WO2014045101A1 - Dérivés de tétrazolo quinoxaline utilisés comme inhibiteurs de la tankyrase - Google Patents

Dérivés de tétrazolo quinoxaline utilisés comme inhibiteurs de la tankyrase Download PDF

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WO2014045101A1
WO2014045101A1 PCT/IB2013/002059 IB2013002059W WO2014045101A1 WO 2014045101 A1 WO2014045101 A1 WO 2014045101A1 IB 2013002059 W IB2013002059 W IB 2013002059W WO 2014045101 A1 WO2014045101 A1 WO 2014045101A1
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tetrazolo
quinoxalin
ylamino
benzoyl
methanone
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PCT/IB2013/002059
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English (en)
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Marcel Muelbaier
Nigel Ramsden
Douglas Thomson
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Cellzome Gmbh
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to a novel class of tankyrase inhibitors, including pharmaceutically acceptable salts thereof, which are useful for modulating protein tankyrase activity for modulating cellular activities such as signal transduction, proliferation, and cytokine secretion. More specifically the invention provides compounds which inhibit, regulate and/or modulate tankyrase activity and signal transduction pathways relating to cellular activities as mentioned above. Furthermore, the present invention relates to pharmaceutical compositions comprising said compounds, e.g. for the treatment of diseases such as immunological, inflammatory, autoimmune, allergic disorders, or proliferative diseases such as cancer, or for neurodegenerative diseases, and processes for preparing said compounds.
  • diseases such as immunological, inflammatory, autoimmune, allergic disorders, or proliferative diseases such as cancer, or for neurodegenerative diseases, and processes for preparing said compounds.
  • PARPs constitute a family of cell signalling enzymes present in eukaryotes which catalyse poly(ADP- ribosylation) (PARsylation) of DNA-binding proteins and other substrate proteins. PARPs are also known as poly(ADP-ribose) synthethases or poly(ADP-ribose) transferases (pARTs). Some PARPs also transfer single ADP-ribosyl-moieties. These enzymes, for example, play an important role in the immediate cellular response to DNA damage.
  • PARPs In response to DNA damage induced by ionizing radiation, oxidative stress and DNA-binding anti-tumour drugs, PARPs add ADP-ribose units to carboxlate groups of aspartic and glutamic residues of target proteins.
  • This poly(ADP-ribosylation) is a posttranslational modification that triggers the inactivation of the acceptor protein through the attachment of a complex branched polymer of ADP-ribose units.
  • ADP ribosylation is a posttranslational protein modification in which the ADP-ribose moiety is transferred from NAD onto specific amino acid side chains of target proteins (Schreiber et al., 2006. Nature Reviews Cell Biology 7, 517-528).
  • PARP family proteins are promising therapeutic targets. PARPl and PARP2 play a role in DNA damage responses and PARP inhibitors sensitize cancer cells for drug and radiation treatment. In addition, PARPl has been linked to other diseases incuding inflammation, neuronal cell death and ischemia.
  • the tankyrases (TNKSl and TNKS2), which share high sequence similarity with PARPl, are also emerging therapeutic targets. They were initially described as regulators of telomerase activity and are linked to DNA damage responses and Wnt signaling (Wahlberg et al., 2012. Nat. Biotechnol. 30(3):283-288).
  • the tankyrase protein family consists of tankyrase 1 (TNKSl) and tankyrase 2 (TNKS2) which share 85% amino acid identity.
  • the biological function of both tankyrases was studied in genetically engineered mice lacking the mouse tankyrase 1 and/or tankyrase 2.
  • Tankyrase 2 deficient mice developed normally and showed no detectable change in telomere length, but did show a significant decrease in total body weight that might reflect a role of tankyrase 2 in glucose or fat metabolism. No defects in telomere length maintenance were detected in in tankyrase 1 deficient mice. However, in double-knockout mice lacking both tankyrase 1 and tankyrase 2 embryonic lethality was observed at embryonic day 10 (Chiang et al., 2008. PLoS One. 2008 Jul 9;3(7):e2639)
  • Beta-catenin ( ⁇ -catenin) is an important component of the canonical Wnt signal transduction pathway. It is associated with E-cadherin at the cell membrane and plays a role in the formation of the adherens junctions. In the cytoplasm, ⁇ -catenin can be a part of multiprotein complexes such as the ⁇ -catenin destruction complex consisting of adenomatous polyposis coli (APC), Axin2, GSK3P, and casein kinase la (CKla).
  • APC adenomatous polyposis coli
  • Axin2 Axin2
  • GSK3P casein kinase la
  • Tankyrase 1 and 2 regulate the stability of the ⁇ - catenin destruction complex through Axin2 by poly(ADP-ribosyl)ation.
  • Active Wnt signalling inhibits the function of the destruction complex so that ⁇ -catenin is not phosphorylated at the N-terminus and degraded, but enters the nucleus.
  • ⁇ - catenin can bind to the transcription factor TCF/LEF and activate the transcription of target genes, such as c-Myc, cyclin Dl and Axin2 (Waaler et al., 2012. Cancer Res. 72(1 1):2822- 2832).
  • Wnt activating mutations are found in a broad range of solid tumours, including colon cancer, gastric cancer, hepatocellular carcinoma, breast cancer, meduUoblastoma, melanoma, non-small cell lung cancer, pancreas adenocarcinoma, and prostate cancer (Waaler et al., 2012. Cancer Res. 72(11):2822-2832).
  • XAV939 stimulates beta-catenin degradation by stabilizing axin, the concentration- limiting component of the destruction complex.
  • XAV939 stabilizes axin by inhibiting the poly-ADP- ribosylating enzymes tankyrase 1 and tankyrase 2.
  • tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin- proteasome pathway (Huang et al., 2009. Nature 461 (7264):614-620). This observation demonstrates that tankyrase inhibitors are promising drugs for the inhibition of Wnt signalling in cancer.
  • JW55 another small molecule inhibitor of the ⁇ -catenin signaling pathway was identified that functions via inhibition of the PARP domain of tankyrase 1 and tankyrase 2 (TNKS1/2). Inhibition of TNKS1/2 poly(ADP-ribosyl)ation activity by JW55 led to stabilization of Axin2, a member of the ⁇ -catenin destruction complex, followed by increased degradation of ⁇ -catenin. In a dose-dependent manner, JW55 inhibited canonical Wnt signaling in colon carcinoma cells that contained mutations in either the APC (adenomatous polyposis coli) locus or in an allele of ⁇ -catenin.
  • APC adenomatous polyposis coli
  • JW55 reduced XWnt8-induced axis duplication in Xenopus embryos and tamoxifen- induced polyposis formation in conditional APC mutant mice.
  • This study shows that canonical Wnt ⁇ -catenin signaling can be inhibited by small molecule inhibitors of the PARP domain of TNKS1/2 (Waaler et al., 2012. Cancer Res. 72(1 1):2822-2832).
  • a tankyrase inhibitor can promote myelination of cells in the oligodendrocyte lineage.
  • therapies to overcome this differentiation block. A lack of forming new myelin is also devisseved in patients with multiple sclerosis.
  • Axin 2 an inhibitory protein of the Wnt pathway, was identified as a new target for drugs promoting myelin formation in the neonatal and adult brain.
  • the importance of Axin2 PARsylation for myelin formation was demonstrated by treatment with the tankyrase inhibitor XAV939, which enhanced myelin regeneration after demyelination in wild-type mice, but not in Axin2-null mice (Fancy et al., 201 1. Nat. Neurosci. 14(8): 1009-1016; Casaccia 2011. Nat. Neurosci. 14(8):945-947).
  • tankyrase inhibitor can promote cardiomyogenic differentiation.
  • the XAV939 tankyrase inhibitor can induce cardiomyogenesis in mouse ES cells (Wang et al., 201 1. ACS Chem. Biol. 6(2): 192- 197).
  • Axin2 is only one of several known tankyrase substrates, most of which play important roles in pathways other than Wnt signalling.
  • tankyrase substrates defects in tankyrase recognition of its substrate 3BP2 lead to the human disease cherubism.
  • Tankyrases via their N-terminal region, bind to defined RxxPDG hexapeptides in their substrates.
  • Co- crystals of TNKS2 and six different substrate peptides have been reported.
  • a rule-based consensus sequence for tankyrase substrates has been derived that rationalized all known tankyrase substrates and predicts many more.
  • tankyrase inhibitors affect important cellular pathways other than the Wnt signal transduction pathway, and that this action is mediated by tankyrase substrates other than Axin2 (Guttler et al, 2011 , Cell, 147, 1340-1354).
  • tankyrase inhibitors have been reported in the literature which may be useful in the medical field, for example as anticancer agents (Shultz et al., 2012. J. Med. Chem. 55(3):1127-1136). It is expected that a selective tankyrase inhibitor that inhibits tankyrase with greater potency than other PARP family members may have advantageous therapeutic properties because inhibition of other PARPs may cause unwanted side effects (Wahlberg et al., 2012. Nat. Biotechnol. 30(3):283-288).
  • Tetrazolo quinoxaline derivatives are known from KR2011 136960, US2009163545, US3987196 and US3389137.
  • tankyrase inhibitors are known in the art there is a need for providing additional tankyrase inhibitors having at least partially more effective pharmaceutically relevant properties, like activity, selectivity, and ADME properties.
  • an object of the present invention is to provide a new class of inhibitors which may be effective in the treatment or prophylaxis of disorders associated with Tankyrase.
  • R 2 is H; OR 5 ; N(R 5 R 5a ); CN; T 1 ; SR 5 ; Ci -6 alkyl; C 2-6 alkenyl; or C 2-6 alkynyl, wherein Ci -6 alkyl; C 2-6 alkenyl; and C 2 . 6 alkynyl are optionally substituted with one to three R 6 , which are the same or different;
  • R and R are joined to form, together with the atoms to which they are attached, an oxo-substituted ring T°;
  • R 5 and R 5a are each independently selected from the group consisting of H; T 1 ; Ci -6 alkyl; C 2-6 alkenyl; and C 2-6 alkynyl, wherein Ci -6 alkyl; C 2-6 alkenyl; and C 2-6 alkynyl are optionally substituted with one to three R 6 , which are the same or different;
  • Each R 4 and R 6 is independently selected from the group consisting of halogen; CN; C(0)OR 7 ; OR 7 ; C(0)R 7 ; C(0)N(R 7 R 7a ); S(0) 2 N(R 7 R 7a ); S(0)N(R 7 R 7a ); S(0) 2 R 7 ; S(0)R 7 ; N(R 7 )S(0) 2 N(R 7a R 7b ); N(R 7 )S(0)N(R 7a R 7b ); SR 7 ; N(R 7 R 7a ); N0 2 ; OC(0)R 7 ; N(R 7 )C(0)R 7a ; N(R 7 )S(0) 2 R 7a ; N(R 7 )S(0)R 7a ; N(R 7 )C(0)N(R 7a R 7b ); N(R 7 )C(0)OR 7a ; OC(0)N(R 7 R 7a ); and T 1 ; Each R 7 , R 7a and R 7b is independently selected from the group
  • T° is 4 to 7 membered at least partly saturated heterocyclyl; or 7 to 11 membered at least partly saturated heterobicyclyl, wherein T° is optionally further substituted with one to three R 8 , which are the same or different;
  • T is phenyl; naphthyl; indenyl; indanyl; C 3-7 cycloalkyl; 4 to 7 membered heterocyclyl; or 7 to 1 1 membered heterobicyclyl, wherein T 1 is optionally substituted with one to three R 8a , which are the same or different;
  • Each R 9 , R 9a and R 9b is independently selected from the group consisting of H; T 2 ; Ci -6 alkyl; C 2-6 alkenyl; and C 2-6 alkynyl, wherein C 1-6 alkyl; C 2-6 alkenyl; and C 2-6 alkynyl are optionally substituted with one to three R 1 ', which are the same or different;
  • Each R 10 and R 11 is independently selected from the group consisting of halogen; CN; C(0)OR 12 ; OR 12 ; C(0)R 12 ; C(0)N(R 12 R 12a ); S(0) 2 N(R 12 R 12a ); S(0)N(R 12 R 12a ); S(0) 2 R 12 ; S(0)R 12 ; N(R 12 )S(0) 2 N(R 12a R 12b ); N(R I2 )S(0)N(R I2a R 12b ); SR 12 ; N(R 12 R 12a ); N0 2 ; OC(0)R 12 ; N(R 12 )C(0)R 12a ; N(R 12 )S(0) 2 R 12a ; N(R 12 )S(0)R 12a ; N(R 1 )C(0)N(R 12a R 12b ); N(R 12 )C(0)OR 12a ; OC(0)N(R 12 R 12a ); and T 2 ;
  • Each R 12 , R 12a and R 12b is independently selected from the group consisting of H; T 2 ; Ci -6 alkyl; C 2-6 alkenyl; and C 2-6 alkynyl, wherein Ci -6 alkyl; C 2-6 alkenyl; and C 2-6 alkynyl are optionally substituted with one to three halogens, which are the same or different;
  • Each T 2 is independently phenyl; naphthyl; indenyl; indanyl; C 3- 7 cycloalkyl; 4 to 7 membered heterocyclyl; or 7 to 11 membered heterobicyclyl, wherein T 2 is optionally substituted with one to three R , which are the same or different;
  • Each R 14 , R 14A and R 14B is independently selected from the group consisting of H; C 1-6 alkyl; C 2-6 alkenyl; and C 2-6 alkynyl, wherein C 1-6 alkyl; C 2- alkenyl; and C 2-6 alkynyl are optionally substituted with one to three halogens, which are the same or different; provided that the following compounds are excluded:
  • variable or substituent can be selected from a group of different variants and such variable or substituent occurs more than once the respective variants can be the same or different.
  • the terms are used as follows:
  • Alkyl means a straight-chain or branched hydrocarbon chain. Each hydrogen of an alkyl carbon may be replaced by a substituent as further specified.
  • Alkenyl means a straight-chain or branched hydrocarbon chain that contains at least one carbon-carbon double bond. Each hydrogen of an alkenyl carbon may be replaced by a substituent as further specified.
  • Alkynyl means a straight-chain or branched hydrocarbon chain that contains at least one carbon-carbon triple bond. Each hydrogen of an alkynyl carbon may be replaced by a substituent as further specified.
  • Ci -4 alkyl means an alkyl chain having 1 - 4 carbon atoms, e.g. if present at the end of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or e.g. -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -, -CH(C 2 H 5 )-, -C(CH 3 ) 2 -, when two moieties of a molecule are linked by the alkyl group.
  • Ci -4 alkyl carbon may be replaced by a substituent as further specified.
  • C] -6 alkyl means an alkyl chain having 1 - 6 carbon atoms, e.g. if present at the end of a molecule: C alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl; tert- butyl, n-pentyl, n-hexyl, or e.g.
  • Each hydrogen of a C 2-6 alkenyl carbon may be replaced by a substituent as further specified.
  • C 2-6 alkynyl means an alkynyl chain having 2 to 6 carbon atoms, e.g. if present at the end of a molecule: -C ⁇ CH, -CH 2 -C ⁇ CH, CH 2 -CH 2 -C ⁇ CH, CH 2 -C ⁇ C-CH 3 , or e.g. -C ⁇ C- when two moieties of a molecule are linked by the alkynyl group.
  • Each hydrogen of a C 2-6 alkynyl carbon may be replaced by a substituent as further specified.
  • C 3-7 cycloalkyl or "C 3-7 cycloalkyl ring” means a cyclic alkyl chain having 3 - 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl.
  • cyloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • Each hydrogen of a cycloalkyl carbon may be replaced by a substituent as further specified herein.
  • the term “C 3-5 cycloalkyl” or "C 3- 5 cycloalkyl ring” is defined accordingly.
  • Halogen means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro.
  • Examples of 4 to 7 membered heterocycles are azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine
  • “Saturated 4 to 7 membered heterocyclyl” or “saturated 4 to 7 membered heterocycle” means fully saturated “4 to 7 membered heterocyclyl” or “4 to 7 membered heterocycle”.
  • “4 to 7 membered at least partly saturated heterocyclyl” or “4 to 7 membered at least partly saturated heterocycle” means an at least partly saturated “4 to 7 membered heterocyclyl” or "4 to 7 membered heterocycle”.
  • heterocycles examples include furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine.
  • heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, tetrazole.
  • Examples of 7 to 1 1 membered heterobicycles are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine.
  • 7 to 11 membered heterobicycle also includes spiro structures of two rings like 6-oxa-2-azaspiro[3,4]octane, 2-oxa-6-azaspiro[3.3]heptan-6-yl or 2,6- diazaspiro[3.3]heptan-6-yl or bridged heterocycles like 8-aza-bicyclo[3.2.1]octane or 2,5- diazabicyclo[2.2.2]octan-2-yl or 3,8-diazabicyclo[3.2.1]octane.
  • saturated 7 to 1 1 membered heterobicyclyl or "saturated 7 to 11 membered heterobicycle” means fully saturated 7 to 1 1 membered heterobicyclyl or 7 to 1 1 membered heterobicycle.
  • Examples of an aromatic 9 to 1 1 membered heterobicycle are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine.
  • Preferred compounds of formula (I) are those compounds in which one or more of the residues contained therein have the meanings given below, with all combinations of preferred substituent definitions being a subject of the present invention. With respect to all preferred compounds of the formula (I) the present invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts. In preferred embodiments of the present invention, the substituents mentioned below independently have the following meaning. Hence, one or more of these substituents can have the preferred or more preferred meanings given below. In one embodiment, X is absent and y is 0.
  • X is absent and y is 1.
  • X is C3 ⁇ 4 and y is 0.
  • R l is H; or CH 3 .
  • R and R are joined to form together with the atoms to which they are attached an oxo-substituted ring T°, wherein T° is optionally further substituted
  • R 1 and R 2 are joined to form together with the atoms to which they are attached an unsubstituted pyrrolidin-2-one; piperazin-2-one, N-substituted with R 8 ; or an unsubstituted morpholin-3-one ring.
  • R and R are not joined to form, together with the atoms to which they are attached, an oxo-substituted ring T°.
  • R 2 is N(R 5 R 5a ); OR 5 ; unsubstituted C 1-6 alkyl or C l-6 alkyl substituted with one R 6 ; or T 1 .
  • R 5a is H or CH 3 .
  • R 5 is H; unsubstituted C 1-6 alkyl; or C 1-6 alkyl substituted with one R 6 .
  • R 6 is N(R 7 R 7a ); OR 7 ; CN; or T l .
  • R 2 ; R 5 ; or R 6 are T 1 .
  • T 1 is morpholinyl; thiomorpholinyl; dioxanyl; oxazolyl; pyrrolidinyl; phenyl; pyridinyl; piperazinyl; tetrahydrofuranyl; 1,2,3,4- tetrahydroisoquinolinyl; cyclopentyl; 3-oxa-8-aza-bicyclo[3.2.1]octan-8-yl; piperidinyl; cyclopropyl, and wherein T 1 is optionally substituted with one or two R 8a .
  • R 8 ; R 8a ; R 9 ; R 9a ; R 10 ; or R u is T 2 .
  • T 2 is phenyl; pyridinyl; tetrahydropyranyl; oxazolyl; pyrimidinyl; furanyl or imidazolyl, and wherein T 2 is optionally substituted with one, or two R 13 .
  • R is Ci -6 alkyl; OCi -6 alkyl; or halogen.
  • Y is CH; or N and R 8a is defined above.
  • Y is CH and R 8a is CN; C(0)NH 2 ; C(0)NHR 9
  • Y is N and R 8a is C(0)R 9 ; or T 2 .
  • R 13 is H; methyl; methoxy; F; or CI.
  • tautomerism like e.g. keto-enol tautomerism
  • the individual forms like e.g. the keto and enol form, are comprised separately and together as mixtures in any ratio.
  • stereoisomers like e.g. enantiomers, cis/trans isomers, conformers and the like.
  • isomers can be separated by methods well known in the art, e.g. by liquid chromatography.
  • enantiomers by using e.g. chiral stationary phases.
  • enantiomers may be isolated by converting them into diastereomers, i.e.
  • any enantiomer of a compound of formula (I) may be obtained from stereoselective synthesis using optically pure starting materials and/or reagents.
  • the compounds of formula (I) may exist in crystalline or amorphous form. Furthermore, some of the crystalline forms of the compounds of formula (I) may exist as polymorphs, which are included within the scope of the present invention. Polymorphic forms of compounds of formula (I) may be characterized and differentiated using a number of conventional analytical techniques, including, but not limited to, X-ray powder diffraction (XRPD) patterns, infrared (IR) spectra, Raman spectra, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid state nuclear magnetic resonance (ssNMR).
  • XRPD X-ray powder diffraction
  • IR infrared
  • Raman spectra Raman spectra
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • ssNMR solid state nuclear magnetic resonance
  • the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts.
  • the compounds of the formula (I) which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
  • Compounds of the formula (I) which contain one or more basic groups i.e.
  • acids which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids.
  • suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p- toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art.
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • the respective salts according to the formula (I) can be obtained by customary methods which are known to the person skilled in the art like, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the present invention also includes all salts of the compounds of the formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • the term "pharmaceutically acceptable” means that the corresponding compound, carrier or molecule is suitable for administration to humans.
  • the present invention furthermore includes all solvates of the compounds according to the invention.
  • the effects of the claimed compounds on tankyrase activity may, for example, be tested using an auto-poly(ADP-ribosyl)ation assay (auto-PARsylation assay).
  • PARP catalytic activity can be monitored using the quantitative liquid chromatography/mass spectrometry (LC-MS) detection of nicotinamide, a product of the autoparsylation reaction (Shultz et al., 2012. J. Med. Chem. 55(3):1127-1136).
  • TNKS1 means the tankyrase 1 protein (Smith et al., 1998. Science. 282(5393): 1484-7).
  • TNKS2 means the tankyrase 2 protein (Lyons et al., 2001. J. Biol. Chem. 276(20):17172-80).
  • the deduced 1,166-amino acid protein has a calculated molecular mass of 130 kD. It shares approximately 83% sequence identity with tankyrase- 1 (TNKS1), differing mainly in the absence of a histidine/proline/serine-rich (HPS) domain. Both proteins possess 24 ankyrin-type repeats, a sterile alpha motif, and a C-terminal poly(ADP-ribose) polymerase (PARP) homology domain. Critical residues required for NAD + binding and catalysis are entirely conserved.
  • the expressions "tankyrase” and “tankyrases” mean both the tankyrase 1 and tankyrase 2 proteins.
  • the present invention provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.
  • “Pharmaceutical composition” means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered orally. Saline and aqueous dextrose are preferred carriers when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions are preferably employed as liquid carriers for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin. Such compositions will contain a therapeutically effective amount of the therapeutic, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.
  • a pharmaceutical composition of the present invention may comprise one or more additional compounds as active ingredients like one or more compounds of formula (I) not being the first compound in the composition or tankyrase inhibitors.
  • Further bioactive compounds for combinations may be EGFR inhibitors such as gefitinib, erlotinib, or ErbB2 inhibtors such as lapatinib.
  • the compounds of the present invention or pharmaceutically acceptable salt(s) thereof and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, this may occur separately or sequentially in any order.
  • the two compounds must be stable and compatible with each other and the other components of the formulation.
  • they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) is administered in combination with another drug or pharmaceutically active agent and/or that the pharmaceutical composition of the invention further comprises such a drug or pharmaceutically active agent.
  • drug or pharmaceutically active agent includes a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • Combined or “in combination” or “combination” should be understood as a functional coadministration, wherein some or all compounds may be administered separately, in different formulations, different modes of administration (for example subcutaneous, intravenous or oral) and different times of administration.
  • the individual compounds of such combinations may be administered either sequentially in separate pharmaceutical compositions as well as simultaneously in combined pharmaceutical compositions.
  • the treatment defined herein may be applied as a sole therapy or may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy.
  • the compounds of the invention can also be used in combination with existing therapeutic agents for the treatment proliferative diseases such as cancer. Suitable agents to be used in combination include:
  • antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents or alkylating-like agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates or fluoropyrimidines like 5- fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinore
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro- 2,3 - methylenedioxyanilino)-7- [2-(4-methylpiperazin- 1 -yl)ethoxy] -5 -tetrahydropyran- 4- yloxy-quinazoline (AZD0530) and N-(2-chloro-6-methylphenyl)-2- ⁇ 6-[4-(2- hydroxyethyl)piperazin-l-yl]-2-methylpyrimidin- 4-ylamino ⁇ thiazole-5-carboxamide (dasatinib, BMS-354825), and metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function);
  • c-Src kinase family inhibitors like 4-(6-chloro- 2,3 - methylenedioxyanilino)-7- [2-(4-methylpipe
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM] and the anti-erbBl antibody cetuximab [C225]); such inhibitors also include, for example, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD 1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)quinazol
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and VEGF receptor tyrosine kinase inhibitors such as 4-(4- bromo- 2-fiuoroanilino)-6-methoxy-7-( 1 -methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6- methoxy-7-(3- pyrrolidin-l-ylpropoxy)quinazoline (AZD2171 ; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU1 1248 (sunitinib; WO 01/60814), and compounds that work by other mechanisms (for example linomide,
  • vascular damaging agents such as combretastatin A4 and compounds disclosed in International Patent Application WO 99/02166;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense agent;
  • gene therapy approaches including approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • immunotherapeutic approaches including ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • NSCLC non-small cell lung cancer
  • EGFR epidermal growth factor
  • tankyrase 1 and 2 that positively regulate canonical Wnt signalling
  • Inhibition of tankyrase with shRNAs or small molecules significantly increased the efficacy of EGFR inhibitors (for example gefitinib) both in vitro and in vivo. Therefore inhibition of tankyrase and EGFR may result in an improved clinical outcome in NSCLC patients.
  • compounds of the invention are used in combination with EGFR inhibitors such as gefitinib, erlotinib, or ErbB2 inhibtors such as lapatinib.
  • compounds of the invention are used in combination with antibodies directed at EGFR family members (the anti-erbB2 antibodies trastuzumab (Herceptin ® ), Pertuzumab (Omnitarg®), the anti-erbBl antibodies cetuximab (Erbitux ® ) and Panitumumab (Vectibix ® ).
  • the compounds of formula (I) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally, for example, as liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Compounds of formula (I) may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of formula (I) are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • a therapeutically effective amount of a compound of the present invention will normally depend upon a number of factors including, for example, the age and weight of the recipient being treated, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration.
  • an effective amount of a compound of formula (I) for the treatment of an inflammatory disease for example rheumatoid arthritis (RA) will generally be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day.
  • the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a pharmaceutically acceptable salt, prodrug or metabolite thereof may be determined as a proportion of the effective amount of the compound of formula (I) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • terapéuticaally effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • Another aspect of the present invention is a compound of the present invention or a pharmaceutically acceptable salt thereof for use as a medicament, provided that the following compounds are not excluded as for compounds as such:
  • compositions and methods for treating, controlling, delaying or preventing conditions according to the present invention are concerned.
  • Another aspect of the present invention is a compound of the present invention or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing a disease or disorder associated with tankyrase.
  • a disease or disorder associated with tankyrase is defined as a disease or disorder where tankyrase is involved.
  • the diseases or disorder associated with tankyrase is an immunological, inflammatory, autoimmune, or allergic disorder or disease.
  • another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method of treating or preventing an immunological, inflammatory, autoimmune, or allergic disorder or disease.
  • an autoimmune disease is a disease which is at least partially provoked by an immune reaction of the body against own components, e.g. proteins, lipids or DNA.
  • the autoimmune disease is selected from the group consisting of rheumatoid arthritis (RA), osteoarthritis, inflammatory bowel disease (IBD; Crohns's disease and ulcerative colitis), psoriasis, systemic lupus erythematosus (SLE), and multiple sclerosis (MS).
  • RA rheumatoid arthritis
  • IBD inflammatory bowel disease
  • SLE systemic lupus erythematosus
  • MS multiple sclerosis
  • MS Multiple sclerosis
  • Axin2 PA sylation for myelin formation was demonstrated by treatment with the tankyrase inhibitor XAV939, which enhanced myelin regeneration after demyelination in wild-type mice, but not in Axin2-null mice (Fancy et al., 201 1. Nat. Neurosci. 14(8): 1009-1016; Casaccia 2011. Nat. Neurosci. 14(8):945-947).
  • the disease or disorder associated with tankyrase is a proliferative disease, especially cancer.
  • another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method of treating or preventing a proliferative disease, especially cancer.
  • Cancer comprises a group of diseases characterized by uncontrolled growth and spread of abnormal cells. All types of cancers generally involve some abnormality in the control of cell growth, division and survival, resulting in the malignant growth of cells. Key factors contributing to said malignant growth of cells are independence from growth signals, insensitivity to anti-growth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, tissue invasion and metastasis, and genome instability (Hanahan and Weinberg, 2000. The Hallmarks of Cancer. Cell 100, 57-70).
  • cancers are classified as hematological cancers (for example leukemias and lymphomas) and solid cancers such as sarcomas and carcinomas (for example cancers of the brain, breast, lung, colon, stomach, liver, pancreas, prostate, ovary).
  • hematological cancers for example leukemias and lymphomas
  • solid cancers such as sarcomas and carcinomas (for example cancers of the brain, breast, lung, colon, stomach, liver, pancreas, prostate, ovary).
  • cancers in which the Wnt pathway is activated for example due to inactivation of tumour suppressor genes or activating mutations in oncogenes are expected to respond to treatment with tankyrase inhibitors.
  • mutations in the adenomatous polyposis coli (APC), ⁇ -catenin, or AXIN genes lead to the accumulation of nuclear ⁇ -catenin and contribute to tumor initiation and progression.
  • alterations in extracellular proteins that silence Wnt signaling including secreted frizzled related proteins, Dickkopf (DICK), and members of the Wnt inhibitor factor (WIF) family, may lead to an abnormal pathway activity (Waaler et al., 201 1. Cancer Res. 71(l):197-205).
  • Wnt-activating mutations are present in a variety of cancers including colon cancer, gastric cancer, hepatocellular carcinoma, breast cancer, Wilms tumor of the kidney, medulloblastoma, melanoma, non-small cell lung cancer, ovarian endometriod cancer, anaplastic thyroid cancer, pancreas adenocarcinoma, and prostate cancer.
  • About 90% of sporadic colon cancers show aberrant Wnt signalling (Waaler et al., 201 1. Cancer Res. 71(l):197-205).
  • the disease or disorder associated with tankyrase is a neurodegenerative disease. Therefore, another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method of treating or preventing a neurodegenerative disease.
  • a tankyrase inhibitor can promote myelination of cells in the oligodendrocyte lineage.
  • a lack of forming new myelin is also deviseved in patients with multiple sclerosis.
  • Axin 2 an inhibitory protein of the Wnt pathway, was identified as a new target for drugs promoting myelin formation in the neonatal and adult brain.
  • the importance of Axin2 PARsylation for myelin formation was demonstrated by treatment with the tankyrase inhibitor XAV939, which enhanced myelin regeneration after demyelination in wild-type mice, but not in Axin2-null mice.
  • tankyrase inhibitor XAV939 favored new myelin formation in slice cultures damaged by exposure to low oxygen. This devissavtion suggests that tankyrase inhibitors may be useful for neuroprotection and the treatment of conditions associated with cerebral palsy and cognitive deficits caused by hypoxia-ischemia or by premature birth (Fancy et al., 2011. Nat. Neurosci. 14(8): 1009- 1016; Casaccia 201 1. Nat. Neurosci. 14(8):945-947).
  • the disease or disorder associated with tankyrase is fibrosis.
  • another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method of treating or preventing fibrosis.
  • the fibrosis is selected from the group consisting of lung fibrosis (pulmonary fibrosis), kidney fibrosis, skin fibrosis and muscle fibrosis.
  • lung fibrosis pulmonary fibrosis
  • kidney fibrosis kidney fibrosis
  • skin fibrosis skin fibrosis
  • muscle fibrosis a novel therapeutic approach to fibrotic disorders such lung fibrosis.
  • FT4001 small molecule tankyrase inhibitor
  • EMT epithelial mesenchymal transition
  • fibrogenesis bleomycin-induced lung injury in mice
  • the compound or pharmaceutical composition is used to induce cardiomyogeneis. Therefore, another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in inducing cardiomyogenesis.
  • Yet another aspect of the present invention is the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing fibrosis.
  • Yet another aspect of the present invention is the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inducing cardiomyogenesis.
  • Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need thereof one or more conditions selected from the group consisting of diseases and disorders associated with tankyrase, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to present invention or a pharmaceutically acceptable salt thereof.
  • Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need thereof one or more conditions selected from the group consisting of an immunological, inflammatory, autoimmune, or allergic disorder or disease, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to present invention or a pharmaceutically acceptable salt thereof.
  • Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need thereof a proliferative disease, especially cancer, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to present invention or a pharmaceutically acceptable salt thereof.
  • Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need thereof one or more conditions selected from the group consisting of a neurodegenerative disease, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to present invention or a pharmaceutically acceptable salt thereof.
  • Yet another aspect of the present invention is a method for inducing cardiomyogenesis, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to present invention or a pharmaceutically acceptable salt thereof.
  • treating or “treatment” is intended to refer to all processes, wherein there may be a slowing, interrupting, arresting, or stopping of the progression of a disease, but does not necessarily indicate a total elimination of all symptoms. All embodiments discussed above with respect to the pharmaceutical composition of the invention also apply to the above mentioned first or second medical uses or methods of the invention. It will be appreciated that novel intermediates described herein form another embodiment of
  • Mass signals were determined using a Waters 3100 Mass Detector.
  • R C0 2 H, CH 2 C0 2 Me, NH(Boc), N O ,
  • reaction mixture was heated to 60°C for 18h and then further lH-pyrazole-l-carboximidamide or N,iV-dimethyl-lH-benzo(d)(l,2,3)triazole-l-carboximidamide (1 equiv.) was added and the reaction mixture was heated to 60°C for a further 5h.
  • the solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC to afford product of the type (XIX).
  • reaction mixture was stirred at room temperature for 3 h and then poured into ethyl acetate and washed with saturated NaHC0 3 (aq) followed by water (x2). The organic phase was then dried over Na 2 S0 4 , filtered and evaporated. The residue was purified by reverse phase column chromatography (using a biotage automated system) and eluting with acetonitrile in water (0-100%). It was then further purified by prep HPLC.
  • reaction mixture was stirred at room temp for 2h and then diluted with DCM and washed with saturated NaHC0 3 (aq) followed by water (x2). The organic phase was dried over Na 2 S0 4 , filtered and evaporated. The residue was purified by column Prep HPLC.
  • N-(4-(tetrazolori,5-a1quinoxalin-4-ylamino)phenyl)oxazole-4-carboxamide (example 5) N 1 -(tetrazolo[l,5-a]quinoxalin-4-yl)benzene-l,4-diamine (XXXII) (25mg, 0.090 mmol, 1.0 equiv.) was dissolved in DMF (1 ml).
  • test compounds are added directly into a cell lysate.
  • Various concentrations of test compounds were added to HeLa cell lysate samples and allowed to bind to the proteins contained in the lysate sample.
  • the affinity matrix was added to capture proteins not bound to the test compound.
  • the beads with captured proteins were separated from the lysate. Bead-bound proteins were then eluted and the presence of TNKS 1 was detected and quantified using specific antibodies and the Odyssey Infrared Detection system. Further experimental protocols can be found in WO201 1/018241.
  • the affinity matrix was washed three times with 5 - 10 volumes of DP buffer (50 mM Tris-HCl pH 7.4, 5% Glycerol, 1.5 mM MgCl 2 , 150 mM NaCl, 1 mM Na 3 V0 4 , 0.4% NP- 40, 1 mM DTT). Beads were collected by centrifugation (2 minutes at 300 x g in a Herareus centrifuge) and finally resuspended in DP buffer to prepare a 3 % beads slurry. Preparation of test compounds
  • Stock solutions of test compounds were prepared in DMSO corresponding to a 50-fold higher concentration compared to the final desired test concentration (e.g. a 10 mM stock solution was prepared for a final test concentration of 200 ⁇ ). This dilution scheme resulted in a final DMSO concentration of 2%.
  • HeLa cells were obtained from an external supplier (CIL SA, Mons, Belgium). The harvested cells were subjected to cell lysis. Preparation of cell lysates
  • lysis buffer 50 mM Tris-HCl pH 7.4, 0.8% NP40, 5% glycerol, 150 mM NaCl, 1.5 mM MgCl 2 , 25 mM NaF, 1 mM sodium vanadate, 1 mM DTT supplemented with protease inhibitors (protease inhibitor cocktail, Roche Diagnostics, 1 873 580; 1 tablet per 25 ml buffer).
  • protease inhibitors protease inhibitor cocktail, Roche Diagnostics, 1 873 580; 1 tablet per 25 ml buffer.
  • the material was dounced 20 times using a mechanized POTTER S, transferred to 50 ml falcon tubes, incubated for 30 minutes rotating at 4°C and centrifuged for 10 minutes at 20,000 x g at 4°C (10,000 rpm in Sorvall SLA600, precooled). The supernatant was transferred to an ultracentrifuge- polycarbonate tube (Beckmann, 355654) and spun for one hour at 145.000 x g at 4°C (40.000 rpm in ⁇ 50.2, precooled). The supernatant was transferred to a fresh 50 ml falcon tube, the protein concentration was determined by a Bradford assay (BioRad) and samples containing 50 mg of protein per aliquot were prepared. The samples were immediately used for experiments or frozen in liquid nitrogen and stored frozen at -80°C.
  • lysate aliquot containing 230 mg of protein was thawed in a 21 °C water bath and then kept at 4°C.
  • the lysate was diluted by adding DP buffer supplemented with protease inhibitors to obtain a final protein concentration of 7.5 mg/ml and a final NP-40 concentration of 0.4% (weight/volume).
  • the filter plate was placed on top of a collection plate (Greiner bio-one, polypropylene microplate 384 well V-shape, 781 280) and the beads were eluted with 20 ⁇ elution buffer (100 mM Tris, pH 7.4, 4% SDS, 0.01% Bromophenol blue, 20% glycerol, 50 mM DTT).
  • 20 ⁇ elution buffer 100 mM Tris, pH 7.4, 4% SDS, 0.01% Bromophenol blue, 20% glycerol, 50 mM DTT.
  • the eluate was stored at -20°C or directly used for spotting on a nitrocellulose membrane.
  • TNKS1 in the eluates was detected and quantified by spotting on nitrocellulose membranes and using a first antibody directed against the protein of interest and a fluorescently labelled secondary antibody (anti -rabbit IRDyeTM antibodies).
  • the Odyssey Infrared Imaging system from LI-COR Biosciences (Lincoln, Iowa, USA) was operated according to instructions provided by the manufacturer (Schutz-Geschiller et al., 2004. Quantitative, two-color Western blot detection with infrared fluorescence. Published May 2004 by LI-COR Biosciences, www.licor.com).
  • the nitrocellulose membranes (BioTrace NT; PALL, BTNT30R) were first blocked by incubation with Odyssey blocking buffer (LICOR, 927- 40000) for one hour at room temperature. Blocked membranes were then incubated for 16 hours at 4°C with the first antibody diluted in Odyssey blocking buffer supplemented with 0.4% Tween 20. Afterwards the membranes were washed three times for 5 minutes with 15 ml PBS buffer containing 0.1% Tween 20 (Sigma, T2700) at room temperature.
  • Odyssey blocking buffer LICOR, 927- 40000
  • the membranes were incubated for 60 minutes at room temperature with the detection antibody (IRDyeTM labelled antibody from LI-COR) diluted in Odyssey blocking buffer (LICOR 927-40000) containing 0.2% Tween 20. Afterwards the membranes were washed four times for 5 minutes each with PBS buffer containing 0.1% Tween 20 at room temperature. Then the membrane was rinsed twice with PBS buffer to remove residual Tween-20. The membranes were then scanned with the Odyssey Infrared Imaging system. Fluorescence signals were recorded and analysed according to the instructions of the manufacturer. Concentration response curves were computed with BioAssay and Tibco Spotfire.
  • This reporter gene assay was used to assess the effect of compounds of the invention on the Wnt signalling pathway.
  • Human HEK293 cells were transiently transfected with a TCF/LEF luciferase reporter plasmid and the Wnt pathway was stimulated at the receptor level by treatment with the human recombinant Wnt-3a ligand and the synergistic activator R-spondin 1.
  • Transduction of the signal through TNKS, axin, and the ⁇ -catenin "destruction complex" results in an increase of liberated dephosphorylated ⁇ -catenin, which accumulates in the nucleus and induces transcription of the reporter gene.
  • HEK293 cells (#ACC-305, DSMZ, Braunschweig, Germany) were transiently transfected with a TCF/LEF luciferase reporter plasmid (#CCS-018L, Qiagen, Hilden, GER) and stimulated with human recombinant Wnt-3a (#5036-WN, R&D, Minneapolis, MN) plus the synergistic activator R-spondin 1 (#4645 -RS, R&D) to induce the Wnt pathway at the cell receptor level.
  • the assay was performed Black-wall flat clear bottom 96-well plates (#3603, Corning, Corning, NY).
  • the transfection mixture was prepared in 1.5 mL tubes (#616201, Greiner, Frickenhausen, GER) prior to cell seeding by subsequent addition of 50 ⁇ , ⁇ OptiMEM (#31985-062, Life Technologies, Carlsbad, CA), 0.1 ⁇ g well Cignal TCF/LEF reporter mix (part of Qiagen #CCS-018L), and 0.5 ⁇ TransIT-LTl transfection reagent (#2300A, Mirus Biosciences, Madison, WI). The solution was incubated at room temperature (RT) for 30 minutes.
  • RT room temperature
  • HEK293 cells were maintained in DMEM medium (#41965, Life Technologies) supplemented with 10% FBS (#10270, Life Technologies; abbreviated "D-10 medium” thereafter) and grown to up to 80% confluency. Cells were detached using Trypsin/EDTA (#25300, Life Technologies) and resuspended in D-10 medium. Cells were counted, centrifuged (260 x g, 5 min, RT), resuspended in DMEM medium (#41965, Life Technologies) supplemented with 2% FBS at a concentration of 0.5 x 10 6 /mL, and distributed at 100 ⁇ over a 96-well assay plate (#3603, Corning). Immediately afterwards 50 ⁇ of the prepared transfection mixture were added to the assay plate. The mixture was slowly released over the cells and the plate was gently swirled. The plates were incubated overnight (20 hours) at 37°C, 5% C02.
  • Wnt-3a (stock solution 100 ⁇ g/mL in PBS (#14190, Life Technologies) supplemented with sterile-filtered (0.22 ⁇ pore size, #16534, Sartorius, Gottingen, GER) BSA solution (#05480, Fluka, Sigma, St Louis, MO) at a final concentration of 0.4%) was stored in single use aliquots at -80°C.
  • R-spondin 1 (stock solution 5 ⁇ in PBS supplemented with 0.22 ⁇ sterile filtered BSA solution at a final concentration of 0.4%) ) was stored in single use aliquots at -80°C.
  • Both Wnt-3a and R-spondin were diluted in D-10 medium to concentrations of 0.80 ⁇ g/mL (Wnt-3a) and 50 nM (R-spondin 1). Of this mixture, 20 ⁇ were added to the assay plate to obtain final concentrations of 0.16 ⁇ g/mL of Wnt-3a and 10 nM of R-spondin 1. The assay plate was incubated for 24 hours at 37°C, 5% C02.
  • Reagents of the Bright Glo luciferase kit (#E2620, Promega) were prepared according to the manufacturer's instructions and 75 ⁇ luciferase substrate was added to the assay plate. The plate was shaken at 300 rpm for 5 minutes at room temperature in the dark (Thermomixer comfort, Eppendorf, Hamburg, GER) and kept resting in the dark for another 5 minutes.
  • Luminescence was measured in a luminometer (Envision 2103, Perkin Elmer, Waltham, MA, or MicroLumat Plus, Berthold Technologies, Bad Wildbad, GER;acquisition time 3 sec/well) and data were analysed by normalizing results to positive controls (Wnt-3a/R-spondin 1 -stimulated cells) and negative controls (unstimulated cells) using Microsoft Excel and GraphPad Prism software.

Abstract

L'invention concerne des composés de formule (I), dans laquelle X, R1, y et R2 ont la signification indiquée dans la description et les revendications. Ces composés sont utiles comme inhibiteurs de la tankyrase pour le traitement ou la prophylaxie de troubles ou maladies immunologiques, inflammatoires, auto-immunes, allergiques, de maladies proliférantes, de maladies neurodégénératives, de la fibrose, ou pour induire la cardiomyogenèse. L'invention concerne également des compositions pharmaceutiques contenant lesdits composés, ainsi que leur utilisation comme médicaments.
PCT/IB2013/002059 2012-09-21 2013-09-19 Dérivés de tétrazolo quinoxaline utilisés comme inhibiteurs de la tankyrase WO2014045101A1 (fr)

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WO2018073602A1 (fr) * 2016-10-20 2018-04-26 Almac Discovery Limited Dérivés de pipéridine utilisés comme inhibiteurs de la protéase spécifique de l'ubiquitine 7
US10391168B1 (en) 2014-08-22 2019-08-27 University Of Bern Anti-CD70 combination therapy
US10722484B2 (en) 2016-03-09 2020-07-28 K-Gen, Inc. Methods of cancer treatment
US11072665B2 (en) 2011-03-16 2021-07-27 Argenx Bvba Antibodies to CD70
US11712468B2 (en) 2018-12-18 2023-08-01 argenx BV CD70 combination therapy

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US11072665B2 (en) 2011-03-16 2021-07-27 Argenx Bvba Antibodies to CD70
US11434298B2 (en) 2011-03-16 2022-09-06 argenx BV Antibodies to CD70
US9193689B2 (en) 2012-03-07 2015-11-24 Institute Of Cancer Research: Royal Cancer Hospital (The) 3-aryl-5-substituted-isoquinolin-1-one compounds and their therapeutic use
US9611223B2 (en) 2013-09-11 2017-04-04 Institute Of Cancer Research: Royal Cancer Hospital (The) 3-aryl-5-substituted-isoquinolin-1-one compounds and their therapeutic use
US11571475B1 (en) 2014-08-22 2023-02-07 University Of Bern Anti-CD70 and BCR-ABL inhibitor combination therapy
US10391168B1 (en) 2014-08-22 2019-08-27 University Of Bern Anti-CD70 combination therapy
US10722484B2 (en) 2016-03-09 2020-07-28 K-Gen, Inc. Methods of cancer treatment
CN110088096A (zh) * 2016-10-20 2019-08-02 阿尔麦克探索有限公司 作为泛素特异性蛋白酶7的抑制剂的哌啶衍生物
US10766903B2 (en) 2016-10-20 2020-09-08 Almac Discovery Limited Piperidine derivatives as inhibitors of ubiquitin specific protease 7
JP7073359B2 (ja) 2016-10-20 2022-05-23 アルマック・ディスカバリー・リミテッド ユビキチン特異的プロテアーゼ７の阻害剤としてのピペリジン誘導体
JP2019535664A (ja) * 2016-10-20 2019-12-12 アルマック・ディスカバリー・リミテッドＡｌｍａｃ Ｄｉｓｃｏｖｅｒｙ Ｌｉｍｉｔｅｄ ユビキチン特異的プロテアーゼ７の阻害剤としてのピペリジン誘導体
WO2018073602A1 (fr) * 2016-10-20 2018-04-26 Almac Discovery Limited Dérivés de pipéridine utilisés comme inhibiteurs de la protéase spécifique de l'ubiquitine 7
US11712468B2 (en) 2018-12-18 2023-08-01 argenx BV CD70 combination therapy

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