Compounds for treating bone marrow diseases associated with chromosomal abnormalities

Abstract

The present invention provides a compound of formula (I): [Formula 1] JPEG2026507675000024.jpg55159 or a pharmaceutically acceptable salt or solvate thereof.

Description

[Technical Field]

[0001] The present invention relates to a compound or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of bone marrow disorders, such as acute myeloid leukemia (AML), in subjects with at least one chromosomal abnormality of 3q21 and / or 3q26. [Background technology]

[0002] Bone marrow disorders, such as acute myeloid leukemia, acute myelomonocytic leukemia, myelodysplastic syndromes, chronic myeloid leukemia, and myeloproliferative neoplasms, are a group of diseases involving cells from the myeloid lineage at various stages of differentiation or maturation, in which immature myeloid cells (myeloid progenitor cells) proliferate abnormally in the bone marrow and / or blood, resulting in dysfunction of bone marrow function, abnormal blood cell production, and impaired immune function.

[0003] One of the hallmarks of these diseases is their significant heterogeneity. Indeed, numerous genetic mutations and / or chromosomal abnormalities have been identified as risk or causative factors for bone marrow disorders.

[0004] For example, approximately half of de novo acute myeloid leukemia (AML) cases are associated with one or more specific chromosomal abnormalities. In particular, abnormalities of chromosome 3, such as inversion inv(3)(q21q26.2) or translocation t(3;3)(q21;q26.2), have been reported in patients with AML and myelodysplastic syndrome (MDS); these diseases are primarily differentiated by the bone marrow blast ratio (a bone marrow blast ratio of less than 20% indicates MDS, and a bone marrow blast ratio of more than 20% indicates AML). AML and MDS with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) are significantly more aggressive and difficult to treat (Raya et al. Hematology vol. 20, 8(2015): 435-441).

[0005] This aspect is particularly problematic because patients with specific chromosomal abnormalities may respond poorly to first-line chemotherapy, thereby increasing mortality and the risk of recurrence.

[0006] Thus, there is an unmet medical need to treat patients suffering from bone marrow disorders with chromosomal abnormalities, particularly 3q21 and / or 3q26 abnormalities. Summary of the Invention

[0007] Accordingly, the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein R1 and R2 are each independently selected from hydrogen; a heterocycle; cyano; -CF3; -NRR'; -OH; a halogen, preferably selected from F, Cl, Br, and I; an alkyl group optionally substituted with one or more groups selected from a heterocycle, NRR', OR, and a solubilizing group; an alkoxy group optionally substituted with one or more groups selected from a heterocycle, NRR', OR, and a solubilizing group; -CO-NRR'; -SO2-NRR'; -NR-CO-R' and -NR-S02R'; wherein R and R' are each independently selected from hydrogen, cycloalkyl, heterocycle, solubilizing group, and alkyl group, optionally substituted with one or more groups selected from OR'', NR''R''', NR''COR''', and solubilizing group; wherein R'' and R''' are each independently selected from hydrogen, alkyl, or cycloalkyl; A is selected from optionally substituted heterocyclic groups, preferably A is a heterocyclic group optionally substituted with one or more groups selected from halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, solubilizing group, -NRR', -alkyl-NRR', -NR-CO-R', -alkyl-NR-CO-R', -CONRR' and -SONRR' groups; wherein R and R' are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups; B is a five-membered heteroaryl group.

[0008] The present invention also relates to a method for treating a bone marrow disorder in a subject in need thereof, said subject having at least one chromosomal abnormality of 3q21 and / or 3q26 (3qabns), said method comprising administering a therapeutically effective dose of a compound of formula (I): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein R1 and R2 are each independently selected from hydrogen; a heterocycle; cyano; -CF3; -NRR'; -OH; a halogen, preferably selected from F, Cl, Br, and I; an alkyl group optionally substituted with one or more groups selected from a heterocycle, NRR', OR, and a solubilizing group; an alkoxy group optionally substituted with one or more groups selected from a heterocycle, NRR', OR, and a solubilizing group; -CO-NRR'; -SO2-NRR'; -NR-CO-R' and -NR-S02R'; wherein R and R' are each independently selected from hydrogen, cycloalkyl, heterocycle, solubilizing group, and alkyl group, optionally substituted with one or more groups selected from OR'', NR''R''', NR''COR''', and solubilizing group; wherein R'' and R''' are each independently selected from hydrogen, alkyl, or cycloalkyl; A is selected from optionally substituted heterocyclic groups, preferably A is a heterocyclic group optionally substituted with one or more groups selected from halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, solubilizing groups, -NRR', -alkyl-NRR'; -NR-CO-R', -alkyl-NR-CO-R', -CONRR' and -SONRR' groups; wherein R and R' are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups; B is a 5-membered heteroaryl group) to the subject.

[0009] In some embodiments, the compound is 1-{4-[2-(5-ethoxymethyl-2-methyl-phenylamino)-oxazol-5-yl]-phenyl}-imidazolidin-2-one of formula (II) [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0010] In some embodiments, the bone marrow disorder comprises or is selected from the group consisting of acute myeloid leukemia (AML), acute myelomonocytic leukemia (AMML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), myeloproliferative neoplasms (MPN), myeloproliferative disorders, acute monoblastic / monocytic leukemia, pure erythroblastic leukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, acute panmyelosis with myelofibrosis, myeloid sarcoma, myeloproliferation associated with Down's syndrome, transient abnormal myelopoiesis, myeloid leukemia associated with Down's syndrome, blastic plasmacytoid dendritic cell neoplasm, acute leukemia of ambiguous lineage, acute undifferentiated leukemia, and acute mixed lineage leukemia.

[0011] In some embodiments, the bone marrow disorder comprises or is selected from the group consisting of acute myeloid leukemia (AML), acute myelomonocytic leukemia (AMML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), and myeloproliferative neoplasms (MPN).

[0012] In some embodiments, the bone marrow disorder is de novo (or primary) AML, secondary AML (s-AML), or therapy-related AML (t-AML).

[0013] In some embodiments, the bone marrow disorder is a relapsed or refractory bone marrow disorder.

[0014] In some embodiments, the chromosomal abnormality comprises or is selected from the group consisting of t(3;8)(q26;q24), inv(3)(q21q26), t(3;3)(q21;q26), t(3;21)(q26;q22), t(1;3)(p36;q21), t(3;5)(q21;q31) / (q21;q35) / (q26;q21), and t(3;12)(q26;p13).

[0015] In some embodiments, the chromosomal abnormality comprises or is selected from the group consisting of t(3;8)(q26;q24), inv(3)(q21q26), and t(3;3)(q21;q26).

[0016] In some embodiments, the chromosomal abnormality is t(3;8)(q26;q24).

[0017] In some embodiments, the chromosomal abnormality is t(3;8)(q26;q24), the bone marrow disorder is refractory AML, and the compound is 1-{4-[2-(5-ethoxymethyl-2-methyl-phenylamino)-oxazol-5-yl]-phenyl}-imidazolidin-2-one of Formula (II): [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0018] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof is or is intended to be administered in the form of a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient and / or carrier.

[0019] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof is the sole active pharmaceutical ingredient.

[0020] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof has a concentration of at least 0.9 mg / m 2 In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof is administered or is intended to be administered at a dose of 0.9 mg / m 2 ~16mg / m 2 It is administered or intended to be administered in a dose range of

[0021] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof is or is intended to be administered intravenously, intraarterially, intramuscularly, intradermally, subcutaneously, transdermally, topically, and / or orally, hi some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof is or is intended to be administered intravenously.

[0022] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof is or will be administered daily. In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof is or will be administered for up to 60 days. In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof is or will be administered for 28 days.

[0023] In some embodiments, the method further comprises administering to said subject at least one other anti-cancer agent.

[0024] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof for use is to be administered in conjunction with at least one other anti-cancer agent.

[0025] In some embodiments, the at least one other anticancer agent is azacitidine. In some embodiments, the azacitidine is administered or is intended to be administered subcutaneously. In some embodiments, the azacitidine is administered at a dose of 75 mg / m 2 is administered or intended to be administered at a dose of

[0026] In some embodiments, the method for treating a bone marrow disorder in a subject in need thereof comprises: (i) detecting chromosomal abnormalities in the bone marrow disorder; (ii) determining whether the subject is susceptible to the compound, or a pharmaceutically acceptable salt or solvate thereof, by determining whether the subject is susceptible to the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein detection of at least one chromosomal abnormality indicates that the subject is susceptible to the compound, or a pharmaceutically acceptable salt or solvate thereof.

[0027] The present invention further relates to a method for identifying a subject suffering from a bone marrow disorder susceptible to a compound or a pharmaceutically acceptable salt or solvate thereof, the method comprising: (i) detecting chromosomal abnormalities in the bone marrow disorder; (ii) determining whether the subject is susceptible to the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein detection of at least one chromosomal abnormality indicates that the subject is susceptible to the compound, or a pharmaceutically acceptable salt or solvate thereof; This compound is a compound of formula (I) [ka] (In the formula, R1 and R2 are each independently selected from hydrogen; a heterocycle; cyano; -CF3; -NRR'; -OH; a halogen, preferably selected from F, Cl, Br, and I; an alkyl group optionally substituted with one or more groups selected from a heterocycle, NRR', OR, and a solubilizing group; an alkoxy group optionally substituted with one or more groups selected from a heterocycle, NRR', OR, and a solubilizing group; -CO-NRR'; -SO2-NRR'; -NR-CO-R' and -NR-S02R'; wherein R and R' are each independently selected from hydrogen, cycloalkyl, heterocycle, solubilizing group, and alkyl group, optionally substituted with one or more groups selected from OR'', NR''R''', NR''COR''', and solubilizing group; wherein R'' and R''' are each independently selected from hydrogen, alkyl, or cycloalkyl; A is selected from optionally substituted heterocyclic groups, preferably A is a heterocyclic group optionally substituted with one or more groups selected from halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, solubilizing groups, -NRR', -alkyl-NRR'; -NR-CO-R', -alkyl-NR-CO-R', -CONRR' and -SONRR' groups; wherein R and R' are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups; B is a 5-membered heteroaryl group. or a pharmaceutically acceptable salt or solvate thereof. [Brief explanation of the drawings]

[0028] [Figure 1]Figures 1A-1C are a series of dot plots showing the efficacy and safety of compounds as described herein in an ex vivo model of NOD SCID mice injected with blasts from the bone marrow of an AML patient with the inv(3)(p23q26) chromosomal abnormality. Figures 1A and 1B show the number and percentage of blasts, respectively, in the blood of the mice. Figure 1C shows the number of CD45+ cells in the blood of the mice. DETAILED DESCRIPTION OF THE INVENTION

[0029] definition In the present invention, the following terms have the following meanings:

[0030] When a chemical substituent is a combination of chemical groups, the point of attachment of the substituent to the molecule is through the last chemical group recited to the right of the substituent name. For example, an arylalkyl substituent is connected to the remainder of the molecule through the alkyl moiety, which can be represented as follows: "arylalkyl-". Unless otherwise indicated, the compounds were named using ChemBioDraw® Ultra 13.0.2 (PerkinElmer).

[0031] "Alkoxy" refers to an alkyl-O- group.

[0032] "Alkyl" refers to a saturated straight or branched hydrocarbon chain typically containing 1 to 16 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, and even more preferably 1 to 6 carbon atoms. Alkyl groups can be monovalent or polyvalent (i.e., "alkylene" groups, which are divalent alkyl groups, are included in the definition of "alkyl"). Alkyl groups can be optionally substituted with one or more substituents (e.g., 1 to 4 substituents, or e.g., 1, 2, 3, or 4 substituents) selected from oxo, halogen, hydroxyl, nitro, amino, cyano, alkylamino, dialkylamino, alkoxy, haloalkyl, acyl, carbamoyl, alkylsulfoxide, sulfamoyl, alkylthio, and carboxyl. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g., n-pentyl, iso-pentyl), and hexyl and its isomers (e.g., n-hexyl, iso-hexyl). Particular examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl (including methylene, ethylene, n-propylene, n-butylene and n-butylene).

[0033] "Aryl" means a monocyclic or polycyclic aromatic radical containing carbon and hydrogen atoms. Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.

[0034] "Cycloalkyl group" means a saturated or partially unsaturated, monocyclic, fused bicyclic, or bridged polycyclic ring assembly containing the indicated number of ring atoms. This includes substituted or unsubstituted cycloalkyl groups. For example, the cycloalkyl group can be a C3-C10 alkyl group, such as C3 or C4, particularly cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl groups.

[0035] "Halogen" refers to a fluorine, chlorine, bromine or iodine atom.

[0036] "Heterocycle" refers collectively to heterocycloalkyl and heteroaryl groups.

[0037] "Heterocycloalkyl" refers to a non-aromatic, fully saturated, or partially unsaturated cyclic group (e.g., a 3- to 7-membered monocyclic, a 7- to 11-membered bicyclic, or a total of 3 to 10 ring atoms) having at least one heteroatom in at least one carbon atom-containing ring. Heterocycloalkyl groups can be particularly 3- to 7-membered, preferably 5- or 6-membered. Heterocycloalkyl groups can be particularly monocyclic or bicyclic, preferably monocyclic. Each ring of a heteroatom-containing heterocycloalkyl group can have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms, where the nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized. In one embodiment, a heterocycloalkyl is bonded to another group or molecule through a carbon atom, i.e., the bond atom is not selected among the heteroatoms contained therein. In one embodiment, a heterocycloalkyl is bonded to another group or molecule through one of the heteroatoms contained therein. When substituted with one or more other groups, heterocycloalkyl can be substituted either through a carbon atom or through a heteroatom (e.g., nitrogen), unless otherwise specified. The rings of polycyclic heterocycloalkyl groups can be fused, bridged, and / or linked through one or more spiro atoms. This definition encompasses polycyclic heterocycloalkyl (e.g., bicyclic) and bridged heterocycloalkyl structures, including rings that are joined together through one atom ("spiro") or through two atoms. Heterocycloalkyl groups can optionally be substituted with one or more substituents (e.g., 1 to 4 substituents, or e.g., 1, 2, 3, or 4 substituents) selected from oxo, halogen, hydroxyl, nitro, amino, cyano, alkyl (e.g., methyl), alkylamino, dialkylamino, alkoxy, haloalkyl, acyl, carbamoyl, alkylsulfoxide, sulfamoyl, alkylthio, and carboxyl.Non-limiting examples of heterocycloalkyl groups include aziridinyl, oxiranyl, thiiranyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, succinimidyl, 3H-indolyl, indolinyl, and isoindolinyl. Tetrahydropyran, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolidinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, oxetanyl, thietanyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioxoimidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophene thiomorpholinyl (e.g., thiomorpholin-4-yl), thiomorpholin-4-yl sulfoxide, thiomorpholin-4-yl sulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 1H-pyrrolidinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl, and morpholinyl (e.g., morpholin-4-yl).

[0038] "Heteroaryl" refers to an aromatic ring or ring system containing 5 to 15 carbon atoms, preferably 4 to 12 carbon atoms, and more preferably 3 to 10 carbon atoms, having one or two rings fused together or covalently linked, where at least one ring is aromatic and one or more carbon atoms in one or more of the rings are replaced by oxygen, nitrogen, and / or sulfur atoms. Heteroaryl groups can be monovalent or polyvalent (e.g., divalent). The nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized (e.g., sulfur can be oxidized as SO or SO). This definition of "heteroaryl" encompasses partially hydrogenated derivatives of the carbocyclic ring systems enumerated herein, as well as ring systems containing one or more fused non-aromatic cycloalkyl and / or heterocycloalkyl rings, so long as at least one ring is aromatic. In one embodiment, a heteroaryl is attached to another group or molecule through a carbon atom, i.e., the attaching atom is not selected among the heteroatoms contained therein. In one embodiment, a heteroaryl is attached to another group or molecule through one of its heteroatoms (e.g., nitrogen). When substituted with one or more other groups, a heteroaryl can be substituted either through a carbon atom or through a heteroatom (e.g., nitrogen), unless otherwise specified. A heteroaryl group can optionally be substituted with one or more substituents (e.g., 1 to 4 substituents, or e.g., 1, 2, 3, or 4 substituents) selected from oxo, halogen, hydroxyl, nitro, amino, cyano, alkyl (e.g., methyl), alkylamino, dialkylamino, alkoxy, haloalkyl, acyl, carbamoyl, alkylsulfoxide, sulfamoyl, alkylthio, and carboxyl.Non-limiting examples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, tetrazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophene, and the like. Indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzisothiazolyl Examples include benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and quinoxalinyl. Non-limiting examples of heteroaryl groups containing at least one fused non-aromatic ring include 2,3-dihydrobenzofuranyl, benzo[d][1,3]dioxolyl, indolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 1,2,3,4-tetrahydroquinoxaline, 3,4-dihydro-2H-benzo[b][1,4]thiazine, and 2,3-dihydrobenzo[b][1,4]oxathiin.

[0039] "Solvate" refers to a molecular complex comprising a compound as described herein that contains stoichiometric or substoichiometric amounts of one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term "hydrate" refers to when the solvent is water.

[0040] "Solubilizing group" refers to a group that increases the solubility of a compound in water or aqueous solutions when compared to a similar compound that does not contain this group. Non-limiting examples of such solubilizing groups include groups that ionize under conditions of use to generate a charged moiety (e.g., carboxylic acid, sulfonic acid, phosphate, amine, etc.); groups that contain a permanent charge (e.g., quaternary ammonium groups); and / or heteroatoms or heteroatomic groups, such as O, S, N, NH, N-(CH) z R, N-(CH2) z -C(O)R, N-(CH2) z -C(O)OR, N-(CH2) z -S(O)R, N-(CH) z -S(O)2OR, N-(CH2) z -C(O)NRR', where z is an integer ranging from 0 to 6; R and R' are each independently selected from hydrogen, alkyl groups containing 1 to 10 carbon atoms and optionally substituted with one or more heteroatoms such as halogen (selected from F, Cl, Br, or I), oxygen, and nitrogen; and alkoxy groups containing 1 to 10 carbon atoms; and aryl and heteroaryl groups.

[0041] In some embodiments, the solubilizing group is a heterocycloalkyl that optionally contains 1 to 5 substituents that may themselves be solubilizing groups.

[0042] In certain embodiments, the solubilizing group is of the formula: [ka] wherein L is selected from the group consisting of CH and N; M is -CH(R)-, -CH2-, -O-, -S-, -NH-, -N(-(CH2)) z -R)-, -N(-(CH2) z-C(O)R)-, -N(-(CH2) z -C(O)OR)-, -N(-(CH2) z -S(O)2R)-, -N(-(CH2) z -S(O)2OR)- and -N(-(CH2) z -C(O)NR-R')-, where z is an integer ranging from 0 to 6, and R and R' are each independently selected from hydrogen, alkyl groups containing 1 to 10 carbon atoms and optionally substituted with one or more heteroatoms such as halogen (selected from F, Cl, Br, or I), oxygen, and nitrogen; and alkoxy groups containing 1 to 10 carbon atoms, NRR' groups (where R and R' are each independently selected from hydrogen, alkyl groups as defined above optionally substituted with at least one heteroatom, particularly oxygen or nitrogen, optionally substituted with an optionally substituted alkyl group containing 1 to 10 carbon atoms; and aryl and heteroaryl groups, with the proviso that L and M, respectively, are not both CH and CH.

[0043] In another particular embodiment, the solubilizing group is morpholinyl, piperidinyl, pyrrolidinyl, N—(C1-C6)alkylpiperidinyl, particularly N-methylpiperidinyl and N-ethylpiperidinyl, N-(4-piperidinyl)piperidinyl, 4-(1-piperidinyl)piperidinyl, 1-pyrrolidinylpiperidinyl, 4-morpholinopiperidinyl, 4-(N-methyl-1-piperazinyl)piperidinyl, piperazinyl, N—(C1-C6)alkylpiperazinyl, particularly N-methylpiperazinyl and and N-ethylpiperazinyl, N-(C3-C6)cycloalkylpiperazinyl, particularly N-cyclohexylpiperazinyl, pyrrolidinyl, N-(C1-C6)alkylpyrrolidinyl, particularly N-methylpyrrolidinyl and N-ethylpyrrolidinyl, diazepinyl, N-(C1-C6)alkylazepinyl, particularly N-methylazepinyl and N-ethylazepinyl, homopiperazinyl, N-methylhomopiperazinyl, N-ethylhomopiperazinyl, imidazolyl, and the like.

[0044] "Solvate isomer" is used herein to describe two or more molecular complexes comprising a compound as described herein and one or more pharmaceutically acceptable solvent molecules, e.g., ethanol, wherein the complexes differ in the number of solvent molecules per compound molecule as described herein. The term "hydrate" is used when the solvent is water.

[0045] "Substituent" or "substituted" means that a hydrogen radical on a compound or group is replaced with any desired group that is substantially stable to the reaction conditions either in unprotected form or when protected with a protecting group. Examples of preferred substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogen, alkyl or aryl groups as defined above, hydroxyl, alkoxy groups as defined above, nitro, thiol, heterocycloalkyl groups, heteroaryl groups, cyano, cycloalkyl groups as defined above, and solubilizing groups, -NRR', -NR-CO-R', -CONRR', -SONRR' groups, where R and R' are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl groups as defined above.

[0046] "About" is used herein to mean approximately, roughly, around, around, or within a range. The term "about" before a numerical value means plus or minus 10% of the numerical value. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the indicated numerical value by 10%.

[0047] "Active pharmaceutical ingredient," "active ingredient," or "therapeutic agent" refers to a compound for therapeutic use and related to health. In particular, a therapeutic agent (e.g., a compound as described herein) may be indicated for treating a disease (e.g., a hematological and / or proliferative disorder, preferably acute myeloid leukemia, myelodysplastic syndrome, and / or other bone marrow disorders). An active ingredient may also be indicated to improve the therapeutic activity of another therapeutic agent.

[0048] "Administration" or variations thereof (e.g., "administering") means providing a therapeutic agent, alone or as part of a pharmaceutically acceptable composition, to a patient whose condition, symptom, or disease is to be treated.

[0049] "Chromosomal abnormality" refers to an abnormal rearrangement of chromosomes, such as a translocation (t), inversion (inv), substitution, deletion (del), or duplication. Typically, chromosomal abnormalities are expressed as follows: x(n1;n2)(y1a.b;y2a.b), where x defines the type of rearrangement (translocation, inversion, etc.), n1 defines chromosome 1, n2 defines optional chromosome 2, y1 and y2 define the short arm (p) or long arm (q) of the chromosome, a defines a band or segment or position on the chromosomal arm, and b defines a subband or subsegment or sublocation on the band or segment or position on the chromosomal arm. In the case of a deletion, y2 is not indicated. In some embodiments, the chromosomal abnormality found in a subject's bone marrow disease treated by the methods of the present invention is located at q21 and / or q26 of chromosome 3, i.e., the chromosomal abnormality is at 3q21 and / or 3q26. Chromosomal abnormalities on the long arm of chromosome 3 are referred to herein as 3qabns.

[0050] The word "Comprise" or variations thereof (e.g., "comprises," "comprising") is used herein in accordance with standard patent application drafting terminology. Thus, "Comprise" preceded by an object and followed by an element means that the element in the object is required (typically as a constituent of a composition), but does not exclude the presence of any additional element in the object. Furthermore, any appearance of "Comprise" or variations thereof in the specification also encompasses the narrower phrase "consists essentially of," the even narrower phrase "consist of," and all variations thereof (e.g., "consists of," "consisting of").

[0051] "Metabolite" is used herein to describe a compound that results from the biochemical transformation of a parent compound by metabolism.

[0052] "Pharmaceutically acceptable" means the components of the composition are compatible with each other and not harmful to the subject to which it is administered.

[0053] A "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to an excipient or carrier that does not produce an adverse, allergic, or other untoward reaction when administered to an animal, preferably a human. This includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by regulatory authorities, e.g., the FDA Office or the EMA. Examples of pharmaceutically acceptable carriers or excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances (e.g., sodium carboxymethylcellulose), polyethylene glycol, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0054] A "pharmaceutical composition" refers to a composition comprising at least one therapeutic agent (eg, a compound as described herein) and at least one pharmaceutically acceptable carrier.

[0055] "Subject" refers to an animal, typically a warm-blooded animal, preferably a mammal, more preferably a primate, and even more preferably a human. In one embodiment, the subject is a "patient" as defined herein. In one embodiment, the subject is suffering from, and preferably has been diagnosed with, a disease, preferably a hematological disease and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome, and / or other bone marrow disorder. In one embodiment, the subject is at risk of developing a disease, preferably a hematological disease and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome, and / or other bone marrow disorder. Examples of risk factors include, but are not limited to, a genetic predisposition or family history of the disease. In some embodiments, the subject is female. In some embodiments, the subject is male. In some embodiments, the subject is an adult.

[0056] A "therapeutically effective amount" (abbreviated "effective amount") refers to an amount of a therapeutic agent (e.g., a compound as described herein) sufficient to achieve the desired therapeutic, prophylactic, or preventative effect in a patient to which it is administered, without causing significant adverse or harmful side effects to that patient. A therapeutically effective amount can be administered prior to the onset of a disease, preferably a hematological disease and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome, and / or other bone marrow disorder, for a prophylactic or preventative effect. Alternatively, or in addition, a therapeutically effective amount can be administered after the onset of a disease, preferably a hematological disease and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome, and / or other bone marrow disorder, for a therapeutic effect.

[0057] "Treating," "treatment," or "alleviation" refers to both therapeutic and prophylactic or preventative treatment, the purpose of which is to prevent or slow (alleviate) the targeted pathological condition or disorder (herein "disease") (e.g., a hematological disease and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome, and / or other bone marrow disorder). Those in need of treatment include those already suffering from the disease, preferably a hematological disease and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome, and / or other bone marrow disorder, as well as those prone to having the disease, preferably a hematological disease and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome, and / or other bone marrow disorder, or those in whom the condition or disease, preferably a hematological disease and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome, and / or other bone marrow disorder, is to be prevented. A patient is successfully "treated" for a disease, preferably a hematological disease and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome and / or other bone marrow disorder, if, after administration of a therapeutic amount of a therapeutic agent (e.g., a compound as described herein), the patient shows an observable and / or measurable reduction or absence of one or more of the following: a reduction in the percent of total diseased cells; and / or alleviation, to some extent, in one or more of the symptoms associated with the specific disease, preferably a hematological disease and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome and / or other bone marrow disorder; a reduction in morbidity and mortality, and an improvement in quality of life issues. The above parameters for assessing successful treatment and improvement in a disease, preferably a hematological disease and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome and / or other bone marrow disorder, are readily measurable by routine procedures well known to physicians.

[0058] Detailed Description The present invention relates to a method for treating a bone marrow disorder in a subject in need thereof, the method comprising administering a therapeutically effective dose of a compound of formula (I) [ka] (In the formula, R1 and R2 are each independently selected from hydrogen; a heterocycle; cyano; -CF3; -NRR'; -OH; a halogen, preferably selected from F, Cl, Br, and I; an alkyl group optionally substituted with one or more groups selected from a heterocycle, NRR', OR, and a solubilizing group; an alkoxy group optionally substituted with one or more groups selected from a heterocycle, NRR', OR, and a solubilizing group; -CO-NRR'; -SO2-NRR'; -NR-CO-R' and -NR-S02R'; wherein R and R' are each independently selected from hydrogen, cycloalkyl, heterocycle, solubilizing group, and alkyl group, optionally substituted with one or more groups selected from OR'', NR''R''', NR''COR''', and solubilizing group; wherein R'' and R''' are each independently selected from hydrogen, alkyl, or cycloalkyl; A is selected from optionally substituted heterocyclic groups, preferably A is a heterocyclic group optionally substituted with one or more groups selected from halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, solubilizing groups, -NRR', -alkyl-NRR'; -NR-CO-R', -alkyl-NR-CO-R', -CONRR' and -SONRR' groups; wherein R and R' are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups; B is a 5-membered heteroaryl group. or a pharmaceutically acceptable salt or solvate thereof to a subject, wherein the subject has at least one chromosomal abnormality of 3q21 and / or 3q26 (3qabns).

[0059] The present invention provides a compound of formula (I) for use in the treatment of a bone marrow disorder in a subject in need thereof [ka] (In the formula, R1 and R2 are each independently selected from hydrogen; a heterocycle; cyano; -CF3; -NRR'; -OH; a halogen, preferably selected from F, Cl, Br, and I; an alkyl group optionally substituted with one or more groups selected from a heterocycle, NRR', OR, and a solubilizing group; an alkoxy group optionally substituted with one or more groups selected from a heterocycle, NRR', OR, and a solubilizing group; -CO-NRR'; -SO2-NRR'; -NR-CO-R' and -NR-S02R'; wherein R and R' are each independently selected from hydrogen, cycloalkyl, heterocycle, solubilizing group, and alkyl group, optionally substituted with one or more groups selected from OR'', NR''R''', NR''COR''', and solubilizing group; wherein R'' and R''' are each independently selected from hydrogen, alkyl, or cycloalkyl; A is selected from optionally substituted heterocyclic groups, preferably A is a heterocyclic group optionally substituted with one or more groups selected from halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, solubilizing groups, -NRR', -alkyl-NRR'; -NR-CO-R', -alkyl-NR-CO-R', -CONRR' and -SONRR' groups; wherein R and R' are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups; B is a 5-membered heteroaryl group. or a pharmaceutically acceptable salt or solvate thereof, wherein the subject has at least one chromosomal abnormality of 3q21 and / or 3q26 (3qabns).

[0060] In one embodiment, in the compounds described herein, R1 represents hydrogen or an alkyl group, preferably R1 represents hydrogen or C1-C3 alkyl, more preferably R1 represents hydrogen, methyl, ethyl or propyl, and even more preferably R1 represents hydrogen or methyl.

[0061] In one embodiment, in the compounds described herein, R represents an alkyl group, preferably R represents C-C alkyl, more preferably R represents methyl, ethyl or propyl, and even more preferably R represents methyl.

[0062] In one embodiment, in the compounds as described herein, R2 represents hydrogen or an alkyl group optionally substituted with alkoxy, preferably R2 represents hydrogen, methyl or -CH2-O-C2H5.

[0063] In one embodiment, in the compounds as described herein, R2 represents hydrogen.

[0064] In some embodiments, the compound is 1-{4-[2-(5-ethoxymethyl-2-methyl-phenylamino)-oxazol-5-yl]-phenyl}-imidazolidin-2-one of formula (II) [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0065] The compound 1-{4-[2-(5-ethoxymethyl-2-methyl-phenylamino)-oxazol-5-yl]-phenyl}-imidazolidin-2-one may be referred to interchangeably as AB8939. [Table 1]

[0066] The compounds described herein may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of formula (I) or formula (II) include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, hydroxybenzo ... Examples of suitable base salts include phosphate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate. Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)-morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine, and zinc salts. Hemisalts of acids and bases can also be formed, including, for example, hemisulfate and hemicalcium salts. When compounds of formula (I) contain an acidic group as well as a basic group, the compounds as described herein may also form internal salts, and such compounds are within the scope of the present invention. When compounds as described herein contain a hydrogen-donating heteroatom (e.g., NH), the present invention also encompasses salts and / or isomers formed by migration of said hydrogen atom to a basic group or atom within the molecule.

[0067] Pharmaceutically acceptable salts of compounds of Formula (I) or Formula (II) can be prepared by one or more of these methods: (i) reacting a compound of Formula (I) with a desired acid; (ii) reacting a compound of Formula (I) or Formula (II) with a desired base; (iii) removing an acid- or base-labile protecting group from a suitable precursor of a compound of Formula (I) or Formula (II) or ring-opening a suitable cyclic precursor, such as a lactone or lactam, using a desired acid; and / or (iv) converting one salt of a compound of Formula (I) or Formula (II) to another salt by reaction with a suitable acid or through a suitable ion exchange column. All of these reactions are typically carried out in solution. The salt precipitates from solution and can be recovered by filtration or by evaporation of the solvent. The degree of ionization in the salt can vary from completely ionized to nearly non-ionized.

[0068] It should be understood that the purpose of the present invention is to treat a bone marrow disease in a subject with 3qabns. Within the scope of the present invention, "treat" shall mean bringing the bone marrow disease into remission. In a preferred embodiment, the remission is maintained for a long period of time.

[0069] Within the scope of this invention, remission is considered "complete remission" when the bone marrow contains less than 5% blast cells, there is no extramedullary disease, blood cell counts return to within normal limits, and there are no signs or symptoms of bone marrow disease.

[0070] Within the scope of the present invention, neutropenia [ANC (absolute neutrophil count) < 1.0 x 10 9 / L] or thrombocytopenia [platelets <100x10 9 If the complete remission criteria are met except for persistent erythrocyte count (P < 0.05, P ...

[0071] Within the scope of the present invention, remission is considered "complete remission in the bone marrow" or "morphologically leukemia-free state" (MLFS) when the bone marrow contains less than 5% blast cells and there is no extramedullary disease (i.e., no hematological recovery is required).

[0072] Within the scope of the present invention, a remission is considered a "partial remission" if the bone marrow contains 5% to 25% blast cells, reducing the bone marrow blast percentage by at least 50% from pre-treatment.

[0073] Patients who do not meet the criteria for remission are categorized as non-responsive before the response landmark. Patients who fail to achieve a response by a designated landmark are designated as having refractory disease.

[0074] Bone marrow disorders, interchangeably referred to as bone marrow diseases, are a group of diseases involving cells from the myeloid lineage in various states of differentiation or maturation. These disorders typically interfere with hematopoiesis and / or immune function.

[0075] In some embodiments, the bone marrow disorder comprises or is selected from the group consisting of acute myeloid leukemia (AML), acute myelomonocytic leukemia (AMML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), myeloproliferative neoplasms (MPN), myeloproliferative disorders, acute monoblastic / monocytic leukemia, pure erythroblastic leukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, acute panmyelosis with myelofibrosis, myeloid sarcoma, myeloproliferation associated with Down's syndrome, transient abnormal myelopoiesis, myeloid leukemia associated with Down's syndrome, blastic plasmacytoid dendritic cell neoplasm, acute leukemia of ambiguous lineage, acute undifferentiated leukemia, and acute mixed lineage leukemia.

[0076] In some embodiments, the bone marrow disorder comprises or is selected from the group consisting of acute myeloid leukemia (AML), acute myelomonocytic leukemia (AMML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), and myeloproliferative neoplasms (MPN).

[0077] In some embodiments, the bone marrow disorder is acute myeloid leukemia (AML). In some embodiments, the AML is characterized by a percentage of blast cells greater than 20%. In some embodiments, the bone marrow disorder is de novo (or primary) AML, secondary AML (s-AML), or therapy-related AML (t-AML). In some embodiments, the bone marrow disorder is M0, M1, M2, M3, M4, M4eo, M5a, M6, or M7 AML.

[0078] As used herein, de novo AML refers to the first occurrence of AML in a subject; secondary AML refers to the second, third, or further occurrence of AML in a subject, where typically secondary AML arises from a previous AML; and therapy-related AML refers to AML that arises after treatment with chemotherapy, radiation, immunosuppressive therapy, or a combination thereof, typically resulting from a mutational event caused by the therapy.

[0079] As used herein, M0 refers to myeloblastic without differentiation, M1 refers to myeloblastic with little maturation, M2 refers to myeloblastic with maturation, M3 refers to promyelocytic, M4 refers to myelomonocytic, M4eo refers to myelomonocytic with eosinophilic, M5a refers to monocytic without differentiation (monoblastic), M5b refers to monocytic with differentiation, M6 refers to erythroleukemia, and M7 refers to megakaryocytic.

[0080] The diagnosis and management of AML is well documented and known in the art (see, e.g., Dohner et al. Blood. 2022;140(12):1345-1377).

[0081] In some embodiments, the bone marrow disorder is acute myelomonocytic leukemia (AMML). In some embodiments, the bone marrow disorder is de novo (or primary) AMML, secondary AMML (s-AMML), or therapy-related AMML (t-AMML).

[0082] In some embodiments, the bone marrow disorder is myelodysplastic syndrome (MDS). In some embodiments, MDS is characterized by a blast cell percentage comprising 5% to 20%.

[0083] In some embodiments, the bone marrow disorder is chronic myeloid leukemia (CML).

[0084] In some embodiments, the bone marrow disorder is a myeloproliferative neoplasm (MPN).

[0085] In some embodiments, the bone marrow disorder is a relapsed and / or refractory bone marrow disorder.

[0086] In some embodiments, the bone marrow disorder is relapsed. As used herein, "relapse" is intended to mean that the bone marrow disorder is temporarily alleviated but not cured after one, two, three, or more treatments.

[0087] In some embodiments, the bone marrow disorder is refractory. As used herein, "refractory" is intended to mean that the bone marrow disorder is partially or completely resistant to treatment.

[0088] In some embodiments, the chromosomal abnormality is located on chromosome 3.

[0089] In some embodiments, the chromosomal abnormality is a translocation or an inversion or a deletion.

[0090] In some embodiments, the chromosomal abnormality is selected from the group comprising or consisting of t(3;3), t(3;n), inv(3), where "n" represents 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, x, or y.

[0091] In some embodiments, the chromosomal abnormality is located on the long arm (q) of chromosome 3.

[0092] In some embodiments, the chromosomal abnormality is located at position 21 and / or 26 of the long arm (q) of chromosome 3. Such chromosomal abnormalities are interchangeably referred to as 3qabns.

[0093] In one embodiment, the chromosomal abnormality is located at position 21 on the long arm (q) of chromosome 3. In another embodiment, the chromosomal abnormality is located at position 26 on the long arm (q) of chromosome 3.

[0094] In some embodiments, the chromosomal abnormality comprises or is selected from the group consisting of t(3;8)(q26;q24), inv(3)(q21q26), t(3;3)(q21;q26), t(3;21)(q26;q22), t(1;3)(p36;q21), t(3;5)(q21;q31) / (q21;q35) / (q26;q21), and t(3;12)(q26;p13).

[0095] In some embodiments, the chromosomal abnormality comprises or is selected from the group consisting of t(3;8)(q26;q24), inv(3)(q21q26), and t(3;3)(q21;q26).

[0096] In some embodiments, the chromosomal abnormality is t(3;8)(q26;q24).

[0097] In some embodiments, the method as described herein is for treating a bone marrow disorder in a subject, wherein the chromosomal abnormality is t(3;8)(q26;q24), wherein the bone marrow disorder is refractory AML, and the compound is 1-{4-[2-(5-ethoxymethyl-2-methyl-phenylamino)-oxazol-5-yl]-phenyl}-imidazolidin-2-one of formula (II): [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0098] In some embodiments, the chromosomal abnormality is t(3;8)(q26;q24), the bone marrow disorder is refractory AML, and the compound for use as described herein is 1-{4-[2-(5-ethoxymethyl-2-methyl-phenylamino)-oxazol-5-yl]-phenyl}-imidazolidin-2-one of formula (II): [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0099] In some embodiments, the bone marrow disorder and / or chromosomal abnormality is associated with altered expression of at least one gene selected from the group including or consisting of EVI1 (interchangeably referred to as MECOM), RPN1, SRSF2, SETBP1, ETV6, RUNX1, RUNX1T1, CBFB, MYH11, PML, RARA, ZBTB16, PLZF, NPM, NUMA, STAT5b, PRKAR1A, FIP1L1, BCOR, KMT2A, MLLT3, DEK, NUP214, OTT, MAL, AFDN, MLLT1, ELL, MLLT10, ABL1, BCR, CEBP alpha, FLT3, ASXL1, TP53, IDH1, IDH2, and combinations thereof.

[0100] In some embodiments, the bone marrow disorder and / or chromosomal abnormality is associated with altered expression of at least one gene selected from the group including or consisting of EVI1 (MECOM), RPN1, SRSF2, SETBP1, ETV6, NPM, CEBP alpha, FLT3, RUNX1, ASXL1, TP53, IDH1, IDH2, and combinations thereof.

[0101] In some embodiments, the bone marrow disorder and / or chromosomal abnormality is associated with altered expression of at least one gene selected from the group including or consisting of EVI1 (MECOM), RPN1, SRSF2, SETBP1, ETV6, and combinations thereof.

[0102] In some embodiments, the bone marrow disorder and / or chromosomal abnormality is associated with altered expression of EVI1 (MECOM) and / or RPN1. In some embodiments, the bone marrow disorder is associated with altered expression of EVI1 (MECOM).

[0103] In some embodiments, the bone marrow disorder and / or chromosomal abnormality is associated with expression of at least one gene fusion selected from the group consisting of: RPN1-MECOM fusion gene; RUNX1-RUNX1T1 fusion gene; CBFB-MYH11 fusion gene; PML-RARA fusion gene; PLZF-RARA fusion gene; NPM-RARA fusion gene; NUMA-RARA fusion gene; STAT5b-RARA fusion gene; PRKAR1A-RARA fusion gene; FIP1L1-RARA fusion gene; ZBTB16-RARA fusion gene; BCOR-RARA fusion gene; KMT2A-MLLT3 fusion gene; DEK-NUP214 fusion gene; OTT-MAL fusion gene; AFDN-KMT2A fusion gene; KMT2A-MLLT1 fusion gene; KMT2A-ELL fusion gene; MLLT10-KMT2A fusion gene; BCR-ABL1 fusion gene; and combinations thereof; preferably the RPN1-MECOM fusion gene.

[0104] In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered or intended to be administered in the form of a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient and / or carrier.

[0105] As known to those skilled in the art, various forms of excipients can be used to suit the mode of administration, some of which may enhance the effectiveness of the active molecule, for example, by promoting a release profile that makes the active molecule more effective overall for the desired treatment.

[0106] In some embodiments, the pharmaceutically acceptable vehicle or excipient is selected from the group comprising or consisting of solvents, diluents, carriers, excipients, dispersion media, coatings, absorption delaying agents, and any combination thereof. The carrier, diluent, solvent, or excipient must be acceptable in the sense of being compatible with the compounds as described herein or their pharmaceutically acceptable salts or solvates, and not harmful when administered to a subject. Typically, the vehicle or excipient does not produce adverse, allergic, or other undesirable reactions when administered to a subject.

[0107] Thus, pharmaceutical compositions as described herein may be administered in various forms, for example, as injectable, crushable or ingestible forms.

[0108] The present invention includes, inter alia, the use of a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising same, for the manufacture of a medicament.

[0109] Such drugs may take the form of pharmaceutical compositions adapted for one or more modes of administration, preferably intravenous administration, which may be formulated in appropriate dosages using pharmaceutically acceptable carriers well known in the art, which allow the pharmaceutical composition to be formulated as a tablet, pill, dragee, capsule, liquid, gel, syrup, slurry, suspension, etc., for ingestion by the patient.

[0110] In some embodiments, a compound, or a pharmaceutically acceptable salt or solvate thereof, as described herein, is the sole active pharmaceutical ingredient.

[0111] In some embodiments, the compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, has a concentration of at least 0.09 mg / m 2 is administered or intended to be administered at a dose of

[0112] As used herein, "at least 0.09 mg / m 2 " means 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg / m 2 or beyond that.

[0113] In some embodiments, the compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is at least 0.9 mg / m 2 is administered or intended to be administered at a dose of

[0114] As used herein, "at least 0.9 mg / m 2 " is 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg / m 2 or beyond that.

[0115] In some embodiments, the compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is at least 1.8, 3.6, 6.0, 9.0, or 12.0 mg / m 2 is administered or intended to be administered at a dose of

[0116] In some embodiments, the compounds as described herein, or pharmaceutically acceptable salts or solvates thereof, are administered in a dose of up to 64 mg / m 2 , preferably up to 32 mg / m 2 , more preferably up to 16 mg / m 2 is administered or intended to be administered at a dose of

[0117] In some embodiments, the compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered in a dose of 0.09 mg / m 2 ~32 mg / m 2It is administered or intended to be administered in a dose range of

[0118] In some embodiments, the compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered in a dose of 0.9 mg / m 2 ~16mg / m 2 It is administered or intended to be administered in a dose range of

[0119] In some embodiments, the compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of 1.8 mg / m 2 ~16mg / m 2 range, 3.6 mg / m 2 ~16mg / m 2 range, 6.0 mg / m 2 ~16mg / m 2 range, 9.0 mg / m 2 ~16mg / m 2 or 12.0 mg / m 2 ~16mg / m 2 It is administered or intended to be administered in a dose range of

[0120] In some embodiments, the compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered in a dose of 0.9 mg / m 2 ~12.0mg / m 2 range, 0.9 mg / m 2 ~9.0mg / m 2 range, 0.9 mg / m 2 ~6.0mg / m 2 range, 0.9 mg / m 2 ~3.6mg / m 2 range or 0.9 mg / m 2 ~1.8mg / m 2 It is administered or intended to be administered in a dose range of

[0121] In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of 0.9, 1.8, 2.7, 3.6, 4.5, 5.4, 6.3, 7.2, 8.1, 9.0, 9.9, 10.8, 11.7, 12.6, 13.5, 14.4, 15.3, 16.2, 17.1, 18.0, 18.9, 19.8, 20.7, 21.6, 22.5, 23.4, 24.3, 25.2, 26.1, 27.0, 27.9, 28.8, 29.7, 30.6, 31.5, 32.4, 33.3, 34.2, 35.1, or 36.0 mg / m 2 is administered or intended to be administered at a dose of

[0122] In preferred embodiments, the compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of 0.9, 1.8, 3.6, 6.0, 9.0, 12.0 or 16.0 mg / m 2 is administered or intended to be administered at a dose of

[0123] In one embodiment, a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of 0.9 mg / m 2 In another embodiment, the compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered or is intended to be administered at a dose of 1.8 mg / m 2 In another embodiment, the compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered or is intended to be administered at a dose of 3.6 mg / m 2 In another embodiment, the compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered or is intended to be administered at a dose of 6.0 mg / m 2 In another embodiment, the compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered or is intended to be administered at a dose of 9.0 mg / m 2In another embodiment, the compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered or is intended to be administered at a dose of 12.0 mg / m 2 In another embodiment, the compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered or is intended to be administered at a dose of 16.0 mg / m 2 is administered or intended to be administered at a dose of

[0124] In one embodiment, the compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is or will be administered as a fixed dose.

[0125] In one embodiment, a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is or will be administered in a variable dose, hi some embodiments, the dose is adapted depending on the subject's response.

[0126] In some embodiments, the dose is increased one, two, three, four or more times.

[0127] In some embodiments, the compounds as described herein, or pharmaceutically acceptable salts or solvates thereof, are or will be administered intravenously, intraarterially, intramuscularly, intradermally, subcutaneously, transdermally, topically and / or orally.

[0128] In some embodiments, the compounds as described herein, or pharmaceutically acceptable salts or solvates thereof, are administered or are intended to be administered intravenously.

[0129] In some embodiments, the compounds as described herein, or pharmaceutically acceptable salts or solvates thereof, are or will be administered monthly, every two weeks, weekly, every six days, every five days, every four days, every three days, every two days, or every day (i.e., daily), preferably daily.

[0130] In some embodiments, the compounds as described herein, or pharmaceutically acceptable salts or solvates thereof, are or will be administered daily.

[0131] In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is or will be administered 5, 4, 3, 2, or 1 times per day, preferably once per day.

[0132] In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered or will be administered for up to 120 days. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered or will be administered for up to 60 days. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered or will be administered for up to 56 days. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered or will be administered for up to 28 days.

[0133] In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered or will be administered for 28 days. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered or will be administered for 21 days. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered or will be administered for 14 days. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered or will be administered for 7 days.

[0134] In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is or will be administered for 1, 2, 3, 4, 5, 6, or 7 days.

[0135] In some embodiments, the methods as described herein further comprise administering to said subject at least one other anti-cancer agent.

[0136] In some embodiments, the compounds for use as described herein, or pharmaceutically acceptable salts or solvates thereof, are to be administered in combination with at least one other anti-cancer agent.

[0137] In some embodiments, the at least one other anti-cancer agent is a pharmacologically active molecule, such as a small molecule or a biologically active peptide / protein. In some embodiments, the at least one additional anti-cancer agent is included in an approved (e.g., FDA or EMA approved) pharmaceutical composition for the treatment of at least one disease. In some embodiments, the at least one additional anti-cancer agent is undergoing at least one preclinical or clinical trial.

[0138] Anticancer drugs are known from the state of the art. Non-limiting examples of anticancer drugs include azacitidine, acalabrutinib, alectinib, alemtuzumab, anastrozole, avapritinib, avelumab, belinostat, bevacizumab, bleomycin, blinatumomab, bosutinib, brigatinib, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, copanlisib, cytarabine, daunorubicin, decitabine, dexamethasone, docetaxel, doxorubicin, encorafenib, erdafitinib, etoposide, everolimus, These include exemestane, fludarabine, 5-fluorouracil, gemcitabine, ifosfamide, imatinib mesylate, leuprolide, lomustine, mechlorethamine, melphalan, methotrexate, mitomycin, nelarabine, paclitaxel, pamidronate, panobinostat, pralatrexate, prednisolone, ofatumumab, rituximab, temozolomide, topotecan, tositumomab, trastuzumab, vandetanib, vincristine, vorinostat, and zanubrutinib.

[0139] In some embodiments, the at least one other anticancer agent is azacitidine.

[0140] In some embodiments, azacitidine is or will be administered intravenously, intraarterially, intramuscularly, intradermally, subcutaneously, transdermally, topically, and / or orally.

[0141] In some embodiments, the azacitidine is or will be administered subcutaneously.

[0142] In some embodiments, azacitidine is administered at 7.5 mg / m 2 ~750mg / m 2 range or 15 mg / m 2 ~375mg / m 2 It is administered or intended to be administered in a dose range of

[0143] In some embodiments, azacitidine is administered at 75 mg / m2 is administered or intended to be administered at a dose of

[0144] In some embodiments, a compound as described herein or a pharmaceutically acceptable salt or solvate thereof and at least one other anti-cancer agent are combined with a separate pharmaceutically acceptable vehicle or excipient.

[0145] In certain embodiments, at least one other anti-cancer agent is to be administered in combination, simultaneously, or sequentially with a combination as described herein.

[0146] In some embodiments, the method for treating a bone marrow disorder in a subject in need thereof comprises: (i) detecting chromosomal abnormalities in the bone marrow disorder; (ii) determining whether the subject is susceptible to the compound or a pharmaceutically acceptable salt or solvate thereof; The method further includes determining whether the subject is susceptible to the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein detection of at least one chromosomal abnormality indicates that the subject is susceptible to the compound, or a pharmaceutically acceptable salt or solvate thereof.

[0147] In some embodiments, the method for treating a bone marrow disorder in a subject in need thereof further comprises collecting at least one sample from the patient. Exemplarily, but not exclusively, the sample may be blood or bone marrow. Suitable routine methods for collecting samples from patients are known in the art. In a preferred embodiment, the at least one sample comprises at least one diseased cell (e.g., a bone marrow disorder, an AML cancer cell, etc.).

[0148] The present invention further relates to a method for identifying a subject suffering from a bone marrow disorder susceptible to a compound, or a pharmaceutically acceptable salt or solvate thereof, as described herein, comprising: (i) detecting chromosomal abnormalities in the bone marrow disorder; (ii) determining whether the subject is susceptible to the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein detection of at least one chromosomal abnormality indicates that the subject is susceptible to the compound, or a pharmaceutically acceptable salt or solvate thereof.

[0149] In some embodiments, a method for identifying a subject suffering from a bone marrow disorder susceptible to a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, comprises providing a sample from the subject.

[0150] In some embodiments, the sample is a bodily fluid or bone marrow. Examples of bodily fluids include, but are not limited to, blood, plasma, serum, lymph, ascetic fluid, cyst fluid, urine, bile, nipple discharge, vomit, breast milk, tears, wound drainage, feces, vaginal secretions, synovial fluid, bronchoalveolar lavage fluid, sputum, amniotic fluid, peritoneal fluid, cerebrospinal fluid, pleural effusion, pericardial fluid, semen, saliva, sweat, and alveolar macrophages. In some embodiments, the sample is a blood sample (including whole blood, plasma, and serum). In some embodiments, the sample is a whole blood sample. In some embodiments, the sample is blood or bone marrow.

[0151] In some embodiments, the sample is previously obtained from the subject, i.e., the method for identifying a subject suffering from a bone marrow disorder susceptible to a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, does not include the active step of collecting a sample from the subject. Consequently, in accordance with this embodiment, the method for identifying a subject suffering from a bone marrow disorder susceptible to a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is a non-invasive method, i.e., the method for identifying a subject suffering from a bone marrow disorder susceptible to a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, is an in vitro method.

[0152] In other words, the present invention relates to an in vitro method for identifying a subject suffering from a bone marrow disorder who is susceptible to a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0153] In some embodiments, detection of at least one chromosomal abnormality is performed by any suitable method known in the art, including, but not limited to, karyotyping, sequencing, and detection of specific markers.

[0154] In some embodiments, the method for treating a bone marrow disorder in a subject in need thereof or the method for identifying a subject suffering from a bone marrow disorder susceptible to a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, further comprises assessing the progression of the bone marrow disorder, hi some embodiments, the progression of the bone marrow disorder is assessed by measuring at least one marker of the bone marrow disorder.

[0155] In some embodiments, the progression of bone marrow damage is assessed by measuring the percentage of myeloblasts in the patient's blood.

[0156] In some embodiments, AML is associated with a percentage of blast cells greater than 20%. In some embodiments, MDS is associated with a percentage of blast cells between 5% and 20%. In some embodiments, remission is associated with a percentage of blast cells less than 5%.

[0157] In some embodiments, the step of assessing the progression of bone marrow damage is performed at least 1, 2, 3, 4, 5 or more times after completion of treatment.

[0158] In some embodiments, the step of assessing the progression of bone marrow damage is performed 1, 2, 3, 4, 5, 6, 7 or more days after completion of treatment. In some embodiments, the step of assessing the progression of bone marrow damage is performed 1, 2, 3, 4, 5, 6, 7 or more weeks after completion of treatment. In some embodiments, the step of assessing the progression of bone marrow damage is performed 1, 2, 3, 4, 5, 6, 7 or more months after completion of treatment.

[0159] The present invention further relates to a pharmaceutical composition for the treatment of or for use in the treatment of a bone marrow disorder in a subject in need thereof, said pharmaceutical composition comprising a compound of formula (I) [ka] (In the formula, R1 and R2 are each independently selected from hydrogen; a heterocycle; cyano; -CF3; -NRR'; -OH; a halogen, preferably selected from F, Cl, Br, and I; an alkyl group optionally substituted with one or more groups selected from a heterocycle, NRR', OR, and a solubilizing group; an alkoxy group optionally substituted with one or more groups selected from a heterocycle, NRR', OR, and a solubilizing group; -CO-NRR'; -SO2-NRR'; -NR-CO-R' and -NR-S02R'; wherein R and R' are each independently selected from hydrogen, cycloalkyl, heterocycle, solubilizing groups, and alkyl groups optionally substituted with one or more groups selected from OR", NR"R'", NR"COR"", and solubilizing groups; and wherein R" and R'" are each independently selected from hydrogen, alkyl, or cycloalkyl; A is selected from optionally substituted heterocyclic groups, preferably A is a heterocyclic group optionally substituted with one or more groups selected from halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, solubilizing groups, -NRR', -alkyl-NRR'; -NR-CO-R', -alkyl-NR-CO-R', -CONRR' and -SONRR' groups; wherein R and R' are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups; B is a 5-membered heteroaryl group. or a pharmaceutically acceptable salt or solvate thereof, wherein the subject has at least one chromosomal abnormality of 3q21 and / or 3q26 (3qabns).

[0160] The present invention further provides a compound of formula (I) in the manufacture of a medicament for treating a bone marrow disorder in a subject in need thereof. [ka] (In the formula, R1 and R2 are each independently selected from hydrogen; a heterocycle; cyano; -CF3; -NRR'; -OH; a halogen, preferably selected from F, Cl, Br, and I; an alkyl group optionally substituted with one or more groups selected from a heterocycle, NRR', OR, and a solubilizing group; an alkoxy group optionally substituted with one or more groups selected from a heterocycle, NRR', OR, and a solubilizing group; -CO-NRR'; -SO2-NRR'; -NR-CO-R' and -NR-S02R'; wherein R and R' are each independently selected from hydrogen, cycloalkyl, heterocycle, solubilizing groups, and alkyl groups optionally substituted with one or more groups selected from OR", NR"R'", NR"COR"", and solubilizing groups; and wherein R" and R'" are each independently selected from hydrogen, alkyl, or cycloalkyl; A is selected from optionally substituted heterocyclic groups, preferably A is a heterocyclic group optionally substituted with one or more groups selected from halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, solubilizing groups, -NRR', -alkyl-NRR'; -NR-CO-R', -alkyl-NR-CO-R', -CONRR' and -SONRR' groups; wherein R and R' are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups; B is a 5-membered heteroaryl group. or a pharmaceutically acceptable salt or solvate thereof, wherein the subject has at least one chromosomal abnormality of 3q21 and / or 3q26 (3qabns). [Example]

[0161] The present invention is further illustrated by the following examples.

[0162] Example 1: Synthesis Methods for synthesizing 1-{4-[2-(5-ethoxymethyl-2-methyl-phenylamino)-oxazol-5-yl]-phenyl}-imidazolidin-2-one have been previously disclosed in WO2016124747, which is incorporated herein by reference.

[0163] By way of example and not limitation, the final step of 1-{4-[2-(5-ethoxymethyl-2-methyl-phenylamino)-oxazol-5-yl]-phenyl}-imidazolidin-2-one is given herein below.

[0164] Materials and Methods overview All chemicals used were commercially available reagent-grade products. Solvents were anhydrous, commercial grade, and used without further purification. Reaction progress was monitored by thin-layer chromatography using pre-coated silica gel 60F 254, Merck TLC plates, which were visualized under UV light. Multiplicities in 1H NMR spectra are indicated as singlets (s), broad singlets (br s), doublets (d), triplets (t), quartets (q), and multiplets (m). NMR spectra were performed on either a Bruker 300 or 500 MHz spectrometer.

[0165] Abbreviation Cs2CO3 Cesium Carbonate EtOAc ethyl acetate MgSO4 Magnesium Sulfate NaCl Sodium chloride Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0166] result Preparation of 1-{4-[2-(5-ethoxymethyl-2-methyl-phenylamino)-oxazol-5-yl]-phenyl}-imidazolidin-2-one (001) [ka] In a sealed tube, to a solution of VIc (500 mg, 1.29 mmol) in dry dioxane (7 mL) were added sequentially 2-imidazolidinone (556 mg, 6.45 mmol), cesium carbonate (1.052 g, 3.23 mmol), and Xantphos (75 mg, 0.13 mmol). The reaction mixture was degassed with nitrogen for 20 min before the addition of Pd2(dba)3 (35 mg, 0.04 mmol). The reaction mixture was then stirred at 110 °C for 16 h. The cooled mixture was diluted with water and extracted twice with EtOAc. The combined organics were washed with water, saturated NaCl solution, dried over MgSO4, filtered, and evaporated. The final product was purified by silica gel chromatography using 10-50% EtOAc / cyclohexane as eluent to give the compound as described herein (260 mg, 52%). 1H NMR(500MHz,DMSO-d6)δ9.16(s,1H),7.84(s,1H),7.63(d,J=8.9Hz,2H),7.52(d,J=8.8Hz,2H),7.28(s,1H),7.16(d,J=7.7Hz,1H),7.00(s ,1H),6.93(d,J=7.6Hz,1H),4.42(s,2H),3.91-3.85(m,2H),3.48(q,J=7.0Hz,2H),3.45-3.38(m,2H),2.28(s,3H),1.15(t,J=7.0Hz,3H).

[0167] Example 2: Preclinical evaluation Materials and Methods Patient-derived xenograft mouse model: experimental design The therapeutic potential of AB8939 was investigated through a series of experiments using blast cells from AML patients or patient-derived xenograft (PDX) mouse models.

[0168] Bone marrow aspirates were obtained from the patients and analyzed for morphology, cytogenetics, and molecular biology.

[0169] Patient-derived xenografts: Blast cells from bone marrow aspirates were then injected into NOD SCID mice. After 3 weeks, colonization of the mouse bone marrow was observed, mimicking the patient-derived leukemia.

[0170] They then treated the mice with various drugs and assessed disease progression by measuring the number of blast cells in the blood, as well as drug toxicity by measuring the number of CD45+ cells in the blood.

[0171] result Comparative drug assay (ex vivo) After purification, mononuclear cells were treated with various concentrations of AB8939 and several anti-cancer drugs for 48 hours and analyzed in a cell proliferation / viability assay. The antiproliferative effects on blasts isolated from AML patients and PDX mice were measured as the concentration of inhibitor required to inhibit a biological process or response by 50% (IC 50 The value is expressed in terms of

[0172] As summarized in Table 2, several anticancer drugs were tested in mice injected with blast cells from three different leukemia patients: AraC (arabinocytosine, also known as cytarabine), AB8939 (1-{4-[2-(5-ethoxymethyl-2-methyl-phenylamino)-oxazol-5-yl]-phenyl}-imidazolidin-2-one, a compound as described herein, see Example 1), azacitidine (Vidaza), decitabine, daunorubicin, and guadecitabine (SGI-110). Results showed that AB8939 exhibited an IC50 sensitivity of nanomolar concentrations. 50 These values ​​indicate that it produced a strong antiproliferative effect on blasts isolated from these refractory AML patients and performed significantly better than standard-of-care AML drugs when treating AML patients with the inv(3)(q26) chromosomal abnormality. [Table 2]

[0173] As summarized in Table 3, blast cells from a primary (naive) inv(3)(q26) AML patient (N=1) and PDX blasts from relapsed / refractory inv(3)(q26) AML patients (N=2) were treated with a compound as described herein (AB8939), cytarabine (ARAC), or azacitidine (AZA). The antiproliferative effect on blasts is expressed in terms of the concentration of drug giving a half-maximal response (EC50 value). The results show that AB8939 produced a strong antiproliferative effect on blasts isolated from primary and refractory AML patients compared to standard of care chemotherapy. [Table 3]

[0174] The results show that for AML patients with the inv(3)(q26) chromosomal abnormality, the EC50 of AB8939 is 2 μM or slightly above 5 μM in the naive setting (patient dependent), and 0.05 μM or 0.013 μM in the relapsed / refractory setting (patient dependent). By comparison, the EC50s of cytarabine and azacitidine are between 20 μM and 50 μM in the naive setting and between 5 μM and 13 μM in the relapsed / refractory setting.

[0175] The results show that AB8939 performed better than cytarabine and azacitidine in treating AML patients with the inv(3)(q26) chromosomal abnormality.

[0176] Comparative drug assay (in vivo) In another line of experiments, AB8939 was compared with azacitidine (Vidaza®), venetoclax, AB8939 in combination with azacitidine, and AB8939 in combination with venetoclax. This experiment was performed using mice injected with blasts from AML patient C1005-P2, who has the inv(3)(p23q26) chromosomal abnormality (see column 1 of Table 2). The results are shown in Figures 1A-C.

[0177] As shown in Figures 1A and 1B, AB8939 alone or in combination with azacitidine was able to potently reduce blast counts compared to untreated controls. Venetoclax performed less well than AB8939 in this experiment.

[0178] Figure 1C shows that AB8939 did not induce a decrease in CD45+ cell count compared to the control, indicating the lack of toxicity of AB8939. Azacitidine, on the other hand, induced a higher toxicity, resulting in a significantly lower CD45+ cell count.

[0179] Overall, these results indicate that AB8939 is safe and worked better than other drugs to reduce the number of blast cells in the blood of mice transplanted with blast cells harboring the inv(3)(p23q26) chromosomal abnormality.

[0180] Example 3: AML case report Materials and Methods Patient Summary The patient is a 65-year-old woman.

[0181] AML History and Treatment: Diagnosed with AML in October 2022, refractory, secondary according to the World Health Organization (WHO) classification, with myelodysplasia-related changes (MD)-related changes.

[0182] Azacitidine (September 26, 2022 - October 14, 2022) Patient's cytogenetic profile: del(11)(q12);t(3;8)(q26;q24) Mixed: no infectious disease; pancytopenia and hyperglycemia AB8939 administration: 1.8 mg / m on December 14, 15, and 16, 2022 2 / day in Cycle #1. 1.8 mg / m 2 Cycle #2 on January 24th, 25th, and 26th, 2023 at / day.

[0183] result Analysis of pre-treatment bone marrow samples Morphology of the bone marrow aspirate showed increased cellularity. Dysplasia was observed in the three hematopoietic lineages, more prominent in the megakaryocytic lineage. There were 20% small and medium-sized blasts, agranular cytoplasm, loose nucleated chromatin nuclei, and sometimes irregular outlines.

[0184] Cytogenetics at the time of diagnosis of the current disease reportedly revealed a deletion of the long arm of chromosome 11, which was observed in all metaphases. Furthermore, six of the cases presented with a translocation t(3;8), which leads to the rearrangement MECOM(EVI1).;Formula ISCN::46,XX,del(11)(q12)[4] / 46,XX,idem,t(3;8)(q26;q24)[6].

[0185] The current molecular biology at the time of disease diagnosis was based on a search for variants that allow determining the diagnosis (World Health Organization 2022), assessing the prognosis (European LeukemiaNet 2022), and guiding therapy through actionable markers for the treatment of AML. The variant c.284_307del was detected; p.(Pro95_Arg102del) in the SRSF2 gene (52.6%), a variant described as pathogenic in myeloid neoplasms but not currently considered to have clinical utility in AML cases. The variant c.2608G>A was detected; p.(Gly870Ser) in the SETBP1 gene (44.3%) and the variant c.600_601dup in the ETV6 gene; p.(Leu201Profs) * 9) (37.4%). Overexpression of the EVI1 gene was detected.

[0186] Immunophenotyping was performed on bone marrow samples at diagnosis. Analysis was performed on the CD34 / CD117-positive bone marrow population, which represented 24% of the total nucleated cell density. The remaining cell density corresponded to 22% granulocytic lineage, 29% erythroid lineage, and 16% lymphocytes. No CD34+ B-lymphoid precursors were identified. CD42a and b: 8%+d. Immunophenotypic changes in the granulocytic and erythroid lineages were observed, suggesting dysplasia, which should be evaluated by cytological studies. A small clone of monoclonal B-lymphoid cells with kappa light chain expression and weakly positive CD20 persisted, representing 7.5% of the total nucleated cell density, as previously reported.

[0187] Analysis of patient treatment response The results are summarized in Table 4.

[0188] [Table 4]

[0189] The results showed that 1.8 mg / m 2 Administration of AB8939 at 1.8 mg / m² / day reduced the blast count from 55% to 5% in 28 days. 2 After a second cycle of AB8939 / day, the treatment response was maintained, with a bone marrow blast count of 10% 28 days after administration, corresponding to a 5-fold reduction compared to baseline.

Claims

1. 1. A compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt or solvate thereof, wherein R1 and R2 are each independently hydrogen; a heterocycle; cyano; or —CF ３ -NRR'; -OH; halogen, preferably selected from F, Cl, Br and I; alkyl groups, optionally substituted with one or more groups selected from heterocycles, NRR', OR and solubilizing groups; alkoxy groups, optionally substituted with one or more groups selected from heterocycles, NRR', OR and solubilizing groups; -CO-NRR'; -SO ２ -NRR'; -NR-CO-R' and -NR-SO ２ R'; wherein R and R' are each independently selected from hydrogen, cycloalkyl, heterocycle, solubilizing group, and alkyl group, optionally substituted with one or more groups selected from OR'', NR''R''', NR''COR''', and solubilizing group; and wherein R'' and R''' are each independently selected from hydrogen, alkyl, or cycloalkyl; A is selected from optionally substituted heterocyclic groups, preferably A is halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, solubilizing group, -NRR', -alkyl-NRR', -NR-CO-R', -alkyl-NR-CO-R', -CONRR' and -SO ２ a heterocyclic group optionally substituted with one or more groups selected from NRR' groups; where R and R' are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl groups; B is a 5-membered heteroaryl group; The subject has at least one chromosomal abnormality of 3q21 and / or 3q26 (3qabns), The compound or a pharmaceutically acceptable salt or solvate thereof.

2. Formula (II): 【Chemistry 2】 2. The compound of claim 1, which is 1-{4-[2-(5-ethoxymethyl-2-methyl-phenylamino)-oxazol-5-yl]-phenyl}-imidazolidin-2-one of the formula: or a pharmaceutically acceptable salt or solvate thereof.

3. 3. The compound of claim 1 or 2, wherein the bone marrow disorder comprises or is selected from the group consisting of acute myeloid leukemia (AML), acute myelomonocytic leukemia (AMML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), myeloproliferative neoplasms (MPN), myeloproliferative disorders, acute monoblastic / monocytic leukemia, pure erythroblastic leukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, acute panmyelosis with myelofibrosis, myeloid sarcoma, myeloproliferation associated with Down's syndrome, transient abnormal myelopoiesis, myeloid leukemia associated with Down's syndrome, blastic plasmacytoid dendritic cell neoplasm, acute leukemia of ambiguous lineage, acute undifferentiated leukemia, and acute mixed lineage leukemia.

4. The bone marrow disorder comprises or is selected from the group consisting of acute myeloid leukemia (AML), acute myelomonocytic leukemia (AMML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), and myeloproliferative neoplasms (MPN). The compound according to any one of claims 1 to 3.

5. The compound according to any one of claims 1 to 4, wherein the bone marrow disorder is de novo (or primary) AML, secondary AML (s-AML) or therapy-related AML (t-AML).

6. The compound according to any one of claims 1 to 5, wherein the bone marrow disorder is a relapsed or refractory bone marrow disorder.

7. 7. The compound of any one of claims 1 to 6, wherein the chromosomal abnormality comprises or is selected from the group consisting of t(3;8)(q26;q24), inv(3)(q21q26), t(3;3)(q21;q26), t(3;21)(q26;q22), t(1;3)(p36;q21), t(3;5)(q21;q31) / (q21;q35) / (q26;q21), and t(3;12)(q26;p13).

8. 8. The compound according to any one of claims 1 to 7, wherein the chromosomal abnormality comprises or is selected from the group consisting of t(3;8)(q26;q24), inv(3)(q21q26) and t(3;3)(q21;q26).

9. The compound according to any one of claims 1 to 8, wherein the chromosomal abnormality is t(3;8)(q26;q24).

10. the chromosomal abnormality is t(3;8)(q26;q24), the bone marrow disorder is refractory AML, and the compound has formula (II): 【Transformation 3】 10. The compound according to any one of claims 1 to 9, which is 1-{4-[2-(5-ethoxymethyl-2-methyl-phenylamino)-oxazol-5-yl]-phenyl}-imidazolidin-2-one, or a pharmaceutically acceptable salt or solvate thereof.

11. 11. The compound according to any one of claims 1 to 10, wherein the compound or a pharmaceutically acceptable salt or solvate thereof is administered in the form of a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient and / or carrier.

12. The compound of any one of claims 1 to 11, wherein the compound or a pharmaceutically acceptable salt or solvate thereof is the sole active pharmaceutical ingredient.

13. The compound or a pharmaceutically acceptable salt or solvate thereof is administered in a concentration of at least 0.9 mg / m ２ The compound according to any one of claims 1 to 12, administered at a dose of

14. The compound or a pharmaceutically acceptable salt or solvate thereof is administered at a dose of 0.9 mg / m ２ ~16 mg / m ２ The compound according to any one of claims 1 to 13, administered at a dose ranging from

15. 15. The compound according to any one of claims 1 to 14, wherein the compound or a pharmaceutically acceptable salt or solvate thereof is administered intravenously, intraarterially, intramuscularly, intradermally, subcutaneously, transdermally, topically and / or orally.

16. 16. The compound of any one of claims 1 to 15, wherein the compound or a pharmaceutically acceptable salt or solvate thereof is administered intravenously.

17. 17. The compound of any one of claims 1 to 16, wherein the compound or a pharmaceutically acceptable salt or solvate thereof is administered daily.

18. 18. The compound of any one of claims 1 to 17, wherein the compound, or a pharmaceutically acceptable salt or solvate thereof, is administered for up to 60 days.

19. 19. The compound of any one of claims 1 to 18, wherein the compound, or a pharmaceutically acceptable salt or solvate thereof, is administered for 28 days.

20. The compound of any one of claims 1 to 19, wherein the compound or a pharmaceutically acceptable salt or solvate thereof is administered in combination with at least one other anti-cancer agent.

21. 21. The compound of claim 20, wherein the at least one other anticancer agent is azacitidine.

22. 22. The compound of claim 21, wherein the azacitidine is administered subcutaneously.

23. Azacitidine at 75 mg / m ２ 22. The compound of claim 21, wherein the compound is administered at a dose of

24. 1. A method for identifying a subject suffering from a bone marrow disorder susceptible to a compound or a pharmaceutically acceptable salt or solvate thereof, comprising: (i) detecting chromosomal abnormalities in the bone marrow disorder; (ii) determining whether the subject is susceptible to the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein detection of at least one chromosomal abnormality indicates that the subject is susceptible to the compound, or a pharmaceutically acceptable salt or solvate thereof; Including, The compound has the formula (I): 【Chemistry 4】 or a pharmaceutically acceptable salt or solvate thereof, wherein R1 and R2 are each independently hydrogen; a heterocycle; cyano; or —CF ３ -NRR'; -OH; halogen, preferably selected from F, Cl, Br and I; alkyl groups, optionally substituted with one or more groups selected from heterocycles, NRR', OR and solubilizing groups; alkoxy groups, optionally substituted with one or more groups selected from heterocycles, NRR', OR and solubilizing groups; -CO-NRR'; -SO ２ -NRR'; -NR-CO-R' and -NR-SO ２ R' is selected from: wherein R and R' are each independently selected from hydrogen, cycloalkyl, heterocycle, solubilizing group, and alkyl group, optionally substituted with one or more groups selected from OR'', NR''R''', NR''COR''', and solubilizing group; wherein R'' and R''' are each independently selected from hydrogen, alkyl, or cycloalkyl; A is selected from optionally substituted heterocyclic groups, preferably A is halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, solubilizing group, -NRR', -alkyl-NRR', -NR-CO-R', -alkyl-NR-CO-R', -CONRR' and -SO ２ a heterocyclic group optionally substituted with one or more groups selected from NRR' groups; where R and R' are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl groups; B is a 5-membered heteroaryl group; method.

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