WO2021053158A1 - Nouveaux inhibiteurs d'histone méthyltransférases - Google Patents

Nouveaux inhibiteurs d'histone méthyltransférases Download PDF

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WO2021053158A1
WO2021053158A1 PCT/EP2020/076131 EP2020076131W WO2021053158A1 WO 2021053158 A1 WO2021053158 A1 WO 2021053158A1 EP 2020076131 W EP2020076131 W EP 2020076131W WO 2021053158 A1 WO2021053158 A1 WO 2021053158A1
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amino
methyl
alkyl
purin
mmol
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PCT/EP2020/076131
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English (en)
Inventor
Roland SCHÜLE
Eric Metzger
Sheng Wang
Manfred Jung
Nicolas P. F. BARTHES
Bernhard Breit
Daad SARRAF
Tabea PAPPERT
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Albert-Ludwigs-Universität Freiburg
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Publication of WO2021053158A1 publication Critical patent/WO2021053158A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • novel histone methyltransferase inhibitors Field of Invention
  • the present invention relates to novel histone methyltransferase (HMT) inhibitors.
  • the present invention is concerned with a compound of formula (I) wherein R 1 , R 2 , R 3 , X 1 and X 2 are as defined herein.
  • the present invention is concerned with a pharmaceutical composition comprising a pharmaceutically effective amount of the compound of formula (I).
  • the present invention also relates to a compound of formula (I) and a pharmaceutical composition comprising a compound of formula (I) for use in medicine.
  • the present invention is concerned with a compound of formula (I) and a pharmaceutical composition comprising a compound of formula (I) for use as inhibitor of a histone methyltransferase of the seven-beta-strand family, preferably for use as inhibitor of KMT9.
  • the present invention is concerned with a compound of formula (I), wherein R 1 , R 2 , R 3 , X 1 and X 2 are as defined herein, for use in the treatment of a cancer selected from the group as defined herein.
  • HMT Histone methyl transferases
  • HMTs There are two families of HMTs, namely the SET domain-containing HMTs (with the four subfamilies SET1 [a specific member here is EZH2], SET2, SUV39 and RIZ) and other HMTs, wherein e.g. DOT1L does not contain a SET domain but is a member of the seven-beta-strand family of histone methyltransferases. Further details in this respect as well as information on the effect of HMT- inhibition and specific inhibitors be found in the review by Morera et al. Clinical Epigenetics, 8:57 (2016), doi: 10.1186/s13148-016-0223-4., 2016. EZH2 and DOT1L have in particular been studied over the last years when it comes to their role in cancer.
  • EZH2 is the catalytic component of the polycomb repressive complex 2 (PRC2), which performs three successive methyl transfer reactions arriving at H3K27me3.
  • PRC2 polycomb repressive complex 2
  • DOT1L is capable of catalyzing mono-, di-, and trimethylation of H3K79. While H3K79 is an activating mark when it comes to gene transcription, H3K27me3 is associated with gene silencing.
  • the inhibition of DOT1L is in particular implicated in the treatment of leukemias presenting a chromosomal translocation of the mixed-lineage leukemia (MLL) gene (chromosome 11q23), such as e.g.
  • AML acute myeloid leukemias
  • ALL acute lymphoblastic leukemias
  • MDL biphenotypic (mixed lineage) leukemias
  • KMT9 a further member of the of the seven-beta-strand family of histone methyltransferases was identified by Metzger et al., namely KMT9, a heterodimer comprised of KMT9alpha and KMT9beta (see Metzger et al., Nat. Struct. Mol. Biol., 2019 May, 26(5): 361).
  • KMT9 writes the methylation mark on lysine 12 of histone H4 and H4K12 methylation has been shown to be implicated in prostate tumor cell proliferation.
  • the present invention therefore relates to a compound of formula (I) or a salt, stereoisomer, or tautomer thereof, wherein X 1 is O or CH 2 ; X 2 is N or CR M ; R 1 is H or C 1 -C 4 -alkyl; R 2 is (C 3 -C 5 -alkyl)-NH-( C 1 -C 3 -alkyl), (C 3 -C 5 -alkyl)-NHR A , (C 2 -C 5 -alkyl)-NR A R H , (C 1 -C 3 -alkyl)- CR B R C NH 2 , (C 2 -C 4 -alkyl)-NR D R E , (C 1 -C 3 -alkyl)-cyclobutane-NHR B , CHR F R G , or (C 1 -C 3 -alkyl)- CHR F R G ; and R 3 is H, C 1 -C 5
  • X 1 is O or CH 2 ;
  • X 2 is N or CR M ;
  • R 1 is H or C 1 -C 4 -alkyl;
  • R 2 is (C 3 -C 5 -alkyl)-NH-( C 1 -C 3 -alkyl), (C 3 -C 5 -alkyl)-NHR A , (C 1 -C 3 -alkyl)-CR B R C NH 2 , (C 2 -C 4 -alkyl)- NR D R E , (C 1 -C 3 -alkyl)-cyclobutane-NHR B , CHR F R G , or (C 1 -C 3 -alkyl)-CHR F R G ; and
  • R 3 is H, C1-C4-alkyl, C1-C4-haloalkyl, or phenyl; and wherein R A is (C 1 -C 4 -alkyl)-phenyl; and
  • the proviso is that when R 2 is (i) (C 3 -C 5 -alkyl)- NH-( C 1 -C 3 -alkyl) or (ii) (C 3 -C 5 -alkyl)-NHR A and R A is unsubstituted (C 1 -C 4 -alkyl)-phenyl, X 1 is CH 2 and X 2 is CH.
  • the proviso is that when R 2 is (i) (C 3 -C 5 -alkyl)- NH-( C 1 -C 3 -alkyl) or (ii) (C 3 -C 5 -alkyl)-NHR A and R A is (C 1 -C 4 -alkyl)-phenyl, X 1 is CH 2 and/or X 2 is CH.
  • the proviso is that when R 2 is (i) (C 3 -C 5 -alkyl)- NH-( C 1 -C 3 -alkyl) or (ii) (C 3 -C 5 -alkyl)-NHR A and R A is (C 1 -C 4 -alkyl)-phenyl, X 1 is CH 2 and X 2 is CH.
  • R 3 is selected from the group consisting of H, methyl, and phenyl. It can be especially preferred that R 3 is H or methyl, in particular H.
  • R 2 is (C 3 -C 4 -alkyl)-NHR A ; wherein R A is (C 1 -C 3 - alkyl)-phenyl or (C 1 -C 3 -alkyl)-naphthyl, preferably (C 2 -C 3 -alkyl)-phenyl or (C 1 -C 3 -alkyl)-naphthyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R W ; wherein R W is H, F, Cl, Br, or phenyloxy, wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents
  • R 2 is (C 3 -alkyl)-NHR A ; wherein R A is (C 1 -C 2 -alkyl)-phenyl or (C 1- C 2 -alkyl)-naphthyl, preferably (C 2 -alkyl)-phenyl or (C 1- C 2 -alkyl)-naphthyl, wherein each substitutable carbon in the phenyl or naphthyl group is independently unsubstituted or substituted with one or more, same or different substituents R W ; wherein R W is H, F, Cl, Br, or phenyloxy, wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents selected from H, F, Cl, or Br.
  • R 2 is (C 3 -alkyl)-NHR A ; wherein R A is (C 1 -C 4 -alkyl)-phenyl, wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R W ; R W is H, or halogen. It is presently assumed that embodiment A3 is a particular preferred embodiment when it comes to the specific inhibition of KMT9. In a preferred embodiment A4 of the first aspect, R 2 is (C 2 -alkyl)-CR B R C NH 2 ; wherein R B is H; and R C is C 1 -C 3 -alkyl.
  • R 2 is (C 1 -alkyl)-CHR F R G ; wherein R F and R G together with the carbon atom to which they are bonded form a 5- or 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one N-atom, wherein said N-atom is non- oxidized, and wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R Z ; wherein R Z is H or (C 1 -C 2 -alkyl)-phenyl.
  • R 2 is (C 1 -alkyl)-CHR F R G ; wherein R F and R G together with the carbon atom to which they are bonded form a 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one N-atom, wherein said N- atom is non-oxidized, and wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R Z ; wherein R Z is H or (C 1 -C 2 -alkyl)-phenyl.
  • R 2 is (C 1 -alkyl)-CHR F R G ; wherein R F and R G together with the carbon atom to which they are bonded form a 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one N- atom, wherein said N-atom is non-oxidized, and wherein each substitutable carbon in the aforementioned groups is independently unsubstituted.
  • R 2 is (C 1 -alkyl)-CHR F R G ; wherein R F and R G together with the carbon atom to which they are bonded form a 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one N- atom, wherein said N-atom is non-oxidized, and wherein each substitutable carbon in the aforementioned groups is substituted with one or more, same or different substituents R Z ; wherein R Z is (C2-alkyl)-phenyl.
  • R 2 is (C 1 -alkyl)-CHR F R G ; wherein R F and R G together with the carbon atom to which they are bonded form a 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more N-atoms, wherein said N- atoms are non-oxidized, and wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R Z ; wherein R Z is H, C 1 -C 3 -alkyl, (C 1 -C 3 -alkyl)-phenyl, or (C 1 -C 2 -alkyl)-cyclohexyl.
  • R 2 is (C1-alkyl)-CHR F R G ; wherein R F and R G together with the carbon atom to which they are bonded form a 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more N-atoms, wherein said N-atoms are non-oxidized, and wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R Z ; wherein R Z (C 1 -C 3 -alkyl)-phenyl, or (C 1 -C 2 - alkyl)-cyclohexyl.
  • R V is a benzoquinone, wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents R Z , preferably wherein R Z is C 1 -C 3 -alkyl, more preferably wherein R Z is methyl. It is also particularly preferred that R V is a benzoquinone, wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more, same or different C 1 -C 3 -alkyl, more preferably wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more methyl.
  • Embodiment A7 is of particular importance when it comes to prodrugs that are considered to be cell-permeable since the definition of R 1 and R 2 results in esters and amides, respectively, that are assumed to be cleaved by cellular enzymes after the respective compounds have entered the cell.
  • X 2 is N or CR M ; wherein R M is F, Cl, or Br. It can be preferred that X 2 is N or CR M ; R 3 is H; wherein R M is F, Cl, or Br. It is in particular preferred that X 2 is N or CH.
  • X 1 is CH 2 .
  • X 1 is CH 2 and X 2 is CH.
  • R 3 is methyl, X 1 is CH 2 , and X 2 is CH. It is presently assumed that embodiment A11 is a particular preferred embodiment when it comes to specific inhibition of seven-beta-strand HMTs.
  • R 1 is H
  • R 2 is C3-alkyl-NHR A
  • R A is C2- alkyl-phenyl, wherein the phenyl is independently unsubstituted or substituted with one or more, same or different substituents R W
  • R W is H, halogen, phenyloxy, or benzyloxy, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R Y
  • R Y is H, halogen, CN, or NO 2
  • R 3 is methyl
  • X 1 is CH 2 and X 2 is CH.
  • R 1 is H
  • R 2 is C 3 -alkyl-NHR A , wherein R A is C2-alkyl-phenyl, wherein the phenyl is substituted in the meta-position by F and in the para-position by phenyloxy, wherein said phenyloxy is substituted in the para position by Cl
  • R 3 is methyl
  • X 1 is CH 2 and X 2 is CH.
  • R 1 is H
  • R 2 is either as defined in embodiment A3 or embodiment A6 above
  • R 3 is methyl
  • X 1 is CH 2
  • X 2 is CH. It is presently assumed that embodiment A13 is a particular preferred embodiment when it comes to the specific inhibition of KMT9.
  • the compound according to formula (I) is selected from the group consisting of (2S)-2-amino-4-(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9- yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(piperidin-3-yl)amino)butanoic acid; (2S)-2-amino- 4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(piperidin-3-ylmethyl)amino)butanoic acid; (2S)-2-amino-4-(((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran
  • the invention relates to a salt of any of the compounds listed in A14.
  • the invention relates to a trifluoroacetate salt of any of the compounds listed in A14.
  • a trifluoroacetate salt may be the mono-trifluoroacetate, the di-trifluoroacetate, the tri- trifluoroacetate, the tetra-trifluoroacetate, and mixtures thereof.
  • the invention relates to the chloride salt of any of the compounds listed in A14.
  • the compound according to formula (I) is selected from the group consisting of
  • R 2 is (C 3 -C 5 -alkyl)-NHR A , wherein R A is (C 1 - C 4 -alkyl)-phenyl, wherein the phenyl is independently unsubstituted or substituted with one or more, same or different substituents R W ; R W is H or NR B -phenyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R Y ; R B is H or C 1 -C 4 -alkyl; and R Y is H, halogen, CN, or NO 2 .
  • R B is H or C1-C4-alkyl
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of the compound as defined in the first aspect (including all embodiments thereof as described herein) and optionally a pharmaceutically acceptable carrier, diluent, or excipient.
  • the present invention relates to the pharmaceutical composition of the second aspect and/or the compounds as defined in the first aspect (including all embodiments thereof as described herein) for use in medicine.
  • the present invention relates to the pharmaceutical composition of the second aspect for use as inhibitor of a histone methyltransferase of the seven-beta-strand family, preferably as inhibitor of KMT9.
  • the present invention relates to the compounds as defined in the first aspect (including all embodiments thereof as described herein) for use in the treatment of cancer, preferably for use in the treatment of cancer selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, colon cancer, glioblastoma, lung cancer, neuroblastoma, osteosarcoma, liposarcoma, leukemia, colorectal cancer, rectal adenocarcinoma, mesothelioma, endometrium adenocarcinoma, erythroleukemia, medulloblastoma, astrocytoma, Ewing sarcoma, myelodysplastic syndrome (MDS), diffuse large B-cell lymphoma, leukemia, myelogenic leuk
  • MDS myelodysplastic syndrome
  • the prostate cancer may be hormone-dependent prostate cancer or castration-resistant prostate cancer, and that the castration-resistant prostate cancer may further be resistant to enzalutamide.
  • the lung cancer may be non-small cell lung cancer or small cell lung cancer.
  • the present invention relates to the compound as defined in the first aspect (including all embodiments thereof as described herein) in the treatment of a cancer selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, colon cancer, colorectal cancer, glioblastoma, lung cancer, neuroblastoma, osteosarcoma, liposarcoma and leukemia.
  • the cancer is selected from the group consisting of prostate cancer, breast cancer, colorectal cancer and lung cancer.
  • the present invention relates to the compound as defined in the first aspect (including all embodiments thereof as described herein) in the treatment of a cancer selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, colon cancer, glioblastoma, lung cancer, neuroblastoma, colorectal cancer, and bladder carcinoma, in particular wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, colon cancer, lung cancer, and bladder carcinoma.
  • the present invention relates to the compound as defined in the first aspect (including all embodiments thereof as described herein) in the treatment of prostate cancer, in particular castration-resistant prostate cancer that may be resistant to enzalutamide.
  • the present invention relates to the compound as defined in the first aspect (including all embodiments thereof as described herein) in the treatment of colorectal cancer.
  • the present invention relates to the compound as defined in the first aspect (including all embodiments thereof as described herein) for use as inhibitor of a histone methyltransferase of the seven-beta-strand family, preferably as inhibitor of KMT9.
  • the present invention relates to a compound of formula (I) or a salt, stereoisomer, or tautomer thereof, wherein X 1 is O or CH 2 ; X 2 is N or CR M ; R 1 is H or C 1 -C 4 -alkyl; R 2 is H, (C 2 -C 5 -alkyl)-NHR A , (C 1 -C 3 -alkyl)-CR B R C NH 2 , (C 2 -C 5 -alkyl)-NR A R H , (C 2 -C 4 -alkyl)-NR D R E , (C 1 -C 3 -alkyl)-cyclobutane-NHR B , CHR F R G , or (C 1 -C 3 -alkyl)
  • the castration-resistant prostate cancer is resistant to enzalutamide. It is to be understood that the preferred embodiments as listed above for the first aspect also apply for the seventh aspect.
  • the present invention relates to a PROTAC molecule consisting of (i) a compound as defined in the first aspect (including all embodiments thereof as described herein) and (ii) a ligand to an E3 ubiquitin ligase, preferably connected by a linker. It can be preferred that the ligand (ii) as mentioned above binds to an E3 ubiquitin ligase selected from the group consisting of MDM2, IPA, VHL and cereblon.
  • the ligand (ii) may be selected from the group consisting of an LCL 161 derivative, VHL-1, a hydroxyproline derivative, pomalidomide, thalidomide, a HIF-1b-derived (R)-hydroxyproline and VHL ligand 2.
  • Figure legends Fig.1 shows that a compound of the present invention blocks proliferation of LNCaP prostate tumour cells, SW-480 colorectal cancer cells, MDA-MB-468 breast cancer cells, and A549 lung tumour cells, while it does not affect proliferation of the KMT9 non-responsive HepG2 cells (compound “KMI95423411” is also referred to as compound 75b in the present application).
  • N6AMT1 controls proliferation of breast cancer cells, ovarian carcinoma cells, colon carcinoma cells and glioblastoma cells.
  • A-D Cell proliferation assays.
  • Breast cancer cells as indicated SK-BR3, MCF-7, MDA-MB-231, or T47-D) (A); Ovarian carcinoma cells (OVCAR- 3) (B); colon carcinoma cells (SW480) (C); and glioblastoma cells (U-251MG or T98G) (D); were transfected with siRNA Ctrl or siRNA against N6AMT1 as indicated.
  • Data represent means ⁇ s.e.m. Fig. 3.
  • N6AMT1 (KMT9alpha) controls proliferation of lung cancer cells and neuroblastoma cells.
  • A, B Cell proliferation assays.
  • Lung tumour cells A549, NCI-H2087, NCIH-1299, A427, ChaGO-K- 1, GLC-2, GLC-1, or NCIH-1792
  • A and neuroblastoma cells
  • SY5Y, LAN-1, SK-N-SH, or SK-N-MC B
  • siRNA Ctrl SY5Y, LAN-1, SK-N-SH, or SK-N-MC
  • Fig. 4 shows that KMT9a controls proliferation and migration of bladder cancer cells.
  • (a-f) depict cell proliferation and migration assays.
  • Bladder cancer cells (TCCSUP, HT-1376, JON, 5637, CAL-29, and T24) were transfected with siRNA Ctrl or two different siRNAs against KMT9a as indicated. Data represent means ⁇ s.d. To verify depletion of KMT9a, Western blots were carried out and the results are also shown. Fig. 5 shows that the KMT9a inhibitor KMI95423512 blocks proliferation of colon, bladder, prostate, breast, and lung cancer cells.
  • (a) depicts the structure of KMI95423512;
  • (b-e, g, and h) depict cell proliferation assays; controls (HepG2, HEK293 KMT9a KO), bladder cancer cells (HT- 1376, 5637, CAL-29, TCCSUP, T24), colon cancer cells (SW480, Caco-2, RKO), prostate cancer cells (LAPC4, PC-3M, C42B, DU145, 22Rv1), breast cancer cells (BT-20, MDA-MB-231), and lung cancer cells (GLC2, PC-9) were incubated with the indicated concentrations of KMI95423712. HepG2 and HEK293 KMT9a KO cells were used as controls. Data represent means ⁇ s.d.
  • HepG2 control cells
  • the bladder cancer cells HT-1376 and CAL-29 were incubated with the indicated concentrations of KMI95423712.
  • Data represent means ⁇ s.d.
  • the singular forms of "a” and “an” also include the respective plurals unless the context clearly dictates otherwise.
  • the terms "about” and “approximately” denote an interval of accuracy that a person skilled in the art will understand to still ensure the technical effect of the feature in question.
  • the term typically indicates a deviation from the indicated numerical value of ⁇ 20 %, preferably ⁇ 15 %, more preferably ⁇ 10 %, and even more preferably ⁇ 5 %. It is to be understood that the term “comprising” is not limiting. For the purposes of the present invention the term “consisting of” is considered to be a preferred embodiment of the term “comprising of”. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is meant to also encompass a group which preferably consists of these embodiments only. Furthermore, the terms “first”, “second”, “third” or "(a)", “(b)”, “(c)”, “(d)” etc.
  • an inhibitor may be a reversible or an irreversible inhibitor.
  • Reversible inhibitors attach to enzymes with non-covalent interactions such as hydrogen bonds, hydrophobic interactions, and ionic bonds. Hence, reversible inhibitors generally do not undergo chemical reactions when bound to the enzyme and can be removed by dilution or dialysis. Irreversible inhibitors bind in general covalently to the enzyme and therefore modify said enzyme. Hence, inhibition cannot be reversed. When it comes to the compounds of the present invention, they may be classified as reversible inhibitors.
  • the term "compound(s) according to the invention", or “compounds of formula (I)” comprises the compound(s) as defined herein as well as a stereoisomer, salt, or tautomer thereof.
  • the compounds according to the invention may have one or more centers of chirality.
  • the invention provides both the single pure enantiomers or pure diastereomers of the compounds according to the invention, and their mixtures and the use according to the invention of the pure enantiomers or pure diastereomers of the compounds according to the invention or their mixtures.
  • Suitable compounds according to the invention also include all possible geometrical stereoisomers (cis/trans isomers or E/Z isomers) and mixtures thereof. Cis/trans isomers may e.g. be present with respect to an amide group.
  • stereoisomer(s) encompasses both optical isomers, such as enantiomers or diastereomers, the latter existing due to more than one center of chirality in the molecule, as well as geometrical isomers (cis/trans isomers).
  • the present invention relates to every possible stereoisomer of the compounds of formula (I), i.e. to single enantiomers or diastereomers, as well as to mixtures thereof.
  • the compounds of formula (I) may be amorphous or may exist in one or more different crystalline states (polymorphs) which may have different macroscopic properties such as stability or show different biological properties such as activities.
  • the present invention relates to amorphous and crystalline compounds of formula (I), mixtures of different crystalline states of the respective compound of formula (I), as well as amorphous or crystalline salts thereof.
  • Salts of the compounds of the formula (I) may be pharmaceutically acceptable salts, such as those containing counterions present in drug products listed in the US FDA Orange Book database. They can be formed in a customary manner, e.g. by reacting the compound with an acid of the anion in question if the compound of formula (I) has a basic functionality, or by reacting acidic compounds according to the invention with a suitable base.
  • Suitable cationic counterions are in particular the ions of the alkali metals, preferably lithium, sodium and potassium, of the alkaline earth metals, preferably calcium, magnesium and barium, and of the transition metals, preferably manganese, copper, silver, zinc and iron, and also ammonium (NH 4 + ) and substituted ammonium in which one to four of the hydrogen atoms are replaced by C 1 -C 4 -alkyl, C 1 -C 4 -hydroxyalkyl, C 1 -C 4 -alkoxy, (C 1 -C 4 -alkoxy)-(C 1 -C 4 -alkyl), hydroxy- (C 1 -C 4 -alkoxy)-(C 1 -C 4 -alkyl), phenyl or benzyl.
  • the alkali metals preferably lithium, sodium and potassium
  • the alkaline earth metals preferably calcium, magnesium and barium
  • the transition metals preferably manganese, copper, silver, zinc and iron
  • substituted ammonium ions comprise methylammonium, isopropylammonium, dimethylammonium, diisopropylammonium, trimethylammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, 2- hydroxyethylammonium, 2-(2-hydroxyethoxy)ethyl-ammonium, bis(2-hydroxyethyl)ammonium, benzyltrimethylammonium and benzyltriethylammonium, furthermore the cations of 1,4- piperazine, meglumine, benzathine and lysine.
  • Suitable anionic counterions are in particular chloride, bromide, hydrogensulfate, sulfate, dihydrogenphosphate, hydrogenphosphate, phosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, and the anions of C 1 -C 4 -alkanoic acids, preferably formate, acetate, trifluoroacetate, propionate and butyrate, furthermore lactate, gluconate, and the anions of poly acids such as succinate, oxalate, maleate, fumarate, malate, tartrate and citrate, furthermore sulfonate anions such as besylate (benzenesulfonate), tosylate (p-toluenesulfonate), napsylate (naphthalene-2-sulfonate), mesylate (methanesulfonate), esylate (ethanesulfon
  • trifluoroacetate salts are trifluoroacetate salts.
  • trifluoroacetate may be the mono-trifluoroacetate, the di-trifluoroacetate, the tri-trifluoroacetate, the tetra-trifluoroacetate, and mixtures thereof.
  • Tautomers may be formed, if a substituent is present at the compound of formula (I), which allows for the formation of tautomers such as keto-enol tautomers, imine-enamine tautomers, or the like.
  • substituted means that a hydrogen atom bonded to a designated atom is replaced with a specified substituent, provided that the substitution results in a stable or chemically feasible compound. Unless otherwise indicated, a substituted atom may have one or more substituents and each substituent is independently selected.
  • substituted when used in reference to a designated atom, means that attached to the atom is a hydrogen, which can be replaced with a suitable substituent. When it is referred to certain atoms or moieties being substituted with “one or more” substituents, the term “one or more” is intended to cover at least one substituent, e.g.
  • substituents preferably 1, 2, 3, 4, or 5 substituents, more preferably 1, 2, or 3 substituents, most preferably 1, or 2 substituents.
  • substituents preferably 1, 2, 3, 4, or 5 substituents, more preferably 1, 2, or 3 substituents, most preferably 1, or 2 substituents.
  • the organic moieties mentioned in the above definitions of the variables are - like the term halogen - collective terms for individual listings of the individual group members.
  • the prefix Cn- C m indicates in each case the possible number of carbon atoms in the group.
  • halogen denotes in each case fluorine, bromine, chlorine, or iodine, in particular fluorine, chlorine, or bromine.
  • hydrocarbyl denotes univalent groups formed by removing a hydrogen atom from a hydrocarbon, e.g. alkyl such as ethyl or phenyl.
  • alkyl as used herein denotes in each case a straight-chain or branched alkyl group having usually from 1 to 5 carbon atoms, preferably from 1 to 4 carbon atoms.
  • Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1- dimethylpropyl, and 1,2-dimethylpropyl. Methyl, ethyl, n-propyl, iso-propyl, and iso-butyl, are particularly preferred.
  • alkoxy denotes in each case a straight-chain or branched alkyl group which is bonded via an oxygen atom and has usually from 1 to 6 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom.
  • alkoxy group examples are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy, tert.-butyloxy, and the like.
  • oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen.
  • Examples include methoxypropoxy, 3,6,9-trioxadecyl and the like. It is to be understood that the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds); it does not refer to doubly bonded oxygen, as would be found in carbonyl groups.
  • thiaalkyl and “azaalkyl” refer to alkyl residues in which one or more carbons had been replaced by sulfur or nitrogen, respectively. Examples of azaalkyl include ethylaminoethyl and aminohexyl.
  • (C n -C m -alkyl) denotes in each case a linker moiety, wherein the thereto attached moieties are attached to the terminal carbons.
  • the skilled person is aware that e.g. the term (C 3 -C 5 -alkyl)-NH-( C 1 -C 3 -alkyl), is to be understood as follows:
  • haloalkyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms, especially 1 or 2 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms.
  • Preferred haloalkyl moieties are selected from C 1 -C 4 -haloalkyl, more preferably from C 1 -C 3 -haloalkyl or C 1 -C 2 -haloalkyl, in particular from C 1 -C 2 -fluoroalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2- trifluoroethyl, pentafluoroethyl, and the like. Trifluoromethyl is particularly preferred according to the invention.
  • cycloalkyl denotes in each case a monocyclic cycloaliphatic radical having usually from 3 to 10 or from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • heterocyclic or “heterocyclyl” includes, unless otherwise indicated, in general a 3- to 9-membered, preferably a 4- to 8-membered or 5- to 7-membered, more preferably 5- or 6- membered, in particular 6-membered monocyclic ring.
  • the heterocycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Hückel rule for aromaticity is not fulfilled, whereas aromatic means that the Hückel (4n + 2) rule is fulfilled.
  • the heterocycle typically comprises one or more, e.g.
  • the heterocycle is an aromatic heterocycle, preferably a 5- or 6- membered aromatic heterocycle comprising one or more, e.g.1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O, and S as ring members, where S-atoms as ring members may be present as S, SO or SO 2 .
  • aromatic heterocycles are provided below in connection with the definition of “hetaryl”.
  • Hetaryls or “heteroaryls” are covered by the term “heterocycles”.
  • the saturated or partially or fully unsaturated heterocycles usually comprise 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO 2 .
  • the heterocycle is a 4- to 6-membered saturated heterocycle comprising one or more, e.g.1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO 2 .
  • saturated heterocycles include pyrrolidine, piperidine, or morpholine.
  • heteroaryl or heteroaryl or aromatic heterocycle or aromatic heterocyclic ring includes monocyclic 5- or 6-membered aromatic heterocycles comprising as ring members 1, 2, 3 or 4 heteroatoms selected from N, O and S, where S-atoms as ring members may be present as S, SO or SO 2 .
  • 5- or 6-membered aromatic heterocycles include pyridyl (also referred to as pyridinyl), i.e.2-, 3-, or 4-pyridyl, pyrimidinyl, i.e.2-, 4- or 5-pyrimidinyl, pyrazinyl, pyridazinyl, i.e.3- or 4-pyridazinyl, thienyl, i.e.2- or 3-thienyl, furyl, i.e.2-or 3-furyl, pyrrolyl, i.e.
  • phenyloxy and “benzyloxy” (i.e. “phenylmethyloxy”) refer to the corresponding groups, which are bonded to the remainder of the molecule via an oxygen atom.
  • (6-Amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol“ refers to the molecule having the following structure: It may further be referred to as constructive(6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol- 4-yl)methanol“.
  • a pharmaceutically acceptable excipient can be defined as being pharmaceutically inactive.
  • the term “seven-beta-strand family of histone methyltransferases” refers to the respective family of enzymes. Presently, this family comprises DOT1L and KMT9.
  • the term “KMT9” means the heterodimer composed of KMT9 alpha and KMT9beta.
  • KMT9alpha refers to the protein “N-6 adenine-specific DNA methyltransferase 1” [Homo sapiens (human)], with the underlying Gene ID: 29104 (updated on 11-Sep-2019, database: https://www.ncbi.nlm.nih.gov/gene). “N6AMT1” or “KMT9alpha” is the corresponding gene. Other names for KMT9alpha are C21orf127, Hemk2, Mtq2, N6amt1, PrmC or PRED28. The sequence of the KMT9alpha protein (isoform 1 [Homo sapiens]) is depicted in SEQ ID NO: 1.
  • KMT9beta refers to the protein “tRNA methyltransferase subunit11-2” [Homo sapiens (human)] with the underlying Gene ID: 51504 (updated on 11-Sep-2019, database: https://www.ncbi.nlm.nih.gov/gene). “TRMT112” or “KMT9beta” is the corresponding gene. The sequence of the KMT9beta protein (isoform 2 [Homo sapiens]) is depicted in SEQ ID NO: 2. The term “PROTAC” means “proteolysis-targeting chimeras”.
  • a pharmaceutical composition according to the present invention may be formulated for oral, buccal, nasal, rectal, topical, transdermal, or parenteral application.
  • Preferred non-parenteral routes include mucosal (e.g., oral, vaginal, nasal, cervical, etc.) routes, of which the oral application may be preferred.
  • Preferred parenteral routes include but, are not limited to, one or more of subcutaneous, intravenous, intra-muscular, intraarterial, intradermal, intrathecal, and epidural administrations. Preferably administration is by subcutaneous, intratumoral or peritumoral routes. Particularly preferred is intratumoral administration.
  • the compound according to formula (I) should be applied in pharmaceutically effective amounts, for example in the amounts as set out herein below.
  • a pharmaceutical composition of the present invention may also be designated as formulation or dosage form.
  • a compound of formula (I) may also be designated in the following as (pharmaceutically) active agent, active ingredient, or active compound.
  • Pharmaceutical compositions may be solid or liquid dosage forms or may have an intermediate, e.g. gel-like character depending inter alia on the route of administration.
  • the inventive dosage forms can comprise various pharmaceutically acceptable excipients which will be selected depending on which functionality is to be achieved for the dosage form.
  • a “pharmaceutically acceptable excipient” in the meaning of the present invention can be any substance used for the preparation of pharmaceutical dosage forms, including coating materials, film-forming materials, fillers, disintegrating agents, release-modifying materials, carrier materials, diluents, binding agents, and other adjuvants.
  • Typical pharmaceutically acceptable excipients include substances like sucrose, mannitol, sorbitol, starch and starch derivatives, lactose, and lubricating agents such as magnesium stearate, disintegrants, and buffering agents.
  • carrier denotes pharmaceutically acceptable organic or inorganic carrier substances with which the active ingredient is combined to facilitate the application.
  • Suitable pharmaceutically acceptable carriers include, for instance, water, aqueous salt solutions, alcohols, oils, preferably vegetable oils, propylene glycol, polyoxyethelene sorbitans, polyethylene- polypropylene block co-polymers such as poloxamer 188 or poloxamer 407, polyethylene glycols such as polyethylene glycol 200, 300, 400, 600, etc., gelatin, lactose, amylose, magnesium stearate, surfactants, perfume oil, fatty acid monoglycerides, diglycerides and triglycerides, polyoxyethylated medium or long chain fatty acids such as ricinoleic acid, and polyoxyethylated fatty acid mono-, di, and triglycerides such as capric or caprilic acids, petroethral fatty acid esters, hydroxymethyl celluloses such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxypropyl acetate succinate, polyvinylpyrrol
  • the pharmaceutical compositions can be sterile and, if desired, mixed with auxiliary agents, like lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compound.
  • auxiliary agents like lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compound.
  • auxiliary agents like lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compound.
  • these can include pharmaceutically acceptable emulsions, solutions, suspensions, and syrups
  • microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer and sweeteners/flavoring agents.
  • particularly suitable vehicles consist of solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants.
  • Pharmaceutical formulations for parenteral administration are particularly preferred and include aqueous solutions of the compounds of formula (I) in water-soluble form. Additionally, suspensions of the compounds of formula (I) may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • dosage forms are injectable preparations of a compound of formula (I).
  • sterile injectable aqueous or oleaginous suspensions can for example be formulated according to the known art using suitable dispersing agents, wetting agents and/or suspending agents.
  • a sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • acceptable vehicles and solvents that can be used are water and isotonic sodium chloride solution.
  • Sterile oils are also conventionally used as solvent or suspending medium.
  • Preferred applications for injectable preparations comprising the compounds of the present invention are intravenous, intratumoral and peritumoral administration.
  • Suppositories for rectal administration of a compound of formula (I) can be prepared by e.g.
  • the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the pharmaceutical composition is an oral dosage form.
  • Oral dosage forms may be liquid or solid and include e.g. tablets, troches, pills, capsules, powders, effervescent formulations, dragees, and granules.
  • compositions for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol
  • cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carb
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • the oral dosage forms may be formulated to ensure an immediate release of the compound of formula (I) or a sustained release of the compound of formula (I).
  • a solid dosage form may comprise a film coating.
  • the inventive dosage form may be in the form of a so-called film tablet.
  • a capsule of the invention may be a two-piece hard gelatin capsule, a two-piece hydroxypropylmethylcellulose capsule, a two-piece capsule made of vegetable or plant-based cellulose or a two-piece capsule made of polysaccharide.
  • the dosage form according to the invention may be formulated for topical application.
  • Suitable pharmaceutical application forms for such an application may be a topical nasal spray, sublingual administration forms and controlled and/or sustained release skin patches.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compositions may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy.
  • the methods can include the step of bringing the compounds into association with a carrier, which constitutes one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • Liquid dose units are vials or ampoules. Solid dose units are tablets, capsules and suppositories.
  • the compound of formula (I) may be administered to a patient in an amount of about 0.001 mg to about 5000 mg per day, preferably of about 0.01 mg to about 1000 mg per day, more preferably of about 0.05 mg to about 250 mg per day, which is the effective amount.
  • the phrase “effective amount” means an amount of compound that, when administered to a mammal in need (i.e. a patient in need) of such treatment, is sufficient to treat or prevent a particular disease or condition.
  • the pharmaceutical composition may contain the compound of formula (I) in the form of a prodrug.
  • a prodrug is generally any compound, which is converted under physiological conditions or by solvolysis to a more potent compound.
  • a prodrug may be inactive or only slightly active prior to administration but may be converted to an active compound of the invention in vivo.
  • R 1 is C 1 -C 4 -alkyl, in particular methyl
  • Compounds with a corresponding definition of R 1 are in particular of interest if the compound is applied without any penetration- enhancers or the like to cells since the data gained by the inventors show that such compounds are capable of crossing an intact cell membrane while then intracellularly still showing the desired strong inhibitory activity. This effect could easily be explained by the presence of carboxyl esterases (CE) that are basically present in each cell.
  • CE carboxyl esterases
  • CE comprise a multigene family capable of hydrolyzing a variety of carboxylic acid esters, wherein the majority of CE isozymes belong to the CE1 and CE2 families.
  • CE1 isozymes hydrolyse compounds esterified with a small alcohol group
  • CE2 isozymes hydrolyze compounds with a relatively small acyl group and a large alcohol group.
  • a pharmaceutical composition that includes a delivery system of an active agent into an intact cell, one would be inclined to use a compound with a strong in vitro inhibitory capacity (with the preferred definition of R 1 being H and R H not being present), while rather a compound assumed to be a prodrug (with the preferred definition of R 1 being C 1 -C 4 -alkyl and/or R H as defined) would be used if the pharmaceutical formulation rather delivers the compound to the cell membrane of an intact cell. Further embodiments of the present application relate to: 1.
  • R 3 is selected from the group consisting of H, methyl, and phenyl.
  • R 2 is (C 3 -C 4 -alkyl)-NHR A ; and wherein R A is (C 2 -C 3 -alkyl)-phenyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R W ; R W is H, F, Cl, Br, or phenyloxy, wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents selected from H, F, Cl, or Br. 4.
  • R 2 is (C 1 -alkyl)-CHR F R G ; and wherein R F and R G together with the carbon atom to which they are bonded form a 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more N-atoms, wherein said N-atoms are non-oxidized, and wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R Z ; R Z is H, C 1 -C 3 -alkyl, (C 1 -C 3 -alkyl)-phenyl, or (C 1 -C 2 -alkyl)-cyclohexyl. 7.
  • a pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of embodiments 1 to 10 and optionally a pharmaceutically acceptable carrier, diluent, or excipient. 12. A compound according to any one of embodiments 1 to 10 for use in medicine. 13.
  • a compound for use according to embodiment 13, wherein the compound for use is the compound of formula (I) according to any one of embodiments 1 to 10.
  • a compound for use according to embodiment 13 or 14, wherein said cancer is selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, colon cancer, glioblastoma, lung cancer, neuroblastoma and colorectal cancer.
  • the present invention is further illustrated by the following examples. Examples 1. Synthesis of compounds List of abbreviations
  • the compounds according to the following examples may be provided as the corresponding salt thereof, such as e.g. a trifluoroacetate.
  • Reagents and solvents were obtained from commercial sources and used without any further purification.
  • Column chromatography was accomplished using MACHEREY-NAGEL silica gel 60® (230-400 mesh).
  • Data for 1 H-NMR are described as following: chemical shift (d in ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad signal), coupling constant (Hz), integration.
  • Data for 13 C-NMR are described in terms of chemical shift (d in ppm).
  • NMR spectra were acquired on a BRUKER Avance 400 spectrometer (400 MHz and 100.6 MHz for 1H and 13C respectively) or a Bruker 500 DRX NMR spectrometer with TBI probe head (499.6 MHz and 125.6 MHz for 1H and 13C respectively) at a temperature of 303 K unless specified.
  • HR- MS were obtained on a THERMO SCIENTIFIC Advantage and a THERMO SCIENTIFIC Exactive instrument (APCI/MeOH: spray voltage 4-5 kV, ion transfer tube: 250-300 °C, vaporizer: 300-400 °C).
  • Boc 2 O was added (1.776 g, 8.14 mmol, 1.1 eq) in 3 mL dry THF at 0°C.
  • Boc2O 807 mg, 3.7 mmol, 0.5 eq was added at 0°C and the reaction was stirred at room temperature for 1 h 30 min. After that, reaction was quenched with NaCl at 0°C, extracted with AcOEt. The combined organics were washed with brine, dried over Na 2 SO 4 and evaporated.
  • the tertiary amine 8a (45.8 mg, 0.053 mmol) were dissolved in 2.6 mL freshly prepared TFA/H 2 O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9a (54.5 mg, quant) as TFA salts as a light yellow foam which was used without purification.
  • methyl 5-ethylpiperidine-3-carboxylate (15).
  • the compound 14 (168 mg, 1 mmol) and Platinum oxide (29 mg, 15 % mol w/w) was solubilised in acetic acid (1.7 ml) and placed in a autoclave.
  • the atmosphere was replaced twice with argon before the introduction of the hydrogen gas.
  • the autoclave was pressurised with H 2 gas (40 bar) and the solution stirred at 40 °C for 48 h.
  • the atmosphere was repalced with argon, the mixture filtered over celiteand the filtrate was concentrated in vacuo to afford the corresponding piperidine as acetic acid salt (67.5 mg, 38%) which was used without purification.
  • the system was alternatively evacuated and filled with argon for three times; 7 mL dry dimethylsulfoxide was introduced, and the mixture was heated at 75-80°C for 45, until the evolution of ydrogen ceased.
  • the resulting solution was cooled in an ice-water bath, and (5.21g, 13.9 mmol, 1 eq) methyltriphenylphosphonium bromide in 13.9 mL warm dimethyl sulfoxide was added.
  • the resulting yellow solution was stirred at room temperature for 10 min before use.
  • Cyclohexanone (1.5 g, 15.3 mmol, 1.1 eq), was added to the ylide solution, and the reaction mixture was stirred at room temperature for 30 min.
  • the tertiary amine 8c (26 mg, 27 ⁇ mol) were dissolved in 1.3 mL freshly prepared TFA/H 2 O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9c (16.6 mg, quant) as TFA salts as a light yellow foam which was used without purification.
  • the tertiary amine 8d (34.8 mg, 36 ⁇ mol) were dissolved in 1.8 mL freshly prepared TFA/H 2 O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9d (35 mg, quant) as TFA salts as a light yellow foam which was used without purification.
  • the reaction was stirred at 125 °C for 16 h. Then the reaction was quenched with water, extracted with AcOEt, washed with brine, dried over Na 2 SO 4 , filtered and evaporate to give the crude. The crude was purified using silica gel column eluting with 90:10 to 50:50 cyclohexane/AcOEt to afford the desired compound as yellow oil (126 mg, 24%).
  • the tertiary amine 8e (31.9 mg, 33 ⁇ mol) were dissolved in 1.65 mL freshly prepared TFA/H 2 O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9e (41 mg, quant) as TFA salts as a light yellow foam which was used without purification.
  • the reaction flask was placed into a stainless steel autoclave. The air was replaced by CO/H 2 (4 bar) and stirred at 65 °C for 16 h.. The autoclave was subsequently cooled at 0 °C and the pressure of CO/H 2 was released. The reaction was filtrate using celite and chromatographed on a silica gel column using 95:5 to 80:20 cyclohexane / AcOEt as eluent to afford the desired compound (187.1 mg, 98%) as yellow oil.
  • aqueous NaOH solution (3 M, 1.1 mL) and 30 % H 2 O 2 (1.1 mL) were added at 0 °C, after which the reaction mixture was allowed to warm up to room temperature. After 1 h, water was added, and the reaction mixture was extracted with AcOEt. The combined organic layers were dried over Na 2 SO 4 . The solution was filtered, and concentrated under reduced pressure to afford the crude alcohol product.
  • DCM 7.2 mL
  • DMP 492 mg, 1.16 mmol, 1.6 eq
  • the tertiary amine 8f (34 mg, 38.8 ⁇ mol) were dissolved in 1.9 mL freshly prepared TFA/H 2 O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9f (17.1 mg) as TFA salts as a light yellow foam which was used without purification.
  • the tertiary amine 8g (20.3 mg, 23 ⁇ mol) were dissolved in 1.2 mL freshly prepared TFA/H 2 O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9g (23 mg, quant) as TFA salts as a light yellow foam which was used without purification.
  • the tertiary amine 8h (25 mg, 27 ⁇ mol) were dissolved in 1.4 mL freshly prepared TFA/H 2 O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9h (27 mg, quant) as TFA salts as a light yellow foam which was used without purification.
  • the tertiary amine 8i (23 mg, 22 ⁇ mol) were dissolved in 1.1 mL freshly prepared TFA/H 2 O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9i (23 mg, quant) as TFA salts as a light yellow foam which was used without purification.
  • the tertiary amine 53 (11.8 mg, 13.6 ⁇ mol) were dissolved in 0.7 mL freshly prepared TFA/H 2 O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9j (20.5 mg, quant) as TFA salts as a light yellow foam which was used without purification.
  • tert-Butyl (S)-2- ((tert-butoxycarbonyl)amino)-4-oxobutanoate 5 (357 mg, 1.31 mmol, 4.0 equiv) and MgSO 4 (118 mg, 0.978 mmol, 3.0 eq) were added to a solution of 5'-Amino-N 6 ,N 6 -bis(tert- butoxycarbonyl)-5'-deoxy-2',3'-O-isopropylidene-adenosine 56 (165 mg, 0.326 mmol, 1.0 eq) in dry MeOH (3.3 mL) at 0 °C and stirred for 30 min before NaBH 3 CN (82 mg, 1.31 mmol, 4.0 eq) was added.
  • 5'-Amino-N 6 ,N 6 -bis(tert- butoxycarbonyl)-5'-deoxy-2',3'-O-isopropylidene-adenosine 56
  • Mass spectra were recorded on an Advion expression CMS using an ASAP® (Atmospheric Solids Analysis Probe; aka APCI: Atmospheric Pressure Chemical Ionization) as ion source, on a Thermo Scientific Exactive mass spectrometer using electrospray ionization (ESI) as ion source and on a 6200 series TOF/6500 series Q-TOF B.09.00 using ESI as ion source.
  • ESI electrospray ionization
  • aqueous phase was then extracted 3 times with CH 2 Cl 2 and the combined organic phases once with brine. Drying over Na 2 SO 4 , filtration and evaporation afforded the crude product that was subjected to silica gel column chromatography eluting with CH 2 Cl 2 /MeOH (mostly 99.5:0.5–94:6) to afford the tertiary amines 71 as yellow oils.
  • Tertiary amines 71 (or secondary amines 70) were dissolved (0.02 M ) in freshly prepared TFA/H 2 O (4:1) solution and stirred at rt for 6–16 h, then evaporated to give the desired products 72 as foams (2 or 3 TFA salt).
  • tert-butyl (7-((3aS,4R,6R,6aR)-6-(((3-((tert-butoxycarbonyl)(3- phenoxyphenethyl)amino)propyl)amino)methyl)-2,2-dimethyltetrahydro-4H- cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)carbamate (73b).
  • aldehyde 7f (0.14 g, 0.356 mmol, 1 eq.) in dry MeOH (1.3 mL) was added 69 (0.158 g, 0.356 mmol, 1 eq.) in 0.5 mL of dry MeOH dropwise and the mixture was stirred overnight at rt. After cooling to 0 °C NaBH 4 (0.022 g, 0.54 mmol, 1.5 eq) was added. The reaction was stirred at rt until the bubbling stops, then the solvent was evaporated and the residue was partitioned between water and AcOEt. The aqueous phase was extracted with AcOEt (3 times).
  • tert-butyl (7-((3aS,4R,6R,6aR)-6-(((3-((tert-butoxycarbonyl)(4- phenoxyphenethyl)amino)propyl)amino)methyl)-2,2-dimethyltetrahydro-4H- cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)carbamate (73c).
  • reaction mixture was stirred at 35 o C for two days.
  • Prep-HPLC was performed at conditions: (Flash: Welchrom C18, 150 x 20 mm); Wavelength 220 nm; Mobile phase: A MeCN (0.1% TFA); B water (0.1% TFA); Flow rate: 25 mL /min; Injection volume: 2 mL; Run time: 30 min; Equilibration: 5 min.
  • aqueous phase was then extracted 3 times with CH 2 Cl 2 and the combined organic phases once with brine. Drying over Na2SO4, filtration and evaporation afforded the crude product that was subjected to silica gel column chromatography eluting with CH 2 Cl 2 /MeOH (mostly 99.5:0.5–94:6) to afford the tertiary amines 180 as yellow oils.
  • Tertiary amines 180 were dissolved (0.02 M) in freshly prepared TFA/H 2 O (4:1) solution and stirred at rt for 6–16 h, then evaporated to give the desired products 190 as foams (2 or 3 TFA salt).
  • Methylation assays were performed to test inhibition of the KMT9 methyltransferase activity by compounds. To test these potential inhibitors, 1 ⁇ L of the compounds, dissolved in DMSO at different concentrations, were added to a 0.5 ml tube (Brand Gmbh&Co KG).
  • reaction mixtures were mixed and incubated in an Eppendorf thermomixer comfort for 2 h at 30°C, shaking at 300 rpm.
  • the reaction was quenched using 5 ⁇ L of 50 % trichloroacetic acid (TCA) in water, mixed and incubated for 5 min at room temperature without shaking.22 ⁇ L of the solution was transferred to a filter binding plate (MultiScreenHTS FB Filter Plate, 1.0/0.65 ⁇ m, opaque, non-sterile, Merck KGaA Darmstadt), vacuum filtered using MultiScreen®HTS Vacuum Manifold (Merck KGaA Darmstadt) and washed with 4x 50 ⁇ L TCA 10% followed by 2x 50 ⁇ L ethanol 100%.
  • TCA trichloroacetic acid
  • IC 50 -values of the tested compounds are shown in the table below as follows: IC50-value > 10 ⁇ M is denoted with a “+”, IC50-value from 10 ⁇ M to 100 nM is denoted with “++”, and IC 50 -value ⁇ 100 nM is denoted with “+++”.
  • Microscale thermophoresis (MST) to test KMT9-binding by compounds of the present invention To determine the binding affinity of a compound to KMT9, microscale thermophoresis (MST) analysis was performed with a NanoTemper Monolith NT.115 instrument (NanoTemper Technologies GmbH). KMT9 was labelled with a RED-Tris-NTA labelling kit (NanoTemper Technologies GmbH) based on the manufacturer’s instructions. Buffer including 25 mM HEPES (pH 7.5), 100mM NaCl, 1mM DTT and 0.05% Tween was used for the reaction buffer. Varying concentrations of compounds were titrated against His-tag labelled KMT9 proteins (20 nM).
  • binding affinity > 10 ⁇ M is denoted with a “+”
  • binding affinity from 10 ⁇ M to 100 nM is denoted with “++”
  • binding affinity ⁇ 100 nM is denoted with “+++”.
  • Compound A has the following structure, which is known from Dowden et al.; Org. Biomol. Chem., 2011, 9, 7814 (see compound 19 therein):
  • Compound B has the following structure, which is known from Mori et al.; Bioorg. Med. Chem., 2010, 18(23), 8158 (see compound 1a therein): Effects of the addition of KMT9-inhibitors to cells on the proliferation of the cells
  • Compounds 75a to 75c, 110, 112, 120, 140, and 200 are assumed to correspond to prodrugs and are therefore examples of compounds that can directly be used in cells since they are membrane-permeable.
  • the ester-moiety (here for compounds 75a to 75c, 110, 112, 120, and 140 a methyl- or ethyl-ester) or the amide-moiety (here for compound 200 a quinone derivative bound via an amide) is cleaved by cellular esterases, amidases and/or other suitable enzymes, resulting in the acid-moiety and the amino-moiety, respectively, found in compounds of the present invention that are active in vitro (see Table 1 above, where all active compounds have a H in the R 1 position and the RH-position).
  • Compound 75b was tested in a proliferation assay in cell culture as described in the following.
  • compound 75b (alternatively referred to as “KMI95423411”) was added to a final concentration of 30 ⁇ M (in the controls, DMSO was added) to cells of the following cell lines: LNCaP, SW-480, A549, MDA-MB-468 and HepG2, and the cells were cultured in the presence of inhibitor or DMSO.
  • the cells were seeded in E-plates and the cell proliferation was determined using the xCelligence RTCA system (Roche) as described below.
  • compound 75b blocks proliferation of LNCaP prostate tumour cells, SW-480 colorectal cancer cells, MDA-MB-468 breast cancer cells, and A549 lung tumour cells.
  • KMI95423411 does not affect proliferation of the KMT9 non-responsive HepG2 cells.
  • Compound 120 was tested in a proliferation assay in cell culture as described in the following. Thus, compound 120 (alternatively referred to as “KMI95423512”) was added to final concentrations as indicated in Fig.
  • DMSO 10, 15, 20 and/or 30 ⁇ M, in the controls, DMSO was added) to cells of the following cell lines: HepG2 and HEK293 with KMT9a KO (as controls); HT-1376, 5637, CAL-29, TCCSUP and T24 (all bladder cancer cells); SW480, Caco2, RKO (all colon cancer cells); LAPC4, PC-3M, C42B, DU145 and 22Rv1 (all prostate cancer cells); BT-20, MDA-MB-231 (both breast cancer cells), as welll as GLC2 and PC-9 (all lung cancer cells). The cells were cultured in the presence of inhibitor or DMSO.
  • the cells were seeded in E-plates and the cell proliferation was determined using the xCelligence RTCA system (Roche) as described below.
  • compound 120 blocks proliferation of bladder cancer cells, colon cancer cells, prostate cancer cells, breast cancer cells and lung cancer cells.
  • Compound 120 does not affect proliferation of the KMT9 non-responsive HepG2 cells and the HEK293 cells, where KMT9a was knocked-down (positive control).
  • the cellular target engagement of Compound 120 for KMT9 in Caco2, PC-3M and RKO cells was tested using a cellular thermal shift assay (CETSA) assay.
  • CETSA cellular thermal shift assay
  • Fig.5f The results are shown in Fig.5f and it can be derived therefrom that Compound 120 binds to KMT9 in Caco2, PC-3M and RKO cells, while it does not bind to KMT5a in Caco2 cells (control). Accordingly, there is target engagement of Compound 120 for KMT9 inside the tested cells, i.e. Compound 120 is membrane-permeable (likely as prodrug) and active inside the cells (likely after cleavage of the ester-moiety by a cellular esterase). Compound 140 was also tested in a proliferation assay in cell culture. Thus, compound 140 (alternatively referred to as “KMI95423712”) was added to final concentrations as indicated in Fig.
  • DMSO was added to cells of the following cell lines: HepG2 (as control), HT-1376 and CAL-29 (bladder cancer cells).
  • the cells were cultured in the presence of inhibitor or DMSO.
  • the cells were seeded in E- plates and the cell proliferation was determined using the xCelligence RTCA system (Roche) as described below.
  • compound 140 blocks proliferation of bladder cancer cells. Compound 140 does not affect proliferation of the KMT9 non-responsive HepG2 cells. Cell proliferation was determined using the X-Celligence RTCA system (Roche).
  • LNCaP, 5637, LAPC4, PC-3M, C42B, GLC2 and PC-9 cells were cultured in RPMI 1640.
  • SW480, A549, MDA-MB-468, HT-1376, CAL-29, TCCSUP, SW480, 22Rv1, MDA-MB-231, HEK293 and HepG2 cells were cultured in DMEM.
  • Caco2, DU145, BT-20 and RKO cells were cultured in EMEM.
  • T24 cells were cultured in McCoy’s 5A. All media were supplemented with 10% fetal calf serum, penicillin/streptomycin, and glutamine.
  • PC-3M, C42B, DU145, and 22Rv1 were cultured under low glucose (1 g/l) conditions.
  • Method for cellular Thermal Shift Assay (CETSA) according to Jafari et al (Nature protocols, 2010, doi:10.1038/nprot.2014.138):
  • CETSA Cell Thermal Shift Assay
  • cells were cultivated at 37 °C and 5 % CO2 according to published procedures and incubated with Compound 120 at a final concentration of 15 ⁇ M or DMSO for 2 hours Then, cells were washed with PBS, trypsinised, and resuspended at (3.6x 107 cells/mL) in PBS with Complete (w/o EDTA, Roche) protease inhibitor.
  • Compound 72b was tested against a plurality of methyltransferases as described in the following. Thus, compound 72b was tested against the methyltransferases as indicated in Table 2 below, wherein the compound was tested in a 10-dose IC50 mode with 3-fold serial dilution, in singlet, starting at 10 mM.
  • Control compounds namely SAH (S-(5'-Adenosyl)-L-homocysteine), Chaetocin, LLY 507, or Ryuvidine (as also indicated in Table 2 below) were tested in 10-dose IC50 mode with 3-fold serial dilution starting at 100 or 200 mM. Reactions were carried out at 1 mM SAM. Curve fits were performed where the enzyme activities at the highest concentration of compounds were less than 65%. Empty cells indicate no inhibition or compound activity that could not be fit to an IC50 curve.
  • Compound 72b is referred to as KMI9542321 in Table 2.
  • KMT9 knockdown has a pronounced effect on the tumor, namely in that the tumor volume and the tumor weight are significantly reduced upon KMT9 knockdown (see in particular Figure 6 of the afore-mentioned publication). This is completely consistent with the effect of a compound of the present invention on the proliferation of LNCaP prostate tumour cells as shown in Figure 1, i.e. by inhibiting KMT9.
  • KMT9 alpha knockdown was furthermore carried out in various cancer cells lines, namely cell lines of breast cancer, ovarian carcinoma, colon cancer, glioblastoma, lung cancer and neuroblastoma and it was observed for all tested cell lines that the knockdown of KMT9alpha results in a proliferation block of these cancer cells lines (see Fig.2 and 3, also for details of the tested cell lines). Accordingly, KMT9 inhibition also results in a proliferation block of these cancer cell lines, which has been confirmed herein explicitly for colorectal cancer, breast cancer cells, and lung tumour cells (see in particular Figure 1).
  • KMT9 alpha knockdown was also carried out in cancer cells lines of bladder cancer cells (TCCSUP, HT-1376, JON, 5637, CAL-29 and T24), and the proliferation as well as the migration (for some of the cell lines) was tested. As indicated in Fig.4, the proliferation and the migration were blocked. Accordingly, KMT9 inhibition results in a proliferation and migration block of bladder cancer cell lines. All cell lines used in this example were cultured according to standard methods, usually in DMEM.
  • RNAiTM siRNAs The sequences of the siRNAs (Stealth RNAiTM siRNAs; Life Technologies) used in the experiments are as following: siCtrl: 5’- GAAAGUCCUAGAUCCACACGCAAAU-3’ [SEQ ID NO: 3]; siKMT9 ⁇ #1 (also referred to as “RNAi N6AMT1” or “RNAi N6AMT1#1” or siKMT9a#1): 5’-ACGCUGUAACAAAGUUCACAUUCAA-3’ [SEQ ID NO: 4]; siKMT9a#2: 5’-CACGCUGUAACAAAGUUCACAUUCA-3’ [SEQ ID NO: 5].
  • Stealth RNAis are comprised of a duplex of single-stranded RNA
  • the respective reverse complement sequences are also given for the sake of completeness: for the siCtrl.: 5’- AUUUGCGUGUGGACUUAGGACUUUC-3’ [SEQ ID NO: 6]
  • siKMT9a#1 5’- UUGAAUGUGAACUUUGUUACAGCGU-3’
  • siKMT9a#2 5’- UGAAUGUGAACUUUGUUACAGCGUG-3’
  • References 1. Moore TW, Zhu S, Randolph R, Shoji M, Snyder JP.

Abstract

La présente invention concerne de nouveaux composés de formule (I) tels que définis dans la description. Les composés sont des inhibiteurs d'histone méthyltransférases de la famille des sept brins bêta, en particulier de KMT9.
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Publication number Priority date Publication date Assignee Title
CN116284188A (zh) * 2023-02-07 2023-06-23 南开大学 一种dna甲基转移酶dnmt1的双底物抑制剂及其应用

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