Compounds and compositions for the treatment of hematological disorders

Abstract

The present invention relates to compounds and compositions for the treatment of hematological disorders. The present invention provides methods for the treatment of hematological disorders, such as acute myeloid leukemia, using substituted heterocyclic compounds and pharmaceutically acceptable salts thereof. The compounds inhibit IRAK4 and FLT-3 kinases.

Description

[0001] This application is a divisional application of Chinese patent application 201880022870.5, "Compounds and compositions for treating blood diseases," filed on March 30, 2018.

[0002] Cross-reference to related applications This application claims priority to Indian Provisional Patent Application Serial No. 201741011785, filed on March 31, 2017, the entire contents of which are incorporated herein by reference. Background Technology

[0003] Acute myeloid leukemia (AML) is a blood cancer with a poor prognosis, typically occurring in adults, with an estimated 5-year survival rate of 20%. Currently, AML treatment can temporarily reduce the number of AML cells to below the detection limit. This condition is called "complete remission." However, AML often relapses after complete remission, and for many patients, relapsed AML leads to death. Specifically, the extremely low survival rate in relapsed cases remains a serious and concerning problem. Therefore, new AML treatments are needed. Summary of the Invention

[0004] This article provides a method for treating or preventing acute myeloid leukemia in a subject, the method comprising administering a compound of formula (I): Or its pharmaceutically acceptable salt; in, Ring Z1 is a heteroaryl group with optional substitution; The ring Z2 is an optionally substituted heterocyclic alkyl group, an optionally substituted heteroaryl group, or a direct bond; R1 is an alkyl group, cyano group, or -NR group. a R b , or optionally substituted groups selected from cycloalkyl, aryl or heterocyclic groups; wherein each substituent is independently alkyl, alkoxy, halogen, hydroxy, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2 or –CH2-OP(O)(O-alkyl)2; R2 is, in each instance, an independently selected substituted group chosen from alkyl or cycloalkyl groups; wherein the substituent is, in each instance, a halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl, or haloalkoxy group; R3 is independently hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, or -NR each time it appears. a R b hydroxyl or hydroxyalkyl; Ra It is hydrogen or alkyl; R b It is hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl, or optionally substituted cycloalkyl; 'm' and 'n' are 1 or 2 independently.

[0005] This article provides a method for treating or preventing acute myeloid leukemia in a subject, the method comprising administering a compound of formula (II): Or its pharmaceutically acceptable salt; in, X1 and X3 are independently CH or N; X2 is CR2 or N; the condition is that one or more of X1, X2 or X3 is N; A is either O or S; Y is either -CH2- or O; Ring Z is aryl or heterocyclic; R1 is independently a halogroup or an optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogroup, hydroxyl, hydroxyalkyl or -NR. a R b ; R2 is hydrogen, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or -NR. a R b The substituents are alkyl, amino, halogenated, or hydroxyl groups. R3 is either alkyl or hydroxyl in each occurrence; R a and R b It can be independently hydrogen, alkyl, acyl, or heterocyclic; 'm' and 'n' are independently 0, 1, or 2; 'p' is 0 or 1.

[0006] This article provides a method for treating or preventing acute myeloid leukemia in a subject, the method comprising administering a compound of formula (III): Or its pharmaceutically acceptable salt; in, Z1 may be an optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, or absent; Z2 is an optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclic group; R1 is hydrogen, optionally substituted alkyl, amino, halogroup, cyanogroup, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted arylalkyl, or optionally substituted heterocyclic alkyl. R2 is, in each instance, an amino group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted arylalkyl group, or an optionally substituted heterocyclic alkyl group. R3, each time it appears, is a hydroxyl group, a halogen group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkyl group, or -NR. a R b ; R a and R b Each time it appears, it is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted arylalkyl or optionally substituted heterocyclic alkyl; m is 0, 1, or 2 each time it appears; and n is 0, 1, or 2 each time it appears.

[0007] In some embodiments, this document discloses the use of the compounds disclosed herein or pharmaceutically acceptable salts or stereoisomers thereof for the treatment and prevention of AML.

[0008] In some embodiments, this document discloses the use of the compounds disclosed herein, or pharmaceutically acceptable salts or stereoisomers thereof (including mixtures thereof in all ratios), as medicaments for the treatment of AML. Attached Figure Description

[0009] Figure 1 The binding of compound A to various kinases (including wild-type and mutant FLT-3) was depicted. d .

[0010] Figure 2A The inhibitory effect of compound A on the proliferation of MV4-11 cells was described. Figure 2B The inhibitory effect of compound B on the proliferation of MV4-11 cells was described.

[0011] Figure 3 The study depicted the increasing inhibition of tumor growth with increasing doses of compound A at 12.5, 25, and 50 mpk.

[0012] Figure 4 The static body weight of animals in the MV4-11 in vivo xenograft model was depicted.

[0013] Figure 5A Depicting subcutaneous MOLM-14 FLT3 -Percentage of tumor growth inhibition (TGI%) in mice with ITD tumors. Figure 5B Depicting MOLM-14 FLT3-Percentage of tumor growth inhibition (TGI%) in mice with ITD / F691L tumors. Figure 5C Depicting MOLM-14 FLT3 -Percentage of tumor growth inhibition (TGI%) in mice with ITD / D835Y tumors. Detailed Implementation

[0014] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject belongs. As used in this specification and the appended claims, unless otherwise stated, the following terms have indicative meanings for the purpose of understanding the invention.

[0015] Unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” encompass the plural indicator.

[0016] As used herein, the terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and such description includes examples of said event or situation occurring and examples of said event or situation not occurring. For example, “optionally substituted alkyl” means that the alkyl group may be substituted, as well as the case where the alkyl group is not substituted.

[0017] It should be understood that those skilled in the art can select the substituents and substitution patterns on the compounds of the present invention to obtain chemically stable compounds that can be readily synthesized from readily available starting materials using techniques known in the art and the methods described below. If the substituent itself is substituted by more than one group, it should be understood that these multiple groups can be on the same carbon or different carbons, as long as a stable structure is produced.

[0018] As used herein, the term "optionally substituted" means that in a given structure, one to six hydrogen groups are replaced by a specified substituent, including but not limited to: hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, halogen, alkyl, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroarylalkyl, cycloalkyl, cycloalkoxy, (cycloalkyl)alkyl, heterocyclic, (heterocyclic)alkyl, amino, aminoalkyl, alkylamino, dialkylamino, acyl, -C(O)₂H, -O (acyl), -NH (acyl), -N (alkyl) (acyl), cyano, hypophosphonate, phosphate, phosphonate, sulfonate, sulfonamide, sulfate, haloalkyl, or haloalkoxy. Preferably, "optionally substituted" means that in a given structure, one to four hydrogen groups are replaced by the above-described substituents. More preferably, one to three hydrogen groups are replaced by the substituents described above. It should be understood that the substituents may be further substituted.

[0019] The term "substituted" refers to a portion having a substituent that replaces a hydrogen atom on one or more carbons of the main chain. It should be understood that "substituted" or "replaced by" includes the implicit condition that such substitution meets the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, such as a compound that does not spontaneously transform as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include all permissible substituents in organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched or unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. For suitable organic compounds, permissible substituents can be one or more, and can be the same or different. For the purposes of this invention, heteroatoms (such as nitrogen) may have hydrogen substituents and / or any permissible substituent in the organic compounds described herein that satisfies the valence of the heteroatom. Substituents may include any substituents described herein, such as halogens, hydroxyl groups, carbonyl groups (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (e.g., thioesters, thioacetates, or thiocarbamates), alkoxy groups, phosphoryl groups, phosphate groups, phosphonates, hypophosphonates, amino groups, amide groups, amidine groups, imine groups, cyano groups, nitro groups, azide groups, mercapto groups, alkylthio groups, sulfate groups, sulfonate groups, aminosulfonyl groups, sulfonamide groups, sulfonyl groups, heterocyclic groups, aralkyl groups, or aromatic or heteroaromatic moieties. Those skilled in the art will understand that substituents themselves may be substituted where appropriate. Unless specifically described as “unsubstituted,” references to chemical parts herein should be understood to include substituted variants. For example, references to “aryl” groups or moieties implicitly include both substituted and unsubstituted variants.

[0020] As used herein, the term "alkyl" refers to a saturated aliphatic group, including but not limited to C1-C1 groups. 10 Straight-chain alkyl groups or C1-C 10 Branched alkyl group. Preferably, the "alkyl" group refers to a C1-C6 straight-chain alkyl group or a C1-C6 branched alkyl group. Most preferably, the "alkyl" group refers to a C1-C4 straight-chain alkyl group or a C1-C4 branched alkyl group. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, or 4-octyl. The "alkyl" group may be optionally substituted.

[0021] The term "acyl" refers to the group R-CO-, where R is an optionally substituted alkyl group as defined above. Examples of "acyl" groups are, but are not limited to, CH3CO-, CH3CH2CO-, CH3CH2CH2CO-, or (CH3)2CHCO-.

[0022] As used herein, the term "alkoxy" refers to a straight-chain or branched saturated aliphatic C1-C atom bonded to an oxygen atom attached to the core structure. 10 Hydrocarbon group. Preferably, the alkoxy group has 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, etc.

[0023] As used herein, the term "haloalkyl" refers to an alkyl group (as defined above) that is substituted with one or more halogens. Monohaloalkyl groups may, for example, have chlorine, bromine, iodine, or fluorine atoms. Dihaloalkyl and polyhaloalkyl groups may each have two or more identical or different halogen atoms. Examples of haloalkyl groups include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, etc.

[0024] As used herein, the term “haloalkoxy” refers to a group in which one or more hydrogen atoms of the alkoxy group are substituted by one or more halogens. Representative examples of “haloalkoxy” groups include, but are not limited to, difluoromethoxy (-OCHF2), trifluoromethoxy (-OCF3), or trifluoroethoxy (-OCH2CF3).

[0025] As used herein, the term "aryl" alone or in combination with other terms means a 6- to 10-membered carbon-cyclic aromatic system containing one or two rings, wherein such rings may be fused. The term "fused" means the attachment or formation of a second ring by having two adjacent atoms shared with the first ring. The term "fused" is equivalent to the term "condensation." Examples of aryl groups include, but are not limited to, phenyl, naphthyl, or indenyl. Unless otherwise stated, all aryl groups described herein may be optionally substituted.

[0026] The terms "amine" and "amino" are recognized in the art and refer to unsubstituted and substituted amines and their salts, such as those represented by the following portions. Each R 10 Independently representing a hydrogen or hydrocarbon group, or two Rs 10 Together with the N atoms to which they are attached, they complete heterocycles with 4 to 8 atoms in the ring structure.

[0027] As used in this article, "aminoalkyl" refers to an amino group as defined above, in which one or both hydrogen atoms are replaced by an alkyl group.

[0028] As used in this article, "nitro" refers to the -NO2 group.

[0029] As used herein, "alkylamino" and "cycloalkylamino" refer to an -N- group, wherein the nitrogen atom of the group is attached to an alkyl or cycloalkyl group, respectively. Representative examples of "alkylamino" and "cycloalkylamino" include, but are not limited to, -NHCH3 and -NH-cyclopropyl. The amino group may optionally be substituted with one or more suitable groups.

[0030] As used herein, the term "cycloalkyl" alone or in combination with other terms refers to C3-C 10 Saturated cyclic hydrocarbon rings. Cycloalkyl groups can be monocyclic, typically containing 3 to 7 carbon ring atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Alternatively, cycloalkyl groups can be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyl groups include bridged, fused, and spirocyclic carbocyclic groups.

[0031] As used in this article, the term "cyano" refers to the -CN group.

[0032] As used herein, the terms “hydroxyl group” or “hydroxyl group” refer to the -OH group.

[0033] As used herein, the term "hydroxyalkyl" or "hydroxyalkyl group" means an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above. Examples of "hydroxyalkyl" include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, propan-2-ol, etc.

[0034] As used herein, the terms “halogen” or “halogen” alone or in combination with other terms refer to fluorine, chlorine, bromine, or iodine.

[0035] As used herein, the term “heterocyclic” includes the definitions of “heterocyclic alkyl” and “heteroaryl”.

[0036] As used herein, the term "heterocyclic alkyl" refers to a 3- to 15-membered non-aromatic, saturated or partially saturated monocyclic or polycyclic system having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2, NH or C(O), with the remaining ring atoms independently selected from carbon, oxygen, nitrogen and sulfur. Examples of "heterocyclic alkyl" include, but are not limited to, azacyclic butyl, oxacyclic butyl, imidazoalkyl, pyrrolyl, oxazolidinyl, thiazoalkyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxacyclohexyl, dioxothiomorpholinyl, oxapirazinyl, oxapiridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopheneyl, dihydropyranyl, indololinyl, indololinylmethyl, 2-aza-bicyclo[2.2.2]octyl, azacyclic octyl, benzodihydropyranyl, xanthonyl and their N-oxides. The attachment of heterocyclic alkyl substituents can be via carbon atoms or heteroatoms. Heterocyclic alkyl groups can optionally be substituted by one or more of the above groups with one or more suitable groups. Preferably, "heterocyclic alkyl" refers to a 5- or 6-membered ring selected from azacyclic butyl, oxacyclic butyl, imidazoalkyl, pyrrolyl, oxazolyl, thiazoalkyl, pyrazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxacyclohexyl, and their N-oxides. More preferably, "heterocyclic alkyl" includes azacyclic butyl, pyrrolyl, morpholinyl, and piperidinyl. All heterocyclic alkyl groups are optionally substituted with one or more of the above groups.

[0037] As used herein, 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, the "heteroaryl" is a 5- to 6-membered ring. The ring may contain 1 to 4 heteroatoms selected from N, O, and S, wherein the N or S atom is optionally oxidized or the N atom is optionally quaternized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure.

[0038] Examples of heteroaryl groups include, but are not limited to: furanyl, thiophene, pyrrole, pyrazolyl, imidazolyl, oxazolyl, cenylyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazoleyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzofuranyl, benzothiophene, benzotriazinyl, phthalazinyl, thiathanthyl, dibenzofuranyl, dibenzothiaphene, benzene The compounds include imidazolyl, indolyl, isoindolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalolinyl, purine, pteridinyl, 9H-carbazolyl, α-carboline, indolazinyl, benzoisothiazolyl, benzoxazolyl, pyrrolopyridinyl, furanopyridinyl, purine, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, carbazolyl, dibenzothiaphenyl, acridineyl, etc. Preferably, "heteroaryl" refers to a 5- to 6-membered ring selected from furanyl, thiophenyl, pyrrololyl, pyrazolyl, imidazolyl, oxazolyl, cenolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrazinyl, and pyridazinyl. More preferably, pyrazolyl, pyridyl, oxazolyl, and furanyl groups. All heteroaryl groups may optionally be substituted with one or more of the aforementioned groups.

[0039] As used herein, the term "compound" includes the compounds disclosed herein.

[0040] As used herein, the terms “comprising” or “including” are generally used in the sense of inclusion, that is, allowing the presence of one or more features or components.

[0041] As used herein, unless otherwise stated, the term "or" means "and / or".

[0042] As used herein, the term "including" and other forms such as "comprise" and "contain" are not restrictive.

[0043] The phrase “pharmaceutical acceptable” refers to a compound or composition that is physiologically tolerable and, when administered to mammals, does not typically produce allergic or similar adverse reactions, including but not limited to stomach upset or dizziness.

[0044] The term "pharmaceutically acceptable salt" refers to the product obtained by reacting the compounds of the present invention with a suitable acid or base. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic bases, such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn, and Mn salts; examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups and inorganic acids, such as hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates, hydrogen sulfates, phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, pantothenates, hydrogen tartrate, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucurons, glycosides, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, 4-methylbenzenesulfonates, or p-toluenesulfonates, etc. Certain compounds of this invention can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine, or metformin. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc salts.

[0045] As used herein, the term "stereoisomer" is used for all isomers of the various compounds of formula (I) that differ only in the spatial orientation of their atoms. The term stereoisomer includes mirror-image isomers (enantiomers) of the compounds of the present invention, mixtures of mirror-image isomers (racemic mixtures) of the compounds of the present invention, geometric (cis / trans or E / Z, R / S) isomers of the compounds of the present invention, and isomers of the compounds of the present invention having more than one chiral center that is not mirror-image of each other (diastereomers).

[0046] In some embodiments, the compounds of the present invention may also contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. For example, the present invention also covers variations of the isotopic labeling of the present invention that are identical to those described herein, but in fact, one or more atoms of the compound are replaced with atoms whose atomic mass or mass number differs from the principal atomic mass or mass number of atoms commonly found in nature. All isotopes of any particular atom or element specified, and their uses, are covered within the scope of the compounds of the present invention. Exemplary isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as... 2 H (“D”), 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 32 P,33 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. The isotope-labeled compounds of the present invention can generally be prepared by following procedures known in the art, for example by replacing non-isotope-labeled reagents with isotope-labeled reagents.

[0047] As used herein, the term “pharmaceuticalally acceptable carrier” refers to any standard pharmaceutical carrier, such as phosphate-buffered saline solutions, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. The composition may also contain stabilizers and preservatives. Examples of carriers, stabilizers, and adjuvants are mentioned in literature such as Martin, Remington's Pharmaceutical Sciences, 15th edition, Mack Publ. Co., Easton, PA

[1975] .

[0048] The term “treatment” means any treatment of a disease in a mammal, including: (a) suppressing the disease, i.e., slowing or stopping the development of clinical symptoms; and / or (b) alleviating the disease, i.e. causing the remission of clinical symptoms; and / or (c) alleviating or eliminating the disease and / or its accompanying symptoms.

[0049] As used herein, the term “prevention” refers to methods for preventing the onset of a disease and / or its accompanying symptoms or for preventing a subject from acquiring the disease. As used herein, “prevention” also includes delaying the onset of a disease and / or its accompanying symptoms and reducing the risk of a subject acquiring the disease.

[0050] As used in this article, the term "subject" refers to an animal, preferably a mammal, and most preferably a human.

[0051] As used herein, the term "therapeuticly effective amount" refers to the amount of a compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof, or a composition comprising a compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof, capable of effectively producing a desired therapeutic response in a specific patient suffering from AML. Specifically, the term "therapeuticly effective amount" includes the amount of a compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof that, upon administration, induces a positive change in the disease or condition to be treated or is sufficient to prevent the development of one or more symptoms of the disease or condition being treated in a subject, or alleviates said symptoms to a certain extent. With regard to therapeutic amounts of compounds, the amount of the compound used to treat the subject is sufficiently low to avoid excessive or serious side effects, and may also be considered within the bounds of reasonable medical judgment. Therapeuticly effective amounts of compounds or compositions will vary depending on the specific condition being treated, the severity of the condition being treated or prevented, the duration of treatment, the nature of concurrent treatment, the age and physical condition of the end user, and the specific compound or composition using the specific pharmaceutically acceptable carrier employed.

[0052] In some embodiments, the compounds of the present invention can be used alone or in combination with another type of therapeutic agent. As used herein, the phrase "combined administration" refers to the administration of any form of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., both compounds are effective in the subject simultaneously, which may include a synergistic effect between the two compounds). For example, different therapeutic compounds can be administered simultaneously or sequentially in the same formulation or separate formulations. In some embodiments, different therapeutic compounds can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or one week of each other. In some embodiments, an additional therapeutic compound is administered approximately 5 minutes before or after the administration of a compound of formula I, formula II, or formula III for approximately 168 hours. Thus, subjects receiving such treatment can benefit from the combined effects of different therapeutic compounds.

[0053] In some embodiments, the combined administration of the compound of the invention with one or more other therapeutic agents (e.g., one or more other chemotherapeutic agents) provides improved efficacy relative to each individual administration of the compound of the invention or one or more other therapeutic agents. In some such embodiments, the combined administration provides an additive effect, wherein the additive effect refers to the sum of the effects of each of the individual applications of the compound of the invention and one or more other therapeutic agents.

[0054] This article provides a method for treating or preventing acute myeloid leukemia in a subject, the method comprising administering a compound of formula (I). Or its pharmaceutically acceptable salt; in Ring Z1 is a heteroaryl group with optional substitution; The ring Z2 is an optionally substituted heterocyclic alkyl group, an optionally substituted heteroaryl group, or a direct bond; R1 is an alkyl group, cyano group, or -NR group. a R b , or optionally substituted groups selected from cycloalkyl, aryl or heterocyclic groups; wherein each substituent is independently alkyl, alkoxy, halogen, hydroxy, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2 or –CH2-OP(O)(O-alkyl)2; R2 is, in each instance, an independently selected substituted group chosen from alkyl or cycloalkyl groups; wherein the substituent is, in each instance, a halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl, or haloalkoxy group; R3 is independently hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, or -NR each time it appears. a R b hydroxyl or hydroxyalkyl; R a It is hydrogen or alkyl; R b It is hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl, or optionally substituted cycloalkyl; 'm' and 'n' are 1 or 2 independently.

[0055] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein ring Z1 is a 5- or 6-membered optionally substituted heteroaryl group.

[0056] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein ring Z1 is an optionally substituted heteroaryl group; wherein the optional substituent is an alkyl group.

[0057] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring Z1 is selected from tetrazolyl, thiophenyl, triazolyl, pyrroleyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, and pyrazolyl.

[0058] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring Z1 is selected from pyridinyl, oxazolyl and furanyl; wherein the pyridinyl group is optionally substituted with an alkyl group; specifically, the alkyl group is methyl.

[0059] In some embodiments, the method of the present invention includes a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring Z2 is a 5- or 6-membered heteroaryl group selected from tetrazolyl, thiophene, triazolyl, pyrrole, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, or pyrazolyl.

[0060] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring Z2 is a 5- or 6-membered heterocyclic alkyl group selected from azacyclobutane, oxacyclobutane, imidazoalkyl, pyrrolidinyl, oxazolidinyl, thiazoalkyl, pyrazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl or 1,4-dioxanehexyl.

[0061] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring Z2 is pyridyl, pyrazolyl, or pyrrolidinyl.

[0062] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring Z2 is a direct bond.

[0063] In some embodiments, the method of the present invention includes a compound of formula (I), which is a compound of formula (IA). Or its pharmaceutically acceptable salt; Z2, R1, R2, R3, 'm', and 'n' are the same as those defined in the compound of formula (I).

[0064] In some embodiments, the method of the present invention includes a compound of formula (I), which is a compound of formula (IB). Or its pharmaceutically acceptable salt; Z2, R1, R2, R3, 'm', and 'n' are the same as those defined in the compound of formula (I).

[0065] In some embodiments, the method of the present invention includes a compound of formula (I), which is a compound of formula (IC). Or its pharmaceutically acceptable salt; Z2, R1, R2, R3, 'm', and 'n' are the same as those defined in the compound of formula (I).

[0066] In some embodiments, the method of the present invention includes a compound of formula (I), wherein for , , or ; R1, R2, and 'm' are the same as those defined in the compound of formula (I).

[0067] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring Z2 is pyridyl.

[0068] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring Z2 is a pyrazolyl group.

[0069] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring Z2 is pyrrolealkyl.

[0070] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted heterocyclic group; wherein the substituent is a halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2 or -CH2-OP(O)(O-alkyl)2.

[0071] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted aziridine, piperidinyl, morpholinyl, pyrrolidinyl or aziridine-heptyl; 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.

[0072] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted piperidinyl group; wherein the substituent is a hydroxyl group.

[0073] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted phenyl group; wherein the substituent is a halogen.

[0074] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is a cycloalkyl group.

[0075] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is cyclopropyl or cyclohexyl.

[0076] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is -NR a Rb ;R a It is hydrogen; R b It is an optionally substituted cycloalkyl group; wherein the substituent is a hydroxyl group.

[0077] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is a cyano group.

[0078] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 is an optionally substituted alkyl group; wherein the substituent is an alkoxy group.

[0079] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 is a cycloalkyl group.

[0080] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen, halogen, alkyl, alkoxy, -NR a R b , hydroxyl or hydroxyalkyl; R a It is hydrogen or alkyl; and R b It can be hydrogen, alkyl, acyl, hydroxyalkyl or -SO2-alkyl.

[0081] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring Z1 is an optionally substituted pyridyl group; ring Z2 is a pyridyl, pyrazolyl, pyrrolidinyl, or direct bond; R1 is an optionally substituted group selected from cyclopropyl, piperidinyl, morpholinyl, or pyrrolidinyl; R2 is an optionally substituted alkyl or cycloalkyl group; and R3 is hydrogen, halogen, alkyl, alkoxy, or -NR. a R b , hydroxyl or hydroxyalkyl; R a It is hydrogen or alkyl; R b It is hydrogen or hydroxyalkyl.

[0082] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring Z1 is an oxazolyl group; ring Z2 is a pyridyl, pyrazolyl, or pyrrolidinyl group; and R1 is a cyano, -NR group, or pyrrolyl group. a R b Alternatively, a substituent group selected from cyclopropyl, cyclohexyl, phenyl, aziridine, piperidinyl, morpholinyl, or pyrrolidinyl may be used; R2 is an optionally substituted alkyl or cycloalkyl group; R3 is hydrogen, halogen, alkyl, alkoxy, or -NR. a R b , hydroxyl or hydroxyalkyl; R a It is hydrogen or alkyl; and R b It can be hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl, or optionally substituted cycloalkyl.

[0083] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R3 is -NR. a R b ;R a It is hydrogen or alkyl; and R b It is hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl or optionally substituted cycloalkyl; wherein the optional substituent is hydroxyl; In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein 'n' is 1.

[0084] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein 'n' is 2.

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

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

[0087] In some embodiments, the method of the present invention comprises compounds selected from formula (I): N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl)pyridineamide; N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(1-methyl-6-(piperidin-1-yl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2-cyclopentyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-cyano-2-cyclopentyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2-Cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl)pyridineamide; N-(2-cyclopentyl-6-morpholino-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 6'-Amino-N-(2-cyclopentyl-6-morpholino-2H-indazol-5-yl)-[2,3'-bipyridine]-6-carboxamide 2,2,2-trifluoroacetate; N-(6-(3-fluorophenyl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-cyclohexyl-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; 6'-Fluoro-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-[2,3'-bipyridine]-6-carboxamide hydrochloride; N-(6-cyclohexyl-2-methyl-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl)pyridineamide hydrochloride; 2'-Fluoro-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-[2,3'-bipyridine]-6-carboxamide; 2-(2-chloropyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4-carboxamide hydrochloride; N-(6-Cyclopropyl-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(1-Cyclopentyl-6-cyclopropyl-1H-indazol-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridineamide; N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridineamide; 6-(1-Methyl-1H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; 2-(6-methoxypyridin-3-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4-carboxamide; N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(3-methylpyridin-4-yl)oxazol-4-carboxamide; 6-Bromo-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; 6-Chloro-5-methyl-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(6-methylpyridin-3-yl)oxazol-4-carboxamide; N-(2-Cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(2-methylpyridin-3-yl)oxazol-4-carboxamide; N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(3-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(6-methylpyridin-3-yl)oxazol-4-carboxamide; 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-5-yl)pyridineamide; N-(1-Cyclopropyl-6-(piperidin-1-yl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; 2-(2-hydroxypyridin-3-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4-carboxamide; (S)-6-(3-aminopyrrolidone-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide 2,2,2-trifluoroacetate; (S)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; N-(1,6-dicyclopropyl-1H-indazol-5-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; N-(1,6-Dicyclopropyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-6-(3-hydroxypyrrolidone-1-yl)pyridineamide; (R)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; (S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; 6-(3-hydroxypyrrolidone-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; (S)-6-(3-aminopyrrolidone-1-yl)-N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)pyridineamide; (R)-6-(3-aminopyrrolidone-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; (R)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4-carboxamide; N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)pyridineamide; (S)-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)pyridineamide; (S)-6-(3-aminopyrrolidone-1-yl)-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)pyridineamide; (S)-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-6-(3-hydroxypyrrolidone-1-yl)pyridineamide; (S)-N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-2-(3-hydroxypyrrolidone-1-yl)oxazol-4-carboxamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)oxazol-4-carboxamide; (S)-2-(3-hydroxypyrrolidone-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4-carboxamide; (S)-N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-2-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)oxazol-4-carboxamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide; (S)-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-2-(3-hydroxypyrrolidone-1-yl)oxazol-4-carboxamide; (S)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; 6-((2-hydroxypropyl)amino)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(azacyclobutan-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(azacyclobutan-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(3-hydroxyazacyclobutane-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(1-methyl-6-(pyrrolidin-1-yl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2-methyl-6-(pyrrolidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(6-(3-hydroxypyrrolidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(6-(3-hydroxypyrrolidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(6-(3-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(6-(3-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(6-(3-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(6-(azacycloheptane-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(azacycloheptane-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2,3-dimethyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(1,3-dimethyl-6-(piperidin-1-yl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-hydroxypiperidin-1-yl)-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-hydroxypiperidin-1-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-fluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(3-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)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-4-yl)oxazol-4-carboxamide; 2-(2-acetamidopyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4-carboxamide; 2-(2-acetamidopyridin-4-yl)-N-(6-(3-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide; 2-(2-aminopyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4-carboxamide hydrochloride; 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-hydroxycyclohexyl)amino)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-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; 2-(2-aminopyridin-4-yl)-N-(6-(4-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide hydrochloride; N-(6-(4-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)pyridineamide; 2-(2-aminopyridin-4-yl)-N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide hydrochloride; N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-5-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)pyridineamide; N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methoxypyridin-4-yl)oxazol-4-carboxamide; 2-(2-acetamidopyridin-4-yl)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide; 2-(2-aminopyridin-4-yl)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-5-yl)oxazol-4-carboxamide hydrochloride; 2-(2-aminopyridin-4-yl)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide hydrochloride; N-(6-(4-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methoxypyridin-4-yl)oxazol-4-carboxamide; 2-(2-aminopyridin-4-yl)-N-(6-(3-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide hydrochloride; 2-(2-methoxypyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4-carboxamide; 2-(2-aminopyridin-4-yl)-N-(6-(3-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide hydrochloride; (R)-2-(2-aminopyridin-4-yl)-N-(6-(3-hydroxypyrrolidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide hydrochloride; 1-(1,3-Dimethyl-5-(2-(2-methylpyridin-4-yl)oxazol-4-carboxamido)-1H-indazol-6-yl)piperidin-4-yl 2-methoxyacetate; N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methoxypyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(6-(4-aminopiperidin-1-yl)-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(6-(4-aminopiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-(2-methoxyethyl)-3-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1,3-dimethyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-aminopyridin-4-yl)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1,3-dimethyl-1H-indazol-5-yl)oxazol-4-carboxamide; N-(6-(4-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-hydroxypyridin-4-yl)oxazol-4-carboxamide; 2-(2,6-Dimethylpyridin-4-yl)-N-(6-(4-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-5-yl)oxazol-4-carboxamide; (S)-N-(6-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-hydroxypiperidin-1-yl)-1-(2-methoxyethyl)-3-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(1-(2-hydroxyethyl)-6-(4-hydroxypiperidin-1-yl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-aminopiperidin-1-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; 2-(2,6-Dimethylpyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4-carboxamide hydrochloride; 2-(2-(dimethylamino)pyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4-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-4-yl)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-1H-indazol-5-yl)oxazol-4-carboxamide; N-(6-(4-(aminomethyl)piperidin-1-yl)-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2,6-Dimethylpyridin-4-yl)-N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide; 2-(2,6-Dimethylpyridin-4-yl)-N-(6-(4-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide; (1-(1-methyl-5-(2-(2-methylpyridin-4-yl)oxazol-4-carboxamido)-1H-indazol-6-yl)piperidin-4-yl)diethyl phosphate; and ((1-(2-methyl-5-(2-(2-methylpyridin-4-yl)oxazol-4-carboxamido)-2H-indazol-6-yl)piperidin-4-yl)methyl)diethyl phosphate; Or its pharmaceutically acceptable salts or stereoisomers.

[0088] This article provides a method for treating or preventing acute myeloid leukemia in a subject, the method comprising administering a compound of formula (II): Or its pharmaceutically acceptable salt; in, X1 and X3 are independently CH or N; X2 is CR2 or N; the condition is that one or more of X1, X2 or X3 is N; A is either O or S; Y is either -CH2- or O; Ring Z is aryl or heterocyclic; R1 is independently a halogroup or an optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogroup, hydroxyl, hydroxyalkyl or -NR. a R b ; R2 is hydrogen, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or -NR. a R b The substituents are alkyl, amino, halogenated, or hydroxyl groups. R3 is either alkyl or hydroxyl in each occurrence; R a and R b It can be independently hydrogen, alkyl, acyl, or heterocyclic; 'm' and 'n' are independently 0, 1, or 2; 'p' is 0 or 1.

[0089] In some embodiments, the method of the present invention comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein the group for R2 is defined as in compound (II).

[0090] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring Z is an aryl or a 5- or 6-membered heterocyclic group.

[0091] In some embodiments, the method of the present invention comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring Z is phenyl, furanyl, thiophene, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazinyl, oxazolyl, thiazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxacyclohexyl, dioxothiomorpholinyl, oxapirazinyl, oxapiridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophene, or dihydropyranyl; wherein each is optionally prefixed with an alkyl, alkoxy, halogen, hydroxy, hydroxyalkyl, or -NR group. a R b Replace; R a and R b It can be hydrogen, alkyl, or acyl on its own.

[0092] In some embodiments, the method of the present invention comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring Z is phenyl, oxazolyl, furanyl, thiophenyl, or pyridyl; wherein each is optionally substituted by one or more R1.

[0093] In some embodiments, the method of the present invention comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein for ; R3 and 'm' are as defined in compound (II).

[0094] In some embodiments, the method of the present invention includes a compound of formula (II), which is a compound of formula (IIA): Or its pharmaceutically acceptable salt; Among them, A, Y, R1, R2, R3, 'm', 'p' and 'n' are the same as those defined in the compound of formula (II).

[0095] In some embodiments, the method of the present invention includes a compound of formula (II), which is a compound of formula (IIB): Or its pharmaceutically acceptable salt; A, Y, R1, R2 and 'n' are the same as those defined in the compound of formula (II).

[0096] In some embodiments, the method of the present invention includes a compound of formula (II), which is a compound of formula (IIC): Or its pharmaceutically acceptable salt; Among them, A, Y, R1, R2, R3 and 'n' are the same as those defined for compounds of formula (I).

[0097] In some embodiments, the method of the present invention comprises 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 method of the present invention comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted heterocyclic group; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxy, hydroxyalkyl, or -NR. a R b ;R a and R b It can be hydrogen, alkyl, or acyl on its own.

[0099] In some embodiments, the method of the present invention comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R1 is pyridinyl, pyrazolyl, pyrrolidinyl, or piperidinyl; wherein each is optionally prefixed with an alkyl, alkoxy, halogen, hydroxy, hydroxyalkyl, or -NR group. a R b Replace; R a and R b It can be hydrogen or acyl group independently.

[0100] In some embodiments, the method of the present invention comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

[0101] In some embodiments, the method of the present invention comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is an optionally substituted cycloalkyl group.

[0102] In some embodiments, the method of the present invention comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is cyclopropyl.

[0103] In some embodiments, the method of the present invention comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is an optionally substituted heterocyclic group; wherein the substituent is an alkyl, amino, halogenated or hydroxyl group.

[0104] In some embodiments, the method of the present invention comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is piperidinyl, pyrrolidinyl, morpholinyl, piperazineyl, aziridine, pyrazolyl, furanyl, pyridinyl, aziridine-heptyl or azirbicyclo[3.2.1]octyl; wherein the substituent is alkyl, amino, halogen or hydroxyl.

[0105] In some embodiments, the method of the present invention comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is an optionally substituted aryl group; wherein the substituent is a halogen group.

[0106] In some embodiments, the method of the present invention comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is an optionally substituted phenyl group; wherein the substituent is fluorine.

[0107] In some embodiments, the method of the present invention comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is -NR. a R b ;where R a and R b It can be a hydrogen or heterocyclic group independently.

[0108] In some embodiments, the method of the present invention comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is -NR. a R b ;where R a and R b It can be hydrogen or pyrroleyl independently.

[0109] In some embodiments, the method of the present invention comprises a compound of formula (IIA) or a pharmaceutically acceptable salt thereof, wherein A is O or S; Y is -CH2- or O; R1 is a halogen group, pyridinyl group, pyrazolyl group, pyrrolidinyl group, wherein each is optionally prefixed with an alkyl group, alkoxy group, halogen group, hydroxy group, hydroxyalkyl group or -NR group. a R bSubstitution; R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic or -NR. a R b The substituents are alkyl, amino, halogenated, or hydroxyl groups; R a and R b It can be hydrogen or alkyl independently.

[0110] In some embodiments, the method of the present invention comprises a compound of formula (IIB) or a pharmaceutically acceptable salt thereof, wherein A is O or S; Y is -CH2- or O; R1 is pyridinyl, pyrazolyl, or pyrrolidinyl; wherein each is optionally prefixed with an alkyl, hydroxyl, hydroxyalkyl, or -NR group. a R b Replace; R a and R b Independently hydrogen; R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic or -NR. a R b The substituents are alkyl, amino, halogenated, or hydroxyl groups; R a and R b It can be hydrogen, alkyl, acyl or heterocyclic group independently.

[0111] In some embodiments, the method of the present invention comprises a compound of formula (IIA), (IIB) or (IIC) or a pharmaceutically acceptable salt thereof, wherein 'n' is 0, 1 or 2.

[0112] In some embodiments, the method of the present invention comprises a compound of formula (IIA) or (IIB) or a pharmaceutically acceptable salt thereof, wherein 'p' is 0 or 1.

[0113] In some embodiments, the method of the present invention comprises a compound of formula (IIA) or (IIB) or a pharmaceutically acceptable salt thereof, wherein 'm' is 0 or 2.

[0114] In some embodiments, the method of the present invention comprises compounds selected from formula (II): 6'-Amino-N-(2-morpholinooxazolo[4,5-b]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide; 6'-Amino-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide hydrochloride; N-(5-Cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridineamide hydrochloride; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridineamide; 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-6-yl)pyridineamide; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridineamide; 2-(2-chloropyridin-4-yl)-N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-3-ylamino)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 6'-Amino-N-(2-morpholinooxazolo[5,4-b]pyridin-5-yl)-[2,3'-bipyridine]-6-carboxamide; 6'-Amino-N-(2-morpholinothiazo[4,5-c]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide; 6'-Amino-N-(2-morpholinothiazo[5,4-b]pyridin-5-yl)-[2,3'-bipyridine]-6-carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 6'-Amino-N-(2-morpholinothiazo[4,5-b]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide; N-(2-morpholinothiazo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridineamide; 3-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazo[4,5-b]pyridin-6-yl)benzamide; 2-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazo[4,5-b]pyridin-6-yl)benzamide; 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridineamide; N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridineamide; N-(2,5-bis(piperidin-1-yl)thiazo[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-4-carboxamide; N-(5-(4-methylpiperazin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-3-yl)oxazol-4-carboxamide; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-hydroxypyridin-3-yl)oxazolo-4-carboxamide; 2-(2-hydroxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(2,5-bis(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-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(3-methylpyridin-4-yl)oxazol-4-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[4,5-b]pyridin-6-yl)pyridineamide; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-methylpyridin-3-yl)oxazol-4-carboxamide; (S)-N-(5-(3-aminopyrrolidone-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-aminopyrrolidone-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)pyridineamide; (S)-6-(3-aminopyrrolidone-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)pyridineamide; (S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(3-hydroxypyrrolidone-1-yl)oxazol-4-carboxamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(5-(piperidin-1-yl)-2-(pyrrolidine-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide hydrochloride; N-(2-(2,6-dimethylmorpholino)-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridineamide hydrochloride; 6-(1-Methyl-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)pyridineamide; N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-3-yl)oxazol-4-carboxamide hydrochloride; N-(2-((2S,6R)-2,6-dimethylmorpholino)-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(2-hydroxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methoxypyridin-4-yl)oxazol-4-carboxamide; 2-(6-methoxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(2-methoxypyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(6-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(3-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-6-(3-aminopyrrolidone-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)pyridineamide; (S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)pyridineamide; (S)-6-(3-aminopyrrolidone-1-yl)-N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)pyridineamide; (S)-N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)pyridineamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-N-(5-(3-aminopyrrolidone-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(5-cyclopropyl-2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(5-Cyclopropyl-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(5-cyclopropyl-2-morpholinothiazo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidone-1-yl)pyridineamide; (S)-N-(5-cyclopropyl-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(3-hydroxypyrrolidone-1-yl)oxazol-4-carboxamide; (S)-N-(5-cyclopropyl-2-morpholinothiazo[4,5-b]pyridin-6-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)pyridineamide; (S)-N-(5-cyclopropyl-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)oxazol-4-carboxamide; N-(5-(3-hydroxypyrrolidone-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; (S)-N-(5-(azacyclobutan-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidone-1-yl)pyridineamide; N-(5-(3-hydroxyazacyclobutane-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; (S)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(5-(azacyclobutan-1-yl)-2-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidine-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidine-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 5-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)furan-2-carboxamide; N-(5-(azacycloheptane-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-aminopyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide hydrochloride; N-(5-(azacyclobutan-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; (S)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)pyridineamide N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride N-(5-(1-methyl-1H-pyrazol-4-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(3-fluorophenyl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; N-(5-(3-hydroxypyrrolidone-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide; N-(5-(azacyclobutan-1-yl)-2-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidine-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 5-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)furan-2-carboxamide; N-(5-(azacyclobutan-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidone-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; (R)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(5-(furan-3-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(3-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(5-(3-aminopiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(1H-pyrazol-4-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(5-(6-fluoropyridin-3-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2-(3-hydroxypiperidin-1-yl)-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-acetamidopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(2-(3-hydroxypiperidin-1-yl)-5-(4-hydroxypiperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-acetamidopyridin-4-yl)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(2-aminopyridin-4-yl)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide hydrochloride; 5-(2-aminopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)furan-3-carboxamide hydrochloride; 2-(2-aminopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide hydrochloride; 2-(2-aminopyridin-4-yl)-N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide hydrochloride; N-(5-(2-fluoropyridin-4-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-fluoropiperidin-1-yl)-2-(3-hydroxypiperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-aminopiperidin-1-yl)-2-(3-hydroxypiperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; and N-(5-(2-hydroxypyridin-4-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; Or its pharmaceutically acceptable salts or stereoisomers.

[0115] This article provides a method for treating or preventing acute myeloid leukemia in a subject, the method comprising administering a compound of formula (III): Or its pharmaceutically acceptable salt; in, Z1 indicates an optional substituted cycloalkyl group, an optional substituted aryl group, an optional substituted heterocyclic group, or none at all; Z2 represents an optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclic group; R1 is hydrogen, optionally substituted alkyl, amino, halogroup, cyanogroup, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted arylalkyl, or optionally substituted heterocyclic alkyl. R2 is, in each instance, an amino group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted arylalkyl group, or an optionally substituted heterocyclic alkyl group. R3, each time it appears, is a hydroxyl group, a halogen group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkyl group, or -NR. a R b ; R a and R b Each time it appears, it is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted arylalkyl or optionally substituted heterocyclic alkyl; m is 0, 1, or 2 each time it appears; and n is 0, 1, or 2 each time it appears.

[0116] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z1 is an optionally substituted heterocyclic group.

[0117] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z1 represents a cycloalkyl, aryl, or heterocyclic group optionally substituted with one or more substituents, said substituents being independently selected each time they appear from hydroxyl, halogen, alkyl, cycloalkyl, or NR. a R b .

[0118] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z1 is an optionally substituted heteroaryl group; wherein the optional substituent is an alkyl or cycloalkyl group.

[0119] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z1 is tetrazolyl, thiophene, triazolyl, pyrrole, pyridinyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, pyrazolyl, benzoisooxazolyl, benzothiazolyl, benzofuranyl, benzothiophene, benzotriazinyl, phthalazinyl, thiathanth, dibenzofuranyl, dibenzothiophene, The following are compounds: benzimidazolyl, indolyl, isoindolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxolinyl, purine, pteridinyl, 9H-carbazolyl, α-carbazolyl, indolazinyl, benzisothiazolyl, benzoxazolyl, pyrrolopyridinyl, furanopyridinyl, purine, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, carbazolyl, dibenzothiophenyl, acridineyl, and pyrazolopyrimidineyl; each of which may be optionally substituted.

[0120] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z1 is tetrazolyl, thiophenyl, triazolyl, pyrroleyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazoleyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, or pyrazolyl.

[0121] In some embodiments, the method of the present invention comprises 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 an alkyl group; specifically, the alkyl group is methyl.

[0122] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z1 is absent.

[0123] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 is a cycloalkyl, aryl, or heterocyclic group.

[0124] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 represents a cycloalkyl, aryl, or heterocyclic group optionally substituted with one or more substituents selected from hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, and -NR groups. a R b Or cycloalkoxy.

[0125] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 is a heterocyclic group.

[0126] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 is an azahexacyclobutane, oxacyclobutane, furanyl, piperidinyl, morpholinyl, piperazine, thiomorpholinyl, 1,4-dioxacyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridinyl, tetrazolyl, thiophene, triazolyl, pyrroloyl, pyridinyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazoalkyl, imidazoyl, thiadiazoyl, thiazoyl, thiazoalkyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrroloalkyl, oxazolalkyl, pyrazolalkyl, benzoisooxazolyl, benzothiazoyl, benzofuranyl, benzothiaphenyl, benzotriazinyl, indolyl, isoindolyl, indolyl, quinolinyl, isoquinolinyl, pyrrolopyridinyl, or pyrazolopyrimidinyl.

[0127] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 is pyridyl, piperazine, pyrimidinyl, pyrrolidinyl, 1,2,3,4-tetrahydropyridyl, piperidinyl, pyrazolopyrimidinyl, or pyrrolopyridyl.

[0128] In some embodiments, the compound of formula (III) is a compound of formula (IIIA). Or its pharmaceutically acceptable salt; Z2, R1, R2, R3, 'm' and 'n' are as defined in compound (III).

[0129] In some embodiments, the compound of formula (III) is a compound of formula (IIIB). Or its pharmaceutically acceptable salt; Z2, R1, R2, R3, 'm' and 'n' are as defined in compound (III).

[0130] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein the group for , , or ; R1, R2, and 'm' are the same as those defined in compound (III).

[0131] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 is pyridyl.

[0132] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 is a pyrrolidinyl group.

[0133] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 is piperidinyl, piperazineyl, tetrahydropyridinyl, pyrimidinyl, or pyrazolopyridinyl.

[0134] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, optionally substituted alkyl, amino, halogen, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted arylalkyl, or optionally substituted heterocyclic alkyl.

[0135] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt, wherein R1 is an alkyl, cycloalkyl, aryl, heterocyclic, or arylalkyl group optionally substituted with one or more substituents, wherein each substituent is independently selected from hydroxyl, halogen, alkyl, or hydroxyalkyl groups each time it appears.

[0136] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt, wherein R1 is a heterocyclic group; which is optionally substituted with a halogen, a hydroxyl group or a hydroxyalkyl group.

[0137] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt, wherein R1 is optionally substituted aziridine, piperidinyl, morpholinyl, pyrrolidinyl or aziridine-heptyl.

[0138] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt, wherein R1 is a piperidinyl group optionally substituted with a hydroxyl group.

[0139] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt, wherein R1 is a pyrrolidinyl compound optionally substituted with a hydroxyl group.

[0140] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt, wherein R2, each time it appears, is an amino group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted arylalkyl group, or an optionally substituted heterocyclic alkyl group.

[0141] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt, wherein R2 is an alkyl, cycloalkyl, aryl, heterocyclic, arylalkyl, or heterocyclic alkyl group optionally substituted with one or more substituents, wherein the substituents are independently selected from alkyl, cycloalkyl, or heterocyclic groups each time they appear.

[0142] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R2 is an optionally substituted alkyl group, preferably methyl.

[0143] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R2 is an optionally substituted cycloalkyl group, preferably cyclopropyl.

[0144] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R3, each time it appears, is a hydroxyl group, a halogen group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkyl group, or -NR. a R b ;where R a It is hydrogen or an optionally substituted alkyl group; and R b It is hydrogen, optionally substituted alkyl, optionally substituted acyl, hydroxyalkyl or -SO2-alkyl.

[0145] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z1 is an optionally substituted pyridyl group; Z2 is a pyrrolidinyl group; R1 is an optionally substituted group selected from piperidinyl or pyrrolidinyl; R2 is an optionally substituted alkyl group; and R3 is a halogen, alkyl, or -NR group. a R b , hydroxyl or hydroxyalkyl; R a It is hydrogen or alkyl; and R b It is hydrogen or hydroxyalkyl.

[0146] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z1 is an oxazolyl group; Z2 is a pyridyl, pyrimidinyl, or pyrrolidinyl, piperidinyl, tetrahydropyridinyl, piperazineyl, or pyrrolopyridinyl group; R1 is an optionally substituted group selected from piperidinyl or pyrrolidinyl; R2 is an optionally substituted alkyl or cyclopropyl group; and R3 is a halogen, alkyl, alkoxy, or -NR group. a R b , hydroxyl, hydroxyalkyl, optionally substituted cyclopropyl; R a It is hydrogen or alkyl; and R b It can be hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl, or optionally substituted cycloalkyl.

[0147] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein 'm' is 0.

[0148] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein 'm' is 1.

[0149] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein 'm' is 2.

[0150] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein 'n' is 0.

[0151] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein 'n' is 1.

[0152] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein 'n' is 2.

[0153] In some embodiments, the method of the present invention comprises compounds selected from formula (III): N-(1-methyl-5-(piperidin-1-yl)-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(2-methyl-5-(piperidin-1-yl)-2H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; (S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-methyl-5-(piperidin-1-yl)-2H-indazol-6-yl)pyridineamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(1-methyl-5-(piperidin-1-yl)-1H-indazol-6-yl)oxazol-4-carboxamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(2-methyl-5-(piperidin-1-yl)-2H-indazol-6-yl)oxazol-4-carboxamide; (S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-methyl-5-(piperidin-1-yl)-2H-indazol-6-yl)oxazol-4-carboxamide; (S)-6-(3-aminopyrrolidone-1-yl)-N-(2-methyl-5-(piperidin-1-yl)-2H-indazol-6-yl)pyridineamide; (S)-6-(3-aminopyrrolidone-1-yl)-N-(1-methyl-5-(piperidin-1-yl)-1H-indazol-6-yl)pyridineamide; (S)-6-(3-hydroxypyrrolidin-1-yl)-N-(1-methyl-5-(piperidin-1-yl)-1H-indazol-6-yl)pyridineamide; (S)-2-(3-hydroxypyrrolidone-1-yl)-N-(1-methyl-5-(piperidin-1-yl)-1H-indazol-6-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(3-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(3-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(3-fluoropiperidin-1-yl)-2-methyl-2H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(2-acetamidopyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)oxazol-4-carboxamide; N-(5-(3-Fluoroperidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(2-aminopyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)oxazol-4-carboxamide; N-(5-(4-fluoropiperidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-(hydroxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(2,6-dimethylpyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(2-aminopyridin-3-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)oxazol-4-carboxamide hydrochloride; 6-((S)-3-hydroxypyrrolidone-1-yl)-N-(5-((R)-3-hydroxypyrrolidone-1-yl)-1-methyl-1H-indazol-6-yl)pyridineamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; 6-((S)-3-hydroxypyrrolidone-1-yl)-N-(5-((S)-3-hydroxypyrrolidone-1-yl)-1-methyl-1H-indazol-6-yl)pyridineamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(2-amino-3-fluoropyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)oxazol-4-carboxamide; (R)-2-(2-aminopyridin-3-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(4-methylpiperazin-1-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(piperazin-1-yl)oxazol-4-carboxamide; (S)-N-(1-ethyl-5-(3-hydroxypyrrolidin-1-yl)-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(1-Cyclopropyl-5-(3-hydroxypyrrolidone-1-yl)-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(5-(3-hydroxypyrrolidone-1-yl)-1-methyl-1H-indazol-6-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyrimidin-4-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-4-methyl-2-(2-methylpyridin-4-yl)oxazol-5-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(piperidin-4-yl)oxazol-4-carboxamide hydrochloride; N-(5-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-5-carboxamide; N-(5-(4-hydroxy-4-(hydroxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-5-methyl-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(2-ethylpyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)oxazol-4-carboxamide; 2-(2-aminopyridin-4-yl)-N-(5-(4-(hydroxymethyl)piperidin-1-yl)-1,3-dimethyl-1H-indazol-6-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-(piperidin-4-ylmethyl)-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-(hydroxymethyl)piperidin-1-yl)-1,3-dimethyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(2-Cyclopropylpyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)oxazol-4-carboxamide; and N-(5-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

[0154] Pharmaceutical Composition In some embodiments, the method of the present invention includes a pharmaceutical composition comprising a compound disclosed herein, optionally mixed with a pharmaceutically acceptable carrier or diluent.

[0155] As used herein, the term "composition" is intended to cover products containing a specified amount of a specified ingredient, and any product directly or indirectly produced from a combination of the specified amounts of the specified ingredients.

[0156] As used herein, the term "pharmaceutical composition" refers to a composition containing a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, and a conventional pharmaceutically acceptable carrier.

[0157] 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 may also be rectally (e.g., in the form of suppositories), or parenterally (e.g., intravenously, intramuscularly, or subcutaneously, in the form of injectable sterile solutions or suspensions), or topically (e.g., in the form of ointments or creams or transdermal agents, in the form of patches, or otherwise, such as in the form of aerosols or nasal sprays).

[0158] Pharmaceutical compositions typically contain about 1% to 99%, for example about 5% to 75%, or about 10% to about 30% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition may range 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 in a wider range of 1 mg to 1000 mg, or in any range higher or lower than the foregoing.

[0159] The present invention also provides a method for formulating the disclosed compounds for drug administration.

[0160] The compositions and methods of the present invention can be used to treat individuals in need. In some 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 present invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are known in the art and include, for example, aqueous solutions (such as water or physiologically buffered saline) or other solvents or media (such as glycols, glycerols, oils (such as olive oil) or injectable organic esters.

[0161] In a preferred embodiment, when this pharmaceutical composition is used for human administration, particularly for invasive routes of administration (i.e., routes that avoid transport or diffusion across the epithelial barrier, such as injection or implantation), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients may be selected, for example, to achieve delayed release of the agent or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition may be in dosage unit form such as tablets, capsules (including dispersible capsules and gelatin capsules), granules, hydrophilic colloids for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition may also be present in transdermal delivery systems such as skin patches. The composition may also be present in solutions suitable for topical application such as eye drops.

[0162] Pharmaceutically acceptable carriers may contain physiologically acceptable agents that serve, for example, to stabilize, increase solubility, or enhance the absorption of compounds such as those of the present invention. Such physiologically acceptable agents include, for example, carbohydrates (e.g., glucose, sucrose, or dextran), antioxidants (e.g., ascorbic acid or glutathione), chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of pharmaceutically acceptable carrier (including physiologically acceptable agents) depends, for example, on the route of administration of the composition. The pharmaceutical composition may be prepared using a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) may also be a liposome or other polymer matrix incorporated therein, such as the compositions of the present invention. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively easy to prepare and administer.

[0163] The phrase “pharmaceutically acceptable” as used in this article refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0164] As used herein, the phrase “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense that it is compatible with other components of the formulation and does not harm the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and Soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0165] The pharmaceutical composition (formulation) may be administered to a subject via any of a number of routes of administration, including, for example, oral (e.g., drenches of aqueous or non-aqueous solutions or suspensions applied to the tongue, tablets, capsules (including dispersible capsules and gelatin capsules), pills, powders, granules, pastes); absorption through the oral mucosa (e.g., sublingual); anal, rectal, or vaginal (e.g., as a pessary, cream, or foam); parenteral (including intramuscular, intravenous, subcutaneous, or intrathecal, e.g., as a sterile solution or suspension); nasal; intraperitoneal; subcutaneous; percutaneous (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 some embodiments, the compound may be dissolved or suspended only in sterile water. Details of suitable routes of administration and compositions thereof can be found, for example, in U.S. Patent Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, and the patents cited therein.

[0166] The formulation can be conveniently provided in unit dosage forms and can be prepared by any method known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific route of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally the amount of the compound that produces the therapeutic effect. Typically, this amount ranges from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%, in percentage terms.

[0167] Methods for preparing these formulations or compositions include the step of associating an active compound (e.g., the compound of the present invention) with a carrier and optionally one or more auxiliary components. Generally, formulations are prepared by homogeneously and closely associating the compound of the present invention with a liquid carrier or a finely powdered solid carrier, or both, and then shaping the product as needed.

[0168] Formulations of the present invention suitable for oral administration may be in the form of capsules (including dispersible capsules and gelatin capsules), flat capsules, pills, tablets, lozenges (using a flavoring matrix, typically sucrose and gum arabic or tragacanth), hydrophilic colloids, powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil emulsions, or as elixirs or syrups, or as soft lozenges (using an inert matrix, such as gelatin and glycerin, or sucrose and gum arabic), and / or as oral washes, each containing a predetermined amount of the compound of the present invention as an active ingredient. The compositions or compounds may also be administered in the form of large pills, granules, or pastes.

[0169] To prepare solid dosage forms (capsules (including dispersible capsules and gelatin capsules), tablets, pills, sugar tablets, powders, granules, etc.) for oral administration, 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 substances: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silica; (2) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; (3) humectants. (3) Disintegrants, such as glycerin; (4) Disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates and sodium carbonate; (5) Solution retarders, such as paraffin; (6) Absorption promoters, such as quaternary ammonium compounds; (7) Wetting agents, such as cetyl alcohol and glyceryl monostearate; (8) Adsorbents, such as kaolin and bentonite; (9) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, 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 dispersible capsules and gelatin capsules), tablets and pills, the pharmaceutical composition may also contain buffers. Similar types of solid compositions may also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0170] Tablets can be prepared by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine.

[0171] Tablets and other solid dosage forms of pharmaceutical compositions, such as tablets, capsules (including dispersible capsules and gelatin capsules), pills, and granules, may optionally be scored or prepared with coatings and shells (e.g., enteric coatings and other coatings known in the field of pharmaceutical formulation). They may also be formulated to allow for the slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose (in varying proportions to provide a desired release profile), other polymer matrices, liposomes, and / or microspheres. They may be sterilized, for example, by filtration through a bacterial trap filter or by incorporation with a sterilizing agent in the form of a sterile solid composition, which may be dissolved in sterile water or some other sterile injectable medium prior to use. These compositions may also optionally contain an opacifying agent and may also be compositions that optionally release the active ingredient in a delayed manner only or preferably in a portion of the gastrointestinal tract. Examples of encapsulation compositions that may be used include polymeric substances and waxes. Where appropriate, the active ingredient may also be in the form of microcapsules having one or more of the excipients described above.

[0172] Liquid dosage forms suitable for oral administration include pharmaceutically acceptable emulsions, hydrophilic colloids for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol, as well as mixtures thereof.

[0173] In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, aroma agents and preservatives.

[0174] In addition to active compounds, suspensions may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum, and mixtures thereof.

[0175] Formulations of pharmaceutical compositions for rectal, vaginal, or urethral administration may be provided in suppository form, which may be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylate, and the suppository being solid at room temperature but liquid at body temperature and thus melting in the rectal or vaginal cavity and releasing the active compound. Formulations of pharmaceutical compositions for oral administration may be provided in the form of oral washes, oral sprays, or oral ointments.

[0176] Alternatively or additionally, the composition may be formulated for delivery via catheter, stent, wire or other endoluminal device. Delivery via such device may be particularly useful for delivery to the bladder, urethra, ureter, rectum or intestine.

[0177] Preparations suitable for vaginal application also include vaginal suppositories, tampons, creams, gels, pastes, foams or sprays containing suitable carriers known in the art.

[0178] Dosage forms for topical or transdermal application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. Active compounds can be mixed under aseptic conditions with pharmaceutically acceptable carriers and any necessary preservatives, buffers, or propellants.

[0179] In addition to active compounds, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth gum, cellulose derivatives, polyethylene glycol, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0180] In addition to the active compound, powders and sprays may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays may also contain commonly used propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0181] Transdermal patches offer the added advantage of controlled delivery of the compounds of this invention into the body. Such dosage forms can be prepared by dissolving or dispensing the active compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of this flux can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0182] Ophthalmic preparations, ointments, powders, solutions, etc., are also contemplated within the scope of this invention. Exemplary ophthalmic preparations are described in U.S. Publications 2005 / 0080056, 2005 / 0059744 and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference. Liquid ophthalmic preparations may, if desired, have properties similar to or compatible with tears, aqueous humor, or vitreous fluid. Preferred routes of administration are topical application (e.g., topical application such as eye drops, or via implantation).

[0183] As used in this article, the terms “parenteral administration” and “post-gastrointestinal administration” refer to modes of administration other than intravenous and local administration, usually by injection, and including but not limited to intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0184] A pharmaceutical composition suitable for parenteral administration comprises one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersants, suspensions, emulsions, or sterile powders, which can be reconstituted into a sterile injectable solution or dispersion just before use. The injectable solution or dispersion may contain antioxidants, buffers, antibacterial agents, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending agents or thickeners.

[0185] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. For example, appropriate flowability can be maintained by using coating materials (such as lecithin), by maintaining the desired particle size (in the case of dispersions), and by using surfactants.

[0186] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers, and dispersants. By including various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenolic sorbic acid, etc.), protection against microbial activity can be ensured. It is also desirable to include isotonic agents in the composition, such as sugars and sodium chloride. Additionally, by including agents that delay absorption, such as aluminum monostearate and gelatin, the absorption of injectable drug forms can be prolonged.

[0187] In some cases, to prolong the action of a drug, it is often desirable to slow the absorption of subcutaneously or intramuscularly injected drugs. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. Therefore, the absorption rate of a drug depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil-based medium.

[0188] Injectable reservoir formulations are prepared by forming a microencapsulated matrix of the subject compound in a biodegradable polymer such as polylactide-polyglycolic acid. The drug release rate can be controlled based on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Reservoir-type annotable formulations are also prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

[0189] For use in the methods of the present invention, the active compound may be provided as is or in the form of a pharmaceutical composition containing, for example, about 0.1% to about 99.5% (more preferably about 0.5% to about 90%) of the active ingredient and a pharmaceutically acceptable carrier.

[0190] Introduction methods can also be provided via rechargeable or biodegradable devices. In recent years, various sustained-release polymer devices have been developed and tested in vitro for the controlled delivery of drugs, including protein biopharmaceuticals. A variety of biocompatible polymers, including hydrogels, both biodegradable and non-degradable, can be used to form implants for the sustained release of compounds at specific target sites.

[0191] The actual dose level of the active ingredient in a pharmaceutical composition can be varied to obtain an amount of active ingredient that can effectively achieve the desired therapeutic effect for a specific patient, composition, and administration method without causing toxicity to the patient.

[0192] The selected dosage level depends on a variety of factors, including the activity of the specific compound or combination of compounds of the present invention or its esters, salts or amides, the route of administration, the time of administration, the excretion rate of the specific compound used, the duration of treatment, other drugs, compounds and / or materials used in combination with the specific composition used, the age, sex, weight, condition, general health status and prior medical history of the patient being treated, and similar factors known in the medical field.

[0193] A physician or veterinarian with ordinary skills in the art can readily determine and prescribe the desired therapeutically effective amount of a pharmaceutical composition. For example, a physician or veterinarian may start with a dose of the pharmaceutical composition or compound below the required dose level to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. The term "therapeutically effective amount" means a concentration of compound sufficient to elicit the desired therapeutic effect. Generally, it should be understood that the effective amount of a compound will vary depending on the subject's weight, sex, age, and medical history. Other factors affecting the effective amount may include, but are not limited to, the severity of the patient's condition, the condition being treated, the stability of the compound, and, if necessary, another class of therapeutic agents administered with the compound of the present invention. A larger total dose can be delivered by multiple administrations. 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 edition, 1814-1882, incorporated herein by reference).

[0194] Generally speaking, the appropriate daily dose of the active compound used in the compositions and methods of the present invention will be the lowest amount of compound that can effectively produce a therapeutic effect. This effective dose usually depends on the factors mentioned above.

[0195] If desired, the effective daily dose of the active compound can be administered as one, two, three, four, five, six or more sub-dose at appropriate intervals throughout the day, optionally in unit dosage form. In some embodiments of the invention, the active compound can be administered two or three times daily. In a preferred embodiment, the active compound is administered once daily.

[0196] Patients receiving this treatment are any animals in need, including primates, especially humans, as well as other mammals such as horses, cattle, pigs, and sheep; and poultry and pets in general.

[0197] Wetting agents, emulsifiers and lubricants (such as sodium lauryl sulfate and magnesium stearate), as well as colorants, release agents, coating agents, sweeteners, flavorings and aromas, preservatives and antioxidants may also be present in the composition.

[0198] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbate palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0199] The compounds of the present invention can be administered in combination with one or more other drugs to (1) supplement and / or enhance the preventive and / or therapeutic efficacy of the compounds of the present invention, (2) modulate pharmacokinetics, improve absorption, or reduce dose reduction of the preventive and / or therapeutic compounds of the present invention, and / or (3) reduce or improve the side effects of the preventive and / or therapeutic compounds of the present invention. As used herein, the phrase “combined administration” means 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 effective in the body (e.g., two compounds are effective in a patient simultaneously, which may include the synergistic effect of the two compounds). For example, different therapeutic compounds may be administered simultaneously or sequentially in the same formulation or separate formulations. In some embodiments, different therapeutic compounds may be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or one week of each other. Thus, individuals receiving such treatment may benefit from the combined effects of different therapeutic compounds. The individual compounds may be administered via the same or different routes and by the same or different methods.

[0200] Companion drugs comprising the compounds of the present invention and other drugs can be administered as a combination formulation in which both components are contained in a single formulation, or as a single formulation. Administration by single formulation includes simultaneous administration and / or administration of formulations separated at certain time intervals. In the case of administration at certain time intervals, 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 effective in the patient for at least some time during the combined treatment. The individual drugs can be administered via the same or different routes and by the same or different methods.

[0201] The dosage of other drugs may be appropriately selected based on clinically used dosages, or may be a dose reduction that is effective when administered in combination with the compound of the present invention. The ratio of the compound of the present invention to other drugs may be appropriately selected based on the age and weight of the subject to be administered, the method of administration, the time of administration, the condition to be treated, the symptoms, and combinations thereof. For example, based on 1 part by weight of the compound of the present invention, other drugs may be used in amounts from about 0.01 to about 100 parts by weight. Another drug may be a combination of two or more drugs in appropriate proportions. Another drug that complements and / or enhances the preventive and / or therapeutic efficacy of the compound of the present invention includes not only those drugs already discovered, but also drugs to be discovered in the future based on the above-described mechanisms.

[0202] In some embodiments, the compounds of the present invention may be administered in combination with non-chemical methods of cancer treatment. In some embodiments, the compounds of the present invention may be administered in combination with radiotherapy. In some embodiments, the compounds of the present invention may be administered in combination with surgery, thermal ablation, focused ultrasound therapy, cryotherapy, or any combination thereof.

[0203] Treatment Acute myeloid leukemia (AML) is a cancer of the myeloid blood cell line, 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. AML is a relatively rare disease, accounting for approximately 1.2% of cancer deaths in the United States.

[0204] AML symptoms are caused by leukemia cells replacing normal bone marrow, leading to a decrease in red blood cells, platelets, and normal white blood cells. Several risk factors and chromosomal abnormalities have been identified, but the exact cause remains unclear. As an acute leukemia, AML progresses rapidly and is often fatal within weeks or months if left untreated. AML differs from chronic myeloid leukemia (CML) because of their different cell differentiation processes. AML involves a higher percentage of dedifferentiated and undifferentiated cells, including more primitive cells (promyelocytes, promonocytes, and promegakaryocytes).

[0205] The diagnosis of AML usually begins with abnormal results from a complete blood count. While an excessive number of abnormal white blood cells (leukocytosis) is a common finding, and leukemic blast cells can sometimes be seen, AML can also present with isolated thrombocytopenia, decreased red blood cell counts, or even low white blood cell counts (leukopenia). Although a presumptive diagnosis of AML can be established by examining a peripheral blood smear in the presence of circulating leukemic blast cells, a definitive diagnosis usually requires adequate bone marrow aspiration and biopsy.

[0206] Genetic studies can also be conducted to identify specific mutations in genes, such as FLT-3 or genes regulating FLT-3 expression, that can affect disease outcomes. Indeed, the ability of many of the compounds disclosed herein to inhibit FLT-3 is believed to contribute to their specific efficacy against AML, which is known to be sensitive to FLT-3 inhibition. Some patients may develop resistance to FLT-3 inhibitors due to mutations in the FLT-3 gene. Such FLT-3 mutations include, but are not limited to, D835H, D835V, D835Y, K663Q, N841I, internal tandem repeats (ITD), ITD and D835V, and ITD and F691L. However, the compounds disclosed herein have been shown to be effective against AML in which AML has developed resistance to FLT-3 inhibitor treatment. Therefore, in some embodiments, the disclosed compounds are capable of effectively treating AML resistant to FLT-3 inhibitors, such as AML characterized by cells having one or more of these mutations.

[0207] The malignant cells in AML are promyelocytes. In normal hematopoiesis, promyelocytes are immature precursors to myeloid leukocytes; normal promyelocytes gradually mature into mature leukocytes. However, in AML, individual promyelocytes accumulate genetic changes that "freeze" the cell in its immature state and prevent differentiation. This mutation alone does not cause leukemia; however, when this "differentiation arrest" combines with other mutations that disrupt genes controlling proliferation, the result is the uncontrolled growth of immature cell clones, leading to the clinical entity of AML.

[0208] Myelodysplastic syndromes (MDS) are a group of cancers in which immature blood cells in the bone marrow fail to mature and become healthy blood cells. Some types may develop into acute myeloid leukemia. Problems with blood cell formation lead to certain combinations of low red blood cell counts, low platelet counts, and low white blood cell counts. Some types of immature blood cells (called blast cells) increase in the bone marrow or blood. Types of MDS are based on specific changes in blood cells and bone marrow.

[0209] MDS is believed to be caused by mutations in pluripotent bone marrow stem cells, but little is known about the specific defects that lead to these diseases. Differentiation of blood progenitor cells is impaired, and the level of apoptotic cell death in bone marrow cells is significantly increased. Clonal expansion of abnormal cells leads to the production of cells that lose their ability to differentiate. Transformation into acute myeloid leukemia is considered to have occurred if the total percentage of bone marrow promyelocytes exceeds a specific cutoff value, such as 20-30%. The progression of MDS to AML demonstrates how a series of mutations occur in initially normal cells and transform them into cancerous cells.

[0210] IRAK-1 is known to be overexpressed in AML and MDS, and inhibition of IRAK-1 has been shown to induce apoptosis in MDS cell lines. See, for example Rhyasen, GW et al. Cancer Cell 2013 24:90-104; Rhyasen, GW et al. British Journal of Cancer 2014, pp. 1-6. The disclosed compounds (including those that are not effective inhibitors of IRAK-1) demonstrate effective activity in AML cell lines (e.g., MV4-11 and MOLM-13) indicating that IRAK-4 is an attractive and effective target for AML and MDS in itself.

[0211] This document discloses methods for treating or preventing acute myeloid leukemia. These methods are also applicable to treating or preventing myelodysplastic syndromes. Similarly, these methods are also applicable to treating or preventing multiple myeloma. In some embodiments, the invention relates to compounds disclosed herein or pharmaceutically acceptable salts thereof for treating or preventing AML and / or MDS. In some embodiments, the invention relates to the use of compounds disclosed herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating or preventing AML and / or MDS.

[0212] Compounds suitable for the compositions and methods disclosed herein can be found in WO2015 / 104662, WO2015 / 104688 and WO2015 / 193846, each of which is incorporated herein by reference in its entirety, particularly the portions relating to the compounds disclosed therein as IRAK4 inhibitors.

[0213] This application also includes the following implementation schemes: 1. A method for treating or preventing acute myeloid leukemia in a subject, the method comprising administering a compound of formula I: Or its pharmaceutically acceptable salt; in, Z1 is a heteroaryl group with optional substitution; Z2 is an optionally substituted heterocyclic alkyl group, an optionally substituted heteroaryl group, or a direct bond; R1 is an alkyl group, cyano group, or -NR group. a R b Or a substituent selected from cycloalkyl, aryl or heterocyclic groups; wherein the substituent is independently alkyl, alkoxy, halogen, hydroxy, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2 or –CH2-OP(O)(O-alkyl)2 when it appears. R2 is, in each instance, an independently selected substituted group chosen from alkyl or cycloalkyl groups; wherein the substituent is, in each instance, a halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl, or haloalkoxy group. R3 is independently hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, or -NR each time it appears. a R b hydroxyl or hydroxyalkyl; R a It is hydrogen or alkyl; R b It is hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl, or optionally substituted cycloalkyl; 'm' and 'n' are 1 or 2 independently.

[0214] 2. The method as described in implementation scheme 1, wherein Z1 is a 5-membered or 6-membered heteroaryl group.

[0215] 3. The method as described in embodiment 1 or 2, wherein Z1 is an optionally substituted heteroaryl group, and the optionally substituted group is an alkyl group.

[0216] 4. The method as described in any of the foregoing embodiments, wherein Z1 is tetrazolyl, thiophenyl, triazolyl, pyrroleyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazoleyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, and pyrazolyl.

[0217] 5. The method as described in any of the foregoing embodiments, wherein Z1 is selected from pyridinyl and oxazolyl.

[0218] 6. The method as described in embodiment 1, wherein the compound is of formula (IA) Or its pharmaceutically acceptable salt; Z2, R1, R2, R3, 'm', and 'n' are the same as those defined in Implementation Scheme 1.

[0219] 7. The method as described in embodiment 1, wherein the compound is of formula (IB) Or its pharmaceutically acceptable salt; Z2, R1, R2, R3, 'm', and 'n' are the same as those defined in Implementation Scheme 1.

[0220] 8. The method as described in embodiment 1, wherein the compound is of formula (IC) Or its pharmaceutically acceptable salt; Z2, R1, R2, R3, 'm', and 'n' are the same as those defined in Implementation Scheme 1.

[0221] 9. The method as described in any of the foregoing embodiments, wherein Z2 is a 5- or 6-membered heterocyclic alkyl group or a 5- or 6-membered heteroaryl group.

[0222] 10. The method as described in any one of embodiments 1-8, wherein Z2 is a heterocyclic alkyl group or a direct bond.

[0223] 11. The method as described in any one of embodiments 1-9, wherein Z2 is an azacyclobutane, oxacyclobutane, imidazoalkyl, pyrrolyl, oxazolyl, thiazoalkyl, pyrazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxacyclohexyl, tetrazolyl, thiopheneyl, triazolyl, pyrrolyl, pyridinyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperazinyl, imidazoyl, oxadiazolyl, thiazoyl, isothiazolyl, oxazolyl, furanyl, and pyrazolyl.

[0224] 12. The method as described in any one of embodiments 1-8, wherein Z2 is pyridinyl, pyrazolyl, pyrrolidinyl, or a direct bond.

[0225] 13. The method as described in any one of embodiments 1-8, wherein Z2 is a direct bond.

[0226] 14. The method as described in any of the foregoing embodiments, wherein m is 1 and n is 1 or 2.

[0227] 15. The method as described in any of the foregoing embodiments, wherein m and n are each 1.

[0228] 16. The method as described in any of the foregoing embodiments, wherein R1 is selected from cyano, cycloalkyl, halogen, -NR a R b , aryl and heterocyclic groups.

[0229] 17. The method as described in any of the foregoing embodiments, wherein R1 is selected from cyano, cycloalkyl, aryl, and heterocyclic groups.

[0230] 18. The method as described in any of the preceding embodiments, wherein R1 is selected from cyclopropyl, cyclohexyl, piperidinyl, and morpholinyl.

[0231] 19. The method of any one of embodiments 1-17, wherein R1 is an optionally substituted heterocyclic group; wherein the substituent is a halogen, hydroxyl, hydroxyalkyl, or amino group.

[0232] 20. The method as described in any one of embodiments 1-17, wherein R1 is an optionally substituted azahexacyclic butyl, piperidinyl, morpholinyl, pyrrolidinyl, or azahexacyclic heptyl.

[0233] 21. The method as described in any of the foregoing embodiments, wherein R1 is optionally substituted piperidinyl or morpholinyl.

[0234] 22. The method of any one of embodiments 1-17, wherein R1 is an optionally substituted phenyl group; wherein the substituent is a halogen.

[0235] 23. The method as described in any one of embodiments 1-17, wherein R1 is cyano or cycloalkyl.

[0236] 24. The method as described in any one of embodiments 1-18, wherein R1 is cyclopropyl or cyclohexyl.

[0237] 25. The method as described in any one of embodiments 1-16, wherein R1 is -NR a R b ;R a It is hydrogen; R b The substituted cycloalkyl group is optionally substituted; wherein the substituent is a hydroxyl group.

[0238] 26. The method as described in any of the foregoing embodiments, wherein R2 is an optionally substituted alkyl group and the substituent is an alkoxy group.

[0239] 27. The method as described in any one of embodiments 1-25, wherein R2 is cyclopropyl or cyclopentyl.

[0240] 28. The method as described in any of the foregoing embodiments, wherein R3 is hydrogen, halogen, alkyl, alkoxy, or -NR. a R b , hydroxyl or hydroxyalkyl; and R a and R b As defined in Implementation Scheme 1.

[0241] 29. The method as described in any of the foregoing embodiments, wherein R3 is selected from hydrogen, halogen, alkyl, alkoxy and hydroxyl.

[0242] 30. The method as described in any of the foregoing embodiments, wherein R3 is selected from hydrogen, alkyl, and -NR. a R b .

[0243] 31. The method as described in any of the foregoing embodiments, wherein R3 is H.

[0244] 32. The method as described in embodiment 1, wherein the compound of formula (I) is selected from: N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl)pyridineamide; N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(1-methyl-6-(piperidin-1-yl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2-cyclopentyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-cyano-2-cyclopentyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2-Cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl)pyridineamide; N-(2-cyclopentyl-6-morpholino-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 6'-Amino-N-(2-cyclopentyl-6-morpholino-2H-indazol-5-yl)-[2,3'-bipyridine]-6-carboxamide 2,2,2-trifluoroacetate; N-(6-(3-fluorophenyl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-cyclohexyl-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; 6'-Fluoro-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-[2,3'-bipyridine]-6-carboxamide hydrochloride; N-(6-cyclohexyl-2-methyl-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl)pyridineamide hydrochloride; 2'-Fluoro-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-[2,3'-bipyridine]-6-carboxamide; 2-(2-chloropyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4-carboxamide hydrochloride; N-(6-Cyclopropyl-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(1-Cyclopentyl-6-cyclopropyl-1H-indazol-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridineamide; N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridineamide; 6-(1-Methyl-1H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; 2-(6-methoxypyridin-3-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4-carboxamide; N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(3-methylpyridin-4-yl)oxazol-4-carboxamide; 6-Bromo-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; 6-Chloro-5-methyl-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(6-methylpyridin-3-yl)oxazol-4-carboxamide; N-(2-Cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(2-methylpyridin-3-yl)oxazol-4-carboxamide; N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(3-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-2-(6-methylpyridin-3-yl)oxazol-4-carboxamide; 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-5-yl)pyridineamide; N-(1-Cyclopropyl-6-(piperidin-1-yl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; 2-(2-hydroxypyridin-3-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4-carboxamide; (S)-6-(3-aminopyrrolidone-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide 2,2,2-trifluoroacetate; (S)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; N-(1,6-dicyclopropyl-1H-indazol-5-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; N-(1,6-Dicyclopropyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-6-(3-hydroxypyrrolidone-1-yl)pyridineamide; (R)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; (S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; 6-(3-hydroxypyrrolidone-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; (S)-6-(3-aminopyrrolidone-1-yl)-N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)pyridineamide; (R)-6-(3-aminopyrrolidone-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; (R)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4-carboxamide; N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)pyridineamide; (S)-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)pyridineamide; (S)-6-(3-aminopyrrolidone-1-yl)-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)pyridineamide; (S)-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-6-(3-hydroxypyrrolidone-1-yl)pyridineamide; (S)-N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-2-(3-hydroxypyrrolidone-1-yl)oxazol-4-carboxamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)oxazol-4-carboxamide; (S)-2-(3-hydroxypyrrolidone-1-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4-carboxamide; (S)-N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-2-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)oxazol-4-carboxamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide; (S)-N-(6-cyclopropyl-2-methyl-2H-indazol-5-yl)-2-(3-hydroxypyrrolidone-1-yl)oxazol-4-carboxamide; (S)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; 6-((2-hydroxypropyl)amino)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(azacyclobutan-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(azacyclobutan-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(3-hydroxyazacyclobutane-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(1-methyl-6-(pyrrolidin-1-yl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2-methyl-6-(pyrrolidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(6-(3-hydroxypyrrolidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(6-(3-hydroxypyrrolidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(6-(3-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(6-(3-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(6-(3-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(6-(azacycloheptane-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(azacycloheptane-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2,3-dimethyl-6-(piperidin-1-yl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(1,3-dimethyl-6-(piperidin-1-yl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-hydroxypiperidin-1-yl)-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-hydroxypiperidin-1-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-fluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(3-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)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-4-yl)oxazol-4-carboxamide; 2-(2-acetamidopyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4-carboxamide; 2-(2-acetamidopyridin-4-yl)-N-(6-(3-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide; 2-(2-aminopyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4-carboxamide hydrochloride; 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-hydroxycyclohexyl)amino)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-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; 2-(2-aminopyridin-4-yl)-N-(6-(4-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide hydrochloride; N-(6-(4-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)pyridineamide; 2-(2-aminopyridin-4-yl)-N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide hydrochloride; N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-5-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)pyridineamide; N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methoxypyridin-4-yl)oxazol-4-carboxamide; 2-(2-acetamidopyridin-4-yl)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide; 2-(2-aminopyridin-4-yl)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-5-yl)oxazol-4-carboxamide hydrochloride; 2-(2-aminopyridin-4-yl)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide hydrochloride; N-(6-(4-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methoxypyridin-4-yl)oxazol-4-carboxamide; 2-(2-aminopyridin-4-yl)-N-(6-(3-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide hydrochloride; 2-(2-methoxypyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4-carboxamide; 2-(2-aminopyridin-4-yl)-N-(6-(3-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide hydrochloride; (R)-2-(2-aminopyridin-4-yl)-N-(6-(3-hydroxypyrrolidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide hydrochloride; 1-(1,3-Dimethyl-5-(2-(2-methylpyridin-4-yl)oxazol-4-carboxamido)-1H-indazol-6-yl)piperidin-4-yl 2-methoxyacetate; N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methoxypyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(6-(4-aminopiperidin-1-yl)-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(6-(4-aminopiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-(2-methoxyethyl)-3-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1,3-dimethyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-aminopyridin-4-yl)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1,3-dimethyl-1H-indazol-5-yl)oxazol-4-carboxamide; N-(6-(4-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-hydroxypyridin-4-yl)oxazol-4-carboxamide; 2-(2,6-Dimethylpyridin-4-yl)-N-(6-(4-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-5-yl)oxazol-4-carboxamide; (S)-N-(6-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-hydroxypiperidin-1-yl)-1-(2-methoxyethyl)-3-methyl-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(1-(2-hydroxyethyl)-6-(4-hydroxypiperidin-1-yl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(6-(4-aminopiperidin-1-yl)-2-(2-methoxyethyl)-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; 2-(2,6-Dimethylpyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4-carboxamide hydrochloride; 2-(2-(dimethylamino)pyridin-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)oxazol-4-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-4-yl)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-1H-indazol-5-yl)oxazol-4-carboxamide; N-(6-(4-(aminomethyl)piperidin-1-yl)-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2,6-Dimethylpyridin-4-yl)-N-(6-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide; 2-(2,6-Dimethylpyridin-4-yl)-N-(6-(4-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)oxazol-4-carboxamide; (1-(1-methyl-5-(2-(2-methylpyridin-4-yl)oxazol-4-carboxamido)-1H-indazol-6-yl)piperidin-4-yl)diethyl phosphate; and ((1-(2-methyl-5-(2-(2-methylpyridin-4-yl)oxazol-4-carboxamido)-2H-indazol-6-yl)piperidin-4-yl)methyl)diethyl phosphate; Or its pharmaceutically acceptable salts or stereoisomers.

[0245] 33. The method of embodiment 1, wherein the compound is selected from: N-(2-cyclopentyl-6-morpholino-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridineamide; N-(6-(4-hydroxypiperidin-1-yl)-2,3-dimethyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; and N-(2-cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridineamide, Or its pharmaceutically acceptable salt.

[0246] 34. The method of embodiment 1, wherein the compound is selected from: N-(6-(3-fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-aminopyridin-4-yl)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1,3-dimethyl-1H-indazol-5-yl)oxazol-4-carboxamide; N-(6-(4-(aminomethyl)piperidin-1-yl)-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; and (S)-N-(6-cyclopropyl-1-methyl-1H-indazol-5-yl)-6-(3-hydroxypyrrolidone-1-yl)pyridineamide, Or its pharmaceutically acceptable salt.

[0247] 35. A method for treating or preventing acute myeloid leukemia in a subject, the method comprising administering a compound of formula II: Or its pharmaceutically acceptable salt; in X1 and X3 are independently CH or N; X2 is CR2 or N; the condition is that one or more of X1, X2 or X3 is N; A is either O or S; Y is either -CH2- or O; Z is an aryl or heterocyclic group; R1 is independently a halogenated or optionally substituted heterocyclic group each time it appears; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogenated, hydroxyl, hydroxyalkyl, or -NR. a R b ; R2 is hydrogen, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, or -NR. a R b The substituent is alkyl, amino, halogenated or hydroxyl. R3 is either alkyl or hydroxyl in each occurrence; R a and R b It can be independently hydrogen, alkyl, acyl, or heterocyclic; 'm' and 'n' are independently 0, 1, or 2; 'p' is 0 or 1.

[0248] 36. The method as described in implementation scheme 35, wherein A is either O or S; Y is either -CH2- or O; Z is an aryl or heterocyclic group; R1 is independently a halogroup or an optionally substituted heterocyclic group each time it appears, wherein the substituent is an alkyl, aminoalkyl, halogroup, or -NR group. a R b ;where R a and R b It can be independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, heterocyclic, or -NR. a R b ; 'm' is 0; and 'n' is 1.

[0249] 37. The method as described in implementation scheme 35, wherein A is either O or S; Y is either -CH2- or O; Z is an aryl or heterocyclic group; R1 is independently a halogenated or optionally substituted heterocyclic group each time it appears; wherein the substituent is an alkyl, alkoxy, aminoalkyl, halogenated, hydroxyl, or -NR. a R b ;where R a and R b It can be independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic group, or -NR. a R b The substituent is selected from amino, halogen, or hydroxyl groups; 'm' and 'n' are independently 0, 1, or 2; and 'p' is 0 or 1.

[0250] 38. The method as described in embodiment 35, or a pharmaceutically acceptable salt thereof, wherein the group for R2 is defined as in implementation scheme 35.

[0251] 39. The method as described in any one of embodiments 35-38, wherein Z is an aryl or a 5- or 6-membered heterocyclic group.

[0252] 40. The method as described in any one of embodiments 35-38, wherein Z is selected from phenyl, furanyl, thiopheneyl, pyrrolyl, pyrazolyl, imidazoleyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazoleyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, aziridine, oxazolyl, imidazoleyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolidine Heterocyclic groups optionally substituted with alkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxacyclohexyl, dioxothiomorpholinyl, oxapirazinyl, oxapiridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopheneyl, dihydropyranyl, and azirbicyclo[3.2.1]octyl; wherein each is optionally substituted with an alkyl, alkoxy, haloyl, hydroxyl, hydroxyalkyl, or -NR group. a R b Replace; and R a and R b It can be hydrogen, alkyl, or acyl on its own.

[0253] 41. The method as described in embodiment 35, wherein the method is based on formula (IIA): Or its pharmaceutically acceptable salt; A, Y, R1, R2, R3, 'm', 'p', and 'n' are the same as those defined in implementation scheme 35.

[0254] 42. The method as described in implementation scheme 41, wherein A is either O or S; Y is either -CH2- or O; R1 is independently a halogroup or an optionally substituted heterocyclic group each time it appears, wherein the substituent is an alkyl, aminoalkyl, halogroup, or -NR group. a R b ;where R a and R b It can be independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, heterocyclic, or -NR. a R b ; 'm' is 0; and 'n' is 1.

[0255] 43. The method as described in implementation scheme 41, wherein A is either O or S; Y is either -CH2- or O; R1 is independently a halogenated or optionally substituted heterocyclic group each time it appears; wherein the substituent is an alkyl, alkoxy, aminoalkyl, halogenated, hydroxyl, or -NR. a R b ;where R a and R b It can be independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic group, or -NR. a R b The substituent is selected from amino, halogen, or hydroxyl groups; and 'm' and 'n' are independently 0, 1, or 2.

[0256] 44. The method as described in embodiment 35, wherein the method is based on formula (IIB): Or its pharmaceutically acceptable salt; A, Y, R1, R2 and 'n' are the same as those defined in implementation scheme 35.

[0257] 45. The method as described in implementation scheme 44, wherein A is either O or S; Y is either -CH2- or O; R1 is independently a halogroup or an optionally substituted heterocyclic group each time it appears, wherein the substituent is an alkyl, aminoalkyl, halogroup, or -NR group. a R b ;where R a and R b It can be independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, heterocyclic, or -NR. a R b ;and 'n' is 1.

[0258] 46. ​​The method as described in implementation scheme 44, wherein A is either O or S; Y is either -CH2- or O; R1 is independently a halogenated or optionally substituted heterocyclic group each time it appears; wherein the substituent is an alkyl, alkoxy, aminoalkyl, halogenated, hydroxyl, or -NR. a R b ;where R a and R b It can be independently hydrogen, alkyl, or heterocyclic; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic group, or -NR. a R b The substituent is selected from amino, halogen, or hydroxyl groups; and 'm' and 'n' are independently 0, 1, or 2.

[0259] 47. The method of formula (I) as described in embodiment 35, wherein the method is a compound of formula (IIC) Or its pharmaceutically acceptable salt; A, Y, R1, R2 and 'n' are the same as those defined in Implementation Scheme 1.

[0260] 48. The method of any one of embodiments 35-47, wherein R1 is an optionally substituted heterocyclic group; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxy, hydroxyalkyl, or -NR. a R b And R a and R b It can be hydrogen or acyl group independently.

[0261] 49. The method of any one of embodiments 36-47, wherein R1 is an optionally substituted heterocyclic group; wherein the substituent is an alkyl, aminoalkyl, halogroup, or -NR. a R b And R a and R b It can be hydrogen or acyl group independently.

[0262] 50. The method as described in any one of embodiments 35-47, wherein R1 is an optionally substituted heterocyclic group; and said substituent is an alkyl, aminoalkyl, halogroup, or -NR group. a R b ;where R a and R b It can be hydrogen, alkyl, or heterocyclic group independently.

[0263] 51. The method as described in any one of embodiments 35-47, wherein R1 is an optionally substituted heterocyclic group; and said substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxyl, or -NR. a R b ;where R aand R b It can be hydrogen, alkyl, or heterocyclic group independently.

[0264] 52. The method as described in any one of embodiments 48-51, wherein R1 is pyridyl, pyrazolyl, pyrrolidinyl, or piperidinyl.

[0265] 53. The method as described in any one of embodiments 48-51, wherein R1 is an optionally substituted pyrazolyl group, wherein the substituent is an alkyl, hydroxyl, or -NR group. a R b .

[0266] 54. The method as described in any one of embodiments 35-47, wherein R1 is a halogen group.

[0267] 55. The method as described in any one of embodiments 35-54, wherein R2 is hydrogen, cycloalkyl, heterocyclic, or -NR. a R b .

[0268] 56. The method as described in any one of embodiments 35-54, wherein R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic group, or -NR. a R b The substituent is selected from amino, halogen, or hydroxyl groups.

[0269] 57. The method of any one of embodiments 35-54, wherein R2 is an optionally substituted heterocyclic group selected from piperidinyl, pyrrolidinyl, morpholinyl, piperazine, aziridine, pyrazolyl, furanyl or azirbicyclo[3.2.1]octyl; wherein the substituent is hydroxyl, halogen, alkyl or amino.

[0270] 58. The method as described in any one of embodiments 35-54, wherein R2 is piperidinyl, pyrrolidinyl, morpholinyl, or piperazineyl.

[0271] 59. The method as described in any one of embodiments 35-54, wherein R2 is hydrogen.

[0272] 60. The method as described in any one of embodiments 35-54, wherein R2 is a cycloalkyl group.

[0273] 61. The method as described in embodiment 60, wherein R2 is cyclopropyl.

[0274] 62. The method as described in embodiments 35-61, wherein R3 is an alkyl group.

[0275] 63. The method as described in any one of embodiments 35-62, wherein m is 0 and p is 1.

[0276] 64. The method as described in any one of embodiments 35-62, wherein m is 0 or 2, and p is 0 or 1.

[0277] 65. The method of embodiment 35, wherein the compound of formula (II) is selected from: 6'-Amino-N-(2-morpholinooxazolo[4,5-b]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide; 6'-Amino-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide hydrochloride; N-(5-Cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridineamide hydrochloride; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridineamide; 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-6-yl)pyridineamide; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridineamide; 2-(2-chloropyridin-4-yl)-N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-3-ylamino)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 6'-Amino-N-(2-morpholinooxazolo[5,4-b]pyridin-5-yl)-[2,3'-bipyridine]-6-carboxamide; 6'-Amino-N-(2-morpholinothiazo[4,5-c]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide; 6'-Amino-N-(2-morpholinothiazo[5,4-b]pyridin-5-yl)-[2,3'-bipyridine]-6-carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 6'-Amino-N-(2-morpholinothiazo[4,5-b]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide; N-(2-morpholinothiazo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridineamide; 3-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazo[4,5-b]pyridin-6-yl)benzamide; 2-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazo[4,5-b]pyridin-6-yl)benzamide; 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridineamide; N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridineamide; N-(2,5-bis(piperidin-1-yl)thiazo[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-4-carboxamide; N-(5-(4-methylpiperazin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-3-yl)oxazol-4-carboxamide; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-hydroxypyridin-3-yl)oxazolo-4-carboxamide; 2-(2-hydroxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(2,5-bis(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-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(3-methylpyridin-4-yl)oxazol-4-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[4,5-b]pyridin-6-yl)pyridineamide; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-methylpyridin-3-yl)oxazol-4-carboxamide; (S)-N-(5-(3-aminopyrrolidone-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-aminopyrrolidone-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)pyridineamide; (S)-6-(3-aminopyrrolidone-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)pyridineamide; (S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(3-hydroxypyrrolidone-1-yl)oxazol-4-carboxamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(5-(piperidin-1-yl)-2-(pyrrolidine-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide hydrochloride; N-(2-(2,6-dimethylmorpholino)-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridineamide hydrochloride; 6-(1-Methyl-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)pyridineamide; N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-3-yl)oxazol-4-carboxamide hydrochloride; N-(2-((2S,6R)-2,6-dimethylmorpholino)-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(2-hydroxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methoxypyridin-4-yl)oxazol-4-carboxamide; 2-(6-methoxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(2-methoxypyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(6-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(3-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-6-(3-aminopyrrolidone-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)pyridineamide; (S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)pyridineamide; (S)-6-(3-aminopyrrolidone-1-yl)-N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)pyridineamide; (S)-N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)pyridineamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-N-(5-(3-aminopyrrolidone-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(5-cyclopropyl-2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(5-Cyclopropyl-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(5-cyclopropyl-2-morpholinothiazo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidone-1-yl)pyridineamide; (S)-N-(5-cyclopropyl-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(3-hydroxypyrrolidone-1-yl)oxazol-4-carboxamide; (S)-N-(5-cyclopropyl-2-morpholinothiazo[4,5-b]pyridin-6-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)pyridineamide; (S)-N-(5-cyclopropyl-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)oxazol-4-carboxamide; N-(5-(3-hydroxypyrrolidone-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; (S)-N-(5-(azacyclobutan-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidone-1-yl)pyridineamide; N-(5-(3-hydroxyazacyclobutane-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; (S)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(5-(azacyclobutan-1-yl)-2-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidine-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidine-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 5-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)furan-2-carboxamide; N-(5-(azacycloheptane-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-aminopyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide hydrochloride; N-(5-(azacyclobutan-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; (S)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)pyridineamide N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride N-(5-(1-methyl-1H-pyrazol-4-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(3-fluorophenyl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; N-(5-(3-hydroxypyrrolidone-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide; N-(5-(azacyclobutan-1-yl)-2-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidine-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 5-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)furan-2-carboxamide; N-(5-(azacyclobutan-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidone-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; (R)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(5-(furan-3-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(3-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(5-(3-aminopiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(1H-pyrazol-4-yl)thiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(5-(6-fluoropyridin-3-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(2-(3-hydroxypiperidin-1-yl)-5-(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-acetamidopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; N-(2-(3-hydroxypiperidin-1-yl)-5-(4-hydroxypiperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; 2-(2-acetamidopyridin-4-yl)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide; 2-(2-aminopyridin-4-yl)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide hydrochloride; 5-(2-aminopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)furan-3-carboxamide hydrochloride; 2-(2-aminopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide hydrochloride; 2-(2-aminopyridin-4-yl)-N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)oxazol-4-carboxamide hydrochloride; N-(5-(2-fluoropyridin-4-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-fluoropiperidin-1-yl)-2-(3-hydroxypiperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-aminopiperidin-1-yl)-2-(3-hydroxypiperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; and N-(5-(2-hydroxypyridin-4-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; Or its pharmaceutically acceptable salts or stereoisomers.

[0278] 66. The method of embodiment 35, wherein the compound of formula (II) is selected from: 6'-Amino-N-(2-morpholinooxazolo[5,4-b]pyridin-5-yl)-[2,3'-bipyridine]-6-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(2,5-bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridineamide hydrochloride; and (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; Or its pharmaceutically acceptable salt.

[0279] 67. The method of embodiment 35, wherein the compound of formula (II) is selected from: N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; N-(5-(azacycloheptane-1-yl)-2-morpholinothiazo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; and N-(2,5-bis(piperidin-1-yl)thiazo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridineamide; Or its pharmaceutically acceptable salt.

[0280] 68. A method for treating or preventing acute myeloid leukemia in a subject, the method comprising administering a compound of formula (III): Or its pharmaceutically acceptable salt; in, Z1 may be an optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, or absent; Z2 is an optionally substituted cycloalkyl, aryl, or heterocyclic group; R1 is hydrogen, optionally substituted alkyl, amino, halogen, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted arylalkyl, or optionally substituted heterocyclic alkyl. R2 is hydrogen, halogen, amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted arylalkyl, or optionally substituted heterocyclic alkyl in each occurrence. R3, each time it appears, is a hydroxyl group, a halogen, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted cycloalkyl group, or -NR. a R b ; R a and R b Each time it appears, it is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, optionally substituted arylalkyl or optionally substituted heterocyclic alkyl; m is 0, 1, or 2 each time it appears; and n is 0, 1, or 2 each time it appears.

[0281] 69. The method as described in embodiment 68, wherein Z1 is an optionally substituted heterocyclic group.

[0282] 70. The method as described in embodiment 68 or 70, wherein Z1 is selected from tetrazolyl, thiophene, triazolyl, pyrrole, pyridinyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazole, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, pyrazolyl, benzoisooxazolyl, benzothiazolyl, benzofuranyl, benzothiophene, benzotriazinyl, phthalazinyl, thiathanth, dibenzofuranyl, dibenzothiophene, and benzimidazole. Heterocyclic groups of the following groups: yl, indolyl, isoindolyl, indazole, quinolinyl, isoquinolinyl, quinazolinyl, quinoxolinyl, purine, pteridinyl, 9H-carbazolyl, α-carbazolyl, indolazinyl, benzoisothiazolyl, benzoxazolyl, pyrrolopyridinyl, furanopyridinyl, purine, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzotriadiazolyl, carbazolyl, dibenzothiaphenyl, acridineyl, and pyrazolopyrimidineyl.

[0283] 71. The method as described in any one of embodiments 68-70, wherein the method is derived from formula (IIIA). Or its pharmaceutically acceptable salt; Z2, R1, R2, R3, m, and n are as defined in implementation scheme 68.

[0284] 72. The method as described in any one of embodiments 68-70, wherein the method is derived from formula (IIIB). Or its pharmaceutically acceptable salt; Z2, R1, R2, R3, m, and n are as defined in implementation scheme 68.

[0285] 73. The method as described in any one of embodiments 68-72, wherein Z2 is a heterocyclic group.

[0286] 74. The method as described in any one of embodiments 68-73, wherein Z2 is a heterocyclic group selected from aza-butane, oxa-butane, imidazolyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxacyclohexyl, tetrazolyl, thiophene, triazolyl, pyrrolyl, pyridinyl, tetrahydropyridinyl, pyranyl, pyrazinyl, pyridinyl, pyrimidinyl, piperazinyl, imidazolyl, oxadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, pyrazolyl, indololinyl, indololinylmethyl, 2-aza-bicyclo[[2.2.2]octyl, benzodihydropyranyl, xanthonyl or pyrrolopyridinyl.

[0287] 75. The method of any one of embodiments 68-74, wherein Z2 is pyrrolidinyl, piperidinyl, piperazine, pyridinyl, pyrimidinyl, tetrahydropyridinyl or pyrrolopyridinyl.

[0288] 76. The method as described in any one of embodiments 68-75, wherein Z2 is pyrrolidinyl or pyridinyl.

[0289] 77. The method as described in any one of embodiments 68-76, wherein R1 is an optionally substituted heterocyclic group.

[0290] 78. The method as described in any one of embodiments 68-77, wherein R1 is a heterocyclic group; which is optionally substituted with a halogen, hydroxyl or hydroxyalkyl group.

[0291] 79. The method as described in any one of embodiments 68-78, wherein R1 is an optionally substituted aza-butyl, piperidinyl, morpholinyl, pyrrolidinyl, or aza-bicyclooctyl.

[0292] 80. The method as described in any one of embodiments 68-79, wherein R1 is piperidinyl.

[0293] 81. The method as described in any one of embodiments 68-80, wherein R2 is an optionally substituted alkyl group.

[0294] 82. The method as described in any one of embodiments 68-81, wherein R2 is an alkyl group optionally substituted with a heterocyclic group.

[0295] 83. The method as described in any one of embodiments 68-80, wherein R2 is hydrogen.

[0296] 84. The method as described in any one of embodiments 68-80, wherein R2 is cyclopropyl.

[0297] 85. The method as described in any one of embodiments 68-84, wherein R3 is a halogen, alkyl, haloalkyl, or -NR. a R b , cycloalkyl, hydroxy or hydroxyalkyl; and R a and R b As defined in implementation scheme 113.

[0298] 86. The method as described in any one of embodiments 68-85, wherein R3 is methyl, hydroxyl or amino.

[0299] 87. The method as described in any one of embodiments 68-86, wherein R3 is a hydroxyl or amino group.

[0300] 88. The method as described in implementation scheme 68, wherein Z1 is an optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclic group; Z2 is an optionally substituted cycloalkyl, aryl, or heterocyclic group; R1 is hydrogen, alkyl, amino, halogen, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, arylalkyl, or heterocyclic alkyl. R2 is an amino group, an alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an arylalkyl group, or a heterocyclic alkyl group; R3 is a hydroxyl, alkyl, alkoxy, or -NR group. a R b ; R a and R b Each time it appears, it is independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, arylalkyl or heterocyclic alkyl; m is 1; and n is 1.

[0301] 89. The method as described in implementation scheme 68, wherein Z1 is a heterocyclic group; Z2 is a heterocyclic group; R1 is an optionally substituted heterocyclic group; R2 is an alkyl group; R3 is a hydroxyl, alkyl, or amino group; m is 1; and n is 1.

[0302] 90. The method of embodiment 68, wherein the compound of formula (III) is selected from: N-(1-methyl-5-(piperidin-1-yl)-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(2-methyl-5-(piperidin-1-yl)-2H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; (S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-methyl-5-(piperidin-1-yl)-2H-indazol-6-yl)pyridineamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(1-methyl-5-(piperidin-1-yl)-1H-indazol-6-yl)oxazol-4-carboxamide; (S)-2-(3-aminopyrrolidone-1-yl)-N-(2-methyl-5-(piperidin-1-yl)-2H-indazol-6-yl)oxazol-4-carboxamide; (S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-methyl-5-(piperidin-1-yl)-2H-indazol-6-yl)oxazol-4-carboxamide; (S)-6-(3-aminopyrrolidone-1-yl)-N-(2-methyl-5-(piperidin-1-yl)-2H-indazol-6-yl)pyridineamide; (S)-6-(3-aminopyrrolidone-1-yl)-N-(1-methyl-5-(piperidin-1-yl)-1H-indazol-6-yl)pyridineamide; (S)-6-(3-hydroxypyrrolidin-1-yl)-N-(1-methyl-5-(piperidin-1-yl)-1H-indazol-6-yl)pyridineamide; (S)-2-(3-hydroxypyrrolidone-1-yl)-N-(1-methyl-5-(piperidin-1-yl)-1H-indazol-6-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(5-(3-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(5-(3-hydroxypiperidin-l-yl)-2-methyl-2H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride ； ]]> N-(5-(3-fluoropiperidin-1-yl)-2-methyl-2H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(2-acetamidopyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)oxazol-4-carboxamide; N-(5-(3-Fluoroperidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(2-aminopyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)oxazol-4-carboxamide; N-(5-(4-fluoropiperidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; N-(5-(4-(hydroxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(2,6-dimethylpyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)oxazol-4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(2-aminopyridin-3-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)oxazol-4-carboxamide hydrochloride; 6-((S)-3-hydroxypyrrolidone-1-yl)-N-(5-((R)-3-hydroxypyrrolidone-1-yl)-1-methyl-1H-indazol-6-yl)pyridineamide; 6-((S)-3-hydroxypyrrolidone-1-yl)-N-(5-((S)-3-hydroxypyrrolidone-1-yl)-1-methyl-1H-indazol-6-yl)pyridineamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(2-amino-3-fluoropyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)oxazol-4-carboxamide; (R)-2-(2-aminopyridin-3-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(4-methylpiperazin-1-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(piperazin-1-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(1-ethyl-5-(3-hydroxypyrrolidin-1-yl)-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(1-Cyclopropyl-5-(3-hydroxypyrrolidone-1-yl)-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(5-(3-hydroxypyrrolidone-1-yl)-1-methyl-1H-indazol-6-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyrimidin-4-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-4-methyl-2-(2-methylpyridin-4-yl)oxazol-5-carboxamide hydrochloride; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(piperidin-4-yl)oxazol-4-carboxamide hydrochloride; N-(5-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-5-carboxamide; N-(5-(4-hydroxy-4-(hydroxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-5-methyl-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide; (S)-2-(2-ethylpyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)oxazol-4-carboxamide; 2-(2-aminopyridin-4-yl)-N-(5-(4-(hydroxymethyl)piperidin-1-yl)-1,3-dimethyl-1H-indazol-6-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-(piperidin-4-ylmethyl)-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(5-(4-(hydroxymethyl)piperidin-1-yl)-1,3-dimethyl-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; (S)-2-(2-Cyclopropylpyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)oxazol-4-carboxamide hydrochloride; N-(5-(4-hydroxypiperidin-1-yl)-2-methyl-2H-indazol-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride; and (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride; Or its pharmaceutically acceptable salts or stereoisomers.

[0303] 91. The method of embodiment 68, wherein the compound of formula (III) is selected from: (S)-2-(3-aminopyrrolidone-1-yl)-N-(2-methyl-5-(piperidin-1-yl)-2H-indazol-6-yl)oxazol-4-carboxamide; 6-((S)-3-hydroxypyrrolidone-1-yl)-N-(5-((S)-3-hydroxypyrrolidone-1-yl)-1-methyl-1H-indazol-6-yl)pyridineamide; (S)-N-(1-ethyl-5-(3-hydroxypyrrolidin-1-yl)-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; and (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyrimidin-4-yl)oxazol-4-carboxamide hydrochloride; Or its pharmaceutically acceptable salt.

[0304] 92. The method of embodiment 68, wherein the compound of formula (III) is selected from: (S)-2-(2-Cyclopropylpyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)oxazol-4-carboxamide hydrochloride; (S)-N-(1-Cyclopropyl-5-(3-hydroxypyrrolidone-1-yl)-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; N-(2-methyl-5-(piperidin-1-yl)-2H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide hydrochloride; and (S)-6-(3-aminopyrrolidone-1-yl)-N-(1-methyl-5-(piperidin-1-yl)-1H-indazol-6-yl)pyridineamide; Or its pharmaceutically acceptable salt.

[0305] 93. The method as described in any of the preceding embodiments, wherein the subject has a mutation in FLT-3 kinase.

[0306] 94. The method of embodiment 93, wherein the mutation is an internal tandem repeat (ITD).

[0307] 95. The method of embodiment 93, wherein the mutation is selected from D835H, D835V, D835Y, K663Q, N841I, ITD, ITD and D835V, and ITD and F691L.

[0308] 96. The method of any of the foregoing embodiments, wherein the AML is resistant to an FLT-3 inhibitor. Example

[0309] Example 1: Inhibition of FLT-3 by compound A The inhibitory effect of the compound on wild-type FLT-3 was tested 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 EAYAAPFAKKK, 10 mM magnesium acetate, and [γ-33P]-ATP (specific activity and concentration as needed). The reaction was initiated by adding a Mg / ATP mixture. After incubation at room temperature for 40 min, the reaction was terminated by adding phosphate to a concentration of 0.5%. 10 μL of the reaction mixture was then spotted onto a P30 filter pad, washed four times for 4 min in 0.425% phosphate, washed once in methanol, and then dried and scintillation counted.

[0310] As described above, compound A for Flt-3 was measured using the Eurofins standard Kinase Profiler. Compound A was also measured for IRAK1 and Flt-3 (D835Y) using the same protocol as for the substrates myelin basic protein (MBP) and EAIYAAPFAKKK. Protein kinases (except ATM(h) and DNA-PK(h)) were measured using the radiometric method, while lipid kinases ATM(h), ATR / ATRIP(h), and DNA-PK(h) were measured using the HTRF® method.

[0311] Compound A was prepared by adding a 50x test compound stock solution to the assay well, followed by the addition of a reaction mixture containing the enzyme and substrate. The reaction was initiated by adding a selected concentration of ATP. The compound was not pre-incubated with the enzyme / substrate mixture prior to the addition of ATP. The compound was a working stock solution at 50x final assay concentration in 100% DMSO.

[0312] The results are expressed as the remaining kinase activity, as a percentage of the DMSO control. This is calculated using the following formula: Mean of sample counts — Mean of blank counts average of control counts For IC 50 Determination was performed using XLFit version 5.3 (ID Business Solutions). S-shaped dose-response (variable slope) curves were fitted based on the average results for each test concentration using nonlinear regression analysis. If the R² decreases by >10% at the top and / or bottom of the curve (100 and 0 respectively), either or both of these limits can be set at 100 and 0 if the QC criteria are met. Table 1 provides the IC50 values ​​for compound A against representative kinase inhibitors. 50 data.

[0313] Table 1 kinase <![CDATA[IC 50 (nM)]]> IRAK4 37 IRAK1 >10,000 FLT3 (D835Y) 11 FLT3 82

[0314] Compound A was also tested using DiscoverX's standard KINOMEscan and KdELECT assays, following relevant standard operating procedures, for each selected kinase. See, for example... Nat. Biotechnol. 2011, 29(11):1046-51. KINOMEscan and KdELECT are competitive binding assays based on the quantitative measurement of a compound's ability to compete with a directional ligand at an immobilized active site. This assay is performed by combining three components: a DNA-tagged kinase; an immobilized ligand; and the test compound. The ability of the test compound to compete with the immobilized ligand is measured by quantitative PCR via a DNA tag. The binding constant (Kd) is calculated using standard dose-response curves.

[0315] Figure 1 The activity of compound A against multiple variants of IRAK1, IRAK4, and FLT-3 is shown, indicating its potency as a dual IRAK / FLT-3 inhibitor. Compounds with similar structures are expected to possess this dual activity to a certain degree of similarity.

[0316] For example, compound A showed aberrant binding to FLT-3 with ITD mutations and mutations in the activation loop (e.g., D835Y). These mutations occur in one-third of all treatment-naïve AML patients. Known inhibitors of FLT-3 with activation loop mutations are not equivalent. See, for example Nguyen, B. et al. Oncotarget 2017, pp. 1-14; Nagoya, J. Med. Sci. 2015 77:7-17. In contrast, compound A binds to the D835Y mutant FLT-3 at 2.5 nM and to the ITD mutant FLT-3 at 7.8 nM.

[0317] Example 2: In vitro assay of AML model MV4-11 The CellTiter Glo luminescent cell viability assay is a highly sensitive homology assay used to determine the number of viable cells in a culture based on the quantification of ATP levels in metabolically active cells. The addition of CTG reagent causes cell lysis and the generation of a luminescent signal proportional to the amount of ATP present. The amount of ATP is proportional to the number of cells present. Luminescence is measured using a multi-label reader capable of measuring luminescence. Increases or decreases in cell number cause corresponding changes in luminescence levels, indicating the effect of the test material on cell proliferation.

[0318] Preparation of solutions / reagents Preparation of CTG reagent: Thaw and equilibrate the CellTiter-Glo buffer to room temperature. Allow the lyophilized CellTiter-Glo substrate to stand at room temperature. Prepare the CTG reagent by reconstitute the lyophilized enzyme / substrate mixture by mixing the CellTiter-Glo buffer (Promega catalog number G7572) into an amber vial containing the CellTiter-Glo substrate. Both the buffer and the lyophilized substrate are provided with the kit.

[0319] Culture medium preparation: Add 1% penicillin-streptomycin and 10% FBS to commercially available liquid IMDM (Iscove modified Dulbecco medium, Invitrogen catalog number 12440046).

[0320] Preparation of 1X PBS (phosphate-buffered saline): Dissolve one packet of PBS powder (Sigma: catalog number P3813) in 1 L of MiliQ water. DMSO is the medium used to dissolve the test items.

[0321] Process (IC 50 Assay) 1. Count the MV4-11 cells and resuspend them in complete IMDM medium to a density of 0.1 x 10⁶ cells / ml. Add 95 μL of this cell suspension to each well of a 96-well plate (a black plate with a clear bottom) to seed approximately 0.1 x 10⁵ cells per well. Incubate the plate at 37°C under a humidified atmosphere of 5% CO₂ for approximately 2 hours before adding the compound.

[0322] 2. Dissolve the test compound in 100% DMSO to prepare 2 / 6 / 10 / 20 mM stock solutions. Prepare the desired final concentration of 200X in DMSO. Then dilute 10 μL of each concentration (200X) in 90 μL of serum-free IMDM to prepare intermediate concentrations of 20X in the culture medium. The DMSO concentration in this step is 10% (intermediate dilution). Then add 5 μL of each intermediate dilution in triplicate to cells pre-seeded in 96-well plates. The final DMSO concentration in the wells is 0.5%. Use cells treated with 0.5% DMSO as a positive control. 100 μL of complete IMDM medium is used as a medium blank for data analysis. Add 200 μL of 1X PBS to all corner wells of the assay plate to prevent evaporation of the medium in the wells. Then incubate the assay plate at 37°C for 72 hours in an incubator containing 5% CO2.

[0323] 3. To terminate the assay, add 50 μL of CTG reagent to each well and incubate the plate on a shaker at room temperature for 15 minutes. Read the plate using a luminescence-mode reader on a multi-label reader capable of measuring luminescence. Plot the luminescence values ​​against the individual concentrations of the test item using GraphPad Prism to calculate the IC50 of the test item. 50 value.

[0324] The inhibition percentage is calculated as follows: The percentage of inhibition (%) was calculated by normalizing the DMSO control value to 0% inhibition using the following formula: Inhibition % = 100 - (L 测试化合物-空白 ) / (L 阳性对照-空白 ) *100, where L is the luminous value The experimental wells contain cells, the test compound, IMDM medium, and 0.5% DMSO. The positive control wells contain cells, IMDM medium, and 0.5% DMSO. The blank control wells contain only IMDM medium.

[0325] The IC50 values ​​for the following compounds are given in Table 2. 50 Values ​​(in μM). A < 0.05 μM, B is 0.05 to 0.5 μM, and C > 0.5 μM.

[0326] Table 2 .

[0327] Example 3: Inhibition of cell proliferation in the MV4-11 xenograft model Using the procedure of Example 2, compounds A and B were evaluated to determine the inhibition percentage of proliferation in MV4-11 cells. The IC50 of compound A was... 50 0.031 μM ( Figure 2A ), IC of compound B 50 6.1e-005μM ( Figure 2B ).

[0328] Example 4: In vivo tumor growth inhibition in the AML xenograft model MV4-11 Compound A was evaluated at doses of 12.5, 25, and 50 mpk using the AML xenograft model MV4-11 protocol. ND-2158 at 100 mpk was used as a control.

[0329] The antitumor activity of compound A was evaluated in male athymic nude mice. MV4-11 cells were grown in Iscove modified Dulbecco medium supplemented with 10% FBS and 1% penicillin and streptomycin. To establish tumors, 15 × 10⁶ MV4-11 cells in 200 µl of 1:1 HBSS and ECM gel were subcutaneously injected into the right ventral region of athymic nude mice. Animals were randomized based on tumor volume. Compound A was administered orally once daily, and ND-2158 was administered intraperitoneally once daily for 21 days. The tumor was evaluated when the mean tumor volume was 333 mm. 3 Treatment was initiated at the designated time. Tumor volume was measured three times a week, and body weight was monitored daily. Treatment with compound A at 12.5, 25, and 50 mg / kg and ND-2158 at 100 mg / kg was well tolerated, with no treatment-related clinical signs or overall pathological changes.

[0330] Figure 3 The study depicted the increasing tumor growth inhibition with escalating doses of compound A. Tumor growth arrest was achieved at 12.5 mpk, and tumor regression was observed after 21 days of treatment at 25 and 50 mpk. Treatment with compound A at 12.5 mg / kg resulted in 92% tumor growth inhibition. Treatment with compound A at 25 mg / kg and 50 mg / kg resulted in partial tumor regression. Treatment with ND-2158 at 100 mg / kg resulted in 68% tumor growth inhibition. Figure 4 As shown, no weight loss was observed.

[0331] Example 5: Antiproliferative activity in AML xenograft models MV4-11 and MOLM-13 The same procedure was used for MV4-11 and MOLM-13 cells. Each cell line had an ITD mutation in FLT-3 kinase.

[0332] Allow cells to grow to approximately 80% confluence, divide them in half, and grow overnight. Seed cells at a density of 5,000 cells / well in 150 μL into all wells of a 96-well black plate (except columns 1 and 12, and rows A and H). Incubate cells overnight in 10% serum, and add HBSS to the peripheral wells. In a 96-well deep plate, add 1000 μL of 10% FBS to wells B2 and D2. Except for well B2, add 750 μL of 10% FBS, 1% DMSO medium per well in row B. Add 5 μL of 20 mM compound to well B2. Transfer 250 μL from column 2 to column 3 and mix. Repeat this process until a 1:4 dilution is obtained in column G. Add 15 μL of the compound mixture to each well of the cell plate (135 μL volume). The IC50 of compound A in each cell line was determined using the CellTiter Glo assay described in Example 2. 50 IC50 value of compound A in the MV4-11 cell line. 50 The concentration was 0.07 μM, and 0.19 μM in the MOLM-13 cell line.

[0333] Example 6: MOLM-14 FLT3 -ITD and MOLM-14 FLT3 In vivo efficacy of compound A in an ITD / KD (kinase domain) mouse xenograft tumor model Carrying subcutaneous MOLM-14 FLT3 -ITD, MOLM-14 FLT3 -ITD / F691L or MOLM-14 FLT3 In athymic nude mice with ITD / D835Y tumors, compound A was administered orally once daily at a dose of 100 mg / kg. The efficacy of compound A was compared with that of mice administered the carrier. Figure 5A , Figure 5B and Figure 5C As shown, the tumor growth inhibition percentage (TGI%) was 90%, 73%, and 98% after 12 or 14 days of administration, respectively.

[0334] Example 7: Cell viability assay The parental MOLM-14 cell line contains FLT3-ITD mutation. Quezatinib-resistant MOLM-14-derived cell line MOLM-14 FLT3 -ITD / D835Y and MOLM-14 FLT3 -ITD / F691L contains dual FLT3 Mutations (original ITD mutations and secondary mutations within the kinase domain).

[0335] All cell lines were cultured in RPMI 1640 + GlutaMAX (hereinafter referred to as culture medium) supplemented with 1X Pen-Strep and 10% FBS. Cells were then placed in a 75cm³ incubator at 37°C under humidification containing 5% CO₂. 2 Or 225cm 2 Culture in tissue culture flasks. Maintain cell density at 0.5-2.0 x 10⁻⁶ cells / mL. 6 Between cells / mL.

[0336] Plating and drug administration Two days prior to compound treatment, cells were pelleted and resuspended in fresh culture medium. On the day of administration, cell counts were performed and cell viability was determined by trypan blue staining. 5,000 viable cells were transferred at 90 μL or 135 μL per well to all wells of a 96-well tissue culture plate and returned to the incubator. Generally, two rows of each cell line to be tested were added per plate (i.e., a maximum of three cell lines per plate). The lower limit of cell viability used for this assay was 80%; most cell lines exhibited >90% viability.

[0337] Remove the compound stock solution prepared in 100% DMSO from the -80°C freezer and thaw at room temperature before use. Discard any unused compound. Create a compound dilution series using a 96-well plate. Transfer 40 μL of the compound stock solution to well B2. Add 30 μL of DMSO to wells B3 through B11. Transfer 10 μL from well B2 to well B3 and mix by 6 up-and-down pipetting motions to obtain a 1 / 4 dilution. Alternative volumes or dilution ratios may have been used. Change pipette tips between dilution steps and continue the dilution series to well B10. Well B11 is a DMSO-treated control sample.

[0338] Transfer 198 μL of culture medium to each well in row BG and columns 2–11 of a new 96-well plate. Take 2 μL from the Compound A DMSO dilution series plate and transfer it to the corresponding well in each row containing 198 μL of culture medium, and mix by aspiration 6 times to create a 10X Compound A dilution series dosing plate.

[0339] From the 10X Compound A dilution series dose plate, add 10 μL or 15 μL of diluted compound to 96-well tissue culture plates containing 90 μL or 135 μL of cells, respectively. Then, briefly mix the plates at 150 rpm for two minutes using a plate mixer. Return the plates to the tissue culture incubator and incubate at 37°C for 72 hours. The final concentration of DMSO added to the cells is 0.1%.

[0340] Each cell line was tested in duplicate in each plate, and the test was repeated at least three times on different days.

[0341] vitality After 72 hours of incubation, cell viability was assessed using the CellTiter-Glo chemiluminescence cell viability assay (2.0) according to the supplier's instructions. After adding CellTiter-Glo reagent (1:1 volume), the plate was covered with a clear plate sealer and then mixed in the dark at room temperature on a plate shaker at 150 rpm for 10 minutes. Luminescence readings were measured using a TopCount 384 instrument.

[0342] EC 50 computing The percentage of inhibition of the compound-treated samples was determined relative to the DMSO-treated cell control samples. EC was calculated using the percentage of inhibition values ​​via GraphPad Prism 7 software. 50 Value. EC cannot be determined by curve fitting. 50 In the determination of the value, the concentration that caused 50% inhibition by linear extrapolation was used as the EC value. 50 Value. The mean EC value is determined from at least three independent viability measurements performed on different days. 50 value.

[0343] MOLM-14 EC 50 = 58nM MOLM-14 FLT3 -ITD / D835Y, EC 50 = 108nM MOLM-14 FLT3 -ITD / F691L, EC 50 = 2488nM.

[0344] Incorporate by reference All publications and patents mentioned herein are incorporated herein by reference in their entirety, as each individual publication or patent is expressly and individually designated as incorporated by reference. In case of any conflict, this application (including any definitions herein) shall prevail.

[0345] equivalent While specific embodiments of the invention have been discussed, the foregoing description is illustrative rather than restrictive. Many variations of the invention will become apparent to those skilled in the art upon reading this specification and the following claims. The full scope of the invention should be determined by reference to the full scope of the claims and their equivalents, as well as the description and such variations.

Claims

1. A method for treating or preventing acute myeloid leukemia in a subject, the method comprising administering a compound of formula I: Or its pharmaceutically acceptable salt; in, Z1 is a heteroaryl group with optional substitution; Z2 is an optionally substituted heterocyclic alkyl group, an optionally substituted heteroaryl group, or a direct bond; R1 is an alkyl group, cyano group, or -NR group. a R b Or a substituent selected from cycloalkyl, aryl or heterocyclic groups; wherein the substituent is independently alkyl, alkoxy, halogen, hydroxy, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2 or –CH2-OP(O)(O-alkyl)2 when it appears. R2 is, in each instance, an independently selected substituted group chosen from alkyl or cycloalkyl groups; wherein the substituent is, in each instance, a halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl, or haloalkoxy group. R3 is independently hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, or -NR each time it appears. a R b hydroxyl or hydroxyalkyl; R a It is hydrogen or alkyl; R b It is hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl, or optionally substituted cycloalkyl; 'm' and 'n' are 1 or 2 independently.

2. The method of claim 1, wherein Z1 is a 5-membered or 6-membered heteroaryl group.

3. The method of claim 1 or 2, wherein Z1 is an optionally substituted heteroaryl group, wherein the optional substituent is an alkyl group.

4. The method as described in any of the preceding claims, wherein Z1 is tetrazolyl, thiophenyl, triazolyl, pyrroleyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazoleyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, and pyrazolyl.

5. The method as described in any of the preceding claims, wherein Z1 is selected from pyridinyl and oxazolyl.

6. The method of claim 1, wherein the compound is of formula (IA). Or its pharmaceutically acceptable salt; Z2, R1, R2, R3, 'm', and 'n' are the same as those defined in claim 1.

7. The method of claim 1, wherein the compound is of formula (IB). Or its pharmaceutically acceptable salt; in, Z2, R1, R2, R3, 'm', and 'n' are the same as those defined in claim 1.

8. The method of claim 1, wherein the compound is of formula (IC). Or its pharmaceutically acceptable salt; Z2, R1, R2, R3, 'm', and 'n' are the same as those defined in claim 1.

9. The method as described in any of the preceding claims, wherein Z2 is a 5- or 6-membered heterocyclic alkyl group or a 5- or 6-membered heteroaryl group.

10. The method according to any one of claims 1-8, wherein Z2 is a heterocyclic alkyl group or a direct bond.

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