Compounds for treating myeloid diseases with chromosomal abnormalities

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of myeloid disorders, such as acute myeloid leukemia (AML), in subjects having at least one chromosome abnormality of 3q21 and / or 3q26.

Description

COMPOUNDS FOR TREATING MYELOID DISEASES WITH CHROMOSOMAL ABNORMALITIESFIELD OF INVENTION

[0001] The present invention relates to compounds, or pharmaceutically acceptable salt or solvate thereof, for use in the treatment of myeloid disorders, such as acute myeloid leukemia (AML), in subjects having at least one chromosome abnormality of 3q21 and / or 3q26.BACKGROUND OF INVENTION

[0002] Myeloid diseases such as acute myeloid leukemia, acute myelomonocytic leukemia, myelodysplastic syndrome, chronic myelogenous leukemia and myeloproliferative neoplasms, are a group of diseases involving cells from the myeloid lineage, at various states of differentiation or maturation, wherein immature myeloid cells (myeloid progenitors) abnormally proliferate in the bone marrow and / or blood, resulting in dysfunctional bone marrow function, abnormal blood cell production, and impaired immune function.

[0003] One of the characteristics of these diseases is their important heterogeneity. Indeed, large numbers of gene mutations and / or chromosomal abnormalities have been identified as risk factors or causative factors for myeloid diseases.

[0004] For example, about 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 the inversion inv(3)(q21q26.2) or the translocation t(3;3)(q21;q26.2) have been reported in patients with AML and myelodysplastic syndrome (MDS); these diseases being differentiated from one another primarily by bone marrow blast rate (with rates below 20% signaling MDS and thoseabove 20% indicating AML). AML and MDS with inv(3)(q21q26.2) or t(3;3)(q21;q26.2), are notably 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 not respond well to first-line chemotherapy, leading to higher mortality rates and increased risk of relapses.

[0006] There is thus an unmet medical need of treating patients suffering from myeloid diseases with chromosomal abnormalities, in particular 3q21 and / or 3q26 abnormalities.SUMMARY

[0007] This invention thus relates to a compound of formula (I)wherein:R1 and R2 are each independently selected from: hydrogen; heterocycle; cyano; -CF3; - NRR’; -OH; halogen preferably selected from F, Cl, Br and I; alkyl group optionally substituted by one or more group selected from heterocycle, NRR’, OR and a solubilizing group; alkoxy group optionally substituted by one or more group selected from heterocycle, NRR’, OR and a solubilizing group; -CO-NRR’; -SO2-NRR’; -NR-CO-R’ and -NR-SO2R’; wherein R and R’ are each independently selected from hydrogen, cycloalkyl, heterocycle, solubilizing group and alkyl group optionally substituted by one or moregroup 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 heterocycle group optionally substituted, preferably A is a heterocycle group optionally substituted by one or more group selected from halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, a solubilizing group, -NRR’, -alkyl-NRR’; -NR-CO-R’, -alkyl-NR-CO-R’, -CONRR’ and -SO2NRR’ group; wherein R and R’ are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups;B is a five-member ring heteroaryl group, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of myeloid disorders in a subject in need thereof, wherein the subject has at least one chromosome abnormality of 3q21 and / or 3q26 (3qabns).

[0008] This invention also relates to a method for treating myeloid disorders in a subject in need thereof, said method comprising administering to the subject a therapeutically effective dose of a compound of formula (I)or a pharmaceutically acceptable salt or solvate thereof, wherein:R1 and R2 are each independently selected from: hydrogen; heterocycle; cyano; -CF3; - NRR’; -OH; halogen preferably selected from F, Cl, Br and I; alkyl group optionally substituted by one or more group selected from heterocycle, NRR’, OR and a solubilizing group; alkoxy group optionally substituted by one or more group selected from heterocycle, NRR’, OR and a solubilizing group; -CO-NRR’; -SO2-NRR’; -NR-CO-R’ and -NR-SO2R’; wherein R and R’ are each independently selected from hydrogen, cycloalkyl, heterocycle, solubilizing group and alkyl group optionally substituted by one or moregroup 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 heterocycle group optionally substituted, preferably A is a heterocycle group optionally substituted by one or more group selected from halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, a solubilizing group, -NRR’, -alkyl-NRR’; -NR-CO-R’, -alkyl-NR-CO-R’, -CONRR’ and -SO2NRR’ group; wherein R and R’ are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups;B is a five-member ring heteroaryl group, and wherein the subject has at least one chromosome abnormality of 3q21 and / or 3q26 (3qabns).

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

[0010] In some embodiments, the myeloid disorder is selected from the group comprising or consisting of acute myeloid leukemia (AML), acute myelomonocytic leukemia (AMML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasms (MPNs), myeloproliferative disorders, acute monoblastic / monocytic leukemia, pure erythroid leukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, acute panmyelosis with myelofibrosis, myeloid sarcoma, myeloid proliferations related to down syndrome, transient abnormal myelopoiesis, myeloid leukemia associated with down syndrome, blastic plasmacytoiddendritic cell neoplasm, acute leukemias of ambiguous lineage, acute undifferentiated leukemia, and mixed-phenotype acute leukemia.

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

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

[0013] In some embodiments, the myeloid disorder is a relapse or refractory myeloid disorder.

[0014] In some embodiments, the chromosome abnormality is selected from the group comprising or consisting of t(3;8)(q26;q24), inv(3)(q21q26), t(3;3)(q21;q26), t(3;21)(q26;q22), t(l;3)(p36;q21), t(3;5) (q21;q31) / (q21;q35) / (q26;q21), and t(3;12)(q26;pl3).

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

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

[0017] In some embodiments, the chromosome abnormality is t(3;8)(q26;q24), wherein the myeloid disorder is a refractory AML, and wherein the compound is l-{4-[2-(5- Ethoxymethyl-2-methyl-phenylamino)-oxazol-5-yl]-phenyl]-imidazolidin-2-one of formula (II)or a pharmaceutically acceptable salt or solvate thereof.

[0018] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, is administered or is 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 pharmaceutically acceptable salt or solvate thereof, is the sole active pharmaceutical ingredient.

[0020] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, is administered or is to be administered at a dose of at least 0.9 mg / m2. In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, is administered or is to be administered at a dose ranging from 0.9 mg / m2to 16 mg / m2.

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

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

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

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

[0025] In some embodiments, the at least one other anticancer agent is azacytidine. In some embodiments, the azacytidine is administered or is to be administered subcutaneously. In some embodiments, the azacytidine is administered or is to be administered at a dose of 75 mg / m2.

[0026] In some embodiments, the method for treating myeloid disorders in a subject in need thereof further comprises the steps of determining if said subject is susceptible to respond to said compound or pharmaceutically acceptable salt or solvate thereof by:(i) detecting chromosomal abnormalities in said myeloid disorder, and(ii) determining if said subject is susceptible to respond to said compound or pharmaceutically acceptable salt or solvate thereof, wherein the detection of at least one chromosomal abnormality means that said subject is susceptible to respond to said compound or pharmaceutically acceptable salt or solvate thereof.

[0027] This invention further relates to a method for identifying a subject suffering from a myeloid disorder susceptible to respond to a compound, or a pharmaceutically acceptable salt or solvate thereof, comprising:(i) detecting chromosomal abnormalities in said myeloid disorder, and(ii) determining if said subject is susceptible to respond to said compound, or pharmaceutically acceptable salt or solvate thereof, wherein the detection of at least one chromosomal abnormality means that said subject is susceptible to respond to said compound, or pharmaceutically acceptable salt or solvate thereof wherein the compound is of formula (I)wherein:R1 and R2 are each independently selected from: hydrogen; heterocycle; cyano; -CF3; - NRR’; -OH; halogen preferably selected from F, Cl, Br and I; alkyl group optionally substituted by one or more group selected from heterocycle, NRR’, OR and a solubilizing group; alkoxy group optionally substituted by one or more group selected from heterocycle, NRR’, OR and a solubilizing group; -CO-NRR’; -SO2-NRR’; -NR-CO-R’ and -NR-SO2R’; wherein R and R’ are each independently selected from hydrogen, cycloalkyl, heterocycle, solubilizing group and alkyl group optionally substituted by one or more group 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 heterocycle group optionally substituted, preferably A is a heterocycle group optionally substituted by one or more group selected from halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, a solubilizing group, -NRR’, -alkyl-NRR’; -NR-CO-R’, -alkyl-NR-CO-R’, -CONRR’ and -SO2NRR’ group; wherein R and R’ are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups;B is a five-member ring heteroaryl group, or a pharmaceutically acceptable salt or solvate thereof.DEFINITIONS

[0028] In the present invention, the following terms have the following meanings:

[0029] Where chemical substituents are combinations of chemical groups, the point of attachment of the substituent to the molecule is by the last chemical group recited on the right of the name of the substituent. For example, an arylalkyl substituent is linked to the rest of the molecule through the alkyl moiety and it may by represented as follows: “aryl alkyl-”. Unless otherwise indicated, the compounds were named using ChemBioDraw® Ultra 13.0.2 (PerkinElmer).

[0030] “Alkoxy” refers to an alkyl-O- group.

[0031] “Alkyl” refers to a saturated linear or branched hydrocarbon chain, typically comprising from 1 to 16 carbon atoms, preferably from 1 to 12 carbon atoms, more preferably from 1 to 8 carbon atoms, furthermore preferably from 1 to 6 carbon atoms. Alkyl groups may be monovalent or polyvalent (i.e., “alkylene” groups, which are divalent alkyl groups, are encompassed in “alkyl” definition). The alkyl group may optionally be substituted by one or more substituent(s) (for example 1 to 4 substituent(s), or for example 1, 2, 3 or 4 substituent(s)) 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).

[0032] “Aryl” means a monocyclic or polycyclic-aromatic radical comprising 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 benzofused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.

[0033] “Cycloalkyl group” means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing the number of ring atoms indicated. This includes substituted or unsubstituted cylcoalkyl groups. For example,cycloalkyl group may be C3-C10 alkyl group, such as C3 or C4, in particular a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group etc.

[0034] “Halogen” refers to a fluorine, chlorine, bromine or iodine atom.

[0035] “Heterocycle” refers collectively to heterocycloalkyl groups and heteroaryl groups.

[0036] “Heterocycloalkyl” refers to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3- to 7-membered monocyclic, 7-to 11-membered bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. Heterocycloalkyl groups may in particular be 3- to 7-membered, preferably 5- or 6-membered. Heterocycloalkyl groups may in particular be monocyclic or bicyclic, preferably monocyclic. Each ring of the heterocycloalkyl group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. In one embodiment, the heterocycloalkyl is bound to another group or molecule through a carbon atom, i.e., the binding atom is not selected among the heteroatoms included therein. In one embodiment, the heterocyclo alkyl is bound to another group or molecule through one of the heteroatoms included therein. When substituted by one or more other group(s), an heterocycloalkyl may be substituted either through a carbon atom or through a heteroatom (e.g., nitrogen), unless otherwise specified. The rings of multi-ring heterocycloalkyl groups may be fused, bridged and / or joined through one or more spiro atoms. This definition encompasses polycyclic heterocycloalkyls (e.g., bicycles) and bridged heterocycloalkyl structures, including cycles bound together through one atom (“spiro”) or through two atoms. The heterocycloalkyl group may optionally be substituted by one or more substituent(s) (for example 1 to 4 substituent(s), or for example 1, 2, 3 or 4 substituent(s)) 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, isoindolinyl tetrahydropyran, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 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-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl (e.g., tetrahydroisoquinolin- 1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl or tetrahydroisoquinolin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), thiomorpholin-4-ylsulfoxide, thiomorpholin-4-ylsulfone, 1, 3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, IH-pyrrolizinyl, tetrahydro- 1,1 -dioxothiophenyl, N-formylpiperazinyl, and morpholinyl (e.g., morpholin-4-yl).

[0037] “Heteroaryl” refers to aromatic rings or aromatic ring systems comprising from 5 to 15 carbon atoms, preferably from 4 to 12 carbon atoms, more preferably from 3 to 10 carbon atoms, having one or two rings which are fused together or linked covalently, wherein at least one ring is aromatic, and wherein one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and / or sulfur atoms. Heteroaryl groups may be monovalent or polyvalent (e.g., divalent). The nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized (e.g., sulfur may be oxidized as SO or SO2). This definition of “heteroaryl” encompasses the partially hydrogenated derivatives of the carbocyclic systems enumerated herein, as well as ring systems including one or more fused non-aromatic cycloalkyl and / or heterocycloalkyl ring(s), as long as at least one ring is aromatic. In one embodiment, the heteroaryl is bound to another group or molecule through a carbon atom, i.e., the binding atom is not selected among the heteroatoms included therein. In one embodiment, the heteroaryl is bound to another group or molecule through one of the heteroatoms included therein (e.g., a nitrogen). When substituted by one or more other group(s), an heteroaryl may be substituted either through a carbon atom or through a heteroatom (e.g., nitrogen), unless otherwise specified. The heteroaryl group may optionally be substituted by one or more substituent(s) (for example 1 to 4 substituent(s),or for example 1, 2, 3 or 4 substituent(s)) 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,l-b][l,3]thiazolyl, thieno[3,2- b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][l,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[l,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1 -benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[l,2- a]pyridinyl, 6-oxo-pyridazin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 6-oxo-pyridazin-l(6H)-yl, 2-oxopyridin-l(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and quinoxalinyl. Non-limiting examples of heteroaryl groups comprising at least one fused non-aromatic ring include 2,3-dihydrobenzofuranyl, benzo[d][l,3]dioxolyl, indolinyl, 2,3-dihydrobenzo[b][l,4]dioxinyl, 3,4-dihydro-2H- benzo[b][l,4]oxazinyl, 1,2,3,4-tetrahydroquinoxaline, 3,4-dihydro-2H- benzo[b][l,4]thiazine and 2,3-dihydrobenzo[b][l,4]oxathiine.

[0038] “Solvate” refers to a molecular complex comprising a compound as described herein and contains stoichiometric or sub-stoichiometric amounts of one or more pharmaceutically acceptable solvent molecule such as, for example, ethanol. The term “hydrate” refers to when the solvent is water.

[0039] “Solubilizing group” means a group which improve the solubility of a compound in water or aqueous solution, as compared to an analog compound that does not include the group. Non-limiting examples of such solubilizing groups are groups that ionize under the conditions of use to form charged moieties (e.g., carboxylic acids, sulfonic acids, phosphoric acids, amines, etc.); groups that include permanent charges (e.g., quaternary ammonium groups); and / or heteroatoms or heteroatomic groups such asO, S, N, NH, N-(CH2)zR, N-(CH2)Z-C(O)R, N-(CH2)Z-C(O)OR, N-(CH2)Z-S(O)2R, N- (CH2)Z-S(O)2OR, N-(CH2)Z-C(O)NRR’ , where z is an integer ranging from 0 to 6; R and R’ each independently are selected from hydrogen, an alkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen; as well as alkoxy group containing from 1 to 10 carbon atoms; as well as aryl and heteroaryl group.In some embodiments, the solubilizing group is a heterocycloalkyl that optionally includes from 1 to 5 substituents, which may themselves be solubilizing groups.In a specific embodiment, the solubilizing group is of the formula:wherein L is selected from the group consisting of CH and N; M is selected from the group consisting of-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)NRR’)-, where z is an integer ranging from 0 to 6, R and R’ each independently are selected from hydrogen, an alkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more hetereoatoms such as halogen (selected from F, Cl, Br or I), oxygen, and nitrogen; as well as alkoxy group containing from 1 to 10 carbon atoms, NRR’ group wherein R and R’ are each independently selected from hydrogen, alkyl group as defined above optionally substituted with at least one heteroatom, notably oxygen or nitrogen optionally substituted with an alkyl group containing from 1 to 10 carbons optionally substituted; as well as aryl and heteroaryl group, with the proviso that L and M are not both simultaneously CH and CH2, respectively.In another specific embodiment, the solubilizing group is selected from the group consisting of morpholinyl, piperidinyl, pyrrolidinyl, N-(C1-C6)alkyl piperidinyl, in particular N-methyl piperidinyl and N-ethyl piperidinyl, N-(4-piperidinyl)piperidinyl, 4- (l-piperidinyl)piperidinyl, 1-pyrrolidinylpiperidinyl, 4-morpholinopiperidinyl, 4-(N- methyl-l-piperazinyl)piperidinyl, piperazinyl, N-(C1-C6)alkylpiperazinyl, in particular N-methyl piperazinyl and N-ethyl piperazinyl, N-(C3-C6)cycloalkyl piperazinyl, in particular N-cyclohexyl piperazinyl, pyrrolidinyl, N-(C1-C6)alkyl pyrrolidinyl, in particular N-methyl pyrrolidinyl and N-ethyl pyrrolidinyl, diazepinyl, N-(C1-C6)alkyl azepinyl, in particular N-methyl azepinyl and N-ethyl azepinyl, homopiperazinyl, N- methyl homopiperazinyl, N-ethyl homopiperazinyl, imidazolyl, and the like.

[0040] “Solvate isomers” is used herein to describe two or more molecular complexes comprising the compound as described herein and one or more pharmaceutically acceptable solvent molecules, for example, ethanol, wherein said complexes differ by their number of solvent molecules per molecule of compound as described herein. The term “hydrate” is employed when said solvent is water.

[0041] “Substituent” or “substituted” means that a hydrogen radical on a compound or group is replaced with any desired group that is substantially stable to reaction conditions in an unprotected form or when protected using 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 group as defined above, nitro, thiol, heterocycloalkyl groups, heteroaryl groups, cyano, cycloalkyl groups as defined above, as well as a solubilizing group, -NRR’, -NR-CO-R’, -CONRR’, -SO2NRR’ group wherein R and R’ are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl groups as defined above.

[0042] “About” is used herein to mean approximately, roughly, around, or in the region of. The term “about” preceding a figure means plus or less 10 % of the value of the figure. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth by 10%.

[0043] “Active pharmaceutical ingredient ”, “active ingredient’’ or “therapeutic agent” refer to a compound for therapeutic use and relating to health. Especially, a therapeutic agent (e.g., a compound as described herein) may be indicated for treating a disease (e.g., a hematological disorder and / or proliferative disorder, preferably acute myeloid leukemia, myelodysplastic syndrome, and / or other myeloid disorders). An active ingredient may also be indicated for improving the therapeutic activity of another therapeutic agent.

[0044] “Administration”, or a variant thereof (e.g., “administering”), means providing a therapeutic agent alone or as part of a pharmaceutically acceptable composition, to the patient in whom / which the condition, symptom, or disease is to be treated.

[0045] “Chromosomal abnormality” refers to an aberrant rearrangement of a chromosome, such as a translocation (t), inversion (inv), substitution, deletion(del), or duplication. Typically, a chromosomal abnormality is expressed as follow: x(nl;n2)(yla.b;y2a.b), wherein x defines the type of rearrangement (translocation, inversion etc.), nl is a first chromosome, n2 is a second optional chromosome, yl and y2 define the short arm (p) or the long arm (q) of a chromosome, a defines a band or segment or location on the arm of a chromosome, b defines a sub-band or sub-segment or sublocation on the band or segment or location of the arm of a chromosome. In the case of a deletion, y2 is not indicated. In some embodiments, the chromosomal abnormality found in the myeloid disease of the subject treated by the method of the present invention is localized on q21 and / or q26 of chromosome 3, i.e., the chromosomal abnormality is 3q21 and / or 3q26. Chromosomal abnormalities on the long arm of chromosome 3 are herein referred to as 3qabns.

[0046] “Comprise” or a variant thereof (e.g., “comprises”, “comprising”) is used herein according to common patent application drafting terminology. Hence, “comprise” preceded by an object and followed by a constituent means that the presence of a constituent in the object is required (typically as a component of a composition), but without excluding the presence of any further constituent(s) in the object. Moreover, any occurrence of “comprise” or a variant thereof in the specification also encompassesnarrower expression “consists essentially of’, further narrower expression “consist of’ and any variants thereof (e.g., “consists of’, “consisting of’).

[0047] “Metabolite” is used herein to describe a compound resulting from the biochemical transformation of a parent compound by metabolism.

[0048] “Pharmaceutically acceptable” means that the ingredients of a composition are compatible with each other and not deleterious to the subject to which / whom it is administered.

[0049] “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. It 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 offices, such as, e.g., FDA Office or EMA. Examples of pharmaceutically acceptable carriers or excipients include, but are not limited to, ion exchangers, alumina, aluminium 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, polyvinyl pyrrolidone, cellulose-based substances (for example sodium carboxymethylcellulose), polyethylene glycol, poly acrylates, waxes, polyethylene- polyoxypropylene- block polymers, polyethylene glycol and wool fat.

[0050] “Pharmaceutical composition” refers to a composition comprising at least one therapeutic agent (e.g., a compound as described herein) and at least one pharmaceutically acceptable carrier.

[0051] “Subject” refers to an animal, typically a warm-blooded animal, preferably a mammal, more preferably a primate, furthermore preferably a human. In one embodiment, the subject is a “patient” as defined herein. In one embodiment, the subjectis affected, preferably is diagnosed, with a disease, preferably a hematological disorder and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome, and / or other myeloid disorders. In one embodiment, the subject is at risk of developing a disease, preferably a hematological disorder and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome, and / or other myeloid disorders. Examples of risks factor include, but are not limited to, genetic predisposition, or familial history of the disease. In some embodiments, the subject is a female. In some embodiments, the subject is a male. In some embodiments, the subject is an adult.

[0052] “Therapeutically effective amount” (in short “effective amount”) refers to the amount of a therapeutic agent (e.g., a compound as described herein) that is sufficient to achieve the desired therapeutic, prophylactic or preventative effect in the patient to which / whom it is administered, without causing significant negative or adverse side effects to said patient. A therapeutically effective amount may be administered prior to the onset of the disease, preferably a hematological disorder and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome, and / or other myeloid disorders, for a prophylactic or preventive action. Alternatively, or additionally, the therapeutically effective amount may be administered after initiation of the disease, preferably a hematological disorder and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome, and / or other myeloid disorders, for a therapeutic action.

[0053] “Treating”, “treatment” or “alleviation” refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder (herein a “disease”) (e.g., a hematological disorder and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome, and / or other myeloid disorders). Those in need of treatment include those already with the disease, preferably a hematological disorder and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome, and / or other myeloid disorders, as well as those prone to have the disease, preferably a hematological disorder and / or proliferative disorder, more preferably acutemyeloid leukemia, myelodysplastic syndrome, and / or other myeloid disorders, or those in whom the condition or disease, preferably a hematological disorder and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome, and / or other myeloid disorders, is to be prevented. A patient is successfully “treated” for a disease, preferably a hematological disorder and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome, and / or other myeloid disorders, if, after receiving a therapeutic amount of a therapeutic agent (e.g., a compound as described herein), the patient shows observable and / or measurable reduction in or absence of one or more of the following: reduction in the percent of total cells that are pathogenic; and / or relief to some extent, in one or more of the symptoms associated with the specific disease, preferably a hematological disorder and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome, and / or other myeloid disorders; reduced morbidity and mortality, and improvement in quality of life issues. The above parameters for assessing successful treatment and improvement in the disease, preferably a hematological disorder and / or proliferative disorder, more preferably acute myeloid leukemia, myelodysplastic syndrome, and / or other myeloid disorders, are readily measurable by routine procedures familiar to a physician.DETAILED DESCRIPTION

[0054] The present invention relates to a method for treating myeloid disorders in a subject in need thereof, said method comprising administering to the subject a therapeutically effective dose of a compound of formula (I)wherein:R1 and R2 are each independently selected from: hydrogen; heterocycle; cyano; -CF3; - NRR’; -OH; halogen preferably selected from F, Cl, Br and I; alkyl group optionally substituted by one or more group selected from heterocycle, NRR’, OR and a solubilizing group; alkoxy group optionally substituted by one or more group selected from heterocycle, NRR’, OR and a solubilizing group; -CO-NRR’; -SO2-NRR’; -NR-CO-R’ and -NR-SO2R’; wherein R and R’ are each independently selected from hydrogen, cycloalkyl, heterocycle, solubilizing group and alkyl group optionally substituted by one or more group 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 heterocycle group optionally substituted, preferably A is a heterocycle group optionally substituted by one or more group selected from halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, a solubilizing group, -NRR’, -alkyl-NRR’; -NR-CO-R’, -alkyl-NR-CO-R’, -CONRR’ and -SO2NRR’ group; wherein R and R’ are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups;B is a five-member ring heteroaryl group, or a pharmaceutically acceptable salt or solvate thereof, and wherein the subject has at least one chromosome abnormality of 3q21 and / or 3q26 (3qabns).

[0055] The present invention also relates to a compound of formula (I)wherein:R1 and R2 are each independently selected from: hydrogen; heterocycle; cyano; -CF3; - NRR’; -OH; halogen preferably selected from F, Cl, Br and I; alkyl group optionally substituted by one or more group selected from heterocycle, NRR’, OR and a solubilizinggroup; alkoxy group optionally substituted by one or more group selected from heterocycle, NRR’, OR and a solubilizing group; -CO-NRR’; -SO2-NRR’; -NR-CO-R’ and -NR-SO2R’; wherein R and R’ are each independently selected from hydrogen, cycloalkyl, heterocycle, solubilizing group and alkyl group optionally substituted by one or more group 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 heterocycle group optionally substituted, preferably A is a heterocycle group optionally substituted by one or more group selected from halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, a solubilizing group, -NRR’, -alkyl-NRR’; -NR-CO-R’, -alkyl-NR-CO-R’, -CONRR’ and -SO2NRR’ group; wherein R and R’ are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups;B is a five-member ring heteroaryl group, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of myeloid disorders in a subject in need thereof, wherein the subject has at least one chromosome abnormality of 3q21 and / or 3q26 (3qabns).

[0056] In one embodiment, in the compound as described herein, R1 represents a hydrogen or an alkyl group, preferably R1 represents hydrogen or C1-C3 alkyl, more preferably R1 represents hydrogen, methyl, ethyl or propyl, even more preferably, R1 represents hydrogen or methyl.

[0057] In one embodiment, in the compound as described herein, R1 represents an alkyl group, preferably R1 represents C1-C3 alkyl, more preferably R1 represents methyl, ethyl or propyl, even more preferably, R1 represents methyl.

[0058] In one embodiment, in the compound as described herein, R2 represents a hydrogen or an alkyl group optionally substituted by an alkoxy, preferably R2 represents hydrogen, methyl or -CH2-O-C2H5.

[0059] In one embodiment, in the compound as described herein, R2 represents a hydrogen.

[0060] In some embodiments, the compound is l-{4-[2-(5-Ethoxymethyl-2-methyl- phenylamino) -oxazol-5-yl]-phenyl]-imidazolidin-2-one of formula (II)or a pharmaceutically acceptable salt or solvate thereof.

[0061] Compound l-{4-[2-(5-Ethoxymethyl-2-methyl-phenylamino) -oxazol-5-yl]- phenyl]-imidazolidin-2-one may be interchangeably referred to as AB8939.

[0062] Table 1: compound as described herein.

[0063] The compounds as 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 which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, borate,camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinafoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, 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 may also be formed, for example, hemisulphate and hemicalcium salts. When the 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 invention. When the compounds as described herein contain a hydrogen donating heteroatom (e.g., NH), the invention also covers salts and / or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.

[0064] Pharmaceutically acceptable salts of compounds of formula (I) or formula (II) may be prepared by one or more of these methods: (i) by reacting the compound of formula (I) with the desired acid; (ii) by reacting the compound of formula (I) or formula (II) with the desired base; (iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or formula (II) or by ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using the desired acid; and / or (iv) by converting one salt of the compound of formula (I) or formula (II) to another by reaction with an appropriate acid or by means of a suitable ion exchange column. All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.

[0065] It is to be understood that the goal of the present invention is to treat a myeloid disease with 3qabns in a subject. Within the scope of the invention, “treat” is intended tomean to put the myeloid disease into remission. In a preferred embodiment, the remission is maintained over time.

[0066] Within the scope of the invention, remission is considered “complete” when the bone marrow contains fewer than 5% blast cells, there is an absence of extramedullary disease, the blood cell counts return to within normal limits, and there are no signs or symptoms of the myeloid disease.

[0067] Within the scope of the invention, remission is considered “complete with incomplete hematologic recovery” when complete remission criteria are met except for residual neutropenia [ANC (absolute neutrophil count) <1.0 x l09 / L] or thrombocytopenia [platelets <100 x 109 / L]).

[0068] Within the scope of the invention, remission is considered “complete within bone marrow” or “morphologic leukemia free state” (MLFS) when the bone marrow contains fewer than 5% blast cells and there is an absence of extramedullary disease (i.e., no hematologic recovery is required).

[0069] Within the scope of the invention, remission is considered “partial” when the bone marrow contains 5% to 25% blast cells, and decrease of pre-treatment bone marrow blast percentage by at least 50%.

[0070] Patients not meeting the criteria for remission are categorized as having no response prior to the response landmark. Patients failing to achieve response by the designated landmark are designated as having refractory disease.

[0071] Myeloid disorders, interchangeably referred to as myeloid diseases, are a group of diseases involving cells from the myeloid lineage, at various states of differentiation or maturation. These disorders typically interfere with hematopoiesis and / or immune function.

[0072] In some embodiments, the myeloid disorder is selected from the group comprising or consisting of acute myeloid leukemia (AML), acute myelomonocytic leukemia (AMML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasms (MPNs), myeloproliferative disorders, acutemonoblastic / monocytic leukemia, pure erythroid leukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, acute panmyelosis with myelofibrosis, myeloid sarcoma, myeloid proliferations related to down syndrome, transient abnormal myelopoiesis, myeloid leukemia associated with down syndrome, blastic plasmacytoid dendritic cell neoplasm, acute leukemias of ambiguous lineage, acute undifferentiated leukemia, and mixed-phenotype acute leukemia.

[0073] In some embodiments, the myeloid disorder is selected from the group comprising or consisting of acute myeloid leukemia (AML), acute myelomonocytic leukemia (AMML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML) and myeloproliferative neoplasms (MPNs).

[0074] In some embodiments, the myeloid disorder is acute myeloid leukemia (AML). In some embodiments, the AML is characterized in that the blast cells percentage is more than 20%. In some embodiments, the myeloid disorder is de novo (or primary) AML, secondary AML (s-AML), or therapy-related AML (t-AML). In some embodiments, the myeloid disorder is M0, Ml, M2, M3, M4, M4eo, M5a, M6, or M7 AML.

[0075] As used herein, de novo AML refers to the first occurrence of AML in a subject; secondary AML refers to the second, third or more occurrence of AML in a subject, typically secondary AML arises from the previous AML; therapy-related AML refers to an AML arising after treatment with chemotherapy, irradiation, immunosuppressive therapy or combination thereof, typically therapy -related AML results from mutational events caused by the therapy.

[0076] As used herein, M0 refers to myeloblastic without differentiation, Ml refers to myeloblastic with little or no maturation, M2 refers to myeloblastic with maturation, M3 refers to promyelocytic, M4 refers to myelomonocytic, M4eo refers to myelomonocytic with eosinophils, M5a refers to monocytic without differentiation (monoblastic), M5b refers to monocytic with differentiation, M6 refers to erythroleukemic, and M7 refers to megakaryocytic.

[0077] Diagnosis and management of AML has been well documented and is known in the art (see, e.g., Dbhner et al. Blood. 2022;140(12):1345-1377).

[0078] In some embodiments, the myeloid disorder is acute myelomonocytic leukemia (AMML). In some embodiments, the myeloid disorder is de novo (or primary) AMML, secondary AMML (s-AMML), or therapy-related AMML (t-AMML).

[0079] In some embodiments, the myeloid disorder is myelodysplastic syndrome (MDS). In some embodiments, the MDS is characterized in that the blast cells percentage is comprised between 5% and 20%.

[0080] In some embodiments, the myeloid disorder is chronic myelogenous leukemia (CML).

[0081] In some embodiments, the myeloid disorder is a myeloproliferative neoplasm (MPN).

[0082] In some embodiments, the myeloid disorder is a relapse and / or refractory myeloid disorder.

[0083] In some embodiments, the myeloid disorder is a relapse. As used herein, “relapse” is intended to mean that the myeloid disorder was transiently alleviated after one, two, three or more treatments, but was not cured.

[0084] In some embodiments, the myeloid disorder is a refractory. As used herein, “refractory” is intended to mean that the myeloid disorder is partially or fully resistant to the treatment.

[0085] In some embodiments, the chromosome abnormality is localized on chromosome 3.

[0086] In some embodiments, the chromosome abnormality is a translocation, or an inversion, or a deletion.

[0087] In some embodiments, the chromosome abnormality is selected from the group comprising or consisting of t(3;3), t(3;n), inv(3), wherein “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.

[0088] In some embodiments, the chromosome abnormality is localized on the long arm (q) of chromosome 3.

[0089] In some embodiments, the chromosome abnormality is localized on positions 21 and / or 26 of the long arm (q) of chromosome 3. Such chromosome abnormality is interchangeably referred to as 3qabns.

[0090] In one embodiment, the chromosome abnormality is localized on position 21 of the long arm (q) of chromosome 3. In another embodiment, the chromosome abnormality is localized on position 26 of the long arm (q) of chromosome 3.

[0091] In some embodiments, the chromosome abnormality is selected from the group comprising or consisting of t(3;8)(q26;q24), inv(3)(q21q26), t(3;3)(q21;q26), t(3;21)(q26;q22), t(l ;3)(p36;q21), t(3;5) (q21 ;q3 l) / (q21 ;q35) / (q26;q21), and t(3;12)(q26;pl3).

[0092] In some embodiments, the chromosome abnormality is selected from the group comprising or consisting of t(3;8)(q26;q24), inv(3)(q21q26) and t(3;3)(q21;q26).

[0093] In some embodiments, the chromosome abnormality is t(3;8)(q26;q24).

[0094] In some embodiments, the method as described herein is for treating a myeloid disorder in a subject, wherein the chromosome abnormality is t(3;8)(q26;q24), wherein the myeloid disorder is a refractory AML, and wherein the compound is l-{4-[2-(5- Ethoxymethyl-2-methyl-phenylamino)-oxazol-5-yl]-phenyl]-imidazolidin-2-one of formula (II)1 or a pharmaceutically acceptable salt or solvate thereof.

[0095] In some embodiments, the chromosome abnormality is t(3;8)(q26;q24), wherein the myeloid disorder is a refractory AML, and wherein the compound for use as described herein is 1 - { 4- [2-(5-Ethoxymethyl-2-methy l-phenylamino)-oxazol-5 -yl] -phenyl } - imidazolidin-2-one of formula (II)or a pharmaceutically acceptable salt or solvate thereof.

[0096] In some embodiments, the myeloid disorder and / or the chromosomal abnormality is associated with altered expression of at least one gene selected from the group comprising 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.

[0097] In some embodiments, the myeloid disorder and / or the chromosomal abnormality is associated with altered expression of at least one gene selected from the group comprising or consisting of EVI1 (MECOM), RPN1, SRSF2, SETBP1, ETV6, NPM, CEBP alpha, FLT3, RUNX1, ASXL1, TP53, IDH1, IDH2, and combinations thereof.

[0098] In some embodiments, the myeloid disorder and / or the chromosomal abnormality is associated with altered expression of at least one gene selected from the group comprising or consisting of EVI1 (MECOM), RPN1, SRSF2, SETBP1, ETV6, and combinations thereof.

[0099] In some embodiments, the myeloid disorder and / or the chromosomal abnormality is associated with altered expression of EVI1 (MECOM) and / or RPN1. In some embodiments, the myeloid disorder is associated with altered expression of EVI1 (MECOM).

[0100] In some embodiments, the myeloid disorder and / or the chromosomal abnormality is associated with expression of at least one gene fusion selected from the group comprising: 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 RPN1 -MECOM fusion gene.

[0101] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered in the form of a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient and / or carrier.

[0102] As is known to the person skilled in the art, various forms of excipients can be used adapted to the mode of administration and some of them can promote the effectiveness of the active molecule, e.g., by promoting a release profile rendering this active molecule overall more effective for the desired treatment.

[0103] In some embodiments, the pharmaceutically acceptable vehicle or excipient is selected in a group comprising or consisting of a solvent, a diluent, a carrier, an excipient, a dispersion medium, a coating, an absorption delaying agent and any combinations thereof. The carrier, diluent, solvent or excipient must be “acceptable” in the sense of being compatible with the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, and not be deleterious upon being administered to a subject.Typically, the vehicle or excipient does not produce an adverse, allergic or other untoward reaction when administered to a subject.

[0104] The pharmaceutical compositions as described herein are thus able to be administered in various forms, for example as injectable, pulverizable or ingestible form.

[0105] The present invention notably covers the use of the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, or the pharmaceutical composition comprising thereof, for the manufacture of a medicament.

[0106] Such medicament can take the form of a pharmaceutical composition adapted for one or more modes of administration, preferably intravenous administration, which can be formulated using pharmaceutically acceptable carriers well known in the art in suitable dosages. Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for ingestion by the patient.

[0107] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is the sole active pharmaceutical ingredient.

[0108] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered at a dose of at least 0.09 mg / m2.

[0109] As used herein, “at least 0.09 mg / m2” 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 / m2, or more.

[0110] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered at a dose of at least 0.9 mg / m2.

[0111] As used herein, “at least 0.9 mg / m2” means 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 / m2, or more.

[0112] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered at a dose of at least 1.8, 3.6, 6.0, 9.0 or 12.0 mg / m2.

[0113] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered at a dose of at most 64 mg / m2, preferably at most 32 mg / m2, more preferably at most 16 mg / m2.

[0114] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered at a dose ranging from 0.09 mg / m2to 32 mg / m2.

[0115] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered at a dose ranging from 0.9 mg / m2to 16 mg / m2.

[0116] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered at a dose ranging from 1.8 mg / m2to 16 mg / m2, ranging from 3.6 mg / m2to 16 mg / m2, ranging from 6.0 mg / m2to 16 mg / m2, ranging from 9.0 mg / m2to 16 mg / m2, or ranging from 12.0 mg / m2to 16 mg / m2.

[0117] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered at a dose ranging from 0.9 mg / m2to 12.0 mg / m2, ranging from 0.9 mg / m2to 9.0 mg / m2, ranging from 0.9 mg / m2to 6.0 mg / m2, ranging from 0.9 mg / m2to 3.6 mg / m2, or ranging from 0.9 mg / m2to 1.8 mg / m2.

[0118] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be 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 / m2.

[0119] In a preferred embodiment, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered at a dose of 0.9, 1.8, 3.6, 6.0, 9.0, 12.0, or 16.0 mg / m2.

[0120] In one embodiment, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered at a dose of 0.9 mg / m2. In another embodiment, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered at a dose of 1.8 mg / m2. In another embodiment, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered at a dose of 3.6 mg / m2. In another embodiment, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered at a dose of 6.0 mg / m2. In another embodiment, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered at a dose of 9.0 mg / m2. In another embodiment, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered at a dose of 12.0 mg / m2. In another embodiment, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered at a dose of 16.0 mg / m2.

[0121] In one embodiment, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered at a fixed dose.

[0122] In one embodiment, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered at a variable dose. In some embodiments, the dose is adapted depending on the response of the subject.

[0123] In some embodiments, the dose is increased 1 time, 2 times, 3 times, 4 times or more.

[0124] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered intravenously, intraarterially, intramuscularly, intradermally, subcutaneously, transdermally, topically and / or orally.

[0125] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered intravenously.

[0126] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered every month, every two weeks, every week, every 6 days, every 5 days, every 4 days, every 3 days, every 2 two days, or every day (i.e., daily), preferably daily.

[0127] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered daily.

[0128] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered 5 times, 4 times, 3 times, 2 times or 1 time per day, preferably one time per day.

[0129] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered for up to 120 days. In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered for up to 60 days. In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered for up to 56 days. In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered for up to 28 days.

[0130] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered for 28 days. In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered for 21 days. In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered for 14 days. In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered for 7 days.

[0131] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is administered or is to be administered for 1, 2, 3, 4, 5, 6 or 7 days.

[0132] In some embodiments, the method as described herein further comprises administering to said subject at least one other anticancer agent.

[0133] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, for use as described herein, is to be administered with at least one other anticancer agent.

[0134] In some embodiments, the at least one other anti-cancer agent is a pharmacologically active molecule, e.g., a small molecule, or a biologically active peptide / protein. In some embodiments, the at least one additional anti-cancer agent is comprised in pharmacological composition approved (e.g., FDA or EMA approved) 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.

[0135] Anticancer agents are known from the state of the art. Non-limitative examples of anticancer agents include azacytidine, 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, 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, zanubrutinib, and the likes.

[0136] In some embodiments, the at least one other anticancer agent is azacytidine.

[0137] In some embodiments, azacytidine is administered or is to be administered intravenously, intraarterially, intramuscularly, intradermally, subcutaneously, transdermally, topically and / or orally.

[0138] In some embodiments, azacytidine is administered or is to be administered subcutaneously.

[0139] In some embodiments, azacytidine is administered or is to be administered at a dose ranging from 7.5 mg / m2to 750 mg / m2or ranging from 15 mg / m2to 375 mg / m2.

[0140] In some embodiments, azacytidine is administered or is to be administered at a dose of 75 mg / m2.

[0141] In some embodiments, the compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, and the at least one other anticancer agent are associated with distinct pharmaceutically acceptable vehicles or excipients.

[0142] In certain embodiments, the at least one other anti-cancer agent is to be administered in combination with, concomitantly or sequentially, the combination as described herein.

[0143] In some embodiments, the method for treating myeloid disorders in a subject in need thereof, further comprises the steps of determining if said subject is susceptible to respond to said compound, or pharmaceutically acceptable salt or solvate thereof, by:(i) detecting chromosomal abnormalities in said myeloid disorder, and(ii) determining if said subject is susceptible to respond to said compound or pharmaceutically acceptable salt or solvate thereof, wherein the detection of at least one chromosomal abnormality means that said subject is susceptible to respond to said compound or pharmaceutically acceptable salt or solvate thereof.

[0144] In some embodiments, the method for treating myeloid disorders in a subject in need thereof, further comprises the step of collecting at least one sample on the patient. Illustratively but not limitedly, samples may be blood or marrow. Suitable routine methods to collect samples from a patient a known in the art. In a preferred embodiment,the at least one sample comprises at least one diseased cell (e.g., myeloid disorder, AML cancerous cell and the like).

[0145] The present invention further relates to a method for identifying a subject suffering from a myeloid disorder susceptible to respond to a compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, comprising:(i) detecting chromosomal abnormalities in said myeloid disorder, and(ii) determining if said subject is susceptible to respond to said compound, or pharmaceutically acceptable salt or solvate thereof, wherein the detection of at least one chromosomal abnormality means that said subject is susceptible to respond to said compound, or pharmaceutically acceptable salt or solvate thereof.

[0146] In some embodiments, the method for identifying a subject suffering from a myeloid disorder susceptible to respond to a compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, comprises a step of providing a sample from a subject.

[0147] In some embodiments, the sample is a bodily fluid or marrow. Examples of bodily fluids include, but are not limited to, blood, plasma, serum, lymph, ascetic fluid, cystic fluid, urine, bile, nipple exudate, vomitus, breast milk, tears, wound drainage, feces, vaginal secretions, synovial fluid, bronchoalveolar lavage fluid, sputum, amniotic fluid, peritoneal fluid, cerebrospinal fluid, pleural fluid, 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 marrow.

[0148] In some embodiments, the sample was previously taken from the subject, i.e., the method for identifying a subject suffering from a myeloid disorder susceptible to respond to a compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, does not comprise an active step of recovering a sample from the subject. Consequently, according to this embodiment, the method for identifying a subject suffering from a myeloid disorder susceptible to respond to a compound, orpharmaceutically acceptable salt or solvate thereof, as described herein, is a non-invasive method, i.e., the method for identifying a subject suffering from a myeloid disorder susceptible to respond to a compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, is an in vitro method.

[0149] In other words, the present invention relates to an in vitro method for identifying a subject suffering from a myeloid disorder susceptible to respond to a compound, or pharmaceutically acceptable salt or solvate thereof, as described herein.

[0150] In some embodiments, detection of at least one chromosomal abnormality is performed by any suitable method known in the art. Non-limitative examples include karyotyping, sequencing, and detection of specific markers.

[0151] In some embodiments, the method for treating myeloid disorders in a subject in need thereof, or the method for identifying a subject suffering from a myeloid disorder susceptible to respond to a compound, or pharmaceutically acceptable salt or solvate thereof, as described herein, further comprises a step of assessing the evolution of the myeloid disorder. In some embodiments, the evolution of the myeloid disorder is assessed by measuring at least one marker of the myeloid disorder.

[0152] In some embodiments, the evolution of the myeloid disorder is assessed by measuring bone marrow blasts proportion in the blood of the patient.

[0153] In some embodiments, a blast cells percentage of more than 20% is associated to AML. In some embodiments, a blast cells percentage comprised between 5% and 20% is associated to MDS. In some embodiments, a blast cells percentage of less than 5% is associated to remission.

[0154] In some embodiments, the step of assessing the evolution of the myeloid disorder is performed at least 1 time, 2 times, 3 times, 4 times, 5 times or more after completion of the treatment.

[0155] In some embodiments, the step of assessing the evolution of the myeloid disorder is performed 1, 2, 3, 4, 5, 6, 7 days or more after completion of the treatment. In some embodiments, the step of assessing the evolution of the myeloid disorder is performed 1,2, 3, 4, 5, 6, 7 weeks or more after completion of the treatment. In some embodiments, the step of assessing the evolution of the myeloid disorder is performed 1, 2, 3, 4, 5, 6, 7 months or more after completion of the treatment.

[0156] The invention further relates to a pharmaceutical composition for treating or for use in the treatment of myeloid disorders in a subject in need thereof, wherein said pharmaceutical composition comprises a compound of formula (I)wherein:R1 and R2 are each independently selected from: hydrogen; heterocycle; cyano; -CF3; - NRR’; -OH; halogen preferably selected from F, Cl, Br and I; alkyl group optionally substituted by one or more group selected from heterocycle, NRR’, OR and a solubilizing group; alkoxy group optionally substituted by one or more group selected from heterocycle, NRR’, OR and a solubilizing group; -CO-NRR’; -SO2-NRR’; -NR-CO-R’ and -NR-SO2R’; wherein R and R’ are each independently selected from hydrogen, cycloalkyl, heterocycle, solubilizing group and alkyl group optionally substituted by one or more group 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 heterocycle group optionally substituted, preferably A is a heterocycle group optionally substituted by one or more group selected from halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, a solubilizing group, -NRR’, -alkyl-NRR’; -NR-CO-R’, -alkyl-NR-CO-R’, -CONRR’ and -SO2NRR’ group; wherein R and R’ are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups;B is a five-member ring heteroaryl group,or a pharmaceutically acceptable salt or solvate thereof, wherein the subject has at least one chromosome abnormality of 3q21 and / or 3q26 (3qabns).

[0157] The invention further relates to the use of a compound of formula (I)wherein:R1 and R2 are each independently selected from: hydrogen; heterocycle; cyano; -CF3; - NRR’; -OH; halogen preferably selected from F, Cl, Br and I; alkyl group optionally substituted by one or more group selected from heterocycle, NRR’, OR and a solubilizing group; alkoxy group optionally substituted by one or more group selected from heterocycle, NRR’, OR and a solubilizing group; -CO-NRR’; -SO2-NRR’; -NR-CO-R’ and -NR-SO2R’; wherein R and R’ are each independently selected from hydrogen, cycloalkyl, heterocycle, solubilizing group and alkyl group optionally substituted by one or more group 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 heterocycle group optionally substituted, preferably A is a heterocycle group optionally substituted by one or more group selected from halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, a solubilizing group, -NRR’, -alkyl-NRR’; -NR-CO-R’, -alkyl-NR-CO-R’, -CONRR’ and -SO2NRR’ group; wherein R and R’ are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups;B is a five-member ring heteroaryl group, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating myeloid disorders in a subject in need thereof, wherein the subject has at least one chromosome abnormality of 3q21 and / or 3q26 (3qabns).BRIEF DESCRIPTION OF THE DRAWINGS

[0158] Figure 1A-1C is a set of dot plots showing the efficacy and safety of the compound as described herein in an ex vivo model of NOD SCID mice injected with blasts from the marrow of a patient having AML with inv(3)(p23q26) chromosomal abnormality. Fig. 1A and Fig. IB show the blast count and the blast percentage, respectively, in the blood of the mice. Fig. 1C shows CD45+ cells count in the blood of the mice.EXAMPLES

[0159] The present invention is further illustrated by the following examples.Example 1: Synthesis

[0160] Methods to synthetize l-{4-[2-(5-Ethoxymethyl-2-methyl-phenylamino) - oxazol-5-yl]-phenyl]-imidazolidin-2-one have been previously disclosed in WO2016124747, incorporated herein by reference.

[0161] As an illustration, and non-limitatively, the last step of l-{4-[2-(5-Ethoxymethyl- 2-methyl-phenylamino) -oxazol-5-yl] -phenyl }-imidazolidin-2-one is presented hereinafter.Materials and MethodsGeneral

[0162] All chemicals used were commercial reagent grade products. Solvents were of anhydrous commercial grade and were used without further purification. The progress of the reactions was monitored by thin layer chromatography using precoated silica gel 60F 254, Merck TLC plates, which were visualized under UV light. Multiplicities in 1H NMR spectra are indicated as singlet (s), broad singlet (br s), doublet (d), triplet (t), quadruplet(q), and multiplet (m) and the NMR spectrum were performed either on a Bruker 300 or 500 MHz spectrometer.AbbreviationsCS2CO3 Cesium carbonateEtOAc Ethyl acetateMgSCE Magnesium sulfateNaCl Sodium chloridePd2(dba)3 Tris(dibenzylidenacetone)dipalladium(0)Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxantheneResultsPreparation of l-{4-[2-(5-Ethoxymethyl-2-methyl-phenylamino) -oxawl- 5 -yl] -phenyl }- imidazolidin-2-one ( 001 )

[0163] In a sealed tube, to a solution of Vic (500 mg, 1.29mmol) in dry dioxane (7 mL) were added successively 2-imidazolidinone (556 mg, 6.45 mmol), cesium carbonate (1.052 g, 3.23 mmol), Xantphos (75 mg, 0.13 mmol). The reaction mixture was degassed with nitrogen for 20 minutes before the addition of Pd2(dba)3 (35 mg, 0.04 mmol). Then, the reaction mixture was stirred at 110°C for 16 hours. The cooled mixture was diluted with water and extracted with EtOAc twice. The combined organics were washed with water, with saturated solution of NaCl, dried over MgSO4, filtered and evaporated. The final product was purified by silica gel chromatography using 10 to 50 % EtOAc / cyclohexane as eluent to give the compound as described herein (260 mg, 52%).1H NMR (500 MHz, DMSO-d6) 5 9.16 (s, 1H), 7.84 (s, 1H), 7.63 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.28 (s, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.00 (s, 1H), 6.93 (d, J = 7.6 Hz, 1H), 4.42 (s, 2H), 3.91 - 3.85 (m, 2H), 3.48 (q, J = 7.0 Hz, 2H), 3.45 - 3.38 (m, 2H), 2.28 (s, 3H), 1.15 (t, J = 7.0 Hz, 3H).Example 2: Preclinical assessmentMaterials and MethodsPatient derived xenograft mouse models: experiment design

[0164] The therapeutic potential of AB 8939 was investigated through a series of experiments using blast cells from AML patients or patient derived xenograft (PDX) mouse models.

[0165] Marrow aspirate were extracted from the patient and analyzed in terms of morphology, cytogenetics ad molecular biology.

[0166] Patient derived xenograft: blast cells from marrow aspirates were then injected to NOD SCID mice. Colonization of the mice’ bone marrow was observed after 3 weeks, mimicking the leukemia from the patient.

[0167] Mice were then treated with various drugs and evolution of the disease was assessed by measuring the blast count in blood. The toxicity of the drug was also evaluated by measuring the CD45+ cells count in blood.ResultsComparative drug assay (ex vivo)

[0168] After purification, mononuclear cells were treated for 48 hours with various concentrations of AB 8939 and several anticancer drugs, and analyzed in a cell proliferation / viability assay. Anti-proliferative action against blasts isolated from AML patients and PDX mice is expressed in terms of the concentration of an inhibitor needed to inhibit a biological process or response by 50% (IC50 values).

[0169] Several anticancer drugs were tested on mice injected with blast cells from 3 different leukemia patients: AraC (arabinocytosine, also referred to as cytarabine), AB 8939 ( 1 - { 4- [2-(5-Ethoxymethyl-2-methyl-phenylamino)-oxazol-5 -yl]-phenyl } - imidazolidin-2-one, compound as described herein, see Example 1), azacytidine (Vidaza), decitabine, daunorubicin, and guadecitabine (SGI- 110), as summarized in Table 2. The results show that AB 8939 produced a strong anti-proliferative action against blasts isolated from these refractory AML patients, with nanomolar sensitivity IC50 values, and performed substantially better than standard of care AML drugs at treating patients having AML with inv(3)(q26) chromosomal abnormality.

[0170] Table 2: comparative anti-proliferative action of AML drugs against blasts isolated from AML PDX mice (IC50 pM).

[0171] Blast cells from primary (naive) inv(3)(q26) AML patients (N=l) and PDX blasts from relap se / refractory inv(3)(q26) AML patients (N=2) were treated with the compound as described herein (AB8939), cytarabine (ARAC) or azacytidine (AZA), as summarized in Table 3. Anti-proliferative action against blasts is expressed in terms of the concentration of a drug that gives half-maximal response (EC50 values). The results show that in comparison to standard of care chemotherapies, AB8939 produced a strong anti-proliferative action against blasts isolated from primary and refractory AML patients.

[0172] Table 3: comparative anti-proliferative action of AML drugs against blasts isolated from naive and relapse AML patients (EC50 pM).

[0173] The results show that, for the patients having AML with inv(3)(q26) chromosomal abnormality, AB8939 had an EC50 slightly above 2 pM or 5 pM (depending on the patient) in naive condition, and an EC50 of 0.05 pM or 0.013 pM (depending on the patient) in relap se / refractory condition. By comparison, cytarabine and azacytidine had an EC50 comprised between 20 pM and 50 pM for the naive condition, and between 5 pM and 13 pM for the relapse / refractory condition.

[0174] The results show that AB8939 performed better than cytarabine and azacytidine at treating patients having AML with inv(3)(q26) chromosomal abnormality.Comparative drug assay (in vivo)

[0175] In another line of experiments, AB8939 was compared to azacytidine (Vidaza®), venetoclax, AB8939 combined with azacytidine, and AB8939 combined with venetoclax. This experiment was performed using mice injected with blasts from patient C1005-P2 (see first row of Table 2) having AML with inv(3)(p23q26) chromosomal abnormality. The results are shown on Figure 1A-C.

[0176] As shown on Figure 1A and Figure IB, AB8939 alone or in combination with azacytidine was able to strongly reduce the blast count compared to untreated controls. In this experiment, venetoclax performed poorly compared to AB8939.

[0177] Figure 1C shows that AB8939 did not induce any decrease in CD45+ cells count compared to control, indicating that AB8939 was not toxic. On the contrary, azacytidine induced higher toxicity, with a very low CD45+ cells count.

[0178] Overall, these results show that AB8939 was safe, and performed better than the other drugs for lowering the blast count in the blood of mice grafted with blast cells harboring a inv(3)(p23q26) chromosomal abnormality.Example 3: AML case reportMaterials and MethodsPatient summary

[0179] The patient is a 65 years old female.

[0180] AML history and treatments: AML diagnosed in October 2022, refractory, secondary, according to the World Health Organization (WHO) classification with myelodysplasia-related changes (MD) related changes.

[0181] Azacitidine (26 / 09 / 2022-14 / 10 / 2022)

[0182] Cytogenetic profile of the patient: del(l l)(ql2); t(3;8)(q26;q24).

[0183] Miscellaneous: no infectious disease; pancytopenia and hyperglycemia

[0184] AB 8939 administration: Cycle #l on 14,15,16 December 2022 at 1.8 mg / m2 / day. Cycle #2 on 24,25,26 January 2023 at 1.8 mg / m2 / day.ResultsAnalysis of pretreatment marrow sample

[0185] Morphology of the marrow aspirate showed increased cellularity. Dysplasia was observed in the three hematopoietic lineages, more striking in the megakaryocytic series. There were 20% of small and medium sized blasts, agranular cytoplasm. Loose nucleated chromatin nucleus and sometimes irregular outline.

[0186] Cytogenetics at diagnosis of the current disease reported a deletion of the long arm of chromosome 11, that was observed in all metaphases. In addition, 6 of them present a translocation t(3;8) leading to the rearrangement of MECOM (EVI1).; Formula ISCN:: 46,XX,del(l l)(ql2)[4] / 46,XX,idem,t(3;8)(q26;q24)[6].

[0187] Molecular biology at the diagnosis of the current disease consisted searching for variants making it possible to determine the diagnosis (World Health Organization 2022), assess the prognosis (European LeukemiaNet 2022) and guide therapy through actionable markers for the treatment of AML. Variant c.284_307del was detected; р.(Pro95_Argl02del) in the SRSF2 gene (52.6%). Variants described as pathogenic in myeloid neoplasms, but currently not considered to be of clinical utility in AML cases. Variant c.2608G>A was detected; p.(Gly870Ser) in the SETBP1 gene (44.3%) and the с.600_601dup variant; p.(Leu201Profs*9) in the ETV6 gene (37.4%). Hyperexpression of the EVI1 gene was detected.

[0188] Immunophenotype at diagnosis was performed on bone marrow sample. Analysis was performed on the CD34 / CD117 positive myeloid population that represents 24% of the total nucleated cellularity. The remaining cellularity corresponds to 22% granulocytic series, 29% erythroid series, and 16% lymphocytes. No CD34+ B lymphoid precursors were identified. CD42a and b: 8%+d. Immunophenotypic alterations of the granulocytic and erythroid series suggestive of dysplasia to be assessed with the cytological study are observed. A small clone of monoclonal B lymphoid cells with expression of kappa light chains and weak positive CD20 persists, representing 7.5% of the total nucleated cellularity already reported in previous studies.Analysis of patient treatment response

[0189] The results are summarized in Table 4.

[0190] Table 4: blast count of case report patient in bone marrow aspirate, over time.

[0191] The results show that administration of AB8939 at 1.8 mg / m2 / day on a patient having AML with a chromosomal abnormality on chromosome 3 (t(3;8)(q26;q24)) reduced the blast count from 55% to 5% in 28 days. Treatment response was maintained after this patient received a second cycle of AB8939 at 1.8 mg / m2 / day, with a bone marrow blast count of 10% at 28 days post administration, corresponding to a 5-fold reduction relative to baseline.

Claims

CLAIMS1. A compound of formula (I)wherein:R1 and R2 are each independently selected from: hydrogen; heterocycle; cyano; - CF3; -NRR’; -OH; halogen preferably selected from F, Cl, Br and I; alkyl group optionally substituted by one or more group selected from heterocycle, NRR’, OR and a solubilizing group; alkoxy group optionally substituted by one or more group selected from heterocycle, NRR’, OR and a solubilizing group; -CO-NRR’; -SO2- NRR’; -NR-CO-R’ and -NR-SO2R’; wherein R and R’ are each independently selected from hydrogen, cycloalkyl, heterocycle, solubilizing group and alkyl group optionally substituted by one or more group 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 heterocycle group optionally substituted, preferably A is a heterocycle group optionally substituted by one or more group selected from halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, a solubilizing group, -NRR’, -alkyl-NRR’; -NR-CO-R’, -alkyl- NR-CO-R’, -CONRR’ and -SO2NRR’ group; wherein R and R’ are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups;B is a five-member ring heteroaryl group,or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of myeloid disorders in a subject in need thereof, wherein the subject has at least one chromosome abnormality of 3q21 and / or 3q26 (3qabns).

2. The compound for use according to claim 1, wherein said compound is l-{4-[2-(5- Ethoxymethyl-2-methyl-phenylamino) -oxazol-5 -yl] -phenyl } -imidazolidin-2-one of formula (II)or a pharmaceutically acceptable salt or solvate thereof.

3. The compound for use according to claim 1 or 2, wherein the myeloid disorder is selected from the group comprising or consisting of acute myeloid leukemia (AML), acute myelomonocytic leukemia (AMML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasms (MPNs), myeloproliferative disorders, acute monoblastic / monocytic leukemia, pure erythroid leukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, acute panmyelosis with myelofibrosis, myeloid sarcoma, myeloid proliferations related to down syndrome, transient abnormal myelopoiesis, myeloid leukemia associated with down syndrome, blastic plasmacytoid dendritic cell neoplasm, acute leukemias of ambiguous lineage, acute undifferentiated leukemia, and mixed-phenotype acute leukemia.

4. The compound for use according to any one of claims 1 to 3, wherein the myeloid disorder is selected from the group comprising or consisting of acute myeloid leukemia (AML), acute myelomonocytic leukemia (AMML), myelodysplasticsyndrome (MDS), chronic myelogenous leukemia (CML) and myeloproliferative neoplasms (MPNs).

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

6. The compound for use according to any one of claims 1 to 5, wherein the myeloid disorder is a relapse or refractory myeloid disorder.

7. The compound for use according to any one of claims 1 to 6, wherein the chromosome abnormality is selected from the group comprising or consisting of t(3;8)(q26;q24), inv(3)(q21q26), t(3;3)(q21;q26), t(3;21)(q26;q22), t(l ;3)(p36;q21), t(3;5) (q21 ;q3 l) / (q21 ;q35) / (q26;q21), and t(3; 12)(q26;pl3).

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

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

10. The compound for use according to any one of claims 1 to 9, wherein the chromosome abnormality is t(3;8)(q26;q24), wherein the myeloid disorder is a refractory AML, and wherein the compound is l-{4-[2-(5-Ethoxymethyl-2-methyl- phenylamino)-oxazol-5-yl]-phenyl}-imidazolidin-2-one of formula (II)or a pharmaceutically acceptable salt or solvate thereof.

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

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

13. The compound for use according to any one of claims 1 to 12, wherein said compound, or pharmaceutically acceptable salt or solvate thereof, is to be administered at a dose of at least 0.9 mg / m2.

14. The compound for use according to any one of claims 1 to 13, wherein said compound, or pharmaceutically acceptable salt or solvate thereof, is to be administered at a dose ranging from 0.9 mg / m2to 16 mg / m2.

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

16. The compound for use according to any one of claims 1 to 15, wherein said compound, or pharmaceutically acceptable salt or solvate thereof, is to be administered intravenously.

17. The compound for use according to any one of claims 1 to 16, wherein said compound, or pharmaceutically acceptable salt or solvate thereof, is to be administered daily.

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

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

20. The compound for use according to any one of claims 1 to 19, wherein said compound, or pharmaceutically acceptable salt or solvate thereof, is to be administered with at least one other anticancer agent.

21. The compound for use according to claim 20, wherein the at least one other anticancer agent is azacytidine.

22. The compound for use according to claim 21, wherein azacytidine is to be administered subcutaneously.

23. The compound for use according to claim 21, wherein azacytidine is to be administered at a dose of 75 mg / m2.

24. A method for identifying a subject suffering from a myeloid disorder susceptible to respond to a compound, or pharmaceutically acceptable salt or solvate thereof, comprising:(i) detecting chromosomal abnormalities in said myeloid disorder, and(ii) determining if said subject is susceptible to respond to said compound, or pharmaceutically acceptable salt or solvate thereof, wherein the detection of at least one chromosomal abnormality means that said subject is susceptible to respond to said compound, or pharmaceutically acceptable salt or solvate thereof wherein the compound is of formula (I)wherein:R1 and R2 are each independently selected from: hydrogen; heterocycle; cyano; - CF3; -NRR’; -OH; halogen preferably selected from F, Cl, Br and I; alkyl group optionally substituted by one or more group selected from heterocycle, NRR’, OR and a solubilizing group; alkoxy group optionally substituted by one or more group selected from heterocycle, NRR’, OR and a solubilizing group; -CO-NRR’; -SO2- NRR’; -NR-CO-R’ and -NR-SO2R’; wherein R and R’ are each independently selected from hydrogen, cycloalkyl, heterocycle, solubilizing group and alkyl group optionally substituted by one or more group 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 heterocycle group optionally substituted, preferably A is a heterocycle group optionally substituted by one or more group selected from halogen, alkyl, aryl, hydroxyl, alkoxy, nitro, thiol, heterocycloalkyl, heteroaryl, cyano, cycloalkyl, a solubilizing group, -NRR’, -alkyl-NRR’; -NR-CO-R’, -alkyl- NR-CO-R’, -CONRR’ and -SO2NRR’ group; wherein R and R’ are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups;B is a five-member ring heteroaryl group, or a pharmaceutically acceptable salt or solvate thereof.

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