WO2024105159A1 - Ligands des lecteurs d'arn m6a - Google Patents

Ligands des lecteurs d'arn m6a Download PDF

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WO2024105159A1
WO2024105159A1 PCT/EP2023/082044 EP2023082044W WO2024105159A1 WO 2024105159 A1 WO2024105159 A1 WO 2024105159A1 EP 2023082044 W EP2023082044 W EP 2023082044W WO 2024105159 A1 WO2024105159 A1 WO 2024105159A1
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alkyl
methyl
compound
pharmaceutically acceptable
acceptable salt
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Inventor
Frantisek ZALESAK
Francesco NAI
Rajiv BEDI
Marcin HEROK
Francesco ERRANI
Annalisa INVERNIZZI
Yaozong LI
Amedeo Caflisch
Michael John Hartshorn
Gordon Saxty
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Zurich Universitaet Institut fuer Medizinische Virologie
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Zurich Universitaet Institut fuer Medizinische Virologie
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a compound for use as a ligand of m6a-RNA readers.
  • N6-Methyladenosine is an abundant modification in mRNA and DNA. It is found within some viruses, and most eukaryotes including mammals, insects, plants and yeast. It is also found in tRNA, rRNA, and small nuclear RNA (snRNA) as well as several long non-coding RNA, such as Xist.
  • the biological functions of m6A are mediated through a group of RNA binding proteins that specifically recognize the methylated adenosine on RNA. These binding proteins are named m6A readers.
  • YTH domain family of proteins (YTHDF1 , YTHDF2, YTHDF3 and YTHDC1) have been characterized as direct m6A readers and have a conserved m6A-binding pocket.
  • YTH domain-containing protein 1 is a protein that in humans is encoded by the YTHDC1 gene.
  • YTHDC1 is a nuclear protein involved in splice site selection that localises to YT bodies; dynamic subnuclear compartments, which first appear at the beginning of S-phase in the cell cycle and disperse during mitosis. Alternative splicing, however is known to be altered in a number of diseases and is particularly relevant to cancer.
  • YTHDC1 has been shown to splice mRNA transcripts which have oncological importance, regulating tumour functions such as hypoxia associated vascular endothelial growth factor (VEGF), DNA damage associated breast cancer 1 (BRCA1) and hormonal growth driver; the progesterone receptor (PGR). It has further been shown that YTHDC1 is overexpressed in acute myeloid leukemia (AML) and that it is required for the proliferation and survival of AML cells, while knockout of YTHDC1 blocks AML development and maintenance as well as self-renewal of leukemia stem cells (LSCs) in vivo.
  • AML acute myeloid leukemia
  • LSCs leukemia stem cells
  • the objective of the present invention is to provide novel ligands of m6A-RNA readers, particularly of YTDC1. This objective is attained by the subject-matter of the independent claims of the present disclosure, with further advantageous embodiments described in the dependent claims, examples, figures and general description of this specification.
  • R 1 is -Ci-C 3 -alkyl
  • R 2 is -L-A or a moiety of formula (II lb) or (I lie),
  • R 7 is aryl or five or six-membered heterocycle, each of which is optionally substituted with
  • R 8 is a four or five membered ring, each of which is optionally substituted with 1 , 2, or 3 R.
  • R 1 is Ci-Cs-alkyl
  • R 7 is aryl or five or six-membered heterocycle, each of which is optionally substituted with 1 , 2, or 3 R;
  • R 8 is a four or five membered ring, each of which is optionally substituted with 1 , 2, or 3 R;
  • R 11 is selected from -H, -F, -Br, -Cl, -CN, -Ci-C 3 -alkyl, and NO 2 .
  • each R 1 is independently selected from -H and -Ci-C 3 -alkyl, R 3 is selected from -F, -Cl, - Br, -CN, -NO 2 , Ci-C 3 -haloalkyl, and -NR 6 R 6 ; R 2 is Ci-C 3 -alkyl or -L-A;
  • R 7 is aryl or five or six-membered heterocycle, each of which is optionally substituted with 1 , 2, or 3 R;
  • One aspect of the invention relates to a compound of formula (I) or (II), particularly of (I) wherein
  • R 1 is independently selected from -H and -Ci-Cs-alkyl, particularly -H and -Me or cyclopropyl, more particularly -H and -Me, wherein at least one of R 1 is H, R 3 is selected from -Br, -Cl, -CN, -F and -NO2, particularly -Cl,
  • R 2 is selected from -Ci-Cs-alkyl and a moiety of formula (III) or (IV), particularly R 2 is a moiety of formula (III) or (IV), wherein
  • L of formula (I) is a linker comprising -(CH2)n- or -(CH2)n-Y- and
  • I is 0 or 1 ,
  • CH or a heteroatom particularly CH or N, more particularly CH, a is 0 or 1 , particularly 1 ,
  • R 4 is independently selected from
  • R 6 is independently selected from
  • R 5 is selected from
  • R 7 is selected from an aryl and a heterocycle, wherein the heterocycle is a five or six-membered heterocycle and wherein the heterocycle is an aliphatic heterocycle or an aromatic heterocycle, and
  • R 8 is a four or five membered ring, s is 0 to 3, or wherein
  • L of formula (I) is a linker comprising -(CH 2 ) n - or -(CH 2 ) n -Y- and
  • n is 0 to 3
  • m is 0 or 1
  • each X and Z are selected from C, NR 3 , SO 2 and O, wherein R 3 is -H or -Ci-C3-alkyl-NH 2 and wherein Z is particularly C, R 4 is defined as above, with the exception of
  • Another aspect of the invention relates to a compound selected from any one of (V) to (XI) for use as a medicament
  • Another aspect of the invention relates to a compound described herein for use in the treatment of a disease, wherein the disease is cancer.
  • references to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.”
  • TSA in the context of the present disclosure relates to thermal shift assay which measures the thermal denaturation temperature and hence stability of a protein under varying conditions such as variations in drug concentration, buffer pH, ionic strength, redox potential or sequence mutation.
  • the thermal denaturation temperature is measured via differential scanning fluorimetry (DSF) using specialised fluorogenic dyes.
  • DSF differential scanning fluorimetry
  • the binding of low molecular weight ligands can increase the thermal stability of a protein.
  • GI50 in the context of the present disclosure relates to the half maximal growth inhibition. GI50 is a quantitative measure that indicates the concentration of a particular inhibitor required to inhibit the cell proliferation by 50%. Any patent document cited herein shall be deemed incorporated by reference herein in its entirety.
  • alkyl in the context of the present disclosure relates to a saturated linear or branched hydrocarbon, or unsaturated linear or branched hydrocarbon.
  • cycloalkyl in the context of the present disclosure relates to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl).
  • the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6- membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycl
  • Cs-Cecycloalkyl in the context of the present disclosure refers to cycloalkyl having three to six carbon atoms (C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl).
  • C7-C3 alkyl in the context of the present disclosure relates to a saturated linear or branched hydrocarbon having 1 , 2 or 3 carbon atoms.
  • Non-limiting examples for a C1-C3 alkyl are methyl, ethyl, propyl, and prop-2-enyl, cyclopropyl.
  • a C1-C3 alkyl is a methyl, ethyl or propyl moiety.
  • the alkyl is a linear alkyl.
  • the alkyl is a branched alkyl.
  • Me is methyl CH3
  • Et is ethyl -CH2CH3
  • Prop is propyl (including -(CH 2 ) 2 CH3 (n-propyl, n-pr) or - CH(CH 3 ) 2 (iso-propyl, i-pr))
  • butyl -C4H9 including -(CF ⁇ hCHs, -CHCH3CH2CH3, - CH 2 CH(CH 3 ) 2 or -C(CH 3 ) 3 ).
  • haloalkyl in the context of the present disclosure refers to alkyl, as defined above, that is substituted by one or more halo radicals, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1 ,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1 ,2-dibromoethyl, and the like.
  • halo radicals e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1 ,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1 ,2-dibromoethyl, and the like.
  • hydroxyalkyl in the context of the present disclosure refers to alkyl, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxy propyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • aminoalkyl in the context of the present disclosure refers to alkyl, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • heteroalkyl in the context of the present disclosure refers to alkyl, as defined above, in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
  • heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl are, for example, -CH2OCH3, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH(CH 3 )OCH 3 , - CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N(CH 3 ) 2 .
  • alkyl also comprises unsaturated hydrocarbons like alkene and alkyne.
  • alkene in the context of the present disclosure relates to a hydrocarbon comprising a double bond.
  • An unsubstituted alkene consists of C and H only.
  • a substituted alkene may comprise substituents as defined herein for substituted alkyl.
  • alkyne in the context of the present disclosure relates to a hydrocarbon comprising a triple bond.
  • Unsubstituted alkyne is of formula -CEC- when being located intramolecularly, and of formula -CECH (-C 2 H) when being a terminal moiety.
  • An unsubstituted alkyne consists of C and H only.
  • a substituted alkyne may comprise substituents as defined herein for substituted alkyl.
  • aryl in the context of the present disclosure relates to a cyclic aromatic C5-C10 hydrocarbon.
  • aryl include, without being restricted to, phenyl and naphthyl.
  • halo or halogen in the context of the present disclosure refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • heterocycle in the context of the present disclosure relates to a cyclic aromatic or aliphatic C3-C9 hydrocarbon that comprises at least one heteroatom (e.g. N, O, S). Examples for heteroaryl include, without being restricted to, pyrrole, thiophene, furan, imidazole, pyrazole, thiazole, oxazole, pyridine, pyrimidine, thiazin, quinoline, benzofuran and indole.
  • the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl.
  • the term heteroaryl in the context of the present disclosure relates to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl.
  • the heteroaryl is a 6- membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1 ,4]dioxepinyl, 1 ,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1 ,2-a]pyri
  • heterocycloalkyl in the context of the present disclosure relates refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur.
  • the heterocycloalkyl is fully saturated.
  • the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heterocycloalkyl comprises one to three nitrogens.
  • the heterocycloalkyl comprises one or two nitrogens.
  • the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (C2-C6 fully saturated heterocycloalkyl or C2- Ce heterocycloalkenyl), from two to five carbon atoms (C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (C2-C4 fully saturated heterocycloalkyl or C2-C4 hetero
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1 ,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydro
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
  • heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).
  • the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl.
  • the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl.
  • cyano in the context of the present disclosure refers to -CN.
  • carboxyl in the context of the present disclosure refers to -COOH.
  • an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., - CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.).
  • any substituents described should generally be understood as having a maximum molecular weight of about 1 ,000 daltons, and more typically, up to about 500 daltons.
  • the term pharmaceutically acceptable earner includes any solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (for example, antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington: the Science and Practice of Pharmacy, ISBN 0857110624).
  • cancer as used in the context of the present disclosure relates to malignant neoplastic disease; the terms “cancer” and “malignant neoplastic disease” are used synonymously herein. They specifically include carcinoma (epithelial derived cancer), sarcoma (connective tissue derived cancer), lymphoma and leukemia, germ-cell derived tumours and blastomas. Particular alternatives of any of the aspects and embodiments disclosed herein are directed at the use of the compounds and compositions of the invention in treatment of solid tumours. Other alternatives of any of the aspects and embodiments disclosed herein are directed at the use of the combinations of the invention in treatment of cancers such as renal cancer, breast cancer, acute myeloid leukemia, hepatocellular carcinoma, and lung adenocarcinoma.
  • inhibitor in the context of the present disclosure relates to any pharmaceutically acceptable agent or compound that may be used to interact with and specifically interfere with the biological activity of its designated target, in case of the present invention YTH protein domain, particularly ZTH domain-containing protein 1 (YTHDC1).
  • YTH protein domain particularly ZTH domain-containing protein 1 (YTHDC1).
  • treating or treatment of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (e.g. slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • treating or treatment refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • treating or treatment refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • One aspect of the invention relates to a compound of formula (I) or (II), particularly of (I) wherein
  • R 1 is independently selected from -H and -Ci-Cs-alkyl, particularly -H and -Me or cyclopropyl, more particularly -H and -Me, wherein at least one of R 1 is H, R 3 is selected from -Br, -Cl, -CN, -F and -NO2, particularly -Cl,
  • R 2 is selected from -Ci-Cs-alkyl and a moiety of formula (III) or (IV), particularly
  • R 2 is a moiety of formula (III) or (IV), wherein
  • I is 0 or 1 ,
  • CH or a heteroatom particularly CH or N, more particularly CH, a is 0 or 1 , particularly 1 ,
  • R 4 is independently selected from
  • R 6 is independently selected from
  • R 5 is selected from
  • R 7 is selected from an aryl and a heterocycle, wherein the heterocycle is a five or six-membered heterocycle and wherein the heterocycle is an aliphatic heterocycle or an aromatic heterocycle, and
  • R 8 is a four or five membered ring, s is 0 to 3, or
  • L of formula (I) is a linker comprising -(CH2)n- or -(CH2)n-Y- and
  • Formula (II) includes all resonance structures of said formula, e.g.
  • the compound is a compound of formula (I) wherein
  • R 1 is independently selected from -H and -Ci-Cs-alkyl, particularly -H and -Me or cyclopropyl, more particularly -H and -Me, wherein at least one of R 1 is H, R 3 is selected from -Br, -Cl, -CN, -F and -NO2, particularly -Cl,
  • R 2 is selected from -Ci-Cs-alkyl and a moiety of formula (III) or (IV), particularly R 2 is a moiety of formula (III) or (IV), wherein
  • I is 0 or 1 ,
  • CH or a heteroatom particularly CH or N, more particularly CH, a is 0 or 1 , particularly 1 ,
  • R 4 is independently selected from - -Cl, -Br, -CH 2 F, -CHF 2 , -CF 3 and
  • R 6 is independently selected from
  • R 5 is selected from
  • R 7 is selected from an aryl and a heterocycle, wherein the heterocycle is a five or six-membered heterocycle and wherein the heterocycle is an aliphatic heterocycle or an aromatic heterocycle, and
  • R 8 is a four or five membered ring, s is 0 to 3, or
  • R 2 is a moiety of formula (III) or (IV).
  • the compound is a compound of formula (la) or (Ila), particularly of (la) wherein
  • R 1 is selected from -H and -Ci-Cs-alkyl, particularly -H and -Me or cyclopropyl, more particularly -Me,
  • R 2 is selected from -Ci-Cs-alkyl and a moiety of formula (Illa) or (IVa), particularly R 2 is a moiety of formula (Illa) or (IVa), (Illa), wherein
  • I is 0 or 1 ,
  • R 4 is selected from
  • R 6 is independently selected from
  • R 5 is selected from
  • R 7 is selected from an aryl or a heterocycle, wherein the heterocycle is a five or six-membered heterocycle and wherein the heterocycle is an aliphatic heterocycle or an aromatic heterocycle, and
  • R 8 is a four or five membered ring, s is 0 to 3, wherein
  • X is independently selected from CH, NR 13 , SO2 and O, wherein R 13 is selected from -H and -Ci-C3-alkyl-NH2,
  • R 4 is defined as above.
  • Formula (Ila) includes all resonance structures of said formula, e.g.,
  • the compound is a compound of formula (la) wherein
  • R 1 is selected from -H and -Ci-Cs-alkyl, particularly -H and -Me or cyclopropyl, more particularly -Me,
  • R 2 is selected from -Ci-Cs-alkyl and a moiety of formula (Illa) or (IVa), particularly R 2 is a moiety of formula (Illa) or (IVa), (Illa), wherein
  • I is 0 or 1 ,
  • R 4 is selected from
  • R 6 is independently selected from
  • R 5 is selected from
  • R 7 is selected from an aryl or a heterocycle, wherein the heterocycle is a five or six-membered heterocycle and wherein the heterocycle is an aliphatic heterocycle or an aromatic heterocycle, and
  • R 8 is a four or five membered ring, s is 0 to 3, wherein
  • X is independently selected from CH, NR 13 , SO2 and O, wherein R 13 is selected from -H and -Ci-C3-alkyl-NH2,
  • R 4 is defined as above.
  • L of formula (I) is a linker comprising -(CH2)n- or -(CH2)n-Y-
  • L is a linker comprising -(CH2)n-. In certain embodiments, L is -(CH2)n- and n is 0 or 1.
  • Y is O.
  • Y is S.
  • Y is -SO2-.
  • Y is -NH-.
  • each R 1 is independently -H or Ci-Ce-alkyl
  • R 3 is -Br, -Cl, -CN, -F, or -NO 2 ;
  • R 7 is aryl or five or six-membered heterocycle, each of which is optionally substituted with 1 , 2, or 3 R;
  • R 8 is a four or five membered ring, each of which is optionally substituted with 1 , 2, or 3 R.
  • R 2 is -L-A or a moiety of formula (lllb) or (lllc),
  • R 7 is aryl or five or six-membered heterocycle, each of which is optionally substituted with 1 , 2, or 3 R;
  • R 8 is a four or five membered ring, each of which is optionally substituted with 1 , 2, or 3 R.
  • disclosed herein is a compound of formula (la), or a pharmaceutically acceptable salt thereof, provided that the compound is not
  • R 7 is aryl or five or six-membered heterocycle, each of which is optionally substituted with 1 , 2, or 3 R;
  • R 8 is a four or five membered ring, each of which is optionally substituted with 1 , 2, or 3 R;
  • R 11 is selected from -H, -F, -Br, -Cl, -CN, -Ci-Cs-alkyl, and NO 2 .
  • R 8 is a four or five membered ring, each of which is optionally substituted with 1 , 2, or 3 R;
  • a compound of formula (XI), or a pharmaceutically acceptable salt thereof provided that the compound is not .
  • each R 1 is independently selected from -H and - Ci-Cs-alkyl. In some embodiments, each R 1 is hydrogen. In some embodiments, each R 1 is - Ci-Cs-alkyl. In some embodiments of Formula (I) or (II), at least one of R 1 is H.
  • R 1 is -H or -Ci-Cs-alkyl.
  • R 1 is hydrogen.
  • R 1 is -Ci-Cs-alkyl.
  • the -Ci-Cs-alkyl is linear Ci-Cs-alkyl.
  • the -Ci-Cs-alkyl is branched Ci-Cs-alkyl.
  • the -Ci-Cs-alkyl is methyl.
  • the -Ci-Cs-alkyl is ethyl.
  • R 1 is methyl or ethyl.
  • R 3 is selected from -Br, -Cl, -NO2, CN, -O- Ci-Cs-alkyl, Ci-Cs-alkyl, C2-C3-haloalkyl, -NR 6 R 6 , -OH, -CH2F, and -CHF2.
  • R 3 is -Br, -Cl, -O-Ci-Cs-alkyl, linear or branched Ci-Cs-alkyl, or -NH2.
  • R 3 is selected from -F, -Cl, -Br, -CN, -NO2, C1-C3- haloalkyl, and -NR 6 R 6 .
  • R 3 is selected from -F, - Cl, -Br, and -NO2.
  • R 3 is -F, -Cl, -Br, Ci-Cs-haloalkyl, or -NH2.
  • R 3 is -Cl, Ci-Cs-haloalkyl, and -NH2.
  • R 3 is -F.
  • R 3 is -Cl. In some embodiments, R 3 is -Br. In some embodiments, R 3 is -NO2. In some embodiments, R 3 is CN. In some embodiments, R 3 is -O-Ci-Cs-alkyl such as O-methyl. In some embodiments, R 3 is Ci-Cs-alkyl. In some embodiments, R 3 is methyl, ethyl, propyl. In some embodiments, R 3 is In some embodiments, R 3 is C2-C3-haloalkyl. In some embodiments, R 3 is Ci-Cs-haloalkyl. In some embodiments, R 3 is not methyl. In some embodiments, R 3 is not CF3. In some embodiments of a compound of Formula (I), (la), (II), or (Ila), R 2 is -L-A.
  • L is -(CH2)n- wherein n is 0, 1 , 2, or 3.
  • L is absent.
  • L is CH2.
  • L is -(CH2)2-.
  • A is phenyl, 5-6 membered heteroaryl, C3-C6 cycloalkyl, naphthyl, or bicyclic heteroaryl, each of which is unsubstituted or substituted. In some embodiments, A is phenyl, 5-6 membered heteroaryl, naphthyl, or bicyclic heteroaryl, each of which is unsubstituted or substituted. In some embodiments, A is phenyl or 5-6 membered heteroaryl, each of which is unsubstituted or substituted.
  • A is naphthyl, or bicyclic heteroaryl, each of which is unsubstituted or substituted.
  • A is phenyl, which is unsubstituted or substituted.
  • A is 5-6 membered heteroaryl, which is unsubstituted or substituted.
  • A is C3-C6 cycloalkyl, which is unsubstituted or substituted.
  • A is naphthyl, which is unsubstituted or substituted.
  • A is bicyclic heteroaryl, which is unsubstituted or substituted.
  • A is unsubstituted or substituted with 1 , 2, 3, or 4 R A . In some embodiments, A is unsubstituted. In some embodiments, A is substituted with 1 , 2, 3, or 4 R A . In some embodiments, A is substituted with 1 , 2, or 3 R A . In some embodiments, A is substituted with 1 or 2 R A . In some embodiments, A is substituted with 1 R A .
  • R A is not F.
  • R A is not Cl.
  • R A is not halogen.
  • each R A is independently selected from F, Cl, Br, I, -CN, -NO2, -OH, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or Ci-Ceaminoalkyl, wherein the alkyl is optionally substituted with 1 , 2, or 3 R.
  • the Ci-Cealkyl is linear Ci-Cealkyl. In some embodiments, the Ci- Cealkyl is branched Ci-Cealkyl. In some embodiments, the Ci-Cealkyl is methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1 -butyl, 3-methyl-1-butyl, 2-methyl- 3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1 -pentyl, 3-methyl-1-pentyl, 4-methyl-1 -pentyl, 2- methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1- butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-
  • the Ci-Cs-alkyl is linear Ci-Cs-alkyl. In some embodiments, the Ci-Cs-alkyl is branched Ci-Cs-alkyl. In some embodiments, the Ci-Cs-alkyl is methyl, ethyl, n- propyl, or isopropyl.
  • R A is R 4 . In some embodiments, R A is R 5 . In some embodiments, at least one R A is R 5 .
  • the difference between the compounds’ biochemical IC50 and biological GI50 values can be a result of a prodrug/drug complementarity (carboxylic acid group-drug vs ester group-prodrug).
  • ZA590 (comprising a -COOCH3) can be considered a prodrug of ZA591 (comprising COOH).
  • R A is Ci-Cehaloalkyl.
  • the Ci-Cehaloalkyl is linear Ci-Cehaloalkyl.
  • the Ci-Cehaloalkyl is branched Ci-Cehaloalkyl.
  • the Ci-Cehaloalkyl is trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1 ,2-difluoroethyl, 3-bromo-2-fluoropropyl, or 1 ,2- dibromoethyl.
  • R A is Ci-Cehydroxyalkyl.
  • the Ci-Cehydroxyalkyl is linear Ci-Cehydroxyalkyl.
  • the Ci-Cehydroxyalkyl is branched Ci-Cehydroxyalkyl.
  • the Ci-Cehydroxyalkyl is hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl.
  • R A is Ci-Ceaminoalkyl.
  • the Ci-Ceaminoalkyl is linear Ci-Ceaminoalkyl.
  • the Ci-Ceaminoalkyl is branched Ci-Ceaminoalkyl.
  • the Ci-Ceaminoalkyl is aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl.
  • R A ’ is -CN, Ci-Cealkyl, Ci-Cehydroxyalkyl, Ci-C 6 aminoalkyl, -NH-SO 2 -Ci-C 3 -alkyl, -NH-SO 2 -(CH 2 ) s -OH, -NH-SO 2 -(CH 2 ) s -R 7 , aryl or heteroaryl, wherein the alkyl, aryl, or heteroaryl is optionally substituted with 1 , 2, or 3 R.
  • R A is Ci-Cealkyl.
  • the Ci-Cealkyl is linear Ci- Cealkyl.
  • the Ci-Cealkyl is branched Ci-Cealkyl.
  • the Ci-Cealkyl is methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2- methyl-1-butyl, 3-methyl-1 -butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1 -propyl, 2-methyl-1-pentyl, 3- methyl-1-pentyl, 4-methyl-1 -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl
  • the Ci-Cs-alkyl is linear Ci-Cs-alkyl. In some embodiments, the Ci-Cs-alkyl is branched Ci-Cs-alkyl. In some embodiments, the Ci- Cs-alkyl is methyl, ethyl, n-propyl, or isopropyl.
  • R A ' is Ci-Cehaloalkyl.
  • the Ci-Cehaloalkyl is linear Ci-Cehaloalkyl.
  • the Ci-Cehaloalkyl is branched Ci-Cehaloalkyl.
  • the Ci-Cehaloalkyl is trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1 ,2-difluoroethyl, 3-bromo-2-fluoropropyl, or 1 ,2- dibromoethyl.
  • R A ' is Ci-Cehydroxyalkyl.
  • the Ci-Cehydroxyalkyl is linear Ci-Cehydroxyalkyl.
  • the Ci-Cehydroxyalkyl is branched Ci-Cehydroxyalkyl.
  • the Ci-Cehydroxyalkyl is hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl.
  • R A ' is Ci-Ceaminoalkyl.
  • the Ci-Ceaminoalkyl is linear Ci-Ceaminoalkyl.
  • the Ci-Ceaminoalkyl is branched Ci-Ceaminoalkyl.
  • the Ci-Ceaminoalkyl is aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl.
  • R 2 is a moiety of In some embodiments of a compound of Formula some embodiments, R 2 is embodiments, some embodiments a compound of Formula (I), (la), (II), or (Ila), R 2 is a moiety of formula (III) or (IV), wherein
  • I is 0 or 1
  • R 5 is selected from -NH-SO 2 -Ci-C 3 -alkyl, -NH-SO 2 -(CH 2 )s-OH and NH-SO 2 -(CH 2 ) s -R 7 , wherein R 7 is selected from an aryl and a heterocycle, wherein the heterocycle is a five or six-membered heterocycle and wherein the heterocycle is an aliphatic heterocycle or an aromatic heterocycle, and -(CH2) S -R 8 , wherein R 8 is a four or five membered ring, s is 0 to 3, or wherein
  • L of formula (I) is a linker comprising -(CH2)n- or -(CH2)n-Y- and
  • R 4 is defined as above.
  • R 2 is para or meta substituted.
  • R 2 is a moiety of
  • R 7 is aryl or five or six-membered heterocycle, each of which is optionally substituted with 1 , 2, or 3 R;
  • R 8 is a four or five membered ring, each of which is optionally substituted with 1 , 2, or 3 R.
  • R 2 is a moiety of formula (111 b).
  • R 2 is a moiety of formula (I I Ic),
  • R 2 is a moiety of formula (Illa) or (IVa). In certain embodiments, R 2 is a moiety of formula (II Ic). In certain embodiments, R 2 is a moiety of formula (lllc’). In certain embodiments, R 2 is a moiety of formula (lllc’). In certain embodiments, R 2 is a moiety of formula (lllc”). In certain embodiments, R 2 is a moiety of formula (lllb). In certain embodiments, R 2 is a moiety of formula (lllb’). In certain embodiments, R 2 is a moiety of formula (lllb”). In certain embodiments, R 2 is a moiety of formula (Hid’).
  • the formula (Illa) of R 2 is , wherein k is 0 to 3, particularly 0 to 2, more particularly 1 or 2
  • R 4 is selected from
  • R 4 is selected from
  • R 4 is selected from
  • R 4 is selected from
  • R 4 is selected from
  • R 4 is -OMe and -Cl.
  • one R 4 is in meta position to L.
  • R 5 is selected from
  • R 7 is selected from an aryl or a heterocycle, wherein the heterocycle is a five or six-membered heterocycle and wherein the heterocycle is an aliphatic heterocycle or an aromatic heterocycle, and -(CH 2 ) S -R 8 , wherein R 8 is a four or five membered ring, s is 0 to 3,
  • R 4 being as defined above.
  • each R 11 is independently -H, -F, -Br, - Cl, -CN, or -Ci-Cs-alkyl. In some embodiments, each R 11 is independently -H, -F, -CN, or -Ci- Cs-alkyl. In some embodiments, each R 11 is independently -H or linear -Ci-Cs-alkyl. In some embodiments, each R 11 is independently -H or branched -Ci-Cs-alkyl. In certain embodiments, R 7 is selected from any one of the moieties
  • R 8 is selected from any one of the moieties wherein R 9 is selected from -H or -Ci-Ce-alkyl. In certain embodiments, R 8 is selected from any one of the moieties wherein R 9 is selected from -H or -Ci-Ce-alkyl.
  • R 8 is selected from any one of the moieties wherein R 9 is selected from -H or -Ci-Ce-alkyl.
  • R 5 is selected from any one of the moieties wherein R 9 is selected from -H or -Ci-Ce-alkyl and wherein s is 0 to 3.
  • R 5 is selected from any one of the moieties wherein R 9 is selected from -H or -Ci-Ce-alkyl and wherein s is 0 to 3.
  • R 5 is selected from any one of the moieties wherein R 9 is selected from -H or -Ci-Ce-alkyl and wherein s is 0 to 3.
  • one of X is SO2.
  • at least one of X is NH.
  • the compound of formula (IVa) of R 2 is selected from any one of the moieties wherein n is 0 or 1.
  • the compound is selected from a compound of formula (FE150),
  • a compound disclosed herein is a compound of Table 1 or a salt thereof. Table 1.
  • a compound disclosed herein is a compound of Table 2, or a salt thereof. Table 2.
  • a compound disclosed herein is a compound of Table 3, or a salt thereof. Table 3.
  • Another aspect of the invention relates to a compound selected from any one of (FE150), (ZA347), (ZA349), (ZA400), (ZA364), (ZA311) and (ZA337) for use as a medicament
  • Another aspect of the invention relates to a compound described herein for use in the treatment of a disease, wherein the disease is cancer.
  • the cancer is selected from renal cancer, breast cancer, acute myeloid leukemia, hepatocellular carcinoma, and lung adenocarcinoma.
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • hydrogen has three naturally occurring isotopes, denoted 1 H (protium), 2 H (deuterium), and 3 H (tritium).
  • Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford some therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.
  • the compounds described herein may be artificially enriched in one or more particular isotopes.
  • the compounds described herein may be artificially enriched in one or more isotopes that are not predominantly found in nature.
  • the compounds described herein may be artificially enriched in one or more isotopes selected from deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 l) or carbon-14 ( 14 C).
  • the compounds described herein are artificially enriched in one or more isotopes selected from 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 CI, 37 CI, 79 Br, 81 Br, 131 l, and 125 l.
  • the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% by molar.
  • the compound is deuterated in at least one position.
  • the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
  • deuterium substituted compounds may be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21 ; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981 , 64(1-2), 9-32.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.
  • Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • Tautomers In some situations, compounds exist as tautomers.
  • the compounds described herein include all possible tautomers within the formulas described herein.
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • a method or treating cancer in a patient in need thereof comprising administering to the patient a compound according to the above description.
  • the compound according to the invention is provided as a pharmaceutical composition, pharmaceutical administration form, or pharmaceutical dosage form, said pharmaceutical composition, pharmaceutical administration form, or pharmaceutical dosage form comprising at least one of the compounds of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • any specifically mentioned drug compound mentioned herein may be present as a pharmaceutically acceptable salt of said drug.
  • Pharmaceutically acceptable salts comprise the ionized drug and an oppositely charged counterion.
  • Non-limiting examples of pharmaceutically acceptable anionic salt forms include acetate, benzoate, besylate, bitatrate, bromide, carbonate, chloride, citrate, edetate, edisylate, embonate, estolate, fumarate, gluceptate, gluconate, hydrobromide, hydrochloride, iodide, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl sulfate, mucate, napsylate, nitrate, pamoate, phosphate, diphosphate, salicylate, disalicylate, stearate, succinate, sulfate, tartrate, tosylate, triethiodide and valerate.
  • the compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.
  • a dosage form for the prevention or treatment of cancer comprising a non-agonist ligand or antisense molecule according to any of the above aspects or embodiments of the invention.
  • the invention further encompasses a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein.
  • compositions of the present invention relate to a dosage form for enteral administration, such as nasal, buccal, rectal, transdermal or oral administration, or as an inhalation form or suppository.
  • pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions).
  • Certain embodiments of the invention relate to a dosage form for parenteral administration, such as subcutaneous, intravenous, intrahepatic or intramuscular injection forms.
  • a pharmaceutically acceptable carrier and/or excipient may be present.
  • the dosage regimen for the compounds of the present invention will vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.
  • the compounds of the invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
  • the pharmaceutical composition or combination of the present invention can be in unit dosage of about 1-1000 mg of active ingredient(s) for a subject of about 50-70 kg.
  • the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
  • compositions of the present invention can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc. They may be produced by standard processes, for instance by conventional mixing, granulating, dissolving or lyophilizing processes. Many such procedures and methods for preparing pharmaceutical compositions are known in the art, see for example L. Lachman et al. The Theory and Practice of Industrial Pharmacy, 4th Ed, 2013 (ISBN 8123922892).
  • the invention further encompasses, as an additional aspect, the use of a compound as identified herein, or its pharmaceutically acceptable salt, as specified in detail above, for use in a method of manufacture of a medicament for the treatment or prevention of cancer.
  • the invention encompasses methods of treatment of a patient having been diagnosed with a disease associated with cancer. This method entails administering to the patient an effective amount of compound as identified herein, or its pharmaceutically acceptable salt, as specified in detail herein.
  • the IC50 values were obtained through an HTRF-based assay.
  • the assay evaluates the binding interaction of the YTHDC1 YTH domain (amino acids 345-509) and a methylated RNA (sequence: 5’-Biotin-AAGAACCGG(m 6 A)CUAAGCU-30).
  • the YTH domain of YTHDC1 is expressed as a GST-fusion protein that is recognized by an anti-GST antibody labelled with Eu 3+ , acting as the Forster resonance energy transfer (FRET) donor.
  • FRET Forster resonance energy transfer
  • the biotinylated RNA is bound by Streptavidin conjugated to XL665, the FRET acceptor.
  • the binding of the methylated RNA to the YTH binding site leads to the formation of a four-member complex constituted by the GST-tagged YTH domain of YTHDC1 , anti-GST Eu 3+ -labelled antibody, biotinylated RNA, and Streptavidin conjugated to XL665.
  • This complex formation subsequently leads to the proximity between the FRET donor and acceptor, resulting in a signal emission.
  • the tested compound can compete with the methylated RNA for the occupation of the YTH active site, the emitted signal decreases.
  • the assay mix includes 25 nM YTHDC1 YTH domain-GST fusion protein, 15 nM biotinylated RNA (Dharmacon), 0.8 nM anti-GST Eu 3+ -conjugated antibody (Cisbio, 61GSTKLB), 1.875 nM XL665-conjugated streptavidin (Cisbio, 610SAXLB), and the compound of interest.
  • the compound concentration in the final mix strictly depends on the assay's aims. It is fixed at 1 mM to investigate the residual signal or set as an array of 1 mM 2-fold dilutions to determine the IC50 values.
  • the assay's components are diluted in a buffer composed of 50 mM HEPES pH 7.5, 150 mM NaCI, 100 mM kF, and 0.1 % BSA.
  • the reagents mix is incubated for 3 h at 24 C, transferred into a white, low volume 384-well plate (Corning, 4513), and measured using an Infinite M1000 plate reader (Tecan).
  • Eu 3+ is excited at a wavelength of 317 nm, and fluorescence emissions are measured at 620 and 665 nm, with an excitation/emission lag time of 60 ps.
  • the IC50 values were obtained by analyzing the dose-response data.
  • Protein sample was buffered in 25 mM HEPES pH 7.2, 150 mM NaCI and assayed in a 96- well plate at a final concentration of 2 pM in 20 pl volume. Fluorescent dye was added as a fluorescence probe at a dilution of 1 :1000. Compound concentrations tested were 12.5 pM, 25 pM, 50 pM, 100 pM and 200 pM. The temperature was raised with a step of 0.5 °C starting from 20 °C to 80 °C and fluorescence readings were taken at each interval. The reported values (ATm) are calculated as the difference between the transition midpoints of an individual sample and the average of the reference wells (containing the protein and the DMSO only) in the same plate. The DMSO concentration was kept at 1 % (v/v).
  • Cells were seeded in white clear-bottom 96-well plates at a density of 6 x 10 3 cells/well in 50 pL of the complete RPMI medium and treated with 50 pL of increasing concentrations of the indicated compounds dissolved in DMSO (final concentration of compounds 1.25 - 160 pM) or DMSO only (0.5 % (v/v)) as a negative control and incubated for 72 h at 37°C with 5 % CO2.
  • Cell viability was determined using a CellTiter-Glo luminescent cell viability assay (Promega) based on the detection of ATP according to manufacturer’s instructions. 100 pL of the reagent was added to each well and incubated for 10 min at room temperature on an orbital shaker.
  • the luminescence was recorded using a Tecan Infinite 3046 M1000 microplate reader from the top. Background luminescence value was obtained from wells containing the CellTiter-Glo reagent and medium without cells. Cell viability curves were plotted in GraphPad Prism 9 and fitted with nonlinear regression, from which GI50 values were determined.
  • Multiplicities are abbreviated as follows: singlet (s), doublet (d) multiplet (m), and broad signal (bs).
  • the reaction was quenched by aq. sol. of NH4CI after 5 hours.
  • the reaction mixture was extracted into EtOAc (3 x 12 mL) and combined organic layers were dried over MgSC>4, filtrated and evaporated.
  • the residue was dissolved in EtOH (4 mL) and 33 % MeNH2 in EtOH (1 mL) was added.
  • the reaction mixture was stirred at rt for 1 hour. After the reaction completion, the volatiles were removed in vacuo.
  • the compound was prepared following Example 4 using 2,6-dichloropurine (0.566 g, 3.00 mmol) and 2-chloro-4-(chloromethyl)-1-methoxybenzene (0.573 g, 3.00 mmol).
  • the N 9 alkylation was performed following Example 4 using 2,6-dichloropurine (0.825 g, 4.37 mmol) and methyl-3-bromomethylbenzoate (1.0 g, 4.37 mmol).
  • the final compound was prepared following Example 5 from corresponding 9-alkyl-2,6- dichloro-9H-purine (0.465 g, 1.38 mmol).
  • the final compound was prepared following Examples 5 starting from ZA348 (0.272 g, 0.867 mmol).
  • the crude product was purified using flash column chromatography (SiO2;
  • the pyrazolo[4,3-d]pyrimidine-5,7(6H)-dione was suspended in POCh (4.6 mL) followed by the addition of DI PEA (0.403 mL, 2.3 mmol).
  • the reaction mixture was heated at 70 °C for 14 hours. The volatiles were removed in vacuo and the residue was poured over ice.
  • the mixture was extracted into EtOAc (3 x 6 mL) and the combined organic layers were dried over MgSCL and filtered. Activated charcoal was added to the filtrate and the mixture was stirred for 10 minutes. After the charcoal removal (filtration paper), the solvent was removed under reduced pressure.
  • the crude product was dissolved in EtOH and 33% MeNH2 in EtOH (0.2 mL) was added into the reaction vessel.
  • the final compound was prepared following Example 5 from corresponding 9-phenyl-2,6- dichloro-9H-purine (0.02 g, 0.075 mmol) that was prepared according to the procedure reported in Tetrahedron Lett 2003, 44 (16), 3359-3362.
  • the final compound was prepared following Example 5 from corresponding 9-alkyl-2,6- dichloro-9H-purine (0.069 g, 0.246 mmol).
  • the final compound was prepared following Example 5 from corresponding 9-alkyl-2,6- dichloro-9H-purine (0.2 g, 0.073 mmol) that was prepared according to the procedure reported in Eur. J. Med. Chem. 2019, 184, 111728.
  • the final compound was prepared following Example 5 from corresponding tert-butyl 3-(2,6- dichloro-9H-purin-9-yl)benzoate (0.02 g, 0.055 mmol) that was prepared according to the procedure reported in Tetrahedron Lett 2003, 44 (16), 3359-3362.
  • the tert-butyl ester (0.014, 0.039 mmol) was dissolved in DCM (0.5 mL) and TFA was added (0.02 mL). The reaction was stirred at rt overnight and neutralized with DI PEA. The volatiles were evaporated in vacuo and the crude product was recrystalized from H2O. The final product was obtained (0.011 g, 93 %).
  • N 9 alkylation was performed following Example 4 using 2,6-dichloropurine (0.2 g, 1.06 mmol) and /V-phenylchloroacetamide (1.0 g , 5.9 mmol), that was prepared according to the procedure reported in Eur J Med Chem 2022, 238, 114444.
  • the final compound was prepared following Example 5 from corresponding 9-alkyl-2,6- dichloro-9H-purine (0.05 g, 0.155 mmol).
  • N 9 alkylation was performed following Example 4 using 2,6-dichloropurine (0.531 g, 2.81 mmol) and tert-butyl (2-(chloromethyl)phenyl)carbamate that was prepared according to the procedure reported in Angewandte Chemie 2014, 126 (36), 9757-9761..
  • the N 9 alkylation was performed following Example 4 using 2,6-dichloropurine (0.48 g, 2.54 mmol) and 1-chloromethyl-2-difluoromethylbenzene (0.449 g, 2.54 mmol).
  • the final compound was prepared following Example 5 starting from corresponding 9-alkyl- 2,6-dichloro-9H-purine (0.080 g, 0.243 mmol).
  • the N 9 alkylation was performed following Example 4 using 2,6-dichloropurine (0.525 g, 2.78 mmol) and 1-chloromethyl-2-trifluoromethylbenzen (0.540 g, 2.78 mmol).
  • the final compound was prepared following Example 5 from corresponding 9-alkyl-2,6- dichloro-9H-purine (0.1 g, 0.288 mmol).
  • N 9 alkylation was performed following Example 4 using 2,6-dichloropurine (0.2 g, 1.06 mmol) and 1-chloromethyl-2-methoxybenzen (0.165 g, 1.06 mmol) that was prepared according to the procedure reported in J Org Chem 2002, 46 (11), 2394-2398.
  • the final compound was prepared following Example 5 starting from corresponding 9-alkyl- 2,6-dichloro-9H-purine (0.048 g, 0.155 mmol).
  • the A/ 9 alkylation was performed following Example 4 using 2,6-dichloropurine (0.5 g, 2.65 mmol) and 1-bromo-3-bromomethylbenzen (0.661 g, 2.65 mmol).
  • the final compound was prepared following Example 5 starting from corresponding 9-alkyl- 2,6-dichloro-9H-purine (0.150 g, 0.419 mmol).
  • the A/ 9 alkylation was performed following Example 4 using 2,6-dichloropurine (0.2 g, 1.06 mmol) and 1-bromomethyl-3-methoxybenzen (0.212 g, 1.06 mmol).
  • N 9 alkylation was performed following Example 4 using 2,6-dichloropurine (0.2 g, 1.06 mmol) and (4-(bromomethyl)phenyl)methanol (0.212 g, 1.06 mmol) that was prepared according to the procedure reported in Org Lett 2003, 5 (13), 2239-2242.
  • the final compound was prepared following Example 5 from corresponding 9-alkyl-2,6- dichloro-9H-purine (0.05 g, 0.264 mmol).
  • N 9 alkylation was performed following Example 4 using 2,6-dichloropurine (0.459 g, 2.43 mmol) and methyl 3-(bromomethyl)-5-chlorobenzoate (0.641 g, 2.43 mmol) that was prepared according to the procedure reported in Molecules 2023, 28 (2), 768.
  • the final compound was prepared following Example 5 from corresponding 9-alkyl-2,6- dichloro-9H-purine (0.337 g, 0.906 mmol).
  • the N 9 alkylation was performed following Example 4 using 2,6-dichloropurine (0.457 g, 2.42 mmol) and 1 ,3-dichloro-5-(chloromethyl)-2-methoxybenzene (0.449 g, 2.54 mmol).
  • the final compound was prepared following Example 5 for S n Ar starting from corresponding 9-alkyl-2,6-dichloro-9H-purine (0.080 g, 0.211 mmol).
  • the N 9 alkylation was performed following Example 4 using 6-chloro-2-fluoro-9H-purine (0.578 g, 3.35 mmol) and 1-(bromomethyl)-3-chlorobenzene (0.688 g, 3.35 mmol).
  • 1 H NMR (400 MHz, DMSO) 6 8.08 (s, 1 H), 7.36 - 7.28 (m, 3H), 7.20 (dt, J 6.7, 1.9 Hz, 1 H), 5.36 (s, 2H).
  • ZA540b 1 H NMR (400 MHz, CDCI3) 6 7.66 (s, 1 H), 7.30 - 7.15 (m, 3H), 7.17 - 7.14 (m, 1 H), 6.16 - 6.02 (bs, 1 H), 5.26 (s, 2H), 3.23 - 3.10 (bs, 3H).
  • the compound was prepared following Example 5 starting from corresponding 9-alkyl-2,6- dichloro-9H-purine (0.07 g, 0.223 mmol) and cyclopropylamine (0.03 mL, 0.433 mmol).
  • N 9 alkylation was performed following Example 4 using 2,6-dichloropurine (0.5 g, 2.65 mmol) and 1-bromomethyl-3-chlorbenzen (0.543 g, 2.65 mmol).
  • Step 1 N-methyl-2-(prop-1-en-2-yl)-9H-purin-6-amine (21)
  • Step 1 methyl 4-(4-chloro-2-(hydroxymethyl)phenyl)butanoate (26)
  • Step 3 methyl 4-(4-chloro-2-((2-chloro-6-(methylamino)-9H-purin-9-yl)methyl)phenyl)- butanoate (28)
  • Step 4 4-(4-chloro-2-((2-chloro-6-(methylamino)-9H-purin-9-yl)methyl)phenyl)butanoic acid (29)
  • Step 1 methyl 2-((2-chloro-6-(methylamino)-9H-purin-9-yl)methyl)benzoate (34)
  • Step 2 methyl 4-((3-(bromomethyl)phenyl)sulfonamido)benzoate (38)
  • Step 3 methyl 4-((3-((2-chloro-6-(methylamino)-9H-purin-9-yl)methyl)phenyl)sulfo- namido)benzoate (39)
  • Step 4 4-((3-((2-chloro-6-(methylamino)-9H-purin-9-yl)methyl)phenyl)sulfonamido)benzoic acid (40)
  • Step 2 methyl 3-((3-((2-chloro-6-(methylamino)-9H-purin-9-yl)methyl)phenyl)sulfo- namido)benzoate (42)
  • Step 3 3-((3-((2-chloro-6-(methylamino)-9H-purin-9-yl)methyl)phenyl)sulfonamido)benzoic acid (43)
  • Step 1 1-chloro-3-(1-chloroethyl)benzene (44)
  • Step 1 methyl (E)-3-(4-chloro-2-formylphenyl)acrylate (50)
  • Step 3 methyl 3-(4-chloro-2-(chloromethyl)phenyl)propanoate (52)
  • Step 4 methyl 3-(4-chloro-2-((2-chloro-6-(methylamino)-9H-purin-9-yl)methyl)phenyl)- propanoate (53)
  • Step 5 3-(4-chloro-2-((2-chloro-6-(methylamino)-9H-purin-9-yl)methyl)phenyl)propanoic acid (54)
  • Step 1 methyl 4-chloro-2-((2-chloro-6-(methylamino)-9H-purin-9-yl)methyl)benzoate (55)
  • Step 2 4-chloro-3-((2-chloro-6-(methylamino)-9H-purin-9-yl)methyl)benzoic acid (56)
  • Step 1 Synthesis of 2-chloro-9a-[(2,4-dimethoxyphenyl)methyl]-9a-methyladenine.
  • 2,6-dichloropurine (10 g, 52.9 mmol, 1.0 eq., cas: 5451-40-1) and N- methyl[(2,4-dimethoxyphenyl)methyl]amine (9.68 g, 53.4 mmol, 1.0 eq., cas: 102502-23-1) in acetonitrile (0.1 L) was added TEA (16.1 g, 159 mmol, 3 eq.) at 20°C.
  • TEA (16.1 g, 159 mmol, 3 eq.
  • Step 3 Synthesis of 1- ⁇ 2-chloro-9-[(m-chlorophenyl)methyl]-9a-[(2,4- dimethoxyphenyl)methyl]-9a-methyl-8-adenineyl ⁇ -1 -ethanone.
  • Step 4 Synthesis of 1- ⁇ 9-[(m-chlorophenyl)methyl]-9a-[(2,4-dimethoxyphenyl)methyl]-2,9a- dimethyl-8-adenineyl ⁇ -1 -ethanone.
  • Step 6 Synthesis of 1- ⁇ 9-[(m-chlorophenyl)methyl]-2,9a-dimethyl-8-adenineyl ⁇ -1-ethanol.
  • Step 2 Synthesis of 1- ⁇ 9-[(m-chlorophenyl)methyl]-9a-[(2,4-dimethoxyphenyl)methyl]-2-ethyl- 9a-methyl-8-adenineyl ⁇ - 1 -ethanone.
  • Step 3 Synthesis of 1- ⁇ 9-[(m-chlorophenyl)methyl]-9a-[(2,4-dimethoxyphenyl)methyl]-2-ethyl- 9a-methyl-8-adenineyl ⁇ - 1 -ethanol.
  • Step 4 Synthesis of 1- ⁇ 9-[(m-chlorophenyl)methyl]-2-ethyl-9a-methyl-8-adenineyl ⁇ -1-ethanol.
  • Step 1 Synthesis of 2-chloro-9a-[(2,4-dimethoxyphenyl)methyl]-9a-methyl-9-(tetrahydro-2H- pyran-2-yl)adenine.
  • 2-chloro-9a-[(2,4-dimethoxyphenyl)methyl]-9a-methyladenine (2 g, 5.99 mmol, synthesized according to procedure described in synthesis of Compound 66) in tetra hydrofuran (20 mL) was added 3,4-dihydro-2H-pyran (1.51 g, 18 mmol, 3 eq.) and 1- pyridylium p-toluenesulfonate (1 .51 g, 5.99 mmol) at 20°C.
  • Step 2 Synthesis of 1- ⁇ 2-chloro-9a-[(2,4-dimethoxyphenyl)methyl]-9a-methyl-9-(tetrahydro- 2H-pyran-2-yl)-8-adenineyl ⁇ -1 -ethanone.
  • N-methoxy-N- methylacetamide (888 mg, 8.61 mmol, 1.5 eq.) stirred at -78°C for 1 h. After completion, the mixture was quenched with H2O (15 mL), extracted with EtOAc (15 mL*3). The organic layer was washed with H2O (15 mL), brine (15 mL), dried over anhydrous Na2SO4, filtrated and concentrated in vacuo to give a residue.
  • Step 3 Synthesis of 1- ⁇ 2-chloro-9a-[(2,4-dimethoxyphenyl)methyl]-9a-methyl-8-adenineyl ⁇ -1- ethanone.
  • Step 4 Synthesis of methyl m-( ⁇ 8-acetyl-2-chloro-9a-[(2,4-dimethoxyphenyl)methyl]-9a- methyl-9-adenineyl ⁇ methyl)benzoate.
  • a mixture of 1- ⁇ 2-chloro-9a-[(2,4-dimethoxyphenyl)methyl]-9a-methyl-8-adenineyl ⁇ -1- ethanone (136 mg, 0.20 mmol) in dimethylformamide (8 mL) was added methyl m- (bromomethyl)benzoate (550 mg, 2.4 mmol, 1.1 eq.) and dicaesium carbonate (1.07 g, 3.27 mmol, 1 .5 eq.) at 25°C.
  • Step 5 Synthesis of methyl m-( ⁇ 2-chloro-9a-[(2,4-dimethoxyphenyl)methyl]-8-(1- hydroxyethyl)-9a-methyl-9-adenineyl ⁇ methyl)benzoate.
  • Step 6 Synthesis of purificationm-( ⁇ 2-chloro-9a-[(2,4-dimethoxyphenyl)methyl]-8-(1- hydroxyethyl)-9a-methyl-9-adenineyl ⁇ methyl)benzoic acid.
  • Step 7 Synthesis of 1- ⁇ 2-chloro-9a-[(2,4-dimethoxyphenyl)methyl]-9a-methyl-8-adenineyl ⁇ -1- ethanone.
  • m-( ⁇ 2-chloro-9a-[(2,4-dimethoxyphenyl)methyl]-8-(1-hydroxyethyl)-9a-methyl- 9-adenineyl ⁇ methyl)benzoic acid 70 mg, 0.14 mmol
  • methanol 1.2 mL
  • trifluoroacetic acid 0.2 mL
  • Step 1 Synthesis of methyl m-( ⁇ 8-acetyl-9a-[(2,4-dimethoxyphenyl)methyl]-2,9a-dimethyl-9- adenineyl ⁇ methyl)benzoate.
  • a mixture of methyl m-( ⁇ 8-acetyl-2-chloro-9a-[(2,4-dimethoxyphenyl)methyl]-9a-methyl-9- adenineyl ⁇ methyl)benzoate (0.2 g, 0.38 mmol, 1 eq, synthesized according to procedure described in synthesis of Compound 67) in 1,4-dioxane (2 mL)/water (0.4 mL) was added potassium trifluoro(methyl)boranuide (931 mg, 7.63 mmol, 20 eq.), [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (55.9 mg, 0.08 mmol, 0.2 eq.)
  • Step 2 Synthesis of methyl m-( ⁇ 9a-[(2,4-dimethoxyphenyl)methyl]-8-(1-hydroxyethyl)-2,9a- dimethyl-9-adenineyl ⁇ methyl)benzoate.
  • Step 3 Synthesis of m-( ⁇ 9a-[(2,4-dimethoxyphenyl)methyl]-8-(1-hydroxyethyl)-2,9a-dimethyl- 9-adenineyl ⁇ methyl)benzoic acid.
  • Step 4 Synthesis of m- ⁇ [8-(1-hydroxyethyl)-2,9a-dimethyl-9-adenineyl]methyl ⁇ benzoic acid.
  • Step 1 Synthesis of 9a-[(2,4-dimethoxyphenyl)methyl]-9a-methyl-2-vinyladenine To a mixture of 2-chloro-9a-[(2,4-dimethoxyphenyl)methyl]-9a-methyladenine (2 g, 5.99 mmol, 1.0 eq., synthesized according to procedure described in synthesis of Compound 66) and 4,4,5,5-tetramethyl-2-vinyl-1 ,3,2-dioxaborolane (2.21 g, 14.4 mmol, 2.4 eq., cas:75927- 49-0.
  • Step 2 Synthesis of 9-[(m-chlorophenyl)methyl]-9a-[(2,4-dimethoxyphenyl)methyl]-9a- methyl-2-vinyladenine.
  • 9a-[(2,4-dimethoxyphenyl)methyl]-9a-methyl-2-vinyladenine (1 g, 3.07 mmol, 1.0 eq.) and m-chloro(chloromethyl)benzene (544 mg, 3.38 mmol, 1.1 eq., cas:620-20-2) in dimethylformamide (10 mL) was added K2CO3 (1.27 g, 9.22 mmol, 3 eq.) at 20°C.
  • K2CO3 1.27 g, 9.22 mmol, 3 eq.
  • Step 3 Synthesis of 9-[(m-chlorophenyl)methyl]-9a-[(2,4-dimethoxyphenyl)methyl]-9a- methyl-2-adenineecarbaldehyde.
  • Step 4 Synthesis of 9-[(m-chlorophenyl)methyl]-2-(difluoromethyl)-9a-[(2,4- dimethoxyphenyl)methyl]-9a-methyladenine.
  • Step 5 Synthesis of 9-[(m-chlorophenyl)methyl]-2-(difluoromethyl)-9a-methyladenine.
  • Step 1 Synthesis of 2-chloro-9-[(m-chlorophenyl)methyl]-9a-[(2,4-dimethoxyphenyl)methyl]- 9a-methyladenine.
  • Step 2 Synthesis of 9-[(m-chlorophenyl)methyl]-9a-[(2,4-dimethoxyphenyl)methyl]-2- ⁇ [(2,4- dimethoxyphenyl)methyl]amino ⁇ -9a-methyladenine.
  • Step 3 Synthesis of 9-[(m-chlorophenyl)methyl]-9a-methyl-2-adenineamine.
  • Step 1 Synthesis of tert-butyl ( ⁇ m-[(mesyloxy)methyl]phenyl ⁇ methyl)carbamate .
  • Step 2 Synthesis of [o-( ⁇ 2-chloro-9a-methyl-9a-[(3,4-xylyl)methyl]-9- adenineyl ⁇ methyl)phenyl]methyl 2-methyl-2-propanecarbamate.
  • Step 3 Synthesis of ⁇ o-[(2-chloro-9a-methyl-9-adenineyl)methyl]phenyl ⁇ methanamine.
  • Step 1 Synthesis of [o-(2-aminoethyl)phenyl]methanol.
  • Step 3 Synthesis of tert-butyl (2- ⁇ o-[(mesyloxy)methyl]phenyl ⁇ ethyl)carbamate.
  • Step 4 Synthesis of 2-[o-( ⁇ 2-chloro-9a-[(2,4-dimethoxyphenyl)methyl]-9a-methyl-9- adenineyl ⁇ methyl)phenyl]ethyl 2-methyl-2-propanecarbamate.
  • Step 5 Synthesis of 2- ⁇ o-[(2-chloro-9a-methyl-9-adenineyl)methyl]phenyl ⁇ ethanamine.
  • Step 1 Synthesis of methyl o-[(E)-2-cyanoethenyl]benzoate.
  • (diethoxyphosphoryl)acetonitrile 3.56 g, 20.1 mmol, 1.1 eq., cas:2537-48-6) in tetrahydrofuran (30 mL) was added sodium hydride (570 mg, 23.8 mmol, 1.3 eq.) in portions at 0°C.
  • the mixture was stirred for 0.5h and methyl o-formylbenzoate (3 g, 18.3 mmol, 1.0 eq., cas:4122-56-9) was added dropwise and the mixture continued stirring at 25°C for 16h.
  • Step 2 Synthesis of methyl o- ⁇ 3-[(tert-butyl)(oxycarbonylamino)]propyl ⁇ benzoate and methyl o-(2-cyanoethyl)benzoate.
  • Step 3 Synthesis of tert-butyl (3-(2-(hydroxymethyl)phenyl)propyl)carbamate and [o-(3- aminopropyl)phenyl]methanol .
  • Step 4 Synthesis of 3-[o-(hydroxymethyl)phenyl]propyl 2-methyl-2-propanecarbamate.
  • Step 5 Synthesis of tert-butyl (3- ⁇ o-[(mesyloxy)methyl]phenyl ⁇ propyl)carbamate.
  • Step 6 Synthesis of 3-[o-( ⁇ 2-chloro-9a-[(2,4-dimethoxyphenyl)methyl]-9a-methyl-9- adenineyl ⁇ methyl)phenyl]propyl 2-methyl-2-propanecarbamate.
  • Step 7 Synthesis of 3- ⁇ o-[(2-chloro-9a-methyl-9-adenineyl)methyl]phenyl ⁇ -1-propanamine.
  • Step 1 Synthesis of [m-(2-aminoethyl)phenyl]methanol.
  • Step 2 Synthesis of 2-[m-(hydroxymethyl)phenyl]ethyl 2-methyl-2-propanecarbamate.
  • Step 3 Synthesis of tert-butyl (2- ⁇ m-[(mesyloxy)methyl]phenyl ⁇ ethyl)carbamate.
  • Step 4 Synthesis of 2-[m-( ⁇ 2-chloro-9a-[(2,4-dimethoxyphenyl)methyl]-9a-methyl-9- adenineyl ⁇ methyl)phenyl]ethanamine.
  • Step 1 Synthesis of methyl m-[(E)-2-cyanoethenyl]benzoate.
  • Step 3 Synthesis of 3-[m-(hydroxymethyl)phenyl]propyl 2-methyl-2-propanecarbamate.
  • Step 4 Synthesis of tert-butyl (3- ⁇ m-[(mesyloxy)methyl]phenyl ⁇ propyl)carbamate.
  • Step 5 Synthesis of 3-[m-( ⁇ 2-chloro-9a-[(2,4-dimethoxyphenyl)methyl]-9a-methyl-9- adenineyl ⁇ methyl)phenyl]-1-propanamine.
  • Step 6 Synthesis of 3- ⁇ m-[(2-chloro-9a-methyl-9-adenineyl)methyl]phenyl ⁇ -1-propanamine.
  • Step 1 Synthesis of 2-(benzyloxy)-9-[(m-chlorophenyl)methyl]-9a-[(2,4- dimethoxyphenyl)methyl]-9a-methyladenine.
  • Step 2 Synthesis of 9-[(m-chlorophenyl)methyl]-9a-methyl-2-adenineol.
  • Step 1 Synthesis of 2-((2-chloro-6-((2,4-dimethoxybenzyl)(methyl)amino)-9H-purin-9- yl)methyl)benzonitrile.
  • Step 2 Synthesis of 9-(2-(1 H-tetrazol-5-yl)benzyl)-2-chloro-N-(2,4-dimethoxybenzyl)-N- methyl-9H-purin-6-amine.
  • Step 3 Synthesis of 9-(2-(1 H-tetrazol-5-yl)benzyl)-2-chloro-N-methyl-9H-purin-6-amine.
  • Step 1 Synthesis of 3-bromo-5-chloro-N-(2,4-dimethoxybenzyl)-N-methyl-2H-pyrazolo[4,3- d]pyrimidin-7-amine.
  • Step 2 Synthesis of 3-bromo-5-chloro-N-(2,4-dimethoxybenzyl)-N-methyl-2-((2- (trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine.
  • Step 3 Synthesis of 5-chloro-3-(3-chlorobenzyl)-N-(2,4-dimethoxybenzyl)-N-methyl-2-((2- (trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine.
  • Step 4 Synthesis of 5-chloro-3-(3-chlorobenzyl)-N-methyl-2H-pyrazolo[4,3-d]pyrimidin-7- amine.
  • Step 2 Synthesis of N-methyl[5-chloro-3-(cyclopropylmethyl)-2H-1,2,4,6-tetraazainden-7- yl]amine
  • Step 2 Synthesis of 5-chloro-3-(cyclohexylmethyl)-N-methyl-2H-pyrazolo[4,3-d]pyrimidin-7- amine.
  • Step 1 Synthesis of 5-chloro-N-(2,4-dimethoxybenzyl)-3-(3-fluorobenzyl)-N-methyl-2-((2- (trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine.
  • Step 2 Synthesis of 5-chloro-3-(3-fluorobenzyl)-N-methyl-2H-pyrazolo[4,3-d]pyrimidin-7- amine.
  • Step 1 Synthesis of [(2,4-dimethoxyphenyl)methyl]-N-methyl ⁇ 5-chloro-3-[(2- naphthyl)methyl]-2- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -2H-1 ,2,4,6-tetraazainden-7-yl ⁇ amine.
  • Step 2 Synthesis of N-methyl ⁇ 5-chloro-3-[(2-naphthyl)methyl]-2H-1 ,2,4,6-tetraazainden-7- yljamine.
  • Step 1 Synthesis of 5-chloro-N-(2,4-dimethoxybenzyl)-N-methyl-3-(3- (trifluoromethyl)benzyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-d]pyrimidin-7- amine.
  • Step 1 Synthesis of (E)-5-chloro-3-(4-chlorostyryl)-N-(2,4-dimethoxybenzyl)-N-methyl-2-((2- (trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine.
  • Step 2 Synthesis of 5-chloro-3-(4-chlorophenethyl)-N-(2,4-dimethoxybenzyl)-N-methyl-2-((2- (trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine.
  • Step 3 Synthesis of 5-chloro-3-(4-chlorophenethyl)-N-methyl-2H-pyrazolo[4,3-d]pyrimidin-7- amine.
  • Step 1 Synthesis of [(2,4-dimethoxyphenyl)methyl]-N-methyl(3-benzyl-5-chloro-2- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ -2H-1 ,2,4,6-tetraazainden-7-yl)amine.
  • Step 2 Synthesis of N-methyl(3-benzyl-5-chloro-2H-1 ,2,4,6-tetraazainden-7-yl)amine.
  • Step 2 Synthesis of N-methyl(5-chloro-3-phenyl-2H-1 ,2,4,6-tetraazainden-7-yl)amine.
  • Step 1 Synthesis of [(2,4-dimethoxyphenyl)methyl]-N-methyl[5-chloro-3-(2-pyridyl)-2- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ -2H-1,2,4,6-tetraazainden-7-yl]amine.
  • Step 2 Synthesis of N-methyl[5-chloro-3-(2-pyridyl)-2H-1,2,4,6-tetraazainden-7-yl]amine.
  • Step 1 Synthesis of [(2,4-dimethoxyphenyl)methyl]-N-methyl[5-chloro-3-(1-methyl-4- pyrazolyl)-2- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -2H-1 ,2,4,6-tetraazainden-7-yl]amine.
  • Step 2 Synthesis of N-methyl[5-chloro-3-(1-methyl-4-pyrazolyl)-2H-1 ,2,4,6-tetraazainden-7- yl]amine.
  • Step 1 Synthesis of [(2,4-dimethoxyphenyl)methyl]-N-methyl[5-chloro-3-(1-methyl-3- pyrazolyl)-2- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -2H-1 ,2,4,6-tetraazainden-7-yl]amine.
  • Step 2 Synthesis of N-methyl[5-chloro-3-(1-methyl-3-pyrazolyl)-2H-1 ,2,4,6-tetraazainden-7- yl]amine
  • Step 1 Synthesis of [(2,4-dimethoxyphenyl)methyl]-N-methyl[5-chloro-3-(3-pyridyl)-2- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ -2H-1 ,2,4,6-tetraazainden-7-yl]amine.
  • Step 2 Synthesis of N-methyl[5-chloro-3-(3-pyridyl)-2H-1 ,2,4,6-tetraazainden-7-yl]amine.

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Abstract

La présente invention concerne un composé de formule (I) ou (II), (I), (II) destiné à être utilisé en tant que médicament dans le traitement du cancer.
PCT/EP2023/082044 2022-11-16 2023-11-16 Ligands des lecteurs d'arn m6a Ceased WO2024105159A1 (fr)

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