WO2017157991A1 - 1-alkyl-pyrazoles et 1-alkyl-indazoles utilisés en tant qu'inhibiteurs de bub1 pour le traitement de maladies hyperprolifératives - Google Patents

1-alkyl-pyrazoles et 1-alkyl-indazoles utilisés en tant qu'inhibiteurs de bub1 pour le traitement de maladies hyperprolifératives Download PDF

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WO2017157991A1
WO2017157991A1 PCT/EP2017/056075 EP2017056075W WO2017157991A1 WO 2017157991 A1 WO2017157991 A1 WO 2017157991A1 EP 2017056075 W EP2017056075 W EP 2017056075W WO 2017157991 A1 WO2017157991 A1 WO 2017157991A1
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alkyl
indazol
methyl
pyrimidin
independently
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PCT/EP2017/056075
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English (en)
Inventor
Marion Hitchcock
Anne Mengel
Thomas Müller
Lars BÄRFACKER
Arwed Cleve
Hans Briem
Gerhard Siemeister
Wilhelm Bone
Amaury Ernesto FERNANDEZ-MONTALVAN
Jens SCHRÖDER
Ursula MÖNNING
Simon Holton
Cornelia PREUSSE
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Bayer Pharma Aktiengesellschaft
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the invention relates to 1 -Alkyl-Pyrazole and -Indazole compounds, a process for their production and the use thereof.
  • the eukaryotic cell division cycle ensures the duplication of the genome and its distribution to the daughter cells by passing through a coordinated and regulated sequence of events.
  • the cell cycle is divided into four successive phases: 1 .
  • the G1 phase represents the time before the DNA replication, in which the cell grows and is sensitive to external stimuli.
  • the passage through the cell cycle is strictly regulated and controlled.
  • the enzymes that are necessary for the progression through the cycle must be activated at the correct time and are also turned off again as soon as the corresponding phase is passed.
  • Corresponding control points stop or delay the progression through the cell cycle if DNA damage is detected, or the DNA replication or the creation of the spindle device is not yet completed.
  • the mitotic checkpoint also known as spindle checkpoint or spindle assembly checkpoint
  • the mitotic checkpoint is active as long as unattached kinetochores are present and generates a wait-signal to give the dividing cell the time to ensure that each kinetochore is attached to a spindle pole, and to correct attachment errors.
  • the mitotic checkpoint prevents a mitotic cell from completing cell division with unattached or erroneously attached chromosomes [Suijkerbuijk SJ and Kops GJ, Biochem. Biophys. Acta 1786, 24, 2008; Musacchio A and Salmon ED, Nat. Rev. Mol. Cell. Biol. 8, 379, 2007].
  • the mitotic checkpoint is established by a complex network of a number of essential proteins, including members of the MAD (mitotic arrest deficient, MAD 1 -3) and Bub (Budding uninhibited by benzimidazole, Bub 1 -3) families, Mps1 kinase, cdc20, as well as other components [reviewed in Bolanos-Garcia VM and Blundell TL, Trends Biochem. Sci. 36, 141 , 2010], many of these being over-expressed in proliferating cells (e.g. cancer cells) and tissues [Yuan B et al., Clin. Cancer Res. 12, 405, 2006].
  • the major function of an unsatisfied mitotic checkpoint is to keep the anaphase-promoting complex/cyclosome (APC/C) in an inactive state.
  • APC/C anaphase-promoting complex/cyclosome
  • ubiquitin-ligase targets cyclin B and securin for proteolytic degradation leading to separation of the paired chromosomes and exit from mitosis.
  • Bub1 Inactive mutations of the Ser/Thr kinase Bub1 prevented the delay in progression through mitosis upon treatment of cells of the yeast S. cerevisiae with microtubule- destabilizing drugs, which led to the identification of Bub1 as a mitotic checkpoint protein [Roberts BT et al., Mol. Cell Biol., 14, 8282, 1994].
  • a number of recent publications provide evidence that Bub1 plays multiple roles during mitosis which, have been reviewed by Elowe [Elowe S, Mol. Cell. Biol. 31 , 3085, 201 1 ].
  • Bub1 is one of the first mitotic checkpoint proteins that binds to the kinetochores of duplicated chromosomes and probably acts as a scaffolding protein to constitute the mitotic checkpoint complex. Furthermore, via phosphorylation of histone H2A, Bub1 localizes the protein shugoshin to the centromeric region of the chromosomes to prevent premature segregation of the paired chromosomes [Kawashima et al. Science 327, 172, 2010]. In addition, together with a Thr-3 phosphorylated Histone H3 the shugoshin protein functions as a binding site for the chromosomal passenger complex which includes the proteins survivin, borealin, INCENP and Aurora B.
  • the chromosomal passenger complex is seen as a tension sensor within the mitotic checkpoint mechanism, which dissolves erroneously formed microtubule-kinetochor attachments such as syntelic (both sister kinetochors are attached to one spindle pole) or merotelic (one kinetochor is attached to two spindle poles) attachments [Watanabe Y, Cold Spring Harb. Symp. Quant. Biol. 75, 419, 2010].
  • Recent data suggest that the phosphorylation of histone H2A at Thr 121 by Bub1 kinase is sufficient to localize AuroraB kinase to fulfill the attachment error correction checkpoint [Ricke et al. J. Cell Biol. 199, 931 -949, 2012].
  • mitotic checkpoint abrogation through pharmacological inhibition of components of the mitotic checkpoint represents a new approach for the treatment of proliferative disorders, including solid tumours such as carcinomas, sarcomas, leukaemias and lymphoid malignancies or other disorders, associated with uncontrolled cellular proliferation.
  • the present invention relates to chemical compounds that inhibit Bub1 kinase.
  • Established anti-mitotic drugs such as vinca alkaloids, taxanes or epothilones activate the mitotic checkpoint, inducing a mitotic arrest either by stabilising or destabilising microtubule dynamics. This arrest prevents separation of the duplicated chromosomes to form the two daughter cells. Prolonged arrest in mitosis forces a cell either into mitotic exit without cytokinesis (mitotic slippage or adaption) or into mitotic catastrophe leading to cell death [Rieder CL and Maiato H, Dev. Cell 7, 637, 2004].
  • inhibitors of Bub1 prevent the establishment and/or functionality of the mitotic checkpoint and/or microtubule-kinetochor attachment error correction mechanisms, which finally results in severe chromosomal missegregation, induction of apoptosis and cell death [Baron A et al. eLife 2016;5:e12187].
  • Bub1 inhibitors should be of therapeutic value for the treatment of proliferative disorders associated with enhanced uncontrolled proliferative cellular processes such as, for example, cancer, inflammation, arthritis, viral diseases, cardiovascular diseases, or fungal diseases in a warm-blooded animal such as man.
  • WO 2013/050438, WO 2013/092512, WO 2013/167698 disclose substituted benzylindazoles, substituted benzylpyrazoles and substituted benzylcycloalkyl- pyrazoles, respectively, which are Bub1 kinase inhibitors.
  • WO 2014/147203, WO 2014/147204, WO2014202590, WO2014202588, WO2014202584, WO2014202583, and WO2015/063003, disclose substituted indazoles, substituted pyrazoles, and substituted cycloalkylpyrazoles, which are Bub1 kinase inhibitors.
  • Inhibitors of Bub1 represent valuable compounds that should complement therapeutic options either as single agents or in combination with other drugs.
  • the invention covers compounds of general formula (I),
  • V, W, Y and Z independently of each other represent CH or CR 2 ,
  • V represents N, and W, Y and Z, independently of each other, represent CH or CR 2 , or,
  • W represents N, and V, Y and Z, independently of each other, represent CH or CR 2 , or,
  • V and Y represent N, and W and Z, independently of each other, represent CH or CR 2 ,
  • R 1 represents a group selected from:
  • cycloalkyl groups are optionally substituted with one or two groups selected independently from:
  • heterocycloalkyl groups are optionally substituted with one or two groups selected independently from:
  • phenyl groups are optionally substituted with one, two or three groups selected independently from:
  • halogen atom hydroxy, Ci -C 6 -alkyl, Ci -C 6 -haloalkyl, Ci -C 6 -hydroxyalkyl, (Ci -C 3 -alkoxy)-(Ci -C 6 -alkyl)-, C 3 -C 6 -cycloalkyl, (C 3 -C6-cycloalkyl)-(Ci -C 3 - alkyl)-, Ci -C 6 -alkoxy, Ci -C 6 -haloalkoxy, (C 2 -C 6 -hydroxyalkyl)-0-, (Ci -C3-alkoxy)-(C2-C6-alkoxy)-, Cs-Ce-cycloalkoxy and
  • alkyl- and alkenyl groups are optionally substituted with one or two groups selected independently from :
  • Ci-C3-alkyl Ci-C3-alkyl, C3-C4-cycloalkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy,
  • R 4 represents a hydrogen atom, or a halogen atom or a group selected from:
  • (Ci-C3-alkoxy)-(C 2 -C6-alkoxy)- and hydroxy represents a hydrogen atom, or a halogen atom or a group selected from: Ci-C 3 -alkyl and C3-C 4 -cycloalkyl,
  • R 8 represents a hydrogen atom, or a halogen atom or a Ci-C 3 -alkyl group, or R 7 and R 8 are linked to one another in such a way that they jointly form a
  • R 1 1 represent hydrogen atoms, represents, independently of each other, a hydrogen atom or a group selected from :
  • Ci-C 3 -alkyl Ci-C 3 -haloalkyl, C 2 -C 3 -hydroxyalkyl, C3-C 4 -cycloalkyl,
  • R 10 represents a hydrogen atom or a group selected from:
  • R 1 1 represents, independently of each other, a hydrogen atom or a halogen atom or a group selected from:
  • a second aspect of the invention are compounds of formula (I) as defined herein, wherein
  • V, W, Y and Z independently of each other represent CH or CR 2 ,
  • V represents N, and W, Y and Z, independently of each other, represent CH or CR 2 , or,
  • W represents N, and V, Y and Z, independently of each other, represent CH or CR 2 ,
  • R 1 represents a group selected from:
  • cycloalkyl groups are optionally substituted with one or two groups selected independently from:
  • heterocycloalkyl groups are optionally substituted with one or two groups selected independently from:
  • phenyl groups are optionally substituted with one, two or three groups selected independently from: halogen atom, Ci-C 6 -alkyl, Ci-C 6 -haloalkyl, Ci -C 6 -alkoxy, Ci-C 6 - haloalkoxy, (C2-C6-hydroxyalkyl)-0- and (Ci-C3-alkoxy)-(C2-C6-alkoxy)-, and,
  • alkyl- and alkenyl groups are optionally substituted with one or two groups selected independently from :
  • R 2 represents, independently of each other, a halogen atom or a group selected from:
  • Ci -C 3 -alkyl, C 3 -C 4 -cycloalkyl, Ci -C 3 -haloalkyl, Ci -C 3 -alkoxy, (C 2 -C 3 - hydroxyalkyl)-0-,-N(H)C( 0)H,
  • R 8 represents a hydrogen atom, or a halogen atom or a Ci-C 3 -alkyl group, or R 7 and R 8 are linked to one another in such a way that they jointly form a
  • R 9 represents, independently of each other, a hydrogen atom or a group selected from:
  • R 10 represents a hydrogen atom or a group selected from:
  • Ci-C 3 -alkyl and C 3 -C 4 -cycloalkyl are Ci-C 3 -alkyl and C 3 -C 4 -cycloalkyl
  • R 1 1 represents, independently of each other, a hydrogen atom or a halogen atom or a group selected from:
  • a third aspect of the invention are compounds of formula (I) as defined herein, wherein
  • V, W, Y and Z independently of each other, represent CH or CR 2 ,
  • V represents N, and W, Y and Z independently of each other represent CH or CR 2 , or,
  • W represents N, and V, Y and Z, independently of each other, represent CH or CR 2 ,
  • R 1 represents a group selected from:
  • cycloalkyl groups are optionally substituted with one or two groups selected independently from:
  • heterocycloalkyl groups are optionally substituted with one or two groups selected independently from:
  • phenyl groups are optionally substituted with one, two or three groups selected independently from:
  • Ci-C3-haloalkyl Ci-C3-alkoxy
  • alkyl- and alkenyl groups are optionally substituted with or two groups selected independently from:
  • R 11 represents hydrogen atoms, represents, independently of each other, a hydrogen atom or a group selected from:
  • Ci-C 3 -alkyl and C 3 -C 4 -cycloalkyl are Ci-C 3 -alkyl and C 3 -C 4 -cycloalkyl
  • R 10 represents a hydrogen atom or a Ci-C 3 -alkyl group
  • R 11 represents, independently of each other, a hydrogen atom or a halogen atom or a group selected from:
  • a fourth aspect of the invention are compounds of formula (I) as defined herein, wherein
  • V, W, Y and Z independently of each other, represent CH or CR 2 ,
  • V represents N, and W, Y and Z, independently of each other, represent CH or CR 2 ,
  • R 1 represents a group selected from:
  • Ci-Cs-alkyl (C 3 -C 7 -cycloalkyl)-(Ci-C2-alkyl)-,
  • heterocycloalkyl groups are optionally substituted with one or two groups selected independently from:
  • alkyl- and alkenyl groups are optionally substituted with one group selected from:
  • R 8 represents a hydrogen atom or a Ci-C 3 -alkyl group, or R 7 and R 8 are linked to one another in such a way that they jointly form a
  • R 9 represents, independently of each other, a hydrogen atom or a
  • R 10 represents a hydrogen atom or a Ci-C 3 -alkyl group
  • R 1 1 represents, independently of each other, a hydrogen atom or a halogen atom or a methyl group, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
  • a fifth aspect of the invention are compounds of formula (I) as defined herein, wherein
  • V, W, Y and Z independently of each other, represent CH or CR 2 ,
  • V represents N, and W, Y and Z, independently of each other, represent CH or CR 2 ,
  • R 1 represents a group selected from:
  • R 2 represents, independently of each other, a group selected from:
  • R 4 represents a hydrogen atom, or a group selected from:
  • methoxy, 3-hydroxypropyloxy and hydroxy represents a bromine atom or an isopropyl group
  • R 8 represents a hydrogen atom or a methyl group, or R 7 and R 8 are linked to one another in such a way that they jointly form a
  • R 11 represent hydrogen atoms, represents, independently of each other, a hydrogen atom or a methyl group
  • R 10 represents a hydrogen atom or a group selected from:
  • R 11 represents, independently of each other, a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
  • a further aspect of the invention are compounds of formula (I), wherein
  • V, W, Y and Z independently of each other, represent CH or CR 2 ,
  • V represents N, and W, Y and Z, independently of each other, represent CH or CR 2 , or,
  • W represents N, and V, Y and Z, independently of each other, represent CH or CR 2 , or,
  • V and Y represent N, and W and Z, independently of each other, represent CH or CR 2 , and
  • R 2 represents, independently of each other, a halogen atom or a group selected from: cyano, Ci-C 3 -alkyl, C 3 -C 4 -cycloalkyl, Ci-C 3 -haloalkyl, Ci-C 3 -alkoxy,
  • R 9 represents, independently of each other, a hydrogen atom or a group selected from:
  • Ci-C 3 -alkyl Ci-C 3 -haloalkyl, C 2 -C 3 -hydroxyalkyl, C 3 -C 4 -cycloalkyl,
  • R 10 represents a hydrogen atom or a group selected from:
  • V, W, Y and Z independently of each other represent CH or CR 2 ,
  • V represents N, and W, Y and Z, independently of each other, represent CH or CR 2 , or,
  • W represents N, and V, Y and Z independently of each other represent CH or CR 2 , and
  • R 2 represents, independently of each other, a halogen atom or a group selected from:
  • R 9 represents, independently of each other, a hydrogen atom or a group selected from:
  • R 10 represents a hydrogen atom or a group selected from:
  • Ci-C 3 -alkyl and C 3 -C -cycloalkyl are compounds of formula (I), in which
  • V, W, Y and Z independently of each other, represent CH or CR 2 ,
  • V represents N, and W, Y and Z, independently of each other, represent CH or CR 2 , or,
  • W represents N, and V, Y and Z, independently of each other, represent CH or CR 2 , and
  • R 2 represents, independently of each other, a halogen atom or a group selected from:
  • R 9 represents, independently of each other, a hydrogen atom or a group selected from:
  • Ci-C 3 -alkyl and C 3 -C 4 -cycloalkyl are Ci-C 3 -alkyl and C 3 -C 4 -cycloalkyl
  • R 10 represents a hydrogen atom or a Ci-C 3 -alkyl group.
  • V, W, Y and Z independently of each other, represent CH or CR 2 ,
  • V represents N, and W, Y and Z, independently of each other, represent CH or CR 2 , and
  • R 2 represents, independently of each other, a group selected from:
  • R 9 represents, independently of each other, a hydrogen atom or a
  • R 10 represents a hydrogen atom or a Ci-C 3 -alkyl group.
  • V, W, Y and Z independently of each other, represent CH or CR 2 ,
  • V represents N, and W, Y and Z, independently of each other, represent CH or CR 2 , and
  • R 2 represents, independently of each other, a group selected from:
  • R 9 represents, independently of each other, a hydrogen atom or a methyl group
  • R 10 represents a hydrogen atom or a group selected from:
  • V, W, Y and Z independently of each other, represent CH or CR 2 .
  • V, W, Y and Z represents CR 2 , and the others represent CH.
  • V, W, Y and Z independently of each other, represent CH or CR 2 ,
  • R 2 represents, independently of each other, a halogen atom or a group selected from:
  • Ci-C3-alkyl Ci-C3-alkyl, C3-C4-cycloalkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy,
  • R 9 represents, independently of each other, a hydrogen atom or a group selected from:
  • Ci-C 3 -alkyl Ci-C 3 -haloalkyl, C 2 -C 3 -hydroxyalkyl, C3-C 4 -cycloalkyl,
  • R 10 represents a hydrogen atom or a group selected from:
  • Ci-C 3 -alkyl Ci-C 3 -haloalkyl, C 2 -C 3 -hydroxyalkyl, C3-C 4 -cycloalkyl,
  • Yet another aspect of the invention are compounds of formula (I), in which V, W, Y and Z, independently of each other, represent CH or CR 2 ,
  • R 2 represents, independently of each other, a halogen atom or a group selected from:
  • R 9 represents, independently of each other, a hydrogen atom or a group selected from:
  • R 10 represents a hydrogen atom or a group selected from:
  • Ci-C 3 -alkyl and C 3 -C 4 -cycloalkyl are Ci-C 3 -alkyl and C 3 -C 4 -cycloalkyl.
  • V, W, Y and Z independently of each other, represent CH or CR 2 ,
  • R 2 represents, independently of each other, a halogen atom or a group selected from:
  • R 9 represents, independently of each other, a hydrogen atom or a group selected from:
  • Ci-C 3 -alkyl and C 3 -C -cycloalkyl are Ci-C 3 -alkyl and C 3 -C -cycloalkyl
  • R 10 represents a hydrogen atom or a Ci-C 3 -alkyl group.
  • V, W, Y and Z independently of each other, represent CH or CR 2 ,
  • R 2 represents, independently of each other, a group selected from:
  • R 9 represents, independently of each other, a hydrogen atom or a
  • R 10 represents a hydrogen atom or a Ci-C 3 -alkyl group.
  • V, W, Y and Z independently of each other, represent CH or CR 2 ,
  • R 2 represents, independently of each other, a group selected from:
  • R 9 represents, independently of each other, a hydrogen atom or a methyl group
  • R 10 represents a hydrogen atom or a group selected from:
  • V represents N, and W, Y and Z, independently of each other, represent CH or CR 2 .
  • V represents N
  • one of W, Y and Z, represents CR 2 , and the others represent CH.
  • V represents N, and W, Y and Z, independently of each other, represent CH or CR 2 , and
  • R 2 represents, independently of each other, a halogen atom or a group selected from:
  • Ci-C 3 -alkyl C 3 -C 4 -cycloalkyl
  • Ci-C 3 -haloalkyl Ci-C 3 -alkoxy
  • R 9 represents, independently of each other, a hydrogen atom or a group selected from:
  • Ci-C 3 -alkyl Ci-C 3 -haloalkyl, C 2 -C3-hydroxyalkyl, C3-C 4 -cycloalkyl,
  • R 10 represents a hydrogen atom or a group selected from:
  • Ci-C 3 -alkyl Ci-C 3 -haloalkyl, C 2 -C 3 -hydroxyalkyl, C 3 -C 4 -cycloalkyl,
  • V represents N, and W, Y and Z, independently of each other, represent CH or CR 2 , and
  • R 2 represents, independently of each other, a halogen atom or a group selected from:
  • R 9 represents, independently of each other, a hydrogen atom or a group selected from:
  • R 10 represents a hydrogen atom or a group selected from:
  • Ci-C 3 -alkyl and C 3 -C -cycloalkyl are Ci-C 3 -alkyl and C 3 -C -cycloalkyl.
  • V represents N, and W, Y and Z, independently of each other, represent CH or CR 2 , and
  • R 2 represents, independently of each other, a halogen atom or a group selected from:
  • R 9 represents, independently of each other, a hydrogen atom or a group selected from:
  • Ci-C 3 -alkyl and C3-C 4 -cycloalkyl are Ci-C 3 -alkyl and C3-C 4 -cycloalkyl
  • R 10 represents a hydrogen atom or a Ci-C 3 -alkyl group.
  • V represents N, and W, Y and Z, independently of each other, represent CH or CR 2 , and
  • R 2 represents, independently of each other, a group selected from:
  • R 9 represents, independently of each other, a hydrogen atom or a
  • R 10 represents a hydrogen atom or a Ci-C 3 -alkyl group.
  • V represents N, and W, Y and Z, independently of each other, represent CH or CR 2 , and
  • R 2 represents, independently of each other, a group selected from:
  • R 9 represents, independently of each other, a hydrogen atom or a methyl group
  • R 10 represents a hydrogen atom or a group selected from:
  • V represents N, and W, Y and Z, independently of each other, represent CH or CR 2 , and
  • R 2 represents, independently of each other, a methyl group.
  • R 1 represents a group selected from:
  • d-Ce-alkyl C 3 -C 8 -cycloalkyl, (C 3 -C 8 -cycloalkyl)-(Ci-C 3 -alkyl)-, (4- to 7-membered heterocycloalkyl)-(Ci-C 3 -alkyl)-, phenyl-(C 2 -C3-alkyl)-,
  • cycloalkyi groups are optionally substituted with one or two groups selected independently from:
  • heterocycloalkyl groups are optionally substituted with one or two groups selected independently from:
  • phenyl groups are optionally substituted with one, two or three groups selected independently from:
  • halogen atom hydroxy, Ci-C 6 -alkyl, Ci-C 6 -haloalkyl, Ci-C 6 -hydroxyalkyl, (Ci-C 3 -alkoxy)-(Ci-C 6 -alkyl)-, C 3 -C 6 -cycloalkyl, (C 3 -C 6 -cycloalkyl)-(Ci-C 3 - alkyl)-, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, (C2-C6-hydroxyalkyl)-0-, (Ci-C 3 -alkoxy)-(C 2 -C 6 -alkoxy)-, C 3 -C 6 -cycloalkoxy and
  • alkyl- and alkenyl groups are optionally substituted with one or two groups selected independently from:
  • R 1 represents a group selected from:
  • Ci-Cs-alkyl C 3 -C 8 -cycloalkyl, (C 3 -C 8 -cycloalkyl)-(Ci-C 3 -alkyl)-,
  • cycloalkyi groups are optionally substituted with one or two groups selected independently from:
  • heterocycloalkyl groups are optionally substituted with one or two groups selected independently from:
  • phenyl groups are optionally substituted with one, two or three groups selected independently from:
  • Ci -Ce-alkyl Ci -Ce-haloalkyl, Ci -Ce-alkoxy, Ci -Ce- haloalkoxy, (C 2 -C 6 -hydroxyalkyl)-0- and (Ci -C3-alkoxy)-(C 2 -C 6 -alkoxy)-, and,
  • alkyl- and alkenyl groups are optionally substituted with one or two groups selected independently from:
  • cycloalkyl groups are optionally substituted with one or two groups selected independently from:
  • heterocycloalkyl groups are optionally substituted with one or two groups selected independently from:
  • alkyl- and alkenyl groups are optionally substituted with one or two groups selected independently from:
  • cycloalkyl groups are optionally substituted with one or two groups selected independently from:
  • heterocycloalkyl groups are optionally substituted with one or two groups selected independently from:
  • phenyl groups are optionally substituted with one, two or three groups selected independently from:
  • Ci -C 3 -haloalkyl Ci -C 3 -alkoxy
  • alkyl- and alkenyl groups are optionally substituted with one or two groups selected independently from:
  • R 1 represents a group selected from:
  • cycloalkyl groups are optionally substituted with one or two groups selected independently from:
  • heterocycloalkyl groups are optionally substituted with one or two groups selected independently from:
  • alkyl- and alkenyl groups are optionally substituted with one or two groups selected independently from:
  • R 1 represents a group selected from:
  • Ci -Cs-alkyl (C 3 -C 7 -cycloalkyl)-(Ci -C 2 -alkyl)-,
  • heterocycloalkyl groups are optionally substituted with one or two groups selected independently from:
  • alkyl- and alkenyl groups are optionally substituted with one group selected from:
  • R 1 represents a group selected from:
  • R 2 represents, independently of each other, a halogen atom or a group selected from:
  • Ci-C 3 -alkyl C3-C 4 -cycloalkyl
  • Ci-C 3 -haloalkyl Ci-C 3 -alkoxy
  • R 2 represents, independently of each other, a halogen atom or a group selected from:
  • R 2 represents, independently of each other, a halogen atom or a group selected from:
  • R 2 represents, independently of each other, a group selected from :
  • R 2 represents, independently of each other, a group selected from :
  • R 4 represents a hydrogen atom, or a halogen atom or a group selected from:
  • R 4 represents a hydrogen atom, or a halogen atom or a group selected from:
  • Ci-Ce-alkoxy (C 2 -C 6 -hydroxyalkyl)-0-, (Ci-C 3 -alkoxy)-(C 2 -C 6 -alkoxy)- and hydroxyl.
  • R 4 represents a hydrogen atom, or a halogen atom or a group selected from:
  • R 4 represents a hydrogen atom, or a group selected from:
  • R 4 represents a hydrogen atom, or a group selected from: methoxy, 3-hydroxypropyloxy and hydroxyl.
  • R 7 represents a hydrogen atom, or a halogen atom or a group selected from:
  • Ci-C 3 -alkyl and C3-C 4 -cycloalkyl are Ci-C 3 -alkyl and C3-C 4 -cycloalkyl
  • R 8 represents a hydrogen atom, or a halogen atom or a Ci-C 3 -alkyl group, or
  • R 7 and R 8 are linked to one another in such a way that they jointly form a
  • R 7 represents a hydrogen atom, or a halogen atom or a group selected from:
  • Ci-C 3 -alkyl and C3-C 4 -cycloalkyl are Ci-C 3 -alkyl and C3-C 4 -cycloalkyl
  • R 8 represents a hydrogen atom, or a halogen atom or a Ci-C 3 -alkyl group, or
  • R 7 and R 8 are linked to one another in such a way that they jointly form a
  • R 7 represents a halogen atom or a Ci-C 3 -alkyl group
  • R 8 represents a hydrogen atom or a Ci-C 3 -alkyl group
  • R 7 and R 8 are linked to one another in such a way that they jointly form a
  • R 8 represents a hydrogen atom or a methyl group
  • R 7 and R 8 are linked to one another in such a way that they jointly form a
  • R 7 represents a hydrogen atom, or a halogen atom or a group selected from:
  • Ci-C3-alkyl and C3-C4-cycloalkyl are Ci-C3-alkyl and C3-C4-cycloalkyl.
  • R 7 represents a halogen atom or a Ci-C 3 -alkyl group.
  • R 7 represents a bromine atom or an isopropyl group.
  • R 8 represents a hydrogen atom, or a halogen atom or a Ci-C 3 -alkyl group.
  • R 8 represents a hydrogen atom or a Ci-C 3 -alkyl group.
  • R 7 and R 8 are linked to one another in such a way that they jointly form a group selected from:
  • R 9 represents, independently of each other, a hydrogen atom or a group selected from:
  • Ci-C 3 -alkyl Ci-C 3 -haloalkyl, C 2 -C3-hydroxyalkyl, C3-C 4 -cycloalkyl,
  • R 9 represents, independently of each other, a hydrogen atom or a group selected from:
  • R 9 represents, independently of each other, a hydrogen atom or a group selected from:
  • Ci-C 3 -alkyl and C 3 -C 4 -cycloalkyl are Ci-C 3 -alkyl and C 3 -C 4 -cycloalkyl.
  • R 9 represents, independently of each other, a hydrogen atom or a
  • Ci-C 3 -alkyl group Ci-C 3 -alkyl group.
  • R 9 represents, independently of each other, a hydrogen atom or a methyl group.
  • R 10 represents a hydrogen atom or a group selected from: Ci-C 3 -alkyl, Ci -C 3 -haloalkyl, C 2 -C3-hydroxyalkyl, C3-C 4 -cycloalkyl,
  • R 10 represents a hydrogen atom or a group selected from:
  • Ci-C 3 -alkyl and C 3 -C 4 -cycloalkyl are Ci-C 3 -alkyl and C 3 -C 4 -cycloalkyl.
  • R 10 represents a hydrogen atom or a Ci-C 3 -alkyl group.
  • R 10 represents a hydrogen atom or a group selected from:
  • R 1 1 represents, independently of each other, a hydrogen atom or a halogen atom or a group selected from:
  • R 1 1 represents, independently of each other, a hydrogen atom or a halogen atom or a group selected from:
  • R 1 1 represents, independently of each other, a hydrogen atom or a halogen atom or a methyl group.
  • R 1 1 represents, independently of each other, a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group.
  • the invention covers compounds of general formula (I),
  • V, W, Y and Z independently of each other represent CH or CR 2 ,
  • R 1 represents a phenyl-(C 2 -C3-alkyl)- group
  • phenyl groups are optionally substituted with one, two or three groups selected independently from:
  • R 2 represents, independently of each other, a group selected from:
  • R 4 represents a hydrogen atom, or a group selected from:
  • R 7 and R 8 are linked to one another in such a way that they jointly form a
  • R 9 represents, independently of each other, a hydrogen atom or a
  • R 11 represents, independently of each other, a hydrogen atom or a halogen atom or a methyl group, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
  • a further aspect of the invention are compounds of formula (I) as defined herein, wherein
  • V, W, Y and Z independently of each other represent CH or CR 2 ,
  • R 1 represents a group selected from :
  • phenyl groups are optionally substituted with one, two or three groups selected independently from:
  • R 4 represents a methoxy group
  • One aspect of the invention are compounds of formula (I) as described in the examples, as characterized by their names in the title, as claimed in claim 6, and their structures as well as the subcombinations of all residues specifically disclosed in the compounds of the examples.
  • Another aspect of the present invention are the intermediates as used for their synthesis.
  • a further aspect of the invention are compounds of formula (I), which are present as their salts.
  • the salt is a pharmaceutically acceptable salt. It is to be understood that the present invention relates to any sub-combination within any embodiment or aspect of the present invention of compounds of general formula (I), supra.
  • the present invention covers compounds of general formula (I) which are disclosed in the Example section of this text, infra.
  • the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein.
  • Another embodiment of the invention are compounds according to the claims as disclosed in the Claims section wherein the definitions are limited according to the preferred or more preferred definitions as disclosed below or specifically disclosed residues of the exemplified compounds and subcombinations thereof.
  • the present invention relates to intermediate compounds which are useful in the preparation of compounds of the present invention of general formula (I), particularly in the method described herein.
  • R 1 , R 4 , R 7 and R 8 are as defined herein.
  • the present invention relates to the use of an intermediate compound of general formula (II) :
  • the present invention relates to the use of an intermediate compound of general formula (III) :
  • the present invention relates to the use of an intermediate compound of general formula (IV) :
  • the present invention relates to the use of an intermediate compound of general formula (V) :
  • the present invention relates to a method of preparing a compound of general formula (I) as defined supra, said method comprising the step of allowing an intermediate compound of general formula (II) :
  • V, W, Y and Z are as defined herein, and X 2 represents F, CI, Br, I, boronic acid or a boronic acid ester, such as for example 4,4,5,5-tetramethyl-2-phenyl-1 ,3,2- dioxaborolane (boronic acid pinacole ester),
  • R 1 , R 4 , R 7 , R 8 , V, W, Y and Z are as defined herein.
  • the present invention relates to a method of preparing a compound of general formula (I) as defined supra, said method comprising the step of allowing an intermediate compound of general formula (III) :
  • R 4 , R 7 , R 8 , V, W, Y and Z are as defined herein, to react with a compound of general formula (V) : in which R 1 is as defined herein, and X 1 represents F, CI, Br, I or a sulfonate, such as for example trifluormethylsulfonate or p-toluolsulfonate,
  • R ⁇ R 4 , R 7 , R 8 , V, W, Y and Z are as defined herein.
  • Constituents which are optionally substituted as stated herein, may be substituted, unless otherwise noted, one or more times, independently from one another at any possible position.
  • each definition is independent.
  • each definition of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , V, W, Y and/or Z occurs more than one time for any compound of formula (I) each definition of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , V, W, Y and/or Z is independent.
  • an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond.
  • a composite substituent be composed of more than one parts, e.g. (C 3 -C 8 -cycloalkyl)-(Ci -C 3 -alkyl)- or phenyl-(C 2 -C 3 -alkyl)-, it is possible for the position of a given part to be at any suitable position of said composite substituent, i.e.
  • the C 3 -C 8 - cycloalkyl part can be attached to any carbon atom of the Ci-C3-alkyl part of said (C 3 -C 8 -cycloalkyl)-(Ci -C 3 -alkyl)- group, or the phenyl part can be attached to any carbon atom of the C2-C3-alkyl part of said phenyl-(C2-C3-alkyl)- group.
  • a hyphen at the beginning or at the end of such a composite substituent indicates the point of attachment of said composite substituent to the rest of the molecule.
  • a ring comprising carbon atoms and optionally one or more heteroatoms, such as nitrogen, oxygen or sulfur atoms for example, be substituted with a substituent
  • substituent it is possible for said substituent to be bound at any suitable position of said ring, be it bound to a suitable carbon atom and/or to a suitable heteroatom.
  • halogen atom halo- or Hal-
  • fluorine chlorine, bromine or iodine atom.
  • Ci -C 8 -alkyl is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5, 6, 7 or 8 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, 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-dimethylbuty
  • said group has 1 , 2, 3, 4, 5 or 6 carbon atoms ("Ci -C 6 - alkyl”), e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso- pentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1 ,2-dimethylpropyl, neo-pentyl, 1 ,1 - dimethylpropyl, hexyl group, more particularly, said group has 1 , 2, 3, 4 or 5 carbon atoms ("Ci -C 5 -alkyl”), e.g.
  • Ci-C 6 -haloalkyl is to be understood as 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.
  • Ci-C 6 -haloalkyl group is, for example, -CF 3 , - CHF 2 , -CH 2 F, -CF2CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CF3, or -CH(CH 2 F) 2 .
  • said group has 1 , 2, 3 or 4 carbon atoms ("Ci-C 4 -haloalkyl”), more particularly 1 , 2 or 3 carbon atoms (“Ci-C3-haloalkyl”), even more particularly 1 or 2 carbon atoms ("Ci-C 2 -haloalkyl").
  • Ci -Ce-alkoxy is to be understood as meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -O-alkyl, in which the term “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.
  • said group has 1 , 2, 3 or 4 carbon atoms ("Ci-C4-alkoxy”), more particularly 1 , 2 or 3 carbon atoms ("Ci-C 3 -alkoxy").
  • Ci-C 6 -haloalkoxy is to be understood as meaning a linear or branched, saturated, monovalent Ci -Ce-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 Ci-Ce-haloalkoxy group is, for example, - OCF3, -OCHF2, -OCH2F, -OCF2CF3, or -OCH2CF3.
  • said group has 1 , 2, 3 or 4 carbon atoms ("Ci -C 4 -haloalkoxy"), more particularly 1 , 2 or 3 carbon atoms ("C1-C3- haloalkoxy").
  • Ci-Ce-hydroxyalkyI 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 hydroxy group, e.g. a hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3- hydroxypropyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 1 ,3-dihydroxypropan-2-yl, 3- hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1 -hydroxy-2-methyl-propyl group.
  • said group has 1 , 2, 3 or 4 carbon atoms ("Ci -C 4 -hydroxyalkyl"), more particularly 1 , 2 or 3 carbon atoms ("Ci -C 3 -hydroxyalkyl").
  • C3-C 8 -cycloalkyl is to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5, 6, 7 or 8 carbon atoms ("C3-C8- cycloalkyl”).
  • Said C3-C 8 -cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl ring.
  • Particularly said group has 3, 4, 5, 6 or 7 carbon atoms ("C3-C 7 -cycloalkyl”).
  • Particularly said group has 3, 4, 5 or 6 carbon atoms ("C3-C 6 -cycloalkyl”).
  • said group has 3 or 4 carbon atoms ("C3-C 4 -cycloalkyl").
  • C3-C 6 -cycloalkoxy means a saturated, monovalent, monocyclic group of formula (C3-C6-cycloalkyl)-0-, which contains 3, 4, 5 or 6 carbon atoms, in which the term "Cs-Ce-cycloalkyl” is defined supra, e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy group.
  • C3-C 8 -alkenyl means a linear or branched, monovalent hydrocarbon group, which contains one double bond, and which has 3, 4, 5, 6, 7 or 8 carbon atoms, particularly 3, 4, 5 or 6 carbon atoms ("C3-C 6 -alkenyl”), more particularly 3, 4 or 5 carbon atoms (“Cs-Cs-alkenyl”).
  • Said alkenyl group is, for example a prop-2-en-1 -yl (or “allyl”), prop-1 -en-1 -yl, but-3-enyl, but-2-enyl, but-1 -enyl, pent-4-enyl, pent-3-enyl, pent-2-enyl, pent-1 -enyl, hex-5-enyl, hex-4-enyl, hex-3-enyl, hex-2-enyl, hex-1 -enyl, prop-1 -en-2-yl (or “isopropenyl”), 2-methylprop-2-enyl, 1 -methylprop-2-enyl,
  • C3-C 8 -alkynyl means a linear or branched, monovalent hydrocarbon group which contains one triple bond, and which contains 3, 4, 5, 6, 7 or 8 carbon atoms, particularly 3, 4, 5 or 6 carbon atoms ("C3-C 6 -alkinyl").
  • Said C3-C 8 -alkynyl group is, for example, prop-1 -ynyl, prop-2-ynyl (or “propargyl"), 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,
  • heterocycloalkyl and “4- to 6-membered heterocycloalkyl” mean a monocyclic, saturated heterocycle with 4, 5, 6 or 7 or, respectively, 4, 5 or 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S, 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, a nitrogen atom.
  • Said heterocycloalkyl group can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1 ,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl,
  • 1 .2- oxazinanyl for example, or a 7-membered ring, such as azepanyl, 1 ,4-diazepanyl or 1 ,4-oxazepanyl, for example.
  • 4- or 5-membered heterocycloalkyl means a monocyclic, saturated heterocycle with 4 or 5 ring atoms in total, containing one ring nitrogen atom or one ring oxygen atom.
  • Ci-Ce as used in the present text, e.g. in the context of the definition of "Ci-Ce-alkyl”, “Ci-C 6 -haloalkyl", “Ci-C 6 -hydroxyalkyl”, “Ci -C 6 -alkoxy” or “Ci-C 6 - haloalkoxy” means a group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • C3-C 8 as used in the present text, e.g. in the context of the definition of "C3-C 8 -cycloalkyl", means a cycloalkyl group having a finite number of carbon atoms of 3 to 8, i.e. 3, 4, 5, 6, 7 or 8 carbon atoms. When a range of values is given, said range encompasses each value and sub-range within said range.
  • Ci -Cs encompasses Ci , C2, C3, C4, C5, Ce, C7, Cs, Ci -Cs, C1 -C7, C1 -C6, C1 -C5, C1 -C4,
  • C1 -C6 encompasses Ci , C2, C3, C4, C5, ⁇ , Ci -C6, C1 -C5, C1 -C4, C1 -C3, C1 -C2, C2-C6,
  • C1 -C3 encompasses Ci , C 2 , C 3 , C1 -C3, C1 -C2 and C 2 -C 3 ;
  • C2-C6 encompasses C2, C3, C4, C5, ⁇ , C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;
  • Cs-Cs encompasses C3, C4, C5, Ce, C7, Cs, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C8, C4-C7, C4-C6, C4-C5, Cs-Cs, C5-C7, C5-C6, Ce-Cs, C6-C7 and C7-C8;
  • C4-C8 encompasses C4, C5, ⁇ , C7, Cs, C4-C8, C4-C7, C4-C6, C4-C5, Cs-Cs, C5-C7, C5-C6, Ce-Cs, C6-C7 and C7-C8;
  • C4-C7 encompasses C 4 , C 5 , C 6 , C 7 , C 4 -C 7 , C 4 -C 6 , C 4 -C 5 , C5-C7, C 5 -C 6 and C 6 -C 7 ;
  • C 4 -C 6 encompasses C 4 , C 5 , Ce, C 4 -C 6 , C 4 -C 5 and C 5 -C 6 ;
  • C 3 -C 6 encompasses C 3 , C 4 , C 5 , C 6 , C 3 -C 6 , C3-C5, C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 .
  • the term "leaving group” means 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: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]- oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropy
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • optionally substituted means optional substitution with the specified groups, radicals or moieties.
  • the term "one or more”, e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning “one, two, three, four or five, particularly one, two, three or four, more particularly one, two or three, even more particularly one or two".
  • the invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I), particularly deuterium-containing compounds of general formula (I).
  • isotopic variant of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
  • Isotopic variant of the compound of general formula (I) is defined as a compound of general formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
  • unnatural proportion means a proportion of such isotope which is higher than its natural abundance.
  • the natural abundances of isotopes to be applied in this context are described in "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70(1 ), 217-235, 1998.
  • isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 6 CI, 82 Br, 123 l, 124 l, 125 l, 129 l and 131 1, respectively.
  • isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 6 CI, 82 Br, 123 l, 124 l, 125 l,
  • the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium ("deuterium-containing compounds of general formula (I)").
  • Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as 3 H or 14 C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability.
  • Positron emitting isotopes such as 18 F or 11 C may be incorporated into a compound of general formula (I).
  • These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications.
  • Deuterium-containing and 13 C- containing compounds of general formula (I) can be used in mass spectrometry analyses in the context of preclinical or clinical studies.
  • Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent.
  • a reagent for an isotopic variant of said reagent preferably for a deuterium-containing reagent.
  • deuterium from D 2 0 can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds.
  • Deuterium gas is also a useful reagent for incorporating deuterium into molecules.
  • Catalytic deuteration of olefinic bonds and acetylenic bonds is a rapid route for incorporation of deuterium.
  • Metal catalysts i.e.
  • deuterated reagents and synthetic building blocks are commercially available from companies such as for example C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.
  • deuterium-containing compound of general formula (I) is defined as a compound of general formula (I), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than the natural abundance of deuterium, which is about 0.015%.
  • the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s).
  • the selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) may alter the physicochemical properties (such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc, 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc, 2005, 127, 9641 ], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271 ]) and/or the metabolic profile of the molecule and may result in changes in the ratio of parent compound to metabolites or in the amounts of metabolites formed.
  • physicochemical properties such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc, 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc, 2005,
  • a compound of general formula (I) may have multiple potential sites of attack for metabolism.
  • deuterium-containing compounds of general formula (I) having a certain pattern of one or more deuterium-hydrogen exchange(s) can be selected.
  • the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P 4 so.
  • the present invention concerns a deuterium-containing compound of general formula (I) having 1 , 2, 3 or 4 deuterium atoms, particularly with 1 , 2 or 3 deuterium atoms.
  • a deuterium-containing compound of general formula (I) having 1 , 2, 3 or 4 deuterium atoms, particularly with 1 , 2 or 3 deuterium atoms.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possible that asymmetry 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.
  • 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 Daicel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable.
  • Enzymatic separations, with or without derivatisation are also useful.
  • the optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. R- or S- isomers, or E- or Z-isomers, in any ratio.
  • Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • the compounds of the present invention may exist as tautomers.
  • the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised.
  • the present invention includes all such possible N-oxides.
  • the present invention also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates.
  • the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds.
  • polar solvents in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds.
  • the amount of polar solvents, in particular water may exist in a stoichiometric or non-stoichiometric ratio.
  • stoichiometric solvates e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri- , tetra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • the compounds of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
  • 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, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)- benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2- naphthoic, nicotinic, pamoic, pectinic, per
  • 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.
  • the salts include water-insoluble and, particularly, water-soluble salts.
  • derivatives of the compounds of formula (I) and the salts thereof which are converted into a compound of formula (I) or a salt thereof in a biological system are covered by the invention.
  • Said biological system is e.g. a mammalian organism, particularly a human subject.
  • the bioprecursor is, for example, converted into the compound of formula (I) or a salt thereof by metabolic processes.
  • the term "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, Ci-C 6 alkoxymethyl esters, e.g. methoxymethyl, Ci -Ce alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters, C 3 -C 8 cycloalkoxy-carbonyloxy-Ci-C 6 alkyl esters, e.g. 1 - cyclohexylcarbonyloxyethyl ; 1 ,3-dioxolen-2-onylmethyl esters, e.g.
  • Ci-C 6 -alkoxycarbonyloxyethyl esters e.g. 1 - methoxycarbonyloxyethyl, and may be formed at any carboxy group in the compounds of this invention.
  • 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), dialkylcarbamoyi and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • the present invention covers all such esters.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
  • pharmacokinetic profile means one single parameter or a combination thereof including permeability, bioavailability, exposure, and pharmacodynamic parameters such as duration, or magnitude of pharmacological effect, as measured in a suitable experiment.
  • Compounds with improved pharmacokinetic profiles can, for example, be used in lower doses to achieve the same effect, may achieve a longer duration of action, or a may achieve a combination of both effects.
  • the term “combination” in the present invention is used as known to persons skilled in the art and may be present as a fixed combination, a non-fixed combination or kit-of- parts.
  • a "fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity.
  • a "fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration, such as in a formulation.
  • Another example of a "fixed combination” is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.
  • a non-fixed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit.
  • a non-fixed combination or kit-of-parts is a combination wherein the said first active ingredient and the said second active ingredient are present separately.
  • the components of the non-fixed combination or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered. Any such combination of a compound of formula (I) of the present invention with an anticancer agent as defined below is an embodiment of the invention.
  • (chemotherapeutic) anti-cancer agents includes but is not limited to
  • said compounds of the present invention have surprisingly been found to effectively inhibit Bub1 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 Bub1 kinase, 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 compounds according to the invention can be prepared according to the following schemes 1 through 6.
  • Scheme 1 Route for the preparation of compounds of general formula (I), wherein R 1 , R 4 , R 7 , R 8 , V, W, Y and Z have the meaning as given for general formula (I), supra.
  • X 1 represents F, CI, Br, I or a sulfonate, e.g. trifluormethylsulfonate or p-toluolsulfonate.
  • X 2 represents F, CI, Br, I, boronic acid or a boronic acid ester, such as for example 4,4,5,5- tetramethyl-2-phenyl-1 ,3,2-dioxaborolane (boronic acid pinacole ester).
  • any of the substituents R 1 , R 4 , R 7 , R 8 , V, W, Y or Z can be achieved before and/or after the exemplified transformations.
  • These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art.
  • These transformations include those which introduce a functionality which allows for further interconversion of substituents.
  • Appropriate protecting groups and their introduction and cleavage are well-known to the 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.
  • a suitably substituted 1 H-pyrazole-3-carboxylic acid of the general formula (1 -1 ) can be reacted with methanol or ethanol in the presence of catalytic amounts of a Broensted acid, such as, for example, hydrochloric acid or sulphuric acid, at temperatures ranging from 0 ⁇ to boiling point of the respective alcohol , preferably the reaction is carried out at 85 ⁇ , to furnish alkyl 1 H-indazole-3-carboxylat e intermediates of general formula (1 -2).
  • a Broensted acid such as, for example, hydrochloric acid or sulphuric acid
  • Intermediates of general formula (1 -5) can be converted to intermediates of general formula (1 -7) by reaction with a suitably substituted 3,3-bis- (dimethylamino)propanenitrile of the general formula (1 -6), such as, for example 3,3- bis(dimethylamino)-2-methoxypropanenitrile, in the presence of a suitable base, such as, for example piperidine, in a suitable solvent system, such as, for example, 3- methylbutan-1 -ol, in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at 100 ⁇ .
  • a suitably substituted 3,3-bis- (dimethylamino)propanenitrile of the general formula (1 -6), such as, for example 3,3- bis(dimethylamino)-2-methoxypropanenitrile in the presence of a suitable base, such as, for example piperidine, in a suitable solvent system, such as, for example, 3- methylbutan-1
  • allylpalladium chloride dimmer dichlorobis(benzonitrile)palladium (II), palladium (II) acetate, palladium (II) chloride, tetrakis(triphenylphosphine)palladium (0), tris(dibenzylideneacetone)dipalladium (0), chloro(2'-amino-1 ,1 '-biphenyl-2- yl)palladium(ll) dimer, (2'-amino-1 ,1 '-biphenyl-2-yl)methanesulfonatopalladium(ll) dimer, trans-di( ⁇ -acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(ll) [cataCXium® C], allylchloro[1 ,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene]pal
  • boronic acid or boronic acid pinacole ester of general formula (1 -8) can be reacted with a suitable boronic acid or boronic acid pinacole ester of general formula (1 -8), such as, for example (2-fluoropyridin-4-yl)boronic acid, in the presence of a suitable base, such as, for example triethylamine, a suitable activating agent such as for example N,N- dimethylpyridin-4-amine and a suitable copper salt, such as for example copper (II) acetate, in a suitable solvent system, such as, for example, trichloromethane, in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at room temperature to furnish compounds of general formula (la).
  • a suitable boronic acid or boronic acid pinacole ester of general formula (1 -8)boronic acid in the presence of a suitable base, such as, for example triethylamine, a suitable activating agent such as
  • Scheme 2 Alternative route for the preparation of compounds of general formula (I), wherein R ⁇ R 4 , R 7 , R 8 , V, W, Y and Z have the meaning as given for general formula (I),
  • X 2 represents F, CI, Br, I, boronic acid or a boronic acid ester, such as for example 4,4,5,5-tetramethyl-2-phenyl-1 ,3,2-dioxaborolane (boronic acid pinacole ester).
  • any of the substituents R 1 , R 4 , R 7 , R 8 , V, W, Y and Z can be achieved before and/or after the exemplified transformations.
  • These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art.
  • These transformations include those which introduce a functionality which allows for further interconversion of substituents.
  • Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3 rd edition, Wiley 1999). Specific examples are described in the subsequent para-graphs.
  • Compound 1 -12 is either commercially available or can be prepared according to procedures available from the public domain, as understandable to the person skilled in the art as referred to below.
  • Intermediates of general formula (1 -5) can be converted to intermediates of general formula (1 -7) by reaction with a suitably substituted 3-methoxyacrylonitrile of the general formula (1 -12), such as, for example (ethoxymethylene)malononitrile, in the presence of a suitable base, such as, for example sodium methanolate, in a suitable solvent system, such as, for example, methanol, in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at 65 ⁇ .
  • a suitably substituted 3-methoxyacrylonitrile of the general formula (1 -12) such as, for example (ethoxymethylene)malononitrile
  • a suitable base such as, for example sodium methanolate
  • a suitable solvent system such as, for example, methanol
  • allylpalladium chloride dimmer dichlorobis(benzonitrile)palladium (II), palladium (II) acetate, palladium (II) chloride, tetrakis(triphenylphosphine)palladium (0), tris(dibenzylideneacetone)dipalladium (0), chloro(2'-amino-1 ,1 '-biphenyl-2- yl)palladium(ll) dimer, (2'-amino-1 ,1 '-biphenyl-2-yl)methanesulfonatopalladium(ll) dimer, trans-di( ⁇ -acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(ll) [cataCXium® C], allylchloro[1 ,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene]pal
  • boronic acid or boronic acid pinacole ester of general formula (1 -8) can be reacted with a suitable boronic acid or boronic acid pinacole ester of general formula (1 -8), such as, for example (2-fluoropyridin-4-yl)boronic acid, in the presence of a suitable base, such as, for example triethylamine, a suitable activating agent such as for example N,N- dimethylpyridin-4-amine and a suitable copper salt, such as for example copper (II) acetate, in a suitable solvent system, such as, for example, trichloromethane, in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at room temperature to furnish compounds of general formula (I).
  • a suitable boronic acid or boronic acid pinacole ester of general formula (1 -8)boronic acid in the presence of a suitable base, such as, for example triethylamine, a suitable activating agent such as
  • Intermediates of general formula (1 -4) can be converted to intermediates of general formula (1 -13) by reaction with ammonia, in a suitable solvent system, such as, for example, methanol, at a temperature between 0 ⁇ an d boiling point of the respective solvent, preferably the reaction is carried out at 50 "C, at a pressure between 1 and 10 bar, preferably the reaction is carried in a sealed vessel.
  • a suitable solvent system such as, for example, methanol
  • Intermediates of general formula (1 -14) can be converted to intermediates of general formula (1 -5) by reaction with a suitable alcoholate, such as, for example sodium methanolate, in a suitable solvent system, such as, for example, the corresponding alcohol, e.g. methanol, at a temperature between room temperature and the boiling point of the respective solvent, preferably the reaction is carried out at room temperature, and subsequent treatment with a suitable source of ammonium, such as for example, ammonium chloride in the presence of a suitable acid, such as for example acetic acid in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at 50 ⁇ .
  • a suitable alcoholate such as, for example sodium methanolate
  • a suitable solvent system such as, for example, the corresponding alcohol, e.g. methanol
  • Scheme 4 Route for the preparation of compounds of general formula (la), wherein R 1 , R 4 , R 7 , R 8 , V, W, Y and Z have the meaning as given for general formula (I), supra, X 1 represents F, CI, Br, I or a sulfonate, e.g. trifluormethylsulfonate or p-toluolsulfonate, and X 2 represents F, CI, Br, I, boronic acid or a boronic acid ester, such as for example 4,4,5,5-tetramethyl-2-phenyl-1 ,3,2-dioxaborolane (boronic acid pinacole ester).
  • X 1 represents F, CI, Br, I or a sulfonate, e.g. trifluormethylsulfonate or p-toluolsulfonate
  • X 2 represents F, CI, Br, I, boronic acid or a boronic acid ester,
  • any of the substituents R 1 , R 4 , R 7 , R 8 , V, W, Y or Z can be achieved before and/or after the exemplified transformations.
  • These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art.
  • These transformations include those which introduce a functionality which allows for further interconversion of substituents.
  • Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3 rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.
  • a suitably substituted 1 H-pyrazole-3-carboxylic acid of the general formula (1 -1 ) can be reacted with methanol or ethanol in the presence of catalytic amounts of a Broensted acid, such as, for example, hydrochloric acid or sulphuric acid, at temperatures ranging from 0 ⁇ to boiling point of the respective alcohol , preferably the reaction is carried out at 85 ⁇ , to furnish alkyl 1 H-pyrazole-3-carboxylat e intermediates of general formula (1 -2).
  • a Broensted acid such as, for example, hydrochloric acid or sulphuric acid
  • Intermediates of general formula (1 -17) can be converted to intermediates of general formula (1 -18) by reaction with a suitably substituted 3,3-bis- (dimethylamino)propanenitrile of the general formula (1 -6), such as, for example 3,3- bis(dimethylamino)-2-methoxypropanenitrile, in the presence of a suitable base, such as, for example piperidine, in a suitable solvent system, such as, for example, 3- methylbutan-1 -ol, in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at 100 ⁇ .
  • a suitably substituted 3,3-bis- (dimethylamino)propanenitrile of the general formula (1 -6), such as, for example 3,3- bis(dimethylamino)-2-methoxypropanenitrile in the presence of a suitable base, such as, for example piperidine, in a suitable solvent system, such as, for example, 3- methylbutan-1
  • Intermediates of general formula (1 -18) can be converted to intermediates of general formula (1 -19) by reaction with a suitably Broensted acid, such as, for example methanesulfonic acid and trifluoroacetic acid, in a suitable solvent system, such as, for example, dichloromethane, in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at room temperature.
  • a suitably Broensted acid such as, for example methanesulfonic acid and trifluoroacetic acid
  • a suitable solvent system such as, for example, dichloromethane
  • Intermediates of the general formula (1 -19) can be converted to intermediates of general formula (1 -7) by reaction with a suitable alkylating agent, such as, for example a substituted benzyl halide (1 -3), in the presence of a suitable base, such as, for example sodium hydride, in a suitable solvent system, such as, for example, DMF, at a temperature between - 20 ⁇ and boiling point of th e respective solvent, preferably the reaction is carried out at 0 ⁇ .
  • a suitable alkylating agent such as, for example a substituted benzyl halide (1 -3
  • a suitable base such as, for example sodium hydride
  • a suitable solvent system such as, for example, DMF
  • allylpalladium chloride dimmer dichlorobis(benzonitrile)palladium (II), palladium (II) acetate, palladium (II) chloride, tetrakis(triphenylphosphine)palladium (0), tris(dibenzylideneacetone)dipalladium (0), chloro(2'-amino-1 ,1 '-biphenyl-2- yl)palladium(ll) dimer, (2'-amino-1 ,1 '-biphenyl-2-yl)methanesulfonatopalladium(ll) dimer, trans-di( -acetato)bis[o-(di-o-tolylphosphino)benzyl]dipallaclium(ll) [cataCXium® C], allylchloro[1 ,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene]
  • boronic acid or boronic acid pinacole ester of general formula (1 -8) can be reacted with a suitable boronic acid or boronic acid pinacole ester of general formula (1 -8), such as, for example (2-fluoropyridin-4-yl)boronic acid, in the presence of a suitable base, such as, for example triethylamine, a suitable activating agent such as for example N,N- dimethylpyridin-4-amine and a suitable copper salt, such as for example copper (II) acetate, in a suitable solvent system, such as, for example, trichloromethane, in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at room temperature to furnish compounds of general formula (I).
  • a suitable boronic acid or boronic acid pinacole ester of general formula (1 -8)boronic acid in the presence of a suitable base, such as, for example triethylamine, a suitable activating agent such as
  • Scheme 5 Route for the preparation of compounds of general formula (I), wherein R 1 , R 4 , R 7 , R 8 , V, W, Y and Z have the meaning as given for general formula (I), supra, X 1 represents F, CI, Br, I or a sulfonate, e.g. trifluormethylsulfonate or p-toluolsulfonate, and X 2 represents F, CI, Br, I, boronic acid or a boronic acid ester, such as for example 4,4,5,5-tetramethyl-2-phenyl-1 ,3,2-dioxaborolane (boronic acid pinacole ester).
  • X 1 represents F, CI, Br, I or a sulfonate, e.g. trifluormethylsulfonate or p-toluolsulfonate
  • X 2 represents F, CI, Br, I, boronic acid or a boronic acid ester,
  • any of the substituents R 1 , R 4 , R 7 , R 8 , V, W, Y or Z can be achieved before and/or after the exemplified transformations.
  • These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art.
  • These transformations include those which introduce a functionality which allows for further interconversion of substituents.
  • Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3 rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.
  • Compounds 1 -3 and 1 -8 are either commercially available or can be prepared according to procedures available from the public domain, as understandable to the person skilled in the art. Specific examples are described in the subsequent paragraphs.
  • allylpalladium chloride dimmer dichlorobis(benzonitrile)palladium (II), palladium (II) acetate, palladium (II) chloride, tetrakis(triphenylphosphine)palladium (0), tris(dibenzylideneacetone)dipalladium (0), chloro(2'-amino-1 ,1 '-biphenyl-2- yl)palladium(ll) dimer, (2'-amino-1 ,1 '-biphenyl-2-yl)methanesulfonatopalladium(ll) dimer, trans-di( ⁇ -acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(ll) [cataCXium® C], allylchloro[1 ,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene]pal
  • intermediates of general formula (1 -18) can be reacted with a suitable boronic acid or boronic acid pinacole ester of general formula (1 -8), such as, for example (2-fluoropyridin-4-yl)boronic acid, in the presence of a suitable base, such as, for example triethylamine, a suitable activating agent such as for example N,N- dimethylpyridin-4-amine and a suitable copper salt, such as for example copper (II) acetate, in a suitable solvent system, such as, for example, trichloromethane, in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at room temperature to furnish compounds of intermediates (1 -20).
  • a suitable boronic acid or boronic acid pinacole ester of general formula (1 -8 such as, for example (2-fluoropyridin-4-yl)boronic acid
  • a suitable base such as, for example triethylamine
  • intermediates of general formula (1 -18) can be reacted with a suitable six membered heterocycle of the general formula (1 -8), such as for example 4-fluoro-2- methyl-pyridine, in the presence of a suitable base, such as, for example sodium hydride, in a suitable solvent system, such as, for example DMF, in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at 90 ⁇ to furnish com pounds of intermediates (1 -20).
  • a suitable six membered heterocycle of the general formula (1 -8) such as for example 4-fluoro-2- methyl-pyridine
  • a suitable base such as, for example sodium hydride
  • a suitable solvent system such as, for example DMF
  • Intermediates of general formula (1 -20) can be converted to intermediates of general formula (1 -21 ) by reaction with a suitably Broensted acid, such as, for example methanesulfonic acid and trifluoroacetic acid, in a suitable solvent system, such as, for example, dichloromethane, in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at room temperature.
  • a suitably Broensted acid such as, for example methanesulfonic acid and trifluoroacetic acid
  • a suitable solvent system such as, for example, dichloromethane
  • Scheme 6 Process for the preparation of compounds of general formula (la) from compounds of general formula (1 -22), which are compounds of general formula (I), whwerein R 4 is OCH 3 , via de-methylation of compounds of general formula (1 -22) to furnish compounds of general formula 1 -23 and subsequent etherification and deprotection to furnish compounds of general formula (la), wherein R 1 , R 7 , R 8 , V, W, Y and Z have the meaning as given for general formula (I), supra, X 1 represents a leaving group such as for example a CI, Br or I, or an aryl sulfonate such as for example p- toluene sulfonate, or a alkyl sulfonate such as for example methane sulfonate or trifluoromethane sulfonate (triflate group), and PG represents an alcohol protecting group as for example ferf-butyldimethylsilyl, ferf-butyldiphenylsily
  • interconversion of any of the substituents R ⁇ R 7 , R 8 , V, W, Y or Z can be achieved before and/or after the exemplified transformations.
  • modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art.
  • transformations include those which introduce a functionality which allows for further interconversion of substituents.
  • Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3 rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.
  • X represents leaving group such as for example a CI, Br or I
  • X stands for an aryl sulfonate such as for example p-toluene sulfonate, or for an alkyl sulfonate such as for example methane sulfonate or trifluoromethane sulfonate (triflate group) or can be prepared according to procedures available from the public domain, as understandable to the person skilled in the art. Specific examples are described in the subsequent paragraphs.
  • Compounds of general formula (1 -22) are converted to compounds of general formula (1 -23) by treatment with a suitable demethylating agent, such as for example benzenethiol, in a suitable solvent, such as, for example, 1 -methylpyrrolidin-2-one, in the presence of a suitable base, such as, for example potassium carbonate, in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at 190 ⁇ .
  • a suitable demethylating agent such as for example benzenethiol
  • a suitable solvent such as, for example, 1 -methylpyrrolidin-2-one
  • a suitable base such as, for example potassium carbonate
  • NMR nuclear magnetic resonance spectroscopy chemical shifts ( ⁇ ) are given in ppm. The chemical shifts were corrected by setting the DMSO signal to 2.50 ppm using unless otherwise stated.
  • PoraPakTM a HPLC column obtainable from Waters
  • NMR peak forms in the following specific experimental descriptions are stated as they appear in the spectra, possible higher order effects have not been considered.
  • the 1 H-NMR data of selected examples are listed in the form of 1 H-NMR peaklists.
  • the ⁇ value in ppm is given, followed by the signal intensity, reported in round brackets.
  • the ⁇ value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: ⁇ (intensityi), ⁇ 2 (intensity2), ... , ⁇ , (intensity,), ... , ⁇ ⁇ (intensity n ).
  • a 1 H-NMR peaklist is similar to a classical 1 H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical 1 H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of target compounds (also the subject of the invention), and/or peaks of impurities.
  • the peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compounds (e.g., with a purity of >90%).
  • Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify the reproduction of our manufacturing process on the basis of "by-product fingerprints".
  • An expert who calculates the peaks of the target compounds by known methods can isolate the peaks of target compounds as required, optionally using additional intensity filters. Such an operation would be similar to peak- picking in classical 1 H-NMR interpretation.
  • Reactions employing microwave irradiation may be run with a Biotage Initator® microwave oven optionally equipped with a robotic unit.
  • the reported reaction times employing microwave heating are intended to be understood as fixed reaction times after reaching the indicated reaction temperature.
  • 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 compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g.
  • the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as 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 ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example.
  • a salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g.
  • A1 water + 0.1 % vol. formic acid (99%)
  • A1 water + 0.1 % vol. formic acid (99%)
  • A1 water + 0.1 % vol. formic acid (99%)
  • SM (cyclopropylme 2H), 0.45 - 0.55 (m, 2H), commerci thyl)-4-methyl- 1.14 - 1.25 (m, 1 H), 1 .29 (t, al 1 H-pyrazole-3- 3H), 2.15 (s, 3H), 4.08 (d, available carboxylate 2H), 4.26 (q, 2H).
  • SM carboximidami 4.233 (16.00), 7.300 (2.32), commerci HCI de, salt with 7.315 (2.00), 7.399 (3.1 1 ), al hydrochloric 7.423 (3.96), 7.450 (3.65),

Abstract

La présente invention concerne des composés de formule (I) et leur utilisation en tant que produits pharmaceutiques.
PCT/EP2017/056075 2016-03-18 2017-03-15 1-alkyl-pyrazoles et 1-alkyl-indazoles utilisés en tant qu'inhibiteurs de bub1 pour le traitement de maladies hyperprolifératives WO2017157991A1 (fr)

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US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
WO2019096922A1 (fr) 2017-11-17 2019-05-23 Bayer Aktiengesellschaft Dérivés d'indole macrocycliques substitués
US10350206B2 (en) 2014-09-19 2019-07-16 Bayer Pharma Aktiengesellschaft Benzyl substituted indazoles as BUB1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10266548B2 (en) 2011-10-06 2019-04-23 Bayer Intellectual Property Gmbh Substituted benzylindazoles for use as Bub1 kinase inhibitors in the treatment of hyperproliferative diseases
US10604532B2 (en) 2011-10-06 2020-03-31 Bayer Intellectual Property Gmbh Substituted benzylindazoles for use as BUB1 kinase inhibitors in the treatment of hyperproliferative diseases
US10350206B2 (en) 2014-09-19 2019-07-16 Bayer Pharma Aktiengesellschaft Benzyl substituted indazoles as BUB1 inhibitors
US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US10385130B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US11535670B2 (en) 2016-05-11 2022-12-27 Huyabio International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US11242335B2 (en) 2017-04-11 2022-02-08 Sunshine Lake Pharma Co., Ltd. Fluorine-substituted indazole compounds and uses thereof
WO2019096922A1 (fr) 2017-11-17 2019-05-23 Bayer Aktiengesellschaft Dérivés d'indole macrocycliques substitués
WO2022231242A1 (fr) * 2021-04-26 2022-11-03 주식회사 스탠다임 Composé indazole ayant une activité inhibitrice de lrrk2
KR20230118694A (ko) * 2021-04-26 2023-08-11 주식회사 스탠다임 Lrrk2 억제 활성을 갖는 인다졸 화합물
KR102588242B1 (ko) * 2021-04-26 2023-10-12 주식회사 스탠다임 Lrrk2 억제 활성을 갖는 인다졸 화합물

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