WO2018118868A1 - Dérivés de triazole utilisés en tant qu'inhibiteurs de tankyrase - Google Patents

Dérivés de triazole utilisés en tant qu'inhibiteurs de tankyrase Download PDF

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Publication number
WO2018118868A1
WO2018118868A1 PCT/US2017/067228 US2017067228W WO2018118868A1 WO 2018118868 A1 WO2018118868 A1 WO 2018118868A1 US 2017067228 W US2017067228 W US 2017067228W WO 2018118868 A1 WO2018118868 A1 WO 2018118868A1
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Prior art keywords
compound
mmol
general formula
pharmaceutically acceptable
methyl
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PCT/US2017/067228
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English (en)
Inventor
Stefan Krauss
Marc Nazare
Upendra Rao ANUMALA
Lari LEHTIO
Jo Waaler
Dan Holsworth
Anita Wegert
Ruben Gerardus George Leenders
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Oslo University Hospital Hf
Forschungsverbund Berlin E.V.
University Of Oulu
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Priority to RU2019121618A priority Critical patent/RU2019121618A/ru
Publication of WO2018118868A1 publication Critical patent/WO2018118868A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to compounds, to pharmaceutical formulations containing such compounds and to their use in therapy, in particular as WNT signaling pathway inhibitors for reducing the proliferation of tumor cells and metastasis and causing an enhanced effect of immunotherapy.
  • the invention further relates to processes for the preparation of such compounds and to intermediates formed during these processes.
  • the WNT family of glycoproteins control a variety of developmental processes including cell fate specification, proliferation, metabolism, migration and immune response. Consequently, the WNT pathway is instrumental in ensuring proper tissue development in embryos and tissue maintenance in adults.
  • WNT signaling is altered in a variety of tumors including tumors emerging from colorectal tissue, uterus, pancreas, skin, liver, thyroid, prostate, ovary, stomach, lung, lymphoid, bladder, brain, breast and kidney.
  • About 90%» of sporadic colon cancers show aberrant WNT signaling whereby mutations in the adenomatous polyposis coli gene (APC), ⁇ -catenin, or Axin genes lead to accumulation of nuclear ⁇ - catenin and hence an activation of the pathway.
  • APC adenomatous polyposis coli gene
  • Blocking canonical WNT activity in WNT deregulated cancers has been shown to cause cell cycle arrest in Gl , altered cellular energy metabolism and an altered differentiation status.
  • Evidence also suggests an involvement of WNT/ -Catenin signaling in the interplay between cancer cells and the immune system.
  • Tankyrase 1 and 2 are members of the poly-ADP-ribose polymerase (PARP) family of enzymes.
  • PARP poly-ADP-ribose polymerase
  • Tankyrase 1/2 has been identified as a positive regulator of the WN T signaling pathway via its interaction with AXIN protein.
  • the inhibition of tankyrase 1/2 produces elevated AXIN protein levels and reduced levels of cellular ⁇ -catenin even in the absence of a functional APC protein. It has been hypothesised that the inhibition of tankyrase 1/2 may offer a novel approach to the treatment of WNT signaling-related diseases such as a variety of cancers including colon cancer and non-small cell lung cancer and fibrotic diseases.
  • Tankyrase also regulates the stability and activity of other target proteins, hence tankyrase inhibitors may also act through WNT independent mechanism.
  • Such compounds are thus suitable for inhibiting tumor cells in general and, in particular, those associated with colorectal cancers, non-small cell lung cancer, breast cancer, CNS cancers, ovary cancer, liver cancer, melanoma and pancreatic adenocarcinoma.
  • the compounds described herein demonstrate greater solubility and/or lower IC 50 values than other known WNT inhibitors based on a triazole core, such as those described in WO 2010/139966 and WO 2012/076898, thereby further improving their suitability for use as active pharmaceutical ingredients.
  • Their improved solubility is advantageous for parenteral administration, e.g. intravenous injection.
  • Z represents an optionally substituted, 5- or 6-membered unsaturated heterocyclic group comprising at least one nitrogen atom
  • L represents a 4-, 5- or 6-membered cycloalkyl group, preferably a cyclobutyl group
  • each R 1 independently represents F, Cl, Br, I, C1-3 alkyl, C1-3 haloalkyl (e.g. -CF3), -CN, -OH or -NO 2 , preferably F, Cl, Br or I, e.g. Cl or F;
  • each R 2 independently represents F, Cl, Br, I, C1-3 alkyl, -CN, -OH or -NO2, preferably F, Cl, Br, I or -CN, e.g. F or -CN;
  • X represents -NR 3 - or -O-;
  • R 3 represents H or a C 1-3 alkyl group (e.g. methyl);
  • n is an integer from 0 to 5, preferably 0 to 3, more preferably 0, 1 or 2, e.g 1; and m is an integer from 0 to 5, preferably 0 to 3, more preferably 0, 1 or 2, e.g.0 or 1;
  • Z represents a 5- or 6-membered unsaturated heterocyclic group comprising at least one nitrogen atom
  • L represents a 4-, 5- or 6-membered cycloalkyl group, preferably a cyclobutyl group
  • each R 1 independently represents F, Cl, Br, I, C1-3 alkyl, -CN, -OH or -NO2, preferably F, Cl, Br or I, e.g. Cl;
  • each R 2 independently represents F, Cl, Br, I, C1-3 alkyl, -CN, -OH or -NO2, preferably F, Cl, Br, I or -CN, e.g. F or -CN;
  • R 3 represents H or a C1-3 alkyl group (e.g. methyl);
  • n is an integer from 0 to 5, preferably 0 to 3, more preferably 0, 1 or 2, e.g 1; and m is an integer from 0 to 5, preferably 0 to 3, more preferably 0, 1 or 2, e.g.0 or 1;
  • Preferred groups Z in the compounds of formulae (I’) and (I) are 5- or 6-membered unsaturated heterocyclic groups comprising two nitrogen atoms such as pyrazolyl, imidazolyl, pyrazolinyl, imidazolinyl, pyridazinyl, pyrimidinyl, or pyrazinyl groups.
  • Z is a pyrimidinyl group.
  • group Z in the compounds of formulae (I’) and (I) is a thiazolyl group, e.g. a 2-thiazolyl or 5-thiazolyl group.
  • any of the Z groups herein described may be substituted by one or more ring substituents. Where the Z groups are substituted, it is preferred that these are substituted by one or two substituent groups, e.g. by one substituent. Suitable substituents are as herein described and include, for example, C1-3 alkyl and C1-3 alkoxy groups. In one embodiment, the Z groups are unsubstituted.
  • Preferred compounds in accordance with the invention are those of general formulae (II) and (III):
  • R 1 , R 2 , R 3 , Z, n and m are as defined herein.
  • Particularly preferred compounds of formula (II) are those of formula (IIa):
  • Particularly preferred compounds of formula (III) are those of formula (IIIa):
  • group R 2 is absent or that a single group R 2 is present on the benzimidazole or benzoxazole ring. In the case where a single group R 2 is present on the benzimidazole ring, this is preferably located as follows:
  • the compounds of the invention are compounds of formula (IV):
  • R 1 , R 2 , R 3 and Z are as defined herein, and n is 0 or 1.
  • Preferred compounds of formula (IV) are those of general formulae (V) and (VI):
  • n is 0 (i.e. the phenyl ring is unsubstituted) or that n is 1 and group R 1 is either Cl or F.
  • m is 0 (i.e. the benzimidazole or benzoxazole ring is unsubstituted) or that m is 1 and group R 2 is Cl, F, or - CN.
  • n is 0 or 1 and R 1 is Cl or F
  • m is 0 or 1 and R 2 is Cl, F or -CN.
  • n 1, m is 1, R 1 is Cl and R 2 is -CN. In certain embodiments, n is 1, m is 1, R 1 is Cl and R 2 is F. In certain embodiments,
  • n is 1, m is 0 and R 1 is Cl.
  • R 3 is H and R 1 , R 2 , L, Z, n and m are as herein described.
  • n is 0 or 1
  • m is 0 or 1
  • R 1 is Cl or F
  • R 2 is Cl, F or -CN
  • R 3 is H
  • n is 1, m is 1, R 1 is Cl, R 2 is -CN, and R 3 is H.
  • n is 1, m is 1, R 1 is Cl, R 2 is F, and R 3 is H.
  • n is 1, m is 0, R 1 is Cl, and R 3 is H.
  • R 3 is methyl and groups R 1 , R 2 , L, Z, n and m are as herein described.
  • n is 0 or 1
  • m is 0 or 1
  • R 1 is Cl or F
  • R 2 is Cl, F or -CN
  • R 3 is methyl
  • n is 1, m is 1, R 1 is Cl, R 2 is -CN, and R 3 is methyl.
  • n is 1, m is 1, R 1 is Cl, R 2 is F, and R 3 is methyl.
  • R 3 is methyl.
  • n is 1, m is 0, R 1 is Cl, and R 3 is methyl.
  • the compounds described herein may exist in various stereoisomeric forms, including enantiomers, diastereomers, and mixtures thereof.
  • the invention encompasses all optical isomers of the compounds described herein and mixtures of optical isomers. Hence, compounds that exist as diastereomers, racemates and/or
  • the invention extends to the enantiomers, diastereomers, and mixtures of diastereomers and/or enantiomers, of any of the compounds having a chiral centre in the group L.
  • linker L is bound to both the triazole- derived moiety and to the benzimidazole or benzoxazole-derived moiety.
  • the bonds between the linker L and the remainder of the molecule i.e. the bond to the triazole-derived moiety and to the benzimidazole or benzoxazole-derived moiety
  • the compounds have the following stereochem istr :
  • Examples of preferred compounds in accordance with the invention include the following, their tautomers, stereoisomers, and pharmaceutically acceptable salts:
  • Compound No. (6) in accordance with the invention preferably has the following stereochemistry:
  • Compound No. (2) in accordance with the invention preferably has the following stereochemistry:
  • Compound No. (4) in accordance with the invention preferably has the following stereochemistry:
  • Compound No. (5) in accordance with the invention preferably has the following stereochemistry:
  • C 1-3 alkyl refers to a saturated hydrocarbon group having one to three carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, and iso-propyl.
  • C1-3 alkoxy refers to an -O-C1-3 alkyl group. Examples of such groups include methoxy, ethoxy and propyloxy.
  • C1-3 haloalkyl refers to a C1-3 alkyl group having one or more halo substituents. Examples of such groups include -CH 2 F, -CHF 2 , -CF 3 , -CCl 3 , - CHCl2,
  • cycloalkyl refers to a saturated, cyclic hydrocarbon group. Examples of such groups which may be present in the compounds herein described include cyclobutyl, cyclopentyl, and cyclohexyl groups.
  • the term "unsaturated heterocyclic group” is intended to cover any 5- or 6-membered, mono-, di or tri-unsaturated heterocyclic ring which contains at least one nitrogen atom. Additional heteroatoms selected from nitrogen, oxygen and sulphur may also be present, although it is preferred that no oxygen or sulphur atoms are present.
  • the heterocyclic group may contain one or two nitrogen atoms, e.g. two nitrogen atoms.
  • the heterocyclic ring structure may be linked to the remainder of the molecule through a carbon atom or through a nitrogen atom. Preferably it will be linked to the remainder of the molecule through a carbon atom.
  • the unsaturated heterocyclic group may be aromatic or non-aromatic.
  • any unsaturated heterocyclic group mentioned herein may optionally be substituted by one or more groups, which may be identical or different.
  • substituent groups include, but are not limited to, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, amino, -CN, -NO 2 , and halogen atoms (e.g. F, Cl or Br).
  • Preferred substituents include C1-3 alkyl (e.g. methyl) and C1-3 alkoxy (e.g. methoxy and ethoxy) groups.
  • unsaturated heterocyclic rings are the heterocycles pyrrole, 2H-pyrrole, pyrroline, pyrazole, imidazole, oxazole, isoxazole, pyrazoline, imidazoline, thiazole, isothiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and triazole.
  • pyrazole, imidazole, pyrazoline, imidazoline, pyridine, pyridazine, pyrimidine and pyrazine are preferred, particularly preferably pyrimidine and pyridine.
  • the compounds according to the invention may be prepared from readily available starting materials using synthetic methods known in the art. Preferably, the compounds are obtained in accordance with the following method which forms part of the invention:
  • the method described above may be used to prepare any compound of formula (I’) or (I) (including compounds of formula (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va), (VI), or (VIa)) as herein described.
  • reaction of the compound of formula (VII) with the compound of formula (VIII) or (VIII’) is conveniently carried out in a solvent or mixture of solvents, such as for example a polar solvent such as acetonitirile, acetone, DMF, DMSO, toluene or dioxane or mixtures thereof.
  • a solvent or mixture of solvents such as for example a polar solvent such as acetonitirile, acetone, DMF, DMSO, toluene or dioxane or mixtures thereof.
  • Toluene is a preferred solvent.
  • the reaction may suitably be carried out under reflux conditions, typically for a time from 12 hours to 2.5 days (e.g.16 hours, 24 hours or 48 hours).
  • R 3 is C 1-3 alkyl (e.g. methyl)
  • this may be introduced by first reacting a compound of formula (VII) with a compound of formula (VIII) wherein R 3 is hydrogen, followed by introduction of a C 1-3 alkyl group into the reaction product such that the C 1-3 alkyl R 3 group replaces the initially-present R 3 hydrogen atom.
  • the C1-3 alkyl (e.g. methyl) group may be introduced using standard techniques known to those skilled in the art, such as deprotonation using a suitable base such as potassium carbonate followed by reaction with a suitable alkylating agent, e.g. methyl iodide.
  • the step of replacing the R 3 hydrogen with an R 3 group which is a C1-3 alkyl (e.g. methyl) group may suitably be carried out after step (a), e.g. immediately following step (a), prior to step (b), prior to step (c), after step (b) or even after step (c) of the method as described above.
  • a compound of formula (VIII) wherein R 3 is C1-3 alkyl may be prepared according to the methods described herein, prior to reaction of the compound of formula (VIII) with the compound of formula (VII).
  • groups L, Z, R 1 , R 2 , R 3 , n and m can be any such group or combination of groups as hereinbefore described with reference to the compounds of general formula (I’), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va), (VI), or (VIa).
  • the compound of general formula (VII) may be obtained by the following method which forms part of the invention:
  • Step (aa) may suitably be performed under conventional amide formation conditions known to those skilled in the art.
  • the compounds of formulae (IX) and (X) may be reacted in the presence of SOCl2 at a temperature of up to 100oC (e.g.80oC) for a period of 1 to 5 hours (e.g.2 hours) followed by reaction with DMAP (4-dimethylaminopyridine) and TEA (triethylamine) in THF (tetrahydrofuran) at a temperature of up to 60oC (e.g.50oC) for a period of 12 hours or more (e.g.2 days).
  • SOCl2 a temperature of up to 100oC (e.g.80oC) for a period of 1 to 5 hours (e.g.2 hours)
  • DMAP dimethylaminopyridine
  • TEA triethylamine
  • THF tetrahydrofuran
  • Step (bb) may be performed using a conventional thionylating agent known to those skilled in the art such as Lawesson’s reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4- dithiadiphosphetane-2,4-dithione) in a suitable solvent such as toluene.
  • a suitable solvent such as toluene.
  • about 0.5 to about 1 molar equivalent of the thionating agent may be employed.
  • the thionation reaction may suitably be performed at a temperature of up to 100oC (e.g.80oC) for a period of 12 to 24 hours (e.g.16 hours).
  • Step (cc) may be performed using a conventional methylation reaction known to those skilled in the art.
  • the compound of general formula (XII) may suitably be reacted with at least one molar equivalent of methyl iodide in the presence of a base such as sodium hydroxide, sodium carbonate, potassium hydroxide or potassium carbonate.
  • the compound of formula (VIII) may be obtained by the following method which forms part of the invention:
  • R 3’ is a C 1-3 alkyl (e.g. methyl) group
  • G denotes a suitable leaving group such as F or Cl.
  • Step (aaa) may suitably be performed in acetonitrile as the solvent and in the presence of a mild base such as potassium carbonate or sodium carbonate.
  • a mild base such as potassium carbonate or sodium carbonate.
  • this step may be carried out at a temperature of up to 100oC (e.g.80oC to 90oC or 75oC to 85oC) for a period of 12 to 48 hours (2 days) (e.g.16 hours or 24 hours (1 day)).
  • Step (bbb) may be performed using any suitable reduction reaction known to those skilled in the art.
  • reaction with SnCl2 in ethanol may be employed as the method of reduction, suitably at a temperature of up to 100oC (e.g.80oC to 90oC or 75oC to 85oC) for a period of 0.5 to 5 hours (e.g.1 hour to 2 hours, such as 1.5 hours).
  • suitable reduction reactions include, for example, palladium- catalysed reduction using aqueous potassium fluoride and polymethylhydrosiloxane or triethylsilane in the presence of Pd(OAc)2; or reaction with iron and CaCl2 in an
  • Step (ccc) may suitably be performed in acetonitrile as the solvent.
  • a temperature of up to 100oC (e.g.60oC) and a reaction time of 12 to 24 hours (e.g.16 hours) may suitably be employed.
  • the reaction can be performed at room temperature (e.g. between 15 and 25oC, such as at about 20oC) for a period of 16 to 24 hours, e.g.20 hours.
  • Step (ddd) when present, can be carried out using standard bases and alkylating agents known to those skilled in the art, such as potassium carbonate as base and methyl iodide as alkylating agent.
  • Any suitable solvent may be used, such as acetonitrile or dimethylformamide (DMF).
  • Step (eee) may suitably be performed using hydrazine in its monohydrate or dihydrate form.
  • Methanol or ethanol may suitably be employed as a solvent.
  • the reaction can be performed at room temperature (e.g. between 15 and 25oC, such as at about 20oC) for a period of 1 to 36 hours (e.g.1.5 hours to 24 hours, such as 2 to 20 hours, e.g.16 or 20 hours).
  • the reaction may be performed at a temperature of up to 100oC (e.g.85oC) and a reaction time of 1 to 36 hours (e.g.1.5 hours to 24 hours, such as 2 to 20 hours, e.g.16 or 20 hours) may suitably be employed.
  • the method of preparing a compound of formula (I’) or (I) may include a step of preparing a compound of formula (VII) and/or a step of preparing a compound of formula (VIII) or (VIII’) prior to carrying out the reaction of the compounds of formulae (VII) and (VIII) or (VIII’).
  • the preparation of the compound of formula (VII) and/or the compound of formula (VIII) or (VIII’) is performed in accordance with the methods described herein.
  • the compounds of general formulae (I’), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va), (VI), or (VIa) may be resolved into their enantiomers and/or diastereomers.
  • these may be provided in the form of a racemate or may be provided as pure enantiomers, i.e. in the R- or S-form.
  • Any of the compounds which occur as racemates may be separated into their enantiomers by methods known in the art, such as column separation on chiral phases or by recrystallisation from an optically active solvent.
  • Those compounds with at least two asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and where these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers.
  • the invention further extends to tautomers of any of the compounds herein disclosed.
  • certain compounds according to the invention may exist in tautomeric forms, i.e. in forms which readily interconvert by way of a chemical reaction which may involve the migration of a proton accompanied by a switch of a single bond and adjacent double bond.
  • R 3 is hydrogen
  • the compounds of the invention may, in particular, undergo keto-enol tautomerism.
  • the compounds may predominantly exist either in the keto or enol form and the invention is not intended to be limited to the particular form shown in any of the structural formulae given herein.
  • the compounds according to the invention may be converted into a salt thereof, particularly into a pharmaceutically acceptable salt thereof with an inorganic or organic acid or base.
  • Acids which may be used for this purpose include hydrochloric acid, hydrobromic acid, sulphuric acid, sulphonic acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid, acetic acid, trifluoroacetic acid and ascorbic acid.
  • Bases which may be suitable for this purpose include alkali and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or cesium hydroxide, ammonia and organic amines such as diethylamine, triethylamine, ethanolamine,
  • compositions comprising a compound of formula (I’), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va), (VI), or (VIa) as herein defined, or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers or excipients.
  • the compounds according to the invention and their pharmaceutically acceptable salts have valuable pharmacological properties, particularly an inhibitory effect on WNT/ß-catenin signaling through inhibition the adenosine binding site of the catalytic domain of tankyrase 1/2 and stabilization of the AXIN protein.
  • the compounds according to the invention and their pharmaceutically acceptable salts are suitable for the treatment and/or prevention of any condition or disease which may be affected by over- activation of signaling in the WNT pathway, in particular those conditions or diseases which involve activation of ß-catenin.
  • the compounds of the invention and their pharmaceutically acceptable salts also have valuable pharmacological properties through affecting other target proteins of tankyrase 1/2.
  • WNT signaling pathway is used to refer to the chain of events normally mediated by WNT, LRP (LDL-receptor related protein), Frizzled, AXIN and ß-catenin, among others, and resulting in changes in gene expression and other phenotypic changes typical of WNT activity.
  • LRP LRP-receptor related protein
  • Frizzled Frizzled
  • AXIN ß-catenin
  • the WNT pathway plays a central role in the pathology of a variety of cancers.
  • the compounds of the invention are thus particularly suitable for preventing and/or retarding proliferation and metastasis of tumor cells, in particular carcinomas such as
  • the compounds are effective in treatment and/or prevention of tumors emerging from colorectal tissue, uterus, pancreas, skin, liver, thyroid, prostate, ovary, stomach, lung, lymphoid, bladder, cervix, thyroid, head and neck, brain, breast and kidney.
  • the compounds herein described may be used in the treatment and/or prevention of colorectal cancer and non-small cell lung cancer.
  • the compounds according to the invention and their pharmaceutically acceptable salts have valuable pharmacological properties that may also be used for treatment or prevention of non-cancer indications that are influenced by the activity of tankyrase 1/2, dependent or independent of its impact on WNT signaling.
  • non-regenerative wound healing viral infections such as Herpes Simplex Virus infections, fibrosis such as pulmonary, dermal-, renal- and liver fibrosis, myocardial fibrosis, and metabolic conditions such as aberrant systemic glucose metabolism,
  • the term “proliferation” refers to cells undergoing mitosis.
  • the term “retarding proliferation” indicates that the compounds inhibit proliferation of a cancer cell.
  • “retarding proliferation” indicates that DNA replication is at least 10% less than that observed in untreated cells, more preferably at least 25% less, yet more preferably at least 50% less, e.g.75%, 90% or 95% less than that observed in untreated cancer cells.
  • carcinoma refers to any malignant growth which arises from epithelial cells.
  • exemplary carcinomas include basal cell carcinoma, squamous cell carcinoma and adenocarcinoma.
  • Adenocarcinomas are malignant tumors originating in the glandular epithelium and include colorectal, pancreatic, breast and prostate cancers.
  • the invention thus provides a compound of formula (I’), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va), (VI), or (VIa) as herein defined, or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, for use in therapy.
  • the term "therapy” as used herein is intended to include both treatment and prevention.
  • the invention provides a compound of formula (I’), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va), (VI), or (VIa) as herein defined, or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a tumor emerging from colorectal tissue, uterus, pancreas, skin, liver, thyroid, prostate, ovary, stomach, lung, lymphoid, bladder, cervix, thyroid, head and neck, brain, breast or kidney, in the treatment of non-regenerative wound healing, or in the treatment or prevention of viral infections such as Herpes Simplex Virus infections, fibrosis such as pulmonary-, dermal-, renal- and liver fibrosis, myocardial fibrosis, or metabolic conditions such as aberrant systemic glucose metabolism.
  • viral infections such as Herpes Simplex Virus infections, fibrosis such as pulmonary-, dermal-,
  • the invention provides the use of a compound of formula (I’), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va), (VI), or (VIa) as herein defined, or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method of treatment or prevention of a tumor emerging from colorectal tissue, uterus, pancreas, skin, liver, thyroid, prostate, ovary, stomach, lung, lymphoid, bladder, cervix, thyroid, head and neck, brain, breast or kidney, in the treatment of non-regenerative wound healing, or in the treatment or prevention of viral infections such as Herpes Simplex Virus infections, fibrosis such as pulmonary-, dermal-, renal- and liver fibrosis, myocardial fibrosis, or metabolic conditions such as aberrant systemic glucose metabolism.
  • viral infections such as Herpes Simplex Virus infections,
  • the present invention provides a method (e.g. an in vitro method) of promoting and/or directing cellular differentiation comprising contacting a progenitor cell with an effective amount of a compound of formula (I’), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va), (VI), or (VIa) as herein defined, or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof.
  • the progenitor cell is contacted with said at least one compound under suitable conditions and for a sufficient time for the progenitor cell to differentiate into a new cell type.
  • the present invention provides the use of at least one compound as herein defined for promoting and/or directing cellular differentiation of a progenitor cell, especially in vitro.
  • the progenitor cell is a totipotent or a pluripotent cell, especially a stem cell such as an embryonic stem cell.
  • a stem cell such as an embryonic stem cell.
  • mammalian progenitor cells such as mouse, rat and human cells, especially human cells.
  • Such stem cells may be obtained from established cell cultures or may be derived directly from mammalian tissue by methods known in the art, including non tissue-destructive methods.
  • the progenitor cell is promoted and/or directed to differentiate into a new cell type which is a myocyte (e.g. a cardiomyocyte), a neuronal cell (e.g. a dopaminergic neuronal cell), an endocrine pancreatic cell or a hepatocyte or a cell type which may further differentiate into a myocyte, a neuronal cell, an endocrine pancreatic cell or a hepatocyte.
  • the progenitor cell is an embryonic stem cell and the new cell type is a cardiomyocyte, a dopaminergic neuronal cell, an endocrine pancreatic cell, a hepatocyte, or a cardiomyocyte.
  • the dosage required to achieve the desired activity of the compounds herein described will depend on the compound which is to be administered, the patient, the nature and severity of the condition, the method and frequency of administration and may be varied or adjusted according to choice. Typically, the dosage may be expected to be in the range from 1 to 100 mg, preferably 1 to 30 mg (when administered intravenously) and from 1 to 1000 mg, preferably from 1 to 200 mg (when administered orally).
  • compositions may be formulated with one or more conventional carriers and/or excipients according to techniques well known in the art.
  • the compositions will be adapted for oral or parenteral administration, for example by intradermal, subcutaneous, intraperitoneal or intravenous injection.
  • Suitable pharmaceutical forms thus include plain or coated tablets, capsules, suspensions and solutions containing the active component optionally together with one or more conventional inert carriers and/or diluents, such as corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propylene glycol, stearylalcohol,
  • inert carriers and/or diluents such as corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propylene glycol, stearylalcohol,
  • Topical compositions include gels, creams, ointments, sprays, lotions, salves, sticks, powders, pessaries, suppositories, aerosols, drops, solutions and any of the other conventional pharmaceutical forms in the art.
  • Topical administration to inaccessible sites may be achieved by techniques known in the art, e.g. by use of catheters or other appropriate drug delivery systems.
  • the compounds may suitably be formulated in a form for parenteral administration, e.g. for intravenous injection.
  • parenteral administration e.g. for intravenous injection.
  • sterile solutions containing the active compounds may be employed.
  • the pharmacological properties of the compounds of the invention can be analysed using standard assays for functional activity. Detailed protocols for testing of the compounds of the invention are provided in the Examples.
  • Figure 1 shows solubility as a function of concentration for Compound (6)
  • Figure 2 shows in vivo concentrations of Compound (6) as a function of time in a mouse pharmacokinetic model when administered orally or intravenously.
  • Trifluoroacetic acid (27.8 ⁇ l) was added and the reaction mixture was heated at 120 o C for 14 hours. After cooling down to room temperature, the reaction mixture was filtered and the residue washed with dichloromethane and methanol. The filtrate was concentrated under reduced pressure to remove the methanol and dichloromethane. A mixture of water and dichloromethane was added and the reaction mixture portioned using a separating funnel. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of dichloromethane / methanol. The fractions containing the product were combined and the solvent evaporated under reduced pressure to yield the title compound (1). Yield: 72 mg. (21%)
  • the crude solid was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield compund (3) as a white solid. The product was obtained as its trifluoracetate salt. Yield: 46 mg. (16%).
  • cyclobutanecarbohydrazide (68.5 mg, 0.25 mmol) was added to a solution of N-(2- chlorophenyl)pyrimidine-4-carboiminethiomethyl (80 mg, 0.30 mmol) in N,N- dimethylacetamide (2 ml).
  • Trifluoroacetic acid (9.6 ⁇ l, 0.125 mmol) was added and the reaction mixture was heated to 120 o C for 14 hours. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure.
  • 4-pyrimidinecarboxylic acid 1 and 2-chloroaniline 2 were reacted for 2 hours at 80oC with SOCl2 and then reacted for 2 days at 50oC with DMAP and TEA in THF, producing 1 of ure com ound 3 and 0.5 of im urities.
  • 1.02 g of pure compound 3 were separated and then reacted with Lawesson’s reagent i toluene at 80oC for 16 hours, yielding 0.6 g of compound 4: reflux
  • Plasmids, constructs, cell lines and conditioned media Plasmids, constructs, cell lines and conditioned media:
  • the L WNT3a-expressing cells were purchased from ATCC (American Type Culture Collection) and, including ST-Luc/Ren HEK293 cells (see below), maintained according to the supplier’s recommendations.
  • a stable HEK293 cell line containing SuperTOP-Flash plasmid (ST-Luc HEK293) (7 X TCF binding sites promoter) was kindly provided by V. Korinek.
  • ST-Luc HEK293 7 X TCF binding sites promoter
  • the pRL-TK (Renilla, Promega) cassette was subcloned into pPUR (Promega) giving rise to the construct pRL-TK-puro.
  • Linearized pRL-TK-puro was transfected (FuGENE6, Roche) into ST-Luc HEK293 before selection (2.5 ⁇ g/mL Puromycin, Sigma).
  • WNT3a containing conditioned media (WNT3a-CM) from L WNT3a expressing cells was collected as described by ATCC. Transfection and luciferase assays:
  • ST-Luc/Ren HEK293 cells were seeded in 96-well plates coated with poly-L lysine. 24 hours after seeding, the cells were incubated for an additional 24 hours with various compound concentrations in 50 % WNT3a-CM. After compound exposures, the cells were lysed and the firefly luciferase and Renilla activities were measured on a GloMax® Luminometer (Promega) using Dual-Glo Luciferase Assay System (Promega).
  • TNKS human TNKS
  • the proteins used in the assays were ARTD5/TNKS1 (residues 1030-1317), ARTD6/TNKS2 (residues 873-1162).
  • the inhibitor potencies were measured with a fluorescence based activity assay (see Narwal et al., 2012 supra).
  • the potencies of the compounds were measured using half log dilutions of the inhibitors and the reactions were done in quadruplicates with protein and inhibitor controls to exclude the effect of autofluorescence.
  • the fluorescence intensity was measured using Tecan Infinity M1000 with excitation/emission wavelengths of 372 nm and 444 nm, respectively.
  • Sigmoidal dose response curves were fitted with four variables using GraphPad Prism version 5.04 for Windows (GraphPad Software).
  • the turbidimetric (kinetic) solubility of Compound (6) was determined as follows. Serial dilutions of Compound (6) were prepared in DMSO at 100 times the final concentration. Test article solutions were diluted 100-fold into PBS buffer in a 96-well plate and mixed. After 2 hours of incubation at 37oC, the presence of precipitate was detected by turbidity (measured by determination of absorbance at 540 nm). Precipitate is formed when maximum aqueous solubility levels are reached.
  • test article Compound (6)
  • 5% DMSO, 50% PEG400, 45% saline was dissolved in 5% DMSO, 50% PEG400, 45% saline to yield a nominal concentration of 0.2 mg/mL for intravenous administration and 0.5 mg/mL for oral administration.
  • the resulting solution (pH ⁇ 7) was clear and colorless solution and was stored at room temperature until picked up for dosing.
  • Blood samples (approximately 500 ⁇ L) were collected via cardiac puncture after euthanasia by carbon dioxide inhalation post-dose (15 min, 1 h, 4 h, 8 h and 24 h). One sample was collected per animal at each time point. Blood samples were placed into tubes containing K2EDTA and centrifuged at 8000 rpm for 6 minutes at 4qC to separate plasma from the samples. Following centrifugation, the resulting plasma was transferred to clean tubes and stored frozen at -80qC pending bioanalysis.
  • AUC (0-t) and AUC (0- ⁇ ) are standard set of parameters including Area Under the Curve (AUC (0-t) and AUC (0- ⁇ ) ), elimination half-life (T1/2), maximum plasma concentration (Cmax), initial concentration (C0), time to reach maximum plasma concentration (T max ), clearance (CL), and steady-state volume of distribution (Vss) were calculated using noncompartmental analysis modules in the FDA certified pharmacokinetic program WinNonlin Professional (Pharsight, USA). Furthermore, the bioavailability was estimated using the following formula:
  • Plasma and brain concentrations from individual animals are tabulated in Table 5.
  • the estimates of the non-compartmental pharmacokinetics parameters are summarized in Table 6.
  • Log-linear plots of the plasma and brain concentration versus time curves are presented in Figure 2.
  • Tmax and Cmax were 0.25 hr and 77.58 ng/mL.
  • the mean values of AUC(0- ⁇ ) were 62.93 hr*ng/mL.
  • Tmax and Cmax were 0.25 hr and 123.48 ng/mL.
  • the mean half-life (T1 ⁇ 2) was 1.51 hr, the mean values of AUC (0-t) and AUC (0- ⁇ ) were 144.66 and 146.97 hr*ng/mL.
  • the CL was 34.02 L/kg.
  • the bioavailability was 46.71%.
  • Table 5 Selected pharmacokinetics parameters of Compound (6) in ICR Mice following intravenous and oral administration
  • the assay was performed by Medicilon (CN) according to their protocols.
  • Compound (6) was dissolved in 5% DMSO, 50% PEG400, 45% saline to yield a nominal concentration of 0.7 mg/mL for intravenous administration and 1.4 mg/mL for oral administration to rats as follows:
  • Blood samples (approximately 200 ⁇ L) were collected via jugular vein at appropriate time points for determination of plasma concentrations. Blood samples were placed into tubes containing K2EDTA and centrifuged at 3500 rpm for 10 minutes at 4 o C to separate plasma from the samples. Following centrifugation, the resulting plasma was transferred to clean tubes and stored frozen at -80 o C pending bioanalysis. Standard set of parameters including Area Under the Curve (AUC(0-t) and AUC(0- ⁇ )), elimination half-life (T1/2), maximum plasma concentration (Cmax), initial concentration (C0), time to reach maximum plasma concentration (Tmax), clearance (CL), and steady-state volume of distribution (Vss) was calculated using non-compartmental analysis modules in the FDA certified
  • Table 7 Selected pharmacokinetics parameters of Compound (6) in male Spraque-Rawley rats following intravenous (IV) and oral (PO) administration
  • t1/2 elimination half-life
  • Tmax time to reach maximum plasma concentration
  • Cmax maximum plasma concentration
  • AUC area under concentration time curve
  • MRT mean residence time
  • F fraction (bioavailability)
  • Example 12 Pharmacokinetic profile of Compound (6) in Beagle dogs following intravenous and oral administration
  • the assay was performed by Medicilon (CN) according to their protocols.
  • Compound (6) was dissolved in 5% DMSO, 50% PEG400, 45% saline to yield a nominal concentration of 1.4 mg/mL for intravenous administration and for oral administration to Beagle dogs as follows:
  • Blood samples (approximately 200 ⁇ L) were collected via jugular vein (after anesthetizia by isoflurane) at appropriate time points for determination of plasma concentrations. Blood samples were placed into tubes containing K3EDTA and centrifuged a t 3500 rpm for 10 minutes at 4o C to separate plasma from the samples. Following centrifugation, the resulting plasma was transferred to clean tubes and stored frozen at -80 o C pending bioanalysis.
  • Table 9 Selected pharmacokinetics parameters of Compound (6) in Beagle dog following intravenous (IV) and oral (PO) administration
  • T max time to reach maximum plasma concentration
  • C max maximum plasma concentration
  • AUC area under concentration time curve
  • MRT mean residence time
  • F fraction (bioavailability)
  • xenografts were established using the human colorectal cancer cell line COLO 320DM cells in male Balb/c nude mice.
  • a 20-ml tube was charged with 4-fluoro-3-hydroxybenzonitrile (0.206 g, 1.5 mmol) and potassium carbonate (0.207 g, 1.500 mmol). It was placed under a nitrogen atmosphere, acetonitrile (anhydrous) (3 ml) was added followed by (bromomethyl)benzene (0.196 ml, 1.650 mmol) and the white suspension was heated in a reaction block at 60°C for 3 hours. The suspension was evaporated to dryness, re-dissolved in a mixture of water and DCM and extracted three times with DCM. After drying over sodium sulfate, filtration and thorough evaporation, a batch of 0.33 g, 100% yield of a white solid was isolated and employed as such in the follow up experiment.
  • Methyl trans-3-amino-cyclobutanecarboxylate hydrochloride (39.94 g, 241 mmol) was suspended in dichloromethane (400 ml). The reaction mixture was cooled to 0°C.
  • Triethylamine 134 ml, 965 mmol
  • BOC-O-BOC 63.2 g, 289 mmol
  • the white suspension was allowed to warm to room temperature and was stirred for 20 hours.
  • the product was extracted with DCM.
  • the organic layer was dried with Na 2 SO 4 , filtered and the solvents removed in vacuo to give a white solid.
  • the reaction mixture was filtered. Water was added to the filtrate and the layers were separated. The organic layer was washed two more times with H2O (300 mL).
  • the combined organic layers were dried over sodium sulfate and concentrated to give a white solid (64.57 g).
  • the product was stirred in heptane during 1 hour, filtered and the residue was dried on air during 1 hour to give the desired product (46.3 g).
  • N-(2-chlorophenyl)thiazole-2-carboxamide (0.985 g, 4.13 mmol) was suspended in toluene (dry) (15 ml). Lawesson's reagent (1.669 g, 4.13 mmol) was added and the beige suspension heated to 80°C for 24 hours. The temperature was raised to 104 degrees and an extra portion of Lawesson's reagent (0.768 g, 1.898 mmol) was added and the reaction stirred overnight. The oil was suspended in 3 ml DCM and purified by column
  • N-(2-chlorophenyl)thiazole-2-carbothioamide (207 mg, 0.813 mmol) was dissolved in acetone (10 ml). Iodomethane (0.061 ml, 0.975 mmol) and potassium carbonate (168 mg, 1.219 mmol) were added and the yellow suspension was stirred at room temperature for 3 hours. The temperature was raised to 34°C and the reaction mixture was stirred overnight. The solids were filtered and the filtrate was evaporated to dryness yielding the product as a yellow smelly oil (345 mg). Used as such.
  • reaction mixture was flushed with nitrogen for 30 min, insolubles removed by filtration over a pad of Celite® while eluting with EtOH/DCM.
  • the light yellow filtrate was evaporated to give the product as a yellow solid (14.54 g). Used as such.
  • the experiment was performed in a 50 mL one-necked round-bottomed flask with magnetic
  • the white suspension was filtered over a p3 glass filter and the resulting product filter cake was eluted with methanol (20 mL) and dried on the filter under suction (with an empty suction flask) and subsequently in a vacuum stove at 40°C for 60 hours affording 6.616 g of the product as a white powder.
  • the mixture was filtered, washed with cold H2O and dried on air to give a purple/brown solid.
  • the batch was placed in a vacuum oven at 40 degrees for 24 hours.
  • the solid was titruated in MeOH over 60 hours.
  • the purple solids were filtered.
  • the filtrate was evaporated under vacuum to a brown oil that solidified on standing (3.2 g). Used as such.
  • Step C N-(2-chlorophenyl)-2-methylpyrimidine-4-carbothioamide (146mg, 0.493 mmol) was dissolved in acetone (15 ml). iodomethane (0.040 ml, 0.640 mmol) and potassium carbonate (102 mg, 0.739 mmol) were added and the yellow suspension was stirred at room temperature for 60 hours. The solids were filtered, the filtrate was evaporated to dryness and dissolved in a 1:1 mixture of H2O and DCM. Separation via phase separator yielded the product as a brown smelly oil (115 mg). Used as such.
  • the filtrate was evaporated to dryness to give the product as a brown oil which solidified on standing.
  • the product was purified further by reveleris 12 gram column using heptane-EtOAc gradient (0 to 25%) to afford a white solid. Used as such.
  • N-(2-chlorophenyl)-5-ethoxypicolinamide 173 mg, 0.525 mmol was suspended in toluene (dry) (4 ml). Lawesson's reagent (212 mg, 0.525 mmol) was added and the beige suspension heated to 80°C for 3 days. The reaction mixture was cooled to room temperature and stirred overnight. The solvents were removed in vacuo. The batch was purified by reveleris using 1-30% EtOAc in heptane 24 gram column. Appropriate fractions were combined and the solvents were removed in vacuo to give as a yellow solid. The product was purified further by reveleris 12 g column using heptane-EtOAc gradient (0 to 15%), to afford the product as a yellow solid (80 mg).
  • N-(2-chlorophenyl)-5-ethoxypyridine-2-carbothioamide (80 mg, 0.273 mmol) was dissolved in acetone (10 ml). Iodomethane (0.022 ml, 0.355 mmol) and potassium carbonate (56.6 mg, 0.410 mmol) were added and the yellow suspension was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was dissolved in a 1:1 mixture of ice/H2O and DCM. Separation via phase separator and removal of the solvents in vacuo yielded the product as a yellow smelly solid (71 mg). Used as such.
  • N-phenylpyrimidine-4-carboxamide (770 mg, 3.87 mmol) was suspended in Toluene (dry) (13 ml). Lawesson's reagent (1563 mg, 3.87 mmol) was added and the beige suspension heated to 80°C for 24 hours. The reaction mixture was cooled to room temperature. The solvents were removed in vacuo, 20 ml DCM was added and the resulting solution washed with 20 ml sat. NaHCO3 and then twice with 10 ml brine. The aqueous phases were back-extracted with DCM (10ml). The organic layers were combined, dried over Na2SO4 and evaporated to give the product as a yellow oil. The batch was repurified by reveleris using 1-30% EtOAc in heptane to afford the product as an orange solid. Used as such.
  • N-phenylpyrimidine-4-carbothioamide (535mg, 2.485 mmol) was dissolved in acetone (10 ml). iodomethane (0.201 ml, 3.23 mmol) and potassium carbonate (515 mg, 3.73 mmol) were added and the yellow suspension was stirred at room temperature over weekend. The solids were filtered and the filtrate was evaporated to dryness and dissolved in a 1:1 mixture of H2O and DCM. Separation via phase separator yielded the product as a brown smelly oil (528 mg). Used as such.
  • the reaction mixture was cooled and the mixture was thoroughly evaporated to dryness.
  • the batch was purified by reveleris (12 g column) using 1-100% EtOAc in heptane. The crude was then flashed on a 12 gram silica gel cartridge eluted with a gradient of methanol (0 to 10%) in DCM, affording the product as a brown oil (35 mg). While MeOH was added for SFC purification, the batch formed crystals, which were filtered and the solids were rinsed with MeOH to give the product as a beige solid. The product was prepared for lyophylaztion. The batch returned as a beige powder (29.2 mg).
  • N-(2-chlorophenyl)-5-methylthiazole-2-carbothioamide (0.271 g, 1.00 mmol) was dissolved in acetone (10 ml), potassium carbonate (0.193 g, 1.400 mmol) was added and the yellow suspension was treated with iodomethane (0.075 ml, 1.200 mmol). The mixture was allowed to stir overnight, then it was evaporated to dryness. After re-suspending in DCM, it was filtered through celite, the yellow solution was concentrated, absorbed on isolute and flashed on a 12 g silica gel column eluted with a gradient ethyl acetate (5 to 50%) in heptane. A yellow-coloured was collected giving 268 mg of the product as a yellow oil.
  • N-(2-chlorophenyl)thiazole-5-carbothioamide (111 mg, 0.436 mmol) was dissolved in acetone (10 ml). iodomethane (0.035 ml, 0.566 mmol) and potassium carbonate (90 mg, 0.654 mmol) were added and the yellow suspension was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was dissolved in a 1:1 mixture of ice/H2O and DCM. Separation via phase separator and removal of the solvents in vacuo yielded the product as a yellow smelly oil (106 mg). Used as such.
  • N-(2-chlorophenyl)-1-methyl-1H-pyrazole-4- carboxamide 44 mg, 0.187 mmol
  • Lawesson's reagent 76 mg, 0.187 mmol
  • the mixture was diluted with acetonitrile and evaporated to dryness.
  • the residue was then adsorbed on isolute and flashed on a 24 gram silica gel cartridge eluted with a gradient of ethyl acetate (5 to 50, the pure EA) in heptane.
  • a second purification by reveleris afforded 38 mg of the product. Used as such.
  • Picolinic acid 250 mg, 2.031 mmol was slurried in N,N-dimethylformamide (dry) (2 ml), DIPEA (0.424 ml, 2.437 mmol) was added followed by HATU (849 mg, 2.234 mmol). After 15 mins 2-chloroaniline (0.236 ml, 2.234 mmol) was added to the brown suspension and the resulting reaction mixture stirred further at room temperature for 72 hours. The reaction mixture was evaporated to dryness. This mixture was added to a cold water/ sat. sodium bicarbonate mixture (2:1, 10 ml) and DCM 10 mL. The product was extracted and the layers were separated over a phase separator.
  • N-(2-chlorophenyl)pyridine-2-carbothioamide (312 mg, 1.254 mmol) was dissolved in
  • N-(2-fluorophenyl)pyrimidine-4-carboxamide (381 mg, 1.754 mmol) was suspended in toluene (dry) (8 ml). Lawesson's reagent (709 mg, 1.754 mmol) was added and the beige suspension heated to 80°C for 24 hours. The batch was cooled and filtered. The filtrate was evaporated to dryness. The smelly orange-red residue was purified on a 12 g silica gel cartridge eluted with a gradient of ethyl acetate 0 to 20% in heptane to afford the product as an orange solid. Used as such.
  • N-(2-fluorophenyl)pyrimidine-4-carbothioamide (317 mg, 1.359 mmol) was dissolved in
  • Step C N-(2,6-dichlorophenyl)pyrimidine-4-carbothioamide (350 mg, 1.232 mmol) was dissolved in acetone (4 ml). Iodomethane (0.100 ml, 1.601 mmol) and potassium carbonate (255 mg, 1.848 mmol) were added and the yellow suspension was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was dissolved in a 1:1 mixture of ice/H2O and DCM. Separation via phase separator and removal of the solvents in vacuo yielded the product as a yellow smelly oil (357 mg). Used as such.
  • a 2-5 microwave vial was charged with a batch of methyl N-(2,6- dichlorophenyl)pyrimidine-4-carbimidothioate (0.089 g, 0.30 mmol), purified first before use by a silica gel column, followed by (1R,3R)-3-(5-cyano-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)cyclobutane-1-carbohydrazide (0.081 g, 0.300 mmol) and 1-butanol (3 ml). The suspension was then heated overnight for 14 hours in a microwave oven set at 150°C. The irradiation was continued for additional 4 hours at 200°C.
  • N-(2,6-difluorophenyl)pyrimidine-4-carbothioamide (310 mg, 1.234 mmol) was dissolved in acetone (4 ml). Iodomethane (0.100 ml, 1.604 mmol) and potassium carbonate (256 mg, 1.851 mmol) were added and the yellow suspension was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was dissolved in a 1:1 mixture of ice/H2O and DCM. Separation via phase separator and removal of the solvents in vacuo yielded the product as a yellow smelly oil (271 mg). Used as such.
  • N-(3-fluorophenyl)pyrimidine-4-carboxamide 580 mg, 2.67 mmol was suspended in toluene (dry) (8 ml). Lawesson's reagent (1080 mg, 2.67 mmol) was added and the beige suspension heated to 80°C and stirred for 60 hours. The batch was cooled, filtered, and the filtrate was evaporated to dryness. The smelly orange-red residue was purified on a 12 g silica gel cartridge eluted with a gradient of ethyl acetate 0 to 20% in heptane.
  • the orange-red residue was purified for a second time using a 24 g silica gel cartridge, eluting with a gradient of ethyl acetate 0 to 20% in heptane.
  • the product was obtained as an orange solid (623 mg). Used as such.
  • N-(3-fluorophenyl)pyrimidine-4-carbothioamide (623 mg, 2.257 mmol) was dissolved in
  • Step B Under a nitrogen atmosphere N-(4-fluorophenyl)pyrimidine-4-carboxamide (630 mg, 2.90 mmol) was suspended in toluene (dry) (8 ml). Lawesson's reagent (1173 mg, 2.90 mmol) was added and the beige suspension heated to 80°C and stirred for 60 hours. The batch was cooled and filtered. The filtrate was evaporated to dryness. The smelly orange-red residue was purified on a 12 g silica gel cartridge eluted with a gradient of ethyl acetate 0 to 20% in heptane. The product was obtained as an orange solid. Used as such.
  • N-(4-fluorophenyl)pyrimidine-4-carbothioamide (677 mg, 2.293 mmol) was dissolved in
  • 6-methylpicolinic acid 500mg, 3.65 mmol was slurried in N,N-dimethylformamide (dry) (4 ml), DIPEA (0.762 ml, 4.38 mmol) was added followed by HATU (1525 mg, 4.01 mmol). After 15 mins 2-chloroaniline (0.422 ml, 4.01 mmol) was added to the brown suspension. The resulting reaction mixture was stirred overnight. The reaction mixture was evaporated to dryness. This mixture was added to a cold water/ sat. sodium bicarbonate mixture (2:1, 20 ml) and DCM 20 mL. The product was extracted and the layers were separated over a phase separator. T he product was purified by revealeris 24 g column using heptane-EtOAc gradient (0 to 30%). Appropriate fractions were combined and solvents removed in vacuo to give the product as a yellow solid. Used as such.
  • N-(2-chlorophenyl)-6-methylpicolinamide (781 mg, 3.17
  • N-(2-chlorophenyl)-6-methylpyridine-2-carbothioamide (542 mg, 2.063 mmol) was dissolved in acetone (6 ml). Iodomethane (0.167 ml, 2.68 mmol) and potassium carbonate (428 mg, 3.09 mmol) were added and the yellow suspension was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in a 1:1 mixture of H 2 O and DCM. Separation via phase separator and removal of the solvents in vacuo afforded the product as a green oil. Used as such.

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Abstract

La présente invention concerne des composés de formule (I'), des tautomères, des stéréo-isomères et des sels pharmaceutiquement acceptables de ceux-ci, des procédés pour les préparer, des formulations pharmaceutiques contenant de tels composés et leur utilisation en thérapie (I') (dans laquelle : Z représente un groupe hétérocyclique insaturé à 5 ou 6 chaînons éventuellement substitué comprenant au moins un atome d'azote; L représente un groupe cycloalkyle à 4, 5 ou 6 chaînons, de préférence un groupe cyclobutyle; chaque R1 représente indépendamment F, Cl, Br, I, un groupe alkyle en C1-3, haloalkyle en C1-3 (par exemple-CF3), -CN, -OH ou -NO2, de préférence F, Cl, Br ou I, par exemple Cl ou F; chaque R2 représente indépendamment F, Cl, Br, I un groupe alkyle en C1-3, -CN, -OH ou NO2, de préférence F, Cl, Br, I ou -CN, par exemple F ou- CN; X représente -N3- ou -O-; R3 représente H ou un groupe alkyle en C1-3 (par exemple méthyle); n est un nombre entier de 0 à 5, de préférence de 0 à 3, mieux encore égal à 0, 1 ou 2, par exemple égal à 1; et m est un nombre entier de 0 à 5, de préférence de 0 à 3, mieux encore égal à 0, 1 ou 2, par exemple égal à 0 ou 1). De tels composés trouvent une utilisation particulière dans le traitement et/ou la prévention des affections ou des maladies qui sont affectées par une hyperactivation de la signalisation dans la voie WNT et la présence accrue de ß-caténine nucléaire. Par exemple, ils peuvent être utilisés dans la prévention et/ou le retardement de la prolifération des cellules tumorales et de métastases, par exemple de carcinomes tels que les carcinomes du côlon.
PCT/US2017/067228 2016-12-19 2017-12-19 Dérivés de triazole utilisés en tant qu'inhibiteurs de tankyrase WO2018118868A1 (fr)

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US11926614B2 (en) 2018-06-19 2024-03-12 Oslo Universitetssykehus Hf 1,2,4-triazole derivatives as tankyrase inhibitors
CN111440147A (zh) * 2020-05-19 2020-07-24 苏州卫生职业技术学院 N-(2-甲基-5-氨基苯基)-4-(3-吡啶基)-2-嘧啶胺的合成方法
CN111440147B (zh) * 2020-05-19 2023-03-07 苏州卫生职业技术学院 N-(2-甲基-5-氨基苯基)-4-(3-吡啶基)-2-嘧啶胺的合成方法
WO2022008896A1 (fr) 2020-07-06 2022-01-13 Golding, Louise Dérivés de triazole et leur utilisation en tant qu'inhibiteurs de la tankyrase

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