[0000] The present disclosure relates to the compounds of formula (I) or their pharmaceutically acceptable salts, or their stereoisomers or mixtures of stereoisomers, either of the compound of formula (I) or of any of its pharmaceutically acceptable salts which are NPM1 inhibitors. It also relates to pharmaceutical compositions containing them, and to their use in medicine, in particular in the treatment and/or prevention of cancer.
1. A compound of formula (I), a pharmaceutically acceptable salt thereof, or any enantiomer or mixtures of enantiomer, either of the compound of formula (I) or of any of its pharmaceutically acceptable salts <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0018" /> wherein: in formula (I) the "bold bonds" and "hashed bonds" refer to the relative stereochemistry of the chiral centers; X is NH or O; R<1> is selected from the group consisting of H, -(C<1>-C<3>)alkyl, -O(C<1>-C<3>)alkyl, halogen, -CF<3>, and -OCF<3>; R<2> is phenyl optionally substituted with one group selected from -(C<1>-C<3>)alkyl, -O-(C<1>-C<3>)alkyl, halogen, -CF<3>, -OCF<3>, -(C<3>-C<6>)cycloalkyl, -NH-(C<1>-C<3>)alkyl, -NH-CO-(C<1>-C<3>)alkyl, and -O(C<3>-C<6>)cycloalkyl; R<3> is selected from the group consisting of H, -(C<1>-C<4>)alkyl, -(C<3>-C<6>)cycloalkyl, -CO-(C<1>-C<6>)alkyl, and -CO-(C<3>-C<6>)cycloalkyl; R<4> is selected from the group consisting of H, -(C<1>-C<4>)alkyl, -(C<3>-C<6>)cycloalkyl, -(CH<2>)-(C<3>-C<6>)cycloalkyl, -(CH<2>CH<2>)-(C<3>-C<6>)C<3>-C<6>cycloalkyl; and wherein R<4> is optionally substituted with halogen; and R<5> is selected from the group consisting of H, -CH<3>, and -COCH<3>. 2. The compound of formula (I) according to claim 1, wherein R<2> is phenyl, optionally substituted with methyl, ethyl, -OCH<3>, -OCH<2>CH<3>, -OCH(CH<3>)<2>, F, Cl, Br, -CF<3>, -OCF<3>, -(C<3>-C<6>)cycloalkyl, -NHCH<3>, -NHCOCH<3> , and -O(C<3>-C<6>)cycloalkyl; R<4> is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0019" /> <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0020" /> wherein the wavy line represents the attaching point. 3. The compound of formula (I) according to any of the claims 1-2, wherein R<1> is selected from the group consisting of H, methyl, ethyl, -OCH<3>, -OCH<2>CH<3>; F, Cl, Br, -CF<3>, and -OCF<3>; R<2> is phenyl optionally substituted with methyl, ethyl, -OCH<3>, -OCH<2>CH<3>, -OCH(CH<3>)<2>, F, Cl, Br, -CF<3>, -OCF<3>, -NHCH<3>, and -NHCOCH<3>; R<3> is selected from the group consisting of H, methyl, ethyl, -COCH<3>, and cyclopropyl; R<4> is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, and <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0021" /> <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0022" /> wherein the wavy line represents the attaching point. 4. The compound of formula (I) according to any of the claims 1-3, wherein R<1> is selected from the group consisting of H, methyl, ethyl, -OCH<3>, -OCH<2>CH<3>, F, Cl, Br, -CF<3>, and -OCF<3>; R<2> is phenyl optionally substituted with methyl, ethyl, -OCH<3>, -OCH<2>CH<3>, F, Cl, -CF<3>, and -OCF<3> ; R<3> is selected from the group consisting of H and methyl; R<4> is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, and <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0023" /> <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0024" /> wherein the wavy line represents the attaching point. 5. The compound of formula (I) according to any of the claims 1-4, wherein X is NH. R<1> is selected from the group consisting of H, F, Cl, methyl, and -OCH<3>; R<2> is phenyl optionally substituted with methyl, ethyl, -OCH<3>, -OCH<2>CH<3>, F, Cl, -CF<3>, and -OCF<3> ; R<3> is selected from the group consisting of H and methyl; R<4> is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, and <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0025" /> <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0026" /> wherein the wavy line represents the attaching point; and R<5> is selected from the group consisting of H, CH<3> and -COCH<3>. 6. The compound of formula (I) according to any of the claims 1-5, wherein X is NH; R<1> is selected from the group consisting of H, F, Cl, methyl, and -OCH<3>; R<2> is phenyl optionally substituted with methyl, ethyl; -OCH<3>, -OCH<2>CH<3>, F, Cl, -CF<3>, and -OCF<3>; R<3> is selected from the group consisting of H and methyl; R<4> is selected from the group consisting of <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0027" /> <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0028" /> wherein the wavy line represents the attaching point; and R<5> is selected from the group consisting of H, CH<3> and -COCH<3>. 7. The compound of formula (I) according to any of the claims 1-6, wherein X is O; R<1> is selected from the group consisting of H, F, Cl, methyl, and -OCH<3>; R<2> is phenyl optionally substituted with methyl, ethyl; -OCH<3>, -OCH<2>CH<3>, F, Cl, -CF<3>, and -OCF<3>; R<3> is selected from the group consisting of H and methyl; R<4> is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, and <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0029" /> <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0030" /> wherein the wavy line represents the attaching point; and R<5> is selected from the group consisting of H, CH<3> and -COCH<3>. 8. The compound of formula (I) according to any of the claims 1-7, wherein X is O; R<1> is selected from the group consisting of H, F, Cl, methyl, and -OCH<3>; R<2> is phenyl optionally substituted with methyl, ethyl; -OCH<3>, -OCH<2>CH<3>, F, Cl, -CF<3>, and -OCF<3> ; R<3> is selected from the group consisting of H and methyl; R<4> is selected from the group consisting of <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0031" /> <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0032" /> wherein the wavy line represents the attaching point; and R<5> is selected from the group consisting of H, CH<3> and -COCH<3>. 9. The compound of formula (I) according to any of the claims 1-8, which is selected from (2R,3R,4R)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-2-phenyl-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Ia); (2R,3R,4R)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-2-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Ib); (2R,3R,4R)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-2-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Ic); (2S,3S,4S)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-2-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Id); (2R,3R,4R)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-2-[4-(trifluoromethyl)phenyl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Ie); (2R,3R,4R)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-2-[4-(trifluoromethoxy)phenyl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine (If); (2R,3S,4R)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-2-(2-fluorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Ig); (2R,3R,4R)-2-(3-Chlorophenyl)-4-{2-[(cyclopropylmethyl) amino]ethyl}-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Ih); (2R,3R,4R)-2-(4-Chlorophenyl)-4-{2-[(cyclopropylmethyl)amino]ethyl}-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Ii); (2R,3R,4R)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-2-(3-methoxyphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Ij); (2R,3S,4R)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-2-(2-methoxyphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Ik); (2R,3R,4R)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-2-(3-methylphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Il); (2R,3R,4R)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-2-(2-methylphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Im); (2R,3S,4R)-2-(2-Chlorophenyl)-4-{2-[(cyclopropylmethyl)amino]ethyl}-2,3,4,9-tetrahydro-1H-carbazol-3-amine (In); (2R,3R,4R)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-2-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Io); (2S,3S,4S)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-2-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Ip); (2R,3R,4R)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-2-(3-fluorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Iq); (2R,3R,4R)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-2-(4-methoxyphenyl)-N-methyl-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Ir); (2S,3S,4S)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-2-(4-methoxyphenyl)-N-methyl-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Is); N-[(2R,3R,4R)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-2-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]acetamide (It); (2R,3R,4R)-4-(2-{[(3,3-Difluorocyclobutyl)methyl]amino}ethyl)-2-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Iu); (2R,3R,4R)-9-Methyl-2-(4-methylphenyl)-4-(2-{[(oxetan-3-yl)methyl]amino}ethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Iv); (2R,3R,4R)-2-(4-Methoxyphenyl)-4-[2-(methylamino)ethyl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Iw); (2R,3R,4R)-2-(4-Methylphenyl)-4-{2-[(2-methylpropyl)amino]ethyl}-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Ix); (2R,3R,4R)-2-(4-Methylphenyl)-4-{2-[(propan-2-yl)amino]ethyl}-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Iy); (2R,3R,4R)-4-[2-(Ethylamino)ethyl]-2-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Iz); (2R,3R,4R)-4-[2-(Cyclopropylamino)ethyl]-2-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Iaa); (2R,3R,4R)-6-Chloro-4-(2-{[(3,3-difluorocyclobutyl)methyl]amino}ethyl)-2-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Iab); (2R,3R,4R)-6-Chloro-4-(2-{[(3,3-difluorocyclobutyl)methyl]amino}ethyl)-N-methyl-2-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Iac); 2-[(2R,3R,4R)-3-amino-2-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-carbazol-4-yl]ethan-1-ol (Iad); (2R,3R,4R)-4-(2-Methoxyethyl)-2-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Iae); (2R,3R,4R)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-6-methoxy-2-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Iaf); (2R,3R,4R)-6-Chloro-4-{2-[(cyclopropylmethyl)amino]ethyl}-2-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Iag); (2R,3R,4R)-6-Chloro-4-{2-[(cyclopropylmethyl)amino]ethyl}-2-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Iah); (2R,3R,4R)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-6-methyl-2-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Iai); (2R,3R,4R)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-6-fluoro-2-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Iaj); (2R,3R,4R)-6-Chloro-4-{2-[(cyclopropylmethyl)amino]ethyl}-N-methyl-2-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Iak); and (2R,3R,4R)-4-{2-[(Cyclopropylmethyl)amino]ethyl}-9-methyl-2-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (Ial). 10. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or any enantiomer or mixtures of enantiomers, either of the compound of formula (I) or of its pharmaceutically acceptable salt as defined in any of the claims 1-9, together with one or more pharmaceutically acceptable excipients or carriers. 11. A compound of formula (I) according to any of the claims 1-9 or a pharmaceutical composition according to claim 10, for use as a medicament. 12. A compound of formula (I) according to any of the claims 1-9 or a pharmaceutical composition according to claim 10, for use in the treatment and/or prevention of cancer mediated by NPM1 dysregulation. 13. The compound for use according to claim 12, wherein the cancer is selected from the group consisting of mixed lineage leukemia (MLL), MLL-related leukemia, MLL-associated leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed lineage leukemia (MLL-r), leukemia associated with a MLL rearrangement or a rearrangement of the MLL gene, acute leukemia, chronic leukemia, indolent leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloid leukemia, myelogenous leukemia, childhood leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), anaplastic large cell lymphoma (ALCL), acute promyelocytic leukemia (APL), acute granulocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), therapy related leukemia, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), myeloproliferative neoplasia (MPN), plasma cell neoplasm, multiple myeloma, myelodysplasia, cutaneous T-cell lymphoma, lymphoid neoplasm, AIDS-related lymphoma, thymoma, thymic carcinoma, mycosis fungoides, Alibert-Bazin syndrome, granuloma fungoides, Sézary Syndrome, hairy cell leukemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, meningeal leukemia, leukemic leptomeningitis, leukemic meningitis, multiple myeloma, Hodgkin's lymphoma, non Hodgkin's lymphoma (malignant lymphoma), or Waldenstrom's macroglobulinemia in a mammal in need thereof. 14. The compound for use according to any of claims 12-13 wherein the cancer is selected from acute myeloid leukemia (AML), anaplastic large cell lymphoma (ALCL), and acute promyelocytic leukemia (APL). 15. A process for the preparation of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or any enantiomer or mixtures of enantiomers, either of the compound of formula (I) or of its pharmaceutically acceptable salt, as defined in any of the claims 1-9, which comprises: a) reductive amination of intermediate of formula (3) with an amine of formula R<4>NH<2> to afford an intermediate of formula (4) wherein R<1>, R<2> and R<4> are as defined in claim 1, and Y is methyl, acetyl or a Protecting group; <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0033" /> b) subsequent reduction of the nitro group of the intermediate (4), optionally followed by removal of the Protecting-group, resulting in final compounds of formula (I) wherein X is NH, R<3> is H, and R<1>, R<2>, R<4> and R<5> are as defined in claim 1; or alternatively a') reductive amination of intermediate of formula (3) with an amine of formula R<4>NH<2> to afford an intermediate of formula (4) wherein R<1>, R<2> and R<4> are as defined in claim 1, and Y is methyl, acetyl or a Protecting group; <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0034" /> b') reduction of the nitro group preceded or followed by N-protection to afford intermediate of formula (5); <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0035" /> c') N-alkylation or N-acylation of intermediate (5) to afford intermediate (6); <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0036" /> d') final deprotection provides compounds of formula (I) wherein X is NH, R<3> is different from H, and R<1>, R<2>, R<4> and R<5> are as defined in claim 1; or a") reduction of the nitro group of intermediate of formula (7) followed by optional N-alkylation or N-acylation and deprotection afford the compounds of formula (I) wherein X is O, R<4> is H, and R<1>, R<2>, R<3> and R<5> are as defined in claim 1; <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0037" /> or alternatively a‴) reduction of the nitro group and in-situ N-protection of intermediate of formula (7) provide intermediate of formula (8); <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0038" /> b‴) O-alkylation with a halogenated derivative of formula R<4>-halogen wherein R<4> is as defined in claim 1, to afford intermediate (9); <img class="EMIRef" id="77dd31e1-f547-4d75-a30f-d5937d0f8455-ib0039" /> c‴) final deprotection and optional N-alkylation or N-acylation of intermediate (9) provides compounds of formula (I) wherein wherein X is O, R<4> is different from H, and R<1>, R<2>, R<3> and R<5> are as defined in claim 1.