or alkyl; and Rb is hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl or optionally substituted cycloalkyl; wherein the optional substituent is hydroxyl;

[0083] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, where 'n' is 1.

[0084] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, where 'n' is 2.

[0085] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein 'm' is 1.

[0086] In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein 'm' is 2.

[0087] In some ways, these methods include a compound of formula (I) selected in:____________________________________ N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl)picolinamide; N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4Petição 870250061458, de 17 / 07 / 2025, pág. 33 / 223 24 / 93 carboxamide; N-(1 -methyl-6-(piperidin-1-yl)-1 H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4carboxamida; N-(2-cyclopentyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol4-carboxamide; N-(6-cyano-2-cyclopentyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4carboxamida; N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4carboxamida; N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-6-(1 H-pyrazol-4-yl)picolinamide; N-(2-cyclopentyl-6-morpholino-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4carboxamida; 2,2,2-trifluoroacetate de 6'-amino-N-(2-cyclopentyl-6-morpholino-2H-indazol-5yl)-[2,3'-bipyridino]-6-carboxamide; N-(6-(3-fluorophenyl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4carboxamida; N-(6-cyclo-hexyl-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4yl)oxazol-4-carboxamida hydrochloride; 6'-fluoro-N-(2-methyl-6-(piperidin-1 -yl)-2H-indazol-5-yl)-[2,3'bipyridino]-6-carboxamide hydrochloride; N-(6-cyclo-hexyl-2-methyl-2H-indazol-5-yl)-6-(1 H-pyrazol-4yl)picolinamide hydrochloride; 2'-fluoro-N-(2-methyl-6-(piperidin-1 -yl)-2H-indazol-5-yl)-[2,3'bipyridine]-6-carboxamide hydrochloride; 2-(2-chloropyridin-4-yl)-N-(2-methyl-6-(piperidin-1 -yl)-2H-indazol-5yl)oxazol-4-carboxamida hydrochloride; Cloridrato de N-(6-ciclopropil-2-metil-2H-indazol-5-il)-2-(2-metilpiridin-4Petição 870250061458, de 17 / 07 / 2025, pág. 34 / 223 25 / 93 il)oxazol-4-carboxamida; N-(1 -ciclopentil-6-ciclopropil-1 H-indazol-5-il)-6-(1-metil-1 H-pirazol-4il)picolinamida; N-(2-ciclopentil-6-ciclopropil-2H-indazol-5-il)-6-(1-metil-1H-pirazol-4il)picolinamida; 6-(1-metil-1 H-pirazol-4-il)-N-(2-metil-6-(piperidin-1 -il)-2H-indazol-5il)picolinamida; N-(2-ciclopentil-6-ciclopropil-2H-indazol-5-il)-2-(6-metoxipiridin-3-il)oxazol-4carboxamida; 2-(6-metoxipiridin-3-il)-N-(2-metil-6-(piperidin-1-il)-2H-indazol-5-il)oxazol-4carboxamida; N-(2-metil-6-(piperidin-1-il)-2H-indazol-5-il)-2-(3-metilpiridin-4-il)oxazol-4carboxamida; 6-bromo-N-(2-metil-6-(piperidin-1-il)-2H-indazol-5-il)picolinamida; 6-Gloro-5-metiJ-N-(2-metil-6-(piperidin212il)-2H2indazol-5-il)picolinamida N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(6-methylpyridin-3-yl)oxazol-4carboxamida; N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(2-methylpyridin-3-yl)oxazol-4carboxamida; N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(3-methylpyridin-4-yl)oxazol-4carboxamida; N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(6-methoxipyridin-3-yl)oxazol-4carboxamida; 6'-amino-3-methyl-N-(2-methyl-6-(piperidin-1 -yl)-2H-indazol-5-yl)[2,3'-bipyridine]-6-carboxamide hydrochloride; 5-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5yl)picolinamide; Petition 870250061458, 17 / 07 / 2025, pág. 35 / 223 26 / 93 N-(1 -cyclopropyl-6-(piperidin-1 -yl)-1 H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol4-carboxamide; 2-(2-hidroxypyridin-3-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4carboxamida; 2,2,2-trifluoroacetate de (S)-6-(3-aminopyrrolidin-1 -yl)-N-(2-methyl-6-(piperidin1-yl)-2H-indazol-5-yl)picolinamide; (S)-6-(1-(2-hidroxypropyl)-1 H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1 -yl)-2Hindazol-5-yl)picolinamide; N-(1,6-dicyclopropyl-1H-indazol-5-yl)-2-(6-methoxipyridin-3-yl)oxazol-4carboxamida; N-(1,6-dicyclopropyl-1 H-indazol-5-yl)-2-(2-methylpyridin-4yl)oxazol-4-carboxamida hydrochloride; (S)-N-(6-cyclopropyl-1 -methyl-1 H-indazol-5-yl)-6-(3-hydroxypyrrolidin-1 yl)picolinamide; (R)-6-(3-hidroxipyrrolidin-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5yl)picolinamide; (S)-6-(3-hidroxipyrrolidin-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5yl)picolinamide; 6-(3-hidroxipyrrolidin-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5yl)picolinamide; (S)-6-(3-aminopyrrolidin-1-yl)-N-(6-cyclopropyl-1-methyl-1H-indazol-5yl)picolinamide; (R)-6-(3-hidroxipyrrolidin-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5yl)picolinamide; (R)-6-(1-(2-hidroxypropyl)-1 H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1 -yl)-2Hindazol-5-yl)picolinamide; (S)-2-(3-aminopyrrolidin-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5Petição 870250061458, dated 17 / 07 / 2025, pág. 36 / 223 27 / 93 il)oxazol-4-carboxamida; N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4carboxamide; (S)-N-(6-cyclopropyl-1 -methyl-1 H-indazol-5-yl)-6-(1-(2-hidroxypropyl)-1 H-pyrazol4-yl)picoJinamida; (S)-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-6-(1-(2-hidroxypropyl)-1H-pyrazol4-yl)picolinamide; (S)-6-(3-aminopyrrolidin-1-yl)-N-(6-cyclopropyl-2-methyl-2H-indazol-5yl)picolinamide; (S)-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-6-(3-hidroxipyrrolidin-1yl)picolinamide; (S)-N-(6-cyclopropyl-1 -methyl-1 H-indazol-5-yl)-2-(3-hidroxipyrrolidin-1 -yl)oxazole4-carboxamida; (S)-2-(3-aminopyrrolidin-1-yl)-N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)oxazol4-carboxamide; (S)-2-(3-hidroxipyrrolidin-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5yl)oxazol-4-carboxamida; (S)-N-(6-cyclopropyl-1 -methyl-1 H-indazol-5-yl)-2-(1-(2-hidroxypropyl)-1 H-pyrazol4-yl)oxazol-4-carboxamida; (S)-2-(3-aminopyrrolidin-1-yl)-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)oxazol4-carboxamide; (S)-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-2-(3-hidroxipyrrolidin-1-yl)oxazol4-carboxamida; (S)-6-(1-(2-hidroxypropyl)-1 H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1 -yl)-2Hindazol-5-yl)picolinamide; 6-((2-hidroxypropyl)amino)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5yl)picolinamide; Petition 870250061458, 17 / 07 / 2025, pág. 37 / 223 28 / 93 N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4yl)oxazol-4-carboxamide; N-(6-(azetidin-1 -yl)-1-methyl-1 H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4carboxamide; N-(6-(azetidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4carboxamide; N-(6-(3-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4yl)oxazol-4-carboxamide; N-(1 -methyl-6-(piperidin-1-yl)-1 H -indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4carboxamide; N-(2-methyl-6-(pyrrolidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4carboxamide; (S)-N-(6-(3-hydroxypyrrolidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4yl)oxazol-4-carboxamide; (R)-N-(6-(3-hydroxypyrrolidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4yl)oxazol-4-carboxamide; N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2carboxamide; N-(6-(4-hydrroxipiperidin-1-il)-2-metil-2H-indazol-5-il)-5-(2-metilpiridin-4il)furan-2-carboxamida; N-(6-(3-hydrroxipiperidin-1-il)-2-metil-2H-indazol-5-il)-2-(2-metilpiridin-4il)oxazol-4-carboxamida; (R)-N-(6-(3-hydrroxipiperidin-1-il)-2-metil-2H-indazol-5-il)-5-(2-metilpiridin-4il)furan-2-carboxamida; N-(6-(3-hydrroxipiperidin-1-il)-2-metil-2H-indazol-5-il)-5-(2-metilpiridin-4il)furan-2-carboxamida; N-(6-(azepan-1-il)-2-metil-2H-indazol-5-il)-2-(2-metilpiridin-4-il)oxazol-4Petição 870250061458, on 07 / 17 / 2025, page. 38 / 223 29 / 93 carboxamida; N-(6-(azepan-1 -il)-1-metil-1 H-indazol-5-il)-2-(2-metilpiridin-4-il)oxazol-4carboxamida; N-(2,3-dimetil-6-(piperidin-1-il)-2H-indazol-5-il)-2-(2-methylpiridin-4-il)oxazol-4carboxamida; N-(1,3-dimetil-6-(piperidin-1 -il)-1 H-indazol-5-il)-2-(2-metilpiridin-4-il)oxazol-4carboxamida; N-(6-(4-hydroxypiperidin-1 -yl)-1 -(2-methoxyethyl)-1 H -indazol-5-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-hydroxypiperidin-1-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-hydroxypiperidin-1 -yl)-1 -methyl-1 H -indazol-5-yl)-2-(2-methylpyridin-4yl)oxazol-4-carboxamide; N-(6-(4-fluoropiperidin-1 -yl)-1 -methyl-1 H -indazol-5-yl)-2-(2-methylpyridin-4yl)oxazol-4-carboxamide; N-(6-(3-hydroxypipendin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpindin-4yl)oxazol-4-carboxamide; N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-hydroxypiperidin-1-yl)-1,3-dimethyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(3-(hydroxymethyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-hydroxypiperidin-1-yl)-2,3-dimethyl-2H-indazol-5-yl)-2-(2-methylpyridin-4yl)oxazol-4-carboxamide; 2-(2-hydroxypyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4carboxamide; Petition 870250061458, de 17 / 07 / 2025, pág. 39 / 223 30 / 93 2-(2-acetamidopyridin-4-yl)-N-(6-(3-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5yl)oxazol-4-carboxamide; Cloridrato de 2-(2-aminopyridin-4-yl)-N-(2-methyl-6-(piperidin-1 -yl)-2H-indazol5-yl)oxazol-4-carboxamide; N-(6-(4-fluoropiperidin-1-yl)-1,3-dimethyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(((1R,4R)-4-hydroxyciclo-hexyl)amino)-2-methyl-2H-indazol-5-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; Cloridrato de 2-(2-aminopyridin-4-yl)-N-(6-(4-fluoropiperidin-1-yl)-2-metil-2Hindazol-5-yl)oxazol-4-carboxamida; Cloridrato de N-(6-(4-fluoropiperidin-1 -yl)-2-metil-2H-indazol-5-yl)-2-(2metilpyridin-4-yl)oxazol-4-carboxamida; (S)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-6-(1-(2hydroxypropyl)-1H-pyrazol-4-yl)picolinamide; Cloridrato de 2-(2-aminopyridin-4-yl)-N-(6-(4-hydroxypiperidin-1 -yl)-2-metil-2Hindazol-5-yl)oxazol-4-carboxamida; N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2methylpyridin-4-yl)oxazole-4-carboxamide; (S)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-5-yl)-6-(1-(2hydroxypropyl)-1H-pyrazol-4-yl)picolinamide; N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl)-2-(2methylpyridin-4-yl)oxazole-4-carboxamide; N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2methoxypyridin-4-yl)oxazol-4-carboxamide; 2-(2-acetamidopyridin-4-yl)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2HPetição 870250061458, de 17 / 07 / 2025, pág. 40 / 223 31 / 93 indazol-5-yl)oxazol-4-carboxamide; Cloridrato de 2-(2-aminopyridin-4-yl)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1methyl-1H-indazol-5-yl)oxazol-4-carboxamide; Cloridrato de 2-(2-aminopyridin-4-yl)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2methyl-2H-indazol-5-yl)oxazol-4-carboxamide; N-(6-(4-hydroxypiperidin-1 -yl)-1 -methyl-1 H -indazol-5-yl)-2-(2-methoxypyridin-4yl)oxazol-4-carboxamide; Cloridrato de 2-(2-aminopyridin-4-yl)-N-(6-(3-hydroxypiperidin-1 -yl)-2-methyl-2Hindazol-5-yl)oxazol-4-carboxamide; 2-(2-hydroxypyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4carboxamide; Cloridrato de 2-(2-aminopyridin-4-yl)-N-(6-(3-fluoropiperidin-1-yl)-2-metil-2Hindazol-5-yl)oxazol-4-carboxamida; Cloridrato de (R)-2-(2-aminopyridin-4-yl)-N-(6-(3-hydroxypiperidin-1-yl)-2-metil2H-indazol-5-yl)oxazol-4-carboxamida; 2-methoxyacetate of 1-(1,3-dimethyl-5-(2-(2-methylpyridin-4-yl)oxazol-4carboxamido)-1H-indazol-6-yl)piperidin-4-yl Cloridrato de N-(6-(4-hydroxypiperidin-1 -yl)-2-metil-2H-indazol-5-yl)-2-(2methoxypyridin-4-yl)oxazol-4-carboxamida; N-(6-(4-hydroxypiperidin-1-yl)-1-(2-methoxyethyl)-1H-indazol-5-yl)-2(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; Cloridrato de N-(6-(4-aminopiperidin-1 -yl)-2-metil-2H-indazol-5-yl)-2-(2metilpyridin-4-yl)oxazol-4-carboxamida; N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-(2-methoxyethyl)-3-methyl-1H-indazol-5-yl)-2(2-methylpyridin-4-yl)oxazole-4-carboxamide; N-(6-(4-(hydroxymetil)piperidin-1 -yl)-1,3-dimethyl-1H-indazol-5-yl)-2-(2metilpyridin-4-yl)oxazol-4-carboxamide; Petition 870250061458, de 17 / 07 / 2025, pág. 41 / 223 32 / 93 2-(2-aminopyridin-4-yl)-N-(6-(4-(hydroxymetil)piperidin-1-yl)-1,3-dimethyl-1 Hindazol-5-yl)oxazol-4-carboxamide; N-(6-(4-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methoxypyridin-4-yl)oxazole-4-carboxamide; 2-(2,6-dimethylpyridin-4-yl)-N-(6-(4-hydroxypiperidin-1-yl)-1 -metil-1 H -indazol-5yl)oxazol-4-carboxamide; (S)-N-(6-(3-hydroxypyrrolidin-1-yl)-1 -metil-1H-indazol-5-yl)-2-(2-metilpyridin-4yl)oxazol-4-carboxamide; N-(6-(4-hydroxypiperidin-1-yl)-1-(2-methoxyethyl)-3-methyl-1H-indazol-5-yl)-2-(2methylpyridin-4-yl)oxazole-4-carboxamide; N-(1-(2-hydroxyethyl)-6-(4-hydroxypiperidin-1-yl)-1H-indazol-5-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamide; Cloridrato de N-(6-(4-aminopiperidin-1 -yl)-2-(2-methoxyethyl)-2H-indazol-5-yl)-2(2-methylpyridin-4-yl)oxazol-4-carboxamide; Cloridrato de 2-(2,6-dimethylpyridin-4-yl)-N-(2-methyl-6-(piperidin-1 -yl)-2Hindazol-5-yl)oxazol-4-carboxamide; 2-(2-(dimethylamino)pyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5jJJoxazoM-carboxamide; N-(6-(4-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-(methylamino)pyridin-4-yl)oxazol-4-carboxamide; N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(2-(methylamino)pyridin-4yl)oxazol-4-carboxamide; N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2(methylsulfonamido)pyridin-4-yl)oxazol-4-carboxamide; 2-(2-(dimethylamino)pyridin-4-yl)-N-(6-(4-hydroxypiperidin-1-yl)-1-methyl-1-hindazol-5-yl)oxazol-4-carboxamide; N-(6-(4-(aminomethyl)piperidin-1 -yl)-1 -(2-methoxyethyl)-1 H-indazol-5-yl)-2-(2Petição 870250061458, de 17 / 07 / 2025, pág. 42 / 223 33 / 93 methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2,6-dimethylpyridin-4-yl)-N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5yl)oxazol-4-carboxamide; 2-(2,6-dimethylpyridin-4-yl)-N-(6-(4-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5yl)oxazol-4-carboxamide; diethyl (1-(1-methyl-5-(2-(2-methylpyridin-4-yl)oxazol-4-carboxamido)-1H-indazol-6yl)piperidin-4-yl)phosphate; and diethyl ((1-(2-methyl-5-(2-(2-methylpyridin-4-yl)oxazol-4-carboxamido)-2H-indazol-6yl)piperidin-4-yl)methyl)phosphate; or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0088] This document provides a method for treating or preventing acute myeloid leukemia in an individual, comprising administering a compound of Formula (II): (II) X1 or a pharmaceutically acceptable salt thereof; in what Xi and X3 are independently either CH or N; X2 is CR2 or N; provided that one and no more than one of Xi, X2, or X3 is N; A is O or S; Y is -CH2- or O; The Z ring is aryl or heterocyclyl; Ri, in each occurrence, is independently a halo or optionally substituted heterocycline; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, Petition 870250061458, dated 07 / 17 / 2025, page 43 / 223 34 / 93 hydroxyl, hydroxyalkyl or -NRaRb; R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or -NRaRb; wherein the substituent is alkyl, amino, halo or hydroxyl; R3, in each occurrence, is either alkyl or hydroxyl; Ra and Rb are independently hydrogen, alkyl, acyl, or heterocyclyl; 'm' and 'n' are independently 0, 1, or 2; 'p' is 0 or 1.

[0089] In some embodiments, the present methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein -KΎ T the groupλι and where R2 is as defined in the compound of formula (II).

[0090] In some embodiments, the present methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein Ring Z is a 5- or 6-membered aryl or heterocycline.

[0091] In some embodiments, the present methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein Ring Z is phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxetanyl, imidazolinidyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, Petition 870250061458, dated 07 / 17 / 2025, p. 44 / 223 35 / 93 pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl or dihydropyranyl; each of which is optionally substituted with alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl or -NRaRb; Ra and Rb are independently hydrogen, alkyl or acyl.

[0092] In some embodiments, the present methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein Ring Z is phenyl, oxazolyl, furanyl, thienyl or pyridyl; each of which is optionally replaced with one or more Ri.

[0093] In some embodiments, the present methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof, where / Vip \ Y N->é where R3 and 'm' are defined in the compound of formula (II).

[0094] In some embodiments, the present methods include a compound of formula (II) that is a compound of formula (IIA): (IIA) or a pharmaceutically acceptable salt thereof; where A, Y, Ri, R2, R3, 'm', 'p' and 'n' are as defined in the compound of formula (II).

[0095] In some embodiments, the present methods include a Petition 870250061458, dated 07 / 17 / 2025, p. 45 / 223 36 / 93 compound of formula (II) which is a compound of formula (IIB): (Rl)n or a pharmaceutically acceptable salt thereof; where A, Y, Ri, R2 and 'n' are as defined in the compound of formula (II).

[0096] In some embodiments, the present methods include a compound of formula (II) that is a compound of formula (IIC): or a pharmaceutically acceptable salt thereof; where A, Y, Ri, R2, R3 and 'n' are as defined in the compound of formula (I).

[0097] In some embodiments, the present methods include a compound of formula (II), (IIA), (IIB) or (IIC) or a pharmaceutically acceptable salt thereof, wherein Y is O or CH2.

[0098] In some embodiments, the present methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein Ri is optionally substituted heterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or -NRaRb; Ra and Rb are independently hydrogen, alkyl or acyl.

[0099] In some embodiments, the present methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein Ri is pyridyl, pyrazolyl, pyrrolidinyl or piperidinyl; each of which is Petition 870250061458, dated 07 / 17 / 2025, p. 46 / 223 37 / 93 optionally substituted with alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl or NRaRb; Ra and Rb are independently hydrogen or acyl.

[00100] In some embodiments, the present methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

[00101] In some embodiments, the present methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is an optionally substituted cycloalkyl.

[00102] In some embodiments, the present methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is cyclopropyl.

[00103] In some embodiments, the present methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof; wherein R2 is an optionally substituted heterocycline; wherein the substituent is alkyl, amino, halo or hydroxyl.

[00104] In some embodiments, the present methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolyl, furanyl, pyridyl, azepanyl or azabicyclo[3.2.1]octanyl; wherein the substituent is alkyl, amino, halo or hydroxyl.

[00105] In some embodiments, the present methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof; where R2 is an optionally substituted aryl; where the substituent is halo.

[00106] In some embodiments, the present methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof; wherein R2 is an optionally substituted phenyl; wherein the optional substituent is fluoro.

[00107] In some embodiments, the present methods include a Petition 870250061458, dated 07 / 17 / 2025, p. 47 / 223 38 / 93 compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is -NRaRb; wherein Ra and Rb are independently hydrogen or heterocycline.

[00108] In some embodiments, the present methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is -NRaRb; wherein Ra and Rb are independently hydrogen or pyrrolidinyl.

[00109] In some embodiments, the present methods include a compound of formula (IIA) or a pharmaceutically acceptable salt thereof, wherein A is O or S; Y is -CH2- or O; Ri is halo, pyridyl, pyrazolyl, pyrrolidinyl, each of which is optionally substituted with alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl or -NRaRb; R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or -NRaRb; wherein the substituent is alkyl, amino, halo or hydroxyl; Ra and Rb are independently hydrogen or alkyl.

[00110] In some embodiments, the present methods include a compound of formula (IIB) or a pharmaceutically acceptable salt thereof, wherein A is O or S; Y is -CH2- or O; Ri is pyridyl, pyrazolyl, pyrrolidinyl; each of which is optionally substituted with alkyl, hydroxyl, hydroxyalkyl or -NRaRb; Ra and Rb are independently hydrogen; R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or -NRaRb; wherein the substituent is alkyl, amino, halo or hydroxyl; Ra and Rb are independently hydrogen, alkyl, acyl or heterocyclyl.

[00111] In some embodiments, the present methods include a compound of formula (IIA), (IIB) or (IIC), or a pharmaceutically acceptable salt thereof, where 'n' is 0, 1 or 2.

[00112] In some embodiments, the present methods include a compound of formula (IIA) or (IIB), or a pharmaceutically acceptable salt thereof, where 'p' is 0 or 1. Petition 870250061458, dated 07 / 17 / 2025, p. 48 / 223 39 / 93

[00113] In some embodiments, the present methods include a compound of formula (IIA) or (IIB), or a pharmaceutically acceptable salt thereof, where 'm' is 0 or 2.

[00114] In some embodiments, the present methods include a compound of formula (II) selected from: 6'-amino-N-(2-morpholino-oxazolo[4,5-b]pyridin-6-yl)-[2,3'-bipyridine]-6carboxamide; 6'-amino-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-[2,3'bipyridine]-6-carboxamide; N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol4-yl)picolinamide hydrochloride; N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol4-carboxamide; N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4yl)picolinamide; 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 6-chloro-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6yl)picolinamide; N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1-methyl-1H-pyrazol-4yl)picolinamide; 2-(2-chloropyridin-4-yl)-N-(2,5-di(piperidin-1-yl)oxazol[4,5-b]pyridin-6yl)oxazol-4-carboxamide; (S)-2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-3-ylamino)oxazolo[4,5b]pyridin-6-yl)oxazol-4 carboxamide; 6'-amino-N-(2-morpholinooxazolo[5,4-b]pyridin-5-yl)-[2,3-bipyridine]-6carboxamide; 6'-amino-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)-[2,3'-bipyridina]-6Petição 870250061458, de 17 / 07 / 2025, pág. 49 / 223 40 / 93 carboxamide; 6'-amino-N-(2-morpholinothiazolo[5,4-b]pyridin-5-yl)-[2,3'-bipyridino]-6carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazol·4carboxamide; 6'-amino-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)-[2,3'-bipyridine]-6carboxamide; N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide; 3-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazolo[4,5-b]pyridin6-yl)benzamide; 2-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazolo[4,5-b]pyridin6-yl)benzamide; 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4yl)picolinamide; N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4yl)picolinamide; N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2,5-dimorpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4carboxamide; N-(5-(4-methylpiperazin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2methylpyridina-4-yl)oxazol-4-carboxamide; N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-3-yl)oxazol4-carboxamide; N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-hydroxypyridin-3-yl)oxazol-4-carboxamide; 2-(2-hydroxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; Petition 870250061458, de 17 / 07 / 2025, pág. 50 / 223 41 / 93 N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-hydroxypyridin-3-yl)oxazol-4-carboxamide; 2-(2-methoxypyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(3-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(3-methylpyridin-4-yl)oxazol4-carboxamide; 2-(6-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 6-(1-methyl-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5b]pyridin-6-yl)picolinamide; N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-methylpyridin-3-yl)oxazol4-carboxamide; (S)-N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(5-(3-fluoropyrrolidine-1-yl)-2-morpholinooxazole[4,5-b]pyridine-6-yl)-2-(2methylpyridine-4-yl)oxazol-4-carboxamida; (R)-N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinooxazole[4,5-b]pyridin-6-yl)-2-(2methylpyridine-4-yl)oxazol-4-carboxamida; (R)-N-(5-(3-hidroxipyrrolidin-1-yl)-2-morpholinooxazole[4,5-b]pyridin-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamida; (S)-2-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5b]pyridin-6-yl)oxazol-4-carboxamide; (S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazol[4,5b]pyridin-6-yl)picolinamida; (S)-6-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5b]pyridin-6-yl)picolinamida; (S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5b]pyridin-6-yl)oxazol-4-carboxamide; Petition 870250061458, 17 / 07 / 2025, pág. 51 / 223 42 / 93 (S)-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(3hydroxypyrrolidin-1-yl)oxazol-4-carboxamide; (S)-2-(3-aminopyrrolidin-1-yl)-N-(5-cyclopropyl-2-morpholinooxazolo[4,5b]pyridin-6-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(5-(piperidin-1 -yl)-2-(pyrrolidin-1 il)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamida hydrochloride; N-(2-(2,6-dimethylmorpholino)-5-(piperidin-1-yl)oxazolo[4,5b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1-methyl-1 Hpirazol-4-yl)picolinamide hydrochloride; 6-(1-methyl-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5b]pyridin-6-yl)picolinamide; N-(2,5-di(piperidin-1 -yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2methylpyridin-3-yl)oxazol-4-carboxamide hydrochloride; N-(2-((2S,6R)-2,6-dimethylmorpholino)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 2-(2-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 2-(2-hydroxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; N-(2,5-di(pipendin-1-yl)thiazolo[4,5-b]pindin-6-yl)-2-(2-methoxypindin-4yl)oxazol-4-carboxamide; 2-(6-methoxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5b]pyridin-6-yl)oxazole-4-carboxamide; 2-(2-methoxypyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; (S)-N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamide; 2-(6-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 2-(3-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6yl)oxazol-4-carboxamida; Petition 870250061458, 17 / 07 / 2025, pág. 52 / 223 43 / 93 (S)-6-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5b]pyridine-6-yl)picolinamide; (S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5b]pyridin-6-yl)picolinamide; (S)-6-(3-aminopyrrolidin-1-yl)-N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6yl)picolinamide; (S)-N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1yl)picolinamide; (S)-2-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5b]pyridin-6-yl)oxazole-4-carboxamide; (S)-N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2methylpyridine-4-yl)oxazole-4-carboxamide; (S)-2-(3-aminopyrrolidin-1-yl)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin6-yl)oxazole-4-carboxamide; N-(5-cyclopropyl-2-morpholinothiazole[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4yl)oxazol-4-carboxamida; (S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(pipendin-1-yl)thiazolo[4,5b]pyridin-6-yl)oxazol-4-carboxamide; (S)-N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(3hydroxypyrrolidin-1-yl)picolinamide; (S)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(3hydroxypyrrolidin-1-yl)oxazol-4-carboxamide; (S)-N-(5-cyclopropyl-2-morpholinothiazole[4,5-b]pyridin-6-yl)-6-(1-(2hidroxypropyl)-1H-pyrazol-4-yl)picolinamide; (S)-N-(5-cyclopropyl-2-morpholinothiazole[4,5-b]pyridin-6-yl)-2-(1-(2hidroxypropyl)-1 H-pyrazol-4-yl)oxazol-4 -carboxamida; N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6methoxypyridin-3-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6methoxypyridin-3-yl)oxazol-4-carboxamide; Petition 870250061458, 17 / 07 / 2025, pág. 53 / 223 44 / 93 (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6methoxypyridin-3-yl)oxazol-4-carboxamide; (S)-N-(5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(3hydroxypyrrolidin-1-yl)picolinamida; N-(5-(3-hidroxiazetidin-1-yl)-2-morpholinothiazole[4,5-b]pyridin-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamida; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2methylpyridin-4-yl)thiophene-2-carboxamide; (S)-N-(5-(3-hydroxypyrrolidine-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2methylpyridine-4-yl)furan-2-carboxamide; (S)-N-(5-(3-hidroxipiperidin-1-yl)-2-morpholinothiazole[4,5-b]pyridin-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamida; N-(5-(4-hidroxipiperidin-1-yl)-2-morpholinothiazole[4,5-b]pyridin-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamida; (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2methylpyridin-4-yl)furan-2-carboxamide; N-(5-(azetidin-1-yl)-2-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin4-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)thiazol[4,5-b]pyridin6-yl)oxazol-4-carboxamida; 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6yl)oxazole-4-carboxamide; 5-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6yl)furan-2-carboxamide; N-(5-(azepan-1-yl)-2-morpholinothiazole[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4yl)oxazol-4-carboxamida; 2-(2-aminopyridin-4-yl)-N-(2-morpholino-5-(piperidin-1 il)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide hydrochloride; N-(5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4yl)oxazole-4-carboxamide; Petition 870250061458, 17 / 07 / 2025, pág. 54 / 223 45 / 93 (R)-N-(5-(3-hidroxipipendin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2methylpyridin-4-yl)furan-2-carboxamide; (S)-6-(1-(2-hidroxypropyl)-1 H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1 yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide; N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2methylpyridin-4-yl)furan-2-carboxamide; N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazole[4,5-b]pyridin-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamida; N-(5-(1-methyl-1 H-pyrazol-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(3-fluorophenyl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4yl)oxazol-4-carboxamide; N-(5-(4-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2methylpyridin-4-yl)furan-2-carboxamide; N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2methylpyridin-4-yl)furan-2-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6methoxypyridin-3-yl)oxazol-4-carboxamide; N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6methoxypyridin-3-yl)oxazol-4-carboxamide; N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6methoxypyridin-3-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hidroxipyrrolidin-1-yl)-2-morpholinooxazole[4,5-b]pyridin-6-yl)-5-(2methylpyridine-4-yl)furan-2-carboxamida; (S)-N-(5-(3-hidroxipyrrolidin-1-yl)-2-morpholinooxazole[4,5-b]pyridin-6-yl)-5-(2methylpyridin-4-yl)thiopheno-2-carboxamida; N-(5-(azetidin-1-yl)-2-(pipendin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamide; Petition 870250061458, 17 / 07 / 2025, pág. 55 / 223 46 / 93 2-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)oxazolo[4,5b]pyridin-6-yl)oxazol-4-carboxamide; 5-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6yl)furan-2-carboxamide; N-(5-(azetidin-1-yl)-2-morpholinooxazole[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4yl)oxazol-4-carboxamida; 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-1-yl)oxazole[4,5-b]pyridin-6yl)oxazol-4-carboxamida; N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2methylpyridin-4-yl)furan-2-carboxamide; (R)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2methylpyridin-4-yl)furan-2-carboxamide; N-(5-(furan-3-yl)-2-morpholinooxazolo[4,5-b]pindin-6-yl)-2-(2-methylpindin-4yl)oxazol-4-carboxamide; N-(5-(3-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(5-(3-aminopiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(1H-pyrazol-4-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; N-(5-(6-fluoropyridin-3-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-2-morpholinothiazolo[4,5-b]pyridin6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamida; N-(2-(3-hidroxipiperidin-1-yl)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamida; 2-(2-acetamidopyridin-4-yl)-N-(5-(4-hidroxipiperidin-1-yl)-2morpholinothiazole[4,5-b]pyridin-6-yl)oxazol-4-carboxamida; Petition 870250061458, 17 / 07 / 2025, pág. 56 / 223 47 / 93 N-(2-(3-hidroxipiperidin-1-yl)-5-(4-hidroxipiperidin-1-yl)thiazolo[4,5-b]pyridin-6yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamida; 2-(2-acetamidopyridin-4-yl)-N-(5-(3-hidroxipiperidin-1-yl)-2morpholinothiazole[4,5-b]pyridin-6-yl)oxazol-4-carboxamida; 2-(2-aminopiridin-4-yl)-N-(5-(3-hidroxipiperidin-1-yl)-2morfolinothiazolo[4,5-b]piridin-6-yl)oxazol-4-carboxamida hydrochloride; 5-(2-aminopiridin-4-yl)-N-(5-(4-hidroxipiperidin-1-yl)-2morfolinothiazolo[4,5-b]piridin-6-yl)furan-3-carboxamida hydrochloride; 2-(2-aminopiridin~4-yl)-N-(5-(4-hidroxipiperidin-1-yl)-2morfolinothiazolo[4,5-b]piridin-6-yl)oxazol-4-carboxamida hydrochloride; 2-(2-aminopyridin-4-yl)-N-(5-(4-fluoropiperidin-1 -yl)-2morpholinothiazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide hydrochloride; N-(5-(2-fluoropyridin-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-fluoropiperidin-1-yl)-2-(3-hidroxipiperidin-1-yl)thiazolo[4,5-b]pyridin-6yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamida; N-(5-(4-aminopiperidin-1-yl)-2-(3-hydroxypiperidin-1yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; and N-(5-(2-hydroxypyridin-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; or a pharmaceutically acceptable salt or a stereoisomer thereof.

[00115] This document provides a method for treating or preventing acute myeloid leukemia in an individual, comprising administering a compound of Formula (III): (III) or a pharmaceutically acceptable salt thereof; in what Petition 870250061458, dated 07 / 17 / 2025, page 57 / 223 48 / 93 Zi represents optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or is absent; Z2 represents optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclyl; Ri is hydrogen, optionally substituted alkyl, amino, halo, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl; R2, in each occurrence, is amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted heterocyclylalkyl; R3, in each occurrence, is hydroxyl, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, or -NRaRb; Ra and Rb, independently for each occurrence, are hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted heterocyclylalkyl; m, in each occurrence, is 0, 1, or 2; en, in each occurrence, is 0, 1, or 2.

[00116] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z1 is an optionally substituted heterocycline.

[00117] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Petition 870250061458, dated 07 / 17 / 2025, page 58 / 223 49 / 93 Zi represents cycloalkyl, aryl, or heterocyclyl, optionally substituted by one or more substituents selected independently for each occurrence from hydroxyl, halo, alkyl, cycloalkyl, or NRaRb.

[00118] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof; wherein Z1 is an optionally substituted heteroaryl; wherein the optional substituent is alkyl or cycloalkyl.

[00119] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically oitable salt thereof, wherein Z1 is tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, imidazolyl,; oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, pyrazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, α-carboline, indolizinyl, benzoisothiazolyl, benzoxazolyl, pyrrolopyridyl, furopyridinyl, purinyl, benzothiadiazolyl, benzo-oxadiazolyl, benzotriazolyl, benzotriadiazolyl, carbazolyl, dibenzothienyl, acridinyl and pyrazolopyrimidil; each of the two quais is optionally substituted.

[00120] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z1 is tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidil, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl or pyrazolyl.

[00121] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z1 is pyridyl or oxazolyl; wherein the oxazolyl group is optionally substituted with alkyl; in particular, the alkyl is methyl. Petition 870250061458, dated 07 / 17 / 2025, p. 59 / 223 50 / 93

[00122] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, in which Zi is absent.

[00123] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 is cycloalkyl, aryl or heterocyclyl.

[00124] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 represents cycloalkyl, aryl or heterocyclyl, optionally substituted by one or more substituents selected from hydroxy, halo, alkyl, cycloalkyl, -NRaRb, or cycloalkoxy.

[00125] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 is heterocycline.

[00126] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically oitable salt thereof, wherein Z2 is azetidinyl, oxetanyl, furanyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,4-dioxanil, tetra-hydropyranyl,; tetra-hydrofuranyl, tetra-hydropyridyl, tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, imidazolidinyl, imidazolyl, thiadiazolyl, thiazolyl, thiazolidinyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolidinyl, oxazolidinyl, pyrazolidinyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinylpyrrolopyridyl or pyrazolopyrimidyl.

[00127] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 is pyridyl, piperazinyl, pyrimidinyl, pyrrolidinyl, 1,2,3,4-tetrahydropyridyl, piperidinyl, pyrazolopyrimidinyl or pyrrolopyridyl. Petition 870250061458, dated 07 / 17 / 2025, p. 60 / 223 51 / 93

[00128] In certain embodiments, the compound of formula (III) is a compound of formula (IIIA) (IIIA) or a pharmaceutically acceptable salt thereof; where Z2, R1, R2, R3, 'm' and 'n' are as defined in the compound of formula (III).

[00129] In certain embodiments, the compound of formula (III) is a compound of formula (IIIB) (IIIB) or a pharmaceutically acceptable salt thereof; where Z2, R1, R2, R3, 'm' and 'n' are as defined in the compound of formula (III).

[00130] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Petition 870250061458, dated 07 / 17 / 2025, p. 61 / 223 52 / 93 R2 OUR2 where R1, R2 and 'm' are as defined in the compound of formula (III).

[00131] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 is a pyridyl.

[00132] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, where Z2 is pyrrolidinyl.

[00133] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 is piperidinyl, piperazinyl, tetrahydropyridyl, pyrimidinyl or pyrazolopyridyl.

[00134] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, optionally substituted alkyl, amino, halo, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl.

[00135] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R1 is alkyl, cycloalkyl, aryl, heterocyclyl, arylalkyl, optionally substituted with one or more substituents selected independently for each occurrence from hydroxyl, halo, alkyl or hydroxyalkyl.

[00136] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R1 is heterocycline; optionally substituted with halogen, hydroxyl or Petition 870250061458, dated 07 / 17 / 2025, p. 62 / 223 53 / 93 hydroxyalkyl.

[00137] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Ri is optionally substituted azetidinyl, piperidinyl, morpholinyl, pyrrolidinyl or azepanil.

[00138] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Ri is a piperidinyl, optionally substituted with a hydroxyl group.

[00139] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Ri is pyrrolidinyl, optionally substituted with hydroxyl.

[00140] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R2, in each occurrence, is amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl.

[00141] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R2 is alkyl, cycloalkyl, aryl, heterocyclyl, arylalkyl, or heterocyclylalkyl optionally substituted with one or more substituents selected independently for each occurrence from alkyl, cycloalkyl, or heterocyclyl.

[00142] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R2 is an optionally substituted alkyl, preferably methyl.

[00143] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Petition 870250061458, dated 07 / 17 / 2025, p. 63 / 223 54 / 93 R2 is an optionally substituted cycloalkyl group, preferably cyclopropyl.

[00144] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R3, in each occurrence, is hydroxy, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl or -NRaRb; wherein Ra is hydrogen or optionally substituted alkyl; and Rb is hydrogen, optionally substituted alkyl, optionally substituted acyl, hydroxyalkyl or -SO2alkyl.

[00145] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Zi is optionally substituted pyridyl; Z2 is pyrrolidinyl; Ri is an optionally substituted group selected from piperidinyl or pyrrolidinyl; R2 is optionally substituted alkyl; R3 is halogen, alkyl, -NRaRb, hydroxyl or hydroxyalkyl; Ra is hydrogen or alkyl; and Rb is hydrogen or hydroxyalkyl.

[00146] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Zi is oxazolyl; Z2 is pyridyl, pyrimidinyl or pyrrolidinyl, piperidinyl, tetrahydropyridyl, piperazinyl, pyrrolopyridyl; Ri is an optionally substituted group selected from piperidinyl or pyrrolidinyl; R2 is optionally substituted alkyl or cyclopropyl; R3 is optionally substituted halogen, alkyl, alkoxy, -NRaRb, hydroxyl, hydroxyalkyl, cyclopropyl; Ra is hydrogen or alkyl; and Rb is optionally substituted hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl or cycloalkyl.

[00147] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein 'm' is 0.

[00148] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Petition 870250061458, dated 07 / 17 / 2025, p. 64 / 223 55 / 93 'm' is 1.

[00149] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein 'm' is 2.

[00150] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, where 'n' is 0.

[00151] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, where 'n' is 1.

[00152] In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, where 'n' is 2.

[00153] In some embodiments, the present methods include a compound of formula (III) selected from:________________________________ Cloridrato de N-(1-metil-5-(piperidin-1-il)-1H-indazol-6-il)-2-(2-metilpiridin-4il)oxazol-4-carboxamida; Cloridrato de N-(2-metil-5-(piperidin-1 -il)-2H-indazol-6-il)-2-(2-metilpiridin-4il)oxazol-4-carboxamida; (S)-6-(3-hidroxipirrolidin-1-il)-N-(2-methyl-5-(piperidin-1-il)-2H-indazol-6il)picolinamida; (S)-2-(3-aminopirrolidin-1-il)-N-(1-metil-5-(piperidin-1-il)-1H-indazol-6il)oxazol-4-carboxamida; (S)-2-(3-aminopirrolidin-1-il)-N-(2-methyl-5-(piperidin-1-il)-2H-indazol-6il)oxazol-4-carboxamida; (S)-2-(3-hidroxipirrolidin-1-il)-N-(2-metil-5-(piperidin-1-il)-2H-indazol-6il)oxazol-4-carboxamida; (S)-6-(3-aminopirrolidin-1-il)-N-(2-methyl-5-(piperidin-1-il)-2H-indazol-6il)picolinamida; Petition: 870250061458, on 07 / 17 / 2025, page. 65 / 223 56 / 93(S)-6-(3-aminopirrolidin-1-il)-N-(1-metil-5-(piperidin-1-il)-1H-indazol-6il)picolinamide; (S)-6-(3-hydroxypyrrolidin-1 -yl)-N-(1-methyl-5-(piperidin-1-yl)-1 H-indazol-6yl)picolinamide; (S)-2-(3-hydroxypyrrolidin-1-yl)-N-(1-methyl-5-(piperidin-1-yl)-1H-indazol-6yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1 -yl)-1-methyl-1 H-indazol-6-yl)-2-(2-methylpyridin-4yl)oxazol-4-carboxamide; N-(5-(3-hydroxypiperidin-1 -yl)-1-methyl-1 H-indazol-6-yl)-2-(2-methylpyridin-4yl)oxazol-4-carboxamide; N-(5-(3-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-6-yl)-2-(2-methylpyridin-4yl)oxazol-4-carboxamide; N-(5-(3-fluoropiperidin-1-yl)-2-methyl-2H-indazol-6-yl)-2-(2-methylpyridin-4yl)oxazol-4-carboxamide; (S)-2-(2-acetamidopyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1-hindazol-6-yl)oxazol-4-carboxamide; N-(5-(3-fluoropiperidin-1-yl)-1-methyl-1 H-indazol-6-yl)-2-(2-methylpyridin-4yl)oxazol-4-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4yl)oxazole-4-carboxamida; (S)-2-(2-aminopyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol6-yl)oxazole-4-carboxamida; N-(5-(4-fluoropiperidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4yl)oxazole-4-carboxamida; N-(5-(4-(hydroxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin4-yl)oxazole-4-carboxamida; (S)-2-(2,6-dimethylpyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1Hindazole-6-yl)oxazole-4-carboxamida; (R)-N-(5-(3-hydroxypyrrolidine-1-yl)-1-methyl-1H-indazole-6-yl)-2-(2-methylpyridine-4yl)oxazole-4-carboxamide; Cloridrato de (S)-2-(2-aminopyridin-3-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1 methyl-1H-indazol-6-yl)oxazol-4-carboxamida; Petição 870250061458, at 17 / 07 / 2025, pág. 66 / 223 57 / 93 6-((S)-3-hidroxipirrolidin-1-yl)-N-(5-((R)-3-hidroxipirrolidin-1 -yl)-1 -methyl-1 Hindazol-6-yl)picolinamida; (S)-N-(5-(3-hidroxipyrrolidin-1 -yl)-1-methyl-1 H-indazol-6-yl)pyrazolo[1,5a]pyrimidine-3-carboxamida; 6-((S)-3-hidroxipirrolidin-1-yl)-N-(5-((S)-3-hidroxipirrolidin-1 -yl)-1 -methyl-1 Hindazol-6-yl)picolinamida; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(1H-pyrrolo[2,3b]pyridin-4-yl)oxazole-4-carboxamide; (S)-N-(5-(3-hidroxipyrrolidin-1-yl)-1H-indazol-6-yl)-2-(2-methylpyridin-4yl)oxazol-4-carboxamida; (S)-2-(2-amino-3-fluoropyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1 -methyl-1 Hindazol-6-yl)oxazol-4-carboxamida; (R)-2-(2-aminopyridin-3-yl)-N-(5-(3-hydroxypyrrolidin-1 -yl)-1 methyl-1 H-indazol-6-yl)oxazol-4-carboxamida hydrochloride; (S)-N-(5-(3-hidroxipyrrolidin-1 -yl)-1-methyl-1 H-indazol-6-yl)-2-(4-methylpiperazin1-yl)oxazol-4-carboxamida; (S)-N-(5-(3-hidroxipyrrolidin-1 -yl)-1-methyl-1 H-indazol-6-yl)-2-(piperazin-1 yl)oxazol-4-carboxamida; (S)-N-(1 -ethyl-5-(3-hydroxypyrrolidin-1 -yl)-1 H-indazol-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(1-cyclopropyl-5-(3-hydroxypyrrolidin-1 -yl)-1 H-indazol-6-yl)2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(5-(3-hydroxypyrrolidin-1 -yl)-1-methyl-1 H-indazol-6-yl)-2(1,2,3,6-tetra-hydropyridin-4-yl)oxazol-4-carboxamida hydrochloride; (S)-N-(5-(3-hidroxipyrrolidin-1 -yl)-1-methyl-1 H-indazol-6-yl)-2-(2-methylpyrimidin4-yl)oxazol-4-carboxamida; (S)-N-(5-(3-hidroxipyrrolidin-1 -yl)-1-methyl-1 H-indazol-6-yl)-4-(2-methylpyridin-4yl)oxazol-5-carboxamida; (S)-N-(5-(3-hydroxypyrrolidin-1 -yl)-1-methyl-1 H-indazol-6-yl)-2(piperidin-4-yl)oxazol-4-carboxamida hydrochloride; N-(5-(3-hydroxi-8-azabiciclo[3.2.1]octan-8-yl)-1-methyl-1H-indazol-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamida; Petição 870250061458, at 17 / 07 / 2025, pág. 67 / 223 58 / 93 (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridine-4yl)oxazole-5-carboxamida; Cloridrato de N-(5-(4-hydroxi-4-(hydroxymethyl)piperidin-1-yl)-1-methyl-1Hindazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamida; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-5-methyl-2-(2methylpyridin-4-yl)oxazol-4-carboxamida; (S)-2-(2-ethylpyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6yl)oxazole-4-carboxamida; Cloridrato de 2-(2-aminopyridin-4-yl)-N-(5-(4-(hydroxymethyl)piperidin-1-yl)-1,3dimethyl-1H-indazol-6-yl)oxazol-4-carboxamida; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-(piperidin-4-ylmethyl)-1H-indazol-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamida; N-(5-(4-(hydroxymethyl)piperidin-1-yl)-1,3-dimethyl-1H-indazol-6-yl)-2-(2methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(2-cyclopropylpyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1-Hindazol-6-yl)oxazol-4-carboxamide; and N-(5-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-6-yl)pyrazolo[1,5a]pyrimidine-3-carboxamide; Pharmaceutical Compositions

[00154] In certain embodiments, the present methods include a pharmaceutical composition comprising the compound as disclosed in this document, optionally mixed with a pharmaceutically acceptable vehicle or diluent.

[00155] As used in this document, the term composition is intended to encompass a product comprising the specified ingredients in the specified quantities, as well as any product that results, directly or indirectly, from a combination of the specified ingredients in the specified quantities.

[00156] As used in this document, the term pharmaceutical composition refers to composition(s) containing a quantity Petition 870250061458, dated 07 / 17 / 2025, page 68 / 223 59 / 93 therapeutically effective of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof; and a conventional pharmaceutically acceptable vehicle.

[00157] The pharmaceutical compositions of the present invention can be administered orally, for example, in the form of tablets, coated tablets, pills, capsules, granules or elixirs. However, administration can also be carried out rectally, for example in the form of suppositories, or parenterally, for example, intravenously, intramuscularly or subcutaneously, in the form of sterile injectable solutions or suspensions, or topically, for example in the form of ointments or creams or transdermal patches, in the form of plasters or other forms, for example in the form of aerosols or nasal sprays.

[00158] Pharmaceutical compositions generally contain from about 1% to 99%, for example, from about 5% to 75%, or from about 10% to about 30% by weight of the compound of formula (I) or pharmaceutically acceptable salts thereof. The amount of the compound of formula (I) or pharmaceutically acceptable salts thereof in pharmaceutical compositions may vary from about 1 mg to about 1000 mg or from about 2.5 mg to about 500 mg or from about 5 mg to about 250 mg or any range that is covered by the wider range of 1 mg to 1000 mg or greater or less than the range mentioned above.

[00159] The present invention also provides methods for formulating the disclosed compounds for pharmaceutical administration.

[00160] The compositions and methods of the present invention can be used to treat an individual in need thereof. In certain embodiments, the individual is a mammal, such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a carrier. Petition 870250061458, dated 07 / 17 / 2025, page 69 / 223 60 / 93 pharmaceutically acceptable. Pharmaceutically acceptable vehicles are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline solution or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.

[00161] In a preferred embodiment, when these pharmaceutical compositions are for human administration, in particular for invasive routes of administration (i.e., routes such as injection or implantation, which bypass transport or diffusion across an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. Excipients may be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition may be in the form of dosage units such as tablets, capsules (including spray capsules and gelatin capsules), granules, lyophilized powder for reconstitution, powder, solution, syrup, suppository injection or similar. The composition may also be present in a transdermal delivery system, for example, a skin patch. The composition may also be present in a solution suitable for topical administration, such as eye drops.

[00162] A pharmaceutically acceptable vehicle may contain physiologically acceptable agents that act, for example, to stabilize, increase the solubility, or enhance the absorption of a compound, such as the compounds of the present invention. These physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextrans; antioxidants such as ascorbic acid or glutathione; chelating agents; low molecular weight proteins; or other stabilizers or excipients. The choice of a pharmaceutically acceptable vehicle, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation of the pharmaceutical composition Petition 870250061458, dated 07 / 17 / 2025, page 70 / 223 61 / 93 may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may also be a liposome or other polymer matrix, which may have incorporated therein, for example, a compound of the invention. Liposomes, for example, comprising phospholipids or other lipids, are pharmaceutically acceptable and metabolizable non-toxic vehicles that are relatively simple to manufacture and administer.

[00163] The term pharmaceutically acceptable is used in this document to refer to those compounds, materials, compositions and / or dosage forms that are, within the scope of medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problem or complication, assessed in accordance with a reasonable risk / benefit ratio.

[00164] The phrase "pharmaceutically acceptable vehicle" used in this document refers to a pharmaceutically acceptable material, composition, or vehicle, such as a filler, diluent, excipient, solvent, or liquid or solid encapsulation material. Each vehicle must be acceptable in the sense of being compatible with the other ingredients in the formulation and not harmful to the patient.Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as glucose, lactose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, sunflower oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and laurate. Petition 870250061458, dated 07 / 17 / 2025, page 71 / 223 62 / 93 ethyl; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other compatible non-toxic substances used in pharmaceutical formulations.

[00165] A pharmaceutical composition (preparation) may be administered to an individual by any number of routes of administration including, for example, orally (e.g., liquid remedies such as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including spray capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the buccal mucosa (e.g., sublingual); anal, rectal or vaginal (e.g., as a pessary, cream or foam); parenteral (including intramuscular, intravenous, subcutaneous or intrathecal as, for example, a sterile solution or suspension); nasal; intraperitoneal; subcutaneous; transdermal (e.g., as a patch applied to the skin); and topical (e.g., as a cream, ointment or spray applied to the skin, or as eye drops). The compound may also be formulated for inhalation. In certain embodiments, a compound may simply be dissolved or suspended in sterile water.Details of appropriate routes of administration and suitable compositions thereof may be found, for example, in U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in the patents cited therein.

[00166] The formulations can conveniently be presented in unit dosage form and can be prepared according to any of the methods known within the scope of pharmaceutical art. The amount of active ingredient that can be combined with the vehicle material to produce a single dosage form will vary depending on the host treated and the specific mode of administration. The amount of active ingredient that can be combined with a Petition 870250061458, dated 07 / 17 / 2025, page 72 / 223 63 / 93 carrier material to produce a single dosage form will generally be the amount of the compound that produces a therapeutic effect. Generally, out of 100%, this amount will vary from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, more preferably from about 10% to about 30%.

[00167] Methods of preparing these formulations or compositions include the step of combining an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately combining a compound of the present invention with liquid carriers or finely divided solid carriers, or both, and then, if necessary, molding the product.

[00168] The formulations of the invention suitable for oral administration may be in the form of capsules (including spray capsules and gelatin capsules), wafers, pills, tablets, lozenges (using a flavored base, typically sucrose and acacia or tragacanth), lyophilized powder, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as lozenges (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouthwashes, and the like, each containing a predetermined amount of a compound in the present invention as the active ingredient. The compositions or compounds may also be administered as a bolus, electuary, or paste.

[00169] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as Petition 870250061458, dated 07 / 17 / 2025, page 73 / 223 64 / 93 such as starches, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retarders, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; (10) complexing agents, such as modified and unmodified cyclodextrins; and (11) coloring agents.In the case of capsules (including spray capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[00170] A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compacted tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactant or dispersant. Molded tablets can be made by molding, in a suitable machine, a mixture of the moistened powder compound with an inert diluent liquid.

[00171] Tablets and other solid dosage forms of Petition 870250061458, dated 07 / 17 / 2025, page 74 / 223 Pharmaceutical compositions, such as dragees, capsules (including spray capsules and gelatin capsules), pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be formulated to provide slow or controlled release of the active ingredient contained therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile, other polymeric matrices, liposomes, and / or nanoparticles. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that may be dissolved in sterile water or some other sterile injectable medium immediately before use.These compositions may also optionally contain opacifying agents and may be of such a composition that they release only the active ingredient(s), or preferably, in a certain portion of the gastrointestinal tract, optionally in a delayed manner. Examples of incorporation compositions that may be used include waxes and polymeric substances. The active ingredient may also be in microencapsulated form, if appropriate, with one or more of the excipients described above.

[00172] Useful liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, lyophilized powders for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, cyclodextrins and their derivatives, solubilizing and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, seed oils of Petition 870250061458, dated 07 / 17 / 2025, page 75 / 223 66 / 93 cotton, peanut, corn, germ, olive, castor and sesame), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and sorbitan fatty acid esters and mixtures thereof.

[00173] In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings, colorings, fragrances and preservatives.

[00174] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum meta-hydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[00175] Formulations of pharmaceutical compositions for rectal, vaginal or urethral administration may be presented as a suppository, prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or vehicles comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature but liquid at body temperature and will therefore melt in the rectum or vaginal cavity and release the active compound. Formulations of pharmaceutical compositions for oral administration may be presented as a mouthwash, an oral spray or an oral ointment.

[00176] Alternatively or additionally, the compositions may be formulated for delivery via catheter, stent, wire, or other intraluminal device. Delivery via these devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or bowel.

[00177] Formulations that are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such vehicles as are known in the art to be appropriate. Petition 870250061458, dated 07 / 17 / 2025, page 76 / 223 67 / 93

[00178] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable vehicle and with any preservatives, buffers, or propellants that may be required.

[00179] Ointments, pastes, creams and gels may contain, in addition to an active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof.

[00180] Powders and sprays may contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may also contain usual propellants such as chlorofluorocarbons and substituted volatile hydrocarbons such as butane and propane.

[00181] Transdermal patches have the added advantage of providing controlled release of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The rate of such flow can be controlled by providing a membrane control rate or by dispersing the compound in a polymer or gel matrix.

[00182] Ophthalmic formulations, eye ointments, powders, solutions and the like are also contemplated as being within the scope of this invention. Exemplary ophthalmic formulations are described in U.S. Publications Nos. 2005 / 0080056, 2005 / 0059744 and U.S. Pat. No. 6,583,124, the contents of which are incorporated herein by reference. If desired, the formulations Petition 870250061458, dated 07 / 17 / 2025, page 77 / 223 68 / 93 ophthalmic liquids have properties similar to or compatible with lacrimal fluids, aqueous humor, or vitreous humor. A preferred route of administration is local administration (e.g., topical administration as eye drops, or administration via an implant).

[00183] The phrases parenteral administration and administered parenterally, as used in this document, mean modes of administration other than enteric and topical administration, typically by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[00184] Pharmaceutical compositions suitable for parenteral administration may include one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous dispersions, suspensions or emulsions, powders or solutions that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostats, solutes that make the formulation isotonic with the blood of the intended recipient or thickening or suspending agents.

[00185] Examples of suitable aqueous and non-aqueous vehicles that can be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[00186] These compositions may also contain adjuvants such as Petition 870250061458, dated 07 / 17 / 2025, page 78 / 223 69 / 93 preservatives, humectants, emulsifying agents and dispersing agents. Prevention of microbial action can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, sorbic acid, phenol and the like. It may also be desirable to include isotonic agents such as, for example, sugars, sodium chloride and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be achieved by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[00187] In some cases, in order to prolong the effect of the drug, it is desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with low solubility in water. The rate of drug absorption then depends on its dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the compound in an oily vehicle.

[00188] Injectable depot formulations are made by forming microencapsulated matrices of the compounds in question in biodegradable polymers such as polylactide-polyglycolide. Depending on the drug-to-polymer ratio and the nature of the polymer used, the drug release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by trapping the drug in liposomes or microemulsions that are compatible with body tissue.

[00189] For use in the methods of the present invention, the active compounds may be given per se or as a pharmaceutical composition containing, for example, from about 0.1 to about 99.5% (more preferably, from about 0.5 to Petition 870250061458, dated 07 / 17 / 2025, p. 79 / 223 70 / 93 (approximately 90%) of active ingredient in combination with a pharmaceutically acceptable vehicle.

[00190] Delivery methods can also be provided by rechargeable or biodegradable devices. Several slow-release polymeric devices have been developed and tested in vivo in recent years for controlled drug delivery, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound to a specific target site.

[00191] The actual dosage levels of the active ingredients in pharmaceutical compositions may be varied in order to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition and route of administration, without being toxic to the patient.

[00192] The dosage level selected will depend on a variety of factors, including the activity of the compound or combination of compounds employed as disclosed in this document, or the ester, or salt, or starch thereof, the route of administration, the time of administration, the excretion rate of the specific compound or compounds to be used, the duration of treatment, other drugs, compounds and / or materials used in combination with the specific compound or compounds employed, the age, gender, weight, condition, general health and previous medical history of the patient to be treated and similar factors well known in medical techniques.

[00193] A physician or veterinarian skilled in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition needed. For example, a physician or veterinarian could start with doses of the pharmaceutical composition or compound at levels lower than Petition 870250061458, dated 07 / 17 / 2025, p. 80 / 223 71 / 93 the amount required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By therapeutically effective amount is meant the concentration of a compound that is sufficient to produce the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the individual's weight, gender, age, and medical history. Other factors influencing the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent to be administered with the compound of the invention. A higher total dose may be provided by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13th ed., 1814-1882, incorporated herein by reference).

[00194] In general, an adequate daily dose of a compound used in the compositions and methods of the invention will be the amount of the compound that is the lowest effective dose to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above.

[00195] If desired, the effective daily dose of the active compound can be administered as two, three, four, five, six or more subdoses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. In certain embodiments of the present invention, the active compound can be administered two or three times a day. In preferred embodiments, the active compound will be administered once a day.

[00196] The patient receiving this treatment is any animal in need, including primates, particularly humans, and other mammals such as horses, cattle, pigs and sheep; and birds and pets in general.

[00197] Wetting, emulsifying and lubricating agents, such as Petition 870250061458, dated 07 / 17 / 2025, page 81 / 223 72 / 93 Sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, softening and flavoring agents, preservatives and antioxidants may also be present in the compositions.

[00198] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.

[00199] The compounds of the present invention may be administered in combination with one or more other drugs (1) to complement and / or enhance the preventive and / or therapeutic efficacy of the preventive and / or therapeutic drug effect of the compound of the present invention, (2) to modulate the pharmacodynamics, enhance absorption, or reduce the dosage of the preventive and / or therapeutic compound of the present invention, and / or (3) to reduce or enhance the side effects of the preventive and / or therapeutic compound of the present invention. As used herein, the phrase "co-administration" refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still in effect in the body (e.g., the two compounds are simultaneously in effect in the patient, which may include synergistic effects of the two compounds).For example, different therapeutic compounds may be administered in the same formulation or in a separate formulation, simultaneously or sequentially. In certain modalities, different therapeutic compounds may be administered within one hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or one week of each other. Thus, an individual who... Petition 870250061458, dated 07 / 17 / 2025, page 82 / 223 Patients receiving this treatment, number 73 / 93, may benefit from a combined effect of different therapeutic compounds. These compounds may be administered via the same or different routes, and by the same or different methods.

[00200] A concomitant medication comprising the compounds of the present invention and another drug may be administered as a combined preparation in which both components are contained in a single formulation or administered as separate formulations. Administration via separate formulations includes simultaneous administration or administration of separate formulations at intervals of time. In the case of administration at intervals of time, the compound of the present invention may be administered first, followed by another drug, or another drug may be administered first, followed by the compound of the present invention, provided that both compounds are simultaneously active in the patient for at least part of the time during the combined therapy. The method of administration of the respective drugs may be by the same route or a different route and by the same method or a different method.

[00201] The dosage of the other drug may be appropriately selected based on a dosage that has been used clinically, or it may be a reduced dosage that is effective when administered in combination with a compound of the present invention. The compositional ratio of the compound of the present invention and the drug may be appropriately selected according to the age and weight of the individual to be administered, method of administration, time of administration, the disorder to be treated, symptoms, and combination thereof. For example, the other drug may be used in an amount of about 0.01 to about 100 parts by mass, based on 1 part by mass of the compound of the present invention. The other drug may be a combination of two or more types of arbitrary drugs in an appropriate ratio. The other drug Petition 870250061458, dated 07 / 17 / 2025, p. 83 / 223 74 / 93 which complements and / or increases the preventive and / or therapeutic efficacy of the compound of the present invention includes not only those that have already been discovered, but also those that will be discovered in the future, based on the mechanism described above.

[00202] In certain embodiments, a compound of the invention may be administered in conjunction with non-chemical methods of cancer treatment. In certain embodiments, a compound of the invention may be administered in conjunction with radiation therapy. In certain embodiments, a compound of the invention may be administered in conjunction with surgery, with thermal ablation, with focused ultrasound therapy, with cryotherapy, or with any combination thereof. Treatment Methods

[00203] Acute myeloid leukemia is a cancer of the myeloid lineage of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence increases with age. Although AML is a relatively rare disease, it accounts for approximately 1.2% of cancer deaths in the United States.

[00204] The symptoms of AML are caused by the replacement of normal bone marrow with leukemic cells, which causes a drop in normal red blood cells, platelets, and white blood cells. Several risk factors and chromosomal abnormalities have been identified, but the specific cause is unclear. As an acute leukemia, AML progresses rapidly and is usually fatal within weeks or months if left untreated. AML differs from chronic myeloid leukemia (CML) because cell differentiation is not the same. AML involves higher percentages of dedifferentiated and undifferentiated cells, including more blasts (myeloblasts, monoblasts, and megakaryoblasts).

[00205] The diagnosis of AML usually begins with a result Petition 870250061458, dated 07 / 17 / 2025, page 84 / 223 75 / 93 is an abnormal result on a complete blood count. Although an excess of abnormal white blood cells (leukocytosis) is commonly found, and leukemic blasts are sometimes seen, AML can also present with isolated decreases in platelets, red blood cells, or even a low white blood cell count (leukopenia). While a presumptive diagnosis of AML can be made by examining a peripheral blood smear when circulating leukemic blasts are present, a definitive diagnosis usually requires proper bone marrow aspiration and biopsy.

[00206] Genetic studies can also be performed to look for specific mutations in genes such as FLT-3 or genes that regulate FLT-3 expression, which may influence disease outcome. In fact, the ability of many of the compounds disclosed in this document to inhibit FLT-3 is believed to contribute to their particular efficacy against AML, which is known to be sensitive to FLT-3 inhibition. Some patients may develop resistance to treatment with an FLT-3 inhibitor due to mutations arising in the FLT-3 gene. Such FLT-3 mutations include, but are not limited to, D835H, D835V, D835Y, K663Q, N841I, internal tandem duplication (ITD), ITD and D835V, and ITD and F691L. However, the compounds as disclosed in this document have demonstrated efficacy against AML that has developed resistance to treatment with FLT-3 inhibitors.Consequently, in some modalities, the disclosed compounds are effective in treating AML that is resistant to an FLT-3 inhibitor, such as AML characterized by cells that possess one or more of these mutations.

[00207] The malignant cell in AML is the myeloblast. In normal hematopoiesis, the myeloblast is an immature precursor of myeloid white blood cells; a normal myeloblast will gradually mature into a mature white blood cell. In AML, however, a single myeloblast accumulates genetic alterations that freeze the cell. Petition 870250061458, dated 07 / 17 / 2025, page 85 / 223 76 / 93 in its immature state and prevent differentiation. This mutation alone does not cause leukemia; however, when this blockage of differentiation is combined with other mutations that disrupt genes controlling proliferation, the result is the uncontrolled growth of an immature clone of cells, leading to the clinical entity of AML.

[00208] Myelodysplastic syndromes (MDS) are a group of cancers in which immature blood cells in the bone marrow fail to mature into healthy blood cells. Some types can progress to acute myeloid leukemia. Problems with blood cell formation result in some combination of low red blood cell, low platelet, and low white blood cell counts. Some types have an increase in immature blood cells, called blasts, in the bone marrow or blood. The types of MDS are based on specific changes in blood cells and bone marrow.

[00209] MDS is believed to arise from mutations in multipotent stem cells in the bone marrow, but the specific defects responsible for these diseases remain poorly understood. Differentiation of precursor blood cells is impaired, and there is a significant increase in the levels of cell death by apoptosis in bone marrow cells. Clonal expansion of abnormal cells results in the production of cells that have lost the ability to differentiate. If the total percentage of bone marrow myeloblasts increases by a specific cutoff point, such as 20-30%, transformation to acute myeloid leukemia is said to have occurred. The progression from MDS to AML indicates how a series of mutations can occur in an initially normal cell and transform it into a cancerous cell.

[00210] IRAK-1 is known to be overexpressed in AML and MDS, and inhibition of IRAK-1 has been shown to cause apoptosis in MDS cell lines. See, for example, Rhyasen, GW, et al. Cancer Cell 2013 24: 90-104; Rhyasen, Petition 870250061458, dated 07 / 17 / 2025, p. 86 / 223 77 / 93 GW, et al. British J. Cancer 2014 pp. 1-6. The potent activity of the compounds revealed, including compounds that are not potent inhibitors of IRAK-1, in affecting AML cell lines such as MV4-11 and MOLM-13, indicates that IRAK-4 is also an attractive and effective target for AML and MDS.

[00211] Methods for treating or preventing acute myeloid leukemia are disclosed in this document. These methods may be equally applicable to the treatment or prevention of myelodysplastic syndrome. Similarly, these methods may be equally applicable to the treatment or prevention of multiple myeloma. In certain embodiments, the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, as disclosed in this document, for the treatment or prevention of AML and / or MDS. In certain embodiments, the present invention relates to the use of a compound or a pharmaceutically acceptable salt thereof, as disclosed in this document, for the preparation of a medicament to treat or prevent AML and / or MDS.

[00212] The compounds suitable for the compositions and methods disclosed in this document can be found in WO2015 / 104662, WO2015 / 104688 and WO2015 / 193846, each of which is incorporated by reference in its entirety, and in particular for the compounds disclosed in the documents in question as IRAK4 inhibitors. Examples Compound A Compound B Example 1: Inhibition of FLT-3 by Compound A

[00213] The inhibition of wild-type FLT-3 by the compounds was tested Petition 870250061458, dated 07 / 17 / 2025, p. 87 / 223 78 / 93 using the substrate peptide EAIYAAPFAKKK. Flt3(h) (14-500, GenBank NM_004119) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 50 μM EAIYAAPFAKKK, 10 mM magnesium acetate, and [gamma-33P]-ATP (specific activity and concentration as needed). The reaction was initiated by adding the Mg / ATP mixture. After incubation for 40 minutes at room temperature, the reaction was stopped by adding phosphoric acid at a concentration of 0.5%. 10 μL of the reaction were then stained on a Filtermat P30 and washed three times for 4 minutes in 0.425% phosphoric acid and once in methanol before drying and scintillation counting.

[00214] Compound A was tested against Flt-3 using the standard KinaseProfiler Eurofins assay as described above. Compound A was also tested against IRAK1 and Flt-3 (D835Y) using the same protocol with myelin basic protein (MBP) and EAIYAAPFAKKK substrates, respectively. Protein kinases (except ATM(h) and DNA-PK(h)) were analyzed in a radiometric format, while lipid kinases ATM(h), ATR / ATRIP(h), and DNA-PK(h) were analyzed using an HTRF® format.

[00215] Compound A was prepared as a 50x stock solution of the test compound and was added to the test well before a reaction mixture containing the enzyme and substrate was added. The reaction was initiated by the addition of ATP at the selected concentration. There was no pre-incubation of the compound with the enzyme / substrate mixture before the addition of ATP. A working stock solution at a final assay concentration of 50x in 100% DMSO.

[00216] Results are expressed as residual kinase activity, as a percentage of the DMSO control. This is calculated using the following formula: Average of Sample Counts - Average of Blank Counts Average of Control Counts Petition 870250061458, dated 07 / 17 / 2025, page 88 / 223 79 / 93

[00217] For IC50 determinations, data were analyzed using XLFit version 5.3 (ID Business Solutions). Sigmoidal dose-response curves (variable slope) are fitted based on the mean result for each test concentration using nonlinear regression analysis. Where the upper and / or lower of the curve is >10% misaligned from 100 and 0, respectively, one or both limits may be restricted to 100 and 0, provided the QC criterion at R2 is met. Table 1 provides IC50 data on the representative kinase inhibition by Compound A. Table 1 Kinase IC50 (nM) IRAK4 37 IRAK1 >10,000 FLT3 (D835Y) 11 FLT3 82

[00218] Compound A was also tested against each of the selected kinases using the standard DiscoverX KINOMEscan and KdELECT assays and following relevant standard operating procedures. See, for example, Nat. Biotechnol. 2011, 29(11): 1046-51. KINOMEscan and KdELECT are based on a competitive binding assay that quantitatively measures a compound's ability to compete with an immobilized ligand directed to the active site. The assay is performed by combining three components: DNA-labeled kinase; immobilized ligand; and a test compound. The ability of the test compound to compete with the immobilized ligand is measured using quantitative PCR of the DNA marker. Binding constants (Kds) were calculated using a standard dose-response curve.

[00219] FIG. 1 shows the activity of Compound A against IRAK1, IRAK4 and numerous FLT-3 variants, indicating its potency as a dual inhibitor of Petition 870250061458, dated 07 / 17 / 2025, page 89 / 223 80 / 93 IRAK / FLT-3. Structurally analogous compounds are expected to possess this dual activity to a similar extent.

[00220] For example, Compound A shows exceptional binding to FLT3 with ITD mutations and with activation cycle mutations such as D835Y. These mutations occur in one-third of all untreated AML patients. Known FLT-3 inhibitors with activation cycle mutations are not equipotent. See, for example, Nguyen, B., et al., Oncotarget 2017 pgs. 1-14; Nagoya, J. Med. Sci. 2015 77:7-17. In contrast, Compound A binds to D835Y mutant FLT-3 at 2.5 nM and ITD mutant FLT-3 at 7.8 nM. Example 2: In vitro assay of the AML MV4-11 model.

[00221] The CellTiter Glo Luminescent cell viability assay is a highly sensitive homogeneous assay for determining the number of viable cells in culture based on the quantification of ATP levels in metabolically active cells. The addition of CTG reagent results in cell lysis and the generation of a luminescent signal proportional to the amount of ATP present. The amount of ATP is directly proportional to the number of cells present in the culture. Luminescence is measured using a multi-label reader capable of measuring luminescence. An increase or decrease in the number of cells results in a concomitant change in the luminescence level, indicating the effect of the test material on cell proliferation. Preparation of solutions / reagents Preparation of the CTG reagent:

[00222] The CellTiter-Glo buffer was thawed and equilibrated to room temperature. The lyophilized CellTiter-Glo substrate was brought to room temperature. The CTG reagent is prepared by mixing CellTiter-Glo buffer (Promega Cat# G7572) in an amber vial containing CellTiter-Glo substrate to reconstitute the lyophilized enzyme / substrate mixture. Both Petition 870250061458, dated 07 / 17 / 2025, pp. 90 / 223 81 / 93 buffer as the freeze-dried substrate are supplied with the kit. Preparation of resources:

[00223] Add 1% streptomycin penicillin and 10% FBS to commercially available liquid IMDM (Iscove's Modified Dulbecco's Medium, Invitrogen Cat# 12440046). Preparation of 1X PBS (Phosphate-Buffered Saline Solution):

[00224] A bag of PBS powder (Sigma: Cat# P3813) was dissolved in 1L of MilliQ water. DMSO is used as a vehicle to dissolve the test item. Procedure (determination of IC50) 1. MV4-11 cells were counted and resuspended to a density of 0.1 x 10⁶ cells / mL in complete IMDM medium. 95 μL of this cell suspension was added per well of a 96-well plate (black plate with transparent bottom) to seed ~0.1 x 10⁵ cells per well. The plates were incubated at 37 °C under a humidified atmosphere of 5% CO₂ for ~2 hours before the addition of the compound. 2. The test compounds were dissolved in 100% DMSO to generate a stock solution at 2 / 6 / 10 / 20 mM. A 200X concentration of the required final concentrations was prepared in DMSO. 10 μL of each concentration (200X) were then diluted in 90 μL of serum-free IMDM to prepare a 20X intermediate concentration in medium. The DMSO concentration at this stage was 10% (intermediate dilution). 5 μL of each intermediate dilution were then added in triplicate to cells previously seeded in a 96-well plate. The final DMSO concentration was 0.5% in the experimental wells. Cells treated with 0.5% DMSO served as a positive control. 100 μL of complete IMDM medium served as a blank medium for data analysis. 200 μl of 1X PBS were added to all corner wells of the assay plate to prevent evaporation of the medium in the wells. Petition 870250061458, dated 07 / 17 / 2025, pp. 91 / 223 82 / 93 experimental plates were then incubated for 72 hours in an incubator with 5% CO2 at 37 °C. 3. To complete the assay, 50 μL of CTG reagent were added to each well, and the plate was incubated at room temperature for 15 minutes on a shaker. The plate was read using the luminescence mode on a multi-label reader capable of measuring luminescence. The luminescence values ​​were plotted against the respective concentrations of the test item using GraphPad Prism to calculate the IC50 value for the test item. The percentage of inhibition is calculated as follows:

[00225] The percentage (%) of inhibition was calculated by normalizing the DMSO control values ​​to 0% inhibition using the formula: % inhibition = 100 - (L of test compound - blank) / (L of positive control - blank) * 100, where L is Luminescence

[00226] Experimental wells contained cells, test compound, IMDM medium, and 0.5% DMSO. Positive control wells contained cells, IMDM medium, and 0.5% DMSO. Blank control wells contained only IMDM medium.

[00227] The IC50 values ​​for the following compounds in μM are presented in Table 2. A is <0.05 μM, B is 0.05 to 0.5 μM and C is >0.5 μM. Table 2 MV4-11 IC50 structure in μΜ 0 Z^O i / z IC t N iCn / -\ O^ / ^ / NH ^NH Λ X hci A Petition 870250061458, dated 07 / 17 / 2025, pp. 92 / 223 83 / 93 Structure MV4-11 IC50 in μΜ C o 6 o^z 0 A CM Λ—ZZ—' c- Οχ^ζ 0 A z^^ 1 Petition 870250061458, dated 07 / 17 / 2025, page 93 / 223 84 / 93 Estrutura MV4-11 IC50 em µM 0 Z^OP oo IC ò - / — Qz o Λ—ZZ—' °» wyz õ A 0 ζ^ω o 1 A CM _6 o °» σ,^Ζ 0 CI obow\j^z 0 CO\ / U JL <^n^n^®NH2 ^S^VNH \ / N^x Λ Λ / x C Petition 870250061458, de 17 / 07 / 2025, pág. 94 / 223 85 / 93 Structure MV4-11 IC50 in μM YNN^2.oh ^s^rNH \ 1X / x C z Cx o Z w^z 0 A r-0 0 N—(\ Jj T '- Ν^Ν^Νθ A z Cj Λ o 9 z δΐ ^z 0 wxji>z 0 ATO b O2 / °r> IZ / w ω>ψ-ζ 0 C ^Ζ'Ζ^Ί^° \ / Gz tf WX^Z 0 A 0 ζ^ω tf° \ \ I \___ oo TC Petition 870250061458, de 17 / 07 / 2025, pág. 95 / 223 86 / 93 Estrutura MV4-11 IC50 em μΜ 0 ζ^ω CP ^ZZ—V \ T \__ / 3 zx O ò rz / Cl z^\ A 0 ζ^ω p . O Vp Is 1 \ ο^-ζ^ A CM -zz cx - 9 ,— / x \ / ^zzz : . z A o^C^X / ^ VnAA η ΝγΝΗ ^νΛνΗ2 I 1 .cf3cooh A 1 zo ΧΊ ZIzv° i / o fí / \, 1 il z' A 1 z ., ' / ± / =\ OZ / > z ΞΕ N> A Petition 870250061458, de 17 / 07 / 2025, pág. 96 / 223 87 / 93 Structure MV4-11 IC50 in μΜ NH —n 2 TA Ύ N NH %' XX 0H AN xjP) 0 H —μ 2 TC 1 z . / zz^( 0 ,—z 0 TB 1 z . ^zz^< 0 0 TB 1 z XJ xX ZT X\\ zy _ < z ^1 o ΞΕ A Petition 870250061458, dated 07 / 17 / 2025, page 97 / 223 88 / 93 Example 3: Inhibition of Cell Proliferation in the MV411 Xenograft Model

[00228] Using the procedure from Example 2, Compounds A and B were evaluated to determine the % inhibition of proliferation in MV4-11 cells. The IC50 of Compound A was 0.031 μM (FIG. 2A) and Compound B was 6.1e-0.005 μM (FIG. 2B). Example 4: In Vivo Inhibition of Tumor Growth in the MV4-11 AML Xenograft Model

[00229] Using an AML MV4-11 Xenograft Model protocol, Compound A was evaluated at doses of 12.5, 25, and 50 mpk. ND-2158 at 100 mpk was used as a control.

[00230] The antitumor activity of Compound A was evaluated in male athymic nude mice. MV4-11 cells were cultured in Iscove-Modified Dulbecco medium supplemented with 10% FBS and 1% streptomycin penicillin. To establish tumors, 15 x 10⁶ MV4-11 cells were injected subcutaneously in 200 μl of 1:1 HBSS and ECM gel into the right flank of athymic nude mice. Animals were randomized based on tumor volumes. For 21 days, Compound A was administered orally once daily and ND-2158 was administered once daily intraperitoneally. Treatments were initiated when the mean tumor volume reached 333 mm³. Tumor volumes were measured three times weekly and body weights were monitored daily. Compound A at 12.5, 25, and 50 mg / kg and the ND2158 100 mg / kg treatments were well tolerated without any treatment-related clinical signs or gross pathological changes.

[00231] FIG. 3 represents the increase in tumor growth inhibition with increasing doses of Compound A. Tumor growth stasis was achieved at 12.5 mpk and tumor regression was observed at 25 and 50 mpk after 21 Petition 870250061458, dated 07 / 17 / 2025, page 98 / 223 Treatment lasted 89-93 days. Compound A at 12.5 mg / kg resulted in 92% inhibition of tumor growth. Compound A at 25 mg / kg and 50 mg / kg resulted in partial tumor regression. Treatment with 100 mg / kg of ND-2158 resulted in 68% inhibition of tumor growth. No reduction in body weight was observed, as shown in FIG. 4. Example 5: Antiproliferative Activity in Xenograft Models of AML MV4-11 and MOLM-13

[00232] The same procedure was used for MV4-11 cells and MOLM-13 cells. Each cell line has an ITD mutation in the FLT3 kinase.

[00233] Cells were cultured to ~80% confluence, split in half, and allowed to grow overnight. Cells were seeded at a density of 5,000 cells / well in a volume of 150 μL in a 96-well black plate in all wells except columns 1 and 12 and rows A and H. They were incubated overnight in 10% serum, and HBSS was added to the wells at the periphery. In a deep 96-well plate, 1000 µl of 10% FBS were added to wells B2 and D2. 750 µl of 10% FBS and 1% DMSO were added per well in row B, except for well B2. 5 µl of 20 mM compound were added to well B2. 250 µl were transferred from column 2 to column 3 and mixed. The process was repeated up to column G to obtain a 1:4 dilution. 15 µl of compound mixture were added to each well of the cell plate (volume of 135 µl). The CellTiter Glo assay described in Example 2 was used to determine the IC50 value for Compound A in each cell line.Compound A had an IC50 of 0.07 pM in the MV4-11 cell line and 0.19 in the MOLM-13 cell line. Example 6: In vivo efficacy of Compound A in mouse xenograft tumor models of MOLM-14 FLT3-ITD and MOLM-14 FLT3-ITD / KD (kinase domain) Petition 870250061458, dated 07 / 17 / 2025, pp. 99 / 223 90 / 93

[00234] Compound A was administered orally at 100 mg / kg once daily to athymic naked mice bearing MOLM-14 FLT3-ITD, MOLM-14 FLT3-ITD / F691L, or MOLM-14 FLT3-ITD / D835Y subcutaneous tumors. The efficacy of Compound A was compared to the vehicle administered to mice. As shown in FIGS. 5A, 5B, and 5C, the percentage of tumor growth inhibition (% TGI) was 90, 73, and 98%, respectively, after 12 or 14 days of dosing. Example 7: Cell Viability Assay

[00235] The parental cell line MOLM-14 contained an FLT3-ITD mutation. The quizartinib-resistant cell lines derived from MOLM-14, MOLM-14 FLT3-ITD / D835Y and MOLM-14 FLT3-ITD / F691L, contained a double FLT3 mutation (the original ITD mutation and a secondary mutation within the kinase domain).

[00236] All cell lines were cultured in RPMI 1640 + GlutaMAX supplemented with 1X Pen-Strep and 10% FBS (referred to as medium hereafter). Cells were cultured in 75 cm2 or 225 cm2 tissue culture flasks in a humidified tissue culture incubator at 37°C with 5% CO2. Cell densities were maintained between 0.5–2.0 x 106 cells / mL. Plating and Dosing

[00237] Two days prior to treatment with the compound, cells were pelleted and resuspended in fresh medium. On the day of dosing, cells were counted and stained with trypan blue to determine cell viability. 5000 viable cells were transferred in a volume of 90 μL or 135 μL per well to all wells of a 96-well tissue culture plate and returned to the tissue culture incubator. In general, two rows of each cell line to be tested were added per plate (i.e., a maximum of 3 cell lines per plate). The lower limit of viability for cells was 80% for utilization. Petition 870250061458, dated 07 / 17 / 2025, pages 100 / 223 91 / 93 in this assay; most cell lines exhibited >90% viability.

[00238] Stock solutions of the compound prepared in 100% DMSO were removed from the freezer at -80°C and thawed at room temperature before use. Unused compound was discarded. A dilution series of the compound was created using a 96-well plate. 40 μL of stock solution of the compound were transferred to well B2. 30 μL of DMSO were added to wells B3 to B11. 10 μL from well B2 were transferred to well B3, mixed by pipetting up and down 6 times resulting in a 1:4 dilution. Alternative volumes or dilution ratios may have been employed. By changing pipette tips between dilution steps, the dilution series continued to well B10. Well B11 is the control sample treated with DMSO.

[00239] 198 μL of medium were transferred to each well of rows BG and columns 2-11 of a new 96-well plate. 2 μL from the Compound A DMSO dilution series plate were transferred to the corresponding wells of each row containing the 198 μL of medium and mixed by pipetting 6 times, creating a 10X Compound A dilution series dosing plate.

[00240] From the dosing plate of the 10X Compound A dilution series, 10 μl or 15 μl of the diluted compounds were added to a 96-well tissue culture plate containing 90 μl or 135 μl of cells, respectively. The plates were then briefly mixed using a plate mixer at 150 rpm for two minutes. The plates were returned to a tissue culture incubator and incubated at 37°C for 72 hours. The final concentration of DMSO added to the cells was 0.1%.

[00241] Each cell line was tested in duplicate per plate and repeated at least 3 times on different days. Feasibility

[00242] After 72 h of incubation, cell viability was assessed using Petition 870250061458, dated 07 / 17 / 2025, pp. 101 / 223 92 / 93 the CellTiter-Glo Luminescent Cell Viability Assay (2.0) according to the vendor's instructions. After adding the CellTiter-Glo reagent (1:1 volume), the plates were covered with transparent plate sealants, followed by mixing on a plate shaker at 150 rpm in the dark for 10 minutes at room temperature. Luminescence readings were measured using a TopCount384 instrument. EC50 Calculation

[00243] The percentage of inhibition of the compound-treated samples was determined relative to the DMSO-treated control cell samples. The percentage inhibition values ​​were used to calculate EC50 values ​​using GraphPad Prism 7 software. In assays where curve fitting failed to determine an EC50 value, the concentration that causes 50% inhibition by linear extrapolation was used as the EC50 value. Average EC50 values ​​from at least 3 independent viability assays performed on different days were determined. MOLM-14 EC50 = 58 nM MOLM-14 FLT3-ITD / D835Y, EC50 = 108 nM MOLM-14 FLT3-ITD / F691L, EC50 = 2488 nM Incorporation by Reference

[00244] All publications and patents mentioned in this document are incorporated by reference in their entirety, as if each individual publication or patent were specifically and individually indicated for incorporation by reference. In case of conflict, this application, including any definitions contained in this document, shall prevail. Equivalents

[00245] Although specific embodiments of the present invention have been discussed, the above descriptive report is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review. Petition 870250061458, dated 07 / 17 / 2025, pp. 102 / 223 93 / 93 of this descriptive report and the claims below. The full scope of the invention shall be determined by reference to the claims, together with their full scope of equivalents, and the descriptive report, together with such variations. Petition 870250061458, dated 07 / 17 / 2025, pp. 103 / 223

Claims

1 / 2 CLAIMS 1. Use of a compound CHARACTERIZED by the fact that it is in the manufacture of a medicament for the treatment of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), wherein AML and MDS are defined by a mutation in the FLT-3 kinase and the compound is either a pharmaceutically acceptable salt thereof.

2. Use according to claim 1, CHARACTERIZED in that the compound is 3. Use, according to claim 1, CHARACTERIZED by the fact that it is a pharmaceutically acceptable salt of 4. Use, according to any one of claims 1 to 3, CHARACTERIZED in that the mutation is selected from D835H, D835V, D835Y, K663Q, N841I, internal tandem duplication (ITD), and F691L.

5. Use, according to any of claims 1 to 3, CHARACTERIZED in that the mutation is an ITD.

6. Use, according to any one of claims 1 to 3, CHARACTERIZED in that the mutation is a D835H mutation.

7. Use, according to any one of claims 1 to 3, CHARACTERIZED by the fact that the mutation is a D835V mutation. Petition 870260035010, dated 04 / 15 / 2026, page 5 / 14 2 / 2 8. Use, according to any one of claims 1 to 3, CHARACTERIZED in that the mutation is a D835Y mutation.

9. Use, according to any one of claims 1 to 3, CHARACTERIZED in that the mutation is a K663Q mutation.

10. Use, according to any one of claims 1 to 3, CHARACTERIZED in that the mutation is an N8411 mutation.

11. Use, according to any one of claims 1 to 3, CHARACTERIZED in that the mutation is an F691L mutation.

12. Use, according to any one of claims 1 to 11, CHARACTERIZED in that the medicine is for the treatment of AML.

13. Use according to claim 12, CHARACTERIZED in that AML is resistant to an FLT-3 inhibitor.

14. Use, according to any one of claims 1 to 11, CHARACTERIZED in that the medicine is for the treatment of MDS.

15. Use according to claim 14, CHARACTERIZED in that MDS is resistant to an FLT-3 inhibitor. Petition 870260035010, dated 04 / 15 / 2026, page 6 / 14

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