Compounds and compositions for treatment of hematological diseases

Abstract

The present invention relates to compounds and compositions for the treatment of hematological diseases. The present invention provides methods of treating 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 No. 201880022870.5, "Compounds and Compositions for the Treatment of Hematological Diseases", with a filing date of March 30, 2018.

[0002] Cross - reference to related applications

[0003] This application claims the priority benefit of Indian Provisional Patent Application Serial No. 201741011785, filed on March 31, 2017, which is hereby incorporated by reference in its entirety. Background of the invention

[0004] Acute myeloid leukemia (hereinafter also referred to as "AML") is a hematological malignancy with a poor prognosis, usually occurring in adults, and its 5 - year survival rate is expected to be 20%. Currently, AML treatment can temporarily reduce the number of AML cells to a level 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, in the case of relapse, the extremely low survival rate has always been a serious concern. Therefore, new AML treatment methods are needed. Summary of the invention

[0005] Provided herein is a method for treating or preventing acute myeloid leukemia in a subject, the method comprising administering a compound of formula (I):

[0006]

[0007] or a pharmaceutically acceptable salt thereof;

[0008] wherein,

[0009] Ring Z1 is an optionally substituted heteroaryl;

[0010] Ring Z2 is an optionally substituted heterocycloalkyl, an optionally substituted heteroaryl or a direct bond;

[0011] R1 is alkyl, cyano, -NR a R b , or an optionally substituted group selected from cycloalkyl, aryl or heterocyclic group; wherein the substituents are independently, each time they occur, 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;

[0012] R2 is, independently at each occurrence, an optionally substituted group selected from alkyl or cycloalkyl; wherein the substituent is, independently at each occurrence, halogen, alkoxy, hydroxy, hydroxyalkyl, haloalkyl or haloalkoxy;

[0013] R3 is, independently at each occurrence, hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, -NR a R b , hydroxy or hydroxyalkyl;

[0014] R a is hydrogen or alkyl;

[0015] R b is hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl or optionally substituted cycloalkyl;

[0016] ‘m’ and ‘n’ are independently 1 or 2.

[0017] There is provided herein a method of treating or preventing acute myeloid leukemia in a subject, the method comprising administering a compound of formula (II):

[0018]

[0019] or a pharmaceutically acceptable salt thereof;

[0020] wherein,

[0021] X1 and X3 are independently CH or N; X2 is CR2 or N; provided that one and no more than one of X1, X2 or X3 is N;

[0022] A is O or S;

[0023] Y is -CH2- or O;

[0024] Ring Z is aryl or heterocyclic;

[0025] R1 is, independently at each occurrence, a halogen or an optionally substituted heterocyclic; wherein the substituent is alkyl, alkoxy, aminoalkyl, halogen, hydroxy, hydroxyalkyl or -NR a R b ;

[0026] R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic or -NR a R b ; wherein the substituent is alkyl, amino, halogen or hydroxy;

[0027] R3 is, at each occurrence, alkyl or hydroxy;

[0028] R a and R bindependently hydrogen, alkyl, acyl or heterocyclic group;

[0029] 'm' and 'n' are independently 0, 1 or 2;

[0030] 'p' is 0 or 1.

[0031] The present disclosure provides a method of treating or preventing acute myeloid leukemia in a subject, the method comprising administering a compound of formula (III):

[0032]

[0033] or a pharmaceutically acceptable salt thereof;

[0034] wherein,

[0035] Z1 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic group or absent;

[0036] Z2 is optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heterocyclic group;

[0037] R1 is hydrogen, optionally substituted alkyl, amino, halogen, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic group, optionally substituted arylalkyl or optionally substituted heterocyclic alkyl;

[0038] R2 is, in each occurrence, amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic group, optionally substituted arylalkyl or optionally substituted heterocyclic alkyl;

[0039] R3 is, in each occurrence, hydroxy, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl or -NR a R b ;

[0040] R a and R b are, in each occurrence, independently hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic group, optionally substituted arylalkyl or optionally substituted heterocyclic alkyl;

[0041] m is, in each occurrence, 0, 1 or 2; and

[0042] n is, in each occurrence, 0, 1 or 2.

[0043] In some embodiments, the present disclosure discloses the use of a compound or a pharmaceutically acceptable salt or stereoisomer thereof disclosed herein for the treatment and prevention of AML.

[0044] In some embodiments, the use of a compound disclosed herein or a pharmaceutically acceptable salt or stereoisomer thereof (including mixtures in all ratios thereof) as a medicament for the treatment of AML is disclosed herein. Description of the Drawings

[0045] Figure 1 Depicts the binding K of Compound A to various kinases, including FLT-3 wild type and its mutants d .

[0046] Figure 2A Depicts the % inhibition of MV4-11 cell proliferation by Compound A. Figure 2B Depicts the % inhibition of MV4-11 cell proliferation by Compound B.

[0047] Figure 3 Depicts the increase in tumor growth inhibition with increasing doses of Compound A at 12.5, 25, and 50 mpk.

[0048] Figure 4 Depicts the static body weights of animals in the MV4-11 xenograft model in vivo.

[0049] Figure 5A Depicts the tumor growth inhibition percentage (TGI%) of mice with subcutaneous MOLM-14 FLT3-ITD tumors. Figure 5B Depicts the tumor growth inhibition percentage (TGI%) of mice with MOLM-14 FLT3-ITD / F691L tumors. Figure 5C Depicts the tumor growth inhibition percentage (TGI%) of mice with MOLM-14 FLT3-ITD / D835Y tumors. Detailed Description

[0050] 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 matter belongs. As used in this specification and the appended claims, unless the context clearly indicates otherwise, the following terms have the indicated meanings for the purpose of understanding the present invention.

[0051] Unless the context clearly indicates otherwise, the singular forms "a", "an", and "the" encompass plural referents.

[0052] As used herein, the term "optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and such description includes examples where the described event or circumstance occurs and examples where the described event or circumstance does not occur. For example, "optionally substituted alkyl" means that the alkyl may be substituted, as well as the case where the alkyl is not substituted.

[0053] It should be understood that those of ordinary skill in the art can select substituents and substitution patterns on the compounds of the present invention to obtain chemically stable compounds, which can be easily synthesized from readily available starting materials by techniques known in the art and those methods described hereinafter. 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.

[0054] As used herein, the term "optionally substituted" means replacing one to six hydrogen groups in a given structure with groups of the designated substituents, and the designated substituents include, but are not limited to: hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, halogen, alkyl, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, cycloalkyl, cycloalkoxy, (cycloalkyl)alkyl, heterocyclic group, (heterocyclic group)alkyl, amino, aminoalkyl, alkylamino, dialkylamino, acyl, -C(O)2H, -O(acyl), -NH(acyl), -N(alkyl)(acyl), cyano, phosphinate, phosphate, phosphonate, sulfonate, sulfonamido, sulfate, haloalkyl or haloalkoxy. Preferably, "optionally substituted" means replacing one to four hydrogen groups in a given structure with the above-mentioned substituents. More preferably, one to three hydrogen groups are replaced by the substituents as described above. It should be understood that the substituents can be further substituted.

[0055] The term "substituted" refers to a moiety having substituents that replace hydrogen on one or more carbons of the backbone. It should be understood that "substitution" or "substituted with" includes the implicit condition that such substitution is in accordance with the allowable valences of the atom being substituted and the substituent, and the substitution results in a stable compound, e.g., a compound that does not spontaneously transform such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include all allowable substituents of organic compounds. In a broad sense, allowable substituents include acyclic and cyclic, branched or unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For suitable organic compounds, the allowable substituents can be one or more and the same or different. For the purposes of the present invention, heteroatoms (such as nitrogen) can have hydrogen substituents and / or any allowable substituents of the organic compounds described herein that satisfy the valence of the heteroatom. Substituents can include any of the substituents described herein, e.g., halogen, hydroxy, carbonyl (such as carboxy, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as thioester, thioacetate or thiocarboxylate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azide, mercapto, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclic group, aralkyl, or aromatic or heteroaromatic moiety. Those skilled in the art will understand that, where appropriate, the substituents themselves can be substituted. Unless specifically described as "unsubstituted", references herein to chemical moieties should be understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes substituted and unsubstituted variants.

[0056] As used herein, the term "alkyl" refers to saturated aliphatic groups, including but not limited to C1-C 10 straight-chain alkyl groups or C1-C 10 branched-chain alkyl groups. Preferably, the "alkyl" group refers to a C1-C6 straight-chain alkyl group or a C1-C6 branched-chain alkyl group. Most preferably, the "alkyl" group refers to a C1-C4 straight-chain alkyl group or a C1-C4 branched-chain 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, etc. The "alkyl" group can be optionally substituted.

[0057] The term "acyl" refers to the group R-CO-, where R is an optionally substituted alkyl group as defined above. Examples of the "acyl" group are but not limited to CH3CO-, CH3CH2CO-, CH3CH2CH2CO- or (CH3)2CHCO-.

[0058] As used herein, the term "alkoxy" refers to a straight-chain or branched-chain saturated aliphatic C1-C 10 hydrocarbyl group attached to an oxygen atom attached to the core structure. Preferably, the alkoxy group has from one to six carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, 3-methylbutoxy, and the like.

[0059] As used herein, the term "haloalkyl" refers to an alkyl group (as defined above) substituted with one or more halogen atoms. A monohaloalkyl group may have, for example, a chlorine, bromine, iodine, or fluorine atom. Dihalo and polyhaloalkyl may have two or more identical or different halogen atoms, respectively. Examples of haloalkyl groups include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, and the like.

[0060] As used herein, the term "haloalkoxy" refers to a group in which one or more hydrogen atoms of an alkoxy group are substituted with one or more halogen atoms. Representative examples of "haloalkoxy" groups include, but are not limited to, difluoromethoxy (-OCHF2), trifluoromethoxy (-OCF3), or trifluoroethoxy (-OCH2CF3).

[0061] As used herein, the term "aryl", alone or in combination with other terms, means a 6- to 10-membered carbocyclic aromatic system containing one or two rings, where such rings may be fused. The term "fused" means attached or formed by having two adjacent atoms in common with a first ring. The term "fused" is equivalent to the term "condensed". Examples of aryl groups include, but are not limited to, phenyl, naphthyl, or indanyl. Unless otherwise specified, all aryls described herein may be optionally substituted.

[0062] The terms "amine" and "amino" are well recognized in the art and refer to unsubstituted and substituted amines and their salts, such as the moiety represented by

[0063]

[0064] where each R 10 independently represents hydrogen or a hydrocarbyl group, or two Rs 10 together with the N atom to which they are attached complete a heterocyclic ring having 4 to 8 atoms in the ring structure.

[0065] As used herein, "aminoalkyl" refers to an amino group as defined above, where one or two hydrogen atoms are replaced by an alkyl group.

[0066] As used herein, "nitro" refers to the -NO2 group.

[0067] As used herein, "alkylamino" and "cycloalkylamino" refer to -N- groups, wherein the nitrogen atom of said 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.

[0068] As used herein, the term "cycloalkyl", alone or in combination with other terms, means a C3-C 10 saturated cycloaliphatic ring. The cycloalkyl can be a monocyclic ring typically containing 3 to 7 carbon ring atoms. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Alternatively, the cycloalkyl can be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged, fused, and spiro cycloaliphatic groups.

[0069] As used herein, the term "cyano" refers to the -CN group.

[0070] As used herein, the term "hydroxy" or "hydroxyl" refers to the -OH group.

[0071] As used herein, the term "hydroxyalkyl" or "hydroxyalkyl" 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, and the like.

[0072] As used herein, the term "halo" or "halogen", alone or in combination with other terms, means fluorine, chlorine, bromine, or iodine.

[0073] As used herein, the term "heterocyclic group" includes the definitions of "heterocycloalkyl" and "heteroaryl".

[0074] As used herein, the term "heterocyclyl" refers to a 3- to 15-membered non-aromatic, saturated or partially saturated monocyclic or polycyclic ring system having at least one heteroatom or hetero-group 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 "heterocyclyl" include, but are not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydropyranyl, indolinyl, indolinylmethyl, 2-aza-bicyclo[2.2.2]octyl, azacyclooctyl, chromanyl, xanthenyl, and their N-oxides. Attachment of heterocyclyl substituents can occur via a carbon atom or a heteroatom. The heterocyclyl group can be optionally substituted by one or more suitable groups by one or more of the above groups. Preferably, "heterocyclyl" refers to a 5- or 6-membered ring selected from azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, and their N-oxides. More preferably, "heterocyclyl" includes azetidinyl, pyrrolidinyl, morpholinyl, and piperidinyl. All heterocyclyls are optionally substituted by one or more of the above groups.

[0075] 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 can be a single ring (monocyclic) or multiple rings (bicyclic, tricyclic, or polycyclic) fused together or covalently linked. Preferably, "heteroaryl" is a 5- to 6-membered ring. The ring can contain 1 to 4 heteroatoms selected from N, O, and S, where the N or S atom is optionally oxidized or the N atom is optionally quaternized. Any suitable ring position of the heteroaryl moiety can be covalently linked to the defined chemical structure.

[0076] Examples of heteroaryl include, but are not limited to: furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuryl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuryl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, α-carboline, indolizinyl, benzisothiazolyl, benzoxazolyl, pyrrolopyridyl, furanopyridyl, purinyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzotriadiazolyl, carbazolyl, dibenzothienyl, acridinyl, etc. Preferably, "heteroaryl" refers to a 5- to 6-membered ring selected from furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl. More preferably, pyrazolyl, pyridyl, oxazolyl, and furyl. All heteroaryls are optionally substituted with one or more of the above groups.

[0077] As used herein, the term "compound" includes the compounds disclosed in the present invention.

[0078] As used herein, the term "comprising" or "including" is generally used in an inclusive sense, that is, allowing for the presence of one or more features or components.

[0079] As used herein, unless otherwise specified, the term "or" means "and / or".

[0080] As used herein, the term "comprising" and other forms such as "including" and "containing" are not restrictive.

[0081] The phrase "pharmaceutically acceptable" refers to a compound or composition that is physiologically tolerable and generally does not produce allergic or similar adverse reactions when administered to a mammal, including but not limited to stomach discomfort or dizziness.

[0082] 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 salts, Na salts, K salts, Ca salts, Mg salts, Fe salts, Cu salts, Al salts, Zn salts, and Mn salts; examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by the amino group with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, galacturonate, formate, benzoate, glutamate, mesylate, esylate, benzenesulfonate, 4-methylbenzenesulfonate or p-toluenesulfonate, etc. Certain compounds of the present 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.

[0083] As used herein, the term "stereoisomer" is a term for all isomers of each compound of formula (I), which differ only in the spatial orientation of their atoms. The term stereoisomers includes mirror image isomers (enantiomers) of the compounds of the present invention, mixtures of mirror image isomers (racemates, 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 are not mirror images of each other (diastereoisomers).

[0084] In certain embodiments, the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more atoms constituting such compounds. For example, the present invention also encompasses isotopically labeled variants 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 having an atomic mass or mass number different from the major atomic mass or mass number of the atoms commonly found in nature. All isotopes of any specific atom or element as designated and their uses are encompassed within the scope of the compounds of the present invention. Exemplary isotopes that can 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 isotopically labeled compounds of the present invention can generally be prepared by following procedures known in the art, for example, by replacing non-isotopically labeled reagents with isotopically labeled reagents.

[0085] As used herein, the term "pharmaceutically acceptable carrier" refers to any standard pharmaceutical carrier, such as phosphate buffered saline solution, 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] .

[0086] The term "treatment" means any treatment of a disease in a mammal, including: (a) inhibiting the disease, i.e., slowing or preventing the development of clinical symptoms; and / or (b) alleviating the disease, i.e., causing the regression of clinical symptoms; and / or (c) relieving or eliminating the disease and / or its accompanying symptoms.

[0087] As used herein, the term "prevention" refers to a method of preventing the onset of a disease and / or its accompanying symptoms or 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.

[0088] As used herein, the term "subject" refers to an animal, preferably a mammal, and most preferably a human.

[0089] As used herein, the term "therapeutically effective amount" refers to an amount of a compound of the invention, or a pharmaceutically acceptable salt or stereoisomer thereof, or a composition comprising a compound of the invention or a pharmaceutically acceptable salt or stereoisomer thereof, that is capable of effectively producing a desired therapeutic response in a particular patient having AML. Specifically, the term "therapeutically effective amount" includes an amount of a compound of the 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 to alleviate such symptoms to some extent. With respect to a compound in a therapeutically effective amount, the amount of the compound used to treat a subject is low enough to avoid undue or severe side effects and may also be considered within the scope of reasonable medical judgment. The therapeutically effective amount of a compound or composition will vary depending on the specific disorder being treated, the severity of the disorder being treated or prevented, the duration of the treatment, the nature of concurrent treatments, the age and physical condition of the end user, and the particular compound or composition used with the particular pharmaceutically acceptable carrier employed.

[0090] In certain embodiments, the compounds of the invention may be used alone or administered in combination with another type of therapeutic agent. As used herein, the phrase "administered in combination" refers to the administration of two or more different therapeutic compounds in any form such that a second compound is administered when a previously administered therapeutic compound is still effective in the body (e.g., both compounds are effective simultaneously in a subject, which may include a synergistic effect of the two compounds). For example, the different therapeutic compounds may be administered simultaneously or sequentially in the same formulation or in separate formulations. In certain embodiments, the 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. In some embodiments, an additional therapeutic compound is administered within about 5 minutes to about 168 hours before or after the administration of a compound of Formula I, a compound of Formula II, or a compound of Formula III. Thus, a subject receiving such treatment may benefit from the combined action of the different therapeutic compounds.

[0091] In certain embodiments, the co-administration of a compound of the invention with one or more additional therapeutic agents (e.g., one or more additional chemotherapeutic agents) provides improved efficacy relative to the administration of each of the compound of the invention or the one or more additional therapeutic agents alone. In certain such embodiments, the co-administration provides an additive effect, where an additive effect refers to the sum of the individual effects of the administration of the compound of the invention and each of the one or more additional therapeutic agents.

[0092] Provided herein is a method of treating or preventing acute myeloid leukemia in a subject, the method comprising administering a compound of formula (I)

[0093]

[0094] or a pharmaceutically acceptable salt thereof;

[0095] wherein

[0096] ring Z1 is an optionally substituted heteroaryl;

[0097] ring Z2 is an optionally substituted heterocycloalkyl, an optionally substituted heteroaryl or a direct bond;

[0098] R1 is alkyl, cyano, -NR a R b , or an optionally substituted group selected from cycloalkyl, aryl or heterocyclic group; wherein the substituents are independently, in each occurrence, 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;

[0099] R2 is independently, in each occurrence, an optionally substituted group selected from alkyl or cycloalkyl; wherein the substituents are independently, in each occurrence, halogen, alkoxy, hydroxy, hydroxyalkyl, haloalkyl or haloalkoxy;

[0100] R3 is independently, in each occurrence, hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, -NR a R b , hydroxy or hydroxyalkyl;

[0101] R a is hydrogen or alkyl;

[0102] R b is hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl or an optionally substituted cycloalkyl;

[0103] ‘m’ and ‘n’ are independently 1 or 2.

[0104] 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.

[0105] 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; wherein the optional substituent is alkyl.

[0106] 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, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furyl and pyrazolyl.

[0107] 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 pyridyl, oxazolyl and furyl; wherein the pyridyl group is optionally substituted with an alkyl group; specifically, the alkyl group is methyl.

[0108] 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 heteroaryl selected from tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furyl or pyrazolyl.

[0109] 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 heterocycloalkyl selected from azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl or 1,4-dioxanyl.

[0110] 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.

[0111] 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.

[0112] In some embodiments, the method of the present invention comprises a compound of formula (I), which is a compound of formula (IA)

[0113]

[0114] or a pharmaceutically acceptable salt thereof;

[0115] wherein Z2, R1, R2, R3,'m' and 'n' are the same as those defined in the compound of formula (I).

[0116] In some embodiments, the method of the present invention comprises a compound of formula (I), which is a compound of formula (IB)

[0117]

[0118] or a pharmaceutically acceptable salt thereof;

[0119] wherein Z2, R1, R2, R3,'m' and 'n' are the same as those defined in the compound of formula (I).

[0120] In some embodiments, the method of the present invention comprises a compound of formula (I), which is a compound of formula (IC)

[0121]

[0122] or a pharmaceutically acceptable salt thereof;

[0123] wherein Z2, R1, R2, R3,'m' and 'n' are the same as those defined in the compound of formula (I). In some embodiments, the method of the present invention comprises a compound of formula (I), wherein is

[0124] wherein R1, R2 and'm' are the same as those defined in the compound of formula (I).

[0125] 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.

[0126] 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 pyrazolyl.

[0127] 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 pyrrolidinyl.

[0128] 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 halogen, hydroxy, hydroxyalkyl, amino, aminoalkyl, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2 or -CH2-OP(O)(O-alkyl)2.

[0129] 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 azetidinyl, piperidinyl, morpholinyl, pyrrolidinyl or azepanyl; wherein the substituent is amino, halogen, hydroxy, hydroxyalkyl, aminoalkyl, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2 or -CH2-OP(O)(O-alkyl)2.

[0130] 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; wherein the substituent is hydroxy.

[0131] 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; wherein the substituent is halogen.

[0132] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is cycloalkyl.

[0133] 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.

[0134] 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 R b ; R a is hydrogen; R b is optionally substituted cycloalkyl; wherein the substituent is hydroxy.

[0135] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is cyano.

[0136] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 is optionally substituted alkyl; wherein the substituent is alkoxy.

[0137] In some embodiments, the method of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 is cycloalkyl.

[0138] 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 , hydroxy or hydroxyalkyl; R a is hydrogen or alkyl; and R b is hydrogen, alkyl, acyl, hydroxyalkyl or -SO2-alkyl.

[0139] 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 optionally substituted pyridyl; ring Z2 is pyridyl, pyrazolyl, pyrrolidinyl or a direct bond; R1 is an optionally substituted group selected from cyclopropyl, piperidinyl, morpholinyl or pyrrolidinyl; R2 is optionally substituted alkyl or cycloalkyl; R3 is hydrogen, halogen, alkyl, alkoxy, -NR a R b , hydroxy or hydroxyalkyl; R a is hydrogen or alkyl; R b is hydrogen or hydroxyalkyl.

[0140] 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 group, a pyrazolyl group or a pyrrolidinyl group; R1 is a cyano group, -NR a R b or an optionally substituted group selected from cyclopropyl, cyclohexyl, phenyl, azetidinyl, piperidinyl, morpholinyl or pyrrolidinyl; R2 is an optionally substituted alkyl or cycloalkyl group; R3 is hydrogen, halogen, alkyl, alkoxy, -NR a R b , hydroxy or hydroxyalkyl; R a is hydrogen or alkyl; and R b is hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl or an optionally substituted cycloalkyl.

[0141] 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 is hydrogen or alkyl; and R b is hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl or an optionally substituted cycloalkyl; wherein the optional substituent is hydroxy;

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] In some embodiments, the method of the present invention comprises a compound of formula (I) selected from the following:

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0154] The present invention provides a method for treating or preventing acute myeloid leukemia in a subject, the method comprising administering a compound of formula (II):

[0155]

[0156] or a pharmaceutically acceptable salt thereof;

[0157] wherein,

[0158] X1 and X3 are independently CH or N; X2 is CR2 or N; provided that one and no more than one of X1, X2 or X3 is N;

[0159] A is O or S;

[0160] Y is -CH2- or O;

[0161] Ring Z is aryl or heterocyclic;

[0162] R1, each occurrence independently, is halo or an optionally substituted heterocyclic group; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxy, hydroxyalkyl or -NR a R b ;

[0163] R2 is hydrogen, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclic group or -NR a R b ; wherein the substituent is alkyl, amino, halo or hydroxy;

[0164] R3, each occurrence, is alkyl or hydroxy;

[0165] R a and R b are independently hydrogen, alkyl, acyl or heterocyclic;

[0166] 'm' and 'n' are independently 0, 1 or 2;

[0167] 'p' is 0 or 1.

[0168] In some embodiments, the method of the present invention comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein the group is

[0169]

[0170] wherein R2 is as defined in the compound of formula (II).

[0171] 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 aryl or a 5- or 6-membered heterocyclic group.

[0172] 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, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxathiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl or dihydropyranyl; each of which is optionally substituted by alkyl, alkoxy, halogen, hydroxy, hydroxyalkyl or -NR a R b substituted; R a and R b are independently hydrogen, alkyl or acyl.

[0173] 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, furyl, thienyl or pyridyl; each of which is optionally substituted by one or more R1.

[0174] In some embodiments, the method of the present invention comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein is

[0175]

[0176] wherein R3 and'm' are as defined in the compound of formula (II).

[0177] In some embodiments, the method of the present invention comprises a compound of formula (II), which is a compound of formula (IIA):

[0178]

[0179] or a pharmaceutically acceptable salt thereof;

[0180] wherein A, Y, R1, R2, R3,'m', 'p' and 'n' are the same as those defined in the compound of formula (II).

[0181] In some embodiments, the method of the present invention comprises a compound of formula (II), which is a compound of formula (IIB):

[0182]

[0183] or a pharmaceutically acceptable salt thereof;

[0184] wherein A, Y, R1, R2 and 'n' are the same as defined in the compound of formula (II).

[0185] In some embodiments, the method of the present invention comprises a compound of formula (II), which is a compound of formula (IIC):

[0186]

[0187] or a pharmaceutically acceptable salt thereof;

[0188] wherein A, Y, R1, R2, R3 and 'n' are the same as defined in the compound of formula (I).

[0189] 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.

[0190] 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, halo, hydroxy, hydroxyalkyl or -NR a R b ; R a and R b are independently hydrogen, alkyl or acyl.

[0191] In some embodiments, the method of the present invention comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R1 is pyridyl, pyrazolyl, pyrrolidinyl or piperidinyl; wherein each is optionally substituted by alkyl, alkoxy, halo, hydroxy, hydroxyalkyl or -NR a R b substituted; R a and R b are independently hydrogen or acyl.

[0192] 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.

[0193] 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.

[0194] 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.

[0195] 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 alkyl, amino, halo or hydroxy.

[0196] 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, piperazinyl, azetidinyl, pyrazolyl, furyl, pyridyl, azepanyl or azabicyclo[3.2.1]octyl; wherein the substituent is alkyl, amino, halo or hydroxy.

[0197] 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; wherein the substituent is halo.

[0198] 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; wherein the substituent is fluoro.

[0199] 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 ; wherein R a and R b are independently hydrogen or a heterocyclic group.

[0200] 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 ; wherein R a and R b are independently hydrogen or pyrrolidinyl.

[0201] 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 halo, pyridyl, pyrazolyl, pyrrolidinyl, each of which is optionally substituted by alkyl, alkoxy, halo, hydroxy, hydroxyalkyl or -NR a R b ; R2 is hydrogen, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclic group or -NR a R b ; wherein the substituent is alkyl, amino, halo or hydroxy; R a and R b are independently hydrogen or alkyl.

[0202] 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 pyridyl, pyrazolyl, pyrrolidinyl; each of which is optionally substituted by alkyl, hydroxy, hydroxyalkyl or -NR a R b substituted; R a and R b are independently hydrogen; R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic group or -NR a R b ; wherein the substituent is alkyl, amino, halogen or hydroxy; R a and R b are independently hydrogen, alkyl, acyl or heterocyclic group.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] In some embodiments, the method of the present invention comprises a compound of formula (II) selected from the following:

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0216] The present invention provides a method for treating or preventing acute myeloid leukemia in a subject, the method comprising administering a compound of formula (III):

[0217]

[0218] or a pharmaceutically acceptable salt thereof;

[0219] wherein,

[0220] Z1 represents an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclic group or is absent;

[0221] Z2 represents an optionally substituted cycloalkyl, an optionally substituted aryl or an optionally substituted heterocyclic group;

[0222] R1 is hydrogen, an optionally substituted alkyl, amino, halogen, cyano, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclic group, an optionally substituted arylalkyl or an optionally substituted heterocyclic alkyl;

[0223] R2 is, in each occurrence, amino, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclic group, an optionally substituted arylalkyl or an optionally substituted heterocyclic alkyl;

[0224] R3 is, in each occurrence, hydroxy, halogen, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted cycloalkyl or -NR a R b ;

[0225] R a and R b are, in each occurrence, independently hydrogen, an optionally substituted alkyl, an optionally substituted acyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclic group, an optionally substituted arylalkyl or an optionally substituted heterocyclic alkyl;

[0226] m is, in each occurrence, 0, 1 or 2; and

[0227] n is, in each occurrence, 0, 1 or 2.

[0228] 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.

[0229] 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 by one or more substituents, the substituents being, in each occurrence, independently selected from hydroxy, halogen, alkyl, cycloalkyl or NR a R b .

[0230] 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; wherein the optional substituent is an alkyl or a cycloalkyl.

[0231] 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, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furyl, pyrazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, α-carboline, indolizinyl, benzisothiazolyl, benzoxazolyl, pyrrolopyridyl, furanopyridyl, purinyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzotriadiazolyl, carbazolyl, dibenzothienyl, acridinyl and pyrazolopyrimidinyl; each of which is optionally substituted.

[0232] 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, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furyl or pyrazolyl.

[0233] 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 by an alkyl; specifically, the alkyl is methyl.

[0234] 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.

[0235] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 is cycloalkyl, aryl or heterocyclic group.

[0236] 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 by one or more substituents selected from hydroxy, halo, alkyl, alkoxy, cycloalkyl, -NR a R b or cycloalkoxy.

[0237] 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.

[0238] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 is azetidinyl, oxetanyl, furyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,4-dioxanyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydropyridyl, tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazolidinyl, imidazolyl, thiadiazolyl, thiazolyl, thiazolidinyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolidinyl, oxazolidinyl, pyrazolidinyl, benzisoxazolyl, benzothiazolyl, benzofuryl, benzothienyl, benzotriazinyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, pyrrolopyridyl or pyrazolopyrimidinyl.

[0239] 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, piperazinyl, pyrimidinyl, pyrrolidinyl, 1,2,3,4-tetrahydropyridyl, piperidinyl, pyrazolopyrimidinyl or pyrrolopyridyl.

[0240] In certain embodiments, the compound of formula (III) is a compound of formula (IIIA)

[0241]

[0242] or a pharmaceutically acceptable salt thereof;

[0243] wherein Z2, R1, R2, R3,'m' and 'n' are as defined in the compound of formula (III).

[0244] In certain embodiments, the compound of formula (III) is a compound of formula (IIIB)

[0245]

[0246] or a pharmaceutically acceptable salt thereof;

[0247] wherein Z2, R1, R2, R3,'m' and 'n' are as defined in the compound of formula (III).

[0248] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein the group is

[0249] wherein R1, R2 and'm' are the same as defined in the compound of formula (III).

[0250] 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.

[0251] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 is pyrrolidinyl.

[0252] 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, piperazinyl, tetrahydropyridyl, pyrimidinyl or pyrazolopyridyl.

[0253] 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 group, optionally substituted arylalkyl or optionally substituted heterocyclic alkyl.

[0254] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt, wherein R1 is alkyl, cycloalkyl, aryl, heterocyclic group, arylalkyl optionally substituted by one or more substituents, and the substituents are independently selected from hydroxy, halogen, alkyl or hydroxyalkyl each time they appear.

[0255] 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 by halogen, hydroxy or hydroxyalkyl.

[0256] 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 azetidinyl, piperidinyl, morpholinyl, pyrrolidinyl or azepanyl.

[0257] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt, wherein R1 is piperidinyl optionally substituted by hydroxy.

[0258] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt, wherein R1 is pyrrolidinyl optionally substituted by hydroxy.

[0259] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R2, each occurrence thereof, is amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic group, optionally substituted arylalkyl or optionally substituted heterocyclic alkyl.

[0260] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R2 is alkyl, cycloalkyl, aryl, heterocyclic group, arylalkyl or heterocyclic alkyl optionally substituted by one or more substituents, and the substituents, each occurrence thereof, are independently selected from alkyl, cycloalkyl or heterocyclic group.

[0261] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R2 is optionally substituted alkyl, preferably methyl.

[0262] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R2 is optionally substituted cycloalkyl, preferably cyclopropyl.

[0263] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R3, each occurrence thereof, is hydroxy, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl or -NR a R b ; wherein R a is hydrogen or optionally substituted alkyl; and R b is hydrogen, optionally substituted alkyl, optionally substituted acyl, hydroxyalkyl or -SO2-alkyl.

[0264] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z1 is optionally substituted pyridyl; Z2 is pyrrolidinyl; R1 is an optionally substituted group selected from piperidinyl or pyrrolidinyl; R2 is optionally substituted alkyl; R3 is halogen, alkyl, -NR a R b 、hydroxy or hydroxyalkyl; R a is hydrogen or alkyl; and R b is hydrogen or hydroxyalkyl.

[0265] In some embodiments, the method of the present invention comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z1 is oxazolyl; Z2 is pyridyl, pyrimidinyl or pyrrolidinyl, piperidinyl, tetrahydropyridyl, piperazinyl, pyrrolo-pyridyl; R1 is an optionally substituted group selected from piperidinyl or pyrrolidinyl; R2 is optionally substituted alkyl or cyclopropyl; R3 is halogen, alkyl, alkoxy, -NR a Rb , hydroxyl, hydroxyalkyl, optionally substituted cyclopropyl; R a is hydrogen or alkyl; and R b is hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl or optionally substituted cycloalkyl.

[0266] 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.

[0267] 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.

[0268] 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.

[0269] 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.

[0270] 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.

[0271] 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.

[0272] In some embodiments, the method of the present invention comprises a compound of formula (III) selected from the following:

[0273]

[0274]

[0275]

[0276]

[0277] Pharmaceutical composition

[0278] In certain embodiments, the method of the present invention comprises a pharmaceutical composition comprising a compound disclosed herein optionally admixed with a pharmaceutically acceptable carrier or diluent.

[0279] As used herein, the term "composition" is intended to encompass a product containing the specified amounts of the specified ingredients, as well as any product directly or indirectly resulting from the combination of the specified amounts of the specified ingredients.

[0280] As used herein, the term "pharmaceutical composition" refers to a composition comprising a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, and a conventional pharmaceutically acceptable carrier.

[0281] The pharmaceutical compositions of the invention can be administered orally, for example in the form of tablets, coated tablets, pills, capsules, granules or elixirs. However, administration can also be carried out rectally (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, e.g., in the form of aerosols or nasal sprays).

[0282] The pharmaceutical compositions generally contain from about 1% to 99% by weight, such as from about 5% to 75% or from about 10% to about 30%, of the 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 can 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 within a broader range falling between 1 mg and 1000 mg or any range higher or lower than the foregoing ranges.

[0283] The invention also provides a method for formulating the disclosed compounds for pharmaceutical administration.

[0284] The compositions and methods of the invention can be used to treat an individual in need thereof. In certain embodiments, the individual is a mammal, such as a human or non-human mammal. When administered to an animal (such as a human), the composition or compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions (such as water or physiological buffer saline) or other solvents or vehicles (such as diols, glycerol, oils (such as olive oil) or injectable organic esters).

[0285] In a preferred embodiment, when such a pharmaceutical composition is for human administration, particularly for invasive routes of administration (i.e., routes that avoid transport or diffusion across an epithelial barrier, such as injection or implantation), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can 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 can be in the form of dosage units such as tablets, capsules (including dispersed capsules and gelatin capsules), granules, lyophilic colloids for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition can also be present in a transdermal delivery system such as a skin patch. The composition can also be present in a solution suitable for topical administration such as eye drops.

[0286] A pharmaceutically acceptable carrier may contain a physiologically acceptable agent that is used, for example, to stabilize, increase solubility, or increase the absorption of a compound such as a compound of the present invention. Such physiologically acceptable agents include, for example, carbohydrates (such as glucose, sucrose, or dextran), antioxidants (such as ascorbic acid or glutathione), chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of pharmaceutically acceptable carrier (including the physiologically acceptable agent) depends, for example, on the route of administration of the composition. The preparation of the pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) can also be a liposome or other polymeric matrix incorporated therein, such as the composition of the present invention. Liposomes containing, for example, phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively easy to prepare and administer.

[0287] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment, suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0288] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to 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; (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 glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0289] A pharmaceutical composition (formulation) can be administered to a subject by any of a number of routes of administration, including, for example, oral (e.g., drenches in aqueous or non-aqueous solution or suspension applied to the tongue, tablets, capsules (including dispersed and gelatin capsules), pills, powders, granules, pastes); absorption through the oral mucosa (such as sublingually); rectal, perirectal 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; transdermal (e.g., as a patch applied to the skin); and topical (e.g., as a cream, ointment or spray applied to the skin, or as an eye drop). The compound can also be formulated for inhalation. In certain embodiments, the compound can be dissolved or suspended only in sterile water. Details of suitable routes of administration and compositions suitable therefor 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.

[0290] The formulations can conveniently be presented in unit dosage form and can be prepared by any methods well known in the pharmaceutical art. 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 particular mode 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 a therapeutic effect. Generally, on a percentage basis of one hundred percent, the amount ranges from about 1% to about 99% of the active ingredient, preferably about 5% to about 70%, and most preferably about 10% to about 30%.

[0291] Methods of preparing these formulations or compositions include the step of associating the active compound (e.g., a compound of the present invention) with a carrier and optionally one or more accessory ingredients. Generally, the formulations are prepared by uniformly and intimately associating the compound of the present invention with a liquid carrier or a finely divided solid carrier or both, and then shaping the product as required.

[0292] Formulations of the present invention suitable for oral administration can be in the form of capsules (including dispersed and gelatin capsules), cachets, pills, tablets, lozenges (using a flavoring base, usually sucrose and gum arabic or tragacanth), lyophilic colloids, powders, granules or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a troche (using an inert base such as gelatin and glycerin, or sucrose and gum arabic) and / or as a mouthwash, etc., each containing a predetermined amount of the compound of the present invention as the active ingredient. The composition or compound can also be administered in the form of boluses, electuaries or pastes.

[0293] For the preparation of solid dosage forms for oral administration (capsules (including dispersed capsules and gelatin capsules), tablets, pills, troches, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or calcium phosphate and / or any of the following: (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; (3) humectants such as glycerol; (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retardants such as paraffin wax; (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 dispersed capsules and gelatin capsules), tablets and pills, the pharmaceutical composition may also contain buffering agents. Similar types of solid compositions may also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (lactose) or milk sugar and high molecular weight polyethylene glycol.

[0294] Tablets may be prepared by compressing or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or croscarmellose sodium), surfactants or dispersing agents. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0295] Tablets and other solid dosage forms of pharmaceutical compositions, such as troches, capsules (including dispersed capsules and gelatin capsules), pills, and granules, may optionally be scored or prepared with coatings and shells (such as enteric coatings and other coatings well known in the pharmaceutical formulation art). They may also be formulated to provide for slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose (in different proportions to provide the desired release profile), other polymeric matrices, liposomes, and / or microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporation of a sterilizing agent in the form of a sterile solid composition which may be dissolved in sterile water or some other sterile injectable medium just prior to use. These compositions may also optionally contain opacifying agents and may also be compositions which release the active ingredient optionally in a delayed manner only, or preferably only, in a certain part of the gastrointestinal tract. Examples of embedding compositions which may be used include polymeric substances and waxes. Where appropriate, the active ingredient may also be in the form of microcapsules with one or more of the above excipients.

[0296] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, lyophilic colloids for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizing agents, and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan anhydride, and mixtures thereof.

[0297] In addition to the inert diluent, the oral compositions may also contain adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, coloring agents, perfuming agents, and preservatives.

[0298] In addition to the active compound, the suspension may also contain suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar, and tragacanth, and mixtures thereof.

[0299] Preparations of pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented in the form of suppositories which may be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycols, suppository waxes, or salicylate esters, and which are solid at room temperature, but liquid at body temperature and will therefore melt in the rectal or vaginal cavity and release the active compound. Preparations of pharmaceutical compositions for administration to the oral cavity may be presented in the form of oral rinses, oral sprays, or oral ointments.

[0300] Alternatively or additionally, the composition can be formulated for delivery via a catheter, stent, wire or other intravascular device. Delivery via such devices may be particularly useful for delivery to the bladder, urethra, ureter, rectum or intestine.

[0301] Preparations suitable for vaginal administration also include vaginal suppositories, tampons, creams, gels, pastes, foams or spray formulations containing suitable carriers known in the art.

[0302] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants as may be required.

[0303] In addition to the active compound, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0304] In addition to the active compound, powders and sprays may also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0305] Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be prepared by dissolving or dispensing the active compound in a suitable medium. Penetration enhancers can also be used to increase the flux of the compound through the skin. The rate of such flux can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0306] Ophthalmic preparations, eye ointments, powders, solutions, etc. are also contemplated within the scope of the present invention. Exemplary ophthalmic preparations are described in U.S. Publication Nos. 2005 / 0080056, 2005 / 0059744 and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic preparations have properties similar to or compatible with tears, aqueous humor or vitreous humor. The preferred route of administration is topical administration (e.g., topical administration such as eye drops, or administration via an implant).

[0307] As used herein, the phrases "parenteral administration" and "administered parenterally" mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0308] A pharmaceutical composition suitable for parenteral administration comprises a combination of one or more active compounds with one or more pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which can be reconstituted into sterile injectable solutions or dispersions immediately before use, and the injectable solutions or dispersions may contain antioxidants, buffers, bacteriostatic agents, solutes to render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0309] 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 fluidity can be maintained by using coating materials such as lecithin, by maintaining the required particle size (in the case of dispersions), and by using surfactants.

[0310] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. By including various antibacterial and antifungal agents (such as parabens, chlorobutanol, phenol, sorbic acid, etc.), the action of microorganisms can be ensured to be prevented. It is also desirable to include isotonic agents such as sugars, sodium chloride, etc. in the compositions. Additionally, by including agents that delay absorption such as aluminum monostearate and gelatin, the absorption of injectable drug forms can be prolonged.

[0311] In some cases, in order to prolong the action of a drug, it is generally desirable to slow down the absorption of a drug administered subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of crystalline or amorphous materials with poor water solubility. Thus, the absorption rate of the drug depends on its dissolution rate, which in turn depends on crystal particle size and crystal form. Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oily vehicle.

[0312] Injectable depot forms are prepared by forming a microencapsulated matrix of the subject compound in a biodegradable polymer such as polylactide-polyglycolide. The rate of drug release can be controlled according to the ratio of the drug to the polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0313] For use in the methods of the present invention, the active compound can be provided as such or in the form of a pharmaceutical composition containing, for example, from about 0.1% to about 99.5% (more preferably from about 0.5% to about 90%) of the active ingredient and a pharmaceutically acceptable carrier.

[0314] The introduction method can also be provided by a rechargeable or biodegradable device. 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), including biodegradable and non-biodegradable polymers, can be used to form implants for the sustained release of compounds at specific target sites.

[0315] The actual dosage level of the active ingredient in the pharmaceutical composition can be varied so as to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic effect for a particular patient, composition, and mode of administration without being toxic to the patient.

[0316] The selected dosage level depends on a variety of factors, including the activity of the particular compound or combination of compounds or their esters, salts, or amides used in the present invention, the route of administration, the time of administration, the rate of excretion of the particular compound used, the duration of the treatment, other drugs, compounds, and / or materials used in combination with the particular composition used, the age, sex, weight, medical condition, general health status, and prior medical history of the patient being treated, and similar factors well known in the medical arts.

[0317] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe a therapeutically effective amount of the required pharmaceutical composition. For example, a physician or veterinarian can start the dosage of the pharmaceutical composition or compound at a level below the required dose to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. A so-called "therapeutically effective amount" means a concentration of the compound sufficient to elicit the desired therapeutic effect. Generally, it should be understood that the effective amount of the compound will vary depending on the weight, sex, age, and medical history of the subject. Other factors affecting the effective amount can include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another class of therapeutic agents administered in combination with the compounds of the present invention. A greater total dose can be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those of skill in the art (Isselbacher et al. (1996), Harrison’s Principles of Internal Medicine, 13th ed., 1814 - 1882, incorporated herein by reference).

[0318] Generally speaking, the suitable daily dose of the active compound for use in the compositions and methods of the present invention will be the amount of the compound that is the lowest dose capable of effectively producing a therapeutic effect. Such effective dose generally depends on the above factors.

[0319] If desired, the effective daily dose of the active compound can be administered as one, two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage forms. In certain embodiments of the present invention, the active compound can be administered two or three times a day. In a preferred embodiment, the active compound is administered once a day.

[0320] The 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 generally poultry and pets.

[0321] Wetting agents, emulsifying agents and lubricants (such as sodium lauryl sulfate and magnesium stearate), as well as coloring agents, release agents, coating agents, sweetening agents, flavoring agents and fragrances, preservatives and antioxidants may also be present in the composition.

[0322] 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 ascorbyl 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.

[0323] The compounds of the present invention can be administered in combination with one or more other drugs, so as to (1) supplement and / or enhance the prophylactic and / or therapeutic efficacy of the prophylactic and / or therapeutic efficacy of the compounds of the present invention, (2) regulate pharmacodynamics, improve absorption, or reduce the dose reduction of the prophylactic and / or therapeutic compounds of the present invention, and / or (3) reduce or improve the side effects of the prophylactic and / or therapeutic compounds of the present invention. As used herein, the phrase "co-administered" refers to the administration of two or more different therapeutic compounds in any form such that the second compound is administered when the previously administered therapeutic compound is still effective in the body (e.g., both compounds are effective in the patient simultaneously, which may include a synergistic effect of the two compounds). For example, the different therapeutic compounds can be administered simultaneously or sequentially in the same formulation or separate formulations. In certain embodiments, the 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. Thus, an individual receiving such treatment can benefit from the combined action of the different therapeutic compounds. Each compound can be administered by the same or different routes and by the same or different methods.

[0324] The concomitant drugs comprising the compounds of the present invention and other drugs can be administered as a combined formulation in which both components are included in a single formulation, or as separate formulations. Administration by separate formulations includes simultaneous administration and / or administration of formulations separated at some time intervals. In the case of administration at certain time intervals, the compound of the present invention can be administered first, followed by another drug, or another drug can be administered first, followed by the compound of the present invention, as long as both compounds are effective in the patient simultaneously for at least some time during the combined treatment. The administration methods of each drug can be administered by the same or different routes and by the same or different methods.

[0325] The dose of the other drug can be appropriately selected based on the dose used in clinical practice, or can be a reduced dose effective when co-administered with the compound of the present invention. The ratio of the compound of the present invention to the other drug can be appropriately selected according to the age and weight of the subject to be administered, the administration method, the administration time, the disease to be treated, the symptoms, and their combination. For example, based on 1 part by mass of the compound of the present invention, the other drug can be used in an amount of about 0.01 to about 100 parts by mass. Another drug can be a combination of two or more arbitrary drugs in an appropriate ratio. Another drug that supplements and / or enhances the prophylactic and / or therapeutic efficacy of the compound of the present invention includes not only those drugs that have been discovered, but also drugs that will be discovered based on the above mechanisms in the future.

[0326] In certain embodiments, the compounds of the invention can be administered in combination with non-chemical methods of cancer treatment. In certain embodiments, the compounds of the invention can be administered in combination with radiotherapy. In certain embodiments, the compounds of the invention can be administered in combination with surgery, thermal ablation, focused ultrasound therapy, cryotherapy, or any combination thereof.

[0327] Treatment method

[0328] Acute myeloid leukemia is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence increases with age. AML is a relatively rare disease, accounting for approximately 1.2% of cancer deaths in the United States.

[0329] The symptoms of AML are caused by the replacement of normal bone marrow by leukemia cells, which results in 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 is unknown. As an acute leukemia, AML progresses rapidly and is usually fatal within weeks or months if left untreated. AML differs from chronic myelogenous leukemia (CML) because of their different cell differentiation. AML involves a higher percentage of dedifferentiated and undifferentiated cells, including more blasts (myeloblasts, monoblasts, and megakaryoblasts).

[0330] The diagnosis of AML usually begins with abnormal results from a complete blood count. While an excess of abnormal white blood cells (leukocytosis) is a common finding and sometimes leukemia blasts can be seen, AML can also present with isolated decreases in platelets, red blood cells, or even a low white blood cell count (leukopenia). While a presumptive diagnosis of AML can be made by examining a peripheral blood smear when circulating leukemia blasts are present, a definitive diagnosis usually requires adequate bone marrow aspiration and biopsy.

[0331] Genetic studies can also be conducted to look for specific mutations in genes, such as FLT-3 or genes that regulate FLT-3 expression, which can affect the outcome of the disease. In fact, it is believed that the ability of many of the compounds disclosed herein to inhibit FLT-3 contributes to their specific efficacy against AML, which is known to be sensitive to FLT-3 inhibition. Due to mutations that occur in the FLT-3 gene, some patients may develop resistance to treatment with FLT-3 inhibitors. Such FLT-3 mutations include, but are not limited to, D835H, D835V, D835Y, K663Q, N841I, internal tandem duplication (ITD), ITD and D835V, and ITD and F691L. However, the compounds disclosed herein have been shown to have efficacy against AML in which AML has developed resistance to FLT-3 inhibitor treatment. Thus, in some embodiments, the disclosed compounds are capable of effectively treating AML that is resistant to FLT-3 inhibitors, such as AML characterized by cells having one or more of these mutations.

[0332] The malignant cells in AML are myeloblasts. In normal hematopoiesis, myeloblasts are immature precursors of myeloid white blood cells; normal myeloblasts gradually mature into mature white blood cells. However, in AML, a single myeloblast accumulates genetic changes that "freeze" the cell in its immature state and prevent differentiation. This single mutation alone does not cause leukemia; however, when this "differentiation arrest" is combined with other mutations that disrupt genes controlling proliferation, the result is uncontrolled growth of a clone of immature cells, leading to the clinical entity of AML.

[0333] Myelodysplastic syndromes (MDS) are a group of cancers in which immature blood cells in the bone marrow do not mature and become healthy blood cells. Certain types may progress to acute myeloid leukemia. Problems with blood cell formation result in certain combinations of low red blood cells, low platelets, and low white blood cells. Some types have an increase in immature blood cells (called blasts) in the bone marrow or blood. The types of MDS are based on specific changes in blood cells and bone marrow.

[0334] MDS is thought to be caused by mutations in pluripotent bone marrow stem cells, but the specific defects that cause these diseases are still poorly understood. 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 results in the production of cells that have lost the ability to differentiate. If the total percentage of bone marrow myeloblasts exceeds a specific cut-off value, such as 20 - 30%, progression to acute myeloid leukemia is considered to have occurred. Progression of MDS to AML demonstrates how a series of mutations can occur in initially normal cells and transform them into cancer cells.

[0335] It is known that IRAK-1 is overexpressed in AML and MDS, and it has been demonstrated that inhibition of IRAK-1 induces apoptosis in MDS cell lines. See, e.g., Rhyasen, G.W. et al., Cancer Cell 2013 24:90-104; Rhyasen, G.W. et al., British J. Cancer 2014, pp. 1-6. The demonstrated potent activity of the disclosed compounds (including compounds that are not potent inhibitors of IRAK-1) in affecting AML cell lines (such as MV4-11 and MOLM-13) suggests that IRAK-4 is an attractive and effective target for AML and MDS in its own right.

[0336] Disclosed herein are methods for treating or preventing acute myeloid leukemia. These methods are equally applicable to treating or preventing myelodysplastic syndromes. Similarly, these methods are equally applicable to treating or preventing multiple myeloma. In certain embodiments, the invention relates to a compound or a pharmaceutically acceptable salt thereof as disclosed herein for treating or preventing AML and / or MDS. In certain embodiments, the invention relates to the use of a compound or a pharmaceutically acceptable salt thereof as disclosed herein in the preparation of a medicament for treating or preventing AML and / or MDS.

[0337] Compounds suitable for the compositions and methods disclosed herein are found in WO2015 / 104662, WO2015 / 104688, and WO2015 / 193846, each of which is incorporated herein by reference in its entirety, particularly with respect to the portions thereof disclosing the compounds as IRAK4 inhibitors.

[0338] The invention also relates to the following embodiments:

[0339] 1. A method for treating or preventing acute myeloid leukemia in a subject, the method comprising administering a compound of formula I:

[0340]

[0341] or a pharmaceutically acceptable salt thereof;

[0342] wherein,

[0343] Z1 is an optionally substituted heteroaryl;

[0344] Z2 is an optionally substituted heterocycloalkyl, an optionally substituted heteroaryl or a direct bond;

[0345] R1 is an alkyl, a cyano, -NR a R b, or an optionally substituted group selected from cycloalkyl, aryl or heterocyclic group; wherein said substituent is independently, in each occurrence, 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;

[0346] R2 is independently, in each occurrence, an optionally substituted group selected from alkyl or cycloalkyl; wherein said substituent is independently, in each occurrence, halogen, alkoxy, hydroxy, hydroxyalkyl, haloalkyl or haloalkoxy;

[0347] R3 is independently, in each occurrence, hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, -NR a R b , hydroxy or hydroxyalkyl;

[0348] R a is hydrogen or alkyl;

[0349] R b is hydrogen, alkyl, acyl, hydroxyalkyl, -SO2-alkyl or optionally substituted cycloalkyl;

[0350] ‘m’ and ‘n’ are independently 1 or 2.

[0351] 2. The method according to embodiment 1, wherein Z1 is a 5- or 6-membered heteroaryl.

[0352] 3. The method according to embodiment 1 or 2, wherein Z1 is an optionally substituted heteroaryl, and the optional substituent is alkyl.

[0353] 4. The method according to any one of the foregoing embodiments, wherein Z1 is tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furyl and pyrazolyl.

[0354] 5. The method according to any one of the foregoing embodiments, wherein Z1 is selected from pyridyl and oxazolyl.

[0355] 6. The method according to embodiment 1, wherein the compound is represented by formula (IA)

[0356]

[0357] or a pharmaceutically acceptable salt thereof;

[0358] wherein Z2, R1, R2, R3, ‘m’ and ‘n’ are the same as those defined in embodiment 1.

[0359] 7. The method according to embodiment 1, wherein the compound is represented by formula (IB)

[0360]

[0361] or a pharmaceutically acceptable salt thereof;

[0362] wherein Z2, R1, R2, R3,'m' and 'n' are the same as defined in embodiment 1.

[0363] 8. The method according to embodiment 1, wherein the compound is represented by formula (IC)

[0364]

[0365] or a pharmaceutically acceptable salt thereof;

[0366] wherein Z2, R1, R2, R3,'m' and 'n' are the same as defined in embodiment 1.

[0367] 9. The method according to any one of the foregoing embodiments, wherein Z2 is a 5- or 6-membered heteroalkyl or a 5- or 6-membered heteroaryl.

[0368] 10. The method according to any one of embodiments 1-8, wherein Z2 is heteroalkyl or a direct bond.

[0369] 11. The method according to any one of embodiments 1-9, wherein Z2 is azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperazinyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furyl and pyrazolyl.

[0370] 12. The method according to any one of embodiments 1-8, wherein Z2 is pyridyl, pyrazolyl, pyrrolidinyl or a direct bond.

[0371] 13. The method according to any one of embodiments 1-8, wherein Z2 is a direct bond.

[0372] 14. The method according to any one of the foregoing embodiments, wherein m is 1 and n is 1 or 2.

[0373] 15. The method according to any one of the foregoing embodiments, wherein m and n are each 1.

[0374] 16. The method according to any one of the foregoing embodiments, wherein R1 is selected from a cyano group, a cycloalkyl group, a halogen, -NR a R b , an aryl group, and a heterocyclic group.

[0375] 17. The method according to any one of the foregoing embodiments, wherein R1 is selected from a cyano group, a cycloalkyl group, an aryl group, and a heterocyclic group.

[0376] 18. The method according to any one of the foregoing embodiments, wherein R1 is selected from a cyclopropyl group, a cyclohexyl group, a piperidinyl group, and a morpholinyl group.

[0377] 19. The method according to any one of embodiments 1-17, wherein R1 is an optionally substituted heterocyclic group; wherein the substituent is a halogen, a hydroxyl group, a hydroxyalkyl group, or an amino group.

[0378] 20. The method according to any one of embodiments 1-17, wherein R1 is an optionally substituted azetidinyl group, piperidinyl group, morpholinyl group, pyrrolidinyl group, or azepanyl group.

[0379] 21. The method according to any one of the foregoing embodiments, wherein R1 is an optionally substituted piperidinyl group or morpholinyl group.

[0380] 22. The method according to any one of embodiments 1-17, wherein R1 is an optionally substituted phenyl group; wherein the substituent is a halogen.

[0381] 23. The method according to any one of embodiments 1-17, wherein R1 is a cyano group or a cycloalkyl group.

[0382] 24. The method according to any one of embodiments 1-18, wherein R1 is a cyclopropyl group or a cyclohexyl group.

[0383] 25. The method according to any one of embodiments 1-16, wherein R1 is -NR a R b ; R a is hydrogen; R b is an optionally substituted cycloalkyl group; wherein the substituent is a hydroxyl group.

[0384] 26. The method according to any one of the foregoing embodiments, wherein R2 is an optionally substituted alkyl group, and the substituent is an alkoxy group.

[0385] 27. The method according to any one of embodiments 1-25, wherein R2 is a cyclopropyl group or a cyclopentyl group.

[0386] 28. The method according to any one of the foregoing embodiments, wherein R3 is hydrogen, a halogen, an alkyl group, an alkoxy group, -NR a R b, a hydroxyl group or a hydroxyalkyl group; and R a and R b is as defined in Embodiment 1.

[0387] 29. The method according to any one of the foregoing embodiments, wherein R3 is selected from hydrogen, halogen, alkyl, alkoxy and hydroxyl.

[0388] 30. The method according to any one of the foregoing embodiments, wherein R3 is selected from hydrogen, alkyl and -NR a R b .

[0389] 31. The method according to any one of the foregoing embodiments, wherein R3 is H.

[0390] 32. The method according to Embodiment 1, wherein the compound of formula (I) is selected from:

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0400] 33. The method according to Embodiment 1, wherein the compound is selected from:

[0401] N-(2-cyclopentyl-6-morpholino-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;

[0402] (R)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-methyl-6-(piperidin-1-yl)-2H-indazol-5-yl)pyridinecarboxamide;

[0403] N-(6-(4-hydroxypiperidin-1-yl)-2,3-dimethyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; and

[0404] N-(2-Cyclopentyl-6-cyclopropyl-2H-indazol-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide,

[0405] or a pharmaceutically acceptable salt thereof.

[0406] 34. The method according to embodiment 1, wherein the compound is selected from:

[0407] N-(6-(3-Fluoropiperidin-1-yl)-2-methyl-2H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;

[0408] 2-(2-Aminopyridin-4-yl)-N-(6-(4-(hydroxymethyl)piperidin-1-yl)-1,3-dimethyl-1H-indazol-5-yl)oxazole-4-carboxamide;

[0409] N-(6-(4-(Aminomethyl)piperidin-1-yl)-1-(2-methoxyethyl)-1H-indazol-5-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; and

[0410] (S)-N-(6-Cyclopropyl-1-methyl-1H-indazol-5-yl)-6-(3-hydroxypyrrolidin-1-yl)picolinamide,

[0411] or a pharmaceutically acceptable salt thereof.

[0412] 35. A method of treating or preventing acute myeloid leukemia in a subject, the method comprising administering a compound of formula II:

[0413]

[0414] or a pharmaceutically acceptable salt thereof;

[0415] wherein

[0416] X1 and X3 are independently CH or N; X2 is CR2 or N; provided that one and no more than one of X1, X2 or X3 is N;

[0417] A is O or S;

[0418] Y is -CH2- or O;

[0419] Z is aryl or heterocyclic;

[0420] R1 is independently at each occurrence halo or an optionally substituted heterocyclic group; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxy, hydroxyalkyl or -NR a R b ;

[0421] R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic group or -NR a R b ; where the substituents are alkyl, amino, halogen or hydroxy;

[0422] R3 is alkyl or hydroxy each time it appears;

[0423] R a and R b are independently hydrogen, alkyl, acyl or heterocyclic group;

[0424] ‘m’ and ‘n’ are independently 0, 1 or 2;

[0425] ‘p’ is 0 or 1.

[0426] 36. The method according to embodiment 35, wherein

[0427] A is O or S;

[0428] Y is -CH2- or O;

[0429] Z is aryl or heterocyclic group;

[0430] R1 is independently halogen or optionally substituted heterocyclic group each time it appears, where the substituents are alkyl, aminoalkyl, halogen or -NR a R b ; where R a and R b are independently hydrogen, alkyl or heterocyclic group;

[0431] R2 is hydrogen, cycloalkyl, heterocyclic group or -NR a R b ;

[0432] ‘m’ is 0; and

[0433] ‘n’ is 1.

[0434] 37. The method according to embodiment 35, wherein

[0435] A is O or S;

[0436] Y is -CH2- or O;

[0437] Z is aryl or heterocyclic group;

[0438] R1 is independently halogen or optionally substituted heterocyclic group each time it appears; where the substituents are alkyl, alkoxy, aminoalkyl, halogen, hydroxy or -NR a R b ; where R a and R b are independently hydrogen, alkyl or heterocyclic group;

[0439] R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic group or -NR a R b , wherein the substituents are selected from amino, halogen or hydroxyl;

[0440] ‘m’ and ‘n’ are independently 0, 1 or 2; and

[0441] ‘p’ is 0 or 1.

[0442] 38. The method according to embodiment 35, or a pharmaceutically acceptable salt thereof, wherein the group is

[0443]

[0444] wherein R2 is as defined in embodiment 35.

[0445] 39. The method according to any one of embodiments 35-38, wherein Z is aryl or a 5- or 6-membered heterocyclic group.

[0446] 40. The method according to any one of embodiments 35-38, wherein Z is an optionally substituted heterocyclic group selected from phenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxathiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, dihydropyranyl and azabicyclo[3.2.1]octyl; wherein each is optionally substituted by alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl or -NR a R b substituted; and R a and R b are independently hydrogen, alkyl or acyl.

[0447] 41. The method according to embodiment 35, the method is represented by formula (IIA):

[0448]

[0449] or a pharmaceutically acceptable salt thereof;

[0450] wherein A, Y, R1, R2, R3, ‘m’, ‘p’ and ‘n’ are the same as those defined in embodiment 35.

[0451] 42. The method according to embodiment 41, wherein

[0452] A is O or S;

[0453] Y is -CH2- or O;

[0454] R1, each occurrence independently, is a halogen group or an optionally substituted heterocyclic group, wherein the substituent is an alkyl group, an aminoalkyl group, a halogen group or -NR a R b ; wherein R a and R b are independently hydrogen, an alkyl group or a heterocyclic group;

[0455] R2 is hydrogen, a cycloalkyl group, a heterocyclic group or -NR a R b ;

[0456] 'm' is 0; and

[0457] 'n' is 1.

[0458] 43. The method according to embodiment 41, wherein

[0459] A is O or S;

[0460] Y is -CH2- or O;

[0461] R1, each occurrence independently, is a halogen group or an optionally substituted heterocyclic group; wherein the substituent is an alkyl group, an alkoxy group, an aminoalkyl group, a halogen group, a hydroxyl group or -NR a R b ; wherein R a and R b are independently hydrogen, an alkyl group or a heterocyclic group;

[0462] R2 is hydrogen, a cycloalkyl group, an optionally substituted heterocyclic group or -NR a R b , wherein the substituent is selected from an amino group, a halogen group or a hydroxyl group; and

[0463] 'm' and 'n' are independently 0, 1 or 2.

[0464] 44. The method according to embodiment 35, the method being represented by formula (IIB):

[0465]

[0466] or a pharmaceutically acceptable salt thereof;

[0467] wherein A, Y, R1, R2 and 'n' are the same as those defined in embodiment 35.

[0468] 45. The method according to embodiment 44, wherein

[0469] A is O or S;

[0470] Y is -CH2- or O;

[0471] R1, each occurrence independently, is a halogen group or an optionally substituted heterocyclic group, wherein the substituent is an alkyl group, an aminoalkyl group, a halogen group or -NR a R b ; wherein R a and R b are independently hydrogen, an alkyl group or a heterocyclic group;

[0472] R2 is hydrogen, a cycloalkyl group, a heterocyclic group or -NR a R b ; and

[0473] ‘n’ is 1.

[0474] 46. The method according to embodiment 44, wherein

[0475] A is O or S;

[0476] Y is -CH2- or O;

[0477] R1, each occurrence independently, is a halogen group or an optionally substituted heterocyclic group; wherein the substituent is an alkyl group, an alkoxy group, an aminoalkyl group, a halogen group, a hydroxyl group or -NR a R b ; wherein R a and R b are independently hydrogen, an alkyl group or a heterocyclic group;

[0478] R2 is hydrogen, a cycloalkyl group, an optionally substituted heterocyclic group or -NR a R b , wherein the substituent is selected from an amino group, a halogen group or a hydroxyl group; and

[0479] ‘m’ and ‘n’ are independently 0, 1 or 2.

[0480] 47. The method of formula (I) according to embodiment 35, which is a compound of formula (IIC)

[0481]

[0482] or a pharmaceutically acceptable salt thereof;

[0483] wherein A, Y, R1, R2 and ‘n’ are the same as defined in embodiment 1.

[0484] 48. The method according to any one of embodiments 35 - 47, wherein R1 is an optionally substituted heterocyclic group; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxy, hydroxyalkyl or -NR a R b ; and R a and R b are independently hydrogen or acyl.

[0485] 49. The method according to any one of embodiments 36 - 47, wherein R1 is an optionally substituted heterocyclic group; wherein the substituent is alkyl, aminoalkyl, halo or -NR a R b ; and R a and R b are independently hydrogen or acyl.

[0486] 50. The method according to any one of embodiments 35 - 47, wherein R1 is an optionally substituted heterocyclic group; and the substituent is alkyl, aminoalkyl, halo or -NR a R b ; wherein R a and R b are independently hydrogen, alkyl or heterocyclic group.

[0487] 51. The method according to any one of embodiments 35 - 47, wherein R1 is an optionally substituted heterocyclic group; and the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxy or -NR a R b ; wherein R a and R b are independently hydrogen, alkyl or heterocyclic group.

[0488] 52. The method according to any one of embodiments 48 - 51, wherein R1 is pyridyl, pyrazolyl, pyrrolidinyl or piperidinyl.

[0489] 53. The method according to any one of embodiments 48 - 51, wherein R1 is an optionally substituted pyrazolyl, wherein the substituent is alkyl, hydroxy or -NR a R b .

[0490] 54. The method according to any one of embodiments 35 - 47, wherein R1 is halo.

[0491] 55. The method according to any one of embodiments 35 - 54, wherein R2 is hydrogen, cycloalkyl, heterocyclic group or -NR a R b .

[0492] 56. The method according to any one of embodiments 35-54, wherein R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic group or -NR a R b , wherein the substituents are selected from amino, halogen or hydroxyl.

[0493] 57. The method according to any one of embodiments 35-54, wherein R2 is an optionally substituted heterocyclic group selected from piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolyl, furyl or azabicyclo[3.2.1]octyl; wherein the substituents are hydroxyl, halogen, alkyl or amino.

[0494] 58. The method according to any one of embodiments 35-54, wherein R2 is piperidinyl, pyrrolidinyl, morpholinyl or piperazinyl.

[0495] 59. The method according to any one of embodiments 35-54, wherein R2 is hydrogen.

[0496] 60. The method according to any one of embodiments 35-54, wherein R2 is cycloalkyl.

[0497] 61. The method according to embodiment 60, wherein R2 is cyclopropyl.

[0498] 62. The method according to any one of embodiments 35-61, wherein R3 is alkyl.

[0499] 63. The method according to any one of embodiments 35-62, wherein m is 0 and p is 1.

[0500] 64. The method according to any one of embodiments 35-62, wherein m is 0 or 2, and p is 0 or 1.

[0501] 65. The method according to embodiment 35, wherein the compound of formula (II) is selected from:

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0511] 66. The method according to embodiment 35, wherein the compound of formula (II) is selected from:

[0512] 6'-Amino-N-(2-morpholinooxazolo[5,4-b]pyridin-5-yl)-[2,3'-bipyridine]-6-carboxamide;

[0513] N-(5-(4-Hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;

[0514] N-(2,5-Bis(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridinecarboxamide hydrochloride; and

[0515] (R)-N-(5-(3-Hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;

[0516] or a pharmaceutically acceptable salt thereof.

[0517] 67. The method according to embodiment 35, wherein the compound of formula (II) is selected from:

[0518] N-(5-(3-Fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide;

[0519] N-(5-(Azepan-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide;

[0520] (R)-N-(5-(3-Hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; and

[0521] N-(2,5-Bis(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)pyridinecarboxamide;

[0522] or a pharmaceutically acceptable salt thereof.

[0523] 68. A method for treating or preventing acute myeloid leukemia in a subject, the method comprising administering a compound of formula (III):

[0524]

[0525] or a pharmaceutically acceptable salt thereof;

[0526] wherein,

[0527] Z1 is an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclic group or absent;

[0528] Z2 is an optionally substituted cycloalkyl, aryl or heterocyclic group;

[0529] R1 is hydrogen, an optionally substituted alkyl, amino, halogen, cyano, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclic group, an optionally substituted arylalkyl or an optionally substituted heterocyclic alkyl;

[0530] R2, each occurrence, is hydrogen, halogen, amino, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclic group, an optionally substituted arylalkyl or an optionally substituted heterocyclic alkyl;

[0531] R3, each occurrence, is hydroxy, halogen, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted cycloalkyl or -NR a R b ;

[0532] R a and R b , each occurrence, are independently hydrogen, an optionally substituted alkyl, an optionally substituted acyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclic group, an optionally substituted arylalkyl or an optionally substituted heterocyclic alkyl;

[0533] m, each occurrence, is 0, 1 or 2; and

[0534] n, each occurrence, is 0, 1 or 2.

[0535] 69. The method according to embodiment 68, wherein Z1 is an optionally substituted heterocyclic group.

[0536] 70. The method according to embodiment 68 or 70, wherein Z1 is a heterocyclic group selected from tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furyl, pyrazolyl, benzisoxazolyl, benzothiazolyl, benzofuryl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuryl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, α-carboline, indolizinyl, benzisothiazolyl, benzoxazolyl, pyrrolopyridyl, furanopyridyl, purinyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzotriadiazolyl, carbazolyl, dibenzothienyl, acridinyl, and pyrazolopyrimidinyl.

[0537] 71. The method according to any one of embodiments 68 - 70, the method being represented by formula (IIIA)

[0538]

[0539] or a pharmaceutically acceptable salt thereof;

[0540] wherein Z2, R1, R2, R3, m, and n are as defined in embodiment 68.

[0541] 72. The method according to any one of embodiments 68 - 70, the method being represented by formula (IIIB)

[0542]

[0543] or a pharmaceutically acceptable salt thereof;

[0544] wherein Z2, R1, R2, R3, m, and n are as defined in embodiment 68.

[0545] 73. The method according to any one of embodiments 68 - 72, wherein Z2 is a heterocyclic group.

[0546] 74. The method according to any one of embodiments 68 - 73, wherein Z2 is a heterocyclic group selected from azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4 - dioxanyl, tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, tetrahydropyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperazinyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furyl, pyrazolyl, indolinyl, indolinylmethyl, 2 - azabicyclo[[2.2.2]octyl, chromanyl, xanthenyl or pyrrolopyridinyl.

[0547] 75. The method according to any one of embodiments 68 - 74, wherein Z2 is pyrrolidinyl, piperidinyl, piperazinyl, pyridyl, pyrimidinyl, tetrahydropyridyl or pyrrolopyridinyl.

[0548] 76. The method according to any one of embodiments 68 - 75, wherein Z2 is pyrrolidinyl or pyridyl.

[0549] 77. The method according to any one of embodiments 68 - 76, wherein R1 is an optionally substituted heterocyclic group.

[0550] 78. The method according to any one of embodiments 68 - 77, wherein R1 is a heterocyclic group; which is optionally substituted by halogen, hydroxy or hydroxyalkyl.

[0551] 79. The method according to any one of embodiments 68 - 78, wherein R1 is an optionally substituted azetidinyl, piperidinyl, morpholinyl, pyrrolidinyl or azabicyclooctyl.

[0552] 80. The method according to any one of embodiments 68 - 79, wherein R1 is piperidinyl.

[0553] 81. The method according to any one of embodiments 68 - 80, wherein R2 is an optionally substituted alkyl.

[0554] 82. The method according to any one of embodiments 68 - 81, wherein R2 is an alkyl optionally substituted by a heterocyclic group.

[0555] 83. The method according to any one of embodiments 68 - 80, wherein R2 is hydrogen.

[0556] 84. The method according to any one of embodiments 68 - 80, wherein R2 is cyclopropyl.

[0557] 85. The method according to any one of embodiments 68 - 84, wherein R3 is halogen, alkyl, haloalkyl, -NR aR b , cycloalkyl, hydroxy or hydroxyalkyl; and R a and R b are as defined in embodiment 113.

[0558] 86. The method according to any one of embodiments 68 - 85, wherein R3 is methyl, hydroxy or amino.

[0559] 87. The method according to any one of embodiments 68 - 86, wherein R3 is hydroxy or amino.

[0560] 88. The method according to embodiment 68, wherein

[0561] Z1 is an optionally substituted cycloalkyl, an optionally substituted aryl or an optionally substituted heterocyclic group;

[0562] Z2 is an optionally substituted cycloalkyl, aryl or heterocyclic group;

[0563] R1 is hydrogen, alkyl, amino, halogen, cyano, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclic group, arylalkyl or heterocyclic alkyl;

[0564] R2 is amino, alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclic group, arylalkyl or heterocyclic alkyl;

[0565] R3 is hydroxy, alkyl, alkoxy or -NR a R b ;

[0566] R a and R b are each independently hydrogen, alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclic group, arylalkyl or heterocyclic alkyl each time they appear;

[0567] m is 1; and

[0568] n is 1.

[0569] 89. The method according to embodiment 68, wherein

[0570] Z1 is a heterocyclic group;

[0571] Z2 is a heterocyclic group;

[0572] R1 is an optionally substituted heterocyclic group;

[0573] R2 is alkyl;

[0574] R3 is hydroxy, alkyl or amino;

[0575] m is 1; and

[0576] n is 1.

[0577] 90. The method according to embodiment 68, wherein the compound of formula (III) is selected from:

[0578]

[0579]

[0580]

[0581] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0582] 91. The method according to embodiment 68, wherein the compound of formula (III) is selected from:

[0583] (S)-2-(3-aminopyrrolidin-1-yl)-N-(2-methyl-5-(piperidin-1-yl)-2H-indazol-6-yl)oxazole-4-carboxamide;

[0584] 6-((S)-3-hydroxypyrrolidin-1-yl)-N-(5-((S)-3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)pyridinecarboxamide;

[0585] (S)-N-(1-ethyl-5-(3-hydroxypyrrolidin-1-yl)-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride; and

[0586] (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)-2-(2-methylpyrimidin-4-yl)oxazole-4-carboxamide hydrochloride;

[0587] or a pharmaceutically acceptable salt thereof.

[0588] 92. The method according to embodiment 68, wherein the compound of formula (III) is selected from:

[0589] (S)-2-(2-cyclopropylpyridin-4-yl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-indazol-6-yl)oxazole-4-carboxamide hydrochloride;

[0590] (S)-N-(1-cyclopropyl-5-(3-hydroxypyrrolidin-1-yl)-1H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride;

[0591] N-(2-methyl-5-(piperidin-1-yl)-2H-indazol-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride; and

[0592] (S)-6-(3-Aminopyrrolidin-1-yl)-N-(1-methyl-5-(piperidin-1-yl)-1H-indazol-6-yl)pyridinecarboxamide;

[0593] or a pharmaceutically acceptable salt thereof.

[0594] 93. The method according to any one of the preceding embodiments, wherein the subject has a mutation in the FLT-3 kinase.

[0595] 94. The method according to embodiment 93, wherein the mutation is an internal tandem duplication (ITD).

[0596] 95. The method according to embodiment 93, wherein the mutation is selected from D835H, D835V, D835Y, K663Q, N841I, ITD, ITD and D835V, and ITD and F691L.

[0597] 96. The method according to any one of the preceding embodiments, wherein the AML is resistant to FLT-3 inhibitors.

[0598] Example

[0599]

[0600] Example 1: Inhibition of FLT-3 by Compound A

[0601] The inhibition of the compound against 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 required). The reaction was initiated by adding the Mg / ATP mixture. After incubation at room temperature for 40 minutes, the reaction was terminated by adding phosphoric acid to a concentration of 0.5%. Then 10 μL of the reaction mixture was spotted on a P30 filter pad, washed four times in 0.425% phosphoric acid for 4 minutes, washed once in methanol, and then dried and subjected to scintillation counting.

[0602] As described above, test compound A was assayed against Flt-3 using the Eurofins standard KinaseProfiler assay. Test compound A was also assayed against IRAK1 and Flt-3 (D835Y) using the same protocol with substrates myelin basic protein (MBP) and EAIYAAPFAKKK, respectively. Protein kinases (except ATM(h) and DNA-PK(h)) were assayed in radioactive form, while lipid kinases ATM(h), ATR / ATRIP(h), and DNA-PK(h) were assayed using form.

[0603] Compound A was prepared by adding a 50x test compound stock solution to the assay wells, followed by the addition of the reaction mixture containing the enzyme and substrate. The reaction was initiated by adding the 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 the final assay concentration in 100% DMSO.

[0604] Results were expressed as the remaining kinase activity as a percentage of the DMSO control. This was calculated using the following formula:

[0605] Average of sample counts — Average of blank counts Mean of control counts

[0606] For IC 50 assays, data were analyzed using XLFit version 5.3 (ID Business Solutions). Using non-linear regression analysis, sigmoidal dose-response (variable slope) curves were fitted based on the mean results at each test concentration. At the top and / or bottom of the curve where the decline > 10% from 100 and 0, respectively, either or both of these limits could be defined at 100 and 0 if the R2 met the QC criteria. Table 1 provides the IC 50 data for the inhibition of representative kinases by compound A.

[0607] Table 1

[0608] Kinase <![CDATA[IC 50 (nM)]]> IRAK4 37 IRAK1 >10,000 FLT3 (D835Y) 11 FLT3 82

[0609] Compound A was also tested against each selected kinase using the DiscoverX standard KINOMEscan and KdELECT assays and following the relevant standard operating procedures. See, for example, Nat. Biotechnol. 2011, 29(11):1046 - 51. KINOMEscan and KdELECT are competitive binding assays based on the quantitative measurement of the ability of a compound to compete with an immobilized active site - directed ligand. The assay is performed by combining three components: a DNA - tagged kinase; an immobilized ligand; and a test compound. The ability of the test compound to compete with the immobilized ligand is measured via quantitative PCR of the DNA tag. The binding constant (Kd) is calculated using a standard dose - response curve.

[0610] Figure 1 The activities of Compound A against multiple variants of IRAK1, IRAK4, and FLT - 3 are shown, indicating its potency as a dual IRAK / FLT - 3 inhibitor. Compounds with a similar structure are expected to have this dual activity to a certain extent.

[0611] For example, Compound A shows abnormal binding to FLT - 3 with an ITD mutation and a mutation in the activation loop (such as D835Y). These mutations occur in one - third of all untreated AML patients. Known inhibitors of the activation - loop - mutated FLT - 3 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.

[0612] Example 2: In vitro assay of the AML model MV4 - 11

[0613] The CellTiter Glo luminescent cell viability assay is a highly sensitive homogeneous assay for determining the number of viable cells in a culture based on the quantification of ATP levels in metabolically active cells. The addition of the 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. An increase or decrease in the number of cells causes a corresponding change in the luminescence level, indicating the effect of the test material on cell proliferation.

[0614] Preparation of solution / reagent

[0615] Preparation of the CTG reagent:

[0616] Thaw the CellTiter-Glo buffer and equilibrate it to room temperature. Bring the lyophilized CellTiter-Glo substrate to room temperature. Prepare the CTG reagent by reconstituting the lyophilized enzyme / substrate mixture by mixing the CellTiter-Glo buffer (Promega catalog number G7572) into the amber bottle containing the CellTiter-Glo substrate. Both the buffer and the lyophilized substrate are provided with the kit.

[0617] Medium preparation:

[0618] Add 1% penicillin-streptomycin and 10% FBS to commercially available liquid IMDM (Iscove's Modified Dulbecco's Medium, Invitrogen catalog number 12440046).

[0619] Preparation of 1X PBS (Phosphate Buffered Saline):

[0620] Dissolve one bag of PBS powder (Sigma: catalog number P3813) in 1 L of MiliQ water. DMSO is the vehicle used to dissolve the test article.

[0621] Process (IC 50 Measurement)

[0622] 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 (black plate with clear bottom) to seed approximately 0.1 x 105 cells per well. Incubate the plate in a humidified atmosphere of 37 °C and 5% CO2 for approximately 2 hours before adding the compounds.

[0623] 2. Dissolve the test compound in 100% DMSO to produce 2 / 6 / 10 / 20 mM stock solutions. Prepare the required final concentrations at 200X in DMSO. Then dilute 10 μL of each concentration (200X) in 90 μL of serum-free IMDM to prepare 20X intermediate concentrations in the medium. The DMSO concentration in this step is 10% (intermediate dilution). Then add 5 μL of each intermediate dilution in triplicate to the cells pre-seeded in the 96-well plate. The final DMSO concentration in the experimental wells is 0.5%. Use the cells treated with 0.5% DMSO as the positive control. 100 μL of complete IMDM medium is used as the medium blank for data analysis. Add 200 μL of 1X PBS to all corner wells of the assay plate to avoid evaporation of the medium in the experimental wells. Then incubate the assay plate in an incubator containing 5% CO2 at 37 °C for 72 hours.

[0624] 3. To terminate the assay, 50 μL of CTG reagent was added to each well and the plate was incubated on a shaker at room temperature for 15 minutes. The plate was read using the luminescence mode on a multimode reader capable of measuring luminescence. The luminescence values were plotted against the respective concentrations of the test article using GraphPad Prism to calculate the IC 50 value.

[0625] The percentage of inhibition was calculated as follows:

[0626] The percent inhibition (%) was calculated by normalizing the DMSO control value to 0% inhibition using the following formula:

[0627] % Inhibition = 100 - (L 测试化合物-空白 ) / (L 阳性对照-空白 ) * 100, where L is the luminescence value

[0628] The experimental wells contained cells, test compound, IMDM medium, and 0.5% DMSO. The positive control wells contained cells, IMDM medium, and 0.5% DMSO. The blank control wells contained only IMDM medium.

[0629] The IC 50 values (in μM) of the following compounds are given in Table 2. A < 0.05 μM, B is 0.05 to 0.5 μM, and C > 0.5 μM.

[0630] Table 2

[0631]

[0632]

[0633]

[0634]

[0635]

[0636] Example 3: Inhibition of cell proliferation in the MV4-11 xenograft model

[0637] Using the procedure of Example 2, Compounds A and B were evaluated to determine the % inhibition of proliferation in MV4-11 cells. The IC 50 of Compound A was 0.031 μM ( Figure 2A ), and the IC 50 of Compound B was 6.1e-005 μM ( Figure 2B ).

[0638] Example 4: Inhibition of in vivo tumor growth in the AML xenograft model MV4-11

[0639] Using the AML xenograft model MV4 - 11 protocol, compound A was evaluated at doses of 12.5, 25, and 50 mpk. ND - 2158 at 100 mpk was used as a control.

[0640] The anti - tumor activity of compound A was evaluated in male athymic nude mice. MV4 - 11 cells were grown in Iscove's Modified Dulbecco's Medium supplemented with 10% FBS and 1% penicillin - streptomycin. To establish tumors, 200 μl of 15 X 106 MV4 - 11 cells in a 1:1 mixture of HBSS and ECM gel were subcutaneously injected into the right flank 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. Treatment was initiated when the mean tumor volume size was 333 mm 3 at the start. Tumor volume was measured three times a week, and body weight was monitored daily. Compound A at 12.5, 25, and 50 mg / kg and ND - 2158 at 100 mg / kg were well - tolerated, with no treatment - related clinical signs and no gross pathological changes.

[0641] Figure 3 Depicted is the increase in tumor growth inhibition with increasing doses of compound A. Tumor growth stasis was achieved at 12.5 mpk, and tumor regression was observed at 25 and 50 mpk after 21 days of treatment. Compound A treated at 12.5 mg / kg resulted in 92% tumor growth inhibition. Compound A treated at 25 mg / kg and 50 mg / kg resulted in partial tumor regression. ND - 2158 at 100 mg / kg treatment resulted in 68% tumor growth inhibition. As Figure 4 shown, no weight loss was observed.

[0642] Example 5: Anti - proliferative activity in the AML xenograft models MV4 - 11 and MOLM - 13

[0643] The same procedure was used for MV4 - 11 cells and MOLM - 13 cells. Each cell line has an ITD mutation in the FLT - 3 kinase.

[0644] Grow the cells to approximately 80% confluence, split them in half and grow overnight. Seed the cells at a density of 5,000 cells / well in a volume of 150 μL into all wells of a 96-well black plate (except columns 1 and 12 and rows A and H). Incubate the cells overnight in 10% serum and add HBSS to the outer wells. In a 96-well deep well plate, add 1000 μL of 10% FBS to wells B2 and D2. Add 750 μL of 10% FBS, 1% DMSO medium per well in row B except well B2. 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). Use the CellTiter Glo assay described in Example 2 to determine the IC 50 value of compound A in each cell line. The IC 50 of compound A in the MV4-11 cell line is 0.07 μM and in the MOLM-13 cell line is 0.19 μM.

[0645] Example 6: In vivo efficacy of compound A in MOLM-14 FLT3-ITD and MOLM-14 FLT3-ITD / KD (kinase domain) mouse xenograft tumor models

[0646] In athymic nude mice bearing subcutaneous MOLM-14 FLT3-ITD, MOLM-14 FLT3-ITD / F691L or MOLM-14 FLT3-ITD / D835Y tumors, compound A was orally administered once daily at 100 mg / kg. The efficacy of compound A was compared to mice receiving vehicle. As Figure 5A , Figure 5B and Figure 5C shown, after 12 or 14 days of dosing, the tumor growth inhibition percentages (TGI%) were 90%, 73% and 98% respectively.

[0647] Example 7: Cell viability assay

[0648] The parental MOLM-14 cell line harbors the FLT3-ITD mutation. The quizartinib-resistant MOLM-14-derived cell lines MOLM-14 FLT3-ITD / D835Y and MOLM-14 FLT3-ITD / F691L contain dual FLT3 mutations (the original ITD mutation and a secondary mutation within the kinase domain).

[0649] All cell lines were cultured in RPMI 1640 + GlutaMAX supplemented with 1X Pen-Strep and 10% FBS (hereinafter referred to as medium). The cells were cultured in 75 cm 2 or 225 cm 2 tissue culture flasks in a humidified tissue culture incubator at 37 °C with 5% CO2. The cell density was maintained between 0.5 - 2.0 x 10 6 cells / mL.

[0650] Seeding and dosing

[0651] Two days prior to compound treatment, the cell pellet was resuspended in fresh medium. On the day of dosing, the cells were counted and stained with trypan blue to determine cell viability. 5,000 live cells were transferred at a volume of 90 μL or 135 μL per well to all wells of a 96-well tissue culture plate and returned to the tissue culture incubator. Generally, two rows of each cell line to be assayed were added per plate (i.e., a maximum of 3 cell lines per plate). The lower limit of cell viability for this assay was 80%; most cell lines exhibited >90% viability.

[0652] The compound stock solution prepared in 100% DMSO was taken out from the -80 °C freezer and thawed at room temperature before use. Unused compound was discarded. A compound dilution series was created using a 96-well plate. 40 μL of the compound stock solution was transferred to well B2. 30 μL of DMSO was added to wells B3 to B11. 10 μL was taken from well B2 and transferred to well B3, and mixed by pipetting up and down 6 times to obtain a 1 / 4 dilution. Alternative volumes or dilution ratios may have been used. The pipette tip was changed between each dilution step, and the dilution series was continued to well B10. Well B11 was the DMSO-treated control sample.

[0653] 198 μL of medium was transferred to each well in rows B - G and columns 2 - 11 of a new 96-well plate. 2 μL was taken from the compound A DMSO dilution series plate and transferred to the corresponding well in each row containing 198 μL of medium, and mixed by pipetting 6 times to create a 10X compound A dilution series dose plate.

[0654] From the 10X compound A dilution series dose plate, 10 μL or 15 μL of the diluted compound was added to the 96-well tissue culture plate containing 90 μL or 135 μL of cells, respectively. Then the plate was briefly mixed for two minutes at 150 rpm using a plate mixer. The plate was returned to the tissue culture incubator and incubated at 37 °C for 72 hours. The final concentration of DMSO added to the cells was 0.1%.

[0655] Each cell line was tested in duplicate per plate and repeated at least 3 times on different days.

[0656] Viability

[0657] After 72 hours of incubation, cell viability was evaluated using the CellTiter-Glo Luminescent Cell Viability Assay (2.0) according to the supplier's instructions. After adding the CellTiter-Glo reagent (1:1 volume), the plate was covered with a clear plate sealer and then mixed on a plate shaker at 150 rpm for 10 minutes at room temperature in the dark. Luminescence readings were measured using a TopCount 384 instrument.

[0658] EC 50 Calculation

[0659] The percentage of inhibition of the compound-treated samples was determined relative to the DMSO-treated cell control samples. Using GraphPad Prism 7 software, the EC 50 value was calculated using the percentage of inhibition values. In assays where curve fitting could not determine the EC 50 value, the concentration causing 50% inhibition by linear extrapolation was used as the EC 50 value. The mean EC 50 value was determined from at least 3 independent viability assays performed on different days.

[0660] MOLM-14 EC 50 = 58 nM

[0661] MOLM-14 FLT3-ITD / D835Y, EC 50 = 108 nM

[0662] MOLM-14 FLT3-ITD / F691L, EC 50 = 2488 nM

[0663] Incorporated by reference

[0664] All publications and patents mentioned herein are hereby incorporated by reference in their entirety, as if each individual publication or patent had been specifically and individually designated to be incorporated by reference. In case of conflict, the present application (including any definitions herein) shall control.

[0665] Equivalent

[0666] Although specific embodiments of the invention have been discussed, the above specification is illustrative and not restrictive. After reading this specification and the following claims, many variations of the invention will become apparent to those skilled in the art. 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 specification and such variations.

Claims

1. Use of a compound in the preparation of a medicament for treating myelodysplastic syndrome (MDS), wherein the compound is represented by formula II: or a pharmaceutically acceptable salt thereof; wherein X1 and X3 are independently CH or N; X2 is CR2 or N; provided that one and no more than one of X1, X2 or X3 is N; A is O or S; Y is -CH2- or O; Z is aryl or heterocyclic group; R1 is independently, each time it appears, a halogen group or an optionally substituted heterocyclic group; wherein the substituent is an alkyl group, an alkoxy group, an aminoalkyl group, a halogen group, a hydroxyl group, a hydroxyalkyl group or -NR a R b ; R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic group or -NR a R b ; wherein the substituent is alkyl, amino, halogen or hydroxyl; R3 is alkyl or hydroxy each time it appears; R a and R b are independently hydrogen, alkyl, acyl or heterocyclic group; 'm' and 'n' are independently 0, 1 or 2; and 'p' is 0 or 1.

2. The use according to claim 1, wherein A is O or S; Y is -CH2- or O; Z is aryl or heterocyclic group; R1, each occurrence independently, is a halogen group or an optionally substituted heterocyclic group, wherein the substituent is alkyl, aminoalkyl, halogen or -NR a R b ; wherein R a and R b are independently hydrogen, alkyl or heterocyclic group; R2 is hydrogen, cycloalkyl, heterocyclic group or -NR a R b ; 'm' is 0; and 'n' is 1.

3. The use according to claim 1, wherein A is O or S; Y is -CH2- or O; Z is aryl or heterocyclic group; R1 is, independently at each occurrence, a halogen group or an optionally substituted heterocyclic group; wherein the substituent is an alkyl group, an alkoxy group, an aminoalkyl group, a halogen group, a hydroxyl group or -NR a R b ; wherein R a and R b are, independently, hydrogen, an alkyl group or a heterocyclic group; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic group or -NR a R b , where the substituents are selected from amino, halogen or hydroxyl; 'm' and 'n' are independently 0, 1 or 2; and 'p' is 0 or 1.

4. The use according to claim 1, wherein is 5. The use according to claim 1, wherein Z is aryl or a 5- or 6-membered heterocyclic group.

6. The use according to claim 1, wherein Z is an optionally substituted heterocyclic group selected from furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxathiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, dihydropyranyl and azabicyclo[3.2.1]octyl; each of which is optionally substituted by alkyl, alkoxy, halogen, hydroxy, hydroxyalkyl or -NR a R b ; and R a and R b are independently hydrogen, alkyl or acyl.

7. The use according to claim 1, wherein the compound represented by formula II is represented by formula (IIA): or a pharmaceutically acceptable salt thereof.

8. The use according to claim 7, wherein A is O or S; Y is -CH2- or O; R1, each occurrence independently, is a halogen group or an optionally substituted heterocyclic group, wherein the substituent is an alkyl group, an aminoalkyl group, a halogen group or -NR a R b ; wherein R a and R b are independently hydrogen, an alkyl group or a heterocyclic group; R2 is hydrogen, cycloalkyl, heterocyclic group or -NR a R b ; 'm' is 0; and 'n' is 1.

9. The use according to claim 7, wherein A is O or S; Y is -CH2- or O; R1 is independently, at each occurrence, a halogen group or an optionally substituted heterocyclic group; wherein the substituent is an alkyl group, an alkoxy group, an aminoalkyl group, a halogen group, a hydroxyl group or -NR a R b ; wherein R a and R b are independently hydrogen, an alkyl group or a heterocyclic group; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclic group or -NR a R b , wherein the substituent is selected from amino, halogen or hydroxyl; and 'm' and 'n' are independently 0, 1 or 2.

10. The use according to claim 1, wherein the compound represented by formula II is represented by formula (IIB): or a pharmaceutically acceptable salt thereof.

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