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WO2015078799A1 - Glucose transport inhibitors - Google Patents

Glucose transport inhibitors 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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PCT/EP2014/075352
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French (fr)
Inventor
Iring Heisler
Thomas Müller
Bernd Buchmann
Ludwig Zorn
Mélanie HÉROULT
Roland Neuhaus
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Bayer Pharma Aktiengesellschaft
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Publication of WO2015078799A1 publication Critical patent/WO2015078799A1/en

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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

The present invention relates to chemical compounds of general formula (I), in which Z, Y1, Y2, Y3, R3, R4, R5, R6, m, and n are as given in the description and in the claims, and which effectively and 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.

Description

GLUCOSE TRANSPORT INHIBITORS
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.
BACKGROUND OF THE INVENTION
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. Facilitated diffusion of glucose through the cellular membrane is otherwise catalyzed by glucose carriers (protein symbol GLUT, gene symbol SLC2 for Solute Carrier Family 2) that belong to 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 (GLUTs) 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.
All known 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. According to this model, 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. Although more than one GLUT protein may be expressed by a particular cell type, cancers frequently overexpress GLUT1 , which is a high affinity glucose transporter, and its expression level is correlated with invasiveness and metastasis potentials of cancers, indicating the importance of upregulation of glucose transport in cancer cell growth and in the severity of cancer malignancy. GLUT1 expression was also found to be significantly higher than that of any other glucose transporters.
Evidence indicates that cancer cells are more sensitive to glucose deprivation than normal cells. Numerous studies strongly suggest that basal glucose transport inhibition induces apoptosis and blocks cancer cell growth. Anti- angiogenesis has been shown to be a very effective way to restrict cancer growth and cause cancer ablation.
Reduced GLUT1 expression following transfection of GLUT1 antisense cDNA into cancer cell lines has been shown to suppress cell growth in vitro and tumor growth in vivo, and to reduce in vitro invasiveness of cells (Noguchi Y. et al. Cancer Lett 154(2), 2000, 175-182; Ito S. et al. J Natl Cancer Inst 94(14), 2002, 1080-1091 ). It has been demonstrated that 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).
Therefore, 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.
Different compounds have been disclosed in prior art which show an inhibitory effect on GLUT1. For example, WO2011 /119866(A1 ) discloses composition and methods for glucose transport inhibition; WO2012/051117(A2) and WO2013/155338(A2) disclose substituted benzamides as GLUT1 inhibitors.
Furthermore, certain compounds featuring structural features somewhat related to the compounds of the present invention, have been disclosed in various biological contexts different from GLUT inhibition. 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.
Furthermore, one 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.
However, the state of the art described above does not specifically disclose the compounds of general formula (I) of the present invention, or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, as described and defined herein, and as hereinafter referred to as "compounds of the present invention", and their pharmacological activity.
SUMMARY of the INVENTION
The present invention covers compounds of general formula (I) :
Figure imgf000007_0001
(I)
in which :
Z represents a phenyl- or pyridinyl- group;
Y1 represents N or C(R1);
Y2 represents S or N(R2);
Y3 represents S or 0; R1 represents a hydrogen atom, a halogen atom or a cyano-, Ci-C&-alkyl-, trifluoromethyl- or C3-C7-cycloalkyl- group;
R2 represents a hydrogen atom or a CrC3-alkyl- or trifluoromethyl- group; R3 represents a phenyl- group;
wherein said phenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R7 groups ; represents a hydrogen atom or a methyl- group; represents a hydrogen atom or a -OH, -SH, -NH2, CrC3-alkoxy-,
HO-CrC3-alkyl-, HO-C2-C3-alkoxy-, halo-CrC3-alkyl-, halo-CrC3-alkoxy-, S-(CrC3-alkyl), -S-(halo-d-C3-alkyl), -N(H)(d-C3-alkyl),
-N(Ci-C3-alkyl)(CrC3-alkyl) or a H2N-Ci-C3-alkyl- group;
independently represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-C6-alkyl-, R8a(R8b)N-d-C6-alkyl-, HO-d-C6-alkyl-, d-Ce-alkoxy-d-Ce-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C2-C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
4- to 10-membered heterocycloalkenyl-, d-G-cycloalkyl-,
-C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8, -N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(R8c)C(=0)C(=0)N(R8a)R8b,
-N(H)C(=0)OR8, -N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; represents a halogen atom, or a -CN, d-d-alkoxy-, d-d-alkyl-, halo-CrC6-alkyl-, R8a(R8b)N-d-C6-alkyl-, R8a(R8b)N-C(=0)(d-C6-alkyl)-, HO-d-d-alkyl-, d-d-alkoxy-d-d-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8,
-N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(H)C(=0)OR8,
-N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; 8a |^8b |^8c
represent, independently from each other, a hydrogen atom, or Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C6-alkyl) C2-C&-alkenyl-, C2-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;
said Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C&-alkyl)-, 3- to 10-membered heterocycloalkyl-,
(3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-,
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 R9; represents a halogen atom, or a CrC3-alkyl-, halo-CrC3-alkyl-, -CN, -C(=0)R10, -C(=0)N(H)R10, -C(=O)N(R10a)R10b, -C(=0)0-R10, -N(R10a)R10b, -N02, -N(H)C(=0)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b,
-N(R10a)C(=O)N(R10b)R10c, -N(H)C(=0)OR10, -N(R10a)C(=O)OR10b,
-N(H)S(=0)2R10, -N(R10a)S(=O)2R10b, -OR10, -0(C=0)R10, -O(C=O)N(R10a)R10b, -0(C=0)OR10, -SR10, -S(=0)R10, -S(=0)2R10, -S(=0)2N(H)R10,
-S(=O)2N(R10a)R10b or -S(=O)(=NR10a)R10b group;
^10a 1 Ob |^10c
represent, independently from each other, a hydrogen atom or a Ci-C&-alkyl- group; is an integer of 0, 1 , 2 or 3 ;
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;
wherein the following compound is excluded:
3-Phenyl-7-(4-phenyl-1 -piperazinyl)-thiazolo[4,5-d]pyrimidine-2(3H)-thione.
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.
DETAILED DESCRIPTION of the INVENTION
The terms as mentioned in the present text have preferably the following meanings : The term "halogen atom" or "halo-" is to be understood as meaning a fluorine, chlorine, bromine or iodine atom.
The term "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-dimethylbutyl, 1 , 1 -dimethylbutyl, 2,3- dimethylbutyl, 1 ,3-dimethylbutyl, or 1 ,2-dimethylbutyl group, or an isomer thereof. Particularly, 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.
The term "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, -CF3, -CHF2, -CH2F, -CF2CF3, or -CH2CF3.
The term "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.
The term "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. Particularly, said halogen atom is F. Said halo-CrCe-alkoxy group is, for example, -OCF3, -OCHF2, -OCH2F, -OCF2CF3, or - OCH2CF3.
The term "CrCe-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. methoxyalkyl, ethoxyalkyl, propyloxyalkyl, /so-propoxyalkyl, butoxyalkyl, /so-butoxyalkyl, tert-butoxyalkyl, sec-butoxyalkyl, pentyloxyalkyl, /so-pentyloxyalkyl, hexyloxyalkyl group, or an isomer thereof.
The term "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. Particularly, said halogen atom is F. Said halo-CrCe-alkoxy-CrCe-alkyl group is, for example, CH2CH2OCF3, -CH2CH2OCHF2, -CH2CH2OCH2F, -CH2CH2OCF2CF3, or
CH2CH2OCH2CF3.
The term "C2-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 ("C2-C3-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)-hex-2-enyl, (f)-hex- l -enyl, (Z)-hex- l -enyl, /so-propenyl, 2-methylprop-2-enyl, 1 -methylprop-2-enyl,
2- methylprop-1 -enyl, (f )-1 -methylprop-1 -enyl, (Z)-1 -methylprop-1 -enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1 -methylbut-3-enyl,
3- methylbut-2-enyl, (f)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (f )-1 -methylbut-2-enyl, (Z)-1 -methylbut-2-enyl, (f )-3-methylbut-1 -enyl, (Z)-3-methylbut-1 -enyl, (f )-2-methylbut-1 -enyl, (Z)-2-methylbut-1 -enyl, (f )-1 -methylbut-1 -enyl, (Z)-1 -methylbut-1 -enyl, 1 , 1 -dimethylprop-2-enyl, 1 -ethylprop-1 -enyl, 1 -propylvinyl, 1 -isopropylvinyl, 4-methylpent-4-enyl, 3- methylpent-4-enyl, 2-methylpent-4-enyl, 1 -methylpent-4-enyl
4- methylpent-3-enyl, ")-3-methylpent-3-enyl, (Z)-3-methylpent-3-enyl (f)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl, (f )-1 -methylpent-3-enyl (Z)-1 -methylpent-3-enyl, (f)-4-methylpent-2-enyl, (Z)-4-methylpent-2-enyl (f)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl, (f)-2-methylpent-2-enyl (Z)-2-methylpent-2-enyl, (f )-1 -methylpent-2-enyl, (Z)-1 -methylpent-2-enyl (f )-4-methylpent-1 -enyl, (Z)-4-methylpent-1 -enyl, (f )-3-methylpent-1 -enyl (Z)-3-methylpent-1 -enyl, (f )-2-methylpent-1 -enyl, (Z)-2-methylpent-1 -enyl
(f)-1 -methylpent-1 -enyl, (Z)-1 -methylpent-1 -en 3-ethylbut-3-enyl 2-ethylbut-3-enyl, 1 -ethylbut-3-enyl, (E)-3-ethylbut-2-enyl (Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl (E)-1 -ethylbut-2-enyl, (Z)-1 -ethylbut-2-enyl, (E)-3-ethylbut-1 -enyl (Z)-3-ethylbut-1 -enyl, 2-ethylbut-1 -enyl, (E)-1 -ethylbut-1 -enyl (Z)-1 -ethylbut-1 -enyl, 2-propylprop-2-enyl, 1 -propylprop-2-enyl 2-isopropylprop-2-enyl, 1 -isopropylprop-2-enyl, (f )-2-propylprop-1 -enyl (Z)-2-propylprop-1 -enyl, (f)-1 -propylprop-1 -enyl, (Z)-1 -propylprop-1 -enyl (f )-2-isopropylprop-1 -enyl, (Z)-2-isopropylprop-1 -enyl (f )-1 -isopropylprop-1 -enyl, (Z)-1 -isopropylprop-1 -enyl (f )-3,3-dimethylprop-1 -enyl, (Z)-3,3-dimethylprop-1 -enyl 1 -(1 , 1 -dimethylethyl)ethenyl, -dienyl, penta-1 ,4-dienyl hexa-1 ,5-dienyl, or methylhexadienyl group. Particularly, said group is vinyl or allyl.
The term "C2-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 ("C2-C3-alkynyl"). Said C2-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,
1 -ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1 -methyl- pent-4-ynyl, 2-methylpent-3-ynyl, 1 -methylpent-3-ynyl, 4-methylpent-2-ynyl, 1 -methylpent-2-ynyl, 4-methylpent-1 -ynyl, 3-methylpent-1 -ynyl, 2-ethylbut-3-ynyl, 1 -ethylbut-3-ynyl, 1 -ethylbut-2-ynyl, 1 -propylprop-2-ynyl, 1 -isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1 , 1 -dimethylbut-3-ynyl, 1 , 1 -dimethylbut-2-ynyl, or 3,3-dimethylbut-1 -ynyl group. Particularly, said alkynyl group is ethynyl, prop-1 -ynyl, or prop-2-ynyl. The term "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 C3-C7-cycloalkyl group is for example a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl ring. Particularly, said ring contains 3, 4, 5 or 6 carbon atoms ("C3-C6-cycloalkyl").
The term "C4-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 ("C4-C6-cycloalkenyl"). Said C4-Cs-cycloalkenyl group is for example a cyclobutenyl, cyclopentenyl, or cyclohexenyl group.
The term "3- to 10-membered heterocycloalkyl", is to be understood as meaning a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or more heteroatom-containing groups selected from C(=0), 0, S, S(=0), S(=0)2, NRa, in which Ra represents a hydrogen atom, or a Ci -C&-alkyl- group ; it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, the nitrogen atom. Particularly, 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").
Particularly, without being limited thereto, 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. The term "4- to 10-membered heterocycloalkenyl", is to be understood as meaning an unsaturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or more heteroatom-containing groups selected from C(=0), 0, S, S(=0), S(=0)2, NRa, in which Ra represents a hydrogen atom or a Ci -C&-alkyl- group ; it being possible for said heterocycloalkenyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, the nitrogen atom. Examples of said heterocycloalkenyl may contain one or more double bonds, e.g. 4H-pyranyl, 2H-pyranyl, 3H-diazirinyl, 2,5-dihydro-1 H-pyrrolyl, [1 , 3]dioxolyl, 4H-[1 ,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothiophenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl, or 4H-[1 ,4]thiazinyl group.
The term "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 "C6-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 "Ci2-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 "Ci4-aryl" group), e.g. an anthracenyl group. Preferably, the aryl group is a phenyl group.
The term "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. Particularly, 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.; or azocinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl, etc..
In general, and unless otherwise mentioned, the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof. Thus, for some illustrative non-restricting example, 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. Preferably, the heteroaryl group is a pyridinyl group.
The term "d-d", as used throughout this text, e.g. in the context of the definition of "C C6-alkyl", "C C6-haloalkyl", "C C6-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. d-d , d-d , C3-C4 , Ci-C2, C1-C3 , C1-C4 , C1-C5 , Ci- C&; particularly Ci-C2, 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-C2.
Similarly, as used herein, the term "d-d", as used throughout this text, e.g. in the context of the definitions of "C2-d-alkenyl" and "C2-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 "C2-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 C2- d.
Further, as used herein, the term "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.
As used herein, 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-trimethyl-benzene)sulfonyloxy, (4-tert-butyl-benzene)sulfonyloxy, benzenesulfonyloxy, and (4-methoxy-benzene)sulfonyloxy. In particular, 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.
As used herein, the term "protective 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. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999; more specifically, 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).
As used herein, 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". Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, 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.
Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations are included within the scope of the present invention.
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. 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. In order to limit different types of isomers from each other reference is made to lUPAC Rules Section E (Pure 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. Examples of 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 2H (deuterium), 3H (tritium), 11C, 13C, 14C, 1 N, 170, 180, 32P, 33P, 33S, 34S, 3 S, 36S, 18F, 36Cl, 82Br, 123l, 124l, 129l and 1311, respectively. Certain isotopic variations of a compound of the invention, for example, those in which one or more radioactive isotopes such as 3H or 14C are incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e. , 14C, 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.
Further, the compounds of the present invention may exist as tautomers. For example, 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. :
Figure imgf000021_0001
1 H-tautomer 2H-tautomer 4H-tautomei
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.
Further, 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. In the case of 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.
Further, 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. The term "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.
Furthermore, 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. In accordance with a first aspect, the present invention relates to compounds of general formula (I ) :
Figure imgf000023_0001
(I)
in which :
Z represents a phenyl- or pyridinyl- group;
Y1 represents N or C(R1 );
Y2 represents S or N(R2);
Y3 represents S or 0;
R1 represents a hydrogen atom, a halogen atom or a cyano-, Ci-C&-alkyl-, trifluoromethyl- or C3-C7-cycloalkyl- group; R2 represents a hydrogen atom or a CrC3-alkyl- or trifluoromethyl- group;
R3 represents a phenyl- group;
wherein said phenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R7 groups ;
R4 represents a hydrogen atom or a methyl- group; represents a hydrogen atom or a -OH, -SH, -NH2, CrC3-alkoxy-, HO-CrC3-alkyl-, HO-C2-C3-alkoxy-, halo-CrC3-alkyl-, halo-CrC3-alkoxy-, - S-(CrC3-alkyl), -S-(halo-d-C3-alkyl), -N(H)(Ci-C3-alkyl),
-N(Ci-C3-alkyl)(CrC3-alkyl) or a H2N-Ci-C3-alkyl- group; each
R6 independently represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-d-alkyl-, R8a(R8b)N-d-C6-alkyl-, HO-d-C6-alkyl-, d-Ce-alkoxy-d-Ce-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C2-C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
4- to 10-membered heterocycloalkenyl-, d-G-cycloalkyl-,
-C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8, -N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(R8c)C(=0)C(=0)N(R8a)R8b,
-N(H)C(=0)OR8, -N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8,
-S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group;
R7 represents a halogen atom, or a -CN, d-d-alkoxy-, d-d-alkyl-, halo-d-d-alkyl-, R8a(R8b)N-d-C6-alkyl-, R8a(R8b)N-C(=0)(d-C6-alkyl)-, HO-d-d-alkyl-, d-d-alkoxy-d-d-alkyl-, halo-Crd-alkoxy-Crd-alkyl-,
C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8, -N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(H)C(=0)OR8,
-N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8,
-S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; 8 [^8a [^8b [^8c represent, independently from each other, a hydrogen atom, or a Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C6-alkyl)-, C2-C&-alkenyl-, C2-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;
said Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C&-alkyl)-, 3- to 10-membered heterocycloalkyl-,
(3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-, 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 R9; represents a halogen atom, or a CrC3-alkyl-, halo-CrC3-alkyl-, -CN -C(=0)R10, -C(=0)N(H)R10, -C(=O)N(R10a)R10b, -C(=0)0-R10, -N(R10a)R10b -N02, -N(H)C(=0)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b -N(R10a)C(=O)N(R10b)R10c, -N(H)C(=0)OR10, -N(R10a)C(=O)OR10b
-N(H)S(=0)2R10, -N(R10a)S(=O)2R10b, -OR10, -0(C=0)R10, -O(C=O)N(R10a)R10b -0(C=0)OR10, -SR10, -S(=0)R10, -S(=0)2R10, -S(=0)2N(H)R10 -S(=O)2N(R10a)R10b or -S(=O)(=NR10a)R10b group; a j^10b |^10c
represent, independently from each other, a hydrogen atom or a
Ci-C&-alkyl- group; is an integer of 0, 1 , 2 or 3 ;
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,
wherein the following compound is excluded:
3-Phenyl-7-(4-phenyl-1 -piperazinyl)-thiazolo[4,5-d]pyrimidine-2(3H)-thione
Figure imgf000026_0001
(CAS Registry No. 385378-67-6).
In a preferred embodiment, Z represents a phenyl- group. In another preferred embodiment, Y1 represents N. In another preferred embodiment, Y2 represents S. In another preferred embodiment, Y2 represents N(R2).
In another preferred embodiment, Y3 represents S. In another preferred embodiment, Y3 represents 0. In another preferred embodiment, Y2 represents S and Y3 represents S. In another preferred embodiment, Y2 represents S and Y3 represents 0. In another preferred embodiment, Y2 represents N(R2) and Y3 represents 0.
In another preferred embodiment, Y1 represents N, Y2 represents S and Y3 represents S.
In another preferred embodiment, Y1 represents N, Y2 represents S and Y3 represents 0. In another preferred embodiment, Y1 represents N, Y2 represents N(R2) and Y3 represents 0.
In another preferred embodiment, Y1 represents N, Y2 represents N(H) and Y3 represents 0.
In another preferred embodiment, R1 represents a hydrogen atom.
In another preferred embodiment, R1 represents a Ci-C&-alkyl- group. In another preferred embodiment, R1 represents a trifluoromethyl- group.
In another preferred embodiment, R1 represents a halogen atom or cyano- group. In another preferred embodiment, R2 represents a hydrogen atom.
In another preferred embodiment, R3 represents a phenyl- group.
In another preferred embodiment, R3 represents a phenyl- group, wherein said phenyl- group is substituted, identically or differently, with 1 or 2 R7 groups. In another preferred embodiment, R3 represents a phenyl- group, wherein said phenyl- group is substituted, identically or differently, with 1 or 2 R7 groups, wherein R7 represents halo; preferably fluoro and/or chloro.
In another preferred embodiment, R3 is selected from:
Figure imgf000028_0001
wherein * indicates the point of attachment of said groups with the rest of the molecule.
In another preferred embodiment, R4 represents a hydrogen atom.
In general formula (I), supra, R5 is located in a 1 ,2-relationship with the nitrogen atom of the neighbouring heteroalicyclic group.
In a preferred embodiment, R5 represents a hydrogen atom or a -OH, -NH2, CrC3-alkoxy-, HO-Ci -C3-alkyl-, HO-C2-C3-alkoxy-, fluoro-CrC3-alkyl-,
fluoro-CrC3-alkoxy-, -S- (Ci -C3-alkyl), -S-(fluoro-Ci -C3-alkyl), -N(H)(Ci -C3-alkyl), or a -N(Ci -C3-alkyl) (CrC3-alkyl) group.
In a preferred embodiment, R5 represents a -OH, -NH2,
CrC3-alkoxy-, HO-Ci -C3-alkyl-, HO-C2-C3-alkoxy-, fluoro-CrC3-alkyl-,
fluoro-CrC3-alkoxy-, -S- (Ci -C3-alkyl), -S-(fluoro-Ci -C3-alkyl), -N(H)(Ci -C3-alkyl), or a -N(Ci -C3-alkyl) (CrC3-alkyl) group.
In a more preferred embodiment, R5 represents a hydrogen atom or a -OH, -NH2, CrC3-alkoxy-, HO-Ci -C3-alkyl-, HO-C2-C3-alkoxy-, or a -S- (Ci -C3-alkyl)- group. In a more preferred embodiment, R5 represents a -OH, -NH2, CrC3-alkoxy-, HO- CrC3-alkyl-, HO-C2-C3-alkoxy-, or a -S-(Ci-C3-alkyl)- group. In another more preferred embodiment, R5 represents a hydroxymethyl- group.
In a particularly preferred embodiment, R5 represents a -OH, -NH2,
CrC2-alkoxy- or a -S-(Ci-C2-alkyl)- group. In another particularly preferred embodiment, R5 represents a -OH group.
In another particularly preferred embodiment, R5 represents a -NH2 group.
In another particularly preferred embodiment, R5 represents a methoxy- group.
In another particularly preferred embodiment, R5 represents an ethoxy- group.
In another particularly preferred embodiment, R5 represents a -SCH3 group. In another particularly preferred embodiment, R5 represents a hydrogen atom.
In another particularly preferred embodiment, R5 represents a hydrogen atom and Y3 represents 0. In another particularly preferred embodiment, each R6 independently represents a halogen atom, or a -CN, -OH, Ci-C&-alkoxy-, Ci-C&-alkyl-, fluoro-CrC3-alkyl-, HO-Ci-C&-alkyl-, phenyl-, 5- or 6-membered heteroaryl-, -C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N(H)C(=0)R8, -N(R8c)C(=0)R8, -N(R8c)C(=0)C(=0)N(R8a)R8b, -N(H)S(=0)2R8, -S(=0)2R8, -S(=0)2N(H)R8 or -S(=0)2N(R8a)R8b group. In another particularly preferred embodiment, each R6 independently represents a halogen atom, or a -CN, -OH, pyridyl-, CrC3-alkoxy-, CrC3-alkyl-, HO-CrC3-alkyl-, -C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N(H)C(=0)R8, -N(R8c)C(=0)C(=0)N(R8a)R8b, -N(H)S(=0)2R8, -S(=0)2R8 or -S(=0)2N(H)R8 group.
In another particularly preferred embodiment, each R6 independently represents a fluoro, chloro, bromo atom, or a -CN, -OH, pyrid-3-yl-, methoxy-, ethoxy-, d-C3-alkyl-, HO-d-C3-alkyl-, -C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -NH2, -N(R8a)R8b, -N(H)C(=0)R8, -N(R8c)C(=0)C(=0)N(R8a)R8b, -N(H)S(=0)2R8, -S(=0)2R8 or -S(=0)2N(H)R8 group.
In another particularly preferred embodiment, m is 1 and R6 represents a fluoro, chloro, bromo atom, or a -CN, -OH, pyrid-3-yl-, methoxy-, ethoxy-, CrC3-alkyl-, HO-d-C3-alkyl-, -C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -NH2, -N(R8a)R8b, -N(H)C(=0)R8, -N(R8c)C(=0)C(=0)N(R8a)R8b, -N(H)S(=0)2R8, -S(=0)2R8 or -S(=0)2N(H)R8 group. In another particularly preferred embodiment, m is 1 and R6 represents a -C(=0)N(H)R8a or a -C(=0)0-R8 group.
In another particularly preferred embodiment, m is 1 and R6 represents a -C(=0)N(H)R8a group.
In another particularly preferred embodiment, m is 1 and R6 represents a -C(=0)0-R8 group.
In another particularly preferred embodiment, m is 1 and R6 represents a -C(=0)NH2 group. In another particularly preferred embodiment, m is 1 and R6 represents a -C(=0)OH group. In another particularly preferred embodiment, m is 1 and R6 represents a -C(=0)N(H)R8a group, wherein R8a represents -CH2-CH2-OH.
In another particularly preferred embodiment, m is 1 and R6 represents a -C(=0)OCH3 group.
In another particularly preferred embodiment, R7 represents halo, preferably fluoro or chloro.
In another particularly preferred embodiment, R7 represents fluoro.
In another particularly preferred embodiment, R8, R8a, R8b, R8c 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 R9.
In another particularly preferred embodiment, R8, R8a, R8b, R8c represent, independently from each other, a hydrogen atom, or a CrC3-alkyl- group; said CrC3-alkyl- group being optionally substituted one or two times, identically or differently, with R9.
In another particularly preferred embodiment, R8, R8a, R8b, R8c represent, independently from each other, a hydrogen atom, or a CrC3-alkyl- group; said CrC3-alkyl- group being optionally substituted one time with R9.
In another particularly preferred embodiment, R9 represents -OH. In another particularly preferred embodiment, m is 0 or 1 . In another particularly preferred embodiment, m is 0.
In another particularly preferred embodiment, m is 1 .
In another particularly preferred embodiment, 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.
Some examples of combinations are given hereinafter. However, the invention is not limited to these combinations.
In a preferred embodiment, the present invention relates to compounds of general formula (I) :
Figure imgf000032_0001
represents a phenyl- group; represents N;
represents S or N(R2);
represents S or 0; represents a hydrogen atom or a CrC3-alkyl- or a trifluoromethyl- group; represents a phenyl- group;
wherein said phenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R7 groups ; represents a hydrogen atom or a methyl- group; represents a -OH, -SH, -NH2, CrC3-alkoxy-,
HO-CrC3-alkyl-, HO-C2-C3-alkoxy-, halo-CrC3-alkyl-, halo-CrC3-alkoxy-, - S-(CrC3-alkyl), -S-(halo-d-C3-alkyl), -N(H)(d-C3-alkyl),
-N(Ci-C3-alkyl)(CrC3-alkyl) or a H2N-Ci-C3-alkyl- group;
independently represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-d-alkyl-, R8a(R8b)N-d-C6-alkyl-, HO-d-C6-alkyl-, d-Ce-alkoxy-d-Ce-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C2-C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
4- to 10-membered heterocycloalkenyl-, d-G-cycloalkyl-,
-C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8, -N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(R8c)C(=0)C(=0)N(R8a)R8b,
-N(H)C(=0)OR8, -N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; R7 represents a halogen atom, or a -CN, Ci-C&-alkoxy-, Ci-C&-alkyl-, halo-CrC6-alkyl-, R8a(R8b)N-d-C6-alkyl-, R8a(R8b)N-C(=0)(d-C6-alkyl)-, HO-d-Ce-alkyl-, CrCe-alkoxy-d-Ce-alkyl-, halo-CrCe-alkoxy-CrCe-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -NO2, -N(H)C(=0)R8, -N(R8c)C(=0)R8,
-N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(H)C(=0)OR8,
-N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group;
R8 R8a R8 R8c
represent, independently from each other, a hydrogen atom, or a Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C6-alkyl)-,
C2-C&-alkenyl-, C2-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 (aryl)-(3- to 10-membered heterocycloalkyl)- group;
said Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C&-alkyl)-, 3- to 10-membered heterocycloalkyl-,
(3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-,
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 R9;
R9 represents a halogen atom, or a CrC3-alkyl-, halo-CrC3-alkyl-, -CN, -C(=0)R10, -C(=0)N(H)R10, -C(=O)N(R10a)R10b, -C(=0)0-R10, -N(R10a)R10b,
Figure imgf000034_0001
-N(R10a)C(=O)N(R10b)R10c, -N(H)C(=0)OR10, -N(R10a)C(=O)OR10b,
-N(H)S(=0)2R10, -N(R10a)S(=O)2R10b, -OR10, -0(C=0)R10, -O(C=O)N(R10a)R10b, -0(C=0)OR10, -SR10, -S(=0)R10, -S(=0)2R10, -S(=0)2N(H)R10,
-S(=O)2N(R10a)R10b or -S(=O)(=NR10a)R10b group;
|^10 |^10a j^10b |^10c
represent, independently from each other, a hydrogen atom or a
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.
In another preferred embodiment, the present invention relates to compounds of general formula (la), (lb), or (lc) :
Figure imgf000035_0001
(la) (lb) (lc), in which :
Z represents a phenyl- or pyridinyl- group; R3 represents a phenyl- group; wherein said phenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R7 groups ; represents a hydrogen atom or a methyl- group; represents a -OH, -SH, -NH2, CrC3-alkoxy-,
HO-CrC3-alkyl-, HO-C2-C3-alkoxy-, halo-CrC3-alkyl-, halo-CrC3-alkoxy-, - S-(CrC3-alkyl), -S-(halo-d-C3-alkyl), -N(H)(d-C3-alkyl),
-N(Ci-C3-alkyl)(CrC3-alkyl) or a H2N-Ci-C3-alkyl- group;
independently represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-d-alkyl-, R8a(R8b)N-d-C6-alkyl-, HO-d-C6-alkyl-, d-Ce-alkoxy-d-Ce-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C2-C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
4- to 10-membered heterocycloalkenyl-, C3-C7-cycloalkyl-,
-C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8, -N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(R8c)C(=0)C(=0)N(R8a)R8b,
-N(H)C(=0)OR8, -N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; represents a halogen atom, or a -CN, d-d-alkoxy-, d-d-alkyl-, halo-CrC6-alkyl-, R8a(R8b)N-d-C6-alkyl-, R8a(R8b)N-C(=0)(d-C6-alkyl)-, HO-d-d-alkyl-, d-d-alkoxy-d-d-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8,
-N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(H)C(=0)OR8,
-N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; [^8a |^8b |^8c
represent, independently from each other, a hydrogen atom, or a
Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C6-alkyl)-, C2-C&-alkenyl-, C2-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;
said Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C&-alkyl)-, 3- to 10-membered heterocycloalkyl-,
(3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-,
aryl-Ci-C&-alkyl-, (aryl)-0-(Ci-C&-alkyl)-, heteroaryl-,
heteroaryl-d-Ce-alkyl- or (aryl)-(3- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R9; represents a halogen atom, or a CrC3-alkyl-, halo-CrC3-alkyl-, -CN, -C(=0)R10, -C(=0)N(H)R10, -C(=O)N(R10a)R10b, -C(=0)0-R10, -N(R10a)R10b, -N02, -N(H)C(=0)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b,
-N(R10a)C(=O)N(R10b)R10c, -N(H)C(=0)OR10, -N(R10a)C(=O)OR10b,
-N(H)S(=0)2R10, -N(R10a)S(=O)2R10b, -OR10, -0(C=0)R10, -O(C=O)N(R10a)R -0(C=0)OR10, -SR10, -S(=0)R10, -S(=0)2R10, -S(=0)2N(H)R10,
-S(=O)2N(R10a)R10b or -S(=O)(=NR10a)R10b group;
10a |^10b [^10c
represent, independently from each other, a hydrogen atom or a
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.
In another preferred embodiment, the present invention relates to compounds of general formula (Id), (le), or (If):
Figure imgf000038_0001
(Id) (le) (if), in which :
Z represents a phenyl- group; Y1 represents N or C(R1 );
R1 represents a hydrogen atom or a Ci-C&-alkyl-, trifluoromethyl- or
C3-C7-cycloalkyl- group;
R3 represents a phenyl- group; wherein said phenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R7 groups ; represents a hydrogen atom or a methyl- group; represents a hydrogen atom or a -OH, -SH, -NH2, CrC3-alkoxy-,
HO-CrC3-alkyl-, HO-C2-C3-alkoxy-, halo-CrC3-alkyl-, halo-CrC3-alkoxy-, - S-(CrC3-alkyl), -S-(halo-d-C3-alkyl), -N(H)(d-C3-alkyl),
-N(Ci-C3-alkyl)(CrC3-alkyl) or a H2N-Ci-C3-alkyl- group;
independently represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-C6-alkyl-, R8a(R8b)N-d-C6-alkyl-, HO-d-C6-alkyl-, d-Ce-alkoxy-d-Ce-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C2-C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
4- to 10-membered heterocycloalkenyl-, d-G-cycloalkyl-,
-C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8, -N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(R8c)C(=0)C(=0)N(R8a)R8b,
-N(H)C(=0)OR8, -N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; represents a halogen atom, or a -CN, d-d-alkoxy-, d-d-alkyl-, halo-CrC6-alkyl-, R8a(R8b)N-d-C6-alkyl-, R8a(R8b)N-C(=0)(d-C6-alkyl)-, HO-d-d-alkyl-, d-d-alkoxy-d-d-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8,
-N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(H)C(=0)OR8,
-N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; [^8a |^8b |^8c
represent, independently from each other, a hydrogen atom, or a
Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C6-alkyl)-,
C2-C&-alkenyl-, C2-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;
said Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C&-alkyl)-, 3- to 10-membered heterocycloalkyl-,
(3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-,
aryl-Ci-C&-alkyl-, (aryl)-0-(Ci-C&-alkyl)-, heteroaryl-,
heteroaryl-d-Ce-alkyl- or (aryl)-(3- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R9; represents a halogen atom, or a CrC3-alkyl-, halo-CrC3-alkyl-, -CN, -C(=0)R10, -C(=0)N(H)R10, -C(=O)N(R10a)R10b, -C(=0)0-R10, -N(R10a)R10b, -N02, -N(H)C(=0)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b,
-N(R10a)C(=O)N(R10b)R10c, -N(H)C(=0)OR10, -N(R10a)C(=O)OR10b,
-N(H)S(=0)2R10, -N(R10a)S(=O)2R10b, -OR10, -0(C=0)R10, -O(C=O)N(R10a)R -0(C=0)OR10, -SR10, -S(=0)R10, -S(=0)2R10, -S(=0)2N(H)R10,
-S(=O)2N(R10a)R10b or -S(=O)(=NR10a)R10b group;
10a |^10b [^10c
represent, independently from each other, a hydrogen atom or a 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,
wherein the following compound is excluded:
3-Phenyl-7-(4-phenyl-1 -piperazinyl)-thiazolo[4,5-d]pyrimidine-2(3H)-thione.
In another preferred embodiment, the present invention relates to compounds of general formula (Ig), (Ih), or (li):
Figure imgf000041_0001
(Ig) (Ih) (li),
represents a phenyl- group;
wherein said phenyl- group is optionally substituted, identically differently, with 1 , 2 or 3 R7 groups ; represents a hydrogen atom or a methyl- group; represents a hydrogen atom or a -OH, -SH, -NH2, CrC3-alkoxy-, HO-CrC3-alkyl-, HO-C2-C3-alkoxy-, halo-Ci-C3-alkyl-, halo-CrC3-alkoxy-, - S-(CrC3-alkyl), -S-(halo-d-C3-alkyl), -N(H)(Ci-C3-alkyl),
-N(Ci-C3-alkyl)(CrC3-alkyl) or a H2N-Ci-C3-alkyl- group; represents a hydrogen atom or a halogen atom, or a -CN, -OH,
CrC6-alkoxy-, d-d-alkyl-, halo-d-d-alkyl-, R8a(R8b)N-d-C6-alkyl-, HO-d-Ce-alkyl-, d-d-alkoxy-d-d-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C2-C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-, 4- to 10-membered heterocycloalkenyl-, d-G-cycloalkyl-,
-C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8, -N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(R8c)C(=0)C(=0)N(R8a)R8b,
-N(H)C(=0)OR8, -N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; represents a halogen atom, or a -CN, d-d-alkoxy-, d-d-alkyl-, halo-CrC6-alkyl-, R8a(R8b)N-d-C6-alkyl-, R8a(R8b)N-C(=0)(d-C6-alkyl)-, HO-d-Ce-alkyl-, d-d-alkoxy-d-d-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8,
-N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(H)C(=0)OR8,
-N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8,
-0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; [^8a [^8b |^8c
represent, independently from each other, a hydrogen atom, or a d-d-alkyl-, d-G-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C&-alkyl)-, C2-C&-alkenyl-, C2-C&-alkynyl-, 3- to 10-membered heterocycloalkyl-, (3- to 10-membered heterocycloalkyl)-(Ci-C6-alkyl)-, aryl-, heteroaryl-, aryl-Ci-C&-alkyl-, (aryl)-0-(Ci-C&-alkyl)-, heteroaryl-Ci-C&-alkyl- or (aryl)-(3- to 10-membered heterocycloalkyl)- group;
said Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C&-alkyl)-, 3- to 10-membered heterocycloalkyl-,
(3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-, 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 R9; represents a halogen atom, or a CrC3-alkyl-, halo-CrC3-alkyl-, -CN, -C(=0)R10, -C(=0)N(H)R10, -C(=O)N(R10a)R10b, -C(=0)0-R10, -N(R10a)R10b, -N02, -N(H)C(=0)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b,
-N(R10a)C(=O)N(R10b)R10c, -N(H)C(=0)OR10, -N(R10a)C(=O)OR10b,
-N(H)S(=0)2R10, -N(R10a)S(=O)2R10b, -OR10, -0(C=0)R10, -O(C=O)N(R10a)R -0(C=0)OR10, -SR10, -S(=0)R10, -S(=0)2R10, -S(=0)2N(H)R10,
-S(=O)2N(R10a)R10b or -S(=O)(=NR10a)R10b group; R10, R10a, R10b, R10c
represent, independently from each other, a hydrogen atom or a
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,
wherein the following compound is excluded:
3-Phenyl-7-(4-phenyl-1-piperazinyl)-thiazolo[4,5-d]pyrimidine-2(3H)-thione. In another preferred embodiment, the present invention relates to compounds of general formula (Ig), (Ih), or (li):
Figure imgf000044_0001
represents a phenyl- group;
wherein said phenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R7 groups ; represents a hydrogen atom or a methyl- group; represents a -OH, -SH, -NH2, CrC3-alkoxy-,
HO-CrC3-alkyl-, HO-C2-C3-alkoxy-, halo-CrC3-alkyl-, halo-CrC3-alkoxy-, S-(CrC3-alkyl), -S-(halo-d-C3-alkyl), -N(H)(d-C3-alkyl),
-N(Ci-C3-alkyl)(CrC3-alkyl) or a H2N-Ci-C3-alkyl- group; represents a hydrogen atom or a halogen atom, or a -CN, -OH,
CrC6-alkoxy-, d-d-alkyl-, halo-d-d-alkyl-, R8a(R8b)N-d-C6-alkyl-, HO-d-d-alkyl-, d-d-alkoxy-Crd-alkyl-, halo-Ci-d-alkoxy-Crd-alkyl-, C2-C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-, 4- to 10-membered heterocycloalkenyl-, d-G-cycloalkyl-, -C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8, -N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(R8c)C(=0)C(=0)N(R8a)R8b,
-N(H)C(=0)OR8, -N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8,
-S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; represents a halogen atom, or a -CN, Ci-C&-alkoxy-, Ci-C&-alkyl-, halo-CrC6-alkyl-, R8a(R8b)N-d-C6-alkyl-, R8a(R8b)N-C(=0)(d-C6-alkyl)-, HO-d-Ce-alkyl-, CrCe-alkoxy-d-Ce-alkyl-, halo-CrCe-alkoxy-CrCe-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8,
-N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(H)C(=0)OR8,
-N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8,
-0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; a |^8b [^8c
represent, independently from each other, a hydrogen atom, or a Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C6-alkyl)-, C2-C&-alkenyl-, C2-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;
said Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C&-alkyl)-, 3- to 10-membered heterocycloalkyl-,
(3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-, 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 R9;
R9 represents a halogen atom, or a CrC3-alkyl-, halo-CrC3-alkyl-, -CN,
-C(=0)R10, -C(=0)N(H )R10, -C(=O)N(R10a)R10b, -C(=0)0-R10, -N(R10a)R10b, -NO2, -N(H )C(=0)R10, -N(R10a)C(=O)R10b, -N(H )C(=O)N(R10a)R10b,
-N(R10a)C(=O)N(R10b)R10c, -N(H )C(=0)OR10, -N(R10a)C(=O)OR10b,
-N(H )S(=0)2R10, -N(R10a)S(=O)2R10b, -OR10, -0(C=0)R10, -O(C=O)N(R10a)R10b, -0(C=0)OR10, -SR10, -S(=0)R10, -S(=0)2R10, -S(=0)2N(H )R1°,
-S(=O)2N(R10a)R10b or -S(=O)(=NR10a)R10b group;
|^10 |^10a j^10b |^10c
represent, independently from each other, a hydrogen atom or a
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.
In another preferred embodiment, the present invention relates to compounds of general formula (Ij), (Ik), or (Im) :
Figure imgf000047_0001
(Ij) (Ik) (Im), in which :
Z represents a phenyl- or pyridinyl- group;
R3 represents a phenyl- group;
wherein said phenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R7 groups ; represents a hydrogen atom or a methyl- group; represents a hydrogen atom or a -OH, -SH, -NH2, CrC3-alkoxy-,
HO-CrC3-alkyl-, HO-C2-C3-alkoxy-, halo-CrC3-alkyl-, halo-CrC3-alkoxy-, S-(CrC3-alkyl), -S-(halo-d-C3-alkyl), -N(H)(d-C3-alkyl),
-N(Ci-C3-alkyl)(CrC3-alkyl) or a H2N-Ci-C3-alkyl- group;
independently represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-d-alkyl-, R8a(R8b)N-d-C6-alkyl-, HO-d-C6-alkyl-, d-d-alkoxy-Crd-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C2-C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
4- to 10-membered heterocycloalkenyl-, C3-C7-cycloalkyl-, -C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8, -N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(R8c)C(=0)C(=0)N(R8a)R8b,
-N(H)C(=0)OR8, -N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8,
-S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; represents a halogen atom, or a -CN, Ci-C&-alkoxy-, Ci-C&-alkyl-, halo-CrC6-alkyl-, R8a(R8b)N-d-C6-alkyl-, R8a(R8b)N-C(=0)(d-C6-alkyl)-, HO-d-Ce-alkyl-, CrCe-alkoxy-d-Ce-alkyl-, halo-CrCe-alkoxy-CrCe-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8,
-N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(H)C(=0)OR8,
-N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8,
-0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; a |^8b [^8c
represent, independently from each other, a hydrogen atom, or a Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C6-alkyl)-, C2-C&-alkenyl-, C2-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;
said Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C&-alkyl)-, 3- to 10-membered heterocycloalkyl-,
(3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-,
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 R9; represents a halogen atom, or a CrC3-alkyl-, halo-CrC3-alkyl-, -CN, -C(=0)R10, -C(=0)N(H)R10, -C(=O)N(R10a)R10b, -C(=0)0-R10, -N(R10a)R10b,
Figure imgf000049_0001
-N(R10a)C(=O)N(R10b)R10c, -N(H)C(=0)OR10, -N(R10a)C(=O)OR10b,
-N(H)S(=0)2R10, -N(R10a)S(=O)2R10b, -OR10, -0(C=0)R10, -O(C=O)N(R10a)R -0(C=0)OR10, -SR10, -S(=0)R10, -S(=0)2R10, -S(=0)2N(H)R1°,
-S(=O)2N(R10a)R10b or -S(=O)(=NR10a)R10b group; 10 |^10a j^10b |^10c
represent, independently from each other, a hydrogen atom or a
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,
wherein the following compound is excluded:
3-Phenyl-7-(4-phenyl-1 -piperazinyl)-thiazolo[4,5-d]pyrimidine-2(3H)-thione.
In another preferred embodiment, the present invention relates to compounds of general formula
Figure imgf000050_0001
(I)
in which :
Z represents a phenyl- or pyridinyl- group;
Y1 represents N or C(R1);
Y2 represents S or N(R2);
Y3 represents S or 0;
R1 represents a hydrogen atom or a Ci-C&-alkyl-, trifluoromethyl- or
C3-C7-cycloalkyl- group;
R2 represents a hydrogen atom;
R3 represents a phenyl- group;
wherein said phenyl- group is optionally substituted, identically or differently, with 1 or 2 R7 groups ;
R4 represents a hydrogen atom; R5 represents a -OH, -SH, -NH2, CrC3-alkoxy-,
HO-CrC3-alkyl-, HO-C2-C3-alkoxy-, halo-CrC3-alkyl-, halo-CrC3-alkoxy-, - S-(CrC3-alkyl), -S-(halo-d-C3-alkyl), -N(H)(d-C3-alkyl),
-N(Ci-C3-alkyl)(CrC3-alkyl) or a H2N-Ci-C3-alkyl- group; each
R6 independently represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, CrC6-alkyl-, halo-d-d-alkyl-, R8a(R8b)N-d-C6-alkyl-, HO-d-C6-alkyl-, Crd-alkoxy-d-d-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C2-C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
4- to 10-membered heterocycloalkenyl-, C3-C7-cycloalkyl-,
-C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8, -N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(R8c)C(=0)C(=0)N(R8a)R8b,
-N(H)C(=0)OR8, -N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; R7 represents a halogen atom;
R8 R8a R8 R8c
represent, independently from each other, a hydrogen atom, or a d-d-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C&-alkyl)-,
C2-C&-alkenyl-, C2-C&-alkynyl-, 3- to 10-membered heterocycloalkyl-,
(3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-, heteroaryl-, aryl-d-d-alkyl-, (aryl)-0-(Ci-C&-alkyl)-, heteroaryl-d-d-alkyl- or (aryl)-(3- to 10-membered heterocycloalkyl)- group;
said d-d-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C&-alkyl)-, 3- to 10-membered heterocycloalkyl-,
(3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-,
aryl-d-d-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 R9; R9 represents a halogen atom, or a CrC3-alkyl-, halo-CrC3-alkyl-, -CN, -C(=0)R10, -C(=0)N(H)R10, -C(=O)N(R10a)R10b, -C(=0)0-R10, -N(R10a)R10b,
Figure imgf000052_0001
-N(R10a)C(=O)N(R10b)R10c, -N(H)C(=0)OR10, -N(R10a)C(=O)OR 10b
-N(H)S(=0)2R10, -N(R10a)S(=O)2R10b, -OR10, -0(C=0)R10, -O(C=O)N(R10a)R10b, -0(C=0)OR10, -SR10, -S(=0)R10, -S(=0)2R10, -S(=0)2N(H)R1°,
-S(=O)2N(R10a)R10b or -S(=O)(=NR10a)R10b group; R10, R10a, R10b, R10c
represent, independently from each other, a hydrogen atom or a
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. In another preferred embodiment, the present invention relates to compounds of general formula
Figure imgf000052_0002
(I) represents a phenyl- group;
represents N;
represents S or N(R2);
represents S or 0; represents a hydrogen atom; represents a phenyl- group;
wherein said phenyl- group is optionally substituted, identically or differently, with 1 or 2 R7 groups ; represents a hydrogen atom; represents a hydrogen atom or a -OH, -SH, -NH2, CrC3-alkoxy-,
HO-CrC3-alkyl-, HO-C2-C3-alkoxy-, halo-CrC3-alkyl-, halo-CrC3-alkoxy-, S-(CrC3-alkyl), -S-(halo-d-C3-alkyl), -N(H)(d-C3-alkyl),
-N(Ci-C3-alkyl)(CrC3-alkyl) or a H2N-Ci-C3-alkyl- group; represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-d-alkyl-, R8a(R8b)N-d-C6-alkyl-, HO-d-d-alkyl-,
d-Ce-alkoxy-d-Ce-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C2-C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
4- to 10-membered heterocycloalkenyl-, C3-C7-cycloalkyl-,
-C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8, -N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8t -N(R8c)C(=0)C(=0)N(R8a)R8b,
-N(H)C(=0)OR8, -N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; R7 represents a halogen atom;
R R R R
represent, independently from each other, a hydrogen atom, or a
Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C6-alkyl)-,
C2-C&-alkenyl-, C2-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;
said Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C&-alkyl)-, 3- to 10-membered heterocycloalkyl-,
(3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-,
aryl-Ci-C&-alkyl-, (aryl)-0-(Ci-C&-alkyl)-, heteroaryl-,
heteroaryl-d-Ce-alkyl- or (aryl)-(3- to 10-membered heterocycloalkyl)- group being optionally substituted one or more times, identically or differently, with R9; represents a halogen atom, or a CrC3-alkyl-, halo-CrC3-alkyl-, -CN, -C(=0)R10, -C(=0)N(H)R10, -C(=O)N(R10a)R10b, -C(=0)0-R10, -N(R10a)R10b, -N02, -N(H)C(=0)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b,
-N(R10a)C(=O)N(R10b)R10c, -N(H)C(=0)OR10, -N(R10a)C(=O)OR10b,
-N(H)S(=0)2R10, -N(R10a)S(=O)2R10b, -OR10, -0(C=0)R10, -O(C=O)N(R10a)R -0(C=0)OR10, -SR10, -S(=0)R10, -S(=0)2R10, -S(=0)2N(H)R10,
-S(=O)2N(R10a)R10b or -S(=O)(=NR10a)R10b group;
10a 1 Ob |^10c
represent, independently from each other, a hydrogen atom or a
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,
wherein the following compound is excluded:
3-Phenyl-7-(4-phenyl-1 -piperazinyl)-thiazolo[4,5-d]pyrimidine-2(3H)-thione.
In another preferred embodiment, the present invention relates to compounds of general formula
Figure imgf000055_0001
(I) represents a phenyl- group;
represents N;
represents S or N(R2);
represents S or 0; represents a hydrogen atom represents a phenyl- group;
wherein said phenyl- group is optionally substituted, identically differently, with 1 or 2 R7 groups ; represents a hydrogen atom; represents a-OH, -SH, -NH2, CrC3-alkoxy-,
HO-CrC3-alkyl-, HO-C2-C3-alkoxy-, halo-CrC3-alkyl-, halo-CrC3-alkoxy-, S-(CrC3-alkyl), -S-(halo-d-C3-alkyl), -N(H)(Ci-C3-alkyl),
-N(Ci -C3-alkyl)(CrC3-alkyl) or a H2N-Ci -C3-alkyl- group; represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-CrC6-alkyl-, R8a(R8b)N-d-C6-alkyl-, HO-d-C6-alkyl-,
d-Ce-alkoxy-d-Ce-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C2-C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
4- to 10-membered heterocycloalkenyl-, d-G-cycloalkyl-,
-C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8, -N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8t -N(R8c)C(=0)C(=0)N(R8a)R8b,
-N(H)C(=0)OR8, -N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group;
R7 represents a halogen atom;
R R R R
represent, independently from each other, a hydrogen atom, or a d-d-alkyl-, d-G-cycloalkyl-, (d-G-cycloalkylHCrd-alkyl)-,
C2-C&-alkenyl-, C2-C&-alkynyl-, 3- to 10-membered heterocycloalkyl-, (3- to 10-membered heterocycloalkyl)- (Ci-C&-alkyl)-, aryl-, heteroaryl-, aryl-d-d-alkyl-, (aryl)-0- (Ci-C&-alkyl)-, heteroaryl-Ci-C&-alkyl- or (aryl)-(3- to 10-membered heterocycloalkyl)- group;
said d-d-alkyl-, d-G-cycloalkyl-, (C3-C7-cycloalkyl)- (Ci-C&-alkyl)-, 3- to 10-membered heterocycloalkyl-,
(3- to 10-membered heterocycloalkyl)-(Ci-C6-alkyl)-, aryl-,
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 R9;
R9 represents a halogen atom, or a CrC3-alkyl-, halo-CrC3-alkyl-, -CN,
-C(=0)R10, -C(=0)N(H)R10, -C(=O)N(R10a)R10b, -C(=0)0-R10, -N(R10a)R10b, -N02, -N(H)C(=0)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b,
-N(R10a)C(=O)N(R10b)R10c, -N(H)C(=0)OR10, -N(R10a)C(=O)OR10b,
-N(H)S(=0)2R10, -N(R10a)S(=O)2R10b, -OR10, -0(C=0)R10, -O(C=O)N(R10a)R10b, -0(C=0)OR10, -SR10, -S(=0)R10, -S(=0)2R10, -S(=0)2N(H)R10,
-S(=O)2N(R10a)R10b or -S(=O)(=NR10a)R10b group;
|^10 |^10a |^10b |^10c
represent, independently from each other, a hydrogen atom or a
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.
In another preferred embodiment, the present invention relates to compounds of general formula (Ij), (Ik), or (Im) :
Figure imgf000058_0001
(Ik) (Im),
represents a phenyl- group; represents a phenyl- group;
wherein said phenyl- group is optionally substituted, identically or differently, with 1 or 2 R7 groups ; represents a hydrogen atom; represents a -OH, -SH, -NH2, CrC3-alkoxy-,
HO-CrC3-alkyl-, HO-C2-C3-alkoxy-, halo-CrC3-alkyl-, halo-CrC3-alkoxy-, S-(CrC3-alkyl), -S-(halo-d-C3-alkyl), -N(H)(d-C3-alkyl),
-N(Ci-C3-alkyl)(CrC3-alkyl) or a H2N-Ci-C3-alkyl- group; represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-d-alkyl-, R8a(R8b)N-d-C6-alkyl-, HO-d-C6-alkyl-,
d-Ce-alkoxy-d-Ce-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C2-C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
4- to 10-membered heterocycloalkenyl-, C3-C7-cycloalkyl-, -C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8, -N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(R8c)C(=0)C(=0)N(R8a)R8b,
-N(H)C(=0)OR8, -N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8,
-S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; represents a halogen atom, or a -CN, Ci-C&-alkoxy-, Ci-C&-alkyl-, halo-CrC6-alkyl-, R8a(R8b)N-d-C6-alkyl-, R8a(R8b)N-C(=0)(d-C6-alkyl)-, HO-d-Ce-alkyl-, CrCe-alkoxy-d-Ce-alkyl-, halo-CrCe-alkoxy-CrCe-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8,
-N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(H)C(=0)OR8,
-N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; a |^8b [^8c
represent, independently from each other, a hydrogen atom, or a Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C6-alkyl)-,
C2-C&-alkenyl-, C2-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;
said Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C&-alkyl)-, 3- to 10-membered heterocycloalkyl-,
(3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-,
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 R9;
R9 represents a halogen atom, or a CrC3-alkyl-, halo-CrC3-alkyl-, -CN,
-C(=0)R10, -C(=0)N(H)R10, -C(=O)N(R10a)R10b, -C(=0)0-R10, -N(R10a)R10b,
Figure imgf000060_0001
-N(R10a)C(=O)N(R10b)R10c, -N(H)C(=0)OR10, -N(R10a)C(=O)OR10b,
-N(H)S(=0)2R10, -N(R10a)S(=O)2R10b, -OR10, -0(C=0)R10, -O(C=O)N(R10a)R10b, -0(C=0)OR10, -SR10, -S(=0)R10, -S(=0)2R10, -S(=0)2N(H)R1°,
-S(=O)2N(R10a)R10b or -S(=O)(=NR10a)R10b group;
|^10 |^10a j^10b |^10c
represent, independently from each other, a hydrogen atom or a
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.
In another preferred embodiment, the present invention relates to compounds of general formula (Ij), (Ik), or (Im) :
Figure imgf000061_0001
(Ij) (Ik) (Im), represents a phenyl- group; represents a phenyl- group;
wherein said phenyl- group is optionally substituted, identically or differently, with 1 or 2 R7 groups; represents a hydrogen atom; represents a -OH, -NH2, CrC3-alkoxy-, HO-Ci-C3-alkyl-,
HO-C2-C3-alkoxy- or -S-(Ci-C3-alkyl)- group; represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-CrC6-alkyl-, R8a(R8b)N-d-C6-alkyl-, HO-d-d-alkyl-,
d-d-alkoxy-Crd-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, -C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02,
-N(H)C(=0)R8, -N(R8c)C(=0)R8, -N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R! -N(R8c)C(=0)C(=0)N(R8a)R8b,
-N(H)C(=0)OR8, -N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; R7 represents a halogen atom;
R R R R
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 R9;
R9 represents a halogen atom, or a CrC3-alkyl-, halo-CrC3-alkyl-, -CN,
-C(=0)R10, -C(=0)N(H)R10, -C(=O)N(R10a)R10b, -C(=0)0-R10, -N(R10a)R10b,
-N02, -N(H)C(=0)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b,
-N(R10a)C(=O)N(R10b)R10c, -N(H)C(=0)OR10, -N(R10a)C(=O)OR10b,
-N(H)S(=0)2R10, -N(R10a)S(=O)2R10b, -OR10, -0(C=0)R10, -O(C=O)N(R10a)R10b, -0(C=0)OR10, -SR10, -S(=0)R10, -S(=0)2R10, -S(=0)2N(H)R10,
-S(=O)2N(R10a)R10b or -S(=O)(=NR10a)R10b group; 10 10a |^1 Ob |^10c represent, independently from each other, a hydrogen atom or a
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. In another preferred embodiment, the present invention relates to compounds of general formula (In) (lo), or (Ip) :
Figure imgf000063_0001
(In) (lo)
represents a phenyl- group;
wherein said phenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R7 groups ; represents a hydrogen atom or a -OH, -SH, -NH2, CrC3-alkoxy-,
HO-CrC3-alkyl-, HO-C2-C3-alkoxy-, halo-CrC3-alkyl-, halo-CrC3-alkoxy-, S-(CrC3-alkyl), -S-(halo-d-C3-alkyl), -N(H)(d-C3-alkyl),
-N(Ci-C3-alkyl)(CrC3-alkyl) or a H2N-Ci-C3-alkyl- group; represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-CrC6-alkyl-, R8a(R8b)N-d-C6-alkyl-, HO-d-C6-alkyl-,
d-Ce-alkoxy-d-Ce-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C2-C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
4- to 10-membered heterocycloalkenyl-, C3-C7-cycloalkyl-,
-C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8, -N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8 -N(R8c)C(=0)C(=0)N(R8a)R8b, -N(H)C(=0)OR8, -N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; R7 represents a halogen atom, or a -CN, Ci-C&-alkoxy-, Ci-C&-alkyl-,
halo-CrC6-alkyl-, R8a(R8b)N-d-C6-alkyl-, R8a(R8b)N-C(=0)(d-C6-alkyl)-, HO-d-Ce-alkyl-, CrCe-alkoxy-d-Ce-alkyl-, halo-CrCe-alkoxy-CrCe-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -NO2, -N(H)C(=0)R8, -N(R8c)C(=0)R8,
-N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(H)C(=0)OR8,
-N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8,
-0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; R8, R8a, R8b, R8c
represent, independently from each other, a hydrogen atom, or a Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C6-alkyl)-, C2-C6-alkenyl-, C2-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
(aryl)-(3- to 10-membered heterocycloalkyl)- group;
said Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C&-alkyl)-, 3- to 10-membered heterocycloalkyl-,
(3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-, 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 R9; R9 represents a halogen atom, or a CrC3-alkyl-, halo-CrC3-alkyl-, -CN, -C(=0)R10, -C(=0)N(H)R10, -C(=O)N(R10a)R10b, -C(=0)0-R10, -N(R10a)R10b,
Figure imgf000065_0001
-N(R10a)C(=O)N(R10b)R10c, -N(H)C(=0)OR10, -N(R10a)C(=O)OR10b,
-N(H)S(=0)2R10, -N(R10a)S(=O)2R10b, -OR10, -0(C=0)R10, -O(C=O)N(R10a)R10b,
-0(C=0)OR10, -SR10, -S(=0)R10, -S(=0)2R10, -S(=0)2N(H)R1°,
-S(=O)2N(R10a)R10b or -S(=O)(=NR10a)R10b group;
10a 1 Ob |^10c represent, independently from each other, a hydrogen atom or a
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:
3-Phenyl-7-(4-phenyl-1 -piperazinyl)-thiazolo[4,5-d]pyrimidine-2(3H)-thione.
In another preferred embodiment, the present invention relates to compounds of general formula (In) (lo), or (Ip) :
Figure imgf000065_0002
in which
R3 represents a phenyl- group;
wherein said phenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R7 groups ;
R5 represents a -OH, -SH, -NH2, CrC3-alkoxy-,
HO-CrC3-alkyl-, HO-C2-C3-alkoxy-, halo-CrC3-alkyl-, halo-CrC3-alkoxy-, - S-(CrC3-alkyl), -S-(halo-d-C3-alkyl), -N(H)(d-C3-alkyl),
-N(Ci-C3-alkyl)(CrC3-alkyl) or a H2N-Ci-C3-alkyl- group;
R6 represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-d-alkyl-, R8a(R8b)N-d-C6-alkyl-, HO-d-C6-alkyl-,
d-Ce-alkoxy-d-Ce-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C2-C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
4- to 10-membered heterocycloalkenyl-, C3-C7-cycloalkyl-,
-C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8, -N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(R8c)C(=0)C(=0)N(R8a)R8b,
-N(H)C(=0)OR8, -N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group;
R7 represents a halogen atom, or a -CN, d-d-alkoxy-, d-d-alkyl-,
halo-CrC6-alkyl-, R8a(R8b)N-d-C6-alkyl-, R8a(R8b)N-C(=0)(d-C6-alkyl)-, HO-d-d-alkyl-, d-d-alkoxy-d-d-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8,
-N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(H)C(=0)OR8, -N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8,
-0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; R8, R8a, R8b, R8c
represent, independently from each other, a hydrogen atom, or a Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C6-alkyl)-, C2-C&-alkenyl-, C2-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;
said Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C&-alkyl)-, 3- to 10-membered heterocycloalkyl-,
(3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-, 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 R9; R9 represents a halogen atom, or a CrC3-alkyl-, halo-CrC3-alkyl-, -CN,
-C(=0)R10, -C(=0)N(H)R10, -C(=O)N(R10a)R10b, -C(=0)0-R10, -N(R10a)R10b, -N02, -N(H)C(=0)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b,
-N(R10a)C(=O)N(R10b)R10c, -N(H)C(=0)OR10, -N(R10a)C(=O)OR10b,
-N(H)S(=0)2R10, -N(R10a)S(=O)2R10b, -OR10, -0(C=0)R10, -O(C=O)N(R10a)R10b, -0(C=0)OR10, -SR10, -S(=0)R10, -S(=0)2R10, -S(=0)2N(H)R10,
-S(=O)2N(R10a)R10b or -S(=O)(=NR10a)R10b group;
|^10 |^10a j^10b |^10c
represent, independently from each other, a hydrogen atom or a
Ci-C&-alkyl- group; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. In another preferred embodiment, the present invention relates to compounds of general formula (In) (lo), or (Ip) :
Figure imgf000068_0001
(In) (lo) in which :
R3 represents a phenyl- group;
wherein said phenyl- group is optionally substituted, identically or differently, with 1 or 2 R7 groups ;
R5 represents a -OH, -NH2, CrC3-alkoxy-, HO-Ci-C3-alkyl-,
HO-C2-C3-alkoxy- or -S-(Ci-C3-alkyl)- group; R6 represents a -C(=0)N(H)R8a, -C(=0)N(R8a)R8b or -C(=0)0-R8 group;
R7 represents a halogen atom; R R R R
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 R9;
R9 represents a -OH group; or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In another preferred embodiment, the present invention relates to compounds of general formula (I ):
Figure imgf000069_0001
(I)
in which :
Z represents a phenyl- or pyridinyl- group;
Y1 represents N or C(R1 );
Y2 represents S or N(R2);
Y3 represents S or 0;
R1 represents a hydrogen atom or a Ci-C&-alkyl-, trifluoromethyl- or
C3-C7-cycloalkyl- group; R2 represents a hydrogen atom or a CrC3-alkyl- or a trifluoromethyl- group; represents a phenyl- group;
wherein said phenyl- group is optionally substituted, identically or differently, with 1 or 2 R7 groups ;
R5 represents a -OH, -NH2, CrC3-alkoxy-, HO-Ci-C3-alkyl-,
HO-C2-C3-alkoxy- or -S-(Ci-C3-alkyl)- group; each
R6 independently represents a -C(=0)N(H)R8a, -C(=0)N(R8a)R8b or -C(=0)0-R8 group; R7 represents a halogen atom;
R8 R8a R8 R8c
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 R9;
R9 represents a -OH group;
m is an integer of 0, 1 or 2 ;
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.
In accordance with another aspect, the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein. In a preferred embodiment, the present invention relates to a method of preparing compounds of general formula (I), supra, in which method an intermediate of general formula
Figure imgf000071_0001
in which Z, R4, R5, R6, m, and n are as defined for the compounds of general formula (I), supra; is allowed to react with a compound of general formula (II)
Figure imgf000071_0002
(II)
in which Y1, Y2, Y3 and R3 are as defined for the compounds of general formula (I), supra, and LG is a leaving group; thus providing a compound of general formula (I) :
Figure imgf000072_0001
(I)
in which Z, Y1, Y2, Y3, R3, R4, R5, R6, m, and n are as defined supra.
In another preferred embodiment, the present invention relates to a method of preparing compounds of general formula (I), supra, in which method an intermediate of general formula (VI) :
Figure imgf000072_0002
(VI)
in which Z, R5, R6 and m are as defined for the compounds of general formula (I), supra, and LG is a leaving group; is allowed to react with a compound of general formula (V)
Figure imgf000073_0001
(V)
in which Y1, Y2, Y3, R3, R4 and n are as defined for the compounds of general formula (I), supra; thus providing a compound of general formula (I) :
Figure imgf000073_0002
(I) in which Z, Y1, Y2, Y3, R3, R4, R5, R6, m, and n are as defined supra.
In accordance with a further aspect, 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. In particular, the present invention covers compounds of general formula (III):
Figure imgf000074_0001
in which Z, R4, R5, R6, m, and n are as defined for the compounds of general formula (I), supra; and of general formula (V):
Figure imgf000074_0002
(V)
in which Y1, Y2, Y3, R3, R4 and n are as defined for the compounds of general formula (I), supra.
In accordance with yet another aspect, the present invention covers the use of the intermediate compounds :
(i) of general formula (II):
Figure imgf000074_0003
(II) in which Y1, Y2, Y3 and R3 are as defined for the compounds of general formula (I), supra, and LG is a leaving group;
(ii) of general formula
Figure imgf000075_0001
in which Z, R4, R5, R6, m, and n are as defined for the compounds of general formula (I), supra; (iii) of general formula (VI)
Figure imgf000075_0002
(VI)
in which Z, R5, R6 and m are as defined for the compounds of general formula (I), supra, and LG is a leaving group; and
(iv) of general formula (V)
Figure imgf000075_0003
(V)
in which Y1, Y2, Y3, R3, R4 and n are as defined for the compounds of general formula (I), supra; for the preparation of compounds of eneral formula (I):
Figure imgf000076_0001
(I) in which Z, Y1, Y2, Y3, R3, R4, R5, R6, m, and n are as defined supra.
As one of ordinary skill in the art is aware of, the methods described above may comprise further steps like e.g. the introduction of a protective group and the cleavage of the protective group.
This invention also relates to pharmaceutical compositions containing one or more compounds of the present invention. These compositions 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. For example, 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, celmoleukin, cetuximab, chlorambucil, chlormadinone, chlormethine, cisplatin, cladribine, clodronic acid, clofarabine, crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, deslorelin, dibrospidium chloride, docetaxel, doxifluridine, doxorubicin, doxorubicin + estrone, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, epirubicin, epitiostanol, epoetin alfa, epoetin beta, eptaplatin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim, fludarabine, fluorouracil, flutamide, formestane, fotemustine, fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glutoxim, goserelin, histamine dihydrochloride, histrelin, hydroxycarbamide, 1-125 seeds, ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferon alfa, interferon beta, interferon gamma, ipilimumab, irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melphalan, mepitiostane, mercaptopurine, methotrexate, methoxsalen, Methyl aminolevulinate, methyltestosterone, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide, nimotuzumab, nimustine, nitracrine, ofatumumab, omeprazole, oprelvekin, oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, pamidronic acid, panitumumab, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, perfosfamide, picibanil, pirarubicin, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polysaccharide- , porfimer sodium, pralatrexate, prednimustine, procarbazine, quinagolide, raloxifene, raltitrexed, ranimustine, razoxane, regorafenib, risedronic acid, rituximab, romidepsin, romiplostim, sargramostim, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tasonermin, teceleukin, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trastuzumab, treosulfan, tretinoin, trilostane, triptorelin, trofosfamide, tryptophan, ubenimex, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, vorozole, yttrium -90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.
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 1th 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, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine.
Other 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. by McGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated by reference, such as aminoglutethimide, L-asparaginase, azathioprine, 5- azacytidine cladribine, busulfan, diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine, ethinyl estradiol, 5- fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine.
Other 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. Such 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, aviscumine, MDX-1307, Her-2 vaccine, APC- 8024, NGR-hTNF, rhH1.3, IGN-311 , Endostatin, volociximab, PRO-1762, lexatumumab, SGN-40, pertuzumab, EMD-273063, L19-IL-2 fusion protein, PRX- 321 , CNTO-328, MDX-214, tigapotide, CAT-3888, labetuzumab, alpha-particle- emitting radioisotope-llinked lintuzumab, EM-1421 , HyperAcute vaccine, tucotuzumab celmoleukin, galiximab, HPV-16-E7, Javelin - prostate cancer, Javelin - melanoma, NY-ESO-1 vaccine, EGF vaccine, CYT-004-MelQbG10, WT1 peptide, oregovomab, ofatumumab, zalutumumab, cintredekin besudotox, WX- G250, Albuferon, aflibercept, denosumab, vaccine, CTP-37, efungumab, or 131 l-chTNT-1 /B. 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.
Generally, the use of 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,
(2) provide for the administration of lesser amounts of the administered chemotherapeutic agents, (3) provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies,
(4) provide for treating a broader spectrum of different cancer types in mammals, especially humans,
(5) provide for a higher response rate among treated patients,
(6) provide for a longer survival time among treated patients compared to standard chemotherapy treatments,
(7) provide a longer time for tumor progression, and/or (8) yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.
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, 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. In accordance with another aspect therefore, 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.
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.
Methods of testing for a particular pharmacological or pharmaceutical property are well known to persons skilled in the art.
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. , psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), 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.
Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
Examples of 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. Examples of 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. Examples of 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.
These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention. The term "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.
Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyper-proliferative disorders and angiogenic disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, 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. In addition, "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, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques 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.
Of course 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. General synthesis of compounds of general formula (I) of the present invention
The following paragraphs outline a variety of synthetic approaches suitable to prepare compounds of formula (I), and intermediates useful for their synthesis. In addition to the routes described below, also other routes may be used to synthesise the target compounds, in accordance with common general knowledge of a person skilled in the art of organic synthesis. The order of transformations exemplified in the following schemes is therefore not intended to be limiting, and suitable synthesis steps from various schemes can be combined to form additional synthesis sequences. In addition, interconversion of any of the substituents, in particular R1, R2, R3, R5 or R6, can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protective groups, cleavage of protective groups, reduction or oxidation of functional groups, halogenation, metallation, metal catalysed coupling reactions, exemplified by but not limited to Suzuki, Sonogashira and Ullmann coupling, ester saponifications, amide coupling reactions, and/or substitution or other reactions known to a person skilled in the art. These transformations include those which introduce a functionality allowing for further interconversion of substituents. Appropriate protective groups and their introduction and cleavage are well-known to a person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs. Further, it is possible that two or more successive steps may be performed without work-up being performed between said steps, e.g. a "one-pot" reaction, as it is well-known to a person skilled in the art.
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 :
Figure imgf000088_0001
(III) coupling
conditions
Figure imgf000088_0002
(I)
Scheme 1 : Preparation of compounds of the formula (I) from intermediates (II) and (III).
This step employs a heterocyclic precursor (II), in which Y1, Y2, Y3, and R3 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, R4, R5, R6, m and n are as defined for the compounds of general formula (I). Synthetic approaches to various chemotypes of compounds (II) are outlined below; intermediates (III), if not commercially available, can be prepared e.g. by amination of cyclic diamines (IV) with arenes (VI) and subsequent deprotection, for the structures of (IV) and (VI) see Scheme 2.
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. Addition of a base, for example triethylamine, DIPEA, DBU, sodium carbonate, potassium carbonate, cesium carbonate or the like, may be advantageous. Alternatively, 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. ). Alternatively, and as outlined in Scheme 2, compounds of the formula (II) in which Y1, Y2, Y3, and R3 are as defined for the compounds of general formula (I), supra, can be elaborated into compounds of the general formula (I) by reaction with a monoprotected cyclic diamine of the formula (IV), in which R4 and n are as defined for the compounds of general formula (I), and in which PG represents a protective group. Said reaction can be accomplished inter alia by a Buchwald amination reaction well known to the person skilled in the art. Subsequent removal of the protective group yields intermediates of the formula (V), being subjected subsequently to another coupling or substitution reaction with intermediates of formula (VI), in which Z, R5, R6 and m are as defined for the compounds of general formula (I), and in which LG stands for a leaving group, giving rise to compounds of the general formula (I). Intermediate arenes of the formula (VI) and monoprotected cyclic diamines of formula (IV) both are well known to the person skilled in the art and are commercially available in many cases. 7(CH2)n 1 ) coupling
conditions
2) deprotection
Figure imgf000090_0001
coupling conditions
Figure imgf000090_0002
(VI)
Figure imgf000090_0003
Scheme 2: Preparation of compounds of the formula (I) from intermediates of the formula (II) and (IV).
Intermediates of the formula (II) can be approached by various synthetic routes known to the person skilled in the art. A general overview on fused bicyclic hetarenes can be found in the chemical literature, for instance in "Y. Yamamoto (editor), Science of Synthesis - Hetarenes and related Ring Systems Volume 16, Thieme, Stuttgart, New York 2004"; D. StC. Black (editor) Science of Synthesis - Hetarenes and related Ring Systems Volume 15, Thieme, Stuttgart, New York 2005". More specifically, compounds of the formula (lla), constituting a sub-compartment of formula (II), in which R3 is as defined for the for the compounds of general formula (I), and in which LG is as defined supra, i.e. 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 R3 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. 530-62-1 ) in a cyclic ether, such as tetrahydrofuran, at elevated temperature, preferably in a sealed vial in a microwave oven, to give intermediates of formula (lla). 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).
Figure imgf000092_0001
Scheme 3: Preparation of intermediates of the formula (I la) from 5- aminopyrimidines of the formula (VII).
Intermediates of the formula (Mb), constituting another sub-compartment of formula (II), in which R3 is as defined for the for the compounds of general formula (I), and in which LG is as defined supra, can be prepared as shown in Scheme 4, starting from cyanoacetamide (X, CAS-No. 107-91 -5) and an isothiocyanate of the formula (XI), in which R3 is as defined for the for the compounds of general formula (I), with sulfur in the presence of a base, e.g. an aliphatic amine, such as triethylamine, in a solvent such as DMF to give compounds of the formula (XII). 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). 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.
Figure imgf000093_0001
Figure imgf000093_0002
Scheme 4: Preparation of intermediates of the formula (Mb) from cyanoacetamide (X) and isothiocyanates of the formula (XI).
As outlined supra, synthetic routes suitable for the preparation of compounds of the general formula (I) are not limited to the methods discussed in this paragraph. Hence, the routes discussed in Schems 1 -4 can be modified in multiple ways. For an instructive alternative synthetic route see e.g. the description of the preparation of Example 7 in the Experimental Section.
EXPERIMENTAL SECTION
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.
Abbreviations
Figure imgf000094_0001
DMSO dimethyl sulfoxide
cone. concentrated
NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.
Intermediates
Intermediate 1A
6-chloro-9- henyl-7,9-dihydro-8H-purin-8-one
Figure imgf000095_0001
To a suspension of 10.0 g (61.0 mmol) 4,6-dichloropyrimidine-5-amine and 5.68 g (61.0 mmol) aniline in 20 mL ethanol and 130 mL water was added 2.0 mL 37% aq HCl. This mixture was heated at 85 °C for 16 hours. The mixture was cooled in an ice bath and the precipitated solid was isolated by filtration, washed with 50 mL water, followed by 50 mL hexane, and dried in vacuo. Using this procedure 6-chloro-N4-phenylpyrimidine-4,5-diamine was obtained without further purification: 11.8 g (85% yield). 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 6.16 (s, 2H), 6.96 - 7.04 (m, 1 H), 7.25 - 7.33 (m, 2H), 7.65 - 7.71 (m, 2H), 7.83 (s, 1 H), 8.73 (s, 1 H).
Ste 2:
A suspension of 1.5 g (6.8 mmol) of intermediate 1A) step 1 ) and 1.43 g (8.84 mmol) 1 ,1'-Carbonyldiimidazole in 20 mL THF was heated for 20 minutes in a microwave reactor at 120°C. After cooling to rt the resulting reaction mixture together with a second batch generated from identical amounts of starting materials was diluted with 100 mL of water and extracted with 150 mL of ethyl acetate. The organic layer was washed three times with water and once with brine. The organic phase was dried over sodium sulfate and after filtration concentrated under reduced pressure to dryness. The crude product was purified with a Biotage column chromatography system (50 g snap silica gel column, hexane / 0 - 100% ethyl acetate, then ethyl acetate / 0 - 75 methanol). Using this procedure the desired material was obtained: 2.5 g (73% yield). 1H-NMR (400 MHz, DMSO d6) δ (ppm) = 7.39 - 7.47 (m, 1 H), 7.49 - 7.56 (m, 2H), 7.56 - 7.62 (m, 2H), 8.38 (s, 1 H), 12.26 (s, 1 H).
Intermediate 2A
6-chloro-9-(2-fluorophenyl)-7,9-dihydro-8H-purin-8-one
Figure imgf000097_0001
Figure imgf000097_0002
In analogy to intermediate 1A) 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-N4-(2-fluorophenyl)pyrimidine-4,5-diamine: 587 mg (24% yield). 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 4.58 (s, 2H), 6.97 - 7.23 (m, 3H), 7.71 - 7.80 (m, 2H), 7.85 (s, 1 H).
Ste 2:
Figure imgf000097_0003
In analogy to intermediate 1A) 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). 1H-NMR (400 MHz, DMSO d6) δ (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).
Intermediate 3A
6-chloro-9-(3-chloro-2-fluorophenyl)-7,9-dihydro-8H-purin-8-one
Figure imgf000098_0001
In analogy to intermediate 1A) 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-N4-(3-chloro-2-fluorophenyl)pyrimidine-4,5- diamine: 4.5 g (90% yield).
1H-NMR (400 MHz, DMSO d6) δ (ppm) = 7.21 (ddd, 1 H), 7.37 (ddd, 1 H), 7.55 (ddd, 1 H), 7.79 (s, 1 H), 8.71 (s, 1 H).
Step 2:
Figure imgf000099_0001
In analogy to intermediate 1A) 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).
1H-NMR (300 MHz, DMSO d6) δ (ppm) = 7.45 (ddd, 1 H), 7.65 (ddd, 1 H), 7.81 (ddd, 1 H), 8.44 (s, 1 H), 12.52 (s, 1 H).
Intermediate 4A
7-chloro-3-(2-fluorophenyl)[1 ,3]thiazolo[4,5-d]pyrimidine-2(3H)-thione
Figure imgf000099_0002
Ste 1 :
Figure imgf000099_0003
After stirring a solution of 4.0 g (48 mmol) cyanoacetamide in 20 mL DMF and 5.64 mL (40 mmol) triethylamine for 10 minutes at rt, 1 .53 g (48 mmol) sulfur was added and stirring was continued for additional 45 minutes. Then 7.29 g (48 mmol) 2-fluorophenylisothiocyanate was added dropwise to the reaction mixture and stirred for 18 hours at rt. The reaction mixture was diluted with 400 mL ethyl acetate and the organic phase was washed twice with 50 mL of a 1 : 1 mixture of water and brine and then with 50 mL brine. The organic phase was dried over sodium sulfate and after filtration concentrated under reduced pressure to dryness. The crude product was suspended in 150 mL ethyl acetate and stirred for 30 minutes at rt, filtered and then the solid dried in vacuo. Using this procedure the desired material 4-amino-3-(2-fluorophenyl)-2-thioxo- 2,3-dihydro-1 ,3-thiazole-5-carboxamide was obtained: 8.14 g (64% yield)
1H-NMR (300 MHz, DMSO d6) δ (ppm)
3H), 7.59 - 7.69 (m, 1 H).
Step 2:
Figure imgf000100_0001
A suspension of 8.14 g (30.2 mmol) of intermediate 4A) step 1 ), 30.2 mL (181 mmol) ethyl orthoformate and 287 mg (1 .51 mmol) 4-toluenesulfonic acid monohydrate was stirred at 130° C for 3 hours. After cooling the desired matrial 3-(2-fluorophenyl)-2-thioxo-2,3-dihydro[1 ,3]thiazolo[4,5-d]pyrimidin- 7(6H)-one was isolated by filtration and dried in vacuo to give: 7.83 g (93% yield). 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 7.36 - 7.71 (m, 4H), 8.22 (s, 1 H),
(s, 1 H). Step 3:
Figure imgf000101_0001
A suspension of 4.5 g (16.1 mmol) of intermediate 4A) step 2) and 37.5 mL (403 mmol) phosphoric trichloride was stirred under reflux for 4 hours. After cooling the mixture was evaporated under reduced pressure. A suspension of the residue in methyl tert-butyl ether was stirred for 3 hours at rt, and the crude product was isolated by filtration and then dried in vacuo. The residue was purified with a Biotage column chromatography system (100 g snap silica gel column, hexane / 0 - 40% ethyl acetate). Using this methodology the desired material 7-chloro-3-(2-fluorophenyl)[1 ,3]thiazolo[4,5-d]pyrimidine-2(3H)- thione was obtained: 4.18 g (87% yield).
1H-NMR (300 MHz, DMSO d6) δ (ppm) = 7.43 - 7.51 (m, 1 H), 7.55 (ddd, 1 H), 7.60 - 7.73 (m, 2H), 8.81 (s, 1 H).
Intermediate 1 B
methyl 4-methoxy-3-(piperazin-1 -yl)benzoate hydrochloride
Figure imgf000102_0001
To a solution of 20.0 g (81 .6 mmol) of methyl 3-bromo-4-methoxybenzoate and 17.2 g (89.8 mmol) tert-butyl piperazine-1 -carboxylate in a mixture of 225 mL toluene and 225 mL tert-butanol, 26.6 g (81 .6 mmol) cesium carbonate, 1 .83 g (8.16 mmol) palladium(ll)acetate and 3.89 g (8.16 mmol) Xphos were added and the reaction mixture was heated at 90 ° C for 3 days under an atmsophere of nitrogen. After cooling to rt the mixture was poured into 100 mL of water and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue was purified with a Biotage column chromatography system (340 g snap silica gel column, hexane / 0 - 100% ethyl acetate). Using this methodology the desired material tert-butyl 4-[2-methoxy- 5-(methoxycarbonyl)phenyl]piperazine-1 -carboxylate was obtained: 18.0 g (60% yield).
1H-NMR (300 MHz, DMSO d6) δ (ppm) = 1 .38 (s, 9H), 2.85 - 2.91 (m, 4H), 3.37 - 3.45 (m, 4H), 3.76 (s, 3H), 3.83 (s, 3H), 7.03 (d, 1 H), 7.39 (d, 1 H), 7.61 (dd, 1 H). Ste 2:
Figure imgf000103_0001
A solution of 12.1 g (34.5 mmol) tert-butyl 4-[2-methoxy-5- (methoxycarbonyl)phenyl]piperazine-1 -carboxylate of step 1 ) in 110 mL 4M HCI in dioxane was stirred for 2 hours at rt. The solvent was evaporated in vacuo and the residue was dried giving the desired material without additional purification: 11g (crude product)
Intermediate 2B
meth l 4-methoxy-3-(piperazin-1 -yl)benzoate
Figure imgf000103_0002
A solution of 10.0 g (28.55 mmol) tert-butyl 4-[2-methoxy-5- (methoxycarbonyl)phenyl]piperazine-1 -carboxylate of intermediate 1 B) step 1 ) in 102 mL 4M HCI in dioxane was strirred for 2 hours at rt. The solvent was evaporated and the residue was solved in a mixture of 209 mL of 1 ,4-dioxane and 22.6 mL of water. After the addition of 22.5 g (163 mmol) potassium carbonate the mixture was stirred for 17 hours at rt. The solid was separated by filtration and washed with ethyl acetate. The organic phase was evaporated and dried in vacuo to give the desired material without further purification: 8.53g (crude product). 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 2.77 - 2.91 (m, 8H), 3.79 (s, 3H), 3.84 (s, 3H), 7.03 (d, 1 H), 7.40 (d, 1 H), 7.60 (dd, 1 H).
Examples Example 1
6-[4-(2-methoxyphenyl)piperazin-1 -yl]-9^henyl-7,9-dihydro-8H^urin-8- one
Figure imgf000104_0001
To a solution of intermediate 1A (500 mg, 2.03 mmol) and 468 mg (2.43 mmol) commercially available 1 -(2-methoxyphenyl)-piperazine in 12.3 mL THF was added 848 μΙ_ (6.08 mmol) triethylamine and then the reaction was heated at 60 °C for 3 days. After cooling to rt, water and ethyl acetate were added to the suspension and stirred at rt. The solid was isolated by filtration, washed with ethyl acetate and dried to give the desired title compound: 537 mg (63% yield).
1H-NMR (400 MHz, DMSO d6) δ (ppm) = 3.01 - 3.08 (m, 4H), 3.68 - 3.74 (m, 4H), 3.79 (s, 3H), 6.84 - 7.00 (m, 4H), 7.35 - 7.42 (m, 1 H), 7.46 - 7.53 (m, 2H), 7.54 - 7.61 (m, 2H), 8.13 (s, 1 H), 11.29 (s, 1 H).
Example 2
methyl 4-methoxy-3-[4-(8-oxo-9-phenyl-8,9-dihydro-7H-purin-6- yl)piperazin-1 -yl]benzoate
Figure imgf000105_0001
A solution of 358 mg (1.45 mmol) of intermediate 1A), 0.50 g (1.74 mmol) methyl 4-methoxy-3-(piperazin-1 -yl)benzoate hydrochloride prepared as intermediate 1 B) and 0.61 mL triethylamine (4.36 mmol) in 16 mL THF was heated at 60°C for 11 days. After cooling to rt, 25 mL water and 25 mL ethyl acetate were added to the reaction mixture, which was then stirred for about 10 minutes. The solid was isolated by filtration and dried in vacuo to give the desired title compound: 263 mg (38 %yield).
1H-NMR (300 MHz, DMSO d6) δ (ppm) = 3.07 - 3.15 (m, 4H), 3.70 - 3.77 (m, 4H), 3.80 (s, 3H), 3.90 (s, 3H), 7.10 (d, 1 H), 7.37 - 7.45 (m, 1 H), 7.45 - 7.62 (m, 5H), 7.66 (dd, 1 H), 8.17 (s, 1 H), 11.35 (s, 1 H).
Example 3
4-methoxy-3-[4-(8-oxo-9-phenyl-8,9-dihydro-7H-purin-6-yl)piperazin yl]benzoic acid
Figure imgf000105_0002
A mixture of 250 mg (0.54 mmol) of example 2) in 2.68 mL MeOH and a solution of 402 mg sodium hydroxide in 5.4 mL water was heated for 2 hours at 40° C. Then the methanol was distilled off and the residue was diluted with water and acidified with 10% sulfuric acid up to pH = 2. The precipitated solid was isolated by filtration and washed with dichloromethane. This solid together with toluene was evaporated in vacuo and dried in vacuo. This procedure gave the desired title compound without further purification: 302 mg.
1H-NMR (400 MHz, DMSO d6) δ (ppm) = 3.06 - 3.15 (m, 4H), 3.72 - 3.78 (m, 4H), 3.89 (s, 3H), 7.07 (d, 1 H), 7.38 - 7.45 (m, 1 H), 7.48 (d, 1 H), 7.52 (t, 2H), 7.59 (d, 2H), 7.64 (dd, 1 H), 8.17 (s, 1 H), 11.33 (s, 1 H).
Example 4
4-methoxy-3-[4-(8-oxo-9-phenyl-8,9-dihydro-7H-purin-6-yl)piperazin-1 - yl]benzamide
Figure imgf000106_0001
To a solution of 150 mg (0.35 mmol) of example 3), 141 mg (0.34 mmol) HATU (0-(7-azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate), 117 μΙ_ (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. The residue was purified first with a Biotage column chromatography system (10 g snap silica gel column, hexane / 0 - 100% ethyl acetate, then ethyl acetate / 0 - 100% methanol)) and finally via HPLC. Using this methodology the desired material was obtained: 5.4 mg (3.3% yield). 1H-NMR (300 MHz, CDCl3) δ (ppm) = 3.18 - 3.30 (m, 4H), 3.87 - 4.03 (m, 7H), 6.91 (d, 1 H), 7.29 (s, 2H), 7.33 - 7.59 (m, 5H), 7.67 (d, 2H), 8.34 (s, 1 H), 11.75
( s, 1 H).
Example 5
N-(2-hydroxyethyl)-4-methoxy-3-[4-(8-oxo-9-phenyl-8,9-dihydro-7H-purin- -yl)piperazin-1 -yl]benzamide
Figure imgf000107_0001
To a solution of 150 mg (0.35 mmol) of example 3), 141 mg (0.34 mmol) HATU (0-(7-azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate), 117 μΙ_ (0.67 mmol) diisopropylethylamine in 2.2 mL DMSO was added 20.5 mg (0.34 mmol) 2-aminoethanol. The mixture was stirred for 16 hours at rt and then diluted with 25 mL water and 35 mL ethyl acetate. The precipitated solid was isolated by filtration and dried in vacuo to give the desired title compound: 54.6 mg (32% yield).
1H-NMR (300 MHz, DMSO d6) δ (ppm) = 3.04 - 3.15 (m, 4H), 3.29 (q, 2H, partially hidden by DMSO signal), 3.48 (q, 2H), 3.71 - 3.81 (m, 4H), 3.86 (s, 3H), 4.71 (t, 1 H), 7.02 (d, 1 H), 7.36 - 7.46 (m, 2H), 7.47 - 7.64 (m, 5H), 8.16 (s, 1 H), 8.31 (t, 1 H), 10.91 (s, 1 H). Example 6
9-(2-fluorophenyl)-6-[4-(2-methoxyphenyl)piperazin-1 -yl]-7,9-dihydro-8H- urin-8-one
Figure imgf000108_0001
To a solution of 115 mg (0.44 mmol) of intermediate 2A) and 94.7 mg (0.48 mmol) 1 -(2-methoxyphenyl)piperazine in a mixture of 0.87 mL toluene and 0.78 mL tert-butanol, 283 mg (0.87 mmol) cesium carbonate, 19.5 mg (0.087 mmol) palladium(ll)acetate and 41.4 mg (0.087 mmol) Xphos were added and the reaction mixture was heated at 105°C for 28.5 hours under an atmosphere of nitrogen. After cooling to rt, the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue was purified via two HPLC-runs and yielded the desired title compound: 13 mg (6.9% yield).
1H-NMR (300 MHz, CDCl3) δ (ppm) = 3.08 - 3.18 (m, 4H), 3.87 - 3.97 (m, 7H), 6.85 (d, 1 H), 6.91 - 7.01 (m, 2H), 7.05 - 7.14 (m, 1 H), 7.15 - 7.28 (m, 2H), 7.37 - 7.47 (m, 1 H), 7.53 (t, 1 H), 8.32 (s, 1 H), 11.40 (s, 1 H).
Example 7
methyl 3-{4-[9-(2-fluorophenyl)-8-oxo-8,9-dihydro-7H-purin-6-yl]piperazin- 1 -yl}-4-methoxybenzoate
Figure imgf000109_0001
Figure imgf000109_0002
To a solution of 4.5 g (23.2 mmol) 4,6-dichloro-5-nitropyrimidine and 6.46 mL (4.7 mmol) triethylamine in 74.7 mL THF was added slowly 4.31 mL (13.9 mmol) 2-fluoroaniline at 0° C. After being stirred for 2.5 hours at rt, the reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtrated and then the solvent was evaporated. The residue was purified with a Biotage column chromatography system (100 g snap silica gel column, hexane / 0 - 50% ethyl acetate. Using this methodology 1 .75 g of a 4: 1 mixture of the desired 6-chloro-N-(2-fluorophenyl)-5-nitropyrimidin-4-amine and N,N'-bis(2-fluorophenyl)-5-nitropyrimidine-4,6-diamine was obtained.
To a solution of 100 mg of said mixture (and in an analogously performed second experiment 1 .6 g of this mixture) in 2.27 (36.3) mL THF was added 1 12 (1790) mg (0.45 mmol) of intermediate 2B) and 0.16 (2.49) mL (1 .12 mmol) triethylamine. After heating at 60° C for 16 hours the mixture was cooled to rt, poured into water and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtrated and then the solvent was evaporated. The combined crude products of both experiments were purified twice with a Biotage column chromatography system (50 g snap silica gel column, hexane / 20 - 80% ethyl acetate. Using this methodology 3.3 g of methyl 3-(4-{6-[(2-fluorophenyl)amino]-5-nitropyrimidin- 4-yl}piperazin-1 -yl)-4-methoxybenzoate was obtained.
1H-NMR (300 MHz, DMSO d6) δ (ppm) = 3.04 - 3.15 (m, 4H), 3.61 - 3.70 (m, 4H), 3.76 - 3.82 (m, 3H), 3.89 (s, 3H), 7.09 (d, 1 H), 7.18 - 7.35 (m, 3H), 7.43 (d, 1 H), 7.66 (dd, 1 H), 7.77 - 7.86 (m, 1 H), 8.1 1 (s, 1 H), 10.04 (s, 1 H).
Ste 2:
Figure imgf000110_0001
A mixture of 100 mg (0.21 mmol) methyl 3-(4-{6-[(2-fluorophenyl)amino]-5- nitropyrimidin-4-yl}piperazin-1 -yl)-4-methoxybenzoate of step 1 , 100 mg (1 .53 mmol) zinc dust in 1 .3 mL water, 2.6 mL ethanol and 0.27 mL acetic acid was heated at 60° C for 2 hours. This mixture, together with one of an analogously performed experiment using 3.2 g (6.63 mmol) of the starting material, was filtered through Celite. The filter cake was washed with ethyl acetate, and the combined filtrates were evaporated in vacuo. The residue was added to water and cone. aq. sodium carbonate and then extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtrated and then the solvent was evaporated. The crude product was purified twice with a Biotage Chromatography system (50 g snap silica gel column, first run: ethyl acetate / 0 - 50% methanol, second run: hexane / 0 - 50% ethyl acetate). Using this methodology 350 mg (1 1 % yield) of methyl 3-(4-{5-amino-6-[(2-fluorophenyl)amino]pyrimidin-4-yl}piperazin-1 -yl)- 4-methoxybenzoate was obtained.
1H-NMR (400 MHz, DMSO d6) δ (ppm) = 3.14 - 3.19 (m, 4H), 3.22 - 3.28 (m, 4H), 3.81 (s, 3H), 3.88 (s, 3H), 4.55 (s, 2H), 7.05 - 7.17 (m, 3H), 7.18 - 7.25 (m, 1 H), 7.51 (d, 1 H), 7.62 - 7.70 (m, 2H), 7.85 (s, 1 H), 7.95 (s, 1 H).
Ste 3:
Figure imgf000111_0001
A solution of 100 mg (0.22 mmol) of 3-(4-{5-amino-6-[(2- fluorophenyl)amino]pyrimidin-4-yl}piperazin-1 -yl)-4-methoxybenzoate of step 2) and 72.6 mg (0.44 mmol) 1 , 1 '-Carbonyldiimidazole in 0.65 mL THF was heated at 120° C for 40 minutes in a microwave reactor. After cooling to rt, the resulting reaction mixture, together with a analogous batch generated in a second experiment using 220 mg (0.49 mmol) of the starting material, was diluted with 100 mL of water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtrated and then the solvent was evaporated. The crude product was purified with a Biotage column chromatography system (10 g snap silica gel column, hexane / 20 - 100% ethyl acetate, then ethyl acetate / 0 - 50% methanol). Using this procedure the desired title compound was obtained: 222 mg (93% yield).
1H-NMR (400 MHz, DMSO d6) δ (ppm) = 3.08 - 3.13 (m, 4H), 3.74 - 3.78 (m, 4H), 3.80 (s, 3H), 3.90 (s, 3H), 7.10 (d, 1 H), 7.34 - 7.40 (m, 1 H), 7.41 - 7.49 (m, 2H), 7.53 - 7.60 (m, 2H), 7.66 (dd, 1 H), 8.12 (s, 1 H), 1 1 .39 (s, 1 H). Example 8
3-{4-[9-(2-fluorophenyl)-8-oxo-8,9-dih^^
methox benzoic acid
Figure imgf000112_0001
In analogy to example 3) 965 mg (2.02 mmol) of the ester of example 7) were reacted with aqueous sodium hydroxide to give the desired title compound: 730 mg (78%).
1H-NMR (300 MHz, DMSO d6) δ (ppm) = 3.06 - 3.13 (m, 4H), 3.72 - 3.80 (m, 4H), 3.89 (s, 3H), 7.07 (d, 1 H), 7.34 - 7.43 (m, 1 H), 7.44 - 7.50 (m, 2H), 7.52 - 7.61 (m, 2H), 7.64 (dd, 1 H), 8.12 (s, 1 H), 1 1 .39 (s, 1 H), 12.55 (s, 1 H).
Example 9
3-{4-[9-(2-fluorophenyl)-8-oxo-8,9-dihydro-7H-purin-6-yl]piperazin
2-hydroxyethyl)-4-methoxybenzamide
Figure imgf000112_0002
To a solution of 100 mg (0.22 mmol) acid of example 8), 90 mg (0.24 mmol)
HATU (0-(7-azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) and 75 μΙ_ (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).
1H-NMR (300 MHz, DMSO d6) δ (ppm) = 3.07 - 3.14 (m, 4H), 3.29 (q, 2H, partially hide by DMSO signal), 3.48 (q, 2H), 3.74 - 3.81 (m, 4H), 3.86 (s, 3H), 4.70 (s, 1 H), 7.02 (d, 1 H), 7.33 - 7.41 (m, 1 H), 7.41 - 7.50 (m, 2H), 7.51 - 7.61 (m, 3H), 8.12 (s, 1 H), 8.30 (t, 1 H), 10.57 (s, 1 H).
Example 10
6-[4-(3-methoxypyridin-2-yl)piperazin-1 -yl]-9-phenyl-7,9-dihydro-8H-purin- -one
Figure imgf000113_0001
In analogy to example 1 ), 150 mg (0.61 mmol) intermediate 1A) were reacted with 141 mg (0.73 mmol) of commercially available 1 -(3-methoxypyridin-2- yl)piperazine by stirring at 60° C for 16 hours to give the desired title compound: 40 mg (16%).
1H-NMR (300 MHz, DMSO d6) δ (ppm) = 3.38 - 3.45 (m, 4H), 3.68 - 3.75 (m, 4H), 3.83 (s, 3H), 6.92 (dd, 1 H), 7.28 (dd, 1 H), 7.37 - 7.45 (m, 1 H), 7.48 - 7.56 (m, 2H), 7.56 - 7.62 (m, 2H), 7.81 (dd, 1 H), 8.16 (s, 1 H), 11.34 (s, 1 H). Example 1 1
6-[4-(3-methoxypyridin-2-yl)piperazi^
-one
Figure imgf000114_0001
In analogy to example 1 ), 100 mg (0.33 mmol) of intermediate 3) were reacted with 77 mg (0.40 mmol) 1 -(2-methoxyphenyl)-piperazine by heating at 120°C for 20 minutes in a microwave reactor. Subsequent HPLC purification yielded the desired title compound: 45 mg (29%). 1H-NMR (300 MHz, DMSO d6) δ (ppm) = 3.00 - 3.12 (m, 4H), 3.72 - 3.80 (m, 4H), 3.81 (s, 3H), 6.84 - 7.04 (m, 4H), 7.37 - 7.46 (m, 1 H), 7.55 - 7.63 (m, 1 H), 7.72 - 7.81 (m, 1 H), 8.13 (s, 1 H), 11.44 (s, 1 H).
Example 12
3-(2-fluorophenyl)-7-[4-(2-methoxyphenyl)piperazin-1 -yl][1 ,3]thiazolo[4,5- d]pyrimidine-2 3H -thione
Figure imgf000114_0002
In analogy to example 1 ), 100 mg (0.34 mmol) of intermediate 4A) were reacted with 77 mg (0.40 mmol) 1 -(2-methoxyphenyl)-piperazine by stirring at rt for 3 days. Subsequent purification via a Biotage column chromatography system (10 g snap silica gel column, hexane / 0 - 40% ethyl acetate) yielded the desired title compound: 127 mg (81%).
1H-NMR (400 MHz, DMSO d6) δ (ppm) = 3.08 - 3.13 (m, 4H), 3.81 (s, 3H), 3.90 - 3.94 (m, 4H), 6.86 - 7.02 (m, 4H), 7.40 - 7.45 (m, 1 H), 7.47 - 7.53 (m, 1 H), 7.53 - 7.59 (m, 1 H), 7.60 - 7.67 (m, 1 H), 8.30 (s, 1 H).
Example 13
methyl 3-{4-[3-(2-fluorophenyl)-2-thioxo-2,3-dihydro[1 ,3]thiazolo[4,5- d]pyrimidin-7-yl]piperazin-1 -yl}-4-methoxybenzoate
Figure imgf000115_0001
In analogy to example 1 ), 432 mg (1.45 mmol) of intermediate 4A) were reacted with 435 mg (1.74 mmol) of intermediate 2B) by stirring at 60°C for 3 hours. Subsequent purification via a Biotage column chromatography system (25 g snap silica gel column, hexane / 30 - 100% ethyl acetate, then ethyl acetate / 0 - 50% methanol) yielded the desired material: 663 mg (85% yield).
1H-NMR (300 MHz, DMSO d6) δ (ppm) = 3.09 - 3.18 (m, 4H), 3.80 (s, 3H), 3.90 (s, 3H), 3.91 - 3.96 (m, 4H), 5.75 (s, 1 H), 7.10 (d, 1 H), 7.38 - 7.58 (m, 4H), 7.58 - 7.70 (m, 2H), 8.31 (s, 1 H). Example 14
3-(2-fluorophenyl)-7-[4-(2-methoxyphenyl)piperazin-1 -yl][1 ,3]thiazolo[4,5- d]pyrimidin-2 3H -one
Figure imgf000116_0001
A solution of 450 mg (0.99 mmol) of the compound of example 12 and 0.19 mL (1.98 mmol) dimethyl sulfate in 0.22 mL DMA was heated for 1 hour at 130°C. After cooling to rt, 5.4 mL water was added to the reaction mixture, which was then stirred for 2 hours at reflux temperature. After cooling to rt, 200 mL of ethyl acetate was added and the organic phase was washed with 30 mL water and 30 mL brine, and then dried with sodium sulfate. After filtration and evaporation in vacuo the crude product was purified by chromatography on TLC plate (thickness of the plate was 2mm, hexane / ethyl acetate 7:3, when the solvent reached the end of the plate, it was dried on air and then run again a second and a third time). Using this methodology the desired title compound was obtained: 7.9 mg (1.6% yield).
1H-NMR (400 MHz, CDCl3) δ (ppm) = 3.19 - 3.27 (m, 4H), 3.94 (s, 3H), 4.03 - 4.08 (m, 4H), 6.92 - 7.00 (m, 3H), 7.06 - 7.13 (m, 1 H), 7.32 - 7.40 (m, 1 H), 7.40 - 7.44 (m, 2H), 7.54 - 7.63 (m, 1 H), 8.36 (s, 1 H).
Example 15
3-(2-fluorophenyl)-7-[4-(2-methoxyphenyl)-1 ,4-diazepan-1 - yl][1 ,3]thiazolo[4,5-d]pyrimidine-2(3H)-thione
Figure imgf000117_0001
In analogy to example 1 ), 100 mg (0.34 mmol) of intermediate 4A) were reacted with 83.1 mg (0.40 mmol) commercially available 1 -(2- methoxyphenyl)-1 ,4-diazepane by stirring at 60°c for 3 hours. Subsequent purification via a Biotage column chromatography system (25 g snap silica gel column, hexane / 30 - 100% ethyl acetate, then ethyl acetate / 0 - 50% methanol) yielded the desired title compound: 142 mg (88% yield).
1H-NMR (300 MHz, DMSO d6) δ (ppm) = 1.96 - 2.06 (m, 2H), 3.19 (t, 2H), 3.39 (t, 2H), 3.75 (s, 3H), 3.84 - 4.06 (m, 4H), 6.77 - 6.93 (m, 4H), 7.38 - 7.66 (m, 4H), 8.24 (s, 1 H).
Further, 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. Similarly, 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.
Biological in vitro assays
The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.
Biological Evaluation
In order that this invention may be better understood, the following examples are set forth. These examples are for the purpose of illustration only, and are not to be construed as limiting the scope of the invention in any manner. All publications mentioned herein are incorporated by reference in their entirety. Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro and in vivo assays that are well known in the art. For example, to demonstrate the efficacy of a pharmaceutical agent to inhibit glucose transporter GLUT1 and/or GLUT2 the following assays may be used.
Indirect measurement of GLUT activity by quantification of intracellular ATP levels It is well known that a combination of small-molecule inhibitors of mitochondrial electron transport chain and glucose catabolism synergistically suppress ATP production and impair cellular viability (Ulanovskaya et al., 2008,2011 ; Liu, et al. 2001 ). We therefore used DLD1 or CHO-K1 cells in combination with an oxidative phosphorylation inhibitor to identify GLUT inhibitors. Cell lines were maintained in DMEM medium supplemented with 10% FCS and 1% Penicillin-Streptomycin solution and 2% Glutamax. The cells were treated with trypsin and seeded into 384 plates at a density of 4000 cells/well. 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.
Table 1 : Measured IC50 values of compounds regarding glucose induced ATP increase (GLUT1 inhibition)
Figure imgf000119_0001
1 DLD1 cells used for ATP level measurements, all I C50 values were standardized to cytochalasin B I C50 values; Table 2: Measured IC50 values of compounds regarding fructose induced ATP increase (GLUT2 inhibition)
Figure imgf000120_0001
Biological Assay: Glucose uptake assay
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 μΐ 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 wash buffer was removed and compound 1 (diluted in KRP buffer) was added and incubated for 30 minutes at 37° C. 200 nM radioligand (radioligand 2[1 ,2] 3H-Deoxy D-Glucose in KRP buffer) were added and incubated for 5 minutes at room temperature. The supernatant was removed and cells were washed with 100 μΐ ice-cold KRP for two times each. 25 μΐ of lysis buffer (1 % Triton-X, 0,5N sodium hydroxide) were added and incubated at room temperature for 5 minutes. 75 μΐ scintillation solution (Microscint-20, PerkinElmer) were added and the plates were shaken for 1 minute. The plates were incubated for 3h at room temperature and the counts were determined by using a Wallace MicroBeta counter (60 seconds per well). Biological assay: Proliferation Assay
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 μΐ of their respective growth medium supplemented 10% fetal calf serum. After 24 hours, the cells of one plate (zero-point plate) were stained with crystal violet (see below), while the medium of the other plates was replaced by fresh culture medium (200 μΐ), to which the test substances were added in various concentrations (0 μΜ, as well as in the range of 0.01 -30 μΜ; 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 μΐ/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. The cells were stained by adding 100 μΐ/measuring point of a 0.1% crystal violet solution (pH 3.0). After three washing cycles of the stained cells with water, the plates were dried at room temperature. The dye was dissolved by adding 100 μΐ/measuring point of a 10% acetic acid solution. The extinction was determined by photometry at a wavelength of 595 nm. The change of cell number, in percent, was calculated by normalization of the measured values to the extinction values of the zero-point plate (=0%) and the extinction of the untreated (0 μητι) cells (=100%). Determination of metabolic stability in vitro
(including calculation of hepatic in vivo blood clearance (CL) and of maximal oral bioavailability (Fmax) ) The metabolic stability of test compounds in vitro was determined by incubating them at 1 μΜ with a suspension liver microsomes in 100 mM phosphate buffer, pH7.4 (NaH2P04 x H20 + Na2HP04 x 2H20) 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 MgCl2 in phosphate buffer, pH 7.4. Organic solvent in the incubations was limited to <0.2 % dimethylsulfoxide (DMSO) and <1 % methanol. During incubation, 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.
The half-life of a test compound was determined from the concentration-time plot. From the half-life the intrinsic clearances were calculated. Together with the additional parameters liver blood flow, specific liver weight and microsomal protein content the hepatic in vivo blood clearance (CL) and the maximal oral bioavailability (Fmax) were calculated for the different species. The following parameter values were used: Liver blood flow - 1 .3 L/h/kg (human), 2.1 L/h/kg (dog), 4.2 L/h/kg (rat); specific liver weight - 21 g/kg (human), 39 g/kg (dog), 32 g/kg (rat); microsomal protein content - 40 mg/g.
With the described assay only 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). Literature
Liu H, Hu YP, Savarai N, Priebe W, Lampadis T. Hypersensitization of tumor cells to glycolytic inhibitors. Biochemistry. 2001 ;40:5542-5547.
Ulanovskaya O, Janjic J, Matsumoto K, Schumacker PT, Kron SJ, Kozmin SA. Synthesis enables identification of the cellular target of leucascandrolide A and neopeltolide. Nat Chem Biol. 2008;4:418-424.
Ulanovskaya O, Jiayue Cui, Stephen J. Kron, and Sergey A. Kozmin. A pairwise chemical genetic screen identifies new inhibitors of glucose transport. Chem Biol. 201 1 February 25; 18(2): 222-230.

Claims

1. A compound of general formula (I) :
Figure imgf000124_0001
(I)
in which :
Z represents a phenyl- or pyridinyl- group;
Y1 represents N or C(R1);
Y2 represents S or N(R2);
Y3 represents S or 0; represents a hydrogen atom, a halogen atom or a cyano-, Ci-C&-alkyl-, trifluoromethyl- or C3-C7-cycloalkyl- group; represents a hydrogen atom or a CrC3-alkyl- or a trifluoromethyl- group; represents a phenyl- group;
wherein said phenyl- group is optionally substituted, identically or differently, with 1 , 2 or 3 R7 groups ;
R4 represents a hydrogen atom or a methyl- group;
R5 represents a hydrogen atom or a -OH, -SH, -NH2, CrC3-alkoxy-, HO-CrC3-alkyl-, HO-C2-C3-alkoxy-, halo-CrC3-alkyl-, halo-CrC3-alkoxy-, - S-(CrC3-alkyl), -S-(halo-d-C3-alkyl), -N(H)(Ci-C3-alkyl),
-N(Ci-C3-alkyl)(CrC3-alkyl) or a H2N-Ci-C3-alkyl- group; each
R6 independently represents a halogen atom, or a -CN, -OH, d-d-alkoxy-, d-d-alkyl-, halo-d-d-alkyl-, R8a(R8b)N-d-C6-alkyl-, HO-d-C6-alkyl-, d-Ce-alkoxy-d-Ce-alkyl-, halo-Crd-alkoxy-Crd-alkyl-, C2-C&-alkenyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-,
4- to 10-membered heterocycloalkenyl-, d-G-cycloalkyl-,
-C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8, -N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(R8c)C(=0)C(=0)N(R8a)R8b,
-N(H)C(=0)OR8, -N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8, -0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8,
-S(=0)2N(H)R8, -S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group;
R7 represents a halogen atom, or a -CN, d-d-alkoxy-, d-d-alkyl-,
halo-d-d-alkyl-, R8a(R8b)N-d-C6-alkyl-, R8a(R8b)N-C(=0)(d-C6-alkyl)-, HO-d-d-alkyl-, d-d-alkoxy-d-d-alkyl-, halo-Crd-alkoxy-Crd-alkyl-,
C2-C6-alkenyl-, C2-C6-alkynyl-, -C(=0)R8, -C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -N(R8a)R8b, -N02, -N(H)C(=0)R8, -N(R8c)C(=0)R8,
-N(H)C(=0)N(R8a)R8b, -N(R8c)C(=0)N(R8a)R8b, -N(H)C(=0)OR8,
-N(R8c)C(=0)OR8, -N(H)S(=0)2R8, -N(R8c)S(=0)2R8, -OR8, -0(C=0)R8,
-0(C=0)N(R8a)R8b, -0(C=0)OR8, -SR8, -S(=0)R8, -S(=0)2R8, -S(=0)2N(H)R8,
-S(=0)2N(R8a)R8b or -S(=0)(=NR8c)R8 group; 8 [^8a [^8b [^8c represent, independently from each other, a hydrogen atom, or a Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C6-alkyl)-,
C2-C&-alkenyl-, C2-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;
said Ci-C&-alkyl-, C3-C7-cycloalkyl-, (C3-C7-cycloalkyl)-(Ci-C&-alkyl)-, 3- to 10-membered heterocycloalkyl-,
(3- to 10-membered heterocycloalkyl)-(Ci-C&-alkyl)-, aryl-,
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 R9; represents a halogen atom, or a CrC3-alkyl-, halo-CrC3-alkyl-, -CN, -C(=0)R10, -C(=0)N(H)R10, -C(=O)N(R10a)R10b, -C(=0)0-R10, -N(R10a)R10b, -N02, -N(H)C(=0)R10, -N(R10a)C(=O)R10b, -N(H)C(=O)N(R10a)R10b,
-N(R10a)C(=O)N(R10b)R10c, -N(H)C(=0)OR10, -N(R10a)C(=O)OR10b,
-N(H)S(=0)2R10, -N(R10a)S(=O)2R10b, -OR10, -0(C=0)R10, -O(C=O)N(R10a)R10b, -0(C=0)OR10, -SR10, -S(=0)R10, -S(=0)2R10, -S(=0)2N(H)R10,
-S(=O)2N(R10a)R10b or -S(=O)(=NR10a)R10b group; a j^10b |^10c
represent, independently from each other, a hydrogen atom or a Ci-C&-alkyl- group; is an integer of 0, 1 , 2 or 3 ;
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,
wherein the following compound is excluded:
3-Phenyl-7-(4-phenyl-1 -piperazinyl)-thiazolo[4,5-d]pyrimidine-2(3H)-thione.
2. A compound according to claim 1 , the compound being characterized by any one of the general formulae (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ij), (Ik), (Im), (In), (lo), and (Ip):
Figure imgf000127_0001
(Id) (le) (If)
Figure imgf000128_0001
Figure imgf000128_0002
Figure imgf000128_0003
in which Y1, Z, m, n, R3, R4, R5, R6 are as defined in claim 1.
3. A compound according to claim 1 or 2, wherein R5 represents a -OH, -NH2, CrC3-alkoxy-, HO-Ci-C3-alkyl-, HO-C2-C3-alkoxy-, or a
-S-(CrC3-alkyl)- group.
4. A compound according to claim 1 or 2, wherein R5 represents a
CrC3-alkoxy- group, preferably a methoxy- group.
5. A compound according to any one of claims 1 to 4, wherein each R6 independently represents a fluoro, chloro, bromo atom, or a -CN, -OH, pyrid-3-yl-, methoxy-, ethoxy-, CrC3-alkyl-, HO-Ci-C3-alkyl-, -C(=0)R8,
-C(=0)N(H)R8a, -C(=0)N(R8a)R8b, -C(=0)0-R8, -NH2, -N(R8a)R8b, -N(H)C(=0)R8, -N(R8c)C(=0)C(=0)N(R8a)R8b, -N(H)S(=0)2R8, -S(=0)2R8 or -S(=0)2N(H)R8 group.
6. A compound according to any one of claims 1 to 4, wherein each R6 independently represents -C(=0)N(H)R8a or -C(=0)0-R8.
7. A compound according to any one of claims 1 to 6, wherein R7 represents a halogen atom.
8. A compound according to any one of claims 1 to 7, wherein R8, R8a, R8b, R8c 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 R9.
9. A compound according to any one of claims 1 to 8, wherein R9 represents -OH.
10. A compound according to claim 1, which is selected from the group consisting of: 6-[4-(2-methoxyphenyl)piperazin-1 -yl]-9^henyl-7,9-dihydro-8H-purin-8-one, methyl 4-methoxy-3-[4-(8-oxo-9-phenyl-8,9-dihydro-7H-purin-6-yl)piperazin-1 - yl]benzoate,
4-methoxy-3-[4-(8-oxo-9-phenyl-8,9-dihydro-7H-purin-6-yl)piperazin-1 - yl] benzoic acid,
4-methoxy-3-[4-(8-oxo-9-phenyl-8,9-dihydro-7H-purin-6-yl)piperazin-1 - yl]benzamide,
N-(2-hydroxyethyl)-4-methoxy-3-[4-(8-oxo-9-phenyl-8,9-dihydro-7H-purin-6- yl)piperazin-1 -yl]benzamide, 9-(2-fluorophenyl)-6-[4-(2-methoxyphenyl)piperazin-1 -yl]-7,9-dihydro-8H-purin- 8-one, methyl 3-{4-[9-(2-fluorophenyl)-8-oxo-8,9-dihydro-7H-purin-6-yl]piperazin-1 - yl}-4-methoxybenzoate,
3-{4-[9-(2-fluorophenyl)-8-oxo-8,9-dihydro-7H-purin-6-yl]piperazin-1 -yl}-4- methoxybenzoic acid,
3-{4-[9-(2-fluorophenyl)-8-oxo-8,9-dihydro-7H-purin-6-yl]piperazin-1 -yl}-N-(2- hydroxyethyl)-4-methoxybenzamide,
6-[4-(3-methoxypyridin-2-yl)piperazin-1 -yl]-9-phenyl-7,9-dihydro-8H-purin-8- one, 6-[4-(3-methoxypyridin-2-yl)piperazin-1 -yl]-9-phenyl-7,9-dihydro-8H-purin-8- one,
3-(2-fluorophenyl)-7-[4-(2-methoxyphenyl)piperazin-1 -yl] [1 ,3]thiazolo[4,5- d]pyrimidine-2(3H)-thione, methyl 3-{4-[3-(2-fluorophenyl)-2-thioxo-2,3-dihydro[1 ,3]thiazolo[4,5- d]pyrimidin-7-yl]piperazin-1 -yl}-4-methoxybenzoate,
3-(2-fluorophenyl)-7-[4-(2-methoxyphenyl)-1 ,4-diazepan-1 -yl] [1 ,3]thiazolo[4,5- d]pyrimidine-2(3H)-thione or a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
1 1 . A method of preparing a compound of general formula (I ) according to any one of claims 1 to 10 in which method an intermediate of general formula
Figure imgf000131_0001
in which Z, R4, R5, R6, m, and n are as defined for the compounds of general formula (I ) in any one of claims 1 to 10; is allowed to react with a compound of general formula (II )
Figure imgf000131_0002
(II )
in which Y1, Y2, Y3 and R3 are as defined for the compounds of general formula (I ) in any one of claims 1 to 10, and LG is a leaving group; thus providing a compound of general formula (I ).
1 2. A method of preparing a compound of general formula (I ) according to any one of claims 1 to 10, in which method an intermediate of general formula (VI )
Figure imgf000132_0001
(VI)
in which Z, R5, R6 and m are as defined for the compounds of general formula (I) in any one of claims 1 to 10, and LG is a leaving group; is allowed to react with a compound of general formula (V) :
Figure imgf000132_0002
(V)
in which Y1, Y2, Y3, R3, R4 and n are as defined for the compounds of general formula (I) in any one of claims 1 to 10; thus providing a compound of general formula (I).
13. A compounds of general formula III):
Figure imgf000132_0003
(HI)
in which Z, R4, R5, R6, m, and n are as defined for the compounds of general formula (I) in any one of claims 1 to 10.
14. A compounds of general formula (V):
Figure imgf000133_0001
(V)
in which Y1, Y2, Y3, R3, R4 and n are as defined for the compounds of general formula (I) in any one of claims 1 to 10.
15. Use of a compound
(i) of general formula (II):
Figure imgf000133_0002
(i i )
in which Y1, Y2, Y3 and R3 are as defined for the compounds of general formula (I) in any one of claims 1 to 10, and LG is a leaving group; (ii) of general formula (III):
Figure imgf000133_0003
in which Z, R4, R5, R6, m, and n are as defined for the compounds of general formula (I) in any one of claims 1 to 10; (iii) of general formula (VI)
Figure imgf000134_0001
(VI)
in which Z, R5, R6 and m are as defined for the compounds of general formula (I) in any one of claims 1 to 10, and LG is a leaving group; or
(iv) of general formula (V)
Figure imgf000134_0002
(V)
in which Y1, Y2, Y3, R3, R4 and n are as defined for the compounds of general formula (I) in any one of claims 1 to 10; the preparation of compounds of eneral formula (I):
Figure imgf000134_0003
(I) in which Z, Y1, Y2, Y3, R3, R4, R5, R6, m, and n are as defined in any one of claims 1 to 10.
16. A compound according to any one of claims 1 to 10, or 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 use in the treatment or prophylaxis of a disease.
17. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 10, or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, and a pharmaceutically acceptable diluent or carrier.
18. A pharmaceutical combination comprising :
- one or more compounds of formula (I ) according to any one of claims 1 to 10, or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same;
and
- one or more agents selected from : a taxane, such as Docetaxel, Paclitaxel, or Taxol; an epothilone, such as Ixabepilone, Patupilone, or Sagopilone; Mitoxantrone; Predinisolone; Dexamethasone; Estramustin; Vinblastin; Vincristin; Doxorubicin; Adriamycin; Idarubicin; Daunorubicin; Bleomycin; Etoposide; Cyclophosphamide; Ifosfamide; Procarbazine; Melphalan; 5- Fluorouracil; Capecitabine; Fludarabine; Cytarabine; Ara-C; 2-Chloro-2 - deoxyadenosine; Thioguanine; an anti-androgen, such as Flutamide, Cyproterone acetate, or Bicalutamide; Bortezomib; a platinum derivative, such as Cisplatin, or Carboplatin; Chlorambucil; Methotrexate; and Rituximab.
19. Use of a compound as defined in any one of claims 1 to 10, or 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.
20. Use of a compound as defined in any one of claims 1 to 10, or 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 preparation of a medicament for the prophylaxis or treatment of a disease.
21. Use according to claim 16, 19 or 20, wherein said disease is a disease of uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is mediated by GLUT1 , more particularly in which the disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is a haemotological tumour, a solid tumour 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.
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