NZ757707B2 - Compounds and compositions for treating hematological disorders - Google Patents

Compounds and compositions for treating hematological disorders Download PDF

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Publication number
NZ757707B2
NZ757707B2 NZ757707A NZ75770718A NZ757707B2 NZ 757707 B2 NZ757707 B2 NZ 757707B2 NZ 757707 A NZ757707 A NZ 757707A NZ 75770718 A NZ75770718 A NZ 75770718A NZ 757707 B2 NZ757707 B2 NZ 757707B2
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New Zealand
Prior art keywords
pyridinyl
oxazolecarboxamide
piperidinyl
methylpyridinyl
compound
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NZ757707A
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NZ757707A (en
Inventor
Wesley Roy Balasubramanian
Girish Daginakatte
Venkateshwar Rao Gummadi
Kavitha Nellore
Susanta Samajdar
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Aurigene Oncology Limited
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Publication date
Application filed by Aurigene Oncology Limited filed Critical Aurigene Oncology Limited
Priority claimed from PCT/IB2018/052232 external-priority patent/WO2018178947A2/en
Publication of NZ757707A publication Critical patent/NZ757707A/en
Publication of NZ757707B2 publication Critical patent/NZ757707B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Abstract

The present invention provides methods of treating acute myeloid leukemia or myelodysplasia syndrome with Formula II, wherein the subject has a mutation in FLT-3 kinase selected from an internal tandem duplication (ITD), a mutation in D835, F691, K663, or N841, and an ITD in combination with a mutation in D835, F691, K663, or N841, or the AML or MDS is resistant to an FLT-3 kinase inhibitor.

Description

nds and Compositions for ng Hematological Disorders CROSS-REFERENCE TO RELATED ATION This application claims the benefit of priority to Indian ional Patent Application serial number 201741011785, filed March 31, 2017, which is hereby incorporated by reference herein in its entirety.
BACKGROUND Acute myeloid leukemia (hereafter also referred to as "AML") is a hematological malignancy with a poor prognosis that often occurs in adults, and the 5-year survival rate thereof is predicted to be 20%. At t, it is possible to temporarily reduce the number of AML cells to a level below the detection limit through AML treatment. This condition is referred to as "complete remission." However, AML often recurs after achieving complete remission, and for many patients, recurrent AML results in death. In particular, a very low survival rate in cases of recurrence has been a serious issue of concern. Accordingly, there is a need for new ents for AML.
SUMMARY Provided herein is a method of treating or preventing acute myeloid leukemia in a subject, comprising administering a nd of Formula (I): (R... E a e R» (1) or a pharmaceutically acceptable salt thereof; wherein, Ring Z1 is an optionally substituted heteroaryl; Ring 22 is a ally substituted heterocycloalkyl, optionally substituted heteroaryl or a direct bond; R1 is alkyl, cyano, -NRaRb, or optionally substituted groups selected from cycloalkyl, aryl or heterocyclyl; wherein the substituent, at each occurrence, independently is alkyl, , halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, -OCO- CHz—O—alkyl, -OP(O)(O-alkyl)2 or P(O)(O-alkyl)2; R2, at each occurrence, independently is an optionally substituted group selected from alkyl or cycloalkyl; wherein the substituent, at each occurrence, is independently halogen, , hydroxyl, hydroxyalkyl, haloalkyl or haloalkoxy; R3, at each occurrence, independently is hydrogen, halogen, alkyl, kyl, haloalkoxy, alkoxy, -NRaRb,hydroxy1 or hydroxyalkyl; Ra is hydrogen or alkyl; Rb is hydrogen, alkyl, acyl, hydroxyalkyl, —SO2-all lkyl; ‘m’ and ‘n’ are independently l or 2.
Provided herein is a method of treating or preventing acute myeloid leukemia in a subject, comprising administering a compound of Formula (II): 0 R1)n Y N‘<\ l (RifL/ N Xlé X2 or a pharmaceutically acceptable salt f; wherein, X1 and X3 independently are CH or N; X2 is CR2 or N; provided one and not more than one of X1, X2 or X3 is N; AisOorS; Y is —CH2- or O; Ring Z is aryl or heterocyclyl; R1, at each occurrence, is independently halo or ally substituted heterocyclyl; Wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or -NRaRb; R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted cyclyl or -NRaRb; n the substituent is alkyl, amino, halo or hydroxyl; R3, at each occurrence, is alkyl or hydroxyl; Ra and Rh are independently hydrogen, alkyl, acyl or cyclyl; ‘m’ and ‘n’ are independently 0, l or 2; ‘p’ is 0 or 1.
Provided herein is a method of treating or preventing acute myeloid leukemia in a subject, comprising administering a compound of Formula (111): N 3)n N N\H/.—.—< (111) or a pharmaceutically acceptable salt thereof; wherein, Z1 is optionally substituted cycloalkyl, ally substituted aryl, optionally substituted heterocyclyl or is absent; 22 is optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl; R1 is en, optionally substituted alkyl, amino, halo, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted cyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl; R2 at each occurrence is amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, ally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl; R3 at each occurrence is hydroxy, halo, optionally substituted alkyl, optionally tuted alkoxy, optionally substituted lkyl or -NRaRb; Ra and Rb, independently for each ence, are hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl; m, at each occurrence, is 0, 1 or 2; and n, at each occurrence, is 0, 1, or 2.
In some ments, disclosed herein is a use of a compound disclosed herein or a pharmaceutically acceptable salt or a stereoisomer thereof for the treatment and prevention of In some embodiments, disclosed herein is a use of compound disclosed herein or a pharmaceutically acceptable salt or a stereoisomer thereof, ing mixtures thereof in all ratios, as a medicament for treating AML.
In a particular embodiment, there is provided use of a compound in the manufacture of a medicament for treating acute d leukemia (AML) or a myelodysplasia syndrome (MDS), wherein: i) the medicament is to be administered to a subject having a mutation in FLT-3 kinase selected from an internal tandem duplication (ITD), a mutation in D835, F691, K663, or N841, and an ITD in combination with a mutation in D835, F691, K663, or N841; or ii) the AML or MDS is resistant to a FLT-3 kinase tor; and the compound has a structure represented by a II: or a pharmaceutically able salt thereof; wherein X1 and X3 independently are CH or N; X2 is CR2 or N; provided one and not more than one of X1, X2 or X3 is N; A is O or S; Y is -CH2- or O; Z is aryl or heterocyclyl; R1, at each occurrence, is independently halo or optionally substituted heterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or -NRaRb; R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally tuted heterocyclyl or -NRaRb; n the substituent is alkyl, amino, halo or hydroxyl; R3, at each occurrence, is alkyl or hydroxyl; Ra and Rb are independently en, alkyl, acyl or heterocyclyl; ‘m’ and ‘n’ are independently 0, 1 or 2; and ‘p’ is 0 or 1.
BRIEF DESCRIPTION OF THE FIGURES depicts the %inhibition of eration in MV4-ll cells by Compound A. depicts the %inhibition of proliferation in MV4-11 cells by nd B. depicts the increase in tumor growth inhibition with increasing doses of Compound A at 12.5, 25, and 50 mpk. depicts the static body weight of animals in an MV4-11 in vivo xenograft model.
(The remainder of this page has been left blank intentionally) s the percent tumor growth inhibition (% TGI) in mice having a subcutaneous MOLM-14 FLT3-ITD tumor. depicts the percent tumor growth inhibition (% TGI) in mice having a MOLM-14 FLT3-ITD/F691L tumor. depicts the percent tumor growth inhibition(% TGI) in mice having a MOLM-14 FLT3-ITD/D835Y tumor.
DETAILED DESCRIPTION Unless d otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning ted in order to facilitate the understanding of the present invention.
The singular forms "a", "an" and "the" encompass plural references unless the context clearly tes otherwise.
As used herein, the terms "optional" or "optionally" mean that the uently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, "optionally substituted alkyl" refers to the alkyl may be substituted as well as where the alkyl is not substituted.
It is understood that substituents and substitution patterns on the nds of the present invention can be selected by one of ordinary skilled person in the art to result chemically stable nds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available ng materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different s, so long as a stable structure results.
As used herein, the term "optionally substituted" refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a ied tuent including, but not limited to: hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, halogen, alkyl, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, cycloalkyl, cycloalkoxy, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, amino, aminoalkyl, alkylamino, lamino, acyl, -C(O)2H, - O(acyl), y1), -N(alkyl)(acyl), cyano, phosphinate, phosphate, onate, sulfonate, sulonamido, sulfate, haloalkyl or haloalkoxy. Preferably, "optionally substituted" refers to the replacement of one to four hydrogen radicals in a given structure With the substituents mentioned above. More preferably, one to three hydrogen radicals are ed by the substituents as mentioned above. It is understood that the tuent can be further substituted.
The term "substituted" refers to moieties having tuents ing hydrogen on one or more carbons of the backbone. It Will be understood that "substitution" or "substituted with" includes the it proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable nd, e. g., which does not spontaneously undergo transformation such as by ngement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and , branched and unbranched, carbocyclic and heterocyclic, aromatic and non- aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible tuents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a rbonyl (such as a thioester, a etate, or a thioformate), an alkoxyl, a oryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It Will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as "unsubstituted," references to chemical moieties herein are understood to include substituted variants. For example, reference to an "aryl" group or moiety itly includes both substituted and unsubstituted variants.
As used herein, the term "alkyl" refers to saturated aliphatic groups, including but not limited to C1-C10 straight—chain alkyl groups or C1-C10 branched-chain alkyl groups. Preferably, the " group refers to C1-C6 straight-chain alkyl groups or C1—C6 branched-chain alkyl groups. Most preferably, the "alkyl" group refers to C1-C4 straight-chain alkyl groups or C1-C4 branched-chain alkyl groups. Examples of "alkyl" include, but are not limited to, methyl, ethyl, l-propyl, 2-propyl, n-butyl, tyl, tert-butyl, l-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, l- hexyl, 2-hexyl, 3-hexyl, 1—heptyl, 2—heptyl, 3-heptyl, 4-heptyl, l—octyl, 2—octyl, 3-octy1 or 4-octyl and the like. The "alkyl" group may be optionally substituted.
The term "acyl" refers to a group R-CO- wherein R is an optionally substituted alkyl group d above. Examples of ‘acyl’ groups are, but not limited to, CH3CO-, CH3CH2CO-, CH3CH2CH2CO- 01' (CH3)2CHCO-.
As used herein, the term "alkoxy" refers to a ht or branched, saturated aliphatic C1- C10 hydrocarbon radical bonded to an oxygen atom that is attached to a core ure. Preferably, alkoxy groups have one to six carbon atoms. es of alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 3- methyl butoxy and the like.
As used herein, the term "haloalkyl" refers to alkyl group (as defined above) is substituted with one or more halogens. A monohaloalkyl l, for example, may have a chlorine, bromine, iodine or ?uorine atom. Dihalo and polyhaloalkyl radicals may have two and more of the same or different halogen atoms respectively. Examples of haloalkyl include, but are not limited to, chloromethyl, romethyl, trichloromethyl, dichloroethyl, dichloropropyl, ethyl, di?uoromethyl, tri?uoromethyl, penta?uoroethyl, hepta?uoropropyl, difluorochloromethyl, dichloro?uoromethyl, difluoroethyl, di?uoropropyl and the like.
As used herein, the term lkoxy" refers to radicals wherein one or more of the hydrogen atoms of the alkoxy group are tuted with one or more halogens. entative examples of lkoxy" groups include, but not limited to, di?uoromethoxy (-OCHFz), trifluoromethoxy (—OCF3) or trifluoroethoxy CF3).
As used herein, the term "aryl" alone or in combination with other term(s) means a 6— to lO-membered carbocyclic aromatic system containing one or two rings wherein such rings may be fused. The term "fused" means that the second ring is ed or formed by having two adjacent atoms in common with the 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 aryl groups described herein may be optionally substituted.
The terms "amine" and "amino" are art—recognized and refer to both tituted and tuted amines and salts thereof, e. g., a moiety that can be represented by R10 R10 / / N or Eli—Rm \RID R10 wherein each R10 independently represents a hydrogen or a arbyl group, or two R10 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring ure.
As used herein, "aminoalkyl" refers to an amino group, as defined above, in which one or two hydrogen atoms are substituted with alkyl group.
As used herein, "nitro" refers to an —N02 group.
As used herein, "alkylamino" and "cycloalkylamino", refer to an up, wherein nitrogen atom of said group being attached to alkyl or cycloalkyl respectively. Representative examples of an "Alkylamino" and "Cycloalkylamino" groups include, but are not limited to - NHCH3 and -NH-cyclopropyl. An amino group can be optionally substituted with one or more of the suitable groups.
As used herein the term "cycloalkyl" alone or in combination with other term(s) means C3—C10 saturated cyclic hydrocarbon ring. A cycloalkyl may be a single ring, which typically contains from 3 to 7 carbon ring atoms. Examples of single-ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. A cycloalkyl may atively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls e bridged, fused, and spirocyclic carbocyclyls.
As used herein, the term " refers to-CN group.
As used herein, the term "hydroxy" or "hydroxyl" refers to -OH group.
As used herein the term xyalkyl" or "hydroxylalkyl" means alkyl substituted with one or more hydroxyl groups, wherein the alkyl groups are as defined above. Examples of "hydroxyalkyl" include but are not limited to hydroxymethyl, hydroxyethyl, hydroxypropyl, propanol and the like.
As used herein, the term "halo" or "halogen" alone or in combination With other term(s) means ?uorine, chlorine, bromine or iodine.
As used herein, the term "heterocyclyl" includes definitions of ocycloalkyl" and "heteroaryl".
As used herein, the term "heterocycloalkyl" refers to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system of 3 to 15 member having at least one heteroatom or group selected from O, N, S, S(O), S(O)2, NH or C(O) with the remaining ring atoms being independently selected from carbon, oxygen, nitrogen, and sulfur. Examples of "heterocycloalkyl" include, but are not limited to azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1 xanyl, dioxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, 2-aza-bicyclo[2.2.2]octanyl, azocinyl, chromanyl, xanthenyl and N-oxides thereof. Attachment of a heterocycloalkyl substituent can occur via either a carbon atom or a heteroatom. A heterocycloalkyl group can be optionally substituted with one or more suitable groups by one or more aforesaid groups.
Preferably "heterocycloalkyl" refers to 5— to 6-membered ring selected from azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, oxanyland N- oxides f. More preferably, ocycloalkyl" es azetidinyl, pyrrolidinyl, morpholinyl and dinyl. All heterocycloalkyl are optionally substituted by one or more aid groups.
As used herein, the term "heteroaryl" refers to an aromatic heterocyclic ring system containing 5 to 20 ring atoms, suitably 5 to 10 ring atoms, Which may be a single ring (monocyclic) or multiple rings (bicyclic, tricyclic or polycyclic) fused er or linked covalently. Preferably, "heteroaryl" is a 5- to 6-membered ring. The rings may contain from 1 to 4 heteroatoms selected from N, O and S, wherein the N or S atom is ally oxidized or the N atom is optionally quarternized. Any suitable ring position of the heteroaryl moiety may be ntly linked to the defined al structure.
Examples of heteroaryl include, but are not limited to: furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, lH-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, othienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, 0t- ine, zinyl, benzoisothiazolyl, benzoxazolyl, pyrrolopyridyl, furopyridinyl, purinyl, benzothiadiazolyl, benzooxadiazolyl, riazolyl, benzotriadiazolyl, carbazolyl, dibenzothienyl, acridinyl and the like. Preferably "heteroaryl" refers to 5- to 6-membered ring selected from furanyl, l, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, lyl, isothiazolyl, lH-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl. More preferably, pyrazolyl, pyridyl, oxazolyl and furanyl. All heteroaryls are optionally substituted by one or more aforesaid groups.
As used herein, the term ‘compound(s)’ comprises the nds disclosed in the present invention.
As used herein, the term "comprise" or "comprising" is generally used in the sense of include, that is to say permitting the presence of one or more features or components.
As used herein, the term "or" means "and/or" unless stated otherwise.
As used herein, the term "including" as well as other forms, such as de7, 6‘includes" and ded" is not limiting.
The phrase "pharmaceutically acceptable" refers to compounds or compositions that are physiologically tolerable and do not typically produce allergic or r untoward reaction, including but not limited to c upset or ess when administered to mammal.
The term aceutically acceptable salt" refers to a product obtained by reaction of the compound of the present invention with a suitable acid or a base. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable nic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts; Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, e, salicylate, citrate, tartrate, henate, bitartrate, ate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate or p- toluenesulfonate salts, and the like. Certain compounds of the invention (can form pharmaceutically acceptable salts with various organic bases such as , arginine, guanidine, diethanolamine or metformin. Suitable base salts include, but are not limited to, aluminum, calcium, m, ium, potassium, sodium, or zinc, salts.
As used herein, the term "stereoisomer" is a term used for all isomers of individual compounds of compound of formula (I) that differ only in the orientation of their atoms in space.
The term stereoisomer includes mirror image isomers (enantiomers) of compounds of the present ion, mixtures of mirror image isomers (racemates, c mixtures) of compounds of the present invention, geometric (cis/trans or E/Z, R/S) isomers of compounds of the present invention and s of compounds of the present invention with more than one chiral center that are not mirror images of one another (diastereoisomers).
In certain embodiments, the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For e, the present invention also embraces isotopically—labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. ary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, ?uorine, chlorine and iodine, such as 2H ("D"), 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32F, 33F, 358, 18F, 36Cl, 123I and 125I. Isotopically labeled compounds of the t inventions can generally be prepared by following procedures well known in the art, such as by substituting an isotopically labeled reagent for a otopically d reagent.
As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, such as a phosphate ed saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. The examples of carriers, stabilizers and adjuvant are mentioned in literature like, Martin, Remington‘s Pharmaceutical Sciences, 15th Ed., Mack Publ. C0., Easton, PA [1975].
The term "treatment"/"treating" means any treatment of a disease in a mammal, including: (a) ting the disease, i.e., slowing or arresting the development of clinical ms; and/or (b) Relieving the disease, i.e., causing the regression of clinical symptoms and/or (c) Alleviating or abrogating a e and/or its attendant symptoms.
As used herein, the term "prevent’3 4‘ , preventing" and "prevention" refer to a method of ting the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease. As used herein, "prevent", "preventing" and "prevention" also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject‘s risk of acquiring a disease.
As used herein, the term "subject" refers to an , preferably a , and most preferably a human.
As used herein, the term, "therapeutically effective amount" refers to an amount of a compound of the present invention or a pharmaceutically acceptable salt or a stereoisomer thereof; or a composition comprising the nd of the present invention or a pharmaceutically acceptable salt or a stereoisomer thereof, effective in producing the d therapeutic se in a particular patient suffering from AML. Particularly, the term "therapeutically effective amount" includes the amount of the compound of the present invention or a pharmaceutically acceptable salt or a stereoisomer f, When administered, that induces a positive modification in the disease or disorder to be treated or is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a subject. In respect of the therapeutic amount of the compound, the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, Within the scope of sound medical judgment can also be ered. The eutically effective amount of the compound or composition Will be varied With the particular condition being treated, the severity of the ion being treated or ted, the duration of the treatment, the nature of concurrent therapy, the age and physical condition of the end user, the specific compound or composition employed the particular pharmaceutically able carrier utilized.
In certain embodiments, compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent. As used herein, the phrase "conjoint administration" refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the usly administered therapeutic compound is still effective in the body (e.g., the two compounds are aneously effective in the subject, which may include synergistic effects of the two compounds). For example, the different therapeutic nds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially. In certain embodiments, the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another. In some embodiments, the additional therapeutic compound is stered within about 5 minutes to within about 168 hours prior to or after stration of the compound of formula I, the compound of a II, or the compound of formula III. Thus, a subject who receives such treatment can benefit from a combined effect of different therapeutic compounds.
In certain embodiments, conjoint administration of compounds of the invention with one or more additional therapeutic agent(s) (e. g., one or more additional chemotherapeutic s)) provides improved efficacy relative to each dual administration of the compound of the invention or the one or more additional therapeutic agent(s). In certain such embodiments, the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound of the invention and the one or more additional therapeutic agent(s).
Provided herein is a method of ng or ting acute myeloid leukemia in a subject, comprising administering a nd of a (I) (MR H N $ @ R.) N\ O or a pharmaceutically acceptable salt thereof; wherein Ring 21 is an optionally substituted aryl; Ring 22 is an optionally substituted heterocycloalkyl, optionally substituted heteroaryl or a direct bond; R1 is alkyl, cyano, -NRaRb, or optionally substituted groups selected from cycloalkyl, aryl or cyclyl; n the tuent, at each occurrence, independently is alkyl, alkoxy, n, hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, -OCO- CH2-O—alkyl, -OP(O)(O—alkyl)2 or —CH2—OP(O)(O-alkyl)2; R2, at each occurrence, independently is an optionally substituted group selected from alkyl or lkyl; wherein the substituent, at each occurrence, is independently halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl or haloalkoxy; R3, at each occurrence, independently is hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, , hydroxyl or hydroxyalkyl; Ra is hydrogen or alkyl; Rb is hydrogen, alkyl, acyl, hydroxyalkyl, —SOz-alkyl or optionally substituted cycloalkyl; ‘m’ and ‘n’ are independently 1 or 2.
In some embodiments, the present methods include a compound of formula (I) or a ceutically acceptable salt thereof; wherein, Ring 21 is a 5- or 6-membered optionally substituted heteroaryl.
In some embodiments, the present methods include a compound of a (I) or a pharmaceutically acceptable salt thereof; wherein Ring Z1 is an optionally substituted heteroaryl; wherein the optional substituent is alkyl.
In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring Z1 is selected from tetrazolyl, thienyl, lyl, yl, pyridyl, pyranyl, pyrazinyl, zinyl, pyrimidyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl and pyrazolyl.
In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt f, wherein Ring Z1 is selected from pyridyl, oxazolyl and furanyl; n the pyridyl group is optionally substituted with alkyl; in particular alkyl is methyl.
In some embodiments, the present s include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring Z2 is a 5- or 6-membered heteroaryl selected from tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl or pyrazolyl.
In some ments, the present methods include a compound of formula (I) or a ceutically acceptable salt thereof, wherein Ring Z2 is a 5- or 6-membered heterocycloalkyl selected from azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl or 1,4-dioxanyl.
In some embodiments, the present s include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring Z2 is pyridyl, pyrazolyl or idinyl.
In some embodiments, the t methods include a nd of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring Z2 is a direct bond.
In some embodiments, the present methods include a compound of formula (I) that is a compound of a (IA) or a pharmaceutically acceptable salt thereof; wherein, Z2, R1, R2, R3, ‘m’ and ‘n’ are same as defined in compound of formula (I).
In some embodiments, the present methods include a compound of a (I) that is a compound of formula (IB) or a pharmaceutically acceptable salt thereof; wherein, 22, R1, R2, R3, ‘m’ and ‘n’ are same as d in compound of formula (I).
In some embodiments, the present methods include a compound of formula (I) that is a compound of formula (IC) N R1 or a pharmaceutically acceptable salt thereof; n, Z2, R1, R2, R3, ‘m’ and ‘n’ are same as defined in compound of formula (I).
In some embodiments, the present methods include a compound of formula (I) wherein (R2 ‘1/ ii/ a: 2/ CCL , N3 \ \ / / R1 / R1 N N R1 is R1 R2 R2 or , , \ E wherein R1, R2 and ‘m’ are same as defined in compound of formula (I).
In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically able salt thereof, wherein Ring Z2 is pyridyl.
In some embodiments, the present methods include a nd of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring 22 is pyrazolyl.
In some embodiments, the present methods include a compound of a (I) or a pharmaceutically acceptable salt thereof, wherein Ring 22 is pyrrolidinyl.
In some ments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted heterocyclyl; wherein the substituent is halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, -OCO-CH2—O- alkyl, (O—alkyl)2 or —CH2-OP(O)(O—all In some ments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is ally substituted azetidinyl, dinyl, morpholinyl, pyrrolidinyl or azepanyl; wherein the substituent is amino, halogen, hydroxyl, hydroxyalkyl, aminoalkyl, -OCO-CH2-O-alkyl, -OP(O)(O-alky1)2 or —CH2-OP(O)(O- alkyl)2.
In some embodiments, the present methods include a compound of a (I) or a ceutically acceptable salt thereof, wherein R1 is optionally substituted piperidinyl; wherein the substituent is hydroxyl.
In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted phenyl; wherein the substituent is halogen.
In some embodiments, the present methods include a compound of formula (I) or a ceutically acceptable salt thereof, wherein R1 is cycloalkyl.
In some ments, the present methods include a compound of formula (I) or a ceutically acceptable salt thereof, wherein R1 is cyclopropyl or cyclohexyl.
In some embodiments, the t methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is -NRaRb; Ra is hydrogen; Rb is optionally substituted cycloalkyl; wherein the substituent is yl.
In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is cyano.
In some embodiments, the present s include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 is optionally substituted alkyl; wherein substituent is alkoxy.
In some embodiments, the present methods include a compound of a (I) or a pharmaceutically acceptable salt thereof, wherein R2 is cycloalkyl.
In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen, halogen, alkyl, alkoxy, - NRaRb, hydroxyl or hydroxyalkyl; Ra is hydrogen or alkyl; and Rb is en, alkyl, acyl, hydroxyalkyl or —SO2-alkyl.
In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring 21 is optionally substituted pyridyl; Ring Z2 is l, pyrazolyl, pyrrolidinyl or 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, , hydroxyl or hydroxyalkyl; R21 is hydrogen or alkyl; and Rb is hydrogen or hydroxyalkyl.
In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring Z1 is oxazolyl; Ring 22 is pyridyl, pyrazolyl or pyrrolidinyl; R1 is cyano, -NRaRb, or an optionally substituted group selected from cyclopropyl, cyclohexyl, phenyl, azetidinyl, piperidinyl, morpholinyl or pyrrolidinyl; R2 is optionally substituted alkyl or cycloalkyl; R3 is hydrogen, n, alkyl, alkoxy, -NRaRb, hydroxyl or yalkyl; Ra is en or alkyl; and Rh is en, alkyl, acyl, hydroxyalkyl, —SOz-alkyl or ally tuted cycloalkyl.
In some embodiments, the present methods include a s compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R3 is -NRaRb; Ra is hydrogen or alkyl; and Rh is en, alkyl, acyl, hydroxyalkyl, lkyl or optionally substituted cycloalkyl; wherein the optional substituent is hydroxyl; In some embodiments, the t methods include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ‘n’ is 1.
In some embodiments, the present s include a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ‘n’ is 2.
In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt f, wherein ‘m’ is 1.
In some embodiments, the present methods include a compound of formula (I) or a pharmaceutically acceptable salt f, n ‘m’ is 2.
In some embodiments, the present methods include a compound of formula (I) selected from: N-(2-methyl(piperidin-l-yl)—2H-indazolyl)(1H-pyrazolyl) picolinamide; N—(2-methyl(piperidin- l -yl)—2H-indazolyl)(2—methylpyridin—4-yl) oxazole—4-carboxamide; N—(l-methyl(piperidinyl)—1H-indazolyl)(2—methylpyridin—4-yl) oxazole—4-carboxamide; N-(2-cyclopenty1(piperidiny1)-2H-indazolyl)(2-methylpyridin yl) oxazolecarboxamide; N-(6-cyanocyclopentyl-ZH—indazol—S-yl)-2—(2-methylpyridinyl) oxazole—4-carboxamide; N—(2-cyclopentylcyclopropyl-ZH-indazol-S-yl)(2-methylpyridinyl) e—4—carboxamide; N-(2-cyclopentylcyclopropyl-2H-indazolyl)( l H-pyrazolyl) picolinamide; N-(2-cyclopentylmorpholino-2H-indazol-5—yl)(2-methylpyridinyl) oxazole—4-carboxamide; 6‘—amino—N—(2-cyclopentylmorpholino-2H—indazol—5-yl)-[2,3‘- bipyridine] carboxamide 2,2,2-trifluoroacetate; N-(6-(3-?uoropheny1)methyl-2H-indazoly1)(2-methylpyridin yl)oxazolecarboxamide; N-(6-cycloheXylmethyl-2H—indazolyl)—2—(2-methylpyridin zolecarboxamide hydrochloride; ro-N-(2-methyl(piperidin- l -yl)-2H-indazol—5-yl)- [2,3‘-bipyridine] — 6—carboxamide hydrochloride; N-(6-cycloheXyl—2-methyl-2H—indazol—5-yl)-6—( l H-pyrazol-4— yl)picolinamide hydrochloride; 2‘—?uoro—N-(2-methyl-6—(piperidiny1)—2H-indazol-5—yl)- [2,3‘-bipyridine] — 6-carboxamide; 2-(2-chloropyridin-4—yl)-N—(2—methyl—6-(piperidin- l —yl)-2H—indazol—5- yl)oxazolecarboxamide hydrochloride; N—(6-cyclopropylmethyl-2H-indazolyl)—2-(2-methylpyridin-4— yl)oxazolecarboxamjde hydrochloride; N—( l -cyclopentylcyclopropyl- l zol-S-yl)( 1 -methyl- lH-pyrazol- 4-yl)picolinamide; N-(2-cyclopentylcyclopropyl-ZH-indazol-S-yl)( 1 l- lH-pyrazol- 4-yl)picolinamide; 6—(1-methyl-lH—pyrazolyl)-N-(2-methyl-6—(piperidin-l-yl)-2H-indazol-5— yl)picolinamide; N—(2-cyclopentyl—6-cyclopropyl—2H-indazol-5—yl)(6—methoxypyridin yl)oxazolecarboxarnide; 2-(6-methoxypyridin—3—yl)-N—(2-methyl(piperidin— l -yl)—2H-indazol yl)oxazolecarboxamide; N—(2-methyl-6—(piperidin— l -yl)-2H-indazol-5—yl)(3—methylpyridin yl)oxazolecarboxamjde; 6-bromo-N—(2-methyl(piperidin- l -yl)-2H-indazol—5-yl)picolinamide; romethyl-N—(2-methy1(piperidin- 1-yl)-2H-indazol olinamide N—(2-methyl-6—(piperidin— l -yl)-2H-indazol-5—yl)(6-methylpyridin-3 - yl)oxazolecarboxarnide; N—(2-cyclopentylcyclopropyl-ZH-indazol-S-yl)(2-methylpyridin yl)oxazolecarboxamjde; N—(2-cyclopentylcyclopropyl-ZH-indazol-S-yl)(3-methylpyridin yl)oxazole-4—carboxamide; N-(2-cyclopentylcyclopropyl-ZH-indazol-S-yl)(6-methylpyridin yl)oxazolecarboxamide; 6'-aminomethyl-N—(2-methyl(piperidin- 1-yl)-2H-indazolyl)—[2,3‘- bipyridine] carboxamide hydrochloride; yl( l-methyl- 1H-pyrazolyl)-N—(2-methyl(piperidin- 1-yl)-2H- indazol—S-yl)picolinamide; N—(1-cyclopropyl(piperidinyl)-lH-indazol-S-yl)—2-(2-methylpyridin-4— yl)oxazolecarboxamjde hydrochloride; 2—(2-hydroxypyridin-3 -yl)-N-(2—methyl—6-(piperidin- l —yl)-2H—indazol yl)oxazolecarboxarnide; (S)(3-aminopyrrolidinyl)-N-(2-methy1(piperidinyl)-2H—indazol- icolinamide 2,2,2—trifluoroacetate; (S)(1—(2-hydroxypropyl)-1H-pyrazolyl)—N—(2-methyl—6-(piperidin yl)-2H-indazolyl)picolinamide; N—(l,6-dicyclopropyl-1H-indazol-S-yl)(6-methoxypyridinyl)oxazole- 4—carboxamide; N-(l,6-dicyclopropyl-1H-indazol-S-yl)(2-methylpyridin-4—yl)oxazole carboxamide hydrochloride; (S)-N—(6—cyclopropyl-1—methyl-1H-indazol-S—yl)(3-hydroxypyrrolidin-lyl )picolinamide; (R)(3—hydroxypyrrolidin- 1-yl)-N—(2—methyl—6-(piperidin- 1—yl)-2H— indazol-S-yl)picolinamide; (S)(3-hydroxypyrrolidinyl)-N—(2-methyl(piperidiny1)-2H- l-S -yl)picolinamide; 6-(3 -hydroxypyrrolidin—l-yl)—N-(2-methyl-6—(piperidinyl)-2H-indazol-5— olinamide; (S)(3—aminopyrrolidin—l-yl)-N—(6-cyclopropylmethyl-1H-indazol yl)picolinamide; (R)(3-aminopyrrolidinyl)—N-(2-methyl(piperidin-l-yl)-2H-indazol- -y1)picolinamide; (R)(1—(2-hydroxypropyl)- 1H-pyrazolyl)—N—(2-methyl-6—(piperidin-l- y1)-2H-indaz01y1)picolinamide; (S)(3—amin0pyrr01idiny1)-N-(2-methy1(piperidinyl)-2H-indaz01— —y1)0Xazolecarb0xamide; yclopr0py1methy1-1H-indazoly1)(2-methylpyridin zolecarb0xamide; (S)-N—(6—cyclopr0py1-1—methy1—1H-indaz01—5—y1)(1-(2-hydr0xypr0py1)- 1H-pyrazolyl)picolinamide; (S)-N—(6—Cyclopr0py1-2—methy1—2H-indaz01—5—y1)(1—(2-hydr0xypr0pyl)- 1H-pyrazolyl)picolinamide; (S)(3-amin0pyrr01idiny1)-N-(6-Cyclopropylmethy1-2H-indazol yl)picolinamide; (S)-N—(6-cyclopr0py1—2—methyl-2H-indaz01-5—y1)(3—hydr0xypyrrolidin- 1— y1)picolinamide; (S)-N—(6-Cyclopr0py1methyl-1H-indazol-S—y1)(3—hydr0xypyrr01idin-1— yl)0xazole0arboxamjde; (S)(3-amin0pyrr01idiny1)—N—(6-cyclopr0py1methy1-1H-indaz01 yl)0xazolecarb0xamide; (S)(3—hydr0xypyrr01idiny1)-N—(2—methy1(piperidin-1—y1)-2H— indazol—S-y1)0xazole-4—carb0xamide; (S)-N—(6—Cyclopr0py1-1—methy1—1H-indaz01—5—y1)( 1—(2-hydr0xypr0py1)- 1H-pyrazolyl)0xazolecarb0xamide; (S)(3-amin0pyrr01idiny1)-N-(6-Cyclopropyl-Z-methyl-ZH-indazol yl)0xazole0arboxamide; (S)-N—(6-cyc10pr0py1—2—methyl-2H-indaz01-5—y1)-2—(3—hydr0xypyrrolidin- 1— yl)0xaz01€carb0xamide; (S)(1—(2-hydr0xypr0py1)-1H-pyraz01y1)—N-(2-methy1(piperidin y1)-2H-indaz01-5—y1)picolinamide; hydr0xypropyl)amino)-N-(2-methy1(piperidiny1)-2H-indaz01 yl)picolinamide; N-(6-(4-hydr0xypiperidiny1)—2-methy1-2H-indaz01—5-y1)-2—(2- pyridin-4—y1)0xazolecarb0xamide; N—(6-(azetidiny1)methy1—1H-indazol-S-y1)(2—methy1pyridin—4- zole—4-0arboxamjde; N-(6-(azetidiny1)methy1-2H-indaz01y1)(2-methy1pyridin yl)0xazolecarb0xamide; N—(6-(3-hydr0xyazetidin- 1-y1)—2-methy1-2H-indaz01y1)(2- methylpyridin-4—y1)0xazole-4—carb0xamide; N—(1-methy1—6-(pyrr01idiny1)—1H-indazol-5—y1)(2—methylpyridin—4- yl)0xazole0arboxamide; N-(2-methy1—6-(pyrr01idinyl)-2H—indaz01y1)(2-methylpyridin yl)0xazole0arboxamide; (S)-N—(6-(3-hydr0xypyrrolidin—1-y1)—2-methyl-2H-indaz01-5—y1)(2- methylpyridin-4—y1)0xazolecarb0xamide; (R)-N—(6-(3-hydr0xypyrr01idiny1)methy1-2H-indaz01—5-y1)(2- methylpyridin-4—yl)0xazolecarb0xamide; N-(2-methy1(piperidiny1)—2H-indaz01y1)-5 -(2—methy1pyridin yl)furan—2-carb0xamide; N-(6-(4-hydr0xypiperidin- 1-y1)—2-methy1-2H-indaz01—5-y1)(2- methylpyridin-4—yl)furan—2-carb0xamide; N—(6-(3-hydr0xypiperidin- 1-y1)—2-methy1-2H—indaz01—5-y1)-2—(2- methylpyridin-4—y1)0xazolecarb0xamide; (R)-N—(6-(3-hydr0xypiperidiny1)methy1-2H-indaz01y1)(2- pyridin-4—yl)furancarb0xamide; N—(6-(3—hydr0xypiperidin— 1 -y1)methy1-2H—indaz01y1)—5-(2- methylpyridin-4—yl)furancarb0xamide; N—(6-(azepan-1—y1)methy1-2H-indaz01—5-y1)(2-methy1pyridin yl)0xazole0arboxamjde; N—(6-(azepany1)methy1-1H-indazol-S-y1)(2-methy1pyridin yl)0xazole-4—carboxamide; N-(2,3 -dimethy1(piperidiny1)-2H—indaz01y1)(2-methylpyridin yl)0xaz01ecarb0xamide; N—(1,3 -dimethyl(piperidiny1)-1H-indazol-S-y1)—2-(2-methy1pyridin yl)0xaz01e—4-carb0xamide; N-(6-(4-hydr0xypiperidiny1)(2-meth0xyethy1)-lH-indazol-S -y1)(2- pyridin—4—yl)0xazole-4—carb0xamide; N—(6-(4-hydr0xypiperidiny1)(2-meth0Xyethy1)-2H-indaz01y1)(2- methylpyridin-4—y1)0xazole-4—carb0xamide; N—(6-(4-hydr0xypiperidiny1)—1-methy1-1H—indaz01—5-y1)-2—(2- methylpyridin-4—y1)0xazolecarb0xamide; N-(6-(4-?u0r0piperidiny1)methy1-1H-indaz01y1)(2- methylpyridin-4—y1)0xazolecarb0xamide; N—(6-(3 —?u0r0piperidiny1)—2—methy1-2H-indazoly1)-2—(2- methylpyridin-4—y1)0xazolecarb0xamide; N—(6-(4—(hydr0xymethy1)piperidiny1)methy1-2H-indaz01-5 -y1)—2-(2- methylpyridin-4—yl)0xazolecarb0xamide; N-(6-(4-hydr0xypiperidiny1)-1,3-dimethy1-1H-indaz01y1)(2- methylpyridin—4—yl)0xazole-4—carb0xamide; N-(6-(3-(hydroxymethy1)piperidiny1)methy1-2H-indaz01y1)(2- methylpyridin-4—y1)0xazole-4—carb0xamide; 4-hydr0xypiperidiny1)—2,3-dimethy1-2H-indaz01y1)(2— methylpyridin-4—y1)0xazolecarb0xamide; 2-(2-acetamid0pyridiny1)-N-(2-methy1(piperidiny1)-2H-indaz01 yl)0xaz01ecarb0xamide; 2-(2-acetamid0pyridin—4-y1)-N—(6-(3—flu0r0piperidin— 1-y1)-2—methy1—2H- l-S-y1)0xazole-4—carb0xamide; 2-(2-aminopyridiny1)-N-(2—methy1—6-(piperidin-1—y1)-2H—indaz01—5- yl)0xaz01ecarb0xamide hydrochloride; N—(6-(4-?u0r0piperidiny1)-1,3-dimethy1-1H-indaz01y1)—2-(2- methylpyridin—4—y1)0xazole—4—carb0xamide; N-(6-(((1R,4R)hydr0xycyclohexyl)amino)—2-methy1-2H-indaz01y1) (2-methylpyridinyl)oxazole—4-carboxamide; N—(6-(4—(hydroxymethyl)piperidinyl)-l-methyl- lH-indazol-S -yl)—2-(2- methylpyridin-4—yl)oxazolecarboxamide; 2-(2-aminopyridinyl)-N—(6-(4-fluoropiperidiny1)methyl-2H- l—S-yl)oxazole—4—carboxamide hydrochloride; N—(6-(4-?uoropiperidin— l -yl)-2—methyl-2H-indazol-5—yl)(2- methylpyridin-4—yl)oxazole-4—carboxamide hydrochloride; (S)-N—(6—(4-(hydroxymethyl)piperidin—1-yl)-2—methyl—2H-indazol-5—yl) (l-(2-hydroxypropyl)-1H-pyrazolyl)picolinamide; 2-(2-aminopyridinyl)-N—(6-(4-hydroxypiperidiny1)methy1-2H- indazol-S -yl)oxazolecarboxamide hydrochloride; N—(6-(4—(hydroxymethyl)piperidin- l —yl)- l -(2—methoxyethyl)— l H-indazol-S— yl)(2-methylpyridinyl)oxazole-4—carboxamide; (6-(4-(hydroxymethyl)piperidin-l-yl)methyl-lH-indazol-S—yl) ( 1—(2-hydroxypropyl)- 1H-pyrazolyl)picolinamide; N-(6-(4-(hydroxymethyl)piperidinyl)(2-methoxyethyl)-2H-indazol yl)(2—methylpyridin—4-yl)oxazole—4-carboxamide; N-(6-(4-(hydroxymethyl)piperidinmethyl-2H-indazol-5 -yl)(2- methoxypyridinyl)oxazole—4-carboxarnide; 2—(2-acetamidopyridin-4—yl)-N—(6-(4-(hydroxymethyl)piperidinyl)—2- methyl-2H-indazolyl)oxazolecarboxamide; 2-(2-aminopyridinyl)-N-(6-(4-(hydroxymethyl)piperidiny1)methyl- 1H-indazol-S-y1)oxazolecarboxamide hloride; minopyridinyl)-N—(6—(4-(hydroxymethyl)piperidin—1-yl)-2—methyl— 2H-indazoly1)oxazolecarboxamide hydrochloride; N—(6-(4—hydroxypiperidinyl)methyl- 1 H—indazol-S-yl)-2—(2- methoxypyridin—4-yl)oxazole-4—carboxamide; 2-(2-aminopyridinyl)-N—(6-(3 -hydroxypiperidin- l-yl)methyl-2H- indazol—S-y1)oxazole—4—carboxamide hydrochloride; 2-(2-methoxypyridin-4—yl)-N—(2-methyl(piperidin- l -yl)-2H-indazol zolecarboxamide; 2-(2-aminopyridinyl)-N—(6-(3 piperidin- l -y1)methyl-2H- indazol-S—y1)oxazole-4—carboxamide hydrochloride; (R)(2-aminopyridinyl)-N-(6-(3-hydroxypyrrolidin- l -yl)methyl-2H- indazol—S-yl)oxazole—4—carboxamide hydrochloride; l—( l ,3-dimethyl—5-(2-(2—methylpyridin—4-yl)oxazolecarboxamido)— 1H- indazol—6-yl)piperidin—4-yl 2-methoxyacetate; N—(6-(4-hydroxypiperidin- l -yl)—2-methyl-2H—indazol—5-yl)-2—(2- methoxypyridinyl)oxazolecarboxamide hydrochloride; N-(6-(4-aminopiperidiny1)(2-methoxyethy1)-1H-indazolyl)(2- methylpyridin-4—yl)oxazolecarboxamide hydrochloride; N—(6-(4—aminopiperidin- 2-methyl-2H—indazol—5-yl)-2—(2- methylpyridin-4—yl)oxazolecarboxamide hydrochloride; N—(6-(4—(hydroxymethyl)piperidin- l -yl)- l-(2—methoxyethyl)—3-methyl- 1H- indazol-5—y1)(2-methylpyridinyl)oxazole—4-carboxamide; 4-(hydroxymethyl)piperidin- l -yl)- l ,3-dimethyl- lH-indazol-S-yl) (2-methylpyridinyl)oxazole—4-carboxamide; 2-(2-aminopyridinyl)-N—(6-(4-(hydroxymethyl)piperidin- l -yl)- l ,3- dimethyl- lH-indazol-S—yl)oxazolecarboxamide; N—(6-(4-hydroxypiperidin- l -yl)— 1 -methyl- 1 H—indazol—S-yl)-2—(2- hydroxypyridin—4-yl)oxazolecarboxamide; 2-(2,6-dimethylpyridinyl)-N-(6-(4-hydroxypiperidin- l -yl)methyl- 1H- indazol-S -yl)oxazolecarboxamide; (S)-N—(6-(3-hydroxypyrrolidin—l-yl)—1-methyl-lH-indazol-S—yl)-2—(2- methylpyridin-4—yl)oxazolecarboxamide; N—(6-(4—hydroxypiperidin- l -yl)- l -(2-methoxyethyl)methyl- lH-indazol-S- (2—methylpyridin—4—yl)oxazole-4—carboxamide; N—(l-(2-hydroxyethyl)(4-hydroxypiperidin-l-yl)-1H-indazolyl)(2- methylpyridin—4—yl)oxazole—4—carboxamide; N-(6-(4-aminopiperidin- l-yl)-2—(2-methoxyethyl)-2H-indazol-S-yl)(2- methylpyridin-4—yl)oxazolecarboxamide hydrochloride; 2-(2,6-dimethylpyridin—4-yl)-N-(2-methyl(piperidinyl)—2H-indazol yl)oxazole—4-carboxamjde hydrochloride; 2-(2-(dimethylamino)pyridinyl)-N—(2-methyl(piperidin- 1 H- indazol—S-yl)oxazole—4—carboxamide; N—(6-(4-hydroxypiperidinyl)methyl- 1 H-indazol—S-yl)-2—(2- (methylamino)pyridin—4-yl)oxazole-4—carboxamide; N—(2-methyl(piperidinyl)—2H-indazolyl)(2— (methylamino)pyridinyl)oxazole-4—carboxamide; N-(6-(4-hydroxypiperidinyl)rnethy1-2H-indazoly1)(2- lsulfonamido) pyridinyl) ecarboxamide; 2-(2-(dimethylamino) pyridin-4—yl)-N—(6-(4-hydroxypiperidin- l -yl)— 1 - methyl- lH-indazol-S-yl) oxazolecarboxamide; N—(6-(4—(aminomethyl)piperidinyl)— l -(2-methoxyethyl)- 1 H-indazol-S - yl)—2-(2—methylpyridin—4—yl)oxazole-4—carboxamide; 2-(2,6-dimethylpyridinyl)-N-(6-(4-hydroxypiperidinyl)methyl-2H- indazol—S-yl) oxazole—4—carboxamide; 2-(2,6-dimethylpyridin—4-yl)-N-(6-(4-?uoropiperidin—l-yl)-2—methyl-2H- indazol—S-yl) oxazole-4—carboxamide; Diethyl (l-( 1 -methyl—5 -(2-(2—methylpyridin—4-yl)oxazole-4—carboxamido)— 1H-indazolyl)piperidinyl) phosphate; and Diethyl ((1-(2-methyl(2-(2-methylpyridiny1) oxazolecarboxamido)- 2H-indazoly1) piperidinyl) methyl) phosphate; or a pharmaceutically acceptable salt or a stereoisomer thereof.
Provided herein is a method of ng or preventing acute myeloid ia in a subject, comprising administering a compound of formula (II): o R)" m X NH A 3\ Mm:WIIX or a pharmaceutically acceptable salt thereof; wherein, X1 and X3 independently are CH or N; X2 is CR2 or N; ed one and not more than one of X1, X2 or X3 is N; A is O or S; Y is -CH2- or O; Ring Z is aryl or heterocyclyl; R1, at each occurrence, is independently halo or optionally substituted heterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or —NRaRb; R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally tuted heterocyclyl or -NRaRb; wherein the substituent is alkyl, amino, halo or yl; R3, at each occurrence, is alkyl or hydroxyl; Ra and Rb are ndently hydrogen, alkyl, acyl or heterocyclyl; ‘m’ and ‘n’ are independently O, 1 or 2; ‘p’ is 0 or 1.
In some ments, the present methods include a compound of formula (II) or a {IIII: pharmaceutically able salt thereof, wherein the group is _ _ N/ N R2 R2 R2 9 ’ 30615\N / N or «Off\N / ; wherein R2 are as defined in compound of a (II).
In some embodiments, the t methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein the Ring Z is aryl or 5 - or 6-membered heterocyclyl.
In some embodiments, the present methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein the Ring Z is phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, razolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl,1,4-dioxanyl, dioxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl or dihydropyranyl; each of which is optionally substituted with alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl or —NRaRb; R21 and Rh are independently are hydrogen, alkyl or acyl.
In some embodiments, the t methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein the Ring Z is phenyl, oxazolyl, furanyl, l or pyridyl; each of which is optionally tuted with one or more R1.
In some embodiments, the present methods e a nd of formula (II) or a Y\ N—E— pharmaceutically acceptable salt f, wherein T" is (RafN- —g O/—\N- — (RslmX—/ 7 gor (Rslm/l:/\N—§— wherein R3 and ‘m’ are defined in compound of formula (II).
In some embodiments, the present methods include a compound of formula (II) that is a compound of formula (HA): 0 1%(Ron W—\ A NH (R3)m N N R2 (IIA) or a ceutically acceptable salt f; wherein, A, Y, R1, R2, R3, ‘m’, ‘p’ and ‘n’ are same as defined in compound of formula (II).
In some embodiments, the present methods e a compound of formula (II) that is a compound of formula (IIB): (R1 )n O \ A NH Y N—<\ | ‘—’ N N R2 (118) or a pharmaceutically acceptable salt thereof; wherein, A, Y, R1, R2 and ‘n’ are same as defined in compound of formula (II).
In some embodiments, the present methods include a compound of formula (II) that is a compound of formula (IIC): (IIC) or a pharmaceutically acceptable salt f; wherein, A, Y, R1, R2, R3 and ‘n’ are same as defined compounds of formula (I).
In some embodiments, the t methods include a compound of formula (II), (IIA), (IIB), or (IIC) or a pharmaceutically acceptable salt thereof, wherein Y is O or CH2.
In some embodiments, the t methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted heterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, yl, hydroxyalkyl or -NRaRb; Ra and Rh are independently hydrogen, alkyl or acyl.
In some embodiments, the t methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R1 is pyridyl, pyrazolyl, pyrrolidinyl or piperidinyl; each of which is optionally tuted with alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl or -NRaRb; Ra and Rh are independently hydrogen or acyl.
In some embodiments, the present methods include a compound of formula (II) or a pharmaceutically able salt thereof, wherein R2 is hydrogen.
In some embodiments, the present methods include a nd of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is optionally substituted cycloalkyl.
In some embodiments, the present s include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is cyclopropyl.
In some embodiments, the present methods include a nd of formula (II) or a pharmaceutically able salt thereof, wherein R2 is optionally substituted heterocyclyl; wherein the substituent is alkyl, amino, halo or hydroxyl.
In some embodiments, the present methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolyl, furanyl, pyridyl, azepanyl or azabicyclo[3.2.l]octanyl; wherein the substituent is alkyl, amino, halo or hydroxyl.
In some embodiments, the present methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is optionally substituted aryl; wherein the substituent is halo.
In some embodiments, the t s include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is optionally substituted phenyl; wherein the substituent is fluoro.
In some embodiments, the present methods include a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is ; wherein Ra and Rb are independently hydrogen or heterocyclyl.
In some embodiments, the present methods e a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R2 is -NRaRb; wherein Ra and Rb are independently hydrogen or pyrrolidinyl.
In some embodiments, the present methods include a compound of formula (IIA) or a pharmaceutically acceptable salt thereof, wherein A is O or S; Y is —CH2- or 0; R1 is halo, pyridyl, pyrazolyl, idinyl each of which is ally substituted with alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl or ; R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted cyclyl or —NRaRb; wherein the substituent is alkyl, amino, halo or yl; Ra and Rh are independently hydrogen or alkyl.
In some embodiments, the t methods include a compound of formula (IIB) or a pharmaceutically acceptable salt thereof, wherein A is O or S; Y is -CH2- or 0; R1 is pyridyl, lyl, pyrrolidinyl; each of which is ally substituted with alkyl, hydroxyl, hydroxyalkyl or -NRaRb; Ra and Rh are independently hydrogen; R2 is hydrogen, optionally substituted lkyl, optionally substituted aryl, optionally substituted heterocyclyl or -NRaRb; wherein the substituent is alkyl, amino, halo or hydroxyl; R5,l and Rh are ndently hydrogen, alkyl, acyl or heterocyclyl.
In some embodiments, the present methods e a compound of formula (IIA), (IIB) or (IIC), or a pharmaceutically acceptable salt thereof, wherein ‘n’ is 0, l or 2.
In some embodiments, the present methods include a compound of formula (IIA) or (IIB), or a pharmaceutically acceptable salt thereof, wherein ‘p’ is 0 or 1.
In some ments, the t methods include a compound of formula (IIA) or (IIB), or a pharmaceutically acceptable salt thereof, wherein ‘m’ is 0 or 2.
In some embodiments, the present methods include a compound of formula (II) selected from: 6‘-amino-N—(2-morpholinooxazolo[4,5-b]pyridinyl)-[2,3‘-bipyridine]—6- carboxamide; 6‘-amino-N—(5-cyclopropyl-2—morpholinooxazolo[4,5-b]pyridin-6—yl)- [2,3‘- bipyridine] carboxamide hloride; N—(S-cyclopropy1morpholinooxazolo[4,5-b]pyridinyl)(2-methylpyridin yl)oxazolecarboxamide hydrochloride; N—(2,5-di(piperidin—1-yl)oxazolo[4,5-b]pyridin-6—yl)(lH-pyrazolyl)picolinamide hydrochloride; -di(piperidinyl)oxazolo[4,5-b]pyridinyl)(2-methylpyridin yl)oxazole-4—carboxamide; N-(2-morpholino(piperidin- l -yl)oxazolo[4,5-b]pyridin—6-yl)-6—( l H-pyrazol-4— yl)picolinamide; ethylpyridin—4-yl)-N—(2-morpholino—5-(piperidin- l—yl)oxazolo[4,5-b]pyridin yl)oxazole-4—carboxamide; 6-chloro-N-(2-morpholino(piperidin- l azolo [4, 5-b]pyridinyl)picolinamide; N—(2,5-di(piperidin—1-yl)oxazolo[4,5-b]pyridin-6—yl)(l—methyl—lH-pyrazol-4— yl)picolinamide; 2-(2-chloropyridinyl)-N—(2,5-di(piperidin- l -yl)oxazolo[4,5 -b]pyridinyl)oxazole- 4-carboxamide; (S)-2—(2-methylpyridinyl)—N—(2-morpholino(pyrrolidinylamino)oxazolo[4,5- b]pyridinyl)oxazolecarboxamide; 6‘-amino-N-(2—morpholinooxazolo[5 ,4-b]pyridin-5—yl)-[2,3‘—bipyridine]-6— carboxamide; 6‘-amin0-N—(2-m0rph01in0thiaz010[4,5-C]pyridiny1)-[2,3‘-bipyridine]—6- amide; 6‘-amin0-N—(2-m0rph01in0thiaz010[5,4-b]pyridiny1)-[2,3‘-bipyridine] carboxamide; ethylpyridiny1)-N-(2-m0rph01in0thiazolo[4,5-b]pyridiny1)0xazole-4— carboxamide; 6‘-amino-N-(2—m0rph01in0thiaz010[4,5-b]pyridin-6—y1)-[2,3‘-bipyridine] -6— carboxamide; N—(2-morph01in0thiazolo[4,5-b]pyridinyl)(1H-pyrazoly1)picolinamide; 3-(4-(amin0methy1)piperidin— 1-y1)f1u0r0—N—(2-m0rph01in0thiazolo[4,5—b]pyridin- 6-y1)benzamide; 2-(4-(amin0methy1)piperidin—1-y1)-5—?u0r0—N-(2-m0rph01in0thiazolo[4,5—b]pyridin- 6-y1)benzamide; 2-(2-methylpyridiny1)-N—(2-m0rph01in0—5 -(piperidin-1—y1)thiazolo[4,5-b]pyridin yl)oxazole-4—Carboxamide; N—(Z-morpholino-S-(piperidiny1)thiaz010[4,5-b]pyridiny1)-6—(1H-pyraz01 yl)picolinamide; N—(2,5-di(piperidin-1—y1)thiaz010[4,5-b]pyridiny1)(1H-pyrazol y1)picolinamide; -di(piperidin— 1 -y1)thiazolo[4,5-b]pyridin-6—y1)(2—methy1pyridin—4- yl)OxazoleCarboxamide; N-(2,S-dimorpholinooxazolo[4,5-b]pyridin—6-yl)-2—(2-methylpyridinyl)OXazole carboxamide; N—(5-(4-methylpiperaziny1)m0rph01in00xaz010[4,5-b]pyridiny1)—2-(2- methylpyridiny1)0xazolecarboxamide; N—(2,5-di(piperidiny1)0Xazolo[4,5-b]pyridiny1)(6-meth0xypyridin y1)0Xazole-4—carb0xamide; N—(2,5-di(piperidin- 1—y1)0xaz010[4,5-b]pyridiny1)(2-methy1pyridin—3 - yl)oxazole-4—Carboxamide; N—(2,5-di(piperidiny1)0xaz010[4,5-b]pyridiny1)(2—hydr0xypyridin yl)Oxazole-4—Carboxamide; 2-(2-hydr0xypyridin—3-y1)-N-(2-m0rph01in0(piperidiny1)0xaz010[4,5-b]pyridin- 6-y1)0xazole—4-carb0xamide; N—(2,5-di(piperidin- xaz010[4,5-b]pyridiny1)(6-hydr0xypyridin yl)0xazole-4—carb0xamide; 2-(2-meth0xypyridin—4-y1)-N—(2-m0rph01in0(piperidin-1—y1)0xaz010[4,5-b]pyridin- 6-y1)0Xazole—4-carb0xamide; ethy1pyridiny1)-N-(2-m0rph01in0(piperidin- 1-y1)0xazolo[4,5-b]pyridin yl)oxazoleCarboxamide; 2-(3—methy1pyridin—4—y1)-N—(2-m0rph01in0—5-(piperidin-1—y1)0Xazolo[4,5-b]pyridin yl)oxazoleCarboxamide; N—(2,5-di(piperidiny1)0Xazolo[4,5-b]pyridiny1)(3—methy1pyridin—4- yl)Oxazole-4—Carboxamide; 2-(6-methylpyridiny1)-N-(2-m0rph01in0(piperidiny1)0xa2010[4,5-b]pyridin yl)oxazole—4—Carboxamide; 6-( 1-methy1-1H-pyraz01y1)-N—(2—m0rph01in0(piperidiny1)0xaz010[4,5- b]pyridiny1)picolinamide; N—(2,5—di(piperidin- 1—y1)0xaz010[4,5—b]pyridiny1)(6—methy1pyridin—3 - yl)oxazole-4—carboxamide; (S)-N-(5-(3-amin0pyrr01idiny1)m0rpholin00xaz010[4,5-b]pyridinyl)(2- methylpyridiny1)0xazolecarb0xamide; (S)-N—(5-(3 xypyrr01idin—1-y1)m0rph01in00xaz010[4,5-b]pyridin—6-y1)—2-(2- methylpyridiny1)0xazolecarb0xamide; (R)-N-(5-(3-amin0pyrr01idiny1)m0rph01in00xaz010[4,5 -b]pyridiny1)(2- methylpyridin-4—y1)0xazole—4-carb0xamide; (R)-N—(5-(3-hydr0xypyrr01idiny1)—2-m0rph01in00xaz010[4,5-b]pyridin—6-y1)-2—(2- methylpyridiny1)0xazole—4-carb0xamide; (S)(3-amin0pyrr01idiny1)-N-(2-m0rph01in0(piperidinyl)0xazolo[4,5- b]pyridinyl)oxazolecarboxamide; (S)(3-hydroxypyrrolidinyl)-N—(2-morpholino-5 -(piperidin- l -yl)oxazolo[4,5- din-6—yl)picolinamide; (S)(3-aminopyrrolidin- l -yl)-N—(2-morpholino-5—(piperidin- l -yl)oxazolo[4,5- b]pyridinyl)picolinamide; (S)(3-hydroxypyrrolidiny1)-N-(2-morpholino-5 -(piperidiny1)oxazolo[4,5- b]pyridinyl)oxazolecarboxamide; (S)-N-(5-cyclopropyl-Z-morpholinooxazolo[4,5-b]pyridinyl)(3- hydroxypyrrolidin- 1 —yl)oxazolecarboxamide; (S)(3-aminopyrrolidin- l —(5-cyclopropylmorpholinooxazolo[4,5-b]pyridin- 6-yl)oxazole—4-carboxamide; 2-(2-methy1pyridiny1)-N-(5-(piperidin- 1-y1)(pyrrolidin- 1-y1)oxazolo[4,5- b]pyridinyl)oxazolecarboxamide hydrochloride; N-(2—(2,6-dimethylmorpholino)-5—(piperidin- l -yl)oxazolo[4,5-b]pyridin—6-yl)-2—(2- methylpyridinyl)oxazolecarboxamide hloride; N—(2,5-di(piperidin- 1-yl)thiazolo[4,5-b]pyridinyl)( l-methyl-lH-pyrazol yl)picolinamide hydrochloride; 6-( l-methyl-1H-pyrazolyl)-N—(2—morpholino(piperidin-l-yl)thiazolo[4,5- b]pyridinyl)picolinamide; N—(2,5-di(piperidin—1-yl)thiazolo[4,5-b]pyridin-6—yl)(2—methylpyridin—3- yl)oxazolecarboxamide hydrochloride; N—(2-((ZS ,6R)-2,6-dimethylmorpholino)(piperidin- hiazolo[4,5-b]pyridin yl)—2—(2-methylpyridin-4—yl)oxazole-4—carboxamide; 2-(2-methylpyridin-3—yl)-N-(2-morpholino—5-(piperidin-1—yl)thiazolo[4,5—b]pyridin yl)oxazole-4—carboxamide; 2-(2—hydroxypyridin—3-yl)—N-(2-morpholino-5 -(piperidin—1-yl)thiazolo[4,5-b]pyridin- 6-yl)oxazolecarboxamide; N-(2,5—di(piperidin-1—y1)thiaz010[4,5—b]pyridiny1)—2-(2—methoxypyridin—4- yl)oxazolecarboxamide; 2-(6-meth0xypyridiny1)-N—(2-m0rph01in0(piperidin—1-y1)thiaz010[4,5-b]pyridin- xazole—4-carb0xamide; 2-(2-meth0xypyridiny1)-N-(2-m0rph01in0(piperidiny1)thiaz010[4,5-b]pyridin- 6-y1)0xazole—4-carb0xamide; (S)-N—(5-(3-?u0r0piperidin- 1 —y1)-2—m0rph01in0thiaz010[4,5—b]pyridiny1)(2— methylpyridiny1)0xazolecarb0xamide; ethylpyridiny1)-N—(2-m0rph01in0—5-(piperidin-1—y1)thiazolo[4,5-b]pyridin yl)oxazole-4—Carboxamide; 2-(3-methy1pyridiny1)-N-(2-m0rph01in0—5 -(piperidiny1)thiazolo[4,5-b]pyridin y1)0Xazole-4—carb0xamide; (S)-6—(3-amin0pyrr01idiny1)-N-(2—m0rph01in0-5—(piperidinyl)thiaz010[4,5 - b]pyridiny1)picolinamide; (S)-6—(3-hydr0xypyrr01idin— 1-y1)-N—(2-m0rph01in0-5 -(piperidiny1)thiazolo[4,5- b]pyridiny1)picolinamide; (S)(3-amin0pyrr01idiny1)-N—(2,5-di(piperidiny1)thiaz010[4,5-b]pyridin yl)picolinamide; (S)-N—(2,5 -di(piperidiny1)thiaz010[4,5-b]pyridin—6-y1)-6—(3-hydroxypyrrolidin—1- y1)picolinamide; (S)-2—(3-amin0pyrr01idin-1—y1)-N-(2-m0rph01in0(piperidiny1)thiaz010[4,5 — b]pyridinyl)0xazole0arboxamide; (S)-N—(5-(3-amin0pyrr01idiny1)-2—m0rph01in0thiaz010[4,5-b]pyridin-6—y1)(2- methylpyridiny1)0xazole—4-carb0xamide; (3-amin0pyrr01idiny1)-N-(5—Cyclopr0py1-2—m0rph01in0thiaz010[4,5- b]pyridiny1)0xazole0arboxamide; N-(5-cyclopropylm0rph01in0thiazolo[4,S—b]pyridinyl)—2-(2-methy1pyridin-4— yl)oxazolecarboxamide; (S)-2—(3-hydr0xypyrr01idin— 1-y1)-N—(2-m0rph01in0-5 -(piperidiny1)thiazolo[4,5- dinyl)0xazole0arboxamide; (S)-N—(5-(3 -hydr0xypyrr01idiny1)—2-m0rph01in0thiaz010[4,5 -b]pyridin—6-y1)-2—(2- pyridiny1)0xazole—4-carb0xamide; (S)-N—(5-Cyclopropyl—2-m0rph01in0thiaz010[4,5-b]pyridin—6—y1)-6—(3- hydroxypyrrolidin- 1-y1)picolinamide; (S)—N—(5-cyclopropylm0rph01in0thiaz010[4,5—b]pyridin—6-y1)—2-(3- hydroxypyrrolidin-1—y1)0xazolecarb0xamide; (S)-N—(5-Cyclopropylm0rph01in0thiaz010[4,5-b]pyridiny1)(1-(2— hydroxypropy1)-1H-pyraz01—4-y1)picolinamide; (S)-N-(5-Cyclopropylm0rph01in0thiaz010[4,5-b]pyridiny1)(1-(2- hydroxypropy1)-1H-pyrazoly1)0xaz01ecarb0xamjde; N—(5-(3-hydr0xypyrr01idiny1)m0rph01in0thiaz010[4,5-b]pyridiny1)(6- methoxypyridiny1)oxazolecarboxamide; (5-(3-hydr0xypyrr01idiny1)—2-m0rph01in0thiaz010[4,5-b]pyridin—6-y1)-2—(6- methoxypyridiny1)0Xazolecarb0xamide; (R)-N—(5 -(3-hydr0xypyrr01idiny1)—2-m0rph01in0thiaz010[4,5-b]pyridin—6-y1)-2—(6- methoxypyridiny1)0Xazolecarb0xamide; (S)—N—(5—(azetidin—1—y1)—2—morph01in0thiazolo[4,5—b]pyridin-6—y1)—6—(3— hydroxypyrrolidin- 1—y1)picolinamide; N-(5—(3-hydr0xyazetidin-1—y1)m0rph01in0thiaz010[4,5—b]pyridin—6-y1)—2-(2- methylpyridin—4-y1)0xazole—4-carb0xamide; (S)-N-(5-(3-hydr0xypyrr01idiny1)m0rph01in0thiaz010[4,5-b]pyridiny1)(2- methylpyridiny1)thiophene-Z-carboxamide; (S)-N—(5-(3-hydr0xypyrr01idiny1)—2-m0rph01in0thiaz010[4,5-b]pyridin—6-y1)(2- methylpyridiny1)furan-2—carb0xamide; (S)-N—(5-(3 -hydr0xypiperidiny1)—2-m0rph01in0thiaz010[4,5-b]pyridiny1)(2- pyridiny1)0xazole—4-carb0xamide; N—(5-(4-hydr0xypiperidin-1—y1)m0rph01in0thiazolo[4,5-b]pyridiny1)—2-(2- methylpyridin—4-y1)oxazole—4—Carb0xamide (R)-N-(5 -(3-hydr0xypyrr01idiny1)m0rph01in0thiaz010[4,5-b]pyridiny1)(2- methylpyridiny1)0xazole—4-carb0xamide; N—(5-(4-hydr0xypiperidin-1—y1)m0rph01in0thiaz010[4,5—b]pyridiny1)—5-(2- methylpyridiny1)furan-2—carb0xamide; N-(5-(azetidin—1-y1)-2—(piperidiny1)thiazolo[4,5—b]pyridiny1)—2-(2- methylpyridiny1)0xazole—4-carb0xamide; 2-(2-methy1pyridiny1)-N-(2-(piperidiny1)(pyrr01idiny1)thiaz010[4,5- b]pyridiny1)0xazole0arboxamide; 2-(2—methy1pyridin—4-y1)-N—(2-m0rph01in0—5-(pyrr01idin—1-y1)thiaz010[4,5-b]pyridin- 6-y1)OxazoleCarboxamide; -(2-methy1pyridiny1)-N—(2-m0rph01in0—5-(piperidin-1—y1)thia2010[4,5-b]pyridin yl)furancarb0xamide; N—(5-(azepany1)-2—m0rph01in0thiaz010[4,5-b]pyridiny1)(2-methy1pyridin yl)oxazole—4—Carboxamide; 2-(2-amin0pyridin-4—y1)-N—(2-m0rph01in0(piperidiny1)thiaz010[4,5—b]pyridin yl)0xazole-4—carb0xamide hydrochloride; N—(5-(azetidin—1-y1)m0rph01in0thiaz010[4,5-b]pyridin-6—yl)(2-methy1pyridin yl)oxazole-4—carboxamide; (R)-N-(5-(3-hydr0xypiperidiny1)m0rph01in0thiaz010[4,5-b]pyridiny1)(2- methylpyridiny1)0xazolecarb0xamide; (R)-N-(5 -(3—hydr0xypiperidiny1)—2-m0rph01in0thiaz010[4,5-b]pyridin—6-y1)-5—(2- methylpyridiny1)furancarb0xamide; ( 1-(2-hydr0xypr0py1)—1H-pyrazoly1)-N—(2—m0rph01in0(piperidin- 1- yl)thiaz010[4,5—b]pyridiny1)picolinamide N—(5-(4-flu0r0piperidinyl)m0rph01in0thiaz010[4,5-b]pyridiny1)(2- methylpyridin-4—y1)furan—2—carb0xamide N—(5-(4-flu0r0piperidiny1)m0rph01in0thiaz010[4,5-b]pyridiny1)-2—(2- methylpyridiny1)0xazole—4-Carboxamide hydrochloride N—(5-(1-methy1-1H-pyraz01—4-y1)-2—m0rph01in0thiaz010[4,5-b]pyridiny1)(2- methylpyridin—4-y1)oxazole—4—Carb0xamide; 3-flu0r0pheny1)m0rph01in0thiaz010[4,5-b]pyridiny1)(2-methylpyridin- 4-y1)0xazole—4-carb0xamide; N—(5-(4-hydr0xypiperidin-1—y1)m0rph01in0thiaz010[4,5—b]pyridiny1)—5-(2- methylpyridiny1)furan-2—carb0xamide; N-(5-(3-flu0r0piperidin- 1-y1)—2-m0rph01in0thiaz010[4,5-b]pyridin—6-y1)-5—(2- methylpyridiny1)furancarb0xamide; (S)-N-(5-(3-hydr0xypyrr01idiny])m0rph01in00xaz010[4,5-b]pyridiny1)(6- methoxypyridiny1)0Xazolecarb0xamide; 3-hydr0xypyrrolidin—1-y1)-2—m0rph01in00xazolo[4,5-b]pyridiny1)(2— pyridiny1)0xazole—4-carb0xamide; (R)-N-(5 -(3-hydr0xypyrr01idiny1)m0rph01in00xaz010[4,5-b]pyridiny1)-2—(6- methoxypyridiny1)oxazole—4-Carboxamide; N—(5-(3-hydr0xypyrr01idiny1)m0rph01in00xazolo[4,5-b]pyridiny1)(6- methoxypyridin—3—y1)oxazolecarboxamide; (S)-N—(5-(3-hydr0xypyrr01idiny1)—2-m0rph01in00xaz010[4,5-b]pyridin—6-y1)-5—(2- methylpyridiny1)furan-2—carb0xamide; (S)-N—(5-(3-hydr0xypyrr01idiny1)—2-m0rph01in00xaz010[4,5-b]pyridin—6-y1)-5—(2- methylpyridiny1)thi0phenecarb0xamide; N-(S-(azetidin-l-y1)(piperidiny1)0xaz010[4,5-b]pyridiny1)(2- methylpyridiny1)0xazolecarb0xamide; 2-(2—methy1pyridin—4—yl)-N—(2-(piperidin— 1—yl)-5—(pyrr01idin— xaz010[4,5- b]pyridiny1)0xaz01€carb0xamide; -(2-methy1pyridin-4—y1)-N—(2-m0rph01in0—5-(piperidin-1—y1)0xazolo[4,5-b]pyridin yl)furancarb0xamide; N—(5-(azetidiny1)m0rph01in00xaz010[4,5-b]pyridiny1)(2-methylpyridin yl)0xaz01e—4—carb0xamide; 2-(2-methylpyridiny1)-N-(2-m0rph01in0—5 -(pyrr01idiny1)0Xaz010[4,5-b]pyridin- 6-y1)oxazole—4-Carb0xamide; N—(5-(4-hydr0xypiperidin-1—y1)m0rph01in00xazolo[4,5-b]pyridiny1)(2- methylpyridin—4-y1)furan-Z-carboxamide; (R)-N-(5 -(3-hydr0xypiperidiny1)—2-m0rph01in00xaz010[4,5-b]pyridiny1)(2- methylpyridiny1)furan-2—carb0xamide; N—(5-(furany1)m0rph01in00xazolo[4,5-b]pyridinyl)(2-methy1pyridin yl)0xaz01€-4—carb0xamide; N-(5-(3-flu0r0piperidiny1)—2-m0rph01in00xaz010[4,5-b]pyridin—6-y1)-2—(2- methylpyridiny1)0xazole—4-carb0xamide; N—(S-(4-hydr0xypiperidinyl)m0rph01inooxazolo[4,5-b]pyridiny1)(2- methylpyridiny1)0xazolecarb0xamide; N-(5—(4-flu0r0piperidin- 1-y1)m0rph01in00xaz010[4,5-b]pyridiny1)—2—(2- methylpyridiny1)0xazole—4-carb0xamide; (S)-N-(5-(3-amin0piperidin—1-y1)-2—m0rph01in0thiazolo[4,5-b]pyridin-6—y1)(2- methylpyridin—4-y1)oxazole—4—Carb0xamide; 2-(2-methy1pyridiny1)-N-(2-m0rph01in0-5 -( 1H-pyraz01—4-y1)thiaz010 [4,5 - din-6—y1)0xazolecarb0xamide; N—(5-(6-?u0r0pyridiny1)m0rph01in0thiaz010[4,5-b]pyridiny1)(2- pyridiny1)0xazole—4-carb0xamide; N—(5-(3-hydr0xyazabicyclo[3.2.1]octany1)-2—m0rph01in0thiaz010[4,5-b]pyridin- 6-y1)(2-methylpyridiny1)Oxazolecarboxamide; N-(2-(3-hydr0xypiperidiny1)(piperidiny1)thiaz010[4,5 -b]pyridiny1)(2- methylpyridiny1)0xazolecarb0xamide; 2-(2—acetamidopyridiny1)—N-(5—(4-hydr0xypiperidin-1—yl) m0rph01in0thiaz010[4,5-b]pyridin-6—y1)0xazolecarb0xamide; N-(2—(3-hydr0xypiperidin-1—y1)(4-hydr0xypiperidiny1)thiazolo[4,5—b]pyridin yl)(2-methylpyridiny1)Oxazole—4-Carboxamide; 2-(2-acetamidopyridiny1)-N-(5-(3-hydr0xypiperidiny1) morpholinothiaz010[4,5—b]pyridin—6-y1)0xazole—4—carb0xamide; 2-(2-amin0pyridin-4—yl)-N—(5 -(3-hydr0xypiperidin—1-y1)-2—m0rph01in0thiaz010[4,5- b]pyridiny1)oxazolecarboxamide hydrochloride; -(2-aminopyridin-4—yl)-N-(5 droxypiperidin- l -yl)-2—morpholinothiazolo[4,5- b]pyridiny1)furan—3—carboxamide hydrochloride; 2-(2-aminopyridin-4—yl)-N—(5 -(4-hydroxypiperidin- l -yl)-2—morpholinothiazolo[4,5- b]pyridin-6—yl)oxazolecarboxamide hydrochloride; 2-(2-aminopyridin-4—yl)-N—(5-(4-fluoropiperidin-1—yl)morpholinothiazolo[4,5— b]pyridinyl)oxazolecarboxamide hydrochloride; N-(5-(2-?uoropyridin—4-yl)-2—morpholinothiazolo[4,5-b]pyridin-6—yl)(2- methylpyridinyl)oxazole—4-carboxamide; N—(S-(4-?uoropiperidin- 1-y1)(3-hydroxypiperidiny1)thiazolo[4,5-b]pyridin yl)(2-methylpyridinyl)oxazolecarboxamide; N-(5—(4-aminopiperidin- l-yl)(3—hydroxypiperidin- l -yl)thiazolo[4,5-b]pyridin—6- (2-methylpyridinyl)oxazole—4-carboxamide hydrochloride; and N—(5—(2-hydroxypyridinyl)morpholinothiazolo[4,5-b]pyridinyl)—2-(2- pyridin—4-yl)oxazole—4—carboxamide hydrochloride; or a ceutically acceptable salt or a stereoisomer thereof.
Provided herein is a method of treating or preventing acute myeloid leukemia in a subject, comprising stering a compound of formula (111): @ R /N NM3)n (111) or a ceutically acceptable salt thereof; wherein, 21 represents optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or is absent; 22 represents optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl; R1 is hydrogen, optionally substituted alkyl, amino, halo, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally tuted heterocyclylalkyl; R2 at each occurrence is amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, ally substituted arylalkyl or optionally substituted heterocyclylalkyl; R3 at each occurrence is hydroxy, halo, optionally substituted alkyl, optionally substituted , ally substituted lkyl or -NRaRb; Ra and Rb, independently for each occurrence, are hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl; m, at each occurrence, is 0, l or 2; and n, at each occurrence, is 0, 1, or 2.
In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically able salt thereof, wherein 21 is an ally substituted heterocyclyl.
In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein 21 represents cycloalkyl, aryl, or heterocyclyl, optionally substituted by one or more substituents selected, independently for each occurrence, from hydroxy, halo, alkyl, cycloalkyl, or NRaRb.
In some embodiments, the present methods include a compound of formula (III) or a ceutically acceptable salt thereof, wherein 21 is an optionally substituted heteroaryl; wherein the optional substituent is alkyl or cycloalkyl.
In some embodiments, the present methods include a compound of a (III) or a ceutically able salt thereof, wherein 21 is olyl, l, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, imidazolyl, zolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl, pyrazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, hienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, inyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, (x-carboline, indolizinyl, benzoisothiazolyl, benzoxazolyl, pyrrolopyridyl, furopyridinyl, purinyl, benzothiadiazolyl, benzooxadiazolyl, benzotriazolyl, benzotriadiazolyl, carbazolyl, othienyl, acridinyl and pyrazolopyrimidyl; each of which is optionally substituted.
In some embodiments, the present methods include a compound of formula (III) or a ceutically acceptable salt f, wherein Z1 is tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, l or pyrazolyl.
In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z1 is pyridyl or oxazolyl; wherein the oxazolyl group is ally substituted with alkyl; in particular alkyl is methyl.
In some embodiments, the present s include a compound of a (III) or a pharmaceutically able thereof, wherein Z1 is absent.
In some ments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 is cycloalkyl, aryl or heterocyclyl.
In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein 22 represents cycloalkyl, aryl, or heterocyclyl, ally substituted by one or more substituents selected from hydroxy, halo, alkyl, alkoxyl, cycloalkyl, -NRaRb, or lkoxy.
In some embodiments, the present methods e a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 is heterocyclyl.
In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein 22 is azetidinyl, oxetanyl, l, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, oxanyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl, tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, imidazolidinyl, imidazolyl, thiadiazolyl, thiazolyl, thiazolidinyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolidinyl, oxazolidinyl, pyrazolidinyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, indolyl, isoindolyl, lyl, quinolinyl, nolinyl pyrrolopyridyl or pyrazolopyrimidyl.
In some embodiments, the present methods include a compound of a (III) or a ceutically acceptable salt thereof, wherein Z2 is pyridyl, zinyl, pyrimidyl, pyrrolidinyl, l,2,3,4—tetrahydropyridyl, piperidinyl, pyrazolopyrimidyl or pyrrolopyridyl.
In certain embodiments, the nd of formula (III) is compound of formula (IIIA) HNjgN/>—@ R ( 3) /N n ( R2),, (IIIA) or a pharmaceutically acceptable salt thereof; wherein, Z2, R1, R2, R3, ‘m’, and ‘n’ are as defined in compound of formula (III).
In certain embodiments, the compound of formula (III) is compound of formula (IIIB) N | N \ N/ N (R3)n ( 1 R2),, (IIIB) or a pharmaceutically acceptable salt thereof; wherein, Z2, R1, R2, R3, ‘m’, and ‘n’ are as defined in compound of formula (III).
In some embodiments, the present s include a compound of formula (III) or a ( R?/O R1 pharmaceutically acceptable salt thereof, wherein the group m is R /N 11/ N 1"/ \2 N 2/ N Rz—N/ \ / \ /N "71/ \ Rz—N N R1 / / \ R1 R1 R2 or R2 , a ; wherein R1, R2 and ‘m’ are same as defined in nd of formula (III).
In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 is pyridyl.
In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Z2 is pyrrolidinyl.
In some ments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein 22 is piperidinyl, piperazinyl, tetrahydropyridyl, pyrimidyl or pyrazolopyridyl.
In some ments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, optionally substituted alkyl, amino, halo, cyano, ally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally tuted arylalkyl or optionally substituted heterocyclylalkyl.
In some embodiments, the present methods include a nd of formula (III) or a ceutically acceptable salt, wherein R1 is alkyl, cycloalkyl, aryl, heterocyclyl, arylalkyl, optionally substituted with one or more substituents selected, independently for each occurrence, from hydroxy, halo, alkyl, or hydroxyalkyl.
In some embodiments, the present s include a compound of formula (III) or a pharmaceutically acceptable salt, wherein R1 is heterocyclyl; optionally substituted with halogen, hydroxyl or hydroxyalkyl.
In some embodiments, the present methods include a nd of formula (III) or a pharmaceutically acceptable salt, wherein R1 is optionally substituted azetidinyl, piperidinyl, morpholinyl, pyrrolidinyl or azepanyl.
In some embodiments, the present methods include a compound of a (III) or a pharmaceutically acceptable salt, n R1 is dinyl, optionally substituted with hydroxyl.
In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt, n R1 is pyrrolidinyl, optionally substituted with hydroxyl.
In some ments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt, wherein R2, at each occurrence, is amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, ally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl.
In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt, wherein R2 is alkyl, cycloalkyl, aryl, heterocyclyl, arylalkyl, or heterocyclylalkyl, optionally substituted with one or more substituents selected, independently for each occurrence, from alkyl, cycloalkyl, or heterocyclyl.
In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R2 is optionally substituted alkyl, preferably, methyl.
In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R2 is optionally substituted cycloalkyl, preferably, ropyl.
In some embodiments, the present methods e a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R3, at each occurrence, is y, halo, optionally substituted alkyl, optionally substituted , optionally tuted cycloalkyl or - NRaRb; wherein R8 is hydrogen or optionally substituted alkyl; and Rb is hydrogen, optionally substituted alkyl, ally substituted acyl, hydroxyalkyl or lkyl.
In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein 21 is optionally substituted l; Z2 is pyrrolidinyl; R1 is an optionally substituted groups selected from piperidinyl or pyrrolidinyl; R2 is optionally substituted alkyl; R3 is halogen, alkyl, , hydroxyl or hydroxyalkyl; Ra is hydrogen or alkyl; and Rb is en or hydroxyalkyl.
In some embodiments, the t methods include a compound of formula (III) or a pharmaceutically acceptable salt f, wherein 21 is oxazolyl; 22 is pyridyl, dyl or pyrrolidinyl, piperidinyl, tetrahydropyridyl, piperazinyl, pyrrolopyridyl; R1 is an optionally substituted group selected from piperidinyl or pyrrolidinyl; R2 is optionally substituted alkyl or cyclopropyl; R3 is halogen, alkyl, alkoxy, -NRaRb, hydroxyl, hydroxyalkyl ally substituted ropyl; Ra is hydrogen or alkyl; and Rh is hydrogen, alkyl, acyl, hydroxyalkyl, —SO2—alkyl or optionally substituted cycloalkyl.
In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ‘m’ is 0.
In some embodiments, the present methods include a compound of formula (III) or a ceutically acceptable salt thereof, wherein ‘m’ is 1.
In some embodiments, the present methods e a compound of formula (III) or a ceutically acceptable salt thereof, wherein ‘m’ is 2.
In some embodiments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ‘n’ is 0.
In some ments, the present methods include a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ‘n’ is 1.
In some embodiments, the present methods include a compound of a (III) or a pharmaceutically acceptable salt thereof, n ‘n’ is 2.
In some embodiments, the present methods include a compound of formula (III) selected from: N-( 1 —methyl-5 -(piperidin- 1 —yl)- l H-indazolyl)—2-(2-methylpyridin-4— yl)oxazole—4-carboxamide hydrochloride; N-(2-methyl(piperidinyl)-2H-indazolyl)(2-methylpyridin yl)oxazolecarboxamide hydrochloride; (S)—6-(3 -hydroxypyrrolidin- l -yl)—N—(2-methyl-5—(piperidin- l -yl)-2H- indazolyl)picolinamide; (S)—2-(3 -aminopyrrolidin— l -yl)-N-( l -methyl(piperidin- l -yl)— l H-indazol- 6-y1)oxazole—4-carboxamide; (3 -aminopyrrolidin- l -yl)-N-(2-methyl(piperidin- l -yl)-2H-indazol- xazolecarboxamide; (S)(3 -hydroxypyrrolidin- l -yl)-N—(2-methyl-5—(piperidin- l -y1)-2H- indazol-6—yl)oxazolecarboxamide; (S)—6-(3 -aminopyrrolidin- l -yl)-N—(2-methyl(piperidin— l -yl)-2H-indazol- 6-yl)picolinamide (3 -aminopyrrolidin-1—yl)-N—(1-methyl(piperidin—1-yl)-lH-indazol- icolinamide; (S)—6-(3 xypyrr01idiny1)—N—( 1 1—5—(piperidiny1)- 1H- indazoly1)picolinamide; (S)(3 -hydr0xypyrr01idiny1)-N—( 1 -methy1—5-(piperidiny1)- 1H- indazol-6—yl)0xazolecarb0xamide; (S)-N-(5 -(3—hydr0xypyrr01idiny1)methy1-1H-indazoly1)—2-(2- methylpyridinyl)0xazolecarb0xamide; N-(5—(3-hydr0xypiperidin—1-y1)-l—methyl—1H-indaz01-6—y1)(2— methylpyridinyl)0xazolecarb0xamide N—(S-(3-hydr0xypiperidiny1)methy1-2H—indaz01—6-yl)(2- methylpyridinyl)0xazolecarb0xamide; N—(5-(3-?u0r0piperidin- 1—yl)methy1—2H-indazoly1)(2— methylpyridinyl)0xazolecarb0xamide; (S)—2-(2-acetamid0pyridiny1)-N-(5 -(3—hydr0xypyrr01idiny1)methy1- 1H—indaz01—6-y1)0xazole-4—Carb0xamide; N—(5-(3 piperidiny1)methy1-1H-indazoly1)(2- methylpyridin-4—yl)0xazolecarb0xamide; N—(5-(4-hydr0xypiperidin—1-y1)-l—methyl—1H-indaz01y1)(2— methylpyridinyl)0xazolecarb0xamide; (S)—2-(2-amin0pyridiny1)-N—(5—(3-hydr0xypyrrolidin— 1 -y1)- 1 —methyl— 1H- indaz01yl)0Xazolecarb0xamide; N—(5-(4-?u0r0piperidiny1)methy1-1H-indaz01y1)(2- methylpyridinyl)0xazolecarb0xamide; N—(5-(4-(hydr0xymethy1)piperidiny1)—1-methy1-1H-indaz01—6-y1)-2—(2- methylpyridinyl)0xazolecarb0xamide; (S)—2-(2,6-dimethylpyridiny1)—N—(5-(3-hydr0xypyrr01idiny1)methyl- 1H—indaz01—6-y1)0xazole-4—Carb0xamide; (R)-N—(5 -(3-hydr0xypyrr01idin-1—y1)methy1-1H-indazoly1)—2-(2- methylpyridin—4—yl)oxazole-4—carboxamide; (S)(2-amin0pyridiny1)-N—(5—(3-hydr0xypyrr01idin—1-y1)-l—methyl—IH- indazolyl)oxazolecarboxarnide Hydrochloride; 6-((S)hydroxypyrrolidin- l -yl)—N—(5-((R)hydroxypyrrolidin- l -yl)— l - methyl- 1 H—indazol—6-yl)picolinamide; (S)-N—(5 -(3—hydroxypyrrolidin- l -yl)methyl- 1 H-indazol yl)pyrazolo[ l ,5-a]pyrimidine-3—carboxamide; 6-((S)hydroxypyrrolidin- l-yl)-N-(5-((S)hydroxypyrrolidin- l -yl)- 1- methyl- 1 H—indazolyl) picolinamide; (5 -(3—hydroxypyrrolidin-l-yl)methyl-1H-indazolyl)—2-( 1H— pyrrolo[2,3-b]pyridinyl)oxazolecarboxamide; (5 droxypyrrolidinyl)-1H—indazoly1)(2-methylpyridin- 4-yl)oxazolecarboxamide; (S)—2-(2-amino-3—fluoropyridin-4—yl)-N—(5-(3-hydroxypyrrolidin- l-yl)— 1- methyl- 1 H—indazol—6-yl)oxazolecarboxamide; (R)—2-(2-aminopyridinyl)-N—(5-(3 -hydroxypyrrolidin-l-yl)methyl-lH- indazolyl)oxazolecarboxamide hydrochloride; (S)-N—(5 -(3—hydroxypyrrolidin- l -yl)methyl- 1 H-indazolyl)(4- methylpiperazin—1—y1)oxazole-4—carboxamide; (S)-N-(5 -(3—hydroxypyrrolidin- l -yl)methyl- 1 H-indazolyl) (piperazin—1-yl)oxazole-4—carboxamide; (S)—N—( l -ethyl(3—hydroxypyrrolidin- 1 —yl)- lH—indazol—6-yl)-2—(2- methylpyridinyl)oxazolecarboxamide hloride; (S)-N-(1-cyclopropy1(3-hydroxypyrrolidinyl)-1H—indazoly1)(2- methylpyridinyl)oxazolecarboxamide hydrochloride; (S)—N—(5-(3—hydroxypyrrolidin-l—yl)-l-methyl-1H-indazolyl)( 6- tetrahydropyridinyl)oxazole-4—carboxarnide hydrochloride; (S)—N—(5 -(3—hydroxypyrrolidin- l —yl)methyl- 1 H-indazolyl)(2- methylpyrimidin-4—yl)oxazolecarboxamide; (S)-N—(5 -(3—hydroxypyrrolidin- l -yl)methyl- 1 H-indazolyl)methyl (2—methy1pyridin—4—y1) oxazole—S—carboxamide; (S)-N-(5 -(3—hydroxypyrrolidin- l -yl)- 1 l- 1 H-indazolyl) (piperidin-4—yl)oxazolecarboxamide hydrochloride; N—(5-(3-hydroxy-8—azabicyclo[3 .2. l]octanyl)— 1 -methyl- 1 zol—6-yl)- 2-(2—methylpyridin—4-yl)oxazole-4—carboxamide; (S)-N—(5 -(3—hydroxypyrrolidin-l-yl)methyl-1H-indazolyl)(2- methylpyridin-4—yl) oxazole-S-carboxamide; N—(5-(4-hydroxy-4—(hydroxymethyl)piperidin-l-yl)methyl-lH-indazol yl)—2-(2-methylpyridin-4—yl)oxazolecarboxamide hydrochloride; (S)—N—(5 -(3—hydroxypyrrolidinyl)methyl-lH-indazolyl)—5-methyl (2-methylpyridin-4—yl)oxazolecarboxamide; (S)-2—(2-ethylpyridinyl)-N-(5 -(3-hydroxypyrrolidin-l-yl)methyl-1H- indazolyl)oxazolecarboxamide; 2-(2—aminopyridin—4-yl)—N-(5-(4—(hydroxymethyl)piperidinyl)-l,3— dimethyl-1H-indazolyl)oxazolecarboxamide hydrochloride; (S)—N—(5 -(3—hydroxypyrrolidin-1—yl)(piperidinylmethyl)-1H-indazol (2-methylpyridinyl)oxazolecarboxamide; N—(5-(4-(hydroxymethyl)piperidin-l-yl)-1 ,3-dimethyl-1H-indazolyl)—2- (2—methylpyridin—4—yl)oxazole—4—carboxamide; (S)(2-cyclopropylpyridinyl)—N—(5-(3 -hydroxypyrrolidin- l—yl) methyl-1H—indazolyl)oxazole—4-carboxamide; and N-(5—(4-hydroxypiperidin—1-yl)-2—methyl—2H-indazol-6—yl)pyrazolo[ 1 ,5— a]pyrimidinecarboxamide; Pharmaceutical compositions In certain ments, the present s include a pharmaceutical composition comprising the nd as disclosed herein, optionally admixed with a pharmaceutically acceptable carrier or diluent.
As used , the term "composition" is intended to encompass a t comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
As used herein, the term "pharmaceutical ition" refers to a ition(s) containing a therapeutically effective amount of at least one compound of formula (I) or its pharmaceutically acceptable salt; and a tional pharmaceutically acceptable carrier.
The pharmaceutical composition(s) of the present invention can be administered orally, for example in the form of s, coated tablets, pills, es, granules or elixirs.
Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or aneously, in the form of able sterile solutions or suspensions, or topically, for example in the form of ointments or creams or transdermals, in the form of patches, or in other ways, for example in the form of ls or nasal sprays.
The pharmaceutical composition(s) usually contain(s) about 1% to 99%, for example, about 5% to 75%, or from about 10% to about 30% by weight of the compound of a (I) or pharmaceutically acceptable salts thereof. The amount of the compound of formula (I) or ceutically acceptable salts thereof in the pharmaceutical composition(s) 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 in any range g within the broader range of 1 mg to 1000 mg or higher or lower than the afore mentioned range.
The present invention also provides methods for formulating the disclosed compounds as for pharmaceutical administration.
The compositions and methods of the present invention may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the 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 physiologically buffered saline or other solvents or vehicles such as glycols, ol, oils such as olive oil, or injectable organic esters.
In a preferred embodiment, when such ceutical compositions are for human administration, ularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or . The ceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin e), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.
A pharmaceutically able carrier can contain physiologically able agents that act, for e, to stabilize, se solubility or to se the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight ns or other stabilizers or excipients.
The choice of a pharmaceutically acceptable carrier, ing a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation of pharmaceutical composition can be a self-emulsifying drug delivery system or a self- microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other , are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, ent, solvent or encapsulating al. Each carrier must be table" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some es of materials which can serve as pharmaceutically acceptable carriers include: (1) , such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato ; (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, saf?ower 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 ; (12) esters, such as ethyl oleate and ethyl laurate; (l3) agar; (14) buffering agents, such as magnesium ide and aluminum hydroxide; (15) alginic acid; (16) n—free water; (17) isotonic saline; (l8) Ringer‘s on; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non—toxic compatible substances employed in pharmaceutical formulations.
A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, ly or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a e solution or suspension); nasally; eritoneally; subcutaneously; transdermally (for example as a patch d to the skin); and topically (for example, as a cream, nt or spray applied to the skin, or as an eye drop). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of stration and compositions suitable for same can be found in, for example, US. Pat. Nos. 6,110,973, ,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.
The formulations may conveniently be presented in unit dosage form and may be prepared by any s well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one d percent, this amount will range from about 1 percent to about ninety-nine t of active ingredient, preferably from about 5 percent to about 70 t, most preferably from about 10 percent to about 30 percent.
Methods of ing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle es and gelatin capsules), cachets, pills, s, lozenges (using a ?avored basis, y sucrose and acacia or tragacanth), lyophile, powders, es, or as a solution or a 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 pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
Compositions or compounds may also be administered as a bolus, electuary or paste.
To prepare solid dosage forms for oral administration (capsules (including le capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, tes, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca , alginic acid, n silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as nary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol earate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium te, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures f; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including le capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a r type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight hylene glycols and the like.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or ypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross—linked sodium carboxymethyl cellulose), e—active or dispersing agent. Molded s may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and n capsules), pills and granules, may optionally be scored or ed with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to e the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for e, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, ally, in a delayed manner.
Examples of embedding compositions that can be used include polymeric substances and waxes.
The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
Liquid dosage forms useful for oral stration include ceutically able emulsions, lyophiles for reconstitution, mulsions, 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, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-buty1ene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, ng, coloring, perfuming and preservative agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, um metahydroxide, bentonite, agar—agar and tragacanth, and mixtures thereof.
Formulations of the pharmaceutical itions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room ature, but liquid at body ature and, therefore, will melt in the rectum or vaginal cavity and release the active nd.
Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral nt.
Alternatively or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine.
Formulations which are le for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
Dosage forms for the topical or transdermal administration include powders, , ointments, pastes, , lotions, gels, solutions, patches and inhalants. The active nd may be mixed under sterile ions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
The nts, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. s and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these nces. Sprays can additionally n customary propellants, such as chloro?uorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or sing the active compound in the proper medium. tion enhancers can also be used to increase the ?ux of the compound across the skin. The rate of such ?ux can be controlled by either ing a rate controlling membrane or dispersing the compound in a polymer matrix or Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being Within the scope of this invention. Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005/0080056, 2005/0059744 and U.S. Pat. No. 6,583,124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic formulations have ties similar to that of lacrimal ?uids, aqueous humor or vitreous humor or are compatable with such ?uids. A preferred route of administration is local administration (e.g., l administration, such as eye drops, or administration via an implant).
The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, ardiac, intradermal, intraperitoneal, transtracheal, aneous, subcuticular, intraarticular, subcapsular, subarachnoid, pinal and intrasternal injection and infusion.
Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile ic aqueous or nonaqueous solutions, dispersions, sions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may n antioxidants, buffers, bacteriostats, s which render the formulation ic with the blood of the intended recipient or suspending or thickening agents.
Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, l, s (such as glycerol, ene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and able organic esters, such as ethyl oleate. Proper ?uidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay tion such as aluminum earate and gelatin.
In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of tion of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed tion of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer ed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by ping the drug in liposomes or mulsions that are compatible with body tissue.
For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, about 0.1 to about 99.5% (more preferably, about 0.5 to about 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
Methods of introduction may also be provided by rechargeable or biodegradable devices.
Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinacious biopharmaceuticals. A variety of patible polymers ding hydrogels), ing both biodegradable and non—degradable polymers, can be used to form an t for the sustained release of a compound at a particular target site.
Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the ular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or als used in ation with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical y of the patient being treated, and like factors well known in the medical arts.
A physician or narian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the ian or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By "therapeutically effective amount" is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is lly understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which in?uence the effective amount may e, but are not d to, the severity of the patient‘s condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et a1. (1996) Harrison‘s ples of Internal Medicine 13 ed., 1814—1882, herein incorporated by reference).
In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an ive dose will generally depend upon the factors described above.
If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub—doses administered tely at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain ments of the present invention, the active compound may be administered two or three times daily. In preferred embodiments, the active nd will be administered once daily.
The patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general.
Wetting agents, emulsifiers and lubricants, such as sodium lauryl e and magnesium stearate, as well as coloring , release agents, coating agents, sweetening, ?avoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, ne hydrochloride, sodium ate, sodium metabisulfite, sodium sulfite and the like; (2) oil—soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated ytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
The compounds of the present invention may be stered in ation with one or more other drugs (1) to complement and/or enhance tion and/or therapeutic efficacy of the preventive and/or eutic drug effect of the compound of the t invention, (2) to modulate pharmacodynamics, improve absorption improvement, or reduce dosage reduction of the tive and/or eutic compound of the present invention, and/or (3) to reduce or rate the side effects of the preventive and/or therapeutic compound of the t invention. As used herein, the phrase "conjoint administration" refers to any form of administration of two or more different therapeutic nds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially. In n embodiments, the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another. Thus, an individual who es such treatment can benefit from a combined effect of different eutic compounds. The respective compounds may be administered by the same or different route and the same or different method.
A concomitant medicine comprising the compounds of the present ion and other drug may be administered as a combination preparation in which both components are contained in a single formulation, or administered as separate formulations. The administration by separate formulations includes simultaneous administration and or administration of the formulations separated by some time intervals. In the case of the stration with some time intervals, the compound of the present invention can be administered first, ed by another drug or another drug can be administered first, followed by the compound of the present invention, so long as the two compounds are simultaneously active in the patient at least some of the time during the conjoint therapy. The administration method of the respective drugs may be administered by the same or different route and the same or ent method.
The dosage of the other drug can be properly selected, based on a dosage that has been clinically used, or may be a reduced dosage that is effective when stered in combination with a compound of the present invention. The compounding ratio of the compound of the present invention and the other drug can be properly selected according to age and weight of a subject to be administered, administration , administration time, disorder to be treated, symptom and combination thereof. For example, the other drug may be used in an amount of about 0.01 to about 100 parts by mass, based on 1 part by mass of the compound of the present invention. The other drug may be a combination of two or more kind of arbitrary drugs in a proper proportion. The other drug that complements and/or enhances the preventive and/or eutic efficacy of the nd of the present invention includes not only those that have already been discovered, but those that will be discovered in future, based on the above mechanism.
In certain embodiments, a compound of the invention may be conjointly administered with non-chemical methods of cancer treatment. In certain embodiments, a compound of the invention may be conjointly administered with radiation therapy. In certain embodiments, a compound of the invention may be conjointly administered with surgery, with thermoablation, with focused ultrasound y, with cryotherapy, or with any combination of these.
Methods of treatment Acute myeloid leukemia is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that build up 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. gh AML is a relatively rare disease, it accounts for roughly 1.2% of cancer deaths in the United States.
The ms of AML are caused by replacement of normal bone marrow with leukemic cells, which causes a drop in red blood cells, ets, and normal white blood cells. l risk factors and chromosomal alities have been identified, but the ic cause is not clear.
As an acute leukemia, AML progresses rapidly and is typically fatal within weeks or months if left untreated. AML differs from chronic myelogenous leukemia (CML) because ar differentiation is not the same. AML es higher percentages of dedifferentiated and undifferentiated cells, including more blasts (myeloblasts, monoblasts, and megakaryoblasts).
Diagnosis of AML often begins with an abnormal result on a complete blood count.
While an excess of abnormal white blood cells (leukocytosis) is a common finding, and leukemic blasts are sometimes seen, AML can also present with isolated decreases in platelets, red blood cells, or even with a low white blood cell count (leukopenia). While a presumptive diagnosis of AML can be made by examination of the peripheral blood smear when there are circulating leukemic blasts, a definitive diagnosis usually requires an adequate bone marrow tion and biopsy.
Genetic s may also be performed to look for specific mutations in genes such as FLT-3 or the genes that regulate FLT-3 expression, which may in?uence the outcome of the disease. Indeed, the ability of many of the compounds disclosed herein to inhibit FLT-3 is believed to contribute to their particular efficacy against AML, which is known to be sensitive to FLT—3 inhibition. Some patients may develop resistance to treatment with a FLT-3 inhibitor due to mutations that arise in the FLT-3 gene. Such FLT-3 ons include, but are not limited to, D835H, D835V, D835Y, K663Q, N84lI, internal tandem duplication (ITD), ITD and D835V, and ITD and F691L. However, compounds as disclosed herein have demonstrated efficacy against AML that has developed resistance against treatment with FLT-3 inhibitors.
Accordingly, in some embodiments, disclosed compounds are effective in treating AML that is resistant to a FLT—3 tor, such as AML that is characterized by cells having one or more of these mutations.
The malignant cell in AML is the myeloblast. In normal hematopoiesis, the myeloblast is an re precursor of myeloid white blood cells; a normal myeloblast will lly mature into a mature white blood cell. In AML, though, a single myeloblast accumulates genetic changes which "freeze" the cell in its immature state and prevent differentiation. Such a mutation alone does not cause leukemia; however, when such a "differentiation arrest" is combined with other mutations which disrupt genes controlling proliferation, the result is the uncontrolled growth of an immature clone of cells, g to the clinical entity of AML. ysplastic mes (MDS) are a group of cancers in which immature blood cells in the bone marrow do not mature and become healthy blood cells. Some types may p into acute myeloid leukemia. Problems with blood cell formation result in some ation 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 the blood cells and bone .
MDS is thought to arise from ons in the multi-potent bone marrow stem cell, but the specific defects responsible for these diseases remain poorly understood. Differentiation of blood precursor cells is impaired, and there is a significant increase in levels of apoptotic cell death in bone marrow cells. Clonal expansion of the al cells results in the production of cells which have lost the ability to differentiate. If the overall percentage of bone marrow myeloblasts rises over a particular cutoff, such as 20-30%, then transformation to acute myelogenous leukemia is said to have occurred. The progression of MDS to AML indicates how a series of ons can occur in an initially normal cell and transform it into a cancer cell.
IRAK-l is known to be overeXpressed in AML and MDS, and inhibition of IRAK-l has been demonstrated to cause apoptosis in MDS cell lines. See, e.g., Rhyasen, G. W., et al. Cancer Cell 2013 24290-104; n, G. W., et al. British J. Cancer 2014 pp. 1-6. The potent activity of the disclosed compounds, ing compounds that are not potent inhibitors of IRAK-l, in affecting AML cell lines, such as MV4—11 and MOLM—l3, indicates that IRAK-4 is an attractive and effective target for AML and MDS in its own right.
Disclosed herein are methods for treating or preventing acute myeloid ia. These s may be equally applicable to treating or preventing myelodysplastic syndrome.
Similarly, these methods may be equally applicable to treating or preventing multiple myeloma.
In certain embodiments, the present invention relates to a nd, or a pharmaceutically acceptable salt thereof as disclosed herein for treating or preventing AML and/or MDS. In certain embodiments, the present ion relates to use of a nd or a pharmaceutically acceptable salt thereof as disclosed herein for the preparation of a medicament for treating or preventing AML and/or MDS.
Compounds suitable for the compositions and methods disclosed herein can be found in are disclosed in WO2015/104662, WO2015/104688, and WO2015/193846, each of which is incorporated by reference in its entirety, and in particular for the compounds disclosed therein as IRAK4 inhibitors.
Examples YEN \ we o / \, N NH NH NH 2 /_\ o \ N/ o N—<\ | U / \N N N N N (?inH / Compound A Compound B Example 1: FLT-3 inhibition by Compound A Inhibition of FLT-3 wild type by the compounds was tested using the ate peptide EAIYAAPFAKKK. Flt3(h) (14—500, GenBank ll9) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 50 MM EAIYAAPFAKKK, 10 mM magnesium acetate and [gamma- 33P]—ATP (specific activity and concentration as required). The reaction was initiated by the addition of the Mg/ATP mix. After incubation for 40 minutes at room temperature, the reaction was d by the addition of phosphoric acid to a concentration of 0.5%. 10 ML of the on was then spotted onto P30 filtermat and washed four times for 4 minutes in 0.425% phosphoric acid and once in methanol prior to drying and scintillation counting.
Compound A was tested against Flt-3 using the Eurofins standard KinaseProfiler assay as depicted above. Compound A was also tested against IRAKl and Flt-3 (D835Y) using the same protocol with the substrates myelin basic protein (MBP) and EAIYAAPFAKKK respectively.
Protein s (with the exception of ATM(h) and DNA—PK(h)) were assayed in a radiometric format, whereas lipid s, ATM(h), ATR/ATRIP(h) and DNA-PK(h) were assayed using an HTRF® format.
Compound A was prepared to the 50x stock of test compound was added to the assay well, before a reaction mix containing the enzyme and substrate was added. The reaction was initiated by the addition of ATP at the selected concentration. There was no cubation of the compound with the /substrate mix prior to ATP addition. a working stock of 50x final assay concentration in 100% DMSO.
Results are expressed as kinase activity remaining, as a percentage of the DMSO control.
This is calculated using the following formula: Mean of Sample Counts — Mean of Blank Counts Mean of Control Counts For IC50 determinations, data were analyzed using XLFit version 5.3 (ID Business Solutions). Sigmoidal dose—response (variable slope) curves are fit based on the mean result for each test concentration using non-linear regression analysis. Where the top and/or bottom of the curve fall >10% out with 100 and 0, respectively, either or both of these limits may be constrained at 100 and 0, ed that the QC criterion on R2 is met. Table 1 provides IC50 data on entative kinase inhibition by Compound A.
Table 1 Compound A was also tested against each of the selected kinases using the DiscoverX standard scan and T assays and following the relevant standard operating procedures.
See, e.g., Nat. Biotechnol. 2011, 29(11):1046-51. KINOMEscan and KdELECT is based on a competition g assay that quantitatively measures the ability of a nd to compete with an immobilized, -site directed ligand. The assay is performed by combining three components: DNA-tagged kinase; lized 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. Binding constants (Kds) were calculated with a standard dose-response curve.
Table 1B shows the activity of Compound A against IRAKl, IRAK4 and numerous variants of FLT-3, indicating its y as a dual IRAK/FLT-3 inhibitor. It is expected that structurally analogous compounds possess this dual activity to a similar extent.
Table 1B Binding Kct of Compound A to various kinases Kinase Kd (nM) IRAK4 23 IRAK1 100-1,000 FLT3 31 FLT3(D835H) 4.6 FLT3(D835V) 44 FLT3(D835Y) 2.5 FLT3 (ITD) 7.8 FLT3 (ITD, D835V) 31 FLT3 (ITD, F691L) 20 FLT3 (K663Q) 47 FLT3 (N8411) 16 For example, Compound A shows exceptional binding to FLT-3 with ITD mutations and with mutations in the activation loop, such as D835Y. These mutations occur in one-third of all treatment-naive AML patients. Known inhibitors of activation loop mutated FLT-3 are not equipotent. See, e.g., Nguyen, B., et al., Oncotarget 2017 pgs. 1-14; , J. Med. Sci. 2015 77:7-17. In st, Compound A binds D835Y mutant FLT-3 at 2.5 nM, and ITD mutant FLT- 3 at 7.8 nM. e 2: AML Model MV 4-11 in vitro Assay The CellTiter Glo Luminescent cell viability assay is a highly sensitive homogenous assay to determine the number of viable cells in culture based on quantitation of ATP levels in metabolically active cells. Addition of CTG reagent results in cell lysis and generation of a (The remainder of this page has been left blank intentionally) luminescent signal proportional to the amount of ATP present. The amount of ATP is proportional to the number of cells present. The luminescence is measured using a multilabel reader capable of measuring luminescence. An se or decrease in cell numbers results in a concomitant change in luminescene level, indicating the effect of the test material on cellular proliferation.
Preparation of solutions/reagents Preparation of CTG t: CellTiter-Glo buffer was thawed and equilibrated to room temperature. Lyophilized CellTiter-Glo substrate was brought to room temperature. CTG reagent is prepared by mixing the CellTiter-Glo buffer (Promega Cat# G7572) into an amber bottle containing CellTiter—Glo substrate to reconstitute the lyophilized enzyme/substrate mixture. Both Buffer and the lyophilized substrate are supplied with the kit.
Media preparation: Add 1% Penicillin Streptomycin and 10% PBS to commercially available liquid IMDM (Iscove‘s Modified Dulbecco‘s Medium, Invitrogen Cat# 12440046).
Preparation of 1X PBS (Phosphate Buffered ): One pouch of PBS powder (Sigma: Cat#P3813) was dissolved in IL MiliQ water. DMSO is used a vehicle do dissolve the test item.
Procedure gleo determination) 1. MV4-11 cells were d and re-suspended to a density of 0.1 x 106 cells/ ml in complete IMDM medium. 95 uL of this cell suspension was added per well of a 96—well plate (black plate with clear bottom) to seed ~0.1 X 105 cells per well. The plates were incubated at 37 CC under a fied atmosphere of 5% C02 for ~ 2 hours before compound addition. 2. Test compounds were dissolved in 100% DMSO to generate a 2/6/10/20 mM stock on. A 200X tration of the required final concentrations was ed in DMSO. 10 uL of each concentration (200X) was then diluted in 90 ML of serum—free IMDM to prepare an intermediate concentration of 20X in medium. The DMSO concentration in this step was 10% (Intermediate dilution). 5 uL of each intermediate on was then added in triplicates to cells previously seeded in 96-well plate. The final DMSO concentration was 0.5% in the experimental wells. Cells treated with 0.5% DMSO served as a positive control. 100 ML of complete IMDM medium served as media blank for data analysis. 200 uL of 1X PBS was added in all corner wells of the assay plate to avoid evaporation of media in experimental wells. Plates were then incubated for 72 hours in an incubator with 5% C02 at 37 °C. 3. To terminate the assay, 50 ML of CTG reagent was added to each well and the plate was incubated at room temperature for 15 minutes on a shaker. The plate was read using the luminescence mode on a multilabel reader capable of measuring luminescence. The luminescence values were plotted against respective concentrations of the test item using GraphPad Prism to calculate the IC50 value for the test item. t inhibition is calculated as follows: Percent (%) Inhibition was calculated by normalizing DMSO l values to 0% inhibition using the formula: % tion = 100 - (L mpounmblan? / (L positive control . blank) *100 where L is Luminescence Experimental wells contained cells, test nd, IMDM medium and 0.5% DMSO. Positive control wells contained cells, IMDM medium and 0.5% DMSO. Blank control wells contained IMDM medium alone.
The IC50 values for the following compounds in HM are given in Table 2. A is <0.05 "M, B is 0.05 to 0.5 uM, and C is > 0.5 uM.
Table 2 MV4-11 MV4-11 MV4-11 MV4-11 Structure Example 3: Cellular Proliferation Inhibition in MV 4-11 Xenograft Model Using the procedure of Example 2, Compounds A and B were assessed to determine the % inhibition of proliferation in MV4-ll cells. The IC50 of Compound A was 0.031 µM () and Compound B was 6.le-005 µM ().
Example 4: In vivo Tumor Growth Inhibition in AML Xenograft Model MV 4-11 Using an AML Xenograft Model MV 4-11 ol, Compound A was evaluated at 12.5, 25, and 50 mpk doses. ND-2158 at 100 mpk was used as a control. The antitumor ty of Compound A was evaluated in male athymic nude mice. MV 4-11 cells were grown in Iscove's Modified Dulbecco's medium supplemented with 10% FBS and 1% llin streptomycin. To establish tumors, 15 x 106 MV4-l l cells were injected subcutaneously in 200 µl of 1:1 HBSS and ECM gel into the right flank of the athymic nude mice. Animals were randomized based on tumor volumes. For 21 days, Compound A was dosed orally once daily and ND-2158 was dosed once daily by i.p. route. Treatments were initiated when the e tumor volume sizes were 333 mm3 Tumor volumes were measured three times a week and body weights were monitored daily. Compound A at 12.5, 25, and 50 mg/kg and ND-2158 100 mg/kg treatments were well tolerated without any treatment related clinical signs and gross pathological changes. depicts the increase m tumor growth inhibition with sing doses of Compound A. Tumor growth stasis was achieved at 12.5 mpk and tumor regression was seen at 25 and 50 mpk after 21 days of treatment. Compound A at 12.5 mg/kg treatment resulted in 92% tumor growth inhibition. nd A at 25 mg/kg and 50 mg/kg ents resulted in l tumor regression. ND-2158 100 mg/kg treatment resulted in 68% tumor growth inhibition. No body weight reduction was observed, as shown in Example 5: Anti-Proliferative Activity in AML Xenograft Models MV4-11 and MOLM- The same procedure was used for both the MV4-ll cells and MOLM-13 cells. Each cell line has an ITD mutation in the FLT-3 kinase.
The cells were grown to -80% confluence, split in half and grown overnight. The cells were seeded at a density of 5,000 cells/well in a volume of 150 µL into a 96-well black plate in all wells except s 1 and 12 and rows A and H. They were incubated overnight in 10% serum and HBSS was added to wells on the periphery. In a deep 96-well plate, 1000 µL of 10% FBS was added into wells B2 and D2. 750 µL of 10% FBS, 1 % DMSO medium per well was added in row B except well B2. 5 µL of 20mM compound was added into well B2. 250 µL was transferred from column 2 to column 3 and mixed. The process was repeated until column G to give a 1 :4 dilution. 15 µL of compound mixture was added to each well of the cell plate (135 µL volume). The CellTiter Glo assay bed in Example 2 was used to determine the ICso value for Compound A in each cell line. Compound A had an ICso of 0.07 µM in the MV 4-11 cell line and 0.19 µMin the MOLM-13 cell line. e 6: In vivo efficacy of Compound A in MOLM-14 FLT3-ITD and MOLM-14 FLT3-ITD/KD (kinase ) mouse xenograft tumor models Compound A was administered orally at 100 mg/kg once-daily in athymic nude mice bearing subcutaneous MOLM-14 FLT3-ITD, MOLM-14 FLT3-ITD/F691L, or MOLM-14 FLT3-ITD/D835Y tumors. Compound A efficacy was compared to mice administered vehicle.
As shown in FIGS. 4A, 4B, and 4C, the percent tumor growth tion(% TGI) was 90, 73 and 98%, respectively, after 12 or 14 days of dosing.
Example 7: Cell Viability Assay The parental MOLM-14 cell line contained a FLT3-ITD mutation. Quizartinib-resistant MOLM-14 tive cell lines MOLM-14 TD/D835Y and MOLM-14 FLT3- ITD/F691L contained a double FLT3 on (the original ITD mutation and a ary mutation within the kinase domain).
All cells lines were cultured in RPMI 1640 + GlutaMAX supplemented with lX PenStrep and 10% FBS (referred to as media hereafter). Cells were cultured in 75 cm2 or 225 cm2 tissue culture flasks in a 37°C humidified tissue culture incubator with 5% CO2. Cell densities were maintained between 0.5-2.0xl06 cells/mL.
Plating and Dosing Two days before compound treatment, cells were pelleted and resuspended in fresh . The day of dosing, cells were counted and stained with trypan blue to determine cell viability. 5,000 viable cells were transferred in a volume of 90 µLor 135 µL per well to all wells of a 96-well tissue culture plate and ed to the tissue culture incubator. In general, two rows of each cell line to be assayed were added per plate (i.e., maximum of 3 cell lines per plate). The lower limit of viability for cells was 80% for use in this assay; the majority of cell lines ted >90% viability.
Compound stock solutions prepared in 100% DMSO were removed 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 compound stock solution was erred to well B2. 30 µL of DMSO was added to wells B3 to B 11. 10 µL from well B2 was transferred to well B3, mixed by pipetting up and down 6 times resulting in a 1 in 4 dilution. ative volumes or dilution ratios may have been employed. Changing pipet tips between on steps, the dilution series was continued until well B10. Well B11 is the DMSO-treated control sample. 198 uL of media was transferred to each well of rows B-G and columns 2-11 of a new 96-well plate. 2 uL from the Compound A DMSO dilution-series plate was transferred to the corresponding wells of each row containing the 198 uL of media and mixed by pipetting 6 times, ng a 10X Compound A dilution-series dosing plate.
From the 10X Compound A dilution-series dosing plate, 10 uL or 15 uL of the diluted compounds were added to the l tissue culture plate containing 90 ML or 135 uL of cells, respectively. Plates were then brie?y mixed using a plate mixer at 150 rpms for two minutes.
The plates were returned to a tissue culture incubator and incubated at 370C for 72 hr. The final concentration of DMSO added to cells was 0.1%.
Each cell line was tested in duplicate per plate, and repeated at least 3 times on ent days.
Viability After 72 h incubation, cell viability was assessed using the CellTiter—Glo Luminescent Cell Viability Assay (2.0) according to the vendor‘s instructions. After addition of the CellTiter- Glo reagent (121 volume), plates were covered with clear plate sealers, followed by mixing on a plate shaker at 150 rpm in the dark for 10 s at emperature. Luminescence readings were measured using a TopCount3 84 instrument.
EC50 Calculation The percent inhibition of the compound treated samples was determined relative to the DMSO-treated cell control samples. The percent inhibition values were used to calculate EC50 values using GraphPad Prism 7 re. In assays where curve fitting failed to ine an EC50 value, the concentration causing 50% inhibition by linear olation was used as the EC50 value. The mean EC50 values from at least 3 independent viability assays performed on different days were determined.
MOLM—14 EC50 = 58 nM MOLM-14 FLT3-ITD/DS35Y, EC50 = 108 nM MOLM-14 FLT3-ITD/F691L, EC50 = 2488 nM Incorporation by Reference All publications and s mentioned herein are hereby orated by reference in their entirety as if each individual ation or patent were specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.
Equivalents While specific embodiments of the t invention have been discussed, the above ication is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.
Prior art Any discussion of the prior art hout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
Comprises or comprising The term "comprise" and variants of the term such as "comprises" or "comprising" are used herein to denote the inclusion of a stated integer or stated integers but not to exclude any other integer or any other integers, unless in the context or usage an exclusive interpretation of the term is required.
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Claims (66)

WE CLAIM:
1. Use of a compound in the manufacture of a medicament for treating acute myeloid leukemia (AML) or a myelodysplasia syndrome (MDS), wherein: i) the medicament is to be administered to a subject having a mutation in FLT-3 kinase selected from an internal tandem duplication (ITD), a on in D835, F691, K663, or N841, and an ITD in combination with a mutation in D835, F691, K663, or N841; or ii) the AML or MDS is ant to an FLT-3 kinase inhibitor; and the compound has a structure represented by formula II: or a pharmaceutically acceptable salt thereof; wherein X1 and X3 independently are CH or N; X2 is CR2 or N; provided one and not more than one of X1, X2 or X3 is N; A is O or S; Y is -CH2- or O; Z is aryl or heterocyclyl; R1, at each occurrence, is independently halo or optionally substituted cyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or -NRaRb; R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or -NRaRb; wherein the tuent is alkyl, amino, halo or hydroxyl; R3, at each occurrence, is alkyl or hydroxyl; Ra and Rb are ndently hydrogen, alkyl, acyl or heterocyclyl; ‘m’ and ‘n’ are independently 0, 1 or 2; and ‘p’ is 0 or 1.
2. The use of claim 1, wherein A is O or S; Y is -CH2- or O; Z is aryl or heterocyclyl; R1, at each occurrence, is independently halo or optionally tuted cyclyl, n the tuent is alkyl, aminoalkyl, halo, or -NRaRb; where R a and Rb are independently hydrogen, alkyl, or heterocyclyl; R2 is hydrogen, cycloalkyl, heterocyclyl or -NRaRb; ‘m’ is 0; and ‘n’ is 1.
3. The use of claim 1, wherein A is O or S; Y is -CH2- or O; Z is aryl or heterocyclyl; R1, at each occurrence, is independently halo or optionally substituted heterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl or -NRaRb; where R a and Rb are independently hydrogen, alkyl, or heterocyclyl; R2 is hydrogen, cycloalkyl, optionally substituted heterocyclyl or -NRaRb, where the substituent is selected from amino, halo or hydroxyl; ‘m’ and ‘n’ are independently 0, 1 or 2; and ‘p’ is 0 or 1.
4. The use of claim 1, or a pharmaceutically acceptable salt thereof, wherein
5. The use of any one of claims 1-4, wherein Z is aryl or 5- or 6-membered cyclyl.
6. The use of any one of claims 1-4, wherein Z is an optionally substituted heterocyclyl ed from phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, azetidinyl, oxetanyl, olidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl and azabicyclo[3.2.1]octanyl; each of which is optionally tuted with alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl or -NRaRb; and Ra and Rb are independently hydrogen, alkyl or acyl.
7. The use of claim 1, wherein the compound ented by a II is represented by formula (IIA): (IIA) or a pharmaceutically acceptable salt thereof.
8. The use of claim 7, wherein A is O or S; Y is -CH2- or O; R1, at each ence, is independently halo or optionally substituted heterocyclyl, wherein the substituent is alkyl, aminoalkyl, halo, or -NRaRb; where R a and Rb are independently en, alkyl, or heterocyclyl; R2 is hydrogen, cycloalkyl, heterocyclyl or -NRaRb; ‘m’ is 0; and ‘n’ is 1.
9. The use of claim 7, wherein A is O or S; Y is -CH2- or O; R1, at each occurrence, is independently halo or optionally substituted heterocyclyl; wherein the substituent is alkyl, alkoxy, lkyl, halo, hydroxyl or -NRaRb; where R a and Rb are independently en, alkyl, or heterocyclyl; R2 is hydrogen, cycloalkyl, optionally substituted cyclyl or -NRaRb, where the substituent is selected from amino, halo or hydroxyl; and ‘m’ and ‘n’ are independently 0, 1 or 2.
10. The use of claim 1, wherein the compound represented by formula II is represented by formula (IIB): (IIB) or a pharmaceutically acceptable salt thereof.
11. The use of claim 10, wherein A is O or S; Y is -CH2- or O; R1, at each occurrence, is independently halo or optionally substituted heterocyclyl, wherein the substituent is alkyl, aminoalkyl, halo, or -NRaRb; wh ere Ra and Rb are ndently hydrogen, alkyl, or cyclyl; R2 is hydrogen, cycloalkyl, heterocyclyl or -NRaRb; and ‘n’ is 1.
12. The use of claim 10, wherein A is O or S; Y is -CH2- or O; R1, at each occurrence, is independently halo or optionally substituted heterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl or -NRaRb; where R a and Rb are independently hydrogen, alkyl, or heterocyclyl; R2 is hydrogen, cycloalkyl, ally substituted heterocyclyl or -NRaRb, where the tuent is selected from amino, halo or hydroxyl; and ‘m’ and ‘n’ are independently 0, 1 or 2.
13. The use of claim 1, wherein the compound represented by formula II is represented by formula (IIC) (IIC) or a pharmaceutically acceptable salt f.
14. The use of any one of claims 1-13, wherein R1 is optionally substituted heterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or ; and Ra and Rb are independently hydrogen or acyl.
15. The use of any one of claims 1-13, wherein R1 is ally substituted heterocyclyl; n the substituent is alkyl, aminoalkyl, halo, or -NRaRb; and Ra and Rb are independently hydrogen or acyl.
16. The use of any one of claims 1-13, wherein R1 is optionally substituted heterocyclyl; and the substituent is alkyl, aminoalkyl, halo, or -NRaRb; where Ra and Rb are independently hydrogen, alkyl, or heterocyclyl.
17. The use of any one of claims 1-13, wherein R1 is optionally substituted heterocyclyl; and the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl or ; where Ra and Rb are independently hydrogen, alkyl, or heterocyclyl.
18. The use of any one of claims 14-17, wherein R1 is pyridyl, pyrazolyl, pyrrolidinyl or piperidinyl.
19. The use of any one of claims 14-17, wherein R1 is ally substituted pyrazolyl, wherein the substituent is alkyl, hydroxyl or -NRaRb.
20. The use of any one of claims 1-13, wherein R1 is halo.
21. The use of any one of claims 1-20, wherein R2 is hydrogen, lkyl, heterocyclyl or - NRaRb.
22. The use of any one of claims 1-20, wherein R2 is hydrogen, cycloalkyl, optionally substituted heterocyclyl or -NRaRb, where the tuent is ed from amino, halo or hydroxyl.
23. The use of any one of claims 1-20, wherein R2 is optionally substituted heterocyclyl ed from piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolyl, furanyl or azabicyclo[3.2.1]octanyl; wherein the substituent is hydroxyl, halo, alkyl or amino.
24. The use of any one of claims 1-20, wherein R2 is piperidinyl, pyrrolidinyl, morpholinyl, or piperazinyl.
25. The use of any one of claims 1-20, wherein R2 is hydrogen.
26. The use of any one of claims 1-20, n R2 is cycloalkyl.
27. The use of claim 26, wherein R2 is cyclopropyl.
28. The use of any one of claims 1-27, wherein R3 is alkyl.
29. The use of any one of claims 1-28, wherein m is 0 and p is 1.
30. The use of any one of claims 1-28, wherein m is 0 or 2, and p is 0 or 1.
31. The use of claim 1, wherein the compound represented by formula (II) is selected from: 6'-amino-N-(2-morpholinooxazolo[4,5-b]pyridinyl)-[2,3'-bipyridine] carboxamide; 6'-amino-N-(5-cyclopropylmorpholinooxazolo[4,5-b]pyridinyl)-[2,3'- bipyridine]carboxamide hydrochloride; N-(5-cyclopropylmorpholinooxazolo[4,5-b]pyridinyl)(2-methylpyridin yl)oxazolecarboxamide hydrochloride; N-(2,5-di(piperidinyl)oxazolo[4,5-b]pyridinyl)(1H-pyrazolyl)picolinamide hydrochloride; N-(2,5-di(piperidinyl)oxazolo[4,5-b]pyridinyl)(2-methylpyridin zolecarboxamide; N-(2-morpholino(piperidinyl)oxazolo[4,5-b]pyridinyl)(1H-pyrazol yl)picolinamide; ethylpyridinyl)-N-(2-morpholino(piperidinyl)oxazolo[4,5-b]pyridin yl)oxazolecarboxamide; 6-chloro-N-(2-morpholino(piperidinyl)oxazolo[4,5-b]pyridinyl)picolinamide; N-(2,5-di(piperidinyl)oxazolo[4,5-b]pyridinyl)(1-methyl-1H-pyrazol yl)picolinamide; 2-(2-chloropyridinyl)-N-(2,5-di(piperidinyl)oxazolo[4,5-b]pyridinyl)oxazole- 4-carboxamide; (S)(2-methylpyridinyl)-N-(2-morpholino(pyrrolidinylamino)oxazolo[4,5- b]pyridinyl)oxazolecarboxamide; 6'-amino-N-(2-morpholinooxazolo[5,4-b]pyridinyl)-[2,3'-bipyridine] amide; no-N-(2-morpholinothiazolo[4,5-c]pyridinyl)-[2,3'-bipyridine] carboxamide; 6'-amino-N-(2-morpholinothiazolo[5,4-b]pyridinyl)-[2,3'-bipyridine] carboxamide; 2-(2-methylpyridinyl)-N-(2-morpholinothiazolo[4,5-b]pyridinyl)oxazole carboxamide; 6'-amino-N-(2-morpholinothiazolo[4,5-b]pyridinyl)-[2,3'-bipyridine] carboxamide; N-(2-morpholinothiazolo[4,5-b]pyridinyl)(1H-pyrazolyl)picolinamide; 3-(4-(aminomethyl)piperidinyl)fluoro-N-(2-morpholinothiazolo[4,5-b]pyridin- 6-yl)benzamide; 2-(4-(aminomethyl)piperidinyl)fluoro-N-(2-morpholinothiazolo[4,5-b]pyridin- 6-yl)benzamide; 2-(2-methylpyridinyl)-N-(2-morpholino(piperidinyl)thiazolo[4,5-b]pyridin yl)oxazolecarboxamide; N-(2-morpholino(piperidinyl)thiazolo[4,5-b]pyridinyl)(1H-pyrazol yl)picolinamide; N-(2,5-di(piperidinyl)thiazolo[4,5-b]pyridinyl)(1H-pyrazol olinamide; N-(2,5-di(piperidinyl)thiazolo[4,5-b]pyridinyl)(2-methylpyridin yl)oxazolecarboxamide; N-(2,5-dimorpholinooxazolo[4,5-b]pyridinyl)(2-methylpyridinyl)oxazole carboxamide; N-(5-(4-methylpiperazinyl)morpholinooxazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; N-(2,5-di(piperidinyl)oxazolo[4,5-b]pyridinyl)(6-methoxypyridin yl)oxazolecarboxamide; N-(2,5-di(piperidinyl)oxazolo[4,5-b]pyridinyl)(2-methylpyridin yl)oxazolecarboxamide; -di(piperidinyl)oxazolo[4,5-b]pyridinyl)(2-hydroxypyridin yl)oxazolecarboxamide; 2-(2-hydroxypyridinyl)-N-(2-morpholino(piperidinyl)oxazolo[4,5-b]pyridin- 6-yl)oxazolecarboxamide; N-(2,5-di(piperidinyl)oxazolo[4,5-b]pyridinyl)(6-hydroxypyridin yl)oxazolecarboxamide; 2-(2-methoxypyridinyl)-N-(2-morpholino(piperidinyl)oxazolo[4,5-b]pyridin- xazolecarboxamide; 2-(2-methylpyridinyl)-N-(2-morpholino(piperidinyl)oxazolo[4,5-b]pyridin yl)oxazolecarboxamide; 2-(3-methylpyridinyl)-N-(2-morpholino(piperidinyl)oxazolo[4,5-b]pyridin yl)oxazolecarboxamide; N-(2,5-di(piperidinyl)oxazolo[4,5-b]pyridinyl)(3-methylpyridin yl)oxazolecarboxamide; 2-(6-methylpyridinyl)-N-(2-morpholino(piperidinyl)oxazolo[4,5-b]pyridin yl)oxazolecarboxamide; 6-(1-methyl-1H-pyrazolyl)-N-(2-morpholino(piperidinyl)oxazolo[4,5- b]pyridinyl)picolinamide; N-(2,5-di(piperidinyl)oxazolo[4,5-b]pyridinyl)(6-methylpyridin zolecarboxamide; (S)-N-(5-(3-aminopyrrolidinyl)morpholinooxazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; (S)-N-(5-(3-hydroxypyrrolidinyl)morpholinooxazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; (R)-N-(5-(3-aminopyrrolidinyl)morpholinooxazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; (R)-N-(5-(3-hydroxypyrrolidinyl)morpholinooxazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; (S)(3-aminopyrrolidinyl)-N-(2-morpholino(piperidinyl)oxazolo[4,5- b]pyridinyl)oxazolecarboxamide; (S)(3-hydroxypyrrolidinyl)-N-(2-morpholino(piperidinyl)oxazolo[4,5- b]pyridinyl)picolinamide; (S)(3-aminopyrrolidinyl)-N-(2-morpholino(piperidinyl)oxazolo[4,5- b]pyridinyl)picolinamide; (S)(3-hydroxypyrrolidinyl)-N-(2-morpholino(piperidinyl)oxazolo[4,5- b]pyridinyl)oxazolecarboxamide; (S)-N-(5-cyclopropylmorpholinooxazolo[4,5-b]pyridinyl)(3- hydroxypyrrolidinyl)oxazolecarboxamide; (S)(3-aminopyrrolidinyl)-N-(5-cyclopropylmorpholinooxazolo[4,5-b]pyridin- 6-yl)oxazolecarboxamide; ethylpyridinyl)-N-(5-(piperidinyl)(pyrrolidinyl)oxazolo[4,5- dinyl)oxazolecarboxamide hydrochloride; N-(2-(2,6-dimethylmorpholino)(piperidinyl)oxazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide hydrochloride; N-(2,5-di(piperidinyl)thiazolo[4,5-b]pyridinyl)(1-methyl-1H-pyrazol yl)picolinamide hydrochloride; 6-(1-methyl-1H-pyrazolyl)-N-(2-morpholino(piperidinyl)thiazolo[4,5- dinyl)picolinamide; N-(2,5-di(piperidinyl)thiazolo[4,5-b]pyridinyl)(2-methylpyridin yl)oxazolecarboxamide hydrochloride; N-(2-((2S,6R)-2,6-dimethylmorpholino)(piperidinyl)thiazolo[4,5-b]pyridin yl)(2-methylpyridinyl)oxazolecarboxamide; 2-(2-methylpyridinyl)-N-(2-morpholino(piperidinyl)thiazolo[4,5-b]pyridin yl)oxazolecarboxamide; 2-(2-hydroxypyridinyl)-N-(2-morpholino(piperidinyl)thiazolo[4,5-b]pyridin- 6-yl)oxazolecarboxamide; N-(2,5-di(piperidinyl)thiazolo[4,5-b]pyridinyl)(2-methoxypyridin yl)oxazolecarboxamide; 2-(6-methoxypyridinyl)-N-(2-morpholino(piperidinyl)thiazolo[4,5-b]pyridin- 6-yl)oxazolecarboxamide; ethoxypyridinyl)-N-(2-morpholino(piperidinyl)thiazolo[4,5-b]pyridin- 6-yl)oxazolecarboxamide; (S)-N-(5-(3-fluoropiperidinyl)morpholinothiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; 2-(6-methylpyridinyl)-N-(2-morpholino(piperidinyl)thiazolo[4,5-b]pyridin yl)oxazolecarboxamide; 2-(3-methylpyridinyl)-N-(2-morpholino(piperidinyl)thiazolo[4,5-b]pyridin yl)oxazolecarboxamide; (S)(3-aminopyrrolidinyl)-N-(2-morpholino(piperidinyl)thiazolo[4,5- b]pyridinyl)picolinamide; (S)(3-hydroxypyrrolidinyl)-N-(2-morpholino(piperidinyl)thiazolo[4,5- b]pyridinyl)picolinamide; (S)(3-aminopyrrolidinyl)-N-(2,5-di(piperidinyl)thiazolo[4,5-b]pyridin yl)picolinamide; (S)-N-(2,5-di(piperidinyl)thiazolo[4,5-b]pyridinyl)(3-hydroxypyrrolidin yl)picolinamide; (S)(3-aminopyrrolidinyl)-N-(2-morpholino(piperidinyl)thiazolo[4,5- dinyl)oxazolecarboxamide; (S)-N-(5-(3-aminopyrrolidinyl)morpholinothiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; (S)(3-aminopyrrolidinyl)-N-(5-cyclopropylmorpholinothiazolo[4,5- b]pyridinyl)oxazolecarboxamide; N-(5-cyclopropylmorpholinothiazolo[4,5-b]pyridinyl)(2-methylpyridin yl)oxazolecarboxamide; (S)(3-hydroxypyrrolidinyl)-N-(2-morpholino(piperidinyl)thiazolo[4,5- b]pyridinyl)oxazolecarboxamide; (S)-N-(5-(3-hydroxypyrrolidinyl)morpholinothiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; (S)-N-(5-cyclopropylmorpholinothiazolo[4,5-b]pyridinyl)(3- hydroxypyrrolidinyl)picolinamide; (S)-N-(5-cyclopropylmorpholinothiazolo[4,5-b]pyridinyl)(3- hydroxypyrrolidinyl)oxazolecarboxamide; (S)-N-(5-cyclopropylmorpholinothiazolo[4,5-b]pyridinyl)(1-(2- hydroxypropyl)-1H-pyrazolyl)picolinamide; (S)-N-(5-cyclopropylmorpholinothiazolo[4,5-b]pyridinyl)(1-(2- hydroxypropyl)-1H-pyrazolyl)oxazolecarboxamide; N-(5-(3-hydroxypyrrolidinyl)morpholinothiazolo[4,5-b]pyridinyl)(6- ypyridinyl)oxazolecarboxamide; (S)-N-(5-(3-hydroxypyrrolidinyl)morpholinothiazolo[4,5-b]pyridinyl)(6- methoxypyridinyl)oxazolecarboxamide; (R)-N-(5-(3-hydroxypyrrolidinyl)morpholinothiazolo[4,5-b]pyridinyl)(6- ypyridinyl)oxazolecarboxamide; (S)-N-(5-(azetidinyl)morpholinothiazolo[4,5-b]pyridinyl)(3- hydroxypyrrolidinyl)picolinamide; N-(5-(3-hydroxyazetidinyl)morpholinothiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; (5-(3-hydroxypyrrolidinyl)morpholinothiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)thiophenecarboxamide; (S)-N-(5-(3-hydroxypyrrolidinyl)morpholinothiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)furancarboxamide; (S)-N-(5-(3-hydroxypiperidinyl)morpholinothiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; N-(5-(4-hydroxypiperidinyl)morpholinothiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide (R)-N-(5-(3-hydroxypyrrolidinyl)morpholinothiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; N-(5-(4-hydroxypiperidinyl)morpholinothiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)furancarboxamide; azetidinyl)(piperidinyl)thiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; 2-(2-methylpyridinyl)-N-(2-(piperidinyl)(pyrrolidinyl)thiazolo[4,5- b]pyridinyl)oxazolecarboxamide; ethylpyridinyl)-N-(2-morpholino(pyrrolidinyl)thiazolo[4,5-b]pyridin- 6-yl)oxazolecarboxamide; 5-(2-methylpyridinyl)-N-(2-morpholino(piperidinyl)thiazolo[4,5-b]pyridin yl)furancarboxamide; N-(5-(azepanyl)morpholinothiazolo[4,5-b]pyridinyl)(2-methylpyridin yl)oxazolecarboxamide; 2-(2-aminopyridinyl)-N-(2-morpholino(piperidinyl)thiazolo[4,5-b]pyridin yl)oxazolecarboxamide hydrochloride; N-(5-(azetidinyl)morpholinothiazolo[4,5-b]pyridinyl)(2-methylpyridin yl)oxazolecarboxamide; (R)-N-(5-(3-hydroxypiperidinyl)morpholinothiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; (R)-N-(5-(3-hydroxypiperidinyl)morpholinothiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)furancarboxamide; (1-(2-hydroxypropyl)-1H-pyrazolyl)-N-(2-morpholino(piperidin yl)thiazolo[4,5-b]pyridinyl)picolinamide N-(5-(4-fluoropiperidinyl)morpholinothiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)furancarboxamide N-(5-(4-fluoropiperidinyl)morpholinothiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide hydrochloride N-(5-(1-methyl-1H-pyrazolyl)morpholinothiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; N-(5-(3-fluorophenyl)morpholinothiazolo[4,5-b]pyridinyl)(2-methylpyridin- 4-yl)oxazolecarboxamide; N-(5-(4-hydroxypiperidinyl)morpholinothiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)furancarboxamide; N-(5-(3-fluoropiperidinyl)morpholinothiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)furancarboxamide; (S)-N-(5-(3-hydroxypyrrolidinyl)morpholinooxazolo[4,5-b]pyridinyl)(6- methoxypyridinyl)oxazolecarboxamide; N-(5-(3-hydroxypyrrolidinyl)morpholinooxazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; (5-(3-hydroxypyrrolidinyl)morpholinooxazolo[4,5-b]pyridinyl)(6- methoxypyridinyl)oxazolecarboxamide; N-(5-(3-hydroxypyrrolidinyl)morpholinooxazolo[4,5-b]pyridinyl)(6- methoxypyridinyl)oxazolecarboxamide; (S)-N-(5-(3-hydroxypyrrolidinyl)morpholinooxazolo[4,5-b]pyridinyl)(2- methylpyridinyl)furancarboxamide; (S)-N-(5-(3-hydroxypyrrolidinyl)morpholinooxazolo[4,5-b]pyridinyl)(2- methylpyridinyl)thiophenecarboxamide; N-(5-(azetidinyl)(piperidinyl)oxazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; 2-(2-methylpyridinyl)-N-(2-(piperidinyl)(pyrrolidinyl)oxazolo[4,5- b]pyridinyl)oxazolecarboxamide; 5-(2-methylpyridinyl)-N-(2-morpholino(piperidinyl)oxazolo[4,5-b]pyridin yl)furancarboxamide; N-(5-(azetidinyl)morpholinooxazolo[4,5-b]pyridinyl)(2-methylpyridin yl)oxazolecarboxamide; ethylpyridinyl)-N-(2-morpholino(pyrrolidinyl)oxazolo[4,5-b]pyridin- 6-yl)oxazolecarboxamide; 4-hydroxypiperidinyl)morpholinooxazolo[4,5-b]pyridinyl)(2- methylpyridinyl)furancarboxamide; (R)-N-(5-(3-hydroxypiperidinyl)morpholinooxazolo[4,5-b]pyridinyl)(2- methylpyridinyl)furancarboxamide; N-(5-(furanyl)morpholinooxazolo[4,5-b]pyridinyl)(2-methylpyridin yl)oxazolecarboxamide; N-(5-(3-fluoropiperidinyl)morpholinooxazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; 4-hydroxypiperidinyl)morpholinooxazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; N-(5-(4-fluoropiperidinyl)morpholinooxazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; (S)-N-(5-(3-aminopiperidinyl)morpholinothiazolo[4,5-b]pyridinyl)(2- pyridinyl)oxazolecarboxamide; 2-(2-methylpyridinyl)-N-(2-morpholino(1H-pyrazolyl)thiazolo[4,5- b]pyridinyl)oxazolecarboxamide; N-(5-(6-fluoropyridinyl)morpholinothiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; N-(5-(3-hydroxyazabicyclo[3.2.1]octanyl)morpholinothiazolo[4,5-b]pyridin- 6-yl)(2-methylpyridinyl)oxazolecarboxamide; N-(2-(3-hydroxypiperidinyl)(piperidinyl)thiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; 2-(2-acetamidopyridinyl)-N-(5-(4-hydroxypiperidinyl) morpholinothiazolo[4,5-b]pyridinyl)oxazolecarboxamide; N-(2-(3-hydroxypiperidinyl)(4-hydroxypiperidinyl)thiazolo[4,5-b]pyridin yl)(2-methylpyridinyl)oxazolecarboxamide; 2-(2-acetamidopyridinyl)-N-(5-(3-hydroxypiperidinyl) morpholinothiazolo[4,5-b]pyridinyl)oxazolecarboxamide; 2-(2-aminopyridinyl)-N-(5-(3-hydroxypiperidinyl)morpholinothiazolo[4,5- b]pyridinyl)oxazolecarboxamide hydrochloride; 5-(2-aminopyridinyl)-N-(5-(4-hydroxypiperidinyl)morpholinothiazolo[4,5- b]pyridinyl)furancarboxamide hydrochloride; 2-(2-aminopyridinyl)-N-(5-(4-hydroxypiperidinyl)morpholinothiazolo[4,5- dinyl)oxazolecarboxamide hydrochloride; 2-(2-aminopyridinyl)-N-(5-(4-fluoropiperidinyl)morpholinothiazolo[4,5- b]pyridinyl)oxazolecarboxamide hydrochloride; N-(5-(2-fluoropyridinyl)morpholinothiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; N-(5-(4-fluoropiperidinyl)(3-hydroxypiperidinyl)thiazolo[4,5-b]pyridin yl)(2-methylpyridinyl)oxazolecarboxamide; N-(5-(4-aminopiperidinyl)(3-hydroxypiperidinyl)thiazolo[4,5-b]pyridin (2-methylpyridinyl)oxazolecarboxamide hloride; and N-(5-(2-hydroxypyridinyl)morpholinothiazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide hydrochloride; or a pharmaceutically acceptable salt thereof.
32. The use of claim 1, wherein the compound represented by formula (II) is selected from: 6'-amino-N-(2-morpholinooxazolo[5,4-b]pyridinyl)-[2,3'-bipyridine]carboxamide; N-(5-(4-hydroxypiperidinyl)morpholinooxazolo[4,5-b]pyridinyl)(2-methylpyridin yl)furancarboxamide; N-(2,5-di(piperidinyl)oxazolo[4,5-b]pyridinyl)(1H-pyrazolyl)picolinamide hydrochloride; and (5-(3-hydroxypyrrolidinyl)morpholinooxazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; or a pharmaceutically acceptable salt thereof.
33. The use of claim 1, wherein the compound represented by formula (II) is selected from: N-(5-(3-fluoropiperidinyl)morpholinothiazolo[4,5-b]pyridinyl)(2-methylpyridin yl)furancarboxamide; N-(5-(azepanyl)morpholinothiazolo[4,5-b]pyridinyl)(2-methylpyridinyl)oxazole- 4-carboxamide; (R)-N-(5-(3-hydroxypyrrolidinyl)morpholinooxazolo[4,5-b]pyridinyl)(2- methylpyridinyl)oxazolecarboxamide; and N-(2,5-di(piperidinyl)thiazolo[4,5-b]pyridinyl)(1H-pyrazolyl)picolinamide; or a pharmaceutically able salt thereof.
34. The use of claim 1, n the compound is or a pharmaceutically acceptable salt thereof.
35. The use of claim 1, n the compound is or a pharmaceutically acceptable salt thereof.
36. The use of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.
37. The use of claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.
38. The use of claim 1, wherein the compound is or a ceutically acceptable salt thereof.
39. The use of claim 1, wherein the compound is .
40. The use of claim 1, wherein the compound is .
41. The use of claim 1, wherein the compound is .
42. The use of claim 1, wherein the compound is .
43. The use of claim 1, wherein the compound is .
44. The use of claim 1, wherein the compound is a pharmaceutically acceptable salt of
45. The use of claim 1, n the compound is a pharmaceutically acceptable salt of
46. The use of claim 1, wherein the compound is a pharmaceutically acceptable salt of
47. The use of claim 1, wherein the compound is a pharmaceutically acceptable salt of
48. The use of claim 1, wherein the nd is a pharmaceutically acceptable salt of
49. The use of claim 1, wherein the compound is .
50. The use of claim 1, wherein the compound is a pharmaceutically acceptable salt of
51. The use of claim 1, wherein the compound is .
52. The use of claim 1, wherein the compound is a pharmaceutically acceptable salt of
53. The use of any one of claims 1-48, n the medicament is to be administered to a t having a on in FLT-3 kinase selected from an internal tandem duplication (ITD), a mutation in D835, F691, K663, or N841, and an ITD in combination with a mutation in D835, F691, K663, or N841.
54. The use of claim 53, wherein the mutation is D835H.
55. The use of claim 53, wherein the mutation is D835V.
56. The use of claim 53, wherein the mutation is D835Y.
57. The use of claim 53, wherein the mutation is K663Q.
58. The use of claim 53, wherein the mutation is N841I.
59. The use of claim 53, wherein the mutation is ITD and D835V.
60. The use of claim 53, wherein the mutation is ITD and F691L.
61. The use of claim 53, wherein the mutation is ITD and D835Y.
62. The use of any one of claims 1-61, wherein the medicament is for treating AML.
63. The use of claim 62, wherein the AML is resistant to a FLT-3 kinase inhibitor.
64. The use of any one of claims 1-61, wherein the medicament is for treating MDS.
65. The use of claim 64, wherein the MDS is resistant to a FLT-3 kinase inhibitor.
66. The use of any one of claims 1-65, substantially as herein described with reference to any one or more of the examples but excluding ative examples.
NZ757707A 2018-03-30 Compounds and compositions for treating hematological disorders NZ757707B2 (en)

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