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WO2015078799A1 - Inhibiteurs de transport de glucose - Google Patents

Inhibiteurs de transport de glucose Download PDF

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Publication number
WO2015078799A1
WO2015078799A1 PCT/EP2014/075352 EP2014075352W WO2015078799A1 WO 2015078799 A1 WO2015078799 A1 WO 2015078799A1 EP 2014075352 W EP2014075352 W EP 2014075352W WO 2015078799 A1 WO2015078799 A1 WO 2015078799A1
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Prior art keywords
alkyl
group
general formula
alkoxy
compounds
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Inventor
Iring Heisler
Thomas Müller
Bernd Buchmann
Ludwig Zorn
Mélanie HÉROULT
Roland Neuhaus
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Bayer Pharma AG
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Bayer Pharma AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/06—Peri-condensed systems

Definitions

  • the present invention relates to chemical compounds that selectively inhibit glucose transporter 1 (GLUT1 ), to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.
  • GLUT1 glucose transporter 1
  • Glucose is an essential substrate for metabolism in most cells. Because glucose is a polar molecule, transport through biological membranes requires specific transport proteins. Transport of glucose through the apical membrane of intestinal and kidney epithelial cells depends on the presence of secondary active NaVglucose symporters, SGLT-1 and SGLT-2, which concentrate glucose inside the cells, using the energy provided by co-transport of Na + ions down their electrochemical gradient.
  • glucose carriers protein symbol GLUT, gene symbol SLC2 for Solute Carrier Family 2
  • transport facilitators major facilitator superfamily
  • organic anion and cation transporters yeast hexose transporter
  • plant hexose/ proton symporters plant hexose/ proton symporters
  • bacterial sugar/ proton symporters a superfamily of transport facilitators (major facilitator superfamily) including organic anion and cation transporters, yeast hexose transporter, plant hexose/ proton symporters, and bacterial sugar/ proton symporters.
  • Basal glucose transporters function as glucose channels and are required for maintaining the basic glucose needs of cells. These GLUTs are constitutively expressed and functional in cells and are not regulated by (or sensitive to) insulin. All cells use both glycolysis and oxidative phosphorylation in mitochondria but rely overwhelmingly on oxidative phosphorylation when oxygen is abundant, switching to glycolysis at times of oxygen deprivation (hypoxia), as it occurs in cancer. In glycolysis, glucose is converted to pyruvate and two ATP molecules are generated in the process. Cancer cells, because of their faster proliferation rates, are predominantly in a hypoxic (low oxygen) state. Therefore, cancer cells use glycolysis (lactate formation) as their predominant glucose metabolism pathway.
  • Such a glycolytic switch not only gives cancer higher potentials for metastasis and invasiveness, but also increases cancer's vulnerability to external interference in glycolysis.
  • the reduction of basal glucose transport is likely to restrict glucose supply to cancer cells, leading to glucose deprivation that forces cancer cells to slow down growth or to starve.
  • GLUT proteins contain 12 transmembrane domains and transport glucose by facilitating diffusion, an energy-independent process.
  • GLUT1 transports glucose into cells probably by alternating its conformation.
  • GLUT1 exposes a single substrate-binding site toward either the outside or the inside of the cell. Binding of glucose to one site triggers a conformational change, releasing glucose to the other side of the membrane.
  • Results of transgenic and knockout animal studies support an important role for these transporters in the control of glucose utilization, glucose storage and glucose sensing.
  • the GLUT proteins differ in their kinetics and are tailored to the needs of the cell types they serve.
  • GLUT1 is a high affinity glucose transporter
  • GLUT1 expression was also found to be significantly higher than that of any other glucose transporters.
  • GLUT1 is the most highly expressed hexose transporter in ErbB2- and PyVMT-induced mouse mammary carcinoma models, and that reducing the level of GLUT1 using shRNA or Cre/lox results in reduced glucose usage, reduced growth on plastic and in soft agar, and impaired tumor growth in nude mice (Christian D. Young et al., PLoS ONE, August 2011 , Volume 6, Issue 8, e23205, 1 -12).
  • inhibition of GLUT1 represents a promising approach for the treatment of proliferative disorders including solid tumours such as carcinomas and sarcomas and leukaemias and lymphoid malignancies or other disorders associated with uncontrolled cellular proliferation.
  • WO2011 /119866(A1 ) discloses composition and methods for glucose transport inhibition
  • WO2012/051117(A2) and WO2013/155338(A2) disclose substituted benzamides as GLUT1 inhibitors.
  • WO2001 /23389(A2) discloses certain alkylene diamine-substituted heterocycles as antagonists of the NPYi receptor.
  • WO2006 / 046023 (A1 ) discloses ortho-condensed pyridine and pyrimidine derivatives as protein kinase inhibitors.
  • WO2003/022214(A2) discloses piperazine and homopiperazine compounds for the treatment of thrombosis.
  • WO2005/010003(A1 ) discloses sulfonyldihydroimid-azopyridinone compounds as 5-hydroxytryptamine-6 ligands.
  • WO2005/1 17909(A2) discloses inhibitors of p70S6 and/or Akt kinases.
  • WO2008/043031 (A1 ) and WO2010/022358(A1 ) disclose 6-substituted 2- (benzimidazolyl)purine and purinone derivatives for immunosuppression.
  • WO2009/073777(A1 ) discloses gamma secretase modulators.
  • WO2009/131687(A2) discloses inhibitors of syk and/or JAK kinase.
  • WO2012/160030(A1 ) discloses pyridine-2(1 H)-one derivatives for the treatment of myeloproliferative disorders, transplant rejection, immune-mediated and inflammatory diseases.
  • WO2007/030574(A2) discloses modulators for members of the peroxisome proliferator-activated receptor family.
  • N-arylated thiazolopyrimidinethione derivative has been indexed by Chemical Abstracts as "chemical library” compound without literature reference (see 3-Phenyl-7-(4-phenyl-1 -piperazinyl)-thiazolo[4,5- d]pyrimidine-2(3H)-thione, CAS registry No. 385378-67-6). No therapeutic application of said compound has been disclosed hitherto.
  • the present invention covers compounds of general formula (I) :
  • Z represents a phenyl- or pyridinyl- group
  • Y 1 represents N or C(R 1 );
  • Y 2 represents S or N(R 2 );
  • Y 3 represents S or 0;
  • R 1 represents a hydrogen atom, a halogen atom or a cyano-, Ci-C&-alkyl-, trifluoromethyl- or C3-C 7 -cycloalkyl- group;
  • R 2 represents a hydrogen atom or a CrC3-alkyl- or trifluoromethyl- group
  • R 3 represents a phenyl- group
  • phenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 7 groups ; represents a hydrogen atom or a methyl- group; represents a hydrogen atom or a -OH, -SH, -NH 2 , CrC3-alkoxy-,
  • halogen atom independently represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-C 6 -alkyl-, R 8a (R 8b )N-d-C 6 -alkyl-, HO-d-C 6 -alkyl-, d-Ce-alkoxy-d-Ce-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C 2 -C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
  • Ci-C&-alkyl- represent, independently from each other, a hydrogen atom, or Ci-C&-alkyl-, C 3 -C 7 -cycloalkyl-, (C 3 -C 7 -cycloalkyl)-(Ci-C6-alkyl) C 2 -C&-alkenyl-, C 2 -C&-alkynyl-, 3- to 10-membered heterocycloalkyl-, (3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-, heteroaryl-, aryl-Ci-C&-alkyl-, (aryl)-0-(Ci-C&-alkyl)-, heteroaryl-Ci-C&-alkyl- or (aryl)-(3- to 10-membered heterocycloalkyl)- group;
  • aryl-Ci-C&-alkyl- (aryl)-0-(Ci-C&-alkyl)-, heteroaryl-,
  • Ci-C&-alkyl- group represents, independently from each other, a hydrogen atom or a Ci-C&-alkyl- group; is an integer of 0, 1 , 2 or 3 ;
  • the present invention further relates to methods of preparing compounds of general formula (I ), to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.
  • halogen atom or halo- is to be understood as meaning a fluorine, chlorine, bromine or iodine atom.
  • Ci-C&-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, /so-propyl, j ' so-butyl, sec-butyl, tert-butyl, /so-pentyl, 2-methylbutyl, 1 -methylbutyl, 1 - ethylpropyl, 1 ,2-dimethylpropyl, neo-pentyl, 1 , 1 -dimethylpropyl, 4- methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 -methylpentyl, 2-ethylbutyl, 1 -ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethyl
  • said group has 1 , 2, 3 or 4 carbon atoms (“CrC4-alkyl”), e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, more particularly 1 , 2 or 3 carbon atoms (“CrC3-alkyl”), e.g. a methyl, ethyl, n-propyl- or iso-propyl group.
  • CrC4-alkyl e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, more particularly 1 , 2 or 3 carbon atoms
  • CrC3-alkyl e.g. a methyl, ethyl, n-propyl- or iso-propyl group.
  • halo-d-Ce-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term " ⁇ - Ce-alkyl” is defined supra, and 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 halo-Ci-C&-alkyl group is, for example, -CF 3 , -CHF 2 , -CH 2 F, -CF 2 CF 3 , or -CH 2 CF 3 .
  • d-Ce-alkoxy is to be understood as preferably meaning a linear or branched, saturated, monovalent group of formula -0-(Ci-C&-alkyl), in which the term “d-Ce-alkyl” is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso- propoxy, n- butoxy, iso- butoxy, tert- butoxy, sec- butoxy, pentoxy, iso- pentoxy, or n-hexoxy group, or an isomer thereof.
  • halo-CrCe-alkoxy is to be understood as preferably meaning a linear or branched, saturated, monovalent Ci-C&-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom.
  • said halogen atom is F.
  • Said halo-CrCe-alkoxy group is, for example, -OCF 3 , -OCHF 2 , -OCH 2 F, -OCF 2 CF 3 , or - OCH 2 CF 3 .
  • Ci-C&-alkoxy-CrCe-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent Ci-C&-alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a Ci-C&-alkoxy group, as defined supra, e.g.
  • halo-Ci-Ce-alkoxy-Ci-Ce-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent CrCe-alkoxy-CrCe-alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom.
  • said halogen atom is F.
  • Said halo-CrCe-alkoxy-CrCe-alkyl group is, for example, CH 2 CH 2 OCF 3 , -CH 2 CH 2 OCHF 2 , -CH 2 CH 2 OCH 2 F, -CH 2 CH 2 OCF 2 CF 3 , or
  • C 2 -C&-alkenyl is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C 2 -C 3 -alkenyl”), it being understood that in the case in which said alkenyl group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other.
  • Said alkenyl group is, for example, a vinyl, allyl, (f)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (f)-but-2-enyl, (Z)-but-2-enyl, (f)-but- l -enyl, (Z)-but- l -enyl, pent-4-enyl, (f)-pent-3-enyl, (Z)-pent-3-enyl, (f)-pent-2-enyl, (Z)-pent-2-enyl, (f)-pent- l -enyl, (Z)-pent- l -enyl, hex-5-enyl, (f)-hex-4-enyl, (Z)-hex-4-enyl, (f)-hex-3-enyl, (Z)-hex-3-enyl, (f)-hex-2-enyl, (Z)-he
  • C 2 -C&-alkynyl is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C 2 -C3-alkynyl").
  • Said C 2 -C&-alkynyl group is, for example, ethynyl, prop-1 -ynyl, prop-2-ynyl, but-1 -ynyl, but-2-ynyl, but-3-ynyl, pent-1 -ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1 -ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1 -methylprop-2-ynyl, 2-methylbut-3-ynyl, 1 -methylbut-3-ynyl, 1 -methylbut-2-ynyl, 3-methylbut-1 -ynyl,
  • said alkynyl group is ethynyl, prop-1 -ynyl, or prop-2-ynyl.
  • C3-C7-cycloalkyl is to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5, 6 or 7 carbon atoms.
  • Said C 3 -C 7 -cycloalkyl group is for example a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl ring.
  • said ring contains 3, 4, 5 or 6 carbon atoms ("C3-C6-cycloalkyl").
  • C 4 -C8-cycloalkenyl is to be understood as preferably meaning a monovalent, monocyclic hydrocarbon ring which contains 4, 5, 6, 7 or 8 carbon atoms and one or two double bonds, in conjugation or not, as the size of said cycloalkenyl ring allows. Particularly, said ring contains 4, 5 or 6 carbon atoms ("C 4 -C6-cycloalkenyl”).
  • Said C 4 -Cs-cycloalkenyl group is for example a cyclobutenyl, cyclopentenyl, or cyclohexenyl group.
  • said 3- to 10-membered heterocycloalkyl can contain 2, 3, 4, 5 or 6 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "3- to 7-membered heterocycloalkyl"), more particularly said heterocycloalkyl can contain 4, 5 or 6 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "4- to 6-membered heterocycloalkyl").
  • 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 trithianyl, or a 7-membered ring, such as a diazepanyl ring, for example.
  • 4-membered ring such as an azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolid
  • heterocycloalkenyl may contain one or more double bonds, e.g.
  • aryl is to be understood as preferably meaning a monovalent, aromatic, mono-, or bi- or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 carbon atoms (a "C&-Ci4-aryl” group), particularly a ring having 6 carbon atoms (a "C 6 -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 or a biphenyl group (a "Ci 2 -aryl” group), or a ring having 13 carbon atoms, (a "Ci3-aryl” group), e.g. a fluorenyl group, or a ring having 14 carbon atoms, (a "Ci 4 -aryl” group), e.g. an anthracenyl group.
  • the aryl group is a phenyl group.
  • heteroaryl is understood as preferably meaning a monovalent, monocyclic- , bicyclic- or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl” group), particularly 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur, and in addition in each case can be benzocondensed.
  • heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl etc., and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, etc.;
  • the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof.
  • the term pyridyl includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
  • the heteroaryl group is a pyridinyl group.
  • d-d as used throughout this text, e.g. in the context of the definition of "C C 6 -alkyl”, “C C 6 -haloalkyl”, “C C 6 -alkoxy”, or “d-d- haloalkoxy” is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “d-d” is to be interpreted as any subrange comprised therein, e.g.
  • Ci-C 2 Ci-C3 , C1-C4 , C1-C5 , Ci- C&; particularly Ci-C 2 , Ci-C3 , C C4 , C1-C5 , CrC6 ; more particularly C1-C4 ; in the case of "d-d-haloalkyl" or "d-d-haloalkoxy" even more particularly Ci-C 2 .
  • d-d as used throughout this text, e.g. in the context of the definitions of "C 2 -d-alkenyl” and “C 2 -d-alkynyl”, is to be understood as meaning an alkenyl group or an alkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C 2 -d” is to be interpreted as any sub-range comprised therein, e.g. d-d , C3-C5 , C3-C4 , d-d , d-d , d-d ; particularly C 2 - d.
  • d-d as used throughout this text, e.g. in the context of the definition of "d-d-cycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 7, i.e. 3, 4, 5, 6 or 7 carbon atoms. It is to be understood further that said term “C3-C7” is to be interpreted as any sub-range comprised therein, e.g. d-d , d- d , C3-C5 , C3-C4 , d-d, C5-C7 ; particularly d-d.
  • the term "leaving group” refers to an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons.
  • the leaving group as used herein is, e.g. a halogen atom, such as fluoro, chloro, bromo or iodo, or a group selected from methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromo-benzene)sulfonyloxy, (4-nitro- benzene)sulfonyloxy, (2-nitro-benzene)-sulfonyloxy, (4-isopropyl- benzene)sulfonyloxy, (2,4,6-tri-isopropyl-benzene)-sulfonyloxy, (2,4,6-tri-
  • LG is a leaving group suitable for nucleophilic aromatic substitution, such as fluoro, chloro, bromo, or a trifluoromethanesulfonyloxy group, or a moiety suitable for metal catalysed amination reactions, e.g. bromo or iodo.
  • protecting group is a protective group attached to a nitrogen in intermediates used for the preparation of compounds of the general formula (I). Such groups are introduced e.g. by chemical modification of the respective amino group in order to obtain chemoselectivity in a subsequent chemical reaction. Protective groups for amino groups are descibed for example in T.W. Greene and P.G.M.
  • said groups can be selected from substituted sulfonyl groups, such as mesyl-, tosyl- or phenylsulfonyl-, acyl groups such as benzoyl, acetyl or tetrahydropyranoyl-, or carbamate based groups, such as tert. -butoxycarbonyl (Boc), or can include silicon, as in e.g. 2-(trimethylsilyl)ethoxymethyl (SEM).
  • substituted sulfonyl groups such as mesyl-, tosyl- or phenylsulfonyl-
  • acyl groups such as benzoyl, acetyl or tetrahydropyranoyl-
  • carbamate based groups such as tert. -butoxycarbonyl (Boc)
  • Boc tert. -butoxycarbonyl
  • Si 2-(trimethylsilyl)ethoxymethyl
  • the term "one or more times”, 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 times, particularly one, two, three or four times, more particularly one, two or three times, even more particularly one or two times".
  • this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.
  • the compounds of this invention contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration. In certain instances, 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.
  • 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.
  • Examples of appropriate acids are tartaric, diacetyltartaric, 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 Diacel, e.g. , Chiracel OD and Chiracel OJ among many others, all routinely selectable.
  • optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • lUPAC Rules Section E Purge Appl Chem 45, 1 1 -30, 1976.
  • 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 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 1 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 3 S, 36 S, 18 F, 36 Cl, 82 Br, 123 l, 124 l, 129 l and 131 1, respectively.
  • Certain isotopic variations of a compound of the invention for example, those in which one or more radioactive isotopes such as 3 H or 14 C are incorporated, 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 may be 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.
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, in any ratio.
  • Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention may be 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, or a triazole moiety for example can exist as a 1 H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said 1 H, 2H and 4H tautomers, viz. :
  • 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.
  • 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. For example, see S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1 -19.
  • 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.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorphs, or as a mixture of more than one polymorphs, in any ratio.
  • the present invention relates to compounds of general formula (I ) :
  • Z represents a phenyl- or pyridinyl- group
  • Y 1 represents N or C(R 1 );
  • Y 2 represents S or N(R 2 );
  • Y 3 represents S or 0
  • R 1 represents a hydrogen atom, a halogen atom or a cyano-, Ci-C&-alkyl-, trifluoromethyl- or C 3 -C 7 -cycloalkyl- group
  • R 2 represents a hydrogen atom or a CrC3-alkyl- or trifluoromethyl- group
  • R 3 represents a phenyl- group
  • phenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 7 groups ;
  • R 4 represents a hydrogen atom or a methyl- group; represents a hydrogen atom or a -OH, -SH, -NH 2 , CrC3-alkoxy-, HO-CrC3-alkyl-, HO-C 2 -C3-alkoxy-, halo-CrC3-alkyl-, halo-CrC3-alkoxy-, - S-(CrC 3 -alkyl), -S-(halo-d-C 3 -alkyl), -N(H)(Ci-C 3 -alkyl),
  • R 6 independently represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-d-alkyl-, R 8a (R 8b )N-d-C 6 -alkyl-, HO-d-C 6 -alkyl-, d-Ce-alkoxy-d-Ce-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C 2 -C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
  • Ci-C&-alkyl- group is an integer of 0, 1 , 2 or 3 ;
  • Z represents a phenyl- group.
  • Y 1 represents N.
  • Y 2 represents S.
  • Y 2 represents N(R 2 ).
  • Y 3 represents S. In another preferred embodiment, Y 3 represents 0. In another preferred embodiment, Y 2 represents S and Y 3 represents S. In another preferred embodiment, Y 2 represents S and Y 3 represents 0. In another preferred embodiment, Y 2 represents N(R 2 ) and Y 3 represents 0.
  • Y 1 represents N
  • Y 2 represents S
  • Y 3 represents S
  • Y 1 represents N
  • Y 2 represents S and Y 3 represents 0.
  • Y 1 represents N
  • Y 2 represents N(R 2 ) and Y 3 represents 0.
  • Y 1 represents N
  • Y 2 represents N(H)
  • Y 3 represents 0.
  • R 1 represents a hydrogen atom.
  • R 1 represents a Ci-C&-alkyl- group. In another preferred embodiment, R 1 represents a trifluoromethyl- group.
  • R 1 represents a halogen atom or cyano- group.
  • R 2 represents a hydrogen atom.
  • R 3 represents a phenyl- group.
  • R 3 represents a phenyl- group, wherein said phenyl- group is substituted, identically or differently, with 1 or 2 R 7 groups.
  • R 3 represents a phenyl- group, wherein said phenyl- group is substituted, identically or differently, with 1 or 2 R 7 groups, wherein R 7 represents halo; preferably fluoro and/or chloro.
  • R 3 is selected from:
  • R 4 represents a hydrogen atom.
  • R 5 is located in a 1 ,2-relationship with the nitrogen atom of the neighbouring heteroalicyclic group.
  • R 5 represents a hydrogen atom or a -OH, -NH 2 , CrC3-alkoxy-, HO-Ci -C3-alkyl-, HO-C 2 -C 3 -alkoxy-, fluoro-CrC 3 -alkyl-,
  • R 5 represents a -OH, -NH 2 ,
  • R 5 represents a hydrogen atom or a -OH, -NH 2 , CrC 3 -alkoxy-, HO-Ci -C 3 -alkyl-, HO-C 2 -C 3 -alkoxy-, or a -S- (Ci -C 3 -alkyl)- group.
  • R 5 represents a -OH, -NH 2 , CrC3-alkoxy-, HO- CrC3-alkyl-, HO-C 2 -C 3 -alkoxy-, or a -S-(Ci-C 3 -alkyl)- group.
  • R 5 represents a hydroxymethyl- group.
  • R 5 represents a -OH, -NH 2 ,
  • R 5 represents a -OH group.
  • R 5 represents a -NH 2 group.
  • R 5 represents a methoxy- group.
  • R 5 represents an ethoxy- group.
  • R 5 represents a -SCH 3 group. In another particularly preferred embodiment, R 5 represents a hydrogen atom.
  • R 5 represents a hydrogen atom and Y 3 represents 0.
  • R 6 represents a flu
  • R 7 represents halo, preferably fluoro or chloro.
  • R 7 represents fluoro
  • R 8 , R 8a , R 8b , R 8c represent, independently from each other, a hydrogen atom, or a Ci-C&-alkyl- group; said Ci-C&-alkyl- group being optionally substituted one or two times, identically or differently, with R 9 .
  • R 8 , R 8a , R 8b , R 8c represent, independently from each other, a hydrogen atom, or a CrC 3 -alkyl- group; said CrC 3 -alkyl- group being optionally substituted one or two times, identically or differently, with R 9 .
  • R 8 , R 8a , R 8b , R 8c represent, independently from each other, a hydrogen atom, or a CrC 3 -alkyl- group; said CrC 3 -alkyl- group being optionally substituted one time with R 9 .
  • R 9 represents -OH.
  • m is 0 or 1 . In another particularly preferred embodiment, m is 0.
  • m is 1 .
  • n is 2. It is to be understood that the present invention relates to any subcombination within any embodiment of compounds of general formula (I), supra.
  • the present invention relates to compounds of general formula (I) :
  • phenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 7 groups ; represents a hydrogen atom or a methyl- group; represents a -OH, -SH, -NH 2 , CrC3-alkoxy-,
  • halogen atom independently represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-d-alkyl-, R 8a (R 8b )N-d-C 6 -alkyl-, HO-d-C 6 -alkyl-, d-Ce-alkoxy-d-Ce-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C 2 -C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
  • R 7 represents a halogen atom, or a -CN, Ci-C&-alkoxy-, Ci-C&-alkyl-, halo-CrC 6 -alkyl-, R 8
  • aryl-Ci-C&-alkyl- (aryl)-0-(Ci-C&-alkyl)-, heteroaryl-,
  • heteroaryl-Ci-C&-alkyl- or (aryl)-(3- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R 9 ;
  • Ci-C&-alkyl- group m is an integer of 0, 1 , 2 or 3 ;
  • n is an integer of 2 or 3 ; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the present invention relates to compounds of general formula (la), (lb), or (lc) :
  • Z represents a phenyl- or pyridinyl- group
  • R 3 represents a phenyl- group; wherein said phenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 7 groups
  • halogen atom independently represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-d-alkyl-, R 8a (R 8b )N-d-C 6 -alkyl-, HO-d-C 6 -alkyl-, d-Ce-alkoxy-d-Ce-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C 2 -C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
  • Ci-C&-alkyl- C 3 -C 7 -cycloalkyl-, (C 3 -C 7 -cycloalkyl)-(Ci-C6-alkyl)-, C 2 -C&-alkenyl-, C 2 -C&-alkynyl-, 3- to 10-membered heterocycloalkyl-, (3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-, heteroaryl-, aryl-Ci-C&-alkyl-, (aryl)-0-(Ci-C&-alkyl)-, heteroaryl-d-Ce-alkyl- or (aryl)-(3- to 10-membered heterocycloalkyl)- group;
  • aryl-Ci-C&-alkyl- (aryl)-0-(Ci-C&-alkyl)-, heteroaryl-,
  • Ci-C&-alkyl- group m is an integer of 0, 1 , 2 or 3 ;
  • n is an integer of 2 or 3 ; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the present invention relates to compounds of general formula (Id), (le), or (If):
  • Z represents a phenyl- group
  • Y 1 represents N or C(R 1 );
  • R 1 represents a hydrogen atom or a Ci-C&-alkyl-, trifluoromethyl- or
  • R 3 represents a phenyl- group; wherein said phenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 7 groups ; represents a hydrogen atom or a methyl- group; represents a hydrogen atom or a -OH, -SH, -NH 2 , CrC3-alkoxy-,
  • halogen atom independently represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-C 6 -alkyl-, R 8a (R 8b )N-d-C 6 -alkyl-, HO-d-C 6 -alkyl-, d-Ce-alkoxy-d-Ce-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C 2 -C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
  • Ci-C&-alkyl- C 3 -C 7 -cycloalkyl-, (C 3 -C 7 -cycloalkyl)-(Ci-C6-alkyl)-,
  • aryl-Ci-C&-alkyl- (aryl)-0-(Ci-C&-alkyl)-, heteroaryl-,
  • n 1 , 2 or 3 ;
  • n is an integer of 2 or 3 ; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same,
  • the present invention relates to compounds of general formula (Ig), (Ih), or (li):
  • phenyl- group is optionally substituted, identically differently, with 1 , 2 or 3 R 7 groups ; represents a hydrogen atom or a methyl- group; represents a hydrogen atom or a -OH, -SH, -NH 2 , CrC3-alkoxy-, HO-CrC3-alkyl-, HO-C 2 -C3-alkoxy-, halo-Ci-C3-alkyl-, halo-CrC3-alkoxy-, - S-(CrC 3 -alkyl), -S-(halo-d-C 3 -alkyl), -N(H)(Ci-C 3 -alkyl),
  • -N(Ci-C3-alkyl)(CrC3-alkyl) or a H 2 N-Ci-C3-alkyl- group represents a hydrogen atom or a halogen atom, or a -CN, -OH,
  • Ci-C&-alkyl- group n is an integer of 2 or 3 ; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same,
  • the present invention relates to compounds of general formula (Ig), (Ih), or (li):
  • phenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 7 groups ; represents a hydrogen atom or a methyl- group; represents a -OH, -SH, -NH 2 , CrC3-alkoxy-,
  • -N(Ci-C3-alkyl)(CrC3-alkyl) or a H 2 N-Ci-C3-alkyl- group represents a hydrogen atom or a halogen atom, or a -CN, -OH,
  • Ci-C&-alkyl- represent, independently from each other, a hydrogen atom, or a Ci-C&-alkyl-, C 3 -C 7 -cycloalkyl-, (C 3 -C 7 -cycloalkyl)-(Ci-C6-alkyl)-, C 2 -C&-alkenyl-, C 2 -C&-alkynyl-, 3- to 10-membered heterocycloalkyl-, (3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-, heteroaryl-, aryl-Ci-C&-alkyl-, (aryl)-0-(Ci-C&-alkyl)-, heteroaryl-Ci-C&-alkyl- or (aryl)-(3- to 10-membered heterocycloalkyl)- group;
  • R 9 represents a halogen atom, or a CrC3-alkyl-, halo-CrC3-alkyl-, -CN,
  • Ci -C&-alkyl- group n is an integer of 2 or 3 ; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the present invention relates to compounds of general formula (Ij), (Ik), or (Im) :
  • Z represents a phenyl- or pyridinyl- group
  • R 3 represents a phenyl- group
  • phenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 7 groups ; represents a hydrogen atom or a methyl- group; represents a hydrogen atom or a -OH, -SH, -NH 2 , CrC3-alkoxy-,
  • halogen atom independently represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-d-alkyl-, R 8a (R 8b )N-d-C 6 -alkyl-, HO-d-C 6 -alkyl-, d-d-alkoxy-Crd-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C 2 -C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
  • Ci-C&-alkyl- represent, independently from each other, a hydrogen atom, or a Ci-C&-alkyl-, C 3 -C 7 -cycloalkyl-, (C 3 -C 7 -cycloalkyl)-(Ci-C6-alkyl)-, C 2 -C&-alkenyl-, C 2 -C&-alkynyl-, 3- to 10-membered heterocycloalkyl-, (3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-, heteroaryl-, aryl-Ci-C&-alkyl-, (aryl)-0-(Ci-C&-alkyl)-, heteroaryl-Ci-C&-alkyl- or (aryl)-(3- to 10-membered heterocycloalkyl)- group;
  • aryl-Ci-C&-alkyl- (aryl)-0-(Ci-C&-alkyl)-, heteroaryl-,
  • Ci-C&-alkyl- group m is an integer of 0, 1 , 2 or 3 ; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same,
  • the present invention relates to compounds of general formula
  • Z represents a phenyl- or pyridinyl- group
  • Y 1 represents N or C(R 1 );
  • Y 2 represents S or N(R 2 );
  • Y 3 represents S or 0
  • R 1 represents a hydrogen atom or a Ci-C&-alkyl-, trifluoromethyl- or
  • R 2 represents a hydrogen atom
  • R 3 represents a phenyl- group
  • phenyl- group is optionally substituted, identically or differently, with 1 or 2 R 7 groups ;
  • R 4 represents a hydrogen atom
  • R 5 represents a -OH, -SH, -NH 2 , CrC3-alkoxy-,
  • R 6 independently represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, CrC 6 -alkyl-, halo-d-d-alkyl-, R 8a (R 8b )N-d-C 6 -alkyl-, HO-d-C 6 -alkyl-, Crd-alkoxy-d-d-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C 2 -C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
  • aryl-d-d-alkyl- (aryl)-0-(Ci-C&-alkyl)-, heteroaryl-,
  • Ci-C&-alkyl- group m is an integer of 0, 1 , 2 or 3 ;
  • n is an integer of 2 or 3 ; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the present invention relates to compounds of general formula
  • (I) represents a phenyl- group
  • phenyl- group is optionally substituted, identically or differently, with 1 or 2 R 7 groups ; represents a hydrogen atom; represents a hydrogen atom or a -OH, -SH, -NH 2 , CrC3-alkoxy-,
  • -N(Ci-C 3 -alkyl)(CrC 3 -alkyl) or a H 2 N-Ci-C 3 -alkyl- group represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-d-alkyl-, R 8a (R 8b )N-d-C 6 -alkyl-, HO-d-d-alkyl-,
  • Ci-C&-alkyl- C 3 -C 7 -cycloalkyl-, (C 3 -C 7 -cycloalkyl)-(Ci-C6-alkyl)-,
  • aryl-Ci-C&-alkyl- (aryl)-0-(Ci-C&-alkyl)-, heteroaryl-,
  • Ci-C&-alkyl- group m is an integer of 0 or 1 ;
  • n is an integer of 2; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same,
  • the present invention relates to compounds of general formula
  • (I) represents a phenyl- group
  • phenyl- group is optionally substituted, identically differently, with 1 or 2 R 7 groups ; represents a hydrogen atom; represents a-OH, -SH, -NH 2 , CrC3-alkoxy-,
  • -N(Ci -C3-alkyl)(CrC3-alkyl) or a H 2 N-Ci -C3-alkyl- group represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-CrC 6 -alkyl-, R 8a (R 8b )N-d-C 6 -alkyl-, HO-d-C 6 -alkyl-,
  • R 7 represents a halogen atom
  • aryl-Ci-C&-alkyl- (aryl)-0-(Ci-C&-alkyl)-, heteroaryl-,
  • heteroaryl-CrCe-alkyl- or (aryl)-(3- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R 9 ;
  • R 9 represents a halogen atom, or a CrC3-alkyl-, halo-CrC3-alkyl-, -CN,
  • Ci-C&-alkyl- group m is an integer of 0 or 1 ;
  • n is an integer of 2; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the present invention relates to compounds of general formula (Ij), (Ik), or (Im) :
  • phenyl- group is optionally substituted, identically or differently, with 1 or 2 R 7 groups ; represents a hydrogen atom; represents a -OH, -SH, -NH 2 , CrC3-alkoxy-,
  • -N(Ci-C 3 -alkyl)(CrC 3 -alkyl) or a H 2 N-Ci-C 3 -alkyl- group represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-d-alkyl-, R 8a (R 8b )N-d-C 6 -alkyl-, HO-d-C 6 -alkyl-,
  • aryl-Ci-C&-alkyl- (aryl)-0-(Ci-C&-alkyl)-, heteroaryl-,
  • heteroaryl-Ci-C&-alkyl- or (aryl)-(3- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R 9 ;
  • R 9 represents a halogen atom, or a CrC3-alkyl-, halo-CrC3-alkyl-, -CN,
  • Ci-C&-alkyl- group m is an integer of 0 or 1 ; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the present invention relates to compounds of general formula (Ij), (Ik), or (Im) :
  • phenyl- group is optionally substituted, identically or differently, with 1 or 2 R 7 groups; represents a hydrogen atom; represents a -OH, -NH 2 , CrC3-alkoxy-, HO-Ci-C3-alkyl-,
  • HO-C 2 -C 3 -alkoxy- or -S-(Ci-C 3 -alkyl)- group represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-CrC 6 -alkyl-, R 8a (R 8b )N-d-C 6 -alkyl-, HO-d-d-alkyl-,
  • Ci-C&-alkyl- group said Ci-C&-alkyl- group being optionally substituted one or two times, identically or differently, with R 9 ;
  • R 9 represents a halogen atom, or a CrC3-alkyl-, halo-CrC3-alkyl-, -CN,
  • n is an integer of 0 or 1 ; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the present invention relates to compounds of general formula (In) (lo), or (Ip) :
  • phenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 7 groups ; represents a hydrogen atom or a -OH, -SH, -NH 2 , CrC3-alkoxy-,
  • -N(Ci-C 3 -alkyl)(CrC 3 -alkyl) or a H 2 N-Ci-C 3 -alkyl- group represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-CrC 6 -alkyl-, R 8a (R 8b )N-d-C 6 -alkyl-, HO-d-C 6 -alkyl-,
  • Ci-C&-alkyl- represent, independently from each other, a hydrogen atom, or a Ci-C&-alkyl-, C 3 -C 7 -cycloalkyl-, (C 3 -C 7 -cycloalkyl)-(Ci-C6-alkyl)-, C 2 -C6-alkenyl-, C 2 -C6-alkynyl-, 3- to 10-membered heterocycloalkyl-, (3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-, heteroaryl-, aryl-Ci-C&-alkyl-, (aryl)-0-(Ci-C&-alkyl)-, heteroaryl-Ci-C&-alkyl- or
  • Ci-C&-alkyl- group or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, wherein the following compound is excluded:
  • the present invention relates to compounds of general formula (In) (lo), or (Ip) :
  • R 3 represents a phenyl- group
  • phenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R 7 groups ;
  • R 5 represents a -OH, -SH, -NH 2 , CrC3-alkoxy-,
  • R 6 represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-d-alkyl-, R 8a (R 8b )N-d-C 6 -alkyl-, HO-d-C 6 -alkyl-,
  • R 7 represents a halogen atom, or a -CN, d-d-alkoxy-, d-d-alkyl-,
  • Ci-C&-alkyl- represent, independently from each other, a hydrogen atom, or a Ci-C&-alkyl-, C 3 -C 7 -cycloalkyl-, (C 3 -C 7 -cycloalkyl)-(Ci-C6-alkyl)-, C 2 -C&-alkenyl-, C 2 -C&-alkynyl-, 3- to 10-membered heterocycloalkyl-, (3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-, heteroaryl-, aryl-Ci-C&-alkyl-, (aryl)-0-(Ci-C&-alkyl)-, heteroaryl-Ci-C&-alkyl- or
  • R 9 represents a halogen atom, or a CrC 3 -alkyl-, halo-CrC 3 -alkyl-, -CN,
  • Ci-C&-alkyl- group or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the present invention relates to compounds of general formula (In) (lo), or (Ip) :
  • R 3 represents a phenyl- group
  • phenyl- group is optionally substituted, identically or differently, with 1 or 2 R 7 groups ;
  • R 5 represents a -OH, -NH 2 , CrC3-alkoxy-, HO-Ci-C3-alkyl-,
  • R 7 represents a halogen atom
  • Ci-C&-alkyl- group represent, independently from each other, a hydrogen atom or a Ci-C&-alkyl- group; said Ci-C&-alkyl- group being optionally substituted one time with R 9 ;
  • R 9 represents a -OH group; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the present invention relates to compounds of general formula (I ):
  • Z represents a phenyl- or pyridinyl- group
  • Y 1 represents N or C(R 1 );
  • Y 2 represents S or N(R 2 );
  • Y 3 represents S or 0
  • R 1 represents a hydrogen atom or a Ci-C&-alkyl-, trifluoromethyl- or
  • R 2 represents a hydrogen atom or a CrC3-alkyl- or a trifluoromethyl- group; represents a phenyl- group;
  • phenyl- group is optionally substituted, identically or differently, with 1 or 2 R 7 groups ;
  • R 5 represents a -OH, -NH 2 , CrC3-alkoxy-, HO-Ci-C3-alkyl-,
  • R 7 represents a halogen atom;
  • Ci-C&-alkyl- group represent, independently from each other, a hydrogen atom or a Ci-C&-alkyl- group; said Ci-C&-alkyl- group being optionally substituted one time with R 9 ;
  • R 9 represents a -OH group
  • n is an integer of 0, 1 or 2 ;
  • n is an integer of 2 or 3 ;
  • the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein.
  • the present invention relates to a method of preparing compounds of general formula (I), supra, in which method an intermediate of general formula
  • the present invention relates to a method of preparing compounds of general formula (I), supra, in which method an intermediate of general formula (VI) :
  • the present invention covers intermediate compounds which are useful in the preparation of compounds of the present invention of general formula (I), particularly in the method described herein.
  • the present invention covers compounds of general formula (III):
  • the present invention covers the use of the intermediate compounds :
  • the methods described above may comprise further steps like e.g. the introduction of a protective group and the cleavage of the protective group.
  • 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 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 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.
  • Preferred additional pharmaceutical agents are: 131 1-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY 80-6946, BAY 1000394, BAY 86-9766 (RDEA 1 19), belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, calcium folinate, calcium levofolinate, capecitabine, carboplatin, carmofur, carmustine, catumaxomab, celecoxib, celmole
  • Optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 1 1 th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednis
  • anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al. , publ.
  • anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to other anti-cancer agents such as epothilone and its derivatives, irinotecan, raloxifen and topotecan.
  • 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.
  • supraagonistic monoclonal antibodies Tuebingen, TRP-1 protein vaccine, Colostrinin, anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab, trastuzumab, denileukin diftitox, rituximab, thymosin alpha 1 , bevacizumab, mecasermin, mecasermin rinfabate, oprelvekin, natalizumab, rhMBL, MFE-CP1 + ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-35, MT-103, rinfabate, AS-1402, B43-genistein, L-19 based radioimmunotherapeutics, AC-9301 , NY-ESO-1 vaccine, IMC-1C11 , CT-322, rhCCIO, r(m)CRP, MORAb-009, expcumine,
  • 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.
  • cytotoxic and/or cytostatic agents in combination with a compound or composition of the present invention will serve to: (1 ) yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to administration of either agent alone,
  • the compounds of formula (I), supra, as described and defined herein have surprisingly been found to effectively and selectively inhibit GLUT1 and may therefore be used for the treatment and/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, 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 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.
  • 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 the use of a compound of general formula (I) described supra for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease.
  • 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 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.
  • Hyper- proliferative disorders include but are not limited, e.g.
  • BPH benign prostate hyperplasia
  • solid tumors 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 leukemias.
  • 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 tumor.
  • Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
  • Tumors 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.
  • Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small- intestine, and salivary gland cancers.
  • Tumors 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 AIDS- 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 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.
  • a general strategy to assemble the molecules of the invention consists in a coupling reaction to form the carbon-nitrogen bond linking the heteroaromatic moiety of compounds of formula (II) and the heteroalicyclic head group of an intermediate of general formula (III) as outlined in Scheme 1 :
  • This step employs a heterocyclic precursor (II), in which Y 1 , Y 2 , Y 3 , and R 3 are as defined for the compounds of general formula (I), supra, and in which LG is a leaving group suitable for nucleophilic aromatic substitution, such as fluoro, chloro, bromo, or a trifluoromethanesulfonyloxy group, or a moiety suitable for metal catalysed amination reactions, e.g. bromo or iodo, which is coupled with an intermediate (III), in which Z, R 4 , R 5 , R 6 , m and n are as defined for the compounds of general formula (I).
  • LG is a leaving group suitable for nucleophilic aromatic substitution, such as fluoro, chloro, bromo, or a trifluoromethanesulfonyloxy group, or a moiety suitable for metal catalysed amination reactions, e.g. bromo or iodo, which is coupled
  • the coupling reaction may be carried out as an aromatic nucleophilic substitution reaction using a dipolar solvent, e.g. DMF, DMSO, HMPA, or acetonitrile at elevated temperatures with or without applying microwave irradiation.
  • a dipolar solvent e.g. DMF, DMSO, HMPA, or acetonitrile
  • Addition of a base for example triethylamine, DIPEA, DBU, sodium carbonate, potassium carbonate, cesium carbonate or the like, may be advantageous.
  • the coupling can be carried out using a metal catalysed coupling reaction known to the person skilled in the art (for a general overview see: D. S. Surry, S. L. Buchwald, Chem. Sci. 201 1 , 2, 27-50. ).
  • a leaving group suitable for nucleophilic aromatic substitution such as fluoro, chloro, bromo, or a trifluoromethanesulfonyloxy group, or a moiety suitable for metal catalysed amination reactions, e.g.
  • bromo or iodo can be prepared, as shown in Scheme 3, starting from 5-amino-pyrimidines of formula (VII ) in which LG and LG ' are as defined supra, by reacting with an aniline of the formula (VIII ), in which R 3 is as defined for the general formula (I ), in an alcohol of the formula Ci-C4-alkyl-OH, such as ethanol, in the presence of a suitable acid, such as aqueous hydrochlorid acid, at elevated temperature, to give compounds of the formula (IX).
  • Said compounds of the formula (IX) can subsequently be cyclised with 1 , 1 ' -Carbonyldiimidazole (CAS-No.
  • 5- Aminopyrimidines of formula (VII ) are well known to the person skilled in the art, and are often commercially available (e.g. 5-amino-4,6- dichloropyrimidine, CAS-No. 5413-85-4).
  • Said compounds of formula (XII) can then be reacted with a Ci synthon, such as an orthoester of formula H-C(0-Ci-C4- alkyl) 3 , e.g. ethyl orthoformate, in the presence of an acid, such as para- toluenesulfonic acid, at elevated temperature, to give pyrimidones of formula (XIII).
  • a Ci synthon such as an orthoester of formula H-C(0-Ci-C4- alkyl) 3 , e.g. ethyl orthoformate
  • an acid such as para- toluenesulfonic acid
  • Said pyrimidones are converted into the intermediates of formula (Mb) e.g. by standard halogenation procedures well known to the person skilled in the art, e.g. by reaction with phosphoric trichloride, phosphoric tribromide, or phosphoroxychloride, if needed at elevated temperature.
  • Chemical compound names were generated using the software ACD Name batch, Version 12.01 , by Advanced Chemical Development, Inc.; in doubt, the chemical identity of intermediates and example compounds is primarily to be defined by their chemical structure as shown in the experimental section.
  • NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.
  • step 1 4.5 g (23.2 mmol) 4,6-dichloro-5- nitropyrimidine and 2.07 g (18.6 mmol) 2-fluoroaniline were reacted to give the desired 6-chloro-N 4 -(2-fluorophenyl)pyrimidine-4,5-diamine: 587 mg (24% yield).
  • step 2) 1.5 g (6.29 mmol) of intermediate 2) of step 1 ) and 1.33 g (8.17 mmol) 1 ,1'-Carbonyldiimidazole were reacted to give the desired title compound: 1.45 g (87% yield).
  • 1 H-NMR (400 MHz, DMSO d 6 ) ⁇ (ppm) 7.38 - 7.43 (m, 1 H), 7.49 (ddd, 1 H), 7.57 - 7.65 (m, 2H), 8.41 (s, 1 H), 12.43 (s, 1 H).
  • step 1 3.0 g (18.3 mmol) 4,6-dichloro-5- nitropyrimidine and 2.66 g (18.3 mmol) 3-chloro-2-fluoroaniline were reacted to give the desired 6-chloro-N 4 -(3-chloro-2-fluorophenyl)pyrimidine-4,5- diamine: 4.5 g (90% yield).
  • step 2) performing three reactions starting from 100 mg (0.37 mmol) and twice 2.20 g (8.06 mmol each) of intermediate 3) of step 1 ) and 77 mg (0.48 mmol) and twice 1.70 g (10.5 mmol each) 1 ,1'- Carbonyldiimidazole resulted in the isolation of the desired title compound: 795 mg (16% yield).
  • 117 ⁇ _ (0.67 mmol) diisopropylethylamine in 2.2 mL DMSO was added 0.67 mL of a 0.5M solution of ammonia in dioxane. The mixture was stirred for 16 hours at rt and an additional 0.2 mL amount of said ammonia solution together with 50 mg HATU was added. After stirring for 3 hours at rt the mixture was diluted with water. The aqueous phase was extracted twice with ethyl acetate. The organic phase was washed with aq. sodium bicarbonate and brine, then dried over sodium sulfate and concentrated in vacuo.
  • HATU (0-(7-azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) and 75 ⁇ _ (0.43 mmol) diisopropylethylamine in 1.4 mL DMSO was added 13.2 mg (0.22 mmol) 2-aminoethanol. The mixture was stirred for 4 days at rt and then directly purified via HPLC. Using this methodology the desired title compound was obtained: 34.5 mg (31% 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.
  • the cells were then cultured overnight in glucose free media containing 1% FCS to reduce intracellular ATP levels. After 24h the cells were incubated at 37 °C containing the appropriate glucose or in case of GLUT2 fructose concentration (1 mM and 30 mM respectively) with or without compounds and 1 uM Rotenone for 15min.
  • the CellTiter-Glo® Luminescent Cell Viability Assay from Promega was then used to measure ATP levels. Compounds able to reduce the ATP levels within 15 min of glucose application were considered to be glucose uptake inhibitors.
  • Cells (e.g. H460 or CHO-K1 ) were cultured under standard conditions. 10000 cells per well were seeded in clear 96 well tissue culture isoplate plates and cultured overnight (PerkinElmer, 1450-516) under standard conditions. Culture medium was removed and cells were washed two times with 100 ⁇ KRP buffer and then incubated for 45 minutes at 37° C (KRP buffer: 10 mM sodium hydrogen phosphate, 130 mM sodium chloride, 5 mM potassium chloride, 1 .3 mM magnesium sulfate, 1 .3 mM calcium chloride (pH 7.5), 50 mM HEPES (pH 7.5), 4.7 mM potassium chloride, 1 .25 mM magnesium sulfate, 1 .25 mM calcium chloride) each.
  • KRP buffer 10 mM sodium hydrogen phosphate, 130 mM sodium chloride, 5 mM potassium chloride, 1 .3 mM magnesium sulfate, 1 .3
  • Cultivated tumor cells (MCF7, hormone dependent human mammary carcinoma cells, ATCC HTB22; NCI-H460, human non-small cell lung carcinoma cells, ATCC HTB-177; DU 145, hormone-independent human prostate carcinoma cells, ATCC HTB-81 ; HeLa-MaTu, human cervical carcinoma cells, EPO-GmbH, Berlin; HeLa- MaTu-ADR, multidrug-resistant human cervical carcinoma cells, EPO-GmbH, Berlin; HeLa human cervical tumor cells, ATCC CCL-2; B16F10 mouse melanoma cells, ATCC CRL-6475) were plated at a density of 5000 cells/ well (MCF7, DU145, HeLa-MaTu-ADR), 3000 cells/well (NCI-H460, HeLa-MaTu, HeLa), or 1000 cells/well (B16F10) in a 96-well multititer plate in 200 ⁇ of their respective growth medium supplemented 10% fetal calf serum
  • the cells of one plate were stained with crystal violet (see below), while the medium of the other plates was replaced by fresh culture medium (200 ⁇ ), to which the test substances were added in various concentrations (0 ⁇ , as well as in the range of 0.01 -30 ⁇ ; the final concentration of the solvent dimethyl sulfoxide was 0.5%).
  • the cells were incubated for 4 days in the presence of test substances.
  • Cell proliferation was determined by staining the cells with crystal violet: the cells were fixed by adding 20 ⁇ /measuring point of an 11% glutaric aldehyde solution for 15 minutes at room temperature. After three washing cycles of the fixed cells with water, the plates were dried at room temperature.
  • test compounds in vitro was determined by incubating them at 1 ⁇ with a suspension liver microsomes in 100 mM phosphate buffer, pH7.4 (NaH 2 P0 4 x H 2 0 + Na 2 HP0 4 x 2H 2 0) at a protein concentration of 0.5 mg/mL and at 37° C.
  • the reaction was activated by adding a co-factor mix containing 1 .2 mg NADP, 3 IU glucose-6-phosphate dehydrogenase, 14.6 mg glucose-6-phosphate and 4.9 mg MgCl 2 in phosphate buffer, pH 7.4.
  • Organic solvent in the incubations was limited to ⁇ 0.2 % dimethylsulfoxide (DMSO) and ⁇ 1 % methanol.
  • DMSO dimethylsulfoxide
  • the microsomal suspensions were continuously shaken and aliquots were taken at 2, 8, 16, 30, 45 and 60 min, to which equal volumes of cold methanol were immediately added. Samples were frozen at -20° C over night, subsequently centrifuged for 15 minutes at 3000 rpm and the supernatant was analyzed with an Agilent 1200 HPLC-system with LCMS/MS detection.
  • phase-l metabolism of microsomes is reflected, e.g. typically oxidoreductive reactions by cytochrome P450 enzymes and flavin mono-oxygenases (FMO) and hydrolytic reactions by esterases (esters and amides).
  • FMO flavin mono-oxygenases

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Abstract

La présente invention concerne des composés chimiques de formule générale (I) : dans laquelle Z, Y1, Y2, Y3, R3, R4, R5, R6, m, et n sont tels que définis dans la description et dans les revendications, qui inhibent efficacement et sélectivement le transporteur de glucose 1 (GLUT1). L'invention concerne également des procédés de préparation de ces composés, des compositions et des combinaisons pharmaceutiques comprenant ces composés, l'utilisation de ces composés dans la fabrication d'une composition pharmaceutique destinée au traitement ou à la prophylaxie d'une maladie, ainsi que des composés intermédiaires utiles dans la préparation de ces composés.
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Publication number Priority date Publication date Assignee Title
WO2016202935A1 (fr) * 2015-06-19 2016-12-22 Bayer Pharma Aktiengesellschaft Inhibiteurs de transport du glucose
WO2018089433A1 (fr) * 2016-11-08 2018-05-17 Navitor Pharmaceuticals, Inc. Inhibiteurs de mtorc phényle et leurs utilisations
US11168068B2 (en) 2016-07-18 2021-11-09 Janssen Pharmaceutica Nv Tau PET imaging ligands
WO2022233782A1 (fr) 2021-05-03 2022-11-10 Lead Discovery Center Gmbh Composition comprenant un inhibiteur de la transcription mitochondriale

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EP0539180A1 (fr) * 1991-10-25 1993-04-28 Sanwa Kagaku Kenkyusho Co., Ltd. Agents antivirals
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WO2011119866A1 (fr) * 2010-03-24 2011-09-29 Ohio University Compositions et procédés pour l'inhibition du transport du glucose
WO2012051117A2 (fr) * 2010-10-11 2012-04-19 The Board Of Trustees Of The Leland Stanford Junior University Benzamides substitués et leurs utilisations
WO2013155338A2 (fr) * 2012-04-12 2013-10-17 The Board Of Trustees Of The Leland Stanford Junior University Benzamides substituées et leurs utilisations
WO2013182612A1 (fr) * 2012-06-07 2013-12-12 Bayer Pharma Aktiengesellschaft Inhibiteurs de transport du glucose

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US4078063A (en) * 1976-09-24 1978-03-07 Merck & Co., Inc. Piperazinylpyridines
EP0539180A1 (fr) * 1991-10-25 1993-04-28 Sanwa Kagaku Kenkyusho Co., Ltd. Agents antivirals
EP0878194A1 (fr) * 1996-01-31 1998-11-18 Sankyo Company Limited Medicaments pour prevenir ou soigner le sida
WO2003022214A2 (fr) * 2001-09-06 2003-03-20 Millennium Pharmaceuticals, Inc. Composes a base de piperazine et d'homopiperazine
EP1568699A1 (fr) * 2002-12-04 2005-08-31 Eisai Co., Ltd. Compose 1,3-dihydro-imidazole a cycle fusionne
WO2005117909A2 (fr) * 2004-04-23 2005-12-15 Exelixis, Inc. Modulateurs des proteines kinases et leurs methodes d'utilisation
WO2011119866A1 (fr) * 2010-03-24 2011-09-29 Ohio University Compositions et procédés pour l'inhibition du transport du glucose
WO2012051117A2 (fr) * 2010-10-11 2012-04-19 The Board Of Trustees Of The Leland Stanford Junior University Benzamides substitués et leurs utilisations
WO2013155338A2 (fr) * 2012-04-12 2013-10-17 The Board Of Trustees Of The Leland Stanford Junior University Benzamides substituées et leurs utilisations
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Publication number Priority date Publication date Assignee Title
WO2016202935A1 (fr) * 2015-06-19 2016-12-22 Bayer Pharma Aktiengesellschaft Inhibiteurs de transport du glucose
US11168068B2 (en) 2016-07-18 2021-11-09 Janssen Pharmaceutica Nv Tau PET imaging ligands
US12006302B2 (en) 2016-07-18 2024-06-11 Janssen Pharmaceutica Nv Tau PET imaging ligands
WO2018089433A1 (fr) * 2016-11-08 2018-05-17 Navitor Pharmaceuticals, Inc. Inhibiteurs de mtorc phényle et leurs utilisations
WO2022233782A1 (fr) 2021-05-03 2022-11-10 Lead Discovery Center Gmbh Composition comprenant un inhibiteur de la transcription mitochondriale

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