WO2020048829A1 - 3,9-diazaspiro[5.5]undecane compounds - Google Patents

3,9-diazaspiro[5.5]undecane compounds Download PDF

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WO2020048829A1
WO2020048829A1 PCT/EP2019/072878 EP2019072878W WO2020048829A1 WO 2020048829 A1 WO2020048829 A1 WO 2020048829A1 EP 2019072878 W EP2019072878 W EP 2019072878W WO 2020048829 A1 WO2020048829 A1 WO 2020048829A1
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Prior art keywords
phenyl
diazaspiro
undecan
methoxy
trifluoro
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PCT/EP2019/072878
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French (fr)
Inventor
Keith Graham
Philipp BUCHGRABER
Nuria AIGUABELLA FONT
Tobias Heinrich
Nico BRÄUER
Lara Patricia KUHNKE
Sven WITTROCK
Martin Lange
Benjamin Bader
Stefan Prechtl
Philip Lienau
Charlotte Christine KOPITZ
Katrin NOWAK-REPPEL
Lisette POTZE
Holger STEUBER
Rebecca Ann HARVEY
Ralph Steven KIRK
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Bayer Aktiengesellschaft
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Publication of WO2020048829A1 publication Critical patent/WO2020048829A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention covers 3,9-diazaspiro[5.5]undecane 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 3,9-diazaspiro[5.5]undecane 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.
  • GTTase I geranylgeranyltransferase I
  • Cancer is the second most prevalent cause of death in the United States, causing around 590,000 deaths in 2015. While significant progress has been made in identifying some of the likely underlying environmental and hereditary causes of cancer, there is a need for novel therapeutic approaches targeting cancer and related diseases.
  • 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 (Flarvey 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 may represent promising targets for therapeutic intervention of various diseases with uncontrolled cell proliferation, including cancer.
  • 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.
  • 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).
  • 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
  • W02005040167A1 describes diazaspiroalkanes and their use for treatment of CCR8 mediated diseases.
  • W02009037168A1 relates to 3,9-diaza-spiro[5.5]undecane and 3,9-diaza-spiro[5.5]undecan-2- one compounds useful for the treatment of a variety of disorders in which modulation of the CCR5 receptor ligand binding is beneficial.
  • WO2009135788A1 relates to 3,9-diaza-spiro[5.5]undecan-2-one compounds useful for thetreatment of a variety of disorders in which modulation of the CCR5 receptor ligand binding is beneficial.
  • 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
  • the present invention covers compounds of general formula (I):
  • R 1 represents a group selected from phenyl and naphtyl
  • phenyl and naphtyl 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 -alkynyl, C3-C 6 -cycloalkyl,
  • Ci-Ce-cyanoalkoxy phenyl, 5- or 6-membered heteroaryl
  • (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the
  • (4- to 7-membered heterocycloalkyl)-(Ci-C3-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 -alkoxy, C3-C 4 -cycloalkyl, -N(R 5 )(R 6 ), -C( 0)OR 8 and oxo, and
  • (5- or 6-membered heteroaryl)-(Ci-C 3 -alkyl)- and (5- or 6-membered heteroaryl)-(Ci-C3-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 Ci-C 2 -haloalkyl, cyano, hydroxy, 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 -alkynyl, Cs-Ce-cycloalkyl, C4-C7-cycloalkenyl, C 4 -C7-hydroxycycloalkenyl, (Ci-C 2 -alkoxy)-(C3-C6-alkenyl)-, Ci-C 6 -hydroxyalkyl, Ci-C 6 -haloalkyl, Ci-C 6 -alkoxy, Ci-C 6 -haloalkoxy, C3-C 6 -cycloalkyloxy, -SH,
  • 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
  • Ci-C 2 -alkyl Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy,
  • 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
  • R 3 represents a hydrogen atom, a halogen atom, or a group selected from
  • (4- to 7-membered heterocycloalkyl)-(Ci-C3-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 Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy,
  • (5- or 6-membered heteroaryl)-(Ci-C 3 -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 Ci-C 2 -haloalkyl, cyano, hydroxy, Ci-C 2 -alkoxy and
  • Ci-C4-alkyl C2-C4-alkenyl, C2-C4-alkynyl, Cs-Ce-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C 4 -haloalkyl, phenyl, phenyl-(Ci-C 2 -alkyl)-, -(Ci-C 2 -alkyl)-N(R 5 )(R 6 ),
  • -(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
  • Ci-C2-alkyl Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy,
  • cycloalkyl group and said phenyl group, and the phenyl part of said phenyl-(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, cyano, hydroxy, Ci-C2-alkoxy and
  • R 3 and R 4 together with the carbon atom to which they are attached represent a 3- to 8-membered cycloalkyl 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
  • 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, Ci-C 4 -haloalkyl, Ci-C 4 -hydroxyalkyl,
  • R 7 represents a hydrogen atom or a Ci-C 4 -alkyl group
  • R 8 represents a Ci-C 4 -alkyl group, 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.
  • 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-C 6 -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,
  • a methyl, ethyl, n-propyl or isopropyl group more particularly 1 or 2 carbon atoms (“Ci-C 2 -alkyl”), e.g. a methyl or ethyl group.
  • 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,
  • 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-Ce-alkyl)-O-, in which the term“Ci-Ce-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-Ce-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-Ce-haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
  • Ci-C 6 -cyanoalkoxy means a linear or branched, saturated, monovalent
  • Ci-C 6 -alkoxy group as defined supra, in which group one of the hydrogen atoms is replaced with a cyano group. Particularly, said group contains 1 , 2, 3 or 4 carbon atoms
  • Ci-C 4 -cyanoalkoxy (“Ci-C 4 -cyanoalkoxy”).
  • Said Ci-C 4 -cyanoalkoxy group is, for example, a cyanomethoxy, 1 -cyanoethoxy, 2-cyanoethoxy, 1 -cyanopropoxy, 2-cyanopropoxy, 3-cyanopropoxy, 1 -cyanobutoxy, 2-cyanobutoxy, 3-cyanobutoxy or 4-cyanobutoxy group, or an isomer thereof.
  • C2-C 6 -hydroxyalkoxy means a linear or branched, saturated, monovalent
  • C2-C 4 -hydroxyalkoxy (“C2-C 4 -hydroxyalkoxy”).
  • Said C2-C 4 -hydoxyalkoxy group is, for example, a 2-hydroxyethoxy, 2-hydroxypropoxy, 3-hydroxypropoxy, 2-hydroxybutoxy, 3-hydroxybutoxy or 4-hydroxybutoxy group, or an isomer thereof.
  • 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”),
  • 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 group.
  • said group has 3 or 4 carbon atoms (“C3-C4-cycloalkyl”), e.g. a cyclopropyl or cyclobutyl group.
  • C 4 -C7-cycloalkenyl means a monocyclic hydrocarbon ring which contains 4, 5, 6 or 7 carbon atoms and one double bond.
  • said ring contains 5 or 6 carbon atoms (“C 5 -C 6 -cycloalkenyl”).
  • Said Cs-Ce-cycloalkenyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyll group.
  • C 4 -C7-hydroxycycloalkenyl means a monocyclic hydrocarbon ring which contains 5 or 6 carbon atoms and one double bond, in which group the term“C 4 -C 7 -cycloalkenyl” is as defined supra , and in which group one hydrogen atom is replaced with a hydroxy group.
  • said ring contains 5 or 6 carbon atoms (“Cs-Ce-hydroxycycloalkenyl”) e.g. a hydroxycyclopentenyl or hydroxycyclohexenyl group.
  • C3-C 6 -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.
  • 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
  • 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, and which is bound via a ring carbon atom.
  • 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 group of formula (5- or 6-membered heteroaryi)-0- in which the term “5- or 6-membered heteroaryl” is as defined supra.
  • 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 as used in the present text, e.g. in the context of the definition of “Ci-Ce-alkyl”, “Ci-C 6 -haloalkyl”, “Ci-C 6 -hydroxyalkyl”, “Ci-C 6 -alkoxy” or “Ci-C 6 -haloalkoxy” means an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • C 3 -C 6 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 group or cycloalkyloxy group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms.
  • C2-C4, C2-C3, C3-C6, C "C 2 -C6" encompasses C 2 , C3, C 4 , C5, Ge, C 2 -C6 , C 2 -C5, C 2 -C 4 , C 2 -C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and Gs-Ge ' ,
  • C 1 -C 4 encompasses Ci , C 2 , C 3 , C 4 , C 1 -C 4 , C 1 -C3, C 1 -C 2 , C 2 -C 4 , C 2 -C3, and C 3 -C 4 ;
  • C 2 -C 4 encompasses C 2 , C 3 , C 4 , C 2 -C 4 , C 2 -C3, and C 3 -C 4 ;
  • C3-C6 encompasses C3, C4, C5, Ge, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and Gs-Ge-
  • 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, 1231 , 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, 1231 , 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 11 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.
  • 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.
  • 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 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 may contain an amide moiety and can exist as an amide, or an imidic acid, or even a mixture in any amount of the two tautomers, namely : amide imidic acid
  • 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 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.
  • 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, C1- Ce alkoxymethyl esters, e.g. methoxymethyl, Ci-Ce alkanoyloxymethyl esters, e.g.
  • esters 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. 5-methyl-1 ,3-dioxolen- 2-onylmethyl; and 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 selected from phenyl and naphtyl
  • phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
  • n represents an integer of 2, 3 or 4,
  • (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
  • (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C 2 -alkoxy, C3-C 4 -cycloalkyl, -N(R 5 )(R 6 ), -C( 0)OR 8 and oxo, and
  • (5- or 6-membered heteroaryl)-(Ci-C 3 -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 Ci-C 2 -alkoxy,
  • phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
  • 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
  • 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 Ci-C 2 -alkyl 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 and a Ci-C 2 -alkyl group,
  • R 3 represents a hydrogen atom, a halogen atom, or a group selected from
  • Ci-C 4 -alkyl C 2 -C 4 -alkenyl, C3-C 6 -cycloalkyl, Ci-C 4 -hydroxyalkyl, Ci-C 4 -haloalkyl, Ci-C 4 -alkoxy, C 2 -C 4 -hydroxyalkoxy, (Ci-C 2 -alkoxy)-(C 2 -C 4 -alkoxy)-,
  • (4- to 7-membered heterocycloalkyl)-(Ci-C 3 -alkoxy)- 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)-(Ci-C 3 -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 and oxo, and
  • (5- or 6-membered heteroaryl)-(Ci-C 3 -alkoxy)-group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C 2 -alkyl group,
  • R 4 represents a hydrogen atom, a halogen atom, or a group selected from
  • Ci-C 4 -alkyl C 2 -C 4 -alkenyl, Ci-C 4 -haloalkyl and (Ci-C 2 -alkoxy)-(Ci-C 2 -alkyl)-, or
  • 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 Ci-C 4 -alkyl group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • R 1 represents a group selected from phenyl and naphtyl
  • phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
  • n represents an integer of 2, 3 or 4,
  • (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- 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)-(Ci-C3-alkoxy)- group is is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci-C 2 -alkoxy, C3-C 4 -cycloalkyl, -N(R 5 )(R 6 ), -C( 0)OR 8 and oxo, and
  • (5- or 6-membered heteroaryl)-(Ci-C 3 -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 and
  • R 2 represents a group selected from phenyl, naphthyl and pyridinyl
  • 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
  • 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 Ci-C 2 -alkyl and oxo, and
  • Ci-C4-alkyl C2-C4-alkenyl, Cs-Ce-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C 4 -alkoxy, C 2 -C 4 -hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C 4 -alkoxy)-,
  • (4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
  • R 4 represents a hydrogen atom, a halogen atom, or a group selected from
  • Ci-C 4 -alkyl C 2 -C 4 -alkenyl and Ci-C 4 -haloalkyl
  • 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
  • Ci-C 4 -alkyl, and C3-C 4 -cycloalkyl are Ci-C 4 -alkyl, and C3-C 4 -cycloalkyl,
  • 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 Ci-C 4 -alkyl group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention covers compounds of general formula (l-a):
  • R 1 represents a group selected from phenyl and naphtyl
  • phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
  • n represents an integer of 2, 3 or 4,
  • (5- or 6-membered heteroaryl)-(Ci-C 3 -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 Ci-C 2 -alkoxy,
  • R 2 represents a group selected from phenyl, naphthyl and pyridinyl
  • phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
  • 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
  • 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 Ci-C 2 -alkyl 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 and a Ci-C 2 -alkyl group,
  • R 3 represents a hydrogen atom, a halogen atom, or a group selected from
  • (4- to 7-membered heterocycloalkyl)-(Ci-C 3 -alkoxy)- 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)-(Ci-C 3 -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 and oxo, and
  • (5- or 6-membered heteroaryl)-(Ci-C 3 -alkoxy)-group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C 2 -alkyl group,
  • R 4 represents a hydrogen atom, a halogen atom, or a group selected from
  • Ci-C 4 -alkyl C 2 -C 4 -alkenyl, Ci-C 4 -haloalkyl and (Ci-C 2 -alkoxy)-(Ci-C 2 -alkyl)-, 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 Ci-C 4 -alkyl group, and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • R 1 represents a group selected from phenyl and naphtyl
  • phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
  • (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- 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)-(Ci-C3-alkoxy)- group is is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • Ci -C 2 -alkoxy, C3-C 4 -cycloalkyl, -N(R 5 )(R 6 ), -C( 0)OR 8 and oxo, and
  • (5- or 6-membered heteroaryl)-(Ci-C 3 -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 and
  • R 2 represents a group selected from phenyl, naphthyl and pyridinyl
  • phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
  • 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
  • 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 Ci-C 2 -alkyl 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 and a Ci-C 2 -alkyl group,
  • R 3 represents a hydrogen atom, a halogen atom, or a group selected from
  • Ci-C 4 -alkyl C 2 -C 4 -alkenyl, C3-C 6 -cycloalkyl, Ci-C 4 -hydroxyalkyl, Ci-C 4 -haloalkyl, Ci-C 4 -alkoxy, C2-C 4 -hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C 4 -alkoxy)-,
  • (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
  • (4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
  • (5- or 6-membered heteroaryl)-(Ci-C 3 -alkoxy)-group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C 2 -alkyl group,
  • R 4 represents a hydrogen atom, a halogen atom, or a group selected from
  • Ci-C 4 -alkyl C 2 -C 4 -alkenyl and Ci-C 4 -haloalkyl
  • 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 8 represents a Ci-C 4 -alkyl group
  • the present invention covers compounds of general formula (l-a), supra , in which:
  • R 1 represents a group wherein "*" represents the point of attachment to the rest of the molecule
  • X 2 represents a hydrogen atom or a halogen atom or a group selected from Ci-C 4 -alkyl, Ci-C 4 -hydroxyalkyl, Ci-C 4 -haloalkyl, Ci-C 4 -alkoxy, C2-C 6 -hydroxyalkoxy, Ci-C 4 -haloalkoxy, Cs-Ce-cycloalkyloxy, (C3-C6-cycloalkyl)-(Ci -C3-alkoxy)-, phenoxy, hydroxy, C 2 -C 4 -hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C 6 -alkoxy)-,
  • n represents an integer of 2, 3 or 4,
  • (4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)- 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)-(Ci -C3-alkoxy)- 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)-(Ci-C 3 -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 Ci-C 2 -alkoxy, wherein X 3 represents a hydrogen atom or a halogen atom or a Ci-C 4 -alkyl group, or,
  • X 5 represents a hydrogen atom or a halogen atom or a Ci-C 4 -alkyl group
  • X 6 represents a hydrogen atom or a halogen atom or a Ci-C 4 -alkyl group
  • R 2 represents a group selected from phenyl, naphthyl and pyridinyl
  • phenyl, naphthyl and pyridinyl 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 optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C 2 -alkyl 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 and a Ci-C 2 -alkyl group,
  • R 3 represents a hydrogen atom, a halogen atom, or a group selected from
  • Ci-C 4 -alkyl C 2 -C 4 -alkenyl, C3-C 6 -cycloalkyl, Ci-C 4 -hydroxyalkyl, Ci-C 4 -haloalkyl, Ci-C 4 -alkoxy, C 2 -C 4 -hydroxyalkoxy, (Ci-C 2 -alkoxy)-(C 2 -C 4 -alkoxy)-,
  • (4- to 7-membered heterocycloalkyl)-(Ci-C 3 -alkoxy)- 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)-(Ci-C 3 -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 and oxo, and
  • (5- or 6-membered heteroaryl-(Ci-C 3 -alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C 2 -alkyl group,
  • R 4 represents a hydrogen atom, a halogen atom, or a group selected from
  • Ci-C 4 -alkyl, C 2 -C 4 -alkenyl, Ci-C 4 -haloalkyl and (Ci-C 2 -alkoxy)-(Ci-C 2 -alkyl)-, 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 Ci-C 4 -alkyl group
  • R 9 represents a hydrogen atom or a halogen atom and a Ci-C 2 -alkyl group
  • the present invention covers compounds of general formula (l-a), supra , in which:
  • R 1 represents a group wherein " * " represents the point of attachment to the rest of the molecule
  • X 2 represents a hydrogen atom or a halogen atom or a group selected from Ci-C 4 -alkyl, Ci-C 4 -hydroxyalkyl, Ci-C 4 -haloalkyl, Ci-C 4 -alkoxy,
  • n represents an integer of 2, 3 or 4,
  • (4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)- 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)-(Ci-C 3 -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 and Ci -C 2 -alkoxy, wherein X 3 represents a hydrogen atom or a halogen atom or a Ci-C 4 -alkyl group, or,
  • X 3 and X 4 are linked to one another in such a way that they jointly form a group selected from -CH2-O-CH2- and -O-CH2-O-, wherein X 5 represents a hydrogen atom or a halogen atom or a Ci-C 4 -alkyl group, wherein X 6 represents a hydrogen atom or a halogen atom,
  • phenyl, naphthyl and pyridinyl 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 optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from Ci-C2-alkyl 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 and a Ci-C 2 -alkyl group,
  • R 3 represents a hydrogen atom, a halogen atom, or a group selected from
  • (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- 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)-(Ci-C3-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 and oxo, and
  • R 4 represents a hydrogen atom, a halogen atom, or a group selected from
  • Ci-C 4 -alkyl C 2 -C 4 -alkenyl and Ci-C 4 -haloalkyl
  • R 5 and R 6 represent, independently from each occurrence, a hydrogen atom or a group
  • Ci-C 4 -alkyl and C3-C 4 -cycloalkyl are Ci-C 4 -alkyl and C3-C 4 -cycloalkyl
  • 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 Ci-C 4 -alkyl group
  • R 9 represents a hydrogen atom or a halogen atom and a Ci-C 2 -alkyl group, and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention covers compounds of general formula (l-a), supra , in which:
  • R 1 represents a group wherein "*" represents the point of attachment to the rest of the molecule
  • X 2 represents a hydrogen atom or a halogen atom or a group selected from Ci -C 4 -alkyl, Ci -C 4 -hydroxyalkyl, Ci -C 4 -haloalkyl, Ci -C 4 -alkoxy, C2-C 6 -hydroxyalkoxy, Ci -C 4 -haloalkoxy, C3-C 6 -cycloalkyloxy, (C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, phenoxy, hydroxy, (Ci-C2-alkoxy)-(C2-C 6 -alkoxy)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)- (Ci-C2-alkoxy)-, phenyl, phenyl-(Ci -C3-alkoxy)-, 5- or 6-membered heteroaryl,
  • (4- to 7-membered heterocycloalkyl)oxy- group and (4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
  • Ci -C 2 -alkyl Ci -C 2 -hydroxyalkyl, cyano, hydroxy and oxo,
  • phenyl group and said 5- or 6-membered heteroaryl group and the (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)-(Ci - C 3 -alkoxy) group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from
  • X 2 and X 3 are linked to one another in such a way that they jointly form a -0-(CH 2 ) 2 - group, wherein X 4 represents a hydrogen atom or a halogen atom, wherein X 5 represents a hydrogen atom or a halogen atom or a Ci-C 2 -alkyl group, wherein X 6 represents a hydrogen atom or a halogen atom or a Ci-C 4 -alkyl group,
  • R 2 represents a group selected from phenyl and naphthyl
  • phenyl and naphthyl 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
  • Ci-C 4 -alkyl Ci-C 4 -alkoxy, hydroxy and Ci-C 4 -haloalkyl
  • R 4 represents a hydrogen atom, a halogen atom, or a group selected from
  • 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 Ci-C 4 -alkyl group
  • R 5 and R 6 together with the nitrogen to which they are attached represent a
  • X 2 represents a hydrogen atom or a group selected from
  • (4- to 7-membered heterocycloalkyl)oxy- group is connected to the rest of the molecule via a carbon atom of the 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 Ci -C2-hydroxyalkyl, hydroxy and oxo
  • 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 and Ci-C 2 -alkoxy, wherein X 3 represents a hydrogen atom, wherein X 4 represents a hydrogen atom or a halogen 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, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
  • R 4 represents a hydrogen atom, a halogen atom, or a group selected from
  • Ci -C 4 -alkyl and Ci-C 4 -haloalkyl are Ci-C 4 -alkyl and Ci-C 4 -haloalkyl
  • the present invention covers compounds of general formula (l-a), supra , in which:
  • X 2 represents a hydrogen atom or a bromine atom, chlorine atom, fluorine atom, or a group selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, phenoxy, diifluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy,
  • R 2 represents a group selected from
  • R 3 and R 4 together with the carbon atom to which they are attached represent a
  • the present invention covers compounds of general formula (l-a), supra , in which:
  • X 2 represents a hydrogen atom or a group selected from methyl, methoxy, 3-methoxypropoxy, tetrahydrofuran-3-yloxy and 3-methoxyphenyl
  • X 3 represents a hydrogen atom
  • X 4 represents a hydrogen atom or a fluorine atom
  • X 5 represents a hydrogen atom
  • X 6 represents a hydrogen atom
  • R 3 represents a hydrogen atom, a fluorine atom, or a group selected from
  • R 4 represents a hydrogen atom, or a fluorine atom, or a group selected from
  • R 3 and R 4 together with the carbon atom to which they are attached represent a
  • the present invention covers compounds of general formula (l-a), supra , in which:
  • R 1 represents a group selected from
  • R 3 represents a hydrogen atom, a fluorine atom, or a group selected from
  • the present invention covers compounds of general formula (l-a), supra, in which:
  • phenyl 4-fluorophenyl, 4-fluoro-2-methylphenyl, 4-fluoro-2-methoxyphenyl,
  • R 3 and R 4 together with the carbon atom to which they are attached represent a

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Abstract

The present invention covers 3,9-diazaspiro[5.5]undecane 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

3, 9-DIAZASPIRO[5.5]UN DECANE COMPOUNDS
The present invention covers 3,9-diazaspiro[5.5]undecane 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 3,9-diazaspiro[5.5]undecane 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.
Cancer is the second most prevalent cause of death in the United States, causing around 590,000 deaths in 2015. While significant progress has been made in identifying some of the likely underlying environmental and hereditary causes of cancer, there is a need for novel therapeutic approaches targeting cancer and related diseases.
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 (Flarvey 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).
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).
WO20191 18973A1 describes 1 -(piperidinocarbonylmethyl)-2-oxopiperazine derivatives for treating cancer.
W02005040167A1 describes diazaspiroalkanes and their use for treatment of CCR8 mediated diseases.
W02009037168A1 relates to 3,9-diaza-spiro[5.5]undecane and 3,9-diaza-spiro[5.5]undecan-2- one compounds useful for the treatment of a variety of disorders in which modulation of the CCR5 receptor ligand binding is beneficial.
WO2009135788A1 relates to 3,9-diaza-spiro[5.5]undecan-2-one compounds useful for thetreatment of a variety of disorders in which modulation of the CCR5 receptor ligand binding is beneficial.
However, the state of the art does not describe the 3,9-diazaspiro[5.5]undecane 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 selected from phenyl and naphtyl,
which phenyl and naphtyl 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-alkynyl, C3-C6-cycloalkyl,
(C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, (C3-C6-cycloalkyloxy)-(Ci-C3-alkyl)-, Ci-Ce-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci -Ce-alkyl)-, Ci-Ce-haloalkyl, Ci-Ce-alkoxy, (C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, C2-C6-hydroxyalkoxy,
(Ci -C2-alkoxy)-(C2-C6-alkoxy)-,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-,
(Ci-C6-alkyl)-S-(Ci-Ce-alkoxy)-, Ci-Ce-haloalkoxy,
(Ci -C2-haloalkoxy)-(Ci -Ce-alkyl)-, C3-Ce-cycloalkyloxy,
Ci-Ce-cyanoalkoxy, phenyl, 5- or 6-membered heteroaryl,
(5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkyl)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci-C3-alkyl)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, phenoxy-(Ci-C3-alkyl)-,
phenoxy-(C2-C3-alkoxy)-, -SH, -S-(Ci-Ce-alkyl), -S(=0)-(Ci-Ce-alkyl),
-S(=0)2-(Ci -Ce-alkyl) , -S-(C3-C6-cycloalkyl) , -S(=0)-(C3-Ce-cycloalkyl) , -S(=0)2-(C3-C6-cycloalkyl), -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), (R5)(R6)N-(C2-C3-alkoxy)-,
4- to 7-membered heterocycloalkyl, (4- to 7-membered heterocycloalkyl)oxy-, -(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl),
(4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)-, -C(=0)N(R5)(R6), -(Ci-C3-alkyl)-C(=0)N(R5)(R6), (R5)(R6)NC(=0)-(Ci -C3-alkoxy)-, -C(=0)OR7, -(Ci-C3-alkyl)-C(=0)0R7, R7OC(=0)-(Ci-C3-alkoxy)-, -C(=0)R7,
-(Ci-C3-alkyl)-C(=0)R7 and (Ci-C2-alkoxy)-(C2-C3-alkoxy)n-,
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) -, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -O-CH2-O-, -0-(CH2)2-0-, -N(R7)-(CH2)2-, -(CH2)2-N(R7)-, -CH2-N(R7)-CH2-, -N(R7)-(CH2)3-, -(CH2)3-N(R7)-,
-CH2-N(R7)-(CH2)2-, -(CH2)2-N(R7)-CH2-, -N(R7)-(CH2)2-N(R7)-, -N(R7)-(CH2)2-0- and -0-(CH2)2-N(R7)-,
wherein n represents an integer of 2, 3, 4 or 5,
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)oxy- group,
-(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl) group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- 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
(4- to 7-membered heterocycloalkyl)oxy- group,
-(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl) group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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, Ci-C2-haloalkyl, Ci-C2-hydroxyalkyl, cyano, hydroxy,
Ci -C2-alkoxy, C3-C4-cycloalkyl, -N(R5)(R6), -C(=0)OR8 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 the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkyl)- and (5- or 6-membered heteroaryl)-(Ci-C3-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, Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl and -N(R5)(R6),
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-alkynyl, Cs-Ce-cycloalkyl, C4-C7-cycloalkenyl, C4-C7-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C6-alkenyl)-, Ci-C6-hydroxyalkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, C3-C6-cycloalkyloxy, -SH,
-S-(Ci -Ce-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), cyano, hydroxy,
-N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)OR7,
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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-0-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -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, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
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, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl and -N(R5)(R6),
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C6-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C6-alkoxy)-, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy, phenyl, phenoxy, phenyl-(Ci-C2-alkyl)-, phenyl-(Ci-C2-alkoxy)-, (5- or 6-membered heteroaryl)oxy,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy), hydroxy, cyano, -N(R5)(R6),
-(Ci-C2-alkyl)-N(R5)(R6), (R5)(R6)N-(C2-C3-alkoxy)-, C4-C7-heterocycloalkyl,
-(Ci-C2-alkyl)-(C4-C7-heterocycloalkyl),
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-, (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 and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- 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 and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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, Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
and wherein said cycloalkyl group and said phenyl group, and the phenyl part of said phenoxy, phenyl-(Ci-C2-alkyl)- and phenyl-(Ci-C2-alkoxy)- group, and the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)oxy- group and
(5- or 6-membered heteroaryl)-(Ci-C3-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, Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy and
-N(R5)(R6),
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Cs-Ce-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, phenyl, phenyl-(Ci-C2-alkyl)-, -(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, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
and
wherein said cycloalkyl group and said phenyl group, and the phenyl part of said phenyl-(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, cyano, hydroxy, Ci-C2-alkoxy and
-N(R5)(R6),
or
R3 and R4 together with the carbon atom to which they are attached represent a 3- 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
seleceted from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(C2-C3-alkyl-), -C(=0)-(Ci-C3-aikyl) and -C(=0)-(Ci-C3-haioalkyl), 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, Ci-C4-haloalkyl, Ci-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(Ci-C3-alkyl)- and oxo,
R7 represents a hydrogen atom or a Ci-C4-alkyl group,
and
R8 represents a Ci-C4-alkyl group, 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-Ce-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-C6-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-Ce-alkyl)-O-, in which the term“Ci-Ce-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-Ce-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-Ce-haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
2.2.2-trifluoroethoxy or pentafluoroethoxy.
The term “Ci-C6-cyanoalkoxy” means a linear or branched, saturated, monovalent
Ci-C6-alkoxy group, as defined supra, in which group one of the hydrogen atoms is replaced with a cyano group. Particularly, said group contains 1 , 2, 3 or 4 carbon atoms
(“Ci-C4-cyanoalkoxy”). Said Ci-C4-cyanoalkoxy group is, for example, a cyanomethoxy, 1 -cyanoethoxy, 2-cyanoethoxy, 1 -cyanopropoxy, 2-cyanopropoxy, 3-cyanopropoxy, 1 -cyanobutoxy, 2-cyanobutoxy, 3-cyanobutoxy or 4-cyanobutoxy group, or an isomer thereof.
The term “C2-C6-hydroxyalkoxy” means a linear or branched, saturated, monovalent
C2-C6-alkoxy group, as defined supra, in which group one of the hydrogen atoms is replaced with a hydroxy group. Particularly, said group contains 2, 3 or 4 carbon atoms
(“C2-C4-hydroxyalkoxy”). Said C2-C4-hydoxyalkoxy group is, for example, a 2-hydroxyethoxy, 2-hydroxypropoxy, 3-hydroxypropoxy, 2-hydroxybutoxy, 3-hydroxybutoxy or 4-hydroxybutoxy group, or an isomer thereof.
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 group. Particularly, said group has 3 or 4 carbon atoms (“C3-C4-cycloalkyl”), e.g. a cyclopropyl or cyclobutyl group. The term“C4-C7-cycloalkenyl” means a monocyclic hydrocarbon ring which contains 4, 5, 6 or 7 carbon atoms and one double bond. Particularly, said ring contains 5 or 6 carbon atoms (“C5-C6-cycloalkenyl”). Said Cs-Ce-cycloalkenyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyll group.
The term“C4-C7-hydroxycycloalkenyl” means a monocyclic hydrocarbon ring which contains 5 or 6 carbon atoms and one double bond, in which group the term“C4-C7-cycloalkenyl” is as defined supra , and in which group one hydrogen atom is replaced with a hydroxy group. Particularly, said ring contains 5 or 6 carbon atoms (“Cs-Ce-hydroxycycloalkenyl”) e.g. a hydroxycyclopentenyl or hydroxycyclohexenyl group.
The term “C3-C6-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 heterocycloalkyl of formula (4- to 7-membered heterocycloalkyi)-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, and which is bound via a ring carbon atom.
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 group of formula (5- or 6-membered heteroaryi)-0- in which the term “5- or 6-membered heteroaryl” is as defined supra.
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 -Ce”, as used in the present text, e.g. in the context of the definition of “Ci-Ce-alkyl”, “Ci-C6-haloalkyl”, “Ci-C6-hydroxyalkyl”, “Ci-C6-alkoxy” or “Ci-C6-haloalkoxy” means an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5 or 6 carbon atoms.
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 group or cycloalkyloxy group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 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
C2-C4, C2-C3, C3-C6, C
Figure imgf000015_0001
"C2-C6" encompasses C2, C3, C4, C5, Ge, C2-C6 , C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and Gs-Ge',
"C1-C4" encompasses Ci , C2, C3, C4, C1-C4, C1 -C3, C1-C2, C2-C4, C2-C3, and C3-C4;
"C2-C4" encompasses C2, C3, C4, C2-C4, C2-C3, and C3-C4;
"C3-C6" encompasses C3, C4, C5, Ge, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and Gs-Ge-
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, 1231 , 124|_ 125| 129| anc| 1311_ 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 11C 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 may contain an amide moiety and can exist as an amide, or an imidic acid, or even a mixture in any amount of the two tautomers, namely :
Figure imgf000020_0001
amide imidic acid
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 HCI", "x CF3COOH", "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, C1- Ce alkoxymethyl esters, e.g. methoxymethyl, Ci-Ce 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 selected from phenyl and naphtyl,
which phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl and Ci-C4-alkoxy, (C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, C2-C6-hydroxyalkoxy,
(Ci -C2-alkoxy)-(C2-C6-alkoxy)-,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-,
(Ci-C4-alkyl)-S-(Ci-C4-alkoxy)-, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy,
Ci-C4-cyanoalkoxy, phenyl, 5- or 6-membered heteroaryl,
(5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, -S-(Ci-C4-alkyl), -S-(Ci-C4-haloalkyl), hydroxy, -N(R5)(R6),
(R5)(R6)N-(C2-C3-alkoxy)-, (4- to 7-membered heterocycloalky l)oxy-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-,
(R5)(R6)NC(=0)-(Ci-C3-aikoxy)- and -C(=0)R7 and
(Ci-C2-alkoxy)-(C2-C3-alkoxy)n-,
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) -, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -O-CH2-O-, -0-(CH2)2-0-, -N(R7)-(CH2)2-, -(CH2)2-N(R7)-, -CH2-N(R7)-CH2-, -N(R7)-(CH2)3-, -(CH2)3-N(R7)-, -CH2-N(R7)-(CH2)2-, -(CH2)2-N(R7)-CH2-, -N(R7)-(CH2)2-N(R7)-, -N(R7)-(CH2)2-0- and -0-(CH2)2-N(R7)-,
wherein n represents an integer of 2, 3 or 4,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is 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-hydroxyalkyl, cyano, hydroxy,
Ci-C2-alkoxy, C3-C4-cycloalkyl, -N(R5)(R6), -C(=0)OR8 and oxo, and
wherein said phenyl and phenoxy group, and the phenyl part of said phenyl-(Ci-C3-alkoxy)- group, and said 5- or 6-membered heteroaryl group, and the (5- or 6-membered heteroaryl) part of said (5- or 6- membered heteroaryl)oxy- and
(5- or 6-membered heteroaryl)-(Ci-C3-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 Ci-C2-alkoxy,
R2 represents a group selected from phenyl, naphthyl and pyridinyl,
which phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkenyl, Cs-Ce-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C4-alkenyl)-, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, cyano, -N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)OR7,
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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-0-CH2-, -0-(CH2)3-, -(CH2)3-O-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -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 and oxo, 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 and a Ci-C2-alkyl group,
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C(=0)OR7,
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
wherein the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-alkyl group,
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Ci-C4-haloalkyl and (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, or
R3 and R4 together with the carbon atom to which they are attached represent a
3- to 6-membered cycloalkyl group,
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
seleceted from
Ci-C4-alkyl, and C3-C4-cycloalkyl, 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-C2-alkyl, C3-C4-cycloalkyl, Ci-C2-haloalkyl, Ci-C2-hydroxyalkyl,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)- and oxo,
R7 represents a hydrogen atom or a Ci-C4-alkyl group,
and
R8 represents a Ci-C4-alkyl group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a variant of the second embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
R1 represents a group selected from phenyl and naphtyl,
which phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl and Ci-C4-alkoxy, (C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, C2-C4-hydroxyalkoxy,
(Ci -C2-alkoxy)-(C2-C4-alkoxy)-,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-,
(Ci-C4-alkyl)-S-(Ci-C4-alkoxy)-, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy,
Ci-C4-cyanoalkoxy, phenyl, 5- or 6-membered heteroaryl,
(5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, -S-(Ci-C4-alkyl), -S-(Ci-C4-haloalkyl), hydroxy, -N(R5)(R6),
(R5)(R6)N-(C2-C3-alkoxy)-, (4- to 7-membered heterocycloalky l)oxy-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-,
(R5)(R6)NC(=0)-(Ci-C3-aikoxy)- and -C(=0)R7 and
(Ci-C2-alkoxy)-(C2-C3-alkoxy)n-, 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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -O-CH2-O-, -0-(CH2)2-0-, -N(R7)-(CH2)2-, -(CH2)2-N(R7)-, -CH2-N(R7)-CH2-, -N(R7)-(CH2)3-, -(CH2)3-N(R7)-, -CH2-N(R7)-(CH2)2-, -(CH2)2-N(R7)-CH2-, -N(R7)-(CH2)2-N(R7)-, -N(R7)-(CH2)2-0- and -0-(CH2)2-N(R7)-,
wherein n represents an integer of 2, 3 or 4,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is 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-hydroxyalkyl, cyano, hydroxy,
Ci-C2-alkoxy, C3-C4-cycloalkyl, -N(R5)(R6), -C(=0)OR8 and oxo, and
wherein said phenyl and phenoxy group, and the phenyl part of said phenyl-(Ci-C3-alkoxy)- group, and said 5- or 6-membered heteroaryl group, and the (5- or 6-membered heteroaryl) part of said (5- or 6- membered heteroaryljoxy- and
(5- or 6-membered heteroaryl)-(Ci-C3-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 and
Ci-C2-alkoxy,
R2 represents a group selected from phenyl, naphthyl and pyridinyl,
which phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkenyl, Cs-Ce-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C4-alkenyl)-, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, cyano, -N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)OR7,
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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -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 and oxo, 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 and a Ci-C2-alkyl group,
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C(=0)0R7,
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
wherein the (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-alkyl group,
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl and Ci-C4-haloalkyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
3- to 6-membered cycloalkyl group,
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
seleceted from
Ci-C4-alkyl, and C3-C4-cycloalkyl,
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-C2-alkyl, C3-C4-cycloalkyl, Ci-C2-haloalkyl, Ci-C2-hydroxyalkyl,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)- and oxo,
R7 represents a hydrogen atom or a Ci-C4-alkyl group,
and
R8 represents a Ci-C4-alkyl group, 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 (l-a):
Figure imgf000030_0001
in which :
R1 represents a group selected from phenyl and naphtyl,
which phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl and Ci-C4-alkoxy, (C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, C2-C6-hydroxyalkoxy,
(Ci -C2-alkoxy)-(C2-C6-alkoxy)-,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-,
(Ci-C4-alkyl)-S-(Ci-C4-alkoxy)-, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy,
Ci-C4-cyanoalkoxy, phenyl, 5- or 6-membered heteroaryl,
(5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, -S-(Ci-C4-alkyl), -S-(Ci-C4-haloalkyl), hydroxy, -N(R5)(R6),
(R5)(R6)N-(C2-C3-alkoxy)-, (4- to 7-membered heterocycloalky l)oxy-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-,
(R5)(R6)NC(=0)-(Ci-C3-alkoxy)- and -C(=0)R7 and
(Ci-C2-alkoxy)-(C2-C3-alkoxy)n-,
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) -, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -O-CH2-O-, -0-(CH2)2-0-, -N(R7)-(CH2)2-, -(CH2)2-N(R7)-, -CH2-N(R7)-CH2-, -N(R7)-(CH2)3-, -(CH2)3-N(R7)-, -CH2-N(R7)-(CH2)2-, -(CH2)2-N(R7)-CH2-, -N(R7)-(CH2)2-N(R7)-, -N(R7)-(CH2)2-0- and -0-(CH2)2-N(R7)-,
wherein n represents an integer of 2, 3 or 4,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is 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-hydroxyalkyl, cyano, hydroxy,
Ci-C2-alkoxy, C3-C4-cycloalkyl, -N(R5)(R6), -C(=0)OR8 and oxo, and
wherein said phenyl and phenoxy group, and the phenyl part of said phenyl-(Ci-C3-alkoxy)- group, and said 5- or 6-membered heteroaryl group, and the (5- or 6-membered heteroaryl) part of said (5- or 6- membered heteroaryl)oxy- and
(5- or 6-membered heteroaryl)-(Ci-C3-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 Ci-C2-alkoxy,
R2 represents a group selected from phenyl, naphthyl and pyridinyl,
which phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkenyl, Cs-Ce-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C4-alkenyl)-, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, cyano, -N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)OR7,
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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-0-CH2-, -0-(CH2)3-, -(CH2)3-O-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -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 and oxo, 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 and a Ci-C2-alkyl group,
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C(=0)OR7,
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
wherein the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-alkyl group,
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Ci-C4-haloalkyl and (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, or
R3 and R4 together with the carbon atom to which they are attached represent a
3- to 6-membered cycloalkyl group,
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
seleceted from
Ci-C4-alkyl, and C3-C4-cycloalkyl, 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-C2-alkyl, C3-C4-cycloalkyl, Ci-C2-haloalkyl, Ci-C2-hydroxyalkyl,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)- and oxo,
R7 represents a hydrogen atom or a Ci-C4-alkyl group,
and
R8 represents a Ci-C4-alkyl group, and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a variant of the third embodiment of the first aspect, the present invention covers compounds of general formula (l-a):
Figure imgf000033_0001
in which
R1 represents a group selected from phenyl and naphtyl,
which phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl and Ci-C4-alkoxy, (C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, C2-C4-hydroxyalkoxy,
(Ci -C2-alkoxy)-(C2-C4-alkoxy)-,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-,
(Ci-C4-alkyl)-S-(Ci-C4-alkoxy)-, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyloxy,
Ci-C4-cyanoalkoxy, phenyl, 5- or 6-membered heteroaryl,
(5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, -S-(Ci-C4-alkyl), -S-(Ci-C4-haloalkyl), hydroxy, -N(R5)(R6), (R5)(R6)N-(C2-C3-alkoxy)-, (4- to 7-membered heterocycloalky l)oxy-,
(4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)-,
(R5)(R6)NC(=0)-(Ci-C3-alkoxy)- and -C(=0)R7 and
(Ci -C2-alkoxy)-(C2-C3-alkoxy)n-,
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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -O-CH2-O-, -0-(CH2)2-0-, -N(R7)-(CH2)2-, -(CH2)2-N(R7)-, -CH2-N(R7)-CH2-, -N(R7)-(CH2)3-, -(CH2)3-N(R7)-,
-CH2-N(R7)-(CH2)2-, -(CH2)2-N(R7)-CH2-, -N(R7)-(CH2)2-N(R7)-, -N(R7)-(CH2)2-0- and -0-(CH2)2-N(R7)-,
wherein n represents an integer of 2, 3 or 4,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is 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-hydroxyalkyl, cyano, hydroxy,
Ci -C2-alkoxy, C3-C4-cycloalkyl, -N(R5)(R6), -C(=0)OR8 and oxo, and
wherein said phenyl and phenoxy group, and the phenyl part of said phenyl-(Ci-C3-alkoxy)- group, and said 5- or 6-membered heteroaryl group, and the (5- or 6-membered heteroaryl) part of said (5- or 6- membered heteroaryljoxy- and
(5- or 6-membered heteroaryl)-(Ci-C3-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 and
Ci -C2-alkoxy, R2 represents a group selected from phenyl, naphthyl and pyridinyl,
which phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkenyl, Cs-Ce-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C4-alkenyl)-, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, cyano, -N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)OR7,
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) -, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -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 and oxo, 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 and a Ci-C2-alkyl group,
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C(=0)0R7,
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
wherein the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-alkyl group,
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl and Ci-C4-haloalkyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
3- to 6-membered cycloalkyl group,
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
seleceted from
Ci-C4-alkyl, and C3-C4-cycloalkyl,
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-C2-alkyl, C3-C4-cycloalkyl, Ci-C2-haloalkyl, Ci-C2-hydroxyalkyl,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)- and oxo,
R7 represents a hydrogen atom or a Ci-C4-alkyl group,
and
R8 represents a Ci-C4-alkyl group,
and tautomers, N-oxides, hydrates, solvates, and salts 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), supra , in which:
R1 represents a group
Figure imgf000037_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C6-hydroxyalkoxy, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyloxy, (C3-C6-cycloalkyl)-(Ci -C3-alkoxy)-, phenoxy, hydroxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C6-alkoxy)-,
(Ci -C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-, (Ci -C4-alkyl)-S-(Ci -C4-alkoxy)-, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy, Ci -C4-cyanoalkoxy, phenyl,
5- or 6-membered heteroaryl, (5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci -C3-alkoxy)-, phenoxy, -S-(Ci-C4-alkyl), -S-(Ci -C4-haloalkyl), hydroxy, -N(R5)(R6), (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)oxy-,
(4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)-, (R5)(R6)NC(=0)-(Ci -C3-alkoxy)-, -C(=0)R7 and (Ci -C2-alkoxy)-(C2-C3-alkoxy)n-,
wherein n represents an integer of 2, 3 or 4,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci -C3-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, Ci -C2-hydroxyalkyl, cyano, hydroxy, -C(=0)0R8 and oxo, and wherein said phenyl and phenoxy group, and the phenyl part of said
phenyl-(Ci -C3-alkoxy)- group, and said 5- or 6-membered heteroaryl group and the (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryljoxy- group and
(5- or 6-membered heteroaryl)-(Ci-C3-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 Ci-C2-alkoxy, wherein X3 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group, or,
wherein X2 and X3 are linked to one another in such a way that they jointly form a group selected from
-C(R9)=C(R9)-C(R9)=C(R9)-, -(CH2)2-N(R7)-, -(CH2)2-N(R7)-, -(CH2)2-N(R7)-, -0-(CH2)2- and -N(R7)-(CH2)3-, wherein X4 represents a hydrogen atom or a halogen atom or a Ci-C4-haloalkyl group, or,
wherein X3 and X4 are linked to one another in such a way that they jointly form a group selected from
-CH2-O-CH2- and -O-CH2-O-, wherein X5 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group, wherein X6 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group,
R2 represents a group selected from phenyl, naphthyl and pyridinyl,
which phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci -C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkenyl, Cs-Ce-hydroxycycloalkenyl, (Ci -C2-alkoxy)-(C3-C4-alkenyl)-, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci -C4-haloalkoxy, cyano, -N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)OR7,
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 -(OH2)3- group, 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 and oxo, 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 and a Ci-C2-alkyl group,
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C(=0)OR7,
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
wherein the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-alkyl group,
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Ci-C4-haloalkyl and (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, or R3 and R4 together with the carbon atom to which they are attached represent a
3- to 6-membered cycloalkyl group,
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
seleceted from
Ci-C4-alkyl and C3-C4-cycloalkyl,
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 Ci-C2-alkyl group and oxo,
R7 represents a hydrogen atom or a Ci-C4-alkyl group,
R8 represents a Ci-C4-alkyl group,
and
R9 represents a hydrogen atom or a halogen atom and a Ci-C2-alkyl group,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a variant of the fourth embodiment of the first aspect, the present invention covers compounds of general formula (l-a), supra , in which:
R1 represents a group
Figure imgf000040_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy,
(C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-, (Ci-C4-alkyl)-S-(Ci-C4-alkoxy)-, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy, Ci-C4-cyanoalkoxy, phenyl,
(5- or 6-membered heteroaryl)oxy-, (5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, -S-(Ci-C4-alkyl), -S-(Ci -C4-haloalkyl), hydroxy, -N(R5)(R6), (R5)(R6)N-(C2-C3-alkoxy)-, (4- to 7-membered heterocycloalkyljoxy-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-, (R5)(R6)NC(=0)-(Ci-C3-alkoxy)-, -C(=0)R7 and (Ci-C2-alkoxy)-(C2-C3-alkoxy)n-,
wherein n represents an integer of 2, 3 or 4,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci -C3-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, Ci -C2-hydroxyalkyl, hydroxy, -C(=0)OR8 and oxo,
and
wherein said phenyl and phenoxy group, and the phenyl part of said
phenyl-(Ci -C3-alkoxy)- group, and the (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)oxy- group and
(5- or 6-membered heteroaryl)-(Ci-C3-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 and Ci -C2-alkoxy, wherein X3 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group, or,
wherein X2 and X3 are linked to one another in such a way that they jointly form a group selected from
-C(R9)=C(R9)-C(R9)=C(R9)-, -(CH2)2-N(R7)-, -(CH2)2-N(R7)-, -(CH2)2-N(R7)-, -0-(CH2)2- and -N(R7)-(CH2)3-, wherein X4 represents a hydrogen atom or a halogen atom or a Ci-C4-haloalkyl group, or,
wherein X3 and X4 are linked to one another in such a way that they jointly form a group selected from -CH2-O-CH2- and -O-CH2-O-, wherein X5 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group, wherein X6 represents a hydrogen atom or a halogen atom,
R2 represents a group selected from phenyl, naphthyl and pyridinyl,
which phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkenyl, Cs-Ce-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C4-alkenyl)-, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, cyano, -N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)OR7,
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 -(OH2)3- group,
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 and oxo, 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 and a Ci-C2-alkyl group,
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C(=0)OR7, wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
wherein the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-alkyl group,
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl and Ci-C4-haloalkyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
3- to 6-membered cycloalkyl group,
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
seleceted from
Ci-C4-alkyl and C3-C4-cycloalkyl,
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 Ci-C2-alkyl group and oxo,
R7 represents a hydrogen atom or a Ci-C4-alkyl group,
R8 represents a Ci-C4-alkyl group,
and
R9 represents a hydrogen atom or a halogen atom and a Ci-C2-alkyl group, and tautomers, N-oxides, hydrates, solvates, and salts 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 imgf000044_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a halogen atom or a group selected from Ci -C4-alkyl, Ci -C4-hydroxyalkyl, Ci -C4-haloalkyl, Ci -C4-alkoxy, C2-C6-hydroxyalkoxy, Ci -C4-haloalkoxy, C3-C6-cycloalkyloxy, (C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, phenoxy, hydroxy, (Ci-C2-alkoxy)-(C2-C6-alkoxy)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)- (Ci-C2-alkoxy)-, phenyl, phenyl-(Ci -C3-alkoxy)-, 5- or 6-membered heteroaryl,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, -N(R5)(R6), (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)oxy- and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-,
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group and (4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group and (4- to 7-membered heterocycloalkyl)-(Ci -C3-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, Ci -C2-hydroxyalkyl, cyano, hydroxy and oxo,
and
wherein said phenyl group and said 5- or 6-membered heteroaryl group and the (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)-(Ci - C3-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 Ci -C2-alkoxy, wherein X3 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl group, or,
wherein X2 and X3 are linked to one another in such a way that they jointly form a -0-(CH2)2- group, wherein X4 represents a hydrogen atom or a halogen atom, wherein X5 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl group, wherein X6 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group,
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy,
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, Ci-C4-alkoxy, hydroxy and Ci-C4-haloalkyl,
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl and (Ci-C2-alkoxy)-(Ci-C2-alkyl)-,
or
R3 and R4 together with the carbon atom to which they are attached represent a
3- to 6-membered cycloalkyl group,
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a Ci-C4-alkyl group,
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 with an oxo group, and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a variant of the fifth embodiment of the first aspect, the present invention covers compounds of general formula (l-a), supra , in which: R1 represents a group
Figure imgf000046_0001
wherein "*" represents the point of attachment to the rest of the molecule, and
wherein X2 represents a hydrogen atom or a group selected from
Ci -C4-alkyl, Ci -C4-alkoxy, (Ci -C2-alkoxy)-(C2-C4-alkoxy)-, phenyl and
(4- to 7-membered heterocycloalkyl)oxy-,
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
wherein the 4- to 7-membered heterocycloalkyl part of said
(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, Ci -C2-hydroxyalkyl, 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 and 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, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci -C4-alkyl, Ci -C4-haloalkyl and Ci -C4-haloalkoxy, R3 represents a hydrogen atom, a halogen atom, or a group selected from Ci -C4-alkyl, Ci -C4-alkoxy and hydroxy,
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci -C4-alkyl and Ci-C4-haloalkyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
3- to 6-membered cycloalkyl group,
and tautomers, N-oxides, hydrates, solvates, and salts 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
Figure imgf000047_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a bromine atom, chlorine atom, fluorine atom, or a group selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, phenoxy, diifluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy,
cyclopropyloxy, cyclopropylm ethoxy, hydroxy, 1 -hydroxyethyl, 2-hydroxypropoxy, 3-hydroxypropoxy, tetrahydrofuran-3-yloxy, 3-methoxyphenyl,
2-hydroxy-2-methylpropoxy, 3-hydroxybutoxy, 3-hydroxy-3-methylbutoxy,
2-hydroxy-3-methoxypropoxy, 2-methoxypropoxy, 2-methoxy-2-methylpropoxy,
3-methoxypropoxy, 3-methoxy-3-methylbutoxy, benzyloxy, methylamino, ethylamino, dimethylamino, (oxetan-2-yl)methoxy, (2-methyloxetan-2-yl)methoxy,
(oxetan-3-yl)methoxy, (3-fluorooxetan-3-yl)methoxy, (3-cyanooxetan-3-yl)methoxy, (3-methyloxetan-3-yl)methoxy, tetrahydropyran-4-yloxy, (tetrahydropyran-3-yl)methoxy, 2-(2-oxoimidazolin-1 -yl)ethoxy, 2-(2-oxo-1 ,3-oxazolidin-3-yl)ethoxy,
2-(morpholin-4-yl)ethoxy, 2-(oxazin-2-yl)ethoxy, 1 -methyl-1 H-pyrazol-4-yl,
2-(imidazol-1 -yl)ethoxy, (1 ,3-oxazol-2-yl)methoxy, (2-methyl-1 ,3-oxazol-4-yl)methoxy, (thiazol-4-yl)methoxy, (2-methylthiazol-4-yl)methoxy, (2-methylthiazol-5-yl)methoxy,
(1 ,3-oxazol-5-yl)methoxy, 2-(1 H-pyrazol-1 -yl)ethoxy, (5-methyl-1 ,3,4-oxadiazol-2-yl)methoxy, (5-methyl-1 ,3,4-thiadiazol-2-yl)methoxy, (pyridin-2-yl)methoxy, (pyridin-3-yl)methoxy, (pyridin-4-yl)methoxy,
(3-fluoropyridin-4-yl)methoxy, (2-methylpyridin-4-yl)methoxy,
(3-methylpyridin-4-yl)methoxy and (2-cyanopyridin-4-yl)methoxy, wherein X3 represents a hydrogen atom or a fluorine atom or a methyl group, or,
wherein X2 and X3 are linked to one another in such a way that they jointly form a -0-(CH2)2- group, wherein X4 represents a hydrogen atom or a fluorine atom, wherein X5 represents a hydrogen atom or a fluorine atom or a methyl group, wherein X6 represents a hydrogen atom or a fluorine atom or a methyl group,
R2 represents a group selected from
phenyl, 3-bromophenyl, 4-bromophenyl, 3-bromo-5-chlorophenyl,
3-bromo-4-fluorophenyl, 3-bromo-5-fluorophenyl, 5-bromo-2-fluorophenyl,
3-bromo-5-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,
3.4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-fluorophenyl, 3-fluoro-5-methylphenyl, 3-fluoro-4-methoxyphenyl, 2-(trifluoromethyl)phenyl,
3-(trifluoromethyl)phenyl, 3-bromo-5-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl,
3.5-dimethylphenyl, 2-(trifluoromethoxy)phenyl, 4-methoxyphenyl and 1 -naphthyl,
R3 represents a hydrogen atom, a fluorine atom, or a group selected from
methyl, methoxy, hydroxy and trifluoromethyl,
R4 represents a hydrogen atom, or a fluorine atom, or a group selected from
methyl, trifluoromethyl and methoxymethyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
cyclopropyl group or a cyclopentyl group,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In accordance with a variant of the sixth embodiment of the first aspect, the present invention covers compounds of general formula (l-a), supra , in which:
R1 represents a group
Figure imgf000049_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from methyl, methoxy, 3-methoxypropoxy, tetrahydrofuran-3-yloxy and 3-methoxyphenyl, 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, 3-bromophenyl, 3-bromo-5-chlorophenyl, 3-bromo-5-fluorophenyl,
5-bromo-2-fluorophenyl, 3-bromo-5-methylphenyl, 3-chlorophenyl, 3,4-dichlorophenyl,
3.5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-fluorophenyl, 3-fluoro-5-methylphenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 3-bromo-5-methylphenyl,
3.5-dimethylphenyl, 2-(trifluoromethoxy)phenyl and 1 -naphthyl,
R3 represents a hydrogen atom, a fluorine atom, or a group selected from
methyl, methoxy and hydroxy,
R4 represents a hydrogen atom, or a fluorine atom, or a group selected from
methyl and trifluoromethyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
cyclopropyl group or a cyclopentyl group, and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same. In accordance with a seventh embodiment of the first aspect, the present invention covers compounds of general formula (l-a), supra , in which:
R1 represents a group selected from
phenyl, 2-bromophenyl, 2-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,
2-chloro-3-fluorophenyl, 2-fluoro-3-methylphenyl, 2-fluoro-6-methylphenyl,
3-fluoro-2-methylphenyl, 4-fluoro-2-methylphenyl, 2-ethyl-4-fluorophenyl,
5-fluoro-2-methylphenyl, 3-fluoro-2-methoxyphenyl, 4-fluoro-2-methoxyphenyl, 5-fluoro-2-methoxyphenyl, 3,6-difluoro-2-methoxyphenyl, 2,3-difluoro-6-methoxyphenyl, 3,4-difluoro-2-methoxyphenyl, 3,5-difluoro-2-methoxyphenyl,
4-fluoro-2-(3-methoxypropoxy)phenyl, 4-fluoro-2-(tetrahydrofuran-3-yloxy)phenyl, 2-ethylphenyl, 2,3-dimethylphenyl, 2,5-dimethylphenyl, 3,5-dimethylphenyl,
2-methoxyphenyl, 2-ethoxyphenyl, 2-phenoxyphenyl, 2-methoxy-5-methylphenyl, 2-(trifluoromethyl)phenyl, 2-(difluoromethoxy)phenyl, 2-(trifluoromethoxy)phenyl, 2-(2,2-difluoroethoxy)phenyl, 2-(2,2,2-trifluoroethoxy)phenyl, 2-(cyclopropyloxy)phenyl, 2-(cyclopropylmethoxy)phenyl, 2-hydroxyphenyl, 2-(1 -hydroxyethyl)phenyl,
2-(2-hydroxypropoxy)phenyl, 2-(3-hydroxypropoxy)phenyl,
2-(2-hydroxy-2-methylpropoxy)phenyl, 2-(3-hydroxybutoxy)phenyl,
2-(3-hydroxy-3-methylbutoxy)phenyl, 2-(2-hydroxy-3-methoxypropoxy)phenyl), 2-(2-methoxypropoxy)phenyl, 2-(2-methoxy-2-methylpropoxy)phenyl,
2-(3-methoxypropoxy)phenyl, 2-(3-methoxy-3-methylbutoxy)phenyl,
2-(benzyloxy)phenyl, 2-(methylamino)phenyl, 2-(ethylamino)phenyl,
2-(dimethylamino)phenyl, 2-[(oxetan-2-yl)methoxy]phenyl,
2-[(2-methyloxetan-2-yl)methoxy]phenyl, 2-[(oxetan-3-yl)methoxy]phenyl,
2-[(3-fluorooxetan-3-yl)methoxy]phenyl, 2-[(3-cyanooxetan-3-yl)methoxy]phenyl, 2-[(3-methyloxetan-3-yl)methoxy]phenyl, 2-(tetrahydropyran-4-yloxy)phenyl,
2-[(tetrahydropyran-3-yl)methoxy]phenyl, 2-[2-(2-oxoimidazolin-1 -yl)ethoxy]phenyl, 2-[2-(2-oxo-1 ,3-oxazolidin-3-yl)ethoxy]phenyl, 2-[2-(morpholin-4-yl)ethoxy]phenyl, 2-[2-(oxazin-2-yl)ethoxy]phenyl, 2-(1 -methyl-1 H-pyrazol-4-yl)phenyl,
2-[2-(imidazol-1 -yl)ethoxy]phenyl, 2-[(1 ,3-oxazol-2-yl)methoxy]phenyl,
2-[(2-methyl-1 ,3-oxazol-4-yl)methoxy]phenyl, 2-[(thiazol-4-yl)methoxy]phenyl,
2-[(2-methylthiazol-4-yl)methoxy]phenyl, 2-[(2-methylthiazol-5-yl)methoxy]phenyl,
2-[(1 ,3-oxazol-5-yl)methoxy]phenyl, 2-[2-(1 H-pyrazol-1 -yl)ethoxy]phenyl,
2-[(5-methyl-1 ,3,4-oxadiazol-2-yl)methoxy]phenyl,
2-[(5-methyl-1 ,3,4-thiadiazol-2-yl)methoxy]phenyl, 2-[(pyridin-2-yl)methoxy]phenyl, 2-[(pyridin-3-yl)methoxy]phenyl, 2-[(pyridin-4-yl)methoxy]phenyl,
2-[(3-fluoropyridin-4-yl)methoxy]phenyl, 2-[(2-methylpyridin-4-yl)methoxy]phenyl, 2-[(3-methylpyridin-4-yl)methoxy]phenyl, 2-[(2-cyanopyridin-4-yl)methoxy]phenyl,
2.3-dihydro-1 -benzofuran-7-yl and 5-fluoro-3'-methoxy[1 ,1 '-biphenyl]-2-yl,
R2 represents a group selected from
phenyl, 3-bromophenyl, 4-bromophenyl, 3-bromo-5-chlorophenyl,
3-bromo-4-fluorophenyl, 3-bromo-5-fluorophenyl, 5-bromo-2-fluorophenyl,
3-bromo-5-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,
3.4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-fluorophenyl, 3-fluoro-5-methylphenyl, 3-fluoro-4-methoxyphenyl, 2-(trifluoromethyl)phenyl,
3-(trifluoromethyl)phenyl, 3-bromo-5-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl,
3.5-dimethylphenyl, 2-(trifluoromethoxy)phenyl, 4-methoxyphenyl and 1 -naphthyl,
R3 represents a hydrogen atom, a fluorine atom, or a group selected from
methyl, methoxy, hydroxy and trifluoromethyl,
R4 represents a hydrogen atom, or a fluorine atom, or a group selected from
methyl, trifluoromethyl and methoxymethyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
cyclopropyl group or a cyclopentyl group, and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a variant of the seventh embodiment of the first aspect, the present invention covers compounds of general formula (l-a), supra, in which:
R1 represents a group selected from
phenyl, 4-fluorophenyl, 4-fluoro-2-methylphenyl, 4-fluoro-2-methoxyphenyl,
4-fluoro-2-(3-methoxypropoxy)phenyl, 4-fluoro-2-(tetrahydrofuran-3-yloxy)phenyl, 2-methoxyphenyl and 5-fluoro-3'-methoxy[1 ,1 '-biphenyl]-2-yl,
R2 represents a group selected from
phenyl, 3-bromophenyl, 3-bromo-5-chlorophenyl, 3-bromo-5-fluorophenyl,
5-bromo-2-fluorophenyl, 3-bromo-5-methylphenyl, 3-chlorophenyl, 3,4-dichlorophenyl,
3.5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-fluorophenyl, 3-fluoro-5-methylphenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 3-bromo-5-methylphenyl,
3.5-dimethylphenyl, 2-(trifluoromethoxy)phenyl and 1 -naphthyl, R3 represents a hydrogen atom, a fluorine atom, or a group selected from methyl, methoxy and hydroxy, R4 represents a hydrogen atom, or a fluorine atom, or a group selected from
methyl and trifluoromethyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
cyclopropyl group or a cyclopentyl group,
and tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
In accordance with a eights embodiment of the first aspect, the present invention covers compounds of general formula (I), supra , which are selected from the group consisting of:
(rac)-2-phenyl-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 -one,
(rac)-2-methyl-2-phenyl-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]propan-1 -one,
(rac)-(1 -phenylcyclopropyl)[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]methanone,
(rac)-(1 -phenylcyclopentyl)[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]methanone,
(rac)-[1 -(3,5-dimethylphenyl)cyclopentyl][7-phenyl-3,9-diazaspiro[5.5]undecan-3- yljmethanone,
[1 -(3,5-dimethylphenyl)cyclopentyl][(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yljmethanone,
[1 -(3,5-dimethylphenyl)cyclopentyl][(7S)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yljmethanone,
(rac)-2-(naphthalen-1 -yl)-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 -one,
(rac)-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]ethan-1 -one, 1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]propan-1 -one (mixture of stereoisomers),
(2S)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]propan- 1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]propan- 1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[(7S)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one, 2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7S)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
3.3.3-trifluoro-2-(4-fluorophenyl)-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3-bromophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
3.3.3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-phenylethan-1 -one,
2.2-difluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-phenylethan-1 - one,
(rac)-1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethyl)phenyl]ethan-1 -one (mixture of stereoisomers),
1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]propan-1 - one (mixture of stereoisomers),
2.2-difluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one, salt with hydrochloric acid,
(rac)-1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 -yl)ethan-1 -one, 1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 -yl)ethan-1 -one, salt with hydrochloric acid,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-(naphthalen-1 - yl)propan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one, salt with hydrochloric acid (mixture of stereoisomers), (2R)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7S)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-hydroxy-2- phenylpropan-1 -one (mixture of stereoisomers),
2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-hydroxypropan-1 -one (mixture of stereoisomers),
2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro- [5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-
3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2R)-2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers), (2R)-3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-
(trifluoromethyl)phenyl]ethan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-[3-
(trifluoromethyl)phenyl]propan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one,
2-(3,5-dichlorophenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 - one,
(2R)-3,3,3-trifluoro-1 -[7-(5-fluoro-3'-methoxy[1 ,1 '-biphenyl]-2-yl)-3,9-diazaspiro[5.5]undecan-
3-yl]-2-methoxy-2-phenylpropan-1 -one, salt with hydrochloric acid, (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-phenylpropan-1 -one, salt with hydrochloric acid, and
(2R)-3,3,3-trifluoro-2-methoxy-1 -[(7S)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-phenylpropan-1 -one, salt with hydrochloric acid,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[(7S)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-phenylpropan-1 -one,
(2R)-1 -[7-(2-chlorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -[(7R)-7-(2-chlorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy- 2-phenylpropan-1 -one,
(2R)-1 -[(7S)-7-(2-chlorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one,
(2R)-1 -[7-(2-bromophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -[(7R)-7-(2-bromophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy- 2-phenylpropan-1 -one,
(2R)-1 -[(7S)-7-(2-bromophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy- 2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(2-ethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one, (2R)-1 -[(7S)-7-(2-ethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -{7-[2-(trifluoromethyl)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}propan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-1 -[7-{2-[(1 R)-1 -hydroxyethyl]phenyl}-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -{7-[2-(difluoromethoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -{(7R)-7-[2-(difluoromethoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro- 2-methoxy-2-phenylpropan-1 -one,
(2R)-1 -{(7S)-7-[2-(difluoromethoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -{7-[2-(trifluoromethoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}propan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-phenoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- phenylpropan-1 -one,
(2R)-1 -[7-(2,3-dihydro-1 -benzofuran-7-yl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2S)-3,3,3-trifluoro-1 -[7-(2-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one (mixture of stereoisomers),
(2S)-3,3,3-trifluoro-1 -[(7R)-7-(2-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2S)-3,3,3-trifluoro-1 -[(7S)-7-(2-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2S)-3,3,3-trifluoro-1 -[7-(3-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one (mixture of stereoisomers),
(2S)-3,3,3-trifluoro-1 -[(7R)-7-(3-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2S)-3,3,3-trifluoro-1 -[(7S)-7-(3-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-(2-fluoro-3-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-methoxy-1 -{7-[2-(methylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3- yl}-2-phenylpropan-1 -one, salt with hydrochloric acid,
(2R)-3,3,3-trifluoro-2-methoxy-1 -{(7R)-7-[2-(methylamino)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one, (2R)-3,3,3-trifluoro-2-methoxy-1 -{(7S)-7-[2-(methylamino)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one,
(2R)-1 -{7-[2-(dimethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -{(7R)-7-[2-(dimethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-1 -{(7S)-7-[2-(dimethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-1 -{(7R)-7-[2-(ethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one, salt with hydrochloric acid,
(2R)-1 -{(7S)-7-[2-(ethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one, salt with hydrochloric acid,
(2R)-1 -{(7R)-7-[2-(ethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-1 -{(7S)-7-[2-(ethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-(3-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-1 -[7-(5-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-1 -[7-(2-fluoro-6-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -[7-(2,3-dimethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one,
(2R)-1 -[7-(3,5-dimethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -[7-(2-chloro-3-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -[7-(2,5-dimethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxy-5-methylphenyl)-3,9-diazaspiro[5.5]undecan- 3-yl]-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-1 -[7-(2-fluoro-6-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-1 -[7-(3-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers), (2R)-3,3,3-trifluoro-1 -[7-(5-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one,
(2R)-1 -[7-(3,6-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -[(7R)-7-(3,6-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3- trifluoro-2-methoxy-2-phenylpropan-1 -one,
(2R)-1 -[(7S)-7-(3,6-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3- trifluoro-2-methoxy-2-phenylpropan-1 -one,
(2R)-1 -[7-(2,3-difluoro-6-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -[7-(3,5-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -[7-(4,5-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -{7-[2-(2,2-difluoroethoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -{7-[2-(2,2,2-trifluoroethoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}propan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(2S)-2-methoxypropoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-{2-[(2S)-2-hydroxy-3-methoxypropoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxy-2-phenylpropan-1 -one,
(2R)-1 -{7-[2-(cyclopropylmethoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-1 -{7-[2-(cyclopropyloxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -{7-[2-(3-methoxypropoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one,
(2R)-1 -[7-(2-ethoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-methoxy-1 -{(7R)-7-[2-(1 -methyl-1 H-pyrazol-4-yl)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -{(7S)-7-[2-(1 -methyl-1 H-pyrazol-4-yl)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one,
(2R)-1 -{(7R)-7-[2-(benzyloxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one, (2R)-1 -{(7S)-7-[2-(benzyloxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-(2-hydroxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one, salt with hydrochloric acid,
(2R)-3,3,3-trifluoro-1 -[7-(2-hydroxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -{7-[2-(3-hydroxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-2- methoxy-2-phenylpropan-1 -one, salt with hydrochloric acid,
(2R)-3,3,3-trifluoro-1 -{7-[2-(3-hydroxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-{2-[(2S)-2-hydroxypropoxy]phenyl}-3,9-diazaspiro[5.5]undecan-3-yl]- 2-methoxy-2-phenylpropan-1 -one, salt with hydrochloric acid,
(2R)-3,3,3-trifluoro-1 -[7-{2-[(2S)-2-hydroxypropoxy]phenyl}-3,9-diazaspiro[5.5]undecan-3-yl]- 2-methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-{2-[(2R)-2-hydroxypropoxy]phenyl}-3,9-diazaspiro[5.5]undecan-3-yl]-
2-methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(3RS)-7-(2-{[3-hydroxybutyl]oxy}phenyl)-3,9-diazaspiro[5.5]undecan-
3-yl]-2-methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-(2-{[(3R)-3-hydroxybutyl]oxy}phenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-(2-{[(3S)-3-hydroxybutyl]oxy}phenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -{7-[2-(2-hydroxy-2-methylpropoxy)phenyl]-3,9-diazaspiro[5.5]undecan- 3-yl}-2-methoxy-2-phenylpropan-1 -one, salt with hydrochloric acid,
(2R)-3,3,3-trifluoro-1 -{7-[2-(2-hydroxy-2-methylpropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-
3-yl}-2-methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -{7-[2-(3-hydroxy-3-methylbutoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3- yl}-2-methoxy-2-phenylpropan-1 -one, salt with hydrochloric acid,
(2R)-3,3,3-trifluoro-1 -{7-[2-(3-hydroxy-3-methylbutoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3- yl}-2-methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -{7-[2-(2-methoxy-2-methylpropoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -{7-[2-(3-methoxy-3-methylbutoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(oxetan-3-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one, (2R)-3,3,3-trifluoro-2-methoxy-1 -[(7R*)-7-{2-[(3-methyloxetan-3-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one
(2R)-3,3,3-trifluoro-1 -[7-{2-[(3-fluorooxetan-3-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxy-2-phenylpropan-1 -one,
3-[(2-{(9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9-diazaspiro[5.5]undecan-1 - yl}phenoxy)methyl]oxetane-3-carbonitrile,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-{[(2RS)-oxetan-2-yl]methoxy}phenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one (mixture of stereosiomers),
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-{[(2R)-oxetan-2-yl]methoxy}phenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-{[(2RS)-2-methyloxetan-2-yl]methoxy}phenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(oxan-4-yl)oxy]phenyl}-3,9-diazaspiro[5.5]undecan-3- yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-{[(3RS)-oxan-3-yl]methoxy}phenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[2-(morpholin-4-yl)ethoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[2-(1 ,2-oxazinan-2-yl)ethoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[7-{2-[(pyridin-4-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[7-{2-[(pyridin-3-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[7-{2-[(pyridin-2-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(1 ,3-oxazol-2-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(1 ,3-oxazol-5-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(2-methyl-1 ,3-oxazol-4-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(5-methyl-1 ,3,4-oxadiazol-2-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[7-{2-[(1 ,3-thiazol-4-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one, (2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(2-methylpyridin-4-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(3-methylpyridin-4-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-{2-[(3-fluoropyridin-4-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(2-methyl-1 ,3-thiazol-4-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(2-methyl-1 ,3-thiazol-5-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(5-methyl-1 ,3,4-thiadiazol-2-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one
4-[(2-{9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9-diazaspiro[5.5]undecan-1 - yl}phenoxy)methyl]pyridine-2-carbonitrile,
(2R)-3,3,3-trifluoro-1 -[7-{2-[2-(1 H-imidazol-1 -yl)ethoxy]phenyl}-3,9-diazaspiro[5.5]undecan- 3-yl]-2-methoxy-2-phenylpropan-1 -one,
1 -[2-(2-{9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9-diazaspiro[5.5]undecan-1 - yl}phenoxy)ethyl]imidazolidin-2-one,
3-[2-(2-{9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9-diazaspiro[5.5]undecan-1 - yl}phenoxy)ethyl]-1 ,3-oxazolidin-2-one,
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[7-{2-[2-(1 H-pyrazol-1 -yl)ethoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxy-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
3,3,3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-
3-yl]propan-1 -one (mixture of stereoisomers),
2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2,2-difluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 - yl)ethan-1 -one,
2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers), 2-(5-bromo-2-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethyl)phenyl]ethan-1 -one (mixture of stereoisomers),
2-(3,5-dichlorophenyl)-1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]ethan- 1 -one (mixture of stereoisomers),
1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one (mixture of stereoisomers),
1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-[3- (trifluoromethyl)phenyl]propan-1 -one (mixture of stereoisomers),
2.2-difluoro-1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one (mixture of stereoisomers),
1 -[7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]ethan-
1 -one,
2-(3,5-dichlorophenyl)-1 -[7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 -one,
2.2-difluoro-1 -[(7R)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 - yl)ethan-1 -one,
1 -[7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-[3- (trifluoromethyl)phenyl]propan-1 -one,
2-(3,5-dichlorophenyl)-2,2-difluoro-1 -[7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3- yl]ethan-1 -one,
3.3.3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(4- methylphenyl)propan-1 -one (mixture of stereoisomers),
2.2-difluoro-1 -[(7R)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one
3.3.3-trifluoro-2-(4-fluorophenyl)-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2.2-difluoro-1 -[7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one,
2-(2,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
3.3.3-trifluoro-2-methoxy-2-(4-methoxyphenyl)-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
3.3.3-trifluoro-2-(3-fluoro-5-methylphenyl)-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers), 2-(2-chlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(2-chlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
2-(4-chlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
3.3.3-trifluoro-2-(3-fluoro-4-methoxyphenyl)-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
3.3.3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- (naphthalen-1 -yl)propan-1 -one,
2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(4-bromophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
(2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(5-bromo-2-fluorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
(2R)-2-(3-bromo-4-fluorophenyl)-3,3,3-trifluoro-2-(methoxymethyl)-1 -[7-(2-methoxyphenyl)- 3,9-diazaspiro[5.5]undecan-3-yl]propan-1 -one, salt with formic acid ,
(2S)-2-(3-bromo-4-fluorophenyl)-3,3,3-trifluoro-2-(methoxymethyl)-1 -[7-(2-methoxyphenyl)- 3,9-diazaspiro[5.5]undecan-3-yl]propan-1 -one, salt with formic acid,
(2R)-3,3,3-trifluoro-2-(4-fluorophenyl)-2-(methoxymethyl)-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
(2S)-3,3,3-trifluoro-2-(4-fluorophenyl)-2-(methoxymethyl)-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one, 2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
1 -[7-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one,
1 -[7-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-[3- (trifluoromethyl)phenyl]propan-1 -one,
2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
1 -[7-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one,
1 -[7-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-[3- (trifluoromethyl)phenyl]propan-1 -one,
2-(4-bromophenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-bromophenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(4-chlorophenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
3.3.3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(4- fluorophenyl)-2-methoxypropan-1 -one (mixture of stereoisomers),
3.3.3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy- 2-(4-methylphenyl)propan-1 -one (mixture of stereoisomers),
2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
2-(2-chlorophenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
2-(2,4-dimethylphenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
3.3.3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy- 2-(naphthalen-1 -yl)propan-1 -one (mixture of stereoisomers),
2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
3.3.3-trifluoro-2-(3-fluoro-4-methoxyphenyl)-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one, 2-(3,5-dichlorophenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
2.2-difluoro-1 -{(7R)-7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3- yl}-2-[2-(trifluoromethoxy)phenyl]ethan-1 -one,
2.2-difluoro-1 -{(7S)-7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3- yl}-2-[2-(trifluoromethoxy)phenyl]ethan-1 -one,
3,3,3-trifluoro-2-methoxy-1 -{7-[2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3- yl}-2-(naphthalen-1 -yl)propan-1 -one
1 -{7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-2-[2- (trifluoromethyl)phenyl]ethan-1 -one (mixture of stereoisomers),
2-(3,5-dichlorophenyl)-1 -{7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}ethan-1 -one (mixture of stereoisomers),
1 -{7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one (mixture of stereoisomers),
1 -{7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-2-methyl-2-[3- (trifluoromethyl)phenyl]propan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-1 -{7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-
3-yl}-2-methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxy-2-phenylpropan-1 -one (mixture of stereoisomers), (2R)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxy-2-phenylpropan-1 -one (Mixture of stereoisomers) ,
1 -[7-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethyl)phenyl]ethan-1 -one (mixture of stereoisomers),
2-(3,5-dichlorophenyl)-1 -[7-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9- diazaspiro[5.5]undecan-3-yl]ethan-1 -one (mixture of stereoisomers),
1 -[7-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one (mixture of stereoisomers), and
1 -[7-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2- [3-(trifluoromethyl)phenyl]propan-1 -one (mixture of stereoisomers),
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and mixtures of same. In accordance with a variant of the eights embodiment of the first aspect, the present invention covers compounds of general formula (I), supra , which are selected from the group consisting of:
(rac)-2-phenyl-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 -one,
(rac)-2-methyl-2-phenyl-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]propan-1 -one,
(rac)-(1 -phenylcyclopropyl)[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]methanone,
(rac)-(1 -phenylcyclopentyl)[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]methanone,
(rac)-[1 -(3,5-dimethylphenyl)cyclopentyl][7-phenyl-3,9-diazaspiro[5.5]undecan-3- yljmethanone,
[1 -(3,5-dimethylphenyl)cyclopentyl][(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yljmethanone,
[1 -(3,5-dimethylphenyl)cyclopentyl][(7S)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yljmethanone,
(rac)-2-(naphthalen-1 -yl)-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 -one,
(rac)-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]ethan-1 -one,
1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]propan-1 -one (mixture of stereoisomers),
(2S)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]propan- 1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]propan-
1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[(7S)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one,
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers), 2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7S)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
3.3.3-trifluoro-2-(4-fluorophenyl)-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3-bromophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
3.3.3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-phenylethan-1 -one,
2.2-difluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-phenylethan-1 - one,
(rac)-1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethyl)phenyl]ethan-1 -one (mixture of stereoisomers),
1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]propan-1 - one (mixture of stereoisomers),
2.2-difluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one, salt with hydrochloric acid,
(rac)-1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 -yl)ethan-1 -one, 1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 -yl)ethan-1 -one, salt with hydrochloric acid,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-(naphthalen-1 - yl)propan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one, salt with hydrochloric acid (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7S)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-hydroxy-2- phenylpropan-1 -one (mixture of stereoisomers),
2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-hydroxypropan-1 -one (mixture of stereoisomers),
2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro-
[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-
3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2R)-2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one, 2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-
(trifluoromethyl)phenyl]ethan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-[3-
(trifluoromethyl)phenyl]propan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one,
2-(3,5-dichlorophenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 - one, (2R)-3,3,3-trifluoro-1 -[7-(5-fluoro-3'-methoxy[1 ,1 '-biphenyl]-2-yl)-3,9-diazaspiro[5.5]undecan- 3-yl]-2-methoxy-2-phenylpropan-1 -one, salt with hydrochloric acid, (mixture of stereoisomers)
(2R)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-phenylpropan-1 -one, salt with hydrochloric acid, and
(2R)-3,3,3-trifluoro-2-methoxy-1 -[(7S)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-phenylpropan-1 -one, salt with hydrochloric acid, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and mixtures of same.
In accordance with a ninth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra , which are selected from the group consisting of:
2-phenyl-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 -one,
2-methyl-2-phenyl-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]propan-1 -one,
(1 -phenylcyclopropyl)[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]methanone,
(1 -phenylcyclopentyl)[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]methanone,
[1 -(3,5-dimethylphenyl)cyclopentyl][(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yljmethanone,
2-(naphthalen-1 -yl)-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 -one,
1 -(7R)-[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]ethan-1 -one,
1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]propan-1 -one (mixture of stereoisomers),
(2S)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one,
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
3,3,3-trifluoro-2-(4-fluorophenyl)-2-methoxy-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3-bromophenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers), 2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
3,3,3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-
3-yl]propan-1 -one (mixture of stereoisomers),
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-phenylethan-1 -one,
2.2-difluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-phenylethan-1 - one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethyl)phenyl]ethan-1 -one (mixture of stereoisomers),
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethyl)phenyl]propan-1 -one (mixture of stereoisomers),
2.2-difluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one, salt with hydrochloric acid,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 -yl)ethan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 -yl)ethan-1 -one, salt with hydrochloric acid,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-(naphthalen-1 - yl)propan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-hydroxy-2- phenylpropan-1 -one,
2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-hydroxypropan-1 -one (mixture of stereoisomers),
2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro- [5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-
3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers), 2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2S)-2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2R)-2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-
(trifluoromethyl)phenyl]ethan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-[3-
(trifluoromethyl)phenyl]propan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one,
2-(3,5-dichlorophenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 - one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(5-fluoro-3'-methoxy[1 ,1 '-biphenyl]-2-yl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxy-2-phenylpropan-1 -one, salt with hydrochloric acid, and
(2R)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-phenylpropan-1 -one, salt with hydrochloric acid, (2R)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(2-chlorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy- 2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(2-bromophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy- 2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(2-ethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -{(7R)-7-[2-(trifluoromethyl)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}propan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-{2-[(1 R)-1 -hydroxyethyl]phenyl}-3,9-diazaspiro[5.5]undecan-3- yl]-2-methoxy-2-phenylpropan-1 -one,
(2R)-1 -{(7R)-7-[2-(difluoromethoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro- 2-methoxy-2-phenylpropan-1 -one,
(2S)-3,3,3-trifluoro-1 -[(7R)-7-(2-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2S)-3,3,3-trifluoro-1 -[(7R)-7-(3-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(2-fluoro-3-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -{(7R)-7-[2-(methylamino)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one,
(2R)-1 -{(7R)-7-[2-(dimethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-1 -{(7R)-7-[2-(ethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one, salt with hydrochloric acid,
(2R)-1 -{(7R)-7-[2-(ethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(3-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(5-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(2-fluoro-6-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(3,5-dimethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one, (2R)-1 -[(7R)-7-(2-chloro-3-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(2,5-dimethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-(2-methoxy-5-methylphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(2-fluoro-6-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(3-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(3,6-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3- trifluoro-2-methoxy-2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(2,3-difluoro-6-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3- trifluoro-2-methoxy-2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(3,5-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3- trifluoro-2-methoxy-2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(4,5-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3- trifluoro-2-methoxy-2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(2-ethoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy- 2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -{(7R)-7-[2-(1 -methyl-1 H-pyrazol-4-yl)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one,
(2R)-1 -{(7R)-7-[2-(benzyloxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxy-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
3,3,3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-
3-yl]propan-1 -one (mixture of stereoisomers), (2R)-3,3,3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
(2S)-3,3,3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2.2-difluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 - yl)ethan-1 -one,
2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(5-bromo-2-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(5-bromo-2-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(5-bromo-2-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(7R)-1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-
(trifluoromethyl)phenyl]ethan-1 -one,
(7R)-2-(3,5-dichlorophenyl)-1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3- yl]ethan-1 -one,
(7R)-1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-
(trifluoromethoxy)phenyl]ethan-1 -one,
(7R)-1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-[3-
(trifluoromethyl)phenyl]propan-1 -one,
(7R)-2,2-difluoro-1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-
(trifluoromethoxy)phenyl]ethan-1 -one,
(7R)-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-
(trifluoromethoxy)phenyl]ethan-1 -one,
(7R)-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-[3-
(trifluoromethyl)phenyl]propan-1 -one,
2.2-difluoro-1 -{(7R)-7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3- yl}-2-[2-(trifluoromethoxy)phenyl]ethan-1 -one, (7R)-1 -{7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-2-[2-
(trifluoromethyl)phenyl]ethan-1 -one,
2-(3,5-dichlorophenyl)-1 -{(7R)-7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}ethan-1 -one,
(7R)-1 -{7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-2-[2-
(trifluoromethoxy)phenyl]ethan-1 -one,
(7R)-1 -{7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-2-methyl-
2-[3-(trifluoromethyl)phenyl]propan-1 -one,
(2R)-3,3,3-trifluoro-1 -{(7R)-7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluoro-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxy-2-phenylpropan-1 -one,
(7R)-1 -[7-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-
(trifluoromethyl)phenyl]ethan-1 -one,
2-(3,5-dichlorophenyl)-1 -[(7R)-7-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9- diazaspiro[5.5]undecan-3-yl]ethan-1 -one,
(7R)-1 -[7-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one, and
(7R)-1 -[7-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methyl-2-[3-(trifluoromethyl)phenyl]propan-1 -one,
and tautomers, an N-oxides, hydrates, solvates, and mixtures of same.
In accordance with a variant of the ninth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra , which are selected from the group consisting of:
2-phenyl-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 -one,
2-methyl-2-phenyl-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]propan-1 -one,
(1 -phenylcyclopropyl)[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]methanone,
(1 -phenylcyclopentyl)[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]methanone,
[1 -(3,5-dimethylphenyl)cyclopentyl][(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yljmethanone, 2-(naphthalen-1 -yl)-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 -one, 1 -(7R)-[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]ethan-1 -one,
1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]propan-1 -one (mixture of stereoisomers),
(2S)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one,
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
3.3.3-trifluoro-2-(4-fluorophenyl)-2-methoxy-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3-bromophenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
3.3.3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-
3-yl]propan-1 -one (mixture of stereoisomers),
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-phenylethan-1 -one,
2,2-difluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-phenylethan-1 - one, 1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethyl)phenyl]ethan-1 -one (mixture of stereoisomers),
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethyl)phenyl]propan-1 -one (mixture of stereoisomers),
2,2-difluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one, salt with hydrochloric acid,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 -yl)ethan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 -yl)ethan-1 -one, salt with hydrochloric acid,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-(naphthalen-1 - yl)propan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-hydroxy-2- phenylpropan-1 -one,
2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-hydroxypropan-1 -one (mixture of stereoisomers),
2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro-
[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-
3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers), (2S)-2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2R)-2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-
(trifluoromethyl)phenyl]ethan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-[3-
(trifluoromethyl)phenyl]propan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-
(trifluoromethoxy)phenyl]ethan-1 -one, 2-(3,5-dichlorophenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 - one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(5-fluoro-3'-methoxy[1 ,1 '-biphenyl]-2-yl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxy-2-phenylpropan-1 -one, salt with hydrochloric acid, and
(2R)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-phenylpropan-1 -one, salt with hydrochloric acid, and tautomers, an N-oxides, hydrates, solvates, 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 phenyl and naphtyl,
which phenyl and naphtyl 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-alkynyl, C3-Ce-cycloalkyl,
(C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, (C3-C6-cycloalkyloxy)-(Ci-C3-alkyl)-, Ci-Ce-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C6-alkyl)-, Ci-C6-haloalkyl, Ci-C6-alkoxy, (C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, C2-C6-hydroxyalkoxy,
(Ci -C2-alkoxy)-(C2-C6-alkoxy)-,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-,
(Ci-C6-alkyl)-S-(Ci-C6-alkoxy)-, Ci-Ce-haloalkoxy,
(Ci -C2-haloalkoxy)-(Ci -Ce-alkyl)-, C3-C6-cycloalkyloxy,
Ci-C6-cyanoalkoxy, phenyl, 5- or 6-membered heteroaryl,
(5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkyl)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci-C3-alkyl)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, phenoxy-(Ci-C3-alkyl)-,
phenoxy-(C2-C3-alkoxy)-, -SH, -S-(Ci-C6-alkyl), -S(=0)-(Ci-C6-aikyl),
-S(=0)2-(Ci -Ce-alkyl) , -S-(C3-C6-cycloalkyl) , -S(=0)-(C3-C6-cycloalkyl) ,
-S(=0)2-(C3-C6-cycloalkyl), -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), (R5)(R6)N-(C2-C3-alkoxy)-,
4- to 7-membered heterocycloalkyl, (4- to 7-membered heterocycloalkyl)oxy-, -(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl),
(4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)-, -C(=0)N(R5)(R6), -(Ci-C3-alkyl)-C(=0)N(R5)(R6), (R5)(R6)NC(=0)-(Ci -C3-alkoxy)-, -C(=0)OR7, -(Ci-C3-alkyl)-C(=0)0R7, R7OC(=0)-(Ci-C3-alkoxy)-, -C(=0)R7,
-(Ci-C3-alkyl)-C(=0)R7 and (Ci-C2-alkoxy)-(C2-C3-alkoxy)n-,
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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -O-CH2-O-, -0-(CH2)2-0-, -N(R7)-(CH2)2-, -(CH2)2-N(R7)-, -CH2-N(R7)-CH2-, -N(R7)-(CH2)3-, -(CH2)3-N(R7)-,
-CH2-N(R7)-(CH2)2-, -(CH2)2-N(R7)-CH2-, -N(R7)-(CH2)2-N(R7)-, -N(R7)-(CH2)2-0- and -0-(CH2)2-N(R7)-,
wherein n represents an integer of 2, 3, 4 or 5,
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)oxy- group,
-(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl) group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- 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
(4- to 7-membered heterocycloalkyl)oxy- group,
-(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl) group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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, Ci-C2-haloalkyl, Ci-C2-hydroxyalkyl, cyano, hydroxy,
Ci -C2-alkoxy, C3-C4-cycloalkyl, -N(R5)(R6), -C(=0)OR8 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 the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)oxy-, (5- or 6-membered heteroaryl)-(Ci-C3-alkyl)- and (5- or 6-membered heteroaryl)-(Ci-C3-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, Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl and -N(R5)(R6),
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-alkynyl, C3-C6-cycloalkyl, C4-C7-cycloalkenyl, C4-C7-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C6-alkenyl)-, Ci-C6-hydroxyalkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, 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), cyano, hydroxy,
-N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)OR7,
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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-0-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -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, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
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, cyano, hydroxy, Ci -C2-alkoxy,
C3-C4-cycloalkyl and -N(R5)(R6),
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci -C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl, Ci -C4-hydroxyalkyl, Ci -C4-haloalkyl, Ci -C4-alkoxy, C2-C6-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C6-alkoxy)-, Ci -C4-haloalkoxy, C3-C6-cycloalkyloxy, phenyl, phenoxy, phenyl-(Ci-C2-alkyl)-, phenyl-(Ci-C2-alkoxy)-, (5- or 6-membered heteroaryl)oxy,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy), hydroxy, cyano, -N(R5)(R6),
-(Ci -C2-alkyl)-N(R5)(R6), (R5)(R6)N-(C2-C3-alkoxy)-, C4-C7-heterocycloalkyl,
-(Ci -C2-alkyl)-(C4-C7-heterocycloalkyl),
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-, (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 and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- 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 and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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, Ci-C2-haloalkyl, cyano, hydroxy, Ci -C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
and
wherein said cycloalkyl group and said phenyl group, and the phenyl part of said phenoxy, phenyl-(Ci-C2-alkyl)- and phenyl-(Ci-C2-alkoxy)- group, and the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)oxy- group and
(5- or 6-membered heteroaryl)-(Ci-C3-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, Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy and
-N(R5)(R6),
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, phenyl, phenyl-(Ci-C2-alkyl)-, -(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, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
and
wherein said cycloalkyl group and said phenyl group, and the phenyl part of said phenyl-(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, cyano, hydroxy, Ci-C2-alkoxy and
-N(R5)(R6),
or
R3 and R4 together with the carbon atom to which they are attached represent a
3- 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 seleceted from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl,
(Ci -C2-alkoxy)-(C2-C3-alkyl-), -C(=0)-(Ci-C3-alkyl) and -C(=0)-(Ci-C3-haloalkyl), 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, Ci-C4-haloalkyl, Ci -C4-hydroxyalkyl,
(Ci -C2-alkoxy)-(Ci-C3-alkyl)- and oxo,
R7 represents a hydrogen atom or a Ci-C4-alkyl group,
and
R8 represents 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:
R1 represents a group
Figure imgf000085_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a halogen atom or a group selected from Ci -C4-alkyl, Ci -C4-hydroxyalkyl, Ci -C4-haloalkyl, Ci -C4-alkoxy,
(C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-, (Ci-C4-alkyl)-S-(Ci-C4-alkoxy)-, Ci -C4-haloalkoxy, C3-C6-cycloalkyloxy, Ci-C4-cyanoalkoxy, phenyl,
(5- or 6-membered heteroaryl)oxy-, (5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, -S-(Ci-C4-alkyl), -S-(Ci -C4-haloalkyl), hydroxy, -N(R5)(R6), (R5)(R6)N-(C2-C3-alkoxy)-, (4- to 7-membered heterocycloalkyl)oxy-, (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-, (R5)(R6)NC(=0)-(Ci-C3-alkoxy)-, -C(=0)R7 and (Ci-C2-alkoxy)-(C2-C3-alkoxy)n-,
wherein n represents an integer of 2, 3 or 4,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci -C3-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, Ci -C2-hydroxyalkyl, hydroxy, -C(=0)OR8 and oxo,
and
wherein said phenyl and phenoxy group, and the phenyl part of said
phenyl-(Ci -C3-alkoxy)- group, and the (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)oxy- group and
(5- or 6-membered heteroaryl)-(Ci-C3-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 and Ci -C2-alkoxy, wherein X3 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group, or,
wherein X2 and X3 are linked to one another in such a way that they jointly form a group selected from
-C(R9)=C(R9)-C(R9)=C(R9)-, -(CH2)2-N(R7)-, -(CH2)2-N(R7)-, -(CH2)2-N(R7)-, -0-(CH2)2- and -N(R7)-(CH2)3-, wherein X4 represents a hydrogen atom or a halogen atom or a Ci-C4-haloalkyl group, or,
wherein X3 and X4 are linked to one another in such a way that they jointly form a group selected from
-CH2-O-CH2- and -O-CH2-O-, wherein X5 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group, wherein X6 represents a hydrogen atom or a halogen atom,
R2 represents a group selected from phenyl, naphthyl and pyridinyl,
which phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkenyl, Cs-Ce-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C4-alkenyl)-, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, cyano, -N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)OR7,
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 -(CH2)3- group,
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 and oxo, 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 and a Ci-C2-alkyl group,
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C(=0)OR7,
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
wherein the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-alkyl group,
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl and Ci-C4-haloalkyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
3- to 6-membered cycloalkyl group,
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
seleceted from
Ci-C4-alkyl and C3-C4-cycloalkyl,
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 Ci-C2-alkyl group and oxo,
R7 represents a hydrogen atom or a Ci-C4-alkyl group,
R8 represents a Ci-C4-alkyl group,
and
R9 represents a hydrogen atom or a halogen atom and a Ci-C2-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:
R1 represents a group
Figure imgf000089_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from
Ci -C4-alkyl, Ci -C4-alkoxy, (Ci -C2-alkoxy)-(C2-C4-alkoxy)-, phenyl and
(4- to 7-membered heterocycloalkyl)oxy-,
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
wherein the 4- to 7-membered heterocycloalkyl part of said
(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, Ci -C2-hydroxyalkyl, 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 and 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, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci -C4-alkyl, Ci -C4-haloalkyl and Ci -C4-haloalkoxy,
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci -C4-alkyl, Ci -C4-alkoxy and hydroxy,
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci -C4-alkyl and Ci-C4-haloalkyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
3- to 6-membered cycloalkyl 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:
R1 represents a group
Figure imgf000090_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from methyl, methoxy, 3-methoxypropoxy, tetrahydrofuran-3-yloxy and 3-methoxyphenyl, 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, 3-bromophenyl, 3-bromo-5-chlorophenyl, 3-bromo-5-fluorophenyl,
5-bromo-2-fluorophenyl, 3-bromo-5-methylphenyl, 3-chlorophenyl, 3,4-dichlorophenyl,
3.5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-fluorophenyl, 3-fluoro-5-methylphenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 3-bromo-5-methylphenyl,
3.5-dimethylphenyl, 2-(trifluoromethoxy)phenyl and 1 -naphthyl,
R3 represents a hydrogen atom, a fluorine atom, or a group selected from
methyl, methoxy and hydroxy,
R4 represents a hydrogen atom, or a fluorine atom, or a group selected from
methyl and trifluoromethyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
cyclopropyl group or a cyclopentyl 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:
R1 represents a group selected from
phenyl, 4-fluorophenyl, 4-fluoro-2-methylphenyl, 4-fluoro-2-methoxyphenyl,
4-fluoro-2-(3-methoxypropoxy)phenyl, 4-fluoro-2-(tetrahydrofuran-3-yloxy)phenyl, 2-methoxyphenyl and 5-fluoro-3'-methoxy[1 ,1 '-biphenyl]-2-yl,
R2 represents a group selected from
phenyl, 3-bromophenyl, 3-bromo-5-chlorophenyl, 3-bromo-5-fluorophenyl,
5-bromo-2-fluorophenyl, 3-bromo-5-methylphenyl, 3-chlorophenyl, 3,4-dichlorophenyl,
3.5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-fluorophenyl, 3-fluoro-5-methylphenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 3-bromo-5-methylphenyl,
3.5-dimethylphenyl, 2-(trifluoromethoxy)phenyl and 1 -naphthyl,
R3 represents a hydrogen atom, a fluorine atom, or a group selected from
methyl, methoxy and hydroxy,
R4 represents a hydrogen atom, or a fluorine atom, or a group selected from
methyl and trifluoromethyl,
or R3 and R4 together with the carbon atom to which they are attached represent a
cyclopropyl group or a cyclopentyl 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 (I), supra , in which:
R1 represents a group
Figure imgf000092_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from
Ci -C4-alkyl, Ci -C4-alkoxy, (Ci -C2-alkoxy)-(C2-C4-alkoxy)- and
(4- to 7-membered heterocycloalkyl)oxy-,
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
wherein the 4- to 7-membered heterocycloalkyl part of said
(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, Ci -C2-hydroxyalkyl, hydroxy and oxo, 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, two, three or four times, each substituent independently selected from a halogen atom or Ci -C4-alkyl group,
R3 represents a Ci-C4-alkoxygroup,
R4 represents a Ci-C4-haloalkylgroup,
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 imgf000093_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from
methyl, methoxy, 3-methoxypropoxy and tetrahydrofuran-3-yloxy, 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 1 -naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or methyl group,
R3 represents a methoxy group, 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:
R1 represents a group
Figure imgf000094_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from
methyl, methoxy, 3-methoxypropoxy and tetrahydrofuran-3-yloxy, 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, 3-bromo-5-chlorophenyl, 3-bromo-5-fluorophenyl, 5-bromo-2-fluorophenyl, 3-bromo-5-methylphenyl, 3-chlorphenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 3-fluoro-5-methylphenyl, 3,5-dimethylphenyl and 1 -naphthyl,
R3 represents a methoxy group,
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 (l-a), supra , in which:
R1 represents a group
Figure imgf000095_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from
Ci -C4-alkyl, Ci -C4-alkoxy, (Ci -C2-alkoxy)-(C2-C4-alkoxy)- and
(4- to 7-membered heterocycloalkyl)oxy-,
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
wherein the 4- to 7-membered heterocycloalkyl part of said
(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, Ci -C2-hydroxyalkyl, hydroxy and oxo, 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, two, three or four times, each substituent independently selected from a halogen atom or Ci -C4-alkyl, group,
R3 represents a Ci-C4-alkoxygroup, R4 represents a Ci-C4-haloalkylgroup,
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 imgf000096_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from
methyl, methoxy, 3-methoxypropoxy and tetrahydrofuran-3-yloxy, 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 1 -naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or methyl group,
R3 represents a methoxy group,
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: R1 represents a group
Figure imgf000097_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from
methyl, methoxy, 3-methoxypropoxy and tetrahydrofuran-3-yloxy, 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, 3-bromo-5-chlorophenyl, 3-bromo-5-fluorophenyl, 5-bromo-2-fluorophenyl, 3-bromo-5-methylphenyl, 3-chlorphenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 3-fluoro-5-methylphenyl, 3,5-dimethylphenyl and 1 -naphthyl,
R3 represents a methoxy group,
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 (I), supra , in which:
R1 represents a group
Figure imgf000097_0002
wherein "*" represents the point of attachment to the rest of the molecule, and
wherein X2 represents a hydrogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-alkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-, -N(R5)(R6) and
(4- to 7-membered heterocycloalkyl)oxy-,
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
wherein the 4- to 7-membered heterocycloalkyl part of said
(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, Ci-C2-hydroxyalkyl, hydroxy and oxo, 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, two, three or four times, each substituent independently selected from a halogen atom or Ci-C4-alkyl group,
R3 represents a Ci-C4-alkoxy group,
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: R1 represents a group
Figure imgf000099_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from
methyl, methoxy, 3-methoxypropoxy, methylamino and tetrahydrofuran-3-yloxy, 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 1 -naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or methyl group,
R3 represents a methoxy group,
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:
R1 represents a group
Figure imgf000099_0002
wherein "*" represents the point of attachment to the rest of the molecule, and
wherein X2 represents a hydrogen atom or a group selected from
methyl, methoxy, 3-methoxypropoxy, methylamino and tetrahydrofuran-3-yloxy, 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, 3-bromo-5-chlorophenyl, 3-bromo-5-fluorophenyl, 5-bromo-2-fluorophenyl, 3-bromo-5-methylphenyl, 3-chlorphenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 3-fluoro-5-methylphenyl, 3,5-dimethylphenyl and 1 -naphthyl,
R3 represents a methoxy group,
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 (l-a), supra , in which:
R1 represents a group
Figure imgf000100_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from
Ci -C4-alkyl, Ci -C4-alkoxy, (Ci -C2-alkoxy)-(C2-C4-alkoxy)-, -N(R5)(R6) and
(4- to 7-membered heterocycloalkyl)oxy-, wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
wherein the 4- to 7-membered heterocycloalkyl part of said
(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, Ci -C2-hydroxyalkyl, hydroxy and oxo, 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, two, three or four times, each substituent independently selected from a halogen atom or Ci -C4-alkyl group,
R3 represents a Ci-C4-alkoxy group,
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:
R1 represents a group
Figure imgf000101_0001
wherein "*" represents the point of attachment to the rest of the molecule, and
wherein X2 represents a hydrogen atom or a group selected from
methyl, methoxy, 3-methoxypropoxy, methylamino and tetrahydrofuran-3-yloxy, 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 1 -naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or methyl group,
R3 represents a methoxy group,
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:
R1 represents a group
Figure imgf000102_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from
methyl, methoxy, 3-methoxypropoxy, methylamino and tetrahydrofuran-3-yloxy, 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, 3-bromo-5-chlorophenyl, 3-bromo-5-fluorophenyl, 5-bromo-2-fluorophenyl, 3-bromo-5-methylphenyl, 3-chlorphenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 3-fluoro-5-methylphenyl, 3,5-dimethylphenyl and 1 -naphthyl,
R3 represents a methoxy group,
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
(I), supra , in which:
R1 represents a group selected from phenyl and naphtyl,
which phenyl and naphtyl 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-alkynyl, C3-Ce-cycloalkyl,
(C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, (C3-C6-cycloalkyloxy)-(Ci-C3-alkyl)-,
Ci-Ce-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C6-alkyl)-, Ci-C6-haloalkyl, Ci-C6-alkoxy, (C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, C2-C6-hydroxyalkoxy,
(Ci -C2-alkoxy)-(C2-C6-alkoxy)-,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-,
(Ci-C6-alkyl)-S-(Ci-C6-alkoxy)-, Ci-Ce-haloalkoxy,
(Ci -C2-haloalkoxy)-(Ci -Ce-alkyl)-, C3-C6-cycloalkyloxy,
Ci-C6-cyanoalkoxy, phenyl, 5- or 6-membered heteroaryl,
(5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkyl)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci-C3-alkyl)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, phenoxy-(Ci-C3-alkyl)-,
phenoxy-(C2-C3-alkoxy)-, -SH, -S-(Ci-C6-alkyl), -S(=0)-(Ci-C6-alkyl),
-S(=0)2-(Ci -Ce-alkyl) , -S-(C3-C6-cycloalkyl) , -S(=0)-(C3-Ce-cycloalkyl) , -S(=0)2-(C3-C6-cycloalkyl), -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), (R5)(R6)N-(C2-C3-alkoxy)-,
4- to 7-membered heterocycloalkyl, (4- to 7-membered heterocycloalkyl)oxy-, -(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl),
(4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)-, -C(=0)N(R5)(R6), -(Ci-C3-alkyl)-C(=0)N(R5)(R6), (R5)(R6)NC(=0)-(Ci -C3-alkoxy)-, -C(=0)OR7, -(Ci-C3-alkyl)-C(=0)0R7, R7OC(=0)-(Ci-C3-alkoxy)-, -C(=0)R7,
-(Ci-C3-alkyl)-C(=0)R7 and (Ci-C2-alkoxy)-(C2-C3-alkoxy)n-,
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) -, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -O-CH2-O-, -0-(CH2)2-0-, -N(R7)-(CH2)2-, -(CH2)2-N(R7)-, -CH2-N(R7)-CH2-, -N(R7)-(CH2)3-, -(CH2)3-N(R7)-,
-CH2-N(R7)-(CH2)2-, -(CH2)2-N(R7)-CH2-, -N(R7)-(CH2)2-N(R7)-, -N(R7)-(CH2)2-0- and -0-(CH2)2-N(R7)-,
wherein n represents an integer of 2, 3, 4 or 5,
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)oxy- group,
-(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl) group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- 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
(4- to 7-membered heterocycloalkyl)oxy- group,
-(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl) group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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, Ci-C2-haloalkyl, Ci-C2-hydroxyalkyl, cyano, hydroxy,
Ci -C2-alkoxy, C3-C4-cycloalkyl, -N(R5)(R6), -C(=0)OR8 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 the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryljoxy-,
(5- or 6-membered heteroaryl)-(Ci -C3-alkyl)- and (5- or 6-membered heteroaryl)-(Ci-C3-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, Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl 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, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C4-C7-cycloalkenyl, C4-C7-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C6-alkenyl)-, Ci-C6-hydroxyalkyl, Ci-Ce-haloalkyl, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, Cs-Ce-cycloalkyloxy, -SH,
-S-(Cr -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), cyano, hydroxy,
-N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)0R7,
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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -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, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
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, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl 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 and naphthyl,
which phenyl and naphthyl 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-alkynyl, C3-C6-cycloalkyl, C4-C7-cycloalkenyl, C4-C7-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C6-alkenyl)-, Ci-Ce-hydroxyalkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, 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), cyano, hydroxy,
-N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)0R7,
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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-0-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -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, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
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, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl 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-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl,
Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C6-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C6-alkoxy)-, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyloxy, phenyl, phenoxy, phenyl-(Ci-C2-alkyl)-, phenyl-(Ci-C2-alkoxy)-, (5- or 6-membered heteroaryl)oxy,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy), hydroxy, cyano, -N(R5)(R6),
-(Ci-C2-alkyl)-N(R5)(R6), (R5)(R6)N-(C2-C3-alkoxy)-, C4-C7-heterocycloalkyl,
-(Ci-C2-alkyl)-(C4-C7-heterocycloalkyl),
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-, (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 and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- 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 and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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, Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
and
wherein said cycloalkyl group and said phenyl group, and the phenyl part of said phenoxy, phenyl-(Ci-C2-alkyl)- and phenyl-(Ci-C2-alkoxy)- group, and the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)oxy- group and
(5- or 6-membered heteroaryl)-(Ci-C3-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, Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy and
-N(R5)(R6),
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, phenyl, phenyl-(Ci-C2-alkyl)-, -(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, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
and
wherein said cycloalkyl group and said phenyl group, and the phenyl part of said phenyl-(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, cyano, hydroxy, Ci-C2-alkoxy and
-N(R5)(R6),
or
R3 and R4 together with the carbon atom to which they are attached represent a
3- 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 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl,
Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C6-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C6-alkoxy)-, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy, phenyl, phenoxy, phenyl-(Ci-C2-alkyl)-, phenyl-(Ci-C2-alkoxy)-, (5- or 6-membered heteroaryl)oxy,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy), hydroxy, cyano, -N(R5)(R6),
-(Ci-C2-alkyl)-N(R5)(R6), (R5)(R6)N-(C2-C3-alkoxy)-, C4-C7-heterocycloalkyl,
-(Ci-C2-alkyl)-(C4-C7-heterocycloalkyl),
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-, (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 and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- 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 and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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, Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
and
wherein said cycloalkyl group and said phenyl group, and the phenyl part of said phenoxy, phenyl-(Ci-C2-alkyl)- and phenyl-(Ci-C2-alkoxy)- group, and the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)oxy- group and
(5- or 6-membered heteroaryl)-(Ci-C3-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, Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy 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, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl,
Ci-C4-haloalkyl, phenyl, phenyl-(Ci-C2-alkyl)-, -(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, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
and
wherein said cycloalkyl group and said phenyl group, and the phenyl part of said phenyl-(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, cyano, hydroxy, Ci-C2-alkoxy 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 and R4 together with the carbon atom to which they are attached represent a
3- 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:
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
seleceted from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(C2-C3-alkyl-), -C(=0)-(Ci-C3-alkyl) and -C(=0)-(Ci-C3-haloalkyl), 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, Ci-C4-haloalkyl, Ci-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(Ci-C3-alkyl)- 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
seleceted from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(C2-C3-alkyl-), -C(=0)-(Ci-C3-alkyl) and -C(=0)-(Ci-C3-haloalkyl), 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, Ci-C4-haloalkyl, Ci-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(Ci-C3-alkyl)- 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 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:
R1 represents a group selected from phenyl and naphtyl,
which phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl and Ci-C4-alkoxy, (C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, C2-C4-hydroxyalkoxy,
(Ci -C2-alkoxy)-(C2-C4-alkoxy)-,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-,
(Ci-C4-alkyl)-S-(Ci-C4-alkoxy)-, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy,
Ci-C4-cyanoalkoxy, phenyl, 5- or 6-membered heteroaryl,
(5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, -S-(Ci-C4-alkyl), -S-(Ci-C4-haloalkyl), hydroxy, -N(R5)(R6),
(R5)(R6)N-(C2-C3-alkoxy)-, (4- to 7-membered heterocycloalky l)oxy-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-,
(R5)(R6)NC(=0)-(Ci-C3-alkoxy)- and -C(=0)R7 and
(Ci-C2-alkoxy)-(C2-C3-alkoxy)n-, 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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -O-CH2-O-, -0-(CH2)2-0-, -N(R7)-(CH2)2-, -(CH2)2-N(R7)-, -CH2-N(R7)-CH2-, -N(R7)-(CH2)3-, -(CH2)3-N(R7)-, -CH2-N(R7)-(CH2)2-, -(CH2)2-N(R7)-CH2-, -N(R7)-(CH2)2-N(R7)-, -N(R7)-(CH2)2-0- and -0-(CH2)2-N(R7)-,
wherein n represents an integer of 2, 3 or 4,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is 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-hydroxyalkyl, cyano, hydroxy,
Ci-C2-alkoxy, C3-C4-cycloalkyl, -N(R5)(R6), -C(=0)OR8 and oxo, and
wherein said phenyl and phenoxy group, and the phenyl part of said phenyl-(Ci-C3-alkoxy)- group, and said 5- or 6-membered heteroaryl group, and the (5- or 6-membered heteroaryl) part of said (5- or 6- membered heteroaryljoxy- and
(5- or 6-membered heteroaryl)-(Ci-C3-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 and C1-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: R2 represents a group selected from phenyl, naphthyl and pyridinyl,
which phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkenyl, Cs-Ce-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C4-alkenyl)-, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, cyano, -N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)OR7,
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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-0-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -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 and oxo, 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 and a Ci-C2-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:
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkenyl, Cs-Ce-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C4-alkenyl)-, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, cyano, -N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)OR7,
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) -, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -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 and oxo, 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 and a Ci-C2-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:
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C(=0)0R7,
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
wherein the (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-alkyl group,
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl and Ci-C4-haloalkyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
3- to 6-membered cycloalkyl 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 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C(=0)0R7,
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
wherein the (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-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:
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl and Ci-C4-haloalkyl,
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
3- to 6-membered cycloalkyl 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:
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
seleceted from
Ci-C4-alkyl, and C3-C4-cycloalkyl,
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-C2-alkyl, C3-C4-cycloalkyl, Ci-C2-haloalkyl, Ci-C2-hydroxyalkyl,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)- 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
seleceted from
Ci-C4-alkyl, and C3-C4-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:
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-C2-alkyl, C3-C4-cycloalkyl, Ci-C2-haloalkyl, Ci-C2-hydroxyalkyl,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)- 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 (l-a), supra , in which:
R1 represents a group selected from phenyl and naphtyl,
which phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from Ci -C4-alkyl, Ci -C4-hydroxyalkyl, Ci -C4-haloalkyl and Ci-C4-alkoxy,
(C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, C2-C4-hydroxyalkoxy,
(Ci -C2-alkoxy)-(C2-C4-alkoxy)-,
(Ci -C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-,
(Ci -C4-alkyl)-S-(Ci-C4-alkoxy)-, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy,
Ci -C4-cyanoalkoxy, phenyl, 5- or 6-membered heteroaryl,
(5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, -S-(Ci -C4-alkyl), -S-(Ci -C4-haloalkyl), hydroxy, -N(R5)(R6),
(R5)(R6)N-(C2-C3-alkoxy)-, (4- to 7-membered heterocycloalky l)oxy-,
(4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)-,
(R5)(R6)NC(=0)-(Ci-C3-alkoxy)- and -C(=0)R7 and
(Ci -C2-alkoxy)-(C2-C3-alkoxy)n-,
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) -, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -O-CH2-O-, -0-(CH2)2-0-, -N(R7)-(CH2)2-, -(CH2)2-N(R7)-, -CH2-N(R7)-CH2-, -N(R7)-(CH2)3-, -(CH2)3-N(R7)-,
-CH2-N(R7)-(CH2)2-, -(CH2)2-N(R7)-CH2-, -N(R7)-(CH2)2-N(R7)-, -N(R7)-(CH2)2-0- and -0-(CH2)2-N(R7)-,
wherein n represents an integer of 2, 3 or 4,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is 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-hydroxyalkyl, cyano, hydroxy,
Ci -C2-alkoxy, C3-C4-cycloalkyl, -N(R5)(R6), -C(=0)OR8 and oxo, and wherein said phenyl and phenoxy group, and the phenyl part of said phenyl-(Ci-C3-alkoxy)- group, and said 5- or 6-membered heteroaryl group, and the (5- or 6-membered heteroaryl) part of said (5- or 6- membered heteroaryljoxy- and
(5- or 6-membered heteroaryl)-(Ci-C3-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 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:
R2 represents a group selected from phenyl, naphthyl and pyridinyl,
which phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkenyl, Cs-Ce-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C4-alkenyl)-, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, cyano, -N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)0R7,
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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-0-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -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 and oxo, 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 and a Ci-C2-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:
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkenyl, Cs-Ce-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C4-alkenyl)-, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, cyano, -N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)0R7,
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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -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 and oxo, 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 and a Ci-C2-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:
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C(=0)OR7,
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
wherein the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-alkyl group,
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl and Ci-C4-haloalkyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
3- to 6-membered cycloalkyl 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 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-, (5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C(=0)OR7,
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
wherein the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-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:
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl and Ci-C4-haloalkyl,
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
3- to 6-membered cycloalkyl 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: R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group seleceted from
Ci-C4-alkyl, and C3-C4-cycloalkyl,
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-C2-alkyl, C3-C4-cycloalkyl, Ci-C2-haloalkyl, Ci-C2-hydroxyalkyl,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)- 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
seleceted from
Ci-C4-alkyl, and C3-C4-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:
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-C2-alkyl, C3-C4-cycloalkyl, Ci-C2-haloalkyl, Ci-C2-hydroxyalkyl,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)- 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: R1 represents a group
Figure imgf000126_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a halogen atom or a group selected from Ci -C4-alkyl, Ci -C4-hydroxyalkyl, Ci -C4-haloalkyl, Ci -C4-alkoxy,
(C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-, (Ci-C4-alkyl)-S-(Ci-C4-alkoxy)-, Ci -C4-haloalkoxy, C3-C6-cycloalkyloxy, Ci-C4-cyanoalkoxy, phenyl,
(5- or 6-membered heteroaryl)oxy-, (5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, -S-(Ci-C4-alkyl), -S-(Ci -C4-haloalkyl), hydroxy, -N(R5)(R6), (R5)(R6)N-(C2-C3-alkoxy)-, (4- to 7-membered heterocycloalkyl)oxy-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-, (R5)(R6)NC(=0)-(Ci-C3-alkoxy)-, -C(=0)R7 and (Ci-C2-alkoxy)-(C2-C3-alkoxy)n-,
wherein n represents an integer of 2, 3 or 4,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci -C3-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, Ci -C2-hydroxyalkyl, hydroxy, -C(=0)OR8 and oxo,
and
wherein said phenyl and phenoxy group, and the phenyl part of said phenyl-(Ci -C3-alkoxy)- group, and the (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)oxy- group and
(5- or 6-membered heteroaryl)-(Ci-C3-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 and Ci -C2-alkoxy, wherein X3 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group, or,
wherein X2 and X3 are linked to one another in such a way that they jointly form a group selected from
-C(R9)=C(R9)-C(R9)=C(R9)-, -(CH2)2-N(R7)-, -(CH2)2-N(R7)-, -(CH2)2-N(R7)-, -0-(CH2)2- and -N(R7)-(CH2)3-, wherein X4 represents a hydrogen atom or a halogen atom or a Ci-C4-haloalkyl group, or,
wherein X3 and X4 are linked to one another in such a way that they jointly form a group selected from
-CH2-0-CH2- and -0-CH2-0-, wherein X5 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group, wherein X6 represents a hydrogen atom or a halogen 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:
R2 represents a group selected from phenyl, naphthyl and pyridinyl,
which phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci -C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkenyl, Cs-Ce-hydroxycycloalkenyl, (Ci -C2-alkoxy)-(C3-C4-alkenyl)-, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci -C4-haloalkoxy, cyano, -N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)0R7,
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 -(CH2)3- group,
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 and oxo, 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 and a Ci-C2-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:
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkenyl, Cs-Ce-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C4-alkenyl)-, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, cyano, -N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)0R7,
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 -(CH2)3- group,
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 and oxo, 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 and a Ci-C2-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:
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C(=0)0R7,
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
wherein the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-alkyl group,
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl and Ci-C4-haloalkyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
3- to 6-membered cycloalkyl 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 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C(=0)OR7,
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
wherein the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-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:
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl and Ci-C4-haloalkyl,
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
3- to 6-membered cycloalkyl 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:
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
seleceted from
Ci-C4-alkyl and C3-C4-cycloalkyl,
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 Ci-C2-alkyl group 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
seleceted from
Ci-C4-alkyl and C3-C4-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:
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 Ci-C2-alkyl group 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:
R9 represents a hydrogen atom or a halogen atom and a Ci-C2-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:
R1 represents a group
Figure imgf000132_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from
Ci -C4-alkyl, Ci -C4-alkoxy, (Ci -C2-alkoxy)-(C2-C4-alkoxy)-, phenyl and
(4- to 7-membered heterocycloalkyl)oxy-,
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
wherein the 4- to 7-membered heterocycloalkyl part of said
(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, Ci -C2-hydroxyalkyl, 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 and 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 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, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl and Ci-C4-haloalkoxy,
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-alkyl, Ci-C4-alkoxy and hydroxy,
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl and Ci-C4-haloalkyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
3- to 6-membered cycloalkyl 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 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, 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: R4 represents a hydrogen atom, a halogen atom, or a group selected from Ci -C4-alkyl and Ci-C4-haloalkyl,
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
3- to 6-membered cycloalkyl 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:
R1 represents a group
Figure imgf000134_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from methyl, methoxy, 3-methoxypropoxy, tetrahydrofuran-3-yloxy and 3-methoxyphenyl, 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:
R2 represents a group selected from phenyl, 3-bromophenyl, 3-bromo-5-chlorophenyl, 3-bromo-5-fluorophenyl,
5-bromo-2-fluorophenyl, 3-bromo-5-methylphenyl, 3-chlorophenyl, 3,4-dichlorophenyl,
3.5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-fluorophenyl, 3-fluoro-5-methylphenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 3-bromo-5-methylphenyl,
3.5-dimethylphenyl, 2-(trifluoromethoxy)phenyl 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 fluorine atom, or a group selected from
methyl, methoxy and hydroxy,
R4 represents a hydrogen atom, or a fluorine atom, or a group selected from
methyl and trifluoromethyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
cyclopropyl group or a cyclopentyl 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 represents a hydrogen atom, a fluorine atom, or a group selected from
methyl, 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 fluorine atom, or a group selected from
methyl and trifluoromethyl,
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
cyclopropyl group or a cyclopentyl 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-bromo-5-chlorophenyl, 3-bromo-5-fluorophenyl,
5-bromo-2-fluorophenyl, 3-bromo-5-methylphenyl, 3-chlorophenyl, 3,4-dichlorophenyl,
3.5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-fluorophenyl, 3-fluoro-5-methylphenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 3-bromo-5-methylphenyl,
3.5-dimethylphenyl, 2-(trifluoromethoxy)phenyl 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 (I), supra , in which:
R1 represents a group
Figure imgf000136_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a halogen atom or a group selected from Ci -C4-alkyl, Ci -C4-hydroxyalkyl, Ci -C4-haloalkyl, Ci -C4-alkoxy,
(C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-, (Ci-C4-alkyl)-S-(Ci-C4-alkoxy)-, Ci -C4-haloalkoxy, Cs-Ce-cycloalkyloxy, Ci-C4-cyanoalkoxy, phenyl,
(5- or 6-membered heteroaryl)oxy-, (5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, -S-(Ci-C4-alkyl), -S-(Ci -C4-haloalkyl), hydroxy, -N(R5)(R6), (R5)(R6)N-(C2-C3-alkoxy)-, (4- to 7-membered heterocycloalkyl)oxy-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-, (R5)(R6)NC(=0)-(Ci-C3-alkoxy)-, -C(=0)R7 and (Ci-C2-alkoxy)-(C2-C3-alkoxy)n-,
wherein n represents an integer of 2, 3 or 4,
and wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci -C3-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, Ci -C2-hydroxyalkyl, hydroxy, -C(=0)OR8 and oxo,
and
wherein said phenyl and phenoxy group, and the phenyl part of said
phenyl-(Ci -C3-alkoxy)- group, and the (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)oxy- group and
(5- or 6-membered heteroaryl)-(Ci-C3-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 and Ci -C2-alkoxy, wherein X3 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group, or,
wherein X2 and X3 are linked to one another in such a way that they jointly form a group selected from
-C(R9)=C(R9)-C(R9)=C(R9)-, -(CH2)2-N(R7)-, -(CH2)2-N(R7)-, -(CH2)2-N(R7)-, -0-(CH2)2- and -N(R7)-(CH2)3-, wherein X4 represents a hydrogen atom or a halogen atom or a Ci-C4-haloalkyl group, or,
wherein X3 and X4 are linked to one another in such a way that they jointly form a group selected from
-CH2-O-CH2- and -O-CH2-O-, wherein X5 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group, wherein X6 represents a hydrogen atom or a halogen 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:
R2 represents a group selected from phenyl, naphthyl and pyridinyl,
which phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkenyl, Cs-Ce-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C4-alkenyl)-, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, cyano, -N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)0R7,
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 -(OH2)3- group,
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 and oxo, 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 and a Ci-C2-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: R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkenyl, Cs-Ce-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C4-alkenyl)-, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, cyano, -N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)OR7,
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 -(CH2)3- group,
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 and oxo, 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 and a Ci-C2-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:
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C(=0)0R7, wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
wherein the (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-alkyl group,
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl and Ci-C4-haloalkyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
3- to 6-membered cycloalkyl 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 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C(=0)OR7,
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
wherein the (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-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:
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl and Ci-C4-haloalkyl,
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
3- to 6-membered cycloalkyl 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:
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
seleceted from
Ci-C4-alkyl and C3-C4-cycloalkyl,
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 Ci-C2-alkyl group 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
seleceted from
Ci-C4-alkyl and C3-C4-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:
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 Ci-C2-alkyl group 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:
R9 represents a hydrogen atom or a halogen atom and a Ci-C2-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: R1 represents a group
Figure imgf000143_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from
Ci -C4-alkyl, Ci -C4-alkoxy, (Ci -C2-alkoxy)-(C2-C4-alkoxy)-, phenyl and
(4- to 7-membered heterocycloalkyl)oxy-,
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
wherein the 4- to 7-membered heterocycloalkyl part of said
(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, Ci -C2-hydroxyalkyl, 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 and 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, 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, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl and Ci-C4-haloalkoxy,
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-alkyl, Ci-C4-alkoxy and hydroxy,
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl and Ci-C4-haloalkyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
3- to 6-membered cycloalkyl 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 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, 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:
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl and Ci-C4-haloalkyl,
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
3- to 6-membered cycloalkyl 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:
R1 represents a group
Figure imgf000145_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from methyl, methoxy, 3-methoxypropoxy, tetrahydrofuran-3-yloxy and 3-methoxyphenyl, 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:
R2 represents a group selected from phenyl, 3-bromophenyl, 3-bromo-5-chlorophenyl, 3-bromo-5-fluorophenyl,
5-bromo-2-fluorophenyl, 3-bromo-5-methylphenyl, 3-chlorophenyl, 3,4-dichlorophenyl,
3.5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-fluorophenyl, 3-fluoro-5-methylphenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 3-bromo-5-methylphenyl,
3.5-dimethylphenyl, 2-(trifluoromethoxy)phenyl 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 fluorine atom, or a group selected from
methyl, methoxy and hydroxy,
R4 represents a hydrogen atom, or a fluorine atom, or a group selected from
methyl and trifluoromethyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
cyclopropyl group or a cyclopentyl 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 represents a hydrogen atom, a fluorine atom, or a group selected from
methyl, 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 fluorine atom, or a group selected from
methyl and trifluoromethyl,
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
cyclopropyl group or a cyclopentyl 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-bromo-5-chlorophenyl, 3-bromo-5-fluorophenyl,
5-bromo-2-fluorophenyl, 3-bromo-5-methylphenyl, 3-chlorophenyl, 3,4-dichlorophenyl,
3.5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-fluorophenyl, 3-fluoro-5-methylphenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 3-bromo-5-methylphenyl,
3.5-dimethylphenyl, 2-(trifluoromethoxy)phenyl 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 (l-a), supra , in which:
R1 represents a group selected from phenyl and naphtyl,
which phenyl and naphtyl 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-alkynyl, Cs-Ce-cycloalkyl,
(C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, (C3-C6-cycloalkyloxy)-(Ci-C3-alkyl)-,
Ci-Ce-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci-C6-alkyl)-, Ci-Ce-haloalkyl, Ci-Ce-alkoxy, (C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, C2-C6-hydroxyalkoxy,
(Ci -C2-alkoxy)-(C2-C6-alkoxy)-,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-,
(Ci-C6-alkyl)-S-(Ci-C6-alkoxy)-, Ci-C6-haloalkoxy,
(Ci -C2-haloalkoxy)-(Ci -Ce-alkyl)-, C3-C6-cycloalkyloxy,
Ci-C6-cyanoalkoxy, phenyl, 5- or 6-membered heteroaryl, (5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkyl)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci-C3-alkyl)-, phenyl-(Ci -C3-alkoxy)-, phenoxy, phenoxy-(Ci -C3-alkyl)-,
phenoxy-(C2-C3-alkoxy)-, -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), -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), (R5)(R6)N-(C2-C3-alkoxy)-,
4- to 7-membered heterocycloalkyl, (4- to 7-membered heterocycloalkyl)oxy-, -(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl),
(4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)-, -C(=0)N(R5)(R6), -(Ci-C3-alkyl)-C(=0)N(R5)(R6), (R5)(R6)NC(=0)-(Ci -C3-alkoxy)-, -C(=0)OR7, -(Ci-C3-alkyl)-C(=0)0R7, R7OC(=0)-(Ci-C3-alkoxy)-, -C(=0)R7,
-(Ci-C3-alkyl)-C(=0)R7 and (Ci-C2-alkoxy)-(C2-C3-alkoxy)n-,
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) -, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -O-CH2-O-, -0-(CH2)2-0-, -N(R7)-(CH2)2-, -(CH2)2-N(R7)-, -CH2-N(R7)-CH2-, -N(R7)-(CH2)3-, -(CH2)3-N(R7)-,
-CH2-N(R7)-(CH2)2-, -(CH2)2-N(R7)-CH2-, -N(R7)-(CH2)2-N(R7)-, -N(R7)-(CH2)2-0- and -0-(CH2)2-N(R7)-,
wherein n represents an integer of 2, 3, 4 or 5,
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)oxy- group,
-(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl) group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- 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
(4- to 7-membered heterocycloalkyl)oxy- group,
-(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl) group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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, Ci-C2-haloalkyl, Ci-C2-hydroxyalkyl, cyano, hydroxy, Ci-C2-alkoxy, C3-C4-cycloalkyl, -N(R5)(R6), -C(=0)OR8 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 the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkyl)- and (5- or 6-membered heteroaryl)-(Ci-C3-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, Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl 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, C2-C6-alkenyl, C2-C6-alkynyl, Cs-Ce-cycloalkyl, C4-C7-cycloalkenyl, C4-C7-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C6-alkenyl)-, Ci-C6-hydroxyalkyl, Ci-Ce-haloalkyl, Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, 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), cyano, hydroxy,
-N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)0R7,
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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -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, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
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, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl 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 and naphthyl,
which phenyl and naphthyl 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-alkynyl, C3-C6-cycloalkyl, C4-C7-cycloalkenyl, C4-C7-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C6-alkenyl)-, Ci-C6-hydroxyalkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, 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), cyano, hydroxy,
-N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)OR7,
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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-0-CH2-, -0-(CH2)3-, -(CH2)3-O-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -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, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
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, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl 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-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C6-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C6-alkoxy)-, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyloxy, phenyl, phenoxy, phenyl-(Ci-C2-alkyl)-, phenyl-(Ci-C2-alkoxy)-, (5- or 6-membered heteroaryl)oxy, (5- or 6-membered heteroaryl)-(Ci-C3-alkoxy), hydroxy, cyano, -N(R5)(R6),
-(Ci-C2-alkyl)-N(R5)(R6), (R5)(R6)N-(C2-C3-alkoxy)-, C4-C7-heterocycloalkyl,
-(Ci-C2-alkyl)-(C4-C7-heterocycloalkyl),
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-, (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 and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- 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 and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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, Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
and
wherein said cycloalkyl group and said phenyl group, and the phenyl part of said phenoxy, phenyl-(Ci-C2-alkyl)- and phenyl-(Ci-C2-alkoxy)- group, and the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)oxy- group and
(5- or 6-membered heteroaryl)-(Ci-C3-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, Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy and
-N(R5)(R6),
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, phenyl, phenyl-(Ci-C2-alkyl)-, -(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, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
and
wherein said cycloalkyl group and said phenyl group, and the phenyl part of said phenyl-(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, cyano, hydroxy, Ci-C2-alkoxy and
-N(R5)(R6),
or
R3 and R4 together with the carbon atom to which they are attached represent a
3- 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 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C6-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C6-alkoxy)-, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyloxy, phenyl, phenoxy, phenyl-(Ci-C2-alkyl)-, phenyl-(Ci-C2-alkoxy)-, (5- or 6-membered heteroaryl)oxy,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy), hydroxy, cyano, -N(R5)(R6),
-(Ci-C2-alkyl)-N(R5)(R6), (R5)(R6)N-(C2-C3-alkoxy)-, C4-C7-heterocycloalkyl,
-(Ci-C2-alkyl)-(C4-C7-heterocycloalkyl),
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-, (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 and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- 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 and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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, Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
and
wherein said cycloalkyl group and said phenyl group, and the phenyl part of said phenoxy, phenyl-(Ci-C2-alkyl)- and phenyl-(Ci-C2-alkoxy)- group, and the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)oxy- group and
(5- or 6-membered heteroaryl)-(Ci-C3-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, Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy 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, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Cs-Ce-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, phenyl, phenyl-(Ci-C2-alkyl)-, -(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, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
and
wherein said cycloalkyl group and said phenyl group, and the phenyl part of said phenyl-(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, cyano, hydroxy, Ci-C2-alkoxy 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 and R4 together with the carbon atom to which they are attached represent a
3- 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:
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
seleceted from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(C2-C3-alkyl-), -C(=0)-(Ci-C3-alkyl) and -C(=0)-(Ci-C3-haloaikyl), 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, Ci-C4-haloalkyl, Ci-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(Ci-C3-alkyl)- 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
seleceted from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(C2-C3-alkyl-), -C(=0)-(Ci-C3-alkyl) and -C(=0)-(Ci-C3-haloalkyl), 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, Ci-C4-haloalkyl, Ci-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(Ci-C3-alkyl)- 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 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 (I), supra , in which:
R1 represents a group selected from phenyl and naphtyl,
which phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl and Ci-C4-alkoxy, (C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, C2-C6-hydroxyalkoxy,
(Ci -C2-alkoxy)-(C2-C6-alkoxy)-,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-,
(Ci-C4-alkyl)-S-(Ci-C4-alkoxy)-, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy,
Ci-C4-cyanoalkoxy, phenyl, 5- or 6-membered heteroaryl,
(5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, -S-(Ci-C4-alkyl), -S-(Ci-C4-haloalkyl), hydroxy, -N(R5)(R6),
(R5)(R6)N-(C2-C3-alkoxy)-, (4- to 7-membered heterocycloalky l)oxy-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-,
(R5)(R6)NC(=0)-(Ci-C3-aikoxy)- and -C(=0)R7 and
(Ci-C2-alkoxy)-(C2-C3-alkoxy)n-, 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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -O-CH2-O-, -0-(CH2)2-0-, -N(R7)-(CH2)2-, -(CH2)2-N(R7)-, -CH2-N(R7)-CH2-, -N(R7)-(CH2)3-, -(CH2)3-N(R7)-, -CH2-N(R7)-(CH2)2-, -(CH2)2-N(R7)-CH2-, -N(R7)-(CH2)2-N(R7)-, -N(R7)-(CH2)2-0- and -0-(CH2)2-N(R7)-,
wherein n represents an integer of 2, 3 or 4,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is 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-hydroxyalkyl, cyano, hydroxy,
Ci-C2-alkoxy, C3-C4-cycloalkyl, -N(R5)(R6), -C(=0)OR8 and oxo, and
wherein said phenyl and phenoxy group, and the phenyl part of said phenyl-(Ci-C3-alkoxy)- group, and said 5- or 6-membered heteroaryl group, and the (5- or 6-membered heteroaryl) part of said (5- or 6- membered heteroaryljoxy- and
(5- or 6-membered heteroaryl)-(Ci-C3-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 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: R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Ci-C4-haloalkyl and (Ci-C2-alkoxy)-(Ci-C2-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 (l-a), supra , in which:
R1 represents a group selected from phenyl and naphtyl,
which phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl and Ci-C4-alkoxy, (C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, C2-C6-hydroxyalkoxy,
(Ci -C2-alkoxy)-(C2-C6-alkoxy)-,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-,
(Ci-C4-alkyl)-S-(Ci-C4-alkoxy)-, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyloxy,
Ci-C4-cyanoalkoxy, phenyl, 5- or 6-membered heteroaryl,
(5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, -S-(Ci-C4-alkyl), -S-(Ci-C4-haloalkyl), hydroxy, -N(R5)(R6),
(R5)(R6)N-(C2-C3-alkoxy)-, (4- to 7-membered heterocycloalky l)oxy-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-,
(R5)(R6)NC(=0)-(Ci-C3-aikoxy)- and -C(=0)R7 and
(Ci-C2-alkoxy)-(C2-C3-alkoxy)n-,
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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -O-CH2-O-, -0-(CH2)2-0-, -N(R7)-(CH2)2-, -(CH2)2-N(R7)-, -CH2-N(R7)-CH2-, -N(R7)-(CH2)3-, -(CH2)3-N(R7)-, -CH2-N(R7)-(CH2)2-, -(CH2)2-N(R7)-CH2-, -N(R7)-(CH2)2-N(R7)-, -N(R7)-(CH2)2-0- and -0-(CH2)2-N(R7)-,
wherein n represents an integer of 2, 3 or 4,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is 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-hydroxyalkyl, cyano, hydroxy,
Ci -C2-alkoxy, C3-C4-cycloalkyl, -N(R5)(R6), -C(=0)OR8 and oxo, and
wherein said phenyl and phenoxy group, and the phenyl part of said phenyl-(Ci-C3-alkoxy)- group, and said 5- or 6-membered heteroaryl group, and the (5- or 6-membered heteroaryl) part of said (5- or 6- membered heteroaryl)oxy- and
(5- or 6-membered heteroaryl)-(Ci-C3-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 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:
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci -C4-alkyl, C2-C4-alkenyl, Ci-C4-haloalkyl and (Ci-C2-alkoxy)-(Ci-C2-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:
R1 represents a group
Figure imgf000160_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C6-hydroxyalkoxy, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy, (C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, phenoxy, hydroxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C6-alkoxy)-,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-, (Ci-C4-alkyl)-S-(Ci-C4-alkoxy)-, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy, Ci-C4-cyanoalkoxy, phenyl,
5- or 6-membered heteroaryl, (5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, -S-(Ci-C4-alkyl), -S-(Ci-C4-haloalkyl), hydroxy, -N(R5)(R6), (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)oxy-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-, (R5)(R6)NC(=0)-(Ci-C3-alkoxy)-, -C(=0)R7 and (Ci-C2-alkoxy)-(C2-C3-alkoxy)n-,
wherein n represents an integer of 2, 3 or 4,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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, Ci-C2-hydroxyalkyl, cyano, hydroxy, -C(=0)OR8 and oxo, and
wherein said phenyl and phenoxy group, and the phenyl part of said
phenyl-(Ci-C3-alkoxy)- group, and said 5- or 6-membered heteroaryl group and the (5- or 6-membered heteroaryl) part of said (5- or 6-membered
heteroaryl)oxy- group and
(5- or 6-membered heteroaryl)-(Ci-C3-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 Ci-C2-alkoxy, wherein X3 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group, or,
wherein X2 and X3 are linked to one another in such a way that they jointly form a group selected from
-C(R9)=C(R9)-C(R9)=C(R9)-, -(CH2)2-N(R7)-, -(CH2)2-N(R7)-, -(CH2)2-N(R7)-, -0-(CH2)2- and -N(R7)-(CH2)3-, wherein X4 represents a hydrogen atom or a halogen atom or a Ci-C4-haloalkyl group, or,
wherein X3 and X4 are linked to one another in such a way that they jointly form a group selected from
-CH2-0-CH2- and -0-CH2-0-, wherein X5 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group, wherein X6 represents a hydrogen atom or a halogen 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:
R2 represents a group selected from phenyl, naphthyl and pyridinyl,
which phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci -C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkenyl, Cs-Ce-hydroxycycloalkenyl, (Ci -C2-alkoxy)-(C3-C4-alkenyl)-, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci -C4-haloalkoxy, cyano, -N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)0R7,
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 -(CH2)3- group,
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 and oxo, 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 and a Ci-C2-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:
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C(=0)0R7,
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
wherein the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-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:
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci -C4-alkyl, C2-C4-alkenyl, Ci-C4-haloalkyl and (Ci-C2-alkoxy)-(Ci-C2-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:
R1 represents a group
Figure imgf000164_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a halogen atom or a group selected from Ci -C4-alkyl, Ci -C4-hydroxyalkyl, Ci -C4-haloalkyl, Ci -C4-alkoxy, C2-C6-hydroxyalkoxy, Ci -C4-haloalkoxy, C3-C6-cycloalkyloxy, (C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, phenoxy, hydroxy, (Ci-C2-alkoxy)-(C2-C6-alkoxy)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)- (Ci-C2-alkoxy)-, phenyl, phenyl-(Ci -C3-alkoxy)-, 5- or 6-membered heteroaryl,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, -N(R5)(R6), (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)oxy- and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-,
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group and (4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group and (4- to 7-membered heterocycloalkyl)-(Ci -C3-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, Ci -C2-hydroxyalkyl, cyano, hydroxy and oxo,
and wherein said phenyl group and said 5- or 6-membered heteroaryl group and the (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)-(Ci- C3-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 Ci-C2-alkoxy, wherein X3 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl group, or,
wherein X2 and X3 are linked to one another in such a way that they jointly form a -0-(CH2)2- group, wherein X4 represents a hydrogen atom or a halogen atom, wherein X5 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl group, wherein X6 represents a hydrogen atom or a halogen 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:
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy, 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-alkyl, Ci-C4-alkoxy, hydroxy and Ci-C4-haloalkyl,
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, a halogen atom, or a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl and (Ci-C2-alkoxy)-(Ci-C2-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 represent, independently from each occurrence, a hydrogen atom or a Ci-C4-alkyl group,
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 with an oxo 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:
R5 and R6 represent, independently from each occurrence, 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:
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 with an oxo 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: R1 represents a group
Figure imgf000167_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a bromine atom, chlorine atom, fluorine atom, or a group selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, phenoxy, diifluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy,
cyclopropyloxy, cyclopropylm ethoxy, hydroxy, 1 -hydroxyethyl, 2-hydroxypropoxy, 3-hydroxypropoxy, tetrahydrofuran-3-yloxy, 3-methoxyphenyl,
2-hydroxy-2-methylpropoxy, 3-hydroxybutoxy, 3-hydroxy-3-methylbutoxy,
2-hydroxy-3-methoxypropoxy, 2-methoxypropoxy, 2-methoxy-2-methylpropoxy,
3-methoxypropoxy, 3-methoxy-3-methylbutoxy, benzyloxy, methylamino, ethylamino, dimethylamino, (oxetan-2-yl)methoxy, (2-methyloxetan-2-yl)methoxy,
(oxetan-3-yl)methoxy, (3-fluorooxetan-3-yl)methoxy, (3-cyanooxetan-3-yl)methoxy, (3-methyloxetan-3-yl)methoxy, tetrahydropyran-4-yloxy, (tetrahydropyran-3-yl)methoxy, 2-(2-oxoimidazolin-1 -yljethoxy, 2-(2-oxo-1 ,3-oxazolidin-3-yl)ethoxy,
2-(morpholin-4-yl)ethoxy, 2-(oxazin-2-yl)ethoxy, 1 -methyl-1 H-pyrazol-4-yl,
2-(imidazol-1 -yl)ethoxy, (1 ,3-oxazol-2-yl)methoxy, (2-methyl-1 ,3-oxazol-4-yl)methoxy, (thiazol-4-yl)methoxy, (2-methylthiazol-4-yl)methoxy, (2-methylthiazol-5-yl)methoxy,
(1 ,3-oxazol-5-yl)methoxy, 2-(1 H-pyrazol-1 -yl)ethoxy,
(5-methyl-1 ,3,4-oxadiazol-2-yl)methoxy, (5-methyl-1 ,3,4-thiadiazol-2-yl)methoxy, (pyridin-2-yl)methoxy, (pyridin-3-yl)methoxy, (pyridin-4-yl)methoxy,
(3-fluoropyridin-4-yl)methoxy, (2-methylpyridin-4-yl)methoxy,
(3-methylpyridin-4-yl)methoxy and (2-cyanopyridin-4-yl)methoxy, wherein X3 represents a hydrogen atom or a fluorine atom or a methyl group, or,
wherein X2 and X3 are linked to one another in such a way that they jointly form a -0-(CH2)2- group, wherein X4 represents a hydrogen atom or a fluorine atom, wherein X5 represents a hydrogen atom or a fluorine atom or a methyl group, wherein X6 represents a hydrogen atom or a fluorine atom or a methyl 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, 4-bromophenyl, 3-bromo-5-chlorophenyl,
3-bromo-4-fluorophenyl, 3-bromo-5-fluorophenyl, 5-bromo-2-fluorophenyl,
3-bromo-5-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,
3.4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-fluorophenyl, 3-fluoro-5-methylphenyl, 3-fluoro-4-methoxyphenyl, 2-(trifluoromethyl)phenyl,
3-(trifluoromethyl)phenyl, 3-bromo-5-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl,
3.5-dimethylphenyl, 2-(trifluoromethoxy)phenyl, 4-methoxyphenyl 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 fluorine atom, or a group selected from
methyl, methoxy, hydroxy and trifluoromethyl,
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 fluorine atom, or a group selected from
methyl, trifluoromethyl and methoxymethyl,
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
phenyl, 2-bromophenyl, 2-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,
2-chloro-3-fluorophenyl, 2-fluoro-3-methylphenyl, 2-fluoro-6-methylphenyl,
3-fluoro-2-methylphenyl, 4-fluoro-2-methylphenyl, 2-ethyl-4-fluorophenyl,
5-fluoro-2-methylphenyl, 3-fluoro-2-methoxyphenyl, 4-fluoro-2-methoxyphenyl, 5-fluoro-2-methoxyphenyl, 3,6-difluoro-2-methoxyphenyl, 2,3-difluoro-6-methoxyphenyl, 3,4-difluoro-2-methoxyphenyl, 3,5-difluoro-2-methoxyphenyl,
4-fluoro-2-(3-methoxypropoxy)phenyl, 4-fluoro-2-(tetrahydrofuran-3-yloxy)phenyl, 2-ethylphenyl, 2,3-dimethylphenyl, 2,5-dimethylphenyl, 3,5-dimethylphenyl,
2-methoxyphenyl, 2-ethoxyphenyl, 2-phenoxyphenyl, 2-methoxy-5-methylphenyl, 2-(trifluoromethyl)phenyl, 2-(difluoromethoxy)phenyl, 2-(trifluoromethoxy)phenyl, 2-(2,2-difluoroethoxy)phenyl, 2-(2,2,2-trifluoroethoxy)phenyl, 2-(cyclopropyloxy)phenyl, 2-(cyclopropylmethoxy)phenyl, 2-hydroxyphenyl, 2-(1 -hydroxyethyl)phenyl,
2-(2-hydroxypropoxy)phenyl, 2-(3-hydroxypropoxy)phenyl,
2-(2-hydroxy-2-methylpropoxy)phenyl, 2-(3-hydroxybutoxy)phenyl,
2-(3-hydroxy-3-methylbutoxy)phenyl, 2-(2-hydroxy-3-methoxypropoxy)phenyl), 2-(2-methoxypropoxy)phenyl, 2-(2-methoxy-2-methylpropoxy)phenyl,
2-(3-methoxypropoxy)phenyl, 2-(3-methoxy-3-methylbutoxy)phenyl,
2-(benzyloxy)phenyl, 2-(methylamino)phenyl, 2-(ethylamino)phenyl,
2-(dimethylamino)phenyl, 2-[(oxetan-2-yl)methoxy]phenyl,
2-[(2-methyloxetan-2-yl)methoxy]phenyl, 2-[(oxetan-3-yl)methoxy]phenyl,
2-[(3-fluorooxetan-3-yl)methoxy]phenyl, 2-[(3-cyanooxetan-3-yl)methoxy]phenyl, 2-[(3-methyloxetan-3-yl)methoxy]phenyl, 2-(tetrahydropyran-4-yloxy)phenyl,
2-[(tetrahydropyran-3-yl)methoxy]phenyl, 2-[2-(2-oxoimidazolin-1 -yl)ethoxy]phenyl, 2-[2-(2-oxo-1 ,3-oxazolidin-3-yl)ethoxy]phenyl, 2-[2-(morpholin-4-yl)ethoxy]phenyl, 2-[2-(oxazin-2-yl)ethoxy]phenyl, 2-(1 -methyl-1 H-pyrazol-4-yl)phenyl,
2-[2-(imidazol-1 -yl)ethoxy]phenyl, 2-[(1 ,3-oxazol-2-yl)methoxy]phenyl,
2-[(2-methyl-1 ,3-oxazol-4-yl)methoxy]phenyl, 2-[(thiazol-4-yl)methoxy]phenyl,
2-[(2-methylthiazol-4-yl)methoxy]phenyl, 2-[(2-methylthiazol-5-yl)methoxy]phenyl,
2-[(1 ,3-oxazol-5-yl)methoxy]phenyl, 2-[2-(1 H-pyrazol-1 -yl)ethoxy]phenyl,
2-[(5-methyl-1 ,3,4-oxadiazol-2-yl)methoxy]phenyl,
2-[(5-methyl-1 ,3,4-thiadiazol-2-yl)methoxy]phenyl, 2-[(pyridin-2-yl)methoxy]phenyl, 2-[(pyridin-3-yl)methoxy]phenyl, 2-[(pyridin-4-yl)methoxy]phenyl,
2-[(3-fluoropyridin-4-yl)methoxy]phenyl, 2-[(2-methylpyridin-4-yl)methoxy]phenyl, 2-[(3-methylpyridin-4-yl)methoxy]phenyl, 2-[(2-cyanopyridin-4-yl)methoxy]phenyl, 2,3-dihydro-1 -benzofuran-7-yl and 5-fluoro-3'-methoxy[1 ,1 '-biphenyl]-2-yl,
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, 4-bromophenyl, 3-bromo-5-chlorophenyl,
3-bromo-4-fluorophenyl, 3-bromo-5-fluorophenyl, 5-bromo-2-fluorophenyl,
3-bromo-5-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,
3.4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-fluorophenyl, 3-fluoro-5-methylphenyl, 3-fluoro-4-methoxyphenyl, 2-(trifluoromethyl)phenyl,
3-(trifluoromethyl)phenyl, 3-bromo-5-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl,
3.5-dimethylphenyl, 2-(trifluoromethoxy)phenyl, 4-methoxyphenyl 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 fluorine atom, or a group selected from
methyl, methoxy, hydroxy and trifluoromethyl,
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 fluorine atom, or a group selected from
methyl, trifluoromethyl and methoxymethyl,
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 (I), supra , in which:
R1 represents a group
Figure imgf000170_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C6-hydroxyalkoxy, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy, (C3-C6-cycloalkyl)-(Ci -C3-alkoxy)-, phenoxy, hydroxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C6-alkoxy)-, (Ci -C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-, (Ci -C4-alkyl)-S-(Ci -C4-alkoxy)-, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy, Ci -C4-cyanoalkoxy, phenyl,
5- or 6-membered heteroaryl, (5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci -C3-alkoxy)-, phenoxy, -S-(Ci-C4-alkyl), -S-(Ci -C4-haloalkyl), hydroxy, -N(R5)(R6), (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)oxy-,
(4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)-, (R5)(R6)NC(=0)-(Ci -C3-alkoxy)-, -C(=0)R7 and (Ci -C2-alkoxy)-(C2-C3-alkoxy)n-,
wherein n represents an integer of 2, 3 or 4,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci -C3-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, Ci -C2-hydroxyalkyl, cyano, hydroxy, -C(=0)OR8 and oxo, and
wherein said phenyl and phenoxy group, and the phenyl part of said
phenyl-(Ci -C3-alkoxy)- group, and said 5- or 6-membered heteroaryl group and the (5- or 6-membered heteroaryl) part of said (5- or 6-membered
heteroaryl)oxy- group and
(5- or 6-membered heteroaryl)-(Ci-C3-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 Ci-C2-alkoxy, wherein X3 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group, or,
wherein X2 and X3 are linked to one another in such a way that they jointly form a group selected from
-C(R9)=C(R9)-C(R9)=C(R9)-, -(CH2)2-N(R7)-, -(CH2)2-N(R7)-, -(CH2)2-N(R7)-, -0-(CH2)2- and -N(R7)-(CH2)3-, wherein X4 represents a hydrogen atom or a halogen atom or a Ci-C4-haloalkyl group, or,
wherein X3 and X4 are linked to one another in such a way that they jointly form a group selected from
-CH2-O-CH2- and -O-CH2-O-, wherein X5 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group, wherein X6 represents a hydrogen atom or a halogen 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:
R2 represents a group selected from phenyl, naphthyl and pyridinyl,
which phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkenyl, Cs-Ce-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C4-alkenyl)-, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, cyano, -N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)OR7,
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 -(OH2)3- group,
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 and oxo, 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 and a Ci-C2-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:
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C(=0)OR7,
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
wherein the (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-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: R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci -C4-alkyl, C2-C4-alkenyl, Ci-C4-haloalkyl and (Ci-C2-alkoxy)-(Ci-C2-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:
R1 represents a group
Figure imgf000174_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a halogen atom or a group selected from Ci -C4-alkyl, Ci -C4-hydroxyalkyl, Ci -C4-haloalkyl, Ci -C4-alkoxy, C2-C6-hydroxyalkoxy, Ci -C4-haloalkoxy, C3-C6-cycloalkyloxy, (C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, phenoxy, hydroxy, (Ci-C2-alkoxy)-(C2-C6-alkoxy)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)- (Ci-C2-alkoxy)-, phenyl, phenyl-(Ci -C3-alkoxy)-, 5- or 6-membered heteroaryl,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, -N(R5)(R6), (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)oxy- and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-,
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group and (4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group and (4- to 7-membered heterocycloalkyl)-(Ci -C3-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, Ci -C2-hydroxyalkyl, cyano, hydroxy and oxo,
and
wherein said phenyl group and said 5- or 6-membered heteroaryl group and the (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)-(Ci - C3-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 Ci-C2-alkoxy, wherein X3 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl group, or,
wherein X2 and X3 are linked to one another in such a way that they jointly form a -0-(CH2)2- group, wherein X4 represents a hydrogen atom or a halogen atom, wherein X5 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl group, wherein X6 represents a hydrogen atom or a halogen 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:
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy, 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-alkyl, Ci-C4-alkoxy, hydroxy and Ci-C4-haloalkyl,
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, a halogen atom, or a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl and (Ci-C2-alkoxy)-(Ci-C2-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 represent, independently from each occurrence, a hydrogen atom or a Ci-C4-alkyl group,
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 with an oxo 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:
R5 and R6 represent, independently from each occurrence, 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:
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 with an oxo 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:
R1 represents a group
Figure imgf000177_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a bromine atom, chlorine atom, fluorine atom, or a group selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, phenoxy, diifluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy,
cyclopropyloxy, cyclopropylm ethoxy, hydroxy, 1 -hydroxyethyl, 2-hydroxypropoxy, 3-hydroxypropoxy, tetrahydrofuran-3-yloxy, 3-methoxyphenyl,
2-hydroxy-2-methylpropoxy, 3-hydroxybutoxy, 3-hydroxy-3-methylbutoxy,
2-hydroxy-3-methoxypropoxy, 2-methoxypropoxy, 2-methoxy-2-methylpropoxy,
3-methoxypropoxy, 3-methoxy-3-methylbutoxy, benzyloxy, methylamino, ethylamino, dimethylamino, (oxetan-2-yl)methoxy, (2-methyloxetan-2-yl)methoxy,
(oxetan-3-yl)methoxy, (3-fluorooxetan-3-yl)methoxy, (3-cyanooxetan-3-yl)methoxy, (3-methyloxetan-3-yl)methoxy, tetrahydropyran-4-yloxy, (tetrahydropyran-3-yl)methoxy, 2-(2-oxoimidazolin-1 -yljethoxy, 2-(2-oxo-1 ,3-oxazolidin-3-yl)ethoxy,
2-(morpholin-4-yl)ethoxy, 2-(oxazin-2-yl)ethoxy, 1 -methyl-1 H-pyrazol-4-yl,
2-(imidazol-1 -yl)ethoxy, (1 ,3-oxazol-2-yl)methoxy, (2-methyl-1 ,3-oxazol-4-yl)methoxy, (thiazol-4-yl)methoxy, (2-methylthiazol-4-yl)methoxy, (2-methylthiazol-5-yl)methoxy,
(1 ,3-oxazol-5-yl)methoxy, 2-(1 H-pyrazol-1 -yl)ethoxy,
(5-methyl-1 ,3,4-oxadiazol-2-yl)methoxy, (5-methyl-1 ,3,4-thiadiazol-2-yl)methoxy, (pyridin-2-yl)methoxy, (pyridin-3-yl)methoxy, (pyridin-4-yl)methoxy,
(3-fluoropyridin-4-yl)methoxy, (2-methylpyridin-4-yl)methoxy,
(3-methylpyridin-4-yl)methoxy and (2-cyanopyridin-4-yl)methoxy, wherein X3 represents a hydrogen atom or a fluorine atom or a methyl group, or,
wherein X2 and X3 are linked to one another in such a way that they jointly form a -0-(CH2)2- group, wherein X4 represents a hydrogen atom or a fluorine atom, wherein X5 represents a hydrogen atom or a fluorine atom or a methyl group, wherein X6 represents a hydrogen atom or a fluorine atom or a methyl 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, 4-bromophenyl, 3-bromo-5-chlorophenyl,
3-bromo-4-fluorophenyl, 3-bromo-5-fluorophenyl, 5-bromo-2-fluorophenyl,
3-bromo-5-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,
3.4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-fluorophenyl, 3-fluoro-5-methylphenyl, 3-fluoro-4-methoxyphenyl, 2-(trifluoromethyl)phenyl,
3-(trifluoromethyl)phenyl, 3-bromo-5-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl,
3.5-dimethylphenyl, 2-(trifluoromethoxy)phenyl, 4-methoxyphenyl 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 fluorine atom, or a group selected from
methyl, methoxy, hydroxy and trifluoromethyl,
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 fluorine atom, or a group selected from
methyl, trifluoromethyl and methoxymethyl, 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
phenyl, 2-bromophenyl, 2-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,
2-chloro-3-fluorophenyl, 2-fluoro-3-methylphenyl, 2-fluoro-6-methylphenyl,
3-fluoro-2-methylphenyl, 4-fluoro-2-methylphenyl, 2-ethyl-4-fluorophenyl,
5-fluoro-2-methylphenyl, 3-fluoro-2-methoxyphenyl, 4-fluoro-2-methoxyphenyl, 5-fluoro-2-methoxyphenyl, 3,6-difluoro-2-methoxyphenyl, 2,3-difluoro-6-methoxyphenyl, 3,4-difluoro-2-methoxyphenyl, 3,5-difluoro-2-methoxyphenyl,
4-fluoro-2-(3-methoxypropoxy)phenyl, 4-fluoro-2-(tetrahydrofuran-3-yloxy)phenyl, 2-ethylphenyl, 2,3-dimethylphenyl, 2,5-dimethylphenyl, 3,5-dimethylphenyl,
2-methoxyphenyl, 2-ethoxyphenyl, 2-phenoxyphenyl, 2-methoxy-5-methylphenyl, 2-(trifluoromethyl)phenyl, 2-(difluoromethoxy)phenyl, 2-(trifluoromethoxy)phenyl, 2-(2,2-difluoroethoxy)phenyl, 2-(2,2,2-trifluoroethoxy)phenyl, 2-(cyclopropyloxy)phenyl, 2-(cyclopropylmethoxy)phenyl, 2-hydroxyphenyl, 2-(1 -hydroxyethyl)phenyl,
2-(2-hydroxypropoxy)phenyl, 2-(3-hydroxypropoxy)phenyl,
2-(2-hydroxy-2-methylpropoxy)phenyl, 2-(3-hydroxybutoxy)phenyl,
2-(3-hydroxy-3-methylbutoxy)phenyl, 2-(2-hydroxy-3-methoxypropoxy)phenyl), 2-(2-methoxypropoxy)phenyl, 2-(2-methoxy-2-methylpropoxy)phenyl,
2-(3-methoxypropoxy)phenyl, 2-(3-methoxy-3-methylbutoxy)phenyl,
2-(benzyloxy)phenyl, 2-(methylamino)phenyl, 2-(ethylamino)phenyl,
2-(dimethylamino)phenyl, 2-[(oxetan-2-yl)methoxy]phenyl,
2-[(2-methyloxetan-2-yl)methoxy]phenyl, 2-[(oxetan-3-yl)methoxy]phenyl,
2-[(3-fluorooxetan-3-yl)methoxy]phenyl, 2-[(3-cyanooxetan-3-yl)methoxy]phenyl, 2-[(3-methyloxetan-3-yl)methoxy]phenyl, 2-(tetrahydropyran-4-yloxy)phenyl,
2-[(tetrahydropyran-3-yl)methoxy]phenyl, 2-[2-(2-oxoimidazolin-1 -yl)ethoxy]phenyl, 2-[2-(2-oxo-1 ,3-oxazolidin-3-yl)ethoxy]phenyl, 2-[2-(morpholin-4-yl)ethoxy]phenyl, 2-[2-(oxazin-2-yl)ethoxy]phenyl, 2-(1 -methyl-1 H-pyrazol-4-yl)phenyl,
2-[2-(imidazol-1 -yl)ethoxy]phenyl, 2-[(1 ,3-oxazol-2-yl)methoxy]phenyl,
2-[(2-methyl-1 ,3-oxazol-4-yl)methoxy]phenyl, 2-[(thiazol-4-yl)methoxy]phenyl,
2-[(2-methylthiazol-4-yl)methoxy]phenyl, 2-[(2-methylthiazol-5-yl)methoxy]phenyl,
2-[(1 ,3-oxazol-5-yl)methoxy]phenyl, 2-[2-(1 H-pyrazol-1 -yl)ethoxy]phenyl,
2-[(5-methyl-1 ,3,4-oxadiazol-2-yl)methoxy]phenyl,
2-[(5-methyl-1 ,3,4-thiadiazol-2-yl)methoxy]phenyl, 2-[(pyridin-2-yl)methoxy]phenyl, 2-[(pyridin-3-yl)methoxy]phenyl, 2-[(pyridin-4-yl)methoxy]phenyl,
2-[(3-fluoropyridin-4-yl)methoxy]phenyl, 2-[(2-methylpyridin-4-yl)methoxy]phenyl, 2-[(3-methylpyridin-4-yl)methoxy]phenyl, 2-[(2-cyanopyridin-4-yl)methoxy]phenyl, 2,3-dihydro-1 -benzofuran-7-yl and 5-fluoro-3'-methoxy[1 ,1 '-biphenyl]-2-yl,
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, 4-bromophenyl, 3-bromo-5-chlorophenyl,
3-bromo-4-fluorophenyl, 3-bromo-5-fluorophenyl, 5-bromo-2-fluorophenyl,
3-bromo-5-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,
3.4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-fluorophenyl, 3-fluoro-5-methylphenyl, 3-fluoro-4-methoxyphenyl, 2-(trifluoromethyl)phenyl,
3-(trifluoromethyl)phenyl, 3-bromo-5-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl,
3.5-dimethylphenyl, 2-(trifluoromethoxy)phenyl, 4-methoxyphenyl 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 fluorine atom, or a group selected from
methyl, methoxy, hydroxy and trifluoromethyl,
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 fluorine atom, or a group selected from
methyl, trifluoromethyl and methoxymethyl,
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 imgf000181_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from
Ci -C4-alkyl, Ci -C4-alkoxy, (Ci -C2-alkoxy)-(C2-C4-alkoxy)- and
(4- to 7-membered heterocycloalkyl)oxy-,
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
wherein the 4- to 7-membered heterocycloalkyl part of said
(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, Ci -C2-hydroxyalkyl, hydroxy and oxo, 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, 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 imgf000182_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from
methyl, methoxy, 3-methoxypropoxy and tetrahydrofuran-3-yloxy, 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:
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or 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:
R2 represents a group selected from phenyl and 1 -naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or methyl 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-bromo-5-chlorophenyl, 3-bromo-5-fluorophenyl, 5-bromo-2-fluorophenyl, 3-bromo-5-methylphenyl, 3-chlorphenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 3-fluoro-5-methylphenyl, 3,5-dimethylphenyl 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 Ci-C4-alkoxygroup,
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 methoxy 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-haloalkylgroup,
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 (l-a), supra , in which:
R1 represents a group
Figure imgf000184_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from
Ci -C4-alkyl, Ci -C4-alkoxy, (Ci -C2-alkoxy)-(C2-C4-alkoxy)- and
(4- to 7-membered heterocycloalkyl)oxy-,
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
wherein the 4- to 7-membered heterocycloalkyl part of said
(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, Ci -C2-hydroxyalkyl, hydroxy and oxo, 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 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 imgf000185_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from
methyl, methoxy, 3-methoxypropoxy and tetrahydrofuran-3-yloxy, 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:
R2 represents a group selected from phenyl and naphthyl,
which phenyl and naphthyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or 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:
R2 represents a group selected from phenyl and 1 -naphthyl,
which phenyl and naphthyl group is optionally substituted, one or two times, each substituent independently selected from a halogen atom or methyl 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-bromo-5-chlorophenyl, 3-bromo-5-fluorophenyl, 5-bromo-2-fluorophenyl, 3-bromo-5-methylphenyl, 3-chlorphenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 3-fluoro-5-methylphenyl, 3,5-dimethylphenyl 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 Ci-C4-alkoxygroup,
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 methoxy 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-haloalkylgroup,
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 (I), supra , in which:
R1 represents a group
Figure imgf000187_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from
Ci -C4-alkyl, Ci -C4-alkoxy, (Ci -C2-alkoxy)-(C2-C4-alkoxy)-, -N(R5)(R6) and
(4- to 7-membered heterocycloalkyl)oxy-,
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
wherein the 4- to 7-membered heterocycloalkyl part of said
(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, Ci -C2-hydroxyalkyl, hydroxy and oxo, 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, 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 imgf000188_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from
methyl, methoxy, 3-methoxypropoxy, methylamino and tetrahydrofuran-3-yloxy, 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 (l-a), supra , in which:
R1 represents a group
Figure imgf000188_0002
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from
Ci -C4-alkyl, Ci -C4-alkoxy, (Ci -C2-alkoxy)-(C2-C4-alkoxy)-, -N(R5)(R6) and
(4- to 7-membered heterocycloalkyl)oxy-,
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and wherein the 4- to 7-membered heterocycloalkyl part of said (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, Ci -C2-hydroxyalkyl, hydroxy and oxo, 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 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 imgf000189_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a group selected from
methyl, methoxy, 3-methoxypropoxy, methylamino and tetrahydrofuran-3-yloxy, 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 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 imgf000190_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 formula (I) and general formula (l-a), supra.
The present invention covers any sub-combination within any embodiment or aspect of the present invention of compounds of general formulae (I), (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), (ll-a), (III), (lll-a), (XVI), (XXI) and (XXII), supra.
The present invention covers the compounds of general formula (I) and general formula (l-a), which are disclosed in the Example Section of this text, infra.
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 formula (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, 6, 7, 8, 9, 10, 1 1 , 12, 13 and 14. The schemes and procedures described below illustrate synthetic routes to the compounds of general formula (I) and general formula (l-a)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, 6, 7, 8, 9, 10, 11 , 12, 13and 14 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, Ra, Rb, Rc, Rd and Re 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.
Several 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, 6, 7, 8, 9, 10, 1 1 , 12, 13 and 14.
Scheme 1
Figure imgf000192_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, Rb ,RC and Rd represent protecting groups. Ra and Rd can be for example (not-limiting), fert-butoxycarbonyl (Boc), benzyl (Bn) and benzyloxycarboxybenzyl (Cbz), and Rb and Rc can be for example (not- limiting), methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and benzyl.
Compounds of general formula (X) can be converted to compounds of general formula (IX) by numerous methods, such as for example, Knoevenagel condensation reaction as described in the literature (see the teachings of Yang et al., Tetrahedron Lett., 2008, 49, 6371 ; WO2004/69256, 2004, A1 ; WO2015/38426, 2015, A1 ; Chauder et al., Synth. Commun., 2006, 36, 279; Sebhat et al., J. Med. Chem., 2002, 45, 4589). Compounds of general formula (IX) can be converted to compounds of general formula (VIII) via a Michael addition with an ester under basic reaction conditions, these types of Michael addition reactions are known (see the teachings of Yang et al., Tetrahedron Lett., 2008, 49, 6371 and US2009/281 133).
Compounds of general formula (VIII) can be converted to compounds of general formula (VII) using decarboxylation methods such as using hexafluoroisopropanol at elevated temperatures, optionally using microwave heating conditions (Yang et al., Tetrahedron Lett., 2008, 49, 6371 ). This decarboxylation step to form compounds of general formula (VII) is also known to those skilled in the art and has been described for similar lower alkyl chain esters using the Krapcho conditions, e.g. lithium chloride, in DMSO, water at elevated temperatures (see the teachings of Yang et al., Tetrahedron Lett., 2008, 49, 6371 and US2009/281133).
Compounds of general formula (VII) can be converted by reductive methods to compounds of general formula (VI), 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 a 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, in the presence of a Lewis acid, such as for example, cobalt(ll) chloride, in a solvent, such as for example, method or ethanol, in a temperature range ranging from -500 to the boiling point of the solvent (see the teachings of: e.g. pressurized catalytic hydrogenations using Nickel, Guengoer et al., J. Med. Chem., 1994, 37, 4307 - 4316; WO2005/97795 A1 ; MacKenzie et al., J. Med. Chem., 2002, 45, 5365 - 5377; WO2016/164284 A1 ; pressurized catalytic hydrogenations using Platinium or Platinium oxide (Pt02), Petit et al., Eur. J. Med. Chem., 1990, 25, 641 - 652; Weinberg et al., Tetrahedron, 2013, 69, 4694 - 4707; sodium borohydride in the presence of cobalt chloride, Yang et al., Tetrahedron Lett., 2008, 49, 6371 - 6374; US2009/93501 A1 ; WO2015/96035;) and give compounds of general formula (VI).
Compounds of general formula (VI) can be converted to compounds of general formula (V) by numerous methods, such as, for example, reductive methods. These reductive methods for converting a lactam to an amine have been described widely in the public domain. The commonly used method is with lithium aluminium hydride (see the teachings of Yang et al., Tetrahedron Lett., 2008, 49, 6371 - 6374; WO2015/96035, 2015, A1 ). Other reductive methods use borane-THF (WO2015/192053, 2015, A1 ; W02009/109608, 2009, A1 ); dimethylsulfide borane complex (Oueslati et al., Org. Lett., 2007, 9, 153) and sodium tetrahydroborate in the presence of boron trifluoride diethyl etherate (EP1200406, 2004, B1 ). Compounds of general formula (V) can be converted to compounds of general formula (IV), using protection methods known to those skilled in the art, such as for example, see for example Greene’s Protective Groups in Organic Synthesis, 4th edition, Editor P.G.M. Wuts in Wiley 2014. For such methods when Rd is fert-butoxycarbonyl (Boc) see the teachings of Dong et al„ WO2015/96035, 2015, A1 ; W02007/30061 , 2007, A1 ; Yang et al., Bioorg. Med. Chem. Lett., 2009, 19, 209. For such methods when Rd is benzyl (Bn) or analogs like para- methoxybenzyl (PMB) see the teachings of Lv et al., see the teachings of Mercer et al., Eur. J. Med. Chem., 2008, 43, 1304 - 1308; Nagase et al., Bioorg. Med. Chem. Lett., 2010, 20, 6302 - 6305; EP892802, 2003, B1 and EP1679069, 2006, A1 Compounds of general formula (IV) can be converted to compounds of general formula (III), using deprotection methods known to those skilled in the art, such as 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 -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 2014), for such methods when R is fert-butoxycarbonyl (Boc) see 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 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 (III) can be converted to compounds of general formula (II) using carboxylic acids of general formula (XXI), 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 (III) to compounds of general formula (II):
i. reacting with a carboxylic acid of general formula (XXI) and a coupling reagent (non limiting), 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).
Compounds of general formula (II) can be converted to compounds of general formula (I), using deprotection methods known to those skilled in the art similar to those described previously in this section (see conversion of compounds of general formula (IV) to compounds of general formula (III)).
Scheme 2
Figure imgf000195_0001
Scheme 2 Synthesis route for the preparation of compounds of general formula (V) in which R1 has the meaning as given for general formula (I), supra , and Ra and Rb represent protecting groups. Ra can be for example (not-limiting), tert- butoxycarbonyl (Boc), benzyl (Bn) and benzyloxycarboxybenzyl (Cbz) and Rb can be for example (not-limiting), methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and benzyl. Compounds of general formula (X) can be converted to compounds of general formula (XIV) by numerous methods, such as, for example, Horner-Wandsworth-Emmons reaction (Sato et al., Heterocycles, 2001 , 54, 747 - 755; Bradley et al., Bioorg. Med. Chem. Lett., 2003, 13, 629 - 632; Sugimoto et al., J. Med. Chem., 1990, 33, 1880 - 1887), Wittig reaction (Gilbert et al Bioorg. Med. Chem. Lett., 2010, 20, 608 - 61 1 ; Peschke et al., Eur. J. Med. Chem., 1999, 34, 363 - 380) and Peterson olefination (Sarkar et al, Tetrahedron Lett., 201 1 , 52, 923 - 927). These types of reactions are typically carried out with a base, such as for example, sodium hydride, in a solvent, such as for example, tetrahydrofuran, toluene in a temperature range ranging from -100Ό to the boiling point of the sol vent.
Compounds of general formula (XIV) can be converted to compounds of general formula (XIII) via a Michael addition with a nitrile under basic reaction conditions, such as for example, sodium hydride, potassium tert-butoxide, lithium hexamethyldisilazide, lithium diisopropylamide, sodium hexamethyldisilazide, in a solvent, such as for example, tetrahydrofuran, in a temperature range ranging from -78Ό to the boiling point of the solvent, these types of Michael addition reactions are known to those skilled and are available in the public domain (see the teachings of Grewe et al., Justus Liebis Ann. Chem., 1962, 653, 97 - 104; Hudkins et al., Bioorg. Med. Chem. Lett., 2012, 22, 194 - 198; Koelsch., J. Am. Chem. Soc., 1943, 65, 437; Banerjee et al., J. Indian Chem. Soc., 1983, 60, 1 163 - 1 168).
Compounds of general formula (XIII) can be converted by reductive methods to compounds of general formula (XII), these compounds of general formula (XII) are usually formed in situ and are cyclized directly to give compounds of general formula (XI), 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 a 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, in the presence of a Lewis acid, such as for example, cobalt(ll) chloride, in a solvent, such as for example, method or ethanol, in a temperature range ranging from -500 to the boiling point of the solvent (see the teachings of: e.g. pressurized catalytic hydrogenations using Nickel, Guengoer et al., J. Med. Chem., 1994, 37, 4307 - 4316; WO2005/97795 A1 ; MacKenzie et al., J. Med. Chem., 2002, 45, 5365 - 5377; WO2016/164284 A1 ; pressurized catalytic hydrogenations using Platinium or Platinium oxide (Pt02), Petit et al., Eur. J. Med. Chem., 1990, 25, 641 - 652; Weinberg et al., Tetrahedron, 2013, 69, 4694 - 4707; sodium borohydride in the presence of cobalt chloride, Yang et al., Tetrahedron Lett., 2008, 49, 6371 - 6374; US2009/93501 A1 ; WO2015/96035;) and give compounds of general formula (XI). Compounds of general formula (XI) can be converted to compounds of general formula (V) by numerous methods, such as, for example, reductive methods. These reductive methods for converting a lactam to an amine have been described widely in the public domain and have been outlined in Scheme 1 for the conversion of compounds of general formula (VI) to compounds of general formula (V).
The remaining steps within Scheme 2 follow the same route and methods as described in Scheme 1 to generate compounds of general formula (I) from compounds of general formula (V).
Scheme 3
Figure imgf000197_0001
Scheme 3 Synthesis route for the preparation of compounds of general formula (VII) in which R1 has the meaning as given for general formula (I), supra , and Ra and Rb represent protecting groups. Ra can be for example (not-limiting), tert- butoxycarbonyl (Boc), benzyl (Bn) and benzyloxycarboxybenzyl (Cbz), and Rb can be for example (not-limiting), methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and benzyl.
Compounds of general formula (X) can be converted to compounds of general formula (XV) by numerous methods, such as for example, Horner-Wandsworth-Emmons reaction (Renslo et al., Bioorg. Med. Chem. Lett., 2007, 17, 5036 - 5040; Contreras et al., J. Med. Chem., 1999, 42, 730 - 741 ).
Compounds of general formula (XV) could be converted to compounds of general formula (VII) via a Michael addition with an ester under basic reaction conditions, these types of Michael addition reactions are known to those skilled in the art and are available in the public domain (see the teachings of Hutchison et al., J. Med. Chem., 1989, 32, 2221 - 2226). Compounds of general formula (VII) can be converted to compounds of general formula (I) as described in detail in Scheme 1. Scheme 4
Figure imgf000198_0001
Scheme 4 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 Rb and Rc represent protecting groups. Rb and Rc can be for example (not-limiting), methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and benzyl.
Compounds of general formula (XXII) can be converted to compounds of general formula (XX) using carboxylic acids of general formula (XXI), 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 (XXI) and a coupling reagent (non limiting), 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).
Compounds of general formula (XX) could be converted to compounds of general formula (XIX) by numerous methods, such as for example, Knoevenagel condensation reaction as described in the literature and described in Scheme 1 for the conversion of compounds of general formula (X) to compounds of general formula (IX).
Compounds of general formula (XIX) could be converted to compounds of general formula (XVIII) via a Michael addition with an ester under basic reaction conditions, these types of Michael addition reactions are known and have been described in Scheme 1 for the conversion of compounds of general formula (IX) to compounds of general formula (VIII). Compounds of general formula (XVIII) could be converted to compounds of general formula (XVII) using known decarboxylation methods and have been described in Scheme 1 for the conversion of compounds of general formula (VIII) to compounds of general formula (VII).
Compounds of general formula (XVII) could be converted by reductive methods to compounds of general formula (XVI) and such methods have been described in Scheme 1 for the conversion of compounds of general formula (VII) to compounds of general formula (VI).
Compounds of general formula (XVI) could be converted to compounds of general formula (I) by numerous methods, such as, for example, reductive methods. These reductive methods for converting a lactam to an amine have been described widely in the public domain and have been outlined in Scheme 1 for the conversion of compounds of general formula (VI) to compounds of general formula (V).
Scheme 5
Figure imgf000200_0001
Scheme 5 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 Rb and Rc represent protecting groups. Rb and Rc can be for example (not-limiting), methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and benzyl.
Compounds of general formula (XX) can be converted to compounds of general formula (XXIV) by numerous methods, such as, for example, Horner-Wandsworth-Emmons reaction and have been described in Scheme 1 for the conversion of compounds of general formula (X) to compounds of general formula (IX).
Compounds of general formula (XXIV) can be converted to compounds of general formula (XXIII) via a Michael addition with a nitrile under basic reaction conditions and such methods have been described in Scheme 2 for the conversion of compounds of general formula (XIV) to compounds of general formula (XIII).
Compounds of general formula (XXIII) can be converted by reductive methods to compounds of general formula (XXII) and such transformations have been described in Scheme 2 for the conversion of compounds of general formula (XIII) to compounds of general formula (XI).
Compounds of general formula (XXII) can be converted by reductive methods to compounds of general formula (I) and such transformations have been described in Scheme 2 for the conversion of compounds of general formula (XI) to compounds of general formula (V). Scheme 6
Figure imgf000201_0001
Scheme 6 Synthesis route for the preparation of compounds of general formula (XXII) in which R1 , R2, R3 and R4 have the meaning as given for general formula (I), supra , and Ra represents protecting groups.
Compounds of general formula (XI) can be converted to compounds of general formula (XXV), using deprotection methods known to those skilled in the art, such as 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 -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 2014), for such methods when R is tert- butoxycarbonyl (Boc) see 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 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 (XXV) can be converted to compounds of general formula (XXII) using carboxylic acids of general formula (XXI), using methods well known by those skilled in the art, and are previously described in Scheme 1.
The conversion of compounds of general formula (XXII) to compounds general formula (I) can be done in a number of steps, these steps have been described in Scheme 5. Scheme 7
Figure imgf000202_0001
Scheme 7 Synthesis route for the preparation of compounds of general formula (XXI) in which R2, R3 and R4 have the meaning as given for general formula (I), supra , and Rb and Rd represent protecting groups, wherein Rd represents a substituent as defined in the claims as a substituent of R3. Rb can be for example (not-limiting), methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and benzyl.
Compounds of general formula (XXVIII) can be converted to compound (XXVII) by methods described in the literature, such as for example, using organometallic chemistry, such as for example, a reaction with a Grignard reagent, (aryl magnesium halide salt), in a solvent, such as for example, tetrahydrofuran, preferably using anhydrous conditions, in a temperature range ranging from -100Ό to the boiling point of the sol vent (see the teachings of: Hoye et al., Org. Lett., 2010, 12, 1768; Blay et al., Tetrahedron, 2002, 58, 8565).
Compounds of general formula (XXVII) can be converted to compound (XXVI) by known methods well-known to those skilled in the art. Such transformations, for example, alkylation reactions, have been described previously, see the teachings of Wang et al., J. Am. Chem. Soc., 2015, 137, 4626; Hoye et al., Org. Lett., 2010, 12, 1768, Barth et al., J. Am. Chem. Soc., 1970, 92, 875.
Compounds of general formula (XXVII) and compounds of general formula (XXVI) can be converted to compound (XXI) by known methods well-known to those skilled in the art. Such transformations, for example, hydrolysis reactions, have been described previously, see the teachings of Wang et al., J. Am. Chem. Soc., 2015, 137, 4626; Thillaye et al., Org. Lett., 2008, 10, 4669, Barth et al., J. Am. Chem. Soc., 1970, 92, 875. Scheme 8
Figure imgf000203_0001
Scheme 8 Synthesis route for the preparation of compounds of general formula (I) and general formula (l-a) in which R1 , R2, R3 and R4 have the meaning as given for general formula (I) or general formula (l-a), supra , and Ra represents a protecting group.
Compounds of general formula (I), (XI), (XXII) and (XXV) 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 , 2, 3, 4, 5 and 6, where the stereoisomers can be separated using various methods known to those skilled in the art, such as, 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-a) and (l-b). 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 (XI) or stereoisomers of compounds of general formula (XXII) or stereoisomers of compounds of general formula (XXV) to give compounds of general formula (Xl-a) and (Xl-b) or stereoisomers of compounds of general formula (XXII-a) and (XXII-b), or stereoisomers of compounds of general formula (XXV-a) and (XXV-b), respectively. The subsequent chemistry transformations using these stereoisomers can be carried out in analogy to the racemic mixtures described earlier. For example, compounds of general formula (Xl-a) can be converted to compounds of general formula (XXV-a) using the methods described for converting compounds of general formula (XI) to compounds of the general formula (XXV) (see Scheme 6). Analogously, compounds of general formula (XXV-a) can be converted to compounds of general formula (XXII-a) using the methods described for converting compounds of general formula (XXV) to compounds of the general formula (XXII) (see Scheme 6). Furthermore, compounds of general formula (XXII-a) can be converted to compounds of general formula (l-a) using the methods described for converting compounds of general formula (XXII) to compounds of the general formula (I) (see Scheme 5).
Scheme 9
Figure imgf000205_0001
Scheme 9 Synthesis route for the preparation of compounds of general formula (I) and general formula (l-a) in which R1 , R2, R3 and R4 have the meaning as given for general formula (I) or general formula (l-a), supra , and Ra and Rd represents a protecting group.
Compounds of general formula (I), (II), (III), (IV) and (V) 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 , 2, 3, 4, 5 and 6, where the stereoisomers can be separated using various methods known to those skilled in the art, such as, 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-a) and (l-b). 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) or stereoisomers of compounds of general formula (IV) or stereoisomers of compounds of general formula (V) to give compounds of general formula (ll-a) and (I l-b) or stereoisomers of compounds of general formula (lll-a) and (lll-b), or stereoisomers of compounds of general formula (IV-a) and (IV-b), or stereoisomers of compounds of general formula (V-a) and (V-b), respectively. The subsequent chemistry transformations using these stereoisomers can be carried out in analogy to the racemic mixtures described earlier. For example, compounds of general formula (V-a) can be converted to compounds of general formula (IV-a) using the methods described for converting compounds of general formula (V) to compounds of the general formula (IV) (see Scheme 1 ). Analogously, compounds of general formula (IV-a) can be converted to compounds of general formula (lll-a) using the methods described for converting compounds of general formula (IV) to compounds of the general formula (III) (see Scheme 1 ). Furthermore, compounds of general formula (lll-a) can be converted to compounds of general formula (ll-a) using the methods described for converting compounds of general formula (III) to compounds of the general formula (II) (see Scheme 1 ). In addition, compounds of general formula (ll-a) can be converted to compounds of general formula (l-a) using the methods described for converting compounds of general formula (II) to compounds of the general formula (I) (see Scheme 1 ).
Scheme 10
Figure imgf000207_0001
Scheme 6 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 Ft1 , Ft2, Ft3 and Ft4 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 , 2, 3, 4, 5, 6 and 7, 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-a) and general formula (l-b), or alternatively, give compounds of general formula (l-c) and general formula (l-d), 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-g). In addition, compounds of general formula (l-b) can give compounds of general formula (l-f) and general formula (l-h). Furthermore, compounds of general formula (l-c) can give compounds of general formula (l-e) and general formula (l-f). Alternatively, compounds of general formula (l-d) can give compounds of general formula (l-g) and general formula (l-h).
Scheme 11
Figure imgf000208_0001
Scheme 11 Synthesis route for the preparation of compounds of general formula (I), which are compounds of general formula (I), in which R1 , R2, R3 and R4 have the meaning as given for general formula (I), supra , and Ra, Rb and Rc represent protecting groups.
Compounds of general formula (XXIII) and there synthesis are described previously in Scheme 5. Compounds of general formula (XXIII) could be converted to compounds of general formula (XXIX) under acidic conditions, such, for example, sulfuric acid, acetic acid, trifluoroacetic anhydride, or mixtures thereof. Reactions are usually carried out at elevated temperatures (see teachings of Hammond et al., J. Fluorine Chem., 1988, 40, 81 ; Basavaiah et al., Org. Biomol. Chem., 2008, 6, 1034 and Roehnert, Chem. Ber., 1957, 90, 1 18). Such transformations can also be carried out under basic conditions (see teachings of Gensler et al., J. Org. Chem., 1975, 40, 733) and lewis acid conditions (see teachings of Singh et al., Tetrahedron, 2006, 37,
8731 ).
Compounds of general formula (XXIX) could be converted to compounds of general formula (I) using reductive methods. Such methods are well known to those skilled in the art, such as using borane (See: WO2007/22936, 2007; W02015/151001 , 2015; Kormos et al., Bioorg. Med. Chem., 2016, 24, 3842), lithium aluminium hydride (See: EP2557082, 2013; W02007/140383; Mimura et al., Chem. Pharm. Bull., 1993, 41 , 1971 ) and Red-AI (See: Epstein et al., J. Med. Chem., 1981 , 24, 481 ).
Scheme 12
Figure imgf000209_0001
Scheme 12 Synthesis route for the preparation of compounds of general formula (I), which are compounds of general formula (I), in which R1 , R2, R3 and R4 have the meaning as given for general formula (I), supra , and Ra, Rb and Rc represent protecting groups.
Compounds of general formula (XIII) and there synthesis are described previously in Scheme 2. Compounds of general formula (XIII) could be converted to compounds of general formula (XXXII) using methods well known by those skilled in the art, and are previously described in Scheme 1 1 for transforming compounds general formula (XXIII) to compounds of general formula (XXIX). Compounds of general formula (XXXII) could be converted to compounds of general formula (XXXI) using deprotection methods well known by those skilled in the art, and are previously described in Schemes 1 and 2.
Compounds of general formula (XXXI) could be converted to compounds of general formula (XXX) using methods well known by those skilled in the art, and are previously described in detail in Scheme 1 . Compounds of general formula (XXX) could be converted to compounds of general formula (I) are previously described in detail in Scheme 1 1 .
Scheme 13
Figure imgf000210_0001
Scheme 13 Synthesis route for the preparation of compounds of general formula (I), which are compounds of general formula (I), in which R1 , R2, R3 and R4 have the meaning as given for general formula (I), supra , and Ra, Rb and Rc represent protecting groups.
Compounds of general formula (XVII) and there synthesis are described previously in Scheme 4. Compounds of general formula (XVII) could be converted to compounds of general formula (XXX) using methods well known by those skilled in the art, and are previously described in Scheme 1 1 for the conversion of compounds of general formula (XXIII) to compounds of general formula (XXIX). The various subsequent transformation of compounds of general formula (XXX) to compounds of general formula (I) have been described in Schemes 1 1 and 12.
Scheme 14
Figure imgf000210_0002
(XXX) (I)
Scheme 14 Synthesis route for the preparation of compounds of general formula (I), which are compounds of general formula (I), in which R1 , R2, R3 and R4 have the meaning as given for general formula (I), supra , and Ra, Rb and Rc represent protecting groups.
Compounds of general formula (VII) and there synthesis are described previously in Scheme 1 . Compounds of general formula (VII) could be converted to compounds of general formula
(XXXII) using methods well known by those skilled in the art, and are previously described in Scheme 13 for the conversion of compounds of general formula (XVII) to compounds of general formula (XXX). The various subsequent transformations of compounds of general formula (XXXII) through to compounds of general formula (I) have already been described in Scheme 12.
Compounds IX, X, XIV, XV, XXI, XXII and XXIV 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 steps of allowing an intermediate compound of general formula
Figure imgf000211_0001
in which R1 is as defined for the compound of general formula (I) as defined supra , and in which Rd represents protecting groups,
to react with a compound of general formula (XXI) :
Figure imgf000211_0002
(XXI),
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 (II) :
Figure imgf000211_0003
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (I) as defined supra , and in which Rd represents protecting groups,
and allowing to react said intermediate of general formula (II) to react with an acid, thereby giving a compound of general formula (I) :
Figure imgf000212_0001
(l),
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 steps of allowing an intermediate compound of general formula
Figure imgf000212_0002
in which R1 is as defined for the compound of general formula (I) as defined supra , and in which Rd represents protecting groups,
to react with a compound of general formula (XXI) :
O
2_ ^0H
R' TS4
(XXI),
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 (II) :
Figure imgf000212_0003
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (I) as defined supra , and in which Rd represents protecting groups,
and allowing to react said intermediate of general formula (II) to react with an acid, thereby giving a compound of general formula (I) :
Figure imgf000213_0001
(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 a fourth 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 (XVI) :
Figure imgf000213_0002
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,
thereby giving a compound of general formula (I) :
Figure imgf000213_0003
(I),
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 (I) as defined supra, said methods comprising the step of allowing an intermediate compound of general formula (XVI) :
Figure imgf000214_0001
(XVI),
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,
thereby giving a compound of general formula (I) :
Figure imgf000214_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 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 (XVI) :
Figure imgf000214_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,
thereby giving a compound of general formula (I) :
Figure imgf000215_0001
(l),
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 (XVI) :
Figure imgf000215_0002
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,
thereby giving a compound of general formula (I) :
Figure imgf000215_0003
(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 a eighth aspect, the present invention covers methods of preparing compounds of general formula (l-a) as defined supra,
said methods comprising the steps of allowing an intermediate compound of general formula ("l-a) :
Figure imgf000216_0001
(IM-a),
in which R1 is as defined for the compound of general formula (l-a) as defined supra , and in which Rd represents protecting groups,
to react with a compound of general formula (XXI) :
Figure imgf000216_0002
(XXI),
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 (ll-a) :
Figure imgf000216_0003
(ll-a),
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (l-a) as defined supra , and in which Rd represents protecting groups,
and allowing to react said intermediate of general formula (ll-a) to react with an acid, thereby giving a compound of general formula (l-a) :
Figure imgf000216_0004
(l-a),
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 (I) as defined supra ,
said methods comprising the steps of allowing an intermediate compound of general formula (l"-a) :
Figure imgf000217_0001
in which R1 is as defined for the compound of general formula (l-a) as defined supra , and in which Rd represents protecting groups,
to react with a compound of general formula (XXI) :
Figure imgf000217_0002
(XXI),
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 (ll-a) :
Figure imgf000217_0003
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (l-a) as defined supra , and in which Rd represents protecting groups,
and allowing to react said intermediate of general formula (ll-a) to react with an acid, thereby giving a compound of general formula (l-a) :
Figure imgf000217_0004
(l-a),
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. The present invention covers methods of preparing compounds of the present invention of general formula (I) and general formula (l-a), said methods comprising the steps as described in the Experimental Section herein.
In accordance with a tenth aspect, the present invention covers intermediate compounds which are useful for the preparation of the compounds of general formula (I), supra.
In accordance with a eleventh aspect, the present invention covers intermediate compounds which are useful for the preparation of the compounds of general formula (l-a), supra.
Particularly, the inventions covers the intermediate compounds of general formula (II) :
Figure imgf000218_0001
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (I) as defined supra , and in which Rd represents protecting groups.
Particularly, the inventions covers the intermediate compounds of general formula (ll-a) :
Figure imgf000218_0002
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (l-a) as defined supra , and in which Rd represents protecting groups.
Particularly, the inventions covers the intermediate compounds of general formula (III) :
Figure imgf000218_0003
in which R1 is as defined for the compound of general formula (I) as defined supra , and in which Rd represents protecting groups.
Particularly, the inventions covers the intermediate compounds of general formula (lll-a) :
Figure imgf000219_0001
in which R1 is as defined for the compound of general formula (l-a) as defined supra , and in which Rd represents protecting groups.
Particularly, the inventions covers the intermediate compounds of general formula (XVI) :
Figure imgf000219_0002
(XVI),
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (I) as defined supra.
Particularly, the inventions covers the intermediate compounds of general formula (XXI) :
Figure imgf000219_0003
(XXI),
in which R2, R3 and R4 are as defined for the compound of general formula (I) as defined supra.
Particularly, the inventions covers the intermediate compounds of general formula (XXII) :
Figure imgf000219_0004
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (I) as defined supra. In accordance with a twelfth aspect, the present invention covers the use of said intermediate compounds for the preparation of a compound of general formula (I) as defined supra.
In accordance with an thirteenth aspect, the present invention covers the use of said 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 imgf000220_0001
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (I) as defined supra , and in which Rd represents protecting groups, 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 (H-a) :
Figure imgf000220_0002
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (l-a) as defined supra , and in which Rd represents protecting groups, 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 (III) :
Figure imgf000220_0003
in which R1 is as defined for the compound of general formula (I) as defined supra , and in which Rd represents protecting groups, 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 (lll-a) :
Figure imgf000221_0001
in which R1 is as defined for the compound of general formula (l-a) as defined supra , and in which Rd represents protecting groups, 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 (XVI) :
Figure imgf000221_0002
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 (XXI) :
Figure imgf000221_0003
(XXI),
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 (XXII) :
Figure imgf000221_0004
in which R1 , R2, R3 and R4 are as defined for the compound of general formula (I) 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), (III), (XVI), (XXI) and (XXII), 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, isomer, 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, 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 skin cancer, liposarcoma, cervical cancer, brain cancer, bladder cancer, endocrine cancer, lung cancer, gliosarcoma, colorectal carcinoma, head & neck cancer, hepatocellular carcinoma, breast cancer, ovarian cancer, gastric cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, sarcoma, lymphoma, leukemia, liver cancer, thyroid cancer and endometrial cancer.
In another aspect, the present invention provides methods of treating cancer, which cancer is selected from Kidney Cancer, Bladder Cancer, Colon Cancer, Mesothelioma, Breast Cancer, Pancreatic Cancer, Ovarian Cancer, Brain Cancer (Glioblastoma, Astrocytoma), Connective Tissue Cancer (Synovial sarcoma, Fibrosarcoma, Liposarcoma), Head & Neck Cancer (Pharynx, Tongue), Upper aerodigestive tract Cancer (Tongue squamous cell carcinoma), Lymphoma, (Diffuse Large B-Cell Lymphoma), Leukemia (Acute myeloid leukemia, Plasma cell leukemia) and Multiple Myeloma.
In another aspect, the present invention provides methods of treating cancer, which cancer is selected from Kidney Cancer, Bladder Cancer, Colon Cancer, Mesothelioma, Breast Cancer, Pancreatic Cancer, Ovarian Cancer, Brain Cancer (Glioblastoma, Astrocytoma), Connective Tissue Cancer (Synovial sarcoma, Fibrosarcoma, Liposarcoma), Head & Neck Cancer (Pharynx, Tongue), Upper aerodigestive tract Cancer (Tongue squamous cell carcinoma), Lymphoma, (Diffuse Large B-Cell Lymphoma), Leukemia (Acute myeloid leukemia, Plasma cell leukemia), Multiple Myeloma, Liver Cancer, Lung Cancer, Skin Cancer, Thyroid Cancer, Endometrial Cancer and Cervical Cancer.
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, 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 skin cancer, liposarcoma, cervical cancer, brain cancer, bladder cancer, endocrine cancer, lung cancer, gliosarcoma, colorectal carcinoma, head & neck cancer, hepatocellular carcinoma, breast cancer, ovarian cancer, gastric cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, sarcoma, lymphoma, leukemia, liver cancer, thyroid cancer and endometrial cancer.
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 Kidney Cancer, Bladder Cancer, Colon Cancer, Mesothelioma, Breast Cancer, Pancreatic Cancer, Ovarian Cancer, Brain Cancer (Glioblastoma, Astrocytoma), Connective Tissue Cancer (Synovial sarcoma, Fibrosarcoma, Liposarcoma), Head & Neck Cancer (Pharynx, Tongue), Upper aerodigestive tract Cancer (Tongue squamous cell carcinoma), Lymphoma, (Diffuse Large B-Cell Lymphoma), Leukemia (Acute myeloid leukemia, Plasma cell leukemia) and Multiple Myeloma.
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 Kidney Cancer, Bladder Cancer, Colon Cancer, Mesothelioma, Breast Cancer, Pancreatic Cancer, Ovarian Cancer, Brain Cancer (Glioblastoma, Astrocytoma), Connective Tissue Cancer (Synovial sarcoma, Fibrosarcoma, Liposarcoma), Head & Neck Cancer (Pharynx, Tongue), Upper aerodigestive tract Cancer (Tongue squamous cell carcinoma), Lymphoma, (Diffuse Large B-Cell Lymphoma), Leukemia (Acute myeloid leukemia, Plasma cell leukemia), Multiple Myeloma, Liver Cancer, Lung Cancer, Skin Cancer, Thyroid Cancer, Endometrial Cancer and Cervical Cancer.
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 quantify, while in other cases the above-mentioned upper limit must be exceeded. In the case of the application of larger quantities, if may be advisable to distribute these in several doses throughout the day.
Nevertheless, if 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 quantify, 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 : Crystal structure of (5R)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]-3,9-diazaspiro[5.5]undecan-2-one (Reference compound 1 ). The displacement ellipsoids are drawn at the 50 % probability level; H(-N) hydrogen atoms, H(-C) hydrogen atoms and fluorine atoms are shown as spheres of arbitrary size.
Figure 2: Firefly luciferase reporter under control of a TEAD-promoter, as described under SEQ ID No. 1 .
Figure 3: Firefly luciferase reporter under control of a TEAD-promoter (base pairs 27-304), as described under SEQ ID No. 2.
Figure 4: 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 imgf000238_0001
Figure imgf000239_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: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1 .7 mih, 50x2.1 mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1 -99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 Ό; DAD scan: 210-400 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: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1 .7 50x2.1 mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1 -99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 Ό; DAD scan: 210-400 nm.
Method 4:
Instrument: Waters Acquity UPLCMS SingleQuad; Colum: Acquity UPLC BEH C18 1 .7 50x2.1 mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1 .6 min 1 -99% B, 1 .6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 Ό; DAD scan: 210-400 nm
Preparative LC-MS Methods:
Method 6:
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 Ό; DAD scan: 210-400 nm
Method 7:
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
tert-butyl 2-(1 -benzylpiperidin-4-ylidene)-2-cyanoacetate
Figure imgf000243_0001
Into a 2000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1 -benzylpiperidin-4-one (100 g, 528.39 mmol, 1 .00 equiv), methylbenzene (1000 mL), tert-butyl 2-cyanoacetate (89 g, 630.46 mmol, 1 .20 equiv), aetic acid (25 g, 416.32 mmol, 0.80 equiv). The resulting solution was stirred overnight at 1 10Ό. The reaction mixture was cooled. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 2 L of water/ice. The resulting solution was extracted with 3x1 L of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x1 L of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :4). This resulted in 80 g (48%) of tert-butyl 2-(1 -benzylpiperidin-4- ylidene)-2-cyanoacetate as a yellow solid.
Intermediate 2
tert-butyl 2-[1 -benzyl-4-(2-ethoxy-2-oxo-1 -phenylethyl)piperidin-4-yl]-2-cyanoacetate
Figure imgf000243_0002
Into a 2000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed DIPA (43.9 g, 433.84 mmol, 1.60 equiv), tetrahydrofuran (800 mL). This was followed by the addition of n-butyllithium (124 mL, 1.20 equiv) dropwise with stirring at -30Ό. The mixture was stirred for 30 min at 0Ό . To this was added a solution of ethyl 2- phenylacetate (47.6 g, 289.89 mmol, 1 .10 equiv) in tetrahydrofuran (50 ml_) dropwise with stirring at -78Ό. The mixture was stirred for 1 h. To the mixture was added a solution of tert- butyl 2-(1 -benzylpiperidin-4-ylidene)-2-cyanoacetate (80 g, 256.08 mmol, 1 .00 equiv) in tetrahydrofuran (100 ml_) dropwise with stirring at -780. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 1 L of ammonium chloride (aq). The resulting solution was extracted with 2x1 L of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x1 L of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :3). This resulted in 90 g (74%) of tert- butyl 2-[1 -benzyl-4-(2-ethoxy-2-oxo-1 -phenylethyl)piperidin-4-yl]-2-cyanoacetate as a yellow solid.
Intermediate 3
ethyl 2-[1 -benzyl-4-(cyanomethyl)piperidin-4-yl]-2-phenylacetate
Figure imgf000244_0001
Into a 2000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl 2-[1 -benzyl-4-(2-ethoxy-2-oxo-1 -phenylethyl)piperidin-4-yl]-2- cyanoacetate (80 g, 167.85 mmol, 1 .00 equiv), DMSO (800 ml_), trifluoroacetic acid (19.15 g, 169.41 mmol, 1 .00 equiv), acetic acid (2 g, 33.31 mmol, 0.20 equiv), silver carbonate (9.35 g, 0.20 equiv). The resulting solution was stirred for 4 h at 120Ό. The reaction mixture was cooled. The reaction was then quenched by the addition of 3 L of water/ice. The resulting solution was extracted with 3x1 L of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x1 L of water. The resulting mixture was washed with 1 x1 L of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :2). This resulted in 40 g (63%) of ethyl 2-[1 -benzyl-4-(cyanomethyl)piperidin-4-yl]-2- phenylacetate as a white solid. Intermediate 4
(rac)-9-benzyl-1 -phenyl-3, 9-diazaspiro[5.5]undecan-2-one
Figure imgf000245_0001
Into a 2000-mL 4-necked round-bottom flask, was placed ethyl 2-[1 -benzyl-4- (cyanomethyl)piperidin-4-yl]-2-phenylacetate (40 g, 106.24 mmol, 1 .00 equiv), tetrahydrofuran (400 mL), methanol (400 mL), nickel (20 g). The resulting solution was stirred overnight at 50Ό. The reaction mixture was cooled. The solids w ere filtered out, washed with 500 mL of methanol. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1 -5:1 ). This resulted in 25 g (70%) of 9-benzyl-1 -phenyl-3, 9-diazaspiro[5.5]undecan-2-one as a white solid.
(racl-lntermediate 5
9-benzyl-1 -phenyl-3, 9-diazaspiro[5.5]undecane
Figure imgf000245_0002
Into a 1000-mL 3-necked round-bottom flask, was placed tetrahydrofuran (600 mL). This was followed by the addition of lithium aluminium hydride (13.3 g, 350.46 mmol, 5.00 equiv) in several batches. To this was added (rac)-9-benzyl-1 -phenyl-3, 9-diazaspiro[5.5]undecan-2-one (24 g, 71.76 mmol, 1 .00 equiv). The resulting solution was stirred overnight at 65Ό. The reaction mixture was cooled. The reaction was then quenched by the addition of 50 mL of water. The solids were filtered out, washed with 500 mL of metanol. The resulting mixture was concentrated under vacuum. This resulted in 20 g (crude) of 9-benzyl-1 -phenyl-3, 9- diazaspiro[5.5]undecane as a white solid. Intermediate 6
tert-butyl 9-benzyl-1 -phenyl-3, 9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000246_0001
Into a 1000-mL 3-necked round-bottom flask, was placed (rac)-9-benzyl-1 -phenyl-3, 9- diazaspiro[5.5]undecane (20 g, 62.41 mmol, 1 .00 equiv), tetrahydrofuran (500 mL), di-tert-butyl dicarbonate (27 g, 123.71 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 500 mL of water. The resulting solution was extracted with 3x500 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :4). This resulted in 12 g (46%) of tert-butyl 9-benzyl-1 -phenyl-3, 9-diazaspiro[5.5]undecane-3- carboxylate as a white solid.
Intermediate 7. Intermediate 8 and Intermediate 9
(rac)-tert-butyl 1 -phenyl-3, 9-diazaspiro[5.5]undecane-3-carboxylate
tert-butyl (1 R)-1 -phenyl-3, 9-diazaspiro[5.5]undecane-3-carboxylate
tert-butyl (1 S)-1 -phenyl-3, 9-diazaspiro[5.5]undecane-3-carboxylate
Intermediate 7
(rac)-tert-butyl 1 -phenyl-3, 9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000246_0002
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (rac)-tert-butyl 9-benzyl-1 -phenyl-3, 9-diazaspiro[5.5]undecane-3- carboxylate (10 g, 23.78 mmol, 1.00 equiv), methanol (200 mL), palladium on carbon (3 g). To the above hydrogen (enough, gas) was introduced in. The resulting solution was stirred for 4 h at 50°C. The reaction mixture was cooled. The solids were filtered out, washed with 200 mL of methanol. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (5:1 ). This resulted in 5.6 g (71 %) of tert-butyl 1 -phenyl-3, 9-diazaspiro[5.5]undecane-3-carboxylate as a white solid.
1 H-NMR: (300MHz, CDCI3, ppm): d 7.31 -7.23 (m, 3H), 7.12-7.10 (d, 2H), 3.95-3.70 (m, 2H), 3.35-3.68 (m, 2H), 3.18-3.13 (t, 1 H), 2.87-2.69 (4H, m), 2.57-2.52 (dd, 1 H), 2.21 -2.14 (dt, 1 H), 1 .70-1 .63 (d, 1 H), 1.58-1 .27 (m, 13H).
The title compound (100 mg) was separated into its enantiomers by preparative chiral HPLC to give stereoisomer 1 (39.4 mg, see intermediate 9) and stereoisomer 2 (35.2 mg, see intermediate 10).
Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000; column: YMC Cellulose SC 5m 250x30mm; eluent : hexane + 0.1 Vol- % Diethylamine (99%)/2-Propanol 50:50; flow 40 ml/min temperature: 25Ό; DAD 220nm.
Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; column: YMC Cellulose SC 3m 100x4.6mm; eluent : hexane + 0.1 Vol-% Diethylamine (99%)/2-Propanol 50:50; flow 1 .4 ml/min temperature: 250; DAD 220nm.
Intermediate 8
tert-butyl 1 -phenyl-3, 9-diazaspiro[5.5]undecane-3-carboxylate (stereoisomer 1 )
Figure imgf000247_0001
For the preparation of the racemic title compound and separation into its enantiomers see Intermediate 7.
Analytical Chiral FIPLC (method see Example 7): Rt = 5.23 min, e.e. >99%.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .107 (16.00), 1.127 (0.40), 1 .361 (1.37), 2.518 (0.69), 2.522 (0.53), 2.558 (0.46), 2.589 (0.55), 7.141 (1 .04), 7.158 (1.27), 7.161 (1 .04), 7.240 (0.78), 7.255 (0.45), 7.258 (0.66), 7.284 (1.24), 7.299 (0.84), 7.303 (1.40), 7.320 (0.50).
Optical rotation (method OR1 ): -18.0°(methanol).
Intermediate 9
tert-butyl 1 -phenyl-3, 9-diazaspiro[5.5]undecane-3-carboxylate (stereoisomer 2)
Figure imgf000248_0001
For the preparation of the racemic title compound and separation into its enantiomers see Intermediate 7.
Analytical Chiral FIPLC (method see Example 7): Rt = 7.15 min, e.e. 95%.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .047 (0.59), 1 .061 (0.77), 1 .108 (16.00), 1.128 (2.12),
1 .162 (2.04), 1 .239 (1 .08), 1 .251 (1.12), 1 .271 (1 .48), 1.282 (1.55), 1 .362 (6.41 ), 1.670 (0.98),
1 .701 (0.92), 2.164 (1 .34), 2.198 (1.29), 2.327 (0.56), 2.559 (3.21 ), 2.589 (3.25), 2.637 (1 .59),
2.669 (1 .10), 3.083 (0.60), 3.609 (0.72), 3.754 (1 .08), 3.789 (1.01 ), 7.141 (4.19), 7.159 (5.07),
7.223 (0.94), 7.241 (2.82), 7.259 (2.49), 7.285 (4.64), 7.303 (5.20), 7.321 (1 .94).
Optical rotation (method OR1 ): 17.2°(methanol).
Intermediate 10
(rac)-tert-butyl 1 -phenyl-9-(phenylacetyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000248_0002
To a solution of phenylacetic acid (90.6 mg, 666 pmol) in DMF (1 .6 ml) under an Argon atmosphere was added HATU (253 mg, 666 pmol) and DIPEA (210 mI, 1 .2 mmol) and stirred at rt for 5 mins and then tert-butyl (rac)-1 -phenyl-3, 9-diazaspiro[5.5]undecane-3-carboxylate (Intermediate 7: 200 mg, 605 pmol) was added. The reaction mixture was stirred at rt for 2h and then purified by preparative HPLC (Method 6) to give the titled compound (23 mg, 8% yield).
1H-NMR (500 MHz, DMSO-d6) d [ppm]: 1 .272 (0.56), 1 .292 (0.47), 1 .384 (16.00), 2.543 (0.42), 2.550 (0.47), 2.564 (0.47), 2.571 (0.45), 3.075 (2.34), 3.198 (0.51 ), 3.621 (0.52), 3.628 (0.52), 3.648 (0.40), 7.063 (0.92), 7.075 (1.03), 7.1 19 (1 .16), 7.132 (1.29), 7.181 (1 .26), 7.195 (0.74), 7.257 (0.73), 7.267 (0.67), 7.270 (1.05), 7.273 (0.80), 7.278 (1.64), 7.292 (1 .50), 7.306 (0.46). Intermediate 11
(rac)-tert-butyl 9-(2-methyl-2-phenylpropanoyl)-1 -phenyl-3, 9-diazaspiro[5.5]undecane-3- carboxylate
Figure imgf000249_0001
Using the method described for intermediate 10, the reaction of Intermediate 7 with 2-methyl- 2-phenylpropanoic acid (109 mg, 666 pmol) gave the titled compound (30.1 mg, 10% yield) after purification by preparative HPLC (Method 6).
1H-NMR (500 MHz, DMSO-d6) d [ppm]: 1 .326 (4.20), 1 .331 (4.50), 1 .360 (16.00), 2.437 (0.43),
2.451 (0.44), 2.459 (0.42), 2.693 (0.42), 3.073 (2.58), 3.565 (0.44), 3.571 (0.45), 3.661 (0.44), 6.985 (1 .12), 6.989 (1 .05), 6.993 (0.62), 7.001 (1 .49), 7.004 (1.34), 7.031 (1 .05), 7.033 (1 .26),
7.046 (1 .34), 7.049 (1 .16), 7.163 (1.20), 7.177 (2.01 ), 7.186 (0.50), 7.286 (0.62), 7.296 (0.71 ),
7.299 (1 .25), 7.304 (1.72), 7.319 (1.46), 7.331 (0.43).
Intermediate 12
(rac)-tert-butyl 1 -phenyl-9-(1 -phenylcyclopropane-1 -carbonyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate
Figure imgf000249_0002
Using the method described for intermediate 10, the reaction of Intermediate 7 with 1 - phenylcyclopropane-1 -carboxylic acid (108 mg, 666 pmol) gave the titled compound (44.4 mg, 15% yield) after purification by preparative HPLC (Method 6).
1H-NMR (500 MHz, DMSO-d6) d [ppm]: 1 .066 (0.65), 1 .128 (1 .62), 1 .195 (0.48), 1 .204 (0.49),
1 .218 (0.45), 1 .224 (0.51 ), 1 .371 (16.00), 2.513 (0.98), 2.517 (0.58), 2.522 (0.62), 3.075 (2.81 ),
3.594 (0.43), 3.601 (0.44), 3.692 (0.44), 3.720 (0.41 ), 6.950 (1.16), 6.955 (0.97), 6.959 (0.92), 6.966 (1 .43), 6.969 (1 .29), 7.064 (0.94), 7.068 (1 .17), 7.078 (1.1 1 ), 7.083 (1 .22), 7.132 (1 .25), 7.137 (1 .15), 7.143 (1.95), 7.146 (1.89), 7.271 (0.60), 7.278 (2.37), 7.280 (2.42), 7.293 (1 .38).
Intermediate 13
(rac)-tert-butyl 1 -phenyl-9-(1 -phenylcyclopentane-1 -carbonyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate
Figure imgf000250_0001
Using the method described for intermediate 10, the reaction of Intermediate 7 with 1 - phenylcyclopentane-1 -carboxylic acid (127 mg, 666 pmol) gave the titled compound (25.7 mg, 8% yield) after purification by preparative HPLC (Method 6).
1H-NMR (500 MHz, DMSO-d6) d [ppm]: 1 .359 (16.00), 1.557 (0.76), 1 .570 (0.74), 2.003 (0.40),
2.201 (0.49), 2.213 (0.47), 2.424 (0.43), 2.438 (0.43), 2.446 (0.40), 2.716 (0.47), 3.076 (2.30),
3.553 (0.47), 3.560 (0.48), 3.580 (0.41 ), 3.657 (0.49), 3.684 (0.44), 6.980 (1 .39), 6.994 (1 .69),
7.005 (1 .10), 7.008 (1 .26), 7.020 (1.17), 7.024 (1 .21 ), 7.102 (0.47), 7.1 15 (1 .15), 7.130 (0.99),
7.138 (0.86), 7.152 (0.58), 7.275 (0.44), 7.277 (0.61 ), 7.287 (2.61 ), 7.301 (1 .43). Intermediate 14
(rac)-tert-butyl 9-[1 -(3,5-dimethylphenyl)cyclopentane-1 -carbonyl]-1 -phenyl-3, 9-diazaspiro- [5.5]undecane-3-carboxylate
Figure imgf000250_0002
Using the method described for intermediate 10, the reaction of Intermediate 7 with 1 -(3,5- dimethylphenyl)cyclopentane-1 -carboxylic acid (145 mg, 666 pmol) gave the titled compound (27.2 mg, 8% yield) after purification by preparative HPLC (Method 6). 1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.088 (0.55), 0.564 (0.62), 0.738 (0.69), 0.834 (0.76), 1 .035 (3.17), 1 .052 (5.79), 1 .070 (3.52), 1 .220 (2.83), 1 .239 (13.38), 1.255 (12.76), 1 .269 (9.86), 1 .317 (10.55), 1.360 (9.59), 1 .545 (4.07), 1.762 (0.69), 1.949 (1 .03), 2.063 (9.66), 2.103 (9.45), 2.322 (2.83), 2.326 (3.93), 2.331 (2.83), 2.518 (16.00), 2.523 (10.21 ), 2.665 (3.93), 2.669 (5.03), 2.673 (3.79), 2.687 (2.21 ), 2.701 (2.28), 2.728 (5.66), 2.758 (2.14), 2.789 (1 .17),
2.888 (4.14), 3.127 (2.21 ), 3.138 (2.00), 3.146 (1 .86), 3.156 (1.72), 3.318 (4.00), 3.348 (2.07),
3.405 (0.90), 3.422 (1 .59), 3.435 (1.45), 3.440 (1 .52), 3.452 (1.45), 3.535 (1 .24), 3.613 (1 .03),
3.623 (1 .03), 3.670 (1 .86), 3.703 (1.66), 4.156 (0.83), 4.344 (0.83), 4.357 (1 .59), 4.370 (0.76),
6.578 (7.31 ), 6.769 (1.59), 7.039 (4.00), 7.219 (0.90), 7.237 (3.59), 7.255 (12.41 ), 7.273 (7.72), 7.288 (2.34), 7.950 (0.55).
Intermediate 15
(rac)-tert-butyl 9-[(naphthalen-1 -yl)acetyl]-1 -phenyl-3, 9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000251_0001
Using the method described for intermediate 10, the reaction of Intermediate 7 with (naphthalen-l -yl)acetic acid (67.6 mg, 363 pmol) gave the titled compound which was used directly in the next step.
LC-MS (method 2): Rt = 1 .48-1.50 min; MS (ES): m/z = 498.3.
Intermediate 16
(rac)-tert-butyl 1 -phenyl-9-{[2-(trifluoromethyl)phenyl]acetyl}-3,9-diazaspiro[5.5]undecane-3- carboxylate
Figure imgf000251_0002
Using the method described for intermediate 10, the reaction of Intermediate 7 with [2- (trifluoromethyl)phenyl]acetic acid (74.1 mg, 363 pmol) gave the titled compound which was used directly in the next step.
LC-MS (method 2): Rt = 1 .48-1.50 min; MS (ES): m/z = 516.2. Intermediate 17
(rac)-tert-butyl 1 -phenyl-9-{2-[2-(trifluoromethyl)phenyl]propanoyl}-3,9-diazaspiro[5.5]- undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000252_0001
Using the method described for intermediate 10, the reaction of Intermediate 7 with 2-[2- (trifluoromethyl)phenyl]propanoic acid (79.2 mg, 363 pmol) gave the titled compound which was used directly in the next step.
LC-MS (method 2): Rt = 1 .56-1.58 min; MS (ES): m/z = 530.2.
Intermediate 18
tert-butyl 1 -phenyl-9-[(2S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9-diazaspiro[5.5]- undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000252_0002
Using the method described for intermediate 10, the reaction of Intermediate 7 with (2S)-3,3,3- trifluoro-2-methoxy-2-phenylpropanoic acid (156 mg, 666 pmol) gave the titled compound (45.6 mg, 13% yield) after purification by preparative HPLC (Method 6).
1H-NMR (500 MHz, DMSO-d6) d [ppm]: 1 .363 (16.00), 3.073 (4.18), 7.164 (0.92), 7.176 (0.62), 7.307 (0.79), 7.313 (0.80), 7.328 (0.47), 7.340 (0.58), 7.425 (0.59). Intermediate 19
tert-butyl 1 -phenyl-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9-diazaspiro[5.5]- undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000253_0001
Using the method described for intermediate 10, the reaction of Intermediate 7 with (2R)-3,3,3- trifluoro-2-methoxy-2-phenylpropanoic acid (156 mg, 666 pmol) gave the titled compound (34.5 mg, 10% yield) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.49), 0.023 (0.84), 0.032 (0.84), 0.056 (0.51 ), 0.066 (0.44), 0.080 (0.46), 0.091 (0.55), 0.1 13 (0.97), 0.124 (0.97), 0.146 (0.60), 0.158 (0.46),
0.516 (0.90), 0.548 (0.79), 0.989 (1.13), 1 .014 (2.18), 1.047 (1.61 ), 1 .080 (1 .66), 1.115 (2.56),
1 .125 (2.32), 1 .149 (1.59), 1 .158 (1 .61 ), 1.301 (13.42), 1.855 (0.90), 1 .890 (0.84), 1 .916 (0.68), 1 .923 (0.66), 1 .950 (0.66), 2.082 (1.04), 2.1 16 (1 .92), 2.151 (0.95), 2.248 (0.79), 2.269 (0.84),
2.280 (0.93), 2.284 (0.90), 2.289 (0.97), 2.294 (0.66), 2.359 (1.02), 2.379 (1 .32), 2.480 (3.00),
2.485 (2.38), 2.516 (0.77), 2.627 (0.60), 2.631 (0.82), 2.636 (0.60), 2.742 (0.57), 2.774 (1 .57),
2.806 (1 .74), 2.840 (1 .06), 2.973 (1.10), 3.001 (1 .77), 3.032 (1.74), 3.063 (0.99), 3.11 1 (2.32),
3.154 (2.98), 3.248 (0.88), 3.263 (0.88), 3.322 (0.66), 3.336 (0.60), 3.362 (1 .32), 3.398 (1 .13),
3.433 (1 .28), 3.467 (1.52), 3.510 (16.00), 3.513 (15.69), 3.565 (1 .04), 3.600 (0.97), 3.641 (0.49), 3.717 (0.99), 4.017 (0.57), 4.049 (0.55), 4.153 (0.90), 4.187 (0.90), 4.213 (0.88), 4.247
(0.82), 6.819 (2.21 ), 6.828 (2.82), 6.837 (2.60), 6.842 (2.32), 6.891 (2.54), 6.896 (2.63), 6.909
(3.97), 6.926 (4.13), 6.945 (2.74), 7.009 (3.97), 7.029 (2.80), 7.046 (2.03), 7.065 (4.81 ), 7.081
(3.75), 7.099 (4.28), 7.1 12 (2.12), 7.121 (2.52), 7.125 (2.49), 7.129 (2.80), 7.142 (1.94), 7.168
(0.42), 7.179 (0.42), 7.186 (1 .46), 7.192 (1 .37), 7.204 (1.08), 7.208 (1 .08), 7.229 (1.99), 7.236
(2.34), 7.244 (2.87), 7.248 (3.64), 7.251 (2.91 ), 7.255 (3.09), 7.260 (2.85), 7.266 (2.21 ), 7.269
(1 .79), 7.282 (7.59), 7.291 (8.70), 7.298 (12.16), 7.307 (5.01 ), 7.313 (6.69), 7.316 (6.33), 7.325 (1 .37), 7.378 (2.52), 7.385 (5.47), 7.388 (5.34), 7.392 (6.20), 7.396 (6.69), 7.399 (4.33), 7.405 (2.89), 7.410 (1.57), 7.413 (1.61 ). Intermediate 20
(rac)-ethyl 2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-hydroxy-propanoate
Figure imgf000254_0001
To a solution of 1 -bromo-3, 5-dimethyl-benzene (89.0 g, 481 mmol, 65.4 mL, 1 .00 eq) and magnesium (17.7 g, 731 mmol, 1 .52 eq) in THF (500 mL) was added iodine (4.88 g, 19.2 mmol, 0.04 eq) at 500 under a nitrogen atmosphere. To a solution of ethyl 3,3,3-trifluoro-2- oxo-propanoate (120 g, 705 mmol, 93.7 mL, 1 .47eq) in THF (400 mL) was added into the above solution dropwise at -780 under a nitrogen a tmosphere. The mixture was stirred at - 780 for 12 h. The mixture was poured into water (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 column chromatography (silica gel, Petroleum EtherEthyl acetate = 1/0 to 50/1 ) to give a crude product, and then dissolved in Petroleum Ether (150 mL) was added dropwise to get yellow slurry. The white solid was collected after filtering (56.0 g, 202 mmol, 42.1 % yield, 100% purity).
LCMS:, Rt = 0.949 min m/z 259 (M-17)+
1 H-NMR: (400MHz, CDCI3, ppm): d = 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 21
(rac)-ethyl 2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-propanoate
Figure imgf000254_0002
To a solution of intermediate 20 (56.0 g, 202 mmol, 1.00 eq) in acetone (550 mL) was added dimethylsulfate (127 g, 1.01 mol, 5.00 eq) and potassium carbonate (140 g, 1 .01 mol, 5.00 eq) at 15Ό. The mixture was stirred at 60Ό for 12 h. The mixture was filtered and the filtrate was concentrated. The residue was diluted with ethyl acetate (300 mL) and washed with 10% aqueous ammonia (200 mL) three times. The organic layer was washed with brine (200 mL) twice, dried with sodium sulfate, filtered and concentrated to give the titled compound (72.0 g, crude) as a colorless oil.
1 H-NMR: (400MHz, CDCI3, ppm): d = 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, J=7.15 Hz, 3 H). Intermediate 22
(rac)-2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoic acid
Figure imgf000255_0001
To a solution of intermediate 21 (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 150. The mixture was stirred at 500 for 2 h and then the mixture was concentrated. Then the residue diluted with water (300 ml_), extracted with ethyl acetate (200 ml_*2). The aqueous layer was adjust pH=3 with 1 M aqueous hydrogen chloride, extracted with ethyl acetate (200 ml_*2). The combined organic layer was washed with brine (300 ml_*1 ), dried with sodium sulfate, filtered and concentrated to give the titled compound (53.0 g, 192 mmol, 72.3% yield, 95% purity) as a white solid.
1H-NMR (400 MHz, DMSO-d6) 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 23
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (stereoisomer 1 )
Figure imgf000255_0002
To a solution of intermediate 22 (25 g, 95.3 mmol, 1.00 eq) 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, 0.5 eq) at 150. The mixture was stirred at 800 fo r 5 h. Then the mixture was cooled to 150 and stirred for 12 h. The mixture was filtered. .And the solid residue was diluted with ethyl acetate (100 ml_), washed with 1 M aqueous hydrogen chloride (80 ml_) three times and brine (100 ml_), dried with sodium sulfate, filtered and concentrated to get the crude product, then purified by column chromatography (silica gel, petrol ether/ethyl acetate = 1/0 to 1/1 ) to give the title compound (5.04 g, 19.2 mmol, 20.1 % yield, 100% purity) 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 24
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (stereoisomer 2)
Figure imgf000256_0001
To a solution of intermediate 22 (15 g, 55.2 mmol, 1.00 eq) in acetonitrile (150 ml_) was added (1 S)-1 -(1 -naphthyl) ethanamine (8.51 g, 49.7 mmol, 0.9 eq) at 15Ό. The mixture was stirred at 800 for 5 h. Then the mixture was cooled to 150 a nd stirred for 12 h. The mixture was filtered. And the solid residue was diluted with ethyl acetate (50 ml_), washed with 1 M aqueous hydrogen chloride (30 ml_) three times and brine (80 ml_), dried with sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ ethyl acetate =1/0 to 1/1 ) to give the title compound (5.7 g, 21 .7 mmol, 39.4% yield, 100% purity) 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).
Intermediate 25
tert-butyl 9-[2-(3, 5-dimethylphenyl)-3, 3, 3-trifluoro-2-methoxypropanoyl]-1 -phenyl-3, 9-diaza- spiro[5.5]undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000257_0001
Using the method described for intermediate 10, the reaction of intermediate 7 with intermediate 23 (95.2 mg, 363 pmol) gave the titled compound which was used directly in the next step.
LC-MS (Method 2): Rt = 1 .65-1.67 min; MS (ES): m/z = 574.3.
Intermediate 26
tert-butyl 9-[2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 -phenyl-3, 9-diaza- spiro[5.5]undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000257_0002
Using the method described for intermediate 10, the reaction of intermediate 7 with intermediate 24 (95.2 mg, 363 pmol) gave the titled compound which was used directly in the next step.
LC-MS (Method 2): R, = 1 .65-1.67 min; MS (ES): m/z = 574.3.
Intermediate 27
tert-butyl 1 -phenyl-9-[3,3,3-trifluoro-2-(4-fluorophenyl)-2-methoxypropanoyl]-3,9-diazaspiro- [5.5]undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000258_0001
Using the method described for intermediate 10, the reaction of Intermediate 7 with 3,3,3- trifluoro-2-(4-fluorophenyl)-2-methoxypropanoic acid (91 .6 mg, 363 pmol) gave the titled compound which was used directly in the next step.
LC-MS (Method 2): Rt = 1 .58-1.60 min; MS (ES): m/z = 564.2.
Intermediate 28
tert-butyl 9-[2-(3-chlorophenyl)-3, 3, 3-trifluoro-2-methoxypropanoyl]-1 -phenyl-3, 9-diazaspiro- [5.5]undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000258_0002
Using the method described for intermediate 10, the reaction of Intermediate 7 with 2-(3- chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (97.5 mg, 363 pmol) gave the titled compound which was used directly in the next step.
LC-MS (Method 2): R, = 1 .63-1.65 min; MS (ES): m/z = 581 .5.
Intermediate 29
(rac)-ethyl 2-(3-bromophenyl)-3,3,3-trifluoro-2-hydroxy-propanoate
Figure imgf000258_0003
To a solution of 1 ,3-dibromobenzene 92 g, 390 mmol, 1.00eq) and iodine (2 mg, 7.88 umol, 2.02e-5 eq) in THF (300 mL) was added magnesium (9.48 g, 390 mmol, 1 .00 eq) portions at 100 under a nitrogen atmosphere. The mixture was s tirred at 400 for 1 h. To a solution of ethyl 3,3,3-trifluoro-2-oxo-propanoate (99.5 g, 585 mmol, 1 .5 eq) in THF (130 mL) was added into the above solution dropwise at -780 under a n itrogen atmosphere. The mixture was stirred at -78Ό for 12 h. The mixture was poured i nto saturated aqueous ammonium chloride solution (800 mL), extracted with ethyl acetate (400 mL) twice. The combined organic layer was washed with brine (500 mL), dried with sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1/0 to 50/1 ) to give the crude product. Then the crude product was purified by preparative- HPLC (acidic condition) to give the titled compound (19 g, 56.3 mmol, 14.4% yield, 97% purity) as a yellow oil.
1 H-NMR: (400MHz, CDCI3, ppm): 8.60 (s, 1 H), 8.26 (s, 1 H), 8.18(m, 1 H), 8.07-8.09 (m, 1 H), 7.93-7.97 (m, 1 H), 4.76-4.84 (m, 2 H), 3.02 (s, 2 H), 1.68-1.75 (m, 3 H).
Intermediate 30
(rac)-ethyl 2-(3-bromophenyl)-3,3,3-trifluoro-2-methoxy-propanoate
Figure imgf000259_0001
To a solution of intermediate 29 (20 g, 61 .1 mmol, 1 .00 eq) in acetone (200 mL) was added dimethylsulfate (54.0 g, 428 mmol, 7 eq) and potassium carbonate (42.2 g, 305 mmol, 5 eq) at 15Ό. The mixture was stirred at 60Ό for 12 h. The mixture was filtered and the filtrate was concentrated. The residue was diluted with ethyl acetate (300 mL) and washed with 10% aqueous ammonia (100 mL) three times. The organic layer was washed with brine (100 ml), dried with sodium sulfate, filtered and concentrated to give the titled compound (20 g, 52.7 mmol, 86.3% yield, 90% purity) as a colorless oil.
1 H-NMR: (400MHz, CDCI3, ppm): d = .72 (s, 1 H), 7.54 (s, 1 H), 7.52(m, 1 H), 8.07-8.09 (m, 1 H), 7.44 (m, 1 H), 4.34-4.41 (m, 2 H), 3.56 (s, 3 H), 1.30-1.34 (m, 3 H). Intermediate 31
(rac)-2-(3-bromophenyl)-3,3,3-trifluoro-2-methoxypropanoic acid
Figure imgf000260_0001
To a solution of intermediate 30 (20 g, 58.6 mmol, 1 eq) in ethanol (200 mL) was added potassium hydroxide (7.89 g, 140 mmol, 2.4 eq). The mixture was stirred at 800 for 12 h and then the mixture was concentrated. Then the residue diluted with ethyl acetate (100 mL), extracted with water (60 mL) twice. The aqueous layer was adjust pH=3 with 1 M aqueous hydrogen chloride, extracted with ethyl acetate (50 mL) three times. The combined organic layer was washed with brine (70 mL), dried with sodium sulfate, filtered, concentrated and filtered to give the titled compound (10.0 g, 31 .4 mmol, 53.6% yield, 98% purity) as a white solid.
1 H-NMR: (400MHz, CDCI3, ppm): 7.78 (s, 1 H), 7.59 (m, 1 H), 7.53(m, 1 H), 7.32 (m, 1 H), 3.57 (s, 3 H).
Intermediate 32
(2R)-2-(3-bromophenyl)-3.3.3-trifluoro-2-methoxypropanoic acid (single stereoisomer)
Figure imgf000260_0002
Kinetic resolution
The reactions were performed as two batches in parallel: to a solution of 2-(3-bromophenyl)- 3,3,3-trifluoro-2-methoxypropanoic acid (78 g) in MeCN (850 mL) was added (R)-(+)-alpha- methyl-benzylamine (15.10 g, 124.57 mmol) with stirring at 18 TT The mixture was stirred at 70 Ό (oil bath temperature) for 2 h. Then the reac tion mixture was stirred at 30 Ό (oil bath temperature) for another 15 h. White solid precipitated out. The reactions were performed as two batches and the combined reaction mixture (two batches) was filtered.
The filter cake was washed with MeCN (100 mL x 2) to afford a white solid (85 g). This solid was stirred in water (200 mL) and the mixture was adjusted to pH ~ 3 with 0.5 M aq. HCI. The resultant mixture was extracted with EA (500 ml_ x 2). The combined organic phase was washed with brine (800 ml_), dried over sodium sulfate, filtered and concentrated by evaporator under reduced pressure to afford (2R)-2-(3-bromophenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (58.5 g, 99+% purity, 95.68% ee) as a light yellow solid.
Optical rotation (method OR1 ): 64.6°(methanol).
The stereochemistry configuration was determined by removing the bromo under catalytic hydrogenation conditions and comparing the optical rotation to the (R)- and (S)-Mosher acids.
Intermediate 33
tert-butyl 9-[2-(3-bromophenyl)-3, 3, 3-trifluoro-2-methoxypropanoyl]-1 -phenyl-3, 9-diazaspiro- [5.5]undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000261_0001
Using the method described for intermediate 10, the reaction of Intermediate 7 with intermediate 32 (1 14 mg, 363 pmol) gave the titled compound which was used directly in the next step.
LC-MS (Method 2): Rt = 1 .64-1.66 min; MS (ES): m/z = 627.4.
Intermediate 34
tert-butyl 9-[2-(3, 5-dichlorophenyl)-3, 3, 3-trifluoro-2-methoxypropanoyl]-1 -phenyl-3, 9-diaza- spiro[5.5]undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000261_0002
Using the method described for intermediate 10, the reaction of Intermediate 7 with intermediate 77 (1 10 mg, 363 pmol) gave the titled compound which was used directly in the next step.
LC-MS (Method 2): Rt = 1 .71 -1.73 min; MS (ES): m/z = 515.5. Intermediate 35
tert-butyl 9-[2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 -phenyl-3, 9- diazaspiro[5.5]undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000262_0001
Using the method described for intermediate 10, the reaction of Intermediate 7 with intermediate 67 (69.0 mg, 241 pmol) gave the titled compound which was used directly in the next step.
LC-MS (Method 2): Rt = 1 .67 min; MS (ES): m/z = 599.6.
Intermediate 36
tert-butyl 9-[2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 -phenyl-3, 9-diaza- spiro[5.5]undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000262_0002
Using the method described for intermediate 10, the reaction of Intermediate 7 with intermediate 77 (88.0 mg, 290 pmol) gave the titled compound which was used directly in the next step.
LC-MS (method 1 ): Rt = 1 .74 min; MS (ES): m/z = 614.2. Intermediate 37
tert-butyl 1 -phenyl-9-[3,3,3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)propanoyl]-3,9-diazaspiro- [5.5]undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000263_0001
Using the method described for intermediate 10, the reaction of Intermediate 7 with 3,3,3- trifluoro-2-methoxy-2-(naphthalen-1 -yl)propanoic acid (103 mg, 363 pmol) gave the titled compound which was used directly in the next step.
LC-MS (Method 2): R, = 1 .63-1.65 min; MS (ES): m/z = 597.8.
Intermediate 38
ethyl (1 -benzylpiperidin-4-ylidene)acetate
Figure imgf000263_0002
To a stirred suspension of sodium hydride (12.79 g, 60% dispersion on mineral oil, 320 mmol) in THF (600 ml_) was added drop-wise a solution of triethyl phosphonoacetate (78.18 g, 349 mmol) in THF (250 ml_) at room temperature.The resultant suspention was stirred at that temperature for 10 minutes (Note, solution goes from a suspesion to a colourless solution). After which time, a solution of 1 -benzylpiperidin-4-one (55 g, 291 mmol) in 250 ml_ THF was added in drop-wise. The reaction mixture was allowed to stir at that temperature for 1 hour. After which time water was added, stirred for 10 mins, followed by ethyl acetate phases separated, aqueous extracted with further ethyl acetate, Product isolated as a yellow oil (70 g, 93%).
1 H-NMR (400 MHz, CHLOROFORM-D) d [ppm] = 1 H-NMR (400 MHz, CHLOROFORM-D) d 7.28-7.35 (m, 5H), 5.66 (s, 1 H), 4.16 (q, J = 7.1 Hz, 2H), 3.55 (s, 2H), 3.01 (t, J = 5.4 Hz, 2H), 2.55 (t, J = 5.4 Hz, 4H), 2.35 (t, J = 5.4 Hz, 2H), 1 .29 (t, J = 7.1 Hz, 3H). Intermediate 39
{1 -benzyl-4-[(2-bromo-4-fluorophenyl)(cyano)methyl]piperidin-4-yl}acetic acid
Figure imgf000264_0001
To a solution of potassium tert-butoxide (16.87 g, 150 mmol) in THF (300mL) at -10 Ό under a nitrogen atmosphere was added a solution of (2-bromo-4-fluorophenyl)acetonitrile (29.71 g, 138.8 mmol) in THF (150 ml_). After stirring at that temperature for 20 minutes a solution of intermediate 38 (30 g, 1 15.7 mmol) in THF (150 ml_) was added kept below -10 Ό and stirred for 3 h. Cold ammonium chloride aq was added, then ethyl acetate, the phases separated, organic washed with brine and concentrated under reduced pressure to give a yellow solid. Extraction of the mixture with ethyl acetate and 1 M sodium hydroxide, separated the titled compound into the aqueous layers and the ethyl ester into the organic layer. The organic layer was dried over magnesium sulfate and evaporated to dryness to give a yellow gum (corresponding ethyl ester). The aqueous layer was acidified to pH 6 and the precipitate was filtered and dried to give the titled compound (25 g, 49%) and the corresponding ethyl ester (24 g, 44%).
Intermediate 40
methyl {1 -benzyl-4-[(2-bromo-4-fluorophenyl)(cyano)methyl]piperidin-4-yl}acetate
Figure imgf000264_0002
To a solution of intermediate 39 (24 g, 53.9 mmol) in methanol (240 ml) was added thionyl chloride (7.86 ml, 108 mmol) dropwise at room temperature. This reaction mixutre was allowed to stir at room temperature for 20 minutes. After which time the reaction mixture was heated to 750 and stirred overnight. All solvents were remov ed in vacuo, with a basic trap to give the desired product as a pale orange solid. (24.5 g, 99%).
1 H-NMR (400 MHz, CHLOROFORM-D) d 7.24-7.39 (m, 7H), 7.04-7.1 1 (m, 2H), 4.60 (d, J = 9.8 Hz, 1 H), 3.74-3.80 (m, 3H), 3.49-3.59 (m, 2H), 2.63-2.81 (m, 2H), 2.14-2.37 (m, 3H), 1.93- 2.00 (m, 1 H), 1 .80-1.87 (m, 1 H), 1 .70-1 .74 (m, 1 H), 1 .48 (dd, J = 13.2, 2.9 Hz, 1 H). 19F-NMR (376 MHz, CHLOROFORM-D) d -1 13.19 (s, 1 F).
Intermediate 41
(rac)-9-benzyl-5-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-2-one
Figure imgf000265_0001
Raney nickel (20g) was washed with sodium hydroxide 2M aq, water (x 3), methanol (x 3) and added to a 1 L autoclave along with Intermediate 40 (20 g, 42.2 mmol) and ammonia in methanol (7M, 450 ml). The autoclave was pressurised to 10 bar with hydrogen and heated to 60 Ό with stirring at 400 rpm for 72 hr. After coo ling and decompressing the reaction mixture was sampled and analysed by UPLC to reveal that the reaction was complete. The reaction liqours were filtered through celite, and the cake washed with methanol, and the volatiles were removed under reduced pressure to titled compound (12 g, 81 %) which was used directly in the next step.
1 H-NMR (400 MHz, CHLOROFORM-D) d = 1 .19-1 .67 (m, 1 H), 1 .49-1 .60 (m, 1 H), 2.16-2.27 (m, 1 H), 2.28-2.85 (m, 2H), 2.41 -2.49 (ss, 1 H), 2.67-2.80 (m, 2H), 2.86-2.96 (m, 1 H), 3.50 (s, 2H), 3.53-3.73 (m, 4H), 6.1 1 (br s, 1 H), 6.96-7.07 (m, 2H), 7.16-7.24 (m, 2H), 7.25-7.39 (m, 5H).
Intermediate 42
(rac)-9-benzyl-1 -(4-fluorophenyl)-3,9-diazaspiro[5.5]undecane
Figure imgf000265_0002
To a solution intermediate 41 (12 g, 34 mmol) in THF (30 mL) was added lithium aluminium hydride (34 ml, 2.0 M in THF, 68 mmol) in THF (100 mL) at rt. This was allowed to stir for 30 minutes at rt. After which time the reaction was heated to 65 Ό and stirred overnight then cooled to 00 and quenched with sodium sulfate deca hydrate and allowed to stir at room temperature overnight. After which time the reaction mixture was filtered over celite and washed with additional THF. The solute was evaporate to dryness to give the titled compound as a yellow oil (9.45 g, 95%) which was used directly in the next step. Intermediate 43, Intermediate 44 and Intermediate 45
(rac)-tert-butyl 9-benzyl-1 -(4-fluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate tert-butyl (1 R)-9-benzyl-1 -(4-fluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate tert-butyl (1 S)-9-benzyl-1 -(4-fluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
Intermediate 43
(rac)-tert-butyl 9-benzyl-1 -(4-fluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000266_0001
To a solution of intermediate 42 (9.45 g, 27.9 mmol) in DCM (180 ml) was added di-tert-butyl dicarbonate (7.7 ml, 34 mmol) followed by DIPEA (7.3 ml, 42 mmol). The reaction was strirred at room temperature for 1 hours. After which time the reaction was quenched with ammonium chloride solution, extracted with DCM, dried over sodium sulfate and concentrated. This was then purified by silica chromatography (ethyl acetate in Heptane) to give the titled product.
1 H NMR (400 MHz CDCI3): d [ppm] = 1 .26-1 .31 (m, 2H), 1.40-1 .50 (n, 10H), 1 .59-1.67 (m, 3H)2.09-2.24 (m, 3H), 2.55-2.64 (m, 3H), 3.35-3.5 (m, 3H), 3.79-3.83 (m, 2H), 6.97-7.01 (m, 2H), 7.09-7.1 1 (m, 2H), 7.22-7.31 (m, 5H)
19FNMR (400 MHz CDCI3):5 [ppm] = -1 16.46 (s).
The title compound (3.65 g) was separated into its enantiomers by preparative chiral HPLC to give stereoisomer 1 (1322 mg, see intermediate 44) and stereoisomer 2 (1941 mg, see intermediate 45).
Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000; column: Reprosil NR 8m 250x30mm; eluent : : hexane + 0.1 Vol-% Diethylamine (99%) / 2-Propanol 85:15; flow 120 ml/min temperature: 25Ό; UV 265nm.
Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; column: Reprosil NR 5m, 100x4.6mm; eluent : hexane + 0.1 Vol-% Diethylamine (99%) / 2-Propanol 80:20; flow 1 .4 ml/min temperature: 250; UV 220nm. Intermediate 44
tert-butyl 9-benzyl-(1 S)-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000267_0001
For the preparation of the racemic title compound and separation into its enantiomers see Intermediate 43.
Analytical Chiral HPLC (method see Example 7): Rt = 2.65 min, e.e. >99%.
Optical rotation (method OR1 ): -3.6° (methanol).
Intermediate 45
tert-butyl 9-benzyl-(1 R)-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000267_0002
For the preparation of the racemic title compound and separation into its enantiomers see Intermediate 43.
Analytical Chiral HPLC (method see Example 7): Rt = 3.41 min, e.e. >91 %.
Optical rotation (method OR1 ): 3.5°(methanol).
The absolute configuration of intermediate 44 and intermediate 45 was determined by a crystal structure of reference compound 1 . The intermediate 48 was used to prepare reference compound 1 and to prepare intermediate 53, which was analytically the same as intermediate 45. Intermediate 46
(rac)-tert-Butyl 4-[cyano(4-fluorophenyl)methyl]-4-(2-ethoxy-2-oxoethyl)piperidine-1 - carboxylate
Figure imgf000268_0001
Potassium tert-butoxide (92.8 ml, 1 .0 M in THF, 92.8 mmol) was added slowly under ice cooling to a mixture of tert-butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1 -carboxylate (25.0 g, 92.8 mmol) and (4-fluorophenyl)acetonitrile (1 1 ml, 93 mmol) in toluene (1 .6 I) and the mixture was then stirred for 2 h at room temperature. For the work-up, ethyl acetate was added and the mixture was washed with water (2x) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica chromatography (hexanes/ethyl acetate) to give the title compound (15.2 g, 40% yield).
1 H-NMR (400 MHz, DMSO -ofe): d [ppm] = 7.44-7.37 (m, 2H), 7.31 -7.24 (m, 2H), 4.60 (s, 1 H), 4.1 1 -4.04 (m, 2H), 3.82-3.65 (m, 2H), 3.16-2.94 (m, 2H), 2.56-2.52 (m, 1 H), 2.32 (d, 1 H), 1 .67- 1 .55 (m, 2H), 1 .54-1.42 (m, 2H), 1 .37 (s, 9H), 1 .21 (t, 3H). Intermediate 47. Intermediate 48 and Intermediate 49
(rac)-tert-Butyl 7-(4-fluorophenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate tert-Butyl (7R)-7-(4-fluorophenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate tert-Butyl (7S)-7-(4-fluorophenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate
Intermediate 47
(rac)-tert-Butyl 7-(4-fluorophenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000269_0001
An autoclave was charged with Intermediate 41 (15.17 g, 37.5 mmol), ammonia (281 ml, 2.0 M in ethanol) and Raney-Nickel (5.5 g 50% wet) and the mixture was stirred under 30 bar hydrogen atmosphere at 800 for 46 h. For the work- up, the mixture 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 and concentrated under reduced pressure The crude product was purified by silica chromatography (hexane : ethyl acetate) to give the title compound (5.6 g, 41 % yield).
1 FI-NMR (400 MHz, DMSO-afe, key signals): d [ppm] = 7.67 (br s, 1 H), 7.32-7.25 (m, 2H), 7.19- 7.12 (m, 2H), 3.77-3.54 (m, 2H), 3.53-3.44 (m, 1 H), 2.38 (br d, 1 H), 2.13 (d, 1 H), 1 .31 (s, 9H).
The title compound (5.6 g) was separated into its enantiomers by preparative chiral HPLC to give (R)-enantiomer (1 .93 g, see intermediate 48) and (S)-enantiomer (1 .85 g, see intermediate 49).
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; column: Chiralpak IA 5pm 250x30mm; eluent A: carbon dioxide, eluent B: ethanol; isocratic: 1 1 %B; flow 100.0 ml/min temperature: 40Ό; BPR: 150bar; MWD @ 220nm.
Analytical chiral HPLC method: Instrument: Agilent: 1260, Aurora SFC-Modul; column: Chiralpak IA 5pm 100x4.6mm; eluent A: carobon dioxide, eluent B: ethanol; isocratic: 1 1 %B; flow 4.0 ml/min; temperature: 37.5Ό; BPR: 10Obar; MWD @ 220nm.
Intermediate 48
tert-Butyl (7R)-7-(4-fluorophenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000270_0001
For the preparation of the racemic title compound and separation into its enantiomers see Intermediate 47.
Analytical Chiral FIPLC (method see Intermediate 10): Rt = 3.14 min, e.e., 96.8%.
Optical rotation (method OR1 ): -13.8°(methanol).
Intermediate 49
tert-Butyl (7S)-7-(4-fluorophenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000270_0002
For the preparation of the racemic title compound and separation into its enantiomers see Intermediate 47.
Analytical Chiral HPLC (method see Intermediate 10): Rt = 7.07 min, e.e., 96.8%.
Optical rotation (method OR1 ): +14.2°(methanol).
Intermediate 50
(5R)-5-(4-Fluorophenyl)-3,9-diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid
Figure imgf000271_0002
Hydrochloric acid (93 ml, 4M in dioxane 372 mmol) was added to a solution of tert-butyl (7R)- 7-(4-fluorophenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate (1 .93 g, 5.33 mmol, Intermediate 48) in ethanol (88 ml) and the mixture was stirred for 2 h at room temperature. For the work-up, the reaction mixture was concentrated to give the title compound 1 .7 g (95 % purity, 101 % yield) which was used in the next step without further purification.
Optical rotation (method OR1 ): -14.4°(DMSO). Reference compound 1
(5R)-5-(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9-diazaspiro-
[5.5]undecan-2-one
Figure imgf000271_0001
A mixture of (5R)-5-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid (74.7 mg, 250 mihoI, Intermediate 50), (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (76.1 mg, 325 pmol), HATU (143 mg, 375 pmol) and N,N-diisopropylethylamine (218 mI, 1 .25 mmol) in DMF (3 ml) was stirred for 12 h at room temperature. For the work-up, the reaction mixture was poured onto water, extracted with ethyl acetate (x3), the combined organic layers were washed with sat. sodium chloride (aq), filtered through a hydrophobic filter and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method 6) to give the title compound (92.2 mg, 74 % yield). LC-MS (Method 2): Rt = 1.22 min; MS (ESIpos): m/z = 479 [M+H]+.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.174 (0.67), 0.195 (1.22), 0.207 (1.22), 0.228 (0.75), 0.637 (1.49), 0.667 (1.29), 0.937 (0.86), 0.958 (1.57), 0.970 (1.76), 0.991 (1.29), 1.003 (1.22),
1.145 (0.90), 1.179 (0.75), 1.270 (0.94), 1.335 (0.71), 1.401 (1.53), 1.429 (1.33), 1.874 (1.33),
1.918 (1.69), 2.111 (2.35), 2.154 (2.98), 2.203 (2.08), 2.247 (1.69), 2.323 (1.69), 2.327 (2.35),
2.331 (1.65), 2.418 (3.76), 2.462 (3.57), 2.518 (9.45), 2.523 (6.35), 2.540 (1.22), 2.586 (1.73),
2.593 (0.86), 2.660 (0.82), 2.665 (1.73), 2.669 (2.35), 2.674 (1.65), 2.801 (1.33), 2.815 (1.73),
2.826 (2.20), 2.838 (2.12), 2.863 (1.80), 2.868 (1.76), 2.889 (1.10), 2.895 (1.02), 2.917 (1.22),
3.027 (0.75), 3.043 (1.76), 3.070 (1.45), 3.101 (2.08), 3.117 (1.10), 3.131 (1.84), 3.138 (1.73),
3.148 (1.49), 3.159 (3.88), 3.172 (3.45), 3.254 (1.57), 3.278 (1.76), 3.343 (9.57), 3.379 (1.14),
3.398 (0.94), 3.545 (1.41), 3.573 (16.00), 4.038 (0.75), 4.072 (0.71), 4.096 (0.67), 4.180 (1.33), 4.214 (1.22), 6.944 (3.02), 6.958 (3.73), 6.966 (4.43), 6.980 (3.80), 7.136 (1.88), 7.158 (4.78),
7.165 (5.10), 7.181 (3.92), 7.188 (7.84), 7.210 (3.49), 7.232 (4.31), 7.251 (6.24), 7.267 (2.39),
7.281 (2.59), 7.289 (2.08), 7.303 (1.69), 7.324 (4.94), 7.343 (7.69), 7.363 (6.04), 7.371 (2.51),
7.429 (1.02), 7.438 (6.78), 7.445 (5.18), 7.455 (3.33), 7.464 (0.82), 7.518 (2.35), 7.536 (3.80),
7.555 (1.65), 7.582 (3.25), 7.637 (2.24).
Optical rotation (method OR1): +13.3°(methanol).
Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; column: Chiralpak IC 3m 100x4.6mm; eluent A: hexanes + 0.1 vol-% diethylamine (99%), eluent B: ethanol; gradient: 20-50%B in 7min; flow 1.4 ml/min; temperature: 25 °C; DAD 254 nm
Analytical Chiral HPLC: Rt = 5.87 min, e.e. >99%.
Single crystals of the title compound have been obtained from DMF at room temperature. A crystal was putted into oil and mounted in a cryo loop. The crystal was then flash-frozen into a nitrogen stream at 100K. Data was collected using a Proteum Microstar X8 instrument.
Crystal Data:
Empirical formula C25 H26 F 4 N2 O3
Formula weight 478.48
Temperature 100(2) K
Wavelength 1.54178 A
Crystal system Orthorhombic
Space group P2(1)2(1)2(1)
Unit cell dimensions a = 8.7539(6) A a= 90°.
b= 18.1035(13) A b= 90°.
C = 29.182(2) A g=90°. Volume 4624.7(6) A3
Z 8
Density (calculated) 1.374 Mg/m3
Absorption coefficient 0.954 mnr1
F(000) 2000
Crystal size 0.6 x 0.4 x 0.2 mm3
Theta range for data collection 2.87 to 60.88°
Index ranges 8<=h<=8, 0<=k<=20, 0<=l<=32
Reflections collected 100566
Independent reflections 6389 [R(int) = 0.0261]
Completeness to theta = 60.88° 92.2%
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 6389/0/615
Goodness-of-fit on F2 1.081
Final R indices [l>2sigma(l)] R1 = 0.0224, wR2 = 0.0582
R indices (all data) R1 = 0.0224, wR2 = 0.0582
Absolute structure parameter 0.04(6)
Largest diff. peak and hole 0.127 and -0.150 e.A 3
Table 2: Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (A2X 103) U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
x y z U(eq)
F11 8168(1) 7952(1) -4076(1) 42(1)
C21 8133(2) 8449(1) -3724(1) 29(1)
C31 7374(2) 9103(1) -3792(1) 30(1)
C41 7361(2) 9612(1) -3436(1) 25(1)
C51 8067(2) 9462(1) -3017(1) 22(1)
C61 8819(2) 8788(1) -2966(1) 25(1)
C71 8850(2) 8275(1) -3322(1) 29(1)
C81 7954(2) 10032(1) -2634(1) 20(1)
C91 9488(2) 10111(1) -2386(1) 23(1)
N101 9398(2) 10564(1) -1970(1) 24(1)
cm 8136(2) 10742(1) -1744(1) 22(1)
0121 8171(1) 11063(1) -1367(1) 32(1)
C131 6627(2) 10568(1) -1966(1) 23(1)
C141 6613(2) 9898(1) -2292(1) 20(1) X y z U(eq)
C151 6782(2) 9168(1) -2029(1) 20(1)
C161 5405(2) 8994(1) -1726(1) 22(1)
N171 3971(2) 9022(1) -1985(1) 21(1)
C181 3722(2) 9717(1) -2238(1) 23(1)
C191 5087(2) 9870(1) -2548(1) 20(1)
C201 2859(2) 8505(1) -1993(1) 23(1)
0211 1632(1) 8595(1) -2185(1) 31(1)
C221 3202(2) 7747(1) -1764(1) 23(1)
0231 3571(1) 7808(1) -1292(1) 27(1)
C241 2602(2) 8261(1) -1011(1) 38(1)
C251 1796(2) 7237(1) -1808(1) 30(1)
F261 525(1) 7513(1) -1617(1) 40(1)
F271 2078(1) 6596(1) -1589(1) 38(1)
F281 1461(1) 7061(1) -2241(1) 36(1)
C291 4547(2) 7377(1) -2004(1) 23(1)
C301 4719(2) 7445(1) -2478(1) 25(1)
C311 5971(2) 7134(1) -2695(1) 29(1)
C321 7064(2) 6764(1) -2448(1) 34(1)
C331 6892(2) 6690(1) -1980(1) 40(1)
C341 5638(2) 6986(1) -1759(1) 34(1)
F12 2005(1) 11389(1) 1792(1) 43(1)
C22 2086(2) 11428(1) 1328(1) 28(1)
C32 2589(2) 12068(1) 1127(1) 28(1)
C42 2682(2) 12089(1) 652(1) 22(1)
C52 2266(2) 11491(1) 381(1) 19(1)
C62 1744(2) 10855(1) 602(1) 22(1)
C72 1658(2) 10822(1) 1078(1) 26(1)
C82 2388(2) 11552(1) -139(1) 19(1)
C92 910(2) 11299(1) -364(1) 24(1)
N102 1008(2) 11229(1) -860(1) 23(1)
C112 2285(2) 11224(1) -1110(1) 21(1)
0122 2260(1) 11100(1) -1528(1) 29(1)
C132 3762(2) 11394(1) -868(1) 20(1)
C142 3798(2) 11169(1) -357(1) 19(1)
C152 5257(2) 11451(1) -127(1) 20(1)
C162 6703(2) 11078(1) -302(1) 22(1) X y z U(eq)
N172 6566(2) 10271(1) -252(1) 20(1)
C182 5232(2) 9959(1) -484(1) 21(1)
C192 3766(2) 10321(1) -312(1) 20(1)
C202 7606(2) 9908(1) 3(1) 20(1)
0212 8663(1) 10221(1) 198(1) 29(1)
C222 7430(2) 9063(1) 61(1) 23(1)
0232 7370(1) 8671(1) -360(1) 30(1)
C242 8384(2) 8900(1) -721(1) 41(1)
C252 8797(2) 8760(1) 338(1) 29(1)
F262 8892(1) 9033(1) 762(1) 32(1)
F272 8662(1) 8025(1) 381(1) 41(1)
F282 10150(1) 8880(1) 134(1) 43(1)
C292 5969(2) 8893(1) 329(1) 22(1)
C302 5525(2) 9352(1) 684(1) 25(1)
C312 4184(2) 9221(1) 919(1) 32(1)
C322 3275(2) 8630(1) 799(1) 40(1)
C332 3722(2) 8165(1) 450(1) 42(1)
C342 5066(2) 8286(1) 216(1) 33(1)
Figure 1 shows the crystal structure of Reference compound 1.
Intermediate 51
(5R)-9-benzyl-5-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-2-one
Figure imgf000275_0001
To (5R)-5-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-2-one (8.16 g, 31.1 mmol) was added potassium hydroxide (2M in water) and extracted with DCM (x3). The organic layers were combined and washed with water, sat. sodium chloride (aq), filtered through a hydrophobic filter and concentrated under reduced pressure. To the residue was added 1 ,2-dichloroethane (240 ml) and the resulting suspension was added benzaldehyde (3.2 ml, 31 mmol) in one portion and stirred at rt for 1h. Then sodium triacetoxyborohydride (13.2 g, 62.2 mmol) was added portionwise and stirred at rt for 16h. The reaction was quenched by careful pouring the reaction mkxture into sat. sodium hydrogen carbonate (aq) and was stirred for 10 mins. The organic layers were extracted with DCM and the organic layers were combined and washed with water, sat. sodium chloride (aq), filtered through a hydrophobic filter and concentrated under reduced pressure to give the title compound (12.5 g) which was used directly in the next step.
Optical rotation (method OR1 ): -20.3° (methanol).
Intermediate 52
(1 R)-9-benzyl-1 -(4-fluorophenyl)-3,9-diazaspiro[5.5]undecane
Figure imgf000276_0001
Using the method described for intermediate 42 with (5R)-9-benzyl-5-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-2-one (3.0 g, 8.51 mmol) gave the title compound (2.8 g, 97%) which was used directly in the next step.
LC-MS (Method 2): Rt = 1 .41 min; MS (ES): m/z = 338.0
Intermediate 53 (same as Intermediate 451
tert-butyl (1 R)-9-benzyl-1 -(4-fluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000276_0002
To a solution of (1 R)-9-benzyl-1 -(4-fluorophenyl)-3,9-diazaspiro[5.5]undecane (2.8 g, 8.27 mmol) in DCM (53 ml) was added di-tert-butyl dicarbonate (2.28 ml, 9.9 mmol) and DIPEA (2.16 ml, 12.41 mmol) and the reaction was stirred at rt for 1 h. The reaction mixture was poured into sat. ammonium chloride (aq), extracted with DCM. The organic layers were combined and washed with water, sat. sodium chloride (aq), filtered through a hydrophobic filter and concentrated under reduced pressure. The residue was purified by silica chromatography (DCM / ethanol) to give title compound (3.0 g, 83%).
Optical rotation (method OR1 ): 5.0°(methanol). Intermediate 54
(rac)-tert-butyl 1 -(4-fluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000277_0001
To a solution of intermediate 43 (2.90 g, 6.61 mmol) in methanol (470 ml) was added a slurry of 10% palladium on carbon (706 mg) in toluene (10 ml). The autoclave was charged with hydrogen 10 atm and stirred at rt for 4 hrs. Filtered over a pad of celite, flushed with methanol and concentrated to give a colourless gum. This was futhur purified by filtering through an SCX cartridge using an eluent system of 100% methanol followed by 4N ammonia in methanol to give the desired compound as a white solid 950 mg (37 %).
1 H NMR (400 MHz, CHLOROFORM-d) d ppm 1 .18 - 1.68 (m, 15 H), 2.00 - 2.26 (m, 1 H), 2.51 - 2.64 (m, 1 H), 2.70 - 2.89 (m, 4 H), 3.19 (m, 1 H), 3.66 - 4.05 (m, 2 H), 6.99 (m, 2 H), 7.10 (m, 2 H).
Intermediate 55
tert-butyl (1 R)-1 -(4-fluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (stereoisomer 1 )
Figure imgf000277_0002
To a solution of intermediate 45 (1 .90 g, 4.33 mmol) in ethanol (50 ml) which had been degassed three times with vacuum and nitrogen was added palladium on carbon (92.4 mg). The reaction vessel was charged with hydrogen and stirred at rt for 4h. Additional palladium on carbon was added and sitirred for a further 6h. The reaction mixture was filtered through celite and concentrated under reduced pressure to give the titled compound (1 .2 g, 79%). Intermediate 56
tert-butyl (1 R)-9-[difluoro(phenyl)acetyl]-1 -(4-fluorophenyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate
Figure imgf000278_0001
Using an analogous method described as intermediate 10: intermediate 55 (120 mg, 344 pmol) was coupled with difluoro(phenyl)acetic acid (71.1 mg, 413 pmol) and gave the titled compound (90 mg, 49%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.614 (0.62), 0.637 (1.06), 0.669 (0.65), 0.725 (0.56), 0.736 (0.67), 0.757 (1.17), 0.767 (1.17), 0.790 (0.80), 0.855 (0.67), 0.873 (1.53), 0.891 (0.73), 0.970 (0.71), 0.993 (1.19), 1.002 (1.17), 1.026 (0.86), 1.055 (1.36), 1.089 (1.23), 1.144 (1.77),
1.156 (1.62), 1.176 (2.29), 1.188 (2.31), 1.209 (1.68), 1.221 (1.51), 1.349 (13.22), 1.395 (5.43), 1.529 (1.01), 1.562 (0.91), 1.820 (0.82), 1.851 (0.78), 2.108 (1.75), 2.125 (1.66), 2.136 (1.66), 2.518 (4.87), 2.523 (3.67), 2.539 (1.49), 2.568 (1.31), 2.883 (0.67), 2.915 (1.45), 2.957 (1.34), 3.013 (1.45), 3.044 (2.52), 3.088 (2.39), 3.121 (1.51), 3.391 (2.22), 3.557 (1.34), 3.696 (2.13), 3.730 (1.96), 4.061 (1.32), 4.093 (2.03), 7.053 (1.68), 7.075 (4.85), 7.092 (6.62), 7.109 (15.70),
7.131 (16.00), 7.154 (5.09), 7.180 (0.50), 7.193 (0.52), 7.324 (2.83), 7.343 (8.11), 7.355 (8.86), 7.373 (11.52), 7.394 (2.28), 7.423 (3.67), 7.442 (5.86), 7.461 (2.74), 7.521 (1.60), 7.539 (2.59), 7.556 (1.23), 7.573 (1.92), 7.591 (2.82), 7.609 (1.12).
Intermediate 57
tert-butyl 1-(4-fluorophenyl)-9-{[2-(trifluoromethyl)phenyl]acetyl}-3,9-diazaspiro[5.5]undecane- 3-carboxylate (mixture of stereoisomers)
Figure imgf000278_0002
To a solution of intermediate 54 (100 mg, 287 pmol), [2-(trifluoromethyl)phenyl]acetic acid (76.2 mg, 373 pmol) and HATU (153 mg, 402 pmol) in DMF (3.4 ml) was added DIPEA (250 mI, 1 .4 mmol) in one portion. This was allowed to stirr at room temperature for one hour. After which time the reaction was quenched with a saturated sodium bicarbonate solution and diluted with ethyl acetate. The ethyl acetate layer was washed thrice more with water, followed by brine and dried over magnesium sulfate. This was then evaporated to dryness under reduced pressure to give a pale yellow solid (140 mg, 91 %) which was used directly in the next step.
Intermediate 58
tert-butyl 1 -(4-fluorophenyl)-9-{2-[2-(trifluoromethyl)phenyl]propanoyl}-3,9-diazaspiro[5.5]- undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000279_0001
Using an analogous method described as intermediate 57: intermediate 54 (300 mg, 861 pmol) was coupled with (rac)-2-[2-(trifluoromethyl)phenyl]propanoic acid (244 mg, 1 .12 mmol) and gave the titled compound (440 mg, 93%) which was used directly in the next step.
Intermediate 59
tert-butyl (1 R)-9-{difluoro[2-(trifluoromethoxy)phenyl]acetyl}-1 -(4-fluorophenyl)-3,9-diaza- spiro[5.5]undecane-3-carboxylate
Figure imgf000279_0002
Using an analogous method described as intermediate 10: intermediate 55 (120 mg, 344 pmol) was coupled with (rac)-difluoro[2-(trifluoromethoxy)phenyl]acetic acid (105.8 mg, 413 pmol) and gave the titled compound (7.1 mg, 3%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.668 (0.65), 0.701 (1 .13), 0.723 (0.70), 0.800 (0.58),
0.810 (0.75), 0.832 (1 .38), 0.843 (1.40), 0.864 (0.97), 0.875 (0.82), 1 .004 (0.80), 1.040 (2.15),
1 .075 (1 .45), 1 .1 13 (0.75), 1 .145 (1.42), 1 .185 (2.12), 1.207 (2.00), 1 .218 (2.20), 1.239 (1 .35), 1 .251 (1 .13), 1 .349 (16.00), 1 .593 (1 .25), 1.627 (1 .16), 1.867 (1 .09), 1 .902 (0.99), 2.163 (2.24), 2.170 (2.44), 2.197 (2.29), 2.205 (2.10), 2.518 (5.33), 2.523 (4.51 ), 2.532 (1 .83), 2.537 (1 .81 ),
2.569 (1 .30), 2.660 (0.46), 2.867 (0.77), 2.900 (1 .98), 2.935 (1.95), 2.966 (1 .04), 3.095 (1 .45),
3.125 (2.56), 3.157 (2.51 ), 3.186 (1.13), 3.357 (2.03), 3.404 (2.08), 3.443 (1 .40), 3.583 (1 .35), 3.753 (1 .81 ), 4.039 (1 .30), 4.076 (2.22), 4.1 13 (1 .16), 7.062 (2.00), 7.083 (5.24), 7.100 (6.88),
7.1 16 (4.51 ), 7.128 (6.93), 7.133 (7.02), 7.150 (9.73), 7.155 (9.56), 7.173 (3.69), 7.178 (3.23),
7.247 (2.05), 7.268 (2.20), 7.357 (1.95), 7.377 (2.12), 7.479 (1.71 ), 7.497 (4.10), 7.523 (4.05),
7.542 (2.37), 7.691 (2.29), 7.703 (4.22), 7.710 (6.73), 7.722 (5.36), 7.728 (5.02), 7.742 (3.09),
7.761 (1 .38). Intermediate 60
tert-butyl 1 -(4-fluorophenyl)-9-[(naphthalen-1 -yl)acetyl]-3,9-diazaspiro[5.5]undecane-3- carboxylate (mixture of stereoisomers)
Figure imgf000280_0001
Using an analogous method described as intermediate 57: intermediate 54 (100 mg, 287 pmol) was coupled with (naphthalen-l -yl)acetyl chloride (64.6 mg, 316 pmol) and gave the titled compound (148 mg, 99%) which was used directly in the next step.
Intermediate 61
tert-butyl (1 R)-1 -(4-fluorophenyl)-9-[(naphthalen-1 -yl)acetyl]-3,9-diazaspiro[5.5]undecane-3- carboxylate
Figure imgf000280_0002
Using an analogous method described as intermediate 10: intermediate 55 (120 mg, 344 pmol) was coupled with (naphthalen-l -yl)acetic acid (77.0 mg, 413 pmol) and gave the titled compound (52.6 mg, 30%) after purification by preparative HPLC (Method 6). 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.992 (0.65), 1.024 (1.41), 1.055 (1.48), 1.086 (0.72), 1.174(1.15), 1.205 (2.63), 1.225 (2.95), 1.237 (2.92), 1.255 (2.02), 1.279 (2.23), 1.366 (12.43),
1.743 (0.79), 1.774 (0.79), 1.820 (0.86), 2.165 (1.23), 2.190 (1.69), 2.223 (1.15), 2.518 (6.74), 2.523 (5.05), 2.539 (0.65), 2.597 (1.95), 2.615 (2.05), 2.660 (0.72), 2.720 (0.65), 2.750 (1.23), 2.780 (1.05), 2.805 (0.94), 3.147 (1.44), 3.180 (1.66), 3.217 (1.44), 3.252 (0.65), 3.613 (1.15), 3.699 (1.77), 3.748 (2.05), 3.781 (1.80), 3.946 (1.48), 3.974 (1.33), 3.986 (3.53), 4.014 (3.75), 4.034 (4.22), 4.042 (4.00), 4.074 (2.41), 4.083 (1.69), 4.104 (1.66), 4.143 (0.94), 7.120 (2.70), 7.136 (6.88), 7.155 (15.24), 7.176 (16.00), 7.192 (5.87), 7.215 (1.26), 7.260 (2.38), 7.280 (3.06), 7.299 (3.39), 7.320 (3.03), 7.338 (2.09) , 7.376 (1.15), 7.393 (3.42), 7.413 (3.89), 7.431 (1.84), 7.458 (2.31), 7.463 (2.38), 7.478 (3.57) , 7.483 (3.46), 7.493 (1.87), 7.500 (1.69), 7.753 (4.61), 7.777 (8.94), 7.798 (5.15), 7.876 (3.10), 7.886 (3.06), 7.894 (2.85), 7.906 (2.77).
Intermediate 62
tert-butyl (1 R)-1 -(4-fluorophenyl)-9-[2-methyl-2-(naphthalen-1 -yl)propanoyl]-3,9-diazaspiro- [5.5]undecane-3-carboxylate
Figure imgf000281_0001
Using an analogous method described as intermediate 10: intermediate 55 (120 mg, 344 pmol) was coupled with 2-methyl-2-(naphthalen-1-yl)propanoic acid (88.5 mg, 413 pmol) and gave the titled compound (75 mg, 38%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.684 (0.61), -0.539 (0.69), 0.264 (0.65), 0.666 (1.21), 0.674 (1.34), 0.690 (1.65), 0.853 (4.64), 0.871 (9.06), 0.889 (4.55), 0.930 (2.43), 0.947 (2.34), 0.995 (0.95), 1.106 (1.99), 1.129 (1.95), 1.167 (1.65), 1.222 (4.38), 1.279 (14.70), 1.334 (16.00), 1.352 (12.79), 1.427 (9.67), 1.588 (1.91), 1.633 (7.72), 1.708 (1.60), 1.852 (0.65), 1.923 (0.74), 1.951 (1.08), 1.986 (1.56), 2.042 (2.43), 2.078 (2.08), 2.169 (1.60), 2.185 (2.60), 2.204 (2.47), 2.219 (0.95), 2.322 (2.08), 2.326 (2.69), 2.331 (2.08), 2.518 (9.67), 2.522 (6.33), 2.539 (4.64), 2.573 (1.30), 2.593 (1.73), 2.617 (1.60), 2.664 (2.64), 2.669 (3.43), 2.673 (2.64), 2.686 (1.39), 2.722 (1.17), 2.762 (2.38), 2.780 (2.60), 2.819 (2.64), 2.924 (1.73), 3.086 (2.08), 3.512 (1.04), 3.623 (1.30), 3.728 (0.87), 3.761 (0.82), 4.339 (1.08), 6.566 (1.52), 6.694 (1.69), 6.934 (3.08), 7.109 (3.69), 7.131 (6.55), 7.153 (5.03), 7.178 (3.99), 7.192 (4.21), 7.199 (3.38), 7.214 (2.34), 7.309 (1.04), 7.454 (3.47), 7.472 (5.29), 7.492 (4.55), 7.519 (5.46), 7.618 (1.21), 7.655 (1.26), 7.758 (2.17), 7.799 (4.51), 7.819 I 4.25), 7.905 (2.91), 7.925 (2.91), 8.557 (0.78). Intermediate 63
tert-butyl 1 -(4-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9-diaza- spiro[5.5]undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000282_0001
To a suspension of intermediate 54 (440 mg, 1 .26 mmol) in DCM (14.4 ml) was added DIPEA (440 mI, 2.5 mmol) at 0 <C. To the mixture was adde d the (2S)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl chloride (260 mI, 1 .39 mmol) dropwise and stirred at rt for 2 h. Purified by flushing through a 10 g SCX cartridge using an eluent system of 100% methanol, followed by 4N ammonia in methanol. This gave the desired compound as a beige solid which was used in the following step without futhur purification (644 mg, 90%).
1 H NMR (400 MHz CDCI3):5 [ppm] = 0.03-0.67 (m, 1 H), 0.77-1 .52 (m, 14H), 1 .67-2.23 (m, 2H), 2.29-3.22 (m, 3H), 3.22-3.45 (m, 1 H), 3.49-4.05 (m, 5H), 4.27-4.66 (m, 1 H), 6.76-6.92 (m, 1 H), 6.94-7.12 (m, 3H), 7.14-7.22 (m, 1 H), 7.23-7.51 m, (4H) UPLC-MS (Short Basic 2-95): Rt = 0.92 min., 98%.
MS (ESLpos): m/z = (M+H)+ 565.
Intermediate 64
tert-butyl (1 R)-9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-1 -(4-fluorophenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000282_0002
Using an analogous method described as intermediate 10: intermediate 55 (120 mg, 344 pmol) was coupled with (rac)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (105 mg, 413 pmol - commercially available at Hansa Fine Chemicals GmbH) and gave the titled compound (83.2 mg, 41 %) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.026 (0.48), -0.000 (0.56), 0.163 (0.56), 0.726 (0.60), 0.758 (0.56), 0.922 (0.60), 0.945 (0.40), 1 .072 (1 .89), 1.156 (1.09), 1 .232 (2.01 ), 1.252 (1 .41 ), 1 .335 (1 1.78), 1 .482 (0.52), 1 .813 (0.60), 1.846 (0.52), 1.950 (0.80), 1 .986 (0.72), 2.039 (0.60), 2.084 (1 .29), 2.128 (0.64), 2.336 (1.41 ), 2.424 (0.64), 2.443 (0.72), 2.518 (9.57), 2.523 (6.59), 2.539 (1 .93), 2.686 (0.76), 2.712 (0.80), 2.777 (0.56), 2.812 (0.48), 2.901 (0.48), 2.933 (1 .01 ), 2.982 (1 .21 ), 3.015 (0.92), 3.567 (1.85), 3.602 (1 .57), 3.728 (1.05), 3.808 (0.48), 4.005 (0.64), 4.036 (0.64), 4.147 (1.01 ), 5.759 (16.00), 6.838 (0.44), 6.903 (1 .09), 6.924 (1 .73), 6.938 (1 .41 ), 6.946 (1 .53), 6.984 (4.02), 6.995 (4.26), 7.005 (2.17), 7.031 (0.92), 7.050 (1 .13), 7.074 (1 .37), 7.093 (1 .93), 7.101 (2.25), 7.1 16 (3.82), 7.123 (4.38), 7.142 (5.43), 7.164 (5.95), 7.178 (2.81 ), 7.185 (2.97), 7.202 (2.21 ), 7.273 (1.53), 7.291 (1 .81 ), 7.321 (2.69), 7.41 1 (3.90), 7.422 (1 .77), 7.433 (1 .01 ), 7.438 (0.92), 7.454 (1.25), 7.459 (1 .45), 7.463 (1.09), 7.473 (3.14), 7.492 (3.94), 7.497 (3.10), 7.523 (1 .29), 7.537 (3.26), 7.553 (2.37), 7.558 (1.97), 7.570 (0.76), 7.585 (1 .05), 7.591 (1 .05), 7.605 (0.52), 7.627 (0.72), 7.806 (0.60), 8.166 (2.85), 8.179 (3.06), 8.216 (3.38), 8.578 (0.80), 8.587 (1.97).
Intermediate 65
(rac)-ethyl 2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-2-hydroxypropanoate
Figure imgf000283_0001
Grignard solution: To a solution of 2-propylmagnesium chloride (2M in THF, 263 ml, 525 mmol) under an Argon atmosphere was added a solution of 1 ,3-dibromo-5-fluorobenzene (100 g, 477 mmol) in THF (250 ml) dropwise and then stirred for 60 mins at rt.
A solution of ethyl 3,3,3-trifluoro-2-oxopropanoate (60 ml, 450 mmol) in anhydrous THF (1 L) was cooled to -700 under an argon atmosphere. To t his solution was added the grignard solution slowly ensuring the reaction temperature did not exceed -65Ό. Ton complete addition the reaction was stirred at -70Ό for 3h. The react ion was quenched by the addition of aqueous hydrochloric acid (1 M, 500 ml). The organic layers were extracted with DCM, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (133.36g) which was used directly in the next step. Intermediate 66
(rac)-ethyl 2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-2-methoxypropanoate
Figure imgf000284_0001
To a solution of intermediate 65 (1 13 g, 376 mmol) in DMF (1 .7 I) at 0Ό under a nitrogen atmosphere was added cesium carbonate (135 g, 413 mmol) and stirred for 30min at OTD, then iodomethane (25 ml, 390 mmol) was added and allowed to warm to rt. The reaction was stirred at rt for 16h. The reaction mixture was diluted with water and extracted with DCM, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1 12.96g) which was used directly in the next step. Intermediate 67
(rac)-2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-2-methoxypropanoic acid
Figure imgf000284_0002
To a solution of intermediate 66 (56.3 g, 179 mmol) in ethanol (2.3 I) and water (540 ml) was added powdered potassium hydroxide (20.1 g, 358 mmol). The reaction was stirred at rt for 2 days. To the reaction mixture was added 180ml 2N hydrochloric acid (aq) and the ethanol was removed under reduced pressure. The remaining aqueous solution was extracted with DCM, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (48.89g) which was used directly in the next step. Intermediate 68
tert-butyl (1 R)-9-[2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 -(4-fluoro- phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000285_0001
Using an analogous method described as intermediate 10: intermediate 55 (120 mg, 344 pmol) was coupled with intermediate 67 (1 18 mg, 413 pmol) and gave the titled compound (81 mg, 38%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.1 1 1 (0.38), 0.852 (0.45), 0.953 (0.45), 1 .079 (1 .02), 1 .090 (1 .08), 1 .173 (0.57), 1 .232 (1.27), 1 .352 (8.54), 1.968 (0.38), 2.003 (0.45), 2.1 19 (0.51 ), 2.156 (0.83), 2.181 (0.51 ), 2.327 (3.57), 2.331 (2.61 ), 2.336 (1 .21 ), 2.410 (0.45), 2.518 (16.00),
2.523 (10.01 ), 2.669 (3.70), 2.673 (2.68), 2.678 (1 .21 ), 2.853 (0.70), 2.888 (0.83), 2.917 (0.57), 3.087 (0.45), 3.120 (0.70), 3.153 (0.83), 3.184 (0.51 ), 3.250 (1.21 ), 3.277 (1 .91 ), 3.307 (1 .53),
3.439 (0.57), 3.481 (0.96), 3.518 (0.76), 3.575 (7.97), 3.749 (0.57), 4.169 (0.45), 4.210 (0.57),
5.759 (1 .91 ), 6.906 (0.57), 6.927 (0.38), 6.951 (0.76), 6.971 (1.40), 6.985 (1 .27), 6.999 (0.70), 7.021 (1 .59), 7.039 (2.10), 7.062 (3.12), 7.086 (2.80), 7.099 (1.66), 7.106 (1 .78), 7.122 (1 .72),
7.127 (1 .53), 7.144 (0.96), 7.150 (0.89), 7.192 (0.70), 7.206 (1.21 ), 7.219 (0.83), 7.227 (0.83),
7.310 (0.45), 7.389 (1.08), 7.494 (1.08), 7.502 (0.70), 7.517 (1.40), 7.540 (0.64).
Intermediate 69
tert-butyl (1 R)-9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 -(4-fluorophenyl)- 3,9-diazaspiro[5.5]undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000285_0002
Using an analogous method described as intermediate 10: intermediate 55 (120 mg, 344 pmol) was coupled with (rac)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoic acid (125 mg, 413 pmol - commercially available at Hansa Fine Chemicals GmbFI) and gave the titled compound (82 mg, 38%) after purification by preparative FIPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.072 (0.89), 0.106 (0.51 ), 0.236 (0.57), 0.258 (0.83), 0.289 (0.51 ), 0.909 (1.33), 1 .041 (1 .21 ), 1.109 (1 .78), 1.232 (1 .40), 1.340 (13.59), 1 .877 (0.76), 1 .912 (0.70), 1 .986 (0.89), 2.025 (0.76), 2.130 (1 .02), 2.162 (1.59), 2.197 (0.83), 2.404 (0.70), 2.435 (1 .46), 2.518 (13.90), 2.523 (9.65), 2.616 (1 .33), 2.910 (1 .46), 3.154 (1 .40), 3.187 (1 .78), 3.222 (1 .14), 3.258 (3.1 1 ), 3.281 (4.76), 3.377 (1 .40), 3.413 (1.14), 3.452 (1 .27), 3.488 (1 .46), 3.584 (16.00), 3.739 (1.14), 4.023 (0.70), 4.160 (0.95), 4.194 (1 .59), 4.221 (0.70), 5.759 (4.95), 6.944 (1 .71 ), 6.966 (2.98), 6.980 (2.48), 7.003 (1 .14), 7.025 (2.73), 7.039 (2.35), 7.058 (6.41 ), 7.080 (9.65), 7.102 (4.51 ), 7.121 (3.75), 7.128 (4.25), 7.138 (5.97), 7.155 (6.10), 7.197 (1 .52), 7.21 1 (2.54), 7.244 (1 .14), 7.290 (6.54), 7.665 (3.49), 7.670 (6.41 ), 7.675 (3.24), 7.785 (4.00), 7.791 (7.49), 7.795 (5.08), 7.799 (5.14), 7.803 (5.14), 7.808 (2.03).
Intermediate 70
(rac)-ethyl 2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanoate
Figure imgf000286_0001
To a solution of (3-bromo-5-methylphenyl)magnesium bromide in THF (73 ml, 0.50 M, 36 mmol) under argon at -700 was added dropwise ethyl 3,3,3-trifluoro-2-oxopropanoate (4.6 ml, 35 mmol). The reaction was stirred at -70Ό for 3h and then quenched by the addition of 1 M hydrochloric acid (aq). The organic layers were extracted with DCM, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography (hexane : ethyl acetate) to give the title compound (7 g). Intermediate 71
(rac)-ethyl 2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-2-methoxypropanoate
Figure imgf000287_0002
To a solution of intermediate 71 (2.50 g, 7.33 mmol) in THF (100 ml) at OO under a nitrogen atmosphere was added sodium hydride (21 1 mg, 8.79 mmol) and stirred for 30min at 0Ό, then iodomethane (500 mI, 8.1 mmol) was added and allowed to warm to rt and then heat at 50Ό for 2h. An additional portion of sodium hydride (1 eq) was added and stirred at rt for 72h. The reaction mixture was diluted with water and extracted with DCM, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica chromatograpy (hexane : ethyl acetate) and preparative HPLC (Instrument: Waters Autopurificationsystem; Column: Phenomenex Kinetex EVO C18 5m 100x30mm; Eluent A: Water + 0.1 Vol-% Formic acid (99%), Eluent B: Acetonitrile; Gradient: 0.00-0.50 min 27% B (25->70mL7min), 0.51-5.50 min 54-72% B (70mL/min), DAD scan: 210-400 nm) to give the title compound (522 mg).
Intermediate 72
(rac)-2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-2-methoxypropanoic acid
Figure imgf000287_0001
To an opaquic solution of intermediate 71 (522 mg, 1.53 mmol) in ethanol / water (3:1 , 20 ml) was added powdered potassium hydroxide (172 mg, 3.06 mmol) and stirred at rt for 16h. Then the reaction mixture was heated at 450 for 4h. The pH of the reaction mixture was adjusted to pH 2 with 2M hydrochloric acid (aq) and the organic layers were extracted with DCM:ethanol (9:1 ), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound which was used directly in the next step.
1 H NMR (400 MHz, DMSO -cfe) d ppm 2.32 - 2.36 (m, 3 H) 3.48 - 3.53 (m, 3 H) 7.30 (s, 1 H) 7.43 (s, 1 H) 7.53 (s, 1 H) Intermediate 73
tert-butyl (1 R)-9-[-2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 -(4-fluoro- phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000288_0001
Using an analogous method described as intermediate 10: intermediate 55 (120 mg, 344 pmol) was coupled with intermediate 72 (135 mg, 413 pmol) and gave the titled compound (84 mg, 37%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.066 (0.47), 0.099 (0.80), 0.124 (0.47), 0.258 (0.42), 0.279 (0.75), 0.290 (0.75), 0.312 (0.47), 0.862 (0.75), 0.896 (0.71 ), 0.936 (0.47), 0.958 (0.75), 0.991 (0.52), 1 .061 (2.12), 1 .074 (2.07), 1 .094 (2.12), 1.154 (1.04), 1 .194 (0.94), 1.232 (1 .46),
1 .334 (12.89), 1.868 (0.71 ), 1 .897 (0.61 ), 1 .969 (0.89), 2.028 (9.08), 2.096 (1 1 .1 1 ), 2.152 (1 .69), 2.190 (0.85), 2.317 (9.93), 2.322 (10.78), 2.331 (2.54), 2.398 (0.85), 2.445 (1 .32), 2.518
(1 1 .25), 2.523 (7.29), 2.614 (0.94), 2.664 (2.02), 2.669 (2.87), 2.673 (2.02), 2.879 (1 .08), 2.897
(1 .22), 2.929 (0.94), 3.064 (1 .22), 3.095 (1 .55), 3.141 (1.18), 3.233 (2.82), 3.254 (3.91 ), 3.350 (1 .65), 3.394 (1 .08), 3.434 (1 .32), 3.474 (1 .41 ), 3.557 (15.29), 3.731 (1 .22), 4.013 (0.71 ), 4.181
(0.89), 4.217 (1 .32), 4.255 (0.66), 5.759 (16.00), 6.863 (2.02), 6.894 (2.21 ), 6.958 (1 .65), 6.980
(2.78), 6.994 (2.35), 7.030 (0.99), 7.050 (2.45), 7.070 (4.00), 7.077 (3.76), 7.093 (6.02), 7.099
(5.55), 7.1 19 (6.64), 7.141 (2.02), 7.149 (1 .93), 7.198 (1.46), 7.210 (2.68), 7.233 (4.19), 7.260
(3.34), 7.405 (3.06), 7.501 (3.76), 7.512 (2.64). Intermediate 74
tert-butyl (1 R)-1 -(4-fluorophenyl)-9-(phenylacetyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000288_0002
Using an analogous method described as intermediate 10: intermediate 55 (120 mg, 344 pmol) was coupled with phenylacetic acid (56.3 mg, 413 pmol) and gave the titled compound (85 mg, 50%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.856 (0.54), 0.878 (0.91), 0.888 (0.91), 0.911 (0.99), 0.922 (1.01), 0.944 (1.09), 0.955 (1.07), 0.977 (0.67), 0.989 (0.61), 1.007 (0.60), 1.029 (1.04),
1.039 (1.03), 1.061 (0.75), 1.072 (0.63), 1.101 (0.47), 1.112 (0.58), 1.133 (1.38), 1.144 (1.53),
1.177 (2.33), 1.358 (9.91), 1.652 (0.66), 1.682 (0.63), 1.776 (0.71), 1.804 (0.65), 2.111 (1.06),
2.135 (1.62), 2.143 (1.50), 2.169 (1.11), 2.326 (0.44), 2.518 (1.70), 2.522 (1.17), 2.539 (1.29),
2.548 (1.74), 2.565 (1.63), 2.575 (1.85), 2.654 (0.58), 2.664 (0.60), 2.669 (0.74), 2.673 (0.78),
2.686 (1.08), 2.716 (0.97), 2.748 (0.79), 2.776 (0.44), 3.040 (0.88), 3.072 (2.27), 3.105 (2.50),
3.136 (1.16), 3.425 (0.54), 3.518 (1.16), 3.538 (1.26), 3.555 (5.17), 3.575 (9.11), 3.589 (5.92),
3.611 (2.75), 3.627 (2.87), 3.659 (1.11), 3.722 (1.11), 3.747 (1.53), 3.755 (1.55), 3.780 (0.91),
4.046 (0.91), 4.084 (1.33), 4.125 (0.79), 7.027 (2.42), 7.034 (2.81), 7.041 (3.79), 7.050 (5.61),
7.064 (3.86), 7.073 (3.26), 7.088 (1.54), 7.095 (1.19), 7.110 (15.38), 7.122 (6.48), 7.129 (16.00), 7.150 (8.42), 7.158 (7.48), 7.166 (5.99), 7.179 (1.68), 7.189 (8.52), 7.195 (7.21), 7.203 (4.20), 7.205 (4.32).
Intermediate 75
(rac)-ethyl 2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoate
Figure imgf000289_0001
To a solution of ethyl 3,3,3-trifluoro-2-oxopropanoate (4.00 g, 23.5 mmol) in THF (52 ml) at - 700 under an argon atmosphere was added slowly dro pwise (3,5-dichlorophenyl)magnesium bromide in THF (49 ml, 0.50 M, 25 mmol). The reaction was stirred at -700 for 3h. The reaction was quenched by the addition of 1M hydrochloric acid (aq), the organic layers were extracted with DCM, combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude title compound was used directly in the next step. Intermediate 76
(rac)-ethyl 2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoate
Figure imgf000290_0001
To a solution of intermediate 75 (6.00 g, 18.9 mmol) in THF (30 ml) at 00 under a nitrogen atmosphere was added sodium hydride (545 mg, 22.7 mmol) and stirred for 30 mins. To the reaction was added iodomethane (1 .3 ml, 21 mmol) and the reaction was allowed to warm to rt and then heat at 600 for 3h. The reaction mixture was diluted with water, the organic layers were extracted with DCM, combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude title compound was purified by silica chromatography (hexane: ethyl acetate) to give the title compound (2.6 g, 41 %).
1 H NMR (400 MHz, DMSO -cfe) d ppm 1 .25 m, 3 H) 3.51 - 3.55 (m, 3 H) 4.33 - 4.46 (m, 2 H) 7.47 (m, 2 H) 7.82 (m, 1 H).
Intermediate 77
(rac)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxypropanoic acid
Figure imgf000290_0002
Using an analogous method described as intermediate 74: intermediate 76 (1 .00 g, 3.02 mmol) was was hydrolyzed to give the titled compound (900 mg, 98%).
1 H NMR (400 MHz, DMSO -cfe) d ppm 3.54 (s, 3 H) 7.49 (m, 2 H) 7.81 (m, 1 H). Intermediate 78
tert-butyl 4-[cyano-(2-methoxyphenyl)methyl]-4-(2-ethoxy-2-oxo-ethyl)piperidine-1 -carboxylate
Figure imgf000291_0001
To a mixture of tert-butyl 4-(2-ethoxy-2-oxo-ethylidene)piperidine-1 -carboxylate (102.63 g, 381 .05 mmol) and 2-(2-methoxyphenyl)acetonitrile (56.08 g, 381 .05 mmol) in THF (1 .5 L) was added NaH (16.76 g, 419.15 mmol, 60% in mineral oil) at -70 ~ -30Ό under N 2. The mixture was then warmed to 15 Ό and stirred for 12 hours. LC-MS indicated the reaction completed. The mixture was poured into sat. aq. ammonium chloride (500 ml_). The suspension was extracted with Ethyl acetate (500 ml_ x 2). The combined organic layer was washed with bine (300 ml_), dried over sodium sulfate, filtered and concentrated by rotary evaporator in vacuum to afford tert-butyl 4-[cyano-(2-methoxyphenyl)methyl]-4-(2-ethoxy-2-oxo-ethyl)piperidine-1 - carboxylate (176 g, 70% purity) as a light red oil.
LC-MS (method 1 ): Rt = 0.949 min; m/z = 439.3 (M+Na)+; m/z = 317.3 (M-100+H)+.
LC-MS instrument type: Agilent 1200V361 10A; column: Chromolith Flash RP-18e 25*2mm; mobile phase A: 0.0375% TFA in water, mobile phase B: 0.01875% TFA in acetonitrile: gradient: 0.01 min 5% B — » 0.80 min 95% B— » 1 .20 min 95% B— 1 .21 min 5.0% B— » 1.5 min 5% B; flow rate: 1 .5 mL/min; oven temperature: 50 O; UV detection: 220 nm & 254 nm
Intermediate 79
tert-butyl 7-(2-methoxyphenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000291_0002
A suspension of tert-butyl 4-[cyano-(2-methoxyphenyl)methyl]-4-(2-ethoxy-2-oxo- ethyl)piperidine-1 -carboxylate (176 g, 295.79 mmol, 70% purity) and Raney-Ni (50 g, 583.60 mmol) in Ethanol (2.5 L) was stirred at 80 Ό under a hydrogen atmosphere (3 MPa) for 14 hours. LC-MS indicated the reaction completed. The mixture was filtered through a pad of Celite. The filtrate was concentrated by rotary evaporator in vacuum. The residue was stirred with methyl tert- butyl ether (300 mL) for 30 min. The solid was collected by filtration to afford tert-butyl 7-(2-methoxyphenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate (86 g) as a white solid. The mother liquid was concentrated by rotary evaporator in vacuum to give 70 g of crude product as a yellow solid.
LC-MS (method 1 ): Rt = 0.949 min; m/z = 439.3 (M+Na)+; m/z = 317.3 (M-100+H)+.
LC-MS instrument type: Agilent 1200\G61 10A; column: Chromolith Flash RP-18e 25*2mm; mobile phase A: 0.0375% TFA in water, mobile phase B: 0.01875% TFA in acetonitrile: gradient: 0.01 min 5% B — » 0.80 min 95% B— » 1 .20 min 95% B— 1 .21 min 5.0% B— » 1 .5 min 5% B; flow rate: 1 .5 mL/min; oven temperature: 50 G; UV detection: 220 nm & 254 nm. Intermediate 80
5-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid
Figure imgf000292_0001
A mixture of tert-butyl 7-(2-methoxyphenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate (144 g, 384.54 mmol) in HCI/dioxane (4 M, 200 mL) and dioxane (400 ml_) was stirred at room temperature for 3 hours. Thin layer chromatography (ethyl acetate: Ethanol = 10: 1 ) indicated the reaction completed. The mixture was concentrated by rotary evaporator in vacuum. The residue was stirred with Methyl fert-butyl ether (500 mL) for 30 min. The solid was collected by filtration to afford 5-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-2-one (148 g, crude, salt with hydrochloric acid) as a white solid. Intermediate 81
9-benzyl-5-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-2-one
Figure imgf000292_0002
The reaction was performed as 3 batches in paralled: to a solution of 5-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-2-one (47.6 g, crude, salt with hydrochloric acid) in DCM (600 mL) was added triethylamine (16.82 g, 166.20 mmol). The mixture was stirred at room temprature for 30 min. Then benzaldehyde (17.99 g, 169.55 mmol), sodium triacetoxyborohydride (87.64 g, 413.49 mmol) and acetic acid (10.25 ml_, 179.23 mmol) were added. The mixture stirred at room tempreature for 4 hours under N2. LC-MS indicated the starting material was transformed into imine intermediate completely. Then methanol (1 .5 L) and sodium borohydride (9.5 g, 251 .12 mmol) were added and the mixture was stirred at room temperature for 1 .5 hours. LC- MS indicated the reaction completed. These reaction mixtures (3 batches) were combined with another batch of reaction mixture (5 g of crude 5-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-2-one hydrochloride was used in this batch) and the combined reaction mixture was filtered. The filtrate was concentrated by rotary evaporator in vacuum. The residue was diluted with water (2 L) and the mixture was washed with methyl ferf-butyl ether (1 L x 2). The organic phase was removed. The aqueous phase was treated with potassium carbonate until pH reached 1 1. Then the mixture was extracted with Ethyl acetate (1 .5 L x 3). The combined organic phase was washed with brine (2 L). The formed solid was collected by filtration to give product (batch 1 ). The filtrate was dried over sodium sulfate, filtered and concentrated by rotary evaporator in vacuum. The residue was combined with the above product (batch 1 ) to afford 9-benzyl-5-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-2- one (100 g, 94% purity) as a white solid.
Intermediate 82
9-benzyl-1 -(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecane
Figure imgf000293_0001
The reaction was performed as 2 batches in paralled: to a solution of 9-benzyl-5-(2- methoxyphenyl)-3,9-diazaspiro[5.5]undecan-2-one (51 .15 g) in THF (800 mL) was added borane dimethylsulfide (10 M, 56 mL) drop-wise at room temperature under N2. After addition, the mixture was stirred at reflux for 31 hours. LC-MS indicated the reaction completed. The reaction was cooled to room temperature and quenched with methanol (600 mL) drop-wise. Then the mixture was concentrated by rotary evaporator in vacuum. The residue was dissolved in n-butanol (600 mL) and the solution was stirred at reflux for 1 hour. The mixture was concentrated by rotary evaporator in vacuum to afford 9-benzyl-1 -(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecane (163 g, crude) as a colorless oil.
LC-MS (Method 2): Rt = 1 .074 min; m/z = 351 .3 (M+H)+. LC-MS instrument type: Shimadzu LCMS-2020; HPLC instrument type: Shimadzu UV SPD- M20A; column: Kinetex EVO C18 2.1 *30mm*5um; mobile phase A: 0.025% NH3Ή2O in water (v/v), mobile phase B: acetonitrile; gradient: 0.00 min 5% B ® 0.80 min 95% B ® 1.2 min 95% B ® 1.21 min 5% B ® 1 .5 min 5% B; flow rate: 1 .5 mL/min; Column Temp: 40 O; UV detection: 220 nm & 254 nm.
Intermediate 83, Intermediate 84 and Intermediate 85
(rac)-tert-butyl 9-benzyl-5-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate tert-butyl (1 R)-9-benzyl-1 -(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate tert-butyl (1 S)-9-benzyl-1 -(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
Intermediate 83
tert-butyl 9-benzyl-5-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000294_0001
The reaction was performed as 3 batches in paralled: to a mixture of 9-benzyl-1 -(2- methoxyphenyl)-3,9-diazaspiro[5.5]undecane (51 g, crude) in DCM (600 ml_) was added di- fert-butyl dicarbonate (47.63 g, 218.26 mmol) at room temperature, followed by 4- dimethylaminopyridine (1 .78 g, 14.55 mmol). The mixture was stirred at room temperature for 16 hours. Another di-fert-butyl dicarbonate (31 .76 g, 145.51 mmol) and TRIETHYLAMINE (20.25 ml_, 145.51 mmol) were added and the mixture was stirred for further 10 hours. The reaction mixtures (3 batches) were combined with another batch of reaction mixture (batch EW8391 -168, 10 g of crude 9-benzyl-1 -(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecane was used in this batch). The combined reaction mixture was washed with water (1 L x 3). The combined aqueous phase was extracted with Ethyl acetate (1 L). The combined organic phase was washed with brine (1 .5 L), dried over magnesium sulfate, filtered and concentrated by rotary evaporator in vacuum. The residue was purified by column chromatography (Petrol ether: ethyl acetate = 30: 1 ) to afford tert-butyl 9-benzyl-5-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (60 g, 97% purity) and 32 g (92% purity) as white solids.
LC-MS (Method 2): Rt = 1 .202 min; m/z = 451 .4 (M+H)+.
LC-MS instrument type: Shimadzu LCMS-2020; HPLC instrument type: Shimadzu UV SPD- M20A; column: Kinetex EVO C18 2.1 *30mm*5um; mobile phase A: 0.025% NH3-H20 in water (v/v), mobile phase B: acetonitrile; gradient: 0.00 min 5% B ® 0.80 min 95% B ® 1.2 min 95% B ® 1.21 min 5% B ® 1 .5 min 5% B; flow rate: 1 .5 mL/min; Column Temp: 40 Ό; UV detection: 220 nm & 254 nm.
tert-butyl 9-benzyl-5-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (85 g) was separated by chiral SFC (condition: Cellucoat _ methanol (DEA)_5_40_3mL-35T ; Column: Cellucoat 50x4.6mm I.D., 3um; Mobile phase: methanol (0.05% DEA) in carbon dioxide from 5% to 40%; Flow rate: 3mL7min; Wavelength: 220nm) to afford Intermediate 84 (30.2 g) and Intermediate 85 (30.5 g) as light yellow solids.
Intermediate 84
tert-butyl 9-benzyl-1 -(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
(Stereoisomer 1 )
Figure imgf000295_0001
For the preparation of the racemic title compound and separation into its enantiomers see Intermediate 83.
1 H NMR (400 MHz, CDCI3): d = 7.31 -7.25 (m, 6H), 7.24-7.22 (m, 1 H), 6.91 -6.87 (m, 2H), 3.91 - 3.79 (m, 5H), 3.46 (s, 2H), 3.14 (s, 2H), 3.1 1 (t, 1 H), 2.66-2.57 (m, 2H), 2.21 -2.13 (m, 3H), 1 .56-1 .30 (m, 14H).
LC-MS (method 1 ): Rt = 0.803 min; m/z = 451 .4 (M+H)+.
SFC (method 3): Rt = 1 .403 min.
Cellucoat _ methanol (DEA)_5_40_3mL-35T: Column: Cellucoat 50x4.6 mm I.D., 3um; Mobile phase: methanol (0.05% DEA) in carbon dioxide from 5% to 40%; Flow rate: 3 mL/min;
Wavelength: 220 nm. Intermediate 85
tert-butyl (1 R)-9-benzyl-1 -(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Stereoisomer 2)
Figure imgf000296_0001
For the preparation of the racemic title compound and separation into its enantiomers see Intermediate 83.
SFC (method 3): Rt = 1 .581 min.
Cellucoat _ methanol (DEA)_5_40_3mL-35T: Column: Cellucoat 50x4.6 mm I.D., 3um; Mobile phase: methanol (0.05% DEA) in carbon dioxide from 5% to 40%; Flow rate: 3 mL/min;
Wavelength: 220 nm.
Intermediate 86
tert-butyl (1 R)-1 -(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000296_0002
Using an analogous method described as intermediate 54: intermediate 84 (5.00 g, 1 1.1 mmol) and gave the titled compound (3.8 g, 95%) after concentrating under reduced pressure and was used without further purification.
Further details: To a solution of intermediate 84 (5.00 g, 1 1 .1 mmol) in ethanol (100 ml) under Argon was added palladium (10% on activated charcoal, 236 mg). The reaction vessel was flushed with hydrogen and stirred under a positive hydrogen pressure for 10h. The reaction was filtered through Celite and concentrated under reduced pressure and gave the titled compound (3.8 g, 95%) which was used without further purification.
Optical rotation (method OR1 ): 19.4°(methanol). 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.112 (0.57), 1.135 (0.40), 1.154 (1.64), 1.172 (3.22),
1.190 (1.81), 1.195 (0.75), 1.208 (0.96), 1.223 (1.73), 1.253 (0.67), 1.277 (3.00), 1.363 (3.91),
1.751 (0.58), 1.783 (0.53), 1.987 (5.05), 2.000 (0.51), 2.029 (0.91), 2.055 (0.76), 2.095 (1.36),
2.121 (0.75), 2.130 (0.89), 2.381 (0.81), 2.410 (0.67), 2.518 (1.62), 2.523 (0.98), 3.116 (0.60),
3.739 (16.00), 3.758 (1.59), 3.795 (0.64), 4.017 (1.09), 4.035 (1.08), 6.894 (0.87), 6.912 (1.86), 6.929 (1.09), 6.931 (1.09), 6.978 (1.86), 6.997 (2.15), 6.999 (2.11), 7.059 (1.53), 7.063 (1.68),
7.078 (1.26), 7.082 (1.26), 7.145 (2.97), 7.161 (4.12), 7.166 (3.88), 7.178 (0.56), 7.186 (2.30),
7.192 (0.57), 7.200 (1.50), 7.204 (2.06), 7.208 (1.92), 7.212 (1.25), 7.227 (5.44), 7.242 (2.68),
7.245 (4.38), 7.250 (1.62), 7.259 (0.64), 7.263 (1.44), 7.266 (0.81 ).
Intermediate 87
tert-butyl 1-(2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecane-3-carboxylate (Stereoisomer 1)
Figure imgf000297_0001
Using an analogous method described as intermediate 10: intermediate 86 (150 mg, 416 pmol) was coupled with (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (117 mg, 499 pmol) gave the titled compound (50 mg, 21%) after purification by preparative HPLC (Method 6) and silica chromatography (Hexane:Ethyl acetate).
Further details: To a solution of intermediate 86 (150 mg, 416 pmol) and (2R)-3,3,3-trifluoro-2- methoxy-2-phenylpropanoic acid (117 mg, 499 pmol) in THF (5 ml) was added to a solution of intermediate 86 (150 mg, 416 pmol) and (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (117 mg, 499 pmol) in THF (5 ml) was added DIPEA (217 mI, 1.25 mmol) followed by HATU (190 mg, 499 pmol). The reaction was stirred ate RT overnight and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Method 6) and gave the titled compound (50 mg, 21%) (217 mI, 1.25 mmol).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.003 (0.42), 1.012 (0.44), 1.150 (4.80), 1.168 (9.56), 1.186 (5.37), 1.216 (0.62), 1.324 (3.01), 1.352 (3.07), 1.983 (16.00), 2.133 (0.46), 2.168 (0.44),
2.836 (0.48), 3.007 (0.66), 3.036 (0.70), 3.070 (0.46), 3.141 (0.94), 3.339 (8.35), 3.464 (0.51),
3.499 (0.43), 3.748 (3.96), 3.756 (9.24), 3.998 (1.25), 4.015 (3.71), 4.033 (3.61), 4.051 (1.16),
4.165 (0.48), 4.197 (0.41), 5.753 (0.65), 6.573 (0.67), 6.591 (0.73), 6.896 (0.44), 6.908 (0.56), 6.926 (0.94), 6.945 (0.48), 6.976 (0.44), 6.993 (1 .25), 7.012 (1.23), 7.1 14 (1 .08), 7.132 (2.10),
7.147 (1 .46), 7.165 (1 .55), 7.185 (0.63), 7.278 (0.52), 7.282 (0.56), 7.299 (0.91 ), 7.317 (0.76),
7.321 (0.77), 7.332 (0.53), 7.340 (0.49), 7.416 (1 .37), 7.423 (1.41 ), 7.432 (1 .04), 7.435 (0.88),
7.439 (1 .16), 7.457 (0.47). Intermediate 88
tert-butyl 1 -(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Stereoisomer 2)
Figure imgf000298_0001
Using an analogous method described as intermediate 54: intermediate 85 (5.00 g, 1 1.1 mmol) and gave the titled compound (3.8 g, 95%) after concentrating under reduced pressure and was used without further purification.
Optical rotation (method OR1 ): -18.1“(methanol).
Intermediate 89
tert-butyl 1 -(2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecane-3-carboxylate (Stereoisomer 2)
Figure imgf000298_0002
Using an analogous method described as for intermediate 10: intermediate 88 (150 mg, 416 pmol) was coupled with (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (1 17 mg, 499 pmol) gave the titled compound (15 mg, 6%) after purification by preparative HPLC (Method 6) and silica chromatography (Hexane:Ethyl acetate).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.056 (0.49), -0.033 (0.88), -0.023 (0.89), 0.000 (0.54), 0.010 (0.45), 0.529 (0.99), 0.562 (0.89), 0.856 (0.43), 1 .007 (0.58), 1 .039 (0.91 ), 1 .069
(0.96), 1.095 (1 .15), 1 .129 (1 .03), 1.160 (0.99), 1 .177 (1.37), 1 .195 (0.87), 1 .238 (1.99), 1 .349
(8.39), 1.913 (0.99), 1 .946 (0.89), 1.992 (1 .94), 2.176 (1.18), 2.210 (1 .05), 2.753 (0.66), 2.784
(1 .28), 2.817 (0.90), 2.877 (0.94), 3.002 (1 .02), 3.035 (1.43), 3.067 (0.81 ), 3.138 (0.53), 3.223 (2.17), 3.294 (0.45), 3.403 (1 .55), 3.439 (1 .38), 3.524 (16.00), 3.546 (1 1 .10), 3.771 (5.32), 4.023 (0.45), 4.040 (0.47), 4.276 (0.94), 4.309 (0.89), 6.900 (0.69), 6.919 (0.56), 6.947 (1 .63),
6.956 (1 .75), 6.966 (3.72), 6.973 (3.70), 6.985 (2.96), 6.990 (2.79), 7.018 (2.64), 7.034 (3.99),
7.045 (4.16), 7.053 (4.12), 7.064 (2.84), 7.091 (0.71 ), 7.108 (0.41 ), 7.127 (0.61 ), 7.170 (0.50), 7.194 (0.47), 7.215 (0.63), 7.334 (2.50), 7.338 (2.56), 7.353 (3.55), 7.372 (1 .62), 7.432 (2.30),
7.437 (2.04), 7.447 (1.48).
Intermediate 90
ethyl {1 -[(4-methoxyphenyl)methyl]piperidin-4-ylidene}acetate
Figure imgf000299_0001
To a stirred suspension of sodium hydride in THF (100 ml_) was added portion-wise a solution of ethyl (diethoxyphosphoryl)acetate (1 1 ml, 55 mmol) in THF (50 ml_) keeping the temperature between 5-10 Ό. The resultant suspention was coole d to 0 Ό and stirred for 5 min at this temperature before the addition of a solution of 1 -[(4-methoxyphenyl)methyl]piperidin-4-one (10.0 g, 45.6 mmol) in THF (50 ml_). The reaction mixture was allowed to warm to ambient temperature with stirring for 2 h. Water was added, stirred for 10 mins. Ethyl acetate was added, the phases were separated, the aqueous phase was extracted with further Ethyl acetate. The combined organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporator in vacuum. The residue was purified by column chromatography using 1 :1 (Ethyl acetate/heptane) to give the titled compound as a oil (10.94 g, 83%).
1 H-NMR (400 MHz, CHLOROFORM-D) d [ppm] = 1 .25-1 .36 (t, 3H), 2.28-2.40 (t, 2H), 2.45- 2.61 (t, 4H), 2.94-3.05 (t, 2H), 3.49 (s, 2H), 3.85 (s, 3H), 4.09-4.22 (q, 2H), 5.65(s, 1 H), 6.78- 6.95 (d, 2H), 7.19-7.35 (m, 2H).
Intermediate 91
ethyl {4-[(2-bromo-4-fluorophenyl)(cyano)methyl]-1 -[(4-methoxyphenyl)methyl]piperidin-4- yl} acetate
Figure imgf000299_0002
To a solution of potassium t-butoxide dry THF (100 mL) at -10 Ό under a nitrogen atmosphere was added a solution of (2-bromo-4-fluorophenyl)acetonitrile (8.08 g, 37.7 mmol) in THF (50 mL). Upon complete addition a solution of ethyl {1 -[(4-methoxyphenyl)methyl]piperidin-4- ylidenejacetate (10.0 g, 34.6 mmol) in THF (50 mL) was added kept below -10 Ό and stirred for 2 h. Cold Ammonium chloride aq was added, then Ethyl acetate, the phases separated, organic washed with brine and concentrated under reduced pressure to give a yellow gum. Purification by column chromatography using 1 :1 (ethyl acetate/heptane) followed by a second column chromatography using 2% methanol / DCM gave the title compound, 8.6 g (49%).
1 H-NMR (400 MHz, CHLOROFORM-D) d = 1 .31 -1 .37 (t, 3H), 1 .62-1 .72 (m, 1 H), 1 .81 -1.93 (m, 1 H), 1 .94-2.04 (m, 1 H), 2.1 1 -2.26 (m, 2H), 2.54-2.72 (m, 2H), 2.73-2.84 m, (1 H), 2.95-3.06 (d, 1 H), 3.39-3.45 (m, 2H), 3.49-3.54 s, (1 H), 3.80 (s, 3H), 4.15-4.30 (q, 2H), 5.17-5.29 (s, 1 H), 6.80-6.89 (m, 2H), 7.08-7.22 (m, 3H), 7.35-7.44 m, (1 H), 7.51 -7.64 (m, 1 H).
Intermediate 92
ethyl {4-[cyano(5-fluoro-3'-methoxy[1 ,1 '-biphenyl]-2-yl)methyl]-1 -[(4- methoxyphenyl)methyl]piperidin-4-yl}acetate
Figure imgf000300_0001
A mixture of ethyl {4-[(S)-(2-bromo-4-fluorophenyl)(cyano)methyl]-1 -[(4-methoxyphenyl)- methyl]piperidin-4-yl}acetate (1 .00 g, 1 .99 mmol), (3-methoxyphenyl)boronic acid (392 mg, 2.58 mmol), 2 M potassium carbonate aqueous solution in DME was desgassed for 30 mins then added the tetrakis(triphenylphosphine)palladium (0) and stirred at 80 Ό for 15 hours in an inert atmosphere. The reaction was quenched with sat. ammonium chloride solution, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude compound was purified by reverse phase chromatography (BIOTAGE ISOLERA, 30 g; SNAP C18 Biotage cartridge) using acetonitrile and water containing 10mM ammonium bicarbonate pH 10 buffer (3:97 to 100:0) to give the titled compound, 750 mg (71 %).
1 H NMR (400 MHz CDCI3): d [ppm] = 1 .09-1 .92 (m, 4H), 1 .50-1 .88 (m, 2H), 1 .90-1.72 (m, 1 H), 1 .95-2.15 (m, 2H), 2.26-2.48 (m, 3H), 2.54-2.67 (m, 1 H), 3.19-3.36 (m, 2H), 3.78 (s, 3H), 3.80- 3.99 (m, 5H), 4.90-4.98 (m, 1 H), 6.72-6.84 (m, 4H), 6.90-7.02 (m, 2H), 7.06-7.17 (m, 3H), 7.30- 7.38 (m, 1 H), 7.56-7.70 (m, 1 H).
Intermediate 93
5-(5-fluoro-3'-methoxy[1 ,1 '-biphenyl]-2-yl)-9-[(4-methoxyphenyl)methyl]-3,9- diazaspiro[5.5]undecan-2-one
Figure imgf000301_0001
In an autoclave, ethyl {4-[(S)-cyano(5-fluoro-3'-methoxy[1 ,1 '-biphenyl]-2-yl)methyl]-1 -[(4- methoxyphenyl)methyl]piperidin-4-yl}acetate (750 mg, 1 .41 mmol) was stirred in ammonia methanol then added Raney nickel and charged with 8 bar hydrogen then heated to 60 Ό for 4 h then at rt overnight. The reaction was heated to 60 Ό for 3 hrs. The reaction mixture was filtered over celite and washed with methanol then Ethyl acetate and concentrated then slurried in methanol and filtered off the solid. The filtrate was concetrated to give a pale yellow solid 750 mg (>100%).
1 H-NMR (400 MHz, CHLOROFORM-D) d = 0.88-0.99 (m, 1 H), 1.16-1.28 (m, 1 H), 1 .32-1.46 (m, 1 H), 1.50-1.60 (m, 1 H), 1 .81 -1.93 (m, 1 H), 1 .95-2.1 1 (m, 2H), 2.40-2.50 (m, 1 H), 2.52-2.70
(m, 2H), 3.26-3.41 (m, 3H), 3.43-3.5 (m, 1 H), 3.59-3.69 (m, 1 H), 3.78 (s, 3H), 3.82 (s, 3H), 5.93 (br s, 1 H), 6.65-7.17 (m, 9H), 7.28-7.39 (m, 2H).
Intermediate 94
1 -(5-fluoro-3'-methoxy[1 ,1 '-biphenyl]-2-yl)-9-[(4-methoxyphenyl)methyl]-3,9- diazaspiro[5.5]undecane
Figure imgf000301_0002
To a solution 5-(5-fluoro-3'-methoxy[1 ,1 '-biphenyl]-2-yl)-9-[(4-methoxyphenyl)methyl]-3,9- diazaspiro[5.5]undecan-2-one (750 mg, 1 .53 mmol) in THF (30 ml) was added lithium aluminium hydride (3.1 ml, 2M in THF) at RT. This was allowed to stir for 30 minutes at rt. After which time the reaction was heated to 50 Ό for 16 h. The reaction mixture was cooled to 0 Ό and quenched with sodium sulfate decahydrate and stirred at rt overnight. The reaction mixture was filtered over a pad of celite, washed with Ethyl acetate and concentrated to give a colourless gum 680 mg (93%), which was used as a crude product without purification.
Intermediate 95
tert-butyl 1 -(5-fluoro-3'-methoxy[1 ,T-biphenyl]-2-yl)-9-[(4-methoxyphenyl)methyl]-3,9-diaza- spiro[5.5]undecane-3-carboxylate
Figure imgf000302_0001
To a solution 1 -(5-fluoro-3'-methoxy[1 ,T-biphenyl]-2-yl)-9-[(4-methoxyphenyl)methyl]-3,9- diazaspiro[5.5]undecane (680 mg, 1 .43 mmol) in DCM (30 ml) was added DIPEA (500 mI, 2.9 mmol) then di-fert-butyl dicarbonate (390 mI, 1 .7 mmol) and stirred at rt for 5 h. The reaction was quenched with sat. Ammonium chloride solution, extracted with DCM, dried over sodium sulfate and concentrated. The crude compound was purified by silica chromatography using neat Ethyl acetate to give a white foam 540 mg (66%).
1 H NMR (400 MHz CDCI3): d [ppm] = 0.55-1.02 (m, 2H), 1 .35-1 .49 (m, 1 1 H), 1.50-1.59 (m, 5H), 1.93-2.11 (m, 2H), 2.27-2.60 (m, 1 H), 2.93-3.40 (m, 4H), 3.73-3.89 (m, 7H), 6.69-7.23 (m, 9H), 7.26-7.35 (m, 2H).
Intermediate 96
tert-butyl 1 -(5-f luoro-3'-methoxy[1 , 1 '-biphenyl]-2-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000303_0001
The tert-butyl 1 -(5-fluoro-3'-methoxy[1 ,T-biphenyl]-2-yl)-9-[(4-methoxyphenyl)methyl]-3,9- diazaspiro[5.5]undecane-3-carboxylate (540 mg, 940 pmol) was stirred in methanol methanol (170 ml) then added palladium hydroxide (264 mg, 1 .88 mmol) and charged with 8 bar hydrogen, then stirred and heated to 60 Ό for 16 h . The reaction was filtered over celite then concentrated. The crude compound was purified by reverse phase chromatography (BIOTAGE ISOLERA, 30 g; SNAP C18 Biotage cartridge) using acetonitrile and water containing 0.1 % ammonium hydroxide (3:97 to 100:0) to give a colourless gum 25 mg (6%).
Intermediate 97
tert-butyl 1 -(5-f luoro-3'-methoxy[1 , 1 '-biphenyl]-2-yl)-9-[(2R)-3,3,3-trif luoro-2-methoxy-2- phenylpropanoyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000303_0002
Intermediate 96 ((25.0 mg, 55.0 pmol) was suspended in DCM (6.2 ml), then DIPEA (29 mI, 160 mihoI) was added at -10 TT To the mixture was a dded the (2S)-3,3,3-trifluoro-2-methoxy- 2-phenylpropanoyl chloride (1 1 mI, 60 mihoI) dropwise and stirred at 0 Ό for 2 h then rt for 2 h. The reaction was quenched with sat. Ammonium chloride, extracted with DCM, washed with water then brine and concentrated. The crude compound was purified by reverse phase chromatography (BIOTAGE ISOLERA, 12 g; SNAP C18 Biotage cartridge) using acetonitrile and water containing 0.1 % ammonium hydroxide (3:97 to 100:0) to give the product as a white solid 40 mg (>100%).
Intermediate 98 - 102
The following intermediates were made using an analogous method described as for intermediate 10 but using the intermediate 55 (Table 3).
Table 3:
Figure imgf000304_0001
Figure imgf000305_0001
Figure imgf000306_0001
Intermediate 103
ethyl 2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoate
Figure imgf000307_0003
Using an analogous method described as intermediate 65: 1 ,3-dibromo-5-chlorobenzene (19 g, 70.3 mmol) gave the titled compound (16 g, 63%) after silica purification (Hexane:Ethyl acetate).
1 H NMR (400 MHz, DMSO-afe) d ppm 1 .22 (t, 3 H) 4.30 (q, 2 H) 7.58 (s, 1 H) 7.68 (s, 1 H) 7.90 (t, 1 H) 8.31 (s, 1 H).
Intermediate 104
ethyl 2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoate
Figure imgf000307_0001
Using an analogous method described as intermediate 66: intermediate 103 (16 g, 44.2 mmol) gave the titled compound (16.2 g, 97%) and was used directly in the next step without further purification.
1 H NMR (400 MHz, DMSO -cfe) d ppm 1 .25 (t, 3 H) 3.51 - 3.57 (m, 3 H) 4.31 - 4.46 (m, 2 H) 7.50 (s, 1 H) 7.59 (s, 1 H) 7.95 (t, 1 H).
Intermediate 105
2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoic acid
Figure imgf000307_0002
Using an analogous method described as intermediate 67: intermediate 104 (16.1 g, 42.9 mmol) gave the titled compound (14.74 g, 99%) and was used directly in the next step without further purification.
1 H NMR (400 MHz, DMSO-afe) d ppm 3.53 - 3.55 (m, 3 H) 7.52 (s, 1 H) 7.61 (s, 1 H) 7.92 (t, 1 H).
Intermediate 106
tert-butyl (1 R)-9-[2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 -(4- fluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000308_0001
Using an analogous method described as intermediate 10: intermediate 55 (200 mg, 574 pmol) was coupled with intermediate 105 (239 mg, 689 pmol) and gave the titled compound (253 mg, 65%) after purification by preparative HPLC (Method 6).
1 H-NMR (400 MHz, DMS0-d6) d [ppm]: 0.099 (0.1 1 ), 0.292 (0.1 1 ), 0.928 (0.17), 0.967 (0.20), 1 .044 (0.21 ), 1 .107 (16.00), 1 .172 (0.27), 1.208 (0.21 ), 1.232 (0.28), 1 .351 (2.03), 1 .850 (0.10), 1 .884 (0.09), 1 .987 (0.31 ), 2.020 (0.12), 2.1 10 (0.15), 2.144 (0.24), 2.179 (0.12), 2.432 (0.26),
2.518 (2.19), 2.522 (1 .35), 2.619 (0.21 ), 2.912 (0.17), 3.1 10 (0.16), 3.193 (0.22), 3.261 (0.47),
3.281 (0.71 ), 3.362 (0.24), 3.397 (0.21 ), 3.467 (0.20), 3.529 (0.22), 3.581 (2.42), 3.719 (0.17),
4.017 (0.13), 4.189 (1 .54), 6.955 (0.22), 6.977 (0.37), 6.991 (0.33), 7.037 (0.38), 7.051 (0.40),
7.059 (0.89), 7.081 (1 .21 ), 7.104 (0.63), 7.120 (0.59), 7.127 (0.70), 7.142 (0.47), 7.150 (0.57), 7.199 (0.25), 7.212 (0.43), 7.233 (0.33), 7.247 (0.22), 7.318 (0.45), 7.336 (0.40), 7.348 (0.40),
7.416 (0.48), 7.779 (0.43), 7.783 (0.78), 7.788 (0.43), 7.897 (0.47), 7.902 (0.92), 7.908 (0.74),
7.913 (0.67), 7.918 (0.26). Intermediate 107
ethyl 3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-2-hydroxypropanoate
Figure imgf000309_0003
Using an analogous method described as intermediate 65: 1 -bromo-3-fluoro-5-methylbenzene (15 g, 79.4 mmol) gave the titled compound (15 g, 67%) after silica purification (Hexane:Ethyl acetate).
1 H NMR (400 MHz, DMSO -cfe) d ppm 1 .21 (t, 3 H) 2.31 - 2.36 (m, 3 H) 4.28 (q, 2 H) 7.1 1 - 7.17 (m, 2 H) 7.21 (s, 1 H) 7.98 (s, 1 H).
Intermediate 108
ethyl 3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-2-methoxypropanoate
Figure imgf000309_0001
Using an analogous method described as intermediate 66: intermediate 107 (10.6 g, 37.8 mmol) gave the titled compound (1 1 .1 g, quant.) and was used directly in the next step without further purification. Intermediate 109
3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-2-methoxypropanoic acid
Figure imgf000309_0002
Using an analogous method described as intermediate 67: intermediate 108 (1 1 .1 g, 37.7 mmol) gave the titled compound (9.34 g, 88%) and was used directly in the next step without further purification. 1 H NMR (400 MHz, DMSO -d6) d ppm 2.36 (s, 3 H) 3.48 - 3.52 (m, 3 H) 7.07 (d, 1 H) 7.14 - 7.19 (m, 2 H).
Intermediate 110
tert-butyl (1 R)-1 -(4-fluorophenyl)-9-[3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-2- methoxypropanoyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000310_0001
Using an analogous method described as intermediate 10: intermediate 55 (200 mg, 574 pmol) was coupled with intermediate 109 (183 mg, 689 pmol) and gave the titled compound (254 mg, 51 %) after purification by preparative HPLC (Method 6).
1 H-NMR (400 MHz, DMS0-d6) d [ppm]: 0.021 (0.08), 0.053 (0.14), 0.075 (0.08), 0.191 (0.08), 0.213 (0.14), 0.249 (0.08), 0.776 (0.14), 0.810 (0.15), 0.898 (0.12), 0.938 (0.14), 0.967 (0.20), 1 .055 (0.37), 1 .090 (0.39), 1 .107 (16.00), 1.144 (0.23), 1 .180 (0.19), 1 .209 (0.20), 1 .232 (0.19),
1 .278 (1 .38), 1 .352 (3.74), 1 .889 (0.14), 1 .921 (0.12), 1.969 (0.12), 2.012 (0.19), 2.071 (1 .84), 2.102 (0.16), 2.131 (2.19), 2.158 (0.24), 2.179 (0.38), 2.206 (0.15), 2.332 (2.13), 2.356 (0.14), 2.380 (0.14), 2.409 (0.15), 2.442 (0.21 ), 2.518 (1 .76), 2.522 (1.16), 2.605 (0.15), 2.664 (0.29), 2.668 (0.40), 2.673 (0.29), 2.781 (0.07), 2.820 (0.18), 2.853 (0.21 ), 2.876 (0.25), 2.905 (0.20), 3.059 (0.18), 3.093 (0.30), 3.127 (0.30), 3.226 (0.38), 3.252 (0.53), 3.288 (0.23), 3.382 (0.14), 3.430 (0.23), 3.466 (0.23), 3.515 (0.33), 3.554 (2.44), 3.558 (2.41 ), 3.753 (0.20), 4.033 (0.10), 4.188 (1 .66), 4.219 (0.19), 4.258 (0.13), 6.746 (0.32), 6.773 (0.53), 6.803 (0.50), 6.868 (0.21 ), 6.901 (0.20), 6.927 (0.30), 6.948 (0.45), 6.962 (0.39), 6.982 (0.53), 7.013 (0.62), 7.027 (0.39), 7.071 (0.69), 7.089 (1 .09), 7.093 (1.06), 7.1 1 1 (0.67), 7.121 (0.74), 7.128 (0.99), 7.150 (0.75), 7.206 (0.41 ), 7.241 (0.19). Intermediate 111
1 -[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]piperidin-4-one
Figure imgf000311_0001
To a solution of (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (15.5 g, 66.2 mmol) in DMF (61 ml) under Argon was added FIATU (25.2 g, 66.2 mmol) and N,N- diisopropylethylamine (42 ml, 241 mmol) and the reaction mixture was stirred at room temperature for 10 min. To the reaction mixture was added piperidin-4-one hydrochloride (8.16 g, 60.2 mmol) and stirred at room temperature for 24h. The reaction mixture was concentrated in vacuo to remove the excess N,N-diisopropylethylamine . The reaction was dissolved in ethyl acetate and washed with sat. sodium bicarbonate solution and brine, filtered through a hydrophobic filter and concentrated in vacuo. The residue was purified by flash chromatography (hexane: ethyl acetate) to give the title compound (15.8 g, 83%).
Optical rotation (method OR1 ): 73.0°(methanol).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .321 (1 .05), 1 .341 (2.39), 1 .360 (2.23), 1 .380 (2.64),
1 .399 (1 .21 ), 1 .904 (1 .07), 1 .916 (2.32), 1 .927 (1 .14), 1.943 (1.02), 1 .955 (2.13), 1.967 (0.99),
1 .988 (0.56), 2.413 (4.31 ), 2.427 (7.08), 2.446 (2.96), 2.518 (2.58), 2.523 (1 .78), 3.498 (3.98),
3.509 (4.43), 3.517 (4.36), 3.529 (3.80), 3.549 (1 .41 ), 3.565 (1.69), 3.568 (1 .85), 3.582 (2.20),
3.598 (1 .83), 3.601 (2.09), 3.616 (1 .47), 3.669 (6.37), 3.673 (16.00), 3.677 (15.43), 4.082 (1 .09), 4.096 (2.35), 4.1 1 1 (1 .47), 4.129 (2.07), 4.144 (0.94), 7.458 (0.86), 7.464 (4.32), 7.471 (4.1 1 ), 7.474 (6.57), 7.483 (15.58), 7.490 (12.47), 7.504 (2.65).
Intermediate 112
ethyl {1 -[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]piperidin-4-ylidene}acetate
Figure imgf000311_0002
To a solution of ethyl (diethoxyphosphoryl)acetate (8.56 g, 38.2 mmol) in THF (60 ml) was added slowly sodium hydride (1 .47 g, 60 % suspension in mineral oil, 36.7 mmol) maintaining a temperature of 5 to 100 and the mixture was stir red for 30 min at that temperature. A solution of 1 -[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]piperidin-4-one (Intermediate 35, 9.63 g, 30.5 mmol)in THF (60 ml) was added slowly at that temperature. Upon complete addition the mixture was allowed to warm to room temperature and stirred at that temperature for 1 h. For the work-up, ethyl acetate and water were added, the phases were separted and the aqeous phase was extracted with ethyl acetate (2x). The combined organic phases were washed with brine, filtered through a hydrophobic filter and then concentrated to give the title compound (12.48 g) which was used in the next step without further purification.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.112 (0.61), 1.117 (3.94), 1.130 (1.30), 1.135 (8.99), 1.148 (4.08), 1.152 (5.03), 1.166 (7.79), 1.171 (3.17), 1.184 (3.66), 1.187 (1.72), 1.189 (1.58),
1.204 (0.62), 1.214 (0.77), 1.232 (1.88), 1.250 (0.79), 1.302 (0.45), 1.352 (0.46), 1.474 (0.42),
1.872 (0.46), 1.907 (0.41), 1.986 (4.33), 2.271 (0.44), 2.369 (0.55), 2.518 (1.01), 2.522 (0.65),
2.741 (0.50), 2.778 (0.47), 3.074 (0.47), 3.127 (0.50), 3.189 (0.96), 3.192 (0.89), 3.217 (1.40),
3.225 (1.50), 3.235 (1.01), 3.242 (1.19), 3.257 (1.10), 3.268 (0.88), 3.281 (0.64), 3.370 (0.74),
3.380 (0.79), 3.392 (0.53), 3.403 (0.56), 3.415 (0.56), 3.637 (9.54), 3.640 (9.24), 3.972 (1.16),
3.990 (3.77), 3.999 (1.00), 4.008 (4.43), 4.017 (1.77), 4.022 (1.89), 4.026 (1.99), 4.035 (1.97),
4.040 (4.21), 4.053 (1.05), 4.057 (3.59), 4.075 (1.01), 5.609 (1.69), 5.707 (1.76), 7.451 (0.97),
7.460(1.14), 7.466 (2.57), 7.473(12.28), 7.478(16.00), 7.490(1.11).
Intermediate 113
ethyl {4-[(2-chlorophenyl)(cyano)methyl]-1-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl]acetate (mixture of stereoisomers)
Figure imgf000312_0001
Using an analogous method described as intermediate 46: intermediate 112 (500 mg, 1.30 mmol) and (2-chlorophenyl)acetonitrile (340 mI, 2.6 mmol) gave the titled compound (540 mg, 70%) after purification by silica chromatography (DCM:EtOH).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.111 (0.82), 1.129 (1.79), 1.147 (0.89), 1.154 (1.42), 1.161 (2.30), 1.172 (2.75), 1.179 (5.36), 1.190 (2.65), 1.196 (3.24), 1.207 (3.47), 1.215 (0.63),
1.225 (1.60), 1.675 (0.41), 1.988 (4.34), 2.419 (0.45), 2.468 (0.92), 2.518 (3.26), 2.523 (2.21),
2.951 (0.44), 2.979 (0.41), 3.010 (0.51), 3.126 (0.45), 3.239 (0.80), 3.416 (0.63), 3.568 (3.61),
3.582 (2.64), 4.000 (0.71), 4.018 (1.33), 4.035 (1.09), 4.053 (0.52), 4.057 (0.68), 4.063 (0.69),
4.067 (1.07), 4.075 (1.66), 4.078 (1.11), 4.085 (1.15), 4.092 (1.57), 4.096 (0.97), 4.102 (0.51),
4.110 (0.49), 4.837 (1.05), 4.869 (0.47), 4.981 (0.51 ), 4.996 (0.44), 5.759 (16.00), 6.981 (0.79), 7.001 (0.51), 7.112 (1.03), 7.125 (0.79), 7.131 (0.76), 7.232 (0.61), 7.252 (0.96), 7.266 (0.46), 7.284 (0.73), 7.305 (0.96), 7.324 (1.10), 7.344 (0.79), 7.436 (1.18), 7.443 (1.35), 7.447 (1.11), 7.452 (1.17), 7.457 (0.86), 7.480 (0.56), 7.504 (0.67), 7.508 (0.93), 7.522 (1.33), 7.527 (1.61), 7.546 (0.97), 7.566 (1.61 ), 7.571 (1.54), 7.576 (1.35), 7.583 (1.49).
Intermediate 114
5-(2-chlorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000313_0001
Using an analogous method described as intermediate 47: intermediate 113 (540 mg, 1.01 mmol) gave the titled compound (225 mg, 43%) after purification by preparative FIPLC (Method 6).
1H-NMR (500 MHz, DMSO-d6) d [ppm]: -0.247 (0.66), -0.238 (0.83), -0.220 (1.53), -0.211
(1.49), -0.193 (0.87), -0.184 (0.70), 0.416 (0. 48), 0.432 (0.92), 0.442 (0.92), 0.459 (0.57), 0.705 (1.18), 0.732 (0.96), 0.761 (1.49), 0.785 (1.40), 0.946 (0.52), 0.955 (0.66), 0.973 (1.22), 0.982 (1.18), 1.000 (0.70), 1.009 (0.52), 1.086 (0.52), 1.095 (0.57), 1.113 (0.66), 1.121 (0.66), 1.148 (0.39), 1.319 (0.48), 1.344 (0.79), 1.371 (1.09), 1.378 (1.14), 1.397 (0.74), 1.493 (2.10), 1.517 (1.49), 1.590 (1.09), 1.618 (1.05), 2.031 (2.10), 2.068 (2.80), 2.105 (0.87), 2.153 (0.57), 2.188 (0.66), 2.236 (1.79), 2.271 (2.23), 2.353 (1.01), 2.368 (1.40), 2.396 (0.48), 2.415 (0.96), 2.451 (0.74), 2.514 (8.83), 2.518 (10.62), 2.522 (6.51), 2.539 (0.44), 2.552 (2.54), 2.683 (3.54), 2.717 (3.19), 2.821 (1.66), 2.844 (2.97), 2.870 (1.57), 2.972 (0.87), 2.982 (1.22), 2.989 (1.22), 2.996 (1.22), 3.007 (1.36), 3.014 (1.75), 3.044 (1.62), 3.067 (1.01), 3.096 (0.87), 3.111 (1.01), 3.117 (1.75), 3.124 (1.92), 3.130 (1.14), 3.135 (1.09), 3.142 (1.14), 3.165 (3.85), 3.223 (0.70), 3.229 (0.74), 3.249 (0.39), 3.276 (1.14), 3.292 (3.06), 3.303 (2.49), 3.315 (3.28), 3.378 (1.66), 3.387 (1.62), 3.396 (1.27), 3.407 (1.14), 3.420 (3.02), 3.450 (1.53), 3.479 (1.18), 3.522 (3.67), 3.547 (3.32), 3.557 (16.00), 3.572 (13.25), 3.609 (0.87), 4.235 (0.92), 4.263 (1.27), 4.356 (1.22), 4.383 (1.14), 6.913 (2.32), 6.928 (4.90), 6.945 (3.76), 6.962 (2.27), 6.965 (2.19), 7.102
(4.50), 7.118 (3.80), 7.202 (2.23), 7.217 (4.07), 7.230 (4.02), 7.244 (4.24), 7.283 (0.83), 7.287 (0.74), 7.293 (1.01), 7.297 (1.27), 7.308 (1.14), 7.315 (4.50), 7.319 (2.93), 7.323 (2.80), 7.330 (6.91), 7.335 (5.16), 7.338 (5.11), 7.346 (4.24), 7.350 (3.54), 7.354 (3.19), 7.363 (1.84), 7.366 (2.01), 7.378 (2.36), 7.381 (2.84), 7.393 (2.32), 7.398 (3.15), 7.403 (5.60), 7.412 (5.16), 7.414 (5.42), 7.422 (3.32), 7.428 (6.73), 7.433 (7.26), 7.438 (4.50), 7.441 (5.64), 7.457 (1.36), 7.467 (3.50), 7.470 (3.50), 7.477 (1.36), 7.483 (4.28), 7.486 (5.38), 7.488 (5.60), 7.492 (2.89), 7.501 (6.08), 7.507 (2.71), 7.513 (2.10), 7.516 (2.05), 7.634 (2.27), 7.673 (3.45), 7.709 (0.96).
Intermediate 115
ethyl {4-[(2-bromophenyl)(cyano)methyl]-1-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000314_0001
Using an analogous method described as intermediate 46: intermediate 112 (1.00 g, 2.59 mmol) and (2-bromophenyl)acetonitrile (670 mI, 5.2 mmol) gave the titled compound (1.16 g, 69%) after purification by silica chromatography (DCM:EtOFI).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.306 (0.59), 0.501 (0.59), 0.511 (0.56), 0.910 (0.40), 0.992 (0.59), 1.027 (0.62), 1.116 (1.80), 1.130 (1.21), 1.134 (4.28), 1.152 (2.70), 1.154 (2.23),
1.169 (8.06), 1.172 (5.09), 1.187 (16.00), 1.1 97 (5.61), 1.205 (8.25), 1.209 (4.31), 1.214 (10.33), 1.227 (1.80), 1.232 (4.78), 1.486 (0.59), 1.507 (0.84), 1.519 (0.81), 1.541 (0.56), 1.551 (0.47), 1.653 (0.96), 1.691 (0.81), 1.751 (0.50), 1.987 (5.64), 2.013 (0.71), 2.411 (1.05), 2.452 (2.39), 2.518 (7.84), 2.522 (5.09), 2.888 (0.84), 2.916 (1.02), 2.948 (1.12), 2.975 (1.05), 3.008 (0.59), 3.059 (0.87), 3.098 (1.30), 3.135 (1.92), 3.174 (1.27), 3.189 (1.64), 3.221 (0.43), 3.252 (0.74), 3.289 (0.56), 3.400 (1.55), 3.541 (0.90), 3.570 (9.52), 3.582 (7.13), 3.634 (0.84), 3.993 (0.62), 4.000 (0.47), 4.010 (1.30), 4.017 (1.27), 4.028 (1.05), 4.035 (1.30), 4.047 (0.59), 4.057 (1.18), 4.063 (1.30), 4.074 (3.29), 4.081 (3.66), 4.084 (2.36), 4.092 (3.88), 4.098 (3.44), 4.108 (2.54), 4.117 (1.24), 4.126 (0.90), 4.304 (0.56), 4.338 (0.62), 4.383 (0.74), 4.416 (0.65), 4.801 (4.59), 4.854 (2.14), 4.944 (1.55), 4.964 (1.30), 5.758 (9.46), 6.944 (1.09), 6.963 (2.48), 6.981 (1.58), 7.064 (1.05), 7.081 (1.18), 7.102 (2.60), 7.120 (2.05), 7.223 (1.61), 7.242 (2.51), 7.256 (1.36), 7.274 (2.17), 7.292 (0.99), 7.307 (1.98), 7.326 (3.60), 7.346 (2.95), 7.364 (1.09), 7.405 (0.84), 7.409 (0.90), 7.428 (1.67), 7.435 (1.98), 7.443 (3.63), 7.447 (2.60), 7.468 (1.64), 7.485 (2.64), 7.498 (1.92), 7.503 (2.36), 7.516 (1.02), 7.535 (1.52), 7.556 (1.67), 7.577 (1.80), 7.603 (1.02), 7.623 (0.43), 7.716 (0.59), 7.719 (0.56), 7.737 (2.33), 7.740 (2.20), 7.749 (2.76), 7.751 (2.95), 7.757 (2.02), 7.760 (1.95), 7.769 (2.20), 7.773 (1.64). Intermediate 116
1 -(2-bromophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecane-2,4-dione (mixture of stereoisomers)
Figure imgf000315_0001
To a mixture of Intermediate 1 15 (1 .15 g, 1.98 mmol) and glacial acetic acid (1 1 ml) was added concentrated sulfuric acid (380mI). The reaction was heated at 120Ό for 16h. The reaction was poured into sat. sodium bicarbonate (aq) and extracted with DCM. The organics were extracted with DCM,. The combined organics were washed with sat. sodium chloride (aq) and filtered through an hydrophobic filter and concentrated under reduced pressure. The titled compound (980 mg, 85%) was obtained after purification by silica chromatography (EtOAc: Hexane).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .231 (4.67), 1 .249 (9.43), 1 .266 (4.47), 1 .432 (0.52), 2.064 (16.00), 2.595 (1.33), 2.599 (0.90), 2.805 (0.49), 2.949 (0.49), 2.994 (0.57), 3.089 (0.55),
3.132 (0.45), 3.320 (0.54), 3.500 (0.46), 3.644 (4.1 1 ), 4.076 (1.05), 4.094 (3.26), 4.112 (3.31 ), 4.130 (1 .08), 4.242 (1 .63), 4.347 (1.25), 4.477 (0.64), 7.122 (0.87), 7.141 (0.61 ), 7.197 (0.59), 7.201 (0.85), 7.207 (0.89), 7.216 (0.76), 7.220 (0.80), 7.226 (0.61 ), 7.301 (0.51 ), 7.320 (0.82), 7.374 (0.80), 7.382 (0.43), 7.387 (0.44), 7.395 (1 .27), 7.413 (0.97), 7.424 (0.59), 7.429 (0.51 ), 7.443 (0.94), 7.446 (0.81 ), 7.462 (0.97), 7.466 (0.76), 7.493 (0.47), 7.497 (0.63), 7.499 (0.55), 7.507 (0.47), 7.512 (1 .1 1 ), 7.515 (0.98), 7.520 (0.52), 7.529 (0.46), 7.559 (0.43), 7.734 (0.53), 7.737 (0.54), 7.754 (0.51 ), 7.757 (0.57), 7.789 (0.72), 7.793 (0.77), 7.809 (0.61 ), 7.812 (0.59), 1 1 .206 (0.49).
Intermediate 117
ethyl {4-[cyano(2-ethylphenyl)methyl]-1 -[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000316_0001
Using an analogous method described as intermediate 46: intermediate 1 12 (1 .26 g, 3.27 mmol) and 2-ethylphenyl)acetonitrile (950 mg, 6.54 mmol) gave the titled compound (960 mg, 55%) after purification by silica chromatography ( Hexane :EtOAc).
Intermediate 118
5-(2-ethylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000316_0002
To a solution of Intermediate 1 17 (398 mg, 750 mihoI) in methanol (1 1 ml) at 0Ό was added (195 mg, 1.50 mmol), followed by the careful addition of sodium borohydride (142 mg, 3.75 mmol). The reaction was stirred at OTD for 3h and t hen at RT for 16h. An additional portion of sodium borohydride (5eq) was added and stirred at RT for 24h. To the reaction was added 1 ml water and the pH adjusted to ph7 with 2M hydrochloric acid (aq). The organics were extracted with DCM,. The combined organics were washed with sat. sodium chloride (aq) and filtered through an hydrophobic filter and concentrated under reduced pressure. The titled compound (168 mg, 46%) was obtained after purification by preparative HPLC (Method 6).
The title compound (168 mg) was separated into its diastereoisomers by preparative chiral HPLC to give diastereoisomer 1 (87 mg, see Intermediate 119) and diastereoisomer 2 (60 mg, see Intermediate 120). Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; Column: Reprosil Chiral NR 8m 250x30mm; eluent A: C02; eluent B: ethanol; isocratic: 38%B; flow: 100 ml/min; temperature: 40Ό; BPR: 150bar; UV: 210nm.
Analytical chiral HPLC method: Instrument: Agilent: 1260, Aurora SFC-Module; Column:
Reprosil Chiral NR 5m 100x4.6mm; eluent A: C02; eluent B: ethanol; isocratic: 38%B; flow: 4 ml/min; temperature: 37.50; BPR: 100bar; UV: 210 n m.
Intermediate 119 and Intermediate 120
(2R)-1 -[(7R)-7-(2-chlorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one
(2R)-1 -[(7S)-7-(2-chlorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one
Intermediate 119
5-(2-ethylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 1 )
For the preparation of the racemic title compound see Intermediate 118.
Analytical Chiral HPLC (method see Intermediate 1 18): Rt = 1.23 min, e.e. >99%.
Optical rotation (method OR1 ): -2.5° (methanol).
Intermediate 120
5-(2-ethylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 2)
For the preparation of the racemic title compound see Intermediate 118.
Analytical Chiral HPLC (method see Intermediate 1 18): Rt = 2.07 min, e.e. >99%.
Optical rotation (method OR1 ): +41 9°(methanol).
Intermediate 121
ethyl (4-{cyano[2-(trifluoromethyl)phenyl]methyl}-1 -[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl)acetate (mixture of stereoisomers)
Figure imgf000318_0001
Using an analogous method described as intermediate 46: intermediate 1 12 (500 mg, 1 .30 mmol) and [2-(trifluoromethyl)phenyl]acetonitrile (480 mg, 2.59 mmol) gave the titled compound (208 mg, 25%) after purification by silica chromatography (DCM:EtOH).
Intermediate 122
9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-5-[2-(trifluoromethyl)phenyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000318_0002
Using an analogous method described as intermediate 47: intermediate 121 (158 mg, 277 pmol) gave the titled compound (97 mg, 63%) after purification by preparative HPLC (Method 6). Intermediate 123
[2-(2-methyl-1 ,3-dioxolan-2-yl)phenyl]acetonitrile
Figure imgf000318_0003
To (2-acetylphenyl)acetonitrile (1 .00 g, 6.28 mmol) in toluene (20 ml) was added ethane-1 , 2- diol (1 .9 ml, 34 mmol) and para-toluenesulfonic acid (14.3 mg, 75.4 pmol) and heated at 1200 for 16h. Another portion of ethane-1 ,2-diol (1 .9 ml, 34 mmol) aded and molecular sieves 4A wered added and heatd at 1200 for 24h. The reactio n was allowed to cool and DCM and sat. sodium bicarbonate (aq) was added. The organics were extracted with DCM. The combined organics were washed with sat. sodium chloride (aq) and filtered through an hydrophobic filter and concentrated under reduced pressure the titled compound (990 mg, 74%) was obtained after purification by silica chromatography (Hexane:EtOAc).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .579 (16.00), 1.987 (0.53), 3.642 (1.26), 3.654 (1 .32),
3.658 (2.85), 3.662 (2.72), 3.668 (1.40), 3.677 (1 .53), 3.989 (1.56), 3.999 (1 .47), 4.004 (2.78),
4.009 (2.87), 4.013 (1 .36), 4.025 (1.26), 4.097 (8.97), 7.345 (1.15), 7.349 (1 .76), 7.358 (2.84),
7.367 (2.32), 7.372 (1 .83), 7.384 (0.51 ), 7.425 (1 .38), 7.429 (0.73), 7.434 (0.54), 7.440 (0.71 ),
7.447 (0.75), 7.51 1 (1.33), 7.517 (0.88), 7.519 (0.86), 7.523 (0.58), 7.528 (0.65), 7.533 (1 .04).
Intermediate 124
ethyl (4-{cyano[2-(2-methyl-1 ,3-dioxolan-2-yl)phenyl]methyl}-1 -[(2R)-3,3,3-trifluoro-2-methoxy- 2-phenylpropanoyl]piperidin-4-yl)acetate (mixture of stereoisomers)
Figure imgf000319_0001
Using an analogous method described as intermediate 46: intermediate 1 12 (500 mg, 1 .30 mmol) and intermediate 123 (527 mg, 2.59 mmol) gave the titled compound (413 mg, 49%) after purification by silica chromatography (Hexane:EtOAc).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.432 (0.62), -0.421 (0.62), 0.794 (0.52), 0.807 (0.46),
0.836 (0.51 ), 0.852 (0.42), 0.971 (0.85), 1 .006 (0.87), 1.046 (0.69), 1 .053 (0.55), 1.058 (0.46),
1 .064 (0.66), 1 .076 (1 .05), 1 .082 (1.08), 1 .090 (1 .24), 1.100 (0.83), 1 .108 (2.29), 1.113 (1 .02),
1 .1 18 (1 .28), 1 .126 (1 .80), 1 .136 (0.59), 1 .145 (0.61 ), 1.154 (3.40), 1 .161 (6.18), 1.172 (6.70),
1 .179 (12.82), 1.189 (3.52), 1 .197 (6.16), 1 .237 (0.73), 1 .259 (0.42), 1.379 (16.00), 1 .481 (6.42), 1.507 (2.69), 1 .513 (2.98), 1.682 (0.74), 1 .710 (0.92), 1 .755 (0.48), 1 .788 (0.48), 1 .841
(0.42), 1 .852 (0.59), 1.873 (0.76), 1 .884 (0.81 ), 1 .905 (0.40), 1 .987 (1 1 .08), 2.424 (1.72), 2.459
(1 .76), 2.518 (3.50), 2.522 (2.21 ), 2.846 (0.56), 2.883 (0.43), 2.930 (0.69), 2.941 (0.86), 2.965
(0.77), 2.977 (0.89), 2.998 (0.95), 3.031 (0.55), 3.044 (0.66), 3.062 (1 .39), 3.080 (2.80), 3.095
(0.78), 3.1 15 (2.15), 3.150 (0.99), 3.183 (0.62), 3.268 (1.18), 3.299 (0.44), 3.522 (0.77), 3.552 (1.80), 3.577 (8.46), 3.607 (5.00), 3.624 (2.19), 3.642 (2.23), 3.659 (1.38), 3.680 (0.48), 3.693 (1.31), 3.710 (2.20), 3.728 (2.20), 3.738 (1.51), 3.745 (1.15), 3.765 (0.92), 3.777 (0.48), 3.785 (0.53), 3.887 (0.52), 3.912 (0.82), 3.920 (1.02), 3.930 (1.17), 3.948 (1.05), 3.958 (1.61), 3.975 (2.58), 3.985 (1.82), 3.989 (1.85), 3.992 (1.81), 4.002 (2.54), 4.013 (1.41), 4.017 (3.52), 4.020 (2.76), 4.035 (4.06), 4.046 (0.99), 4.054 (2.99), 4.063 (1.42), 4.072 (0.94), 4.081 (1.07), 4.279 (0.47), 4.315 (0.40), 4.439 (0.72), 4.472 (0.64), 4.896 (5.66), 4.962 (2.28), 5.043 (0.83), 5.069 (0.98), 6.856 (1.21), 6.875 (2.69), 6.894 (1.65), 6.931 (0.66), 6.947 (0.68), 7.090 (1.18), 7.109 (2.27), 7.112 (2.27), 7.118 (2.63), 7.127 (1.61), 7.138 (2.24), 7.329 (1.25), 7.348 (1.59), 7.357 (0.69), 7.365 (1.16), 7.376 (1.13), 7.382 (1.22), 7.392 (1.26), 7.427 (1.71), 7.434 (2.69), 7.441 (2.67), 7.450 (3.80), 7.459 (2.25), 7.469 (1.78), 7.472 (1.76), 7.487 (1.67), 7.505 (2.34), 7.511 (3.85), 7.519 (3.59), 7.526 (3.46), 7.534 (3.79), 7.544 (0.73), 7.559 (0.48), 7.576 (1.05), 7.585 (2.46), 7.593 (2.34), 7.599 (2.54), 7.608 (1.39), 7.612 (1.16), 7.617 (1.55).
Intermediate 125
5-[2-(2-methyl-1 ,3-dioxolan-2-yl)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]- 3,9-diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000320_0001
Using an analogous method described as intermediate 47: intermediate 124 (470 mg, 798 mihoI) gave the titled compound (190 mg, 41%) after purification by preparative FIPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.306 (0.46), -0.283 (0.77), -0.272 (0.77), -0.250 (0.46), 0.691 (0.86), 0.722 (0.77), 1.439(16.00), 1.490 (0.41), 1.513 (6.21), 1.532 (2.64), 1.549 (2.80), 1.572 (0.66), 1.605 (1.07), 1.674 (0.55), 1.696 (0.68), 1.706 (0.73), 1.903 (1.21), 1.946
(1.32), 2.099 (0.59), 2.143 (0.52), 2.323 (0.52), 2.327 (0.77), 2.332 (0.61), 2.518 (2.94), 2.523
(2.07), 2.539 (3.23), 2.665 (0.46), 2.669 (0.64), 2.673 (0.48), 2.710 (0.68), 2.743 (1.78), 2.754
(0.73), 2.786 (1.68), 2.817 (0.73), 2.845 (1.05), 2.861 (0.55), 2.868 (0.50), 2.877 (0.59), 2.973
(2.16), 2.988 (1.93), 3.007 (1.48), 3.015 (1.00), 3.048 (1.07), 3.081 (1.09), 3.106 (0.43), 3.299
(1.27), 3.363 (1.07), 3.392 (1.46), 3.422 (1.00), 3.442 (0.77), 3.479 (1.80), 3.492 (1.37), 3.508
(0.82), 3.521 (0.80), 3.537 (1.39), 3.561 (8.88), 3.592 (3.30), 3.605 (0.80), 3.623 (1.09), 3.636
(1.14), 3.652 (0.57), 3.672 (0.96), 3.686 (1.46), 3.689 (1.46), 3.705 (2.16), 3.718 (3.10), 3.731 (2.07), 3.749 (1.46), 3.764 (0.77), 3.929 (0.80), 3.947 (1.71), 3.962 (2.18), 3.975 (1.14), 3.991 (1.05), 4.000 (0.61), 4.010 (0.80), 4.024 (0.64), 4.383 (0.73), 4.416 (0.68), 6.800 (0.55), 6.820 (0.64), 6.837 (1.34), 6.856 (2.89), 6.875 (1.75), 7.061 (1.27), 7.079 (2.09), 7.098 (0.93), 7.126 (2.71), 7.145 (2.39), 7.230 (0.57), 7.237 (0.57), 7.249 (0.57), 7.280 (0.77), 7.283 (0.71), 7.302 (1.48), 7.309 (0.84), 7.322 (1.68), 7.332 (1.09), 7.350 (1.43), 7.357 (1.64), 7.361 (1.59), 7.374 (4.05), 7.394 (2.89), 7.413 (1.75), 7.418 (1.50), 7.431 (2.71), 7.441 (1.71), 7.447 (1.71), 7.452 (1.34), 7.522 (0.59), 7.540 (0.86), 7.561 (2.14), 7.569 (2.64), 7.575 (2.32), 7.580 (1.30), 7.588 (1.68), 7.592 (1.37), 7.622 (1.98), 7.627 (1.82).
Intermediate 126
5-(2-acetylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000321_0001
To a solution of Intermediate 125 (180 mg, 329 pmol) in methanol (5.5ml) and water (1.3 ml) was added concentrated sulfuric acid (300 mI, 5.6 mmol) and stirred at RT for 24h. Water was added to the reaction and the solid was collected by filtration and gave the titled compound (139 mg, 67%).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.308 (0.40), -0.286 (0.74), -0.275 (0.74), -0.254
(0.43), 0.434 (0.60), 0.464 (0.54), 1.232 (0.43), 1.312 (0.74), 1.345 (0.54), 1.439 (4.21), 1.484 (0.80), 1.513 (1.51), 1.532 (0.51), 1.549 (0.71), 1.824 (0.85), 1.866 (0.91), 1.944 (0.48), 2.044 (0.65), 2.088 (0.54), 2.261 (16.00), 2.322 (1.34) 2.327 (1.79), 2.331 (1.34), 2.409 (0.48), 2.518 (6.74), 2.523 (4.69), 2.556 (3.64), 2.564 (0.82), 2.575 (3.55), 2.651 (1.34), 2.659 (0.74), 2.665 (1.28), 2.669 (1.73), 2.673 (1.25), 2.695 (1.19), 2.742 (0.48), 2.786 (0.77), 2.798 (0.63), 2.824 (0.97), 2.848 (0.57), 2.972 (0.88), 2.987 (1.25), 2.995 (0.77), 3.012 (1.51), 3.047 (0.63), 3.078 (0.48), 3.109 (0.60), 3.212 (1.08), 3.284 (0.54), 3.361 (0.54), 3.370 (0.43), 3.378 (0.43), 3.391 (0.71), 3.432 (1.45), 3.478 (0.60), 3.492 (0.48), 3.518 (0.65), 3.545 (7.87), 3.563 (5.60), 3.583 (1.48), 3.609 (0.45), 3.704 (0.54), 3.718 (0.77), 3.732 (0.51), 3.947 (0.43), 3.963 (0.51), 4.344 (0.51), 4.379 (0.65), 5.759 (6.05), 6.856 (0.71), 6.875 (0.45), 6.946 (1.22), 6.965 (2.44), 6.985 (1.39), 7.093 (2.07), 7.113 (1.62), 7.144 (0.63), 7.215 (0.85), 7.234 (1.19), 7.268 (0.88), 7.286 (1.53), 7.305 (0.94), 7.324 (1.59), 7.343 (1.79), 7.362 (1.22), 7.375 (1.19), 7.395 (1.82), 7.416 (1.93), 7.427 (1.59), 7.434 (2.22), 7.441 (1.45), 7.452 (1.28), 7.468 (0.77), 7.500 (0.88), 7.503 (0.88), 7.511 (0.60), 7.519 (2.07), 7.522 (1.76), 7.536 (1.62), 7.541 (1.51), 7.544 (1.45), 7.549 (1.42), 7.563 (1.39), 7.568 (1.53), 7.575 (0.65), 7.581 (0.68), 7.587 (0.71), 7.599 (0.65), 7.622 (0.57), 7.650 (1.51), 7.692 (0.91), 7.696 (1.05), 7.711 (2.19), 7.716 (2.33), 7.730 (1.17), 7.734 (1.14).
Intermediate 127
ethyl (4-{cyano[2-(difluoromethoxy)phenyl]methyl}-1-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl)acetate (mixture of stereoisomers)
Figure imgf000322_0001
Using an analogous method described as intermediate 46: intermediate 112 (500 mg, 1.30 mmol) and [2-(difluoromethoxy)phenyl]acetonitrile (380 mI, 2.6 mmol) gave the titled compound (475 mg, 58%) after purification by silica chromatography (Hexane:EtOAc).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.470 (0.48), 0.481 (0.45), 0.936 (0.61), 0.971 (0.69), 1.006 (0.45), 1.084 (0.74), 1.112 (1.87), 1.130 (3.83), 1.148 (2.03), 1.154 (7.92), 1.163 (1.85), 1.172(16.00), 1.180 (5.78), 1.190 (8.16), 1.197 (9.56), 1.214(4.01), 1.259 (0.42), 1.439 (0.45), 1.460 (0.66), 1.471 (0.71 ), 1.493 (0.45), 1.681 (0.53), 1.725 (0.77), 1.759 (0.63), 1.988 (15.60), 2.318 (0.48), 2.322 (1.06), 2.327 (1.48), 2.332 (1.08), 2.336 (0.45), 2.442 (1.00), 2.457 (0.79),
2.518 (5.94), 2.523 (4.01), 2.539 (0.69), 2.660 (0.69), 2.664 (1.35), 2.669 (1.69), 2.673 (1.24),
2.678 (0.53), 2.819 (0.69), 2.858 (0.58), 2.893 (0.71), 2.917 (0.45), 2.932 (0.71), 2.950 (0.95),
2.983 (0.92), 3.105 (0.48), 3.135 (0.77), 3.167 (0.45), 3.237 (0.58), 3.367 (1.69), 3.469 (1.90),
3.512 (0.71), 3.551 (1.08), 3.575 (6.97), 3.582 (6.23), 3.990 (0.69), 3.996 (0.84), 4.000 (1.40),
4.008 (0.79), 4.017 (4.15), 4.032 (2.06), 4.035 (4.75), 4.041 (0.90), 4.050 (4.88), 4.053 (2.69),
4.059 (1.82), 4.067 (4.94), 4.077 (1.74), 4.084 (2.30), 4.094 (0.79), 4.102 (0.58), 4.259 (0.45),
4.293 (0.42), 4.352 (0.50), 4.387 (0.48), 4.640 (2.51), 4.708 (1.24), 4.834 (1.19), 4.843 (1.32),
6.883 (1.06), 7.034 (0.95), 7.054 (2.24), 7.060 (1.82), 7.066 (2.46), 7.073 (1.58), 7.090 (1.06),
7.094 (1.11), 7.105 (1.14), 7.109 (1.29), 7.113 (1.16), 7.159 (2.14), 7.179 (1.58), 7.220 (0.53),
7.237 (1.56), 7.244 (3.12), 7.254 (4.44), 7.275 (2.40), 7.288 (2.01), 7.295 (2.27), 7.314 (3.64),
7.329 (2.19), 7.332 (2.17), 7.348 (1.37), 7.361 (3.38), 7.377 (2.17), 7.404 (1.11), 7.427 (1.85),
7.433 (2.17), 7.438 (3.04), 7.446 (1.95), 7.450 (1.56), 7.455 (1.50), 7.471 (1.32), 7.476 (0.87), 7.490 (1.00), 7.508 (1.40), 7.527 (0.98), 7.529 (1.24), 7.533 (1.14), 7.539 (0.77), 7.554 (1.19), 7.564 (0.95), 7.571 (1.06), 7.580 (0.71), 7.585 (0.95), 7.591 (0.69), 7.601 (0.55), 7.608 (0.53).
Intermediate 128
5-[2-(difluoromethoxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000323_0001
Using an analogous method described as intermediate 47: intermediate 127 (475 mg, 835 mihoI) gave the titled compound (320 mg, 69%) after purification by preparative HPLC (Method 6).
1H-NMR (500 MHz, DMSO-d6) d [ppm]: -0.235 (0.73), -0.218 (1.24), -0.208 (1.20), -0.190
(0.73), 0.376 (0.90), 0.638 (1.33), 0.664 (1.24), 0.734 (1.11), 0.758 (0.98), 0.907 (0.60), 0.925 (1.16), 0.935 (1.03), 0.952 (0.68), 1.136 (1.16), 1.316 (1.11), 1.344 (0.81), 1.391 (1.37), 1.425 (2.70), 1.452 (2.01), 1.492 (0.43), 1.979 (0.98), 1.989 (2.10), 2.014 (1.20), 2.024 (2.35), 2.049 (0.64), 2.084 (0.77), 2.124 (1.75), 2.159 (2.05), 2.313 (0.77), 2.392 (1.28), 2.426 (1.54), 2.450 (0.68), 2.514 (7.74), 2.518 (7.36), 2.522 (5.90), 2.551 (2.87), 2.586 (2.44), 2.614 (2.99), 2.649 (2.78), 2.815 (0.98), 2.842 (1.75), 2.849 (1.58), 2.864 (1.03), 2.876 (1.11), 2.932 (0.64), 2.982 (1.07), 2.989 (1.11), 3.006 (1.11), 3.028 (0.98), 3.052 (2.44), 3.067 (1.28), 3.077 (1.71), 3.106 (1.54), 3.128 (2.44), 3.139 (1.54), 3.221 (4.62), 3.252 (2.14), 3.262 (1.97), 3.294 (1.84), 3.357 (0.86), 3.425 (3.89), 3.448 (1.63), 3.485 (2.05), 3.510 (2.05), 3.534 (1.16), 3.559 (16.00), 3.568 (13.30), 4.070 (0.43), 4.201 (1.33), 4.225 (0.98) , 4.330 (1.11), 4.358 (1.11), 6.807 (2.22), 6.914 (1.84), 6.926 (2.05), 6.947 (2.44), 6.955 (5.26), 6.962 (5.18), 6.978 (3.04), 7.045 (1.67), 7.074 (0.90), 7.102 (2.52), 7.117 (4.24), 7.131 (3.59), 7.156 (0.90), 7.172 (3.38), 7.189 (6.63), 7.193 (6.63), 7.211 (5.52), 7.221 (2.74), 7.242 (1.97), 7.257 (3.12), 7.274 (2.01), 7.289 (3.98), 7.302 (5.43), 7.307 (4.19), 7.318 (3.34), 7.323 (2.91), 7.340 (4.11), 7.349 (3.68), 7.358 (3.89), 7.374 (1.93), 7.389 (1.84), 7.404 (3.29), 7.421 (2.48), 7.428 (3.98), 7.433 (5.73), 7.439 (4.53), 7.446 (2.82), 7.452 (2.48), 7.455 (1.97), 7.469 (2.82), 7.478 (1.63), 7.483 (1.71), 7.487 (1.67), 7.492 (2.48), 7.507 (1.03), 7.616 (2.44), 7.660 (2.91), 7.689 (1.16). Intermediate 129
ethyl (4-{cyano[2-(trifluoromethoxy)phenyl]methyl}-1-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl)acetate (mixture of stereoisomers)
Figure imgf000324_0001
Using an analogous method described as intermediate 46: intermediate 112 (500 mg, 1.30 mmol) and [2-(trifluoromethoxy)phenyl]acetonitrile (400 mI, 2.6 mmol) gave the titled compound (515 mg, 61%) after purification by silica chromatography (Hexane:EtOAc).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.198 (0.47), 0.433 (0.58), 0.444 (0.58), 0.852 (0.49), 0.917 (0.79), 0.947 (0.76), 1.014 (0.56), 1.025 (0.54), 1.105 (1.82), 1.123 (4.58), 1.140 (2.16), 1.151 (6.85), 1.169 (16.00), 1.188 (13.67), 1.206 (4.74), 1.237 (1.10), 1.419 (0.51), 1.430 (0.51), 1.452 (0.79), 1.464 (0.79), 1.497 (0.76), 1.683 (0.65), 1.717 (0.63), 1.744 (0.94), 1.777 (0.78), 1.987 (4.46), 2.518 (10.30), 2.522 (7.38), 2.577 (0.56), 2.673 (0.76), 2.791 (1.30), 2.833 (1.06), 2.901 (0.41), 2.935 (1.57), 2.955 (0.79), 2.980 (1.37), 3.021 (0.69), 3.102 (0.56), 3.133
(0.90), 3.166 (0.54), 3.240 (0.69), 3.271 (0.47), 3.354 (2.38), 3.472 (1.88), 3.531 (0.85), 3.569
(9.11), 3.582 (7.09), 3.986 (0.78), 3.991 (0.94), 3.999 (0.52), 4.004 (0.94), 4.009 (1.21), 4.017
(1.23), 4.027 (1.86), 4.032 (2.13), 4.034 (1.73), 4.038 (1.37), 4.050 (5.84), 4.057 (2.51), 4.067
(5.65), 4.074 (2.20), 4.085 (1.91), 4.092 (0.69), 4.281 (0.56), 4.316 (0.54), 4.374 (0.67), 4.409
(0.63), 4.710 (4.15), 4.729 (2.51), 4.861 (1.62), 4.874 (1.46), 7.029 (1.19), 7.048 (2.78), 7.067
(1.91), 7.153 (2.72), 7.173 (2.06), 7.211 (1.26), 7.216 (1.30), 7.231 (1.50), 7.235 (1.46), 7.249
(1.59), 7.268 (2.72), 7.292 (1.24), 7.308 (3.34), 7.326 (3.57), 7.347 (1.98), 7.359 (1.17), 7.367
(1.21), 7.378 (0.78), 7.436 (5.03), 7.442 (4.49), 7.455 (4.04), 7.459 (4.04), 7.490 (2.49), 7.506
(1.75), 7.514 (1.23), 7.525 (0.96), 7.535 (2.02), 7.540 (1.53), 7.556 (2.16), 7.576 (1.05), 7.610
(1.19), 7.614 (1.57), 7.634 (1.88), 7.651 (1.86), 7.655 (1.62), 7.672 (1.48), 7.690 (0.74), 7.694
(0.72). Intermediate 130
5-[2-(trifluoromethoxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000325_0001
Using an analogous method described as intermediate 47: intermediate 127 (510 mg, 870 pmol) gave the titled compound (190 mg, 38%) after purification by preparative HPLC (Method 6).
LC-MS (method 4): Rt = 1.27 min; MS (ESIpos): m/z = 545 [M+H]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.282 (0.52), -0.272 (0.68), -0.250 (1.20), -0.238 (1.24), -0.217 (0.72), -0.205 (0.60), 0.285 (0.44), 0.307 (0.80), 0.317 (0.84), 0.339 (0.52), 0.607 (1.44), 0.637 (1.32), 0.710 (1.08), 0.742 (0.92), 0.873 (0.44), 0.883 (0.56), 0.906 (0.96),
0.917 (1.00), 0.939 (0.60), 0.950 (0.48), 1.045 (0.52), 1.074 (0.72), 1.099 (0.52), 1.159 (0.52),
1.275 (0.56), 1.298 (1.04), 1.308 (1.08), 1.340 (0.84), 1.371 (0.56), 1.401 (0.44), 1.440 (1.64),
1.477 (2.73), 1.510 (1.20), 2.025 (2.01), 2.069 (2.29), 2.116 (0.44), 2.159 (0.56), 2.209 (1.44),
2.254 (1.88), 2.323 (0.76), 2.327 (1.04), 2.332 (0.84), 2.351 (0.72), 2.380 (0.48), 2.396 (0.68),
2.408 (0.84), 2.444 (1.40), 2.539 (7.82), 2.547 (2.53), 2.660 (3.21), 2.669 (1.48), 2.703 (2.53),
2.822 (1.08), 2.836 (1.08), 2.856 (1.96), 2.869 (1.96), 2.882 (1.28), 2.897 (1.28), 2.971 (1.04),
2.980 (1.08), 2.988 (0.92), 3.001 (1.20), 3.009 (1.12), 3.029 (1.00), 3.044 (1.76), 3.058 (2.61),
3.071 (2.41), 3.085 (2.73), 3.124 (2.73), 3.152 (2.37), 3.165 (4.69), 3.232 (0.68), 3.262 (1.00),
3.284 (1.36), 3.298 (1.28), 3.373 (1.56), 3.411 (3.05), 3.450 (1.48), 3.487 (1.40), 3.556 (16.00), 3.568 (14.16), 3.597 (1.48), 4.207 (1.24), 4.240 (1.20), 4.345 (1.20), 4.379 (1.12), 6.929 (2.25), 6.948 (5.01), 6.967 (3.21), 7.024 (1.60), 7.043 (1.68), 7.103 (4.73), 7.122 (3.85), 7.208 (4.09),
7.227 (6.10), 7.243 (1.64), 7.290 (2.81), 7.309 (4.61), 7.329 (3.61), 7.350 (3.17), 7.368 (3.69),
7.382 (3.77), 7.397 (1.60), 7.410 (3.45), 7.414 (3.29), 7.428 (7.06), 7.433 (6.02), 7.445 (4.73),
7.452 (6.78), 7.456 (6.82), 7.466 (7.90), 7.475 (4.17), 7.494 (2.93), 7.511 (1.84), 7.530 (2.25),
7.542 (1.68), 7.551 (2.01 ), 7.562 (1.52), 7.573 (0.88), 7.653 (2.53), 7.697 (3.49), 7.725 (1.04). The title compound (176 mg) was separated into its diastereoisomers by preparative chiral HPLC to give diastereoisomer 1 (64 mg, see Intermediate 131 ) and diastereoisomer 2 (56 mg, see Intermediate 132).
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; Column: Reprosil Chiral NR 8m 250x30mm; Eluent A: C02; Eluent B: 2-Propanol + 0.4% Diethylamine (99%); Isocratic: 30%B; Flow: 100 ml/min; Temperature: 400; BPR: 150 bar; UV: 220 nm.
Analytical chiral HPLC method Instrument: Agilent: 1260, Aurora SFC-Module; Column: Reprosil Chiral NR 5m 100x4.6mm; Eluent A: C02; Eluent B: 2-Propanol + 0.2% Diethylamine (99%); Isocratic: 30%B; Flow: 4 ml/min; Temperature: 37.50; BPR: 100bar; UV: 220 nm Intermediate 131 and Intermediate 132
(5R)-5-[2-(trifluoromethoxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one
(5S)-5-[2-(trifluoromethoxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one Intermediate 131
5-[2-(trifluoromethoxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 1 )
For the preparation of the racemic title compound see Intermediate 130.
Analytical Chiral HPLC (method see Intermediate 130): Rt = 1.20 min, e.e. >99%.
Optical rotation (method OR1 ): +25.2°(methanol).
Intermediate 132
5-[2-(trifluoromethoxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 2)
For the preparation of the racemic title compound see Intermediate 130.
Analytical Chiral HPLC (method see Intermediate 130): Rt = 1.90 min, e.e. >99%.
Optical rotation (method OR1 ): +23.4° (methanol). Intermediate 133
ethyl {4-[cyano(2-phenoxyphenyl)methyl]-1-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000327_0001
Using an analogous method described as intermediate 46: intermediate 112 (500 mg, 1.30 mmol) and [2-(trifluoromethoxy)phenyl]acetonitrile (543 mg, 2.6 mmol) gave the titled compound (544 mg, 70%) after purification by silica chromatography (Hexane:EtOAc).
1H-NMR (40C I MHz, DMSC '-d6) d [ppm]: 0.988 (3.09), 1.006 (7.16), 1.023 (4.07), 1.040 (3.01), 1.052 (2.69), 1.057 (2.19), 1.070 (5.32), 1.075 (2.66), 1.087 (2.51), 1.092 (1.31), 1.107 (1.03), 1.154 (4.02), 1.172 (8.06), 1.190 (4.42), 1.234 (0.78), 1.353 (0.43), 1.592 (0.65), 1.603 (0.60), 1.625 (0.50), 1.771 (0.93), 1.805 (0.78), 1.987 (16.00) 2.518 (7.56), 2.522 (4.45), 2.776 (0.78), 2.816 (0.58), 2.937 (0.50), 2.979 (0.68), 3.014 (0.73), 3.034 (0.53), 3.125 (0.40), 3.159 (0.80), 3.188 (0.45), 3.254 (0.53), 3.291 (0.45), 3.416 (1.51), 3.464 (1.41), 3.540 (0.93), 3.582 (6.73), 3.595 (4.37), 3.882 (0.40), 3.887 (0.60), 3.900 (1.23), 3.905 (0.80), 3.910 (1.18), 3.915 (2.21), 3.928 (2.96), 3.932 (2.54), 3.934 (2.16), 3.946 (2.76), 3.953 (1.48), 3.963 (0.90), 3.972 (0.58), 3.999 (1.23), 4.017 (3.54), 4.035 (3.52), 4.053 (1.28), 4.398 (0.53), 4.434 (0.48), 4.735 (0.75), 4.788 (1.46), 4.914 (0.93), 5.758 (2.19), 6.673 (2.11), 6.693 (2.26), 6.723 (1.51), 6.725 (1.63), 6.744 (1.58), 6.746 (1.58), 6.821 (1.08), 6.829 (0.88), 6.839 (1.11), 6.842 (1.11), 6.849 (0.90), 6.901 (1.53), 6.904 (1.78), 6.923 (1.98), 6.925 (1.56), 6.983 (0.88), 6.985 (1.08), 6.987 (1.03), 7.002 (1.00), 7.004 (1.11), 7.007 (1.08), 7.106 (0.85), 7.125 (2.06), 7.143 (1.63), 7.153 (0.90), 7.157 (0.88), 7.176 (2.26), 7.179 (1.96), 7.198 (3.87), 7.201 (3.22), 7.214 (2.59), 7.216 (2.74), 7.226 (2.16), 7.252 (1.88), 7.270 (1.96), 7.288 (1.98), 7.310 (1.53), 7.328 (1.88), 7.349 (1.23), 7.354 (0.85), 7.367 (2.21), 7.382 (3.77), 7.402 (4.62), 7.414 (1.73), 7.422 (4.60), 7.432 (3.04), 7.436 (3.11), 7.441 (3.39), 7.446 (3.14), 7.452 (2.56), 7.459 (2.54), 7.476 (0.93), 7.479 (0.93), 7.528 (0.55), 7.547 (0.50). Intermediate 134
5-(2-phenoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000328_0001
Using an analogous method described as intermediate 47: intermediate 133 (544 mg, 915 pmol) gave the titled compound (290 mg, 53%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.52), 0.013 (0.50), 0.563 (0.57), 0.594 (0.54), 0.746 (0 56), 0.773 (0.71 ), 0.957 (8.42), 0.975 (16.00), 0.992 (8.98), 1 .029 (1 .00), 1 .047 (1 .40), 1 .066 (1 32), 1 .076 (0.96), 1 .087 (0.56), 1 .094 (1 .44), 1.1 12 (0.88), 1 .153 (3.33), 1.367 (0.88), 1 .410 (0 82), 1 .449 (1 .15), 1 .479 (0.42), 1 .838 (0.77), 1.857 (0.46), 1 .884 (0.82), 1.909 (2.26), 1 .996 (0 56), 2.040 (0.65), 2.306 (0.42), 2.350 (0.44), 2.440 (5.99), 2.445 (3.66), 2.483 (0.88), 2.508 (0 40), 2.587 (1 .03), 2.591 (1.32), 2.596 (1 .01 ), 2.619 (1.1 1 ), 2.771 (0.42), 2.803 (0.67), 2.839 (0 75), 2.849 (0.61 ), 2.886 (0.63), 2.909 (0.67), 2.917 (0.75), 2.940 (0.80), 2.977 (1 .00), 3.008 (0 71 ), 3.092 (0.59), 3.122 (0.50), 3.163 (2.37), 3.207 (0.78), 3.319 (1 .24), 3.327 (1 .49), 3.339 (1 38), 3.344 (3.12), 3.357 (3.31 ), 3.362 (3.43), 3.374 (3.58), 3.379 (1 .65), 3.392 (1 .45), 3.456 (0 71 ), 3.484 (7.02), 3.506 (5.30), 3.581 (0.40), 3.921 (0.57), 3.932 (0.44), 3.939 (0.75), 3.949 (0 46), 3.957 (0.61 ), 4.067 (0.52), 4.102 (0.48), 4.267 (1.72), 4.280 (3.22), 4.292 (1 .63), 4.31 1 (0 48), 4.347 (0.46), 5.681 (1.70), 6.546 (2.07), 6.566 (2.20), 6.673 (1 .13), 6.693 (1 .24), 6.763 (1 61 ), 6.770 (1 .67), 6.783 (1.89), 6.789 (1 .80), 6.819 (1.26), 6.840 (1 .59), 6.864 (0.71 ), 6.875 (0 73), 6.894 (0.77), 6.950 (0.86), 6.969 (1 .93), 6.988 (1.44), 7.013 (0.54), 7.030 (1 .51 ), 7.046 (2 28), 7.064 (1 .57), 7.078 (2.39), 7.098 (1 .70), 7.1 16 (1.67), 7.135 (2.62), 7.153 (2.56), 7.173 (2 20), 7.186 (0.80), 7.206 (0.65), 7.224 (2.28), 7.243 (3.37), 7.250 (2.55), 7.269 (3.60), 7.276 (3 10), 7.294 (4.78), 7.313 (3.96), 7.331 (1 .47), 7.354 (1.70), 7.360 (3.04), 7.365 (2.58), 7.377 (2. 01 ), 7.392 (0.88), 7.41 1 (0.90), 7.429 (0.42), 7.507 (0.92), 7.565 (1 .57).
The title compound (200 mg) was separated into its diastereoisomers by preparative chiral HPLC to give diastereoisomer 1 (140 mg, see Intermediate 135) and diastereoisomer 2 (105 mg, see Intermediate 136). Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; Column: Reprosil NR 8pm 250x30mm; Eluent A: C02, Eluent B: Ethanol; Isocratic: 65%B; Flow: 100.0 ml/min Temperature: 400; BPR: 150bar; MWD @ 220nm.
Analytical chiral HPLC method Instrument: Agilent: 1260, Aurora SFC-Module; Column: Reprosil NR 5pm 100x4.6mm; Eluent A: C02, Eluent B: Ethanol; Isocratic: 65%B; Flow: 4.0 ml/min; Temperature: 37.50; BPR: 100bar; MWD @ 220 nm.
Intermediate 135 and Intermediate 136
(5R)-5-(2-phenoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one
(5S)-5-(2-phenoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one
Intermediate 135
5-(2-phenoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 1 )
For the preparation of the racemic title compound see Intermediate 134.
Analytical Chiral HPLC (method see Intermediate 134): Rt = 1.02 min, e.e. >99%.
Optical rotation (method OR1 ): -41 .2° (methanol).
Intermediate 136
5-(2-phenoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 2)
For the preparation of the racemic title compound see Intermediate 134.
Analytical Chiral HPLC (method see Intermediate 134): Rt = 1.89 min, e.e. >99%.
Optical rotation (method OR1 ): +71 0°(methanol).
Intermediate 137
ethyl {4-[cyano(2,3-dihydro-1 -benzofuran-7-yl)methyl]-1 -[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000330_0001
Using an analogous method described as intermediate 46: intermediate 1 12 (500 mg, 1 .30 mmol) and (6-fluoro-2,3-dihydro-1 -benzofuran-7-yl)acetonitrile (460 mg, 2.59 mmol) gave the titled compound (476 mg, 61 %) after purification by silica chromatography (Hexane:EtOAc).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .122 (0.60), 1 .140 (1 .30), 1 .151 (0.84), 1 .154 (4.26), 1 .157 (2.39), 1 .169 (1 .82), 1 .173 (9.04), 1 .175 (4.92), 1.187 (0.96), 1 .190 (4.96), 1.194 (4.28), 1 .21 1 (1 .27), 1 .988 (16.00), 2.518 (3.42), 2.523 (2.45), 2.531 (0.68), 3.186 (0.50), 3.206 (0.78), 3.226 (0.70), 3.247 (0.52), 3.506 (0.92), 3.547 (0.73), 3.578 (2.22), 3.584 (1 .79), 3.990 (0.53),
4.000 (1 .29), 4.008 (0.54), 4.013 (0.59), 4.017 (3.66), 4.027 (0.67), 4.035 (3.59), 4.040 (0.74),
4.045 (1 .22), 4.053 (1 .23), 4.058 (0.74), 4.063 (1 .40), 4.081 (0.80), 4.242 (0.42), 4.399 (0.96),
4.418 (0.43), 4.428 (1 .52), 4.440 (0.64), 4.460 (0.60), 4.490 (0.42), 4.506 (0.46), 4.527 (0.53),
4.631 (0.49), 4.658 (0.49), 6.912 (1.37), 6.924 (1 .38), 6.928 (0.68), 7.161 (0.88), 7.179 (0.71 ),
7.207 (0.82), 7.226 (0.59), 7.294 (0.61 ), 7.312 (0.88), 7.323 (0.54), 7.347 (0.56), 7.366 (0.88),
7.387 (0.74), 7.390 (0.63), 7.394 (0.57), 7.412 (0.52), 7.429 (0.71 ), 7.433 (0.63), 7.441 (0.78),
7.447 (0.54).
Intermediate 138
5-(2,3-dihydro-1 -benzofuran-7-yl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000330_0002
Using an analogous method described as intermediate 47: intermediate 137 (476 mg, 874 mihoI) gave the titled compound (300 mg, 66%) after purification by preparative HPLC (Method 6).
1H-NMR (500 MHz, DMSO-d6) d [ppm]: -0.035 (0.67), -0.026 (0.79), -0.008 (1.42), 0.000 (1.46), 0.018 (0.83), 0.027 (0.67), 0.478 (0.87), 0.497 (0.63), 0.632 (1.54), 0.657 (1.58), 0.982 (0.40), 1.078 (0.63), 1.096 (1.15), 1.104 (1.07), 1.122 (0.67), 1.256 (0.75), 1.314 (0.67), 1.342 (1.26), 1.358 (1.19), 1.424 (1.70), 1.451 (2.13), 1.476 (1.07), 1.851 (0.91), 1.885 (1.03), 1.923 (2.13), 1.957 (2.49), 1.988 (0.79), 2.119 (1.38), 2.154 (1.74), 2.245 (0.51), 2.411 (0.63), 2.508 (6.95), 2.512 (6.64), 2.516 (5.18), 2.613 (3.40), 2.647 (3.16), 2.829 (0.95), 2.850 (1.62), 2.879 (1.58), 2.902 (1.90), 2.927 (1.34), 2.951 (1.78), 2.962 (1.58), 2.970 (2.21), 2.977 (2.05), 3.009 (1.15), 3.031 (2.05), 3.058 (1.86), 3.088 (1.54), 3.112 (1.54), 3.170 (3.36), 3.188 (3.28), 3.210 (2.41), 3.228 (1.58), 3.257 (1.54), 3.271 (1.58), 3.290 (1.50), 3.300 (1.42), 3.395 (1.54), 3.423 (1.54), 3.443 (3.60), 3.488 (1.19), 3.515 (1.34), 3.551 (16.00), 3.566 (11.93), 4.032 (0.55),
4.059 (0.51), 4.153 (1.46), 4.180 (1.07), 4.319 (1.62), 4.336 (1.98), 4.353 (2.77), 4.372 (0.99),
4.400 (1.82), 4.414 (1.78), 4.444 (1.03), 4.453 (0.83), 4.462 (0.95), 4.470 (1.11), 4.488 (1.03),
4.503 (0.95), 4.519 (0.67), 6.646 (1.03), 6.747 (0.71), 6.763 (1.38), 6.772 (1.03), 6.778 (0.87),
6.787 (1.86), 6.802 (1.19), 6.815 (1.94), 6.830 (3.28), 6.845 (2.57), 6.862 (2.13), 6.876 (1.34),
6.966 (2.65), 6.981 (5.18), 6.996 (3.40), 7.097 (5.29), 7.113 (5.41), 7.129 (1.22), 7.143 (2.45),
7.156 (2.17), 7.238 (4.78), 7.253 (5.77), 7.286 (1.11), 7.300 (1.90), 7.315 (0.99), 7.330 (2.17),
7.346 (4.54), 7.361 (4.27), 7.422 (2.77), 7.425 (2.73), 7.436 (5.06), 7.439 (3.44), 7.446 (2.05),
7.449 (1.86), 7.490 (1.58), 7.504 (2.73), 7.520 (1.22), 7.546 (2.57), 7.578 (3.04).
The title compound (104 mg) was separated into its diastereoisomers by preparative chiral HPLC to give diastereoisomer 1 (51 mg, see Intermediate 138) and diastereoisomer 2 (43 mg, see Intermediate 139).
Preparative chiral HPLC method Instrument: Sepiatec: Prep SFC100; Column: Reprosil NR 8pm 250x30mm; Eluent A: C02, Eluent B: Ethanol; Isocratic: 42%B; Flow: 100.0 ml/min Temperature: 40Ό; BPR: 150bar; MWD @ 220nm.
Analytical chiral HPLC method Instrument: Agilent: 1260, Aurora SFC-Module; Column: Reprosil NR 5pm 100x4.6mm; Eluent A: C02, Eluent B: Ethanol; Isocratic: 42%B;
Flow: 4.0 ml/min; Temperature: 37.5Ό; BPR: 100bar; MWD @ 220nm.
Intermediate 139 and Intermediate 140
(5R)-5-(2,3-dihydro-1-benzofuran-7-yl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-
3,9-diazaspiro[5.5]undecan-2-one
(5S)-5-(2,3-dihydro-1-benzofuran-7-yl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-
3,9-diazaspiro[5.5]undecan-2-one Intermediate 139
5-(2,3-dihydro-1 -benzofuran-7-yl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 1 )
For the preparation of the racemic title compound see Intermediate 138.
Analytical Chiral FIPLC (method see Intermediate 138): Rt = 1.54 min, e.e. >99%.
Optical rotation (method OR1 ): -40.6° (methanol).
Intermediate 140
5-(2,3-dihydro-1 -benzofuran-7-yl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 2)
For the preparation of the racemic title compound see Intermediate 138.
Analytical Chiral HPLC (method see Intermediate 138): Rt = 2.66 min, e.e. >99%.
Optical rotation (method OR1 ): +50.4°(methanol).
Intermediate 141
tert-butyl 4-[cyano(2-fluorophenyl)methyl]-4-(2-ethoxy-2-oxoethyl)piperidine-1 -carboxylate (mixture of stereoisomers)
Figure imgf000332_0001
Using an analogous method described as intermediate 46: tert-butyl 4-(2-ethoxy-2- oxoethylidene)piperidine-1 -carboxylate (2.69 g, 10.0 mmol) and (2-fluorophenyl)acetonitrile (1 .3 ml, 10 mmol) gave the titled compound (1 .6 g, 38%) after purification by silica chromatography ( Hexane :EtOAc).
1H-NMR (400 MHz, CHLOROFORM-d) d [ppm]: 1 .249 (0.72), 1 .267 (1.54), 1 .285 (0.76), 1 .295 (2.08), 1 .313 (4.31 ), 1.331 (1 .95), 1 .414 (16.00), 1.472 (1 .03), 1.510 (0.49), 2.054 (2.41 ), 2.661 (1 .56), 4.120 (0.55), 4.138 (0.55), 4.200 (1 .01 ), 4.202 (0.94), 4.218 (1 .00), 4.220 (0.93), 4.932 (0.96), 7.1 12 (0.42), 7.218 (0.57), 7.220 (0.54). Intermediate 142
tert-butyl 7-(2-fluorophenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000333_0001
Using an analogous method described as intermediate 47: intermediate 141 (476 mg, 874 pmol) gave the titled compound (300 mg, 66%) which was used directly in the next step without further purification.
Intermediate 143
5-(2-fluorophenyl)-3,9-diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid (mixture of stereoisomers), salt with hydrochloric acid
Figure imgf000333_0002
Using an analogous method described as intermediate 50: intermediate 142 (1.30 g, 3.59 mmol) gave the titled compound (1.2 g) which was used directly in the next step without further purification.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.144 (0.90), 1.163 (0.56), 1.173 (0.90), 1.182 (1.11),
1.191 (1.81), 1.199 (0.63), 1.209 (0.90), 1.370 (1.11), 1.380 (1.32), 1.403 (2.43), 1.414 (2.50),
1.436 (1.81), 1.448 (1.81), 1.470 (1.67), 1.505 (2.50), 1.595 (4.66), 1.628 (4.59), 1.653 (1.32),
1.663 (1.11), 1.752 (1.25), 1.907 (1.18), 2.271 (3.69), 2.318 (5.29), 2.323 (4.59), 2.327 (4.94),
2.331 (3.34), 2.337 (1.53), 2.518 (16.00), 2.523 (11.69), 2.536 (4.10), 2.580 (2.78), 2.660 (1.39), 2.665 (3.06), 2.669 (4.17), 2.673 (2.92), 2.678 (1.39), 2.974 (3.20), 3.005 (3.90), 3.051
(3.76), 3.082 (4.80), 3.264 (1.74), 3.271 (2.16), 3.277 (2.78), 3.284 (2.99), 3.313 (5.77), 3.336
(2.92), 3.583 (2.30), 4.051 (0.56), 4.063 (0.77), 4.069 (0.56), 4.080 (0.77), 7.207 (3.27), 7.210
(3.97), 7.223 (3.76), 7.230 (6.33), 7.234 (5.01), 7.238 (9.32), 7.257 (10.30), 7.341 (2.23), 7.345
(2.71), 7.354 (2.57), 7.359 (4.45), 7.365 (3.62), 7.378 (4.03), 7.384 (2.23), 7.397 (4.10), 7.414
(4.87), 7.433 (2.43), 7.774 (7.44), 8.122 (1.46), 8.135 (1.39), 8.627 (1.88), 8.648 (1.81). Intermediate 144
(5RS)-5-(2-fluorophenyl)-9-[(2S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000334_0001
Using an analogous method described as intermediate 10: intermediate 143 (100 mg, 335 pmol) was coupled with (2S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (102 mg, 435 pmol) and gave the titled compound (92 mg, 55%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.648 (0.46), 0.683 (0.58), 0.917 (1 .90), 0.931 (15.62), 0.934 (5.38), 0.948 (16.00), 0.952 (2.94), 0.996 (0.44), 1.147 (0.44), 1 .275 (0.42), 1 .374 (0.40),
1 .463 (0.77), 1 .497 (0.71 ), 2.020 (0.69), 2.029 (0.48), 2.062 (0.83), 2.185 (0.44), 2.229 (0.58), 2.322 (0.87), 2.326 (1 .29), 2.331 (1.19), 2.387 (0.58), 2.404 (1.83), 2.422 (1 .79), 2.440 (0.65),
2.464 (0.94), 2.518 (5.02), 2.522 (3.44), 2.627 (1 .06), 2.664 (0.98), 2.669 (1 .85), 2.834 (0.56), 2.865 (1 .00), 2.898 (0.52), 2.924 (0.52), 2.941 (1 .10), 2.957 (1.60), 2.974 (1 .10), 2.990 (0.60), 3.025 (0.67), 3.047 (0.98), 3.061 (0.90), 3.092 (0.62), 3.121 (1.10), 3.142 (0.81 ), 3.149 (0.90), 3.235 (1 .77), 3.308 (1 .13), 3.420 (1.33), 3.470 (0.54), 3.560 (5.65), 3.571 (5.17), 6.943 (1 .06), 6.962 (2.15), 6.981 (1 .38), 7.105 (1.71 ), 7.124 (1 .37), 7.166 (0.81 ), 7.186 (1 .48), 7.190 (1 .48), 7.204 (1 .85), 7.21 1 (1 .83), 7.223 (2.19), 7.236 (1 .65), 7.253 (1.62), 7.280 (1 .58), 7.299 (2.17), 7.319 (1 .54), 7.340 (1 .21 ), 7.345 (1.37), 7.357 (1 .42), 7.364 (1.37), 7.384 (0.90), 7.402 (0.40), 7.426 (1 .46), 7.433 (2.37), 7.440 (2.19), 7.450 (1 .23), 7.473 (0.92), 7.492 (1 .10), 7.510 (0.46), 7.61 1 (0.94), 7.652 (1.10), 7.679 (0.54).
Intermediate 145
tert-butyl 4-[cyano(3-fluorophenyl)methyl]-4-(2-ethoxy-2-oxoethyl)piperidine-1 -carboxylate (mixture of stereoisomers)
Figure imgf000335_0001
Using an analogous method described as intermediate 46: tert-butyl 4-(2-ethoxy-2- oxoethylidene)piperidine-1 -carboxylate (2.00 g, 7.43 mmol) and (3-fluorophenyl)acetonitrile (880 mI, 7.4 mmol) gave the titled compound (1 .2 g, 40%) after purification by silica chromatography ( Hexane :EtOAc).
Intermediate 146
tert-butyl 7-(3-fluorophenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000335_0002
Using an analogous method described as intermediate 47: intermediate 144 (1 .20 g, 2.97 mmol) gave the titled compound (800 mg, 74%) which was used directly in the next step without further purification.
Intermediate 147
5-(3-fluorophenyl)-3,9-diazaspiro[5.5]undecan-2-one (mixture of stereoisomers), salt with hydrochloric acid
Figure imgf000335_0003
Using an analogous method described as intermediate 50: intermediate 146 (520 mg, 1.43 mmol) gave the titled compound (482 mg) which was used directly in the next step without further purification.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.035 (6.86), 1.052(14.75), 1.070 (6.44), 1.114(0.62), 1.144 (0.90), 1.291 (0.62), 1.303 (0.83), 1.326 (1.25), 1.335 (1.25), 1.358 (0.90), 1.370 (0.83),
1.503 (0.76), 1.539 (4.02), 1.562 (1.66), 1.579 (2.15), 1.594 (2.70), 1.616 (0.48), 2.152 (2.84),
2.195 (3.39), 2.336 (1.32), 2.518 (16.00), 2.523 (11.29), 2.589 (4.43), 2.632 (3.74), 2.678 (1.32), 3.000 (1.87), 3.043 (2.29), 3.084 (2.01), 3.097 (2.98), 3.108 (3.32), 3.121 (2.56), 3.247
(1.11), 3.255 (1.25), 3.260 (1.18), 3.268 (1.18), 3.279 (1.59), 3.287 (1.59), 3.300 (1.18), 3.410
(2.84), 3.428 (7.48), 3.445 (7.69), 3.463 (3.19), 3.587 (4.78), 3.620 (2.35), 5.760 (0.62), 7.114
(3.12), 7.135 (5.47), 7.141 (3.46), 7.146 (4.50), 7.152 (2.56), 7.168 (4.78), 7.382 (1.52), 7.400
(1.87), 7.405 (2.01), 7.423 (1.94), 7.440 (0.97), 7.759 (3.32), 8.004 (0.76), 8.512 (0.90).
Intermediate 148
(5RS)-5-(3-fluorophenyl)-9-[(2S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000336_0001
Using an analogous method described as intermediate 10: intermediate 147 (100 mg, 335 mihoI) was coupled with (2S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (102 mg, 435 pmol) and gave the titled compound (92 mg, 55%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.055 (0.51), -0.033 (0.82), -0.022 (0.86), 0.000 (0.51), 0.010 (0.43), 0.265 (0.66), 0.276 (0.62), 0.713 (0.93), 0.735 (1.21), 0.763 (0.74), 0.975 (1.91), 0.989 (15.81), 0.992 (5.33), 1.006 (16.00), 1.010 (2.73), 1.026 (0.82), 1.049 (0.66), 1.060 (0.62), 1.255 (0.51), 1.290 (0.55), 1.314 (0.82), 1.339 (1.25), 1.370 (0.51), 1.383 (0.51),
1.476 (1.79), 1.510 (1.56), 1.815 (0.51), 1.944 (0.62), 1.989 (0.82), 2.016 (1.44), 2.060 (1.67),
2.159 (1.25), 2.203 (1.56), 2.225 (0.78), 2.272 (1.17), 2.316 (0.82), 2.394 (0.74), 2.445 (0.55),
2.462 (1.71), 2.480 (1.71), 2.498 (0.58), 2.523 (2.84), 2.576 (9.03), 2.580 (6.03), 2.629 (2.45),
2.643 (0.58), 2.672 (1.99), 2.736 (0.74), 2.815 (0.74), 2.828 (0.93), 2.842 (0.97), 2.856 (0.90),
2.886 (0.62), 2.897 (1.17), 2.911 (1.64), 2.920 (1.83), 2.935 (1.79), 2.946 (0.82), 2.963 (0.58),
2.974 (0.66), 2.982 (0.43), 2.999 (0.93), 3.015 (1.21), 3.032 (0.90), 3.106 (1.09), 3.123 (1.48), 3.136 (2.80), 3.154 (1.60), 3.168 (2.65), 3.197 (0.93), 3.204 (1.28), 3.210 (1.21), 3.354 (0.93),
3.409 (4.40), 3.423 (1.05), 3.437 (0.74), 3.458 (0.82), 3.477 (1.40), 3.519 (0.93), 3.548 (3.35),
3.577 (1.32), 3.623 (10.39), 3.631 (9.23), 3.657 (1.13), 4.252 (0.70), 4.286 (0.66), 4.373 (0.74),
4.408 (0.70), 6.780 (1.05), 6.805 (1.01), 6.859 (1.48), 6.878 (1.56), 6.956 (1.09), 6.981 (2.61), 7.000 (1.64), 7.064 (1.64), 7.084 (3.70), 7.102 (2.61), 7.146 (2.92), 7.167 (2.26), 7.182 (0.97), 7.199 (3.97), 7.220 (3.58), 7.236 (0.78), 7.242 (0.74), 7.254 (0.70), 7.260 (0.82), 7.267 (1.67), 7.282 (4.05), 7.286 (3.43), 7.301 (4.36), 7.357 (2.76), 7.376 (4.09), 7.396 (2.53), 7.411 (1.95), 7.422 (3.35), 7.431 (2.61), 7.441 (3.15), 7.461 (2.65), 7.481 (3.23), 7.486 (2.02), 7.498 (4.24), 7.504 (2.73), 7.515 (1.60), 7.523 (1.75), 7.541 (2.10), 7.560 (0.90), 7.655 (1.67), 7.704 (2.14), 7.714(1.99).
Intermediate 149
ethyl {4-[cyano(2-fluoro-3-methylphenyl)methyl]-1-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000337_0001
Using an analogous method described as intermediate 46: intermediate 112 (500 mg, 1.30 mmol) and (2-fluoro-3-methylphenyl)acetonitrile (387 mg, 2.59 mmol) gave the titled compound (410 mg, 53%) after purification by silica chromatography (Hexane:EtOAc).
LC-MS (Method 2): Rt = 1.49 min; MS (ESIpos): m/z = 535 [M+H]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.031 (0.73), 0.477 (0.70), 0.497 (0.39), 0.835 (0.52), 0.853 (0.67), 0.976 (1.03), 1.010 (1.00), 1.117 (2.76), 1.135 (4.97), 1.147 (3.58), 1.156 (7.94), 1.164 (6.24), 1.174 (16.00), 1.182 (4.52), 1.188 (12.09), 1.206 (5.27), 1.237 (1.58), 1.338 (1.27), 1.430 (0.61), 1.452 (1.03), 1.461 (1.18), 1.496 (1.12), 1.703 (0.82), 1.747 (1.39), 1.783 (1.27), 1.907 (0.45), 1.988 (9.94), 2.233 (3.79), 2.250 (14.58), 2.327 (1.94), 2.332 (1.55), 2.355 (0.55), 2.376 (0.91), 2.394 (1.00), 2.438 (1.88), 2.551 (5.52), 2.665 (1.64), 2.669 (2.09), 2.674 (1.61), 2.687 (1.76), 2.728 (1.39), 2.826 (1.45), 2.866 (1.18), 2.929 (0.52), 2.959 (0.88), 2.986 (0.97), 3.015 (1.09), 3.046 (0.64), 3.121 (0.61), 3.154 (1.12), 3.185 (0.76), 3.237 (0.97), 3.266 (0.85), 3.476 (3.21 ), 3.501 (1.52), 3.536 (4.42), 3.577 (11.21 ), 3.586 (9.09), 3.979 (0.88), 3.996 (1.85), 4.014 (3.21), 4.017 (3.21), 4.031 (3.21), 4.036 (4.55), 4.053 (6.15), 4.071 (5.21), 4.089 (1.97), 4.278 (0.67), 4.312 (0.70), 4.347 (0.88), 4.381 (0.85), 4.590 (2.97), 4.607 (4.58), 4.814 (1.64), 4.832 (1.67), 6.938 (0.61), 6.956 (1.24), 6.972 (0.76), 7.095 (2.15), 7.114 (5.15), 7.133 (4.00), 7.150 (1.39), 7.159 (1.36), 7.169 (1.12), 7.186 (3.97), 7.203 (3.48), 7.217 (3.79), 7.236
(1.85), 7.275 (2.58), 7.293 (4.00), 7.316 (4.64), 7.334 (6.21), 7.353 (2.73), 7.383 (3.27), 7.406
(1.76), 7.430 (3.97), 7.442 (4.15), 7.448 (3.61), 7.458 (1.79), 7.475 (1.33), 7.494 (1.70), 7.511
(0.79).
Intermediate 150
5-(2-fluoro-3-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000338_0001
Using an analogous method described as intermediate 47: intermediate 149 (405 mg, 758 mihoI) gave the titled compound (225 mg, 57%) after purification by preparative FIPLC (Method 6).
LC-MS (method 4): Rt = 1.23 min; MS (ESIpos): m/z = 493 [M+FI]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.075 (0.42), -0.065 (0.51), -0.042 (0.93), -0.032 (0.93), -0.009 (0.54), 0.000 (0.47), 0.390 (0.56), 0.715 (1.38), 0.749 (1.35), 1.033 (0.42), 1.056 (0.89), 1.066 (0.91), 1.089 (0.61), 1.099 (0.58), 1.225 (0.79), 1.251 (0.54), 1.336 (0.44), 1.360 (0.91), 1.370 (0.96), 1.394 (0.72), 1.402 (0.72), 1.439 (0.86), 1.536 (1.47), 1.560 (1.24), 2.060 (0.61), 2.078 (1.66), 2.103 (0.77), 2.122 (1.96), 2.172 (0.44), 2.252 (1.21), 2.297 (3.92), 2.319 (16.00), 2.369 (0.61), 2.397 (1.47), 2.400 (1.12), 2.405 (0.75), 2.411 (0.58), 2.440 (0.77), 2.537 (2.01), 2.592 (3.24), 2.597 (2.22), 2.613 (0.75), 2.725 (2.66), 2.738 (0.68), 2.743 (0.84), 2.747 (0.63), 2.768 (2.36), 2.897 (1.21), 2.928 (2.29), 2.960 (1.26), 3.002 (0.47), 3.019 (0.40), 3.037 (0.65), 3.068 (1.00), 3.077 (0.93), 3.099 (1.56), 3.105 (1.59), 3.139 (2.19), 3.172 (2.54), 3.200 (1.91), 3.210 (1.56), 3.321 (3.78), 3.348 (1.24), 3.369 (1.54), 3.495 (2.78), 3.509 (1.54), 3.544 (1.24), 3.631 (13.76), 3.644 (10.57), 4.285 (0.79), 4.318 (0.75), 4.422 (0.98), 4.456 (0.93), 6.811 (0.68), 7.016 (1.94), 7.035 (4.34), 7.054 (2.80), 7.116 (0.91), 7.139 (1.21), 7.165 (3.94), 7.185 (3.41), 7.192 (2.85), 7.213 (3.27), 7.226 (2.71), 7.244 (1.73), 7.263 (1.89), 7.283 (4.55), 7.303 (6.32), 7.320 (1.45), 7.363 (1.84), 7.382 (3.52), 7.401 (2.52), 7.415 (2.12), 7.425 (1.82), 7.434 (1.73), 7.501 (2.38), 7.508 (4.45), 7.515 (3.36), 7.519 (2.01), 7.524 (1.87), 7.546 (1.07), 7.565 (1.63), 7.583 (0.70), 7.674 (2.29), 7.725 (2.89), 7.741 (1.07). Intermediate 151
[2-(benzylamino)phenyl]acetonitrile
Figure imgf000339_0001
To (2-aminophenyl)acetonitrile (10 g, 75.7 mmol) in DMF (100 ml) was added benzyl bromide (12.9 g, 75.7 mmol) and potassium carbonate (16.6 g, 1 13.5 mmol) at RT. The reaction was stirred at RT overnight. Reaction was filtered and the solvent was removed. The resulting mixture was extracted with EtOAc and washed with water and sat. sodium chloride (aq). The organic layer was dried, then solvent was removed. The mixture was chromatographed on silica gel (Hexand:EtOAc) and gave the titled compound (9.94g, 59%). Intermediate 152
{2-[benzyl(methyl)amino]phenyl}acetonitrile
Figure imgf000339_0002
The mixture of [2-(benzylamino)phenyl]acetonitrile (9.90 g, 44.5 mmol), formaldehyde (5.0 ml, 37 % purity, 67 mmol), sodium triacetoxyborohydride (18.9 g, 89.1 mmol) in acetic acid (7.6 ml) and DMF (99 ml) was stirred overnight at RT. The reaction was concentrated and the mixture was partitioned between EtOAc and water. The organic layer was washed by sat. sodium chloride (aq), dried and concentrated. The titled compound (7.85 g, 75%) was obtained after purification by silica chromatography (Hexane:EtOAc). Intermediate 153
ethyl {4-[(RS)-{2-[benzyl(methyl)amino]phenyl}(cyano)methyl]-1 -[(2R)-3,3,3-trifluoro-2- methoxy-2-phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000340_0001
To a solution of Intermediate 1 12 (8.52 g, 22.1 mmol) and {2-
[benzyl(methyl)amino]phenyl}acetonitrile (7.84 g, 33.2 mmol) in THF (81 ml) at OO under Argon was added potassium tert-butoxide (27 ml, 1 .0 M in tert-butanol, 27 mmol) dropwise over 45 mins. The reaction was poured onto ice-water and extracted with EtOAc. The combined organics were washed with sat. sodium chloride (aq) and filtered through an hydrophobic filter and concentrated under reduced pressure. The titled compound (9.13 g, 53%) was obtained after purification by silica chromatography (Hexane: EtOAc).
Intermediate 154 and Intermediate 155
(5R)-5-{2-[benzyl(methyl)amino]phenyl}-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-
3,9-diazaspiro[5.5]undecan-2-one
(5S)-5-{2-[benzyl(methyl)amino]phenyl}-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]- 3,9-diazaspiro[5.5]undecan-2-one
Intermediate 154
5-{2-[benzyl(methyl)amino]phenyl}-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 1)
Figure imgf000341_0001
Using an analogous method described as intermediate 47: intermediate 153 (9.10 g, 14.6 mmol) gave Intermediate 154 (2.03g, 23%) and Intermediate 155 (2.93 g, 33%) after silica chromatography (DCM:EtOH).
Optical rotation (method OR1): +16.7°(methanol).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.008 (0.41), 0.000 (16.00), 0.008 (0.44), 0.727
(0.46), 0.904 (0.67), 1.038 (2.57), 1.055 (4.80), 1.073 (2.78), 1.491 (0.57), 1.525 (0.43), 1.984
(0.43), 2.068 (0.90), 2.101 (0.70), 2.145 (0.80), 2.371 (6.81), 2.403 (0.62), 2.446 (0.58), 2.467
(3.39), 2.521 (1.36), 2.525 (1.00), 2.540 (0.90), 2.584 (0.73), 2.963 (0.67), 2.995 (0.58), 3.097
(0.61), 3.125 (0.88), 3.154 (0.60), 3.215 (1.96), 3.421 (0.41), 3.425 (1.31), 3.437 (1.35), 3.443
(1.14), 3.455 (1.22), 3.460 (0.40), 3.472 (0.40), 3.548 (0.52), 3.576 (4.55), 3.692 (0.61), 3.726
(0.87), 3.740 (0.47), 3.755 (0.52), 3.764 (0.51), 3.778 (0.45), 3.819 (0.53), 3.866 (0.99), 3.901
(0.70), 3.935 (0.57), 4.345 (0.87), 4.358 (1.70), 4.370 (0.84), 5.761 (1.71), 6.799 (0.82), 6.817
(0.94), 7.118 (0.51), 7.158 (0.46), 7.163 (0.50), 7.179 (0.77), 7.193 (0.50), 7.199 (0.50), 7.234
(1.28), 7.252 (2.84), 7.280 (2.34), 7.290 (6.65), 7.299 (3.93), 7.302 (3.21), 7.309 (2.75), 7.320
(1.31), 7.323 (1.53), 7.330 (1.77), 7.337 (2.82), 7.342 (2.39), 7.358 (2.62), 7.363 (1.05), 7.366
(1.02), 7.375 (1.83), 7.394 (0.90), 7.432 (1.90), 7.439 (1.58), 7.446 (1.52), 7.449 (1.44), 7.464
(1.14), 7.482 (0.48), 7.543 (1.07), 7.619 (0.58). Intermediate 155
5-{2-[benzyl(methyl)amino]phenyl}-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 2)
Figure imgf000342_0001
For the preparation and separation of the diastereoisomeris title compound see Intermediate 154.
Optical rotation (method OR1): +44.6°(methanol).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.155 (0.52), -0.144 (0.52), -0.008 (0.47), 0.000 (16.00), 0.008 (0.48), 0.699 (0.58), 0.731 (0.54), 1.038 (3.32), 1.055 (6.96), 1.073 (3.57), 1.435 (0.47), 1.465 (1.18), 1.910 (0.84), 1.953 (0.91), 2.067 (0.49), 2.208 (8.88), 2.482 (2.04), 2.520
(1.80), 2.525 (1.17), 2.704 (1.17), 2.748 (1.40), 2.778 (0.41), 2.840 (0.49), 3.035 (0.64), 3.378
(1.62), 3.407 (1.40), 3.420 (1.15), 3.424 (2.11), 3.437 (2.12), 3.442 (1.92), 3.455 (1.85), 3.460
(0.65), 3.472 (0.63), 3.546 (6.27), 3.574 (1.34), 3.616 (0.60), 3.629 (0.66), 3.646 (0.52), 3.659
(0.45), 3.804 (1.42), 3.838 (0.99), 4.346 (1.42), 4.359 (2.66), 4.371 (1.25), 4.389 (0.46), 5.761
(1.01), 6.886 (1.00), 6.906 (2.18), 6.925 (1.36), 7.069 (1.96), 7.089 (1.63), 7.165 (1.98), 7.183
(2.90), 7.186 (2.91), 7.205 (1.88), 7.219 (2.94), 7.227 (2.18), 7.232 (1.51), 7.245 (1.49), 7.267
(0.72), 7.281 (2.46), 7.299 (2.85), 7.317 (1.28), 7.329 (0.85), 7.347 (0.76), 7.377 (0.80), 7.395
(1.72), 7.417 (1.03), 7.423 (1.72), 7.430 (1.09), 7.437 (1.37), 7.453 (0.40), 7.576 (1.17), 7.582
(1.20).
Intermediate 156 and Intermediate 157
(2R)-1-[(7R)-7-{2-[benzyl(methyl)amino]phenyl}-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3- trifluoro-2-methoxy-2-phenylpropan-1-one
(2R)-1-[(7S)-7-{2-[benzyl(methyl)amino]phenyl}-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3- trifluoro-2-methoxy-2-phenylpropan-1-one Intermediate 156
(2R)-1 -[7-{2-[benzyl(methyl)amino]phenyl}-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (Stereoisomer 1 )
Figure imgf000343_0001
Using an analogous method described as intermediate 47: intermediate 154 (2.00 g, 3.45 mmol) gave the titled compound (646 mg, 33%) after purification by Biotage NH-Phase (Hexane:EtOAc, then DCM:EtOH) and purified again by silica chromatography (DCM:EtOH).
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.008 (0.45), 0.000 (16.00), 0.008 (0.45), 0.801
(0.79), 0.818 (0.85), 0.824 (0.86), 0.843 (0.42), 0.889 (0.46), 0.907 (0.92), 0.925 (0.50), 1 .038 (7.87), 1 .055 (12.93), 1.073 (8.21 ), 1 .192 (0.47), 1.233 (0.71 ), 1.258 (0.53), 2.329 (0.46), 2.376 (0.49), 2.414 (5.36), 2.433 (3.19), 2.521 (1 .47), 2.525 (1.02), 2.662 (0.54), 2.667 (0.64), 2.671
(0.60), 2.676 (0.41 ), 2.728 (0.47), 2.748 (1 .00), 2.755 (1.06), 2.787 (0.61 ), 2.912 (0.42), 2.941
(0.41 ), 3.035 (0.44), 3.087 (1 .55), 3.409 (0.57), 3.420 (0.85), 3.426 (1 .53), 3.437 (1.62), 3.443
(1 .74), 3.455 (1 .70), 3.472 (0.94), 3.555 (3.87), 3.729 (0.42), 3.762 (0.72), 3.877 (0.93), 3.91 1
(0.69), 3.919 (0.56), 4.082 (0.44), 4.1 13 (0.41 ), 4.347 (0.57), 4.360 (1 .01 ), 4.372 (0.54), 6.674
(0.43), 6.692 (0.47), 7.061 (0.65), 7.065 (0.62), 7.074 (0.47), 7.080 (0.83), 7.132 (0.95), 7.151
(1 .70), 7.191 (1 .68), 7.210 (1 .99), 7.230 (0.87), 7.260 (1.47), 7.268 (0.92), 7.272 (0.88), 7.281
(2.18), 7.286 (2.00), 7.293 (2.67), 7.308 (3.93), 7.318 (2.50), 7.329 (0.78), 7.336 (0.69), 7.351
(5.42), 7.357 (1 .94), 7.367 (1 .74), 7.424 (1 .46), 7.431 (1.27), 7.440 (1 .09), 7.446 (0.54), 7.449
(0.68), 7.468 (0.94), 7.486 (0.42). Intermediate 157
(2R)-1-[7-{2-[benzyl(methyl)amino]phenyl}-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1-one (Stereoisomer 2)
Figure imgf000344_0001
Using an analogous method described as intermediate 47: intermediate 155 (87 mg, 150 pmol) gave the titled compound (29 mg, 32%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.011 (0.51), 0.033 (0.87), 0.045 (0.93), 0.066 (0.56), 0.078 (0.45), 0.616 (0.99), 0.647 (0.87), 1.023 (0.62), 1.057 (0.42), 1.163 (0.56), 1.207 (1.24), 1.942 (1.10), 1.976 (0.99), 2.110 (16.00), 2.129 (1.41), 2.163 (1.13), 2.241 (0.93), 2.265 (0.96), 2.272 (0.93), 2.307 (1.27), 2.312 (0.65), 2.408 (3.10), 2.493 (8.14), 2.498 (5.49), 2.515 (0.70),
2.648 (1.38), 2.653 (0.79), 2.667 (0.48), 2.726 (2.45), 2.749 (1.44), 2.782 (0.68), 2.880 (0.96),
2.911 (1.69), 2.942 (0.93), 3.006 (0.62), 3.040 (1.13), 3.068 (0.68), 3.215 (2.03), 3.259 (1.30),
3.266 (1.55), 3.346 (0.99), 3.380 (0.76), 3.458 (1.94), 3.491 (2.93), 3.506 (10.62), 3.724 (2.39), 3.757 (1.92), 3.773 (0.42), 3.881 (0.59), 3.915 (0.54), 4.267 (0.87), 4.300 (0.85), 6.848 (1.77), 6.867 (3.86), 6.886 (2.51), 6.997 (3.38), 7.018 (3.75), 7.038 (2.14), 7.111 (1.18), 7.115 (1.30),
7.136 (4.42), 7.153 (5.21), 7.156 (4.42), 7.182 (0.99), 7.194 (2.14), 7.200 (2.99), 7.215 (3.86),
7.218 (3.49), 7.230 (1.72), 7.251 (4.65), 7.269 (5.63), 7.283 (4.06), 7.287 (4.56), 7.299 (2.56),
7.302 (2.45), 7.321 (6.31), 7.334 (2.06), 7.397 (1.92), 7.404 (1.49), 7.413 (0.99).
Intermediate 158
ethyl (4-{cyano[2-(dimethylamino)phenyl]methyl}-1-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl)acetate (mixture of stereoisomers)
Figure imgf000345_0001
Using an analogous method described as intermediate 46: intermediate 112 (500 mg, 1.30 mmol) and [2-(dimethylamino)phenyl]acetonitrile (416 mg, 2.59 mmol; CAS: 1000512-16-2) gave the titled compound (470 mg, 60%) after purification by silica chromatography (Hexane:EtOAc).
LC-MS (Method 2): Rt = 1.52 min; MS (ESIpos): m/z = 546 [M+H]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.918 (0.52), 0.948 (0.47), 1.115 (0.91), 1.132 (2.02), 1.150 (1.64), 1.154 (3.28), 1.157 (3.91), 1.167 (1.65), 1.172 (7.67), 1.175 (9.12), 1.184 (2.90),
1.191 (7.39), 1.202 (1.37), 1.208 (2.33), 1.237 (0.71), 1.519 (0.60), 1.530 (0.55), 1.552 (0.41),
1.693 (0.90), 1.731 (0.49), 1.987 (6.82), 2.295 (16.00), 2.323 (0.79), 2.327 (1.01 ), 2.331 (0.77),
2.402 (1.15), 2.419 (1.17), 2.433 (10.94), 2.468 (1.70), 2.518 (9.76), 2.523 (8.72), 2.610 (0.39), 2.622 (0.80), 2.664 (1.12), 2.669 (1.17), 2.673 (0.85), 2.886 (0.98), 2.923 (0.90), 2.973 (0.55),
3.004 (0.44), 3.118 (0.60), 3.223 (0.49), 3.384 (1.31), 3.474 (0.57), 3.511 (1.57), 3.566 (5.07),
3.586 (3.34), 3.999 (0.80), 4.004 (0.55), 4.017 (2.11), 4.024 (0.77), 4.035 (2.46), 4.042 (1.39),
4.051 (2.14), 4.061 (2.16), 4.068 (2.46), 4.079 (1.91), 4.086 (1.76), 4.096 (0.85), 4.104 (0.50),
4.360 (0.43), 4.393 (0.41), 4.913 (1.83), 4.925 (2.77), 5.042 (0.85), 5.056 (0.74), 7.033 (0.79),
7.053 (1.91), 7.063 (0.98), 7.072 (1.48), 7.082 (0.90), 7.086 (0.82), 7.136 (1.80), 7.155 (1.37),
7.229 (0.76), 7.242 (2.72), 7.245 (2.60), 7.258 (1.23), 7.261 (1.23), 7.281 (0.82), 7.284 (1.04),
7.291 (1.80), 7.303 (1.78), 7.312 (3.83), 7.331 (1.81), 7.354 (0.85), 7.372 (1.06), 7.402 (1.40),
7.420 (2.43), 7.427 (1.69), 7.436 (2.25), 7.441 (2.02), 7.452 (0.82), 7.472 (0.68), 7.479 (0.66),
7.488 (0.61), 7.494 (0.80), 7.498 (0.61), 7.509 (0.50), 7.514 (0.76), 7.517 (0.69), 7.536 (0.80). Intermediate 159
5-[2-(dimethylamino)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000346_0001
Using an analogous method described as intermediate 47: intermediate 158 (460 mg, 843 pmol) gave the titled compound (315 mg, 70%) after purification by preparative HPLC (Method 6).
LC-MS (method 4): Rt = 1 .27 min; MS (ESIpos): m/z = 504 [M+H]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: - 0.196 (0.47), -0.185 (0.47), 0.639 (0.52), 0.670 (0.48), 1 .372 (0.45), 1 .383 (0.48), 1 .448 (0.84), 1 .475 (0.52), 1.881 (0.77), 1 .925 (0.81 ), 2.054 (0.50),
2.098 (0.59), 2.314 (16.00), 2.455 (10.17), 2.518 (1 .02), 2.523 (0.84), 2.536 (5.17), 2.548 (4.06), 2.678 (1 .10), 2.722 (0.96), 2.839 (0.53), 2.844 (0.53), 2.979 (0.73), 3.012 (1.31 ), 3.042 (0.52), 3.196 (1 .70), 3.230 (0.49), 3.367 (0.58), 3.372 (0.57), 3.402 (0.54), 3.448 (1.36), 3.483 (0.40), 3.513 (0.80), 3.545 (5.92), 3.570 (3.55), 3.644 (0.42), 4.333 (0.44), 4.367 (0.41 ), 6.789 (0.57), 6.806 (0.63), 6.912 (0.84), 6.931 (1 .87), 6.950 (1.21 ), 7.064 (1 .91 ), 7.082 (1.49), 7.124 (0.65), 7.177 (1 .12), 7.192 (3.03), 7.206 (1 .77), 7.210 (1.45), 7.228 (2.65), 7.236 (1.70), 7.241 (1 .82), 7.247 (2.15), 7.260 (1 .69), 7.281 (1 .73), 7.342 (0.70), 7.351 (0.78), 7.362 (1.35), 7.365 (1 .23), 7.373 (0.78), 7.381 (2.12), 7.393 (0.60), 7.401 (1.23), 7.408 (0.55), 7.419 (1.04), 7.427 (1 .46), 7.434 (1 .26), 7.444 (0.72), 7.490 (0.52), 7.509 (0.77), 7.599 (0.81 ), 7.641 (1.25), 7.647 (1 .38).
Intermediate 160
{2-[benzyl(ethyl)amino]phenyl}acetonitrile
Figure imgf000347_0001
Using an analogous method described as intermediate 152: intermediate 151 (1.50 g, 6.75 mmol) and acetaldehyde (460 mI, 8.1 mmol) gave the titled compound (1 .56 g, 88%) after purification by silica chromatography (Hexane:EtOAc).
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.889 (6.32), 0.907 (15.27), 0.925 (6.58), 2.518 (1 .09), 2.522 (0.70), 2.865 (1 .77), 2.883 (6.08), 2.900 (6.01 ), 2.918 (1.71 ), 4.003 (16.00), 4.040 (12.17), 7.1 13 (1 .23), 7.122 (1 .14), 7.125 (1 .59), 7.132 (1 .59), 7.135 (1 .70), 7.140 (1 .18), 7.145
(1 .79), 7.154 (1 .73), 7.188 (0.42), 7.192 (0.83), 7.196 (0.53), 7.203 (0.59), 7.209 (2.20), 7.216
(0.85), 7.223 (1 .00), 7.227 (2.03), 7.231 (1 .21 ), 7.262 (2.39), 7.266 (1 .33), 7.277 (2.29), 7.282
(6.54), 7.296 (7.63), 7.298 (12.22), 7.307 (9.30), 7.31 1 (8.95), 7.322 (0.99), 7.328 (2.58), 7.332
(1 .85), 7.379 (2.93), 7.397 (2.33).
Intermediate 161
ethyl {4-[{2-[benzyl(ethyl)amino]phenyl}(cyano)methyl]-1 -[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000347_0002
Using an analogous method described as intermediate 153: intermediate 1 12 (1.57 g, 4.07 mmol) and Intermediate 160 (387 mg, 2.59 mmol) gave the titled compound (1 .38 g) after silica chromatography ( Hexane :EtOAc). Intermediate 162 and Intermediate 163
(5R)-5-{2-[benzyl(ethyl)amino]phenyl}-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-
3,9-diazaspiro[5.5]undecan-2-one
(5S)-5-{2-[benzyl(ethyl)amino]phenyl}-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-
3,9-diazaspiro[5.5]undecan-2-one
Intermediate 162
5-{2-[benzyl(ethyl)amino]phenyl}-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 1 )
Figure imgf000348_0001
Using an analogous method described as intermediate 47: intermediate 161 (1 .37 g, 2.15 mmol) gave Intermediate 162 (230 mg, 17%) and Intermediate 163 (340 mg, 25%) after silica chromatography (DCM:EtOH).
Optical rotation (method OR1 ): +23.1“(methanol).
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.597 (0.69), 0.620 (1 .21 ), 0.651 (0.79), 0.685 (0.69), 0.703 (1 .43), 0.720 (0.69), 0.781 (4.17), 0.798 (10.67), 0.816 (4.91 ), 0.852 (0.84), 0.884 (2.48),
0.902 (5.12), 0.920 (2.43), 0.992 (0.53), 1 .009 (0.58), 1.036 (0.84), 1 .054 (0.79), 1.071 (1 .06),
1 .108 (0.42), 1 .126 (0.79), 1 .130 (0.74), 1 .145 (0.74), 1.148 (0.69), 1 .152 (0.90), 1.159 (1 .16),
1 .182 (0.95), 1 .200 (0.79), 1 .232 (1.90), 1 .338 (0.69), 1.375 (1.1 1 ), 1 .399 (1 .21 ), 1.432 (1 .06),
1 .503 (0.79), 1 .526 (0.84), 1 .953 (0.48), 1 .972 (1 .37), 2.016 (1.58), 2.066 (0.90), 2.081 (2.22),
2.124 (2.43), 2.318 (1 .37), 2.322 (2.48), 2.327 (3.33), 2.332 (2.48), 2.336 (1 .27), 2.349 (0.79),
2.378 (0.42), 2.437 (2.1 1 ), 2.518 (1 1 .93), 2.523 (8.24), 2.618 (2.53), 2.664 (3.80), 2.669 (4.01 ), 2.673 (3.01 ), 2.718 (0.48), 2.781 (4.38), 2.798 (4.38), 2.813 (4.07), 2.829 (2.80), 2.846 (2.43),
2.877 (1 .53), 2.909 (0.84), 3.069 (1.48), 3.095 (2.59), 3.125 (2.43), 3.161 (7.87), 3.224 (0.79),
3.262 (1 .32), 3.288 (1.06), 3.529 (2.38), 3.571 (15.31 ), 3.633 (0.42), 3.781 (2.80), 3.815 (4.33),
3.855 (1 .00), 3.891 (1 .69), 3.91 1 (1.85), 3.947 (1 .16), 3.981 (1.00), 3.993 (0.58), 4.010 (0.95),
4.095 (1 .32), 4.128 (1.16), 4.209 (0.74), 4.242 (0.74), 5.759 (16.00), 6.765 (3.01 ), 6.784 (2.96),
6.927 (0.79), 6.946 (0.58), 7.081 (1.64), 7.100 (2.59), 7.121 (1.37), 7.161 (1 .69), 7.168 (1 .64), 7.176 (2.06), 7.182 (2.53), 7.195 (2.06), 7.202 (2.38), 7.228 (5.91 ), 7.246 (8.82), 7.266 (12.94), 7.278 (12.30), 7.290 (6.28), 7.308 (10.83), 7.327 (15.31 ), 7.347 (9.98), 7.367 (2.38), 7.425 (8.13), 7.431 (6.18), 7.439 (3.64), 7.442 (4.01 ), 7.450 (1.48), 7.459 (0.95), 7.472 (2.64), 7.491 (3.96), 7.509 (4.33), 7.549 (0.42), 7.595 (1 .80).
Intermediate 163
5-{2-[benzyl(ethyl)amino]phenyl}-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 2)
Figure imgf000349_0001
For the preparation and separation of the diastereoisomeris title compound see Intermediate
162.
Optical rotation (method OR1 ): +42.0°(methanol).
1 H-NMR (400 MHz, DMSO-d6) d [ppml: -0.181 (0.67), -0.160 (1 .21 ), -0.148 (1 .18), -0.127
(0.70), 0.591 (1 .06), 0.625 (0.97), 0.686 (4.60), 0.703 (10.22), 0.720 (4.81 ), 0.798 (0.48), 0.815 (0.42), 0.884 (0.79), 0.902 (1 .48), 0.920 (0.73), 1 .036 (0.60), 1 .053 (1 .09), 1 .071 (0.82), 1 .233 (0.70), 1.479 (3.36), 1 .909 (2.39), 1.953 (2.57), 2.018 (0.42), 2.066 (1 .00), 2.323 (1.36), 2.327 (2.00), 2.332 (1 .51 ), 2.405 (0.64), 2.448 (0.79), 2.518 (7.41 ), 2.523 (5.26), 2.552 (0.82), 2.569 (1 .06), 2.583 (1 .42), 2.601 (1 .33), 2.651 (1 .72), 2.665 (3.21 ), 2.669 (4.63), 2.673 (5.47), 2.717 (2.96), 2.779 (0.82), 2.789 (0.85), 2.818 (1 .72), 2.839 (1.45), 2.852 (0.94), 2.972 (0.82), 3.005 (1 .63), 3.036 (0.97), 3.357 (2.45), 3.440 (0.51 ), 3.452 (0.45), 3.529 (16.00), 3.713 (0.85), 3.800 (1 .33), 3.838 (1 .09), 3.890 (0.70), 4.355 (1 .57), 4.387 (1 .30), 5.759 (14.64), 6.908 (2.42), 6.928 (5.32), 6.947 (3.42), 7.080 (5.20), 7.099 (4.36), 7.147 (2.84), 7.165 (3.60), 7.173 (3.18), 7.176 (3.51 ), 7.183 (2.00), 7.195 (4.84), 7.202 (4.57), 7.224 (7.41 ), 7.239 (4.02), 7.257 (6.41 ), 7.276 (6.62), 7.294 (3.12), 7.308 (2.30), 7.326 (3.12), 7.341 (2.69), 7.402 (1 .66), 7.409 (1.66), 7.422 (4.39), 7.428 (3.18), 7.438 (2.15), 7.553 (2.42). Intermediate 164 and Intermediate 165
(2R)-1-[(7R)-7-{2-[benzyl(ethyl)amino]phenyl}-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro- 2-methoxy-2-phenylpropan-1 -one
(2R)-1-[(7S)-7-{2-[benzyl(ethyl)amino]phenyl}-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro- 2-methoxy-2-phenylpropan-1 -one
Intermediate 164
(2R)-1-[7-{2-[benzyl(ethyl)amino]phenyl}-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1-one (Stereoisomer 1)
Figure imgf000350_0001
Using an analogous method described as intermediate 47: intermediate 162 (210 mg, 354 pmol) gave the titled compound (148 mg, 69%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.372 (0.75), 0.394 (1.23), 0.427 (0.75), 0.642 (0.75), 0.659 (1.72), 0.677 (0.81), 0.873 (6.87), 0.891 (6.77), 0.908 (2.68), 0.960 (0.91), 0.995 (1.45),
1.027 (1.18), 1.042 (1.23), 1.080 (1.13), 1.116 (1.99), 1.167 (1.45), 1.194 (0.97), 1.247 (1.93),
1.282 (2.04), 1.314(1.13), 1.352(12.19), 1.401 (1.40), 1.832 (0.75), 1.870(0.64), 1.933 (0.97), 1.968 (1.13), 2.117 (1.77), 2.150 (1.72), 2.181 (1.77), 2.230 (1.18), 2.261 (1.23), 2.322 (2.74), 2.326 (3.60), 2.332 (2.79), 2.365 (0.91 ), 2.518 (11.87), 2.522 (8.16), 2.539 (2.31 ), 2.594 (0.81 ), 2.627 (1.66), 2.660 (2.85), 2.664 (3.54), 2.669 (3.87), 2.673 (3.11), 2.684 (2.58), 2.715 (4.13),
2.744 (2.85), 2.781 (4.67), 2.797 (5.32), 2.813 (3.54), 2.857 (1.93), 2.874 (1.34), 2.900 (1.56),
2.932 (0.81), 2.996 (1.07), 3.026 (1.93), 3.067 (6.01), 3.160 (0.81), 3.191 (0.75), 3.225 (0.64),
3.237 (0.75), 3.445 (3.44), 3.471 (2.95), 3.488 (2.09), 3.508 (2.74), 3.547 (16.00), 3.788 (1.83), 3.824 (2.79), 3.898 (1.02), 3.954 (1.56), 3.992 (1.83), 4.048 (1.40), 4.083 (1.40), 4.135 (0.75),
5.199 (0.64), 6.622 (1.88), 6.641 (2.04), 6.869 (1.18), 6.891 (0.81), 6.910 (0.59), 7.018 (1.56),
7.039 (2.42), 7.047 (2.15), 7.052 (2.20), 7.068 (3.22), 7.087 (2.04), 7.125 (4.30), 7.143 (7.57),
7.160 (2.74), 7.188 (6.82), 7.206 (8.00), 7.227 (5.37), 7.250 (8.48), 7.257 (6.66), 7.266 (7.79),
7.278 (13.21), 7.289 (7.95), 7.303 (5.48), 7.322 (11.87), 7.339 (6.60), 7.357 (1.88), 7.381 (0.75), 7.402 (1.13), 7.418 (7.52), 7.425 (6.23), 7.434 (4.67), 7.455 (2.52), 7.473 (3.87), 7.492 (1.72).
Intermediate 165
(2R)-1-[7-{2-[benzyl(ethyl)amino]phenyl}-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1-one (Stereoisomer 2)
Figure imgf000351_0001
Using an analogous method described as intermediate 47: intermediate 163 (100 mg, 168 pmol) gave the titled compound (67 mg, 65%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.66), 0.022 (1.14), 0.033 (1.14), 0.055 (0.69), 0.571 (1.21 ), 0.606 (1.24), 0.638 (4.77), 0.655 (10.23), 0.673 (4.87), 0.876 (1.21 ), 1.017 (0.52),
1.048 (0.97), 1.151 (0.52), 1.228 (1.24), 1.266 (1.35), 1.275 (1.35), 1.300 (0.90), 1.349 (0.41),
1.423 (0.41), 1.462 (0.48), 1.969 (1.45), 2.001 (1.38), 2.128 (1.80), 2.161 (1.83), 2.201 (0.83),
2.514 (8.57), 2.519 (5.98), 2.536 (1.28), 2.571 (1.35), 2.587 (1.42), 2.602 (1.07), 2.621 (0.79),
2.670 (1.87), 2.729 (2.66), 2.758 (5.11), 2.789 (1.83), 2.851 (1.14), 2.882 (1.59), 2.913 (0.83),
2.982 (0.86), 3.014 (1.62), 3.045 (1.00), 3.234 (3.04), 3.291 (2.07), 3.414 (1.56), 3.504 (16.00), 3.809 (1.69), 3.844 (1.52), 4.284 (1.35), 4.317 (1.28), 6.301 (0.45), 6.562 (0.45), 6.868 (2.28),
6.887 (4.94), 6.906 (3.21), 7.012 (4.87), 7.031 (4.01), 7.068 (2.28), 7.088 (3.01), 7.151 (3.97),
7.168 (6.22), 7.195 (4.49), 7.213 (3.32), 7.222 (2.87), 7.240 (4.87), 7.255 (7.57), 7.273 (7.43),
7.291 (3.08), 7.309 (4.01), 7.315 (3.80), 7.325 (3.32), 7.335 (3.63), 7.353 (1.14), 7.418 (2.76),
7.424 (2.28), 7.434 (1.52). Intermediate 166
ethyl {4-[cyano(3-fluoro-2-methylphenyl)methyl]-1-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000352_0001
Using an analogous method described as intermediate 46: intermediate 112 (500 mg, 1.30 mmol) and (3-fluoro-2-methylphenyl)acetonitrile (387 mg, 2.59 mmol) gave the titled compound (351 mg, 46%) after purification by silica chromatography (Hexane:EtOAc).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.337 (0.57), 0.965 (0.94), 0.995 (0.70), 1.084 (1.11), 1.101 (1.68), 1.112 (2.05), 1.118 (3.57), 1.130 (2.54), 1.136 (1.76), 1.147 (1.44), 1.152 (1.97), 1.154 (3.49), 1.167 (7.55), 1.172 (7.14), 1.179 (4.92), 1.185(16.00), 1.190 (4.39), 1.197 (9.31), 1.203 (8.04), 1.215 (4.10), 1.403 (0.74), 1.440 (0.53), 1.461 (1.03), 1.472 (0.98), 1.494 (0.74),
1.505 (0.53), 1.654 (1.35), 1.687 (1.07), 1.842 (6.81), 1.848 (6.77), 1.886 (0.57), 1.916 (0.70),
1.988 (11.12), 2.120 (4.55), 2.126 (4.55), 2.201 (3.41), 2.207 (3.20), 2.383 (0.82), 2.395 (0.70), 2.425 (1.03), 2.435 (0.90), 2.467 (1.85), 2.518 (10.63), 2.523 (7.18), 2.799 (0.41 ), 2.840 (0.98), 2.879 (0.98), 2.927 (1.44), 2.955 (1.44), 2.988 (0.74), 3.003 (1.23), 3.044 (1.07), 3.076 (0.66),
3.114 (1.76), 3.155 (0.98), 3.223 (0.66), 3.254 (0.62), 3.271 (0.49), 3.304 (1.81), 3.427 (1.72),
3.533 (0.98), 3.563 (10.67), 3.580 (6.77), 3.631 (1.56), 3.962 (0.74), 3.980 (0.74), 3.993 (1.07), 3.999 (1.07), 4.011 (1.07), 4.017 (2.67), 4.025 (1.35), 4.035 (3.16), 4.043 (3.12), 4.053 (3.24),
4.061 (3.24), 4.065 (3.57), 4.069 (4.27), 4.082 (3.49), 4.087 (3.41), 4.100 (1.11), 4.104 (0.90),
4.303 (0.62), 4.349 (0.90), 4.389 (0.74), 4.671 (5.91), 4.681 (2.50), 4.781 (1.27), 4.815 (1.35),
6.808 (1.23), 6.828 (1.31), 7.004 (1.31), 7.023 (3.08), 7.042 (2.13), 7.119 (4.47), 7.138 (3.82),
7.198 (0.57), 7.229 (1.23), 7.248 (3.20), 7.268 (3.20), 7.287 (2.05), 7.322 (0.98), 7.333 (2.05),
7.344 (2.79), 7.351 (3.41), 7.369 (3.12), 7.389 (2.26), 7.408 (1.97), 7.419 (1.27), 7.433 (1.97),
7.441 (2.91 ), 7.447 (2.09), 7.452 (2.30), 7.458 (1.64), 7.511 (0.78), 7.530 (1.27), 7.548 (0.53). Intermediate 167
5-(3-fluoro-2-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000353_0001
Using an analogous method described as intermediate 47: intermediate 166 (351 mg, 657 pmol) gave the titled compound (120 mg, 35%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.379 (0.60), -0.368 (0.75), -0.347 (1.35), - 0.335 (1.35), -0.313 (0.75), -0.302 (0.60), 0.398 (0.67), 0.408 (0.67), 0.429 (0.45), 0.627 (1.42), 0.656 (1.35), 0.710 (0.90), 0.739 (0.75), 0.895 (0.45), 0.917 (0.90), 0.929 (0.90), 0.951 (0.60), 1.249 (0.52), 1.345 (0.45), 1.368 (1.05), 1.376 (1.05), 1.399 (0.75), 1.470 (0.90), 1.505 (2.84), 1.539 (1.57), 1.741 (0.45), 1.748 (0.45), 1.757 (1.50), 1.766 (0.45), 1.774 (0.52), 1.883 (12.34), 1.889 (12.19), 2.086 (1.87), 2.111 (0.67), 2.139 (7.93), 2.145 (7.70), 2.207 (3.14), 2.212 (2.84), 2.228 (2.32), 2.234 (2.24), 2.250 (0.52), 2.269 (1.35), 2.313 (2.02), 2.336 (1.12), 2.518 (10.92), 2.522 (7.63), 2.532 (2.99), 2.539 (4.34), 2.575 (1.64), 2.678 (1.27), 2.686 (3.14), 2.729 (2.84), 2.754 (0.45), 2.787 (1.05), 2.798 (1.12), 2.825 (1.79), 2.858 (1.05), 2.919 (0.75), 2.931 (1.12), 2.941 (1.12), 2.950 (1.05), 2.962 (1.20), 2.971 (0.97), 2.988 (0.90), 3.022 (1.50), 3.052 (1.64), 3.071 (2.39), 3.083 (2.02), 3.101 (2.24), 3.113 (2.24), 3.141 (3.59), 3.159 (1.05), 3.171 (0.75), 3.184 (1.50), 3.195 (1.27), 3.231 (1.20), 3.258 (1.27), 3.285 (0.97), 3.292 (0.97), 3.372 (0.45), 3.394 (2.32), 3.437 (1.35), 3.474 (1.57), 3.504 (0.52), 3.527 (1.64), 3.553 (16.00), 3.571 (9.42), 3.582 (2.09), 3.585 (2.17), 3.599 (1.57), 3.615 (1.12), 4.224 (0.75), 4.258 (0.67), 4.344 (1.27), 4.377 (1.05), 6.590 (1.79), 6.609 (1.87), 6.903 (2.24), 6.922 (4.86), 6.941 (3.07), 7.048 (3.14), 7.075 (5.23), 7.095 (3.89), 7.105 (2.62), 7.129 (2.77), 7.136 (2.24), 7.154 (3.44), 7.173 (2.02), 7.188 (1.87), 7.209 (3.07), 7.231 (4.41), 7.249 (3.89), 7.258 (1.72), 7.264 (1.87), 7.284 (2.17), 7.301 (2.09), 7.323 (4.04), 7.342 (5.01), 7.362 (2.32), 7.423 (2.32), 7.431 (2.39), 7.435 (3.14), 7.440 (2.77), 7.451 (1.12), 7.498 (1.50), 7.516 (2.32), 7.535 (0.97), 7.576 (1.79), 7.627 (2.84), 7.634 (2.69), 7.666 (0.67). Intermediate 168
ethyl {4-[cyano(5-fluoro-2-methylphenyl)methyl]-1-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000354_0001
Using an analogous method described as intermediate 46: intermediate 112 (500 mg, 1.30 mmol) and (5-fluoro-2-methylphenyl)acetonitrile (340 mI, 2.6 mmol) gave the titled compound (290 mg, 38%) after purification by silica chromatography (Hexane:EtOAc).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.248 (0.66), 0.428 (0.51), 0.450 (0.92), 0.461 (0.95), 0.483 (0.55), 0.833 (0.62), 0.852 (0.95), 0.960 (1.83), 0.991 (1.46), 1.084 (1.14), 1.101 (2.31),
1.119 (5.49), 1.130 (1.43), 1.137 (2.53), 1.154 (4.28), 1.158 (7.21), 1.164 (2.75), 1.172 (8.68),
1.176 (16.00), 1.182 (5.97), 1.185 (8.46), 1.190 (5.49), 1.194 (8.35), 1.203 (15.96), 1.220 (7.43), 1.237 (1.87), 1.475 (0.62), 1.495 (1.14), 1.508 (1.03), 1.529 (0.70), 1.685 (1.57), 1.718 (1.24), 1.907 (1.17), 1.965 (10.80), 1.988 (11.72), 2.196 (13.77), 2.275 (6.48), 2.323 (1.57), 2.327 (2.16), 2.331 (1.61), 2.387 (2.12), 2.428 (2.53), 2.463 (2.34), 2.523 (10.40), 2.665 (1.57), 2.669 (2.12), 2.673 (1.50), 2.791 (0.70), 2.841 (0.66), 2.862 (0.73), 2.889 (1.32), 2.927 (1.57),
2.959 (1.43), 2.992 (0.81), 3.033 (2.05), 3.053 (1.35), 3.074 (2.27), 3.095 (1.24), 3.114 (1.28),
3.145 (0.70), 3.200 (0.62), 3.231 (1.21), 3.268 (0.77), 3.483 (2.42), 3.532 (1.14), 3.570 (11.31), 3.585 (11.79), 3.631 (1.28), 3.941 (0.44), 3.960 (1.28), 3.975 (1.28), 3.993 (0.70), 3.999 (1.06), 4.011 (0.88), 4.017 (2.78), 4.030 (2.97), 4.035 (3.30), 4.047 (5.97), 4.058 (3.70), 4.065 (6.88),
4.076 (3.70), 4.082 (4.21), 4.094 (1.32), 4.100 (1.03), 4.109 (0.48), 4.316 (1.03), 4.348 (0.99),
4.408 (0.81), 4.576 (4.10), 4.625 (3.92), 4.700 (1.35), 4.728 (1.21), 6.678 (1.39), 6.685 (1.54),
6.704 (1.43), 6.709 (1.46), 7.028 (2.64), 7.046 (4.54), 7.065 (2.56), 7.124 (0.51), 7.130 (0.62),
7.144 (1.06), 7.151 (1.32), 7.167 (3.95), 7.186 (2.75), 7.205 (0.95), 7.211 (0.95), 7.226 (2.38),
7.233 (2.20), 7.247 (2.12), 7.254 (2.16), 7.270 (3.55), 7.277 (4.61), 7.284 (5.16), 7.291 (4.21),
7.315 (6.00), 7.334 (7.14), 7.354 (4.87), 7.363 (2.56), 7.436 (2.89), 7.442 (3.73), 7.448 (2.67),
7.459 (2.89), 7.478 (2.42), 7.497 (0.92). Intermediate 169
5-(5-fluoro-2-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000355_0001
Using an analogous method described as intermediate 47: intermediate 168 (290 mg, 543 mihoI) gave the titled compound (185 mg, 66%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.321 (0.50), -0.309 (0.60), -0.288 (1.10), -0.277
(1.10), -0.255 (0.65), -0.243 (0.55), 0.373 (0 i.50), 0.395 (0.95), 0.405 (0.95), 0.427 (0.55), 0.643 (1.15), 0.674 (1.10), 0.786 (1.25), 0.816 (1.05), 0.863 (0.55), 0.875 (0.65), 0.897 (1.15), 0.908 (1.20), 0.931 (0.75), 0.941 (0.65), 1.261 (0.55), 1.292 (0.50), 1.340 (0.45), 1.364 (0.90), 1.374 (0.90), 1.397 (0.65), 1.480 (1.30), 1.520 (2.56), 1.553 (1.35), 1.985 (15.65), 2.057 (1.66), 2.074 (0.60), 2.081 (0.70), 2.101 (1.86), 2.125 (0.75), 2.175 (0.45), 2.223 (2.66), 2.235 (16.00), 2.274 (5.47), 2.298 (3.96), 2.332 (2.31), 2.336 (1.35), 2.518 (15.15), 2.522 (9.58), 2.539 (1.05), 2.562 (0.90), 2.599 (2.71), 2.642 (2.31), 2.681 (2.71), 2.725 (2.36), 2.765 (0.55), 2.788 (1.10), 2.822 (1.66), 2.841 (1.45), 2.867 (0.75), 2.929 (0.90), 2.938 (0.90), 2.947 (0.75), 2.959 (1.05), 2.967 (1.00), 2.995 (2.46), 3.012 (1.66), 3.026 (3.11), 3.032 (2.76), 3.062 (0.80), 3.102 (1.00), 3.115 (1.45), 3.142 (4.71), 3.250 (1.61), 3.277 (2.06), 3.306 (1.86), 3.426 (3.26), 3.487 (1.61), 3.516 (2.26), 3.558 (12.34), 3.576 (12.29), 3.635 (0.90), 4.223 (1.00), 4.257 (0.95), 4.362 (1.10), 4.397 (0.95), 6.505 (1.66), 6.511 (1.81), 6.532 (1.71), 6.539 (1.71), 6.907 (2.01), 6.927 (4.46), 6.946 (2.76), 6.962 (0.65), 6.969 (0.45), 6.984 (1.15), 6.991 (0.80), 7.005 (0.65), 7.011 (0.45), 7.027 (1.00), 7.034 (1.15), 7.048 (3.26), 7.055 (3.51), 7.076 (2.51), 7.081 (2.06), 7.107 (5.02), 7.122 (4.71), 7.128 (5.87), 7.142 (1.55), 7.149 (1.61), 7.167 (1.76), 7.186 (2.96), 7.205 (1.40), 7.228 (6.52), 7.249 (8.78), 7.264 (2.96), 7.295 (3.76), 7.313 (6.22), 7.333 (3.66), 7.423 (2.56), 7.440 (5.12), 7.446 (2.46), 7.456 (3.81), 7.473 (1.05), 7.578 (2.36), 7.634 (2.71), 7.675 (0.80). Intermediate 170
ethyl {4-[cyano(2-fluoro-6-methylphenyl)methyl]-1-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000356_0001
Using an analogous method described as intermediate 46: intermediate 112 (500 mg, 1.30 mmol) and (2-fluoro-6-methylphenyl)acetonitrile (387 mg, 2.59 mmol) gave the titled compound (375 mg, 49%) after purification by silica chromatography (Hexane:EtOAc).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.202 (0.56), 0.393 (0.45), 0.852 (0.45), 0.908 (0.52),
1.019 (0.63), 1.052 (0.59), 1.090 (0.87), 1.108 (2.13), 1.130(1.36), 1.154 (8.17), 1.172 (16.00), 1.190 (8.73), 1.195 (6.99), 1.213 (2.86), 1.237 (0.94), 1.286 (0.45), 1.319 (0.70), 1.352 (0.45), 1.722 (0.87), 1.755 (0.73), 1.906 (0.77), 1.932 (0.59), 1.987 (14.43), 2.006 (9.29), 2.112 (0.94), 2.304 (7.13), 2.327 (2.83), 2.331 (3.39), 2.343 (2.27), 2.558 (1.33), 2.668 (1.99), 2.673 (1.54), 2.873 (0.70), 2.906 (0.87), 2.940 (1.08), 2.971 (0.56), 2.993 (0.42), 3.089 (0.45), 3.124 (0.87), 3.152 (2.06), 3.193 (1.78), 3.231 (1.33), 3.398 (1.29), 3.532 (0.91), 3.566 (8.14), 3.578 (6.99), 3.630 (0.80), 3.999 (1.43), 4.017 (4.23), 4.035 (5.03), 4.038 (4.44), 4.056 (3.74), 4.068 (1.68), 4.073 (1.36), 4.080 (1.43), 4.098 (0.66), 4.293 (0.73), 4.335 (0.94), 4.375 (0.63), 4.585 (2.76), 4.670 (2.13), 4.730 (0.49), 4.752 (0.56), 6.961 (1.12), 6.980 (2.45), 6.999 (1.54), 7.136 (3.18), 7.156 (3.63), 7.177 (3.56), 7.196 (3.42), 7.206 (2.72), 7.226 (2.93), 7.241 (1.15), 7.260 (1.61), 7.272 (1.68), 7.291 (2.20), 7.311 (1.19), 7.348 (0.91), 7.389 (0.59), 7.409 (0.94), 7.430 (1.61), 7.443 (2.27), 7.452 (2.10), 7.458 (2.03), 7.472 (1.12), 7.492 (0.59), 7.501 (0.77), 7.520 (1.12), 7.538 (0.49).
Intermediate 171
5-(2-fluoro-6-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000357_0001
Using an analogous method described as intermediate 47: intermediate 168 (365 mg, 683 mihoI) gave the titled compound (205 mg, 58%) after purification by preparative HPLC (Method 6).
LC-MS (method 4): Rt = 1.20 min; MS (ESIpos): m/z = 493 [M+H]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.077 (0.41), -0.065 (0.54), -0.044 (0.95), -0.032 (0.95), -0.011 (0.55), 0.000 (0.43), 0.373 (0.57), 0.781 (0.97), 0.809 (0.88), 0.900 (0.74), 0.932
(0.67), 1.045 (0.41), 1.067 (0.76), 1.079 (0.76), 1.100 (0.45), 1.338 (0.62), 1.370 (0.95), 1.401 (0.47), 1.568 (0.76), 1.596 (0.69), 1.651 (1.17), 1.681 (0.88), 2.150 (16.00), 2.194 (1.48), 2.207 (0.50), 2.237 (1.98), 2.279 (0.43), 2.324 (1.14), 2.367 (1.38), 2.405 (0.62), 2.409 (0.90), 2.424 (12.25), 2.433 (4.11), 2.466 (3.90), 2.487 (0.41) , 2.600 (2.45), 2.605 (1.61), 2.622 (0.98), 2.636 (0.57), 2.680 (2.14), 2.723 (1.55), 2.747 (0.66), 2.756 (2.71), 2.799 (2.05), 2.878 (0.69), 2.886 (0.67), 2.905 (1.14), 2.912 (1.42), 2.920 (1.36), 2.938 (0.85), 2.951 (0.88), 3.070 (0.78), 3.080
(1.35), 3.091 (1.17), 3.101 (1.31), 3.111 (1.90), 3.120 (1.23), 3.141 (2.11), 3.157 (0.90), 3.170 (1.93), 3.200 (0.98), 3.235 (0.71), 3.262 (0.78), 3.281 (2.14), 3.304 (0.69), 3.380 (0.43), 3.489 (1.92), 3.529 (0.85), 3.565 (0.72), 3.648 (12.05) , 3.655 (9.70), 3.691 (0.86), 3.855 (0.93), 3.885 (1.62), 3.914 (0.76), 4.288 (0.62), 4.322 (0.59), 4.388 (0.81), 4.422 (0.78), 7.004 (1.66), 7.024 (3.45), 7.043 (2.33), 7.068 (0.50), 7.085 (0.98), 7.104 (0.97), 7.116 (0.98), 7.136 (0.88), 7.151 (1.16), 7.163 (4.06), 7.182 (5.73), 7.201 (1.23), 7.229 (4.35), 7.247 (4.82), 7.269 (1.59), 7.293 (2.04), 7.313 (3.45), 7.324 (1.40), 7.338 (1.36), 7.345 (3.09), 7.363 (3.52), 7.379 (1.42), 7.384 (1.85), 7.392 (1.28), 7.398 (1.90), 7.412 (1.90), 7.417 (1.55), 7.431 (1.21), 7.445 (0.66), 7.500
(1.36), 7.503 (0.97), 7.512 (2.07), 7.519 (4.40), 7.526 (2.17), 7.536 (1.69), 7.646 (1.33), 7.654 (1.33), 7.693 (2.16), 7.700 (2.12), 7.731 (0.43), 7.739 (0.41). Intermediate 172
ethyl {4-[cyano(2,3-dimethylphenyl)methyl]-1 -[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000358_0001
Using an analogous method described as intermediate 46: intermediate 1 12 (500 mg, 1 .30 mmol) and (2-fluoro-6-methylphenyl)acetonitrile (387 mg, 2.59 mmol) gave the titled compound (479 mg, 63%) after purification by silica chromatography (Hexane:EtOAc).
Intermediate 173
5-(2,3-dimethylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000358_0002
To a solution of intermediate 172 (479 mg, 903 pmol) in methanol (15 ml) at 0Ό was added cobalt(ll) chloride (234 mg, 1 .81 mmol), followed by the portionwise addition of sodium borohydride (171 mg, 4.51 mmol) over 1 h. The reaction was allowed to warm to RT and stirred for 3h. Another portion of sodium borohydride (2eq) was added and stirred at RT for 16h. Another portion of sodium borohydride (2eq) was added and stirred at RT for 1 h. Another portion of sodium borohydride (2eq) was added and stirred at RT for 2h. The reaction was quenched by the addition of water and then the pH was adjusted to pH7 with 2M hydrochloric acid (aq). The methanol was removed under reduced pressure. The aqueous residue was diluted with sat. ammonium chloride (aq) and extracted with EtOAc. The combined organics were washed with sat. sodium chloride (aq) and filtered through an hydrophobic filter and concentrated under reduced pressure. The titled compound (176 mg, 40%) was obtained after purification by preparative HPLC (Method 6) 1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.245 (0.49), -0.234 (0.49), -0.213 (0.99), -0.201 (0.99), -0.180 (0.49), -0.168 (0.49), 0.61 1 (0.99), 0.640 (0.99), 0.704 (0.49), 0.737 (0.49), 0.867 (0.49), 0.885 (0.49), 0.905 (1.15), 0.916 (0.49), 1.210 (0.49), 1 .232 (0.66), 1.415 (0.49),
1 .436 (1 .15), 1 .470 (1.15), 1 .503 (1 .48), 1.533 (0.66), 1.873 (15.67), 2.083 (1.48), 2.099 (0.49),
2.137 (8.74), 2.194 (3.46), 2.213 (3.46), 2.246 (4.29), 2.259 (9.90), 2.292 (1 .32), 2.31 1 (16.00),
2.322 (2.64), 2.327 (2.97), 2.331 (1 .98), 2.336 (0.99), 2.454 (0.66), 2.518 (10.23), 2.523 (6.76),
2.551 (1 .32), 2.594 (0.99), 2.659 (0.99), 2.665 (1 .98), 2.669 (2.80), 2.673 (2.31 ), 2.678 (2.80),
2.723 (2.14), 2.775 (0.49), 2.793 (0.82), 2.808 (0.82), 2.818 (1.15), 2.824 (1 .15), 2.850 (0.66),
2.890 (0.49), 2.902 (0.82), 2.91 1 (0.82), 2.919 (0.82), 2.929 (0.82), 2.941 (0.66), 2.977 (0.66),
3.006 (1 .48), 3.046 (0.82), 3.062 (1.98), 3.099 (0.82), 3.137 (0.49), 3.155 (0.99), 3.168 (0.99),
3.184 (1 .15), 3.197 (0.99), 3.244 (0.82), 3.265 (2.80), 3.287 (0.49), 3.298 (0.66), 3.371 (3.63),
3.413 (1 .15), 3.468 (0.49), 3.495 (0.49), 3.525 (1 .48), 3.542 (10.72), 3.564 (5.94), 3.585 (0.99), 4.191 (0.49), 4.227 (0.49), 4.352 (0.82), 4.384 (0.82), 6.572 (0.66), 6.580 (0.82), 6.595 (0.66),
6.844 (1 .48), 6.863 (3.30), 6.882 (2.14), 7.029 (3.63), 7.041 (3.79), 7.046 (4.62), 7.058 (2.64),
7.095 (1 .81 ), 7.103 (1 .98), 7.1 1 1 (4.12), 7.125 (1 .48), 7.144 (3.63), 7.161 (3.46), 7.163 (3.13),
7.179 (1 .32), 7.198 (3.79), 7.219 (2.80), 7.325 (2.31 ), 7.344 (2.97), 7.364 (1 .48), 7.419 (1 .48),
7.427 (1 .48), 7.432 (2.31 ), 7.436 (1.81 ), 7.439 (1 .65), 7.448 (0.99), 7.500 (0.82), 7.519 (1 .48),
7.537 (1 .48), 7.594 (2.14), 7.601 (1.98), 7.633 (0.49), 8.088 (1.32).
The title compound (176 mg) was separated into its diastereoisomers by preparative chiral HPLC to give diastereoisomer 1 (50 mg, see Intermediate 174) and diastereoisomer 2 (80 mg, see Intermediate 175).
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IA 5m 250x30mm; eluent A: C02; eluent B: methanol; isocratic: 25%B; flow: 100 ml/min; temperature: 40Ό; BPR: 150bar; UV: 220 nm.
Analytical chiral HPLC method Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Chiralpak IA 5m 100x4.6mm; eluent A: C02; eluent B: methanol; isocratic: 25%B; flow: 4 ml/min; temperature: 37.5Ό; BPR: 100bar; UV: 220 n m.
Intermediate 174 and Intermediate 175
(5R)-5-(2,3-dimethylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one
(5S)-5-(2,3-dimethylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one Intermediate 174
5-(2,3-dimethylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 1 )
For the preparation of the racemic title compound see Intermediate 173.
Analytical Chiral HPLC (method see Intermediate 138): Rt = 1.33 min, e.e. 96.8%.
Optical rotation (method OR1 ): +51 .3°(methanol).
Intermediate 175
5-(2,3-dimethylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 2)
For the preparation of the racemic title compound see Intermediate 173.
Analytical Chiral HPLC (method see Intermediate 138): Rt = 2.01 min, e.e. 99%.
Optical rotation (method OR1 ): -25.2° (methanol).
Intermediate 176
ethyl {4-[cyano(3,5-dimethylphenyl)methyl]-1 -[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000360_0001
Using an analogous method described as intermediate 46: intermediate 1 12 (500 mg, 1 .30 mmol) and (3,5-dimethylphenyl)acetonitrile (377 mg, 2.59 mmol) gave the titled compound (426 mg, 62%) after purification by silica chromatography (Hexane:EtOAc). Intermediate 177
5-(3,5-dimethylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000361_0002
Using an analogous method described as intermediate 173: intermediate 168 (426 mg, 803 pmol) gave the titled compound (160 mg, 41%) after purification by preparative HPLC (Method 6).
Intermediate 178
ethyl {4-[(2-chloro-3-fluorophenyl)(cyano)methyl]-1-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000361_0001
Using an analogous method described as intermediate 46: intermediate 112 (500 mg, 1.30 mmol) and (2-chloro-3-fluorophenyl)acetonitrile (440 mg, 2.59 mmol) gave the titled compound (505 mg, 63%) after purification by silica chromatography (Hexane:EtOAc).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.373 (0.47), 0.459 (0.45), 0.470 (0.45), 0.833 (0.43),
0.852 (0.68), 1.005 (0.86), 1.040 (0.68), 1.102 (1.35), 1.112 (1.94), 1.120 (3.79), 1.130 (3.99),
1.134 (1.65), 1.138 (1.78), 1.147 (2.37), 1.152 (3.39), 1.154 (3.27), 1.165 (7.56), 1.169 (2.60),
1.172 (5.06), 1.175 (2.39), 1.183 (16.00), 1.190 (3.75), 1.193 (3.97), 1.201 (9.52), 1.203 (10.61 ), 1.211 (2.10), 1.221 (4.42), 1.237 (1.44), 1.433 (0.45), 1.454 (0.90), 1.466 (0.97), 1.487 (0.70), 1.498 (0.65), 1.671 (1.22), 1.700 (0.83), 1.926 (0.52), 1.952 (0.59), 1.987 (7.02), 2.332
(0.88), 2.418 (0.81), 2.518 (11.31), 2.522 (8.64), 2.673 (0.95), 2.822 (0.41), 2.880 (0.41), 2.915
(0.77), 2.927 (1.15), 2.948 (1.40), 2.986 (1.08), 3.020 (1.26), 3.062 (0.74), 3.103 (0.61), 3.135
(1.56), 3.166 (0.93), 3.241 (0.79), 3.270 (0.74), 3.448 (1.49), 3.571 (10.40), 3.583 (6.63), 3.630 (2.26), 3.976 (0.72), 3.981 (0.65), 3.993 (1.60), 3.999 (1.08), 4.010 (1.49), 4.017 (1.67), 4.024 (1.02), 4.028 (0.61), 4.035 (1.62), 4.041 (1.13), 4.048 (1.06), 4.057 (1.81), 4.066 (2.69), 4.072 (2.89), 4.075 (3.61), 4.083 (4.04), 4.090 (2.53), 4.093 (3.50), 4.101 (3.05), 4.111 (1.47), 4.118 (0.88), 4.128 (0.45), 4.319 (0.56), 4.367 (0.86), 4.407 (0.74), 4.876 (4.56), 4.993 (1.22), 5.017 (1.31), 6.969 (0.74), 6.991 (1.49), 7.012 (2.28), 7.031 (1.56), 7.136 (2.55), 7.154 (2.03), 7.212 (1.02), 7.230 (1.67), 7.249 (0.79), 7.267 (1.15), 7.285 (2.50), 7.306 (2.12), 7.324 (3.29), 7.345 (2.39), 7.364 (1.11), 7.399 (0.54), 7.418 (1.31), 7.426 (1.24), 7.438 (2.08), 7.440 (2.44), 7.445 (2.17), 7.451 (2.66), 7.458 (2.01), 7.485 (1.76), 7.491 (1.65), 7.500 (1.33), 7.518 (1.22), 7.535 (0.86), 7.552 (1.42), 7.556 (1.42), 7.573 (2.32), 7.578 (2.17), 7.588 (1.49), 7.594 (1.49), 7.608 (0.90), 7.630 (1.24), 7.649 (1.65), 7.670 (0.74).
Intermediate 179
5-(2-chloro-3-fluorophenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000362_0001
Using an analogous method described as intermediate 47: intermediate 178 (490 mg, 883 pmol) gave the titled compound (250 mg, 52%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.368 (0.51), -0.356 (0.64), -0.335 (1.15), -0.324 (1.15), -0.301 (0.68), -0.291 (0.54), 0.376 (0.57), 0.386 (0.57), 0.690 (0.78), 0.721 (0.64), 0.759 (1.25), 0.788 (1.18), 0.960 (0.41), 0.981 (0.71), 0.992 (0.71), 1.014 (0.44), 1.290 (0.44),
1.299 (0.47), 1.323 (1.15), 1.331 (1.15), 1.356 (0.78), 1.470 (0.54), 1.500 (1.59), 1.530 (1.08),
1.588 (0.74), 1.623 (0.74), 2.045 (1.65), 2.072 (0.44), 2.089 (1.89), 2.145 (0.51), 2.225 (0.41),
2.265 (1.05), 2.309 (1.42), 2.323 (0.47), 2.327 (0.64), 2.331 (0.54), 2.366 (0.51), 2.409 (0.61),
2.458 (0.81 ), 2.522 (1.76), 2.539 (16.00), 2.549 (1.52), 2.669 (0.51 ), 2.703 (2.53), 2.747 (2.26), 2.812 (1.18), 2.844 (2.30), 2.876 (1.28), 2.980 (0.68), 2.992 (1.01), 3.001 (1.08), 3.010 (1.55),
3.019 (1.25), 3.032 (1.01), 3.044 (1.45), 3.081 (1.15), 3.117 (1.22), 3.138 (0.64), 3.148 (1.08),
3.155 (1.05), 3.168 (0.57), 3.235 (2.33), 3.257 (0.41), 3.271 (1.01), 3.304 (1.86), 3.317 (1.92),
3.381 (1.52), 3.394 (1.28), 3.404 (0.95), 3.418 (0.88), 3.435 (2.16), 3.487 (1.55), 3.521 (1.69),
3.535 (1.96), 3.559 (13.97), 3.571 (9.22), 3.594 (1.42), 3.618 (0.64), 4.248 (0.78), 4.282 (0.74), 4.350 (1.05), 4.384 (0.95), 6.804 (1.22), 6.824 (1.32), 6.937 (1.89), 6.956 (4.15), 6.975 (2.67), 7.115 (3.98), 7.134 (3.34), 7.150 (1.82), 7.169 (2.67), 7.187 (1.18), 7.243 (2.67), 7.265 (3.38), 7.293 (0.68), 7.310 (3.17), 7.329 (4.69), 7.350 (3.11), 7.369 (1.05), 7.376 (1.96), 7.379 (1.82), 7.402 (2.19), 7.417 (1.42), 7.421 (1.82), 7.429 (3.41), 7.436 (3.85), 7.445 (2.40), 7.454 (2.43), 7.474 (3.65), 7.479 (2.97), 7.488 (1.96), 7.496 (3.58), 7.514 (0.95), 7.517 (1.08), 7.659 (1.65), 7.694 (2.80), 7.700 (2.77), 7.727 (0.61).
Intermediate 180
ethyl {4-[cyano(2,5-dimethylphenyl)methyl]-1-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000363_0001
Using an analogous method described as intermediate 46: intermediate 112 (500 mg, 1.30 mmol) and (2,5-dimethylphenyl)acetonitrile (377 mg, 2.59 mmol) gave the titled compound (383 mg, 50%) after purification by silica chromatography (Flexane:EtOAc).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.215 (0.55), 0.576 (0.47), 0.833 (0.40), 0.852 (0.64),
0.982 (0.66), 1.016 (1.60), 1.057 (1.42), 1.106 (1.77), 1.112 (0.91), 1.124 (3.95), 1.130 (1.93), 1.134 (0.91), 1.142 (2.11), 1.147 (1.29), 1.154 (3.62), 1.158 (6.70), 1.172 (7.68), 1.176 (16.00), 1.182 (5.53), 1.190 (5.04), 1.193 (9.74), 1.199 (10.45), 1.210 (2.84), 1.217 (4.81 ), 1.237 (1.37), 1.398 (0.56), 1.526 (0.42), 1.547 (0.84), 1.558 (0.84), 1.580 (0.62), 1.590 (0.53), 1.669 (1.35), 1.703 (1.00), 1.769 (2.13), 1.907 (0.82), 1.927 (9.34), 1.961 (0.66), 1.987 (9.21), 2.158 (10.08), 2.177 (1.77), 2.240 (9.03), 2.256 (1.80), 2.280 (6.53), 2.323 (9.77), 2.367 (11.34), 2.399 (1.42), 2.440 (1.66), 2.458 (1.58), 2.523 (5.55), 2.665 (0.84), 2.669 (1.13), 2.673 (0.82), 2.787 (0.60), 2.826 (0.78), 2.844 (0.62), 2.885 (0.66), 2.927 (1.31), 2.953 (1.47), 2.980 (1.35), 3.022 (1.47), 3.068 (1.29), 3.098 (1.09), 3.131 (0.66), 3.218 (0.76), 3.256 (2.53), 3.423 (2.58), 3.499 (0.86), 3.564 (9.72), 3.581 (7.24), 3.630 (1.00), 3.959 (0.49), 3.976 (1.66), 3.994 (1.82), 3.999 (0.95), 4.011 (1.06), 4.017 (2.28), 4.024 (0.76), 4.035 (3.51), 4.041 (1.84), 4.053 (5.08), 4.059 (3.82), 4.061 (2.95), 4.070 (4.71), 4.077 (3.49), 4.079 (2.73), 4.088 (1.75), 4.094 (1.15), 4.104 (0.47), 4.337 (0.67), 4.372 (1.27), 4.408 (0.76), 4.524 (4.44), 4.541 (2.55), 4.651 (1.62), 4.707 (1.87), 6.825 (2.44), 6.978 (2.24), 6.997 (2.95), 7.016 (2.09), 7.042 (2.20), 7.070 (1.02), 7.087 (1.67), 7.105 (0.62), 7.128 (4.22), 7.142 (8.50), 7.172 (3.93), 7.198 (3.04), 7.215 (1.98), 7.247 (1.49), 7.256 (1.55), 7.266 (2.64), 7.275 (3.20), 7.295 (2.57), 7.313 (2.88), 7.334 (1.78), 7.353 (1.31), 7.364 (0.98), 7.373 (0.95), 7.419 (0.80), 7.432 (2.38), 7.442 (3.37), 7.449 (3.20), 7.459 (1 .91 ), 7.470 (1 .37), 7.488 (1.46), 7.506 (0.64).
Intermediate 181
5-(2,5-dimethylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000364_0001
Using an analogous method described as intermediate 47: intermediate 180 (447 mg, 842 pmol) gave the titled compound (210 mg, 48%) after purification by preparative FIPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.249 (0.52), -0.226 (0.95), -0.214 (0.92), -0.193
(0.54), -0.181 (0.43), 0.518 (0.49), 0.528 (0.52) , 0.602 (0.98), 0.631 (0.90), 0.781 (0.65), 0.810 (0.54), 0.952 (0.62), 0.963 (0.43), 0.975 (0.68), 0.986 (0.79), 1 .463 (0.90), 1 .506 (1.74), 1 .533 (1 .14), 1 .963 (15.46), 2.034 (1 .44), 2.054 (0.46) , 2.075 (1 .60), 2.098 (0.54), 2.140 (0.46), 2.193 (9.34), 2.226 (9.51 ), 2.244 (4.21 ), 2.266 (12.14) , 2.318 (0.87), 2.322 (1 .33), 2.327 (1 .74), 2.332 (1 .36), 2.337 (0.95), 2.350 (16.00), 2.518 (6.14) , 2.523 (4.13), 2.539 (0.92), 2.551 (0.76), 2.571 (1 .58), 2.614 (1 .25), 2.665 (1 .17), 2.669 (1 .87), 2.676 (2.53), 2.720 (1 .98), 2.801 (0.73), 2.833 (1 .1 1 ), 2.857 (0.60), 2.898 (0.52), 2.910 (0.79), 2.919 (0.84), 2.927 (0.52), 2.941 (0.95), 2.948 (1 .01 ), 2.959 (1 .47), 2.973 (0.65), 2.987 (1 .77), 3.000 (1.20), 3.022 (1 .55), 3.051 (1.41 ), 3.068 (1 .06), 3.091 (3.42), 3.105 (1 .01 ), 3.1 18 (0.92), 3.149 (0.62), 3.236 (0.62), 3.261 (0.81 ), 3.288 (0.76), 3.315 (0.92), 3.406 (3.40), 3.445 (0.73), 3.481 (1 .25), 3.51 1 (2.09), 3.552 (10.73), 3.575 (6.52), 4.242 (0.52), 4.276 (0.49), 4.370 (0.81 ), 4.402 (0.76), 6.594 (1 .96), 6.848 (1.68), 6.868 (3.61 ), 6.887 (2.23), 6.933 (0.95), 6.953 (1 .25), 6.975 (0.95), 7.003 (3.59), 7.057 (3.53), 7.077 (7.20), 7.085 (12.03), 7.095 (3.75), 7.125 (1 .63) , 7.143 (2.66), 7.162 (1 .17), 7.242 (1 .47), 7.261 (2.91 ), 7.290 (2.61 ), 7.309 (3.61 ), 7.329 (1 .85), 7.349 (0.90), 7.358 (0.87), 7.419 (2.04), 7.428 (1 .93), 7.438 (3.12), 7.445 (2.25), 7.454 (2.28), 7.472 (1.60), 7.490 (0.65), 7.558 (1.33), 7.599 (2.31 ), 7.642 (0.60). Intermediate 182
(2-methoxy-5-methylphenyl)acetonitrile
Figure imgf000365_0001
A mixture of 2-(chloromethyl)-1 -methoxy-4-methylbenzene (1 .00 g, 5.86 mmol; CAS: 7048-41 - 1 ), sodium iodide (176 mg, 1 .17 mmol) and sodium cyanide (1 .72 g, 35.2 mmol) in DMF:water
(5:1 , 27 ml) were stirred at RT for 2h. The reaction was diluted with water and sat. sodium bicarbonate (aq) and extracted with EtOAc. The combined organics were washed with sat. sodium bicarbonate (aq) and filtered through an hydrophobic filter and concentrated under reduced pressure to give the titled compound (865 mg, 87%) which was used without further purification.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 2.242 (9.95), 3.789 (8.09), 3.794 (16.00), 6.927 (1 .51 ), 6.939 (0.46), 6.950 (1.87), 7.126 (1.98), 7.131 (1 .72), 7.138 (1.15).
Intermediate 183
ethyl {4-[cyano(2-methoxy-5-methylphenyl)methyl]-1 -[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000365_0002
Using an analogous method described as intermediate 46: intermediate 1 12 (2.08 g, 5.40 mmol) and (2-methoxy-5-methylphenyl)acetonitrile (870 mg, 5.40 mmol; Intermediate 182) gave the titled compound (1 .16 g, 37%) after purification by silica chromatography (Hexane:EtOAc).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.571 (0.55), 0.849 (0.91 ), 0.879 (0.80), 1 .084 (0.47), 1 .107 (0.77), 1 .123 (2.54), 1 .130 (1.69), 1 .141 (5.00), 1.154 (3.09), 1 .158 (8.90), 1.164 (3.48), 1 .172 (5.31 ), 1 .176 (14.15), 1 .182 (9.28), 1 .190 (3.21 ), 1 .194 (7.24), 1.199 (12.08), 1 .217 (4.73), 1.232 (0.77), 1 .259 (0.86), 1.353 (0.47), 1 .455 (0.66), 1 .465 (0.72), 1 .487 (0.97), 1 .498 (0.94), 1.520 (0.58), 1.694 (0.91), 1.730 (1.41), 1.767 (0.80), 1.987 (6.02), 2.252 (6.83), 2.300 (9.70), 2.311 (10.06), 2.322 (1.77), 2.326 (1.85), 2.331 (1.35), 2.343 (0.94), 2.375 (0.88), 2.413 (1.85), 2.442 (0.94), 2.464 (1.41), 2.518 (5.83), 2.522 (3.51), 2.634 (1.02), 2.664 (1.38), 2.669
(1.85), 2.673 (1.88), 2.724 (0.61), 2.768 (0.58), 2.948 (0.69), 2.975 (1.02), 3.003 (0.80), 3.029
(0.44), 3.077 (0.53), 3.107 (0.99), 3.139 (0.69), 3.183 (0.53), 3.212 (0.75), 3.243 (0.50), 3.468
(3.26), 3.513 (3.68), 3.535 (16.00), 3.573 (8.79), 3.583 (7.21), 3.648 (15.14), 3.718 (6.44), 3.730 (7.02), 3.794 (0.55), 3.975 (0.64), 3.993 (2.24), 3.999 (0.80), 4.010 (2.40), 4.017 (1.96),
4.027 (1.69), 4.035 (2.93), 4.045 (1.93), 4.054 (3.48), 4.059 (2.96), 4.062 (2.74), 4.072 (4.01),
4.091 (2.46), 4.110 (0.69), 4.118 (0.55), 4.238 (0.58), 4.273 (0.58), 4.328 (0.69), 4.363 (0.66),
4.624 (0.91), 4.812 (0.99), 5.758 (9.98), 6.855 (1.88), 6.859 (1.91), 6.941 (2.38), 6.952 (2.93),
6.960 (4.09), 6.973 (2.82), 6.981 (4.31), 7.103 (0.91), 7.122 (1.96), 7.155 (2.60), 7.176 (0.97),
7.199 (3.56), 7.220 (2.24), 7.240 (1.44), 7.261 (1.22), 7.283 (1.27), 7.301 (3.29), 7.315 (2.93),
7.334 (2.98), 7.354 (1.35), 7.369 (2.16), 7.387 (3.54), 7.405 (1.11), 7.430 (2.87), 7.436 (2.60),
7.440 (2.98), 7.447 (2.76), 7.457 (1.66), 7.473 (1.19), 7.491 (1.52), 7.509 (0.66).
Intermediate 184
1-(2-methoxy-5-methylphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecane-2,4-dione (mixture of stereoisomers)
Figure imgf000366_0001
Using an analogous method described as intermediate 116: intermediate 183 (1.16 g, 2.12 mmol) gave the titled compound (1.06 g, 92%) after work-up.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.454 (0.43), 0.801 (0.78), 0.834 (0.82), 1.042 (0.43),
1.052 (0.47), 1.070 (0.43), 1.154 (0.47), 1.172 (0.74), 1.190 (0.66), 1.232 (1.29), 1.575 (0.74),
1.987 (0.70), 1.993 (0.43), 2.199 (3.67), 2.223 (5.74), 2.281 (10.93), 2.322 (1.40), 2.326 (1.91), 2.332 (1.40), 2.453 (0.70), 2.518 (7.88), 2.522 (5.07), 2.602 (1.05), 2.664 (2.22), 2.669 (2.89),
2.673 (2.38), 2.678 (1.64), 2.793 (0.51), 2.827 (0.86), 2.858 (2.15), 2.901 (1.48), 3.057 (0.62),
3.122 (0.55), 3.159 (11.94), 3.171 (11.71), 3.286 (0.62), 3.371 (1.40), 3.393 (1.17), 3.451 (1.37), 3.486 (3.71), 3.569 (14.87), 3.611 (16.00), 3.919 (0.51), 4.017 (0.43), 4.086 (0.86), 4.100 (2.15), 4.113 (2.07), 4.126 (0.74), 4.213 (1.01), 4.245 (0.98), 5.758 (15.77), 6.698 (1.33), 6.847 (1.44), 6.868 (1.68), 6.919 (0.74), 6.946 (2.42), 6.967 (2.54), 7.053 (0.70), 7.074 (1.99), 7.090 (1.37), 7.133 (1.01), 7.154 (2.81), 7.163 (2.15), 7.171 (2.97), 7.188 (4.57), 7.206 (1.44),
7.297 (2.30), 7.347 (1.72), 7.367 (2.93), 7.371 (2.46), 7.389 (2.69), 7.403 (1.17), 7.407 (1.48),
7.412 (3.08), 7.418 (2.22), 7.426 (1.33), 7.429 (1.33), 7.445 (4.21), 7.451 (2.54), 7.462 (3.12),
7.480 (0.74), 10.967 (0.43).
Intermediate 185
ethyl {4-[cyano(2-fluoro-6-methoxyphenyl)methyl]-1-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000367_0001
Using an analogous method described as intermediate 46: intermediate 112 (500 mg, 1.30 mmol) and (2-fluoro-6-methoxyphenyl)acetonitrile (429 mg, 2.59 mmol) gave the titled compound (340 mg, 45%) after purification by silica chromatography (Hexane:EtOAc).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.087 (0.46), 0.393 (0.44), 0.928 (0.66), 0.956 (0.86), 1.006 (0.40), 1.084 (0.88), 1.107 (0.92), 1.125(1.71), 1.132(1.36), 1.154 (7.69), 1.172 (14.86), 1.184 (4.48), 1.190 (7.82), 1.202 (6.26), 1.220 (2.81), 1.234 (0.46), 1.260 (0.57), 1.310 (0.73), 1.341 (0.57), 1.392 (0.42), 1.693 (0.46), 1.727 (0.44), 1.767 (0.99), 1.802 (0.90), 1.988 (16.00), 2.458 (1.30), 2.518 (7.65), 2.523 (5.38), 2.539 (1.19), 2.546 (1.21), 2.573 (0.42), 2.899 (1.32), 2.927 (2.51), 2.940 (1.25), 2.967 (1.74), 2.989 (0.53), 3.095 (0.57), 3.127 (0.97), 3.158 (0.59), 3.217 (0.64), 3.249 (0.42), 3.414 (1.34), 3.490 (1.34), 3.548 (1.21), 3.575 (10.46), 3.601 (12.13), 3.638 (2.26), 3.779 (8.88), 3.795 (2.00), 3.806 (4.00), 3.978 (0.57), 3.999 (1.74), 4.017 (4.33), 4.035 (4.35), 4.048 (2.73), 4.053 (2.20), 4.057 (1.49), 4.066 (3.38), 4.075 (3.03), 4.084 (2.37), 4.093 (3.05), 4.102 (0.77), 4.111 (1.25), 4.248 (0.42), 4.281 (0.51), 4.339 (0.62), 4.373 (0.51), 4.514 (0.68), 4.583 (0.59), 4.715 (2.88), 4.791 (2.18), 4.901 (0.79), 6.878 (0.57), 6.901 (0.77), 6.931 (0.92), 6.956 (2.53), 6.977 (3.89), 6.996 (1.98), 7.036 (1.10), 7.056 (2.31), 7.075 (1.52), 7.112 (0.62), 7.131 (0.46), 7.175 (2.09), 7.194 (1.67), 7.212 (0.92), 7.226 (2.79), 7.245 (2.51), 7.277 (1.49), 7.295 (2.00), 7.315 (1.03), 7.334 (1.08), 7.352 (1.65), 7.371 (1.43), 7.437 (2.62), 7.460 (0.70), 7.471 (0.57), 7.483 (1.41), 7.491 (1.27), 7.501 (2.20), 7.519 (1.43), 7.523 (1.56), 7.540(1.03), 7.561 (0.44). Intermediate 186
5-(2-fluoro-6-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000368_0001
Using an analogous method described as intermediate 116: intermediate 185 (340 mg, 618 pmol) gave the titled compound (290 mg, 88%) after preparative HPLC (Method 6).
LC-MS (method 4): Rt = 1.18 min; MS (ESIpos): m/z = 509 [M+H]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.155 (0.58), -0.144 (0.57), 0.265 (0.52), 0.636 (0.77), 0.665 (0.58), 0.801 (0.51), 0.832 (0.62), 0.945 (0.50), 0.956 (0.51), 1.118 (0.52), 1.158 (0.42),
1.192 (0.53), 1.422 (0.60), 1.451 (0.58), 1.515 (0.40), 1.536 (0.76), 1.566 (0.54), 1.942 (0.97),
1.986 (1.28), 2.086 (0.76), 2.129 (0.88), 2.442 (0.72), 2.463 (0.58), 2.514 (0.96), 2.549 (0.46),
2.563 (1.19), 2.606 (1.04), 2.618 (0.55), 2.660 (1.96), 2.703 (1.24), 2.785 (0.44), 2.819 (0.86),
2.835 (0.88), 2.865 (0.62), 2.899 (0.44), 2.908 (0.43), 2.940 (1.18), 2.951 (1.10), 2.972 (1.06),
2.982 (1.18), 3.019 (0.89), 3.053 (1.02), 3.068 (0.71), 3.104 (0.82), 3.120 (0.45), 3.133 (0.73),
3.145 (0.48), 3.256 (1.27), 3.292 (0.81), 3.359 (0.78), 3.395 (1.37), 3.424 (0.64), 3.436 (0.75),
3.448 (1.01), 3.464 (1.08), 3.476 (0.85), 3.520 (4.03), 3.557 (10.56), 3.560 (10.86), 3.569 (16.00), 3.600 (0.46), 3.733 (1.39), 3.756 (1.45), 3.787 (12.22), 3.799 (5.13), 3.805 (3.30), 3.820 (1.03), 3.851 (0.50), 4.170 (0.44), 4.202 (0.50), 4.291 (0.66), 4.325 (0.49), 6.770 (0.43),
6.792 (0.62), 6.801 (0.75), 6.814 (0.58), 6.822 (0.94), 6.830 (1.44), 6.851 (1.54), 6.860 (1.58),
6.866 (1.92), 6.877 (2.20), 6.886 (2.11), 6.895 (2.02), 6.931 (1.13), 6.950 (2.33), 6.969 (1.44),
6.985 (0.43), 7.004 (0.82), 7.024 (0.54), 7.127 (2.08), 7.147 (1.94), 7.182 (1.44), 7.198 (3.61),
7.236 (1.03), 7.247 (1.85), 7.251 (1.76), 7.254 (1.91), 7.266 (2.67), 7.286 (1.55), 7.312 (0.66),
7.328 (1.24), 7.332 (1.64), 7.348 (1.95), 7.369 (0.76), 7.379 (0.69), 7.389 (0.69), 7.396 (1.01),
7.400 (1.33), 7.417 (1.67), 7.422 (2.40), 7.425 (2.71), 7.427 (2.84), 7.437 (1.85), 7.441 (1.64),
7.446 (1.61 ), 7.464 (0.55), 7.543 (0.97), 7.550 (1.00), 7.576 (0.97), 7.590 (1.55), 7.598 (1.39). Intermediate 187
ethyl {4-[cyano(3-fluoro-2-methoxyphenyl)methyl]-1 -[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000369_0001
Using an analogous method described as intermediate 46: intermediate 1 12 (2.10 g, 5.45 mmol) and (3-fluoro-2-methoxyphenyl)acetonitrile (1 .80 g, 10.9 mmol) gave the titled compound (2.69 g, 90%) after purification by silica chromatography ( Hexane :EtOAc).
Intermediate 188
5-(3-fluoro-2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000369_0002
Using an analogous method described as intermediate 1 16: intermediate 187 (390 mg, 708 mmol) gave the titled compound (240 mg, 63%) after preparative HPLC (Method 6).
LC-MS (method 4): Rt = 1 .20 min; MS (ESIpos): m/z = 509 [M+H]+
1H-NMR (500 MHz, DMSO-d6) d [ppm]: -0.253 (0.73), -0.235 (1 .25), -0.226 (1.21 ), -0.209 (0.69), 0.371 (0.64), 0.636 (1 .45), 0.660 (1 .37), 0.700 (0.97), 0.723 (0.85), 0.947 (0.93), 0.976
(0.60), 1.1 1 1 (0.93), 1 .296 (0.52), 1.320 (1 .21 ), 1 .348 (0.97), 1 .368 (0.97), 1 .452 (1.93), 1 .479
(1 .69), 1.956 (0.60), 1 .977 (2.10), 1.991 (0.77), 2.01 1 (2.22), 2.071 (0.40), 2.156 (1.53), 2.190
(1 .85), 2.295 (0.77), 2.329 (0.56), 2.392 (0.97), 2.514 (7.86), 2.518 (7.50), 2.522 (6.41 ), 2.662 (2.82), 2.697 (2.54), 2.818 (1 .01 ), 2.840 (2.18), 2.866 (1.93), 2.887 (0.69), 2.966 (1.37), 2.988
(1 .21 ), 3.024 (0.93), 3.048 (1 .69), 3.080 (1 .53), 3.1 1 1 (1.93), 3.135 (0.69), 3.193 (1.25), 3.205 (1 .25), 3.217 (1 .89), 3.227 (1 .57), 3.240 (1 .17), 3.263 (5.24), 3.41 1 (1 .33), 3.448 (3.10), 3.470 (2.38), 3.495 (3.10), 3.519 (1 .01 ), 3.561 (16.00), 3.572 (1 1 .32), 3.587 (13.38), 3.590 (13.50), 3.775 (7.50), 3.810 (4.96), 3.813 (4.96), 3.826 (2.98), 4.191 (0.89), 4.218 (0.81 ), 4.348 (1 .13),
4.376 (1 .09), 6.619 (1 .21 ), 6.635 (1.25), 6.967 (2.10), 6.983 (4.39), 6.998 (2.82), 7.042 (2.10),
7.057 (2.98), 7.073 (0.85), 7.104 (1.89), 7.1 16 (5.00), 7.131 (5.24), 7.147 (2.82), 7.158 (1 .93),
7.163 (1 .53), 7.173 (1 .29), 7.190 (2.66), 7.205 (4.19), 7.220 (2.74), 7.227 (3.35), 7.244 (4.1 1 ),
7.296 (1 .81 ), 7.317 (3.63), 7.333 (4.55), 7.347 (3.39), 7.428 (2.50), 7.433 (4.1 1 ), 7.439 (3.55),
7.447 (1 .97), 7.481 (1.01 ), 7.496 (1.53), 7.51 1 (0.69), 7.598 (2.06), 7.646 (3.39), 7.668 (0.97).
Intermediate 189
ethyl {4-[cyano(5-fluoro-2-methoxyphenyl)methyl]-1 -[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000370_0001
Using an analogous method described as intermediate 46: intermediate 1 12 (2.10 g, 5.45 mmol) and ((5-fluoro-2-methoxyphenyl)acetonitrile (1.80 g, 10.9 mmol) gave the titled compound (2.17 g, 69%) after purification by silica chromatography (Flexane:EtOAc).
Intermediate 190
5-(5-fluoro-2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000370_0002
Using an analogous method described as intermediate 116: intermediate 189 (1.34 g, 2.43 mmol) gave the titled compound (1 .24 g, 95%). The title compound (1240 mg) was separated into its diastereoisomers by preparative chiral HPLC to give diastereoisomer 1 (480 mg, see Intermediate 191 ) and diastereoisomer 2 (500 mg, see Intermediate 192).
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; Column: Reprosil Chiral NR 8m 250x30mm; eluent A: C02; eluent B: ethanol; isocratic: 39%B; flow: 100 ml/min; temperature: 40Ό; BPR: 150bar; UV: 220 nm.
Analytical chiral HPLC method: Instrument: Agilent: 1260, Aurora SFC-Modul; Saule: Reprosil Chiral NR 5m 100x4.6mm; Eluent A: C02; Eluent B: Ethanol; Isokratisch: 39%B; FluB: 4 ml/min; Temperatur: 37.50; BPR: 100bar; UV: 220 nm . Intermediate 191 and Intermediate 192
(5R)-5-(5-fluoro-2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one
(5S)-5-(5-fluoro-2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one Intermediate 191
5-(5-fluoro-2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 1 )
For the preparation of the racemic title compound see Intermediate 190.
Analytical Chiral HPLC (method see Intermediate 190): Rt = 1.29 min, e.e. >99%.
Optical rotation (method OR1 ): -20.6° (methanol).
Intermediate 192
5-(5-fluoro-2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 2 - active)
For the preparation of the racemic title compound see Intermediate 190.
Analytical Chiral HPLC (method see Intermediate 190): Rt = 1.98 min, e.e. >99%.
Optical rotation (method OR1 ): +50.1“(methanol). Intermediate 193
ethyl [4-[cyano(3,6-difluoro-2-methoxyphenyl)methyl]-1 -[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl]acetate (mixture of stereoisomers)
Figure imgf000372_0001
Using an analogous method described as intermediate 46: intermediate 1 12 (500 mg, 1 .30 mmol) and (3,6-difluoro-2-methoxyphenyl)acetonitrile (475 mg, 2.59 mmol) gave the titled compound (512 mg, 62%) after purification by silica chromatography (Hexane:EtOAc).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .1 18 (0.56), 1 .136 (0.43), 1 .154 (0.95), 1 .161 (0.81 ), 1 .172 (1 .52), 1 .179 (1 .41 ), 1 .190 (0.96), 1 .197 (1 .04), 1.987 (1.69), 2.518 (0.87), 2.522 (0.60), 3.329 (16.00), 3.684 (0.92), 3.691 (0.91 ), 3.888 (0.66), 3.894 (0.67), 3.915 (0.62), 4.017 (0.51 ), 4.035 (0.55), 4.062 (0.45), 4.067 (0.48), 4.074 (0.41 ), 4.080 (0.45), 4.085 (0.46), 4.737 (0.45), 7.091 (0.41 ), 7.259 (0.69), 7.279 (0.72), 7.433 (0.50), 7.437 (0.61 ), 7.444 (0.41 ), 7.450 (0.41 ).
Intermediate 194
5-(3,6-difluoro-2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000372_0002
Using an analogous method described as intermediate 1 16: intermediate 193 (500 mg, 879 mmol) gave the titled compound (345 mg, 71 %) after preparative HPLC (Method 6).
LC-MS (method 4): Rt = 1 .19 min; MS (ESIpos): m/z = 527 [M+H]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.214 (0.67), -0.204 (0.67), 0.178 (0.59), 0.653 (0.81 ), 0.686 (0.76), 0.814 (0.73), 0.848 (0.53), 0.936 (0.56), 0.946 (0.56), 1 .161 (0.59), 1.190 (0.78), 1.413 (0.59), 1.441 (0.59), 1.521 (0.48), 1.555 (0.92), 1.588 (0.59), 1.989 (0.95), 2.034 (1.37),
2.144 (0.81), 2.186 (0.95), 2.263 (0.48), 2.447 (0.73), 2.456 (0.67), 2.518 (5.76), 2.522 (3.89),
2.539 (0.92), 2.592 (1.43), 2.616 (0.56), 2.634 (1.20), 2.660 (0.90), 2.699 (1.57), 2.742 (1.43),
2.791 (0.42), 2.817 (1.03), 2.845 (1.09), 2.878 (0.64), 3.029 (1.59), 3.048 (1.37), 3.059 (2.38),
3.091 (1.01), 3.116 (1.06), 3.281 (0.81), 3.299 (1.65), 3.311 (1.48), 3.380 (0.92), 3.394 (0.78),
3.432 (1.15), 3.508 (0.78), 3.536 (1.29), 3.573 (16.00), 3.622 (10.18), 3.627 (10.66), 3.632 (3.30), 3.640 (2.69), 3.689 (0.39), 3.774 (0.70), 3.803 (1.23), 3.813 (0.78), 3.820 (0.76), 3.830
(1.12), 3.836 (1.29), 3.849 (2.69), 3.856 (9.76), 3.861 (8.78), 3.877 (1.68), 3.882 (1.57), 4.219
(0.53), 4.249 (0.50), 4.338 (0.73), 4.371 (0.56), 6.944 (0.42), 6.957 (0.45), 6.967 (0.53), 6.983
(1.68), 7.002 (2.85), 7.012 (1.45), 7.022 (3.16), 7.033 (0.87), 7.039 (0.90), 7.046 (1.73), 7.056
(0.95), 7.061 (0.98), 7.074 (0.73), 7.084 (0.64), 7.172 (2.46), 7.185 (2.63), 7.192 (2.69), 7.215
(1.37), 7.225 (2.01), 7.237 (5.85), 7.250 (3.08), 7.268 (2.97), 7.289 (1.20), 7.298 (0.87), 7.311
(0.70), 7.321 (0.81), 7.325 (0.81), 7.338 (1.17), 7.348 (1.51), 7.361 (1.54), 7.384 (0.87), 7.396
(0.84), 7.407 (0.81), 7.412 (0.90), 7.426 (1.68), 7.430 (1.48), 7.435 (2.99), 7.444 (2.88), 7.447
(2.29), 7.461 (0.76), 7.596 (1.03), 7.604 (1.03), 7.638 (1.59), 7.646 (1.71 ).
Intermediate 195
ethyl {4-[cyano(2,3-difluoro-6-methoxyphenyl)methyl]-1-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000373_0001
Using an analogous method described as intermediate 46: intermediate 112 (500 mg, 1.30 mmol) and (2,3-difluoro-6-methoxyphenyl)acetonitrile (475 mg, 2.59 mmol) gave the titled compound (440 mg, 54%) after purification by silica chromatography (Hexane:EtOAc).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.278 (0.45), 0.835 (0.89), 0.852 (1.42), 0.949 (0.97), 0.983 (0.79), 1.102 (0.87), 1.119 (1.55), 1.137 (1.76), 1.150 (3.78), 1.154 (5.01), 1.168 (7.03),
1.172 (6.82), 1.186 (6.22), 1.190 (3.70), 1.204 (6.69), 1.222 (3.36), 1.237 (2.62), 1.307 (0.63),
1.715 (0.55), 1.748 (0.71), 1.792 (0.76), 1.824 (0.68), 1.987 (7.79), 2.322 (1.08), 2.326 (1.50),
2.332 (1.05), 2.464 (1.44), 2.518 (6.69), 2.522 (5.01), 2.561 (1.10), 2.664 (1.34), 2.668 (1.68),
2.673 (1.23), 2.929 (1.65), 2.950 (1.02), 2.970 (1.55), 2.981 (1.52), 3.021 (1.05), 3.133 (0.73),
3.168 (0.47), 3.203 (0.47), 3.234 (0.68), 3.476 (1.00), 3.533 (1.99), 3.579 (10.99), 3.588 (16.00), 3.629 (2.20), 3.778 (11.15), 3.800 (3.33), 3.967 (0.45), 3.984 (0.47), 4.000 (1.00), 4.017 (2.54), 4.035 (2.62), 4.043 (1.99), 4.053 (1.29), 4.060 (2.54), 4.066 (1.29), 4.078 (1.84),
4.085 (2.99), 4.102 (2.83), 4.120 (0.97), 4.270 (0.47), 4.304 (0.63), 4.354 (0.63), 4.389 (0.39),
4.547 (0.84), 4.598 (0.55), 4.747 (2.44), 4.841 (2.47), 4.924 (0.45), 6.958 (1.29), 6.981 (1.10), 7.079 (0.87), 7.098 (1.94), 7.118 (1.39), 7.145 (0.47), 7.238 (2.28), 7.256 (6.95), 7.267 (9.23),
7.349 (0.73), 7.367 (1.68), 7.386 (1.31), 7.414 (0.39), 7.425 (1.00), 7.436 (2.62), 7.446 (1.94),
7.484 (0.50), 7.509 (0.47), 7.554 (0.84), 7.577 (1.65), 7.602 (1.52), 7.626 (0.58).
Intermediate 196
5-(2,3-difluoro-6-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000374_0001
Using an analogous method described as intermediate 116: intermediate 195 (430 mg, 756 mmol) gave the titled compound (305 mg, 63%) after preparative HPLC (Method 6).
LC-MS (method 4): Rt = 1.18 min; MS (ESIpos): m/z = 527 [M+H]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.205 (0.52), -0.194 (0.54), 0.148 (0.54), 0.179 (0.42), 0.666 (0.64), 0.697 (0.54), 0.851 (0.78), 0.885 (0.64), 0.925 (0.64), 0.937 (0.64), 0.958 (0.40),
1.137 (0.76), 1.437 (0.83), 1.468 (0.81), 1.536 (0.44), 1.567 (0.83), 1.597 (0.52), 1.975 (0.93),
2.019 (1.41), 2.062 (0.60), 2.074 (0.68), 2.112 (0.95), 2.156 (1.13), 2.263 (0.44), 2.323 (0.78),
2.327 (1.15), 2.331 (0.85), 2.426 (0.64), 2.522 (6.68), 2.539 (3.18), 2.591 (1.59), 2.635 (1.41), 2.644 (0.78), 2.669 (2.50), 2.687 (0.70), 2.713 (1.17), 2.785 (0.52), 2.819 (1.19), 2.853 (1.07),
2.964 (0.50), 3.000 (1.45), 3.021 (0.95), 3.032 (1.93), 3.069 (0.87), 3.096 (0.74), 3.129 (1.03),
3.162 (0.50), 3.359 (2.05), 3.435 (1.51), 3.457 (1.03), 3.474 (1.09), 3.487 (1.43), 3.519 (4.53),
3.536 (1.01), 3.563 (16.00), 3.571 (12.14), 3.635 (0.70), 3.725 (1.21), 3.748 (1.33), 3.765 (0.60), 3.785 (15.66), 3.792 (7.75), 3.799 (3.60), 3.824 (0.50), 4.110 (0.44), 4.198 (0.56), 4.233 (0.66), 4.319 (0.62), 4.348 (0.46), 6.855 (1.51 ), 6.865 (1.57), 6.879 (1.49), 6.983 (1.01 ), 7.002
(2.19), 7.022 (1.51), 7.032 (1.11), 7.051 (0.72), 7.184 (2.76), 7.203 (2.54), 7.228 (7.69), 7.239
(7.12), 7.264 (1.11), 7.282 (1.41), 7.301 (0.72), 7.329 (0.54), 7.351 (1.37), 7.372 (1.45), 7.381 (1.15), 7.394 (2.09), 7.403 (0.97), 7.419 (1.43), 7.433 (1.61), 7.439 (2.37), 7.445 (2.37), 7.473
(1.15), 7.497 (0.46), 7.603 (1.75), 7.639 (1.29), 7.648 (1.21 ).
Intermediate 197
ethyl {4-[cyano(3,5-difluoro-2-methoxyphenyl)methyl]-1-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000375_0001
Using an analogous method described as intermediate 46: intermediate 112 (500 mg, 1.30 mmol) and (3,5-difluoro-2-methoxyphenyl)acetonitrile (475 mg, 2.59 mmol) gave the titled compound (439 mg, 54%) after purification by silica chromatography (Hexane:EtOAc).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.444 (0.53), 0.454 (0.53), 0.835 (0.59), 0.852 (0.99), 0.934 (0.75), 0.963 (0.66), 1.083 (0.68), 1.112 (3.14), 1.116 (2.74), 1.130 (6.06), 1.133 (6.32), 1.147 (3.26), 1.152 (6.90), 1.154 (6.29), 1.163 (6.69), 1.172 (10.56), 1.180 (15.43), 1.190
(6.14), 1.196(13.10), 1.198 (8.77), 1.214(5.40), 1.237(1.79), 1.441 (0.41), 1.463 (0.69), 1.474 (0.66), 1.496 (0.60), 1.528 (0.45), 1.712(0.77), 1.734(1.19), 1.761 (0.71), 1.987 (16.00), 2.348 (0.68), 2.371 (0.57), 2.410 (0.83), 2.444 (0.96), 2.518 (3.47), 2.522 (2.48), 2.534 (1.35), 2.724
(1.37), 2.764 (1.13), 2.816 (0.41), 2.927 (1.74), 2.954 (1.50), 2.988 (1.13), 3.020 (0.44), 3.109
(0.44), 3.140 (0.78), 3.171 (0.51), 3.220 (0.83), 3.242 (0.57), 3.257 (0.95), 3.270 (0.92), 3.283
(0.56), 3.563 (2.72), 3.588 (13.40), 3.616 (0.44), 3.630 (2.62), 3.634 (2.62), 3.655 (7.46), 3.660
(7.58), 3.674 (0.42), 3.770 (8.71), 3.776 (8.74), 3.783 (0.84), 3.831 (3.43), 3.835 (6.08), 3.840
(3.88), 3.974 (1.35), 3.984 (0.89), 3.993 (2.84), 3.999 (1.71), 4.002 (1.07), 4.006 (0.86), 4.010
(2.60), 4.017 (4.50), 4.024 (2.03), 4.028 (1.32), 4.034 (4.98), 4.041 (3.19), 4.050 (2.80), 4.052
(2.71), 4.059 (5.07), 4.068 (2.59), 4.076 (4.74), 4.086 (0.99), 4.093 (1.50), 4.281 (0.54), 4.314
(0.53), 4.343 (0.60), 4.378 (0.56), 4.643 (2.05), 4.820 (1.61), 5.562 (0.47), 6.717 (0.75), 6.739
(0.71), 6.885 (0.78), 6.908 (0.77), 7.126 (0.48), 7.147 (0.50), 7.181 (0.90), 7.200 (2.23), 7.219
(1.79), 7.270 (2.71), 7.288 (1.70), 7.325 (1.40), 7.340 (9.41), 7.347 (3.85), 7.355 (3.74), 7.377
(1.58), 7.397 (1.86), 7.409 (1.19), 7.418 (2.08), 7.430 (3.37), 7.435 (2.74), 7.442 (4.08), 7.451
(4.12), 7.458 (3.49), 7.463 (1.91), 7.468 (2.18), 7.476 (1.31), 7.490 (0.72), 7.498 (1.19), 7.506
(0.77), 7.512 (0.68), 7.520 (1.19), 7.527 (0.77), 7.533 (0.69), 7.541 (1.10), 7.549 (0.68), 7.563
(0.59), 7.571 (0.59). Intermediate 198
5-(3,5-difluoro-2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000376_0001
Using an analogous method described as intermediate 116: intermediate 197 (430 mg, 756 mmol) gave the titled compound (265 mg, 63%) after preparative HPLC (Method 6).
LC-MS (method 4): Rt = 1.21 min; MS (ESIpos): m/z = 527 [M+H]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.299 (0.60), -0.287 (0.63), 0.275 (0.48), 0.648 (0.74), 0.677 (0.71), 0.742 (0.63), 0.774 (0.57), 0.900 (0.54), 0.912 (0.54), 1.121 (0.46), 1.245 (0.57),
1.368 (0.51), 1.451 (0.94), 1.478 (0.80), 1.977 (1.05), 2.020 (1.20), 2.140 (0.97), 2.183 (1.14),
2.322 (1.11), 2.326 (1.51), 2.332 (1.08), 2.336 (0.51), 2.358 (0.43), 2.518 (5.86), 2.522 (3.90),
2.539 (1.48), 2.551 (1.20), 2.594 (0.94), 2.664 (2.36), 2.668 (1.88), 2.673 (1.20), 2.706 (1.22),
2.811 (0.83), 2.844 (1.54), 2.876 (0.80), 2.961 (0.65), 2.974 (0.60), 2.992 (0.63), 3.030 (0.68),
3.056 (1.34), 3.092 (0.74), 3.128 (0.65), 3.177 (0.54), 3.189 (0.54), 3.207 (0.65), 3.218 (0.63),
3.284 (2.85), 3.304 (1.14), 3.399 (0.46), 3.419 (0.83), 3.478 (1.79), 3.504 (1.42), 3.533 (1.00),
3.566 (16.00), 3.575 (8.88), 3.610 (0.54), 3.757 (6.63), 3.778 (2.82), 3.781 (2.82), 3.798 (1.71), 4.211 (0.57), 4.242 (0.54), 4.352 (0.57), 4.383 (0.54), 6.473 (0.68), 6.498 (0.65), 6.989 (0.83),
7.022 (1.62), 7.041 (2.73), 7.061 (1.82), 7.167 (2.51), 7.186 (1.96), 7.207 (1.11), 7.225 (1.88),
7.247 (1.74), 7.266 (3.39), 7.280 (3.10), 7.288 (1.14), 7.297 (3.22), 7.309 (1.00), 7.317 (2.22),
7.324 (0.83), 7.339 (1.05), 7.347 (1.22), 7.362 (0.94), 7.371 (0.94), 7.379 (0.77), 7.393 (0.71),
7.400 (1.28), 7.409 (1.14), 7.431 (3.19), 7.435 (3.25), 7.442 (1.94), 7.448 (1.62), 7.627 (1.40),
7.672(1.74), 7.697 (0.51).
Intermediate 199
ethyl {4-[cyano(4,5-difluoro-2-methoxyphenyl)methyl]-1-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000377_0001
Using an analogous method described as intermediate 46: intermediate 112 (500 mg, 1.30 mmol) and (4,5-difluoro-2-methoxyphenyl)acetonitrile (475 mg, 2.59 mmol) gave the titled compound (413 mg, 50%) after purification by silica chromatography (Hexane:EtOAc).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.852 (0.49), 0.922 (0.48), 0.952 (0.45), 1.089 (0.49), 1.114(1.89), 1.132 (3.60), 1.150 (2.24), 1.154 (6.09), 1.172(13.22), 1.176 (4.14), 1.190 (6.66), 1.194 (7.56), 1.211 (3.28), 1.237 (1.04), 1.420 (0.43), 1.432 (0.43), 1.698 (0.91), 1.728 (0.87), 1.987 (6.55), 2.310 (0.51), 2.391 (0.49), 2.410 (0.48), 2.423 (0.65), 2.463 (1.31), 2.518 (3.23), 2.522 (2.23), 2.689 (0.85), 2.729 (0.73), 2.979 (0.62), 3.125 (0.51), 3.216 (0.54), 3.530 (0.94), 3.566 (2.52), 3.586 (16.00), 3.699 (11.41), 3.760 (3.60), 3.770 (4.68), 3.979 (0.99), 3.996
(1.11), 4.017 (1.75), 4.021 (0.97), 4.034 (2.41), 4.038 (1.28), 4.048 (2.01), 4.052 (3.05), 4.062 (1.41), 4.066 (2.03), 4.070 (2.60), 4.079 (1.16), 4.088 (0.96), 4.259 (0.40), 4.607 (0.54), 4.805 (0.43), 7.023 (0.42), 7.050 (0.59), 7.072 (0.45), 7.157 (0.53), 7.176 (1.16), 7.193 (1.13), 7.215 (0.65), 7.243 (0.60), 7.264 (1.96), 7.288 (1.93), 7.302 (0.97), 7.308 (0.85), 7.321 (1.31), 7.338 (6.71), 7.345 (2.55), 7.351 (2.88), 7.373 (0.96), 7.392 (0.90), 7.407 (0.88), 7.426 (1.50), 7.432
(1.50), 7.438 (1.25), 7.444 (2.54), 7.450 (1.99), 7.457 (1.19), 7.464 (0.88), 7.472 (0.96), 7.478 (1.04), 7.492 (0.43).
Intermediate 200
5-(4,5-difluoro-2-methoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000377_0002
Using an analogous method described as intermediate 116: intermediate 199 (410 mg, 721 pmol) gave the titled compound (282 mg, 71%) after preparative HPLC (Method 6).
LC-MS (method 4): Rt = 1.21 min; MS (ESIpos): m/z = 527 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.340 (0.42), -0.317 (0.69), -0.306 (0.74), -0.283 (0.44), 0.293 (0.65), 0.316 (0.44), 0.633 (0.83), 0.668 (0.83), 0.685 (0.90), 0.718 (0.74), 0.913
(0.42), 0.934 (0.90), 0.945 (0.86), 0.968 (0.62), 1.087 (0.46), 1.144 (0.49), 1.177 (0.74), 1.210
(0.44), 1.317 (0.65), 1.404 (0.90), 1.437 (1.46), 1.472 (0.92), 1.904 (0.42), 1.926 (1.16), 1.947
(0.55), 1.969 (1.29), 2.112 (1.27), 2.156 (1.57), 2.293 (0.42), 2.304 (0.58), 2.323 (0.95), 2.327
(1.32), 2.331 (1.09), 2.349 (0.46), 2.472 (2.43), 2.630 (1.73), 2.673 (2.47), 2.805 (0.53), 2.831
(1.23), 2.863 (1.32), 2.890 (1.18), 2.907 (0.72), 2.918 (0.79), 3.018 (1.71), 3.055 (0.69), 3.084
(0.53), 3.115 (0.90), 3.153 (1.13), 3.165 (0.92), 3.183 (1.09), 3.194 (1.11), 3.272 (3.03), 3.310
(0.90), 3.364 (2.89), 3.404 (1.13), 3.477 (2.34), 3.512 (1.69), 3.546 (16.00), 3.564 (9.71), 3.575 (10.27), 3.719 (14.80), 3.770 (4.76), 3.776 (3.56), 4.182 (0.74), 4.217 (0.69), 4.322 (0.72),
4.356 (0.65), 6.794 (0.86), 6.818 (1.02), 6.824 (1.06), 6.848 (0.90), 7.012 (1.36), 7.031 (3.01),
7.050 (1.99), 7.127 (1.25), 7.145 (1.76), 7.153 (1.57), 7.160 (1.97), 7.171 (4.35), 7.190 (2.80),
7.203 (1.46), 7.253 (1.60), 7.272 (4.67), 7.285 (3.56), 7.303 (4.69), 7.324 (1.94), 7.338 (1.60),
7.357 (3.26), 7.429 (2.40), 7.437 (3.33), 7.444 (2.89), 7.450 (2.64), 7.467 (0.83), 7.594 (1.85),
7.633 (2.08).
Intermediate 201
ethyl {4-[[2-(benzyloxy)phenyl](cyano)methyl]-1-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000378_0001
Using an analogous method described as intermediate 46: intermediate 112 (10 g, 25.9 mmol) and ([2-(benzyloxy)phenyl]acetonitrile (11.6 g, 51.9 mmol) gave the titled compound (14.01 g, 89%) after purification by silica chromatography ( Hexane :EtOAc).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.815 (0.41), 0.960 (1.59), 0.978 (3.35), 0.995 (1.65), 1.025 (0.70), 1.043 (1.61), 1.057 (1.75), 1.061 (1.54), 1.075 (0.93), 1.080 (1.59), 1.098 (0.70), 1.154 (4.17), 1.172 (8.09), 1.191 (4.03), 1.575 (0.45), 1.611 (0.45), 1.988 (16.00), 2.331 (1.07), 2.366 (0.91), 2.403 (0.86), 2.518 (6.91), 2.523 (4.56), 2.673 (1.00), 2.924 (0.50), 2.955 (0.70),
2.989 (0.45), 3.074 (0.48), 3.238 (0.88), 3.274 (0.66), 3.568 (5.14), 3.715 (0.50), 3.726 (0.61),
3.744 (0.54), 3.832 (0.43), 3.858 (0.54), 3.876 (0.50), 4.000 (1.20), 4.018 (3.67), 4.035 (3.60),
4.053 (1.25), 4.623 (0.75), 4.760 (0.43), 4.969 (0.97), 4.998 (0.77), 5.088 (0.57), 5.109 (0.93),
5.121 (0.45), 5.142 (0.57), 5.152 (0.57), 7.027 (0.97), 7.047 (1.45), 7.066 (0.91), 7.117 (1.97), 7.136 (1.29), 7.186 (1.02), 7.207 (1.75), 7.231 (0.95), 7.239 (1.07), 7.255 (1.75), 7.261 (1.68),
7.274 (1.36), 7.280 (1.65), 7.301 (0.88), 7.337 (1.43), 7.343 (1.45), 7.353 (2.24), 7.363 (3.13),
7.381 (2.63), 7.402 (2.31), 7.420 (2.45), 7.434 (2.29), 7.445 (1.43), 7.452 (1.61), 7.473 (1.00),
7.496 (0.97), 7.514 (0.82).
Intermediate 202
5-(2-hydroxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one
Figure imgf000379_0001
To a solution of Intermediate 201 (880 mg, 1.55 mmol) in methanol (25 ml) was added a couple of drops of 3M hydrochloric acid (aq) under Argon was added palladium on charcoal (10%, 17 mg). The reaction was flushed with hydrogen. The reaction under a positive hydrogen pressure was stirred at RT for 3h. The reaction was filtered and the filtrate was concentrated under reduced pressure and gave the titled compound (623 mg, 80%) which was used without further purification.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.083 (0.73), 0.105 (0.47), 0.713 (1.20), 0.746 (1.04), 0.798 (0.41), 0.814 (0.60), 0.821 (0.50), 1.035 (1.23), 1.052 (1.96), 1.070 (1.10), 1.231 (0.41), 1.315 (0.54), 1.411 (1.64), 1.497 (0.76), 1.878 (0.44), 1.907 (0.57), 1.924 (0.60), 1.937 (0.57), 1.960 (1.42), 1.980 (0.69), 2.003 (1.48), 2.067 (0.73), 2.111 (0.85), 2.224 (0.50), 2.268 (0.41), 2.379 (0.41), 2.518 (8.52), 2.523 (5.87), 2.565 (1.80), 2.608 (1.26), 2.825 (0.69), 2.858 (1.14), 2.878 (0.73), 2.896 (0.69), 2.955 (0.92), 2.977 (1.29), 3.008 (1.07), 3.044 (1.10), 3.078 (0.92), 3.113 (0.63), 3.146 (0.54), 3.165 (16.00), 3.221 (3.79), 3.559 (10.04), 3.600 (0.63), 4.132 (0.60), 4.163 (0.60), 4.317 (0.76), 4.346 (0.73), 6.661 (0.57), 6.680 (0.69), 6.709 (0.50), 6.730 (0.95), 6.753 (0.85), 6.772 (0.66), 6.797 (1.36), 6.808 (2.65), 6.828 (4.13), 6.842 (2.30), 6.983 (1.64), 7.003 (3.53), 7.022 (2.59), 7.036 (1.29), 7.057 (1.10), 7.093 (1.77), 7.118 (4.26), 7.141 (3.72), 7.160 (2.18), 7.184 (1.99), 7.206 (2.30), 7.233 (1.96), 7.250 (0.95), 7.271 (0.47), 7.298 (1.26), 7.317 (2.08), 7.338 (1.80), 7.350 (1.77), 7.358 (1.83), 7.370 (1.42), 7.423 (3.28), 7.429 (3.76), 7.437 (3.16), 7.447 (1.77), 7.472 (0.69), 7.490 (0.92), 7.519 (1.17), 7.575 (1.74), 7.598 (1.33), 9.236 (1.48), 9.413 (0.76), 9.509 (0.92), 9.527 (0.95). The title compound (550 mg) was separated into its diastereoisomers by preparative chiral HPLC to give diastereoisomer 1 (194 mg, see Intermediate 203) and diastereoisomer 2 (180 mg, see Intermediate 204).
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; Column: Reprosil Chiral NR 8pm 250x30mm; Eluent A: C02, Eluent B: Ethanol; Isocratic: 33%B; Flow: 100.0 ml/min Temperatur: 400; BPR: 150bar; MWD @ 280nm.
Analytical chiral HPLC method: Instrument: Agilent: 1260, Aurora SFC-Module; Column:
Reprosil Chiral NR 5pm 100x4.6mm; Eluent A: C02, Eluent B: Ethanol; Isocratic: 38%B; Flow: 4.0 ml/min; Temperature: 37.50; BPR: 100bar; MWD @ 280nm. Intermediate 203 and Intermediate 204
(5R)-5-(2-hydroxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one
(5S)-5-(2-hydroxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one Intermediate 203
5-(2-hydroxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoiosmer 1 )
For the preparation of the racemic title compound see Intermediate 202.
Analytical Chiral HPLC (method see Intermediate 202): Rt = 1.20 min, e.e. >99%.
Optical rotation (method OR1 ): +1 .7°(methanol).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .058 (16.00), 2.469 (0.60), 2.473 (0.44), 3.393 (0.56), 3.509 (1 .44), 4.144 (1 .63), 6.778 (0.49), 6.954 (0.57), 6.973 (0.42), 7.070 (0.66), 7.092 (0.58), 7.373 (0.46).
Intermediate 204
5-(2-hydroxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoiosmer 2)
For the preparation of the racemic title compound see Intermediate 202.
Analytical Chiral HPLC (method see Intermediate 202): Rt = 2.24 min, e.e. 98.4%.
Optical rotation (method OR1 ): +50.4°(methanol). 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.107 (16.00), 2.518 (0.72), 2.522 (0.54), 3.221 (0.74), 3.568 (1.22), 4.190 (1.60), 6.820 (0.53), 6.840 (0.47), 7.207 (0.47), 7.317 (0.48), 7.430 (0.55), 7.438 (0.44).
Intermediate 205
5-[2-(2,2-difluoroethoxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 2)
Figure imgf000381_0001
A mixture of Intermediate 204 (50 mg, 105 mihoI), 2-bromo-1 ,1-difluoroethane (30.4 mg, 210 mihoI) and cesium carbonate (68.4 mg, 210 mihoI) in DMF (1 ml) was heated at 800 for 16h. The reaction was filtered and the titled compound (41 mg, 69%) was obtained after preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.359 (0.42), 0.380 (0.75), 0.390 (0.75), 0.411 (0.47), 0.787 (1.00), 0.818 (0.92), 0.856 (0.64), 0.878 (0.92), 0.890 (0.92), 0.912 (0.61), 0.923 (0.50),
1.143 (1.14), 1.232 (0.69), 1.294 (0.42), 1.327 (0.67), 1.425 (1.39), 1.457 (1.11), 1.923 (0.78),
1.967 (0.94), 2.009 (1.31), 2.052 (1.47), 2.337 (0.78), 2.345 (1.14), 2.388 (0.92), 2.518 (16.00), 2.523 (12.50), 2.540 (5.11), 2.616 (1.39), 2.644 (1.81), 2.678 (0.83), 2.688 (1.67), 2.809 (0.67), 2.838 (1.14), 2.877 (0.75), 2.908 (1.06), 2.917 (1.22), 2.947 (1.22), 2.964 (0.69), 3.102 (1.44),
3.133 (1.06), 3.164 (0.67), 3.249 (4.61), 3.281 (1.22), 3.312 (2.61), 3.385 (1.78), 3.396 (1.81),
3.414 (1.42), 3.424 (1.08), 3.436 (0.94), 3.445 (0.67), 3.466 (0.83), 3.479 (0.78), 3.500 (0.47),
3.566 (10.86), 3.786 (0.89), 4.133 (1.25), 4.168 (1.22), 4.253 (1.03), 4.260 (1.17), 4.269 (0.94), 4.282 (1.39), 4.290 (1.97), 4.296 (2.08), 4.305 (1.44), 4.326 (1.47), 4.356 (0.56), 6.270 (0.50),
6.279 (1.03), 6.287 (0.53), 6.407 (1.00), 6.415 (1.97), 6.423 (1.03), 6.551 (0.89), 6.559 (0.53),
6.737 (1.44), 6.757 (1.75), 6.970 (0.58), 6.988 (1.19), 7.006 (0.69), 7.046 (1.22), 7.063 (5.00),
7.084 (4.22), 7.158 (2.86), 7.178 (4.11), 7.237 (0.92), 7.257 (2.53), 7.267 (2.86), 7.276 (2.36),
7.286 (4.31), 7.306 (3.25), 7.329 (3.03), 7.346 (2.33), 7.350 (2.33), 7.433 (3.94), 7.440 (3.31),
7.450 (2.39), 7.478 (1.39), 7.496 (2.14), 7.514 (0.97), 7.567 (2.08), 7.575 (2.14), 7.658 (1.17). Intermediate 206
5-[2-(2,2,2-trifluoroethoxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 2)
Figure imgf000382_0001
Using an analogous method described as intermediate 46: intermediate 204 (50 mg, 105 mihoI) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (24.4 mg, 105 mihoI) gave the titled compound (56 mg, 90%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.041 (1 .99), 0.289 (0.56), 0.722 (0.75), 0.752 (0.70), 0.826 (0.68), 0.837 (0.66), 0.859 (0.41 ), 1.028 (16.00), 1 .065 (0.63), 1 .232 (0.43), 1 .282 (0.81 ),
1 .316 (0.88), 1 .851 (0.66), 1 .876 (1.72), 1 .895 (0.84), 1.922 (1.1 1 ), 2.243 (1 .58), 2.247 (1 .47),
2.252 (1 .04), 2.285 (0.66), 2.438 (6.24), 2.443 (3.77), 2.582 (1.83), 2.590 (1 .56), 2.594 (1 .08),
2.625 (1 .24), 2.702 (0.81 ), 2.739 (0.52), 2.772 (0.90), 2.799 (0.66), 2.826 (0.52), 2.862 (1 .97),
2.871 (0.99), 3.028 (0.43), 3.059 (0.79), 3.089 (0.47), 3.194 (3.75), 3.330 (1 .36), 3.486 (8.25),
4.052 (0.86), 4.087 (0.84), 4.1 13 (1.36), 4.622 (0.59), 4.645 (1.36), 4.671 (1 .69), 4.694 (1 .27),
4.718 (0.75), 4.740 (0.50), 6.691 (1.13), 6.707 (1 .29), 6.936 (0.45), 6.954 (0.88), 6.973 (0.52),
7.009 (0.93), 7.029 (3.16), 7.042 (1.45), 7.051 (2.55), 7.077 (2.19), 7.096 (3.01 ), 7.180 (2.35),
7.199 (3.66), 7.219 (1 .94), 7.256 (1.88), 7.275 (2.42), 7.295 (0.75), 7.356 (2.80), 7.363 (2.33),
7.372 (1 .65), 7.396 (1.02), 7.415 (1.56), 7.432 (0.68), 7.507 (1.63), 7.514 (1 .63), 7.590 (0.97).
Intermediate 207
5-{2-[(2S)-2-methoxypropoxy]phenyl}-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 2)
Figure imgf000382_0002
Using an analogous method described as intermediate 46: intermediate 204 (50 mg, 105 pmol) and (2S)-2-methoxypropyl methanesulfonate (17.7 mg, 105 mihoI, for synthesis see US2019/77784) gave the titled compound (48 mg, 79%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.419 (0.46), 0.428 (0.42), 0.787 (0.57), 0.821 (0.50), 0.921 (0.51 ), 0.931 (0.64), 1 .149 (0.42), 1 .163 (4.50), 1.178 (7.71 ), 1 .193 (6.15), 1.218 (0.57),
1 .479 (0.72), 1 .51 1 (0.73), 1 .922 (0.55), 1 .966 (0.73), 1.978 (0.84), 2.022 (0.90), 2.283 (0.73),
2.327 (1 .05), 2.332 (0.50), 2.518 (1.85), 2.523 (1 .36), 2.636 (1.10), 2.669 (0.59), 2.679 (1 .06),
2.850 (0.42), 2.883 (0.75), 2.917 (0.62), 2.926 (0.66), 2.939 (0.55), 2.948 (0.61 ), 2.957 (0.66),
2.966 (0.57), 3.143 (0.62), 3.159 (2.75), 3.172 (3.12), 3.235 (0.50), 3.254 (1 1 .58), 3.297 (3.76),
3.308 (2.29), 3.325 (16.00), 3.351 (1 .03), 3.365 (0.61 ), 3.413 (0.73), 3.425 (0.79), 3.441 (0.55),
3.453 (0.50), 3.481 (0.44), 3.498 (0.64), 3.568 (6.75), 3.618 (0.53), 3.629 (0.70), 3.634 (0.97),
3.644 (0.97), 3.649 (0.88), 3.659 (0.66), 3.806 (0.62), 3.81 1 (0.83), 3.819 (0.59), 3.826 (0.79),
3.836 (1 .14), 3.845 (0.75), 3.851 (0.90), 3.942 (0.94), 3.951 (0.94), 3.967 (0.68), 3.977 (0.62),
4.018 (0.53), 4.026 (0.55), 4.043 (0.46), 4.052 (0.42), 4.100 (1.06), 4.1 13 (0.92), 4.126 (0.59),
4.138 (0.75), 6.719 (0.88), 6.736 (1.03), 6.901 (0.42), 6.919 (0.84), 6.937 (0.50), 6.979 (1 .17),
6.992 (2.09), 7.002 (1 .32), 7.012 (2.39), 7.167 (1 .78), 7.187 (2.37), 7.199 (0.62), 7.203 (0.68),
7.222 (2.02), 7.241 (1 .43), 7.270 (0.90), 7.273 (0.99), 7.281 (1.69), 7.292 (1 .72), 7.300 (2.64),
7.308 (1 .01 ), 7.312 (0.92), 7.319 (1.41 ), 7.332 (0.75), 7.337 (0.86), 7.347 (1 .08), 7.355 (1 .03),
7.425 (0.46), 7.434 (2.86), 7.441 (2.29), 7.450 (1 .63), 7.480 (0.83), 7.498 (1 .30), 7.516 (0.55),
7.553 (1 .32), 7.559 (1.34), 7.634 (0.88).
Intermediate 208
5-{2-[(2S)-2-hydroxy-3-methoxypropoxy]phenyl}-9-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]-3,9-diazaspiro[5.5]undecan-2-one (Stereoisomer 2)
Figure imgf000383_0001
Using an analogous method described as intermediate 46: intermediate 204 (50 mg, 105 mihoI) and (R)-(-)-methyl glycidyl ether (9.4 mI, 100 mihoI) gave the titled compound (48 mg, 77%) after purification by preparative HPLC (Method 6). 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.406 (0.50), 0.778 (0.66), 0.811 (0.61), 0.855 (0.61), 0.866 (0.57), 1.154 (0.77), 1.479 (0.79), 1.512 (0.59), 1.956 (0.50), 2.000 (0.57), 2.065 (0.86),
2.108 (0.97), 2.331 (0.57), 2.349 (0.70), 2.392 (0.59), 2.518 (3.47), 2.522 (2.09), 2.539 (0.55),
2.639 (1.16), 2.673 (0.70), 2.682 (1.03), 2.832 (0.70), 2.870 (0.48), 2.888 (0.50), 2.908 (0.83),
2.917 (0.70), 2.927 (0.64), 3.096 (0.40), 3.127 (0.72), 3.158 (0.44), 3.183 (0.48), 3.190 (1.10),
3.230 (3.97), 3.236 (9.15), 3.259 (1.03), 3.290 (16.00), 3.390 (2.22), 3.404 (2.17), 3.420 (2.81 ), 3.433 (2.85), 3.506 (0.72), 3.518 (0.79), 3.535 (0.79), 3.564 (7.88), 3.780 (0.40), 3.798 (1.12),
3.808 (1.25), 3.819 (0.79), 3.825 (0.81), 3.944 (2.79), 3.962 (1.56), 4.118 (0.59), 4.154 (0.79),
5.126 (1.25), 5.139 (1.23), 5.163 (1.95), 5.175 (1.89), 6.690 (1.01), 6.707 (1.10), 6.912 (0.79),
6.931 (0.46), 6.971 (2.85), 6.991 (3.45), 7.007 (0.92), 7.153 (1.95), 7.173 (2.68), 7.194 (0.59),
7.214 (1.67), 7.233 (1.21), 7.267 (1.08), 7.274 (1.82), 7.286 (1.89), 7.293 (2.92), 7.313 (1.54),
7.331 (0.86), 7.340 (1.05), 7.348 (0.99), 7.428 (2.46), 7.435 (2.09), 7.445 (1.49), 7.478 (0.86),
7.497 (1.38), 7.515 (0.61 ), 7.540 (1.36), 7.546 (1.38), 7.634 (0.83).
Intermediate 209
5-[2-(cyclopropylmethoxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 2)
Figure imgf000384_0001
Using an analogous method described as intermediate 46: intermediate 204 (75 mg, 157 pmol) and bromomethyl)cyclopropane (15 mI, 160 mihoI) gave the titled compound (85 mg) after work up
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.281 (2.50), 0.293 (3.20), 0.307 (2.62), 0.432 (0.58), 0.462 (1.02), 0.486 (0.70), 0.517 (1.86), 0.522 (1.86), 0.543 (4.16), 0.563 (2.69), 0.785 (1.15), 0.818 (0.90), 0.984 (0.64), 1.006 (1.02), 1.039 (0.64), 1.137 (1.73), 1.192 (0.83), 1.211 (0.90), 1.229 (1.09), 1.254 (0.70), 1.291 (0.64), 1.386 (0.58), 1.427 (0.45), 1.465 (1.28), 1.501 (0.96), 1.902 (0.96), 1.945 (1.15), 2.009 (1.54), 2.053 (1.79), 2.301 (1.28), 2.331 (2.82), 2.344 (1.22), 2.518 (16.00), 2.522 (9.54), 2.563 (0.83), 2.584 (2.43), 2.627 (1.98), 2.673 (2.75), 2.912 (0.70), 2.941 (1.28), 2.979 (1.28), 2.992 (1.54), 2.999 (1.28), 3.010 (1.15), 3.019 (1.41), 3.126 (0.70), 3.157 (1.22), 3.187 (0.70), 3.224 (1.02), 3.235 (0.70), 3.250 (1.28), 3.280 (8.26), 3.378 (0.77), 3.410 (0.64), 3.440 (1.41), 3.454 (1.41), 3.467 (1.22), 3.480 (0.96), 3.519 (1.86), 3.538 (1.60), 3.572 (12.54), 3.735 (0.77), 3.761 (2.11), 3.779 (3.84), 3.797 (2.30), 3.808 (1.79), 3.826 (1.86), 3.847 (1 .22), 3.874 (0.38), 4.080 (0.96), 4.1 13 (1 .09), 4.165 (0.58), 6.742 (1 .66), 6.762 (1 .98),
6.882 (0.70), 6.901 (1 .47), 6.919 (0.96), 6.941 (2.94), 6.963 (4.80), 6.975 (2.1 1 ), 6.983 (1 .47),
7.179 (3.78), 7.198 (5.31 ), 7.214 (1.60), 7.240 (1 .92), 7.260 (2.43), 7.279 (3.90), 7.298 (4.67),
7.318 (2.37), 7.345 (1 .60), 7.353 (1.92), 7.363 (1 .86), 7.438 (5.31 ), 7.445 (4.22), 7.455 (2.62),
7.464 (1 .98), 7.483 (2.30), 7.502 (1.09), 7.571 (2.37), 7.640 (1.60).
Intermediate 210
5-[2-(cyclopropyloxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000385_0001
Using an analogous method described as intermediate 46: intermediate 202 (75 mg, 157 pmol) and bromocyclopropane (67 mI, 840 mihoI) gave the titled compound (149 mg, 62%) after silica chromatography (DCM: methanol)
The title compound (145 mg) was separated into its diastereoisomers by preparative chiral HPLC to give diastereoisomer 1 (62 mg, see Intermediate 211 ) and diastereoisomer 2 (44 mg, see Intermediate 212).
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; Column: Reprosil Chiral NR 8pm 250x30mm; Eluent A: C02, Eluent B: Ethanol; Isocratic: 30%B; Flow: 100.0 ml/min Temperature: 40Ό; BPR: 150bar; MWD @ 220nm.
Analytical chiral HPLC method: Instrument: Agilent: 1260, Aurora SFC-Module; Column:
Reprosil Chiral NR 5pm 100x4.6mm; Eluent A: C02, Eluent B: Ethanol; Isocratic: 30%B; Flow: 4.0 ml/min; Temperature: 37.5Ό; BPR: 100bar; MWD @ 220nm.
Intermediate 211 and Intermediate 212
(5R)-5-[2-(cyclopropyloxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one
(5S)-5-[2-(cyclopropyloxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one Intermediate 211
5-[2-(cyclopropyloxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one
For the preparation of the racemic title compound see Intermediate 210.
Analytical Chiral FIPLC (method see Intermediate 210): Rt = 2.26 min, e.e. 97.1 %.
Optical rotation (method OR1 ): -29.3° (methanol).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.647 (0.56), 0.661 (0.65), 0.925 (0.52), 1 .066 (16.00), 2.476 (0.59), 2.498 (1 .61 ), 2.573 (0.44), 2.616 (0.41 ), 3.130 (0.42), 3.400 (0.50), 3.505 (2.37),
4.152 (1 .12), 6.921 (0.78), 6.940 (0.54), 6.974 (0.48), 7.037 (0.73), 7.056 (0.57), 7.122 (0.44), 7.210 (0.68), 7.229 (1.12), 7.321 (0.46), 7.343 (0.46), 7.380 (0.41 ), 7.547 (0.44), 7.553 (0.45).
Intermediate 212
5-[2-(cyclopropyloxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one
5-[2-(cyclopropyloxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one
For the preparation of the racemic title compound see Intermediate 210.
Analytical Chiral HPLC (method see Intermediate 210): Rt = 3.48 min, e.e. 99.6%.
Optical rotation (method OR1 ): -+53.6° (methanol).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .107 (16.00), 2.539 (1 .83), 3.221 (0.69), 3.565 (1 .46), 4.196 (1 .21 ), 7.202 (0.43), 7.221 (0.62), 7.290 (0.75), 7.314 (0.46), 7.334 (0.70), 7.353 (0.46),
7.432 (0.57), 7.438 (0.45).
Intermediate 213
tert-butyl 4-[cyano(2-methoxyphenyl)methyl]-4-(2-ethoxy-2-oxoethyl)piperidine-1 -carboxylate
Figure imgf000386_0001
Using an analogous method described as intermediate 46: tert-butyl 4-(2-ethoxy-2- oxoethylidene)piperidine-1 -carboxylate (14.0 g, 52.0 mmol) and (2-methoxyphenyl)acetonitrile (15.3 g, 104 mmol) gave the titled compound (18.61 g, 86%) after purification by silica chromatography ( Hexane :EtOAc). Intermediate 214
tert-butyl 7-(2-methoxyphenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000387_0001
Using an analogous method described as intermediate 116: intermediate 213 (27.6 g, 66.3 mmol) gave the titled compound (17.1 g, 69%) after silica chromatography (DCM:EtOH).
The title compound (17210 mg) was separated into its diastereoisomers by preparative chiral HPLC to give diastereoisomer 1 (8860 mg, see Intermediate 214) and diastereoisomer 2 (10280 mg, see Intermediate 215).
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; Column: Reprosil NR 8pm 250x30mm; Eluent A: C02, Eluent B: Methanol; Isocratic: 28%B; Flow: 100.0 ml/min Temperature: 40Ό; BPR: 150bar; MWD @ 220nm.
Analytical chiral HPLC method: Instrument: Agilent: 1260, Aurora SFC-Module; Column:
Reprosil NR 5pm 100x4.6mm; Eluent A: C02, Eluent B: Methanol; Isocratic: 28%B; Flow: 4.0 ml/min; Temperature: 37.5Ό; BPR: 100bar; MWD @ 220 nm. Intermediate 215 and Intermediate 216
tert-butyl (7R)-7-(2-methoxyphenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate tert-butyl (7S)-7-(2-methoxyphenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate
Intermediate 215
tert-butyl 7-(2-methoxyphenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate
(Stereoisomer 1 )
For the preparation of the racemic title compound see Intermediate 214.
Analytical Chiral FIPLC (method see Intermediate 214): Rt = 1.62 min, e.e. >99%. Optical rotation (method OR1 ): -44.9° (methanol).
Intermediate 216
tert-butyl 7-(2-methoxyphenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate
(Stereoisomer 2)
For the preparation of the racemic title compound see Intermediate 214.
Analytical Chiral HPLC (method see Intermediate 214): Rt = 2.09 min, e.e. >99%.
Optical rotation (method OR1 ): +34.4° (methanol).
Intermediate 217
5-(2-hydroxyphenyl)-3,9-diazaspiro[5.5]undecan-2-one (Stereoisomer 2)
Figure imgf000388_0001
To a solution of Intermediate 217 (1 .80 g, 4.81 mmol) in DCM (32 ml) at -780 was added boron tribromide (9.6 ml, 1 M solution in DCM, 9.6 mmol). The reaction was stirred at -780 for 2h, then at RT for 3h. Another portion of boron tribromide (2 ml, 1 M solution in DCM, 2 mmol) was added and the reaction was tirred at RT for 16h. The reaction was diluted with water and extracted with DCM. The combined organics were filtered through an hydrophobic filter and concentrated under reduced pressure to give the titled compound (1.7g) which was used without further purification.
Intermediate 218
tert-butyl 7-(2-hydroxyphenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate
(Stereoisomer 2)
Figure imgf000388_0002
To a suspension of Intermediate 217 in THF (50 ml) was added di-tert-butyl dicarbonate (2.26 g, 10.4 mmol) and triethylamine (2.9 ml, 21 mmol) and 4-dimethylaminopyridine (253 mg, 2.07 mmol). The reaction was stirred at RT for 3h. The reaction was diluted with water and extracted with DCM. The combined organics were filtered through an hydrophobic filter and concentrated under reduced pressure to give the titled compound (2.2g, 88%) which was used without further purification.
Intermediate 219
tert-butyl 7-[2-(3-methoxypropoxy)phenyl]-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate (Stereoisomer 2)
Figure imgf000389_0001
A mixture of Intermediate 218 (800 mg, 105 mihoI), 2-bromo-1 ,1 -difluoroethane (30.4 mg, 210 mihoI) and potassium carbonate (1 .23 g, 8.88 mmol) in DMF (10 ml) was heated at 100Ό for 16h. The reaction was diluted with water and extracted with DCM. The combined organics were filtered through an hydrophobic filter and concentrated under reduced pressure to give the titled compound (850 mg, 89%) after silica chromatography (DCM:EtOH).
Intermediate 220
5-[2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-2-one (Stereoisomer 2)
Figure imgf000389_0002
Using an analogous method described as intermediate 50: intermediate 219 (850 mg, 1 .97 mmol) gave the titled compound (600 mg, 92%) which was used directly in the next step without further purification.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .081 (0.57), 1 .099 (0.47), 1 .185 (0.68), 1 .217 (0.56), 1 .232 (0.52), 1 .301 (2.68), 1 .338 (0.66), 1 .352 (0.54), 1.386 (0.43), 1 .399 (0.57), 1.417 (0.53),
1 .430 (0.55), 1 .478 (0.52), 1 .952 (1.26), 1 .967 (1 .92), 1.983 (1.32), 1 .998 (0.42), 2.034 (0.72),
2.048 (0.60), 2.077 (0.85), 2.091 (0.76), 2.446 (0.70), 2.518 (1.97), 2.523 (1 .39), 2.541 (1 .48),
2.552 (1 .56), 2.575 (2.17), 2.665 (0.74), 2.669 (0.96), 2.673 (0.90), 2.702 (0.48), 3.122 (0.47),
3.128 (0.54), 3.138 (0.55), 3.147 (0.61 ), 3.155 (0.47), 3.165 (0.49), 3.173 (0.46), 3.204 (0.47), 3.216 (0.71 ), 3.242 (16.00), 3.264 (0.60), 3.444 (1 .32), 3.464 (2.22), 3.487 (2.00), 3.502 (2.52),
3.518 (1 .13), 3.765 (5.60), 3.772 (0.91 ), 3.967 (0.60), 3.982 (1.46), 3.997 (1 .36), 4.013 (0.53),
5.759 (3.13), 6.903 (0.47), 6.913 (0.50), 6.921 (0.96), 6.932 (0.74), 6.940 (0.60), 6.974 (0.88),
6.993 (1 .50), 7.010 (0.77), 7.195 (0.54), 7.199 (0.86), 7.216 (2.39), 7.234 (1 .84), 7.238 (1 .23),
7.599 (0.87).
Intermediate 221
5-[2-(3-methoxypropoxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 2)
Figure imgf000390_0001
Using an analogous method described as intermediate 10: intermediate 220 (1 15 mg, 346 pmol) was coupled with (2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (97.2 mg, 415 pmol) and gave the titled compound (50 mg, 25%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .152 (0.45), 1 .420 (0.52), 1 .452 (0.48), 1 .912 (1 .00), 1 .928 (1 .81 ), 1 .943 (1 .74), 1 .958 (0.83), 2.046 (0.55), 2.089 (0.63), 2.346 (0.43), 2.518 (0.72),
2.523 (0.49), 2.597 (0.80), 2.641 (0.68), 2.883 (0.50), 3.137 (0.42), 3.202 (6.05), 3.238 (2.01 ),
3.257 (1 1 .23), 3.276 (0.75), 3.306 (0.54), 3.332 (16.00), 3.395 (0.56), 3.408 (0.70), 3.422 (0.49), 3.441 (1 .10), 3.457 (1 .66), 3.472 (1 .89), 3.487 (2.23), 3.502 (1 .05), 3.528 (0.41 ), 3.928
(0.46), 3.936 (0.41 ), 3.944 (0.50), 3.951 (0.87), 3.967 (0.72), 3.974 (0.46), 3.990 (0.72), 4.006
(0.46), 4.014 (0.45), 4.025 (0.42), 4.145 (0.42), 6.727 (0.59), 6.744 (0.70), 6.909 (0.48), 6.961
(0.52), 6.980 (2.22), 6.989 (0.68), 7.000 (1 .74), 7.008 (0.66), 7.175 (1 .24), 7.195 (1.95), 7.219
(1 .1 1 ), 7.238 (0.81 ), 7.259 (0.56), 7.263 (0.58), 7.286 (1.28), 7.305 (1 .79), 7.326 (1.24), 7.341
(0.64), 7.350 (0.62), 7.429 (1 .72), 7.436 (1 .39), 7.445 (1.00), 7.477 (0.56), 7.495 (0.89), 7.555
(0.86), 7.560 (0.88), 7.641 (0.49). Intermediate 222
ethyl {4-[cyano(2-ethoxyphenyl)methyl]-1-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000391_0001
Using an analogous method described as intermediate 46: intermediate 112 (500 mg, 1.30 mmol) and (2-ethoxyphenyl)acetonitrile (418 mg, 2.59 mmol) gave the titled compound (366 mg, 46%) after purification by silica chromatography (Flexane:EtOAc).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.112 (1.63), 1.130 (3.72), 1.147 (1.80), 1.154 (4.66), 1.160 (1.94), 1.164 (0.86), 1.172 (9.61), 1.178 (4.22), 1.182 (1.79), 1.184 (1.71), 1.190 (5.05), 1.196 (2.44), 1.202 (2.83), 1.215 (1.93), 1.220 (1.46), 1.232 (0.93), 1.312 (0.90), 1.326 (0.97),
1.343 (0.49), 1.988 (16.00), 2.427 (0.44), 2.518 (3.60), 2.523 (2.40), 3.461 (0.62), 3.571 (2.59), 3.583 (1.76), 3.970 (0.52), 3.987 (0.66), 3.992 (0.61), 3.999 (1.47), 4.010 (0.73), 4.017 (4.04),
4.029 (0.61), 4.035 (4.08), 4.047 (1.06), 4.053 (1.67), 4.062 (1.09), 4.066 (1.41), 4.080 (0.83),
4.085 (1.18), 7.036 (0.76), 7.056 (1.74), 7.076 (1.42), 7.128 (0.69), 7.147 (0.50), 7.217 (0.60), 7.236 (0.70), 7.306 (0.51), 7.326 (1.16), 7.345 (1.27), 7.363 (0.72), 7.427 (0.67), 7.433 (0.86),
7.440 (0.87), 7.446 (0.61 ), 7.456 (0.75), 7.511 (0.41 ).
Intermediate 223
5-(2-ethoxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000391_0002
Using an analogous method described as intermediate 116: intermediate 222 (366 mg, 670 mmol) gave the titled compound (203 mg, 58%). 1H-NMR (500 MHz, DMSO-d6) d [ppm]: -0.130 (0.71), -0.112 (1.27), -0.103 (1.27), -0.086 (0.74), 0.462 (0.74), 0.478 (0.52), 0.679 (1.38), 0.705 (1.30), 0.746 (0.89), 0.772 (0.71), 0.985 (0.82), 1.012(0.56), 1.116(0.60), 1.170 (6.40), 1.184(13.43), 1.198 (6.66), 1.264 (3.72), 1.278 (7.89), 1.292 (4.06), 1.301 (3.16), 1.315 (6.55), 1.329 (3.91), 1.333 (3.24), 1.346 (4.17), 1.360
(2.57), 1.387 (2.01), 1.414 (1.08), 1.452 (0.97), 1.483 (0.93), 1.911 (0.74), 1.946 (0.89), 1.962
(2.60), 1.996 (2.75), 2.064 (1.38), 2.098 (1.56), 2.284 (0.82), 2.320 (0.74), 2.353 (1.30), 2.387
(0.89), 2.514 (6.96), 2.518 (6.51), 2.522 (5.02), 2.536 (2.57), 2.571 (2.05), 2.586 (3.42), 2.622
(3.13), 2.807 (0.97), 2.827 (1.53), 2.853 (0.82), 2.893 (0.60), 2.918 (1.67), 2.935 (1.41), 2.942
(1.60), 2.960 (1.34), 3.012 (1.82), 3.037 (2.34), 3.062 (1.00), 3.110 (0.56), 3.134 (1.00), 3.159
(0.60), 3.234 (4.39), 3.246 (1.67), 3.258 (2.68), 3.268 (2.23), 3.280 (2.27), 3.396 (1.60), 3.423
(5.02), 3.457 (1.97), 3.481 (2.08), 3.505 (2.01), 3.531 (1.34), 3.557 (16.00), 3.569 (10.60), 3.655 (0.41), 3.669 (1.49), 3.683 (1.64), 3.688 (1.86), 3.702 (1.75), 3.717 (0.52), 3.908 (0.52),
3.923 (1.79), 3.937 (1.97), 3.942 (2.05), 3.959 (3.50), 3.973 (3.76), 3.988 (2.01), 4.002 (1.93),
4.009 (1.34), 4.016 (1.64), 4.022 (1.08), 4.031 (0.89), 4.105 (0.78), 4.130 (1.12), 4.309 (1.15),
4.336 (1.12), 6.757 (1.38), 6.771 (1.71), 6.861 (0.52), 6.874 (0.97), 6.887 (0.67), 6.899 (1.04),
6.915 (0.60), 6.960 (5.58), 6.976 (9.71), 6.989 (5.36), 7.106 (4.28), 7.122 (3.50), 7.160 (2.60),
7.173 (2.27), 7.192 (3.01), 7.201 (2.34), 7.208 (4.50), 7.216 (3.42), 7.231 (1.90), 7.252 (1.30),
7.255 (1.34), 7.271 (3.05), 7.288 (3.50), 7.300 (2.83), 7.313 (5.51), 7.330 (5.21), 7.345 (3.65),
7.354 (2.20), 7.424 (3.09), 7.428 (2.98), 7.434 (5.17), 7.439 (3.94), 7.447 (2.16), 7.477 (1.19),
7.492 (1.97), 7.507 (0.86), 7.560 (1.90), 7.606 (2.75), 7.632 (1.12).
LC-MS (method 4): Rt = 1.27 min; MS (ESIpos): m/z = 505 [M+H]+
1H-NMR (500 MHz, DMSO-d6) d [ppm]: -0.130 (0.74), -0.112 (1.28), -0.103 (1.22), -0.086 (0.74), 0.435 (0.47), 0.462 (0.81), 0.480 (0.47), 0.680 (1.35), 0.703 (1.28), 0.745 (0.88), 0.775 (0.74), 0.966 (0.47), 0.985 (0.81), 0.994 (0.81), 1.011 (0.54), 1.114 (0.61), 1.170 (6.48), 1.184 (13.50), 1.198 (6.68), 1.264 (3.78), 1.278(8.03), 1.292 (4.12), 1.301 (3.24), 1.315(6.89), 1.329 (4.05), 1.333 (3.31), 1.346 (4.25), 1.360 (2.50), 1.387 (2.03), 1.409 (1.15), 1.450 (0.95), 1.481 (0.95), 1.911 (0.68), 1.945 (0.88), 1.962 (2.57), 1.996 (2.77), 2.064 (1.35), 2.099 (1.55), 2.285 (0.81), 2.320 (0.74), 2.353 (1.82), 2.368 (1.35), 2.387 (0.88), 2.514 (12.56), 2.518 (12.15), 2.522 (9.72), 2.535 (2.63), 2.570 (2.09), 2.586 (3.38), 2.621 (3.17), 2.642 (1.28), 2.807 (1.01), 2.827 (1.49), 2.833 (1.55), 2.853 (0.95), 2.895 (0.61), 2.917 (1.69), 2.934 (1.35), 2.942 (1.69), 2.949 (1.49), 3.012 (1.89), 3.037 (2.30), 3.062 (1.01), 3.110 (0.54), 3.135 (0.95), 3.160 (0.61), 3.234 (4.32), 3.246 (1.69), 3.257 (2.70), 3.268 (2.30), 3.279 (2.30), 3.305 (0.74), 3.396 (1.62), 3.422 (5.00), 3.456 (1.96), 3.480 (2.09), 3.503 (2.03), 3.532 (1.28), 3.557 (16.00), 3.569
(10.60), 3.655 (0.47), 3.669 (1.55), 3.683 (1.69), 3.688 (1.82), 3.702 (1.76), 3.716 (0.54), 3.909 (0.61), 3.923 (1.82), 3.937 (2.03), 3.942 (2.03), 3.959 (3.51), 3.973 (3.71), 3.988 (2.03), 4.002 (1.89), 4.009 (1.22), 4.017 (1.69), 4.023 (1.15), 4.031 (0.95), 4.103 (0.81), 4.130 (1.08), 4.309 (1 .15), 4.336 (1 .08), 6.757 (1 .35), 6.771 (1 .62), 6.860 (0.47), 6.876 (0.95), 6.889 (0.68), 6.901 (0.95), 6.914 (0.61 ), 6.960 (5.54), 6.976 (9.72), 6.990 (5.40), 7.106 (4.19), 7.122 (3.58), 7.161 (2.63), 7.173 (2.23), 7.192 (2.97), 7.201 (2.43), 7.208 (4.46), 7.216 (3.31 ), 7.231 (1.89), 7.252 (1 .28), 7.255 (1 .35), 7.271 (3.04), 7.288 (3.51 ), 7.300 (2.84), 7.314 (5.60), 7.330 (5.20), 7.345 (3.78), 7.361 (1 .42), 7.424 (3.04), 7.428 (2.90), 7.434 (5.27), 7.439 (3.98), 7.448 (2.30), 7.477 (1 .28), 7.492 (1.89), 7.507 (0.88), 7.561 (1 .82), 7.605 (2.77), 7.631 (1 .08).
Intermediate 224
ethyl {4-[(2-bromophenyl)(cyano)methyl]-1 -[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of isomers)
Figure imgf000393_0001
Using an analogous method described as intermediate 46: intermediate 1 12 (4.70 g, 12.2 mmol) and (2-bromophenyl)acetonitrile (3.2 ml, 24 mmol) gave the titled compound (5.64 g, 72%) after purification by silica chromatography ( Hexane :EtOAc).
Intermediate 225
ethyl (4-{cyano[2-(1 -methyl-1 H-pyrazol-4-yl)phenyl]methyl}-1 -[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl)acetate (mixture of stereoisomers)
Figure imgf000393_0002
A mixture of Intermediate 224 (660 mg, 1 .14 mmol), 1 -methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (248 mg, 1 .19 mmol), bis(triphenylphosphine)palladium(ll) dichloride (9.8 mg, 56.8 pmol) and triphenylphosphine (14.9 mg, 56.8 pmol) in 1 -propanol (7.5 ml) was heated at 105Ό for 1 h. Allowed to cool and the reaction was diluted with water and extracted with EtOAc. The combined organics were concentrated under reduced pressure and the titled compound (610 mg, 92%) was isolated after silica chromatography (DCM: methanol).
Intermediate 226
5-[2-(1 -methyl-1 H-pyrazol-4-yl)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]- 3,9-diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000394_0001
Using an analogous method described as intermediate 1 16: intermediate 225 (710 mg, 1 .22 mmol) gave the titled compound (497 mg, 75%) after after silica chromatography (DCM: methanol).
The title compound (498 mg) was separated into its diastereoisomers by preparative chiral FIPLC to give diastereoisomer 1 (190 mg, see Intermediate 227) and diastereoisomer 2 (180 mg, see Intermediate 228).
Preparative chiral FIPLC method: Instrument: Sepiatec: Prep SFC100; Column: Reprosil Chiral NR 8m 250x30mm; eluent A: C02; eluent B: ethanol + 0.2 vol % aqueous ammonia (32%); isocratic: 30%B; flow: 100 ml/min; temperature: 40°C; BPR: 150bar; UV: 210nm.
Analytical chiral HPLC method: Instrument: Agilent: 1260, Aurora SFC-Module; Column:
Reprosil Chiral NR 5m 100x4.6mm; eluent A: C02; eluent B: ethanol + 0.2 vol % aqueous ammonia (32%); isocratic: 30%B; flow: 4 ml/min; temperature: 37.50; BPR: 100bar; UV: 210 nm.
Intermediate 227 and Intermediate 228
(5R)-5-[2-(1 -methyl-1 H-pyrazol-4-yl)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]-3,9-diazaspiro[5.5]undecan-2-one
(5S)-5-[2-(1 -methyl-1 H-pyrazol-4-yl)phenyl]-9-[(2R)-3, 3, 3-trifluoro-2-methoxy-2- phenylpropanoyl]-3,9-diazaspiro[5.5]undecan-2-one
Intermediate 227 5-[2-(1 -methyl-1 H-pyrazol-4-yl)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]- 3,9-diazaspiro[5.5]undecan-2-one (Stereoisomer 1 )
For the preparation of the racemic title compound see Intermediate 226.
Analytical Chiral HPLC (method see Intermediate 226): Rt = 2.70 min, e.e. >99%.
Optical rotation (method OR1 ): -20.0° (methanol).
Intermediate 228
5-[2-(1 -methyl-1 H-pyrazol-4-yl)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]- 3,9-diazaspiro[5.5]undecan-2-one (Stereoisomer 2)
For the preparation of the racemic title compound see Intermediate 226.
Analytical Chiral HPLC (method see Intermediate 226): Rt = 4.84 min, e.e. >99%.
Optical rotation (method OR1 ): +61 .8°(methanol).
Intermediate 229
ethyl {4-[[2-(benzyloxy)phenyl](cyano)methyl]-1 -[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]piperidin-4-yl}acetate (mixture of stereoisomers)
Figure imgf000395_0001
Using an analogous method described as intermediate 46: intermediate 1 12 (5.00 g, 13.0 mmol) and [2-(benzyloxy)phenyl]acetonitrile (5.79 g, 25.9 mmol) gave the titled compound (7.66 g, 97%) after purification by silica chromatography (Hexane:EtOAc).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.960 (1 .49), 0.977 (3.22), 0.995 (1 .54), 1 .025 (0.68), 1 .043 (1 .58), 1 .057 (1 .67), 1 .061 (1.45), 1 .074 (0.85), 1.080 (1.72), 1 .097 (0.73), 1.154 (2.78),
1 .171 (5.28), 1 .189 (2.50), 1 .987 (9.33), 2.366 (0.79), 2.404 (0.74), 2.518 (1 .68), 2.522 (1 .1 1 ),
2.923 (0.47), 2.954 (0.61 ), 3.074 (0.42), 3.159 (2.44), 3.173 (2.53), 3.239 (0.79), 3.274 (0.56),
3.567 (4.55), 3.715 (0.43), 3.726 (0.55), 3.743 (0.47), 3.858 (0.50), 3.875 (0.47), 3.896 (3.26),
3.999 (0.74), 4.017 (2.23), 4.034 (2.14), 4.052 (0.73), 4.098 (0.55), 4.1 1 1 (0.55), 4.624 (0.65),
4.969 (0.91 ), 4.997 (0.72), 5.087 (0.52), 5.107 (0.86), 5.120 (0.43), 5.141 (0.53), 5.151 (0.55),
5.199 (2.67), 5.758 (16.00), 6.972 (0.70), 6.975 (0.72), 6.991 (0.42), 6.993 (0.43), 7.027 (0.89), 7.046 (1.33), 7.066 (0.82), 7.117 (2.35), 7.136 (1.82), 7.186 (0.91), 7.207 (1.72), 7.230 (0.83),
7.238 (0.93), 7.254 (1.42), 7.261 (1.55), 7.273 (1.15), 7.280 (1.51), 7.301 (1.17), 7.317 (0.82),
7.321 (0.91), 7.329 (1.08), 7.336 (1.72), 7.345 (1.76), 7.348 (2.40), 7.352 (2.48), 7.362 (3.27),
7.381 (3.05), 7.397 (2.02), 7.401 (3.60), 7.419 (2.97), 7.421 (2.49), 7.434 (2.14), 7.438 (2.02),
7.445 (1.26), 7.451 (1.56), 7.455 (1.41), 7.473 (0.93), 7.497 (0.90), 7.508 (1.51), 7.525 (1.02),
7.529 (0.89).
Intermediate 230 and Intermediate 231
(5R)-5-[2-(benzyloxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one
(5S)-5-[2-(benzyloxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one
Intermediate 230
5-[2-(benzyloxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 1)
Figure imgf000396_0001
Using an analogous method described as intermediate 173: intermediate 229 (12.5 g, 20.5 mmol) gave Intermediate 230 (2.36 g, 20%) and Intermediate 231 (3.52 g, 30%) after silica chromatography (DCM:EtOH) along with recovery of starting material (3.5 g, 28%).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.428 (0.42), 0.450 (0.78), 0.460 (0.78), 0.483 (0.49), 0.757 (1.02), 0.786 (0.86), 0.884 (0.42), 0.901 (0.91), 0.920 (0.49), 0.948 (0.42), 0.958 (0.51), 0.980 (0.93), 0.991 (1.06), 1.014 (0.58), 1.025 (0.49), 1.035 (0.47), 1.052 (0.91), 1.070 (0.84), 1.105 (0.71), 1.170 (0.49), 1.196 (0.60), 1.231 (1.02), 1.263 (0.71), 1.400 (1.33), 1.434 (1.37), 1.888 (8.09), 1.921 (1.09), 1.964 (1.31), 1.997 (1.46), 2.041 (1.62), 2.065 (1.35), 2.264 (1.51), 2.322 (1.02), 2.326 (1.33), 2.331 (0.95), 2.437 (0.53), 2.518 (4.90), 2.522 (3.19), 2.531 (0.69), 2.580 (1.99), 2.624 (1.73), 2.673 (0.93), 2.808 (0.69), 2.841 (1.15), 2.869 (0.66), 2.918 (0.73), 2.945 (0.51), 2.980 (0.80), 2.990 (0.82), 2.999 (0.86), 3.008 (0.91), 3.085 (0.64), 3.115 (1.15), 3.146 (0.78), 3.174 (5.89), 3.216 (0.95), 3.242 (1.57), 3.271 (2.39), 3.451 (1.48), 3.464 (1.44), 3.478 (1.20), 3.491 (1.02), 3.516 (1.11), 3.532 ;2.30), 3.547 (1.97), 3.563 (11.32), 4.046 (0.60), 4.081 (0.58), 4.130 (0.86), 4.164 (0.82), 5.067 (0.73), 5.083 (0.86), 5.097 (4.41), 5.107 (4.92),
5.129 (2.70), 5.137 (0.86), 5.159 (0.66), 5.758 (16.00), 6.757 (1.62), 6.773 (1.84), 6.922 (0.82),
6.940 (1.66), 6.958 (1.04), 6.990 (1.22), 7.008 (2.26), 7.026 (1.17), 7.086 (2.30), 7.105 (3.97),
7.124 (1.84), 7.165 (2.61), 7.184 (4.34), 7.228 (3.77), 7.246 (6.43), 7.267 (3.28), 7.275 (1.55),
7.279 (1.48), 7.297 (2.44), 7.318 (3.30), 7.336 (4.08), 7.351 (4.90), 7.369 (3.77), 7.386 (1.71),
7.404 (1.71), 7.424 (6.74), 7.436 (14.74), 7.440 (15.87), 7.448 (5.56), 7.453 (5.43), 7.469 (1.20), 7.561 (2.13), 7.634 (1.84).
Intermediate 231
5-[2-(benzyloxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 2)
Figure imgf000397_0001
For the preparation and separation of the diastereoisomeric title compound see Intermediate 230.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.066 (0.46), -0.044 (0.81), -0.033 (0.81), -0.011
(0.48), 0.000 (0.40), 0.629 (1.02), 0.663 (0.93), 0.944 (0.65), 1.077 (0.81), 1.095 (1.80), 1.112 (0.88), 1.415 (1.77), 1.425 (1.83), 1.896 (1.13), 1.912 (1.58), 1.955 (1.77), 1.991 (0.49), 2.107 (0.99), 2.249 (0.54), 2.293 (0.45), 2.374 (0.67), 2.480 (0.62), 2.560 (5.57), 2.605 (1.80), 2.716 (0.69), 2.813 (0.41), 2.833 (0.75), 2.847 (0.64), 2.866 (0.75), 2.992 (0.73), 3.000 (0.78), 3.010
(1.18), 3.016 (1.20), 3.030 (0.75), 3.047 (1.18), 3.079 (0.80), 3.248 (2.33), 3.265 (0.99), 3.279 (0.97), 3.291 (1.28), 3.305 (1.13), 3.439 (0.97), 3.467 (1.20), 3.495 (1.34), 3.524 (0.65), 3.590 (9.89), 3.643 (0.49), 4.340 (0.83), 4.371 (0.78), 4.803 (1.95), 4.832 (2.46), 5.024 (2.49), 5.053 (1.99), 5.136 (0.85), 5.172 (0.86), 5.801 (16.00) 6.967 (0.77), 6.978 (1.64), 6.997 (3.46), 7.016
(2.19), 7.045 (1.02), 7.064 (2.17), 7.082 (1.28), 7.131 (3.68), 7.151 (3.16), 7.179 (2.15), 7.199 (2.49), 7.251 (1.96), 7.271 (1.67), 7.287 (0.70), 7.297 (0.43), 7.306 (0.57), 7.334 (1.56), 7.344 (3.45), 7.353 (3.45), 7.361 (5.65), 7.364 (5.25), 7.373 (2.52), 7.380 (3.05), 7.394 (3.01), 7.413 (2.03), 7.426 (4.23), 7.444 (5.06), 7.462 (3.46), 7.479 (0.99), 7.522 (1.34), 7.539 (0.81), 7.651 (2.06), 7.682 (0.72). Intermediate 232
tert-butyl 1 -[2-(benzyloxy)phenyl]-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecane-3-carboxylate (Stereoisomer 1 )
Figure imgf000398_0001
To a solution of Example 123 (2.30 g, 4.16 mmol) in DCM (54 ml) was added di-tert-butyl dicarbonate (1.9 ml, 8.3 mmol) and 4-dimethylaminopyridine (102 mg, 832 pmol). The reaction was stirred at RT for 16h. The reaction was diluted with water and extracted with DCM. The combined organics were washed with 1 M hydrochloric acid (aq), water, sat. sodium bicarbonate (aq) and filtered through an hydrophobic filter and concentrated under reduced pressure to give the titled compound (1 .87 g, 65%) after purification by silica chromatography (Hexane:EtOAc).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .040 (0.42), 1 .073 (0.65), 1 .154 (2.76), 1 .172 (5.29), 1 .190 (2.74), 1 .238 (1 .34), 1 .278 (1.82), 1 .353 (1 .43), 1.988 (9.97), 2.518 (3.01 ), 2.523 (2.10),
3.069 (0.95), 3.159 (1 .87), 3.172 (2.12), 3.467 (0.44), 3.551 (3.77), 4.000 (0.76), 4.017 (2.32),
4.035 (2.30), 4.053 (0.80), 4.097 (0.46), 4.1 1 1 (0.42), 5.094 (0.90), 5.123 (1 .57), 5.134 (1 .29),
5.164 (0.55), 5.758 (16.00), 6.575 (0.58), 6.578 (0.62), 6.594 (0.69), 6.597 (0.65), 6.956 (0.69), 7.100 (0.88), 7.1 19 (2.00), 7.128 (2.07), 7.134 (1 .64), 7.146 (1.64), 7.167 (0.62), 7.289 (0.46),
7.292 (0.46), 7.310 (0.83), 7.320 (0.71 ), 7.331 (1 .15), 7.337 (1.45), 7.346 (1 .20), 7.351 (1 .29),
7.355 (1 .1 1 ), 7.370 (0.95), 7.386 (1.10), 7.391 (0.74), 7.406 (2.17), 7.425 (2.05), 7.431 (2.19),
7.436 (3.1 1 ), 7.456 (1.18), 7.460 (1.08).
Intermediate 233
tert-butyl 1 -(2-hydroxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9- diazaspiro[5.5]undecane-3-carboxylate (Stereoisomer 1 )
Figure imgf000398_0002
Using an analogous method described as intermediate 202 without the addition of HCI: intermediate 232 (2.06 g, 3.16 mmol) gave the titled compound (1.69 g, 86%) after concentrated and was used without further purification.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.222 (0.65), 0.245 (1.17), 0.278 (0.67), 1.075 (1.76), 1.097 (2.08), 1.107 (1.89), 1.132 (1.67), 1.208 (1.65), 1.241 (2.08), 1.325 (11.05), 1.353 (11.40), 1.978 (0.61), 2.013 (0.56), 2.144 (1.35), 2.178 (1.22), 2.413 (0.48), 2.518 (4.67), 2.522 (3.26), 2.673 (0.91), 2.789 (1.17), 2.819 (2.02), 2.851 (1.30), 2.950 (1.48), 3.006 (1.09), 3.040
(2.00), 3.073 (1.91), 3.123 (3.08), 3.159 (5.30), 3.172 (5.21), 3.216 (7.06), 3.238 (0.65), 3.471
(1.61), 3.503 (1.43), 3.552 (16.00), 3.661 (0.65), 3.697 (0.65), 3.759 (0.85), 4.096 (1.09), 4.110 (1.17), 4.122 (0.74), 4.161 (1.61), 4.194 (1.22), 4.518 (0.85), 4.537 (0.85), 6.464 (2.02), 6.483
(2.24), 6.720 (0.72), 6.737 (1.52), 6.755 (2.19), 6.773 (2.56), 6.791 (1.39), 6.808 (1.30), 6.832
(3.76), 6.836 (3.47), 6.853 (3.91), 7.007 (2.56), 7.025 (2.89), 7.043 (0.76), 7.096 (3.39), 7.103
(3.47), 7.106 (3.93), 7.115 (6.99), 7.139 (5.34), 7.157 (5.84), 7.177 (2.37), 7.327 (2.02), 7.336
(2.02), 7.412 (2.87), 7.416 (3.06), 7.421 (5.32), 7.429 (6.93), 7.437 (4.58), 7.448 (1.85), 9.352
(2.93), 9.397 (0.93).
Intermediate 234
(5R)-9-[2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-phenyl-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000399_0001
Using an analogous method as described for intermediate 10: (5R)-5-phenyl-3,9- diazaspiro[5.5]undecan-2-one - salt with hydrochloric acid (200 mg, 712 pmol) was coupled with intermediate racemic 2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (218 mg, 855 pmol) and gave the titled compound (140 mg, 39%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.023 (0.41), 0.000 (0.74), 0.032 (0.46), 0.195 (0.57),
0.215 (0.95), 0.226 (0.95), 0.247 (0.63), 0.643 (1.17), 0.679 (1.01), 0.744 (0.84), 0.779 (0.90),
0.868 (14.61), 0.884 (13.63), 0.923 (0.95), 0.946 (1.69), 0.957 (1.74), 0.989 (1.42), 1.192 (2.18), 1.240 (1.12), 1.253 (1.04), 1.276 (1.88), 1.306 (1.25), 1.339 (1.96), 1.374 (1.44), 1.851
(1.34), 1.895 (1.88), 1.947 (1.64), 1.982 (1.14), 2.049 (1.69), 2.093 (2.56), 2.124 (1.34), 2.143 (1 .96), 2.167 (0.95), 2.187 (1 .55), 2.230 (2.92), 2.273 (2.02), 2.342 (1 .47), 2.386 (2.24), 2.447 (7.71 ), 2.452 (4.80), 2.469 (16.00), 2.616 (0.74), 2.657 (0.98), 2.668 (2.04), 2.681 (3.1 1 ), 2.709 (1 .77), 2.743 (1 .01 ), 2.866 (3.43), 2.896 (3.30), 2.924 (1.85), 2.949 (0.79), 3.047 (0.68), 3.072
(0.82), 3.153 (0.74), 3.171 (1 .20), 3.224 (1 .77), 3.246 (2.56), 3.363 (1 .39), 3.382 (1.44), 3.398
(1 .69), 3.429 (0.82), 3.453 (1 .34), 3.486 (1 .17), 3.555 (0.49), 3.587 (1 .06), 3.623 (0.95), 3.907
(1 .06), 3.942 (0.74), 4.01 1 (1 .09), 4.045 (1 .04), 4.1 1 1 (0.79), 4.146 (0.74), 6.789 (1.01 ), 6.809
(2.73), 6.828 (2.24), 6.851 (2.13), 6.870 (4.93), 6.887 (4.17), 6.999 (1 .88), 7.009 (2.13), 7.018
(2.51 ), 7.036 (2.18), 7.056 (2.29), 7.127 (1 .94), 7.144 (3.65), 7.157 (3.73), 7.185 (1.50), 7.194
(1 .91 ), 7.203 (4.96), 7.210 (2.48), 7.220 (6.65), 7.226 (7.82), 7.245 (1 1 .99), 7.259 (12.02), 7.271 (5.42), 7.291 (4.61 ), 7.31 1 (2.26), 7.356 (5.51 ), 7.377 (4.63), 7.392 (1 .36), 7.397 (1 .85),
7.41 1 (4.28), 7.415 (3.54), 7.431 (3.30), 7.436 (3.27), 7.452 (0.87), 7.457 (0.84), 7.533 (3.65),
7.546 (4.17), 7.553 (4.77), 8.140 (4.72), 8.180 (9.24), 8.194 (7.03).
Intermediate 235
(5R)-9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-phenyl-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000400_0001
Using an analogous method as described for intermediate 10: (5R)-5-phenyl-3,9- diazaspiro[5.5]undecan-2-one - salt with hydrochloric acid (1 g, 3.5 mmol) was coupled with intermediate racemic 2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (1235 mg, 4.3 mmol) and gave the titled compound (1 .3 g, 71 %) after purification by preparative HPLC (Method 6).
The title compound was separated into its diastereoisomers by preparative chiral HPLC to give diastereoisomer 1 (302 mg, see Intermediate 236) and diastereoisomer 2 (265 mg, see Intermediate 237).
Preparative chiral HPLC method: Instrument: PrepCon Labomatic HPLC; Column: Chiralpak IG 5m, 250x30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 80%A+20%B; flow: 40 ml/min; temperature: 2513; UV: 220 nm. Analytical chiral HPLC method: Instrument: Waters Alliance 2695; Column: Chiralpak IG 3m, 100x4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 80%A+20%B; flow: 1.4 ml/min; temperature: 25‘C; UV: 220 nm.
Intermediate 236 and Intermediate 237
(5R)-9-[(2R)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-phenyl-3,9- diazaspiro[5.5]undecan-2-one
(5R)-9-[(2S)-2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-phenyl-3,9- diazaspiro[5.5]undecan-2-one
Intermediate 236
(5R)-9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-phenyl-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 1 )
For the preparation of the racemic title compound see Intermediate 235.
Analytical Chiral HPLC (method see Intermediate 235): Rt = 1.99 min, e.e. >99%.
Optical rotation (method OR1 ): -4.4° (methanol). Intermediate 237
(5R)-9-[2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxypropanoyl]-5-phenyl-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 2)
For the preparation of the racemic title compound see Intermediate 235.
Analytical Chiral HPLC (method see Intermediate 235): Rt = 2.60 min, e.e. >99%.
Optical rotation (method OR1 ): -30.4° (methanol).
Intermediate 238
(5R)-5-phenyl-9-[3,3,3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)propanoyl]-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000401_0001
Using an analogous method as described for intermediate 10: (5R)-5-phenyl-3,9- diazaspiro[5.5]undecan-2-one - salt with hydrochloric acid (1 g, 3.5 mmol) was coupled with intermediate racemic 3,3, 3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)propanoic acid (1 .01 g, 3.56 mmol) and gave the titled compound (1.4 g, 76%) after purification by preparative HPLC (Method 6).
LC-MS (Method 4): Rt = 1 .28 min; MS (ESIpos): m/z = 51 1 [M+H]+
Intermediate 239
(5R)-9-[2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000402_0001
Using an analogous method as described for intermediate 10: (5R)-5-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-2-one - salt with hydrochloric acid (4.13 g, 80 % purity, 1 1 .1 mmol) was coupled with intermediate racemic 2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-2- methoxypropanoic acid (4.76 g, 14.4 mmol) and gave the titled compound (5.78) after purification on silica gel (dichloro methane/EtOH 0-10%).
The title compound was separated into its diastereoisomers by preparative chiral HPLC to give diastereoisomer 1 (2.3 g, see Intermediate 240) and diastereoisomer 2 (2.2 mg, see Intermediate 241 ).
Preparative chiral HPLC method: Instrument: PrepCon Labomatic HPLC; Column: Chiralpak IG 5m, 250x30; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 80%A+20%B; flow: 40 ml/min; temperature: 250; UV: 220 nm.
Analytical chiral HPLC method: Waters Alliance 2695; Column: Chiralpak IG 3m, 100x4.6; eluent A: hexane + 0.1 vol % diethylamine; eluent B: ethanol; isocratic: 80%A+20%B; flow: 1 .4 mUmin; temperature: 25Ό; UV: 220 nm.
Intermediate 240 and Intermediate 241
(5R)-9-[(2R)-2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4- fluorophenyl)-3,9-diazaspiro[5.5]undecan-2-one
(5R)-9-[(2S)-2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4- fluorophenyl)-3,9-diazaspiro[5.5]undecan-2-one Intermediate 240
(5R)-9-[2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 1 )
For the preparation of the racemic title compound see Intermediate 239.
Analytical Chiral FIPLC (method see Intermediate 239): Rt = 1.85 min, e.e. >99%.
Optical rotation (method OR1 ): -5.1“(methanol).
Intermediate 241
(5R)-9-[2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-5-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 2)
For the preparation of the racemic title compound see Intermediate 239.
Analytical Chiral HPLC (method see Intermediate 239): Rt = 3.16 min, e.e. >99%.
Optical rotation (method OR1 ): -27.5° (methanol).
Intermediate 242
(5R)-9-[difluoro(naphthalen-1 -yl)acetyl]-5-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-2-one
Figure imgf000403_0001
Using an analogous method as described for intermediate 10: (5R)-5-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-2-one (100 mg, 381 pmol) was coupled with intermediate difluoro(naphthalen-1 -yl)acetic acid (102 mg, 457 pmol; CAS-RN:[73790-14-4]) and gave the titled compound 65.8 mg (35 % yield)after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.559 (1 .17), 0.582 (2.02), 0.612 (1 .33), 0.800 (0.92), 0.832 (1 .74), 0.854 (1 .42), 0.962 (2.56), 0.992 (2.49), 1.023 (1.96), 1 .033 (1 .86), 1.055 (1 .29),
1 .066 (1 .17), 1 .100 (2.59), 1 .122 (2.52), 1 .138 (3.28), 1.158 (1.14), 1 .170 (1 .17), 1.191 (2.05),
1 .223 (1 .70), 1 .299 (2.93), 1 .331 (1.83), 1 .430 (2.18), 1.464 (1.93), 2.025 (3.72), 2.069 (4.51 ),
2.107 (3.12), 2.151 (4.36), 2.321 (5.87), 2.364 (3.53), 2.427 (5.33), 2.470 (6.44), 2.522 (8.33),
2.539 (5.30), 2.665 (1 .33), 2.669 (1.83), 2.673 (1 .39), 2.852 (4.01 ), 2.866 (5.65), 2.886 (4.32),
2.985 (1 .48), 3.014 (3.85), 3.045 (3.91 ), 3.083 (2.21 ), 3.1 17 (3.44), 3.150 (4.17), 3.176 (3.35),
3.186 (3.00), 3.248 (1 .39), 3.266 (2.46), 3.367 (1 .39), 3.389 (2.40), 3.412 (2.59), 3.442 (1 .86),
3.556 (2.21 ), 3.590 (1 .89), 3.660 (1.89), 3.695 (1 .64), 4.060 (1.99), 4.094 (1 .93), 4.161 (2.18), 4.196 (2.08), 7.033 (4.07), 7.055 (12.47), 7.065 (12.81), 7.072 (15.40), 7.077 (14.83), 7.093 (16.00), 7.107 (8.87), 7.115 (6.56), 7.129 (3.47), 7.167 (0.57), 7.197 (0.63), 7.280 (0.73), 7.484 (3.12), 7.503 (5.68), 7.516 (4.39), 7.521 (6.34), 7.533 (7.79), 7.537 (8.62), 7.554 (10.38), 7.559 (11.01), 7.578 (8.39), 7.592 (8.27), 7.611 (4.73), 7.640 (12.09), 7.673 (1.07), 7.731 (5.46), 7.749 (4.86), 7.765 (5.02), 7.784 (4.01), 7.980 (4.95), 7.999 (7.76), 8.015 (6.94), 8.036 (4.01), 8.070 (5.40), 8.088 (6.41), 8.104 (4.92), 8.167 (4.51), 8.187 (4.32).
Intermediate 243
ethyl {1-benzyl-4-[cyano(4-fluorophenyl)methyl]piperidin-4-yl}acetate
Figure imgf000404_0001
Using an analogous method described as intermediate 46: ethyl (1 -benzylpiperidin-4- ylidene)acetate (70.0 g, 270 mmol) and (4-fluorophenyl)acetonitrile (70.0 g, 270 mmol) gave the titled compound (87.5 g) after purification by silica chromatography (DCM:EtOH).
LC-MS (Method 2): Rt = 1.47 min; MS (ESIpos): m/z = 395[M+H]+
Intermediate 244
9-benzyl-5-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-2-one
Figure imgf000404_0002
Using an analogous method described as intermediate 47: intermediate 243 (61.3 g, 155 mmol) gave the titled compound 54.2 g (90 % purity, 89 % yield).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.035 (0.52), 1.053 (1.00), 1.070 (0.49), 1.192 (1.07), 1.224 (1.95), 1.245 (1.52), 1.252 (1.33), 1.275 (0.97), 1.285 (0.78), 1.345 (1.49), 1.373 (0.90),
1.395 (0.73), 1.406 (0.80), 1.427 (1.12), 1.435 (1.11), 1.458 (0.64), 1.468 (0.54), 2.035 (2.50),
2.053 (1.63), 2.059 (1.68), 2.078 (3.97), 2.099 (1.55), 2.106 (1.51), 2.129 (0.81), 2.277 (3.34),
2.321 (2.68), 2.518 (2.55), 2.522 (1.67), 2.546 (1.51), 2.575 (1.23), 2.669 (0.43), 2.947 (1.23),
2.961 (1.69), 2.968 (1.70), 2.982 (1.34), 3.283 (0.80), 3.289 (0.92), 3.297 (0.99), 3.302 (1.09),
3.335 (16.00), 3.437 (1.46), 3.458 (1.40), 3.465 (1.10), 3.487 (0.81), 7.129 (3.21), 7.151 (7.07), 7.173 (4.36), 7.181 (1.41), 7.193 (4.60), 7.204 (4.45), 7.212 (7.32), 7.219 (3.90), 7.254 (6.63), 7.266 (6.03), 7.271 (6.50), 7.279 (5.78), 7.287 (4.83), 7.301 (3.13), 7.639 (3.13). Intermediate 244 was separated into its enantiomers via chiral HPLC to give enantiomer 1 (Intermediate 245) and enantiomer 2 (intermediate 246).
Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; column: YMC Amylose SA 3m 100x4.6mm; eluent A: acetonitrile; eluent B: ethanol; isocratic: 75%A+25%B; flow 1 .0 mUmin; temperature: 25 Ό; DAD 220 nm.
Preparative chiral HPLC method: Labomatic HD3000, Knauer Pump 100, Labcol Vario 4000 Plus, Knauer DAD 2600; column YMC Amylose SA 5m 250x50mm Nr.026; eluent A: acetonitrile; eluent B: ethanol; isocratic: 75%A+25%B; flow 150.0 mL/min; UV @ 220 nm.
Intermediate 245
(5R)-9-benzyl-5-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-2-one
Figure imgf000405_0001
Analytical Chiral HPLC: Rt = 2.9 min
1H-NMR (400 MHz, DMS0-d6) d [ppm]: 0.967 (0.41 ), 1 .108 (16.00), 1 .192 (0.50), 1.208 (0.47), 1 .222 (0.88), 1 .244 (0.62), 1 .255 (0.58), 1 .274 (0.48), 1.285 (0.40), 1 .346 (0.68), 1.373 (0.44),
1 .427 (0.51 ), 1 .436 (0.53), 2.035 (1.15), 2.059 (0.69), 2.078 (1.79), 2.100 (0.72), 2.278 (1 .53),
2.321 (1 .30), 2.327 (0.60), 2.518 (4.48), 2.523 (3.60), 2.545 (1.67), 2.575 (1 .00), 2.669 (0.41 ),
2.948 (0.50), 2.962 (0.70), 2.969 (0.76), 2.983 (0.63), 3.289 (0.41 ), 3.297 (0.45), 3.303 (0.47),
3.314 (0.82), 3.397 (4.79), 3.435 (0.76), 3.459 (0.69), 3.466 (0.58), 3.487 (0.44), 4.194 (1 .52),
7.130 (1 .45), 7.152 (3.41 ), 7.174 (2.10), 7.183 (0.58), 7.187 (0.84), 7.191 (1 .69), 7.194 (2.00),
7.205 (2.03), 7.212 (3.21 ), 7.214 (3.30), 7.221 (1 .83), 7.255 (2.99), 7.266 (2.60), 7.272 (2.93),
7.276 (2.06), 7.280 (2.69), 7.287 (2.26), 7.291 (1 .60), 7.294 (1.21 ), 7.302 (1 .56), 7.639 (1 .41 ).
Intermediate 246
(1 R)-9-benzyl-1 -(4-fluorophenyl)-3,9-diazaspiro[5.5]undecane
Figure imgf000405_0002
To a solution of Intermediate 244 (5R)-9-benzyl-5-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan- 2-one (3.00 g, 8.51 mmol) in THF (130 ml, 1 .6 mol; CAS-RN:[109-99-9]) and water (5.1 ml, 280 mmol) LAH (17 ml, 1 .0 M, 17 mmol; CAS-RN:[16853-85-3]) was added dropwise under temperature control. Then the reaction mixture was stirred for 4 hours at 65Ό, cooled down and 5 ml_ water were carefully added. The precipitate was removed by filtation and the solvent was removed in vacuo to give 2.8g of the title compound.
LC-MS (Method 2): Rt = 1 .4 min; MS (ESIpos): m/z = 339[M+H]+
Intermediate 247
tert-butyl (1 R)-9-benzyl-1 -(4-fluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000406_0001
(1 R)-9-benzyl-1 -(4-fluorophenyl)-3,9-diazaspiro[5.5]undecane (400 mg, 1 .18 mmol) was dissolved in dichloromethane (7.6 ml, 120 mmol; CAS-RN:[75-09-2]), N,N- diisopropylethylamine (310 mI, 1.8 mmol; CAS-RN:[7087-68-5]) and (330 mI, 1.4 mmol; CAS- RN:[24424-99-5]) were added. After stirring for 1 hour 5 mL of saturated aqueous ammonium chloride solution were added. After extraction with dichloromethane, the combined organic phase was dryed and concentrated in vacuo to give 420 mg (81 % yield) of the title compound after purification on silica cichloromethane/EtOH 100% -> 9:1 .
LC-MS (Method 2): Rt = 1 .67 min; MS (ESIpos): m/z = 439[M+H]+
Intermediate 248
tert-butyl (1 R)-1 -(4-fluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000406_0002
Intermediate 247(3.00 g, 6.84 mmol) was dissolved in ethanol (550 ml_) under an athmosphere of nitrogen. Then Palladium, 10% on activated carbon, Pearlman (50-70% wetted powder) (364 mg, 3.42 mmol; CAS-RN:[7440-05-3])was added. The reaction mixture was stirred under an atmosphere of hydrogen for 12 hours then the reaction mixture was filtered through Celite® and the solvent was removed in vacuo.
LC-MS (Method 2): Rt = 1 .35 min; MS (ESIpos): m/z = 349[M+H]+
Intermediate 249 tert-butyl (1 R)-9-[2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 -(4- fluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000407_0002
Using an analogous method as described for intermediate 10: Intermediate 248 (200 mg, 574 mihoI) was coupled with intermediate 2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-2- methoxypropanoic acid (228 mg, 689 pmol) and gave the titled compound 250 mg (66% yield) after purification on silica gel (dichloromethane/EtOH 100% -> 9:1).
LC-MS (Method 4): Rt = 1 .66 min; MS (ESIpos): m/z = 661 [M+FI]+
Intermediate 250
tert-butyl (1 R)-9-[(2RS)-2-(5-bromo-2-fluorophenyl)-3,3,3-trifluoro-2-methoxypropanoyl]-1 -(4- fluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000407_0001
Using an analogous method as described for intermediate 249: Intermediate 248 (200 mg, 574 pmol) was coupled with intermediate 2-(5-bromo-2-fluorophenyl)-3,3,3-trifluoro-2- methoxypropanoic acid (228 mg, 689 pmol) and gave the titled compound 150 mg (95 % purity, 38 % yield) after purification by HPLC.
LC-MS (Method 4): Rt = 1 .64 min; MS (ESIpos): m/z = 661 [M+H]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .049 (0.51 ), 1 .081 (0.54), 1 .139 (0.82), 1 .352 (16.00), 2.160 (0.47), 2.180 (1 .69), 2.518 (3.52), 2.522 (2.26), 2.818 (0.64), 2.845 (0.69), 2.877 (0.42), 3.081 (0.54), 3.102 (0.54), 3.213 (1.04), 3.242 (1 .37), 3.271 (0.73), 3.551 (6.55), 3.723 (0.55),
4.205 (0.44), 6.389 (0.47), 6.654 (0.42), 6.868 (0.77), 6.969 (0.63), 6.982 (0.85), 6.991 (0.98),
7.004 (0.83), 7.028 (0.61 ), 7.049 (0.90), 7.063 (0.74), 7.105 (0.45), 7.122 (0.99), 7.127 (0.95),
7.144 (0.71 ), 7.149 (0.63), 7.200 (1.53), 7.206 (1 .90), 7.222 (2.55), 7.228 (2.41 ), 7.244 (1 .15),
7.251 (0.99), 7.280 (0.53), 7.301 (0.61 ), 7.306 (0.45), 7.328 (0.41 ), 7.693 (0.89), 7.697 (0.86), 7.709 (1 .84), 7.719 (1 .56), 7.731 (1.76), 7.793 (0.41 ), 7.804 (0.50), 7.815 (0.47), 7.822 (0.48), 7.825 (0.48).
Intermediate 251
ethyl {1 -benzyl-4-[cyano(4-fluoro-2-methylphenyl)methyl]piperidin-4-yl}acetate (racemic mixture)
Figure imgf000408_0001
Using an analogous method described as intermediate 46: ethyl (1 -benzylpiperidin-4- ylidene)acetate (17.4 g, 67.0 mmol) and (4-fluoro-2-methylphenyl)acetonitrile (20.0 g, 134 mmol) gave the titled compound (40g) as a crude product.
LC-MS (Method 2): Rt = 1 .54 min; MS (ESIpos): m/z = 410[M+H]+
Intermediate 252
9-benzyl-5-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-2-one (racemic mixture)
Figure imgf000408_0002
A mixture of ethyl {1 -benzyl-4-[(R)-cyano(4-fluoro-2-methylphenyl)methyl]piperidin-4-yl}acetate (40.0 g, 97.9 mmol) and Cobalt (II) chloride hexahydrate (46.6 g, 196 mmol) was stirred in methanol (600 ml, 15 mol; CAS-RN:[67-56-1 ]) at 0Ό for 10 min. After that sodiumboronhydrid: (74.1 g, 1 .96 mol; CAS-RN:[16940-66-2]) was added in portions. The resulting mixture was stirred at rt for 2 days. Hydrochloric acid (490 ml, 3.0 M, 1 .5 mol; CAS-RN:[7647-01 -0]) was added followed by saturated ammonium chloride solution. The mixture was extracted with dichloro methane, dryed and evaporated to dryness. Purification on silica gel gave the title compound 23.6 g (66 % yield)
LC-MS (Method 2): Rt = 1 .22 min; MS (ESIpos): m/z = 367[M+H]+
Intermediate 253
9-benzyl-1 -(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecane (racemic mixture)
Figure imgf000409_0001
To a solution of Intermediate 252 9-benzyl-5-(4-fluoro-2-methylphenyl)-3,9- diazaspiro[5.5]undecan-2-one (10.0 g, 27.3 mmol) in THF (300 ml) under Argon was added bhorane dimethylsulfide (96 ml, 2.0 M, 190 mmol; CAS-RN:[13292-87-0]) and the reaction was heated at 80Ό for 17h. To the reaction was added E tOH (400 ml) and heated at 800 for 20h. The reaction was concentrated under reduced pressure and and the titled compound 5.30 g (55 % yield) was obtained after purification on silica gel.
LC-MS (Method 2): Rt = 1 .50 min; MS (ESIpos): m/z = 353[M+H]+
Intermediate 254
tert-butyl-9-benzyl-1 -(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (racemic mixture)
Figure imgf000409_0002
The title compound was synthesized according to the procedure described for Intermediate 247 starting from intermediate 253 (5.3 g, 15 mmol) to give 4g of the title compound (59% yield)
LC-MS (Method 2): Rt = 1 .71 min; MS (ESIpos): m/z = 453[M+H]+
Intermediate 255
tert-butyl (1 S)-1 -(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
Figure imgf000409_0003
The title compound was synthesized according to the procedure described for Intermediate 248 starting from intermediate 254 (4.00 g, 8.84 mmol) to give 1 .6g of the title compound (50% yield)
LC-MS (Method 2): Rt = 1 .59 min; MS (ESIpos): m/z = 363[M+H]+ Intermediate 256 to Intermediate 259 (Table: Intermediates for Example Table 4)
Using an analogous method as described for intermediate 10: Intermediate 255 was coupled with the respective substituted phenyl acetic acid and gave the titled compound after purification on silica gel.
Table 4:
Figure imgf000410_0001
Figure imgf000411_0002
Intermediate 260 to Intermediate 282 (Table: Intermediates for Example Table 5)
Using an analogous method as described for intermediate 10: Intermediate 86 was coupled with the respective acid and gave the titled compound after purification on silica gel or HPLC.
Table 5:
Figure imgf000411_0001
Figure imgf000412_0001
Figure imgf000413_0001
Figure imgf000414_0001
Figure imgf000415_0001
Figure imgf000416_0001
Figure imgf000417_0001
Figure imgf000418_0001
Figure imgf000419_0001
Figure imgf000420_0001
Intermediate 283
ethyl {1 -benzyl-4-[cyano(4-fluoro-2-methylphenyl)methyl]piperidin-4-yl}acetate
Figure imgf000421_0001
Using an analogous method described as intermediate 46: ethyl (1 -benzylpiperidin-4- ylidene)acetate (5.65 g, 21 .9 mmol) and (4-fluoro-2-methylphenyl)acetonitrile (6.5 g, 43.6 mmol) gave the titled compound (31 .5 g) after work-up which was used directly in the next step.
Intermediate 284
9-benzyl-5-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000421_0002
Using an analogous method described as intermediate 173: Intermediate 283 (12.9 g, 31 .6 mmol), CoCI2.6H20 (15.0 g, 63.2 mmol) and sodium borohydride (23.9 g, 632 mmol) gave the titled compound (2.4 g, 21 %) after silica chromatography.
LC-MS (Method 2): Rt = 1 .23 min; MS (ESIpos): m/z = 367.7 [M+H]+
Intermediate 285
5-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000421_0003
Using an analogous method described as intermediate 248: Intermediate 284 (2.40 g, 6.55 mmol) gave the titled compound (1 .8 g, 99%) after work-up which was used directly in the next step.
LC-MS (Method 2): Rt = 0.84 min; MS (ESIpos): m/z = 277.6 [M+H]+
Intermediate 286
9-{difluoro[2-(trifluoromethoxy)phenyl]acetyl}-5-(4-fluoro-2-methylphenyl)-3,9- diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000422_0001
Using an analogous method as described for intermediate 10: Intermediate 285 (300 mg, 1 .09 mmol) was coupled with difluoro[2-(trifluoromethoxy)phenyl]acetic acid (306 mg, 1.19 mmol) and gave the titled compound (240 mg, 43%) after purification by silica chromatography.
LC-MS (Method 4): Rt = 1 .21 min; MS (ESIpos): m/z = 532.6 [M+H]+
Intermediate 287
(2R)-2-(3-bromo-4-fluorophenyl)-3,3,3-trifluoro-2-(methoxymethyl)propanoic acid
Figure imgf000422_0002
This compound was synthesized in analogy to similar compounds published by Holmes et al., J. Am. Chem. Soc., 2017, 139, 81 14-81 17.
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .231 (1 .21 ), 2.522 (0.90), 3.225 (16.00), 4.247 (2.85), 4.254 (4.07), 4.259 (2.80), 7.402 (0.97), 7.425 (2.60), 7.446 (1.81 ), 7.473 (0.61 ), 7.475 (0.71 ), 7.478 (0.74), 7.481 (0.69), 7.485 (0.73), 7.487 (0.77), 7.490 (0.78), 7.493 (0.84), 7.497 (0.48), 7.499 (0.46), 7.502 (0.42), 7.768 (1.04), 7.772 (1 .04), 7.784 (1.06), 7.788 (1 .02).
Optical rotation (method OR1 ): +9.9°(methanol). Intermediate 288
(2S)-2-(3-bromo-4-fluorophenyl)-3,3,3-trifluoro-2-(methoxymethyl)propanoic acid
Figure imgf000423_0001
This compound was synthesized in analogy to similar compounds published by Holmes et al., J. Am. Chem. Soc., 2017, 139, 8114-8117.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.232 (2.12), 1.256 (0.48), 2.518 (2.50), 2.523 (1.53), 3.224 (16.00), 4.248 (2.62), 4.254 (3.78), 4.260 (2.71), 7.403 (1.14), 7.425 (2.65), 7.447 (1.82), 7.460 (0.48), 7.473 (0.57), 7.476 (0.67), 7.478 (0.72), 7.481 (0.80), 7.485 (0.72), 7.488 (0.74), 7.490 (0.72), 7.493 (0.79), 7.497 (0.44), 7.500 (0.43), 7.768 (0.98), 7.772 (0.95), 7.785 (0.99), 7.789 (0.95).
Optical rotation (method OR1): -6.5°(methanol).
Intermediate 289
tert-butyl 9-[(2R)-2-(3-bromo-4-fluorophenyl)-3,3,3-trifluoro-2-(methoxymethyl)propanoyl]-1-(2- methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Stereoisomer 1 )
Figure imgf000423_0002
Using an analogous method described as intermediate 10: intermediate 86 (80.0 mg, 222 pmol) was coupled with Intermediate 287 (84.2 mg, 244 pmol) and gave the titled compound (100 mg, 66%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.988 (1.08), 1.068 (2.63), 1.164 (1.55), 1.277 (3.78), 1.352 (13.43), 1.877 (0.95), 1.911 (0.88), 2.108 (1.22), 2.144 (1.08), 2.323 (3.11), 2.327 (4.32), 2.332 (3.04), 2.518 (16.00), 2.523 (10.94), 2.665 (5.81), 2.669 (8.10), 2.674 (9.38), 2.679 (9.86), 2.753 (1.42), 2.795 (1.69), 2.808 (1.35), 2.858 (1.08), 3.072 (1.69), 3.286 (0.95), 3.315 (2.70), 3.445 (1.01), 3.476 (1.01), 3.627 (0.68), 3.739 (14.11), 3.761 (5.87), 3.826 (1.42), 3.852 (1.42), 4.108 (1.96), 4.135 (1.82), 4.273 (1.35), 4.305 (0.95), 6.901 (2.90), 6.919 (4.66), 6.937
(2.57), 6.961 (1.96), 6.981 (2.63), 7.001 (1.42), 7.058 (2.30), 7.076 (1.82), 7.192 (1.76), 7.213
(2.03), 7.234 (1.08), 7.287 (0.68), 7.390 (1.28), 7.412 (2.30), 7.433 (1.55), 7.510 (0.68), 8.548
(0.47).
Intermediate 290
tert-butyl 9-[(2S)-2-(3-bromo-4-fluorophenyl)-3,3,3-trifluoro-2-(methoxymethyl)propanoyl]-1-(2- methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Stereoisomer 1 )
Figure imgf000424_0001
Using an analogous method described as intermediate 10: intermediate 86 (80.0 mg, 222 pmol) was coupled with Intermediate 288 (84.2 mg, 244 pmol) and gave the titled compound (100 mg, 66%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.338 (0.52), 0.711 (0.58), 1.101 (2.67), 1.276 (4.17), 1.350 (16.00), 1.491 (0.41), 1.608 (0.87), 1.874 (0.64), 2.072 (1.16), 2.106 (1.62), 2.147 (0.81), 2.322 (2.67), 2.326 (3.65), 2.331 (2.61), 2.518 (13.45), 2.522 (9.04), 2.664 (3.65), 2.668 (4.81), 2.673 (3.94), 2.794 (1.22), 2.808 (1.68), 2.853 (2.49), 2.905 (9.22), 3.079 (1.22), 3.474 (1.16),
3.601 (5.80), 3.627 (1.10), 3.765 (11.94), 3.911 (1.22), 3.937 (1.51), 4.158 (2.49), 4.186 (3.07),
4.232 (1.97), 6.682 (0.46), 6.782 (0.64), 6.877 (1.97), 6.896 (1.33), 6.975 (3.13), 6.997 (3.54),
7.008 (3.54), 7.028 (2.67), 7.065 (1.57), 7.193 (2.32), 7.211 (2.78), 7.332 (1.10), 7.412 (1.28),
7.433 (2.14), 7.455 (1.16), 7.491 (2.49), 8.548 (0.46).
Intermediate 291
ethyl {1-benzyl-4-[cyano(4-fluoro-2-methoxyphenyl)methyl]piperidin-4-yl}acetate
Figure imgf000424_0002
Using an analogous method described as intermediate 46: ethyl (1 -benzylpiperidin-4- ylidene)acetate (12.7 g, 49.0 mmol) and (4-fluoro-2-methoxyphenyl)acetonitrile (8.90 g, 53.9 mmol) gave the titled compound (14.8 g, 71 %) after silica chromatography.
Intermediate 292
9-benzyl-5-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000425_0001
Using an analogous method described as intermediate 47: intermediate 291 (86.1 g, 203 mmol) gave the titled compound (63.8 g, 82%) after purification by silica chromatography (DCM:EtOH).
The title compound (65.4 g) was separated into its diastereoisomers by preparative chiral HPLC to give stereoisomer 1 (27.4 g, see Intermediate 293) and stereoisomer 2 (26 g, see Intermediate 294).
Preparative chiral HPLC method: Labomatic HD3000, Knauer Pump 100, Labcol Vario 4000 Plus, Knauer DAD 2600; Column: YMC Amylose SB 5m 250x50mm; Eluent A: Hexane; Eluent B: 2-Propanol + 0.2% Diethylamine; Isocratic: 75%A+25%B; Flow: 150.0 ml/min; UV @ 220 nm.
Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; Column: YMC Amylose SB 3m 100x4.6mm; Eluent A: Hexane; Eluent B: 2-Propanol + 0.2% Diethylamine; Isocratic:
75%A+25%B; Flow: 1.0 ml/min; Temperatur: 25 Ό; DAD 220 nm.
Intermediate 293 and Intermediate 294
(5R)-9-benzyl-5-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-2-one
(5S)-9-benzyl-5-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-2-one
Intermediate 293
9-benzyl-5-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-2-one (Stereoisomer 1 )
For the preparation of the racemic title compound see Intermediate 292. Analytical Chiral HPLC (method see Intermediate 292): Rt = 2.70 min, e.e. >99%.
Optical rotation (method OR1 ): -35.2° (methanol).
Intermediate 294
9-benzyl-5-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-2-one (Stereoisomer 2) For the preparation of the racemic title compound see Intermediate 292.
Analytical Chiral HPLC (method see Intermediate 292): Rt = 3.30 min, e.e. >99%.
Optical rotation (method OR1 ): +35.0°(methanol).
Intermediate 295
9-benzyl-1 -(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecane (Stereoisomer 1 )
Figure imgf000426_0001
To a solution of Intermediate 293 (5 g, 13 mmol) in anhydrous THF (84 ml) was added slowly dropwise a solution lithium aluminiumhydride (26 ml, 1 M in THF). On complete addition, the reaction was heated at 650 for 3h. The reaction wa s allowed to cool. The reaction was quenched by the careful addition of water. The reaction was extracted with EtOAc, the organic layers were combined, washed with sat. NaCI (aq), filtered through an hydrophobic filter and concentrated under reduced pressure and was used directly without further purification.
Intermediate 296
tert-butyl 9-benzyl-1 -(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Stereoisomer 1 )
Figure imgf000426_0002
To a solution of Intermediate 295 (4.6 g, 12.5 mmol) in anhydrous DCM (80 ml) was added BOC20 (3.27 g, 15 mmol) followed by N,N-diisopropylethylamine (3.26 ml, 18.7 mmol) and stirred at RT for 1 h. The reaction was added to sat. ammonium chloride (aq) and was extracted with DCM, the organic layers were combined, washed with water, filtered through an hydrophobic filter and concentrated under reduced pressure and gave the titled compound (5.5 g, 94%) which was used directly without further purification.
Intermediate 297
tert-butyl 1 -(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
(Stereoisomer 1 )
Figure imgf000427_0001
Using an analogous method described as intermediate 248: Intermediate 296 (5.5 g, 1 1 .7 mmol) gave the titled compound (2.5 g, 56%) after purification by silica chromatography (DCM:EtOH).
Intermediate 298
9-benzyl-1 -(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecane (stereoisomer 2)
Figure imgf000427_0002
Using an analogous method described as intermediate 295: intermediate 294 (5.00 g, 13.1 mmol) gave the titled compound (3.2 g, 66%) which was used directly without further purification. Intermediate 299
tert-butyl 9-benzyl-1 -(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (stereoisomer 2)
Figure imgf000428_0001
Using an analogous method described as intermediate 296: intermediate 298 (3.20 g, 8.68 mmol) gave the titled compound (4 g, 98%) which was used directly without further purification.
Intermediate 300
tert-butyl 1 -(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
(stereoisomer 2)
Figure imgf000428_0002
Using an analogous method described as intermediate 297: intermediate 299 (4.00 g, 8.54 mmol) gave the titled compound (2.9 g, 90%) after purification by silica chromatorgraphy (DCM:EtOH).
Intermediate 301 to Intermediate 303 (Table: Intermediates for Example Table 6)
Using an analogous method as described for intermediate 10: Intermediate 297 was coupled with the respective acid and gave the titled compound after purification on silica gel or HPLC.
Table 6:
Figure imgf000428_0003
Figure imgf000429_0001
Intermediate 304 to Intermediate 306 (Table: Intermediates for Example Table 7)
Using an analogous method as described for intermediate 10: Intermediate 300 was coupled with the respective acid and gave the titled compound after purification on silica gel or HPLC. Table 7:
Figure imgf000430_0001
Figure imgf000431_0003
Intermediate 307
ethyl {1-benzyl-4-[[2-(benzyloxy)-4-fluorophenyl](cyano)methyl]piperidin-4-yl}acetate
Figure imgf000431_0001
Using an analogous method described as intermediate 46: ethyl (1 -benzylpiperidin-4- ylidene)acetate (30.0 g, 116 mmol) and [2-(benzyloxy)-4-fluorophenyl]acetonitrile (55.8 g, 231 mmol) gave the titled compound (40.5 g, 70%) after purification by silica chromatography (Hexane:EtOAc).
Intermediate 308
9-benzyl-5-[2-(benzyloxy)-4-fluorophenyl]-3,9-diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000431_0002
Using an analogous method described as intermediate 173: Intermediate 307 (11.5 g, 23.0 mmol) gave the titled compound after purification by silica chromatography ( Hexane :EtOAc). 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.154 (3.50), 1.171 (7.68), 1.189 (4.39), 1.212 (1.03),
1.223 (1.34), 1.242 (1.44), 1.255 (1.13), 1.264 (1.31), 1.323 (1.30), 1.354 (0.81), 1.461 (0.51),
1.471 (0.63), 1.492 (0.96), 1.502 (0.96), 1.524 (0.55), 1.534 (0.46), 1.939 (1.90), 1.986 (16.00), 2.013 (1.86), 2.041 (1.84), 2.071 (0.71), 2.396 (2.93), 2.408 (1.29), 2.439 (3.13), 2.518 (1.78),
2.523 (1.53), 2.532 (1.18), 2.561 (1.04), 3.148 (1.00), 3.155 (0.86), 3.166 (0.93), 3.173 (1.17), 3.41 1 (0.67), 3.435 (1 .40), 3.462 (3.74), 3.471 (1 .94), 3.495 (0.66), 3.999 (1 .05), 4.017 (3.19), 4.034 (3.17), 4.052 (1.04), 5.123 (10.28), 6.764 (0.89), 6.770 (1 .04), 6.786 (1 .79), 6.791 (1 .97), 6.807 (1 .03), 6.813 (1 .04), 6.999 (2.15), 7.005 (2.30), 7.027 (2.19), 7.034 (2.20), 7.164 (4.1 1 ),
7.181 (6.23), 7.185 (5.53), 7.192 (1.39), 7.199 (3.22), 7.204 (0.93), 7.213 (2.00), 7.216 (2.41 ),
7.247 (5.98), 7.265 (6.81 ), 7.278 (1.36), 7.282 (2.27), 7.285 (1.74), 7.289 (1 .74), 7.321 (0.98),
7.324 (0.73), 7.332 (0.75), 7.338 (2.73), 7.344 (1 .13), 7.352 (1.37), 7.356 (2.41 ), 7.360 (1 .53),
7.389 (2.87), 7.409 (6.04), 7.426 (3.84), 7.446 (6.41 ), 7.464 (3.15), 7.468 (2.29), 7.626 (2.65).
Intermediate 309
5-(4-fluoro-2-hydroxy-phenyl)-3,9-diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000432_0001
Using an analogous method described as intermediate 248: Intermediate 308 (5 g, 10.9 mmol) gave the titled compound (2.35 g, 77%) after purification by preparative RP Biotage chromatography (acetonitrile:Water).
Intermediate 310
tert-butyl 7-(4-fluoro-2-hydroxyphenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate (mixture of stereoisomers)
Figure imgf000432_0002
To a solution Intermediate 309 (4.23 g, 15.2 mmol) in acetonitrile (98 ml) was added di-tert- butyl dicarbonate (4.98 g, 22.8 mmol) and 4-dimethylaminopyridine (557 mg, 4.56 mmol) and triethylamine (6.4 ml, 46 mmol). The reaction was stirred at RT for 8h. The reaction was quenched with sat. ammoniumchloride (aq), extracted with EtOAc. The organics were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The titled compound was used directly in the next step without further purification.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .107 (0.65), 1 .312 (10.21 ), 1 .358 (0.73), 1 .406 (1 .70), 1 .485 (16.00), 1 .493 (1.88), 2.518 (1 .02), 2.523 (0.68), 2.989 (2.74), 3.159 (0.71 ), 3.172 (0.77), 3.604 (0.76), 6.599 (1 .03), 6.626 (0.53), 7.162 (0.73), 7.182 (0.42), 7.210 (0.51 ), 7.216 (0.46), 7.233 (0.48), 7.240 (0.44), 7.631 (0.49), 7.714 (0.56), 10.036 (1.13).
Intermediate 311
tert-butyl (7S)-7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-10-oxo-3,9-diazaspiro[5.5]undecane-3- carboxylate (mixture of stereoisomers)
Figure imgf000433_0001
A mixture of Intermediate 310 (1 .87 g, 4.94 mmol), 1 -bromo-3-methoxypropane (1.13 g, 7.41 mmol), potassiumcarbonate (2.73 g, 19.8 mmol) in DMF (28 ml) were heated at 12013 for 12h. The reaction was cooled to RT, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography to give the titled compound (1 .64 g, 71 %).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .154 (0.46), 1 .172 (0.88), 1 .189 (0.43), 1 .262 (0.51 ), 1 .305 (14.34), 1 .340 (0.46), 1 .351 (0.42), 1.380 (0.50), 1.952 (1 .02), 1 .968 (1 .55), 1 .983 (1 .08), 1 .987 (1 .92), 2.1 15 (0.50), 2.159 (0.60), 2.460 (0.64), 2.518 (0.78), 2.523 (0.51 ), 3.330 (16.00),
3.419 (0.63), 3.428 (0.90), 3.461 (0.53), 3.470 (1 .23), 3.485 (2.47), 3.501 (1 .04), 3.983 (0.46),
3.999 (0.98), 4.006 (0.48), 4.013 (0.52), 4.017 (0.69), 4.021 (0.79), 4.035 (0.60), 6.737 (0.61 ),
6.744 (0.69), 6.877 (0.65), 6.883 (0.67), 6.905 (0.68), 6.912 (0.66), 7.221 (0.53), 7.238 (0.65),
7.242 (0.63), 7.260 (0.50), 7.668 (0.87).
The title compound (1640 mg) was separated into its stereoisomers by preparative chiral HPLC to give stereoisomer 1 (660 mg, see Intermediate 312) and stereoisomer 2 (615 mg, see Intermediate 313).
Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000, Column: Chiralpak IA 5m 250x30mm; Eluent A: Acetonitrile + 0.1 Vol- % Diethylamine (99%); Eluent B: MTBE; Isocratic: 50%A+50%B; FIOw: 50.0 ml/min; UV 220 nm.
Analytical chiral HPLC method Instrument: Agilent HPLC 1260; Column: Chiralpak IA 3m 100x4, 6mm; Eluent A: Acetonitrile + 0.1 Vol-% Diethylamine (99%); Eluent B: MTBE; Isocratic: 50%A+50%B; Flow: 1.4 ml/min; Temperature: 25 Ό; DA D 280 nm. Intermediate 312 and Intermediate 313
tert-butyl (7R)-7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-10-oxo-3,9-diazaspiro[5.5]undecane-3- carboxylate
tert-butyl (7S)-7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-10-oxo-3,9-diazaspiro[5.5]undecane-3- carboxylate
Intermediate 312
tert-butyl 7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-10-oxo-3,9-diazaspiro[5.5]undecane-3- carboxylate (Stereoisomer 1 )
For the preparation of the racemic title compound see Intermediate 31 1 .
Analytical Chiral FIPLC (method see Intermediate 31 1 ): Rt = 3.17 min, e.e. 91 .2%.
Optical rotation (method OR1 ): -34.9° (methanol).
Intermediate 313
tert-butyl 7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-10-oxo-3,9-diazaspiro[5.5]undecane-3- carboxylate
For the preparation of the racemic title compound see Intermediate 31 1 .
Analytical Chiral HPLC (method see Intermediate 31 1 ): Rt = 4.03 min, e.e. 97.1 %.
Optical rotation (method OR1 ): +38.6°(methanol).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .103 (0.72), 1 .261 (0.56), 1 .305 (14.88), 1.339 (0.48), 1 .351 (0.43), 1 .381 (0.52), 1 .952 (1.04), 1 .967 (1 .62), 1.983 (1.09), 2.1 15 (0.53), 2.159 (0.64),
2.460 (0.72), 2.518 (0.93), 2.522 (0.60), 3.330 (16.00), 3.418 (0.66), 3.429 (0.98), 3.461 (0.55),
3.469 (1 .27), 3.485 (2.56), 3.501 (1.09), 3.983 (0.47), 3.998 (0.93), 4.005 (0.50), 4.014 (0.53),
4.022 (0.80), 4.037 (0.41 ), 6.737 (0.63), 6.743 (0.72), 6.876 (0.68), 6.882 (0.71 ), 6.905 (0.71 ),
6.91 1 (0.70), 7.221 (0.53), 7.238 (0.68), 7.242 (0.68), 7.260 (0.52), 7.667 (0.93).
Intermediate 314
5-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid (Stereoisomer 1 )
Figure imgf000434_0001
To a solution of Intermediate 312 (600 mg, 1 .33 mmol) in THF (7.1 ml) at 0Ό was added 4M hydrochloric acid in dioxane (3.3 ml). The reaction was stirred for 48h and an additional portion of 4M hydrochloric acid in dioxane (7 eq) were added and stirred for 64h. The reaction was concentrated under reduced pressure to give the titled compound which was used directly in the next step.
Intermediate 315
9-{difluoro[2-(trifluoromethoxy)phenyl]acetyl}-5-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 1 )
Figure imgf000435_0001
Using an analogous method as described for intermediate 10: Intermediate 313 (70 mg, 200 mihoI) was coupled with difluoro[2-(trifluoromethoxy)phenyl]acetic acid (69.5 mg, 271 pmol) and gave the titled compound 84 mg (77% yield) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.438 (0.47), 0.448 (0.47), 0.932 (1 .06), 0.948 (1 .07), 1 .055 (0.78), 1 .096 (0.75), 1 .158 (0.53), 1 .325 (0.40), 1.399 (0.72), 1 .845 (1 .15), 1.861 (1 .79), 1 .876 (1 .23), 1 .935 (0.89), 1 .950 (1.34), 1 .966 (0.96), 2.030 (0.84), 2.074 (0.92), 2.141 (0.56), 2.185 (0.67), 2.322 (0.67), 2.327 (0.89), 2.331 (0.67), 2.518 (3.41 ), 2.523 (2.24), 2.543 (0.81 ), 2.587 (0.64), 2.620 (1 .20), 2.664 (1.79), 2.669 (1 .23), 2.673 (0.78), 2.807 (0.81 ), 2.914 (0.70), 2.945 (0.70), 3.015 (0.42), 3.024 (0.45), 3.034 (0.42), 3.046 (0.47), 3.121 (1 .03), 3.155 (0.58), 3.204 (16.00), 3.243 (10.41 ), 3.304 (1.48), 3.372 (1 .65), 3.388 (3.44), 3.402 (2.35), 3.464 (1 .18), 3.480 (2.61 ), 3.495 (1 .26), 3.513 (0.79), 3.542 (0.40), 3.832 (0.58), 3.840 (0.50), 3.856 (0.87), 3.904 (0.42), 3.919 (0.90), 3.935 (0.53), 3.943 (0.70), 3.958 (0.58), 3.966 (0.44), 3.982 (0.76), 4.006 (0.87), 4.022 (0.75), 4.179 (0.45), 4.212 (0.42), 6.707 (0.40), 6.713 (0.48), 6.728 (0.81 ), 6.734 (0.89), 6.749 (0.47), 6.756 (0.50), 6.789 (0.58), 6.796 (0.62), 6.873 (0.67), 6.879 (0.65), 6.901 (0.82), 6.909 (1 .21 ), 6.917 (0.96), 6.939 (0.92), 6.945 (0.86), 7.054 (0.48), 7.071 (0.61 ), 7.093 (0.44), 7.160 (0.73), 7.181 (0.81 ), 7.193 (0.78), 7.210 (0.89), 7.232 (0.65), 7.454 (0.48), 7.473 (1 .1 1 ), 7.491 (1 .34), 7.512 (1 .15), 7.533 (0.90), 7.551 (0.56), 7.656 (1.95), 7.695 (0.65), 7.716 (2.77), 7.736 (2.23). Intermediate 316
5-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-2-one, salt with hydrochloric acid (Stereoisomer 2)
Figure imgf000436_0001
To a solution of Intermediate 313 (600 mg, 1 .33 mmol) in THF (7.1 ml) at 0Ό was added 4M hydrochloric acid in dioxane (3.3 ml). The reaction was stirred for 48h and an additional portion of 4M hydrochloric acid in dioxane (7 eq) were added and stirred for 64h. The reaction was concentrated under reduced pressure to give the titled compound which was used directly in the next step.
Intermediate 317
9-{difluoro[2-(trifluoromethoxy)phenyl]acetyl}-5-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9- diazaspiro[5.5]undecan-2-one (Stereoisomer 2)
Figure imgf000436_0002
Using an analogous method as described for intermediate 10: Intermediate 316 (70 mg, 200 pmol) was coupled with difluoro[2-(trifluoromethoxy)phenyl]acetic acid (76.7 mg, 300 pmol) and gave the titled compound 73 mg (37% yield) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.439 (0.45), 0.449 (0.46), 0.931 (3.25), 0.934 (1 .01 ), 0.948 (3.19), 0.952 (0.51 ), 1 .055 (0.75), 1 .097 (0.75), 1.158 (0.50), 1 .401 (0.69), 1.845 (1 .15),
1 .860 (1 .77), 1 .876 (1 .23), 1 .934 (0.87), 1 .950 (1 .33), 1.966 (0.92), 2.031 (0.83), 2.075 (0.92),
2.142 (0.56), 2.185 (0.66), 2.327 (0.58), 2.332 (0.41 ), 2.518 (2.66), 2.523 (1 .79), 2.544 (0.82),
2.587 (0.64), 2.620 (1 .16), 2.665 (1.45), 2.669 (0.92), 2.673 (0.54), 2.915 (0.70), 2.941 (0.75),
2.957 (0.52), 3.025 (0.45), 3.034 (0.42), 3.043 (0.44), 3.122 (1 .03), 3.155 (0.57), 3.204 (16.00), 3.244 (10.23), 3.292 (0.77), 3.304 (1 .17), 3.373 (1 .54), 3.389 (3.37), 3.403 (2.39), 3.464 (1 .13), 3.480 (2.54), 3.495 (1 .19), 3.513 (0.77), 3.833 (0.56), 3.841 (0.48), 3.857 (0.87), 3.904 (0.40),
3.919 (0.89), 3.927 (0.43), 3.935 (0.54), 3.943 (0.71 ), 3.958 (0.56), 3.965 (0.42), 3.981 (0.72), 3.997 (0.51 ), 4.007 (0.83), 4.022 (0.72), 4.180 (0.44), 4.213 (0.41 ), 6.713 (0.48), 6.728 (0.81 ),
6.734 (0.90), 6.749 (0.46), 6.756 (0.48), 6.789 (0.56), 6.796 (0.64), 6.872 (0.66), 6.879 (0.66),
6.901 (0.78), 6.909 (1 .21 ), 6.917 (0.93), 6.939 (0.91 ), 6.945 (0.86), 7.054 (0.48), 7.072 (0.62),
7.093 (0.44), 7.160 (0.72), 7.180 (0.81 ), 7.193 (0.79), 7.21 1 (0.87), 7.214 (0.87), 7.232 (0.67),
7.454 (0.50), 7.473 (1 .14), 7.492 (1.37), 7.512 (1 .18), 7.532 (0.92), 7.551 (0.58), 7.657 (1 .95),
7.695 (0.66), 7.717 (2.77), 7.737 (2.21 ).
Intermediate 318
5-[2-(3-methoxypropoxy)phenyl]-9-[3,3,3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)propanoyl]- 3,9-diazaspiro[5.5]undecan-2-one (Stereoiosmer 1 )
Figure imgf000437_0001
Using an analogous method as described for intermediate 10: Intermediate 314 ((200 mg, 602 pmol) was coupled with 3,3,3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)propanoic acid (205 mg, 722 pmol) and gave the titled compound 39 mg and its diastereoisomer 32 mg (see Intemediate 319) after purification by chiral preparative FIPLC.
Optical rotation (method OR1 ): +21 .9°(methanol). 5415
Intermediate 319
5-[2-(3-methoxypropoxy)phenyl]-9-[3,3,3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)propanoyl]- 3,9-diazaspiro[5.5]undecan-2-one (Stereoiosmer 2)
Figure imgf000437_0002
For the preparation of the racemic title compound see Intermediate 318.
Optical rotation (method OR1 ): +25.9° (methanol). Intermediate 320
(3S)-oxolan-3-yl 4-methylbenzene-1 -sulfonate
Figure imgf000438_0001
A mixture of (3S)-oxolan-3-ol (910 mI, 1 1 mmol), triethylamine (2.4 ml, 17 mmol) and trimethylamine hydrochloride (108 mg, 1 .13 mmol) in DCM (14 ml) was cooled to OTD and stirred for 10 minutes. Thereafter 4-methylbenzene-1 -sulfonyl chloride (2.38 g, 12.5 mmol) was added in 2 portions. The solution was stirred at rt overnight under nitrogen. The reaction mixture was treated with N,N-dimethylethylenediamine to consume the unreacted 4- methylbenzene-1 -sulfonyl chloride. Water was added to the mixture. Afterwards the aqueous phase was extracted with DCM (3 x) and concentrated to dryness. The titled compound (1 .8 g, 65%) was obtained after silica chromatography purification.
Intermediate 321
9-benzyl-5-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9-diazaspiro[5.5]undecan-2-one (mixture of stereoisomers)
Figure imgf000438_0002
Using an analogous method as described for intermediate 31 1 : Intermediate 309 (1.75 g, 4.75 mmol) and 3S)-oxolan-3-yl 4-methylbenzene-1 -sulfonate (1 .73 g, 7.12 mmol - Intermediate 320) gave the titled compound 2.35 g after purification by silica chromatography.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .154 (2.93), 1 .172 (6.22), 1 .190 (3.21 ), 1 .346 (0.40), 1 .987 (1 1.41 ), 1 .995 (0.75), 2.002 (1 .01 ), 2.024 (0.66), 2.045 (1 .04), 2.064 (0.44), 2.416 (0.68), 2.434 (0.81 ), 2.460 (0.66), 2.477 (0.91 ), 2.518 (1 .26), 2.522 (0.81 ), 2.579 (0.41 ), 2.589 (0.41 ), 2.727 (13.10), 2.729 (12.96), 2.888 (16.00), 3.372 (2.12), 3.397 (0.45), 3.409 (0.64), 3.740
(0.68), 3.751 (0.69), 3.761 (1 .02), 3.772 (1 .16), 3.781 (1.06), 3.799 (0.57), 3.807 (0.63), 3.817
(0.45), 3.853 (0.61 ), 3.864 (0.66), 3.878 (0.50), 3.892 (0.54), 3.999 (0.77), 4.017 (2.28), 4.034
(2.19), 4.053 (0.70), 6.765 (0.59), 6.858 (0.43), 6.865 (0.68), 6.872 (0.45), 6.887 (0.46), 6.894 (0.70), 6.901 (0.43), 7.181 (1 .53), 7.200 (2.85), 7.215 (0.85), 7.231 (0.58), 7.249 (2.39), 7.266 (1 .68), 7.270 (1.52), 7.284 (0.60), 7.614 (0.91 ), 7.950 (1.89).
Intermediate 322
9-benzyl-1 -(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9-diazaspiro[5.5]undecane (mixture of stereoisomers)
Figure imgf000439_0001
To a solution of Intermediate 321 (2.35 g, 5.36 mmol) in THF (98 ml) under Argon was added borane— (methylsulfanyl)methane (1/1 ) (19 ml, 2.0 M, 38 mmol) and heated at reflux conditions for 48h. The reaction was colled and EtOH was added carefully and the reaction heated for a further 48h under reflux conditions. The reaction was concentrated under reduced pressure and used directly in the next step.
Intermediate 323
tert-butyl 9-benzyl-1 -(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate (mixture of stereoisomers)
Figure imgf000439_0002
Using an analogous method as described for intermediate 310: Intermediate 322 (3.00 g, 50 % purity, 3.53 mmol) gave the titled compound 2.44 g (70%) after purification by silica chromatography.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (1 .87), 1 .172 (0.96), 1 .219 (1 .38), 1 .236 (2.90), 1 .254 (1 .89), 1 .262 (0.91 ), 1 .272 (0.81 ), 1 .294 (0.92), 1.336 (4.04), 1 .344 (4.13), 1.424 (2.98),
1 .446 (13.40), 1.468 (8.94), 1 .476 (1 .75), 1 .482 (3.44), 1 .488 (16.00), 1 .510 (0.63), 1 .526 (0.73), 2.051 (3.31 ), 2.089 (0.69), 2.143 (0.61 ), 2.177 (0.62), 2.208 (0.41 ), 2.216 (0.78), 2.222
(2.14), 2.251 (0.41 ), 2.265 (0.44), 2.278 (0.48), 2.299 (0.47), 2.332 (0.54), 2.340 (0.48), 2.391
(0.47), 2.483 (0.47), 2.582 (1 .73), 2.586 (1 .13), 3.004 (1.10), 3.414 (0.85), 3.428 (1.27), 3.800
(1 .01 ), 3.810 (1 .01 ), 3.821 (1 .37), 3.827 (1 .44), 3.842 (0.89), 3.865 (0.64), 3.886 (0.55), 3.918 (0.49), 3.929 (0.52), 3.937 (0.58), 3.949 (0.57), 3.963 (0.50), 4.076 (0.59), 4.082 (0.67), 4.094
(0.57), 4.099 (0.68), 5.1 19 (0.68), 6.813 (0.50), 6.818 (0.42), 6.957 (0.43), 7.141 (0.41 ), 7.161
(0.75), 7.218 (1 .27), 7.236 (2.47), 7.239 (2.19), 7.256 (1.84), 7.262 (0.86), 7.270 (0.73), 7.274
(0.87), 7.298 (1.57), 7.316 (1.71 ), 7.327 (1 .16), 7.333 (0.84), 7.344 (0.41 ).
Intermediate 324
tert-butyl 1 -(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate (mixture of stereoisomers)
Figure imgf000440_0001
Using an analogous method as described for intermediate 309: Intermediate 323 (950 mg, 1 .81 mmol) gave the titled compound 805 g (84%) after filtration and concentration under reduced pressure.
Intermediate 325
tert-butyl 1 -(4-fluoro-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate (mixture of stereoisomers)
Figure imgf000440_0002
Starting with (3R)-oxolan-3-ol instead of the (3S)-oxolan-3-ol and using the similar chemical tranformations as described for Intermediates 320 through to 326, the Intermediate 327 was synthesized. EXPERIMENTAL SECTION - EXAMPLES
Example 1
(rac)-2-phenyl-1-[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1-one
Figure imgf000441_0001
To intermediate 10 (80.0 mg, 178 pmol) was added 4M hydrochloric acid in dioxane (0.5 ml) and stirred at rt for 16h. The reaction was concentrated under reduced pressure and purified by preparative HPLC (method 6) to give the title compound (43.5 mg, 66 % yield).
LC-MS (Method 2): Rt = 1.13 min; MS (ESIpos): m/z = 349 [M+H]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.954 (0.66), 0.964 (0.80), 0.987 (1.54), 0.996 (2.03), 1.029 (2.10), 1.040 (1.51), 1.062 (0.89), 1.073 (0.75), 1.101 (0.76), 1.142 (4.32), 1.151 (5.21),
1.162 (5.25), 1.187 (2.37), 1.199 (2.20), 1.218 (3.02), 1.227 (3.38), 1.254 (0.53), 1.754 (1.43), 1.788 (1.31), 1.851 (1.54), 1.885 (1.39), 2.088 (2.09), 2.095 (2.13), 2.102 (2.22), 2.111 (1.67), 2.122 (2.04), 2.129 (1.98), 2.136 (1.94), 2.522 (3.82), 2.530 (2.09), 2.539 (0.60), 2.621 (2.53), 2.627 (2.51), 2.654 (3.42), 2.687 (2.09), 2.697 (1.79), 2.721 (2.21), 2.730 (2.61), 2.760 (3.05), 2.784 (3.57), 3.019 (1.71), 3.051 (3.42), 3.084 (3.52), 3.096 (2.34), 3.117 (2.22), 3.136 (1.13), 3.546 (15.24), 3.564 (16.00), 3.596 (1.45), 3.623 (1.52), 3.658 (1.31), 4.041 (1.49), 4.075 (1.39), 4.112 (1.43), 4.145 (1.34), 7.013 (3.56), 7.019 (4.31), 7.027 (5.88), 7.036 (8.59), 7.041 (6.25), 7.053 (5.14), 7.060 (6.25), 7.069 (6.72), 7.076 (6.65), 7.079 (7.33), 7.086 (7.82), 7.090 (7.57), 7.095 (7.14), 7.136 (1.90), 7.145 (13.35), 7.152 (10.93), 7.157 (5.60), 7.159 (6.46),
7.162 (7.15), 7.167 (2.38), 7.170 (2.97), 7.174 (3.12), 7.181 (12.31), 7.186 (11.63), 7.194 (6.13), 7.199 (6.62), 7.209 (2.46), 7.218 (4.43), 7.223 (4.66), 7.235 (5.81), 7.239 (5.73), 7.250 (12.24), 7.268 (12.18), 7.285 (3.89).
Example 2
(rac)-2-methyl-2-phenyl-1-[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]propan-1-one
Figure imgf000441_0002
Using the method described for Example 1 with intermediate 11 (200 mg, 420 pmol) gave the titled compound (107 mg, 64%) after preparative HPLC purification (Method 6).
LC-MS (method 2): Rt = 1 .31 min; MS (ESIpos): m/z = 377 [M+H]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.587 (1 .64), 1 .027 (2.73), 1 .196 (8.15), 1 .360 (7.37), 1 .824 (0.85), 1 .991 (3.67), 2.024 (3.41 ), 2.074 (0.40), 2.323 (1.78), 2.327 (2.30), 2.332 (2.01 ),
2.337 (1 .64), 2.396 (2.06), 2.518 (4.10), 2.523 (3.84), 2.539 (3.13), 2.565 (4.22), 2.624 (4.17),
2.660 (4.98), 2.665 (5.33), 2.669 (5.33), 2.674 (4.84), 2.696 (7.37), 3.013 (2.28), 3.269 (2.47),
4.168 (1 .00), 6.933 (8.44), 6.975 (1 1 .45), 6.993 (1 1 .97), 7.082 (2.54), 7.176 (4.81 ), 7.238 (2.49), 7.257 (6.04), 7.274 (8.27), 7.286 (15.86), 7.305 (16.00), 7.321 (5.45). Example 3
(rac)- (1 -phenylcyclopropyl)[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]methanone
Figure imgf000442_0001
Using the method described for Example 1 with intermediate 12 (150 mg, 316 pmol) gave the titled compound (79.4 mg, 64%) after preparative HPLC purification (Method 6).
LC-MS (method 2): Rt = 1 .21 min; MS (ESIpos): m/z = 375 [M+H]+
Example 4
(rac)- (1 -phenylcyclopentyl)[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]methanone
Figure imgf000442_0002
Using the method described for Example 1 with intermediate 13 (150 mg, 298 pmol) gave the titled compound (61 .6 mg, 49%) after preparative HPLC purification (Method 6). 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.470 (0.96), 0.603 (2.15), 1 .010 (2.12), 1 .177 (2.44), 1 .254 (1 .16), 1 .482 (4.08), 1 .553 (4.02), 1 .809 (1 .06), 2.043 (5.56), 2.209 (2.09), 2.322 (2.54),
2.326 (3.05), 2.331 (2.57), 2.404 (1.51 ), 2.518 (8.35), 2.522 (6.55), 2.539 (7.61 ), 2.559 (3.73),
2.632 (2.73), 2.664 (4.31 ), 2.669 (4.95), 2.673 (4.43), 2.678 (3.82), 2.704 (6.55), 2.874 (1 .25),
3.050 (1 .83), 3.1 18 (1 .51 ), 3.322 (4.69), 4.149 (1 .03), 4.212 (1.00), 6.961 (8.51 ), 7.119 (3.95),
7.170 (1 .70), 7.266 (16.00), 7.284 (1 1.53), 7.298 (4.08), 8.520 (0.48).
Example 5, Example 6 and Example 7
(rac)-[1 -(3,5-dimethylphenyl)cyclopentyl][7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]methanone
[1 -(3,5-dimethylphenyl)cyclopentyl][(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]methanone
[1 -(3,5-dimethylphenyl)cyclopentyl][(7S)-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]methanone
Example 5
(rac)-[1 -(3,5-dimethylphenyl)cyclopentyl][7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]methanone
Figure imgf000443_0001
Using the method described for Example 1 with intermediate 14 (150 mg, 283 pmol) gave the titled compound (70.3 mg, 55%) after preparative HPLC purification (Method 6).
LC-MS (method 2): Rt = 1 .60 min; MS (ESIpos): m/z = 431 [M+H]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.089 (0.53), 0.597 (0.96), 0.772 (2.26), 1 .040 (2.57), 1 .215 (1 .92), 1 .417 (2.57), 1 .538 (7.04), 2.051 (16.00), 2.074 (13.40), 2.104 (15.29), 2.322 (1 .55), 2.327 (2.02), 2.331 (1 .58), 2.414 (2.73), 2.518 (6.91 ), 2.522 (4.37), 2.539 (4.34), 2.551 (3.38), 2.575 (4.16), 2.636 (3.63), 2.665 (7.16), 2.668 (7.41 ), 2.718 (7.66), 2.741 (6.85), 2.769 (2.64), 2.779 (2.54), 3.043 (1 .86), 3.322 (3.13), 4.126 (0.99), 4.210 (1 .05), 6.568 (10.85), 6.728 (2.48), 6.762 (2.45), 7.023 (8.62), 7.037 (9.30), 7.173 (1.86), 7.191 (6.57), 7.208 (8.06), 7.222 (12.99), 7.241 (13.49), 7.257 (4.87).
The title compound (60 mg) was separated into its enantiomers by preparative chiral HPLC to give stereoisomer 1 (22 mg, see Example 6) and stereoisomer 2 (23 mg, see Example 7). Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000; column: Cellulose SC 5m 250x30mm; eluent A: Methanol + 0.1 Vol-% Diethylamine (99%), eluent B: Ethanol; isocratic; flow 35 ml/min temperature: 250; UV 220nm.
Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; column: Cellulose SC 3m 100x4.6mm; eluent A: Methanol + 0.1 Vol-% Diethylamine (99%), eluent B: Ethanol; isocratic; flow 1 .4 ml/min temperature: 25Ό; UV 220nm.
Example 6
[1 -(3,5-dimethylphenyl)cyclopentyl][-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]methanone (stereoisomer 1 )
Figure imgf000444_0001
For the preparation of the racemic title compound and separation into its enantiomers see Example 5.
Analytical Chiral FIPLC (method see Example 5): Rt = 1 .72 min, e.e., 99.4%.
Optical rotation (method OR1 ): -13.8°(methanol).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.581 (0.85), 0.769 (1 .64), 0.797 (2.61 ), 0.802 (1 .72), 0.814 (2.47), 0.820 (2.49), 0.839 (1.35), 0.849 (0.75), 0.885 (1.16), 0.903 (2.18), 0.922 (1 .14),
1 .052 (1 .54), 1 .070 (2.12), 1 .088 (2.55), 1 .107 (2.39), 1.137 (3.18), 1 .159 (2.39), 1.230 (3.59),
1 .414 (2.97), 1 .536 (6.20), 1 .867 (1 .62), 1 .936 (1 .83), 2.045 (13.57), 2.096 (16.00), 2.209 (1 .20), 2.229 (0.73), 2.322 (0.93), 2.327 (1 .20), 2.332 (0.93), 2.387 (0.48), 2.392 (0.50), 2.405
(0.54), 2.41 1 (0.73), 2.518 (6.52), 2.523 (4.69), 2.539 (1.68), 2.640 (2.72), 2.669 (7.22), 2.698
(6.41 ), 2.730 (4.94), 2.758 (3.36), 2.827 (3.28), 3.090 (2.41 ), 4.135 (1 .06), 4.228 (1.00), 6.562
(9.94), 6.726 (2.18), 6.762 (2.24), 7.019 (7.64), 7.033 (8.18), 7.199 (2.14), 7.217 (7.93), 7.223
(3.32), 7.233 (10.36), 7.243 (15.56), 7.262 (14.26), 7.277 (4.57). Example 7
[1 -(3,5-dimethylphenyl)cyclopentyl][7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]methanone (stereoisomer 2)
Figure imgf000445_0001
For the preparation of the racemic title compound and separation into its enantiomers see Example 5.
Analytical Chiral FIPLC (method see Example 5): Rt = 2.09 min, e.e., 98.8%.
Optical rotation (method OR1 ): 13.7°(methanol).
Example 8
(rac)-2-(naphthalen-1 -yl)-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 -one
Figure imgf000445_0002
Using the method described for Example 1 with intermediate 15 (150 mg, 301 pmol) gave the titled compound (66.6 mg, 53%) after preparative HPLC purification (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .072 (1 .02), 1 .105 (1 .77), 1 .138 (2.51 ), 1 .160 (3.44), 1 .190 (3.26), 1 .256 (4.56), 1 .270 (4.05), 1 .315 (1 .53), 1.346 (1.67), 1 .368 (0.79), 1.844 (1 .72),
1 .897 (1 .86), 1 .930 (1 .49), 2.161 (2.51 ), 2.323 (2.79), 2.518 (7.95), 2.530 (4.09), 2.551 (3.67),
2.559 (3.95), 2.629 (3.07), 2.660 (5.35), 2.664 (5.02), 2.689 (1.30), 2.722 (2.70), 2.750 (3.77),
2.798 (6.79), 3.051 (1 .77), 3.080 (3.86), 3.108 (3.77), 3.137 (2.65), 3.167 (2.37), 3.195 (2.09),
3.218 (2.65), 3.257 (2.37), 3.649 (1.77), 3.700 (2.00), 3.734 (1.77), 3.922 (1 .53), 3.948 (1 .53), 3.963 (5.02), 3.994 (6.70), 4.01 1 (5.35), 4.035 (2.23), 4.051 (2.84), 4.083 (1 .63), 4.120 (1 .72),
4.153 (1 .63), 7.075 (3.40), 7.094 (6.47), 7.1 13 (4.79), 7.127 (9.35), 7.146 (1 1 .21 ), 7.233 (2.88), 7.252 (5.02), 7.271 (6.09), 7.289 (16.00), 7.307 (1 1 .58), 7.353 (1 .72), 7.373 (4.79), 7.393 (5.49), 7.412 (2.37), 7.449 (3.26), 7.453 (3.30), 7.469 (5.16), 7.486 (2.74), 7.710 (3.86), 7.736 (8.79), 7.758 (1 1.16), 7.778 (3.77), 7.863 (4.51 ), 7.873 (4.65), 7.883 (4.33), 7.894 (3.95).
Example 9
(rac)-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]ethan-1 -one
Figure imgf000446_0001
Using the method described for Example 1 with intermediate 16 (150 mg, 290 pmol) gave the titled compound (55.8 mg, 44%) after preparative HPLC purification (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .035 (0.74), 1 .046 (0.87), 1 .068 (1 .55), 1 .078 (1 .57), 1 .100 (1 .05), 1 .1 14 (1 .30), 1 .127 (1.01 ), 1 .161 (2.36), 1.195 (3.07), 1 .236 (4.80), 1.249 (4.42), 1 .289 (1 .85), 1 .300 (1 .72), 1 .320 (1.67), 1 .331 (1 .58), 1.353 (0.67), 1 .364 (0.54), 1.867 (2.90),
1 .902 (2.60), 2.166 (3.1 1 ), 2.194 (2.88), 2.323 (0.48), 2.326 (0.62), 2.331 (0.47), 2.522 (1 .83),
2.539 (4.26), 2.568 (3.89), 2.669 (3.19), 2.673 (3.08), 2.701 (2.34), 2.742 (2.18), 2.780 (3.00),
2.815 (3.80), 3.085 (1 .65), 3.1 15 (2.59), 3.134 (2.14), 3.165 (2.41 ), 3.210 (2.26), 3.241 (1 .32),
3.582 (2.97), 3.606 (3.15), 3.634 (3.24), 3.654 (2.74), 3.675 (5.38), 3.695 (8.63), 3.721 (4.66), 3.762 (1 .48), 3.995 (1 .71 ), 4.030 (1.63), 4.059 (1 .73), 4.092 (1.60), 7.124 (1 1.12), 7.142
(16.00), 7.159 (6.55), 7.177 (3.61 ), 7.219 (1 .46), 7.237 (4.38), 7.254 (5.44), 7.271 (10.31 ), 7.289 (10.68), 7.305 (3.78), 7.370 (1 .15), 7.388 (3.84), 7.405 (5.31 ), 7.420 (4.91 ), 7.437 (3.34), 7.449 (2.92), 7.467 (3.21 ), 7.485 (1.24), 7.597 (4.24), 7.605 (4.52), 7.624 (3.46).
Example 10
1 -[-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]propan-1 -one
(mixture of stereoisomers)
Figure imgf000446_0002
Using the method described for Example 1 with intermediate 17 (160 mg, 302 pmol) gave the titled compound (63.8 mg, 47%) after preparative HPLC purification (Method 6). 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.298 (0.64), 0.321 (1.12), 0.357 (1.17), 0.391 (1.41), 0.401 (1.39), 0.423 (0.86), 0.771 (1.41), 0.802 (1.31), 0.922 (0.81), 0.932 (0.93), 0.954 (1.60), 0.965 (1.55), 0.987 (0.98), 1.095 (3.84), 1.107 (3.51), 1.128 (3.25), 1.156 (6.97), 1.172 (11.46), 1.187 (7.69), 1.201 (14.19), 1.217 (16.00), 1.229 (11.03), 1.293 (0.74), 1.324 (0.81), 1.335
(0.79), 1.356 (0.43), 1.470 (1.39), 1.504 (1.29), 1.719 (0.69), 1.753 (0.60), 1.840 (2.13), 1.873
(1.53), 1.946 (1.43), 1.980 (1.31), 2.106 (2.08), 2.139 (1.89), 2.300 (1.65), 2.309 (1.91), 2.327 (3.06), 2.336 (2.24), 2.380 (1.46), 2.388 (1.74), 2.409 (1.81), 2.418 (1.81), 2.522 (5.18), 2.539 (5.47), 2.631 (2.13), 2.664 (5.09), 2.668 (4.99), 2.699 (4.39), 2.720 (5.56), 2.745 (6.23), 2.887 (0.91), 2.918 (1.39), 2.948 (0.79), 2.993 (1.24), 3.023 (2.32), 3.047 (2.36), 3.077 (3.30), 3.107 (3.20), 3.139 (1.62), 3.259 (2.60), 3.293 (2.91), 3.381 (6.50), 4.017 (3.20), 4.034 (3.65), 4.051 (3.99), 4.068 (3.08), 4.094 (2.20), 4.117 (2.05), 4.159 (1.19), 4.209 (1.55), 4.242 (1.46), 6.853 (3.34), 6.861 (3.56), 6.872 (4.42), 6.889 (4.42), 6.906 (5.78), 6.927 (5.28), 6.936 (3.58), 6.958 (4.37), 6.980 (3.70), 7.105 (1.55), 7.123 (2.77), 7.146 (4.80), 7.167 (5.35), 7.221 (11.92), 7.235
(9.53), 7.266 (4.61), 7.284 (5.06), 7.313 (4.66), 7.332 (3.08), 7.403 (1.43), 7.421 (3.63), 7.438 (4.08), 7.457 (1.98), 7.597 (1.96), 7.615 (7.19), 7.634 (4.92), 7.670 (3.41), 7.687 (5.35), 7.704 (3.08).
Example 11
(2S)-3,3,3-trifluoro-2-methoxy-2-phenyl-1-[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]propan-1- one (mixture of stereoisomers)
Figure imgf000447_0001
Using the method described for Example 1 with intermediate 18 (150 mg, 274 pmol) gave the titled compound (87.3 mg, 68%) after preparative HPLC purification (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.65), 0.009 (0.74), 0.033 (1.34), 0.044 (1.34), 0.066 (0.77), 0.076 (0.68), 0.108 (0.85), 0.119 (1.08), 0.141 (1.99), 0.152 (2.02), 0.174 (1.22), 0.185 (0.99), 0.444 (1.85), 0.477 (1.56), 0.930 (1.28), 0.963 (2.07), 0.992 (2.10), 1.004 (2.27), 1.027 (2.67), 1.037 (3.18), 1.060 (2.64), 1.072 (2.90), 1.107 (1.93), 1.119 (1.62), 1.141 (3.18), 1.149 (2.96), 1.174 (2.44), 1.182 (2.53), 1.203 (1.93), 1.238 (1.17), 1.274 (1.56), 1.306 (1.25), 1.317 (0.94), 1.338 (0.88), 1.482 (0.71), 1.515 (0.57), 1.829 (0.57), 1.861 (1.39), 1.888 (3.18), 1.921 (2.44), 2.042 (1.73), 2.068 (3.13), 2.101 (2.10), 2.213 (1.99), 2.222 (2.30), 2.242 (2.39), 2.251 (2.27), 2.287 (1.45), 2.291 (2.13), 2.296 (1.65), 2.334 (2.36), 2.343 (2.25), 2.363 (2.93), 2.372 (2.56), 2.396 (0.60), 2.483 (9.55), 2.487 (8.41), 2.504 (1.99), 2.535 (1.48), 2.565 (2.73), 2.596 (2.59), 2.629 (2.76), 2.633 (3.33), 2.638 (3.01), 2.642 (2.50), 2.676 (4.77), 2.702 (5.66),
2.753 (3.44), 2.780 (3.44), 2.787 (3.75), 2.804 (2.84), 2.812 (2.90), 2.836 (1.90), 2.921 (1.14),
2.953 (3.67), 2.984 (4.97), 3.026 (3.75), 3.062 (6.37), 3.128 (7.22), 3.184 (1.39), 3.233 (2.25),
3.269 (2.53), 3.343 (2.76), 3.377 (2.10), 3.420 (1.68), 3.456 (1.45), 4.009 (0.80), 4.044 (0.85),
4.096 (0.57), 4.133 (1.36), 4.165 (1.31), 4.219 (1.82), 4.253 (1.76), 6.795 (3.27), 6.800 (3.95),
6.809 (4.35), 6.819 (3.69), 6.856 (4.18), 6.864 (5.40), 6.874 (5.17), 6.895 (3.89), 6.916 (8.36),
6.935 (5.91), 6.998 (7.73), 7.017 (5.34), 7.034 (2.90), 7.053 (7.62), 7.066 (6.62), 7.084 (6.56),
7.105 (4.83), 7.124 (5.94), 7.144 (4.55), 7.163 (1.76), 7.209 (3.33), 7.215 (3.07), 7.228 (7.87),
7.246 (10.43), 7.251 (11.34), 7.257 (11.45), 7.265 (16.00), 7.276 (14.58), 7.282 (13.78), 7.372 (2.73), 7.375 (2.98), 7.385 (13.84), 7.389 (9.61), 7.392 (12.11), 7.401 (7.22), 7.406 (3.21), 7.410 (2.27).
Example 12. Example 13 and Example 14
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1-[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]propan-1- one (mixture of stereoisomers)
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1-[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1-one
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1-[(7S)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1-one
Example 12
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1-[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]propan-1- one (mixture of stereoisomers)
Figure imgf000448_0001
Using the method described for Example 1 with intermediate 19 (150 mg, 274 pmol) gave the titled compound (30 mg, 23%) after preparative HPLC purification (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.66), 0.012 (0.79), 0.033 (1.45), 0.044 (1.42), 0.066 (0.84), 0.077 (0.74), 0.108 (0.76), 0.119 (1.00), 0.141 (1.84), 0.152 (1.87), 0.174 (1.11),
0.186 (0.92), 0.444 (1.76), 0.477 (1.47), 0.933 (1.29), 0.965 (2.08), 0.992 (2.11), 1.005 (2.00),
1.027 (2.45), 1.038 (2.97), 1.061 (2.53), 1.073 (3.05), 1.108 (2.18), 1.119 (1.82), 1.142 (3.26),
1.151 (3.66), 1.184 (3.18), 1.198 (3.45), 1.239 (1.29), 1.275 (1.55), 1.306 (1.21), 1.317 (0.89),
1.326 (0.84), 1.339 (0.92), 1.359 (0.47), 1.484 (0.68), 1.518 (0.58), 1.830 (0.63), 1.864 (1.37), 1 .893 (3.03), 1 .925 (2.42), 2.044 (1.89), 2.072 (3.00), 2.105 (2.1 1 ), 2.216 (1 .84), 2.225 (2.16),
2.245 (2.21 ), 2.254 (2.13), 2.288 (1.37), 2.292 (1 .97), 2.297 (1.61 ), 2.338 (2.29), 2.347 (2.34),
2.368 (2.95), 2.376 (2.47), 2.396 (0.61 ), 2.483 (9.26), 2.488 (7.50), 2.540 (1 .37), 2.571 (2.68),
2.601 (2.63), 2.630 (2.42), 2.634 (3.05), 2.639 (2.79), 2.681 (4.97), 2.706 (5.74), 2.752 (3.08),
2.763 (3.03), 2.780 (3.21 ), 2.793 (3.92), 2.805 (3.1 1 ), 2.813 (2.92), 2.823 (2.39), 2.837 (1 .89),
2.925 (1 .1 1 ), 2.958 (3.82), 2.988 (5.63), 3.027 (3.87), 3.062 (7.03), 3.129 (7.00), 3.183 (1 .63),
3.236 (2.45), 3.270 (2.68), 3.344 (2.66), 3.379 (2.00), 3.422 (1.84), 3.458 (1 .58), 4.01 1 (0.76),
4.047 (0.82), 4.097 (0.63), 4.135 (1.50), 4.168 (1 .42), 4.221 (1.68), 4.255 (1 .61 ), 6.802 (4.26),
6.81 1 (4.76), 6.820 (4.05), 6.857 (3.84), 6.865 (5.00), 6.875 (4.82), 6.896 (3.55), 6.916 (7.71 ),
6.935 (5.37), 6.999 (7.18), 7.018 (4.97), 7.035 (3.24), 7.054 (8.32), 7.066 (7.03), 7.085 (7.08),
7.106 (4.66), 7.125 (5.63), 7.144 (4.24), 7.166 (1 .76), 7.21 1 (3.18), 7.216 (3.16), 7.229 (7.00),
7.248 (9.05), 7.253 (1 1 .66), 7.259 (12.1 1 ), 7.269 (16.00), 7.278 (14.50), 7.283 (13.47), 7.373 (2.66), 7.377 (2.82), 7.387 (12.87), 7.394 (1 1 .55), 7.403 (7.05), 7.408 (3.29).
The title compound (24 mg) was separated into its enantiomers by preparative chiral HPLC to give stereoisomer 1 (8 mg, see Example 13) and stereoisomer 2 (7 mg, see Example 14).
Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000; column: Cellulose SB 5m 250x30mm Eluent A: hexane + 0.1 Vol-% Diethylamine (99%); Eluent B: Ethanol; Isocratic: 75%A+25%B; flow 50 ml/min; temperature: 250; UV 220nm.
Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; column: Cellulose SB 3m 100x4.6mm; Eluent A: hexane + 0.1 Vol-% Diethylamine (99%); Eluent B: Ethanol; Isocratic: 75%A+25%B; flow 1 .4 ml/min temperature: 25Ό; UV 22 Onm.
Example 13
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]propan-1 - one (Stereoisomer 1 )
Figure imgf000449_0001
For the preparation of the racemic title compound and separation into its enantiomers see Example 12.
Analytical Chiral FIPLC (method see Example 12): Rt = 2.84 min, e.e., >99%.
Optical rotation (method OR1 ): 3.2°(methanol). Example 14
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]propan-1 - one (Stereoisomer 2)
Figure imgf000450_0001
For the preparation of the racemic title compound and separation into its enantiomers see Example 12.
Analytical Chiral FIPLC (method see Example 12): Rt = 3.70 min, e.e., >99%.
Optical rotation (method OR1 ): 19.1“(methanol).
Example 15, Example 16 and Example 17
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers)
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-
3-yl]propan-1 -one
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7S)-7-phenyl-3,9-diazaspiro[5.5]undecan- 3-yl]propan-1 -one
Example 15
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers)
Figure imgf000450_0002
Using the method described for Example 1 with intermediate 25 (170 mg, 296 pmol) gave the titled compound (71 .4 mg, 48%) after preparative HPLC purification (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .028 (0.48), 1 .047 (0.61 ), 1 .080 (0.83), 1 .115 (0.83), 1 .130 (0.77), 1 .142 (0.69), 1 .152 (0.65), 1 .162 (0.71 ), 1.306 (0.79), 1 .326 (0.68), 1.337 (0.79), 1 .354 (0.62), 1 .897 (0.69), 1 .944 (0.70), 1 .996 (10.24), 2.023 (0.54), 2.078 (10.94), 2.126 (0.79), 2.161 (0.42), 2.259 (16.00), 2.275 (0.67), 2.301 (0.67), 2.323 (0.74), 2.342 (0.47), 2.351 (0.45), 2.387 (0.52), 2.396 (0.54), 2.415 (0.89), 2.443 (0.46), 2.522 (1 .55), 2.539 (1.51 ), 2.632
(0.83), 2.665 (0.99), 2.669 (1 .05), 2.694 (0.54), 2.723 (1.43), 2.749 (1 .21 ), 2.838 (0.58), 2.855
(0.63), 2.866 (0.84), 2.894 (0.96), 2.924 (0.61 ), 2.989 (0.95), 3.018 (1 .32), 3.063 (2.20), 3.129
(2.27), 3.435 (0.65), 3.471 (0.50), 3.499 (0.46), 3.519 (5.62), 6.741 (2.19), 6.773 (2.27), 6.913
(4.22), 6.931 (1 .17), 6.936 (1 .17), 6.983 (1 .16), 6.998 (2.49), 7.041 (1 .76), 7.151 (0.98), 7.160
(1 .24), 7.172 (1 .58), 7.177 (1 .91 ), 7.213 (2.61 ), 7.223 (2.78), 7.241 (2.46), 7.260 (1.52), 7.279
(0.53).
The title compound (65 mg) was separated into its enantiomers by preparative chiral HPLC to give stereoisomer 1 (28 mg, see Example 16) and stereoisomer 2 (28 mg, see Example 17).
Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000; column: Cellulose SB 5m 250x30mm Eluent A: hexane + 0.1 Vol-% Diethylamine (99%); Eluent B: Ethanol; Gradient: 20% - 40% B in 14 min; flow: 40 ml/min; temperature: 25Ό; UV 220nm.
Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; column: Cellulose SB 3m 100x4.6mm; Eluent A: hexane + 0.1 Vol-% Diethylamine (99%); Eluent B: Ethanol; Isocratic: 80%A+20%B; flow 1 .4 ml/min temperature: 25Ό; UV 22 Onm.
Example 16
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (Stereoisomer 1 )
Figure imgf000451_0001
For the preparation of the racemic title compound and separation into its enantiomers see Example 15.
Analytical Chiral FIPLC (method see Example 15): Rt = 2.38 min, e.e., 98.6%.
Optical rotation (method OR1 ): -8.3° (methanol).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.967 (0.51 ), 0.995 (0.42), 1 .084 (0.43), 1 .108 (16.00), 1 .129 (0.53), 1 .137 (0.53), 1 .144 (0.65), 1 .151 (0.55), 1.162 (0.53), 1 .259 (0.42), 1.339 (0.58), 2.078 (10.20), 2.259 (7.59), 2.393 (0.41 ), 2.414 (0.54), 2.518 (1 .59), 2.522 (1 .01 ), 2.533 (0.48), 2.636 (0.51 ), 2.665 (0.60), 2.669 (0.72), 2.722 (0.82), 2.740 (0.53), 2.855 (0.48), 2.863 (0.45),
2.889 (0.78), 2.922 (0.46), 3.022 (0.52), 3.065 (1 .82), 3.437 (0.41 ), 3.525 (3.68), 6.773 (2.05),
6.912 (1 .84), 6.931 (1 .01 ), 6.937 (1.07), 6.999 (1 .25), 7.042 (0.83), 7.161 (0.83), 7.181 (1 .27),
7.201 (0.79), 7.21 1 (1.93), 7.228 (1.12), 7.248 (0.87), 7.266 (0.79). Example 17
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (Stereoisomer 2)
Figure imgf000452_0001
For the preparation of the racemic title compound and separation into its enantiomers see Example 15.
Analytical Chiral FIPLC (method see Example 15): Rt = 3.29 min, e.e., >99%.
Optical rotation (method OR1 ): 1 1.4°(methanol).
Example 18
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers)
Figure imgf000452_0002
Using the method described for Example 1 with intermediate 26 (170 mg, 296 pmol) gave the titled compound (65.9 mg, 45%) after preparative HPLC purification (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .047 (0.63), 1 .080 (0.84), 1 .1 15 (0.83), 1 .129 (0.78), 1 .141 (0.71 ), 1 .163 (0.71 ), 1 .307 (0.83), 1 .338 (0.80), 1 .946 (0.68), 1 .996 (10.18), 2.078
(10.76), 2.128 (0.79), 2.162 (0.42), 2.259 (16.00), 2.275 (0.63), 2.326 (0.86), 2.344 (0.47), 2.390 (0.48), 2.398 (0.54), 2.416 (0.83), 2.444 (0.44), 2.522 (1.95), 2.539 (1 .98), 2.633 (0.83), 2.664 (1 .09), 2.668 (1 .17), 2.696 (0.56), 2.725 (1 .45), 2.751 (1.21 ), 2.839 (0.58), 2.855 (0.62), 2.868 (0.83), 2.888 (0.85), 2.898 (0.91), 2.922 (0.54), 2.991 (0.93), 3.020 (1.35), 3.063 (2.17),
3.129 (2.20), 3.436 (0.54), 3.469 (0.42), 3.519 (5.60), 6.740 (2.20), 6.773 (2.25), 6.913 (4.19),
6.931 (1.16), 6.937 (1.18), 6.983 (1.17), 6.999 (2.49), 7.041 (1.78), 7.151 (0.96), 7.160 (1.24),
7.172 (1.60), 7.178 (1.90), 7.214 (2.62), 7.223 (2.80), 7.242 (2.48), 7.261 (1.54), 7.278 (0.56).
Example 19
3,3,3-trifluoro-2-(4-fluorophenyl)-2-methoxy-1-[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1-one (mixture of stereoisomers)
Figure imgf000453_0001
Using the method described for Example 1 with intermediate 27 (170 mg, 301 pmol) gave the titled compound (74.4 mg, 51%) after preparative HPLC purification (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.51), 0.023 (0.89), 0.033 (0.89), 0.055 (0.53), 0.118 (0.47), 0.130 (0.58), 0.151 (1.05), 0.163 (1.09), 0.186 (0.65), 0.196 (0.55), 0.546 (0.91), 0.579 (0.84), 1.010 (1.33), 1.026 (1.88), 1.056 (1.75), 1.067 (1.61), 1.088 (1.52), 1.100 (1.56), 1.117 (1.79), 1.147 (1.38), 1.168 (1.18), 1.179 (1.22), 1.202 (0.85), 1.213 (0.76), 1.241 (1.63), 1.273 (1.53), 1.311 (0.98), 1.330 (0.73), 1.341 (0.70), 1.363 (0.51), 1.371 (0.49), 1.898 (2.99), 1.948 (1.61), 1.976 (1.27), 2.020 (2.37), 2.085 (1.09), 2.117 (1.98), 2.148 (1.11), 2.281 (1.04), 2.290 (1.23), 2.311 (1.29), 2.319 (1.71), 2.381 (1.11), 2.389 (1.32), 2.410 (1.72), 2.418 (1.46), 2.439 (0.62), 2.519 (5.37), 2.536 (5.89), 2.576 (0.64), 2.609 (1.09), 2.639 (1.15), 2.661 (1.22), 2.665 (1.37), 2.669 (1.19), 2.683 (0.95), 2.725 (2.60), 2.750 (3.11), 2.791 (1.78), 2.817 (1.63), 2.842 (1.98), 2.848 (2.00), 2.865 (1.51), 2.875 (1.37), 2.967 (0.46), 2.996 (1.18), 3.025 (1.89), 3.055 (2.51), 3.094 (4.33), 3.124 (1.23), 3.161 (3.19), 3.201 (0.80), 3.339 (3.95), 3.386 (2.63), 3.428 (1.81), 3.468 (1.84), 3.515 (1.86), 3.542 (16.00), 3.545 (15.44), 3.888 (1.26), 4.045 (0.42), 4.082 (0.49), 4.165 (0.92), 4.196 (0.89), 4.251 (1.04), 4.284 (0.99), 6.720 (1.81), 6.742 (3.79), 6.763 (2.08), 6.868 (3.13), 6.887 (4.77), 6.911 (5.59), 6.932 (5.32), 7.058 (2.01), 7.071 (2.48), 7.092 (2.29), 7.103 (2.34), 7.115 (2.51), 7.137 (3.08), 7.155 (2.99), 7.173 (2.19), 7.198 (0.97), 7.249 (3.93), 7.260 (6.51), 7.276 (8.47), 7.293 (6.41), 7.317 (1.77), 7.322 (1.96), 7.343 (2.22), 7.349 (2.50), 7.357 (2.22), 7.365 (1.46), 7.371 (1.38). Example 20
2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxy-1-[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1-one (mixture of stereoisomers)
Figure imgf000454_0001
Using the method described for Example 1 with intermediate 28 (180 mg, 310 pmol) gave the titled compound (70.3 mg, 45%) after preparative HPLC purification (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.095 (0.78), 0.118 (1.38), 0.129 (1.41), 0.151 (0.84), 0.195 (0.69), 0.206 (0.89), 0.228 (1.56), 0.239 (1.61), 0.261 (0.98), 0.273 (0.81), 0.637 (1.50),
0.669 (1.35), 1.013 (2.77), 1.037 (3.75), 1.046 (3.60), 1.067 (2.25), 1.082 (2.42), 1.103 (2.34),
1.119 (3.17), 1.127 (3.46), 1.160 (3.40), 1.182 (1.59), 1.279 (3.95), 1.314 (4.53), 1.345 (1.47),
1.356 (1.50), 1.378 (1.12), 1.409 (0.58), 1.550 (0.75), 1.585 (0.66), 1.729 (0.95), 1.763 (0.92),
1.861 (0.75), 1.905 (5.36), 1.947 (2.77), 1.981 (1.01), 2.027 (3.49), 2.078 (1.79), 2.109 (2.68),
2.136 (1.76), 2.292 (1.76), 2.312 (1.82), 2.322 (2.57), 2.327 (2.31), 2.331 (1.59), 2.387 (1.87),
2.409 (2.10), 2.416 (2.31), 2.448 (1.44), 2.523 (13.98), 2.540 (9.14), 2.603 (1.33), 2.632 (3.34),
2.665 (4.06), 2.669 (3.92), 2.674 (3.11), 2.687 (2.36), 2.725 (5.36), 2.748 (5.36), 2.782 (1.67),
2.816 (2.45), 2.839 (3.78), 2.870 (5.33), 2.902 (2.94), 2.926 (1.07), 2.962 (1.21), 2.991 (2.71),
3.020 (3.57), 3.046 (2.85), 3.076 (3.11), 3.114 (8.68), 3.150 (2.16), 3.176 (7.90), 3.244 (2.97),
3.337 (7.01), 3.417 (2.62), 3.452 (1.96), 3.500 (0.75), 4.028 (0.86), 4.062 (1.12), 4.107 (0.81),
4.143 (1.47), 4.176 (1.44), 4.220 (1.53), 4.255 (1.50), 6.746 (6.69), 6.763 (3.52), 6.782 (1.21),
6.796 (2.31), 6.815 (2.68), 6.873 (4.84), 6.887 (4.70), 6.893 (4.87), 6.929 (4.12), 6.938 (4.21),
6.947 (4.06), 6.981 (2.36), 7.001 (4.21), 7.021 (2.16), 7.149 (3.03), 7.166 (7.01), 7.182 (6.03),
7.200 (2.36), 7.253 (7.18), 7.268 (14.30), 7.285 (16.00), 7.294 (8.13), 7.351 (9.43), 7.396 (2.42), 7.401 (4.01), 7.407 (2.10), 7.414 (2.22), 7.418 (3.69), 7.424 (2.05), 7.460 (3.00), 7.481 (6.54), 7.500 (4.53), 7.527 (4.30), 7.531 (7.01), 7.547 (2.88), 7.552 (5.13). Example 21
2-(3-bromophenyl)-3,3,3-trifluoro-2-methoxy-1-[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1-one (mixture of stereoisomers)
Figure imgf000455_0001
Using the method described for Example 1 with intermediate 33 (180 mg, 288 pmol) gave the titled compound (75.3 mg, 47%) after preparative HPLC purification (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.110 (0.40), 0.132 (0.75), 0.142 (0.73), 0.164 (0.42), 0.218 (0.46), 0.240 (0.82), 0.251 (0.84), 0.273 (0.51), 0.284 (0.42), 0.651 (0.79), 0.682 (0.68), 0.995 (0.82), 1.011 (1.21), 1.041 (1.81), 1.052 (1.68), 1.085 (1.35), 1.118 (1.54), 1.130 (1.70), 1.152 (1.68), 1.164 (1.77), 1.186 (0.95), 1.197 (0.77), 1.266 (1.04), 1.297 (1.90), 1.323 (1.28), 1.352 (0.73), 1.388 (0.60), 1.537 (0.42), 1.853 (0.42), 1.906 (1.72), 1.941 (1.19), 1.976 (0.53), 2.028 (0.84), 2.064 (0.95), 2.074 (0.93), 2.095 (1.52), 2.127 (0.90), 2.281 (0.79), 2.289 (0.95), 2.309 (1.02), 2.318 (1.35), 2.322 (1.37), 2.326 (1.43), 2.332 (1.08), 2.374 (0.86), 2.382 (1.04), 2.402 (1.08), 2.410 (1.06), 2.456 (0.97), 2.518 (6.82), 2.523 (5.32), 2.539 (3.40), 2.546 (2.43), 2.603 (0.79), 2.634 (1.88), 2.664 (2.56), 2.668 (2.56), 2.673 (2.01), 2.686 (1.28), 2.722 (2.89), 2.745 (2.82), 2.788 (0.75), 2.819 (1.39), 2.836 (1.68), 2.845 (1.68), 2.869 (2.21), 2.903 (1.26), 2.935 (0.44), 2.957 (0.64), 2.983 (1.37), 3.012 (1.88), 3.041 (1.77), 3.071 (1.43), 3.115 (4.74), 3.151 (0.95), 3.175 (4.30), 3.235 (1.24), 3.403 (1.35), 3.438 (0.93), 3.554 (16.00), 3.899 (0.44), 4.015 (0.46), 4.050 (0.64), 4.093 (0.42), 4.140 (0.77), 4.173 (0.75), 4.214 (0.79), 4.247 (0.73), 6.659 (0.84), 6.679 (2.03), 6.699 (1.39), 6.751 (1.48), 6.770 (0.95), 6.810 (1.06), 6.829 (1.48), 6.885 (2.71), 6.905 (4.02), 6.925 (2.74), 6.939 (2.43), 6.946 (2.69), 6.958 (2.14), 7.152 (1.79), 7.169 (3.91), 7.187 (3.05), 7.200 (1.32), 7.244 (2.23), 7.249 (2.45), 7.270 (8.50), 7.287 (9.84), 7.393 (2.69), 7.413 (4.83), 7.433 (2.32), 7.495 (2.16), 7.501 (2.67), 7.506 (3.13), 7.520 (3.00), 7.532 (1.83), 7.535 (1.99), 7.537 (1.52), 7.540 (1.30), 7.552 (1.61), 7.554 (1.68), 7.557 (1.54), 7.559 (1.19), 7.659 (2.21), 7.665 (2.54), 7.668 (1.99), 7.671 (1.72), 7.673 (1.70), 7.679 (1.85), 7.685(2.27), 7.691 (1.61). Example 22
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy-1-[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1-one (mixture of stereoisomers)
Figure imgf000456_0001
Using the method described for Example 1 with intermediate 34 (180 mg, 292 pmol) gave the titled compound (72.4 mg, 46%) after preparative HPLC purification (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.214 (0.47), 0.247 (0.86), 0.271 (0.51), 0.372 (0.46), 0.392 (0.77), 0.403 (0.81), 0.425 (0.49), 0.882 (0.81), 0.911 (0.75), 0.963 (0.49), 0.986 (1.17),
0.998 (0.96), 1.023 (1.38), 1.059 (1.96), 1.100 (2.68), 1.124 (2.12), 1.166 (1.54), 1.202 (0.95), 1.318 (1.44), 1.351 (1.81), 1.384 (2.31), 1.564 (0.63), 1.599 (0.54), 1.863 (1.09), 1.898 (1.02),
1.921 (0.54), 1.950 (0.79), 1.980 (1.28), 2.012 (0.82), 2.032 (0.53), 2.062 (1.05), 2.074 (1.75),
2.096 (1.61), 2.125 (0.88), 2.327 (1.89), 2.347 (1.02), 2.383 (1.19), 2.401 (1.33), 2.411 (1.30),
2.539 (7.61), 2.579 (3.58), 2.664 (3.28), 2.669 (3.01), 2.733 (3.73), 2.749 (3.31), 2.898 (2.28),
2.921 (2.49), 2.950 (1.66), 2.976 (1.52), 2.991 (1.56), 3.004 (1.63), 3.019 (1.45), 3.034 (1.12), 3.046 (1.33), 3.078 (1.09), 3.120 (6.83), 3.151 (1.79), 3.182 (7.38), 3.228 (2.30), 3.377 (4.66),
3.423 (1.45), 3.499 (0.67), 3.573 (16.00), 4.002 (0.67), 4.047 (0.96), 4.099 (1.00), 4.135 (0.89), 4.161 (0.82), 4.193 (0.74), 6.928 (2.66), 6.941 (2.56), 6.947 (2.68), 6.977 (2.12), 6.988 (2.21), 6.996 (2.10), 7.114 (4.61), 7.142 (6.03), 7.169 (5.61), 7.187 (5.26), 7.205 (10.81), 7.218 (6.20), 7.247 (3.86), 7.276 (9.94), 7.499 (0.88), 7.647 (2.00), 7.651 (3.05), 7.757 (2.61), 7.761 (3.63), 7.786 (3.89), 7.791 (5.82).
Example 23
2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-2-methoxy-1-[7-phenyl-3,9-diazaspiro[5.5]undecan-
3-yl]propan-1-one (mixture of stereoisomers)
Figure imgf000456_0002
Using the method described for Example 1 with intermediate 35 (120 mg, 200 pmol) gave the titled compound (45.3 mg, 43%) after preparative HPLC purification (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.021 (0.52), 0.000 (0.93), 0.011 (0.93), 0.033 (0.55), 0.098 (0.55), 0.120 (0.93), 0.130 (0.93), 0.153 (0.57), 0.163 (0.48), 0.602 (0.91), 0.633 (0.82), 0.918 (0.93), 0.935 (1.55), 0.958 (2.09), 0.970 (1.95), 1.022 (1.61), 1.038 (1.89), 1.046 (1.61), 1.067 (2.27), 1.080 (1.89), 1.100 (1.25), 1.113 (0.91), 1.212 (1.41), 1.241 (2.93), 1.273 (1.59), 1.505 (0.43), 1.796 (0.45), 1.859 (1.45), 1.891 (1.52), 2.001 (1.18), 2.034 (2.07), 2.067 (1.09), 2.226 (0.93), 2.235 (1.14), 2.244 (1.32), 2.249 (1.77), 2.254 (2.00), 2.310 (1.27), 2.330 (1.32), 2.338 (1.30), 2.372 (0.55), 2.378 (0.50), 2.384 (0.86), 2.389 (1.77), 2.393 (2.50), 2.440 (8.86), 2.444 (5.39), 2.461 (3.30), 2.467 (2.91), 2.524 (0.80), 2.554 (1.95), 2.586 (2.66), 2.590 (2.68), 2.596 (2.02), 2.608 (1.11), 2.622 (1.16), 2.652 (3.52), 2.674 (3.43), 2.714 (1.14), 2.749 (1.82), 2.784 (2.25), 2.803 (2.09), 2.815 (2.23), 2.830 (1.32), 2.844 (1.27), 2.889 (0.73), 2.913 (1.45), 2.944 (2.34), 2.974 (1.77), 3.032 (5.11), 3.060 (1.73), 3.098 (5.05), 3.162 (1.59), 3.363 (1.45), 3.398 (1.64), 3.485 (16.00), 3.961 (0.48), 4.008 (0.59), 4.062 (1.02), 4.095 (0.93), 4.143 (0.91), 4.175 (0.84), 6.605 (0.77), 6.626 (1.86), 6.648 (1.16), 6.729 (0.95), 6.821 (4.32), 6.838 (5.07), 6.860 (3.00), 6.876 (3.84), 6.894 (2.52), 6.915 (0.95), 7.066 (1.66), 7.083 (3.80), 7.103 (3.55), 7.122 (1.50), 7.137 (1.45), 7.153 (4.61), 7.172 (8.02), 7.194 (6.75), 7.201 (4.61), 7.218 (2.84), 7.370 (3.05), 7.383 (3.20), 7.388 (3.48), 7.396 (1.91), 7.406 (2.80), 7.414 (1.73), 7.428 (3.20), 7.450(1.57).
Example 24
2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-methoxy-1-[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1-one (mixture of stereoisomers)
Figure imgf000457_0001
Using the method described for Example 1 with intermediate 36 (140 mg, 227 pmol) gave the titled compound (84.4 mg, 68%) after preparative HPLC purification (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.215 (0.67), 0.238 (1.11), 0.248 (1.13), 0.271 (0.67), 0.360 (0.50), 0.372 (0.65), 0.393 (1.09), 0.405 (1.13), 0.426 (0.71), 0.437 (0.56), 0.881 (1.07),
0.912 (0.96), 0.952 (0.54), 0.964 (0.65), 0.986 (1.36), 0.998 (1.32), 1.021 (1.92), 1.058 (2.66),
1.069 (2.36), 1.092 (3.20), 1.102 (3.24), 1.124 (2.68), 1.133 (2.70), 1.168 (1.97), 1.202 (1.15),
1.284 (0.48), 1.322 (2.32), 1.352 (2.43), 1.382 (2.80), 1.560 (0.86), 1.594 (0.73), 1.862 (1.51),
1.895 (1.38), 1.947 (1.13), 1.976 (1.80), 2.010 (1.13), 2.060 (1.46), 2.074 (0.88), 2.092 (2.28), 2.124 (1.23), 2.318 (1.61), 2.326 (2.53), 2.332 (1.53), 2.345 (1.55), 2.353 (1.46), 2.371 (1.55),
2.380 (1.80), 2.399 (1.84), 2.407 (1.80), 2.446 (0.50), 2.456 (0.48), 2.461 (0.50), 2.466 (0.48),
2.518 (7.34), 2.522 (5.96), 2.539 (6.17), 2.546 (4.89), 2.578 (3.97), 2.631 (1.88), 2.660 (3.74),
2.664 (3.56), 2.669 (3.60), 2.673 (3.20), 2.679 (2.97), 2.689 (2.72), 2.731 (4.98), 2.750 (4.20), 2.849 (1.19), 2.867 (2.13), 2.895 (3.39), 2.922 (3.64), 2.957 (2.36), 2.973 (1.86), 2.988 (2.24),
3.002 (2.20), 3.015 (1.88), 3.031 (1.44), 3.042 (1.69), 3.073 (1.23), 3.087 (1.30), 3.121 (9.77),
3.151 (2.24), 3.182 (10.69), 3.218 (2.68), 3.228 (2.87), 3.263 (2.64), 3.308 (4.62), 3.335 (4.25), 3.377 (3.43), 3.389 (2.74), 3.425 (1.74), 3.498 (0.50), 4.002 (0.92), 4.047 (1.28), 4.100 (1.30),
4.135 (1.17), 4.160 (1.11), 4.194 (0.98), 6.929 (3.91), 6.941 (3.53), 6.948 (3.97), 6.977 (3.16), 6.987 (3.03), 6.996 (3.10), 7.114 (6.65), 7.144 (8.41), 7.169 (7.84), 7.187 (7.05), 7.204 (16.00),
7.218 (8.55), 7.230 (2.57), 7.244 (5.06), 7.247 (5.25), 7.263 (6.73), 7.276 (14.49), 7.645 (3.18),
7.649 (6.15), 7.654 (3.16), 7.755 (3.76), 7.759 (6.88), 7.764 (3.58), 7.784 (6.13), 7.789 (11.34),
7.794 (5.61).
Example 25
3,3,3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1-one (mixture of stereoisomers)
Figure imgf000458_0001
Using the method described for Example 1 with intermediate 37 (180 mg, 302 pmol) gave the titled compound (61.1 mg, 39%) after preparative HPLC purification (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.407 (0.69), 0.439 (0.60), 0.971 (1.20), 1.110 (1.45), 1.127 (1.80), 1.233 (0.85), 1.301 (1.29), 1.335 (0.92), 1.394 (0.60), 1.465 (3.91), 1.792 (0.57),
1.897 (3.44), 2.074 (1.20), 2.322 (1.64), 2.326 (2.05), 2.332 (1.58), 2.432 (1.74), 2.518 (6.79),
2.522 (4.20), 2.539 (3.41), 2.630 (1.80), 2.660 (2.24), 2.664 (2.84), 2.669 (3.31), 2.673 (2.97),
2.686 (2.49), 2.797 (0.82), 2.831 (1.36), 2.858 (1.48), 2.888 (1.74), 2.923 (1.36), 2.974 (1.17), 3.000 (1.29), 3.162 (5.68), 3.208 (1.29), 3.234 (6.28), 3.621 (16.00), 4.115 (0.44), 4.229 (0.85),
4.263 (0.85), 4.323 (0.60), 6.801 (0.66), 7.131 (2.40), 7.148 (4.45), 7.164 (3.57), 7.178 (2.75),
7.193 (3.03), 7.211 (2.11), 7.238 (3.31), 7.257 (4.73), 7.271 (4.54), 7.289 (2.37), 7.511 (3.38),
7.516 (3.31), 7.525 (3.19), 7.543 (1.58), 7.573 (1.51), 7.602 (1.33), 7.646 (0.63), 7.666 (0.54),
7.929 (1.61), 7.950 (1.48), 7.965 (2.87), 7.988 (4.58), 8.015 (3.47), 8.036 (3.06), 8.105 (0.79), 8.125(0.76). Example 26
1-[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-phenylethan-1-one
Figure imgf000459_0001
Using the method described for Example 1 with intermediate 74 (85 mg, 182 pmol) gave the titled compound (30.5 mg, 43%) after preparative HPLC purification (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.856 (0.60), 0.866 (0.73), 0.888 (1.27), 0.898 (1.29), 0.921 (1.35), 0.932 (1.36), 0.954 (1.36), 0.965 (1.34), 0.987 (0.84), 0.998 (0.71), 1.026 (0.54),
1.036 (0.64), 1.058 (1.36), 1.069 (1.38), 1.090 (1.43), 1.100 (1.54), 1.135 (3.83), 1.147 (3.34),
1.159 (3.70), 1.180 (2.06), 1.192 (1.57), 1.237 (1.74), 1.268 (0.91), 1.692 (1.26), 1.724 (1.17), 1.806 (1.34), 1.839 (1.24), 2.063 (1.74), 2.072 (2.80), 2.082 (2.08), 2.088 (1.97), 2.097 (1.84),
2.106 (1.54), 2.116 (1.72), 2.518 (2.72), 2.530 (3.22), 2.540 (2.43), 2.630 (2.45), 2.657 (2.32),
2.696 (2.08), 2.704 (1.74), 2.729 (2.88), 2.736 (2.98), 2.769 (3.72), 2.975 (0.76), 3.007 (1.58),
3.026 (1.98), 3.038 (1.69), 3.053 (2.42), 3.071 (1.67), 3.078 (1.76), 3.084 (1.65), 3.104 (1.90),
3.109 (1.85), 3.136 (1.27), 3.143 (1.19), 3.509 (1.31), 3.526 (1.23), 3.547 (6.58), 3.563 (13.43), 3.577 (7.46), 3.601 (2.60), 3.615 (2.63), 3.656 (1.25), 4.040 (1.33), 4.073 (1.29), 4.104 (1.37),
4.138 (1.28), 7.024 (3.30), 7.031 (3.81), 7.034 (4.22), 7.038 (5.02), 7.039 (4.88), 7.047 (8.28),
7.053 (8.82), 7.059 (6.81), 7.071 (8.36), 7.076 (16.00), 7.098 (15.37), 7.117 (10.02), 7.139 (4.36), 7.148 (11.24), 7.156 (10.06), 7.164 (8.61), 7.175 (2.61), 7.185 (12.75), 7.191 (10.21), 7.199(5.76), 7.201 (6.26). Example 27
2,2-difluoro-1-[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-phenylethan-1-one
Figure imgf000459_0002
Using the method described for Example 1 with intermediate 56 (90 mg, 179 pmol) gave the titled compound (19.4 mg, 26%) after preparative HPLC purification (Method 6). 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.605 (0.41), 0.614 (0.49), 0.637 (0.85), 0.647 (0.84), 0.670 (0.52), 0.679 (0.44), 0.746 (0.40), 0.757 (0.49), 0.779 (0.91), 0.790 (0.91), 0.812 (0.61),
0.822 (0.51), 0.964 (0.51), 0.995 (1.51), 1.007 (1.19), 1.027 (1.04), 1.040 (0.61), 1.050 (0.50),
1.088 (0.77), 1.098 (0.65), 1.111 (0.84), 1.124 (0.91), 1.156 (1.07), 1.169 (0.76), 1.190 (1.23),
1.201 (0.98), 1.223 (0.76), 1.234 (0.61), 1.310 (1.10), 1.340 (0.67), 1.553 (0.86), 1.586 (0.80),
1.859 (0.86), 1.892 (0.80), 2.047 (1.16), 2.055 (1.00), 2.068 (1.42), 2.074 (1.37), 2.081 (1.29),
2.092 (0.97), 2.101 (1.15), 2.427 (1.04), 2.435 (1.27), 2.454 (1.28), 2.463 (1.32), 2.518 (1.37),
2.522 (1.48), 2.539 (0.65), 2.572 (1.12), 2.600 (1.31), 2.660 (0.74), 2.669 (0.65), 2.673 (0.59),
2.687 (0.66), 2.752 (1.88), 2.851 (0.70), 2.882 (1.60), 2.913 (1.87), 2.943 (1.52), 2.982 (1.37),
3.019 (1.61), 3.048 (1.44), 3.077 (1.42), 3.108 (1.13), 3.113 (1.10), 3.168 (2.17), 3.347 (0.98),
3.392 (1.24), 3.431 (0.79), 4.048 (0.92), 4.082 (0.93), 4.094 (0.88), 4.103 (0.96), 4.137 (0.85),
7.037 (0.84), 7.059 (4.34), 7.073 (16.00), 7.092 (11.07), 7.114 (1.48), 7.317 (2.08), 7.335 (5.74), 7.348 (6.50), 7.367 (8.62), 7.387 (1.68), 7.412 (2.78), 7.431 (4.32), 7.451 (1.99), 7.515 (1.16), 7.533 (1.83), 7.551 (0.89), 7.565 (1.35), 7.583 (1.99), 7.601 (0.80).
Example 28
(rac)-1-[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]ethan- 1-one (mixture of stereoisomers)
Figure imgf000460_0001
To a solution of intermediate 57 (140 mg, 262 pmol) in methanol (3 ml) was added 4M HCI in CPME (9.9 ml) and stirred at rt for 3h then left standing o/n. After which time the reaction was concentrated to dryness and filtered through an SCX cartridge using an eluent system of 100% methanol followed by 4N NH3 in methanol to give the title compound 371.6 (112 mg, 83%).
1H NMR (400 MHz DMSO):5 [ppm] = 8.46 (s, 1H), 7.61-7.64 (m, 1H), 7.30-7.35 (m, 2H), 7.11- 7.15 (m, 1 H), 6.97-7.05 (m, 4H), 4.41-4.53 (m, 1H), 3.50-3.82 (m, 6H), 3.27-3.34 (m, 2H), 2.97- 3.17 (m, 3H), 2.63-2.76 (m, 1H), 2.33-2.36 (m, 1H).1.68-1.87 (m, 2H), 1.17-1.49 (m, 2H). Example 29
1-[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]propan-1- one (mixture of stereoisomers)
Figure imgf000461_0001
Using the method described for Example 28 with intermediate 58 (440 mg, 802 pmol) gave the titled compound (171 mg, 44%).
1H-NMR (400 MHz, CHLOROFORM-D) d 8.48 (s, 1H), 7.47-7.68 (m, 1H), 7.28-7.37 (m, 2H), 6.99-7.06 (m, 2H), 6.93 (td, J = 8.4, 4.2 Hz, 1H), 6.73-6.80 (m, 2H), 4.37-4.62 (m, 1H), 4.06- 4.13 (m, 2H), 3.51-3.64 (m, 1H), 2.56-3.32 (m, 6H), 2.15-2.32 (m, 1H), 1.16-1.85 (m, 7H), 0.85 (m, 0.5 H), 0.31-0.44 (m, 0.5H).
MS (ESLpos): m/z = (M+H)+ 449.
Example 30
2,2-difluoro-1-[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1-one, salt with hydrochloric acid
Figure imgf000461_0002
Using the method described for Example 1 with intermediate 59 (100 mg, 170 pmol) gave the titled compound (56.1 mg, 60%) after concentration of the reaction mixture under reduced pressure.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.621 (0.42), 0.808 (0.49), 0.818 (0.49), 0.994 (0.44), 1.029 (0.81), 1.063 (0.49), 1.178 (0.56), 1.189 (0.54), 1.222 (0.41), 1.314 (0.76), 1.352 (1.52),
1.403 (0.52), 1.437 (0.47), 1.463 (0.51), 1.751 (0.52), 1.782 (0.51), 2.039 (0.51), 2.074 (0.46),
2.083 (0.91), 2.404 (0.88), 2.440 (0.91), 2.518 (4.13), 2.522 (2.56), 2.810 (0.58), 2.853 (1.08),
2.886 (1.66), 2.917 (0.64), 2.968 (0.41), 3.004 (0.81), 3.032 (1.22), 3.117 (0.66), 3.150 (1.20), 3.185 (1 .07), 3.336 (16.00), 3.385 (1 .57), 3.398 (1 .22), 3.430 (0.86), 3.489 (0.52), 3.519 (0.54),
4.093 (0.49), 4.128 (0.81 ), 4.167 (0.42), 7.065 (1 .07), 7.087 (2.23), 7.100 (2.44), 7.1 19 (1 .39),
7.185 (1 .63), 7.195 (1 .78), 7.207 (2.76), 7.217 (2.78), 7.229 (1.41 ), 7.240 (1 .85), 7.260 (0.78),
7.337 (0.78), 7.356 (0.88), 7.479 (0.61 ), 7.500 (1 .37), 7.517 (1.44), 7.536 (1 .37), 7.555 (0.85), 7.694 (2.27), 7.713 (2.52), 7.726 (1.57), 7.735 (1 .27), 7.746 (1.15), 7.755 (1 .07), 7.775 (0.49),
8.786 (0.52), 9.069 (0.52).
Example 31
(rac)-1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 -yl)ethan-1 -one (mixture of stereoisomers)
Figure imgf000462_0001
Using the method described for Example 28 with intermediate 60 (440 mg, 802 pmol) gave the titled compound (113 mg, 86%).
1 H-NMR (400 MHz, CHLOROFORM-D) d 8.51 (s, 1 H), 7.87 (d, J = 5.4 Hz, 2H), 7.72-7.77 (m, 1 H), 7.48 (m, 2H), 7.21 -7.30 (m, 1 H), 6.00-7.1 1 (m, 5H), 4.46-4.60 (m, 1 H), 3.99-4.26 (m, 2H), 3.51 (m, 1 H), 2.73-3.18 (m, 5H), 2.57 (m, 1 H), 2.64 (s, 3H), 2.25-2.32 (m, 1 H), 1 .58-1.67 (m, 2
MS (ESLpos): m/z = (M+H)+ 417
Example 32
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 -yl)ethan-1 -one, salt with hydrochloric acid
Figure imgf000462_0002
Using the method described for Example 1 with intermediate 60 (50 mg, 96.8 pmol) gave the titled compound (31 .6 mg, 43%) after concentration of the reaction mixture under reduced pressure. 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.977 (1.19), 0.994 (1.21), 1.009 (1.19), 1.116 (0.42), 1.130 (0.48), 1.151 (1.10), 1.163 (1.16), 1.184 (1.38), 1.195 (1.30), 1.225 (2.17), 1.269 (1.38),
1.303 (0.79), 1.463 (0.87), 1.498 (1.55), 1.533 (0.85), 1.926 (0.93), 1.959 (0.90), 2.007 (1.02),
2.042 (0.93), 2.083 (1.16), 2.322 (0.96), 2.326 (1.30), 2.331 (0.93), 2.423 (1.72), 2.458 (1.81),
2.518 (5.47), 2.522 (3.41), 2.664 (1.10), 2.669 (1.55), 2.673 (1.44), 2.678 (1.30), 2.716 (2.12),
2.749 (1.10), 2.922 (2.09), 2.947 (2.20), 2.954 (2.23), 3.036 (2.54), 3.065 (3.08), 3.130 (0.82),
3.163 (1.72), 3.196 (2.60), 3.385 (3.84), 3.395 (0.45), 3.515 (1.38), 3.643 (16.00), 3.709 (1.78), 3.730 (1.95), 3.741 (2.17), 3.764 (1.19), 3.927 (1.33), 3.968 (3.39), 4.010 (2.93), 4.028 (2.88),
4.045 (2.85), 4.068 (1.35), 4.085 (1.02), 4.140 (0.90), 4.183 (1.27), 4.222 (0.90), 7.057 (0.48),
7.086 (2.17), 7.104 (2.88), 7.127 (2.43), 7.148 (1.27), 7.170 (4.29), 7.189 (9.26), 7.202 (5.02),
7.212 (7.20), 7.237 (3.33), 7.257 (2.54), 7.275 (2.00), 7.279 (2.09), 7.299 (2.37), 7.318 (1.55),
7.358 (0.99), 7.377 (3.05), 7.397 (3.30), 7.415 (1.47), 7.456 (1.75), 7.464 (1.89), 7.474 (2.77),
7.482 (2.68), 7.493 (1.55), 7.500 (1.38), 7.720 (2.54), 7.742 (2.43), 7.755 (4.20), 7.778 (5.33),
7.800 (2.06), 7.875 (2.54), 7.890 (2.93), 7.908 (2.12), 8.950 (1.07), 9.165 (1.50), 9.190 (1.24).
Example 33
1-[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-(naphthalen-1- yl)propan-1-one
Figure imgf000463_0001
Using the method described for Example 1 with intermediate 62 (75 mg, 138 pmol) gave the titled compound (39.5 mg, 61%) after preparative HPLC purification (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.658 (0.71), -0.509 (0.77), 0.221 (0.84), 0.594 (1.03), 0.711 (1.48), 0.836 (1.74), 1.043 (1.16), 1.233 (1.48), 1.423 (10.32), 1.629 (8.32), 1.796 (0.97), 2.010 (1.74), 2.075 (2.13), 2.323 (3.61), 2.327 (4.77), 2.332 (3.74), 2.518 (16.00), 2.523
(10.65), 2.540 (5.61), 2.603 (5.03), 2.665 (4.45), 2.669 (5.55), 2.673 (4.26), 2.775 (2.19), 2.815
(2.65), 3.031 (1.23), 4.342 (0.90), 6.618 (1.68), 6.689 (2.06), 6.891 (2.97), 6.984 (1.81), 7.070 (1.81), 7.197 (2.39), 7.299 (1.16), 7.458 (3.94), 7.476 (6.13), 7.496 (6.06), 7.516 (6.13), 7.651 (1.35), 7.764 (2.58), 7.801 (5.68), 7.821 (5.03), 7.900 (3.23), 7.921 (3.10). Example 34. Example 35 and Example 36
(2R)-3,3,3-trifluoro-1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one (mixture of stereoisomers)
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one
(2R)-3,3,3-trifluoro-1 -[(7S)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one
Example 34
(2R)-3,3,3-trifluoro-1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one, salt with hydrochloric acid (mixture of stereoisomers)
Figure imgf000464_0001
Using the method described for Example 28 with intermediate 60 (440 mg, 802 pmol) gave the titled compound (96 mg, 26%) after trituration with ether.
1 H NMR (400 MHz DMSO):5 [ppm] = 0.36-0.64 (m, 1 H), 0.83-1 .53 (m, 4H), 1.90-2.14 (m, 1 H), 2.18-2.43 (m, 1 H), 2.64-3.22 (m, 6H), 3.36-3.62 (m, 3H), 4.13-4.38 (m, 1 H), 6.88-7.60 (m, 9H),
8.68-9.28 (m, 2H).
The title compound (96 mg) was separated into its enantiomers by preparative chiral HPLC to give stereoisomer 1 (18 mg, see Example 35) and stereoisomer 2 (15 mg, see Example 36).
Preparative chiral HPLC method: Instrument: Waters Autopurification System; Column: Chiralpak IC 5pm 20x250mm; eluent A: heptane; eluent B: ethanol with 0.1 % vol diethylamine (99%), Gradient: isocratic, 20% B; Flow 18mL/min over 25 min; temperature: 25 O, BPR: 150 bar, PAD 210-350 nm. Example 35
(2R)-3,3,3-trifluoro-1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one (Stereoisomer 1 )
Figure imgf000465_0001
For the preparation of the racemic title compound and separation into its enantiomers see Example 34.
Chiral HPLC (method see Example 34): Rt = 1 1.25 min.
1 H NMR (300 MHz CDCI3):5 [ppm] = 0.12-0.30 (m, 1 H), 1.00-1 .50 (m, 4H), 1 .70-2.20 (m, 3H), 2.30-2.60 (m, 1 H), 2.65-3.00 (m, 5H), 3.03-3.27 (m, 1 H), 3.50-3.80 (m, 3H), 4.40-4.50 (m, 1 H), 6.85-7.15 (m, 5H), 7.20-7.45 (m, 4H).
Example 36
(2R)-3,3,3-trifluoro-1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one (Stereoisomer 2)
Figure imgf000465_0002
1 H NMR (300 MHz CDCI3):5 [ppm] = 0.20-0.60 (m, 1 H), 0.80-1 .35 (m, 5H), 1 .40-2.10 (m, 1 H), 2.13-3.15 (m, 7H), 3.32 (d, 1 H), 3.50-3.75 (m, 3H), 4.30-4.60 (m, 1 H), 6.80-7.10 (m, 5H), 7.18- 7.29 (m, 2H), 7.35-7.45 (m, 2H).
For the preparation of the racemic title compound and separation into its enantiomers see Example 34.
Chiral HPLC (method see Example 34): Rt = 18.64 min. Example 37
(2R)-3,3,3-trifluoro-1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-hydroxy-2- phenylpropan-1 -one (mixture of stereoisomers)
Figure imgf000466_0001
To a solution of intermediate 63 (150 mg, 266 mihoI) in DCM at -5 Ό under an inert atmosphere was added dropwise boron tribromide in DCM (800 mI, 1 .0 M, 800 mihoI) and the resultant mixture was stirred at 0 Ό for 3 hrs the n at rt for 16 h. The reaction was quenched with water and stirred for 30 mins then basified with 2N aqueous sodium hydroxide solution, extracted with DCM, washed with water, dried over sodium sulfate and concentrated. The product was purified by RP Isolera using acid method (30 g SNAP Ultra column) then triturated with ether/heptane (1 :5) to give the tilte compound (25 mg, 21 %).
1 H NMR (400 MHz CD30D):5 [ppm] = 0.12-0.80 m, (1 H), 1 .05-1 .68 m, (3H), 1 .70-2.22 (m, 1 H), 2.30-2.62 (m, 2H), 2.65-2.97 m, (3H), 2.98-3.30 (m, 2H), 3.46-3.74 (m, 1 H), 3.82-4.15 (m, 1 H), 4.15-4.56 (m, 1 H), 6.80-7.57 (m, 9H), 8.32-8.62 (br s, 1 H). Example 38
2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- hydroxypropan-1 -one (mixture of stereoisomers)
Figure imgf000466_0002
Using the method described for Example 1 with intermediate 64 (140 mg, 227 pmol) gave the titled compound (26.2 mg, 39%) after preparative HPLC purification (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.012 (0.40), 0.161 (0.53), 0.172 (0.53), 0.662 (0.60),
0.695 (0.46), 0.831 (0.40), 0.920 (0.53), 1 .01 1 (0.79), 1.044 (0.93), 1 .075 (1 .26), 1.119 (0.86),
1 .154 (0.60), 1 .254 (1 .12), 1 .289 (1.72), 1 .349 (0.46), 1.842 (0.79), 1 .883 (0.86), 1.921 (0.60), 1 .997 (0.60), 2.038 (0.93), 2.071 (0.60), 2.282 (0.73), 2.331 (3.70), 2.394 (0.79), 2.423 (0.99), 2.518 (16.00), 2.522 (9.72), 2.539 (2.45), 2.594 (1 .06), 2.636 (1 .32), 2.669 (5.42), 2.673 (4.17), 2.714 (2.51 ), 2.745 (2.12), 2.812 (0.86), 2.841 (0.99), 2.871 (0.53), 2.917 (0.73), 2.952 (1 .39),
2.982 (1 .98), 3.012 (1 .32), 3.555 (1.12), 3.583 (0.86), 3.648 (0.46), 4.002 (0.53), 4.103 (0.46),
4.162 (0.53), 4.197 (0.53), 6.894 (0.79), 6.914 (1 .32), 6.929 (1.12), 6.944 (0.99), 6.971 (3.17),
6.982 (3.31 ), 7.020 (0.79), 7.041 (1.06), 7.057 (1 .52), 7.064 (1.92), 7.080 (2.98), 7.086 (3.97),
7.106 (4.10), 7.129 (3.04), 7.149 (1.85), 7.169 (2.18), 7.184 (1.79), 7.201 (0.99), 7.264 (1 .26),
7.282 (1 .45), 7.306 (1 .92), 7.319 (1.65), 7.402 (1 .85), 7.421 (1.19), 7.431 (0.79), 7.437 (0.73),
7.450 (0.86), 7.469 (2.12), 7.490 (2.45), 7.495 (2.51 ), 7.515 (0.73), 7.527 (0.99), 7.547 (0.93),
8.159 (1 .72), 8.173 (2.12), 8.208 (3.77), 8.465 (0.73).
Example 39, Example 40 and Example 41
(2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]- undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers)
(2S)-2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one
(2R)-2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one
Example 39
2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]- undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers)
Figure imgf000467_0001
Using the method described for Example 1 with intermediate 68 (80 mg, 130 pmol) gave the titled compound (48.2 mg, 68%) after preparative HPLC purification (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.044 (0.83), -0.033 (1 .04), -0.01 1 (1 .83), 0.000
(1 .83), 0.022 (1 .04), 0.033 (0.87), 0.097 (0.96), 0.109 (1.17), 0.131 (2.09), 0.142 (2.13), 0.163
(1 .22), 0.175 (1 .00), 0.715 (2.09), 0.746 (1 .87), 0.928 (0.91 ), 0.938 (1 .13), 0.961 (2.00), 0.971
(2.04), 0.995 (1 .43), 1 .005 (2.13), 1.040 (3.17), 1 .058 (3.65), 1 .070 (4.13), 1 .081 (3.91 ), 1 .103
(4.83), 1.1 14 (3.43), 1 .136 (3.65), 1.161 (1 .35), 1 .273 (0.43), 1 .306 (5.74), 1 .340 (6.30), 1 .372 (0.83), 1.514 (0.78), 1 .550 (0.70), 1.804 (0.83), 1 .839 (0.74), 1 .914 (3.09), 1 .947 (2.96), 2.069
(2.48), 2.079 (1 .87), 2.100 (4.22), 2.133 (2.52), 2.170 (0.52), 2.230 (0.91 ), 2.327 (4.61 ), 2.332
(5.22), 2.336 (4.83), 2.355 (3.35), 2.363 (3.22), 2.393 (2.61 ), 2.402 (3.04), 2.421 (3.00), 2.430
(3.09), 2.464 (1 .74), 2.523 (16.00), 2.528 (13.04), 2.544 (7.00), 2.564 (2.30), 2.572 (2.26), 2.587 (1 .61 ), 2.620 (3.30), 2.630 (2.57), 2.644 (3.35), 2.652 (3.48), 2.664 (2.87), 2.669 (3.26),
2.674 (4.35), 2.678 (3.52), 2.683 (3.04), 2.695 (2.26), 2.720 (7.26), 2.743 (6.83), 2.803 (1 .70),
2.829 (4.57), 2.857 (5.74), 2.887 (4.96), 2.917 (3.26), 2.951 (3.48), 2.967 (2.09), 2.982 (4.09),
2.993 (1 .91 ), 3.01 1 (2.13), 3.024 (1.17), 3.076 (1 .52), 3.108 (2.83), 3.125 (1 .91 ), 3.154 (2.96),
3.188 (1 .96), 3.219 (8.70), 3.260 (10.48), 3.338 (7.52), 3.422 (2.48), 3.458 (1 .96), 3.484 (2.22),
3.520 (1 .87), 4.028 (0.96), 4.061 (1.70), 4.094 (0.87), 4.156 (1.96), 4.189 (1 .87), 4.225 (2.00),
4.259 (1 .91 ), 6.877 (2.00), 6.899 (4.52), 6.922 (2.91 ), 6.936 (3.26), 6.950 (4.78), 6.957 (7.17),
6.972 (8.22), 6.995 (8.13), 7.001 (9.78), 7.009 (9.22), 7.024 (15.61 ), 7.047 (1 1 .74), 7.071 (6.43), 7.085 (1 1 .35), 7.094 (9.17), 7.101 (8.17), 7.109 (4.74), 7.1 16 (3.61 ), 7.167 (0.61 ), 7.206 (2.48), 7.220 (3.04), 7.227 (3.30), 7.233 (3.30), 7.242 (3.30), 7.252 (2.83), 7.267 (1.78), 7.278
(1 .70), 7.283 (1 .87), 7.289 (1 .91 ), 7.299 (2.13), 7.305 (2.26), 7.310 (2.09), 7.316 (1.78), 7.372
(6.00), 7.389 (6.00), 7.484 (3.22), 7.491 (5.91 ), 7.501 (3.48), 7.506 (3.26), 7.514 (7.57), 7.536
(3.35).
The title compound (42 mg) was separated into its enantiomers by preparative chiral HPLC to give stereoisomer 1 (14 mg, see Example 40) and stereoisomer 2 (12 mg, see Example 41 ).
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IC 5m 250x30mm; Eluent A: carbon dioxide; Eluent B: Methanol + 0.2 Vol-% aqueous Ammonia (32%); Isocratic: 25%B; Flow: 100 ml/min; Temperature: 400; BPR: 150bar; UV: 220 nm.
Analytical chiral HPLC method: Instrument: Agilent: 1260, Aurora SFC-Module; column: Chiralpak IC 5m 100x4.6mm; Eluent A: carbon dioxide; Eluent B: Methanol + 0.1 Vol-% aqueous Ammonia (32%); Isocratic: 25%B; Flow: 4 ml/min; Temperature: 37.50; BPR: 100bar; UV: 220 nm.
Example 40
2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro- [5.5]undecan-3-yl]-2-methoxypropan-1 -one (Stereoisomer 1 )
Figure imgf000468_0001
For the preparation of the racemic title compound and separation into its enantiomers see Example 39.
Chiral FIPLC (method see Example 39): Rt = 1.43 min. e.e. >95%
Optical rotation (method OR1 ): 3.2°(methanol). Example 41
2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (Stereoisomer 2)
Figure imgf000469_0001
For the preparation of the racemic title compound and separation into its enantiomers see Example 39.
Chiral HPLC (method see Example 39): Rt = 2.94 min. e.e. >95%
Optical rotation (method OR1 ): -22.9° (methanol).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.032 (0.61 ), 0.043 (0.59), 0.617 (0.63), 0.649 (0.59), 0.765 (0.84), 0.861 (0.71 ), 0.873 (3.17), 0.907 (0.50), 0.960 (0.58), 0.970 (0.58), 1 .013 (16.00), 1 .050 (1 .69), 1 .138 (0.60), 1 .232 (0.71 ), 1 .295 (0.53), 1.818 (0.78), 1 .849 (0.73), 1.990 (0.86),
2.005 (0.57), 2.038 (0.54), 2.233 (1.05), 2.238 (1 .00), 2.259 (0.70), 2.429 (2.09), 2.468 (0.47),
2.535 (0.51 ), 2.571 (0.78), 2.575 (0.79), 2.652 (1 .22), 2.704 (0.50), 2.737 (0.82), 2.766 (0.47),
2.827 (0.43), 2.855 (0.70), 2.887 (0.70), 3.027 (0.46), 3.058 (0.83), 3.089 (0.57), 3.161 (3.05),
3.324 (0.81 ), 3.360 (0.59), 3.473 (6.69), 4.099 (0.41 ), 4.128 (0.61 ), 4.161 (0.56), 6.779 (0.53), 6.801 (1 .18), 6.823 (0.72), 6.875 (0.75), 6.896 (1 .91 ), 6.91 1 (2.15), 6.929 (2.42), 6.950 (2.69),
6.972 (1 .20), 6.989 (1 .28), 7.01 1 (0.75), 7.108 (0.66), 7.122 (0.76), 7.142 (0.52), 7.278 (0.90),
7.292 (0.90), 7.392 (0.93), 7.403 (0.53), 7.415 (1 .05), 7.437 (0.46). Example 42
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-1-[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-methoxypropan-1-one (mixture of stereoisomers)
Figure imgf000470_0001
Using the method described for Example 1 with intermediate 69 (80 mg, 126 pmol) gave the titled compound (11.1 mg, 16%) after preparative FIPLC purification (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.49), 0.021 (0.84), 0.032 (0.89), 0.054 (0.53), 0.191 (0.49), 0.213 (0.84), 0.224 (0.84), 0.246 (0.53), 0.257 (0.40), 0.780 (0.89), 0.816 (0.98),
0.853 (0.84), 0.864 (0.84), 0.887 (0.49), 0.985 (2.13), 0.997 (2.44), 1.031 (1.86), 1.045 (1.42), 1.078 (0.98), 1.110 (0.58), 1.273 (2.22), 1.306 (2.26), 1.326 (1.11), 1.338 (1.06), 1.717 (0.44),
1.746 (0.40), 1.831 (0.93), 1.861 (1.15), 1.877 (1.06), 1.911 (0.62), 2.004 (1.24), 2.037 (2.04),
2.069 (1.24), 2.256 (1.15), 2.260 (2.13), 2.264 (2.84), 2.269 (2.26), 2.274 (1.60), 2.285 (1.29),
2.305 (1.33), 2.313 (1.33), 2.324 (1.24), 2.333 (1.42), 2.352 (1.46), 2.361 (1.51 ), 2.455 (11.35), 2.460 (7.05), 2.477 (6.47), 2.485 (2.93), 2.543 (1.20), 2.573 (2.08), 2.602 (3.55), 2.607 (3.94), 2.611 (2.97), 2.616 (2.04), 2.624 (1.24), 2.655 (2.97), 2.675 (2.61), 2.775 (1.46), 2.805 (2.93),
2.841 (2.26), 2.875 (1.73), 2.883 (1.64), 2.896 (1.24), 2.914 (1.91), 2.944 (1.15), 3.034 (0.66),
3.063 (1.24), 3.095 (0.98), 3.122 (1.11), 3.162 (4.79), 3.201 (4.79), 3.327 (0.84), 3.379 (1.02),
3.415 (0.84), 3.515 (16.00), 3.926 (0.49), 3.957 (0.71), 3.983 (0.44), 4.075 (0.93), 4.109 (0.89), 4.135 (0.84), 4.170 (0.75), 6.873 (1.60), 6.887 (2.26), 6.894 (3.10), 6.909 (2.66), 6.941 (3.41), 6.952 (8.11), 6.975 (8.78), 6.997 (3.94), 7.005 (1.68), 7.019 (2.84), 7.027 (2.88), 7.042 (1.86),
7.049 (1.91), 7.064 (4.96), 7.087 (5.63), 7.149 (1.11), 7.164 (1.42), 7.172 (1.46), 7.177 (1.46),
7.191 (1.46), 7.219 (6.52), 7.222 (6.25), 7.600 (3.19), 7.605 (5.72), 7.610 (3.01), 7.709 (3.24),
7.714 (6.07), 7.719 (3.15), 7.727 (1.99), 7.731 (4.17), 7.735 (4.12), 7.739 (1.91), 8.482 (0.40). Example 43, Example 44 and Example 45
2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1-[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]- undecan-3-yl]-2-methoxypropan-1-one (mixture of stereoisomers)
(2S)-2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1-[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1-one
(2R)-2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1-[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1-one
Example 43
2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1-[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]- undecan-3-yl]-2-methoxypropan-1-one (mixture of stereoisomers)
Figure imgf000471_0001
Using the method described for Example 1 with intermediate 73 (80 mg, 122 pmol) gave the titled compound (28.8 mg, 40%) after preparative HPLC purification (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.51), 0.023 (0.88), 0.033 (0.83), 0.056 (0.51), 0.184 (0.42), 0.194 (0.51), 0.217 (0.92), 0.227 (0.92), 0.249 (0.55), 0.260 (0.46), 0.717 (0.97),
0.745 (0.83), 0.858 (0.51), 0.881 (0.88), 0.892 (0.92), 0.914 (1.11), 0.961 (1.71), 0.976 (2.03),
0.997 (2.36), 1.009 (2.13), 1.029 (1.53), 1.060 (0.88), 1.089 (0.55), 1.240 (1.85), 1.263 (2.22),
1.299(1.16), 1.689 (0.42), 1.810(1.43), 1.839(1.71), 1.872 (0.65), 1.929(12.67), 1.976 (1.34), 2.001 (15.03), 2.046 (1.34), 2.234 (13.09), 2.243 (3.65), 2.249 (2.73), 2.253 (2.03), 2.262 (1.29), 2.281 (1.25), 2.289 (1.25), 2.305 (1.11), 2.313 (1.29), 2.331 (1.29), 2.340 (1.29), 2.435 (12.72), 2.439 (8.14), 2.449 (2.82), 2.456 (6.84), 2.483 (1.11), 2.492 (1.11), 2.522 (0.83), 2.551 (2.13), 2.577 (2.87), 2.581 (3.75), 2.586 (3.93), 2.590 (3.05), 2.595 (2.08), 2.603 (1.43), 2.634
(3.47), 2.645 (2.50), 2.655 (2.77), 2.735 (0.74), 2.755 (1.43), 2.763 (1.39), 2.768 (1.39), 2.783
(2.45), 2.796 (1.29), 2.815 (2.45), 2.850 (1.62), 2.861 (1.71), 2.870 (1.16), 2.891 (2.13), 2.920
(1.20), 2.963 (0.69), 2.996 (1.20), 3.026 (1.29), 3.054 (1.16), 3.087 (0.79), 3.116 (4.39), 3.155
(5.46), 3.190 (1.06), 3.341 (1.02), 3.376 (0.83), 3.467 (16.00), 3.895 (0.51), 3.927 (0.79), 3.955
(0.46), 4.075 (0.92), 4.107 (0.88), 4.143 (0.88), 4.177 (0.79), 6.762 (2.40), 6.799 (2.59), 6.873
(1.43), 6.888 (2.13), 6.895 (3.05), 6.909 (2.59), 6.943 (4.58), 6.953 (7.54), 6.966 (8.55), 6.975 (6.29), 6.983 (2.96), 6.988 (3.19), 6.997 (3.79), 7.005 (3.14), 7.019 (2.45), 7.028 (4.76), 7.134 (1 .34), 7.156 (5.50), 7.170 (5.60), 7.192 (0.97), 7.318 (3.51 ), 7.408 (3.75), 7.426 (3.24).
The title compound (25 mg) was separated into its enantiomers by preparative chiral HPLC to give stereoisomer 1 (10 mg, see Example 44HET03682-1 ) and stereoisomer 2 (8 mg, see Example 45HET03788-1 ).
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IC 5m 250x30mm; Eluent A: carbon dioxide; Eluent B: Methanol + 0.2 Vol-% aqueous Ammonia (32%); Isocratic: 25%B; Flow: 100 ml/min; Temperature: 40Ό; BPR: 150bar; UV: 220 nm.
Analytical chiral HPLC method: Instrument: Agilent: 1260, Aurora SFC-Module; column: Chiralpak IC 5m 100x4.6mm; Eluent A: carbon dioxide; Eluent B: Methanol + 0.1 Vol-% aqueous Ammonia (32%); Isocratic: 25%B; Flow: 4 ml/min; Temperature: 37.50; BPR: 100bar; UV: 220 nm.
Example 44
2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (Stereoisomer 1 )
Figure imgf000472_0001
For the preparation of the racemic title compound and separation into its enantiomers see Example 43
Chiral HPLC (method see Example 43): Rt = 1.93 min. e.e. >95%
Optical rotation (method OR1 ): -9.0° (methanol).
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.082 (0.07), 0.104 (0.1 1 ), 0.136 (0.07), 0.852 (0.07), 0.859 (0.10), 0.950 (0.06), 0.967 (0.14), 1.037 (0.18), 1 .057 (0.19), 1.093 (0.31 ), 1 .107 (16.00), 1 .125 (0.1 1 ), 1 .144 (0.14), 1 .162 (0.1 1 ), 1 .190 (0.08), 1.232 (0.24), 1 .261 (0.08), 1.319 (0.18),
1 .351 (0.53), 1 .383 (0.38), 2.01 1 (0.07), 2.049 (0.09), 2.083 (1.91 ), 2.1 14 (0.13), 2.318 (1 .19),
2.418 (0.15), 2.444 (0.17), 2.518 (0.59), 2.522 (0.35), 2.539 (0.20), 2.566 (0.19), 2.665 (0.22),
2.669 (0.26), 2.673 (0.22), 2.746 (0.20), 2.865 (0.17), 2.898 (0.30), 2.928 (0.17), 3.01 1 (0.08),
3.048 (0.12), 3.081 (0.18), 3.1 12 (0.1 1 ), 3.193 (0.60), 3.237 (0.15), 3.427 (0.17), 3.463 (0.13), 3.553 (1.47), 4.161 (0.14), 4.192 (0.41), 6.881 (0.35), 6.958 (0.19), 6.979 (0.39), 6.993 (0.32), 7.033 (0.41), 7.055 (0.59), 7.076 (0.29), 7.093 (0.31), 7.114 (0.36), 7.247 (0.62), 7.490 (0.51), 7.513(0.28).
Example 45
2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1-[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (Stereoisomer 2)
Figure imgf000473_0001
For the preparation of the racemic title compound and separation into its enantiomers see Example 43
Chiral FIPLC (method see Example 43): Rt = 5.69 min. e.e. >95%
Optical rotation (method OR1): -10.2°(methanol).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.107 (16.00), 2.010 (1.67), 2.315 (1.17), 2.518 (0.73),
2.522 (0.50), 3.233 (0.68), 3.547 (1.37), 7.041 (0.68), 7.048 (0.47), 7.063 (0.62), 7.086 (0.41),
7.233 (0.53), 7.400 (0.50).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.274 (0.07), 0.296 (0.12), 0.307 (0.12), 0.328 (0.07),
0.800 (0.13), 0.833 (0.14), 0.853 (0.09), 0.859 (0.10), 0.938 (0.08), 0.950 (0.08), 0.967 (0.21),
0.994 (0.08), 1.107(16.00), 1.144 (0.10), 1.232 (0.27), 1.260 (0.08), 1.324 (0.17), 1.350 (0.13), 1.463 (0.07), 1.903 (0.14), 1.935 (0.14), 2.010 (1.67), 2.051 (0.06), 2.116 (0.09), 2.152 (0.09),
2.315 (1.17), 2.326 (0.22), 2.331 (0.15), 2.365 (0.11), 2.389 (0.12), 2.518 (0.73), 2.522 (0.50),
2.566 (0.16), 2.664 (0.22), 2.669 (0.26), 2.673 (0.21), 2.770 (0.16), 2.817 (0.11), 2.849 (0.16),
2.882 (0.10), 2.968 (0.14), 3.005 (0.12), 3.107 (0.09), 3.139 (0.16), 3.171 (0.11), 3.233 (0.68),
3.504 (0.11), 3.547 (1.37), 3.989 (0.07), 4.022 (0.06), 4.192 (0.19), 4.230 (0.13), 4.264 (0.11),
6.842 (0.33), 7.041 (0.68), 7.048 (0.47), 7.063 (0.62), 7.086 (0.41), 7.108 (0.39), 7.233 (0.53),
7.256 (0.28), 7.400 (0.50), 7.509 (0.27). Example 46, Example 47 and Example 48
2-(3-chlorophenyl)-3,3,3-trifluoro-1-[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxypropan-1-one (mixture of stereoisomers)
(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-1-[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-methoxypropan-1 -one
(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-1-[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-methoxypropan-1 -one
Example 46
2-(3-chlorophenyl)-3,3,3-trifluoro-1-[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxypropan-1-one (mixture of stereoisomers)
Figure imgf000474_0001
Using the method described for Example 1 with intermediate 102 (250 mg, 122 pmolHET03744) gave the titled compound (76 mg, 36%) after preparative HPLC purification (Method 6).
LC-MS (Method 2): Rt = 1.41 min; MS (ESIpos): m/z = 499 [M+H]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.022 (0.47), 0.000 (0.76), 0.011 (0.73), 0.032 (0.47), 0.116 (0.41), 0.129 (0.44), 0.149 (0.79), 0.161 (0.79), 0.183 (0.50), 0.646 (0.85), 0.679 (0.70),
0.910 (0.47), 0.932 (0.79), 0.942 (0.82), 0.979 (1.02), 0.994 (1.02), 1.017 (1.49), 1.037 (1.49),
1.051 (1.54), 1.071 (1.75), 1.083 (1.54), 1.104 (1.43), 1.232 (0.85), 1.268 (1.69), 1.299 (1.66),
1.455 (0.32), 1.758 (0.35), 1.862 (1.19), 1.895 (1.40), 2.032 (1.05), 2.062 (1.63), 2.096 (1.02),
2.287 (1.25), 2.301 (1.87), 2.306 (2.80), 2.309 (2.24), 2.314 (1.69), 2.371 (1.22), 2.390 (1.19),
2.399 (1.34), 2.496 (8.36), 2.500 (6.35), 2.518 (5.22), 2.545 (0.73), 2.565 (0.76), 2.594 (1.69),
2.624 (1.78), 2.642 (1.78), 2.647 (2.65), 2.652 (2.21), 2.656 (1.69), 2.685 (2.94), 2.710 (2.62),
2.776 (1.19), 2.804 (2.19), 2.820 (1.19), 2.835 (1.49), 2.854 (1.69), 2.883 (1.40), 2.923 (1.25),
2.934 (0.96), 2.954 (1.75), 2.982 (0.87), 3.022 (0.70), 3.055 (1.14), 3.103 (1.17), 3.136 (0.73),
3.194 (3.29), 3.232 (4.08), 3.384 (0.90), 3.419 (0.96), 3.455 (0.76), 3.541 (16.00), 4.021 (0.64), 4.132 (0.79), 4.166 (0.76), 4.198 (0.79), 4.231 (0.76), 6.724 (0.17), 6.877 (1.63), 6.890 (2.21),
6.897 (2.89), 6.911 (5.42), 6.925 (2.80), 6.934 (1.75), 6.948 (2.94), 6.955 (2.74), 6.969 (3.00), 7.046 (3.50), 7.053 (3.53), 7.060 (3.32), 7.069 (6.85), 7.075 (6.21 ), 7.092 (5.22), 7.113 (1 .43),
7.145 (0.35), 7.184 (1 .02), 7.222 (2.51 ), 7.241 (4.63), 7.335 (2.42), 7.414 (1 .31 ), 7.419 (1 .52),
7.428 (1 .78), 7.432 (1 .08), 7.436 (1.43), 7.441 (2.04), 7.461 (2.21 ), 7.481 (1 .46), 7.508 (1 .95),
7.534 (2.56), 7.537 (2.07), 7.554 (1.49), 7.557 (1 .52).
The title compound (73.2 mg) was separated into its enantiomers by preparative chiral HPLC to give stereoisomer 1 (35 mg, see Example 47HET03852-1 ) and stereoisomer 2 (32 mg, see Example 45HET03857-1 ).
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IC 5m 250x30mm; Eluent A: carbon dioxide; Eluent B: Methanol + 0.2 Vol-% aqueous Ammonia (32%); Isocratic: 30%B; Flow: 100 ml/min; Temperature: 400; BPR: 150bar; UV: 220 nm.
Analytical chiral HPLC method: Instrument: Agilent: 1260, Aurora SFC-Module; column: Chiralpak IC 5m 100x4.6mm; Eluent A: carbon dioxide; Eluent B: Methanol + 0.1 Vol-% aqueous Ammonia (32%); Isocratic: 30%B; Flow: 4 ml/min; Temperature: 37.50; BPR: 100bar; UV: 220 nm.
Example 47
2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxypropan-1 -one (Stereoisomer 1 )
Figure imgf000475_0001
For the preparation of the racemic title compound and separation into its enantiomers see Example 46
Chiral HPLC (method see Example 46): Rt = 1.28 min. e.e. >95%
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.09), 0.01 1 (0.09), 0.945 (0.24), 0.987 (0.08), 1 .000 (0.08), 1 .017 (0.10), 1 .038 (0.12), 1.049 (0.1 1 ), 1.073 (0.27), 1.085 (16.00), 1 .106 (0.15), 1 .1 16 (0.13), 1 .122 (0.21 ), 1 .202 (0.07), 1 .209 (0.07), 1.238 (0.12), 1 .268 (0.20), 1.301 (0.10),
1 .326 (0.06), 2.024 (0.08), 2.039 (0.09), 2.062 (0.10), 2.072 (0.08), 2.377 (0.10), 2.397 (0.1 1 ),
2.404 (0.1 1 ), 2.496 (0.23), 2.501 (0.21 ), 2.518 (0.21 ), 2.599 (0.10), 2.627 (0.10), 2.642 (0.08),
2.647 (0.09), 2.652 (0.09), 2.691 (0.18), 2.785 (0.08), 2.815 (0.18), 2.847 (0.21 ), 2.881 (0.1 1 ),
3.022 (0.08), 3.054 (0.13), 3.086 (0.09), 3.193 (0.39), 3.215 (0.12), 3.298 (0.26), 3.421 (0.12), 3.457 (0.09), 4.135 (0.1 1 ), 4.168 (0.19), 6.877 (0.18), 6.891 (0.24), 6.898 (0.28), 6.912 (0.23), 6.945 (0.15), 6.964 (0.18), 7.047 (0.31 ), 7.070 (0.65), 7.092 (0.57), 7.1 1 1 (0.16), 7.210 (0.09), 7.223 (0.18), 7.253 (0.32), 7.334 (0.15), 7.442 (0.08), 7.462 (0.19), 7.482 (0.13), 7.508 (0.10), 7.510 (0.13), 7.513 (0.12), 7.515 (0.1 1 ), 7.531 (0.23), 7.533 (0.26), 7.536 (0.22), 7.538 (0.19), 7.551 (0.17), 7.553 (0.18), 7.557 (0.18).
Example 48
2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R) -7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxypropan-1 -one (Stereoisomer 2)
Figure imgf000476_0001
For the preparation of the racemic title compound and separation into its enantiomers see Example 46
Chiral HPLC (method see Example 46): Rt = 2.59 min. e.e. >95%
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.150 (0.07), 0.172 (0.12), 0.183 (0.12), 0.205 (0.07), 0.667 (0.12), 0.700 (0.1 1 ), 0.859 (0.07), 0.921 (0.06), 0.932 (0.07), 0.954 (0.13), 0.967 (0.44), 0.989 (0.08), 1 .000 (0.09), 1 .017 (0.08), 1.045 (0.13), 1 .080 (0.16), 1.093 (0.16), 1 .107 (16.00), 1 .144 (0.22), 1 .224 (0.07), 1 .231 (0.08), 1 .320 (0.14), 1.887 (0.17), 1 .921 (0.16), 2.074 (0.07), 2.083 (0.18), 2.121 (0.12), 2.313 (0.14), 2.322 (0.10), 2.327 (0.14), 2.331 (0.18), 2.459 (0.1 1 ), 2.518 (0.27), 2.523 (0.20), 2.539 (0.21 ), 2.570 (0.09), 2.622 (0.1 1 ), 2.652 (0.1 1 ), 2.664 (0.12), 2.669 (0.12), 2.673 (0.1 1 ), 2.678 (0.10), 2.687 (0.10), 2.716 (0.15), 2.739 (0.25), 2.790 (0.10), 2.819 (0.16), 2.851 (0.09), 2.921 (0.07), 2.940 (0.13), 2.952 (0.14), 2.980 (0.16), 3.01 1 (0.08), 3.095 (0.09), 3.124 (0.16), 3.157 (0.1 1 ), 3.254 (0.60), 3.326 (0.24), 3.372 (0.20), 3.408 (0.13), 4.191 (0.16), 4.220 (0.13), 4.254 (0.12), 6.932 (0.53), 6.945 (0.41 ), 6.956 (0.24), 6.970 (0.30), 6.977 (0.35), 6.991 (0.28), 7.060 (0.14), 7.075 (0.40), 7.082 (0.37), 7.098 (0.59), 7.120 (0.25), 7.205 (0.13), 7.219 (0.16), 7.226 (0.14), 7.241 (0.20), 7.262 (0.48), 7.359 (0.20), 7.434 (0.20), 7.440 (0.22), 7.442 (0.19), 7.449 (0.28), 7.453 (0.17), 7.457 (0.20), 7.462 (0.27), 7.481 (0.25), 7.501 (0.17), 7.526 (0.14), 7.529 (0.17), 7.531 (0.15), 7.534 (0.14), 7.546 (0.08), 7.549 (0.08), 7.551 (0.08). Example 49, Example 50 and Example 51
2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers)
(2R)-2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one
(2S)-2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one
Example 49
2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers)
Figure imgf000477_0001
Using the method described for Example 1 with intermediate 106 (250 mg, 369 pmol) gave the titled compound (69 mg, 32%) after preparative HPLC purification (Method 6).
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.101 (0.77), 0.137 (0.43), 0.276 (0.56), 0.297 (0.90), 0.309 (0.86), 0.331 (0.51 ), 0.877 (0.90), 0.903 (1 .12), 0.923 (0.99), 0.958 (0.56), 1.028 (1 .20), 1 .061 (2.57), 1 .095 (2.02), 1 .122 (1.16), 1 .167 (0.77), 1.330 (1.89), 1 .370 (2.02), 1.397 (1 .03), 1 .470 (0.43), 1 .769 (0.47), 1 .868 (0.90), 1 .904 (1 .12), 1.945 (0.90), 2.045 (1 .07), 2.083 (1 .80), 2.1 18 (1 .24), 2.322 (2.10), 2.326 (2.87), 2.331 (2.27), 2.336 (1.72), 2.347 (1 .37), 2.365 (1 .29), 2.375 (1 .50), 2.388 (1.37), 2.406 (1 .29), 2.414 (1 .33), 2.518 (10.29), 2.522 (7.25), 2.539 (3.82), 2.550 (2.57), 2.615 (1 .07), 2.640 (2.02), 2.659 (2.23), 2.664 (3.09), 2.668 (4.29), 2.673 (3.30), 2.720 (2.79), 2.737 (2.57), 2.838 (1.46), 2.867 (2.27), 2.906 (1.93), 2.940 (2.10), 2.969 (1 .97), 2.998 (1 .16), 3.089 (0.56), 3.122 (1.16), 3.154 (1 .16), 3.186 (1.24), 3.226 (4.72), 3.262 (5.45), 3.421 (0.90), 3.457 (0.73), 3.575 (16.00), 4.006 (0.73), 4.131 (0.77), 4.186 (0.86), 4.221 (0.73), 6.958 (1 .16), 6.980 (2.66), 6.994 (2.27), 7.021 (1 1 .41 ), 7.039 (10.38), 7.060 (2.79), 7.080 (3.09), 7.088 (2.83), 7.103 (2.02), 7.1 1 1 (2.23), 7.1 19 (2.45), 7.146 (2.32), 7.217 (1.33), 7.246 (1 .54), 7.280 (0.82), 7.313 (3.26), 7.344 (2.53), 7.409 (3.17), 7.776 (3.13), 7.780 (5.71 ), 7.785 (3.05), 7.883 (2.87), 7.888 (5.15), 7.892 (2.83), 7.898 (2.10), 7.903 (5.02), 7.908 (4.93), 7.912 (1 .80). The title compound (66 mg) was separated into its enantiomers by preparative chiral HPLC to give stereoisomer 1 (28 mg, see Example 50HETO3858-1 ) and stereoisomer 2 (26 mg, see Example 51 HETO3890-2).
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IC 5m 250x30mm; Eluent A: carbon dioxide; Eluent B: Methanol + 0.2 Vol-% aqueous Ammonia (32%); Isocratic: 30%B; Flow: 100 ml/min; Temperature: 400; BPR: 150bar; UV: 220 nm.
Analytical chiral HPLC method: Instrument: Agilent: 1260, Aurora SFC-Module; column: Chiralpak IC 5m 100x4.6mm; Eluent A: carbon dioxide; Eluent B: Methanol + 0.1 Vol-% aqueous Ammonia (32%); Isocratic: 30%B; Flow: 4 ml/min; Temperature: 37.50; BPR: 100bar; UV: 220 nm.
Example 50
2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]- undecan-3-yl]-2-methoxypropan-1 -one (Stereoisomer 1 )
Figure imgf000478_0001
For the preparation of the racemic title compound and separation into its enantiomers see Example 49
Chiral HPLC (method see Example 49): Rt = 1.38 min. e.e. >95%
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.886 (0.63), 1 .026 (16.00), 1 .063 (0.42), 1 .288 (0.42), 2.437 (0.74), 2.442 (0.55), 3.145 (0.93), 3.496 (2.05), 4.109 (0.54), 6.899 (0.59), 6.913 (0.50), 6.935 (0.66), 6.957 (0.93), 7.008 (0.51 ), 7.065 (0.50), 7.263 (0.55), 7.802 (0.64), 7.806 (1 .13),
7.810 (0.62), 7.821 (0.42), 7.826 (0.74), 7.830 (0.41 ). Example 51
2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (Stereoisomer 2)
Figure imgf000479_0001
For the preparation of the racemic title compound and separation into its enantiomers see Example 49.
Chiral FIPLC (method see Example 49): Rt = 3.18 min. e.e. >95%
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.265 (0.07), 0.277 (0.08), 0.297 (0.13), 0.309 (0.13), 0.331 (0.08), 0.342 (0.07), 0.852 (0.07), 0.859 (0.14), 0.875 (0.15), 0.903 (0.19), 0.922 (0.17),
0.935 (0.15), 0.967 (0.35), 1 .067 (0.14), 1.107 (16.00), 1 .144 (0.20), 1 .224 (0.12), 1 .232 (0.13),
1 .330 (0.21 ), 1 .475 (0.07), 1 .870 (0.14), 1 .907 (0.16), 1.950 (0.07), 2.084 (0.14), 2.120 (0.12),
2.322 (0.16), 2.327 (0.21 ), 2.331 (0.17), 2.350 (0.17), 2.369 (0.17), 2.518 (0.76), 2.523 (0.53),
2.555 (0.26), 2.567 (0.26), 2.595 (0.09), 2.643 (0.14), 2.665 (0.26), 2.669 (0.31 ), 2.673 (0.28),
2.718 (0.18), 2.751 (0.26), 2.839 (0.10), 2.872 (0.17), 2.907 (0.14), 2.941 (0.15), 2.974 (0.21 ),
3.003 (0.15), 3.154 (0.09), 3.185 (0.20), 3.223 (0.15), 3.262 (0.83), 3.572 (1 .51 ), 3.976 (0.08),
4.009 (0.08), 4.189 (0.68), 4.221 (0.13), 7.022 (1 .58), 7.041 (1.09), 7.060 (0.24), 7.082 (0.42),
7.104 (0.27), 7.120 (0.37), 7.217 (0.20), 7.231 (0.22), 7.252 (0.15), 7.313 (0.32), 7.325 (0.41 ),
7.409 (0.29), 7.775 (0.50), 7.780 (0.91 ), 7.784 (0.49), 7.898 (0.32), 7.902 (0.57), 7.907 (0.30).
Example 52. Example 53 and Example 54
3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers)
(2R)-3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one
(2S)-3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one Example 52
3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers)
Figure imgf000480_0001
Using the method described for Example 1 with intermediate 1 10 (250 mg, 419 pmol) gave the titled compound (77 mg, 37%) after preparative HPLC purification (Method 6).
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.022 (0.27), 0.000 (0.53), 0.034 (0.29), 0.160 (0.31 ), 0.181 (0.58), 0.193 (0.54), 0.213 (0.35), 0.659 (0.56), 0.691 (0.53), 0.852 (0.31 ), 0.874 (0.56),
0.885 (0.54), 0.909 (0.35), 0.987 (1.27), 1 .009 (1 .22), 1.020 (1.49), 1 .054 (1 .05), 1.083 (0.36),
1 .226 (0.73), 1 .261 (1 .67), 1 .417 (0.22), 1 .666 (0.13), 1.738 (0.22), 1 .847 (0.76), 1.877 (0.78),
1 .928 (0.33), 1 .998 (8.23), 2.025 (1.07), 2.064 (9.08), 2.085 (0.80), 2.272 (9.72), 2.292 (0.91 ),
2.301 (0.84), 2.341 (0.82), 2.360 (0.84), 2.368 (0.91 ), 2.460 (5.76), 2.464 (3.96), 2.481 (16.00), 2.528 (0.56), 2.560 (1 .18), 2.589 (1.22), 2.606 (1 .29), 2.61 1 (1.63), 2.616 (1 .40), 2.653 (1 .94),
2.676 (1 .80), 2.739 (0.51 ), 2.766 (1.34), 2.795 (1 .34), 2.820 (1.29), 2.853 (0.93), 2.894 (0.85),
2.925 (1 .25), 2.954 (0.67), 2.985 (0.51 ), 3.016 (0.82), 3.037 (0.65), 3.046 (0.58), 3.066 (0.84),
3.098 (0.65), 3.135 (2.1 1 ), 3.177 (2.47), 3.351 (0.76), 3.386 (0.56), 3.446 (0.67), 3.491 (9.32),
3.948 (0.27), 3.983 (0.45), 4.101 (0.54), 4.133 (0.53), 4.172 (0.54), 4.206 (0.53), 6.695 (2.69),
6.733 (1 .73), 6.813 (0.76), 6.845 (1.34), 6.866 (1 .71 ), 6.881 (1.42), 6.917 (2.63), 6.939 (1 .53),
6.970 (2.60), 6.988 (3.47), 6.992 (3.45), 7.010 (2.29), 7.024 (1.62), 7.032 (1 .54), 7.054 (1 .67),
7.077 (1 .13), 7.148 (0.74), 7.168 (1.16), 7.182 (1 .07), 7.204 (0.49).
The title compound (73 mg) was separated into its enantiomers by preparative chiral HPLC to give stereoisomer 1 (33 mg, see Example 53HET03853-1 ) and stereoisomer 2 (49 mg, see Example 54 HET03856-1 ).
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IC 5m 250x30mm; Eluent A: carbon dioxide; Eluent B: Methanol + 0.2 Vol-% aqueous Ammonia (32%); Isocratic: 25%B; Flow: 100 ml/min; Temperature: 40Ό; BPR: 150bar; UV: 220 nm.
Analytical chiral HPLC method: Instrument: Agilent: 1260, Aurora SFC-Module; column: Chiralpak IC 5m 100x4.6mm; Eluent A: carbon dioxide; Eluent B: Methanol + 0.1 Vol-% aqueous Ammonia (32%); Isocratic: 25%B; Flow: 4 ml/min; Temperature: 37.50; BPR: 100bar; UV: 220 nm.
Example 53
3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (Stereoisomer 1 )
Figure imgf000481_0001
For the preparation of the racemic title compound and separation into its enantiomers see Example 52
Chiral HPLC (method see Example 52): Rt = 1.62 min. e.e. >95%
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.033 (0.08), 0.043 (0.08), 0.983 (0.07), 0.995 (0.07),
1 .009 (0.11 ), 1 .019 (0.12), 1 .042 (0.14), 1.054 (0.15), 1 .067 (0.16), 1.081 (16.00), 1 .1 18 (0.07), 1 .121 (0.07), 1 .198 (0.07), 1 .204 (0.06), 1 .235 (0.07), 1.253 (0.12), 1 .292 (0.18), 1.326 (0.14),
2.013 (0.07), 2.022 (0.1 1 ), 2.064 (0.10), 2.095 (1 .38), 2.304 (0.67), 2.378 (0.1 1 ), 2.399 (0.12),
2.407 (0.12), 2.513 (0.27), 2.595 (0.10), 2.625 (0.09), 2.638 (0.07), 2.643 (0.07), 2.647 (0.07), 2.694 (0.16), 2.812 (0.12), 2.844 (0.20), 2.878 (0.10), 3.016 (0.07), 3.047 (0.12), 3.079 (0.08),
3.165 (0.33), 3.226 (0.07), 3.258 (0.08), 3.323 (0.10), 3.480 (0.10), 4.135 (0.1 1 ), 4.166 (0.21 ),
6.714 (0.12), 6.738 (0.12), 6.766 (0.27), 6.877 (0.17), 6.892 (0.21 ), 6.899 (0.26), 6.913 (0.21 ),
6.945 (0.14), 6.998 (0.25), 7.020 (0.41 ), 7.042 (0.25), 7.063 (0.18), 7.085 (0.24), 7.105 (0.17),
7.125 (0.1 1 ), 7.199 (0.08), 7.206 (0.08), 7.213 (0.10), 7.221 (0.10).
Example 54
3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (Stereoisomer 2)
Figure imgf000482_0001
For the preparation of the racemic title compound and separation into its enantiomers see Example 52
Chiral FIPLC (method see Example 52): Rt = 3.43 min. e.e. >95%
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.205 (0.13), 0.216 (0.15), 0.238 (0.27), 0.248 (0.26), 0.271 (0.15), 0.281 (0.12), 0.719 (0.27), 0.749 (0.27), 0.852 (0.09), 0.859 (0.14), 0.901 (0.18), 0.91 1 (0.17), 0.934 (0.29), 0.967 (0.76), 1.023 (0.15), 1 .054 (0.32), 1.107 (16.00), 1 .144 (0.42),
1 .224 (0.15), 1 .232 (0.16), 1 .260 (0.08), 1 .327 (0.28), 1.388 (0.12), 1 .483 (0.10), 1.518 (0.08),
1 .91 1 (0.36), 1 .945 (0.34), 1 .985 (0.10), 2.055 (3.63), 2.083 (0.15), 2.121 (0.28), 2.153 (0.26),
2.329 (2.16), 2.363 (0.32), 2.371 (0.30), 2.522 (0.39), 2.540 (0.34), 2.578 (0.17), 2.636 (0.24),
2.665 (0.33), 2.668 (0.34), 2.720 (0.32), 2.754 (0.49), 2.792 (0.29), 2.825 (0.36), 2.858 (0.21 ), 2.925 (0.20), 2.957 (0.27), 2.972 (0.27), 3.000 (0.34), 3.030 (0.18), 3.095 (0.22), 3.124 (0.35),
3.156 (0.25), 3.232 (1 .10), 3.271 (0.30), 3.319 (0.51 ), 3.412 (0.32), 3.447 (0.24), 4.013 (0.1 1 ),
4.045 (0.1 1 ), 4.191 (0.24), 4.232 (0.26), 4.265 (0.23), 6.728 (0.35), 6.753 (1 .12), 6.872 (0.18),
6.894 (0.18), 6.963 (0.43), 6.977 (0.95), 6.984 (0.87), 6.998 (0.70), 7.012 (0.52), 7.031 (1 .1 1 ),
7.053 (1 .18), 7.075 (0.53), 7.085 (0.58), 7.107 (0.34), 7.126 (0.21 ), 7.149 (0.21 ), 7.205 (0.28), 7.219 (0.35), 7.240 (0.21 ).
Examples 55 - 59
The following examples were made using an analogous method described as for intermediate Example 1 but with intermediates 98, 99, 100, 101 and 97, resprectively (Table 8).
Table 8:
Figure imgf000483_0001
Figure imgf000484_0001
Figure imgf000485_0001
Figure imgf000486_0002
Example 60 and Example 61
(2R)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- phenylpropan-1 -one
(2R)-3,3,3-trifluoro-2-methoxy-1 -[(7S)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- phenylpropan-1 -one
Example 60
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- phenylpropan-1 -one, salt with hydrochloric acid (Stereoisomer 1 )
Figure imgf000486_0001
Using the method described for Example 1 with intermediate 87 (50 mg, 86.7 pmol) gave the titled compound (12 mg, 22%) after concentration of the reaction mixture under reduced pressure.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.896 (0.44), 0.907 (0.45), 1 .237 (0.97), 1 .270 (0.90), 1 .285 (1 .03), 1 .421 (0.43), 2.290 (0.57), 2.327 (0.51 ), 2.700 (0.79), 2.733 (0.97), 2.848 (0.45),
2.959 (0.45), 2.980 (1 .78), 3.026 (0.87), 3.053 (0.53), 3.143 (0.42), 3.174 (0.53), 3.319 (4.82),
3.338 (1 .92), 3.370 (1 .53), 3.379 (1.46), 3.392 (1 .37), 3.404 (1.23), 3.413 (1 .33), 3.420 (1 .14),
3.444 (0.99), 3.487 (6.00), 3.497 (13.65), 3.705 (3.14), 4.1 16 (0.75), 4.138 (0.52), 4.156 (0.55), 5.693 (16.00), 6.285 (0.77), 6.468 (0.88), 6.471 (0.89), 6.487 (0.97), 6.490 (0.92), 6.875 (0.46), 6.894 (0.86), 6.91 1 (1 .24), 6.930 (0.64), 6.947 (0.45), 6.966 (0.55), 6.982 (1 .22), 7.004 (1 .70),
7.012 (1 .40), 7.030 (2.55), 7.050 (1.80), 7.068 (2.18), 7.089 (0.95), 7.246 (0.48), 7.253 (0.46),
7.280 (0.70), 7.283 (0.70), 7.301 (1.13), 7.319 (0.57), 7.323 (0.52), 7.354 (1 .14), 7.363 (1 .55),
7.371 (1 .03), 7.382 (1.16), 7.399 (0.51 ). Example 61
(2R)-3,3,3-trifluoro-2-methoxy-1-[7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- phenylpropan-1-one, salt with hydrochloric acid (Stereoisomer 2)
Figure imgf000487_0001
Using the method described for Example 1 with intermediate 89 (20 mg, 34.7 pmol) gave the titled compound (7.2 mg, 32%) after concentration of the reaction mixture under reduced pressure.
LC-MS (method 2): Rt = 1.36 min; MS (ESIpos): m/z = 477 [M+H]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.046 (0.73), -0.034 (0.67), -0.011 (0.40), 0.552 (0.79), 0.585 (0.70), 0.868 (0.47), 1.040 (0.45), 1.051 (0.45), 1.074 (0.85), 1.108 (0.55), 1.184
(1.11), 1.197 (1.39), 1.205 (1.15), 1.250 (2.02), 1.286 (0.63), 1.330 (0.76), 1.349 (0.70), 1.361
(0.88), 1.370 (0.90), 1.395 (0.55), 2.014 (0.76), 2.046 (0.71), 2.346 (0.44), 2.380 (0.91), 2.416
(0.83), 2.688 (0.41), 2.770 (0.65), 2.800 (1.03), 2.836 (1.18), 2.868 (0.78), 2.967 (0.41), 3.020
(0.97), 3.051 (1.44), 3.084 (0.99), 3.154 (0.99), 3.173 (1.98), 3.297 (0.74), 3.303 (0.74), 3.330
(1.63), 3.337 (1.96), 3.403 (2.40), 3.443 (1.50), 3.462 (0.80), 3.478 (1.33), 3.486 (1.47), 3.498
(2.34), 3.506 (3.38), 3.513 (2.84), 3.519 (2.40), 3.528 (1.69), 3.543 (16.00), 3.559 (8.73), 3.592 (0.83), 3.598 (0.91), 3.605 (1.07), 3.615 (1.79), 3.618 (1.72), 3.632 (0.49), 3.685 (0.86), 3.697
(0.92), 3.709 (0.76), 3.767 (0.59), 3.776 (1.12), 3.793 (0.67), 3.805 (3.85), 3.818 (1.29), 4.037
(0.51), 4.153 (0.77), 4.158 (0.46), 4.239 (0.74), 4.251 (0.79), 4.262 (0.64), 4.307 (0.73), 4.324
(0.41), 4.342 (0.68), 4.347 (0.69), 4.648 (2.65), 4.651 (1.69), 4.663 (2.54), 4.668 (1.27), 4.682
(0.47), 5.778 (0.86), 6.945 (1.40), 6.964 (3.08), 6.983 (2.15), 7.006 (0.59), 7.024 (1.82), 7.040
(6.17), 7.059 (2.48), 7.089 (2.34), 7.109 (2.52), 7.137 (0.45), 7.280 (0.45), 7.342 (0.58), 7.351
(0.72), 7.365 (1.25), 7.384 (1.78), 7.394 (1.12), 7.399 (1.39), 7.410 (1.07), 7.415 (1.31), 7.431
(0.76), 7.437 (0.79), 7.454 (1.68), 7.460 (1.37), 7.469 (0.90), 8.261 (1.01), 8.722 (0.45), 9.180
(0.49), 9.205 (0.45). Example 62
(2R)-3,3,3-trifluoro-2-methoxy-1-[7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- phenylpropan-1-one (Stereoisomer 1)
Figure imgf000488_0001
To a solution of intermediate 87 (200 mg, 347 mihoI) in dioxane (2ml) was added hydrochloric acid (4M in dioxane, 1.7 mmol) and stirred at RT for 16h. The reaction was concentrated and purified by preparative HPLC (Method 6) to give the title compound (116 mg, 67%).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.212 (0.55), 0.222 (0.55), 0.986 (0.71), 0.997 (0.79), 1.019 (0.72), 1.031 (0.57), 1.050 (0.49), 1.118 (0.55), 1.128 (0.67), 1.149 (0.40), 1.161 (0.54), 1.173 (0.42), 1.199 (0.83), 1.233 (0.68), 1.285 (0.70), 1.318 (0.60), 2.081 (0.66), 2.115 (0.64),
2.323 (0.68), 2.327 (0.74), 2.332 (0.68), 2.355 (0.74), 2.518 (1.05), 2.523 (0.72), 2.540 (0.99),
2.587 (0.61), 2.616 (0.43), 2.696 (1.01), 2.724 (1.14), 2.757 (1.01), 2.789 (0.67), 2.801 (0.62),
2.829 (0.89), 2.834 (0.89), 2.862 (0.52), 2.986 (0.51), 2.997 (0.48), 3.023 (1.24), 3.053 (1.02),
3.104 (2.34), 3.444 (0.65), 3.479 (0.56), 3.742 (6.30), 3.757 (16.00), 4.129 (0.62), 4.161 (0.61), 6.549 (1.02), 6.552 (1.06), 6.568 (1.16), 6.571 (1.13), 6.879 (0.73), 6.884 (0.82), 6.902 (1.43),
6.921 (0.72), 6.939 (0.60), 6.960 (1.92), 6.981 (1.61), 7.091 (1.46), 7.110 (3.55), 7.131 (2.69),
7.150 (3.15), 7.170 (1.45), 7.242 (0.66), 7.260 (1.10), 7.278 (0.54), 7.319 (0.72), 7.327 (0.70),
7.418 (2.68), 7.422 (1.69), 7.425 (1.82), 7.433 (2.31 ), 7.436 (2.05), 7.440 (1.23), 7.454 (0.76).
Example 63
(2R)-1 -[7-(2-chlorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one (mixture of stereoisomers)
Figure imgf000489_0001
To a solution of Intermediate 1 14 (150 mg, 303 mihoI) in THF (2 ml) under Argon was added borane dimethylsulfide (1 .1 ml, 2.0 M in THF, 2.1 mmol) and the reaction was heated at 70Ό for 3h. To the reaction was added EtOH (1 ml) and heated at 700 for 16h. The reaction was concentrated under reduced pressure and and the titled compound (86 mg, 56%) was obtained after purification by preparative HPLC (Method 6)
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .143 (16.00), 2.157 (0.41 ), 2.554 (0.74), 2.558 (0.49), 2.766 (0.62), 2.804 (0.45), 2.967 (0.40), 2.996 (0.41 ), 3.026 (0.43), 3.056 (0.40), 3.088 (0.52),
3.092 (0.54), 3.122 (0.42), 3.154 (0.49), 3.274 (0.67), 3.462 (0.41 ), 3.581 (2.34), 3.588 (1 .83),
6.960 (0.73), 6.979 (0.47), 7.089 (0.68), 7.108 (0.53), 7.177 (1.23), 7.194 (0.67), 7.248 (0.43),
7.271 (0.41 ), 7.302 (0.46), 7.320 (0.94), 7.323 (0.75), 7.327 (0.42), 7.334 (0.69), 7.339 (0.56),
7.342 (0.55), 7.346 (0.49), 7.351 (0.48), 7.368 (1 .20), 7.376 (0.76), 7.383 (0.83), 7.391 (0.86),
7.456 (0.63), 7.460 (0.49), 7.465 (0.91 ), 7.473 (0.92), 7.479 (0.79), 7.491 (0.58), 7.498 (0.81 ),
7.513 (0.51 ).
The title compound (77 mg) was separated into its diastereo isomers by preparative chiral HPLC to give diastereoisomer 1 (44.9 mg, see Example 64) and diastereoisomer 2 (39.5 mg, see Example 65).
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; Column: Reprosil Chiral NR 8m 250x30mm; Eluent A: C02; Eluent B: 2-Propanol + 0.4% Diethylamine (99%); Isocratic: 30%B; Flow: 100 ml/min; Temperatur: 40Ό; BPR: 150b ar; UV: 220 nm.
Analytical chiral HPLC method: Instrument: Agilent: 1260, Aurora SFC-Module; Column:
Reprosil Chiral NR 5m 100x4.6mm; Eluent A: C02; Eluent B: 2-Propanol + 0.2% Diethylamine (99%); Isocratic: 30%B; Flow: 4 ml/min; Temperature: 37.5Ό; BPR: 100bar; UV: 220 nm.
Example 64 and Example 65
(2R)-1 -[(7R)-7-(2-chlorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one (2R)-1-[(7S)-7-(2-chlorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1-one
Example 64
(2R)-1-[7-(2-chlorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1-one (Stereoisomer 1)
For the preparation of the racemic title compound see Example 63.
Analytical Chiral HPLC (method see Example 63): Rt = 2.30 min, e.e. >99%.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.078 (0.67), -0.066 (0.88), -0.045 (1.57), -0.033 (1.58), -0.011 (0.91), 0.000 (0.76), 0.665 (1.53), 0.694 (1.39), 1.056 (0.55), 1.069 (0.70), 1.101 (1.62), 1.115 (1.30), 1.135 (1.69), 1.142 (1.66), 1.147 (1.51), 1.169 (0.99), 1.182 (1.11), 1.195
(0.82), 1.229 (0.48), 1.266 (0.54), 1.538 (0.43), 1.991 (1.59), 2.020 (1.38), 2.156 (1.91), 2.189
(1.87), 2.351 (0.42), 2.357 (0.61), 2.361 (0.79), 2.366 (0.65), 2.371 (0.54), 2.420 (1.51), 2.426
(1.68), 2.449 (1.74), 2.455 (1.59), 2.552 (3.13), 2.557 (2.15), 2.574 (1.08), 2.586 (0.61), 2.638
(0.49), 2.698 (0.98), 2.704 (1.36), 2.708 (1.11), 2.736 (1.68), 2.765 (3.38), 2.804 (2.15), 2.837
(1.37), 2.863 (0.55), 2.935 (1.19), 2.942 (1.04), 2.965 (2.90), 2.970 (2.84), 2.995 (2.89), 3.025
(2.84), 3.053 (1.71), 3.087 (1.81), 3.092 (1.80), 3.121 (1.15), 3.201 (0.64), 3.210 (0.64), 3.228
(0.57), 3.237 (0.51 ), 3.271 (3.66), 3.467 (1.51 ), 3.502 (1.25), 3.579 (16.00), 4.306 (1.32), 4.339 (1.26), 6.940 (2.56), 6.960 (5.74), 6.979 (3.69), 7.089 (5.28), 7.108 (4.10), 7.248 (2.19), 7.258
(2.29), 7.265 (2.48), 7.272 (2.68), 7.299 (1.91), 7.301 (2.70), 7.317 (3.46), 7.320 (4.86), 7.335
(1.78), 7.338 (2.23), 7.366 (8.05), 7.375 (5.63), 7.382 (6.02), 7.391 (6.70), 7.400 (1.01), 7.444
(1.24), 7.448 (1.36), 7.455 (0.58), 7.464 (4.53), 7.468 (2.58), 7.470 (2.97), 7.481 (1.91), 7.489
(0.96), 7.498 (4.41), 7.505 (2.20), 7.508 (2.12), 7.512 (2.96), 7.521 (3.06), 7.531 (0.44).
Example 65
(2R)-1-[(7R)-7-(2-chlorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1-one (Stereoisomer 2)
For the preparation of the racemic title compound see Example 63.
Analytical Chiral HPLC (method see Example 63): Rt = 4.76 min, e.e.95.6%. Example 66
(2R)-1-[7-(2-bromophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1-one (mixture of stereoisomers)
Figure imgf000491_0001
Using the method described for Example 63: intermediate 11650.0 mg, 90.4 pmol) gave titled compound (32 mg, 61%) after purification by silica chromatography ( Hexane :EtOAc, then EtOAc: methanol).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.067 (0.63), -0.055 (0.79), -0.033 (1.36), -0.022 (1.42), 0.000 (0.84), 0.012 (0.68), 0.210 (0.52), 0.232 (0.89), 0.242 (0.94), 0.265 (0.52), 0.737
(1.42), 0.771 (1.42), 1.021 (0.58), 1.032 (0.73), 1.053 (1.31), 1.065 (1.47), 1.087 (1.47), 1.101
(1.47), 1.121 (1.73), 1.134 (1.68), 1.155 (1.99), 1.167 (1.84), 1.189 (2.05), 1.221 (1.94), 1.261
(2.20), 1.298 (2.31), 1.332 (1.52), 1.382 (0.52), 1.438 (0.68), 1.446 (0.94), 1.453 (2.36), 1.460
(1.00), 1.469 (0.73), 1.548 (1.26), 1.577 (1.10), 1.637 (0.68), 1.924 (0.52), 1.977 (1.73), 2.009
(1.89), 2.018 (1.63), 2.161 (2.31), 2.196 (2.26), 2.367 (1.42), 2.380 (0.68), 2.457 (2.78), 2.486
(3.78), 2.549 (14.53), 2.553 (9.44), 2.623 (1.26), 2.651 (1.78), 2.774 (5.19), 2.800 (2.94), 2.816 (2.15), 2.845 (2.47), 2.876 (1.73), 2.886 (2.15), 2.920 (1.26), 2.937 (1.36), 2.966 (2.62), 2.973
(2.57), 3.000 (2.57), 3.028 (2.94), 3.056 (2.89), 3.084 (3.36), 3.102 (1.89), 3.117 (2.41), 3.139
(1.47), 3.166 (3.93), 3.191 (6.82), 3.200 (7.03), 3.232 (1.00), 3.266 (3.25), 3.291 (4.56), 3.472
(1.57), 3.507 (1.31), 3.579 (16.00), 3.586 (13.38), 3.596 (4.25), 3.685 (1.84), 3.786 (0.73),
3.814 (1.26), 4.142 (1.21), 4.210 (1.26), 4.243 (0.94), 4.299 (1.21), 4.333 (1.15), 4.401 (0.52), 5.789 (15.11 ), 6.742 (1.68), 6.757 (1.78), 6.938 (2.31 ), 6.957 (5.04), 6.976 (3.20), 7.089 (4.93), 7.109 (3.93), 7.159 (2.73), 7.178 (6.30), 7.189 (5.77), 7.208 (5.14), 7.229 (2.15), 7.245 (2.73),
7.250 (2.68), 7.264 (3.88), 7.279 (3.04), 7.282 (2.83), 7.297 (4.35), 7.315 (4.72), 7.318 (4.67),
7.334 (2.94), 7.338 (3.25), 7.342 (3.10), 7.361 (6.14), 7.368 (5.51), 7.375 (4.35), 7.399 (3.20),
7.403 (3.04), 7.418 (3.30), 7.441 (1.47), 7.454 (3.20), 7.461 (5.14), 7.467 (3.62), 7.477 (2.15),
7.484 (2.05), 7.502 (2.57), 7.506 (1.57), 7.519 (1.31), 7.627 (1.05), 7.638 (1.57), 7.644 (1.36),
7.653 (3.41), 7.656 (4.04), 7.673 (2.78), 7.676 (2.73), 7.685 (3.78), 7.688 (3.78), 7.705 (3.41),
7.708 (3.15). The title compound (30 mg) was separated into its diastereo isomers by preparative chiral HPLC to give diastereoisomer 1 (12 mg, see Example 67) and diastereoisomer 2 (9 mg, see Example 68).
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; Column: Reprosil Chiral NR 8m 250x30mm; eluent A: C02; eluent B: methanol + 0.2 vol % aqueous ammonia (32%); isocratic: 25%B; flow: 100 ml/min; temperature: 40°C; BPR: 150bar; UV: 210 nm.
Analytical chiral HPLC method Instrument: Agilent: 1260, Aurora SFC-Module; Column:
Reprosil Chiral NR 5m 100x4.6mm; Eluent A: C02; Eluent B: Methanol + 0.2 Vol-% aq.
ammonia (32%); Isocratic: 25%B; Flow: 4 ml/min; Temperature: 37.50; BPR: 100bar; UV: 210 nm.
Example 67 and Example 68
(2R)-1 -[(7R)-7-(2-bromophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one
(2R)-1 -[(7S)-7-(2-chlorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one
Example 67
(2R)-1 -[7-(2-bromophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one (Stereoisomer 1 )
For the preparation of the racemic title compound see Example 66.
Analytical Chiral HPLC (method see Example 66): Rt = 2.06 min, e.e. >99%.
Optical rotation (method OR1 ): -27.2°(methanol).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.079 (0.67), -0.067 (0.84), -0.045 (1.50), -0.033 (1 .53), -0.012 (0.87), 0.000 (0.72), 0.723 (1.53), 0.756 (1 .40), 1 .063 (0.75), 1 .083 (1 .08), 1 .109 (1 .30), 1.121 (1 .40), 1 .144 (1 .53), 1.155 (5.18), 1 .177 (1.30), 1 .187 (1 .20), 1 .21 1 (0.72), 1 .248
(2.09), 1.276 (0.47), 1 .310 (0.53), 1.590 (0.45), 1 .619 (0.66), 1 .956 (1 .55), 1 .989 (1.45), 2.132
(2.81 ), 2.170 (1 .44), 2.339 (0.91 ), 2.344 (1 .01 ), 2.348 (0.73), 2.367 (0.47), 2.427 (1.47), 2.450
(1 .59), 2.495 (1 .70), 2.535 (4.46), 2.540 (3.1 1 ), 2.595 (0.73), 2.631 (0.58), 2.660 (0.53), 2.681
(1 .12), 2.686 (1 .55), 2.690 (1 .42), 2.725 (1 .89), 2.752 (3.72), 2.787 (2.19), 2.819 (1.20), 2.875
(0.69), 2.908 (1 .48), 2.935 (2.79), 2.942 (2.67), 2.966 (2.29), 2.996 (2.25), 3.025 (1.05), 3.042
(1 .23), 3.071 (2.08), 3.104 (1 .36), 3.156 (0.52), 3.186 (0.83), 3.204 (0.78), 3.213 (0.80), 3.279
(4.59), 3.456 (1 .76), 3.492 (1 .44), 3.564 (16.00), 4.284 (1 .34), 4.318 (1 .25), 6.926 (2.42), 6.945
(5.48), 6.964 (3.54), 7.077 (5.12), 7.096 (4.14), 7.125 (0.52), 7.130 (0.47), 7.146 (0.89), 7.166
(0.84), 7.176 (0.44), 7.236 (2.29), 7.255 (2.93), 7.261 (2.12), 7.265 (1 .69), 7.283 (4.85), 7.301
(5.68), 7.320 (2.33), 7.337 (1 .51 ), 7.354 (2.50), 7.361 (2.04), 7.382 (2.31 ), 7.385 (2.31 ), 7.401 (3.09), 7.404 (3.04), 7.420 (1.36), 7.446 (3.50), 7.453 (2.70), 7.463 (1.76), 7.608 (1.01), 7.629 (0.95), 7.668 (3.75), 7.671 (3.79), 7.688 (3.47), 7.691 (3.26).
Example 68
(2R)-1-[7-(2-bromophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1-one (Stereoisomer 2)
For the preparation of the racemic title compound see Example 66.
Analytical Chiral FIPLC (method see Example 66): Rt = 2.95 min, e.e. >99%.
Optical rotation (method OR1): +10.4°(methanol).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.008 (0.80), -0.003 (0.80), 0.181 (0.76), 0.203 (1.28), 0.214 (1.28), 0.237 (0.76), 0.852 (0.49), 0.990 (0.76), 1.002 (0.94), 1.024 (1.74), 1.035 (1.74),
1.057 (1.15), 1.069 (1.18), 1.137 (7.05), 1.183 (1.53), 1.232 (3.82), 1.266 (3.02), 1.299 (1.77),
1.517 (1.60), 1.547 (1.49), 1.885 (0.56), 1.924 (0.52), 1.964 (0.97), 1.999 (0.56), 2.031 (0.49),
2.038 (0.49), 2.084 (0.56), 2.116 (2.95), 2.129 (1.63), 2.162 (1.63), 2.408 (1.74), 2.439 (1.94),
2.518 (10.97), 2.523 (7.11), 2.576 (1.42), 2.609 (2.12), 2.640 (1.25), 2.715 (2.64), 2.741 (1.94),
2.769 (1.67), 2.798 (2.74), 2.829 (2.64), 2.858 (2.05), 2.891 (1.21), 2.981 (0.66), 3.023 (1.28), 3.058 (3.37), 3.068 (2.36), 3.088 (2.78), 3.139 (4.96), 3.167 (1.01), 3.497 (1.56), 3.556 (16.00), 3.655 (0.62), 4.176 (1.70), 4.209 (1.35), 4.561 (0.45), 6.711 (2.29), 6.727 (2.33), 7.130 (3.23),
7.148 (7.81), 7.159 (7.25), 7.178 (6.73), 7.198 (2.78), 7.206 (1.91), 7.210 (1.77), 7.226 (3.05),
7.244 (2.33), 7.248 (2.19), 7.309 (2.92), 7.328 (5.69), 7.343 (3.05), 7.368 (1.25), 7.384 (0.66),
7.423 (4.03), 7.431 (3.75), 7.440 (2.98), 7.453 (2.39), 7.457 (1.53), 7.471 (3.51), 7.489 (1.67),
7.606 (1.67), 7.620 (4.13), 7.623 (5.24), 7.640 (3.57), 7.643 (3.40), 9.086 (0.49), 9.091 (0.42).
Example 69 and Example 70
(2R)-1-[(7R)-7-(2-ethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1-one
(2R)-1-[(7S)-7-(2-ethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1-one Example 69
(2R)-1 -[7-(2-ethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one (Stereoisomer 1 )
Figure imgf000494_0002
Using the method described for Example 63: intermediate 1 19 (79.0 mg, 162 pmol) gave titled compound (44.8 mg, 55%) after purification by preparative HPLC (Method 6).
Optical rotation (method OR1 ): -7.4°(methanol).
Example 70
(2R)-1 -[7-(2-ethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one (Stereoisomer 2)
Figure imgf000494_0001
Using the method described for Example 63: intermediate 120 (52.0 mg, 106 pmol) gave titled compound (27.8 mg, 52%) after purification by preparative HPLC (Method 6).
Optical rotation (method OR1 ): +21 .3°(methanol). Example 71
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[7-[2-(trifluoromethyl)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}propan-1 -one (mixture of stereoisomers)
Figure imgf000495_0001
Using the method described for Example 63: intermediate 122 (32.0 mg, 60.5 pmol) gave titled compound (15.9 mg, 48%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .107 (16.00), 2.323 (0.48), 2.327 (0.68), 2.332 (0.49), 2.518 (2.75), 2.523 (1 .87), 2.660 (0.62), 2.665 (0.84), 2.669 (0.92), 2.673 (0.68), 2.678 (0.41 ),
2.692 (0.41 ), 2.726 (0.64), 2.746 (0.46), 2.898 (0.43), 2.927 (0.41 ), 3.374 (0.56), 3.549 (2.57), 3.567 (1 .01 ), 4.190 (0.74), 5.759 (0.87), 6.841 (0.67), 6.860 (0.41 ), 7.077 (0.73), 7.096 (0.64),
7.138 (0.58), 7.216 (0.41 ), 7.266 (0.44), 7.433 (0.67), 7.440 (0.51 ), 7.507 (0.52), 7.525 (0.45),
7.544 (0.62), 7.563 (0.44), 7.677 (0.53), 7.692 (0.42), 7.739 (0.55), 7.742 (0.55), 7.759 (0.47).
Example 72
(2R)-3,3,3-trifluoro-1 -[7-[2-[1 -hydroxyethyl]phenyl}-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers)
Figure imgf000495_0002
Using the method described for Example 63: intermediate 126 (33.0 mg, 65.7 pmol) gave titled compound (13 mg, 38%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.994 (1 .02), 1 .008 (1 .02), 1 .107 (5.61 ), 1 .123 (1 .76), 1 .144 (2.28), 1 .159 (4.79), 1 .174 (3.47), 1 .231 (0.97), 1.295 (1.12), 1 .328 (0.92), 1.365 (0.64),
1 .392 (0.79), 1 .400 (0.67), 1 .407 (0.72), 1 .957 (0.42), 1.987 (0.57), 2.069 (0.40), 2.142 (0.47),
2.177 (0.42), 2.261 (1 .09), 2.300 (0.69), 2.331 (1 .61 ), 2.404 (0.50), 2.518 (5.83), 2.522 (4.02), 2.539 (16.00), 2.556 (0.42), 2.575 (0.55), 2.606 (0.64), 2.639 (0.55), 2.673 (1.56), 2.744 (1.71 ), 2.769 (1.22), 2.808 (1.02), 2.836 (0.79), 2.882 (0.42), 2.896 (0.42), 2.923 (0.52), 2.950 (0.55),
2.979 (0.77), 3.008 (0.69), 3.036 (0.82), 3.059 (1.14), 3.210 (3.13), 3.245 (0.79), 3.538 (3.52),
3.551 (3.27), 4.193 (0.42), 4.690 (1.07), 5.082 (1.39), 5.097 (1.22), 5.106 (0.99), 6.437 (0.42),
6.456 (0.45), 6.839 (0.50), 6.886 (0.45), 6.906 (0.94), 6.925 (0.60), 7.004 (0.52), 7.024 (0.69),
7.045 (1.51), 7.062 (1.27), 7.108 (1.34), 7.126 (2.36), 7.158 (1.74), 7.176 (2.38), 7.196 (1.41),
7.243 (0.42), 7.259 (0.62), 7.277 (0.69), 7.290 (0.84), 7.318 (1.22), 7.324 (1.12), 7.334 (1.34),
7.343 (1.19), 7.414 (1.02), 7.422 (1.36), 7.431 (3.65), 7.437 (2.75), 7.448 (1.74), 7.458 (0.87),
7.461 (0.84), 7.479 (0.82), 7.548 (0.84), 7.552 (0.92), 7.566 (0.77), 7.571 (0.72), 7.586 (0.62),
7.602 (0.97), 7.617 (0.55).
Example 73
(2R)-1-{7-[2-(difluoromethoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1-one (mixture of stereoisomers)
Figure imgf000496_0001
Using the method described for Example 63: intermediate 128 (100 mg, 190 pmol) gave titled compound (45 mg, 44%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.078 (0.48), -0.066 (0.61), -0.045 (1.08), -0.033 (1.08), -0.011 (0.65), 0.000 (0.52), 0.148 (0.43), 0.170 (0.78), 0.181 (0.78), 0.205 (0.48), 0.577 (1.08), 0.608 (0.95), 0.997 (0.43), 1.007 (0.52), 1.030 (1.04), 1.042 (1.17), 1.062 (1.21), 1.076
(1.60), 1.087 (1.69), 1.108 (1.78), 1.120 (1.99), 1.140 (1.56), 1.171 (1.60), 1.205 (1.21), 1.239
(0.52), 1.292 (1.30), 1.317 (1.73), 1.344 (1.00), 1.390 (0.48), 1.971 (1.43), 1.999 (1.47), 2.160
(1.65), 2.185 (1.65), 2.352 (0.39), 2.380 (2.38), 2.385 (1.43), 2.415 (1.47), 2.436 (2.25), 2.445
(2.34), 2.467 (1.39), 2.476 (1.30), 2.566 (10.67), 2.571 (6.85), 2.588 (1.78), 2.596 (1.43), 2.635
(1.60), 2.666 (1.00), 2.722 (2.60), 2.726 (1.52), 2.749 (2.95), 2.776 (3.86), 2.818 (3.73), 2.848
(4.42), 2.855 (3.21), 2.879 (1.82), 2.888 (1.65), 2.922 (0.91), 2.960 (1.47), 2.969 (1.56), 2.990
(1.21), 3.000 (2.17), 3.031 (2.25), 3.060 (2.69), 3.079 (2.43), 3.113 (1.95), 3.140 (0.95), 3.181
(2.95), 3.267 (3.64), 3.455 (1.95), 3.495 (1.30), 3.525 (1.17), 3.559 (1.08), 3.593 (16.00), 3.596 (14.96), 4.215 (1 .04), 4.248 (0.87), 4.313 (1 .00), 4.346 (0.95), 6.707 (2.25), 6.739 (1 .56), 6.756 (1 .69), 6.892 (3.04), 6.975 (1 .91 ), 6.995 (4.16), 7.014 (2.73), 7.071 (0.95), 7.077 (2.30), 7.097 (2.99), 7.109 (4.03), 7.128 (3.12), 7.164 (13.18), 7.176 (9.19), 7.197 (3.47), 7.202 (3.43), 7.224
(4.29), 7.244 (2.86), 7.248 (2.91 ), 7.256 (2.17), 7.263 (2.04), 7.275 (5.77), 7.280 (6.24), 7.290
(3.77), 7.312 (1 .86), 7.332 (0.74), 7.352 (2.34), 7.370 (5.07), 7.380 (2.86), 7.389 (2.99), 7.392
(3.08), 7.396 (2.21 ), 7.415 (2.12), 7.420 (1 .91 ), 7.427 (1.47), 7.436 (2.04), 7.441 (2.51 ), 7.447
(1 .30), 7.456 (1 .26), 7.469 (4.77), 7.475 (5.77), 7.482 (4.68), 7.486 (4.38), 7.492 (2.82), 7.500
(1 .43), 7.508 (0.69).
The title compound (41 mg) was separated into its diastereoisomers by preparative chiral HPLC to give diastereoisomer 1 (17 mg, see Example 74) and diastereoisomer 2 (18 mg, see Example 75).
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; Column: Reprosil Chiral NR 8m 250x30mm; Eluent A: C02; Eluent B: 2-Propanol + 0.4% Diethylamine (99%); Isocratic: 30%B; Flow: 100 ml/min; Temperature: 40Ό; BPR: 150 bar; UV: 220 nm.
Analytical chiral HPLC method Instrument: Agilent: 1260, Aurora SFC-Module; Column:
Reprosil Chiral NR 5m 100x4.6mm; Eluent A: C02; Eluent B: 2-Propanol + 0.2% Diethylamine (99%); Isocratic: 30%B; Flow: 4 ml/min; Temperature: 37.50; BPR: 100bar; UV: 220 nm.
Example 74 and Example 75
(2R)-1 -{(7R)-7-[2-(difluoromethoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one
(2R)-1 -{(7S)-7-[2-(difluoromethoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one
Example 74
(2R)-1 -{7-[2-(difluoromethoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (Stereoisomer 1 )
For the preparation of the racemic title compound see Example 73.
Analytical Chiral HPLC (method see Example 73): Rt = 1.66 min, e.e. >99%.
Optical rotation (method OR1 ): -12.0°(methanol).
Example 75
(2R)-1 -{7-[2-(difluoromethoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (Stereoisomer 2)
For the preparation of the racemic title compound see Example 73. Analytical Chiral HPLC (method see Example 73): Rt = 2.96 min, e.e. 96.2%.
Optical rotation (method OR1 ): +10.3°(methanol).
Example 76
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[7-[2-(trifluoromethoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}propan-1 -one (Stereoisomer 2)
Figure imgf000498_0001
Using the method described for Example 63: intermediate 132 (40 mg, 73.5 pmol) gave titled compound (30.1 mg, 70%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .067 (16.00), 2.478 (1 .31 ), 2.483 (0.82), 2.789 (0.55), 3.510 (1 .51 ), 4.151 (1 .00), 7.060 (0.43), 7.082 (1 .09), 7.099 (0.55), 7.292 (0.53), 7.304 (0.50),
7.381 (0.56), 7.384 (0.50), 7.389 (0.51 ), 7.392 (0.50), 7.398 (0.56), 7.403 (0.44).
Example 77
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-phenoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- phenylpropan-1 -one (Stereoisomer 2)
Figure imgf000498_0002
Using the method described for Example 63: intermediate 136 (50 mg, 90.5 pmol) gave titled compound (24 mg, 47%) after purification by preparative FIPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.222 (0.58), 1 .029 (0.48), 1 .052 (0.82), 1 .082 (0.68),
1 .168 (0.39), 1 .191 (0.73), 1 .202 (0.77), 1 .225 (0.77), 1.235 (0.73), 1 .268 (0.97), 1.300 (1 .89), 1 .333 (0.77), 1 .945 (0.53), 2.088 (0.92), 2.122 (0.87), 2.318 (0.97), 2.323 (2.13), 2.327 (3.05), 2.332 (2.22), 2.337 (1.16), 2.376 (1 .1 1 ), 2.399 (1 .26), 2.518 (16.00), 2.523 (10.39), 2.575 (0.87), 2.605 (0.63), 2.660 (1 .84), 2.665 (2.80), 2.669 (3.63), 2.673 (2.85), 2.679 (1.79), 2.796
(0.68), 2.824 (1 .45), 2.853 (2.08), 2.868 (1 .64), 2.903 (0.53), 2.967 (0.53), 3.018 (0.58), 3.034
(0.58), 3.050 (0.97), 3.082 (0.58), 3.195 (2.42), 3.497 (0.73), 3.560 (7.64), 4.168 (0.82), 4.200
(0.77), 6.731 (1 .16), 6.748 (1 .26), 6.836 (1 .40), 6.856 (1.93), 6.862 (3.38), 6.864 (3.77), 6.871
(2.51 ), 6.874 (2.51 ), 6.883 (4.54), 6.891 (2.66), 6.894 (2.27), 6.899 (1 .06), 7.053 (0.53), 7.071
(1 .93), 7.090 (2.76), 7.108 (1 .40), 7.132 (1 .79), 7.146 (10.20), 7.160 (4.83), 7.202 (0.58), 7.207 (0.58), 7.223 (0.73), 7.286 (1 .1 1 ), 7.290 (1 .16), 7.306 (1.64), 7.324 (1 .69), 7.332 (2.22), 7.345
(1 .74), 7.350 (4.50), 7.369 (4.1 1 ), 7.372 (4.54), 7.385 (1.31 ), 7.391 (2.32), 7.425 (2.85), 7.431
(2.22), 7.443 (2.08), 7.451 (1.45), 7.458 (1 .1 1 ), 7.465 (1.02), 7.472 (0.73), 7.480 (0.44).
Example 78
(2R)-1 -[7-(2,3-dihydro-1 -benzofuran-7-yl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (Stereoisomer 2)
Figure imgf000499_0001
Using the method described for Example 63: intermediate 141 (16 mg, 31 .8 pmol) gave titled compound (13.3 mg, 81 %) after purification by preparative FIPLC (Method 6).
Optical rotation (method OR1 ): +5.3°(methanol).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .103 (0.58), 1 .128 (0.49), 1 .232 (1 .04), 2.071 (0.44), 2.104 (0.43), 2.323 (0.49), 2.327 (0.69), 2.331 (0.49), 2.394 (0.50), 2.518 (3.13), 2.523 (2.15), 2.539 (16.00), 2.582 (0.67), 2.610 (0.44), 2.665 (0.69), 2.669 (0.92), 2.673 (0.77), 2.694 (1 .16), 2.780 (0.50), 2.812 (0.62), 2.850 (0.73), 2.883 (0.42), 2.993 (0.44), 3.024 (0.72), 3.055 (0.46),
3.148 (2.29), 3.166 (1 .46), 3.444 (0.65), 3.475 (0.53), 3.549 (6.14), 4.151 (0.53), 4.408 (0.55),
4.430 (0.67), 4.452 (0.51 ), 4.479 (0.62), 4.499 (0.49), 6.747 (0.70), 6.765 (0.95), 6.783 (1 .20),
6.801 (0.63), 7.045 (0.45), 7.062 (0.41 ), 7.1 13 (1 .15), 7.134 (3.68), 7.149 (2.33), 7.167 (2.16),
7.187 (0.84), 7.330 (0.63), 7.338 (0.59), 7.422 (2.26), 7.430 (1.61 ), 7.439 (1 .96), 7.457 (0.48). Example 79
(2S)-3,3,3-trifluoro-1 -[7-(2-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one (mixture of stereoisomers)
Figure imgf000500_0001
Using the method described for Example 63: intermediate 145 (70 mg, 146 pmol) gave titled compound (41 .2 mg, 59%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.57), 0.040 (0.46), 0.079 (0.46), 0.524 (0.74), 0.558 (0.68), 1 .044 (1 .77), 1 .077 (1.31 ), 1 .130 (0.97), 1.149 (1.02), 1 .181 (0.91 ), 1.254 (0.85),
1 .289 (0.85), 1 .375 (0.46), 1 .973 (1.25), 2.008 (1 .08), 2.141 (1.20), 2.161 (1 .14), 2.340 (1 .31 ),
2.345 (2.45), 2.350 (3.47), 2.354 (2.68), 2.358 (1 .48), 2.395 (0.57), 2.439 (1 .14), 2.540 (16.00), 2.545 (10.36), 2.562 (1.77), 2.607 (1 .54), 2.638 (0.97), 2.682 (1 .99), 2.687 (3.30), 2.691 (4.21 ), 2.696 (3.36), 2.700 (2.28), 2.718 (2.16), 2.749 (3.02), 2.797 (1.65), 2.833 (2.16), 2.871 (1 .31 ),
2.901 (0.85), 3.033 (1 .20), 3.061 (1.82), 3.094 (1 .82), 3.134 (2.1 1 ), 3.207 (2.45), 3.442 (1 .25),
3.478 (0.91 ), 3.513 (0.80), 3.569 (13.27), 4.204 (0.85), 4.236 (0.85), 4.296 (0.80), 4.329 (0.74), 6.740 (0.46), 6.961 (1 .20), 6.979 (2.62), 6.998 (1 .77), 7.078 (3.42), 7.097 (2.56), 7.126 (8.31 ),
7.139 (4.78), 7.162 (3.25), 7.185 (3.76), 7.201 (3.07), 7.209 (3.30), 7.261 (0.85), 7.277 (0.85),
7.300 (0.74), 7.318 (1 .31 ), 7.341 (2.62), 7.354 (2.85), 7.379 (1.54), 7.385 (1 .42), 7.399 (1 .08),
7.443 (3.25), 7.450 (5.07), 7.457 (3.53), 7.467 (1 .99).
The title compound (33 mg) was separated into its diastereoisomers by preparative chiral HPLC to give diastereoisomer 1 (16 mg, see Example 80) and diastereoisomer 2 (16 mg, see Example 81 ).
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IC 5m 250x30mm; Eluent A: C02; Eluent B: Methanol + 0.2 Vol-% aqueous ammonia (32%); Isocratic: 30%B; Flow: 100 ml/min; Temperature: 40°C; BPR: 150bar; UV: 220 nm.
Analytical chiral HPLC method Instrument: Agilent: 1260, Aurora SFC-Module; Column:
Chiralpak IC 5m 100x4.6mm; Eluent A: C02; Eluent B: Methanol + 0.2 Vol-% aqueous ammonia (32%); Isocratic: 30%B; Flow: 4 ml/min; Temperature: 37.50; BPR: 100bar; UV: 220 nm. Example 80 and Example 81
(2S)-3,3,3-trifluoro-1 -[(7R)-7-(2-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one
(2S)-3,3,3-trifluoro-1 -[(7S)-7-(2-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one
Example 80
(2S)-3,3,3-trifluoro-1 -[(7-(2-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one (Stereoisomer 2)
For the preparation of the racemic title compound see Example 79.
Analytical Chiral HPLC (method see Example 79): Rt = 1.88 min, e.e. >99%.
Example 81
(2S)-3,3,3-trifluoro-1 -[7-(2-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one (Stereoisomer 2)
For the preparation of the racemic title compound see Example 79.
Analytical Chiral HPLC (method see Example 79): Rt = 3.23 min, e.e. 98.1%.
Example 82
(2S)-3,3,3-trifluoro-1 -[7-(3-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one (mixture of stereoisomers)
Figure imgf000501_0001
Using the method described for Example 63: intermediate 148 (70 mg, 146 pmol) gave titled compound (31 .2 mg, 45%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.980 (0.65), 1 .007 (0.77), 1 .017 (0.77), 1 .040 (0.60),
1 .052 (0.53), 1 .088 (0.43), 1 .120 (16.00), 1.140 (0.43), 1.157 (0.46), 1 .162 (0.48), 1 .173 (0.69),
1 .207 (0.53), 1 .292 (0.43), 1 .362 (0.48), 1 .917 (0.46), 2.073 (0.48), 2.100 (0.72), 2.134 (0.50),
2.297 (0.41 ), 2.306 (0.48), 2.345 (1.10), 2.421 (0.43), 2.429 (0.50), 2.450 (0.60), 2.457 (0.69), 2.531 (6.85), 2.535 (4.50), 2.571 (0.60), 2.603 (0.67), 2.687 (1.51 ), 2.691 (1 .01 ), 2.707 (1 .22),
2.736 (1 .20), 2.771 (0.41 ), 2.781 (0.55), 2.809 (0.79), 2.831 (0.55), 2.839 (0.53), 2.856 (0.50),
2.863 (0.50), 2.980 (0.55), 3.010 (0.91 ), 3.041 (0.67), 3.086 (0.55), 3.229 (1 .01 ), 3.263 (1 .27),
3.427 (0.48), 3.564 (6.95), 4.204 (1.20), 6.626 (0.41 ), 6.652 (0.41 ), 6.741 (0.93), 6.762 (1 .13),
6.792 (0.69), 7.003 (0.72), 7.023 (1.70), 7.042 (1 .29), 7.052 (0.60), 7.097 (1 .56), 7.116 (1 .51 ),
7.139 (5.01 ), 7.154 (2.51 ), 7.176 (0.62), 7.278 (0.60), 7.296 (1.05), 7.318 (0.91 ), 7.334 (1 .32),
7.338 (1 .29), 7.353 (1 .82), 7.370 (0.81 ), 7.373 (0.81 ), 7.390 (0.67), 7.399 (0.48), 7.406 (0.53),
7.412 (0.46), 7.436 (1.29), 7.441 (1.58), 7.448 (1 .13), 7.453 (0.93).
The title compound (26 mg) was separated into its diastereo isomers by preparative chiral HPLC to give diastereoisomer 1 (12 mg, see Example 83) and diastereoisomer 2 (13 mg, see Example 84).
Preparative chiral HPLC method: Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IC 5m 250x30mm; Eluent A: C02; Eluent B: Ethanol + 0.2 Vol-% aqueous ammonia (32%); Isocratic: 30%B; Flow: 100 ml/min; Temperature: 40°C; BPR: 150bar; UV: 254 nm.
Analytical chiral HPLC method Instrument: Agilent: 1260, Aurora SFC-Module; Column: Chiralpak IC 5m 100x4.6mm; Eluent A: C02; Eluent B: Ethanol + 0.1 Vol-% aqueous ammonia (32%); Isocratic: 30%B; Flow: 4 ml/min; Temperature: 37.5Ό; BPR: 100bar; UV: 254 nm.
Example 83 and Example 84
(2S)-3,3,3-trifluoro-1 -[(7R)-7-(3-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one
(2S)-3,3,3-trifluoro-1 -[(7S)-7-(3-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one
Example 83
(2S)-3,3,3-trifluoro-1 -[7-(3-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one (Stereoisomer 1 )
For the preparation of the racemic title compound see Example 82.
Analytical Chiral HPLC (method see Example 82): Rt = 1.55 min, e.e. >99%.
Example 84
(2S)-3,3,3-trifluoro-1 -[7-(3-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one (Stereoisomer 2)
For the preparation of the racemic title compound see Example 82.
Analytical Chiral HPLC (method see Example 82): Rt = 3.60 min, e.e. >99%. Example 85
(2R)-3,3,3-trifluoro-1-[7-(2-fluoro-3-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy- 2-phenylpropan-1-one (mixture of stereoisomers)
Figure imgf000503_0001
Using the method described for Example 63: intermediate 150 (150 mg, 305 pmol) gave titled compound (40 mg, 26%) after purification by preparative FIPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.030 (0.75), 0.063 (0.69), 0.092 (0.54), 0.508 (0.85), 0.541 (0.74), 0.839 (0.42), 1.062 (1.59), 1.079 (1.58), 1.094 (1.74), 1.220 (3.21), 1.244 (1.40),
1.285 (0.86), 1.311 (0.62), 1.971 (1.26), 2.002 (1.18), 2.055 (0.44), 2.062 (0.44), 2.152 (0.86), 2.169 (1.54), 2.209 (3.63), 2.256 (16.00), 2.314 (0.59), 2.319 (0.79), 2.323 (0.81), 2.358 (0.51),
2.514 (2.28), 2.531 (1.26), 2.609 (0.74), 2.640 (1.00), 2.651 (0.88), 2.655 (0.99), 2.661 (1.11),
2.665 (1.03), 2.775 (3.72), 2.803 (3.05), 2.833 (1.81), 2.877 (1.75), 3.001 (0.90), 3.038 (1.91),
3.072 (2.52), 3.091 (2.90), 3.156 (0.85), 3.190 (2.42), 3.239 (0.69), 3.277 (0.82), 3.536 (14.72), 4.184 (0.78), 4.214 (0.78), 4.291 (0.94), 4.324 (0.86), 5.746 (2.85), 6.511 (0.66), 6.918 (1.47), 6.937 (3.19), 6.955 (2.63), 6.971 (1.33), 6.989 (0.90), 7.016 (1.14), 7.044 (4.19), 7.052 (3.02),
7.063 (3.49), 7.090 (2.74), 7.106 (8.89), 7.120 (4.34), 7.198 (0.74), 7.217 (1.32), 7.230 (1.45),
7.247 (1.89), 7.258 (1.51), 7.276 (1.89), 7.295 (1.10), 7.315 (1.53), 7.324 (1.67), 7.397 (0.76),
7.404 (1.19), 7.412 (3.20), 7.420 (4.63), 7.427 (3.41), 8.413 (0.54).
Example 86
(2R)-3,3,3-trifluoro-2-methoxy-1-{7-[2-(methylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}- 2-phenylpropan-1-one, salt with hydrochloric acid (Stereoisomer 1)
Figure imgf000503_0002
To a solution of Intermediate 156 (600 mg, 1.06 mmol) in methanol (33 ml) was added 2M hydrochloric acid (aq, 1.6 ml) and Palladium on activated charcoal (10%, 56 mg) was added and stirred under a hydrogen atmosphere at 450 for 3h. The reaction was filtered and concentrated and gave the titled compound (579 mg, 90%).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (3.52), 2.077 (16.00), 2.330 (0.52), 2.335 (0.49),
2.339 (0.48), 2.345 (0.53), 2.521 (0.83), 2.526 (0.56), 2.759 (2.31), 2.774 (5.99), 2.810 (0.47),
3.035 (1.13), 3.056 (0.49), 3.087 (0.45), 3.111 (0.41), 3.179 (0.40), 6.441 (0.41), 6.779 (0.49),
7.116 (0.88), 7.135 (1.36), 7.187 (1.21), 7.205 (1.55), 7.226 (0.75), 7.272 (0.51), 7.424 (0.70),
7.434 (0.72), 7.441 (0.74), 7.462 (0.53), 7.481 (0.85).
Example 87
(2R)-3,3,3-trifluoro-2-methoxy-1-{7-[2-(methylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}- 2-phenylpropan-1-one (Stereoisomer 1)
Figure imgf000504_0001
Example 86 (579 mg, 1.06 mmol) was purified by preparative HPLC (Method 6) to give the titled compound (258 mg, 49%).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.008 (0.58), 0.000 (16.00), 0.008 (0.55), 0.360 (0.65), 0.370 (0.65), 0.985 (0.43), 1.007 (0.76), 1.018 (0.76), 1.040 (0.46), 1.218 (1.42), 1.233
(1.51), 1.292 (0.60), 1.483 (0.80), 1.513 (0.72), 1.925 (0.72), 1.959 (0.69), 2.068 (0.85), 2.101
(0.82), 2.320 (1.29), 2.324 (1.35), 2.329 (1.35), 2.334 (1.12), 2.343 (1.02), 2.524 (2.79), 2.542
(5.84), 2.581 (0.47), 2.612 (0.83), 2.640 (0.61), 2.671 (1.76), 2.676 (1.80), 2.683 (3.40), 2.695
(4.49), 2.703 (7.95), 2.715 (7.53), 2.745 (1.75), 2.758 (1.37), 2.773 (1.02), 2.787 (1.31), 2.813
(1.20), 2.840 (0.61), 2.974 (0.47), 3.006 (1.18), 3.036 (0.99), 3.067 (3.06), 3.445 (0.72), 3.479
(0.63), 3.545 (7.94), 4.130 (0.65), 4.163 (0.87), 5.072 (1.04), 5.084 (1.15), 5.096 (0.82), 5.108
(0.50), 6.346 (1.17), 6.362 (1.40), 6.455 (0.72), 6.483 (1.75), 6.503 (1.84), 6.514 (1.69), 6.533
(1.98), 6.551 (0.85), 6.883 (0.58), 6.900 (0.54), 7.000 (0.61), 7.082 (0.88), 7.097 (3.02), 7.116
(3.84), 7.161 (2.35), 7.180 (3.35), 7.201 (1.61), 7.311 (0.88), 7.320 (0.93), 7.416 (2.54), 7.420
(2.30), 7.424 (2.55), 7.432 (2.25), 7.437 (2.19), 7.456 (0.91). Example 88
(2R)-3,3,3-trifluoro-2-methoxy-1-{7-[2-(methylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}- 2-phenylpropan-1-one, salt with hydrochloric acid (Stereoisomer 2)
Figure imgf000505_0001
Using the method described for Example 86: intermediate 157 (29 mg, 51.3 pmol) gave titled compound (27 mg, 91%).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.056 (0.45), -0.033 (0.78), -0.022 (0.78), 0.000 (0.45), 0.912 (1.02), 0.938 (0.96), 1.220 (0.51), 1.242 (0.93), 1.254 (1.02), 1.266 (1.71), 1.418
(0.63), 1.446 (1.08), 1.480 (0.66), 1.786 (0.42), 2.044 (1.02), 2.077 (0.90), 2.356 (2.08), 2.360
(2.86), 2.365 (2.29), 2.383 (1.26), 2.398 (1.80), 2.552 (6.41), 2.556 (4.42), 2.573 (8.78), 2.609
(16.00), 2.694 (0.66), 2.698 (1.35), 2.702 (1.77), 2.707 (1.32), 2.712 (0.69), 2.742 (0.51), 2.770 (6.65), 2.800 (1.44), 2.832 (1.62), 2.861 (2.74), 2.891 (1.20), 2.922 (0.45), 2.953 (0.54), 3.037
(1.17), 3.070 (1.83), 3.100 (1.02), 3.129 (0.69), 3.159 (0.66), 3.200 (1.08), 3.234 (3.46), 3.416
(1.95), 3.445 (1.59), 3.638 (0.48), 3.940 (3.91), 4.167 (0.51), 4.202 (0.45), 4.337 (1.05), 4.371
(0.96), 6.632 (0.39), 6.652 (0.60), 6.672 (0.54), 6.715 (1.02), 6.735 (1.47), 6.754 (1.20), 6.905
(1.74), 6.925 (1.68), 6.933 (2.29), 6.952 (4.24), 6.971 (2.68), 7.043 (3.79), 7.063 (2.62), 7.150
(0.69), 7.280 (1.14), 7.299 (3.28), 7.318 (3.61), 7.336 (1.29), 7.363 (0.84), 7.373 (0.99), 7.382
(0.93), 7.472 (2.98), 7.478 (2.35), 7.489 (1.53), 7.565 (0.60), 8.518 (0.66), 9.102 (0.69), 9.130
(0.63).
Example 89
(2R)-1 -{7-[2-(dimethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers)
Figure imgf000506_0001
Using the method described for Example 63: intermediate 159 (70 mg, 139 pmol) gave titled compound (26.6 mg, 37%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .100 (16.00), 2.275 (6.63), 2.319 (0.44), 2.51 1 (2.50), 2.515 (3.06), 2.532 (2.00), 2.657 (0.45), 2.662 (0.55), 2.666 (0.42), 2.734 (0.52), 2.748 (0.60),
2.965 (0.40), 3.272 (0.64), 3.523 (2.06), 3.538 (1 .05), 4.184 (0.56), 5.751 (0.62), 6.935 (0.72),
6.954 (0.51 ), 7.019 (1 .05), 7.038 (0.90), 7.1 18 (0.43), 7.139 (0.47), 7.145 (0.45), 7.196 (0.63),
7.199 (0.62), 7.215 (0.76), 7.229 (0.87), 7.248 (0.72), 7.292 (0.44), 7.409 (0.72), 7.416 (0.55),
7.426 (0.44).
The title compound (21 mg) was separated into its diastereoisomers by preparative chiral HPLC to give diastereoisomer 1 (7 mg, see Example 90) and diastereoisomer 2 (13 mg, see Example 91 ).
Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000, Column: Chiralcel OH-H 5m 250x20mm; Eluent A: Hexane + 0.1 Vol- % Diethylamine (99%); Eluent B: Ethanol; Isocratic: 90%A+10%B; Flow: 20.0 ml/min; UV 254 nm.
Analytical chiral HPLC method Instrument: Agilent HPLC 1260; Column: Chiralcel OD-H 3m 100x4, 6mm; Eluent A: Hexane + 0.1 Vol-% Diethylamine (99%); Eluent B: Ethanol; Isocratic: 90%A+10%B; Flow: 1 .4 ml/min; Temperature: 25 Ό; DA D 254 nm.
Example 90
(2R)-1 -{7-[2-(dimethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (Stereoisomer 1 )
For the preparation of the racemic title compound see Example 89.
Analytical Chiral HPLC (method see Example 89): Rt = 3.67 min, e.e. >99%. Example 91
(2R)-1-{7-[2-(dimethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1-one (Stereoisomer 2)
For the preparation of the racemic title compound see Example 89.
Analytical Chiral HPLC (method see Example 89): Rt = 6.49 min, e.e. >99%.
Example 92
(2R)-1-{7-[2-(ethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1-one, salt with hydrochloric acid (Stereoisomer 1)
Figure imgf000507_0001
Using the method described for Example 86: intermediate 164 (136 mg, 235 pmol) gave titled compound (103 mg, 74%) after filtration and concentrating under reduced pressure and an freeze-drying step.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.300 (0.53), 0.933 (0.41), 1.036 (0.82), 1.054 (0.45), 1.133 (1.45), 1.139 (0.64), 1.151 (3.11), 1.170 (4.53), 1.179 (1.09), 1.188 (8.34), 1.206 (3.89),
1.231 (0.74), 1.352 (1.29), 1.381 (0.63), 1.607 (0.66), 1.634 (0.70), 2.044 (0.41), 2.318 (0.70),
2.323 (1.07), 2.327 (1.47), 2.332 (1.33), 2.337 (1.15), 2.376 (0.74), 2.518 (4.14), 2.523 (2.85),
2.540 (0.47), 2.660 (0.41), 2.665 (0.86), 2.669 (1.19), 2.674 (0.84), 2.729 (0.49), 2.768 (0.94),
2.787 (1.04), 2.815 (1.00), 2.848 (0.55), 2.907 (0.57), 2.933 (0.68), 3.038 (2.77), 3.059 (1.15),
3.093 (0.78), 3.164 (16.00), 3.181 (2.01 ), 3.200 (2.83), 3.257 (0.88), 3.504 (0.80), 3.544 (1.68), 3.561 (7.62), 4.192 (1.13), 4.227 (1.31), 4.255 (1.19), 4.290 (1.39), 6.459 (0.57), 6.822 (0.66),
6.881 (0.41), 6.893 (0.43), 6.912 (0.49), 7.029 (0.49), 7.114 (1.93), 7.134 (3.01), 7.192 (2.42),
7.210 (3.30), 7.231 (1.70), 7.258 (0.76), 7.272 (0.78), 7.293 (0.92), 7.301 (0.92), 7.311 (0.86),
7.423 (1.78), 7.431 (1.78), 7.440 (1.88), 7.464 (1.07), 7.483 (1.70), 7.502 (0.78), 8.673 (0.45),
8.971 (0.43). Example 93
(2R)-1-{7-[2-(ethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1-one (Stereoisomer 1)
Figure imgf000508_0001
Example 92 (97 mg, 172 pmol) was purified by preparative HPLC (Method 6) to give the titled compound (48 mg, 54%).
Optical rotation (method OR1): +48.4°(methanol).
Example 94
(2R)-1-{7-[2-(ethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one, salt with hydrochloric acid (Stereoisomer 2)
Figure imgf000508_0002
Using the method described for Example 86: intermediate 165 (50 mg, 86 pmol) gave titled compound (47 mg, 92%) after filtration and concentrating under reduced pressure and an freeze-drying step.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.86), 0.923 (1.38), 0.958 (1.29), 0.977 (0.66), 1.093 (7.66), 1.111 (16.00), 1.128 (7.89), 1.195(1.32), 1.213(2.61), 1.232(2.12), 1.235 (3.41), 1.253 (7.28), 1.270 (4.04), 1.303 (2.61), 1.332 (1.18), 1.482 (0.60), 1.541 (0.86), 1.567 (1.43),
1.576 (1.43), 1.602 (0.92), 1.654 (0.43), 1.685 (0.60), 1.723 (0.46), 1.751 (0.46), 1.842 (0.72),
1.874 (0.66), 2.109 (1.66), 2.143 (1.58), 2.256 (0.72), 2.292 (0.72), 2.395 (1.92), 2.399 (2.72), 2.404 (2.84), 2.408 (2.61), 2.445 (1.92), 2.590 (6.65), 2.595 (4.42), 2.737 (1.32), 2.741 (1.72),
2.745 (1.23), 2.770 (0.49), 2.804 (0.89), 2.829 (1.66), 2.863 (2.95), 2.878 (2.35), 2.881 (2.35),
2.896 (2.24), 2.910 (1.95), 2.973 (1.09), 2.996 (2.06), 3.013 (1.86), 3.027 (2.75), 3.044 (2.61),
3.061 (1.86), 3.089 (4.76), 3.120 (5.68), 3.150 (2.09), 3.179 (1.20), 3.213 (1.26), 3.233 (1.15), 3.252 (2.27), 3.290 (6.65), 3.365 (0.46), 3.398 (1 .89), 3.431 (1.55), 3.465 (2.78), 3.502 (1 .81 ),
3.674 (1 .32), 3.825 (0.43), 4.21 1 (2.04), 4.243 (2.24), 4.382 (2.64), 4.415 (2.32), 6.962 (4.01 ),
6.981 (7.34), 7.000 (4.87), 7.033 (1.69), 7.103 (6.82), 7.122 (5.13), 7.206 (0.60), 7.225 (0.75),
7.310 (2.87), 7.328 (4.73), 7.347 (2.61 ), 7.375 (1 .63), 7.403 (1.95), 7.413 (2.04), 7.422 (1 .92), 7.512 (5.48), 7.518 (4.30), 7.528 (2.87), 7.537 (0.80), 7.586 (0.40), 7.603 (1 .00), 8.714 (0.89),
8.739 (0.89), 9.152 (0.46), 9.230 (1.09).
Example 95
(2R)-1 -{7-[2-(ethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one (Stereoisomer 2)
Figure imgf000509_0001
Example 92 (42 mg, 75 pmol) was purified by preparative HPLC (Method 6) to give the titled compound (30 mg, 78%).
Optical rotation (method OR1 ): -54.8°(methanol).
Example 96
(2R)-3,3,3-trifluoro-1 -[7-(3-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy- 2-phenylpropan-1 -one (mixture of stereoisomers)
Figure imgf000509_0002
Using the method described for Example 63: intermediate 167 (150 mg, 305 pmol) gave titled compound (30 mg, 20%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.242 (0.58), -0.230 (0.67), -0.209 (1.26), -0.197 (1 .26), -0.176 (0.72), -0.165 (0.58), 0.231 (0.63), 0.243 (0.63), 0.505 (1 .26), 0.535 (1 .17), 0.934 (0.45), 0.954 (0.85), 0.967 (0.85), 0.988 (0.54), 0.999 (0.45), 1.041 (0.72), 1.073 (1.75),
1.085 (1.48), 1.107 (1.93), 1.118 (1.71), 1.146 (1.53), 1.180 (0.94), 1.212 (0.54), 1.258 (0.90),
1.293 (0.85), 1.321 (0.94), 1.353 (1.03), 1.739 (0.63), 1.783 (11.64), 1.790 (11.46), 1.954 (1.57), 1.987 (1.71), 2.073 (0.40), 2.127 (2.29), 2.163 (11.24), 2.169 (10.25), 2.186 (2.56), 2.192 (2.43), 2.268 (0.45), 2.303 (0.67), 2.322 (2.38), 2.327 (3.06), 2.331 (2.47), 2.336 (1.39), 2.361 (2.16), 2.370 (1.71), 2.393 (1.84), 2.402 (1.57), 2.518 (10.79), 2.522 (6.79), 2.539 (1.30), 2.571 (0.63), 2.599 (1.21), 2.629 (2.02), 2.636 (1.93), 2.659 (2.70), 2.664 (3.78), 2.668 (3.91),
2.673 (2.70), 2.678 (1.57), 2.695 (2.07), 2.722 (3.96), 2.734 (3.60), 2.749 (2.70), 2.762 (2.34),
2.790 (2.43), 2.798 (2.34), 2.836 (1.21), 2.843 (1.12), 2.870 (0.85), 2.895 (0.63), 2.924 (0.72),
2.950 (1.62), 2.981 (2.74), 3.011 (2.25), 3.046 (1.80), 3.065 (0.85), 3.080 (1.08), 3.116 (2.29),
3.232 (2.74), 3.442 (1.44), 3.485 (1.48), 3.547 (16.00), 4.179 (0.76), 4.212 (0.76), 4.258 (1.12), 4.291 (1.08), 6.375 (1.44), 6.394 (1.48), 6.845 (2.43), 6.865 (2.70), 6.923 (1.98), 6.942 (4.45),
6.961 (3.46), 6.977 (1.57), 6.999 (0.67), 7.049 (4.31), 7.067 (4.22), 7.089 (1.35), 7.103 (1.35),
7.125 (4.18), 7.147 (6.83), 7.162 (4.90), 7.180 (4.22), 7.201 (2.56), 7.216 (2.61), 7.232 (3.46),
7.250 (1.57), 7.325 (1.44), 7.333 (1.12), 7.419 (2.11), 7.426 (2.07), 7.431 (2.97), 7.435 (2.47),
7.445 (2.16), 7.448 (1.75), 7.459 (1.30), 7.462 (1.98), 7.480 (0.90).
Example 97
(2R)-3,3,3-trifluoro-1-[7-(5-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy- 2-phenylpropan-1-one (mixture of stereoisomers)
Figure imgf000510_0001
Using the method described for Example 63: intermediate 167 (50.0 mg, 102 pmol) gave titled compound (22 mg, 42%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.967 (0.46), 1.107(16.00), 1.144 (0.44), 1.380 (0.62),
1.886 (2.31), 2.234 (2.62), 2.258 (0.65), 2.331 (0.74), 2.518 (3.79), 2.523 (2.35), 2.673 (0.85),
2.678 (0.54), 2.711 (0.47), 2.725 (0.68), 2.744 (0.84), 3.283 (0.62), 3.550 (2.07), 3.557 (1.83),
4.192 (0.96), 5.758 (0.69), 6.942 (0.66), 6.961 (0.46), 7.072 (0.62), 7.093 (0.46), 7.162 (1.63),
7.179 (0.82), 7.229 (0.47), 7.275 (0.47), 7.434 (0.51). Example 98
(2R)-3,3,3-trifluoro-1-[7-(2-fluoro-6-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy- 2-phenylpropan-1-one (mixture of stereoisomers)
Figure imgf000511_0001
Using the method described for Example 63: intermediate 169 (150 mg, 305 pmol) gave titled compound (51 mg, 33%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.174 (16.00), 2.025 (1.53), 2.377 (0.47), 2.386 (1.31), 2.584 (0.70), 2.589 (0.49), 3.616 (1.22), 3.624 (1.04), 7.142 (0.42), 7.161 (0.46), 7.224 (0.40), 7.263 (0.42). Example 99
(2R)-1-[7-(2,3-dimethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1-one (Stereoisomer 1)
Figure imgf000511_0002
Using the method described for Example 63: intermediate 174 (44 mg, 90 pmol) gave titled compound (20 mg, 44%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.295 (0.43), 0.319 (0.74), 0.328 (0.74), 0.351 (0.43),
0.949 (0.43), 0.960 (0.49), 0.968 (1.04), 0.982 (0.92), 0.994 (0.98), 1.015 (0.61), 1.026 (0.49),
1.086 (0.49), 1.108(16.00), 1.144 (0.92), 1.159 (0.74), 1.192 (0.86), 1.210(0.80), 1.232 (1.04), 1.251 (1.16), 1.287 (1.29), 1.300 (1.16), 1.333 (0.86), 1.349 (0.80), 1.978 (0.80), 2.012 (0.80), 2.120 (1.23), 2.157 (8.58), 2.162 (15.08), 2.236 (5.64), 2.275 (14.41), 2.323 (3.74), 2.327
(4.97), 2.331 (3.86), 2.356 (1.29), 2.364 (1.16), 2.518 (13.00), 2.523 (9.07), 2.576 (0.43), 2.604
(0.92), 2.636 (0.67), 2.660 (1.29), 2.665 (2.82), 2.669 (3.92), 2.673 (2.88), 2.678 (1.41), 2.707 (1 .35), 2.740 (2.08), 2.770 (1 .47), 2.801 (1 .41 ), 2.831 (1.10), 2.838 (1 .16), 2.865 (0.67), 2.886
(1 .16), 2.895 (1 .23), 2.915 (0.86), 2.923 (0.74), 2.985 (1.04), 3.017 (3.62), 3.037 (0.74), 3.052
(0.67), 3.246 (0.43), 3.454 (0.80), 3.488 (0.80), 3.505 (0.61 ), 3.51 1 (0.55), 3.544 (9.13), 4.153
(0.74), 4.190 (2.02), 6.371 (1 .53), 6.390 (1 .59), 6.934 (0.61 ), 6.975 (1 .29), 6.982 (2.51 ), 7.001 (3.13), 7.020 (1 .72), 7.067 (2.39), 7.093 (2.39), 7.1 12 (3.86), 7.157 (3.13), 7.176 (4.23), 7.196
(2.02), 7.308 (0.92), 7.316 (0.86), 7.414 (2.51 ), 7.422 (2.15), 7.431 (1 .84), 7.437 (1.16), 7.440
(1 .59), 7.459 (2.39), 7.477 (1.04), 8.548 (0.67).
Example 100
(2R)-1 -[7-(3,5-dimethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one (mixture of stereoisomers)
Figure imgf000512_0001
Using the method described for Example 63: intermediate 177 (134 mg, 274 pmol) gave titled compound (78 mg, 59%) after purification by preparative FIPLC (Method 6).
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .107 (16.00), 1 .249 (0.49), 1 .261 (0.48), 2.230 (2.80), 2.274 (5.92), 2.292 (5.63), 2.322 (0.63), 2.326 (0.67), 2.332 (0.47), 2.462 (0.41 ), 2.518 (2.51 ),
2.522 (1 .64), 2.664 (0.53), 2.668 (0.68), 2.673 (0.54), 2.701 (0.42), 2.709 (0.41 ), 2.726 (0.49),
3.157 (0.51 ), 3.21 1 (0.55), 3.545 (2.67), 4.192 (0.96), 6.457 (0.91 ), 6.492 (0.54), 6.730 (0.43),
6.906 (0.57), 6.942 (0.64), 6.950 (0.72), 6.970 (0.45), 7.048 (0.61 ), 7.067 (0.44), 7.108 (2.14),
7.1 19 (1 .43), 7.271 (0.46), 7.425 (0.83), 7.431 (0.75), 7.440 (0.52).
Example 101
(2R)-1-[7-(2-chloro-3-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy- 2-phenylpropan-1-one (mixture of stereoisomers)
Figure imgf000513_0001
Using the method described for Example 63: intermediate 179 (150 mg, 292 pmol) gave titled compound (34 mg, 22%) after purification by preparative FIPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.324 (0.54), -0.312 (0.68), -0.291 (1.21), -0.279 (1.22), -0.258 (0.69), -0.246 (0.57), 0.033 (0.57), 0.043 (0.56), 0.529 (1.23), 0.560 (1.14), 0.852 (0.42), 0.874 (0.74), 0.885 (0.75), 0.907 (0.53), 0.921 (0.73), 0.935 (1.02), 0.957 (1.45),
0.968 (1.96), 0.987 (1.23), 1.000 (1.32), 1.028 (0.54), 1.039 (0.60), 1.060 (0.84), 1.070 (0.80),
1.092 (1.14), 1.129 (2.26), 1.155 (1.26), 1.195 (0.90), 1.343 (0.75), 1.371 (0.67), 1.866 (1.55),
1.898 (1.29), 1.973 (4.94), 2.040 (1.79), 2.074 (1.61), 2.224 (0.40), 2.229 (0.51), 2.234 (0.47),
2.238 (0.45), 2.278 (0.45), 2.311 (1.85), 2.340 (1.99), 2.420 (1.74), 2.424 (1.10), 2.442 (0.71),
2.476 (0.80), 2.508 (1.05), 2.539 (0.63), 2.567 (0.60), 2.571 (0.83), 2.576 (0.79), 2.610 (1.59),
2.639 (3.53), 2.671 (2.41), 2.704 (1.88), 2.723 (0.91), 2.735 (0.93), 2.751 (1.02), 2.756 (1.02),
2.783 (0.60), 2.827 (0.99), 2.860 (2.63), 2.877 (1.75), 2.890 (0.75), 2.905 (1.65), 2.934 (1.57),
2.962 (1.97), 2.986 (1.52), 2.995 (1.88), 3.013 (1.01), 3.022 (0.87), 3.075 (2.34), 3.105 (1.04),
3.133 (1.20), 3.172 (4.53), 3.377 (1.46), 3.413 (1.83), 3.452 (16.00), 4.087 (0.73), 4.121 (0.60), 4.173 (1.08), 4.206 (1.02), 5.656 (1.61), 6.471 (0.76), 6.485 (0.97), 6.493 (0.74), 6.828 (1.91),
6.848 (4.27), 6.866 (2.75), 6.949 (1.50), 6.955 (1.32), 6.963 (2.20), 6.981 (4.30), 7.000 (3.22),
7.063 (8.46), 7.075 (4.70), 7.097 (0.75), 7.106 (1.86), 7.125 (2.81), 7.143 (1.49), 7.154 (0.86),
7.166 (0.58), 7.175 (0.45), 7.205 (0.57), 7.215 (0.96), 7.225 (2.70), 7.230 (2.90), 7.239 (4.27),
7.251 (2.02), 7.258 (2.44), 7.272 (0.49), 7.284 (2.55), 7.287 (2.61), 7.297 (4.43), 7.309 (2.39),
7.316 (4.09), 7.324 (2.12), 7.331 (3.42), 7.337 (2.57), 7.346 (1.93), 7.352 (1.14), 7.360 (1.11),
7.368 (0.84), 7.373 (0.67), 7.382 (0.41). Example 102
(2R)-1 -[7-(2,5-dimethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one (mixture of stereoisomers)
Figure imgf000514_0001
Using the method described for Example 63: intermediate 181 (150 mg, 307 pmol) gave titled compound (66 mg, 43%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .184 (16.00), 1.937 (2.20), 2.282 (0.62), 2.295 (1 .62),
2.309 (1 .56), 2.315 (2.38), 2.390 (2.34), 2.403 (0.41 ), 2.594 (1.04), 2.599 (0.62), 2.805 (0.55),
2.840 (0.46), 3.305 (0.52), 3.618 (1.74), 3.627 (1 .23), 4.268 (0.65), 5.835 (1 .67), 6.899 (0.47), 6.956 (0.57), 6.971 (0.61 ), 7.104 (0.73), 7.1 19 (0.58), 7.159 (0.53), 7.219 (1 .10), 7.236 (0.48),
7.319 (0.42), 7.508 (0.75), 7.515 (0.45).
Example 103
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxy-5-methylphenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-phenylpropan-1 -one (mixture of stereoisomers)
Figure imgf000514_0002
Using the method described for Example 63: intermediate 181 (400 mg, 771 pmol) gave titled compound (170 mg, 43%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.45), 0.01 1 (0.43), 0.507 (0.45), 0.538 (0.43), 1 .025 (0.71 ), 1 .036 (0.84), 1 .070 (1.00), 1 .106 (0.79), 1.149 (0.60), 1 .189 (0.73), 1.218 (0.52), 1 .244 (0.72), 1 .283 (0.57), 1 .308 (0.70), 1 .343 (0.61 ), 1.925 (0.48), 1 .959 (0.62), 2.079 (0.52),
2.089 (1 .34), 2.154 (0.98), 2.189 (0.97), 2.225 (4.31 ), 2.261 (7.83), 2.301 (7.17), 2.328 (0.56),
2.333 (0.73), 2.338 (0.71 ), 2.440 (0.82), 2.463 (0.76), 2.471 (0.90), 2.524 (3.21 ), 2.528 (2.21 ), 2.545 (0.95), 2.621 (0.41 ), 2.653 (0.72), 2.670 (0.66), 2.675 (0.86), 2.679 (0.86), 2.738 (0.70), 2.767 (1 .32), 2.790 (1 .57), 2.836 (1.15), 2.881 (1 .00), 2.913 (0.62), 2.931 (0.46), 2.963 (0.72), 2.970 (0.78), 3.003 (0.80), 3.031 (1.32), 3.068 (1 .28), 3.076 (1.25), 3.099 (0.78), 3.143 (1 .39), 3.166 (0.47), 3.210 (1.58), 3.364 (3.47), 3.445 (2.08), 3.474 (10.72), 3.543 (5.94), 3.553 (5.88), 3.671 (1 .60), 3.71 1 (3.35), 3.727 (3.91 ), 3.737 (10.82), 4.177 (0.60), 4.212 (0.53), 4.284 (0.45), 4.318 (0.42), 5.764 (16.00), 6.393 (1 .29), 6.812 (1 .36), 6.831 (0.59), 6.837 (0.65), 6.852 (0.82), 6.858 (0.72), 6.878 (1 .76), 6.885 (1.59), 6.899 (2.21 ), 6.906 (2.20), 6.924 (0.57), 6.947 (0.83), 6.967 (2.19), 6.985 (1 .53), 7.049 (1.74), 7.069 (2.25), 7.096 (1.45), 7.1 19 (6.14), 7.132 (3.55), 7.329 (1 .50), 7.347 (1 .68), 7.366 (0.68), 7.402 (0.56), 7.409 (0.86), 7.417 (1 .16), 7.425 (1 .91 ), 7.432 (2.41 ).
Example 104
(2R)-3,3,3-trifluoro-1 -[7-(2-fluoro-6-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers)
Figure imgf000515_0001
Using the method described for Example 63: intermediate 186 (92 mg, 181 pmol) gave titled compound (54 mg, 55%) after purification by preparative HPLC (Method 6).
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .248 (0.55), 2.338 (0.56), 2.343 (0.77), 2.347 (0.60), 2.533 (4.1 1 ), 2.538 (2.57), 2.680 (0.84), 2.685 (0.99), 2.689 (0.72), 2.693 (0.44), 2.708 (0.43),
2.743 (0.62), 2.777 (0.52), 3.045 (0.44), 3.126 (0.45), 3.175 (0.44), 3.186 (0.44), 3.263 (0.40),
3.276 (0.65), 3.292 (0.49), 3.308 (0.43), 3.452 (1 .33), 3.533 (4.49), 3.560 (3.33), 3.567 (2.60),
3.581 (2.39), 3.757 (0.54), 3.789 (1 .72), 3.810 (2.88), 5.774 (16.00), 6.776 (0.48), 6.806 (0.48),
6.851 (0.45), 6.870 (0.95), 6.891 (0.72), 6.928 (0.45), 6.947 (0.84), 6.966 (0.51 ), 7.094 (0.77),
7.1 14 (0.66), 7.160 (1 .07), 7.170 (0.66), 7.188 (0.62), 7.326 (0.54), 7.334 (0.59), 7.344 (0.90),
7.348 (0.76), 7.353 (0.72), 7.360 (0.51 ), 7.363 (0.54), 7.370 (0.59), 7.446 (0.61 ), 7.450 (0.56),
7.460 (0.43). Example 105
(2R)-3,3,3-trifluoro-1-[7-(3-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1-one (mixture of stereoisomers)
Figure imgf000516_0001
Using the method described for Example 63: intermediate 188 (40 mg, 79 pmol) gave titled compound (19.3 mg, 47%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.012 (0.52), 0.000 (0.52), 0.582 (0.52), 0.611 (0.48), 1.020 (0.94), 1.047 (0.46), 1.063 (0.46), 1.089 (0.55), 1.116 (0.73), 1.160 (16.00), 1.197 (0.78),
1.262 (0.94), 1.284 (1.00), 1.323 (0.50), 1.991 (0.68), 2.025 (0.55), 2.163 (0.71), 2.197 (0.66), 2.426 (1.00), 2.457 (0.98), 2.571 (7.67), 2.575 (4.88), 2.636 (0.66), 2.667 (0.46), 2.758 (1.26), 2.785 (1.85), 2.824 (0.98), 2.856 (0.66), 2.889 (0.94), 2.911 (0.96), 2.918 (0.98), 2.970 (1.03), 2.999 (1.23), 3.029 (0.50), 3.052 (0.46), 3.087 (0.68), 3.124 (0.80), 3.159 (0.43), 3.219 (1.05), 3.304 (1.39), 3.514 (0.64), 3.564 (7.40), 3.568 (7.24), 3.603 (8.72), 3.820 (1.76), 3.824 (1.85), 3.837 (4.20), 3.842 (4.20), 3.848 (1.94), 3.852 (1.73), 4.244 (0.98), 4.334 (0.50), 4.369 (0.48), 5.811 (0.80), 6.443 (0.48), 6.463 (0.50), 6.921 (0.87), 6.941 (1.03), 7.007 (0.94), 7.026 (2.05), 7.045 (1.46), 7.067 (0.62), 7.088 (1.00), 7.101 (0.68), 7.111 (0.66), 7.132 (2.92), 7.151 (2.17), 7.166 (0.82), 7.180 (0.59), 7.198 (3.04), 7.215 (1.62), 7.234 (0.71), 7.253 (0.78), 7.274 (0.68), 7.282 (1.42), 7.301 (1.71), 7.319 (0.62), 7.380 (0.68), 7.387 (0.75), 7.474 (1.46), 7.480 (1.85), 7.486(1.64), 7.491 (1.48).
Example 106
(2R)-3,3,3-trifluoro-1 -[7-(5-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one (Stereoisomer 2)
Figure imgf000517_0001
Using the method described for Example 63: intermediate 192 (20 mg, 39 pmol) gave titled compound (9 mg, 42%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.022 (0.53), 0.032 (0.53), 0.869 (0.69), 0.881 (0.69), 0.903 (0.47), 0.914 (0.41 ), 0.939 (1.07), 0.957 (2.10), 0.974 (1.00), 0.987 (0.47), 1.01 1 (5.18),
1 .029 (0.69), 1 .061 (0.60), 1 .093 (0.78), 1 .137 (1 .10), 1.202 (0.72), 1 .237 (0.60), 1.661 (0.97), 1 .949 (0.63), 1 .973 (0.72), 2.006 (0.66), 2.236 (1 .73), 2.240 (1.16), 2.249 (0.66), 2.271 (0.75),
2.280 (0.69), 2.422 (7.53), 2.427 (4.71 ), 2.443 (1 .13), 2.471 (0.78), 2.502 (0.53), 2.578 (1 .98),
2.582 (1 .41 ), 2.596 (1 .41 ), 2.626 (1.44), 2.657 (0.66), 2.707 (0.66), 2.735 (0.94), 2.768 (0.47),
2.902 (1 .10), 2.932 (1 .22), 2.965 (0.47), 3.1 13 (1 .38), 3.383 (0.63), 3.415 (0.63), 3.456 (7.06),
3.486 (0.41 ), 3.503 (0.75), 3.637 (4.17), 3.651 (16.00), 4.049 (0.69), 4.082 (0.56), 4.094 (0.50), 6.272 (0.60), 6.279 (0.66), 6.297 (0.63), 6.303 (0.60), 6.856 (0.56), 6.863 (1 .04), 6.870 (0.69),
6.875 (1 .19), 6.885 (1 .60), 6.897 (1.60), 6.968 (0.91 ), 6.975 (1.04), 6.988 (1 .10), 6.996 (1 .19),
7.010 (0.66), 7.018 (0.66), 7.036 (0.78), 7.050 (7.91 ), 7.056 (3.26), 7.065 (3.26), 7.086 (0.63),
7.234 (0.53), 7.244 (0.53), 7.263 (0.47), 7.269 (0.72), 7.277 (0.85), 7.284 (0.88), 7.290 (0.72),
7.299 (0.53), 7.328 (1.38), 7.335 (1.13), 7.345 (0.88).
Example 107
(2R)-1 -[7-(3,6-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers)
Figure imgf000518_0001
Using the method described for Example 63: intermediate 194 (150 mg, 285 pmol) gave titled compound (55 mg, 36%) after purification by preparative HPLC (Method 6).
The title compound (49 mg) was separated into its diastereoisomers by preparative chiral HPLC to give diastereoisomer 1 (18 mg, see Example 108) and diastereoisomer 2 (21 mg, see Example 109).
Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241 , Labcol Vario 4000, Column: Chiralcel OD-H 5m 250x20mm; Eluent A: Hexane + 0.1 Vol- % Diethylamine (99%); Eluent B: Ethanol; Isocratic: 85%A+15%B; Flow: 20.0 ml/min; UV 220 nm.
Analytical chiral HPLC method Instrument: Agilent HPLC 1260; Column: Chiralcel OD-H 3m 100x4, 6mm; Eluent A: Hexane + 0.1 Vol-% Diethylamine (99%); Eluent B: Ethanol; Isocratic: 85%A+15%B; Flow: 1 .4 ml/min; Temperature: 25 Ό; DA D 220 nm.
Example 108 and Example 109
(2R)-1 -[(7R)-7-(3,6-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro- 2-methoxy-2-phenylpropan-1 -one
(2R)-1 -[(7S)-7-(3,6-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro- 2-methoxy-2-phenylpropan-1 -one
Example 108
(2R)-1 -[7-(3,6-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (Stereoisomer 1 )
For the preparation of the racemic title compound see Example 107.
Analytical Chiral HPLC (method see Example 107): Rt = 3.06 min, e.e. >99%. 1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.066 (0.42), -0.033 (0.73), 0.000 (0.41), 0.773 (3.03), 0.792 (6.77), 0.810 (3.82), 0.816 (1.95), 0.822 (0.68), 0.833 (2.22), 0.841 (1.96), 0.852 (1.25),
0.859 (2.85), 0.868 (1.02), 0.877 (1.28), 0.884 (0.48), 0.926 (0.71), 0.933 (0.73), 0.956 (1.30),
0.971 (1.81), 0.983 (1.02), 0.990 (1.25), 1.003 (7.08), 1.010 (1.20), 1.026 (1.17), 1.031 (3.55),
1.047 (2.16), 1.081 (9.79), 1.097 (2.45), 1.105 (1.73), 1.135 (1.62), 1.202 (2.46), 1.228 (2.88),
1.257 (10.73), 1.277 (1.43), 1.284 (1.83), 1.301 (1.41 ), 1.315 (1.64), 1.333 (1.15), 1.350 (0.95), 1.372 (0.81), 1.389 (1.25), 1.403 (1.28), 1.420 (1.95), 1.422 (1.86), 1.438 (1.62), 1.441 (1.61),
1.456 (0.71), 1.460 (0.65), 1.485 (0.42), 1.503 (0.65), 1.525 (0.80), 1.535 (0.67), 1.540 (0.72),
1.558 (0.44), 1.570 (0.51), 1.590 (0.60), 1.598 (0.46), 1.607 (0.58), 1.620 (0.46), 1.626 (0.46),
1.756 (0.49), 1.760 (0.44), 1.772 (0.54), 1.786 (0.63), 1.801 (0.47), 2.060 (0.46), 2.081 (0.44),
2.086 (0.41), 2.113 (0.60), 2.141 (1.40), 2.175 (1.28), 2.307 (0.43), 2.321 (0.42), 2.325 (0.52),
2.330 (0.48), 2.450 (1.10), 2.516 (2.07), 2.521 (1.53), 2.538 (1.90), 2.561 (1.13), 2.595 (0.87),
2.662 (0.61), 2.668 (0.73), 2.672 (0.66), 2.716 (1.46), 2.740 (1.49), 2.778 (1.32), 2.811 (1.77),
2.844 (0.94), 2.864 (0.52), 2.894 (0.55), 3.006 (1.15), 3.039 (4.47), 3.065 (1.48), 3.106 (0.67),
3.138 (1.43), 3.162 (2.38), 3.535 (5.05), 3.542 (5.76), 3.559 (16.00), 3.803 (3.98), 3.807 (3.98), 3.826 (13.82), 3.831 (13.89), 3.847 (0.49), 4.185 (1.17), 4.218 (1.23), 6.915 (0.98), 6.925 (1.14), 6.941 (1.79), 6.950 (1.92), 6.964 (1.36), 6.974 (1.35), 7.151 (3.58), 7.162 (6.35), 7.171 (12.24), 7.182 (10.97), 7.205 (0.72), 7.244 (0.83), 7.256 (1.12), 7.270 (1.28), 7.278 (1.35), 7.283 (1.35), 7.294 (1.17), 7.306 (1.72), 7.321 (1.43), 7.376 (0.61), 7.386 (0.68), 7.399 (0.52),
7.418 (2.31), 7.422 (1.83), 7.425 (1.94), 7.431 (1.58), 7.434 (1.45), 7.441 (1.20), 7.452 (1.66),
7.463 (2.14), 7.474 (1.60), 7.484 (0.63).
Example 109
(2R)-1-[7-(3,6-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1-one (Stereoisomer 2)
For the preparation of the racemic title compound see Example 107.
Analytical Chiral HPLC (method see Example 107): Rt = 4.63 min, e.e. >99%.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.077 (0.56), -0.066 (0.70), -0.044 (1.22), -0.033 (1.21), -0.011 (0.70), 0.000 (0.57), 0.528 (1.11), 0.557 (0.96), 0.800 (1.83), 0.818 (3.99), 0.837 (2.35), 0.843 (1.19), 0.860 (1.39), 0.868 (1.24), 0.878 (0.77), 0.885 (1.77), 0.895 (0.66), 0.904
(0.85), 0.928 (0.52), 0.940 (0.53), 0.959 (0.79), 0.972 (1.05), 0.991 (1.17), 0.997 (1.37), 1.008
(1.28), 1.030 (4.65), 1.058 (2.39), 1.074 (1.17), 1.108 (5.61), 1.124 (1.13), 1.162 (0.89), 1.228
(1.03), 1.255 (1.56), 1.283 (6.02), 1.303 (0.58), 1.310 (0.66), 1.327 (0.55), 1.341 (0.60), 1.360
(0.46), 1.382 (0.57), 1.398 (0.45), 1.416 (0.73), 1.429 (0.73), 1.446 (1.14), 1.448 (1.09), 1.464
(0.96), 1.468 (0.94), 1.483 (0.44), 1.552 (0.48), 1.567 (0.43), 1.812 (0.44), 1.837 (0.41), 2.048
(1.14), 2.086 (1.00), 2.186 (1.14), 2.220 (1.07), 2.347 (0.46), 2.351 (0.64), 2.357 (0.52), 2.542
(2.67), 2.547 (1.69), 2.564 (0.43), 2.584 (0.51), 2.676 (0.59), 2.690 (0.67), 2.694 (0.92), 2.707 (1.45), 2.740 (1.30), 2.770 (2.21), 2.801 (2.01), 2.835 (0.81), 2.959 (1.02), 2.982 (1.24), 3.072
(1.15), 3.106 (1.56), 3.135 (1.01), 3.192 (0.62), 3.270 (1.88), 3.445 (1.25), 3.520 (1.22), 3.561
(14.98), 3.567 (16.00), 3.581 (12.12), 3.809 (0.87), 3.815 (0.90), 3.835 (3.00), 3.842 (3.08), 3.858 (0.41), 3.868 (2.39), 3.873 (2.49), 4.328 (1.03), 4.361 (0.96), 6.916 (0.53), 6.927 (0.55), 6.939 (0.50), 6.960 (0.92), 6.971 (1.60), 6.982 (2.57), 6.998 (4.91), 7.009 (2.40), 7.018 (3.26),
7.154 (4.21), 7.173 (3.45), 7.234 (1.51), 7.253 (2.48), 7.271 (1.11), 7.288 (0.48), 7.307 (0.79),
7.321 (1.09), 7.334 (1.04), 7.349 (1.31), 7.356 (1.67), 7.361 (1.79), 7.372 (1.66), 7.384 (1.31),
7.457 (2.06), 7.463 (1.63), 7.471 (0.96), 7.474 (0.97).
Example 110
(2R)-1-[7-(2,3-difluoro-6-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1-one (mixture of stereoisomers)
Figure imgf000520_0001
Using the method described for Example 63: intermediate 196 (150 mg, 285 pmol) gave titled compound (61 mg, 40%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.093 (0.84), 1.111 (2.04), 1.129(0.97), 1.166(16.00), 1.816 (0.76), 2.103 (1.23), 2.577 (1.35), 2.582 (0.88), 3.477 (0.70), 3.559 (2.60), 3.611 (1.58), 3.620 (1.39), 3.657 (0.67), 3.816 (1.26), 3.842 (2.67), 4.251 (0.55), 7.030 (0.43), 7.187 (0.55), 7.208 (0.75), 7.225 (1.16), 7.236 (0.41), 7.399 (0.59), 7.421 (0.45).
Example 111
(2R)-1-[7-(3,5-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1-one (mixture of stereoisomers)
Figure imgf000521_0001
Using the method described for Example 63: intermediate 198 (150 mg, 285 pmol) gave titled compound (68 mg, 44%) after purification by preparative FIPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.154 (0.42), -0.133 (0.76), -0.122 (0.78), -0.099 (0.46), 0.023 (0.56), 0.033 (0.56), 0.550 (0.74), 0.581 (0.68), 0.919 (0.69), 0.930 (0.71), 0.954
(0.64), 0.965 (0.69), 0.992 (1.12), 1.001 (1.01), 1.023 (1.09), 1.072 (0.77), 1.104 (1.05), 1.127 (0.80), 1.181 (0.76), 1.215 (0.65), 1.254 (0.73), 1.287 (0.61), 1.876 (0.84), 1.908 (0.68), 2.055
(1.42), 2.088 (1.36), 2.293 (0.55), 2.298 (0.78), 2.302 (0.65), 2.306 (0.41), 2.346 (0.80), 2.355
(0.92), 2.364 (1.12), 2.372 (1.39), 2.385 (1.09), 2.394 (1.17), 2.402 (0.98), 2.488 (3.09), 2.493
(2.14), 2.510 (0.91), 2.537 (1.05), 2.564 (0.94), 2.623 (0.44), 2.635 (0.85), 2.640 (1.17), 2.649
(1.72), 2.656 (1.80), 2.671 (2.01), 2.678 (2.15), 2.686 (2.09), 2.700 (2.48), 2.731 (1.12), 2.743 (1.20), 2.776 (1.67), 2.804 (2.04), 2.843 (0.91 ), 2.863 (1.37), 2.873 (1.41 ), 2.892 (1.73), 2.921
(0.79), 2.976 (0.68), 3.015 (1.35), 3.049 (1.41), 3.083 (0.74), 3.252 (3.27), 3.447 (1.09), 3.468
(12.11), 3.472 (12.46), 3.529 (16.00), 3.705 (3.13), 3.707 (3.16), 3.723 (10.04), 3.726 (10.15), 3.732 (3.37), 3.735 (2.99), 4.151 (0.63), 4.184 (0.59), 4.250 (0.74), 4.284 (0.71), 6.229 (0.66),
6.253 (0.66), 6.790 (0.82), 6.814 (0.81), 6.999 (1.50), 7.018 (3.36), 7.037 (2.29), 7.116 (3.31), 7.135 (2.81), 7.147 (3.97), 7.154 (3.63), 7.161 (8.78), 7.194 (0.61), 7.201 (0.68), 7.223 (2.09),
7.238 (2.21), 7.246 (1.37), 7.254 (2.13), 7.276 (0.79), 7.284 (0.78), 7.301 (0.90), 7.319 (1.45),
7.325 (1.37), 7.334 (1.04), 7.341 (1.00), 7.347 (0.81), 7.355 (0.60), 7.389 (0.46), 7.398 (3.04),
7.405 (2.38), 7.415 (1.53). Example 112
(2R)-1 -[7-(4,5-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers)
Figure imgf000522_0001
Using the method described for Example 63: intermediate 200 (40 mg, 76 pmol) gave titled compound (19 mg, 46%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .048 (16.00), 2.268 (0.48), 2.272 (0.43), 2.459 (1 .43), 2.464 (0.99), 2.610 (0.52), 2.614 (0.43), 2.631 (0.40), 3.455 (2.69), 3.493 (1 .57), 3.496 (1 .39), 3.686 (0.62), 3.695 (2.31 ), 3.700 (0.92), 4.132 (0.67), 6.990 (0.48), 7.082 (0.64), 7.101 (0.76), 7.1 18 (0.88), 7.366 (0.63).
Example 113
(2R)-1 -[7-[2-(2,2-difluoroethoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (Stereoisomer 2)
Figure imgf000522_0002
Using the method described for Example 63: intermediate 205 (20 mg, 37 pmol) gave titled compound (12.6 mg, 61 %) after purification by preparative FIPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.173 (0.50), 0.183 (0.55), 0.852 (0.50), 0.967 (0.60), 0.979 (0.40), 1 .002 (0.80), 1 .012 (0.80), 1.035 (0.70), 1 .046 (0.70), 1.076 (0.70), 1 .107 (16.00), 1 .144 (0.55), 1 .232 (3.13), 1 .257 (1.04), 1 .299 (0.89), 1.333 (0.75), 1 .352 (0.50), 1.836 (0.60), 2.107 (0.80), 2.140 (0.75), 2.336 (1 .14), 2.352 (0.70), 2.360 (0.65), 2.518 (1 1 .88), 2.522 (7.80),
2.560 (0.65), 2.586 (0.70), 2.618 (0.45), 2.678 (1 .19), 2.696 (1.09), 2.723 (0.84), 2.763 (0.70),
2.794 (1 .34), 2.824 (0.84), 2.833 (0.99), 2.867 (0.45), 2.983 (0.70), 3.019 (1 .54), 3.049 (1 .14),
3.165 (1 .99), 3.225 (0.45), 3.448 (0.65), 3.482 (0.80), 3.488 (0.94), 3.544 (7.06), 4.129 (0.60), 4.162 (0.60), 4.190 (0.70), 4.230 (0.70), 4.239 (0.94), 4.248 (0.45), 4.267 (1.44), 4.275 (1.64), 4.302 (1.24), 4.311 (1.14), 4.338 (0.60), 6.288 (0.55), 6.393 (0.40), 6.415 (0.55), 6.424 (1.09), 6.432 (0.55), 6.558 (1.24), 6.573 (1.14), 6.941 (0.75), 6.949 (0.99), 6.967 (1.64), 6.984 (1.04), 7.000 (0.89), 7.008 (1.54), 7.029 (1.79), 7.083 (0.94), 7.105 (5.61), 7.122 (2.98), 7.143 (0.99), 7.159 (0.45), 7.175 (0.50), 7.257 (1.19), 7.261 (1.19), 7.278 (1.59), 7.299 (0.84), 7.321 (0.84), 7.330 (0.75), 7.405 (0.60), 7.410 (1.04), 7.415 (0.84), 7.423 (2.93), 7.427 (2.43), 7.439 (1.54), 7.444 (0.94).
Example 114
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1-{7-[2-(2,2,2-trifluoroethoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}propan-1-one (Stereoisomer 2)
Figure imgf000523_0001
Using the method described for Example 63: intermediate 206 (45 mg, 81 pmol) gave titled compound (26.8 mg, 55%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.141 (0.43), 0.165 (0.53), 0.967 (1.16), 0.995 (0.73), 1.010 (0.93), 1.025 (1.10), 1.037 (1.26), 1.058 (1.06), 1.071 (0.83), 1.107 (16.00), 1.144 (1.20),
1.191 (0.73), 1.209 (1.50), 1.232 (3.09), 1.276 (1.56), 1.348 (0.77), 1.389 (0.47), 1.853 (0.70), 2.121 (0.86), 2.155 (0.86), 2.209 (0.43), 2.244 (0.43), 2.331 (2.03), 2.336 (1.36), 2.359 (0.80), 2.423 (0.77), 2.518 (7.88), 2.522 (5.09), 2.539 (0.80), 2.552 (0.83), 2.586 (1.03), 2.618 (0.67), 2.673 (1.80), 2.678 (1.06), 2.695 (1.36), 2.722 (1.13), 2.762 (0.60), 2.774 (0.90), 2.805 (1.93), 2.836 (1.50), 2.874 (0.63), 2.990 (1.70), 3.021 (1.63), 3.072 (1.16), 3.169 (2.03), 3.438 (0.50), 3.463 (0.77), 3.505 (0.90), 3.518 (1.13), 3.544 (10.71), 3.796 (0.83), 4.127 (0.60), 4.163 (0.83),
4.191 (0.90), 4.659 (0.70), 4.689 (1.33), 4.711 (1.23), 4.720 (0.70), 4.733 (0.57), 4.743 (0.80), 4.754 (0.47), 4.766 (1.10), 4.788 (1.10), 4.794 (0.96), 4.816 (0.80), 5.758 (0.50), 6.558 (0.53), 6.577 (1.53), 6.593 (1.16), 6.962 (0.43), 6.980 (0.73), 6.990 (1.06), 7.008 (1.96), 7.025 (1.66), 7.044 (2.89), 7.064 (2.53), 7.084 (5.46), 7.100 (8.95), 7.117 (3.69), 7.136 (1.23), 7.155 (0.47), 7.177 (0.43), 7.198 (0.53), 7.282 (1.23), 7.286 (1.30), 7.304 (2.46), 7.321 (1.96), 7.341 (0.70), 7.363 (0.67), 7.384 (0.40), 7.408 (0.86), 7.413 (1.56), 7.424 (3.56), 7.429 (3.16), 7.434 (2.69), 7.441 (1.90).
Example 115 (2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(2S)-2-methoxypropoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one (Stereoisomer 2)
Figure imgf000524_0001
Using the method described for Example 63: intermediate 207 (20.0 mg, 36.5 pmol) gave titled compound (12.7 mg, 62%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .016 (0.42), 1 .107 (2.86), 1 .183 (1 .42), 1 .199 (1 .57),
1 .216 (3.41 ), 1 .232 (4.28), 1 .259 (0.49), 2.322 (0.62), 2.326 (0.80), 2.332 (0.68), 2.518 (2.37),
2.522 (1 .56), 2.664 (0.48), 2.669 (0.64), 2.673 (0.50), 2.706 (0.51 ), 2.789 (0.48), 2.839 (0.41 ),
3.055 (0.52), 3.064 (0.47), 3.155 (1.02), 3.254 (3.96), 3.283 (0.41 ), 3.332 (16.00), 3.350 (10.33), 3.482 (0.41 ), 3.488 (0.51 ), 3.545 (3.24), 3.820 (0.56), 3.834 (0.48), 3.845 (0.82), 3.859
(0.59), 3.958 (0.53), 3.969 (0.56), 3.983 (0.55), 6.523 (0.45), 6.542 (0.48), 6.887 (0.45), 6.905
(0.69), 6.920 (0.52), 6.950 (0.68), 6.969 (0.74), 7.081 (0.61 ), 7.100 (1 .44), 7.1 17 (1.21 ), 7.135
(1 .34), 7.156 (0.55), 7.226 (0.43), 7.244 (0.64), 7.414 (0.58), 7.421 (1 .04), 7.429 (1.19), 7.432
(1 .1 1 ), 7.437 (0.86).
Example 116
(2R)-3,3,3-trifluoro-1 -[7-{2-[(2S)-2-hydroxy-3-methoxypropoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxy-2-phenylpropan-1 -one (Stereoisomer 2)
Figure imgf000524_0002
Using the method described for Example 63: intermediate 208 (20.0 mg, 35.4 pmol) gave titled compound (12 mg, 58%) after purification by preparative HPLC (Method 6). 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.987 (0.48), 0.998 (0.45), 1.107 (11.40), 1.138 (0.45), 1.232 (1.52), 1.256 (0.76), 1.343 (0.55), 1.352 (0.52), 1.375 (0.45), 2.108 (0.48), 2.141 (0.48),
2.332 (1.90), 2.336 (0.93), 2.355 (0.48), 2.518 (8.33), 2.522 (5.60), 2.539 (1.49), 2.601 (0.48),
2.673 (1.56), 2.678 (0.76), 2.711 (0.83), 2.756 (0.48), 2.787 (0.79), 2.818 (0.48), 2.832 (0.69), 2.981 (0.45), 3.014 (0.59), 3.095 (0.52), 3.124 (0.55), 3.147 (1.56), 3.192 (1.35), 3.226 (0.76),
3.238 (6.46), 3.250 (0.62), 3.303 (16.00), 3.403 (1.04), 3.414 (1.14), 3.427 (0.45), 3.452 (1.76), 3.457 (1.76), 3.465 (1.66), 3.469 (1.56), 3.482 (0.73), 3.545 (5.18), 3.813 (0.83), 3.824 (1.00),
3.841 (0.66), 3.901 (0.69), 3.915 (0.55), 3.936 (0.69), 3.948 (1.56), 3.963 (1.24), 4.118 (0.48),
4.190 (0.66), 5.073 (0.41), 5.085 (0.48), 5.095 (0.97), 5.107 (0.93), 6.511 (0.73), 6.528 (0.76), 6.870 (0.55), 6.879 (0.66), 6.898 (1.17), 6.918 (0.69), 6.942 (1.49), 6.963 (1.21), 7.081 (1.00),
7.100 (2.28), 7.119 (2.14), 7.137 (2.49), 7.158 (1.04), 7.217 (0.76), 7.221 (0.79), 7.239 (0.90),
7.256 (0.48), 7.316 (0.59), 7.416 (1.80), 7.423 (1.49), 7.432 (2.07), 7.450 (0.55).
Example 117
(2R)-1-{7-[2-(cyclopropylmethoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (Stereoisomer 2)
Figure imgf000525_0001
Using the method described for Example 63: intermediate 209 (85.0 mg, 160 pmol) gave titled compound (68 mg, 44%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.186 (0.89), 0.210 (1.59), 0.219 (1.59), 0.241 (1.11), 0.319 (2.74), 0.331 (2.56), 0.346 (2.48), 0.375 (0.85), 0.523 (1.70), 0.527 (1.56), 0.544 (1.78),
0.547 (1.67), 0.578 (4.96), 0.592 (2.11), 0.599 (5.30), 1.029 (0.93), 1.041 (1.15), 1.063 (2.11),
1.076 (2.00), 1.096 (2.04), 1.109 (1.93), 1.144 (0.85), 1.186 (1.19), 1.217 (3.52), 1.233 (3.44),
1.246 (3.07), 1.344 (2.07), 1.374 (2.07), 1.822 (0.48), 1.858 (0.44), 1.912 (0.59), 1.947 (0.67),
2.107 (1.52), 2.140 (1.52), 2.209 (0.78), 2.254 (0.63), 2.322 (2.33), 2.326 (3.26), 2.331 (2.63), 2.357 (1.41 ), 2.399 (0.44), 2.428 (0.74), 2.518(11.15), 2.523 (7.30), 2.539 (1.59), 2.589 (1.67),
2.620 (1.33), 2.664 (1.93), 2.669 (2.52), 2.673 (1.96), 2.697 (2.56), 2.725 (1.85), 2.747 (1.48),
2.777 (2.44), 2.808 (1.78), 2.827 (1.48), 2.859 (1.93), 2.888 (1.07), 2.953 (0.56), 2.984 (1.41),
3.024 (1.74), 3.055 (1.19), 3.082 (1.74), 3.091 (1.74), 3.122 (5.37), 3.171 (0.85), 3.188 (1.04),
3.250 (0.85), 3.440 (1.33), 3.473 (1.19), 3.547 (16.00), 3.733 (2.04), 3.751 (2.19), 3.758 (3.37),
3.776 (3.07), 3.813 (1.30), 3.831 (3.70), 3.848 (2.78), 3.856 (2.41), 3.873 (1.59), 4.087 (0.56), 4.131 (1.44), 4.165 (1.22), 6.525 (1.93), 6.541 (2.11), 6.837 (0.78), 6.856 (1.74), 6.862 (1.89),
6.881 (3.37), 6.887 (2.11), 6.907 (4.26), 6.925 (3.67), 7.079 (2.56), 7.097 (7.04), 7.108 (7.67),
7.125 (7.11), 7.146 (2.85), 7.174 (0.89), 7.199 (2.22), 7.203 (2.04), 7.221 (2.78), 7.238 (1.48),
7.312 (1.52), 7.322 (1.96), 7.331 (1.89), 7.404 (2.15), 7.408 (1.48), 7.422 (4.63), 7.426 (6.74),
7.433 (4.81), 7.440 (3.89), 7.443 (3.48), 8.089 (0.41).
Example 118
(2R)-1-{7-[2-(cyclopropyloxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1-one (Stereoisomer 1)
Figure imgf000526_0001
Using the method described for Example 63: intermediate 211 (31 mg, 60.0 pmol) gave titled compound (8.5 mg, 27%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.034 (0.40), -0.011 (0.71), 0.000(0.71), 0.021 (0.42), 0.065 (0.52), 0.077 (0.47), 0.084 (0.61), 0.089 (0.71), 0.096 (0.68), 0.437 (0.85), 0.445 (1.06), 0.452 (1.13), 0.471 (0.66), 0.479 (0.78), 0.621 (0.42), 0.631 (0.78), 0.647 (1.46), 0.652 (1.72), 0.658 (1.58), 0.662 (1.51), 0.668 (1.68), 0.673 (1.39), 0.688 (0.66), 0.771 (0.83), 0.785 (0.83), 0.952 (0.42), 0.995 (0.52), 1.029 (0.50), 1.063 (0.73), 1.092(16.00), 1.119(0.50), 1.129 (0.50), 1.217 (0.92), 1.245 (0.50), 1.916 (0.73), 1.947 (0.68), 2.067 (0.83), 2.100 (0.83), 2.317 (1.77), 2.322 (1.30), 2.345 (0.94), 2.353 (0.83), 2.504 (6.58), 2.508 (4.41), 2.659 (1.27), 2.664 (0.78), 2.705 (1.98), 2.740 (1.01), 2.773 (0.66), 2.813 (0.78), 2.821 (0.73), 2.844 (1.16), 2.851 (1.04), 2.893 (0.40), 2.922 (1.09), 2.952 (1.23), 2.983 (0.85), 3.018 (1.04), 3.052 (0.59), 3.196 (1.79), 3.372 (0.92), 3.491 (0.80), 3.495 (0.80), 3.503 (1.06), 3.517 (9.30), 3.532 (1.04), 4.177 (0.59), 4.257 (0.66), 4.289 (0.61), 5.744 (0.47), 6.869 (0.50), 6.921 (0.80), 6.937 (2.76), 6.957 (4.04), 6.976 (2.57), 6.980 (2.29), 6.984 (2.01), 6.999 (1.01), 7.003 (0.90), 7.028 (2.88), 7.047 (1.86), 7.153 (0.45), 7.211 (1.49), 7.229 (2.24), 7.231 (2.15), 7.265 (1.13), 7.269 (1.11), 7.282 (1.23), 7.286 (1.53), 7.290 (1.56), 7.293 (1.53), 7.296 (1.18), 7.303 (1.35), 7.308 (2.12), 7.312 (2.62), 7.326 (0.99), 7.329 (1.09), 7.406 (1.70), 7.413 1.42), 7.423 (0.94). Example 119
(2R)-3,3,3-trifluoro-2-methoxy-1-{7-[2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan- 3-yl}-2-phenylpropan-1-one (Stereoisomer 2)
Figure imgf000527_0001
Using the method described for Example 63: intermediate 221 (40 mg, 60.0 pmol) gave titled compound (10.2 mg 25%) after purification by preparative FIPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.214 (0.44), 0.224 (0.44), 1.014 (0.60), 1.026 (0.68), 1.049 (0.53), 1.061 (0.54), 1.107 (0.43), 1.116 (0.44), 1.224 (0.87), 1.260 (0.79), 1.269 (0.84),
1.304 (0.46), 1.916 (0.74), 1.931 (0.97), 1.946 (0.90), 1.958 (1.30), 1.973 (1.66), 1.989 (1.15), 2.107 (0.57), 2.142 (0.53), 2.322 (0.58), 2.327 (0.47), 2.345 (0.54), 2.352 (0.53), 2.518 (0.75),
2.523 (0.63), 2.590 (0.53), 2.699 (0.87), 2.724 (0.74), 2.741 (0.64), 2.772 (0.91), 2.803 (0.56),
2.811 (0.54), 2.845 (0.65), 2.850 (0.66), 2.985 (0.56), 3.021 (0.77), 3.031 (0.81), 3.040 (0.79),
3.060 (0.74), 3.069 (0.55), 3.122 (1.95), 3.212 (7.11), 3.221 (1.04), 3.271 (16.00), 3.287 (0.49), 3.303 (0.61), 3.319 (0.57), 3.442 (1.07), 3.457 (1.69), 3.473 (0.86), 3.480 (0.60), 3.495 (0.52), 3.504 (1.13), 3.507 (1.12), 3.519 (2.01), 3.523 (2.01), 3.932 (0.68), 3.939 (0.75), 3.948 (0.65),
3.955 (1.16), 3.963 (0.63), 3.971 (0.71), 3.987 (0.49), 3.997 (0.55), 4.013 (1.03), 4.021 (0.43),
4.029 (0.55), 4.037 (0.60), 4.128 (0.53), 4.160 (0.48), 6.519 (0.81), 6.535 (0.88), 6.538 (0.86),
6.867 (0.59), 6.875 (0.69), 6.886 (0.49), 6.893 (1.20), 6.912 (0.63), 6.925 (0.50), 6.946 (1.58),
6.967 (1.30), 7.084 (1.04), 7.103 (2.58), 7.120 (2.47), 7.138 (2.73), 7.158 (1.28), 7.217 (0.59),
7.221 (0.63), 7.238 (1.01), 7.256 (0.50), 7.259 (0.50), 7.299 (0.45), 7.306 (0.53), 7.314 (0.64),
7.322 (0.62), 7.414 (2.29), 7.418 (1.44), 7.422 (1.52), 7.431 (2.25), 7.447 (0.41), 7.450 (0.60).
Example 120
(2R)-1-[7-(2-ethoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1-one (mixture of stereoisomers)
Figure imgf000528_0001
Using the method described for Example 63: intermediate 223 (20 mg, 99 pmol) gave titled compound (15.4 mg 30%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO -d6) d [ppm]: 0.023 (0.61), 0.034 (0.61), 0.523 (0.63), 0.553 (0.56), 0.977 (0.42), 1.008 (0.80), 1.013 (1.53), 1.031 (2.65), 1.036 (0.85), 1.048 (1.50), 1.068 (3.99), 1.085 (16.00) , 1.103 (3.92) , 1.187 (0.61) , 1.211 (0.80) 1.267 (0.82), 1.284(1.10), 1.305 (1.41), 1.312 (1.48), 1.323 (2.73), 1.329 (3.01), 1.340 (1.34), 1.346 (1.36), 1.736 (1.01), 1.752 (0.40), 1.871 (0.82), 1.905 (0.75), 2.023 (0.63), 2.077 (0.89), 2.110 (0.85), 2.296 (0.73), 2.301 (1.25), 2.305 (1.69), 2.310 (1.29), 2.314 (0.78), 2.327 (1.15), 2.353 (1.01), 2.496 (5.66), 2.501 (4.04), 2.517 (0.59), 2.563 (0.47), 2.643 (1.46), 2.647 (1.74), 2.652 (1.32), 2.657 (0.78), 2.671 (1.08), 2.703 (1.81), 2.743 (1.22), 2.775 (0.68), 2.823 (0.49), 2.885 (0.56), 2.919 (1.83), 2.924 (1.62), 2.952 (0.99), 2.984 (0.63), 2.991 (0.73), 3.025 (1.17), 3.054 (0.70), 3.107 (0.70), 3.173 (1.62), 3.390 (0.63), 3.412 (0.47), 3.518 (7.87), 3.571 (0.49), 3.577 (0.85), 3.588 (0.92), 3.594 (0.70), 3.606 (0.82), 3.612 (0.94), 3.629 (0.87), 3.832 (0.87), 3.850 (0.96), 3.856 (0.85), 3.873 (0.75), 3.942 (0.47), 3.956 (1.13), 3.966 (0.82), 3.973 (1.15), 3.983 (0.87), 3.990 (0.66), 4.227 (0.54), 4.262 (0.54), 6.830 (0.49), 6.844 (0.40), 6.862 (0.63), 6.870 (0.82), 6.878 (0.78), 6.888 (1.81), 6.895 (0.80), 6.907 (1.43), 6.917 (1.67), 6.929 (1.39), 6.938 (2.14), 6.946 (2.61), 6.965 (1.86), 6.978 (1.39), 6.981 (1.43), 6.997 (1.01), 7.000 (0.96), 7.025 (2.35), 7.044 (1.62), 7.080 (1.36), 7.094 (1.27), 7.112 (1.39), 7.132 (0.66), 7.211 (1.17), 7.215 (1.10), 7.233 (1.34), 7.250 (0.66), 7.254 (0.61), 7.300 (1.60), 7.318 (2.23), 7.337 (0.82), 7.387 (0.49), 7.391 (0.49), 7.401 (2.28), 7.407 (2.00), 7.417 (1.20), 7.423 (0.59). Example 121 and Example 122
(2R)-3,3,3-trifluoro-2-methoxy-1 -{(7R)-7-[2-(1 -methyl-1 H-pyrazol-4-yl)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one
(2R)-3,3,3-trifluoro-2-methoxy-1 -{(7S)-7-[2-(1 -methyl-1 H-pyrazol-4-yl)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one
Example 121
(2R)-3,3,3-trifluoro-2-methoxy-1 -{7-[2-(1 -methyl-1 H-pyrazol-4-yl)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one (Stereoisomer 1 )
Figure imgf000529_0001
Using the method described for Example 63: intermediate 227 (133 mg, 246 pmol) gave titled compound (18 mg 13%) after purification by NH Biotage chromatography and preparative HPLC (Method 6).
Optical rotation (method OR1 ): -47.6°(methanol).
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.123 (0.56), -0.11 1 (0.56), -0.084 (1 .18), -0.008 (1 .67), 0.008 (1 .74), 0.761 (0.49), 0.781 (0.47), 0.796 (0.53), 1 .144 (0.54), 1 .168 (0.67), 1 .177
(0.67), 1.897 (0.58), 1 .930 (0.53), 2.005 (0.81 ), 2.039 (0.83), 2.151 (0.77), 2.320 (0.54), 2.325
(0.90), 2.329 (1 .19), 2.334 (0.93), 2.338 (0.53), 2.458 (0.40), 2.520 (3.67), 2.525 (2.67), 2.542
(0.58), 2.552 (0.86), 2.560 (0.95), 2.582 (0.86), 2.590 (0.84), 2.631 (0.46), 2.662 (0.54), 2.667
(1 .02), 2.671 (1 .48), 2.676 (1 .53), 2.681 (1 .60), 2.688 (1.67), 2.701 (1 .63), 2.726 (1.21 ), 2.756
(0.61 ), 2.882 (1 .09), 2.892 (1 .37), 2.909 (1 .83), 2.916 (1.67), 2.960 (1 .19), 2.990 (1.07), 3.019
(0.40), 3.255 (0.67), 3.283 (2.09), 3.31 1 (1 .35), 3.510 (8.1 1 ), 3.607 (2.16), 3.636 (0.63), 3.718
(0.90), 3.813 (16.00), 3.827 (1 .30), 3.879 (4.39), 4.223 (0.65), 4.257 (0.51 ), 6.855 (0.63), 7.013 (1 .18), 7.032 (2.63), 7.049 (7.03), 7.059 (3.42), 7.078 (1.48), 7.165 (1 .37), 7.175 (2.63), 7.179
(2.25), 7.186 (2.02), 7.190 (1 .76), 7.197 (2.32), 7.215 (0.44), 7.279 (0.68), 7.286 (0.98), 7.301
(2.58), 7.304 (2.55), 7.31 1 (3.39), 7.317 (2.42), 7.322 (3.00), 7.361 (3.88), 7.373 (0.70), 7.403
(1 .41 ), 7.407 (1 .19), 7.415 (2.35), 7.420 (2.34), 7.431 (1.19), 7.437 (0.95), 7.463 (1.25), 7.795
(1 .1 1 ). Example 122
(2R)-3,3,3-trifluoro-2-methoxy-1 -{7-[2-(1 -methyl-1 H-pyrazol-4-yl)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one (Stereoisomer 2)
Figure imgf000530_0001
Using the method described for Example 63: intermediate 228 (140 mg, 259 pmol) gave titled compound (9 mg 6%) after purification by NH Biotage chromatography and preparative HPLC (Method 6).
Optical rotation (method OR1 ): +33.5°(methanol).
1 H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.008 (1 .53), 0.008 (1.46), 0.317 (0.51 ), 0.327 (0.51 ), 0.645 (0.46), 0.678 (0.60), 0.836 (0.65), 0.846 (0.76), 0.869 (0.92), 0.880 (1 .09), 0.912 (0.53),
1 .234 (0.83), 1 .244 (0.86), 1 .276 (0.72), 2.01 1 (0.69), 2.045 (0.67), 2.320 (0.69), 2.325 (1 .18),
2.329 (1 .55), 2.334 (1 .09), 2.338 (0.53), 2.521 (4.55), 2.525 (3.47), 2.558 (0.95), 2.567 (0.76),
2.584 (0.69), 2.612 (0.49), 2.662 (1.29), 2.667 (1 .80), 2.671 (2.15), 2.676 (1 .66), 2.680 (1 .02),
2.694 (0.99), 2.728 (0.86), 2.735 (0.92), 2.768 (0.97), 2.798 (1.13), 2.828 (0.65), 2.949 (0.42), 2.980 (0.76), 2.997 (0.44), 3.016 (0.55), 3.026 (0.51 ), 3.087 (0.72), 3.095 (0.81 ), 3.1 15 (0.69),
3.123 (0.60), 3.160 (2.52), 3.414 (0.58), 3.449 (0.55), 3.531 (6.50), 3.859 (6.73), 3.879 (0.72),
3.893 (16.00), 3.982 (0.55), 4.014 (0.49), 6.669 (0.88), 6.688 (0.95), 7.134 (1 .78), 7.153 (2.59),
7.175 (1 .83), 7.181 (2.13), 7.194 (1.76), 7.198 (2.17), 7.207 (1.09), 7.222 (1 .64), 7.226 (1 .73),
7.232 (2.43), 7.240 (1 .62), 7.251 (3.33), 7.253 (3.38), 7.272 (2.66), 7.276 (1 .69), 7.294 (1 .09), 7.302 (0.88), 7.31 1 (0.88), 7.351 (0.49), 7.369 (0.39), 7.403 (1.97), 7.410 (1 .71 ), 7.419 (1 .60),
7.422 (2.20), 7.424 (2.20), 7.442 (4.02), 7.496 (1 .02), 7.514 (1.64), 7.533 (0.72), 7.774 (5.1 1 ). Example 123
(2R)-1-{(7-[2-(benzyloxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1-one (Stereoisomer 1)
Figure imgf000531_0001
Using the method described for Example 63: intermediate 230 (2.36 g, 4.2 mmol) gave titled compound (2.32 g 96%) after work up.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.215 (0.63), 0.237 (1.07), 0.248 (1.07), 0.271 (0.67), 0.979 (0.76), 1.018 (1.43), 1.026 (1.34), 1.042 (1.03), 1.058 (1.74), 1.082 (1.88), 1.093 (1.92),
1.116 (1.07), 1.127 (0.94), 1.200 (0.80), 1.231 (2.99), 1.246 (2.64), 1.276 (1.65), 1.823 (0.54),
1.855 (0.54), 1.892 (0.80), 1.926 (0.89), 2.081 (1.88), 2.115 (1.74), 2.318 (2.15), 2.322 (3.13),
2.326 (4.11), 2.331 (2.73), 2.336 (1.83), 2.347 (1.88), 2.357 (1.56), 2.370 (1.12), 2.402 (0.54),
2.518 (10.50), 2.522 (7.37), 2.544 (1.43), 2.577 (1.52), 2.607 (1.07), 2.664 (3.44), 2.668 (4.56), 2.673 (3.93), 2.678 (2.77), 2.694 (2.59), 2.739 (1.88), 2.769 (2.86), 2.789 (1.34), 2.799 (1.65),
2.817 (1.83), 2.851 (0.98), 2.927 (0.63), 2.945 (0.85), 2.976 (1.79), 3.013 (2.06), 3.042 (6.21),
3.087 (1.65), 3.096 (1.79), 3.117 (1.52), 3.126 (1.39), 3.159 (2.41), 3.171 (2.64), 3.180 (1.70),
3.207 (1.07), 3.450 (1.30), 3.485 (1.16), 3.544 (15.28), 4.087 (0.67), 4.116 (1.83), 4.149 (1.12), 4.655 (0.58), 4.684 (0.67), 4.879 (0.72), 4.907 (0.58), 5.038 (2.37), 5.068 (4.83), 5.104 (5.85), 5.118 (5.05), 5.148 (2.41), 5.758 (16.00), 6.560 (2.10), 6.577 (2.28), 6.867 (0.80), 6.885 (1.70), 6.906 (2.01), 6.927 (3.22), 6.944 (1.70), 6.970 (1.07), 6.989 (1.43), 7.007 (0.76), 7.023 (1.39),
7.042 (2.06), 7.062 (1.21), 7.077 (3.71), 7.096 (5.59), 7.110 (7.96), 7.118 (8.67), 7.136 (6.70),
7.149 (2.50), 7.157 (2.64), 7.164 (1.12), 7.193 (1.12), 7.209 (1.39), 7.213 (1.16), 7.225 (1.07),
7.243 (2.50), 7.247 (2.55), 7.265 (2.73), 7.282 (1.52), 7.286 (1.56), 7.293 (0.80), 7.297 (0.76),
7.317 (2.77), 7.322 (2.68), 7.329 (3.66), 7.334 (4.16), 7.341 (3.71), 7.347 (5.18), 7.352 (3.49),
7.367 (4.34), 7.386 (3.80), 7.403 (2.59), 7.407 (2.46), 7.413 (4.83), 7.418 (5.50), 7.422 (6.66),
7.431 (14.17), 7.441 (5.94), 7.449 (7.11), 7.457 (2.06), 7.474 (7.78), 7.491 (3.80), 8.547 (0.80). Example 124
(2R)-1-{7-[2-(benzyloxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1-one (Stereoisomer 2)
Figure imgf000532_0001
Using the method described for Example 63: intermediate 231 (1.57 g, 2.77 mmol) gave titled compound (646 g 40%) after purification by preparative HPLC (Method 6) and a further preparative HPLC (Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IC 5m 250x30mm; eluent A: C02; eluent B: methanol + 0.2 vol % aqueous ammonia (32%); isocratic: 25%B; flow: 100 ml/min; temperature: 40Ό; BPR: 150bar; UV: 220 nm).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.000 (0.60), 0.012 (0.76), 0.034 (1.36), 0.045 (1.36),
0.068 (0.85), 0.080 (0.67), 0.383 (1.57), 0.415 (1.29), 0.856 (0.95), 1.008 (0.41), 1.042 (0.88),
1.066 (1.29), 1.076 (1.31), 1.101 (0.85), 1.179 (0.90), 1.211 (0.60), 1.262 (0.60), 1.818 (0.44),
1.866 (1.43), 1.902 (1.29), 2.020 (4.13), 2.030 (2.56), 2.055 (1.38), 2.269 (1.31), 2.274 (1.84),
2.278 (1.71 ), 2.291 (1.66), 2.318 (1.73), 2.464 (6.20), 2.469 (4.31 ), 2.486 (10.31 ), 2.536 (0.46), 2.611 (2.07), 2.615 (2.95), 2.620 (2.90), 2.644 (3.07), 2.686 (1.87), 2.720 (1.01), 2.781 (0.46),
2.845 (1.08), 2.879 (2.88), 2.899 (1.87), 2.928 (2.58), 2.958 (2.28), 2.992 (1.11), 3.128 (3.41),
3.170 (0.53), 3.352 (1.43), 3.484 (16.00), 4.215 (1.31 ), 4.247 (1.24), 4.604 (3.07), 4.632 (3.90), 4.826 (4.08), 4.855 (3.27), 4.979 (0.55), 5.009 (1.34), 5.044 (1.36), 5.073 (0.58), 5.705 (1.54),
6.825 (0.51), 6.843 (0.90), 6.859 (0.58), 6.901 (1.71), 6.917 (5.53), 6.936 (7.84), 6.955 (4.01), 6.983 (3.34), 7.009 (6.06), 7.028 (3.60), 7.078 (3.18), 7.097 (4.06), 7.112 (1.08), 7.140 (5.79),
7.156 (6.87), 7.160 (5.53), 7.241 (2.42), 7.244 (2.81), 7.263 (7.26), 7.276 (4.24), 7.280 (6.34),
7.284 (4.66), 7.290 (2.65), 7.296 (7.61), 7.310 (4.61), 7.314 (7.31), 7.331 (2.74), 7.335 (1.89),
7.346 (2.67), 7.349 (2.74), 7.365 (6.76), 7.383 (3.80), 7.387 (2.72), 7.417 (2.03), 7.434 (1.11). Example 125
(2R)-3,3,3-trifluoro-1-[7-(2-hydroxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1-one, salt with hydrochloric acid (Stereoisomer 1)
Figure imgf000533_0001
To a solution of Example 124 (50 mg, 90.5 pmol) in methanol (10 ml) was added a few drops of 3M HCI (aq). The reaction was flushed with hydrogen. The reaction under a positive hydrogen pressure was stirred at RT for 1h. The reaction was filtered and the filtrate was concentrated under reduced pressure and gave the titled compound (45 mg, 95%) which was used without further purification.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.171 (0.59), 0.195 (0.98), 0.204 (0.98), 0.228 (0.59), 1.070 (0.59), 1.093 (1.14), 1.104 (1.37), 1.128 (0.91), 1.139 (1.04), 1.154 (1.31), 1.172 (1.96),
1.189 (1.18), 1.231 (0.75), 1.294 (1.70), 1.335 (2.25), 1.373 (1.53), 1.417 (0.82), 1.447 (1.08),
1.482 (0.62), 1.907 (0.91), 1.987 (3.20), 2.029 (0.56), 2.061 (0.42), 2.213 (0.52), 2.248 (0.46),
2.323 (1.67), 2.327 (2.45), 2.331 (2.12), 2.336 (1.63), 2.347 (1.63), 2.383 (1.37), 2.518 (8.03),
2.523 (5.16), 2.540 (0.82), 2.660 (0.72), 2.665 (1.40), 2.669 (1.89), 2.673 (1.37), 2.711 (0.46),
2.744 (0.88), 2.767 (1.96), 2.799 (2.81), 2.831 (1.14), 2.889 (0.85), 2.920 (1.21), 2.946 (0.98),
3.037 (4.67), 3.056 (2.16), 3.106 (1.70), 3.134 (1.80), 3.164 (16.00), 3.194 (1.11), 3.221 (1.37), 3.449 (3.07), 3.492 (1.76), 3.558 (14.82), 4.016 (0.75), 4.034 (0.78), 4.198 (1.11), 4.231 (1.47), 6.452 (1.86), 6.470 (2.09), 6.763 (0.59), 6.781 (1.14), 6.801 (1.86), 6.820 (2.61), 6.839 (1.63),
6.860 (1.11), 6.882 (1.63), 6.889 (2.81), 6.910 (3.13), 6.942 (1.14), 6.961 (0.82), 6.989 (0.95),
7.006 (0.78), 7.031 (0.72), 7.051 (1.08), 7.074 (1.73), 7.084 (3.10), 7.103 (5.88), 7.127 (5.22),
7.146 (6.47), 7.164 (3.62), 7.181 (2.91), 7.202 (1.93), 7.250 (0.49), 7.268 (0.46), 7.309 (1.44),
7.324 (1.70), 7.421 (4.02), 7.423 (3.89), 7.429 (3.79), 7.437 (4.83), 7.441 (4.57), 7.460 (1.63),
8.618 (0.85), 8.886 (0.82), 9.301 (0.78), 9.618 (5.26), 9.660 (1.80), 10.003 (0.42). Example 126
(2R)-3,3,3-trifluoro-1-[7-(2-hydroxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1-one (Stereoisomer 1)
Figure imgf000534_0001
Example 125 (45 mg, 86 pmol) was dissolved in sat. NaHC03 (aq) and extracted with EtOAc. The combined organics were washed with sat. NaHC03 (aq) and filtered through an hydrophobic filter and concentrated under reduced pressure. The titled compound (32 mg, 81%) was obtained.
1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.222 (0.41), -0.188 (0.54), 0.000 (0.44), 0.022 (0.54), 0.031 (0.56), 1.011 (0.51), 1.023 (0.51), 1.056 (0.73), 1.098 (4.80), 1.116 (9.54), 1.134 (5.07),
1.150 (1.49), 1.175 (2.46), 1.254 (0.98), 1.287 (1.07), 1.346 (0.61), 1.370 (0.46), 1.541 (0.44),
1.748 (0.66), 1.783 (0.59), 1.823 (0.39), 1.931 (16.00), 2.017 (0.44), 2.051 (0.41), 2.084 (0.41),
2.137 (0.54), 2.170 (0.54), 2.196 (1.17), 2.267 (1.12), 2.271 (1.54), 2.275 (1.15), 2.280 (0.63),
2.337 (0.44), 2.462 (6.34), 2.467 (4.00), 2.531 (0.46), 2.560 (0.49), 2.608 (1.88), 2.613 (2.20),
2.617 (1.54), 2.699 (1.41), 2.717 (2.02), 2.747 (2.76), 2.816 (0.78), 2.848 (1.22), 2.882 (0.71),
2.962 (0.80), 2.985 (0.95), 2.994 (0.95), 3.035 (1.59), 3.071 (0.85), 3.082 (0.90), 3.115 (0.63),
3.139 (0.68), 3.398 (0.68), 3.439 (0.59), 3.491 (3.46), 3.509 (6.61), 3.545 (0.93), 3.590 (0.73),
3.637 (3.71), 3.943 (1.34), 3.961 (3.59), 3.979 (3.68), 3.997 (1.44), 4.082 (0.46), 4.116 (0.41),
4.151 (0.61), 4.187 (0.59), 5.702 (3.80), 6.337 (1.12), 6.353 (2.49), 6.367 (0.49), 6.380 (0.51),
6.401 (0.56), 6.435 (1.37), 6.455 (1.66), 6.480 (1.05), 6.499 (0.76), 6.544 (1.02), 6.547 (1.07),
6.564 (1.15), 6.678 (0.49), 6.695 (0.68), 6.714 (0.49), 6.740 (0.41), 6.750 (0.78), 6.771 (0.85),
6.800 (0.73), 6.806 (0.76), 6.816 (0.76), 6.821 (1.00), 6.826 (0.63), 6.835 (0.63), 6.842 (0.61),
6.907 (1.17), 6.925 (1.41), 6.945 (1.20), 6.966 (1.02), 6.988 (0.44), 7.011 (0.51), 7.029 (1.22),
7.049 (1.71), 7.071 (1.17), 7.090 (1.41), 7.110 (0.56), 7.269 (0.44), 7.327 (0.66), 7.343 (1.07),
7.368 (3.37), 7.387 (3.54), 7.394 (4.07), 7.399 (3.34), 7.408 (1.61), 7.413 (1.46), 7.422 (1.02),
7.430 (1.32), 7.444 (2.90), 7.463 (3.66), 7.477 (0.98), 9.200 (0.56). Syntheses of Examples 127 to Example 170
The first step was alkylation of the phenol under basic conditions , as shown in the Scheme and General Method below:
Figure imgf000535_0001
General Method: To a solution of Intermediate 223 (50-100 mg) in DMF (1 -2 ml) was added cesium carbonate (2eq) and alkylating agent (1 eq).
For purification: either concentrated under reduced pressure and purified by silica chromatography (Hexane:EtOAc or DCM:EtOH) or the reaction was filtered and purified by preparative HPLC (Method 6) to give the titled compounds.
The second step was the removal of the Boc protecting group under acidic conditions , as shown in the Scheme and General Method below:
Figure imgf000535_0002
General Method: To a solution of the Boc protected intermediate in dioxane was added 4M hydrochloric acid in dioxane (10 eq) and stirrer at RT. After the reaction was complete, the reaction was concentrated under reduced pressure to give the HCI salt.
Alternatively, for the oxetane containing Examples 141 - 147, the Boc protected intermediate was absorbed on silica and heated at 80 - 120Ό und er vacuum. The titled compounds were eluted from the silica (DCM:EtOH).
For purification: either concentrated under reduced pressure to give directly HCI salt or purified by preparative HPLC (Method 6) to give the titled compounds. Table 9:
Figure imgf000536_0001
Figure imgf000537_0001
Figure imgf000538_0001
Figure imgf000539_0001
Figure imgf000540_0001
Figure imgf000541_0001
Figure imgf000542_0001
Figure imgf000543_0001
Figure imgf000544_0001
Figure imgf000545_0001
Figure imgf000546_0001
Figure imgf000547_0001
Figure imgf000548_0001
Figure imgf000549_0001
Figure imgf000550_0001
Figure imgf000551_0001
Figure imgf000552_0002
Example 171
2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxy-1-[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1-one (mixture of stereoisomers)
Figure imgf000552_0001
Using the method described for Example 63: intermediate 234 (140 mg, 291 pmol) gave titled compound (18 mg, 13%) after work up an purification by preparative HPLC (Method 6).
LC-MS (Method 4): Rt = 1.34 min; MS (ESIpos): m/z = 467[M+H]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.851 (0.40), 1.023 (1.58), 1.057 (2.90), 1.094 (1.83), 1.137 (2.93), 1.167 (2.34), 1.176 (2.15), 1.233 (4.19), 1.257 (3.60), 1.297 (1.99), 1.328 (1.83),
1.347 (1.91), 1.368 (1.72), 1.398 (0.94), 2.001 (4.05), 2.044 (5.91), 2.083 (0.48), 2.116 (1.18),
2.168 (1.15), 2.208 (7.33), 2.252 (8.35), 2.278 (4.91), 2.310 (4.05), 2.331 (4.11), 2.361 (1.42),
2.540 (2.98), 2.572 (1.83), 2.669 (1.72), 2.835 (5.53), 2.867 (7.70), 3.007 (6.60), 3.042 (4.59),
3.300 (3.03), 3.403 (3.11), 3.423 (3.11), 3.454 (1.77), 6.407 (3.28), 7.189 (10.17), 7.207 (13.15), 7.233 (2.12), 7.250 (6.47), 7.267 (6.50), 7.287 (12.13), 7.306 (12.16), 7.323 (4.13),
7.345 (1.66), 7.350 (1.61), 7.365 (5.21), 7.370 (5.07), 7.384 (11.95), 7.388 (16.00), 7.403 (2.47), 7.408 (2.71), 7.464 (6.17), 7.482 (4.43), 7.562 (9.93), 7.605 (6.71). Example 172
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxy-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (single stereoisomer)
Figure imgf000553_0001
Using the method described for Example 63: intermediate 236 (270 mg, 524 pmol) gave titled compound (6.5 mg, 2%) after work up an purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .063 (1 .38), 1 .095 (1 .69), 1 .139 (1 .00), 1 .167 (4.52), 1 .196 (1 .07), 1 .238 (2.51 ), 1 .268 (1.57), 1 .329 (1 .00), 1.352 (1.57), 1 .379 (0.75), 2.001 (2.64),
2.045 (3.64), 2.221 (4.58), 2.241 (1.13), 2.264 (5.21 ), 2.293 (3.70), 2.308 (3.70), 2.318 (4.08), 2.322 (4.02), 2.327 (4.45), 2.332 (3.26), 2.456 (1 .13), 2.461 (1 .51 ), 2.465 (1 .57), 2.518 (16.00),
2.523 (1 1.23), 2.546 (0.56), 2.665 (2.70), 2.669 (3.95), 2.673 (2.95), 2.780 (2.89), 2.815 (3.45), 2.835 (1 .69), 2.854 (2.38), 2.868 (1.82), 3.040 (3.64), 3.076 (2.76), 3.289 (1 .32), 3.412 (1 .69),
3.431 (1 .63), 3.463 (1 .00), 6.548 (0.94), 6.578 (0.63), 6.654 (7.34), 7.188 (5.77), 7.204 (7.47),
7.209 (6.27), 7.236 (1 .25), 7.254 (4.96), 7.271 (4.20), 7.288 (7.72), 7.306 (7.09), 7.322 (2.45), 7.447 (0.44), 7.489 (0.56), 7.532 (12.1 1 ), 7.537 (13.55), 7.589 (6.40), 7.594 (10.29), 7.599
(6.09), 7.606 (4.58).
Example 173
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxy-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (single stereoisomer)
Figure imgf000553_0002
Using the method described for Example 63: intermediate 237 (280 mg, 543 pmol) gave titled compound (6.8 mg, 2%) after work up an purification by preparative HPLC (Method 6). 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.903 (0.43), 1.068 (1.73), 1.099 (2.04), 1.148 (0.98), 1.167(13.88), 1.198(1.69), 1.209(1.49), 1.232 (3.14), 1.268 (2.94), 1.309(1.22), 1.330 (1.65), 1.340 (1.65), 1.361 (1.02), 1.751 (0.63), 1.993 (3.18), 2.036 (4.20), 2.214 (1.29), 2.238 (7.22),
2.281 (4.98), 2.318 (2.90), 2.322 (2.75), 2.327 (2.90), 2.332 (2.27), 2.347 (2.20), 2.357 (2.31), 2.387 (1.61 ), 2.430 (2.20), 2.461 (1.92), 2.518 (10.00), 2.523 (6.67), 2.539 (0.90), 2.665 (1.92),
2.669 (2.63), 2.673 (1.92), 2.779 (3.53), 2.815 (4.16), 2.843 (1.92), 2.863 (2.78), 2.876 (2.31),
2.967 (0.59), 3.003 (0.43), 3.046 (4.35), 3.082 (3.33), 3.274 (1.25), 3.282 (1.33), 3.289 (1.41),
3.301 (2.08), 3.306 (2.24), 3.418 (1.84), 3.438 (1.84), 3.445 (1.53), 3.467 (1.22), 5.399 (0.59),
6.563 (1.22), 6.578 (2.04), 6.646 (6.75), 7.058 (0.55), 7.119 (0.47), 7.191 (7.22), 7.208 (9.37), 7.211 (7.69), 7.231 (1.84), 7.235 (1.76), 7.242 (1.57), 7.250 (6.12), 7.256 (2.59), 7.264 (3.76),
7.267 (4.94), 7.287 (8.59), 7.306 (8.39), 7.322 (2.90), 7.484 (1.88), 7.489 (1.88), 7.525 (14.35), 7.529 (16.00), 7.558 (0.82), 7.563 (1.29), 7.568 (0.71), 7.580 (7.49), 7.585 (12.08), 7.589 (6.00), 7.603 (5.10), 7.658 (0.39).
Example 174
3,3,3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1-one (mixture of stereoisomers)
Figure imgf000554_0001
Using the method described for Example 63: intermediate 238 (1.39 g, 2.72 mmol) gave titled compound (10 mg, 1%) after work up an purification by preparative HPLC (Method 6). LC-MS (Method 4): Rt = 1.46 min; MS (ESIpos): m/z = 497 [M+H]+
Example 175
2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-1-[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (single stereoisomer)
Figure imgf000554_0002
Using the method described for Example 63: intermediate 240 (50.0 mg, 86.9 pmol) gave titled compound (9 mg) after work up an purification by preparative HPLC (Method 6). LC-MS (Method 2): Rt = 1 .61 min; MS (ESIpos): m/z = 561 [M+H]+
Example 176
2,2-difluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 - yl)ethan-1 -one
Figure imgf000555_0001
Using the method described for Example 63: intermediate 242 (60.0 mg, 129 pmol) gave titled compound (1 mg, 2 %) after work up an purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.867 (12.16), 0.882 (13.13), 1 .083 (3.56), 1 .1 16 (5.10), 1.212 (3.50), 1 .243 (2.52), 1.267 (1 .72), 1 .277 (1.95), 1 .298 (2.47), 1 .307 (2.52), 1 .328
(1 .43), 1.353 (1 .38), 1 .745 (0.40), 1.983 (4.87), 2.026 (6.42), 2.059 (0.63), 2.195 (5.10), 2.252
(7.74), 2.296 (6.37), 2.322 (3.04), 2.327 (4.13), 2.331 (4.01 ), 2.362 (4.47), 2.390 (4.99), 2.418
(4.01 ), 2.432 (4.59), 2.518 (13.53), 2.523 (9.52), 2.536 (3.44), 2.564 (2.24), 2.645 (0.57), 2.665
(2.52), 2.669 (3.50), 2.673 (2.75), 2.888 (2.87), 2.902 (3.78), 2.910 (3.84), 2.923 (3.44), 3.077
(0.86), 3.1 17 (0.86), 3.152 (5.16), 3.191 (9.86), 3.229 (4.70), 3.242 (2.81 ), 3.255 (2.06), 3.261
(2.18), 3.273 (2.98), 3.279 (3.27), 3.287 (2.87), 3.400 (4.07), 3.425 (3.04), 3.454 (1.89), 3.742
(3.04), 6.965 (0.40), 7.087 (0.86), 7.108 (0.86), 7.134 (6.19), 7.157 (16.00), 7.179 (10.38), 7.219 (8.77), 7.233 (10.32), 7.240 (7.23), 7.255 (5.79), 7.396 (0.46), 7.426 (1 .09), 7.462 (2.81 ), 7.466 (3.15), 7.479 (5.10), 7.483 (6.65), 7.488 (3.56), 7.501 (5.96), 7.505 (9.00), 7.524 (12.27), 7.543 (12.50), 7.561 (3.96), 7.579 (2.41 ), 7.607 (8.95), 7.633 (8.32), 7.649 (5.73), 7.726 (1 .43), 7.743 (1 .15), 7.959 (0.92), 7.976 (7.00), 7.996 (6.31 ), 7.999 (6.02), 8.010 (1 .49), 8.030 (8.37), 8.051 (6.88), 8.074 (1.09), 8.101 (4.99), 8.122 (4.59), 8.180 (0.75), 8.199 (0.69).
Syntheses of Examples 177 to Example 178
The BOC protecting group was the removed under acidic conditions, as shown in the Scheme and General Method below:
Figure imgf000556_0001
General Method: To a solution of the Boc protected intermediate 249 or 250 in dioxane was added 4M hydrochloric acid in dioxane (10 eq) and stirred at RT. After the reaction was complete, the reaction was concentrated under reduced pressure to give the salt with hydrochloric acid.
For purification: either concentrated under reduced pressure to give directly HCI salt or purified by preparative HPLC (Method 6) to give the titled compounds.
Table 10:
Figure imgf000556_0002
Figure imgf000557_0002
Syntheses of Examples 179 to Example 182
The BOC protecting group was the removed under acidic conditions, as shown in the Scheme and General Method below:
Figure imgf000557_0001
General Method: To a solution of the Boc protected intermediate 256, 257, 258 or 259 in dioxane was added 4M hydrochloric acid in dioxane (10 eq) and stirred at RT. After the reaction was complete, the reaction was concentrated under reduced pressure to give the salt with hydrochloric acid.
For purification: either concentrated under reduced pressure to give directly HCI salt or purified by preparative HPLC (Method 6) to give the titled compounds.
Table 11 :
Figure imgf000558_0001
Figure imgf000559_0001
Figure imgf000560_0002
Example 183
2,2-difluoro-1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one (mixture of stereoisomers)
Figure imgf000560_0001
Using the method described for Example 63: Intermediate 285 (218 mg, 424 pmol) gave titled compound (10 mg, 5 % yield) after work up an purification by preparative HPLC (Method 6). LC-MS (Method 2): Rt = 1 .61 min; MS (ESIpos): m/z = 561 [M+H]+
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.945 (0.50), 0.960 (0.62), 0.977 (0.66), 0.988 (0.50), 1 .003 (0.43), 1 .246 (1 .05), 1 .272 (1.42), 1 .298 (1 .08), 1.414 (0.49), 1 .437 (0.68), 1.446 (0.70),
2.081 (1 .39), 2.124 (1.66), 2.306 (16.00), 2.322 (0.68), 2.326 (0.79), 2.332 (0.66), 2.336 (0.47), 2.364 (1 .42), 2.392 (3.10), 2.416 (0.83), 2.518 (3.24), 2.522 (2.28), 2.534 (2.46), 2.664 (0.46),
2.669 (0.64), 2.673 (0.45), 2.964 (1.79), 3.002 (3.63), 3.040 (1.60), 3.053 (0.61 ), 3.066 (0.74),
3.074 (0.76), 3.083 (0.68), 3.091 (0.71 ), 3.096 (0.82), 3.104 (0.71 ), 3.154 (1 .00), 3.167 (0.79), 3.180 (1 .22), 3.193 (0.95), 3.415 (0.93), 3.444 (1 .35), 3.472 (0.67), 6.962 (0.59), 6.970 (0.77),
6.984 (1 .26), 6.991 (1 .60), 7.005 (0.74), 7.012 (0.88), 7.036 (1.63), 7.043 (1 .42), 7.062 (1 .65),
7.069 (1 .36), 7.199 (1 .42), 7.214 (1.52), 7.221 (1 .33), 7.237 (1.18), 7.387 (1 .28), 7.397 (1 .50),
7.405 (2.93), 7.423 (2.45), 7.521 (2.18), 7.525 (2.54), 7.542 (1.79), 7.546 (1 .62), 7.586 (1 .54),
7.591 (1 .87), 7.604 (2.99), 7.625 (0.91 ), 7.629 (0.77).
Examples 184 to Example 214 were prepared in analogy to the Examples 179 to 182 General method: To a solution of the Boc protected intermediate 260 - 282 in dioxane was added 4M HCI in dioxane (10 eq) and stirred at RT. After the reaction was complete, the reaction was concentrated under reduced pressure to give the HCI salt.
For purification: either concentrated under reduced pressure to give directly HCI salt or purified by preparative HPLC (Method 6) to give the titled compounds.
Table 12:
Figure imgf000561_0001
Figure imgf000562_0001
Figure imgf000563_0001
Figure imgf000564_0001
Figure imgf000565_0001
Figure imgf000566_0001
Figure imgf000567_0001
Figure imgf000568_0001
Figure imgf000569_0001
Figure imgf000570_0001
Figure imgf000571_0001
Figure imgf000572_0001
Figure imgf000573_0001
Figure imgf000574_0001
Figure imgf000575_0001
Figure imgf000576_0001
Figure imgf000577_0001
Figure imgf000578_0001
Figure imgf000579_0001
Figure imgf000580_0001
Figure imgf000581_0001
Figure imgf000582_0002
Example 215
(2R)-2-(3-bromo-4-fluorophenyl)-3,3,3-trifluoro-2-(methoxymethyl)-1-[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1-one, salt with formic acid
Figure imgf000582_0001
Intermediate 289 (15 mg, 22 mihoI) was dissolved in formic acid (1 ml) and stirred at RT for 30min. Reaction concentrated under reduced pressure. The residue was diluted with water and freeze-dried overnight and gave the titled compound (15 mg).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.980 (0.94), 1.009 (0.94), 1.064 (1.52), 1.095 (0.87), 1.129 (1.01), 1.159 (1.67), 1.192 (1.16), 1.233 (0.87), 1.313 (0.58), 1.350 (1.23), 1.929 (1.01),
1.961 (0.94), 2.128 (1.30), 2.165 (1.01), 2.318 (1.45), 2.323 (3.19), 2.327 (4.56), 2.332 (3.26),
2.336 (1.52), 2.518 (15.71), 2.523 (10.64), 2.540 (0.87), 2.567 (1.01), 2.599 (1.45), 2.653 (11.00), 2.665 (4.92), 2.669 (5.79), 2.673 (4.34), 2.679 (2.46), 2.724 (1.59), 2.762 (1.09), 2.791 (1.30), 2.805 (1.59), 2.862 (2.82), 3.023 (0.65), 3.052 (0.58), 3.122 (1.01), 3.153 (1.81), 3.183 (1.67), 3.228 (3.11), 3.257 (3.04), 3.620 (1.01), 3.736 (12.38), 3.761 (3.40), 3.773 (3.69), 3.805
(1.38), 3.831 (1.38), 4.104 (1.95), 4.131 (1.74), 4.168 (0.65), 4.251 (0.72), 4.290 (1.01), 4.322
(0.87), 6.869 (1.01), 6.898 (2.03), 6.917 (3.76), 6.935 (2.53), 6.944 (2.10), 6.964 (2.32), 6.997
(1.23), 7.049 (1.81), 7.065 (1.45), 7.175 (2.03), 7.195 (1.95), 7.214 (1.01), 7.284 (0.58), 7.386
(1.16), 7.409 (2.10), 7.431 (1.45), 7.456 (1.38), 7.507 (0.58), 8.387 (16.00). Example 216
(2S)-2-(3-bromo-4-fluorophenyl)-3,3,3-trifluoro-2-(methoxymethyl)-1-[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1-one, salt with formic acid
Figure imgf000583_0001
Intermediate 290 (27.1 mg, 30.1 pmol) was dissolved in formic acid (1 ml) and stirred at RT for 30min. Reaction concentrated under reduced pressure. The residue was diluted with water and freeze-dried overnight and gave the titled compound (18 mg).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.032 (0.56), 1.070 (0.77), 1.107 (1.12), 1.133 (0.82), 1.239 (0.77), 1.274 (1.12), 1.305 (0.61), 1.350 (0.97), 1.677 (0.56), 1.710 (0.51), 1.892 (1.07),
1.931 (0.41), 2.111 (0.66), 2.145 (1.02), 2.318 (1.02), 2.322 (2.25), 2.326 (3.12), 2.331 (2.15),
2.336 (1.02), 2.423 (0.92), 2.518(11.19), 2.522 (7.72), 2.539 (5.98), 2.606 (1.07), 2.638 (1.43), 2.659 (1.79), 2.664 (3.02), 2.668 (3.99), 2.673 (3.17), 2.678 (1.89), 2.709 (0.82), 2.742 (0.82),
2.789 (1.23), 2.844 (2.45), 2.874 (8.08), 3.050 (0.77), 3.081 (1.18), 3.114 (1.23), 3.140 (2.10),
3.325 (8.43), 3.354 (5.37), 3.361 (5.37), 3.592 (4.40), 3.621 (1.23), 3.712 (0.72), 3.769 (7.36),
3.899 (0.87), 3.925 (1.02), 4.155 (1.74), 4.182 (1.84), 4.232 (1.12), 6.856 (0.61), 6.875 (1.23),
6.893 (0.82), 6.967 (1.64), 6.989 (2.30), 6.997 (2.25), 7.017 (1.58), 7.056 (0.82), 7.182 (1.33),
7.201 (1.74), 7.302 (0.46), 7.320 (0.66), 7.411 (0.82), 7.433 (1.33), 7.454 (0.72), 7.491 (1.38),
8.373(16.00).
Example 217
(2R)-3,3,3-trifluoro-2-(4-fluorophenyl)-2-(methoxymethyl)-1-[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1-one (Stereoisomer 1)
Figure imgf000583_0002
To a solution of Example 215 (30.0 mg, 47.4 pmol) in methanol (12 ml) under argon was added Palladium on carbon (10%, 5 mg). The reaction vessel was fluched with hydrogen and stirred at RT for 16h. The reaction was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method 6) and gave the titled compound (18 mg, 71%).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.528 (0.57), 0.883 (0.40), 1.001 (3.31), 1.125 (1.54), 1.158 (1.54), 1.231 (1.29), 1.290 (0.89), 1.320 (0.73), 1.352 (0.57), 1.897 (1.29), 1.932 (1.21),
2.016 (2.26), 2.048 (1.54), 2.163 (0.48), 2.322 (3.72), 2.326 (5.01), 2.331 (3.72), 2.397 (3.07),
2.425 (4.20), 2.518 (16.00), 2.522 (10.51), 2.539 (0.89), 2.575 (1.54), 2.606 (2.18), 2.664 (14.95), 2.668 (10.91), 2.673 (6.71), 2.704 (4.77), 2.725 (4.53), 2.796 (1.13), 2.824 (1.21), 2.876 (0.97), 2.969 (0.81), 2.999 (1.54), 3.031 (1.13), 3.081 (2.42), 3.717 (12.69), 3.742 (2.51), 3.766 (6.71), 3.790 (1.78), 4.091 (2.34), 4.117 (2.18), 4.167 (1.13), 4.229 (1.21), 4.257 (0.81),
4.283 (1.13), 4.316 (1.05), 6.817 (1.05), 6.894 (3.23), 6.912 (3.88), 6.933 (2.67), 7.004 (3.64),
7.037 (2.99), 7.055 (2.02), 7.165 (4.44), 7.204 (3.31), 7.226 (3.88), 7.248 (1.86), 7.272 (1.05).
Example 218
(2S)-3,3,3-trifluoro-2-(4-fluorophenyl)-2-(methoxymethyl)-1-[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1-one (Stereoisomer 1)
Figure imgf000584_0001
Using an analogous method described for Example 221: Example 216 (32.0 mg, 50.5 pmol) gave the titled compound (15 mg, 55%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.299 (0.67), 0.553 (1.01), 0.587 (0.81), 1.035 (1.41), 1.111 (2.08), 1.255 (1.08), 1.288 (0.87), 1.353 (0.40), 1.622 (0.81), 1.654 (0.81), 1.921 (0.94),
1.954 (0.94), 1.988 (1.01), 2.022 (1.08), 2.052 (1.21), 2.084 (1.08), 2.162 (0.40), 2.323 (3.36),
2.327 (4.57), 2.331 (3.43), 2.357 (1.14), 2.388 (1.75), 2.407 (2.22), 2.442 (1.61), 2.518 (16.00), 2.523 (10.42), 2.580 (1.61 ), 2.610 (1.82), 2.638 (1.41 ), 2.665 (4.77), 2.669 (6.05), 2.673 (4.91 ), 2.717 (2.96), 2.810 (2.89), 2.841 (2.08), 2.873 (8.07), 2.926 (1.34), 2.959 (1.14), 2.988 (3.56),
3.093 (1.34), 3.124 (0.87), 3.582 (8.87), 3.726 (1.01), 3.757 (8.20), 3.873 (0.94), 3.898 (1.14),
4.144 (2.55), 4.172 (3.50), 4.215 (2.08), 4.241 (1.55), 4.284 (0.87), 6.780 (1.21), 6.829 (1.01),
6.845 (1.61), 6.864 (1.21), 6.934 (2.96), 6.952 (3.36), 6.967 (2.76), 6.989 (3.76), 7.011 (2.82), 7.041 (1 .95), 7.058 (1 .28), 7.141 (0.94), 7.161 (1 .61 ), 7.202 (2.62), 7.230 (2.42), 7.252 (2.69), 7.298 (0.94), 7.317 (1.41 ), 7.334 (0.74).
Syntheses of Examples 219 to Example 221 (Table 131 and Examples 222 to Example 224 (Table 14)
The BOC protecting group was the removed under acidic conditions, as shown in the Scheme and General Method below:
Figure imgf000585_0001
General Method: To a solution of the Boc protected intermediate 301 to 306 in dioxane was added 4M HCI in dioxane (10 eq) and stirred at RT. After the reaction was complete, the reaction was concentrated under reduced pressure to give the HCI salt.
For purification: either concentrated under reduced pressure to give directly HCI salt or purified by preparative HPLC (Method 6) to give the titled compounds.
Table 13:
Figure imgf000585_0002
Figure imgf000586_0001
Figure imgf000587_0001
Table 14:
Figure imgf000588_0001
Figure imgf000589_0001
Figure imgf000590_0001
Svntheses of Examples 225 to Example 238 (Table 151
Using analogous methods described for previous Examples, the following route was used to synthesize Example 225 to Example 238, via a two step procedure illustrated below; i) first step of coupling the respective acid to the intermediate, 5-(4-fluoro-2-methoxy-phenyl)-3,9- diazaspiro[5.5]undecan-2-one (see Intermediate 10 for method); ii) reduction of the spirolactam to the spiroamine (see Example 63 for method).
Figure imgf000591_0001
Figure imgf000592_0001
Figure imgf000593_0001
Figure imgf000594_0001
Figure imgf000595_0001
Figure imgf000596_0001
Figure imgf000597_0001
Figure imgf000598_0001
Figure imgf000599_0001
Figure imgf000600_0001
Figure imgf000601_0001
Figure imgf000602_0001
Figure imgf000603_0002
Example 239 and Example 240
2.2-difluoro-1 -{(7R)-7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}- 2-[2-(trifluoromethoxy)phenyl]ethan-1 -one
2,2-difluoro-1 -{(7S)-7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}- 2-[2-(trifluoromethoxy)phenyl]ethan-1 -one
Example 239
2.2-difluoro-1 -{7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one (Stereoisomer 1 )
Figure imgf000603_0001
Using the method described for Example 63: intermediate 315 (73 mg, 124 pmol) gave titled compound (3 mg, 4%) after purification by preparative HPL C(Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .088 (0.48), 1 .920 (0.96), 1 .935 (1 .44), 1 .951 (0.98), 2.009 (0.57), 2.053 (0.69), 2.319 (0.90), 2.326 (0.58), 2.332 (0.52), 2.336 (0.59), 2.342 (0.57),
2.363 (0.85), 2.407 (0.54), 2.418 (0.51 ), 2.518 (1 .43), 2.522 (0.92), 2.973 (0.72), 3.01 1 (1 .43),
3.048 (0.65), 3.218 (16.00), 3.225 (0.66), 3.348 (0.82), 3.356 (0.64), 3.449 (1 .14), 3.464 (2.39),
3.480 (1 .07), 3.963 (0.53), 3.969 (0.61 ), 3.978 (1 .06), 3.985 (0.99), 3.993 (0.59), 4.000 (0.47),
6.734 (0.57), 6.741 (0.64), 6.855 (0.76), 6.861 (0.77), 6.884 (0.77), 6.891 (0.75), 7.169 (0.47),
7.187 (0.60), 7.208 (0.44), 7.404 (1.00), 7.423 (1 .60), 7.441 (0.72), 7.540 (0.89), 7.544 (1 .06),
7.561 (0.76), 7.565 (0.70), 7.601 (1.18), 7.619 (0.82).
Example 240
2,2-difluoro-1 -{7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one (Stereoisomer 2)
Figure imgf000604_0001
Using the method described for Example 63: intermediate 317 (56 mg, 95 pmol) gave titled compound (2 mg, 3%) after purification by preparative HPLC (Method 6).
1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1 .088 (0.47), 1 .920 (0.87), 1 .936 (1 .30), 1 .951 (0.91 ), 2.009 (0.53), 2.053 (0.65), 2.319 (0.89), 2.327 (0.70), 2.331 (0.61 ), 2.337 (0.62), 2.363 (0.79),
2.408 (0.54), 2.518 (2.15), 2.523 (1.38), 2.669 (0.45), 2.973 (0.66), 3.01 1 (1 .31 ), 3.049 (0.60),
3.218 (16.00), 3.450 (1.03), 3.465 (2.15), 3.480 (0.97), 3.963 (0.48), 3.970 (0.57), 3.978 (0.97), 3.985 (0.91 ), 3.994 (0.55), 4.001 (0.44), 6.734 (0.51 ), 6.741 (0.58), 6.856 (0.69), 6.862 (0.71 ),
6.884 (0.69), 6.891 (0.67), 7.169 (0.43), 7.187 (0.55), 7.405 (0.91 ), 7.424 (1 .46), 7.441 (0.65),
7.541 (0.81 ), 7.545 (0.97), 7.561 (0.69), 7.566 (0.64), 7.601 (1.10), 7.617 (0.76).
Example 241 and Example 242
(2R)-3,3,3-trifluoro-2-methoxy-1 -[(7S)-7-[2-(3-methoxypropoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 -yl)propan-1 -one
(2S)-3,3,3-trifluoro-2-methoxy-1 -[(7S)-7-[2-(3-methoxypropoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 -yl)propan-1 -one Or
(2R)-3,3,3-trifluoro-2-methoxy-1 -{(7R)-7-[2-(3-methoxypropoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-(naphthalen-1 -yl)propan-1 -one
(2S)-3,3,3-trifluoro-2-methoxy-1 -{(7R)-7-[2-(3-methoxypropoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-(naphthalen-1 -yl)propan-1 -one
Example 241
3,3,3-trifluoro-2-methoxy-1 -{7-[2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}- 2-(naphthalen-1 -yl)propan-1 -one (Stereoisomer 1 )
Figure imgf000605_0001
Using the method described for Example 63: intermediate 318 (29 mg, 48 pmol) gave titled compound (1 1 mg, 35%) after purification by preparative HPLC (Method 6).
Optical rotation (method OR1 ): -6.7° (methanol).
Example 242
3,3,3-trifluoro-2-methoxy-1 -{7-[2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}- 2-(naphthalen-1 -yl)propan-1 -one (Stereoisomer 2)
Figure imgf000605_0002
Using the method described for Example 63: intermediate 319 (23 mg, 38 pmol) gave titled compound (8 mg, 32%) after purification by preparative HPLC (Method 6).
Optical rotation (method OR1 ): +34.6°(methanol). Syntheses of Examples 243 to Example 247 (Table 161
Using analogous methods described for previous Examples, the following route was used to synthesize Example 243 to Example 247, via a two step procedure illustrated below; i) first step of coupling the respective acid to the intermediate, 5-[4-fluoro-2-(3- methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-2-one (see Intermediate 10 for method); ii) reduction of the spirolactam to the spiroamine (see Example 63 for method).
Figure imgf000606_0001
Table 16:
Figure imgf000607_0001
Figure imgf000608_0001
Figure imgf000609_0001
Figure imgf000610_0001
Figure imgf000611_0001
Syntheses of Examples 248 to Example 252 (Table 171
Using analogous methods described for previous Examples, the following route was used to synthesize Example 248 to Example 252, via a two step procedure illustrated below; i) first step of coupling the respective acid to the intermediate 324 or 325 (see Intermediate 10 for method); ii) cleavage of the BOC-group and iii) reduction of the spirolactam to the spiroamine (see Example 63 for method).
Figure imgf000612_0001
Table 17:
Figure imgf000612_0002
Figure imgf000613_0001
Figure imgf000614_0001
Figure imgf000615_0001
Figure imgf000616_0001
Figure imgf000617_0001
Figure imgf000618_0002
Example 254
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- phenylpropan-1 -one (Stereoisomer 2)
Figure imgf000618_0001
Using the method described for Example 1 with intermediate 89 (200 mg, 347 pmol). After concentration of the reaction mixture under reduced pressure and preparative HPLC (Method 6), the title compound (10.5 mg, 23%) was obtained. 1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.022 (0.73), -0.010 (0.69), 0.012 (0.42), 0.499 (0.76), 0.532 (0.62), 1 .019 (0.66), 1 .071 (0.52), 1 .106 (0.90), 1.233 (0.48), 1 .922 (0.90), 1.951 (0.73),
2.099 (0.90), 2.134 (0.87), 2.323 (1.90), 2.327 (2.53), 2.332 (1.97), 2.337 (1 .45), 2.368 (0.97),
2.460 (0.94), 2.518 (8.48), 2.523 (5.61 ), 2.539 (0.87), 2.548 (0.42), 2.665 (1 .90), 2.669 (2.39), 2.674 (1 .77), 2.694 (0.94), 2.722 (2.01 ), 2.755 (1 .14), 2.786 (0.59), 2.889 (0.52), 2.925 (1 .42),
2.945 (1 .18), 2.974 (1 .18), 3.002 (0.73), 3.028 (1 .00), 3.064 (0.59), 3.198 (1 .73), 3.366 (0.87),
3.401 (0.62), 3.506 (16.00), 3.535 (7.45), 3.743 (0.97), 3.755 (5.06), 4.266 (0.62), 4.297 (0.59), 6.871 (0.55), 6.917 (0.87), 6.934 (2.87), 6.953 (4.12), 6.972 (2.04), 6.984 (3.32), 7.005 (2.81 ),
7.027 (2.56), 7.047 (1 .66), 7.091 (0.52), 7.1 10 (0.73), 7.149 (0.48), 7.271 (0.94), 7.275 (0.90),
7.292 (1 .32), 7.314 (1.07), 7.331 (1.59), 7.349 (1 .90), 7.367 (0.90), 7.424 (1 .77), 7.431 (1 .39).
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 MgCI2, 10 mM KCI, 50 mM ZnCI2, 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 100-fold concentrated form by serial dilution with two separate dilutions for each compound (n=2). IC5o values were calculated by 4-parameter fitting using a commercial software package (Genedata Screener, Switzerland).
Table 18: IC50 values of Example Compounds in Assay 1 (GGTase-1 )
Figure imgf000621_0001
Figure imgf000622_0001
Figure imgf000623_0001
Figure imgf000624_0001
Figure imgf000625_0001
Figure imgf000626_0001
Figure imgf000627_0001
Figure imgf000628_0001
Figure imgf000629_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 -1 dOΌ 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. IC50 values were calculated by 4-parameter fitting using a commercial software package (Genedata Screener, Switzerland).
Table 19: IC5o values of Example Compounds in Assay 2 (MDA-MB231 -TEAD-Luc reporter cells)
Figure imgf000630_0001
Figure imgf000631_0001
Figure imgf000632_0001
Figure imgf000633_0001
Figure imgf000634_0001
Figure imgf000635_0001
Figure imgf000636_0001
Figure imgf000637_0001
Figure imgf000638_0001
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 Sarcoma cells (HT-1080) and mouse melanoma cells (B16-F10) 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); HT-1080 MEM Earle's; (Biochrom; # FG 0325; , 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 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 2.67-fold dilution series starting at a maximum final assay concentration of 10 mM. After 72 h incubation in a humidified 370 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 20: IC5o values of Example Compounds in Assay 3 (cancer cell proliferation assay)
Figure imgf000640_0001
Figure imgf000641_0001
Figure imgf000642_0001
Figure imgf000643_0001
Figure imgf000644_0001
Figure imgf000645_0001
Figure imgf000646_0001
Figure imgf000647_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 7860 (Kidney Cancer), 769-P (Kidney Cancer), T-24 (Bladder Cancer), Colo-678 (Colon Cancer), RKO (Colon Cancer), SW620 (Colon Cancer), SW640 (Colon Cancer), NCI-H2052 (Mesothelioma), MDA-MB-231 (Breast Cancer), HPAF-II (Pancreatic Cancer), CFPAC-1 (Pancreatic Cancer), FIUP-T4 (Pancreatic Cancer), IGROV1 (Ovarian Cancer), T98G (Brain Cancer: Glioblastoma), SW 1783 (Brain Cancer: Astrocytoma), H4 (Brain Cancer: Glioblastoma), A172 (Brain Cancer: Glioblastoma), SNB-19 (Brain Cancer: Astrocytoma), SW 872 (Connective Tissue Cancer Liposarcoma), SW-982 (Connective Tissue Cancer: Synovial sarcoma), SW684 (Connective Tissue Cancer: Fibrosarcoma), HT-1080 (Connective Tissue Cancer: Fibrosarcoma), Detroit-562 (Head & Neck Cancer: Pharynx), FaDu (Head & Neck Cancer: Pharynx), CAL-33 (Head & Neck Cancer: Tongue), CAL-27 (Head & Neck Cancer: Tongue), SCC-9 (Head & Neck Cancer: Tongue), HSC-3 (Upper aerodigestive tract Cancer: Tongue squamous cell carcinoma), DB (Diffuse Large B-Cell Lymphoma), L-363 (Leukemia: plasma cell leukemia), MOLM-16 (Leukemia: acute myeloid leukemia), RPMI-8226 (Multiple Myeloma), U266B1 (Multiple Myeloma), JMSU1 (Bladder Cancer) , HUH7 (Liver Cancer), NCI-H661 (Lung Cancer), IGR-1 (Skin Cancer), 5637 (Bladder Cancer), SW-579 (Thyroid Cancer), SNG-M (Endometrial Cancer), NCI-H28 (Mesothelioma), MSTO-21 1 H H28 (Mesothelioma), KNS-81 (Brain Cancer: Glioblastoma), KNS-60 (Brain Cancer: Glioblastoma), KMRC-1 (Kidney Cancer), JHH-4 (Liver Cancer), GB-1 (Brain Cancer: Glioblastoma), GAMG (Brain Cancer: Glioblastoma), DoTc2-4510 (Cervical Cancer), DBTRG- 05-MG (Brain Cancer: Glioblastoma), HCC-44 (Lung Cancer), SCC-25 (Squamos Carcinoma), NCI-H226 (Mesothelioma), MFE-280 (Endometrial Cancer), HT-1 197 (Bladder Cancer), CAL- 29 (Bladder Cancer), Caki-2 (Kidney 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 asses sed 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 was required to achieve 50% inhibition of luminescence. IC50 is 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 21 : IC50 values of Example Compound 13 in Assay 4 (cancer cell proliferation assay)
Figure imgf000648_0001
Figure imgf000649_0001
Table 22: IC5o values of Example Compound 62 in Assay 4 (cancer cell proliferation assay)
Figure imgf000649_0002

Claims

1 . A compound of general formula (I):
Figure imgf000650_0001
in which :
R1 represents a group selected from phenyl and naphtyl,
which phenyl and naphtyl 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-alkynyl, C3-C6-cycloalkyl,
(C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, (C3-C6-cycloalkyloxy)-(Ci-C3-alkyl)-,
Ci-Ce-hydroxyalkyl, (Ci-C2-alkoxy)-(Ci -Ce-alkyl)-, Ci-Ce-haloalkyl, Ci-Ce-alkoxy, (C3-Ce-cycloalkyl)-(Ci-C3-alkoxy)-, C2-C6-hydroxyalkoxy,
(Ci -C2-alkoxy)-(C2-C6-alkoxy)-,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-,
(Ci-C6-alkyl)-S-(Ci-Ce-alkoxy)-, Ci-Ce-haloalkoxy,
(Ci -C2-haloalkoxy)-(Ci -Ce-alkyl)-, C3-Ce-cycloalkyloxy,
Ci-Ce-cyanoalkoxy, phenyl, 5- or 6-membered heteroaryl,
(5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkyl)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci-C3-alkyl)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, phenoxy-(Ci-C3-alkyl)-,
phenoxy-(C2-C3-alkoxy)-, -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-Ce-cycloalkyl), -S-(Ci-Ce-haloalkyl), -S(=0)-(Ci-C6-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), (R5)(R6)N-(C2-C3-alkoxy)-,
4- to 7-membered heterocycloalkyl, (4- to 7-membered heterocycloalkyl)oxy-, -(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl),
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-, -C(=0)N(R5)(R6), -(Ci-C3-alkyl)-C(=0)N(R5)(R6), (R5)(R6)NC(=0)-(Ci-C3-alkoxy)-, -C(=0)0R7, -(Ci-C3-alkyl)-C(=0)0R7, R7OC(=0)-(Ci-C3-alkoxy)-, -C(=0)R7, -(Ci-C3-alkyl)-C(=0)R7 and (Ci-C2-alkoxy)-(C2-C3-alkoxy)n-, 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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -O-CH2-O-, -0-(CH2)2-0-, -N(R7)-(CH2)2-, -(CH2)2-N(R7)-, -CH2-N(R7)-CH2-, -N(R7)-(CH2)3-, -(CH2)3-N(R7)-,
-CH2-N(R7)-(CH2)2-, -(CH2)2-N(R7)-CH2-, -N(R7)-(CH2)2-N(R7)-, -N(R7)-(CH2)2-0- and -0-(CH2)2-N(R7)-,
wherein n represents an integer of 2, 3, 4 or 5,
wherein said 4- to 7-membered heterocycloalkyl group and the
(4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyljoxy- group,
-(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl) group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- 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
(4- to 7-membered heterocycloalkyl)oxy- group,
-(Ci-C4-alkyl)-(4- to 7-membered heterocycloalkyl) group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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, Ci-C2-haloalkyl, Ci-C2-hydroxyalkyl, cyano, hydroxy,
Ci -C2-alkoxy, C3-C4-cycloalkyl, -N(R5)(R6), -C(=0)OR8 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 the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkyl)- and (5- or 6-membered heteroaryl)-(Ci-C3-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, Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl and -N(R5)(R6),
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-alkynyl, C3-C6-cycloalkyl, C4-C7-cycloalkenyl, C4-C7-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C6-alkenyl)-, Ci-C6-hydroxyalkyl, Ci-Ce-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, Cs-Ce-cycloalkyloxy, -SH, -S-(Cr -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), cyano, hydroxy,
-N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)OR7,
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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-0-CH2-, -0-(CH2)3-, -(CH2)3-O-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -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, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
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, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl and -N(R5)(R6),
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C6-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C6-alkoxy)-, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy, phenyl, phenoxy, phenyl-(Ci-C2-alkyl)-, phenyl-(Ci-C2-alkoxy)-, (5- or 6-membered heteroaryl)oxy,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy), hydroxy, cyano, -N(R5)(R6),
-(Ci-C2-alkyl)-N(R5)(R6), (R5)(R6)N-(C2-C3-alkoxy)-, C4-C7-heterocycloalkyl,
-(Ci-C2-alkyl)-(C4-C7-heterocycloalkyl),
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-, (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 and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- 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 and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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, Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
and
wherein said cycloalkyl group and said phenyl group, and the phenyl part of said phenoxy, phenyl-(Ci-C2-alkyl)- and phenyl-(Ci-C2-alkoxy)- group, and the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)oxy- group and
(5- or 6-membered heteroaryl)-(Ci-C3-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, Ci-C2-haloalkyl, cyano, hydroxy, Ci-C2-alkoxy and
-N(R5)(R6),
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, phenyl, phenyl-(Ci-C2-alkyl)-, -(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, cyano, hydroxy, Ci-C2-alkoxy,
C3-C4-cycloalkyl, -N(R5)(R6) and oxo,
and
wherein said cycloalkyl group and said phenyl group, and the phenyl part of said phenyl-(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, cyano, hydroxy, Ci-C2-alkoxy and
-N(R5)(R6),
or
R3 and R4 together with the carbon atom to which they are attached represent a
3- 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 seleceted from
Ci-C4-alkyl, C3-C4-cycloalkyl, C2-C4-haloalkyl, C2-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(C2-C3-alkyl-), -C(=0)-(Ci-C3-alkyl) and -C(=0)-(Ci-C3-haloalkyl), 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, Ci-C4-haloalkyl, Ci-C4-hydroxyalkyl,
(Ci-C2-alkoxy)-(Ci-C3-alkyl)- and oxo,
R7 represents a hydrogen atom or a Ci-C4-alkyl group,
and
R8 represents a Ci-C4-alkyl group, 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 selected from phenyl and naphtyl,
which phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl and Ci-C4-alkoxy, (C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, C2-C6-hydroxyalkoxy,
(Ci -C2-alkoxy)-(C2-C6-alkoxy)-,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-,
(Ci-C4-alkyl)-S-(Ci-C4-alkoxy)-, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy,
Ci-C4-cyanoalkoxy, phenyl, 5- or 6-membered heteroaryl,
(5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, -S-(Ci-C4-alkyl), -S-(Ci-C4-haloalkyl), hydroxy, -N(R5)(R6),
(R5)(R6)N-(C2-C3-alkoxy)-, (4- to 7-membered heterocycloalky l)oxy-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-,
(R5)(R6)NC(=0)-(Ci-C3-alkoxy)- and -C(=0)R7 and
(Ci-C2-alkoxy)-(C2-C3-alkoxy)n-, 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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -O-CH2-O-, -0-(CH2)2-0-, -N(R7)-(CH2)2-, -(CH2)2-N(R7)-, -CH2-N(R7)-CH2-, -N(R7)-(CH2)3-, -(CH2)3-N(R7)-, -CH2-N(R7)-(CH2)2-, -(CH2)2-N(R7)-CH2-, -N(R7)-(CH2)2-N(R7)-, -N(R7)-(CH2)2-0- and -0-(CH2)2-N(R7)-,
wherein n represents an integer of 2, 3 or 4,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is 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-hydroxyalkyl, cyano, hydroxy,
Ci-C2-alkoxy, C3-C4-cycloalkyl, -N(R5)(R6), -C(=0)OR8 and oxo, and
wherein said phenyl and phenoxy group, and the phenyl part of said phenyl-(Ci-C3-alkoxy)- group, and said 5- or 6-membered heteroaryl group, and the (5- or 6-membered heteroaryl) part of said (5- or 6- membered heteroaryljoxy- and
(5- or 6-membered heteroaryl)-(Ci-C3-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 Ci-C2-alkoxy,
R2 represents a group selected from phenyl, naphthyl and pyridinyl,
which phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkenyl, Cs-Ce-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C4-alkenyl)-, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, cyano, -N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)OR7,
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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -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 and oxo, 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 and a Ci-C2-alkyl group,
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C(=0)0R7,
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
wherein the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-alkyl group,
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Ci-C4-haloalkyl and (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, or
R3 and R4 together with the carbon atom to which they are attached represent a
3- to 6-membered cycloalkyl group,
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
seleceted from
Ci-C4-alkyl, and C3-C4-cycloalkyl,
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-C2-alkyl, C3-C4-cycloalkyl, Ci-C2-haloalkyl, Ci-C2-hydroxyalkyl,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)- and oxo,
R7 represents a hydrogen atom or a Ci-C4-alkyl group,
and
R8 represents a Ci-C4-alkyl group, 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, which is of general formula (l-a),
Figure imgf000658_0001
in which : R1 represents a group selected from phenyl and naphtyl,
which phenyl and naphtyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl and Ci-C4-alkoxy, (C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, C2-C6-hydroxyalkoxy,
(Ci -C2-alkoxy)-(C2-C6-alkoxy)-,
(Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-,
(Ci-C4-alkyl)-S-(Ci-C4-alkoxy)-, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyloxy,
Ci-C4-cyanoalkoxy, phenyl, 5- or 6-membered heteroaryl,
(5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci-C3-alkoxy)-, phenoxy, -S-(Ci-C4-alkyl), -S-(Ci-C4-haloalkyl), hydroxy, -N(R5)(R6),
(R5)(R6)N-(C2-C3-alkoxy)-, (4- to 7-membered heterocycloalky l)oxy-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-,
(R5)(R6)NC(=0)-(Ci-C3-alkoxy)- and -C(=0)R7 and
(Ci-C2-alkoxy)-(C2-C3-alkoxy)n-,
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) -, -0-(CH2)2-, -(CH2)2-0-, -CH2-O-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -O-CH2-O-, -0-(CH2)2-0-, -N(R7)-(CH2)2-, -(CH2)2-N(R7)-, -CH2-N(R7)-CH2-, -N(R7)-(CH2)3-, -(CH2)3-N(R7)-, -CH2-N(R7)-(CH2)2-, -(CH2)2-N(R7)-CH2-, -N(R7)-(CH2)2-N(R7)-, -N(R7)-(CH2)2-0- and -0-(CH2)2-N(R7)-,
wherein n represents an integer of 2, 3 or 4,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is 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-hydroxyalkyl, cyano, hydroxy,
Ci-C2-alkoxy, C3-C4-cycloalkyl, -N(R5)(R6), -C(=0)0R8 and oxo, and
wherein said phenyl and phenoxy group, and the phenyl part of said phenyl-(Ci-C3-alkoxy)- group, and said 5- or 6-membered heteroaryl group, and the (5- or 6-membered heteroaryl) part of said (5- or 6- membered heteroaryl)oxy- and
(5- or 6-membered heteroaryl)-(Ci-C3-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 Ci-C2-alkoxy,
R2 represents a group selected from phenyl, naphthyl and pyridinyl,
which phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkenyl, Cs-Ce-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C4-alkenyl)-, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, cyano, -N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)OR7,
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-, -0-(CH2)2-, -(CH2)2-0-, -CH2-0-CH2-, -0-(CH2)3-, -(CH2)3-0-, -CH2-0-(CH2)2-, -(CH2)2-0-CH2-, -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 and oxo, 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 and a Ci-C2-alkyl group,
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C(=0)OR7,
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and
wherein the (5- or 6-membered heteroaryl) part of said
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-alkyl group,
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, Ci-C4-haloalkyl and (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, or
R3 and R4 together with the carbon atom to which they are attached represent a
3- to 6-membered cycloalkyl group,
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
seleceted from
Ci-C4-alkyl, and C3-C4-cycloalkyl,
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-C2-alkyl, C3-C4-cycloalkyl, Ci-C2-haloalkyl, Ci -C2-hydroxyalkyl,
(Ci -C2-alkoxy)-(Ci-C2-alkyl)- and oxo,
R7 represents a hydrogen atom or a Ci-C4-alkyl group,
and
R8 represents a Ci-C4-alkyl group,
or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
4. The compound according to claim 1 , 2 or 3, wherein:
R1 represents a group
Figure imgf000662_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C6-hydroxyalkoxy, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy, (C3-C6-cycloalkyl)-(Ci -C3-alkoxy)-, phenoxy, hydroxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C6-alkoxy)-,
(Ci -C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)-(Ci-C2-alkoxy)-, (Ci -C4-alkyl)-S-(Ci -C4-alkoxy)-, Ci-C4-haloalkoxy, C3-C6-cycloalkyloxy, Ci -C4-cyanoalkoxy, phenyl,
5- or 6-membered heteroaryl, (5- or 6-membered heteroaryl)oxy-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, phenyl-(Ci -C3-alkoxy)-, phenoxy, -S-(Ci-C4-alkyl), -S-(Ci -C4-haloalkyl), hydroxy, -N(R5)(R6), (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)oxy-,
(4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)-, (R5)(R6)NC(=0)-(Ci -C3-alkoxy)-, -C(=0)R7 and (Ci -C2-alkoxy)-(C2-C3-alkoxy)n-,
wherein n represents an integer of 2, 3 or 4,
and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci -C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyljoxy- group and
(4- to 7-membered heterocycloalkyl)-(Ci -C3-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, Ci -C2-hydroxyalkyl, cyano, hydroxy, -C(=0)OR8 and oxo, and
wherein said phenyl and phenoxy group, and the phenyl part of said phenyl-(Ci -C3-alkoxy)- group, and said 5- or 6-membered heteroaryl group and the (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)oxy- group and
(5- or 6-membered heteroaryl)-(Ci-C3-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 Ci-C2-alkoxy, wherein X3 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group, or,
wherein X2 and X3 are linked to one another in such a way that they jointly form a group selected from
-C(R9)=C(R9)-C(R9)=C(R9)-, -(CH2)2-N(R7)-, -(CH2)2-N(R7)-, -(CH2)2-N(R7)-, -0-(CH2)2- and -N(R7)-(CH2)3-, wherein X4 represents a hydrogen atom or a halogen atom or a Ci-C4-haloalkyl group, or,
wherein X3 and X4 are linked to one another in such a way that they jointly form a group selected from
-CH2-O-CH2- and -O-CH2-O-, wherein X5 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group, wherein X6 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group,
R2 represents a group selected from phenyl, naphthyl and pyridinyl,
which phenyl, naphthyl and pyridinyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from Ci-C4-alkyl, C2-C4-alkenyl, Cs-Ce-cycloalkenyl, Cs-Ce-hydroxycycloalkenyl, (Ci-C2-alkoxy)-(C3-C4-alkenyl)-, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, cyano, -N(R5)(R6), -C(=0)N(R5)(R6), -C(=0)OR7,
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 -(OH2)3- group,
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 and oxo, 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 and a Ci-C2-alkyl group,
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, C2-C4-alkenyl, C3-C6-cycloalkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C4-hydroxyalkoxy, (Ci-C2-alkoxy)-(C2-C4-alkoxy)-,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, hydroxy, (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- and -C(=0)0R7,
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group,
and
wherein the (4- to 7-membered heterocycloalkyl) part of said
(4- to 7-membered heterocycloalkyl)-(Ci-C3-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 and oxo, and wherein the (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl-(Ci-C3-alkoxy)- group is optionally substituted, one or two times, each substituent independently selected from a halogen atom and a Ci-C2-alkyl group,
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci -C4-alkyl, C2-C4-alkenyl, Ci-C4-haloalkyl and (Ci-C2-alkoxy)-(Ci-C2-alkyl)-, or
R3 and R4 together with the carbon atom to which they are attached represent a
3- to 6-membered cycloalkyl group,
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a group
seleceted from
Ci-C4-alkyl and C3-C4-cycloalkyl,
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 Ci-C2-alkyl group and oxo,
R7 represents a hydrogen atom or a Ci-C4-alkyl group,
R8 represents a Ci-C4-alkyl group,
and
R9 represents a hydrogen atom or a halogen atom and a Ci-C2-alkyl group, or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
5. The compound according to claim 1 , 2, 3, or 4, wherein:
R1 represents a group
Figure imgf000665_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-hydroxyalkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, C2-C6-hydroxyalkoxy, Ci-C4-haloalkoxy, Cs-Ce-cycloalkyloxy, (C3-C6-cycloalkyl)-(Ci-C3-alkoxy)-, phenoxy, hydroxy, (Ci-C2-alkoxy)-(C2-C6-alkoxy)-, (Ci-C2-alkoxy)-(Ci-C2-alkyl)-CH(OH)- (Ci-C2-alkoxy)-, phenyl, phenyl-(Ci-C3-alkoxy)-, 5- or 6-membered heteroaryl,
(5- or 6-membered heteroaryl)-(Ci-C3-alkoxy)-, -N(R5)(R6), (R5)(R6)N-(C2-C3-alkoxy)-,
(4- to 7-membered heterocycloalkyl)oxy- and
(4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)-,
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group and (4- to 7-membered heterocycloalkyl)-(Ci-C3-alkoxy)- group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group, and
wherein the 4- to 7-membered heterocycloalkyl part of said
(4- to 7-membered heterocycloalkyl)oxy- group and (4- to 7-membered heterocycloalkyl)-(Ci-C3-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, Ci-C2-hydroxyalkyl, cyano, hydroxy and oxo,
and
wherein said phenyl group and said 5- or 6-membered heteroaryl group and the (5- or 6-membered heteroaryl) part of said (5- or 6-membered heteroaryl)-(Ci- C3-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 Ci-C2-alkoxy, wherein X3 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl group, or,
wherein X2 and X3 are linked to one another in such a way that they jointly form a -0-(CH2)2- group, wherein X4 represents a hydrogen atom or a halogen atom, wherein X5 represents a hydrogen atom or a halogen atom or a Ci-C2-alkyl group, wherein X6 represents a hydrogen atom or a halogen atom or a Ci-C4-alkyl group, R2 represents a group selected from phenyl and naphthyl, which phenyl and naphthyl group is optionally substituted, one, two, three or four times, each substituent independently selected from a halogen atom or a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy,
R3 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, Ci-C4-alkoxy, hydroxy and Ci-C4-haloalkyl,
R4 represents a hydrogen atom, a halogen atom, or a group selected from
Ci-C4-alkyl, Ci-C4-haloalkyl and (Ci-C2-alkoxy)-(Ci-C2-alkyl)-,
or
R3 and R4 together with the carbon atom to which they are attached represent a
3- to 6-membered cycloalkyl group,
R5 and R6 represent, independently from each occurrence, a hydrogen atom or a Ci-C4-alkyl group,
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 with an oxo group, or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
6. The compound according claim 1 , 2, 3, 4 or 5, wherein:
R1 represents a group
Figure imgf000667_0001
wherein "*" represents the point of attachment to the rest of the molecule,
and
wherein X2 represents a hydrogen atom or a bromine atom, chlorine atom, fluorine atom, or a group selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, phenoxy, diifluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy,
cyclopropyloxy, cyclopropylm ethoxy, hydroxy, 1 -hydroxyethyl, 2-hydroxypropoxy, 3-hydroxypropoxy, tetrahydrofuran-3-yloxy, 3-methoxyphenyl,
2-hydroxy-2-methylpropoxy, 3-hydroxybutoxy, 3-hydroxy-3-methylbutoxy, 2-hydroxy-3-methoxypropoxy, 2-methoxypropoxy, 2-methoxy-2-methylpropoxy,
3-methoxypropoxy, 3-methoxy-3-methylbutoxy, benzyloxy, methylamino, ethylamino, dimethylamino, (oxetan-2-yl)methoxy, (2-methyloxetan-2-yl)methoxy,
(oxetan-3-yl)methoxy, (3-fluorooxetan-3-yl)methoxy, (3-cyanooxetan-3-yl)methoxy, (3-methyloxetan-3-yl)methoxy, tetrahydropyran-4-yloxy, (tetrahydropyran-3-yl)methoxy, 2-(2-oxoimidazolin-1 -yl)ethoxy, 2-(2-oxo-1 ,3-oxazolidin-3-yl)ethoxy,
2-(morpholin-4-yl)ethoxy, 2-(oxazin-2-yl)ethoxy, 1 -methyl-1 H-pyrazol-4-yl,
2-(imidazol-1 -yl)ethoxy, (1 ,3-oxazol-2-yl)methoxy, (2-methyl-1 ,3-oxazol-4-yl)methoxy, (thiazol-4-yl)methoxy, (2-methylthiazol-4-yl)methoxy, (2-methylthiazol-5-yl)methoxy,
(1 ,3-oxazol-5-yl)methoxy, 2-(1 H-pyrazol-1 -yl)ethoxy,
(5-methyl-1 ,3,4-oxadiazol-2-yl)methoxy, (5-methyl-1 ,3,4-thiadiazol-2-yl)methoxy, (pyridin-2-yl)methoxy, (pyridin-3-yl)methoxy, (pyridin-4-yl)methoxy,
(3-fluoropyridin-4-yl)methoxy, (2-methylpyridin-4-yl)methoxy,
(3-methylpyridin-4-yl)methoxy and (2-cyanopyridin-4-yl)methoxy, wherein X3 represents a hydrogen atom or a fluorine atom or a methyl group, or,
wherein X2 and X3 are linked to one another in such a way that they jointly form a -0-(CH2)2- group, wherein X4 represents a hydrogen atom or a fluorine atom, wherein X5 represents a hydrogen atom or a fluorine atom or a methyl group, wherein X6 represents a hydrogen atom or a fluorine atom or a methyl group,
R2 represents a group selected from
phenyl, 3-bromophenyl, 4-bromophenyl, 3-bromo-5-chlorophenyl,
3-bromo-4-fluorophenyl, 3-bromo-5-fluorophenyl, 5-bromo-2-fluorophenyl,
3-bromo-5-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,
3.4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-fluorophenyl, 3-fluoro-5-methylphenyl, 3-fluoro-4-methoxyphenyl, 2-(trifluoromethyl)phenyl,
3-(trifluoromethyl)phenyl, 3-bromo-5-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl,
3.5-dimethylphenyl, 2-(trifluoromethoxy)phenyl, 4-methoxyphenyl and 1 -naphthyl,
R3 represents a hydrogen atom, a fluorine atom, or a group selected from
methyl, methoxy, hydroxy and trifluoromethyl, R4 represents a hydrogen atom, or a fluorine atom, or a group selected from
methyl, trifluoromethyl and methoxymethyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
cyclopropyl group or a cyclopentyl group, or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
7. The compound according claim 1 , 2, 3, 4, 5 or 6, wherein:
R1 represents a group selected from
phenyl, 2-bromophenyl, 2-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,
2-chloro-3-fluorophenyl, 2-fluoro-3-methylphenyl, 2-fluoro-6-methylphenyl,
3-fluoro-2-methylphenyl, 4-fluoro-2-methylphenyl, 2-ethyl-4-fluorophenyl,
5-fluoro-2-methylphenyl, 3-fluoro-2-methoxyphenyl, 4-fluoro-2-methoxyphenyl, 5-fluoro-2-methoxyphenyl, 3,6-difluoro-2-methoxyphenyl, 2,3-difluoro-6-methoxyphenyl, 3,4-difluoro-2-methoxyphenyl, 3,5-difluoro-2-methoxyphenyl,
4-fluoro-2-(3-methoxypropoxy)phenyl, 4-fluoro-2-(tetrahydrofuran-3-yloxy)phenyl, 2-ethylphenyl, 2,3-dimethylphenyl, 2,5-dimethylphenyl, 3,5-dimethylphenyl,
2-methoxyphenyl, 2-ethoxyphenyl, 2-phenoxyphenyl, 2-methoxy-5-methylphenyl, 2-(trifluoromethyl)phenyl, 2-(difluoromethoxy)phenyl, 2-(trifluoromethoxy)phenyl, 2-(2,2-difluoroethoxy)phenyl, 2-(2,2,2-trifluoroethoxy)phenyl, 2-(cyclopropyloxy)phenyl, 2-(cyclopropylmethoxy)phenyl, 2-hydroxyphenyl, 2-(1 -hydroxyethyl)phenyl,
2-(2-hydroxypropoxy)phenyl, 2-(3-hydroxypropoxy)phenyl,
2-(2-hydroxy-2-methylpropoxy)phenyl, 2-(3-hydroxybutoxy)phenyl,
2-(3-hydroxy-3-methylbutoxy)phenyl, 2-(2-hydroxy-3-methoxypropoxy)phenyl), 2-(2-methoxypropoxy)phenyl, 2-(2-methoxy-2-methylpropoxy)phenyl,
2-(3-methoxypropoxy)phenyl, 2-(3-methoxy-3-methylbutoxy)phenyl,
2-(benzyloxy)phenyl, 2-(methylamino)phenyl, 2-(ethylamino)phenyl,
2-(dimethylamino)phenyl, 2-[(oxetan-2-yl)methoxy]phenyl,
2-[(2-methyloxetan-2-yl)methoxy]phenyl, 2-[(oxetan-3-yl)methoxy]phenyl,
2-[(3-fluorooxetan-3-yl)methoxy]phenyl, 2-[(3-cyanooxetan-3-yl)methoxy]phenyl, 2-[(3-methyloxetan-3-yl)methoxy]phenyl, 2-(tetrahydropyran-4-yloxy)phenyl,
2-[(tetrahydropyran-3-yl)methoxy]phenyl, 2-[2-(2-oxoimidazolin-1 -yl)ethoxy]phenyl, 2-[2-(2-oxo-1 ,3-oxazolidin-3-yl)ethoxy]phenyl, 2-[2-(morpholin-4-yl)ethoxy]phenyl, 2-[2-(oxazin-2-yl)ethoxy]phenyl, 2-(1 -methyl-1 H-pyrazol-4-yl)phenyl,
2-[2-(imidazol-1 -yl)ethoxy]phenyl, 2-[(1 ,3-oxazol-2-yl)methoxy]phenyl,
2-[(2-methyl-1 ,3-oxazol-4-yl)methoxy]phenyl, 2-[(thiazol-4-yl)methoxy]phenyl,
2-[(2-methylthiazol-4-yl)methoxy]phenyl, 2-[(2-methylthiazol-5-yl)methoxy]phenyl, 2-[(1 ,3-oxazol-5-yl)methoxy]phenyl, 2-[2-(1 H-pyrazol-1 -yl)ethoxy]phenyl,
2-[(5-methyl-1 ,3,4-oxadiazol-2-yl)methoxy]phenyl,
2-[(5-methyl-1 ,3,4-thiadiazol-2-yl)methoxy]phenyl, 2-[(pyridin-2-yl)methoxy]phenyl, 2-[(pyridin-3-yl)methoxy]phenyl, 2-[(pyridin-4-yl)methoxy]phenyl,
2-[(3-fluoropyridin-4-yl)methoxy]phenyl, 2-[(2-methylpyridin-4-yl)methoxy]phenyl,
2-[(3-methylpyridin-4-yl)methoxy]phenyl, 2-[(2-cyanopyridin-4-yl)methoxy]phenyl,
2.3-dihydro-1 -benzofuran-7-yl and 5-fluoro-3'-methoxy[1 ,1 '-biphenyl]-2-yl,
R2 represents a group selected from
phenyl, 3-bromophenyl, 4-bromophenyl, 3-bromo-5-chlorophenyl,
3-bromo-4-fluorophenyl, 3-bromo-5-fluorophenyl, 5-bromo-2-fluorophenyl,
3-bromo-5-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,
3.4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-fluorophenyl, 3-fluoro-5-methylphenyl, 3-fluoro-4-methoxyphenyl, 2-(trifluoromethyl)phenyl,
3-(trifluoromethyl)phenyl, 3-bromo-5-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl,
3.5-dimethylphenyl, 2-(trifluoromethoxy)phenyl, 4-methoxyphenyl and 1 -naphthyl,
R3 represents a hydrogen atom, a fluorine atom, or a group selected from
methyl, methoxy, hydroxy and trifluoromethyl,
R4 represents a hydrogen atom, or a fluorine atom, or a group selected from
methyl, trifluoromethyl and methoxymethyl,
or
R3 and R4 together with the carbon atom to which they are attached represent a
cyclopropyl group or a cyclopentyl group, or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
8. The compound according to claim 1 or 2 which is selected from the group consisting of: (rac)-2-phenyl-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 -one,
(rac)-2-methyl-2-phenyl-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]propan-1 -one,
(rac)-(1 -phenylcyclopropyl)[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]methanone,
(rac)-(1 -phenylcyclopentyl)[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]methanone,
(rac)-[1 -(3,5-dimethylphenyl)cyclopentyl][7-phenyl-3,9-diazaspiro[5.5]undecan-3- yljmethanone,
[1 -(3,5-dimethylphenyl)cyclopentyl][(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yljmethanone, [1 -(3,5-dimethylphenyl)cyclopentyl][(7S)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yljmethanone,
(rac)-2-(naphthalen-1 -yl)-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 -one,
(rac)-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]ethan-1 -one, 1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]propan-1 -one (mixture of stereoisomers),
(2S)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]propan- 1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]propan-
1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[(7S)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one,
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7S)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
3.3.3-trifluoro-2-(4-fluorophenyl)-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3-bromophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
3.3.3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)-1 -[7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-phenylethan-1 -one,
2,2-difluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-phenylethan-1 - one, (rac)-1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethyl)phenyl]ethan-1 -one (mixture of stereoisomers),
1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]propan-1 - one (mixture of stereoisomers),
2,2-difluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one, salt with hydrochloric acid,
(rac)-1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 -yl)ethan-1 -one, 1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 -yl)ethan-1 -one, salt with hydrochloric acid,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-(naphthalen-1 - yl)propan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one, salt with hydrochloric acid (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7S)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-hydroxy-2- phenylpropan-1 -one (mixture of stereoisomers),
2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-hydroxypropan-1 -one (mixture of stereoisomers),
2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro- [5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-
3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2R)-2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-methoxypropan-1 -one (mixture of stereoisomers), (2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-
(trifluoromethyl)phenyl]ethan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-[3-
(trifluoromethyl)phenyl]propan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one,
2-(3,5-dichlorophenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 - one,
(2R)-3,3,3-trifluoro-1 -[7-(5-fluoro-3'-methoxy[1 ,1 '-biphenyl]-2-yl)-3,9-diazaspiro[5.5]undecan-
3-yl]-2-methoxy-2-phenylpropan-1 -one, salt with hydrochloric acid, (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-phenylpropan-1 -one, salt with hydrochloric acid, and
(2R)-3,3,3-trifluoro-2-methoxy-1 -[(7S)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-phenylpropan-1 -one, salt with hydrochloric acid,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[(7S)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-phenylpropan-1 -one,
(2R)-1 -[7-(2-chlorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one (mixture of stereoisomers), (2R)-1 -[(7R)-7-(2-chlorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy- 2-phenylpropan-1 -one,
(2R)-1 -[(7S)-7-(2-chlorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one,
(2R)-1 -[7-(2-bromophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -[(7R)-7-(2-bromophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy- 2-phenylpropan-1 -one,
(2R)-1 -[(7S)-7-(2-bromophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy- 2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(2-ethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one,
(2R)-1 -[(7S)-7-(2-ethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -{7-[2-(trifluoromethyl)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}propan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-1 -[7-{2-[(1 R)-1 -hydroxyethyl]phenyl}-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -{7-[2-(difluoromethoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -{(7R)-7-[2-(difluoromethoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro- 2-methoxy-2-phenylpropan-1 -one,
(2R)-1 -{(7S)-7-[2-(difluoromethoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -{7-[2-(trifluoromethoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}propan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-phenoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- phenylpropan-1 -one,
(2R)-1 -[7-(2,3-dihydro-1 -benzofuran-7-yl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2S)-3,3,3-trifluoro-1 -[7-(2-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one (mixture of stereoisomers),
(2S)-3,3,3-trifluoro-1 -[(7R)-7-(2-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2S)-3,3,3-trifluoro-1 -[(7S)-7-(2-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one, (2S)-3,3,3-trifluoro-1 -[7-(3-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one (mixture of stereoisomers),
(2S)-3,3,3-trifluoro-1 -[(7R)-7-(3-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2S)-3,3,3-trifluoro-1 -[(7S)-7-(3-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-(2-fluoro-3-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-methoxy-1 -{7-[2-(methylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3- yl}-2-phenylpropan-1 -one, salt with hydrochloric acid,
(2R)-3,3,3-trifluoro-2-methoxy-1 -{(7R)-7-[2-(methylamino)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -{(7S)-7-[2-(methylamino)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one,
(2R)-1 -{7-[2-(dimethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -{(7R)-7-[2-(dimethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-1 -{(7S)-7-[2-(dimethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-1 -{(7R)-7-[2-(ethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one, salt with hydrochloric acid,
(2R)-1 -{(7S)-7-[2-(ethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one, salt with hydrochloric acid,
(2R)-1 -{(7R)-7-[2-(ethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-1 -{(7S)-7-[2-(ethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-(3-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-1 -[7-(5-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-1 -[7-(2-fluoro-6-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -[7-(2,3-dimethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one, (2R)-1 -[7-(3,5-dimethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -[7-(2-chloro-3-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -[7-(2,5-dimethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxy-5-methylphenyl)-3,9-diazaspiro[5.5]undecan- 3-yl]-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-1 -[7-(2-fluoro-6-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-1 -[7-(3-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-1 -[7-(5-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one,
(2R)-1 -[7-(3,6-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -[(7R)-7-(3,6-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3- trifluoro-2-methoxy-2-phenylpropan-1 -one,
(2R)-1 -[(7S)-7-(3,6-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3- trifluoro-2-methoxy-2-phenylpropan-1 -one,
(2R)-1 -[7-(2,3-difluoro-6-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -[7-(3,5-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -[7-(4,5-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-1 -{7-[2-(2,2-difluoroethoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -{7-[2-(2,2,2-trifluoroethoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}propan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(2S)-2-methoxypropoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-{2-[(2S)-2-hydroxy-3-methoxypropoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxy-2-phenylpropan-1 -one,
(2R)-1 -{7-[2-(cyclopropylmethoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one, (2R)-1 -{7-[2-(cyclopropyloxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -{7-[2-(3-methoxypropoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one,
(2R)-1 -[7-(2-ethoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-methoxy-1 -{(7R)-7-[2-(1 -methyl-1 H-pyrazol-4-yl)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -{(7S)-7-[2-(1 -methyl-1 H-pyrazol-4-yl)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one,
(2R)-1 -{(7R)-7-[2-(benzyloxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-1 -{(7S)-7-[2-(benzyloxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-(2-hydroxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one, salt with hydrochloric acid,
(2R)-3,3,3-trifluoro-1 -[7-(2-hydroxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -{7-[2-(3-hydroxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-2- methoxy-2-phenylpropan-1 -one, salt with hydrochloric acid,
(2R)-3,3,3-trifluoro-1 -{7-[2-(3-hydroxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-{2-[(2S)-2-hydroxypropoxy]phenyl}-3,9-diazaspiro[5.5]undecan-3-yl]- 2-methoxy-2-phenylpropan-1 -one, salt with hydrochloric acid,
(2R)-3,3,3-trifluoro-1 -[7-{2-[(2S)-2-hydroxypropoxy]phenyl}-3,9-diazaspiro[5.5]undecan-3-yl]- 2-methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-{2-[(2R)-2-hydroxypropoxy]phenyl}-3,9-diazaspiro[5.5]undecan-3-yl]-
2-methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(3RS)-7-(2-{[3-hydroxybutyl]oxy}phenyl)-3,9-diazaspiro[5.5]undecan-
3-yl]-2-methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-(2-{[(3R)-3-hydroxybutyl]oxy}phenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-(2-{[(3S)-3-hydroxybutyl]oxy}phenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -{7-[2-(2-hydroxy-2-methylpropoxy)phenyl]-3,9-diazaspiro[5.5]undecan- 3-yl}-2-methoxy-2-phenylpropan-1 -one, salt with hydrochloric acid, (2R)-3,3,3-trifluoro-1 -{7-[2-(2-hydroxy-2-methylpropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-
3-yl}-2-methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -{7-[2-(3-hydroxy-3-methylbutoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3- yl}-2-methoxy-2-phenylpropan-1 -one, salt with hydrochloric acid,
(2R)-3,3,3-trifluoro-1 -{7-[2-(3-hydroxy-3-methylbutoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3- yl}-2-methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -{7-[2-(2-methoxy-2-methylpropoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -{7-[2-(3-methoxy-3-methylbutoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(oxetan-3-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[(7R*)-7-{2-[(3-methyloxetan-3-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one
(2R)-3,3,3-trifluoro-1 -[7-{2-[(3-fluorooxetan-3-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxy-2-phenylpropan-1 -one,
3-[(2-{(9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9-diazaspiro[5.5]undecan-1 - yl}phenoxy)methyl]oxetane-3-carbonitrile,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-{[(2RS)-oxetan-2-yl]methoxy}phenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one (mixture of stereosiomers),
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-{[(2R)-oxetan-2-yl]methoxy}phenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-{[(2RS)-2-methyloxetan-2-yl]methoxy}phenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(oxan-4-yl)oxy]phenyl}-3,9-diazaspiro[5.5]undecan-3- yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-{[(3RS)-oxan-3-yl]methoxy}phenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[2-(morpholin-4-yl)ethoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[2-(1 ,2-oxazinan-2-yl)ethoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[7-{2-[(pyridin-4-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[7-{2-[(pyridin-3-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one, (2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[7-{2-[(pyridin-2-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(1 ,3-oxazol-2-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(1 ,3-oxazol-5-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(2-methyl-1 ,3-oxazol-4-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(5-methyl-1 ,3,4-oxadiazol-2-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[7-{2-[(1 ,3-thiazol-4-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(2-methylpyridin-4-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(3-methylpyridin-4-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[7-{2-[(3-fluoropyridin-4-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(2-methyl-1 ,3-thiazol-4-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(2-methyl-1 ,3-thiazol-5-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[7-{2-[(5-methyl-1 ,3,4-thiadiazol-2-yl)methoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one
4-[(2-{9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9-diazaspiro[5.5]undecan-1 - yl}phenoxy)methyl]pyridine-2-carbonitrile,
(2R)-3,3,3-trifluoro-1 -[7-{2-[2-(1 H-imidazol-1 -yl)ethoxy]phenyl}-3,9-diazaspiro[5.5]undecan- 3-yl]-2-methoxy-2-phenylpropan-1 -one,
1 -[2-(2-{9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9-diazaspiro[5.5]undecan-1 - yl}phenoxy)ethyl]imidazolidin-2-one,
3-[2-(2-{9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-3,9-diazaspiro[5.5]undecan-1 - yl}phenoxy)ethyl]-1 ,3-oxazolidin-2-one,
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[7-{2-[2-(1 H-pyrazol-1 -yl)ethoxy]phenyl}-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxy-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers), 2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
3.3.3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-
3-yl]propan-1 -one (mixture of stereoisomers),
2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2.2-difluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 - yl)ethan-1 -one,
2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
2-(5-bromo-2-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethyl)phenyl]ethan-1 -one (mixture of stereoisomers),
2-(3,5-dichlorophenyl)-1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]ethan- 1 -one (mixture of stereoisomers),
1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one (mixture of stereoisomers),
1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-[3- (trifluoromethyl)phenyl]propan-1 -one (mixture of stereoisomers),
2.2-difluoro-1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one (mixture of stereoisomers),
1 -[7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]ethan-
1 -one,
2-(3,5-dichlorophenyl)-1 -[7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 -one,
2.2-difluoro-1 -[(7R)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 - yl)ethan-1 -one,
1 -[7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-[3- (trifluoromethyl)phenyl]propan-1 -one,
2-(3,5-dichlorophenyl)-2,2-difluoro-1 -[7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3- yl]ethan-1 -one,
3.3.3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(4- methylphenyl)propan-1 -one (mixture of stereoisomers),
2.2-difluoro-1 -[(7R)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one
3.3.3-trifluoro-2-(4-fluorophenyl)-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2,2-difluoro-1 -[7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one,
2-(2,4-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
3.3.3-trifluoro-2-methoxy-2-(4-methoxyphenyl)-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
3.3.3-trifluoro-2-(3-fluoro-5-methylphenyl)-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(2-chlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(2-chlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
2-(4-chlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
3.3.3-trifluoro-2-(3-fluoro-4-methoxyphenyl)-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
3.3.3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- (naphthalen-1 -yl)propan-1 -one,
2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(4-bromophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
(2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers), 2-(5-bromo-2-fluorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
(2R)-2-(3-bromo-4-fluorophenyl)-3,3,3-trifluoro-2-(methoxymethyl)-1 -[7-(2-methoxyphenyl)- 3,9-diazaspiro[5.5]undecan-3-yl]propan-1 -one, salt with formic acid ,
(2S)-2-(3-bromo-4-fluorophenyl)-3,3,3-trifluoro-2-(methoxymethyl)-1 -[7-(2-methoxyphenyl)- 3,9-diazaspiro[5.5]undecan-3-yl]propan-1 -one, salt with formic acid,
(2R)-3,3,3-trifluoro-2-(4-fluorophenyl)-2-(methoxymethyl)-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
(2S)-3,3,3-trifluoro-2-(4-fluorophenyl)-2-(methoxymethyl)-1 -[7-(2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
1 -[7-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one,
1 -[7-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-[3- (trifluoromethyl)phenyl]propan-1 -one,
2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
1 -[7-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one,
1 -[7-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-[3- (trifluoromethyl)phenyl]propan-1 -one,
2-(4-bromophenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-bromophenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(4-chlorophenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
3.3.3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(4- fluorophenyl)-2-methoxypropan-1 -one (mixture of stereoisomers),
3.3.3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy- 2-(4-methylphenyl)propan-1 -one (mixture of stereoisomers),
2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers), 2-(2-chlorophenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
2-(2,4-dimethylphenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
3.3.3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy- 2-(naphthalen-1 -yl)propan-1 -one (mixture of stereoisomers),
2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
3.3.3-trifluoro-2-(3-fluoro-4-methoxyphenyl)-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
2.2-difluoro-1 -{(7R)-7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3- yl}-2-[2-(trifluoromethoxy)phenyl]ethan-1 -one,
2.2-difluoro-1 -{(7S)-7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3- yl}-2-[2-(trifluoromethoxy)phenyl]ethan-1 -one,
3.3.3-trifluoro-2-methoxy-1 -{7-[2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3- yl}-2-(naphthalen-1 -yl)propan-1 -one
1 -{7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-2-[2- (trifluoromethyl)phenyl]ethan-1 -one (mixture of stereoisomers),
2-(3,5-dichlorophenyl)-1 -{7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}ethan-1 -one (mixture of stereoisomers),
1 -{7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one (mixture of stereoisomers),
1 -{7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-2-methyl-2-[3- (trifluoromethyl)phenyl]propan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-1 -{7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-
3-yl}-2-methoxy-2-phenylpropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxy-2-phenylpropan-1 -one (mixture of stereoisomers), (2R)-3,3,3-trifluoro-1 -[7-(4-fluoro-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxy-2-phenylpropan-1 -one (Mixture of stereoisomers) , 1 -[7-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethyl)phenyl]ethan-1 -one (mixture of stereoisomers),
2-(3,5-dichlorophenyl)-1 -[7-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9- diazaspiro[5.5]undecan-3-yl]ethan-1 -one (mixture of stereoisomers),
1 -[7-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one (mixture of stereoisomers), and
1 -[7-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2- [3-(trifluoromethyl)phenyl]propan-1 -one (mixture of stereoisomers),
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a mixture of same.
9. The compound according to claim 1 , 2, 3, 4, 5, 6 or 7 which is selected from the group consisting of:
2-phenyl-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 -one,
2-methyl-2-phenyl-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]propan-1 -one, (1 -phenylcyclopropyl)[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]methanone,
(1 -phenylcyclopentyl)[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]methanone,
[1 -(3,5-dimethylphenyl)cyclopentyl][(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yljmethanone,
2-(naphthalen-1 -yl)-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 -one,
1 -(7R)-[7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]ethan-1 -one,
1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-(trifluoromethyl)phenyl]propan-1 -one (mixture of stereoisomers),
(2S)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one,
2-(3,5-dimethylphenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
3,3,3-trifluoro-2-(4-fluorophenyl)-2-methoxy-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3-chlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3-bromophenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers), 2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
2-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one (mixture of stereoisomers),
3,3,3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-
3-yl]propan-1 -one (mixture of stereoisomers),
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-phenylethan-1 -one,
2.2-difluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-phenylethan-1 - one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethyl)phenyl]ethan-1 -one (mixture of stereoisomers),
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethyl)phenyl]propan-1 -one (mixture of stereoisomers),
2.2-difluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one, salt with hydrochloric acid,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 -yl)ethan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 -yl)ethan-1 -one, salt with hydrochloric acid,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-(naphthalen-1 - yl)propan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-hydroxy-2- phenylpropan-1 -one,
2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-hydroxypropan-1 -one (mixture of stereoisomers),
2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro- [5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-chloro-4-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-
3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers), (2S)-2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2R)-2-(3-bromo-5-methylphenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-bromo-5-chlorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-3,3,3-trifluoro-2-(3-fluoro-5-methylphenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-
(trifluoromethyl)phenyl]ethan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-[3-
(trifluoromethyl)phenyl]propan-1 -one,
1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one,
2-(3,5-dichlorophenyl)-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]ethan-1 - one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(5-fluoro-3'-methoxy[1 ,1 '-biphenyl]-2-yl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxy-2-phenylpropan-1 -one, salt with hydrochloric acid, and
(2R)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-phenylpropan-1 -one, salt with hydrochloric acid,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-(2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3- yl]-2-phenylpropan-1 -one, (2R)-1 -[(7R)-7-(2-chlorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy- 2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(2-bromophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy- 2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(2-ethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy-2- phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl-1 -{(7R)-7-[2-(trifluoromethyl)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}propan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-{2-[(1 R)-1 -hydroxyethyl]phenyl}-3,9-diazaspiro[5.5]undecan-3- yl]-2-methoxy-2-phenylpropan-1 -one,
(2R)-1 -{(7R)-7-[2-(difluoromethoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro- 2-methoxy-2-phenylpropan-1 -one,
(2S)-3,3,3-trifluoro-1 -[(7R)-7-(2-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2S)-3,3,3-trifluoro-1 -[(7R)-7-(3-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methoxy-2- phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(2-fluoro-3-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -{(7R)-7-[2-(methylamino)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one,
(2R)-1 -{(7R)-7-[2-(dimethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-1 -{(7R)-7-[2-(ethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one, salt with hydrochloric acid,
(2R)-1 -{(7R)-7-[2-(ethylamino)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(3-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(5-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(2-fluoro-6-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(3,5-dimethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(2-chloro-3-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one, (2R)-1 -[(7R)-7-(2,5-dimethylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -[(7R)-7-(2-methoxy-5-methylphenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(2-fluoro-6-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(3-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methoxy-2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(3,6-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3- trifluoro-2-methoxy-2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(2,3-difluoro-6-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3- trifluoro-2-methoxy-2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(3,5-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3- trifluoro-2-methoxy-2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(4,5-difluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3- trifluoro-2-methoxy-2-phenylpropan-1 -one,
(2R)-1 -[(7R)-7-(2-ethoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-3,3,3-trifluoro-2-methoxy- 2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-2-methoxy-1 -{(7R)-7-[2-(1 -methyl-1 H-pyrazol-4-yl)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-phenylpropan-1 -one,
(2R)-1 -{(7R)-7-[2-(benzyloxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-3,3,3-trifluoro-2- methoxy-2-phenylpropan-1 -one,
2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxy-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-3- yl]propan-1 -one (mixture of stereoisomers),
(2R)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
(2S)-2-(3-chlorophenyl)-3,3,3-trifluoro-2-hydroxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
2-(3,5-dichlorophenyl)-3,3,3-trifluoro-2-hydroxy-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
3,3,3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)-1 -[(7R)-7-phenyl-3,9-diazaspiro[5.5]undecan-
3-yl]propan-1 -one (mixture of stereoisomers),
(2R)-3,3,3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one, (2S)-3,3,3-trifluoro-2-methoxy-2-(naphthalen-1 -yl)-1 -[(7R)-7-phenyl-3,9- diazaspiro[5.5]undecan-3-yl]propan-1 -one,
2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2.2-difluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-(naphthalen-1 - yl)ethan-1 -one,
2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(3-bromo-5-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
2-(5-bromo-2-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one (mixture of stereoisomers),
(2R)-2-(5-bromo-2-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(2S)-2-(5-bromo-2-fluorophenyl)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluorophenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxypropan-1 -one,
(7R)-1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-
(trifluoromethyl)phenyl]ethan-1 -one,
(7R)-2-(3,5-dichlorophenyl)-1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3- yl]ethan-1 -one,
(7R)-1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-
(trifluoromethoxy)phenyl]ethan-1 -one,
(7R)-1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-[3-
(trifluoromethyl)phenyl]propan-1 -one,
(7R)-2,2-difluoro-1 -[7-(4-fluoro-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-
(trifluoromethoxy)phenyl]ethan-1 -one,
(7R)-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-
(trifluoromethoxy)phenyl]ethan-1 -one,
(7R)-1 -[7-(4-fluoro-2-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-methyl-2-[3-
(trifluoromethyl)phenyl]propan-1 -one,
2.2-difluoro-1 -{(7R)-7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3- yl}-2-[2-(trifluoromethoxy)phenyl]ethan-1 -one,
(7R)-1 -{7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-2-[2-
(trifluoromethyl)phenyl]ethan-1 -one, 2-(3,5-dichlorophenyl)-1 -{(7R)-7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}ethan-1 -one,
(7R)-1 -{7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-2-[2-
(trifluoromethoxy)phenyl]ethan-1 -one,
(7R)-1 -{7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9-diazaspiro[5.5]undecan-3-yl}-2-methyl-
2-[3-(trifluoromethyl)phenyl]propan-1 -one,
(2R)-3,3,3-trifluoro-1 -{(7R)-7-[4-fluoro-2-(3-methoxypropoxy)phenyl]-3,9- diazaspiro[5.5]undecan-3-yl}-2-methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxy-2-phenylpropan-1 -one,
(2R)-3,3,3-trifluoro-1 -[(7R)-7-(4-fluoro-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-3,9- diazaspiro[5.5]undecan-3-yl]-2-methoxy-2-phenylpropan-1 -one,
(7R)-1 -[7-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2-
(trifluoromethyl)phenyl]ethan-1 -one,
2-(3,5-dichlorophenyl)-1 -[(7R)-7-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9- diazaspiro[5.5]undecan-3-yl]ethan-1 -one,
(7R)-1 -[7-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2-[2- (trifluoromethoxy)phenyl]ethan-1 -one, and
(7R)-1 -[7-(4-fluoro-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-3,9-diazaspiro[5.5]undecan-3-yl]-2- methyl-2-[3-(trifluoromethyl)phenyl]propan-1 -one,
or a tautomer, an N-oxide, a hydrate, a solvate, or a mixture of same.
10. A method of preparing a compound of general formula (I) according to any one of claims 1 , 2 or 8, said method comprising the step of allowing an intermediate compound of general formula (III) :
Figure imgf000690_0001
in which R1 is as defined for the compound of general formula (I) according to any one of claims 1 , 2 or 8, and in which Rd represents a protecting group,
to react with a compound of general formula (XXI) :
Figure imgf000690_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 or 8,
thereby giving a compound of general formula (II) :
Figure imgf000691_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 or 8, and in which Rd represents a protecting group,
and allowing said compound of general formula (II) to react with an acid,
thereby giving a compound of general formula (I) :
Figure imgf000691_0002
in which 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 or 8,
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.
1 1 . A compound of general formula (I) according to any one of claims 1 to 9 or of general formula (l-a) according to any one of claims 1 to 9, for use in the treatment and/or prophylaxis of a disease.
12. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 9 or of general formula (l-a) according to any one of claims 1 to 9 and one or more pharmaceutically acceptable excipients.
13. 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 9 or of general formula (l-a) according to any one of claims 1 to 9, and
• one or more further active ingredients, in particular anti-cancer agents.
14. Use of a compound of general formula (I) according to any one of claims 1 to 9 or of general formula (l-a) according to any one of claims 1 to 9 for the treatment and/or prophylaxis of a disease.
15. Use of a compound of general formula (I) according to any one of claims 1 to 9 or of general formula (l-a) according to any one of claims 1 to 9 for the preparation of a medicament for the treatment or prophylaxis of a disease.
16. Use according to claim 1 1 , 14 or 15, wherein the disease is a hyperproliferative disorder.
17. Use according to claim 16, wherein the disease is a cancer.
18. Use according to claim 17, wherein the cancer disease is selected from Kidney Cancer, Bladder Cancer, Colon Cancer, Mesothelioma, Breast Cancer, Pancreatic Cancer, Ovarian Cancer, Brain Cancer (Glioblastoma, Astrocytoma), Connective Tissue Cancer (Synovial sarcoma, Fibrosarcoma, Liposarcoma), Head & Neck Cancer (Pharynx, Tongue), Upper aerodigestive tract Cancer (Tongue squamous cell carcinoma), Lymphoma, (Diffuse Large B- Cell Lymphoma), Leukemia (Acute myeloid leukemia, Plasma cell leukemia), Multiple Myeloma, Liver Cancer, Lung Cancer, Skin Cancer, Thyroid Cancer, Endometrial Cancer and Cervical Cancer.
19. Use of a compound of general formula
Figure imgf000692_0001
Figure imgf000692_0002
in which R1 is as defined for the compound of general formula (I) according to any one of claims 1 , 2 or 8, and in which Rd represents a protecting group,
for the preparation of a compound of general formula (I) according to any one of claims 1 , 2 or 8.
20. Use of a compound of general formula (XXI)
Figure imgf000692_0003
(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 or 8,
for the preparation of a compound of general formula (I) according to any one of claims 1 , 2 or 8.
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