WO2018078005A1 - Amido-substituted azaspiro derivatives as tankyrase inhibitors - Google Patents

Amido-substituted azaspiro derivatives as tankyrase inhibitors Download PDF

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WO2018078005A1
WO2018078005A1 PCT/EP2017/077420 EP2017077420W WO2018078005A1 WO 2018078005 A1 WO2018078005 A1 WO 2018078005A1 EP 2017077420 W EP2017077420 W EP 2017077420W WO 2018078005 A1 WO2018078005 A1 WO 2018078005A1
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Prior art keywords
ring
alkyl
oxo
azaspiro
trans
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PCT/EP2017/077420
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French (fr)
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Philipp BUCHGRABER
Knut Eis
Sarah WAGNER
Detlev Sülzle
Franz Von Nussbaum
Eckhard Bender
Volkhart Min-Jian Li
Ningshu Liu
Franziska SIEGEL
Philipp Lienau
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Bayer Pharma Aktiengesellschaft
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Publication of WO2018078005A1 publication Critical patent/WO2018078005A1/en

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    • C07D403/02—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 two hetero rings
    • C07D403/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Definitions

  • the present invention relates to amido-substituted cyclohexane compounds of general formula (I) as described and defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms, as a sole agent or in combination with other active ingredients.
  • cancer stem cells represent the apex in the hierarchical model of tumor genesis, heterogeneity and metastasis.
  • CSCs possess the capacity for unlimited self-renewal, the ability to give rise to progeny cells, and also an innate resistance to cytotoxic therapeutics [Meacham CE and Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature 2013, 501:328]. Thus, there is need to develop drugs for cancer therapy addressing distinct features of established tumors.
  • Wnt signaling cascades have classified into two categories: canonical and non-canonical, differentiated by their dependence on ⁇ -catenin.
  • Non-canonical Wnt pathways such as the planar cell polarity (PCP) and Ca 2+ pathway, function through ⁇ -catenin independent mechanisms.
  • Canonical Wnt signalling is initiated when a Wnt ligand engages co-receptors of the Frizzled (Fzd) and low- density lipoprotein receptor related protein (LRP) families, ultimately leading to ⁇ -catenin stabilization, nuclear translocation and activation of target genes [Angers S, Moon RT. Proximal events in Wnt signal transduction. Nat Rev Mol Cell Biol. 2009, 10: 468.
  • ⁇ -catenin In the absence of Wnt stimulus, ⁇ -catenin is held in an inactive state by a multimeric "destruction" complex comprised of adenomatous polyposis coli (APC), Axin, glycogen synthase kinase 3 ⁇ (GSK33) and casein kinase 1 a (CK1 a).
  • APC and Axin function as a scaffold, permitting GSK33- and CK1 a-mediated phosphorylation of critical residues within ⁇ - catenin.
  • TCF/LEF T-cell factor/lymphoid enhancer factor
  • Tankyrases play a key role in the destruction complex by regulating the stability of the rate- limiting AXIN proteins, RNF146 and tankyrase itself.
  • the E3 ubiquitin ligase RNF146 recognizes tankyrase-mediated PARsylation and eartags AXIN, tankyrase and itself for proteasome-mediated degradation.
  • tankyrases control the protein stability and turnover of key components of the destruction complex, and consequently the cellular levels of ⁇ - catenin [Huang SMA, Mishina YM, Liu S, Cheung A, Stegmeier F, et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.
  • RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling. Nature Cell Biology 2011, 13:623, 2011].
  • Wnt/3-catenin signaling pathway Aberrant regulation of the Wnt/3-catenin signaling pathway is a common feature across a broad spectrum of human cancers and evolves as a central mechanism in cancer biology.
  • Wnt overexpression could lead to malignant transformation of mouse mammary tissue [Klaus A, BirchmeierW. Wnt signalling and its impact on development and cancer. Nat Rev Cancer 2008, 8: 387 ⁇ .
  • Second, tumor genome sequencing discovered the mutations in Wnt/ ⁇ - catenin pathway components as well as epigenetic mechanisms that altered the expression of genes relevant to Wnt/3-catenin pathway [Ying Y. et al. Epigenetic disruption of the WNT/beta- catenin signaling pathway in human cancers. Epigenetics 2009, 4:307 ⁇ .
  • Wnt/3-catenin pathway also cooperates with other oncogenic signaling pathways in cancer and regulates tumorigenesis, growth, and metastasis [Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer 8: 387-398, 2008].
  • WNT signaling between tumor and stromal cell interaction leading to tumorigenesis and metastasis [Shahi P, Park D, Pond AC, Seethammagari M, Chiou S-H, Cho K et al. Activation of Wnt signaling by chemically induced dimerization of LRP5 disrupts cellular homeostasis.
  • PLoS ONE 2012, 7: e30814
  • stem-like colon cells with a high level of ⁇ - catenin signaling have a much greater tumorigenic potential than counterpart cells with low ⁇ - catenin signaling
  • ⁇ - catenin signaling Vermeulen L, De Sousa EMF, van der Heijden M, Cameron K, de Jong JH, Borovski T, Tuynman JB, Todaro M, Merz C, Rodermond H, Sprick MR, Kemper K, Richel DJ, Stassi G, Medema JP.
  • Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol. 2010, 12: 468
  • activation of Wnt/3-catenin signalling pathway is also one of the major mechanism causing tumor recurrence and drug resistance. All these provide clear rationale to develop therapeutics targeting Wnt/3-catenin signaling pathway for the treatment of cancer.
  • Inhibition of TNKS blocks PARsylation of AXIN1 and AXIN2 and prevents their proteasomal degradation.
  • TNKS inhibition enhances the activity of the ⁇ -catenin destruction complex and suppresses ⁇ -catenin nuclear transclocation and the expression of ⁇ -catenin target genes.
  • tankyrases are also implicated in other cellular functions, including telomere homeostasis, mitotic spindle formation, vesicle transport linked to glucose metabolism, and viral replication. In these processes, tankyrases interact with target proteins, catalyze poly (ADP-ribosyl)ation, and regulate protein interactions and stability.
  • TNKS1 controls telomere homeostasis, which promotes telomeric extension by PARsylating TRF1 .
  • TRF1 is then targeted for proteasomal degradation by the E3 ubiquitin ligases F-box only protein 4 and/or RING finger LIM domain-binding protein (RLIM/RNF12), which facilitates telomere maintenance [Donigian JR and de Lange T. The role of the poly(ADP-ribose) polymerase tankyrasel in telomere length control by the TRF1 component of the shelterin complex. J Biol Chem 2007, 282:22662]. In addition, telomeric end-capping also requires canonical DNA repair proteins such as DNA-dependent protein kinase (DNAPK).
  • DNAPK DNA-dependent protein kinase
  • TNKS1 stabilizes the catalytic subunit of DNAPK (DNAPKcs) by PARsylation [Dregalla RC, Zhou J, Idate RR, Battaglia CL, Liber HL, Bailey SM. Regulatory roles of tankyrase 1 at telomeres and in DNA repair: suppression of T-SCE and stabilization of DNA-PKcs. Aging 2010, 2(10):691]. Altered expression of TNKS1 and/or TNKS2, as well as genetic alterations in the tankyrase locus, have been detected in multiple tumors, e.g.
  • tankyrases appear to have impact on viral infections.
  • TNKS1 knockout mice appeared to have reduced fat pads, suggesting a potential connection of TNKS and obesity. TNKS may also play a role in tissue fibrosis.
  • tankyrases are promising drug targets in regulating WNT signaling, telomere length (e.g. telomere shortening and DNA damage induced cell death), lung fibrogenesis, myelination and viral infection.
  • the invention presented here describes a novel class of tankyrase inhibitors and their potential clinical utility for the treatment of various diseases, such as cancer, aging, metabolic diseases (e.g. diabetes and obesity), fibrosis (e.g. lung fibrogenesis) and viral infection.
  • WO2016/177658 discloses amido-substituted cyclohexane derivatives which inhibit TNKS 1 and/or TNKS 2 and that may be useful for the treatment of disorders mediated by TNKS1 and/or TNKS2.
  • said compounds of the present invention have surprising and advantageous properties.
  • said compounds of the present invention have surprisingly been found to effectively inhibit TNKS1 and/or TNKS2 and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses mediated by TNKS1 and/or TNKS2 and/or mediated by the Wnt pathway, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g.
  • leukaemias and myelodysplastic syndrome malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
  • Compounds of the present invention may additionally show improved selectivity for TNKS1 and/or TNKS2 (e.g.
  • PARP poly(ADP-ribose)-polymerase
  • A represents a ring group selected from:
  • ring A1 represents a phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms; said phenyl and 6-membered heteroaryl ring being optionally substituted one, two or three times, independently from each other, with R 5 , whereby two substituents R 5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, and c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR 20 , O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, wherein said rings are fused with ring A1 , said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings
  • a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR 20 , O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
  • R 4 represents a hydrogen atom
  • R 6 represents hydrogen, halogen, hydroxy, Ci-C 3 -alkyl or Ci -C 3 -alkoxy;
  • R 7 represents hydrogen
  • R 6 , R 7 represent, independently of each other, halogen
  • R 8 represents hydrogen, or Ci -C 3 -alkyl
  • R 9 and R 10 together represent a group selected from:
  • R 11 represents a group selected from : aryl, and heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one, two, three or four groups, which are independently of each other selected from :
  • Ci -Ce-alkyl C3-C 6 -cycloalkyl, C 2 -C 6 -hydroxyalkyl-, and
  • (Ci -C3-alkoxy)-(C 2 -C 6 -alkyl)-, and R 1 5 are independently of each other selected from : hydrogen, Ci -C 6 -alkyl, C3-C 6 -cycloalkyl, (C3-C 6 -cycloalkyl)-(Ci -C 6 -alkyl)-, C 2 -C 6 - hydroxyalkyl, (Ci -C 3 -alkoxy)-(C 2 -C 6 -alkyl)-, Ci -C 6 -haloalkyl, H 2 N-(C 2 -C 6 -alkyl)-, (C1 -C3- alkyl)N(H)(C 2 -C 6 -alkyl)-, (Ci -C3-alkyl) 2 N(C 2 -C 6 -alkyl)-, -C 6 -alkyl)-, and -C 6 -alkyl
  • R 16 represents, independently of each other, hydrogen, or Ci -C 3 -alkyl
  • R 17 represents hydrogen, Ci -Ce-alkyl, Ci -Ce-hydroxyalkyl, CVCe-cycloalkyl, Ci -C 6 -haloalkyl, (Ci -C3-alkoxy)-(Ci -C 6 -alkyl)-, aryl, or heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently of each other selected from :
  • R 22 represents Ci -C4-alkyl, or C 3 -C4-cycloalkyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, with the proviso that:
  • ring A2 is a imidazolyl or a 1 ,3-oxazolyl group
  • said group is connected to the rest of the molecule via the carbon atom at position 2 of the imidazolyl or 1 ,3-oxazolyl ring, as shown below: wherein * indicates the point of attachment of said group with the rest of the molecule;
  • - ring A2 is not a unsubstituted or substituted group, wherein * indicates the point of attachment of said group with the rest of the molecule, and in which : ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C3-alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms,
  • ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms.
  • Constituents which are optionally substituted as stated herein may be substi-tuted, unless otherwise noted, one or more times, independently from one another at any possible position. When any variable occurs more than one time in any constituent, each definition is independent.
  • each definition is independent.
  • R 5 , R 5 , R 5a , R 5b , R 13 , R 14 , R 15 , R 16 , R 17 , R 20 , R 21 , and/or R 22 occur more than one time in any compound of formula (I) each definition of R 5 , R 5' , R 5a , R 5b , R 13 , R 14 , R 15 , R 16 , R 17 , R 20 , R 21 , and R 22 is independent.
  • a hyphen at the beginning or at the end of the constituent marks the point of attachment to the rest of the molecule. Should a ring be substituted the substitutent could be at any suitable position of the ring, also on a ring nitrogen atom if suitable.
  • halogen fluorine, chlorine, bromine or iodine atom.
  • Ci -Ce-alkyl is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5, or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1 ,2-dimethylpropyl, neo-pentyl, 1 ,1 -dimethylpropyl, 4- methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 -methylpentyl, 2-ethylbutyl, 1 -ethylbutyl, 3,3- dimethylbutyl, 2,2-dimethylbutyl, 1 ,1 -
  • said group has 1 , 2, 3 or 4 carbon atoms ("Ci -C 4 -alkyl”), e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert- butyl group, more particularly 1 , 2 or 3 carbon atoms ("Ci -C3-alkyl”), e.g. a methyl, ethyl, n- propyl- or iso-propyl group, more particularly 1 or 2 carbon atoms ("Ci -C 2 -alkyl”), e.g. a methyl, ethyl group, even more particularly 1 carbon atom ("Ci-alkyl”), a methyl group.
  • Ci -C 4 -alkyl e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-but
  • Ci -Ce-hydroxyalkyl 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 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.
  • Ci-C 6 -haloalkyl is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C 6 -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 -Ce-haloalkyl group is, for example, -CF 3 , -CHF 2 , -CH 2 F, -CF 2 CF 3 , -CH 2 CH 2 F, -CH 2 CHF 2 , - CH 2 CF 3 , or -CH 2 CH 2 CF 3 .
  • Ci-C4-alkoxy is to be understood as meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -O-alkyl having 1 , 2, 3, or 46 carbon atoms, in which the term “alkyl” is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy, n- butoxy, iso-butoxy, or tert-butoxy, or an isomer thereof.
  • Ci -C 4 -haloalkoxy is to be understood as meaning a linear or branched, saturated, monovalent Ci -C 4 -alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom. Particularly, said halogen atom is F.
  • Said Ci-C 4 -haloalkoxy group is, for example, -OCF 3 , -OCHF 2 , -OCH 2 F, -OCF 2 CF 3 , or - OCH 2 CF 3 .
  • C 3 -C 6 -cycloalkyl is to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms ("C 3 -C 6 -cycloalkyl").
  • Said C 3 -C 6 -cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.
  • C 3 -C6-cycloalkoxy is to be understood as meaning a saturated, monovalent, hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms of formula -O-cycloalkyl, in which the term “cycloalkyi” is defined supra, e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy.
  • said heterocycloalkyi can be a 4-membered ring, such as an azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or N-methylpiperazinyl.
  • said heterocycloalkyi can be benzo fused.
  • 4- to 6-membered heterocycloalkyi can be selected from piperazinyl, tetrahydro-2H- pyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, 2-oxoimidazolidinyl, 2-oxopyrrolidinyl and 1 ,1 -dioxidothiomorpholinyl.
  • 4- to 6-membered heterocycloalkyi can be selected from piperazin-1 -yl, tetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, pyrrolidin-1 -yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-4-yl, piperidin-1 -yl, piperidin-2-yl, piperidin-3-yl, morpholin-4-yl, azetidin-1 -yl, tetrahydrofuran-2-yl, 2-oxoimidazolidin-1 -yl, 2-oxopyrrolidin-1 -yl and 1 ,1 -dioxidothiomorpholin-4-yl.
  • B 1 represents CH 2 , -CH 2 CH 2 -, NH, -CH 2 -NH-, N(Ci-C 3 -alkyl), -CH 2 -N(Ci -C 3 -alkyl), N(Ci-C 3 - haloalkyl), -CH 2 -N(Ci -C 3 -haloalkyl)-, O, -CH 2 -0-, S, -CH 2 -S-, S(O), -CH 2 -S(0)-, S(0) 2 , or -CH 2 - S(0) 2 -.
  • the present invention includes all R 14 , R 15 groups described supra.
  • aryl is to be understood as meaning a monovalent, aromatic or partially aromatic, mono- or bicyclic hydrocarbon ring having 6, 7, 8, 9 or 10 carbon atoms (a "C 6 -Cio-aryl” group), particularly a ring having 6 carbon atoms (a "C 6 -aryl” group), e.g. a phenyl group; or a ring having 9 carbon atoms (a "C 9 -aryl” group), e.g. an indanyl or indenyl group, or a ring having 10 carbon atoms (a "Cio-aryl” group), e.g. a tetralinyl, dihydronaphthyl, or naphthyl group.
  • heteroaryl is understood as meaning a monovalent, monocyclic aromatic ring system having 5 or 6 ring atoms (a “5- to 6-membered heteroaryl” group), which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen, NH or sulfur.
  • heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl etc., or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.
  • heteroaryl can be selected from pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, thienyl, and furanyl.
  • heteroaryl can be selected from oxazolyl, imidazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl and thiazolyl.
  • the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof.
  • the term pyridinyl or pyridinylene includes pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-yl and pyridin-4-ylene; or the term thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene.
  • heteroarylic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof.
  • pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.
  • aromatic and non-aromatic (hetero)cyclic groups may optionally be substituted as defined herein.
  • the substituents may be present both when said aromatic and non-aromatic (hetero)cyclic groups exist as a (unitary) constituent, such as, for example, Cs-Ce-cycloalkyl, 4- to 6-membered heterocycloalkyl, aryl and heteroaryl groups, or as part of a constituent composed of more than one part, such as, for example, (C 3 -C 6 - cycloalkyl)-Ci -C 6 -alkyl-, (4- to 6-membered heterocycloalkyl)-(C 2 -C 6 -alkyl)-, aryl-(Ci-C 6 -alkyl)-, and heteroaryl-(Ci-C 6 -alkyl)-, for example.
  • the present invention includes all suitably substituted aromatic and non-aromatic (hetero)cyclic groups
  • ring A is a mono or bicyclic ring as defined herein, in which ring A is connected to the rest of the compound of formula (I) via a carbon atom the ring.
  • ring A represents a bicyclic aromatic ring. Unless defined otherwise, the total count of nitrogen atoms on each member of the bicyclic system includes any nitrogen atoms which are shared by both rings.
  • the total count of nitrogen atoms on each member of the bicyclic ring system includes any nitrogen atoms which are shared by both rings.
  • ring A contains at least one NH heteroatom. It is understood that in such embodiments, if suitable, a substituent R 5 or R 5 may replace the hydrogen atom in said NH group, including to form a ring with an adjacent R 5 or R 5 substitutent, as defined herein.
  • ring A represents: - a 5-membered heteroaryl ring which contains one NH, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
  • a substituent R 5 may replace the hydrogen atom in the NH group, including to form a ring with an adjacent R 5 substitutent, as defined herein.
  • groups according to the present invention can be as represented below:
  • groups according to the present invention can be as represented below:
  • groups according to the present invention can be as represented below:
  • groups according to the present invention can be as represented below:
  • R 5 is as defined herein.
  • groups according to the present invention can be as represented below:
  • groups according to the present invention can be as represented below:
  • ring D1 being optionally substituted independently with one or two R 5 groups, and
  • groups according to the present invention can be as represented below:
  • the present invention includes all ring A groups described supra, including, but not limited to the ones depicted supra.
  • C2-C6 as used throughout this text, e.g. in the context of the definitions of "C2-C 6 -alkyl", and “C2-C 6 -hydroxyalkyl” is to be understood as meaning an alkyl group or a hydroxyalkyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C 2 -C 6 " is to be interpreted as any sub-range comprised therein, e.g. C 2 -C 6 , C3-C5 , C3-C4 , C2-C3 , C 2 -C 4 , C2-C5 ; particularly
  • C3-C 6 as used throughout this text, e.g. in the context of the definition of "Cs-Ce-cycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C3-C 6 " is to be interpreted as any sub-range comprised therein, e.g. C 3 - C 6 , C4-C5 , C3-C5 , C3-C4 , C 4 -C 6 , Cs-Ce ; particularly C 3 -C 6 .
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • Ring system substituent means a substituent attached to an aromatic or nonaromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • the term "one or more”, e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning “one, two, three, four or five, particularly one, two, three or four, more particularly one, two or three, even more particularly one or two".
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature.
  • isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 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, 36 CI, 82 Br, 123 l, 124 l, 125 l, 129 l and 131 1, respectively.
  • isotopic variations of a compound of the invention are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence is preferred in some circumstances.
  • isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds of this invention optionally contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms is present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric centre, and diastereomeric mixtures in the case of multiple asymmetric centres.
  • asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • the compounds of the present invention optionally contain sulphur atoms which are asymmetric, such as an asymmetric sulfoxide, of structure: , for example, in which * indicates atoms to which the rest of the molecule can be bound.
  • 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, E- or Z-isomers, or cis or trans, 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 the methods provided herein or by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 are as defined herein for the compound of formula (I) and n is 1 or 2.
  • the present invention includes all cis and trans isomers of the compounds of the present invention as single isomers, or as any mixture of said isomers, in any ratio.
  • the compounds of the present invention may exist as tautomers.
  • any compound of the present invention which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1 H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, namely :
  • the present invention 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
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1 ,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl- aminomethane, aminopropandiol, sovak-base, 1 -amino-2,3,4-butantriol.
  • basic nitrogen containing groups may be quaternised with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides ; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate ; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate
  • diamyl sulfates long chain halides such as decyl, la
  • acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • in vivo hydrolysable ester is understood as meaning an in vivo hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, Ci-C 6 alkoxymethyl esters, e.g. methoxymethyl, Ci-C 6 alkanoyloxymethyl esters, e.g.
  • An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • [alpha]-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N- alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • the present invention covers all such esters.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
  • the present invention covers compounds of general formula (I), supra, in which :
  • A represents a group selected from :
  • ring A2 represents:
  • a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR 20 , O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
  • R 4 represents a hydrogen atom
  • R 6 represents hydrogen
  • R 7 represents hydrogen
  • R 8 represents hydrogen
  • R 9 and R 10 together represent a group selected from:
  • Ci-C 3 -alkyl wherein * indicates the point of attachment of said group to the rest of the molecule at
  • R 9 , and # indicates the point of attachment of said group to the rest of the molecule at R 10 ; represents a group selected from : phenyl, and heteroaryl , wherein phenyl and heteroaryl groups are optionally substituted with one, two, three or four groups, which are independently of each other selected from :
  • Ci-C4-alkyl Ci-C2-alkoxy, Ci-C3-hydroxyalkyl, C3-C4-cycloalkyl, Ci-C2-haloalkyl, Ci-C 2 -haloalkoxy, halogen, cyano, and hydroxy, represents a group selected from :
  • R 20 represents, independently of each other, a group selected from : hydrogen, Ci-C 3 -alkyl , Ci-C 3 -haloalkyl, C 3 -C 4 -cycloalkyl, - and phenyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, with the proviso that: - when ring A2 is a imidazolyl or a 1 ,3-oxazolyl group, then said group is connected to the rest of the molecule via the carbon atom at position 2 of the imidazolyl or 1 ,3-oxazolyl ring, as shown below: wherein * indicates the point of attachment of said group with the rest of the molecule;
  • - ring A2 is not a unsubstituted or substituted group, wherein * indicates the point of attachment of said group with the rest of the molecule, wherein said point of attachment is a carbon atom and in which : ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C3-alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms, and, ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms.
  • the present invention covers compounds of general formula (I), supra, in which : A represents a group selected from :
  • phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms represents a phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms; said phenyl and 6-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R 5 , whereby two substituents R 5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, and c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR 20 , O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, wherein said rings are fused with ring A1 ,
  • ring A2 represents: - a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR 20 , O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
  • a 5-membered heterocyclic ring optionally partially unsaturated, which contains one heteroatom-containing group selected from NR 20 , in which one or two carbon atoms of the heterocyclyl ring are optionally replaced by a heteroatom-containing group selected from
  • N said 5-membered heteroaryl and 5-membered heterocyclic rings being optionally substituted one, two or three times, independently from each other, with R 5 , whereby two substituents R 5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR 20 , O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R 5 ; or whereby two substituents R 5 when they are in
  • R 4 represents a hydrogen atom
  • R 6 represents hydrogen
  • R 7 represents hydrogen; or R 8 represents hydrogen
  • R 9 and R 10 together represent a group selected from:
  • R 11 represents a group selected from phenyl, wherein phenyl groups is optionally substituted with one, two, or three groups, which are independently of each other selected from :
  • Ci-alkyl fluorine and chlorine
  • R 13 represents Ci-C 3 -alkyl
  • ring A2 is a imidazolyl or a 1 ,3-oxazolyl group
  • said group is connected to the rest of the molecule via the carbon atom at position 2 of the imidazolyl or 1 ,3-oxazolyl ring, as shown below: wherein * indicates the point of attachment of said group with the rest of the molecule;
  • ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C3-alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms,
  • ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms.
  • the present invention covers compounds of general formula (I), supra, in which ring A represents:
  • ring G1 represents a phenyl or a 6-membered heteroaryl ring which contains one or two nitrogen atoms
  • ring H1 represents phenyl or a 6-membered heteroaryl ring which contains one or two nitrogen atoms, with the proviso that when G1 or H1 is phenyl, then the other is a 6-membered heteroaryl group which contains one or two nitrogen atoms, said ring G1 and ring H1 being optionally substituted independently with one or two R 5 groups.
  • the present invention covers compounds of general formula (I), supra, in which :
  • ring A represents: wherein * indicates the point of attachment of said groups with the rest of the molecule, and in which : ring F1 represents phenyl or a 6-membered heteroaryl group which contains one or two nitrogen atoms, ring E1 represents a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR 20 , O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or said ring E1 and ring F1 being optionally substituted independently with one or two R 5 groups.
  • the present invention covers compounds of general formula (I), supra, in which :
  • ring A represents: wherein * indicates the point of attachment of said groups with the rest of the molecule, and in which : ring F1 ' represents phenyl or a 6-membered heteroaryl group which contains one or two nitrogen atoms,
  • R 5a and R 5b are linked to one another in such a way that they jointly form a ethyleneoxy, or a trimethyleneoxy group, said ring F1 ' being optionally substituted one time with a group selected from : fluorine, chlorine, bromine, hydroxy, Ci-C 4 -alkyl, C 3 -cycloalkyl, Ci-alkoxy, -NH 2 , and -
  • the present invention covers compounds of general formula (I), supra, in which :
  • ring A represents: wherein * indicates the point of attachment of said groups with the rest of the molecule, and in which : ring C1 represents a 5-membered heteroaryl ring (with a nitrogen atom in the position shown), in which one or two ring carbon atoms are optionally further replaced by a heteroatom selected from N, NR 20 , O and S, ring D1 is a 6-membered heteroaryl ring (with a nitrogen atom in the position shown) in which one ring carbon atom is optionally further replaced by a nitrogen atom, ring D1 ' is a 5-membered heteroaryl ring (with a nitrogen atom in the position shown) in which one ring carbon atom is optionally further replaced by a heteroatom selected from N, NR 20 , O and S, said rings D1 and D1 ' being optionally substituted independently with one or two R 5 groups.
  • the present invention covers compounds of general formula (I), supra, in which ring A represents a group selected from: phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl, said groups being optionally substituted independently with one or two R 5 groups.
  • the present invention covers compounds of general formula (I), supra, in which ring A represents a group selected from: imidazol-2-yl, pyrazolyl, 1 ,3-thiazolyl, and 1 ,2-oxazolyl, said groups being optionally substituted independently with one or two R 5 groups.
  • the present invention covers a compound of general formula (I), supra, which is selected from the group consisting of :
  • the invention relates to compounds of formula (I) supra, wherein: A represents: wherein * indicates the point of attachment of said group with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
  • R 4 represents a hydrogen atom
  • R 6 represents hydrogen, halogen, hydroxy, Ci -C 3 -alkyl or Ci-C 3 -alkoxy;
  • R 7 represents hydrogen
  • R 6 , R 7 represent, independently of each other, halogen
  • R 8 represents hydrogen, or Ci -C 3 -alkyl
  • R 9 and R 10 together represent a group selected from:
  • # indicates the point of attachment of said group to the rest of the molecule at R 10 ; represents a group selected from : aryl, and heteroaryl , wherein aryl and heteroaryl groups are optionally substituted with one, two, three or four groups, which are independently of each other selected from :
  • R 1 3 represents a group selected from :
  • R 1 4 and R 1 5 are independently of each other selected from : hydrogen, Ci -C 6 -alkyl, C3-C 6 -cycloalkyl, (C3-C 6 -cycloalkyl)-(Ci -C 6 -alkyl)-, C 2 -C 6 -hydroxyalkyl, (Ci -C 3 -alkoxy)-(C 2 -C 6 -alkyl)-, Ci -C 6 -haloalkyl, H 2 N-(C 2 -C 6 -alkyl)-, (Ci -C 3 -alkyl)N(H)(C 2 -C 6 -alkyl)-, (Ci -C 3 -alkyl) 2 N(C 2 -C 6 -alkyl)-,
  • R 1 6 represents, independently of each other, hydrogen, or Ci -C3-alkyl
  • R 1 7 represents hydrogen, Ci -C 6 -alkyl, Ci -C 6 -hydroxyalkyl, C3-C 6 -cycloalkyl, Ci -Ce-haloalkyl, (Ci -C3-alkoxy)-(Ci -C 6 -alkyl)-, aryl, or heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently of each other selected from :
  • R 22 represents Ci-C 4 -alkyl, or C 3 -C -cycloalkyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the invention relates to compounds of formula (I) supra, wherein: A represents:
  • a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR 20 , O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
  • R 4 represents a hydrogen atom
  • R 6 , R 7 represent, independently of each other, halogen; represents hydrogen, or Ci -C3-alkyl,
  • R 9 and R 10 together represent a group selected from: wherein said groups are optionally substituted with one or two groups, which are independently of each other selected from : halogen, Ci -C3-alkyl, Ci -C3-alkoxy, hydroxy, Ci -C3-haloalkyl, and Ci -C3-hydroxyalkyl, wherein * indicates the point of attachment of said group to the rest of the molecule at
  • R 11 represents a group selected from : aryl, and heteroaryl , wherein aryl and heteroaryl groups are optionally substituted with one, two, three or four groups, which are independently of each other selected from :
  • Ci -Ce-alkyl, C3-C 6 -cycloalkyl, C 2 -C 6 -hydroxyalkyl-, and (Ci -C3-alkoxy)-(C 2 -C 6 -alkyl)-, R 14 and R 15 are independently of each other selected from hydrogen, Ci -Ce-alkyl, CVCe-cycloalkyl, (C3-C6-cycloalkyl)-(Ci -C6-alkyl)-, C 2 -C 6 -hydroxyalkyl, (Ci -C 3 -alkoxy)-(C2-C 6 -alkyl)-, Ci -C 6 -haloalkyl, H 2 N-(C2-C 6 -alkyl)-, (Ci -C 3 -alkyl)N(H)(C2-C6-alkyl)-, (Ci -C3-alkyl) 2 N(C2-C 6 -alkyl)-,
  • R 17 represents hydrogen, Ci -C 6 -alkyl, Ci -C 6 -hydroxyalkyl, C 3 -C 6 -cycloalkyl, Ci -Ce-haloalkyl, (Ci -C 3 -alkoxy)-(Ci -C 6 -alkyl)-, aryl, or heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently of each other selected from : Ci -C 3 -alkyl, C 3 -C 6 -cycloalkyl, Ci -C 3 -alkoxy, C 3 -C 6 -cycloalkoxy,
  • Ci -C 3 -haloalkyl Ci -C 3 -haloalkoxy, halogen, cyano, and hydroxy
  • R 22 represents Ci-C 4 -alkyl, or C3-C 4 -cycloalkyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, with the proviso that: - when ring A2 is a imidazolyl or a 1 ,3-oxazolyl group, then said group is connected to the rest of the
  • - ring A2 is not a unsubstituted or substituted group, wherein * indicates the point of attachment of said group with the rest of the molecule, wherein said point of attachment is a carbon atom and in which : ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C3-alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms,
  • ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms.
  • the invention relates to compounds of formula (I) supra, wherein A represents a group: A1 wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
  • ring A1 represents a phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms; said phenyl and 6-membered heteroaryl ring being optionally substituted one, two or three times, independently from each other, with R 5 , whereby two substituents R 5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, and c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR 20 , O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, wherein said rings are fused with ring A1 , said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings
  • R 4 represents a hydrogen atom
  • R 6 represents hydrogen
  • R 7 represents hydrogen
  • R 8 represents hydrogen, R 9 and R 10 together represent a group selected from:
  • Ci-C 3 -alkyl wherein * indicates the point of attachment of said group to the rest of the molecule at
  • R 11 represents a group selected from : phenyl, and heteroaryl , wherein phenyl and heteroaryl groups are optionally substituted with one, two, three or four groups, which are independently of each other selected from :
  • Ci-C 4 -alkyl Ci-C 2 -alkoxy, Ci-C 3 -hydroxyalkyl, C 3 -C 4 -cycloalkyl, Ci-C 2 -haloalkyl, Ci-C2-haloalkoxy, halogen, cyano, and hydroxy,
  • R 13 represents a group selected from : Ci-C 3 -alkyl, and C 3 -C 4 -cycloalkyl,
  • R 14 and R 15 are independently of each other selected from hydrogen, Ci-C 3 -alkyl, and C3-C 4 -cycloalkyl, or,
  • R 20 represents, independently of each other, a group selected from : hydrogen, Ci-C 3 -alkyl, Ci-C 3 -haloalkyl, C 3 -C 4 -cycloalkyl,
  • the invention relates to compounds of formula (I) supra, wherein: A represents a group:
  • ring A2 represents: - a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR 20 , O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
  • R 4 represents a hydrogen atom
  • R 6 represents hydrogen
  • R 7 represents hydrogen
  • R 8 represents hydrogen, R 9 and R 10 together represent a group selected from:
  • Ci-C 3 -alkyl wherein * indicates the point of attachment of said group to the rest of the molecule at
  • R 11 represents a group selected from : phenyl, and heteroaryl , wherein phenyl and heteroaryl groups are optionally substituted with one, two, three or four groups, which are independently of each other selected from :
  • Ci-C 4 -alkyl Ci-C 2 -alkoxy, Ci-C 3 -hydroxyalkyl, C 3 -C 4 -cycloalkyl, Ci-C 2 -haloalkyl, Ci-C2-haloalkoxy, halogen, cyano, and hydroxy,
  • R 13 represents a group selected from : Ci-C 3 -alkyl, and C 3 -C 4 -cycloalkyl,
  • R 14 and R 15 are independently of each other selected from hydrogen, Ci-C 3 -alkyl, and C3-C 4 -cycloalkyl, or,
  • R 20 represents, independently of each other, a group selected from : hydrogen, Ci-C 3 -alkyl, Ci-C 3 -haloalkyl, C 3 -C 4 -cycloalkyl,
  • ring A2 is a imidazolyl or a 1 ,3-oxazolyl group
  • said group is connected to the rest of the molecule via the carbon atom at position 2 of the imidazolyl or 1 ,3-oxazolyl ring, as shown below: wherein * indicates the point of attachment of said group with the rest of the molecule;
  • - ring A2 is not a unsubstituted or substituted group, wherein * indicates the point of attachment of said group with the rest of the molecule, wherein said point of attachment is a carbon atom and in which : ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C3-alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms,
  • ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms.
  • the invention relates to compounds of formula (I) supra, wherein: A represents a group: wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
  • ring A1 represents a phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms; said phenyl and 6-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R 5 , whereby two substituents R 5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, and c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR 20 , O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, wherein said rings are fused with ring A1 , said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being
  • R 4 represents a hydrogen atom
  • R 6 represents hydrogen
  • R 7 represents hydrogen
  • R 8 represents hydrogen, R 9 and R 10 together represent a group selected from:
  • R 9 , and # indicates the point of attachment of said group to the rest of the molecule at R 10 ; represents a group selected from : phenyl, wherein phenyl groups is optionally substituted with one, two, or three groups, which are independently of each other selected from :
  • Ci-alkyl fluorine and chlorine
  • R 13 represents Ci-C3-alkyl
  • the invention relates to compounds of formula (I) supra, wherein: A represents a group:
  • ring A2 represents:
  • a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR 20 , O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
  • R 4 represents a hydrogen atom
  • R 5 represents, independently of each other, a group selected from : fluorine, chlorine, bromine, Ci-alkyl, C 3 -cycloalkyl, and a 6-membered heteroaryl which contains one nitrogen atom,
  • R 6 represents hydrogen
  • R 7 represents hydrogen
  • R 8 represents hydrogen
  • R 9 and R 10 together represent a group selected from :
  • R 9 , and # indicates the point of attachment of said group to the rest of the molecule at R 10 ;
  • R 11 represents a group selected from : phenyl, wherein phenyl groups is optionally substituted with one, two, or three groups, which are independently of each other selected from :
  • Ci-alkyl fluorine and chlorine
  • R 13 represents Ci-C 3 -alkyl
  • - ring A2 is not a unsubstituted or substituted group, wherein * indicates the point of attachment of said group with the rest of the molecule, wherein said point of attachment is a carbon atom and in which : ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C3-alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms,
  • ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms.
  • the invention relates to compounds
  • said 5-membered heterocyclic rings being substituted two or three times, independently from each other, with R 5 , whereby two substituents R 5 are in adjacent positions of the ring A2 and linked to one another in such a way that together with the atoms to which they are attached they jointly form : a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR 20 , O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R 5 ; or whereby two substituents R 5 are in adjacent positions of the ring A2 and linked to one another in such a way that they jointly form
  • the invention relates to compounds
  • the invention relates to compounds
  • the invention relates to compounds of formula (I), supra, wherein ring A represents:
  • ring G1 represents a phenyl or a 6-membered heteroaryl ring which contains one or two nitrogen atoms
  • ring H1 represents phenyl or a 6-membered heteroaryl ring which contains one or two nitrogen atoms, with the proviso that when G1 or H1 is phenyl, then the other is a 6-membered heteroaryl group which contains one or two nitrogen atoms, said ring G1 and ring H1 being optionally substituted independently with one or two R 5 groups.
  • the invention relates to compounds of formula (I), supra, wherein ring A represents:
  • ring F1 represents phenyl or a 6-membered heteroaryl group which contains one or two nitrogen atoms
  • ring E1 represents a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR 20 , O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or said ring E1 and ring F1 being optionally substituted independently with one or two R 5 groups.
  • the invention relates to compounds of formula (I), supra, wherein ring A represents:
  • ring F1 ' represents phenyl or a 6-membered heteroaryl group which contains one or two nitrogen atoms
  • R 5a and R 5b are linked to one another in such a way that they jointly form a ethyleneoxy, or a trimethyleneoxy group, said ring F1 ' being optionally substituted one time with a group selected from : fluorine, chlorine, bromine, hydroxy, Ci-C4-alkyl, C3-cycloalkyl, Ci-alkoxy, -NH 2 , and -
  • the invention relates to compounds of formula (I), supra, wherein ring A represents:
  • ring C1 represents a 5-membered heteroaryl ring (with a nitrogen atom in the position shown), in which one or two ring carbon atoms are optionally further replaced by a heteroatom selected from N, NR 20 , O and S
  • ring D1 is a 6-membered heteroaryl ring (with a nitrogen atom in the position shown), in which one ring carbon atom is optionally further replaced by a nitrogen atom
  • ring D1 ' is a 5-membered heteroaryl ring (with a nitrogen atom in the position shown), in which one ring carbon atom is optionally further replaced by a heteroatom selected from N, NR 20 , O and S
  • said rings D1 and D1 ' being optionally substituted independently with one or two R 5 groups.
  • the invention relates to compounds of formula (I), supra, wherein ring A represents: phenyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl, said groups being optionally substituted independently with one or two R 5 groups.
  • the invention relates to compounds of formula (I), supra, wherein ring A represents: phenyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.
  • the invention relates to compounds of formula (I), supra, wherein ring A represents: imidazol-2-yl, pyrazolyl, 1 ,3-thiazolyl, or 1 ,2-oxazolyl, said groups being optionally substituted independently with one or two R 5 groups.
  • the invention relates to compounds of formula (I), supra, wherein ring A represents: imidazol-2-yl, pyrazolyl, 1 ,3-thiazolyl, or 1 ,2-oxazolyl. In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), supra, wherein ring A represents:
  • X b represents CH or N
  • X a represents CH or N
  • said ring A being optionally substituted independently with one or two R 5 groups.
  • the invention relates to compounds of formula (I), supra, wherein ring A represents:
  • X c represents CH or N
  • X d represents CH or N
  • X e represents CH or N
  • X f represents CH or N, with the proviso that when one of X c , X d , X e , or X f is N the others are CH, said ring A being optionally substituted independently with one or two R 5 groups.
  • the invention relates to compounds of formula (I), wherein the compound of formula (I) has the cis configuration :
  • the invention relates to compounds of formula (I), wherein the compound of formula (I) has the cis configuration :
  • the invention relates to compounds of formula (I), wherein the compound of formula (I) has the trans configuration :
  • the invention relates to compounds of formula (I), wherein the compound of formula (I) has the trans configuration :
  • the invention relates to compounds of formula (I), wherein :
  • A represents a ring group selected from:
  • a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR 20 , O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
  • the invention relates to compounds of formula (I), wherein : ring A represents wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
  • phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms represents a phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms; said phenyl and 6-membered heteroaryl ring being optionally substituted one, two or three times, independently from each other, with R 5 , whereby two substituents R 5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, with the proviso that ring A1 is not phenyl, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, and c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR 20 , O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen
  • ring A2 represents:
  • the invention relates to compounds of formula (I), wherein :
  • A represents a ring group selected from:
  • ring A1 represents a phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms; said phenyl and 6-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R 5 , whereby two substituents R 5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, and c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR 20 , O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, wherein said rings are fused with ring A1 , said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being
  • a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR 20 , O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
  • a 5-membered heterocyclic ring optionally partially unsaturated, which contains one heteroatom-containing group selected from NR 20 , in which one or two carbon atoms of the heterocyclyl ring are optionally replaced by a heteroatom-containing group selected from
  • N said 5-membered heteroaryl and 5-membered heterocyclic rings being optionally substituted one, two or three times, independently from each other, with R 5 , whereby two substituents R 5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR 20 , O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R 5 ; or whereby two substituents R 5 when they are in
  • the invention relates to compounds of formula (I), wherein :
  • ring A1 represents a phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms; said phenyl and 6-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R 5 , whereby two substituents R 5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, and c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR 20 , O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, wherein said rings are fused with ring A1 , said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being
  • the invention relates to compounds of formula (I), wherein :
  • ring A2 represents:
  • a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR 20 , O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
  • the invention relates to compounds of formula (I), wherein :
  • ring A2 represents:
  • a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR 20 , O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or said 5-membered heteroaryl ring being optionally substituted one, two or three times, independently from each other, with R 5 , whereby two substituents R 5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR 20 , O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl
  • the invention relates to compounds of formula (I), wherein :
  • A represents wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
  • the invention relates to compounds of formula (I), wherein :
  • R 4 represents a hydrogen atom.
  • R 5 represents, independently of each other, a group
  • the invention relates to compounds of formula (I), wherein :
  • R 5 represents, independently of each other, a group selected from : fluorine, chlorine, bromine, Ci-alkyl, C3-cycloalkyl, and a 6-membered heteroaryl which contains one nitrogen atom.
  • the invention relates to compounds of formula (I), wherein :
  • R 6 represents hydrogen, halogen , hydroxy, Ci-C 3 -alkyl or Ci-C 3 -alkoxy.
  • the invention relates to compounds of formula (I), wherein :
  • R 6 represents hydrogen
  • the invention relates to compounds of formula (I), wherein :
  • R 7 represents hydrogen.
  • the invention relates to compounds of formula (I), wherein :
  • R 6 , R 7 represent, independently of each other, halogen.
  • the invention relates to compounds of formula (I), wherein :
  • R 8 represents hydrogen
  • the invention relates to compounds of formula (I), wherein :
  • R 8 represents hydrogen, or Ci-C 3 -alkyl.
  • the invention relates to compounds of formula (I), wherein : R 9 and R 10 together represent a group selected from:
  • R 9 indicates the point of attachment of said group to the rest of the molecule at R 10 .
  • the invention relates to compounds of formula (I), wherein : together represent a group selected from
  • R 9 indicates the point of attachment of said group to the rest of the molecule at R 10 .
  • the invention relates to compounds of formula (I), wherein : represents a group selected from aryl, and heteroaryl , wherein aryl and heteroaryl groups are optionally substituted with one, two, three or four groups, which are independently of each other selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 11 represents a group selected from : phenyl, and heteroaryl , wherein phenyl and heteroaryl groups are optionally substituted with one, two, three or four groups, which are independently of each other selected from :
  • Ci -C4-alkyl Ci -C2-alkoxy, Ci -C3-hydroxyalkyl, C3-C4-cycloalkyl, Ci -C2-haloalkyl, Ci -C 2 -haloalkoxy, halogen, cyano, and hydroxy.
  • the invention relates to compounds of formula (I), wherein :
  • R 11 represents a group selected from : phenyl, wherein phenyl groups is optionally substituted with one, two, or three groups, which are independently of each other selected from :
  • Ci-alkyl fluorine and chlorine, preferably fluorine and chlorine.
  • the invention relates to compounds of formula (I), wherein :
  • R 13 represents a group selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 13 represents a group selected from :
  • Ci -C 3 -alkyl, and C3-C 4 -cycloalkyl are independently selected from the group consisting of the following compounds:
  • the invention relates to compounds of formula (I), wherein : R 13 represents Ci-C 3 -alkyl.
  • the invention relates to compounds of formula (I), wherein : R 14 and R 15 are independently of each other selected from : hydrogen, Ci-C 6 -alkyl, C3-C 6 -cycloalkyl, (C3-C 6 -cycloalkyl)-(Ci-C 6 -alkyl)-, C 2 -C 6 -hydroxyalkyl, (Ci-C 3 -alkoxy)-(C2-C 6 -alkyl)-, Ci-C 6 -haloalkyl, H 2 N-(C2-C 6 -alkyl)-, (Ci-C 3 -alkyl)N(H)(C2-C6-alkyl)-, (Ci-C3-alkyl) 2 N(C2-C 6 -alkyl)-,
  • the invention relates to compounds of formula (I), wherein :
  • the invention relates to compounds of formula (I), wherein :
  • the invention relates to compounds of formula (I), wherein : R 14 and R 15 are independently of each other selected from : hydrogen, Ci-C3-alkyl, and C3-C4-cycloalkyl, or,
  • the invention relates to compounds of formula (I), wherein : R 14 and R 15 are independently of each other selected from : hydrogen, Ci-C 3 -alkyl, and C 3 -C 4 -cycloalkyl.
  • the invention relates to compounds of formula (I), wherein :
  • R 14 is hydrogen
  • R 15 is selected from : hydrogen, Ci-C 3 -alkyl, and C 3 -C 4 -cycloalkyl.
  • the invention relates to compounds of formula (I), wherein :
  • the invention relates to compounds of formula (I), wherein : R 16 represents, independently of each other, hydrogen, or Ci-C 3 -alkyl.
  • the invention relates to compounds of formula (I), wherein :
  • R 17 represents hydrogen, Ci-Ce-alkyl, Ci-Ce-hydroxyalkyl, C 3 -C6-cycloalkyl, Ci-Ce-haloalkyl, (Ci-C 3 -alkoxy)-(Ci-C 6 -alkyl)-, aryl, or heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently of each other selected from :
  • the invention relates to compounds of formula (I), wherein :
  • R 20 represents, independently of each other, a group selected from : hydrogen, Ci-C 3 -alkyl, Ci-C 3 -haloalkyl, C 3 -C 4 -cycloalkyl,
  • the invention relates to compounds of formula (I), wherein :
  • the invention relates to compounds of formula (I), wherein : represents Ci-C 4 -alkyl, or C3-C 4 -cycloalkyl.
  • the present invention relates to compounds of formula (I) as described herein, in which: when ring A2 is a imidazolyl or a 1 ,3-oxazolyl group, then said group is connected to the rest of the molecule via the carbon atom at position 2 of the imidazolyl or 1 ,3-oxazolyl ring, as shown below: wherein * indicates the point of attachment of said group with the rest of the molecule.
  • the present invention relates to compounds of formula (I) as described herein, in which:
  • - ring A2 is not a unsubstituted or substituted group, wherein * indicates the point of attachment of said group with the rest of the molecule, wherein said point of attachment is a carbon atom and in which : ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C3-alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms, ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms.
  • the present invention relates to compounds of formula (I) as described herein, in which:
  • ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C3-alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms, said ring A2' being optionally substituted with one or two R 5 groups
  • ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms, said ring A2" being optionally substituted with one, two or three R 12 groups
  • R 5 represents, independently of each other, a group selected from : halogen, hydroxy, Ci-C 4 -alkyl, C3-C 4 -cycloalkyl, Ci-C 3 -alkoxy, Ci-C 3 -haloalkoxy, - N(R 18' )R 19' , -C(0)R 13' , and - C(0)OR 13' , wherein Ci-C 4 -alkyl is optionally substituted one, two or three times with a group independently selected from halogen, hydroxy, Ci-C3-alkoxy, -NH 2 , -NH(Ci-C3-alkyl) and -N(Ci-C 3 -alkyl) 2 ;
  • R 12 represents, independently of each other, halogen, hydroxy, Ci-C 6 -alkyl, C 3 -C 6 - cycloalkyl, Ci-C 4 -alkoxy, Ci-C 4 -haloalkoxy, -N(
  • ring A2 is not:
  • X 1 represents NR 3 or O
  • R 1 represents a group selected from :
  • R 2 represents a group selected from : hydrogen, Ci-C 3 -alkyl, and C3-C 4 -cycloalkyl
  • R 3 represents a hydrogen atom
  • ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C 3 -alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms, said ring A2' being optionally substituted with one or two R 5 groups
  • ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms, said ring A2" being optionally substituted with one, two or three R 12 groups;
  • R 5 represents, independently of each other, a group selected from : halogen, hydroxy, Ci-C 4 -alkyl, C3-C 4 -cycloalkyl, Ci-C 3 -alkoxy, Ci-C 3 -haloalkoxy, -
  • Ci-C4-alkyl is optionally substituted one, two or three times with a group independently selected from halogen, hydroxy, Ci-C 3 -alkoxy, -NH 2 , -NH(Ci-C 3 -alkyl) and -N(Ci-C 3 -alkyl) 2 ;
  • R 12 represents, independently of each other, halogen, hydroxy, Ci-C 6 -alkyl, C 3 -C 6 - cycloalkyl, Ci-C 4 -alkoxy, Ci-C 4 -haloalkoxy, -N(R 18 )R 19 , -C(0)R 13 , or -C(0)OR 13 , wherein Ci-C 6 -alkyl is optionally substituted one, two or three times with a substituent independently selected from halogen, hydroxy, Ci-C 3 -alkoxy,
  • R 13 represents a group selected from :
  • R 14 and R 15 are independently of each other selected from : hydrogen, Ci-Ce-alkyl, C 3 -C6-cycloalkyl, (C 3 -C6-cycloalkyl)-(Ci-C6-alkyl)-,
  • 4- to 6-membered heterocycloalkyl groups are optionally substituted with one, two, three or four substituents, which are independently of each other selected from :
  • R 14" and R 15 together with the nitrogen atom to which they are attached form a group selected from :
  • R 16 represents, independently of each other, hydrogen, or Ci-C 3 -alkyl
  • R 18 and R 19 are, independently of each other, selected from : hydrogen, Ci-C 6 -alkyl , C3-C 6 -cycloalkyl, (C3-C 6 -cycloalkyl)-(Ci-C 6 -alkyl)-, C 2 -C 6 - hydroxyalkyl-, (Ci-C 3 -alkoxy)-(C2-C 6 -alkyl)-, Ci-C 6 -haloalkyl, H 2 N-(C2-C 6 -alkyl)-, (C1-C3- alkyl)N(H)(C 2 -C 6 -alkyl)-, (Ci-C3-alkyl) 2 N(C2-C 6 -alkyl)-,
  • 4- to 6-membered heterocycloalkyi groups are optionally substituted with one two, three or four substituents, which are independently of each other selected from :
  • Ci-C 3 -alkyl halogen, cyano
  • R 20 represents, independently of each other, a group selected from : hydrogen, Ci-C 3 -alkyl , Ci-C 3 -haloalkyl, and C 3 -C 4 -cycloalkyl.
  • the invention relates to compounds of formula (I), according to any of the above-mentioned embodiments, in the form of or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the present invention covers compounds of general formula (I) which disclosed in the Example section of this text, infra.
  • the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein.
  • Another aspect of the invention relates to the the intermediates described herein and their use for preparing a compound of formula (I) as defined supra or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
  • Chemical names were generated using ACD/Name. Stereodescriptors were manually adapted as defined above. In case there is discrepancy between the chemical name of a compound and its chemical structure, the chemical structure shall prevail. In some cases generally accepted names of commercially available reagents were used in place of ACD generated names.
  • stereoisomers such as, for example enantiomers, diastereomers, or cis/trans isomers
  • these isomers can be separated by methods described herein or by methods known to the person skilled in the art such as, but not limited to, chromatography, chiral chromatography and crystallization. All reagents used for the preparation of the compounds of the invention are either commercially available or can be prepared as described.
  • Scheme 1 Synthesis of 4-aminocyclohexanecarboxylate derivatives, wherein R 6 , R 7 , R 11 , and R 13 are as defined herein for the compound of general formula (I) and R 8 is hydrogen, and R 9 and R 10 (not shown) together represent a group selected from:
  • PG represents a protecting group, such as for instance a tert-butyl(dimethyl)silyl group
  • W represents a leaving group such as, for instance a bromide, chloride, iodide or a O-tosyl or O-mesyl group
  • V represents a halide, for instance a bromide, chloride or iodide, or an alkyloxy group, preferably a methoxy group and n is 1 or 2.
  • Cyclohexanecarboxylate derivatives of type 1-8 can be alkylated at the appropriate position by treatment with a suitable base such as, for example, lithium diisopropylamide, in an appropriate solvent such as, for example, tetrahydrofuran or diethylether, followed by addition of a suitable electrophile of type 1-13 to give compounds of type 1-14.
  • a suitable base such as, for example, lithium diisopropylamide
  • an appropriate solvent such as, for example, tetrahydrofuran or diethylether
  • compounds of type 1-17 can be obtained by reaction of compounds of type 1-14 (where V represents alkoxy group, such as for example, methoxy, and PG is preferably a hydrogen) with aromatic or heteroaromatic amines of type 1-15 in the presence of a lewis acid, such as for instance diethylaluminium chloride.
  • V represents alkoxy group, such as for example, methoxy
  • PG is preferably a hydrogen
  • a lewis acid such as for instance diethylaluminium chloride.
  • Deprotection of the protected amine of type 1-18 bearing a phthalimide group can be achieved, for example, by treatment with hydrazine hydrate or methylamine at elevated temperature (e.g. at reflux) to give amine derivatives of type 1-19 (C).
  • W represents a leaving group such as, for instance a bromide, chloride, iodide or a O-tosyl or O-mesyl group
  • V represents a halide, for instance, a chloride, bromide, or iodide, or an alkoxy group, preferably a methoxy group and n is 1 or 2.
  • Cyclohexanecarboxylate derivatives of type 1-20 can be alkylated at the appropriate position by treatment with a suitable base such as for example, lithium hexamethyldisilazide, in an appropriate solvent such as for example tetrahydrofuran or diethylether, followed by addition of a suitable electrophile 1-13 to give compounds of type 1-21.
  • a suitable base such as for example, lithium hexamethyldisilazide
  • an appropriate solvent such as for example tetrahydrofuran or diethylether
  • ketones of type 1-23 with amines, such as for example benzyl amine, under standard reaction conditions for reductive animation reactions, employing for example sodium triacetoxyborohydride as reducing agent, yields protected amine derivatives of type 1-24.
  • amines such as for example benzyl amine
  • deprotection of the protected amine of type 1-24 in case of a benzyl protecting group for example, employing a palladium on charcoal catalyst and hydrogen gas, yields amine derivatives of type 1-19 (C).
  • n 1
  • PG represents a protecting group, such as a tert-butyl(dimethyl)silyl group
  • W represents a leaving group such as, for instance a bromide, chloride, iodide or a O-tosyl or O-mesyl group
  • V represents a halide, for instance a bromide, chloride or iodide, or an alkyloxy group, preferably a methoxy group and n is 1.
  • Cyclohexanecarboxylate derivatives of type 1-8 can be alkylated at the appropriate position by treatment with a suitable base such as for example, lithium hexamethyldisilazide, in an appropriate solvent such as for example tetrahydrofuran or diethylether, followed by addition of a suitable electrophile 1-32 to give compounds of type 1-33.
  • a suitable base such as for example, lithium hexamethyldisilazide
  • an appropriate solvent such as for example tetrahydrofuran or diethylether
  • amines of type 1-33 Reduction of nitriles of type 1-33 using, for example Raney-Nickel catalyst in ammonia and ethanol under hydrogen pressure, yields amines of type 1-34, which can convert directly into lactames of type 1-35.
  • Alternative amines of type 1-34 can be cyclizied at elevated temperatures in solvents such as for instance toluene, in the absence or presence of an base, such as for example trimethylamine.
  • Lactames of type 1-35 can be converted into compounds of type 1-16 using aryl or heteroaryl halides of type 1-36 (in which W is a halide, preferably iodide) as coupling partner, applying transition metal catalyized coupling reactions such as for instance Ullmann type coupling reactions using for example copper(l) iodide and ⁇ , ⁇ '-dimethylethylenediamine, potassium carbonate as base and dioxane as solvent at elevated temperatures, for example applying microwave heating.
  • W is a halide, preferably iodide
  • transition metal catalyized coupling reactions such as for instance Ullmann type coupling reactions using for example copper(l) iodide and ⁇ , ⁇ '-dimethylethylenediamine, potassium carbonate as base and dioxane as solvent at elevated temperatures, for example applying microwave heating.
  • PG represents a protecting group, such as a tert-butyl(dimethyl)silyl group
  • W represents a leaving group such as, for instance a bromide, chloride, iodide
  • R 25 represents a hydrogen atom or a group selected from Ci-C3-alkyl, Ci-C3-haloalkyl and Ci-C3-hydroxyalkyl.
  • Cyclohexanecarboxylate derivatives of type 1-8 can be alkylated at the appropriate position by treatment with a suitable base such as, for example lithium diisopropylamide, in an appropriate solvent such as, for example tetrahydrofuran or diethylether, followed by addition of a suitable electrophile of type 1-38 to give compounds of type 1-39.
  • a suitable base such as, for example lithium diisopropylamide
  • an appropriate solvent such as, for example tetrahydrofuran or diethylether
  • a suitable electrophile of type 1-38 to give compounds of type 1-39.
  • Ozonolysis of compounds of type 1-39 yields compounds of type 1-40.
  • Compounds of type 1- 40 can be reacted with hydroxylamine in the presence of a suitable base, such as for example, trimethylamine, to give compounds of type 1-41.
  • Compounds of type 1-41 can be reduced and cyclized to compounds of type 1-42 using for instance Pd/C in methanol under an hydrogen atmosphere followed by treatment with a suitable base, such as trimethylamine, in a suitable solvent, such as toluene, at eleveated temperatures.
  • a suitable base such as trimethylamine
  • a suitable solvent such as toluene
  • Compounds of type 1-43 can be obtained by reaction of compounds of type 1-42 with compounds of type 1-37 in the presence of a catalyst, such as for example copper(l)iodide and bases such as ⁇ , ⁇ '-dimethylethylenediamine and potassium carbonate in a suitbale solvent like, for example, dioxane.
  • a catalyst such as for example copper(l)iodide and bases such as ⁇ , ⁇ '-dimethylethylenediamine and potassium carbonate in a suitbale solvent like, for example, dioxane.
  • R 7 and R 11 are as defined for the compound of general formula (I) and R 8 is hydrogen, and R 9 and R 10 (not shown) together represent a group selected from:
  • n 1 or 2
  • W represents a leaving group such as, for instance a O-tosyl or O-mesyl group and n is 1 or 2.
  • 4-aminocyclohexanecarboxylate derivatives of type of 4-aminocyclohexanecarboxylate derivatives (C) can be any suitable aminocyclohexanecarboxylate derivatives (C).
  • Compounds of formula (I) can be obtained starting from 4-aminocyclohexanecarboxylate derivativesof type (C), upon standard amide bond forming reaction conditions, for example using a carboxylic acid of type 2-1 in the presence of a coupling agent such as, for example, PyBOP or HATU.
  • compounds of formula (I) can be obtained in a two step procedure by first converting carboxylic acids of type 2-1 to the corresponding acid chlorides applying chlorinating agents, such as for example thionyl chloride or 1 -chloro-N,N,2- trimethylprop-1 -en-1 -amine, followed by reaction with amines of type (C) in the presence of a suitable base, such as for example trimethylamine or pyridine.
  • chlorinating agents such as for example thionyl chloride or 1 -chloro-N,N,2- trimethylprop-1 -en-1 -amine
  • NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.
  • the 1 H-NMR data of selected examples are listed in the form of 1 H-NMR peaklists. For each signal peak the ⁇ value in ppm is given, followed by the signal intensity, reported in round brackets. The ⁇ value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: ⁇ (intensityi), ⁇ 2 (intensity 2 ), ... , ⁇ , (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.
  • Method 1 Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1 .7 ⁇ , 50x2.1 mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1 -99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 ⁇ ; DAD s can: 210-400 nm.
  • Instrument MS Waters ZQ; Instrument HPLC: Waters UPLC Acquity; Column: Acquity BEH C18 (Waters), 50mm x 2.1 mm, 1 .7 ⁇ ; eluent A: water +0,1 vol% formic acid, eluent B: acetonitrile (Lichrosolv Merck); gradient: 0.0 min 99 % A - 1 .6 min 1 % A - 1 .8 min 1 % A - 1 .81 min 99 % A - 2.0 min 99 % A; temperature: 60 ⁇ ; flow: 0.8 ml/min; UV-Detection PDA 210- 400 nm.
  • Instrument Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5 ⁇ 100x30mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient eluent A/ eluent B, flow 70 ml/min; temperature: 25 "C; DAD scan: 210-400 nm.
  • tert-Butyldimethylsilyl chloride (26.3 g, 174 mmol) was added to a solution of ethyl 4- hydroxycyclohexanecarboxylate (25.0 g, 145 mmol, mixture of cis-/trans-isomers, Cas No 17159-80-7) and imidazole (24.7 g, 363 mmol) in N,N-dimethylformamide (36 ml) and the mixture was stirred over night at room temperature. For work-up, water was added and the mixture was extracted with tert-butyl methyl ether (3x).
  • Lithium diisopropylamide (20.9 ml, 41 .9 mmol, 1 .8 M solution in tetrahydrofuran) was added dropwise to a solution of ethyl 4- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ cyclohexanecarboxylate (10.0 g, 34.9 mmol) in tetrahydrofuran (47 ml) at -78 ⁇ and the mixture was stirred for 30 min at that temperature. 1 -Bromo-2-chloroethane (4.3 ml, 52 mmol) was added and the mixture was stirred for 1 h at -78 ⁇ and then warmed during 2 h to room temperature.
  • Lithium hexamethyldisilazide (22.9 ml, 22.9 mmol, 1 M solution in tetrahydrofuran) was added over 5 min to solution of 2-chloro-4-fluoroaniline (1 .84 g, 12.6 mmol, Cas No 2106-02-7) in tetrahydrofuran (60 ml) at -78 ⁇ and the mixture was stired at -78 ⁇ for 1 h.
  • Tetra-N-butylammonium fluoride (9.1 ml, 9.1 mmol, 1 M solution in tetrahyrofuran) was added to a solution of 8- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2-(2-chloro-4-fluorophenyl)-2- azaspiro[4.5]decan-1 -one (isomer 1 ) (1.88 g, fraction 1 ) in tetrahydrofuran (43 ml) and the mixture was stirred at room temperature for 12 h.
  • Diisopropyl azodicarboxylate (1 .1 ml, 5.4 mmol) was added dropwise to a mixture of 2-(2- chloro-4-fluorophenyl)-8-hydroxy-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (1 .08 g, 3.61 mmol), phthalimide (797 mg, 5.42 mmol) and triphenylphosphine (1 .42 g, 5.42 mmol) in tetrahydrofuran (30 ml) and the mixture was stirred for 12 h at room temperature.
  • reaction mixture was concentrated and the residue was purified by flash chromatography (hexanes/ethyl acetate gradient) to yield 2-[2-(2-chloro-4-fluorophenyl)-1 -oxo-2- azaspiro[4.5]dec-8-yl]-1 H-isoindole-1 ,3(2H)-dione (isomer 1 ) (697 mg).
  • Lithium hexamethyldisilazide (43 ml, 43 mmol, 2 M solution in tetrahydrofuran) was added drop wise over 20 min to a solution of 4-fluoroaniline (2.63 g, 23.6 mmol, CAS No 371 -40-4) in tetrahydrofuran (190 ml) at -78 ⁇ and the mixture w as stirred for 1 h at that temperature, ethyl trans-4- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -1 -(2-chloroethyl) cyclohexanecarboxylate(mixture of cis- /trans-isomers) (7.50 g, 21 .5 mmol) was added drop wise during 1 h and the mixture was then stirred for 2 h at -78 ⁇ .
  • Tetra-n-butyl ammonium fluoride (32 ml, 32 mmol, 1 M solution in tetrahyrofuran) was added to a solution of 8- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2-(4-fluorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (4.07 g, 10.8 mmol) in tetrahydrofuran (93 ml) and the mixture was stirred at room temperature for 20 h.
  • Lithium bis(trimethylsilyl)amide (43 ml, 1 .0 M in THF, 43 mmol) was added during 15 minutes drop wise to a solution of aniline (2.20 g, 23.6 mmol) in tetrahydrofuran (200 ml) at -78 ⁇ and the mixture was stirred for 1 h at that temperature.
  • Tetra-N-butylammonium fluoride 35 ml, 35 mmol, 1 M solution in tetrahyrofuran
  • the mixture was poured into water, extracted with ethyl acetate (3x) and the combined organic phases were washed with saturated sodium bicarbonate solution and brine, filtrated through a silicone filter and concentrated under reduced pressure.
  • the residue was purified by flash chromatography to give the title compound (2.57 g).
  • Lithium diisopropylamide (21 ml, 2 M solution in tetrahydrofruan, 42 mmol) was added drop wise to a solution of ethyl 4- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ cyclohexanecarboxylate (mixture of cis-/trans-isomers) (13.2 g, 46.1 mmol) in tetrahydrofruan(62 ml) at -73 ⁇ and the mixture was stirred for 30 min at that temperature.
  • Bromoacetonitrile (4.8 ml, 69 mmol, CAS No 590-17-0) was added drop wise and the mixture was then stirred for 1 h at the same temperature and then warmed to room temperature over 2.5h.
  • water was added and the mixture was extracted with ethyl acetate (3x) and the combined organic phases were washed with brine, filtrated through a silicone filter and concentrated.
  • fraction 1 (0.33 g, 2% yield, single isomer based on 1 H NMR, isomer 2)
  • fraction 2 (4.26 g, 28 % yield, mixture of isomer 1 and isomer 2, ca. 9:1 based on 1 H NMR)
  • fraction 3 (3.17 g, 21 % yield, single isomer based on 1 H NMR, isomer 1 ).
  • Tetra-N-butylammonium fluoride (4.4 ml, 1 M solution in tetrahydrofuran, 4.4 mmol) was added to a solution of 8- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ -2-(3,5-difluorophenyl)-2-azaspiro[4.5]decan-1 - one (isomer 1 ) (575 mg, 1 .45 mmol) in tetrahydrofuran (12 ml) and the mixture was stirred at room temperature for 20 h.
  • Diisopropyl azodicarboxylate (370 ⁇ , 1 .9 mmol) was added drop wise to a mixture of 2-(3,5- difluorophenyl)-8-hydroxy-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (355 mg, 1 .26 mmol), phthalimide (279 mg, 1.89 mmol, CAS No 85-41 -6) and triphenylphosphine (497 mg, 1 .89 mmol) in tetrahydrofuran (15 ml) and the mixture was stirred at room temperature overnight.
  • reaction mixture was concentrated and the residue was purified by flash chromatography (25 g Snap Cartridge, hexanes/ethyl acetate gradient, 0% -> 50% ethyl acetate) followed by recrystallization from methanol to give the title compound (203 mg) as single isomer, together with unknown impurities.
  • Lithium di(propan-2-yl)azanide (98 ml, 2.0 M, 200 mmol, CAS No 41 1 1 -54-0) was added drop wise to a solution of ethyl 4- ⁇ [tert-butyl(diphenyl)silyl]oxy ⁇ cyclohexanecarboxylate (64.2 g, 156 mmol)in tetrahydrofuran (230 ml) at -78 ⁇ to -70 ⁇ , then the mixture was stirred 30 minutes at -78 ⁇ .
  • Lithium 1 ,1 ,1 ,3,3,3-hexamethyldisilazan-2-ide 42 ml, 1 M solution in tetrahyrofuran, 42 mmol, CAS No 4039-32-1 ) was added drop wise within 5 minutes to a solution of 2-chloroaniline (2.5 ml, 23 mmol, CAS 95-51 -2) in tetrahydrofuran (1 10 ml) at -78 ⁇ and the mixture was stirred for 60 min at that temperature.
  • Triethylamine (1 .7 ml) was added to a solution of 2-(2-chlorophenyl)-8-hydroxy-2- azaspiro[4.5]decan-1 -one (isomer 1 ) (2.86 g, 10.2 mmol) in methylene chloride (24 ml) at - 20 ⁇ , then methanesulfonyl chloride (960 ⁇ , 12 mmo I) was added drop wise and the mixture was stirred for 60 min at room temperature. The reaction mixture was diluted with methylene chloride and then washed with sodium bicarbonate and sodium chloride, the organic phase was filtrated through a hydrophobic filter and was then concentrated under reduced pressure to give the title compound (3.68 g).
  • Lithium 1 ,1 ,1 ,3,3,3-hexamethyldisilazan-2-ide 42 ml, 1 M solution in tetrahyrofuran, 42 mmol
  • Triethylamine (1.7 ml) was added to a solution of 2-(2-chloro-4-fluoro-5-methylphenyl)-8- hydroxy-2-azaspiro[4.5]decan-1-one (isomer 1) (3.05 g, 9.78 mmol) in methylene chloride (23 ml) at -20 ⁇ , then methanesulfonyl chloride (920 ⁇ , 12 mmol) was added drop wise and the mixture was stirred for 60 min at room temperature. The reaction mixture was diluted with methylene chloride and then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, the organic phase was filtrated through a hydrophobic filter and was then concentrated under reduced pressure to give the title compound (3.89 g).
  • Lithium 1 ,1 ,1 ,3,3,3-hexamethyldisilazan-2-ide 42 ml, 1 M solution in tetrahydrofuran, 42 mmol, CAS No 4039-32-1
  • 2-chloro-4,5- difluoroaniline 3.88 g, 23.2 mmol
  • tetrahydrofuran 1 10 ml
  • -78 C and the mixture was stirred for 1 h at that temperature.
  • fraction 1 (7.53 g, single isomer based on 1 H NMR, isomer 1 , contains impurities from aniline and isomer 2), fraction 2 (1 .13 g, isomer 2).
  • N,N,N-tributylbutan-1 -aminium fluoride (38 ml, 1 .0 M in THF, 38 mmol, CAS No 429-41 -4) was added to a solution of 8- ⁇ [tert-butyl(diphenyl)silyl]oxy ⁇ -2-(2-chloro-4,5-difluorophenyl)-2- azaspiro [4.5]decan-1 -one (isomer 1 ) (14.2 g, 25.1 mmol) in tetrahydrofuran (200 ml) and the mixture was stirred at 80 ⁇ for 6 h.
  • the reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate and sodium chloride, dried over sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by flash chromatography (120 g Snap cartridge, methylene chloride/ethyl acetate gradient, 0% -> 10% ethyl acetate) the product containing fractions were concentrated under reduced pressure and the residue was purifies a second time by flash chromatography (120 g Snap cartridge, hexane/ethyl acetate gradient, 20% -> 100% ethyl acetate to give the title compound (5.31 g).
  • Triethylamine (1 .6 ml) and methanesulfonyl chloride (890 ⁇ , 1 1 mmol) were added at 0 ⁇ to a solution of 2-(2-chloro-4,5-difluorophenyl)-8-hydroxy-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (3.00 g, 9.50 mmol) in methylene chloride (23 ml), the mixture was stirred at ⁇ ' ⁇ for 30 minutes. For work-up, the mixture was diluted with methylene chloride, extracted with sodium bicarbonate and with sodium chloride and dried over sodium sulfate, then concentrated under reduced pressure to give the title compound (3.37 g).

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Abstract

The present invention relates to amido-substituted cyclohexane compounds of general formula (I) : in which A, R4, R6, R7, R8, R9, R10 and R11 are as defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms, as a sole agent or in combination with other active ingredients.

Description

AMIDO-SUBSTITUTED AZASPIRO DERIVATIVES AS TANKYRASE
INHIBITORS
The present invention relates to amido-substituted cyclohexane compounds of general formula (I) as described and defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms, as a sole agent or in combination with other active ingredients.
BACKGROUND OF THE INVENTION Cancer is the leading cause of death in developed countries and the second leading cause of death in developing countries. Deaths from cancer worldwide are projected to continue rising, with an estimated 12 million deaths in 2030. While substantial progress has been made in developing effective therapies, there is a need for additional therapeutic modalities that target cancer and related diseases.
The complexity of cancer disease arises after a selection process for cells with acquired functional capabilities to enhance survival and/or resistance towards apoptosis and a limitless proliferative potential. In addition, bi-direction interaction of cancer cells and stromal cells provides further advantage of cancer cell survival and distant metastasis to the secondary organs and tissues [Liotta LA, Kohn EC. The microenvironment of the tumour-host interface. Nature 2001, 411:375]. Furthermore, cancer stem cells (CSCs) represent the apex in the hierarchical model of tumor genesis, heterogeneity and metastasis. CSCs possess the capacity for unlimited self-renewal, the ability to give rise to progeny cells, and also an innate resistance to cytotoxic therapeutics [Meacham CE and Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature 2013, 501:328]. Thus, there is need to develop drugs for cancer therapy addressing distinct features of established tumors.
The discovery that Drosophila segment polarity gene Wingless had a common origin with the murine oncogene lnt-1 led to intensive studies on Wnt signaling pathway and identification of 19 mammalian Wnts and 10 Wnt receptors [Rijsewijk F, Schuermann M, Wagenaar E, Parren P, Weigel D, Nusse R. The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless. Cell. 1987, 50: 649]. Wnts are secreted glycoproteins which bind to cell surface receptors to initiate signaling cascades. Wnt signaling cascades have classified into two categories: canonical and non-canonical, differentiated by their dependence on β-catenin. Non-canonical Wnt pathways, such as the planar cell polarity (PCP) and Ca2+ pathway, function through β-catenin independent mechanisms. Canonical Wnt signalling is initiated when a Wnt ligand engages co-receptors of the Frizzled (Fzd) and low- density lipoprotein receptor related protein (LRP) families, ultimately leading to β-catenin stabilization, nuclear translocation and activation of target genes [Angers S, Moon RT. Proximal events in Wnt signal transduction. Nat Rev Mol Cell Biol. 2009, 10: 468. Cadigan KM, Liu Yl. Wnt signaling: complexity at the surface. J Cell Sci. 2006, 119: 395. Gordon MD, Nusse R. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem. 2006, 281: 22429. Huang H, He X. Wnt/beta-catenin signaling: new (and old) players and new insights. Curr Opin Cell Biol. 2008, 20: 119. Polakis P. The many ways of Wnt in cancer. Curr Opin Genet Dev. 2007, 17: 45. Rao TP, Kuhl M. An updated overview on Wnt signaling pathways: a prelude for more. Circ Res. 2010, 106: 1798].
In the absence of Wnt stimulus, β-catenin is held in an inactive state by a multimeric "destruction" complex comprised of adenomatous polyposis coli (APC), Axin, glycogen synthase kinase 3β (GSK33) and casein kinase 1 a (CK1 a). APC and Axin function as a scaffold, permitting GSK33- and CK1 a-mediated phosphorylation of critical residues within β- catenin. These phosphorylation events mark β-catenin for ubiquitination recognition by the E3 ubiquitin ligase β-transducin-repeat-containing protein and lead to subsequent proteasomal degradation [He X, Semenov M, Tamai K, Zeng X. LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. Development.2004, 131:1663. Kimelman D, Xu W. beta-catenin destruction complex: insights and questions from a structural perspective. Oncogene 2006, 25: 7482].
In the presence of Wnt stimulus, Axin, ΘβΙΟβ and Dvl are recruited to the co-receptor complex Fzd and LRP5/6 and lead to disruption of the β-catenin destruction complex. Therefore, β- catenin is stabilized and translocated to the nucleus. Once in the nucleus, β-catenin forms a complex with members of the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors, recruiting co-factors such as CBP, p300, TNIK, Bcl9 and Pygopus, and ultimately driving transcription of target genes including c-myc, Oct4, cyclin D, survivin. [Curtin JC and Lorenzi MV. Drug Discovery Approaches to Target Wnt Signaling in Cancer Stem Cells. Oncotarget 2010, 1: 552].
Tankyrases play a key role in the destruction complex by regulating the stability of the rate- limiting AXIN proteins, RNF146 and tankyrase itself. The E3 ubiquitin ligase RNF146 recognizes tankyrase-mediated PARsylation and eartags AXIN, tankyrase and itself for proteasome-mediated degradation. Thus, tankyrases control the protein stability and turnover of key components of the destruction complex, and consequently the cellular levels of β- catenin [Huang SMA, Mishina YM, Liu S, Cheung A, Stegmeier F, et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 2009, 461:614, Zhang Y, Liu S, Mickanin C, Feng Y, Charlat O, et al. RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling. Nature Cell Biology 2011, 13:623, 2011].
Aberrant regulation of the Wnt/3-catenin signaling pathway is a common feature across a broad spectrum of human cancers and evolves as a central mechanism in cancer biology. First of all, Wnt overexpression could lead to malignant transformation of mouse mammary tissue [Klaus A, BirchmeierW. Wnt signalling and its impact on development and cancer. Nat Rev Cancer 2008, 8: 387\. Second, tumor genome sequencing discovered the mutations in Wnt/β- catenin pathway components as well as epigenetic mechanisms that altered the expression of genes relevant to Wnt/3-catenin pathway [Ying Y. et al. Epigenetic disruption of the WNT/beta- catenin signaling pathway in human cancers. Epigenetics 2009, 4:307\. Third, Wnt/3-catenin pathway also cooperates with other oncogenic signaling pathways in cancer and regulates tumorigenesis, growth, and metastasis [Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer 8: 387-398, 2008]. In addition, there is an additional role of WNT signaling between tumor and stromal cell interaction leading to tumorigenesis and metastasis [Shahi P, Park D, Pond AC, Seethammagari M, Chiou S-H, Cho K et al. Activation of Wnt signaling by chemically induced dimerization of LRP5 disrupts cellular homeostasis. PLoS ONE 2012, 7: e30814]. Furthermore, growing body of evidence indicates a critical role of β-catenin in CSCs [Eaves CJ, Humphries RK. Acute myeloid leukemia and the Wnt pathway. N Engl J Med. 2010, 362: 2326; Nusse R, Fuerer C, Ching W, Harnish K, Logan C, Zeng A, ten Berge D, Kalani Y. Wnt signaling and stem cell control. Cold Spring Harb Symp Quant Biol. 2008, 73: 59; Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature 2005, 434: 843]. For example, stem-like colon cells with a high level of β- catenin signaling have a much greater tumorigenic potential than counterpart cells with low β- catenin signaling [Vermeulen L, De Sousa EMF, van der Heijden M, Cameron K, de Jong JH, Borovski T, Tuynman JB, Todaro M, Merz C, Rodermond H, Sprick MR, Kemper K, Richel DJ, Stassi G, Medema JP. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol. 2010, 12: 468] Finally, activation of Wnt/3-catenin signalling pathway is also one of the major mechanism causing tumor recurrence and drug resistance. All these provide clear rationale to develop therapeutics targeting Wnt/3-catenin signaling pathway for the treatment of cancer.
One of the approaches to inhibit Wnt/3-catenin signaling pathway is to target druggable tankyrases. Tankyrase 1 (TNKS1 ) and tankyrase 2 (TNKS2) are poly(ADP-ribosyl)ases that are distinguishable from other members of the enzyme family by the structural features of the catalytic domain, and the presence of a sterile a-motif multimerization domain and an ankyrin repeat protein-interaction domain. Inhibition of TNKS blocks PARsylation of AXIN1 and AXIN2 and prevents their proteasomal degradation. As the consequence, TNKS inhibition enhances the activity of the β-catenin destruction complex and suppresses β-catenin nuclear transclocation and the expression of β-catenin target genes.
In addition to its function in Wnt signaling through modulation of β-catenin destruction, tankyrases are also implicated in other cellular functions, including telomere homeostasis, mitotic spindle formation, vesicle transport linked to glucose metabolism, and viral replication. In these processes, tankyrases interact with target proteins, catalyze poly (ADP-ribosyl)ation, and regulate protein interactions and stability. For example, TNKS1 controls telomere homeostasis, which promotes telomeric extension by PARsylating TRF1 . TRF1 is then targeted for proteasomal degradation by the E3 ubiquitin ligases F-box only protein 4 and/or RING finger LIM domain-binding protein (RLIM/RNF12), which facilitates telomere maintenance [Donigian JR and de Lange T. The role of the poly(ADP-ribose) polymerase tankyrasel in telomere length control by the TRF1 component of the shelterin complex. J Biol Chem 2007, 282:22662]. In addition, telomeric end-capping also requires canonical DNA repair proteins such as DNA-dependent protein kinase (DNAPK). TNKS1 stabilizes the catalytic subunit of DNAPK (DNAPKcs) by PARsylation [Dregalla RC, Zhou J, Idate RR, Battaglia CL, Liber HL, Bailey SM. Regulatory roles of tankyrase 1 at telomeres and in DNA repair: suppression of T-SCE and stabilization of DNA-PKcs. Aging 2010, 2(10):691]. Altered expression of TNKS1 and/or TNKS2, as well as genetic alterations in the tankyrase locus, have been detected in multiple tumors, e.g. fibrosarcoma, ovarian cancer, glioblastoma, pancreatic adenocarcinoma, breast cancer, astrocytoma, lung cancer, gastric cancer, and colon cancer [Lehti L, Chi N-W and Krauss S. Tankyrases as drug targets. FEBS Journal 2013, 280: 3576]. In addition, tankyrases appear to have impact on viral infections. For example, in HSV infection, it was shown that the virus cannot replicate efficiently in cells with depletion of both TNKS1 and TNKS2 [Li Z, Yamauchi Y, Kamakura M, Murayama T, Goshima F, Kimura H, Nishiyama Y, Herpes Simplex Virus Requires Poly(ADP-Ribose) Polymerase Activity for Efficient Replication and Induces Extracellular Signal-Related Kinase-Dependent Phosphorylation and ICPO-Dependent Nuclear Localization of Tankyrase 1. Journal of Virology 2012, 86(1): 492].
Furthermore, a connection between tankyrases and glucose metabolism has been indicated. Thus, DNA polymorphism in a chromosomal region encoding tankyrase/methionine sulfoxide reductase A is robustly associated with early-onset obesity. TNKS1 knockout mice appeared to have reduced fat pads, suggesting a potential connection of TNKS and obesity. TNKS may also play a role in tissue fibrosis.
In summary, tankyrases are promising drug targets in regulating WNT signaling, telomere length (e.g. telomere shortening and DNA damage induced cell death), lung fibrogenesis, myelination and viral infection. The invention presented here describes a novel class of tankyrase inhibitors and their potential clinical utility for the treatment of various diseases, such as cancer, aging, metabolic diseases (e.g. diabetes and obesity), fibrosis (e.g. lung fibrogenesis) and viral infection.
The following list of selected references relates to inhibitors of TNKS1 and/or TNKS2 described in the literature or in patents. However, the chemical structures and compound classes of the inhibitors described in these references are completely different from the chemical structures of the present invention:
Cancer Research 2013, 73 (10): 3132; J Med Chem 2013, 56 (16): 6495; J Med Chem 2013, 56(3): 1341 ; J Med Chem 2013, 56(17): 7049; J Med Chem 2013, 56(24): 10003; J Med Chem
2013, 56(7): 3012; J Med Chem 2013, 56(20): 7880; J Med Chem 2013, 56(1 1 ): 4320; ChemMedChem 2013, 8(12): 1978; ACS Med Chem Lett 2013, 4(12): 1173; ACS Med Chem Lett 2013, 4(12): 1218; Acta Crystallogr Sect F Struct Biol Cryst Commun 2012, 68(Part 2): 1 15; J Med Chem 2012, 55(3): 1360; WO 2009059994, WO2013164061 , WO2014023390, WO 2012076898, WO 2013093508, WO 2013010092, WO 2013189905, WO 2013189865, WO 2013177349, WO 2013012723, WO 2013134079, WO 2013182546, ACS Med Chem Lett,
2014, 6(3): 254, WO 2015150449, WO2017/055313, WO2017/055316.
WO2016/177658 discloses amido-substituted cyclohexane derivatives which inhibit TNKS 1 and/or TNKS 2 and that may be useful for the treatment of disorders mediated by TNKS1 and/or TNKS2.
However, the state of the art described above does not describe the specific substituted cyclohexane compounds of general formula (I) of the present invention.
It has now been found, and this constitutes the basis of the present invention, that said compounds of the present invention have surprising and advantageous properties. In particular, said compounds of the present invention have surprisingly been found to effectively inhibit TNKS1 and/or TNKS2 and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses mediated by TNKS1 and/or TNKS2 and/or mediated by the Wnt pathway, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof. Compounds of the present invention may additionally show improved selectivity for TNKS1 and/or TNKS2 (e.g. over other PARP (poly(ADP-ribose)-polymerase) enzymes), for the treatment of TNKS1 and/or TNKS2 driven diseases, by reaching sufficient efficacious dose without inducing toxicity driven by, for example, other PARPs inhibition.
DESCRIPTION of the INVENTION
In accordance with a first aspect, compounds of general formula
Figure imgf000007_0001
(I)
(I) : in which,
A represents a ring group selected from:
Figure imgf000007_0002
wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom;
ring A1
Figure imgf000008_0001
represents a phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms; said phenyl and 6-membered heteroaryl ring being optionally substituted one, two or three times, independently from each other, with R5, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, and c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, wherein said rings are fused with ring A1 , said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5; or, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O, S, S(=0) and S(=0)2;
Figure imgf000008_0002
represents: - a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
- a 5-membered heterocyclic ring, optionally partially unsaturated, which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two carbon atoms of the heterocyclyl ring are optionally replaced by a heteroatom-containing group selected from (C=0), N, NR20, O, S, S(=0) and S(=0)2, said 5-membered heteroaryl and 5-membered heterocyclic rings being optionally substituted one, two or three times, independently from each other, with R5 , whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one ring carbon atom is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5 ; or, whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O, S, S(=0) and S(=0)2;
R4 represents a hydrogen atom,
R5 represents, independently of each other, a group selected from : halogen, hydroxy, Ci-C4-alkyl, C3-C4-cycloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, - N(R14)R15, -C(0)OR13, -C(0)OH, phenyl and a 6-membered heteroaryl which contains one or two nitrogen atoms, wherein Ci-C4-alkyl is optionally substituted one, two or three times with a group independently selected from halogen, hydroxy, oxo (C=0), Ci-C3-alkoxy, C3-C6- cycloalkyl, -NH2, -NH(Ci-C3-alkyl) and -N(Ci-C3-alkyl)2;
R5 represents, independently of each other, a group selected from : halogen, hydroxy, Ci-C4-alkyl, C3-C4-cycloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, - N(R14)R15, -C(0)OR13, -C(0)OH, phenyl and 6-membered heteroaryl which contains one or two nitrogen atoms, wherein Ci-C4-alkyl is optionally substituted one, two or three times with a group independently selected from halogen, hydroxy, oxo (C=0), Ci-C3-alkoxy, C3-Ce- cycloalkyl, -NH2, -NH(Ci-C3-alkyl) and -N(Ci-C3-alkyl)2;
R6 represents hydrogen, halogen, hydroxy, Ci-C3-alkyl or Ci -C3-alkoxy;
R7 represents hydrogen; or
R6, R7 represent, independently of each other, halogen;
R8 represents hydrogen, or Ci -C3-alkyl,
R9 and R10 together represent a group selected from:
* # * #
\ CH C /H2 and \ CH CH C /H2 wherein said groups are optionally substituted with one or two groups, which are independently of each other selected from : halogen, Ci-C3-alkyl, Ci-C3-alkoxy, hydroxy, Ci-C3-haloalkyl, and Ci-C3-hydroxyalkyl, wherein * indicates the point of attachment of said group to the rest of the molecule at R9, and
# indicates the point of attachment of said group to the rest of the molecule at R10 ; R11 represents a group selected from : aryl, and heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one, two, three or four groups, which are independently of each other selected from :
Ci -Ce-alkyl, Ci -C3-alkoxy, Ci -C3-hydroxyalkyl, C3-C6-cycloalkyl, C3-C6- cycloalkoxy, Ci -C3-haloalkyl , Ci -C3-haloalkoxy, halogen , cyano, nitro, hydroxy, (Ci -Ce-alkyl)-S-, (Ci -C6-alkyl)-S(=0)-, (Ci -C6-alkyl)-S(=0)2-,
-S(=0) (=N R21 ) R22, -N( R1 4) R1 5, R1 4(R15)N-(Ci -C6-alkyl)-,
R1 4(R1 5)N-(C2-C6-alkoxy)-, phenyl, phenoxy, -N( R1 6)C(=0) R1 7, -C(=0)OH, - C(=0)OR1 3, and -C(=0)N( R1 6)2, whereby two substituents of said aryl group, when they are in ortho-position to one another, can be linked to one another in such a way that they jointly form methanediylbisoxy, ethane-1 ,2-diylbisoxy, propane-1 ,3-diyl, or butane-1 ,4-diyl, represents a group selected from :
Ci -Ce-alkyl, C3-C6-cycloalkyl, C2-C6-hydroxyalkyl-, and
(Ci -C3-alkoxy)-(C2-C6-alkyl)-, and R1 5 are independently of each other selected from : hydrogen, Ci -C6-alkyl, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci -C6-alkyl)-, C2-C6- hydroxyalkyl, (Ci -C3-alkoxy)-(C2-C6-alkyl)-, Ci -C6-haloalkyl, H2N-(C2-C6-alkyl)-, (C1 -C3- alkyl)N(H)(C2-C6-alkyl)-, (Ci -C3-alkyl)2N(C2-C6-alkyl)-,
Figure imgf000011_0001
-C6-alkyl)-, and
Figure imgf000011_0002
-C6-alkyl)-,
and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, in which one carbon atom is optionally replaced by a further heteroatom-containing group selected from NR20, O, S, S(=0) and S(=0)2, and in which one additional ring atom is optionally replaced by C(=0), said 4- to 7-membered heterocycloalkyl group being optionally substituted with one, two, three or four groups, which are independently of each other selected from :
Ci -C3-alkyl, Ci -C3-haloalkyl, Ci -C3-alkoxy, Ci -C3-haloalkoxy, C3-C4-cycloalkyl, C3-C4- cycloalkoxy, -N(CH3)2, NH2, N(CH3)H, hydroxy, a halogen atom , and cyano, whereby when two substituents are attached to the same ring carbon atom, together with the carbon atom to which they are attached, can be linked to one another in such a way that they jointly form a cyclobutane, cyclopentane, azetidine, pyrrolidine, oxetane, tetrahydrofuran, thietane, tetrahydrothiophene, thietane 1 -oxide, tetrahydrothiophene 1 - oxide, thietane 1 ,1 -dioxide or a tetrahydrothiophene 1 ,1 -dioxide group;
R16 represents, independently of each other, hydrogen, or Ci -C3-alkyl,
R17 represents hydrogen, Ci -Ce-alkyl, Ci -Ce-hydroxyalkyl, CVCe-cycloalkyl, Ci -C6-haloalkyl, (Ci -C3-alkoxy)-(Ci -C6-alkyl)-, aryl, or heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently of each other selected from :
Ci -C3-alkyl, C3-C6-cycloalkyl, Ci -C3-alkoxy, CVCe-cycloalkoxy, Ci -C3-haloalkyl, Ci -C3-haloalkoxy, halogen, cyano, and hydroxy, R20 represents, independently of each other, a group selected from : hydrogen, Ci -C3-alkyl, Ci -C3-haloalkyl, C3-C4-cycloalkyl,
Figure imgf000012_0001
-C(=0)OCi - C4-alkyl and phenyl,
R21 represents hydrogen, cyano, (Ci -C3-alkyl)-C(=0)-, or (Ci -C3-haloalkyl)-C(=0)-,
R22 represents Ci -C4-alkyl, or C3-C4-cycloalkyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, with the proviso that:
- when ring A2 is a imidazolyl or a 1 ,3-oxazolyl group, then said group is connected to the rest of the molecule via the carbon atom at position 2 of the imidazolyl or 1 ,3-oxazolyl ring, as shown below:
Figure imgf000012_0002
wherein * indicates the point of attachment of said group with the rest of the molecule;
Figure imgf000012_0003
- ring A2 is not a unsubstituted or substituted group, wherein * indicates the point of attachment of said group with the rest of the molecule, and in which : ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C3-alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms,
, and ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms.
Definitions
Constituents which are optionally substituted as stated herein, may be substi-tuted, unless otherwise noted, one or more times, independently from one another at any possible position. When any variable occurs more than one time in any constituent, each definition is independent.
When any variable occurs more than one time in any compound of general formula (I) as described herein, each definition is independent. For example, when R5, R5 , R5a, R5b, R13, R14, R15, R16, R17, R20, R21 , and/or R22 occur more than one time in any compound of formula (I) each definition of R5, R5', R5a, R5b, R13, R14, R15, R16, R17, R20, R21 , and R22 is independent.
A hyphen at the beginning or at the end of the constituent marks the point of attachment to the rest of the molecule. Should a ring be substituted the substitutent could be at any suitable position of the ring, also on a ring nitrogen atom if suitable.
The terms as mentioned in the present text have preferably the following meanings The term "comprising" when used in the specification includes "consisting of". If it is referred to "as mentioned above" or "mentioned above" "as mentioned supra" , "as described supra" within the description it is referred to any of the disclosures made within the specification in any of the preceding pages.
If it is referred to "as mentioned herein", "as described herein", "as defined herein", "as provided herein" or "as stated herein" within the description it is referred to any of the disclosures made within the specification in any of the preceding or subsequent pages.
The term "halogen", "halogen atom", "halo-" or "Hal-" is to be understood as meaning fluorine, chlorine, bromine or iodine atom.
The term "Ci -Ce-alkyl" is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5, or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1 ,2-dimethylpropyl, neo-pentyl, 1 ,1 -dimethylpropyl, 4- methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 -methylpentyl, 2-ethylbutyl, 1 -ethylbutyl, 3,3- dimethylbutyl, 2,2-dimethylbutyl, 1 ,1 -dimethylbutyl, 2,3-dimethylbutyl, 1 ,3-dimethylbutyl, or 1 ,2- dimethylbutyl group, or an isomer thereof. Particularly, said group has 1 , 2, 3 or 4 carbon atoms ("Ci -C4-alkyl"), e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert- butyl group, more particularly 1 , 2 or 3 carbon atoms ("Ci -C3-alkyl"), e.g. a methyl, ethyl, n- propyl- or iso-propyl group, more particularly 1 or 2 carbon atoms ("Ci -C2-alkyl"), e.g. a methyl, ethyl group, even more particularly 1 carbon atom ("Ci-alkyl"), a methyl group.
The term "Ci -Ce-hydroxyalkyl" 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 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. The term "Ci-C6-haloalkyl" is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C6-alkyl" is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in identically or differently, i.e. one halogen atom being independent from another. Particularly, said halogen atom is F. Said Ci -Ce-haloalkyl group is, for example, -CF3, -CHF2, -CH2F, -CF2CF3, -CH2CH2F, -CH2CHF2, - CH2CF3, or -CH2CH2CF3.
The term "Ci-C4-alkoxy" is to be understood as meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -O-alkyl having 1 , 2, 3, or 46 carbon atoms, in which the term "alkyl" is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy, n- butoxy, iso-butoxy, or tert-butoxy, or an isomer thereof.
The term "Ci -C4-haloalkoxy" is to be understood as meaning a linear or branched, saturated, monovalent Ci -C4-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom. Particularly, said halogen atom is F. Said Ci-C4-haloalkoxy group is, for example, -OCF3, -OCHF2, -OCH2F, -OCF2CF3, or - OCH2CF3.
The term "C3-C6-cycloalkyl" is to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms ("C3-C6-cycloalkyl"). Said C3-C6-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.
The term "C3-C6-cycloalkoxy" is to be understood as meaning a saturated, monovalent, hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms of formula -O-cycloalkyl, in which the term "cycloalkyi" is defined supra, e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy.
Unless defined otherwise, the terms "4- to 7-membered heterocycloalkyl" and "4- to 6- membered heterocycloalkyl", are to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon ring with 4 to 7 or, respectively, 4 to 6 ring atoms in total, and which contains a heteroatom-containing group selected from N, NR20, O, S, S(=0) and S(=0)2, wherein:
- one ring carbon atom is optionally replaced by a further heteroatom-containing group selected from NR20, O, S, S(=0) and S(=0)2, in which R20 represents a hydrogen, Ci-C3-alkyl, Ci-C3-haloalkyl, C3-C4-cycloalkyl,
Figure imgf000016_0001
or a phenyl group, and
- one additional ring carbon atom is optionally replaced by C(=0); it being possible for said heterocycloalkyi group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, the nitrogen atom. The term "heteroatom-containing group" as defined herein is to be understood as meaning a group containing a heteroatom, such as NR20, S(=0) and S(=0)2, and/or a heteroatom such as N, O and S, wherein R20 is as defined herein.
Particularly, without being limited thereto, said heterocycloalkyi can be a 4-membered ring, such as an azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or N-methylpiperazinyl. Optionally, said heterocycloalkyi can be benzo fused. Particularly, without being limited thereto, 4- to 6-membered heterocycloalkyi can be selected from piperazinyl, tetrahydro-2H- pyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, 2-oxoimidazolidinyl, 2-oxopyrrolidinyl and 1 ,1 -dioxidothiomorpholinyl. More particularly, without being limited thereto, 4- to 6-membered heterocycloalkyi can be selected from piperazin-1 -yl, tetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, pyrrolidin-1 -yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-4-yl, piperidin-1 -yl, piperidin-2-yl, piperidin-3-yl, morpholin-4-yl, azetidin-1 -yl, tetrahydrofuran-2-yl, 2-oxoimidazolidin-1 -yl, 2-oxopyrrolidin-1 -yl and 1 ,1 -dioxidothiomorpholin-4-yl.
In certain embodiments, R14 and R15 together with the nitrogen atom to which they are attached form a 4-to 7- membered heterocycloalkyi group, in which one ring carbon atom is optionally replaced by a further heteroatom-containing group selected from NR20, O, S, S(=0) and S(=0)2, and one additional ring carbon atom is optionally replaced by C(=0), said 4- to 7-membered heterocycloalkyi group being optionally substituted with one, two , three or four groups, which are independently of each other selected from : Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy , Ci-C3-haloalkoxy, C3-C4-cycloalkyl, C3-C4- cycloalkoxy, -N(CH3)2, N(H)2, N(CH3)H, hydroxy, a halogen atom, and cyano, whereby when two substituents are attached to the same ring carbon atom, together with the carbon atom to which they are attached, can be linked to one another in such a way that they jointly form a cyclobutanyl, cyclopentanyl, azetidine, pyrrolidine, oxetane, tetrahydrofuran, thietane, tetrahydrothiophene, thietane 1 -oxide, tetrahydrothiophene 1 -oxide, thietane 1 ,1 - dioxide or tetrahydrothiophene 1 ,1 -dioxide group;
Particularly, without being limited thereto, when two substituents are attached to the same ring carbon atom of said 4- to 7-membered heterocycloalkyi group, together with the carbon atom to which they are attached, can be linked to one another in such a way that they jointly form groups according to the present invention such as the ones represented below:
Figure imgf000017_0001
wherein: * indicates the point of attachment of said group with the rest of the molecule, and B1 represents CH2, -CH2CH2-, NH, -CH2-NH-, N(Ci-C3-alkyl), -CH2-N(Ci -C3-alkyl), N(Ci-C3- haloalkyl), -CH2-N(Ci -C3-haloalkyl)-, O, -CH2-0-, S, -CH2-S-, S(O), -CH2-S(0)-, S(0)2, or -CH2- S(0)2-.
The present invention includes all R14, R15 groups described supra.
Unless defined otherwise, the term "aryl" is to be understood as meaning a monovalent, aromatic or partially aromatic, mono- or bicyclic hydrocarbon ring having 6, 7, 8, 9 or 10 carbon atoms (a "C6-Cio-aryl" group), particularly a ring having 6 carbon atoms (a "C6-aryl" group), e.g. a phenyl group; or a ring having 9 carbon atoms (a "C9-aryl" group), e.g. an indanyl or indenyl group, or a ring having 10 carbon atoms (a "Cio-aryl" group), e.g. a tetralinyl, dihydronaphthyl, or naphthyl group.
Unless, defined otherwise, the term "heteroaryl" is understood as meaning a monovalent, monocyclic aromatic ring system having 5 or 6 ring atoms (a "5- to 6-membered heteroaryl" group), which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen, NH or sulfur. Particularly, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl etc., or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. More particularly, without being limited thereto, heteroaryl can be selected from pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, thienyl, and furanyl. Even more particularly, without being limited thereto, heteroaryl can be selected from oxazolyl, imidazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl and thiazolyl.
In general, and unless otherwise mentioned, the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof. Thus, for some illustrative non-restricting example, the term pyridinyl or pyridinylene includes pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-yl and pyridin-4-ylene; or the term thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene. In general, and unless otherwise mentioned, the heteroarylic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof. Thus, for some illustrative non- restricting example, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.
In general, and unless otherwise mentioned, aromatic and non-aromatic (hetero)cyclic groups, may optionally be substituted as defined herein. The substituents may be present both when said aromatic and non-aromatic (hetero)cyclic groups exist as a (unitary) constituent, such as, for example, Cs-Ce-cycloalkyl, 4- to 6-membered heterocycloalkyl, aryl and heteroaryl groups, or as part of a constituent composed of more than one part, such as, for example, (C3-C6- cycloalkyl)-Ci -C6-alkyl-, (4- to 6-membered heterocycloalkyl)-(C2-C6-alkyl)-, aryl-(Ci-C6-alkyl)-, and heteroaryl-(Ci-C6-alkyl)-, for example. The present invention includes all suitably substituted aromatic and non-aromatic (hetero)cyclic groups both as a (unitary) constituent, or as part of a constituent composed of more than one part.
In the context of the present invention "suitably" is to be understood as meaning chemically possible to be made by methods within the knowledge of a skilled person.
According to the present invention ring A is a mono or bicyclic ring as defined herein, in which ring A is connected to the rest of the compound of formula (I) via a carbon atom the ring.
According to certain embodiments ring A represents a bicyclic aromatic ring. Unless defined otherwise, the total count of nitrogen atoms on each member of the bicyclic system includes any nitrogen atoms which are shared by both rings.
Figure imgf000019_0001
For example, when ring A represents the groups
Figure imgf000019_0002
indicates the point of attachment of said group with the rest of the molecule, said point of attachment being a carbon atom of the ring, and rings G1 , H1 , E1 , F1 , C1 , D1 , D1 ' are as defined herein, the total count of nitrogen atoms on each member of the bicyclic ring system includes any nitrogen atoms which are shared by both rings.
According to certain embodiments ring A contains at least one NH heteroatom. It is understood that in such embodiments, if suitable, a substituent R5 or R5 may replace the hydrogen atom in said NH group, including to form a ring with an adjacent R5 or R5 substitutent, as defined herein.
For example, according to certain embodiments ring A represents: - a 5-membered heteroaryl ring which contains one NH, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
- a 5-membered heterocyclic ring, optionally partially unsaturated, which contains one NH group, in which one or two carbon atoms of the heterocyclyl ring are optionally replaced by a heteroatom-containing group selected from (C=0), N, NR20, O and S, said 5-membered heteroaryl and 5-membered heterocyclic rings being optionally substituted one, two or three times, independently from each other, with R5.
It is understood that in such embodiments, if suitable, a substituent R5 may replace the hydrogen atom in the NH group, including to form a ring with an adjacent R5 substitutent, as defined herein.
Figure imgf000020_0001
Particularly, without being limited thereto, groups according to the present invention can be as represented below:
Figure imgf000020_0002
wherein: - * indicates the point of attachment of said group with the rest of the molecule, said groups being optionally substituted independently with one or two R5 groups, and
- R5 is as defined herein.
Figure imgf000021_0001
Particularly, without being limited thereto, groups according to the present invention can be as represented below:
Figure imgf000021_0002
Figure imgf000021_0003
- * indicates the point of attachment of said group with the rest of the molecule, said groups being optionally substituted independently with one or two R5 groups, and
- R5 is as defined herein.
Figure imgf000021_0004
Particularly, without being limited thereto, groups according to the present invention can be as represented below:
Figure imgf000021_0005
- * indicates the point of attachment of said group with the rest of the molecule, said group being optionally substituted independently with one or two R5 groups, and
- R5 is as defined herein.
Figure imgf000022_0001
Particularly, without being limited thereto, groups according to the present invention can be as represented below:
Figure imgf000022_0002
Figure imgf000022_0003
- * indicates the point of attachment of said group with the rest of the molecule, said group being optionally substituted independently with one or two R5 groups, and
R5 is as defined herein.
Figure imgf000022_0004
Particularly, without being limited thereto, groups according to the present invention can be as represented below:
Figure imgf000022_0005
- * indicates the point of attachment of said group with the rest of the molecule, said ring F1 ' being optionally substituted one time with a group selected from : fluorine, chlorine, bromine, hydroxy, Ci-C4-alkyl, C3-cycloalkyl, Ci-alkoxy, -NH2, and - C(0)OR13, wherein Ci-C4-alkyl is optionally substituted one or two times with a group independently selected from fluorine, oxo (C=0), and -NH(Ci-alkyl).
Figure imgf000023_0001
Particularly, without being limited thereto, groups according to the present invention can be as represented below:
Figure imgf000023_0002
- * indicates the point of attachment of said group with the rest of the molecule, ring D1 being optionally substituted independently with one or two R5 groups, and
- R5 is as defined herein.
Figure imgf000023_0003
Particularly, without being limited thereto, groups according to the present invention can be as represented below:
Figure imgf000023_0004
- * indicates the point of attachment of said group with the rest of the molecule, ring D1 ' being optionally substituted independently with one R5 groups, and
- R5 is as defined herein.
The present invention includes all ring A groups described supra, including, but not limited to the ones depicted supra. The term "Ci -C6", as used throughout this text, e.g. in the context of the definition of "Ci -C6- alkyl", "Ci -C6-haloalkyl", or "Ci -C6-hydroxyalkyl", is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term "Ci -C6" is to be interpreted as any sub-range comprised therein, e.g. Ci -C6 , C2-C5 , C3-C4 , C1 -C2 , C1 -C3 , C1 -C4 , Ci -C5 ; particularly C1 -C2 , Ci -C3 , Ci -C4 , C1 -C5, Ci -C6; more particularly C1 -C4 ; in the case of "Ci -C6-haloalkyl" or "Ci -C6-haloalkoxy" even more particularly C1 -C2.
Similarly, as used herein, the term "C2-C6", as used throughout this text, e.g. in the context of the definitions of "C2-C6-alkyl", and "C2-C6-hydroxyalkyl" is to be understood as meaning an alkyl group or a hydroxyalkyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term "C2-C6" is to be interpreted as any sub-range comprised therein, e.g. C2-C6 , C3-C5 , C3-C4 , C2-C3 , C2-C4 , C2-C5 ; particularly
Further, as used herein, the term "C3-C6", as used throughout this text, e.g. in the context of the definition of "Cs-Ce-cycloalkyl", is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term "C3-C6" is to be interpreted as any sub-range comprised therein, e.g. C3- C6 , C4-C5 , C3-C5 , C3-C4 , C4-C6, Cs-Ce ; particularly C3-C6.
The term "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.
The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties. Ring system substituent means a substituent attached to an aromatic or nonaromatic ring system which, for example, replaces an available hydrogen on the ring system.
As used herein, the term "one or more", e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning "one, two, three, four or five, particularly one, two, three or four, more particularly one, two or three, even more particularly one or two".
The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 11C, 13C, 14C, 15N, 170, 180, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36CI, 82Br, 123l, 124l, 125l, 129l and 1311, respectively. Certain isotopic variations of a compound of the invention, for example, those in which one or more radioactive isotopes such as 3H or 14C are incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence is preferred in some circumstances. Isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.
By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The compounds of this invention optionally contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms is present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric centre, and diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
The compounds of the present invention optionally contain sulphur atoms which are asymmetric, such as an asymmetric sulfoxide, of structure:
Figure imgf000026_0001
, for example, in which * indicates atoms to which the rest of the molecule can be bound.
Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention.
Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.
The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. 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.
In order to limit different types of isomers from each other reference is made to lUPAC Rules Section E (Pure Appl Chem 45, 1 1 -30, 1976).
The 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, E- or Z-isomers, or cis or trans, 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 the methods provided herein or by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
Particularly, the relative configuration of the amino substituent (NR4) relative to the carbonyl group on the central cyclohexane ring can be depicted as follows:
Figure imgf000027_0001
cis-(l) trans-(l)
wherein A, R4, R6, R7, R8, R9, R10, R11 are as defined herein for the compound of formula (I) and n is 1 or 2.
With respect to the cyclohexane ring, the relative configuration of the amino (NR4) and carbonyl group substituents on said cyclohexane ring is to be understood as follows:
- the term "cis" is to be understood as the relative configuration in which said amino (NR4) and carbonyl groups are on the same side of the cyclohexane ring (irrespective of substituents R8 and R9). - the term "trans" is to be understood as the relative configuration in which said amino (NR4) and carbonyl groups are on the opposite side of the cyclohexane ring (irrespective of substituents R8 and R9).
The present invention includes all cis and trans isomers of the compounds of the present invention as single isomers, or as any mixture of said isomers, in any ratio.
Further, the compounds of the present invention may exist as tautomers. For example, any compound of the present invention which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1 H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, namely :
Figure imgf000028_0001
1 H-tautomer 2H-tautomer
The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
Further, the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides.
The present invention also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates.
The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds. The amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri- , tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.
Further, the compounds of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy.
The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1 -19.
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, persulfuric, 3-phenylpropionic, picric, pivalic, 2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic, dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic, methansulfonic, 2- naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.
Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is 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. Additionally, 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.
Those skilled in the art will further recognise that 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. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
In the present text, in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is, in most cases, unknown.
Unless specified otherwise, suffixes to chemical names or structural formulae such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCI", "x CF3COOH", "x Na+", for example, are to be understood as not a stoichiometric specification, but solely as a salt form.
This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates, such as hydrates with (if defined) unknown stoichiometric composition.
As used herein, 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-C6 alkoxymethyl esters, e.g. methoxymethyl, Ci-C6 alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters, C3-C8 cycloalkoxy- carbonyloxy-Ci-Ce alkyl esters, e.g. 1 -cyclohexylcarbonyloxyethyl ; 1 ,3-dioxolen-2-onylmethyl esters, e.g. 5-methyl-1 ,3-dioxolen-2-onylmethyl ; and Ci-C6-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. Examples of [alpha]-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N- alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. The present invention covers all such esters.
Furthermore, 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.
In accordance with a second aspect, the present invention covers compounds of general formula (I), supra, in which :
A represents a group selected from :
Figure imgf000031_0001
wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom;
Figure imgf000031_0002
represents a phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms; said phenyl and 6-membered heteroaryl ring being optionally substituted one, two or three times, independently from each other, with R5, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, and c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, wherein said rings are fused with ring A1 , said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5; or, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O and S;
Figure imgf000032_0001
ring A2 represents:
- a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
- a 5-membered heterocyclic ring, optionally partially unsaturated, which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two carbon atoms of the heterocyclyl ring are optionally replaced by a heteroatom-containing group selected from (C=0), N, NR20, O and S, said 5-membered heteroaryl and 5-membered heterocyclic rings being optionally substituted one, two or three times, independently from each other, with R5 , whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5 ; or whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O and S;
R4 represents a hydrogen atom,
R5 represents, independently of each other, a group selected from : halogen, hydroxy, Ci-C4-alkyl, C3-C4-cycloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, - N(R14)R15, - C(0)OR13, phenyl and 6-membered heteroaryl which contains one or two nitrogen atoms, wherein Ci-C4-alkyl is optionally substituted one, two or three times with a group independently selected from halogen, hydroxy, oxo (C=0), Ci-C3-alkoxy, C3-C6- cycloalkyl, -NH2, -NH(Ci-C3-alkyl) and -N(Ci-C3-alkyl)2;
R5 represents, independently of each other, a group selected from : halogen, hydroxy, Ci-C4-alkyl, C3-C4-cycloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, - N(R14)R15, -C(0)OR13, phenyl and 6-membered heteroaryl which contains one or two nitrogen atoms, wherein Ci-C4-alkyl is optionally substituted one, two or three times with a group independently selected from halogen, hydroxy, oxo (C=0), Ci-C3-alkoxy, C3-C6- cycloalkyl, -NH2, -NH(Ci-C3-alkyl) and -N(Ci-C3-alkyl)2;
R6 represents hydrogen; R7 represents hydrogen; or
R8 represents hydrogen,
R9 and R10 together represent a group selected from:
* #
\ CH C /H2 and CH CH CH2 wherein said groups are optionally substituted with one or two groups, which are independently of each other selected from :
Ci-C3-alkyl, wherein * indicates the point of attachment of said group to the rest of the molecule at
R9, and # indicates the point of attachment of said group to the rest of the molecule at R10 ; represents a group selected from : phenyl, and heteroaryl , wherein phenyl and heteroaryl groups are optionally substituted with one, two, three or four groups, which are independently of each other selected from :
Ci-C4-alkyl , Ci-C2-alkoxy, Ci-C3-hydroxyalkyl, C3-C4-cycloalkyl, Ci-C2-haloalkyl, Ci-C2-haloalkoxy, halogen, cyano, and hydroxy, represents a group selected from :
Ci-C3-alkyl, and C3-C4-cycloalkyl, and R15 are independently of each other selected from : hydrogen, Ci-C3-alkyl, and C3-C4-cycloalkyl, R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycloalkyl group, in which one carbon atom is optionally replaced by a further heteroatom-containing group selected from NR20 and O and in which one additional ring atom is optionally replaced by C(=0), said 4- to 6-membered heterocycloalkyl group being optionally substituted with one, two, three or four groups, which are independently of each other selected from :
Ci-alkyl, d-haloalkyl, Ci-alkoxy, Ci-haloalkoxy, C3-C4-cycloalkyl, -N(CH3)2, NH2, N(CH3)H, hydroxy, a halogen atom, and cyano,
R20 represents, independently of each other, a group selected from : hydrogen, Ci-C3-alkyl , Ci-C3-haloalkyl, C3-C4-cycloalkyl,
Figure imgf000035_0001
-
Figure imgf000035_0002
and phenyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, with the proviso that: - when ring A2 is a imidazolyl or a 1 ,3-oxazolyl group, then said group is connected to the rest of the molecule via the carbon atom at position 2 of the imidazolyl or 1 ,3-oxazolyl ring, as shown below:
Figure imgf000035_0003
wherein * indicates the point of attachment of said group with the rest of the molecule;
Figure imgf000035_0004
- ring A2 is not a unsubstituted or substituted group, wherein * indicates the point of attachment of said group with the rest of the molecule, wherein said point of attachment is a carbon atom and in which : ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C3-alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms, and, ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms.
In accordance with a third aspect, the present invention covers compounds of general formula (I), supra, in which : A represents a group selected from :
Figure imgf000036_0001
wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
Figure imgf000036_0002
represents a phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms; said phenyl and 6-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, and c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, wherein said rings are fused with ring A1 , said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, or two times, independently from each other, with R5; or, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that they jointly form a ethyleneoxy, or trimethyleneoxy group;
Figure imgf000037_0001
ring A2 represents: - a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
- a 5-membered heterocyclic ring, optionally partially unsaturated, which contains one heteroatom-containing group selected from NR20, in which one or two carbon atoms of the heterocyclyl ring are optionally replaced by a heteroatom-containing group selected from
(C=0), N, said 5-membered heteroaryl and 5-membered heterocyclic rings being optionally substituted one, two or three times, independently from each other, with R5 , whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5 ; or whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O and S;
R4 represents a hydrogen atom, R5 represents, independently of each other, a group selected from : fluorine, chlorine, bromine, hydroxy, Ci-C4-alkyl, C3-cycloalkyl, Ci-alkoxy, -NH2, - C(0)OR13, , wherein Ci-C4-alkyl is optionally substituted one or two times with a group independently selected from fluorine, oxo (C=0), -NH(Ci-alkyl); R5 represents, independently of each other, a group selected from : fluorine, chlorine, bromine, Ci-alkyl, C3-cycloalkyl, a 6-membered heteroaryl which contains one nitrogen atom,
R6 represents hydrogen;
R7 represents hydrogen; or R8 represents hydrogen,
R9 and R10 together represent a group selected from:
,# * #
\ CH C /H2 and CH CH CH2 wherein * indicates the point of attachment of said group to the rest of the molecule at R9, and # indicates the point of attachment of said group to the rest of the molecule at R10 ;
R11 represents a group selected from phenyl, wherein phenyl groups is optionally substituted with one, two, or three groups, which are independently of each other selected from :
Ci-alkyl, fluorine and chlorine,
R13 represents Ci-C3-alkyl,
R20 represents, independently of each other, a group selected from : hydrogen, Ci-C3-alkyl, -C(=0)Ci-alkyl, -C(=0)OC4-alkyl and phenyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, with the proviso that:
- when ring A2 is a imidazolyl or a 1 ,3-oxazolyl group, then said group is connected to the rest of the molecule via the carbon atom at position 2 of the imidazolyl or 1 ,3-oxazolyl ring, as shown below:
Figure imgf000039_0001
wherein * indicates the point of attachment of said group with the rest of the molecule;
Figure imgf000039_0002
wherein * indicates the point of attachment of said group with the rest of the molecule, wherein said point of attachment is a carbon atom and in which : ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C3-alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms,
, and ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms.
In accordance with a fourth aspect, the present invention covers compounds of general formula (I), supra, in which ring A represents:
Figure imgf000040_0001
wherein * indicates the point of attachment of said groups with the rest of the molecule, and in which : ring G1 represents a phenyl or a 6-membered heteroaryl ring which contains one or two nitrogen atoms, ring H1 represents phenyl or a 6-membered heteroaryl ring which contains one or two nitrogen atoms, with the proviso that when G1 or H1 is phenyl, then the other is a 6-membered heteroaryl group which contains one or two nitrogen atoms, said ring G1 and ring H1 being optionally substituted independently with one or two R5 groups.
In accordance with a fifth aspect, the present invention covers compounds of general formula (I), supra, in which :
Figure imgf000040_0002
ring A represents: wherein * indicates the point of attachment of said groups with the rest of the molecule, and in which : ring F1 represents phenyl or a 6-membered heteroaryl group which contains one or two nitrogen atoms, ring E1 represents a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or said ring E1 and ring F1 being optionally substituted independently with one or two R5 groups.
In accordance with a sixth aspect, the present invention covers compounds of general formula (I), supra, in which :
Figure imgf000041_0001
ring A represents: wherein * indicates the point of attachment of said groups with the rest of the molecule, and in which : ring F1 ' represents phenyl or a 6-membered heteroaryl group which contains one or two nitrogen atoms,
R5a and R5b are linked to one another in such a way that they jointly form a ethyleneoxy, or a trimethyleneoxy group, said ring F1 ' being optionally substituted one time with a group selected from : fluorine, chlorine, bromine, hydroxy, Ci-C4-alkyl, C3-cycloalkyl, Ci-alkoxy, -NH2, and -
C(0)OR13, wherein Ci-C4-alkyl is optionally substituted one or two times with a group independently selected from fluorine, oxo (C=0), and -NH(Ci-alkyl).
In accordance with a seventh aspect, the present invention covers compounds of general formula (I), supra, in which :
Figure imgf000041_0002
ring A represents: wherein * indicates the point of attachment of said groups with the rest of the molecule, and in which : ring C1 represents a 5-membered heteroaryl ring (with a nitrogen atom in the position shown), in which one or two ring carbon atoms are optionally further replaced by a heteroatom selected from N, NR20, O and S, ring D1 is a 6-membered heteroaryl ring (with a nitrogen atom in the position shown) in which one ring carbon atom is optionally further replaced by a nitrogen atom, ring D1 ' is a 5-membered heteroaryl ring (with a nitrogen atom in the position shown) in which one ring carbon atom is optionally further replaced by a heteroatom selected from N, NR20, O and S, said rings D1 and D1 ' being optionally substituted independently with one or two R5 groups.
In accordance with a eighth aspect, the present invention covers compounds of general formula (I), supra, in which ring A represents a group selected from: phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl, said groups being optionally substituted independently with one or two R5 groups.
In accordance with a ninth aspect, the present invention covers compounds of general formula (I), supra, in which ring A represents a group selected from: imidazol-2-yl, pyrazolyl, 1 ,3-thiazolyl, and 1 ,2-oxazolyl, said groups being optionally substituted independently with one or two R5 groups.
In accordance with a tenth aspect, the present invention covers a compound of general formula (I), supra, which is selected from the group consisting of :
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5- carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyridine-2-carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 ,5-naphthyridine-4- carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-6-methoxy-1 ,5- naphthyridine-4-carboxamide N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-y ]-4-methylpyridine-2- carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-y ]-1 H-pyrrolo[3,2- b]pyridine-5-carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-y ]pyrazolo[1 ,5-a]pyrimidine- 2-carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-y ]-1 H-benzimidazole-5- carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-y ]pyrazine-2-carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-y ]-3-methyl-1 ,2-oxazole-5- carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-y ]-1 H-benzotriazole-5- carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-y ]-5-oxo-1 -phenyl-4,5- dihydro-1 H-pyrazole-3-carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-y ]quinoline-8-carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-y ]-1 H-1 ,2,4-triazole-5- carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-y ]pyrimidine-4-carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-y ]-1 H-imidazole-2- carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-y ]quinoline-7-carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-y ]pyrazolo[1 ,5-a]pyridine-2- carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-y ]-1 -methyl-1 H- benzimidazole-5-carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-y ]imidazo[1 ,2-a]pyridine-6- carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-5-methyl-1 ,3-oxazole-4- carboxamide tert-butyl 3-chloro-2-{[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8- yl]carbamoyl}-5,6-dihydroimidazo[1 ,2-a]pyrazine-7(8H)-carboxylate
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-3-cyclopropyl-6,7- dihydro-5H-pyrrolo[2,1 -c][1 ,2,4]triazole-5-carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-3- cyclopropyl[1 ,2,4]triazolo[4,3-a]pyridine-6-carboxamide
6-bromo-N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyrazolo[1 ,5- a]pyrimidine-2-carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-4-methoxybenzamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]isoquinoline-1 - carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoline-2-carboxamide
2-amino-N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyridine-3- carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-5,7- dimethylpyrazolo[1 ,5-a]pyrimidine-2-carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-2- carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-2-(pyridin-3-yl)-1 ,3- thiazole-4-carboxamide
6-chloro-N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyrazine-2- carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 ,2-oxazole-5- carboxamide
5-bromo-N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-2,3-dihydro-1 - benzofuran-7-carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 ,8-naphthyridine-2- carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 ,3-thiazole-4- carboxamide
5- chloro-N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyridine-2- carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-5-cyclopropyl-1 H- pyrazole-3-carboxam ide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]imidazo[2,1 - b][1 ,3]thiazole-6-carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-5-cyclopropyl-1 ,2- oxazole-3-carboxam ide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-6-hydroxypyridine-2- carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 ,2-oxazole-3- carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 H-indazole-7- carboxamide
6- bromo-N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoline-8- carboxamide
1 -acetyl-N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-3-hydroxy-1 H- indazole-6-carboxamide
6-bromo-N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 -(propan-2-yl)- 1 H-indazole-3-carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-6- (difluoromethyl)pyridine-2-carboxamide
N-[(trans)-2-(4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5-carboxamide N-[(trans)-2-(2-chloro-4-fluoro-5-methylphenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyrimidine-4- carboxamide
N-[(trans)-2-(2-chloro-4-fluoro-5-methylphenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-3- fluoropyridine-2-carboxamide
N-[(trans)-2-(2-chloro-4-fluoro-5-methylphenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoline-2- carboxamide
N-[(trans)-2-(2-chloro-4-fluoro-5-methylphenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-5-fluoro-6- methylpyridine-2-carboxamide
N-[(trans)-2-(2-chloro-4-fluoro-5-methylphenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 H- pyrazolo[3,4-b]pyridine-5-carboxamide
N-[(trans)-2-(2-chloro-4-fluoro-5-methylphenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-4,6- dimethylpyrimidine-2-carboxamide
N-[(trans)-2-(2-chloro-4-fluoro-5-methylphenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5- carboxamide
N-[(trans)-2-(2-chloro-4,6-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5- carboxamide
N-[(trans)-2-(3,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5-carboxamide
N-[(trans)-1 -oxo-2-phenyl-2-azaspiro[4.5]dec-8-yl]quinoxaline-5-carboxamide
N-[(trans)-2-(3-chlorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5-carboxamide
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 ,8-naphthyridine-2- carboxamide
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-4-methoxyquinoline- 2-carboxamide methyl6-{[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8- yl]carbamoyl}pyridine-3-carboxylate
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyridazine-3- carboxamide
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-3-methoxypyrazine- 2-carboxamide
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-3-methylpyrazine-2- carboxamide
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-8-hydroxyquinoline- 7-carboxamide
2-tert-butyl-N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 ,3- benzoxazole-6-carboxamide
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 ,6-naphthyridine-2- carboxamide
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-4,6- dimethylpyrimidine-2-carboxamide
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-5-fluoro-6- methylpyridine-2-carboxamide
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-2,3-dihydro-1 - benzofuran-7-carboxamide
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5- carboxamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[5.5]undec-9-yl]quinoxaline-5- carboxamide
N-[(trans)-2-(2-chlorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5-carboxamide, and N-[(trans)-2-(2-chlorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyridine-2-carboxamide, and N-[(cis)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5-carboxamide,
2-chloro-4-fluoro-N-[(trans)-1 -oxo-2-(pyridin-2-yl)-2-azaspiro[4.5]decan-8-yl]benzamide or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In a further aspect, the invention relates to compounds of formula (I) supra, wherein: A represents:
Figure imgf000048_0001
wherein * indicates the point of attachment of said group with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
Figure imgf000048_0002
represents a phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms; said phenyl and 6-membered heteroaryl ring being optionally substituted one, two or three times, independently from each other, with R5, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, and c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, wherein said rings are fused with ring A1 , said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5; or, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O, S, S(=0) and S(=0)2;
R4 represents a hydrogen atom, R5 represents, independently of each other, a group selected from : halogen, hydroxy, Ci-C4-alkyl, C3-C4-cycloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, - N(R14)R15, - C(0)OR13, -C(0)OH, phenyl and 6-membered heteroaryl which contains one or two nitrogen atoms, wherein Ci-C4-alkyl is optionally substituted one, two or three times with a group independently selected from halogen, hydroxy, oxo (C=0), Ci-C3-alkoxy, C3-C6- cycloalkyl, -NH2, -NH(Ci-C3-alkyl) and -N(Ci-C3-alkyl)2;
R6 represents hydrogen, halogen, hydroxy, Ci -C3-alkyl or Ci-C3-alkoxy;
R7 represents hydrogen; or
R6, R7 represent, independently of each other, halogen;
R8 represents hydrogen, or Ci -C3-alkyl,
R9 and R10 together represent a group selected from:
\ CH C /H2 and CH CH CH2 wherein said groups are optionally substituted with one or two groups, which are independently of each other selected from : halogen, Ci-C3-alkyl, Ci-C3-alkoxy, hydroxy, Ci-C3-haloalkyl, and Ci-C3-hydroxyalkyl, wherein * indicates the point of attachment of said group to the rest of the molecule at R9, and
# indicates the point of attachment of said group to the rest of the molecule at R10 ; represents a group selected from : aryl, and heteroaryl , wherein aryl and heteroaryl groups are optionally substituted with one, two, three or four groups, which are independently of each other selected from :
Ci-Ce-alkyl, Ci-C3-alkoxy, Ci -C3-hydroxyalkyl, C3-C6-cycloalkyl, C3-C6- cycloalkoxy, Ci -C3-haloalkyl, Ci -C3-haloalkoxy, halogen, cyano, nitro, hydroxy, (Ci -C6-alkyl)-S-, (Ci -C6-alkyl)-S(=0)-,
Figure imgf000049_0001
- N( R1 4) R1 5, R1 4( R1 5)N-(Ci -C6-alkyl)-, R1 4(R15)N-(C2-C6-alkoxy)-, phenyl, phenoxy, -N(R16)C(=0) R1 7, -C(=0)OH, -C(=0)OR13, and -C(=0)N( R1 6)2, whereby two substituents of said aryl group, when they are in ortho-position to one another, can be linked to one another in such a way that they jointly form methanediylbisoxy, ethane-1 ,2-diylbisoxy, propane-1 ,3-diyl, or butane-1 ,4-diyl,
R1 3 represents a group selected from :
Ci -Ce-alkyl, C3-C6-cycloalkyl, C2-C6-hydroxyalkyl-, and (Ci -C3-alkoxy)-(C2-C6-alkyl)-,
R1 4 and R1 5 are independently of each other selected from : hydrogen, Ci -C6-alkyl, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci -C6-alkyl)-, C2-C6-hydroxyalkyl, (Ci -C3-alkoxy)-(C2-C6-alkyl)-, Ci -C6-haloalkyl, H2N-(C2-C6-alkyl)-, (Ci -C3-alkyl)N(H)(C2-C6-alkyl)-, (Ci -C3-alkyl)2N(C2-C6-alkyl)-,
Figure imgf000050_0001
Figure imgf000050_0002
or,
R1 4 and R1 5 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, in which one carbon atom is optionally replaced by a further heteroatom-containing group selected from N R20 , O, S, S(=0) and S(=0)2, and in which one additional ring atom is optionally replaced by C(=0), said 4- to 7-membered heterocycloalkyl group being optionally substituted with one, two, three or four groups, which are independently of each other selected from :
Ci -C3-alkyl, Ci -C3-haloalkyl, Ci -C3-alkoxy, Ci -C3-haloalkoxy, C3-C4-cycloalkyl, C3-C4- cycloalkoxy, -N(CH3)2, NH2, N(CH3)H, hydroxy, a halogen atom , and cyano, whereby when two substituents are attached to the same ring carbon atom, together with the carbon atom to which they are attached, can be linked to one another in such a way that they jointly form a cyclobutane, cyclopentane, azetidine, pyrrolidine, oxetane, tetrahydrofuran, thietane, tetrahydrothiophene, thietane 1 -oxide, tetrahydrothiophene 1 - oxide, thietane 1 ,1 -dioxide or tetrahydrothiophene 1 ,1 -dioxide group;
R1 6 represents, independently of each other, hydrogen, or Ci -C3-alkyl,
R1 7 represents hydrogen, Ci -C6-alkyl, Ci -C6-hydroxyalkyl, C3-C6-cycloalkyl, Ci -Ce-haloalkyl, (Ci -C3-alkoxy)-(Ci -C6-alkyl)-, aryl, or heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently of each other selected from :
Ci-C3-alkyl, C3-C6-cycloalkyl, Ci-C3-alkoxy, C3-C6-cycloalkoxy, Ci-C3-haloalkyl, Ci-C3-haloalkoxy, halogen, cyano, and hydroxy, R20 represents, independently of each other, a group selected from : hydrogen, Ci-C3-alkyl, Ci-C3-haloalkyl, C3-C4-cycloalkyl,
Figure imgf000051_0001
-C(=0)OCi- C4-alkyl and phenyl,
R21 represents hydrogen, cyano, (Ci-C3-alkyl)-C(=0)-, or (Ci-C3-haloalkyl)-C(=0)-,
R22 represents Ci-C4-alkyl, or C3-C -cycloalkyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In a further aspect, the invention relates to compounds of formula (I) supra, wherein: A represents:
Figure imgf000051_0002
wherein * indicates the point of attachment of said group with the rest of the molecule, and wherein said point of attachment is a carbon atom;
Figure imgf000051_0003
- a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
- a 5-membered heterocyclic ring, optionally partially unsaturated, which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two carbon atoms of the heterocyclyl ring are optionally replaced by a heteroatom-containing group selected from (C=0), N, NR20, O, S, S(=0) and S(=0)2, said 5-membered heteroaryl and 5-membered heterocyclic rings being optionally substituted one, two or three times, independently from each other, with R5 , whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5 ; or whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O, S, S(=0) and S(=0)2;
R4 represents a hydrogen atom,
R5 represents, independently of each other, a group selected from : halogen, hydroxy, Ci-C4-alkyl, C3-C4-cycloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, - N(R14)R15, -C(0)OR13, -C(0)OH, phenyl and 6-membered heteroaryl which contains one or two nitrogen atoms, wherein Ci-C4-alkyl is optionally substituted one, two or three times with a group independently selected from halogen, hydroxy, oxo (C=0), Ci-C3-alkoxy, C3-C6- cycloalkyl, -NH2, -NH(Ci-C3-alkyl) and -N(Ci-C3-alkyl)2; represents hydrogen, halogen, hydroxy, Ci -C3-alkyl or Ci -C3-alkoxy; represents hydrogen; or
R6, R7 represent, independently of each other, halogen; represents hydrogen, or Ci -C3-alkyl,
R9 and R10 together represent a group selected from:
Figure imgf000053_0001
wherein said groups are optionally substituted with one or two groups, which are independently of each other selected from : halogen, Ci -C3-alkyl, Ci -C3-alkoxy, hydroxy, Ci -C3-haloalkyl, and Ci -C3-hydroxyalkyl, wherein * indicates the point of attachment of said group to the rest of the molecule at
R9, and
* indicates the point of attachment of said group to the rest of the molecule at R10 ;
R11 represents a group selected from : aryl, and heteroaryl , wherein aryl and heteroaryl groups are optionally substituted with one, two, three or four groups, which are independently of each other selected from :
Ci -Ce-alkyl, Ci -C3-alkoxy, Ci -C3-hydroxyalkyl, C3-C6-cycloalkyl, C3-C6- cycloalkoxy, Ci -C3-haloalkyl, Ci -C3-haloalkoxy, halogen, cyano, nitro, hydroxy, (Ci -Ce-alkyl)-S-, (Ci -C6-alkyl)-S(=0)-, (Ci -C6-alkyl)-S(=0)2-, -S(=0)(=NR21)R22, - N(R14)R15, R14(R15)N-(Ci -C6-alkyl)-, R14(R15)N-(C2-C6-alkoxy)-, phenyl, phenoxy, -N(R16)C(=0)R17, -C(=0)OH, -C(=0)OR13, and -C(=0)N(R16)2, whereby two substituents of said aryl group, when they are in ortho-position to one another, can be linked to one another in such a way that they jointly form methanediylbisoxy, ethane-1 ,2-diylbisoxy, propane-1 ,3-diyl, or butane-1 ,4-diyl, R13 represents a group selected from :
Ci -Ce-alkyl, C3-C6-cycloalkyl, C2-C6-hydroxyalkyl-, and (Ci -C3-alkoxy)-(C2-C6-alkyl)-, R14 and R15 are independently of each other selected from hydrogen, Ci -Ce-alkyl, CVCe-cycloalkyl, (C3-C6-cycloalkyl)-(Ci -C6-alkyl)-, C2-C6-hydroxyalkyl, (Ci -C3-alkoxy)-(C2-C6-alkyl)-, Ci -C6-haloalkyl, H2N-(C2-C6-alkyl)-, (Ci -C3-alkyl)N(H)(C2-C6-alkyl)-, (Ci -C3-alkyl)2N(C2-C6-alkyl)-,
Figure imgf000054_0001
Figure imgf000054_0002
or,
R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, in which one carbon atom is optionally replaced by a further heteroatom-containing group selected from NR20, O, S, S(=0) and S(=0)2, and in which one additional ring atom is optionally replaced by C(=0), said 4- to 7-membered heterocycloalkyl group being optionally substituted with one, two, three or four groups, which are independently of each other selected from :
Ci -C3-alkyl, Ci -C3-haloalkyl, Ci -C3-alkoxy, Ci -C3-haloalkoxy, C3-C4-cycloalkyl, C3-C - cycloalkoxy, -N(CH3)2, NH2, N(CH3)H, hydroxy, a halogen atom , and cyano, whereby when two substituents are attached to the same ring carbon atom, together with the carbon atom to which they are attached, can be linked to one another in such a way that they jointly form a cyclobutane, cyclopentane, azetidine, pyrrolidine, oxetane, tetrahydrofuran, thietane, tetrahydrothiophene, thietane 1 -oxide, tetrahydrothiophene 1 - oxide, thietane 1 ,1 -dioxide or tetrahydrothiophene 1 ,1 -dioxide group; R16 represents, independently of each other, hydrogen, or Ci -C3-alkyl,
R17 represents hydrogen, Ci -C6-alkyl, Ci -C6-hydroxyalkyl, C3-C6-cycloalkyl, Ci -Ce-haloalkyl, (Ci -C3-alkoxy)-(Ci -C6-alkyl)-, aryl, or heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently of each other selected from : Ci -C3-alkyl, C3-C6-cycloalkyl, Ci -C3-alkoxy, C3-C6-cycloalkoxy,
Ci -C3-haloalkyl, Ci -C3-haloalkoxy, halogen, cyano, and hydroxy,
R20 represents, independently of each other, a group selected from : hydrogen, Ci -C3-alkyl, Ci -C3-haloalkyl, C3-C4-cycloalkyl,
Figure imgf000054_0003
-C(=0)OCi - C -alkyl and phenyl, R21 represents hydrogen, cyano, (Ci -C3-alkyl)-C(=0)-, or (Ci -C3-haloalkyl)-C(=0)-, R22 represents Ci-C4-alkyl, or C3-C4-cycloalkyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, with the proviso that: - when ring A2 is a imidazolyl or a 1 ,3-oxazolyl group, then said group is connected to the rest of the molecule via the carbon atom at position 2 of the imidazolyl or 1 ,3-oxazolyl ring, as shown below:
Figure imgf000055_0001
wherein * indicates the point of attachment of said group with the rest of the molecule;
Figure imgf000055_0002
- ring A2 is not a unsubstituted or substituted group, wherein * indicates the point of attachment of said group with the rest of the molecule, wherein said point of attachment is a carbon atom and in which : ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C3-alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms,
, and ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms.
In a further aspect, the invention relates to compounds of formula (I) supra, wherein A represents a group: A1 wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
Figure imgf000056_0001
ring A1 represents a phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms; said phenyl and 6-membered heteroaryl ring being optionally substituted one, two or three times, independently from each other, with R5, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, and c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, wherein said rings are fused with ring A1 , said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5; or, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O and S;
R4 represents a hydrogen atom,
R5 represents, independently of each other, a group selected from halogen, hydroxy, Ci-C4-alkyl, C3-C4-cycloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, - N(R14)R15, - C(0)OR13, phenyl and 6-membered heteroaryl which contains one or two nitrogen atoms, wherein Ci-C4-alkyl is optionally substituted one, two or three times with a group independently selected from halogen, hydroxy, oxo (C=0), Ci-C3-alkoxy, C3-C6- cycloalkyl, -NH2, -NH(Ci-C3-alkyl) and -N(Ci-C3-alkyl)2;
R6 represents hydrogen;
R7 represents hydrogen; or
R8 represents hydrogen, R9 and R10 together represent a group selected from:
* #
\ CH C /H2 and CH CH CH2 wherein said groups are optionally substituted with one or two groups, which are independently of each other selected from :
Ci-C3-alkyl, wherein * indicates the point of attachment of said group to the rest of the molecule at
R9, and
# indicates the point of attachment of said group to the rest of the molecule at R10 ; R11 represents a group selected from : phenyl, and heteroaryl , wherein phenyl and heteroaryl groups are optionally substituted with one, two, three or four groups, which are independently of each other selected from :
Ci-C4-alkyl , Ci-C2-alkoxy, Ci-C3-hydroxyalkyl, C3-C4-cycloalkyl, Ci-C2-haloalkyl, Ci-C2-haloalkoxy, halogen, cyano, and hydroxy,
R13 represents a group selected from : Ci-C3-alkyl, and C3-C4-cycloalkyl,
R14 and R15 are independently of each other selected from hydrogen, Ci-C3-alkyl, and C3-C4-cycloalkyl, or,
R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycloalkyi group, in which one carbon atom is optionally replaced by a further heteroatom-containing group selected from NR20 and O and in which one additional ring atom is optionally replaced by C(=0), said 4- to 6-membered heterocycloalkyi group being optionally substituted with one, two, three or four groups, which are independently of each other selected from :
Ci-alkyl, Ci-haloalkyl, Ci-alkoxy , Ci-haloalkoxy, C3-C4-cycloalkyl, -N(CH3)2, NH2, N(CH3)H, hydroxy, a halogen atom, and cyano,
R20 represents, independently of each other, a group selected from : hydrogen, Ci-C3-alkyl, Ci-C3-haloalkyl, C3-C4-cycloalkyl,
Figure imgf000058_0001
C -alkyl and phenyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In a further aspect, the invention relates to compounds of formula (I) supra, wherein: A represents a group:
Figure imgf000058_0002
wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
Figure imgf000058_0003
ring A2 represents: - a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
- a 5-membered heterocyclic ring, optionally partially unsaturated, which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two carbon atoms of the heterocyclyl ring are optionally replaced by a heteroatom-containing group selected from (C=0), N, NR20, O and S, said 5-membered heteroaryl and 5-membered heterocyclic rings being optionally substituted one, two or three times, independently from each other, with R5 , whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5 ; or whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O and S;
R4 represents a hydrogen atom,
R5 represents, independently of each other, a group selected from : halogen, hydroxy, Ci-C4-alkyl, C3-C4-cycloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, - N(R14)R15, -C(0)OR13, phenyl and 6-membered heteroaryl which contains one or two nitrogen atoms, wherein Ci-C4-alkyl is optionally substituted one, two or three times with a group independently selected from halogen, hydroxy, oxo (C=0), Ci-C3-alkoxy, C3-C6- cycloalkyl, -NH2, -NH(Ci-C3-alkyl) and -N(Ci-C3-alkyl)2;
R6 represents hydrogen;
R7 represents hydrogen; or
R8 represents hydrogen, R9 and R10 together represent a group selected from:
* #
\ CH C /H2 and CH CH CH2 wherein said groups are optionally substituted with one or two groups, which are independently of each other selected from :
Ci-C3-alkyl, wherein * indicates the point of attachment of said group to the rest of the molecule at
R9, and
# indicates the point of attachment of said group to the rest of the molecule at R10 ; R11 represents a group selected from : phenyl, and heteroaryl , wherein phenyl and heteroaryl groups are optionally substituted with one, two, three or four groups, which are independently of each other selected from :
Ci-C4-alkyl , Ci-C2-alkoxy, Ci-C3-hydroxyalkyl, C3-C4-cycloalkyl, Ci-C2-haloalkyl, Ci-C2-haloalkoxy, halogen, cyano, and hydroxy,
R13 represents a group selected from : Ci-C3-alkyl, and C3-C4-cycloalkyl,
R14 and R15 are independently of each other selected from hydrogen, Ci-C3-alkyl, and C3-C4-cycloalkyl, or,
R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycloalkyl group, in which one carbon atom is optionally replaced by a further heteroatom-containing group selected from NR20 and O and in which one additional ring atom is optionally replaced by C(=0), said 4- to 6-membered heterocycloalkyl group being optionally substituted with one, two, three or four groups, which are independently of each other selected from :
Ci-alkyl, Ci-haloalkyl, Ci-alkoxy , Ci-haloalkoxy, C3-C4-cycloalkyl, -N(CH3)2, NH2, N(CH3)H, hydroxy, a halogen atom, and cyano,
R20 represents, independently of each other, a group selected from : hydrogen, Ci-C3-alkyl, Ci-C3-haloalkyl, C3-C4-cycloalkyl,
Figure imgf000061_0001
C -alkyl and phenyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, with the proviso that:
- when ring A2 is a imidazolyl or a 1 ,3-oxazolyl group, then said group is connected to the rest of the molecule via the carbon atom at position 2 of the imidazolyl or 1 ,3-oxazolyl ring, as shown below:
Figure imgf000061_0002
wherein * indicates the point of attachment of said group with the rest of the molecule;
Figure imgf000061_0003
- ring A2 is not a unsubstituted or substituted group, wherein * indicates the point of attachment of said group with the rest of the molecule, wherein said point of attachment is a carbon atom and in which : ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C3-alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms,
, and ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms.
In a further aspect, the invention relates to compounds of formula (I) supra, wherein: A represents a group:
Figure imgf000062_0001
wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
Figure imgf000062_0002
ring A1 represents a phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms; said phenyl and 6-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, and c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, wherein said rings are fused with ring A1 , said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, or two times, independently from each other, with R5; or, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that they jointly form a ethyleneoxy, or trimethyleneoxy group;
R4 represents a hydrogen atom,
R5 represents, independently of each other, a group selected from : fluorine, chlorine, bromine, hydroxy, Ci-C4-alkyl, C3-cycloalkyl, Ci-alkoxy, -NH2, - C(0)OR13, wherein Ci-C4-alkyl is optionally substituted one or two times with a group independently selected from fluorine, oxo (C=0), and -NH(Ci-alkyl);
R6 represents hydrogen;
R7 represents hydrogen;
R8 represents hydrogen, R9 and R10 together represent a group selected from:
* #
\ CH C /H2 and CH CH CH2 wherein * indicates the point of attachment of said group to the rest of the molecule at
R9, and # indicates the point of attachment of said group to the rest of the molecule at R10 ; represents a group selected from : phenyl, wherein phenyl groups is optionally substituted with one, two, or three groups, which are independently of each other selected from :
Ci-alkyl, fluorine and chlorine,
R13 represents Ci-C3-alkyl, R20 represents, independently of each other, a group selected from : hydrogen, Ci-C3-alkyl , -C(=0)Ci-alkyl, -C(=0)OC4-alkyl and phenyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
In a further aspect, the invention relates to compounds of formula (I) supra, wherein: A represents a group:
Figure imgf000064_0001
wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
Figure imgf000064_0002
ring A2 represents:
- a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
- a 5-membered heterocyclic ring, optionally partially unsaturated, which contains one heteroatom-containing group selected from NR20, in which one or two carbon atoms of the heterocyclyl ring are optionally replaced by a heteroatom-containing group selected from (C=0), N, said 5-membered heteroaryl and 5-membered heterocyclic rings being optionally substituted one, two or three times, independently from each other, with R5 , whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5 ; or whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O and S;
R4 represents a hydrogen atom,
R5 represents, independently of each other, a group selected from : fluorine, chlorine, bromine, Ci-alkyl, C3-cycloalkyl, and a 6-membered heteroaryl which contains one nitrogen atom,
R6 represents hydrogen;
R7 represents hydrogen;
R8 represents hydrogen,
R9 and R10 together represent a group selected from :
* # * #
\ CH C /H2 and \ CH CH C /H2 wherein * indicates the point of attachment of said group to the rest of the molecule at
R9, and # indicates the point of attachment of said group to the rest of the molecule at R10 ; R11 represents a group selected from : phenyl, wherein phenyl groups is optionally substituted with one, two, or three groups, which are independently of each other selected from :
Ci-alkyl, fluorine and chlorine,
R13 represents Ci-C3-alkyl, R20 represents, independently of each other, a group selected from : hydrogen, Ci-C3-alkyl , -C(=0)Ci-alkyl, -C(=0)OC4-alkyl and phenyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, with the proviso that: - when ring A2 is a imidazolyl or a 1 ,3-oxazolyl group, then said group is connected to the rest of the molecule via the carbon atom at position 2 of the imidazolyl or 1 ,3-oxazolyl ring, as shown below:
Figure imgf000066_0001
wherein * indicates the point of attachment of said group with the rest of the molecule;
Figure imgf000066_0002
- ring A2 is not a unsubstituted or substituted group, wherein * indicates the point of attachment of said group with the rest of the molecule, wherein said point of attachment is a carbon atom and in which : ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C3-alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms,
, and ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds
Figure imgf000067_0001
of formula (I), supra, wherein ring A2 , * indicates the point of attachment of said groups with the rest of the molecule, represents:
- a 5-membered heterocyclic ring, optionally partially unsaturated, which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two carbon atoms of the heterocyclyl ring are optionally replaced by a heteroatom-containing group selected from (C=0), N, NR20, O, S, S(=0) and S(=0)2,
said 5-membered heterocyclic rings being substituted two or three times, independently from each other, with R5 , whereby two substituents R5 are in adjacent positions of the ring A2 and linked to one another in such a way that together with the atoms to which they are attached they jointly form : a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5 ; or whereby two substituents R5 are in adjacent positions of the ring A2 and linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom-containing group selected from (C=0), NR20, O, S, S(=0) and S(=0)2.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds
Figure imgf000068_0001
of formula (I), supra, wherein ring A2 , * indicates the point of attachment of said groups with the rest of the molecule, represents:
- a 5-membered heterocyclic ring, optionally partially unsaturated, which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two carbon atoms of the heterocyclyl ring are optionally replaced by a heteroatom-containing group selected from (C=0), N, NR20, O and S, said 5-membered heterocyclic ring being substituted two or three times, independently from each other, with R5 , whereby two substituents R5 are in adjacent positions of the ring A2 and linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5 ; or whereby two substituents R5 are in adjacent positions of the ring A2 and linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom-containing group selected from (C=0), NR20, O and S.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds
Figure imgf000069_0001
of formula (I), supra, wherein ring A2 , * indicates the point of attachment of said groups with the rest of the molecule, represents:
- a 5-membered heterocyclic ring, optionally partially unsaturated, which contains one heteroatom-containing group selected from NR20, in which one or two carbon atoms of the heterocyclyl ring are optionally replaced by a heteroatom-containing group selected from (C=0), N, said 5-membered heterocyclic rings being substituted two or three times, independently from each other, with R5 , whereby two substituents R5 are in adjacent positions of the ring A2 and linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5 ; or whereby two substituents R5 are in adjacent positions of the ring A2 and linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom-containing group selected from (C=0), NR20, O and S.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), supra, wherein ring A represents:
Figure imgf000070_0001
wherein * indicates the point of attachment of said groups with the rest of the molecule, and in which : ring G1 represents a phenyl or a 6-membered heteroaryl ring which contains one or two nitrogen atoms, ring H1 represents phenyl or a 6-membered heteroaryl ring which contains one or two nitrogen atoms, with the proviso that when G1 or H1 is phenyl, then the other is a 6-membered heteroaryl group which contains one or two nitrogen atoms, said ring G1 and ring H1 being optionally substituted independently with one or two R5 groups.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), supra, wherein ring A represents:
Figure imgf000070_0002
wherein * indicates the point of attachment of said groups with the rest of the molecule, and in which : ring F1 represents phenyl or a 6-membered heteroaryl group which contains one or two nitrogen atoms, ring E1 represents a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or said ring E1 and ring F1 being optionally substituted independently with one or two R5 groups.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), supra, wherein ring A represents:
Figure imgf000071_0001
wherein * indicates the point of attachment of said groups with the rest of the molecule, and in which : ring F1 ' represents phenyl or a 6-membered heteroaryl group which contains one or two nitrogen atoms,
R5a and R5b are linked to one another in such a way that they jointly form a ethyleneoxy, or a trimethyleneoxy group, said ring F1 ' being optionally substituted one time with a group selected from : fluorine, chlorine, bromine, hydroxy, Ci-C4-alkyl, C3-cycloalkyl, Ci-alkoxy, -NH2, and -
C(0)OR13, wherein Ci-C4-alkyl is optionally substituted one or two times with a group independently selected from fluorine, oxo (C=0), and -NH(Ci-alkyl).
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), supra, wherein ring A represents:
Figure imgf000071_0002
wherein * indicates the point of attachment of said groups with the rest of the molecule, and in which : ring C1 represents a 5-membered heteroaryl ring (with a nitrogen atom in the position shown), in which one or two ring carbon atoms are optionally further replaced by a heteroatom selected from N, NR20, O and S, ring D1 is a 6-membered heteroaryl ring (with a nitrogen atom in the position shown), in which one ring carbon atom is optionally further replaced by a nitrogen atom, ring D1 ' is a 5-membered heteroaryl ring (with a nitrogen atom in the position shown), in which one ring carbon atom is optionally further replaced by a heteroatom selected from N, NR20, O and S, said rings D1 and D1 ' being optionally substituted independently with one or two R5 groups.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), supra, wherein ring A represents: phenyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl, said groups being optionally substituted independently with one or two R5 groups.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), supra, wherein ring A represents: phenyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), supra, wherein ring A represents: imidazol-2-yl, pyrazolyl, 1 ,3-thiazolyl, or 1 ,2-oxazolyl, said groups being optionally substituted independently with one or two R5 groups.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), supra, wherein ring A represents: imidazol-2-yl, pyrazolyl, 1 ,3-thiazolyl, or 1 ,2-oxazolyl. In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), supra, wherein ring A represents:
Figure imgf000073_0001
wherein * indicates the point of attachment of said groups with the rest of the molecule, in which:
Xb represents CH or N, Xa represents CH or N, said ring A being optionally substituted independently with one or two R5 groups.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), supra, wherein ring A represents:
Figure imgf000073_0002
wherein * indicates the point of attachment of said groups with the rest of the molecule, in which:
Xc represents CH or N,
Xd represents CH or N,
Xe represents CH or N,
Xf represents CH or N, with the proviso that when one of Xc, Xd, Xe, or Xf is N the others are CH, said ring A being optionally substituted independently with one or two R5 groups. In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein the compound of formula (I) has the cis configuration :
Figure imgf000074_0001
cis-(l)
wherein A, R4, R6, R7, R8, R9, R10, R11 are as defined herein for the compound of formula (I).
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein the compound of formula (I) has the cis configuration :
Figure imgf000074_0002
cis-(l)
in which A, R4, R6, R7, R8, R11 are as defined herein for the compound of formula (I), and n is 1 or 2.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein the compound of formula (I) has the trans configuration :
Figure imgf000075_0001
trans-(l)
wherein A, R4, R6, R7, R8, R9, R10, R11 are as defined herein for the compound of formula (I).
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein the compound of formula (I) has the trans configuration :
Figure imgf000075_0002
trans-(l)
in which A, R4, R6, R7, R8, R11 are as defined herein for the compound of formula (I), and n is 1 or 2.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
A represents a ring group selected from:
Figure imgf000075_0003
wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
Figure imgf000076_0001
represents a phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms; said phenyl and 6-membered heteroaryl ring being optionally substituted one, two or three times, independently from each other, with R5, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, and c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, wherein said rings are fused with ring A1 , said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5; or, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O, S, S(=0) and S(=0)2;
Figure imgf000076_0002
represents: - a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
- a 5-membered heterocyclic ring, optionally partially unsaturated, which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two carbon atoms of the heterocyclyl ring are optionally replaced by a heteroatom-containing group selected from (C=0), N, NR20, O, S, S(=0) and S(=0)2, said 5-membered heteroaryl and 5-membered heterocyclic rings being optionally substituted one, two or three times, independently from each other, with R5 , whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5 ; or whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O, S, S(=0) and S(=0)2.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein : ring A represents
Figure imgf000078_0001
wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
Figure imgf000078_0002
represents a phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms; said phenyl and 6-membered heteroaryl ring being optionally substituted one, two or three times, independently from each other, with R5, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, with the proviso that ring A1 is not phenyl, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, and c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, wherein said rings are fused with ring A1 , said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5; or, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O, S, S(=0) and S(=0)2. In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
Figure imgf000079_0001
represents wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
Figure imgf000079_0002
ring A2 represents:
- a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or - a 5-membered heterocyclic ring, optionally partially unsaturated, which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two carbon atoms of the heterocyclyl ring are optionally replaced by a heteroatom-containing group selected from (C=0), N, NR20, O, S, S(=0) and S(=0)2, said 5-membered heteroaryl and 5-membered heterocyclic rings being optionally substituted one, two or three times, independently from each other, with R5 , whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5 ; or whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O, S, S(=0) and S(=0)2.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
A represents a ring group selected from:
Figure imgf000080_0001
wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
ring A1
Figure imgf000080_0002
represents a phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms; said phenyl and 6-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, and c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, wherein said rings are fused with ring A1 , said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, or two times, independently from each other, with R5; or, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that they jointly form a ethyleneoxy, or trimethyleneoxy group;
Figure imgf000081_0001
represents:
- a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
- a 5-membered heterocyclic ring, optionally partially unsaturated, which contains one heteroatom-containing group selected from NR20, in which one or two carbon atoms of the heterocyclyl ring are optionally replaced by a heteroatom-containing group selected from
(C=0), N, said 5-membered heteroaryl and 5-membered heterocyclic rings being optionally substituted one, two or three times, independently from each other, with R5 , whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5 ; or whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O and S.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
Figure imgf000082_0001
represents wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
Figure imgf000082_0002
ring A1 represents a phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms; said phenyl and 6-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, and c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, wherein said rings are fused with ring A1 , said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, or two times, independently from each other, with R5; or, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that they jointly form a ethyleneoxy, or trimethyleneoxy group.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
Figure imgf000083_0001
represents wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
Figure imgf000083_0002
ring A2 represents:
- a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
- a 5-membered heterocyclic ring, optionally partially unsaturated, which contains one heteroatom-containing group selected from NR20, in which one or two carbon atoms of the heterocyclyl ring are optionally replaced by a heteroatom-containing group selected from (C=0), N, said 5-membered heteroaryl and 5-membered heterocyclic rings being optionally substituted one, two or three times, independently from each other, with R5 , whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5 ; or whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O and S.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
Figure imgf000084_0001
represents wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
Figure imgf000085_0001
ring A2 represents:
- a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or said 5-membered heteroaryl ring being optionally substituted one, two or three times, independently from each other, with R5 , whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5 ; or whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O and S.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
Figure imgf000086_0001
A represents wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
Figure imgf000086_0002
represents:
- a 5-membered heterocyclic ring, optionally partially unsaturated, which contains one heteroatom-containing group selected from NR20, in which one or two carbon atoms of the heterocyclyl ring are optionally replaced by a heteroatom-containing group selected from (C=0), and N, said 5-membered heterocyclic rings being substituted two or three times, independently from each other, with R5 , whereby two substituents R5 are in adjacent positions of the ring A2 and linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5 ; or whereby two substituents R5 are in adjacent positions of the ring A2 and linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom-containing group selected from (C=0), NR20, O and S.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
R4 represents a hydrogen atom.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein : R5 represents, independently of each other, a group selected from : halogen, hydroxy, Ci-C4-alkyl, C3-C4-cycloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, - N(R14)R15, - C(0)OR13, -C(0)OH, phenyl and 6-membered heteroaryl which contains one or two nitrogen atoms, wherein Ci-C4-alkyl is optionally substituted one, two or three times with a group independently selected from halogen, hydroxy, oxo (C=0), Ci-C3-alkoxy, C3-C6- cycloalkyl, -NH2, -NH(Ci-C3-alkyl) and -N(Ci-C3-alkyl)2.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein : R5 represents, independently of each other, a group selected from : halogen, hydroxy, Ci-C4-alkyl, C3-C4-cycloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, - N(R14)R15, -C(0)OR13, -C(0)OH, phenyl and 6-membered heteroaryl which contains one or two nitrogen atoms, wherein Ci-C4-alkyl is optionally substituted one, two or three times with a group independently selected from halogen, hydroxy, oxo (C=0), Ci-C3-alkoxy, C3-C6- cycloalkyl, -NH2, -NH(Ci-C3-alkyl) and -N(Ci-C3-alkyl)2. In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
R5 represents, independently of each other, a group selected from : fluorine, chlorine, bromine, hydroxy, Ci-C4-alkyl, C3-cycloalkyl, Ci-alkoxy, -NH2, - C(0)OR13, wherein Ci-C4-alkyl is optionally substituted one or two times with a group independently selected from fluorine, oxo (C=0), and -NH(Ci-alkyl).
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
R5 represents, independently of each other, a group selected from : fluorine, chlorine, bromine, Ci-alkyl, C3-cycloalkyl, and a 6-membered heteroaryl which contains one nitrogen atom.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
R6 represents hydrogen, halogen , hydroxy, Ci-C3-alkyl or Ci-C3-alkoxy.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
R6 represents hydrogen.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
R7 represents hydrogen. In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
R6, R7 represent, independently of each other, halogen.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
R8 represents hydrogen.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
R8 represents hydrogen, or Ci-C3-alkyl.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein : R9 and R10 together represent a group selected from:
* # * #
\ CH C /H2 and \ CH CH C /H2 wherein said groups are optionally substituted with one or two groups, which are independently of each other selected from : halogen, Ci-C3-alkyl, Ci-C3-alkoxy, hydroxy, Ci-C3-haloalkyl, and Ci-C3-hydroxyalkyl, wherein * indicates the point of attachment of said group to the rest of the molecule at
R9, and # indicates the point of attachment of said group to the rest of the molecule at R10.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein : together represent a group selected from
\ CH C /H2 and CH CH CH2 wherein said groups are optionally substituted with one or two groups, which are independently of each other selected from Ci-C3-alkyl, wherein * indicates the point of attachment of said group to the rest of the molecule at
R9, and # indicates the point of attachment of said group to the rest of the molecule at R10 .
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein : represents a group selected from aryl, and heteroaryl , wherein aryl and heteroaryl groups are optionally substituted with one, two, three or four groups, which are independently of each other selected from :
Ci-Ce-alkyl, Ci-C3-alkoxy, Ci-C3-hydroxyalkyl, Cs-Ce-cycloalkyl, C3-C6- cycloalkoxy, Ci-C3-haloalkyl , Ci-C3-haloalkoxy, halogen , cyano, nitro, hydroxy, (Ci-Ce-alkyl)-S-, (Ci-C6-alkyl)-S(=0)-, (Ci-C6-alkyl)-S(=0)2-,
-S(=0)(=NR21)R22, -N(R14)R15, R14(R15)N-(Ci-C6-alkyl)-,
R14(R15)N-(C2-C6-alkoxy)-, phenyl, phenoxy, -N(R16)C(=0)R17, -C(=0)OH, - C(=0)OR13, and -C(=0)N(R16)2, whereby two substituents of said aryl group, when they are in ortho-position to one another, can be linked to one another in such a way that they jointly form methanediylbisoxy, ethane-1 ,2-diylbisoxy, propane-1 ,3-diyl, or butane-1 ,4-diyl.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
R11 represents a group selected from : phenyl, and heteroaryl , wherein phenyl and heteroaryl groups are optionally substituted with one, two, three or four groups, which are independently of each other selected from :
Ci -C4-alkyl , Ci -C2-alkoxy, Ci -C3-hydroxyalkyl, C3-C4-cycloalkyl, Ci -C2-haloalkyl, Ci -C2-haloalkoxy, halogen, cyano, and hydroxy.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
R11 represents a group selected from : phenyl, wherein phenyl groups is optionally substituted with one, two, or three groups, which are independently of each other selected from :
Ci-alkyl, fluorine and chlorine, preferably fluorine and chlorine.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
R13 represents a group selected from :
Ci -Ce-alkyl, Cs-Ce-cycloalkyl, C2-C6-hydroxyalkyl-, and (Ci -C3-alkoxy)-(C2-C6-alkyl)-.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
R13 represents a group selected from :
Ci -C3-alkyl, and C3-C4-cycloalkyl.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein : R13 represents Ci-C3-alkyl.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein : R14 and R15 are independently of each other selected from : hydrogen, Ci-C6-alkyl, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C6-alkyl)-, C2-C6-hydroxyalkyl, (Ci-C3-alkoxy)-(C2-C6-alkyl)-, Ci-C6-haloalkyl, H2N-(C2-C6-alkyl)-, (Ci-C3-alkyl)N(H)(C2-C6-alkyl)-, (Ci-C3-alkyl)2N(C2-C6-alkyl)-,
Figure imgf000092_0001
Figure imgf000092_0002
or,
R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, in which one carbon atom is optionally replaced by a further heteroatom-containing group selected from NR20, O, S, S(=0) and S(=0)2, and in which one additional ring atom is optionally replaced by C(=0), said 4- to 7-membered heterocycloalkyl group being optionally substituted with one, two, three or four groups, which are independently of each other selected from :
Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy , Ci-C3-haloalkoxy, C3-C4-cycloalkyl, C3-C4- cycloalkoxy, -N(CH3)2, NH2, N(CH3)H, hydroxy, a halogen atom , and cyano, whereby when two substituents are attached to the same ring carbon atom, together with the carbon atom to which they are attached, can be linked to one another in such a way that they jointly form a cyclobutane, cyclopentane, azetidine, pyrrolidine, oxetane, tetrahydrofuran, thietane, tetrahydrothiophene, thietane 1 -oxide, tetrahydrothiophene 1 - oxide, thietane 1 ,1 -dioxide or a tetrahydrothiophene 1 ,1 -dioxide group.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
R14 and R15 are independently of each other selected from : hydrogen, Ci-C6-alkyl, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C6-alkyl)-, C2-C6-hydroxyalkyl, (Ci-C3-alkoxy)-(C2-C6-alkyl)-, Ci-C6-haloalkyl, H2N-(C2-C6-alkyl)-, (Ci -C3-alkyl)N(H)(C2-C6-alkyl)-, (Ci -C3-alkyl)2N(C2-C6-alkyl)- , HOC(=0)
Figure imgf000093_0001
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
R14 is selected from hydrogen, Ci -C6-alkyl , and C3-C6-cycloalkyl, preferably hydrogen, is selected from hydrogen, Ci -Ce-alkyl, CVCe-cycloalkyl, (C3-C6-cycloalkyl)-(Ci -C6-alkyl)- C2-C6-hydroxyalkyl, (Ci -C3-alkoxy)-(C2-C6-alkyl)-, Ci -C6-haloalkyl, H2N-(C2-C6-alkyl)- (Ci -C3-alkyl)N(H)(C2-C6-alkyl)-, (Ci -C3-alkyl)2N(C2-C6-alkyl)- , HOC(=0)-(Ci -C6-alkyl)-
Figure imgf000093_0002
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein : R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, in which one carbon atom is optionally replaced by a further heteroatom-containing group selected from NR20, O, S, S(=0) and S(=0)2, and in which one additional ring atom is optionally replaced by C(=0), said 4- to 7-membered heterocycloalkyl group being optionally substituted with one, two , three or four groups, which are independently of each other selected from :
Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy , Ci-C3-haloalkoxy, C3-C4-cycloalkyl, C3-C4- cycloalkoxy, -N(CH3)2, NH2, N(CH3)H, hydroxy, a halogen atom, and cyano, whereby when two substituents are attached to the same ring carbon atom, together with the carbon atom to which they are attached, can be linked to one another in such a way that they jointly form a cyclobutane, cyclopentane, azetidine, pyrrolidine, oxetane, tetrahydrofuran, thietane, tetrahydrothiophene, thietane 1 -oxide, tetrahydrothiophene 1 - oxide, thietane 1 ,1 -dioxide or tetrahydrothiophene 1 ,1 -dioxide group.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein : R14 and R15 are independently of each other selected from : hydrogen, Ci-C3-alkyl, and C3-C4-cycloalkyl, or,
R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycloalkyl group, in which one carbon atom is optionally replaced by a further heteroatom-containing group selected from NR20 and O and in which one additional ring atom is optionally replaced by C(=0), said 4- to 6-membered heterocycloalkyl group being optionally substituted with one, two , three or four groups, which are independently of each other selected from : Ci-alkyl, Ci-haloalkyl, Ci-alkoxy, Ci-haloalkoxy, C3-C4-cycloalkyl, -N(CH3)2, NH2,
N(CH3)H, hydroxy, a halogen atom, and cyano.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein : R14 and R15 are independently of each other selected from : hydrogen, Ci-C3-alkyl, and C3-C4-cycloalkyl.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
R14 is hydrogen,
R15 is selected from : hydrogen, Ci-C3-alkyl, and C3-C4-cycloalkyl.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycloalkyl group, in which one carbon atom is optionally replaced by a further heteroatom-containing group selected from NR20 and O and in which one additional ring atom is optionally replaced by C(=0), said 4- to 6-membered heterocycloalkyl group being optionally substituted with one, two, three or four groups, which are independently of each other selected from : Ci-alkyl, Ci -haloalkyl, Ci-alkoxy, Ci-haloalkoxy, C3-C4-cycloalkyl, -N(CH3)2, NH2,
N(CH3)H, hydroxy, a halogen atom, and cyano.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein : R16 represents, independently of each other, hydrogen, or Ci-C3-alkyl.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
R17 represents hydrogen, Ci-Ce-alkyl, Ci-Ce-hydroxyalkyl, C3-C6-cycloalkyl, Ci-Ce-haloalkyl, (Ci-C3-alkoxy)-(Ci-C6-alkyl)-, aryl, or heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently of each other selected from :
Ci-C3-alkyl, C3-C6-cycloalkyl, Ci-C3-alkoxy, C3-C6-cycloalkoxy, Ci-C3-haloalkyl, Ci-C3-haloalkoxy, halogen, cyano, and hydroxy.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
R20 represents, independently of each other, a group selected from : hydrogen, Ci-C3-alkyl, Ci-C3-haloalkyl, C3-C4-cycloalkyl,
Figure imgf000095_0001
C4-alkyl and phenyl.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein : R20 represents, independently of each other, a group selected from : hydrogen, Ci-C3-alkyl ,
Figure imgf000096_0001
-C(=0)OC4-alkyl and phenyl.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein :
R21 represents hydrogen, cyano,
Figure imgf000096_0002
or (Ci-C3-haloalkyl)-C(=0)-,
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), wherein : represents Ci-C4-alkyl, or C3-C4-cycloalkyl.
In accordance with a preferred embodiment the present invention relates to compounds of formula (I) as described herein, in which: when ring A2 is a imidazolyl or a 1 ,3-oxazolyl group, then said group is connected to the rest of the molecule via the carbon atom at position 2 of the imidazolyl or 1 ,3-oxazolyl ring, as shown below:
Figure imgf000096_0003
wherein * indicates the point of attachment of said group with the rest of the molecule.
In accordance with a preferred embodiment the present invention relates to compounds of formula (I) as described herein, in which:
Figure imgf000096_0004
- ring A2 is not a unsubstituted or substituted group, wherein * indicates the point of attachment of said group with the rest of the molecule, wherein said point of attachment is a carbon atom and in which : ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C3-alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms, ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms.
In accordance with a preferred embodiment the present invention relates to compounds of formula (I) as described herein, in which:
Figure imgf000097_0001
wherein * indicates the point of attachment of said group with the rest of the molecule, wherein said point of attachment is a carbon atom and in which : ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C3-alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms, said ring A2' being optionally substituted with one or two R5 groups, and ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms, said ring A2" being optionally substituted with one, two or three R12 groups,
R5 represents, independently of each other, a group selected from : halogen, hydroxy, Ci-C4-alkyl, C3-C4-cycloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, - N(R18')R19', -C(0)R13', and - C(0)OR13', wherein Ci-C4-alkyl is optionally substituted one, two or three times with a group independently selected from halogen, hydroxy, Ci-C3-alkoxy, -NH2, -NH(Ci-C3-alkyl) and -N(Ci-C3-alkyl)2; R12 represents, independently of each other, halogen, hydroxy, Ci-C6-alkyl, C3-C6- cycloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, -N(R18)R19 , -C(0)R13 , or -C(0)OR13 , wherein Ci-C6-alkyl is optionally substituted one, two or three times with a substituent independently selected from halogen, hydroxy, Ci-C3-alkoxy, Ci-C3-haloalkoxy, and - N(R18')R19'; whereby two substituents R12 when they are in adjacent positions of the ring to which they are attached, can be linked to one another in such a way that they jointly form methanediylbisoxy, ethane-1 ,2-diylbisoxy, propane-1 ,3-diyl, or butane-1 ,4-diyl.
In accordance with a preferred embodiment the present invention relates to compounds of formula (I) as described herein, in which: ring A2 is not:
Figure imgf000098_0001
wherein * indicates the point of attachment of said groups with the rest of the molecule, wherein said point of attachment is a carbon atom and in which:
X1 represents NR3 or O,
R1 represents a group selected from :
-OR13', and -N(R14')R15', R2 represents a group selected from : hydrogen, Ci-C3-alkyl, and C3-C4-cycloalkyl, R3 represents a hydrogen atom, ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C3-alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms, said ring A2' being optionally substituted with one or two R5 groups, and ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms, said ring A2" being optionally substituted with one, two or three R12 groups;
R5 represents, independently of each other, a group selected from : halogen, hydroxy, Ci-C4-alkyl, C3-C4-cycloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, -
N(R18')R19', -C(0)R13', and - C(0)OR13', wherein Ci-C4-alkyl is optionally substituted one, two or three times with a group independently selected from halogen, hydroxy, Ci-C3-alkoxy, -NH2, -NH(Ci-C3-alkyl) and -N(Ci-C3-alkyl)2; R12 represents, independently of each other, halogen, hydroxy, Ci-C6-alkyl, C3-C6- cycloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, -N(R18)R19 , -C(0)R13 , or -C(0)OR13 , wherein Ci-C6-alkyl is optionally substituted one, two or three times with a substituent independently selected from halogen, hydroxy, Ci-C3-alkoxy, Ci-C3-haloalkoxy, and -
N(R18')R19'; whereby two substituents R12 when they are in adjacent positions of the ring to which they are attached, can be linked to one another in such a way that they jointly form methanediylbisoxy, ethane-1 ,2-diylbisoxy, propane-1 ,3-diyl, or butane-1 ,4-diyl;
R13 represents a group selected from :
Ci-Ce-alkyl, C3-C6-cycloalkyl, C2-C6-hydroxyalkyl-, and (Ci -C3-alkoxy)-(C2-C6-alkyl)-,
R14 and R15 are independently of each other selected from : hydrogen, Ci-Ce-alkyl, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C6-alkyl)-,
C2-C6-hydroxyalkyl, (Ci-C3-alkoxy)-(C2-C6-alkyl)-, Ci-C6-haloalkyl,
H2N-(C2-C6-alkyl)-, (Ci-C3-alkyl)N(H)(C2-C6-alkyl)-, (Ci-C3-alkyl)2N(C2-C6-alkyl)- ,
Figure imgf000099_0001
4- to 6-membered heterocycloalkyl, 6-membered heterocycloalkyl)-(Ci-C6-alkyl)-, aryl, heteroaryl, alkyl)-, and heteroaryl-(Ci-C6-alkyl)-,
wherein 4- to 6-membered heterocycloalkyl groups are optionally substituted with one, two, three or four substituents, which are independently of each other selected from :
Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, C3-C4-cycloalkyl, C3-C4-cycloalkoxy, -NH2, -NH(Ci-C3-alkyl), -N(Ci-C3-alkyl)2, hydroxy, a halogen atom, and cyano, and, wherein aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently of each other selected from :
Ci-C3-alkyl, C3-C6-cycloalkyl, Ci-C3-alkoxy, C3-C6-cycloalkoxy, Ci-C3-haloalkyl, Ci-C3-haloalkoxy, halogen, cyano, -C(=0)OH, -C(=0)OR13 , and -C(=0)N(R16 )2, or,
R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, in which one carbon atom is optionally replaced by a further heteroatom-containing group selected from NR20 , O, S, S(=0) and S(=0)2, and in which one additional ring atom is optionally replaced by C(=0), said 4- to 7-membered heterocycloalkyl group being optionally substituted with one, two
, three or four groups, which are independently of each other selected from :
Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, C3-C4-cycloalkyl, C3-C - cycloalkoxy, -N(CH3)2, NH2, N(CH3)H, hydroxy, a halogen atom, and cyano, whereby when two substituents are attached to the same ring carbon atom, together with the carbon atom to which they are attached, can be linked to one another in such a way that they jointly form a cyclobutane, cyclopentane, azetidine, pyrrolidine, oxetane, tetrahydrofuran, thietane, tetrahydrothiophene, thietane 1 -oxide, tetrahydrothiophene 1 - oxide, thietane 1 ,1 -dioxide or tetrahydrothiophene 1 ,1 -dioxide group; said azetidine and pyrrolidine being optionally substituted one time with Ci-C3-alkyl or Ci-C3-haloalkyl, or,
R14" and R15 together with the nitrogen atom to which they are attached form a group selected from :
Figure imgf000101_0001
wherein * indicates the point of attachment of said group with the rest of the molecule,
R16 represents, independently of each other, hydrogen, or Ci-C3-alkyl,
R18 and R19 are, independently of each other, selected from : hydrogen, Ci-C6-alkyl , C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C6-alkyl)-, C2-C6- hydroxyalkyl-, (Ci-C3-alkoxy)-(C2-C6-alkyl)-, Ci-C6-haloalkyl, H2N-(C2-C6-alkyl)-, (C1-C3- alkyl)N(H)(C2-C6-alkyl)-, (Ci-C3-alkyl)2N(C2-C6-alkyl)-,
Figure imgf000101_0002
Figure imgf000101_0003
4- to 6-membered heterocycloalkyi, (4- to 6-membered heterocycloalkyl)-(Ci-C6-alkyl)-, aryl, and heteroaryl,
wherein 4- to 6-membered heterocycloalkyi groups are optionally substituted with one two, three or four substituents, which are independently of each other selected from :
Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, C3-C4-cycloalkyl, C3-C4-cycloalkoxy, -NH2, hydroxy, a halogen atom, and cyano, and, wherein aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently of each other selected from :
Ci-C3-alkyl, halogen, cyano,
R18 and R19 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyi group, in which one carbon atom is optionally replaced by a further heteroatom-containing group selected from NR20 , O, S, S(=0) and S(=0)2, in which heterocycloalkyl group one additional ring atom is optionally replaced by C(=0), said 4- to 7-membered heterocycloalkyl group being optionally substituted with one, two, three or four groups, which are independently of each other selected from : Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, C3-C4-cycloalkyl, C3-C4- cycloalkoxy, -N(CH3)2, N(H)2, N(CH3)H, hydroxy, a halogen atom, and cyano, whereby when two substituents are attached to the same ring carbon atom, together with the carbon atom to which they are attached, can be linked to one another in such a way that they jointly form a cyclobutane, cyclopentane, azetidine, pyrrolidine, oxetane, tetrahydrofuran, thietane, tetrahydrothiophene, thietane 1 -oxide, tetrahydrothiophene 1 - oxide, thietane 1 ,1 -dioxide or tetrahydrothiophene 1 ,1 -dioxide group, said azetidine and pyrrolidine being optionally substituted one time with Ci-C3-alkyl or Ci-C3- haloalkyl;
R20 represents, independently of each other, a group selected from : hydrogen, Ci-C3-alkyl , Ci-C3-haloalkyl, and C3-C4-cycloalkyl.
In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I), according to any of the above-mentioned embodiments, in the form of or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
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.
More particularly still, the present invention covers compounds of general formula (I) which disclosed in the Example section of this text, infra. In accordance with another aspect, the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein.
Another aspect of the invention relates to the the intermediates described herein and their use for preparing a compound of formula (I) as defined supra or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
The intermediates used for the synthesis of the compounds of claims 1 to 10 as described below, as well as their use for the synthesis of the compounds of claims 1 to 10, are one further aspect of the present invention. Preferred intermediates are the Intermediate Examples as disclosed below.
Experimental section General part
Chemical names were generated using ACD/Name. Stereodescriptors were manually adapted as defined above. In case there is discrepancy between the chemical name of a compound and its chemical structure, the chemical structure shall prevail. In some cases generally accepted names of commercially available reagents were used in place of ACD generated names.
The following table lists the abbreviations used in this paragraph and in the Intermediate Examples and Examples section as far as they are not explained within the text body. A comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears presented in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained therein, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
Figure imgf000103_0001
Abbreviation Meaning
DAST (diethylamino)sulfur trifluoride [CAS No. 38078-09-0]
DCM dichloromethane
d doublet (NMR)
dd doublet of doublet (NMR)
dt doublet of triplet (NMR)
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
EDTA ethylenediaminetetraacetic acid
ESI electrospray (ES) ionisation
h hour(s)
1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]-pyridinium 3-
HATU
oxid hexafluorophosphate
HCI hydrochloric acid
HPLC high performance liquid chromatography
HRP horseradish peroxidase
LCMS liquid chromatography-mass spectrometry
m multiplet (NMR)
min minute(s)
MS mass spectrometry
MTP microtiter plate
nuclear magnetic resonance spectroscopy : chemical shifts (δ) are
NMR given in ppm. The chemical shifts were corrected by setting the DMSO signal to 2.50 ppm using unless otherwise stated.
NAD+ nicotinamide adenine dinucleotide
NMP N-Methylpyrrolidone
PBS phosphate buffered saline
PDC pyridinium dichromate
PG protecting group
Ph phenyl
PyBOP benzotriazol-1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate q quartet (NMR)
Rt, Rt Retention time
s singulet (NMR)
SPA Scintillation proximity assay
T3P 1 -propanephosphonic anhydride
TBAF tetrabutylammonium fluoride Abbreviation Meaning
t triplet (NMR)
td triplet of doublet (NMR)
TFA trifluoro acetic acid
THF tetrahydrufuran
[3H]- tritium
δ chemical shift
Other abbreviations have their meanings customary per se to the skilled person.
The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way. 1. Syntheses of Compounds (Overview):
The compounds of the present invention can be prepared as described in the following section. Schemes 1 to 6 and the procedures described below illustrate general synthetic routes to the compounds of general formula (I) of the invention and are not intended to be limiting. It is clear to the person skilled in the art that the order of transformations as exemplified in Schemes 1 to 6 can be modified in various ways. The order of transformations as exemplified in the Schemes 1 to 6 are therefore not intended to be limiting. In addition, interconversion of any of the substituents, R6, R7, R10, R11 and -N(R10)R11 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, exchange, 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. Further, it is possible that two or more successive steps may be performed without work-up being performed between said steps, e.g. a "one-pot" reaction, as is well-known to the person skilled in the art.
In case mixtures of stereoisomers, such as, for example enantiomers, diastereomers, or cis/trans isomers are formed during a reaction, these isomers can be separated by methods described herein or by methods known to the person skilled in the art such as, but not limited to, chromatography, chiral chromatography and crystallization. All reagents used for the preparation of the compounds of the invention are either commercially available or can be prepared as described.
1.1 Synthesis of amines intermediates
Aliphatic amines as intermediates for the synthesis of compounds of the can be synthesized depicted in scheme 1 to 5.
Figure imgf000106_0001
1 -17 1 -18 1 -19 (C)
Scheme 1 : Synthesis of 4-aminocyclohexanecarboxylate derivatives, wherein R6, R7, R11 , and R13 are as defined herein for the compound of general formula (I) and R8 is hydrogen, and R9 and R10 (not shown) together represent a group selected from:
.# * #
\ CH C /HP and CH— CH— CH . m .
^ ^ ^ ^ ^ ^ e n is 1 o 2), and in which PG represents a protecting group, such as for instance a tert-butyl(dimethyl)silyl group, W represents a leaving group such as, for instance a bromide, chloride, iodide or a O-tosyl or O-mesyl group,
V represents a halide, for instance a bromide, chloride or iodide, or an alkyloxy group, preferably a methoxy group and n is 1 or 2.
Cyclohexanecarboxylate derivatives of type 1-8, can be alkylated at the appropriate position by treatment with a suitable base such as, for example, lithium diisopropylamide, in an appropriate solvent such as, for example, tetrahydrofuran or diethylether, followed by addition of a suitable electrophile of type 1-13 to give compounds of type 1-14.
Reaction of compounds of type 1-14 (where V represents a halide, such as for example a chloride, bromide or idodide) with primary aromatic or heteroaromatic amines of type 1-15 in the presence of a base, such as for instance lithium bis(trimethylsilyl)amide, to give compounds of type 1-16.
Deprotection of a protect alcohol of type 1-16, in case of a tert-butyl(dimethyl)silyl group for example, employing tetra-N-butylammonium fluoride (TBAF) results in alcohol derivatives of type 1-17.
Alternatively compounds of type 1-17 can be obtained by reaction of compounds of type 1-14 (where V represents alkoxy group, such as for example, methoxy, and PG is preferably a hydrogen) with aromatic or heteroaromatic amines of type 1-15 in the presence of a lewis acid, such as for instance diethylaluminium chloride.
Reaction of alcohol derivatives of type 1-17 with phthalimide under Mitsunobu reaction conditions, employing for example diisopropyl azodicarboxylate (DIAD) and triphenylphosphine as reagents, yields compounds of type 1-18.
Deprotection of the protected amine of type 1-18 bearing a phthalimide group can be achieved, for example, by treatment with hydrazine hydrate or methylamine at elevated temperature (e.g. at reflux) to give amine derivatives of type 1-19 (C).
Figure imgf000107_0001
1 -23 1-24 1 -19 (C)
Scheme 2: Alternative synthesis of 4-aminocyclohexanecarboxylate derivatives, wherein R6, R7, R11 ,and R13 are as defined for the compound of general formula (I) supra, R8 is hydrogen, and R9 and R10 (not shown) together represent a group selected from:
.# * #
\ CCHH--CC /HH.P and CH— CH— CH
^ ^ ^ ^ ^ e η is 1 or 2), and W represents a leaving group such as, for instance a bromide, chloride, iodide or a O-tosyl or O-mesyl group, V represents a halide, for instance, a chloride, bromide, or iodide, or an alkoxy group, preferably a methoxy group and n is 1 or 2.
Cyclohexanecarboxylate derivatives of type 1-20, can be alkylated at the appropriate position by treatment with a suitable base such as for example, lithium hexamethyldisilazide, in an appropriate solvent such as for example tetrahydrofuran or diethylether, followed by addition of a suitable electrophile 1-13 to give compounds of type 1-21.
Reaction of compounds of type 1-21 (where V represents a halide) with primary amines of type 1-15 in the presence of a base, such as for instance lithium bis(trimethylsilyl)amide give compounds of type 1-22.
Treatment of compounds of type 1-22 with aqueous mineral acid gives compounds of type 1- 23.
Reaction of ketones of type 1-23 with amines, such as for example benzyl amine, under standard reaction conditions for reductive animation reactions, employing for example sodium triacetoxyborohydride as reducing agent, yields protected amine derivatives of type 1-24. Deprotection of the protected amine of type 1-24, in case of a benzyl protecting group for example, employing a palladium on charcoal catalyst and hydrogen gas, yields amine derivatives of type 1-19 (C).
Figure imgf000108_0001
1 -19 (C) Scheme 3: Alternative synthesis of 4-aminocyclohexanecarboxylate derivatives, wherein R6, R7, R11 and R13 are as defined herein for the compound of general formula I and R8 is
Figure imgf000109_0001
hydrogen, and R9 and R10 (not shown) together represent a group: (i.e. n is 1 ), and in which PG represents a protecting group, such as a tert-butyl(dimethyl)silyl group, W represents a leaving group such as, for instance a bromide, chloride, iodide or a O-tosyl or O-mesyl group, V represents a halide, for instance a bromide, chloride or iodide, or an alkyloxy group, preferably a methoxy group and n is 1.
Cyclohexanecarboxylate derivatives of type 1-8, can be alkylated at the appropriate position by treatment with a suitable base such as for example, lithium hexamethyldisilazide, in an appropriate solvent such as for example tetrahydrofuran or diethylether, followed by addition of a suitable electrophile 1-32 to give compounds of type 1-33.
Reduction of nitriles of type 1-33 using, for example Raney-Nickel catalyst in ammonia and ethanol under hydrogen pressure, yields amines of type 1-34, which can convert directly into lactames of type 1-35. Alternative amines of type 1-34 can be cyclizied at elevated temperatures in solvents such as for instance toluene, in the absence or presence of an base, such as for example trimethylamine.
Lactames of type 1-35 can be converted into compounds of type 1-16 using aryl or heteroaryl halides of type 1-36 (in which W is a halide, preferably iodide) as coupling partner, applying transition metal catalyized coupling reactions such as for instance Ullmann type coupling reactions using for example copper(l) iodide and Ν,Ν'-dimethylethylenediamine, potassium carbonate as base and dioxane as solvent at elevated temperatures, for example applying microwave heating.
Compounds of type 1-19 (C) can be obtained in three steps from compounds of type 1-16 in analogy to the synthesis described in scheme 1 , 2 or scheme 5.
Figure imgf000110_0001
Figure imgf000110_0002
1 -41 1 -42 1 -43
Figure imgf000110_0003
1 -44 (C)
Scheme 4: Alternative synthesis of substituted 4-aminocyclohexanecarboxylate derivatives, wherein R6, R7, R11 ,and R13 are as defined for the compound of general formula (I) and R8 is hydrogen, and R9 and R10 (not shown) together represent a group selected from:
* # * #
\ CH-C /hL and \ CH-CH C /H2
^ ^ (i.e. n is 1 or 2), and in which PG represents a protecting group, such as a tert-butyl(dimethyl)silyl group, W represents a leaving group such as, for instance a bromide, chloride, iodide, and R25 represents a hydrogen atom or a group selected from Ci-C3-alkyl, Ci-C3-haloalkyl and Ci-C3-hydroxyalkyl.
Cyclohexanecarboxylate derivatives of type 1-8 can be alkylated at the appropriate position by treatment with a suitable base such as, for example lithium diisopropylamide, in an appropriate solvent such as, for example tetrahydrofuran or diethylether, followed by addition of a suitable electrophile of type 1-38 to give compounds of type 1-39. Ozonolysis of compounds of type 1-39 yields compounds of type 1-40. Compounds of type 1- 40 can be reacted with hydroxylamine in the presence of a suitable base, such as for example, trimethylamine, to give compounds of type 1-41.
Compounds of type 1-41 can be reduced and cyclized to compounds of type 1-42 using for instance Pd/C in methanol under an hydrogen atmosphere followed by treatment with a suitable base, such as trimethylamine, in a suitable solvent, such as toluene, at eleveated temperatures.
Compounds of type 1-43 can be obtained by reaction of compounds of type 1-42 with compounds of type 1-37 in the presence of a catalyst, such as for example copper(l)iodide and bases such as Ν,Ν'-dimethylethylenediamine and potassium carbonate in a suitbale solvent like, for example, dioxane.
Compounds of type 1-44 (C) can be obtained in three or four steps from compounds of type 1- 43 in analogy the synthesis described in scheme 1 , 2 or scheme 5.
An alternative synthesis route of derivatives of the present invention is depicted in scheme 5.
Figure imgf000111_0001
1 -46 1 -19 (C)
Scheme 5: Alternative synthesis of 4-aminocyclohexanecarboxylate derivatives, wherein R6,
R7 and R11 are as defined for the compound of general formula (I) and R8 is hydrogen, and R9 and R10 (not shown) together represent a group selected from:
* ,# * #
\ CH-C /H? and CH— CH— CH2 r . , m , . . ,
z z Δ (i.e. n is 1 or 2), and in which W represents a leaving group such as, for instance a O-tosyl or O-mesyl group and n is 1 or 2.
Reaction of the alcohol derivatives of type 1-17 with, for example, W-CI in the precence of a suitable base, for example pyridine, yields compunds of type 1-45. Treatment of compounds of type 1-45 with sodium azide in a suitable solvent, such as for instance DMF, yields compunds of type 1-46. Reduction of azide derivatives of type 1-46 with, for example, triphenylphosphine gives compounds of type 1-19 (C).
1.2 Synthesis of dicarbonyl compounds
A synthesis route of heterocylic derivatives of the present invention is depicted in scheme 6.
Figure imgf000112_0001
(C) (I)
Scheme 6: Synthesis of dicarbonyl compounds starting from aminocyclohexane derivatives of type (C), wherein A, R6, R7, R8, R9, R10 and R11 are as defined herein for the compound of general formula (I), and in which W represents a hydroxyl group or a chloride.
4-aminocyclohexanecarboxylate derivatives of type of 4-aminocyclohexanecarboxylate derivatives (C) can
Compounds of formula (I) can be obtained starting from 4-aminocyclohexanecarboxylate derivativesof type (C), upon standard amide bond forming reaction conditions, for example using a carboxylic acid of type 2-1 in the presence of a coupling agent such as, for example, PyBOP or HATU. Alternatively, compounds of formula (I) can be obtained in a two step procedure by first converting carboxylic acids of type 2-1 to the corresponding acid chlorides applying chlorinating agents, such as for example thionyl chloride or 1 -chloro-N,N,2- trimethylprop-1 -en-1 -amine, followed by reaction with amines of type (C) in the presence of a suitable base, such as for example trimethylamine or pyridine. NMR data:
NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.
The 1 H-NMR data of selected examples are listed in the form of 1 H-NMR peaklists. For each signal peak the δ value in ppm is given, followed by the signal intensity, reported in round brackets. The δ value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: δι (intensityi), δ2 (intensity2), ... , δ, (intensity,), ... , δη (intensityn).
The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown. A 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 (MestReC, ACD simulation, or by use of empirically evaluated expectation values), 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. A detailed description of the reporting of NMR data in the form of peaklists can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (cf. Research Disclosure Database Number 605005, 2014, 01 Aug 2014, or http://www.researchdisclosure.com/searching-disclosures). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be adjusted between 1 % and 4%. Depending on the chemical structure and/or depending on the concentration of the measured compound it may be reasonable to set the parameter "MinimumHeight" <1 %.
Analytical HPLC Methods:
Method 1 : Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1 .7 μιτι, 50x2.1 mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1 -99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 Ό; DAD s can: 210-400 nm.
Method 2:
Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1 .7 μιτι, 50x2.1 mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1 .6 min 1 -99% B, 1 .6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 Ό; DAD scan: 210-400 nm.
Method 3:
Instrument: Waters Acquity UPLCMS SingleQuad; Colum: Acquity UPLC BEH C18 1 .7 50x2.1 mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1 .6 min 1 -99% B, 1 .6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 Ό; DAD scan: 210-400 nm.
Method 4:
Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1 .7 50x2.1 mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1 -99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 Ό; DAD s can: 210-400 nm.
Method 5:
Instrument MS: Waters ZQ; Instrument HPLC: Waters UPLC Acquity; Column: Acquity BEH C18 (Waters), 50mm x 2.1 mm, 1 .7μιη; eluent A: water +0,1 vol% formic acid, eluent B: acetonitrile (Lichrosolv Merck); gradient: 0.0 min 99 % A - 1 .6 min 1 % A - 1 .8 min 1 % A - 1 .81 min 99 % A - 2.0 min 99 % A; temperature: 60 Ό; flow: 0.8 ml/min; UV-Detection PDA 210- 400 nm.
Preparative HPLC methods:
Method 6:
Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5μ 100x30mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient eluent A/ eluent B, flow 70 ml/min; temperature: 25 "C; DAD scan: 210-400 nm.
Method 7:
Instrument: Waters Autopurification MS SingleQuad; Colum: Waters XBrigde C18 5μ 100x30mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: eluent A / eluent B; flow 70 ml/min; temperature: 25 "C; DAD scan: 210-400 nm.
Analytical GC-MS Methods: Method 8:
Instruments: Agilent 7890A and Waters GCT Premier; Colum: 29 m HP-5MS, 0.25 mm / 0.25μιη; Gas: Helium 1 ml/min, Oven: Start 50Ό 1 min, linear to 26CC at l OO/min.
3. Intermediates Intermediate 15
ethyl 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (mixture of cis-/trans-isomers)
Figure imgf000116_0001
tert-Butyldimethylsilyl chloride (26.3 g, 174 mmol) was added to a solution of ethyl 4- hydroxycyclohexanecarboxylate (25.0 g, 145 mmol, mixture of cis-/trans-isomers, Cas No 17159-80-7) and imidazole (24.7 g, 363 mmol) in N,N-dimethylformamide (36 ml) and the mixture was stirred over night at room temperature. For work-up, water was added and the mixture was extracted with tert-butyl methyl ether (3x). The combined organic phases were washed with brine, filtrated through a silicone filter and concentrated under reduced pressure to yield ethyl 4-{[ferf-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (43.1 g, 104% yield) which was used in the next step without further purification.
1 H-NMR (400 MHz, DMSO-cfe, mixture of isomers): δ [ppm] = 4.10-3.99 (m, 2H), 3.93-3.86 (m, 0.7H), 3.63-3.51 (m, 0.3H), 2.39-2.28 (m, 0.8H), 2.27-2.14 (m, 0.3H), 1.91 -1 .21 (m, 8H), 1.20- 1 .13 (m, 3H), 0.89-0.79 (m, 9H), 0.08-0.00 (m, 6H).
Intermediate I6
ethyl 4-{[tert-butyl(dimethyl)silyl]oxy}-1 -(2-chloroethyl)cyclohexanecarboxylate (mixture of cis- /trans-isomers)
Figure imgf000116_0002
Lithium diisopropylamide (20.9 ml, 41 .9 mmol, 1 .8 M solution in tetrahydrofuran) was added dropwise to a solution of ethyl 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (10.0 g, 34.9 mmol) in tetrahydrofuran (47 ml) at -78Ό and the mixture was stirred for 30 min at that temperature. 1 -Bromo-2-chloroethane (4.3 ml, 52 mmol) was added and the mixture was stirred for 1 h at -78Ό and then warmed during 2 h to room temperature. For wor k-up, water was added and the mixture was extracted with tert-butyl methyl ether (3x). The combined organic phases were washed with brine and filtrated through a silicone filter and concentrated under reduced pressure. The crude product (12 g) was purified by flash chromatogryph (340 g Snap cartridge, hexanes/ethyl acetate gradient) to give ethyl 4-{[tert-butyl(dimethyl)silyl]oxy}-1 - (2-chloroethyl)cyclohexanecarboxylate (9.1 g, 75% yield as mixture of isomers, ratio 5:1 by GC-MS).
GC-MS (Method 8): Rt = 20.27 min (minor isomer); 20.50 min (major isomer); MS (CI) m/z = 366.2 [M+NH4]+ and 349.2 [M+H]+.
Intermediate I7
8-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-chloro-4-fluorophenyl)-2-azaspiro[4.5]decan-1 -
Figure imgf000117_0001
Lithium hexamethyldisilazide (22.9 ml, 22.9 mmol, 1 M solution in tetrahydrofuran) was added over 5 min to solution of 2-chloro-4-fluoroaniline (1 .84 g, 12.6 mmol, Cas No 2106-02-7) in tetrahydrofuran (60 ml) at -78Ό and the mixture was stired at -78Ό for 1 h. A solution of ethyl 4-{[tert-butyl(dimethyl)silyl]oxy}-1 -(2-chloroethyl)cyclohexanecarboxylate (mixture of cis-/trans- isomers) (4.00 g, 1 1 .5 mmol) in tetrahydrofuran (60 ml) was added and the mixture was stirred for 2 h at -78Ό and the for 3 days at room temperature. For work-up, the reaction mixture was poured into a mixture of water and saturated sodium bicarbonate solution, extracteted with ethyl acetate (3x) and the combined organic phases were washed with brine, filtrated through a silicone filter and concentrated under reduced pressured. The residue was purified by flash chromatography (Snap Cartdidge, hexanes/ethyl acetate gradient) to give 8-{[tert- butyl(dimethyl)silyl]oxy}-2-(2-chloro-4-f luorophenyl)-2-azaspiro[4.5]decan-1 -one in 2 fractions. Fraction 1 (1 .88 g, isomer 1 , contains ca 20mol% 2-chloro-4-fluoroaniline) and fraction 2 (485 mg, isomer 2).
Fraction 1 (isomer 1 ):
LC-MS (Method 1 ): Rt = 1 .68 min; MS (ESIpos) m/z = 412.2 [M+H]+. 1 H-NMR (400 MHz, DMSO-afe): δ [ppm] = 7.58 (dd, 1 H), 7.46 (dd, 1 H), 7.30 (td, 1 H), 3.97-3.92 (m, 1 H), 3.59 (t, 2H), 2.06 (t, 2H), 2.01 -1 .92 (m, 2H), 1.71 -1.54 (m, 4H), 1 .36-1 .29 (m, 2H), 0.92-0.86 (m, 9H), 0.08-0.03 (m, 6H).
Fraction 2 (isomer 2):
LC-MS (Method 1 ): Rt = 1 .67 min; MS (ESIpos) m/z = 412.2 [M+H]+.
1 H-NMR (400 MHz, DMSO-afe): δ [ppm] = 7.57 (dd, 1 H), 7.45 (dd, 1 H), 7.33-7.25 (m, 1 H), 3.70- 3.52 (m, 3H), 2.07 (t, 2H), 1 .84-1 .74 (m, 2H), 1.62-1 .54 (m, 4H), 1 .42-1.28 (m, 2H), 0.89-0.83 (m, 9H), 0.07-0.01 (m, 6H)
Intermediate I8
2-(2-chloro-4-fluorophenyl)-8-hydroxy-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000118_0001
Tetra-N-butylammonium fluoride (9.1 ml, 9.1 mmol, 1 M solution in tetrahyrofuran) was added to a solution of 8-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-chloro-4-fluorophenyl)-2- azaspiro[4.5]decan-1 -one (isomer 1 ) (1.88 g, fraction 1 ) in tetrahydrofuran (43 ml) and the mixture was stirred at room temperature for 12 h. The mixture was poured into water, extracted with ethyl acetate (3x) and the combined organic phases were washed with saturated sodium bicarbonate solution and brine, filtrated through a silicone filter and concentrated under reduced pressure. The residue was purified by flash chromatography (Snap cartridge, hexanes/ethyl acetate gradient, 20% -> 50% ethyl acetate) to provide 2-(2-chloro-4- fluorophenyl)-8-hydroxy-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (1 .08 g).
LC-MS (Method 2): R, = 0.98 min; MS (ESIpos) m/z = 298.1 [M+H]+.
1 H-NMR (400 MHz, DMSO-de): δ [ppm] = 7.58 (dd, 1 H), 7.46 (dd, 1 H), 7.30 (td, 1 H), 4.40 (d, 1 H), 3.78-3.72 (m, 1 H), 3.59 (t, 2H), 2.04 (t, 2H), 2.00-1 .90 (m, 2H), 1 .74-1 .62 (m, 2H), 1.60- 1 .47 (m, 2H), 1 .36-1.23 (m, 2H). Intermediate I9
2-(2-chloro-4-fluorophenyl)-8-hydroxy-2-azaspiro[4.5]decan-1 -one (isomer 2)
Figure imgf000119_0001
Was prepared in analogy to the synthesis of 2-(2-chloro-4-fluorophenyl)-8-hydroxy-2- azaspiro[4.5]decan-1 -one (isomer 1 ) from of 8-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-chloro-4- fluorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 2) (480 mg, fraction 2) using tetra-N- butylammonium fluoride (2.3 ml, 2.3 mmol, 1 M solution in tetrahyrofuran) go give 2-(2-chloro- 4-fluorophenyl)-8-hydroxy-2-azaspiro[4.5]decan-1 -one (isomer 2) (300 mg).
LC-MS (Method 2): R, = 0.90 min; MS (ESIpos) m/z = 298.1 [M+H]+.
1 H-NMR (400 MHz, DMSO-cfe): δ [ppm] = 7.58 (dd, 1 H), 7.46 (dd, 1 H), 7.34-7.27 (m, 1 H), 4.63 (d, 1 H), 3.59 (t, 2H), 3.47-3.35 (m, 1 H), 2.07 (t, 2H), 1.85-1.76 (m, 2H), 1 .62-1.49 (m, 4H), 1 .35-1 .18 (m, 2H).
Intermediate 110
2-[2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 H-isoindole-1 ,3(2H)-dione (isomer 1 )
Figure imgf000119_0002
Diisopropyl azodicarboxylate (1 .1 ml, 5.4 mmol) was added dropwise to a mixture of 2-(2- chloro-4-fluorophenyl)-8-hydroxy-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (1 .08 g, 3.61 mmol), phthalimide (797 mg, 5.42 mmol) and triphenylphosphine (1 .42 g, 5.42 mmol) in tetrahydrofuran (30 ml) and the mixture was stirred for 12 h at room temperature. For work-up, the reaction mixture was concentrated and the residue was purified by flash chromatography (hexanes/ethyl acetate gradient) to yield 2-[2-(2-chloro-4-fluorophenyl)-1 -oxo-2- azaspiro[4.5]dec-8-yl]-1 H-isoindole-1 ,3(2H)-dione (isomer 1 ) (697 mg).
LC-MS (Method 2): R, = 1 .31 min; MS (ESIpos) m/z = 427.2 [M+H]+. 1 H-NMR (400 MHz, DMSO-cfe): δ [ppm] = 7.90-7.82 (m, 4H), 7.63-7.56 (m, 1 H), 7.49 (dd, 1 H), 7.32 (td, 1 H), 4.12-3.98 (m, 1 H), 3.66 (t, 2H), 2.35-2.17 (m, 4H), 1 .80-1.58 (m, 6H).
Intermediate 111
2-[2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 H-isoindole-1 ,3(2H)-dione (isomer 2)
Figure imgf000120_0001
Was prepared in analogy to 2-[2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 H- isoindole-1 ,3(2H)-dione (isomer 1 ) using 2-(2-chloro-4-fluorophenyl)-8-hydroxy-2- azaspiro[4.5]decan-1 -one (isomer 2) (308 mg, 1 .03 mmol) as starting material to give 2-[2-(2- chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 H-isoindole-1 ,3(2H)-dione (isomer 2) (190mg).
LC-MS (Method 1 ): Rt = 1 .34 min; MS (ESIpos) m/z = 427.2 [M+H]+.
1 H-NMR (400 MHz, DMSO-c/6): δ [ppm] = 7.87-7.79 (m, 1 H), 7.61 (dd, 1 H), 7.52 (dd, 1 H), 7.33 (td, 1 H), 4.10-3.98 (m, 1 H), 3.61 (t, 2H), 2.90-2.75 (m, 2H), 2.15-2.05 (m, 2H), 2.00 (t, 2H), 1 .62-1 .49 (m, 4H).
Intermediate 112
8-amino-2-(2-chloro-4-fluorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000120_0002
A mixture of 2-[2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 H-isoindole- 1 ,3(2H)-dione (isomer 1 ) (585 mg, 1.37 mmol) and hydrazine hydrate (0.34 ml) in ethanol (12 ml) was stirred at 80Ό for 3 h. Upon cooling, the precipitate was filtrated o ff, washed with ethanol and the filtrate was concentrated to give the title compound (457 mg).
LC-MS (Method 2): R, = 0.94 min; MS (ESIpos) m/z = 297.1 [M+H]+. Intermediate 113
8-amino-2-(2-chloro-4-fluorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 2)
Figure imgf000121_0001
A mixture of 2-[2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 H-isoindole- 1 ,3(2H)-dione (isomer 2) (188 mg, 0.440 mmol) and hydrazine hydrate (150 μΙ) in ethanol (4.0 ml) was stirred at 80Ό for 3 h. The reaction mixture was concentrated under reduced pressure and the crude product was codestilled with dichloromethane (2x) to give the title compound (200 mg) which was then used without further purification in the next step.
Intermediate 114
8-amino-2-(2-chloro-4,5-difluorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000121_0002
Was prepared in analogy to the synthesis of 8-amino-2-(2-chloro-4-fluorophenyl)-2- azaspiro[4.5]decan-1 -one (isomer 1 , intermediate 112 in 4 steps from ethyl 4-{[tert- butyl(dimethyl)silyl]oxy}-1 -(2-chloroethyl)cyclohexanecarboxylate (mixture of cis-/trans- isomers) (2.00 g, 5.73 mmol) and 2-chloro-4,5-difluoroaniline (1 .03 g, 6.30 mmol, CAS No 2613-32-3) as starting materials to give the title compound as crude product (326 mg) which was used in the next step without further prufification.
LC-MS (Method 2): Rt = 0.96 min; MS (ESIpos) m/z = 315.1 [M+H]+.
For an alternative synthesis see intermediate I45. Intermediate 115
8-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)-2-azaspiro[4.5]decan-1 -one
Figure imgf000122_0001
Lithium hexamethyldisilazide (43 ml, 43 mmol, 2 M solution in tetrahydrofuran) was added drop wise over 20 min to a solution of 4-fluoroaniline (2.63 g, 23.6 mmol, CAS No 371 -40-4) in tetrahydrofuran (190 ml) at -78Ό and the mixture w as stirred for 1 h at that temperature, ethyl trans-4-{[tert-butyl(dimethyl)silyl]oxy}-1 -(2-chloroethyl) cyclohexanecarboxylate(mixture of cis- /trans-isomers) (7.50 g, 21 .5 mmol) was added drop wise during 1 h and the mixture was then stirred for 2 h at -78Ό. A catalytic amount of pot assium iodide was added and the mixture was warmed to room temperature and stirred overnight. For work-up, sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate (3x). The combined organic phases were washed with brine, filtrated through a silicone filter and concentrated. The residue was purified by flash chromatography (340 g Snap Cartridge, hexanes/ethyl acetate gradient, 0% -> 10% ethyl acetate) to give 8-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)-2- azaspiro[4.5]decan-1 -one in 3 fractions: Fraction 1 (4.08 g, isomer 1 ), fraction 2 (0.66 g, mixture of isomer 1 and isomer 2, 6:4), and fraction 3 (0.450 g, isomer 2).
Fraction 1 (Isomer 1 ): LC-MS (Method 2): Rt = 1 .77 min; MS (ESIpos) m/z = 378.3 [M+H]+.
1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.76-7.63 (m, 1 H), 7.25-7.16 (m, 1 H), 3.99-3.92 (m, 1 H), 3.75 (t, 2H), 2.04-1 .88 (m, 4H), 1 .70-1 .52 (m, 6H), 1 .32-1.20 (m, 2H), 0.89 (s, 9H), 0.05 (s, 6H)
Fraction 3 (isomer 2): LC-MS (Method 2): Rt = 1.74 min; MS (ESIpos) m/z = 378.3 [M+H]+.
1 H-NMR (400 MHz, DMSO-c/6): δ [ppm] = 7.75-7.63 (m, 2H), 7.26-7.13 (m, 2H), 3.76 (t, 2H), 3.68-3.56 (m, 1 H), 2.02 (t, 2H), 1 .84-1 .72 (m, 2H), 1 .65-1 .47 (m, 4H), 1.43-1 .26 (m, 2H), 0.86 (s, 9H), 0.06 (s, 6H)
Intermediate 116
2-(4-fluorophenyl)-8-hydroxy-2-azaspiro[4.5]decan-1 -one (isomer 1
Figure imgf000123_0001
Tetra-n-butyl ammonium fluoride (32 ml, 32 mmol, 1 M solution in tetrahyrofuran) was added to a solution of 8-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (4.07 g, 10.8 mmol) in tetrahydrofuran (93 ml) and the mixture was stirred at room temperature for 20 h. For work-up, the mixture was poured into water, extracted with ethyl acetate (3x) and the combined organic phases were washed with saturated sodium bicarbonate solution and brine, filtrated through a silicone filter and concentrated under reduced pressure. The residue was stirred with toluene, the precipitate formed was collected by filtration, washed with hexanes and dried to give the title compound (1 .37 g). The mother liquor was concentrated and purified by flash chromatography (50 g snap cartridge, hexanes/ethyl acetate-gradient, 0 -> 100% ethyl acetate) to give a second fraction of the title compound (1 .08 g).
LC-MS (Method 2): R, = 0.96 min; MS (ESIneg): m/z = 264.2 [M+H]+
1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.74-7.65 (m, 2H), 7.26-7.16 (m, 2H), 4.40 (d, 1 H), 3.80-3.71 (m, 3H), 2.03-1 .88 (m, 4H), 1 .73-1 .61 (m, 2H), 1.59-1 .49 (m, 2H), 1 .30-1.20 (m, 2H)
Intermediate 117
2-[2-(4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 H-isoindole-1 ,3(2H)-dione (isomer 1 )
Figure imgf000123_0002
Diisopropyl azodicarboxylate (1 .5 ml, 7.8 mmol) was added drop wise to a mixture of 2-(4- fluorophenyl)-8-hydroxy-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (1 .37 g, 5.02 mmol), phthalimide (1.15 g, 7.80 mmol) and triphenylphosphine (2.05 g, 7.80 mmol) in tetrahydrofuran (62 ml) and the mixture was stirred at room temperature overnight. For work-up, the reaction mixture was concentrated and the crude product was stirred with a mixture of ethyl acetate and methanol. The precipitate was collected by filtration, and dried to give the title compound (0.68 g).
LC-MS (Method 2): R, = 1 .29 min; MS (ESIpos): m/z = 393.3 [M+H]+ 1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.90-7.80 (m, 4H), 7.76-7.68 (m, 2H), 7.28-7.19 (m, 2H), 4.10-3.99 (m, 1H), 3.83 (t, 2H), 2.32-2.18 (m, 2H), 2.13 (t, 2H), 1.79-1.60 (m, 6H)
Intermediate 118
8-amino-2-(4-fluorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000124_0001
A mixture of 2-[2-(4-fluorophenyl)-1-oxo-2-azaspiro[4.5]dec-8-yl]-1 H-isoindole-1 ,3(2H)-dione (isomer 1) (650 mg, 1.66 mmol) and hydrazine hydrate (410 μΙ, 8.3 mmol) in ethanol (14 ml) was stirred at 80Ό for 3.5 h. Upon cooling, the precipitate was filtrated off, washed with ethanol and the filtrate was concentrated to give the title compound (473 mg), which was used in the next step without further purification.
LC-MS (Method 2): R, = 0.92 min; MS (ESIneg): m/z = 263.2 [M+H]-
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (0.96), 1.052 (2.14), 1.070 (1.47), 1.075 (1.34), 1.087 (1.34), 1.106 (3.66), 1.118 (3.61), 1.134 (3.91), 1.146 (3.78), 1.166 (1.89), 1.178 (1.83), 1.487 (1.53), 1.495 (1.75), 1.513 (11.79), 1.519 (13.89), 1.543 (5.00), 1.552 (5.79), 1.576 (1.26), 1.585 (1.40), 1.691 (4.46), 1.700 (4.54), 1.712 (2.46), 1.724 (4.21), 1.734 (3.86), 1.969 (8.64), 1.978 (1.78), 1.986 (14.80), 1.995 (1.80), 2.003 (8.99), 2.323 (0.73), 2.327 (0.99), 2.331 (0.74), 2.523 (3.96), 2.534 (4.15), 2.544 (2.18), 2.551 (1.29), 2.561 (1.95), 2.571 (0.98), 2.665 (0.82), 2.669 (1.10), 2.673 (0.85), 3.269 (2.76), 3.411 (0.98), 3.428 (1.31), 3.446 (1.20), 3.732 (9.69), 3.740 (1.89), 3.749 (15.42), 3.757 (1.95), 3.766 (9.36), 7.176 (0.73), 7.184 (9.43), 7.190 (2.88), 7.197 (1.29), 7.202 (3.56), 7.207 (16.00), 7.212 (3.80), 7.217 (1.51), 7.224 (3.03), 7.229 (10.48), 7.238 (0.96), 7.666 (0.87), 7.674 (10.20), 7.680 (3.37), 7.687 (10.70), 7.692 (5.38), 7.698 (9.95), 7.704 (3.23), 7.710 (9.38), 7.719 (0.95), 7.757 (1.66), 7.765 (1.48), 7.772 (1.51), 7.780 (1.94), 8.022 (2.00), 8.030 (1.53), 8.037 (1.50), 8.045 (1.61 ).
Intermediate 119
8-{[tert-butyl(dimethyl)silyl]oxy}-2-phenyl-2-azaspiro[4.5]decan-1-one (mixture of cis-/trans- isomers)
Figure imgf000125_0001
Lithium bis(trimethylsilyl)amide (43 ml, 1 .0 M in THF, 43 mmol) was added during 15 minutes drop wise to a solution of aniline (2.20 g, 23.6 mmol) in tetrahydrofuran (200 ml) at -78Ό and the mixture was stirred for 1 h at that temperature. A solution of ethyl 4-{[tert- butyl(dimethyl)silyl]oxy}-1 -(2-chloroethyl)cyclohexanecarboxylate (mixture of cisVtrans- isomers) (7.50 g, 21.5 mmol) in tetrahydrofuran (200 ml) was added drop wise over 1 h and the mixture was stirred for 2 h at -78Ό. The mixtu re was warmed to room temperature and a catalytic amount of potassium iodide was added and the mixture was warmed to room temperature and stirred overnight. For work-up, sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate (3x). The combined organic phases were washed with brine, filtrated through a silicone filter and concentrated. The residue was purified by flash chromatography (340 g Snap Cartridge, hexanes/ethyl acetate gradient, 0% -> 15% ethyl acetate) to give 8-{[tert-butyl(dimethyl)silyl]oxy}-2-phenyl-2-azaspiro[4.5]decan-1 -one in 3 fractions: Fraction 1 (4.22 g, isomer 1 ), fraction 2 (0.10 g, mixture of isomer 1 and isomer 2 ca. 7:3), and fraction 3 (0.720 g, isomer 2).
Fraction 1 (isomer 1 ):
1 H-NMR (400 MHz, DMSO-cfe): δ [ppm] = 7.68-7.63 (m, 2H), 7.37-7.31 (m, 2H), 7.13-7.06 (m, 1 H), 3.97-3.89 (m, 1 H), 3.73 (t, 2H), 2.01 -1.86 (m, 4H), 1 .68-1 .48 (m, 4H), 1.29-1.20 (m, 2H), 0.87 (s, 9H), 0.04 (s, 6H)
Fraction 3 (isomer 2):
LC-MS (Method 2): R, = 1 .75 min; MS (ESIpos): m/z = 360.3 [M+H]+
1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.70-7.64 (m, 2H), 7.40-7.33 (m, 2H), 7.16-7.09 (m, 1 H), 3.77 (t, 2H), 3.68-3.59 (m, 1 H), 2.02 (t, 2H), 1 .84-1.74 (m, 2H), 1 .65-1 .51 (m, 4H), 1.41 - 1 .28 (m, 2H), 0.87 (s, 9H), 0.07 (s, 6H)
Intermediate I20
8-hydroxy-2-phenyl-2-azaspiro[4.5]decan-1 -one (isomer 1
Figure imgf000126_0001
Tetra-N-butylammonium fluoride (35 ml, 35 mmol, 1 M solution in tetrahyrofuran) was added to a solution 8-{[tert-butyl(dimethyl)silyl]oxy}-2-phenyl-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (4.22 g, 1 1 .7 mmol) in tetrahydrofuran (100 ml) and the mixture was stirred at room temperature for 20 h. The mixture was poured into water, extracted with ethyl acetate (3x) and the combined organic phases were washed with saturated sodium bicarbonate solution and brine, filtrated through a silicone filter and concentrated under reduced pressure. The residue was purified by flash chromatography to give the title compound (2.57 g).
LC-MS (Method 2): R, = 0.94 min; MS (ESIpos) m/z = 246.2 [M+H]+
1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.70-7.65 (m, 2H), 7.40-7.34 (m, 2H), 7.15-7.09 (m, 1 H), 4.40 (d, 1 H), 3.80-3.72 (m, 3H), 2.02-1 .89 (m, 4H), 1.73-1.62 (m, 2H), 1 .60-1 .49 (m, 2H), 1 .30-1 .21 (m, 2H)
Intermediate 121
2-[1 -oxo-2-phenyl-2-azaspiro[4.5]dec-8-yl]-1 H-isoindole-1 ,3(2H)-dione (isomer 1 )
Figure imgf000126_0002
Diisopropyl azodicarboxylate (3.1 ml, 16 mmol) was added drop wise to a mixture of 8- hydroxy-2-phenyl-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (2.57 g, 10.5 mmol), phthalimide (2.31 g, 15.7 mmol) and triphenylphosphine (4.12 g, 15.7 mmol) in tetrahydrofuran (120 ml) and the mixture was stirred at room temperature for 12 h. For work-up, the reaction mixture was concentrated and the residue was stirred with methanol. The precipitate was collected by filtration, washed with methanol and dried to give the title compound (1 .55 g).
LC-MS (Method 2): R, = 1 .29 min; MS (ESIpos): m/z = 375.2 [M+H]+
1 H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1 .643 (1 .29), 1 .650 (1 .67), 1 .665 (4.54), 1 .672 (5.19), 1 .687 (5.97), 1 .694 (10.51 ), 1 .715 (5.81 ), 1.720 (6.64), 1.737 (4.60), 1 .743 (3.98), 1 .759 (0.83), 2.124 (6.62), 2.136 (1 1.32), 2.147 (6.91 ), 2.223 (1 .34), 2.230 (1 .72), 2.245 (3.87), 2.252 (4.25), 2.265 (4.01), 2.273 (3.87), 2.287 (1.43), 2.294 (1.29), 2.381 (1.05), 2.384 (1.43), 2.387 (1.08), 2.482 (3.87), 2.486 (5.43), 2.515 (4.28), 2.518 (4.57), 2.521 (5.00), 2.526 (3.04), 2.609 (1.05), 2.612 (1.37), 2.615 (0.99), 3.292 (3.58), 3.330 (2.93), 3.332 (2.02), 3.821 (7.07), 3.827 (2.21), 3.832 (12.83), 3.838 (1.94), 3.844 (6.96), 4.022 (0.83), 4.029 (1.67), 4.035 (1.05), 4.043 (1.83), 4.050 (3.20), 4.056 (1.77), 4.064 (1.02), 4.070 (1.56), 4.077 (0.81), 7.123 (1.86), 7.125 (3.04), 7.127 (2.07), 7.135 (4.17), 7.137 (6.67), 7.148 (2.61), 7.149 (3.60), 7.151 (2.42), 7.364 (1.48), 7.367 (7.34), 7.371 (3.04), 7.379 (10.03), 7.382 (10.08), 7.391 (3.07), 7.394 (7.26), 7.687 (10.49), 7.689 (11.19), 7.698 (4.22), 7.701 (10.81), 7.703 (8.61), 7.831 (4.95), 7.835 (5.08), 7.837 (6.10), 7.838 (6.13), 7.841 (7.07), 7.845 (15.35), 7.850 (7.37), 7.851 (7.72), 7.856 (16.00), 7.860 (7.64), 7.862 (5.89), 7.864 (6.10), 7.865 (5.24), 7.870 (5.08).
Intermediate I22
8-amino-2-phenyl-2-azaspiro[4.5]decan-1-one (isomer 1)
Figure imgf000127_0001
A mixture of 2-[1-oxo-2-phenyl-2-azaspiro[4.5]dec-8-yl]-1 H-isoindole-1 ,3(2H)-dione (isomer 1) (1.52 g, 4.06 mmol) and hydrazine hydrate (1.0 ml, 20 mmol) in ethanol (35 ml) was stirred at 80Ό for 4 h. Upon cooling, the precipitate was fil trated off, washed with ethanol and the filtrate was concentrated and the residue was stirred with dichloromethane. The solid was filtrated off and the filtrated was washed with water and brine, filtrated through a silicone filter and concentrated to give the title compound (958 mg), which was used for the next step without further purification.
LC-MS (Method 2): R, = 0.89 min; MS (ESIpos): m/z = 245 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.064 (1.39), 1.076 (1.43), 1.096 (3.87), 1.107 (3.73), 1.124 (4.08), 1.135 (4.07), 1.156 (2.00), 1.168 (2.05), 1.486 (3.05), 1.496 (3.28), 1.517 (15.63), 1.526(12.73), 1.548 (6.21), 1.557 (6.92), 1.581 (1.83), 1.590(1.97), 1.686(4.76), 1.695 (4.69), 1.707 (2.54), 1.719 (4.39), 1.729 (3.95), 1.974 (8.96), 1.983 (1.90), 1.991 (15.09), 2.000 (1.77), 2.009 (9.33), 2.323 (0.68), 2.327 (0.92), 2.523 (3.98), 2.541 (1.91), 2.665 (0.69), 2.669 (0.92), 2.674 (0.68), 3.742 (10.14), 3.751 (1.87), 3.759 (16.00), 3.767 (2.00), 3.776 (9.73), 5.760 (4.33), 7.096 (2.00), 7.098 (3.51), 7.101 (1.94), 7.117 (7.97), 7.132 (2.99), 7.135 (4.69), 7.138 (2.57), 7.336 (1.20), 7.341 (9.36), 7.346 (3.36), 7.354 (1.91), 7.360 (11.38), 7.363 (12.49), 7.368 (2.16), 7.376 (3.14), 7.381 (9.20), 7.386 (1.46), 7.652 (1.46), 7.658 (12.44), 7.660
(13.69), 7.663 (7.17), 7.674 (3.70), 7.679 (13.01), 7.683 (9.56), 7.687 (1.93). Intermediate 123
ethyl 4-{[tert-butyl(dimethyl)silyl]oxy}-1 -(cyanomethyl)cyclohexanecarboxylate (mixture of cis- /trans-isomers)
Figure imgf000128_0001
Lithium diisopropylamide (21 ml, 2 M solution in tetrahydrofruan, 42 mmol) was added drop wise to a solution of ethyl 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (mixture of cis-/trans-isomers) (13.2 g, 46.1 mmol) in tetrahydrofruan(62 ml) at -73Ό and the mixture was stirred for 30 min at that temperature. Bromoacetonitrile (4.8 ml, 69 mmol, CAS No 590-17-0) was added drop wise and the mixture was then stirred for 1 h at the same temperature and then warmed to room temperature over 2.5h. For work-up, water was added and the mixture was extracted with ethyl acetate (3x) and the combined organic phases were washed with brine, filtrated through a silicone filter and concentrated. The residue was purified by flash chromatography (340 g Snap Cartridge, hexanes/ethyl acetate gradient, 10% -> 18% ethyl acetate) to give the title compound in 3 fractions: fraction 1 (0.33 g, 2% yield, single isomer based on 1 H NMR, isomer 2), fraction 2 (4.26 g, 28 % yield, mixture of isomer 1 and isomer 2, ca. 9:1 based on 1 H NMR), fraction 3 (3.17 g, 21 % yield, single isomer based on 1 H NMR, isomer 1 ).
Fraction 1 (isomer 2):
1 H-NMR (400 MHz, DMSO-afe): δ [ppm] = 4.14 (q, 2H), 3.87-3.80 (m, 1 H), 2.80 (s, 2H), 1 .87- 1 .67 (m, 4H), 1 .62-1.42 (m, 4H), 1 .20 (t, 3H), 0.86 (s, 9H), 0.04 (s, 6H)
Fraction 3 (isomer 1 ):
1 H-NMR (400 MHz, DMSO-de): δ [ppm] = 4.15 (q, 2H), 3.71 -3.62 (m, 1 H), 2.78 (s, 2H), 2.16- 2.04 (m, 2H), 1 .76-1.66 (m, 2H), 1 .44-1 .25 (m, 4H), 1 .21 (t, 3H), 0.85 (s, 9H), 0.03 (s, 6H)
Intermediate I24
8-{[tert-butyl(dimethyl)silyl]oxy}-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000128_0002
An autoclave was charged with a mixture of ethyl 4-{[tert-butyl(dimethyl)silyl]oxy}-1 - (cyanomethyl)cyclohexanecarboxylate (mixture of cis-/trans-isomers) (7.40 g, 22.7 mmol) , Raney-Nickel catalyst (4.67 g) and ammonia (102 ml, 2 M in ethanol, 204 mmol) and then pressurized with hydrogen (30 bar). The mixture was stirred at 40Ό over night. Upon cooling, the catalyst was filtrated off, washed with ethanol and the filtrate was concentrated under reduced pressure. The residue was dissolved in toluene (59 ml), triethylamine (6 ml) was added and the mixture was refluxed for 24 h. For work-up, the reaction mixture was concentrated and the residue was purified by flash chromatography (hexanes/ethyl acetate gradient) to give the title compound (4.40 g) as single isomer.
1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.41 (br. s., 1 H), 3.93-3.84 (m, 1 H), 3.09 (t, 2H), 1 .89-1 .75 (m, 4H), 1.62-1 .39 (m, 4H), 1 .13-1 .03 (m, 2H), 0.85 (s, 9H), 0.01 (s, 6H)
Intermediate I25
8-{[tert-butyl(dimethyl)silyl]oxy}-2-(3,5-difluorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000129_0001
A mixture of 8-{[tert-butyl(dimethyl)silyl]oxy}-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (425 mg, 1 .50 mmol), 1 ,3-difluoro-5-iodobenzene (360 mg, 1 .50 mmol, CAS No 2265-91 -0), copper(l) iodide (143 mg, 0.750 mmol), N,N'-dimethylethylenediamine (164 μΙ, 1 .50 mmol) and potassium carbonate (435 mg, 3.15 mmol) in dioxane (26 ml) was heated to 160Ό for 2 h in a microwave reactor. Upon cooling, the reaction mixture was filtrated through a pad of celite, and the filtrate was concentrated and the residue was purified by flash chromatography (25 g Snap Cartrige, hexanes/ethyl acetate-gradient, 0% -> 50% ethyl acetate) to give the title compound as single isomer (575 mg).
LC-MS (Method 2): Rt = 1 .79 min; MS (ESIpos): m/z = 396.3 [M+H]+
1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.50-7.41 (m, 2H), 6.98-6.91 (m, 1 H), 3.94-3.88 (m, 1 H), 3.72 (t, 2H), 2.00-1 .85 (m, 4H), 1 .63-1 .47 (m, 4H), 1 .28-1.20 (m, 2H), 0.85 (s, 9H), 0.01 (s, 6H)
Intermediate I26
2-(3,5-difluorophenyl)-8-hydroxy-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000130_0001
Tetra-N-butylammonium fluoride (4.4 ml, 1 M solution in tetrahydrofuran, 4.4 mmol) was added to a solution of 8-{[tert-butyl(dimethyl)silyl]oxy}-2-(3,5-difluorophenyl)-2-azaspiro[4.5]decan-1 - one (isomer 1 ) (575 mg, 1 .45 mmol) in tetrahydrofuran (12 ml) and the mixture was stirred at room temperature for 20 h. The mixture was poured into water, extracted with ethyl acetate (3x) and the combined organic phases were washed with saturated sodium bicarbonate solution and brine, filtrated through a silicone filter and concentrated under reduced pressure. The residue was purified by flash chromatography (25 g Snap cartridge, hexanes/ethyl acetate-gradient, 0% -> 100% ethyl acetate) to give the title compound (360 mg) as single isomer.
LC-MS (Method 1 ): Rt = 1 .05 min; MS (ESIpos): m/z = 282.1 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .172 (0.92), 1 .225 (2.23), 1 .236 (4.58), 1 .246 (2.71 ), 1 .258 (2.69), 1 .269 (4.97), 1 .279 (2.62), 1 .493 (1 .16), 1.501 (1.88), 1 .510 (1 .33), 1.534 (4.19), 1 .555 (2.58), 1 .564 (3.63), 1 .572 (2.07), 1 .623 (1 .63), 1.635 (4.43), 1 .647 (4.73), 1.658 (2.80), 1 .669 (2.91 ), 1 .681 (2.69), 1 .693 (1.00), 1 .892 (3.17), 1.902 (3.43), 1 .925 (4.73), 1.932 (4.38), 1 .954 (3.20), 1 .963 (8.89), 1 .980 (12.37), 1.988 (3.52), 1 .997 (7.1 1 ), 2.327 (0.75), 2.523 (1 .72), 2.669 (0.76), 3.735 (9.42), 3.745 (4.95), 3.752 (16.00), 3.770 (7.96), 4.404 (8.55), 4.41 1 (8.77), 6.958 (1 .28), 6.964 (2.69), 6.970 (1.62), 6.981 (2.59), 6.987 (5.17), 6.993 (3.07), 7.004 (1 .38), 7.010 (2.63), 7.016 (1 .49), 7.460 (1.20), 7.467 (1 .49), 7.472 (6.64), 7.478 (7.94), 7.482 (3.17), 7.498 (7.85), 7.504 (6.53), 7.509 (1.39), 7.515 (1 .32).
Intermediate I27
2-[2-(3,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 H-isoindole-1 ,3(2H)-dione (isomer 1 )
Figure imgf000130_0002
Diisopropyl azodicarboxylate (370 μΙ, 1 .9 mmol) was added drop wise to a mixture of 2-(3,5- difluorophenyl)-8-hydroxy-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (355 mg, 1 .26 mmol), phthalimide (279 mg, 1.89 mmol, CAS No 85-41 -6) and triphenylphosphine (497 mg, 1 .89 mmol) in tetrahydrofuran (15 ml) and the mixture was stirred at room temperature overnight. For work-up, the reaction mixture was concentrated and the residue was purified by flash chromatography (25 g Snap Cartridge, hexanes/ethyl acetate gradient, 0% -> 50% ethyl acetate) followed by recrystallization from methanol to give the title compound (203 mg) as single isomer, together with unknown impurities.
LC-MS (Method 1 ): Rt = 1.40 min; MS (ESIpos): m/z = 411.3 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.172 (0.71), 1.645 (1.93), 1.655 (2.38), 1.677 (1.77), 1.699 (4.64), 1.705 (4.64), 1.730 (3.01), 1.738 (2.67), 1.988 (1.06), 2.116 (3.10), 2.134 (5.42), 2.151 (3.27), 2.219 (1.57), 2.230 (1.87), 2.251 (1.70), 2.262 (1.65), 2.327 (1.01), 2.518 (2.97), 2.523 (2.08), 2.665 (0.71), 2.669 (1.02), 3.821 (3.42), 3.839 (5.73), 3.856 (3.34), 4.034 (0.94),
4.045 (1.42), 6.994 (1.39), 7.000 (0.91), 7.012 (1.42), 7.017 (2.81), 7.023 (1.73), 7.041 (1.34),
7.046 (0.83), 7.499 (3.35), 7.505 (4.00), 7.509 (1.54), 7.525 (3.96), 7.530 (3.34), 7.815 (12.58), 7.823 (2.53), 7.830 (1.68), 7.834 (3.76), 7.841 (4.21), 7.846 (14.71), 7.854 (16.00), 7.860 (5.45), 7.866 (3.96), 7.870 (1.65), 7.877 (2.20). Intermediate I28
8-amino-2-(3,5-difluorophenyl)-2-azas iro[4.5]decan-1 -one (isomer 1 )
Figure imgf000131_0001
A mixture of 2-[2-(3,5-difluorophenyl)-1-oxo-2-azaspiro[4.5]dec-8-yl]-1 H-isoindole-1 ,3(2H)- dione (isomer 1) (203 mg, 495 μιηοΙ) and hydrazine hydrate (120 μΙ, 2.5 mmol) in ethanol (4.2 ml) was stirred at 80Ό for 3 h. Upon cooling, the precipitate was filtrated off, washed with ethanol and the filtrate was concentrated to give the title compound (105 mg), which was used in the next step without further purification.
LC-MS (Method 2): Rt = 1.03 min; MS (ESIpos): m/z = 281.2 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.030 (0.57), 1.048 (1.25), 1.065 (1.80), 1.082 (1.55), 1.092 (3.05), 1.108 (3.48), 1.123 (3.82), 1.141 (3.44), 1.151 (2.12), 1.168 (2.00), 1.507 (13.82), 1.516 (16.00), 1.524 (7.74), 1.533 (11.06), 1.541 (7.10), 1.566 (0.96), 1.575 (0.86), 1.683 (4.85), 1.693 (4.98), 1.705 (2.73), 1.717 (4.60), 1.726 (4.30), 1.766 (1.02), 1.973 (8.33), 1.990 (14.43), 2.008 (8.60), 2.318 (1.09), 2.323 (1.43), 2.327 (1.09), 2.331 (0.64), 2.525 (4.42), 2.535 (2.53), 2.544 (1.50), 2.553 (1.98), 2.563 (1.07), 2.659 (1.14), 2.665 (1.52), 2.669 (1.23), 3.317 (2.96), 3.424 (0.96), 3.442 (0.82), 3.742 (8.63), 3.752 (2.37), 3.761 (14.34), 3.768 (2.64), 3.778 (8.40), 6.961 (1.39), 6.967 (2.89), 6.973 (1.91), 6.984 (2.89), 6.990 (5.64), 6.996 (3.53), 7.008 (1.52), 7.013 (2.84), 7.019 (1 .73), 7.450 (0.66), 7.456 (1.46), 7.462 (1 .87), 7.467 (7.12), 7.473 (9.01 ), 7.493 (9.01 ), 7.499 (7.74), 7.504 (1 .96), 7.51 1 (1.48), 7.518 (0.75), 7.758 (1.41 ), 7.766 (1.32), 7.773 (1.32), 7.781 (1.57), 8.018 (1 .66), 8.026 (1.30), 8.032 (1 .30), 8.041 (1 .30).
Intermediate I29
ethyl 4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexanecarboxylate
Figure imgf000132_0001
Tert-butyl(chloro)diphenylsilane (18 ml, 68 mmol, CAS No 58479-61 -1 ) was added drop wise to a mixture of ethyl 4-hydroxycyclohexanecarboxylate (9.4 ml, 57 mmol, CAS No 17159-80-7), 1 H-imidazole (9.68 g, 142 mmol, CAS No 16681 -56-4) and N,N-dimethylpyridin-4-amine (348 mg, 2.85 mmol, CAS No 1 122-58-3) in dimethylformamid (81 ml), and the mixture was stirred at room temperature for 24 h. For work-up, the mixture was poured into water, extracted with ethyl acetate (3x) and the combined organic phases were washed until pH=7 as reached. The organic phase was dried over sodium sulfate and was concentrated under reduced pressure. The residue was purified by flash chromatography (340 g Snap cartridge, hexane/ethyl acetate gradient, 5% -> 30% ethyl acetate) to give the title compound (21 g).
Intermediate I30
ethyl 4-{[tert-butyl(diphenyl)silyl]oxy}-1 -(2-chloroethyl)cyclohexanecarboxylate (mixture of cis/trans isomers)
Figure imgf000132_0002
Lithium di(propan-2-yl)azanide (98 ml, 2.0 M, 200 mmol, CAS No 41 1 1 -54-0) was added drop wise to a solution of ethyl 4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexanecarboxylate (64.2 g, 156 mmol)in tetrahydrofuran (230 ml) at -78Ό to -70Ό, then the mixture was stirred 30 minutes at -78Ό. 1 -Bromo-2-chloroethane (20 ml, 230 mmol, CAS No 107-04-0) was added drop wise to the reaction and the mixture was warmed to room temperature within 2 h, then stirred at room temperature for 1 .5 h. For work-up, water was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with half saturated sodium chloride solution (2x) and with saturated sodium chloride solution. The organic phase was filtrated over a hydrophobic filter and concentrated. The residue was purified by flash chromatography (750 g Snap Cartridge, hexane /ethyl acetate gradient, 0% -> 20% ethyl acetate) to give the title compound (68.51 g).
Intermediate 131
8-{[tert-butyl(diphenyl)silyl]oxy}-2-(2-chlorophenyl)-2-azaspiro[4.5]decan-1 -one (mixture of cis- /trans-isomers)
Figure imgf000133_0001
Lithium 1 ,1 ,1 ,3,3,3-hexamethyldisilazan-2-ide (42 ml, 1 M solution in tetrahyrofuran, 42 mmol, CAS No 4039-32-1 ) was added drop wise within 5 minutes to a solution of 2-chloroaniline (2.5 ml, 23 mmol, CAS 95-51 -2) in tetrahydrofuran (1 10 ml) at -78Ό and the mixture was stirred for 60 min at that temperature. A solution of ethyl 4-{[tert-butyl(diphenyl)silyl]oxy}-1 -(2- chloroethyl)cyclohexanecarboxylate (mixture of cis/trans isomers) (10.0 g, 21 .1 mmol) in tetrahydrofuran (1 10 ml) was added and the mixture was stirred for 2 h at -78Ό. The mixture was warmed to room temperature and stirred for 4 d. For work-up, the reaction was added to a solution of water and sodium bicarbonate and the mixture was extracted with ethyl acetate (3x). The combined organic phases were washed with a saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure, the residue was purified by flash chromatography (hexane/ethyl acetate gradient, 0% -> 25% ethyl acetate) to give the title compound in 2 fractions: fraction 1 (6.58 g, single isomer based on 1 H NMR, isomer 1 ), fraction 2 (1 .38 g, single isomer based on 1 H NMR, isomer 2).
Fraction 1 (isomer 1 ):
1 H-NMR (400 MHz, DMSO-afe): δ [ppm] = 7.67-7.55 (m, 5H), 7.52-7.30 (m, 9H), 3.97 (br s, 1 H), 3.60 (t, 2H), 2.15-2.07 (m, 2H), 2.04 (t, 2H), 1 .76-1 .63 (m, 2H), 1 .58-1 .45 (m, 2H), 1 .39-1 .27 (m, 2H), 1 .05 (s, 9H). LC-MS (Method 1): Rt = 1.80 min; MS (ESIpos): m/z = 518.3 [M+H]+
Fraction 2 (isomer 2):
1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 7.68-7.60 (m, 4H), 7.57-7.30 (m, 10H), 3.71-3.62 (m, 1 H), 3.60 (t, 2H), 2.09 (t, 2H), 1.83-1.73 (m, 2H), 1.61 -1.35 (m, 6H), 1.03 (s, 9H).
LC-MS (Method 1): Rt = 1.82 min; MS (ESIpos): m/z = 518.2 [M+H]+ Intermediate I32
2-(2-chlorophenyl)-8-hydroxy-2-azaspiro[4.5]decan-1 -one (isomerl )
Figure imgf000134_0001
A solution of 8-{[tert-butyl(diphenyl)silyl]oxy}-2-(2-chlorophenyl)-2-azaspiro[4.5]decan-1-one (isomerl) (6.58 g, 12.7 mmol) and tetra-butylamonium fluoride (19 ml, 1.0 M, 19 mmol, CAS No 429-41-4) in tetrahydrofuran (100 ml) was stirred overnight at room temperature, then the mixture was heated to reflux and was stirred under reflux for 6 h. For work-up the mixture was concentrated, and the residue was purified by flash chromatography (methylene chloride/ethyl acetate gradient, 0% -> 100% ethyl acetate), the product containing fractions were concentrated and the resulting precipitate was filtrated off and washed with ethyl acetate to give the title compound (2.87 g).
LC-MS (Method 1): Rt = 0.95 min; MS (ESIpos): m/z = 280.2 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.266 (1.31), 1.277 (2.48), 1.288 (1.54), 1.299 (1.50), 1.310 (2.68), 1.321 (1.50), 1.517 (1.13), 1.544 (2.15), 1.552 (2.32), 1.560 (1.32), 1.570 (1.50), 1.579(2.09), 1.587(1.23), 1.667(2.31), 1.679(2.44), 1.691 (1.47), 1.701 (1.59), 1.714(1.43), 1.924 (1.88), 1.934 (1.98), 1.952 (2.17), 1.957 (2.50), 1.962 (2.31 ), 1.967 (2.07), 1.985 (1.68), 1.988 (1.48), 1.995 (1.43), 2.023 (4.60), 2.040 (8.41), 2.057 (4.78), 3.584 (5.50), 3.601 (9.02), 3.618 (5.21), 3.736 (1.68), 3.743 (1.66), 4.387 (6.30), 4.395 (6.08), 7.346 (1.34), 7.354 (1.75), 7.360 (1.85), 7.364 (1.31), 7.369 (4.25), 7.376 (1.80), 7.379 (3.50), 7.386 (12.67), 7.390 (16.00), 7.394 (8.00), 7.398 (1.43), 7.402 (2.42), 7.405 (2.71 ), 7.409 (1.23), 7.538 (0.76), 7.542 (3.23), 7.546 (3.78), 7.549 (2.58), 7.560 (2.60), 7.563 (4.00), 7.567 (2.82).
Intermediate I33
2-(2-chlorophenyl)-1-oxo-2-azaspiro[4.5]dec-8-yl methanesulfonate (isomer 1)
Figure imgf000135_0001
Triethylamine (1 .7 ml) was added to a solution of 2-(2-chlorophenyl)-8-hydroxy-2- azaspiro[4.5]decan-1 -one (isomer 1 ) (2.86 g, 10.2 mmol) in methylene chloride (24 ml) at - 20Ό, then methanesulfonyl chloride (960 μΙ, 12 mmo I) was added drop wise and the mixture was stirred for 60 min at room temperature. The reaction mixture was diluted with methylene chloride and then washed with sodium bicarbonate and sodium chloride, the organic phase was filtrated through a hydrophobic filter and was then concentrated under reduced pressure to give the title compound (3.68 g).
LC-MS (Method 1 ): Rt = 1 .03 min; MS (ESIpos): m/z = 358.0 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.074 (1 .35), 2.091 (2.54), 2.109 (1 .41 ), 3.195 (16.00), 3.331 (10.85), 3.350 (1.28), 3.613 (1 .63), 3.631 (2.80), 3.648 (1 .56), 7.369 (0.85), 7.381 (1 .17), 7.400 (2.48), 7.405 (3.41 ), 7.408 (4.42), 7.415 (1 .22), 7.418 (1.60), 7.553 (1 .01 ), 7.557 (1 .49), 7.559 (0.85), 7.571 (0.82), 7.575 (1.27).
Intermediate I34
8-azido-2-(2-chlorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000135_0002
A suspension of 2-(2-chlorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl methanesulfonate (isomer 1 ) (3.67 g, 10.3 mmol) and sodium azide (867 mg, 13.3 mmol, CAS No 26628-22-8) in N,N- dimethylformamide (32 ml) was stirred at 80Ό for 5 .5 h. The mixture was poured into water, stirred for 15 minutes, the resulting precipitate was filtrated off to give the title compound (2.58 g), which was used immediately in the next step without further purification.
LC-MS (Method 1 ): Rt = 1 .23 min; MS (ESIpos): m/z = 305.1 [M+H]+ Intermediate I35 8-amino-2-(2-chlorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000136_0001
To the solution of 8-azido-2-(2-chlorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (2.58 g, 8.47 mmol) in tetrahydrofuran (29 ml), were added triphenylphosphane (2.66 g, 10.2 mmol,) and distilled water (460 μΙ). The mixture was stirred for 15 h at room temperature and then at 5CC for 2 h. For work up the mixture was concentra ted under reduced pressure and the residue was purified by flash chromatography (25 g Snap cartridge, methylene chloride/methanol gradient, 0% -> 100% methanol), to give the title compound (1.93 g).
LC-MS (Method 2): R, = 0.88 min; MS (ESIpos): m/z = 279.2 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .077 (0.64), 1 .098 (1 .28), 1 .128 (2.06), 1 .157 (1 .61 ), 1 .180 (0.91 ), 1 .515 (2.39), 1 .541 (5.41 ), 1 .549 (6.94), 1.564 (6.62), 1 .572 (7.02), 1.703 (2.34), 1 .710 (2.38), 1 .722 (1 .34), 1 .733 (2.18), 1 .743 (2.04), 2.044 (5.13), 2.052 (0.81 ), 2.061 (8.77), 2.071 (0.84), 2.078 (5.31 ), 2.327 (0.53), 2.518 (3.70), 2.523 (1.79), 2.527 (1 .36), 2.534 (0.76), 2.544 (1 .03), 2.554 (0.48), 2.669 (0.55), 3.590 (5.77), 3.599 (0.92), 3.608 (8.73), 3.617 (0.92), 3.625 (5.57), 7.348 (1 .09), 7.355 (1.57), 7.363 (2.48), 7.370 (5.30), 7.376 (3.51 ), 7.382 (6.60), 7.387 (16.00), 7.392 (7.51 ), 7.403 (3.80), 7.407 (0.94), 7.417 (0.59), 7.422 (0.75), 7.426 (0.50), 7.542 (5.55), 7.547 (3.46), 7.552 (1.73), 7.557 (1 .18), 7.562 (4.24), 7.567 (2.31 ), 7.571 (0.87).
Intermediate I36
8-{[tert-butyl(diphenyl)silyl]oxy}-2-(2-chloro-4-fluoro-5-methylphenyl)-2-azaspiro[4.5]decan-1 - one (mixture of cisVtrans-isomers)
Figure imgf000136_0002
Lithium 1 ,1 ,1 ,3,3,3-hexamethyldisilazan-2-ide (42 ml, 1 M solution in tetrahyrofuran, 42 mmol,
CAS No 4039-32-1 ) was added drop wise within 5 minutes to a solution of 2-chloro-4-fluoro-5- methylaniline (3.79 g, 23.2 mmol, CAS No 124185-35-9) in tetrahydrofuran (1 10 ml) at -78Ό. The mixture was stirred for 30 min at that temperature. A solution of ethyl 4-{[tert- butyl(diphenyl)silyl]oxy}-1 -(2-chloroethyl)cyclohexanecarboxylate (mixture of cis/trans isomers) (10.0 g, 21 .1 mmol) in tetrahydrofuran (1 10 ml) was added and the mixture was stirred for 2 h at -78Ό. The mixture was warmed to room temperatur e and stirred for 4 d. For work-up, the reaction was added to a solution of water and sodium bicarbonate and the mixture was extracted with ethyl acetate (3x). The combined organic phases were washed with sodium chloride, dried over sodium sulfate and concentrated under reduced pressure, the residue was purified by flash chromatography (100 g Snap cartridge, hexane/ethyl acetate gradient, 5% -> 30% ethyl acetate) the product containing fractions were concentrated and were then purified a second time by flash chromatography (120 g Snap cartridge, hexane/ethyl acetate gradient, 5% -> 40% ethyl acetate to give the title compound in 2 fractions: fraction 1 (5.85 g, single isomer based on 1 H NMR, isomer 1 ), fraction 2 (1 .21 g, single isomer based on 1 H NMR, isomer 2).
Fraction 1 (isomer 1 ):
1 H-NMR (400 MHz, DMSO-de): δ [ppm] = 7.65-7.58 (m, 4H), 7.52-7.34 (m, 8H), 3.96 (br s, 1 H), 3.56 (t, 2H), 2.23 (d, 3H), 2.09 (td, 2H), 2.04-1 .99 (m, 2H), 1 .72-1 .59 (m, 2H), 1 .56-1 .45 (m, 2H), 1.31 (m, 2H), 1.04 (s, 9H).
Fraction 2 (isomer 2):
1 H-NMR (400 MHz, DMSO-d6) δ [ppm] = 7.66-7.59 (m, 4H), 7.50-7.41 (m, 7H), 7.33 (d, 1 H), 3.70-3.60 (m, 1 H), 3.58-3.52 (m, 2H), 2.20 (d, 3H), 2.07 (t, 2H), 1 .77 (br dd, 2H), 1 .58-1.33 (m, 6H), 1.02 (s, 9H).
Intermediate I37
2-(2-chloro-4-f luoro-5-methylphenyl)-8-hydroxy-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000137_0001
A mixture of 8-{[tert-butyl(diphenyl)silyl]oxy}-2-(2-chloro-4-fluoro-5-methylphenyl)-2- azaspiro[4.5]decan-1 -one (isomer 1 ) (5.85 g, 10.6 mmol) and N,N,N-tributylbutan-1 -aminium fluoride (16 ml, 1 .0 M, 16 mmol, CAS No 429-41 -4) in tetrahydrofuran (86 ml), was stirred overnight at 40Ό. The reaction was heated to reflu x and was stirred for 6 h under reflux. For work-up, the mixture was concentrated under reduced pressure, the residue was purified by flash chromatography (100g Snap cartridge, methylene chloride/ethyl acetate gradient, 0% -> 100% ethyl acetate) to give the title compound (3.08 g).
LC-MS (Method 1 ): Rt = 1.07 min; MS (ESIpos): m/z = 312.2 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.908 (0.90), 1.251 (1.39), 1.262 (2.68), 1.275 (1.73), 1.283 (1.75), 1.295 (3.03), 1.307 (1.69), 1.503 (0.77), 1.511 (1.22), 1.520 (0.90), 1.537 (2.42), 1.545 (2.58), 1.564 (1.70), 1.572 (2.25), 1.582 (1.24), 1.648 (0.99), 1.659 (2.42), 1.672 (2.60), 1.683 (1.59), 1.693 (1.71), 1.705 (1.54), 1.911 (1.90), 1.921 (2.07), 1.944 (2.71), 1.953 (2.22), 1.972 (1.73), 1.982 (1.46), 1.988 (0.84), 2.007 (4.49), 2.024 (8.49), 2.041 (4.70), 2.215 (15.90), 2.220 (16.00), 2.518 (1.55), 2.523 (1.10), 3.545 (5.40), 3.553 (1.05), 3.563 (8.86), 3.571 (1.08), 3.579 (5.13), 3.731 (1.81), 3.738 (1.81), 4.385 (7.03), 4.392 (7.00), 7.345 (4.32), 7.347 (4.05), 7.364 (4.02), 7.367 (3.93), 7.471 (6.69), 7.495 (6.65).
Intermediate I38
2-(2-chloro-4-fluoro-5-methylphenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl methanesulfonate (isomer 1)
Figure imgf000138_0001
Triethylamine (1.7 ml) was added to a solution of 2-(2-chloro-4-fluoro-5-methylphenyl)-8- hydroxy-2-azaspiro[4.5]decan-1-one (isomer 1) (3.05 g, 9.78 mmol) in methylene chloride (23 ml) at -20Ό, then methanesulfonyl chloride (920 μΙ , 12 mmol) was added drop wise and the mixture was stirred for 60 min at room temperature. The reaction mixture was diluted with methylene chloride and then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, the organic phase was filtrated through a hydrophobic filter and was then concentrated under reduced pressure to give the title compound (3.89 g).
LC-MS (Method 1): Rt = 1.15 min; MS (ESIpos): m/z = 390.1 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.896 (0.42), 0.914 (1.00), 0.932 (0.49), 1.158 (0.67), 1.175 (1.45), 1.194 (0.73), 1.451 (0.89), 1.461 (0.53), 1.484 (0.82), 1.494 (0.52), 1.784 (0.82), 1.811 (0.58), 1.817 (0.98), 1.840 (1.02), 1.845 (0.99), 1.870 (0.97), 1.907 (0.46), 1.976 (0.70), 1.985 (0.69), 1.996 (0.59), 2.010 (0.64), 2.021 (0.53), 2.057 (1.35), 2.074 (2.55), 2.091 (1.38), 2.219 (5.20), 2.223 (5.27), 2.291 (1 .15), 3.193 (16.00), 3.350 (0.94), 3.359 (1 .43), 3.575 (1 .57), 3.592 (2.72), 3.609 (1 .50), 4.854 (0.59), 4.861 (0.72), 4.867 (0.59), 7.369 (1 .34), 7.389 (1 .33), 7.482 (1 .97), 7.505 (1.97).
Intermediate I39
8-azido-2-(2-chloro-4-f luoro-5-methylphenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000139_0001
A mixture of 2-(2-chloro-4-fluoro-5-methylphenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl methanesulfonate (isomer 1 ) (3.88 g, 9.95 mmol) and sodium azide (841 mg, 12.9 mmol, CAS No 26628-22-8) in N,N-dimethylformamide (31 ml, 400 mmol) was stirred at 80Ό for 5.5 h. The mixture was poured into water, stirred for 15 minutes, the resulting precipitate was filtrated off to give the title compound (3.23 g), which was used immediately in the next step without further purification.
Intermediate I40
8-amino-2-(2-chloro-4-fluoro-5-methylphenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000139_0002
To the solution of 8-azido-2-(2-chloro-4-fluoro-5-methylphenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (3.23 g, 9.59 mmol) in tetrahydrofuran (33 ml, 400 mmol), was added triphenylphosphane (3.02 g, 1 1 .5 mmol) and distilled water (520 μΙ, 29 mmol). The mixture was stirred for 15 h at room temperature and then for 2h at 50Ό. The mixture was concentrated and the residue was purified by flash chromatography (25 g Snap cartridge, methylene chloride/methanol gradient, 0% -> 100% methanol), to give the title compound (2.47 g).
LC-MS (Method 2): Rt = 1 .02 min; MS (ESIpos): m/z = 31 1 .2 [M+H]+ 1 H-NMR (400 MHz, DMSO-c!6) δ [ppm]: 1 .420 (1 .60), 1 .434 (2.04), 1 .450 (1 .93), 1 .463 (2.30), 1 .585 (1 .1 1 ), 1 .610 (2.98), 1 .619 (2.98), 1 .648 (5.92), 1.891 (2.48), 1 .914 (2.24), 2.043 (3.71 ), 2.060 (7.26), 2.078 (3.98), 2.216 (15.15), 2.220 (16.00), 3.156 (3.78), 3.580 (4.20), 3.597 (7.23), 3.614 (4.07), 5.754 (13.93), 7.346 (4.03), 7.348 (4.01 ), 7.365 (4.04), 7.367 (3.87), 7.480 (5.98), 7.504 (5.98).
Intermediate 141
8-{[tert-butyl(diphenyl)silyl]oxy}-2-(2-chloro-4,5-difluorop
(mixture of cis-/trans-isomers)
Figure imgf000140_0001
Lithium 1 ,1 ,1 ,3,3,3-hexamethyldisilazan-2-ide (42 ml, 1 M solution in tetrahydrofuran, 42 mmol, CAS No 4039-32-1 ) was added drop wise within 5 minutes to a solution of 2-chloro-4,5- difluoroaniline (3.88 g, 23.2 mmol) in tetrahydrofuran (1 10 ml) at -78(C and the mixture was stirred for 1 h at that temperature. A solution of ethyl 4-{[tert-butyl(diphenyl)silyl]oxy}-1 -(2- chloroethyl)cyclohexanecarboxylate (10.0 g, 21 .1 mmol) in tetrahydrofuran (1 10 ml) was added and the mixture was stirred for 2 h at -78(C. The mix ture was warmed to room temperature and stirred for 4 d. For work-up, the reaction mixture was added to a mixture of water and sodium bicarbonate solution and the mixture was extracted with ethyl acetate (3x). The combined organic phases were washed with sodium chloride, dried over sodium sulfate and concentrated under reduced pressure, the residue was purified by flash chromatography (340 g Snap cartridge, hexane/ethyl acetate gradient, 5% -> 25% ethyl acetate). The product containing fractions were concentrated and were purified a second time by flash chromatography (120 g Snap cartridge, hexane/ethyl acetate gradient, 5% -> 25% ethyl acetate) to give the title compound in 2 fractions: fraction 1 (7.53 g, single isomer based on 1 H NMR, isomer 1 , contains impurities from aniline and isomer 2), fraction 2 (1 .13 g, isomer 2). Fraction 1 (isomer 1 ):
1 H-NMR (400 MHz, DMSO-afe): δ [ppm] = 7.67-7.55 (m, 5H), 7.52-7.30 (m, 9H), 3.97 (br s, 1 H), 3.60 (t, 2H), 2.15-2.07 (m, 2H), 2.04 (t, 2H), 1 .76-1 .63 (m, 2H), 1 .58-1 .45 (m, 2H), 1 .39-1 .27 (m, 2H), 1 .05 (s, 9H). LC-MS (Method 1 ): Rt = 1 .80 min; MS (ESIpos): m/z
Intermediate I42
2-(2-chloro-4,5-difluorophenyl)-8-hydroxy-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000141_0001
N,N,N-tributylbutan-1 -aminium fluoride (38 ml, 1 .0 M in THF, 38 mmol, CAS No 429-41 -4) was added to a solution of 8-{[tert-butyl(diphenyl)silyl]oxy}-2-(2-chloro-4,5-difluorophenyl)-2- azaspiro [4.5]decan-1 -one (isomer 1 ) (14.2 g, 25.1 mmol) in tetrahydrofuran (200 ml) and the mixture was stirred at 80Ό for 6 h. For work-up, the reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate and sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (120 g Snap cartridge, methylene chloride/ethyl acetate gradient, 0% -> 10% ethyl acetate) the product containing fractions were concentrated under reduced pressure and the residue was purifies a second time by flash chromatography (120 g Snap cartridge, hexane/ethyl acetate gradient, 20% -> 100% ethyl acetate to give the title compound (5.31 g).
1 H-NMR (400 MHz, DMSO-afe): δ [ppm] = 7.87 (dd, 1 H), 7.70 (dd, 1 H), 4.40 (d, 1 H), 3.74 (br d, 1 H), 3.60 (t, 2H), 2.04 (t, 2H), 1 .99-1.90 (m, 2H), 1 .69 (dq, 2H), 1 .60-1 .49 (m, 2H), 1 .35-1 .24 (m, 2H)
Intermediate I43
2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl methanesulfonate (isomer 1 )
Figure imgf000141_0002
Triethylamine (1 .6 ml) and methanesulfonyl chloride (890 μΙ, 1 1 mmol) were added at 0Ό to a solution of 2-(2-chloro-4,5-difluorophenyl)-8-hydroxy-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (3.00 g, 9.50 mmol) in methylene chloride (23 ml), the mixture was stirred at Ο'Ό for 30 minutes. For work-up, the mixture was diluted with methylene chloride, extracted with sodium bicarbonate and with sodium chloride and dried over sodium sulfate, then concentrated under reduced pressure to give the title compound (3.37 g).
LC-MS (Method 1 ): Rt = 1 .09 min; MS (ESIpos) : m/z = 394.0 [M+H]+
1 H-NMR (400 MHz, DMSO-de): δ [ppm] = 7.88 (dd, 1 H), 7.73 (dd, 1 H), 4.92-4.80 (m , 1 H), 3.63 (t, 2H), 3.20 (s, 3H), 2.09 (t, 2H), 2.05-1 .96 (m, 2H), 1 .93-1 .74 (m, 4H), 1 .55-1 .43 (m, 2H).
Intermediate I44
8-azido-2-(2-chloro-4,5-difluorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000142_0001
Sodium azide (1 .23 g, 18.9 mmol, CAS No 26628-22-8) was added to a solution of 2-(2-chloro- 4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl methanesulfonate (isomer 1 ) (5.74 g, 14.6 mmol) in dimethylformamide (45 ml), the mixture was stirred at 65Ό for 12 h. For work-up, the mixture was poured in water, the precipitate was filtrated off and washed with water to give the title compound (2.96 g).
LC-MS (Method 1 ): Rt = 1 .29 min; MS (ESIpos) : m/z = 341 .2 [M+H]+ Intermediate I45
8-amino-2-(2-chloro-4,5-difluorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000142_0002
To a solution of 8-azido-2-(2-chloro-4,5-difluorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (2.96 g, 8.69 mmol) and triphenylphosphane (2.73 g, 10.4 mmol) in tetrahydrofuran (30 ml) was added distilled water (470 μΙ), the mixture was stirred at room temperature for 24 h. For work-up t e reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (100 g Snap Cartridge, methylene chloride/methanol gradient, 10% methanol) to give the title compounds (963 mg).
LC-MS (Method 1 ): Rt = 0.72 min; MS (ESIpos): m/z = 315.2 [M+H]+
For an alternative synthesis see intermediate 114
Intermediate I46
8-{[tert-butyl(diphenyl)silyl]oxy}-2-(3-chlorophenyl)-2-azaspiro[4.5]decan-1 -one (mixture of cis/trans isomers)
Figure imgf000143_0001
Bis-(trimethylsilyl)-lithiumamid lithium 1 ,1 ,1 ,3,3,3-hexamethyldisilazan-2-ide (42 ml, 1 .0 M in THF, 42 mmol) was added over a period of 5 minutes drop wise to a solution of 3-chloroaniline (2.5 ml, 23 mmol, CAS No 108-42-9) in tetrahydrofuran (1 10 ml) at -78Ό and the mixture was stirred for 1 h at -78Ό. A solution of ethyl 4-{[ter t-butyl(diphenyl)silyl]oxy}-1 -(2- chloroethyl)cyclohexanecarboxylate (10.0 g, 21 .1 mmol) in tetrahydrofuran (1 10 ml) was added and the mixture was stirred for 2 h at -78Ό an d then at room temperature for 4 d. For work-up, a solution of water and sodium bicarbonate was added and the mixture was extracted with ethyl acetate (3x). The combined organic phases were washed with sodium chloride, dried over sodium sulfate, and were concentrated under reduced pressure. The residue was purified by flash chromatography (100 g Snap Cartridge, hexane /ethyl acetate gradient, 7% -> 60% ethyl acetate) the product containing fractions were combined and were concentrated under reduced pressure. The residue was purified a second time by flash chromatography (120 g Snap Cartridge, hexane /ethyl acetate gradient, 5% -> 30% ethyl acetate) to give the title compound in 2 fractions: fraction 1 (6.41 g, single isomer based on 1 H NMR, isomer 1 ), fraction 2 (1 .58 g, isomer 2).
Fraction 1 (isomer 1 ):
1 H-NMR (400 MHz, DMSO-de): δ [ppm] = 7.94 (t, 1 H), 7.66-7.55 (m, 5H), 7.52-7.37 (m, 7H), 7.20 (ddd, 1 H), 3.97 (br s, 1 H), 3.76 (t, 2H), 2.15-2.04 (m, 2H), 1 .97 (t, 2H), 1 .70-1 .59 (m, 2H), 1 .54-1 .42 (m, 2H), 1.32-1 .26 (m, 2H), 1 .06 (s, 9H). Intermediate 147
2-(3-chlorophenyl)-8-hydroxy-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000144_0001
N,N,N-tributylbutan-1 -aminium fluoride (25 ml, 1 .0 M in THF, 25 mmol) was added at room temperature to a solution of 8-{[tert-butyl(diphenyl)silyl]oxy}-2-(3-chlorophenyl)-2- azaspiro[4.5]decan-1 -one (isomer 1 ) (6.41 g, 12.4 mmol) in tetrahydrofuran (120 ml), t e mixture was stirred at 80Ό for 5 h. For work-up, th e mixture was poured into water, extracted with ethyl acetate (3x), the combined organic phases were washed with diluted sodium bicarbonate and with brine. The organic phase was filtrated trough a silicone filter and concentrated under reduced pressure. The residue was purified by flash chromatography (120 g Snap Cartridge, hexane /ethyl acetate gradient, 20% -> 100% ethyl acetate) to give the title compound (3.1 g).
1 H-NMR (400 MHz, DMSO-afe): δ [ppm] = 7.90 (t, 1 H), 7.58 (ddd, 1 H), 7.40 (t, 1 H), 7.19 (ddd, 1 H), 4.41 (d, 1 H), 3.81 -3.69 (m, 3H), 3.41 -3.33 (m, 1 H), 3.36-3.28 (m, 1 H), 2.02-1 .89 (m, 4H), 1 .72-1 .62 (m, 2H), 1 .58-1 .49 (m, 2H), 1 .26 (dt, 2H).
Intermediate I48
2-(3-chlorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl methanesulfonate (isomer 1 )
Figure imgf000144_0002
Triethylamine (1 .9 ml) and methanesulfonyl chloride (1 .0 ml, 13 mmol) were added at ΟΌ to a solution of 2-(3-chlorophenyl)-8-hydroxy-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (3.10 g, 1 1 .1 mmol) in methylene chloride (26 ml), the mixture was stirred at 0Ό for 30 minutes. For workup, the mixture was diluted with methylene chloride, and the organic phase was washed with sodium bicarbonate and with sodium chloride. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give t e title compound (3.68 g), which was used in the next step without further purification.
1 H-NMR (400 MHz, DMSO-afe): δ [ppm] = 7.89 (t, 1 H), 7.62-7.52 (m, 1 H), 7.41 (t, 1 H), 7.20 (ddd, 1 H), 4.92-4.83 (m, 1 H), 3.80 (t, 2H), 3.21 (s, 3H), 2.07-1 .94 (m, 4H), 1 .92-1 .74 (m, 4H), 1 .51 -1 .42 (m, 2H).
Intermediate I50
8-amino-2-(3-chlorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000145_0001
To a solution of 8-azido-2-(3-chlorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (3.22 g, 10.6 mmol) and triphenylphosphane (3.33 g, 12.7 mmol) in tetrahydrofuran (36 ml) distilled water (570 μΙ) was added, then stirred at room temperature for 48 h. For work-up the reaction mixture concentrated under reduced pressure and the residue was purified by flash chromatography (25 g Snap Cartridge, dichloromethane/ methanol, 10% ->100% methanol) to give the title compound (2.1 g). Intermediate 151
ethyl 4-{[tert-butyl(dimethyl)silyl]oxy}-1 -(2-methoxyethyl)cyclohexanecarboxylate
Figure imgf000145_0002
A solution of ethyl 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (mixture of cis-
/trans-isomers) (7.50 g, 26.2 mmol) in tetrahydrofuran (59 ml) was added over 25 min to a solution of lithium diisopropylamine (35 ml, 2 M solution in tetrahyrofuran, 71 mmol) in tetrahydrofuran (39 ml) at -5Ό and the mixture was stirred for 2.5 h at that temperature. 2-
Bromoethyl methyl ether (6.6 ml, 71 mmol, CAS No 6482-24-2) was added over 20 min and the mixture was stirred for 2 h at room temperature. For work-up, water was added and the mixture was extracted with ethyl acetate (2x ) and the combined organic phases were washed with brine, filtrated through a silicone filter and concentrated. The residue was purified by flash chromatography (340 g Snap Cartridge, hexanes/ethyl acetate gradient, 0% -> 10% ethyl acetate) to give ethyl 4-{[tert-butyl(dimethyl)silyl]oxy}-1 -(2- methoxyethyl)cyclohexanecarboxylate as mixture of isomers: Fraction 1 (5.30 g, cis/trans ca. 3.3:1 , based on 1 H NMR); Fraction 2 (2.10 g, cis-isomer based on 1 H NMR).
Fraction 1 (mixture of cis-/trans-isomers):
1 H-NMR (400 MHz, DMSO-cfe, characteristic signals trans-isomer): δ [ppm] = 3.88-3.82 (m, 1 H), 1.52-1.41 (m, 4H), 0.87 (s, 6H)
Fraction 2 (cis-isomer):
1 H-NMR (400 MHz, DMSO-afe): δ [ppm] = 4.08 (q, 1 H), 3.64-3.53 (m, 1 H), 3.25 (t, 2H), 3.15 (s, 3H), 2.10-1.97 (br. s., 2H), 1 .76-1 .51 (m, 4H), 1.28-1 .12 (m, 7H), 0.84 (s, 9H), 0.02 (s, 9H)
Intermediate I52
ethyl cis-4-hydroxy-1 -(2-methoxyethyl)cyclohexanecarboxylate
Figure imgf000146_0001
Tetra-n-butylammonium fluoride (17 ml, 1 M solution in tetrahyrofuran, 17 mmol) was added to a solution of ethyl cis-4-{[tert-butyl(dimethyl)silyl]oxy}-1 -(2- methoxyethyl)cyclohexanecarboxylate (fraction 2) (2.00 g, 5.80 mmol) in tetrahydrofuran (50 ml) and the mixture was stirred at room temperature for 20 h. For work-up, the mixture was poured into water, extracted with ethyl acetate (3x) and the combined organic phases were washed with saturated sodium bicarbonate solution and brine, filtrated through a silicone filter and concentrated under reduced pressure. The residue was purified by flash chromatography (50 g Snap cartridge, hexanes/ethyl acetate gradient, 40% -> 90% ethyl acetate) to give the title compound (1 .15 g).
1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 4.48 (d, 1 H), 4.08 (q, 2H), 3.39-3.30 (m, 1 H), 3.25 (t, 2H), 3.15 (s, 3H), 2.1 1 -1 .99 (m, 2H), 1 .89-1 .49 (m, 5H), 1 .22-1 .02 (m, 7H)
Intermediate I53 ethyl 4-hydroxy-1 -(2-methoxyethyl)cyclohexanecarboxylate (mixture of cis-/trans isomers)
Figure imgf000147_0001
Was prepared in analogy to the synthesis of ethyl cis-4-hydroxy-1 -(2- methoxyethyl)cyclohexanecarboxylate using ethyl 4-{[tert-butyl (dimethyl) silyl]oxy}-1 -(2- methoxyethyl)cyclohexanecarboxylate (mixture of cisVtrans-isomers) (4.10 g, 1 .9 mmol, cis/trans: ca 3.3:1 based on 1 H NMR) as starting material to give ethyl 4-hydroxy-1 -(2- methoxyethyl)cyclohexanecarboxylate (mixture of cisVtrans isomers) (2.27 g, 81 % yield, ca. 2.8:1 cisVtrans-mixture based on 1 H NMR).
1 H-NMR (400 MHz, DMSO-d6, only characteristic signals trans-isomer): δ [ppm] = 4.41 (d, 1 H), 3.65-3.56 (m, 1 H), 3.16 (s, 3H)
Intermediate I49
8-azido-2-(3-chlorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000147_0002
Sodium azide (869 mg, 13.4 mmol) was added to a solution of 2-(3-chlorophenyl)-1 -oxo-2- azaspiro[4.5]dec-8-yl methanesulfonate (isomer 1 ) (3.68 g, 10.3 mmol) in dimethylformamide (32 ml), the reaction was stirred at 65Ό for 10 h. For work-up, the mixture has been poured into water, the precipitate was filtrated off and washed with water to give the title compound (3.22 g), which was used immediately in the next step without further purification.
Intermediate I54
2-(2-chloro-4,6-difluorophenyl)-8-hydroxy-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000148_0001
A mixture of ethyl 4-hydroxy-1 -(2-methoxyethyl)cyclohexanecarboxylate (mixture of cisVtrans- isomers) (2.50 g, 10.9 mmol), 2-chloro-4,6-difluoroaniline (1 .95 g, 1 1 .9 mmol, CAS No 36556- 56-6) and dimethylaluminiumchloride (22 ml, 1 M solution in hexane, 22 mmol) in toluene (57 ml), was stirred under argon atmosphere for 4 h at room temperature followed by 6 h under reflux. For work-up, the mixture was poured into ice water, extracted with ethyl acetate (3x) and the combined organic phases were washed with brine, filtrated through a silicone filter and concentrated under reduced pressure. The residue was purified by flash chromatography (25g Snap cartridge, hexanes/ethyl acetate gradient, 20% -> 50% ethyl acetate) to give the title compound (2.31 g) as single isomer (isomer 1 ).
LC-MS (Method 2): Rt = 1 .01 min; MS (ESIpos): m/z = 316.1 [M+H]+
1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.57-7.46 (m, 2H), 4.41 (d, 1 H), 3.78-3.68 (m, 1 H), 3.64-3.55 (m, 1 H), 3.52-3.43 (m, 1 H), 2.07 (t, 2H), 1 .97-1 .87 (m, 2H), 1 .74-1 .61 (m, 2H), 1.60- 1 .47 (m, 2H), 1 .34-1.22 (m, 2H)
Intermediate I55
2-[2-(2-chloro-4,6-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 H-isoindole-1 ,3(2H)-dione (isomer 1 )
Figure imgf000148_0002
Diisopropyl azodicarboxylate (2.2 ml, 1 1 mmol) was added drop wise to a mixture of 2-(2- chloro-4,6-difluorophenyl)-8-hydroxy-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (2.31 g, 7.32 mmol), phthalimide (1 .61 g, 1 1 .0 mmol, CAS No 85-41 -6) and triphenylphosphine (2.88 g, 1 1 .0 mmol) in tetrahydrofuran (87 ml) and the mixture was stirred for 12 h at room temperature. For work-up, the reaction mixture was concentrated and the residue was purified by flash chromatography (100 g Snap cartridge, hexanes/ethyl acetate gradient, 0% -> 50% ethyl acetate) to give the title compound (4.58 g) as single isomer based on 1 H NMR together with impurities. This material was used in the next step. A small amount was further purified by preparative HPLC for 1 H NMR characterization: LC-MS (Method 2): R, = 1.34 min; MS (ESIpos): m/z = 445.2 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.658 (1.11), 1.669 (2.14), 1.679 (1.46), 1.701 (3.50), 1.710 (3.71), 1.722 (3.83), 1.752 (2.68), 2.221 (2.53), 2.224 (2.57), 2.240 (4.74), 2.258 (4.04), 2.281 (1.52), 2.293 (1.46), 2.322 (1.19), 2.327 (1.52), 2.332 (1.01), 2.518 (4.43), 2.523 (2.76), 2.539 (0.91 ), 2.664 (0.86), 2.669 (1.26), 2.673 (0.91 ), 3.549 (1.63), 3.555 (1.38), 3.566 (1.07), 3.573 (1.94), 3.590 (0.99), 3.643 (1.05), 3.658 (1.75), 3.661 (1.54), 3.667 (1.15), 3.677 (1.38), 3.682 (1.54), 4.049 (1.30), 7.506 (1.13), 7.513 (1.67), 7.528 (1.50), 7.537 (2.90), 7.544 (2.41), 7.547 (2.08), 7.551 (1.46), 7.554 (1.85), 7.559 (2.47), 7.565 (2.47), 7.569 (2.02), 7.572 (1.11), 7.576 (1.44), 7.824 (1.85), 7.830 (1.26), 7.835 (3.58), 7.841 (3.79), 7.846 (14.58), 7.853 (16.00), 7.859 (5.25), 7.865 (3.67), 7.870 (1.32), 7.876 (1.79).
Intermediate I56
8-amino-2-(2-chloro-4,6-difluorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000149_0001
A mixture of 2-[2-(2-chloro-4,6-difluorophenyl)-1-oxo-2-azaspiro[4.5]dec-8-yl]-1 H-isoindole- 1 ,3(2H)-dione (isomer 1, Intermediate I55) (4.40 g, 9.89 mmol) and methanamine (7.1 ml, 40 % aqueous solution, 99 mmol, CAS No 74-89-5) in ethanol (25 ml, 430 mmol), was stirred for 3 h at 60Ό. For work-up, the reaction mixture was co ncentrated under reduced pressure and the residue was stirred with acetonitrile. The precipitate formed was collected by filtration, stirred with a mixture of dichloromethane and methanol (4:1) and precipitate was collected by filtration and dried to give the title compound (627 mg, 55 % purity by LC-MS) which was used in the next step without further purification.
LC-MS (Method 2): Rt = 0.96 min; MS (ESIpos): m/z = 315.1 [M+H]+ Intermediate I57
ethyl4-{[tert-butyl(dimethyl)silyl]oxy}-1-(3-chloropropyl)cyclohexane carboxylate (mixture of cis- /trans-isomers)
Figure imgf000150_0001
Lithium diisopropylamide (10.5 ml, 21 mmol, 2 M solution in tetrahydrofuran) was added dropwise to a solution of ethyl 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (5.00 g, 17.5 mmol) in tetrahydrofuran (24 ml) at -78Ό and the mixture was stirred for 30 min at that temperature. 1 -Bromo-2-chloroproane (2.6 ml, 26.2 mmol) was added and the mixture was stirred for 1 h at -78Ό. The mixture was warmed du ring 2 h to room temperature. For work-up, water was added and the mixture was extracted with ferf-butyl methyl ether (3x). The combined organic phases were washed with brine, filtrated through a silicone filter and concentrated under reduced pressure. The crude product was purified by flash chromatogryph (100 g Snap cartridge, hexanes/ethyl acetate gradient) to give ethyl4-{[tert- butyl(dimethyl)silyl]oxy}-1 -(3-chloropropyl)cyclohexane carboxylate (4.19 g, as mixture of isomers, ratio 5:1 by GC-MS ).
GC-MS (Method 8): Rt = 21 .20 min (minor isomer); 21 .51 min (major isomer); MS (CI) m/z = 363.2 [M+H]+ and 382.2 [M+NH4]+.
Intermediate I58
9-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-chloro-4-fluorophenyl)-2-azaspiro[5.5]undecan-1 -
Figure imgf000150_0002
Lithium hexamethyldisilazide (13.7 ml, 13.7 mmol, 1 M solution in tetrahydrofuran) was added over 5 min to solution of 2-chloro-4-fluoroaniline (1 .10 g, 7.57 mmol, Cas No 2106-02-7) in tetrahydrofuran (45 ml) at -78Ό and the mixture wa s stirred at -78Ό for 1 h. A solution of ethyl4-{[tert-butyl(dimethyl)silyl]oxy}-1 -(3-chloropropyl)cyclohexane carboxylate (mixture of cis- /trans-isomers) (2.50 g, 6.89 mmol) in tetrahydrofuran (30 ml) was added and the mixture was stirred for 2 h at -78Ό and then for 4 days at roo m temperature. For work-up, the reaction mixture was poured into a mixture of water and saturated sodium bicarbonate solution, extracteted with ethyl acetate and the combined organic phases were washed with brine, filtrated through a silicone filter and concentrated under reduced pressured. The residue was purified by flash chromatography (hexanes/ethyl acetate gradient) to give 9-{[tert- butyl(dimethyl)silyl]oxy}-2-(2-chloro-4-fluoroprienyl)-2-azaspiro[5.5]undecan-1 -one in 2 fractions. Fraction 1 (700 mg, isomer 1 ) and fraction 2 (420 mg, isomer 2 ).
Fraction 1 (isomer 1 ) :
1 H-NMR (400 MHz, DMSO-afe,): δ [ppm] = 7.55 (dd, 1 H), 7.41 (dd, 1 H), 7.27 (td, 1 H), 3.87 (br. s., 1 H), 3.56-3.46 (m, 1 H), 2.24-2.1 1 (m, 2H), 1.94-1.78 (m, 4H), 1.65-1.49 (m, 4H), 1.41 -1.22 (m, 2H), 0.91 -0.82 (m, 9H), 0.03 (s, 6H).
Fraction 2 (isomer 2):
1 H-NMR (400 MHz, DMSO-afe): δ [ppm] = 7.54 (dd, 1 H), 7.42 (dd, 1 H), 7.27 (td, 1 H), 3.66-3.57 (m, 1 H), 3.56-3.47 (m, 1 H), 1 .93-1.56 (m, 10H), 1.43-1.30 (m, 2H), 0.86 (s, 9H), 0.05 (s, 6H). Intermediate I59
2-(2-chloro-4-f luorophenyl)-9-hydroxy-2-azaspiro[5.5]undecan-1 -one (isomer 1 )
Figure imgf000151_0001
Tetra-N-butylammonium fluoride (3.43 ml, 3.43 mmol, 1 M solution in tetrahyrofuran) was added to a solution of 9-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-chloro-4-fluorophenyl)-2- azaspiro[5.5]undecan-1 -one (isomer 1 ) (730 mg, fraction 1 ) in tetrahydrofuran (13 ml) and the mixture was stirred at room temperature for 18 h. Then tetra-N-butylammonium fluoride (3.43 ml, 3.43 mmol, 1 M solution in tetrahyrofuran) was added and the mixture was stirred at room temperature for 1 day. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (dichloromethane/ethyl acetate gradient) to provide 2-(2- chloro-4-fluorophenyl)-9-hydroxy-2-azaspiro[5.5]undecan-1 -one (isomer 1 ) (485 mg, 1 .56 mmol).
1 H-NMR (400 MHz, DMSO-afe): δ [ppm] = 7.54 (dd, 1 H), 7.42 (dd, 1 H), 7.27 (td, 1 H), 4.32 (d, 1 H), 3.70-3.63 (m, 1 H), 3.58-3.48 (m, 1 H), 3.33-3.28 (m, 1 H), 2.20-2.09 (m, 2H), 1 .96-1 .75 (m, 4H), 1.69-1.46 (m, 4H), 1 .41 -1 .20 (m, 2H). Intermediate I60
2-(2-chloro-4-fluorophenyl)-9-hydroxy-2-azaspiro[5.5]undecan-1 -one (isomer 2)
Figure imgf000152_0001
Was prepared in analogy to the synthesis of 2-(2-chloro-4-fluorophenyl)-9-hydroxy-2- azaspiro[5.5]undecan-1 -one (isomer 1 ) from 9-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-chloro-4- fluorophenyl)-2-azaspiro[5.5]undecan-1 -one (isomer 2) (445 mg, fraction 2) using tetra-N- butylammonium fluoride to give 2-(2-chloro-4-fluorophenyl)-9-hydroxy-2-azaspiro[5.5]undecan-
1 - one (isomer 2) (242 mg, 0.78 mmol).
1 H-NMR (400 MHz, DMSO-afe): δ [ppm] = 7.54 (dd, 1 H), 7.41 (dd, 1 H), 7.27 (td, 1 H), 4.57 (d, 1 H), 3.56-3.47 (m, 1 H), 3.44-3.36 (m, 1 H), 1 .92-1 .74 (m, 6H), 1 .74-1 .64 (m, 3H), 1 .58 (dd, 1 H), 1 .38-1 .22 (m, 2H). Intermediate 161
2- [2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[5.5]undec-9-yl]-1 H-isoindole-1 ,3(2H)-dione (isomer 1 )
Figure imgf000152_0002
Diisopropyl azodicarboxylate (0.46 ml, 1 .03 mmol) was added dropwise to a mixture of 2-(2- chloro-4-fluorophenyl)-9-hydroxy-2-azaspiro[5.5]undecan-1 -one (isomer 1 ) (480 mg, 1 .54 mmol), phthalimide (340 mg, 2.31 mmol) und triphenylphosphine (606 mg, 2.31 mmol) in tetrahydrofuran (12 ml) and the mixture was stirred for 3 days at room temperature. For workup, the reaction mixture was concentrated and the residue was purified by flash chromatography (hexanes/ethyl acetate gradient) to yield the 2-[2-(2-chloro-4-fluorophenyl)-1 - oxo-2-azaspiro[5.5]undec-9-yl]-1 H-isoindole-1 ,3(2H)-dione (isomer 1 ) (270 mg, 0.56 mmol)
LC-MS (Method 1 ): Rt = 1 .35 min; MS (ESIpos) m/z = 441 .2 [M+H]+.
1 H-NMR (400 MHz, DMSO-afe): δ [ppm] 7.90-7.81 (m, 4H), 7.56 (dd, 1 H), 7.45 (dd, 1 H), 7.29 (td, 1 H), 4.09-3.95 (m, 1 H), 3.61 -3.50 (m, 1 H), 3.42-3.36 (m, 1 H), 2.31 -2.20 (m, 2H), 2.10-1 .82 (m, 7H), 1 .77 (d, 1 H), 1 .66-1 .56 (m, 2H).
Intermediate I62
9-amino-2-(2-chloro-4-fluorophenyl)-2-azaspiro[5.5]undecan-1 -one (isomer 1 )
Figure imgf000153_0001
A mixture of 2-[2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[5.5]undec-9-yl]-1 H-isoindole- 1 ,3(2H)-dione (isomer 1 ) (262 mg, 0.59 mmol) and hydrazine hydrate (146 μΙ) in ethanol (9 ml) was stirred at 80Ό for 3.5 h. The reaction mixture was concentrated under reduced pressure and the crude product was codestilled with dichloromethane (2x) and then used with out further purification in the next step.
Intermediate I63
8-{[tert-butyl(dimethyl)silyl]oxy}-2-(pyridin-2-yl)-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000153_0002
A mixture of 8-{[tert-butyl(dimethyl)silyl]oxy}-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (593 mg, 2.09 mmol), 2-iodopyridine (515 mg, 2.51 mmol) copper(l) iodide (79.7 mg, 418 μιηοΙ), Ν,Ν'- dimethylethylenediamine (91 μΙ, 840 μιηοΙ) and potassium phosphate (888 mg, 4.18 mmol) in toluene (14 ml) was heated to 80Ό for 18 h. Upon c ooling, the reaction mixture was filtrated through a pad of celite, and the filtrate was concentrated and the residue was purified by flash chromatography (Snap Cartrige, hexanes/ethyl acetate, 20 % ethyl acetate) to give the title compound as single isomer (751 mg).
LC-MS (Method 2): R, = 1 .72 min; MS (ESIpos): m/z = 361 [M+H]+
1 H-NMR (400 MHz, DMSO-c/6): δ [ppm] = 8.40-8.37 (m, 1 H), 8.34-8.30 (m, 1 H), 7.83-7.78 (m, 1 H), 7.15-7.1 1 (m, 1 H), 3.98-3.89 (m, 3H), 2.03-1 .94 (m, 4H), 1 .68-1 .55 (m, 4H), 1 .31 (dt, 2H), 0.92-0.89 (m, 9H), 0.06 (s, 6H)
Intermediate I64
8-hydroxy-2-(pyridin-2-yl)-2-azaspiro[4.5]decan-1 -one (isomer 1 )
Figure imgf000154_0001
Was prepared in analogy to the synthesis of 2-(3,5-difluorophenyl)-8-hydroxy-2- azaspiro[4.5]decan-1-one (isomer 1, intermediate I26) using 8-{[tert-butyl(dimethyl)silyl]oxy}-2- (pyridin-2-yl)-2-azaspiro[4.5]decan-1-one (isomer 1) (746 mg, 2.07 mmol) as starting material to give the title compound 421 mg (83 % yield).
LC-MS (Method 2): R, = 0.82 min; MS (ESIpos): m/z = 247 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.171 (0.66), 1.243 (2.47), 1.253 (5.10), 1.263 (2.92), 1.276 (2.90), 1.286 (5.53), 1.296 (2.90), 1.500 (1.42), 1.508 (2.16), 1.517 (1.50), 1.541 (4.60), 1.551 (2.58), 1.563 (2.81), 1.571 (3.96), 1.580 (2.36), 1.636 (1.86), 1.647 (5.00), 1.659 (5.24), 1.670 (3.11 ), 1.681 (3.27), 1.693 (3.05), 1.704 (1.11 ), 1.921 (3.71 ), 1.930 (3.91 ), 1.948 (11.76), 1.964 (16.00), 1.983 (11.93), 1.987 (4.15), 1.992 (3.05), 2.322 (0.75), 2.327 (1.04), 2.332 (0.77), 2.518 (3.53), 2.523 (2.17), 2.664 (0.75), 2.669 (1.08), 2.673 (0.77), 3.757 (3.43), 3.764 (3.40), 3.776 (1.64), 3.889 (9.79), 3.901 (3.60), 3.907 (13.77), 3.912 (3.93), 3.924 (9.64), 4.407 (9.57), 4.414 (9.77), 7.110 (4.57), 7.113 (4.71), 7.122 (4.91), 7.125 (5.46), 7.128 (5.37), 7.131 (4.97), 7.141 (5.10), 7.143 (4.91), 7.775 (4.46), 7.780 (4.37), 7.792 (4.26), 7.796 (5.64), 7.797 (5.55), 7.801 (5.48), 7.814 (4.62), 7.819 (4.53), 8.302 (5.48), 8.305 (10.68), 8.307 (6.10), 8.324 (5.11), 8.326 (9.06), 8.328 (5.59), 8.368 (4.99), 8.369 (5.41), 8.372 (5.61), 8.375 (5.13), 8.380 (5.26), 8.382 (5.39), 8.385 (5.48), 8.387 (4.66).
Intermediate I65
2-[1 -oxo-2-(pyridin-2-yl)-2-azaspiro[4.5]decan-8-yl]-1 H-isoindole-1 ,3(2H)-dione (isomer 1 )
Figure imgf000154_0002
Diisopropyl azodicarboxylate (500 μΙ, 2.6 mmol) was added dropwise to a mixture of 8- hydroxy-2-(pyridin-2-yl)-2-azaspiro[4.5]decan-1-one (isomer 1) (419 mg, 1.70 mmol), phthalimide (375 mg, 2.55 mmol) and triphenylphosphine (669 mg, 2.55 mmol) in tetrahydrofuran (28 ml) and the mixture was stirred at room temperature overnight. For workup, the reaction mixture was concentrated and the residue was purified by flash chromatography (25 g Snap Cartridge, hexanes/ethyl acetate gradient, 20% -> 100% ethyl acetate) to give the title compound (551 mg) as single isomer, together with unknown impurities.
LC-MS (Method 2): R, = 1.20 min; MS (ESIpos): m/z = 376 [M+H]+ Intermediate I66
8-amino-2-(pyridin-2-yl)-2-azaspiro[4.5]decan-1-one (isomer 1)
Figure imgf000155_0001
A mixture 2-[1-oxo-2-(pyridin-2-yl)-2-azaspiro[4.5]decan-8-yl]-1 H-isoindole-1 ,3(2H)-dione (isomer 1) (548 mg) and hydrazine hydrate (440 μΙ, 80 % purity, 7.3 mmol) in ethanol (12 ml) was stirred at 80Ό for 3 h. Upon cooling, the reaction mixture was concentrated and the residue was purified by flash chromatography (Snap Cartridge NH2, dichloromethane/methanol, 9:1) to give the title compound (151 mg) as single stereoisomer.
LC-MS (Method 2): R, = 0.81 min; MS (ESIpos): m/z = 246 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.065 (1.30), 1.079 (1.35), 1.094 (3.29), 1.108 (3.59), 1.125 (3.90), 1.141 (3.59), 1.154 (2.10), 1.170 (3.76), 1.186 (2.43), 1.486 (2.25), 1.515 (2.34), 1.524 (2.74), 1.534 (13.35), 1.543 (16.00), 1.555 (5.88), 1.564 (6.00), 1.572 (6.19), 1.597 (1.16), 1.605 (1.28), 1.688 (4.42), 1.697 (4.44), 1.709 (2.46), 1.721 (4.16), 1.731 (3.76), 1.962 (9.12), 1.974 (3.29), 1.979 (12.74), 1.984 (3.31), 1.997 (9.45), 2.323 (0.99), 2.327 (1.37), 2.331 (0.97), 2.518 (7.78), 2.523 (4.06), 2.529 (2.32), 2.537 (1.28), 2.547 (1.77), 2.557 (0.85), 2.665 (1.02), 2.669 (1.39), 2.674 (0.97), 3.160 (1.06), 3.170 (1.11), 3.900 (10.54), 3.912 (3.31), 3.918 (13.14), 3.923 (3.64), 3.936 (10.02), 7.115 (4.25), 7.117 (4.37), 7.127 (4.61), 7.129 (5.13), 7.132 (5.08), 7.135 (4.80), 7.145 (4.77), 7.148 (4.58), 7.776 (4.06), 7.781 (4.40), 7.794 (4.44), 7.797 (5.44), 7.799 (5.18), 7.802 (4.66), 7.815 (3.95), 7.820 (4.28), 8.295 (5.22), 8.297 (9.97), 8.300 (5.72), 8.316 (4.92), 8.318 (8.63), 8.321 (5.36), 8.372 (4.61), 8.374 (5.27), 8.377 (5.62), 8.379 (4.66), 8.384 (4.87), 8.386 (5.29), 8.389 (4.99), 8.391 (4.54).
Examples Example 1
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1-oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5- carboxamide
Figure imgf000156_0001
PyBOP (206 mg, 396 μιηοΙ) was added to a mixture of 8-amino-2-(2-chloro-4-fluorophenyl)-2- azaspiro[4.5]decan-1 -one (isomer 1 ) (100 mg, 330 μιηοΙ, Intermediate 112), quinoxaline-5- carboxylic acid (71 .9 mg, 413 μιηοΙ) and N,N-diisopropylethylamine (290 μΙ, 1 .7 mmol) in DMF (3.7 ml) and the mixture was stirred over night at room temperature. For work-up, the reaction mixture was concentrated and the residue was purified by preparative HPLC to give the title compound 65.0 mg (43 % yield).
LC-MS (Method 1 ): Rt = 1 .14 min; MS (ESIpos): m/z = 453 [M+H]+
1 H-NMR (400 MHz, DMSO-afe): δ [ppm] = 9.78 (d, 1 H), 9.10-9.06 (m, 2H), 8.44 (dd, 1 H), 8.27 (dd, 1 H), 7.98 (dd, 1 H), 7.62-7.58 (m, 1 H), 7.49 (dd, 1 H), 7.35-7.28 (m, 1 H), 3.96-3.85 (m, 1 H), 3.66-3.60 (m, 2H), 2.16 (t, 2H), 2.09-2.00 (m, 2H), 1 .76-1 .66 (m, 4H), 1.60-1 .38 (m, 2H)
The following examples were prepared in analogy to the syntheis of N-[(trans)-2-(2-chloro-4- fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5-carboxamide (Example 1 ). In some cases crystaliztion was used for purification.
Structure
lUPAC-Name
Example
LC-MS (method): Retention time; Mass found
1H-NMR
Figure imgf000157_0001
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-6-methoxy-1 ,5- naphthyridine-4-carboxamide
LC-MS (Method 1 ): Rt = 1 .2 min; MS (ESIpos): m/z = 483.2 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .693 (3.20), 1 .702 (3.53), 1 .719 (2.28), 1 .725 (1 .82), 2.062 (1 .09), 2.071 (1 .14), 2.094 (1 .08), 2.102 (1 .00), 2.126 (1 .93), 2.144 (3.62), 2.161 (2.03), 2.332 (0.66), 2.518 (3.69), 2.523 (2.66), 2.673 (0.66), 2.728 (0.82), 2.888 (1 .06), 3.61 1 (2.06), 3.628 (3.55), 3.645 (1 .98), 3.930 (0.87), 4.1 1 1 (16.00), 7.290 (0.85), 7.297 (0.89), 7.312 (1 .30), 7.319 (1 .49), 7.333 (1 .01 ), 7.340 (1 .08), 7.41 1 (4.1 1 ), 7.434 (4.27), 7.467 (1 .88), 7.482 (1 .98), 7.489 (1 .60), 7.504 (1 .47), 7.580 (1 .88), 7.587 (1 .84), 7.601 (1 .87), 7.609 (1 .79), 8.203 (3.97), 8.214 (3.97), 8.420 (4.67), 8.443 (4.38), 8.948 (4.26), 8.960 (4.13), 9.967 (1 .47), 9.986 (1 .42).
Figure imgf000159_0001
Example 7
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyrazolo[1 ,5-a]pyrimidine- 2-carboxamide
Figure imgf000160_0001
To 8-amino-2-(2-chloro-4-fluorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 ) (44.5 mg, 150 μιηοΙ, Intermediate 112), in NMP (1 .0 ml) was added pyrazolo[1 ,5-a]pyrimidine-2-carboxylic acid (31 .8 mg, 195 μπιοΙ) in NMP (0.34 ml). HATU (74.1 mg) in NMP (0.5 ml) and N,N- diisopropylethylamine (50.4 mg, 0.390 mmol) in NMP (0.5 ml) were added. The resulting mixture was shaked for 16 h. The reaction mixture was filtered and the filtrate containing the crude product was subjected to preparative HPLC purification to give the title compound (13.4 mg, 18% yield).
LC-MS (Method 5): Rt = 1 .02 min; MS (ESIpos): m/z = 442 [M+H]+
The following examples were prepared in analogy to the synthesis of N-[(trans)-2-(2-chloro-4- fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyrazolo[1 ,5-a]pyrimidine-2-carboxamide
Example 7):
Figure imgf000160_0002
Figure imgf000161_0001
pyrazole-3-carboxamide
Figure imgf000162_0001
azaspiro[4.5]dec-8-yl]- 1 H-im idazole-2-carboxam ide
Figure imgf000163_0001
azaspiro[4.5]dec-8-yl]imidazo[1 ,2-a]pyridine-6-carboxamide
Figure imgf000164_0001
pyrrolo[2,1 -c][1 ,2,4]triazole-5-carboxamide
Figure imgf000165_0001
azaspiro[4.5]dec-8-yl]isoquinoline-1 -carboxamide
Figure imgf000166_0001
azaspiro[4.5]dec-8-yl]quinoxaline-2-carboxamide
Figure imgf000167_0001
carboxamide
Figure imgf000168_0001
carboxamide
Figure imgf000169_0001
azaspiro[4.5]dec-8-yl]-1 ,2-oxazole-3-carboxamide
Figure imgf000170_0001
carboxamide
Figure imgf000171_0001
Example 49
N-[(trans)-2-(4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5-carboxamide
Figure imgf000171_0002
PyBOP (153 mg, 295 μmol) was added to a mixture of 8-amino-2-(4-fluorophenyl)-2- azaspiro[4.5]decan-1 -one (isomer 1 , Intermediate 118) (64.4 mg, 246 μιηοΙ), quinoxaline-5- carboxylic acid (56.3 mg, 307 μιηοΙ) and N,N-diisopropylethylamine (210 μΙ, 1 .2 mmol) in DMF (1 .0 ml) and the mixture was stirred over night at room temperature. For work-up, water was added and the mixture was extracted with dichloromethane. The organic phase was washed with water, filtered through a silicone filter and concentrated to give the title compound 93.0 mg (89 % yield).
LC-MS (Method 1 ): Rt = 1 .12 min; MS (ESIneg): m/z = 417 [M-H]-
1 H-NMR (400 MHz, DMSO-afe): δ [ppm] = 9.77 (d, 1 H), 9.09-9.05 (m, 2H), 8.43 (dd, 1 H), 8.26 (dd, 1 H), 7.97 (dd, 1 H), 7.75-7.68 (m, 2H), 7.26-7.19 (m, 2H), 3.96-3.84 (m, 1 H), 3.79 (t, 2H), 2.12-1 .99 (m, 4H), 1.75-1 .60 (m, 4H), 1 .59-1 .45 (m, 2H)
Example 50 N-[(trans)-2-(2-chloro-4-fluoro-5-methylphenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyrimidine-4- carboxamide
Figure imgf000172_0001
PyBOP (134 mg, 257 μιηοΙ) was added to a mixture of pyrimidine-4-carboxylic acid (29.0 mg, 234 μιηοΙ), 8-amino-2-(2-chloro-4-fluoro-5-methylphenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 , Intermediate I40) (80.0 mg, 257 μιηοΙ) and N,N-diisopropylethylamine (160 μΙ, 940 μmol) in DMF (2.4 ml) and the mixture was stirred for 2 h at room temperature. For work-up, water (45 ml) and methanol (2 ml) were added and the mixture was stirred over night. The precipitate was collected by filtration, washed with water and dried to give the title compound 71 .0 mg (71 % yield).
LC-MS (Method 1 ): Rt = 1 .1 1 min; MS (ESIpos): m/z = 417 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.934 (0.71 ), 0.950 (0.68), 1 .233 (0.50), 1 .619 (1 .41 ), 1 .648 (15.82), 1.655 (11 .28), 1 .682 (1.94), 1 .693 (1 .56), 1 .712 (0.80), 1 .722 (0.68), 1.744 (0.68), 1 .781 (4.36), 1.802 (1 .83), 2.104 (4.04), 2.121 (7.70), 2.139 (4.24), 2.222 (16.00), 2.226 (15.64), 2.518 (3.24), 2.523 (2.35), 2.729 (0.43), 2.888 (0.51 ), 3.590 (4.43), 3.607 (7.70), 3.624 (4.21 ), 3.837 (1 .00), 7.359 (4.10), 7.378 (4.06), 7.486 (6.03), 7.509 (6.01 ), 8.017 (5.23), 8.020 (5.54), 8.029 (5.13), 8.033 (5.58), 8.850 (2.96), 8.871 (2.92), 9.061 (8.80), 9.074 (8.47), 9.335 (8.19), 9.338 (8.68).
The following examples were prepared in analogy to the syntheis of N-[(trans)-2-(2-chloro-4- fluoro-5-methylphenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyrimidine-4-carboxamide (Example 50):
Structure
lUPAC-Name
Example
LC-MS (method): Retention time; Mass found
1H-NMR
N-[(trans)-2-(2-chloro-4-fluoro-5-methylphenyl)-1-oxo-2-azaspiro[4.5]dec-8-yl]-3- fluoropyridine-2-carboxamide
LC-MS (Method 1 ): Rt = 1.18 min; MS (ESIpos): m/z = 434 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (0.87), 0.948 (0.89), 1.232 (0.60), 1.495 (0.47), 1.517(1.00), 1.526(1.11), 1.546 (2.07), 1.568 (2.14), 1.597(1.65), 1.606(1.16), 1.632 (4.95), 1.640 (7.02), 1.663 (5.44), 1.814(2.41), 1.823 (2.34), 1.844 (2.27), 1.852 (2.07), 2.089 (4.37), 2.106 (8.07), 2.123 (4.46), 2.223 (16.00), 2.227 (15.93), 2.337 (0.42), 2.518 (5.10), 2.523 (3.63), 2.679 (0.42), 2.728 (0.40), 2.889 (0.49), 3.585 (4.75), 3.592 (1.16), 3.603 (8.02), 3.611 (1.11), 3.620 (4.41 ), 3.739 (0.47), 3.760 (0.82), 3.767 (1.07), 3.777 (1.00), 3.788 (1.05), 3.797 (0.80), 3.815 (0.42), 7.361 (4.28), 7.380 (4.19), 7.487 (6.51), 7.510 (6.46), 7.637 (2.21), 7.647 (2.83), 7.658 (5.04), 7.668 (3.41), 7.679 (3.32), 7.830 (2.99), 7.834 (3.01), 7.851 (2.56), 7.855 (2.65), 7.857 (2.83), 7.860 (2.79), 7.879 (2.54), 7.882 (2.50), 8.465 (2.72), 8.468 (4.52), 8.472 (2.85), 8.477 (2.72), 8.480 (4.21), 8.483 (2.76), 8.514(3.23), 8.535 (3.16).
Figure imgf000174_0001
Figure imgf000175_0001
N-[(trans)-2-(2-chloro-4-fluoro-5-methylphenyl)-1 -oxo-2-azaspiro[4.5]dec-8- yl]quinoxaline-5-carboxamide
LC-MS (Method 1 ): Rt =1 .21 min; MS (ESIpos): m/z = 467 [M+H]+
56 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.503 (1.53), 1 .518 (1.82), 1 .534 (2 10),
1 .548 (1 .98), 1 .563 (1.13), 1 .578 (0.95), 1 .687 (7.07), 1 .696 (8.17), 1.714 (4 19),
1 .722 (3.08), 2.025 (2.43), 2.035 (2.56), 2.058 (2.40), 2.066 (2.24), 2.133 (4 17),
2.151 (7.82), 2.168 (4.38), 2.227 (15.95), 2.231 (16.00), 2.327 (0.81 ), 2.518 (2.61 ),
2.523 (1 .76), 2.669 (0.83), 3.600 (4.41 ), 3.608 (1 .23), 3.618 (7.79), 3.627 (1 21 ),
3.635 (4.32), 3.887 (1.00), 3.898 (1.25), 3.906 (1 .02), 3.916 (1.21 ), 3.926 (0 94),
7.377 (4.17), 7.379 (4.07), 7.397 (4.19), 7.399 (3.99), 7.494 (6.31 ), 7.518 (6 28),
7.961 (3.98), 7.979 (4.63), 7.982 (4.94), 8.000 (4.70), 8.254 (4.91 ), 8.258 (5 17),
8.275 (4.33), 8.279 (4.30), 8.430 (4.71 ), 8.434 (4.74), 8.449 (4.42), 8.452 (3 99),
9.072 (5.21 ), 9.076 (13.69), 9.080 (12.99), 9.085 (4.90), 9.772 (3.30), 9.791 (3.24).
Example 57
N-[(trans)-2-(2-chloro-4,6-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5- carboxamide
Figure imgf000176_0001
PyBOP (164 mg, 315 μιηοΙ) was added to a mixture of 8-amino-2-(2-chloro-4,6-difluorophenyl)- 2-azaspiro[4.5]decan-1 -one (isomer 1 , intermediate I56) (150 mg, 55 % purity, 262 μιηοΙ), quinoxaline-5-carboxylic acid (57.1 mg, 328 μιηοΙ) and N,N-diisopropylethylamine (230 μΙ, 1 .3 mmol) in DMF (2.9 ml) and the mixture was stirred over night at room temperature. For workup, the reaction mixture was concentrated and the residue was purified by preparative HPLC to give the title compound 61 .3 mg (49 % yield). LC-MS (Method 1): Rt = 1.17 min; MS (ESIpos): m/z = 471 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.485 (0.75), 1.498 (0.85), 1.515 (2.19), 1.527 (2.38), 1.546 (2.66), 1.557 (2.60), 1.576 (1.35), 1.588 (1.22), 1.700 (5.70), 1.709 (5.70), 2.028 (2.94), 2.036 (3.07), 2.060 (2.85), 2.067 (2.63), 2.187 (3.41), 2.204 (6.95), 2.221 (4.07), 2.327 (1.88), 2.523 (4.79), 2.665 (1.41), 2.669 (1.91), 2.673 (1.41), 3.511 (1.03), 3.530 (2.32), 3.535 (2.00), 3.552 (2.88), 3.570 (1.41), 3.621 (1.47), 3.637 (2.60), 3.655 (1.91), 3.661 (2.16), 3.679 (0.97), 3.896 (1.16), 3.906 (1.44), 3.916 (1.19), 3.925 (1.41), 3.935 (1.13), 7.507 (1.47), 7.514 (2.07), 7.530 (2.22), 7.538 (4.04), 7.545 (3.19), 7.549 (3.01), 7.556 (2.54), 7.561 (3.13), 7.567 (3.23), 7.578 (1.78), 7.961 (3.57), 7.981 (5.01), 8.000 (4.26), 8.255 (4.76), 8.258 (4.85), 8.275 (4.23), 8.279 (4.07), 8.428 (4.60), 8.431 (4.54), 8.446 (4.32), 8.449 (3.98), 9.078 (16.00), 9.079 (15.72), 9.763 (3.66), 9.782 (3.60).
Example 58
N-[(trans)-2-(3,5-difluorophenyl)-1-oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5-carboxamide
Figure imgf000177_0001
PyBOP (100 mg, 193 μιηοΙ) was added to a mixture of 8-amino-2-(3,5-difluorophenyl)-2- azaspiro[4.5]decan-1-one (isomer 1; Intermediate I28) (50.0 mg, 161 μιηοΙ), quinoxaline-5- carboxylic acid (30.8 mg, 177 μιηοΙ) and N,N-diisopropylethylamine (140 μΙ, 800 μιηοΙ) in DMF (1.8 ml) and the mixture was stirred over night at room temperature. For work-up, the reaction mixture was concentrated and the residue was stirred with methanol. The precipitate was collected by filtration, washed with water and methanol and then dried to give the title compound 53.5 mg (76 % yield).
LC-MS (Method 1): Rt = 1.23 min; MS (ESIpos): m/z = 437 [M+H]+
1H-NMR (400 MHz, DMSO-afe): δ [ppm] = 9.78 (d, 1H), 9.10-9.05 (m, 2H), 8.44 (dd, 1H), 8.27 (dd, 1H), 7.98 (dd, 1H), 7.56-7.48 (m, 2H), 7.02 (tt, 1H), 3.96-3.78 (m, 3H), 2.14-2.00 (m, 4H), 1.75-1.62 (m, 4H), 1.61-1.43 (m, 2H)
Example 59
N-[(trans)-1-oxo-2-phenyl-2-azaspiro[4.5]dec-8-yl]quinoxaline-5-carboxamide
Figure imgf000178_0001
PyBOP (153 mg, 295 μιηοΙ) was added to a mixture of 8-amino-2-phenyl-2- azaspiro[4.5]decan-1 -one (isomer 1 ; Intermediate I22) (60.0 mg, 246 μιηοΙ), quinoxaline-5- carboxylic acid (56.3 mg, 307 μιηοΙ) and N,N-diisopropylethylamine (210 μΙ, 1 .2 mmol) in DMF (1 .0 ml) and the mixture was stirred over night at room temperature. For work-up, water was added and the mixture was extracted with dichloromethane. The combined organic phases were washed with water, filtered through a silicone filter and concentrated to give the title compound 75.0 mg (75 % yield).
LC-MS (Method 1 ): Rt = 1 .1 1 min; MS (ESIneg): m/z = 399 [M-H]- 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .467 (0.86), 1 .477 (1 .02), 1 .498 (2.79), 1 .508 (2.90), 1 .528 (3.17), 1 .538 (3.28), 1 .559 (1.77), 1 .569 (1 .61 ), 1.643 (1.88), 1 .679 (8.70), 1.713 (3.60), 1 .721 (3.97), 1 .746 (1 .02), 1 .754 (0.97), 2.016 (3.44), 2.025 (3.65), 2.048 (3.33), 2.057 (3.06), 2.080 (5.58), 2.097 (9.99), 2.1 15 (5.74), 2.327 (0.75), 2.523 (1.61 ), 2.669 (0.75), 2.727 (0.91 ), 2.888 (1 .13), 3.792 (6.01 ), 3.809 (10.26), 3.827 (5.74), 3.869 (0.75), 3.887 (1 .40), 3.898 (1 .72), 3.906 (1 .34), 3.916 (1 .72), 3.925 (1.29), 7.1 18 (2.63), 7.136 (5.80), 7.155 (3.44), 7.361 (6.71 ), 7.382 (9.40), 7.401 (6.23), 7.690 (10.20), 7.709 (8.97), 7.959 (4.40), 7.978 (5.80), 7.980 (6.01 ), 7.999 (5.37), 8.253 (5.64), 8.256 (5.96), 8.273 (4.99), 8.277 (4.94), 8.429 (5.64), 8.433 (5.48), 8.448 (5.32), 8.451 (4.78), 9.070 (6.23), 9.075 (15.95), 9.079 (16.00), 9.083 (5.96), 9.767 (4.19), 9.785 (4.13). Example 60
N-[(trans)-2-(3-chlorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5-carboxamide
Figure imgf000178_0002
PyBOP (149 mg, 287 μιηοΙ) was added to a mixture of quinoxaline-5-carboxylic acid (45.4 mg, 261 μιηοΙ), 8-amino-2-(3-chlorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 , Intermediate I50) (80.0 mg, 287 μιηοΙ) and N,N-diisopropylethylamine (180 μΙ, 1 .0 mmol) in DMF (2.6 ml) and the mixture was stirred over night at room temperature. For work-up, water (45 ml) and methanol (2 ml) were added and the mixture was stirred for 4 h. The precipitate was collected by filtration, washed with a mixture of water and methanol (4:1 ) and dried to give the title compound 109 mg (93 % yield).
LC-MS (Method 1 ): Rt = 1 .22 min; MS (ESIpos): m/z = 435 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .494 (2.45), 1 .506 (2.64), 1 .524 (2.94), 1 .535 (2.88) 1 .555 (1 .60), 1 .566 (1.50), 1 .650 (1 .19), 1.660 (1 .47), 1.683 (10.64), 1.706 (3.13), 1 .714 (3.63) 2.012 (3.13), 2.023 (3.32), 2.046 (3.09), 2.055 (2.76), 2.081 (5.42), 2.099 (9.45), 2.116 (5.61 )
2.327 (0.87), 2.518 (2.62) 2.523 (1.85), 2.669 (0.91 ), 2.729 (0.63), 2.888 (0.76), 3.804 (5.72) 3.813 (1 .63), 3.822 (9.67) 3.829 (1.66), 3.839 (5.52), 3.888 (1.32), 3.898 (1 .62), 3.907 (1 .29) 3.917 (1 .57), 3.927 (1 .22) 7.189 (3.31 ), 7.191 (3.67), 7.194 (3.70), 7.196 (3.56), 7.209 (3.89) 7.21 1 (4.22), 7.214 (4.32) 7.216 (4.10), 7.394 (5.26), 7.415 (9.49), 7.435 (5.33), 7.589 (3.61 ) 7.591 (3.98), 7.594 (3.89) 7.596 (3.88), 7.610 (3.00), 7.61 1 (3.01 ), 7.615 (3.35), 7.617 (2.95) 7.910 (5.41 ), 7.916 (10.28), 7.921 (5.48), 7.960 (5.22), 7.977 (5.64), 7.981 (6.35), 7.999 (5.99) 8.253 (6.1 1 ), 8.257 (6.58), 8.274 (5.36), 8.278 (5.38), 8.430 (6.23), 8.433 (6.27), 8.448 (5.77) 8.452 (5.22), 9.069 (7.93), 9.074 (16.00), 9.080 (15.91 ), 9.084 (7.60), 9.770 (4.17), 9.788 (4.13).
Example 61
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 ,8-naphthyridine-2- carboxamide
Figure imgf000179_0001
PyBOP (132 mg, 254 μιηοΙ) was added to a mixture of 1 ,8-naphthyridine-2-carboxylic acid (40.2 mg, 231 μιηοΙ), 8-amino-2-(2-chloro-4,5-difluorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 1 , Intermediate I45 ) (80.0 mg, 254 μιηοΙ) and N,N-diisopropylethylamine (160 μΙ, 920 μιηοΙ) in DMF (2.3 ml) and the mixture was stirred for 2 h at room temperature. For work-up, water (45 ml) and methanol (2 ml) were added and the mixtre was stirred over night. The precipitate was collected by filtration, washed with water and dried to give the title compound 87.0 mg (79 % yield). LC-MS (Method 1 ): Rt = 1.08 min; MS (ESIpos): m/z = 471 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (1.28), 0.949 (1.24), 1.231 (1.28), 1.352 (0.85), 1.591 (0.43), 1.634 (0.73), 1.657 (3.54), 1.665 (3.07), 1.689 (16.00), 1.696 (15.91), 1.732 (4.05), 1.742 (3.41), 1.761 (3.46), 1.772 (3.11), 1.791 (1.62), 1.801 (1.37), 1.855 (5.29), 1.877 (3.07), 1.886 (2.69), 2.069 (0.43), 2.155 (7.04), 2.172 (13.78), 2.190 (7.51), 2.337 (0.81), 2.518 (9.26), 2.523 (6.53), 2.674 (1.79), 2.679 (0.81), 2.888 (0.47), 3.612 (0.51), 3.639 (7.59), 3.656 (13.87), 3.674 (7.34), 3.871 (0.73), 3.897 (1.75), 3.908 (1.66), 3.919 (1.75), 3.946 (0.73), 7.697 (5.21), 7.717 (5.72), 7.724 (5.59), 7.732 (9.13), 7.743 (11.05), 7.753 (8.02), 7.763 (9.30), 7.863 (5.38), 7.884 (5.63), 7.889 (5.80), 7.910 (5.63), 8.264 (15.15), 8.285 (15.66), 8.580 (7.55), 8.586 (7.89), 8.601 (7.64), 8.606 (7.17), 8.680 (15.27), 8.701 (13.82), 8.822 (6.10), 8.844 (5.89), 9.197 (8.96), 9.202 (9.17), 9.208 (8.41), 9.212 (7.94).
The following examples were prepared in anlogy to the synthesis of N-[(trans)-2-(2-chloro-4,5- difluorophenyl)-1-oxo-2-azaspiro[4.5]dec-8-yl]-1 ,8-naphthyridine-2-carboxamide (Example 61). Some compounds were purified by preparative HPLC:
Figure imgf000180_0001
methyl 6-{[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8- yl]carbamoyl}pyridine-3-carboxylate
LC-MS (Method 1 ): Rt = 12.10 min; MS (ESIpos) : m/z = 478 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .622 (0.53), 1 .631 (0.69), 1 .657 (4.98), 1 .679 (0.95), 1 .689 (0.73), 1 .793 (1 .49), 1 .813 (0.62), 2.1 15 (1 .48), 2.132 (2.82), 2.149 (1 .54), 2.332 (0.60), 2.518 (2.94), 2.523 (2.10), 2.674 (0.59), 3.622 (1 .57), 3.630 (0.42), 3.640 (2.77), 3.656 (1 .49), 3.926 (16.00), 7.686 (1 .03), 7.706 (1 .16), 7.713 (1 .08), 7.734 (1 .06), 7.858 (1 .09), 7.879 (1 .16), 7.884 (1 .16), 7.905 (1 .15), 8.165 (2.03), 8.168 (2.24), 8.186 (2.25), 8.188 (2.41 ), 8.471 (2.24), 8.477 (2.24), 8.492 (1 .71 ), 8.497 (2.07), 8.765 (1 .25), 8.786 (1 .21 ), 9.106 (2.44), 9.108 (2.48), 9.1 1 1 (2.36), 9.1 14 (2.10).
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyridazine- 3-carboxamide
LC-MS (Methodl ): Rt = 1 .02 min; MS (ESIpos): m/z = 421 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (0.76), 0.948 (0.79), 1 .233 (0.82), 1 .352 (0.63), 1 .600 (0.87), 1 .631 (2.40), 1 .639 (1 .86), 1 .666 (16.00), 1 .688 (4.59), 1 .716 (2.27), 1 .726 (2.27), 1 .747 (1 .04), 1 .758 (0.93), 1 .810 (4.01 ), 1 .824 (2.57), 1 .834 (2.08), 2.069 (0.57), 2.1 16 (5.27), 2.134 (10.10), 2.151 (5.57), 2.337 (0.52), 2.518 (5.98), 2.523 (4.29), 2.679 (0.52), 2.728 (0.82), 2.889 (1 .04), 3.613 (0.71 ), 3.627 (6.01 ), 3.644 (10.21 ), 3.654 (1 .31 ), 3.661 (5.60), 3.886 (1 .12), 3.897 (1 .15), 3.907 (1 .20), 7.688 (3.69), 7.709 (4.04), 7.716 (3.99), 7.736 (3.77), 7.860 (3.90), 7.870 (0.60), 7.880 (4.04), 7.886 (4.20), 7.898 (7.67), 7.906 (4.29), 7.91 1 (7.21 ), 7.920 (7.26), 7.932 (7.62), 8.195 (8.14), 8.198 (7.67), 8.215 (7.40), 8.220 (6.91 ), 9.092 (3.96), 9.1 13 (3.85), 9.402 (8.19), 9.407 (8.1 1 ), 9.415 (8.05), 9.420 (6.83). N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1-oxo-2-azaspiro[4.5]dec-8-yl]-3- methoxypyrazine-2-carboxam ide
LC-MS (Method 1 ): Rt = 1.08 min; MS (ESIpos): m/z = 451 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.424 (0.46), 1.438 (0.59), 1.454 (0.57) 1.468 (0.60), 1.628 (1.08), 1.638 (1.41), 1.655 (1.83), 1.664 (1.74), 1.842 (0.75) 1.850 (0.77), 1.874 (0.70), 1.881 (0.62), 2.075 (1.29), 2.092 (2.40), 2.109 (1.32) 2.326 (0.47), 2.518 (2.03), 2.522 (1.30), 2.669 (0.47), 3.612 (1.40), 3.629 (2.35) 3.646 (1.32), 3.928 (16.00), 7.687 (0.86), 7.707 (0.96), 7.714 (0.91), 7.735 (0.85) 7.858 (0.91), 7.878 (0.97), 7.885 (0.96), 7.904 (0.92), 8.216 (3.75), 8.223 (3.66) 8.333 3.78), 8.340 (3.72), 8.423 (0.99), 8.443 (0.95).
Figure imgf000182_0001
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1-oxo-2-azaspiro[4.5]dec-8-yl]-3- methylpyrazine-2-carboxamide
LC-MS (Method 1 ): Rt = 1.08 min; MS (ESIpos): m/z = 435 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.516(0.61), 1.530 (0.85), 1.544 (0.78), 1.559 (1.05), 1.572 (0.54), 1.587 (0.73), 1.603 (0.71 ), 1.609 (0.66), 1.634 (1.74), 1.643 (2.00), 1.662 (2.26), 1.670 (2.51), 1.825(1.16), 1.834(1.14), 1.857(1.03), 1.864 (0.93), 2.092 (1.99), 2.109 (3.68), 2.126 (2.03), 2.518 (1.97), 2.522 (1.35), 2.673 (0.40), 2.707 (16.00), 3.616 (2.19), 3.624 (0.56), 3.634 (3.66), 3.643 (0.49), 3.651 (2.03), 3.786 (0.51), 3.796 (0.46), 3.806 (0.49), 7.686 (1.36), 7.706 (1.49), 7.714 (1.42), 7.734 (1.36), 7.858 (1.38), 7.878 (1.52), 7.884 (1.54), 7.905 (1.43), 8.519 (2.56), 8.525 (2.61 ), 8.577 (1.46), 8.598 (1.44), 8.661 (3.76), 8.667 (3.49).
Figure imgf000183_0001
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-8- hydroxyquinoline-7-carboxamide
LC-MS (Method 1 ): Rt = 1 .14 min; MS (ESIneg) : m/z = 484 [M-H]"
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.850 (0.42), 1 .232 (1 .26), 1 .502 (1 .15), 1 .532 (3.25), 1 .546 (4.20), 1 .560 (3.88), 1 .575 (4.62), 1 .604 (2.36), 1 .638 (2.10), 1 .646 (2.26), 1 .671 (8.66), 1 .681 (10.96), 1 .698 (12.43), 1 .705 (1 1 .96), 1 .924 (5.51 ), 1 .931 (5.67), 1 .954 (5.30), 2.074 (0.89), 2.137 (8.45), 2.154 (15.74), 2.171 (8.50), 2.326 (3.04), 2.331 (2.20), 2.518 (12.54), 2.522 (8.18), 2.668 (3.04), 2.673 (2.26), 3.336 (2.41 ), 3.638 (9.23), 3.655 (16.00), 3.673 (8.55), 3.875 (1 .21 ), 3.894 (2.15), 3.903 (2.62), 3.913 (2.26), 3.922 (2.57), 3.932 (1 .99), 7.41 1 (10.49), 7.433 (1 1 .17), 7.628 (8.24), 7.639 (8.13), 7.649 (8.18), 7.660 (8.50), 7.702 (5.46), 7.722 (6.30), 7.729 (5.93), 7.749 (5.61 ), 7.866 (5.72), 7.886 (6.35), 7.892 (6.19), 7.912 (5.88), 8.006 (12.90), 8.028 (1 1 .44), 8.332 (7.97), 8.335 (7.97), 8.353 (7.92), 8.356 (7.34), 8.705 3.36), 8.723 (3.25), 8.903 (8.92), 8.907 (9.39), 8.914 (9.23), 8.918 (8.34).
Figure imgf000183_0002
2-tert-butyl-N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]- 1 ,3-benzoxazole-6-carboxamide
LC-MS (Method 1 ): Rt = 1 .31 min; MS (ESIpos): m/z = 516 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .449 (16.00), 1 .670 (0.70), 2.109 (0.45), 2.126 (0.85), 2.144 (0.47), 2.518 (0.53), 3.633 (0.49), 3.650 (0.86), 3.667 (0.47), 7.743 (0.66), 7.764 (0.83), 7.861 (0.83), 7.864 (0.67), 7.882 (0.74), 7.885 (0.56), 7.888 (0.45), 8.156 (0.79), 8.158 (0.77). N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 ,6- naphthyridine-2-carboxamide
LC-MS (Method 1 ): Rt = 1 .1 1 min; MS (ESIneg): m/z = 469 [M-H]"
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.931 (0.76), 0.947 (0.74), 1 .230 (0.62), 1 .351 (0.62), 1 .601 (0.47), 1 .621 (0.44), 1 .653 (1 .83), 1 .686 (16.00), 1.725 (2.27), 1 .735 (2.03), 1 .757 (0.84), 1 .853 (4.49), 1 .876 (2.16), 2.069 (0.49), 2.150 (4.74), 2.167 (8.97), 2.184 (4.92), 2.518 (4.85), 2.523 (3.36), 2.729 (0.80), 2.888 (1 .02), 3.612 (0.53), 3.640 (5.03), 3.657 (9.03), 3.674 (4.79), 3.880 (1.07), 3.901 (1 .18), 7.696 (3.49), 7.716 (3.72), 7.723 (3.65), 7.744 (3.29), 7.864 (3.49), 7.875 (0.56), 7.884 (3.69), 7.890 (3.72), 7.910 (3.60), 8.027 (6.43), 8.042 (6.41 ), 8.288 (9.92), 8.309 (9.63), 8.777 (6.14), 8.798 (5.87), 8.800 (5.74), 8.842 (13.51 ), 8.857 (10.50), 8.866 4.12), 9.527 (12.53), 9.529 (12.49).
Figure imgf000184_0001
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-4,6- dimethylpyrimidine-2-carboxamide
LC-MS (Method 1 ): Rt = 1 .12 min; MS (ESIpos): m/z = 449 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.233 (1.32), 1 .352 (0.96), 1 .541 (0.64), 1 .570 (1 .92), 1 .584 (2.99), 1 .594 (2.79), 1 .608 (6.54), 1 .640 (13.05), 1.655 (7.18), 1 .668 (7.18), 1 .800 (4.03), 1 .826 (4.87), 2.052 (0.52), 2.069 (0.96), 2.087 (0.60), 2.1 16 (6.26), 2.133 (12.05), 2.150 (6.62), 2.518 (8.82), 2.523 (6.58), 2.652 (0.60), 2.674 (1 .64), 2.679 (0.76), 3.346 (0.60), 3.566 (0.48), 3.595 (0.68), 3.621 (6.94), 3.638 (1 1 .89), 3.648 (1.64), 3.655 (6.50), 3.783 (1.48), 3.804 (1 .12), 7.404 (16.00), 7.676 (0.52), 7.687 (4.31 ), 7.696 (0.76), 7.707 (4.87), 7.714 (4.59), 7.724 (0.68), 7.734 (4.35), 7.850 (0.56), 7.859 (4.43), 7.870 (0.84), 7.879 (4.91 ), 7.886 (4.99), 7.896 (0.76), 7.906 (4.63), 8.487 (4.95), 8.509 (4.87).
Figure imgf000185_0001
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-5-fluoro-6- methylpyridine-2-carboxamide
LC-MS (Method 1 ): Rt = 1 .3 min; MS (ESIpos): m/z = 452 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .232 (0.42), 1 .352 (0.52), 1 .617 (2.79), 1 .642 (9.06), 1 .649 (10.09), 1 .766 (0.73), 1 .799 (3.69), 2.070 (0.45), 2.126 (3.81 ), 2.144 (7.20), 2.161 (3.93), 2.518 (3.45), 2.523 (2.72), 2.533 (16.00), 2.541 (15.90), 2.729 (0.52), 2.888 (0.65), 3.613 (0.61 ), 3.624 (4.16), 3.642 (7.22), 3.659 (3.86), 3.803 (0.89), 7.686 (2.64), 7.706 (2.96), 7.713 (2.82), 7.734 (2.66), 7.764 (2.69), 7.786 (4.24), 7.809 (3.52), 7.858 (2.76), 7.870 (0.45), 7.878 (2.93), 7.884 (3.02), 7.896 (0.45), 7.905 (2.95), 7.913 (2.88), 7.924 (2.96), 7.935 (2.20), 7.945 (2.1 1 ), 8.377 (2.99), 8.399 (2.92).
Figure imgf000186_0001
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1-oxo-2-azaspiro[4.5]dec-8-yl]-2,3- dihydro-1-benzofuran-7-carboxamide
LC-MS (Method 1 ): Rt = 1.29 min; MS (ESIpos): m/z = 461 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.232(1.14), 1.352 (0.84), 1.396 (0.87), 1.418 (1.86), 1.427 (2.05), 1.447 (3.46), 1.470 (2.80), 1.499 (1.53), 1.600 (1.56), 1.610(1.14), 1.644 (9.98), 1.659 (9.32), 1.667 (9.26), 1.798 (0.42), 1.823 (0.42), 1.892 (3.76), 1.900 (3.91 ), 1.923 (3.64), 1.931 (3.31 ), 2.052 (0.60), 2.069 (1.17), 2.086 (0.66), 2.117 (7.07), 2.135 (13.14), 2.152 (7.31), 2.336 (0.54), 2.454 (0.60), 2.460 (0.72), 2.465 (0.87), 2.518 (6.98), 2.522 (4.90), 2.678 (0.60), 2.727 (1.14), 2.888 (1.35), 3.216 (4.87), 3.238 (10.23), 3.259 (5.26), 3.595 (0.78), 3.613 (8.27),
3.631 (13.20), 3.648 (7.31), 3.746 (0.81), 3.765 (1.56), 3.775 (1.95), 3.784 (1.62), 3.794 (1.95), 3.804 (1.47), 3.823 (0.75), 4.693 (8.27), 4.715 (16.00), 4.736 (7.82), 6.920 (7.25), 6.939 (9.59), 6.958 (7.91), 7.381 (5.68), 7.385 (5.74), 7.400 (5.56), 7.403 (5.47), 7.599 (5.86), 7.603 (6.26), 7.613 (5.74), 7.619 (6.53), 7.622 (6.05),
7.632 (5.38), 7.675 (0.57), 7.691 (4.93), 7.703 (0.87), 7.711 (5.32), 7.719 (5.14), 7.739 (4.93), 7.849 (0.66), 7.857 (5.08), 7.869 (0.90), 7.877 (5.47), 7.883 (5.41), 7.896 (0.87), 7.903 (5.26).
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline- 5-carboxamide
LC-MS (Method 1 ): Rt = 1 .17 min; MS (ESIpos): m/z = 471 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.473 (0.85), 1 .496 (2.02), 1 .503 (2.02), 1 .527 (3.46), 1 .546 (2.85), 1 .576 (1.50), 1 .690 (10.25), 1 .699 (12.06), 1 .721 (7.73), 2.026 (3.81 ), 2.034 (4.00), 2.058 (3.68), 2.066 (3.51 ), 2.139 (5.91 ), 2.155 (1 1 .35), 2.172 (6.17), 2.322 (0.70), 2.326 (0.96), 2.522 (3.07), 2.668 (1.01 ), 2.673 (0.74), 3.632 (6.26), 3.649 (1 1.30), 3.666 (6.02), 3.871 (0.76), 3.889 (1 .50), 3.898 (1 .83), 3.908 (1 .57), 3.917 (1.83), 3.927 (1.47), 3.945 (0.71 ), 7.705 (3.79), 7.725 (4.24), 7.733 (4.14), 7.753 (3.83), 7.865 (3.75), 7.886 (4.19), 7.892 (4.40), 7.912 (3.95), 7.960 (4.54), 7.979 (5.66), 7.981 (6.77), 8.000 (5.53), 8.254 (5.83), 8.258 (6.40), 8.275 (5.14), 8.279 (5.41 ), 8.431 (5.66), 8.435 (6.12), 8.449 (5.42), 8.453 (5.33), 9.070 (6.91 ), 9.075 (15.56), 9.080 (16.00), 9.084 (7.95), 9.775 (4.74), 9.794 (4.70).
Example 74
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[5.5]undec-9-yl]quinoxaline-5- carboxamide
Figure imgf000187_0001
PyBOP (156 mg, 300 μιηοΙ) was added to a mixture of quinoxaline-5-carboxylic acid (50.0 mg, 95 % purity, 273 μιηοΙ), 9-amino-2-(2-chloro-4-fluorophenyl)-2-azaspiro[5.5]undecan-1 -one (isomer 1 , Intermediate I62) (1 17 mg, 80 % purity, 300 μιηοΙ) and N,N-diisopropylethylamine (190 μΙ, 1 .1 mmol) in DMF (2.8 ml) and the mixture was stirred for 5 h at room temperature. For work-up, the reaction mixture was concentrated and the residue was purified by flash chromatography (dichloromethane/methanol gradient, 0% -> 10% methanol) to give after trituration with methanol the title compound (45 mg).
LC-MS (Method 1 ): Rt = 1 .19 min; MS (ESIpos): m/z = 467 [M+H]+ 1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm] : 0.000 (6.00), 1.500 (16.00), 1.522 (1 16)
1.532 (1.31), 1.540 (1.24), 1.550 (1.78), 1 560 (1 39), 1 568 (1 31) 1.578 (1 28), 1 592 (0 63)
1.600 (0.57), 1.609 (0.49), 1.683 (1.07), 1 690 (1 09), 1 718 (1 20) 1.724 (1 26), 1 802 (1 09)
1.809 (1.01), 1.837 (1.28), 1.843 (1.21), 1 892 (0 52), 1 904 (0 71) 1.920 (1 15), 1 927 (1 38)
1.939 (1.65), 1.950 (2.10), 1.973 (3.19), 1 980 (1 79), 1 997 (1 21) 2.010 (1 63), 2 018 (2 38)
2.044 (1.85), 2.055 (1.64), 2.068 (1.62), 2 078 (1 23), 2 089 (2 00) 2.099 (2 12), 2 117 (1 87)
2.149 (1.86), 2.159 (1.59), 2.166 (1.37), 2 176 (1 05), 2 182 (1 06) 2.199 (1 86), 2 209 (1 45)
2.233 (0.84), 2.242 (0.64), 3.417 (0.91), 3 431 (1 72), 3 447 (2 02) 3.462 (2 13), 3 475 (2 12)
3.491 (1.41), 3.505 (0.65), 4.068 (0.47), 4 077 (0 49), 4 085 (0 89) 4.096 (1 13), 4 105 (0 89)
4.114 (1.12), 4.124 (0.86), 4.142 (0.45), 6 931 (1 58), 6 938 (1 71) 6.951 (1 97), 6 953 (2 21)
6.958 (2.18), 6.960 (2.43), 6.973 (1.84), 6 980 (1 97), 7 129 (3 74) 7.134 (3 68), 7 141 (4 30)
7.143 (4.53), 7.151 (3.42), 7.154 (3.87), 7 161 (3 63), 7 165 (3 30) 7.180 (0 47), 7 840 (3 12)
7.859 (3.92), 7.860 (4.21), 7.879 (3.46), 8 186 (3 53), 8 190 (3 76) 8.207 (3 23), 8 211 (3 17)
8.813 (6.84), 8.817 (7.40), 8.840 (3.59), 8 844 (3 65), 8 859 (3 43) 8.863 (3 30), 8 902 (7 05)
8.907 (6.43), 10.321 (1.64), 10.340 (1.64).
Example 75
N-[(trans)-2-(2-chlorophenyl)-1-oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5-carboxamide
Figure imgf000188_0001
To a solution of 8-amino-2-(2-chlorophenyl)-2-azaspiro[4.5]decan-1-one (isomer 1 Intermediate I35), (80.0 mg, 287 μηιοΙ) in DMF (2.6 ml) was added PyBOP (149 mg, 287 μιηοΙ), N,N-diisopropylethylamine (180 μΙ, 1.0 mmol) quinoxaline-5-carboxylic acid (45.4 mg, 261 μιηοΙ) and the reaction was stirred for 6 h at room temperature. For work-up, water (45 ml) and methanol (2 ml) were added and the mixture was stirred for 1 h. The resulting precipitate was collected by filtration, washed with water/methanol (4:1) and dried to give the title compound 88.0 mg.
LC-MS (Method 1 ): Rt = 1.11 min; MS (ESIpos): m/z = 435 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.511 (1.32), 1.535 (1.90), 1.553 (1.86), 1.566 (1.15), 1.583 (0.94), 1.701 (6.81), 1.710 (7.70), 1.718 (4.21), 1.727 (4.89), 2.031 (2.37), 2.040 (2.45), 2.062 (2.30), 2.072 (2.09), 2.151 (3.91), 2.167 (7.46), 2.185 (4.20), 2.327 (0.71), 2.523 (2.11), 2.669 (0.74), 3.639 (4.24), 3.657 (7.45), 3.674 (4.09), 3.893 (0.95), 3.902 (1.18), 3.912 (0.99), 3.921 (1.16), 3.931 (0.92), 7.366 (0.91), 7.378 (2.34), 7.384 (0.94), 7.389 (2.78), 7.395 (1.80) 7.397 (1.97), 7.408 (5.72), 7.414 (9.89), 7.417 (11.90), 7.426 (4.60), 7.431 (1.87), 7.563 (2.52) 7.567 (4.20), 7.570 (2.67), 7.582 (2.11), 7.585 (3.42), 7.588 (2.18), 7.962 (3.09), 7.980 (3.80) 7.983 (4.01), 8.001 (3.67), 8.255 (4.10), 8.259 (4.31), 8.276 (3.62), 8.279 (3.59), 8.432 (3.87) 8.436 (3.99), 8.451 (3.77), 8.454 (3.48), 9.074 (3.30), 9.079 (16.00), 9.086 (3.50), 9.774 (2.94) 9.793 (2.89).
Example 76
N-[(trans)-2-(2-chlorophenyl)-1-oxo-2-azaspiro[4.5]dec-8-yl]pyridine-2-carboxamide
Figure imgf000189_0001
To a solution of pyridine-2-carboxylic acid (35.0 mg, 276 μιηοΙ) and 8-amino-2-(2- chlorophenyl)-2-azaspiro[4.5]decan-1-one (isomer 1, Intermediate I35) (84.6 mg, 303 μιηοΙ) in DMF (2.8 ml) was added PyBOP (158 mg, 303 Mmol), N,N-diisopropylethylamine (190 μΙ, 1.1 mmol) and the reaction was stirred for 17 h at room temperature. For work-up, the reaction mixture was concentrated and the residue was purified by flash chromatography (dichloromethane/methanol gradient, 0.2% -> 10% methanol) to give after trituration with diethyl ether the title compound (74 mg).
LC-MS (Method 1): Rt = 1.10 min; MS (ESIpos): m/z = 384 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.071 (0.62), 1.088 (1.33), 1.105 (0.69), 1.629 (2.50), 1.660(16.00), 1.711 (0.70), 1.719(0.49), 1.727(1.03), 1.735 (0.46), 1.744(0.49), 1.781 (1.13), 1.810 (4.09), 2.127 (4.41), 2.144 (8.31), 2.161 (4.60), 2.327 (0.56), 2.332 (0.41), 2.518 (2.10), 2.523 (1.27), 2.665 (0.41), 2.669 (0.55), 2.673 (0.40), 3.005 (0.66), 3.014 (0.64), 3.370 (0.67), 3.388 (0.65), 3.627 (4.81), 3.644 (8.35), 3.661 (4.56), 3.824 (1.03), 5.760 (0.75), 7.360 (1.05), 7.369 (1.62), 7.374 (1.73), 7.377 (1.25), 7.383 (3.45), 7.392 (2.77), 7.395 (3.52), 7.404 (11.78), 7.412 (4.21), 7.418 (2.72), 7.422 (1.19), 7.437 (0.42), 7.550 (0.61), 7.556 (2.90), 7.559 (4.61), 7.563 (2.68), 7.573 (2.33), 7.577 (3.71), 7.580 (2.41), 7.590 (2.47), 7.594 (2.44), 7.602 (2.34), 7.606 (2.71), 7.608 (2.91), 7.612 (2.47), 7.620 (2.54), 7.624 (2.47), 7.977 (1.64), 7.982 (1.71), 7.997 (3.65), 8.002 (3.74), 8.015 (3.25), 8.020 (3.32), 8.033 (3.88), 8.036 (5.55), 8.039 (4.17), 8.053 (1.81), 8.055 (2.30), 8.059 (1.50), 8.576 (3.07), 8.598 (3.02), 8.640 (2.83), 8.642 (3.38), 8.644 (3.65), 8.646 (2.93), 8.652 (2.88), 8.654 (3.47), 8.658 (2.72). Example 77
N-[(cis)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5-carboxamide
Figure imgf000190_0001
To a solution of 8-amino-2-(2-chloro-4-fluorophenyl)-2-azaspiro[4.5]decan-1 -one (isomer 2 Intermediate 113), (75.0 mg, 253 μπιοΙ) in DMF (2.6 ml) was added PyBOP (145 mg, 278 μιηοΙ), N,N-diisopropylethylamine (180 μΙ, 1.0 mmol) and quinoxaline-5-carboxylic acid (44.0 mg, 253 μιηοΙ) and the reaction was stirred for 16 h at room temperature. For work-up, brine (45 ml) was added and the resulting precipitate was filtrated. The residue was dissolved in DMSO and the crude product was purified by HPLC (Method 6) to give after trituration with water the title product (54 mg)
LC-MS (Method 4): Rt = 1 .15 min; MS (ESIpos): m/z = 453 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1 .548 (5.49), 1 .581 (5.92), 1 .788 (2.48), 1 .820 (5.92), 1 .848 (5.61 ), 1 .901 (6.65), 1 .992 (4.72), 2.001 (4.87), 2.026 (6.99), 2.052 (3.52), 2.124 (6.90), 2.142 (12.41 ), 2.158 (6.99), 2.327 (1 .99), 2.539 (3.37), 2.668 (1 .96), 3.628 (7.72), 3.645 (13.55), 3.662 (7.1 1 ), 4.224 (3.62), 7.293 (2.54), 7.299 (2.85), 7.314 (5.06), 7.321 (5.27), 7.335 (3.13), 7.343 (3.03), 7.485 (5.24), 7.499 (5.85), 7.507 (5.06), 7.521 (4.14), 7.579 (5.33), 7.586 (5.36), 7.600 (5.39), 7.607 (5.00), 7.975 (4.54), 7.995 (7.88), 8.014 (5.33), 8.270 (7.1 1 ), 8.274 (7.05), 8.291 (6.50), 8.295 (6.50), 8.300 (3.92), 8.522 (7.02), 8.526 (6.80), 8.541 (6.59), 9.079 (16.00), 9.087 (15.66), 10.452 (3.80), 10.471 (3.65). Example 78
2-chloro-4-fluoro-N-[(trans)-1 -oxo-2-(pyridin-2-yl)-2-azaspiro[4.5]decan-8-yl]benzamide
Figure imgf000190_0002
A solution of 2-chloro-4-fluorobenzoyl chloride (42 μΙ, 310 μιηοΙ) in THF (1 .0 ml) was added dropwise at 0Ό to a mixture of 8-amino-2-(pyridin- 2-yl)-2-azaspiro[4.5]decan-1 -one (isomer 1 , intermediate I66) (75.0 mg, 306 μιηοΙ) and triethylamine (130 μΙ, 920 μιηοΙ) in THF (1 .5 ml) and DMF (0.31 ml) and the mixture was stirred over night at room temperature. For work-up, water was added and the mixture was extracted with ethyl acetate (3x). The combined organic phases were filtrated through a silicone filter and concentrated under reduced pressure. The crude product was recrystallized from ethanol to give the title compound 40.1 mg (32 % yield).
LC-MS (Method 2): Rt = 1 .05 min; MS (ESIneg) : m/z = 400 [M-H]-
1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (0.84), 1 .415 (1 .19), 1 .438 (2.57), 1 .446 (2.73), 1 .458 (2.96), 1 .468 (4.50), 1 .487 (3.37), 1 .498 (2.94), 1 .519 (1 .85), 1 .703 (13.80), 1 .712 (16.00), 1 .728 (10.57), 1 .734 (9.71 ), 1 .929 (4.94), 1 .939 (5.16), 1 .950 (3.06), 1 .962 (4.79), 1 .971 (4.34), 2.056 (9.48), 2.074 (13.72), 2.091 (9.97), 2.389 (0.74), 2.393 (1 .07), 2.398 (0.76), 2.584 (3.70), 2.589 (2.41 ), 2.731 (0.78), 2.735 (1 .09), 2.740 (0.76), 3.225 (0.95), 3.238 (0.99), 3.756 (0.99), 3.767 (1 .1 1 ), 3.776 (2.04), 3.786 (2.51 ), 3.795 (2.06), 3.805 (2.49), 3.815 (1 .95), 3.824 (1 .1 1 ), 3.834 (0.99), 3.994 (10.10), 4.006 (4.34), 4.012 (13.86), 4.016 (4.81 ), 4.029 (9.64), 7.193 (6.03), 7.196 (6.00), 7.205 (5.47), 7.208 (6.05), 7.21 1 (6.40), 7.214 (5.76), 7.224 (6.19), 7.226 (6.31 ), 7.318 (4.09), 7.324 (4.59), 7.339 (8.21 ), 7.346 (9.17), 7.360 (4.81 ), 7.366 (5.35), 7.526 (8.78), 7.541 (8.99), 7.547 (8.06), 7.557 (9.21 ), 7.563 (14.27), 7.580 (8.62), 7.586 (8.23), 7.859 (5.39), 7.864 (5.49), 7.877 (5.49), 7.880 (6.33), 7.882 (5.94), 7.885 (5.94), 7.898 (5.08), 7.903 (5.41 ), 8.379 (6.36), 8.381 (12.55), 8.384 (7.24), 8.400 (6.15), 8.403 (10.39), 8.405 (6.36), 8.446 (10.61 ), 8.449 (13.14), 8.451 (10.90), 8.454 (7.92), 8.459 (7.61 ), 8.461 (8.08), 8.464 (8.90), 8.466 (10.41 ).
Further, the compounds of formula (I) of the present invention can be converted to any salt as described herein, by any method which is known to the person skilled in the art. Similarly, any salt of a compound of formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
Pharmaceutical compositions of the compounds of the invention
This invention also relates to pharmaceutical compositions containing one or more compounds of the present invention. These compositions can be utilised to achieve the desired pharmacological effect by administration to a patient in need thereof. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention. A pharmaceutically acceptable carrier is preferably a carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A pharmaceutically effective amount of compound is preferably that amount which produces a result or exerts an influence on the particular condition being treated. The compounds of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like.
For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled gelatine type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
In another embodiment, the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatine, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, colouring agents, and flavouring agents such as peppermint, oil of wintergreen, or cherry flavouring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavouring and colouring agents described above, may also be present.
The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1 ) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate ; one or more colouring agents ; one or more flavouring agents ; and one or more sweetening agents such as sucrose or saccharin.
Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavouring and colouring agents.
The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in preferably a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1 ,1 -dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants.
Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates ; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates ; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers ; and amphoteric detergents, for example, alkyl-beta- aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
The parenteral compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimise or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) preferably of from about 12 to about 17. The quantity of surfactant in such formulation preferably ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia ; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.
A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycol.
Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued June 1 1 , 1991 , incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art.
It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in US Patent No. 5,01 1 ,472, issued April 30, 1991.
The compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.
Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M.F. et al., "Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-31 1 ; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1 " PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349 ; and Nema, S. et al., "Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical Science & Technology 1997, 51 (4), 166-171. Commonly used pharmaceutical ingredients that can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid) ; alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine) ; adsorbents (examples include but are not limited to powdered cellulose and activated charcoal) ; aerosol propellents (examples include but are not limited to carbon dioxide, CCI2F2, F2CIC-
Figure imgf000196_0001
air displacement agents (examples include but are not limited to nitrogen and argon) ; antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate) ; antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal) ; antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite) ; binding materials (examples include but are not limited to block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene-butadiene copolymers) ; buffering agents (examples include but are not limited to potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate) carrying agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection) chelating agents (examples include but are not limited to edetate disodium and edetic acid) colourants (examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red) ; clarifying agents (examples include but are not limited to bentonite) ; emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate) ; encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate) flavourants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin) ; humectants (examples include but are not limited to glycerol, propylene glycol and sorbitol) ; levigating agents (examples include but are not limited to mineral oil and glycerin) ; oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil) ; ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment) ; penetration enhancers (transdermal delivery) (examples include but are not limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas) plasticizers (examples include but are not limited to diethyl phthalate and glycerol) ; solvents (examples include but are not limited to ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation) ; stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax) ; suppository bases (examples include but are not limited to cocoa butter and polyethylene glycols (mixtures)) ; surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono-palmitate) ; suspending agents (examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum) ; sweetening agents (examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose) ; tablet anti-adherents (examples include but are not limited to magnesium stearate and talc) ; tablet binders (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch) ; tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch) ; tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac) ; tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate) ; tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch) ; tablet glidants (examples include but are not limited to colloidal silica, corn starch and talc) ; tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate) ; tablet/capsule opaquants (examples include but are not limited to titanium dioxide) ; tablet polishing agents (examples include but are not limited to carnuba wax and white wax) ; thickening agents (examples include but are not limited to beeswax, cetyl alcohol and paraffin) ; tonicity agents (examples include but are not limited to dextrose and sodium chloride) ; viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth) ; and wetting agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).
Pharmaceutical compositions according to the present invention can be illustrated as follows: Sterile IV Solution: A 5 mg/ml solution of the desired compound of this invention can be made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 - 2 mg/ml with sterile 5% dextrose and is administered as an IV infusion over about 60 min.
Lvophilised powder for IV administration: A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lyophilised powder, (ii) 32- 327 mg/ml sodium citrate, and (iii) 300 - 3000 mg Dextran 40. The formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/ml, which is further diluted with saline or dextrose 5% to 0.2 - 0.4 mg/ml, and is administered either IV bolus or by IV infusion over 15 - 60 min. Intramuscular suspension: The following solution or suspension can be prepared, for intramuscular injection:
50 mg/ml of the desired, water-insoluble compound of this invention 5 mg/ml sodium carboxymethylcellulose 4 mg/ml TWEEN 80 9 mg/ml sodium chloride 9 mg/ml benzyl alcohol
Hard Shell Capsules: A large number of unit capsules are prepared by filling standard two- piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
Soft Gelatin Capsules: A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 1 1 mg of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
Immediate Release Tablets/Capsules: These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
Combination therapies 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. One example of 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. One example of a non-fixed combination or kit-of-parts is a combination wherein the said first active ingredient and the said second active ingredient are present separately. The components of the non-fixed combination or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
The compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. The present invention relates also to such combinations. For example, the compounds of this invention can be combined with known chemotherapeutic agents or anti-cancer agents, e.g. anti-hyper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof. Other indication agents include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, anti-metabolites, DNA-intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, toposisomerase inhibitors, biological response modifiers, or anti-hormones.
The term "chemotherapeutic anti-cancer agents", includes but is not limited to 131 1-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, carbamazepine carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib , crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, 1-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neridronic acid, netupitant/palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, rucaparib, samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.
The compounds of the invention may also be administered in combination with protein therapeutics. Such protein therapeutics suitable for the treatment of cancer or other angiogenic disorders and for use with the compositions of the invention include, but are not limited to, an interferon (e.g., interferon .alpha., .beta., or .gamma.) supraagonistic monoclonal antibodies,
Tuebingen, TRP-1 protein vaccine, Colostrinin, anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab, trastuzumab, denileukin diftitox, rituximab, thymosin alpha 1 , bevacizumab, mecasermin, mecasermin rinfabate, oprelvekin, natalizumab, rhMBL, MFE-CP1
+ ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-35, MT-103, rinfabate, AS-1402,
B43-genistein, L-19 based radioimmunotherapeutics, AC-9301 , NY-ESO-1 vaccine, IMC- 1 C1 1 , CT-322, rhCCI O, r(m)CRP, MORAb-009, aviscumine, MDX-1307, Her-2 vaccine, APC- 8024, NGR-hTNF, rhH1 .3, IGN-31 1 , Endostatin, volociximab, PRO-1762, lexatumumab, SGN- 40, pertuzumab, EMD-273063, L19-IL-2 fusion protein, PRX-321 , CNTO-328, MDX-214, tigapotide, CAT-3888, labetuzumab, alpha-particle-emitting radioisotope-llinked lintuzumab, EM-1421 , HyperAcute vaccine, tucotuzumab celmoleukin, galiximab, HPV-16-E7, Javelin - prostate cancer, Javelin - melanoma, NY-ESO-1 vaccine, EGF vaccine, CYT-004-MelQbG10, WT1 peptide, oregovomab, ofatumumab, zalutumumab, cintredekin besudotox, WX-G250, Albuferon, aflibercept, denosumab, vaccine, CTP-37, efungumab, or 131 l-chTNT-1/B. Monoclonal antibodies useful as the protein therapeutic include, but are not limited to, muromonab-CD3, abciximab, edrecolomab, daclizumab, gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevicizumab, efalizumab, adalimumab, omalizumab, muromomab- CD3, rituximab, daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.
A compound of general formula (I) as defined herein can optionally be administered in combination with one or more of the following: ARRY-162, ARRY-300, ARRY-704, AS-703026, AZD-5363, AZD-8055, BEZ-235, BGT-226, BKM-120, BYL-719, CAL-101 , CC-223, CH- 5132799, deforolimus, E-6201 , enzastaurin , GDC-0032, GDC-0068, GDC-0623, GDC-0941 , GDC-0973, GDC-0980, GSK-21 10183, GSK-2126458, GSK-2141795, MK-2206, novolimus, OSI-027, perifosine, PF-04691502, PF-05212384, PX-866, rapamycin, RG-7167, RO- 4987655, RO-5126766, selumetinib, TAK-733, trametinib, triciribine, UCN-01 , WX-554, XL- 147, XL-765, zotarolimus, ZSTK-474.
Generally, the use of cytotoxic and/or cytostatic agents in combination with a compound or composition of the present invention will serve to:
(1 ) yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to administration of either agent alone,
(2) provide for the administration of lesser amounts of the administered chemotherapeutic agents,
(3) provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies,
(4) provide for treating a broader spectrum of different cancer types in mammals, especially humans,
(5) provide for a higher response rate among treated patients, (6) provide for a longer survival time among treated patients compared to standard chemotherapy treatments,
(7) provide a longer time for tumor progression, and/or
(8) yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.
Methods of Sensitizing Cells to Radiation
In a distinct embodiment of the present invention, a compound of the present invention may be used to sensitize a cell to radiation. That is, treatment of a cell with a compound of the present invention prior to radiation treatment of the cell renders the cell more susceptible to DNA damage and cell death than the cell would be in the absence of any treatment with a compound of the invention. In one aspect, the cell is treated with at least one compound of the invention. Thus, the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the invention in combination with conventional radiation therapy.
The present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of the invention prior to the treatment of the cell to cause or induce cell death. In one aspect, after the cell is treated with one or more compounds of the invention, the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell.
In one embodiment, a cell is killed by treating the cell with at least one DNA damaging agent. That is, after treating a cell with one or more compounds of the invention to sensitize the cell to cell death, the cell is treated with at least one DNA damaging agent to kill the cell. DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g., cisplatinum), ionizing radiation (X-rays, ultraviolet radiation), carcinogenic agents, and mutagenic agents. In another embodiment, a cell is killed by treating the cell with at least one method to cause or induce DNA damage. Such methods include, but are not limited to, activation of a cell signalling pathway that results in DNA damage when the pathway is activated, inhibiting of a cell signalling pathway that results in DNA damage when the pathway is inhibited, and inducing a biochemical change in a cell, wherein the change results in DNA damage. By way of a non-limiting example, a DNA repair pathway in a cell can be inhibited, thereby preventing the repair of DNA damage and resulting in an abnormal accumulation of DNA damage in a cell.
In one aspect of the invention, a compound of the invention is administered to a cell prior to the radiation or other induction of DNA damage in the cell. In another aspect of the invention, a compound of the invention is administered to a cell concomitantly with the radiation or other induction of DNA damage in the cell. In yet another aspect of the invention, a compound of the invention is administered to a cell immediately after radiation or other induction of DNA damage in the cell has begun.
In another aspect, the cell is in vitro. In another embodiment, the cell is in vivo.
As mentioned supra, the compounds of the present invention have surprisingly been found to effectively inhibit tankyrases and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses are affected by inhibition of tankyrases, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
In accordance with another aspect therefore, the present invention covers a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described and defined herein, for use in the treatment or prophylaxis of a disease, as mentioned supra.
Another particular aspect of the present invention is therefore the use of a compound of general formula (I), described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of a disease.
Another particular aspect of the present invention is therefore the use of a compound of general formula (I) described supra or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease.
Another aspect of the present invention is the use of a compound of formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described herein, in the manufacture of a medicament for the treatment or prophylaxis of a disease.
The diseases referred to in the three preceding paragraphs are diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, 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 term "inappropriate" within the context of the present invention, in particular in the context of "inappropriate cellular immune responses, or inappropriate cellular inflammatory responses", as used herein, is to be understood as meaning a response which is less than, or greater than normal, and which is associated with, responsible for, or results in, the pathology of said diseases. Preferably, the use is in the treatment or prophylaxis of diseases, wherein the diseases are haemotological tumours, solid tumours and/or metastases thereof.
Diseases further included in the context of the present invention are metabolic diseases diabetes and obesity), fibrosis (e.g. lung fibrogenesis) and viral infection.
Method of treating hyper-proliferative disorders
The present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat mammalian hyper-proliferative disorders. Compounds can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof ; etc. which is effective to treat the disorder. Hyperproliferative disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukaemias.
Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
Examples of cancers of the respiratory tract include, but are not limited to small-cell and non- small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour.
Tumours of the male reproductive organs include, but are not limited to prostate and testicular cancer. Tumours of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
Tumours of the digestive tract include, but are not limited to anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers. Tumours of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell. Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.
The term "treating" or "treatment" as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma.
Methods of treating angiogenic disorders
The present invention also provides methods of treating disorders and diseases associated with excessive and/or abnormal angiogenesis.
Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism. A number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity [Aiello et al. New Engl. J. Med. 1994, 331 , 1480 ; Peer et al. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD ; see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855], neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc. In addition, the increased blood supply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumour enlargement and metastasis. Moreover, the growth of new blood and lymph vessels in a tumour provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer. Thus, compounds of the present invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis disorders, e.g., by inhibiting and/or reducing blood vessel formation ; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.
Dose and administration
Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyper-proliferative disorders and angiogenic disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
Preferably, the diseases of said method are haematological tumours, solid tumour and/or metastases thereof.
The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth.
Methods of testing for a particular pharmacological or pharmaceutical property are well known to persons skilled in the art.
The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.
Experimerimental Part - Biological Assays:
Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein • the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and
• the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the medianis the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.
Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch(es).
6 Biochemical assays
6.1 TNKS1 Assays
TNKS1 Assay A
The potency of the compounds according to the invention was assessed by applying an in vitro inhibition assay. The TNKS1 catalyzed NAD+-dependent ribosylation of a suitable protein substrate was detected using a commercially available biotin/streptavidin binding based assay format [TNKS1 Histone Ribosylation Assay Kit (Biotin-labeled NAD+), Catalog #80579; BPS Bioscience, San Diego, USA]. Here, the incorporation of a biotin-labeled NAD+ during the TNKS1 catalyzed ribosylation reaction was detected with a streptavidin-HRP coupled chemi- luminescent readout. The intensity of the readout signal is proportional to the incorporated NAD+. Inhibition of TNKS1 leads to a decreased incorporation of NAD+ and consequently to a lower readout signal intensity. The concentration of a test compound which inhibits the enzyme activity by 50% (corresponds to half of the normed readout signal intensity) is reported as IC5o. Protocol
The assay was conducted in a 384 well MTP format according to the manufacturer's protocol [http://www.bpsbioscience.com/poly-adp-ribose-polymerase/assay-kit/tnks1 -histone- ribosylation-assay-kit-biotin-labeled-nad-80579 referencing: Brown, J. A., Marala, R.B. J. Pharmacol. Toxicol. Methods 2002 47:137] and using a BMG Pherastar MTP reader [BMG- Labtech, Offenburg, Germany].
TNKS1 Assay B
The potency of selected compounds according to the invention was assessed applying a modified in vitro inhibition assay. Here, the TNKS1 catalyzed NAD+-dependent ribosylation of the enzyme itself (auto-parsylation) was detected using [3H]-NAD+ as substrate and applying the scintillation proximity assay (SPA) method to detect tritium-labeled, parsylated TNKS1 . The intensity of the readout signal is proportional to the incorporated [3H]-NAD+. Inhibition of TNKS1 leads to a decreased incorporation of [3H]-NAD+ and consequently to a lower readout signal intensity. The concentration of a test compound which inhibits the enzyme activity by 50% (corresponds to half of the normed readout signal intensity) is reported as IC5o.
Protocol Auto-Parsylation Assay
The assay was conducted in a 96 well MTP format with the identical TNKS1 enzyme sample and NAD+ sample as in the histone ribosylation assay with the following modifications: TNKS1 enzyme sample was diluted with a modified assay buffer (50 mM MES pH 7.0, 1 mM DTT, 0.01 % Triton X-100) to a final concentration of 6 nM TNKS1 and 10x NAD+ solution was diluted with the modified assay buffer (s. above) to a final 0.445x NAD+ solution doped with 100 Bq/μΙ [3H]-NAD+ [Catalog #NET443H050UC, Perkin Elmer, Waltham , Massachusetts, USA ]. Substrate solution (10 μΙ) was incubated with different test compound concentrations (2.5 μΙ in 10 % DMSO in modified assay buffer) or control (2.5 μΙ 10 % DMSO in modified assay buffer only) and enzyme (10 μΙ) over night at room temperature. Incorporated tritium was measured after addition of 50 μΙ SPA beads (1 mg/ml) [Catalog #RPNQ0095 20 mg/ml, Perkin Elmer, Waltham, Massachusetts, USA; diluted 1 :10 with Dulbecco's phosphate buffered saline, PBS Catalog #D8537, Sigma-Aldrich, Steinheim, Germany] and detection of the photon emission with a beta count plate reader [Wallac MicroBeta®, Perkin Elmer, Waltham , Massachusetts, USA].
6.2 TNKS2 Assays
TNKS2 Assay A
The potency of the compounds according to the invention was assessed applying an in vitro inhibition assay. The TNKS2 catalyzed NAD+-dependent ribosylation of a suitable protein substrate was detected using a commercially available biotin/streptavidin binding based assay format [TNKS2 Histone Ribosylation Assay Kit (Biotin-labeled NAD+), Catalog #80572; BPS Bioscience, San Diego, USA]. Here, the incorporation of a biotin-labeled NAD+ during the TNKS2 catalyzed ribosylation reaction was detected with a streptavidin-HRP coupled chemi- luminescent readout. The intensity of the readout signal is proportional to the incorporated NAD+. Inhibition of TNKS2 leads to a decreased incorporation of NAD+ and consequently to a lower readout signal intensity. The concentration of a test compound which inhibits the enzyme activity by 50% (corresponds to half of the normed readout signal intensity) is reported as IC50.
Protocol The assay was conducted in a 384 well MTP format according to the manufacturer's protocol [http://www.bpsbioscience.com/poly-adp-ribose-polymerase/assay-kit/tnks2-histone- ribosylation-assay-kit-biotin-labeled-nad-80572 referencing: Brown, J. A., Marala, R.B. J. Pharmacol. Toxicol. Methods 2002 47:137]. and using a BMG Pherastar MTP reader [BMG- Labtech, Offenburg, Germany].
TNKS2 Assay B
The potency of selected compounds according to the invention was assessed applying a modified in vitro inhibition assay. Here, the TNKS2 catalyzed NAD+-dependent ribosylation of the enzyme itself (auto-parsylation) was detected using [3H]-NAD+ as substrate and applying the scintillation proximity assay (SPA) method to detect tritium-labeled, parsylated TNKS2. The intensity of the readout signal is proportional to the incorporated [3H]-NAD+. Inhibition of TNKS2 leads to a decreased incorporation of [3H]-NAD+ and consequently to a lower readout signal intensity. The concentration of a test compound which inhibits the enzyme activity by 50% (corresponds to half of the normed readout signal intensity) is reported as IC5o.
Protocol Auto-Parsylation Assay
The assay was conducted in a 96 well MTP format with the identical TNKS2 enzyme sample and NAD+ sample as in the histone ribosylation assay with the following modifications: TNKS2 enzyme sample was diluted with a modified assay buffer (50 mM MES pH 7.0, 1 mM DTT, 0.01 % Triton X-100) to a final concentration of 6 nM TNKS2 and 10x NAD+ solution was diluted with the modified assay buffer (s. above) to a final 0.445x NAD+ solution doped with 100 Bq/μΙ [3H]-NAD+ [Catalog #NET443H050UC, Perkin Elmer, Waltham , Massachusetts, USA]. Substrate solution (10 μΙ) was incubated with different test compound concentrations (2.5 μΙ in 10 % DMSO in modified assay buffer) or control (2.5 μΙ 10 % DMSO in modified assay buffer only) and enzyme (10 μΙ) over night at room temperature. Incorporated tritium was measured after addition of 50 μΙ SPA beads (1 mg/ml) [Catalog #RPNQ0095 20 mg/ml, Perkin Elmer, Waltham, Massachusetts, USA; diluted 1 :10 with Dulbecco's phosphate buffered saline, PBS Catalog #D8537, Sigma-Aldrich, Steinheim, Germany] and detection of the photon emission with a beta count plate reader [Wallac MicroBeta®, Perkin Elmer, Waltham , Massachusetts, USA].
6.3 PARP1 Assay
The potency of the compounds according to the invention was assessed using a commercially available biotin/streptavidin binding assay kits from BPS Bioscience, San Diego, USA (Catalog #80551 ). The incorporation of a biotin-labeled NAD+ during the PARP1 catalyzed ribosylation of a suitable protein substrate was detected using with a streptavidin-HRP coupled chemi- luminescent readout. The intensity of the readout signal is proportional to the incorporated NAD+. Inhibition of PARP1 leads to a decreased incorporation of NAD+ and consequently to a lower readout signal intensity. The concentration of a test compound that inhibits the enzyme activity by 50% (corresponds to half of the normed readout signal intensity) is reported as IC50. Protocol
The assay was conducted in a 96 well MTP format according to the manufacturer's protocol (Catalog No. 80551 ) and using a BMG Pherastar MTP reader [BMG-Labtech, Offenburg, Germany].
6.4 PARP2 Assay
The potency of the compounds according to the invention was assessed using a commercially available biotin/streptavidin binding assay kits from BPS Bioscience, San Diego, USA (Catalog #80551 ). The incorporation of a biotin-labeled NAD+ during the PARP2 catalyzed ribosylation of a suitable protein substrate was detected using with a streptavidin-HRP coupled chemi- luminescent readout. The intensity of the readout signal is proportional to the incorporated NAD+. Inhibition of PARP2 leads to a decreased incorporation of NAD+ and consequently to a lower readout signal intensity. The concentration of a test compound that inhibits the enzyme activity by 50% (corresponds to half of the normed readout signal intensity) is reported as IC50.
Protocol
The assay was conducted in a 96 well MTP format according to the manufacturer's protocol (Catalog No. 80552) and using a BMG Pherastar MTP reader [BMG-Labtech, Offenburg, Germany].
7 Cellular Assays
7.1 Measurement of the inhibitory activity of selected compounds on the Wildtype Wnt signaling cascade: HEK293 TOP/FOP Assay
In order to discover and characterize small molecules which inhibit the wildtype Wnt pathway, a cellular reporter assay was employed. The corresponding assay cell was generated by transfection of the mammalian cell line HEK293 (ATCC, #CRL-1573) with the Super TopFlash vector (Morin, Science 275, 1997, 1787-1790; Molenaar et al., Cell 86 (3), 1996, 391 -399). The HEK293 cell line is cultivated at 37Ό and 5% CO 2 in DMEM (Life Technologies, #41965-039), supplemented with 2 mM glutamine, 20 mM HEPES, 1 .4 mM pyruvate, 0.15% Na-bicarbonate and 10% foetal bovine serum (GIBCO, #10270). Stable transfectants were generated by selection with 300 \g/m\ Hygromycin.
In a parallel approach, HEK293 cells were cotransfected with the FOP control vector and pcDNA3. The FOP vector is identical to the TOP construct, but it contains instead of functional TCF elements a randomized, non-functional sequence. For this transfection a stable transfected cell line was generated as well, based on selection with Geneticin (1 mg/ml).
In preparation of the assay, the two cell lines were plated 24 h before beginning the test at 10000 cells per well in a 384 micro titre plate (MTP) in 30 μΙ growth medium. Before compound testing a dose response curve for the Wnt dependent luciferase expression was recorded by stimulating the assay cell line with human recombinant Wnt-3a (R&D, #5036-WN-010) at different concentrations for 16 h at 37Ό and 5% C02 followed by subsequent luciferase measurement, to determine the Wnt-3a EC5o for the HEK293 TOP cell line on the day of testing. The recombinant human Wnt-3a was thereby applied between 2500 and 5 ng/ml in two-fold dilution steps.
Selective inhibitory activity for small molecules on the wildtype Wnt pathway was determined after parallel incubation of both (TOP and FOP) HEK293 reporter cell lines with a compound dilution series from 50 μΜ to 15 nM in steps of 3.16-fold dilutions in CAFTY buffer (130 mM sodium chloride, 5 mM potassium chloride, 20 mM HEPES, 1 mM magnesium chloride, 5 mM sodium bicarbonate, pH 7.4) containing 2 mM Ca2+ and 0.01 % BSA.
The compounds were thereby serially prediluted in 100% DMSO and thereafter 50 fold into the CAFTY compound dilution buffer (described above). From this dilution 10 μΙ were added in combination with the EC5o concentration of recombinant Wnt3a to the cells in 30 μΙ growth medium and incubated for 16 hours at 37Ό and 5% C02. Thereafter luciferase assay buffer (1 :1 mixture of luciferase substrate buffer (20 mM Tricine, 2.67 mM magnesium sulfate, 0.1 mM EDTA, 4 mM DTT, 270 μΜ Coenzyme A, 470 μΜ Luciferin, 530 μΜ ATP, ph adjusted to pH 7.8 with a sufficient volume of 5M sodium hydroxide) and Triton buffer (30 ml Triton X-100, 1 15 ml glycerol, 308 mg Dithiothreitol, 4.45 g disodium hydrogen phosphate dihydrate, 3.03 g Tris . HCI, ad 11 H20, pH 7.8) was added in an equal volume to determine luciferase expression as a measure of Wnt signaling activity in a luminometer. The Wnt inhibitory activity was determined as IC5o of resulting dose response curves.
7.2 Axin Stabilization Assay
The in vitro and in vivo effect of Tankyrase inhibition on the stabilization of cellular Axin was assessed using Peggy Simple Western assay with size-based separation and immunodetection of Axin2. SW403 cells (but not limited to) were seeded at 50000 cells per well in 96-well plates. After overnight incubation, cells were treated with testing compounds and vehicle at 37 "C for 24 hours. Thereafter, cell s were washed with PBS and then lysed in 15 μΙ of lysis buffer (M-PER buffer, Thermo Scientific # 78505) with complete proteinase and phosphatase inhibitors (Roche, #1 1836153001 and # 04906837001 ). The lysates were centrifuged and the supernatants were harvested for analysis. Tumor xenografts from in vivo studies were homogenized in a 2 ml tubes of Precellys®24 (Bertin Technologies, Villeurbanne, France) following with centrafugation to obtain tumor lysates. Capillary electrophoresis-based Simple Western assays were carried out with Peggy Sue™ NanoPro 1000 (ProteinSimple, California, USA). The protein amounts of Axin2 (but not limited to) were detected using anti- Axin2 antibody (Cell Signaling, Catalog #2151 ), quantified using the area under the curve, and normalized against GAPDH (anti-GAPDH, Zytomed Systems GmbH, Catalog #RGM2-6C5, Berlin, Germany).
7.3 Real-time RT-PCR for quantitative analysis of gene transcription
Real-time RT-PCR using a TaqMan fluorogenic detection system is a simple and sensitive assay for quantitative analysis of gene transcription. The TaqMan fluorogenic detection system can monitor PCR in real time using a dual-labeled fluorogenic hybridization probe (TaqMan probe) and a polymerase with 5'-3' exonuclease activity.
Cells from different cancer cell lines (as HCT1 16, but not limited to) were grown at 500-1000 cells/well in 384 well cell culture plates. For cell lysis the cell medium was carefully removed. The cells were washed carefully once with 50 μΙ/well PBS. Then 9.75 μΙ/well cell lysis buffer (50 mM Tris HCI pH 8,0, 40 mM sodium chloride, 1 ,5 mM magnesium chloride, 0,5 % IGEPAL CA 630, 50mM Guanidium thiocyanate) and 0.25 μΙ RNASeOUT (40 U/μΙ, Invitrogen, 10777- 019)) per well were added. The plate was incubated for 5 min at room temperature. Then 30 μΙ DNAse/RNAse-free water per well was added and the lysates mixed. Isolation of total RNA from tumor tissues was conducted using InviTrap® Spin Tissue RNA Mini Kit (#1062100300, STRATEC MOLECULAR).
For the One-Step RT-PCR 2 μΙ lysate (each) was transferred to a 384 well PCR plate. The PCR reaction was composed by 5 μΙ 2x One Step RT qPCR MasterMix Plus, 0.05 μΙ Euroscript RT/RNAse Inhibitor (50 U/μΙ, 20 U/μΙ) and 200 nM of the appropriate Primer/Hydrolysis Probe mix (primer sequences of forward, reverse and probe are given below for each analysed gene of interest or house keeping gene). 10 μΙ water were added per well. The plate was sealed with an adhesive optical film. The RT-PCR protocol was setup with 30 min 48Ό, then 10 min 95"C followed by 50 cycles of 15 sec 95Ό/1 min 6CC and a cooling step of 40Ό for 30 sec using a Lightcycler LS440 from Roche. Relative expression was calculated using CP values from the gene of interest (e.g. AXIN2, but not limited to) and a house keeping gene (L32).
Used primers
L32 (forward primer: AAGTTCATCCGGCACCAGTC (SEQ ID NO. 1 ); reverse primer: TGGCCCTTGAATCTTCTACGA (SEQ ID NO. 2); probe: CCCAGAGGCATTGACAACAGGG (SEQ ID NO. 3)) AXIN2 (forward primer: AGGCCAGTGAGTTGGTTGTC (SEQ ID NO. 4); reverse primer: AGCTCTGAGCCTTCAGCATC (SEQ ID NO. 5); probe:
TCTGTGGGGAAGAAATTCCATACCG (SEQ ID NO. 6))
8 In vivo Efficacy in xenograft models
Subcutaneous xenograft models in immunocompromised mice were used to evaluate in vivo anti-tumor efficacy of the compounds.
8.1 Maximum tolerable dose (MTD) studies
Prior to efficacy studies, the maximal tolerable dose (MTD) was determined by the following protocol: Female nude mice (NMRI (nu/nu), Taconic M&B A/S) received a defined oral dose of the test compound daily or bi-daily for 7 consecutive days followed by a 7 day observation period without dosing. Individual body weight and lethality were monitored daily.
The MTD is defined as the maximal applicable dose with a) no animal losing more than 10% body weight compared to initial body weight and b) no lethality during treatment phase.
8.2 In vivo efficacy studies
To measure anti-tumor efficacy, the test compounds were analysed in xenograft models on mice. Test compounds were dosed orally at their respective MTD as well as at sub-MTD dosages. In case the MTD could not be determined in previous MTD studies, the compounds were dosed at a maximum daily dose of 200 mg/kg (applied either in one single dose or split in 2 doses at 100 mg/kg).
Compounds were primarily analyzed in an ovarian teratocarcinoma model (PA-1 ) and in various colorectal cancer models on female immunocompromised mice.
For this purpose, 1 -5x106 tumor cells (suspended in 0.1 ml of 50% cell culture medium/50% Matrigel) were subcutanously injected into the flank of each animal. Animals were randomized into treatment groups when tumors had reached an average area of 20-30 mm2 and treatment was started. Body weight and tumor area of each animal were measured 2-3 times weekly, depending on tumor growth. Studies were terminated, when animals in the control groups (receiving only compound vehicle solutions) or treatment groups reached tumor areas -150 mm2. At that time point, all groups in the study were terminated, tumors were isolated and weighed.
As primary parameter for anti-tumor efficacy the Treatment/Control (T/C) ratio of the final tumor weights were calculated (mean tumor weight of treatment group divided by mean tumor weight of vehicle group).
8.3 In vivo Mode of Action studies To determine in vivo Mode of Action (MoA) of the test compounds, the same in vivo models as described under 8.2 were utilized. Tumor-bearing animals were treated for at least 3 days at MTD and also sub-MTD dosages. At study end, tumors were isolated and snap frozen in liquid nitrogen. Total RNA and protein were isolated from tumor samples following standard protocols.
Wnt/3-catenin target gene expression and Axin2 protein abundance were measured by standard qRT-PCR and Western blotting methods (see 7.2 and 7.3).
Table 1 : ICso values for selected examples in cellular HEK293 TOP and FOP assay as well as in TNKS1 and TNKS 2 biochemical assay
HEK293 TOP HEK293 FOP TNKS1 Assay B TNKS2 Assay B
Example
ICso [μΜ] ICso [μΜ] ICso [μΜ] ICso [μΜ]
1 0.0013 14 0.0064 0.0028
2 0.1 3 0.50 0.1 1
3 0.00022 50 0.0057
4 0.00023 50 0.0064
5 0.1 3 34 0.18
6 0.040 50 0.070
7 0.27 50 0.45
8 0.088 50 0.67
9 0.38 50 2.3
10 0.52 50 1 .2
11 0.49 50 0.36
12 2.6 14 2.3
13 0.00082 16 0.0068
14 8.9 50 > 10
15 0.059 50 0.70
16 0.079 50 0.35
17 0.094 50 0.90
18 0.026 17 0.17
19 0.25 50 2.4
20 0.086 50 0.26 HEK293 TOP HEK293 FOP TNKS1 Assay B TNKS2 Assay B
Example
ICso [μΜ] ICso [μΜ] ICso [μΜ] ICso [μΜ]
21 18 50 > 10
22 4.9 5.8 > 10
23 50 50 > 10
24 0.29 50 0.89
25 0.046 50 0.20
26 0.067 50 0.33
27 4.7 50 > 10
28 0.0068 27 0.025
29 1 .7 50 > 10
30 0.0095 50 0.44
31 0.023 50 0.24
32 0.0010 50 0.016
33 0.1 6 50 1 .1
34 0.79 50 3.5
35 0.059 50 0.19
36 0.024 50 0.12
37 0.1 0 50 0.15
38 0.018 50 0.075
39 0.087 50 1 .3
40 0.1 3 50 0.30
41 1 .6 50 2.4
42 1 .1 50 10
43 2.5 50 5.8
44 0.41 50 0.43
45 0.046 50 > 10
46 3.7 50 0.62
47 50 50 > 10
48 0.020 50 0.22
49 0.026 50 0.13
50 0.26 42 0.092
51 12 50 5.1 HEK293 TOP HEK293 FOP TNKS1 Assay B TNKS2 Assay B
Example
ICso [μΜ] ICso [μΜ] ICso [μΜ] ICso [μΜ]
52 0.034 14 0.016
53 0.042 7.8 0.033
54 0.38 16 0.24
55 9.3 50 > 3.3
56 0.00052 18 0.0026
57 0.00059 15 0.0077
58 0.0074 50 0.35
59 0.019 50 0.22
60 0.0023 14 0.14
61 0.012 14 0.013
62 0.041 8.8 0.066
63 0.0085 5.8 0.068
64 0.031 33 0.080
65 0.40 50 2.1
66 1 .6 50 > 10
67 0.1 7 1 .1 0.23
68 0.038 5.5 0.058
69 0.0030 7.1 0.0078
70 1 .7 12 > 10
71 0.0046 9.2 0.020
72 0.00084 30 0.013
73 0.000040 8.2 0.0015
74 0.0079 50 0.031
75 0.0012 10 0.0056
76 0.21 50 0.44
77 0.30 15 2.5
78 1 .3 50 4.0

Claims

1 . A compound of formula (I) :
Figure imgf000222_0001
(I) in which, A represents a ring group selected from:
Figure imgf000222_0002
wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
ring A1
Figure imgf000222_0003
represents a phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms; said phenyl and 6-membered heteroaryl ring being optionally substituted one, two or three times, independently from each other, with R5, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that together with the atoms to which they are attached they jointly form : a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, and c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, wherein said rings are fused with ring A1 , said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5; or, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O, S, S(=0) and S(=0)2;
Figure imgf000223_0001
represents:
- a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
- a 5-membered heterocyclic ring, optionally partially unsaturated, which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two carbon atoms of the heterocyclyl ring are optionally replaced by a heteroatom-containing group selected from (C=0), N, NR20, O, S, S(=0) and S(=0)2,
said 5-membered heteroaryl and 5-membered heterocyclic rings being optionally substituted one, two or three times, independently from each other, with R5 , whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5 ; or whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O, S, S(=0) and S(=0)2;
R4 represents a hydrogen atom,
R5 represents, independently of each other, a group selected from : halogen, hydroxy, Ci-C4-alkyl, C3-C4-cycloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, - N(R14)R15, - C(0)OR13, -C(0)OH, phenyl and 6-membered heteroaryl which contains one or two nitrogen atoms, wherein Ci-C4-alkyl is optionally substituted one, two or three times with a group independently selected from halogen, hydroxy, oxo (C=0), Ci-C3-alkoxy, C3-C6- cycloalkyl, -NH2, -NH(Ci-C3-alkyl) and -N(Ci-C3-alkyl)2;
R5 represents, independently of each other, a group selected from : halogen, hydroxy, Ci-C4-alkyl, C3-C4-cycloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, - N(R14)R15, -C(0)OR13, -C(0)OH, phenyl and 6-membered heteroaryl which contains one or two nitrogen atoms, wherein Ci-C4-alkyl is optionally substituted one, two or three times with a group independently selected from halogen, hydroxy, oxo (C=0), Ci-C3-alkoxy, C3-C6- cycloalkyl, -NH2, -NH(Ci-C3-alkyl) and -N(Ci-C3-alkyl)2;
R6 represents hydrogen, halogen, hydroxy, Ci-C3-alkyl or Ci-C3-alkoxy;
R7 represents hydrogen; or R6, R7 represent, independently of each other, halogen; represents hydrogen, or Ci -C3-alkyl,
R9 and R10 together represent a group selected from:
Figure imgf000225_0001
CH CH2 and H 2 wherein said groups are optionally substituted with one or two groups, which are independently of each other selected from : halogen, Ci -C3-alkyl, Ci -C3-alkoxy, hydroxy, Ci -C3-haloalkyl, and Ci -C3-hydroxyalkyl, wherein * indicates the point of attachment of said group to the rest of the molecule at R9, and
# indicates the point of attachment of said group to the rest of the molecule at R10 ;
R11 represents a group selected from : aryl, and heteroaryl , wherein aryl and heteroaryl groups are optionally substituted with one, two, three or four groups, which are independently of each other selected from :
Ci -Ce-alkyl, Ci -C3-alkoxy, Ci -C3-hydroxyalkyl, C3-C6-cycloalkyl, C3-Ce- cycloalkoxy, Ci -C3-haloalkyl, Ci -C3-haloalkoxy, halogen, cyano, nitro, hydroxy, (Ci -Ce-alkyl)-S-, (Ci -C6-alkyl)-S(=0)-, (Ci -C6-alkyl)-S(=0)2-, -S(=0)(=NR21)R22, - N(R14)R15, R14(R15)N-(Ci -C6-alkyl)-, R14(R15)N-(C2-C6-alkoxy)-, phenyl, phenoxy, -N(R16)C(=0)R17, -C(=0)OH, -C(=0)OR13, and -C(=0)N(R16)2, whereby two substituents of said aryl group, when they are in ortho-position to one another, can be linked to one another in such a way that they jointly form methanediylbisoxy, ethane-1 ,2-diylbisoxy, propane-1 ,3-diyl, or butane-1 ,4-diyl, represents a group selected from :
Ci -Ce-alkyl, C3-C6-cycloalkyl, C2-C6-hydroxyalkyl-, and (Ci -C3-alkoxy)-(C2-C6-alkyl)-, j R15 are independently of each other selected from : hydrogen, Ci -C6-alkyl, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci -C6-alkyl)-,
C2-C6-hydroxyalkyl, (Ci -C3-alkoxy)-(C2-C6-alkyl)-, Ci -C6-haloalkyl, H2N-(C2-C6-alkyl)-, (Ci -C3-alkyl)N(H)(C2-C6-alkyl)-, (Ci -C3-alkyl)2N(C2-C6-alkyl)-, HOC(=0)
Figure imgf000226_0001
or, and R15 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, in which one carbon atom is optionally replaced by a further heteroatom-containing group selected from NR20, O, S, S(=0) and S(=0)2, and in which one additional ring atom is optionally replaced by C(=0), said 4- to 7-membered heterocycloalkyl group being optionally substituted with one, two, three or four groups, which are independently of each other selected from :
Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, C3-C4-cycloalkyl, C3-C - cycloalkoxy, -N(CH3)2, NH2, N(CH3)H, hydroxy, a halogen atom , and cyano, whereby when two substituents are attached to the same ring carbon atom, together with the carbon atom to which they are attached, can be linked to one another in such a way that they jointly form a cyclobutane, cyclopentane, azetidine, pyrrolidine, oxetane, tetrahydrofuran, thietane, tetrahydrothiophene, thietane 1 -oxide, tetrahydrothiophene 1 - oxide, thietane 1 ,1 -dioxide or tetrahydrothiophene 1 ,1 -dioxide group; represents, independently of each other, hydrogen, or Ci-C3-alkyl, represents hydrogen, Ci -Ce-alkyl, Ci -Ce-hydroxyalkyl, C3-C6-cycloalkyl, Ci -Ce-haloalkyl, (Ci-C3-alkoxy)-(Ci-C6-alkyl)-, aryl, or heteroaryl, wherein aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently of each other selected from :
Ci-C3-alkyl, C3-C6-cycloalkyl, Ci-C3-alkoxy, C3-C6-cycloalkoxy, Ci-C3-haloalkyl, Ci-C3-haloalkoxy, halogen, cyano, and hydroxy, represents, independently of each other, a group selected from : hydrogen, Ci-C3-alkyl, Ci -C3-haloalkyl, C3-C4-cycloalkyl,
Figure imgf000226_0002
-C(=0)OCi - C -alkyl and phenyl, represents hydrogen, cyano, (Ci-C3-alkyl)-C(=0)-, or (Ci-C3-haloalkyl)-C(=0)-, represents Ci-C -alkyl, or C3-C -cycloalkyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, with the proviso that:
- when ring A2 is a imidazolyl or a 1 ,3-oxazolyl group, then said group is connected to the rest of the molecule via the carbon atom at position 2 of the imidazolyl or 1 ,3-oxazolyl ring, as shown below:
Figure imgf000227_0001
wherein * indicates the point of attachment of said group with the rest of the molecule;
Figure imgf000227_0002
ring A2 is not a unsubstituted or substituted group, wherein * indicates the point of attachment of said group with the rest of the molecule, wherein said point of attachment is a carbon atom and in which : ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C3-alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms, , and ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms.
2. The compound of formula (I) according to claim 1 , wherein: A represents a group selected from :
Figure imgf000227_0003
wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
Figure imgf000228_0001
represents a phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms; said phenyl and 6-membered heteroaryl ring being optionally substituted one, two or three times, independently from each other, with R5, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, and c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, wherein said rings are fused with ring A1 , said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5; or, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O and S;
Figure imgf000228_0002
represents: - a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
- a 5-membered heterocyclic ring, optionally partially unsaturated, which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two carbon atoms of the heterocyclyl ring are optionally replaced by a heteroatom-containing group selected from (C=0), N, NR20, O and S, said 5-membered heteroaryl and 5-membered heterocyclic rings being optionally substituted one, two or three times, independently from each other, with R5 , whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5 ; or whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O and S;
R4 represents a hydrogen atom,
R5 represents, independently of each other, a group selected from : halogen, hydroxy, Ci-C4-alkyl, C3-C4-cycloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, - N(R14)R15, - C(0)OR13, phenyl and 6-membered heteroaryl which contains one or two nitrogen atoms, wherein Ci-C4-alkyl is optionally substituted one, two or three times with a group independently selected from halogen, hydroxy, oxo (C=0), Ci-C3-alkoxy, C3-C6- cycloalkyl, -NH2, -NH(Ci-C3-alkyl) and -N(Ci-C3-alkyl)2;
R5 represents, independently of each other, a group selected from : halogen, hydroxy, Ci-C4-alkyl, C3-C4-cycloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, - N(R14)R15, -C(0)OR13, phenyl and 6-membered heteroaryl which contains one or two nitrogen atoms, wherein Ci-C4-alkyl is optionally substituted one, two or three times with a group independently selected from halogen, hydroxy, oxo (C=0), Ci-C3-alkoxy, C3-Ce- cycloalkyl, -NH2, -NH(Ci-C3-alkyl) and -N(Ci-C3-alkyl)2;
R6 represents hydrogen; R7 represents hydrogen; or
R8 represents hydrogen, together represent a group selected from:
Figure imgf000230_0001
CH CH2 and CH H H2 wherein said groups are optionally substituted with one or two groups, which are independently of each other selected from :
Ci-C3-alkyl, wherein * indicates the point of attachment of said group to the rest of the molecule at R9, and
# indicates the point of attachment of said group to the rest of the molecule at R1 represents a group selected from : phenyl, and heteroaryl , wherein phenyl and heteroaryl groups are optionally substituted with one, two, three or four groups, which are independently of each other selected from :
Ci-C4-alkyl , Ci-C2-alkoxy, Ci-C3-hydroxyalkyl, C3-C4-cycloalkyl, Ci-C2-haloalkyl, Ci-C2-haloalkoxy, halogen, cyano, and hydroxy, R13 represents a group selected from :
Ci-C3-alkyl, and C3-C4-cycloalkyl,
R14 and R15 are independently of each other selected from : hydrogen, Ci-C3-alkyl, and C3-C4-cycloalkyl, or, R14 and R15 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycloalkyl group, in which one carbon atom is optionally replaced by a further heteroatom-containing group selected from NR20 and O and in which one additional ring atom is optionally replaced by C(=0), said 4- to 6-membered heterocycloalkyl group being optionally substituted with one, two, three or four groups, which are independently of each other selected from :
Ci-alkyl, Ci-haloalkyl, Ci-alkoxy , Ci-haloalkoxy, C3-C4-cycloalkyl, -N(CH3)2, NH2, N(CH3)H, hydroxy, a halogen atom, and cyano,
R20 represents, independently of each other, a group selected from : hydrogen, Ci-C3-alkyl, Ci-C3-haloalkyl, C3-C4-cycloalkyl,
Figure imgf000231_0001
-C(=0)OCi- C -alkyl and phenyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, with the proviso that:
- when ring A2 is a imidazolyl or a 1 ,3-oxazolyl group, then said group is connected to the rest of the molecule via the carbon atom at position 2 of the imidazolyl or 1 ,3-oxazolyl ring, as shown below:
Figure imgf000232_0001
wherein * indicates the point of attachment of said group with the rest of the molecule;
Figure imgf000232_0002
ring A2 is not a unsubstituted or substituted group, wherein * indicates the point of attachment of said group with the rest of the molecule, wherein said point of attachment is a carbon atom and in which : ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C3-alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms,
, and ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms.
3. The compound of formula (I) according to claim 1 or 2, wherein: A represents a ring group selected from:
Figure imgf000232_0003
wherein * indicates the point of attachment of said groups with the rest of the molecule, and wherein said point of attachment is a carbon atom ;
Figure imgf000232_0004
ring A1 represents a phenyl ring or a 6-membered heteroaryl ring which contains one or two nitrogen atoms; said phenyl and 6-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, and c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, wherein said rings are fused with ring A1 , said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, or two times, independently from each other, with R5; or, whereby two substituents R5 when they are in adjacent positions of the ring A1 , can be linked to one another in such a way that they jointly form a ethyleneoxy, or trimethyleneoxy group;
Figure imgf000233_0001
ring A2 represents:
- a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or
- a 5-membered heterocyclic ring, optionally partially unsaturated, which contains one heteroatom-containing group selected from NR20, in which one or two carbon atoms of the heterocyclyl ring are optionally replaced by a heteroatom-containing group selected from (C=0), N, said 5-membered heteroaryl and 5-membered heterocyclic rings being optionally substituted one, two or three times, independently from each other, with R5 , whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that together with the atoms to which they are attached they jointly form: a) a phenyl ring, b) a 6-membered heteroaryl ring which contains one or two nitrogen atoms, or c) a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one ring carbon atoms is optionally further replaced by a nitrogen atom, wherein said rings are fused with ring A2, said phenyl, 6-membered heteroaryl and 5-membered heteroaryl rings being optionally substituted one, two or three times, independently from each other, with R5 ; or whereby two substituents R5 when they are in adjacent positions of the ring A2, can be linked to one another in such a way that they jointly form a methylenedioxy, ethylenedioxy, ethyleneoxy, trimethyleneoxy, trimethylene or tetramethylene group, in which one carbon atom of said groups is optionally replaced by a heteroatom- containing group selected from (C=0), NR20, O and S; represents a hydrogen atom, represents, independently of each other, a group selected from : fluorine, chlorine, bromine, hydroxy, Ci-C4-alkyl, C3-cycloalkyl, Ci-alkoxy, -NH2, - C(0)OR13, wherein Ci-C4-alkyl is optionally substituted one or two times with a group independently selected from fluorine, oxo (C=0), and -NH(Ci-alkyl); represents, independently of each other, a group selected from : fluorine, chlorine, bromine, Ci-alkyl, C3-cycloalkyl, and a 6-membered heteroaryl which contains one nitrogen atom, represents hydrogen; represents hydrogen; R8 represents hydrogen,
R9 and R10 together represent a group selected from:
* # * #
\ CH C /H2 and \ CH CH C /H2 wherein * indicates the point of attachment of said group to the rest of the molecule at
R9, and # indicates the point of attachment of said group to the rest of the molecule at R10 ;
R1 represents a group selected from : phenyl, wherein phenyl groups is optionally substituted with one, two, or three groups, which are independently of each other selected from :
Ci-alkyl, fluorine and chlorine,
R13 represents Ci-C3-alkyl, R20 represents, independently of each other, a group selected from : hydrogen, Ci-C3-alkyl , -C(=0)Ci-alkyl, -C(=0)OC4-alkyl and phenyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, with the proviso that:
- when ring A2 is a imidazolyl or a 1 ,3-oxazolyl group, then said group is connected to the rest of the molecule via the carbon atom at position 2 of the imidazolyl or 1 ,3-oxazolyl ring, as shown below:
Figure imgf000235_0001
wherein * indicates the point of attachment of said group with the rest of the molecule;
Figure imgf000236_0001
- ring A2 is not a unsubstituted or substituted group, wherein * indicates the point of attachment of said group with the rest of the molecule, wherein said point of attachment is a carbon atom and in which : ring A2' represents a 5-membered heteroaryl group which contains one heteroatom-containing group selected from N, NH, and N(Ci-C3-alkyl), in which one or two carbon atoms are optionally further replaced by one or two N atoms,
, and ring A2" represents a phenyl group or a 6-membered heteroaryl group which contains one, two or three nitrogen heteroatoms.
4. The compound according to any one of claims 1 to 3, wherein ring A represents:
Figure imgf000236_0002
wherein * indicates the point of attachment of said groups with the rest of the molecule, and in which : ring G1 represents a phenyl or a 6-membered heteroaryl ring which contains one or two nitrogen atoms, ring H1 represents phenyl or a 6-membered heteroaryl ring which contains one or two nitrogen atoms, with the proviso that when G1 or H1 is phenyl, then the other is a 6-membered heteroaryl group which contains one or two nitrogen atoms, said ring G1 and ring H1 being optionally substituted independently with one or two R5 groups.
5. The com ound according to any one of claims 1 to 3, wherein ring A represents:
Figure imgf000237_0001
wherein * indicates the point of attachment of said groups with the rest of the molecule, and in which : ring F1 represents phenyl or a 6-membered heteroaryl group which contains one or two nitrogen atoms, ring E1 represents a 5-membered heteroaryl ring which contains one heteroatom-containing group selected from N, NR20, O and S, in which one or two ring carbon atoms are optionally further replaced by one or two nitrogen atoms, or said ring E1 and ring F1 being optionally substituted independently with one or two R5 groups.
6. The com ound according to any one of claims 1 to 3, wherein ring A represents:
Figure imgf000237_0002
wherein * indicates the point of attachment of said groups with the rest of the molecule, and in which : ring F1 ' represents phenyl or a 6-membered heteroaryl group which contains one or two nitrogen atoms,
R5a and R5b are linked to one another in such a way that they jointly form a ethyleneoxy, or a trimethyleneoxy group, said ring F1 ' being optionally substituted one time with a group selected from : fluorine, chlorine, bromine, hydroxy, Ci-C4-alkyl, C3-cycloalkyl, Ci-alkoxy, -NH2, and -
C(0)OR13, wherein Ci-C4-alkyl is optionally substituted one or two times with a group independently selected from fluorine, oxo (C=0), and -NH(Ci-alkyl).
7. The compound according to any one of claims 1 to 3, wherein ring A represents:
Figure imgf000238_0001
wherein * indicates the point of attachment of said groups with the rest of the molecule, and in which : ring C1 represents a 5-membered heteroaryl ring (with a nitrogen atom in the position shown), in which one or two ring carbon atoms are optionally further replaced by a heteroatom selected from N, NR20, O and S, ring D1 is a 6-membered heteroaryl ring (with a nitrogen atom in the position shown), in which one ring carbon atom is optionally further replaced by a nitrogen atom, ring D1 ' is a 5-membered heteroaryl ring (with a nitrogen atom in the position shown), in which one ring carbon atom is optionally further replaced by a heteroatom selected from N, NR20, O and S, said rings D1 and D1 ' being optionally substituted independently with one or two R5 groups.
8. The compound according to any one of claims 1 to 3, wherein ring A represents a group selected from: phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl, said groups being optionally substituted independently with one or two R5 groups.
9. The compound according to any one of claims 1 to 3, wherein ring A represents a group selected from: imidazol-2-yl, pyrazolyl, 1 ,3-thiazolyl, and 1 ,2-oxazolyl, said groups being optionally substituted independently with one or two R5 groups.
10. The compound according to any one of claims 1 to 3, which is selected from the group consisting of : N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5- carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-yl]pyridine-2-carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-yl]-1 ,5-naphthyridine-4- carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-yl]-6-methoxy-1 ,5- naphthyridine-4-carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-yl]-4-methylpyridine-2- carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-yl]-1 H-pyrrolo[3,2- b]pyridine-5-carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-yl]pyrazolo[1 ,5-a]pyrimidine- 2-carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-yl]-1 H-benzimidazole-5- carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-yl]pyrazine-2-carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-yl]-3-methyl-1 ,2-oxazole-5- carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-yl]-1 H-benzotriazole-5- carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-yl]-5-oxo-1 -phenyl-4,5- dihydro-1 H-pyrazole-3-carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-yl]quinoline-8-carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-yl]-1 H-1 ,2,4-triazole-5- carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-yl]pyrimidine-4- carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl oxo-2-azaspiro[4.5]dec-8-yl]-1 H-imidazole-2- carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoline-7-carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyrazolo[1 ,5-a]pyridine-2- carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 -methyl-1 H- benzimidazole-5-carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]imidazo[1 ,2-a]pyridine-6- carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-5-methyl-1 ,3-oxazole-4- carboxamide, tert-butyl 3-chloro-2-{[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8- yl]carbamoyl}-5,6-dihydroimidazo[1 ,2-a]pyrazine-7(8H)-carboxylate
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-3-cyclopropyl-6,7- dihydro-5H-pyrrolo[2,1 -c][1 ,2,4]triazole-5-carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-3- cyclopropyl[1 ,2,4]triazolo[4,3-a]pyridine-6-carboxamide,
6-bromo-N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyrazolo[1 ,5- a]pyrimidine-2-carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-4-methoxybenzamide
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]isoquinoline-1 - carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoline-2-carboxamide,
2-amino-N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyridine-3- carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-5,7- dimethylpyrazolo[1 ,5-a]pyrimidine-2-carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-2- carboxamide, N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-2-(pyridin-3-yl)-1 ,3- thiazole-4-carboxamide,
6-chloro-N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyrazine-2- carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 ,2-oxazole-5- carboxamide,
5-bromo-N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-2,3-dihydro-1 - benzofuran-7-carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 ,8-naphthyridine-2- carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 ,3-thiazole-4- carboxamide,
5- chloro-N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyridine-2- carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-5-cyclopropyl-1 H- pyrazole-3-carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]imidazo[2,1 - b][1 ,3]thiazole-6-carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-5-cyclopropyl-1 ,2- oxazole-3-carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-6-hydroxypyridine-2- carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 ,2-oxazole-3- carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 H-indazole-7- carboxamide,
6- bromo-N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoline-8- carboxamide, 1 -acetyl-N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-3-hydroxy-1 H- indazole-6-carboxamide,
6-bromo-N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 -(propan-2-yl)- 1 H-indazole-3-carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-6- (difluoromethyl)pyridine-2-carboxamide,
N-[(trans)-2-(4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5-carboxamide,
N-[(trans)-2-(2-chloro-4-fluoro-5-methylphenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyrimidine-4- carboxamide,
N-[(trans)-2-(2-chloro-4-fluoro-5-methylphenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-3- fluoropyridine-2-carboxamide,
N-[(trans)-2-(2-chloro-4-fluoro-5-methylphenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoline-2- carboxamide,
N-[(trans)-2-(2-chloro-4-fluoro-5-methylphenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-5-fluoro-6- methylpyridine-2-carboxamide,
N-[(trans)-2-(2-chloro-4-fluoro-5-methylphenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 H- pyrazolo[3,4-b]pyridine-5-carboxamide,
N-[(trans)-2-(2-chloro-4-fluoro-5-methylphenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-4,6- dimethylpyrimidine-2-carboxamide,
N-[(trans)-2-(2-chloro-4-fluoro-5-methylphenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5- carboxamide,
N-[(trans)-2-(2-chloro-4,6-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5- carboxamide,
N-[(trans)-2-(3,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5-carboxamide, N-[(trans)-1 -oxo-2-phenyl-2-azaspiro[4.5]dec-8-yl]quinoxaline-5-carboxamide, N-[(trans)-2-(3-chlorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5-carboxamide, N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 ,8-naphthyridine-2- carboxamide,
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-4-methoxyquinoline- 2-carboxamide, methyl6-{[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8- yl]carbamoyl}pyridine-3-carboxylate
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyridazine-3- carboxamide,
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-3-methoxypyrazine- 2-carboxamide,
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-3-methylpyrazine-2- carboxamide,
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-8-hydroxyquinoline- 7-carboxamide,
2-tert-butyl-N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 ,3- benzoxazole-6-carboxamide,
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-1 ,6-naphthyridine-2- carboxamide,
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-4,6- dimethylpyrimidine-2-carboxamide,
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-5-fluoro-6- methylpyridine-2-carboxamide,
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]-2,3-dihydro-1 - benzofuran-7-carboxamide,
N-[(trans)-2-(2-chloro-4,5-difluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5- carboxamide,
N-[(trans)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[5.5]undec-9-yl]quinoxaline-5- carboxamide,
N-[(trans)-2-(2-chlorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5-carboxamide, N-[(trans)-2-(2-chlorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]pyridine-2-carboxamide, and N-[(cis)-2-(2-chloro-4-fluorophenyl)-1 -oxo-2-azaspiro[4.5]dec-8-yl]quinoxaline-5-carboxamide,
2-chloro-4-fluoro-N-[(trans)-1 -oxo-2-(pyridin-2-yl)-2-azaspiro[4.5]decan-8-yl]benzamide or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
1 1 . A compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to any one of claims 1 to 10, for use in the treatment or prophylaxis of a disease.
12. A pharmaceutical composition comprising a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to any one of claims 1 to 10, and a pharmaceutically acceptable diluent or carrier.
13. A pharmaceutical combination comprising - one or more first active ingredients selected from a compound of general formula (I) according to any of claims 1 to 10, and
- one or more second active ingredients selected from chemotherapeutic anti-cancer agents.
14. Use of a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to any one of claims 1 to 10, for the prophylaxis or treatment of a disease.
15. Use of a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to any one of claims 1 to 10, for the preparation of a medicament for the prophylaxis or treatment of a disease.
16. Use according to claim 1 1 , 14 or 15, wherein said disease is a disease of uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, particularly in which the disease of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is a haematological tumour, a solid tumour and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
17. Use of a compound of formula (C) or a salt thereof:
Figure imgf000245_0001
(C)
in which,
R6, R7, R8, R9, R10 and R11 are as defined for the compound of general formula (I) in any one of claims 1 to 10, for the preparation of a compound of general formula (I) according to any one of claims 1 to 10.
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