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WO2012160029A1 - Triazolopyridines substituées - Google Patents

Triazolopyridines substituées Download PDF

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Publication number
WO2012160029A1
WO2012160029A1 PCT/EP2012/059393 EP2012059393W WO2012160029A1 WO 2012160029 A1 WO2012160029 A1 WO 2012160029A1 EP 2012059393 W EP2012059393 W EP 2012059393W WO 2012160029 A1 WO2012160029 A1 WO 2012160029A1
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Prior art keywords
alkyl
halo
alkoxy
group
general formula
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Inventor
Volker Schulze
Dirk Kosemund
Antje Margret Wengner
Gerhard Siemeister
Detlef STÖCKIGT
Philip Lienau
Hans Briem
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Bayer Intellectual Property GmbH
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Bayer Intellectual Property GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to substituted triazolopyridine compounds of general formula (I ) as described and defined herein, 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 com pounds useful in the preparation of said compounds.
  • the present invention relates to chemical compounds that inhibit Mps-1 (Monopolar Spindle 1 ) kinase (also known as Tyrosine Threonine Kinase, TTK).
  • Mps-1 is a dual specificity Ser/Thr kinase which plays a key role in the activation of the mitotic checkpoint (also known as spindle checkpoint, spindle assembly checkpoint) thereby ensuring proper chromosome segregation during mitosis [Abrieu A et a/., Cell, 2001 , 106, 83-93] . Every dividing cell has to ensure equal separation of the replicated chromosomes into the two daughter cells.
  • ch romosomes are attached at their kinetochores to the microtubules of the spindle apparatus.
  • the mitotic checkpoint is a surveillance mechanism that is active as long as unattached kinetochores are present and prevents mitotic cells from entering anaphase and thereby com pleti ng cell division with u nattached ch romosomes [Suijkerbuijk SJ and Kops GJ, Biochemica et Biophysica Acta, 2008, 1786, 24- 31 ; Musacchio A and Salmon ED, Nat Rev Mol Cell Biol., 2007, 8, 379-93]. Once all kinetochores are attached in a correct amphitelic, i.e.
  • the mitotic checkpoint consists of complex network of a number of essential proteins, including members of the MAD (mitotic arrest deficient, MAD 1 -3 ) and Bub ( Budding u ni n hi bited by benzimidazole, Bub 1 -3) families, the motor protein CENP-E, Mps-1 kinase as well as other components, many of these being over-expressed in proliferating cells (e.g. cancer cells) and tissues [Yuan B et al. , Clinical Cancer Research, 2006, 12, 405-10].
  • Mps-1 kinase activity in mitotic checkpoint signalling has been shown by shRNA-silencing, chemical genetics as well as chemical inhibitors of Mps-1 kinase [Jelluma N et al. , PLos ONE, 2008, 3, e2415; Jones MH et al. , Current Biology, 2005, 15, 160-65; Dorer RK et al., Current Biology, 2005, 15, 1070-76; Schmidt M et al. , EMBO Reports, 2005, 6, 866-72].
  • mitotic checkpoint abrogation through pharmacological inhibition of Mps-1 kinase or other components of the mitotic checkpoint represents a new 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.
  • WO 2009/024824 A1 discloses 2-Anilinopurin-8-ones as inhibitors of Mps-1 for the treatment of proliferate disorders.
  • WO 201 0/ 1 24826 A1 discloses substituted imidazoquinoxaline compounds as inhibitors of Mps-1 kinase.
  • WO 2011 /026579 A1 discloses substituted aminoquinoxalines as Mps-1 inhibitors.
  • WO 2008/025821 A1 relates to triazole derivatives as kinase inhibitors, especially inhibitors of ITK or PI3K, for the treatment or prophylaxis of immunological, inflammatory or allergic disorders.
  • Said triazole derivatives are exemplified as possessing an amide, urea or aliphatic amine substituent in position 2.
  • WO 2009/047514 A1 relates to [1 ,2,4]-triazolo-[1 ,5-a]-pyridine and [1 ,2,4]- triazolo-[1 ,5-c]-pyrimidine compounds which inhibit AXL receptor tyrosine kinase function, and to the treatment of diseases and conditions that are mediated by AXL receptor tyrosine kinase, that are ameliorated by the inhibition of AXL receptor tyrosine kinase function etc., including proliferative conditions such as cancer, etc..
  • Said compounds are exemplified as possessing a substituent in the 5-position of said compounds and a substituent in the 2- position.
  • WO 2009/010530 A1 discloses bicyclic heterorayl compounds and their use as phosphatidylinositol (PI) 3-kinase. Among other compounds also substituted triazolopyridines are mentioned.
  • WO 2009/027283 A1 discloses triazolopyridine compounds and their use as ASK (apoptosis signal-regulating kinase) inhibitors for the treatment of autoimmune diseases and neurodegenerative diseases.
  • WO 2010/092041 A1 relates to [1 ,2,4]-triazolo-[1 ,5-a]-pyridines, which are said to be useful as selective kinase inhibitors, to methods for producing such compounds and methods for treating or ameliorating kinase-mediated disorder.
  • WO 201 1 /063907 A1 WO 201 1 /064328 A1 , WO 201 1 /063908 A1 , and WO 201 1 / 157688 A1 relate to [1 ,2,4]-triazolo-[1 ,5-a]-pyridines and their use for inhibition of Mps-1 kinase.
  • said compounds of the present invention have surprisingly been found to effectively inhibit Mps-1 kinase and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by Mps-1 kinase, such as, for example, haemotological 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 compounds of general formula (I) :
  • R 1 represents an aryl or heteroaryl group
  • R 2 represents a
  • Q 1 represents an atom or a group or atoms selected from: N, CH, C-(CrC&-alkyl), C-(Ci-C&-alkoxy), C-halo ;
  • Q 2 represents an atom or a group of atoms selected from: N, CH, C-(CrC&-alkyl), C-(Ci-C&-alkoxy), C-halo ;
  • Q 3 represents an atom or a group of atoms selected from: N, CH, C-(CrC&-alkyl), C-(Ci-C&-alkoxy), C-halo ;
  • R a represents a group selected from:
  • R b represents a group selected from:
  • halo-CrCe-alkoxy-CrCe-alkyl- represents a hydrogen atom, a halogen atom, a hydroxy-, amino- cyano-, nitro-, Ci -C4-alkyl-, halo-Ci -C4-alkyl-, Ci -C4-alkoxy-,
  • q represents an integer of 0, 1 , or 2 ; or a stereoisomer, a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • 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, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-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 ,
  • 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 (“Ci-C3-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
  • Si-C3-alkyl e.g. a methyl, ethyl, n-propyl- or iso-propyl group.
  • halo-CrCe-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci- Ce-alkyl” is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in identically or differently, i.e. one halogen atom being independent from another. Particularly, said halogen atom is F.
  • Said 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, hydrocarbon 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-C6-alkoxy-CrC6-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, (E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)- but-2-enyl, (Z)-but-2-enyl, (E)-but- l -enyl, (Z)-but- l -enyl, pent-4-enyl, (E)- pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent- l -enyl, (Z)-pent- l -enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)- hex-3-enyl, (E )-hex-2-enyl, (Z)
  • 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-inyl, hex-3-inyl, hex-4-ynyl, hex-5-ynyl, l -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
  • C3-C&-cycloalkyl is to be understood as preferably meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms.
  • Said C3-C&-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl or a bicyclic hydrocarbon ring.
  • Said cycloalkyl ring can optionally contain one or more double bonds e.g.
  • cycloalkenyl such as a cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group, wherein the bond between said ring with the rest of the molecule may be to any carbon atom of said ring, be it saturated or unsaturated.
  • heterocyclic ring as used in the term “4-, 5-, 6-, 7-, 8-, 9- or 10- membered heterocyclic ring”, or “4- to 6-membered heterocyclic ring” or “5- to 6-membered heterocyclic ring”, for example, as used in the definition of compounds of general formula (I ) as defined herein, is to be understood as meaning a saturated or partially unsaturated, mono-, bi- or poly-cyclic nitrogen atom-containi ng ri ng, said nitrogen atom being the poi nt of attachment of said heterocyclic ring with the rest of the molecule.
  • said nitrogen atom-containing ring can be bicyclic, such as, without being limited thereto, a 5, 5-membered ring, e.g. a hexahydrocyclopenta[c]pyrrol-2(1H)-yl) ring, or a 5, 6-membered bicyclic ring, e.g. a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring, or for example.
  • said nitrogen atom-containing ring can be partially unsaturated, i.e.
  • it can contain one or more double bonds, such as, without being limited thereto, a 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5- dihydrooxazolyl, or 4H-[1,4]thiazinyl ring, for example, or, it may be benzo- fused, such as, without being limited thereto, a dihydroisoquinolinyl ring, for example.
  • double bonds such as, without being limited thereto, a 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5- dihydrooxazolyl, or 4H-[1,4]thiazinyl ring, for example, or, it may be benzo- fused, such as, without being limited thereto, a dihydroisoquinolinyl ring, for example.
  • said ring can contain 2, 3, 4, or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "3- to 6-membered heterocycloalkyl"), more particularly said ring can contain 4 or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "5- to 6-membered heterocycloalkyl").
  • Said heterocycloalkyl ring is for example, a monocyclic heterocycloalkyl ring such as an oxyranyl, oxetanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, or chinuclidinyl group.
  • said heterocycloalkyl ring can 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- d i h yd ro f u ra n yl , 2 , 3-dihydrofuranyl, 2,5-dihydrothiophenyl, 2,3- dihydrothiophenyl, 4,5-dihydro-1 ,3-oxazolyl, 4,4-dimethyl-4,5-dihydro-1 ,3- oxazolyl , or 4H-[1 ,4]thiazinyl group, or, it may be benzo fused.
  • aryl is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, mono-, or bi- or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 carbon atoms (a "C 6 -Ci4-aryl” group), particularly a ring having 6 carbon atoms (a "C 6 -aryl” group), e.g. a phenyl group, or a biphenyl 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.
  • heteroaryl is understood as preferably meaning a monovalent, aromatic, mono- or bicyclic 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 can be monocyclic, bicyclic, or tricyclic, 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.
  • pyridyl pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, etc. ; or azocinyl, indolizinyl, purinyl, etc.
  • heteroaryl is selected from pyridyl, benzofuranyl, benzisoxazolyl, indazolyl, quinazolinyl, thienyl, quinolinyl, benzothienyl, pyrazolyl, or furanyl.
  • alkylene is understood as preferably meaning an optionally substituted hydrocarbon chain (or “tether”) having 1 , 2, 3, 4, 5, or 6 carbon atoms, i.e. an optionally substituted -CH 2 - ("methylene” or “single membered tether” or, for example -C(Me) 2 -), -CH 2 -CH 2 - ("ethylene”, “dimethylene”, or “two-membered tether"), -CH 2 -CH 2 -CH 2 - ("propylene”, “trimethylene”, or “three-membered tether"), -CH 2 -CH 2 -CH 2 -CH 2 - ("butylene”, “tetramethylene”, or “four-membered tether"), -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - ("pentylene”, “pentamethylene” or "five-membered ether”), or -CH 2 -CH 2 -CH 2 -CH
  • said alkylene tether has 1 , 2, 3, 4, or 5 carbon atoms, more particularly 1 or 2 carbon atoms.
  • the term "Ci -C&”, as used throughout this text, e.g. in the context of the definition of "d-d-alkyl”, “d-d-haloalkyl”, “d-d-alkoxy”, or “d-C 6 - 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 “Ci -C&" is to be interpreted as any sub- range comprised therein, e.g.
  • C 2 -C& as used throughout this text, e.g. in the context of the definitions of "C 2 -C&-alkenyl” and “C 2 -C&-alkyny , 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 -C&” is to be interpreted as any sub-range comprised therein, e.g. C 2 -C&, C3-C5 , C3-C4, C2-C3, C 2 -C4, C 2 -Cs ; particularly C 2 - C 3 .
  • C3-C& as used throughout this text, e.g. in the context of the definition of "C3-C&-cycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e.3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C3- C&” is to be interpreted as any sub-range comprised therein, e.g. C3-C6 , C4-C5 , C3-C5 , C3-C4 , C4-C6, C5-C6 ; particularly C3-C6.
  • C7-C10 as used throughout this text, e.g. in the context of the definition of "C 7 -Cio-cycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 7 to 10, i.e.7, 8, 9, or 10 carbon atoms. It is to be understood further that said term “C 7 -Cio” is to be interpreted as any sub-range comprised therein, e.g. C 7 -Cio , C8-C9, G-C9, C 7 -C8, Ce-Cio, C9-C10; particularly C7-C10.
  • a 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.
  • a leaving group is selected from the group comprising: halo, in particular chloro, bromo or iodo, 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)sulfony
  • 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".
  • the compounds of this invention may contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms may be present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric centre, and diastereomeric mixtures in the case of multiple asymmetric centres.
  • asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), 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.
  • 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.
  • 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), 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 achi eved by any suitable state of the art m ethod , 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. 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.
  • 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.
  • a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, l a u ri c , b e n z o i c , sa l i cy l i c , 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentaneprop
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N- methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1 ,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1 - amino-2,3,4-butantriol.
  • basic nitrogen containing groups may be quaternised with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides ; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate ; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate
  • diamyl sulfates long chain halides such as decyl, la
  • acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • in vivo hydrolysable ester is understood as meaning an in vivo hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, CrC& alkoxymethyl esters, e.g. methoxymethyl, CrC& alkanoyloxymethyl esters, e.g.
  • An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha] -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • inorganic esters such as phosphate esters and [alpha] -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • [alpha]-acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • the present invention covers all such esters.
  • the present invention includes all possible crystalline forms, polymorphs, of the compounds of the present invention, either as sing polymorphs, or as a mixture of more than one polymorphs, in any ratio.
  • the present invention covers compounds of general formula (I) :
  • CrCe-alkoxy-d-Ce-alkyl-, halo-CrCe-alkoxy-CrCe-alkyl- ; represents a
  • Q 1 represents a group selected from: N, CH, C-(Ci -C&-alkyl), C-(Ci -C&-alkoxy), C-halo ;
  • Q 2 represents a group selected from: N, CH, C-(Ci -C&-alkyl), C-(Ci -C&-alkoxy), C-halo ;
  • Q 3 represents a group selected from: N, CH, C-(Ci -C&-alkyl), C-(Ci -C&-alkoxy), C-halo ;
  • R a represents a group selected from:
  • 5b represents a group selected from:
  • R 4 represents a hydrogen atom, a halogen atom, a hydroxy-, amino-,
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from :
  • q represents an integer of 0, 1 , or 2 ; or a stereoisomer, a tautomer, an N -oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • R 1 represents a substituted aryl or a substituted heteroaryl group.
  • the aryl group preferably is a phenyl group.
  • the heteroaryl group preferably is a pyridyl group.
  • R 1 can be further substituted, one or more times, identically or differently, with a substituent R xy selected from :
  • Preferred substituents are: halo-, Ci-C&-alkyl-, halo-Ci-C&-alkyl-, Ci-C&-alkoxy-, and halo-d-Ce-alkoxy-.
  • the invention relates to compounds of formula (I), supra, wherein :
  • R 1 represents an aryl or heteroaryl group
  • the invention relates to compounds of formula (I), supra, wherein :
  • R 1 represents an aryl group, preferably a phenyl group ; - which is substituted, one or more times, identically or differently, with a substituent selected from :
  • Ci-C&-alkoxy- Ci-C&-alkoxy-, halo-Ci-C&-alkoxy-, hydroxy-d-Ce-alkyl-,
  • the invention relates to compounds of formula (I), supra, wherein :
  • R 1 represents a heteroaryl group, preferably a pyridyl group ;
  • Ci-C&-alkoxy- Ci-C&-alkoxy-, halo-Ci-C&-alkoxy-, hydroxy-Ci-C&-alkyl-,
  • the invention relates to compounds of formula (I), supra, wherein :
  • R 1 represents an aryl or heteroaryl group
  • R xy selected from : halo-, hydroxy!-, cyano-, nitro-, Ci-C&-alkyl-, halo-Ci-C&-alkyl-,
  • Ci-C&-alkoxy- Ci-C&-alkoxy-, halo-Ci-C&-alkoxy-, hydroxy-Ci-C&-alkyl-,
  • the invention relates to compounds of formula (I), supra, wherein :
  • R 1 represents an aryl or heteroaryl group
  • Ci-C&-alkoxy- Ci-C&-alkoxy-, halo-Ci-C&-alkoxy-, hydroxy-d-Ce-alkyl-,
  • the invention relates to compounds of formula (I), supra, wherein :
  • R 1 represents an aryl or heteroaryl group
  • R 1 represents a substituted phenyl group or a substituted pyridyl group.
  • the invention relates to compounds of formula (I), supra, wherein :
  • R 3 represents a hydrogen atom, a halogen atom, a Ci -C4-alkyl- or a halo-Cr C 4 -alkyl- group.
  • R 3 is H.
  • the invention relates to compounds of formula (I), supra, wherein :
  • R 4 represents a hydrogen atom, a halogen atom, a CrC 4 -alkyl- or a halo-Cr C 4 -alkyl- group.
  • R 4 is H.
  • the invention relates to compounds of formula (I), supra, wherein :
  • R a represents a group selected from:
  • R b is a substituted or unsubstituted cr group.
  • the invention relates to compounds of formula (I), supra, wherein :
  • R b represents a cr group
  • Ci-C&-alkyl preferably Ci-C&-alkyl
  • the invention relates to compounds of formula (I), supra, wherein :
  • R b represents a
  • Ci-C&-alkyl preferably Ci-C&-alkyl
  • the invention relates to compounds of formula (I), supra, wherein :
  • R 6 represents a group selected from :
  • R 6 is -(CH 2 )q- (C3-C6-cycloalkyl) or -(CH 2 ) q -aryl; more preferably, R 6
  • R 6 can be optionally substituted, one or more times, identically or differently, with a substituent selected from :
  • the invention relates to compounds of formula (I), supra, wherein :
  • R 6 represents a group selected from :
  • the invention relates to compounds of formula (I), supra, wherein :
  • R 6 represents a group selected from :
  • the invention relates to compounds of formula (I), supra, wherein :
  • R 6 represents a -(CH 2 ) q -aryl group
  • the invention relates to compounds of formula (I), supra, wherein :
  • R 6 represents a -(CH 2 ) q -aryl group
  • the invention relates to compounds of formula (I), supra, wherein :
  • Q 1 represents a group selected from: N, CH.
  • Q 1 is CH.
  • the invention relates to compounds of formula (I), supra, wherein :
  • Q 2 represents a group selected from: N, CH.
  • Q 2 is CH.
  • the invention relates to compounds of formula (I), supra, wherein :
  • Q 3 represents a group selected from: N, CH.
  • Q 3 is CH.
  • the invention relates to compounds of formula (I), supra, wherein :
  • q represents an integer of 1 or 2.
  • q is 1 .
  • R 1 represents an aryl (preferably phenyl) or a heteroaryl (preferably
  • halo-, Ci-C&-alkyl-, halo-Ci-C&-alkyl-, Ci-C&-alkoxy-, halo-Ci-C&-alkoxy-. represents a
  • Q 1 represents a group selected from: N, CH, C-(Ci-C&-alkyl),
  • Q 2 represents a group selected from: N, CH, C-(Ci-C&-alkyl),
  • Q 3 represents a group selected from: N, CH, C-(Ci-C&-alkyl),
  • R a represents a group selected from:
  • halo-Ci-C&-alkoxy- hydroxy-Ci-C&-alkyl-, CrCe-alkoxy-d-Ce-alkyl-, halo-CrCe-alkoxy-d-Ce-alkyl-, (C3-C&-cycloalkyl)-0- ; represents a group selected from:
  • R 3 represents a hydrogen atom, a halogen atom, a Ci-C4-alkyl- or a
  • R 4 represents a hydrogen atom, a halogen atom, a Ci-C4-alkyl- or a halo-CrC4-alkyl - group
  • R 5 represents a hydrogen atom
  • halo-CrCe-alkoxy- represents an integer of 0, 1 , or 2.
  • the invention relates to compounds of formula (I ):
  • R 1 represents an aryl (preferably phenyl) or a heteroaryl (preferably
  • halo-, Ci-C&-alkyl-, halo-Ci-C&-alkyl-, Ci-C&-alkoxy-, halo-Ci-C&-alkoxy- ; represents a
  • Q 1 represents a group selected from: N, CH, C-(Ci-C&-alkyl),
  • Q 2 represents a group selected from: N, CH, C-(Ci-C&-alkyl),
  • Q 3 represents a group selected from: N, CH, C-(Ci-C&-alkyl),
  • R a represents a group selected from:
  • R b represents a group selected from: wherein * indicates the point of attachment of said group with the rest of the molecule ;
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from :
  • the invention relates to compounds of ula (I ):
  • R 1 represents an aryl (preferably phenyl) or a heteroaryl (preferably
  • halo-, Ci-C&-alkyl-, halo-Ci-C&-alkyl-, Ci-C&-alkoxy-, halo-Ci-C&-alkoxy- ; represents a
  • Q 1 represents a group selected from: N, CH, C-(Ci-C&-alkyl),
  • Q 2 represents a group selected from: N, CH, C-(Ci-C&-alkyl),
  • Q 3 represents a group selected from: N, CH, C-(Ci-C&-alkyl),
  • R a represents a group selected from:
  • R b represents a group selected from:
  • Ci -C&-alkyl- halo-Ci -C&-alkyl- ; represents an integer of 0, 1 , or 2.
  • : represents an aryl (preferably phenyl) or a heteroaryl (preferably pyridyl) group ;
  • halo-, Ci-C&-alkyl-, halo-Ci-C&-alkyl-, Ci-C&-alkoxy-, halo-Ci-C&-alkoxy-; represents a
  • Q 1 represents N or CH ;
  • Q 2 represents N or CH ;
  • Q 3 represents N or CH ;
  • R a represents a group selected from:
  • R b represents a group selected from:
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6 represents a group selected from :
  • q represents an integer of 0, 1 , or 2.
  • R 1 represents an aryl (preferably phenyl) or a heteroaryl (preferably
  • R 2 represents a
  • Q 1 represents CH ;
  • Q 2 represents CH ;
  • Q 3 represents CH ;
  • R a represents a group selected from:
  • R b represents a group
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom ; represents a group selected from :
  • the invention relates to a stereoisomer, a tautomer, an N- oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, of any of the compounds of formula (I).
  • the present invention covers compounds of general formula (I) which are disclosed in the Example section of this text, infra.
  • the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein.
  • the present invention relates to a method of preparing compounds of general formula (I), supra, in which method an intermediate compound of general formula (5) :
  • R 2 is as defined for the compounds of general formula (I), supra, and Y represents a leaving group, such as a halogen atom or a trifluoromethylsulphonyloxy or nonafluorobutylsulphonyloxy group for example, thus providing a compound of eneral formula (I)
  • the present invention relates to a method of preparing compounds of general formula (I), supra, in which method an intermediate compound of general formula (7) :
  • R 2 , R 3 , R 4 , and R 5 are as defined for the compounds of general formula (I ), supra, and R 1a is an aryl or heteroaryl group to which an -NH 2 substituent is bound, and to which one or more R xy substituents are optionally bound, is allowed to react with a compound of general formula (7a)
  • a coupling reaction such as an amide coupling reaction for example
  • the present invention relates to a method of preparing compounds of general formula (I), supra, in which method an intermediate compound of general formula (7) :
  • R 2 , R 3 , R 4 , and R 5 are as defined for the compounds of general formula (I), supra, and R 1a is an aryl or heteroaryl group to which a -COOH substituent is bound, and to which one or more R xy substituents are optionally bound (R xy being as defined for the compounds of general formula (I), supra), is allowed to react with a compound of general formula (7a) :
  • R 1b is -NHR 6 (R 6 being as defined as for the compounds of general formula (I), supra), and X is a suitable functional group (e.g. a hydrogen atom), via which the R 1b of the R 1b -X compound (7a) can be coupled, via a coupling reaction, such as an amide coupling reaction for example, onto the -COOH substituent bound to the aryl or heteroaryl group R 1a of compound (7), thereby replacing said X with said R 1a ,
  • a coupling reaction such as an amide coupling reaction for example
  • the present invention relates to a method of preparing compounds of general formula (I ), supra, in which method an intermediate compound of eneral formula (4) :
  • R 2 , R 3 , R 4 , and R 5 are as defined for the compound of general formula (I), supra, and Y represents a leaving group, such as a halogen atom or a trifluoromethylsulphonyloxy or nonafluorobutylsulphonyloxy group for example, is allowed to react with a compound of general formula :
  • R 1 -Z in which R 1 is as defined for the compounds of general formula (I), supra, and Z represents a suitable functional group like for example a boronic acid or a boronic ester, thus providing a compound of eneral formula (I)
  • 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 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 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 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
  • R 2 , R 3 , R 4 , and R 5 are as defined for the compounds of general formula (I), supra, and R 1a is an aryl or heteroaryl group to which an -NH 2 substituent is bound,
  • R 2 , R 3 , R 4 , and R 5 are as defined for the compounds of general formula (I), supra, and Y represents a leaving group, such as a halogen atom or a trifluoromethylsulphonyloxy or nonafluorobutylsulphonyloxy group for example,
  • the present invention covers the use of the intermediate compounds :
  • R 2 , R 3 , R 4 , and R 5 are as defined for the compounds of general formula (I), supra, and R 1a is an aryl or heteroaryl group to which an -NH 2 substituent is bound, or (b) of general formula (4) :
  • R 2 , R 3 , R 4 , and R 5 are as defined for the compounds of general formula (I), supra, and Y represents a leaving group, such as a halogen atom or a trifluoromethylsulphonyloxy or nonafluorobutylsulphonyloxy group for example, or
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined for the compounds of general formula (I), supra, and Y represents a leaving group, such as a halogen atom or a trifluoromethylsulphonyloxy or nonafluorobutylsulphonyloxy group for example, and Z represents a suitable functional group via which the R 1 of the R 1 -Z compound can be coupled, by a coupling reaction, onto the Y-bearing carbon atom of a compound (4), thereby replacing said Y with said R 1 moiety.
  • Many aryl halides of the formula R 2 -Y may be obtained commercially.
  • Reagents of the general structure R 1a -Z and R 1 -Z can for example be aryl boronic acids or aryl boronic esters. Many such reagents of the general structures R 1a -Z and R 1 -Z are also commercially available. Reagents of the general structures R 1a -Z and R 1 -Z can be prepared from aryl halides [see for example K. L Billingslay, T. E. Barde, S . L Buchwald , Angew. Chem . 2007, 1 1 9 , 5455 or T. G raeni ng, sympatheticen aus der Chemie, Jan 2009, 57, 34] .
  • R 1a can be converted to R 1 in one or several steps.
  • R 1a can be a protected aryl-amine, especially -aryl-NH-Boc, or an aryl-carboxylic acid, [-aryl-C(0)OH] or an -aryl-carboxylic acid ester [ aryl-C(0)0-alkyl] .
  • the aryl or heteroaryl group of R 1a can optionally be substituted with one or more substituents R xy (R xy being as defined as for compounds of general formula (I ) of the present invention as defined supra).
  • R 1a is an aryl group to which one or more substituents R xy are optionally bound, and to which an -NH 2 substituent is bound
  • a suitably substituted 5-halo-pyridin-2-ylamine intermediate of general formula (1 ) is converted to the corresponding intermediate of general formula (2) by reaction with a suitable oxycarbonylisothiocyanat, such as for example ethoxycarbonylisothiocyanat at temperatures ranging from room temperature to the boiling point of the solvent, preferably room temperature [see for example M. Nettekoven, B. Piillmann, S. Schmitt, Synthesis 2003, 1643 - 1652].
  • a suitable oxycarbonylisothiocyanat such as for example ethoxycarbonylisothiocyanat
  • I ntermediates of general form ula (2 ) may be converted to 6-Halo- [1 ,2,4]triazolo[1 ,5-a]pyridin-2-ylamine intermediates of general formula (3) by reaction with a suitable reagent, for example hydroxylamine hydrochloride, in presence of a suitable base, such as, for example DIPEA in a suitable solvent system, such as, for example, methanol, ethanol, 1 -propanol, 2-propanol or mixtures of these solvents at elevated temperatures, e.g. 60° C. [see for example M. Nettekoven, B. Piillmann, S. Schmitt, Synthesis 2003, 1643 - 1652].
  • a suitable reagent for example hydroxylamine hydrochloride
  • a suitable base such as, for example DIPEA
  • a suitable solvent system such as, for example, methanol, ethanol, 1 -propanol, 2-propanol or mixtures of these solvents at
  • Intermediates of general formula (3) can be converted to intermediates of general formula (4) by reaction with suitable aryl compounds R 2 -Y, preferably aryl bromides, or aryl iodides or for example aryl trifluoromethylsulphonates or aryl nonafluorobutylsulphonates in the presence of a suitable base, such as, for example NaOtBu or caesium carbonate or potassium phosphate, and a suitable catalyst/ligand system, such as for example Pd 2 (dba) 3 /rac-BINAP, Pd 2 dba 3 /X- Phos, Pd 2 dba 3 /tBu-X-Phos, Pd 2 dba 3 /Brett-Phos, Pd-X-Phos-pre-cat/X-Phos, Pd- tBu-X-Phos-pre-cat/tBu-X-Phos, Pd-Brett-Phos-pre-cat/Brett-
  • Intermediates of general formula (4) can be converted to compounds of general formula (I ) by reaction with a suitable reagent, like for example a boronic acid derivative in the presence of a suitable catalyst system, like for example Pd(OAc) 2 and P(oTol) 3 , or PdCl 2 (PPh 3 ) 2 and PPh 3 and a suitable base, like for example aqueous potassium carbonate in a suitable solvent, like for example THF, DME, ethanol or 1 -propanol or mixtures of these solvents at temperatures ranging from room temperature to 200° C, prefereably the boiling point of the used solvent.
  • a suitable reagent like for example a boronic acid derivative in the presence of a suitable catalyst system, like for example Pd(OAc) 2 and P(oTol) 3 , or PdCl 2 (PPh 3 ) 2 and PPh 3 and a suitable base, like for example aqueous potassium carbonate in a suitable solvent, like for example THF, DME
  • Intermediates of general formula (3) can be reacted reacted with a suitable reagent, like for example a boronic acid derivative in the presence of a suitable catalyst system, like for example Pd(OAc) 2 and P(oTol) 3 , or PdCl 2 (PPh 3 ) 2 and PPh 3 and a suitable base, like for example aqueous potassium carbonate in a suitable solvent, like for example THF, DME, ethanol or 1 - propanol or mixtures of these solvents at temperatures ranging from room temperature to 200° C, prefereably the boiling point of the used solvent to furnish intermediates of the general formula (5).
  • a suitable reagent like for example a boronic acid derivative in the presence of a suitable catalyst system, like for example Pd(OAc) 2 and P(oTol) 3 , or PdCl 2 (PPh 3 ) 2 and PPh 3 and a suitable base, like for example aqueous potassium carbonate in a suitable solvent, like for example THF
  • aryl compounds R 2 -Y preferably aryl bromides, or aryl iodides or for example aryl trifluoromethylsulphonates or aryl nonafluorobutylsulphonates in the presence of a suitable base, such as, for example NaOtBu or caesium carbonate or potassium phosphate, and a suitable catalyst/ligand system, such as for example Pd 2 (dba) 3 /rac-BINAP, Pd 2 dba 3 /X- Phos, Pd 2 dba 3 /tBu-X-Phos, Pd 2 dba 3 /Brett-Phos, Pd-X-Phos-pre-cat/X-Phos, Pd- tBu-X-Phos-pre-cat/tBu-X-Phos, Pd-Brett-Phos-pre-cat/Brett-
  • Scheme 2 Synthesis of compounds of general formula (1 1 ), wherein R 2 , R 3 , R 4 , R 5 , R 6 and R xy are as defined for the compounds of general formula (I), supra.
  • Y is a leaving group, e.g. a halogen, a) coupling reaction using conditions as described supra for synthesis of intermediates of general formula (5); b) coupling reaction using conditions as described supra for synthesis of intermediates of general formula (4); c) removal of a Boc-protecting group using conditions known to the person skilled in the art (see for example T.W. Greene and P.G.M.
  • Scheme 3 Synthesis of compounds of general formula (15), wherein R 2 , R 3 , R 4 , R 5 and R xy are as defined for the compounds of general formula (I), supra.
  • R xz is a leaving group, e.g. a halogen.
  • R Het is 3- to 10-membered heterocycloalkyl, as defined supra, a) Conditions for the formation of an amide bond, e.g. using coupling reagents like for example HATU or TBTU and a base like for example potassium carbonate or DIPEA in an inert solvent like for example THF, DMF, DCM or NMP.
  • an acid chloride and a base like for example pyridine can be used in an inert solvent like for example THF or DCM.
  • a heterocyclic amine like e.g. piperidine in a polar solvent like for example DMF or NMP using a base like for example potassium carbonate and optionally using a catalytic ammount of potassium iodide.
  • the compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same com pound . I n some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallisation. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash chromatography, using for example pre-packed silica gel cartridges, e.g.
  • Separtis such as Isolute® Flash silica gel (silica gel chromatography) or Isolute® Flash NH2 silica gel (aminophase-silica-gel chromatography) in combination with a suitable chromatographic system such as a Flashmaster II (Separtis) or an Isolera system (Biotage) and eluents such as, for example, gradients of hexane/ethyl acetate or DCM/methanol.
  • a suitable chromatographic system such as a Flashmaster II (Separtis) or an Isolera system (Biotage)
  • eluents such as, for example, gradients of hexane/ethyl acetate or DCM/methanol.
  • the compounds may be purified by preparative H PLC using, for example, a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionisation mass spectrometer in combination with a suitable pre-packed reverse phase column and eluants such as, for example, gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionisation mass spectrometer in combination with a suitable pre-packed reverse phase column and eluants such as, for example, gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • Method A System: UPLC Acquity (Waters) with PDA Detector und Waters ZQ mass spectrometer; Column: Acquity BEH C18 1 .7 ⁇ 2.1x50mm; Temperature: 60° C; Solvent A: Water + 0.1 % formic acid; Solvent B: acetonitrile; Gradient: 99 % A - 1 % A (1 .6 min) -> 1 % A (0.4 min) ; Flow: 0.8 mL/min; Injection Volume: 1.0 ⁇ _ (0.1 mg-1 mg/ml_ sample concentration); Detection: PDA scan range 210-400 nm - Fixed and ESI (+), scan range 170-800 m/z
  • Names of compounds were generated using ACD/Name Batch ver. 12.00 or ACD/Name Batch ver. 12.01 .
  • Names of compounds in table format were generated using ACD/Name Batch ver. 12.00.
  • Ethoxycarbonylisothiocyanat (16.7 g) was added to a stirred solution of 2- amino-5-brompyridine (20 g) in dioxane (200 mL). The mixture was stirred for 2 h at r.t. A white solid precipitated. Hexane (20 mL) was added and the white solid was collected by filtration.
  • Hydroxylammoniumchlorid 39.8 g was suspended in methanol (200 mL) and ethanol (190 mL) and Hiinig Base (59 mL) was added at r.t. The mixture was heated to 60°C, Int01.01 (30 g) was added portionwise, and the mixture was stirred at 60° C for 2 h. The solvent was removed in vacuum and water (150 mL) was added. A solid was collected by filtration and was washed with water and dried in vacuum.
  • Int02.04 was prepared analogously to the procedure for the preparation of Int2.3. Yield: 5.1 g of the title compound.
  • Int02.06 was prepared analogously to the procedure for the preparation of Int02.01.
  • Int02.07 was prepared analogously to the procedure for the preparation of Int02.02.
  • Int02.08 was prepared analogously to the procedure for the preparation of Int02.03.
  • Int03.06 was prepared analogously to the procedure for the preparation of Int03.03. Yield: 564 mg of the title compound.
  • Int03.07 was prepared analogously to the procedure for the preparation of Int03.03. Yield: 610 mg of the title compound.
  • Int10.03 was prepared analogously to the procedure for the preparation of Int09.01. Yield: 7.9 g of the title compound.
  • Int10.04 was prepared analogously to the procedure for the preparation of Int09.01. Yield: 1.31 g of the title compound.
  • Int10.06 was prepared analogously to the procedure for the preparation of Int09.01. Yield: 1.4 g of the title compound.
  • Int10.07 was prepared analogously to the procedure for the preparation of Int09.05. Yield: 1 .47 g of the title compound.
  • Int10.08 was prepared analogously to the procedure for the preparation of Int09.05. Yield: 991 mg of the title compound.
  • the compound was prepared analogously to Intermediate Example Int1 1.02 from Intermediate Example Int13.01 and 2,2,2-trifluoroethyl trifluoro- methanesulfonate.
  • Int1 1.04 (800 mg) and 2-oxa-6-azaspiro[3.3]heptane ethane- dioate (2: 1 ) (540 mg)
  • Int1 1.06 was prepared analogously to the procedure for the preparation of Int09.05. Yield: 626 mg of the title compound.
  • the mixture was heated for 6 h to 130 °C, then diluted with saturated sodium carbonate solution and extracted with DCM. The organic layer was dried over sodium sulfate, and the solvent was evaporated.
  • the crude product was purified by flash chromatography on silica gel (20 g, eluent: ethyl acetate/ cyclohexane gradient 2:1 to 8: 1 ). The product was then triturated with n-pentane and collected by suction filtration to yield 61 mg (39%) of the title compound.
  • Example02.30 was prepared analogously to the procedure for the preparation of Example02.15.

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Abstract

La présente invention porte sur des composés triazolopyridines substitués représentés par la formule générale (I) : dans laquelle R1, R2, R3, R4 et R5 sont tels que donnés dans la description et dans les revendications, sur des procédés de préparation desdits composés, sur des compositions pharmaceutiques et des associations comprenant lesdits composés, sur l'utilisation desdits composés pour la fabrication d'une composition pharmaceutique pour le traitement ou la prophylaxie d'une maladie telle que des tumeurs et des maladies prolifératives, ainsi que sur des composés intermédiaires utiles dans la préparation desdits composés.
PCT/EP2012/059393 2011-05-23 2012-05-21 Triazolopyridines substituées Ceased WO2012160029A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014009219A1 (fr) * 2012-07-10 2014-01-16 Bayer Pharma Aktiengesellschaft Procédé de préparation de triazolopyridines substituées
WO2014020043A1 (fr) * 2012-08-02 2014-02-06 Bayer Pharma Aktiengesellschaft Combinaisons pour le traitement du cancer
WO2014198645A1 (fr) * 2013-06-11 2014-12-18 Bayer Pharma Aktiengesellschaft Combinaisons pour le traitement du cancer comprenant un inhibiteur de la kinase mps-1 et un inhibiteur de la mitose
US20160207928A1 (en) * 2013-06-10 2016-07-21 Bayer Pharma Aktiengesellschaft Novel compounds for the treatment of cancer

Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5011472A (en) 1988-09-06 1991-04-30 Brown University Research Foundation Implantable delivery system for biological factors
US5023252A (en) 1985-12-04 1991-06-11 Conrex Pharmaceutical Corporation Transdermal and trans-membrane delivery of drugs
WO2006018325A1 (fr) 2004-08-17 2006-02-23 Galderma Research & Development, S.N.C. Nouveaux composes bioaromatiques activant les recepteurs de type ppar et leur utilisation dans des compositions cosmetiques ou pharmaceutiques
WO2008025821A1 (fr) 2006-08-30 2008-03-06 Cellzome Limited Dérivés de triazole en tant qu'inhibiteurs de kinase
WO2009010530A1 (fr) 2007-07-18 2009-01-22 Novartis Ag Composés hétéroaryliques bicycliques et leur utilisation comme inhibiteurs de kinase
WO2009024824A1 (fr) 2007-08-23 2009-02-26 Astrazeneca Ab Composés chimiques 1-994
WO2009027283A1 (fr) 2007-08-31 2009-03-05 Merck Serono S.A. Composés de triazolopyridine et leur utilisation comme inhibiteurs de ask
WO2009047514A1 (fr) 2007-10-10 2009-04-16 Cancer Research Technology Limited Composés [1,2,4]triazolo[1,5-a]pyridine et [1,2,4]triazolo[1,5-c]pyrimidine et leur utilisation
WO2009068482A1 (fr) * 2007-11-27 2009-06-04 Cellzome Limited Aminotriazoles comme inhibiteurs de p13k
WO2010092041A1 (fr) 2009-02-13 2010-08-19 Fovea Pharmaceuticals Sa [1, 2, 4] triazolo [1, 5 -a] pyridines servant d'inhibiteurs de kinases
WO2010124826A1 (fr) 2009-04-29 2010-11-04 Bayer Schering Pharma Aktiengesellschaft Imidazoquinoxalines substituées
WO2011026579A1 (fr) 2009-09-04 2011-03-10 Bayer Schering Pharma Aktiengesellschaft Aminoquinoxalines substituées servant d'inhibiteurs de tyrosine-thréonine kinases
WO2011064328A1 (fr) 2009-11-30 2011-06-03 Bayer Schering Pharma Aktiengesellschaft Derives de triazolopyridines
WO2011063907A1 (fr) 2009-11-30 2011-06-03 Bayer Schering Pharma Aktiengesellschaft Triazolopyridines substituées
WO2011063908A1 (fr) 2009-11-30 2011-06-03 Bayer Schering Pharma Aktiengesellschaft Triazolopyridines
WO2011157688A1 (fr) 2010-06-16 2011-12-22 Bayer Pharma Aktiengesellschaft Triazolopyridines substituées

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5023252A (en) 1985-12-04 1991-06-11 Conrex Pharmaceutical Corporation Transdermal and trans-membrane delivery of drugs
US5011472A (en) 1988-09-06 1991-04-30 Brown University Research Foundation Implantable delivery system for biological factors
WO2006018325A1 (fr) 2004-08-17 2006-02-23 Galderma Research & Development, S.N.C. Nouveaux composes bioaromatiques activant les recepteurs de type ppar et leur utilisation dans des compositions cosmetiques ou pharmaceutiques
WO2008025821A1 (fr) 2006-08-30 2008-03-06 Cellzome Limited Dérivés de triazole en tant qu'inhibiteurs de kinase
WO2009010530A1 (fr) 2007-07-18 2009-01-22 Novartis Ag Composés hétéroaryliques bicycliques et leur utilisation comme inhibiteurs de kinase
WO2009024824A1 (fr) 2007-08-23 2009-02-26 Astrazeneca Ab Composés chimiques 1-994
WO2009027283A1 (fr) 2007-08-31 2009-03-05 Merck Serono S.A. Composés de triazolopyridine et leur utilisation comme inhibiteurs de ask
WO2009047514A1 (fr) 2007-10-10 2009-04-16 Cancer Research Technology Limited Composés [1,2,4]triazolo[1,5-a]pyridine et [1,2,4]triazolo[1,5-c]pyrimidine et leur utilisation
WO2009068482A1 (fr) * 2007-11-27 2009-06-04 Cellzome Limited Aminotriazoles comme inhibiteurs de p13k
WO2010092041A1 (fr) 2009-02-13 2010-08-19 Fovea Pharmaceuticals Sa [1, 2, 4] triazolo [1, 5 -a] pyridines servant d'inhibiteurs de kinases
WO2010124826A1 (fr) 2009-04-29 2010-11-04 Bayer Schering Pharma Aktiengesellschaft Imidazoquinoxalines substituées
WO2011026579A1 (fr) 2009-09-04 2011-03-10 Bayer Schering Pharma Aktiengesellschaft Aminoquinoxalines substituées servant d'inhibiteurs de tyrosine-thréonine kinases
WO2011064328A1 (fr) 2009-11-30 2011-06-03 Bayer Schering Pharma Aktiengesellschaft Derives de triazolopyridines
WO2011063907A1 (fr) 2009-11-30 2011-06-03 Bayer Schering Pharma Aktiengesellschaft Triazolopyridines substituées
WO2011063908A1 (fr) 2009-11-30 2011-06-03 Bayer Schering Pharma Aktiengesellschaft Triazolopyridines
WO2011157688A1 (fr) 2010-06-16 2011-12-22 Bayer Pharma Aktiengesellschaft Triazolopyridines substituées

Non-Patent Citations (27)

* Cited by examiner, † Cited by third party
Title
"the Merck Index", 1996
ABRIEU A ET AL., CELL, vol. 106, 2001, pages 83 - 93
AIELLO ET AL., NEW ENGL. J. MED., vol. 331, 1994, pages 1480
DORER RK ET AL., CURRENT BIOLOGY, vol. 15, 2005, pages 1070 - 76
GOODMAN; GILMAN'S ET AL.: "The Pharmacological Basis of Therapeutics", 1996, MCGRAW-HILL, pages: 1225 - 1287
JELLUMA N ET AL., PLOS ONE, vol. 3, 2008, pages E2415
JONES MH ET AL., CURRENT BIOLOGY, vol. 15, 2005, pages 160 - 65
K.L. BILLINGSLAY; T.E. BARDE; S.L BUCHWALD, ANGEW. CHEM., vol. 119, 2007, pages 5455
KING RW, BIOCHIMICA ET BIOPHYSICA ACTA, vol. 1786, 2008, pages 4 - 14
KOPS GJ ET AL., NATURE REVIEWS CANCER, vol. 5, 2005, pages 773 - 85
LOPEZ ET AL., INVEST. OPTHTHALMOL. VIS. SCI., vol. 37, 1996, pages 855
M. NETTEKOVEN; B. PULLMANN; S. SCHMITT, SYNTHESIS, 2003, pages 1643 - 1652
MUSACCHIO A; SALMON ED, NAT REV MOL CELL BIOL., vol. 8, 2007, pages 379 - 93
NEMA, S. ET AL.: "Excipients and Their Use in Injectable Products", PDA JOURNAL OF PHARMACEUTICAL SCIENCE & TECHNOLOGY, vol. 51, no. 4, 1997, pages 166 - 171
PEER ET AL., LAB. INVEST., vol. 72, 1995, pages 638
POWELL, M.F. ET AL.: "Compendium of Excipients for Parenteral Formulations", PDA JOURNAL OF PHARMACEUTICAL SCIENCE & TECHNOLOGY, vol. 52, no. 5, 1998, pages 238 - 311, XP009119027
PURE APPL CHEM, vol. 45, 1976, pages 11 - 30
S. M. BERGE ET AL.: "Pharmaceutical Salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19, XP002675560, DOI: doi:10.1002/jps.2600660104
SCHMIDT M ET AL., EMBO REPORTS, vol. 6, 2005, pages 866 - 72
SCHMIDT M; BASTIANS H, DRUG RESISTANCE UPDATES, vol. 10, 2007, pages 162 - 81
SCHMIDT M; MEDEMA RH, CELL CYCLE, vol. 5, 2006, pages 159 - 63
STRICKLEY, R.G: "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1", PDA JOURNAL OF PHARMACEUTICAL SCIENCE & TECHNOLOGY, vol. 53, no. 6, 1999, pages 324 - 349
SUIJKERBUIJK SJ; KOPS GJ, BIOCHEMICA ET BIOPHYSICA ACTA, vol. 1786, 2008, pages 24 - 31
T.GRAENING, NACHRICHTEN AUS DER CHEMIE, vol. 57, January 2009 (2009-01-01), pages 34
T.W. GREENE; P.G.M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY
WEAVER BA; CLEVELAND DW, CANCER RESEARCH, vol. 67, 2007, pages 10103 - 5
YUAN B ET AL., CLINICAL CANCER RESEARCH, vol. 12, 2006, pages 405 - 10

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* Cited by examiner, † Cited by third party
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WO2014009219A1 (fr) * 2012-07-10 2014-01-16 Bayer Pharma Aktiengesellschaft Procédé de préparation de triazolopyridines substituées
EA027544B1 (ru) * 2012-07-10 2017-08-31 Байер Фарма Акциенгезельшафт Способ получения замещенных триазолопиридинов
WO2014020043A1 (fr) * 2012-08-02 2014-02-06 Bayer Pharma Aktiengesellschaft Combinaisons pour le traitement du cancer
US20160207928A1 (en) * 2013-06-10 2016-07-21 Bayer Pharma Aktiengesellschaft Novel compounds for the treatment of cancer
WO2014198645A1 (fr) * 2013-06-11 2014-12-18 Bayer Pharma Aktiengesellschaft Combinaisons pour le traitement du cancer comprenant un inhibiteur de la kinase mps-1 et un inhibiteur de la mitose
CN105283178A (zh) * 2013-06-11 2016-01-27 拜耳制药股份公司 用于治疗癌症的包含mps-1激酶抑制剂和有丝分裂抑制剂的组合

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