WO2017055313A1 - Composés azole amido-substitués - Google Patents

Composés azole amido-substitués Download PDF

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WO2017055313A1
WO2017055313A1 PCT/EP2016/073040 EP2016073040W WO2017055313A1 WO 2017055313 A1 WO2017055313 A1 WO 2017055313A1 EP 2016073040 W EP2016073040 W EP 2016073040W WO 2017055313 A1 WO2017055313 A1 WO 2017055313A1
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compound
alkyl
general formula
carbamoyl
phenyl
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PCT/EP2016/073040
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English (en)
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Knut Eis
Jens Ackerstaff
Sarah WAGNER
Philipp BUCHGRABER
Detlev Sülzle
Eckhard Bender
Volkhart Min-Jian Li
Ningshu Liu
Franziska SIEGEL
Philip Lienau
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Bayer Pharma Aktiengesellschaft
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to amido-substituted azole compounds of general formula (I) as described and defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms, as a sole agent or in combination with other active ingredients.
  • Cancer is the leading cause of death in developed countries and the second leading cause of death in developing countries. Deaths from cancer worldwide are projected to continue rising, with an estimated 12 million deaths in 2030. While substantial progress has been made in developing effective therapies, there is a need for additional therapeutic modalities that target cancer and related diseases.
  • cancer stem cells represent the apex in the hierarchical model of tumor genesis, heterogeneity and metastasis.
  • CSCs possess the capacity for unlimited self-renewal, the ability to give rise to progeny cells, and also an innate resistance to cytotoxic therapeutics [Meacham CE and Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature 2013 , 501 :328]. Thus, there is need to develop drugs for cancer therapy addressing distinct features of established tumors.
  • Wnt signaling cascades have classified into two categories: canonical and non- canonical, differentiated by their dependence on ⁇ -catenin.
  • Non-canonical Wnt pathways such as the planar cell polarity (PCP) and Ca 2+ pathway, function through ⁇ -catenin independent mechanisms.
  • Canonical Wnt signalling is initiated when a Wnt ligand engages co- receptors of the Frizzled (Fzd) and low- density lipoprotein receptor related protein (LRP) families, ultimately leading to ⁇ -catenin stabilization, nuclear translocation and activation of target genes [Angers S, Moon RT. Proximal events in Wnt signal transduction. Nat Rev Mol Cell Biol. 2009, 10: 468.
  • ⁇ -catenin In the absence of Wnt stimulus, ⁇ -catenin is held i n an inactive state by a multimeric "destruction" complex comprised of adenomatous polyposis coli (APC), Axin , glycogen synthase kinase 36 (GSK36) and casein kinase 1 a (CK1 a).
  • APC and Axin function as a scaffold, permitting GSK36- and CK1 a-mediated phosphorylation of critical residues within ⁇ -catenin.
  • ⁇ -catenin is stabilized and translocated to the nucleus.
  • 6- catenin forms a complex with members of the T-cell factor/lymphoid enhancer factor (TCF/ LEF) family of transcription factors, recruiting co-factors such as CBP, p300, TNIK, Bcl9 and Pygopus, and ultimately driving transcription of target genes including c-myc, 0ct4, cyclin D, survivin.
  • TCF/ LEF T-cell factor/lymphoid enhancer factor
  • Tankyrases play a key role in the destruction complex by regulating the stability of the rate-limiting AXIN proteins, RNF1 6 and tankyrase itself.
  • the E3 ubiquitin ligase RNF1 6 recognizes tankyrase-mediated PARsylation and eartags AXIN, tankyrase and itself for proteasome-mediated degradation.
  • tankyrases control the protein stability and turnover of key components of the destruction complex, and consequently the cellular levels of ⁇ -catenin [Huang SMA, Mishina YM, Liu S, Cheung A, Stegmeier F, et al.
  • Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 2009, 461:614, Zhang Y, Liu S, Mickanin C, Feng Y, Charlat 0, et al.
  • RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling. Nature Cell Biology 2011, 13:623, 2011].
  • Wnt/B-catenin signaling pathway Aberrant regulation of the Wnt/B-catenin signaling pathway is a common feature across a broad spectrum of human cancers and evolves as a central mechanism in cancer biology.
  • Wnt overexpression could lead to malignant transformation of mouse mammary tissue [Klaus A, BirchmeierW. Wnt signalling and its impact on development and cancer. Nat Rev Cancer 2008, 8: 387] .
  • Second, tumor genome sequencing discovered the mutations in Wnt/B-catenin pathway components as well as epigenetic mechanisms that altered the expression of genes relevant to Wnt/ B-catenin pathway [Ying Y. et al. Epigenetic disruption of the WNT I beta-catenin signaling pathway in human cancers. Epigenetics 2009, 4:307] .
  • Wnt/B-catenin pathway also cooperates with other oncogenic signaling pathways in cancer and regulates tumorigenesis, growth, and metastasis [Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer 8: 387-398, 2008].
  • WNT signaling between tumor and stromal cell interaction leading to tumorigenesis and metastasis [Shahi P, Park D, Pond AC, Seethammagari M, Chiou S-H, Cho K, et al. Activation of Wnt signaling by chemically induced dimerization of LRP5 disrupts cellular homeostasis.
  • PLoS ONE 2012, 7: e30814
  • stem- like colon cells with a high level of B-catenin signaling have a much greater tumorigenic potential than counterpart cells with low ⁇ -catenin signaling
  • ⁇ -catenin signaling Vermeulen L, De Sousa EMF, van der Heijden M, Cameron K, de Jong JH, Borovski T, Tuynman JB, Todaro M, Merz C, Rodermond H, Sprick MR, Kemper K, Richel DJ, Stassi G, Medema JP.
  • Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol. 2010, 12: 468].
  • activation of Wnt/6-catenin signalling pathway is also one of the major mechanism causing tumor recurrence and drug resistance. All these provide clear rationale to develop therapeutics targeting Wnt/6-catenin signaling pathway for the treatment of cancer.
  • Inhibition of TNKS blocks PARsylation of AXIN1 and AXIN2 and prevents their proteasomai degradation.
  • TNKS inhibition enhances the activity of the ⁇ -catenin destruction complex and suppresses 6- catenin nuclear transclocation and the expression of ⁇ -catenin target genes.
  • tankyrases are also implicated in other cellular functions, including telomere homeostasis, mitotic spindle formation, vesicle transport linked to glucose metabolism, and viral replication. In these processes, tankyrases interact with target proteins, catalyze poly (ADP-ribosyl)ation, and regulate protein interactions and stability.
  • TNKS1 controls telomere homeostasis, which promotes telomeric extension by PARsylating TRF1.
  • TRF1 is then targeted for proteasomai degradation by the E3 ubiquitin ligases F- box only protein 4 and/or RING finger LIM domain-binding protein (RLIM/RNF12), which facilitates telomere maintenance [Donigian JR and de Lange T. The role of the poly(ADP-ribose) polymerase tankyrase 1 in telomere length control by the TRF1 component of the shel terin complex. J Biol Chem 2007, 282:22662]. In addition, telomeric end-capping also requires canonical DNA repair proteins such as DNA-dependent protein kinase (DNAPK).
  • DNAPK DNA-dependent protein kinase
  • TNKS1 stabilizes the catalytic subunit of DNAPK (DNAPKcs) by PARsylation [Dregalla RC, Zhou J, Idate RR, Battaglia CL, Liber HL, Bailey SM. Regulatory roles of tankyrase 1 at telomeres and in DNA repair: suppression of T-SCE and stabilization of DNA-PKcs. Aging 2010, 2(10):691] . Altered expression of TNKS1 and/or TNKS2, as well as genetic alterations in the tankyrase locus, have been detected in multiple tumors, e.g.
  • tankyrases appear to have impact on viral infections. For example, in HSV infection, it was shown that the virus cannot replicate efficiently in cells with depletion of both TNKS1 and TNKS2 [Li I, Yamauchi Y,
  • TNKS1 knockout mice appeared to have reduced fat pads, suggesting a potential connection of TNKS and obesity. TNKS may also play a role in tissue fibrosis.
  • tankyrases are promising drug targets in regulating WNT signaling, telomere length (e.g. telomere shortening and DNA damage induced cell death), lung fibrogenesis, myelination and viral infection.
  • the invention presented here describes a novel class of tankyrase inhibitors and their potential clinical utility for the treatment of various diseases, such as cancer, aging, metabolic diseases (e.g. diabetes and obesity), fibrosis (e.g. lung fibrogenesis) and viral infection.
  • WO 2001 /000575 discloses heterocyclic dicarboxylic acid diamide derivatives as insecticides, including amido-substituted azole compounds.
  • R' represents -OR 9 , or -N(R ,0 )R n , which are as defined herein,
  • X 2 represents CR 6 or N, and R 4 , R 5 , R 6 , R 7 and R 8 are as defined herein, and
  • R 2 represents a group selected from hydrogen, d-Cralkyl, and CrCi-cycloalkyl ;
  • said compounds of the present invention have surprisingly been found to effectively inhibit TNKS1 and/or TNKS2 and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses mediated by TNKS1 and/or TNKS2 and/or mediated by the Wnt pathway, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g.
  • leukaemias and myelodysplastic syndrome malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
  • Compounds of the present invention may additionally show improved selectivity for TNKS1 and/or TNKS2 (e.g.
  • the present invention covers compounds of general formula (I) :
  • X 1 represents NR 3 or 0,
  • X 2 represents CR 6 or N
  • R 1 represents a group selected from :
  • R 2 represents a group selected from :
  • R 3 represents hydrogen
  • R 4 represents hydrogen
  • R 5 represents a group selected from :
  • R 6 represents a group selected from :
  • R 7 represents hydrogen
  • R 8 represents a group selected from :
  • aryl aryl-(Ci-C4-alkyl)-, heteroaryl, and heteroaryl- (Ci-Gralkyl)-,
  • aryl and heteroaryl groups are optionally substituted with one, two or three substituents, which are independently of each other selected from : G-G-alky , G-Gralkoxy, G-Grhydroxyalkyl, GrG-cycloalkyl, G-G-cycloalkoxy, G-Grhaloalkyl, G-G-haloalkoxy, halogen, cyano, nitro, hydroxy, -N(R'°)R" , R'°(R" )N-(G-G.-alkyl)-, R 10 (R 11 )N-(C 2 -C 4 -alkoxy)-,
  • R 9 represents G-Gralkyl
  • R 10 and R" are independently of each other selected from :
  • G-G-hydroxyalkyl (G-G-alkoxy)-(G-G-alkyl)-, G-G-haloalkyl, H 2 N-(GrG-alkyl)- , (G -G- alkyl)N(H)(G-G-alkyl)-, (G-G-alkyl) 2 N(G-G-alkyl)-, 4-6 membered heterocycloalkyl, (4-6 membered heterocycloalkyl)- (G-G-alkyl)-,
  • 4-6-membered heterocycloalkyl groups are optionally substituted with one or two substituents, which are independently of each other selected from :
  • R 12 represents a group selected from :
  • each definition is independent.
  • R 10 , R 11 , and/or R 12 occur more than one time in any compound of formula (I ) each definition of R'°, R" , and R 12 is independent.
  • a hyphen at the beginning or at the end of the constituent marks the point of attachment to the rest of the molecule. Should a ring be substituted the substitutent could be at any suitable position of the ring, also on a ring nitrogen atom if suitable.
  • halogen halogen atom
  • halo- halo- or Hal-
  • fluorine chlorine, bromine or iodine atom.
  • Ci-Ct-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, or 4, carbon atoms, e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, more particularly 1 , 2 or 3 carbon atoms ("G -Cralkyl ”) , e.g. a methyl, ethyl, n-propyl- or iso- propyl group, even more particularly 1 or 2 carbon atoms ("Ci -Cj-alkyl”), e.g. a methyl, ethyl group.
  • C2-C4-alkyl is to be understood as preferably meaning a linear or branched , saturated, monovalent hydrocarbon group having 2, 3 , or 4, carbon atoms, e.g. a ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, more particularly 2 or 3 carbon atoms e.g. a ethyl, n-propyl- or iso-propyl group, even more particularly 2 carbon atoms (“Cralkyl”) , i. e. a ethyl group.
  • G-Cs-hydroxya kyl is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "G -Cralkyl” is defined supra, and in which one or more hydrogen atoms is replaced by a hydroxy group, e.g. a hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3- hydroxypropyl , 2-hydroxypropyl, 2, 3-dihydroxypropyl, 1 , 3-dihydroxypropan-2-yl group.
  • G-G-hydroxyalkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "G-G-alkyl” is defined supra, and in which one or more hydrogen atoms is replaced by a hydroxy group, e.g. a 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2, 3-dihydroxypropyl, 3-hydroxy- 2-methyl-propyl , 2-hydroxy-2-methyl-propyl group.
  • CrC4-haloalkyl is to be understood as preferably meaning a linear or branched , saturated, monovalent hydrocarbon group in which the term "G-G-alkyl” is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom , in identically or differently, i. e. one halogen atom being independent from another. Particularly, said halogen atom is F.
  • Said G-G-ha oa kyl group is, for example, CF), -CHF2, -CH2F, -CF2CF3, - CH2CH2F, -CH2CHF2, -CH2CF3, or -CH2CH2CF3.
  • G -G-alkoxy is to be understood as preferably meaning a linear or branched, saturated , monovalent, hydrocarbon group of formula 0-alkyl having 1 , 2 , or 3 carbon atoms, in which the term “alkyl” is defined supra, e.g. a methoxy, ethoxy, n-propoxy, or iso-propoxy group, or an isomer thereof.
  • G-Crhaloalkoxy is to be understood as preferably meaning a linear or branched, saturated, monovalent G-Ci-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom. Particularly, said halogen atom is F.
  • Said G-Crhaloalkoxy group is, for example, OCF3, - OCHF?, -OCH7F, -OCF 2 CF 3) or -OCH2CF3.
  • C3-C -cycloalkyl is to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, or 4, carbon atoms (“CrG-cycloalkyl”).
  • Said G-G-cyc oa ky group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, or cyclobutyl ring.
  • C3-G-cycloalkoxy is to be understood as preferably meaning a saturated, monovalent, hydrocarbon ring which contains 3. or 4 carbon atoms of formula 0- cycloalkyl, in which the term "cycloalkyl” is defined supra, e.g. a cyclopropyloxy, or cyclobutyloxy.
  • said heterocycloalkyl can be a 4-membered ring, such as an azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or N- methylpiperazinyl.
  • said heterocycloalkyl can be benzo fused.
  • 4- to 6-membered heterocycloalkyl can be selected from piperazinyl, tetrahydro-2H-pyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, 2-oxoimidazolidinyl, 2-oxopyrrolidinyl and 1 , 1 - dioxidothiomorpholinyl.
  • 4- to 6- membered heterocycloalkyl can be selected from piperazin-1 -yl, tetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, pyrrolidin-1 -yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-4-yl, piperidin-1 -yl, piperidin-2-yl, piperidin-3-yl, morpholin-4-yl, azetidin-1 -yl, tetrahydrofuran-2-yl, 2-oxoimidazolidin-1 -yl, 2-oxopyrrolidin-1 -yl and 1 , 1 - dioxidothiomorpholin-4-yl.
  • aryl is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, mono- or bicyclic hydrocarbon ring having 6, 7, 8, 9 or 10 carbon atoms (a "C6-Cio-aryl” group), particularly a ring having 6 carbon atoms (a "Ce-aryl” group), e.g. a phenyl group; or a ring having 9 carbon atoms (a "Cg-aryl” group), e.g. an indanyl or indenyl group, or a ring having 10 carbon atoms (a "Cio-aryl” group), e.g. a tetralinyl, dihydronaphthyl, or naphthyl group.
  • aryl is phenyl.
  • heteroaryl is understood as preferably meaning a monovalent, monocyclic aromatic ring system having 5 or 6 ring atoms (a "5- to 6-membered heteroaryl” group), which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen, NH or sulfur.
  • heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl etc.
  • heteroaryl can be selected from pyrazolyl, thienyl, pyridyl, furanyl, thiazolyl, oxazolyl, and pyrazinyl.
  • the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof.
  • the term pyridinyl or pyridinylene includes pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-yl and pyridin-4-ylene; or the term thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3- ylene.
  • heteroarylic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof.
  • pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.
  • aromatic and non-aromatic (hetero)cyclic groups may optionally be substituted as defined herein.
  • the substituents may be present both when said aromatic and non-aromatic (hetero)cyclic groups exist as a (unitary) constituent, such as, for example, G-G-cycloalkyl, 4- to 6-membered heterocycloalkyl, aryl and heteroaryl groups, or as part of a constituent composed of more than one part, such as, for example, (G-G-cycloalkyl)-G-G-alkyl-, (4- to 6-membered heterocycloalkyl)- (CrC -alkyl)- , aryl-(G-G-alkyl)-, and heteroaryl- (C i -G-alkyl )- , for example.
  • the present invention includes all suitably substituted aromatic and non-aromatic (hetero)cyclic groups both as a (unitary) constituent, or as part of a constituent composed of more than one part.
  • aromatic and non-aromatic (hetero)cyclic groups both as a (unitary) constituent, or as part of a constituent composed of more than one part.
  • suitable is to be understood as meaning chemically possible to be made by methods within the knowledge of a skilled person.
  • Ci-G as used throughout this text, e.g. in the context of the definition of "G- G-alkyl", or “G-G-haloalkyl”, is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 4, i.e. 1 , 2, 3, or 4 carbon atoms. It is to be understood further that said term “G-G,” is to be interpreted as any sub-range comprised therein, e.g. G-G. , G- , G-G , G-G , G-G ; particularly G-G , G-G , G-G. Similarly, as used herein, the term "C2-C4", as used throughout this text, e.g.
  • C2-C4-alkyl in the context of the definitions of "C2-C4-alkyl", and "C2-C4-hydroxyalkyl” is to be understood as meaning an a Iky I group or a hydroxyalkyl group having a finite number of carbon atoms of 2 to 4, i. e. 2, 3, or 4 carbon atoms. It is to be understood further that said term "C2-C4" is to be interpreted as any sub-range comprised therein, e.g. C2-C4 , C3-C4 , C2-C3; particularly
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded , and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • Ring system substituent means a substituent attached to an aromatic or nonaromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • the term "one or more”, e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning “one, two, three, four or five, particularly one, two, three or four, more particularly one, two or three, even more particularly one or two".
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature.
  • isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as H (deuterium), 3 H (tritium), "C, 13 C, 14 C, 15 N, ,7 0, 18 0, 32 P, 33 P, 3 S, 34 S, 35 S, 36 S, 18 F, 6Cl, 82 Br, 123 l, 124 l, 125 l, 129 l and 131 l, respectively.
  • isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as H (deuterium), 3 H (tritium), "C, 13 C, 14 C, 15 N, ,7 0, 18 0, 32 P, 33 P, 3 S, 34 S, 35 S, 36 S, 18 F, 6Cl, 82 Br, 123 l, 124
  • isotopic variations of a compound of the invention are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e. , 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence is preferred in some circumstances.
  • isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds of this invention optionally contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms is present in the (R) or (S) configuration , resulting in racemic mixtures in the case of a single asymmetric centre, and diastereomeric mixtures in the case of multiple asymmetric centres.
  • asymmetry may also be present due to restricted rotation about a given bond , for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • the compounds of the present invention optionally contain sulphur atoms which are asymmetric, such as an asymmetric sulfoxide, of structure: , for example,
  • Preferred compounds are those which produce the more desirable biological activity.
  • Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • appropriate acids are tartaric, diacetyl tartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g. , chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable chiral HPLC columns are manufactured by Daicel, e.g. , Chiracel OD and Chiracel OJ among many others, all routinely selectable.
  • Enzymatic separations, with or without derivatisation are also useful.
  • the optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. R- or S- isomers, or E- or Z-isomers, in any ratio.
  • Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method , such as chromatography, especially chiral chromatography, for example.
  • the compounds of the present invention may exist as tautomers.
  • any compound of the present invention which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1 H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, namely :
  • the present invention can exist as one of the below tautomers, or even in a mixture in any amount of the two tautomers, namely:
  • the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised.
  • the present invention includes all such possible N-oxides.
  • the present invention also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates.
  • the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds.
  • polar solvents in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds.
  • the amount of polar solvents, in particular water may exist in a stoichiometric or non-stoichiometric ratio.
  • stoichiometric solvates e.g. a hydrate, hemi-, (semi-), mono- , sesqui-, di- , tri- , tetra- , penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • the compounds of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
  • SCO S. M. Berge, er al. “Pharmaceutical Salts, " J. Pharm. Sci. 1977, 66, 1 -19.
  • a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bi sulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic,
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1 ,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1 -amino-2, 3,4- butantriol.
  • basic nitrogen containing groups may be quaternised with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides ; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate ; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate
  • diamyl sulfates long chain halides such as decyl, la
  • acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • in vivo hydrolysable ester is understood as meaning an in vivo hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, G-Ce alkoxymethyl esters, e.g. methoxymethyl, G-Ce alkanoyloxymethyl esters, e.g.
  • An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha] -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • inorganic esters such as phosphate esters and [alpha] -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • [alpha] -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • the present invention covers all such esters.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
  • the present invention covers compounds of general formula (I), supra, in which :
  • X 1 represents NR ;t ,
  • X 2 represents CR 6 ,
  • R' represents a group selected from :
  • R 2 represents a group selected from :
  • R 3 represents hydrogen
  • R 4 represents hydrogen
  • R 5 represents a group selected from :
  • R 6 represents a group selected from :
  • R 7 represents hydrogen
  • R 8 represents a group selected from :
  • aryl aryl-(CrC4-alkyl)-, heteroaryl, and heteroaryl- (Ci -C4-alkyl)-,
  • aryl and heteroaryl groups are optionally substituted with one, two or three substituents, which are independently of each other selected from :
  • G-G-alkyl G-Cs-a koxy, G-Cs-hydroxya kyl, G-Grhaloalkyl, halogen, cyano, -N(R 10 )R 11 ,
  • R 9 represents G-G-alkyl
  • R'° and R" are independently of each other selected from :
  • G-Grhydroxyalkyl (Ci-alkoxy)- (C2-C3-alkyl)-, G-G-ha oalky , HjN-iGi-G-alkyl)-, (G- alkyl)N(H)(G-G-alkyl)-, (G-alkyl) 2 N(G-G-alkyl)-, (4-6 membered heterocycloalkyl)- (G-G- alkyl)-, wherein 4-6-membered heterocycloalkyl groups are optionally substituted with one or two substituents, which are independently of each other selected from :
  • R' 2 represents a group selected from :
  • the present invention covers compounds of general formula (I ), supra, in which :
  • X 1 represents NR 3 ,
  • X 2 represents CR 6 ,
  • R 1 represents -N (R , 0 )R" ,
  • R 2 represents hydrogen
  • R 3 represents hydrogen
  • R 4 represents hydrogen
  • R 5 represents hydrogen
  • R0 represents hydrogen
  • R 7 represents hydrogen
  • R 8 represents a group selected from
  • aryl is optionally substituted with one, two or three substituents, which are independently of each other selected from :
  • R'° and R 11 are independently of each other selected from :
  • Ci -G-alkyl C3-C4-cycloalkyl, (C3-C4-cycloalkyl)-(Ci -alkyl)-,
  • the present invention covers compounds of general formula (I ), supra, in which :
  • X 1 represents NR 3
  • X 2 represents CR 6
  • R' represents -N(R 10 )R 11 ,
  • R 2 represents hydrogen
  • R 3 represents hydrogen
  • R4 represents hydrogen
  • R 5 represents hydrogen
  • R 6 represents hydrogen
  • R 7 represents hydrogen
  • R 8 represents a group selected from
  • aryl is optionally substituted with one, two or three substituents, which are independently of each other selected from :
  • R 10 and R" are independently of each other selected from :
  • the present invention covers a compound of general formula (I), supra, which is selected from the group consisting of :
  • the invention relates to compounds of formula (I), wherein :
  • X 1 represents NR 3 ,
  • X 2 represents CR 6 ,
  • R 1 represents -N(R !0 )R
  • R 2 represents hydrogen
  • R 3 represents hydrogen
  • R 4 represents hydrogen
  • R 5 represents hydrogen
  • R 6 represents hydrogen
  • R 7 represents hydrogen
  • R 8 represents a group selected from
  • aryl is optionally substituted with one, two or three substituents, which are independently of each other selected from :
  • R'° and R 11 are independently of each other selected from :
  • the invention relates to compounds of formula (I), wherein :
  • X 1 represents NR ⁇
  • X 2 represents CR 6 ,
  • R 1 represents -N (R , 0 )R" ,
  • R 2 represents hydrogen
  • R 3 represents hydrogen
  • R 4 represents hydrogen
  • R 5 represents hydrogen
  • R 6 represents hydrogen
  • R 7 represents hydrogen
  • R 8 represents a group selected from
  • aryl is optionally substituted with one, or two substituents, which are independently of each other selected from :
  • R'° and R" are independently of each other selected from :
  • the invention relates to compounds of formula (I), wherein :
  • X 1 represents NR 3 or 0.
  • the invention relates to compounds of formula (I), wherein :
  • X 1 represents NR 3 .
  • the invention relates to compounds of formula (I), wherein :
  • X 1 represents 0.
  • the invention relates to compounds of formula (I), wherein :
  • X 2 represents CR 6 or N ,
  • the invention relates to compounds of formula (I), wherein :
  • X 2 represents CR 6 .
  • the invention relates to compounds of formula (I), wherein :
  • X 2 represents N.
  • the invention relates to compounds of formula (I), wherein :
  • R 1 represents a group selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 1 represents a group selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 1 represents a group selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 2 represents a group selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 2 represents a group selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 2 represents hydrogen
  • the invention relates to compounds of formula (I), wherein :
  • R 5 represents a group selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 5 represents a group selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 5 represents hydrogen
  • the invention relates to compounds of formula (I), wherein :
  • R 6 represents a group selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 6 represents a group selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 6 represents hydrogen.
  • the invention relates to compounds of formula (I), wherein :
  • R 8 represents a group selected from :
  • aryl and heteroaryl groups are optionally substituted with one, two or three substituents, which are independently of each other selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 8 represents a group selected from :
  • aryl aryl-(Ci-Ct-alkyl)-, heteroaryl, and heteroaryl- (G-Oalkyl)-,
  • aryl and heteroaryl groups are optionally substituted with one, two or three substituents, which are independently of each other selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 8 represents a group selected from :
  • aryl is optionally substituted with one, two or three substituents, which are independently of each other selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 8 represents a group selected from :
  • aryl is optionally substituted with one, two or three substituents, which are independently of each other selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 8 represents aryl optionally substituted with one, two or three substituents, which are independently of each other selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 8 represents aryl-(Ci -Cralkyl)- wherein aryl is optionally substituted with one, two or three substituents, which are independently of each other selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 8 represents a group selected from :
  • aryl is optionally substituted with one, or two substituents, which are independently of each other selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 8 aryl, wherein aryl is optionally substituted with one, or two substituents, which are independently of each other selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 8 represents aryl-(Ci -G-alkyl)-, wherein aryl is optionally substituted with one, or two substituents, which are independently of each other selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 9 represents Ci-Cj-alkyl.
  • the invention relates to compounds of formula (I), wherein :
  • R 9 represents Ci -C 2 -alkyl.
  • the invention relates to compounds of formula (I), wherein :
  • R'° and R 11 are independently of each other selected from :
  • Ci Ci -Ca-alkyl, C3-C4-cycloalkyl, (C3-C4-cycloalkyl)-(0-C4-alkyl)-,
  • Ci-alkyl O-haloalkyl, Ci -alkoxy, Ci -haloalkoxy, halogen, and hydroxyl.
  • the invention relates to compounds of formula (I), wherein :
  • R'° and R 11 are independently of each other selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R'° is selected from hydrogen, and G -Ct-alkyl, preferably hydrogen,
  • R" is selected from :
  • 4- to 6-membered heterocycloalkyl groups are optionally substituted with one or two substituents, which are independently of each other selected from :
  • the invention relates to compounds of formula (I), wherein :
  • said 4-to 6-membered heterocycloalkyl group being optionally substituted with one or two substituents, which are independently of each other selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R'° and R" are independently of each other selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R'° is selected from hydrogen, and Ci -Ca-alkyl, preferably hydrogen,
  • R" is selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R'° and R 11 are independently of each other selected from : hydrogen, Ci-Cj-alkyl, CrC4-cycloalkyl, (CrC4-cycloalkyl)-(G-alkyl)-,
  • the invention relates to compounds of formula (I), wherein :
  • R 10 is selected from hydrogen, and G-G-alkyl, preferably hydrogen,
  • R" is selected from :
  • G-G-hydroxyalkyl (G-alkoxy)- (G-G-alkyl)-, G-Grhaloalkyl, H2N-(Cralkyl)-, (G- alkyl)N(H)(G-alkyl)-, (Ci-alkyl) 2 N(C2-alkyl)-, (6-membered heterocycloalkyl)-(C 2 -alkyl)-.
  • the invention relates to compounds of formula (I), wherein :
  • R 10 and R" are independently of each other selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R'° is selected from hydrogen, and CrC 2 -alkyl, preferably hydrogen,
  • R 11 is selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R'° and R" are independently of each other selected from :
  • R'° and R" are independently of each other selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 10 is selected from hydrogen, and Ci-Cralkyl, preferably hydrogen,
  • R n is selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R'° is selected from hydrogen, and Ci-C?-alkyl, preferably hydrogen,
  • R" is selected from :
  • R' 2 represents a group selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 12 represents a group selected from :
  • R 12 represents a group selected from :
  • the invention relates to compounds of formula (I), according to any of the above-mentioned embodiments, in the form of or a stereoisomer, a tautomer, an N- oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the present invention covers compounds of general formula (I) which are disclosed in the Example section of this text, infra.
  • the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein.
  • another aspect of the present invention relates to a method of preparing a compound of general formula (I) as defined herein, said method comprising the step of allowing an intermediate compound of general formula (III) :
  • Another aspect of the present invention relates to a method of preparing a compound of general formula (I) as defined herein, said method comprising the step of allowing an intermediate compound of general formula (3-4) :
  • Another aspect of the present invention relates to a method of preparing a compound of general formula (I ) as defined, said method comprising the step of allowing an intermediate compound of general formula (VI) : in which Xi represents NR 3 , X 2 , R 2 , R 3 , R 4 , R 5 , R 7 and R 8 are as defined herein for the compound of general formula (I),
  • Another aspect of the present invention relates to a method of preparing a compound of general formula (I) as defined herein, said method comprising the step of allowing an intermediate compound of general formula (IV) : in which X 1 represents N , and X 2 , R 2 , R 4 , R 5 , R 7 and R 8 are as defined herein for the compound of general formula (I),
  • X 1 represents NR 3 and X 2 , R ⁇ R 2 , R 3 , R 4 , R 5 , R 7 , and R 8 are as defined herein for the compound of general formula (I ).
  • Another aspect of the present invention relates to a method of preparing a compound of general formula (I ) as defined herein , said method comprising the step of allowing an intermediate compound of general formula (VII ) : in which X 2 , R 4 , R 5 , R 7 , and R 8 are as defined herein for the compound of general formula (I), to react with a compound of general formula (4-1 ) :
  • Another aspect of the invention is intermediate (3-4) or a salt thereof:
  • Xt represents NR 3 , X 2 , R ⁇ R 2 , R 3 , R 4 , R 5 , and R 9 are as defined herein for the compound of general formula (! ) and R 13 represents R 9 , or H.
  • Another aspect of the invention is intermediate (VI ) or a salt thereof:
  • Another aspect of the invention is intermediate (VII) or a salt thereof:
  • the present invention covers the use of the intermediate compounds of general formula (III), (3-4), (VI), (IV) and (VII), or a salt thereof for the preparation of a compound of general formula (I)
  • Another aspect of the invention relates to the intermediates or salts thereof described herein and their use for preparing a compound of formula (I) as defined supra or an N- oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
  • Aromatic amines as intermediates for the synthesis of compounds of the invention are either commercially available or can be synthesized as depicted in scheme 1 .
  • Scheme 1 Synthesis of aromatic amines, wherein X 2 , R 4 , R 5 , R 7 and R 8 are as defined for the compound of general formula (I) supra, and in which PG represents a protecting group, such as a BOC group, and W represents a hydroxy group or a chlorine atom.
  • PG represents a protecting group, such as a BOC group
  • W represents a hydroxy group or a chlorine atom.
  • amides of type 1 -3 can be obtained by reaction with amines of type 1-2 in the presence of a coupling agent such as, for example, HATU or PyBOP, or via the formation of the corresponding acid chloride of type 1 - 1.
  • a coupling agent such as, for example, HATU or PyBOP
  • amides of type 1 -3 can be obtained by reaction with amines of type 1 -2 in the presence of a coupling agent such as, for example, HATU or PyBOP, or via the formation of the corresponding acid chloride of type 1 - 1.
  • a coupling agent such as, for example, HATU or PyBOP
  • Scheme 2 Synthesis of 3,4 dicarboxylic acid substituted imidazoles, wherein X 1 represents NR 3 , and R 2 and R 3 are as defined for the compounds of general formula (I) supra.
  • benzene-1 ,2-diamine 2-1 can be reacted with carboxyclic acids at elevated temperatures to give compounds of type 2-2.
  • Scheme 3 Synthesis of compounds starting from dicarboxylic acid precursors, wherein Xt represents NR ⁇ except for compounds 3-1 and (III) wherein X 1 represents N, and X 2 , R' , R 2 , R ⁇ R 4 , R 5 , R 7 , R 8 , R 9 , R'° and R 1 1 are as defined for the compound of general formula (I) supra, and R 13 represents R 9 or H.
  • Compounds of general formula (I) can be obtained directly by reacting compounds of general formula (III) with a fully decorated aromatic amine of general formula (II) at room temperature or at elevated temperature (e.g. under reflux).
  • an intermediate of type 3-4 can be obtained by reacting a compound of general formula (III) with a suitably substituted aromatic amine of type 3-3 at room temperature or elevated temperature (e.g. under reflux).
  • compounds of general formula (I) can be obtained in a 2 step procedure from esters of type 3-4a via, first, ester hydrolysis to afford carboxylic acid 3-4b, for example, under basic conditions, followed by standard amide bond forming reactions, for example with amines of type 1 -2 in the presence of a coupling agent such as, for example, T3P, HATU, PyBOP, or alternatively in a three step procedure after hydrolysis of the ester, generation of corresponding acid chloride, for example using thionylchloride or 1 -chloro- N, N,2-tri methyl- 1 -propenylamine and reaction with amines of type 1 -2 under basic conditions in presence of , for example, N, N-diisopropylethylamine or pyridine.
  • a coupling agent such as, for example, T3P, HATU, PyBOP
  • a base such as, for example, N,N-diisopropylethylamine
  • Compounds of general formula (IV) can be transformed to compounds of general formula (I) by reaction with nucleophiles of type 3-2, such as, for example, amines HN(R'°)R" , or alcohols HOR 9 , optionally in the presence of a base, such as, for example N, N- diisopropylethylamine.
  • nucleophiles of type 3-2 such as, for example, amines HN(R'°)R" , or alcohols HOR 9 , optionally in the presence of a base, such as, for example N, N- diisopropylethylamine.
  • Compounds of general formula (VI) can be transformed into amides of general formula (I), according to the invention, for example by treatment with different amines of type HN(R ,0 )(R , , ) ) optionally in presence of a base, such as, for example, N,N- diisopropylethylamine.
  • a base such as, for example, N,N- diisopropylethylamine.
  • R 1 N(R 10 )R 11
  • a base such as, for example, N,N- diisopropylethylamine
  • a base such as, for example,N- diisopropy
  • Chemical names were generated using ACD/Name Batch Version 12.02.. In case there is discrepancy between the chemical name of a compound and its chemical structure, the chemical structure shall prevail. In some cases generally accepted names of commercially available reagents were used in place of ACD generated names.
  • NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.
  • the 1 H-NMR data of selected examples are listed in the form of ⁇ -NMR peaklists. For each signal peak the ⁇ value in ppm is given, followed by the signal intensity, reported in round brackets. The ⁇ value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: ⁇ (intensity! ), ⁇ ? (intensity?), ... , ⁇ ,- (intensity.), ... , ⁇ ⁇ (intensity,,).
  • the intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown.
  • a ⁇ -NMR peaklist is similar to a classical ' H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation.
  • peaklists can show solvent signals, signals derived from stereoisomers of target compounds (also the subject of the invention), and/or peaks of impurities.
  • the peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compounds (e.g. , with a purity of >90%).
  • Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify the reproduction of our manufacturing process on the basis of "by-product fingerprints".
  • An expert who calculates the peaks of the target compounds by known methods can isolate the peaks of target compounds as required , optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical ⁇ -NMR interpretation.
  • Method 2lnstrument Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1 .7 ⁇ , 50x2.1 mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1 .6 min 1 -99% B, 1 .6-2.0 min 99% B; flow 0.8 ml/ min; temperature: 60 C; DAD scan: 210-400 nm.
  • Method 4 Instrument: Waters Acquity UPLCMS Tof; column: Kinetex C 18 (Phenomenex) 2.6 ⁇ , 50x2.1 mm; eluent A: water + 0.05 Vol-% formic acid (99%), eluent B: acetonitrile + 0.05% formic acid; gradient: 0-0.2 min 98% A, 0.2-1 .7 min 98-10% A, 1 .7-1.9 min 10% A, 1.9-2.0 min 10-98% A, 2.0-2.5 min 98% A; flow 1.3 ml/min; temperature: 60 C; DAD scan: 210-400 nm
  • Instrument Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5 ⁇ 100x30mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient eluent A/ eluent B, flow 70 ml/min; temperature: 25 C; DAD scan: 210-400 nm.
  • Benzotriazol-1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (1 17 mg, 225 mol) and N.N-diisopropylethylamine (140 ⁇ , 820 mol) were added to a mixture of lithium 4- ⁇ [(4- ⁇ [2-(piperidin-1-yl)ethy[]carbamoy[ ⁇ -1H-imidazo[-5-yl)carbony[]amino ⁇ benzoate (100 mg, 80 % purity, 204 ⁇ ) and 1 -(3-chlorophenyl)methanamine (31.8 mg, 225 ⁇ ) and the mixture was stirred at room temperature for 12 h. For work-up, the reaction mixture was concentrated and the residue was purified by preparative HPLC (Method 6) followed by recrystallization from ethyl acetate to give the title compound (12.5 mg).
  • reaction mixture was concentrated and the residue was stirred with ethanol.
  • reaction mixture was concentrated and the residue was purified by flash column chromatography (25 g Snap cartridge, dichloromethane/ methanol-gradient, 20% -> 100% methanol) followed by trituration with dichloromethane to give the title compound (130 mg, 41%yield).
  • reaction mixture was concentrated and the residue was purified by flash column chromatography (25 g Snap cartridge, dichloromethane/ methanol-gradient, 20% -> 100% methanol) followed by trituration with dichloromethane to give the title compound (56 mg, 17 % yield).
  • reaction mixture was concentrated and the residue was purified by flash column chromatography (25 g Snap cartridge, dichloromethane/ methanol-gradient, 20% -> 100% methanol) followed by trituration with dichloromethane to give the title compound (417 mg, 80 % yield).
  • the compounds of formula (I) of the present invention can be converted to any salt as described herein, by any method which is known to the person skilled in the art.
  • any salt of a compound of formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
  • compositions containing one or more compounds of the present invention can be utilised to achieve the desired pharmacological effect by administration to a patient in need thereof.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention.
  • a pharmaceutically acceptable carrier is preferably a carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
  • a pharmaceutically effective amount of compound is preferably that amount which produces a result or exerts an influence on the particular condition being treated.
  • the compounds of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like.
  • the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
  • the solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled gelatine type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
  • the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatine, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, colouring agents, and flavouring agents such as peppermint, oil of wintergreen, or cherry flavouring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
  • binders such as acacia, corn starch or gelatine
  • disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid
  • Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
  • Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavouring and colouring agents described above, may also be present.
  • the pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
  • Suitable emulsifying agents may be (1 ) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol.
  • T e suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p- hydro xybenzoate ; one or more colouring agents ; one or more flavouring agents ; and one or more sweetening agents such as sucrose or saccharin.
  • Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavouring and colouring agents.
  • the compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in preferably a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1 ,1 -dioxolane-4-methanol, ethers such as polyethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant
  • Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid.
  • Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
  • Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates ; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates ; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers ; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quaternary ammonium salts, as well as mixtures.
  • suitable detergents include cationic detergents
  • compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimise or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile- lipophile balance (HLB) preferably of from about 12 to about 17. The quantity of surfactant in such formulation preferably ranges from about 5% to about 15% by weight.
  • the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
  • surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • compositions may be in the form of sterile injectable aqueous suspensions.
  • suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia ; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca- ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions.
  • sterile fixed oils are conventionally employed as solvents or suspending media.
  • any bland, fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can be used in the preparation of injectables.
  • composition of the invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are, for example, cocoa butter and polyethylene glycol.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g. , US Patent No. 5,023,252, issued June 1 1 . 1991 , incorporated herein by reference).
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art.
  • a mechanical delivery device It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device.
  • the construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art.
  • Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier.
  • One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body is described in US Patent No. 5,01 1 ,472, issued April 30, 1991 .
  • compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired.
  • Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M. F. et al. , "Compendium of Excipients for Parenteral Formulations” PDA Journal of Pharmaceutical Science 6t Technology 1998, 52(5), 238-31 1 ; Strickley, R.G “Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1 " PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349 ; and Nema, S. et al. , "Excipients and Their Use in Injectable Products” PDA Journal of Pharmaceutical Science & Technology 1997, 51 (4), 166-171 .
  • compositions for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid) ;
  • alkali nizing agents examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine) ;
  • adsorbents examples include but are not limited to powdered cellulose and activated charcoal
  • aerosol propellents examples include but are not limited to carbon dioxide, CCI 2 F 2 , F 2 C C- CClFz and CCIF3
  • air displacement agents examples include but are not limited to nitrogen and argon
  • antifungal preservatives examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate
  • benzoic acid examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate
  • antimicrobial preservatives examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal
  • examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal
  • antioxidants examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite) ;
  • binding materials examples include but are not limited to block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene- butadiene copolymers
  • buffering agents examples include but are not limited to potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate
  • carrying agents examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection
  • examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection
  • chelating agents examples include but are not limited to edetate disodium and edetic acid
  • colourants examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red
  • FD&C Red No. 3 examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red
  • clarifying agents examples include but are not limited to bentonite
  • emulsifying agents examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate) ;
  • encapsulating agents examples include but are not limited to gelatin and cellulose acetate phthalate
  • flavourants examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin
  • examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin
  • humectants examples include but are not limited to glycerol, propylene glycol and sorbitol
  • levigating agents examples include but are not limited to mineral oil and glycerin
  • oils examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil) ;
  • ointment bases examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment
  • examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment
  • penetration enhancers include but are not limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas
  • monohydroxy or polyhydroxy alcohols mono-or polyvalent alcohols
  • saturated or unsaturated fatty alcohols saturated or unsaturated fatty esters
  • saturated or unsaturated dicarboxylic acids saturated or unsaturated dicarboxylic acids
  • essential oils phosphatidyl derivatives
  • cephalin cephalin
  • terpenes amides, ethers, ketones and ureas
  • plasticizers examples include but are not limited to diethyl phthalate and glycerol
  • solvents examples include but are not limited to ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation
  • water for injection examples include but are not limited to diethyl phthalate and glycerol
  • solvents examples include but are not limited to ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation
  • stiffening agents examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax
  • stiffening agents include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax
  • suppository bases examples include but are not limited to cocoa butter and polyethylene glycols (mixtures)
  • surfactants examples include but are not limited to benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono-palmitate
  • examples include but are not limited to cocoa butter and polyethylene glycols (mixtures)
  • surfactants examples include but are not limited to benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono-palmitate
  • suspending agents examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum
  • agar bentonite
  • carbomers carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum
  • sweetening agents examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose
  • sweetening agents include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose
  • tablet anti-adherents examples include but are not limited to magnesium s tea rate and talc
  • tablet binders examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch
  • examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch
  • tablet and capsule diluents examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch) ;
  • tablet coating agents examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac) ;
  • tablet direct compression excipients examples include but are not limited to dibasic calcium phosphate
  • tablet disintegrants examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross- linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch
  • examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross- linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch
  • tablet glidants examples include but are not limited to colloidal silica, corn starch and talc) ;
  • tablet lubricants examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate
  • examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate
  • tablet/capsule opaquants examples include but are not limited to titanium dioxide
  • tablet polishing agents examples include but are not limited to carnuba wax and white wax
  • thickening agents examples include but are not limited to beeswax , cetyl alcohol and paraffin
  • tonicity agents examples include but are not limited to dextrose and sodium chloride
  • viscosity increasing agents examples include but are not limited to alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth
  • wetting agents examples include but are not limited to heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).
  • compositions according to the present invention can be illustrated as follows:
  • Sterile IV Solution A 5 mg/mL solution of the desired compound of this invention can be made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 - 2 mg/mL with sterile 5% dextrose and is administered as an IV infusion over about 60 min.
  • a sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lyophilised powder, (ii) 32- 327 mg/mL sodium citrate, and (iii) 300 - 3000 mg Dextran 40.
  • the formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose 5% to 0.2 - 0.4 mg/mL, and is administered either IV bolus or by IV infusion over 15 60 min.
  • Intramuscular suspension The following solution or suspension can be prepared, for intramuscular injection:
  • Hard Shell Capsules A large number of unit capsules are prepared by filling standard two- piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
  • Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
  • Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 1 1 mg of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
  • Immediate Release Tablets/ Capsules These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication.
  • the active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin , pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques.
  • the drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
  • a "fixed combination” in the present invention is used as known to persons skilled in the art and may be present as a fixed combination, a non-fixed combination or kit-of-parts.
  • a "fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity.
  • a "fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration, such as in a formulation.
  • Another example of a "fixed combination” is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.
  • a non-fixed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit.
  • a non-fixed combination or kit-of-parts is a combination wherein the said first active ingredient and the said second active ingredient are present separately.
  • the components of the non-fixed combination or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
  • the compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
  • the present invention relates also to such combinations.
  • the compounds of this invention can be combined with known chemotherapeutic agents or anti-cancer agents, e.g. anti-hyper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof.
  • Other indication agents include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, anti-metabolites, DNA-intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, toposisomerase inhibitors, biological response modifiers, or anti-hormones.
  • chemotherapeutic anti-cancer agents includes but is not limited to
  • the compounds of the invention may also be administered in combination with protein therapeutics.
  • protein therapeutics suitable for the treatment of cancer or other angiogenic disorders and for use with the compositions of the invention include, but are not limited to, an interferon (e.g. , interferon .alpha. , .beta. , or .gamma.
  • Monoclonal antibodies useful as the protein therapeutic include, but are not limited to, muromonab-CD3, abciximab, edrecolomab, daclizumab, gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevicizumab, efalizumab, adalimumab, omalizumab, muromomab-CD3, rituximab, daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.
  • a compound of general formula (I ) as defined herein can optionally be administered in combination with one or more of the following: ARRY-1 62, ARRY-300, ARRY-704, AS- 703026, AZD-5363, AZD-8055, BEZ-235, BGT-226, B KM- 1 20, BYL-719, CAL- 101 , CC-223, CH- 51 32799, deforolimus, E-6201 , enzastaurin , GDC-0032, GDC-0068 , GDC-0623 , GDC-0941 , GDC-0973, GDC-0980, GSK-21 10183 , GSK-2126458, GSK-2141795, MK-2206, novolimus, OSI- 027, perifosine, PF-04691 502, PF-05212384, PX-866, rapamycin , RG-7167, RO-4987655, R0- 5126766, selumetinib, T
  • cytotoxic and/or cytostatic agents in combination with a compound or composition of the present invention will serve to:
  • a compound of the present invention may be used to sensitize a cell to radiation. That is, treatment of a cell with a compound of the present invention prior to radiation treatment of the cell renders the cell more susceptible to DNA damage and cell death than the cell would be in the absence of any treatment with a compound of the invention.
  • the cell is treated with at least one compound of the invention.
  • the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the invention in combination with conventional radiation therapy.
  • the present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of the invention prior to the treatment of the cell to cause or induce cell death.
  • the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell.
  • a cell is killed by treating the cell with at least one DNA damaging agent. That is, after treating a cell with one or more compounds of the invention to sensitize the cell to cell death, the cell is treated with at least one DNA damaging agent to kill the cell.
  • DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g. , cisplatinum), ionizing radiation (X-rays, ultraviolet radiation), carcinogenic agents, and mutagenic agents.
  • a cell is killed by treating the cell with at least one method to cause or induce DNA damage.
  • methods include, but are not limited to, activation of a cell signalling pathway that results in DNA damage when the pathway is activated, inhibiting of a cell signalling pathway that results in DNA damage when the pathway is inhibited, and inducing a biochemical change in a cell, wherein the change results in DNA damage.
  • a DNA repair pathway in a cell can be inhibited, thereby preventing the repair of DNA damage and resulting in an abnormal accumulation of DNA damage in a cell.
  • a compound of the invention is administered to a cell prior to the radiation or other induction of DNA damage in the cell. In another aspect of the invention, a compound of the invention is administered to a cell concomitantly with the radiation or other induction of DNA damage in the cell. In yet another aspect of the invention, a compound of the invention is administered to a cell immediately after radiation or other induction of DNA damage in the cell has begun.
  • the cell is in vitro. In another embodiment, the cell is in vivo.
  • the compounds of the present invention have surprisingly been found to effectively inhibit tankyrases and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses are affected by inhibition of tankyrases, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g.
  • leukaemias and myelodysplastic syndrome including leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
  • the present invention covers a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described and defined herein, for use in the treatment or prophylaxis of a disease, as mentioned supra.
  • Another particular aspect of the present invention is therefore the use of a compound of general formula (I), described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of a disease.
  • Another particular aspect of the present invention is therefore the use of a compound of general formula (I) described supra or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease.
  • Another aspect of the present invention is the use of a compound of formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described herein, in the manufacture of a medicament for the treatment or prophylaxis of a disease.
  • the diseases referred to in the four preceding paragraphs are diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g.
  • leukaemias and myelodysplastic syndrome including leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
  • inappropriate within the context of the present invention, in particular in the context of "inappropriate cellular immune responses, or inappropriate cellular inflammatory responses", as used herein, is to be understood as meaning a response which is less than, or greater than normal, and which is associated with, responsible for, or results in, the pathology of said diseases.
  • the use is in the treatment or prophylaxis of diseases, wherein the diseases are haemotological tumours, solid tumours and/or metastases thereof.
  • Diseases further included in the context of the present invention are metabolic diseases (e.g. diabetes and obesity), fibrosis (e.g. lung fibrogenesis) and viral infection.
  • metabolic diseases e.g. diabetes and obesity
  • fibrosis e.g. lung fibrogenesis
  • the present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat mammalian hyper-proliferative disorders.
  • Compounds can be utilized to inhibit, block, reduce, decrease, etc. , cell proliferation and/or cell division, and/or produce apoptosis.
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof ; etc. which is effective to treat the disorder.
  • Hyperproliferative disorders include but are not limited, e.g.
  • BPH benign prostate hyperplasia
  • solid tumours such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
  • Those disorders also include lymphomas, sarcomas, and leukaemias.
  • breast cancer examples include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour.
  • Tumours of the male reproductive organs include, but are not limited to prostate and testicular cancer.
  • Tumours of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • Tumours of the digestive tract include, but are not limited to anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Tumours of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
  • Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi 's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.
  • Lymphomas include, but are not limited to AlDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • treating or “treatment” as stated throughout this document is used conventionally, e.g. , the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc. , of a disease or disorder, such as a carcinoma.
  • the present invention also provides methods of treating disorders and diseases associated with excessive and/or abnormal angiogenesis.
  • Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism.
  • a number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g. , diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity [Aiello et al. New Engl. J. Med. 1994, 331 , 1 80 ; Peer et al. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD ; see, Lopez et al. Invest. Opththalmol. Vis. Sci.
  • neovascular glaucoma neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc.
  • RA rheumatoid arthritis
  • the increased blood supply associated with cancerous and neoplastic tissue encourages growth, leading to rapid tumour enlargement and metastasis.
  • the growth of new blood and lymph vessels in a tumour provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer.
  • compounds of the present invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis disorders, e.g. , by inhibiting and/or reducing blood vessel formation ; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death or apop
  • the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered will generally range from about 0.001 mg/ kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/ kg body weight per day.
  • Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing.
  • "drug holidays" in which a patient is not dosed with a drug for a certain period of time may be beneficial to the overall balance between pharmacological effect and tolerability.
  • a unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day.
  • the average daily dosage for administration by injection will preferably be from 0.01 to 200 mg/ kg of total body weight.
  • the average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
  • the diseases of said method are haematological tumours, solid tumour and/or metastases thereof.
  • the compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth.
  • the average value also referred to as the arithmetic mean value
  • the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.
  • Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.
  • the potency of the compounds according to the invention was assessed by applying an in vitro inhibition assay.
  • the TNKS1 catalyzed NAD'-dependent ribosylation of a suitable protein substrate was detected using a commercially available biotin/streptavidin binding based assay format [TNKS1 Histone Ribosylation Assay Kit (Biotin-labeled NAD+), Catalog #80579; BPS Bioscience, San Diego, USA] .
  • biotin/streptavidin binding based assay format [TNKS1 Histone Ribosylation Assay Kit (Biotin-labeled NAD+), Catalog #80579; BPS Bioscience, San Diego, USA] .
  • the incorporation of a biotin-labeled NAD+ during the TNKS1 catalyzed ribosylation reaction was detected with a streptavidin-HRP coupled chemi-luminescent readout.
  • the intensity of the readout signal is proportional to the incorporated NAD'. Inhibition of TNKS1 leads to a decreased incorporation of NAD * and consequently to a lower readout signal intensity.
  • concentration of a test compound which inhibits the enzyme activity by 50% is reported as ICw.
  • the assay was conducted in a 384 well MTP format according to the manufacturer's protocol [http: / /www.bpsbioscience.com/poly-adp-ribose-polymerase/assay-kit/tnks1 - histone-ribosylation-assay-kit-biotin-labeled-nad-80579 referencing: Brown, J. A. , Marala, R. B. J. Pharmacol. Toxicol. Methods 2002 47: 137] and using a BMG Pherastar MTP reader [BMG-Labtech, Offenburg, Germany] .
  • TNKS1 Assay B The potency of selected compounds according to the invention was assessed applying a modified in vitro inhibition assay.
  • the TNKS1 catalyzed NAD+-dependent ribosylation of the enzyme itself (auto-parsylation) was detected using [ H]-NAD * as substrate and applying the scintillation proximity assay (SPA) method to detect tritium-labeled, parsylated TNKS1 .
  • the intensity of the readout signal is proportional to the incorporated [ 3 H]-NAD * .
  • Inhibition of TNKS1 leads to a decreased incorporation of [ 3 H]-NAD + and consequently to a lower readout signal intensity.
  • the concentration of a test compound which inhibits the enzyme activity by 50% is reported as IC».
  • TNKS1 enzyme sample was diluted with a modified assay buffer (50 mM MES pH 7.0, 1 mM DTT, 0.01 % Triton X-100) to a final concentration of 6 nM TNKS1 and 10x NAD * solution was diluted with the modified assay buffer (s. above) to a final 0.445x NAD' solution doped with 100 Bq/ ⁇ [ 3 H]-NAD + [Catalog #NET443H050UC, Perkin Elmer, Waltham , Massachusetts, USA ].
  • Substrate solution (10 ⁇ ) was incubated with different test compound concentrations (2.5 ul in 10 % DMSO in modified assay buffer) or control (2.5 ul 10 % DMSO in modified assay buffer only) and enzyme (10 ⁇ ) over night at room temperature.
  • the potency of the compounds according to the invention was assessed applying an in vitro inhibition assay.
  • the TNKS2 catalyzed NAD'-dependent ribosylation of a suitable protein substrate was detected using a commercially available biotin/streptavidin binding based assay format [TNKS2 Histone Ribosylation Assay Kit (Biotin-labeled NAD'), Catalog #80572; BPS Bioscience, San Diego, USA].
  • biotin/streptavidin binding based assay format [TNKS2 Histone Ribosylation Assay Kit (Biotin-labeled NAD'), Catalog #80572; BPS Bioscience, San Diego, USA].
  • the incorporation of a biotin-labeled NAD * during the TNKS2 catalyzed ribosylation reaction was detected with a streptavidin-HRP coupled chemi-luminescent readout.
  • the intensity of the readout signal is proportional to the incorporated NAD * .
  • Inhibition of TNKS2 leads to a decreased incorporation of NAD * and consequently to a lower readout signal intensity.
  • concentration of a test compound which inhibits the enzyme activity by 50% is reported as IC 3 ⁇ 4 o.
  • the assay was conducted in a 384 well MTP format according to the manufacturer's protocol [http: / /www. bpsbioscience.com/ poly-adp-ribose-polymerase/assay-kit/tnks2- histone-ribosylation-assay-kit-biotin-labeled-nad-80572 referencing: Brown, J. A. , Marala, R. B. J. Pharmacol. Toxicol. Methods 2002 47: 137] . and using a BMG Pherastar MTP reader [BMG-Labtech, Offenburg, Germany] .
  • the potency of selected compounds according to the invention was assessed applying a modified in vitro inhibition assay.
  • the TNKS2 catalyzed NAD'-dependent ribosylation of the enzyme itself was detected using [ 3 H] -NAD * as substrate and applying the scintillation proximity assay (SPA) method to detect tritium-labeled, parsylated TNKS2.
  • SPA scintillation proximity assay
  • the intensity of the readout signal is proportional to the incorporated [ 3 H] -NAD ⁇ I nhibition of TNKS2 leads to a decreased incorporation of [ 3 H]-NAD * and consequently to a lower readout signal intensity.
  • the concentration of a test compound which inhibits the enzyme activity by 50% is reported as IC».
  • TNKS2 enzyme sample was diluted with a modified assay buffer (50 mM MES pH 7.0, 1 mM DTT, 0.01 % Triton X-100) to a final concentration of 6 nM TNKS2 and 10x NAD' solution was diluted with the modified assay buffer (s. above) to a final 0.445x NAD * solution doped with 100 Bq/ ⁇ [ 3 H] -NAD + [Catalog #NET443H050UC, Perkin Elmer, Waltham , Massachusetts, USA] .
  • Substrate solution (10 ⁇ ) was incubated with different test compound concentrations (2.5 ⁇ in 10 % DMS0 in modified assay buffer) or control (2.5 ⁇ 10 % DMS0 in modified assay buffer only) and enzyme (10 ⁇ ) over night at room temperature.
  • Incorporated tritium was measured after addition of 50 ul SPA beads (1 mg/ ml) [Catalog #RPNQ0095 20 mg/ ml, Perkin Elmer, Waltham , Massachusetts, USA; diluted 1 : 10 with Dulbecco's phosphate buffered saline, PBS Catalog #08537, Sigma- Aldrich, Steinheim, Germany] and detection of the photon emission with a beta count plate reader [Wallac Micro Beta®, Perkin Elmer, Waltham , Massachusetts, USA].
  • the potency of the compounds according to the invention was assessed using a commercially available biotin/streptavidin binding assay kits from BPS Bioscience, San Diego, USA (Catalog #80551 ).
  • the incorporation of a biotin-labeled NAD' during the PARP1 catalyzed ribosylation of a suitable protein substrate was detected using with a streptavidin-HRP coupled chemi-luminescent readout.
  • the intensity of the readout signal is proportional to the incorporated NAD * .
  • Inhibition of PARP1 leads to a decreased incorporation of NAD' and consequently to a lower readout signal intensity.
  • the concentration of a test compound that inhibits the enzyme activity by 50% is reported as ICso-
  • the assay was conducted in a 96 well MTP format according to the manufacturer's protocol (Catalog No. 80551 ) and using a BMG Pherastar MTP reader [BMG-Labtech, Offenburg, Germany].
  • the potency of the compounds according to the invention was assessed using a commercially available biotin/streptavidin binding assay kits from BPS Bioscience, San Diego, USA (Catalog #80551 ).
  • the incorporation of a biotin-labeled NAD * during the PARP2 catalyzed ribosylation of a suitable protein substrate was detected using with a streptavidin-HRP coupled chemi-luminescent readout.
  • the intensity of the readout signal is proportional to the incorporated NAD'.
  • Inhibition of PARP2 leads to a decreased incorporation of NAD * and consequently to a lower readout signal intensity.
  • the concentration of a test compound that inhibits the enzyme activity by 50% is reported as ICso.
  • the assay was conducted in a 96 well MTP format according to the manufacturer's protocol (Catalog No. 80552) and using a BMG Pherastar MTP reader [BMG-Labtech, Offenburg, Germany]. 7 Cellular Assays
  • a cellular reporter assay was employed.
  • the corresponding assay cell was generated by transfection of the mammalian cell line HEK293 (ATCC, #CRL-1 73) with the Super TopFlash vector (Morin, Science 275, 1997, 1787-1790; Molenaar et al., Cell 86 (3), 1996, 391 -399).
  • the HEK293 cell line is cultivated at 37oC and 5% C02 in DMEM (Life Technologies, #41965-039), supplemented with 2 m glutamine, 20 mM HEPES, 1.4 mM pyruvate, 0.15% Na-bicarbonate and 10% foetal bovine serum (GIBCO, #10270). Stable transfectants were generated by selection with 300 g/ml Hygromycin.
  • HEK293 cells were cotransfected with the FOP control vector and pcDNA3.
  • the FOP vector is identical to the TOP construct, but it contains instead of functional TCF elements a randomized, non-functional sequence.
  • a stable transfected cell line was generated as well, based on selection with Geneticin (1 mg/ml).
  • the two cell lines were plated 24 h before beginning the test at 10000 cells per well in a 384 micro tit re plate (MTP) in 30 ⁇ growth medium.
  • MTP micro tit re plate
  • a dose response curve for the Wnt dependent luciferase expression was recorded by stimulating the assay cell line with human recombinant Wnt-3a (R&D, #5036- WN-010) at different concentrations for 16 h at 37 C and 5% CO2 followed by subsequent luciferase measurement, to determine the Wnt-3a EC50 for the HEK293 TOP cell line on the day of testing.
  • the recombinant human Wnt-3a was thereby applied between 2500 and 5 ng/ml in two-fold dilution steps.
  • the compounds were thereby serially prediluted in 100% DMSO and thereafter 50 fold into the CAFTY compound dilution buffer (described above). From this dilution 10 ⁇ were added in combination with the EC 50 concentration of recombinant Wnt3a to the cells in 30 ⁇ growth medium and incubated for 16 hours at 37 C and 5% CO ? .
  • luciferase assay buffer (1 : 1 mixture of luciferase substrate buffer (20 mM Tricine, 2.67 mM magnesium sulfate, 0.1 mM EDTA, 4 mM DTT, 270 ⁇ Coenzyme A, 470 ⁇ Luciferin, 530 ⁇ ATP, ph adjusted to pH 7.8 with a sufficient volume of 5M sodium hydroxide) and Triton buffer (30 ml Triton X-100, 1 15 ml glycerol, 308 mg Dithiothreitol, 4.45 g disodium hydrogen phosphate di hydrate, 3.03 g Tris .
  • HQ, ad 11 H?0, pH 7.8 was added in an equal volume to determine luciferase expression as a measure of Wnt signaling activity in a luminometer.
  • the Wnt inhibitory activity was determined as IC50 of resulting dose response curves.
  • SW403 cells (but not limited to) were seeded at 50000 cells per well in 96-well plates. After overnight incubation, cells were treated with testing compounds and vehicle at 37 C for 24 hours. Thereafter, cells were washed with PBS and then lysed in 15 ⁇ of lysis buffer (M-PER buffer, Thermo Scientific # 78505) with complete proteinase and phosphatase inhibitors (Roche, #11836153001 and # 04906837001 ). The lysates were centrifuged and the supernatants were harvested for analysis.
  • Tumor xenografts from in vivo studies were homogenized in a 2 ml tubes of Precellysl24 (Bertin Technologies, Villeurbanne, France) following with centrafugation to obtain tumor lysates.
  • Capillary electrophoresis-based Simple Western assays were carried out with Peggy SueTM NanoPro 1000 (ProteinSimple, California, USA).
  • the protein amounts of Axin2 (but not limited to) were detected using anti-Axin2 antibody (Cell Signaling, Catalog #2151 ), quantified using the area under the curve, and normalized against GAPDH (anti-GAPDH, Zytomed Systems GmbH, Catalog #RGM2-6C5, Berlin, Germany).
  • Real-time RT-PCR using a TaqMan fluorogenic detection system is a simple and sensitive assay for quantitative analysis of gene transcription.
  • the TaqMan fluorogenic detection system can monitor PCR in real time using a dual-labeled fluorogenic hybridization probe (TaqMan probe) and a polymerase with 5'-3' exonuclease activity.
  • TaqMan probe dual-labeled fluorogenic hybridization probe
  • a polymerase with 5'-3' exonuclease activity.
  • Cells from different cancer cell lines (as HCT116, but not limited to) were grown at 500- 1000 cells/well in 384 well cell culture plates. For cell lysis the cell medium was carefully removed. The cells were washed carefully once with 50 ⁇ /well PBS.
  • RT-PCR 2 ⁇ lysate (each) was transferred to a 384 well PCR plate.
  • the PCR reaction was composed by 5 ⁇ 2x One Step RT qPCR MasterMix Plus, 0.05 ⁇ Euroscript RT/RNAse Inhibitor (50 U/ ⁇ , 20 SJ/ ⁇ ) and 200 nM of the appropriate Primer/ Hydrolysis Probe mix (primer sequences of forward, reverse and probe are given below for each analysed gene of interest or house keeping gene). 10 ⁇ water were added per well. The plate was sealed with an adhesive optical film.
  • the RT-PCR protocol was setup with 30 min 48 C, then 10 min 95 C followed by 50 cycles of 15 sec 95 C/1 min 60 C and a cooling step of 40 C for 30 sec using a Lightcycler LS440 from Roche. Relative expression was calculated using CP values from the gene of interest (e.g. AXIN2, but not limited to) and a house keeping gene (L32).
  • the gene of interest e.g. AXIN2, but not limited to
  • L32 house keeping gene
  • AXIN2 forward primer: AGG CCAGTG AGTTG GTTGTC (SEQ ID NO. 4); reverse primer: AGCTCTGAGCCTTCAGCATC (SEQ ID NO. 5); probe: TCTGTGGGGAAGAAATTCCATACCG (SEQ ID NO. 6)
  • MTD maximal tolerable dose
  • the MTD is defined as the maximal applicable dose with a) no animal losing more than 10% body weight compared to initial body weight and b) no lethality during treatment phase.
  • test compounds were analysed in xenograft models on mice. Test compounds were dosed orally at their respective MTD as well as at sub-MTD dosages. In case the MTD could not be determined in previous MTD studies, the compounds were dosed at a maximum daily dose of 200 mg/kg (applied either in one single dose or split in 2 doses at 100 mg/ kg).
  • tumor cells 1 -5x10* tumor cells (suspended in 0.1 ml of 50% cell culture medium / 50% Matrigel) were subcutanously injected into the flank of each animal. Animals were randomized into treatment groups when tumors had reached an average area of 20-30 mm 2 and treatment was started. Body weight and tumor area of each animal were measured 2-3 times weekly, depending on tumor growth. Studies were terminated , when animals in the control groups (receiving only compound vehicle solutions) or treatment groups reached tumor areas - 1 50 mm 2 . At that time point, all groups in the study were terminated, tumors were isolated and weighed.
  • T/C Treatment/Control
  • RNA and protein were isolated from tumor samples following standard protocols.
  • Wnt/B-catenin target gene expression and Axin2 protein abundance were measured by standard qRT-PCR and Western blotting methods (see 7.2 and 7.3).
  • Table 1 IC3 ⁇ 4o values for selected examples in cellular HEK293 TOP and FOP assay as well as in TNKS1 and TNKS2 biochemical assay

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Abstract

La présente invention concerne des composés de formule générale (I), où X1, X2, R1, R2, R4, R5, R7 et R8 sont tels que définis dans la description, des procédés de préparation desdits composés, des composés intermédiaires utilisés pour préparer lesdits composés, des compositions pharmaceutiques et des associations comprenant lesdits composés et l'utilisation desdits composés pour fabriquer une composition pharmaceutique destinée à traiter ou prévenir une maladie, en particulier les néoplasmes, en monothérapie ou en association avec d'autres principes actifs.
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