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WO2020048826A1 - 5-substituted 1-oxa-3,9-diazaspiro[5.5]undecan-2-one compounds - Google Patents

5-substituted 1-oxa-3,9-diazaspiro[5.5]undecan-2-one compounds Download PDF

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Publication number
WO2020048826A1
WO2020048826A1 PCT/EP2019/072874 EP2019072874W WO2020048826A1 WO 2020048826 A1 WO2020048826 A1 WO 2020048826A1 EP 2019072874 W EP2019072874 W EP 2019072874W WO 2020048826 A1 WO2020048826 A1 WO 2020048826A1
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WIPO (PCT)
Prior art keywords
group
alkyl
oxa
undecan
trifluoro
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PCT/EP2019/072874
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French (fr)
Inventor
Keith Graham
Tobias Heinrich
Nuria AIGUABELLA FONT
Martin Lange
Benjamin Bader
Stefan Prechtl
Philip Lienau
Katrin NOWAK-REPPEL
Lisette POTZE
Original Assignee
Bayer Aktiengesellschaft
Bayer Pharma Aktiengesellschaft
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Publication of WO2020048826A1 publication Critical patent/WO2020048826A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention covers 5-substituted 1 -oxa-3,9-diazaspiro[5.5]undecan-2-one compounds of general formula (I) and general formula (l-a) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.
  • the present invention covers 5-substituted 1 -oxa-3,9-diazaspiro[5.5]undecan-2-one compounds of general formula (I) and general formula (l-a) which inhibit the activity of geranylgeranyltransferase I (GGTase I), leading to inactivation of downstream YAP1 and/or TAZ and blockade of cancer cell proliferation.
  • Rho GTPases belong to the larger family of Ras GTPases, consisting of over 50 proteins with related characteristics. Rho GTPases are master regulators for signal transduction from the extracellular matrix to the cytoplasm and nucleus. They are involved in the regulation of cell proliferation, survival and differentiation by modulating cytoskeletal structure and properties of cell adhesion. Abberant Rho GTPase activity is observed in human cancer. Members of the pathway are therefore potential therapeutic targets. Activity of Rho GTPases is regulated by protein prenylation (farnesylation and geranylgeranylation) of the CAAX box motif. Prenylated Rho GTPases are primed for membrane localization and subsequent activon.
  • GGTase II is selective for Rab proteins and shows a different Mode of Action compared to GGTase I and FTase.
  • GGTase I inhibition reduces tumor formation of lung cancer as well as myeloproliferative disease and that the anti-tumor effect depended on the inhibition of protein geranyl-geranylation Sjogren AKM et al, J. Clin. Invest. 1 17:1294-1304 (2007).
  • Rho GTPases A recently discovered downstream target of Rho GTPases are YAP1 and TAZ (gene name WWTR1 ). It has been shown that geranylgeranylated Rho GTPases such as RhoA activate downstream YAP1/TAZ in breast cancer (Mi W et al Oncogene 2015). YAP1 and TAZ (gene name WWTR1 ) are two highly related transcriptional coactivators that are frequently aberrantly activated in human cancers (Zanconato F, Cancer Cell. 2016 783-803). YAP1/TAZ are important for the activation of several hallmarks of cancer (Harvey KF, Nat Rev Cancer. 2013 246-57).
  • YAP1/TAZ shuttle between the cytoplasm and the cells ' nucleus, where they interact with TEAD transcription factors1 -4 (TEAD1 -4) to activate target genes important for cell survival and cell cycle progression (S. Piccolo Physiol. Rev., 2014 1287-1312. Zanconato F, et al. Nat Cell Biol. 2015 1218-27).
  • Abberant YAP1/TAZ expression induces cell proliferation (Zhao B Genes Dev., 2007, 2747-2761 ).
  • high levels of YAP1/TAZ can overcome the induction of programmed cell death and apoptosis by upregulation of anti- apoptotic proteins (Rosenbluh J. Cell, 2012. 1457-1473).
  • YAP1/TAZ also confers Cancer Stem Cells (CSC) traits and are required for CSC expansion within tumors (Cordenonsi M. Cell, 201 1 , 759-772). In line with this, the ability to initiate tumor formation and induce metastasis depends on YAP1/TAZ (Bartucci M, Oncogene, 2015, 681-690 Lau AN EMBO J. 2014, 468-481 ). Blockade of YAP1/TAZ function by RNAi-mediated knockdown reduces the viability of several cancer cells in vitro (Pan J Oncol. Rep., 2012 179-185).
  • CSC Cancer Stem Cells
  • YAP1/TAZ may represent promising targets for therapeutic intervention of various diseases with uncontrolled cell proliferation, including cancer.
  • the present invention relates to chemical compounds that have been found to
  • GGTase I inhibitors have been developed (reviewed in Ullah N et al Current Cancer Drug Targets 2016, 16, 563-571 ), but no GGTase I inhibitor is currently approved for treatment of patients.
  • WO-03017939 WO-2010088457.
  • GGTI-2418 US 2012/0035184 A1 .ln cancer cell lines, GGTase I inhibitors cause cell cycle arrest in G0/G1 phase via blockade of cyclin- dependent kinases downstream of Rho Sun J et al, J. Biol. Chem., 1999, 274, 6930-; Vogt A et al, J. Biol. Chem., 1997, 272, 27224-27229.
  • Cyclic peptides inhibiting the YAP1 -TEAD protein-protein interaction have been described in Zhang Z. et al., ACS Med. Chem. Lett., 2014, 5, 993-998.
  • a peptide mimicking VGLL4 function has been proposed to act as a YAP1 antagonist in preclinical models of gastric cancer in Jiao S, et al., Cancer Cell, 2014, 25, 166- 180.
  • a number of publications report inhibitors of YAP1 , for example, the Tankyrase inhibitor XAV939 (Wang et al., Cell Reports, 2015, 13, 524-532) is reported to target YAP1 for cancer treatment.
  • Peptide 17 has been reported to inhibit the YAP1 -TEAD protein-protein interaction (Zhang Z. et al., ACS Med. Chem. Lett., 2014, 5, 993-998 and Zhou et al., FASEB J., 2015, 29, 724-732).
  • Verteporfin has also reported to be a YAP1 inhibitor (Szeto et al., J. Am. Soc. Nephrol., 2016, 27, 31 17-3128 and Liu-Chittenden et al., Gens Dev., 2012, 26, 1300-1305).
  • Latrunculin A, Blebbistatin, Y27632 and ML7 have been reported to inhibit YAP1 nuclear localization as well as YAP1 and TEAD activity (see Nature Reviews Drug Discovery, 2014, 13, 63-79).
  • WO20191 18973A1 describes 1 -(piperidinocarbonylmethyl)-2-oxopiperazine derivatives for treating cancer.
  • W02005075484 A2 discloses 1 -oxa-3,8-diazaspiro[4.5]decan-2-one and 1 -oxa-3,9-diazaspiro- [5.5]undecan-2-one compounds, which modulate the chemokine CCR5 receptors.
  • W02003057698 A2 discloses spiroazacyclic compounds as monoamine receptor modulators.
  • W02002092604 A1 discloses 1 -oxa-3,9-diazaspiro[5.5]undecan-2-one derivatives and its use as antagonists of the neurokinin receptor.
  • W020051 10992 relates to amido compounds as modulators of 1 1 -b hydroxyl steroid dehydrogenase type 1 (11 b HSD1 ) and/or mineralocorticoid receptor (MR).
  • 1 1 -b hydroxyl steroid dehydrogenase type 1 11 b HSD1
  • MR mineralocorticoid receptor
  • the compounds of the present invention have surprisingly been found to effectively inhibit the activity of geranylgeranyltransferase I (GGTase I), leading to inactivation of downstream YAP1 and/or TAZ and blockade of cancer cell proliferation, and may therefore be used for the treatment or prophylaxis of hyperproliferative disorders, such as cancer, for example.
  • GTTase I geranylgeranyltransferase I
  • R 1 represents a group wherein X 2 represents a hydrogen atom or a halogen atom or a substituent selected from
  • Ci -Ce-alkyl C2-C 6 -alkenyl, C2-C 6 -alkinyl, C3-C 6 -cycloalkyl,
  • (C 4 -C 6 -cycloalkenyl) -(Ci-C 3 -alkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C2-alkyl Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano and hydroxy
  • Ci-C2-alkyl Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano and hydroxy
  • -(Ci-C 4 -alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • X 4 represents a hydrogen atom or a halogen atom or a substituent selected from Ci-C 2 -alkyl and Ci-C 2 -haloalkyl, or,
  • X 5 represents a hydrogen atom or a halogen atom or a substituent selected from Ci -C 2 -alkyl and Ci-C 2 -alkoxy
  • X 6 represents a hydrogen atom or a halogen atom or a substituent selected from Ci -C 2 -alkyl and Ci-C 2 -alkoxy
  • R 2 represents a group selected from phenyl, naphthyl and 5- or 6-membered heteroaryl, which phenyl, naphthyl and 5- or 6-membered heteroaryl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
  • Ci -Ce-alkyl C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl, Cs-Ce-cycloalkyl, C4-C6-cycloalkenyl, Ci -C 6 -hydroxyalkyl, Ci -C 6 -haloalkyl, Ci -C 6 -alkoxy, Ci -C 6 -haloalkoxy,
  • 5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of said
  • 5- to 7-membered heterocycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • C3-C 6 -cycloalkyl group and C -Ce-cycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl, Ci-C 2 -haloalkyl, Ci-C 2 -alkoxy, cyano, hydroxy and oxo and
  • C 2 -C 6 -alkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C 2 -alkoxy group,
  • phenyl group and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl, Ci-C 2 -haloalkyl, Ci-C 2 -alkoxy, C3-C4-cycloalkyl, cyano, hydroxy and -N(R 5 )(R 6 ),
  • R 3 represents a hydrogen atom, a halogen atom, or a group selected from
  • -(Ci-C 2 -alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group
  • (4- to 7-membered heterocycloalkyl) part of said -(Ci-C 2 -alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • R 4 represents a hydrogen atom, or a group selected from
  • Ci-C 4 -alkyl C 2 -C 4 -alkenyl, C 2 -C 4 -alkinyl, C3-C 6 -cycloalkyl, Ci-C 4 -hydroxyalkyl,
  • Ci-C 4 -haloalkyl -(Ci-C 2 -alkyl)-N(R 5 )(R 6 ), C 4 -C 7 -heterocycloalkyl,
  • -(Ci-C 2 -alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group
  • -(Ci-C 2 -alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • cycloalkyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C 2 -alkyl Ci-C 2 -haloalkyl, Ci-C 2 -alkoxy, cyano, hydroxy and -N(R 5 )(R 6 ), or
  • R 3 and R 4 together with the carbon atom to which they are attached represent a
  • R 5 and R 6 represent, independently from each occurrence, a hydrogen atom or a group
  • R 5 and R 6 together with the nitrogen to which they are attached represent a
  • R 7 represents a hydrogen atom or a Ci-C 4 alkyl group
  • R 8 represents a hydrogen atom or a group selected from
  • R 9 represents a hydrogen atom or a group selected from
  • Ci-C 6 alkyl C 2 -C 6 haloalkyl, 0 3 -0 6 cycloalkyl,
  • cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
  • R 10 represents a group selected from
  • R 11 represents a group selected from
  • cycloalkyl group is optionally substituted one or two or times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C 2 -alkyl Ci-C 2 -haloalkyl, Ci-C 2 -alkoxy, cyano, hydroxy and oxo, and
  • phenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl, Ci-C 2 -haloalkyl, C3-C 4 -cycloalkyl, Ci-C 2 -alkoxy, cyano, hydroxy, 4- to 7-membered heterocycloalkyl and -N(R 5 )(R 6 ), and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • substituted means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.
  • optionally substituted means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, it is possible for the number of optional substituents, when present, to be 1 , 2, 3 or 4, in particular 1 , 2 or 3.
  • an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond.
  • ring substituent means a substituent attached to an aromatic or nonaromatic ring which replaces an available hydrogen atom on the ring.
  • halogen atom means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.
  • Ci-Ce-alkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, fert-butyl, pentyl, isopentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl,
  • said group has 1 , 2, 3 or 4 carbon atoms (“Ci-C 4 -alkyl”), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or fert-butyl group, more particularly 1 , 2 or 3 carbon atoms (“Ci-C3-alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group, more particularly 1 or 2 carbon atoms (“Ci-C2-alkyl”), e.g. a methyl or ethyl group.
  • Ci-C 4 -alkyl e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or fert-butyl group, more particularly 1 , 2 or 3 carbon atoms (“Ci-C3-alkyl
  • Ci-Ce-hydroxyalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term“Ci-Ce-alkyl” is defined supra , and in which 1 or 2 hydrogen atoms are replaced with a hydroxy group, e.g. a hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1 -hydroxypropyl, 1 -hydroxypropan-2-yl,
  • Ci-Ce-haloalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term“Ci-Ce-alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom.
  • said halogen atom is a fluorine atom.
  • Ci-C 6 -haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1 ,3-difluoropropan-2-yl.
  • the term“Ci-C 6 -alkoxy” means a linear or branched, saturated, monovalent group of formula (Ci-C 6 -alkyi)-0-, in which the term“Ci-C 6 -alkyl” is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, ferf-butoxy, pentyloxy, isopentyloxy or n-hexyloxy group, or an isomer thereof.
  • Ci-C 6 -haloalkoxy means a linear or branched, saturated, monovalent Ci-C 6 -alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom.
  • said halogen atom is a fluorine atom.
  • Said Ci-C 6 -haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.
  • C2-C 6 -alkenyl means a linear or branched, monovalent hydrocarbon group, which contains one or two double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, it being understood that in the case in which said alkenyl group contains two double bonds, then it is possible for said double bonds to be conjugated with each other, or to form an allene.
  • Said alkenyl group is, for example, an ethenyl (or“vinyl”), prop-2-en-1 -yl (or“allyl”), prop-1 -en-1 -yl, but-3-enyl, but-2-enyl, but-1 -enyl, pent-4-enyl, pent-3-enyl, pent-2-enyl, pent-1 -enyl, hex-5-enyl, hex-4-enyl, hex-3-enyl, hex-2-enyl, hex-1 -enyl, prop-1 -en-2-yl (or“isopropenyl”),
  • C2-C6-alkynyl means a linear or branched, monovalent hydrocarbon group which contains one triple bond, and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly 2, 3 Oder 4 carbon atoms (“C 2 -C4-alkynyl”).
  • Said C2-C 6 -alkynyl group is, for example, ethynyl, prop-1 -ynyl, prop-2-ynyl (or “propargyl”), but-1 -ynyl, but-2-ynyl, but-3-ynyl, pent-1 -ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1 -ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1 -methylprop-2-ynyl, 2-methylbut-3-ynyl, 1 -methylbut-3-ynyl, 1 -methylbut-2-ynyl, 3-methylbut-1 -ynyl, 1 -ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-
  • Cs-Ce-cycloalkyl means a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms.
  • Said C3-C 6 -cycloalkyl group is for example a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • said group has 3 or 4 carbon atoms (“C3-C4-cycloalkyl”), e.g. a cyclopropyl or cyclobutyl group.
  • Cs-Cs-cycloalkyl means a saturated, monovalent, monocyclic hydrocarbon ring which contains 5, 6, 7 or 8 carbon atoms.
  • Said C3-C 5 -cycloalkyl group is for example a cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
  • C 4 -C 6 -cycloalkenyl means a monovalent, monocyclic hydrocarbon ring which contains one double bond and 4, 5 or 6 carbon atoms.
  • Said C 4 -C 6 -cycloalkenyl group is for example a cyclobutenyl, cyclopentenyl or cyclohexenyl group.
  • Cs-Ce-cycloalkyloxy means a saturated, monovalent group of formula (C 3 -C 6 -cycloalkyl)-0-, in which the term “Cs-Ce-cycloalkyl” is as defined supra , e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy group.
  • the term“4- to 7-membered heterocycloalkyl” means a monocyclic, saturated heterocycle with 4, 5, 6 or 7 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S.
  • Said heterocycloalkyl group can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1 ,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1 ,1 -dioxidothiolanyl, 1 ,2-oxazolidinyl, 1 ,3-oxazolidinyl or 1 ,3-thiazolidinyl, for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1 ,3-dioxanyl
  • (4- to 7-membered heterocycloalkyl)oxy means a monocyclic, saturated heterocycle of formula (4- to 7-membered heterocycloalkyl)-0-, in which the term “4- to 7-membered heterocycloalkyl” is as defined supra.
  • heterocycloalkenyl means a monocyclic, unsaturated, non aromatic heterocycle with 5, 6 or 7 ring atoms in total, which contains one or two double bonds and one or two identical or different ring heteroatoms from the series N, O and S.
  • Said heterocycloalkenyl group is, for example, 4/-/-pyranyl, 2/-/-pyranyl, 2,5-dihydro-1 /-/-pyrrolyl, [1 ,3]dioxolyl, 4/-/-[1 ,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothio- phenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl or 4/-/-[1 ,4]thiazinyl.
  • nitrogen containing 4- to 7-membered heterocycloalkyl group means a monocyclic, saturated heterocycle with 4, 5, 6 or 7 ring atoms in total, which contains one ring nitrogen atom and optionally one further ring heteroatom from the series N, O and S.
  • Said nitrogen containing 4- to 7-membered heterocycloalkyl group can be a 4-membered ring, such as azetidinyl, for example; or a 5-membered ring, such as pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1 ,2-oxazolidinyl, 1 ,3-oxazolidinyl or 1 ,3-thiazolidinyl, for example; or a 6-membered ring, such as piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or 1 ,2-oxazinanyl, for example, or a 7-membered ring, such as azepanyl, 1 ,4-diazepanyl or 1 ,4-oxazepanyl, for example.
  • a 4-membered ring such as azetidinyl, for example
  • 5- or 6-membered heteroaryl means a monovalent aromatic ring having 5 or 6 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S.
  • Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl.
  • a 5-membered heteroaryl group such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl
  • (5- or 6-membered heteroaryl)oxy means a monovalent aromatic ring having 5 or 6 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S of formula (5- or 6-membered heteroaryi)-0-, in which the term“5- or 6-membered heteroaryl” is as defined supra , and which is bound via a ring carbon atom.
  • heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g .: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule.
  • pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
  • Ci-Ce-alkyl in the context of the definition of “Ci-Ce-alkyl”, “Ci-Ce-haloalkyl”, “Ci-Ce-hydroxyalkyl”, “Ci-C 6 -alkoxy” or “Ci-C 6 -haloalkoxy” means an alkyl, haloalkyl, hydroxyalkyl, alkoxy or haloalkoxy group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • C2-C 6 as used in the present text, e.g. in the context of the definition of “C2-C 6 -alkenyl” or“C2-C 6 -alkinyl” means an alkenyl or alkinyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5 or 6 carbon atoms.
  • C3-C6 as used in the present text, e.g. in the context of the definition of “Cs-Ce-cycloalkyl” or“C3-C 6 -cycloalkyloxy”, means a cycloalkyl or cycloalkyloxy group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms.
  • C 4 -C 6 means a cycloalkenyl group having a finite number of carbon atoms of 4 to 6, i.e. 4, 5 or 6 carbon atoms.
  • Cs-Cs as used in the present text, e.g. in the context of the definition of “Cs-Cs-cycloalkyl”, means a cycloalkyl group having a finite number of carbon atoms of 5 to 8, i.e. 5, 6, 7 or 8 carbon atoms.
  • Ci-Ce encompasses Ci , C2, C3, C4, C5, Ce, C1-C6, C1-C5, C1-C4, C1-C3, C1 -C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;
  • C2-C6 encompasses C2, C3, C4, C5, Ce, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;
  • C1-C4 encompasses Ci , C2, C3, C4, C1-C4, C1 -C3, C1-C2, C2-C 4, C2-C3, and C3-C4;
  • C 2 -C 4 encompasses C 2 , C 3 , C 4 , C 2 -C 4 , C 2 -C3, and C 3 -C 4 ;
  • C 3 -C 6 encompasses C 3 , C 4 , C 5 , C 6 , C 3 -Ce, C3-C5, C 3 -C 4 , C 4 -C 6, C4-C5, and C5-C6.
  • C3-C8 encompasses C3, C4, C5, Ce, C7, Cs, C3-C8, C3-C7, C; i-C6, C3-C5, C3-C4, C4-C8, C4-C7, C4-C6, C4-C5, Cs-Cs, C5-C7, C5-C6, Cs-Cs, Ce-C7 and C7-C8.
  • Cs-Cs encompasses C5, Ce, C7, Cs, Cs-Cs, C5-C7, C5-C6, Ce-Cs, C6-C7 and C7-C8.
  • the term“leaving group” means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons.
  • a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)- sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropy
  • the invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I) and general formula (l-a), particularly deuterium-containing compounds of general formula (I) and general formula (l-a).
  • Isotopic variant of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
  • Isotopic variant of the compound of general formula (I) and general formula (l-a) is defined as a compound of general formula (I) or general formula (l-a) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
  • the expression“unnatural proportion” means a proportion of such isotope which is higher than its natural abundance.
  • the natural abundances of isotopes to be applied in this context are described in“Isotopic Compositions of the Elements 1997”, Pure Appl. Chem., 70(1 ), 217-235, 1998.
  • isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 1 1 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, 1 , 124
  • isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 1 1 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, 1 , 124
  • the isotopic variant(s) of the compounds of general formula (I) or general formula (l-a) preferably contain deuterium (“deuterium-containing compounds of general formula (I) or general formula (l-a)”).
  • deuterium-containing compounds of general formula (I) or general formula (l-a) are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability.
  • Positron emitting isotopes such as 18 F or 1 1 C may be incorporated into a compound of general formula (I) or general formula (l-a). These isotopic variants of the compounds of general formula (I) or (l-a) are useful for in vivo imaging applications.
  • Deuterium-containing and 13 C-containing compounds of general formula (I) or general formula (l-a) can be used in mass spectrometry analyses in the context of preclinical or clinical studies.
  • Isotopic variants of the compounds of general formula (I) and general formula (l-a) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent.
  • a reagent for an isotopic variant of said reagent preferably for a deuterium-containing reagent.
  • deuterium from D 2 0 can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds.
  • Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic bonds and acetylenic bonds is a direct route for incorporation of deuterium.
  • Metal catalysts i.e. Pd, Pt, and Rh
  • deuterium gas can be used to directly exchange deuterium for hydrogen in functional groups containing hydrocarbons.
  • deuterated reagents and synthetic building blocks are commercially available from companies such as for example C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.
  • deuterium-containing compound of general formula (I) or general formula (l-a) is defined as a compound of general formula (I) or general formula (l-a), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general formula (I) or general formula (l-a) is higher than the natural abundance of deuterium, which is about 0.015%.
  • the abundance of deuterium at each deuterated position of the compound of general formula (I) or general formula (l-a) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s).
  • the selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) or general formula (l-a) may alter the physicochemical properties (such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271 ]) and/or the metabolic profile of the molecule and may result in changes in the ratio of parent compound to metabolites or in the amounts of metabolites formed.
  • physicochemical properties such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am
  • a compound of general formula (I) or general formula (l-a) may have multiple potential sites of attack for metabolism.
  • deuterium-containing compounds of general formula (I) or general formula (l-a) having a certain pattern of one or more deuterium-hydrogen exchange(s) can be selected.
  • the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) or general formula (l-a) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I) or general formula (l-a), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P450.
  • the present invention concerns a deuterium-containing compound of general formula (I) or general formula (l-a) having 1 , 2, 3 or 4 deuterium atoms, particularly with 1 , 2 or 3 deuterium atoms.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds of the present invention of the structural formula (I) optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. Preferred isomers 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 the present 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 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.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • 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.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g ., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable.
  • Enzymatic separations, with or without derivatisation are also useful.
  • the optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • the present invention includes all possible diastereomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, in any ratio.
  • Isolation of a single stereoisomer, e.g. a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • the compounds of the present invention may exist as tautomers.
  • the compounds of the present invention contain a cyclohexanone moiety and can exist as a keton, or an enol, or even a mixture in any amount of the two tautomers, namely:
  • keton enol 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 atom of the compounds of the present invention is oxidised.
  • the present invention includes all such possible N-oxides.
  • the present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or 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, dimethylsulfoxide, tetrahydrofuran, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to 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.
  • the compounds of the present invention may exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to 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, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
  • “pharmaceutically acceptable salt” refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • 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, or“mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, 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, nico
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt
  • acid addition salts of the claimed compounds to 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 present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • the term“in vivo hydrolysable ester” means 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. pivaloyloxymethyl, phthalidyl esters, C 3 -C 8 cycloalkyloxy-carbonyloxy-Ci-C 6 alkyl esters, e.g. 1 - cyclohexyloxycarbonyloxyethyl ; 1 ,3-dioxolen-2-onylmethyl esters, e.g.
  • Ci-C 6 -alkoxycarbonyloxyethyl esters e.g. 1 -methoxycarbonyloxyethyl, it being possible for said esters to be formed at any carboxy group in the compounds of the present 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 a-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 a-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • a-acyloxyalkyl ethers include acetoxym ethoxy and 2,2- dimethylpropionyloxymethoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted alkanoyl, benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), N,N-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 also includes prodrugs of the compounds according to the invention.
  • prodrugs here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.
  • the present invention covers compounds of general formula (I), supra , in which:
  • R 1 represents a group wherein X 2 represents a hydrogen atom or a halogen atom or a substituent selected from Ci-Ce-alkyl, Cs-Ce-cycloalkyl, C4-C6-cycloalkenyl, Ci-Ce-alkoxy,
  • Ci-C 6 -haloalkoxy (Ci-C6-alkoxy)-(C 2 -C4-alkoxy)-,
  • Cs-Ce-cycloalkyl group and C 4 -C 6 -cycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C2-alkyl cyano and hydroxy
  • (4- to 7-membered heterocycloalkyl)oxy group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C 2 -alkyl Ci-C 2 -alkyl, cyano and hydroxy
  • 5- or 6-membered heteroaryl group and (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)oxy- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C2-alkyl, cyano and hydroxy wherein X 3 represents a hydrogen atom or a halogen atom or a Ci-C 2 -alkyl substituent, wherein X 4 represents a hydrogen atom or a halogen atom or a Ci-C 2 -alkyl substituent, wherein X 5 represents a hydrogen atom or a halogen atom or a Ci-C 2 -alkyl substituent, wherein X 6 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent,
  • R 2 represents a group selected from phenyl, naphthyl and 5- or 6-membered heteroaryl, which phenyl, naphthyl and 5- or 6-membered heteroaryl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
  • R 3 represents a hydrogen atom, a halogen atom, or a group selected from
  • R 4 represents a hydrogen atom or Ci-C 4 -haloalkyl group
  • R 3 and R 4 together with the carbon atom to which they are attached represent a
  • cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
  • R 5 and R 6 represent, independently from each occurrence, a hydrogen atom or a group
  • Ci-C4-alkyl C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl and
  • R 5 and R 6 together with the nitrogen to which they are attached represent a
  • R 7 represents a hydrogen atom or a C 1 -C 4 alkyl group
  • R 8 represents a hydrogen atom or a group selected from
  • the present invention covers compounds of general formula (I), supra , in which :
  • R 1 represents a group wherein X 2 represents a hydrogen atom or a halogen atom or a substituent selected from
  • phenyl part of said phenyl-(Ci -C 2 -alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci -C 2 -alkyl, cyano and hydroxy wherein X 3 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X 4 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X 5 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X 6 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent,
  • R 2 represents a group selected from phenyl and naphthyl
  • phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a Ci-C 4 -alkyl group,
  • R 3 represents a group selected from Ci-C 4 -alkoxy and hydroxy
  • R 4 represents a Ci-C 4 -haloalkyl group
  • R 3 and R 4 together with the carbon atom to which they are attached represent a
  • cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
  • the present invention covers compounds of general formula (l-a):
  • X 2 represents a hydrogen atom or a halogen atom or a substituent selected from
  • phenyl part of said phenyl-(Ci-C 2 -alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C 2 -alkyl, cyano and hydroxy wherein X 3 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X 4 represents a hydrogen atom or a chlorine atom or a fluorine atomor a methyl substituent, wherein X 5 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X 6 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent,
  • R 2 represents a group selected from phenyl and naphthyl
  • phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a Ci -C4-alkyl group,
  • R 3 represents a group selected from
  • R 4 represents a Ci-C4-haloalkyl group
  • R 3 and R 4 together with the carbon atom to which they are attached represent a
  • cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
  • the present invention covers compounds of general formula (l-a), supra , in which:
  • R 1 represents a group wherein X 2 represents a hydrogen atom or a substituent selected from methyl, methoxy and benzyloxy, wherein X 3 represents a hydrogen atom, wherein X 4 represents a hydrogen atom or a fluorine atom, wherein X 5 represents a hydrogen atom, wherein X 6 represents a hydrogen atom,
  • R 2 represents a group selected from phenyl and naphthyl
  • phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a bromine atom and a chlorine atom or a methyl group,
  • R 3 represents a group selected from methoxy and hydroxy
  • R 4 represents a trifluoromethyl group
  • R 3 and R 4 together with the carbon atom to which they are attached represent a group
  • the present invention covers compounds of general formula (l-a), supra , in which:
  • R 1 represents a group selected from
  • R 2 represents a group selected from
  • phenyl 3-bromophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dihydro-1 H-inden-5-yl and 1 -naphthyl,
  • R 3 represents a group selected from
  • R 4 represents a trifluoromethyl group
  • R 3 and R 4 together with the carbon atom to which they are attached represent a group
  • the present invention covers compounds of general formula (I), supra , which are selected from the group consisting of:
  • the present invention covers compounds of general formula (l-a), supra , which are selected from the group consisting of:
  • the present invention covers compounds of formula (I), supra , in which:
  • R 1 represents a group wherein X 2 represents a hydrogen atom or a halogen atom or a substituent selected from
  • phenyl part of said phenyl-(Ci-C 2 -alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C 2 -alkyl, cyano and hydroxy wherein X 3 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X 4 represents a hydrogen atom or a chlorine atom or a fluorine atomor a methyl substituent, wherein X 5 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X 6 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent,
  • R 2 represents a group selected from phenyl and naphthyl
  • phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a Ci-C 4 -alkyl group,
  • R 3 represents a group selected from
  • R 4 represents a Ci-C 4 -haloalkyl group
  • R 3 and R 4 together with the carbon atom to which they are attached represent a
  • cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
  • the present invention covers compounds of formula (I), supra , in which:
  • R 1 represents a group wherein X 2 represents a hydrogen atom or a substituent selected from methyl, methoxy and benzyloxy, wherein X 3 represents a hydrogen atom, wherein X 4 represents a hydrogen atom or a fluorine atom, wherein X 5 represents a hydrogen atom, wherein X 6 represents a hydrogen atom, R 2 represents a group selected from phenyl and naphthyl,
  • phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a bromine atom and a chlorine atom or a methyl group,
  • R 3 represents a group selected from methoxy and hydroxy
  • R 4 represents a trifluoromethyl group
  • R 3 and R 4 together with the carbon atom to which they are attached represent a group
  • cyclopentyl and cyclohexyl selected from cyclopentyl and cyclohexyl, and stereoisomers, hydrates, and solvates thereof, and mixtures of same.
  • the present invention covers compounds of formula (I), supra , in which:
  • R 1 represents a group selected from
  • R 2 represents a group selected from
  • phenyl 3-bromophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dihydro-1 H-inden-5-yl and 1 -naphthyl,
  • R 3 represents a group selected from
  • R 4 represents a trifluoromethyl group
  • R 3 and R 4 together with the carbon atom to which they are attached represent a group
  • the present invention covers compounds of formula (l-a), supra , in which:
  • R 1 represents a group wherein X 2 represents a hydrogen atom or a halogen atom or a substituent selected from
  • Ci -Ce-alkyl C2-C6-alkenyl, C2-C6-alkinyl, Cs-Ce-cycloalkyl,
  • (C 4 -C 6 -cycloalkenyl) -(Ci-C 3 -alkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C 2 -alkyl Ci-C 2 -haloalkyl, Ci-C 2 -alkoxy, cyano and hydroxy, and
  • Ci-C 2 -alkyl Ci-C 2 -haloalkyl, Ci-C 2 -alkoxy, cyano and hydroxy, and
  • -(Ci-C 4 -alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • (5- or 6-membered heteroaryl)oxy-(C 2 -C 3 -alkoxy) and (5- or 6-membered heteroaryljoxy- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • X 4 represents a hydrogen atom or a halogen atom or a substituent selected from Ci-C 2 -alkyl and Ci-C 2 -haloalkyl, or,
  • R 2 represents a group selected from phenyl, naphthyl and 5- or 6-membered heteroaryl, which phenyl, naphthyl and 5- or 6-membered heteroaryl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
  • 5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of said
  • 5- to 7-membered heterocycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Cs-Ce-cycloalkyl group and C4-C6-cycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl, Ci-C 2 -haloalkyl, Ci-C 2 -alkoxy, cyano, hydroxy and oxo and
  • phenyl group and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl, Ci-C 2 -haloalkyl, Ci-C 2 -alkoxy, C3-C 4 -cycloalkyl, cyano, hydroxy and -N(R 5 )(R 6 ),
  • R 3 represents a hydrogen atom, a halogen atom, or a group selected from
  • Ci-C 4 -haloalkyl (Ci-C 2 -haloalkoxy)-(Ci-C 2 -alkyl)-, Ci-C 4 -alkoxy, Ci-C 4 -haloalkoxy, C3-C 6 -cycloalkyloxy, hydroxy, cyano, -N(R 5 )(R 6 ), -(Ci-C 2 -alkyl)-N(R 5 )(R 6 ),
  • -(Ci-C 2 -alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group
  • -(Ci-C 2 -alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • R 4 represents a hydrogen atom, or a group selected from
  • Ci-C 4 -alkyl C 2 -C 4 -alkenyl, C 2 -C 4 -alkinyl, C3-C 6 -cycloalkyl, Ci-C 4 -hydroxyalkyl,
  • Ci-C 4 -haloalkyl -(Ci-C 2 -alkyl)-N(R 5 )(R 6 ), C 4 -C 7 -heterocycloalkyl,
  • -(Ci-C 2 -alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group
  • -(Ci-C 2 -alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • cycloalkyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C 2 -alkyl Ci-C 2 -haloalkyl, Ci-C 2 -alkoxy, cyano, hydroxy and -N(R 5 )(R 6 ), or
  • R 3 and R 4 together with the carbon atom to which they are attached represent a
  • cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C 2 -alkyl, Ci-C 2 -haloalkyl, Ci-C 2 -alkoxy, cyano, hydroxy and oxo, R 5 and R 6 represent, independently from each occurrence, a hydrogen atom or a group selected from
  • R 5 and R 6 together with the nitrogen to which they are attached represent a
  • R 7 represents a hydrogen atom or a Ci-C 4 alkyl group
  • R 8 represents a hydrogen atom or a group selected from
  • R 9 represents a hydrogen atom or a group selected from
  • cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
  • R 1 0 represents a group selected from
  • Ci-C 4 -alkyl, Ci-C 4 -haloalkyl and C3-C6 cycloalkyl are examples of substituents for the following properties:
  • R 1 1 represents a group selected from
  • cycloalkyl group is optionally substituted one or two or times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C 2 -alkyl Ci-C 2 -haloalkyl, Ci-C 2 -alkoxy, cyano, hydroxy and oxo, and
  • phenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl, Ci -C 2 -haloalkyl, C3-C 4 -cycloalkyl, Ci-C 2 -alkoxy, cyano, hydroxy, 4- to 7-membered heterocycloalkyl and -N(R 5 )(R 6 ), and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention covers compounds of formula (l-a), supra , in which:
  • R 1 represents a group wherein X 2 represents a hydrogen atom or a halogen atom or a substituent selected from
  • C3-C 6 -cycloalkyl group and C 4 -C 6 -cycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci -C 2 -alkyl Ci -C 2 -alkyl, cyano and hydroxy
  • (4- to 7-membered heterocycloalkyl)oxy group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci -C 2 -alkyl cyano and hydroxy
  • phenyl part of said phenyl-(Ci-C3-alkoxy)- group, and said 5- or 6-membered heteroaryl group and (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)oxy- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C 2 -alkyl, cyano and hydroxy wherein X 3 represents a hydrogen atom or a halogen atom or a Ci-C 2 -alkyl substituent, wherein X 4 represents a hydrogen atom or a halogen atom or a Ci-C 2 -alkyl substituent, wherein X 5 represents a hydrogen atom or a halogen atom or a Ci-C 2 -alkyl substituent, wherein X 6 represents a hydrogen atom or a halogen atom or a Ci-C 2 -alkyl substituent,
  • R 2 represents a group selected from phenyl, naphthyl and 5- or 6-membered heteroaryl, which phenyl, naphthyl and 5- or 6-membered heteroaryl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
  • R 3 represents a hydrogen atom, a halogen atom, or a group selected from
  • R 4 represents a hydrogen atom or Ci-C4-haloalkyl group
  • cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
  • R 5 and R 6 represent, independently from each occurrence, a hydrogen atom or a group
  • Ci-C 4 -alkyl C 3 -C 4 -cycloalkyl, C 2 -C 4 -haloalkyl, C 2 -C 4 -hydroxyalkyl and
  • R 5 and R 6 together with the nitrogen to which they are attached represent a
  • Ci-C 4 -alkyl C 3 -C 4 -cycloalkyl, C 2 -C 4 -haloalkyl, C 2 -C 4 -hydroxyalkyl,
  • R 7 represents a hydrogen atom or a C 1 -C 4 alkyl group
  • R 8 represents a hydrogen atom or a group selected from
  • the present invention covers compounds of formula (I), supra , in which:
  • R 1 represents a group wherein X 2 represents a hydrogen atom or a halogen atom or a substituent selected from
  • Ci-Ce-alkyl C2-C 6 -alkenyl, C2-C 6 -alkinyl, C3-C 6 -cycloalkyl,
  • (C 4 -C 6 -cycloalkenyl) -(Ci-C 3 -alkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C 2 -alkyl Ci-C 2 -haloalkyl, Ci-C 2 -alkoxy, cyano and hydroxy, and
  • Ci-C 2 -alkyl Ci-C 2 -haloalkyl, Ci-C 2 -alkoxy, cyano and hydroxy, and
  • -(Ci-C 4 -alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • (5- or 6-membered heteroaryl)oxy- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • X 4 represents a hydrogen atom or a halogen atom or a substituent selected from Ci -C 2 -alkyl and Ci-C 2 -haloalkyl, or,
  • X 5 represents a hydrogen atom or a halogen atom or a substituent selected from Ci -C 2 -alkyl and Ci-C 2 -alkoxy
  • X 6 represents a hydrogen atom or a halogen atom or a substituent selected from Ci -C 2 -alkyl and Ci-C 2 -alkoxy
  • the present invention covers compounds of formula (I), supra , in which:
  • R 1 represents a group wherein X 2 represents a hydrogen atom or a halogen atom or a substituent selected from
  • Ci-Ce-alkyl C3-C 6 -cycloalkyl, C -Ce-cycloalkenyl, Ci-C 6 -alkoxy,
  • Ci-Ce-haloalkoxy (Ci-C6-alkoxy)-(C2-C 4 -alkoxy)-,
  • Cs-Ce-cycloalkyl group and C 4 -C 6 -cycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C 2 -alkyl Ci-C 2 -alkyl, cyano and hydroxy
  • (4- to 7-membered heterocycloalkyl)oxy group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C2-alkyl cyano and hydroxy
  • 5- or 6-membered heteroaryl group and (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)oxy- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C 2 -alkyl, cyano and hydroxy wherein X 3 represents a hydrogen atom or a halogen atom or a Ci-C 2 -alkyl substituent, wherein X 4 represents a hydrogen atom or a halogen atom or a Ci-C 2 -alkyl substituent, wherein X 5 represents a hydrogen atom or a halogen atom or a Ci-C 2 -alkyl substituent, wherein X 6 represents a hydrogen atom or a halogen atom or a Ci-C 2 -alkyl substituent,
  • the present invention covers compounds of formula (I), supra , in which:
  • R 1 represents a group wherein X 2 represents a hydrogen atom or a halogen atom or a substituent selected from
  • phenyl part of said phenyl-(Ci-C 2 -alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C 2 -alkyl, cyano and hydroxy wherein X 3 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X 4 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X 5 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X 6 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent,
  • the present invention covers compounds of formula (I), supra , in which:
  • R 1 represents a group wherein X 2 represents a hydrogen atom or a substituent selected from methyl, methoxy and benzyloxy, wherein X 3 represents a hydrogen atom, wherein X 4 represents a hydrogen atom or a fluorine atom, wherein X 5 represents a hydrogen atom, wherein X 6 represents a hydrogen atom,
  • the present invention covers compounds of formula (I), supra , in which:
  • R 1 represents a group selected from
  • R 2 represents a group selected from
  • phenyl 3-bromophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dihydro-1 H-inden-5-yl and 1 -naphthyl,
  • R 3 represents a group selected from
  • R 4 represents a trifluoromethyl group
  • R 3 and R 4 together with the carbon atom to which they are attached represent a group selected from
  • the present invention covers compounds of formula (I), supra , in which:
  • R 2 represents a group selected from phenyl, naphthyl and 5- or 6-membered heteroaryl, which phenyl, naphthyl and 5- or 6-membered heteroaryl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
  • Ci -Ce-alkyl, C2-C 6 -alkenyl, C2-C 6 -alkinyl, C3-C 6 -cycloalkyl, C ⁇ Ce-cycloalkenyl, Ci-Ce-hydroxyalkyl, Ci-C 6 -haloalkyl, Ci-C 6 -alkoxy, Ci-C 6 -haloalkoxy, (Ci-C 4 -alkoxy)-(Ci-C 6 -alkyl)-, (Ci-C 4 -haloalkoxy)-( Ci-C 6 -alkyl)-, (Ci-C 4 -alkoxy)-(C2-C6-alkoxy)-, (Ci-C 4 -haloalkoxy)-( C2-C6-alkoxy)-, C3-C 6 -cycloalkyloxy, -SH, -S-(Ci -Ce-alkyl), -S( 0)-(Ci-C
  • 5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of said
  • 5- to 7-membered heterocycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • C3-C 6 -cycloalkyl group and C ⁇ Ce-cycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl, Ci-C 2 -haloalkyl, Ci-C 2 -alkoxy, cyano, hydroxy and oxo and
  • C 2 -C 6 -alkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C 2 -alkoxy group,
  • phenyl group and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl, Ci-C 2 -haloalkyl, Ci-C 2 -alkoxy, C3-C4-cycloalkyl, cyano, hydroxy and -N(R 5 )(R 6 ),
  • the present invention covers compounds of formula (I), supra , in which:
  • R 2 represents a group selected from phenyl, naphthyl and 5- or 6-membered heteroaryl, which phenyl, naphthyl and 5- or 6-membered heteroaryl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
  • two substituents of said phenyl group when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a group selected from -(CH 2 ) 3 -, -(CH 2 )4-, -(CH 2 ) 2 -0-, -CH 2 -0-CH 2 -, -(CH 2 )3-0-, -CH 2 -0-(CH 2 ) 2 -, -0-CH 2 -0- and -0-(CH 2 ) 2 -0-,
  • the present invention covers compounds of formula (I), supra , in which:
  • R 2 represents a group selected from phenyl and naphthyl
  • phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a Ci -C4-alkyl group,
  • the present invention covers compounds of formula (I), supra , in which:
  • R 2 represents a group selected from phenyl and naphthyl
  • phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a bromine atom and a chlorine atom or a methyl group,
  • the present invention covers compounds of formula (I), supra , in which: R 2 represents a group selected from
  • phenyl 3-bromophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dihydro-1 H-inden-5-yl and 1 -naphthyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention covers compounds of formula (I), supra , in which:
  • R 3 represents a hydrogen atom, a halogen atom, or a group selected from
  • C2-C4-alkyl C2-C4-alkenyl, C2-C4-alkinyl, Cs-Ce-cycloalkyl, Ci-C4-hydroxyalkyl,
  • -(Ci-C 2 -alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group
  • -(Ci-C 2 -alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • the present invention covers compounds of formula (I), supra , in which:
  • R 3 represents a hydrogen atom, a halogen atom, or a group selected from
  • the present invention covers compounds of formula (I), supra , in which:
  • R 3 represents a group selected from Ci-C 4 -alkoxy and hydroxy
  • the present invention covers compounds of formula (I), supra , in which:
  • R 3 represents a group selected from methoxy and hydroxy
  • the present invention covers compounds of formula (I), supra , in which:
  • R 4 represents a hydrogen atom, or a group selected from
  • Ci-C 4 -alkyl C 2 -C 4 -alkenyl, C 2 -C 4 -alkinyl, C3-C 6 -cycloalkyl, Ci-C 4 -hydroxyalkyl,
  • Ci-C 4 -haloalkyl -(Ci-C 2 -alkyl)-N(R 5 )(R 6 ), C 4 -C 7 -heterocycloalkyl,
  • -(Ci-C 2 -alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group
  • -(Ci-C 2 -alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • cycloalkyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • the present invention covers compounds of formula (I), supra , in which:
  • R 4 represents a hydrogen atom or Ci-C 4 -haloalkyl group
  • the present invention covers compounds of formula (I), supra , in which:
  • R 4 represents a Ci-C 4 -haloalkyl group
  • the present invention covers compounds of formula (I), supra , in which:
  • R 4 represents a trifluoromethyl group
  • the present invention covers compounds of formula (I), supra , in which:
  • R 3 and R 4 together with the carbon atom to which they are attached represent a
  • cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
  • the present invention covers compounds of formula (I), supra , in which:
  • R 3 and R 4 together with the carbon atom to which they are attached represent a group
  • the present invention covers compounds of formula (I), supra , in which:
  • R 5 and R 6 represent, independently from each occurrence, a hydrogen atom or a group
  • R 5 and R 6 together with the nitrogen to which they are attached represent a
  • the present invention covers compounds of formula (I), supra , in which:
  • R 5 and R 6 represent, independently from each occurrence, a hydrogen atom or a group
  • the present invention covers compounds of formula (I), supra , in which:
  • R 5 and R 6 together with the nitrogen to which they are attached represent a
  • the present invention covers compounds of formula (I), supra , in which:
  • R 7 represents a hydrogen atom or a Ci-C 4 alkyl group
  • the present invention covers compounds of formula (I), supra , in which:
  • R 8 represents a hydrogen atom or a group selected from
  • the present invention covers compounds of formula (I), supra , in which:
  • R 9 represents a hydrogen atom or a group selected from
  • cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
  • the present invention covers compounds of formula (I), supra , in which:
  • R 1 0 represents a group selected from
  • the present invention covers compounds of formula (I), supra , in which:
  • R 1 1 represents a group selected from
  • cycloalkyl group is optionally substituted one or two or times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C 2 -alkyl Ci-C 2 -haloalkyl, Ci-C 2 -alkoxy, cyano, hydroxy and oxo, and
  • phenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C2-alkyl, Ci -C2-haloalkyl, C3-C4-cycloalkyl, Ci-C2-alkoxy, cyano, hydroxy, 4- to 7-membered heterocycloalkyl and -N(R 5 )(R 6 ),
  • the present invention covers compounds of formula (l-a), supra , in which:
  • R 1 represents a group wherein X 2 represents a hydrogen atom or a halogen atom or a substituent selected from
  • Ci -Ce-alkyl C2-C 6 -alkenyl, C2-C 6 -alkinyl, C3-C 6 -cycloalkyl,
  • (C4-C6-cycloalkenyl) -(Ci-C3-alkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C 2 -alkyl Ci-C 2 -haloalkyl, Ci-C 2 -alkoxy, cyano and hydroxy, and
  • Ci-C 2 -alkyl Ci-C 2 -haloalkyl, Ci-C 2 -alkoxy, cyano and hydroxy, and
  • -(Ci-C 4 -alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • X 4 represents a hydrogen atom or a halogen atom or a substituent selected from Ci-C 2 -alkyl and Ci-C 2 -haloalkyl, or,
  • X 5 represents a hydrogen atom or a halogen atom or a substituent selected from Ci-C 2 -alkyl and Ci-C 2 -alkoxy
  • X 6 represents a hydrogen atom or a halogen atom or a substituent selected from Ci -C 2 -alkyl and Ci-C 2 -alkoxy
  • the present invention covers compounds of formula (l-a), supra , in which:
  • R 1 represents a group wherein X 2 represents a hydrogen atom or a halogen atom or a substituent selected from
  • Cs-Ce-cycloalkyl group and C4-C6-cycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci -C 2 -alkyl Ci -C 2 -alkyl, cyano and hydroxy
  • (4- to 7-membered heterocycloalkyl)oxy group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci -C 2 -alkyl Ci -C 2 -alkyl, cyano and hydroxy
  • 5- or 6-membered heteroaryl group and (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)oxy- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C 2 -alkyl, cyano and hydroxy wherein X 3 represents a hydrogen atom or a halogen atom or a Ci-C 2 -alkyl substituent, wherein X 4 represents a hydrogen atom or a halogen atom or a Ci-C 2 -alkyl substituent, wherein X 5 represents a hydrogen atom or a halogen atom or a Ci-C 2 -alkyl substituent, wherein X 6 represents a hydrogen atom or a halogen atom or a Ci-C 2 -alkyl substituent,
  • the present invention covers compounds of formula (l-a), supra , in which:
  • R 1 represents a group wherein X 2 represents a hydrogen atom or a halogen atom or a substituent selected from
  • phenyl part of said phenyl-(Ci-C 2 -alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C 2 -alkyl, cyano and hydroxy wherein X 3 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X 4 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X 5 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X 6 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent,
  • the present invention covers compounds of formula (l-a), supra , in which:
  • R 1 represents a group wherein X 2 represents a hydrogen atom or a substituent selected from methyl, methoxy and benzyloxy, wherein X 3 represents a hydrogen atom, wherein X 4 represents a hydrogen atom or a fluorine atom, wherein X 5 represents a hydrogen atom, wherein X 6 represents a hydrogen atom,
  • the present invention covers compounds of formula (l-a), supra , in which:
  • R 1 represents a group selected from
  • R 2 represents a group selected from phenyl, 3-bromophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dihydro-1 H-inden-5-yl and 1 -naphthyl,
  • R 3 represents a group selected from

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Abstract

The present invention covers 5-substituted 1-oxa-3,9-diazaspiro[5.5]undecan-2-one compounds of general formula (I) and general formula (I-a), in which R1, R2, R3 and R4 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment and/or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.

Description

5-SUBSTITUTED 1-OXA-3,9-DIAZASPIRO[5.5]UNDECAN-2-ONE COMPOUNDS
The present invention covers 5-substituted 1 -oxa-3,9-diazaspiro[5.5]undecan-2-one compounds of general formula (I) and general formula (l-a) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.
BACKGROUND
The present invention covers 5-substituted 1 -oxa-3,9-diazaspiro[5.5]undecan-2-one compounds of general formula (I) and general formula (l-a) which inhibit the activity of geranylgeranyltransferase I (GGTase I), leading to inactivation of downstream YAP1 and/or TAZ and blockade of cancer cell proliferation.
Rho GTPases belong to the larger family of Ras GTPases, consisting of over 50 proteins with related characteristics. Rho GTPases are master regulators for signal transduction from the extracellular matrix to the cytoplasm and nucleus. They are involved in the regulation of cell proliferation, survival and differentiation by modulating cytoskeletal structure and properties of cell adhesion. Abberant Rho GTPase activity is observed in human cancer. Members of the pathway are therefore potential therapeutic targets. Activity of Rho GTPases is regulated by protein prenylation (farnesylation and geranylgeranylation) of the CAAX box motif. Prenylated Rho GTPases are primed for membrane localization and subsequent activitation. The three enzymes required of this post-translation modification are called protein prenyl-transferases (farnesyl-transferase, geranylgeranyl-transferase I and geranylgeranyl-transferase II). GGTase II is selective for Rab proteins and shows a different Mode of Action compared to GGTase I and FTase. Studies in mouse models have demonstrated that GGTase I inhibition reduces tumor formation of lung cancer as well as myeloproliferative disease and that the anti-tumor effect depended on the inhibition of protein geranyl-geranylation Sjogren AKM et al, J. Clin. Invest. 1 17:1294-1304 (2007). AKM et al, Leukemia (201 1 ) 25, 186-189
A recently discovered downstream target of Rho GTPases are YAP1 and TAZ (gene name WWTR1 ). It has been shown that geranylgeranylated Rho GTPases such as RhoA activate downstream YAP1/TAZ in breast cancer (Mi W et al Oncogene 2015). YAP1 and TAZ (gene name WWTR1 ) are two highly related transcriptional coactivators that are frequently aberrantly activated in human cancers (Zanconato F, Cancer Cell. 2016 783-803). YAP1/TAZ are important for the activation of several hallmarks of cancer (Harvey KF, Nat Rev Cancer. 2013 246-57). Functionally, YAP1/TAZ shuttle between the cytoplasm and the cells' nucleus, where they interact with TEAD transcription factors1 -4 (TEAD1 -4) to activate target genes important for cell survival and cell cycle progression (S. Piccolo Physiol. Rev., 2014 1287-1312. Zanconato F, et al. Nat Cell Biol. 2015 1218-27). Abberant YAP1/TAZ expression induces cell proliferation (Zhao B Genes Dev., 2007, 2747-2761 ). Moreover, high levels of YAP1/TAZ can overcome the induction of programmed cell death and apoptosis by upregulation of anti- apoptotic proteins (Rosenbluh J. Cell, 2012. 1457-1473). YAP1/TAZ also confers Cancer Stem Cells (CSC) traits and are required for CSC expansion within tumors (Cordenonsi M. Cell, 201 1 , 759-772). In line with this, the ability to initiate tumor formation and induce metastasis depends on YAP1/TAZ (Bartucci M, Oncogene, 2015, 681-690 Lau AN EMBO J. 2014, 468-481 ). Blockade of YAP1/TAZ function by RNAi-mediated knockdown reduces the viability of several cancer cells in vitro (Pan J Oncol. Rep., 2012 179-185). Moreover, it reduces the growth of tumor cells in mouse models of cancer in vivo (Nguyen LT Cancer Cell, 2015 797-808, He C, EMBO Mol. Med., 2015 1426-1449 Wang Q, Mol. Med. Rep., 2015 982-988 Feng X Cancer Cell, 2014 831 -845). Given the crucial role various stages of tumor development, YAP1/TAZ may represent promising targets for therapeutic intervention of various diseases with uncontrolled cell proliferation, including cancer.
The present invention relates to chemical compounds that have been found to
• Inhibit the activity of GGTasel
• inhibit the transcriptional regulation activity of YAP1 and/or TAZ
• block cell proliferation in tumor cells.
GGTase I inhibitors have been developed (reviewed in Ullah N et al Current Cancer Drug Targets 2016, 16, 563-571 ), but no GGTase I inhibitor is currently approved for treatment of patients. WO-03017939 , WO-2010088457. GGTI-2418 US 2012/0035184 A1 .ln cancer cell lines, GGTase I inhibitors cause cell cycle arrest in G0/G1 phase via blockade of cyclin- dependent kinases downstream of Rho Sun J et al, J. Biol. Chem., 1999, 274, 6930-; Vogt A et al, J. Biol. Chem., 1997, 272, 27224-27229. Furthermore, induction of apoptosis by GGTase I inhibitors has been reported Dan HC et al Oncogene, 2004, 23, 706-715. Morgan MA et al, Leukemia, 2003, 17, 1508-1520. Stark W et al, Am. J. Physiol., 1998, 275, L55-63. In Xenograft models of breast cancer, application of a GGTase I inhibitor caused tumor regression Kazi A et al, Cell Biol. ,2009, 29, 2254-2263. Watanabe M et al (J. Biol. Chem. 2008, 283:9571 -9579) , described the identification of inhibitors of protein geranylgeranyltransferase I and Rab geranylgeranyltransferase from a Library of allenoate- derived compounds. YAP1/TAZ small molecule modulators have been described in Johnson R et al, Nature Reviews Drug Discovery, 2014, 13, 63-79 and in Stahn L.C., Master Thesis, University Rostock, 2017. Dey A et al, (Trends in Cancer, Vol. 5, No. 5, 297-307, 2019) reported on compounds to modulate hippo pathway activity, among them compounds that inhibit YAP- TEAD interaction or decrease YAP expressions. Cyclic peptides inhibiting the YAP1 -TEAD protein-protein interaction have been described in Zhang Z. et al., ACS Med. Chem. Lett., 2014, 5, 993-998. A peptide mimicking VGLL4 function has been proposed to act as a YAP1 antagonist in preclinical models of gastric cancer in Jiao S, et al., Cancer Cell, 2014, 25, 166- 180. A number of publications report inhibitors of YAP1 , for example, the Tankyrase inhibitor XAV939 (Wang et al., Cell Reports, 2015, 13, 524-532) is reported to target YAP1 for cancer treatment. Peptide 17 has been reported to inhibit the YAP1 -TEAD protein-protein interaction (Zhang Z. et al., ACS Med. Chem. Lett., 2014, 5, 993-998 and Zhou et al., FASEB J., 2015, 29, 724-732). Verteporfin has also reported to be a YAP1 inhibitor (Szeto et al., J. Am. Soc. Nephrol., 2016, 27, 31 17-3128 and Liu-Chittenden et al., Gens Dev., 2012, 26, 1300-1305). Latrunculin A, Blebbistatin, Y27632 and ML7 have been reported to inhibit YAP1 nuclear localization as well as YAP1 and TEAD activity (see Nature Reviews Drug Discovery, 2014, 13, 63-79).
WO20191 18973A1 describes 1 -(piperidinocarbonylmethyl)-2-oxopiperazine derivatives for treating cancer.
W02005075484 A2 discloses 1 -oxa-3,8-diazaspiro[4.5]decan-2-one and 1 -oxa-3,9-diazaspiro- [5.5]undecan-2-one compounds, which modulate the chemokine CCR5 receptors.
W02003057698 A2 discloses spiroazacyclic compounds as monoamine receptor modulators.
W02002092604 A1 discloses 1 -oxa-3,9-diazaspiro[5.5]undecan-2-one derivatives and its use as antagonists of the neurokinin receptor.
W020051 10992 relates to amido compounds as modulators of 1 1 -b hydroxyl steroid dehydrogenase type 1 (11 b HSD1 ) and/or mineralocorticoid receptor (MR).
However, the state of the art does not describe the 5-substituted 1 -oxa-3,9- diazaspiro[5.5]undecan-2-one compounds of general formula (I) and general formula (l-a) of the present invention as described and defined herein.
It has now been found, and this constitutes the basis of the present invention, that the compounds of the present invention have surprising and advantageous properties.
In particular, the compounds of the present invention have surprisingly been found to effectively inhibit the activity of geranylgeranyltransferase I (GGTase I), leading to inactivation of downstream YAP1 and/or TAZ and blockade of cancer cell proliferation, and may therefore be used for the treatment or prophylaxis of hyperproliferative disorders, such as cancer, for example.
DESCRIPTION of the INVENTION In accordance with a first aspect, the present invention covers compounds of general formula (I):
Figure imgf000005_0001
in which :
R1 represents a group
Figure imgf000005_0002
wherein X2 represents a hydrogen atom or a halogen atom or a substituent selected from
Ci -Ce-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C6-cycloalkyl,
(C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, C4-C6-cycloalkenyl,
(C4-C6-cycloalkenyl)-(Ci-C3-alkyl)-, Ci -C6-hydroxyalkyl,
(Ci -C2-alkoxy)-(Ci-C6-alkyl)-, (Ci -C2-haloalkoxy)-(Ci -C6-alkyl)-, Ci-C6-haloalkyl, Ci -Ce-alkoxy, Ci-Ce-haloalkoxy, Cs-Ce-cycloalkyloxy,
(C3-C6-cycloalkyloxy)-(Ci -C3-alkyl)-, (Ci -C6-alkoxy)-(C2-C4-alkoxy)-, (C3-C6-cycloalkyloxy)-(C2-C4-alkoxy)-, phenyl, 5- or 6-membered heteroaryl, phenyl-(Ci -C3-alkyl)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, phenoxy-(Ci -C3-alkyl)-, phenoxy-(C2-C3-alkoxy)-, (5- or 6-membered heteroaryl)-(Ci -C3-alkyl)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-,
(5- or 6-membered heteroaryl)oxy-(C2-C3-alkoxy)-,
(5- or 6-membered heteroaryl)oxy-, -SH, -S-(Ci -Ce-alkyl), -S(=0)-(Ci -C6-alkyl), -S(=0)2-(Ci -Ce-alkyl) , -S-(C3-C6-cycloalkyl) , -S(=0)-(C3-C6-cycloalkyl) ,
-S(=0)2-(C3-C6-cycloalkyl) , (Ci -C6-alkyl)-S-(Ci -Cs-alkyl)- ,
(Ci -C6-alkyi)-S(=0)-(Ci -C3-alkyl)-, (Ci-C6-alkyl)-S(=0)2-(Ci -C3-alkyl)-, (C3-C6-cycloalkyl)-S-(Ci-C3-alkyl)-, (C3-C6-cycloalkyl)-S(=0)-(Ci-C3-alkyl), (C3-C6-cycloalkyl)-S(=0)2-(Ci -C3-alkyl) , -S-(Ci -C6-haloalkyl) ,
-S(=0)-(Ci-C6-haloalkyl), -S(=0)2-(Ci-C6-haloalkyl), -S-phenyl, -S(=0)-phenyl, -S(=0)2-phenyl, -cyano, hydroxy, -N(R5)(R6), -(Ci-C4-alkyl)-N(R5)(R6),
4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, -(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl),
(4- to 7-membered heterocycloalkyl)oxy-, -C(=0)R8, C(=0)N(R5)(R6),
-C(=0)OR7, -N(R7)C(=0)R8, -N(R7)C(=0)OR1°, -N(R7)C(=0)N(R5)(R6), -0C(=0)N(R5)(R6), -OC(=0)R8 and -N(R7)S(=0)2R11 ,
wherein said Cs-Ce-cycloalkyl group and C4-C6-cycloalkenyl group and the (C3-C6-cycloalkyl) part of said (C3-C6-cycloalkyl)-(Ci -C3-alkyl) group and the (C^Ce-cycloalkenyl) part of said
(C4-C6-cycloalkenyl) -(Ci-C3-alkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano and hydroxy, and
wherein said C3-C6-cycloalkyloxy group and the (C3-C6-cycloalkyloxy) part of said (C3-C6-cycloalkyloxy)-(Ci-C3-alkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano and hydroxy, and
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the
4- to 7-membered heterocycloalkyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and
(4- to 7-membered heterocycloalkyl)oxy group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, C3-C4-cycloalkyl, Ci-C2-alkoxy, cyano, hydroxy, -N(R5)(R6) and oxo, and
wherein said phenyl and phenoxy group, and the phenyl part of said phenyl-(Ci-C3-alkyl)-, phenyl-(Ci-C3-alkoxy)-, phenoxy-(Ci-C3-alkyl)-, phenoxy-(C2-C3-alkoxy)-, -S-phenyl, -S(=0)-phenyl and -S(=0)2-phenyl group, and said 5- or 6-membered heteroaryl group and
(5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)-(Ci-C3-alkyl),
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy),
(5- or 6-membered heteroaryl)oxy-(C2-C3-alkoxy) and
(5- or 6-membered heteroaryljoxy- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy and -N(R5)(R6), wherein X3 represents a hydrogen atom or a halogen atom or a substituent selected from Ci-C2-alkyl and Ci-C2-alkoxy, or,
wherein X2 and X3 are linked to one another in such a way that they jointly form a group selected from
-(CH2)2-0-, -0-(CH2)2-, -CH2-O-CH2-, -(CH2)3-0-, -0-(CH2)3-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, O-CH2-O-, -0-(CH2)2-0-, -(CH2)2-N(R9)-, -N(R9)-(CH2)2-, -CH2-N(R9)-CH2-, -(CH2)3-N(R9)-, -N(R9)-(CH2)3-, -CH2-N(R9)-(CH2)2-,
-(CH2)2-N(R9)-CH2-, -N(R9)-(CH2)2-N(R9)-, -N(R9)-(CH2)2-0- and
-0-(CH2)2-N(R9)-,
wherein X4 represents a hydrogen atom or a halogen atom or a substituent selected from Ci-C2-alkyl and Ci-C2-haloalkyl, or,
wherein X3 and X4 are linked to one another in such a way that they jointly form a group selected from
-(CH2)2-0-, -0-(CH2)2-, -CH2-0-CH2-, -(CH2)3-0-, -0-(CH2)3-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, 0-CH2-0-, -0-(CH2)2-0-, -(CH2)2-N(R9)-, -N(R9)-(CH2)2-, -CH2-N(R9)-CH2-, -(CH2)3-N(R9)-, -N(R9)-(CH2)3-, -CH2-N(R9)-(CH2)2-, -(CH2)2-N(R9)-CH2-, -N(R9)-(CH2)2-N(R9)-, -N(R9)-(CH2)2-0- and
-0-(CH2)2-N(R9)-, wherein X5 represents a hydrogen atom or a halogen atom or a substituent selected from Ci -C2-alkyl and Ci-C2-alkoxy, wherein X6 represents a hydrogen atom or a halogen atom or a substituent selected from Ci -C2-alkyl and Ci-C2-alkoxy,
R2 represents a group selected from phenyl, naphthyl and 5- or 6-membered heteroaryl, which phenyl, naphthyl and 5- or 6-membered heteroaryl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci -Ce-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, Cs-Ce-cycloalkyl, C4-C6-cycloalkenyl, Ci -C6-hydroxyalkyl, Ci -C6-haloalkyl, Ci -C6-alkoxy, Ci -C6-haloalkoxy,
(Ci -C4-alkoxy)-(Ci-C6-alkyl)-, (Ci -C4-haloalkoxy)-( Ci-C6-alkyl)-, (Ci -C4-alkoxy)-(C2-C6-alkoxy)-, (Ci-C4-haloalkoxy)-( C2-C6-alkoxy)-, Cs-Ce-cycloalkyloxy, -SH, -S-(Ci -C6-alkyl), -S(=0)-(Ci-C6-alkyl), -S(=0)2-(Ci-C6-alkyl), -S-(Ci-Ce-haloalkyl), -S(=0)-(Ci-C6-haloalkyl),
-S(=0)2-(Ci-C6-haloalkyl), -S-(C3-C6-cycloalkyl), -S(=0)-(C3-C6-cycloalkyl), -S(=0)2-(C3-C6-cycloalkyl), -S(=0)2N(R5)R6, -(Ci -C4-alkyl)-S(=0)2N(R5)R6, cyano, hydroxy, -N(R5)(R6), -(Ci-C4-alkyl)-N(R5)(R6), -N(R7)C(=0)R8,
-N(R7)C(=0)0R1°, -N(R7)C(=0)N(R5)(R6), -0C(=0)R8, -C(=0)0R7, -C(=0)N(R5)R6, 4- to 7-membered heterocycloalkyl,
5- to 7-membered heterocycloalkenyl, phenyl and 5- or 6-membered heteroaryl, or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a group selected from
-(CH2)3-, -(CH2)4-, -(CH2)2-0-, -CH2-0-CH2-, -(CH2)3-0-, -CH2-0-(CH2)2-, -0-CH2-0- and -0-(CH2)2-0-,
wherein said 4- to 7-membered heterocycloalkyl group and
5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of said
4- to 7-membered heterocycloalkyl group and
5- to 7-membered heterocycloalkenyl group,
and wherein said 4- to 7-membered heterocycloalkyl group and
5- to 7-membered heterocycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy, -N(R5)(R6) and oxo,
and
wherein said C3-C6-cycloalkyl group and C -Ce-cycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo and
wherein said C2-C6-alkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-alkoxy group,
and
wherein said phenyl group and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy and -N(R5)(R6),
R3 represents a hydrogen atom, a halogen atom, or a group selected from
C2-C4-alkyl, C2-C4-alkenyl, C2-C4-alkinyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl,
Ci-C4-haloalkyl, (Ci-C2-haloalkoxy)-(Ci-C2-alkyl)-, Ci-C4-alkoxy, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyloxy, hydroxy, cyano, -N(R5)(R6), -(Ci-C2-alkyl)-N(R5)(R6),
C4-C7-heterocycloalkyl, -(Ci-C2-alkyl)-(C4-C7-heterocycloalkyl),
(Ci-C2-haloalkoxy)-(Ci-C2-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-,
(C3-C4-cycloalkyloxy)-(Ci-C2-alkyl)-, -C(=0)N(R5)(R6) and -C(=0)OR7,
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C2-alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said -(Ci-C2-alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy,
-N(R5)(R6) and oxo,
and
wherein said cycloalkyl group and is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and -N(R5)(R6),
R4 represents a hydrogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkinyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl,
Ci-C4-haloalkyl, -(Ci-C2-alkyl)-N(R5)(R6), C4-C7-heterocycloalkyl,
-(Ci-C2-alkyl)-( C4-C7-heterocycloalkyl), (Ci-C2-haloalkoxy)-(Ci-C2-alkyl)-,
(Ci -C2-alkoxy)-(Ci -C2-alkyl)- and (C3-C4-cycloalkyloxy)-(Ci -C2-alkyl)-,
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C2-alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C2-alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy,
-N(R5)(R6) and oxo,
and
wherein said cycloalkyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and -N(R5)(R6), or
R3 and R4 together with the carbon atom to which they are attached represent a
5- to 8-membered cycloalkyl group, wherein said cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo,
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
selected from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl and
(Ci-C2-alkoxy)-(C2-C3-alkyl-),
or
R5 and R6 together with the nitrogen to which they are attached represent a
nitrogen containing 4- to 7-membered heterocycloalkyl group,
wherein said 4- to 7-membered nitrogen containing heterocycloalkyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(C2-C3-alkyl)-, cyano, hydroxy and oxo,
R7 represents a hydrogen atom or a Ci-C4 alkyl group,
R8 represents a hydrogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl and Cs-Ce-cycloalkyl,
R9 represents a hydrogen atom or a group selected from
Ci-C6 alkyl, C2-C6 haloalkyl, 03-06 cycloalkyl,
wherein said cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo,
R10 represents a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl and 03-06 cycloalkyl,
and R11 represents a group selected from
Ci-C4-alkyl and Ci-C4-haloalkyl, C3-C6-cycloalkyl and phenyl,
wherein said cycloalkyl group is optionally substituted one or two or times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo, and
wherein said phenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C2-alkyl, Ci-C2-haloalkyl, C3-C4-cycloalkyl, Ci-C2-alkoxy, cyano, hydroxy, 4- to 7-membered heterocycloalkyl and -N(R5)(R6), and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
DEFINITIONS
The term“substituted” means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.
The term“optionally substituted” means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, it is possible for the number of optional substituents, when present, to be 1 , 2, 3 or 4, in particular 1 , 2 or 3.
When groups in the compounds according to the invention are substituted, it is possible for said groups to be mono-substituted or poly-substituted with substituent(s), unless otherwise specified. Within the scope of the present invention, the meanings of all groups which occur repeatedly are independent from one another. It is possible that groups in the compounds according to the invention are substituted with one, two or three identical or different substituents, particularly with one substituent.
As used herein, an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond. The term“ring substituent” means a substituent attached to an aromatic or nonaromatic ring which replaces an available hydrogen atom on the ring.
Should a composite substituent be composed of more than one part, e.g.
(Ci-C2-alkoxy)-(Ci-C6-alkyl)-, it is possible for a given part to be attached at any suitable position of said composite substituent, e.g. it is possible for the Ci-C2-alkoxy part to be attached to any suitable carbon atom of the Ci-C6-alkyl part of said
(Ci-C2-alkoxy)-(Ci-C6-alkyl)- group. A hyphen at the beginning or at the end of such a composite substituent indicates the point of attachment of said composite substituent to the rest of the molecule. Should a ring, comprising carbon atoms and optionally one or more heteroatoms, such as nitrogen, oxygen or sulfur atoms for example, be substituted with a substituent, it is possible for said substituent to be bound at any suitable position of said ring, be it bound to a suitable carbon atom and/or to a suitable heteroatom.
The term“comprising” when used in the specification includes“consisting of”.
If within the present text any item is referred to as“as mentioned herein”, it means that it may be mentioned anywhere in the present text.
The terms as mentioned in the present text have the following meanings:
The term“halogen atom” means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.
The term“Ci-Ce-alkyl” means a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, fert-butyl, pentyl, isopentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl,
1 .2-dimethylpropyl, neo-pentyl, 1 ,1 -dimethylpropyl, hexyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 -ethylbutyl, 2-ethylbutyl, 1 ,1 -dimethylbutyl, 2,2-dimethylbutyl,
3.3-dimethylbutyl, 2,3-dimethylbutyl, 1 ,2-dimethylbutyl or 1 ,3-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, isopropyl, butyl, sec-butyl isobutyl, or fert-butyl group, more particularly 1 , 2 or 3 carbon atoms (“Ci-C3-alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group, more particularly 1 or 2 carbon atoms (“Ci-C2-alkyl”), e.g. a methyl or ethyl group.
The term“Ci-Ce-hydroxyalkyl” means a linear or branched, saturated, monovalent hydrocarbon group in which the term“Ci-Ce-alkyl” is defined supra , and in which 1 or 2 hydrogen atoms are replaced with a hydroxy group, e.g. a hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1 -hydroxypropyl, 1 -hydroxypropan-2-yl,
2-hydroxypropan-2-yl, 2,3-dihydroxypropyl, 1 ,3-dihydroxypropan-2-yl,
3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1 -hydroxy-2-methyl-propyl,
1 -hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl group, or an isomer thereof. The term“Ci-Ce-haloalkyl” means a linear or branched, saturated, monovalent hydrocarbon group in which the term“Ci-Ce-alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. Said Ci-C6-haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1 ,3-difluoropropan-2-yl.
The term“Ci-C6-alkoxy” means a linear or branched, saturated, monovalent group of formula (Ci-C6-alkyi)-0-, in which the term“Ci-C6-alkyl” is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, ferf-butoxy, pentyloxy, isopentyloxy or n-hexyloxy group, or an isomer thereof.
The term“Ci-C6-haloalkoxy” means a linear or branched, saturated, monovalent Ci-C6-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. Said Ci-C6-haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.
The term“C2-C6-alkenyl” means a linear or branched, monovalent hydrocarbon group, which contains one or two double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms, it being understood that in the case in which said alkenyl group contains two double bonds, then it is possible for said double bonds to be conjugated with each other, or to form an allene. Said alkenyl group is, for example, an ethenyl (or“vinyl”), prop-2-en-1 -yl (or“allyl”), prop-1 -en-1 -yl, but-3-enyl, but-2-enyl, but-1 -enyl, pent-4-enyl, pent-3-enyl, pent-2-enyl, pent-1 -enyl, hex-5-enyl, hex-4-enyl, hex-3-enyl, hex-2-enyl, hex-1 -enyl, prop-1 -en-2-yl (or“isopropenyl”),
2-methylprop-2-enyl, 1 -methylprop-2-enyl, 2-methylprop-1 -enyl, 1 -methylprop-1 -enyl,
3-methylbut-3-enyl, 2-methylbut-3-enyl, 1 -methylbut-3-enyl, 3-methylbut-2-enyl,
2-methylbut-2-enyl, 1 -methylbut-2-enyl, 3-methylbut-1 -enyl, 2-methylbut-1 -enyl,
1 -methylbut-1 -enyl, 1 ,1 -dimethylprop-2-enyl, 1 -ethylprop-1 -enyl, 1 -propylvinyl, 1 -isopropylvinyl,
4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, 1 -methylpent-4-enyl,
4-methylpent-3-enyl, 3-methylpent-3-enyl, 2-methylpent-3-enyl, 1 -methylpent-3-enyl,
4-methylpent-2-enyl, 3-methylpent-2-enyl, 2-methylpent-2-enyl, 1 -methylpent-2-enyl,
4-methylpent-1 -enyl, 3-methylpent-1 -enyl, 2-methylpent-1 -enyl, 1 -methylpent-1 -enyl,
3-ethylbut-3-enyl, 2-ethylbut-3-enyl, 1 -ethylbut-3-enyl, 3-ethylbut-2-enyl, 2-ethylbut-2-enyl, 1 -ethylbut-2-enyl, 3-ethylbut-1 -enyl, 2-ethylbut-1 -enyl, 1 -ethylbut-1 -enyl, 2-propylprop-2-enyl, 1 -propylprop-2-enyl, 2-isopropylprop-2-enyl, 1 -isopropylprop-2-enyl, 2-propylprop-1 -enyl, 1 -propylprop-1 -enyl, 2-isopropylprop-1 -enyl, 1 -isopropylprop-1 -enyl, 3,3-dimethylprop-1 -enyl, 1 -(1 ,1 -dimethylethyl)ethenyl, buta-1 ,3-dienyl, penta-1 ,4-dienyl or hexa-1 ,5-dienyl group. The term“C2-C6-alkynyl” means a linear or branched, monovalent hydrocarbon group which contains one triple bond, and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly 2, 3 Oder 4 carbon atoms (“C2-C4-alkynyl”). Said C2-C6-alkynyl group is, for example, ethynyl, prop-1 -ynyl, prop-2-ynyl (or “propargyl”), but-1 -ynyl, but-2-ynyl, but-3-ynyl, pent-1 -ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1 -ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1 -methylprop-2-ynyl, 2-methylbut-3-ynyl, 1 -methylbut-3-ynyl, 1 -methylbut-2-ynyl, 3-methylbut-1 -ynyl, 1 -ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1 -methyl- pent-4-ynyl, 2-methylpent-3-ynyl, 1 -methylpent-3-ynyl, 4-methylpent-2-ynyl, 1 -methyl- pent-2-ynyl, 4-methylpent-1 -ynyl, 3-methylpent-1 -ynyl, 2-ethylbut-3-ynyl, 1 -ethylbut-3-ynyl, 1 -ethylbut-2-ynyl, 1 -propylprop-2-ynyl, 1 -isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1 ,1 -dimethylbut-3-ynyl, 1 ,1 -dimethylbut-2-ynyl or 3,3-dimethylbut-1 -ynyl group.
The term “Cs-Ce-cycloalkyl” means a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms. Said C3-C6-cycloalkyl group is for example a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Particularly, said group has 3 or 4 carbon atoms (“C3-C4-cycloalkyl”), e.g. a cyclopropyl or cyclobutyl group.
The term “Cs-Cs-cycloalkyl” means a saturated, monovalent, monocyclic hydrocarbon ring which contains 5, 6, 7 or 8 carbon atoms. Said C3-C5-cycloalkyl group is for example a cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
The term “C4-C6-cycloalkenyl” means a monovalent, monocyclic hydrocarbon ring which contains one double bond and 4, 5 or 6 carbon atoms. Said C4-C6-cycloalkenyl group is for example a cyclobutenyl, cyclopentenyl or cyclohexenyl group.
The term “Cs-Ce-cycloalkyloxy” means a saturated, monovalent group of formula (C3-C6-cycloalkyl)-0-, in which the term “Cs-Ce-cycloalkyl” is as defined supra , e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy group.
The term“4- to 7-membered heterocycloalkyl” means a monocyclic, saturated heterocycle with 4, 5, 6 or 7 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S.
Said heterocycloalkyl group, without being limited thereto, can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1 ,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1 ,1 -dioxidothiolanyl, 1 ,2-oxazolidinyl, 1 ,3-oxazolidinyl or 1 ,3-thiazolidinyl, for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl or 1 ,2-oxazinanyl, for example, or a 7-membered ring, such as azepanyl, 1 ,4-diazepanyl or 1 ,4-oxazepanyl, for example. The term“(4- to 7-membered heterocycloalkyl)oxy” means a monocyclic, saturated heterocycle of formula (4- to 7-membered heterocycloalkyl)-0-, in which the term “4- to 7-membered heterocycloalkyl” is as defined supra.
The term “5- to 7-membered heterocycloalkenyl” means a monocyclic, unsaturated, non aromatic heterocycle with 5, 6 or 7 ring atoms in total, which contains one or two double bonds and one or two identical or different ring heteroatoms from the series N, O and S.
Said heterocycloalkenyl group is, for example, 4/-/-pyranyl, 2/-/-pyranyl, 2,5-dihydro-1 /-/-pyrrolyl, [1 ,3]dioxolyl, 4/-/-[1 ,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothio- phenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl or 4/-/-[1 ,4]thiazinyl.
The term nitrogen containing 4- to 7-membered heterocycloalkyl group means a monocyclic, saturated heterocycle with 4, 5, 6 or 7 ring atoms in total, which contains one ring nitrogen atom and optionally one further ring heteroatom from the series N, O and S.
Said nitrogen containing 4- to 7-membered heterocycloalkyl group, without being limited thereto, can be a 4-membered ring, such as azetidinyl, for example; or a 5-membered ring, such as pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1 ,2-oxazolidinyl, 1 ,3-oxazolidinyl or 1 ,3-thiazolidinyl, for example; or a 6-membered ring, such as piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or 1 ,2-oxazinanyl, for example, or a 7-membered ring, such as azepanyl, 1 ,4-diazepanyl or 1 ,4-oxazepanyl, for example.
The term“5- or 6-membered heteroaryl” means a monovalent aromatic ring having 5 or 6 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S.
Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl.
The term“(5- or 6-membered heteroaryl)oxy” means a monovalent aromatic ring having 5 or 6 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S of formula (5- or 6-membered heteroaryi)-0-, in which the term“5- or 6-membered heteroaryl” is as defined supra , and which is bound via a ring carbon atom.
In general, and unless otherwise mentioned, the heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g .: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule. Thus, for some illustrative non-restricting examples, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl. The term “Ci-C6”, as used in the present text, e.g. in the context of the definition of “Ci-Ce-alkyl”, “Ci-Ce-haloalkyl”, “Ci-Ce-hydroxyalkyl”, “Ci-C6-alkoxy” or “Ci-C6-haloalkoxy” means an alkyl, haloalkyl, hydroxyalkyl, alkoxy or haloalkoxy group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5 or 6 carbon atoms.
Further, as used herein, the term“C2-C6”, as used in the present text, e.g. in the context of the definition of “C2-C6-alkenyl” or“C2-C6-alkinyl” means an alkenyl or alkinyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5 or 6 carbon atoms.
Further, as used herein, the term“C3-C6”, as used in the present text, e.g. in the context of the definition of “Cs-Ce-cycloalkyl” or“C3-C6-cycloalkyloxy”, means a cycloalkyl or cycloalkyloxy group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms.
Further, as used herein, the term“C4-C6”, as used in the present text, e.g. in the context of the definition of “C4-C6-cycloalkenyl” means a cycloalkenyl group having a finite number of carbon atoms of 4 to 6, i.e. 4, 5 or 6 carbon atoms.
Further, as used herein, the term“Cs-Cs”, as used in the present text, e.g. in the context of the definition of “Cs-Cs-cycloalkyl”, means a cycloalkyl group having a finite number of carbon atoms of 5 to 8, i.e. 5, 6, 7 or 8 carbon atoms.
When a range of values is given, said range encompasses each value and sub-range within said range.
For example:
"Ci-Ce" encompasses Ci , C2, C3, C4, C5, Ce, C1-C6, C1-C5, C1-C4, C1-C3, C1 -C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;
"C2-C6" encompasses C2, C3, C4, C5, Ce, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;
"C1-C4" encompasses Ci , C2, C3, C4, C1-C4, C1 -C3, C1-C2, C2-C 4, C2-C3, and C3-C4;
"C2-C4" encompasses C2, C3, C4, C2-C4, C2-C3, and C3-C4;
"C3-C6" encompasses C3, C4, C5, C6, C3-Ce, C3-C5, C3-C4, C4-C 6, C4-C5, and C5-C6.
"C3-C8" encompasses C3, C4, C5, Ce, C7, Cs, C3-C8, C3-C7, C; i-C6, C3-C5, C3-C4, C4-C8, C4-C7, C4-C6, C4-C5, Cs-Cs, C5-C7, C5-C6, Cs-Cs, Ce-C7 and C7-C8.
"Cs-Cs" encompasses C5, Ce, C7, Cs, Cs-Cs, C5-C7, C5-C6, Ce-Cs, C6-C7 and C7-C8.
As used herein, the term“leaving group” means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons. In particular, such a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)- sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-fert-butyl- phenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.
It is possible for the compounds of general formula (I) and general formula (l-a) to exist as isotopic variants. The invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I) and general formula (l-a), particularly deuterium-containing compounds of general formula (I) and general formula (l-a).
The term“Isotopic variant” of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
The term“Isotopic variant of the compound of general formula (I) and general formula (l-a)” is defined as a compound of general formula (I) or general formula (l-a) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
The expression“unnatural proportion” means a proportion of such isotope which is higher than its natural abundance. The natural abundances of isotopes to be applied in this context are described in“Isotopic Compositions of the Elements 1997”, Pure Appl. Chem., 70(1 ), 217-235, 1998.
Examples of such isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 1 1 C, 13C, 14C, 15N, 170, 180, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36CI, 82Br, 1 , 124|_ 125| 129| anc| 131 _ respectively.
With respect to the treatment and/or prophylaxis of the disorders specified herein the isotopic variant(s) of the compounds of general formula (I) or general formula (l-a) preferably contain deuterium (“deuterium-containing compounds of general formula (I) or general formula (l-a)”). Isotopic variants of the compounds of general formula (I) or general formula (l-a) in which one or more radioactive isotopes, such as 3H or 14C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability. Positron emitting isotopes such as 18F or 1 1 C may be incorporated into a compound of general formula (I) or general formula (l-a). These isotopic variants of the compounds of general formula (I) or (l-a) are useful for in vivo imaging applications. Deuterium-containing and 13C-containing compounds of general formula (I) or general formula (l-a) can be used in mass spectrometry analyses in the context of preclinical or clinical studies.
Isotopic variants of the compounds of general formula (I) and general formula (l-a) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent. Depending on the desired sites of deuteration, in some cases deuterium from D20 can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds. Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic bonds and acetylenic bonds is a direct route for incorporation of deuterium. Metal catalysts (i.e. Pd, Pt, and Rh) in the presence of deuterium gas can be used to directly exchange deuterium for hydrogen in functional groups containing hydrocarbons. A variety of deuterated reagents and synthetic building blocks are commercially available from companies such as for example C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.
The term“deuterium-containing compound of general formula (I) or general formula (l-a)” is defined as a compound of general formula (I) or general formula (l-a), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general formula (I) or general formula (l-a) is higher than the natural abundance of deuterium, which is about 0.015%. Particularly, in a deuterium-containing compound of general formula (I) or general formula (l-a) the abundance of deuterium at each deuterated position of the compound of general formula (I) or general formula (l-a) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s).
The selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) or general formula (l-a) may alter the physicochemical properties (such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271 ]) and/or the metabolic profile of the molecule and may result in changes in the ratio of parent compound to metabolites or in the amounts of metabolites formed. Such changes may result in certain therapeutic advantages and hence may be preferred in some circumstances. Reduced rates of metabolism and metabolic switching, where the ratio of metabolites is changed, have been reported (A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes in the exposure to parent drug and metabolites can have important consequences with respect to the pharmacodynamics, tolerability and efficacy of a deuterium-containing compound of general formula (I) or general formula (l-a). In some cases deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases the major effect of deuteration is to reduce the rate of systemic clearance. As a result, the biological half-life of the compound is increased. The potential clinical benefits would include the ability to maintain similar systemic exposure with decreased peak levels and increased trough levels. This could result in lower side effects and enhanced efficacy, depending on the particular compound’s pharmacokinetic/ pharmacodynamic relationship. ML-337 (C. J. Wenthur et al., J. Med. Chem., 2013, 56, 5208) and Odanacatib (K. Kassahun et al., WO2012/1 12363) are examples for this deuterium effect. Still other cases have been reported in which reduced rates of metabolism result in an increase in exposure of the drug without changing the rate of systemic clearance (e.g. Rofecoxib: F. Schneider et al., Arzneim. Forsch. / Drug. Res., 2006, 56, 295; Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs showing this effect may have reduced dosing requirements (e.g. lower number of doses or lower dosage to achieve the desired effect) and/or may produce lower metabolite loads.
A compound of general formula (I) or general formula (l-a) may have multiple potential sites of attack for metabolism. To optimize the above-described effects on physicochemical properties and metabolic profile, deuterium-containing compounds of general formula (I) or general formula (l-a) having a certain pattern of one or more deuterium-hydrogen exchange(s) can be selected. Particularly, the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) or general formula (l-a) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I) or general formula (l-a), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P450.
In another embodiment the present invention concerns a deuterium-containing compound of general formula (I) or general formula (l-a) having 1 , 2, 3 or 4 deuterium atoms, particularly with 1 , 2 or 3 deuterium atoms.
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 the present invention of the structural formula (I) optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. Preferred isomers 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 the present 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 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. The optically active bases or acids are then liberated from the separated diastereomeric salts. 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. A different process for separation of optical isomers involves the use of chiral chromatography ( e.g ., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
In order to distinguish different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 1 1 -30, 1976).
In case stereogenic centres are present, other than the one specified in the structural formulae (l-a), (l-b), (l-c), (l-d), (l-e), (l-f), (l-g) and (l-h), the present invention includes all possible diastereomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, in any ratio. Isolation of a single stereoisomer, e.g. a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
Further, it is possible for the compounds of the present invention to exist as tautomers. For example, the compounds of the present invention contain a cyclohexanone moiety and can exist as a keton, or an enol, or even a mixture in any amount of the two tautomers, namely:
Figure imgf000021_0001
keton enol 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 atom of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides.
The present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or 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, dimethylsulfoxide, tetrahydrofuran, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to 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, it is possible for the compounds of the present invention to exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to 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, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
The term“pharmaceutically acceptable salt" refers to an 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, or“mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, 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, 3-phenylpropionic, pivalic, 2-hydroxyethanesulfonic, itaconic, trifluoromethanesulfonic, dodecylsulfuric, ethanesulfonic, benzenesulfonic, para-toluenesulfonic, methanesulfonic, 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, 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, magnesium or strontium salt, or an aluminium or a zinc salt, or an ammonium salt derived from ammonia or from an organic primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, A/-methylmorpholine, arginine, lysine, 1 ,2-ethylenediamine, A/-methylpiperidine, A/-methyl-glucamine, A/,A/-dimethyl-glucamine, A/-ethyl-glucamine, 1 ,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1 ,3- propanediol, 3-amino-1 , 2-propanediol, 4-amino-1 ,2,3-butanetriol, or a salt with a quarternary ammonium ion having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, A/-benzyl-A/,A/,A/- trimethylammonium, choline or benzalkonium.
Those skilled in the art will further recognise that it is possible for acid addition salts of the claimed compounds to 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 present invention are prepared by reacting the compounds of the present 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 relating to salts, such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x FICI", "x CF3COOFI", "x Na+", for example, mean a salt form, the stoichiometry of which salt form not being specified.
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, unless defined, unknown stoichiometric composition. As used herein, the term“in vivo hydrolysable ester” means 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 cycloalkyloxy-carbonyloxy-Ci-C6 alkyl esters, e.g. 1 - cyclohexyloxycarbonyloxyethyl ; 1 ,3-dioxolen-2-onylmethyl esters, e.g. 5-methyl-1 ,3-dioxolen- 2-onylmethyl; and Ci-C6-alkoxycarbonyloxyethyl esters, e.g. 1 -methoxycarbonyloxyethyl, it being possible for said esters to be formed at any carboxy group in the compounds of the present 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 a-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 a-acyloxyalkyl ethers include acetoxym ethoxy and 2,2- dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted alkanoyl, benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), N,N-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.
Moreover, the present invention also includes prodrugs of the compounds according to the invention. The term “prodrugs” here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.
In accordance with a second embodiment of the first aspect, the present invention covers compounds of general formula (I), supra , in which:
R1 represents a group
Figure imgf000024_0001
wherein X2 represents a hydrogen atom or a halogen atom or a substituent selected from Ci-Ce-alkyl, Cs-Ce-cycloalkyl, C4-C6-cycloalkenyl, Ci-Ce-alkoxy,
Ci-C6-haloalkoxy, (Ci-C6-alkoxy)-(C2-C4-alkoxy)-,
(C3-C6-cycloalkyloxy)-(C2-C4-alkoxy)-, 5- or 6-membered heteroaryl, phenyl-(Ci-C3-alkoxy)-, (5- or 6-membered heteroaryl)oxy-, -N(R5)(R6), -(Ci-C4-alkyl)-N(R5)(R6), 4- to 7-membered heterocycloalkyl,
(4- to 7-membered heterocycloalkyl)oxy-, and -N(R7)C(=0)R8,
wherein said Cs-Ce-cycloalkyl group and C4-C6-cycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, cyano and hydroxy,
wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of the
4- to 7-membered heterocycloalkyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and
(4- to 7-membered heterocycloalkyl)oxy group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, cyano and hydroxy,
and
wherein the phenyl part of said phenyl-(Ci-C3-alkoxy)- group, and said
5- or 6-membered heteroaryl group and (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)oxy- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, cyano and hydroxy, wherein X3 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent, wherein X4 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent, wherein X5 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent, wherein X6 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent,
R2 represents a group selected from phenyl, naphthyl and 5- or 6-membered heteroaryl, which phenyl, naphthyl and 5- or 6-membered heteroaryl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci -Ce-alkyl and Ci-C6-alkoxy,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a group selected from
-(CH2)3-, -(CH2)4-, -(CH2)2-0-, -CH2-O-CH2-, -(CH2)3-0-, -CH2-0-(CH2)2-, -O-CH2-O- and -0-(CH2)2-0-,
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkoxy and hydroxy,
R4 represents a hydrogen atom or Ci-C4-haloalkyl group,
or
R3 and R4 together with the carbon atom to which they are attached represent a
5- to 8-membered cycloalkyl group,
wherein said cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo,
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
selected from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl and
(Ci-C2-alkoxy)-(C2-C3-alkyl-),
or
R5 and R6 together with the nitrogen to which they are attached represent a
nitrogen containing 4- to 7-membered heterocycloalkyl group, wherein said 4- to 7-membered nitrogen containing heterocycloalkyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl,
(Ci -C2-alkoxy)-(C2-C3-alkyl)-, cyano, hydroxy and oxo,
R7 represents a hydrogen atom or a C1-C4 alkyl group,
and
R8 represents a hydrogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl and C3-C6-cycloalkyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a third embodiment of the first aspect, the present invention covers compounds of general formula (I), supra , in which :
R1 represents a group
Figure imgf000027_0001
wherein X2 represents a hydrogen atom or a halogen atom or a substituent selected from
Ci -C4-alkyl, Ci -C4-alkoxy and phenyl-(Ci -C2-alkoxy)-,
wherein the phenyl part of said phenyl-(Ci -C2-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci -C2-alkyl, cyano and hydroxy, wherein X3 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X4 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X5 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X6 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent,
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a Ci-C4-alkyl group,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
R3 represents a group selected from Ci-C4-alkoxy and hydroxy,
R4 represents a Ci-C4-haloalkyl group,
or
R3 and R4 together with the carbon atom to which they are attached represent a
5- to 8-membered cycloalkyl group,
wherein said cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo,
and stereoisomers, tautomers, hydrates, and solvates thereof, and mixtures of same.
In accordance with a fourth embodiment of the first aspect, the present invention covers compounds of general formula (l-a):
Figure imgf000029_0001
in which
Figure imgf000029_0002
wherein X2 represents a hydrogen atom or a halogen atom or a substituent selected from
Ci-C4-alkyl, Ci-C4-alkoxy and phenyl-(Ci-C2-alkoxy)-,
wherein the phenyl part of said phenyl-(Ci-C2-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, cyano and hydroxy, wherein X3 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X4 represents a hydrogen atom or a chlorine atom or a fluorine atomor a methyl substituent, wherein X5 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X6 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent,
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a Ci -C4-alkyl group,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
R3 represents a group selected from
Ci -C4-alkoxy and hydroxy,
R4 represents a Ci-C4-haloalkyl group,
or
R3 and R4 together with the carbon atom to which they are attached represent a
5- to 8-membered cycloalkyl group,
wherein said cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci -C2-alkyl, Ci -C2-haloalkyl, Ci -C2-alkoxy, cyano, hydroxy and oxo, and tautomers, hydrates, and solvates thereof, and mixtures of same.
In accordance with a fifth embodiment of the first aspect, the present invention covers compounds of general formula (l-a), supra , in which:
R1 represents a group
Figure imgf000030_0001
wherein X2 represents a hydrogen atom or a substituent selected from methyl, methoxy and benzyloxy, wherein X3 represents a hydrogen atom, wherein X4 represents a hydrogen atom or a fluorine atom, wherein X5 represents a hydrogen atom, wherein X6 represents a hydrogen atom,
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a bromine atom and a chlorine atom or a methyl group,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
R3 represents a group selected from methoxy and hydroxy,
R4 represents a trifluoromethyl group,
or
R3 and R4 together with the carbon atom to which they are attached represent a group
selected from cyclopentyl and cyclohexyl, and hydrates, and solvates thereof, and mixtures of same.
In accordance with a sixth embodiment of the first aspect, the present invention covers compounds of general formula (l-a), supra , in which:
R1 represents a group selected from
4-fluorophenyl, 4-fluoro-2-methylphenyl, 2-methoxyphenyl and 2-(benzyloxy)phenyl,
R2 represents a group selected from
phenyl, 3-bromophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dihydro-1 H-inden-5-yl and 1 -naphthyl,
R3 represents a group selected from
methoxy and hydroxy,
R4 represents a trifluoromethyl group,
or
R3 and R4 together with the carbon atom to which they are attached represent a group
selected from cyclopentyl and cyclohexyl,
and hydrates, and solvates thereof, and mixtures of same.
In accordance with a seventh embodiment of the first aspect, the present invention covers compounds of general formula (I), supra , which are selected from the group consisting of:
(rac) 9-{[1 -(3,5-dimethylphenyl)cyclopentyl]carbonyl}-5-(4-fluorophenyl)-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one,
(5R)-9-{[1 -(3,5-dimethylphenyl)cyclopentyl]carbonyl}-5-(4-fluorophenyl)-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one (single stereoisomer),
(5S)-9-{[1 -(3,5-dimethylphenyl)cyclopentyl]carbonyl}-5-(4-fluorophenyl)-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one (single stereoisomer),
(rac) 9-{[1 -(3-chlorophenyl)cyclopentyl]carbonyl}-5-(4-fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]- undecan-2-one,
(rac) 9-{[1 -(3-bromophenyl)cyclopentyl]carbonyl}-5-(4-fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]- undecan-2-one,
(rac) 5-(4-fluorophenyl)-9-[(1 -phenylcyclohexyl)carbonyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2- one,
5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9-diazaspi ro- [5.5]undecan-2-one (mixture of stereoisomers),
(5R)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5S)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of diastereoisomers),
(5R)-9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one, (5R)-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-
3.9-diazaspiro[5.5]undecan-2-one,
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of diastereoisomers),
(5R)-9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
9-[2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of diastereoisomers),
(5R)-9-[(2S)-2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2R)-2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2S)-2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
9-[2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-
3.9-diazaspiro[5.5]undecan-2-one (mixture of diastereoisomers), (5R)-9-[(2S)-2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluoro- phenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2R)-2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluoro- phenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2S)-2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluoro- phenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluoro- phenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
5-(4-fluorophenyl)-9-[3,3,3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers),
(5R)-5-(4-fluorophenyl)-9-[(2S)-3,3,3-trifluoro-2-methoxy-2-(1 -naphthyl)propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5R)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-(1 -naphthyl)propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5S)-5-(4-fluorophenyl)-9-[(2S)-3,3,3-trifluoro-2-methoxy-2-(1 -naphthyl)propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5S)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-(1 -naphthyl)propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
5-(2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one (mixture of two stereoisomers),
(5R)-5-(2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5S)-5-(2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
5-[2-(benzyloxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of two stereoisomers),
(5R)-5-(4-fluoro-2-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one (5S)-5-(4-fluoro-2-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of diastereomers),
(5R)-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
5-[2-(benzyloxy)phenyl]-9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers),
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of diastereomers),
(5R)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one, (5S)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
5-[2-(benzyloxy)phenyl]-9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one (mixture of diastereomers),
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy- propanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy- propanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy- propanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy- propanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
9-[(2R)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one (mixture of two stereoisomers),
9-[(2S)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one (mixture of two stereoisomers),
5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one (mixture of two stereoisomers),
5-[2-(benzyloxy)phenyl]-9-[(2S)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one (mixture of two stereoisomers),
5-(4-fluorophenyl)-9-[3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9-diazaspiro[5.5]- undecan-2-one (mixture of two diastereomers),
5-(4-fluorophenyl)-9-[(2S)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one (single stereoisomer),
5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one (single stereoisomer), 9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one (mixture of two diastereomers),
9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer),
9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer),
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of two diastereomers),
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of two diastereomers),
9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer),
9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer),
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of two stereoisomers),
9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one (single stereoisomer),
9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one (single stereoisomer),
9-[2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of two stereoisomers),
9-[(2R)-2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one (single stereoisomer),
9-[(2S)-2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one (single stereoisomer),
5-(4-fluoro-2-methylphenyl)-9-[3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one (mixture of two stereoisomers), 5-(4-fluoro-2-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer),
5-(4-fluoro-2-methylphenyl)-9-[(2S)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer), and
(rac) 5-(4-fluorophenyl)-9-[(1 -phenylcyclopentyl)carbonyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2- one, and stereoisomers, hydrates, solvates, or mixtures of same.
In accordance with an eights embodiment of the first aspect, the present invention covers compounds of general formula (l-a), supra , which are selected from the group consisting of:
(5R)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5S)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2R)-2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2R)-2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluoro- phenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one, (5S)-9-[(2R)-2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluoro- phenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-(1 -naphthyl)propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5S)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-(1 -naphthyl)propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5R)-5-(2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5S)-5-(2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5R)-5-(4-fluoro-2-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one
(5S)-5-(4-fluoro-2-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one
(5R)-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one, (5S)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy- propanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy- propanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2R)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-
1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2- methoxypropanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2- methoxypropanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one (single stereoisomer),
9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer),
9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer),
9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer),
9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa- 3,9-diazaspiro[5.5]undecan-2-one (single stereoisomer),
9-[(2R)-2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa- 3,9-diazaspiro[5.5]undecan-2-one (single stereoisomer), and
5-(4-fluoro-2-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer), and hydrates, solvates, or mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R1 represents a group
Figure imgf000041_0001
wherein X2 represents a hydrogen atom or a halogen atom or a substituent selected from
Ci-C4-alkyl, Ci-C4-alkoxy and phenyl-(Ci-C2-alkoxy)-,
wherein the phenyl part of said phenyl-(Ci-C2-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, cyano and hydroxy, wherein X3 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X4 represents a hydrogen atom or a chlorine atom or a fluorine atomor a methyl substituent, wherein X5 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X6 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent,
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a Ci-C4-alkyl group,
or two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
R3 represents a group selected from
Ci -C4-alkoxy and hydroxy,
R4 represents a Ci-C4-haloalkyl group,
or
R3 and R4 together with the carbon atom to which they are attached represent a
5- to 8-membered cycloalkyl group,
wherein said cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci -C2-alkyl, Ci -C2-haloalkyl, Ci -C2-alkoxy, cyano, hydroxy and oxo, and stereoisomers, tautomers, hydrates, and solvates thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R1 represents a group
Figure imgf000042_0001
wherein X2 represents a hydrogen atom or a substituent selected from methyl, methoxy and benzyloxy, wherein X3 represents a hydrogen atom, wherein X4 represents a hydrogen atom or a fluorine atom, wherein X5 represents a hydrogen atom, wherein X6 represents a hydrogen atom, R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a bromine atom and a chlorine atom or a methyl group,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
R3 represents a group selected from methoxy and hydroxy,
R4 represents a trifluoromethyl group,
or
R3 and R4 together with the carbon atom to which they are attached represent a group
selected from cyclopentyl and cyclohexyl, and stereoisomers, hydrates, and solvates thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R1 represents a group selected from
4-fluorophenyl, 4-fluoro-2-methylphenyl, 2-methoxyphenyl and 2-(benzyloxy)phenyl,
R2 represents a group selected from
phenyl, 3-bromophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dihydro-1 H-inden-5-yl and 1 -naphthyl,
R3 represents a group selected from
methoxy and hydroxy,
R4 represents a trifluoromethyl group,
or
R3 and R4 together with the carbon atom to which they are attached represent a group
selected from
cyclopentyl and cyclohexyl, and stereoisomers, hydrates, and solvates thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R1 represents a group
Figure imgf000044_0001
wherein X2 represents a hydrogen atom or a halogen atom or a substituent selected from
Ci -Ce-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, Cs-Ce-cycloalkyl,
(C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, C^Ce-cycloalkenyl,
(C4-C6-cycloalkenyl)-(Ci-C3-alkyl)-, Ci -C6-hydroxyalkyl,
(Ci -C2-alkoxy)-(Ci-C6-alkyl)-, (Ci -C2-haloalkoxy)-(Ci -C6-alkyl)-, Ci-C6-haloalkyl, Ci -C6-alkoxy, Ci-C6-haloalkoxy, C3-C6-cycloalkyloxy,
(C3-C6-cycloalkyloxy)-(Ci -C3-alkyl)-, (Ci -C6-alkoxy)-(C2-C4-alkoxy)-, (C3-C6-cycloalkyloxy)-(C2-C4-alkoxy)-, phenyl, 5- or 6-membered heteroaryl, phenyl-(Ci -C3-alkyl)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, phenoxy-(Ci -C3-alkyl)-, phenoxy-(C2-C3-alkoxy)-, (5- or 6-membered heteroaryl)-(Ci -C3-alkyl)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-,
(5- or 6-membered heteroaryl)oxy-(C2-C3-alkoxy)-,
(5- or 6-membered heteroaryl)oxy-, -SH, -S-(Ci -Ce-alkyl), -S(=0)-(Ci -C6-alkyl), -S(=0)2-(Ci -Ce-alkyl) , -S-(C3-C6-cycloalkyl) , -S(=0)-(C3-C6-cycloalkyl) ,
-S(=0)2-(C3-C6-cycloalkyl) , (Ci -C6-alkyl)-S-(Ci -C3-alkyl)-,
(Ci -C6-alkyl)-S(=0)-(Ci -C3-alkyl)-, (Ci-C6-alkyl)-S(=0)2-(Ci -C3-alkyl)-,
(C3-C6-cycloalkyl)-S-(Ci -C3-alkyl)-, (C3-C6-cycloalkyl)-S(=0)-(Ci-C3-alkyl), (C3-C6-cycloalkyl)-S(=0)2-(Ci -C3-alkyl) , -S-(Ci -Ce-haloalkyl) ,
-S(=0)-(Ci-C6-haloalkyl), -S(=0)2-(Ci-C6-haloalkyl), -S-phenyl, -S(=0)-phenyl, -S(=0)2-phenyl, -cyano, hydroxy, -N(R5)(R6), -(Ci-C4-alkyl)-N(R5)(R6),
4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, -(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl),
(4- to 7-membered heterocycloalkyl)oxy-, -C(=0)R8, C(=0)N(R5)(R6),
-C(=0)0R7, -N(R7)C(=0)R8, -N(R7)C(=0)0R1°, -N(R7)C(=0)N(R5)(R6),
-0C(=0)N(R5)(R6), -0C(=0)R8 and -N(R7)S(=0)2R1 1 , wherein said Cs-Ce-cycloalkyl group and C4-C6-cycloalkenyl group and the (C3-C6-cycloalkyl) part of said (C3-C6-cycloalkyl)-(Ci -C3-alkyl) group and the (C -Ce-cycloalkenyl) part of said
(C4-C6-cycloalkenyl) -(Ci-C3-alkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano and hydroxy, and
wherein said C3-C6-cycloalkyloxy group and the (C3-C6-cycloalkyloxy) part of said (C3-C6-cycloalkyloxy)-(Ci-C3-alkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano and hydroxy, and
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the
4- to 7-membered heterocycloalkyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and
(4- to 7-membered heterocycloalkyl)oxy group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, C3-C4-cycloalkyl, Ci-C2-alkoxy, cyano, hydroxy, -N(R5)(R6) and oxo,
and
wherein said phenyl and phenoxy group, and the phenyl part of said phenyl-(Ci-C3-alkyl)-, phenyl-(Ci-C3-alkoxy)-, phenoxy-(Ci-C3-alkyl)-, phenoxy-(C2-C3-alkoxy)-, -S-phenyl, -S(=0)-phenyl and -S(=0)2-phenyl group, and said 5- or 6-membered heteroaryl group and
(5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)-(Ci-C3-alkyl),
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy),
(5- or 6-membered heteroaryl)oxy-(C2-C3-alkoxy) and (5- or 6-membered heteroaryljoxy- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy and -N(R5)(R6), wherein X3 represents a hydrogen atom or a halogen atom or a substituent selected from Ci-C2-alkyl and Ci-C2-alkoxy, or,
wherein X2 and X3 are linked to one another in such a way that they jointly form a group selected from
-(CH2)2-0-, -0-(CH2)2-, -CH2-O-CH2-, -(CH2)3-0-, -0-(CH2)3-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, O-CH2-O-, -0-(CH2)2-0-, -(CH2)2-N(R9)-, -N(R9)-(CH2)2-, -CH2-N(R9)-CH2-, -(CH2)3-N(R9)-, -N(R9)-(CH2)3-, -CH2-N(R9)-(CH2)2-,
-(CH2)2-N(R9)-CH2-, -N(R9)-(CH2)2-N(R9)-, -N(R9)-(CH2)2-0- and
-0-(CH2)2-N(R9)-,
wherein X4 represents a hydrogen atom or a halogen atom or a substituent selected from Ci-C2-alkyl and Ci-C2-haloalkyl, or,
wherein X3 and X4 are linked to one another in such a way that they jointly form a group selected from
-(CH2)2-0-, -0-(CH2)2-, -CH2-O-CH2-, -(CH2)3-0-, -0-(CH2)3-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, 0-CH2-0-, -0-(CH2)2-0-, -(CH2)2-N(R9)-, -N(R9)-(CH2)2-, -CH2-N(R9)-CH2-, -(CH2)3-N(R9)-, -N(R9)-(CH2)3-, -CH2-N(R9)-(CH2)2-,
-(CH2)2-N(R9)-CH2-, -N(R9)-(CH2)2-N(R9)-, -N(R9)-(CH2)2-0- and
-0-(CH2)2-N(R9)-, wherein X5 represents a hydrogen atom or a halogen atom or a substituent selected from Ci-C2-alkyl and Ci-C2-alkoxy, wherein X6 represents a hydrogen atom or a halogen atom or a substituent selected from Ci-C2-alkyl and Ci-C2-alkoxy, R2 represents a group selected from phenyl, naphthyl and 5- or 6-membered heteroaryl, which phenyl, naphthyl and 5- or 6-membered heteroaryl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci -Ce-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C6-cycloalkyl, C4-C6-cycloalkenyl, Ci-Ce-hydroxyalkyl, Ci-Ce-haloalkyl, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy,
(Ci-C4-alkoxy)-(Ci-C6-alkyl)-, (Ci-C4-haloalkoxy)-( Ci-C6-alkyl)-, (Ci-C4-alkoxy)-(C2-C6-alkoxy)-, (Ci-C4-haloalkoxy)-( C2-C6-alkoxy)-, Cs-Ce-cycloalkyloxy, -SH, -S-(Ci -Ce-alkyl), -S(=0)-(Ci-C6-alkyl), -S(=0)2-(Ci-C6-alkyl), -S-(Ci-C6-haloalkyl), -S(=0)-(Ci-C6-haloalkyl),
-S(=0)2-(Ci-C6-haloalkyl), -S-(C3-C6-cycloalkyl), -S(=0)-(C3-C6-cycloalkyl), -S(=0)2-(C3-C6-cycloalkyl), -S(=0)2N(R5)R6, -(Ci-C4-alkyl)-S(=0)2N(R5)R6, cyano, hydroxy, -N(R5)(R6), -(Ci-C4-alkyl)-N(R5)(R6), -N(R7)C(=0)R8,
-N(R7)C(=0)OR1°, -N(R7)C(=0)N(R5)(R6), -OC(=0)R8, -C(=0)OR7, -C(=0)N(R5)R6, 4- to 7-membered heterocycloalkyl,
5- to 7-membered heterocycloalkenyl, phenyl and 5- or 6-membered heteroaryl, or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a group selected from
-(CH2)3-, -(CH2) -, -(CH2)2-0-, -CH2-O-CH2-, -(CH2)3-0-, -CH2-0-(CH2)2-, -O-CH2-O- and -0-(CH2)2-0-,
wherein said 4- to 7-membered heterocycloalkyl group and
5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of said
4- to 7-membered heterocycloalkyl group and
5- to 7-membered heterocycloalkenyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and
5- to 7-membered heterocycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy, -N(R5)(R6) and oxo,
and wherein said Cs-Ce-cycloalkyl group and C4-C6-cycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo and
wherein said C2-C6-alkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-alkoxy group,
and
wherein said phenyl group and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy and -N(R5)(R6),
R3 represents a hydrogen atom, a halogen atom, or a group selected from
C2-C4-alkyl, C2-C4-alkenyl, C2-C4-alkinyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl,
Ci-C4-haloalkyl, (Ci-C2-haloalkoxy)-(Ci-C2-alkyl)-, Ci-C4-alkoxy, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy, hydroxy, cyano, -N(R5)(R6), -(Ci-C2-alkyl)-N(R5)(R6),
C4-C7-heterocycloalkyl, -(Ci-C2-alkyl)-(C4-C7-heterocycloalkyl),
(Ci-C2-haloalkoxy)-(Ci-C2-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-,
(C3-C4-cycloalkyloxy)-(Ci-C2-alkyl)-, -C(=0)N(R5)(R6) and -C(=0)OR7,
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C2-alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C2-alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy,
-N(R5)(R6) and oxo,
and wherein said cycloalkyl group and is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and -N(R5)(R6),
R4 represents a hydrogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkinyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl,
Ci-C4-haloalkyl, -(Ci-C2-alkyl)-N(R5)(R6), C4-C7-heterocycloalkyl,
-(Ci-C2-alkyl)-( C4-C7-heterocycloalkyl), (Ci-C2-haloalkoxy)-(Ci-C2-alkyl)-,
(Ci -C2-alkoxy)-(Ci -C2-alkyl)- and (C3-C4-cycloalkyloxy)-(Ci -C2-alkyl)-,
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C2-alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C2-alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy,
-N(R5)(R6) and oxo,
and
wherein said cycloalkyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and -N(R5)(R6), or
R3 and R4 together with the carbon atom to which they are attached represent a
5- to 8-membered cycloalkyl group,
wherein said cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo, R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group selected from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl and
(Ci-C2-alkoxy)-(C2-C3-alkyl-),
or
R5 and R6 together with the nitrogen to which they are attached represent a
nitrogen containing 4- to 7-membered heterocycloalkyl group,
wherein said 4- to 7-membered nitrogen containing heterocycloalkyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(C2-C3-alkyl)-, cyano, hydroxy and oxo,
R7 represents a hydrogen atom or a Ci-C4 alkyl group,
R8 represents a hydrogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl and C3-C6-cycloalkyl,
R9 represents a hydrogen atom or a group selected from
Ci-Ce alkyl, C2-Ce haloalkyl, C3-C6 cycloalkyl,
wherein said cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo,
R1 0 represents a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl and C3-C6 cycloalkyl,
and
R1 1 represents a group selected from
Ci-C4-alkyl and Ci-C4-haloalkyl, Cs-Ce-cycloalkyl and phenyl,
wherein said cycloalkyl group is optionally substituted one or two or times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo, and
wherein said phenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C2-alkyl, Ci -C2-haloalkyl, C3-C4-cycloalkyl, Ci-C2-alkoxy, cyano, hydroxy, 4- to 7-membered heterocycloalkyl and -N(R5)(R6), and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R1 represents a group
Figure imgf000051_0001
wherein X2 represents a hydrogen atom or a halogen atom or a substituent selected from
Ci -Ce-alkyl, C3-C6-cycloalkyl, C^Ce-cycloalkenyl, Ci-C6-alkoxy, Ci -C6-haloalkoxy, (Ci-C6-alkoxy)-(C2-C4-alkoxy)-,
(C3-C6-cycloalkyloxy)-(C2-C4-alkoxy)-, 5- or 6-membered heteroaryl, phenyl-(Ci -C3-alkoxy)-, (5- or 6-membered heteroaryl)oxy-, -N(R5)(R6), -(Ci-C4-alkyl)-N(R5)(R6), 4- to 7-membered heterocycloalkyl,
(4- to 7-membered heterocycloalkyl)oxy-, and -N(R7)C(=0)R8,
wherein said C3-C6-cycloalkyl group and C4-C6-cycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci -C2-alkyl, cyano and hydroxy,
wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of the
4- to 7-membered heterocycloalkyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and
(4- to 7-membered heterocycloalkyl)oxy group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci -C2-alkyl, cyano and hydroxy, and
wherein the phenyl part of said phenyl-(Ci-C3-alkoxy)- group, and said 5- or 6-membered heteroaryl group and (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)oxy- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, cyano and hydroxy, wherein X3 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent, wherein X4 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent, wherein X5 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent, wherein X6 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent,
R2 represents a group selected from phenyl, naphthyl and 5- or 6-membered heteroaryl, which phenyl, naphthyl and 5- or 6-membered heteroaryl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci -Ce-alkyl and Ci-C6-alkoxy,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a group selected from
-(CH2)3-, -(CH2)4-, -(CH2)2-0-, -CH2-0-CH2-, -(CH2)3-0-, -CH2-0-(CH2)2-, -0-CH2-0- and -0-(CH2)2-0-,
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkoxy and hydroxy,
R4 represents a hydrogen atom or Ci-C4-haloalkyl group,
or R3 and R4 together with the carbon atom to which they are attached represent a
5- to 8-membered cycloalkyl group,
wherein said cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo,
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
selected from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl and
(Ci-C2-alkoxy)-(C2-C3-alkyl-),
or
R5 and R6 together with the nitrogen to which they are attached represent a
nitrogen containing 4- to 7-membered heterocycloalkyl group,
wherein said 4- to 7-membered nitrogen containing heterocycloalkyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(C2-C3-alkyl)-, cyano, hydroxy and oxo,
R7 represents a hydrogen atom or a C1-C4 alkyl group,
R8 represents a hydrogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl and C3-C6-cycloalkyl,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
Further embodiments of the first aspect of the present invention:
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R1 represents a group
Figure imgf000053_0001
wherein X2 represents a hydrogen atom or a halogen atom or a substituent selected from
Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C6-cycloalkyl,
(C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, C^Ce-cycloalkenyl,
(C4-C6-cycloalkenyl)-(Ci-C3-alkyl)-, Ci-Ce-hydroxyalkyl,
(Ci-C2-alkoxy)-(Ci-C6-alkyl)-, (Ci-C2-haloalkoxy)-(Ci-C6-alkyl)-, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, C3-C6-cycloalkyloxy,
(C3-C6-cycloalkyloxy)-(Ci-C3-alkyl)-, (Ci-C6-alkoxy)-(C2-C4-alkoxy)-,
(C3-C6-cycloalkyloxy)-(C2-C4-alkoxy)-, phenyl, 5- or 6-membered heteroaryl, phenyl-(Ci-C3-alkyl)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, phenoxy-(Ci-C3-alkyl)-, phenoxy-(C2-C3-alkoxy)-, (5- or 6-membered heteroaryl)-(Ci-C3-alkyl)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-,
(5- or 6-membered heteroaryl)oxy-(C2-C3-alkoxy)-,
(5- or 6-membered heteroaryl)oxy-, -SH, -S-(Ci-Ce-alkyl), -S(=0)-(Ci-C6-alkyl), -S(=0)2-(Ci -Ce-alkyl) , -S-(C3-C6-cycloalkyl) , -S(=0)-(C3-C6-cycloalkyl) , -S(=0)2-(C3-C6-cycloalkyl) , (Ci -C6-alkyl)-S-(Ci -C3-alkyl)-,
(Ci -C6-alkyl)-S(=0)-(Ci -C3-alkyl)-, (Ci-C6-alkyl)-S(=0)2-(Ci -C3-alkyl)-,
(C3-C6-cycloalkyl)-S-(Ci-C3-alkyl)-, (C3-C6-cycloalkyl)-S(=0)-(Ci-C3-alkyl), (C3-C6-cycloalkyl)-S(=0)2-(Ci -C3-alkyl) , -S-(Ci -Ce-haloalkyl) ,
-S(=0)-(Ci-C6-haloalkyl), -S(=0)2-(Ci-C6-haloalkyl), -S-phenyl, -S(=0)-phenyl, -S(=0)2-phenyl, -cyano, hydroxy, -N(R5)(R6), -(Ci-C4-alkyl)-N(R5)(R6),
4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, -(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl),
(4- to 7-membered heterocycloalkyl)oxy-, -C (=0)N(R5)(R6),
-C(=0)OR7, -N(R7)C(=0)R8, -N(R7)C(=0)O C(=0)N(R5)(R6), -0C(=0)N(R5)(R6), -OC(=0)R8 and -N(R7)S
wherein said C3-C6-cycloalkyl group
Figure imgf000054_0001
cycloalkenyl group and the (C3-C6-cycloalkyl) part of said (C3-C6-cycloalkyl)-(Ci -C3-alkyl) group and the (C4-C6-cycloalkenyl) part of said
(C4-C6-cycloalkenyl) -(Ci-C3-alkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano and hydroxy, and
wherein said Cs-Ce-cycloalkyloxy group and the (Cs-Ce-cycloalkyloxy) part of said (C3-C6-cycloalkyloxy)-(Ci-C3-alkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano and hydroxy, and
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the
4- to 7-membered heterocycloalkyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and
(4- to 7-membered heterocycloalkyl)oxy group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, C3-C4-cycloalkyl, Ci-C2-alkoxy, cyano, hydroxy, -N(R5)(R6) and oxo,
and
wherein said phenyl and phenoxy group, and the phenyl part of said phenyl-(Ci-C3-alkyl)-, phenyl-(Ci-C3-alkoxy)-, phenoxy-(Ci-C3-alkyl)-, phenoxy-(C2-C3-alkoxy)-, -S-phenyl, -S(=0)-phenyl and -S(=0)2-phenyl group, and said 5- or 6-membered heteroaryl group and
(5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)-(Ci-C3-alkyl),
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy),
(5- or 6-membered heteroaryl)oxy-(C2-C3-alkoxy) and
(5- or 6-membered heteroaryl)oxy- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy and -N(R5)(R6), wherein X3 represents a hydrogen atom or a halogen atom or a substituent selected from Ci-C2-alkyl and Ci-C2-alkoxy, or, wherein X2 and X3 are linked to one another in such a way that they jointly form a group selected from
(CH2)2-0-, -0-(CH2) CH2-0-CH2-, -(CH2)3-0-, -0-(CH2) CH2-0-(CH2);
(CH2)2-0-CH2-, 0-CH2-0-, -0-(CH2)2-0-, -(CH2)2-N(R9)-, -N(R9)-(CH2);
CH2-N(R9)-CH2-, -(CH2)3-N(R9)-, -N(R9)-(CH2): CH2-N(R9)-(CH2);
-(CH2)2-N(R9)-CH2-, -N(R9)-(CH2)2-N(R9)-, -N(R9)-(CH2)2-0- and
-0-(CH2)2-N(R9)-,
wherein X4 represents a hydrogen atom or a halogen atom or a substituent selected from Ci -C2-alkyl and Ci-C2-haloalkyl, or,
wherein X3 and X4 are linked to one another in such a way that they jointly form a group selected from
-(CH2)2-0-, -0-(CH2)2-, -CH2-0-CH2-, -(CH2)3-0-, -0-(CH2)3-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, 0-CH2-0-, -0-(CH2)2-0-, -(CH2)2-N(R9)-, -N(R9)-(CH2)2-, -CH2-N(R9)-CH2-, -(CH2)3-N(R9)-, -N(R9)-(CH2)3-, -CH2-N(R9)-(CH2)2-,
-(CH2)2-N(R9)-CH2-, -N(R9)-(CH2)2-N(R9)-, -N(R9)-(CH2)2-0- and
-0-(CH2)2-N(R9)-, wherein X5 represents a hydrogen atom or a halogen atom or a substituent selected from Ci -C2-alkyl and Ci-C2-alkoxy, wherein X6 represents a hydrogen atom or a halogen atom or a substituent selected from Ci -C2-alkyl and Ci-C2-alkoxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R1 represents a group
Figure imgf000056_0001
wherein X2 represents a hydrogen atom or a halogen atom or a substituent selected from
Ci-Ce-alkyl, C3-C6-cycloalkyl, C -Ce-cycloalkenyl, Ci-C6-alkoxy,
Ci-Ce-haloalkoxy, (Ci-C6-alkoxy)-(C2-C4-alkoxy)-,
(C3-C6-cycloalkyloxy)-(C2-C4-alkoxy)-, 5- or 6-membered heteroaryl, phenyl-(Ci-C3-alkoxy)-, (5- or 6-membered heteroaryl)oxy-, -N(R5)(R6), -(Ci-C4-alkyl)-N(R5)(R6), 4- to 7-membered heterocycloalkyl,
(4- to 7-membered heterocycloalkyl)oxy-, and -N(R7)C(=0)R8,
wherein said Cs-Ce-cycloalkyl group and C4-C6-cycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, cyano and hydroxy,
wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of the
4- to 7-membered heterocycloalkyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and
(4- to 7-membered heterocycloalkyl)oxy group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, cyano and hydroxy,
and
wherein the phenyl part of said phenyl-(Ci-C3-alkoxy)- group, and said
5- or 6-membered heteroaryl group and (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)oxy- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, cyano and hydroxy, wherein X3 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent, wherein X4 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent, wherein X5 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent, wherein X6 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R1 represents a group
Figure imgf000058_0001
wherein X2 represents a hydrogen atom or a halogen atom or a substituent selected from
Ci-C4-alkyl, Ci-C4-alkoxy and phenyl-(Ci-C2-alkoxy)-,
wherein the phenyl part of said phenyl-(Ci-C2-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, cyano and hydroxy, wherein X3 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X4 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X5 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X6 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R1 represents a group
Figure imgf000059_0001
wherein X2 represents a hydrogen atom or a substituent selected from methyl, methoxy and benzyloxy, wherein X3 represents a hydrogen atom, wherein X4 represents a hydrogen atom or a fluorine atom, wherein X5 represents a hydrogen atom, wherein X6 represents a hydrogen atom,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R1 represents a group selected from
4-fluorophenyl, 4-fluoro-2-methylphenyl, 2-methoxyphenyl and 2-(benzyloxy)phenyl,
R2 represents a group selected from
phenyl, 3-bromophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dihydro-1 H-inden-5-yl and 1 -naphthyl,
R3 represents a group selected from
methoxy and hydroxy,
R4 represents a trifluoromethyl group,
or R3 and R4 together with the carbon atom to which they are attached represent a group selected from
cyclopentyl and cyclohexyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R2 represents a group selected from phenyl, naphthyl and 5- or 6-membered heteroaryl, which phenyl, naphthyl and 5- or 6-membered heteroaryl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci -Ce-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C6-cycloalkyl, C^Ce-cycloalkenyl, Ci-Ce-hydroxyalkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, (Ci-C4-alkoxy)-(Ci-C6-alkyl)-, (Ci-C4-haloalkoxy)-( Ci-C6-alkyl)-, (Ci-C4-alkoxy)-(C2-C6-alkoxy)-, (Ci-C4-haloalkoxy)-( C2-C6-alkoxy)-, C3-C6-cycloalkyloxy, -SH, -S-(Ci -Ce-alkyl), -S(=0)-(Ci-C6-aikyl), -S(=0)2-(Ci-C6-alkyl), -S-(Ci-C6-haloalkyl), -S(=0)-(Ci-C6-haloaikyl), -S(=0)2-(Ci-C6-haloalkyl), -S-(C3-C6-cycloalkyl), -S(=0)-(C3-C6-cycloalkyl), -S(=0)2-(C3-C6-cycloalkyl), -S(=0)2N(R5)R6, -(Ci-C4-aikyl)-S(=0)2N(R5)R6, cyano, hydroxy, -N(R5)(R6), -(Ci-C4-alkyl)-N(R5)(R6), -N(R7)C(=0)R8, -N(R7)C(=0)0R1°, -N(R7)C(=0)N(R5)(R6), -0C(=0)R8, -C(=0)0R7, -C(=0)N(R5)R6, 4- to 7-membered heterocycloalkyl,
5- to 7-membered heterocycloalkenyl, phenyl and 5- or 6-membered heteroaryl, or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a group selected from
-(CH2)3-, -(CH2) -, -(CH2)2-0-, -CH2-O-CH2-, -(CH2)3-0-, -CH2-0-(CH2)2-, -O-CH2-O- and -0-(CH2)2-0-,
wherein said 4- to 7-membered heterocycloalkyl group and
5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of said
4- to 7-membered heterocycloalkyl group and
5- to 7-membered heterocycloalkenyl group,
and wherein said 4- to 7-membered heterocycloalkyl group and
5- to 7-membered heterocycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy, -N(R5)(R6) and oxo,
and
wherein said C3-C6-cycloalkyl group and C^Ce-cycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo and
wherein said C2-C6-alkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-alkoxy group,
and
wherein said phenyl group and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy and -N(R5)(R6),
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R2 represents a group selected from phenyl, naphthyl and 5- or 6-membered heteroaryl, which phenyl, naphthyl and 5- or 6-membered heteroaryl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci -Ce-alkyl and Ci-C6-alkoxy,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a group selected from -(CH2)3-, -(CH2)4-, -(CH2)2-0-, -CH2-0-CH2-, -(CH2)3-0-, -CH2-0-(CH2)2-, -0-CH2-0- and -0-(CH2)2-0-,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a Ci -C4-alkyl group,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a bromine atom and a chlorine atom or a methyl group,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which: R2 represents a group selected from
phenyl, 3-bromophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dihydro-1 H-inden-5-yl and 1 -naphthyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R3 represents a hydrogen atom, a halogen atom, or a group selected from
C2-C4-alkyl, C2-C4-alkenyl, C2-C4-alkinyl, Cs-Ce-cycloalkyl, Ci-C4-hydroxyalkyl,
Ci-C4-haloalkyl, (Ci-C2-haloalkoxy)-(Ci-C2-alkyl)-, Ci-C4-alkoxy, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy, hydroxy, cyano, -N(R5)(R6), -(Ci-C2-alkyl)-N(R5)(R6),
C4-C7-heterocycloalkyl, -(Ci-C2-alkyl)-(C4-C7-heterocycloalkyl),
(Ci-C2-haloalkoxy)-(Ci-C2-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-,
(C3-C4-cycloalkyloxy)-(Ci-C2-alkyl)-, -C(=0)N(R5)(R6) and -C(=0)0R7,
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C2-alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C2-alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy,
-N(R5)(R6) and oxo,
and
wherein said cycloalkyl group and is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and -N(R5)(R6),
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkoxy and hydroxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R3 represents a group selected from Ci-C4-alkoxy and hydroxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R3 represents a group selected from methoxy and hydroxy,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R4 represents a hydrogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkinyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl,
Ci-C4-haloalkyl, -(Ci-C2-alkyl)-N(R5)(R6), C4-C7-heterocycloalkyl,
-(Ci-C2-alkyl)-( C4-C7-heterocycloalkyl), (Ci-C2-haloalkoxy)-(Ci-C2-alkyl)-,
(Ci -C2-alkoxy)-(Ci -C2-alkyl)- and (C3-C4-cycloalkyloxy)-(Ci -C2-alkyl)-,
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C2-alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C2-alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy,
-N(R5)(R6) and oxo,
and
wherein said cycloalkyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and -N(R5)(R6), and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R4 represents a hydrogen atom or Ci-C4-haloalkyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R4 represents a Ci-C4-haloalkyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R4 represents a trifluoromethyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R3 and R4 together with the carbon atom to which they are attached represent a
5- to 8-membered cycloalkyl group,
wherein said cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R3 and R4 together with the carbon atom to which they are attached represent a group
selected from cyclopentyl and cyclohexyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
selected from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl and
(Ci-C2-alkoxy)-(C2-C3-alkyl-),
or
R5 and R6 together with the nitrogen to which they are attached represent a
nitrogen containing 4- to 7-membered heterocycloalkyl group,
wherein said 4- to 7-membered nitrogen containing heterocycloalkyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(C2-C3-alkyl)-, cyano, hydroxy and oxo,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
selected from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl and
(Ci-C2-alkoxy)-(C2-C3-alkyl-),
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R5 and R6 together with the nitrogen to which they are attached represent a
nitrogen containing 4- to 7-membered heterocycloalkyl group,
wherein said 4- to 7-membered nitrogen containing heterocycloalkyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(C2-C3-alkyl)-, cyano, hydroxy and oxo,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R7 represents a hydrogen atom or a Ci-C4 alkyl group,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R8 represents a hydrogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl and Cs-Ce-cycloalkyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R9 represents a hydrogen atom or a group selected from
Ci-C6 alkyl, C2-C6 haloalkyl, C3-C6 cycloalkyl,
wherein said cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R1 0 represents a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl and C3-C6 cycloalkyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R1 1 represents a group selected from
Ci-C4-alkyl and Ci-C4-haloalkyl, C3-C6-cycloalkyl and phenyl,
wherein said cycloalkyl group is optionally substituted one or two or times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo, and
wherein said phenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C2-alkyl, Ci -C2-haloalkyl, C3-C4-cycloalkyl, Ci-C2-alkoxy, cyano, hydroxy, 4- to 7-membered heterocycloalkyl and -N(R5)(R6),
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R1 represents a group
Figure imgf000069_0001
wherein X2 represents a hydrogen atom or a halogen atom or a substituent selected from
Ci -Ce-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C6-cycloalkyl,
(C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, C4-C6-cycloalkenyl,
(C4-C6-cycloalkenyl)-(Ci-C3-alkyl)-, Ci -C6-hydroxyalkyl,
(Ci -C2-alkoxy)-(Ci-C6-alkyl)-, (Ci -C2-haloalkoxy)-(Ci -C6-alkyl)-, Ci-C6-haloalkyl, Ci -C6-alkoxy, Ci-C6-haloalkoxy, C3-C6-cycloalkyloxy,
(C3-C6-cycloalkyloxy)-(Ci -C3-alkyl)-, (Ci -C6-alkoxy)-(C2-C4-alkoxy)-, (C3-C6-cycloalkyloxy)-(C2-C4-alkoxy)-, phenyl, 5- or 6-membered heteroaryl, phenyl-(Ci -C3-alkyl)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, phenoxy-(Ci -C3-alkyl)-, phenoxy-(C2-C3-alkoxy)-, (5- or 6-membered heteroaryl)-(Ci -C3-alkyl)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-,
(5- or 6-membered heteroaryl)oxy-(C2-C3-alkoxy)-,
(5- or 6-membered heteroaryl)oxy-, -SH, -S-(Ci -C6-alkyl), -S(=0)-(Ci -C6-alkyl), -S(=0)2-(Ci -Ce-alkyl) , -S-(C3-C6-cycloalkyl) , -S(=0)-(C3-C6-cycloalkyl) ,
-S(=0)2-(C3-C6-cycloalkyl) , (Ci -C6-alkyl)-S-(Ci -Cs-alkyl)-,
(Ci -Ce-aikyl)-S(=0)-(Ci -C3-alkyl)-, (Ci-C6-alkyl)-S(=0)2-(Ci -Cs-alkyl)-,
(C3-C6-cycloalkyl)-S-(Ci -C3-alkyl)-, (C3-C6-cycloalkyl)-S(=0)-(Ci-C3-alkyl), (C3-C6-cycloalkyl)-S(=0)2-(Ci -C3-alkyl) , -S-(Ci -Ce-haloalkyl) ,
-S(=0)-(Ci-C6-haloalkyl), -S(=0)2-(Ci-C6-haloalkyl), -S-phenyl, -S(=0)-phenyl, -S(=0)2-phenyl, -cyano, hydroxy, -N(R5)(R6), -(Ci-C4-alkyl)-N(R5)(R6),
4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, -(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl),
(4- to 7-membered heterocycloalkyl)oxy-, -C(=0)R8, C(=0)N(R5)(R6), -C(=0)0R7, -N(R7)C(=0)R8, -N(R7)C(=0)0R1°, -N(R7)C(=0)N(R5)(R6), -0C(=0)N(R5)(R6), -0C(=0)R8 and -N(R7)S(=0)2R11 ,
wherein said C3-C6-cycloalkyl group and C^Ce-cycloalkenyl group and the (C3-C6-cycloalkyl) part of said (C3-C6-cycloalkyl)-(Ci -C3-alkyl) group and the (C^Ce-cycloalkenyl) part of said
(C4-C6-cycloalkenyl) -(Ci-C3-alkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano and hydroxy, and
wherein said C3-C6-cycloalkyloxy group and the (C3-C6-cycloalkyloxy) part of said (C3-C6-cycloalkyloxy)-(Ci-C3-alkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano and hydroxy, and
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the
4- to 7-membered heterocycloalkyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and
(4- to 7-membered heterocycloalkyl)oxy group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, C3-C4-cycloalkyl, Ci-C2-alkoxy, cyano, hydroxy, -N(R5)(R6) and oxo,
and
wherein said phenyl and phenoxy group, and the phenyl part of said phenyl-(Ci-C3-alkyl)-, phenyl-(Ci-C3-alkoxy)-, phenoxy-(Ci-C3-alkyl)-, phenoxy-(C2-C3-alkoxy)-, -S-phenyl, -S(=0)-phenyl and -S(=0)2-phenyl group, and said 5- or 6-membered heteroaryl group and
(5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)-(Ci-C3-alkyl), (5- or 6-membered heteroaryl)-(Ci-C3-alkoxy),
(5- or 6-membered heteroaryl)oxy-(C2-C3-alkoxy) and
(5- or 6-membered heteroaryljoxy- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy and -N(R5)(R6), wherein X3 represents a hydrogen atom or a halogen atom or a substituent selected from Ci-C2-alkyl and Ci-C2-alkoxy, or,
wherein X2 and X3 are linked to one another in such a way that they jointly form a group selected from
-(CH2)2-0-, -0-(CH2)2-, -CH2-O-CH2-, -(CH2)3-0-, -0-(CH2)3-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, O-CH2-O-, -0-(CH2)2-0-, -(CH2)2-N(R9)-, -N(R9)-(CH2)2-, -CH2-N(R9)-CH2-, -(CH2)3-N(R9)-, -N(R9)-(CH2)3-, -CH2-N(R9)-(CH2)2-,
-(CH2)2-N(R9)-CH2-, -N(R9)-(CH2)2-N(R9)-, -N(R9)-(CH2)2-0- and
-0-(CH2)2-N(R9)-,
wherein X4 represents a hydrogen atom or a halogen atom or a substituent selected from Ci-C2-alkyl and Ci-C2-haloalkyl, or,
wherein X3 and X4 are linked to one another in such a way that they jointly form a group selected from
-(CH2)2-0-, -0-(CH2)2-, -CH2-0-CH2-, -(CH2)3-0-, -0-(CH2)3-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, 0-CH2-0-, -0-(CH2)2-0-, -(CH2)2-N(R9)-, -N(R9)-(CH2)2-, -CH2-N(R9)-CH2-, -(CH2)3-N(R9)-, -N(R9)-(CH2)3-, -CH2-N(R9)-(CH2)2-,
-(CH2)2-N(R9)-CH2-, -N(R9)-(CH2)2-N(R9)-, -N(R9)-(CH2)2-0- and
-0-(CH2)2-N(R9)-, wherein X5 represents a hydrogen atom or a halogen atom or a substituent selected from Ci-C2-alkyl and Ci-C2-alkoxy, wherein X6 represents a hydrogen atom or a halogen atom or a substituent selected from Ci -C2-alkyl and Ci-C2-alkoxy,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R1 represents a group
Figure imgf000072_0001
wherein X2 represents a hydrogen atom or a halogen atom or a substituent selected from
Ci -Ce-alkyl, Cs-Ce-cycloalkyl, C4-C6-cycloalkenyl, Ci-Ce-alkoxy, Ci -C6-haloalkoxy, (Ci-C6-alkoxy)-(C2-C4-alkoxy)-,
(C3-C6-cycloalkyloxy)-(C2-C4-alkoxy)-, 5- or 6-membered heteroaryl, phenyl-(Ci -C3-alkoxy)-, (5- or 6-membered heteroaryl)oxy-, -N(R5)(R6), -(Ci-C4-alkyl)-N(R5)(R6), 4- to 7-membered heterocycloalkyl,
(4- to 7-membered heterocycloalkyl)oxy-, and -N(R7)C(=0)R8,
wherein said Cs-Ce-cycloalkyl group and C4-C6-cycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci -C2-alkyl, cyano and hydroxy,
wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of the
4- to 7-membered heterocycloalkyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and
(4- to 7-membered heterocycloalkyl)oxy group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci -C2-alkyl, cyano and hydroxy,
and
wherein the phenyl part of said phenyl-(Ci -C3-alkoxy)- group, and said
5- or 6-membered heteroaryl group and (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)oxy- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, cyano and hydroxy, wherein X3 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent, wherein X4 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent, wherein X5 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent, wherein X6 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R1 represents a group
Figure imgf000073_0001
wherein X2 represents a hydrogen atom or a halogen atom or a substituent selected from
Ci-C4-alkyl, Ci-C4-alkoxy and phenyl-(Ci-C2-alkoxy)-,
wherein the phenyl part of said phenyl-(Ci-C2-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, cyano and hydroxy, wherein X3 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X4 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X5 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X6 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R1 represents a group
Figure imgf000074_0001
wherein X2 represents a hydrogen atom or a substituent selected from methyl, methoxy and benzyloxy, wherein X3 represents a hydrogen atom, wherein X4 represents a hydrogen atom or a fluorine atom, wherein X5 represents a hydrogen atom, wherein X6 represents a hydrogen atom,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R1 represents a group selected from
4-fluorophenyl, 4-fluoro-2-methylphenyl, 2-methoxyphenyl and 2-(benzyloxy)phenyl,
R2 represents a group selected from phenyl, 3-bromophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dihydro-1 H-inden-5-yl and 1 -naphthyl,
R3 represents a group selected from
methoxy and hydroxy,
R4 represents a trifluoromethyl group,
or
R3 and R4 together with the carbon atom to which they are attached represent a group
selected from
cyclopentyl and cyclohexyl,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula
(l-a), supra , in which:
R2 represents a group selected from phenyl, naphthyl and 5- or 6-membered heteroaryl, which phenyl, naphthyl and 5- or 6-membered heteroaryl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, Cs-Ce-cycloalkyl, C4-C6-cycloalkenyl, Ci-Ce-hydroxyalkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy,
(Ci-C4-alkoxy)-(Ci-C6-alkyl)-, (Ci-C4-haloalkoxy)-( Ci-Ce-alkyl)-, (Ci-C4-alkoxy)-(C2-C6-alkoxy)-, (Ci-C4-haloalkoxy)-( C2-C6-alkoxy)-, C3-C6-cycloalkyloxy, -SH, -S-(Ci-C6-alkyl), -S(=0)-(Ci-C6-aikyl), -S(=0)2-(Ci-C6-alkyl), -S-(Ci-C6-haloalkyl), -S(=0)-(Ci-C6-haloaikyl),
-S(=0)2-(Ci-C6-haloalkyl), -S-(C3-C6-cycloalkyl), -S(=0)-(C3-C6-cycloalkyl), -S(=0)2-(C3-C6-cycloalkyl), -S(=0)2N(R5)R6, -(Ci-C4-alkyl)-S(=0)2N(R5)R6, cyano, hydroxy, -N(R5)(R6), -(Ci-C4-alkyl)-N(R5)(R6), -N(R7)C(=0)R8,
-N(R7)C(=0)0R1°, -N(R7)C(=0)N(R5)(R6), -0C(=0)R8, -C(=0)0R7, -C(=0)N(R5)R6, 4- to 7-membered heterocycloalkyl,
5- to 7-membered heterocycloalkenyl, phenyl and 5- or 6-membered heteroaryl, or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a group selected from -(CH2)3-, -(CH2)4-, -(CH2)2-0-, -CH2-0-CH2-, -(CH2)3-0-, -CH2-0-(CH2)2-, -0-CH2-0- and -0-(CH2)2-0-,
wherein said 4- to 7-membered heterocycloalkyl group and
5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of said
4- to 7-membered heterocycloalkyl group and
5- to 7-membered heterocycloalkenyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and
5- to 7-membered heterocycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy, -N(R5)(R6) and oxo,
and
wherein said C3-C6-cycloalkyl group and C -Ce-cycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo and
wherein said C2-C6-alkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-alkoxy group,
and
wherein said phenyl group and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy and -N(R5)(R6),
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R2 represents a group selected from phenyl, naphthyl and 5- or 6-membered heteroaryl, which phenyl, naphthyl and 5- or 6-membered heteroaryl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci -Ce-alkyl and Ci-C6-alkoxy,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a group selected from
-(CH2)3-, -(CH2)4-, -(CH2)2-0-, -CH2-0-CH2-, -(CH2)3-0-, -CH2-0-(CH2)2-, -0-CH2-0- and -0-(CH2)2-0-,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a Ci-C4-alkyl group,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a bromine atom and a chlorine atom or a methyl group,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R2 represents a group selected from
phenyl, 3-bromophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dihydro-1 H-inden-5-yl and 1 -naphthyl, and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R3 represents a hydrogen atom, a halogen atom, or a group selected from
C2-C4-alkyl, C2-C4-alkenyl, C2-C4-alkinyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl,
Ci-C4-haloalkyl, (Ci -C2-haloalkoxy)-(Ci -C2-alkyl)-, Ci-C4-alkoxy, Ci -C4-haloalkoxy, Cs-Ce-cycloalkyloxy, hydroxy, cyano, -N(R5)(R6), -(Ci-C2-alkyl)-N(R5)(R6),
C4-C7-heterocycloalkyl, -(Ci-C2-alkyl)-(C4-C7-heterocycloalkyl),
(Ci -C2-haloalkoxy)-(Ci -C2-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-,
(C3-C4-cycloalkyloxy)-(Ci-C2-alkyl)-, -C(=0)N(R5)(R6) and -C(=0)OR7,
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C2-alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C2-alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci -C2-alkyl, Ci -C2-haloalkyl, Ci -C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy,
-N(R5)(R6) and oxo,
and wherein said cycloalkyl group and is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and -N(R5)(R6),
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkoxy and hydroxy,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R3 represents a group selected from Ci-C4-alkoxy and hydroxy,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R3 represents a group selected from methoxy and hydroxy,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R4 represents a hydrogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkinyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl,
Ci-C4-haloalkyl, -(Ci-C2-alkyl)-N(R5)(R6), C4-C7-heterocycloalkyl,
-(Ci-C2-alkyl)-( C4-C7-heterocycloalkyl), (Ci-C2-haloalkoxy)-(Ci-C2-alkyl)-,
(Ci -C2-alkoxy)-(Ci -C2-alkyl)- and (C3-C4-cycloalkyloxy)-(Ci -C2-alkyl)-,
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C2-alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C2-alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy,
-N(R5)(R6) and oxo,
and
wherein said cycloalkyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and -N(R5)(R6), and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R4 represents a hydrogen atom or Ci-C4-haloalkyl group,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R4 represents a Ci-C4-haloalkyl group,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R4 represents a trifluoromethyl group,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R3 and R4 together with the carbon atom to which they are attached represent a
5- to 8-membered cycloalkyl group,
wherein said cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo, and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R3 and R4 together with the carbon atom to which they are attached represent a group
selected from cyclopentyl and cyclohexyl,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
selected from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl and
(Ci-C2-alkoxy)-(C2-C3-alkyl-),
or
R5 and R6 together with the nitrogen to which they are attached represent a
nitrogen containing 4- to 7-membered heterocycloalkyl group,
wherein said 4- to 7-membered nitrogen containing heterocycloalkyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(C2-C3-alkyl)-, cyano, hydroxy and oxo,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
selected from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl and
(Ci-C2-alkoxy)-(C2-C3-alkyl-),
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R5 and R6 together with the nitrogen to which they are attached represent a
nitrogen containing 4- to 7-membered heterocycloalkyl group,
wherein said 4- to 7-membered nitrogen containing heterocycloalkyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(C2-C3-alkyl)-, cyano, hydroxy and oxo,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R7 represents a hydrogen atom or a Ci-C4 alkyl group,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R8 represents a hydrogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl and Cs-Ce-cycloalkyl,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which: R9 represents a hydrogen atom or a group selected from
Ci-C6 alkyl, C2-C6 haloalkyl, C3-C6 cycloalkyl,
wherein said cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo, and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R10 represents a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl and C3-C6 cycloalkyl,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R11 represents a group selected from
Ci-C4-alkyl and Ci-C4-haloalkyl, Cs-Ce-cycloalkyl and phenyl,
wherein said cycloalkyl group is optionally substituted one or two or times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo, and
wherein said phenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C2-alkyl, Ci-C2-haloalkyl, C3-C4-cycloalkyl, Ci-C2-alkoxy, cyano, hydroxy, 4- to 7-membered heterocycloalkyl and -N(R5)(R6),
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a further embodiment of the first aspect, the present invention covers compounds of general formula (I):
Figure imgf000084_0001
in which :
R1 represents a group
Figure imgf000084_0002
wherein X2 represents a hydrogen atom or a substituent selected from
Ci-Ce-alkyl, Ci-C6-alkoxy and phenyl-(Ci-C3-alkoxy)-,
wherein X3 represents a hydrogen atom,
wherein X4 represents a hydrogen atom or a halogen atom,
wherein X5 represents a hydrogen atom,
wherein X6 represents a hydrogen atom,
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a Ci-C6-alkyl group,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
R3 represents a group selected from Ci-C4-alkoxy and hydroxy,
R4 represents a Ci-C4-haloalkyl group,
and stereoisomers, hydrates, and solvates thereof, and mixtures of same.
In accordance with a further embodiment of the first aspect, the present invention covers compounds of general formula (I), supra , in which: R1 represents a group
Figure imgf000085_0001
wherein X2 represents a hydrogen atom or a substituent selected from
Ci-C4-alkyl, Ci-C4-alkoxy and phenyl-(Ci-C2-alkoxy)-,
wherein X3 represents a hydrogen atom,
wherein X4 represents a hydrogen atom or a halogen atom,
wherein X5 represents a hydrogen atom,
wherein X6 represents a hydrogen atom,
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a Ci-C4-alkyl group,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
R3 represents a group selected from Ci-C2-alkoxy and hydroxy,
R4 represents a Ci-C4-haloalkyl group,
and stereoisomers, hydrates, and solvates thereof, and mixtures of same.
In accordance with a further embodiment of the first aspect, the present invention covers compounds of general formula (I), supra , in which:
R1 represents a group
Figure imgf000085_0002
wherein X2 represents a hydrogen atom or a substituent selected from methyl, methoxy and benzyloxy,
wherein X3 represents a hydrogen atom,
wherein X4 represents a hydrogen atom or a fluorine atom,
wherein X5 represents a hydrogen atom, wherein X6 represents a hydrogen atom,
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a chlorine atom or a methyl group, or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
R3 represents a group selected from methoxy and hydroxy,
R4 represents a trifluoromethyl group,
and stereoisomers, hydrates, and solvates thereof, and mixtures of same.
In accordance with a further embodiment of the first aspect, the present invention covers compounds of general formula (l-a):
Figure imgf000086_0001
in which :
R1 represents a group
Figure imgf000086_0002
wherein X2 represents a hydrogen atom or a substituent selected from
Ci -Ce-alkyl, Ci-C6-alkoxy and phenyl-(Ci-C3-alkoxy)-,
wherein X3 represents a hydrogen atom,
wherein X4 represents a hydrogen atom or a halogen atom,
wherein X5 represents a hydrogen atom,
wherein X6 represents a hydrogen atom,
R2 represents a group selected from phenyl and naphthyl, which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a Ci-C6-alkyl group,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
R3 represents a group selected from Ci-C4-alkoxy and hydroxy,
R4 represents a Ci-C4-haloalkyl group,
and hydrates, and solvates thereof, and mixtures of same.
In accordance with a further embodiment of the first aspect, the present invention covers compounds of general formula (l-a), supra , in which:
R1 represents a group
Figure imgf000087_0001
wherein X2 represents a hydrogen atom or a substituent selected from
Ci-C4-alkyl, Ci-C4-alkoxy and phenyl-(Ci-C2-alkoxy)-,
wherein X3 represents a hydrogen atom,
wherein X4 represents a hydrogen atom or a halogen atom,
wherein X5 represents a hydrogen atom,
wherein X6 represents a hydrogen atom,
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a Ci-C4-alkyl group,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
R3 represents a group selected from Ci-C2-alkoxy and hydroxy, R4 represents a Ci-C4-haloalkyl group,
and hydrates, and solvates thereof, and mixtures of same.
In accordance with a further embodiment of the first aspect, the present invention covers compounds of general formula (l-a), supra , in which:
R1 represents a group
Figure imgf000088_0001
wherein X2 represents a hydrogen atom or a substituent selected from methyl, methoxy and benzyloxy,
wherein X3 represents a hydrogen atom,
wherein X4 represents a hydrogen atom or a fluorine atom,
wherein X5 represents a hydrogen atom,
wherein X6 represents a hydrogen atom,
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a chlorine atom or a methyl group, or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
R3 represents a group selected from methoxy and hydroxy,
R4 represents a trifluoromethyl group,
and hydrates, and solvates thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which: R1 represents a group
Figure imgf000089_0001
wherein X2 represents a hydrogen atom or a substituent selected from
Ci-Ce-alkyl, Ci-C6-alkoxy and phenyl-(Ci-C3-alkoxy)-,
wherein X3 represents a hydrogen atom,
wherein X4 represents a hydrogen atom or a halogen atom,
wherein X5 represents a hydrogen atom,
wherein X6 represents a hydrogen atom,
and stereoisomers, hydrates, and solvates thereof, and mixtures of same.
In accordance with a further embodiment of the first aspect, the present invention covers compounds of general formula (I), supra , in which:
R1 represents a group
Figure imgf000089_0002
wherein X2 represents a hydrogen atom or a substituent selected from
Ci-C4-alkyl, Ci-C4-alkoxy and phenyl-(Ci-C2-alkoxy)-,
wherein X3 represents a hydrogen atom,
wherein X4 represents a hydrogen atom or a halogen atom,
wherein X5 represents a hydrogen atom,
wherein X6 represents a hydrogen atom,
and stereoisomers, hydrates, and solvates thereof, and mixtures of same.
In accordance with a further embodiment of the first aspect, the present invention covers compounds of general formula (I), supra , in which:
R1 represents a group
Figure imgf000089_0003
wherein X2 represents a hydrogen atom or a substituent selected from methyl, methoxy and benzyloxy,
wherein X3 represents a hydrogen atom, wherein X4 represents a hydrogen atom or a fluorine atom, wherein X5 represents a hydrogen atom,
wherein X6 represents a hydrogen atom,
and stereoisomers, hydrates, and solvates thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a Ci-Ce-alkyl group,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
and stereoisomers, hydrates, and solvates thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a Ci-C4-alkyl group,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
and stereoisomers, hydrates, and solvates thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a chlorine atom or a methyl group, or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
and stereoisomers, hydrates, and solvates thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R3 represents a group selected from Ci-C4-alkoxy and hydroxy,
and stereoisomers, hydrates, and solvates thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R3 represents a group selected from Ci-C2-alkoxy and hydroxy,
and stereoisomers, hydrates, and solvates thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R3 represents a group selected from methoxy and hydroxy,
and stereoisomers, hydrates, and solvates thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R4 represents a Ci-C4-haloalkyl group,
and stereoisomers, hydrates, and solvates thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R4 represents a trifluoromethyl group,
and stereoisomers, hydrates, and solvates thereof, and mixtures of same. In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R1 represents a group
Figure imgf000092_0001
wherein X2 represents a hydrogen atom or a substituent selected from
Ci-Ce-alkyl, Ci-C6-alkoxy and phenyl-(Ci-C3-alkoxy)-,
wherein X3 represents a hydrogen atom,
wherein X4 represents a hydrogen atom or a halogen atom,
wherein X5 represents a hydrogen atom,
wherein X6 represents a hydrogen atom,
and hydrates, and solvates thereof, and mixtures of same.
In accordance with a further embodiment of the first aspect, the present invention covers compounds of general formula (l-a), supra , in which:
R1 represents a group
Figure imgf000092_0002
wherein X2 represents a hydrogen atom or a substituent selected from
Ci-C4-alkyl, Ci-C4-alkoxy and phenyl-(Ci-C2-alkoxy)-,
wherein X3 represents a hydrogen atom,
wherein X4 represents a hydrogen atom or a halogen atom,
wherein X5 represents a hydrogen atom,
wherein X6 represents a hydrogen atom,
and hydrates, and solvates thereof, and mixtures of same.
In accordance with a further embodiment of the first aspect, the present invention covers compounds of general formula (l-a), supra , in which: R1 represents a group
Figure imgf000093_0001
wherein X2 represents a hydrogen atom or a substituent selected from methyl, methoxy and benzyloxy,
wherein X3 represents a hydrogen atom,
wherein X4 represents a hydrogen atom or a fluorine atom,
wherein X5 represents a hydrogen atom,
wherein X6 represents a hydrogen atom,
and hydrates, and solvates thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra , in which:
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a Ci-C6-alkyl group,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
and hydrates, and solvates thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a Ci-C4-alkyl group,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group, and hydrates, and solvates thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a chlorine atom or a methyl group, or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
and hydrates, and solvates thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R3 represents a group selected from Ci-C4-alkoxy and hydroxy,
and hydrates, and solvates thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R3 represents a group selected from Ci-C2-alkoxy and hydroxy,
and hydrates, and solvates thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R3 represents a group selected from methoxy and hydroxy,
and hydrates, and solvates thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R4 represents a Ci-C4-haloalkyl group, and hydrates, and solvates thereof, and mixtures of same.
In a further embodiment of the first aspect, the present invention covers compounds of formula (l-a), supra , in which:
R4 represents a trifluoromethyl group,
and hydrates, and solvates thereof, and mixtures of same.
In accordance with an embodiment of the first aspect of the present invention, general formula (I) is divided into general sub-formulae (l-a), (l-b), (l-c), (l-d), (l-e), (l-f), (l-g) and (l-h):
Figure imgf000095_0001
in which R1 , R2, R3 and R4 are as defined above for the compounds of formula (I), supra , and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
It is to be understood that all aspects, embodiments, pharmaceutical compositions, combinations, uses and/or methods of the present invention defined herein for the compounds of formula (I) also refer to more specific embodiments of the compounds of formula (I), such as, but not limited to, the compounds of formulae (l-a), (l-b), (l-c), (l-d), (l-e), (l-f), (l-g) and/or (l-h), for example.
In a particular further embodiment of the first aspect, the present invention covers combinations of two or more of the above mentioned embodiments under the heading“further embodiments of the first aspect of the present invention”.
The present invention covers any sub-combination within any embodiment or aspect of the present invention of compounds of general formulae (l-a), (l-b), (l-c), (l-d), (l-e), (l-f), (l-g) and (l-h), supra. The present invention covers any sub-combination within any embodiment or aspect of the present invention of intermediate compounds of general formulae (II), (VII), (Vll-a), (VIII), (Vlll-a), (XII) and (Xll-a).
The present invention covers the compounds of general formula (I) and general formulae (l-a), (l-b), (l-c), (l-d), (l-e), (l-f), (l-g) and (l-h), which are disclosed in the Example Section of this text, infra.
The compounds according to the invention of general formula (I) and general formulae (l-a), (l-b), (l-c), (l-d), (l-e), (l-f), (l-g) and (l-h) can be prepared according to the following Schemes 1 , 2, 3, 4, 5 and 6. The schemes and procedures described below illustrate 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 , 2, 3, 4, 5 and 6 can be modified in various ways. The order of transformations exemplified in these schemes is therefore not intended to be limiting. In addition, interconversion of any of the substituents, R1 , R2, R3, R4, and Ra can be achieved before and/or after the exemplified transformations. These transformations can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 4th edition, Wiley 2006). Specific examples are described in the subsequent paragraphs.
Two routes for the preparation of compounds of general formula (I) and general formulae (l-a), (l-b), (l-c), (l-d), (l-e), (l-f), (l-g) and (l-h) are described in Schemes 1 , 2, 3, 4, 5 and 6.
Scheme 1
Figure imgf000097_0001
Scheme 1 Synthesis route for the preparation of compounds of general formula (I) in which R1 , R2, R3 and R4 have the meaning as given for general formula (I), supra , and Ra represents a protecting group. Ra can be for example (not-limiting), tert- butoxycarbonyl (Boc), benzyl (Bn) and benzyloxycarboxybenzyl (Cbz).
Compounds of general formula (VI) can be converted to compounds of general formula (V) by reaction with compounds of general formula (XI) under basic conditions using, such as, for example, n-butyllithium (WO2014/210354 A1 , WO2010/56564 A1 ), lithium hexamethyldisilazide (US2017/101406 A1 ) lithium diisopropylamide (WO2017/16669 A1 ) and potassium tert-butoxide. These types of reactions are typically carried out, in a solvent, such as for example, tetrahydrofuran, toluene, hexane, ethyl benzene, preferably tetrahydrofuran, in a temperature range ranging from -1000 to the boil ing point of the solvent. Compounds of general formula (V) can be converted by reductive methods to compounds of general formula (IV), such reductive transformations are well-known to those skilled in the art, such transformations can be carried out with a catalyst, such as for example, Raney-Nickel with a base, such as for example, ammonia, under an optionally over-pressurized atmosphere of hydrogen, in a solvent, such as for example, methanol or ethanol in a temperature range ranging from ambient temperature to the boiling point of the solvent or using other methods, such as for example, with a reducing agent, such as for example sodium borohydride, lithium aluminiumborohydride, optionally in the presence of a Lewis acid, such as for example, cobalt(ll) chloride, in a solvent, such as for example, methanol or ethanol, in a temperature range ranging from -50Ό to the boiling point of th e solvent (see the teachings of: e.g. pressurized catalytic hydrogenations using Nickel, WO2006/94934 A1 ; sodium borohydride in the presence of cobalt chloride, Rotstein et al., Bioorg. Med. Chem. Lett., 2009, 19, 5401 - 5406; US2005/176703 A1 ; lithium aluminium borohydride, Rotstein et al., Bioorg. Med. Chem. Lett., 2009, 19, 5401 - 5406; US2005/176703 A1 ; WO2017/79641 A1 ) and give compounds of general formula (IV). Compounds of general formula (IV) can be converted to compounds of general formula (III), using cyclization methods known to those skilled in the art, such as for example, using reagents, such as, for example, phosgene (Bassus et al., Eur. J. Med. Chem., 1974, 9, 416 - 423; bis(trichloromethyl) carbonate (Gasch et al., Tetrahedron, 2009, 65, 4149 and US201 1/251 169 A1 ), 1 ;T-carbonyl diimidazole (Rotstein et al., Bioorg. Med. Chem. Lett., 2009, 19, 5401 - 5406). These types of reactions can be carried out in a suitable solvents, such as, for example (not-limiting), dichloromethane, tetrahydrofuran, DMF, acetonitrile, optionally, in the presence of a base, such as, for example (not-limiting), diisopropylethylamine, triethylamine, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, caesium carbonate, in a temperature range ranging from - 1000 to the boiling point of the solvent, to obtai n compounds of general formula (III). Compounds of general formula (III) can be converted to compounds of general formula (II), using deprotection methods known to those skilled in the art and adapted to the protecting group Ra of choice (see for example Greene’s Protective Groups in Organic Synthesis, 4th edition, Editor P.G.M. Wuts in Wiley 2006). In the case where Ra is fert-butoxycarbonyl (Boc), such reaction can be carried out for example, using an acid, such as for example, hydrochloric acid or trifluoroacetic acid, in a solvent, such as for example, dioxane, methanol, dichloromethane, in a temperature range ranging from -500 to the boiling point of the solvent. See for example the teachings of Bissantz et al., US2007/155761 A1 and WO2008/68159 A1 , (hydrochloric acid in methanol); WO2015/96035 A1 and W02015/100147 A1 (trifluoroacetic acid in dichloromethane); for such methods when R is benzyl (Bn), see for example the teachings of WO2005/97795 A1 , Yang et al., Bioorg. Med. Chem. Lett., 2009, 19, 209 - 213 and Leonardi et al., J Med. Chem., 2004, 47, 1900 - 1918 (palladium on charcoal, hydrogen gas); US2009/281 133 A1 and US2009/93501 A1 (palladium hydroxide, hydrogen gas). Compounds of general formula (II) can be converted to compounds of general formula (I) using carboxylic acids of general formula (XII), using methods well known by those skilled in the art. Such transformations can be carried out with a coupling reagent, such as for example, benzotriazol-1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), with a base, such as for example, N,N-diisopropylethylamine, triethylamine, in a solvent, such as for example, dimethylformamide, in a temperature range ranging from 0Ό to the boiling point of the solvent. See the teachings listed below for such transformations of compounds of general formula (II) to compounds of general formula (I):
i. reacting with a carboxylic acid of general formula (XII) and a coupling reagent, such as, for example, diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), 1 -ethyl-(3- (3-dimethylamino)propyl)-carbodiimide hydrochloride (EDC), propanephosphonic acid anhydride (T3P), benzotriazol-1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), optionally in the presence of a base and optionally with
1 -hydroxybenzotriazole (HOBt) or 1 -hydroxy-7-azabenzotriazole (HOAt).
ii. reacting with a carboxylic acid anhydride in the presence of a base (e.g. Leonardi et al., J Med. Chem., 2004, 47, 1900 - 1918).
iii. reacting with an acid chloride in the presence of a base (e.g. Qiao et al., J Med. Chem., 2013, 56, 9275 - 9295).
Scheme 2
Figure imgf000099_0001
Scheme 2 Synthesis route for the preparation of compounds of general formula (I) in which R1 , R2, R3 and R4 have the meaning as given for general formula (I), supra.
4-Piperidinone (X) can be converted to compounds of general formula (IX) using carboxylic acids of general formula (XII), using methods well known by those skilled in the art, and are previously described in Scheme 1 , such as, for example,
i. reacting with a carboxylic acid of general formula (XII) and a coupling reagent, such as, for example, diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), 1 -ethyl-(3- (3-dimethylamino)propyl)-carbodiimide hydrochloride (EDC), propanephosphonic acid anhydride (T3P), benzotriazol-1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), optionally in the presence of a base and optionally with 1 -hydroxybenzotriazole (HOBt) or 1 -hydroxy-7-azabenzotriazole (HOAt). See the teachings of Mangana et al., Tetrahedron Lett., 2015, 56, 1960 - 1963; WO2007/3934 A2; W02008/124756 A1 and US2016/318866 A1 ).
ii. reacting with a carboxylic acid anhydride in the presence of a base (e.g.
WO2007/124136 A1 ).
iii. reacting with an acid chloride in the presence of a base (e.g. W02005/95402 A1 ; Van Der Klein et al., J Med. Chem., 1999, 42, 3629 - 3635; WO2015/74123).
The remaining steps within Scheme 2 follow similar routes and methods as described in Scheme 1 to generate compounds of general formula (I). For example, the methods used to convert compounds of general formula (X) to compounds of general formula (IX) are similar as those described in Scheme 1 whereby compounds of general formula (II) are converted to compounds of general formula (I). Additionally, the methods used to convert compounds of general formula (IX) to compounds of general formula (VIII) are similar as those described in Scheme 1 to convert compounds of general formula (VI) to compounds of general formula (V). Furthermore, the methods used to convert compounds of general formula (VIII) to compounds of general formula (VII) are similar as those described in Scheme 1 whereby compounds of general formula (V) are converted to compounds of general formula (IV). Finally, the methods used to convert compounds of general formula (VII) to compounds of general formula (I) are similar as those described in Scheme 1 to convert compounds of general formula (IV) to compounds of general formula (III). Scheme 3
Figure imgf000101_0001
Scheme 3 Synthesis route for the preparation of compounds of general formula (I) and general formulae (l-c) and (l-d) in which R1 , R2, R3 and R4 have the meaning as given for general formula (I) or general formulae (l-c) or (l-d), supra , and Ra represents a protecting group. Ra can be for example (not-limiting), fert-butoxycarbonyl (Boc), benzyl (Bn) and benzyloxycarboxybenzyl (Cbz).
Compounds of general formula (I), (II) and (III) can be a mixture of stereoisomers.
To those skilled in the art it is possible to carry out the chemical reactions described in Schemes 1 and 2, where the stereoisomers can be separated using various methods known to those skilled in the art, such as (but not exclusively), for example, separation using chiral HPLC purification. The separation of these stereoisomers can be carried out on compounds of general formula (I), to give stereoisomers of general formula (l-c) and (l-d). Alternatively, the separation of these stereoisomers can be carried at an earlier stage in the synthetic route, such as, for example, the separation of the stereoisomers of compounds of general formula (II) or stereoisomers of compounds of general formula (III) to give compounds of general formula (ll-c) and (ll-d) or stereoisomers of compounds of general formula (lll-c) and (lll-d), respectively. The subsequent chemistry transformations using these stereoisomers can be carried out in analogy to the racemic mixtures described supra. For example, compounds of general formula (lll-c) can be converted to compounds of general formula (ll-d) using the methods described for converting compounds of general formula (III) to compounds of the general formula (II) (see Schemes 1 and 2). Analogously, compounds of general formula (ll-c) can be converted to compounds of general formula (l-c) using the methods described for converting compounds of general formula (II) to compounds of the general formula (I) (see Schemes 1 and 2).
Scheme 4
Figure imgf000102_0001
Scheme 4 Synthesis route for the preparation of compounds of general formulae (l-a), (l-b), (I- c), (l-d), (l-e), (l-f), (l-g) and (l-h) in which R1 , R2, R3 and R4 have the meaning as given for general formula (I) or general formulae (l-a), (l-b), (l-c), (l-d), (l-e), (l-f), (l-g) or (l-h), supra.
To those skilled in the art it is possible to carry out the chemical reactions described in Schemes 1 and 2, where the stereoisomers can be separated using various methods known to those skilled in the art, such as (but not exclusively), for example, separation using chiral HPLC purification. The separation of these stereoisomers can be carried out on compounds of general formula (I), to give mixtures of stereoisomers or single stereoisomers of general formula (l-a), (l-b), (l-c), (l-d), (l-e), (l-f), (l-g) and (l-h). Alternatively, the separation of these stereoisomers of general formula (I) can be carried out differently. For example, the separation of the stereoisomers of compounds of general formula (I) can give compounds of general formula (l-c) and general formula (l-d) as described in Scheme 3, or alternatively, give compounds of general formula (l-a) and general formula (l-b), or compounds of general formula (I) can give compounds of general formula (l-e), general formula (l-f), general formula (l-g) and general formula (l-h). Additionally, compounds of general formula (l-a) can give compounds of general formula (l-e) and general formula (l-f). In addition, compounds of general formula (l-b) can give compounds of general formula (l-g) and general formula (l-h). Furthermore, compounds of general formula (lc) can give compounds of general formula (l-e) and general formula (l-g). Alternatively, compounds of general formula (l-d) can give compounds of general formula (l-f) and general formula (l-h).
Scheme 5
Figure imgf000104_0001
Scheme 5 Synthesis routes for the preparation of compounds of general formula (l-a) in which R\ R2, R3 and R4 have the meaning as given for general formula (I) or general formula (l-a), supra.
To those skilled in the art it is possible to carry out the chemical reactions described in Schemes 1 and 2, where the stereoisomers can be separated using various methods known to those skilled in the art, such as (but not exclusively), for example, separation using chiral HPLC purification. The separation of these stereoisomers can be carried out at different stages in the synthetic route, such as, for example, the separation of the stereoisomers of compounds of general formula (IX) to give the compounds of general formula (IX-a) and general formula (IX-b).
Alternatively, compounds of general formula (IX-a) can be synthesized by reacting 4-piperidinone (X) with compounds of general formula (Xll-a) using coupling methods known to those skilled in the art and such methods have been described in Schemes 1 and 2. The subsequent chemistry transformations using these stereoisomers can be carried out in analogy to the methods described supra to give compounds of the general formula (l-a) (see Schemes 1 and 2). Employing the analogous reaction sequences, compounds of general formula (l-b) can be synthesized.
Alternatively, compounds of general formula (l-a) can be synthesized by reacting compounds of general formula (II) with compounds of general formula (Xll-a) using coupling methods known to those skilled in the art and such methods have been described in Schemes 1 and 2.
Scheme 6
Figure imgf000106_0001
Scheme 6 Synthesis route for the preparation of compounds of general formula (XII-1 ), (XII-2), (Xll-a1 ), (Xll-b1 ), (Xll-a2) and (Xll-b2), which are compounds of general formula (XII), in which R2 has the meaning as given for general formula (I), supra , R3 represents a hydroxy or an alkoxy group, as given for general formula (I), supra , R4 represents a trifluoromethyl group, and LG represents a leaving group, such as, for example, F, Cl, Br, I or aryl sulfonate such as for example p-toluene sulfonate, or alkyl sulfonate such as for example methane sulfonate or trifluoromethane sulfonate. Rb can be for example (not-limiting), alkyl, methyl (Me), ethyl (Et) and tert-butyl (tBu). Rc can be for example (not-limiting), alkyl, methyl (Me) and ethyl (Et). X can be for example (not-limiting), hydrogen; a halide, such as, for example, chloride, bromide, iodide; a magnesium halide, such as, for example, magnesium chloride, magnesium bromide.
Compounds of general formula (XVII) can be converted to compounds of general formula (XV) by reacting compounds of general formula (XV) with compounds of general formula (XVI) under basic conditions using, such as, for example, n-butyllithium (WO2014/210354 A1 , WO2010/56564 A1 ), magnesium, optionally in the presence of additives, such as, for example, isopropylmagnesium chloride or phenyl magnesium chloride, lithium chloride (see the teachings of Malherbe et al„ US2007/27204 A1 ; US2010/168094 A1 , W02010/141550 A2, Wan et al„ ACS Med. Chem. Lett., 2013, 4, 118 - 123; Hanney et al„ US2005/277681 A1 , 2005; WO2007/38444 A2; Blay et al„ Tetrahedron, 2002, 58, 8565 - 8571 ).
Alternatively, the conversions of compounds of general formula (XVII) to compounds of general formula (XV) can be carried out by reacting compounds of general formula (XVII) with compounds of general formula (XVI) as Friedel-Crafts alkylations with catalysts, such as, for example, samarium iodide (Soueidan et al., Tetrahedron Lett., 2006, 47, 5467 - 5470); copper(ll) bis(trifluoromethanesulfonate) in the presence of a ligand, such as, for example, 2,2'-isopropylidenebis[(3aR,8aS)-3a,8a-dihydro-8H-indene[1 ,2-d]oxazole] (Ren et al., Org. Lett., 2015, 17, 4886 - 4889) or in the presence of an acid, such as, for example, trifluoromethansulfonic acid (Prakesh et al., Synlett., 2003, 527 - 531 ). These types of reactions are typically carried out, in a solvent, such as for example, tetrahydrofuran, toluene, hexane, benzene, toluene, dichloromethane, tetrachloromethane, 1 ,2-dichloroethane, preferably tetrahydrofuran, in a temperature range ranging from -1000 to the boiling point of the solvent.
The conversions of compounds of general formula (XV) to compounds of general formula (XIII) can be carried out by reacting compounds of general formula (XV) with suitable alkylating agents of general formula (XIV), such as, for example a dialkyl sulfate or an alkyl halide, in the presence of a suitable base, such as, for example potassium carbonate, in a suitable solvent system, such as, for example, acetone, at a temperature between - 20Ό and boiling point of the respective solvent.
Compounds of general formulae (XV) and (XIII) can be converted to compounds of general formulae (XI 1-1 ) and (XII-2), using deprotection methods known to those skilled in the art, such as for example, using basic conditions, such as for example, lithium hydroxide, sodium hydroxide or potassium hydroxide, in a solvent, such as for example, dioxane, methanol, ethanol, water, or mixtures thereof, in a temperature range ranging from -50Ό to the boiling point of the solvent (see for example Greene’s Protective Groups in Organic Synthesis, 4th edition, Editor P.G.M. Wuts in Wiley 2006), for such methods when Rb is methyl (Me) see the teachings of Bissantz et al., WO2006/54162 A1 ; for such methods when R ethyl (Et), see the teachings of Blay et al., Tetrahedron, 2002, 58, 8565 - 8571 .
To those skilled in the art it is possible to carry out the chemical reactions described in Scheme 6, where the stereoisomers can be separated using various methods known to those skilled in the art, such as, for example (but not only), separation using chiral HPLC purification. The separation of these stereoisomers can be carried out at different stages in the synthetic route, such as, for example, the separation of the stereoisomers of compounds of general formula (XII-1 ) to give the compounds of general formula (Xll-a1 ) and general formula (Xll-b1 ), or the separation of the stereoisomers of compounds of general formula (XII-2) to give the compounds of general formula (Xll-a2) and general formula (Xll-b2), see the teachings of Hoye et al., Org. Lett., 2010, 12, 1768 - 1771 ; Mosher et al., J. Am. Chem. Soc., 1969, 34,
2543 - 2549. Alternative methods for synthesizing compound of general formulae (XIII), (XII), (Xll-a) and (Xll-b) are described in the literature and known to those skilled in the art, see the teachings of Hoye et al., Org. Lett., 2010, 12, 1768 - 1771 ; Holmes et al., J. Am. Chem. Soc., 2017, 139, 81 14 - 81 17; Wang et al., J. Am. Chem. Soc., 2015, 137, 4626 - 4629, Choudhury- Mukherjee et al., J. Med. Chem., 2003,, 46, 2494. In an analoguous manner the separation of the stereoisomers of compounds of general formulae (XIII) and (XV) can be achieved.
The compounds of general formulae (XII-1 ), (XII-2), (Xll-a1 ), (XI l-b1 ), (Xll-a2) and (Xll-b2) can be used to synthesize compounds of general formula (I) employing the reaction sequences described in Schemes 1 , 2, 3 and 5.
Compounds of general formulae (XI), (XII), (XIII), (XIV), (XV), (XVI) and (XVII) are either commercially available or can be prepared according to procedures which are known to the person skilled in the art. Specific examples are described in the Experimental Section.
In accordance with a second aspect, the present invention covers methods of preparing compounds of general formula (I) as defined supra ,
said methods comprising the step of allowing an intermediate compound of general formula
Figure imgf000108_0002
in which R1 is as defined for the compound of general formula (I) as defined supra ,
to react with a compound of general formula (XII) :
Figure imgf000108_0001
(XII),
in which R2, R3 and R4 are as defined for the compound of general formula (I) as defined supra , thereby giving a compound of general formula (I) :
Figure imgf000109_0001
in which R1 , R2, R3 and R4 are as defined supra.
In accordance with a third aspect, the present invention covers methods of preparing compounds of general formula (I) as defined supra,
said methods comprising the step of allowing an intermediate compound of general formula
Figure imgf000109_0002
(II),
in which R1 is as defined for the compound of general formula (I) as defined supra , to react with a compound of general formula (XII) :
Figure imgf000109_0003
(XII),
in which R2, R3 and R4 are as defined for the compound of general formula (I) as defined supra ,
thereby giving a compound of general formula (I) :
Figure imgf000109_0004
in which R1 , R2, R3 and R4 are as defined supra , then optionally converting said compound into solvates, salts and/or solvates of such salts using the corresponding (i) solvents and/or (ii) bases or acids.
In accordance with a fourth aspect, the present invention covers methods of preparing compounds of general formula (l-a) as defined supra,
said methods comprising the step of allowing an intermediate compound of general formula
Figure imgf000110_0002
in which R1 is as defined for the compound of general formula (l-a) as defined supra, to react with a compound of general formula (Xll-a) :
O
O H
- 4
R3 R
(Xll-a),
in which R2, R3 and R4 are as defined for the compound of general formula (l-a) as defined supra,
thereby giving a compound of general formula (l-a) :
Figure imgf000110_0001
in which R1 , R2, R3 and R4 are as defined supra.
In accordance with a fifth aspect, the present invention covers methods of preparing compounds of general formula (l-a) as defined supra,
said methods comprising the step of allowing an intermediate compound of general formula
Figure imgf000111_0001
in which R1 is as defined for the compound of general formula (l-a) as defined supra , to react with a compound of general formula (Xll-a) :
Figure imgf000111_0002
(Xll-a),
in which R2, R3 and R4 are as defined for the compound of general formula (I) as defined supra ,
thereby giving a compound of general formula (l-a) :
Figure imgf000111_0003
in which R1 , R2, R3 and R4 are as defined supra ,
then optionally converting said compound into solvates, salts and/or solvates of such salts using the corresponding (i) solvents and/or (ii) bases or acids.
In accordance with a sixth aspect, the present invention covers methods of preparing compounds of general formula (I) as defined supra ,
said methods comprising the step of allowing an intermediate compound of general formula (VIII) :
Figure imgf000111_0004
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (I) as defined supra , to react with a reducing agent, such as for example Raney-Nickel, with a base, such as for example ammonia, under a hydrogen atmosphere,
or to react with a reducing agent, such as for example sodium borohydride, in the presence of a Lewis acid, such as for example cobalt(ll) chloride,
thereby giving a compound of general formula (VII) :
Figure imgf000112_0001
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (I) as defined supra ,
which compound of general formula (VII) cyclizes, thereby giving a compound of general formula (I) :
Figure imgf000112_0002
in which R1 , R2, R3 and R4 are as defined supra.
In accordance with a seventh aspect, the present invention covers methods of preparing compounds of general formula (I) as defined supra ,
said methods comprising the step of allowing an intermediate compound of general formula (VIII) :
Figure imgf000112_0003
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (I) as defined supra ,
to react with a reducing agent, such as for example Raney-Nickel, with a base, such as for example ammonia, under a hydrogen atmosphere, or to react with a reducing agent, such as for example sodium borohydride, in the presence of a Lewis acid, such as for example cobalt(ll) chloride,
thereby giving a compound of general formula (VII) :
Figure imgf000113_0001
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (I) as defined supra ,
which compound of general formula (VII) cyclizes, thereby giving a compound of general formula (I) :
Figure imgf000113_0002
(I),
in which R1 , R2, R3 and R4 are as defined supra,
then optionally converting said compound into solvates, salts and/or solvates of such salts using the corresponding (i) solvents and/or (ii) bases or acids.
In accordance with an eights aspect, the present invention covers methods of preparing compounds of general formula (l-a) as defined supra,
said methods comprising the step of allowing an intermediate compound of general formula (Vlll-a) :
Figure imgf000113_0003
(Vlll-a),
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (l-a) as defined supra,
to react with a reducing agent, such as for example Raney-Nickel, with a base, such as for example ammonia, under a hydrogen atmosphere, or to react with a reducing agent, such as for example sodium borohydride, in the presence of a Lewis acid, such as for example cobalt(ll) chloride,
thereby giving a compound of general formula (Vll-a) :
Figure imgf000114_0001
(Vll-a),
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (l-a) as defined supra ,
which compound of general formula (Vll-a) cyclizes, thereby giving a compound of general formula (l-a) :
Figure imgf000114_0002
in which R1 , R2, R3 and R4 are as defined supra.
In accordance with a ninth aspect, the present invention covers methods of preparing compounds of general formula (l-a) as defined supra ,
said methods comprising the step of allowing an intermediate compound of general formula (Vlll-a) :
Figure imgf000114_0003
(Vlll-a),
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (l-a) as defined supra ,
to react with a reducing agent, such as for example Raney-Nickel, with a base, such as for example ammonia, under a hydrogen atmosphere,
or to react with a reducing agent, such as for example sodium borohydride, in the presence of a Lewis acid, such as for example cobalt(ll) chloride, thereby giving a compound of general formula (Vll-a) :
Figure imgf000115_0001
(Vll-a),
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (l-a) as defined supra ,
which compound of general formula (Vll-a) cyclizes, thereby giving a compound of general formula (l-a) :
Figure imgf000115_0002
in which R1 , R2, R3 and R4 are as defined supra ,
then optionally converting said compound into solvates, salts and/or solvates of such salts using the corresponding (i) solvents and/or (ii) bases or acids.
In accordance with an tenth aspect, the present invention covers the use of intermediate compounds for the preparation of a compound of general formula (I) as defined supra.
In accordance with an eleventh aspect, the present invention covers the use of intermediate compounds for the preparation of a compound of general formula (l-a) as defined supra.
Particularly, the inventions covers the use of intermediate compounds of general formula (II) :
Figure imgf000115_0003
in which R1 is as defined for the compound of general formula (I) as defined supra , for the preparation of a compound of general formula (I) as defined supra.
Particularly, the inventions covers the use of intermediate compounds of general formula (XII) :
Figure imgf000116_0001
(XII),
in which R2, R3 and R4 are as defined for the compound of general formula (I) as defined supra , for the preparation of a compound of general formula (I) as defined supra.
Particularly, the inventions covers the use of intermediate compounds of general formula (VIII) :
Figure imgf000116_0002
(VIII),
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (I) as defined supra , for the preparation of a compound of general formula (I) as defined supra.
Particularly, the inventions covers the use of intermediate compounds of general formula (VII) :
Figure imgf000116_0003
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (I) as defined supra , for the preparation of a compound of general formula (I) as defined supra.
Particularly, the inventions covers the use of intermediate compounds of general formula (Xll-a) :
Figure imgf000116_0004
(Xll-a),
in which R2, R3 and R4 are as defined for the compound of general formula (l-a) as defined supra , for the preparation of a compound of general formula (l-a) as defined supra.
Particularly, the inventions covers the use of intermediate compounds of general formula (Vlll-a) :
Figure imgf000117_0001
(Vlll-a),
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (l-a) as defined supra , for the preparation of a compound of general formula (l-a) as defined supra.
Particularly, the inventions covers the use of intermediate compounds of general formula (Vll-a) :
Figure imgf000117_0002
(Vll-a),
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (l-a) as defined supra , for the preparation of a compound of general formula (l-a) as defined supra.
The present invention covers the intermediate compounds which are disclosed in the Experimental Section of this text, infra.
The present invention covers any sub-combination within any embodiment or aspect of the present invention of intermediate compounds of general formulae (II), (VII), (Vll-a), (VIII), (Vlll-a), (XII) and (Xll-a), supra.
The compounds of general formula (I) of the present invention can be converted to any salt, preferably pharmaceutically acceptable salts, as described herein, by any method which is known to the person skilled in the art. Similarly, any salt of a compound of general 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.
Compounds of general formula (I) and general formula (l-a) of the present invention demonstrate a valuable pharmacological spectrum of action, which could not have been predicted. Compounds of the present invention have surprisingly been found to effectively inhibit the activity of geranylgeranyltransferase I (GGTase I), leading to inactivation of downstream YAP1 and/or TAZ and blockade of cancer cell proliferation and it is possible therefore that said compounds be used for the treatment or prophylaxis of diseases, preferably hyperproliferative disorders in humans and animals.
Compounds of the present invention can be utilized to effectively inhibit the activity of geranylgeranyltransferase I (GGTase I), leading to inactivation of downstream YAP1 and/or TAZ and blockade of cancer cell proliferation. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of general formula (I) or general formula (l-a) of the present invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, which is effective to treat the disorder.
Another aspect of the invention is a method of inhibiting proliferation of a cell, comprising contacting the cell with a compound of formula (I) or general formula (l-a).
Hyperproliferative disorders include, but are not limited to, for example : hematological tumors such as leukemia, lymphoma, multiple myeloma, 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 sarcomas.
One aspect of the invention is the use of the compounds of formula (I) or general formula (l-a) for the treatment of cancer, the compounds of formula (I) or general formula (l-a) for use in the treatment of cancer as well as a method of treatment of cancer diseases comprising administering a specific amout of a compound of formula (I) or general formula (l-a).
Examples of breast cancers 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.
Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
Lung cancers include, but are not limited to, Bronchogenic Carcinoma Small, Cell Lung Carcinoma, Non-small cell lung carcinoma, Lung Anaplastic Carcinoma, Lung Squamous Cell Carcinoma.
Mesothelioma include, but are not limited to, Mesothelioma I sarcomatoid and Mesothelioma I biphasic mesothelioma.
Endocrine cancers include, but are not limited to, Adrenal gland and Thyroid cancers.
Hematopoietic and lymphoid cancers include, but are not limited to Acute T cell leukemia, multiple Myeloma and Mantle cell lymphoma.
Another aspect of the invention is a method for controlling cancer in humans and animals by administering an effective amount of at least one compound of general formula (I) or general formula (l-a) of the present invention, or a pharmaceutically acceptable salt, polymorph, metabolite, hydrate, solvate or ester thereof, or of a medicament, comprising at least one compound of general formula (I) or general formula (l-a) of the present invention.
In another aspect, the present invention provides the use of a compound of general formula (I) or general formula (l-a) of the present invention, or a pharmaceutically acceptable salt, polymorph, metabolite, hydrate, solvate or ester thereof, for the preparation of a medicament for the treatment or prophylaxis of a disease.
Compounds of the present invention can be utilized to inhibit the activity of geranylgeranyltransferase I (GGTase I), leading to inactivation of downstream YAP1 and/or TAZ and blockade of cancer cell proliferation. 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, stereoisomer, polymorph, metabolite, hydrate, solvate or ester thereof; which is effective to treat the disorder.
In another aspect, the present invention provides methods of treating cancer, which cancer is selected from skin cancer, liposarcoma, cervical cancer, brain cancer, bladder cancer, endocrine cancer, lung cancer, glioblastoma, gliosarcoma, colorectal carcinoma, head & neck cancer, hepatocellular carcinoma, breast cancer, ovarian cancer, gastric cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, sarcoma, lymphoma and leukemia.
In another aspect, the present invention provides methods of treating cancer, which cancer is selected from melanoma, lung cancer, glioblastoma, colorectal carcinoma, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, lymphoma and leukemia.
In another aspect, the present invention provides the use of a compound of general formula (I) or general formula (l-a) of the present invention, or a pharmaceutically acceptable salt, polymorph, metabolite, hydrate, solvate or ester thereof, for the treatment of cancer, which cancer is selected from skin cancer, liposarcoma, cervical cancer, brain cancer, bladder cancer, endocrine cancer, lung cancer, glioblastoma, gliosarcoma, colorectal carcinoma, head & neck cancer, hepatocellular carcinoma, breast cancer, ovarian cancer, gastric cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, sarcoma, lymphoma and leukemia.
In another aspect, the present invention provides the use of a compound of general formula (I) or general formula (l-a) of the present invention, or a pharmaceutically acceptable salt, polymorph, metabolite, hydrate, solvate or ester thereof, for the treatment of cancer, which cancer is selected from melanoma, lung cancer, glioblastoma, colorectal carcinoma, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, lymphoma and 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, for example the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a carcinoma.
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.
Generally, the use of chemotherapeutic agents and/or anti-cancer agents in combination with a compound or pharmaceutical composition of the present invention will serve to:
1 . yield better efficacy in reducing the growth of a tumour or even eliminate the tumour 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 tumour 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.
In addition, the compounds of general formula (I) and general formula (l-a) of the present invention can also be used in combination with radiotherapy and/or surgical intervention.
In a further embodiment of the present invention, the compounds of general formula (I) and general formula (l-a) of the present invention may be used to sensitize a cell to radiation, i.e. 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 present invention. In one aspect, the cell is treated with at least one compound of general formula (I) or general formula (l-a) of the present invention.
Thus, the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the present 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 general formula (I) or general formula (l-a) of the present 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 general formula (I) or general formula (l-a) of the present 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 other embodiments of the present invention, a cell is killed by treating the cell with at least one DNA damaging agent, i.e. after treating a cell with one or more compounds of general formula (I) of the present 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 . cis platin), ionizing radiation (X-rays, ultraviolet radiation), carcinogenic agents, and mutagenic agents.
In other embodiments, 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 general formula (I) or general formula (l-a) of the present 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 general formula (I) of the present 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 general formula (I) or general formula (l-a) of the present 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.
In the context of the present invention, the term treating” or“treatment” means combatting, inhibiting, delaying, hindering, alleviating, diminishing, limiting, reducing, suppressing, repressing or curing of a disease, of a complaint, of an illness, of an injury or of a health disorder, or of the development, the course or the progression of same.
In the context of the present invention, the term“prevention” or“prophylaxis” means avoiding or decreasing of the risk of getting, suffering from, sustaining or having a disease, a complaint, an illness, an injury or health disorder, or the development, the course, the progression or the symtoms of same.
Said treatment and/or prevention of a disease, a complaint, an illness, an injury or health disorder can be carried out partially or totally.
The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of hyperproliferative disorders, more particularly cancer.
In accordance with a further aspect, the present invention covers compounds of general formula (I), as described supra , or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or prophylaxis of diseases, in particular hyperproliferative disorders, particularly benign hyperproliferative disorders, more particularly cancer.
In accordance with a further aspect, the present invention covers compounds of general formula (l-a), as described supra , or tautomers, hydrates, and solvates thereof, , or mixtures of same, for use in the treatment or prophylaxis of diseases, in particular hyperproliferative disorders, particularly benign hyperproliferative disorders, more particularly cancer.
In accordance with a further aspect, the present invention covers compounds of general formula (I) and general formula (l-a), as described supra , or stereoisomers, tautomers, N- oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or prophylaxis of diseases, in particular hyperproliferative disorders, particularly benign hyperproliferative disorders, more particularly cancer.
The pharmacological activity of the compounds according to the invention can be explained by their ability to effectively inhibit the activity of geranylgeranyltransferase I (GGTase I), leading to inactivation of downstream YAP1 and/or TAZ and blockade of cancer cell proliferation .
In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra , or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the treatment and/or prophylaxis of diseases, in particular hyperproliferative disorders, particularly cancer.
In accordance with a further aspect, the present invention covers the use of compounds of general formula (l-a), as described supra , or tautomers, hydrates or solvates thereof, or mixtures of same, for the treatment and/or prophylaxis of diseases, in particular hyperproliferative disorders, particularly cancer.
In accordance with a further aspect, the present invention covers the use of compounds of general formula (I) and general formula (l-a), as described supra , or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the treatment and/or prophylaxis of diseases, in particular hyperproliferative disorders, particularly cancer.
In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra , or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, in a method of treatment and/or prophylaxis of diseases, in particular hyperproliferative disorders, particularly cancer disorders. In accordance with a further aspect, the present invention covers the use of compounds of general formula (l-a), as described supra , tautomers, hydrates or solvates thereof, or mixtures of same, in a method of treatment and/or prophylaxis of diseases, in particular hyperproliferative disorders, particularly cancer disorders.
In accordance with a further aspect, the present invention covers the use of compounds of general formula (I) and general formula (l-a), as described supra , or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, in a method of treatment and/or prophylaxis of diseases, in particular hyperproliferative disorders, particularly cancer disorders.
In accordance with a further aspect, the present invention covers use of a compound of general formula (I), as described supra , or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the preparation of a pharmaceutical composition, preferably a medicament, for the prophylaxis or treatment of diseases, in particular hyperproliferative disorders, particularly cancer disorders.
In accordance with a further aspect, the present invention covers use of a compound of general formula (l-a), as described supra , or tautomers, hydrates or solvates thereof, or mixtures of same, for the preparation of a pharmaceutical composition, preferably a medicament, for the prophylaxis or treatment of diseases, in particular hyperproliferative disorders, particularly cancer disorders.
In accordance with a further aspect, the present invention covers use of a compound of general formula (I) or general formula (l-a), as described supra , or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the preparation of a pharmaceutical composition, preferably a medicament, for the prophylaxis or treatment of diseases, in particular hyperproliferative disorders, particularly cancer disorders.
In accordance with a further aspect, the present invention covers a method of treatment or prophylaxis of diseases, in particular hyperproliferative disorders, particularly cancer, using an effective amount of a compound of general formula (I), as described supra , or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.
In accordance with a further aspect, the present invention covers a method of treatment or prophylaxis of diseases, in particular hyperproliferative disorders, particularly cancer, using an effective amount of a compound of general formula (l-a), as described supra , or tautomers, hydrates or solvates thereof, or mixtures of same. In accordance with a further aspect, the present invention covers a method of treatment or prophylaxis of diseases, in particular hyperproliferative disorders, particularly cancer, using an effective amount of a compound of general formula (I) or general formula (l-a), as described supra , or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.
In accordance with a further aspect, the present invention covers pharmaceutical compositions, in particular medicaments, comprising compounds of general formula (I), as described supra , or stereoisomers, tautomers, N-oxides, hydrates, solvates, salts thereof, particularly pharmaceutically acceptable salts, or mixtures of same, and one or more excipient(s), in particular one or more pharmaceutically acceptable excipient(s).
In accordance with a further aspect, the present invention covers pharmaceutical compositions, in particular medicaments, comprising compounds of general formula (l-a), as described supra , or tautomers, hydrates or solvates thereof, or mixtures of same, and one or more excipient(s), in particular one or more pharmaceutically acceptable excipient(s).
In accordance with a further aspect, the present invention covers pharmaceutical compositions, in particular medicaments, comprising compounds of general formula (I) and general formula (l-a), as described supra , or stereoisomers, tautomers, N-oxides, hydrates, solvates, salts thereof, particularly pharmaceutically acceptable salts, or mixtures of same, and one or more excipient(s), in particular one or more pharmaceutically acceptable excipient(s).
The present invention furthermore covers pharmaceutical compositions, in particular medicaments, which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipients, and to their use for the above mentioned purposes.
It is possible for the compounds according to the invention to have systemic and/or local activity. For this purpose, they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
For these administration routes, it is possible for the compounds according to the invention to be administered in suitable administration forms.
For oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally- disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.
Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.
Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear- rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
The compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia,
• fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos®)),
• ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols),
• bases for suppositories (for example polyethylene glycols, cacao butter, hard fat),
• solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins),
• surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitan fatty acid esters (such as, for example, Span®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®), • buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine),
• isotonicity agents (for example glucose, sodium chloride),
• adsorbents (for example highly-disperse silicas),
• viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl- cellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol®); alginates, gelatine),
• disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab®), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol®)),
• flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)),
• coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®)),
• capsule materials (for example gelatine, hydroxypropylmethylcellulose),
• synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),
• plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate),
• penetration enhancers,
• stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate),
• preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), • colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide),
• flavourings, sweeteners, flavour- and/or odour-masking agents.
The present invention furthermore relates to pharmaceutical compositions which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.
In accordance with another aspect, the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) or general formula (l-a) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of a hyperproliferative disorder, particularly cancer.
Particularly, the present invention covers a pharmaceutical combination, which comprises:
• one or more first active ingredients, in particular compounds of general formula (I) as defined supra, and
• one or more further active ingredients, in particular anti-cancer agents.
The term“combination” in the present invention is used as known to persons skilled in the art, it being possible for said combination to be a fixed combination, a non-fixed combination or a 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, for example, a first active ingredient, such as one or more compounds of general formula (I) or general formula (l-a) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity. One example of a “fixed combination” is a pharmaceutical composition wherein a first active ingredient and a further 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 a first active ingredient and a further 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 a first active ingredient and a further 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 first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of- parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered. The compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects. The present invention also covers such pharmaceutical combinations. For example, the compounds of the present invention can be combined with known anti-cancer agents.
Examples of anti-cancer agents include:
131 1-chTNT, abarelix, abemaciclib, abiraterone, acalabrutinib, 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, apalutamide, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, avelumab, axicabtagene ciloleucel, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, bosutinib, buserelin, brentuximab vedotin, brigatinib, 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, durvalumab, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, enasidenib, 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, I- 125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, inotuzumab ozogamicin, 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, lutetium Lu 177 dotatate, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, midostaurin, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, mvasi, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neratinib, neridronic acid, netupitant/palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, niraparib, 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, ribociclib, risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, rucaparib, samarium (153Sm) lexidronam, sargramostim, sarilumab, 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, tisagenlecleucel, 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 present invention can be administered as the sole pharmaceutical agent or in combination with one or more medical therapeutic means (e.g. surgical intervention, irradiation) and/or medical devices or appliances (e.g. breathing apparatuses, pacemaker implants, electrostimulation, stents).
Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyperproliferative 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 active ingredients or medicaments that are used to treat these conditions, the effective dosage of the compounds of the present 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. Therapeutically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, it is possible for "drug holidays", in which a patient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability. It is possible for a unit dosage to 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 body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg 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 body weight.
Nevertheless, it may be necessary to deviate from the stated amounts, depending on the body weight, the route of administration, the individual behavior towards the active substance, the type of preparation and the time or interval at which the application takes place. Thus, in some cases, it may be sufficient to get by with less than the aforementioned minimum quantity, while in other cases the above-mentioned upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several doses throughout the day.
Nevertheless, it may be necessary to deviate from the stated amounts, depending on the body weight, the route of administration, the individual behavior towards the active substance, the type of formulation and the time or interval at which the application takes place. Thus, in some cases, it may be possible to achieve the desired effect with less than the aforementioned minimum quantity, while in other cases the above-mentioned upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several doses throughout the day.
Description of the Figures
Figure 1 : Firefly luciferase reporter under control of a TEAD-promoter, as described under SEQ ID No. 1 .
Figure 2: Stable Firefly luciferase reporter under control of a TEAD-promoter (base pairs 27- 304), as described under SEQ ID No. 2.
Figure 3: Recognition sequence of geranylgeranyl pyrophosphate (GGPP), as described under SEQ ID No. 3.
EXPERIMENTAL SECTION Chemical names were generated using the ACD/Name software from ACD/Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD/Name generated names.
The following table 1 lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person.
Table 1 : Abbreviations
Figure imgf000132_0001
Figure imgf000133_0001
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.
The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.
EXPERIMENTAL SECTION - GENERAL PART
All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.
The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be removed by trituration using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartridges KP-Sil® or KP-NH® in combination with a Biotage autopurifier system (SP4® or Isolera Four®) and eluents such as gradients of hexane/ethyl acetate or DCM/methanol. In flash column chromatography, unmodified (“regular”) silica gel may be used as well as aminophase functionalized silica gel. If reference is made to flash column chromatography or to flash chromatography in the experimenta section without specification of a stationary phase, regular silica gel was used.
In some cases, the compounds may be purified by preparative FIPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
Analytical LC-MS Methods:
Method 1 :
Instrument: Shimadzu LCMS-2020; Colum: CORTECS C18 2.7m 50x2.1 mm; eluent A: water + 0.09 vol % formic acid, eluent B: acetonitrile + 0.1 vol % formic acid; gradient: 0-1.2 min 5- 100% B, 1 .2-1 .7 min 100% B; 1 .7-1 .75 min 100-5% B, 1.75-2.0 min 5% B flow 1 .0 ml/min; temperature: 40 Ό; DAD scan: 190-400 nm
Method 2:
Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1 .7 pm, 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: Shimadzu LCMS-2020; Colum: Ascentis Express C18 2.7m 50x2.1 mm; eluent A: water + 0.05 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.05 vol % trifluoroacetic acid; gradient: 0-1 .2 min 5-100% B, 1 .2-1 .7 min 100% B; 1 .7-1.75 min 100-5% B, 1 .75-2.0 min 5% B flow 1 .0 ml/min; temperature: 40 Ό; DAD scan: 190- 400 nm
Method 4:
Instrument: Shimadzu LCMS-2020; Colum: Ascentis Express C18 2.7m 50x2.1 mm; eluent A: water + 0.05 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.05 vol % trifluoroacetic acid; gradient: 0-2.0 min 5-95% B, 2.0-2.6 min 95% B; 2.6-2.7 min 95-5% B, 2.7-3.0 min 5% B; flow 1 .0 ml/min; temperature: 40 Ό; DAD scan: 190-400 n m
Method 5:
Instrument: Shimadzu LCMS-2020; Column: CORTECS C18 2.7m 50x2.1 mm; eluent A: water + 0.05 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.05 vol % trifluoroacetic acid; gradient: 0-2.0 min 5-100% B, 2.0-2.8 min 100% B; 2.8-2.9 min 100-5% B, 2.8-3.0 min 5% B; flow 1 .0 ml/min; temperature: 40 O; DAD scan: 190- 400 nm
Method 6:
Instrument: Shimadzu LCMS-2020; Column: Kinetex 2.6um EVO C18 2.67m 50x3.0mm; eluent A: water + 5mM ammonium hydrogen carbonate, eluent B: acetonitrile; gradient: 0-2.1 min 10- 95% B, 2.1 -2.7 min 95% B; 2.7-2.75 min 95-10% B, 2.75-3.0 min 10% B flow 1 .2 ml/min; temperature: 40 Ό; DAD scan: 190-400 nm
Preparative LC-MS Methods:
Method 7:
Instrument: Waters Autopurification MS SingleQuad; Colum: Waters XBrigde C18 5m 100x30mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 ml/min; temperature: 25 TD; DAD scan: 210-400 nm
Method 8:
Instrument: pump: Labomatic HD-5000 or HD-3000, head HDK 280, lowpressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 pm, 125x30mm; solvent A: water + 0.1 vol-% formic acid, solvent B: acetonitrile; gradient: 0.00- 0.50 min 30% B (150 ml/min), 0.50-6.00 min 30-70% B (150 ml/min), 6.00-6.10 min 70-100% B (150 ml/min), 6.10-8.00 min 100% B (150 ml/min); UV-Detection.
Specific Optial Rotation Methods:
Method OR1 :
Instrument: JASCO P2000 Polarimeter; wavelength 589 nm; temperature: 20 O; integration time 10 s; path length 100 mm.
NMR Spectra:
The multiplicities of proton signals in 1 H-NMR spectra given in the following paragraphs reflect the observed signal form and do not take into account any higher-order signal phenomena. As a rule, the chemical shift data refers to the center of the signal in question. In the case of wide multiplets, a range is specified. Signals hidden by solvent or water were either assigned tentatively or are not listed. Strongly broadened signals - e.g. caused by rapid rotation of molecular moieties or by interchanging protons - have also been assigned tentatively (often referred to as a broad multiplet or broad singlet) or are not shown.
The 1 H-NMR data of selected compounds are listed in the form of 1 H-NMR peaklists. Therein, for each signal peak the d value in ppm is given, followed by the signal intensity, reported in round brackets. The d value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: di (intensityi), 62 (intense), ... , (intensity,), ... , dh (intensity,,).
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 the particular target compound, peaks of impurities, 13C satellite peaks, and/or spinning sidebands. The peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compound (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 a reproduction of the manufacturing process on the basis of "by-product fingerprints". An expert who calculates the peaks of the target compound by known methods (MestReC, ACD simulation, or by use of empirically evaluated expectation values), can isolate the peaks of the target compound 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. http://www.researchdisclosure.com/searching-disclosures, Research Disclosure Database Number 605005, 2014, 01 Aug 2014). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be adjusted between 1 % and 4%. However, 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 %.
EXPERIMENTAL SECTION - INTERMEDIATES
Intermediate 1
(rac) tert-butyl 4-[cyano(4-fluorophenyl)methyl]-4-hydroxypiperidine-1 -carboxylate
Figure imgf000137_0001
To a solution of 2-(4-fluorophenyl)acetonitrile, 10 g (74 mmol), in 100 ml of tetrahydrofuran was added n-butyllithium (35 ml , 2.5 M in n-hexane) at -78Ό and the resulting mixture was stirred at this temperature for 30 min. Then a solution of tert-butyl 4-oxopiperidine-1 -carboxylate 16.3 g (8.14 mmol), in 100 ml of THF was added to the above solution at -780 and the resulting mixture was stirred at this temperature for 5 hours under nitrogen atmosphere. Aqueous ammonium chloride solution was added at -78 O and the mixture was warmed up to room temperature. The resulting solution was extracted with dichloromethane (three times) and the combined organic layer was dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give the desired product (23 g, 84% yield).
LC-MS (Method 1 ): Rt = 1 .099 min; MS (ESIpos): m/z = 235 [M+H-Boc]+.
Intermediate 2
(rac) tert-butyl 4-[2-amino-1 -(4-fluorophenyl)ethyl]-4-hydroxypiperidine-1 -carboxylate
Figure imgf000138_0001
To a solution of (rac) tert-butyl 4-(cyano-(4-fluorophenyl)methyl)-4-hydroxypiperidine-1 - carboxylate, 10 g (29.9 mmol), and 5 g of Raney-Nickel 250 ml of methanol was added a solution of ammonia in methanol solution (10 ml , 7M). The resulting mixture was stirred at 50 Ό for 4 hours under hydrogen atmosphere (10 atm). The catalyst was removed by filtration and the filter cake was washed with methanol for 5 times. The filtrate was concentrated in vacuo to give 10 g (81 %) of the desired product as a gummy solid.
LC-MS (Method 3): Rt = 0.803 min; MS (ESIpos): m/z = 339 [M+H]+. Intermediate 3
(rac) tert-butyl 5-(4-fluorophenyl)-2-oxo-1 -oxa-3,9-diazaspiro[5.5]undecane-9-carboxylate
Figure imgf000139_0001
To a solution of (rac) tert-butyl 4-(2-amino-1 -(4-fluorophenyl)ethyl)-4-hydroxypiperidine-1 - carboxylate, 10 (29.5 mmol), in 500 ml of dry DCM was added di(1 H-imidazol-1 -yl)methanone, 7.2 g (44.2 mmol), and the resulting mixture was stirred at 40 Ό for 4 h, The solvent was removed in vacuo and the residue was purified with C18 reverse phase column (column : Ultimate XB-C18 50 x 250mm 10pm; phase A : water+10 Mmol ammonium bicarbonate; phase B : acetonitrile; gradient : 25%-55% in 30min) to give 9 g (83%) of the title compound as a white solid.
LC-MS (Method 4): Rt = 3.063 min; MS (ESIpos): m/z = 729 [2M+H]+.
1 H-NMR (400 MHz, CDCIs) d [ppm]: 1 .41 (s, 9H), 1 .45 - 1.58 (m, 2H), 1 .74 - 1 .85 (m, 2H), 3.04 - 3.24 (m, 3H), 3.60 - 3.67 (m, 2H), 3.91 - 3.94 (m, 2H), 5.60 (s, 1 H), 7.03 - 7.08 (m, 2H), 7.18 - 7.26 (m, 2H).
The title compound (1080 mg) was separated into its enantiomers by preparative chiral HPLC to give enantiomer 1 (403 mg, see Intermediate 4), enantiomer 2 (405 mg, see Intermediate 5).
Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000, Column: YMC Cellulose SC 5m 250x30mm; Eluent: Acetonitrile/Ethanol 95:5%; Flow 40.0 ml/min; UV 254 nm
Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; Column: YMC Cellulose SC 3m 100x4, 6mm; Eluent: acetonitrile + 0.1 Vol-% diethylamine (99%)/ethanol 90:10; Flow 1 .4 ml/min; Temperature: 25 Ό; DAD 254 nm.
Intermediate 4 and Intermediate 5
tert-butyl (5R)-5-(4-fluorophenyl)-2-oxo-1 -oxa-3,9-diazaspiro[5.5]undecane-9-carboxylate tert-butyl (5S)-5-(4-fluorophenyl)-2-oxo-1 -oxa-3,9-diazaspiro[5.5]undecane-9-carboxylate
Intermediate 4
tert-butyl -5-(4-fluorophenyl)-2-oxo-1 -oxa-3,9-diazaspiro[5.5]undecane-9-carboxylate (single stereoisomer 1 )
Figure imgf000140_0001
For the preparation of the racemic title compound and separation into its enantiomer see Intermediate 3.
1 FI-NMR (400MFIz, DMSO-de): d [ppm]= 1 .30 - 1 .41 (m, 1 1 FI), 1.57 (br d, 1 FI), 1 .81 (br d, 1 FI), 2.80 - 3.09 (m, 2H), 3.19 (t, 1 H), 3.36 - 3.52 (m, 2H), 3.75 (br d, 2H), 7.18 (t, 2H), 7.31 - 7.36
(m, 2H), 7.49 (s, 1 H).
Analytical Chiral FIPLC (method see Intermediate 3): Rt = 1.39 min, e.e. >99%.
Optical rotation (method OR1 ): +5.2°(methanol).
Intermediate 5
tert-butyl 5-(4-fluorophenyl)-2-oxo-1 -oxa-3,9-diazaspiro[5.5]undecane-9-carboxylate (single stereoisomer 2)
Figure imgf000140_0002
For the preparation of the racemic title compound and separation into its enantiomer see Intermediate 3.
1 H-NMR (400MHz, DMSO-de): d [ppm]= 1 .30 - 1 .41 (m, 1 1 H), 1 .57 (br d, 1 H), 1 .77 - 1 .85 (m, 1 H), 2.98 (br s, 2H), 3.15 - 3.21 (m, 1 H), 3.35 - 3.53 (m, 2H), 3.75 (br d, 2H), 7.18 (t, 2H), 7.31 - 7.36 (m, 2H), 7.49 (s, 1 H).
Analytical Chiral HPLC (method see Intermediate 3): Rt = 1.72 min, e.e. >99%.
Optical rotation (method OR1 ): -4.8° (methanol). Intermediate 6
(rac) 5-(4-fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid
Figure imgf000141_0001
To a solution of intermediate 3 (10 g, 27.44 mmol), in 220 ml of methanol was added 24 ml of concentrated hydrochloric acid. The resulting mixture was stirred at RT for overnight. The solvent was removed in vacuo and the residue was dried in lyphilization to give 7.06 g (86%) the product as a white solid.
1 H-NMR (500MHz, DMSO-de): d [ppm]= 1 .74 - 1 .88 (m, 3H), 2.02 (br m, 1 H), 2.92 - 3.09 (m, 2H), 3.17 (br d, 2H), 3.25 (m, 1 H), 3.43 (m, 1 H), 3.54 (m, 1 H), 7.19 (t, 2H), 7.33 - 7.39 (m, 3H), 8.72 (br s, 1 H), 9.14 (br s, 1 H).
Intermediate 7 and Intermediate 8
(5R)-5-(4-fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid (5S)-5-(4-fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid
Intermediate 7
5-(4-fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid (single stereoisomer 1 )
Figure imgf000141_0002
To a solution of intermediate 4 (350 mg, 960 mihoI) in dioxane (10 ml) under an Argon atmosphere was added 4M hydrochloric acid in dioxane (2.4ml, 9.6 mmol) and the reaction was heated at 50Ό for 2h and then at RT for 16h. A nother portion of 4M hydrochloric acid in dioxane (2.4 ml, 9.6 mmol) was added and the reaction was heated at 500 for 3h. The reaction was concentrated in vacuo to give the title compound (290 mg, quantitative).
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .607 (0.25), 1 .617 (0.25), 1 .641 (0.23), 1 .652 (0.23),
1 .681 (0.25), 1 .690 (0.24), 1 .715 (0.20), 1 .726 (0.16), 1.875 (0.31 ), 1 .907 (0.23), 1.964 (0.29), 2.000 (0.25), 2.518 (0.79), 2.522 (0.49), 2.902 (0.19), 2.930 (0.20), 2.989 (0.19), 3.017 (0.20),
3.158 (0.48), 3.188 (0.35), 3.254 (0.26), 3.269 (0.40), 3.278 (0.34), 3.292 (0.45), 3.319 (0.30),
3.327 (0.38), 3.371 (0.27), 3.384 (0.21 ), 3.565 (16.00), 3.584 (0.33), 3.610 (0.37), 3.638 (0.22), 7.208 (0.77), 7.231 (1 .74), 7.253 (0.99), 7.369 (0.86), 7.374 (0.41 ), 7.382 (0.98), 7.391 (0.83), 7.400 (0.32), 7.405 (0.69), 7.610 (0.65), 7.615 (0.65), 8.850 (0.18), 8.874 (0.17).
Optical rotation (method OR1 ): +25.1“(methanol).
Intermediate 8
5-(4-fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid (single stereoisomer 2)
Figure imgf000142_0001
Following the method described for intermediate 7: intermediate 5 (380 mg, 1 .04 mmol ) gave the title compound (320 mg, quantitative).
Optical rotation (method OR1 ): -19.5°(Methanol).
Intermediate 9
(rac) tert-butyl 4-[cyano(2-methoxyphenyl)methyl]-4-hydroxypiperidine-1 -carboxylate
Figure imgf000143_0001
To a solution of (2-methoxyphenyl)acetonitrile (5 g, 33.97 mmol) in anhydrous TFIF (140 ml) under Argon at -700 was added slowly dropwise an s olution of n-butyllithium (21 .33 ml, 1 .6 M, 33.97 mmol). After stirring at -700 for 40 min, a solution of tert-butyl 4-oxopiperidine-1 - carboxylate (6.77 g, 33.97 mmol) in anhydrous TFIF (38 ml) was added dropwise. The reaction stirred at -700 for 3h and then poured carefully o nto a mixture of ice with 150 ml sat. Ammonium chloride solution. The organics were extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica chromatography (Biotage NH phase; hexane:ethyl acetate) to give the title compound (8.57 g, 73 % yield) and was used directly in the next step.
Intermediate 10
(rac) tert-butyl 4-[2-amino-1 -(2-methoxyphenyl)ethyl]-4-hydroxypiperidine-1 -carboxylate
Figure imgf000143_0002
An autoclave was charged with (rac) tert-butyl 4-[cyano(2-methoxyphenyl)methyl]-4- hydroxypiperidine-1 -carboxylate (8.57 g, 85% purity 21 .03 mmol), ammonia (300 ml, 2.0 M in ethanol) and Raney-Nickel (3.7 g 50% wet) and the mixture was stirred under 30 bar hydrogen atmosphere at 800 for 26 h. For the work-up, the m ixture was filtered through a pad of celite, eluted with ethanol and the combined filtrates were concentrated under reduced pressure. The residue was titurated with ethyl acetate, collected by filtration and washed with hexanes to give the title compound which was used in the next step without further purification. Intermediate 11
(rac) tert-butyl 5-(2-methoxyphenyl)-2-oxo-1 -oxa-3,9-diazaspiro[5.5]undecane-9-carboxylate
Figure imgf000144_0001
To a solution of (rac) tert-butyl 4-[2-amino-1 -(2-methoxyphenyl)ethyl]-4-hydroxypiperidine-1 - carboxylate (9.67 g, 80% purity, 22.07 mmol) in DCM (454 ml) und carbodiimidazole (5.369 g, 33.1 1 mmol) was heated at 40Ό for 3h and then stir red at RT for 16h. The reaction mixture was absorbed onto Isolute and after silica chromatography (hexane:ethyl acetate) the title compound was isolated (4.29 g, 52% yield).
The title compound (4290 mg) was separated into its enantiomers by preparative chiral HPLC to give enantiomer 1 (1 .42 g, see Intermediate 12), enantiomer 2 (1 .12 g, see Intermediate 13).
Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000, Column: Chiralpak l@ 5m 250x30mm; Eluent A: acetonitrile + 0.1 Vol- % diethylamine (99%); Eluent B: ethanol; Isocratic: 90%A+10%B; Flow 50.0 ml/min; UV 254 nm.
Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; Column: Chiralpak l@ 3m 100x4, 6mm; Eluent A: tert-butylmethylether + 0.1 Vol-% diethylamine (99%); Eluent B: ethanol; Isocratic: 90%A+10%B; Flow 1 .4 ml/min; Temperature: 25 Ό; DAD 254 nm.
Intermediate 12 and Intermediate 13
tert-butyl (5R)-5-(2-methoxyphenyl)-2-oxo-1 -oxa-3,9-diazaspiro[5.5]undecane-9-carboxylate tert-butyl (5S)-5-(2-methoxyphenyl)-2-oxo-1 -oxa-3,9-diazaspiro[5.5]undecane-9-carboxylate
Intermediate 12
tert-butyl 5-(2-methoxyphenyl)-2-oxo-1 -oxa-3,9-diazaspiro[5.5]undecane-9-carboxylate (single stereoisomer 1)
Figure imgf000145_0001
For the preparation of the racemic title compound and separation into its enantiomer see Intermediate 11.
1H-NMR (400MHz, CHLOROFORM-d): d [ppm]= 1.38 - 1.49 (m, 10H), 1.55 - 1.70 (m, 2H), 1.71 - 1.81 (m, 1 H), 1.95 (br dd, 1 H), 3.08 - 3.25 (m, 2H), 3.46 - 3.57 (m, 1 H), 3.64 (br d, 1 H), 3.81 -3.95 (m, 6H), 5.72 (brs, 1H), 6.90-6.97 (m, 2H), 7.17 (dd, 1H), 7.27-7.31 (m, 1H). Analytical Chiral HPLC (method see Intermediate 11): Rt = 2.54 min, e.e. >99%.
Optical rotation (method OR1): -53.6° (methanol).
Intermediate 13
tert-butyl-5-(2-methoxyphenyl)-2-oxo-1-oxa-3,9-diazaspiro[5.5]undecane-9-carboxylate (single stereoisomer 2)
Figure imgf000145_0002
For the preparation of the racemic title compound and separation into its enantiomer see Intermediate 11.
1H-NMR (400MHz, CHLOROFORM-d): d [ppm]= 1.39 - 1.49 (m, 10H), 1.64 (td, 1H), 1.71 - 1.81 (m, 2H), 1.95 (br dd, 1 H), 3.09 - 3.26 (m, 2H), 3.46 - 3.54 (m, 1 H), 3.64 (br d, 1 H), 3.78 -
3.95 (m, 6H), 5.55 (brs, 1 H), 6.90 - 7.00 (m, 2H), 7.17 (dd, 1 H), 7.26 - 7.31 (m, 1H).
Analytical Chiral HPLC (method see Intermediate 11): Rt = 3.96 min, e.e. >99%.
Optical rotation (method OR1): +57.8°(methanol). Intermediate 14
(rac) 5-(2-methoxyphenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid
Figure imgf000146_0002
Following the method described for intermediate 7: intermediate 1 1 (920 mg, 2.44 mmol) gave the title compound which was used directly in the next steps.
Intermediate 15 and Intermediate 16
(5R)-5-(2-methoxyphenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid (5S)-5-(2-methoxyphenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid
Intermediate 15
5-(2-methoxyphenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid (single stereoisomer 1 )
Figure imgf000146_0001
Following the method described for intermediate 7: intermediate 12 (1 .42 g, 3.77 mmol) gave the title compound (1 .37 g, quantitative) which was used directly in the next steps.
LC-MS (Method 2): Rt = 0.78 min; MS (ESIpos): m/z = 553 [2M+H]+.
Optical rotation (method OR1 ): -64.4°(methanol). Intermediate 16
5-(2-methoxyphenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid (single stereoisomer 2)
Figure imgf000147_0001
Following the method described for intermediate 7: intermediate 13 (1 .12 g, 2.98 mmol) gave the title compound (1 .07 g, quantitative) which was used directly in the next steps.
LC-MS (Method 2): Rt = 0.79 min; MS (ESIpos): m/z = 553 [2M+FI]+.
Optical rotation (method OR1 ): +57.3°(methanol).
Intermediate 17
(rac) tert-butyl 4-[[2-(benzyloxy)phenyl](cyano)methyl]-4-hydroxypiperidine-1 -carboxylate
Figure imgf000147_0002
Following the method described for intermediate 9: tert-butyl 4-oxopiperidine-1 -carboxylate (8.92 g, 44.9 mmol) and 2-benzyloxyphenylacetonitrile (10.00 g, 44.9 mmol) gave the title compound (18.49 g, 97% yield) after silica chromatography (hexane:ethyl acetate) which was used directly in the next step.
LC-MS (Method 2): Rt = 1 .39 min; MS (ESIpos): m/z = 423 [M+H]+ and 323 [M+H-Boc]+ Intermediate 18
(rac) tert-butyl 4-{(1 R)-2-amino-1 -[2-(benzyloxy)phenyl]ethyl}-4-hydroxypiperidine-1 - carboxylate
Figure imgf000148_0001
To a solution of intermediate 17 (9.726 g, 23.02 mmol) in methanol (234 ml) was added cobalt(ll) chloride hexahydrate (10.95 g, 46.04 mmol) and to this was added slowly and carefully small portions of sodium borohydride (8.709 g, 230.2 mmol). The reaction was stirred at RT for 3h, then slowly and carefully to the reaction mixture was added 4M ammonium chloride (aq) solution. The reaction mixture was diluted with water and the organic solvents were removed in vacuo and the organics were extracted with DCM:methanol (9:1 ). The organics were combined and washed with sat. ammonium chloride solution. The organic layer was dried over sodium sulfate, filtered and concentrated to give the crude title compound (9.4 g, 96%) which was used directly in the next step.
LC-MS (Method 2): Rt = 1 .36 min; MS (ESIpos): m/z = 427 [M+H]+.
Intermediate 19
(rac) tert-butyl 5-[2-(benzyloxy)phenyl]-2-oxo-1 -oxa-3,9-diazaspiro[5.5]undecane-9-carboxylate
Figure imgf000148_0002
Following the method described for intermediate 1 1 : intermediate 18 (9.40 g, 20.1 mmol) gave the title compound (5.84 g, 64% yield) after silica chromatography (DCM:ethanol).
1 H-NMR (400MHz, CHLOROFORM-d): d [ppm]= 1 .39 (s, 9H), 1 .65 (br s, 1 H), 1 .80 (br d, 1 H), 1 .90 (br d, 1 H), 3.15 (br s, 2H), 3.29 - 3.52 (m, 1 H), 3.56 - 4.1 1 (m, 4H), 5.02 - 5.12 (m, 2H), 5.67 (br s, 1 H), 6.93 - 7.06 (m, 2H), 7.20 (d, 1 H), 7.26 - 7.31 (m, 1 H), 7.33 - 7.46 (m, 5H). The title compound (27.8 g) was separated into its enantiomers by preparative chiral HPLC to give enantiomer 1 (10.47 g, see Intermediate 20), enantiomer 21 (10.43 g, see Intermediate 21 ).
Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000, Column: YMC Amylose SA 5m 250x50mm; Eluent A: tert.- butylmethylether; Eluent B: acetonitrile; Isocratic: 65%A+35%B; Flow 150 ml/min; UV 280 nm.
Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; Column: YMC Amylose SA 3m 100x4, 6mm; Eluent A: tert.-Butylmethylether + 0.1 Vol-% diethylamine (99%); Eluent B: acetonitrile; Isocratic: 50%A+50%B; Flow 1 .4 ml/min; Temperature: 25 TD; DAD 280 nm.
Intermediate 20 and Intermediate 21
tert-butyl (5R)-5-[2-(benzyloxy)phenyl]-2-oxo-1 -oxa-3,9-diazaspiro[5.5]undecane-9-carboxylate tert-butyl (5S)-5-[2-(benzyloxy)phenyl]-2-oxo-1 -oxa-3,9-diazaspiro[5.5]undecane-9-carboxylate
Intermediate 20
tert-butyl 5-[2-(benzyloxy)phenyl]-2-oxo-1 -oxa-3,9-diazaspiro[5.5]undecane-9-carboxylate (single stereoisomer 1 )
Figure imgf000149_0001
For the preparation of the racemic title compound and separation into its enantiomer see Intermediate 19.
1 H-NMR (400MHz, DMSO-de): d [ppm]= 1.23 - 1 .33 (m, 10H), 1 .44 (td, 1 H), 1.64 - 1.79 (m, 2H), 2.90 (br s, 2H), 3.26 - 3.32 (m, 1 H), 3.45 - 3.57 (m, 1 H), 3.60 - 3.81 (m, 3H), 5.09 - 5.18 (m, 2H), 6.96 (t, 1 H), 7.16 (d, 1 H), 7.26 - 7.48 (m, 8H).
Analytical Chiral HPLC (method see Intermediate 19): Rt = 2.93 min, e.e. >99%.
Optical rotation (method OR1 ): -90.8° (methanol). Intermediate 21
tert-butyl 5-[2-(benzyloxy)phenyl]-2-oxo-1 -oxa-3,9-diazaspiro[5.5]undecane-9-carboxylate (single stereoisomer 2)
Figure imgf000150_0001
For the preparation of the racemic title compound and separation into its enantiomer see Intermediate 19.
1 H-NMR (400MHz, DMSO-de): d [ppm]= 1.24 - 1 .37 (m, 10H), 1 .44 (td, 1 H), 1.64 - 1.79 (m, 2H), 2.91 (br s, 2H), 3.26 - 3.31 (m, 1 H), 3.45 - 3.57 (m, 1 H), 3.59 - 3.81 (m, 3H), 5.09 - 5.18 (m, 2H), 6.96 (t, 1 H), 7.16 (d, 1 H), 7.26 - 7.48 (m, 8H).
Analytical Chiral HPLC (method see Intermediate 19): Rt = 3.96 min, e.e. >95%.
Optical rotation (method OR1 ): +90.0°(methanol).
Intermediate 22
(rac) 5-[2-(benzyloxy)phenyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid
Figure imgf000150_0002
To a solution of (rac) tert-butyl 5-[2-(benzyloxy)phenyl]-2-oxo-1 -oxa-3,9-diazaspiro[5.5]- undecane-9-carboxylate (820 mg, 1 .81 mmol, Intermediate 19) in dioxane (14 ml) was added 4M hydrochloric acid in dioxane (4.53 ml, 18.1 mmol) and stirred at RT for 64 h. The reaction was concentrated and used directly in the next step.
LC-MS (Method 2): Rt = 1 .03 min; MS (ESIpos): m/z = 705 [2M+H]+. Intermediate 23
(rac) tert-butyl 4-[cyano(4-fluoro-2-methylphenyl)methyl]-4-hydroxypiperidine-1 -carboxylate
Figure imgf000151_0001
2-(4-Fluoro-2-methylphenyl)acetonitrile (5.00 g, 33.5 mmol), was dissolved in 50 ml of tetrahydrofuran under nitrogen atmosphere. Then n-butyllithium, 14.7 ml (36.8 mmol, 2.5 M), was added dropwise at -78 Ό and the resulting mixt ure was stirred at this temperature for 30 min. Then tert-butyl 4-oxopiperidine-1 -carboxylate, 7.0 g (35.2 mmol, in 50 ml of tetrahydrofuran), was added to the reaction mixture dropwise and the resulting mixture was stirred at -78 Ό for 4 h. The resulting mixture wa s quenched by hydrochloric acid (0.5 M). The pH value of the mixture was adjusted to 7-8 with hydrochloric acid (0.5 M). Then the resulting mixture was extracted with ethyl acetate and concentrated in vacuo, and the residue was purified with silica gel column chromatography (petroleum ether: ethyl acetate) to give 5.3 g (40 %) of the title product as white solid.
LC-MS (Method 5): Rt = 1 .506 min; MS (ESIpos): m/z = 249 [M+H-Boc]+.
Intermediate 24
(rac) tert-butyl 4-[2-amino-1 -(4-fluoro-2-methylphenyl)ethyl]-4-hydroxypiperidine-1 -carboxylate
Figure imgf000151_0002
(rac) tert-Butyl 4-[cyano(4-fluoro-2-methylphenyl)methyl]-4-hydroxypiperidine-1 -carboxylate (5.00 g, 87 % purity, 12.5 mmol) was dissolved in 200 ml of methanol, then Raney-Nickel, 3.00 g (50 mmol), and ammonia, 5 ml (7M in methanol) were added. The resulting mixture was stirred at 50 Ό for 6 h under hydrogen atmosphere (10 atm). The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 3 g (33%) of the product as a yellow solid. The product was used next step without further purification.
LC-MS (Method 1 ): Rt = 0.760 min; MS (ESIpos): m/z = 353 [M+H]+.
Intermediate 25
(rac) tert-butyl 5-(4-fluoro-2-methylphenyl)-2-oxo-1 -oxa-3,9-diazaspiro[5.5]undecane-9- carboxylate
Figure imgf000152_0001
(rac) tert-butyl 4-[2-amino-1 -(4-fluoro-2-methylphenyl)ethyl]-4-hydroxypiperidine-1 -carboxylate, 5 g (33% purity, 4.68 mmol), was dissolved in 50 ml of dichloromethane, then carbodiimidazole, 2.57 g (6.8 mmol), was added at room temperature. Then the resulting mixture was stirred at 40 Ό for 4 h under nitrogen atmosphere. After cooled to room temperature, the resulting mixture was washed with water and organic phase was concentrated under vaccum to give 3 g (crude) as a yellow solid. Then the crude product was purified with prep-HPLC (Ultimate XB-C18, 50 x 250 mm, 10 pm; Mobile Phase A: water (0.1 % ammonium bicarbonate), Mobile Phase B: acetonitrile; Gradient: 25 % B to 60 % B in 35 min; 210 nm) to give 1 .36 g (74 %) as a white solid.
LC-MS (Method 6): Rt = 1 .477 min; MS (ESIpos): m/z = 379 [M+H]+.
The title compound (1.26 g) was separated into its enantiomers by preparative chiral HPLC to give enantiomer 1 (561 mg, see Intermediate 26), enantiomer 21 (559 mg, see Intermediate 27).
Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000, Column: Chiralpak IA 5p 250x30mm; Eluent A: hexane + 0.1 Vol-% diethylamine (99%); Eluent B: ethanol; 100x4: 20%B; Flow 40.0 ml/min; UV 220 nm.
Analytical chiral HPLC method Instrument: Agilent HPLC 1260; Column: Chiralpak IA 3p 100x4.6mm; Eluent A: hexane + 0.1 Vol-% diethylamine (99%); Eluent B: ethanol; Isocratic: 20%B; Flow 1 .4 ml/min; Temperature: 25 Ό; DAD 220 nm. Intermediate 26 and Intermediate 27
tert-butyl (5R)-5-(4-fluoro-2-methylphenyl)-2-oxo-1 -oxa-3,9-diazaspiro[5.5]undecane-9- carboxylate
tert-butyl (5S)-5-(4-fluoro-2-methylphenyl)-2-oxo-1 -oxa-3,9-diazaspiro[5.5]undecane-9- carboxylate
Intermediate 26
tert-butyl 5-(4-fluoro-2-methylphenyl)-2-oxo-1 -oxa-3,9-diazaspiro[5.5]undecane-9-carboxylate (single stereoisomer 1 )
Figure imgf000153_0001
For the preparation of the racemic title compound and separation into its enantiomer see Intermediate 25.
1 H-NMR (400MHz, DMSO-de): d [ppm]= 1 .26 - 1 .49 (m, 1 1 H), 1 .73 (br d, 1 H), 1 .80 - 1 .87 (m, 1 H), 2.36 (s, 3H), 2.91 (br d, 2H), 3.35 - 3.47 (m, 3H), 3.78 (br s, 2H), 6.99 - 7.11 (m, 2H), 7.27 (dd, 1 H), 7.47 (s, 1 H).
Analytical Chiral HPLC (method see Intermediate 25): Rt = 2.72 min, e.e. >99%.
Optical rotation (method OR1 ): +18.5°(methanol).
Intermediate 27
tert-butyl 5-(4-fluoro-2-methylphenyl)-2-oxo-1 -oxa-3,9-diazaspiro[5.5]undecane-9-carboxylate (single stereoisomer 2)
Figure imgf000153_0002
For the preparation of the racemic title compound and separation into its enantiomer see Intermediate 25. 1 H-NMR (400MHz, DMSO-de): d [ppm]= 1 .20 - 1 .49 (m, 1 1 H), 1 .73 (br d, 1 H), 1 .79 - 1 .88 (m, 1 H), 2.36 (s, 3H), 2.93 (br s, 2H), 3.34 - 3.43 (m, 3H), 3.78 (br s, 2H), 6.99 - 7.11 (m, 2H), 7.27 (dd, 1 H), 7.47 (s, 1 H).
Analytical Chiral HPLC (method see Intermediate 25): Rt = 3.82 min, e.e. >99%.
Optical rotation (method OR1 ): -14.7°(methanol).
Intermediate 28
5-(4-fluoro-2-methylphenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid (single stereoiomer 1 )
Figure imgf000154_0001
Following the method described for intermediate 7: intermediate 26 (530 mg, 1 .4 mmol) gave the title compound (518 mg, quantitative) which was used directly in the next steps.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 2.382 (5.20), 2.518 (2.09), 2.522 (1 .49), 3.167 (0.48), 3.396 (0.81 ), 3.410 (0.46), 3.418 (0.66), 3.432 (0.52), 3.487 (0.43), 3.565 (16.00), 7.065 (0.42), 7.073 (0.55), 7.1 14 (0.54), 7.121 (0.47), 7.140 (0.55), 7.147 (0.46), 7.288 (0.49), 7.303 (0.53),
7.309 (0.49), 7.324 (0.43), 7.600 (0.69), 7.604 (0.70).
Optical rotation (method OR1 ): +25.2°(methanol).
Intermediate 29
5-(4-fluoro-2-methylphenyl)-1-oxa-3,9-diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid (single stereoiomer 2)
Figure imgf000155_0001
Following the method described for intermediate 7: intermediate 27 (530 mg, 1.4 mmol) gave the title compound (493 mg, quantitative) which was used directly in the next steps.
1H-NMR (400 MHz, DMSO-de) d [ppm]: 1.592 (0.58), 1.610 (0.52), 1.633 (0.88), 1.644 (0.90), 1.668 (0.61), 1.679 (0.53), 1.844 (0.79), 1.855 (0.78), 1.877 (0.76), 1.888 (0.69), 1.917 (1.27), 1.953 (0.55), 1.986 (0.58), 2.004 (1.01 ), 2.037 (0.85), 2.380 (16.00), 2.518 (2.95), 2.522 (2.09), 2.900 (0.64), 2.931 (0.82), 2.967 (0.82), 2.997 (0.71), 3.136 (0.94), 3.159 (1.49), 3.185 (0.80),
3.309 (0.50), 3.316 (0.63), 3.322 (0.78), 3.330 (0.88), 3.337 (0.85), 3.345 (0.88), 3.351 (1.13),
3.358 (1.12), 3.384 (1.90), 3.401 (7.85), 3.427 (2.19), 3.476 (1.28), 3.502 (1.18), 3.525 (0.64),
7.039 (0.58), 7.047 (0.79), 7.061 (1.30), 7.068 (1.70), 7.083 (0.79), 7.090 (0.96), 7.110 (1.65),
7.117 (1.49), 7.136 (1.71), 7.143 (1.45), 7.283 (1.49), 7.298 (1.66), 7.305 (1.52), 7.319 (1.33), 7.602 (2.23), 8.471 (0.50), 8.496 (0.51), 9.022 (0.63), 9.046 (0.63).
Optical rotation (method OR1): -25.4° (methanol).
Intermediate 30
(rac) ethyl 2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-hydroxypropanoate
Figure imgf000155_0002
To a solution of 1 -bromo-3, 5-dimethyl-benzene (89.0 g, 481 mmol, 65.4 ml, 1 .00 eg) and Mg (17.7 g, 731 mmol, 1 .52 eg) in THF (500 ml) was added iodine (4.88 g, 19.2 mmol, 0.04 eg) at 500 under nitrogen atmosphere. The reaction mxture was allowed to cool to RT and then cooled to -780. To this reaction mixture was added dropwise a solution of ethyl 3,3,3-trifluoro- 2-oxo-propanoate (120 g, 705 mmol, 93.7 ml, 1 .47 eg) in THF (400 ml). The mixture was stirred at -780 for 12 h. The mixture was poured into wate r (1 L), extracted with ethyl acetate (1 L, twice). The combined organic layer was washed with brine (1 L), dried with sodium sulfate, filtered and concentrated. The residue was purified by silica chromatography (petroleum etherethyl acetate) to give a crude product, and then dissolved in petroleum ether (150 ml) was added drop wise to get yellow slurry. The white solid was collected by filtration and dried in vacuo to give the title compound (56.0 g, 42% yield) as a white solid.
1H-NMR (400 MHz, CDCIs) d [ppm]: 7.39 (s, 2H), 7.06 (s, 1 H), 4.40-4.48 (m, 2H), 4.25 (s, 1 H), 2.36 (s, 6H), 1 .37-1 .42 (m, 3H).
Intermediate 31
(rac) ethyl 2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoate
Figure imgf000156_0001
To a solution of Intermediate 30 (56.0 g, 202 mmol) in acetone (550 ml) was added dimethyl sulfate (127 g, 1 .01 mol) and potassium carbonate (140 g, 1 .01 mol) at 150. The reaction mixture was stirred at 60Ό for 12 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was diluted with ethyl acetate (300 ml) and washed with 10% ammonia solution (200 ml, three times). The organic layer was washed with brine (200 ml, twice), dried with sodium sulfate, filtered and concentrated to give title compound as a colorless oil.
1H-NMR (400 MHz, CDCI3) d [ppm]: 7.12 (s, 2 H) 7.04 (s, 1 H), 4.37-4.43 (m, 2H), 3.97 (s, 3H), 3.56 (m, 3H), 2.34 (s, 6H), 1 .33-1 38(t, 3 H). Intermediate 32
(rac) 2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoic acid
Figure imgf000157_0001
To a solution of Intermediate 31 (77.0 g, 265 mmol, 1.00 eq) in ethanol (700 ml) was added potassium hydroxide (35.8 g, 639 mmol, 2.41 eq) at 15Ό. The mixture was stirred at 500 for 2 h. The reaction mixture was concentrated and the residue was diluted with water (300 ml), extracted with ethyl acetate (200 ml, twice). The aqueous layer was adjusted to pH=3 with 1 M hydrochloric acid and then extracted with ethyl acetate (200 ml x 2). The combined organic layer was washed with brine (300 ml x 1 ), dried with sodium sulfate, filtered and concentrated to give the title compound (53.0 g, 192 mmol, 72% yield) as a white solid.
1H-NMR (400 MHz, CDCI3) d [ppm]: 9.75 (s, 1 H) 7.17 (s, 2 H) 7.09 (s, 1 H) 3.56 (s, 3 H) 2.36 (s, 6 H).
Intermediate 33 and Intermediate 34
(2R)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoic acid
(2S)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoic acid
Intermediate 33
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (single stereoisomer 1 )
Figure imgf000157_0002
To a solution of Intermediate 32 (25 g, 95.3 mmol) in acetonitrile (250 ml) was added (R)-(6- methoxy-4-quinolyl)-[(2S,4S,5R)-5-vinylquinuclidin-2-yl]methanol (15.4 g, 47.6 mmol) at 15Ό. The mixture was stirred at 80Ό for 5 h. Then the m ixture was cooled to 15Ό and stirred for 12 h. The mixture was filtered and the solid residue was diluted with ethyl acetate (100 ml), washed with 1 M hydrochloric acid (80 ml, three times) and brine (100 ml), dried with sodium sulfate, filtered and concentrated to get the crude product, which was purified by silica chromatography (petroleum etherethyl acetate) to give the title compound (5.04 g, 20% yield) as a white solid.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 2.292 (16.00), 2.518 (0.74), 2.523 (0.46), 3.471 (5.87), 7.083 (6.01 ).
Optical rotation (method OR1 ): -60.4°(methanol).
Intermediate 34
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (single stereoisomer 2)
Figure imgf000158_0001
To a solution of Intermediate 32 (15 g, 55.2 mmol) in acetonitrile (150 ml) was added (1 S)-1 - (1 -naphthyl) ethanamine (8.51 g, 49.7 mmol, 0.9 eg) at 150. The mixture was stirred at 800 for 5 h. Then the mixture was cooled to 150 and st irred for 12 h. The mixture was filtered. And the solid residue was diluted with ethyl acetate (50 ml), washed with 1 M Hydrochloric acid (30 ml x 3) and brine (80 ml), dried with sodium sulfate, filtered and concentrated to get the crude product, which was purified by silica chromatography (silica gel, petroleum etherethyl acetate) to give the title compound was purified by silica chromatography (petroleum etherethyl acetate) to give the title (5.7 g, 39% yield) as a white solid.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.172 (0.54), 1 .987 (0.96), 2.292 (16.00), 2.518 (0.47), 7.083 (5.87).
Optical rotation (method OR1 ): +57.9°(methanol). EXPERIMENTAL SECTION - EXAMPLES
Example 1
(rac) 9-{[1 -(3,5-dimethylphenyl)cyclopentyl]carbonyl}-5-(4-fluorophenyl)-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one
Figure imgf000159_0001
A mixture of 1 -(3,5-dimethylphenyl)cyclopentanecarboxylic acid (75.0 mg, 344 mihoI, CAS-RN: 919017-14-4), PYBOP (193 mg, 370 pmol) and N,N-diisopropylethylamine (140 pL, 790 pmol) in DMF (1 .1 mL) was stirred for 5 min. Then (rac) 5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one hydrochloride (79.5 mg, 264 pmol, Intermediate 6) was added and the reaction mixture was stirred for 1 h at room temperature under an atmosphere of argon. The reaction mixture was filtered using a CHROMAFIL filter (PET-45/15 MS, Pore Size: 0,45 pm) and the final purification was conducted via preparative HPLC (Method 7) to give the title compound 100 mg (95 % purity, 81 % yield).
LC-MS (method 2): Rt = 1 .32 min; MS (ESIpos): m/z = 465 [M+H]+.
1 H-NMR (500 MHz, DMSO-d6, at 80Ό) d [ppm]: 1 .572 (0.77), 1 .583 (1 .22), 1 .598 (1 .41 ), 1 .613 (1 .13), 1 .638 (0.53), 2.144 (16.00), 2.254 (0.81 ), 2.268 (0.46), 2.513 (1 .56), 2.517 (1 .15), 2.521 (0.90), 2.766 (0.48), 2.787 (0.69), 2.790 (0.67), 2.81 1 (0.49), 2.817 (0.40), 2.883 (0.46),
2.904 (0.69), 2.908 (0.67), 2.929 (0.46), 3.023 (0.69), 3.035 (0.88), 3.040 (0.94), 3.052 (0.88),
3.338 (0.53), 3.344 (0.53), 3.351 (0.48), 3.356 (0.44), 3.403 (0.54), 3.420 (0.54), 6.680 (4.32),
6.781 (1 .64), 7.108 (1 .37), 7.1 12 (0.53), 7.125 (3.33), 7.143 (2.15), 7.158 (1 .22), 7.195 (1 .42),
7.206 (1 .63), 7.212 (1.24), 7.223 (0.95).
The title compound (60 mg) was separated into its enantiomers by preparative chiral HPLC to give enantiomer 1 (25 mg, see Example 2, ), enantiomer 2 (25 mg, see Example 3).
Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000; column: YMC Cellulose SC 5p 250x30mm; eluent A: acetonitrile, eluent B: ethanol; isocratic: 15%B; flow 40 mUmin; UV 220nm Analytical chiral HPLC method:
Instrument: Waters Alliance 2695; column: YMC Cellulose SC 3m 100x4, 6mm; eluent A: acetonitrile, eluent B: ethanol; isocratic: 10%B; flow 1.4 mL/min; DAD 220nm
Example 2 and Example 3
(5R)-9-{[1 -(3,5-dimethylphenyl)cyclopentyl]carbonyl}-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one
(5S)-9-{[1 -(3,5-dimethylphenyl)cyclopentyl]carbonyl}-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one
Example 2
9-{[1 -(3,5-dimethylphenyl)cyclopentyl]carbonyl}-5-(4-fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]- undecan-2-one (single stereoisomer 1 )
Figure imgf000160_0001
For the preparation of the racemic title compound and separation into its enantiomers see Example 1 .
1 H-NMR (500 MHz, DMSO-d6, at 800) d [ppm]: 0.994 (0.87), 1 .137 (3.39), 1 .176 (0.51 ), 1 .233 (0.45), 1 .262 (0.77), 1 .571 (0.75), 1 .583 (1 .18), 1.598 (1.35), 1 .612 (1 .02), 1.638 (0.51 ), 2.144 (16.00), 2.268 (0.44), 2.513 (2.40), 2.517 (2.00), 2.521 (1 .71 ), 2.766 (0.49), 2.787 (0.69), 2.790 (0.67), 2.81 1 (0.48), 2.816 (0.40), 2.883 (0.46), 2.904 (0.68), 2.907 (0.66), 2.928 (0.47),
2.934 (0.40), 3.023 (0.69), 3.035 (0.86), 3.040 (0.92), 3.052 (0.87), 3.338 (0.52), 3.344 (0.53),
3.351 (0.48), 3.356 (0.44), 3.403 (0.53), 3.420 (0.54), 6.680 (4.22), 6.781 (1 .59), 7.108 (1 .45),
7.1 13 (0.53), 7.122 (0.69), 7.126 (3.65), 7.131 (0.70), 7.139 (0.67), 7.144 (2.32), 7.158 (1 .17),
7.195 (1 .40), 7.206 (1.62), 7.212 (1.23), 7.223 (0.97).
Analytical Chiral HPLC (method see Example 1 ): Rt = 2.87 min, e.e. >99%.
Optical rotation (method OR1 ): +5.00°+/-0.51 °(chl oroform). Example 3
9-{[1-(3,5-dimethylphenyl)cyclopentyl]carbonyl}-5-(4-fluorophenyl)-1-oxa-3,9-diazaspiro[5.5]- undecan-2-one (single stereoisomer 2)
Figure imgf000161_0001
For the preparation of the racemic title compound and separation into its enantiomers see Example 1.
1H-NMR (500 MHz, DMSO-d6, at 800) d [ppm]: 0.995 (0.80), 1.137 (4.76), 1.177 (0.49), 1.262 (0.84), 1.571 (0.77), 1.583(1.21), 1.598(1.39), 1.612(1.08), 1.638 (0.53), 2.144 (16.00), 2.267 (0.45), 2.514 (3.21), 2.518 (2.69), 2.522 (2.26), 2.766 (0.50), 2.787 (0.69), 2.790 (0.67), 2.811 (0.50), 2.817 (0.41), 2.883 (0.47), 2.904 (0.68), 2.908 (0.67), 2.929 (0.47), 2.935 (0.40),
3.024 (0.70), 3.035 (0.88), 3.040 (0.94), 3.052 (0.92), 3.339 (0.52), 3.344 (0.53), 3.351 (0.49),
3.356 (0.44), 3.403 (0.53), 3.420 (0.54), 6.680 (4.24), 6.781 (1.59), 7.108 (1.49), 7.113 (0.56),
7.122 (0.74), 7.126 (3.72), 7.131 (0.74), 7.139 (0.72), 7.144 (2.38), 7.158 (1.20), 7.195 (1.42),
7.206 (1.64), 7.212 (1.25), 7.223 (0.97).
Analytical Chiral HPLC (method see Example 1): Rt = 5.23 min, e.e. >99%.
Optical rotation (method OR1): +1.21°+/-0.23°(chl oroform).
Example 4
(rac) 9-{[1 -(3-chlorophenyl)cyclopentyl]carbonyl}-5-(4-fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]- undecan-2-one
Figure imgf000162_0001
A mixture of 1 -(3-chlorophenyl)cyclopentanecarboxylic acid (75.0 mg, 332 mihoI, CAS-RN: 143328-21 -6), HATU (126 mg, 332 pmol) and N,N-diisopropylethylamine (230 mI_, 1 .3 mmol) in DMF (870 mI_) was stirred for 5 min, then (rac) 5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one hydrochloride (100 mg, 332 mihoI, Intermediate 6) was added and the reaction mixture was stirred for 1 h at room temperature under an atmosphere of argon. The reaction mixture was filtered using a CHROMAFIL filter (PET-45/15 MS, Pore Size: 0,45 pm) and the final purification was conducted via preparative HPLC (method 8) to give the title compound 80 mg (95 % purity, 51 % yield).
LC-MS (method 2): Rt = 1 .27 min; MS (ESIpos): m/z = 471 [M+H]+.
1 H-NMR (500 MHz, DMSO-d6, at 80Ό) d [ppm]: 0.947 (0.49), 0.963 (2.14), 0.976 (2.47), 1 .032 (1 .05), 1 .430 (0.79), 1 .596 (4.18), 1 .610 (7.87), 1.615 (8.86), 1 .865 (1 .15), 1.934 (1 .19),
2.049 (0.66), 2.263 (1 .71 ), 2.277 (2.04), 2.289 (3.09), 2.303 (2.1 1 ), 2.316 (1 .81 ), 2.353 (0.69),
2.368 (0.72), 2.513 (12.81 ), 2.517 (10.27), 2.521 (8.26), 2.627 (0.69), 2.642 (0.72), 2.782 (1 .81 ), 2.788 (2.24), 2.809 (3.03), 2.812 (2.96), 2.834 (2.21 ), 2.839 (1 .84), 2.891 (1.74), 2.896
(2.1 1 ), 2.918 (2.96), 2.921 (2.93), 2.942 (2.17), 2.947 (1.84), 3.034 (2.90), 3.047 (3.75), 3.050
(4.15), 3.329 (1 .15), 3.334 (1 .25), 3.340 (1 .28), 3.346 (1.38), 3.354 (2.73), 3.359 (2.83), 3.365
(2.57), 3.370 (2.40), 3.392 (2.63), 3.408 (2.57), 3.429 (1.19), 3.769 (0.46), 7.015 (3.09), 7.018
(4.61 ), 7.021 (3.56), 7.030 (3.69), 7.033 (5.47), 7.036 (4.21 ), 7.098 (6.16), 7.102 (1 1 .13), 7.106 (6.09), 7.1 13 (0.92), 7.1 19 (6.12), 7.124 (2.37), 7.132 (3.19), 7.137 (16.00), 7.141 (3.19), 7.150 (3.09), 7.155 (1 1 .00), 7.167 (5.43), 7.178 (3.33), 7.186 (8.36), 7.197 (10.21 ), 7.203 (6.68), 7.210 (5.47), 7.215 (5.30), 7.226 (5.50), 7.242 (2.44). Example 5
(rac) 9-{[1 -(3-bromophenyl)cyclopentyl]carbonyl}-5-(4-fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]- undecan-2-one
Figure imgf000163_0001
A mixture of 1 -(3-bromophenyl)cyclopentanecarboxylic acid (89.5 mg, 332 mihoI, CAS-RN: 143328-23-8), HATU (126 mg, 332 pmol) and N,N-diisopropylethylamine (230 mI_, 1 .3 mmol) in DMF (870 mI_) was stirred for 5 min, then (rac) 5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one hydrochloride (100 mg, 332 mihoI, Intermediate 6) was added and the reaction mixture was stirred for 1 h at room temperature under an atmosphere of argon. The reaction mixture was filtered using a CHROMAFIL filter (PET-45/15 MS, Pore Size: 0,45 pm) and the final purification was conducted via preparative HPLC (Method 8) to give the title compound 80 mg (95 % purity, 47 % yield).
LC-MS (method 2): Rt = 1 .27 min; MS (ESIpos): m/z = 516 [M+H]+.
1 H-NMR (500 MHz, DMSO-d6, at 80Ό) d [ppm]: 0.964 (0.57), 0.977 (0.61 ), 1 .039 (0.88), 1 .41 1 (0.61 ), 1 .615 (6.88), 1 .874 (0.96), 2.049 (2.81 ), 2.089 (0.48), 2.286 (2.32), 2.31 1 (1 .53),
2.354 (0.83), 2.514 (9.12), 2.518 (7.63), 2.522 (6.27), 2.538 (0.53), 2.627 (0.83), 2.642 (0.83),
2.783 (1 .36), 2.789 (1 .67), 2.81 1 (2.28), 2.814 (2.24), 2.835 (1.67), 2.841 (1 .36), 2.890 (1 .32),
2.895 (1 .62), 2.916 (2.28), 2.920 (2.24), 2.941 (1 .67), 2.947 (1.40), 3.033 (2.37), 3.048 (3.68),
3.346 (0.66), 3.365 (2.28), 3.370 (2.32), 3.382 (3.81 ), 3.402 (2.10), 3.423 (0.70), 7.063 (2.76),
7.080 (4.30), 7.122 (6.01 ), 7.139 (16.00), 7.157 (9.12), 7.170 (4.12), 7.191 (5.79), 7.202 (6.36), 7.208 (4.34), 7.219 (3.38), 7.248 (4.78), 7.251 (8.77), 7.255 (4.91 ), 7.366 (3.02), 7.382 (2.72). Example 6
(rac) 5-(4-fluorophenyl)-9-[(1-phenylcyclohexyl)carbonyl]-1-oxa-3,9-diazaspiro[5.5]undecan-2- one
Figure imgf000164_0001
A mixture of 1-phenylcyclohexanecarboxylic acid (88,3 mg, 432 mihoI, CAS-RN: 1135-67-7), PYBOP (242 mg, 465 pmol) and N,N-diisopropylethylamine (170 mI_, 1 mmol) in DMF (1.4 mL) was stirred for 5 min. Then (rac) 5-(4-fluorophenyl)-1-oxa-3,9-diazaspiro[5.5]undecan-2-one hydrochloride (100 mg, 332 mihoI, Intermediate 6) was added and the reaction mixture was stirred for 1 h at room temperature under an atmosphere of argon. The reaction mixture was filtered using a CHROMAFIL filter (PET-45/15 MS, Pore Size: 0,45 pm) and the final purification was conducted via preparative HPLC (method 7) to give the title compound 100 mg (95 % purity, 63 % yield).
LC-MS (method 2): Rt = 1.26 min; MS (ESIpos): m/z = 451 [M+H]+.
1H-NMR (500 MHz, DMSO-d6, at 80Ό) d [ppm]: 0.944 (0.77), 1.017 (0.81), 1.236 (0.92), 1.247 (0.96), 1.358 (0.90), 1.384 (0.82), 1.465 (0.98), 1.550 (5.72), 1.564 (4.97), 1.585 (2.40),
1.610 (1.21), 1.637 (1.34), 1.658 (0.65), 2.150 (2.57), 2.174 (1.46), 2.513 (4.64), 2.517 (3.65),
2.521 (3.11), 2.642 (0.52), 2.729 (1.23), 2.734 (1.42), 2.755 (2.03), 2.759 (1.98), 2.780 (1.44),
2.785 (1.25), 2.837 (1.19), 2.843 (1.42), 2.864 (2.05), 2.867 (1.96), 2.889 (1.44), 2.894 (1.23),
3.008 (2.01), 3.021 (2.55), 3.026 (2.71), 3.038 (2.42), 3.294 (1.04), 3.300 (1.11), 3.306 (1.07),
3.311 (1.15), 3.318 (1.92), 3.324 (1.98), 3.330 (1.75), 3.336 (1.63), 3.380 (1.84), 3.382 (1.88),
3.399 (1.90), 3.421 (1.04), 3.746 (0.63), 3.821 (0.59), 7.106 (3.89), 7.110 (5.10), 7.117 (4.55),
7.119 (4.59), 7.125 (7.41), 7.137 (6.31), 7.150 (2.40), 7.155 (9.82), 7.160 (2.34), 7.168 (2.24),
7.172 (9.21), 7.177 (9.32), 7.184 (12.93), 7.188 (16.00), 7.195 (8.77), 7.207 (3.41). Example 7
5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9-diazaspiro- [5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000165_0001
A mixture of (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (253 mg, 1 .08 mmol, CAS- RN: 20445-31 -2), HATU (442 mg, 1 .16 mmol) and N,N-diisopropylethylamine (230 mI_, 1 .3 mmol) in DMF (3.5 mL) was stirred for 5 min, then (rac) 5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one hydrochloride (250 mg, 831 mihoI, Intermediate 6) was added and the reaction mixture was stirred for 1 h at room temperature under an atmosphere of argon. The reaction mixture was filtered using a CHROMAFIL filter (PET-45/15 MS, Pore Size: 0,45 pm) and the final purification was conducted via preparative HPLC (method 8) to give the title compound 300 mg (95 % purity, 71 % yield).
LC-MS (method 2): Rt = 1 .20 min; MS (ESIpos): m/z = 481 [M+H]+.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.067 (0.35), -0.055 (0.44), -0.033 (0.67), -0.021 (0.67), 0.000 (0.47), 0.012 (0.38), 0.106 (0.32), 0.1 18 (0.47), 0.140 (0.67), 0.150 (0.67), 0.173
(0.44), 0.186 (0.38), 1 .039 (0.79), 1.073 (1 .46), 1 .103 (0.73), 1 .195 (0.38), 1 .207 (0.47), 1 .229
(0.76), 1.240 (0.76), 1 .262 (0.52), 1.274 (0.41 ), 1 .328 (0.67), 1 .350 (0.73), 1 .362 (0.82), 1 .385
(0.58), 1.396 (0.55), 1 .480 (0.29), 1.502 (0.58), 1 .532 (0.64), 1 .566 (0.50), 1 .626 (0.35), 1 .658
(0.20), 1.857 (1 .52), 1 .892 (1 .37), 1.962 (0.17), 2.096 (1.63), 2.339 (0.50), 2.421 (0.20), 2.539
(9.82), 2.544 (6.30), 2.863 (0.58), 2.889 (0.96), 2.896 (0.99), 2.928 (0.58), 2.938 (0.58), 2.950
(1 .25), 2.964 (1 .25), 2.982 (1 .37), 2.989 (1 .57), 3.015 (0.61 ), 3.035 (0.93), 3.049 (1.02), 3.060
(1 .02), 3.073 (1 .05), 3.103 (0.52), 3.137 (1 .19), 3.146 (0.73), 3.167 (1 .14), 3.176 (0.87), 3.182
(0.99), 3.191 (1 .54), 3.208 (1 .25), 3.222 (1 .98), 3.244 (1.08), 3.258 (0.73), 3.395 (1.43), 3.420
(0.67), 3.460 (0.61 ), 3.473 (0.82), 3.508 (3.41 ), 3.528 (2.07), 3.548 (1 .19), 3.577 (1.46), 3.613
(16.00), 3.645 (0.64), 3.674 (0.70), 3.709 (0.58), 4.194 (0.29), 4.227 (0.44), 4.345 (0.64), 4.384 (0.79), 4.429 (0.64), 7.01 1 (1 .40), 7.031 (3.03), 7.051 (2.21 ), 7.055 (2.19), 7.069 (2.01 ), 7.077
(2.62), 7.091 (2.27), 7.159 (0.52), 7.181 (1 .66), 7.186 (1.95), 7.198 (3.79), 7.206 (8.28), 7.216
(7.14), 7.220 (5.25), 7.228 (5.86), 7.237 (4.46), 7.250 (2.48), 7.265 (1 1 .28), 7.278 (6.18), 7.282
(3.26), 7.301 (2.42), 7.314 (1 .52), 7.335 (0.85), 7.376 (0.55), 7.394 (1 .43), 7.413 (1.17), 7.446 (1 .78), 7.460 (1 .95), 7.465 (1 .69), 7.482 (4.55), 7.486 (4.78), 7.496 (2.48), 7.501 (1.89), 7.510 (1 .22), 7.519 (1.28), 7.526 (0.90), 7.531 (0.73), 7.539 (0.47).
The title compound (220 mg) was separated into its stereoisomers by preparative chiral HPLC to give stereoisomer 1 (86 mg, see Example 8), stereoisomer 2 (87 mg, see Example 9).
Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000,
column : Chiralpak IA 5m 250x30mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%);
eluent B: ethanol; gradient: 20 - 50% B in 20 min; flow 40.0 mL/min; UV 254 nm.
Analytical chiral HPLC method:
Instrument: Agilent HPLC 1260; column : Chiralpak IA 3m 100x4, 6mm; eluent A: hexane + 0.1 vol-% diethylamine (99%); eluent B: ethanol; gradient: 20 - 50% B in 7 min; flow 1 .4 mL/min; temperature: 25 Ό; DAD 254 nm.
Example 8 and Example 9
(5R)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one
(5S)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one
Example 8
5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9-diazaspiro- [5.5]undecan-2-one (stereoisomer 1 )
Figure imgf000166_0001
For the preparation of the title compound as a mixture of stereoisomers and separation of the stereoisomers see Example 7.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.21 ), 0.012 (0.25), 0.033 (0.40), 0.045 (0.38), 0.067 (0.27), 0.078 (0.22), 0.882 (0.41 ), 0.932 (0.48), 0.962 (0.43), 1.022 (16.00), 1 .060 (0.25), 1 .089 (0.22), 1 .101 (0.29), 1 .124 (0.54), 1 .134 (0.46), 1.156 (0.38), 1 .168 (0.27), 1.373 (0.17), 1 .397 (0.30), 1 .426 (0.27), 1 .437 (0.24), 1 .465 (0.24), 1.517 (0.22), 1 .750 (0.48), 1.779 (0.43), 2.251 (0.27), 2.433 (3.48), 2.438 (2.35), 2.575 (0.29), 2.843 (0.32), 2.850 (0.35), 2.875 (0.59), 2.882 (0.57), 2.908 (0.32), 2.928 (0.41 ), 2.943 (0.57), 2.953 (0.57), 2.967 (0.56), 2.997 (0.30), 3.025 (0.49), 3.057 (0.32), 3.086 (0.43), 3.101 (0.68), 3.1 16 (0.67), 3.124 (0.44), 3.130 (0.37), 3.138 (0.30), 3.286 (0.73), 3.315 (0.33), 3.355 (0.21 ), 3.369 (0.19), 3.400 (1 .95), 3.441 (0.19), 3.507 (4.59), 3.567 (0.40), 3.603 (0.35), 4.089 (0.17), 4.105 (1.59), 4.122 (0.16), 4.239 (0.38), 4.271 (0.38), 6.949 (0.97), 6.963 (1.16), 6.971 (1 .53), 6.985 (1.32), 7.079 (0.48), 7.100 (2.1 1 ), 7.122 (2.94), 7.144 (1 .29), 7.159 (5.97), 7.172 (3.35), 7.194 (0.86), 7.208 (0.68), 7.216 (0.51 ), 7.230 (0.41 ), 7.288 (0.49), 7.307 (0.64), 7.334 (1 .00), 7.376 (1.87), 7.380 (1 .81 ), 7.390 (0.94), 7.395 (0.83), 7.398 (0.79), 7.403 (0.67), 7.406 (0.59), 7.412 (0.73), 7.420 (0.52), 7.424 (0.43), 7.433 (0.25).
Analytical Chiral HPLC (method see Example 7): Rt = 3.14 min, e.e. >99%.
Optical rotation (method OR1 ): 21.5°+/-0.33°(meth anol).
Example 9
5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one (stereoisomer 2)
Figure imgf000167_0001
For the preparation of the title compound as a mixture of stereoisomers and separation into its stereoisomers see Example 7.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.067 (0.23), -0.055 (0.30), -0.033 (0.45), -0.022 (0.45), 0.000 (0.30), 0.012 (0.25), 0.988 (0.39), 1 .072 (0.53), 1 .104 (0.53), 1 .128 (16.00), 1 .165 (0.26), 1.229 (0.20), 1 .255 (0.20), 1.280 (0.17), 1 .317 (0.33), 1 .327 (0.44), 1 .350 (0.48), 1 .360
(0.54), 1.384 (0.37), 1 .395 (0.36), 1.861 (0.51 ), 1 .890 (0.47), 2.357 (0.28), 2.538 (3.35), 2.543
(2.23), 2.698 (0.28), 2.861 (0.34), 2.889 (0.62), 2.894 (0.61 ), 2.921 (0.34), 2.948 (0.48), 2.963
(0.62), 2.975 (0.59), 2.990 (0.61 ), 3.137 (0.31 ), 3.145 (0.37), 3.151 (0.36), 3.160 (0.37), 3.166
(0.47), 3.175 (0.48), 3.182 (0.56), 3.189 (0.61 ), 3.224 (0.59), 3.242 (0.36), 3.250 (0.42), 3.257
(0.42), 3.396 (0.19), 3.477 (0.19), 3.527 (1 .25), 3.546 (0.56), 3.575 (0.93), 3.612 (5.57), 3.643
(0.37), 4.210 (1 .65), 4.395 (0.44), 4.428 (0.42), 7.01 1 (0.92), 7.030 (1 .98), 7.049 (1.25), 7.158 (0.34), 7.180 (1 .03), 7.196 (2.32), 7.205 (3.05), 7.215 (4.31 ), 7.219 (2.86), 7.236 (2.46), 7.260 (0.92), 7.263 (0.95), 7.282 (1 .37), 7.297 (0.65), 7.300 (0.78), 7.309 (0.45), 7.317 (0.36), 7.331 (0.28), 7.375 (0.33), 7.394 (0.44), 7.459 (1 .04), 7.463 (1.00), 7.476 (1 .45), 7.482 (1 .23).
Analytical Chiral HPLC (method see Example 7): Rt = 4.21 min, e.e. >98%.
Optical rotation (method OR1 ): 10.5°+/-0.25°(meth anol).
Example 10
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of diastereoisomers)
Figure imgf000168_0001
A mixture of (rac) 2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (168 mg, 624 mihoI, CAS-RN: 1785123-94-5), HATU (237 mg, 624 pmol) and N,N-diisopropylethylamine (250 mI_, 1 .4 mmol) in DMF (1 .5 ml_) was stirred for 5 min, then (rac) 5-(4-fluorophenyl)-1 -oxa- 3,9-diazaspiro[5.5]undecan-2-one hydrochloride (150 mg, 568 mihoI, Intermediate 6) was added and the reaction mixture was stirred for 1 h at room temperature under an atmosphere of argon. The reaction mixture was filtered using a CHROMAFIL filter (PET-45/15 MS, Pore Size: 0,45 pm) and the final purification was conducted via preparative HPLC (method 8) to give the title compound 150 mg (95 % purity, 49 % yield).
LC-MS (method 2): Rt = 1 .27 min; MS (ESIpos): m/z = 515 [M+H]+.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .032 (16.00), 1 .087 (0.19), 1 .121 (0.22), 1.772 (0.20), 1 .806 (0.18), 2.442 (1 .22), 2.447 (0.76), 2.920 (0.23), 2.953 (0.17), 3.082 (0.18), 3.116 (0.28),
3.130 (0.20), 3.144 (0.20), 3.377 (0.16), 3.421 (0.54), 3.442 (0.32), 3.481 (0.19), 3.527 (2.05),
4.1 13 (1 .44), 6.900 (0.20), 6.995 (0.27), 7.009 (0.30), 7.016 (0.40), 7.030 (0.36), 7.040 (0.18),
7.064 (0.22), 7.092 (0.51 ), 7.109 (0.73), 7.1 15 (1 .13), 7.130 (0.99), 7.156 (0.26), 7.176 (0.41 ),
7.196 (0.25), 7.204 (0.36), 7.218 (0.35), 7.226 (0.45), 7.239 (0.21 ), 7.258 (0.34), 7.310 (0.17),
7.328 (0.24), 7.333 (0.20), 7.351 (0.20), 7.364 (0.26), 7.369 (0.26), 7.405 (0.38), 7.443 (0.23),
7.462 (0.22), 7.482 (0.17), 7.518 (0.22), 7.521 (0.21 ), 7.538 (0.19), 7.541 (0.20). The title compound (150 mg) was separated into its diastereoisomers by preparative chiral FIPLC to give diastereoisomer 1 (27 mg, see Example 11 ), diastereoisomer 2 (30 mg, see Example 12), diastereoisomer 3 (26 mg, see Example 13) and diastereoisomer 4 (32 mg, see Example 14).
Preparative chiral FIPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000, column: Chiralpak IA 5m 250x30mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: 2-propanol; gradient: 20 - 40% B in 15 min; flow 40.0 mUmin; UV 220 nm
Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; column: Chiralpak IA 3m 100x4, 6mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: 2-propanol; gradient: 20 - 50% B in 7 min; flow 1 .4 mUmin; temperature: 25 Ό; DAD 220 nm
Example 11 , Example 12. Example 13 and Example 14
(5R)-9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one
(5R)-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one
(5S)-9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one
(5S)-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one
Example 11
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (singe stereoisomer 1 )
Figure imgf000169_0001
For the preparation of the diastereomeric title compound and separation into its diastereoisomers see Example 10. 1H-NMR (500 MHz, DMSO-d6, at 800) d [ppm]: 0.179 (0.38), 0.196 (0.59), 0.206 (0.59), 0.224 (0.42), 0.233 (0.35), 1.028 (0.21), 1.040 (0.21), 1.137 (0.21), 1.167 (1.04), 1.195 (1.29),
1.213 (0.52), 1.232 (0.56), 1.256 (0.28), 1.493 (0.42), 1.516 (0.56), 1.545 (0.56), 1.666 (0.31),
1.692 (0.24), 1.855 (0.70), 1.878 (0.66), 2.357 (1.53), 2.361 (2.12), 2.365 (1.60), 2.518 (16.00), 2.522 (12.90), 2.631 (1.63), 2.635 (2.16), 2.638 (1.70), 2.924 (0.35), 2.969 (0.49), 2.995 (0.87), 3.017 (0.49), 3.032 (0.66), 3.045 (0.83), 3.052 (0.83), 3.063 (0.80), 3.135 (0.45), 3.159 (0.80),
3.192 (1.32), 3.205 (1.01), 3.404 (0.80), 3.427 (0.90), 3.449 (0.83), 3.497 (2.92), 3.603 (6.40),
3.637 (0.66), 3.666 (0.56), 4.178 (0.28), 4.204 (0.28), 4.315 (0.59), 4.341 (0.59), 7.075 (1.22),
7.085 (1.60), 7.092 (2.05), 7.103 (1.81), 7.119 (0.94), 7.135 (1.04), 7.172 (2.33), 7.189 (4.10),
7.207 (1.98), 7.236 (1.11), 7.252 (1.98), 7.267 (0.97), 7.282 (1.29), 7.294 (1.39), 7.311 (0.73),
7.333 (1.67), 7.426 (1.08), 7.439 (1.46), 7.478 (0.87), 7.503 (0.52), 7.519 (1.11), 7.535 (0.73),
7.559 (0.73), 7.577 (0.38), 7.595 (1.22), 7.598 (1.15), 7.612 (1.04).
Analytical Chiral HPLC (method see Example 10): Rt = 2.49 min
Optical rotation (method OR1): 22.1°+/-0.50°(meth anol).
Example 12
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1-oxa-3,9-diaza- spiro[5.5]undecan-2-one (single stereoisomer 2)
Figure imgf000170_0001
For the preparation of the diastereomeric title compound and separation into its diastereoisomers see Example 10.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.011 (0.26), 0.000 (0.26), 0.021 (0.52), 0.033 (0.52), 0.055 (0.39), 0.066 (0.26), 0.779 (0.26), 0.800 (0.26), 0.954 (0.13), 0.975 (0.79), 0.990 (0.79),
1.032 (0.13), 1.085 (0.26), 1.163 (0.66), 1.181 (0.92), 1.193 (0.79), 1.225 (0.39), 1.236 (0.39),
1.258 (0.52), 1.269 (0.66), 1.292 (0.52), 1.303 (0.52), 1.351 (0.13), 1.467 (0.26), 1.489 (0.13),
1.794 (0.66), 1.825 (0.52), 1.869 (0.13), 1.907 (0.13), 2.022 (1.18), 2.275 (1.70), 2.280 (1.18),
2.285 (0.52), 2.467 (16.00), 2.471 (12.20), 2.617 (1.70), 2.622 (1.18), 2.627 (0.52), 2.826 (0.39), 2.852 (0.66), 2.857 (0.66), 2.885 (0.39), 2.915 (0.52), 2.930 (0.79), 2.942 (0.79), 2.956 (0.79), 3.091 (0.39), 3.101 (0.39), 3.114 (0.39), 3.121 (0.52), 3.130 (0.52), 3.144 (0.39), 3.167 (0.66), 3.204 (0.66), 3.397 (0.39), 3.432 (0.26), 3.445 (0.26), 3.466 (1.70), 3.505 (1.18), 3.551 (6.16), 4.167 (0.13), 4.301 (0.52), 4.311 (0.52), 4.338 (0.52), 6.905 (0.52), 6.925 (1.31), 6.945 (0.92), 7.006 (0.92), 7.025 (0.66), 7.089 (0.52), 7.111 (1.31), 7.132 (3.54), 7.139 (3.15), 7.153 (5.64), 7.211 (0.39), 7.227 (0.92), 7.249 (1.84), 7.332 (1.05), 7.334 (1.18), 7.337 (1.05), 7.339 (0.92), 7.351 (1.57), 7.354 (1.44), 7.356 (1.31), 7.429 (1.57), 7.444 (0.79), 7.464 (0.52), 7.481 (0.39), 7.484 (0.52), 7.489 (0.39), 7.506 (0.26).
Analytical Chiral HPLC (method see Example 10): Rt = 2.85 min
Optical rotation (method OR1): 14.1°+/-0.44°(DMSO ).
Example 13
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 3)
Figure imgf000171_0001
For the preparation of the diastereomeric title compound and separation into its diastereoisomers see Example 10.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.64), 0.012 (0.80), 0.033 (1.29), 0.045 (1.29), 0.067 (0.84), 0.078 (0.68), 0.735 (0.24), 0.754 (0.56), 0.773 (0.36), 0.796 (0.44), 0.811 (0.60),
0.821 (0.44), 0.965 (0.48), 0.987 (4.22), 0.994 (0.68), 1.002 (4.38), 1.044 (0.84), 1.066 (0.20),
1.097 (1.17), 1.176 (1.77), 1.193 (2.25), 1.205 (1.97), 1.219 (1.85), 1.236 (0.92), 1.247 (1.01),
1.271 (1.49), 1.281 (1.57), 1.308 (1.25), 1.315 (1.41), 1.344 (0.52), 1.371 (0.52), 1.400 (0.32),
1.447 (0.40), 1.469 (0.52), 1.477 (0.52), 1.500 (0.40), 1.806 (1.53), 1.837 (1.37), 1.860 (0.52),
1.880 (0.48), 1.919 (0.52), 2.075 (0.48), 2.282 (1.73), 2.286 (2.33), 2.291 (1.69), 2.370 (0.28),
2.396 (0.60), 2.482 (6.63), 2.624 (1.73), 2.629 (2.33), 2.633 (1.65), 2.837 (0.96), 2.864 (1.73),
2.870 (1.73), 2.897 (0.96), 2.927 (1.41), 2.941 (2.01), 2.954 (1.85), 2.968 (2.13), 3.001 (0.32),
3.103 (0.88), 3.111 (1.09), 3.116 (1.05), 3.125 (1.09), 3.132 (1.33), 3.141 (1.29), 3.156 (1.01),
3.179 (1.73), 3.194 (0.80), 3.216 (1.65), 3.246 (1.09), 3.333 (0.56), 3.351 (0.44), 3.397 (0.72), 3.408 (0.92), 3.442 (0.68), 3.477 (4.50), 3.516 (3.10), 3.545 (1.85), 3.564 (16.00), 3.719 (0.16), 3.724 (0.20), 3.734 (0.24), 3.739 (0.20), 3.749 (0.16), 4.179 (0.44), 4.213 (0.40), 4.304 (1.17),
4.314 (1.81), 4.349 (1.25), 4.518 (0.20), 6.915 (1.45), 6.935 (3.42), 6.955 (2.29), 7.016 (2.57),
7.036 (1.73), 7.101 (1.13), 7.123 (3.18), 7.144 (9.01), 7.151 (7.56), 7.165 (14.71), 7.189 (0.52), 7.223 (0.88), 7.239 (2.09), 7.252 (2.05), 7.264 (4.38), 7.344 (2.65), 7.346 (2.81), 7.349 (2.69),
7.363 (3.98), 7.436 (3.90), 7.440 (4.14), 7.456 (2.05), 7.475 (1.29), 7.493 (1.05), 7.496 (1.33),
7.517 (0.60), 10.473 (0.16), 10.809 (0.32).
Analytical Chiral HPLC (method see Example 10): Rt = 3.14 min
Optical rotation (method OR1): -8.9°+/-0.35°(DMSO ). Example 14
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 4)
Figure imgf000172_0001
For the preparation of the diastereomeric title compound and separation into its diastereoisomers see Example 10.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.162 (0.62), 0.173 (0.74), 0.195 (1.18), 0.206 (1.18), 0.229 (0.81), 0.240 (0.62), 0.776 (0.25), 0.795 (0.62), 0.813 (0.43), 0.836 (0.56), 0.852 (0.68),
1.005 (0.56), 1.026 (5.15), 1.041 (5.09), 1.069 (0.56), 1.084 (1.30), 1.105 (0.62), 1.137 (0.81),
1.163 (2.23), 1.185 (1.92), 1.195 (2.67), 1.232 (2.67), 1.259 (1.55), 1.289 (1.18), 1.296 (0.93), 1.304 (1.12), 1.348 (0.74), 1.520 (1.18), 1.549 (1.24), 1.664 (0.93), 1.702 (0.62), 1.851 (1.49),
1.881 (1.36), 1.904 (0.50), 1.959 (0.25), 1.975 (3.60), 2.115 (0.31), 2.517 (16.00), 2.522
(10.98), 2.570 (0.43), 2.900 (0.43), 2.926 (0.56), 2.963 (1.18), 2.990 (1.74), 2.996 (1.80), 3.029
(1.92), 3.043 (1.67), 3.052 (1.61), 3.067 (1.55), 3.129 (0.87), 3.159 (1.61), 3.192 (2.85), 3.205
(1.98), 3.357 (1.05), 3.370 (0.74), 3.399 (1.43), 3.426 (1.80), 3.452 (1.43), 3.496 (6.26), 3.580 (1.36), 3.603 (14.51), 3.634 (1.30), 3.668 (1.05), 3.749 (0.19), 3.764 (0.25), 3.774 (0.25), 4.174
(0.56), 4.209 (0.56), 4.312 (1.24), 4.343 (1.92), 4.354 (1.55), 6.492 (0.37), 6.735 (0.43), 6.884
(0.25), 6.976 (0.19), 7.070 (2.48), 7.084 (3.16), 7.092 (4.59), 7.106 (4.16), 7.115 (2.11), 7.136
(2.42), 7.168 (5.09), 7.190 (8.99), 7.211 (4.22), 7.231 (2.73), 7.252 (4.65), 7.272 (2.60), 7.280 (3.04), 7.294 (2.91 ), 7.316 (1 .49), 7.333 (3.91 ), 7.389 (0.43), 7.426 (2.36), 7.439 (3.10), 7.479
(2.05), 7.499 (1 .05), 7.518 (2.42), 7.538 (1 .80), 7.558 (1.74), 7.563 (1 .43), 7.580 (0.81 ), 7.593
(2.67), 7.596 (2.54), 7.613 (2.29), 7.617 (2.29), 8.012 (0.37), 8.636 (0.62), 8.641 (0.56), 9.717
(0.56), 10.513 (0.25), 10.634 (0.19), 10.849 (0.43). Analytical Chiral HPLC (method see Example 10): Rt = 4.35 min
Optical rotation (method OR1 ): -16.8°+/-0.42°(met hanol).
Example 15
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of diastereoisomers)
Figure imgf000173_0001
A mixture of (rac) 2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (189 mg, 624 pmol), HATU (237 mg, 624 pmol) and N,N-diisopropylethylamine (250 mI_, 1 .4 mmol) in DMF (1 .5 ml_) was stirred for 5 min, then (rac) 5-(4-fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-
2-one hydrochloride (150 mg, 568 mihoI, Intermediate 6) was added and the reaction mixture was stirred for 1 h at room temperature under an atmosphere of argon. The reaction mixture was filtered using a CHROMAFIL filter (PET-45/15 MS, Pore Size: 0,45 pm) and the final purification was conducted via preparative HPLC (method 8) to give the title compound 150 mg (95 % purity, 46 % yield).
LC-MS (method 2): Rt = 1 .38 min; MS (ESIpos): m/z = 549 [M+H]+.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.200 (0.18), 0.21 1 (0.18), 0.238 (0.24), 0.261 (0.30), 0.271 (0.28), 0.294 (0.20), 0.967 (0.22), 1.107 (16.00), 1.121 (0.18), 1 .133 (0.20), 1 .144 (0.18), 1 .155 (0.32), 1 .166 (0.32), 1 .188 (0.20), 1 .200 (0.18), 1.209 (0.22), 1 .277 (0.18), 1.290 (0.18), 1 .323 (0.41 ), 1 .363 (0.40), 1 .404 (0.28), 1 .512 (0.22), 1.529 (0.32), 1 .542 (0.34), 1.720 (0.18),
1 .875 (0.36), 1 .903 (0.36), 2.074 (0.18), 2.336 (0.32), 2.518 (3.87), 2.523 (2.86), 2.678 (0.32),
2.922 (0.20), 2.954 (0.28), 3.002 (0.26), 3.027 (0.49), 3.034 (0.61 ), 3.050 (0.55), 3.064 (0.77), 3.075 (0.43), 3.089 (0.41 ), 3.180 (0.51 ), 3.202 (0.83), 3.209 (0.91 ), 3.232 (0.40), 3.285 (0.18),
3.374 (0.34), 3.389 (0.22), 3.454 (0.55), 3.494 (1 .80), 3.520 (0.85), 3.551 (0.38), 3.580 (0.41 ),
3.613 (5.12), 3.643 (0.32), 3.679 (0.26), 4.190 (1 .56), 4.223 (0.18), 4.303 (0.28), 4.340 (0.32),
4.383 (0.16), 7.1 19 (0.55), 7.136 (3.20), 7.142 (1 .68), 7.149 (1.92), 7.157 (2.03), 7.164 (1 .13),
7.167 (1 .13), 7.190 (2.17), 7.21 1 (0.99), 7.226 (2.1 1 ), 7.245 (0.43), 7.284 (0.69), 7.297 (0.77),
7.306 (0.65), 7.314 (0.75), 7.319 (0.93), 7.334 (1 .19), 7.338 (1.13), 7.464 (0.71 ), 7.469 (0.73),
7.495 (1 .03), 7.639 (0.73), 7.644 (1.24), 7.649 (0.69), 7.784 (0.26), 7.789 (0.53), 7.793 (0.26),
7.807 (0.57), 7.812 (1.17), 7.816 (0.63), 7.823 (1 .24), 7.828 (2.05), 7.832 (1 .17).
The title compound (150 mg) was separated into its diastereoisomers by preparative chiral HPLC to give diastereoisomer 1 (22 mg, see Example 16), diastereoisomer 2 (19 mg, see Example 17), diastereoisomer 3 (20 mg, see Example 18) and diastereoisomer 4 (22 mg, see Example 19).
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; column: Reprosil Chiral NR 8pm 250x30mm; eluent A: C02, eluent B: ethanol; isocratic: 21 %B; flow 100.0 mL/min, temperature: 40Ό; BPR: 150bar; MWD @ 220nm
Analytical chiral HPLC method: Instrument: Agilent: 1260, Aurora SFC-Modul; column: Reprosil Chiral NR 5pm 100x4.6mm; eluent A: C02, Eluent B: ethanol; isocratic: 21 %B; flow 4.0 mL/min; temperature: 37.5Ό; BPR: 100bar; MWD @ 220nm
Example 16, Example 17, Example 18 and Example 19
(5R)-9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one
(5R)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one
(5S)-9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one
(5S)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one Example 16
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 1 )
Figure imgf000175_0001
For the preparation of the diastereomeric title compound and separation into its diastereoisomers see Example 15.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.179 (0.42), 0.200 (0.65), 0.212 (0.65), 0.233 (0.42), 0.798 (0.73), 0.815 (0.79), 0.822 (0.84), 0.840 (0.45), 0.886 (0.39), 0.905 (0.87), 0.923 (0.42),
1 .205 (0.73), 1 .256 (0.53), 1 .278 (0.67), 1 .289 (0.70), 1.31 1 (0.51 ), 1 .323 (0.39), 1.375 (0.84), 1 .404 (1 .12), 1 .891 (0.73), 1 .928 (0.76), 2.518 (16.00), 2.523 (11 .44), 2.539 (4.36), 2.660
(0.53), 2.922 (0.48), 2.948 (0.84), 2.954 (0.87), 2.981 (0.62), 3.021 (0.93), 3.036 (0.93), 3.048
(0.98), 3.062 (0.93), 3.159 (0.45), 3.168 (0.53), 3.181 (0.56), 3.189 (0.70), 3.198 (0.87), 3.214
(0.90), 3.283 (0.48), 3.373 (0.56), 3.450 (0.51 ), 3.485 (0.45), 3.521 (2.53), 3.551 (1.35), 3.579
(1 .55), 3.614 (7.54), 4.349 (0.65), 4.387 (0.65), 7.120 (1.49), 7.142 (3.96), 7.164 (3.04), 7.190 (4.61 ), 7.209 (2.39), 7.223 (2.59), 7.231 (1 .94), 7.245 (1.43), 7.283 (0.82), 7.297 (0.96), 7.306
(0.90), 7.314 (2.22), 7.318 (2.39), 7.502 (2.22), 7.640 (2.39), 7.644 (4.33), 7.649 (2.28), 7.784
(0.87), 7.789 (1.63), 7.794 (0.87).
Analytical Chiral HPLC (method see Example 15): Rt = 2.08 min
Optical rotation (method OR1 ): -13.6°+/-0.49°(met hanol).
Example 17
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 2)
Figure imgf000176_0001
For the preparation of the diastereomeric title compound and separation into its diastereoisomers see Example 15.
1 H-NMR (400 MHz, DMSO-d6) d [ppm] 0.227 (0.20), 0.239 (0.27), 0.261 (0.42), 0.271 (0.42), 0.294 (0.30), 0.305 (0.25), 0.798 (1.74) 0.804 (0.82), 0.815 (1.94), 0.822 (2.02), 0.840 (1 .02), 0.859 (0.17), 0.878 (0.17), 0.887 (0.95) 0.904 (2.07), 0.923 (1.07), 1 .068 (0.25), 1.109 (0.17), 1 .124 (0.32), 1 .132 (0.32), 1 .142 (0.32) 1 .155 (0.50), 1.166 (0.52), 1 .189 (0.35), 1.205 (1 .12), 1 .222 (0.20), 1 .237 (0.25), 1 .256 (0.25) 1 .327 (0.50), 1.357 (0.47), 1 .503 (0.30), 1.541 (0.50), 1 .716 (0.27), 1 .750 (0.20), 1 .874 (0.50) 1 .904 (0.47), 2.171 (0.20), 2.190 (0.17), 2.202 (0.50), 2.21 1 (0.32), 2.231 (0.27), 2.359 (0.30) 2.375 (0.35), 2.389 (0.37), 2.394 (0.40), 2.407 (0.42),
2.413 (0.55), 2.431 (0.17), 2.518 (16.00), 2.523 (12.54), 2.539 (5.50), 2.635 (0.35), 2.905 (0.17), 2.929 (0.22), 3.001 (0.35), 3.027 (0.60), 3.034 (0.62), 3.051 (0.52), 3.065 (0.92), 3.076
(0.67), 3.089 (0.67), 3.179 (0.62), 3.195 (0.97), 3.202 (1.00), 3.209 (1 .22), 3.234 (0.57), 3.371
(0.65), 3.457 (0.67), 3.494 (2.64), 3.512 (0.70), 3.613 (4.78), 3.643 (0.57), 3.678 (0.45), 4.191
(0.22), 4.224 (0.22), 4.303 (0.42), 4.336 (0.42), 7.136 (4.26), 7.150 (2.49), 7.158 (2.74), 7.168
(0.90), 7.181 (0.60), 7.190 (1 .42), 7.212 (1 .00), 7.228 (2.66), 7.284 (0.72), 7.298 (0.82), 7.306
(0.67), 7.320 (0.57), 7.334 (1 .69), 7.338 (1 .72), 7.465 (1.07), 7.471 (1 .09), 7.496 (0.75), 7.809
(0.72), 7.813 (1.44), 7.818 (0.77), 7.824 (1 .47), 7.829 (2.79), 7.833 (1 .52).
Analytical Chiral HPLC (method see Example 15): Rt = 2.70 min
Optical rotation (method OR1 ): 8.9°+/-0.90°(metha nol). Example 18
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 3)
Figure imgf000177_0001
For the preparation of the diastereomeric title compound and separation into its diastereoisomers see Example 15.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.227 (0.24), 0.239 (0.33), 0.261 (0.49), 0.272 (0.49), 0.294 (0.35), 0.306 (0.28), 0.798 (2.68), 0.803 (1.29), 0.815 (2.85), 0.822 (2.99), 0.840 (1.58), 0.859 (0.24), 0.878 (0.24), 0.886 (1.46), 0.904 (3.13), 0.923 (1.58), 1.068 (0.28), 1.091 (0.16), 1.109 (0.26), 1.124 (0.45), 1.142 (0.47), 1.154 (0.59), 1.166 (0.61), 1.188 (0.40), 1.205 (1.46), 1.222 (0.28), 1.237 (0.38), 1.241 (0.31), 1.256 (0.35), 1.275 (0.24), 1.289 (0.16), 1.327 (0.59), 1.357 (0.56), 1.504 (0.35), 1.541 (0.59), 1.720 (0.31), 1.750 (0.24), 1.800 (0.21), 1.816 (0.21), 1.874 (0.61), 1.904 (0.54), 2.171 (0.31), 2.190 (0.26), 2.202 (0.68), 2.211 (0.52), 2.231 (0.42), 2.359 (0.45), 2.374 (0.56), 2.389 (0.59), 2.394 (0.64), 2.399 (0.38), 2.407 (0.64), 2.413 (0.82), 2.425 (0.24), 2.431 (0.26), 2.518 (16.00), 2.523 (12.12), 2.603 (0.68), 2.636 (0.31), 2.905 (0.19), 2.933 (0.28), 2.959 (0.16), 3.001 (0.42), 3.027 (0.68), 3.034 (0.73), 3.051 (0.61), 3.065 (1.06), 3.076 (0.78), 3.089 (0.75), 3.179 (0.73), 3.195 (1.11), 3.202 (1.18), 3.209 (1.44), 3.234 (0.66), 3.371 (0.68), 3.457 (0.80), 3.494 (3.08), 3.511 (0.82), 3.613 (5.60), 3.643 (0.66), 3.679 (0.49), 4.190 (0.26), 4.224 (0.26), 4.303 (0.49), 4.336 (0.47), 7.136 (4.99), 7.150 (2.87), 7.158 (3.13), 7.168 (1.06), 7.181 (0.68), 7.190 (1.62), 7.212 (1.15), 7.228 (3.11), 7.284 (0.85), 7.298 (0.96), 7.306 (0.80), 7.320 (0.66), 7.334 (1.98), 7.338 (2.00), 7.465 (1.22), 7.471 (1.29), 7.497 (0.87), 7.808 (0.80), 7.813 (1.60), 7.818 (0.92), 7.824 (1.74), 7.829 (3.01), 7.833 (1.74).
Analytical Chiral HPLC (method see Example 15): Rt = 3.06 min
Optical rotation (method OR1): -8.4°+/-0.45°(meth anol). Example 19
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (singe stereoisomer 4)
Figure imgf000178_0001
For the preparation of the diastereomeric title compound and separation into its diastereoisomers see Example 15.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.166 (0.71), 0.178 (0.86), 0.200 (1.36), 0.212 (1.29), 0.233 (0.86), 0.244 (0.71), 0.798 (0.93), 0.806 (0.64), 0.814 (1.07), 0.822 (1.14), 0.840 (0.79), 0.859 (0.36), 0.877 (0.50), 0.886 (0.50), 0.896 (0.29), 0.904 (1.00), 0.923 (0.50), 0.949 (0.29), 0.982 (0.36), 1.018 (0.29), 1.068 (0.79), 1.143 (0.21), 1.168 (0.21), 1.205 (2.50), 1.244 (0.86), 1.256 (1.07), 1.279 (1.43), 1.289 (1.36), 1.312 (1.00), 1.323 (0.79), 1.375 (1.79), 1.404 (2.43), 1.443 (0.57), 1.479 (0.43), 1.515 (0.50), 1.545 (0.43), 1.889 (1.71), 1.928 (1.57), 1.975 (0.50), 2.085 (0.14), 2.130 (0.21), 2.141 (0.21), 2.202 (1.29), 2.327 (4.07), 2.331 (2.93), 2.373 (0.21), 2.413 (0.36), 2.518 (16.00), 2.523 (10.50), 2.539 (1.14), 2.669 (4.14), 2.673 (3.00), 2.921 (1.00), 2.948 (1.79), 2.953 (1.79), 2.981 (1.29), 3.021 (1.86), 3.036 (1.86), 3.048 (1.93), 3.062
(1.79), 3.159 (0.93), 3.167 (1.14), 3.181 (1.07), 3.188 (1.43), 3.198 (1.79), 3.214 (1.71), 3.230 (0.79), 3.283 (1.07), 3.372 (0.71), 3.391 (0.57), 3.452 (1.00), 3.481 (0.86), 3.520 (5.29), 3.551
(2.79), 3.580 (3.29), 3.614 (15.50), 3.842 (0.29), 4.232 (0.50), 4.267 (0.50), 4.349 (1.36), 4.388 (1.36), 7.120 (3.07), 7.142 (8.07), 7.164 (6.14), 7.190 (9.57), 7.209 (4.64), 7.223 (4.93), 7.231
(3.57), 7.245 (2.64), 7.283 (1.64), 7.297 (1.93), 7.306 (1.86), 7.313 (4.64), 7.318 (4.79), 7.503
(4.57), 7.640 (4.64), 7.645 (8.00), 7.650 (4.36), 7.785 (1.71), 7.790 (3.21), 7.794 (1.57), 11.739 (0.43).
Analytical Chiral HPLC (method see Example 15): Rt = 4.20 min
Optical rotation (method OR1): 15.9°+/-0.30°(meth anol). Example 20
9-[2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of diastereoisomers)
Figure imgf000179_0001
A mixture of (rac) 2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (164 mg, 624 pmol), HATU (237 mg, 624 pmol) and N,N-diisopropylethylamine (250 mI_, 1 .4 mmol) in DMF (1 .5 ml_) was stirred for 5 min, then (rac) 5-(4-fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan- 2-one hydrochloride (150 mg, 568 mihoI, Intermediate 6) was added and the reaction mixture was stirred for 1 h at room temperature under an atmosphere of argon. The reaction mixture was filtered using a CHROMAFIL filter (PET-45/15 MS, Pore Size: 0,45 pm) and the final purification was conducted via preparative FIPLC (method 8) to give the title compound 150 mg (95 % purity, 49 % yield).
LC-MS (method 2): Rt = 1 .29 min; MS (ESIpos): m/z = 509 [M+H]+.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.021 (0.19), 0.032 (0.19), 0.1 14 (0.19), 0.125 (0.18), 0.960 (0.22), 0.995 (0.22), 1 .017 (16.00), 1.055 (0.25), 1.164 (0.22), 1 .176 (0.22), 1 .274 (0.28), 1 .285 (0.25), 1 .390 (0.18), 1 .782 (0.23), 1 .815 (0.44), 1.850 (0.23), 1 .917 (2.74), 1.985 (0.20),
2.019 (3.13), 2.055 (3.29), 2.1 19 (0.88), 2.129 (0.98), 2.137 (1.77), 2.148 (1 .68), 2.181 (3.39),
2.428 (2.56), 2.433 (1 .66), 2.763 (0.18), 2.789 (0.34), 2.822 (0.17), 2.851 (0.20), 2.885 (0.46),
2.901 (0.31 ), 2.915 (0.58), 2.930 (0.54), 2.939 (0.32), 2.953 (0.27), 3.021 (0.28), 3.032 (0.19),
3.046 (0.31 ), 3.052 (0.32), 3.068 (0.23), 3.086 (0.37), 3.101 (0.27), 3.1 16 (0.40), 3.124 (0.45),
3.132 (0.28), 3.141 (0.29), 3.148 (0.31 ), 3.312 (0.31 ), 3.336 (0.32), 3.370 (1 .17), 3.382 (0.67),
3.442 (0.18), 3.475 (4.41 ), 3.493 (0.54), 3.522 (0.37), 3.560 (0.18), 3.585 (0.19), 3.619 (0.17),
4.101 (1 .55), 4.252 (0.19), 4.285 (0.19), 4.318 (0.19), 4.349 (0.18), 6.558 (0.32), 6.578 (0.43),
6.686 (0.32), 6.707 (0.24), 6.804 (0.24), 6.823 (0.39), 6.873 (0.69), 6.893 (0.41 ), 6.928 (0.66),
6.949 (0.32), 6.962 (0.76), 6.983 (0.40), 6.998 (0.49), 7.006 (0.80), 7.019 (0.70), 7.049 (0.35),
7.058 (1 .03), 7.080 (1 .41 ), 7.097 (1.59), 7.120 (1 .80), 7.134 (1.15), 7.142 (0.43), 7.157 (0.23),
7.187 (0.36), 7.201 (0.42), 7.209 (0.38), 7.223 (0.28), 7.344 (0.49), 7.380 (0.67), 7.387 (0.85).
The title compound (150 mg) was separated into its diastereoisomers by preparative chiral HPLC to give diastereoisomer 1 (20 mg, see Example 21 ), diastereoisomer 2 (27 mg, see Example 22), diastereoisomer 3 (22 mg, see Example 23) and diastereoisomer 4 (30 mg, see Example 24).
For the isolation of diastereoisomer 1 , diastereoisomer 2 and a mixture of diastereoisomer 3 and diastereoisomer 4 the following method was used.
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; column: Reprosil Chiral NR 8pm 250x30mm; eluent A: C02, eluent B: ethanol; isocratic: 21 %B; flow 100.0 mL/min, temperature: 40Ό; BPR: 150bar; MWD @ 220nm
The mixture of diastereoisomer 3 and diastereoisomer 4 was separated with the following method.
Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000, column Chiralpak IE 5m 250x30mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: ethanol; gradient: 20 - 50% B in 20 min; flow 40.0 mL/min; UV 220 nm
Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; column: Chiralpak IG 3m 100x4, 6mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: ethanol; isocratic 70% A + 30% B; flow 1 .4 mUmin; temperature: 25 Ό; DAD 220 nm
Example 21. Example 22. Example 23 and Example 24
(5R)-9-[(2S)-2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one
(5R)-9-[(2R)-2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one
(5S)-9-[(2S)-2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one
(5S)-9-[(2R)-2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one Example 21
9-[2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 1)
Figure imgf000181_0001
For the preparation of the diastereomeric title compound and separation into its diastereoisomers see Example 20.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.45), 0.011 (0.59), 0.033 (0.95), 0.044 (0.95), 0.066 (0.61), 0.078 (0.49), 0.698 (0.16), 0.717 (0.38), 0.736 (0.36), 0.744 (0.28), 0.759 (0.26),
0.766 (0.24), 0.774 (0.28), 0.784 (0.26), 0.827 (0.20), 0.928 (0.32), 0.957 (0.22), 1.007 (0.63),
1.030 (1.19), 1.064 (1.09), 1.128 (0.26), 1.157 (0.69), 1.182 (0.87), 1.253 (0.57), 1.265 (0.81),
1.286 (1.46), 1.298 (1.31), 1.320 (0.75), 1.331 (0.63), 1.344 (0.24), 1.366 (0.26), 1.389 (0.26),
1.420 (0.22), 1.431 (0.20), 1.824 (1.34), 1.862 (1.17), 1.928 (13.45), 2.067 (16.00), 2.131 (4.15), 2.141 (4.11), 2.278 (0.18), 2.301 (0.30), 2.311 (0.22), 2.324 (0.22), 2.336 (0.20), 2.440
(5.26), 2.445 (3.38), 2.774 (0.73), 2.801 (1.31), 2.806 (1.29), 2.834 (0.73), 2.865 (0.20), 2.898
(1.17), 2.913 (1.31), 2.927 (1.33), 2.941 (1.29), 3.034 (0.65), 3.044 (0.81), 3.058 (0.79), 3.064
(0.99), 3.073 (0.99), 3.081 (2.91), 3.087 (0.85), 3.094 (3.16), 3.135 (1.52), 3.161 (0.81), 3.313
(0.44), 3.330 (0.65), 3.394 (2.47), 3.419 (0.32), 3.454 (0.34), 3.486 (11.02), 3.505 (2.29), 3.535 (1.78), 3.572 (0.81), 4.007 (0.22), 4.021 (0.65), 4.034 (0.65), 4.047 (0.20), 4.138 (0.24), 4.170
(0.24), 4.329 (0.95), 4.362 (0.91), 6.569 (1.58), 6.590 (2.12), 6.698 (1.58), 6.717 (1.21), 6.940
(3.22), 6.958 (0.59), 7.061 (1.21), 7.083 (1.68), 7.087 (1.78), 7.109 (5.30), 7.132 (7.67), 7.146
(4.27), 7.154 (2.00), 7.162 (0.69), 7.169 (1.05), 7.203 (0.73), 7.217 (0.83), 7.225 (0.69), 7.239
(0.55), 7.391 (2.47), 7.399 (2.97), 10.775 (0.32).
Analytical Chiral HPLC (method see Example 20): Rt = 2.90 min
Optical rotation (method OR1): 12.2°+/-0.24°(meth anol). Example 22
9-[2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 2)
Figure imgf000182_0001
For the preparation of the diastereomeric title compound and separation into its diastereoisomers see Example 20.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.169 (0.43), 0.182 (0.60), 0.203 (0.90), 0.214 (0.90), 0.236 (0.60), 0.248 (0.47), 0.776 (0.38), 0.795 (0.85), 0.814 (0.73), 0.822 (0.55), 0.837 (0.43),
0.844 (0.38), 0.852 (0.34), 0.862 (0.51), 0.880 (0.26), 0.887 (0.26), 0.904 (0.38), 0.923 (0.21),
1.006 (0.77), 1.035 (0.73), 1.049 (1.49), 1.084 (2.30), 1.100 (0.38), 1.108 (0.43), 1.142 (0.30),
1.205 (0.90), 1.222 (0.64), 1.233 (1.32), 1.259 (2.90), 1.288 (0.81), 1.300 (0.60), 1.374 (0.30),
1.391 (0.30), 1.422 (0.30), 1.441 (0.43), 1.459 (0.43), 1.488 (0.85), 1.506 (0.68), 1.515 (0.77),
1.539 (0.81), 1.574 (0.34), 1.643 (0.60), 1.678 (0.38), 1.788 (0.17), 1.871 (1.11), 1.902 (1.66),
1.947 (0.17), 2.006 (1.37), 2.109 (14.85), 2.145 (1.66), 2.202 (0.47), 2.210 (0.60), 2.227 (7.94),
2.237 (7.89), 2.270 (16.00), 2.451 (0.47), 2.518 (15.23), 2.523 (9.90), 2.844 (0.38), 2.870 (0.55), 2.897 (0.34), 2.940 (0.77), 2.967 (1.32), 2.973 (1.41), 3.005 (1.66), 3.018 (1.45), 3.028
(1.41), 3.042 (1.28), 3.074 (0.68), 3.106 (1.19), 3.134 (0.81), 3.160 (0.60), 3.174 (1.28), 3.190
(1.15), 3.199 (0.85), 3.205 (0.85), 3.212 (0.85), 3.221 (1.02), 3.230 (0.98), 3.236 (0.90), 3.401
(1.15), 3.426 (1.32), 3.460 (5.46), 3.530 (0.60), 3.564 (11.90), 3.611 (0.26), 3.674 (0.90), 3.709 (0.81), 4.187 (0.47), 4.221 (0.47), 4.341 (0.90), 4.374 (0.90), 6.647 (0.17), 6.667 (0.21), 6.776
(0.17), 6.891 (1.11), 6.912 (1.88), 6.963 (3.24), 6.982 (1.92), 7.019 (0.38), 7.051 (3.58), 7.073
(1.79), 7.087 (2.35), 7.095 (3.71), 7.109 (3.24), 7.147 (4.74), 7.163 (2.60), 7.169 (5.80), 7.185
(3.84), 7.191 (2.86), 7.207 (2.73), 7.224 (1.75), 7.277 (1.49), 7.290 (1.71), 7.298 (1.41), 7.312
(1.11), 7.437 (2.35), 7.474 (1.75), 10.515 (0.34), 10.635 (0.26), 10.851 (0.90).
Analytical Chiral HPLC (method see Example 20): Rt = 3.14 min
Optical rotation (method OR1): 130.4°+/-0.15°(met hanol). Example 23
9-[2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 3)
Figure imgf000183_0001
For the preparation of the diastereomeric title compound and separation into its diastereoisomers see Example 20.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.169 (0.44), 0.182 (0.52), 0.204 (0.83), 0.214 (0.79), 0.236 (0.57), 0.248 (0.44), 0.798 (0.48), 0.814 (0.52), 0.822 (0.52), 0.840 (0.35), 0.852 (0.26),
0.886 (0.22), 0.904 (0.44), 0.923 (0.26), 1.006 (0.17), 1.049 (1.01), 1.084 (1.14), 1.119 (1.44), 1.137 (3.02), 1.155 (1.49), 1.205 (0.48), 1.233 (1.27), 1.254 (1.09), 1.265 (1.01), 1.288 (0.66),
1.299 (0.52), 1.452 (0.35), 1.487 (0.74), 1.515 (0.66), 1.539 (0.66), 1.575 (0.26), 1.647 (0.52),
1.678 (0.35), 1.871 (1.01), 1.906 (1.40), 2.109 (13.86), 2.202 (0.31), 2.227 (7.34), 2.237 (7.34), 2.270 (14.95), 2.336 (0.92), 2.452 (0.35), 2.518 (16.00), 2.523 (10.27), 2.844 (0.35), 2.875 (1.18), 2.893 (0.96), 2.940 (0.70), 2.967 (1.18), 2.973 (1.22), 3.004 (1.44), 3.019 (1.27), 3.027 (1.27), 3.042 (1.18), 3.074 (0.66), 3.103 (1.05), 3.134 (0.70), 3.160 (0.48), 3.174 (1.14), 3.190
(1.05), 3.198 (0.74), 3.205 (0.66), 3.213 (0.70), 3.221 (0.92), 3.230 (0.87), 3.243 (0.66), 3.401
(1.05), 3.426 (1.18), 3.460 (5.03), 3.530 (0.48), 3.564 (10.05), 3.674 (0.83), 3.709 (0.74), 4.188 (0.44), 4.222 (0.44), 4.341 (0.83), 4.374 (0.83), 6.892 (1.05), 6.912 (1.75), 6.963 (3.02), 6.983
(1.79), 7.051 (3.32), 7.073 (1.66), 7.087 (2.19), 7.095 (3.45), 7.109 (3.02), 7.147 (4.42), 7.163 (2.23), 7.169 (5.38), 7.185 (3.23), 7.191 (2.49), 7.207 (2.19), 7.224 (1.22), 7.277 (1.36), 7.290
(1.57), 7.298 (1.27), 7.312 (1.01), 7.438 (2.19), 7.474 (1.44).
Analytical Chiral HPLC (method see Example 20): Rt = 4.73 min
Optical rotation (method OR1): -218°+/-1.12° (met hanol). Example 24
9-[2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 4)
Figure imgf000184_0001
For the preparation of the diastereomeric title compound and separation into its diastereoisomers see Example 20.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.46), 0.013 (0.58), 0.033 (0.94), 0.045 (0.91), 0.066 (0.61), 0.078 (0.51), 0.721 (0.71), 0.726 (0.33), 0.738 (0.81), 0.745 (0.81), 0.764 (0.48),
0.775 (0.28), 0.810 (0.36), 0.828 (0.74), 0.846 (0.41), 0.930 (0.20), 1.007 (0.43), 1.039 (1.80),
1.057 (2.95), 1.076 (1.70), 1.128 (0.48), 1.158 (0.74), 1.182 (0.56), 1.253 (0.53), 1.265 (0.79),
1.287 (1.40), 1.298 (1.24), 1.320 (0.71), 1.331 (0.58), 1.366 (0.23), 1.401 (0.25), 1.420 (0.20),
1.431 (0.20), 1.829 (1.63), 1.862 (1.12), 1.883 (0.28), 1.929 (13.38), 2.031 (0.61), 2.068 (16.00), 2.133 (4.17), 2.141 (4.11), 2.160 (0.41), 2.193 (0.63), 2.282 (0.18), 2.299 (0.30), 2.313 (0.28), 2.317 (0.23), 2.330 (0.23), 2.336 (0.30), 2.441 (8.89), 2.446 (5.82), 2.775 (0.91), 2.791
(0.86), 2.802 (1.40), 2.808 (1.85), 2.834 (0.74), 2.865 (0.23), 2.899 (1.19), 2.913 (1.30), 2.928
(1.37), 2.942 (1.32), 3.035 (0.66), 3.044 (0.79), 3.058 (0.81), 3.065 (0.99), 3.074 (0.94), 3.089
(0.74), 3.094 (0.69), 3.101 (0.76), 3.136 (1.47), 3.162 (0.84), 3.317 (0.41), 3.331 (0.63), 3.396
(2.44), 3.420 (0.30), 3.455 (0.33), 3.487 (11.05), 3.506 (2.29), 3.536 (1.75), 3.573 (0.81), 4.137 (0.25), 4.171 (0.23), 4.330 (0.91), 4.363 (0.86), 6.571 (1.55), 6.590 (2.08), 6.700 (1.52), 6.718
(1.17), 6.941 (3.12), 6.958 (0.61), 7.061 (1.19), 7.084 (1.73), 7.088 (1.83), 7.110 (5.38), 7.132
(7.75), 7.147 (4.32), 7.154 (2.01), 7.170 (1.07), 7.204 (0.76), 7.217 (0.89), 7.225 (0.74), 7.239
(0.58), 7.392 (2.41), 7.400 (2.95), 10.774 (0.15).
Analytical Chiral HPLC (method see Example 20): Rt = 5.41 min
Optical rotation (method OR1): -8.5°+/-0.56°(meth anol). Example 25
9-[2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa- 3,9-diazaspiro[5.5]undecan-2-one (mixture of diastereoisomers)
Figure imgf000185_0001
A mixture of (rac) 2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoic acid (171 mg, 624 mihoI), HATU (237 mg, 624 mihoI) and N,N-diisopropylethylamine (250 mI_, 1 .4 mmol) in DMF (1 .5 mL) was stirred for 5 min, then (rac) 5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one hydrochloride (150 mg, 568 mihoI, Intermediate 6) was added and the reaction mixture was stirred for 1 h at room temperature under an atmosphere of argon. The reaction mixture was filtered using a CHROMAFIL filter (PET-45/15 MS, Pore Size: 0,45 pm) and the final purification was conducted via preparative FIPLC (method12) to give the title compound 150 mg (95 % purity, 48 % yield).
LC-MS (method 2): Rt = 1 .32 min; MS (ESIpos): m/z = 521 [M+H]+.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .107 (16.00), 1 .879 (0.16), 1 .912 (0.30), 1.947 (0.30), 1 .966 (0.22), 1 .984 (0.21 ), 2.001 (0.27), 2.019 (0.34), 2.031 (0.37), 2.050 (0.51 ), 2.068 (0.34),
2.075 (0.20), 2.323 (0.27), 2.327 (0.39), 2.332 (0.27), 2.518 (1.55), 2.523 (1 .05), 2.665 (0.33),
2.669 (0.53), 2.673 (0.39), 2.769 (0.22), 2.788 (0.38), 2.807 (0.25), 2.831 (0.22), 2.853 (0.48),
2.870 (0.56), 2.892 (0.47), 2.919 (0.43), 2.936 (0.27), 2.968 (0.22), 2.975 (0.21 ), 2.997 (0.21 ),
3.012 (0.22), 3.029 (0.25), 3.038 (0.20), 3.052 (0.18), 3.109 (0.20), 3.133 (0.19), 3.139 (0.19),
3.173 (0.20), 3.212 (0.28), 3.235 (0.16), 3.242 (0.20), 3.391 (0.20), 3.415 (0.23), 3.445 (0.19),
3.463 (0.73), 3.547 (0.26), 3.568 (2.63), 3.605 (0.19), 4.189 (1.48), 6.787 (0.22), 6.868 (0.18),
6.949 (0.18), 6.969 (0.26), 7.041 (0.42), 7.062 (0.39), 7.074 (0.57), 7.097 (0.65), 7.11 1 (0.48),
7.138 (0.98), 7.161 (0.91 ), 7.185 (0.67), 7.192 (0.64), 7.207 (0.39), 7.214 (0.71 ), 7.230 (0.50),
7.239 (0.43), 7.281 (0.46), 7.292 (0.30), 7.301 (0.41 ), 7.314 (0.19), 7.437 (0.34), 7.475 (0.50).
The title compound (150 mg) was separated into its diastereoisomers by preparative chiral HPLC to give diastereoisomer 1 (30 mg, see Example 26), diastereoisomer 2 (25 mg, see Example 27), diastereoisomer 3 (30 mg, see Example 28) and diastereoisomer 4 (30 mg, see Example 29). Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000, column: Chiralpak IG 5m 250x30mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: 2-propanol; isocratic 70% A + 30% B; flow 50.0 mL/min; UV 220 nm
Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; column: Chiralpak IG 3m 100x4, 6mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: ethanol; isocratic 70% A + 30% B; flow 1 .4 mUmin; temperature: 25 Ό; DAD 220 nm
Example 26, Example 27. Example 28 and Example 29
(5R)-9-[(2S)-2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4- fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one
(5R)-9-[(2R)-2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4- fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one
(5S)-9-[(2S)-2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4- fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one
(5S)-9-[(2R)-2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4- fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one
Example 26
9-[2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa- 3,9-diazaspiro[5.5]undecan-2-one (single stereoisomer 1 )
Figure imgf000186_0001
For the preparation of the diastereomeric title compound and separation into its diastereoisomers see Example 25.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.67), 0.012 (0.88), 0.033 (1 .41 ), 0.044 (1 .41 ),
0.066 (0.88), 0.078 (0.74), 0.688 (0.46), 0.707 (1 .23), 0.710 (1.73), 0.726 (2.1 1 ), 0.733 (1 .90),
0.752 (1 .20), 0.764 (0.70), 0.774 (0.81 ), 0.798 (0.92), 0.816 (1.69), 0.835 (0.81 ), 0.918 (0.92), 0.946 (0.53), 0.995 (1.87), 1.007 (1.23), 1.026 (2.08), 1.064 (1.69), 1.116 (1.20), 1.145 (2.04),
1.171 (2.57), 1.253 (0.95), 1.264 (1.30), 1.285 (2.43), 1.297 (2.04), 1.319 (1.27), 1.332 (1.16),
1.351 (0.63), 1.375 (0.53), 1.417 (0.42), 1.522 (0.21), 1.714 (0.25), 1.825 (2.50), 1.840 (2.22),
1.859 (4.30), 1.877 (3.24), 1.896 (2.57), 1.914 (1.97), 1.933 (1.13), 2.027 (0.21), 2.082 (0.25),
2.114 (0.56), 2.122 (0.32), 2.143 (0.25), 2.235 (1.55), 2.238 (2.11), 2.243 (1.62), 2.271 (0.56),
2.286 (0.78), 2.301 (1.23), 2.319 (1.69), 2.341 (1.59), 2.577 (1.59), 2.581 (2.11), 2.585 (1.69),
2.598 (0.99), 2.618 (1.48), 2.638 (1.55), 2.658 (1.52), 2.680 (2.26), 2.699 (3.31), 2.709 (3.28),
2.727 (1.83), 2.746 (1.55), 2.764 (3.07), 2.797 (2.15), 2.831 (1.20), 2.875 (0.56), 2.894 (1.52),
2.908 (2.04), 2.923 (1.76), 2.937 (1.83), 3.021 (0.99), 3.030 (1.23), 3.050 (1.48), 3.060 (1.44),
3.073 (1.02), 3.094 (1.09), 3.124 (2.64), 3.156 (1.16), 3.322 (0.99), 3.388 (3.74), 3.426 (0.49),
3.459 (2.40), 3.480 (16.00), 3.517 (2.61), 3.557 (1.27), 4.135 (0.39), 4.168 (0.35), 4.327 (1.48), 4.359 (1.37), 6.678 (2.11), 6.698 (2.96), 6.779 (2.50), 6.799 (1.80), 6.981 (4.65), 7.051 (0.88),
7.074 (2.26), 7.082 (2.43), 7.104 (6.94), 7.127 (9.23), 7.142 (6.52), 7.165 (1.73), 7.172 (1.44),
7.194 (1.87), 7.208 (1.27), 7.216 (1.06), 7.229 (0.78), 7.382 (3.56), 7.389 (4.23), 10.426 (0.32), 10.547 (0.28), 10.763 (0.74), 11.651 (0.18).
Analytical Chiral HPLC (method see Example 25): Rt = 2.95 min
Optical rotation (method OR1): 11.8°+/-0.20°(meth anol).
Example 27
9-[2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1-oxa- 3,9-diazaspiro[5.5]undecan-2-one (single stereoisomer 2)
Figure imgf000187_0001
For the preparation of the diastereomeric title compound and separation into its diastereoisomers see Example 25.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.177 (0.87), 0.198 (1.34), 0.210 (1.39), 0.232 (0.93),
0.776 (0.51), 0.798 (1.65), 0.814 (1.95), 0.821 (1.80), 0.840 (1.18), 0.862 (0.82), 0.886 (0.77),
0.904 (1.44), 0.923 (0.77), 1.006 (0.98), 1.034 (2.16), 1.071 (2.06), 1.084 (2.11), 1.108 (0.67),
1.137 (0.82), 1.160 (0.46), 1.205 (1.23), 1.235 (2.73), 1.259 (2.93), 1.270 (1.95), 1.280 (1.80), 1.303 (1.13), 1.315 (0.93), 1.422 (0.46), 1.493 (1.39), 1.539 (1.39), 1.656 (0.93), 1.692 (0.67),
1.877 (1.70), 1.906 (1.70), 2.000 (1.75), 2.019 (2.88), 2.031 (3.76), 2.049 (5.04), 2.067 (3.40),
2.086 (1.08), 2.115 (0.41), 2.202 (0.62), 2.231 (0.31), 2.327 (3.09), 2.373 (0.57), 2.413 (0.98),
2.612 (0.67), 2.630 (1.18), 2.651 (1.49), 2.669 (4.63), 2.770 (1.18), 2.789 (2.06), 2.808 (1.59),
2.829 (1.80), 2.852 (3.19), 2.870 (4.94), 2.893 (3.96), 2.917 (3.96), 2.936 (2.98), 2.973 (2.11),
3.015 (1.65), 3.029 (2.06), 3.038 (2.11), 3.052 (1.85), 3.073 (1.13), 3.103 (1.80), 3.135 (1.18),
3.159 (2.37), 3.172 (3.09), 3.188 (1.08), 3.211 (1.29), 3.225 (1.23), 3.235 (1.59), 3.242 (1.59),
3.390 (1.80), 3.415 (1.95), 3.446 (2.11 ), 3.463 (7.51 ), 3.569 (16.00), 3.669 (1.44), 3.705 (1.29), 4.096 (0.41), 4.110 (0.36), 4.200 (0.77), 4.231 (0.72), 4.344 (1.39), 4.377 (1.34), 6.949 (1.95),
6.968 (2.78), 7.041 (4.12), 7.061 (3.09), 7.075 (3.76), 7.097 (6.33), 7.111 (4.63), 7.138 (9.26),
7.160 (7.61), 7.185 (4.84), 7.208 (2.32), 7.241 (2.62), 7.279 (3.60), 7.291 (2.83), 7.299 (3.55),
7.313(1.59), 7.439 (3.65), 7.476 (2.42), 10.514(0.31), 10.635 (0.26), 10.851 (0.77).
Analytical Chiral HPLC (method see Example 25): Rt = 3.31 min
Optical rotation (method OR1): 25.5°+/-0.55°(meth anol).
Example 28
9-[2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1-oxa- 3,9-diazaspiro[5.5]undecan-2-one (single stereoisomer 3)
Figure imgf000188_0001
For the preparation of the diastereomeric title compound and separation into its diastereoisomers see Example 25.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.66), 0.011 (0.81), 0.032 (1.38), 0.043 (1.38), 0.065 (0.85), 0.077 (0.72), 0.686 (0.34), 0.708 (1.19), 0.725 (1.38), 0.732 (1.32), 0.750 (0.94),
0.772 (0.72), 0.797 (0.56), 0.815 (0.91), 0.833 (0.47), 0.916 (0.72), 0.945 (0.47), 0.994 (1.47),
1.031 (1.94), 1.064 (1.69), 1.115 (1.00), 1.146 (1.53), 1.170 (2.10), 1.263 (1.28), 1.285 (2.38),
1.297 (2.04), 1.318 (1.28), 1.331 (1.13), 1.350 (0.59), 1.374 (0.53), 1.416 (0.41), 1.697 (0.25),
1.825 (2.57), 1.839 (2.25), 1.858 (4.23), 1.876 (3.19), 1.895 (2.47), 1.914 (1.91), 1.931 (1.13),
2.027 (0.19), 2.112 (0.47), 2.141 (0.19), 2.238 (1.91), 2.269 (0.53), 2.304 (1.13), 2.318 (1.53), 2.340 (1.63), 2.580 (1.97), 2.599 (0.97), 2.617 (1.44), 2.637 (1.50), 2.657 (1.47), 2.680 (2.07),
2.698 (3.19), 2.707 (3.26), 2.726 (1.94), 2.744 (1.66), 2.763 (3.10), 2.801 (2.19), 2.830 (1.32),
2.875 (0.59), 2.893 (1.41), 2.908 (1.94), 2.922 (1.66), 2.936 (1.75), 3.034 (1.22), 3.049 (1.44),
3.059 (1.41), 3.094 (1.06), 3.124 (2.60), 3.155 (1.16), 3.321 (1.00), 3.387 (3.63), 3.422 (0.53),
3.458 (2.32), 3.479 (16.00), 3.517 (2.57), 3.557 (1.32), 4.135 (0.41), 4.168 (0.34), 4.325 (1.44), 4.359 (1.38), 6.678 (1.97), 6.697 (2.85), 6.778 (2.44), 6.799 (1.75), 6.882 (0.19), 6.981 (4.60),
7.051 (1.06), 7.073 (2.19), 7.080 (2.29), 7.103 (6.23), 7.126 (8.52), 7.141 (6.20), 7.163 (1.72),
7.192 (1.85), 7.207 (1.32), 7.229 (0.78), 7.388 (4.13), 10.425 (0.25), 10.545 (0.19), 10.761 (0.59).
Analytical Chiral HPLC (method see Example 25): Rt = 3.90 min
Optical rotation (method OR1): -17.0°+/-0.33°(met hanol).
Example 29
9-[2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl] -5-(4-fluorophenyl)-1 -oxa- 3,9-diazaspiro[5.5]undecan-2-one (single stereoisomer 4)
Figure imgf000189_0001
For the preparation of the diastereomeric title compound and separation into its diastereoisomers see Example 25.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.177 (0.84), 0.198 (1.41), 0.210 (1.37), 0 .232 (0.92), 0.243 (0.76), 0.776 (0.72), 0.797 (1.89), 0.814 (2.45), 0.821 (2.17), 0.840 (1.53), 0.852 (1.09), 0.862 (1.25), 0.886 (0.96), 0.904 (1.53), 0.922 (0.84), 1.006 (1.53), 1.034 (2.45), 1068 (1.93), 1.083 (2.97), 1.100 (0.60), 1.116 (1.41), 1.134 (2.69), 1.152 (1.49), 1.205 (1.81), 1.235 (3.02), 1.259 (4.26), 1.269 (2.25), 1.280 (2.01), 1.303 (1.29), 1.315 (1.01), 1.391 (0.60), 1405 (0.56), 1.422 (0.72), 1.443 (0.80), 1.458 (0.80), 1.486 (1.49), 1.538 (1.57), 1.572 (0.68), 1658 (1.01), 1.689 (0.68), 1.788 (0.40), 1.877 (1.81), 1.906 (1.69), 2.000 (1.73), 2.018 (2.93), 2031 (3.86), 2.049 (5.15), 2.067 (3.50), 2.086 (1.05), 2.115 (0.28), 2.202 (0.80), 2.211 (0.36), 2231 (0.28), 2.327 (2.45), 2.359 (0.40), 2.374 (0.56), 2.394 (0.68), 2.413 (0.92), 2.612 (0.68), 2630 (1.25), 2.651 (1.53), 2.669 (4.06), 2.770 (1.05), 2.788 (1.93), 2.808 (1.57), 2.829 (1.85), 2852 (3.46), 2.869 (5.79), 2.889 (4.42), 2.917 (4.18), 2.935 (3.06), 2.974 (2.09), 3.015 (1 .65), 3.030 (2.09),
3.038 (2.17), 3.051 (1 .93), 3.074 (1.17), 3.105 (1 .89), 3.136 (1.17), 3.158 (0.88), 3.173 (1 .77),
3.188 (1 .09), 3.212 (1 .21 ), 3.224 (1.25), 3.234 (1 .61 ), 3.242 (1.61 ), 3.390 (1 .89), 3.416 (2.01 ),
3.445 (2.21 ), 3.463 (7.76), 3.569 (16.00), 3.670 (1 .49), 3.705 (1 .33), 4.199 (0.84), 4.233 (0.76), 4.345 (1 .49), 4.377 (1 .45), 6.949 (2.01 ), 6.968 (2.89), 7.041 (4.18), 7.061 (3.10), 7.075 (3.74),
7.097 (6.55), 7.1 1 1 (4.74), 7.138 (9.45), 7.160 (7.64), 7.184 (4.90), 7.207 (2.21 ), 7.241 (2.65),
7.279 (3.74), 7.291 (2.85), 7.299 (3.62), 7.313 (1 .57), 7.439 (3.82), 7.476 (2.33), 10.514 (0.52), 10.635 (0.44), 10.851 (1.17), 1 1 .151 (0.20), 1 1.739 (0.24).
Analytical Chiral HPLC (method see Example 25): Rt = 4.59 min
Optical rotation (method OR1 ): -21 .7°+/-0.50°(met hanol).
Example 30
5-(4-fluorophenyl)-9-[3,3,3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000190_0001
A mixture of (rac) 3,3,3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)propanoic acid (177 mg, 624 mihoI, CAS-RN: 1058658-57-3), HATU (237 mg, 624 pmol) and N,N-diisopropylethylamine (200 mI_, 1 .1 mmol) in DMF (1 .5 ml_) was stirred for 5 min, then (rac) 5-(4-fluorophenyl)-1 -oxa- 3,9-diazaspiro[5.5]undecan-2-one hydrochloride (150 mg, 568 mihoI, Intermediate 6) was added and the reaction mixture was stirred for 1 h at room temperature under an atmosphere of argon. The reaction mixture was filtered using a CHROMAFIL filter (PET-45/15 MS, Pore Size: 0,45 pm) and the final purification was conducted via preparative HPLC (method12) to give the title compound 150 mg (95 % purity, 47 % yield).
LC-MS (method 2): Rt = 1 .26 min; MS (ESIpos): m/z = 531 [M+H]+.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.691 (0.28), 0.722 (0.28), 0.886 (0.57), 0.967 (0.42), 1 .107 (13.73), 1 .144 (0.28), 1 .232 (0.57), 1.488 (0.42), 1.808 (0.71 ), 2.074 (0.57), 2.318 (0.71 ), 2.323 (1 .56), 2.327 (2.41 ), 2.332 (1.70), 2.336 (0.57), 2.518 (9.06), 2.523 (6.80), 2.539 (6.51 ), 2.660 (1 .13), 2.665 (2.12), 2.669 (2.83), 2.673 (2.12), 2.679 (1.13), 2.851 (0.57), 2.881 (0.71 ),
2.964 (0.85), 2.991 (0.85), 3.121 (0.99), 3.136 (0.99), 3.150 (0.57), 3.181 (0.57), 3.197 (0.42),
3.240 (0.28), 3.373 (1 .13), 3.389 (1.42), 3.403 (1 .27), 3.441 (0.85), 3.473 (0.99), 3.504 (0.85),
3.544 (2.55), 3.568 (2.12), 3.667 (16.00), 4.194 (1 .13), 4.249 (0.28), 4.282 (0.42), 4.430 (0.57),
4.463 (0.57), 4.487 (0.71 ), 4.522 (0.57), 6.744 (0.42), 6.91 1 (0.57), 7.046 (1 .27), 7.112 (1 .13),
7.135 (1 .84), 7.152 (1 .56), 7.157 (1.56), 7.174 (2.27), 7.197 (1.70), 7.232 (1 .13), 7.250 (1 .70),
7.264 (1 .42), 7.286 (0.85), 7.354 (1.98), 7.407 (2.27), 7.523 (1.70), 7.526 (1 .42), 7.536 (1 .56),
7.547 (2.12), 7.561 (0.85), 7.580 (0.85), 7.599 (0.71 ), 7.61 1 (0.71 ), 7.742 (0.42), 7.906 (0.99),
7.978 (2.41 ), 7.996 (2.69), 8.022 (1.13), 8.034 (2.27), 8.045 (1.56), 8.055 (1 .98), 8.067 (0.85),
8.088 (0.42).
The title compound (142 mg) was separated into its diastereoisomers by preparative chiral HPLC to give diastereoisomer 1 (30 mg, see Example 31 ), diastereoisomer 2 (20 mg, see Example 32), diastereoisomer 3 (20 mg, see Example 33) and diastereoisomer 4 (35 mg, see Example 34).
For the isolation of diastereoisomer 1 , a mixture of diastereoisomer 2 and diastereoisomer 3 and diastereoisomer 4 the following method was used.
Preparative chiral FIPLC method: Instrument: Sepiatec: Prep SFC100; column: Reprosil Chiral NR 8pm 250x30mm; eluent A: C02, eluent B: ethanol; isocratic: 31 % B; flow 100.0 mL/min temperature: 40Ό; BPR: 150bar; MWD @ 220nm.
The mixture of diastereoisomer 2 and diastereoisomer 3 was separated with the following method.
Preparative chiral FIPLC method: Instrument: Sepiatec: Prep SFC100; column: Chiralpak IG 5pm 250x30mm; eluent A: C02, eluent B: ethanol; isocratic: 24% B; flow 100.0 mL/min temperature: 40Ό; BPR: 150bar; MWD @ 220nm.
Analytical chiral HPLC method: Instrument: Agilent: 1260, Aurora SFC-Modul; column: Reprosil Chiral NR 5pm 100x4.6mm; eluent A: C02, eluent B: ethanol; isocratic: 31 %B; flow 4.0 mL/min; temperature: 37.5Ό; BPR: 100bar; MWD @ 220nm. Example 31, Example 32. Example 33 and Example 34
(5R)-5-(4-fluorophenyl)-9-[(2S)-3,3,3-trifluoro-2-methoxy-2-(1-naphthyl)propanoyl]-1-oxa-3,9- diazaspiro[5.5]undecan-2-one
(5R)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-(1-naphthyl)propanoyl]-1-oxa-3,9- diazaspiro[5.5]undecan-2-one
(5S)-5-(4-fluorophenyl)-9-[(2S)-3,3,3-trifluoro-2-methoxy-2-(1-naphthyl)propanoyl]-1-oxa-3,9- diazaspiro[5.5]undecan-2-one
(5S)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-(1-naphthyl)propanoyl]-1-oxa-3,9- diazaspiro[5.5]undecan-2-one
Example 31
5-(4-fluorophenyl)-9-[-3,3,3-trifluoro-2-methoxy-2-(naphthalen-1-yl)propanoyl]-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 1)
Figure imgf000192_0001
For the preparation of the diastereomeric title compound and separation into its diastereoisomers see Example 30.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.798 (3.23), 0.803 (1.45), 0.815 (3.44), 0.821 (3.57), 0.840 (2.09), 0.859 (0.64), 0.877 (0.67), 0.886 (2.09), 0.904 (4.11), 0.922 (2.22), 0.949 (0.37), 0.974 (0.30), 1.017 (0.30), 1.068 (0.47), 1.090 (0.30), 1.109 (0.37), 1.124 (0.40), 1.137 (3.84), 1.142 (0.77), 1.161 (0.37), 1.180 (0.17), 1.205 (2.46), 1.222 (0.40), 1.237 (0.57), 1.241 (0.47), 1.256 (0.57), 1.270 (0.34), 1.274 (0.37), 1.289 (0.27), 1.484 (0.24), 1.508 (0.17), 1.799 (0.64), 1.815 (0.64), 1.833 (0.67), 2.084 (0.51), 2.115 (1.68), 2.141 (0.17), 2.170 (0.37), 2.190 (0.34), 2.202 (1.25), 2.210 (0.57), 2.230 (0.47), 2.318 (0.51), 2.322 (1.11), 2.326 (1.55), 2.332 (1.18), 2.336 (0.57), 2.359 (0.51), 2.374 (0.57), 2.389 (0.67), 2.394 (0.71), 2.399 (0.40), 2.406 (0.67), 2.412 (0.91), 2.425 (0.27), 2.430 (0.30), 2.478 (1.65), 2.518 (16.00), 2.522 (11.96), 2.660 (0.71), 2.664 (1.31), 2.669 (1.75), 2.673 (1.41), 2.678 (0.81), 2.850 (0.40), 2.881 (0.71), 2.911 (0.47), 3.001 (0.37), 3.110 (0.47), 3.166 (0.37), 3.181 (0.54), 3.197 (0.37), 3.408 (1.15), 3.439 (0.84), 3.480 (0.51), 3.569 (1.92), 3.667 (8.39), 4.281 (0.17), 4.315 (0.17), 4.489 (0.61), 4.522 (0.57), 4.560 (0.74), 6.917 (0.54), 7.041 (0.71), 7.112 (0.98), 7.135 (1.68), 7.157 (1.21), 7.232
(0.91), 7.245 (0.94), 7.268 (0.64), 7.414 (1.65), 7.523 (1.08), 7.532 (0.74), 7.539 (0.84), 7.547
(1.21), 7.558 (0.51), 7.579 (0.64), 7.599 (0.40), 7.758 (0.37), 7.906 (0.91), 7.979 (0.61), 7.995
(0.61 ), 8.003 (0.57), 8.022 (0.77), 8.043 (0.64), 11.739 (0.27).
Analytical Chiral HPLC (method see Example 30): Rt = 1.55 min
Optical rotation (method OR1): -21.5°+/-0.38°(met hanol).
Example 32
5-(4-fluorophenyl)-9-[3,3,3-trifluoro-2-methoxy-2-(naphthalen-1-yl)propanoyl]-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 2)
Figure imgf000193_0001
For the preparation of the diastereomeric title compound and separation into its diastereoisomers see Example 30.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.704 (0.40), 0.787 (0.46), 0.798 (1.71), 0.803 (0.92), 0.814 (1.84), 0.821 (1.91), 0.840 (1.32), 0.859 (0.66), 0.877 (0.92), 0.886 (1.19), 0.896 (0.66),
0.904 (2.04), 0.923 (1.19), 0.949 (0.59), 1.004 (0.46), 1.017 (0.40), 1.068 (0.92), 1.137 (2.04),
1.205 (3.69), 1.237 (0.46), 1.403 (0.66), 1.451 (0.59), 1.493 (0.66), 1.802 (0.79), 1.890 (0.40),
2.084 (0.46), 2.115 (0.99), 2.140 (0.40), 2.202 (2.11), 2.331 (2.83), 2.336 (1.32), 2.374 (0.46),
2.388 (0.46), 2.394 (0.46), 2.407 (0.59), 2.413 (0.66), 2.518 (16.00), 2.523 (10.14), 2.539 (4.15), 2.669 (4.02), 2.673 (2.96), 2.962 (1.45), 2.994 (1.25), 3.121 (1.32), 3.136 (1.51), 3.150
(0.86), 3.233 (0.72), 3.376 (0.92), 3.386 (0.99), 3.472 (1.12), 3.503 (1.12), 3.545 (4.87), 3.667
(15.14), 4.248 (0.53), 4.283 (0.46), 4.430 (1.19), 4.462 (1.12), 6.736 (0.79), 7.049 (1.25), 7.153 (1.71), 7.175 (3.56), 7.197 (2.44), 7.250 (1.84), 7.264 (2.04), 7.271 (1.58), 7.286 (1.25), 7.355
(3.69), 7.408 (1.84), 7.510 (0.53), 7.522 (1.38), 7.526 (1.98), 7.536 (2.17), 7.546 (1.91), 7.562
(0.66), 7.592 (0.79), 7.612 (1.05), 7.976 (3.95), 7.997 (4.21), 8.016 (1.45), 8.035 (3.95), 8.056
(3.56), 8.068 (1.65), 11.740 (0.66).
Analytical Chiral HPLC (method see Example 30): Rt = 2.00 min
Optical rotation (method OR1): -23.0°+/-0.33°(met hanol). Example 33
5-(4-fluorophenyl)-9-[3,3,3-trifluoro-2-methoxy-2-(naphthalen-1-yl)propanoyl]-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 3)
Figure imgf000194_0001
For the preparation of the diastereomeric title compound and separation into its diastereoisomers see Example 30.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.787 (0.55), 0.806 (1.24), 0.824 (0.83), 0.837 (0.55),
0.859 (0.90), 0.877 (1.38), 0.890 (0.62), 0.896 (0.90), 0.949 (0.76), 0.974 (0.41), 0.984 (0.62),
0.992 (0.41), 1.018 (0.55), 1.068 (1.72), 1.137 (4.76), 1.168 (0.83), 1.205 (9.10), 1.233 (0.41), 1.405 (0.69), 1.423 (0.55), 1.492 (0.48), 1.782 (0.55), 2.084 (1.10), 2.116 (2.14), 2.130 (0.55),
2.141 (0.69), 2.152 (0.41), 2.202 (4.97), 2.409 (0.48), 2.518 (16.00), 2.523 (10.34), 2.539 (7.31), 2.659 (1.45), 2.962 (1.10), 2.994 (1.10), 3.121 (0.90), 3.136 (1.10), 3.150 (0.62), 3.376
(0.76), 3.476 (0.83), 3.507 (0.76), 3.544 (3.66), 3.667 (11.24), 4.388 (0.69), 4.429 (0.90), 4.462
(0.83), 4.560 (0.90), 6.738 (0.55), 7.043 (0.90), 7.153 (1.31), 7.176 (2.69), 7.198 (1.79), 7.250 (1.38), 7.264 (1.52), 7.272 (1.17), 7.286 (0.97), 7.355 (2.76), 7.408 (1.38), 7.526 (1.52), 7.536
(1.66), 7.547 (1.45), 7.562 (0.48), 7.594 (0.62), 7.610 (0.83), 7.976 (2.90), 7.996 (3.10), 8.016
(1.10), 8.035 (2.90), 8.056 (2.69), 8.068 (1.24), 11.740 (1.03).
Analytical Chiral HPLC (method see Example 30): Rt = 2.13 min
Optical rotation (method OR1): 25.4°+/-0.75°(meth anol).
Example 34
5-(4-fluorophenyl)-9-[3,3,3-trifluoro-2-methoxy-2-(naphthalen-1-yl)propanoyl]-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 4)
Figure imgf000195_0001
For the preparation of the diastereomeric title compound and separation into its diastereoisomers see Example 30.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.798 (7.50), 0.803 (3.34), 0.814 (7.94), 0.821 (8.06), 0.840 (4.54), 0.851 (1.01), 0.859 (1.07), 0.877 (1.20), 0.886 (4.60), 0.904 (8.82), 0.923 (4.28),
0.949 (0.57), 0.974 (0.50), 0.992 (0.50), 1.017 (0.50), 1.068 (0.88), 1.090 (0.63), 1.109 (0.76), 1.124 (0.88), 1.137 (4.72), 1.142 (1.32), 1.161 (0.76), 1.168 (0.44), 1.205 (4.66), 1.222 (0.88),
1.237 (1.32), 1.241 (1.07), 1.255 (1.20), 1.270 (0.63), 1.274 (0.76), 1.289 (0.57), 1.799 (1.20),
1.816 (1.13), 1.833 (1.13), 2.084 (0.44), 2.115 (2.02), 2.170 (0.82), 2.190 (0.76), 2.202 (2.46),
2.211 (1.26), 2.230 (1.07), 2.331 (2.65), 2.336 (1.20), 2.359 (1.07), 2.374 (1.32), 2.388 (1.51),
2.394 (1.64), 2.399 (0.94), 2.407 (1.64), 2.413 (2.14), 2.425 (0.63), 2.431 (0.69), 2.518 (16.00), 2.523 (10.08), 2.539 (3.84), 2.673 (2.96), 2.678 (1.51), 2.851 (0.63), 2.881 (1.13), 2.912 (0.76),
2.994 (0.63), 3.111 (0.76), 3.165 (0.50), 3.181 (0.76), 3.197 (0.50), 3.373 (0.69), 3.404 (1.39), 3.440 (1.20), 3.481 (0.82), 3.569 (3.28), 3.667 (14.05), 4.488 (1.01), 4.519 (0.94), 4.560 (0.82), 6.915 (0.76), 7.043 (1.01), 7.113 (1.45), 7.136 (2.58), 7.158 (1.89), 7.233 (1.45), 7.247 (1.51),
7.268 (1.01), 7.415 (2.71), 7.523 (1.70), 7.533 (1.20), 7.540 (1.39), 7.548 (1.89), 7.557 (0.82), 7.581 (1.07), 7.599 (0.69), 7.752 (0.57), 7.906 (1.45), 7.979 (1.01), 7.995 (0.94), 8.003 (0.94),
8.022 (1.26), 8.044 (1.07), 11.740 (0.44).
Analytical Chiral HPLC (method see Example 30): Rt = 2.13 min
Optical rotation (method OR1): 23.8°+/-0.28°(meth anol). Example 35
5-(2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of two stereoisomers)
Figure imgf000196_0001
A mixture of (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (100 mg, 320 pmol, CAS- RN: 20445-31 -2), HATU (134 mg, 352 pmol) and N,N-diisopropylethylamine (170 mI_, 960 pmol) in DMF (2 mL) was stirred for 5 min, then (rac) 5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one hydrochloride (150 mg, 568 pmol, Intermediate 14) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC (methodl 1 ) to give the title compound 69 mg (90 % purity, 39 % yield).
LC-MS (method 2): Rt = 1 .22 min; MS (ESIpos): m/z = 493 [M+H]+.
1 H-NMR (500 MHz, DMSO-d6, at 80Ό) d [ppm]: 0.041 (0.86), 0.414 (0.80), 1 .036 (1 .55), 1 .081 (1 .09), 1 .107 (1 .03), 1 .144 (8.89), 1 .158 (8.32), 1.174 (0.80), 1 .264 (0.97), 1.310 (0.97), 1 .421 (1 .26), 1 .438 (1 .03), 1 .854 (1.09), 1 .883 (1 .15), 1.927 (0.92), 2.353 (1 .26), 2.357 (2.52), 2.361 (3.56), 2.365 (2.64), 2.368 (1 .38), 2.517 (16.00), 2.521 (10.44), 2.538 (1 .15), 2.627 (1 .32), 2.631 (2.52), 2.635 (3.61 ), 2.638 (2.52), 2.642 (1.26), 2.728 (0.46), 2.743 (0.75), 2.757 (0.52), 2.864 (0.75), 2.892 (1 .26), 2.915 (0.86), 2.978 (0.75), 3.003 (1 .20), 3.024 (0.80), 3.136 (0.97), 3.182 (0.69), 3.210 (1 .20), 3.236 (1 .43), 3.261 (1.26), 3.31 1 (1 .03), 3.395 (1.89), 3.444 (5.96), 3.447 (5.91 ), 3.469 (2.58), 3.540 (1 .38), 3.565 (1 .78), 3.650 (1 1 .18), 3.682 (1.61 ), 3.695 (1 .15), 3.709 (0.92), 3.755 (7.63), 3.797 (5.85), 4.212 (0.46), 4.385 (1 .03), 4.410 (0.92), 6.874 (1 .15), 6.889 (1 .43), 6.926 (2.58), 6.941 (4.19), 6.956 (2.24), 6.998 (4.07), 7.013 (5.39), 7.026 (3.04), 7.053 (2.12), 7.070 (1 .89), 7.142 (3.27), 7.187 (5.91 ), 7.202 (5.05), 7.303 (7.80), 7.385 (2.64), 7.431 (4.53), 7.435 (4.87), 7.446 (5.22), 7.454 (4.76), 7.553 (1 .38), 7.596 (0.69). Example 36 and Example 37
(5R)-5-(2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one
(5S)-5-(2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one
Example 36
5-(2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one (single stereoisomer 1 )
Figure imgf000197_0001
A mixture of (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (82.9 mg, 354 mihoI, CAS- RN: 20445-31 -2), HATU (135 mg, 354 pmol) and N,N-diisopropylethylamine (170 mI_, 970 mmol) in DMF (2 ml_) was stirred for 5 min, then 5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one hydrochloride (150 mg, 322 mihoI, intermediate 15, single stereoisomer 1 ) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC (method 7) to give the title compound 105 mg (90 % purity, 60 % yield).
LC-MS (method 2): Rt = 1 .17 min; MS (ESIpos): m/z = 493 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.299 (0.60), 0.31 1 (0.78), 0.332 (1 .27), 0.344 (1 .21 ), 0.366 (0.86), 0.377 (0.68), 0.940 (2.83), 0.972 (1 .56), 1.206 (0.66), 1 .217 (0.84), 1.239 (1 .37),
1 .251 (1 .35), 1 .273 (0.92), 1 .285 (0.74), 1 .478 (0.41 ), 1.488 (0.41 ), 1 .648 (0.49), 1.677 (0.70),
1 .883 (1 .42), 1 .914 (1 .27), 2.422 (0.45), 2.453 (0.72), 2.518 (5.33), 2.523 (3.47), 2.865 (0.49),
2.916 (1 .15), 2.941 (1 .85), 2.948 (1.85), 2.974 (1 .07), 3.096 (1.60), 3.129 (1 .00), 3.227 (1 .23),
3.237 (1 .25), 3.306 (0.96), 3.363 (0.82), 3.415 (1 .23), 3.445 (4.47), 3.474 (0.55), 3.507 (0.43),
3.585 (14.60), 3.615 (1.37), 3.649 (1 .13), 3.740 (16.00), 3.786 (9.13), 4.330 (1 .23), 4.362 (1 .17), 6.840 (1 .58), 6.858 (2.17), 6.915 (0.59), 6.930 (2.75), 6.948 (3.75), 6.967 (1.60), 6.986 (3.30), 7.005 (3.92), 7.019 (1.05), 7.039 (1.21), 7.202 (0.96), 7.206 (1.05), 7.221 (0.88), 7.225
(0.92), 7.252 (2.52), 7.273 (13.81), 7.282 (3.61), 7.290 (6.91), 7.311 (2.11), 7.317 (1.70), 7.321
(1.50), 7.365 (1.11), 7.384 (1.46), 7.409 (3.51), 7.432 (1.33), 7.457 (4.14), 7.460 (4.33), 7.472
(3.00), 7.476 (3.69), 7.481 (1.89), 7.489 (1.00), 7.494 (1.42), 7.498 (0.94).
Optical rotation (method OR1): -40.8°+/-0.35°(met hanol).
Example 37
5-(2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 2)
Figure imgf000198_0001
A mixture of (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (82.4 mg, 352 mihoI, CAS- RN: 20445-31-2), HATU (134 mg, 352 pmol) and N,N-diisopropylethylamine (170 mI_, 970 mihoI) in DMF (2 ml_) was stirred for 5 min, then 5-(2-methoxyphenyl)-1-oxa-3,9- diazaspiro[5.5]undecan-2-one hydrochloride (115 mg, 320 mihoI, intermediate 16, single stereoisomer 2) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC (method 7) to give the title compound 50 mg (90 % purity, 29 % yield).
LC-MS (method 2): Rt = 1.17 min; MS (ESIpos): m/z = 493 [M+H]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.299 (0.60), 0.311 (0.78), 0.332 (1.27), 0.344 (1.21), 0.366 (0.86), 0.377 (0.68), 0.940 (2.83), 0.972 (1.56), 1.206 (0.66), 1.217 (0.84), 1.239 (1.37), 1.251 (1.35), 1.273 (0.92), 1.285 (0.74), 1.478 (0.41), 1.488 (0.41), 1.648 (0.49), 1.677 (0.70), 1.883 (1.42), 1.914 (1.27), 2.422 (0.45), 2.453 (0.72), 2.518 (5.33), 2.523 (3.47), 2.865 (0.49), 2.916 (1.15), 2.941 (1.85), 2.948 (1.85), 2.974 (1.07), 3.096 (1.60), 3.129 (1.00), 3.227 (1.23), 3.237 (1.25), 3.306 (0.96), 3.363 (0.82), 3.415 (1.23), 3.445 (4.47), 3.474 (0.55), 3.507 (0.43), 3.585 (14.60), 3.615 (1.37), 3.649 (1.13), 3.740 (16.00), 3.786 (9.13), 4.330 (1.23), 4.362 (1.17), 6.840 (1.58), 6.858 (2.17), 6.915 (0.59), 6.930 (2.75), 6.948 (3.75), 6.967 (1.60), 6.986 (3.30), 7.005 (3.92), 7.019 (1.05), 7.039 (1.21), 7.202 (0.96), 7.206 (1.05), 7.221 (0.88), 7.225 (0.92), 7.252 (2.52), 7.273 (13.81 ), 7.282 (3.61 ), 7.290 (6.91 ), 7.31 1 (2.1 1 ), 7.317 (1 .70), 7.321 (1 .50), 7.365 (1 .1 1 ), 7.384 (1 .46), 7.409 (3.51 ), 7.432 (1.33), 7.457 (4.14), 7.460 (4.33), 7.472 (3.00), 7.476 (3.69), 7.481 (1.89), 7.489 (1 .00), 7.494 (1.42), 7.498 (0.94).
Optical rotation (method OR1 ): -45.8°+/-0.27°(met hanol). Example 38
5-[2-(benzyloxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of two stereoisomers)
Figure imgf000199_0001
A mixture of (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (66.0 mg, 282 mihoI, CAS RN: 20445-31 -2), HATU (107 mg, 282 pmol) and N,N-diisopropylethylamine (130 mI_, 770 mmol) in DMF (1 .6 mL) was stirred for 5 min, then (rac) 5-[2-(benzyloxy)phenyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one hydrochloride (120 mg, , 256 mihoI, intermediate 22) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC (method 7) to give the title compound 82 mg (95 % purity, 53 % yield).
LC-MS (method 2): Rt = 1 .33 min; MS (ESIpos): m/z = 569 [M+H]+
Example 39 and Example 40
(5R)-5-(4-fluoro-2-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one
(5S)-5-(4-fluoro-2-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one
Example 39
5-(4-fluoro-2-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 1 )
Figure imgf000200_0001
A mixture of (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (80.0 mg, 342 mihoI, CAS- RN: 20445-31 -2), HATU (130 mg, 342 pmol) and N,N-diisopropylethylamine (270 mI_, 1500 pmol) in DMF (1 .0 mL) was stirred for 5 min, then 5-(4-fluoro-2-methylphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid (100 mg, 285 pmol, intermediate 28, single stereoisomer 1 ) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC (method 7) to give the title compound 1 15 mg (95 % purity, 78 % yield).
LC-MS (method 2): Rt = 1 .20 min; MS (ESIpos): m/z = 495 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.214 (0.43), 0.226 (0.55), 0.248 (0.86), 0.259 (0.84), 0.282 (0.58), 0.293 (0.46), 1 .014 (1.04), 1 .045 (0.95), 1.235 (0.49), 1 .247 (0.61 ), 1.268 (1 .01 ),
1 .280 (1 .01 ), 1 .302 (0.63), 1 .314 (0.52), 1 .720 (0.46), 1.741 (0.49), 1 .903 (1 .04), 1.933 (0.92),
1 .938 (0.89), 2.255 (16.00), 2.322 (0.55), 2.327 (0.92), 2.337 (6.23), 2.518 (2.68), 2.523 (1 .82),
2.539 (0.81 ), 2.664 (0.46), 2.669 (0.66), 2.673 (0.49), 2.823 (0.40), 2.909 (0.58), 2.915 (0.72),
2.941 (1 .24), 2.948 (1 .24), 2.974 (0.69), 2.980 (0.55), 3.089 (0.66), 3.1 18 (1 .15), 3.150 (0.72),
3.167 (0.61 ), 3.183 (1 .85), 3.200 (2.45), 3.234 (2.42), 3.241 (2.25), 3.250 (1 .70), 3.264 (0.86),
3.280 (0.78), 3.293 (0.75), 3.309 (0.55), 3.41 1 (0.43), 3.420 (0.40), 3.486 (3.37), 3.596 (10.44), 3.661 (0.89), 3.696 (0.81 ), 4.357 (0.86), 4.384 (0.78), 4.390 (0.81 ), 6.808 (1 .24), 6.824 (1 .41 ),
6.830 (1 .70), 6.845 (1 .53), 7.001 (0.84), 7.009 (1 .27), 7.022 (1.50), 7.030 (2.05), 7.046 (2.31 ),
7.053 (1 .96), 7.072 (2.28), 7.078 (1.64), 7.095 (0.66), 7.102 (0.55), 7.207 (0.63), 7.222 (0.66),
7.229 (0.58), 7.244 (0.52), 7.305 (13.87), 7.317 (7.61 ), 7.339 (0.69), 7.364 (0.95), 7.378 (1 .04), 7.384 (1 .21 ), 7.425 (3.00), 7.437 (1.35), 7.446 (0.72), 7.451 (0.84), 7.459 (2.77), 7.463 (2.36),
7.469 (0.89), 7.478 (2.08), 7.486 (1.59), 7.492 (1 .38), 7.500 (1.70), 7.508 (1 .15), 7.513 (0.92),
7.521 (0.55).
Optical rotation (method OR1 ): 32.9°+/-0.32°(meth anol).
Example 40
5-(4-fluoro-2-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 2)
Figure imgf000201_0001
A mixture of (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (80.0 mg, 342 mihoI, CAS- RN: 20445-31 -2), HATU (130 mg, 342 pmol) and N,N-diisopropylethylamine (270 mI_, 1500 mmol) in DMF (1 .0 mL) was stirred for 5 min, then 5-(4-fluoro-2-methylphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid (100 mg, 285 mihoI, intermediate 29 single stereoisomer 2) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC (method 7) to give the title compound 1 15 mg (95 % purity, 78 % yield).
LC-MS (method 2): Rt = 1 .20 min; MS (ESIpos): m/z = 495 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.276 (0.45), -0.263 (0.59), -0.242 (0.95), -0.230 (0.92), -0.209 (0.57), -0.197 (0.46), 1.047 (1 .02), 1.077 (0.97), 1 .369 (0.46), 1.381 (0.56), 1 .403 (0.92), 1 .414 (0.90), 1 .437 (0.73), 1 .448 (0.53), 1.907 (0.42), 1 .922 (1 .06), 1.953 (1 .13), 2.072 (16.00), 2.322 (0.50), 2.327 (0.76), 2.332 (0.62), 2.336 (0.46), 2.352 (3.57), 2.518 (2.13), 2.523 (1 .47), 2.539 (0.78), 2.669 (0.53), 2.824 (0.73), 2.852 (1.29), 2.857 (1 .33), 2.884 (0.74), 2.888 (0.77), 3.034 (0.56), 3.048 (0.85), 3.057 (0.95), 3.076 (1.17), 3.086 (2.25), 3.102 (0.53), 3.1 12 (1 .45), 3.127 (0.95), 3.150 (0.52), 3.157 (0.66), 3.185 (1.10), 3.218 (0.70), 3.224 (0.57), 3.351 (0.92), 3.365 (0.42), 3.503 (2.71 ), 3.528 (1 .93), 3.554 (0.90), 3.592 (10.80), 3.634 (0.71 ), 3.639 (0.71 ), 4.378 (0.88), 4.410 (0.84), 6.928 (1 .62), 6.948 (3.50), 6.966 (2.15), 6.982 (0.48),
7.061 (0.81 ), 7.067 (1 .02), 7.081 (1.36), 7.088 (2.06), 7.102 (0.80), 7.109 (1 .01 ), 7.121 (1 .79), 7.128 (1 .50), 7.147 (2.00), 7.154 (2.39), 7.161 (3.43), 7.180 (2.84), 7.208 (0.48), 7.217 (1 .23),
7.220 (1 .64), 7.238 (2.76), 7.250 (1.65), 7.254 (1 .38), 7.257 (1.64), 7.260 (1 .26), 7.265 (1 .75),
7.272 (1 .43), 7.287 (1 .24), 7.349 (0.50), 7.354 (0.57), 7.364 (0.80), 7.373 (0.70), 7.447 (4.36),
7.452 (3.48), 7.465 (0.95).
Optical rotation (method OR1 ): -4.43°+/-0.49°(met hanol). Example 41
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of diastereomers)
Figure imgf000202_0001
A mixture of (rac) 2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (94.5 mg, 352 mihoI, CAS-RN: 1785123-94-5), HATU (134 mg, 352 pmol) and N,N-diisopropylethylamine (170 mI_, 960 mihoI) in DMF (2.0 ml_) was stirred for 5 min, then (rac) 5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one hydrochloride (100 mg, 320 mihoI, intermediate 14) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC (method 7) to give the title compound 65 mg (95 % purity, 37 % yield).
LC-MS (method 2): Rt = 1 .26 min; MS (ESIpos): m/z = 527 [M+H]+ Example 42. Example 43, Example 44 and Example 45
(5R)-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one
(5S)-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one
(5R)-9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one
(5S)-9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one Example 42
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 1 )
Figure imgf000203_0001
A mixture of (rac) 2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (95.1 mg, 354 pmol, CAS-RN: 1785123-94-5), FIATU (134 mg, 352 pmol) and N,N-diisopropylethylamine (168 pl_, 965 pmol) in DMF (2.0 mL) was stirred for 5 min, then 5-(2-methoxyphenyl)-1 -oxa- 3,9-diazaspiro[5.5]undecan-2-one hydrochloride (1 17 mg, 322 pmol, intermediate 15, single stereoisomer 1 ) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative FIPLC to give the title compound 57 mg (95 % purity, 29 % yield).
Preparative chiral FIPLC method: Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IG 5pm 250x30mm; Eluent A: C02, Eluent B: ethanol; Isocratic: 33%B; Flux 100.0 ml/min Temperature: 4013; BPR: 150bar; MWD @ 220nm.
Analytical chiral HPLC method: Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Chiralpak IG 5pm 100x4.6mm; Eluent A: C02, Eluent B: ethanol; Isocratic: 33%B; Flux 4.0 ml/min; Temperature: 37.5Ό; BPR: 100bar; MWD @ 220 nm. Analytical Chiral HPLC: Rt = 1 .04 min, e.e. >99%.
1 H-NMR (500 MHz, DMSO-d6) d [ppm]: 1 .720 (0.16), 2.269 (0.22), 2.273 (0.16), 2.426 (1 .12), 2.429 (0.70), 2.543 (0.22), 2.982 (16.00), 3.073 (0.21 ), 3.284 (0.31 ), 3.302 (0.32), 3.440 (0.18),
4.799 (0.18), 4.918 (0.20), 5.01 1 (0.19), 5.031 (0.26), 6.882 (0.23), 6.900 (0.24), 6.916 (0.35),
6.931 (0.27), 7.043 (0.40), 7.057 (0.39), 7.098 (0.59), 7.1 13 (0.52), 7.125 (0.43), 7.128 (0.43),
7.140 (0.36), 7.143 (0.37), 7.159 (0.30), 7.217 (0.47), 7.231 (0.60), 7.247 (0.33), 7.260 (0.46),
7.275 (0.47), 7.302 (0.99), 7.316 (1.05), 7.330 (0.62), 7.339 (1.00).
Optical rotation (method OR1 ): -21 .7°+/-0.27°(met hanol).
Example 43
9-[(2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 2)
Figure imgf000204_0001
For the preparation of the title compound as a mixture of stereoisomers and separation of the stereoisomers see Example 42. Obtained: 54.0 mg (95 % purity, 28 % yield).
Analytical Chiral FIPLC (method see Example 42): Rt = 1.59 min, e.e. >99%.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.365 (0.17), 0.387 (0.27), 0.398 (0.26), 0.420 (0.18), 1 .035 (0.25), 1 .069 (0.24), 1 .230 (0.20), 1 .252 (0.30), 1.264 (0.28), 1 .286 (0.18), 1.712 (0.19),
1 .917 (0.29), 1 .947 (0.26), 2.518 (0.95), 2.523 (0.67), 2.938 (0.22), 2.965 (0.38), 2.971 (0.37),
2.998 (0.21 ), 3.1 10 (0.20), 3.139 (0.34), 3.171 (0.21 ), 3.285 (0.33), 3.329 (16.00), 3.370 (0.19),
3.418 (0.27), 3.435 (0.35), 3.454 (1.08), 3.736 (3.63), 3.789 (2.52), 4.327 (0.27), 4.359 (0.25),
6.922 (1 .27), 6.937 (0.81 ), 6.955 (0.24), 6.982 (0.86), 7.002 (0.92), 7.022 (0.26), 7.041 (0.31 ),
7.1 14 (0.43), 7.133 (0.53), 7.207 (0.24), 7.21 1 (0.28), 7.226 (0.22), 7.230 (0.22), 7.254 (0.71 ),
7.260 (0.52), 7.274 (1 .55), 7.281 (0.69), 7.287 (0.53), 7.294 (0.80), 7.303 (0.34), 7.398 (0.93),
7.419 (0.44), 7.436 (0.86), 7.494 (0.20), 7.514 (0.46), 7.533 (0.32), 7.551 (0.25), 7.554 (0.32),
7.559 (0.25), 7.580 (0.64), 7.583 (0.69), 7.586 (0.61 ), 7.588 (0.56), 7.601 (0.54), 7.603 (0.54),
7.606 (0.53), 7.608 (0.47).
Optical rotation (method OR1 ): -46.5°+/-0.44°(met hanol). Example 44
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 3)
Figure imgf000205_0001
A mixture of (rac) 2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (94.5 mg, 352 mihoI, CAS-RN: 1785123-94-5), HATU (134 mg, 352 pmol) and N,N-diisopropylethylamine (168 mI_, 965 mihoI) in DMF (2.0 mL) was stirred for 5 min, then 5-(2-methoxyphenyl)-1 -oxa- 3,9-diazaspiro[5.5]undecan-2-one hydrochloride (1 15 mg, 320 mihoI, intermediate 16, single stereoisomer 2) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC to give the title compound 42 mg (95 % purity, 29 % yield).
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; Column: Reprosil NR 8pm 250x30mm; Eluent A: C02, Eluent B: Ethanol; Isocratic: 38%B; Flux 100.0 ml/min Temperature: 40Ό; BPR: 150bar; MWD @ 220nm.
Analytical chiral HPLC method: Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Reprosil NR 5pm 100x4.6mm; Eluent A: CO2, Eluent B: ethanol; Isocratic: 38%B; Flux 4.0 ml/min; Temperature: 37.5Ό; BPR: 100bar; MWD @ 220 nm.
Analytical Chiral HPLC: Rt = 1 .29 min, e.e. >99%.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.353 (0.58), 0.365 (0.73), 0.387 (1 .19), 0.398 (1 .15), 0.421 (0.81 ), 0.432 (0.62), 0.798 (1.23), 0.803 (0.58), 0.815 (1.38), 0.822 (1 .42), 0.840 (0.73),
0.877 (0.42), 0.886 (0.73), 0.905 (1.54), 0.922 (0.69), 1.036 (1.12), 1 .068 (1 .50), 1.154 (0.42),
1 .205 (2.27), 1 .219 (0.69), 1 .230 (0.96), 1 .252 (1 .46), 1.264 (1.27), 1 .286 (0.88), 1.298 (0.69),
1 .479 (0.42), 1 .497 (0.46), 1 .518 (0.46), 1 .681 (0.54), 1.71 1 (0.85), 1 .917 (1 .31 ), 1.947 (1 .19),
2.075 (0.58), 2.202 (1 .12), 2.318 (0.69), 2.518 (8.12), 2.523 (5.85), 2.660 (0.69), 2.881 (0.54),
2.938 (0.96), 2.965 (1 .69), 2.971 (1.65), 2.998 (0.92), 3.1 10 (0.88), 3.140 (1 .54), 3.171 (0.96),
3.285 (1 .50), 3.368 (0.88), 3.385 (0.81 ), 3.418 (1 .23), 3.434 (1.58), 3.454 (4.81 ), 3.502 (0.50),
3.596 (14.96), 3.621 (1.23), 3.644 (0.65), 3.737 (16.00), 3.790 (10.73), 4.225 (0.46), 4.260 (0.38), 4.326 (1 .19), 4.359 (1 .12), 6.907 (0.81 ), 6.922 (5.58), 6.937 (3.65), 6.955 (1.12), 6.982
(3.77), 7.003 (4.04), 7.022 (1 .23), 7.041 (1 .35), 7.1 13 (1.88), 7.133 (2.38), 7.207 (1.04), 7.210
(1 .23), 7.226 (0.96), 7.230 (1 .00), 7.254 (3.12), 7.260 (2.38), 7.274 (6.77), 7.282 (3.08), 7.287
(2.38), 7.294 (3.50), 7.303 (1 .54), 7.397 (4.15), 7.419 (2.00), 7.436 (3.96), 7.494 (0.88), 7.514 (1 .96), 7.533 (1 .42), 7.552 (1 .15), 7.555 (1 .42), 7.560 (1.12), 7.572 (0.62), 7.581 (2.81 ), 7.583
(2.96), 7.586 (2.65), 7.589 (2.58), 7.601 (2.27), 7.603 (2.46), 7.606 (2.46), 7.608 (2.15), 1 1 .737 (0.42).
Optical rotation (method OR1 ): 41.3°+/-0.53°(meth anol).
Example 45
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 4)
Figure imgf000206_0001
For the preparation of the title compound as a mixture of stereoisomers and separation of the stereoisomers see Example 44. Obtained: 34.0 mg (95 % purity, 23 % yield).
Analytical Chiral FIPLC (method see Example 44): Rt = 1.72 min, e.e. >99%.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.068 (0.43), -0.045 (0.69), -0.034 (0.69), -0.011 (0.43), 0.854 (1 .83), 0.860 (0.77), 0.871 (1 .95), 0.878 (1.97), 0.897 (1 .00), 0.933 (0.49), 0.942
(1 .06), 0.961 (2.38), 0.979 (1 .09), 1.124 (0.63), 1 .199 (0.43), 1 .210 (1 .17), 1 .217 (1.00), 1 .246
(0.86), 1.261 (2.98), 1 .330 (0.52), 1.341 (0.54), 1 .363 (0.86), 1 .375 (0.80), 1 .397 (0.57), 1 .408 (0.52), 1.562 (0.46), 1 .892 (0.92), 1.923 (0.74), 2.258 (1.40), 2.374 (0.49), 2.450 (0.43), 2.463
(0.49), 2.469 (0.60), 2.574 (5.92), 2.579 (4.21 ), 2.716 (0.52), 2.888 (0.63), 2.915 (1.12), 2.921
(1 .12), 2.947 (0.60), 3.076 (0.49), 3.085 (0.63), 3.090 (0.72), 3.099 (0.74), 3.106 (0.77), 3.1 15
(0.72), 3.120 (0.69), 3.128 (0.57), 3.251 (0.57), 3.279 (0.97), 3.312 (0.63), 3.428 (0.77), 3.443
(0.86), 3.530 (1 .97), 3.595 (0.49), 3.655 (10.13), 3.674 (0.97), 3.700 (16.00), 3.854 (4.69), 4.399 (0.83), 4.433 (0.72), 4.443 (0.72), 6.755 (0.83), 6.776 (1.80), 6.795 (1 .06), 6.922 (1 .37),
6.942 (1 .09), 6.966 (0.54), 7.015 (0.94), 7.033 (2.00), 7.051 (1.17), 7.070 (0.52), 7.089 (0.60),
7.1 19 (2.09), 7.122 (2.20), 7.140 (2.55), 7.237 (1 .37), 7.247 (0.94), 7.255 (1 .17), 7.317 (0.74),
7.335 (0.66), 7.402 (1 .29), 7.406 (1.29), 7.423 (1 .83), 7.441 (1.06), 7.445 (1 .03), 7.464 (3.18), 7.469 (2.83), 7.493 (3.21 ), 7.498 (2.81 ), 7.533 (0.40), 7.553 (0.89), 7.572 (0.60), 7.592 (0.49), 7.595 (0.60), 7.597 (0.54), 7.600 (0.49), 1 1.793 (0.52).
Optical rotation (method OR1 ): 20.0°+/-0.72°(meth anol).
Example 46
5-[2-(benzyloxy)phenyl]-9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000207_0001
A mixture of (rac) 2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (75.7 mg, 282 mihoI, CAS-RN: 1785123-94-5), HATU (107 mg, 282 pmol) and N,N-diisopropylethylamine (130 mI_, 770 mihoI) in DMF (1 .6 ml_) was stirred for 5 min, then (rac) 5-[2-(benzyloxy)phenyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one hydrochloride (120 mg, 256 mihoI, intermediate 22) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC (method 7) to give the title compound 87mg (95 % purity, 54 % yield).
LC-MS (method 2): Rt = 1 .40 min; MS (ESIpos): m/z = 603 [M+H]+
Example 47. Example 48, Example 49 and Example 50
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one Example 47
5-[2-(benzyloxy)phenyl]-9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 1)
Figure imgf000208_0001
For the preparation of the diasteromeric mixture, see Example 46. Separation of the there described mixture yielded the title compound 11 mg (95 % purity, 14 % yield).
Preparative chiral FIPLC method: Instrument: Labomatic FID5000, Labocord-5000; Gilson GX- 241, Labcol Vario 4000, Column: Chiralpak IG 5m 250x30mm; Eluent A: hexane + 0.1 Vol-% diethylamine (99%); Eluent B: ethanol; Gradient: 20 - 50% B in 20 min; Flux 40.0 ml/min; UV 280 nm.
Analytical chiral FIPLC method: Instrument: Agilent FIPLC 1260; Column: Chiralpak IG 3m 100x4, 6mm; Eluent A: hexane + 0.1 Vol-% diethylamine (99%); Eluent B: ethanol; Gradient: 20 - 50% B in 7 min; Flux 1.4 ml/min; Temperatuer: 25 G; DAD 280 nm.
Analytical Chiral HPLC: Rt = 3.72 min, e.e. >99%.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.068 (0.58), -0.056 (0.76), -0.033 (1.17), -0.023 (1.17), 0.000 (0.76), 0.011 (0.64), 0.804 (1.23), 0.809 (0.64), 0.821 (1.40), 0.828 (1.40), 0.847
(0.82), 0.858 (0.53), 0.893 (0.70), 0.911 (1.34), 0.929 (0.76), 1.007 (1.46), 1.040 (1.46), 1.095
(0.47), 1.113 (1.11), 1.133 (0.53), 1.144 (0.53), 1.151 (0.93), 1.169 (0.53), 1.229 (0.88), 1.239
(1.93), 1.265 (0.58), 1.322 (0.70), 1.345 (1.23), 1.355 (1.23), 1.379 (0.76), 1.389 (0.64), 1.448
(0.47), 1.477 (0.47), 1.506 (0.53), 1.854 (1.40), 1.887 (1.23), 1.913 (1.23), 1.966 (0.64), 2.400
(0.47), 2.524 (16.00), 2.529 (10.74), 2.685 (1.11), 2.814 (0.93), 2.842 (1.69), 2.847 (1.69), 2.875 (0.93), 3.012 (0.76), 3.026 (1.05), 3.035 (1.17), 3.042 (1.17), 3.051 (1.11), 3.064 (0.88),
3.148 (0.82), 3.177 (1.52), 3.210 (0.93), 3.312 (3.39), 3.360 (1.69), 3.374 (1.46), 3.407 (0.76),
3.555 (1.87), 3.600 (15.07), 3.664 (0.41 ), 4.342 (1.23), 4.375 (1.17), 4.808 (1.75), 4.835 (2.28), 4.997 (2.92), 5.025 (2.22), 5.091 (0.47), 5.120 (1.11), 5.152 (1.05), 5.182 (0.47), 6.657 (1.28),
6.677 (2.74), 6.697 (1.64), 6.814 (2.10), 6.833 (1.64), 6.947 (0.76), 6.964 (0.41), 7.003 (1.34),
7.021 (2.80), 7.040 (1.64), 7.139 (0.64), 7.158 (0.82), 7.232 (4.79), 7.251 (5.43), 7.276 (0.82), 7.312 (4.03), 7.328 (5.55), 7.342 (1.58), 7.346 (1 .64), 7.353 (1.17), 7.361 (4.20), 7.379 (5.31 ), 7.382 (3.97), 7.403 (9.40), 7.418 (6.01 ), 7.422 (8.99), 7.439 (5.14), 7.442 (4.91 ), 7.478 (5.49), 7.491 (1 .81 ), 7.498 (1.28), 7.51 1 (2.45), 7.534 (2.57), 7.552 (0.53).
Example 48
5-[2-(benzyloxy)phenyl]-9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 2)
Figure imgf000209_0001
For the preparation of the diasteromeric mixture, see Example 46. Separation of the there described mixture with the FIPLC conditions described for Example 47 yielded a mixed fraction (Rt = 4.15-4.35 min) that was separated using the following FIPLC conditions to yield the title compound 10.8 mg (95 % purity, 14 % yield).
Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000, Column: Chiralpak IA 5m 250x30mm; Eluent A: methyl-tert-butylether + 0.1 Vol-% diethylamine (99%); Eluent B: acetonitrile; isocratic 50% A + 50% B; Flux 40.0 ml/min; UV 280 nm.
Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; Column: Chiralpak IA 3m 100x4,6 mm; Eluent A: methyl-tert-butylether + 0.1 Vol-% diethylamine (99%); Eluent B: acetonitrile; isocratic 50% A + 50% B; Flux 1 .4 ml/min; Temperature: 25 Ό; DAD 280 nm.
Analytical Chiral HPLC: Rt = 3.14 min, e.e. >99%.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.068 (0.62), -0.056 (0.74), -0.033 (0.86), -0.021 (0.79), 0.000 (0.47), 0.858 (0.50), 1.007 (0.86), 1 .037 (0.81 ), 1 .073 (0.48), 1 .161 (4.75), 1 .179
(9.56), 1.196 (4.88), 1 .207 (7.80), 1.239 (2.19), 1 .322 (0.45), 1 .344 (0.72), 1 .356 (0.67), 1 .379
(0.45), 1 .853 (0.79), 1.890 (0.69), 1 .994 (16.00), 2.524 (3.69), 2.530 (2.52), 2.816 (0.55), 2.842 (0.95), 2.876 (0.54), 3.013 (0.41 ), 3.026 (0.59), 3.036 (0.66), 3.042 (0.66), 3.052 (0.64), 3.064
(0.48), 3.148 (0.47), 3.177 (0.86), 3.210 (0.52), 3.312 (1.59), 3.362 (0.86), 3.374 (0.74), 3.409
(0.41 ), 3.555 (1 .04), 3.600 (8.53), 3.619 (1 .05), 3.633 (0.43), 4.006 (1 .19), 4.024 (3.64), 4.042
(3.66), 4.059 (1 .21 ), 4.071 (0.40), 4.078 (0.41 ), 4.343 (0.67), 4.377 (0.66), 4.809 (0.98), 4.836
(1 .29), 4.997 (1 .66), 5.025 (1 .28), 5.120 (0.60), 5.153 (0.64), 6.657 (0.72), 6.677 (1.62), 6.697 (0.93), 6.814 (1 .19), 6.834 (0.93), 6.946 (0.41 ), 7.003 (0.72), 7.022 (1 .55), 7.040 (0.91 ), 7.159
(0.47), 7.232 (2.68), 7.251 (3.09), 7.277 (0.45), 7.312 (2.26), 7.329 (3.1 1 ), 7.342 (0.85), 7.346
(0.90), 7.354 (0.62), 7.361 (2.38), 7.379 (3.00), 7.382 (2.16), 7.403 (5.47), 7.418 (3.45), 7.422
(5.09), 7.439 (2.80), 7.442 (2.80), 7.478 (3.14), 7.491 (1.05), 7.499 (0.72), 7.512 (1.42), 7.534
(1 .47).
Example 49
5-[2-(benzyloxy)phenyl]-9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 3)
Figure imgf000210_0001
For the preparation of the diasteromeric mixture, see Example 46. Separation of the there described mixture with the FIPLC conditions described for Example 47 yielded a mixed fraction (Rt = 4.15-4.35 min) that was separated using the following FIPLC conditions to yield the title compound 9.40 mg (95 % purity, 12 % yield).
Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000, Column: Chiralpak IA 5m 250x30mm; Eluent A: methyl-tert-butylether + 0.1 Vol-% diethylamine (99%); Eluent B: acetonitrile; isocratic 50% A + 50% B; Flux 40.0 ml/min; UV 280 nm.
Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; Column: Chiralpak IA 3m 100x4,6 mm; Eluent A: methyl-tert-butylether + 0.1 Vol-% diethylamine (99%); Eluent B: acetonitrile; isocratic 50% A + 50% B; Flux 1 .4 ml/min; Temperature: 25 Ό; DAD 280 nm.
Analytical Chiral HPLC: Rt = 4.07 min, e.e. >99%.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.397 (0.61 ), 0.430 (1 .03), 0.452 (0.61 ), 0.852 (0.70),
1 .187 (0.98), 1 .209 (1 .50), 1 .233 (4.40), 1 .255 (2.39), 1.289 (1.36), 1 .440 (0.61 ), 1.484 (0.61 ),
1 .520 (0.61 ), 1 .552 (0.70), 1 .640 (1 .03), 1.780 (1 .40), 1 .81 1 (1 .22), 2.518 (1 1 .93), 2.523 (7.91 ), 2.838 (0.42), 2.865 (0.70), 2.895 (0.42), 2.928 (0.89), 2.962 (1.54), 2.989 (0.89), 3.124 (1 .64), 3.154 (1 .50), 3.186 (0.94), 3.360 (6.74), 3.404 (1 .92), 3.539 (0.98), 3.595 (13.80), 3.618 (2.1 1 ), 3.651 (1 .03), 4.174 (0.56), 4.206 (0.56), 4.288 (1 .08), 4.321 (1.08), 5.069 (0.80), 5.100 (1 .73),
5.136 (4.40), 5.150 (3.23), 5.179 (0.75), 5.758 (16.00), 6.894 (1 .31 ), 6.939 (0.84), 6.958 (3.51 ), 6.976 (4.16), 6.993 (2.39), 7.009 (2.62), 7.046 (1.64), 7.067 (2.43), 7.086 (1.12), 7.121 (2.81), 7.142 (4.68), 7.161 (1.82), 7.228 (1.78), 7.248 (1.54), 7.253 (1.36), 7.272 (2.11), 7.288 (3.13), 7.292 (2.99), 7.309 (2.99), 7.326 (2.67), 7.344 (2.90), 7.352 (4.87), 7.370 (4.87), 7.392 (6.46), 7.411 (4.02), 7.429 (6.32), 7.445 (8.98), 7.457 (4.73), 7.462 (4.49), 7.493 (1.36), 7.513 (3.27), 7.524 (2.06), 7.532 (2.57), 7.542 (1.87), 7.553 (1.92), 7.556 (2.06), 7.561 (1.59), 7.573 (0.84), 7.578 (0.94).
Example 50
5-[2-(benzyloxy)phenyl]-9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 4)
Figure imgf000211_0001
For the preparation of the diasteromeric mixture, see Example 46. Separation of the there described mixture yielded the title compound 10.0 mg (95 % purity, 13 % yield).
Preparative chiral FIPLC method: Instrument: Labomatic FID5000, Labocord-5000; Gilson GX- 241, Labcol Vario 4000, Column: Chiralpak IG 5m 250x30mm; Eluent A: hexane + 0.1 Vol-% diethylamine (99%); Eluent B: ethanol; Gradient: 20 - 50% B in 20 min; Flux 40.0 ml/min; UV 280 nm.
Analytical chiral FIPLC method: Instrument: Agilent FIPLC 1260; Column: Chiralpak IG 3m 100x4, 6mm; Eluent A: hexane + 0.1 Vol-% diethylamine (99%); Eluent B: ethanol; Gradient: 20 - 50% B in 7 min; Flux 1.4 ml/min; Temperatuer: 25 G; DAD 280 nm.
Analytical Chiral HPLC: Rt = 7.02 min, e.e. >99%.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.396 (0.71), 0.419 (1.18), 0.429 (1.18), 0.451 (0.76), 0.798 (2.03), 0.803 (1.13), 0.814 (2.31), 0.821 (2.41), 0.840 (1.46), 0.851 (0.85), 0.877 (0.52),
0.886 (1.09), 0.904 (2.12), 0.923 (1.04), 0.974 (0.42), 0.991 (0.66), 1.009 (0.42), 1.068 (0.76),
1.088 (0.80), 1.107 (1.09), 1.134 (1.65), 1.152 (3.35), 1.170 (2.08), 1.186 (1.09), 1.209 (1.84),
1.222 (3.07), 1.232 (4.01), 1.255 (3.16), 1.288 (1.65), 1.334 (0.71), 1.353 (0.71), 1.403 (0.52),
1.439 (0.76), 1.469 (0.66), 1.483 (0.71), 1.520 (0.76), 1.552 (0.66), 1.641 (1.23), 1.677 (0.85),
1.780 (1.75), 1.815 (1.56), 1.907 (0.99), 1.959 (1.09), 2.373 (0.42), 2.388 (0.42), 2.394 (0.47),
2.407 (0.57), 2.413 (0.61), 2.460 (1.79), 2.465 (2.27), 2.517 (13.97), 2.522 (8.97), 2.533 (2.22), 2.537 (1 .84), 2.542 (1 .32), 2.839 (0.52), 2.865 (0.85), 2.895 (0.80), 2.913 (1 .09), 2.931 (1 .65),
2.956 (1 .89), 2.988 (0.99), 3.124 (1.94), 3.155 (1 .84), 3.186 (1.09), 3.359 (8.07), 3.405 (2.31 ),
3.535 (1 .23), 3.595 (16.00), 3.617 (2.55), 3.654 (1 .32), 4.172 (0.66), 4.207 (0.66), 4.288 (1 .32), 4.320 (1 .23), 5.071 (0.94), 5.104 (2.12), 5.136 (5.14), 5.150 (3.63), 5.180 (0.85), 6.894 (1 .60),
6.939 (1 .04), 6.957 (4.01 ), 6.976 (4.86), 6.993 (2.64), 7.008 (3.07), 7.047 (1 .94), 7.067 (2.78),
7.086 (1 .23), 7.121 (3.26), 7.141 (5.33), 7.162 (2.08), 7.228 (1.94), 7.248 (1 .75), 7.253 (1 .46),
7.272 (2.45), 7.287 (3.59), 7.308 (3.45), 7.327 (3.02), 7.344 (3.30), 7.352 (5.47), 7.370 (5.52),
7.393 (7.13), 7.41 1 (5.10), 7.429 (7.46), 7.445 (10.53), 7.457 (5.38), 7.462 (5.05), 7.493 (1 .56), 7.513 (3.45), 7.522 (2.45), 7.533 (2.88), 7.542 (2.22), 7.555 (2.27), 7.578 (0.99).
Example 51
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of diastereomers)
Figure imgf000212_0001
A mixture of (rac) 2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (107 mg, 352 pmol), FIATU (134 mg, 352 pmol) and N,N-diisopropylethylamine (170 mI_, 960 mihoI) in DMF (2.0 ml_) was stirred for 5 min, then (rac) 5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one hydrochloride (100 mg, 320 mihoI, intermediate 14) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via silica gel chromatography using mixtures of hexanes/ethyl acetate of increasing polarity to give the title compound as a mixture of diastereomers 42 mg (90 % purity, 21 % yield).
LC-MS (method 2): Rt = 1 .41 min; MS (ESIpos): m/z = 561 [M+FI]+ Example 52. Example 53, Example 54 and Example 55
(5R)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-
1 -oxa-3,9-diazaspiro[5.5]undecan-2-one
(5R)-9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-
1 -oxa-3,9-diazaspiro[5.5]undecan-2-one
(5S)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-
1 -oxa-3,9-diazaspiro[5.5]undecan-2-one
(5S)-9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one
Example 52
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 1 )
Figure imgf000213_0001
A mixture of (rac) 2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (107 mg, 352 pmol), FIATU (134 mg, 352 pmol) and N,N-diisopropylethylamine (170 mI_, 960 mmol) in DMF (2.0 mL) was stirred for 5 min, then 5-(2-methoxyphenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2- one hydrochloride (100 mg, 320 mihoI, intermediate 15, single stereoisomer 1 ) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. Purification by silica gel chromatography using DCM/ethanol as solvent system followed by chiral FIPLC yielded the title compound 37.0 mg (95 % purity, 23 % yield).
Preparative chiral FIPLC method: Instrument: Sepiatec: Prep SFC100; Column: Reprosil NR 8pm 250x30mm; Eluent A: C02, Eluent B: ethanol; isocratic: 33%B; Flux 100.0 ml/min Temperature: 40Ό; BPR: 150bar; MWD @ 220nm
Analytical chiral HPLC method: Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Reprosil NR 5pm 100x4.6mm; Eluent A: C02, Eluent B: ethanol; isocratic: 33%B; Flux 4.0 ml/min; Temperature: 37.5Ό; BPR: 100bar; MWD @ 220 nm. Analytical Chiral HPLC: Rt = 1.33 min, e.e. >99%.
1H-NMR (400 MHz, DMS0-d6) d [ppm]: 0.034 (0.58), 0.045 (0.56), 1.133 (0.58), 1.159 (1.11), 1.175 (1.11), 1.185 (0.96), 1.209 (0.55), 1.220 (0.45), 1.327 (0.71), 1.357 (0.68), 1.462 (0.51),
1.690 (0.60), 1.724 (0.51), 2.446 (3.44), 2.451 (2.57), 2.798 (0.46), 2.825 (0.83), 2.831 (0.81), 2.858 (0.61), 3.056 (0.50), 3.063 (0.53), 3.071 (0.55), 3.078 (0.53), 3.085 (0.50), 3.092 (0.43),
3.184 (0.45), 3.215 (0.80), 3.234 (0.40), 3.304 (0.80), 3.339 (0.56), 3.405 (2.74), 3.435 (0.50),
3.546 (6.97), 3.574 (0.70), 3.609 (16.00), 3.727 (5.76), 4.238 (0.58), 4.270 (0.55), 6.824 (0.45), 6.831 (0.80), 6.843 (0.91), 6.849 (1.63), 6.861 (0.56), 6.866 (0.93), 6.917 (1.64), 6.920 (1.73),
6.938 (2.09), 6.941 (2.21), 6.963 (0.71), 7.076 (1.23), 7.092 (1.03), 7.124 (0.60), 7.127 (0.68), 7.153 (3.59), 7.171 (0.55), 7.175 (0.45), 7.192 (0.55), 7.213 (1.24), 7.217 (1.06), 7.235 (1.66),
7.240 (1.99), 7.244 (1.84), 7.251 (0.96), 7.255 (0.78), 7.391 (2.11), 7.616 (2.14), 7.714 (0.95),
7.719(1.69), 7.724 (0.88).
Optical rotation (method OR1): -33.1°+/-0.24°(met hanol).
Example 53
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 2)
Figure imgf000214_0001
For the preparation of the title compound as a mixture of stereoisomers and separation of the stereoisomers see Example 52. Obtained: 50.0 mg (95 % purity, 31 % yield).
Analytical Chiral HPLC: Rt = 1.64 min, e.e. >99%.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.413 (0.63), 0.425 (0.79), 0.447 (1.25), 0.458 (1.21), 0.481 (0.83), 0.492 (0.67), 1.130 (1.08), 1.164 (0.96), 1.205 (0.83), 1.236 (0.92), 1.258 (1.25),
1.269 (1.25), 1.292 (0.75), 1.491 (0.71), 1.502 (0.46), 1.511 (0.50), 1.523 (0.79), 1.557 (0.42),
1.692 (0.67), 1.728 (0.46), 1.761 (0.63), 1.792 (0.50), 1.963 (1.29), 1.997 (1.12), 2.336 (0.75), 2.454 (0.71), 2.459 (0.92), 2.464 (1.04), 2.518 (8.46), 2.523 (6.29), 2.539 (0.63), 2.564 (0.67),
2.678 (0.71), 2.888 (0.67), 2.919 (0.42), 2.968 (1.00), 2.995 (1.79), 3.001 (1.75), 3.027 (1.00),
3.145 (0.96), 3.174 (1.67), 3.206 (1.04), 3.288 (0.67), 3.368 (1.21), 3.377 (1.21), 3.450 (6.08),
3.506 (0.63), 3.579 (2.08), 3.604 (15.71), 3.734 (16.00), 3.793 (14.38), 4.234 (0.54), 4.268 (0.50), 4.327 (1 .25), 4.360 (1 .17), 6.876 (1 .58), 6.879 (1.71 ), 6.897 (3.71 ), 6.916 (3.25), 6.937
(1 .63), 6.956 (1 .00), 6.974 (4.04), 6.988 (3.08), 6.993 (5.04), 7.003 (2.04), 7.024 (1.58), 7.043
(1 .83), 7.214 (1 .37), 7.218 (1 .63), 7.233 (3.33), 7.237 (3.17), 7.254 (3.96), 7.273 (3.92), 7.282
(8.75), 7.326 (4.42), 7.330 (4.29), 7.466 (4.00), 7.804 (2.42), 7.808 (4.29), 7.813 (2.25), 7.839
(5.25), 7.844 (10.58), 7.848 (4.83).
Optical rotation (method OR1 ): -7.4°+/-0.20°(meth anol).
Example 54
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 3)
Figure imgf000215_0001
A mixture of (rac) 2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (106 mg, 352 pmol), HATU (134 mg, 352 pmol) and N,N-diisopropylethylamine (167 mI_, 960 mmol) in DMF (2.0 mL) was stirred for 5 min, then 5-(2-methoxyphenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2- one hydrochloride (1 15 mg, 320 mihoI, intermediate 16, single stereoisomer 2) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. Purification by silica gel chromatography using DCM/ethanol as solvent system followed by chiral HPLC yielded the title compound 50.0 mg (95 % purity, 30 % yield).
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; Column: Reprosil NR 8pm 250x30mm; Eluent A: C02, Eluent B: Ethanol; isocratic: 30%B; Flux 100.0 ml/min Temperature: 400; BPR: 150bar; MWD @ 220nm
Analytical chiral HPLC method: Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Reprosil NR 5pm 100x4.6mm; Eluent A: C02, Eluent B: Ethanol; isocratic: 30%B; Flux 4.0 ml/min; Temperature: 37.50; BPR: 100bar; MWD @ 220 nm.
Analytical Chiral HPLC: Rt = 1 .66 min, e.e. >99%.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.412 (0.49), 0.424 (0.66), 0.447 (1 .07), 0.457 (1 .07), 0.480 (0.74), 0.491 (0.57), 0.798 (0.41 ), 0.814 (0.49), 0.821 (0.49), 0.904 (0.49), 1.129 (1 .07), 1.161 (0.98), 1.205 (0.49), 1.237 (1.31), 1.256 (1.39), 1.269 (1.31), 1.292 (0.74), 1.489 (0.66),
1.522 (0.74), 1.557 (0.41), 1.690 (0.57), 1.727 (0.41), 1.758 (0.57), 1.792 (0.49), 1.960 (1.15),
1.996 (1.07), 2.327 (3.53), 2.331 (2.54), 2.518 (16.00), 2.522 (10.01), 2.563 (0.74), 2.597 (0.41), 2.669 (3.61), 2.673 (2.63), 2.886 (0.57), 2.967 (0.90), 2.994 (1.56), 3.000 (1.56), 3.027 (0.82), 3.145 (0.90), 3.175 (1.48), 3.206 (0.90), 3.450 (5.33), 3.507 (0.57), 3.580 (1.81), 3.603
(13.70), 3.733 (13.37), 3.792 (10.75), 4.235 (0.49), 4.267 (0.41), 4.328 (1.15), 4.360 (1.07), 6.879 (1.31), 6.896 (3.12), 6.916 (2.63), 6.937 (1.31), 6.954 (0.82), 6.974 (3.28), 6.987 (2.63),
6.993 (4.27), 7.003 (1.81), 7.024 (1.31), 7.043 (1.56), 7.217 (1.31), 7.233 (2.63), 7.237 (2.46),
7.254 (3.28), 7.281 (7.71), 7.326 (3.77), 7.330 (3.61), 7.466 (3.53), 7.804 (1.56), 7.809 (2.79), 7.814 (1.48), 7.840 (3.77), 7.844 (6.81), 7.849 (3.45).
Optical rotation (method OR1): 8.0°+/-0.34°(metha nol).
Example 55
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (single stgereoisomer 4)
Figure imgf000216_0001
For the preparation of the title compound as a mixture of stereoisomers and separation of the stereoisomers see Example 54. Obtained: 40.0 mg (95 % purity, 24 % yield).
Analytical Chiral FIPLC: Rt = 2.32 min, e.e. >99%.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.012 (0.40), 0.034 (0.62), 0.045 (0.62), 0.068 (0.40), 0.727 (1.94), 0.732 (0.90), 0.743 (2.11), 0.750 (2.17), 0.769 (1.10), 0.815 (1.08), 0.833 (2.22),
0.851 (1.08), 1.066 (0.64), 1.133 (0.61), 1.152 (0.61), 1.175 (0.77), 1.185 (0.95), 1.209 (0.48),
1.221 (0.40), 1.326 (0.75), 1.363 (0.73), 1.463 (0.55), 1.692 (0.66), 1.727 (0.68), 2.261 (0.77),
2.317 (0.40), 2.322 (0.42), 2.336 (0.42), 2.341 (0.57), 2.447 (4.75), 2.451 (3.05), 2.603 (0.79), 2.798 (0.51), 2.825 (0.90), 2.831 (0.90), 2.858 (0.68), 3.056 (0.57), 3.063 (0.59), 3.071 (0.61),
3.079 (0.61), 3.184 (0.48), 3.214 (0.86), 3.313 (0.88), 3.405 (2.99), 3.435 (0.55), 3.547 (7.54),
3.575 (0.73), 3.610 (16.00), 3.728 (5.82), 4.237 (0.62), 4.270 (0.59), 6.831 (0.83), 6.850 (1.74), 6.862 (0.61), 6.867 (1.01), 6.920 (1.78), 6.942 (2.33), 6.964 (0.77), 7.077 (1.32), 7.093 (1.12), 7.128 (0.73), 7.153 (3.89), 7.172 (0.57), 7.175 (0.48), 7.192 (0.61 ), 7.213 (1 .25), 7.217 (1 .08), 7.241 (2.15), 7.245 (1 .98), 7.252 (0.97), 7.256 (0.81 ), 7.392 (2.29), 7.617 (2.24), 7.715 (0.83), 7.720 (1 .50), 7.725 (0.79).
Optical rotation (method OR1 ): 41.1 °+/-0.26°(meth anol). Example 56
5-[2-(benzyloxy)phenyl]-9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 -oxa- 3,9-diazaspiro[5.5]undecan-2-one (mixture of diastereomers)
Figure imgf000217_0001
A mixture of (rac) 2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (85.7 mg, 283 pmol), HATU (108 mg, 283 pmol) and N,N-diisopropylethylamine (130 mI_, 770 pmol) in DMF (1 .6 mL) was stirred for 5 min, then (rac) 5-[2-(benzyloxy)phenyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one hydrochloride (100 mg, 257 pmol, intermediate 22) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The crude was purified via silica gel chromatography using mixtures of hexanes/ethyl acetate of increasing polarity to give the title compound as a mixture of diastereomers 73.0 mg (95 % purity, 42 % yield).
LC-MS (method 2): Rt = 1 .54 min; MS (ESIpos): m/z = 637 [M+H]+
Example 56, Example 57. Example 58, Example 59
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2- methoxypropanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2- methoxypropanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2- methoxypropanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2- methoxypropanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one
Example 57
5-[2-(benzyloxy)phenyl]-9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 -oxa- 3,9-diazaspiro[5.5]undecan-2-one (single stereoisomer 1 )
Figure imgf000218_0001
For the preparation of the diasteromeric mixture, see Example 56. Separation of the there described mixture yielded the title compound 12.7 mg (95 % purity, 23 % yield).
Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000, Column: Chiralpak IG 5m 250x30mm; Eluent A: hexane + 0.1 Vol-% diethylamine (99%); Eluent B: ethanol; isocratic: 70%A+30%B; Flux 50.0 ml/min; UV 220 nm
Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; Column: Chiralpak IG 3m 100x4, 6mm; Eluent A: hexane + 0.1 Vol-% diethylamine (99%); Eluent B: ethanol; isocratic: 70%A+30%B; Flux 1 .4 ml/min; Temperatuer: 25 Ό; DAD 280 nm.
Analytical Chiral HPLC: Rt = 2.29 min, e.e. >99%.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.134 (1 .10), 0.150 (0.84), 0.171 (1 .32), 0.183 (1 .32),
0.206 (0.84), 0.216 (0.66), 0.798 (1.24), 0.803 (0.66), 0.814 (1.53), 0.821 (1 .42), 0.840 (0.88),
0.851 (0.77), 0.862 (0.58), 0.886 (0.66), 0.904 (1 .21 ), 0.922 (0.62), 1 .005 (0.62), 1.034 (0.40),
1 .084 (1 .17), 1 .107 (0.51 ), 1 .137 (0.44), 1 .144 (0.55), 1.214 (1.83), 1 .233 (2.96), 1.251 (2.26), 1.259 (2.89), 1.287 (1.46), 1.297 (1.35), 1.321 (0.91), 1.443 (0.55), 1.489 (1.39), 1.526 (1.06), 1.705 (1.97), 1.855 (1.53), 1.887 (1.57), 1.906 (0.95), 1.924 (0.88), 1.960 (0.58), 2.322 (1.57), 2.326 (2.12), 2.331 (1.53), 2.443 (0.51), 2.522 (6.68), 2.539 (1.86), 2.664 (1.57), 2.668 (2.16), 2.673 (1.57), 2.856 (0.99), 2.883 (1.75), 2.889 (1.79), 2.917 (1.28), 2.952 (0.62), 2.994 (0.47), 3.058 (0.84), 3.072 (1.21), 3.081 (1.42), 3.088 (1.46), 3.101 (1.42), 3.110 (1.32), 3.205 (0.95), 3.235 (1.79), 3.267 (1.17), 3.300 (5.15), 3.406 (2.26), 3.420 (2.08), 3.563 (2.45), 3.606 (16.00), 3.658 (1.13), 4.211 (0.55), 4.245 (0.51), 4.321 (1.35), 4.355 (1.24), 4.829 (2.01), 4.857 (2.56), 5.030 (3.98), 5.059 (3.11), 5.086 (0.84), 5.117 (2.08), 5.147 (2.05), 5.177 (0.80), 5.967 (0.95), 6.597 (1.50), 6.934 (1.61), 6.952 (3.29), 6.970 (2.01), 7.053 (0.91), 7.076 (1.02), 7.126 (3.40), 7.145 (4.24), 7.211 (8.07), 7.246 (1.50), 7.251 (1.39), 7.272 (1.46), 7.295 (4.79), 7.304 (2.78), 7.319 (5.99), 7.332 (7.45), 7.348 (4.46), 7.357 (2.19), 7.362 (3.14), 7.366 (3.51), 7.387 (7.12), 7.402 (4.97), 7.406 (6.79), 7.416 (4.05), 7.423 (3.07), 7.426 (2.19), 7.434 (2.16), 7.465 (3.54), 7.473 (3.98), 7.491 (3.00), 7.590 (1.06), 7.612 (1.06), 7.627 (4.46), 7.738 (3.98), 7.775 (1.94), 7.780 (3.32), 7.784 (1.64), 7.791 (0.47), 7.796 0.44).
Optical rotation (method OR1): -53.5°+/-0.45°(met hanol).
Example 58
5-[2-(benzyloxy)phenyl]-9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1-oxa- 3,9-diazaspiro[5.5]undecan-2-one (single stereoisomer 2)
Figure imgf000219_0001
For the preparation of the diasteromeric mixture, see Example 56. Separation of the there described mixture with the FIPLC conditions described for Example 57 yielded a mixed fraction (Rt = 2.58 min) that was separated using the following HPLC conditions to yield the title compound 24.8 mg (95 % purity, 46 % yield).
Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241, Labcol Vario 4000, Column: YMC-Cellulose SB 5m 250x30mm; Eluent A: tert.- butylmethylether; Eluent B: acetonitrile; each with 0.1 Vol-% diethylamine (99%); isocratic: 60%A+40%B; Flux 45.0 ml/min; UV 225/275 nm. Analytical chiral FIPLC method: Instrument: Agilent FIPLC 1260; Column: YMC-Cellulose SB 3m 100x4, 6mm; Eluent A: tert-butylmethylether + 0.1 Vol-% diethylamine (99%); Eluent B: acetonitrile; Isocratic: 50%A+50%B; Flux 1.4 ml/min; Temperature: 25 Ό; DAD 280 nm.
Analytical Chiral FIPLC: Rt = 1.73 min, e.e. >99%.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.149 (0.48), 0.172 (0.77), 0.182 (0.73), 0.206 (0.48), 0.522 (0.48), 1.137 (1.41), 1.168 (0.69), 1.191 (0.81), 1.232 (1.93), 1.287 (0.85), 1.320 (0.52),
1.444 (0.89), 1.476 (1.17), 1.528 (0.85), 1.560 (0.40), 1.639 (0.52), 1.698 (0.48), 1.808 (0.73),
1.850 (1.05), 1.886 (0.77), 2.115 (0.52), 2.336 (0.73), 2.453 (0.56), 2.518 (9.23), 2.522 (6.17),
2.539 (4.23), 2.560 (0.48), 2.849 (0.69), 2.883 (1.33), 2.916 (0.85), 2.958 (0.60), 2.992 (0.85),
3.026 (0.44), 3.072 (0.69), 3.081 (0.81), 3.088 (0.93), 3.102 (1.05), 3.170 (0.48), 3.201 (1.21),
3.236 (1.37), 3.266 (0.64), 3.301 (2.82), 3.352 (4.55), 3.379 (1.41), 3.407 (2.18), 3.421 (2.10),
3.563 (1.81), 3.606 (16.00), 3.659 (0.93), 4.218 (0.56), 4.281 (0.56), 4.321 (1.13), 4.355 (0.69), 4.830 (1.17), 4.858 (1.49), 5.031 (2.38), 5.059 (1.89), 5.087 (0.77), 5.107 (1.33), 5.116 (1.69),
5.137 (2.78), 5.151 (2.38), 5.177 (0.73), 6.892 (0.64), 6.911 (1.61), 6.930 (1.73), 6.953 (2.42),
6.971 (1.65), 7.091 (1.57), 7.112 (2.02), 7.126 (2.02), 7.145 (3.26), 7.164 (1.33), 7.212 (4.76),
7.227 (5.12), 7.251 (2.10), 7.255 (2.42), 7.273 (1.85), 7.292 (3.06), 7.304 (1.61), 7.322 (6.17),
7.327 (6.17), 7.345 (3.39), 7.349 (4.39), 7.362 (2.86), 7.367 (3.10), 7.371 (3.43), 7.388 (5.72),
7.397 (2.26), 7.402 (3.83), 7.406 (5.92), 7.416 (4.59), 7.423 (5.04), 7.426 (5.44), 7.433 (2.98),
7.445 (3.02), 7.462 (3.39), 7.473 (2.94), 7.491 (1.81), 7.738 (2.74), 7.775 (1.09), 7.780 (1.97),
7.785 (1.09), 7.805 (1.45), 7.810 (2.74), 7.815 (1.37).
Optical rotation (method OR1): 44.5°+/-0.21°(meth anol).
Example 59
5-[2-(benzyloxy)phenyl]-9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1-oxa- 3,9-diazaspiro[5.5]undecan-2-one (single stereoisomer 3)
Figure imgf000220_0001
For the preparation of the diasteromeric mixture, see Example 56. Separation of the there described mixture yielded the title compound 13.2 mg (95 % purity, 24 % yield). Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241, Labcol Vario 4000, Column: Chiralpak IG 5m 250x30mm; Eluent A: hexane + 0.1 Vol-% diethylamine (99%); Eluent B: ethanol; isocratic: 70%A+30%B; Flux 50.0 ml/min; UV 220 nm
Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; Column: Chiralpak IG 3m 100x4, 6mm; Eluent A: hexane + 0.1 Vol-% diethylamine (99%); Eluent B: ethanol; isocratic: 70%A+30%B; Flux 1.4 ml/min; Temperatuer: 25 Ό; DAD 280 nm.
Analytical Chiral HPLC: Rt = 3.54 min, e.e. >99%.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.500 (0.62), 0.521 (1.08), 0.554 (0.69), 0.776 (0.81), 0.795 (1.92), 0.798 (2.23), 0.803 (1.23), 0.815 (2.85), 0.822 (2.62), 0.836 (1.46), 0.840 (1.73),
0.852 (1.58), 0.862 (1.31), 0.880 (0.58), 0.886 (1.12), 0.905 (2.08), 0.923 (1.12), 1.007 (1.46),
1.035 (0.92), 1.085 (2.62), 1.100 (0.42), 1.131 (0.65), 1.138 (0.73), 1.150 (1.15), 1.168 (1.31),
1.190 (1.58), 1.206 (1.92), 1.234 (5.04), 1.259 (4.27), 1.353 (0.46), 1.392 (0.62), 1.425 (1.73),
1.441 (1.92), 1.459 (1.73), 1.505 (0.88), 1.527 (1.23), 1.560 (0.88), 1.572 (0.81), 1.639 (1.35),
1.676 (0.85), 1.704 (1.42), 1.735 (0.88), 1.804 (1.77), 1.838 (1.46), 2.323 (1.65), 2.327 (2.27),
2.332 (1.69), 2.395 (0.42), 2.407 (0.46), 2.413 (0.62), 2.523 (8.15), 2.555 (1.46), 2.586 (0.73),
2.665 (1.73), 2.669 (2.31), 2.673 (1.69), 2.849 (0.65), 2.878 (1.08), 2.905 (0.73), 2.967 (1.00),
2.995 (1.73), 3.026 (1.04), 3.131 (1.15), 3.171 (1.08), 3.201 (1.81), 3.233 (1.12), 3.250 (0.65),
3.352 (9.62), 3.408 (2.31 ), 3.422 (2.35), 3.558 (1.23), 3.606 (16.00), 3.661 (1.38), 4.188 (0.88), 4.221 (0.88), 4.282 (1.23), 4.316 (1.19), 5.079 (0.81), 5.108 (2.77), 5.138 (5.92), 5.153 (4.42),
5.183 (1.08), 6.893 (1.35), 6.911 (3.38), 6.930 (2.65), 6.941 (1.50), 6.959 (3.77), 6.978 (2.38),
7.092 (3.31), 7.112 (4.15), 7.146 (2.00), 7.166 (2.58), 7.230 (9.23), 7.256 (4.23), 7.266 (3.12),
7.274 (2.73), 7.294 (1.46), 7.328 (9.23), 7.341 (4.42), 7.345 (4.69), 7.353 (5.46), 7.363 (2.81),
7.371 (5.31), 7.393 (3.92), 7.411 (8.08), 7.427 (10.15), 7.446 (6.23), 7.463 (3.85), 7.479 (2.77),
7.629 (1.08), 7.747 (3.00), 7.805 (2.73), 7.810 (4.92), 7.815 (2.73).
Example 60 and Example 61
(5R)-9-[(2S)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-
1-oxa-3,9-diazaspiro[5.5]undecan-2-one
(5R)-9-[(2R)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-
1-oxa-3,9-diazaspiro[5.5]undecan-2-one
(5S)-9-[(2S)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-
1-oxa-3,9-diazaspiro[5.5]undecan-2-one
(5S)-9-[(2R)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-
1-oxa-3,9-diazaspiro[5.5]undecan-2-one Example 60
9-[2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of two stereoisomers)
Figure imgf000222_0001
A mixture of 2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (92.2 mg, 352 mihoI, Intermediate 33, single stereoisomer 1 ), FIATU (134 mg, 352 pmol) and N,N- diisopropylethylamine (170 mI_, 960 pmol) in DMF (2.0 ml_) was stirred for 5 min, then (rac) 5- (2-methoxyphenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one hydrochloride (100 mg, 320 pmol, Intermediate 14) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative FIPLC (method 7) to give the title compound 55 mg (95 % purity, 31 % yield).
LC-MS (method 2): Rt = 1 .40 min; MS (ESIpos): m/z = 521 [M+FI]+
1 H-NMR (400 MHz, DMSO-d6) delta [ppm]: 0.11 1 (0.42), 0.419 (0.42), 0.999 (0.66), 1.016 (0.49), 1.091 (0.49), 1 .1 14 (0.49), 1.130 (0.59), 1 .201 (0.83), 1 .237 (1 .15), 1 .283 (0.77), 1 .293
(0.59), 1.486 (0.52), 1 .667 (0.42), 1.791 (0.56), 1 .825 (0.45), 1 .912 (0.63), 1 .950 (0.59), 2.042
(13.18), 2.163 (14.92), 2.271 (5.57), 2.284 (16.00), 2.305 (1 .43), 2.826 (0.52), 2.852 (0.94), 2.858 (0.94), 2.888 (0.63), 2.913 (0.52), 2.940 (0.42), 2.966 (0.66), 2.973 (0.70), 3.069 (0.80),
3.099 (0.97), 3.131 (0.42), 3.166 (0.45), 3.198 (0.83), 3.226 (0.80), 3.306 (0.66), 3.372 (1 .04),
3.412 (2.12), 3.429 (2.19), 3.433 (3.23), 3.437 (2.99), 3.501 (0.66), 3.530 (0.80), 3.561 (6.37),
3.570 (7.17), 3.636 (9.43), 3.671 (1.01 ), 3.737 (3.86), 3.789 (4.97), 3.798 (3.93), 4.355 (0.80),
4.388 (0.80), 6.850 (3.03), 6.861 (0.94), 6.883 (1 .57), 6.898 (3.76), 6.918 (0.83), 6.940 (3.76),
6.959 (2.43), 6.989 (1 .46), 7.001 (1.74), 7.010 (1 .98), 7.019 (2.40), 7.035 (0.87), 7.046 (2.19),
7.061 (1 .53), 7.072 (0.97), 7.128 (1.84), 7.176 (0.94), 7.195 (1.15), 7.204 (0.66), 7.209 (0.66),
7.214 (0.42), 7.225 (0.45), 7.228 (0.45), 7.245 (1 .01 ), 7.250 (0.87), 7.256 (0.49), 7.264 (1 .22),
7.266 (1 .32), 7.284 (0.90), 7.288 (1.46), 7.292 (1 .18), 7.309 (1.25), 7.326 (0.73), 7.331 (0.63),
7.418 (1 .25), 7.442 (2.05), 7.718 (0.49), 7.771 (0.49). Example 61
9-[2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of two stereoisomers)
Figure imgf000223_0001
A mixture of 2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (92.2 mg, 352 mihoI, Intermediate 34, single stereoisomer 2), FIATU (134 mg, 352 pmol) and N,N- diisopropylethylamine (170 mI_, 960 mmol) in DMF (2.0 ml_) was stirred for 5 min, then (rac) 5- (2-methoxyphenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one hydrochloride (100 mg, 320 mihoI, Intermediate 14) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative FIPLC (method 7) to give the title compound 64 mg (95 % purity, 37 % yield).
LC-MS (method 2): Rt = 1 .27 min; MS (ESIneg): m/z = 519 [M-H]-
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.1 1 1 (0.45), 0.430 (0.45), 0.998 (0.60), 1 .016 (0.49), 1 .090 (0.52), 1 .1 14 (0.56), 1 .128 (0.64), 1 .202 (0.90), 1.236 (1.20), 1 .282 (0.82), 1.487 (0.52), 1 .669 (0.41 ), 1 .789 (0.56), 1 .824 (0.49), 1 .914 (0.71 ), 1 .948 (0.64), 2.042 (14.02), 2.163 (16.00), 2.271 (5.91 ), 2.284 (15.89), 2.305 (1 .53), 2.336 (0.79), 2.518 (8.00), 2.523 (5.61 ), 2.605 (0.60), 2.678 (0.67), 2.826 (0.56), 2.852 (1 .01 ), 2.858 (1.01 ), 2.888 (0.71 ), 2.912 (0.86),
2.940 (0.45), 2.966 (0.71 ), 2.973 (0.71 ), 2.999 (0.41 ), 3.069 (0.86), 3.098 (1 .05), 3.132 (0.45),
3.166 (0.45), 3.197 (0.90), 3.226 (0.82), 3.305 (0.71 ), 3.375 (1.08), 3.41 1 (2.28), 3.428 (2.21 ),
3.433 (3.10), 3.437 (2.88), 3.502 (0.71 ), 3.532 (0.86), 3.561 (6.92), 3.570 (7.70), 3.636 (9.91 ),
3.672 (1 .08), 3.737 (4.19), 3.789 (5.20), 3.798 (4.15), 3.826 (0.45), 4.355 (0.86), 4.389 (0.82),
6.850 (3.25), 6.861 (1 .01 ), 6.882 (1.72), 6.898 (4.07), 6.919 (0.90), 6.940 (4.07), 6.959 (2.65),
6.989 (1 .61 ), 7.001 (1 .94), 7.010 (2.24), 7.019 (2.58), 7.035 (0.93), 7.046 (2.39), 7.059 (1 .50),
7.128 (1 .72), 7.177 (1 .01 ), 7.195 (1.23), 7.205 (0.71 ), 7.209 (0.71 ), 7.225 (0.49), 7.228 (0.49),
7.245 (1 .08), 7.250 (0.90), 7.266 (1.38), 7.288 (1 .53), 7.308 (1.31 ), 7.326 (0.75), 7.330 (0.67),
7.418 (1 .35), 7.442 (2.21 ), 7.637 (0.56), 7.719 (0.49), 7.772 (0.49). Example 62 and Example 63
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2- methoxypropanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2S)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2- methoxypropanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2- methoxypropanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2S)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2- methoxypropanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one Example 62
5-[2-(benzyloxy)phenyl]-9-[2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 -oxa- 3,9-diazaspiro[5.5]undecan-2-one (mixture of two diastereomers)
Figure imgf000224_0001
A mixture of 2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (72.4 mg, 283 pmol, Intermediate 33, single stereoisomer 1 ), HATU (108 mg, 283 pmol) and N,N- diisopropylethylamine (130 mI_, 770 pmol) in DMF (1 .6 ml_) was stirred for 5 min, then (rac) 5- [2-(benzyloxy)phenyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one hydrochloride (100 mg, 257 pmol, Inermediate 22) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC (method 7) to give the title compound 50.0 mg (95 % purity, 31 % yield).
LC-MS (method 2): Rt = 1 .40 min; MS (ESIpos): m/z = 597 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.198 (0.59), 0.209 (0.56), 1 .018 (0.72), 1 .050 (0.65),
1 .197 (0.52), 1 .209 (0.56), 1 .232 (0.43), 1 .308 (0.75), 1.342 (0.92), 1 .364 (0.49), 1.444 (0.39),
1 .475 (0.46), 1 .610 (0.72), 1 .644 (0.46), 1 .782 (0.62), 1.813 (0.56), 1 .883 (0.92), 1.915 (0.82), 1 .991 (13.42), 2.095 (16.00), 2.261 (5.69), 2.285 (9.78), 2.332 (1 .47), 2.336 (0.65), 2.518 (6.94), 2.523 (5.07), 2.673 (1 .37), 2.678 (0.59), 2.813 (0.69), 2.845 (1 .18), 2.874 (0.65), 2.922
(0.49), 2.954 (0.75), 2.993 (0.72), 3.005 (0.62), 3.015 (0.69), 3.022 (0.69), 3.036 (0.72), 3.045
(0.72), 3.083 (0.79), 3.109 (0.82), 3.134 (0.92), 3.165 (0.49), 3.263 (1 .44), 3.306 (0.56), 3.360 (0.95), 3.375 (0.88), 3.431 (0.92), 3.562 (13.71 ), 3.596 (1 .70), 3.677 (0.56), 3.708 (0.39), 4.316
(0.46), 4.348 (0.46), 4.379 (0.65), 4.41 1 (0.59), 4.716 (1.05), 4.744 (1 .24), 5.017 (1.70), 5.045
(1 .47), 5.080 (0.59), 5.109 (1 .31 ), 5.134 (2.03), 5.147 (2.19), 5.177 (0.65), 6.844 (3.24), 6.860
(3.24), 6.882 (0.56), 6.901 (1 .18), 6.929 (2.09), 6.938 (1.41 ), 6.960 (3.80), 6.989 (2.58), 6.998
(2.72), 7.046 (0.75), 7.072 (1 .18), 7.1 16 (1 .31 ), 7.137 (2.42), 7.143 (1 .96), 7.164 (2.22), 7.223 (3.14), 7.239 (3.93), 7.254 (1 .90), 7.273 (1 .24), 7.293 (0.79), 7.306 (0.69), 7.312 (1.21 ), 7.316
(1 .15), 7.326 (1 .24), 7.332 (2.32), 7.341 (2.36), 7.348 (4.25), 7.355 (2.22), 7.361 (3.01 ), 7.366
(5.14), 7.373 (4.29), 7.387 (3.08), 7.391 (4.16), 7.397 (2.29), 7.407 (1 .64), 7.413 (2.26), 7.417
(3.14), 7.435 (5.27), 7.450 (2.26), 7.455 (1 .96), 7.461 (1.64), 7.473 (1 .60), 7.494 (0.65).
Example 63
5-[2-(benzyloxy)phenyl]-9-[2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 -oxa- 3,9-diazaspiro[5.5]undecan-2-one (mixture of two diastereomers)
Figure imgf000225_0001
A mixture of 2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (72.4 mg, 283 mihoI, Intermediate 34, single stereoisomer 2), HATU (108 mg, 283 pmol) and N,N- diisopropylethylamine (130 mI_, 770 mihoI) in DMF (1 .6 ml_) was stirred for 5 min, then (rac) 5- [2-(benzyloxy)phenyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one hydrochloride (100 mg, 257 mihoI, Intermediate 22) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC (method 7) to give the title compound 52.0 mg (95 % purity, 32 % yield).
LC-MS (method 2): Rt = 1 .40 min; MS (ESIpos): m/z = 597 [M+H]+ 1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.199 (0.57), 0.209 (0.57), 1 .019 (0.73), 1 .050 (0.67), 1 .197 (0.51 ), 1 .209 (0.51 ), 1 .232 (0.41 ), 1 .309 (0.76), 1.342 (0.95), 1 .365 (0.51 ), 1.444 (0.44),
1 .474 (0.48), 1 .610 (0.73), 1 .643 (0.44), 1 .782 (0.60), 1.813 (0.54), 1 .884 (0.92), 1.915 (0.82),
1 .991 (13.59), 2.095 (16.00), 2.260 (5.77), 2.285 (9.82), 2.332 (1 .39), 2.336 (0.63), 2.518 (7.22), 2.523 (5.13), 2.673 (1 .36), 2.678 (0.60), 2.812 (0.73), 2.846 (1 .20), 2.874 (0.63), 2.921
(0.48), 2.959 (0.76), 2.992 (0.73), 3.005 (0.63), 3.015 (0.67), 3.022 (0.70), 3.036 (0.73), 3.045
(0.73), 3.081 (0.76), 3.1 10 (0.82), 3.135 (0.92), 3.164 (0.54), 3.263 (1 .49), 3.306 (0.51 ), 3.360
(0.98), 3.374 (0.89), 3.430 (0.92), 3.562 (13.85), 3.595 (1 .74), 3.675 (0.57), 3.710 (0.41 ), 4.316 (0.44), 4.347 (0.48), 4.379 (0.67), 4.412 (0.60), 4.716 (1.08), 4.744 (1 .27), 5.017 (1.71 ), 5.044
(1 .46), 5.080 (0.57), 5.109 (1 .33), 5.134 (2.06), 5.147 (2.22), 5.177 (0.70), 6.844 (3.26), 6.859
(3.26), 6.883 (0.57), 6.901 (1 .17), 6.929 (2.12), 6.938 (1.39), 6.960 (3.77), 6.989 (2.63), 6.998
(2.76), 7.046 (0.76), 7.072 (1 .20), 7.1 16 (1 .30), 7.137 (2.44), 7.143 (2.00), 7.164 (2.22), 7.223
(3.10), 7.240 (3.96), 7.254 (1 .93), 7.268 (1 .17), 7.273 (1.27), 7.284 (1 .05), 7.293 (0.76), 7.297
(0.67), 7.306 (0.70), 7.312 (1 .24), 7.316 (1 .17), 7.326 (1.20), 7.333 (2.34), 7.341 (2.34), 7.348
(4.28), 7.355 (2.22), 7.361 (2.98), 7.366 (5.10), 7.373 (4.37), 7.387 (3.10), 7.391 (4.21 ), 7.397
(2.34), 7.407 (1 .68), 7.417 (3.14), 7.435 (5.29), 7.450 (2.34), 7.455 (2.03), 7.463 (1.68), 7.473
(1 .65), 7.493 (0.73).
Example 64
5-(4-fluorophenyl)-9-[3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9-diazaspiro[5.5]- undecan-2-one (mixture of two diastereomers)
Figure imgf000226_0001
A mixture of (rac) 3,3,3-trifluoro-2-hydroxy-2-phenylpropanoic acid (1 14 mg, 519 mihoI, CAS- RN: 55519-22-7), PYBOP (31 1 mg, 598 pmol) and N,N-diisopropylethylamine (210 mI, 1 .2 mmol) in DMF was stirred for 5 min, then 5-(4-fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan- 2-one hydrochloride (120 mg, 399 mihoI, Intermediate 7, single stereoisomer 1 ) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC to give the title compound 100 mg (95 % purity, 51 % yield).
Preparative HPLC conditions: Instrument: pump: Labomatic HD-5000 or HD-3000, head HDK 280, lowpressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 pm, 125x30mm; Eluent: solvent A: water + 0.2 Vol-% ammonia (32%), solvent B: acetonitrile; Gradient: 0.00-0.50 min 15% B (150 ml/min), 0.50-6.00 min 15- 55% B (150 ml/min), 6.00-6.10 min 55-100% B (150 ml/min), 6.10-8.00 min 100% B (150 ml/min); UV-Detection.
LC-MS (method 2): Rt = 1 .07 min; MS (ESIpos): m/z = 467 [M+H]+
Example 65 and Example 66
5-(4-fluorophenyl)-9-[(2S)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one
5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one
Example 65
5-(4-fluorophenyl)-9-[3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9-diazaspiro[5.5]- undecan-2-one (single stereoisomer 1 )
Figure imgf000227_0001
For the preparation of the diasteromeric mixture, see Example 64. Separation of the there described mixture yielded the title compound 30.0 mg (95 % purity, 32 % yield).
Preparative chiral FIPLC method: Instrument: Labomatic FID5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000, Column: YMC Cellulose SC 5m 250x30mm; Eluent: hexane/2- propanol 50:50; Flux 40.0 ml/min; UV 254 nm
Analytical chiral FIPLC method: Instrument: Agilent FIPLC 1260; Column: YMC Cellulose SC 3m 100x4, 6mm; Eluent: hexane + 0.1 Vol-% diethylamine (99%)/2-propanol 50:50; Flux 1 .4 ml/min; Temperature: 25 Ό; DAD 254 nm. Analytical Chiral HPLC: Rt = 2.02 min, e.e. >99%.
1H-NMR (400 MHz, DMS0-d6) d [ppm]: 0.033 (0.18), 0.044 (0.16), 0.801 (0.25), 0.908 (0.63), 0.947 (0.22), 0.978 (0.20), 1.048 (16.00), 1.085 (0.47), 1.117 (0.20), 1.128 (0.18), 1.329 (0.22), 1.463 (0.22), 1.729 (0.20), 1.760 (0.18), 2.273 (0.34), 2.277 (0.16), 2.459 (1.89), 2.464 (1.21), 2.481 (3.82), 2.615 (0.36), 2.619 (0.16), 2.778 (0.22), 2.783 (0.22), 2.915 (0.22), 2.935 (0.29),
2.948 (0.36), 2.957 (0.29), 2.972 (0.22), 3.054 (0.18), 3.062 (0.18), 3.076 (0.16), 3.142 (0.18),
3.150 (0.18), 3.241 (0.29), 3.315 (0.18), 3.319 (0.18), 3.465 (0.16), 3.766 (0.18), 4.135 (1.42),
4.191 (0.22), 4.221 (0.22), 6.956 (0.38), 6.970 (0.47), 6.978 (0.61), 6.991 (0.49), 7.109 (0.58),
7.118 (0.43), 7.131 (1.06), 7.140 (0.85), 7.153 (0.52), 7.162 (0.45), 7.184 (0.22), 7.205 (0.85), 7.223 (1.80), 7.247 (0.61), 7.261 (0.47), 7.269 (0.38), 7.282 (0.29), 7.330 (0.36), 7.349 (1.10),
7.377 (0.90), 7.395 (0.94), 7.411 (0.52), 7.428 (0.18), 7.928 (0.94), 8.050 (1.35).
Optical rotation (method OR1): +36.9°+/-0.64°(met hanol).
Example 66
5-(4-fluorophenyl)-9-[3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1-oxa-3,9-diazaspiro[5.5]- undecan-2-one (single stereoisomer 2)
Figure imgf000228_0001
For the preparation of the title compound as a mixture of stereoisomers and separation of the stereoisomers see Example 65. Obtained: 30.0 mg (95 % purity, 32 % yield).
Analytical Chiral HPLC: Rt = 2.80 min, e.e. >99%.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.011 (0.22), 0.000 (0.22), 0.910 (0.24), 1.018 (0.60), 1.098 (0.27), 1.134 (0.30), 1.157(16.00), 1.194 (0.40), 1.283 (0.24), 1.310(0.20), 1.339 (0.30), 1.349 (0.29), 1.373 (0.27), 1.384 (0.24), 1.536 (0.31), 1.838 (0.27), 1.867 (0.35), 2.568 (3.04),
2.573 (1.99), 2.589 (4.12), 2.724 (0.52), 2.767 (0.17), 2.793 (0.30), 2.825 (0.16), 2.880 (0.16),
2.960 (0.22), 2.974 (0.29), 2.987 (0.29), 3.001 (0.27), 3.108 (0.29), 3.139 (0.16), 3.178 (0.19), 3.201 (0.31), 3.213 (0.30), 3.238 (0.17), 3.553 (0.31), 3.583 (0.54), 3.611 (0.26), 3.836 (0.21),
3.869 (0.20), 4.239 (1.56), 4.355 (0.22), 4.387 (0.21), 7.058 (0.54), 7.077 (1.09), 7.096 (0.72),
7.195 (0.21), 7.218 (1.12), 7.230 (1.77), 7.251 (1.61), 7.265 (1.31), 7.282 (1.00), 7.296 (0.64), 7.314 (0.27), 7.356 (0.37), 7.370 (0.44), 7.377 (0.36), 7.391 (0.27), 7.432 (0.32), 7.452 (0.71 ), 7.477 (0.92), 7.491 (1.16), 8.045 (0.92), 8.163 (1 .76).
Optical rotation (method OR1 ): -15.8°+/- 0.64° (methanol).
Example 67
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one (mixture of two diastereomers)
Figure imgf000229_0001
A mixture of (rac) 2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (1 10 mg, 432 mihoI, CAS-RN: 1507285-78-0), HATU (190 mg, 499 pmol) and N,N-diisopropylethylamine (170 mI, 1 .0 mmol) in DMF was stirred for 5 min, then 5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one hydrochloride (100 mg, 332 mihoI, Intermediate 7, single stereoisomer 1 ) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC to give the title compound 50 mg (95 % purity, 29 % yield).
Preparative HPLC conditions: Instrument: pump: Labomatic HD-5000 or HD-3000, head HDK 280, lowpressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 pm, 125x30mm; Eluent: solvent A: water + 0.2 Vol-% ammonia (32%), solvent B: acetonitrile; Gradient: 0.00-0.50 min 30% B (150 ml/min), 0.50-6.00 min 30- 70% B (150 ml/min), 6.00-6.10 min 70-100% B (150 ml/min), 6.10-8.00 min 100% B (150 ml/min); UV-Detection.
LC-MS (method 2): Rt = 1 .15 min; MS (ESIpos): m/z = 501 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.082 (0.30), 0.185 (0.23), 1 .107 (16.00), 1 .144 (0.60), 1 .209 (0.73), 1 .232 (0.73), 1 .307 (0.40), 1 .366 (0.66), 1.482 (0.36), 1 .527 (0.66), 1.751 (0.40), 1 .791 (0.56), 1 .827 (0.76), 2.779 (0.99), 2.810 (1 .66), 2.832 (1.56), 2.978 (0.56), 3.012 (0.50), 3.115 (0.60), 3.150 (0.73), 3.185 (0.76), 3.377 (0.89), 3.404 (0.50), 3.432 (0.30), 3.503 (0.93),
3.533 (1.03), 3.561 (0.53), 3.675 (0.33), 3.785 (0.33), 4.243 (0.63), 4.275 (0.70), 4.314 (0.36),
7.007 (0.50), 7.075 (0.89), 7.094 (1.03), 7.114 (0.60), 7.153 (1.06), 7.174 (4.01), 7.190 (5.37),
7.216 (1.19), 7.305 (1.66), 7.317 (1.72), 7.343 (1.39), 7.461 (1.76), 7.499 (1.06), 7.556 (0.40),
7.580 (0.53), 8.285 (0.30).
Example 68 and Example 69
9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(4-fluorophenyl)-1-oxa-3,9- diazaspiro[5.5]undecan-2-one
9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(4-fluorophenyl)-1-oxa-3,9- diazaspiro[5.5]undecan-2-one
Example 68
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(4-fluorophenyl)-1-oxa-3,9-diaza- spiro[5.5]undecan-2-one (single stereoisomer 1)
Figure imgf000230_0001
For the preparation of the diasteromeric mixture, see Example 67. Separation of the there described mixture by silica gel chromatography (Biotage Isolera, SNAP KP-Sil 10g column, DCM/DCM+ethanol (8/2) 90:10-65:35) afforded the title compound 19.2 mg (95% purity, 30% yield).
LC-MS (method 2): Rt = 1.14 min; MS (ESIpos): m/z = 501 [M+FI]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.145 (0.44), 0.157 (0.58), 0.179 (0.87), 0.189 (0.87), 0.211 (0.58), 0.851 (0.58), 0.867 (0.87), 0.885 (0.73), 0.904 (1.16), 0.923 (0.58), 0.967 (0.73),
0.994 (0.15), 1.009 (0.29), 1.052 (0.29), 1.107(16.00), 1.123 (0.58), 1.134 (0.73), 1.144 (1.02),
1.156 (2.04), 1.189 (1.60), 1.208 (0.73), 1.232 (2.18), 1.255 (0.58), 1.295 (0.58), 1.347 (0.87),
1.377 (0.87), 1.389 (1.02), 1.411 (0.87), 1.465 (0.44), 1.488 (0.73), 1.519 (0.73), 1.576 (1.02),
1.605 (0.58), 1.729 (0.87), 1.764 (0.73), 1.805 (1.02), 1.836 (1.02), 1.906 (0.29), 2.419 (0.73),
2.451 (1.31), 2.518 (15.13), 2.522 (9.31), 2.717 (0.58), 2.744 (1.02), 2.777 (0.58), 2.835 (0.73), 2.867 (1.16), 2.895 (0.73), 2.989 (0.73), 3.015 (1.75), 3.027 (1.75), 3.037 (1.31), 3.051 (1.75), 3.105 (0.73), 3.119 (1.02), 3.127 (1.02), 3.141 (1.02), 3.190 (0.73), 3.206 (0.87), 3.214 (0.87),
3.297 (1.31), 3.376 (1.89), 3.403 (1.75), 3.431 (0.87), 3.504 (1.16), 3.532 (1.02), 3.557 (0.58),
3.657 (0.87), 3.688 (0.73), 3.796 (0.87), 3.832 (0.87), 4.195 (1.60), 4.241 (1.89), 4.276 (1.45),
7.054 (1.75), 7.068 (2.33), 7.075 (3.05), 7.089 (2.62), 7.153 (2.91), 7.175 (5.53), 7.180 (4.36),
7.202 (4.51), 7.224 (2.33), 7.258 (1.89), 7.277 (3.20), 7.298 (3.05), 7.309 (3.20), 7.322 (2.91),
7.329 (2.18), 7.344 (1.75), 7.367 (3.35), 7.436 (4.36), 7.474 (2.76), 7.494 (2.47), 7.514 (3.20),
7.519 (2.91 ), 7.539 (0.87), 7.559 (1.89), 7.580 (1.60), 8.088 (1.75), 8.229 (5.24), 8.353 (6.69).
Optical rotation (method OR1): 29.6°+/- 1.93°(met hanol).
Example 69
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(4-fluorophenyl)-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 2)
Figure imgf000231_0001
For the preparation of the title compound as a mixture of stereoisomers and separation of the stereoisomers see Example 68. Obtained: 27.1 mg (95 % purity, 45 % yield).
LC-MS (method 2): Rt = 1.15 min; MS (ESIpos): m/z = 501 [M+H]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.23), 0.011 (0.23), 0.032 (0.17), 0.888 (0.25), 1.028(16.00), 1.065 (0.19), 1.130 (0.36), 1.155 (0.47), 1.168 (0.51), 1.222 (0.32), 1.256 (0.21), 1.276 (0.17), 1.447 (0.45), 1.713 (0.32), 1.747 (0.49), 1.781 (0.19), 2.243 (1.04), 2.249 (1.32),
2.253 (1.06), 2.271 (0.21), 2.443 (4.46), 2.586 (0.96), 2.590 (1.25), 2.595 (0.93), 2.671 (0.23),
2.699 (0.36), 2.730 (0.30), 2.764 (0.23), 2.875 (0.28), 2.890 (0.34), 2.902 (0.34), 2.917 (0.32),
3.006 (0.19), 3.037 (0.36), 3.073 (0.53), 3.087 (0.47), 3.096 (0.45), 3.111 (0.45), 3.426 (0.38),
3.454 (0.59), 3.482 (0.30), 3.588 (0.21), 3.622 (0.19), 3.664 (0.25), 3.698 (0.23), 4.112 (1.55),
4.140 (0.19), 4.168 (0.23), 4.204 (0.28), 4.235 (0.25), 6.911 (0.34), 6.931 (0.81), 6.951 (0.53),
7.017 (0.62), 7.036 (0.42), 7.091 (1.66), 7.096 (1.70), 7.111 (3.04), 7.123 (1.17), 7.145 (0.55),
7.209 (0.36), 7.227 (0.85), 7.241 (0.66), 7.250 (0.57), 7.263 (1.27), 7.282 (0.64), 7.301 (0.51),
7.353 (0.76), 7.384 (0.96), 7.406 (0.59), 7.424 (0.87), 8.010 (0.17), 8.154 (1.23), 8.278 (1.83).
Optical rotation (method OR1): -13.7°+/- 0.64°(me thanol). Example 70
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of two diastereomers)
Figure imgf000232_0001
A mixture of (rac) 2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (1 12 mg, 389 pmol, CAS-RN: 1508432-14-1 ), PYBOP (234 mg, 449 pmol) and N,N-diisopropylethylamine (160 mI, 0.9 mmol) in DMF was stirred for 5 min, then 5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one hydrochloride (90.0 mg, 299 mihoI, Intermediate 7, single stereoisomer 1 ) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC to give the title compound 15.0 mg (95 % purity, 9 % yield).
Preparative HPLC conditions: Instrument: pump: Labomatic HD-5000 or HD-3000, head HDK 280, lowpressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 pm, 125x30mm; Eluent: solvent A: water + 0.2 Vol-% ammonia (32%), solvent B: acetonitrile; Gradient: 0.00-0.50 min 30% B (150 ml/min), 0.50-6.00 min 30- 70% B (150 ml/min), 6.00-6.10 min 70-100% B (150 ml/min), 6.10-8.00 min 100% B (150 ml/min); UV-Detection.
LC-MS (method 2): Rt = 1 .22 min; MS (ESIpos): m/z = 535 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.223 (0.21 ), 0.257 (0.21 ), 0.860 (0.21 ), 0.967 (0.75), 1 .107 (16.00), 1 .144 (0.63), 1 .209 (0.24), 1.233 (0.45), 1 .323 (0.30), 1 .348 (0.42), 1 .376 (0.30), 1 .388 (0.30), 1 .41 1 (0.24), 1 .507 (0.18), 1 .548 (0.30), 1.619 (0.21 ), 1 .712 (0.36), 1.720 (0.36),
1 .729 (1 .02), 1 .737 (0.51 ), 1 .745 (0.42), 1 .770 (0.15), 1.823 (0.33), 1 .853 (0.33), 2.332 (1 .26),
2.336 (0.57), 2.518 (7.52), 2.522 (4.82), 2.539 (2.58), 2.673 (1.26), 2.678 (0.57), 2.774 (0.21 ),
2.810 (0.21 ), 2.857 (0.21 ), 2.866 (0.24), 2.898 (0.27), 2.989 (0.24), 2.999 (0.39), 3.005 (0.75),
3.015 (0.72), 3.022 (0.60), 3.032 (0.48), 3.054 (0.42), 3.078 (0.24), 3.108 (0.18), 3.133 (0.24),
3.146 (0.24), 3.178 (0.39), 3.193 (0.36), 3.203 (0.36), 3.306 (0.66), 3.434 (0.18), 3.461 (0.24), 3.510 (0.33), 3.544 (0.42), 3.566 (0.21 ), 3.647 (0.27), 3.681 (0.24), 4.189 (1 .56), 4.236 (0.36),
4.267 (0.39), 5.766 (0.18), 7.1 1 1 (0.54), 7.1 19 (1 .02), 7.126 (1.23), 7.133 (1 .38), 7.148 (0.96),
7.154 (0.63), 7.170 (0.24), 7.182 (0.63), 7.204 (1 .56), 7.226 (1.83), 7.261 (1 .23), 7.264 (1 .23),
7.312 (0.63), 7.334 (1 .38), 7.344 (1.62), 7.348 (1 .53), 7.457 (0.48), 7.483 (0.75), 7.599 (0.36),
7.604 (0.69), 7.608 (0.36), 7.744 (0.30), 7.749 (0.54), 7.753 (0.33), 7.759 (0.45), 7.765 (0.81 ),
7.769 (0.45), 7.785 (0.48), 7.791 (0.84), 7.795 (0.45), 8.442 (1.71 ), 8.573 (2.13).
Example 71
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of two diastereomers)
Figure imgf000233_0001
A mixture of (rac) 2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (106 mg, 416 mihoI, CAS-RN: 1507285-78-0), PYBOP (250 mg, 480 pmol) and N,N-diisopropylethylamine (170 mI, 960 mihoI) in DMF was stirred for 5 min, then 5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one hydrochloride (100 mg, 320 mihoI, Intermediate 16, single stereoisomer 2) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC to give the title compound 49.0 mg (95 % purity, 28 % yield).
Preparative HPLC conditions: Instrument: pump: Labomatic HD-5000 or HD-3000, head HDK 280, lowpressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 pm, 125x30mm; Eluent: solvent A: water + 0.2 Vol-% ammonia (32%), solvent B: acetonitrile; Gradient: 0.00-0.50 min 30% B (150 ml/min), 0.50-6.00 min 30- 70% B (150 ml/min), 6.00-6.10 min 70-100% B (150 ml/min), 6.10-8.00 min 100% B (150 ml/min); UV-Detection.
LC-MS (method 2): Rt = 1 .15 min; MS (ESIpos): m/z = 513 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.055 (0.23), -0.033 (0.46), -0.022 (0.46), 0.000 (0.23), 0.417 (0.23), 0.438 (0.46), 0.448 (0.34), 0.472 (0.23), 1.103 (0.46), 1.137 (0.34), 1.226
(0.69), 1.248 (0.57), 1.262 (0.80), 1.285 (0.57), 1.298 (0.57), 1.307 (0.69), 1.319 (0.69), 1.331
(0.57), 1.354 (0.57), 1.363 (0.57), 1.387 (0.46), 1.400 (0.34), 1.440 (0.23), 1.508 (0.34), 1.526
(0.46), 1.535 (0.46), 1.555 (0.57), 1.567 (0.46), 1.587 (0.57), 1.622 (0.57), 1.651 (0.46), 1.696
(0.80), 1.709 (0.80), 1.727 (1.26), 1.744 (1.37), 1.777 (0.57), 1.806 (0.23), 1.830 (0.23), 1.867
(0.57), 1.900 (0.57), 1.941 (0.57), 1.983 (0.80), 2.063 (0.46), 2.149 (0.69), 2.160 (0.34), 2.364
(0.23), 2.400 (0.91), 2.405 (1.03), 2.409 (0.80), 2.476 (0.34), 2.507 (0.69), 2.600 (3.54), 2.617
(16.00), 2.645 (0.57), 2.657 (0.34), 2.742 (0.80), 2.747 (1.03), 2.751 (0.80), 2.775 (0.57), 2.808 (1.03), 2.841 (0.57), 2.870 (0.46), 2.903 (0.91), 2.934 (0.46), 3.046 (0.34), 3.077 (0.69), 3.118
(0.91), 3.155 (0.69), 3.186 (0.46), 3.488 (1.60), 3.519 (0.80), 3.537 (0.80), 3.548 (0.69), 3.556
(0.69), 3.566 (0.80), 3.584 (0.57), 3.605 (0.69), 3.627 (0.91), 3.657 (0.57), 3.719 (8.57), 3.801
(5.03), 3.830 (0.69), 3.862 (7.20), 3.875 (5.49), 3.901 (0.57), 4.289 (0.46), 4.370 (0.80), 6.817
(0.69), 6.837 (1.60), 6.857 (0.91), 6.983 (2.17), 7.000 (1.37), 7.026 (1.71), 7.042 (1.83), 7.048
(1.94), 7.058 (0.91), 7.070 (1.37), 7.080 (0.34), 7.100 (0.80), 7.115 (1.14), 7.125 (1.60), 7.134
(1.26), 7.146 (1.49), 7.239 (1.60), 7.258 (1.83), 7.283 (1.37), 7.299 (0.80), 7.328 (0.69), 7.344
(1.49), 7.355 (1.83), 7.363 (2.29), 7.375 (2.63), 7.394 (1.26), 7.417 (0.80), 7.435 (1.14), 7.456
(0.69), 7.472 (1.49), 7.508 (5.26), 7.519 (4.23), 7.535 (1.03), 7.545 (0.80), 7.549 (0.69), 7.559
(1.14), 7.567 (1.94), 7.579 (1.83), 7.584 (2.63), 7.590 (3.09), 7.594 (3.43), 7.610 (0.80), 7.624
(1.03), 7.644 (0.80), 8.142 (2.29), 8.353 (2.17), 8.369 (1.71), 8.425 (2.86), 8.458 (3.43).
Example 72 and Example 73:
9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1-oxa-3,9- diazaspiro[5.5]undecan-2-one
9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1-oxa-3,9- diazaspiro[5.5]undecan-2-one
Example 72
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single steroisomer 1 )
Figure imgf000235_0001
For the preparation of the diasteromeric mixture, see Example 71. Separation of the there described mixture yielded the title compound 16.0 mg (95 % purity, 33 % yield).
Preparative chiral FIPLC method: Instrument: Labomatic FID5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000, Column: Cellulose SC 5m 250x30mm; Eluent A: hexane + 0.1 Vol-% diethylamine (99%); Eluent B: 2-propanol; Gradient: 20 - 50% B in 20 min; Flux 40.0 ml/min; UV 220 nm.
Analytical chiral FIPLC method: Instrument: Agilent FIPLC 1260; Column: Cellulose SC 3m 100x4, 6mm; Eluent A: hexane + 0.1 Vol-% diethylamine (99%); Eluent B: 2-propanol; Gradient: 20 - 50% B in 7 min; Flux 1 .4 ml/min; Temperature: 25 O; DAD 220 nm
Analytical Chiral HPLC: Rt = 4.13 min, e.e. >99%.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.340 (0.54), 0.362 (0.89), 0.373 (0.84), 0.395 (0.59),
0.851 (0.25), 1 .026 (1 .14), 1 .035 (1.53), 1 .043 (1 .09), 1.052 (2.17), 1 .061 (2.02), 1.070 (1 .48),
1 .079 (0.89), 1 .185 (0.64), 1 .208 (1.04), 1 .219 (1 .14), 1.232 (1.68), 1 .455 (0.49), 1.477 (0.79),
1 .487 (0.84), 1 .509 (0.94), 1 .532 (0.84), 1 .564 (0.69), 1.622 (1.04), 1 .670 (0.89), 1.709 (0.59),
1 .751 (0.20), 1 .792 (0.15), 1 .867 (1 .04), 1.902 (1 .78), 2.396 (0.59), 2.428 (0.99), 2.518 (1 1 .31 ), 2.523 (7.26), 2.539 (3.41 ), 2.547 (0.79), 2.707 (0.74), 2.733 (1.04), 2.766 (0.54), 2.790 (0.74),
2.817 (1 .28), 2.850 (0.69), 2.966 (0.69), 2.995 (1 .28), 3.028 (0.74), 3.159 (8.74), 3.172 (8.49),
3.275 (1 .83), 3.297 (1 .78), 3.417 (1.73), 3.435 (1 .14), 3.452 (0.74), 3.544 (0.89), 3.644 (0.74),
3.664 (0.84), 3.726 (1 1.06), 3.786 (16.00), 4.083 (0.69), 4.096 (2.02), 4.1 10 (1 .93), 4.122 (0.64), 4.220 (0.74), 4.264 (1 .09), 4.302 (0.89), 4.344 (0.25), 4.356 (0.44), 4.369 (0.20), 6.907
(4.10), 6.924 (2.52), 6.948 (2.17), 6.972 (2.86), 6.993 (2.86), 7.038 (1 .88), 7.058 (2.22), 7.159
(1 .63), 7.179 (2.12), 7.208 (1 .83), 7.223 (1 .48), 7.252 (1.23), 7.258 (1 .09), 7.277 (3.16), 7.296
(5.04), 7.317 (2.77), 7.434 (6.07), 7.438 (6.22), 7.472 (0.99), 7.492 (2.52), 7.512 (3.01 ), 7.517
(2.96), 7.538 (0.89), 7.549 (2.07), 7.569 (1 .68), 8.270 (4.69), 8.335 (6.22), 8.369 (0.20). Optical rotation (method OR1): +54.6° +/-1.15°(met hanol).
Example 73
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (single steroisomer 2)
Figure imgf000236_0001
For the preparation of the title compound as a mixture of stereoisomers and separation of the stereoisomers see Example 72. Obtained: 17.0 mg (95 % purity, 36 % yield).
Analytical Chiral FIPLC: Rt = 5.09 min, e.e. >99%.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.055 (0.49), -0.033 (0.79), -0.022 (0.75), 0.000 (0.49), 0.926 (0.23), 1.071 (0.94), 1.089 (1.95), 1.102 (0.75), 1.107 (1.01), 1.117 (0.64), 1.163 (0.19), 1.226 (1.05), 1.258 (0.98), 1.308 (1.35), 1.319 (0.90), 1.330 (0.75), 1.337 (0.75), 1.352 (0.98), 1.363 (0.98), 1.384 (0.79), 1.401 (0.71), 1.415 (0.53), 1.435 (0.34), 1.596 (0.30), 1.626 (0.68), 1.660 (0.41), 1.692 (0.45), 1.715 (0.23), 1.827 (0.49), 1.867 (1.20), 1.900 (0.90), 1.920 (0.56), 1.968 (0.86), 2.360 (0.38), 2.393 (1.24), 2.593 (9.43), 2.597 (6.12), 2.644 (0.41), 2.662 (0.38), 2.772 (0.68), 2.804 (1.16), 2.831 (0.64), 2.873 (0.34), 2.900 (0.56), 2.933 (0.34), 3.103 (0.83), 3.117 (1.35), 3.148 (1.20), 3.181 (0.68), 3.234 (12.36), 3.246 (11.91), 3.293 (0.45), 3.448 (0.86), 3.597 (0.71), 3.626 (0.86), 3.655 (0.75), 3.719 (16.00), 3.755 (0.60), 3.790 (0.49), 3.875 (9.13), 3.899 (0.83), 4.158 (0.98), 4.171 (2.70), 4.184 (2.63), 4.197 (0.90), 4.280 (0.45), 4.313 (0.41), 4.365 (0.86), 4.397 (0.83), 6.815 (1.35), 6.835 (3.08), 6.854 (1.84), 6.969 (1.80), 6.988 (1.39), 7.009 (0.64), 7.021 (1.24), 7.028 (1.43), 7.039 (2.33), 7.057 (1.31), 7.099 (1.16), 7.124 (2.48), 7.146 (2.55), 7.241 (1.54), 7.263 (1.80), 7.282 (0.90), 7.339 (0.68), 7.360 (1.88), 7.378 (1.46), 7.411 (1.24), 7.415 (1.20), 7.432 (1.95), 7.451 (1.05), 7.455 (1.01), 7.471 (1.62), 7.500 (4.28), 7.505 (4.28), 7.523 (3.49), 7.537 (0.71), 7.557 (1.58), 7.574 (2.33), 7.579 (2.10), 7.599 (0.45), 8.364 (2.67), 8.446 (4.96).
Optical rotation (method OR1): +16.3°+/-0.55°(met hanol). Example 74
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of two stereoisomers)
Figure imgf000237_0001
A mixture of (rac) 2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (120 mg, 416 mihoI, CAS-RN: 1508432-14-1 ), PYBOP (250 mg, 480 pmol) and N,N-diisopropylethylamine (170 mI, 960 mihoI) in DMF was stirred for 5 min, then 5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one hydrochloride (100 mg, 320 mihoI, Intermediate 16, single stereoisomer 2) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC to give the title compound 19.0 mg (95 % purity, 10 % yield).
Preparative HPLC conditions: Instrument: pump: Labomatic HD-5000 or HD-3000, head HDK 280, lowpressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 pm, 125x30mm; Eluent: solvent A: water + 0.2 Vol-% ammonia (32%), solvent B: acetonitrile; Gradient: 0.00-0.50 min 30% B (150 ml/min), 0.50-6.00 min 30- 70% B (150 ml/min), 6.00-6.10 min 70-100% B (150 ml/min), 6.10-8.00 min 100% B (150 ml/min); UV-Detection.
LC-MS (method 2): Rt = 1 .24 min; MS (ESIpos): m/z = 547 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .106 (16.00), 1 .230 (0.24), 1 .670 (0.19), 1.899 (0.24), 2.327 (0.32), 2.331 (0.24), 2.518 (1.41 ), 2.523 (0.93), 2.539 (8.93), 2.669 (0.32), 2.673 (0.24),
3.386 (0.37), 3.509 (0.19), 3.675 (1.33), 3.725 (0.66), 3.788 (1.20), 3.799 (0.98), 4.201 (1 .57),
6.888 (0.21 ), 6.907 (0.24), 6.952 (0.29), 6.968 (0.35), 6.980 (0.27), 6.987 (0.27), 6.999 (0.21 ),
7.044 (0.19), 7.060 (0.16), 7.185 (0.16), 7.212 (0.24), 7.231 (0.21 ), 7.251 (0.58), 7.268 (0.24),
7.286 (0.29), 7.31 1 (0.53), 7.331 (0.45), 7.336 (0.45), 7.344 (0.48), 7.437 (0.43), 7.441 (0.43),
7.453 (0.50), 7.540 (0.43), 7.645 (0.21 ), 7.673 (0.19), 7.678 (0.29), 7.743 (0.27), 7.759 (0.35), 7.764 (0.32), 7.795 (0.19), 7.800 (0.29), 7.804 (0.16), 8.486 (0.27), 8.500 (0.24), 8.563 (0.21 ), 8.598 (0.21 ).
Example 75 and Example 76
9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one
9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one
Example 75
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 1 )
Figure imgf000238_0001
For the preparation of the diasteromeric mixture, see Example 74. Separation of the there described mixture yielded the title compound 5.0 mg (95 % purity, 13 % yield).
Preparative chiral FIPLC method: Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IC 5pm 250x30mm; Eluent A: C02, Eluent B: ethanol; Isocratic: 15%B; Flux 100.0 ml/min Temperature: 40Ό; BPR: 150bar; MWD @ 220nm
Analytical chiral HPLC method: Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Chiralpak IC 5pm 100x4.6mm; Eluent A: C02, Eluent B: ethanol; Isocratic: 15%B; Flux 4.0 ml/min; Temperature: 37.5Ό; BPR: 100bar; MWD @ 220 nm
Analytical Chiral HPLC: Rt = 3.89 min, e.e. >99%.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.406 (0.18), 0.428 (0.27), 0.462 (0.18), 1 .035 (0.53), 1 .052 (0.96), 1 .070 (0.55), 1 .107 (0.34), 1 .132 (0.25), 1.166 (0.25), 1 .227 (0.48), 1.456 (0.23),
1 .490 (0.39), 1 .512 (0.32), 1 .564 (0.37), 1 .595 (0.32), 1.674 (0.53), 1 .705 (0.37), 1.901 (0.32),
1 .936 (0.27), 2.073 (5.42), 2.331 (0.53), 2.518 (3.46), 2.522 (2.27), 2.539 (0.57), 2.673 (0.53),
2.726 (0.21 ), 2.755 (0.37), 2.786 (0.21 ), 2.810 (0.23), 2.836 (0.39), 2.870 (0.23), 3.001 (0.21 ), 3.031 (0.37), 3.063 (0.21 ), 3.308 (1.19), 3.364 (0.89), 3.385 (0.37), 3.422 (0.76), 3.435 (0.64),
3.439 (0.62), 3.452 (0.46), 3.549 (0.32), 3.661 (0.32), 3.725 (3.30), 3.789 (5.56), 4.220 (0.27),
4.264 (0.39), 4.302 (0.27), 4.360 (0.25), 5.758 (16.00), 6.000 (0.21 ), 6.750 (0.21 ), 6.868 (0.30),
6.887 (0.76), 6.905 (0.50), 6.933 (0.37), 6.952 (0.80), 6.968 (1.56), 6.987 (1 .12), 7.041 (0.69), 7.061 (0.78), 7.213 (0.66), 7.230 (0.89), 7.251 (0.64), 7.269 (0.69), 7.287 (0.78), 7.312 (2.38),
7.315 (2.33), 7.346 (2.24), 7.350 (2.15), 7.453 (1 .65), 7.756 (0.78), 7.761 (1 .35), 7.766 (0.78),
7.797 (0.82), 7.801 (1.40), 7.806 (0.78), 8.487 (1 .14), 8.560 (1.17).
Example 76
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 2)
Figure imgf000239_0001
For the preparation of the title compound as a mixture of stereoisomers and separation of the stereoisomers see Example 75. Obtained: 5.0 mg (95 % purity, 13 % yield).
Analytical Chiral FIPLC: Rt = 5.24 min, e.e. >99%.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.023 (0.24), 0.033 (0.23), 0.787 (0.18), 0.794 (0.33), 0.902 (0.41 ), 1 .042 (16.00), 1 .079 (0.28), 1.125 (0.16), 1.146 (0.28), 1 .160 (0.46), 1 .167 (0.46), 1 .179 (0.25), 1 .191 (0.20), 1 .269 (0.24), 1 .281 (0.27), 1.316 (0.44), 1 .352 (0.29), 1.529 (0.41 ),
1 .564 (0.27), 1 .665 (0.29), 1 .699 (0.25), 1 .797 (0.26), 1.831 (0.23), 2.258 (0.18), 2.262 (0.25),
2.267 (0.18), 2.334 (0.26), 2.363 (0.16), 2.458 (0.67), 2.600 (0.16), 2.605 (0.23), 2.609 (0.17), 2.662 (0.17), 2.693 (0.32), 2.721 (0.17), 2.791 (0.25), 3.038 (0.35), 3.069 (0.54), 3.101 (0.20),
3.171 (0.19), 3.301 (0.26), 3.315 (0.26), 3.326 (0.28), 3.437 (0.32), 3.532 (0.20), 3.612 (4.67),
3.674 (0.26), 3.736 (3.41 ), 3.781 (0.26), 3.816 (0.23), 4.127 (1.63), 4.184 (0.32), 4.222 (0.24),
5.693 (1 .87), 5.934 (0.41 ), 6.686 (0.17), 6.826 (0.29), 6.844 (0.60), 6.863 (0.39), 6.870 (0.30),
6.890 (0.51 ), 6.915 (0.67), 6.936 (0.70), 6.961 (0.50), 6.981 (0.58), 7.066 (0.53), 7.086 (0.50), 7.130 (0.46), 7.147 (0.40), 7.186 (1.83), 7.200 (0.39), 7.219 (0.76), 7.238 (0.69), 7.258 (0.38),
7.269 (1 .61 ), 7.384 (0.72), 7.581 (0.82), 7.674 (0.56), 7.678 (0.94), 7.683 (0.54), 8.433 (1 .13),
8.526 (1 .30). Example 77
9-[2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of two stereoisomers)
Figure imgf000240_0001
A mixture of (rac) 2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (120 mg, 416 mihoI, CAS-RN: 1508619-37-1 ), PYBOP (250 mg, 480 pmol) and N,N-diisopropylethylamine (170 mI, 960 mihoI) in DMF was stirred for 5 min, then 5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one hydrochloride (100 mg, 320 mihoI, Intermediate 16, single stereoisomer 2) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC to give the title compound 42.0 mg (90 % purity, 22 % yield).
Preparative HPLC conditions: Instrument: pump: Labomatic HD-5000 or HD-3000, head HDK 280, lowpressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-18 10 pm, 125x30mm; Eluent: solvent A: water + 0.2 Vol-% ammonia (32%), solvent B: acetonitrile; Gradient: 0.00-0.50 min 30% B (150 ml/min), 0.50-6.00 min 30- 70% B (150 ml/min), 6.00-6.10 min 70-100% B (150 ml/min), 6.10-8.00 min 100% B (150 ml/min); UV-Detection.
LC-MS (method 2): Rt = 1 .24 min; MS (ESIpos): m/z = 547 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .106 (16.00), 1 .143 (0.19), 1 .220 (0.56), 1.229 (0.64), 1 .237 (1 .09), 1 .254 (1 .1 1 ), 1 .267 (0.70), 1 .298 (0.17), 1.327 (0.25), 1 .356 (0.17), 1.424 (0.17),
1 .476 (0.19), 1 .488 (0.19), 1 .508 (0.19), 1 .522 (0.19), 1.536 (0.19), 1 .569 (0.22), 1.654 (0.36),
1 .672 (0.42), 1 .71 1 (0.31 ), 1 .727 (0.42), 1 .744 (0.17), 1.833 (0.22), 1 .864 (0.42), 1.906 (0.45),
2.073 (0.70), 2.322 (0.56), 2.326 (0.72), 2.331 (0.58), 2.522 (2.14), 2.539 (3.26), 2.665 (0.53),
2.669 (0.72), 2.673 (0.53), 2.714 (0.22), 2.744 (0.39), 2.775 (0.22), 2.799 (0.17), 2.831 (0.28),
2.988 (0.17), 3.005 (0.36), 3.015 (0.47), 3.031 (0.25), 3.048 (0.28), 3.068 (0.28), 3.106 (0.28),
3.136 (0.22), 3.418 (0.58), 3.476 (0.25), 3.504 (0.22), 3.544 (0.31 ), 3.578 (0.31 ), 3.626 (2.64), 3.654 (0.28), 3.686 (0.22), 3.727 (1.84), 3.785 (2.50), 3.797 (1.84), 3.81 1 (0.61 ), 4.199 (0.50),
4.264 (0.22), 4.302 (0.31 ), 4.331 (0.17), 6.904 (0.39), 6.921 (0.81 ), 6.931 (0.58), 6.950 (1 .06),
6.975 (0.47), 6.994 (0.75), 7.015 (0.67), 7.027 (0.86), 7.049 (0.58), 7.057 (0.36), 7.098 (0.17),
7.188 (0.64), 7.205 (0.95), 7.225 (0.28), 7.266 (0.53), 7.287 (0.92), 7.305 (0.58), 7.351 (0.25),
7.368 (0.42), 7.386 (0.22), 7.404 (0.19), 7.442 (0.97), 7.51 1 (0.67), 7.531 (0.58), 7.585 (1 .39),
7.606 (0.67), 7.677 (0.31 ), 7.695 (0.19), 7.712 (0.45), 7.722 (0.56), 7.731 (0.83), 7.743 (0.58),
7.752 (0.42), 8.190 (0.67), 8.391 (0.78), 8.405 (0.61 ), 8.482 (1.1 1 ), 8.509 (1 .28).
Example 78 and Example 79
9-[(2R)-2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one
9-[(2S)-2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one
Example 78
9-[2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 1 )
Figure imgf000241_0001
For the preparation of the diasteromeric mixture, see Example 77. Separation of the there described mixture yielded the title compound 17.0 mg (95 % purity, 43 % yield).
Preparative chiral FIPLC method: Instrument: Labomatic FID5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000, Column: Chiralpak IC 5m 250x30mm; Eluent A: hexane + 0.1 Vol-% diethylamine (99%); Eluent B: ethanol; Gradient: 32% B; Flux 45.0 ml/min; UV 220 nm
Analytical chiral FIPLC method: Instrument: Agilent FIPLC 1260; Column: Chiralpak IC 3m 100x4, 6mm; Eluent A: hexane + 0.1 Vol-% diethylamine (99%); Eluent B: ethanol; Gradient: 20% B; Flux 1.4 ml/min; Temperature: 25 Ό; DAD 220 nm.
Analytical Chiral HPLC: Rt = 2.57 min, e.e. >99%.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.033 (0.49), -0.023 (0.61 ), 0.000 (1 .00), 0.01 1 (0.98), 0.033 (0.61 ), 0.045 (0.51 ), 0.759 (0.18), 0.781 (0.84), 0.786 (0.47), 0.797 (1 .00), 0.804 (0.96), 0.823 (0.59), 0.845 (0.26), 0.869 (0.41), 0.887 (0.80), 0.906 (0.41), 0.989 (0.35), 1.017 (0.20),
1.042 (0.33), 1.060 (0.61), 1.067 (0.53), 1.078 (0.35), 1.120 (0.59), 1.212 (1.75), 1.242 (1.81),
1.283 (0.92), 1.315 (1.55), 1.340 (0.98), 1.405 (0.18), 1.517 (0.39), 1.550 (0.82), 1.576 (0.61),
1.596 (0.59), 1.630 (0.27), 1.816 (1.37), 1.847 (1.65), 1.875 (0.69), 1.885 (0.73), 2.057 (0.18),
2.306 (0.71), 2.310 (0.98), 2.315 (0.96), 2.320 (0.94), 2.355 (0.80), 2.378 (0.55), 2.389 (0.51),
2.395 (0.43), 2.506 (3.10), 2.648 (0.63), 2.652 (0.84), 2.657 (0.63), 2.700 (0.88), 2.727 (1.61),
2.759 (0.84), 2.793 (0.45), 2.820 (0.75), 2.853 (0.41), 3.010 (0.67), 3.023 (1.00), 3.032 (1.08),
3.038 (1.10), 3.052 (1.57), 3.060 (1.47), 3.090 (1.43), 3.122 (0.84), 3.142 (0.61), 3.155 (0.61),
3.211 (0.63), 3.358 (0.71), 3.403 (1.10), 3.468 (0.51), 3.494 (0.41), 3.531 (0.79), 3.560 (1.47),
3.610 (16.00), 3.643 (0.80), 3.677 (0.67), 3.712 (0.18), 3.782 (9.87), 4.191 (0.57), 4.224 (0.53),
4.284 (1.16), 4.316 (1.08), 6.916 (2.18), 6.936 (4.08), 6.959 (2.69), 6.978 (4.06), 6.999 (3.49),
7.012 (5.05), 7.033 (3.36), 7.173 (2.28), 7.186 (1.88), 7.248 (0.84), 7.270 (2.14), 7.291 (1.51),
7.330 (1.53), 7.334 (1.49), 7.352 (2.45), 7.370 (1.28), 7.410 (1.69), 7.426 (2.81), 7.433 (2.73),
7.565 (4.20), 7.569 (4.71), 7.695 (2.36), 7.716 (2.08), 8.387 (2.63), 8.489 (4.06).
Optical rotation (method OR1): +26.9°+/-0.75°(met hanol).
Example 79
9-[2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 2)
Figure imgf000242_0001
For the preparation of the title compound as a mixture of stereoisomers and separation of the stereoisomers see Example 75. Obtained: 15.0 mg (95 % purity, 38 % yield).
Analytical Chiral FIPLC: Rt = 3.92 min, e.e. >99%.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.379 (0.66), 0.403 (1.06), 0.413 (1.01), 0.435 (0.71), 1.035 (1.27), 1.052 (2.38), 1.069 (1.32), 1.112 (1.67), 1.131 (1.77), 1.149 (1.52), 1.196 (0.76),
1.218 (1.22), 1.230 (1.57), 1.251 (0.86), 1.424 (0.46), 1.455 (0.51), 1.478 (0.86), 1.487 (0.86),
1.510 (0.86), 1.538 (0.86), 1.569 (0.61), 1.647 (1.22), 1.678 (1.62), 1.709 (0.71), 1.870 (1.27),
1.905 (1.32), 2.711 (0.61), 2.740 (1.06), 2.772 (0.66), 2.797 (0.81), 2.825 (1.47), 2.859 (1.06),
2.918 (0.25), 2.984 (0.76), 3.013 (1.42), 3.047 (0.76), 3.158 (1.22), 3.171 (1.32), 3.264 (1.27), 3.367 (1 .47), 3.422 (2.18), 3.434 (2.33), 3.452 (1 .57), 3.545 (1.01 ), 3.653 (0.91 ), 3.686 (0.91 ), 3.727 (12.91 ), 3.786 (16.00), 4.098 (0.30), 4.1 1 1 (0.30), 4.226 (0.81 ), 4.264 (1 .52), 4.303 (1 .06), 4.346 (0.41 ), 4.359 (0.76), 4.371 (0.35), 6.885 (0.71 ), 6.904 (2.58), 6.920 (5.22), 6.949
(2.28), 6.968 (1 .32), 6.989 (2.78), 7.010 (3.29), 7.038 (2.03), 7.058 (2.38), 7.188 (1.87), 7.209 (3.95), 7.226 (1 .72), 7.266 (2.89), 7.288 (4.30), 7.303 (2.78), 7.309 (2.28), 7.319 (1.72), 7.436
(4.20), 7.510 (4.56), 7.531 (3.95), 7.585 (3.85), 7.607 (3.24), 7.722 (3.49), 7.743 (3.19), 8.388
(4.81 ), 8.477 (6.13).
Example 80
5-(4-fluoro-2-methylphenyl)-9-[3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one (mixture of two stereoisomers)
Figure imgf000243_0001
A mixture of (rac) 3,3,3-trifluoro-2-hydroxy-2-phenylpropanoic acid (163 mg, 740 mihoI, CAS- RN: 55519-22-7), PYBOP (444 mg, 854 pmol) and N,N-diisopropylethylamine (400 mI, 2.3 mmol) in DMF (2.0 mL) was stirred for 5 min, then 5-(4-fluoro-2-methylphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid (200 mg, 569 mihoI, Intermediate 28, single stereoisomer 1 ) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC (method 7) to give the title compound 90.0 mg (95 % purity, 31 % yield).
LC-MS (method 2): Rt = 1 .1 1 min; MS (ESIneg): m/z = 481 [M+H]+
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.288 (0.18), -0.267 (0.31 ), -0.254 (0.29), -0.233 (0.18), 0.207 (0.23), 0.218 (0.23), 1.001 (0.31 ), 1 .035 (0.64), 1 .053 (0.37), 1 .070 (0.37), 1 .199 (0.17), 1.222 (0.31 ), 1 .233 (0.41 ), 1.255 (0.20), 1 .343 (0.29), 1 .368 (0.37), 1 .375 (0.35), 1 .399
(0.21 ), 1.41 1 (0.18), 1 .464 (0.28), 1.475 (0.29), 1 .496 (0.38), 1 .507 (0.43), 1 .541 (0.31 ), 1 .607
(0.24), 1.634 (0.28), 1 .655 (0.17), 1.802 (0.23), 1 .876 (0.63), 1 .907 (0.51 ), 2.064 (4.87), 2.074
(3.66), 2.237 (3.81 ), 2.323 (0.66), 2.327 (0.90), 2.338 (3.12), 2.370 (2.51 ), 2.518 (3.67), 2.523
(2.25), 2.665 (0.57), 2.669 (0.78), 2.673 (0.63), 2.692 (0.32), 2.724 (0.46), 2.755 (0.34), 2.772 (0.23), 2.799 (0.35), 2.831 (0.20), 2.943 (0.18), 2.974 (0.34), 3.007 (0.38), 3.038 (0.63), 3.070 (1 .19), 3.093 (0.47), 3.107 (0.31 ), 3.159 (15.07), 3.172 (16.00), 3.209 (0.43), 3.229 (0.54), 3.249 (0.40), 3.264 (0.43), 3.278 (0.69), 3.291 (0.67), 3.302 (0.57), 3.387 (0.24), 3.400 (0.28),
3.422 (0.41 ), 3.447 (0.18), 3.485 (0.21 ), 3.512 (0.57), 3.535 (0.20), 3.700 (0.34), 3.731 (0.32),
3.838 (0.44), 3.872 (0.40), 4.085 (1.18), 4.098 (3.28), 4.1 1 1 (3.29), 4.124 (1 .10), 4.321 (0.60),
5.758 (4.67), 6.791 (0.29), 6.806 (0.37), 6.812 (0.43), 6.827 (0.38), 6.941 (0.69), 6.961 (1 .35),
6.981 (0.98), 6.991 (0.34), 7.013 (0.69), 7.037 (1 .12), 7.053 (0.61 ), 7.062 (0.80), 7.069 (0.84),
7.075 (0.92), 7.089 (0.63), 7.096 (0.70), 7.109 (0.83), 7.135 (0.58), 7.142 (0.47), 7.198 (1 .44),
7.220 (1 .53), 7.246 (1 .03), 7.268 (0.64), 7.284 (0.29), 7.297 (0.37), 7.317 (1 .15), 7.335 (1 .58),
7.343 (1 .64), 7.361 (0.52), 7.386 (0.81 ), 7.407 (2.17), 7.433 (2.94), 7.470 (0.69), 7.488 (0.24),
7.989 (0.80), 8.018 (0.72), 8.1 16 (1.21 ), 8.137 (1 .49).
Example 81 and Example 82
5-(4-fluoro-2-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one
5-(4-fluoro-2-methylphenyl)-9-[(2S)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one
Example 81
5-(4-fluoro-2-methylphenyl)-9-[3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 1 )
Figure imgf000244_0001
For the preparation of the diasteromeric mixture, see Example 80. Separation of the there described mixture yielded the title compound 350 mg (95 % purity, 39% yield).
Preparative chiral FIPLC method: Instrument: Labomatic FID5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000, Column: Chiralpak IC 5m 250x30mm; Eluent: hexane + 0.1 Vol-% diethylamine (99%)/ethanol 68:32; Flux 45.0 ml/min; UV 230 nm
Analytical chiral FIPLC method: Instrument: Agilent FIPLC 1260; Column: Chiralpak IC 3m 100x4, 6mm; hexane + 0.1 Vol-% diethylamine (99%)/ethanol 75:25; Flux 1 .4 ml/min; Temperatur: 25 Ό; DAD 220 nm. Analytical Chiral HPLC: Rt = 3.30 min, e.e. >99%.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.173 (0.36), 0.185 (0.42), 0.206 (0.72), 0.217 (0.68),
0.239 (0.46), 0.250 (0.36), 0.998 (0.88), 1.031 (0.88), 1.187 (0.39), 1.199 (0.49), 1.220 (0.91),
1.232 (1.11), 1.255 (0.59), 1.267 (0.46), 1.441 (0.33), 1.462 (0.85), 1.473 (0.88), 1.494 (1.01),
1.507 (0.91), 1.529 (0.42), 1.540 (0.36), 1.605 (0.75), 1.634 (0.52), 1.797 (0.68), 1.852 (0.94),
1.887 (0.81), 2.063 (1.11), 2.074 (12.52), 2.084 (0.55), 2.237 (11.61), 2.323 (1.66), 2.327 (2.28), 2.337 (9.46), 2.369 (0.72), 2.518 (4.78), 2.523 (3.22), 2.539 (16.00), 2.665 (1.37), 2.669 (1.79), 2.673 (1.37), 2.699 (0.75), 2.730 (0.42), 2.772 (0.59), 2.798 (1.01), 2.831 (0.55), 2.943
(0.55), 2.974 (0.98), 2.994 (0.33), 3.005 (0.59), 3.036 (0.16), 3.068 (0.26), 3.140 (0.55), 3.157
(1.40), 3.173 (1.53), 3.209 (1.24), 3.230 (1.66), 3.249 (0.94), 3.264 (0.94), 3.278 (1.79), 3.290
(1.72), 3.302 (1.66), 3.385 (0.65), 3.412 (0.81), 3.445 (0.26), 3.700 (0.59), 3.731 (0.55), 3.842
(0.75), 3.879 (0.68), 4.305 (1.04), 4.325 (0.94), 6.790 (0.91), 6.806 (1.11), 6.812 (1.30), 6.827
(1.14), 6.941 (0.16), 6.960 (0.29), 6.985 (0.65), 6.991 (0.85), 7.013 (1.82), 7.037 (2.54), 7.062
(1.92), 7.069 (1.24), 7.088 (1.07), 7.096 (0.98), 7.113 (1.11), 7.120 (0.85), 7.135 (0.16), 7.198
(0.29), 7.217 (0.33), 7.247 (1.04), 7.262 (1.04), 7.269 (0.98), 7.284 (0.81), 7.296 (1.11), 7.317
(3.51), 7.334 (5.01), 7.342 (4.88), 7.360 (1.46), 7.387 (1.63), 7.407 (4.23), 7.414 (3.90), 7.433
(4.26), 7.452 (3.87), 7.471 (1.89), 7.483 (0.55), 7.488 (0.72), 7.992 (2.31 ), 8.118 (3.41 ).
Optical rotation (method OR1): +43.8°+/-0.35°(met hanol).
Example 82
5-(4-fluoro-2-methylphenyl)-9-[3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1-oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer 2)
Figure imgf000245_0001
For the preparation of the title compound as a mixture of stereoisomers and separation of the stereoisomers see Example 81. Obtained: 35.0 mg (95 % purity, 39 % yield).
Analytical Chiral FIPLC: Rt = 4.88 min, e.e. >99%.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.301 (0.47), -0.289 (0.59), -0.268 (1.01), -0.256 (0.97), -0.235 (0.61), -0.223 (0.47), 0.814 (0.18), 0.980 (0.18), 1.032 (1.13), 1.062 (1.08), 1.259 (0.18), 1.303 (0.27), 1.315 (0.38), 1.335 (0.92), 1.344 (0.90), 1.367 (1.22), 1.375 (1.15), 1.399 (0.68), 1.410 (0.54), 1.509 (0.45), 1.538 (0.68), 1.634 (0.38), 1.656 (0.50), 1.665 (0.50), 1.689 (0.27), 1.876 (1.74), 1.906 (1.55), 2.063 (16.00), 2.084 (0.81), 2.221 (0.45), 2.253 (0.70), 2.284 (0.38), 2.327 (1.33), 2.331 (0.99), 2.369 (8.18), 2.518 (4.94), 2.523 (3.15), 2.539 (2.39),
2.669 (1.37), 2.673 (1.01), 2.691 (0.81), 2.718 (1.37), 2.750 (1.04), 2.781 (0.65), 2.814 (0.36),
3.006 (0.74), 3.038 (2.07), 3.069 (3.88), 3.093 (1.51), 3.107 (0.99), 3.264 (0.52), 3.285 (0.70),
3.398 (0.65), 3.424 (0.65), 3.447 (0.34), 3.485 (0.70), 3.512 (1.85), 3.536 (0.68), 3.699 (0.54),
3.732 (0.50), 3.830 (0.90), 3.866 (0.81), 4.263 (0.47), 4.321 (1.01), 4.352 (0.92), 6.941 (2.32),
6.961 (4.46), 6.980 (2.93), 7.016 (0.50), 7.030 (0.79), 7.037 (1.01), 7.053 (1.24), 7.068 (1.58),
7.075 (2.70), 7.089 (1.01), 7.098 (1.46), 7.109 (2.32), 7.117 (1.60), 7.136 (1.85), 7.143 (1.46),
7.198 (4.73), 7.220 (4.66), 7.245 (2.50), 7.267 (1.24), 7.384 (1.26), 7.389 (1.10), 7.404 (2.82),
7.427 (4.75), 7.434 (5.21), 7.460 (0.56), 8.019 (2.95), 8.138 (6.49).
Optical rotation (method OR1): +1.7°+/-0.24°(meth anol).
Example 83
(rac) 5-(4-fluorophenyl)-9-[(1-phenylcyclopentyl)carbonyl]-1-oxa-3,9-diazaspiro[5.5]undecan-2- one
Figure imgf000246_0001
A mixture of 1-phenylcyclopentane-1 -carboxylic acid (41.1 mg, 216 mM, CAS-RN: 77-55-4), PYBOP (121 mg, 233 pmol) and N,N-diisopropylethylamine (87 mI, 0.5 mmol) in DMF was stirred for 5 min, then (rac) 5-(4-fluorophenyl)-1-oxa-3,9-diazaspiro[5.5]undecan-2-one hydrochloride (55.0 mg, 166 mihoI, Intermediate 6) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC (method 11) to give the title compound 50.0 mg (95 % purity, 65 % yield).
LC-MS (method 2): Rt = 1.18 min; MS (ESIpos): m/z = 437 [M+H]+
1H-NMR (500 MHz, DMSO-d6, at 80Ό) delta [ppm]: 0.980 (0.46), 1.386 (0.43), 1.500 (0.46), 1.606 (4.36), 1.615 (4.68), 1.630 (2.34), 1.864 (0.62), 1.944 (0.65), 2.285 (1.32), 2.756 (1.16), 2.761 (1.37), 2.782 (1.88), 2.786 (1.86), 2.807 (1.45), 2.813 (1.21), 2.865 (1.13), 2.871 (1.40), 2.892 (1 .91 ), 2.896 (1 .86), 2.917 (1.43), 2.923 (1 .21 ), 3.008 (1.69), 3.020 (2.12), 3.024 (2.34),
3.036 (2.10), 3.302 (0.75), 3.307 (0.81 ), 3.314 (0.83), 3.319 (0.89), 3.326 (1 .53), 3.332 (1 .59),
3.338 (1 .43), 3.344 (1 .34), 3.375 (1.37), 3.394 (1 .43), 3.416 (0.70), 7.063 (3.63), 7.068 (3.85),
7.070 (3.58), 7.075 (4.49), 7.082 (5.35), 7.090 (0.97), 7.129 (2.85), 7.134 (1 .83), 7.146 (12.40),
7.151 (5.16), 7.158 (8.09), 7.164 (16.00), 7.177 (6.96), 7.184 (3.31 ), 7.196 (1 .69).
Synthesis of reference compounds
Reference Compound 1
(rac) 9-[3,5-bis(trifluoromethyl)benzoyl]-5-(4-fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2- one
Figure imgf000247_0001
A mixture of 3,5-bis(trifluoromethyl)benzoic acid (47.2 mg, 183 mihoI, CAS-RN: 725-89-3), HATU (69.5 mg, 183 pmol) and N,N-diisopropylethylamine (87 mI, 500 mihoI) in DMF (440 mI_) was stirred for 5 min, then (rac) 5-(4-fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one hydrochloride (50.0 mg, 166 mihoI, Intermediate 6) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC (method 7) to give the title compound 31 .6 mg (95 % purity, 36 % yield).
LC-MS (method 2): Rt = 1 .22 min; MS (ESIpos): m/z = 505 [M+H]+
1 H-NMR (500 MHz, DMSO-d6, at 80Ό) d [ppm]: 1 .575 (1 .87), 1 .597 (3.02), 1 .624 (2.43), 1 .632 (2.29), 1 .650 (1 .36), 1 .659 (1.22), 1 .934 (1 .05), 2.353 (0.42), 2.357 (0.80), 2.361 (1 .13),
2.365 (0.86), 2.368 (0.42), 2.517 (5.41 ), 2.521 (3.63), 2.627 (0.44), 2.631 (0.88), 2.635 (1 .22),
2.638 (0.88), 2.642 (0.44), 3.190 (3.02), 3.202 (6.04), 3.215 (3.82), 3.323 (0.90), 3.422 (1 .59),
3.425 (1 .64), 3.435 (1 .55), 3.439 (1.72), 3.446 (2.79), 3.450 (2.77), 3.460 (2.56), 3.464 (2.39),
3.497 (2.41 ), 3.502 (2.54), 3.509 (2.54), 3.513 (2.47), 3.522 (1.61 ), 3.526 (1 .55), 3.534 (1 .34),
3.538 (1 .26), 7.144 (5.22), 7.162 (1 1 .60), 7.180 (6.52), 7.252 (5.05), 7.315 (6.46), 7.319 (3.54), 7.326 (7.40), 7.332 (6.65), 7.339 (2.94), 7.343 (5.43), 8.037 (16.00), 8.104 (6.94). Reference Compound 2
(rac) 9-benzoyl-5-(4-fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one
Figure imgf000248_0001
A mixture of benzoic acid (52.8 mg, 432 mitioI), PYBOP (242 mg, 465 pmol) and N,N- diisopropylethylamine (170 mI, 1 .0 mmol) in DMF (1 .4 mL) was stirred for 5 min, then (rac) 5-(4- fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one hydrochloride (100.0 mg, 332 mihoI, Intermediate 6) was added and the reaction mixture was stirred for 12 h at room temperature under an atmosphere of argon. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with three times with dichloromethane. The combined organic layers were filtered using a Whatman filter and concentrated. The final purification was conducted via preparative HPLC (method 7) to give the title compound 60.0 mg (95 % purity, 44 % yield).
LC-MS (method 2): Rt = 0.93 min; MS (ESIpos): m/z = 369 [M+H]+
1 H-NMR (500 MHz, DMSO-d6, at 80Ό) d [ppm]: 0.948 (0.64), 0.964 (5.51 ), 0.977 (5.79), 1 .481 (0.87), 1 .491 (0.98), 1 .509 (1.91 ), 1 .519 (2.04), 1.533 (2.84), 1 .543 (2.01 ), 1.550 (2.03), 1 .558 (1 .87), 1 .576 (1.82), 1 .586 (2.84), 1.617 (1 .12), 1 .734 (4.28), 1.741 (4.24), 1 .747 (1 1 .70), 1 .754 (4.28), 1 .761 (4.51 ), 1 .774 (0.49), 1 .904 (1 .87), 1.930 (1.42), 2.057 (0.68), 2.092 (0.66),
2.459 (0.68), 2.473 (0.78), 2.513 (4.41 ), 2.518 (3.39), 2.521 (2.86), 2.993 (0.49), 3.006 (0.40),
3.028 (2.99), 3.036 (4.62), 3.041 (7.95), 3.044 (3.62), 3.049 (8.18), 3.054 (4.92), 3.150 (1 .31 ),
3.172 (0.87), 3.192 (3.20), 3.204 (6.32), 3.217 (4.20), 3.239 (1.27), 3.423 (1 .40), 3.428 (1 .44),
3.437 (1 .23), 3.441 (1 .34), 3.448 (3.09), 3.452 (2.95), 3.462 (2.76), 3.466 (2.73), 3.483 (2.78),
3.488 (2.88), 3.495 (2.82), 3.499 (2.80), 3.507 (1 .50), 3.512 (1.40), 3.519 (1 .23), 3.524 (1 .17),
3.895 (0.44), 7.138 (0.64), 7.144 (6.53), 7.148 (2.23), 7.158 (2.86), 7.162 (14.16), 7.166 (2.78), 7.175 (2.56), 7.180 (7.82), 7.186 (0.89), 7.242 (4.47), 7.305 (7.50), 7.310 (5.83), 7.31 1 (5.47), 7.313 (4.18), 7.315 (4.89), 7.321 (13.97), 7.324 (13.78), 7.333 (8.35), 7.340 (7.23), 7.347 (2.80), 7.351 (6.42), 7.387 (1 .36), 7.390 (1 .02), 7.395 (3.01 ), 7.399 (2.52), 7.406 (9.66), 7.409 (5.57), 7.41 1 (5.89), 7.416 (16.00), 7.420 (15.85), 7.425 (3.28), 7.430 (1 .72), 7.439 (0.51 ), 7.443 (0.55). EXPERIMENTAL SECTION - BIOLOGICAL ASSAYS
The parmacological activity of the compounds according to the invention can be assessed using in vitro- and/or in vivo- assays, as known to the person skilled in the art. The following examples describe the biological activity of the compounds according to the invention, without the invention being limited to said examples.
Example compounds according to the invention 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 median is 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.
The in vitro activity of the compounds of the present invention can be demonstrated in the following assays:
Assay 1 : Assay for the detection of inhibitory effects on enzymatic activity of purified human Geranylgeranyltransferase type 1 (GGTase-1)
The biochemical GGTase-1 assay measures the inhibitory effect of compounds on enzymatic activity of human GGTase-1 . The assay principle uses the activity of GGTase-1 to transfer a Geranyl geranyl moiety from Geranylgeranyl pyrophosphate (GGPP) to a peptide or protein with the recognition sequence GCVLL. In the assay, GGTase-1 transfers the Geranylgeranyl moiety to a Dansyl-coupled GCVLL peptide resulting in a fluorescence intensity increase as Dansyl is protected from solvation by the prenyl residue in near proximity. The assay was established according to Mansha et al., European Journal of Medicinal Chemistry, 2016, further optimized and miniaturized to result in a high-throughput amenable add-only assay.
The human beta subunit of GGTase-1 (PGGTI b, amino acids M1 -T377, protein sequence NP 005014.2) and the human alpha subunit of Farnesyltransferase (FNTA, amino acids M1 - Q379, protein sequence NP 002018.1 ), which are essential to constitute the functional GGTase-1 complex, were expressed in insect Hi-5 cells and purified by size exclusion chromatography. The assay was performed in white 384-well microplates (Greiner Bio-One, Frickenhausen, Germany) with a total volume of five microliter (mI). Fifty nanoliter (nl) of a 100- fold concentrated solution of the test compound in DMSO were transferred into a 384-well microtiter test plate. For this, a Flummingbird liquid handler (Digilab, MA, USA) was used. Five nM (or 2nM, Assay 1 *) of GGTase-1 in 2.5 mI assay buffer (50 mM T ris-HCI (pH 7.4), 5 mM MgCl2, 10 mM KCI, 50 mM ZnCE, 5 mM DTT, 0.04% n-Dodecyl beta-D-maltoside, 5 mM ATP) were added to the compounds. After a 15 minutes pre-incubation at room temperature the reaction was started by addition of 2.5 mI with 2 micromolar (mM) (or 0.3mM, Assay 1 *) Dansyl- GCVLL peptide and 2 mM GGPP in assay buffer. Fluorescence intensity of the reaction mixture was measured after 60 minutes at room temperature with a Pherastar by BMG (Germany) by using a module for excitation at 380 nm and emission at 510 nm.
Data were normalized (neutral control containing complete reaction mixture but DMSO instead of a compound = 0% inhibition, inhibitor control containing complete reaction mixture but no enzyme and no compound = 100% inhibition). For dose-response evaluation, compounds were tested in duplicates at up to 1 1 concentrations (20 mM, 5.7 mM, 1 .6 mM, 0.47 mM, 0.13 mM, 38 hM, 1 1 hM, 3.1 hM, 0.89 hM, 0.25 hM and 0.073 hM). Dilution series were made prior to the assay in a 1 00-fold concentrated form by serial dilution with two separate dilutions for each compound (n=2). IC50 values were calculated by 4-parameter fitting using a commercial software package (Genedata Screener, Switzerland).
Table 1 : I C50 values of Example Compounds in Assay 1 (GGTase-1 )
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Assay 2: Assay for the detection of YAP1/TAZ activity in MDA-MB-231-TEAD-Luc reporter cells
The YAP/TAZ Dual Reporter Assay quantifies the activity of endogenous YAP1 and/or TAZ in MDA-MB-231 cells. The cells contain a stable Firefly luciferase reporter under control of a TEAD-promoter (base pairs 27-304), as described under SEQ ID No. 1 , as well as a thymidine kinase (TK)-Renilla reporter construct (pGL4.74, Promega) for toxicity control. Signals are detected by measuring the firefly luminescence followed by the renilla luminescence using the DualGlo-luciferase assay system detection kit (Promega, part # E2920, E2940).
The cells were kept in routine culture in DMEM low glucose, 10% fetal bovine serum (FBS), 1 % Glutamax, 250 pg/ml Hygromycin, 0,5 pg/ml Puromycin, harvested, cryopreserved in 90% culture medium + 10% dimethylsulphoxide (DMSO) and stored as frozen aliquots of typically 10-50 million cells/vial at -150Ό or below until f urther use.
For the assay, sufficient cells were rapidly thawed in a 37Ό water bath and pipetted into pre- warmed assay medium (DMEM/Ham’s 12, 5 ml Glutamine, 5 ml Penicillin/Streptomycin, 4% FBS). The cells were centrifuged for 5 min at 44 x g (gravitational force). The supernatant was removed and the cell pellet was resuspended in fresh medium to give a suspension of 2.0E+05 cells / ml. The cell concentration may vary depending on the cryopreserved cell batch used. The inhibitor control solution contained assay medium without cells.
The assay was performed in white 384-well or 1536-well microplates (Greiner Bio-One, Frickenhausen, Germany) with a total volume of five microliter (mI) or four mI, respectively. Fifty nl (40 nl in 1536-well microplates) of a 100-fold concentrated solution of the test compound in DMSO were transferred into a 384-well microtiter test plate. For this, either a Hummingbird liquid handler (Digilab, MA, USA) or an Echo acoustic system (Labcyte, CA, USA) was used. Five mI of a freshly prepared cell suspension were added to the wells of a test plate. The inhibitor control cell suspension was added to empty wells at the side of the test plate, followed by incubation at 370 in a 5% carbon dioxide atmosp here for 20-24 hours.
For luminescence detection, one mI of the Dual-Glo-Luciferase detection solution, prepared as recommended by the supplier, were added to all wells. The test plate was centrifuged for two minutes at 1200 rpm in a microplate centrifuge (Eppendorf model 5810), incubated at 200 for 10 min before measurement of the luminescence in a microplate reader (typically Pherastar by BMG, Germany, or ViewLux by Perkin-Elmer, USA). Then, one mI of the Dual-Glo-Stop&Glo Luciferase detection solution, prepared as recommended by the supplier, were added to all wells. The test plate was centrifuged for two minutes at 1200 rpm, incubated at 200 for 10 min before measurement of the renilla luminescence in a microplate reader
Data were normalized (control wells containing cell solution without inhibitor = 0% inhibition, assay medium control = 100% inhibition). For dose-response evaluation, compounds were tested in duplicates at up to 1 1 concentrations (for example 20 mM, 5.7 mM, 1 .6 mM, 0.47 mM, 0.13 mM, 38 hM, 1 1 hM, 3.1 hM, 0.89 hM, 0.25 hM and 0.073 hM). Dilution series were made prior to the assay in a 100-fold concentrated form by serial dilution. IC5o values were calculated by 4-parameter fitting using a commercial software package (Genedata Screener, Switzerland).
Table 2: IC5o values of Example Compounds in Assay 2 (MDA-MB231 -TEAD-Luc reporter cells)
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Reference Compounds 1 and 2 did not inhibit the activity of YAP1 and/or TAZ.
Assay 3: Cancer Cell proliferation assay The Cancer Cell proliferation assay quantifies the effect of test compound addition on viability of cancer cells. Human breast cancer cells MDA-MB-231 , human ovarian cancer cells IGR- OV1 and B16-F10 mouse melanoma cells were seeded at 800 cells in 30 mI of their appropriate growth medium (MDA-MB-231 : DMEM / Ham's F12; Biochrom; # FG 4815, with stable Glutamine, 10% FBS Biochrom FBS Superior # S0415); IGR-OV1 RPMI 1640; Biochrom; # FG 1215, with stable Glutamine, 10% FCS Biochrom; # S 0415); B16F10 DMEM / Ham's F12; Biochrom; # FG 4815, with stable Glutamine, 10% FCS Sigma; # F2442)) in 384- well plates and incubated in a humidified 37Ό incu bator. Cells were allowed to recover for 24 h, then test compounds were added to cells by means of an HP D300 digital dispenser in a 10- step 2.67-fold dilution series starting at a maximum final assay concentration of 10 mM. After 72 h incubation in a humidified 37Ό incubator, 30 mI Cell Titer-Glo Luminescent Cell Viability Assay reagent (Promega, G7573) was added and the incubation was continued for 10 min at room temperature. Luminescence, which corresponds to cell viability, was determined on a VICTOR V plate reader. (Perkin Elmer). The half-maximal growth inhibition (IC5o) was calculated as compound concentration, which was required to achieve 50% inhibition of luminescence. IC5o were determined by means of a 4-parameter fit on measurement data which were normalized to vehicle (DMSO) treated cells (=100%) and measurement readings taken immediately before compound exposure (=0%).
Table 3: IC5o values of Example Compounds in Assay 3 (cancer cell proliferation assay)
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Assay 4: Cancer Cell proliferation assay
The Cancer Cell proliferation assay quantifies the effect of test compound addition on viability of cancer cells. Cancer cells JJN-3 (Plasma cell leukemia), DU145 (Prostate Cancer), THP-1 (Acute monocytic leukemia), RAJI (Burkitt lymphoma), NCI-H292 (Non-Small Cell Lung Cancer), MDA-MB-435 (Melanoma), HCC-38 (Breast Cancer), HCC-1806 (Breast Cancer), A549 (Non-Small Cell Lung Cancer), A2780 (Ovarian Cancer), U251 (Glioblastoma), NCI-H23 (Non-Small Cell Lung Cancer), LOVO (Colorectal Cancer), HT-144 (Melanoma) BxPC3 (Pancreatic Cancer) were seeded at appropriate cells numbers in 30 mI of their appropriate growth medium in 384-well plates and incubated in a humidified 370 incubator. Cells were allowed to recover for 24 h, then test compounds were added to cells by means of an HP D300 digital dispenser in a 10-step dilution series. After 72 h incubation in a humidified 370 incubator, Cell viability was assessed by addition of 30 mI Cell Titer-Glo Luminescent Cell Viability Assay reagent (Promega, G7573). Luminescence, which corresponds to cell viability, was determined on a VICTOR V plate reader. (Perkin Elmer). The half-maximal growth inhibition (IC50) was calculated as compound concentration, which is required to achieve 50% inhibition of luminescence. IC50 was determined by means of a 4-parameter fit on measurement data which was normalized to vehicle (DMSO) treated cells (=100%) and measurement readings taken immediately before compound exposure (=0%).
Table 4: IC50 values of Example Compounds 2 and 15 in Assay 4 (cancer cell proliferation assay)
Figure imgf000261_0001
Figure imgf000262_0001

Claims

1 . A compound of general formula (I):
Figure imgf000263_0001
in which
Figure imgf000263_0002
wherein X2 represents a hydrogen atom or a halogen atom or a substituent selected from
Ci -Ce-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C6-cycloalkyl,
(C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, C4-C6-cycloalkenyl,
(C4-C6-cycloalkenyl)-(Ci-C3-alkyl)-, Ci-C6-hydroxyalkyl,
(Ci-C2-alkoxy)-(Ci-C6-alkyl)-, (Ci-C2-haloalkoxy)-(Ci -Ce-alkyl)-, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, C3-C6-cycloalkyloxy,
(C3-C6-cycloalkyloxy)-(Ci-C3-alkyl)-, (Ci-C6-alkoxy)-(C2-C4-alkoxy)-, (C3-C6-cycloalkyloxy)-(C2-C4-alkoxy)-, phenyl, 5- or 6-membered heteroaryl, phenyl-(Ci-C3-alkyl)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, phenoxy-(Ci-C3-alkyl)-, phenoxy-(C2-C3-alkoxy)-, (5- or 6-membered heteroaryl)-(Ci-C3-alkyl)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-,
(5- or 6-membered heteroaryl)oxy-(C2-C3-alkoxy)-,
(5- or 6-membered heteroaryl)oxy-, -SH, -S-(Ci -Ce-alkyl), -S(=0)-(Ci-Ce-alkyl), -S(=0)2-(Ci -Ce-alkyl) , -S-(C3-C6-cycloalkyl) , -S(=0)-(C3-C6-cycloalkyl) , -S(=0)2-(C3-Ce-cycloalkyl) , (Ci -Ce-alkyl)-S-(Ci -C3-alkyl)-,
(Ci-Ce-alkyl)-S(=0)-(Ci-C3-alkyl)-, (Ci-Ce-alkyl)-S(=0)2-(Ci -C3-alkyl)-,
(C3-Ce-cycloalkyl)-S-(Ci-C3-alkyl)-, (C3-Ce-cycloalkyl)-S(=0)-(Ci-C3-alkyl), (C3-Ce-cycloalkyl)-S(=0)2-(Ci -C3-alkyl) , -S-(Ci -Ce-haloalkyl) ,
-S(=0)-(Ci-Ce-haloalkyl), -S(=0)2-(Ci-Ce-haloalkyl), -S-phenyl, -S(=0)-phenyl, -S(=0)2-phenyl, -cyano, hydroxy, -N(R5)(R6), -(Ci-C4-alkyl)-N(R5)(R6),
4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkenyl, -(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl),
(4- to 7-membered heterocycloalkyl)oxy-, -C(=0)R8, C(=0)N(R5)(R6),
-C(=0)OR7, -N(R7)C(=0)R8, -N(R7)C(=0)OR1°, -N(R7)C(=0)N(R5)(R6), -0C(=0)N(R5)(R6), -OC(=0)R8 and -N(R7)S(=0)2R11 ,
wherein said C3-C6-cycloalkyl group and C -Ce-cycloalkenyl group and the (Cs-Ce-cycloalkyl) part of said (C3-C6-cycloalkyl)-(Ci -C3-alkyl) group and the (C -Ce-cycloalkenyl) part of said
(C4-C6-cycloalkenyl) -(Ci-C3-alkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano and hydroxy, and
wherein said C3-C6-cycloalkyloxy group and the (C3-C6-cycloalkyloxy) part of said (C3-C6-cycloalkyloxy)-(Ci-C3-alkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano and hydroxy, and
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the
4- to 7-membered heterocycloalkyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and
(4- to 7-membered heterocycloalkyl)oxy group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, C3-C4-cycloalkyl, Ci-C2-alkoxy, cyano, hydroxy, -N(R5)(R6) and oxo,
and
wherein said phenyl and phenoxy group, and the phenyl part of said phenyl-(Ci-C3-alkyl)-, phenyl-(Ci-C3-alkoxy)-, phenoxy-(Ci-C3-alkyl)-, phenoxy-(C2-C3-alkoxy)-, -S-phenyl, -S(=0)-phenyl and -S(=0)2-phenyl group, and said 5- or 6-membered heteroaryl group and (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)-(Ci-C3-alkyl),
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy),
(5- or 6-membered heteroaryl)oxy-(C2-C3-alkoxy) and
(5- or 6-membered heteroaryljoxy- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy and -N(R5)(R6), wherein X3 represents a hydrogen atom or a halogen atom or a substituent selected from Ci-C2-alkyl and Ci-C2-alkoxy, or,
wherein X2 and X3 are linked to one another in such a way that they jointly form a group selected from
-(CH2)2-0-, -0-(CH2)2-, -CH2-O-CH2-, -(CH2)3-0-, -0-(CH2)3-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, O-CH2-O-, -0-(CH2)2-0-, -(CH2)2-N(R9)-, -N(R9)-(CH2)2-, -CH2-N(R9)-CH2-, -(CH2)3-N(R9)-, -N(R9)-(CH2)3-, -CH2-N(R9)-(CH2)2-,
-(CH2)2-N(R9)-CH2-, -N(R9)-(CH2)2-N(R9)-, -N(R9)-(CH2)2-0- and
-0-(CH2)2-N(R9)-,
wherein X4 represents a hydrogen atom or a halogen atom or a substituent selected from Ci-C2-alkyl and Ci-C2-haloalkyl, or,
wherein X3 and X4 are linked to one another in such a way that they jointly form a group selected from
-(CH2)2-0-, -0-(CH2)2-, -CH2-O-CH2-, -(CH2)3-0-, -0-(CH2)3-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, 0-CH2-0-, -0-(CH2)2-0-, -(CH2)2-N(R9)-, -N(R9)-(CH2)2-, -CH2-N(R9)-CH2-, -(CH2)3-N(R9)-, -N(R9)-(CH2)3-, -CH2-N(R9)-(CH2)2-,
-(CH2)2-N(R9)-CH2-, -N(R9)-(CH2)2-N(R9)-, -N(R9)-(CH2)2-0- and
-0-(CH2)2-N(R9)-, wherein X5 represents a hydrogen atom or a halogen atom or a substituent selected from Ci-C2-alkyl and Ci-C2-alkoxy, wherein X6 represents a hydrogen atom or a halogen atom or a substituent selected from Ci-C2-alkyl and Ci-C2-alkoxy,
R2 represents a group selected from phenyl, naphthyl and 5- or 6-membered heteroaryl, which phenyl, naphthyl and 5- or 6-membered heteroaryl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci -Ce-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C6-cycloalkyl, C^Ce-cycloalkenyl, Ci-C6-hydroxyalkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy,
(Ci-C4-alkoxy)-(Ci-C6-alkyl)-, (Ci-C4-haloalkoxy)-( Ci-C6-alkyl)-, (Ci-C4-alkoxy)-(C2-C6-alkoxy)-, (Ci-C4-haloalkoxy)-( C2-C6-alkoxy)-, C3-C6-cycloalkyloxy, -SH, -S-(Ci -Ce-alkyl), -S(=0)-(Ci-C6-alkyl), -S(=0)2-(Ci-C6-alkyl), -S-(Ci-C6-haloalkyl), -S(=0)-(Ci-C6-haloalkyl),
-S(=0)2-(Ci-C6-haloalkyl), -S-(C3-C6-cycloalkyl), -S(=0)-(C3-C6-cycloalkyl), -S(=0)2-(C3-C6-cycloalkyl), -S(=0)2N(R5)R6, -(Ci-C4-alkyl)-S(=0)2N(R5)R6, cyano, hydroxy, -N(R5)(R6), -(Ci-C4-alkyl)-N(R5)(R6), -N(R7)C(=0)R8,
-N(R7)C(=0)OR1°, -N(R7)C(=0)N(R5)(R6), -OC(=0)R8, -C(=0)OR7, -C(=0)N(R5)R6, 4- to 7-membered heterocycloalkyl,
5- to 7-membered heterocycloalkenyl, phenyl and 5- or 6-membered heteroaryl, or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a group selected from
-(CH2)3-, -(CH2)4-, -(CH2)2-0-, -CH2-0-CH2-, -(CH2)3-0-, -CH2-0-(CH2)2-, -0-CH2-0- and -0-(CH2)2-0-,
wherein said 4- to 7-membered heterocycloalkyl group and
5- to 7-membered heterocycloalkenyl group is connected to the rest of the molecule via a carbon atom of said
4- to 7-membered heterocycloalkyl group and
5- to 7-membered heterocycloalkenyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and
5- to 7-membered heterocycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy, -N(R5)(R6) and oxo,
and
wherein said Cs-Ce-cycloalkyl group and C4-C6-cycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo and
wherein said C2-C6-alkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-alkoxy group,
and
wherein said phenyl group and 5- or 6-membered heteroaryl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy and -N(R5)(R6),
R3 represents a hydrogen atom, a halogen atom, or a group selected from
C2-C4-alkyl, C2-C4-alkenyl, C2-C4-alkinyl, Cs-Ce-cycloalkyl, Ci-C4-hydroxyalkyl,
Ci-C4-haloalkyl, (Ci-C2-haloalkoxy)-(Ci-C2-alkyl)-, Ci-C4-alkoxy, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy, hydroxy, cyano, -N(R5)(R6), -(Ci-C2-alkyl)-N(R5)(R6),
C4-C7-heterocycloalkyl, -(Ci-C2-alkyl)-(C4-C7-heterocycloalkyl),
(Ci-C2-haloalkoxy)-(Ci-C2-alkyl)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-,
(C3-C4-cycloalkyloxy)-(Ci-C2-alkyl)-, -C(=0)N(R5)(R6) and -C(=0)OR7,
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C2-alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C2-alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy,
-N(R5)(R6) and oxo,
and
wherein said cycloalkyl group and is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and -N(R5)(R6),
R4 represents a hydrogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkinyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl,
Ci-C4-haloalkyl, -(Ci-C2-alkyl)-N(R5)(R6), C4-C7-heterocycloalkyl,
-(Ci-C2-alkyl)-( C4-C7-heterocycloalkyl), (Ci-C2-haloalkoxy)-(Ci-C2-alkyl)-,
(Ci -C2-alkoxy)-(Ci -C2-alkyl)- and (C3-C4-cycloalkyloxy)-(Ci -C2-alkyl)-,
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C2-alkyl)-(4- to 7-membered heterocycloalkyl) group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
-(Ci-C2-alkyl)-(4- to 7-membered heterocycloalkyl) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, C3-C4-cycloalkyl, cyano, hydroxy,
-N(R5)(R6) and oxo,
and
wherein said cycloalkyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and -N(R5)(R6), or
R3 and R4 together with the carbon atom to which they are attached represent a
5- to 8-membered cycloalkyl group, wherein said cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo,
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
selected from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl and
(Ci-C2-alkoxy)-(C2-C3-alkyl-),
or
R5 and R6 together with the nitrogen to which they are attached represent a
nitrogen containing 4- to 7-membered heterocycloalkyl group,
wherein said 4- to 7-membered nitrogen containing heterocycloalkyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(C2-C3-alkyl)-, cyano, hydroxy and oxo,
R7 represents a hydrogen atom or a Ci-C4 alkyl group,
R8 represents a hydrogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl and Cs-Ce-cycloalkyl,
R9 represents a hydrogen atom or a group selected from
Ci-C6 alkyl, C2-C6 haloalkyl, 03-06 cycloalkyl,
wherein said cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo,
R10 represents a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl and 03-06 cycloalkyl,
and R1 1 represents a group selected from
Ci-C4-alkyl and Ci -C4-haloalkyl, C3-C6-cycloalkyl and phenyl,
wherein said cycloalkyl group is optionally substituted one or two or times, each substituent independently selected from a halogen atom or a group selected from
Ci -C2-alkyl, Ci -C2-haloalkyl, Ci -C2-alkoxy, cyano, hydroxy and oxo, and
wherein said phenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C2-alkyl, Ci -C2-haloalkyl, C3-C4-cycloalkyl, Ci-C2-alkoxy, cyano, hydroxy, 4- to 7-membered heterocycloalkyl and -N(R5)(R6), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
2. The compound according to claim 1 , wherein:
R1 represents a group
Figure imgf000270_0001
wherein X2 represents a hydrogen atom or a halogen atom or a substituent selected from
Ci -Ce-alkyl, C3-C6-cycloalkyl, C^Ce-cycloalkenyl, Ci-C6-alkoxy, Ci -C6-haloalkoxy, (Ci-C6-alkoxy)-(C2-C4-alkoxy)-,
(C3-C6-cycloalkyloxy)-(C2-C4-alkoxy)-,
5- or 6-membered heteroaryl, phenyl-(Ci -C3-alkoxy)-,
(5- or 6-membered heteroaryl)oxy-, -N(R5)(R6), -(Ci -C4-alkyl)-N(R5)(R6),
4- to 7-membered heterocycloalkyl, (4- to 7-membered heterocycloalkyl)oxy-, and -N(R7)C(=0)R8,
wherein said C3-C6-cycloalkyl group and C^Ce-cycloalkenyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci -C2-alkyl, cyano and hydroxy, wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of the
4- to 7-membered heterocycloalkyl group,
and
wherein said 4- to 7-membered heterocycloalkyl group and
(4- to 7-membered heterocycloalkyl)oxy group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, cyano and hydroxy,
and
wherein the phenyl part of said phenyl-(Ci-C3-alkoxy)- group, and said
5- or 6-membered heteroaryl group and (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)oxy- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, cyano and hydroxy, wherein X3 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent, wherein X4 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent, wherein X5 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent, wherein X6 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl substituent,
R2 represents a group selected from phenyl, naphthyl and 5- or 6-membered heteroaryl, which phenyl, naphthyl and 5- or 6-membered heteroaryl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-Ce-alkyl and Ci-C6-alkoxy,
or two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a group selected from
-(CH2)3-, -(CH2) -, -(CH2)2-0-, -CH2-O-CH2-, -(CH2)3-0-, -CH2-0-(CH2)2-, -O-CH2-O- and -0-(CH2)2-0-,
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkoxy and hydroxy,
R4 represents a hydrogen atom or Ci-C4-haloalkyl group,
or
R3 and R4 together with the carbon atom to which they are attached represent a
5- to 8-membered cycloalkyl group,
wherein said cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo,
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
selected from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl and
(Ci-C2-alkoxy)-(C2-C3-alkyl-),
or
R5 and R6 together with the nitrogen to which they are attached represent a
nitrogen containing 4- to 7-membered heterocycloalkyl group,
wherein said 4- to 7-membered nitrogen containing heterocycloalkyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(C2-C3-alkyl)-, cyano, hydroxy and oxo,
R7 represents a hydrogen atom or a Ci-C4 alkyl group,
R8 represents a hydrogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl and C3-C6-cycloalkyl, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
3. The compound according to claim 1 or 2, wherein:
R1 represents a group
Figure imgf000273_0001
wherein X2 represents a hydrogen atom or a halogen atom or a substituent selected from
Ci -C4-alkyl, Ci-C4-alkoxy and phenyl-(Ci -C2-alkoxy)-,
wherein the phenyl part of said phenyl-(Ci -C2-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci -C2-alkyl, cyano and hydroxy, wherein X3 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X4 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X5 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X6 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent,
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a Ci -C4-alkyl group,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)S- group,
R3 represents a group selected from Ci-C4-alkoxy and hydroxy,
R4 represents a Ci-C4-haloalkyl group,
or
R3 and R4 together with the carbon atom to which they are attached represent a
5- to 8-membered cycloalkyl group,
wherein said cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo,
or a stereoisomer, a tautomer, a hydrate, a solvate, or a mixture of same.
4. The compound according to claim 1 , 2 or 3, which is of general formula (l-a),
Figure imgf000274_0001
in which
R1 represents a group
Figure imgf000274_0002
wherein X2 represents a hydrogen atom or a halogen atom or a substituent selected from
Ci-C4-alkyl, Ci-C4-alkoxy and phenyl-(Ci-C2-alkoxy)-,
wherein the phenyl part of said phenyl-(Ci-C2-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, cyano and hydroxy, wherein X3 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X4 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X5 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent, wherein X6 represents a hydrogen atom or a chlorine atom or a fluorine atom or a methyl substituent,
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a Ci-C4-alkyl group,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
R3 represents a group selected from
Ci-C4-alkoxy and hydroxy,
R4 represents a Ci-C4-haloalkyl group,
or
R3 and R4 together with the carbon atom to which they are attached represent a
5- to 8-membered cycloalkyl group,
wherein said cycloalkyl group is optionally substituted one or two times, each substituent independently selected from a halogen atom or a group selected from
Ci-C2-alkyl, Ci-C2-haloalkyl, Ci-C2-alkoxy, cyano, hydroxy and oxo, or a tautomer, a hydrate, a solvate, or a mixture of same.
5. The compound according to claim 1 , 2, 3 or 4, wherein:
R1 represents a group
Figure imgf000276_0001
wherein X2 represents a hydrogen atom or a substituent selected from methyl, methoxy and benzyloxy, wherein X3 represents a hydrogen atom, wherein X4 represents a hydrogen atom or a fluorine atom, wherein X5 represents a hydrogen atom, wherein X6 represents a hydrogen atom,
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a bromine atom and a chlorine atom or a methyl group,
or
two substituents of said phenyl group, when they are attached to adjacent ring atoms, are optionally linked to one another in such a way that they jointly form a -(CH2)3- group,
R3 represents a group selected from methoxy and hydroxy,
R4 represents a trifluoromethyl group,
or
R3 and R4 together with the carbon atom to which they are attached represent a group selected from cyclopentyl and cyclohexyl, or a hydrate, a solvate, or a mixture of same.
6. The compound according claim 1 , 2, 3, 4 or 5, wherein: R1 represents a group selected from
4-fluorophenyl, 4-fluoro-2-methylphenyl, 2-methoxyphenyl and 2-(benzyloxy)phenyl, R2 represents a group selected from
phenyl, 3-bromophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,
3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dihydro-1 H-inden-5-yl and 1 -naphthyl,
R3 represents a group selected from
methoxy and hydroxy,
R4 represents a trifluoromethyl group,
or
R3 and R4 together with the carbon atom to which they are attached represent a group
selected from
cyclopentyl and cyclohexyl,
or a hydrate, a solvate, or a mixture of same.
7. The compound according to claim 1 , 2 or 3 which is selected from the group consisting of:
(rac) 9-{[1 -(3,5-dimethylphenyl)cyclopentyl]carbonyl}-5-(4-fluorophenyl)-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one,
(5R)-9-{[1 -(3,5-dimethylphenyl)cyclopentyl]carbonyl}-5-(4-fluorophenyl)-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one (single stereoisomer),
(5S)-9-{[1 -(3,5-dimethylphenyl)cyclopentyl]carbonyl}-5-(4-fluorophenyl)-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one (single stereoisomer),
(rac) 9-{[1 -(3-chlorophenyl)cyclopentyl]carbonyl}-5-(4-fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]- undecan-2-one,
(rac) 9-{[1 -(3-bromophenyl)cyclopentyl]carbonyl}-5-(4-fluorophenyl)-1 -oxa-3,9-diazaspiro[5.5]- undecan-2-one,
(rac) 5-(4-fluorophenyl)-9-[(1 -phenylcyclohexyl)carbonyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2- one, 5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9-diazaspi ro- [5.5]undecan-2-one (mixture of stereoisomers),
(5R)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5S)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of diastereoisomers),
(5R)-9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one,
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of diastereoisomers),
(5R)-9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
9-[2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of diastereoisomers), (5R)-9-[(2S)-2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2R)-2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2S)-2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
9-[2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa- 3,9-diazaspiro[5.5]undecan-2-one (mixture of diastereoisomers),
(5R)-9-[(2S)-2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluoro- phenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2R)-2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluoro- phenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2S)-2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluoro- phenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluoro- phenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
5-(4-fluorophenyl)-9-[3,3,3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers),
(5R)-5-(4-fluorophenyl)-9-[(2S)-3,3,3-trifluoro-2-methoxy-2-(1 -naphthyl)propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5R)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-(1 -naphthyl)propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5S)-5-(4-fluorophenyl)-9-[(2S)-3,3,3-trifluoro-2-methoxy-2-(1 -naphthyl)propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5S)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-(1 -naphthyl)propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one, 5-(2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one (mixture of two stereoisomers),
(5R)-5-(2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5S)-5-(2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
5-[2-(benzyloxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of two stereoisomers),
(5R)-5-(4-fluoro-2-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one
(5S)-5-(4-fluoro-2-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of diastereomers),
(5R)-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
5-[2-(benzyloxy)phenyl]-9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers),
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one, (5S)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of diastereomers),
(5R)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
5-[2-(benzyloxy)phenyl]-9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one (mixture of diastereomers),
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy- propanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy- propanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy- propanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy- propanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
9-[(2R)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one (mixture of two stereoisomers),
9-[(2S)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one (mixture of two stereoisomers), 5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one (mixture of two stereoisomers),
5-[2-(benzyloxy)phenyl]-9-[(2S)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one (mixture of two stereoisomers),
5-(4-fluorophenyl)-9-[3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9-diazaspiro[5.5]- undecan-2-one (mixture of two diastereomers),
5-(4-fluorophenyl)-9-[(2S)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one (single stereoisomer),
5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one (single stereoisomer),
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one (mixture of two diastereomers),
9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer),
9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer),
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of two diastereomers),
9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of two diastereomers),
9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer),
9-[(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer),
9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of two stereoisomers),
9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa- 3,9-diazaspiro[5.5]undecan-2-one (single stereoisomer), 9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one (single stereoisomer),
9-[2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (mixture of two stereoisomers),
9-[(2R)-2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one (single stereoisomer),
9-[(2S)-2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one (single stereoisomer),
5-(4-fluoro-2-methylphenyl)-9-[3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one (mixture of two stereoisomers),
5-(4-fluoro-2-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer),
5-(4-fluoro-2-methylphenyl)-9-[(2S)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer), and
(rac) 5-(4-fluorophenyl)-9-[(1 -phenylcyclopentyl)carbonyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2- one, or a stereoisomer, a hydrate, a solvate, or a mixture of same.
8. The compound according to claim 1 , 2, 3, 4, 5 or 6 which is selected from the group consisting of:
(5R)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5S)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one, (5R)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2R)-2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(3,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2R)-2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluoro- phenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(2,3-dihydro-1 H-inden-5-yl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluoro- phenyl)-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-(1 -naphthyl)propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5S)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-(1 -naphthyl)propanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5R)-5-(2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5S)-5-(2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one,
(5R)-5-(4-fluoro-2-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one
(5S)-5-(4-fluoro-2-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1 -oxa-
3,9-diazaspiro[5.5]undecan-2-one (5R)-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy- propanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy- propanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-9-[(2R)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-
1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-9-[(2R)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(2-methoxyphenyl)-1 - oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2- methoxypropanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2R)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2- methoxypropanoyl]-1 -oxa-3,9-diazaspiro[5.5]undecan-2-one,
5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9-diaza- spiro[5.5]undecan-2-one (single stereoisomer),
9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer), 9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(4-fluorophenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer),
9-[(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer),
9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa- 3,9-diazaspiro[5.5]undecan-2-one (single stereoisomer),
9-[(2R)-2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-(2-methoxyphenyl)-1 -oxa- 3,9-diazaspiro[5.5]undecan-2-one (single stereoisomer), and
5-(4-fluoro-2-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoyl]-1 -oxa-3,9- diazaspiro[5.5]undecan-2-one (single stereoisomer), or a hydrate, a solvate, or a mixture of same.
9. A method of preparing a compound of general formula (I) according to any one of claims 1 , 2, 3 or 7, said method comprising the step of allowing an intermediate compound of general formula (II) :
Figure imgf000286_0001
in which R1 is as defined for the compound of general formula (I) according to any one of claims 1 , 2,3 or 7 6,
to react with a compound of general formula (XII) :
Figure imgf000286_0002
(XII),
in which R2, R3 and R4 are as defined for the compound of general formula (I) according to any one of claims 1 , 2, 3 or 7,
thereby giving a compound of general formula (I) :
Figure imgf000287_0001
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (I) according to any one of claims 1 , 2, 3 or 7,
then optionally converting said compound into solvates, salts and/or solvates of such salts using the corresponding (i) solvents and/or (ii) bases or acids.
10. A compound of general formula (I) according to any one of claims 1 to 8 or of general formula (l-a) according to any one of claims 1 to 8, for use in the treatment and/or prophylaxis of a disease.
1 1 . A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 8 or of general formula (l-a) according to any one of claims 1 to 8 and one or more pharmaceutically acceptable excipients.
12. A pharmaceutical combination comprising:
• one or more first active ingredients, in particular compounds of general formula (I) according to any one of claims 1 to 8 or of general formula (l-a) according to any one of claims 1 to 8, and
• one or more further active ingredients, in particular anti-cancer agents.
13. Use of a compound of general formula (I) according to any one of claims 1 to 8 or of general formula (l-a) according to any one of claims 1 to 8 for the treatment and/or prophylaxis of a disease.
14. Use of a compound of general formula (I) according to any one of claims 1 to 8 or of general formula (l-a) according to any one of claims 1 to 8 for the preparation of a medicament for the treatment or prophylaxis of a disease.
15. Use according to claim 10, 13 or 14 wherein the disease is a hyperproliferative disorder.
16. Use according to claim 15, wherein the disease is a cancer.
17. Use according to claim 16, wherein the cancer disease is selected from melanoma, lung cancer, glioblastoma, colorectal carcinoma, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, lymphoma and leukemia.
18. Use of a compound of general formula (II)
Figure imgf000288_0001
in which R1 is as defined for the compound of general formula (I) according to any one of claims 1 , 2, 3 or 7,
for the preparation of a compound of general formula (I) according to any one of claims 1 , 2, 3 or 7.
19. Use of a compound of general formula (XXI)
Figure imgf000288_0002
(XXI),
in which R2, R3 and R4 are as defined for the compound of general formula (I) according to any one of claims 1 , 2, 3 or 7,
for the preparation of a compound of general formula (I) according to any one of claims 1 , 2, 3 or 7.
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