WO2017108204A1 - Novel substituted spiro-[indoline heterocycloalkane] compounds as phosphodiesterase inhibitors - Google Patents

Novel substituted spiro-[indoline heterocycloalkane] compounds as phosphodiesterase inhibitors Download PDF

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Publication number
WO2017108204A1
WO2017108204A1 PCT/EP2016/025187 EP2016025187W WO2017108204A1 WO 2017108204 A1 WO2017108204 A1 WO 2017108204A1 EP 2016025187 W EP2016025187 W EP 2016025187W WO 2017108204 A1 WO2017108204 A1 WO 2017108204A1
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Prior art keywords
pyrimidin
indoline
spiro
alkyl
oxetan
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PCT/EP2016/025187
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French (fr)
Inventor
Ingo Konetzki
Florian JAKOB
Markus Wagener
André Welbers
Christian Hesslinger
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Grünenthal GmbH
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Publication of WO2017108204A1 publication Critical patent/WO2017108204A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to novel substituted spiro-indoline heterocycloalkane compounds that are useful as medicaments.
  • This invention also relates to uses of the compounds to make medicaments and treatments comprising the administration of the compounds to humans in need of the treatments.
  • This invention also relates to the preparation of said novel compounds.
  • this invention relates to pharmaceutical compositions and kits comprising the compounds.
  • Phosphodiesterases (abbreviated as PDEs), or more accurately 3',5'-cyclonucleotide phosphor- diesterases, are enzymes that catalyse the hydrolysis of the second messengers cAMP (cyclic adenosine monophosphate) and cGMP (cyclic guanosine monophosphate) to 5'-AMP (5'-adenosine mono- phosphate)-and 5'-GMP (5'-guanosine monophosphate).
  • Phosphodiesterases are a group of enzymes encompassing 1 1 gene families (PDE1-1 1 ), which differ inter alia through their affinity to cAMP and cGMP. Inhibition of phosphodiesterases thus represents a mechanism for modulating cellular processes and can be used to alleviate or cure disease conditions. Inhibitors of specific PDEs are known.
  • PDE4 isoenzymes as targets for anti-asthma drugs. European Respiratory Journal 8, 1 179- 1 183), has led to the development of PDE4 inhibitors having an anti-inflammatory effect.
  • PDE4 inhibitor having an anti-inflammatory effect is roflumilast for example (trade name Daxas ® ), which was approved as a medicament for the treatment of COPD (chronic obstructive pulmonary disease).
  • PDE4 inhibtor is apremilast (Otezla ® ) that was recently approved for the treatment of psoriatic athritis and plaque psoriasis.
  • apremilast Otezla ®
  • side-effects such as nausea, diarrhoea and headaches are observed, which limit their dose in humans.
  • Undesired side-effects in humans were not only observed with roflumilast and apremilast but also with other PDE4 inhibitors, so that the therapeutic range (therapeutic window) of such medicaments is relatively narrow.
  • PDE4 inhibitors having less severe or fewer side-effects and a better therapeutic window would therefore be desirable.
  • Phosphodiesterase 4 (PDE4) is cAMP-specific and encompasses 4 different subtypes (PDE4A, PDE4B, PDE4C and PDE4D).
  • PDE4A, PDE4B, PDE4C and PDE4D are cAMP-specific and encompasses 4 different subtypes.
  • PDE4A, PDE4B, PDE4C and PDE4D As is described below, efforts are being made to find subtype-selective PDE4 inhibitors, above all PDE4B-selective inhibitors, that have less severe or no side-effects, thus increasing the therapeutic range for such compounds significantly.
  • the inhibition of PDE4D is associated with the occurrence of undesired side-effects, such as for example diarrhoea, vomiting and nausea (see in this regard Mori, F. et al.
  • the therapeutic range of a pharmaceutical active ingredient describes the gap between its therapeutic dose and a dose that would lead to a toxic or an undesired effect.
  • the therapeutic range is often also referred to as the therapeutic window or therapeutic index. These names are used synonymously in the present application.
  • the inventors have now found novel substituted spiro-indoline heterocycloalkane compounds that possess the desired inhibiting and PDE4B-selective properties. These spiro-indoline heterocycloalkane compounds are therefore particularly suitable for the treatment of diseases and conditions in which inhibition of the PDE4 enzyme, in particular PDE4B, is advantageous.
  • the first aspect of the invention thus relates to a compound characterized in that the compound has the general formula (I)
  • A, B and C independently represent CH or N;
  • n 0, 1 , 2 or 3, with the proviso that the sum (m + n) is 2, 3 or 4;
  • R is selected from Ci_ 6 -alkyl, unsubstituted or mono- or polysubstituted; or
  • R 2 is selected from H or Ci-C6-alkyl, unsubstituted or mono- or polysubstituted;
  • R and R 2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyi
  • said 3- to 12-membered heterocycloalkyi may contain one or two additional heteroatoms selected from the group consisting of O, S and N and may be mono- or bicyclic and
  • G represents a phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or said 5- or 6-membered heteroaryl is unsubstituted or substituted with one, two, three or four substituents Z;
  • Z at each occurcence is independently selected from the group consisting of halogen, OH, CN, SH, N0 2 , Ci-C6-alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl, (Ci-C6)-hydroxyalkyl, (d-d)-cyanoalkyl, Ci-C6-alkoxy, (d-d)- thioalkyl, (C C 6 )-haloalkyl, (d-C 6 -alkoxy)-(d-C 6 -alkylenyl), (d-C 6 -alkoxy)-d-C 6 -alkoxy, (d-C 6 )-thio- haloalkyl, (C C 6 )-haloalkoxy, (d-d-thioalkyl)-(d-d-alkylenyl), d-d-cycloalkyl, (d-d-cycloalkyl)-(d
  • single stereoisomer in the sense of the present invention preferably means an individual enantiomer or diastereomer.
  • mixture of stereoisomers means in the sense of this invention the racemate and mixtures of enantiomers and/or diastereomers in any mixing ratio.
  • physiologically acceptable salt in the sense of this invention preferably comprises a salt of at least one compound according to the present invention and at least one physiologically acceptable acid or base.
  • a physiologically acceptable salt of at least one compound according to the present invention and at least one physiologically acceptable acid or one physiologically acceptable base preferably refers in the sense of this invention to a salt of at least one compound according to the present invention with at least one inorganic or organic acid or with at least one inorganic or organic base respectively which is physiologically acceptable - in particular when used in human beings and/or other mammals.
  • physiologically acceptable solvate in the sense of this invention preferably comprises an adduct of one compound according to the present invention and/or a physiologically acceptable salt of at least one compound according to the present invention with distinct molecular equivalents of one solvent or more solvents.
  • the invention also includes isotopic isomers of a compound of the invention, wherein at least one atom of the compound is replaced by an isotope of the respective atom which is different from the naturally predominantly occurring isotope, as well as any mixtures of isotopic isomers of such a compound.
  • Preferred isotopes are 2 H (deuterium), 3 H (tritium), 3 C and 4 C.
  • Isotopic isomers of a compound of the invention can generally be prepared by conventional procedures known to a person skilled in the art.
  • halogen represents the radicals F, CI, Br and I, preferably the radicals F and CI, particularly preferred F.
  • -C 6 -alkyl is understood to mean branched and unbranched alkyl groups consisting of 1 to 6 carbon atoms.
  • -C 6 -alkyl radicals are CH 3 , CH 2 CH 3 , (CH 2 )2CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , n-pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 1 ,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, n-hexyl, 1-methylpentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl.
  • Ci-C4-alkyl radicals are preferred, in particular CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 or CH(CH 3 ) 2 .
  • -C 6 -alkoxy is understood to mean branched and unbranched alkoxy groups consisting of 1 to 6 carbon atoms.
  • -C 6 -alkoxy radicals are OCH 3 , OCH 2 CH 3 , 0(CH 2 ) 2 CH 3 , OCH(CH 3 ) 2 , 0(CH 2 ) 3 CH 3 , OCH(CH 3 )CH 2 CH 3 , OCH 2 CH(CH 3 ) 2 , OC(CH 3 ) 3 , 0(CH 2 ) 4 CH 3 , 0(CH 2 ) 2 CH(CH 3 ) 2 , OCH 2 CH(CH 3 )CH 2 CH 3 , OCH(CH 3 )(CH 2 ) 2 CH 3 , OC(CH 3 ) 2 CH 2 CH 3 , OCH 2 C(CH 3 ) 3 , 0(CH 2 ) 5 CH 3 , 0(CH 2 ) 3 CH(CH 3 ).
  • Ci-C 4 -alkoxy radicals are preferred, in particular OCH 3 , OCH 2 CH 3 , 0(CH 2 ) 2 CH 3 or OCH(CH 3 ) 2 .
  • the term "(Ci-C6)-haloalkyl” is understood to be a Ci-C6-alkyl in which at least one hydrogen is exchanged for a halogen atom, preferably for F or CI, particularly preferably for F.
  • the haloalkyi can be branched or unbranched and optionally mono- or polysubstituted.
  • -C 6 )-halo- alkyl radicals are (C C 3 )-haloalkyl radicals, in particular CHF 2 , CH 2 F, CF 3 , CH 2 CH 2 F, CH 2 CHF 2 and CH 2 CF 3
  • (Ci-C6)-haloalkoxy is understood to be a Ci-C6-alkoxy in which at least one hydrogen is exchanged for a halogen atom, preferably for F or CI, particularly preferably for F.
  • the haloalkoxy radicals can be branched or unbranched and optionally mono- or polysubstituted.
  • -C 6 )-haloalkoxy radicals are (C-
  • (Ci-C6)-hydroxyalkyl is understood to be a Ci-C6-alkyl in which at least one hydrogen is exchanged for a hydroxyl group.
  • the hydroxyalkyl radicals can be branched or unbranched and optionally mono- or polysubstituted.
  • Preferred (Ci-C6)-hydroxyalkyl radicals are (C1-C3)- hydroxyalkyl radicals, in particular CH 2 OH, CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH and CH 2 CH(OH)CH 2 OH .
  • -C 6 )-cyanoalkyl is understood to be a C-
  • the hydroxyalkyl radicals can be branched or unbranched and optionally mono- or polysubstituted.
  • Preferred (Ci-Ce)-cyanoalkyl radicals are (Ci-C 3 )- cyanoalkyl radicals, in particular CH 2 CN, CH 2 CH 2 CN and CH 2 CH 2 CH 2 CN.
  • (Ci-C6)-thioalkyl is understood to mean branched and unbranched thioalkyl groups consisting of 1 to 6 carbon atoms.
  • Examples of (Ci-C6)-thioalkyl radicals are SCH 3 , SCH 2 CH 3 , S(CH 2 ) 2 CH 3 , SCH(CH 3 ) 2 , S(CH 2 ) 3 CH 3 , SCH(CH 3 )CH 2 CH 3 , SCH 2 CH(CH 3 ) 2 , SC(CH 3 ) 3 , S(CH 2 ) 4 CH 3 , S(CH 2 ) 2 CH(CH 3 ) 2 , SCH 2 CH(CH 3 )CH 2 CH 3 , SCH(CH 3 )(CH 2 ) 2 CH 3 , SC(CH 3 ) 2 CH 2 CH 3 , SCH 2 C(CH 3 ) 3 , S(CH 2 ) 5 CH 3 , S(CH 2 ) 3 CH(CH 3 ) 2
  • (Ci-C6)-thiohaloalkyl is understood to be a (Ci-Ce)-thioalkyl in which at least one hydrogen is exchanged for a halogen atom, preferably for F or CI, particularly preferably for F.
  • the thiohaloalkyl radicals can be branched or unbranched and optionally mono- or polysubstituted.
  • Preferred (Ci-C6)-thiohaloalkyl radicals are (Ci-C 3 )-thiohaloalkyl radicals, in particular SCHF 2 , SCH 2 F, SCF 3 , SCF 2 CH 3 , SCH 2 CH 2 F, SCH 2 CHF 2 and SCH 2 CF 3 .
  • Ci_C 3 -alkylen and “d-C 6 -alkylen” are understood to be an acyclic saturated hydrocarbon radicals having 1 , 2 or 3 carbon atoms or 1 , 2, 3, 4, 5 or 6 carbon atoms, which can be branched or unbranched and unsubstituted or substituted once or several times, for example 2, 3, 4 or 5 times, by identical or different substituents and which link a corresponding moiety to the main structure.
  • Alkylene groups can preferably be chosen from the group consisting of CH 2 , CH 2 CH 2 , CH(CH 3 ), CH 2 CH 2 CH 2 , CH(CH 3 )CH 2 , C(CH 3 ) 2 , CH(CH 2 CH 3 ).
  • the alkylene groups can particularly preferably be chosen from the group consisting of CH 2 , CH 2 CH 2 and CH 2 CH 2 CH 2 .
  • C 2 -C 6 -alkenyl is understood to mean branched and unbranched unsaturated alkyl groups consisting of 2 to 6 carbon atoms and having at least one double bond.
  • C 2 -C 6 -alkenyls examples are ethenyl (also referred to as vinyl), prop-1-enyl, prop-2-enyl (also referred to as allyl), but-1-enyl, but-2-enyl, but-3-enyl, pent-1-enyl and hex-1-enyl.
  • the designation C 2 -C 6 -alkenyl includes all possible isomers, i.e. structural isomers (constitutional isomers) and stereoisomers ((Z) and (E) isomers).
  • C 2 -C 6 -alkinyl is understood to mean branched and unbranched unsaturated alkyl groups consisting of 2 to 6 carbon atoms and having at least one triple bond.
  • Examples of C 2 -C 6 -alkinyls are ethinyl.
  • C 3 . 6 -cycloalkyl denotes cyclic saturated hydrocarbons having 3, 4, 5 or 6 carbon atoms respectively, which can be unsubstituted or substituted once or several times, for example by 2, 3, 4 or 5 identical or different radicals, on one or more ring members.
  • C 3 . 6 -cycloalkyl can preferably be chosen from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • 3- to 7-membered heterocycloalkyl and "3- to 12-membered heterocycloalkyl” are understood to mean heterocycloaliphatic saturated or unsaturated (but not aromatic) residues having 3 to 7, i.e. 3, 4, 5, 6 or 7, or having 3 to 12, i.e.
  • the heterocycloalkyl residues may be mono- or bi- cyclic.
  • the term "5- or 6-membered heteroaryl” is understood to represent a 5- or 6- membered cyclic aromatic residue containing at least 1 , if appropriate also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are each preferably selected independently of one another from the group S, N and O and the heteroaryl residue can be unsubstituted or mono- or polysubstituted, including the formation of N-oxides; e.g. substituted by 2, 3, 4 or 5 substituents, whereby the substituents can be the same or different and be in any desired and possible position of the heteroaryl.
  • the binding to the superordinate general structure can be carried out via any desired and possible ring member of the heteroaryl residue if not indicated otherwise.
  • the heteroaryl may be condensed with a 4-, 5-, 6- or 7- membered ring, being carbocyclic or heterocyclic, wherei the heteroatoms of the heterocyclic ring are each preferably selected independently of one another from the group S, N and O, and wherein said condensed ring may be saturated, partially unsaturated or aromatic and may be unsubstituted or mono- or polysubstituted; e.g. substituted by 2, 3, 4 or 5 substituents, whereby the substituents can be the same or different and be in any desired and possible position.
  • heteroaryl moieties are benzofuranyl, benzoimidazolyl, benzo-thienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl, quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl, furyl (furanyl), imidazolyl, imidazo-thiazolyl, indazolyl, indolizinyl, indolyl, isoquinolinyl, isoxazoyl, isothiazolyl, indolyl, naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pyrazolyl, pyridyl (2-pyridyl, 3-pyridyl,
  • the substituents may be selected from the group consisting of F, CI, Br, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, CN, (Ci-C 6 )-alkyl, (d-C 6 )-hydroxyalkyl, (d-C 6 )-alkoxy, (d-C 6 )-hydroxyalkoxy, C 3 -C 6 -cyclo- alkyl, NH 2 , NH(d-C 6 -alkyl), N(d-C6-alkyl)CO(d-C 6 -alkyl), NHCO(d-C 6 -hydroxyalkyl), N(d-C 6 -alkyl)- CO(Ci-C 6 -hydroxyalkyl), N(d-C 6 -alkyl) 2 , NH(d-C 6 -hydroxyalkyl), N(Ci-C6-alkyl)(d-C 6 -hydroxyalkyl), NHCO(
  • the substituents may be selected from the group consisting of F, CI, Br, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, CN, (C C 6 )-alkyl, (C C 6 )-hydroxyalkyl, (C C 6 )-alkoxy, C 3 -C 6 -cycloalkyl, NH 2 , NH(C C 6 - alkyl), N(d-C 6 -alkyl) 2 , NHCO(d-C 6 -alkyl), NH-CONH(d-C 6 -alkyl), NHCON(d-C 6 -alkyl) 2 , NHS(0) 2 (d- C 6 -alkyl), CONH 2 , CONH(d-C 6 -alkyl), CON(d-C 6 -alkyl) 2 , S(0)(d-C 6 -alkyl) and S(0) 2 (d-C 6 -alkyl).
  • residues containing two or more residues of the same type such as d-d-alky! in N(Ci-C6-alkyl) 2
  • the two or more residues may be identical or different from each other. If the residues may be substituted, then it is understood that each residue may be independently substituted.
  • N(d-C 6 -alkyl) 2 encompasses for example inter alia N(CH 3 ) 2 , N(CH 3 )(CH 2 CH 3 ), N(CH 2 CH 3 ) 2 , N(CH 3 )(CH 2 CH 2 OH) and N(CH 2 CH 2 OH) 2 .
  • the compound of formula (I) is characterized in that each of A, B and C represents CH. ln another embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that
  • n 1 (thus forming a 3,3-oxetanylen) or
  • n is 2 (thus forming a 3,3-tetrahydrofuranylen) or
  • n 2 (thus forming a 4,4-tetrahydropyranylen) or
  • n 3 (thus forming a 3,3-tetrahydropyranylen),
  • n is 1 or m is 1 and n is 2 or m is 2 and n is 2, preferably m is 1 and n is 1. More preferably, the compound of formula (I) is characterized in that m is 1 and n is 1.
  • the compound of formula (I) is characterized in that G is one of the following groups G1 to G44
  • R 2 is selected from the group consisting of H, CH 3 or CH 2 CH 3 ;
  • k at each occurrence is 0, 1 , 2, 3 or 4;
  • Z at each occurcence is independently selected from the group consisting of F, CI, Br, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , OH, CN, d-Ce-alkyl, Ci-C 6 -hydroxyalkyl, Ci-C 6 -alkoxy, C 3 -C 6 -cycloalkyl, 3- to 7- membered heterocycloalkyl, NH 2 , NH(C C 6 -alkyl), N(C C 6 -alkyl) 2 , NHCO(C C 6 -alkyl), NHCONH(C C 6 - alkyl), NHCON(C C 6 -alkyl) 2 , (C C 6 -alkylen)NH 2 , (C 1 -C 6 -alkylen)NH(C 1 -C 6 -alkyl), (C 1 -C 6 -alkylen)N(C 1 -C 6 - al
  • the compound of formula (I) is characterized in that G is one of the groups G1 to G44
  • R 2 is selected from the group consisting of H, CH 3 or CH 2 CH 3 ;
  • k at each occurrence is 0, 1 , 2, 3 or 4;
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2
  • R 2 is selected from the group consisting of H, CH 3 or CH 2 CH 3 ;
  • k at each occurrence is 0, 1 , 2, 3 or 4;
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 CN, SOCH 3 , S0 2 CH 3 ,
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 ,
  • the compound of formula (I) is characterized in that G is one of the groups G1 to G44
  • R 2 is selected from the group consisting of H, CH 3 or CH 2 CH 3 ;
  • k at each occurrence is 0, 1 , 2, 3 or 4;
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH(CH 3 ) 2 NH 2 , CH(CH 3 ) 2 NH 2
  • G is selected from G1 or G2, wherein
  • k at each occurrence is 0, 1 , 2 or 3;
  • Z at each occurcence is independently selected from the group consisting of F, CI, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, CN, Ci-C 6 -alkyl, (Ci-C 6 )-hydroxyalkyl, d-C 6 -alkoxy, C 3 -C 6 -cycloalkyl, 3- to 7-membered heterocycloalkyl, NH 2 , NH(d-C 6 -alkyl), N(d-C 6 -alkyl) 2 , NHCO(d-C 6 -alkyl), CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), NH-S(0) 2 (d-C 6 -alkyl), CONH 2 , CONH(d-C 6 - alkyl), CO-N(d-C 6 -alkyl) 2 ,
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH(CH 3 ) 2 NH 2 , CH(CH 3 ) 2 NH 2 , CH(
  • G is selected from G1 or G2, wherein
  • k at each occurrence is 0, 1 , 2 or 3;
  • Z at each occurcence is independently selected from the group consisting of
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH(CH 3 ) 2 NH 2 , CH(CH 3 ) 2 NH 2 , CH(
  • the compound of formula (I) is characterized in that G is one of the following groups G45 or G2
  • k at each occurrence is 0, 1 or 2;
  • Z A is H or F
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2
  • the compound of formula (I) is characterized in that G is one of the following groups G45 or G2
  • k at each occurrence is 0, 1 or 2;
  • Z A is H or F
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3
  • the compound of formula (I) is characterized in that
  • R is selected from Ci-C6-alkyl, C 3 -C 6 -cycloalkyl or 3- to 7-membered heterocycloalkyl,
  • R 2 is selected from H or Ci-C6-alkyl
  • -C 6 -alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, OH, C-
  • R and R 2 together with the nitrogen atom to which they are attached form a 3- to 12-membered
  • said 3- to 12-membered heterocycloalkyl may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
  • R is selected from Ci-C6-alkyl, C 3 -C 6 -cycloalkyl or 3- to 7-membered heterocycloalkyl,
  • said 3- to 7-membered heterocycloalkyl may contain one or two heteroatoms selected from the group consisting of O, S and N and
  • R 2 is selected from H or Ci-C6-alkyl
  • Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, OH, C-
  • R and R 2 together with the nitrogen atom to which they are attached form a 3- to 12-membered
  • heterocycloalkyl wherein said 3- to 12-membered heterocycloalkyi may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
  • R denotes Ci_ 6 -alkyl
  • CN F, CI, Br, CF 3 , CHF 2 , CH 2 F, OCF 3 , d-C 6 -alkyl, d-C 6 -alkoxy, NH 2 , NH(d-C 6 -alkyl), N(d-d alkyl) 2 , NHCO(d-C 6 -alkyl), C0 2 H, COO(d-C 6 -alkyl), CONH 2 , CONH(d-C 6 -alkyl) and CON(d- C 6 -alkyl) 2 , and
  • R is H, (Ci-C 6 -alkyl), (Ci-C 6 )- ydroxyalkyl, (Ci-C 6 )-cyanoalkyl, C 3 -C 6 -cycloalkyl, CO(Ci-C 6 -alkyl) or S0 2 (Ci-C 6 -alkyl);
  • m 0, 1 , 2, 3, 4 or 5
  • X 3 at each occurrence is independently selected from the group consisting of
  • OH, 0, CN, F, CI, Br, CF 3 , CHF 2 , CH 2 F, OCF 3 , C C 6 -alkyl, C C 6 -alkoxy, NH 2 , NH(C C 6 -alkyl), N(d-C6-alkyl) 2 , NHCO(Ci-C e -alkyl), C0 2 H, COO(Ci-C e -alkyl). CONH 2 , CONH(Ci-C e -alkyl) and CON(Ci-Ce-alkyl)2,
  • R 2 is selected from H, C-
  • R is selected from one of the following substructures M1 to M76:
  • R 2 is selected from H , Ci-C6-alkyl, (CrC6)-hydroxyalkyl or (Ci-C6-alkoxy)-Ci-C6-alkyl,
  • R 2 is selected from H or CH 3 .
  • R and R 2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyi
  • said 3- to 12-membered heterocycloalkyi may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
  • R and R 2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyi
  • R 5 is selected from the group consisting of H, C-
  • p is 0, 1 , 2, 3, 4 or 5;
  • R and R 2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyi
  • the 3- to 12-membered heterocydoalkyi is selected from the qroup consisting of Q'8, Q'23, Q'32, Q'40 and Q'44.
  • the compound of formula (I) is characterized in that
  • Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, Ci-C6-alkoxy, (Ci-d- alkoxy)-C C 6 -alkoxy, (hydroxy)-C C 6 -alkoxy, NH 2 , NH(C C 6 -alkyl), N(C C 6 -alkyl) 2 , NH(C C 6 - hydroxyalkyl), N(C 1 -C 6 -alkyl)(C 1 -C 6 -hydroxyalkyl), N(C C 6 -hydroxyalkyl) 2 , NHCO(C C 6 -alkyl),
  • said 3- to 7-membered heterocydoalkyi may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
  • the compound of formula (I) is characterized in that
  • R is selected from OH, CN, Ci-d-alkyl, NH 2 , NH(d-C 6 -alkyl), N(d-C 6 -alkyl) 2 , C 3 -C 6 -cycloalkyl or 3- to 7-membered heterocydoalkyi,
  • d-C 6 -alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, NH 2 , d-d-alkoxy, C 3 -C 6 -cycloalkyl and 3- to 7-membered heterocydoalkyi;
  • said 3- to 7-membered heterocydoalkyi may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
  • R is selected from Ci-C6-alkyl, C 3 -C 6 -cycloalkyl or 3- to 7-membered heterocycloalkyl,
  • Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, Ci-C6-alkoxy, (C1-C6- alkoxy)-Ci-C 6 -alkoxy, (hydroxy)-Ci-C 6 -alkoxy, NH 2 , NH(Ci-C 6 -alkyl), N(Ci-C 6 -alkyl) 2 , NH(d-C 6 - hydroxyalkyl), N(Ci-C 6 -alkyl)(Ci-C 6 -hydroxyalkyl), N(Ci-C 6 -hydroxyalkyl) 2 , NHCO(Ci-C 6 -alkyl), Nid-Ce-alkylJCOiCrCe-alkyl), NHCO(C C 6 -hydroxyalkyl), N(d-C e -alkyl)CO(
  • said 3- to 7-membered heterocycloalkyl may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
  • the compound according to general formula (I) is selected from one of the general formula (la), (lb), (lc) (Id) or (le),
  • the compound of formula (I) is a compound according to formula (la),
  • R and R 2 together with the nitrogen atom to which they are attached form one of the following heterocycles Q19, Q23, Q25 or Q26,
  • R 5 is H, CH 3 , CH 2 CH 3 , CH2CH2CH3, CH(CH 3 ) 2 , cyclopropyl, C(0)CH 3 , C(0)CH 2 CH 3 , C(0)CH 2 CH 2 CH 3 , C(0)CH(CH 3 ) 2 , C(0)-cyclopropyl, CH 2 CH 2 CN, CH 2 CH 2 OH or CH 2 CH 2 OCH 3 ;
  • p is 0, 1 , 2 or 3;
  • each X 6 idependently represents H, CH 3 , CH 2 CH 3 , OH, OCH 3 , CH 2 OH, CH 2 CH 2 OH or CH 2 CH 2 OCH 3 . or
  • R is CH 3 , CH 2 CH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, CH 2 CH(CH 3 )OH, CH(CH 3 )CH 2 OH, CH 2 C(0)N(CH 3 ) 2 , CH 2 C(0)NH(CH 3 ) or CH 2 C(0)NH 2 and
  • R 2 is H or CH 3 , preferably R 2 is CH 3 ;
  • G is selected from the group consisting of G1 to G44 as defined above,
  • R 2 at each occurrence is independently selected from the group consisting of H, CH 3 and CH 2 CH 3 ;
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC2H5, OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2 ,
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH(CH 3 ) 2 NH 2 , CH(CH 3 ) 2 NH 2 , CH(
  • R is selected from the group consisting of CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CONH 2 , CH 2 CON(CH 3 ) 2 , CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, CH(CH 3 )CH 2 OH, CH 2 CH(CH 3 )OH, C(CH 3 ) 2 CH 2 OH, CH(CH 3 )CH 2 CH 2 OH, cyclopropyl, cyclobutyl and 3- oxetanyl;
  • G is selected from the group consisting of G1 to G44 as defined above,
  • R 2 at each occurrence is independently selected from the group consisting of H, CH 3 and CH 2 CH 3 ;
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH(CH 3 ) 2 NH 2 , CH(CH 3 ) 2 NH 2 , CH(
  • the compound of formula (I) is a compound according to formula (lc), wherein R is selected from the group consisting of CH 3 , CH 2 CH 3 , (CH 2 ) 2 CI-l3, CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CONH 2 , CH 2 CON(CH 3 ) 2 , CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, CH(CH 3 )CH 2 OH, CH 2 CH(CH 3 )OH, C(CH 3 ) 2 CH 2 OH, CH(CH 3 )CH 2 CH 2 OH, cyclopropyl, cyclobutyl and 3- oxetanyl;
  • G is selected from the group consisting of G1 to G44 as defined above,
  • R 2 at each occurrence is independently selected from the group consisting of H, CH 3 and CH 2 CH 3 ;
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH(CH 3 ) 2 NH 2 , CH(CH 3 ) 2 NH 2 , CH(
  • the compound according to general formula (I) is selected from one of the general formula (la), (lb), (lc),
  • G is select from G1 or G2, wherein
  • k at each occurrence is 0, 1 , 2 or 3;
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH(CH 3 ) 2 NH 2 , CH(CH 3 ) 2 NH 2 , CH(
  • G is selected from G1 or G2, wherein
  • k at each occurrence is 0, 1 , 2 or 3;
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3
  • the compound according to general formula (I) has the general formula (la), (Id) or (le)
  • R and R 2 together with the nitrogen atom to which they are attached form a heterocycle wherein said heterocycle is selected from the heterocycles Q'1 to Q'65
  • R is CH 3 , CH 2 CH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, CH 2 CH(CH 3 )OH, CH(CH 3 )CH 2 OH, CH 2 C(0)N(CH 3 ) 2 or
  • R 2 is CH 3 ;
  • G is select from G1 or G2, wherein
  • k at each occurrence is 0, 1 , 2 or 3;
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH(CH 3 ) 2 NH 2 , CH(CH 3 ) 2 NH 2 , CH(
  • R is selected from the group consisting of CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CONH 2 , CH 2 CON(CH 3 ) 2 , CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, CH(CH 3 )CH 2 OH, CH 2 CH(CH 3 )OH, C(CH 3 ) 2 CH 2 OH, CH(CH 3 )CH 2 CH 2 OH, cyclopropyl, cyclobutyl and 3- oxetanyl;
  • G is select from G1 or G2, wherein
  • k at each occurrence is 0, 1 , 2 or 3;
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCH 3 , CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH 3 , CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH(CH 3 ) 2 NH 2 , CH(CH 3 ) 2 NH 2 , CH(
  • the invention relates to a compound selected from the group consisting of
  • the compounds according to the first aspect of the invention are suitable for the treatment of various diseases or conditions in which inhibition of the PDE4 enzyme is advantageous.
  • One of the advantages of the compounds according to the first aspect of the invention is that they are selective PDE4B inhibitors.
  • PDE4D is not inhibited or is only partly inhibited, and hence the use of such selective PDE4B inhibitors gives rise to no side-effects or to significantly reduced side-effects, such as emesis and nausea, in particular indisposition, vomiting and sickness.
  • the therapeutic range of the compounds according to the invention is therefore advantageous.
  • a second aspect of the invention is a pharmaceutical composition (medicament) containing at least one compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (Ic) or (Id).
  • a third aspect of the invention is a compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (Ic) or (Id), for the use as a medicament, in particular for the treatment of conditions or diseases that can be treated by inhibition of the PDE4 enzyme, in particular the PDE4B enzyme.
  • a fourth aspect of the invention is a compound according to the first aspect of the invention, in particular of the general structure of formulae (I), (la), (lb), (lc) or (Id), for the use as a medicament for the treatment of inflammatory diseases of the joints; and/or inflammatory diseases of the skin; and/or inflammatory diseases of the eyes; gastrointestinal diseases and complaints; inflammatory diseases of the internal organs; and/or hyperplastic diseases; respiratory or lung diseases associated with elevated mucus production, inflammation and/or obstruction of the respiratory tract; diseases of the fibrotic spectrum; cancers; metabolic diseases; psychological disorders; and/or diseases of the peripheral or central nervous system.
  • the invention therefore also provides a compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb) or (lc), for the use as a medicament for the treatment of inflammatory diseases of the joints, the skin, of respiratory or lung diseases associated with elevated mucus production, inflammation and/or obstruction of the respiratory tract,of metabolic diseases and/or cardiovascular diseases.
  • a fifth aspect of the invention is the use of a compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (lc) or (Id), for the preparation of a medicament for the treatment of the diseases and conditions according to the fourth aspect of the invention.
  • a sixth aspect of the invention is a method for the treatment of the diseases and conditions according to the fourth aspect of the invention in a human, which is characterised in that a therapeutically effective amount of at least one compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (lc) or (Id), is administered.
  • the amount of active ingredient to be administered to the person or patient varies and is dependent on the patient's weight, age and medical history and on the type of administration, the indication and the severity of the illness.
  • the medicaments, drugs and pharmaceutical compositions according to the invention can take the form of and be administered as liquid, semi-solid or solid dosage forms and as for example injection solutions, drops, juices, syrups, sprays, suspensions, granules, tablets, pastilles, pellets, transdermal therapeutic systems, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions or aerosols and contain, in addition to at least one compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (lc) or (Id), according to the pharmaceutical form and depending on the administration route, pharmaceutical auxiliary substances such as for example carrier materials, fillers, solvents, diluting agents, surface-active substances, dyes, preservatives, disintegrants, slip additives, lubricants, flavourings and/or binders.
  • pharmaceutical auxiliary substances such as for example carrier materials, fillers, solvents, diluting agents, surface-active
  • auxiliary substances and the amounts thereof depends on whether the medicament is administered by oral, subcutaneous, parenteral, intravenous, vaginal, pulmonary, intraperitoneal, transdermal, intramuscular, nasal, buccal or rectal means or locally, for example on the skin, mucous membranes and eyes, and whether the medicament is designed to deliver the active ingredient by immediate, sustained, delayed or extended release.
  • Preparation of the medicaments and pharmaceutical compositions according to the invention takes place using agents, equipment, methods and procedures that are well-known from the prior art, such as "Remington's Pharmaceutical Sciences", Ed. A.R. Gennaro, 17 th edition, Mack Publishing Company, Easton PD (1985), in particular in part 8, chapters 76 to 93.
  • the compounds according to the invention can be synthesized according to general knowledge in the field of organic chemistry and in a manner as described here (cf. reaction schemes below) or analogously.
  • the reaction conditions in the synthesis routes described herein are known to the skilled person and are for some cases exemplified in the synthesis examples herein.
  • the necessary starting materials are either commercially available or can also be obtained according to general knowledge in the field of organic chemistry. If not stated otherwise, all chemical moieties; variables and indices in the compounds shown in the following reaction schemes are as defined in the context of the compound of formula (I) and the various embodiments thereof.
  • PdCI 2 bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(ll);
  • APCI atmospheric pressure chemical ionization; calc.
  • Mobile phase A 10 mM ammonium acetate in water
  • B acetonitrile
  • Mobile phase A 0.05% formic acid in water
  • B acetonitrile
  • Mobile phase A 0.05% formic acid in water
  • B acetonitrile
  • the compounds according to formula (I) may be prepared according to general reaction schemes 01 to 07.
  • KOf-Bu (460 mg, 4.102 mmol, 1.1 eq) was added in portions at rt over 30 min to a stirred solution of compound 1 e) (1.6 g, 3.729 mmol, 1.0 eq) in pyridine (30 mL) followed by addition of 4-toluenesulfonyl chloride (853 mg, 4.474 mmol, 1.2 eq) and additional KOf-Bu (502 mg, 4.474 mmol, 1.2 eq). The mixture was stirred at 100°C for 16 h, then cooled to rt, diluted with water (10 mL) and extracted with EtOAc (2x 10 mL).
  • TEA 0.4 mL, 3.20 mmol, 2.2 eq
  • PdCI2(dppf) (238 mg, 0.291 mmol, 0.1 eq) were added to a solution of 1f) (600 mg, 1.459 mmol, 1.0 eq) in DMF/MeOH(1 : 1 , 10 mL) that was kept under an inert atmosphere in an autoclave.
  • the mixture was pressurized with 600 psi of carbon monoxide gas and stirred for 48h at 1 10°C.
  • the reaction mixture was then cooled to rt, diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL).
  • PdCI 2 (dppf) was added at rt to a solution of lnt-1 b (32 g, 107.38 mmol) and TEA (33 mL, 236.2 mmol) in MeOH/DMF (5: 1 , 480 mL) that was kept under Ar in a Parr autoclave.
  • the reaction mixture was then stirred for 16 h at 1 10°C under CO gas atmosphere at a pressure of 220 psi.
  • the autoclave was cooled to rt and the mixture was filtered through a plug of celite. The filter was washed with MeOH and the filtrate was concentrated. The residue was diluted with EtOAc, washed with water and brine and dried.
  • Examples 4 to 7 were prepared three steps from lnt-1 in analogy to synthesis example 3.
  • PdCI 2 (dppf) 24 mg, 0.029 mmol was added to a solution of compound 8b) (0.25 g, 0.58 mmol), bis(pinacolato)diboron (0.24 g, 0.93 mmol) and potassium acetate (0.17 g, 1 .74 mmol) in dry dioxane (10 mL) that was stirred at rt under Ar.
  • KOf-Bu 0.574 g, 5.1 1 mmol was added portion wise at rt to a stirred solution of lnt-2b (2 g, 4.64 mmol, 1 .0 eq) in pyridine (38 mL), followed by addition of 4-toluenesulfonyl chloride (1.06 g, 5.56 mmol) and further KOf-Bu (0.63 g, 5.56 mmol).
  • the reaction mixture was stirred at 100°C for 16 h, cooled to rt, diluted with water (20 mL) and extracted with EtOAc (2x 50 mL).
  • Example 1 N-(2-Amino-2-oxoethyl)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)-N-methylspironndoline-3,3'- oxetanel-6-carboxamide
  • Synthesis examples 14 and 15 were obtained from a Suzuki coupling of (1-(5-bromopyrimidin-2- yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)methanone (compound 8b) and the respective phenyl boronic acids utilizing reaction conditions as described in protocol 3a.
  • Example 14 Morpholino(1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)spironndoline-3,3'-oxetanl-6-yl)- methanone
  • Synthesis examples 16 and 17 were prepared from 1 -(5-bromopyrimidin-2-yl)spiro[indoline-3,3'-oxetane]- 6-carboxylic acid (compound 8a) in two chemical steps comprising an amide coupling with 2- (methylamino)ethanol and TBTU as reagent and a Suzuki reaction (protocol 3a).
  • Example 16 1 -(5-(2-Fluoro-5-(trifluoromethyl)phenyl)pyrimidin ⁇
  • Examples 18 to 21 were obtained from lnt-2 and the respective amines via an amide coupling with TBTU (procedure 3c).
  • Examples 23 and 24 were prepared from 1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'- oxetane]-6-carboxylic acid (TBTU coupling analogously to procedure 3c).
  • Example 25 (1 S,4S)-2,5-Diazabicvclo[2.2.1lheptan-2-yl(1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro- nndoline-3,3'-oxetanl-6-yl)methanone
  • Synthesis examples 31 and 32 were obtained from a Suzuki coupling of (1-(5-bromopyrimidin-2- yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)methanone (compound 8b) and the respective phenyl boronic acids utilizing reaction conditions as described in protocol 3a.
  • Examples 34 to 36 were prepared from 1 -(5-bromopyrimidin-2-yl)spiro[indoline-3,3'-oxetane]-6-carboxylic acid (compound 8a) analogously to synthesis example 8.
  • the pinacol boronates obtained as intermediates were coupled in a Suzuki reaction with 2-bromopyridine (example 34), 2-chloro-4- cyclopropylpyridine (example 35) and 2-bromo-4-methoxypyridine (example 36).
  • Example 34 (1-(5-(Pyridin-2-yl)pyrimidin-2-yl)spironndoline-3,3'-oxetanl-6-yl)(pyrrolidin-1-yl) methanone
  • Example 36 (1-(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl) (pyrrolidin-1- vPmethanone
  • Tetrakis(triphenylphosphine)palladium(0) 80 mg, 0.07 mmol was added at rt to a solution of compound 8b (150 mg, 0.35 mmol), 3-fluorophenylboronic acid (98 mg, 0.7 mmol) and 2 M Na 2 C0 3 solution (0.34 ml) in DME/EtOH (1 : 1 , 12 ml) stirred under Ar.
  • the reaction mixture was stirred at 100°C for 6 h, cooled to rt and filtered through a pad of celite. The filtrate was evaporated and the residue purified by flash column chromatography [DCM with 5% MeOH] followed by trituration with DCM /hexane (1 :2). Light yellow solid.
  • Examples 38 to 41 were obtained from compound 8b according to the procedure for synthesis example
  • Example 40 (1 -(5-(2,3-Difluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl)(morpholino) methanone
  • Examples 42 to 46 were prepared from 1 -(5-bromopyrimidin-2-yl)spiro[indoline-3,3'-oxetane]-6-carboxylic acid (compound 8a) in two chemical steps comprising an amide coupling with 2-(methylamino)ethanol followed by a Suzuki reaction analogously to example 37.
  • Examples 47 to 51 were prepared from lnt-1 in three steps comprising a Suzuki coupling (analogously to synthesis example 37), an ester hydrolysis (protocol 3b) and amide coupling with 2-(methyl- amino)acetamide (protocol 3c).
  • Example 50 N-(2-Amino-2-oxoethyl)-1-(5-(2,3-difluorophenyl)pyrimidin-2-yl)-N-methylspiro [indoline-3,3 1 - oxetanel-6-carboxamide
  • PdCI 2 (dppf) (0.065 g, 0.08 mmol, 0.05 eq) was added to a solution of compound 52h (0.6 g, 1.58 mmol, 1 eq), potassium acetate (0.31 g, 3.17 mmol, 2 eq) and bis(pinacolato)diboron (0.8 g, 3.17 mmol, 2 eq) in dioxane that was stirred under Ar at rt.
  • the reaction mixture was refluxed for 16 h, cooled to rt and filtered through a plug of celite. The filter was rinsed with EtOAc and the filtrate was washed with water (20 ml) and brine (20 ml), dried over Na 2 S0 4 and concentrated.
  • MMPP (673 mg, 1.97 mmol, 4 eq) was slowly added at 0°C to a stirred solution of 6-(ethylthio)-1-(5-(4- methoxypyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane] (200 mg, 0.49 mmol, 1 eq) prepared under example 56 in THF (20 ml). The reaction mixture was stirred for 2 h at rt, then quenched with saturated NaHC0 3 solution and extracted with EtOAc (2x 15 ml). The combined organic layers were washed with brine (10 ml), dried over Na 2 S0 4 and evaporated.
  • Example 60 1 -(5-(4-Ethylpyridin-2-yl)pyrimidin-2-yl)-N-( ⁇
  • Example 63 1-(5-(4-Ethoxypyridin-2-yl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro[indoline-3,3'- oxetanel-6-carboxamide
  • Example 65 N-(2-Hvdroxyethyl)-N-methyl-1-(5-(4-(trifluoromethyl)pyridin-2-yl)pyrimidin-2-yl)spiro- nndoline-3,3'-oxetanel-6-carboxami
  • Examples 67 to 73 were prepared analogously to synthesis example 8.
  • the racemate was prepared in two steps from compound 52h and 1-(3-bromo-4-fluorophenyl)ethanol analogously to synthesis example 57 (yield: 330 mg, white solid).
  • the two enantiomers were obtained from the racemic mixture through chiral HPLC utilizing a chiral pack-IA column and hexane/EtOAc/EtOH/diethylamine (50/25/25/0.1 ) as mobile phase.
  • Example 75 2-(2-(2-(6-(Ethylsulfonyl)spiro[indoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2- ol
  • Example 76 2-(2-(2-(6-(Ethylsulfinyl)spiro[indoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)pyridin-4-yl) propan-2- ol
  • the racemic sulfone (350 mg) was prepared in two steps from compound 52h and 1-(2-bromopyridin-4- yl)ethanol analogously to synthesis example 57.
  • the two enantiomers were derived from this racemate via chiral HPLC utilizing a chiral pack-IE column and hexane/EtOAc/EtOH/diethylamine (50/25/25/0.1 ) as mobile phase.
  • Synthesis examples 79 and 96 were obtained from 1-(5-bromopyrimidin-2-yl)spiro[indoline-3,3'-oxetane]- 6-carboxylic acid (compound 8a) in two chemical steps comprising an amide coupling with 2- (methylamino)ethanol and TBTU as reagent and a Suzuki reaction (protocol 3a).
  • Example 80 N-(2-Hydroxyethyl)-N-methyl-1 -(5-(m-tolyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanel -6- carboxamide
  • Example 81 1-(5-(3-Cvclopropylphenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro[indoline-3,3'- oxetanel-6-carboxamide
  • Example 83 1-(5-(3-Ethoxyphenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro[indoline-3,3'- oxetanel-6-carboxamide
  • Example 84 1-(5-(3-Chlorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro[indoline-3,3'- oxetanel-6-carboxamide
  • Example 90 1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro [indoline- 3,3'-oxetanel-6-carboxamide
  • Example 91 1-(5-(5-Cvclopropyl-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro nndoline-3,3'-oxetanel-6-carboxamide
  • Example 96 1-(5-(5-(Ethylamino)-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro nndoline-3,3'-oxetanel-6-carboxamide

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Abstract

The invention relates to novel spiro-[indoline heterocycloalkane] compounds characterized in that the compound has general formula (I) in which the chemical groupings, substituents, variables and indices are as defined in the description, and to their use as medicaments, in particular as medicaments for the treatment of conditions and diseases that can be treated by inhibition of the PDE4 enzyme.

Description

Novel substituted Spiro-[indoline heterocycloalkane] compounds as Phosphodiesterase Inhibitors
FIELD OF THE INVENTION
The present invention relates to novel substituted spiro-indoline heterocycloalkane compounds that are useful as medicaments. This invention also relates to uses of the compounds to make medicaments and treatments comprising the administration of the compounds to humans in need of the treatments. This invention also relates to the preparation of said novel compounds. Moreover this invention relates to pharmaceutical compositions and kits comprising the compounds. BACKGROUND OF THE INVENTION
Phosphodiesterases (abbreviated as PDEs), or more accurately 3',5'-cyclonucleotide phosphor- diesterases, are enzymes that catalyse the hydrolysis of the second messengers cAMP (cyclic adenosine monophosphate) and cGMP (cyclic guanosine monophosphate) to 5'-AMP (5'-adenosine mono- phosphate)-and 5'-GMP (5'-guanosine monophosphate). Phosphodiesterases are a group of enzymes encompassing 1 1 gene families (PDE1-1 1 ), which differ inter alia through their affinity to cAMP and cGMP. Inhibition of phosphodiesterases thus represents a mechanism for modulating cellular processes and can be used to alleviate or cure disease conditions. Inhibitors of specific PDEs are known.
The discovery that the second messenger cAMP plays an important role in many inflammatory processes and that PDE4 is strongly expressed in cells that control inflammation processes (see inter alia Schudt, C. et al. (1995). PDE isoenzymes as targets for anti-asthma drugs. European Respiratory Journal 8, 1 179- 1 183), has led to the development of PDE4 inhibitors having an anti-inflammatory effect. One such PDE4 inhibitor having an anti-inflammatory effect is roflumilast for example (trade name Daxas®), which was approved as a medicament for the treatment of COPD (chronic obstructive pulmonary disease). Another PDE4 inhibtor is apremilast (Otezla®) that was recently approved for the treatment of psoriatic athritis and plaque psoriasis. In addition to the desired anti-inflammatory effect of roflumilast and apremilast, however, side-effects such as nausea, diarrhoea and headaches are observed, which limit their dose in humans. Undesired side-effects in humans were not only observed with roflumilast and apremilast but also with other PDE4 inhibitors, so that the therapeutic range (therapeutic window) of such medicaments is relatively narrow. The provision of PDE4 inhibitors having less severe or fewer side-effects and a better therapeutic window would therefore be desirable. Phosphodiesterase 4 (PDE4) is cAMP-specific and encompasses 4 different subtypes (PDE4A, PDE4B, PDE4C and PDE4D). As is described below, efforts are being made to find subtype-selective PDE4 inhibitors, above all PDE4B-selective inhibitors, that have less severe or no side-effects, thus increasing the therapeutic range for such compounds significantly. The inhibition of PDE4D is associated with the occurrence of undesired side-effects, such as for example diarrhoea, vomiting and nausea (see in this regard Mori, F. et al. (2010): The human area postrema and other nuclei related to the emetic reflex express cAMP phosphodiesterases 4B and 4D, Journal of Chemical Neuroanatomy 40, 36-42; Press, N.J.; Banner K. H (2009): PDE4 inhibitors - A review of the current field, Progress in Medicinal Chemistry 47, 37-74; Robichaud, A. et al. (2002): Deletion of PDE4D in mice shortens a2-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis, The Journal of Clinical Investigation 110, 1045-52; Lee et al., (2007): Dynamic regulation of CFTR by competitive interactions of molecular adaptors, Journal of Biological Chemistry 282, 10414-10422; Giembycz, M.A. (2002): 4D or not 4D - the emetogenic basis of PDE4 inhibitors uncovered?, Trends in Pharmacological Sciences 23, 548). Several compounds exhibiting PDE4B selectivity have been disclosed (Naganuma et al. US2006/0293343; Naganuma et al. Bioorg. Med. Chem. Lett. 19 (2009) 3174-3176; Goto et al. Bioorg. Med. Chem. Lett. 24 (2014) 893-899; Hagen et al. Bioorg. Med. Chem. Lett. 24 (2014) 4031-4034; Chappie et al. US 2014/0235612). Based on the above, there is a need for compounds (active ingredients) that are preferably PDE4B- selective (which means that with a given amount of active ingredient inhibit PDE4B but without inhibiting or only weakly inhibiting the PDE4D subtype). The advantage of such a PDE4B selectivity is that various side-effects do not occur or occur only to a small extent and that therefore a greater therapeutic range of the pharmaceutical active ingredient may be obtained. The therapeutic range of a pharmaceutical active ingredient describes the gap between its therapeutic dose and a dose that would lead to a toxic or an undesired effect. The greater the therapeutic range is, the rarer or more unlikely is the occurrence of certain toxic or undesired side-effects and hence the safer and more acceptable the pharmaceutical active ingredient or medicament. The therapeutic range is often also referred to as the therapeutic window or therapeutic index. These names are used synonymously in the present application.
SUMMARY OF THE INVENTION
The inventors have now found novel substituted spiro-indoline heterocycloalkane compounds that possess the desired inhibiting and PDE4B-selective properties. These spiro-indoline heterocycloalkane compounds are therefore particularly suitable for the treatment of diseases and conditions in which inhibition of the PDE4 enzyme, in particular PDE4B, is advantageous.
The first aspect of the invention thus relates to a compound characterized in that the compound has the general formula (I)
Figure imgf000004_0001
(I), wherein
A, B and C independently represent CH or N;
m is 0, 1 , 2 or 3 and n is 0, 1 , 2 or 3, with the proviso that the sum (m + n) is 2, 3 or 4;
L is selected from the group consisting of C(=0)NR2, S(=0), S(=0)2, S(=0)2NR2, P(=0)(R2), O or bond; R is selected from Ci_6-alkyl, unsubstituted or mono- or polysubstituted; or
C3-6-cycloalkyl or 3- to 7-membered heterocycloalkyi, in each case unsubstituted or mono- or polysubstituted;
and
R2 is selected from H or Ci-C6-alkyl, unsubstituted or mono- or polysubstituted;
or
R and R2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyi,
wherein said 3- to 12-membered heterocycloalkyi may contain one or two additional heteroatoms selected from the group consisting of O, S and N and may be mono- or bicyclic and
wherein said 3- to 12-membered heterocycloalkyi is unsubstituted or mono- or polysubstituted; and
G represents a phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or said 5- or 6-membered heteroaryl is unsubstituted or substituted with one, two, three or four substituents Z;
wherein
Z at each occurcence is independently selected from the group consisting of halogen, OH, CN, SH, N02, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, (Ci-C6)-hydroxyalkyl, (d-d)-cyanoalkyl, Ci-C6-alkoxy, (d-d)- thioalkyl, (C C6)-haloalkyl, (d-C6-alkoxy)-(d-C6-alkylenyl), (d-C6-alkoxy)-d-C6-alkoxy, (d-C6)-thio- haloalkyl, (C C6)-haloalkoxy, (d-d-thioalkyl)-(d-d-alkylenyl), d-d-cycloalkyl, (d-d-cycloalkyl)-(d- d-alkylenyl), 3- to 7-membered heterocycloalkyi, (3- to 7-membered heterocycloalkyl)-(d-C3-alkylenyl), said C3.6-cycloalkyl and said 3- to 7-membered heterocycloalkyi being in each case unsubstituted or mono- or polysubstituted, NH2, NH(d-d-alkyl), N(d-C6-alkyl)2, NHCO(d-d-alkyl), NHC02(d-C6-alkyl), NHC(0)NH2, NHCONH(d-d-alkyl), NHCON(d-d-alkyl)2, (d-d-alkylen)NH2, (d-d-alkylen)NH(d-d- alkyl), (d-d-alkylen)N(d-C6-alkyl)2, (d-d-alkylen)NHCO(d-d-alkyl), (d-d-alkylen)NHC02(d-d- alkyl), (d-d-alkylen)NHC(0)NH2, (d-d-alkylen)NHCONH(d-d-alkyl), (d-d-alkylen)NHCON(d-d- alkyl)2, NH(d-C6-alkylen)-C02(d-C6-alkyl), NH(C C6-alkylen)-CONH2, NH(d-C6-alkylen)-CONH(d-C6- alkyl), NH(d-C6-alkylen)-CON(d-C6-alkyl)2, NHS(0)2OH, NHS(0)2(d-C6-alkyl), NHS(0)20(d-C6-alkyl), NHS(0)2NH2, NHS(0)2NH(d-C6-alkyl), NHS(0)2N(d-d-alkyl)2, NH(d-d-alkylen)-S(0)2OH, NH(d-d- alkylen)-S(0)2(d-d-alkyl), NH(d-d-alkylen)-S(0)20(d-C6-alkyl), NH(d-d-alkylen)-S(0)2NH2, NH(d- C6-alkylen)-S(0)2NH(d-C6-alkyl), C02H, CO(d-d-alkyl), C02(d-d-alkyl), O-CO(d-d-alkyl), O- C02(d-d-alkyl), CONH2, CONH(d-d-alkyl), CON(d-d-alkyl)2, OCONH(d-d-alkyl), OCON(d-d- alkyl)2, OS(0)2(d-C6-alkyl), OS(0)2OH, OS(0)20(d-d-alkyl), OS(0)2NH2, OS(0)2NH(d-C6-alkyl), OS(0)2N(d-C6-alkyl)2, S(0)(d-C6-alkyl), S(0)2(d-C6-alkyl), S(0)2OH, S(0)20(d-C6-alkyl), S(0)2NH2, S(0)2NH(d-C6-alkyl), and S(0)2N(C C6-alkyl)2;
optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a physiologically acceptable solvate thereof. DETAILED DESCRIPTION
The term "single stereoisomer" in the sense of the present invention preferably means an individual enantiomer or diastereomer. The term "mixture of stereoisomers" means in the sense of this invention the racemate and mixtures of enantiomers and/or diastereomers in any mixing ratio.
The term "physiologically acceptable salt" in the sense of this invention preferably comprises a salt of at least one compound according to the present invention and at least one physiologically acceptable acid or base. A physiologically acceptable salt of at least one compound according to the present invention and at least one physiologically acceptable acid or one physiologically acceptable base preferably refers in the sense of this invention to a salt of at least one compound according to the present invention with at least one inorganic or organic acid or with at least one inorganic or organic base respectively which is physiologically acceptable - in particular when used in human beings and/or other mammals.
The term "physiologically acceptable solvate" in the sense of this invention preferably comprises an adduct of one compound according to the present invention and/or a physiologically acceptable salt of at least one compound according to the present invention with distinct molecular equivalents of one solvent or more solvents.
The invention also includes isotopic isomers of a compound of the invention, wherein at least one atom of the compound is replaced by an isotope of the respective atom which is different from the naturally predominantly occurring isotope, as well as any mixtures of isotopic isomers of such a compound. Preferred isotopes are 2H (deuterium), 3H (tritium), 3C and 4C. Isotopic isomers of a compound of the invention can generally be prepared by conventional procedures known to a person skilled in the art.
In the context of the present invention, the term "halogen" represents the radicals F, CI, Br and I, preferably the radicals F and CI, particularly preferred F. Unless otherwise specified, the term "C-|-C6-alkyl" is understood to mean branched and unbranched alkyl groups consisting of 1 to 6 carbon atoms. Examples of C-|-C6-alkyl radicals are CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, n-pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 1 ,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, n-hexyl, 1-methylpentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl. Ci-C4-alkyl radicals are preferred, in particular CH3, CH2CH3, (CH2)2CH3 or CH(CH3)2.
Unless otherwise specified, the term "C-|-C6-alkoxy" is understood to mean branched and unbranched alkoxy groups consisting of 1 to 6 carbon atoms. Examples of C-|-C6-alkoxy radicals are OCH3, OCH2CH3, 0(CH2)2CH3, OCH(CH3)2, 0(CH2)3CH3, OCH(CH3)CH2CH3, OCH2CH(CH3)2, OC(CH3)3, 0(CH2)4CH3, 0(CH2)2CH(CH3)2, OCH2CH(CH3)CH2CH3, OCH(CH3)(CH2)2CH3, OC(CH3)2CH2CH3, OCH2C(CH3)3, 0(CH2)5CH3, 0(CH2)3CH(CH3)2, 0(CH2)2CH(CH3)CH2CH3, OCH2CH(CH3)(CH2)2CH3, OCH2C(CH3)2CH2CH3, OCH2CH(CH3)(CH2)2CH3, OCH(CH3)(CH2)3CH3, OC(CH3)2(CH2)2CH3,
0(CH2)2C(CH3)3. Ci-C4-alkoxy radicals are preferred, in particular OCH3, OCH2CH3, 0(CH2)2CH3 or OCH(CH3)2. Unless otherwise specified, the term "(Ci-C6)-haloalkyl" is understood to be a Ci-C6-alkyl in which at least one hydrogen is exchanged for a halogen atom, preferably for F or CI, particularly preferably for F. The haloalkyi can be branched or unbranched and optionally mono- or polysubstituted. Preferred (C-|-C6)-halo- alkyl radicals are (C C3)-haloalkyl radicals, in particular CHF2, CH2F, CF3, CH2CH2F, CH2CHF2 and CH2CF3
Unless otherwise specified, the term "(Ci-C6)-haloalkoxy" is understood to be a Ci-C6-alkoxy in which at least one hydrogen is exchanged for a halogen atom, preferably for F or CI, particularly preferably for F. The haloalkoxy radicals can be branched or unbranched and optionally mono- or polysubstituted.
Preferred (C-|-C6)-haloalkoxy radicals are (C-|-C3)-haloalkoxy radicals, in particular OCHF2, OCH2F, OCF3, OCF2CH3, OCH2CH2F, OCH2CHF2 and OCH2CF3.
Unless otherwise specified, the term "(Ci-C6)-hydroxyalkyl" is understood to be a Ci-C6-alkyl in which at least one hydrogen is exchanged for a hydroxyl group. The hydroxyalkyl radicals can be branched or unbranched and optionally mono- or polysubstituted. Preferred (Ci-C6)-hydroxyalkyl radicals are (C1-C3)- hydroxyalkyl radicals, in particular CH2OH, CH2CH2OH, CH2CH2CH2OH and CH2CH(OH)CH2OH .
Unless otherwise specified, the term "(C-|-C6)-cyanoalkyl" is understood to be a C-|-C6-alkyl in which at least one hydrogen is exchanged for a cyano group. The hydroxyalkyl radicals can be branched or unbranched and optionally mono- or polysubstituted. Preferred (Ci-Ce)-cyanoalkyl radicals are (Ci-C3)- cyanoalkyl radicals, in particular CH2CN, CH2CH2CN and CH2CH2CH2CN.
Unless otherwise specified, the term "(Ci-C6)-thioalkyl" is understood to mean branched and unbranched thioalkyl groups consisting of 1 to 6 carbon atoms. Examples of (Ci-C6)-thioalkyl radicals are SCH3, SCH2CH3, S(CH2)2CH3, SCH(CH3)2, S(CH2)3CH3, SCH(CH3)CH2CH3, SCH2CH(CH3)2, SC(CH3)3, S(CH2)4CH3, S(CH2)2CH(CH3)2, SCH2CH(CH3)CH2CH3, SCH(CH3)(CH2)2CH3, SC(CH3)2CH2CH3, SCH2C(CH3)3, S(CH2)5CH3, S(CH2)3CH(CH3)2, S(CH2)2CH(CH3)CH2CH3, SCH2CH(CH3)(CH2)2CH3, SCH2C(CH3)2CH2CH3, SCH2CH(CH3)(CH2)2CH3, SCH(CH3)(CH2)3CH3, SC(CH3)2(CH2)2CH3,
S(CH2)2C(CH3)3. (Ci-C4)-thioalkyl radicals are preferred, in particular SCH3, SCH2CH3, SCH2CH2CH3 or SCH(CH3)2.
Unless otherwise specified, the term "(Ci-C6)-thiohaloalkyl" is understood to be a (Ci-Ce)-thioalkyl in which at least one hydrogen is exchanged for a halogen atom, preferably for F or CI, particularly preferably for F. The thiohaloalkyl radicals can be branched or unbranched and optionally mono- or polysubstituted. Preferred (Ci-C6)-thiohaloalkyl radicals are (Ci-C3)-thiohaloalkyl radicals, in particular SCHF2, SCH2F, SCF3, SCF2CH3, SCH2CH2F, SCH2CHF2 and SCH2CF3. ln the context of the present invention, the terms "Ci_C3-alkylen" and "d-C6-alkylen"are understood to be an acyclic saturated hydrocarbon radicals having 1 , 2 or 3 carbon atoms or 1 , 2, 3, 4, 5 or 6 carbon atoms, which can be branched or unbranched and unsubstituted or substituted once or several times, for example 2, 3, 4 or 5 times, by identical or different substituents and which link a corresponding moiety to the main structure. Alkylene groups can preferably be chosen from the group consisting of CH2, CH2CH2, CH(CH3), CH2CH2CH2, CH(CH3)CH2, C(CH3)2, CH(CH2CH3). The alkylene groups can particularly preferably be chosen from the group consisting of CH2, CH2CH2 and CH2CH2CH2.
Unless otherwise specified, the term "C2-C6-alkenyl" is understood to mean branched and unbranched unsaturated alkyl groups consisting of 2 to 6 carbon atoms and having at least one double bond.
Examples of C2-C6-alkenyls are ethenyl (also referred to as vinyl), prop-1-enyl, prop-2-enyl (also referred to as allyl), but-1-enyl, but-2-enyl, but-3-enyl, pent-1-enyl and hex-1-enyl. The designation C2-C6-alkenyl includes all possible isomers, i.e. structural isomers (constitutional isomers) and stereoisomers ((Z) and (E) isomers). Unless otherwise specified, the term "C2-C6-alkinyl" is understood to mean branched and unbranched unsaturated alkyl groups consisting of 2 to 6 carbon atoms and having at least one triple bond. Examples of C2-C6-alkinyls are ethinyl.
Unless otherwise specified, the term "C3.6-cycloalkyl" denotes cyclic saturated hydrocarbons having 3, 4, 5 or 6 carbon atoms respectively, which can be unsubstituted or substituted once or several times, for example by 2, 3, 4 or 5 identical or different radicals, on one or more ring members. C3.6-cycloalkyl can preferably be chosen from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
Unless otherwise specified, the term "3- to 7-membered heterocycloalkyl" and "3- to 12-membered heterocycloalkyl" are understood to mean heterocycloaliphatic saturated or unsaturated (but not aromatic) residues having 3 to 7, i.e. 3, 4, 5, 6 or 7, or having 3 to 12, i.e. 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12, ring members, in which in each case at least one, if appropriate also two or three carbon atoms are replaced by a heteroatom or a heteroatom group each selected independently of one another from the group consisting of O, S, S(=0), S(=0)2, N, NH and N(Ci_6-alkyl) such as N(CH3), wherein the ring members can be unsubstituted or mono- or polysubstituted. The heterocycloalkyl residues may be mono- or bi- cyclic.
Unless otherwise specified, the term "5- or 6-membered heteroaryl" is understood to represent a 5- or 6- membered cyclic aromatic residue containing at least 1 , if appropriate also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are each preferably selected independently of one another from the group S, N and O and the heteroaryl residue can be unsubstituted or mono- or polysubstituted, including the formation of N-oxides; e.g. substituted by 2, 3, 4 or 5 substituents, whereby the substituents can be the same or different and be in any desired and possible position of the heteroaryl. The binding to the superordinate general structure can be carried out via any desired and possible ring member of the heteroaryl residue if not indicated otherwise. The heteroaryl may be condensed with a 4-, 5-, 6- or 7- membered ring, being carbocyclic or heterocyclic, wherei the heteroatoms of the heterocyclic ring are each preferably selected independently of one another from the group S, N and O, and wherein said condensed ring may be saturated, partially unsaturated or aromatic and may be unsubstituted or mono- or polysubstituted; e.g. substituted by 2, 3, 4 or 5 substituents, whereby the substituents can be the same or different and be in any desired and possible position. Examples of such heteroaryl moieties are benzofuranyl, benzoimidazolyl, benzo-thienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl, quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl, furyl (furanyl), imidazolyl, imidazo-thiazolyl, indazolyl, indolizinyl, indolyl, isoquinolinyl, isoxazoyl, isothiazolyl, indolyl, naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pyrazolyl, pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, purinyl, phenazinyl, thienyl (thiophenyl), triazolyl, tetrazolyl, thiazolyl, thiadiazolyl and triazinyl.
Unless otherwise specified, the term "substituted" in connection with the non-aromatic moieties "alkyl", "alkenyl", "alkinyl" and "alkylen", in the context of this invention is understood as meaning replacement of a hydrogen radical by a substituent selected from the group consisting of =0, OH, CN, halogen, SH, N02, C-|-C6-alkoxy, (C-|-C6)-hydroxyalkoxy, (C-|-C6)-thioalkyl, (C-|-C6-alkoxy)-C-|-C6-alkoxy, (C-|-C6)-thiohaloalkyl, (d-C6)-haloalkoxy, C3-C6-cycloalkyl, 3- to 7-membered heterocycloalkyl, NH2, NH(C1-C6-alkyl), N(C1-C6- alkyl)2, NH(Ci-C6-hydroxyalkyl), N(Ci-C6-alkyl)(Ci-C6-hydroxyalkyl), N(d-C6- hydroxyalkyl)2, =NH, =N(d- C6-alkyl), =N(OH), NHCO(d-C6-alkyl), N(d-C6-alkyl)CO(d-C6-alkyl), NHCO(d-C6-hydroxyalkyl), N(d- C6-alkyl)CO(d-d-hydroxyalkyl), NHCOO(d-C6-alkyl), NH-C(0)NH2, NHCONH(d-C6-alkyl), NHCON(C C6-alkyl)2, NH(d-C6-alkylen)-COO(d-d-alkyl), NH(d-C6-alkylen)-CONH2, NH(d-C6-alkylen)-CONH(d- C6-alkyl), NH(d-d-alkylen)-CON(d-d-alkyl)2, NHS(0)2OH, NHS(0)2(d-C6-alkyl), NHS(0)20(d-C6- alkyl), NHS(0)2NH2, NHS(0)2NH(d-C6-alkyl), NHS(0)2N(d-C6-alkyl)2, NH(d-C6-alkylen)-S(0)2OH, NH(d-C6-alkylen)-S(0)2(d-C6-alkyl), NH(d-C6-alkylen)-S(0)20(d-C6-alkyl), NH(C C6-alkylen)- S(0)2NH2, NH(d-C6-alkylen)-S(0)2NH(d-C6-alkyl), C02H, CO(C C6-alkyl), COO(C C6-alkyl), OCO(C C6-alkyl), OCOO(d-C6-alkyl), CONH2, CONH(d-C6-alkyl), CON(d-C6-alkyl)2, OCONH(d-C6-alkyl), OCON(d-d-alkyl)2, OS(0)2(d-C6-alkyl), OS(0)2OH, OS(0)2-(d-C6-alkoxy), OS(0)2NH2, OS(0)2NH(C C6-alkyl), 0-S(0)2-N(d-C6-alkyl)2, S(0)(d-C6-alkyl), S(0)2(d-C6-alkyl), S(0)2OH, S(0)20(d-C6-alkyl), S(0)2NH2, S(0)2NH(Ci-d-alkyl), and S(0)2N(d-C6-alkyl)2. If a moiety is substituted with more than 1 substituent (polysubstituted), e.g. by 2, 3, 4, or 5 substituents, these substituents may be present either on different or on the same atoms, e.g. as in the case of CF3 or CH2CF3, or at different places, as in the case of CH(CI)-CH=CH-CHCI2. Substitution with more than 1 substituent may include identical or different substituents, such as, for example, in the case of CH(OH)-CH=CH-CHCI2.
Preferably, the substituents may be selected from the group consisting of F, CI, Br, CF3, CHF2, CH2F, OCF3, OH, CN, (Ci-C6)-alkyl, (d-C6)-hydroxyalkyl, (d-C6)-alkoxy, (d-C6)-hydroxyalkoxy, C3-C6-cyclo- alkyl, NH2, NH(d-C6-alkyl), N(d-C6-alkyl)CO(d-C6-alkyl), NHCO(d-C6-hydroxyalkyl), N(d-C6-alkyl)- CO(Ci-C6-hydroxyalkyl), N(d-C6-alkyl)2, NH(d-C6-hydroxyalkyl), N(Ci-C6-alkyl)(d-C6-hydroxyalkyl), NHCO(C C6-alkyl), NH-CONH(C C6-alkyl), NHCON(C C6-alkyl)2, NHS(0)2(C C6-alkyl), CONH2, CONH(C C6-alkyl), CON(C C6-alkyl)2, S(0)(C C6-alkyl) and S(0)2(C C6-alkyl).
Unless otherwise specified, the term "substituted" in connection with the moieties "cycloalkyl" and "heterocycloalkyl", in the context of this invention is understood as meaning replacement of a hydrogen radical by a substituent selected from the group consisting of =0, OH, CN, halogen, SH, N02, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, (Ci-C6)-hydroxyalkyl, (d-d^cyanoalkyl, Ci-C6-alkoxy, (Ci-C6)-thioalkyl, (d- C6)-haloalkyl, (Ci-C6-alkoxy)-(Ci-C6-alkylenyl), (Ci-C6-alkoxy)-Ci-C6-alkoxy, (Ci-C6)-thiohaloalkyl, (d-d)- haloalkoxy, (Ci-C6-thioalkyl)-(Ci-C6-alkylenyl), C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(CrC3-alkylenyl), 3- to 7-membered heterocycloalkyl, (3- to 7-membered heterocycloalkyl)-(Ci-C3-alkylenyl), NH2, NH(Ci-C6- alkyl), N(d-C6-alkyl)2, NHCO(d-d-alkyl), NHCOO(d-d-alkyl), NH-C(0)NH2, NHCONH(d-d-alkyl), NHCON(d-C6-alkyl)2, , (C C6-alkylen)NH2, (d-C6-alkylen)NH(d-C6-alkyl), (d-C6-alkylen)N(d-C6- alkyl)2, (d-C6-alkylen)NHCO(d-C6-alkyl), (C C6-alkylen)NHC02(d-C6-alkyl), (C C6- alkylen)NHC(0)NH2, (d-d-alkylen)NHCONH(d-C6-alkyl), (d-d-alkylen)NHCON(d-d-alkyl)2, NH(d- C6-alkylen)-COO(d-d-alkyl), NH(d-C6-alkylen)-CONH2, NH(d-d-alkylen)-CONH(d-d-alkyl), NH(d- C6-alkylen)-CON(d-d-alkyl)2, NHS(0)2OH, NHS(0)2(d-d-alkyl), NHS(0)20(d-d-alkyl), NHS(0)2NH2, NHS(0)2NH(d-d-alkyl), NHS(0)2N(d-C6-alkyl)2, NH(d-d-alkylen)-S(0)2OH, NH(d-d-alkylen)- S(0)2(d-d-alkyl), NH(d-d-alkylen)-S(0)20(d-d-alkyl), NH(d-C6-alkylen)-S(0)2NH2, NH(d-d- alkylen)-S(0)2NH(d-d-alkyl), C02H, CO(C C6-alkyl), COO(C C6-alkyl), OCO(C C6-alkyl), OCOO(C C6-alkyl), CONH2, CONH(C C6-alkyl), CON(C C6-alkyl)2, OCONH(C C6-alkyl), OCON(C C6-alkyl)2, OS(0)2(d-d-alkyl), OS(0)2OH, OS(0)2-(d-d-alkoxy), OS(0)2NH2, OS(0)2NH(d-d-alkyl), 0-S(0)2- N(d-d-alkyl)2, S(0)(d-d-alkyl), S(0)2(d-d-alkyl), S(0)2OH, S(0)20(d-C6-alkyl), S(0)2NH2,
S(0)2NH(d-C6-alkyl), and S(0)2N(d-d-alkyl)2. If a moiety is substituted with more than 1 substituent (polysubstituted), e.g. by 2, 3, 4, or 5 substituents, these substituents may be present either on different or on the same atoms or at different places, and may include identical or different substituents.
Preferably, the substituents may be selected from the group consisting of F, CI, Br, CF3, CHF2, CH2F, OCF3, OH, CN, (C C6)-alkyl, (C C6)-hydroxyalkyl, (C C6)-alkoxy, C3-C6-cycloalkyl, NH2, NH(C C6- alkyl), N(d-C6-alkyl)2, NHCO(d-C6-alkyl), NH-CONH(d-C6-alkyl), NHCON(d-C6-alkyl)2, NHS(0)2(d- C6-alkyl), CONH2, CONH(d-C6-alkyl), CON(d-C6-alkyl)2, S(0)(d-C6-alkyl) and S(0)2(d-C6-alkyl).
Unless otherwise specified, for superordinate residues containing two or more residues of the same type, such as d-d-alky! in N(Ci-C6-alkyl)2, it is understood that the two or more residues may be identical or different from each other. If the residues may be substituted, then it is understood that each residue may be independently substituted. As an example, N(d-C6-alkyl)2, wherein d-C6-alkyl may be unsubstituted or substituted by OH, encompasses for example inter alia N(CH3)2, N(CH3)(CH2CH3), N(CH2CH3)2, N(CH3)(CH2CH2OH) and N(CH2CH2OH)2.
Within the scope of the present invention, the symbols
Figure imgf000010_0001
used in the formulae denote a link of a corresponding residue to the respective superordinate general structure.
In one embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that each of A, B and C represents CH. ln another embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that
m is 1 and n is 1 (thus forming a 3,3-oxetanylen) or
m is 1 and n is 2 (thus forming a 3,3-tetrahydrofuranylen) or
m is 2 and n is 2 (thus forming a 4,4-tetrahydropyranylen) or
m is 1 and n is 3 (thus forming a 3,3-tetrahydropyranylen),
preferably m is 1 and n is 1 or m is 1 and n is 2 or m is 2 and n is 2, preferably m is 1 and n is 1. More preferably, the compound of formula (I) is characterized in that m is 1 and n is 1.
In another embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that G is one of the following groups G1 to G44
Figure imgf000011_0001
Figure imgf000012_0001
in which the site marked with an asterisk (*) indicates the binding site, which is bonded to the pyrimidine ring;
R 2 is selected from the group consisting of H, CH3 or CH2CH3;
k at each occurrence is 0, 1 , 2, 3 or 4; and
Z at each occurcence is independently selected from the group consisting of F, CI, Br, CF3, CHF2, CH2F, OCF3, OCHF2, OH, CN, d-Ce-alkyl, Ci-C6-hydroxyalkyl, Ci-C6-alkoxy, C3-C6-cycloalkyl, 3- to 7- membered heterocycloalkyl, NH2, NH(C C6-alkyl), N(C C6-alkyl)2, NHCO(C C6-alkyl), NHCONH(C C6- alkyl), NHCON(C C6-alkyl)2, (C C6-alkylen)NH2, (C1-C6-alkylen)NH(C1-C6-alkyl), (C1-C6-alkylen)N(C1-C6- alkyl)2, NHS(0)2(d-C6-alkyl), CONH2, CONH(d-C6-alkyl), CON(d-C6-alkyl)2, S(0)2NH2, S(0)2NH(d-d- alkyl), S(0)2N(d-d-alkyl)2, S(0)(d-C6-alkyl) and S(0)2(d-d-alkyl),
wherein said d-Ce-alkyl, said C3-C6-cycloalkyl and said 3- to 7-membered heterocycloalkyl is unsubstituted or mono- or polysubstituted. In a preferred embodiment, the compound of formula (I) is characterized in that G is one of the groups G1 to G44
wherein
R 2 is selected from the group consisting of H, CH3 or CH2CH3;
k at each occurrence is 0, 1 , 2, 3 or 4; and
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3), CH(CH3)NH(CH3), CH2N(CH3)2, CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN, SOCH3, S02CH3, SOCH2CH3, S02CH2CH3, S02NH2, pyrrolidinyl, piperidinyl, aziridinyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein said pyrrolidinyl, piperidinyl, aziridinyl, oxetanyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, and NHCOCH3. In a preferred embodiment, the compound of formula (I) is characterized in that G is one of the groups G1 to G44
wherein
R 2 is selected from the group consisting of H, CH3 or CH2CH3;
k at each occurrence is 0, 1 , 2, 3 or 4; and
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OCHF2, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2CN, SOCH3, S02CH3,
SOCH2CH3, S02CH2CH3, S02NH2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-oxetanyl, 1 - pyrrolidinyl, 1-piperidinyl and 1-morpholinyl.
Preferably Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2,
CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3),
CH(CH3)NH(CH3), CH2N(CH3)2, CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN,
SOCH3,S02CH3, cyclopropyl, cyclobutyl, 3-oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl, wherein said cyclopropyl, cyclobutyl, 3-oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, CI, CN, CF3, OCF3, OH, OCH3, CH3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), N(CH3)2 and NHCOCH3.
In a preferred embodiment, the compound of formula (I) is characterized in that G is one of the groups G1 to G44
wherein
R 2 is selected from the group consisting of H, CH3 or CH2CH3;
k at each occurrence is 0, 1 , 2, 3 or 4; and
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OCHF2, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, S02CH3, SOCH2CH3, S02CH2CH3, S02NH2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-oxetanyl, 1 -pyrrolidinyl, 1-piperidinyl and 1-morpholinyl.
In a preferred embodiment of the first aspect of the invention, the compound of formula (I) is
characterized in that G is selected from G1 or G2, wherein
k at each occurrence is 0, 1 , 2 or 3; and
Z at each occurcence is independently selected from the group consisting of F, CI, CF3, CHF2, CH2F, OCF3, OH, CN, Ci-C6-alkyl, (Ci-C6)-hydroxyalkyl, d-C6-alkoxy, C3-C6-cycloalkyl, 3- to 7-membered heterocycloalkyl, NH2, NH(d-C6-alkyl), N(d-C6-alkyl)2, NHCO(d-C6-alkyl), CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), NH-S(0)2(d-C6-alkyl), CONH2, CONH(d-C6- alkyl), CO-N(d-C6-alkyl)2, S(0)2NH2, S(0)2NH(d-C6-alkyl), S(0)2N(d-C6-alkyl)2, S(0)(d-C6-alkyl) and S(0)2(d-C6-alkyl),
preferably, Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, S02CH3 cyclopropyl, cyclobutyl, 3-oxetanyl, 1-pyrrolidinyl, 1- piperidinyl and 1-morpholinyl.
In a preferred embodiment of the first aspect of the invention, the compound of formula (I) is
characterized in that G is selected from G1 or G2, wherein
k at each occurrence is 0, 1 , 2 or 3; and
Z at each occurcence is independently selected from the group consisting of
F, CI, CF3, CHF2, CH2F, OCF3, OH, CN, Ci-d-alkyl, (d-C6)-hydroxyalkyl, d-C6-alkoxy, C3-C6-cycloalkyl, 3- to 7-membered heterocycloalkyl, NH2, NH(d-C6-alkyl), N(d-C6-alkyl)2, NHCO(d-C6-alkyl), CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), NH-S(0)2(d-C6-alkyl), CONH2, CONH(d-C6- alkyl), CO-N(d-C6-alkyl)2, S(0)2NH2, S(0)2NH(d-C6-alkyl), S(0)2N(d-C6-alkyl)2, S(0)(d-C6-alkyl) and S(0)2(d-C6-alkyl),
preferably, Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, S02CH3 cyclopropyl, cyclobutyl, 3-oxetanyl, 1-pyrrolidinyl, 1- piperidinyl and 1-morpholinyl.
In more preferred embodiment, the compound of formula (I) is characterized in that G is one of the following groups G45 or G2
Figure imgf000014_0001
G45
in which the site marked with an asterisk (*) indicates the binding site, which is bonded to the pyrimidine ring;
k at each occurrence is 0, 1 or 2; and
ZA is H or F;
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3), CH(CH3)NH(CH3), CH2N(CH3)2, CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN, SOCH3,S02CH3, cyclopropyl, cyclobutyl, 3- oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl, wherein said cyclopropyl, cyclobutyl, 3-oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1 -morpholinyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, CI, CN, CF3, OCF3, OH, OCH3, CH3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), N(CH3)2 and NHCOCH3.
In more preferred embodiment, the compound of formula (I) is characterized in that G is one of the following groups G45 or G2
Figure imgf000015_0001
G45 G2
in which the site marked with an asterisk (*) indicates the binding site, which is bonded to the pyrimidine ring;
k at each occurrence is 0, 1 or 2; and
ZA is H or F;
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2,
CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, S02CH3, cyclopropyl, cyclobutyl, 3-oxetanyl, 1-pyrrolidinyl, 1 -piperidinyl and 1 -morpholinyl.
In another embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that L is selected from C(=0)NR2, S(=0), S(=0)2 , P(=0)(R2), S(=0)2NR2 or bond.
In another embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that
L is selected from C(=0)NR2, S(=0), S(=0)2, S(=0)2NR2 or bond; and
R is selected from Ci-C6-alkyl, C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl,
wherein said Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, =0, =NH, NH2, NH(C C6-alkyl), N(C C6- alkyl)2, C-|-C6-alkoxy, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyl;
and
wherein said 3- to 7-membered heterocycloalkyl may contain one or two heteroatoms selected from the group consisting of O, S and N and wherein said C3-C6-cycloalkyl and said 3- to 7-membered heterocycloalkyl is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, =0, NH2, NH(CrCe-alkyl), N(Ci-Ce-alkyl)2, CrCe-alkyl, (d-Cej-hydroxyalkyl, (d-C6)- haloalkyl and Ci-C6-alkoxy;
and
R2 is selected from H or Ci-C6-alkyl
wherein said C-|-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, OH, C-|-C6-alkoxy and C3-C6-cycloalkyl;
or
R and R2 together with the nitrogen atom to which they are attached form a 3- to 12-membered
heterocycloalkyl,
wherein said 3- to 12-membered heterocycloalkyl may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
wherein said 3- to 12-membered heterocycloalkyl is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of of halogen, CN, OH, =0, NH2, NH(d-C6- alkyl), N(Ci-C6-alkyl)2, Ci-C6-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-haloalkyl and Ci-C6-alkoxy.
Preferably,
L is selected from C(=0)NR2, S(=0) or S(=0)2.
In a preferred embodiment of the first aspect of the invention, the compound of formula (I) is
characterized in that
L is C(=0)NR2;
R is selected from Ci-C6-alkyl, C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl,
wherein said Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, =0, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, Ci-C6-alkoxy, C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl;
and
wherein said 3- to 7-membered heterocycloalkyl may contain one or two heteroatoms selected from the group consisting of O, S and N and
wherein said C3-C6-cycloalkyl and said 3- to 7-membered heterocycloalkyl is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, =0, NH2, C-i-Ce-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-haloalkyl and Ci-C6-alkoxy ;
and
R2 is selected from H or Ci-C6-alkyl
wherein said Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, OH, C-|-C6-alkoxy and C3-C6-cycloalkyl;
or
R and R2 together with the nitrogen atom to which they are attached form a 3- to 12-membered
heterocycloalkyl, wherein said 3- to 12-membered heterocycloalkyi may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
wherein said 3- to 12-membered heterocycloalkyi is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of of halogen, CN, OH, =0, NH2, NH(Ci-C6- alkyl), N(Ci-C6-alkyl)2, Ci-C6-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-haloalkyl and Ci-C6-alkoxy.
Preferably,
L is C(=0)NR2;
R denotes Ci_6-alkyl,
wherein said Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, =0, OH, Ci-C6-alkoxy, (Ci-C6-alkoxy)-Ci-C6- alkoxy, (hydroxy)-C C6-alkoxy, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, NH(Ci-C6-hydroxyalkyl), N(d- C6-alkyl)(Ci-C6-hydroxyalkyl), N(Ci-C6-hydroxyalkyl)2, NHCO(d-C6-alkyl), N(Ci-C6-alkyl)CO(Ci-C6- alkyl), NHCO(C C6-hydroxyalkyl), N(d-C6-alkyl)CO(d-C6-hydroxyalkyl), CONH2, CONH(C C6- alkyl), CON(C C6-alkyl)2, CONH(C C6-hydroxyalkyl), CON(C1-C6-alkyl)(C1-C6-hydroxyalkyl), CON(Ci-C6-hydroxyalkyl)2, C3-C6-cycloalkyl, and 3- to 7-membered heterocycloalkyi;
or
denotes one of the following groups U1 to U8
wherein at each occurrence X2 is independently selected from the group consisting of OH, =0,
CN, F, CI, Br, CF3, CHF2, CH2F, OCF3, d-C6-alkyl, d-C6-alkoxy, NH2, NH(d-C6-alkyl), N(d-d alkyl)2, NHCO(d-C6-alkyl), C02H, COO(d-C6-alkyl), CONH2, CONH(d-C6-alkyl) and CON(d- C6-alkyl)2, and
wherein said group U1 to U8 may be connected to L via a d_3-alkylen, which in turn is unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from the group consisting of F, CI, CF3, =0, OCF3 and OH,
or denotes one of the following groups V1 to V33:
Figure imgf000017_0001
Figure imgf000018_0001
wherein
R is H, (Ci-C6-alkyl), (Ci-C6)- ydroxyalkyl, (Ci-C6)-cyanoalkyl, C3-C6-cycloalkyl, CO(Ci-C6-alkyl) or S02(Ci-C6-alkyl);
at each occurence m is 0, 1 , 2, 3, 4 or 5, and
X3 at each occurrence is independently selected from the group consisting of
OH, =0, CN, F, CI, Br, CF3, CHF2, CH2F, OCF3, C C6-alkyl, C C6-alkoxy, NH2, NH(C C6-alkyl), N(d-C6-alkyl)2, NHCO(Ci-Ce-alkyl), C02H, COO(Ci-Ce-alkyl). CONH2, CONH(Ci-Ce-alkyl) and CON(Ci-Ce-alkyl)2,
and wherein said group V1 to V13 may be connected to L via a Ci_3-alkylen, which in turn may be unsubstituted or substituted with at least one substituent independently selected from the group consisting of F, CI, CF3, =0, OCF3 and OH.
and
R2 is selected from H, C-|-C6-alkyl, (C-|-C6)-hydroxyalkyl or (C-|-C6-alkoxy)-C-|-C6-alkyl, preferably R2 is selected from H or CH3.
More preferably,
L is C(=0)NR2;
R is selected from one of the following substructures M1 to M76:
Figure imgf000018_0002
Figure imgf000019_0001
Figure imgf000020_0001
and
R2 is selected from H , Ci-C6-alkyl, (CrC6)-hydroxyalkyl or (Ci-C6-alkoxy)-Ci-C6-alkyl,
preferably R2 is selected from H or CH3.
Still preferably,
L is C(=0)NR2; and
R and R2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyi,
wherein said 3- to 12-membered heterocycloalkyi may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
wherein said 3- to 12-membered heterocycloalkyi is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, =0, NH2, C-|-C6-alkyl, (C-|-C6)-hydroxyalkyl, (C-|-C6)-haloalkyl and C-|-C6-alkoxy.
Still preferably,
L is C(=0)NR2; and
R and R2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyi,
wherein said 3- to 12-membered heterocycloalkyi denotes one of the following groups Q1 to Q34:
Figure imgf000020_0002
Figure imgf000021_0001
in which the site marked with an asterisk (*) indicates the binding site, which is bonded to the carbonyl group of L;
R5 is selected from the group consisting of H, C-|-C6-alkyl, (C-|-C6)-hydroxyalkyl, (C-|-C6)-cyanoalkyl, C3-C6- cycloalkyl, CO(Ci-C6-alkyl) and S02-(Ci-C6)-alkyl;
at each occurrence p is 0, 1 , 2, 3, 4 or 5; and
X6 at each occurrence is independently selected from the group consisting of OH, =0, CN, F, CI, Br, CF3 CHF2, CH2F, OCF3, d-Ce-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-cyanoalkyl, (d-C6)-alkoxy, (C3-C6)- cycloalkyl, NH2, NH(d-C6-alkyl), N(d-C6-alkyl)2, NHCO(d-C6-alkyl), C02H, CO(d-C6-alkyl), COO(d- C6-alkyl), CONH2, CONH(C C6-alkyl) and CON(C C6-alkyl)2.
More preferably,
L is C(=0)NR2; and
R and R2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyi,
wherein said 3- to 12-membered heterocycloalkyi denotes one of the following groups Q'1 to Q'65:
Figure imgf000021_0002
Figure imgf000022_0001
Preferably, the 3- to 12-membered heterocydoalkyi is selected from the qroup consisting of Q'8, Q'23, Q'32, Q'40 and Q'44.
In another preferred embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that
L is S(=0) or S(=0)2 and R is selected from OH, CN, Ci-C6-alkyl, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, C3-C6-cycloalkyl or 3- to 7-membered heterocydoalkyi,
wherein said Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, Ci-C6-alkoxy, (Ci-d- alkoxy)-C C6-alkoxy, (hydroxy)-C C6-alkoxy, NH2, NH(C C6-alkyl), N(C C6-alkyl)2, NH(C C6- hydroxyalkyl), N(C1-C6-alkyl)(C1-C6-hydroxyalkyl), N(C C6-hydroxyalkyl)2, NHCO(C C6-alkyl),
N(d-C6-alkyl)CO(d-C6-alkyl), NHCO(d-C6-hydroxyalkyl), N(d-C6-alkyl)CO(d-C6- hydroxyalkyl); CONH2, CONH(d-C6-alkyl), CON(d-C6-alkyl)2, CONH(d-C6-hydroxyalkyl), CON(Ci-d-alkyl)(Ci-d-hydroxyalkyl), CON(d-C6-hydroxyalkyl)2, C3-C6-cycloalkyl, and 3- to 7- membered heterocydoalkyi;
and
wherein said 3- to 7-membered heterocydoalkyi may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
wherein said C3-C6-cycloalkyl and said 3- to 7-membered heterocydoalkyi is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, =0, NH2, Ci-d-alkyl, (d-C6)-hydroxyalkyl, (d-C6)-haloalkyl and Ci-d-alkoxy.
Preferably, the compound of formula (I) is characterized in that
L is S(=0) or S(=0)2 and
R is selected from OH, CN, Ci-d-alkyl, NH2, NH(d-C6-alkyl), N(d-C6-alkyl)2, C3-C6-cycloalkyl or 3- to 7-membered heterocydoalkyi,
wherein said d-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, NH2, d-d-alkoxy, C3-C6-cycloalkyl and 3- to 7-membered heterocydoalkyi;
and
wherein said 3- to 7-membered heterocydoalkyi may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
wherein said 3- to 7-membered heterocydoalkyi is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, =0, NH2, d-C6-alkyl, (d-C6)-hydroxyalkyl, (Ci-C6)-haloalkyl and d-d-alkoxy.
Yet preferably, the compound of formula (I) is characterized in that L is S(=0) or S(=0)2 and
R is selected from Ci-C6-alkyl, C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl,
wherein said Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, Ci-C6-alkoxy, (C1-C6- alkoxy)-Ci-C6-alkoxy, (hydroxy)-Ci-C6-alkoxy, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, NH(d-C6- hydroxyalkyl), N(Ci-C6-alkyl)(Ci-C6-hydroxyalkyl), N(Ci-C6-hydroxyalkyl)2, NHCO(Ci-C6-alkyl), Nid-Ce-alkylJCOiCrCe-alkyl), NHCO(C C6-hydroxyalkyl), N(d-Ce-alkyl)CO(d-Ce- hydroxyalkyl); CONH2, CONH(C C6-alkyl), CON(C C6-alkyl)2, CONH(C C6-hydroxyalkyl), CON(Ci-C6-alkyl)(Ci-C6-hydroxyalkyl), CON(Ci-C6-hydroxyalkyl)2, C3-C6-cycloalkyl, and 3- to 7- membered heterocycloalkyl;
and
wherein said 3- to 7-membered heterocycloalkyl may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
wherein said C3-C6-cycloalkyl and said 3- to 7-membered heterocycloalkyl is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, =0, NH2, Ci-C6-alkyl, (Ci-C6)-hydroxyalkyl, (d-C6)-haloalkyl and Ci-C6-alkoxy.
Preferably, L is S(=0) or S(=0)2 and R is selected from one of the above substructures M1 to M76. More preferably,
L is S(=0) and R is selected from the group consisting of CH3, CH2CH3, (CH2)2CH3, CH(CH3)2,
(CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CH2CONH2, CH2CON(CH3)2, CH2CH2OH, CH2CH2CH2OH, CH(CH3)CH2OH, CH2CH(CH3)OH, C(CH3)2CH2OH, CH(CH3)CH2CH2OH, cyclopropyl, cyclobutyl and 3-oxetanyl.
Still more preferably,
L is S(=0)2 and R is selected from the group consisting of CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CH2CONH2, CH2CON(CH3)2, CH2CH2OH, CH2CH2CH2OH, CH(CH3)CH2OH, CH2CH(CH3)OH, C(CH3)2CH2OH, CH(CH3)CH2CH2OH, cyclopropyl, cyclobutyl and 3-oxetanyl.
In yet another embodiment of the first aspect of the invention, the compound of formula (I) is
characterized in that the compound according to general formula (I) is selected from one of the general formula (la), (lb), (lc) (Id) or (le),
Figure imgf000025_0001
Preferably, the compound of formula (I) is a compound according to formula (la),
wherein R and R2 together with the nitrogen atom to which they are attached form one of the following heterocycles Q19, Q23, Q25 or Q26,
Figure imgf000025_0002
in which the site marked with an asterisk (*) indicates the binding site, which is bonded to the carbonyl group of L;
R5 is H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, C(0)CH3, C(0)CH2CH3, C(0)CH2CH2CH3, C(0)CH(CH3)2, C(0)-cyclopropyl, CH2CH2CN, CH2CH2OH or CH2CH2OCH3;
at each occurrence p is 0, 1 , 2 or 3; and
each X6 idependently represents H, CH3, CH2CH3, OH, OCH3, CH2OH, CH2CH2OH or CH2CH2OCH3. or
wherein
R is CH3, CH2CH3, CH2CH2OH, CH2CH2CH2OH, CH2CH(CH3)OH, CH(CH3)CH2OH, CH2C(0)N(CH3)2, CH2C(0)NH(CH3) or CH2C(0)NH2 and
R2 is H or CH3, preferably R2 is CH3;
and G is selected from the group consisting of G1 to G44 as defined above,
R 2 at each occurrence is independently selected from the group consisting of H, CH3 and CH2CH3;
k at each occurrence 0, 1 , 2, 3, 4 or 5; and
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3), CH(CH3)NH(CH3), CH2N(CH3)2, CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN, SOCH3,S02CH3, cyclopropyl, cyclobutyl, 3- oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl, wherein said cyclopropyl, cyclobutyl, 3-oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1 -morpholinyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, CI, CN, CF3, OCF3, OH, OCH3, CH3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), N(CH3)2 and NHCOCH3,
preferably Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, S02CH3, cyclopropyl, cyclobutyl, 3-oxetanyl, 1-pyrrolidinyl, 1-piperidinyl and 1 -morpholinyl. Preferably, the compound of formula (I) is a compound according to formula (lb),
wherein R is selected from the group consisting of CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CH2CONH2, CH2CON(CH3)2, CH2CH2OH, CH2CH2CH2OH, CH(CH3)CH2OH, CH2CH(CH3)OH, C(CH3)2CH2OH, CH(CH3)CH2CH2OH, cyclopropyl, cyclobutyl and 3- oxetanyl;
and G is selected from the group consisting of G1 to G44 as defined above,
R 2 at each occurrence is independently selected from the group consisting of H, CH3 and CH2CH3;
k at each occurrence 0, 1 , 2, 3, 4 or 5; and
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3), CH(CH3)NH(CH3), CH2N(CH3)2, CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN, SOCH3,S02CH3, cyclopropyl, cyclobutyl, 3- oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl, wherein said cyclopropyl, cyclobutyl, 3-oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1 -morpholinyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, CI, CN, CF3, OCF3, OH, OCH3, CH3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), N(CH3)2 and NHCOCH3,
preferably Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, S02CH3, cyclopropyl, cyclobutyl, 3-oxetanyl, 1-pyrrolidinyl, 1-piperidinyl and 1 -morpholinyl.
Preferably, the compound of formula (I) is a compound according to formula (lc), wherein R is selected from the group consisting of CH3, CH2CH3, (CH2)2CI-l3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CH2CONH2, CH2CON(CH3)2, CH2CH2OH, CH2CH2CH2OH, CH(CH3)CH2OH, CH2CH(CH3)OH, C(CH3)2CH2OH, CH(CH3)CH2CH2OH, cyclopropyl, cyclobutyl and 3- oxetanyl;
and G is selected from the group consisting of G1 to G44 as defined above,
R 2 at each occurrence is independently selected from the group consisting of H, CH3 and CH2CH3;
k at each occurrence 0, 1 , 2, 3, 4 or 5; and
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3), CH(CH3)NH(CH3), CH2N(CH3)2, CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN, SOCH3,S02CH3, cyclopropyl, cyclobutyl, 3- oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl, wherein said cyclopropyl, cyclobutyl, 3-oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1 -morpholinyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, CI, CN, CF3, OCF3, OH, OCH3, CH3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), N(CH3)2 and NHCOCH3,
preferably Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, S02CH3, cyclopropyl, cyclobutyl, 3-oxetanyl, 1-pyrrolidinyl, 1-piperidinyl and 1 -morpholinyl.
More preferably,
the compound according to general formula (I) is selected from one of the general formula (la), (lb), (lc),
(Id) or (le),
wherein
G is select from G1 or G2, wherein
k at each occurrence is 0, 1 , 2 or 3;
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3), CH(CH3)NH(CH3), CH2N(CH3)2, CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN, SOCH3,S02CH3, cyclopropyl, cyclobutyl, 3- oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl, wherein said cyclopropyl, cyclobutyl, 3-oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1 -morpholinyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, CI, CN, CF3, OCF3, OH, OCH3, CH3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), N(CH3)2 and NHCOCH3,
preferably Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, S02CH3, cyclopropyl, cyclobutyl, 3-oxetanyl, 1-pyrrolidinyl, 1 -piperidinyl and 1 -morpholinyl. More preferably, the compound according to the general formula (la), (lb), (Ic), (Id) or (le) is characterized in that
G is selected from G1 or G2, wherein
k at each occurrence is 0, 1 , 2 or 3;
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2,
CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, S02CH3, cyclopropyl and cyclobutyl. Even more preferably, the compound according to general formula (I) has the general formula (la), (Id) or (le)
wherein
R and R2 together with the nitrogen atom to which they are attached form a heterocycle wherein said heterocycle is selected from the heterocycles Q'1 to Q'65
or
R is CH3, CH2CH3, CH2CH2OH, CH2CH2CH2OH, CH2CH(CH3)OH, CH(CH3)CH2OH, CH2C(0)N(CH3)2 or
CH2C(0)NH2 and
R2 is CH3;
and
G is select from G1 or G2, wherein
k at each occurrence is 0, 1 , 2 or 3;
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3), CH(CH3)NH(CH3), CH2N(CH3)2, CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN, SOCH3,S02CH3, cyclopropyl, cyclobutyl, 3- oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl, wherein said cyclopropyl, cyclobutyl, 3-oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1 -morpholinyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, CI, CN, CF3, OCF3, OH, OCH3, CH3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), N(CH3)2 and NHCOCH3,
preferably Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, S02CH3, cyclopropyl, cyclobutyl, 3-oxetanyl, 1-pyrrolidinyl, 1 -piperidinyl and 1 -morpholinyl. Even more preferably, the compound according to general formula (I) is selected from one of the general formula (lb) or (lc), ,
wherein
wherein R is selected from the group consisting of CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CH2CONH2, CH2CON(CH3)2, CH2CH2OH, CH2CH2CH2OH, CH(CH3)CH2OH, CH2CH(CH3)OH, C(CH3)2CH2OH, CH(CH3)CH2CH2OH, cyclopropyl, cyclobutyl and 3- oxetanyl;
and G is select from G1 or G2, wherein
k at each occurrence is 0, 1 , 2 or 3;
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3), CH(CH3)NH(CH3), CH2N(CH3)2, CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN, SOCH3,S02CH3, cyclopropyl, cyclobutyl, 3- oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl, wherein said cyclopropyl, cyclobutyl, 3-oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1 -morpholinyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, CI, CN, CF3, OCF3, OH, OCH3, CH3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), N(CH3)2 and NHCOCH3,
preferably Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, S02CH3, cyclopropyl, cyclobutyl, 3-oxetanyl, 1-pyrrolidinyl, 1 -piperidinyl and 1 -morpholinyl.
In yet another preferred embodiment, the invention relates to a compound selected from the group consisting of
1 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-N,N-dimethylspiro[indoline-3,3'-oxetane]-6-carboxamide
2 (1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)methanone N-(2-Amino-2-oxoethyl)-1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-N- methylspiro[indoline-3,3'-oxetane]-6-carboxamide
morpholino(1-(5-phenylpyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)methanone
N-(2-amino-2-oxoethyl)-1-(5-(2-fluoro-5-methoxyphenyl)pyrimidin-2-yl)-N- methylspiro[indoline-3,3'-oxetane]-6-carboxamide
N-(2-amino-2-oxoethyl)-N-methyl-1-(5-phenylpyrimidin-2-yl)spiro[indoline-3,3'-oxetane carboxamide
N-(2-amino-2-oxoethyl)-1-(5-(5-ethyl-2-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[in 3,3'-oxetane]-6-carboxamide
morpholino(1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)metha^^
(1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6- yl)(morpholino)methanone
(1-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholi methanone
N-(2-amino-2-oxoethyl)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[indolin oxetane]-6-carboxamide
N-(2-amino-2-oxoethyl)-1-(5-(5-ethoxy-2-fluorophenyl)pyrimidin-2-yl)-N- methylspiro[indoline-3,3'-oxetane]-6-carboxamide
N-(2-amino-2-oxoethyl)-N-methyl-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3 oxetane]-6-carboxamide
morpholino(1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)spiro[indoline-3,3 -^^
methanone
(1-(5-(2-fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)- (morpholino)methanone
1-(5-(2-fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro- [indoline-3,3'-oxetane]-6-carboxamide
N-(2-hydroxyethyl)-N-methyl-1 -(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)spiro[indoli 3,3'-oxetane]-6-carboxamide
(1-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(pyrrolidin-1- yl)methanone
(1-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(piperazin-1- yl)methanone
1-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3'- oxetane]-6-carboxamide
(1 S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl(1-(5-(2-fluorophenyl)pyrimidin-2- yl)spiro[indoline-3,3'-oxetan]-6-yl)methanone
(1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3^'-oxetan]-6-yl)(piperazin-1-yl)- methanone
(1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3^'-oxetan]-6-yl)(pyrrolidin-1-yl^ methanone
N-(2-hydroxyethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'- oxetane]-6-carboxamide
(1 S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl(1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro- [indoline-3,3'-oxetan]-6-yl)methanone
N-(2-amino-2-oxoethyl)-1-(5-(3-cyclopropylphenyl)pyrimidin-2-yl)-N-methylspiro[indoline- 3,3'-oxetane]-6-carboxamide
N-(2-Amino-2-oxoethyl)-N-methyl-1-(5-(m-tolyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]-6- carboxamide (S)-N-(2-amino-2-oxoethyl)-1-(5-(2-fluoro-5-(1-hydroxyethyl)phenyl)pyrimidin-2-yl)-N- methylspiro[indoline-3,3'-oxetane]-6-carboxamide
(R)-N-(2-amino-2-oxoethyl)-1-(5-(2-fluoro-5-(1-hydroxyethyl)phenyl)pyrimidin-2-yl)-N- methylspiro[indoline-3,3'-oxetane]-6-carboxamide
N-(2-amino-2-oxoethyl)-1-(5-(2-fluoro-5-(2-hydroxypropan-2-yl)phenyl)pyrimidin-2-yl)-N- methylspiro[indoline-3,3'-oxetane]-6-carboxamide
Morpholino(1-(5-(m-tolyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)methanone
(1-(5-(2-fluoro-5-methoxyphenyl)pyrimidin-2-y
methanone
(1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholi methanone
(1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(pyrrolidin-1-yl)methanone
(1-(5-(4-cyclopropylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(pyrrolidin-1- yl)methanone
(1-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(pyrrolidii methanone
(1-(5-(3-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)methanone (1-(5-(4-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)methanone
(1-(5-(2,5-difluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6- yl)(morpholino)methanone
(1-(5-(2,3-Difluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino) methanone
(1-(5-(3,5-Difluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino) methanone
1-(5-(3-Fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3'- oxetane]-6-carboxamide
1-(5-(4-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3'-oxetane]- 6-carboxamide
1-(5-(2,5-difluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3'- oxetane]-6-carboxamide
1-(5-(2,3-difluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3'- oxetane]-6-carboxamide
1-(5-(3,5-difluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3'- oxetane]-6-carboxamide
N-(2-amino-2-oxoethyl)-1-(5-(3-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[indoline-3,3'- oxetane]-6-carboxamide
N-(2-amino-2-oxoethyl)-1-(5-(4-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[indoline-3,3'- oxetane]-6-carboxamide
N-(2-amino-2-oxoethyl)-1-(5-(2,5-difluorophenyl)pyrimidin-2-yl)-N-methylspiro[indoline-3,3'- oxetane]-6-carboxamide
N-(2-Amino-2-oxoethyl)-1-(5-(2,3-difluorophenyl)pyrimidin-2-yl)-N-methylspiro [indoline-3,3'- oxetane]-6-carboxamide
N-(2-Amino-2-oxoethyl)-1-(5-(3,5-difluorophenyl)pyrimidin-2-yl)-N-methylspiro [indoline-3,3 - oxetane]-6-carboxamide
6-(Ethylsulfinyl)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]
6-(Ethylsulfonyl)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]
6-(ethylsulfinyl)-1 -(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane] 6-(Ethylsulfonyl)-1-(5-(2-fluoro-5-methyl^
6-(ethylsulfinyl)-1 -(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3
6-(Ethylsulfonyl)-1-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan 1-(5-(4-cyclopropylpyridin-2-yl)pyrimidin-2-yl)-6-(ethylsulfinyl)spiro[indoline-3,3'-o^
1-(5-(4-cyclopropylpyridin-2-yl)pyrimidin-2-yl)-6-(ethylsulfonyl)spiro[indoline-3,3'-oxet^
1-(5-(4-ethylpyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3 - oxetane]-6-carboxamide
1-(5-(4-cyclopropylpyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoli 3,3'-oxetane]-6-carboxamide
N-(2-hydroxyethyl)-1-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[indolin oxetane]-6-carboxamide
1- (5-(4-ethoxypyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3 oxetane]-6-carboxamide
N-(2-hydroxyethyl)-N-methyl-1 -(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan carboxamide
N-(2-hydroxyethyl)-N-methyl-1-(5-(4-(trifluoromethyl)pyridin-2-yl)pyrimidin-2- yl)spiro[indoline-3,3'-oxetane]-6-carboxamide
N-(2-hydroxyethyl)-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro- [indoline-3,3'-oxetane]-6-carboxamide
(1-(5-(4-(2-Hydroxypropan-2-yl)pyridin-2-yl)pyrim^
(pyrrolidin-l-yl)methanone
(1-(5-(4-ethoxypyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(pyrrolidin methanone
pyrrolidin-1-yl(1-(5-(4-(trifluoromethyl)pyridin-2-yl)pyrimidin-2-yl)spiro[in
6-yl)methanone
(1-(5-(4-ethylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(pyrrolidi yl)methanone
(S)- or (R)-1-(3-(2-(6-(ethylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)-4- fluorophenyl)ethanol
(R)- or (S)-1-(3-(2-(6-(ethylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)-4-fluoro- phenyl)ethanol
2- (3-(2-(6-(ethylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)-4- fluorophenyl)propan-2-ol
2-(3-(2-(6-(ethylsulfinyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)-4- fluorophenyl)propan-2-ol
2-(2-(2-(6-(Ethylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)pyridin^
ol
2-(2-(2-(6-(Ethylsulfinyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)pyridin^
ol
(S)- or (R)-1-(2-(2-(6-(ethylsulfonyl)spiro[indoline-3^
yl)ethanol
(R)- or (S)-1-(2-(2-(6-(ethylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)pyridin^ yl)ethanol
N-(2-hydroxyethyl)-N-methyl-1 -(5-phenylpyrimidin-2-yl)spiro[indoline-3,3'-oxetan carboxamide
N-(2-Hydroxyethyl)-N-methyM-(5-(m4olyl)pyrimidm^
carboxamide 1-(5-(3-cyclopropylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoli oxetane]-6-carboxamide
N-(2-hydroxyethyl)-1-(5-(3-methoxyphenyl)pyrimidin-2-yl)-N-methylspiro[indoline-3,3'- oxetane]-6-carboxamide
1-(5-(3-ethoxyphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline- -3,3'- oxetane]-6-carboxamide
1-(5-(3-chlorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-■3,3'- oxetane]-6-carboxamide
N-(2-hydroxyethyl)-N-methyl-1 -(5-(3-(trifluoromethoxy)phenyl)pyrimidin-2-yl)spiro[ind 3,3'-oxetane]-6-carboxamide
1-(5-(3-aminophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline- ooxxeettaannee]j--6o--ccaarrobooxxaammiidaee
g7 N-(2-hydroxyethyl)-N-methyl-1-(5-(3-(pyrrolidin --11--yyll))pphheennyyll))pf yrimidin-2-yl)spiro[indoli oxetane]-6-carboxamide
gg N-(2-hydroxyethyl)-1-(5-(3-(1-hydroxyethyl)phenyl)pyrimidin-2-yl)-N-methylspiro[indoline 3,3'-oxetane]-6-carboxamide
gg 1-(5-(3,4-difluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3 - oxetane]-6-carboxamide
QQ 1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[in
oxetane]-6-carboxamide
1-(5-(5-cyclopropyl-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N- methylspiro[indoline-3,3'-oxetane]-6-carboxamide
Q2 1-(5-(2-fluoro-5-methoxyphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indolin 3,3'-oxetane]-6-carboxamide
gg 1-(5-(5-ethoxy-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indolin oxetane]-6-carboxamide
g4 1-(5-(2-fluoro-5-(trifluoromethoxy)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N- methylspiro[indoline-3,3'-oxetane]-6-carboxamide
gg 1-(5-(5-amino-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoli oxetane]-6-carboxamide
gg 1-(5-(5-(ethylamino)-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N- methylspiro[indoline-3,3'-oxetane]-6-carboxamide
g^ 1-(5-(3-(ethylamino)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indolin
oxetane]-6-carboxamide
gg 1-(5-(2-fluoro-5-(pyrrolidin-1-yl)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N- methylspiro[indoline-3,3'-oxetane]-6-carboxamide
QQ 2-(2-(2-(6-(methylsulfinyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5 i--yyll))ppyyrriiddiinn^-4-yl)propan- SS 22--ooll
nn 22--((22--((22--((66--((mmeetthhyyllssuullffoonnyyll))ssppiirroo[[iinnddoolliinnee--33,,33''--ooxxeettaann^]-1-yl)pyrimidin-5-yl)pyridin-4-^
2-ol
101 1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-N,N-dimethylspiro[indoline-3,3'-oxetane sulfonamide
102 1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[in
oxetane]-6-sulfonamide
N,N-dimethyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxet^ sulfonamide
N-(2-hydroxyethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'- oxetane]-6-sulfonamide N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-N-(oxetan-3-ylmethyl)spi
105
oxetane]-6-carboxamide
N-(cyclopropylmethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoli
106
oxetane]-6-carboxamide
N-((3,3-difluorocyclobutyl)methyl)-N-methyl-1-(5-(4-m
107
[indoline-3,3'-oxetane]-6-carboxamide
108 6-(ethylsulfinyl)-1-(5-(pyridazin-3-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]
109 6-(ethylsulfonyl)-1-(5-(pyridazin-3-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]
110 2-(3-(2-(6-(ethylsulfinyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)phenyl)propan-2-^
111 2-(3-(2-(6-(ethylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)phenyl)propan-2-ol
112 6-(ethylsulfinyl)-1-(5-(5-methylpyridazin-3-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane
113 6-(ethylsulfonyl)-1-(5-(5-methylpyridazin-3-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]
1 14 2-(6-(2-(6-(Ethylsulfinyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)pyridazin-4-yl)p
2-ol
2-(6-(2-(6-(ethylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)pyridazin-4-yl)propa
115
2-ol
2-((1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)sulfinyl) ethanol 2-((1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)sulfonyl)^^
2-(2-(2-(6-((2-hydroxyethyl)sulfinyl)spiro[indoline-3,3'-oxetan]-1 -yl)pyrimidin-5-yl)pyridi
118
yl)propan-2-ol
2- (2-(2-(6-((2-hydroxyethyl)sulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)pyridi 119
yl)propan-2-ol
3- ((1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl) sulfinyl)propan- 120
1 -ol
3-((1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl) sulfonyl)propan- 121
1 -ol
3-((1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrim^
122
sulfinyl)propan-1-ol
3-((1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrim^
124
sulfonyl)propan-1-ol
(1-(5-(6-hydroxypyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino
125
methanone
(1-(5-(3-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholi
126
methanone
(1-(5-(2-fluoro-3-hydroxyphenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)- 127
methanone
(1-(5-(3-amino-2-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)- 128
methanone
129 (1-(6-methyl-[4,5'-bipyrimidin]-2'-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)methanone
(1-(5-(2-fluoro-6-hydroxyphenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)- 130
methanone
(1-(5-(2-amino-6-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)-
131
methanone
(1-(5-(6-aminopyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)-
132
methanone
133 (1-(5-(2-fluoro-3-methylphenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)- methanone
(1-(5-(2-fluoro-6-methylphenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(m
134
methanone
135 (1-(4-methyl-[2,5'-bipyrimidin]-2'-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)met
(1-(4,6-dimethyl-[2,5'-bipyrimidin]-2'-yl)spiro[indoline-3,3'-oxetan]-6- 136
yl)(morpholino)methanone
1-([2,5'-bipyrimidin]-2'-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3'-oxetane]-6-
137
carboxamide
N-(2-hydroxyethyl)-N-methyl-1 -(5-(pyrazin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]-6- 138
carboxamide
N-(2-hydroxyethyl)-N-methyl-1 -(5-(6-methylpyridin-2-yl)pyrimidin-2-yl)spiro [indoline-3,3'- 139
oxetane]-6-carboxamide
N-(2-hydroxyethyl)-1-(5-(6-hydroxypyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[indoline-3,3'- 140
oxetane]-6-carboxamide
N-(2-hydroxyethyl)-1-(5-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro- 141
[indoline-3,3'-oxetane]-6-carboxamide
(1-(5-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6
142 -y (morpholino)methanone
(1-(5-(6-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholi
143
methanone
N-((3-hydroxyoxetan-3-yl)methyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro- 144
[indoline-3,3'-oxetane]-6-carboxamide
N-((1-hydroxycyclopropyl)methyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro- 145
[indoline-3,3'-oxetane]-6-carboxamide
1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N,N-dimethylspiro[indoline-3,3'- 146
oxetane]-6-carboxamide
1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[indoline-3,3'- 147
oxetane]-6-carboxamide
N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]-6- 148
carboxamide
N-(2-hydroxyethyl)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]-6- 149
carboxamide
N-(2-hydroxyethyl)-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[indoline- 150
3,3'-oxetane]-6-carboxamide
1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)spiro[indoline-3,3'-oxetane]- 151
6-carboxamide
(1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)- 152
(morpholino)methanone
1-(5-(2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)spiro[indoline-3,3'-oxetane]-6- 153
carboxamide
N-(2-hydroxyethyl)-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro- 154
[indoline-3,3'-oxetane]-6-sulfonamide
N-(2-hydroxyethyl)-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[indoline- 155
3,3'-oxetane]-6-sulfonamide
N-(2-hydroxyethyl)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]-6- 156
sulfonamide
N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]-6- 157
sulfonamide 1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[ind
158
oxetane]-6-sulfonamide
159 6-(ethylsulfinyl)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan^^
161 6-(ethylsulfinyl)-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]
163 6-(ethylsulfonyl)-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]
2-(6-(2-(6-(ethylsulfinyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)pyridin-2-yl)pr^
164
ol
2-(6-(2-(6-(ethylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)pyridin-2-yl)propa
166
ol
167 2-((1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)sulfinyl)ethanol
169 2-((1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)sulfonyl)ethanol
2-(2-(2-(6-(ethylsulfinyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)pyridin-4^
amine
2-(2-(2-(6-(ethylsulfonyl)spiro[indoline-3,3'-oxetan^
amine
172 2-(2-(6-(ethylsulfinyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)isonicotinamide
173 2-(2-(6-(ethylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)isonicotinamide
2-(2-(6-(morpholine-4-carbonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5- yl)isonicotinamide
1- (5-(4-carbamoylpyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3'-
175
oxetane]-6-carboxamide
2- (2-(6-(morpholine-4-carbonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5- 176
yl)isonicotinonitrile
1- (5-(4-cyanopyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3'- 177
oxetane]-6-carboxamide
N-(2-hydroxyethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-2',3',5',6'-tetrahydro- 178
spiro[indoline-3,4'-pyran]-6-carboxamide
2- (4-fluoro-3-(2-(6-(1-(methylamino)cyclopropyl)spiro[indoline-3,3'-oxetan]-1-yl) pyrimidin-5- 179
yl)phenyl)propan-2-ol
1-(1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)-N-methylcyclopropan- 180
amine
1-(1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)-N- 181
methylcyclopropanamine
1- (1-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)-N-methylcyclo- 182
propanamine
2- (2-(2-(6-(1-(methylamino)cyclopropyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5- 183
yl)pyridin-4-yl)propan-2-ol
N-methyl-1-(1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)cyclo- 184
propanamine
N-ethyl-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'- 185
oxetane]-6-sulfonamide
1-(5-(4-(2-aminopropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[indoline-3,3'- 186
oxetane]-6-sulfonamide
1-(5-(4-(2-aminopropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N,N-dimethylspiro[indoline-3,3'- 187
oxetane]-6-sulfonamide
N-(2-hydroxyethyl)-N-methyl-1 '-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-4,5-dihydro-2H- 188
spiro[furan-3,3'-indoline]-6'-carboxamide 2-(2-(6-(ethylsulfinyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)is^
2-(2-(6-(ethylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)isonicotin
(1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)di
192
phosphine oxide
(1-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl) dimethylphosphine
193
oxide
optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a physiologically acceptable solvate thereof.
Owing to their excellent pharmacological activity, the compounds according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (Ic) or (Id), are suitable for the treatment of various diseases or conditions in which inhibition of the PDE4 enzyme is advantageous.
Such conditions and diseases are inter alia
- inflammatory diseases of the joints;
- inflammatory diseases of the skin;
- gastrointestinal diseases and complaints;
- inflammatory diseases of the internal organs;
- hyperplastic diseases;
- respiratory or lung diseases associated with elevated mucus production, inflammation and/or obstruction of the respiratory tract;
- diseases of the fibrotic spectrum;
- cancers;
- metabolic diseases;
- psychological disorders; and
- diseases of the peripheral or central nervous system.
One of the advantages of the compounds according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (Ic) or (Id), is that they are selective PDE4B inhibitors. Preferably, PDE4D is not inhibited or is only partly inhibited, and hence the use of such selective PDE4B inhibitors gives rise to no side-effects or to significantly reduced side-effects, such as emesis and nausea, in particular indisposition, vomiting and sickness. The therapeutic range of the compounds according to the invention is therefore advantageous.
A second aspect of the invention is a pharmaceutical composition (medicament) containing at least one compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (Ic) or (Id).
A third aspect of the invention is a compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (Ic) or (Id), for the use as a medicament, in particular for the treatment of conditions or diseases that can be treated by inhibition of the PDE4 enzyme, in particular the PDE4B enzyme.
A fourth aspect of the invention is a compound according to the first aspect of the invention, in particular of the general structure of formulae (I), (la), (lb), (lc) or (Id), for the use as a medicament for the treatment of inflammatory diseases of the joints; and/or inflammatory diseases of the skin; and/or inflammatory diseases of the eyes; gastrointestinal diseases and complaints; inflammatory diseases of the internal organs; and/or hyperplastic diseases; respiratory or lung diseases associated with elevated mucus production, inflammation and/or obstruction of the respiratory tract; diseases of the fibrotic spectrum; cancers; metabolic diseases; psychological disorders; and/or diseases of the peripheral or central nervous system.
In a preferred embodiment of the fourth aspect of the invention, the invention therefore also provides a compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb) or (lc), for the use as a medicament for the treatment of inflammatory diseases of the joints, the skin, of respiratory or lung diseases associated with elevated mucus production, inflammation and/or obstruction of the respiratory tract,of metabolic diseases and/or cardiovascular diseases. A fifth aspect of the invention is the use of a compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (lc) or (Id), for the preparation of a medicament for the treatment of the diseases and conditions according to the fourth aspect of the invention. A sixth aspect of the invention is a method for the treatment of the diseases and conditions according to the fourth aspect of the invention in a human, which is characterised in that a therapeutically effective amount of at least one compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (lc) or (Id), is administered. The amount of active ingredient to be administered to the person or patient varies and is dependent on the patient's weight, age and medical history and on the type of administration, the indication and the severity of the illness. Conventionally 0.1 to 5000 mg/kg, in particular 0.5 to 500 mg/kg, preferably 1 to 250 mg/kg of body weight of at least one compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (lc) or (Id), are administered.
All embodiments, in particular the preferred embodiments, of the first aspect of the invention apply mutatis mutandis to all other aspects of the invention.
The medicaments, drugs and pharmaceutical compositions according to the invention can take the form of and be administered as liquid, semi-solid or solid dosage forms and as for example injection solutions, drops, juices, syrups, sprays, suspensions, granules, tablets, pastilles, pellets, transdermal therapeutic systems, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions or aerosols and contain, in addition to at least one compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (lc) or (Id), according to the pharmaceutical form and depending on the administration route, pharmaceutical auxiliary substances such as for example carrier materials, fillers, solvents, diluting agents, surface-active substances, dyes, preservatives, disintegrants, slip additives, lubricants, flavourings and/or binders.
The choice of auxiliary substances and the amounts thereof depends on whether the medicament is administered by oral, subcutaneous, parenteral, intravenous, vaginal, pulmonary, intraperitoneal, transdermal, intramuscular, nasal, buccal or rectal means or locally, for example on the skin, mucous membranes and eyes, and whether the medicament is designed to deliver the active ingredient by immediate, sustained, delayed or extended release. Preparation of the medicaments and pharmaceutical compositions according to the invention takes place using agents, equipment, methods and procedures that are well-known from the prior art, such as "Remington's Pharmaceutical Sciences", Ed. A.R. Gennaro, 17th edition, Mack Publishing Company, Easton PD (1985), in particular in part 8, chapters 76 to 93.
Unless indicated otherwise the compounds according to the invention can be synthesized according to general knowledge in the field of organic chemistry and in a manner as described here (cf. reaction schemes below) or analogously. The reaction conditions in the synthesis routes described herein are known to the skilled person and are for some cases exemplified in the synthesis examples herein. The necessary starting materials are either commercially available or can also be obtained according to general knowledge in the field of organic chemistry. If not stated otherwise, all chemical moieties; variables and indices in the compounds shown in the following reaction schemes are as defined in the context of the compound of formula (I) and the various embodiments thereof.
Examples:
The compounds according to the invention are specified in the table below, without limiting the invention The following abbreviations are used in the descriptions of the experiments:
(AtaPhos)2PdCI2 = bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(ll); APCI = atmospheric pressure chemical ionization; calc. = calculated; d = day; dba = dibenzylidene-acetone; DCM = dichloromethane; DIPEA = diisopropylethylamine; DME = dimethoxyethane; DMF = N,N-dimethyl- formamide; DMSO = dimethylsulfoxide; dppp = 1 ,3-bis(diphenylphosphino)propane; EtOAc = ethyl acetate; EtOH = ethanol; EDCxHCI = 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride; ES- MS = electrospray mass spectrometry (ES-MS); eq. = equivalent; h = hour(s); HOAt = 1-hydroxy-7-aza- 1 H-benzotriazole; KOf-Bu = potassium tert-butoxide; LiHMDS = lithium bis(trimethylsilyl)amid; mCPBA = m-chloroperoxybenzoic acid; min = minute(s); MeOH = methanol; MMPP = magnesium mono- peroxyphthalate; MTBE = methyl-tert-butylether; PdCI2(dppf) = [1 ,1 '-bis(diphenylphosphino)ferrocene] dichloropalladium(ll) DCM complex; Pd2(dba)3(0) = tris(dibenzylideneacetone)dipalladium(0); PE = petroleum ether; rt = room temperature; Rt = retention time; SFC = supercritical fluid chromatography; TBDPS = tert-butyldiphenylsilyl; TBTU = 2-(1 H-benzotriazol-1-yl)-1 , 1 ,3,3-tetramethyluronium tetrafluoro- borate; TCCA = trichloroisocyanuric acid; tert = tertiary; TEA = triethylamine; TFA = 2,2,2-trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin layer chromatography; TOFMS = time-of-f light mass spectrometer; Xantphos = 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene.
The following analytical HPLC methods were used:
Method 1 :
Column: XBridge C18 (150 mm x 4.6 mm, 5.0 μιη); Column temperature: 35°C; Flow rate: 1.2 mL/min; Injection volume: 2 μΙ; Detection: 215 nm
Mobile phase A: 10 mM ammonium acetate in water; B: acetonitrile; mobile phase
Gradient:
Figure imgf000040_0001
Method 2:
Column: Resteck (30 mm x 2.1 mm, 1.8 μιη); Column temperature: 50°C; Instrument: Waters ACQUITY UPLC; Flow rate: 1.5 mL/min; Injection volume: 2 μΙ; Detection: 210 to 400 nm (DAD)
Mobile phase A: 0.05% formic acid in water; B: acetonitrile; mobile phase
Gradient:
Figure imgf000040_0002
Mass spectrometry conditions:
Instrument: ACQUITY SQD Mass Spectrometer from Waters (Single quadruple mass spectrometer) Ionization technique: ESI; Mass range: 100 to 800 Da; Polarity: + Ve
Method 3:
Column: Zorbax Extend C18 (4.6 x 50 mm, 5 μιη); column temperature: 25°C; Instrument: Shimadzu Prominence; Flow rate: 1.2 mL/min; Injection volume: 2 μί; Detection: 220 and 260 nm
Mobile phase A: 10 mM ammonium acetate in water; Mobile phase B: acetonitrile Gradient:
Figure imgf000041_0001
Method 4:
Column: Zorbax Extend C18 (4.6 x 50 mm, 5 μιη); column temperature: 25°C; Instrument: Shimadzu Prominence; Flow rate: 1.2 mL/min; Injection volume: 2 μΙ_; Detection: 220 and 260 nm
Mobile phase A: 10 mM ammonium acetate in water; Mobile phase B: acetonitrile
Gradient:
Figure imgf000041_0002
Method 5:
Column: Zorbax Extend C18 (4.6 x 50 mm, 5 μιη); Instrument: Shimadzu Prominence; Column temperature: 25°C; Injection volume: 2 μΙ; Flow rate: 1.0 mL/min; Detection: 220 and 260 nm
Mobile phase A: 10 mM ammonium acetate in water; Mobile phase B: acetonitrile
Gradient:
Figure imgf000041_0003
Mass spectrometry conditions (for Methods 3 to 5):
Instrument: API 2000 LC/MS/MS from Applied Biosystem; Ionization technique: ESI using API source; Declustering Potential: 10-70 V depending on the ionization of compound; Mass range: 100-800 amu; Scan type: Q1 ; Polarity: + Ve; Ion Source: Turbo spray; Ion spray voltage: +5500 for +Ve mode; Mass Source temperature: 200°C
Method 6:
Column: Resteck (30 mm x 2.1 mm, 1.8 μιη); Column temperature: 50°C; Instrument: Waters ACQUITY UPLC; Flow rate: 1 mL/min; Injection volume: 2 μΙ; Detection: 210 to 400 nm (DAD)
Mobile phase A: 0.05% formic acid in water; B: acetonitrile; mobile phase
Gradient:
Time in min % A % B Flow rate in ml/min
0 98 2 1 1.00 98 2 1
5.00 50 50 1
8.00 10 90 1
10.00 10 90 1
12.00 95 5 1
Mass spectrometry conditions:
Instrument: ACQUITY SQD Mass Spectrometer from Waters (Single quadruple mass spectrometer) Ionization technique: ESI; Mass range: 100 to 800 Da; Polarity: + Ve
Method 7:
Column: Zorbax Extend C18 (4.6 x 50 mm, 5 μιη); column temperature: 25°C; Instrument: Shimadzu Prominence; Flow rate: 1.2 mL/min; Injection volume: 2 μΙ_; Detection: 220 and 260 nm
Mobile phase A: 10 mM ammonium acetate in water; Mobile phase B: acetonitrile
Gradient:
Figure imgf000042_0002
Mass spectroscopy conditions:
Instrument: API 2000 LC/MS/MS from Applied Biosystem; Ionization technique: ESI using API source; Declustering Potential: 10-70 V depending on the ionization of compound; Mass range: 100-800 amu; Scan type: Q1 ; Polarity: + Ve; Ion Source: Turbo spray; Ion spray voltage: +5500 for +Ve mode; Mass Source temperature: 200°C
SYNTHESIS OF EXAMPLE COMPOUNDS
The compounds according to formula (I) may be prepared according to general reaction schemes 01 to 07.
Reaction scheme 01
(vi)
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Reaction scheme 06
Figure imgf000045_0001
(XXXVIII)
Figure imgf000045_0002
1a) tert-Butyl 6-bromo-2-oxoindoline-1-carboxylate NaHC03 (23 g, 283 mmol, 2.0 eq) and di-tert-butyl dicarbonate (46 mL, 212 mmol, 1.5 eq) were added to a stirred solution of 6-bromoindolin-2-one (30 g, 141.5 mmol, 1.0 eq) in THF (300 mL) at rt. The mixture was refluxed for 3 h, then cooled to rt, diluted with water (100 mL) and extracted with EtOAc (2x 100 mL). The combined organic layers were washed with brine (50 mL), dried and evaporated under reduced pressure. The raw product was purified by column chromatography [silica gel 100-200 mesh, PE/EtOAc = 9:1]. White solid. Yield: 35 g, (79%). 1 H NMR (400 MHz, CDCI3, δ ppm): 8.03 (d, J = 1.2 Hz, 1 H), 7.27 (dd, J = 8.0, 1.6 Hz, 1 H), 7.12 (d, J = 8.0 Hz, 1 H), 3.58 (s, 2H), 1.64 (s, 9H).
1 b) tert-Butyl 6-bromo-3,3-bis(hvdroxymethyl)-2-oxoindoline-1-carboxylate
Compound 1a) (35 g, 1 12.5 mmol, 1 .0 eq), K2C03 (46 g, 337 mmol, 3.0 eq) and paraformaldehyde (81 g, 2700 mmol, 24 eq) in THF (200 mL) were stirred for 1 h at rt. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2x 200 mL). The combined organic layers were washed with brine (100 mL), dried and evaporated under reduced pressure. The remnant was purified by column chromatography [silica gel 100-200 mesh, PE/EtOAc = 1 : 1]. White solid. Yield: 40 g (95%). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 7.89 (s, 1 H), 7.39 (d, J = 7.2 Hz, 2H), 4.96 (t, J = 5.2 Hz, 2H), 3.73-3.64 (m, 4H), 1.56 (s, 9H).
1 c) 6-Bromo-3,3-bis(hvdroxymethyl)indolin-2-one
TFA (50 mL) was added dropwise at 0°C to a stirred solution of compound 1 b) (40 g, 107 mmol, 1 .0 eq) in DCM (200 mL). The reaction mixture was warmed to rt and stirred for 1 h. The mixture was then washed with cold water (2x 25 mL), dried over Na2S04 and evaporated under reduced pressure affording the target compound as white solid that was used for the next step without further purification. Yield: 23 g (79%). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 10.1 (s, 1 H), 7.22 (d, J = 8.0 Hz, 1 H), 7.10 (dd, J = 8.0, 1.6 Hz, 1 H), 6.91 (d, J = 1.6 Hz, 1 H), 4.73 (t, J = 5.2 Hz, 2H), 3.69 (d, J = 10.4 Hz, 2H), 3.56 (d, J = 10.4 Hz, 2H).
1d) (6-Bromoindoline-3,3-diyl)diMeOH
Compound 1 c) (10 g, 36.90 mmol, 1.0 eq) in THF (50 mL) was added at 0°C to a stirred solution of LiAIH4 (2.8 g, 73.80 mmol, 2.0 eq) in THF (50 mL) that was kept under N2. The mixture was stirred for 3 h at 60°C, then diluted at rt with saturated Na2S04 solution (20 mL) and filtered. The filtrate was extracted with EtOAc (2x 50 mL) and the combined the organic layers were washed with brine (2x 20 mL), dried and concentrated under reduced pressure. The residue was purified through washing with pentane providing the final product after drying as semifluid liquid. Yield: 5.0 g (53%). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 6.89 (d, J = 7.6 Hz, 1 H), 6.57 (dd, J = 7.8, 1 .8 Hz, 1 H), 6.52 (d, J = 1.6 Hz, 1 H), 5.69 (s, 1 H), 4.67 (t, J = 5.2 Hz, 2H), 3.48-3.46 (m, 4H), 3.28 (s, 2H).
1 e) (6-Bromo-1-(5-(2-fluorophenyl)pyrimidin-2-yl)indoline-3,3-diyl)diMeOH
Sulfuric acid (0.5 mL) was added at rt to a stirred solution of compound 1d) (5.0 g, 19.45 mmol, 1 .0 eq) and 2-chloro-5-(2-fluorophenyl)pyrimidine (4.8 g, 23.34 mmol, 1.2 eq) in n-butanol (20 mL). The mixture was refluxed for 8h, cooled to rt, diluted with water (20 mL) and extracted with EtOAc (2x 20 mL). The combined organic layers were washed with brine (2x 20 mL), dried and concentrated under reduced pressure. The remnant was purified by column chromatography [silica gel 100-200 mesh, PE/EtOAc = 3:7]. Semifluid liquid. Yield: 3.4 g (41 %). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.86 (d, J = 1.2 Hz, 2H), 8.54 (d, J = 1.6 Hz, 1 H), 7.67-6.64 (m, 1 H), 7.45-7.43 (m, 1 H), 7.39-7.34 (m, 2H), 7.23 (d, J = 8.0 Hz, 1 H), 6.52 (dd, J = 7.8, 1.8 Hz, 1 H), 4.92 (t, J = 5.2 Hz, 2H), 4.13 (s, 2H), 3.64-3.56 (m, 4H).
1f) 6-Bromo-1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanel
KOf-Bu (460 mg, 4.102 mmol, 1.1 eq) was added in portions at rt over 30 min to a stirred solution of compound 1 e) (1.6 g, 3.729 mmol, 1.0 eq) in pyridine (30 mL) followed by addition of 4-toluenesulfonyl chloride (853 mg, 4.474 mmol, 1.2 eq) and additional KOf-Bu (502 mg, 4.474 mmol, 1.2 eq). The mixture was stirred at 100°C for 16 h, then cooled to rt, diluted with water (10 mL) and extracted with EtOAc (2x 10 mL). The combined organic layers were washed with 1 N HCI (20 mL) and brine (20 mL), dried and evaporated under reduced pressure. The raw product was purified by column chromatography [silica gel 100-200 mesh, PE/EtOAc = 4: 1]. White solid. Yield: 600 mg (62%). 1 .0 g of the starting material compound 1 e) was also recovered. 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.86 (dd, J = 6.8, 1.2 Hz, 2H), 8.52 (dd, J = 21.6, 2.0 Hz, 1 H), 7.71-7.64 (m, 2H), 7.48-7.44 (m, 2H), 7.23 (dd, J = 8.0, 2.0 Hz, 1 H), 7.02- 7.00 (m, 1 H), 4.76 (dd, J = 2.8, 6.0 Hz, 2H), 4.59 (s, 1 H), 4.27 (s, 2H), 4.02 (d, J = 4.4 Hz, 1 H).
1g) Methyl 1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane1-6-carboxylate
TEA (0.4 mL, 3.20 mmol, 2.2 eq) and PdCI2(dppf) (238 mg, 0.291 mmol, 0.1 eq) were added to a solution of 1f) (600 mg, 1.459 mmol, 1.0 eq) in DMF/MeOH(1 : 1 , 10 mL) that was kept under an inert atmosphere in an autoclave. The mixture was pressurized with 600 psi of carbon monoxide gas and stirred for 48h at 1 10°C. The reaction mixture was then cooled to rt, diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (20 mL), dried and concentrated under reduced pressure. The remnant was purified by column chromatography [silica gel 100-200 mesh, PE/EtOAc = 7:3]. White solid. Yield: 350 mg (61 %). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.91 (d, J = 1.6 Hz, 1 H), 8.88 (d, J = 1.2 Hz, 2H), 7.89 (d, J = 8.0 Hz, 1 H), 7.75 (dd, J = 7.8, 1.4 Hz, 1 H), 7.72-7.69 (m, 1 H), 7.48-7.44 (m, 1 H), 7.39-7.33 (m, 2H), 4.76 (d, J = 6.4 Hz, 2H), 4.78 (d, J = 6.4 Hz, 2H), 4.63 (s, 2H), 3.88 (s, 3H). 1 h) 1-(5-(2-Fluorophenyl)pyrimidin-2-yl)spironndoline-3,3'-oxetane1-6-carboxylic acid
Compound 1g) (400 mg, 1 .023 mmol, 1.0 eq) and LiOH (171 mg, 4.092 mmol, 4.0 eq) in MeOH/water (1 :1 ; 10 mL) were stirred for 16h at rt. The solvents were removed in vacuo and the residue was diluted with water (10 mL) and acidified with 1 N HCI solution (pH~4). The precipitating solid was filtered off and dried. White solid. Yield: 230 mg (60%). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 12.9 (s, 1 H), 8.91 (d, J = 1.2 Hz, 1 H), 8.88 (d, J = 1.2 Hz, 2H), 7.85 (d, J = 7.6 Hz, 1 H), 7.74-7.68 (m, 2H), 7.49-7.44 (m, 1 H), 7.43- 7.32 (m, 2H), 4.89 (d, J = 6.4 Hz, 2H), 4.78 (d, J = 6.0 Hz, 2H), 4.62 (s, 2H).
1 i) 1-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N-dimethylspiro[indoline-3,3'-oxetane1-6-carboxamide
TEA (0.096 mL, 0.688 mmol, 2.0 eq), HOAt (23 mg, 0.172 mmol, 0.5 eq) and EDCxHCI (72 mg, 0.378 mmol, 1.1 eq) were added at rt to a solution of compound 1 h) (130 mg, 0.344 mmol, 1.0 eq) in DMF (10 mL) stirred under N2. Dimethylamine (0.25 mL, 0.517 mmol, 1.5 eq) was added after 15 min and stirring was continued for 16h. The reaction mixture was diluted with brine (10 mL) and extracted with EtOAc (2x 10 mL). The organic layers were washed with brine (2x 10 mL), dried and evaporated under reduced pressure. The remnant was purified by preparative TLC using DCM with 3% MeOH as eluent. White solid. Yield: 80 mg (58%). Melting range: 174-177°C. HPLC (method 1 ): Rt = 6.48 min. m/z: [M+H]+ = 405.0. 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.62 (d, J = 1.6 Hz, 2H), 8.34 (d, J = 1 .2 Hz, 1 H), 7.85 (d, J = 7.6 Hz, 1 H), 7.68-7.63 (m, 1 H), 7.47-7.43 (m, 1 H), 7.39-7.32 (m, 2H), 7.10 (d, J = 1.2 Hz, 1 H), 4.88 (d, J = 6.4 Hz, 2H), 4.78 (d, J = 6.0 Hz, 2H), 4.6 (s, 2H), 2.98 (d, J = 26.0 Hz, 6H).
Figure imgf000048_0001
Prepared from compound 1 h) (100 mg, 0.265 mmol, 1.0 eq) according to the synthesis protocol 1 i). White solid. Yield: 70 mg (59%). Melting range: 240-243°C. HPLC (method 1 ): Rt = 6.33 min. m/z: [M+H]+ = 447.0. 1 H NMR (300 MHz, DMSO-d6, δ ppm): 8.86 (s, 2H), 8.38 (s, 1 H), 7.80 (d, J = 7.8 Hz, 1 H), 7.69- 7.63 (m, 1 H), 7.47-7.32 (m, 3H), 7.10 (d, J = 7.8 Hz, 1 H), 4.88 (d, J = 6.3 Hz, 2H), 4.78 (d, J = 5.7 Hz, 2H), 4.61 (s, 2H), 3.61-3.38 (m, 8H).
Intermediate 1 : Methyl 1 -(5-bromopyrimid -2-yl)spiro[indoline-3,3'-oxetanel-6-carboxylate (lnt-1 )
Figure imgf000048_0002
lnt-1a) 6'-Bromo-2,2-dimethylspiro[[1 ,3ldioxane-5,3'-indolinl-2'-one
A solution of 6-bromo-3,3-bis(hydroxymethyl)indolin-2-one (compound 1 c, 78 g, 287 mmol), 2,2- dimethoxy-propane (106.6 mL, 860.3 mmol) and 4-toluenesulfonyl chloride monohydrate (4.4 g) in dry DMF (1 L) was stirred at 80°C for 6 h. The reaction mixture was cooled to rt, poured onto ice-water and extracted with MTBE (3 x 1 L). The combined organic layers were washed with saturated NaHC03 solution, dried over Na2S04 and concentrated. White solid. Yield: 70 g (78%). HPLC (method 3): Rt = 3.17 min., m/z: [M+H]+ = 314 (MW calc. 312.16). lnt-1 b) 6'-Bromo-2,2-dimethylspiro[[1 ,3ldioxane-5,3'-indolinel Red-AI (66 mL, 224.3 mmol) was added drop wise at rt to a solution of lnt-1a (35 g, 1 12.17 mmol) in dry toluene (2.4 L). The reaction mixture was then stirred at 80°C for 1.5 h and quenched at 0°C with 2 N NaOH solution. The aqueous layer was separated and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine, dried over Na2S04 and evaporated. Light brown solid. Yield: 30 g (94%). HPLC (method 3): Rt = 3.43 min., m/z: [M+H]+ = 300.1 (MW calc. 298.18). lnt-1 c) Methyl 2,2-dimethylspiro[[1 ,3ldioxane-5,3'-indolinel-6'-carboxylate
PdCI2(dppf) was added at rt to a solution of lnt-1 b (32 g, 107.38 mmol) and TEA (33 mL, 236.2 mmol) in MeOH/DMF (5: 1 , 480 mL) that was kept under Ar in a Parr autoclave. The reaction mixture was then stirred for 16 h at 1 10°C under CO gas atmosphere at a pressure of 220 psi. The autoclave was cooled to rt and the mixture was filtered through a plug of celite. The filter was washed with MeOH and the filtrate was concentrated. The residue was diluted with EtOAc, washed with water and brine and dried. The solvent was removed under reduced pressure and the remnant was purified by flash column chromatography [silica; hexane with 6-15% acetone]. White solid. Yield: 21.5 g (72%). HPLC (method 3): Rt = 3.12 min., m/z: [M+H]+ = 278.1 (MW calc. 277.32). lnt-1 d) Methyl 3,3-bis(hydroxymethyl)indoline-6-carboxylate
2N HCI solution (349 mL, 698.5 mmol) was added at rt to lnt-1 c (21 .5 g, 77.61 mmol) in THF (215 mL) and the mixture was stirred at this temperature for 3 h. The reaction mixture was concentrated, neutralized with saturated NaHC03 solution and extracted with EtOAc (10 x 250 mL). The combined organic layers were dried over Na2S04 and evaporated. Light yellow solid. Yield: 13.5 g (73%). HPLC (method 3): Rt = 1.68 min., m/z: [M+H]+ = 238.1 (MW calc. 237.25). lnt-1 e) Methyl 1-(5-bromopyrimidin-2-yl)-3,3-bis(hvdroxymethyl)indoline-6-carboxylate
lnt-1d (3.5 g, 14.76 mmol), 5-bromo-2-chloro-pyrimidine (4.28 g, 22.15 mmol) and DIPEA (6.1 mL, 36.9 mmol) in n-butanol (82 mL) were stirred in a sealed tube at 130°C for 36 h. The reaction mixture was cooled to rt and the precipitating solid was filtered off and washed with a blend of diethylether and hexane. White solid. Yield: 3.6 g (61 %). HPLC (method 3): Rt = 2.94 min., m/z: [M+H]+ = 396 (MW calc. 394.22). lnt-1 f) Methyl 1-(5-bromopyrimidin-2-yl)-3-(hvdroxymethyl)-3-((tosyloxy)methyl)indoline-6-carboxylate LiHMDS (12.69 mL, 12.69 mmol) was added drop wise at -50°C over a period of 30 min to a solution of lnt-1 e (5.0 g, 12.69 mmol) in dry THF (500 mL). The reaction mixture was stirred at this temperature for 30 min followed by slow addition 4-toluenesulfonyl chloride (2.41 g, 12.69 mmol) in THF (100 mL). The reaction mixture was further stirred at rt for 1.5 h and then quenched with saturated NH4CI solution and extracted with EtOAc (3 x 250 mL). The combined organic layers were dried over Na2S04 and the raw product was purified by flash column chromatography [silica; hexane with 10-20% EtOAc]. White solid. Yield: 4 g (57%). HPLC (method 3): Rt = 3.63 min., m/z: [M+H]+ 548.1 (MW calc. 548.41 ). lnt-1 g) Methyl 1-(5-bromopyrimidin-2-yl)spironndoline-3,3'-oxetane1-6-carboxylate lnt-1 e (8.0 g, 14.59 mmol) and K2C03 (4.0 g, 29.19 mmol) in MeOH (288 mL) were stirred at 80°C for 16 h. The solvent was evaporated and the residue was diluted with water (50 mL) and extracted with DCM (3x 300 mL). The combined organic layers were dried, the solvent was removed under reduced pressure and the raw product was triturated with ether affording the target compound as white solid. The aqueous phase of the reaction mixture was acidified with NaHS04 and the appearing precipitate was filtered off and dried thereby yielding 1.1 g of 1-(5-bromopyrimidin-2-yl)spiro[indoline-3,3'-oxetane]-6-carboxylic acid. Yield: 3.7 g of the methyl ester (67%). HPLC (method 3): Rt = 3.56 min., m/z: [M+H]+ 378.0 (MW calc. 376.20). Example 3: N-(2-Amino-2-oxoethyl)-1 -(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-N-methylspiro[indoline- 3,3'-oxetanel-6-carboxamide
Figure imgf000050_0001
3a) Methyl 1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spironndoline-3,3'-oxetanel-6-carboxylate K2C03 (0.33 g, 2.4 mmol) and (AtaPhos)2PdCI2 (56 mg, 0.08 mmol) were added to a solution of lnt-1 (0.30 g, 0.80 mmol) and 2-fluoro-5-methylphenylboronic acid (0.25 g, 1.60 mmol) in amyl alcohol (8.0 mL) and water (0.8 mL) kept under Ar. The resulting mixture was stirred at 90°C for 5 h, then cooled and filtered over a plug of celite. The filtrate was concentrated and the residue purified by flash column chromatography [silica gel; DCM with 3% MeOH]. Light yellow solid. Yield: 0.15 g (46%)
HPLC (method 3): Rt = 3.89 min., m/z: [M+H]+ = 406.1 (MW calc. 405.42)
3b) 1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanel-6-carboxylic acid
LiOH H20 (62 mg, 1.48 mmol) was added at 0°C to a solution of compound 3a) (0.15 g, 0.37 mmol) in a blend of THF, MeOH and water (1 :1 :1 , 6 mL). The reaction mixture was stirred first at rt for 16 h and then 2 h at 60°C. The solvents were evaporated and the solid residue was acidified with saturated KHS04solution and filtered through a sintered funnel. Residual solvents were removed by repeated co- distillation with toluene. White solid. Yield: 0.14 g (96%). HPLC (method 2): Rt = 2.77 min, m/z: [M+H]+ = 392.36 (MW calc. 391.40)
3c) N-(2-Amino-2-oxoethyl)-1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-N-methylspiro [indoline-3,31- oxetanel-6-carboxamide
TBTU (0.14 g, 0.423 mmol), N-methylmorpholine (0.08 mL, 0.72 mmol) and 2-methylamino-acetamide hydrochloride (69 mg, 0.54 mmol) were added at 0°C to a solution of compound 3b) (0.14 g, 0.36 mmol) in dry DMF (4 mL) and the reaction mixture was stirred at rt for 16 h. The mixture was quenched with ice- cold water and the precipitating solid was filtered off and washed with water. The solid material was dissolved in DCM and purified by flash column chromatography [silica gel; DCM with 3% MeOH] followed by trituration in DCM/hexane (1 :2). White solid. Yield: 75 mg (45%). HPLC (method 2): Rt = 1.61 min., m/z: [M+H]+ = 462.1 (MW calc.461.49). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.80 (s, 2H), 8.40 (s, 1 H), 7.78 (d, 1 H, J = 7.5 Hz), 7.44 (d, 1 H, J = 7.3 Hz), 7.23-7.14 (m, 3H), 6.91 (s, 2H), 4.89 (d, 2H, J = 5.9 Hz), 4.82 (d, 2H, J = 6.0 Hz), 4.61 (s, 2H), 3.97 (s, 2H), 2.99 (s, 3H), 2.37 (s, 3H).
Examples 4 to 7 were prepared three steps from lnt-1 in analogy to synthesis example 3.
Figure imgf000051_0001
White solid. Yield: 55 mg. HPLC (method 2): Rt = 1.68 min., m/z: [M+H]+ = 429.1 (MW calc.428.48). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.0 (s, 2H), 8.39 (s, 1 H), 7.81-7.75 (m, 3H), 7.52-7.48 (m, 2H), 7.41-7.38 (m, 1 H), 7.14 (d, 1 H, J = 7.7 Hz), 4.89 (d, 2H, J = 6.0 Hz), 4.80 (d, 2H, J = 6.0 Hz), 4.61 (s, 2H), 3.63-3.39 (m, 8H).
Example 5: N-(2-Amino-2-oxoethyl)-1 -(5-(2-fluoro-5-methoxyphenyl)pyrimidin-2-yl)-N- methylspironndoline-3,3'-oxetane1- -carboxamide
Figure imgf000051_0002
White solid. Yield: 90 mg. HPLC (method 2): Rt = 1.56 min., m/z: [M+H]+ = 478.1 (MW calc. 477.49). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.83 (s, 2H), 8.40 (s, 1 H), 7.79 (d, 1 H, J = 7.6 Hz), 7.26-7.21 (m, 1 H), 7.18-7.15 (m, 2H), 7.0-6.92 (m, 3H), 4.89 (d, 2H, J = 6.0 Hz), 4.82 (d, 2H, J = 6.0 Hz), 4.62 (s, 2H), 3.97 (s, 2H), 3.84 (s, 3H), 2.99 (s, 3H). Example 6: N-(2-Amino-2-oxoethyl)-N-methyl-1 -(5-phenylpyrimidin-2-yl)spironndoline-3,3'-oxetane1-6- carboxamide
Figure imgf000052_0001
White solid. Yield: 70 mg. HPLC (method 2): Rt = 1.53 min., m/z: [M+H]+ = 430.1 (MW calc. 429.47). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.93 (s, 2H), 8.41 (s, 1 H), 7.78-7.71 (m, 3H), 7.51-7.48 (m, 2H), 7.41 (d, 1 H, J = 7.6 Hz), 7.15 (d, 1 H, J = 7.1 Hz), 6.93 (bs, 2H), 4.89 (d, 2H, J = 5.8 Hz), 4.82 (d, 2H, J = 5.9 Hz), 4.61 (s, 2H), 3.98 (s, 2H), 3.0 (s, 3H).
Example 7: N-(2-Amino-2-oxoethyl)-1 -(5-(5-ethyl-2-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[indoline-
3,3'-oxetanel-6-carboxamide
Figure imgf000052_0002
White solid. Yield: 90 mg. HPLC (method 3): Rt = 3.1 1 min., m/z: [M+H]+ = 476.2 (MW calc. 475.51 ). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.82 (s, 2H), 8.41 (s, 1 H), 7.78 (d, 1 H, J = 7.5 Hz), 7.46 (d, 1 H, J = 7.5 Hz), 7.26-7.15 (m, 3H), 6.89 (s, 2H), 4.89 (d, 2H, J = 5.7 Hz), 4.82 (d, 2H, J = 5.7 Hz), 4.62 (s, 2H), 3.98 (s, 2H), 2.99 (s, 3H), 2.72-2.67 (m, 2H), 1.28-1.24 (m, 3H). Example 8: Morpholino(1-(5-(pyridin- -yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl)methanone
Figure imgf000052_0003
8a) 1-(5-Bromopyrimidin-2-yl)spironndoline-3,3'-oxetanel-6-carboxylic acid
LiOH H20 (98 mg, 2.34 mmol) was added at 0°C to a solution of lnt-1 (0.22 g, 0.58 mmol) in a mixture of THF/water (1 : 1 , 10 mL) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated and the solid residue was acidified with saturated KHS04 solution and filtered through a sintered funnel. Residual solvents were removed by co-distillation with toluene. White solid. Yield: 0.20 g (95%). HPLC (method 3): Rt = 2.18 min., m/z: [M+H]+ = 362.2 / 364.2 (MW calc. 362.18)
8b) (1-(5-Bromopyrimidin-2-yl)spironndoline-3,3'-oxetanl-6-yl)(morpholino)methanone
TBTU (0.21 g, 0.66 mmol), N-methylmorpholine (0.12 mL, 1.10 mmol) and morpholine (0.063 mL, 0.72 mmol) were added at 0°C to a solution of compound 8a) (0.20 g, 0.55 mmol) in dry DMF (3.5 mL). The reaction mixture was stirred at rt for 16 h and then quenched with ice-cold water. A precipitate was filtered off and washed with water. Residual solvents were removed by azeotropic distillation with toluene. White solid. Yield: 0.17 g (72%). HPLC (method 3): Rt = 2.97 min., m/z: [M+H]+ = 431 .2 / 433.2 (MW calc. 431.28)
8c) Morpholino(1-(5-(pyridin-2-yl)pyrimidin-2-yl)spironndoline-3,3'-oxetanl-6-yl)methanone
PdCI2(dppf) (24 mg, 0.029 mmol) was added to a solution of compound 8b) (0.25 g, 0.58 mmol), bis(pinacolato)diboron (0.24 g, 0.93 mmol) and potassium acetate (0.17 g, 1 .74 mmol) in dry dioxane (10 mL) that was stirred at rt under Ar. After stirring at 1 10°C for 1 .5 h, 2-bromo-pyridine (0.085 mL, 0.87 mmol), aqueous K2C03 solution (2M, 0.9 mL) and tetrakis(triphenylphosphine)palladium(0) (33.5 mg, 0.029 mmol) were added successively. The reaction mixture was further stirred at 100°C for 4 h, cooled to rt and filtered through a sintered funnel. The filtrate was concentrated and the residue purified by flash column chromatography [silica; DCM with 2% MeOH] followed by trituration with DCM/hexane (1 :2). White solid. Yield: 80 mg (32%). HPLC (method 3): Rt = 2.88 min., m/z: [M+H]+ = 430.3 (MW calc. 429.47). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.31 (s, 2H), 8.68 (d, 1 H, J = 3.3 Hz), 8.42 (s, 1 H), 8.04 (d, 1 H, J = 8.0 Hz), 7.93-7.89 (m, 1 H), 7.82 (d, 1 H, J = 7.5 Hz), 7.38-7.36 (m, 1 H), 7.16 (d, 1 H, J = 7.5 Hz), 4.89 (d, 2H, J = 5.9 Hz), 4.79 (d, 2H, J = 5.9 Hz), 4.63 (s, 2H), 3.63-3.42 (m, 8H). Examples 9 and 10 were prepared analogously to synthesis example 8.
Example 9: (1-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)spironndoline-3,3'-oxetanl-6-yl)(morpholino) methanone
Figure imgf000053_0001
White solid. Yield: 60 mg. HPLC (method 3): Rt = 2.92 min., m/z: [M+H]+ = 444.1 (MW calc. 443.50). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.29 (s, 2H), 8.53 (d, 1 H, J = 4.9 Hz), 8.41 (s, 1 H), 7.88 (s, 1 H), 7.82 (d, 1 H, J = 7.5 Hz), 7.21 (d, 1 H, J = 4.4 Hz), 7.16 (d, 1 H, J = 7.7 Hz), 4.89 (d, 2H, J = 6.0 Hz), 4.79 (d, 2H, J = 6.1 Hz), 4.62 (s, 2H), 3.64 (s, 8H), 2.39 (s, 3H). Example 10: (1-(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spironn^
yl)(morpholino)methanone
Figure imgf000054_0001
White solid. Yield: 80 mg. HPLC (method 2): Rt = 1.42 min., m/z: [M+H]+ = 460.1 (MW calc. 459.50). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.31 (s, 2H), 8.49 (d, 1 H, J = 5.6 Hz), 8.42 (s, 1 H), 7.82 (d, 1 H, J = 7.6 Hz), 7.59 (s, 1 H), 7.16 (d, 1 H, J = 7.7 Hz), 6.97 (d, 1 H, J = 3.5 Hz), 4.89 (d, 2H, J = 6.1 Hz), 4.79 (d, 2H, J = 6.0 Hz), 4.63 (s, 2H), 3.92 (s, 3H), 3.63-3.40 (m, 8H).
Figure imgf000054_0002
lnt-2a) (6-Bromoindoline-3,3-diyl)dimethanol
Borane dimethyl sulfide complex solution (10.1 M in THF, 17.4 mL, 183.7 mmol) was added over a period of 20 min to a suspension of 6-bromo-3,3-bis(hydroxymethyl)indolin-2-one (compound 1 c, 10 g, 36.75 mmol) in anhydrous THF (1 10 mL) at 0°C. The reaction mixture was stirred overnight at rt, then quenched by slow addition of crushed ice followed concentrated HCI (10.3 mL). The solution was warmed to rt, stirred for 15 min and then concentrated under reduced pressure. MeOH was repeatedly (4x) added to the residue and removed under vacuum. White solid. Yield: 9 g (95%). HPLC (method 2): Rt = 0.75 min., m/z: [M+H]+ = 260.0 (MW calc. 258.1 1 ) lnt-2b) (6-Bromo-1-(5-(2-fluorophenyl)pyrimidin-2-yl)indoline-3,3-diyl)diMeOH
Sulfuric acid (0.65 mL) and 2-chloro-5-(2-fluoro-phenyl)-pyrimidine (5.5 g, 26.5 mmol) were added at rt to a suspension of lnt-2a (6.5 g, 22.13 mmol) in n-butanol (52 mL). The reaction mixture was stirred at 120°C for 18 h, then cooled to rt, diluted with water and extracted with EtOAc (3x 200 mL). The combined organic layers were dried over Na2S04 and concentrated. The remnant was purified by flash column chromatography [silica, EtOAc/hexane = 1 : 1]. White solid. Yield: 2.3 g (24%). HPLC (method 3): Rt = 3.55 min., m/z: [M+H]+ = 432.0 (MW calc. 430.27) lnt-2c) 6-Bromo-1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanel
KOf-Bu (0.574 g, 5.1 1 mmol) was added portion wise at rt to a stirred solution of lnt-2b (2 g, 4.64 mmol, 1 .0 eq) in pyridine (38 mL), followed by addition of 4-toluenesulfonyl chloride (1.06 g, 5.56 mmol) and further KOf-Bu (0.63 g, 5.56 mmol). The reaction mixture was stirred at 100°C for 16 h, cooled to rt, diluted with water (20 mL) and extracted with EtOAc (2x 50 mL). The combined organic layers were washed with 1 N HCI solution (20x 3 mL) and brine (20 mL), dried over Na2S04 and concentrated. The residue was purified by flash column chromatography [silica, EtOAc with 10-20% hexane]. White solid. Yield: 0.96 g (50%). HPLC (method 3): Rt = 2.46 min., m/z: [M+H]+ = 414.2 (MW calc. 412.26) lnt-2d) Methyl 1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanel-6-carboxylate
TEA (0.7 mL, 5.06 mmol) and PdCI2(dppf) (0.17 g, 0.228 mmol) were added to a stirred solution of lnt-2c (0.94 g, 2.28 mmol) in DMF (15 mL) and MeOH (25 mL) kept under Ar in an autoclave. The mixture was stirred for 48h at 1 10°C and 250 psi of CO gas. The reaction mixture was cooled to rt, diluted with water (25 mL) and extracted with EtOAc (2x 30 mL). The combined organic layers were washed with brine (20 mL), dried and concentrated under reduced pressure. The raw product was purified by flash column chromatography [silica; hexane with 15-25% EtOAc]. White solid. Yield: 0.46 g (52%). HPLC (method 3): Rt = 3.71 min., m/z: [M+H]+ = 392.2 (MW calc. 391.40) lnt-2e) 1-(5-(2-Fluorophenyl)pyrimidin-2-yl)spironndoline-3,3'-oxetanel-6-carboxylic acid
A mixture of LiOH H20 (0.2 g, 4.7 mmol) and lnt-2d (0.46 g, 1.17 mmol) in a blend of THF, MeOH and water (1 :1 : 1 , 30 mL) was stirred first at rt for 16 h and then 2 h at 60°C. The reaction mixture was cooled to rt and concentrated. The solid residue was acidified with saturated KHS04 solution and filtered through a sintered funnel. Residual solvents were removed by repeated azeotropic distillation of toluene. White solid. Yield: 0.4 g (91 %). HPLC (method 3): Rt = 2.64 min., m/z: [M+H]+ = 378.2 (MW calc. 377.37)
Example 1 1 : N-(2-Amino-2-oxoethyl)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)-N-methylspironndoline-3,3'- oxetanel-6-carboxamide
Figure imgf000055_0001
HOAt (48 mg, 0.349 mmol), EDCxHCI (67 mg, 0.349 mmol), TEA (0.122 mL, 0.873 mmol) and 2-methyl- amino-acetamide hydrochloride (55 mg, 0.437 mmol) were added at 0°C to a solution of lnt-2 (0.1 1 g, 0.29 mmol) in dry DMF (3 mL). The reaction mixture was stirred at rt for 16 and then quenched with crushed ice. A precipitating sold was filtered off and washed with water. The solid was dissolved in DCM and purified by flash column chromatography [silica; DCM with 3-4% MeOH] followed by trituration with DCM/hexane (1 :5). White solid. Yield: 60 mg (46%). HPLC (method 3): Rt = 2.81 min., m/z: [M+H]+ = 448.3 (MW calc. 447.46). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.82 (s, 2H), 8.40 (s, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.65-7.61 (m, 1 H), 7.44 (s, 1 H), 7.34-7.29 (m, 2H), 7.15 (d, J = 8.0 Hz, 1 H), 6.91 (bs, 2H), 4.87 (bs, 2H), 4.81 (bs, 2H), 4.62 (s, 2H), 3.97 (bs, 2H), 2.99 (s, 3H).
Example 12: N-(2-Amino-2-oxoethyl)-1-(5-(5-ethoxy-2-fluorophenyl)pyrimidin-2-yl)-N-methylspironndoline- 3,3'-oxetanel-6-carboxamide
Figure imgf000056_0001
Synthesized from lnt-1 analogousl to the synthesis example 3. White solid. Yield: 80 mg. HPLC (method 2): Rt = 1.61 min., m/z: [M+H]+ = 492.1 (MW calc. 491.51 ). 1 H NMR (300 MHz, DMSO-d6, δ ppm): 8.84- 8.86 (m, 2H), 8.38 (s, 1 H), 7.81 -7.76 (m, 1 H), 7.46-7.41 (m, 1 H), 7.29-7.24 (m, 1 H), 7.17-7.10 (m, 3H), 6.97 (bs, 1 H), 4.87 (bs, 2H), 4.79 (bs, 2H), 4.60 (bs, 2H), 4.09-4.03 (m, 3H), 3.84 (s, 1 H), 2.95 (s, 3H), 1.35-1.32 (m, 3H). Example 13: N-(2-Amino-2-oxoethyl)-N-methyl-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spironndoline-3,3'- oxetanel-6-carboxamide
Figure imgf000056_0002
Prepared from compound lnt-1 in an analogues manner to synthesis example 3. White solid. Yield: 0.1 g. HPLC (method 2): Rt = 1.40 min., m/z: [M+H]+ = 431 .0 (MW calc. 430.46). 1 H NMR (300 MHz, DMSO-d6, 100°C, δ ppm): 9.25 (s, 2H), 8.67 (d, 1 H, J = 4.5 Hz, 1 H), 8.43 (s, 1 H), 7.96 (d, 1 H, J = 8.0 Hz), 7.90-7.86 (m, 1 H), 7.78 (d, 1 H, J = 8.0 Hz), 7.36-7.33 (m, 1 H), 7.17 (d, 1 H, J = 7.5 Hz), 6.92 (bs, 2H), 4.89 (d, 2H, J = 5.7 Hz), 4.81 (d, 2H, J = 6.0 Hz), 4.63 (s, 2H), 3.98 (s, 2H), 3.00 (s, 3H). Synthesis examples 14 and 15 were obtained from a Suzuki coupling of (1-(5-bromopyrimidin-2- yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)methanone (compound 8b) and the respective phenyl boronic acids utilizing reaction conditions as described in protocol 3a. Example 14: Morpholino(1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)spironndoline-3,3'-oxetanl-6-yl)- methanone
Figure imgf000057_0001
White solid. Yield: 0.1 g. HPLC (method 2): Rt = 1.74 min., m/z: [M+H]+ = 497.1 (MW calc. 496.48). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.09 (s, 2H), 8.40 (s, 1.0H), 8.12-8.07 (m, 2H), 7.82 (d, 1 H, J = 7.6 Hz), 7.74-7.7 (m, 2H), 7.15-7.13 (m, 1 H), 4.89 (d, 2H, J = 6.1 Hz), 4.8 (d, 2 H, J = 6 Hz), 4.61 (s, 2H), 3.63-3.4 (m, 8H).
Example 15: (1-(5-(2-Fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)spironndoline-3,3'-oxetanl-6-yl)-
(morpholino)methanone
Figure imgf000057_0002
White solid. Yield: 0.25 g. HPLC (method 2): Rt = 1.74 min., m/z: [M+H]+ = 515.1 (MW calc. 514.47). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.93 (s, 2H), 8.39 (s, 1 H), 8.07 (d, 1 H, J = 5.1 Hz), 7.82-7.8 (m, 2H), 7.64-7.6 (m, 1 H), 7.16 (d, 1 H, J = 7.4 Hz), 4.87 (d, 2H, J = 6.1 Hz), 4.78 (d, 2H, J = 6 Hz), 4.61 (s, 2H), 3.62-3.4 (m, 8H).
Synthesis examples 16 and 17 were prepared from 1 -(5-bromopyrimidin-2-yl)spiro[indoline-3,3'-oxetane]- 6-carboxylic acid (compound 8a) in two chemical steps comprising an amide coupling with 2- (methylamino)ethanol and TBTU as reagent and a Suzuki reaction (protocol 3a). Example 16: 1 -(5-(2-Fluoro-5-(trifluoromethyl)phenyl)pyrimidin^
Figure imgf000058_0001
White solid. Yield: 53 mg. HPLC (method 2): Rt = 1.66 min., m/z: [M+H]+ = 503.1 (MW calc. 502.46). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.81 (s, 2H), 8.37 (s, 1 H), 8.01 (d, 1 H, J = 6.7 Hz), 7.79-7.77 (m, 2H), 7.59-7.54 (m, 1 H), 7.15 (d, 1 H, J = 7.6 Hz), 4.88 (d, 2H, J = 6.0 Hz), 4.81 (d, 2H, J = 5.9 Hz), 4.63 (s, 2H), 4.4 (bs, 1 H), 3.63-3.61 (m, 2H), 3.45 (bs, 2H), 3.02 (s, 3H).
Example 17: N-(2-Hvdroxyethyl)-N-methyl-1 -(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)spiro [indoline- 3,3'-oxetanel-6-carboxamide
Figure imgf000058_0002
White solid. Yield: 0.1 1 g. HPLC (method 2): Rt = 1.67 min., m/z: [M+H]+ = 485.1 (MW calc. 484.47). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.01 (s, 2H), 8.39 (s, 1 H), 8.03 (bs, 2H), 7.86-7.71 (m, 3H), 7.12 (d, 1 H, J = 7.3 Hz), 4.88 (bs, 2H), 4.82 (bs, 2H), 4.63 (s, 2H), 4.41 (bs, 1 H), 3.62 (bs, 2H), 3.45 (bs, 2H), 3.02 (s, 3H).
Examples 18 to 21 were obtained from lnt-2 and the respective amines via an amide coupling with TBTU (procedure 3c). Example 18: (1-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl)(pyrrolidin-1-yl)- methanone
Figure imgf000059_0001
White solid. Yield: 60 mg. HPLC (method 3): Rt = 3.38 min., m/z: [M+H]+ = 431.1 (MW calc. 430.47). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.83 (s, 2H), 8.46 (s, 1 H), 7.78 (d, J = 7.5 Hz, 1 H), 7.65-7.61 (m, 1 H), 7.45-7.44 (m, 1 H), 7.34-7.29 (m, 2H), 7.23 (d, J = 7.4 Hz, 1 H), 4.89 (d, J = 5.5 Hz, 2H), 4.81 (d, J = 5.6 Hz, 2H), 4.62 (s, 2H), 3.48 (bs, 4H), 1.88 (bs, 4H).
Example 19: (1-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl)(piperazin-1-yl)- methanone
Figure imgf000059_0002
White solid. Yield: 50 mg. HPLC (method 3): Rt = 2.71 min., m/z: [M+H]+ = 446.0 (MW calc. 445.49). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.82 (s, 2H), 8.36 (s, 1 H), 7.79 (d, J = 7.6 Hz, 1 H), 7.65-7.61 (m, 1 H), 7.45-7.44 (m, 1 H), 7.35-7.29 (m, 2H), 7.1 1 (d, J = 8.0 Hz, 1 H), 4.89 (d, J = 5.7 Hz, 2H), 4.81 (d, J = 6.0 Hz, 2H), 4.62 (s, 2H), 3.48 (bs, 4H), 2.79 (bs, 4H). Example 20: 1-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspironndoline-3,3'-oxetanel-
6-carboxamide
Figure imgf000059_0003
White solid. Yield: 60 mg. HPLC (method 3): Rt = 3.02 min., m/z: [M+H]+ = 435.2 (MW calc. 434.46). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.85 (s, 2H), 8.35 (s, 1 H), 7.78 (s, 1 H), 7.66 (t, J = 8.3 Hz, 1 H), 7.46- 7.45 (m, 1 H), 7.39-7.32 (m, 2H), 7.13 (d, J = 7.0 Hz, 1 H), 4.88 (d, J = 5.6 Hz, 2H), 4.81-4.79 (m, 3H), 4.61 (s, 2H), 3.64 (bs, 1 H), 3.52 (bs, 2H), 3.32 (1 H, masked with DMSO/water peak), 3.00-2.98 (m, 3H).
Example 21 : (1 S,4S)-2,5-Diazabicvclo[2.2.1lheptan-2-yl(1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro nndoline-3,3'-oxetanl-6-yl)methanon
Figure imgf000060_0001
White solid. Yield: 55 mg. HPLC (method 2): Rt = 1.40 min., m/z: [M+H]+ = 458.1 (MW calc. 457.50). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.82 (s, 2H), 8.49 (s, 1 H), 7.80 (d, J = 7.2 Hz, 1 H), 7.63 (bs, 1 H), 7.45 (bs, 1 H), 7.33 (bs, 2H), 7.24 (d, J = 7.3 Hz, 1 H), 4.89 (d, J = 5.3 Hz, 2H), 4.81 (s, 2H), 4.62 (s, 2H), 4.44 (bs, 1 H), 3.75 (bs, 1 H), 3.56-3.53 (m, 1 H), 3.46-3.45 (m, 1 H), 3.10-2.97 (m, 3H), 1.78 (bs, 1 H), 1.66 (bs, 1 H).
Example 22: (1-(5-(4-Methylpyridin-2-yl)pyrimidin-2-^
methanone
Figure imgf000060_0002
22a) Methyl 1 -(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spironndoline-3,3'-oxetanel-6-carboxylate
Bis(pinacolato)diboron (1.45 g, 5.74 mmol) and potassium acetate (1.05 g, 10.77 mmol) were added at rt to a solution of lnt-1 (1.35 g, 3.59 mmol) in dry dioxane (80 mL) stirred under Ar. PdCI2(dppf) (0.146 g, 0.179 mmol) was added and the mixture was stirred at 100°C for 20 min. Next, 2-bromo-4-methyl-pyridine (0.926 g, 5.38 mmol), a 2M aqueous solution of K2C03 (6.7 mL) and tetrakis(triphenylphosphine)- palladium(O) (0.208 g, 0.179 mmol) were added successively and the reaction mixture was further stirred at 100°C for 5 h. The reaction mixture was then cooled to rt and filtered through a sintered funnel. The filtrate was concentrated and the remnant was purified by flash column chromatography [silica; DCM with 1.2% MeOH). White solid. Yield: 0.82 g (59%). HPLC (method 3): Rt = 3.46 min., m/z: [M+H]+ = 389.2 (MW calc. 388.42) 22b) 1-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan acid LiOH H20 (0.355 g, 8.45 mmol) was added at 0°C to a solution of compound 22a) (0.82 g, 2.1 1 mmol) in a blend of THF, water and MeOH (1 : 1 :1 , 45 mL). The reaction mixture was stirred at 80°C for 3 h and then concentrated. The solid residue was acidified with KHS04 solution and filtered through a sintered funnel. Residual solvents were removed by repeated azeotropic distillation of toluene. Light yellow solid. Yield: 0.72 g (91 %). HPLC (method 4): Rt = 2.64 min., m/z: [M+H]+ = 373.0 (MW calc. 374.39)
22c) (1-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl)(piperazin-1-yl)- methanone
TBTU (0.371 g, 1.15 mmol), N-methylmorpholine (0.2 mL, 1.92 mmol) and piperazine (0.166 g, 1.92 mmol) were added at 0°C to a solution of compound 22b) (0.36 g, 0.962 mmol) in dry DMF (10 mL). The reaction mixture was stirred at rt for 16 h, then quenched with crushed ice and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2S04 and concentrated under reduced pressure. The residue was purified through flash column chromatography [silica equilibrated with ammonia; DCM with 5-8% MeOH]. White solid. Yield: 60 mg (14%). HPLC (method 3): Rt = 2.63 min., m/z: [M+H]+ = 443.2 (MW calc. 442.51 ). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.24 (s, 2H), 8.52 (d, J = 4.9 Hz, 1 H), 8.39 (s, 1 H), 7.80-7.78 (m, 2H), 7.18 (d, J = 4.1 Hz, 1 H), 7.12 (d, J = 7.6 Hz, 1 H), 4.89 (d, J = 5.7 Hz, 2H), 4.81 (d, J = 5.8 Hz, 2H), 4.62 (s, 2H), 3.49 (bs, 4H), 2.80 (bs, 4H), 2.41 (s, 3H). Examples 23 and 24 were prepared from 1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'- oxetane]-6-carboxylic acid (TBTU coupling analogously to procedure 3c).
Example 23: (1-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)spironndoline-3,3'-oxetanl-6-yl)(pyrrolidin-1- vDmethanone
Figure imgf000061_0001
Light yellow solid. Yield: 65 mg. HPLC (method 2): Rt = 1.65 min., m/z: [M+H]+ = 428.1 (MW calc. 427.50). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.23 (s, 2H), 8.51 (d, J = 4.9 Hz, 2H), 7.79-7.77 (m, 2H), 7.24 (d, J = 7.6 Hz, 1 H), 7.17 (d, J = 4.6 Hz, 1 H), 4.89 (d, J = 5.9 Hz, 2H), 4.81 (d, J = 5.9 Hz, 2H), 4.63 (s, 2H), 3.49 (bs, 4H), 2.32 (s, 3H), 1.88 (bs, 4H).
Example 24: N-(2-Hvdroxyethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'- oxetanel-6-carboxamide
Figure imgf000062_0001
White solid. Yield: 100 mg. HPLC (method 2): Rt = 1.43 min., m/z: [M+H]+ = 432.0 (MW calc. 431.49). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.23 (s, 2H), 8.51 (d, J = 4.8 Hz, 1 H), 8.39 (s, 1 H), 7.79-7.76 (m, 2H), 7.18-7.12 (m, 2H), 4.89 (d, J = 5.9 Hz, 2H), 4.81 (d, J = 6.0 Hz, 2H), 4.63 (s, 2H), 4.41 (bs, 1 H), 3.64 (bs, 2H), 3.46 (bs, 2H), 3.03 (s, 3H), 2.32 (s, 3H).
Example 25: (1 S,4S)-2,5-Diazabicvclo[2.2.1lheptan-2-yl(1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro- nndoline-3,3'-oxetanl-6-yl)methanone
Figure imgf000062_0002
Prepared from 1-(5-bromopyrimidin-2-yl)spiro[indoline-3,3'-oxetane]-6-carboxylic acid and (1 S,4S)-tert- butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate in an analogous manner as described for synthesis example 8. The protecting group was removed in the final step with TFA in DCM. Light yellow solid. Yield: 0.1 g. HPLC (method 3): Rt = 2.56 min., m/z: [M+H]+ = 455.0 (MW calc. 454.52). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.23 (s, 2H), 8.52 (s, 2H), 7.80 (s, 2H), 7.25 (d, J = 7.5 Hz, 1 H), 7.17 (s, 1 H), 4.89 (d, J = 5.0 Hz, 2H), 4.81 (bs, 2H), 4.63 (s, 2H), 4.45 (bs, 1 H), 3.69 (s, 1 H), 3.55-3.53 (m, 1 H), 3.29- 3.27 (m, 1 H), 3.08-3.06 (m, 1 H), 2.41 (s, 3H), 1.77-1.75 (m, 1 H), 1 .64-1.62 (m, 1 H).
Example 26: N-(2-Amino-2-oxoethyl)-1-(5-(3-cvclopropylphenyl)pyrimidin-2-yl)-N-methylspiro [indoline- 3,3'-oxetanel-6-carboxamide
Figure imgf000063_0001
Prepared from lnt-1 and (3-cyclopropylphenyl)boronic acid analogously to synthesis example 3. White solid. Yield: 70 mg. HPLC (method 2): Rt = 1.63 min., m/z: [M+H]+ = 470.1 (MW calc. 469.54). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.92 (s, 2H), 8.41 (s, 1 H), 7.78 (d, 1 H, J = 7.3 Hz), 7.48-7.34 (m, 3H), 7.15-7.1 1 (m, 2H), 6.92 (s, 2H), 4.89 (d, 2H, J = 5.7 Hz), 4.82 (d, 2H, J = 5.8 Hz), 4.61 (s, 2H), 3.98 (s, 2H), 3.00 (s, 3H), 2.02 (s, 1 H), 0.99 (d, 2H, J = 6.2 Hz), 0.79 (d, 2H, J = 3.0 Hz).
Example 27: N-(2-Amino-2-oxoethyl)-N-methyl-1-(5-(m-tolyl)pyrimidin-2-yl)spironndoline-3,3'-oxetanel-6- carboxamide
Figure imgf000063_0002
Prepared from lnt-1 and m-tolylboronic acid analogously to synthesis example 3. White solid. Yield: 0.14 g. HPLC (method 2): Rt = 1.59 min., m/z: [M+H]+ = 444.1 (MW calc. 443.50). 1 H NMR (400 MHz, DMSO- d6, 100°C, δ ppm): 8.91 (s, 2H), 8.41 (s, 1 H), 7.78 (d, 1 H, J = 7.6 Hz), 7.53-7.49 (m, 2H), 7.39-7.35 (m, 1 H), 7.22 (d,1 H, J = 8.0 Hz), 7.15-7.13 (m, 1 H), 6.91 (s, 2H), 4.89 (d, 2H, J = 6.0 Hz), 4.82 (d, 2H, J = 6.0 Hz), 4.61 (s, 2H), 3.98 (s, 2H), 3.0 (s, 3H), 2.40 (s, 3H).
Example 28: (S)-N-(2-Amino-2-oxoethyl)-1-(5-(2-fluoro-5-(1-hvdroxyethyl)phenyl)pyrimidin-2-yl)-N- methylspironndoline-3,3'-oxetanel-6-carboxamide
Figure imgf000064_0001
F
Prepared from lnt-1 and (S)-1 -(3-bromo-4-fluorophenyl)ethanol analogously to synthesis example 22. White solid. Yield: 55 mg. HPLC (method 2): Rt = 1.47 min., m/z: [M+H]+ = 492.2 (MW calc. 491.51 ). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.81 (s, 2H), 8.40 (s, 1 H), 7.78 (d, 1 H, J = 7.6 Hz), 7.57 (d, 1 H, J = 7.6 Hz), 7.42 (s, 1 H), 7.27-7.23 (m, 1 H), 7.16 (d, 1 H, J = 7.4 Hz), 6.92 (s, 2H), 4.89-4.81 (m, 6 H), 4.62 (s, 2H), 3.97 (s, 2 H), 2.97 (s, 3 H), 1.35 (d, 3H, J = 6.4 Hz).
Example 29: (R)-N-(2-Amino-2-oxoethyl)-1-(5-(2-fluoro-5-(1-hvdroxyethyl)phenyl)pyrimidin-2-yl)-N-methyl-
Figure imgf000064_0002
Prepared from lnt-1 and (R)-1-(3-bromo-4-fluorophenyl)ethanol analogously to synthesis example 22. White solid. Yield: 0.10 g. HPLC (method 2): Rt = 1.47 min., m/z: [M+H]+ = 492.1 (MW calc. 491.51 ). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.85-8.83 (m, 2H), 8.38 (s, 1 H), 7.80-7.76 (m, 1 H), 7.57 (d, 1 H, J = 7.2 Hz), 7.46-7.40 (m, 2H), 7.32-7.28 (m, 1 H), 7.13-7.09 (m, 2H), 5.25 (s, 1 H), 4.88 (d, 2H, J = 6.5 Hz), 4.80 (d, 3H, J = 5.5 Hz), 4.60 (s, 2H), 4.04 (s, 1 H), 3.84 (s, 1 H), 2.95 (s, 3H), 1 .37 (d, 3H, J = 6.4 Hz).
Example 30: N-(2-Amino-2-oxoethyl)-1-(5-(2-fluoro-5-(2-hvdroxypropan-2-yl)phenyl)pyrimidin-2-yl)-N- methylspironndoline-3,3'-oxetanel-6-carboxamide
Figure imgf000065_0001
Prepared from lnt-1 and 2-(3-bromo-4-fluorophenyl)propan-2-ol analogously to synthesis example 22. White solid. Yield: 0.10 g. HPLC (method 3): Rt = 2.74 min., m/z: [M+H]+ = 506.2 (MW calc. 505.54). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.82 (s, 2H), 8.40 (s, 1 H), 7.78 (d, 1 H, J = 7.6 Hz), 7.68-7.66 (m, 1 H), 7.55-7.52 (m, 1 H), 7.25-7.14 (m, 2H), 6.91 (s, 2H), 4.89 (d, 2H, J = 6.0 Hz), 4.82 (d, 2H, J = 6.0 Hz), 4.76 (s, 1 H), 4.62 (s, 2H), 3.97 (s, 2H), 2.99 (s, 3H), 1 .51 (s, 6H).
Synthesis examples 31 and 32 were obtained from a Suzuki coupling of (1-(5-bromopyrimidin-2- yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)methanone (compound 8b) and the respective phenyl boronic acids utilizing reaction conditions as described in protocol 3a.
Figure imgf000065_0002
White solid. Yield: 65 mg. HPLC (method 3): Rt = 3.42 min., m/z: [M+H]+ = 443.3 (MW calc. 442.51 ). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.98 (s, 2H), 8.38 (s, 1 H), 7.80-7.79 (d, 1 H), 7.57-7.52 (m, 2H), 7.37- 7.35 (t, 1 H), 7.21-7.20 (d, 1 H), 7.13-7.1 1 (d, 1 H), 4.88-4.86 (d, 1 H), 4.79-4.78 (d, 1 H), 4.60 (d, 2H), 3.63 (bs, 8H), 2.38 (s, 3H).
Example 32: (1 -(5-(2-Fluoro-5-methoxyphenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl)(morpholino)- methanone
Figure imgf000066_0001
White solid. Yield: 75 mg. HPLC (method 3): Rt = 3.20 min., m/z: [M+H]+ = 477 (MW calc. 476.50). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.87 (s, 2H), 8.38 (s, 1 H), 7.81-7.79 (d, 1 H), 7.31-7.26 (m, 1 H), 7.20- 7.19 (d, 1 H), 7.14-7.13 (d, 1 H), 6.99 (m, 1 H), 4.88-4.87 (d, 1 H), 4.80-4.78 (d, 1 H), 4.60 (d, 2H), 3.81 (s, 3H), 3.63 (bs, 8H).
Example 33: (1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spironndoline-3,3'-oxetanl-6-yl)(morpholino)- methanone
Figure imgf000066_0002
Prepared in three steps from lnt-1 analogously to synthesis example 3. White solid. Yield: 57 mg. HPLC (method 3): Rt = 3.38 min., m/z: = 461 (MW calc. 460.50). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.84 (s, 2H), 8.38 (s, 1 H), 7.81 -7.79 (d, 1 H), 7.47-7.45 (d, 1 H), 7.25-7.23 (d, 2H), 7.14-7.13 (d, 1 H), 4.88-4.87 (d, 1 H), 4.79-4.78 (d, 1 H), 4.60 (d, 2H), 3.62 (bs, 8H), 2.38 (s, 3H). Examples 34 to 36 were prepared from 1 -(5-bromopyrimidin-2-yl)spiro[indoline-3,3'-oxetane]-6-carboxylic acid (compound 8a) analogously to synthesis example 8. The pinacol boronates obtained as intermediates were coupled in a Suzuki reaction with 2-bromopyridine (example 34), 2-chloro-4- cyclopropylpyridine (example 35) and 2-bromo-4-methoxypyridine (example 36). Example 34: (1-(5-(Pyridin-2-yl)pyrimidin-2-yl)spironndoline-3,3'-oxetanl-6-yl)(pyrrolidin-1-yl) methanone
Figure imgf000067_0001
White solid. Yield: 65 mg. m/z: = 414.0 (MW calc.413.47).1H NMR (400 MHz, DMSO-d6, δ ppm): 9.30 (s, 2H), 8.67-8.66 (d, 1H), 8.51 (s, 1H), 8.03-8.01 (d, 1H), 7.92-7.90 (m, 1H), 7.80-7.78 (d, 1H), 7.38-7.35 (m, 1H), 7.27-7.25 (d, 1H), 4.89-4.88 (d, 1H), 4.79-4.78 (d, 1H), 4.63 (d, 2H), 3.51-3.40 (m, 4H), 1.91-1.80 (m,4H).
Example 35: (1-(5-(4-Cvclopropylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl) (pyrrolidin-1- vDmethanone
Figure imgf000067_0002
White solid. Yield: 90 mg. m/z: = 453.8 (MW calc.453.54).1H NMR (400 MHz, DMSO-d6, δ ppm): 9.29 (s, 2H), 8.51 (s, 1H), 8.46-8.45 (d, 1H), 7.80-7.78 (d, 1H), 7.69 (s, 1H), 7.26-7.24 (d, 1H), 7.07 (m, 1H), 4.89-4.88 (d, 1H), 4.79-4.78 (d, 1H), 4.62 (s, 2H), 3.49-3.42 (m, 4H), 1.99 (m, 1H), 1.89-1.82 (m, 4H), 1.10-1.08 (d,2H), 0.93 (d, 2H). Example 36: (1-(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl) (pyrrolidin-1- vPmethanone
Figure imgf000067_0003
White solid. Yield: 1 10 mg. m/z: = 444.3 (MW calc. 443.50). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.30 (s, 2H), 8.50 (s, 1 H), 8.48-8.46 (d, 1 H), 7.80-7.78 (d, 1 H), 7.58 (s, 1 H), 7.26-7.24 (d, 1 H), 6.95-6.94 (d, 1 H), 4.89-4.88 (d, 1 H), 4.79-4.77 (d, 1 H), 4.62 (s, 2H), 3.91 (s, 3H), 3.50-3.40 (m, 4H), 1.99 (m, 1 H), 1.91- 1.82 (m, 4H) .
Figure imgf000068_0001
Tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.07 mmol) was added at rt to a solution of compound 8b (150 mg, 0.35 mmol), 3-fluorophenylboronic acid (98 mg, 0.7 mmol) and 2 M Na2C03 solution (0.34 ml) in DME/EtOH (1 : 1 , 12 ml) stirred under Ar. The reaction mixture was stirred at 100°C for 6 h, cooled to rt and filtered through a pad of celite. The filtrate was evaporated and the residue purified by flash column chromatography [DCM with 5% MeOH] followed by trituration with DCM /hexane (1 :2). Light yellow solid. Yield: 50 mg (32%). HPLC (method 3): Rt = 3.26 min., m/z: [M+H]+ = 447.1 (MW calc. 446.47). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.04 (s, 2H), 8.39 (s, 1 H), 7.80 (d, J = 7.2 Hz, 1 H), 7.68- 7.61 (m, 2H), 7.54-7.52 (m, 1 H), 7.23-7.19 (m, 1 H), 7.13 (d, J = 7.6 Hz, 1 H), 4.87 (d, J = 6 Hz, 2H), 4.78 (d, J = 6 Hz, 2H), 4.60 (s, 2H), 3.62 (bs, 8H).
Examples 38 to 41 were obtained from compound 8b according to the procedure for synthesis example
37.
Figure imgf000068_0002
White solid. Yield: 50 mg. HPLC (method 3): Rt = 3.15 min., m/z: [M+H]+ = 447.0 (MW calc. 446.47). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.98 (s, 2H), 8.38 (s, 1 H), 7.80-7.79 (m, 3H), 7.36-7.31 (m, 2H), 7.13- 7.1 1 (m, 1 H), 4.87 (d, J = 6 Hz, 2H), 4.79 (d, J = 5.6 Hz, 2H), 4.60 (s, 2H), 3.63 (bs, 8H). Example 39: (1 -(5-(2,5-Difluorophenyl)pyrimidin-2-yl)spironnd
Figure imgf000069_0001
White solid. Yield: 42 mg. HPLC (method 3): Rt = 3.21 min., m/z: [M+H]+ = 464.8 (MW calc. 464.46). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.89 (s, 2H), 8.38 (s, 1 H), 7.82-7.80 (m, 1 H), 7.61 (m, 1 H), 7.42 (m, 1 H), 7.29 (m, 1 H), 7.15 (d, J = 7.6 Hz, 1 H), 4.87 (d, J = 5.6 Hz, 2H), 4.79 (d, J = 5.6 Hz, 2H), 4.61 (s, 2H), 3.63 (bs, 8H).
Example 40: (1 -(5-(2,3-Difluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl)(morpholino) methanone
Figure imgf000069_0002
Yield: 75 mg. Light yellow solid. HPLC (method 3): Rt = 3.26 min., m/z: [M+H]+ = 465.3 (MW calc. 464.46). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.89 (s, 2H), 8.38 (s, 1 H), 7.81 (d, J = 7.6 Hz, 1 H), 7.49- 7.45 (m, 2H), 7.35 (m, 1 H), 7.15 (d, J = 7.2 Hz, 1 H), 4.88 (d, J = 6 Hz, 2H), 4.79 (d, J = 6 Hz, 2H), 4.61 (s, 2H), 3.62 (bs, 8H).
Example 41 (1 -(5-(3,5-Difluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl)(morpholino) methanone
Figure imgf000070_0001
White solid. Yield: 65 mg. HPLC (method 2): Rt = 1.72 min., m/z: [M+H]+ = 465.1 (MW calc. 464.46). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.08 (s, 2H), 8.39 (s, 1 H), 7.81 (d, J = 7.6 Hz, 1 H), 7.60 (d, J = 7.6 Hz, 2H), 7.27-7.24 (m, 1 H), 7.15 (d, J = 7.6 Hz, 1 H), 4.88 (d, J = 6 Hz, 2H), 4.78 (d, J = 6 Hz, 2H), 4.61 (s, 2H), 3.63 (bs, 8H).
Examples 42 to 46 were prepared from 1 -(5-bromopyrimidin-2-yl)spiro[indoline-3,3'-oxetane]-6-carboxylic acid (compound 8a) in two chemical steps comprising an amide coupling with 2-(methylamino)ethanol followed by a Suzuki reaction analogously to example 37.
Example 42: 1-(5-(3-Fluorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspironndoline-3,3'-oxetanel-
6-carboxamide
Figure imgf000070_0002
White solid. Yield: 60 mg. HPLC (method 3): Rt = 2.89 min., m/z: [M+H]+ = 434.8 (MW calc. 434.46). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.03 (s, 2H), 8.36 (s, 1 H), 7.78-7.77 (m, 1 H), 7.67-7.61 (m, 2H), 7.53- 7.52 (m, 1 H), 7.21 (t, J = 7.8 Hz, 1 H), 7.12 (d, J = 7.6 Hz, 1 H), 4.88 (d, J = 6 Hz, 2H), 4.79-4.78 (m, 3H), 4.61 (s, 2H), 3.64 (m, 1 H), 3.52 (bs, 2H), 3.0 (m, 3H).
Example 43: 1-(5-(4-Fluorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspironndoline-3,3'-oxetanel- 6-carboxamide
Figure imgf000071_0001
Brown solid. Yield: 55 mg. HPLC (method 3): Rt = 3.35 min., m/z: [M+H]+ = 435.4 (MW calc. 434.46). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.97 (s, 2H), 8.35 (s, 1 H), 7.79-7.78 (m, 3H), 7.33 (t, J = 8.4 Hz, 2H), 7.1 1 (d, J = 7.2 Hz, 1 H), 4.87 (d, J = 5.6 Hz, 2H), 4.80-4.78 (m, 3H), 4.60 (s, 2H), 3.64 (m, 3H), 3.0 (m, 3H).
Example 44: 1-(5-(2,5-Difluorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspironndoline oxetanel-6-carboxamide
Figure imgf000071_0002
White solid. Yield: 1 10 mg. HPLC (method 2): Rt = 1.61 min., m/z: [M+H]+ = 453.0 (MW calc. 452.45). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.88 (s, 2H), 8.35 (s, 1 H), 7.79-7.77 (m, 1 H), 7.62-7.58 (m, 1 H), 7.43- 7.39 (m, 1 H), 7.31-7.28 (m, 1 H), 7.13 (d, J = 7.6 Hz, 1 H), 4.87 (d, J = 6 Hz, 2H), 4.80-4.78 (m, 3H), 4.61 (s, 2H), 3.63-3.51 (m, 3H), 3.0 (m, 3H). Example 45: 1-(5-(2,3-Difluorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspironndoline-3,3'- oxetanel-6-carboxamide
Figure imgf000071_0003
White solid. Yield: 90 mg. HPLC (method 3): Rt = 2.91 min., m/z: [M+H]+ = 452.8 (MW calc. 452.45). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.88 (s, 2H), 8.35 (s, 1 H), 7.79-7.77 (m, 1 H), 7.50-7.46 (m, 2H), 7.35- 7.33 (m, 1 H), 7.13 (d, J = 7.8 Hz, 1 H), 4.88 (d, J = 6.4 Hz, 2H), 4.80-4.79 (m, 3H), 4.61 (s, 2H), 3.64 (m, 1 H), 3.52 (bs, 2H), 3.0 (m, 3H).
Example 46: 1-(5-(3,5-Difluorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspironndoline-3,3'- oxetanel-6-carboxamide
Figure imgf000072_0001
White solid. Yield: 77 mg. HPLC (method 3): Rt = 2.96 min., m/z: [M+H]+ = 452.8 (MW calc. 452.45). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.07 (s, 2H), 8.36 (s, 1 H), 7.79-7.77 (m, 1 H), 7.59 (d, J = 7.6 Hz, 2H), 7.24 (t, J = 9.6 Hz, 1 H), 7.13 (d, J = 7.2 Hz, 1 H), 4.88 (d, J = 6 Hz, 2H), 4.80-4.78 (m, 3H), 4.61 (s, 2H), 3.64 (m, 1 H), 3.52 (bs, 2H), 3.0 (m, 3H).
Examples 47 to 51 were prepared from lnt-1 in three steps comprising a Suzuki coupling (analogously to synthesis example 37), an ester hydrolysis (protocol 3b) and amide coupling with 2-(methyl- amino)acetamide (protocol 3c).
Example 47: N-(2-Amino-2-oxoethyl)-1-(5-(3-fluorophenyl)pyrimidin-2-yl)-N-methylspironndoline-3,3'- oxetanel-6-carboxamide
Figure imgf000072_0002
White solid. Yield: 55 mg. HPLC (method 3): Rt = 2.75 min., m/z: [M+H]+ = 448.0 (MW calc. 447.49). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.05-9.02 (m, 2H), 8.39 (s, 1 H), 7.89-7.76 (m, 1 H), 7.68-7.61 (m, 2H), 7.54-7.42 (m, 2H), 7.23-7.18 (m, 2H), 7.10-7.08 (m, 1 H), 4.86 (d, J = 6.4 Hz, 2H), 4.79 (m, 2H), 4.61 (s, 2H), 4.04 (s, 1 H), 3.84 (s, 1 H), 2.96 (s, 3H). Example 48: N-(2-Amino-2-oxoethyl)-1-(5-(4-fluorophenyl)pyrim^
oxetanel-6-carboxamide
Figure imgf000073_0001
White solid. Yield: 125 mg. HPLC (method 3): Rt = 3.23 min., m/z: [M+H]+ = 448.4 (MW calc. 447.49). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.98-8.96 (m, 2H), 8.39 (s, 1 H), 7.80 (m, 3H), 7.46-7.41 (m, 1 H), 7.33 (m, 2H), 7.16-7.09 (m, 2H), 4.87 (m, 2H), 4.79 (m, 2H), 4.59 (s, 2H), 4.04 (s, 1 H), 3.84 (s, 1 H), 2.96 (s, 3H).
Example 49: N-(2-Amino-2-oxoethyl)-1-(5-(2,5-difluorophenyl)pyrimidin-2-yl)-N-methylspiro [indoline-3,31- oxetanel-6-carboxamide
Figure imgf000073_0002
White solid. Yield: 60 mg. HPLC (method 3): Rt = 2.77 min., m/z: [M+H]+ = 465.8 (MW calc. 465.46). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.91-8.87 (m, 2H), 8.38 (s, 1 H), 7.82-7.76 (m, 1 H), 7.61 (m, 1 H), 7.45-7.41 (m, 2H), 7.29 (m, 1 H), 7.19-7.09 (m, 2H), 4.87 (m, 2H), 4.79 (m, 2H), 4.60 (s, 2H), 4.04 (s, 1 H), 3.84 (s, 1 H), 2.95 (s, 3H).
Example 50: N-(2-Amino-2-oxoethyl)-1-(5-(2,3-difluorophenyl)pyrimidin-2-yl)-N-methylspiro [indoline-3,31- oxetanel-6-carboxamide
Figure imgf000074_0001
White solid. Yield: 95 mg. HPLC (method 3): Rt = 2.77 min., m/z: [M+H]+ = 466.3 (MW calc. 465.46). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.89-8.87 (m, 2H), 8.38 (s, 1 H), 7.79-7.77 (m, 1 H), 7.61 (m, 1 H), 7.49-7.35 (m, 4H), 7.19-7.09 (m, 2H), 4.87- 4.80 (m, 4H), 4.60 (s, 2H), 4.04 (s, 1 H), 3.84 (s, 1 H), 2.95 (s, 3H).
Example 51 : N-(2-Amino-2-oxoethyl)-1-(5-(3,5-difluorophenyl)pyrimidin-2-yl)-N-methylspiro [indoline-3,31- oxetanel-6-carboxamide
Figure imgf000074_0002
White solid. Yield: 120 mg. HPLC (method 2): Rt = 1.58 min., m/z: [M+H]+ = 466.0 (MW calc. 465.46). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.09-9.05 (m, 2H), 8.40 (s, 1 H), 7.78-7.76 (m, 1 H), 7.61-7.59 (m, 2H), 7.46-7.42 (m, 1 H), 7.24-7.09 (m, 3H), 4.87 (m, 2H), 4.79 (m, 2H), 4.60 (s, 2H), 4.04 (s, 1 H), 3.84 (s, 1 H), 2.95 (s, 3H).
Figure imgf000074_0003
52a) 6-(Ethylthio)indolin-2-one
Pd2(dba)3 (5.3 g, 5.8 mmol, 0.05 eq), Xanthphos (6.8 g, 1 1.7 mmol, 0.1 eq) and ethanethiol (9.1 ml, 1 17 mmol) were added to a solution of 6-bromoindolin-2-one (25 g, 1 17 mmol) and DIPEA (43.4 ml, 235 mmol, 2 eq) in 1 ,4-dioxane (750 ml) that was stirred under N2. The reaction mixture was then refluxed for 16 h, cooled to rt and filtered through a pad of celite. The filter was rinsed with EtOAc and the filtrate was washed with water (80 ml) and brine (80 ml), dried over Na2S04 and concentrated. The residue was purified by column chromatography [100-200 mesh silica gel; EtOAc/hexane = 2:3]. Brown solid. Yield: 20 g (88%).
52b) tert-Butyl 6-(ethylthio)-2-oxoindoline-1-carboxylate
NaHC03 (23.5 g, 280 mmol, 3 eq) followed by di-tert-butyl dicarbonate (51 ml, 233 mmol, 2.5 eq) were added to a stirred solution of compound 52a (18 g, 93.26 mmol, 1 eq) in THF (200 ml) at rt. The mixture was refluxed for 16 h, filtered and concentrated under reduced pressure. The remnant was purified by column chromatography [100-200 mesh silica gel; EtOAc/hexane = 1 :9]. Brown gum. Yield: 21 g (77%). m/z: [M+H]+ = 294.1
52c) tert-Butyl 6-(ethylthio)-3,3-bis(hvdroxymethyl)-2-oxoindoline-1-carboxylate
K2C03 (24 g, 174.06 mmol, 3.0 eq) and paraformaldehyde (42.19 g, 1392 mmol, 24 eq) were added at rt to a stirred solution of compound 52b (17 g, 58.02 mmol, 1.0 eq) in THF (200 mL) and the mixture was stirred for 1 h. The reaction mixture was then filtered and the filtrate was evaporated. The residue was purified by column chromatography [silica gel 100-200 mesh, EtOAc/hexane = 3:2]. White solid. Yield: 17 g (83%).
52d) 6-(Ethylthio)-3,3-bis(hvdroxymethyl)indolin-2-one
TFA (4 ml, 49.47 mmol, 3.5 eq) was added drop wise at 0°C to a stirred solution of compound 52c (5 g, 14.16 mmol, 1 .0 eq) in DCM (50 mL). The mixture was stirred for 1 h at rt and then quenched with ice. The aqueous layer was separated and extracted with EtOAc (4 x 40 ml). The combined organic layers were washed with brine (20 ml), dried over Na2S04 and concentrated. This material was used for the next step without any further purification. White solid. Yield: 3 g (84%). m/z: [M+H]+ = 254.0.
52e) (6-(Ethylthio)indoline-3,3-diyl)dimethanol
Borane dimethyl sulfide complex solution (8.7 ml, 98.8 mmol, 5 eq) slowly at 0°C to a stirred solution of compound 52d (5 g, 19.76 mmol, 1 eq) in THF (50 ml). The reaction mixture was stirred for 16 h at rt, cooled to 0°C, quenched with concentrated hydrogen chloride (7 ml) and stirred for 15 min. The solvents were evaporated under reduced pressure and residual water was removed via azeotropic distillation with MeOH. The resulting white solid was used in the next step without any further purification. Yield: 3.5g. m/z: [M+H]+ = 240.2.
52f) (1-(5-Bromopyrimidin-2-yl)-6-(ethylthio)indoline-3,3-diyl)dimethanol
Compound 52e (2.6 g, 9.45 mmol, 1 eq), 5-bromo-2-chloro-pyrimidine (2 g, 10.39 mmol, 1.1 eq), DIPEA (12 ml, 66.15 mmol, 7 eq) in n-butanol (20 ml) were stirred at 140°C for 16 h in a sealed tube. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic phase was washed with water (40 ml) and brine (40 ml), dried over Na2S04 and concentrated. The raw product was purified by column chromatography [100-200 mesh silica gel, EtOAc/hexane = 1 : 1]. White solid. Yield: 2 g (48%). m/z: [M+H]+ = 396.1 .
52g) (1-(5-Bromopyrimidin-2-yl)-6-(ethylthio)-3-(hvdroxymethyl)indolin-3-yl)methyl 4-methyl-benzene- sulfonate
LiHMDS (1 M solution in THF, 3.28 ml, 3.28 mmol, 1 eq) was slowly added at -78°C to a stirred solution of compound 52f (1 .3 g, 3.28 mmol, 1 eq) in THF (150 ml). The solution was stirred for 20 min., tosylchloride (0.62 g, 3.28 mmol, 1 eq) dissolved in THF was added and stirring was continued for 2 h at -78°C. The reaction mixture was quenched with saturated NH4CI solution and extracted with EtOAc (2x 50 ml). The combined organic layers were washed with brine (30 ml), dried over Na2S04 and concentrated. The remnant was purified by column chromatography [silica gel 100-200 mesh, EtOAc/hexane = 2:3]. White solid. Yield: 1.0 g (55%).
52 h) 1-(5-Bromopyrimidin-2-yl)-6-(ethylthio)spironndoline-3,3'-oxetane1
Compound 52g (0.7 g, 1.27 mmol, 1 eq) and KOH (0.213 g, 3.81 mmol, 3 eq) in tert-butanol (80 ml) were stirred at 50°C for 30 min. The solvent was evaporated under reduced pressure and the residue was suspended EtOAc, washed with water (20 ml) and brine (20 ml), dried over Na2S04 and concentrated. The resulting white solid was used for the next step without any further purification. Yield: 0.45 g (94%). m/z: [M+H]+ = 380.2.
52i) 6-(Ethylthio)-1 -(5-(2-fluorophenyl)pyrimidin-2-yl)spironndoline-3,3'-oxetane1
(AtaPhos)2PdCI2 (0.05 g, 0.06 mmol, 0.1 eq) was added to a solution of compound 52h (0.26 g, 0.68 mmol, 1 eq), (2-fluorophenyl)boronic acid (0.125 g, 0.89 mmol, 1.3 eq) and 10% aqueous K2C03 solution (0.8 ml) in amyl alcohol (10 ml) that was stirred under N2 at rt. The reaction mixture was then stirred at 80°C for 16 h and filtered through a plug of celite. The filter was rinsed with EtOAc and the filtrate was washed with water (10 ml) and brine (10 ml), dried over Na2S04 and concentrated. The remnant was purified by column chromatography [EtOAc/hexane = 3:7]. White solid. Yield: 0.23 g (85%). m/z: [M+H]+ = 394.3. 52j) 6-(Ethylsulfinyl)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane1
mCPBA (68 mg, 0.3 mmol, 0.8 eq) was slowly added to a stirred solution of compound 52i (150 mg, 0.38 mmol, 1 eq) in THF (10 ml) at 0°C. The mixture was stirred for 2 h at rt and then quenched with saturated NaHC03 solution and extracted with EtOAc (2x 15 ml). The combined organic layers were washed with brine (10 ml), dried over Na2S04 and concentrated. The remnant was purified by column chromatography [100-200 mesh silica gel, hexane/EtOAc = 1 :4]. White solid. Yield: 60 mg (38%). m/z: [M+H]+ = 410.2. 1 H NMR (400 MHz, CDCI3, δ ppm): 8.75 (s, 2H), 8.64 (s, 1 H), 7.88 (d, J = 7.6 Hz, 1 H), 7.44 (m, 3H), 7.27 (m, 1 H), 7.19 (m, 1 H), 4.94 (s, 4H), 4.63 (s, 2H), 2.98 (m, 1 H), 2.86 (m, 1 H), 1 .27 (t, J = 14.2 Hz, 3H).
Example 53: 6-(Ethylsulfonyl)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane1
Figure imgf000077_0001
mCPBA (114 mg, 0.5 mmol, 2 eq) was slowly added at 0°C to a stirred solution of compound 52i (100 mg, 0.25 mmol, 1 eq) in THF (10 ml) and the resulting mixture was stirred for 2 h at the rt. Work up as described for under protocol 52j. White solid. Yield: 35 mg (32%). m/z: [M+H]+ = 426.4. 1H NMR (400 MHz, CDCI3, δ ppm): 8.95 (s, 1H), 8.76 (s, 2H), 7.90 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 7.72 Hz, 1H), 7.44 (m, 2H), 7.28 (m, 1H), 7.2 (m, 1H), 4.97 (d, J = 6.1 Hz, 2H), 4.92 (d, J = 6.1 Hz, 2H), 4.64 (s, 2H), 3.21 (m,2H), 1.34 (t, J = 14.7 Hz, 3H).
Figure imgf000077_0002
White solid. Yield: 70 mg (34%). m/z: [M+H]+ = 424.1.1H NMR (400 MHz, CDCI3, δ ppm): 8.73 (s, 2H), 8.63 (s, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.41 (dd, J = 9.08 Hz, 1H), 7.20 (m, 1H), 7.14 (m, 1H), 7.07 (m, 1H), 4.94 (m, 4H), 4.62 (s, 2H), 2.98 (m, 1H), 2.86 (m, 1H), 2.38 (s, 3H), 1.27 (t, J = 14.8 Hz, 3H).
Figure imgf000077_0003
White solid. Yield: 110 mg (51%). m/z: [M+H]+ = 440.0.1H NMR (400 MHz, CDCI3, δ ppm): 8.94 (s, 1H), 8.75 (s, 2H), 7.90 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.21 (m, 1H), 7.15 (m, 1H), 7.07 (m, 1H), 4.97 (m, 4H), 4.64 (s, 2H), 3.21 (m, 2H), 2.38 (s, 3H), 1.34 (t, J = 14.6 Hz, 3H).
Figure imgf000078_0001
PdCI2(dppf) (0.065 g, 0.08 mmol, 0.05 eq) was added to a solution of compound 52h (0.6 g, 1.58 mmol, 1 eq), potassium acetate (0.31 g, 3.17 mmol, 2 eq) and bis(pinacolato)diboron (0.8 g, 3.17 mmol, 2 eq) in dioxane that was stirred under Ar at rt. The reaction mixture was refluxed for 16 h, cooled to rt and filtered through a plug of celite. The filter was rinsed with EtOAc and the filtrate was washed with water (20 ml) and brine (20 ml), dried over Na2S04 and concentrated. The pinacol boronate (0.7 g) thus obtained was dissolved in dioxane (25 ml). 2-Bromo-4-methoxypyridine (0.265 g, 1.41 mmol), 10% aqueous K2C03 solution (3.5 ml) and finally tetrakis(triphenylphosphine)palladium(0) (0.07 g, 0.06 mmol) were added. The mixture was refluxed for 16 h, cooled to rt and filtered through a plug of celite. The filter was rinsed with EtOAc and the filtrate was washed with water (20 ml), brine (20 ml), dried over Na2S04 and concentrated. The remnant was purified by column chromatography [EtOAc/hexane = 1 :1 ]. White solid. Yield: 0.27 g. m/z: [M+H]+ = 406.8.
The product (200 mg, 0.49 mmol) of the Suzuki coupling was oxidized with mCPBA to the corresponding sulfoxide analogously to procedure 52j. Yield: 60 mg (30%). m/z: [M+H]+ = 423.0. 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H), 8.61 (s, 1 H), 8.48 (d, J = 5.6 Hz, 1 H), 7.94 (d, J = 7.8 Hz, 1 H), 7.62 (s, 1 H), 7.36 (d, J = 3.4 Hz, 1 H), 6.95 (d, J = 3.4 Hz, 1 H), 4.9 (d, J = 6.0 Hz, 2H), 4.79 (d, J = 5.7 Hz, 1 H), 4.65 (s, 2H), 3.03 (m, 1 H), 2.79 (m, 1 H), 1.1 (t, J = 13.5 Hz, 3H).
Figure imgf000078_0002
MMPP (973 mg, 1.97 mmol, 4 eq) was slowly added at 0°C to a stirred solution of 6-(ethylthio)-1-(5-(4- methoxypyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane] (200 mg, 0.49 mmol, 1 eq) prepared under example 56 in THF (20 ml). The reaction mixture was stirred for 2 h at rt, then quenched with saturated NaHC03 solution and extracted with EtOAc (2x 15 ml). The combined organic layers were washed with brine (10 ml), dried over Na2S04 and evaporated. The residue was purified by column chromatography [100-200 mesh silica gel, EtOAc/hexane = 1:1]. White solid. Yield: 100 mg (47%). m/z: [M+H]+ = 439.1. 1H NMR (400 MHz, CDCI3, δ ppm): 9.36 (s, 2H), 8.83 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.66 (m, 2H), 6.96 (m, 1H), 4.91 (d, J = 5.9 Hz, 2H), 4.79 (d, J = 6.1 Hz, 2H), 4.67 (s, 2H), 3.92 (s, 3H), 3.32 (m, 2H), 1.16 (t, J = 14.5 Hz, 3H).
Figure imgf000079_0001
Prepared from compound 52h analogously to example 56. White solid. Yield: 130 mg. m/z: [M+H]+ = 433.1.1H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2H), 8.61 (s, 1H), 8.46 (d, J = 5.0 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.71 (s, 1H), 7.35 (d, J = 7.1 Hz, 1H), 7.09 (d, J = 4.4 Hz, 1H), 4.9 (d, J = 6.1 Hz, 2H), 4.79 (d, J = 5.9 Hz, 1H), 4.65 (s, 2H), 3.03 (m, 1H), 2.79 (m, 1H), 1.08 (m, 5H), 0.95 (m, 2H).
Figure imgf000079_0002
Prepared analogously to example 57. White solid. Yield: 120 mg. m/z: [M+H]+ = 449.0. 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.34 (s, 2H), 8.83 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.73 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.1 (d, J = 4.9 Hz, 1H), 4.91 (d, J = 6.1 Hz, 2H), 4.79 (d, J = 6.1 Hz, 2H), 4.67 (s, 2H), 3.28 (s, 2H), 1.98 (m, 1H), 1.16 (m, 5H), 0.96 (m, 2H).
The examples 60 to 66 were prepared analogously to synthesis example 22. Example 60: 1 -(5-(4-Ethylpyridin-2-yl)pyrimidin-2-yl)-N-(^^
oxetanel-6-carboxamide
Figure imgf000080_0001
White solid. Yield: 48 mg. HPLC (method 2): Rt = 1.44 min., m/z: [M+H]+ = 446.05 (MW calc. 445.51 ). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.25 (s, 2H), 8.53 (d, 1 H, J = 4.8 Hz), 8.4 (s, 1 H), 7.81 -7.76 (m, 2H), 7.2 (s, 1 H), 7.12 (d, 1 H, J = 7.4 Hz), 4.89-4.8 (m, 4H), 4.63 (s, 2H), 4.41 (bs, 1 H), 3.64 (bs, 2H), 3.46 (bs, 2H), 3.03 (s, 3H), 2.75-2.66 (m, 2H), 1.3-1.26 (m, 3H).
Example 61 : 1-(5-(4-Cvclopropylpyridin-2-yl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro [indoline- 3,3'-oxetanel-6-carboxamide
Figure imgf000080_0002
White solid. Yield: 105 mg. HPLC (method 2): Rt = 1.41 min., m/z: [M+H]+ = 458.1 (MW calc. 457.52). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.25 (s, 2H), 8.45 (d, 1 H, J = 5.1 Hz), 8.4 (s, 1 H), 7.76 (d, 1 H, J = 7.6 Hz), 7.64 (s, 1 H), 7.12 (d, 1 H, J = 7.5 Hz), 7.04 (d, 1 H, J = 5.0 Hz), 4.88 (d, 2H, J = 6 Hz), 4.8 (d, 2H, J = 6 Hz), 4.63 (s, 2H), 4.42 (bs, 1 H), 3.62 (d, 2H, J = 5.4 Hz), 3.46 (bs, 2H), 3.21 (s, 3H), 2.05-1.99 (m, 1 H), 1.12-1 .07 (m, 2H), 0.94-0.9 (m, 2H).
Example 62: N-(2-Hvdroxyethyl)-1-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)-N-methylspiro findoline-3,3'- oxetanel-6-carboxamide
Figure imgf000081_0001
White solid. Yield: 79 mg. HPLC (method 2): Rt = 1.32 min., m/z: [M+H]+ = 448.1 (MW calc. 447.49). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.25 (s, 2H), 8.46 (d, 1 H, J = 5.6 Hz), 8.4 (s, 1 H), 7.76 (d, 1 H, J = 7.6 Hz), 7.51 (s, 1 H), 7.12 (d, 1 H, J = 7.4 Hz), 6.93-6.91 (m, 1 H), 4.88 (d, 2H, J = 5.9 Hz), 4.81 (d, 2H, J = 5.9 Hz), 4.63 (s, 2H), 3.93 (s, 3H), 3.63 (bs, 2H), 3.46 (bs, 2H), 3.02 (merged with DMSO-water peak, 4H).
Example 63: 1-(5-(4-Ethoxypyridin-2-yl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro[indoline-3,3'- oxetanel-6-carboxamide
Figure imgf000081_0002
White solid. Yield: 125 mg. HPLC (method 2): Rt = 1.36 min., m/z: [M+H]+ = 462.1 (MW calc. 461.51 ). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.29 (s, 2H), 8.45 (d, 1 H, J = 5.5 Hz), 8.33 (s, 1 H), 7.78 (bs, 1 H), 7.56 (s, 1 H), 7.12 (d, 1 H, J = 7.3 Hz), 6.92 (bs, 1 H), 4.88-4.78 (m, 5H), 4.61 (s, 2H), 4.24-4.2 (m, 2H), 3.64 (bs, 1 H), 3.52 (bs, 2H), 3-2.98 (m, 3H), 1 .39-1 .35 (m, 3H).
Example 64: N-(2-Hvdroxyethyl)-N-methyl-1 -(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan carboxamide
Figure imgf000081_0003
White solid. Yield: 80 mg. HPLC (method 2): Rt = 1.40 min., m/z: [M+H]+ = 418.1 (MW calc. 417.46). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.25 (s, 2H), 8.66 (d, 1 H, J = 4.4 Hz), 8.4 (s, 1 H), 7.96 (d, 1 H, J = 7.8 Hz), 7.89-7.85 (m, 1 H), 7.76 (d, 1 H, J = 7.6 Hz), 7.35-7.32 (m, 1 H), 7.12 (d, 1 H, J = 7.6 Hz), 4.88 (d, 2H, J = 8.0 Hz), 4.8 (d, 2H, J = 8.0 Hz), 4.63 (s, 2H), 4.42 (bs, 1 H), 3.64-3.63 (m, 2H), 3.46 (bs, 2H), 3.03 (s, 3H).
Example 65: N-(2-Hvdroxyethyl)-N-methyl-1-(5-(4-(trifluoromethyl)pyridin-2-yl)pyrimidin-2-yl)spiro- nndoline-3,3'-oxetanel-6-carboxami
Figure imgf000082_0001
White solid. Yield: 150 mg. HPLC (method 2): Rt = 1.57 min., m/z: [M+H]+ = 486.1 (MW calc. 485.46). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.35 (s, 2H), 8.92 (bs, 1 H), 8.42 (s, 1 H), 8.29 (s, 1 H), 7.78 (d, 1 H, J = 7.6 Hz), 7.65 (d, 1 H, J = 4.8 Hz), 7.14 (d, 1 H, J = 7.6 Hz), 4.9 (d, 2H, J = 6.1 Hz), 4.8 (d, 2H, J = 6 Hz), 4.65 (s, 2H), 4.42 (bs, 1 H), 3.64-3.63 (m, 2H), 3.46 (bs, 2H), 3.03 (s, 3H). Example 66: N-(2-Hvdroxyethyl)-1-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro- nndoline-3,3'-oxetanel-6-carboxami
Figure imgf000082_0002
White solid. Yield: 75 mg. HPLC (method 2): Rt = 1.37 min. m/z: [M+H]+ = 476.1 (MW calc. 475.54). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.25 (s, 2H), 8.57 (d, 1 H, J = 4.9 Hz), 8.4 (s, 1 H), 7.97 (s, 1 H), 7.76 (d, 1 H, J = 7.4 Hz), 7.42 (d, 1 H, J = 4.8 Hz), 7.14-7.12 (m, 1 H), 4.94-4.8 (m, 5H), 4.42 (s, 2H), 4.42 (bs, 1 H), 3.6 (bs, 2H), 3.46 (bs, 2H), 3.03 (s, 3H), 1 .52 (s, 6H).
Examples 67 to 73 were prepared analogously to synthesis example 8. Example 67: (1-(5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[indoline
(pyrrolidin-1-vDmethanone
Figure imgf000083_0001
White solid. Yield: 80 mg. HPLC (method 2): Rt = 1.48 min. m/z: [M+H]+ = 472.13 (MW calc. 471.55). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.26 (s, 2H), 8.57 (d, 1 H, J = 5.2 Hz), 8.51 (s, 1 H), 7.98 (s, 1 H), 7.77 (d, 1 H, J = 7.6 Hz), 7.43 (d, 1 H, J = 4.8 Hz), 7.23 (d, 1 H, J = 7.6 Hz), 4.95 (s, 1 H), 4.89 (d, 2H, J = 6.0 Hz), 4.8 (d, 2H, J = 6 Hz), 4.64 (s, 2H), 3.49 (bs, 4H), 1.89 (bs, 4H), 1.52 (s, 6H).
Example 68: (1 -(5-(4-Ethoxypyridin-2-yl)pyrimidin-2-yl)spi
methanone
Figure imgf000083_0002
White solid. Yield: 0.09 g. HPLC (method 2): Rt = 1.48 min. m/z: [M+H]+ = 458.15 (MW calc. 457.52). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.25 (s, 2H), 8.5-8.44 (m, 2H), 7.7 (d, 1 H, J = 7.5 Hz), 7.48 (s, 1 H), 7.22 (d, 1 H, J = 7.7 Hz), 6.89 (d, 1 H, J = 3.3 Hz), 4.89 (d, 2H, J = 5.8 Hz), 4.8 (d, 2H, J = 5.9 Hz), 4.63 (s, 2H), 4.28-4.23 (m, 2H), 3.48 (bs, 4H), 1.88 (bs, 4H), 1.41-1.38 (m, 3H).
Example 69: Pyrrolidin-1-yl(1-(5-(4-(trifluoromethyl)p
vPmethanone
Figure imgf000084_0001
White solid. Yield: 0.085 g. HPLC (method 2): Rt = 1.72 min. m/z: [M+H]+ = 482.09 (MW calc. 481.47). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.4 (s, 2H), 8.93 (s, 1 H), 8.52 (s, 1 H), 8.39 (s, 1 H), 7.79 (d, 1 H, J = 7.5 Hz), 7.72 (d, 1 H, J = 3.3 Hz), 7.27 (d, 1 H, J = 7.5 Hz), 4.8 (d, 2H, J = 6.2 Hz), 4.78 (d, 2H, J = 5.8 Hz), 4.6 (bs, 2H), 3.49-3.43 (m, 4H), 1.89-1.82 (m, 4H).
Example 70: (1-(5-(4-Ethylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl)(pyrrolidin^ methanone
Figure imgf000084_0002
White solid. Yield: 0.070 g. HPLC (method 2): Rt = 1.61 min. m/z: [M+H]+ = 442.1 (MW calc. 441.53). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.25 (s, 2H), 8.54-8.5 (m, 2H), 7.81-7.77 (m, 2H), 7.24-7.19 (m, 2H), 4.88 (d, 2H, J = 5.5 Hz), 4.81 (d, 2H, J = 5.8 Hz), 4.62 (s, 2H), 3.49 (bs, 4H), 2.74-2.69 (m, 2H), 1.88 (bs, 4H), 1 .3-1 .26 (m, 3H). Examples 71 and 72: 1 -(3-(2-(6-(Ethylsulfonyl)spironndoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)-4-fluoro- phenvDethanol (faster and slower elutinq enantiomer)
Figure imgf000084_0003
The racemate was prepared in two steps from compound 52h and 1-(3-bromo-4-fluorophenyl)ethanol analogously to synthesis example 57 (yield: 330 mg, white solid). The two enantiomers were obtained from the racemic mixture through chiral HPLC utilizing a chiral pack-IA column and hexane/EtOAc/EtOH/diethylamine (50/25/25/0.1 ) as mobile phase.
Faster eluting enantiomer (example 71 ): Yield = 77 mg. White solid, m/z: [M+H]+ = 470.3. Specific optical rotation: [a]589 25 = -15.65° (c. 0.4090, CHCI3). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.89 (s, 2H), 8.79 (s, 1 H), 8.02 (d, J = 7.8 Hz, 1 H), 7.63 (m, 2H), 7.44 (m, 1 H), 7.33 (m, 1 H), 5.25 (d, J = 4.4 Hz, 1 H), 4.91 (d, J = 6.2 Hz, 2H), 4.80 (t, J = 1 1 .2Hz, 3H), 4.66 (s, 2H), 3.29 (m, 2H), 1.38 (d, J = 6.4 Hz, 3H), 1.16 (t, J = 14.6 Hz, 3H).
Slower eluting enantiomer (example 72): Yield = 65 mg. White solid, m/z: [M+H]+ = 470.3. Specific optical rotation: [a]589 25 = +13.06° (c. 0.4058, CHCI3). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.89 (s, 2H), 8.79 (s, 1 H), 8.02 (d, J = 7.9 Hz, 1 H), 7.63 (m, 2H), 7.44 (m, 1 H), 7.33 (m, 1 H), 5.25 (d, J = 4.3 Hz, 1 H), 4.91 (d, J = 6.2 Hz, 2H), 4.80 (t, J = 1 1.2 Hz, 3H), 4.66 (s, 2H), 3.29 (m, 2H), 1.38 (d, J = 6.4 Hz, 3H), 1.16 (t, J = 14.6 Hz, 3H).
Example 73: 2-(3-(2-(6-(Ethylsulfonyl)spiro[indoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)-4-fluoro-phenyl)- propan-2-ol
Figure imgf000085_0001
Prepared in 2 steps from compound 52h and 2-(3-bromo-4-fluorophenyl)propan-2-ol analogously to synthesis example 57. White solid. Yield: 0.075 g. m/z: [M+H]+ = 484.2. 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.9 (s, 2H), 8.8 (s, 1 H), 8.0 (d, J = 7.8 Hz, 1 H), 8.06 (m, 2H), 7.70 (dd, J = 9.7 Hz, 1 H), 7.63 (dd, J = 9.2 Hz, 1 H), 5.13 (s, 1 H), 4.91 (d, J = 6.2 Hz, 2H), 4.80 (d, J = 6.2 Hz, 2H), 4.66 (s, 2H), 3.32 (m, 2H), 1.47 (s, 6H), 1.16 (t, J = 14.6 Hz, 3H). Example 74: 2-(3-(2-(6-(Ethylsulfinyl)spiro[indoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)-4-fluoro-phenyl)- propan-2-ol
Figure imgf000086_0001
Prepared in two steps from compound 52h and 2-(3-bromo-4-fluorophenyl)propan-2-ol analogously to synthesis example 56. White solid. Yield: 0.075 g. m/z: [M+H]+ = 468.0. 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.87 (s, 2H), 8.58 (s, 1 H), 7.94 (d, J = 7.9 Hz, 1 H), 7.69 (dd, J = 10.0 Hz, 1 H), 7.55 (m, 1 H), 7.35 (dd, J = 9.1 Hz, 1 H), 7.30 (m, 1 H), 5.12 (s, 1 H), 4.89 (d, J = 6.2 Hz, 2H), 4.8 (d, J = 5.8 Hz, 2H), 4.64 (s, 2H), 3.03 (m, 1 H), 2.79 (m, 1 H), 1.47 (s, 6H), 1.1 (t, J = 14.7 Hz, 3H).
Example 75: 2-(2-(2-(6-(Ethylsulfonyl)spiro[indoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2- ol
Figure imgf000086_0002
Prepared in 2 steps from compound 52h and 2-(2-bromopyridin-4-yl)propan-2-ol analogously to synthesis example 57. White solid. Yield: 100 mg. m/z: [M+H]+ = 467.1. 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.36 (s, 2H), 8.84 (s, 1 H), 8.6 (d, J = 5.0 Hz, 1 H), 8.06 (m, 2H), 7.63 (d, J = 8.0 Hz, 1 H), 7.48 (d, J = 4.0 Hz, 1 H), 5.29 (s, 1 H), 4.92 (d, J = 6.2 Hz, 2H), 4.79 (d, J = 6.2 Hz, 2H), 4.67 (s, 2H), 3.28 (m, 2H), 1 .49 (s, 6H), 1.17 (t, J = 14.5 Hz, 3H).
Example 76: 2-(2-(2-(6-(Ethylsulfinyl)spiro[indoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)pyridin-4-yl) propan-2- ol
Figure imgf000087_0001
Prepared in 2 steps from compound 52h and 2-(2-bromopyridin-4-yl)propan-2-ol analogously to synthesis example 56. White solid. Yield: 100 mg. m/z: [M+H]+ = 451 .2. 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H), 8.62 (m, 2H), 8.04 (s, 1 H), 7.94 (d, J = 7.7 Hz 1 H), 7.47 (d, J = 3.7 Hz, 1 H), 7.36 (d, J = 7.7 Hz, 1 H), 5.29 (s, 1 H), 4.9 (d, J = 6.0 Hz, 2H), 4.79 (d, J = 4.8 Hz, 2H), 4.65 (s, 2H), 3.04 (m, 1 H), 2.80 (m. 1 H), 1.48 (s, 6H), 1 .1 (t, J = 14.5 Hz, 3H).
Examples 77 and 78: 1-(2-(2-(6-(Ethylsulfonyl)spironndoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)pyridin-4-
Figure imgf000087_0002
The racemic sulfone (350 mg) was prepared in two steps from compound 52h and 1-(2-bromopyridin-4- yl)ethanol analogously to synthesis example 57. The two enantiomers were derived from this racemate via chiral HPLC utilizing a chiral pack-IE column and hexane/EtOAc/EtOH/diethylamine (50/25/25/0.1 ) as mobile phase.
Faster eluting enantiomer (example 77): Yield = 68 mg. White solid, m/z: [M+H]+ = 453.0. Specific optical rotation: [a]589 25 = -14.84° (c. 0.4042, CHCI3). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.31 (s, 2H), 8.8 (s, 1 H), 8.58 (d, J = 5.2 Hz, 1 H), 8.0 (m, 2H), 7.61 (d, J = 7.8 Hz, 1 H), 7.34 (d, J = 4.8 Hz, 1 H), 5.42 (d, J = 4.4 Hz, 1 H), 4.89 (d, J = 6.2 Hz, 2H), 4.77 (d, J = 6.2 Hz, 3H), 4.64 (s, 2H), 3.25 (m, 2H), 1.37 (d, J = 6.5 Hz, 3H), 1.14 (t, J = 14.6 Hz, 3H).
Slower eluting enantiomer (example 78): Yield = 75 mg. White solid. Mass spectroscopy: m/z: [M+H]+ = 453.1. Specific optical rotation: [a]589 25 = +15.23° (c. 0.4072, CHCI3). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.34 (s, 2H), 8.83 (s, 1 H), 8.61 (d, J = 4.5 Hz, 1 H), 8.02 (m, 2H), 7.63 (d, J = 7.5 Hz, 1 H), 7.37 (d, J = 3.4 Hz, 1 H), 5.46 (d, J = 4 Hz, 1 H), 4.92 (d, J = 5.7 Hz, 2H), 4.79 (d, J = 5.8 Hz, 3H), 4.67 (s, 2H), 3.25 (m, 2H), 1.40 (d, J = 6.2 Hz, 3H), 1.17 (t, J = 14.2 Hz, 3H). Synthesis examples 79 and 96 were obtained from 1-(5-bromopyrimidin-2-yl)spiro[indoline-3,3'-oxetane]- 6-carboxylic acid (compound 8a) in two chemical steps comprising an amide coupling with 2- (methylamino)ethanol and TBTU as reagent and a Suzuki reaction (protocol 3a).
Example 79: N-(2-Hvdroxyethyl)-N-methyl-1-(5-phenylpyrimidin-2-yl)spironndoline-3,3'-oxetanel-6- carboxamide
Figure imgf000088_0001
White solid. Yield: 80 mg. m/z: [M+H]+ = 416.8 (MW calc. 416.47). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.99 (s, 2H), 8.36 (s, 1 H), 7.76-7.74 (m, 3H), 7.51-7.47 (m, 2H), 7.41-7.37 (m, 1 H), 7.12-7.10 (m, 1 H), 4.88-4.87 (d, 2H), 4.80-4.75 (m, 3H), 4.60 (s, 2H), 3.64-3.52 (m, 4H), 3.00-2.98 (d, 3H).
Example 80: N-(2-Hydroxyethyl)-N-methyl-1 -(5-(m-tolyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanel -6- carboxamide
Figure imgf000088_0002
White solid. Yield: 90 mg. m/z: [M+H]+ = 431.1 (MW calc. 430.50). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.96 (s, 2H), 8.36 (s, 1 H), 7.78 (m, 1 H), 7.57-7.52 (m, 2H), 7.39-7.35 (t, 1 H), 7.21-7.19 (d, 1 H), 7.12-7.10 (m, 1 H), 4.88-4.87 (d, 2H), 4.80-4.78 (m, 3H), 4.60 (s, 2H), 3.64-3.37 (m, 4H), 3.00-2.98 (d, 3H), 2.38 (s, 3H).
Example 81 : 1-(5-(3-Cvclopropylphenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro[indoline-3,3'- oxetanel-6-carboxamide
Figure imgf000089_0001
White solid. Yield: 80 mg. m/z: [M+H]+ = 457.10 (MW calc. 456.54). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.97 (s, 2H), 8.36 (s, 1 H), 7.78 (m, 1 H), 7.49-7.48 (d, 1 H), 7.41 (s, 1 H), 7.37-7.33 (t, 1 H), 7.1 1-7.08 (m, 2H), 4.88-4.87 (d, 2H), 4.80-4.75 (m, 3H), 4.60 (s, 2H), 3.65-3.52 (m, 4H), 3.00-2.96 (m, 3H), 1.99- 1.95 (m, 1 H), 0.98-0.97 (m, 2H), 0.79-0.78 (m, 2H).
Example 82: N-(2-Hvdroxyethyl)-1 -(5-(3-methoxyphenyl)pyrimidin-2-yl)-N-methylspiro[indoline-3,3'- oxetanel-6-carboxamide
Figure imgf000089_0002
White solid. Yield: 125 mg. m/z: [M+H]+ = 447.3 (MW calc. 446.50). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.93 (s, 2H), 8.37 (s, 1 H), 7.77-7.75 (d, 1 H), 7.42-7.38 (t, 1 H), 7.29-7.27 (m, 2H), 7.12- 7.10 (d, 1 H), 6.97-6.95 (d, 1 H), 4.89-4.87 (d, 2H), 4.82-4.81 (d, 2H), 4.61 (s, 2H), 4.41-4.40 (m, 1 H), 3.86 (s, 3H), 3.63-3.61 (m, 2H), 3.45 (m, 2H), 3.02 (s, 3H). Example 83: 1-(5-(3-Ethoxyphenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro[indoline-3,3'- oxetanel-6-carboxamide
Figure imgf000089_0003
White solid. Yield: 1 15 mg. m/z: [M+H]+ = 461.3 (MW calc. 460.53). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.92 (s, 2H), 8.37 (s, 1 H), 7.77-7.75 (d, 1 H), 7.40-7.36 (t, 1 H), 7.27-7.25 (m, 2H), 7.12- 7.10 (d, 1 H), 6.95-6.93 (d, 1 H), 4.89-4.87 (d, 2H), 4.82-4.80 (d, 2H), 4.61 (s, 2H), 4.41 (m, 1 H), 4.18-4.14 (m, 2H), 3.62 (m, 2H), 3.45 (m, 2H), 3.02 (s, 3H), 1.39-1.35 (t, 3H).
Example 84: 1-(5-(3-Chlorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro[indoline-3,3'- oxetanel-6-carboxamide
Figure imgf000090_0001
White solid. Yield: 62 mg. m/z: [M+H]+ = 451.4 (MW calc. 450.92). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.02 (s, 2H), 8.36 (s, 1 H), 7.86 (m, 1 H), 7.77 (m, 1 H), 7.74-7.72 (m, 1 H), 7.51-7.49 (m, 1 H), 7.45- 7.43 (m, 1 H), 7.13-7.1 1 (d, 1 H), 4.88-4.87 (d, 2H), 4.80-4.79 (m, 3H), 4.61 (s, 2H), 3.64-3.52 (m, 4H), 3.00-2.98 (d, 3H).
Example 85: N-(2-Hvdroxyethyl)-N-methyl-1-(5-(3-(trifluoromethoxy)phenyl)pyrimidin-2-yl)spiro [indoline- 3,3'-oxetanel-6-carboxamide
Figure imgf000090_0002
White solid. Yield: 85 mg. m/z: [M+H]+ = 501 (MW calc. 500.48). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.05 (s, 2H), 8.37 (s, 1 H), 7.82-7.79 (m, 3H), 7.64-7.60 (t, 1 H), 7.39-7.37 (d, 1 H), 7.13-7.1 1 (d, 1 H), 4.89- 4.87 (d, 2H), 4.80-4.79 (m, 3H), 4.61 (s, 2H), 3.64-3.51 (m, 4H), 3.00 (d, 3H).
Example 86: 1-(5-(3-Aminophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspironndoline-3,3'-oxetanel- 6-carboxamide
Figure imgf000091_0001
White solid. Yield: 80 mg. m/z: [M+H]+ = 432.1 (MW calc. 431.50). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.83 (s, 2H), 8.34 (s, 1 H), 7.77 (m, 1 H), 7.14-7.09 (m, 2H), 6.84 (m, 2H), 6.60-6.58 (d, 1 H), 5.22 (s, 2H), 4.87-4.86 (d, 2H), 4.79-4.78 (m, 3H), 4.59 (s, 2H), 3.64-3.52 (m, 4H), 3.00 (m, 3H).
Example 87: N-(2-Hvdroxyethyl)-N-methyl-1-(5-(3-(pyrrolidin-1-yl)phenyl)pyrimidin-2-yl)spiro [indoline- 3,3'-oxetanel-6-carboxamide
Figure imgf000091_0002
White solid. Yield: 50 mg. m/z: [M+H]+ = 485.8 (MW calc. 485.59). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.95 (s, 2H), 8.34 (s, 1 H), 7.77 (m, 1 H), 7.27-7.23 (m, 2H), 7.10-7.09 (d, 1 H), 6.92-6.90 (d,1 H), 6.80 (s, 1 H), 6.56-6.54 (d, 1 H), 4.88-4.86 (d, 2H), 4.80-4.79 (m, 3H), 4.60 (s, 2H), 3.64-3.51 (m, 4H), 3.31 (m, 4H), 3.00-2.97 (m, 3H), 1.97 (m, 4H).
Example 88: N-(2-Hvdroxyethyl)-1 -(5-(3-(1-hvdroxyethyl)phenyl)pyrimidin-2-yl)-N-methylspiro [indoline- 3,3'-oxetanel-6-carboxamide
Figure imgf000091_0003
White solid. Yield: 82 mg. m/z: [M+H]+ = 460.8 (MW calc. 460.53). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.97 (s, 2H), 8.36 (s, 1 H), 7.78 (m, 1 H), 7.67 (s, 1 H), 7.59-7.57 (d, 1 H), 7.45-7.41 (m, 1 H), 7.38- 7.37 (m, 1 H), 7.12-7.10 (d, 1 H), 5.21-5.20 (d, 1 H), 4.89-4.87 (d, 2H), 4.80-4.79 (m, 4H), 4.60 (s, 2H), 3.64-3.52 (m, 4H), 3.00 (d, 3H), 1.38-1.37 (d, 3H).
Example 89: 1-(5-(3,4-Difluorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspironndoline-3,3'- oxetanel-6-carboxamide
Figure imgf000092_0001
White solid. Yield: 82 mg. m/z: [M+H]+ = 453 (MW calc. 452.46). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.98 (s, 2H), 8.32 (s, 1 H), 7.90-7.86 (m, 1 H), 7.75 (m, 1 H), 7.59-7.56 (m, 1 H), 7.54-7.49 (m, 1 H), 7.10- 7.08 (d, 1 H), 4.85-4.84 (d, 2H), 4.77-4.72 (m, 3H), 4.57 (s, 2H), 3.61-3.49 (m, 3H), 3.27 (m, 1 H), 2.97- 2.93 (m, 3H).
Example 90: 1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro [indoline- 3,3'-oxetanel-6-carboxamide
Figure imgf000092_0002
White solid. Yield: 85 mg. m/z: [M+H]+ = 449.1 (MW calc. 448.50). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.83 (s, 2H), 8.34 (s, 1 H), 7.78 (m, 1 H), 7.46-7.45 (d, 1 H), 7.24-7.22 (d, 2H), 7.13-7.1 1 (m, 1 H), 4.88-4.87 (d, 2H), 4.80-4.78 (m, 3H), 4.60 (s, 2H), 3.64-3.51 (m, 4H), 3.00 (s, 3H), 2.35 (s, 3H).
Example 91 : 1-(5-(5-Cvclopropyl-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro nndoline-3,3'-oxetanel-6-carboxamide
Figure imgf000093_0001
White solid. Yield: 45 mg. m/z: [M+H]+ = 474.8 (MW calc. 474.53). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.84 (s, 2H), 8.35 (s, 1 H), 7.78 (m, 1 H), 7.31-7.30 (m, 1 H), 7.22-7.20 (m, 1 H), 7.13 (m, 1 H), 4.88- 4.87 (m, 2H), 4.80-4.79 (m, 3H), 4.60 (s, 2H), 3.64-3.51 (m, 4H), 3.00 (d, 3H), 1.97 (m, 1 H), 0.96-0.95 (m, 2H), 0.75 (m, 2H).
Example 92: 1-(5-(2-Fluoro-5-methoxyphenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro [indoline-
3,3'-oxetane1-6-carboxamide
Figure imgf000093_0002
White solid. Yield: 82 mg. m/z: [M+H]+ = 464.8 (MW calc. 464.49). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.86 (s, 2H), 8.35 (s, 1 H), 7.78 (m, 1 H), 7.30-7.26 (m, 1 H), 7.19 (m, 1 H), 7.13-7.1 1 (m, 1 H), 6.99- 6.97 (m, 1 H), 4.88-4.87 (d, 2H), 4.80-4.79 (m, 3H), 4.60 (s, 2H), 3.81 (s, 3H), 3.63-3.52 (m, 4H), 3.00 (d, 3H). Example 93: 1-(5-(5-Ethoxy-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro [indoline-
3,3'-oxetanel-6-carboxamide
Figure imgf000093_0003
White solid. Yield: 85 mg. m/z: [M+H]+ = 479 (MW calc. 478.52). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.85 (s, 2H), 8.35 (s, 1 H), 7.78 (m, 1 H), 7.29-7.24 (m, 1 H), 7.17 (m, 1 H), 7.13-7.1 1 (m, 1 H), 6.97 (m, 1 H), 4.88-4.87 (d, 2H), 4.80-4.79 (m, 3H), 4.60 (s, 2H), 4.09-4.07 (m, 2H), 3.64-3.51 (m, 4H), 3.00 (d, 3H), 1.35-1.32 (m, 3H).
Example 94: 1-(5-(2-Fluoro-5-(trifluoromethoxy)phenv0
Figure imgf000094_0001
White solid. Yield: 80 mg. m/z: [M+H]+ = 518.8 (MW calc. 518.46). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.89 (s, 2H), 8.35 (s, 1 H), 7.77 (m, 2H), 7.53-7.50 (m, 2H), 7.13-7.1 1 (d, 1 H), 4.89-4.87 (d, 2H), 4.80-4.79 (m, 3H), 4.61 (s, 2H), 3.64-3.51 (m, 4H), 3.00 (d, 3H).
Example 95: 1-(5-(5-Amino-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro [indoline-3,31- oxetanel-6-carboxamide
Figure imgf000094_0002
White solid. Yield: 80 mg. m/z: [M+H]+ = 450.4 (MW calc. 449.48). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.74 (s, 2H), 8.33 (s, 1 H), 7.78 (m, 1 H), 7.12-7.10 (m, 1 H), 7.02-6.97 (d, 1 H), 6.70-6.68 (m, 1 H), 6.60-6.57 (m, 1 H), 5.08 (s, 2H), 4.88-4.86 (d, 2H), 4.79-4.78 (m, 3H), 4.59 (s, 2H), 3.64-3.52 (m, 4H), 3.00-2.97 (d, 3H).
Example 96: 1-(5-(5-(Ethylamino)-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro nndoline-3,3'-oxetanel-6-carboxamide
Figure imgf000095_0001
Prepared from lnt-1 and 3-bromo-N-ethyl-4-fluoroaniline in 3 steps analogously to synthesis example 22. White solid. Yield: 65 mg. m/z: [M+H]+ = 478.2 (MW calc. 477.22). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.78 (s, 2H), 8.34 (s, 1 H), 7.78 (m, 1 H), 7.12-7.10 (m, 1 H), 7.06 (m, 1 H), 6.66-6.65 (m, 2H), 6.59- 6.57 (m, 1 H), 5.56 (m, 1 H), 4.88-4.86 (d, 2H), 4.80-4.79 (m, 3H), 4.60 (s, 2H), 3.63-3.51 (m, 4H), 3.07- 3.04 (m, 2H), 3.00 (m, 3H), 1.18-1.15 (m, 3H).
Example 97: 1-(5-(3-(Ethylamino)phenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspironndoline -3,3'- oxetanel-6-carboxamide
Figure imgf000095_0002
Prepared from lnt-1 and 3-bromo-N-ethylaniline in 3 steps analogously to synthesis example 22. White solid. Yield: 75 mg. m/z: [M+H]+ = 460.6 (MW calc. 459.55). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.88 (s, 2H), 8.35 (s, 1 H), 7.77-7.76 (m, 1 H), 7.18-7.16 (t, 1 H), 7.10-7.09 (d, 1 H), 6.85-6.81 (m, 2H), 6.59-6.57 (d, 1 H), 5.64 (m, 1 H), 4.88-4.86 (d, 2H), 4.80-4.78 (m, 3H), 4.59 (s, 2H), 3.63-3.52 (m, 4H), 3.12-3.09 (m, 2H), 3.00 (m, 3H), 1 .20-1.16 (m, 3H).
Example 98: 1 -(5-(2-Fluoro-5-(pyrrolidin-1-yl)phenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro- nndoline-3,3'-oxetanel-6-carboxamide
Figure imgf000096_0001
98a) Methyl 1 -(5-(5-amino-2-fluorophenyl)pyrimidi^^
Prepared from lnt-1 (400 mg, 1.063 mmol) and 3-bromo-4-fluoroaniline (403.98 mg, 2.126 mmol) analogously to synthesis protocol 22a. Light brown solid. Yield: 230 mg (53%). m/z: [M+H]+ = 407.2 (MW calc. 406.41 ). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.90 (s, 1 H), 8.77 (s, 2H), 7.89-7.87 (d, 1 H), 7.75- 7.73 (d, 1 H), 7.03-6.98 (m, 1 H), 6.74-6.71 (m, 1 H), 6.61-6.57 (m, 1 H), 5.08 (s, 2H), 4.89-4.88 (d, 2H), 4.78-4.77 (d, 2H), 4.61 (s, 2H), 3.88 (s, 3H).
98b) Methyl 1-(5-(2-fluoro-5-(pyrrolidin-1-yl)phenyl)pyrimidin-2-yl)spironndoline-3,3'-oxetanel-6- carboxylate
Compound 98a (230 mg, 0.566 mmol), 1 ,4-dibromobutane (0.068 ml, 0.0566 mmol) and DIPEA (0.327 ml, 1.981 mmol) were stirred in toluene for 16 h at 1 10°C. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography [EtOAc/hexane = 3:2]. Yellow solid. Yield: 140 mg (54%). m/z: [M+H]+ = 461 .1 (MW calc. 460.50). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.91 (s, 1 H), 8.87 (s, 2H), 7.89-7.87 (d, 1 H), 7.75-7.73 (d, 1 H), 7.18-7.13 (m, 1 H), 6.69-6.67 (m, 1 H), 6.56-6.53 (m, 1 H), 4.90-4.88 (d, 2H), 4.79-4.77 (d, 2H), 4.62 (s, 2H), 3.88 (s, 3H), 3.26 (m, 4H), 1 .98- 1.96 (m, 4H).
98c) 1-(5-(2-Fluoro-5-(pyrrolidin-1-yl)phenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro [indoline- 3,3'-oxetanel-6-carboxamide
Obtained from compound 98b in two steps (ester hydrolysis with LiOH, then TBTU-mediated coupling with 2-(methylamino)ethanol). White solid. Yield: 1 10 mg. m/z: [M+H]+ = 503.8 (MW calc. 503.57). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.84 (s, 2H), 8.35 (s, 1 H), 7.78 (m, 1 H), 7.17-7.10 (m, 2H), 6.64 (m, 1 H), 6.55 (m, 1 H), 4.88-4.87 (d, 2H), 4.80-4.79 (m, 3H), 4.60 (s, 2H), 3.63-3.51 (m, 4H), 3.25 (m, 4H), 3.00 (m, 3H), 1.96 (m, 4H).
Example 99: 2-(2-(2-(6-(Methylsulfinyl)spiro[indoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2- ol
Figure imgf000097_0001
99a) 6'-Bromo-2,2-dimethylspiro[[1 ,3ldioxane-5,3'-indolinl-2'-one
lnt-1a (6.0 g, 19.22 mmol) in dry THF (100 mL) was added drop wise at -30°C to a suspension of KH (30% in mineral oil, 2.56 g, 19.22 mmol) in dry THF (120 mL). The reaction mixture was stirred at this temperature for 30 min, tert-BuLi (2 M in pentane, 22.1 mL, 44.2 mmol) was added and stirring was continued at -78°C for 30 min. A solution of dimethyl disulfide (10.2 mL, 1 15.32 mmol) in dry THF (30 mL) was added drop wise at this temperature and the reaction mixture was slowly brought to RT and stirred for 16 h. The mixture was quenched with saturated NH4CI solution and extracted with EtOAc (3x 100 mL). The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash column chromatography [silica; EtOAc/hexane = 1 :3]. White solid. Yield: 1 .3 g (24%). HPLC (method 3): Rt = 3.19 min., m/z: [M+H]+ = 280.4 (MW calc. 279.36).
99b) 2,2-Dimethyl-6'-(methylthio)spiro[[1 ,3ldioxane-5,3'-indolinl-2'-one
Red-AI (3.15 mL, 10.73 mmol) was added drop wise at RT to a solution of compound 99a (1.5 g, 5.36 mmol) in dry toluene (40 mL) and the reaction mixture was heated at 80°C for 4 h. The mixture was cooled to 0°C and quenched with 2 N NaOH solution. The aqueous phase was separated and extracted with EtOAc (3x 50 mL). The combined organic layers were washed with brine, dried over Na2S04 and concentrated. White solid. Yield: 0.7 g (50%). HPLC (method 3): Rt = 3.23 min., m/z: [M+H]+ = 266.0 (MW calc. 265.37).
99c) 2,2-Dimethyl-6'-(methylthio)spiro[[1 ,3ldioxane-5,3'-indolinel
2N hydrogen chloride solution (35.6 mL) was added to 99b (2.1 g, 7.91 mmol) in THF (21 .2 mL) and the reaction mixture was stirred at RT for 3 h. The mixture was concentrated, basified with saturated NaHC03 solution and extracted with EtOAc (10x 25 mL). The combined organic layers were dried over Na2S04 and concentrated. White solid. Yield: 1 .9 g. HPLC (method 3): Rt = 1.94 min., m/z: [M+H]+ = 226.1 (MW calc. 225.31 ).
99d) (1-(5-Bromopyrimidin-2-yl)-6-(methylthio)indoline-3,3-diyl)dimethanol
99c (1.9 g, 8.43 mmol), DIPEA (6.9 mL, 42.15 mmol) and 5-bromo-2-chloro-pyrimidine (3.2 g, 16.86 mmol) in n-BuOH (10 mL) were stirred in a sealed tube at 130°C for 16 h. The reaction mixture was cooled to RT and the precipitate was filtered off with a sintered funnel and washed with ether/hexane. Brown solid. Yield: 1.5 g (47%). HPLC (method 3): Rt = 3.14 min., m/z: [M+H]+ = 382.0 (MW calc. 382.28).
99e) (1-(5-Bromopyrimidin-2-yl)-3-(hvdroxymethyl)-6-(methylthio)indolin-3-yl)methyl 4-methyl-benzene- sulfonate
LiHMDS (3 mL, 3.92 mmol) was added drop wise at -78°C over a time period of 30 min to a solution of compound 99d (1.5 g, 3.92 mmol) in dry THF (1 10 mL). The reaction mixture was stirred at this temperature for 30 min, tosyl chloride (0.75 g, 3.92 mmol) in THF (40 mL) was slowly added and stirring was continued at -78°C for 2 h. The reaction mixture was quenched with saturated NH4CI solution and extracted with EtOAc (3x 250 mL). The combined organic layers were dried over Na2S04 and concentrated. The remnant was purified by flash column chromatography [silica; EtOAc/hexane = 3:7]. White solid. Yield: 1 .5 g (71 %). HPLC (method 3): Rt = 3.78 min, m/z: [M+H]+ = 538.2 (MW calc. 536.46).
99f) 1-(5-Bromopyrimidin-2-yl)-6-(methylthio)spironndoline-3,3'-oxetanel
Compound 99e (1 .5 g, 2.79 mmol) and pestled KOH (0.7 g) in t-BuOH (40 mL) were stirred at 70°C for 30 min. The reaction mixture was cooled to RT and the solvent was evaporated. The residue was diluted with water (50 mL) and extracted with EtOAc (3x 30 mL). The combined organic layers were dried and concentrated. Trituration of the residue afforded the target compound as white solid. Yield: 0.75 g (75%). HPLC (method 3): Rt = 3.85 min., m/z: [M+H]+ = 364.2 (MW calc. 364.26).
99g) 2-(2-(2-(6-(Methylsulfinyl)spiro[indoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)pyridin-4-yl) propan-2-ol Prepared from 99f and 2-(2-bromopyridin-4-yl)propan-2-ol in analogy to example 56. White solid. Yield: 0.15 g. HPLC (method 2): Rt = 1 .45 min, m/z: [M+H]+ = 437.1 (MW calc. 436.53). H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H), 8.67 (s, 1 H), 8.59 (d, 1 H, J = 4.9 Hz), 8.04 (s, 1 H), 7.94 (d, 1 H, J = 7.7 Hz), 7.47 (d, 1 H, J = 3.9 Hz), 7.40 (d, 1 H, J = 6.6 Hz), 5.29 (bs, 1 H), 4.90 (d, 2H, J = 6 Hz), 4.79 (d, 2H, J = 4 Hz), 4.65 (s, 2H), 2.76 (s, 3H), 1.48 (s, 6H).
Example 100: 2-(2-(2-(6-(Methylsulfonyl)spiro[indoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)pyridin-4-yl)propan-
Figure imgf000098_0001
Prepared from 99f and 2-(2-bromopyridin-4-yl)propan-2-ol in analogy to example 57. White solid. Yield: 0.16 g. HPLC (method 2): Rt = 1 .47 min, m/z: [M+H]+ = 453.1 (MW calc. 452.53). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.35 (s, 2H), 8.87 (s, 1 H), 8.60 (d, 1 H, J = 4.9 Hz), 8.06 (s, 1 H), 8.02 (d, 1 H, J = 7.7 Hz), 7.69 (d, 1 H, J = 7.7 Hz), 7.48 (d, 1 H, J = 4.9 Hz), 5.29 (bs, 1 H), 4.92 (d, 2H, J = 6 Hz), 4.79 (d, 2H, J = 5.9 Hz), 4.67 (s, 2H), 3.17 (s, 3H), 1.49 (s, 6H). Examples 101 to 104 were synthesized from lnt-5 in analogy to synthesis example 154.
Example 101 : 1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-N,N-dimethylspironndoline-3,3'-oxetanel-6- sulfonamide
Figure imgf000099_0001
White solid. Yield: 0.09 g. HPLC (method 3): Rt = 3.79 min, m/z: [M+H]+ = 455.1 (MW calc. 454.52). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.88 (s, 2H), 8.69 (s, 1 H), 8.00 (d, 1 H, J = 7.8 Hz), 7.51-7.47 (m, 2H), 7.25 (d, 2H, J = 8.3), 4.90 (d, 2H, J = 6.2 Hz), 4.80 (d, 2H, J = 6.2 Hz), 4.65 (s, 2H), 2.66 (s, 6H), 2.35 (s, 3H). Example 102: 1 -(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro [indoline-
3,3'-oxetanel-6-sulfonamide
Figure imgf000099_0002
White solid. Yield: 0.12 g. HPLC (method 2): Rt = 1.69 min, m/z: [M+H]+ = 485.1 (MW calc. 484.54). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.88 (s, 2H), 8.71 (s, 1 H), 7.98 (d, 1 H, J = 7.8 Hz), 7.51 (d, 2H, J = 7.5Hz), 7.25 (d, 2H, J = 8.2 Hz), 4.90 (d, 2H, J = 5.9 Hz), 4.80-4.78 (m, 3H), 4.65 (s, 2H), 3.54-3.53 (m, 2H), 3.06-3.03 (m, 2H), 2.77 (s, 3H), 2.35 (s, 3H).
Example 103: N,N-Dimethyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanel-6- sulfonamide
Figure imgf000100_0001
White solid. Yield: 65 mg. HPLC (method 2): Rt = 1.63 min, m/z: [M+H]+ = 438.08 (MW calc. 437.52). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.28 (s, 2H), 8.76 (s, 1 H), 8.52 (s, 1 H), 7.97 (d, 1 H, J = 7.8 Hz), 7.85 (s, 1 H), 7.51 (d, 1 H, J = 7.4 Hz), 7.19 (s, 1 H), 4.92 (d, 2H, J = 6.1 Hz), 4.82 (d, 2H, J = 6.0 Hz), 4.68 (s, 2H), 2.74 (s, 6H), 2.41 (s, 3H).
Example 104: N-(2-Hvdroxyethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro [indoline-3,31- oxetanel-6-sulfonamide
Figure imgf000100_0002
White solid. Yield: 75 mg. HPLC (method 2): Rt = 1.51 min, m/z: [M+H]+ = 468.08 (MW calc. 467.54). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2H), 8.75 (s, 1 H), 8.52 (s, 1 H), 7.98-7.94 (m, 2H), 7.51 (d, 1 H, J = 7.6), 7.21 (d, 1 H, J = 4.8 Hz), 4.90 (d, 2H, J = 6.2 Hz), 4.82-4.77 (m, 3H), 4.66 (s, 2H), 3.54 (bs, 2H), 3.06-3.03 (m, 2H), 2.78 (s, 3H), 2.39 (s, 3H). Example 105: N-Methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-N-(oxetan-3-ylmethyl)spiro [indoline-
3,3'-oxetanel-6-carboxamide
Figure imgf000100_0003
TBTU coupling of compound 22b with N-methyl-1-(oxetan-3-yl)methanamine (see also procedure 22c). White solid. Yield: 0.1 g. HPLC (method 3): Rt = 2.82 min, m/z: [M+H]+ = 457.9 (MW calc. 457.52). 1 H NMR (400 MHz, DMSO-c!6, 100°C, δ ppm): 9.24 (s, 2H), 8.52 (d, 1 H, J = 4.8 Hz), 8.37 (s, 1 H), 7.83-7.8 (m, 2H), 7.18 (d, 1 H, J = 4.7 Hz), 7.1 1 (d, 1 H, J = 7.6 Hz), 4.90 (d, 2H, J = 6 Hz), 4.82 (d, 2H, J = 6 Hz), 4.70-4.66 (m, 2H), 4.63 (s, 2H), 4.36 (t, 2H, J = 6.0 Hz), 3.75 (d, 2H, J = 7Hz), 3.39-3.34 (m, 1 H), 2.95 (s, 3H), 2.41 (s, 3H).
Example 106: N-(Cvclopropylmethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-v
3,3'-oxetanel-6-carboxamide
Figure imgf000101_0001
Prepared from compound 22b and 1-cyclopropyl-N-methylmethanamine in analogy to procedure 22c. White solid. Yield: 95 mg. HPLC (method 3): Rt = 3.34 min, m/z: [M+H]+ = 442.2 (MW calc. 441.53). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.23 (s, 2H), 8.51 (d, 1 H, J = 4.8 Hz), 8.38 (s, 1 H), 7.79-7.77 (m, 2H), 7.18 (d, 1 H, J = 4.6 Hz), 7.1 1 (d, 1 H, J = 7.5 Hz), 4.90 (d, 2H, J = 6 Hz), 4.82 (d, 2H, J = 5.9 Hz), 4.63 (s, 2H), 3.29 (d, 2H, J = 6.4 Hz), 3.05 (s, 3H), 2.40 (s, 3H), 1.05 (bs, 1 H), 0.54-0.50 (m, 2H), 0.22 (d, 2H, J = 4.1 Hz).
Example 107: N-((3,3-Difluorocvclobutyl)methyl)-N-methyl-1 -(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro-
Figure imgf000101_0002
Amide coupling of compound 22b with 1-(3,3-difluorocyclobutyl)-N-methylmethanamine analogously to procedure 22c. Light yellow solid. Yield: 70 mg. HPLC (method 2): Rt = 1.67 min, m/z: [M+H]+ = 492.2 (MW calc. 491 .53). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.23 (s, 2H), 8.52 (d, 1 H, J = 4.9 Hz), 8.37 (s, 1 H), 7.79-7.78 (m, 2H), 7.18 (d, 1 H, J = 4.8 Hz), 7.1 1 (d, 1 H, J = 7.6 Hz), 4.90 (d, 2H, J = 5.7 Hz), 4.81 (d, 2H, J = 5.9 Hz), 4.63 (s, 2H), 3.60 (d, 2H, J = 6.9 Hz), 2.97 (s, 3H), 2.76 (bs, 2H), 2.40 (bs, 5H). Example 108: 6-(Ethylsulfinyl)-1-(5-(pyridazin-3-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanel
Figure imgf000102_0001
Prepared from intermediate 52h and 3-bromopyridazine analogously to synthesis example 56. White solid. Yield: 0.15 g. HPLC (method 2): Rt = 1.50 min, m/z: [M+H]+ = 394.04 (MW calc. 393.46). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.40 (s, 2H), 9.22 (d, 1 H, J = 3.6 Hz), 8.63 (s, 1 H), 8.34-8.31 (m, 1 H), 7.95 (d, 1 H, J = 7.8 Hz), 7.83-7.79 (m, 1 H), 7.38 (d, 1 H, J = 7.6 Hz), 4.91 (d, 2H, J = 6.0 Hz), 4.80 (d, 2H, J = 5.7 Hz), 4.67 (s, 2H), 3.04-2.99 (m, 1 H), 2.80-2.75 (m, 1 H), 1.10-1.06 (t, 3H, J = 7.2 Hz).
Figure imgf000102_0002
Prepared from intermediate 52h and 3-bromopyridazine analogously to synthesis example 56. White solid. Yield: 90 mg. HPLC (method 3): Rt = 2.60 min, m/z: [M+H]+ = 410.0 (MW calc. 409.46). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.42 (s, 2H), 9.23-9.21 (m, 1 H), 8.84 (s, 1 H), 8.35-8.33 (m, 1 H), 8.04-8.02 (m, 1 H), 7.83-7.79 (m, 1 H), 7.66-7.64 (m, 1 H), 4.92 (d, 2H, J = 6.2), 4.80 (d, 2H, J = 6.2), 4.69 (s, 2H), 3.29-3.27 (m, 2H), 1.15 (t, 3H, J = 7.3 Hz).
Example 1 10: 2-(3-(2-(6-(Ethylsulfinyl)spironndoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)phenyl)-propan-2-ol
Figure imgf000102_0003
Prepared from intermediate 52h and 2-(3-bromophenyl)propan-2-ol analogously to synthesis example 56. White solid. Yield: 70 mg. HPLC (method 3): Rt = 2.89 min, m/z: [M+H]+ = 449.6 (MW calc. 449.57). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.00 (s, 2H), 8.59 (s, 1 H), 7.93 (d, 1 H, J = 7.7 Hz), 7.80 (s, 1 H), 7.58 (d, 1 H, J = 7.4 Hz), 7.51 (d, 1 H, J = 7.7 Hz), 7.43-7.40 (m, 1 H), 7.34-7.32 (m, 1 H), 5.07 (s, 1 H), 4.89 (d, 2H, J = 6.0 Hz), 4.80 (d, 2H, J = 5.8 Hz), 4.63 (s, 2H), 3.03-2.98 (m, 1 H), 2.79-2.74 (m, 1 H), 1.48 (s, 6H), 1.08 (t, 3H, J = 7.2 Hz).
Figure imgf000103_0001
Prepared from intermediate 52h and 2-(3-bromophenyl)propan-2-ol analogously to synthesis example 56. White solid. Yield: 70 mg. HPLC (method 3): Rt = 3.05 min, m/z: [M+H]+ = 465.8 (MW calc. 465.57). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.03 (s, 2H), 8.80 (s, 1 H), 8.02 (d, 1 H, J = 7.8 Hz), 7.81 (s, 1 H), 7.61- 7.58 (m, 2H), 7.52 (d, 1 H, J = 7.7 Hz), 7.44-7.40 (m, 1 H), 5.07 (s, 1 H), 4.91 (d, 2H, J = 6.4 Hz), 4.80 (d, 2H, J = 6.1 Hz), 4.65 (s, 2H), 3.29-3.25 (m, 2H), 1.48 (s, 6H), 1.15 (t, 3H, J = 7.2 Hz).
Figure imgf000103_0002
Prepared from intermediate 52h and 5-methylpyridazin-3-yl trifluoromethanesulfonate analogously to synthesis example 56. White solid. Yield: 70 mg. HPLC (method 3): Rt = 2.56 min, m/z: [M+H]+ = 408.0 (MW calc. 407.49). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.37 (s, 2H), 9.09 (s, 1 H), 8.62 (s, 1 H), 8.18 (s, 1 H), 7.95 (d, 1 H, J = 7.7 Hz), 7.38 (d, 1 H, J = 7.6 Hz), 4.91 (d, 2H, J = 6.0 Hz), 4.80 (d, 2H, J = 5.9 Hz), 4.63 (s, 2H), 3.06-2.97 (m, 1 H), 2.82-2.75 (m, 1 H), 2.39 (s, 3H), 1.08 (t, 3H, J = 7.1 Hz).
Example 1 13: 6-(Ethylsulfonyl)-1-(5-(5-methylpyridazin-3-yl)pyrimidin-2-yl)spironndoline-3,3'-oxetanel
Figure imgf000104_0001
Prepared from intermediate 52h and 5-methylpyridazin-3-yl trifluoromethanesulfonate analogously to synthesis example 56. White solid. Yield: 60 mg. HPLC (method 3): Rt = 2.71 min, m/z: [M+H]+ = 424.0 (MW calc. 423.49). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.40 (s, 2H), 9.10 (s, 1 H), 8.84 (s, 1 H), 8.21 (s, 1 H), 8.04 (d, 1 H, J = 7.8 Hz), 7.66-7.64 (m, 1 H), 4.92 (d, 2H, J = 6.3 Hz), 4.80 (d, 2H, J = 6.2 Hz), 4.69 (s, 2H), 3.28-3.27 (m, 2H), 2.39 (s, 3H), 1.17-1.13 (t, 3H, J = 7.3 Hz).
Example 1 14: 2-(6-(2-(6-(Ethylsulfinyl)spiro[indoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)pyridazin-4-yl)propan- 2-ol
Figure imgf000104_0002
1 14a) 2-(6-(2-(6-(Ethylthio)spironndoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)pyridazin-4-yl)propan-2-ol Methyl magnesium bromide (3 M in ether, 2.02 mL, 6.06 mmol) was added drop wise at -78°C to a solution of 1-(6-(2-(6-(ethylthio)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)pyridazin-4-yl)ethanone (0.85 g, 2.03 mmol, prepared from intermediate 52h and 1-(6-chloropyridazin-4-yl)ethanone analogously to synthesis example 56) in THF (150 mL). The resulting mixture was stirred at -78°C for 1 h, quenched with NH4CI solution and extracted with EtOAc (100 mL). The organic phase was dried over Na2S04 and evaporated and the residue was purified by flash column chromatography [silica; DCM with 2-3.5% MeOH]. Yield: 0.4 g (45%). HPLC (method 3): Rt = 3.21 min., m/z: [M+H]+ = 436.1 (MW calc. 435.54). 1 14b) 2-(6-(2-(6-(Ethylsulfinyl)spiro[indoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)pyridazin-4-yl)propan-2-ol A solution of mCPBA (80 mg, 0.454 mmol) in THF (2 mL) was added drop wise to 1 14a (0.2 g, 0.459 mmol) in THF (40 mL). The resulting mixture was stirred at RT for 1 h and then diluted with EtOAc (30 mL). The organic phase was washed successively with saturated NaHC03 solution (2x 15 mL) and brine (15 mL), dried over Na2S04 and evaporated. The remnant was purified by flash column chromatography (silica; DCM with 5% MeOH). White solid. Yield: 75 mg (36%). HPLC (method 3): Rt = 2.51 min, m/z: [M+H]+ = 452.0 (MW calc. 451.54). 1 H NMR (400 MHz, DMSO-c!6, δ ppm): 9.41 (s, 2H), 9.34 (s, 1 H), 8.64 (s, 1 H), 8.25 (s, 1 H), 7.95 (d, 1 H, J = 7.7 Hz), 7.38 (d, 1 H, J = 7.7), 5.54 (s, 1 H), 4.91 (d, 2H, J = 6.0 Hz), 4.80 (d, 2H, J = 5.6 Hz), 4.67 (s, 2H), 3.04-2.97 (m, 1 H), 2.80-2.75 (m, 1 H), 1.52 (s, 6H), 1 .08 (t, 3H, J = 7.3 Hz).
Example 1 15: 2-(6-(2-(6-(Ethylsulfonyl)spironndoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)pyridazin propan-2-ol
Figure imgf000105_0001
Oxidation of 1 14a with mCPBA. White solid. Yield: 70 mg. 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.45 (s, 2H), 9.35 (s, 1 H), 8.86 (s, 1 H), 8.27 (s, 1 H), 8.04 (d, 1 H, J = 7.8 Hz), 7.66 (d, 1 H, J = 7.7 Hz), 5.54 (s, 1 H), 4.93 (d, 2H, J = 6.1 Hz), 4.80 (d, 2H, J = 6.1 Hz), 4.70 (s, 2H), 3.29-3.27 (m, 2H), 1.52 (s, 6H), 1.08 (t, 3H, J = 7.3 Hz).
Intermediate 3: 1-(5-Bromopyrimidin-2-yl)-6-((2-((tert-butyldiphenylsilyl)oxy)ethyl)thio)spiro-[indoline-3,3'- oxetanel (lnt-3)
Figure imgf000105_0002
lnt-3a) 2-((2,2-Dimethylspiro[[1 ,3ldioxane-5,3'-indolinl-6'-yl)thio)ethanol
A solution of 6'-bromo-2,2-dimethylspiro[[1 ,3]dioxane-5,3'-indoline] (15 g, 50.3 mmol), 2-mercapto-ethanol (3.5 ml, 50.3 mmol) and DIPEA (17.5 mL, 100.6 mmol) in dry dioaxane (450 mL) was flushed with Ar. Xantphos (2.9 g, 5.03 mmol) and Pd2(dba)3 (2.3 g, 2.51 mmol) were added and the resulting mixture was heated at 120°C for 16 h. The reaction mixture was cooled and filtered through a pad of celite. The filtrate was evaporated and the residue purified by flash column chromatography [silica gel; DCM with 1.5% MeOH]. Brown liquid. Yield: 14.8 g (100%). HPLC (method 3): Rt = 2.73 min, m/z: [M+H]+ = 296.0 (MW calc. 295.40).
Int-3b) 6'-((2-((tert-Butyldiphenylsilyl)oxy)ethyl)thio)-2,2-dimethylspiro[[1 ,3ldioxane-5,3'-indolinel To a solution of lnt-3a (14.8 g, 50.17 mmol) in dry DMF (10 mL) were added at 0°C imidazole (9.56 g, 140.47 mmol) and TBDPS (19.7 ml, 75.25 mmol). The reaction mixture was stirred at RT for 2 h. Ice- water was added and the reaction mixture was extracted with MTBE (100 mL). The aqueous phase was separated and extracted with MTBE (2x 60 mL). The combined organic layers were washed with brine (60 mL), dried over Na2S04 and concentrated. The residue was purified by column chromatography [silica; EtOAc/hexane = 1 :9]. Brown liquid. Yield: 22 g (82 %). HPLC (method 3): Rt = 3.13 min, m/z: [M+H]+ = 534.2 (MW calc. 533.80).
Int-3c) (6-((2-((tert-Butyldiphenylsilyl)oxy)ethyl)thio)indoline-3,3-diyl)dimethanol
lnt-3b (22 g, 41.27 mmol) in THF (220 mL) was stirred at RT in the presence 0.5N HCI (742 mL) for 2 h. The reaction mixture was concentrated, basified with sat. NaHC03 solution and extracted with EtOAc (10x 100 mL). The combined organic layers were dried over Na2S04 and concentrated. Light brown liquid. Yield: 19 g. HPLC (method 3): Rt = 2.10 min, m/z: [M+H]+ = 494.3 (MW calc. 493.73). lnt-3d) (1 -(5-Bromopyrimidin-2-yl)-6-((2-((tert-butyldiphenylsilyl)oxy)ethyl)thio)indoline-3,3-diyl) dimethanol lnt-3c (9.5 g, 19.27 mmol), 5-bromo-2-chloro-pyrimidine (7.4 g, 38.54 mmol) and DIPEA (17.2 mL, 96.35 mmol) in n-BuOH (180 mL) were heated in a sealed tube at 140°C for 16 h. The reaction mixture was concentrated and the remnant was purified by flash column chromatography [silica; DCM with 2% MeOH]. Light brown solid. The reaction was done in two batches of 9.5 g each and the combined yield was 15 g (60%). HPLC (method 3): Rt = 3.08 min, m/z: [M+H]+ = 652.0 (MW calc. 650.70).
Int-3e) (1-(5-Bromopyrimidin-2-yl)-6-((2-((tert-butyldiphenylsilyl)oxy)ethyl)thio)-3-(hvdroxymethyl)indolin- 3-vDmethyl 4-methylbenzenesulfonate
LiHMDS (1 1.5 mL, 1 1.53 mmol) was added over 30 min drop wise to a solution of lnt-3d (7.5 g, 1 1.53 mmol) in dry THF (750 mL) at -78°C. The reaction mixture was stirred at the same temperature for 30 min, tosylchloride (2.2 g, 1 1.53 mmol) in dry THF (50 mL) was added and stirring was continued at -78°C for 2 h. The reaction mixture was quenched with sat. NH4CI solution and extracted with EtOAc (3x 250 mL). The combined organic layers were dried over Na2S04 and concentrated. The residue was purified by flash column chromatography [silica; EtOAc/hexane = 3:7]. Yellow semi solid. The reaction was done in two batches of 7.5 g each and the combined yield was 7 g. HPLC (method 3): Rt = 3.65 min, m/z: [M+H]+ = 806.0 (MW calc. 804.89).
Int-3f) 1-(5-Bromopyrimidin-2-yl)-6-((2-((tert-butyldiphenylsilyl)oxy)ethyl)thio)spiro-[indoline-3,3'-oxetane1 (lnt-3)
KOH (0.95 g, 16.96 mmol) was added to a solution of lnt-3e (3.5 g, 4.35 mmol) in t-BuOH (140 mL) at RT. The reaction mixture was stirred for 4 h, then diluted with water (50 mL) and extracted with EtOAc (3x100 mL). The combined organic layers were dried over Na2S04 and concentrated. The raw product was triturated with ether; white solid. The reaction was done in two batches of 3.5 g each and the combined yield was 6 g. HPLC (method 3): Rt = 3.70 min, m/z: [M+H]+ = 633.8 (MW calc. 632.69). Intermediate 4: 1-(5-Bromopyrimidin-2-yl)-6-((3-((tert-butyldiphenylsilyl)oxy)propyl)thi [indoline-3,31- oxetanel (lnt-4)
Figure imgf000107_0001
Prepared analogously to lnt-3. White solid. HPLC (method 7): Rt = 5.62 min., m/z: [M+H]+ = 648.0 (MW calc. 646.71 ).
Figure imgf000107_0002
1 16a) 6-((2-((tert-Butyldiphenylsilyl)oxy)ethyl)sulfinyl)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro- [indoline-3,3'-oxetanel
m-CPBA (0.15 g, 0.62 mmol) in DCM (5 mL) was slowly added to an ice-cooled solution of 6-((2-((tert- butyldiphenylsilyl)oxy)ethyl)thio)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan (0.5 g, 0.77 mmol, prepared from lnt-3 and 2-bromo-4-methylpyridine analogously to procedure 8c) in DCM (50 mL). The resulting mixture was stirred at RT for 1 h, then diluted with DCM (50 mL) and washed successively with saturated NaHC03 solution (2x 50 mL) and brine (50 mL). The organic layer was dried over Na2S04 and evaporated. The remnant was purified by flash column chromatography [silica; DCM with 3% MeOH]. White solid. Yield: 0.43 g (84%). HPLC (method 3): Rt = 2.85 min, m/z: [M+H]+ = 661.1 (MW calc. 660.90). 1 16b) 2-((1-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl)sulfinyl) ethanol
Tetrabutyl ammonium fluoride solution (1 M in THF, 2.3 mL, 2.28 mmol) was added drop wise at 0°C to 1 16a (0.43 g, 0.65 mmol) in THF (20 mL). The reaction mixture was stirred at RT for 1 h, and then quenched with sat. NH4CI solution and extracted with EtOAc (3x 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2S04 and concentrated. The remnant was purified by flash column chromatography [silica; DCM with 5% MeOH] followed by trituration with DCM/pentane (1 :2). White solid. Yield: 0.18 g (66%). HPLC (method 2): Rt = 1.41 min, m/z: [M+H]+ = 423.0 (MW calc. 422.50). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.3 (s, 2H), 8.63 (s, 1 H), 8.52 (d, 1 H, J = 4.9 Hz), 7.94-7.9 (m, 2H), 7.36 (dd, 1H, J = 1.3, 7.6 Hz), 7.19 (d, 1H, J = 4.8 Hz), 5.11-5.08 (m, 1H), 4.88 (d, 2H, J = 6.2 Hz), 4.77 (d, 2H, J = 5.9 Hz), 4.64 (s, 2H), 3.88-3.8 (m, 1H), 3.71-3.65 (m, 1H), 3.02-2.95 (m, 1H), 2.91-2.85 (m, 1H), 2.38 (s, 3H). Synthesis examples 117 to 119 were obtained from lnt-3 in analogy to example 116.
Figure imgf000108_0001
White solid. Yield: 0.16 g. HPLC (method 3): Rt = 2.86 min, m/z: [M+H]+ = 439.2 (MW calc.438.50).1H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2H), 8.82 (s, 1H), 8.51 (d, 1H, J = 4.9 Hz), 8.01 (d, 1H, J = 7.8 Hz), 7.93 (s, 1H), 7.65 (dd, 1H, J = 1.3 & 7.8 Hz), 7.2 (d, 1H, J = 4.8 Hz), 4.91-4.89 (m, 3H), 4.77 (d, 2H, J = 6.2 Hz), 4.66 (s, 2H), 3.74-3.69 (m, 2H), 3.47-3.43 (m, 2H), 2.38 (s, 3H).
Example 118: 2-(2-(2-(6-((2-Hvdroxyethyl)sulfinyl)spiro[indoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)pyridin-4- yl)propan-2-ol
Figure imgf000108_0002
White solid. Yield: 90 mg. HPLC (method 2): Rt = 1.39 min, m/z: [M+H]+ = 467.1 (MW calc.466.55).1H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H), 8.65 (s, 1H), 8.59 (d, 1H, J = 5.1 Hz), 8.04 (s, 1H), 7.94 (d, 1H, J = 7.7 Hz), 7.47 (d, 1H, J = 4.1 Hz), 7.37 (dd, 1H, J = 0.9, 7.8 Hz), 5.3 (s, 1H), 5.11 (t, 1H, J = 4.96 Hz), 4.9 (d, 2H, J = 6.2 Hz), 4.79 (d, 2H, J = 6.1 Hz), 4.65 (s, 2H), 3.86-3.81 (m, 1H), 3.71-3.66 (m, 1H), 3.02-2.95 (m, 1H), 2.91-2.87 (m, 1H), 1.48 (s, 6H).
Example 119: 2-(2-(2-(6-((2-Hvdroxyethyl)sulfonyl)spironndoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)pyridin-4- yl)propan-2-ol
Figure imgf000109_0001
White solid. Yield: 0.2 g. HPLC (method 3): Rt = 2.71 min, m/z: [M+H]+ = 483.2 (MW calc. 482.55). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.35 (s, 2H), 8.84 (s, 1 H), 8.59 (d, 1 H, J = 4.9 Hz), 8.06 (s, 1 H), 7.99 (d, 1 H, J = 7.7 Hz), 7.63 (d, 1 H, J = 7.2 Hz), 7.47 (d, 1 H, J = 4.4 Hz), 5.29 (s, 1 H), 4.92-4.88 (m, 3H), 4.79-4.78 (m, 2H), 4.67 (s, 2H), 3.74-3.69 (m, 2H), 3.46-3.31 (m, 2H), 1.49 (s, 6H).
Synthesis examples 120 to 124 were obtained from lnt-4 in analogy to example 1 16.
Example 120: 3-((1-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl) sulfinvDpropan- 1-ol
Figure imgf000109_0002
White solid. Yield: 0.15 g. HPLC (method 2): Rt = 1.43 min, m/z: [M+H]+ = 437.1 (MW calc. 436.53). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.3 (s, 2H), 8.61 (s, 1 H), 8.52 (d, 1 H, J = 4.9 Hz), 7.94-7.91 (m, 2H), 7.35 (d, 1 H, J = 7.3 Hz), 7.19 (d, 1 H, J = 4.7 Hz), 4.9 (d, 2H, J = 6.1 Hz), 4.79-4.78 (m, 2H), 4.65 (s, 2H), 4.62-4.59 (m, 1 H), 3.49-3.44 (m, 2H), 3.01-2.94 (m, 1 H), 2.85-2.78 (m, 1 H), 2.38 (s, 3H), 1.82-1.75 (m, 1 H), 1.64-1.6 (m, 1 H).
Example 121 : 3-((1-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl)sulfonyl)propan-
1-ol
Figure imgf000110_0001
White solid. Yield: 0.10 g. HPLC (method 2): Rt = 1.46 min, m/z: [M+H]+ = 453.1 (MW calc. 452.53). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H), 8.82 (s, 1 H), 8.52 (d, 1 H, J = 4.9 Hz), 8.03 (d, 1 H, J = 7.8 Hz), 7.94 (s, 1 H), 7.62 (d, 1 H, J = 6.9 Hz), 7.2 (d, 1 H, J = 4.5 Hz), 4.91-4.9 (m, 2H), 4.79-4.78 (m, 2H), 4.67-4.62 (m, 3H), 3.43 (bs, 2H), 3.31 (2H, merged with DMSO-water peak), 2.39 (s, 3H), 1.71 (bs, 2H).
Example 122 and 123: 3-((1-(5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-
Figure imgf000110_0002
The racemic sulfoxide (200 mg) was separated into its single enantiomers via chiral preparative HPLC (column: Chiralpak 21 x 250 mm, particle size 5 μιη; mobile phase: hexane/EtOAc/ethanol /diethylamine = 50/25/25/0.1 ; flow rate: 21.0 ml/min; detection: UV (326 nM); run time: 25 min).
Faster eluting enantiomer (example 122): Yield: 80 mg. Enantiomeric excess: 100% (chiral HPLC). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H), 8.64 (s, 1 H), 8.59 (d, 1 H, J = 5.0 Hz), 8.04 (s, 1 H), 7.94 (d, 1 H, J = 7.7 Hz), 7.46 (d, 1 H, J = 4.5 Hz), 7.37 (d, 1 H, J = 7.9 Hz), 5.29 (s, 1 H), 4.91-4.89 (m, 2H), 4.8- 4.78 (m, 2H), 4.66-4.6 (m, 3H), 3.49-3.44 (m, 2H), 3.02-2.94 (m, 1 H), 2.85-2.78 (m, 1 H), 1.79-1 .77 (m, 1 H), 1.66-1.58 (m, 1 H), 1.49 (s, 6H). Specific optical rotation: [a]D 25 = -184.64° (c. 0.358%, CHCI3) Slower eluting enantiomer (example 123): Yield: 90 mg. Enantiomeric excess: 100% (chiral HPLC). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H), 8.64 (s, 1 H), 8.59 (d, 1 H, J = 5.0 Hz), 8.04 (s, 1 H), 7.94 (d, 1 H, J = 7.7 Hz), 7.46 (d, 1 H, J = 4.5 Hz), 7.37 (d, 1 H, J = 7.9 Hz), 5.29 (s, 1 H), 4.91-4.89 (m, 2H), 4.8- 4.78 (m, 2H), 4.66-4.6 (m, 3H), 3.49-3.44 (m, 2H), 3.02-2.94 (m, 1 H), 2.85-2.78 (m, 1 H), 1.79-1 .77 (m, 1 H), 1.66-1.58 (m, 1 H), 1.49 (s, 6H). Specific optical rotation: [a]D 25 = +169.29° (c. 0.56%, CHCI3) Example 124: 3-((1-(5-(4-(2-Hvdroxypropan-2-yl)pyridi^
yl)sulfonyl)propan-1-ol
Figure imgf000111_0001
White solid. Yield: 0.17 g. HPLC (method 2): Rt = 1.43 min, m/z: [M+H]+ = 496.1 (MW calc. 496.58). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.35 (s, 2H), 8.84 (s, 1 H), 8.59 (d, 1 H, J = 5.0 Hz), 8.06 (s, 1 H), 8.03 (d, 1 H, J = 7.8 Hz), 7.64-7.62 (m, 1 H), 7.47 (d, 1 H, J = 5.0 Hz), 5.28 (s, 1 H), 4.92-4.9 (m, 2H), 4.79-4.78 (m, 2H), 4.67 (s, 2H), 4.62 (t, 1 H, J = 5.2 Hz), 3.45-3.4 (m, 2H), 3.28 (2H, merged with DMSO-water signals), 1.75-1.68 (m, 2H), 1.49 (s, 6H). The examples 125 to 132 were prepared in analogy to example 8.
Example 125: (1-(5-(6-Hvdroxypyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl)(morpholino)- methanone
Figure imgf000111_0002
Yellow solid. Yield: 0.1 1 g. HPLC (method 3): Rt = 2.41 min, m/z: [M+H]+ = 445.9 (MW calc. 444.47). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 1 1.03 (bs, 1 H), 9.04 (s, 2H), 8.39 (s, 1 H), 7.81 (d, 1 H, J = 7.6 Hz), 7.56 (t, 1 H, J = 7.7 Hz), 7.17 (d, 1 H, J = 7.5 Hz), 6.88 (d, 1 H, J = 5.7 Hz), 6.45 (d, 1 H, J = 8.7 Hz), 4.89 (d, 2H, J = 6 Hz), 4.81 (d, 2H, J = 6 Hz), 4.62 (s, 2H), 3.65 (t, 4H, J = 4.2 Hz), 3.55 (d, 4H, J = 4.5 Hz).
Example 126: (1-(5-(3-Methylpyridin-2-yl)pyrimidin-2-yl)spironndoline-3,3'-oxetanl-6-yl)(morpholino)- methanone
Figure imgf000112_0001
White solid. Yield: 75 mg. HPLC (method 3): Rt = 2.80 min, m/z: [M+H]+ = 443.8 (MW calc. 443.50). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.89 (s, 2H), 8.53 (d, 1 H, J = 3.9 Hz), 8.40 (d, 1 H, J = 0.7 Hz), 7.81 (d, 1 H, J = 7.6 Hz), 7.77 (d, 1 H, J = 7.6 Hz), 7.34-7.31 (m, 1 H), 7.14-7.12 (m, 1 H), 4.89 (d, 2H, J = 6.1 Hz), 4.80 (d, 2H, J = 6.1 Hz), 4.62 (s, 2H), 3.63-3.37 (m, 8H), 2.43 (s, 3H).
Example 127: (1-(5-(2-Fluoro-3-hvdroxyphenyl)pyrimidin-2-yl)spironndoline-3,3'-oxetanl-6- yl)(morpholino)methanone
Figure imgf000112_0002
White solid. Yield: 0.07 g. HPLC (method 3): Rt = 2.89 min, m/z: [M+H]+ = 463.1 (MW calc. 462.47). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 10.04 (bs, 1 H), 8.82 (s, 2H), 8.37 (s, 1 H), 7.81 (d, 1 H, J = 7.6 Hz), 7.14-7.07 (m, 2H), 7.01-6.97 (m, 2H), 4.88 (d, 2H, J = 6 Hz), 4.79 (d, 2H, J = 6 Hz), 4.60 (s, 2H), 3.63- 3.40 (m, 8H). Example 128: (1-(5-(3-Amino-2-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl)
(morpholino)methanone
Figure imgf000112_0003
White solid. Yield: 61 mg. HPLC (method 2): Rt = 1.56 min, m/z: [M+H]+ = 462.2 (MW calc. 461.49). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.80 (s, 2H), 8.37 (s, 1 H), 7.81 (d, 1 H, J = 7.5 Hz), 7.14 (d, 1 H, J = 7.4 Hz), 6.97 (t, 1 H, J = 7.8 Hz), 6.80 (t, 1 H, J = 7.8 Hz), 6.70 (t, 1 H, J = 6.6 Hz), 5.29 (s, 2H), 4.88 (d, 2H, J = 5.8 Hz), 4.79 (d, 2H, J = 5.8 Hz), 4.60 (s, 2H), 3.62-3.40 (m, 8H).
Figure imgf000113_0001
White solid. Yield: 0.05 g. HPLC (method 3): Rt = 2.64 min, m/z: [M+H]+ = 445.3 (MW calc. 444.49). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.38 (s, 2H), 9.07 (s, 1 H), 8.42 (s, 1 H), 8.04 (s, 1 H), 7.84 (d, 1 H, J = 7.5 Hz), 7.19 (d, 1 H, J = 7.5 Hz), 4.89 (d, 2H, J = 6.1 Hz), 4.79 (d, 2H, J = 6.1 Hz), 4.64 (s, 2H), 3.63 (bs, 8H), 2.52 (s, 3H).
Example 130: (1 -(5-(2-Fluoro-6-hvdroxyphenyl)pyrimidin-2-yl)spironndoline-3,3'-oxetanl-6-yl)-
(morpholino)methanone
Figure imgf000113_0002
White solid. Yield: 0.07 g. HPLC (method 3): Rt = 2.93 min, m/z: [M+H]+ = 463.0 (MW calc. 462.47). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 10.23 (bs, 1 H), 8.67 (s, 2H), 8.36 (s, 1 H), 7.80 (d, 1 H, J = 7.5 Hz), 7.22 (t, 1 H, J = 7.4 Hz), 7.13 (d, 1 H, J = 6.7 Hz), 6.84-6.76 (m, 2H), 4.88 (d, 2H, J = 5.9 Hz), 4.80 (d, 2H, J = 5.8 Hz), 4.59 (s, 2H), 3.62-3.38 (m, 8H).
Example 131 : (1-(5-(2-Amino-6-fluorophenyl)pyrimidin-2-yl)spironndoline-3,3'-oxetanl-6-yl)(morpholino)- methanone
Figure imgf000114_0001
White solid. Yield: 45 mg. HPLC (method 2): Rt = 1.57 min, m/z: [M+H]+ = 462.2 (MW calc. 461. 49). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.56 (s, 2H), 8.37 (s, 1 H), 7.81 (d, 1 H, J = 7.6 Hz), 7.13-7.04 (m, 2H), 6.58 (d, 1 H, J = 8.1 Hz), 6.42 (t, 1 H, J = 8.8 Hz), 5.26 (s, 2H), 4.88 (d, 2H, J = 6.1 Hz), 4.80 (d, 2H, J = 6 Hz), 4.59 (s, 2H), 3.62-3.35 (m, 8H).
Example 132: (1-(5-(6-Aminopyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl)(morpholi methanone
Figure imgf000114_0002
White solid. Yield: 0.1 g. HPLC (method 2): Rt = 1.33 min, m/z: [M+H]+ = 445.2 (MW calc. 444.49). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.17 (s, 2H), 8.39 (s, 1 H), 7.81 (d, 1 H, J = 7.6 Hz), 7.46 (t, 1 H, J = 7.8 Hz), 7.14-7.09 (m, 2H), 6.43 (d, 1 H, J = 8.2 Hz), 6.06 (s, 2H), 4.88 (d, 2H, J = 6.1 Hz), 4.78 (d, 2H, J = 6 Hz), 4.60 (s, 2H), 3.62-3.41 (m, 8H). The examples 133 and 134 were prepared from (1-(5-bromopyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6- yl)(morpholino)methanone 8b applying Suzuki reaction conditions as described under 3a.
Example 133: (1-(5-(2-Fluoro-3-methylphenyl)pyrimidin-2-yl)spironndoline-3,3'-oxetanl-6-yl)(morpholino)- methanone
Figure imgf000114_0003
White solid. Yield: 59 mg. HPLC (method 2): Rt = 1.73 min, m/z: [M+H]+ = 461.2 (MW calc. 460.50). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.84 (s, 2H), 8.38 (s, 1 H), 7.81 (d, 1 H, J = 7.6 Hz), 7.45 (t, 1 H, J = 6.8 Hz), 7.33 (t, 1 H, J = 7.2 Hz), 7.24-7.20 (m, 1 H), 7.14 (d, 1 H, J = 7.6 Hz), 4.88 (d, 2H, J = 6.1 Hz), 4.79 (d, 2H, J = 6 Hz), 4.60 (s, 2H), 3.63-3.39 (m, 8H), 2.31 (s, 3H).
Example 134: (1-(5-(2-Fluoro-6-methylphenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl) (morpholino)- methanone
Figure imgf000115_0001
White solid. Yield: 0.1 1 g. HPLC (method 3): Rt = 3.20 min, m/z: [M+H]+ = 461.4 (MW calc. 460.50). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.65 (s, 2H), 8.37 (s, 1 H), 7.81 (d, 1 H, J = 7.6 Hz), 7.36 (t, 1 H, J = 6.2 Hz), 7.22-7.12 (m, 3H), 4.88 (d, 2H, J = 6 Hz), 4.80 (d, 2H, J = 5.8 Hz), 4.61 (s, 2H), 3.62-3.39 (m, 8H), 2.23 (s, 3H).
The examples 135 and 141 were prepared from lnt-1 analogously to synthesis example 22.
Example 135: (1-(4-Mthyl-[2,5'-bipyrimidinl-2'-yl)spironndoline-3,3'-oxetanl-6-yl)(morpholino) methanone
Figure imgf000115_0002
White solid. Yield: 0.09 g. HPLC (method 3): Rt = 2.80 min, m/z: [M+H]+ = 445.1 (MW calc. 444.49). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.43 (s, 2H), 8.74 (d, 1 H, J = 5.1 Hz), 8.42 (s, 1 H), 7.83 (d, 1 H, J = 7.6 Hz), 7.34 (d, 1 H, J = 5 Hz), 7.16 (t, 1 H, J = 7.6 Hz), 4.89 (d, 2H, J = 6.2 Hz), 4.78 (d, 2H, J = 6.1 Hz), 4.63 (s, 2H), 3.64 (bs, 8H), 2.54 (s, 3H).
Example 136: (1-(4,6-Dimethyl-[2,5'-bipyrimidinl-2'-yl)spironndoline-3,3'-oxetanl-6-yl)(morpholino) methanone
Figure imgf000116_0001
White solid. Yield: 76 mg. HPLC (method 2): Rt = 1.71 min, m/z: [M+H]+ = 459.3 (MW calc. 458.51 ). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.52-9.48 (m, 2H), 8.56 (s, 1 H), 7.78 (d, 1 H, J = 7.4 Hz), 7.20 (d, 1 H, J = 7.4 Hz), 6.92 (s, 1 H), 4.95-4.90 (m, 4H), 4.63 (s, 2H), 3.81-3.69 (m, 6H), 3.53 (s, 2H), 2.51 (s, 6H).
Example 137: 1-([2,5'-Bipyrimidinl-2'-yl)-N-(2-hvdroxyethyl)-N-methylspiro[indoline-3,3'-oxetanel-6- carboxamide
Figure imgf000116_0002
White solid. Yield: 0.1 1 g. HPLC (method 3): Rt = 2.52 min, m/z: [M+H]+ = 419.4 (MW calc. 418.45). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.43 (s, 2H), 8.87 (d, 2H, J = 4.5 Hz), 8.41 (s, 1 H), 7.80 (d, 1 H, J = 7.5 Hz), 7.40 (d, 1 H, J = 4.8 Hz), 7.17 (d, 1 H, J = 7.5 Hz), 4.90 (d, 2H, J = 5.8 Hz), 4.81 (d, 3H, J = 5.9 Hz), 4.65 (s, 2H), 3.64-3.62 (m, 2H), 3.46 (bs, 2H), 2.97 (bs, 3H).
Example 138: N-(2-Hvdroxyethyl)-N-methyl-1-(5-(pyrazin-2-yl)pyrimidin-2-yl)spironndoline-3,3'-oxetanel- 6-carboxamide
Figure imgf000116_0003
White solid. Yield: 0.07 g. HPLC (method 2): Rt = 1.43 min, m/z: [M+H]+ = 419.2 (MW calc. 418.45). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.34 (s, 2H), 9.30 (s, 1 H), 8.71 (s, 1 H), 8.62 (d, 1 H, J = 2.3 Hz), 8.39 (s, 1 H), 7.80-7.78 (m, 1 H), 7.16 (d, 1 H, J = 7.6 Hz), 4.89 (d, 2H, J = 6.1 Hz), 4.80 (d, 2H, J = 6 Hz), 4.63 (s, 2H), 3.64-6.53 (m, 3H), 3.32 (s, 1 H), 3.01-2.98 (m, 3H). Example 139: N-(2-Hvdroxyethyl)-N-methyl-1-(5-(6-methylpyridin-2-yl)pyrimidin-2-yl)spiro [indoline-3,31- oxetanel-6-carboxamide
Figure imgf000117_0001
White solid. Yield: 0.07 g. HPLC (method 3): Rt = 3.95 min, m/z: [M+H]+ = 432.4 (MW calc. 431.49). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.23 (s, 2H), 8.39 (s, 1 H), 7.78-7.72 (m, 3H), 7.21 (d, 1 H, J = 6.2 Hz), 7.14 (d, 1 H, J = 7.6 Hz), 4.89 (d, 2H, J = 6 Hz), 4.82 (d, 2H, J = 6 Hz), 4.63 (s, 2H), 4.42 (s, 1 H), 3.62 (t, 2H, J = 5.3 Hz), 3.46 (bs, 2H), 3.03 (s, 3H), 2.56 (s, 3H). Example 140: N-(2-Hvdroxyethyl)-1-(5-(6-hvdroxypyridin-2-yl)pyrimidin-2-yl)-N-methylspiro [indoline-3,31- oxetanel-6-carboxamide
Figure imgf000117_0002
Light yellow solid. Yield: 60 mg. HPLC (method 2): Rt = 1.37 min, m/z: [M+H]+ = 434.3 (MW calc. 433.46). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 1 1.01 (bs, 1 H), 9.03 (s, 2H), 8.37 (s, 1 H), 7.79 (d, 1 H, J = 7.6 Hz), 7.56 (t, 1 H, J = 7.3 Hz), 7.15 (d, 1 H, J = 7.6 Hz), 6.86 (s, 1 H), 6.45 (d, 1 H, J = 8.6 Hz), 4.89 (d, 2H, J = 5.9 Hz), 4.81 (d, 2H, J = 6 Hz), 4.62 (s, 2H), 4.41 (s, 1 H), 3.63-3.62 (m, 2H), 3.46 (bs, 2H), 3.02 (s, 3H).
Example 141 : N-(2-Hvdroxyethyl)-1 -(5-(6-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methyl- spironndoline-3,3'-oxetanel-6-carboxamide
Figure imgf000118_0001
White solid. Yield: 0.15 g. HPLC (method 2): Rt = 1.50 min, m/z: [M+H]+ = 476.3 (MW calc. 475.54). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.28 (s, 2H), 8.40 (s, 1 H), 7.85 (t, 1 H, J = 8.2 Hz), 7.78 (t, 2H, J = 4.9 Hz), 7.61 (d, 1 H, J = 7.7 Hz), 7.13 (d, 1 H, J = 7.5 Hz), 4.89 (t, 3H, J = 4.7 Hz), 4.82 (d, 2H, J = 5.9 Hz), 4.63 (s, 2H), 4.41 (t, 1 H, J = 4.4 Hz), 3.63 (d, 2H, J = 5.4 Hz), 3.46 (s, 2H), 3.03 (s, 3H), 1.55 (s, 6H).
The examples 142 to 143 were prepared in analogy to example 8.
Example 142: (1 -(5-(6-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl)- (morpholino)methanone
Figure imgf000118_0002
White solid. Yield: 0.14 g. HPLC (method 2): Rt = 1.58 min, m/z: [M+H]+ = 488.2 (MW calc. 487.55). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H), 8.41 (s, 1 H), 7.87-7.80 (m, 3H), 7.61 (d, 1 H, J = 6 Hz), 7.15 (d, 1 H, J = 7.4 Hz), 5.26 (s, 1 H), 4.89 (d, 2H, J = 5.8 Hz), 4.79 (d, 2H, J = 6 Hz), 4.62 (s, 2H), 3.92 (bs, 8H), 1.51 (s, 6H).
Example 143: (1-(5-(6-Methylpyridin-2-yl)pyrimidin-2-yl)spironndoline-3,3'-oxetanl-6-yl)(morpholino)- methanone
Figure imgf000118_0003
White solid. Yield: 187 mg. HPLC (method 2): Rt = 1.51 min., m/z: [M+H]+ = 444.2 (MW calc. 443.50). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.27 (s, 2H), 8.41 (s, 1 H), 7.80 (bs, 3H), 7.23 (d, 1 H, J = 6.4 Hz), 7.15 (d, 1 H, J = 6.9 Hz), 4.89 (d, 2H, J = 5.6 Hz), 4.79 (d, 2H, J = 5.5 Hz), 4.61 (s, 2H), 3.64 (bs, 8H), 2.54 (s, 3H).
Example 144: N-((3-Hydroxyoxetan-3-yl)methyl)-N-methyl-1 -(5-(4-m
nndoline-3,3'-oxetanel-6-carboxami
Figure imgf000119_0001
Prepared from compound 22b. White solid. Yield: 60 mg. HPLC (method 2): Rt = 1.43 min, m/z: [M+H]+ = 474.2 (MW calc. 473.52). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.23 (s, 2H), 8.52 (d, 1 H, J = 4.7 Hz), 8.41 (s, 1 H), 7.80-7.77 (m, 2H), 7.18-7.12 (m, 2H), 5.69-5.66 (m, 1 H), 4.90 (d, 2H, J = 5.9 Hz), 4.81 (d, 2H, J = 6 Hz), 4.63 (s, 2H), 4.53 (d, 2H, J = 6.1 Hz), 4.47 (d, 2H, J = 6.4 Hz), 3.83 (s, 2H), 3.03 (s, 3H), 2.41 (s, 3H). Example 145: N-((1-Hvdroxycvclopropyl)methyl)-N-methyl-1 -(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro- nndoline-3,3'-oxetanel-6-carboxami
Figure imgf000119_0002
Prepared from compound 22b and 1-((methylamino)methyl)cyclopropanol in analogy to procedure 22c). White solid. Yield: 50 mg. HPLC (method 3): Rt = 2.84 min, m/z: [M+H]+ = 458.3 (MW calc. 457.52). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.23 (s, 2H), 8.52 (d, 1 H, J = 5 Hz), 8.40 (s, 1 H), 7.78 (t, 2H, J = 6 Hz), 7.16 (t, 2H, J = 6.1 Hz), 5.05 (s, 1 H), 4.90 (d, 2H, J = 6 Hz), 4.82 (d, 2H, J = 6 Hz), 4.63 (s, 2H), 3.53 (s, 2H), 3.10 (s, 3H), 2.96 (s, 1 H), 2.40 (s, 3H), 0.66 (s, 2H), 0.52 (s, 2H).
Examples 146 and 147 were obtained from 1-(5-bromopyrimidin-2-yl)spiro[indoline-3,3'-oxetane]-6- carboxylic acid 8a in analogy to synthesis example 8. Example 146: 1-(5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N,N-dim [indoline-3,3'- oxetanel-6-carboxamide
Figure imgf000120_0001
White solid. Yield: 62 mg. HPLC (method 3): Rt = 2.67 min, m/z: [M+H]+ = 446.1 (MW calc. 445.51 ). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.30 (s, 2H), 8.58 (s, 1 H), 8.40 (s, 1 H), 8.00 (s, 1 H), 7.80 (d, 1 H, J = 6.2 Hz), 7.45 (s, 1 H), 7.13 (d, 1 H, J = 6.6 Hz), 5.31 (s, 1 H), 4.88 (s, 2H), 4.79 (s, 2H), 4.61 (s, 2H), 2.95 (s, 6H), 1.48 (s, 6H).
Example 147: 1 -(5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspironndoline-3,3 '- oxetanel-6-carboxamide
Figure imgf000120_0002
White solid. Yield: 75 mg. HPLC (method 3): Rt = 2.57 min, m/z: [M+H]+ = 432.2 (MW calc. 431.49). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.31 (s, 2H), 8.80 (s, 1 H), 8.59 (d, 1 H, J = 4.7 Hz), 8.41 (s, 1 H), 7.03 (s, 1 H), 7.82 (d, 1 H, J = 7.8 Hz), 7.57 (d, 1 H, J = 7.5 Hz), 7.46 (d, 1 H, J = 3.7 Hz), 5.32 (s, 1 H), 4.90 (d, 2H, J = 5.8 Hz), 4.79 (d, 2H, J = 5.7 Hz), 4.62 (s, 2H), 2.80 (d, 3H, J = 3.2 Hz), 1 .48 (s, 6H).
The following two examples were obtained from compound 22b via TBTU coupling with methylamine (2 M in THF) and 2-aminoethanol, respectively. Example 148: N-Methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanel-6- carboxamide
Figure imgf000121_0001
White solid. Yield: 80 mg. HPLC (method 2): Rt = 1.48 min, m/z: [M+H]+ = 388.1 (MW calc. 387.43). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.29 (s, 2H), 8.79 (s, 1 H), 8.53 (d, 1 H, J = 4.8 Hz), 8.39 (s, 1 H), 7.90 (s, 1 H), 7.81 (d, 1 H, J = 7.7 Hz), 7.56 (d, 1 H, J = 7.6 Hz), 7.20 (d, 1 H, J = 4.4 Hz), 4.89 (d, 2H, J = 5.8 Hz), 4.79 (d, 2H, J = 5.9 Hz), 4.62 (s, 2H), 2.80 (d, 3H, J = 4.0 Hz), 2.32 (s, 3H).
Example 149: N-(2-Hvdroxyethyl)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanel-6- carboxamide
Figure imgf000121_0002
White solid. Yield: 70 mg. HPLC (method 2): Rt = 1.40 min, m/z: [M+H]+ = 418.1 (MW calc. 417.46). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.29 (s, 2H), 8.79 (s, 1 H), 8.53 (d, 1 H, J = 4.6 Hz), 8.38 (s, 1 H), 7.90 (s, 1 H), 7.82 (d, 1 H, J = 7.7 Hz), 7.60 (d, 1 H, J = 7.6 Hz), 7.21 (d, 1 H, J = 4.2 Hz), 4.90 (d, 2H, J = 5.9 Hz), 4.79 (d, 2H, J = 5.8 Hz), 4.74-4.72 (m, 1 H), 4.62 (s, 2H), 3.54-3.51 (m, 2H), 3.35-3.34 (m, 2H), 2.32 (s, 3H).
Example 150: N-(2-Hvdroxyethyl)-1-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro [indoline- 3,3'-oxetanel-6-carboxamide
Figure imgf000121_0003
Prepared from INT-1 analogously to procedures for synthesis example 22. White solid. Yield: 0.1 g. HPLC (method 3): Rt = 2.45 min, m/z: [M+H]+ = 462.3 (MW calc. 461.51 ). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.27 (s, 2H), 8.80 (s, 1 H), 8.59 (d, 1 H, J = 5.1 Hz), 7.99 (s, 1 H), 7.94 (s, 1 H), 7.80 (d, 1 H, J = 7.6 Hz), 7.59 (d, 1 H, J = 7.7 Hz), 7.44 (d, 1 H, J = 4.9 Hz), 4.94-4.89 (m, 3H), 4.81 (d, 2H, J = 6 Hz), 4.64 (s, 2H), 4.36 (s, 1 H), 3.60 (d, 2H, J = 5.1 Hz), 3.43-3.40 (m, 2H), 1.52 (s, 6H).
Example 151 : 1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)spiro[indoline-3,3'- oxetanel-6-carboxamide
Figure imgf000122_0001
TBTU coupling of intermediate 3b with 2-aminoethanol. White solid. Yield: 80 mg. HPLC (method 2): Rt = 1.64 min, m/z: [M+H]+ = 435.08 (MW calc. 434.46). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.84 (s, 2H), 8.76 (s, 1 H), 8.40-8.39 (m, 1 H), 7.81 (d, 1 H, J = 8 Hz), 7.59 (d, 1 H, J = 7.6 Hz), 7.48 (d, 1 H, J = 7.6 Hz), 7.25 (d, 2H, J = 8.4 Hz), 4.89 (d, 2H, J = 6.4 Hz), 4.79-4.72 (m, 3H), 4.60 (s, 2H), 3.54-3.50 (m, 2H), 3.36- 3.34 (m, 2H), 2.35 (s, 3H).
Example 152: (1-(5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl -6- yl)(morpholino)methanone
Figure imgf000122_0002
Prepared from (1-(5-bromopyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)methanone 8b in analogy to example 8. White solid. Yield: 80 mg. HPLC (method 3): Rt = 2.80 min, m/z: [M+H]+ = 488.0 (MW calc. 487.55). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.30 (s, 2H), 8.59-8.58 (m, 1 H), 8.42 (s, 1 H), 8.01 (s, 1 H), 7.82 (d, 1 H, J = 7.6 Hz), 7.46-7.45 (m, 1 H), 7.15-7.13 (m, 1 H), 5.31 (s, 1 H), 4.89 (d, 2H, J = 6.1 Hz), 4.79 (d, 2H, J = 6.0 Hz), 4.62 (s, 2H), 3.67-3.42 (m, 8H), 1.48 (s, 6H). Example 153: 1-(5-(2-Fluorophenyl)pyrimidin-2-viy^
Figure imgf000123_0001
TBTU coupling of lnt-2 and 2-aminoethanol. White solid. Yield: 75 mg. HPLC (method 3): Rt = 2.85 min, m/z: [M+H]+ = 420.9 (MW calc. 420.44). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.86 (s, 2H), 8.76 (s, 1 H), 8.38 (t, 1 H, J = 5.1 Hz), 7.81 (d, 1 H, J = 7.7 Hz), 7.67 (t, 1 H, J = 8 Hz), 7.59 (d, 1 H, J = 7.8 Hz), 7.48-7.43 (m, 1 H), 7.39-7.32 (m, 2H), 4.89 (d, 2H, J = 6 Hz), 4.79 (d, 2H, J = 6 Hz), 4.72 (t, 1 H, J = 5.5 Hz), 4.60 (s, 2H), 3.55-3.50 (m, 2H), 3.35 (t, 2H, J = 5.8 Hz).
Figure imgf000123_0002
lnt-5a) 6'-(Benzylthio)-2,2-dimethylspiro[[1 ,3ldioxane-5,3'-indolinel
Xantphos (3.46 g , 6.04 mmol) and Pd2(dba)3 (2.75 g, 3.02 mmol) were added to a stirred solution of 6'- bromo-2,2-dimethylspiro[[1 ,3]dioxane-5,3'-indoline] (lnt-1 b, 18 g, 60.4 mmol), phenyl-methanethiol (7.0 mL, 60.4 mmol) and DIPEA (21 mL, 120.8 mmol) in dry dioxane (800 mL) that was kept under Ar. The resulting mixture was heated at 120°C for 16 h, then cooled and filtered through a plug of celite. The filtrate was evaporated and the remnant purified by flash column chromatography [silica gel; hexane with 10-15% EtOAc]. White solid. Yield: 18 g (87%). HPLC (method 3): Rt = 3.73 min, m/z: [M+H]+ = 341 .9 (MW calc. 341 .47).
Int-5b) (6-(Benzylthio)indoline-3,3-diyl)dimethanol
2N Hydrochloride solution (304 mL) was added at RT to lnt-5a (18.0 g, 52.7 mmol) in THF (200 mL). The reaction mixture was stirred at this temperature for 3 h, concentrated, basified with sat. NaHC03 solution and extracted with EtOAc (10x 250 mL). The combined organic layers were dried over Na2S04 and evaporated. White solid. Yield: 16 g. HPLC (method 3): Rt = 2.97 min, m/z: [M+H]+ = 302.0 (MW calc. 301.40). lnt-5c) (6-(Benzylthio)-1-(5-bromopyrimidin-2-yl)indoline-3,3-diyl)dimethanol lnt-5b (5.2 g, 17.27 mmol), DIPEA (7.6 mL, 43.18 mmol) and 5-bromo-2-chloro-pyrimidine (4.99 g, 25.9 mmol) in n-butanol (80 mL) were heated in a sealed tube at 130°C for 16 h. The solvent was removed in vacuo and the raw product was purified by flash column chromatography [silica; DCM with 1.5% MeOH]. White solid. Combined yield of three batches of 5.2 g lnt-5b: 18 g (74%). HPLC (method 3): Rt = 3.50 min, m/z: [M+H]+ = 460.0 (MW calc. 458.37).
Int-5d) (6-(Benzylthio)-1-(5-bromopyrimidin-2-yl)-3-(hvdroxymethyl)indolin-3-yl)methyl 4-methyl-benzene- sulfonate
LiHMDS (39.3 mL, 39.30 mmol) was added drop wise over 30 min to a solution of lnt-5c (18 g, 39.30 mmol) in dry THF (2 L) that was stirred at -78°C. The mixture was stirred at this temperature for 30 min followed by slow addition of tosyl chloride (7.7 g, 39.30 mmol) in dry THF (100 mL) at -78°C. The reaction mixture was further stirred for 2 h at this temperature, then quenched with sat. NH4CI solution and extracted with EtOAc (3x 250 mL). The combined organic layers were dried over Na2S04 and concentrated. The residue was purified by flash column chromatography [silica; hexane with 20-25% EtOAc]. White solid. Yield: 15 g (62%). HPLC (method 3): Rt = 2.29 min, m/z: [M+H]+ = 614.2 (MW calc. 612.56).
Int-5e) 6-(Benzylthio)-1-(5-bromopyrimidin-2-yl)spiro[indoline-3,3'-oxetanel
lnt-5d (15 g, 24.5 mmol) and KOH (5.2 g, 95.5 mmol) in t-BuOH (620 mL) were heated at 50°C for 30 min. The reaction mixture was cooled to RT and the solvent was evaporated. The residue was diluted with water (100 mL) and extracted with EtOAc (3x 300 mL). The combined organic layers were dried over Na2S04 and concentrated. White solid. Yield: 8 g (75%). HPLC (method 3): Rt = 4.25 min, m/z: [M+H]+ = 442.2 (MW calc. 440.36). lnt-5g) 1-(5-Bromopyrimidin-2-yl)spironndoline-3,3'-oxetanel-6-sulfonyl chloride (lnt-5)
1 ,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione (3.94 g, 20.45 mmol) was added portion wise at -5°C to a solution of lnt-5e (6 g, 13.63 mmol) in acetonitrile (120 mL), acetic acid (5.5 mL) and water (3.6 mL). The reaction mixture was stirred for 20 min at this temperature, then concentrated under reduced pressure at a temperature below <25°C, diluted with DCM (250 mL) and washed with water (200 mL). The organic layer was dried over Na2S04 and concentrated (temperature <25°C) to yield the target compound as light brown solid that was used without further purification. Yield: 5 g (92%).
Example 154: N-(2-Hvdroxyethyl)-1 -(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methyl- spironndoline-3,3'-oxetanel-6-sulfonamide
Figure imgf000125_0001
154a) 1-(5-Bromopyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-m
TEA (0.5 mL, 3.6 mmol) and 2-methylamino-ethanol (136 mg, 1.8 mmol) were added at 0°C to a solution of sulfonyl chloride lnt-5 (0.5 g, 1.2 mmol) in DCM (10 mL) and the resulting mixture was stirred at RT for 2 h. The reaction mixture was diluted with DCM (20 mL) and washed with sat. NH4CI solution (15 mL) and brine (15 mL). The organic layer was dried over Na2S04 and concentrated. The remnant was purified by flash column chromatography [silica; DCM with 0-0.5% MeOH]. White solid. Yield: 0.3 g (54%). HPLC (method 3): Rt = 3.10 min, m/z: [M+H]+ = 456.5 (MW calc. 455.33). 154b) N-(2-Hvdroxyethyl)-1-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro- nndoline-3,3'-oxetanel-6-sulfonamide
PdCI2(dppf) (26 mg, 0.032 mmol) was added at RT to a solution of 154a) (0.30 g, 0.65 mmol), bis(pinacolato)diboron (0.334 g, 1.3 mmol) and KOAc (0.223 g, 2.27 mmol) in dry dioxane (15 mL) stirred at RT under Ar. The reaction mixture was heated at 90°C for 30 min. 2-(2-Bromopyridin-4-yl)propan-2-ol (0.210 g, 0.97 mmol), 2M K2C03 solution (1.5 mL) and tetrakis(triphenylphosphine)palladium(0) (38 mg, 0.032 mmol) were added successively and the reaction mixture was heated at 90°C for further 16 h. After cooling to RT, the mixture was filtered through a sintered funnel, the filtrate was concentrated and the residue was purified by flash column chromatography [silica; DCM with 1.5% MeOH]. White solid. Yield: 90 mg (27%). HPLC (method 3): Rt = 2.72 min, m/z: [M+H]+ = 512.1 (MW calc. 51 1.59). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.35 (s, 2H), 8.76 (s, 1 H), 8.59 (d, 1 H, J = 4.7 Hz), 8.06 (s, 1 H), 7.98 (d, 1 H, J = 7.7 Hz), 7.51-7.46 (m, 2H), 5.30 (s, 1 H), 4.91 (d, 2H, J = 6 Hz), 4.79 (d, 3H, J = 5.8 Hz), 4.67 (s, 2H), 3.55 (d, 2H, J = 5.2 Hz), 3.05 (s, 2H), 2.78 (s, 3H), 1.49 (s, 6H).
Examples 155 to 158 were prepared analogously to synthesis example 154.
Example 155: N-(2-Hvdroxyethyl)-1-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro [indoline-
3,3'-oxetane1-6-sulfonamide
Figure imgf000126_0001
White solid. Yield: 70 mg. HPLC (method 3): Rt = 2.56 min, m/z: [M+H]+ = 498.2 (MW calc. 497.57). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H), 8.82 (s, 1 H), 8.60 (d,1 H, J = 4.9 Hz), 8.05 (s, 1 H), 7.96 (d, 1 H, J = 7.8 Hz), 7.65 (d, 1 H, J = 5.9 Hz), 7.56 (d, 1 H, J = 6.6 Hz), 7.47 (s, 1 H, J = 4.3 Hz), 5.30 (s, 1 H), 4.91 (d, 2H, J = 5.9 Hz), 4.79 (d, 2H, J = 6 Hz), 4.68 (d, 3H, J = 7.6 Hz), 3.40-3.37 (m, 2H), 2.84-2.81 (m, 2H), 1.49 (s, 6H).
Example 156: N-(2-Hvdroxyethyl)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanel-6- sulfonamide
Figure imgf000126_0002
White solid. Yield: 50 mg. HPLC (method 3): Rt = 2.81 min, m/z: [M+H]+ = 454.1 (MW calc. 453.52). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.31 (s, 2H), 8.80 (s, 1 H), 8.53 (s, 1 H, J = 4.6 Hz), 7.95 (d, 2H, J = 10.4 Hz), 7.66-7.63 (m, 1 H), 7.56 (d, 1 H, J = 7.5 Hz), 7.21 (d, 1 H, J = 4.3 Hz), 4.90 (d, 2H, J = 6 Hz), 4.79 (d, 2H, J = 6 Hz), 4.69-4.64 (m, 3H), 3.42-3.38 (m, 2H,), 2.86-2.83 (m, 2H), 2.39 (s, 3H).
Example 157: N-Methyl-1 -(5-(4-methylpyridin-2-yl)pyrimi
amide
Figure imgf000126_0003
White solid. Yield: 0.1 g. HPLC (method 3): Rt = 3.15 min, m/z: [M+H]+ = 423.8 (MW calc. 423.49). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.27 (s, 2H), 8.81 (s, 1 H), 8.53 (d, 1 H, J = 4.9 Hz), 7.93 (d, 1 H, J = 7.6 Hz), 7.84 (s, 1 H), 7.56 (d, 1 H, J = 7.8 Hz), 7.19 (d, 1 H, J = 4.7 Hz), 7.13 (s, 1 H), 4.91 (d, 2H, J = 6 Hz), 4.81 (d, 2H, J = 6 Hz), 4.67 (s, 2H), 2.54 (s, 3H), 2.41 (s, 3H).
Example 158: 1 -(5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspironndoline-3,3'- oxetanel-6-sulfonamide
Figure imgf000127_0001
White solid. Yield: 80 mg. HPLC (method 2): Rt = 1.60 min, m/z: [M+H]+ = 468.2 (MW calc. 467.54). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.33 (s, 2H), 8.81 (s, 1 H), 8.60 (d, 1 H, J = 4.5 Hz), 8.05 (s, 1 H), 7.97 (d, 1 H, J = 7.6 Hz), 7.54-7.47 (m, 3H), 5.30 (s, 1 H), 4.91 (d, 2H, J = 5.7 Hz), 4.79 (d, 2H, J = 5.6 Hz), 4.66 (s, 2H), 2.46 (d, 3H, J = 4.4 Hz), 1.49 (s, 6H).
Example 159 and 160: 6-(Ethylsulfinyl)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-
Figure imgf000127_0002
The racemic sulfoxide was prepared from intermediate 52h in analogy to synthesis example 56. The two enantiomers were obtained from this racemate through preparative chiral HPLC.
Faster eluting enantiomer (example 159): Yield = 1 10 mg. White solid. MS: m/z: [M+H]+ = 470.3. Specific optical rotation: [a]589 25 = - 157.34° (c. 0.2860, CHCI3). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.30 (s, 2H), 8.60 (s, 1 H), 8.52 (d, 1 H, J = 4.8Hz), 7.93 (d, 2H, J = 7.5Hz), 7.35 (d, 1 H, J = 7.6Hz), 7.21 (d, 1 H, J = 4.4Hz), 4.89 (d, 2H, J = 6.0Hz), 4.78 (d, 2H, J = 5.8Hz), 4.65 (s, 2H), 3.04-2.98 (m, 1 H), 2.80-2.74 (m, 1 H), 2.39 (s, 3H), 1.08 (t, 3H, J = 7.2Hz). Chiral HPLC: Rt = 5.68 min (Chiralpak IA column (250 mm x 4.6 mm, 5 μιη) and hexane/DCM/EtOH/diethylamine (50/25/25/0.1 ) as mobile phase; flow rate = 1.0 ml/min). Slower eluting enantiomer (example 160): Yield = 122 mg. White solid. MS: m/z: [M+H]+ = 470.2. Specific optical rotation: [a]589 25 = +140.81 ° (c. 0.2784, CHCI3). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.30 (s, 2H), 8.60 (s, 1 H), 8.52 (d, 1 H, J = 4.8 Hz), 7.93 (d, 2H, J = 6.8Hz), 7.35 (d, 1 H, J = 7.5Hz), 7.21 (d, 1 H, J = 4.6Hz), 4.89 (d, 2H, J = 6.1 Hz), 4.78 (d, 2H, J = 5.5Hz), 4.65 (s, 2H), 3.04-2.98 (m, 1 H), 2.80-2.75 (m, 1 H), 2.39 (s, 3H), 1 .08 (t, 3H, J = 7.2Hz). Chiral HPLC: Rt = 8.1 1 min (same conditions as for peak 1 ).
Example 161 and 162: 6-(Ethylsulfinyl)-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanel (faster
Figure imgf000128_0001
The racemic sulfoxide was prepared from intermediate 52h in analogy to synthesis example 56. The two enantiomers were obtained from this racemate through preparative chiral HPLC.
Faster eluting enantiomer (example 161 ): Yield = 80 mg. White solid. MS: m/z: [M+H]+ = 393.0. 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2H), 8.68 (s, 1 H), 8.60 (s, 1 H), 8.06 (d, 1 H, J = 7.6 Hz), 7.94-7.88 (m, 2H), 7.36-7.36 (m, 2H), 4.90 (d, 2H, J = 5.8 Hz), 4.79 (d, 2H, J = 4.8 Hz), 4.65 (s, 2H), 3.04-2.98 (q, 1 H), 2.80-2.75 (q, 1 H), 1.08 (t, 3H, J = 7.2 Hz). Chiral HPLC: Rt = 5.85 min (column: Chiralpak IA (250 mm x 4.6 mm, 5 μιη); mobile phase: hexane/DCM/EtOH/diethylamine = 50/25/25/0.1 ; flow rate = 1.0 ml/min).
Slower eluting enantiomer (example 162): Yield = 80 mg. White solid. MS: m/z: [M+H]+ = 392.9. 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2H), 8.68 (d, 1 H, J = 4 Hz), 8.60 (s, 1 H), 8.06 (d, 1 H, J = 8 Hz), 7.94-7.88 (m, 2H), 7.36 (t, 2H, J = 7.7 Hz), 4.90 (d, 2H, J = 6 Hz), 4.79 (d, 2H, J = 5.4 Hz), 4.65 (s, 2H), 3.00 (t, 1 H, J = 6.6 Hz), 2.78 (t, 1 H, J = 7.2 Hz), 1 .08 (t, 3H, J = 7.1 Hz). Chiral HPLC: Rt = 8.95 min (same analytical method as for other enantiomer).
Figure imgf000128_0002
The racemic sulfoxide was prepared from intermediate 52h in analogy to synthesis example 56 and then oxidized with MMPP (see example 57). White solid. Yield: 0.08 g. HPLC (method 3): Rt = 3.07 min., m/z: [M+H]+ = 409.1 (MW calc. 408.47). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2H), 8.82 (s, 1 H), 8.68 (d, 1 H, J = 4.3 Hz), 8.09 (d, 1 H, J = 7.8 Hz), 8.03 (d, 1 H, J = 7.7 Hz), 7.91 (t, 1 H, J = 7.5 Hz), 7.64 (d, 1 H, J = 7.2 Hz), 7.38 (t, 1 H, J = 5.3 Hz), 4.91 (d, 2H, J = 6.2 Hz), 4.79 (d, 2H, J = 6.1 Hz), 4.67 (s, 2H), 3.32-3.26 (m, 2H), 1.15 (t, 3H, J = 7.2 Hz).
Example 164 and 165: 2-(6-(2-(6-(Ethylsulfinyl)spironndoline-3,3'-oxetanl-1^
Figure imgf000129_0001
The racemic sulfoxide was prepared from intermediate 52h in analogy to synthesis example 56. The two enantiomers were obtained from this racemate through preparative chiral HPLC.
Faster eluting enantiomer (example 164): Yield = 1 15 mg. White solid. HPLC (method 3): Rt = 1 .62 min, m/z: [M+H]+ = 451.02 (MW calc. 450.55). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.36 (s, 2H), 8.62 (s, 1 H), 7.93 (d, 1 H, J = 7.2 Hz), 7.88 (s, 2H), 7.61 (bs, 1 H), 7.35 (d, 1 H, J = 8.1 Hz), 5.27 (s, 1 H), 4.89 (d, 2H, J = 6.0 Hz), 4.80 (bs, 2H), 4.65 (s, 2H), 3.02-3.00 (m, 1 H), 2.78 (bs, 1 H), 1.51 (s, 6H), 1 .08 (t, 3H, J = 7.2 Hz). Chiral HPLC: Rt = 6.34 min (column: Chiralpak IA 250 mm x 4.6 mm, 5 μιη; mobile phase: hexane/DCM/EtOH/diethylamine = 50/25/25/0.1 ; flow rate = 1.0 ml/min). Specific optical rotation: [a]589 25 = -130.6° (c. 0.2588, CHCI3).
Slower eluting enantiomer (example 165): Yield = 1 10 mg. White solid. HPLC (method 3): Rt = 1.62 min, m/z: [M+H]+ = 451.02 (MW calc. 450.55). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.36 (s, 2H), 8.62 (s, 1 H), 7.93 (d, 1 H, J = 7.2 Hz), 7.88 (s, 2H), 7.61 (bs, 1 H), 7.35 (d, 1 H, J = 8.1 Hz), 7.43-7.40 (m, 1 H), 5.28 (s, 1 H), 4.89 (d, 2H, J = 6.0 Hz), 4.80 (d, 2H, J = 4.8 Hz), 4.65 (s, 2H), 3.02-2.99 (m, 1 H), 2.80-2.75 (m, 1 H), 1.51 (s, 6H), 1.08 (t, 3H, J = 7.2 Hz). Chiral HPLC: Rt = 8.63 min (column: Chiralpak IA 250 mm x 4.6 mm, 5 μιη; mobile phase: hexane/DCM/EtOH/diethylamine = 50/25/25/0.1 ; flow rate = 1.0 ml/min). Specific optical rotation: [a]589 25 = +129.9° (c. 0.2832, CHCI3).
Example 166: 2-(6-(2-(6-(Ethylsulfonyl)spiro[indoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)pyridin-2-yl)propan-2- ol
Figure imgf000130_0001
Prepared in analogy to example 56. White solid. Yield: 400 mg. HPLC (method 3): Rt = 3.15 min, m/z: [M+H]+ = 467.1 (MW calc. 466.55). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.39 (s, 2H), 8.83 (s, 1 H), 8.02 (d, 1 H, J = 7.7 Hz), 7.89-7.85 (m, 2H), 7.62 (t, 2H, J = 6.3 Hz), 5.28 (s, 1 H), 4.91 (d, 2H, J = 5.9 Hz), 4.80 (d, 2H, J = 6.0 Hz), 4.67 (s, 2H), 3.32-3.28 (m, 2H), 1.51 (s, 6H), 1.15 (t, 3H, J = 7.0 Hz).
Example 167 and 168: 2-((1-(5-(Pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl)sulfinyl)ethanol
Figure imgf000130_0002
The racemic sulfoxide was prepared from lnt-3 in analogy to example 1 16. Subsequent preparative chiral HPLC provided the single enantiomers.
Faster eluting enantiomer (example 167): Yield = 80 mg. White solid. Mass spectroscopy: m/z: [M+H]+ = 409.4. 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2 H), 8.68 (d, 1 H, J = 4.5 Hz), 8.63 (d, 1 H, J = 0.7 Hz), 8.06 (d, 1 H, J = 8 Hz), 7.95-7.88 (m, 2H), 7.39-7.35 (m, 2H), 5.09 (t, 1 H, J = 4.8 Hz), 4.90 (d, 2H, J = 6.2 Hz), 4.79 (d, 2H, J = 5.9 Hz), 4.65 (s, 2H), 3.85-3.81 (m, 1 H), 3.70-3.66 (m, 1 H), 3.01 -2.95 (m, 1 H), 2.91 -2.87 (m, 1 H). Chiral HPLC: Rt = 7.24 min (column: Chiralpak IA (250 mm x 4.6 mm, 5 μιη); mobile phase: hexane/DCM/EtOH/diethylamine = 50/25/25/0.1 ; flow rate = 1.0 ml/min).
Slower eluting enantiomer (example 168): Yield = 81 mg. White solid. Mass spectroscopy: m/z: [M+H]+ = 409.2. 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2 H), 8.68 (d, 1 H, J = 4.3 Hz), 8.63 (s, 1 H), 8.06 (d, 1 H, J = 7.9 Hz), 7.95-7.88 (m, 2H), 7.39-7.35 (m, 2H), 5.09 (t, 1 H, J = 4.8 Hz), 4.90 (d, 2H, J = 6.2 Hz), 4.79 (d, 2H, J = 6.2 Hz), 4.65 (s, 2H), 3.86-3.81 (m, 1 H), 3.70-3.66 (m, 1 H), 3.01-2.95 (m, 1 H), 2.90-2.86 (m, 1 H). Chiral HPLC: Rt = 19.18 min (same analytical method as for other enantiomer).
Example 169: 2-((1-(5-(Pyridin-2-yl)pyrimidin-2-yl)spironndoline-3,3'-oxetanl-6-yl)sulfonyl)ethanol
Figure imgf000131_0001
Obtained from 6-((2-((te rt-butyldiphenylsilyl)oxy)ethyl)thio)-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro
3,3'-oxetane] in two steps comprising an oxidation with MMPP (example 57) and a protecting group removal (procedure 1 16b). Yield: 0.09 g. HPLC (method 3): Rt = 2.63 min, m/z: [M+H]+ = 425.1 (MW calc. 424.47). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.35 (s, 2 H), 8.83 (d, 1 H, J = 1 .3 Hz), 8.68 (d, 1 H, J = 4.4 Hz), 8.09 (d, 1 H, J = 8 Hz), 8.01 (d, 1 H, J = 7.8 Hz), 7.91 (t, 1 H, J = 7.7 Hz), 7.66-7.63 (m, 1 H), 7.39- 7.36 (m, 1 H), 4.90 (t, 3H, J = 5.5 Hz), 4.79 (d, 2H, J = 6.2 Hz), 4.67 (s, 2H), 3.74-3.69 (m, 2H), 3.45 (t, 2H, J = 6.4 Hz). Example 170: 2-(2-(2-(6-(Ethylsulfinyl)spiro[indoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2- amine
Figure imgf000131_0002
Prepared in two steps from compound 52h and 2-(2-bromopyridin-4-yl)propan-2-amine analogously to synthesis example 56. Brown solid. Yield: 40 mg. HPLC (method 2): Rt = 1 .33 min, m/z: [M+H]+ = 450.1 (MW calc. 449.57). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.31 (s, 2H), 8.64 (s, 1 H), 8.57 (d, 1 H, J = 3.9 Hz), 8.10 (s, 1 H), 7.93 (d, 1 H, J = 7.4 Hz), 7.47 (s, 1 H), 7.37 (d, 1 H, J =8 Hz), 4.91 -4.80 (m, 4H), 4.67 (s, 2H), 2.82-2.77 (m, 1 H), 2.82 (m, 1 H, merged with DMSO-water signal), 1.47 (s, 6H), 1 .16 (t, 3H, J = 7.3 Hz). Example 171 : 2-(2-(2-(6-(Ethylsulfonyl)spiro[indoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2- amine
Figure imgf000132_0001
MMPP oxidation of the corresponding thioether (example 170). White solid. Yield: 60 mg. HPLC (method 3): Rt = 2.55 min, m/z: [M+H]+ = 466.1 (MW calc. 465.57). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.38 (s, 2H), 8.84 (d, 1 H, J = 1.4 Hz), 8.57 (d, 1 H, J = 5.2 Hz), 8.18 (s, 1 H), 8.03 (d, 1 H, J = 7.8 Hz), 7.64-7.61 (m, 1 H), 7.50-7.48 (m, 1 H), 4.92 (d, 2H, J = 6.2 Hz), 4.80 (d, 2H, J = 6.2 Hz), 4.67 (s, 2H), 3.31-3.26 (m, 2H), 2.27 (bs, 2H), 1.41 (s, 6H), 1.17 (t, 3H, J = 7.3 Hz).
Figure imgf000132_0002
Prepared from compound 52h and 2-bromoisonicotinamide analogously to synthesis example 56. White solid. Yield: 0.10 g. HPLC (method 2): Rt = 1.46 min, m/z: [M+H]+ = 436.2 (MW calc. 435.50). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.35 (s, 2H), 8.80 (d, 1 H, J = 5 Hz), 8.63 (s, 1 H), 8.40 (s, 1 H), 8.27 (s, 1 H), 7.94 (d, 1 H, J = 7.7 Hz), 7.81 (s, 1 H), 7.73 (d, 1 H, J = 4.9 Hz), 7.37 (t, 1 H, J = 7.7 Hz), 4.90 (d, 2H, J = 6.1 Hz), 4.80 (d, 2H, J = 6 Hz), 4.66 (s, 2H), 3.06-2.97 (m, 1 H), 2.82-2.73 (m, 1 H), 1.10 (t, 3H, J = 7.2 Hz).
Figure imgf000133_0001
mCPBA oxidation of the corresponding thioether. White solid. Yield: 0.15 g. HPLC (method 2): Rt = 1.47 min, m/z: [M+H]+ = 452.2 (MW calc. 451.50). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.38 (s, 2H), 8.84- 8.79 (m, 2H), 8.43 (s, 1 H), 8.27 (s, 1 H), 8.03 (d, 1 H, J = 7.8 Hz), 7.81 (s, 1 H), 7.73 (t, 1 H, J = 0.7 Hz), 7.65-7.62 (m, 1 H), 4.92 (d, 2H, J = 6.2 Hz), 4.80 (d, 2H, J = 6.2 Hz), 4.68 (s, 2H), 3.31-3.26 (m, 2H), 1.17 (t, 3H, J = 7.2 Hz).
Examples 174 and 175 were prepared from methyl 1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline- 3,3'-oxetane]-6-carboxylate in analogy to synthesis example 22.
Example 174: 2-(2-(6-(Morpholine-4-carbonyl)spironndoline-3,3'-oxetanl-1 -yl)pyrimidin-5-yl) isonicotin- amide
Figure imgf000133_0002
White solid. Yield: 40 mg. HPLC (method 3): Rt = 2.38 min, m/z: [M+H]+ = 473.2 (MW calc. 472.50). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.33 (s, 2H), 8.80 (d, 1 H, J = 5 Hz), 8.42 (s, 1 H), 8.37 (s, 1 H), 8.28 (s, 1 H), 7.83 (t, 2H, J = 3.5 Hz), 7.73 (t, 1 H, J = 0.8 Hz), 7.17 (t, 1 H, J = 7.6 Hz), 4.90 (d, 2H, J = 6.1 Hz), 4.79 (d, 2H, J = 6.1 Hz), 4.63 (s, 2H), 3.63-3.41 (m, 8H). Example 175: 1 -(5-(4-Carbamoylpyridin-2-yl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro [indoline-
3,3'-oxetanel-6-carboxamide
Figure imgf000134_0001
White solid. Yield: 30 mg. HPLC (method 2): Rt = 1.40 min, m/z: [M+H]+ = 461.1 (MW calc. 460.49). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2H), 8.80 (d, 1 H, J = 4.9 Hz), 8.40-8.36 (m, 2H), 8.27 (s, 1 H), 7.80 (bs, 2H), 7.72 (d, 1 H, J = 4.6 Hz), 7.15 (d, 1 H, J = 7.6 Hz), 4.90 (d, 2H J = 6 Hz), 4.80 (d, 3H, J = 6 Hz), 4.64 (s, 2H), 3.64-3.31 (m, 4H), 3.01 (s, 3H).
Example 176: 2-(2-(6-(Morpholine-4-carbonyl)spiro[indoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)iso- nicotinonitrile
Figure imgf000134_0002
Synthesized from intermediate 8b analogously to procedure 8c. White solid. Yield: 40 mg. HPLC (method 2): Rt = 1.62 min, m/z: [M+H]+ = 455.3 (MW calc. 454.48). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.35 (s, 2H), 8.91 (d, 1 H, J = 4.7 Hz), 8.54 (s, 1 H), 8.41 (s, 1 H), 7.83-7.81 (m, 2H), 7.18 (d, 1 H, J = 7.3 Hz), 4.89 (d, 2H, J = 5.7 Hz), 4.79 (d, 2H, J = 5.8 Hz), 4.63 (s, 2H), 3.63-3.38 (m, 8H). Example 177: 1 -(5-(4-Cvanopyridin-2-yl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro [indoline-3,31- oxetanel-6-carboxamide
Figure imgf000135_0001
Synthesized from rom 1-(5-bromopyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3'-oxetane]- 6-carboxamide in analogy to procedure 8c. White solid. Yield: 45 mg. HPLC (method 3): Rt = 2.66 min, m/z: [M+H]+ = 443.2 (MW calc. 442.47). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H), 8.90 (d, 1 H, J = 4.8 Hz), 8.51 (s, 1 H), 8.38 (s, 1 H), 7.81 -7.80 (m, 2H), 7.16 (d, 1 H, J = 7.5 Hz), 4.89 (d, 2H, J = 6 Hz), 4.79 (d, 2H, J = 6 Hz), 4.63 (s, 2H), 3.65-3.53 (m, 4H, one proton merged with DMSO-water signal), 3.01 (s, 3H).
Example 178: N-(2-Hvdroxyethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-2',3',5',6'-tetrahvdro-
Figure imgf000135_0002
178a) 6-Bromo-2',3',5',6'-tetrahvdrospiro[indoline-3,4'-pyranl-2-one
n-BuLi (2M in hexane, 22.6 mL, 45.27 mmol) was added drop wise at -40°C to a solution of 6-bromo- indolin-2-one (3 g, 14.14 mmol) and diisopropylamine (6.3 mL, 45.27 mmol) in THF (60 mL). The mixture was stirred for 45 min at -40°C, 1-bromo-2-(2-bromoethoxy)ethane was added drop wise at this temperature and stirring was continued at RT for 16 h. The reaction mixture was quenched with 4N hydrogen chloride solution (40 mL) and the aqueous phase was separated and extracted with EtOAc (3x 60 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04 and concentrated. The raw product was triturated with hexane (20 mL) and filtered. The filter was washed with hexane/EtOAc = 4:1 (100 mL) affording the target compound as light brown solid. Yield: 1.2 g (31 %). HPLC (method 1 ): Rt = 2.94 min, m/z [M+H]+ = 282.1 (MW calc. 282.13).
178b) 6-Bromo-2',3',5',6'-tetrahydrospironndoline-3,4'-pyranl
LiAIH4 (0.54 g, 14.18 mmol) was added portion wise at 0°C to a solution of 178a (1.6 g, 5.67 mmol) in THF (500 mL). The reaction mixture was heated at 80°C for 4 h, cooled, then sequentially quenched with water (0.54 mL), 20% NaOH solution (0.54 mL) and water (1.08 mL) and stirred for 1 h at RT. The mixture was filtered through a plug of celite and the filter was rinsed with DCM/MeOH = 4: 1 (3x 50 mL). The filtrate was evaporated and the residue was purified by flash column chromatography [silica gel; hexane /EtOAc 4:1 ]. Light yellow solid. Yield: 1.1 g (73%). HPLC (method 1 ): Rt = 3.27 min, m/z [M+H]+ = 270.2 (MW calc. 268.15).
178c) Methyl 2',3',5',6'-tetrahvdrospironndoline-3,4'-pyran1-6-carboxylate
Compound 178b (0.82 g, 3.06 mmol) and TEA (0.93 mL, 6.73 mmol) in MeOH (25 mL) and DMF (15 mL) were placed in an autoclave under an inert atmosphere. PdCI2(dppf) (0.22 g, 0.305 mmol) was added and the autoclave was pressurized to 250 psi with carbon monoxide gas. The mixture was stirred at 100°C for 16h, cooled and filtered through a plug of celite. The filter was rinsed with MeOH and the filtrate was concentrated and then diluted with EtOAc. The organic phase was washed with water and brine, dried and evaporated. Flash column chromatography (silica; hexane/EtOAc = 7:3] of the residue afforded the product as light yellow solid. Yield: 0.5 g (66%). HPLC (method 5): Rt = 1.44 min, m/z [M+H]+ = 248.08 (MW calc. 247.29).
178d) Methyl 1-(5-bromopyrimidin-2-yl)-2',3',5',6'-tetrahvdrospironndoline-3,4'-pyran1-6-carboxylate
Compound 178c (0.4 g, 1.62 mmol), 5-bromo-2-chloro-pyrimidine (0.62 g, 3.24 mmol) and DIPEA (1.4 mL, 8.09 mmol) in n-butanol (10 mL) were stirred at 140°C for 20h. The reaction mixture was cooled and diluted with ice. The precipitate was filtered off, washed with diethyl ether (50 mL) and then purified by flash column chromatography [silica gel; hexane/EtOAc = 4: 1]. Light yellow solid. Yield: 0.44 g (67%). HPLC (method 1 ): Rt = 3.74 min, m/z [M+H]+ = 404.0 (MW calc. 404.26).
Intermediate 178d was reacted with 2-bromo-4-methylpyridine and then further converted into synthesis example 178 in analogy to the protocols of example 2. Light yellow solid. Yield: 85 mg. HPLC (method 1 ): Rt = 2.81 min, m/z: [M+H]+ = 460.2 (MW calc.459.54). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.23 (s, 2H), 8.52 (d, 1 H, J= 4.8 Hz), 8.43 (s, 1 H), 7.78 (s, 1 H), 7.36 (d, 1 H, J = 7.4 Hz), 7.17 (d, 1 H, J = 4.5 Hz), 7.04 (d, 1 H, J = 7.6 Hz), 4.41 (bs, 1 H), 4.31 (s, 2H), 3.94-3.92 (m, 2H), 3.65-3.59 (m, 4H), 3.46 (bs, 2H), 3.02 (s, 3H), 2.40 (s, 3H), 2.03-1.97 (m, 2H), 1 .67-1.63 (m, 2H). Example 179: 2-(4-Fluoro-3-(2-(6-(1-(methylamino)cvclopropyl)spiro[indoline-3,3'-oxetan1-1-yl) pyrimidin- 5-yl)phenyl)propan-2-ol
Figure imgf000136_0001
179a) 1 '-tert-Butyl 6'-methyl 2,2-dimethylspiro[[1 ,31dioxane-5,3'-indoline1-1 ',6'-dicarboxylate A solution of lnt-1 c (500 mg, 1 .81 mmol), di-tert-butyl dicarbonate (669 mg, 3.07 mmol) and TEA (0.8 ml, 5.42 mmol) in dry THF (10 ml) was stirred at RT for 16 h. The reaction mixture was concentrated and the residue purified by flash column chromatography [silica, EtOAc/hexane = 1 :9] followed by triturating with hexane. White solid. Yield: 500 mg (73%). HPLC (method 1 ): Rt = 3.42 min, m/z: [M+H]+ = 378.4 (MW calc. 377.43).
179b) tert-Butyl 6'-(1-hvdroxycvclopropyl)-2,2-dimethylspiro[[1 ,3ldioxane-5,3'-indolinel-1 '-carboxylate Ethyl magnesium bromide (1.06 ml, 3.183 mmol) was slowly added at -78°C to a stirred solution of Ti(Oi- Pr)4 (0.5 ml, 1.59 mmol) in diethyl ether (10 ml) and stirring was continued at this temperature for 1 h. 179a (300 mg, 0.795 mmol) dissolved in diethyl ether (5 ml) was slowly added and the reaction mixture was warmed to RT and stirred for 1 h. The mixture was cooled to 0°C, quenched with saturated NH4CI solution, stirred for 10 min. and extracted with EtOAc (3x 50 ml). The combined organic layers were washed with brine (40 ml), dried over Na2S04 and concentrated. The remnant was purified by column chromatography [230-400 mesh silica gel, EtOAc/hexane = 1 :4]. White solid. Yield: 173 mg (58%).
179c) tert-Butyl 6'-(1-(1 ,3-dioxoisoindolin-2-yl)cvclopropyl)-2,2-dimethylspiro[[1 ,31dioxane-5,3'-indoline1-1 '- carboxylate
Compound 179b (22 g, 58.67 mmol), triphenylphosphine (16.9 g, 64.53 mmol), phthalimide (9.48 g, 64.53 mmol) and diethyl azodicarboxylate (1 1.3 g 64.53 mmol) in THF were stirred at 80°C for 16 h under an inert atmosphere. The reaction mixture was diluted with EtOAc (1000 ml), washed with water (500 ml) and brine (500 ml), dried over Na2S04 and concentrated. The residue was purified by column chromatography [240-400 mesh silica gel, EtOAc/ hexane = 15:85]. White solid. Yield: 17.1 g (58%). HPLC (method 1 ): Rt = 3.92 min, m/z: [M+H]+ = 378.4 (MW calc. 377.43). 179d) tert-Butyl 6'-(1-aminocvclopropyl)-2,2-dimethylspiro[[1 ,31dioxane-5,3'-indoline1-1 '-carboxylate
Compound 179c (1 g, 1 .984 mmol) and hydrazine hydrate (1 ml) in ethanol (20 ml) were stirred at 60°C for 2 h. The reaction mixture was concentrated and the remnant was purified by column chromatography [240-400 mesh silica gel, DCM with 2% MeOH]. Yield: 500 mg (67%). HPLC (method 1 ): Rt = 3.20 min, m/z: [M+H]+ = 375.0 (MW calc. 374.47).
179e) tert-Butyl 6'-(1-(((benzyloxy)carbonyl)amino)cvclopropyl)-2,2-dimethylspiro[[1 ,31dioxane-5,3'- indolinel-1 '-carboxylate
Compound 179d (10 g, 33.3 mmol) in THF (1 10 ml) was cooled to 0°C, DIPEA (18 ml, 99.9 mmol) and benzyl chloroformate (7.1 ml, 49.99 mmol) were added and the mixture was stirred for 16 h at RT. The reaction mixture was diluted with EtOAc (500 ml), washed with saturated NaHC03 solution (200 ml), water (200 ml) and brine (200 ml), dried over Na2S04 and concentrated. The raw product was purified by column chromatography [100-200 mesh silica gel, EtOAc/hexane = 1 :3]. White solid. Yield: 5.3 g (31 %). HPLC (method 1 ): Rt = 3.72 min, m/z: [M+H]+ = 509.4 (MW calc. 508.61 ). 179f) tert-Butyl 6'-(1-(((benzyloxy)carbonyl)(methyl)amino)cvclopropyl)-2,2-dimethylspiro [[1 ,31dioxane- 5, 3'-indoline1-1 '-carboxylate NaHe (50%, 751 mg, 15.64 mmol) was added portion wise at 0°C to a stirred solution of compound 179e (5.3 g, 10.43 mmol) in DMF (50 ml). Stirring was continued for 20 min, methyl iodide (2.0 ml, 31 .28 mmol) was added and the mixture was further stirred for 2 h. The reaction mixture was quenched with ice and extracted with EtOAc (3x 200 ml). The combined organic layers were washed with water (3x 200 ml) and brine (250 ml), dried over Na2S04 and concentrated. The raw product was purified by column chromatography [100-200 mesh silica gel, EtOAc/hexane = 1 :4]. White solid. Yield: 5.31g (97%). HPLC (method 1 ): Rt = 4.55 min., m/z: [M+H]+ = 523.6 (MW calc. 522.63).
179g) tert-Butyl 6-(1-(((benzyloxy)carbonyl)(methyl)amino)cvclopropyl)-3,3-bis(hvdroxymethyl) indoline-1- carboxylate
Compound 179f (5.9 g, 1 1.302 mmol) in THF (50 ml) was stirred in the presence of 2N hydrogen chloride solution (12 ml) at RT for 2 h. The reaction mixture was concentrated, basified with saturated NaHC03 solution and extracted with EtOAc (10 x 50 ml). The combined organic layers were dried over Na2S04 and evaporated. Light brown solid. Yield: 5.1g (94%). HPLC (method 1 ): Rt = 3.26 min, m/z: [M+H]+ = 483.2 (MW calc. 482.57).
179h) tert-Butyl 6-(1-(((benzyloxy)carbonyl)(methyl)amino)cvclopropyl)-3-(hvdroxymethyl)-3-((tosyloxy)- methyl)indoline-1 -carboxylate
LiHMDS (10.3 mL, 10.37 mmol) was added drop wise at -78°C over a time period of 30 min to a solution of compound 179i (5.0 g, 10.37 mmol) in dry THF (100 ml). The reaction mixture was stirred at this temperature for 30 min followed by addition of tosylchloride (1.98 g, 10.37 mmol) in dry THF (50 ml). After stirring for further 2 h at -78°C, the reaction mixture was quenched with saturated NH4CI solution (100 ml) and extracted with EtOAc (3x 100 ml). The combined organic layers were dried over Na2S04 and concentrated. The remnant was purified by flash column chromatography [230-400 mesh silica, hexane with 15-40% EtOAc]. White solid. Yield: 3.6 g (55%). HPLC (method 1 ): Rt = 2.17 min, m/z: [M+18]+ = 654.3 (MW calc. 636.76).
179i) tert-Butyl 6-(1-(((benzyloxy)carbonyl)(methyl)amino)cvclopropyl)spironndoline-3,3'-oxetane1 -1- carboxylate
Compound 179h (3.6g, 5.65 mmol) and KOH (950 mg, 16.96 mmol) in tert-butanol (150 ml) were stirred at 80°C for 30 min. The reaction mixture was cooled to RT and the solvent was distilled off under reduced pressure. The residue was diluted with water (50 ml) and extracted with EtOAc (3x 50 ml). The combined organic layers were dried over Na2S04 and concentrated. The raw product thus obtained was triturated with ether providing the target compound as white solid. Yield: 2.2 g (83%). HPLC (method 2): Rt = 1.79 min, m/z: [M+18]+ = 465.21 (MW calc. 464.55).
179j) Benzyl methyl(1-(spiro[indoline-3,3'-oxetan1-6-yl)cvclopropyl)carbamate
TFA (5 ml) was added at 0°C to compound 179i (2.2 g, 4.739 mmol) in DCM (25 ml) and the resulting mixture was stirred at RT for 3h. The volatile matter was removed under reduced pressure and the residue was washed with diethyl ether. White solid. Yield: 1.6 g (93%). HPLC (method 1 ): Rt = 3.24 min, m/z: [M+H]+ = 365.1 (MW calc. 364.44). 179k) Benzyl (1-(1-(5-bromopyrimidin-2-yl)spironn^ carbamate Compound 179j (1 .6 g, 4.39 mmol), 5-bromo-2-chloropyrimidine (1.25 g, 6.59 mmol) and DIPEA (5.4 ml, 30.73 mmol) in n-butanol (20 ml) were stirred in a sealed tube at 140°C for 20 h. The reaction mixture was cooled to RT and the precipitate was filtered off and washed with hexane (2x 100 ml) and water (100 ml). Light yellow solid. Yield: 1 .2 g (52%). HPLC (method 1 ): Rt = 3.91 min, m/z: [M+H]+ = 521 (MW calc. 521.41 ).
1791) Benzyl methyl(1-(1-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)spiro [indoline-3,31- oxetanl-6-yl)cvclopropyl)carbamate
Potassium acetate (56.4 mg, 0.575 mmol) and bis(pinacolato)diboron (97.2 mg, 0.384 mmol) were added to compound 179k (100 mg, 0.192 mmol) in dioxane (10 ml). PdCI2(dppf) (7.8 mg, 0.010 mmol) was added under Ar and the reaction mixture was refluxed for 16 h. The volatile parts were removed under reduced pressure and the residue was used in the next step without further purification. Yield: 109 mg. HPLC (method 1 ): Rt = 4.75 min, m/z: [M+H]+ = 569.4 (MW calc. 568.47).
179m) Benzyl (1-(1-(5-(2-fluoro-5-(2-hvdroxypropan-2-yl)phenyl)pyrimidin-2-yl)spironndoline-3,3'-oxetanl- 6-yl)cvclopropyl)(methyl)carbamate
Tetrakis(triphenylphosphine)palladium(0) (1 1.1 mg, 0.010 mmol) was added to a suspension of compound 1791 (109 mg, 0.192 mmol), 2-(3-bromo-4-fluorophenyl)propan-2-ol (66.7 mg, 0.288 mmol) and 20% K2C03 solution (2 ml) in 1 ,4-dioxane (20 ml) kept under an inert atmosphere. The reaction mixture was stirred for 16 h at 100°C, then cooled to RT and filtered through a plug of celite. The filtrate was concentrated under reduced pressure and the residue was dissolved in EtOAc (50 ml) and washed with water (2x 20 ml) and brine (20 ml). The organic phase was dried over anhydrous Na2S04 and evaporated. The raw product was purified by column chromatography [230-400 mesh silica gel; DCM with 5% MeOH]. White solid. Yield: 109 mg (95%). HPLC (method 1 ): Rt = 3.71 min., m/z: [M+H]+ = 595.2 (MW calc. 594.68).
179n) 2-(4-Fluoro-3-(2-(6-(1-(methylamino)cvclopropyl)spiro[indoline-3,3'-oxetanl-1-yl)pyrimidin-5-yl)- phenyl)propan-2-ol
A solution of compound 179m (200 mg, 0.337 mmol) in ethanol was stirred at RT and in the presence of Pearlman's catalyst (100 mg) for 1 h under H2 atmosphere. The catalyst was removed by filtration and the filter was rinsed with EtOH. The filtrate was concentrated and the raw product was purified by column chromatography [230-400 mesh silica, DCM with 2% MeOH]. White solid. Yield: 22 mg. HPLC (method 1 ): Rt = 2.95 min, m/z: [M+H]+ = 461 (MW calc. 460.54). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.83 (s, 2H), 8.33 (s, 2H), 7.66 (t, J = 8.1 Hz, 1 H), 7.51 (bs, 1 H), 7.26 (t, J = 9.0 Hz, 1 H), 7.12 (d, J = 7.7 Hz, 1 H), 4.30 (s, 2H), 5.13 (s, 1 H), 4.85 (d, J = 5.2 Hz, 1 H), 4.77 (d, J = 5.2 Hz, 1 H), 4.56 (s, 1 H), 2.17 (s, 3H), 1.47 (s, 5H), 0.90-0.85 (m, 4H). Examples 180 and 181 were prepared in analogy to synthesis example 179 with the difference that protocol 3a was used for the Suzuki reaction. Example 180: 1-(1-(5-(2-Fluorophenyl)pyrimidin-2-v0spiro^
propanamine
Figure imgf000140_0001
White solid. Yield: 12 mg. HPLC (method 1 ): Rt = 3.33 min, m/z: [M+H]+ = 403.4 (MW calc. 402.46). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.84 (s, 2H), 8.34 (s, 2H), 7.67 (d, J = 7.6 Hz, 1 H), 7.50 (bs, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 7.15 (d, J = 7.7 Hz, 1 H), 4.85 (d, J = 6.0 Hz, 1 H), 4.77 (d, J = 5.7 Hz, 1 H), 4.57 (s, 2H), 2.20 (s, 3H), 0.95-0.88 (m, 4H). Example 181 : 1-(1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl)-N-methyl- cyclopropanamine
Figure imgf000140_0002
White solid. Yield: 22 mg. HPLC (method 1 ): Rt = 3.59 min., m/z: [M+H]+ = 417.6 (MW calc. 416.49). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.82 (s, 2H), 8.35 (s, 2H), 7.68 (bs, 1 H), 7.48 (d, J = 7.7 Hz, 1 H), 7.24 (d, J = 7.6 Hz, 1 H), 7.16 (bs, 1 H), 4.85 (d, J = 5.2 Hz, 2H), 4.77 (d, J = 5.2 Hz, 2H), 4.57 (s, 2H), 0.98-0.91 (m, 4H).
Examples 182 to 184 were synthesized in analogy to synthesis exam Example 182: 1-(1-(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spironndoline-3,3'-oxetanl-6-yl)-N-methyl- cyclopropanamine
Figure imgf000141_0001
White solid. Yield: 30 mg. HPLC (method 1 ): Rt = 3.01 min, m/z: [M+H]+ = 416.2 (MW calc. 415.49). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2H), 8.50 (s, 1 H), 8.47 (d, J = 5.7 Hz, 2H), 7.79 (d, J = 7.7 Hz, 1 H), 7.62 (d, J = 2.2 Hz, 1 H), 7.30 (d, J = 7.3 Hz, 1 H), 6.96-6.94 (m, 1 H), 4.87 (d, J = 6.2 Hz, 2H), 4.77 (d, J = 6.1 Hz, 2H), 4.61 (s, 2H), 3.92 (s, 3H), 2.40 (s, 3H), 1.39 (bs, 2H), 1 .1 1 -1 .08 (m, 2H)
Example 183: 2-(2-(2-(6-(1-(Methylamino)cvclopropyl)spiro[indoline-3,3'-oxetanl-1-yl)pyrimidin-5-v pyridin-4-yl)propan-2-ol
Figure imgf000141_0002
White solid. Yield: 25 mg. HPLC (method 1 ): Rt = 2.56 min, m/z: [M+H]+ = 444.2 (MW calc. 443.54). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.30 (s, 2H), 8.58 (d, J = 5.2 Hz, 1 H), 8.40 (s, 1 H), 8.03 (s, 1 H), 7.70 (m, 1 H), 7.45 (d, J = 3.6 Hz, 1 H), 7.20 (m, 1 H), 5.29 (s, 2H), 4.86 (d, J = 6Hz, 2H), 4.76 (d, J = 6.0 Hz, 2H), 4.59 (s, 2H), 1 .48 (s, 6H), 2.40 (s, 3H), 1.23 (s, 3H), 0.91-0.83 (m, 4H). Example 184: N-methyl-1-(1-(5-(4-methylpyridin-2-yl)pyrim^
propanamine
Figure imgf000141_0003
White solid. Yield: 16 mg. HPLC (method 1 ): Rt = 2.94 min, m/z: [M+H]+ = 400.4 (MW calc. 399.49). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.27 (s, 2H), 8.51 (d, J = 5 Hz, 1 H), 8.36 (s, 1 H), 7.91 (s, 1 H), 7.65 (d, J = 7.8 Hz, 1 H), 7.19 (d, J = 4.8 Hz, 1 H), 7.12 (d, J = 7.8 Hz, 1 H), 4.85 (d, J = 5.2 Hz, 2H), 4.76 (d, J = 5.2 Hz, 2H), 4.58 (s, 2H), 2.38 (s, 3H), 2.18 (s, 3H), 0.91-0.86 (m, 4H).
Example 185: N-Ethyl-1-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,^ oxetanel-6-sulfonamide
Figure imgf000142_0001
White solid. Yield: 80 mg. HPLC (method 2): Rt = 1.53 min, m/z: [M+H]+ = 482.1 (MW calc. 481.57). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H), 8.82 (s, 1 H), 8.60 (d, 1 H, J = 5.1 Hz), 8.05 (s, 1 H), 7.95- 7.93 (d, 1 H, J = 7.8 Hz), 7.59 (t, 1 H, J = 5.6 Hz), 7.55 (d, 1 H, J = 7.7 Hz), 7.46 (d, 1 H, J = 4.9 Hz), 5.29 (s, 1 H), 4.91 (d, 2H, J = 6.2 Hz), 4.79 (d, 2H, J = 6.1 Hz), 4.66 (s, 2H), 2.86-2.79 (m, 2H), 1.49 (s, 6H), 1.03 (t, 3H, J = 7.2 Hz). The examples 185 to 187 were prepared analogously to example 154.
Example 186: 1-(5-(4-(2-Aminopropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspironndoline-3,3'- oxetanel-6-sulfonamide
Figure imgf000142_0002
White solid. Yield: 0.12 g. HPLC (method 2): Rt = 1.30 min, m/z: [M+H]+ = 467.1 (MW calc. 466.56). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.35 (s, 2H), 8.81 (s, 1 H), 8.57-8.56 (m, 1 H), 8.17 (s, 1 H), 7.96 (d, 1 H, J = 7.5 Hz), 7.54-7.48 (m, 3H), 4.91 (d, 2H, J = 5.5 Hz), 4.79 (d, 2H, J = 5.5 Hz), 4.66 (s, 2H), 2.46 (s, 3H), 1.41 (s, 6H). Example 187: 1-(5-(4-(2-Aminopropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N,N-dimeth [indoline-3,3'-
Figure imgf000143_0001
White solid. Yield: 45 mg. HPLC (method 2): Rt = 1.36 min, m/z: [M+H]+ = 481.0 (MW calc. 480.58). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.37 (s, 2H), 8.75 (d, 1 H, J = 1.3 Hz), 8.55 (d, 1 H, J = 5.2 Hz), 8.18 (s, 1 H), 7.99 (d, 1 H, J = 7.8 Hz), 7.50-7.47 (m, 2H), 4.92 (d, 2H, J = 6.2 Hz), 4.80 (d, 2H, J = 6.2 Hz), 4.67 (s, 2H), 2.67 (s, 6H), 2.12 (bs, 2H), 1.41 (s, 6H).
Example 188: N-(2-Hvdroxyethyl)-N-methyl-1 '-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-4,5-dihydro-2H-
Figure imgf000143_0002
188a) N-(5-(Benzyloxy)-2-bromophenyl)tetrahydrofuran-3-carboxamide
A solution of tetrahydrofuran-3-carboxylic acid (1 .58 mL, 16.5 mmol) and 5-(benzyloxy)-2-bromoaniline (4.59 g, 16.5 mmol) in pyridine (75 mL) was cooled to -15°C. POCI3 (1.69 mL, 18.2 mmol) was added drop wise and stirring was continued for 45 min at -15°C. Ice-cold water (-300 mL) was added and the mixture was allowed to warm to RT. The suspension was filtered off and the filter was dried. Yield: 4.08 g (66%). MS: m/z: = 376.1/378.1 (MW calc. 376.05/378.05).
188b) N-(5-(benzyloxy)-2-bromophenyl)-N-(4-methoxybenzyl)tetrahydrofuran-3-carboxamide
A mixture of 188a (4.37 g, 1 1.6 mmol), 4-methoxybenzyl chloride (1.73 mL, 12.8 mmol) and Cs2C03 (10.60 g, 32.5 mmol) in dry acetonitrile (100 mL) was refluxed for 1 .5 h. The mixture was allowed to cool to RT and filtered over celite. The filter cake was rinsed with acetonitrile and EtOAc, the filtrate was concentrated and the remnant was purified by flash chromatography [silica, heptane/EtOAc = 4:1 to 1 : 1]. Yield: 5.77 g (100%). MS: m/z: = 496.1/498.1 (MW calc. 496.10/498.10). 188c) 6 Benzyloxy)-1 W4-methoxybenzyl)-4,5-dihydro-2H-spiro[furan-3,3'-indolinl-2'-one A solution of 188b (5.98 g, 12.1 mmol), Pd(OAc)2 (270 mg, 1.21 mmol) and NaOtBu (1 .74 g, 18.1 mmol) in dry 1 ,4-dioxane (1 15 mL) was prepared in a glovebox. Tricyclohexylphosphine (338 mg, 1.21 mmol) was added and the obtained brown solution was removed from the glovebox and stirred at 75°C overnight. The mixture was allowed to cool to RT and poured into an aqueous saturated NH4CI solution (700 mL). The aqueous layer was extracted with EtOAc (2x 500 mL) and the combined organic layers were washed with brine (200 mL), dried (Na2S04) and concentrated. The residue was purified by flash chromatography [silica, heptane/EtOAc = 3: 1 to 1 :1]. Yield: 2.75 g (55%). MS: m/z: = 416.2 (MW calc. 416.18).
188d) 6'-(Benzyloxy)-1 '-(4-methoxybenzyl)-4,5-dihydro-2H-spiro[furan-3,3'-indolinel
A solution of 3.5 M Red-AI in toluene (10.7 mL, 37.5 mmol) was added drop wise to compound 188c (2.6 g, 6.26 mmol) in dry toluene (70 mL) stirred at 80°C under Ar. The resulting mixture was stirred at this temperature for 2 h, then cooled with an ice-bath and cautiously quenched with ice-cold aqueous 2 M NaOH solution. The mixture was further diluted with aqueous 2 M NaOH solution (-400 mL total) and extracted with EtOAc (3x 150 mL). The combined organic layers were dried (Na2S04) and concentrated. Purification by flash chromatography [silica, heptane/EtOAc = 7: 1 to 1 : 1]. Yield: 2.32 g (92%). MS: m/z: = 402.2 (MW calc. 402.20). 188e) 4,5-dihydro-2H-spiro[furan-3,3'-indolin1-6'-ol
Compound 188d (2.31 g, 5.75 mmol) in a solution of aqueous hydrogen chloride (37%, 4.72 mL, 57.5 mmol), EtOH (40 mL) and MeOH (60 mL) was hydrogenated overnight using Palladium on carbon (10%, 612 mg, 0.58 mmol) as catalyst. The mixture was filtered over a pad of celite, the filter was rinsed with MeOH and the filtrate was concentrated. Yield: 1.72 g (hydrochloride salt). MS: m/z: = 192.1 (MW calc. 192.09).
188f) 1 5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)-4,5-dihydro-2H-spiro[furan-3,3'-indolin1-6'-ol
Pd(OAc)2 (129 mg, 0.57 mmol) and Xantphos (666 mg, 1.15 mmol) were added to a mixture of compound
188e (1.72 g, max. 5.75 mmol), 2-chloro-5-(4-methylpyridin-2-yl)pyrimidine (1 .30 g, 6.33 mmol) and Cs2C03 (5.25 g, 16.1 mmol) in dry 1 ,4-dioxane (90 mL) and trifluorotoluene (10 mL) that was stirred under Ar. The closed flask was heated at 1 10°C for 2 h. A cooler was attached and the mixture was stirred at 120°C overnight. The mixture was diluted with water (400 mL) and EtOAc (400 mL) and filtered. The organic layer was separated, washed with water (100 mL), dried (Na2S04) and concentrated. The residue was purified by flash chromatography [silica, heptane/EtOAc = 3:2 to 0:1 ] and the isolated material was further triturated in hot MeOH/acetonitrile (-1 : 1 , 100 mL). Yield: 930 mg (45% for the last to steps). MS: m/z: = 361.2 (MW calc. 361.16).
188g) 1 '-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)-4,5-dihydro-2H-spiro[furan-3,3'-indolin1-6'-yl trifluoro- methanesulfonate
Trifluoromethanesulfonic acid anhydride (419 μί, 2.48 mmol) was added drop wise at -15°C to a suspension of 188f (447 mg, 1 .24 mmol) and TEA (864 μί, 6.20 mmol) in DCM (25 mL) and acetonitrile (10 mL). After stirring for 15 min, the mixture was allowed to warm to RT and further trifluoromethane- sulfonic acid anhydride (210 μί, 1 .24 mmol) was added drop wise 30 min later. The mixture was stirred at RT for 1 h, then diluted with DCM (100 mL) and washed with saturated aqueous NaHC03 solution (200 mL). The aqueous layer was extracted with DCM (100 mL) and the combined organic layers were dried (Na2S04) and concentrated. Purification by flash chromatography [silica, heptane/EtOAc = 3:2 to 1 :4]. Yield: 340 mg (56%). MS: m/z: = 493.1 (MW calc. 493.1 1 ).
188h) Methyl 1 '-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-4,5-dihvdro-2H-spiro[furan-3,3'-indoline1-6'- carboxylate
A solution of compound 188g (530 mg, 1.08 mmol) and TEA (600 μί, 4.30 mmol) in MeOH (4.35 mL, 108 mmol) and dry DMF (30 mL) was placed in an autoclave and flushed with argon for 15 min. Pd(OAc)2 (24.2 mg, 108 μιηοΙ) and dppp (44.4 mg, 108 μιηοΙ) were added and the autoclave was stirred under a carbon monoxide atmosphere (5 bar) at 70°C for 1 h and at 90°C overnight. The reaction mixture was cooled to 0°C, diluted with EtOAc (100 mL) and washed with water (2x 200 mL). The organic phase was dried (Na2S04) and concentrated under reduced pressure. Purification by flash chromatography [silica, heptane/EtOAc = 4:1 to 0: 1] afforded the methyl ester. Yield: 360 mg (83%). MS: m/z: = 403.2 (MW calc. 403.17).
188i) 1 5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)-4,5-dihvdro-2H-spiro[furan-3,3'-indoline1-6'-carboxylic acid
To a solution of methyl ester 188h (350 mg, 0.87 mmol) in THF (20 mL), MeOH (10 mL) and water (10 mL) was added LiOH H20 (182 mg, 4.35 mmol) and the mixture was stirred at RT. The mixture was concentrated, diluted with water (50 mL) and washed with diethyl ether (2 x 50 mL). The aqueous layer was acidified with 1 M hydrogen chloride solution (~8 mL). The appearing precipitate was filtered off, rinsed with water and triturated with diethyl ether/pentane (50 mL, 1 : 1 ). Yield: 308 mg (91 %). MS: m/z: = 389.2 (MW calc. 389.15).
188j) N-(2-Hvdroxyethyl)-N-methyl-1 '-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-4,5-dihydro-2H-spiro- [furan-3,3'-indoline1-6'-carboxamide
N-methylmorpholine (164 μί, 1.49 mmol), 2-(methylamino)ethanol (180 μί, 2.23 mmol) and TBTU (287 mg, 893 μιηοΙ) were added to a solution of carboxylic acid 188i (289 mg, 744 μιηοΙ) in dry DMF (10 mL) and the mixture was stirred at RT for 45 min. The mixture was added drop wise to ice-cold water (-100 mL) and extracted with EtOAc (100 mL and 50 mL). The combined organic layers were washed with brine (2x 200 mL), dried (Na2S04) and concentrated to dryness. The residue was purified by flash chromatography [silica, EtOAc]. Yield: 205 mg (62%). MS: m/z: [M+H]+ = 446.2 (MW calc. 446.21 ). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.28 (s, 2H), 8.52 (d, J = 5.0 Hz, 1 H), 8.42 (s, 1 H), 7.88 (s, 1 H), 7.39 (d, J = 7.6 Hz, 1 H), 7.21 (d, J = 4.9 Hz, 1 H), 7.04 (d, J = 7.4 Hz, 1 H), 4.81 (br s, 1 H), 4.31 (d, J = 1 1.8 Hz, 1 H), 4.24 (d, J = 1 1 .8 Hz, 1 H), 4.08 (td, J = 8.5, 4.7 Hz, 1 H), 3.97 (q, J = 7.9 Hz, 1 H), 3.89 (d, J = 8.3 Hz, 1 H), 3.74 (d, J = 8.4 Hz, 1 H), 3.59 (br m, 4H), 3.00 (d, J = 7.5 Hz, 3H), 2.39 (s, 3H), 2.29 (ddt, J = 16.2, 12.7, 7.9 Hz, 2H). Example 189 and 190: 2-(2-(6-(Ethylsulfinyl)spiro[indoline-3,3'-oxetanl-1 -yl)pyrimidin-5-yl)^
(faster and slower eluting enantiomer)
Figure imgf000146_0001
The racemic sulfoxide was prepared from 52h analogously to example 56 and then separated into its single enantiomers via chiral preparative HPLC (column: Chiralpak IA 21 x 250 mm, particle size 5 μιη; mobile phase: hexane/ethanol/DCM/diethylamine = 50/25/25/0.1 ; flow rate: 21.0 ml/min; detection: UV, 344 nm; run time: 20 min).
Faster eluting enantiomer (example 189): White solid. Yield: 90 mg. Enantiomeric excess: 100% (chiral HPLC). HPLC (method 2): Rt = 1 .63 min, m/z: [M+H]+ = 418.0 (MW calc. 417.48). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.35 (s, 2H), 8.90 (d, 1 H, J = 5.0 Hz), 8.60 (s, 1 H), 8.55 (s, 1 H), 7.94 (d, 1 H, J = 7.8 Hz), 7.81-7.80 (m, 1 H), 7.38-7.35 (m, 1 H), 4.90 (d, 2H, J = 6.2 Hz), 4.79 (d, 2H, J = 6.12 Hz), 4.65 (s, 2H), 3.04-2.97 (m, 1 H), 2.82-2.75 (m, 1 H), 1 .08 (t, 3H, J = 7.3 Hz).
Slower eluting enantiomer (example 190): White solid. Yield: 90 mg. Enantiomeric excess: 100% (chiral HPLC). HPLC (method 2): Rt = 1 .63 min, m/z: [M+H]+ = 418.1 (MW calc. 417.48). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.35 (s, 2H), 8.90 (d, 1 H, J = 5.0 Hz), 8.60 (s, 1 H), 8.55 (s, 1 H), 7.94 (d, 1 H, J = 7.8 Hz), 7.81-7.80 (m, 1 H), 7.37-7.35 (m, 1 H), 4.90 (d, 2H, J = 6.2 Hz), 4.79 (d, 2H, J = 6.12 Hz), 4.65 (s, 2H), 3.06-2.97 (m, 1 H), 2.82-2.73 (m, 1 H), 1 .08 (t, 3H, J = 7.3 Hz).
Figure imgf000146_0002
Prepared from 52h analogously to example 56. Yellowish solid. Yield: 120 mg. HPLC (method 2): Rt = 1.63 min, m/z: [M+H]+ = 434.1 (MW calc. 433.48). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.38 (s, 2H), 8.91 (d, 1 H, J = 4.9 Hz), 8.82 (s, 1 H), 8.57 (s, 1 H), 8.03 (d, 1 H, J = 7.8 Hz), 7.82 (d, 1 H, J = 4.8 Hz), 7.66 (d, 1 H, J = 7.8 Hz), 4.92 (d, 2H, J = 6.2 Hz), 4.79 (d, 2H, J = 6.12 Hz), 4.67 (s, 2H), 3.28-3.27 (m, 2H), 1.15 (t, 3H, J = 7.3 Hz).
Figure imgf000147_0001
lnt-6a) (2,2-Dimethylspiro[[1 ,31dioxane-5,3'-indolinl-6'-yl)dimethylphosphine oxide
Xantphos (0.49 g , 0.838 mmol) and Pd2(dba)3 (0.77 g, 0.838 mmol) were added to a solution of lnt-1 b (5 g, 16.76 mmol), dimethylphosphine oxide (1.9 g, 25.15 mmol) and triethylamine (7.06 mL, 50.28 mmol) in dry dioxane (100 mL) stirred under Ar. The resulting mixture was heated at 1 10°C for 16 h, then cooled and filtered over a plug of celite. The filtrate was evaporated and the residue purified by column chromatography [silica gel; DCM with 0-10% MeOH]. The isolated white solid was used in the next step without further purification. Yield: quantitative (~5 g). HPLC (method 3): Rt = 2.17 min., m/z: [M+H]+ = 296.2 (MW calc. 295.31 ).
Intermediate 6 was prepared in 4 chemical steps from lnt-6a analogously to aforementioned procedures (1 d, 1 e, 1f and 1 g). White solid. Yield: 0.32 g (77% of theory). HPLC (method 4): Rt = 3.21 min, m/z: [M+H]+ = 394.0 (MW calc. 394.2).
Example 192: (1-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl)dimethyl- phosphine oxide
Figure imgf000147_0002
Prepared from lnt-6 and (2-fluoro-5-methylphenyl)boronic acid in analogy to procedure 3a. White solid. Yield: 0.09 g. HPLC (method 3): Rt = 3.05 min, m/z: [M+H]+ = 423.9 (MW calc. 423.42). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.85 (s, 2H), 8.74 (d, 1 H, J = 12.4 Hz), 7.89-7.87 (m, 1 H), 7.50-7.46 (m, 2H), 7.25-7.23 (m, 2H), 4.89 (d, 2H, J = 6.1 Hz), 4.79 (d, 2H, J = 6.0 Hz), 4.60 (s, 2H), 2.35 (s, 3H), 1.68 (s, 3H), 1.65 (s, 3H). Example 193: (1-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetanl-6-yl) dimethylphosphine
Figure imgf000148_0001
Prepared from lnt-6 and (2-fluorophenyl)boronic acid in analogy to procedure 3a. White solid. Yield: 0.1 g. HPLC (method 2): Rt = 1.72 min, m/z: [M+H]+ = 410.1 (MW calc. 409.39). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.87 (s, 2H), 8.74 (d, 1 H, J = 12.5 Hz), 7.89-7.87 (m, 1 H), 7.70-7.66 (m, 1 H), 7.51-7.43 (m, 2H), 7.39-7.32 (m, 2H), 4.89 (d, 2H, J = 6.2 Hz), 4.79 (d, 2H, J = 6.1 Hz), 4.60 (s, 2H), 1.68 (s, 3H), 1.65 (s, 3H).
Biological testing
TR-FRET assay using the LANCE® Ultra cAMP kit to determine the activity of hPDE4B1
The effects of the compounds on the activity of the human PDE4B1 was quantified by measuring the production of 5ΆΜΡ from cAMP using a human recombinant enzyme expressed in Sf9 cells and the LANCE® Ultra cAMP kit, a TR-FRET detection method from PerkinElmer. The human PDE4B1 enzyme was purchased from SignalChem Lifesciences (Catalog# P92-31 BG, Lot# H296-2).
The test compound, reference compound or water (control) was mixed with the enzyme (0.96 U) in a reaction buffer containing 50 mM Tris-HCI, 50 mM MgCI2 and 5 mM DTT (pH 8.5). Thereafter, the reaction was initiated by addition of 500 nM cAMP (substrate) and the mixture was incubated for 30 min at rt. For control basal measurements, the enzyme was omitted from the reaction mixture. After 30 min, the reaction was stopped and diluted by a factor of 100 with the reaction buffer supplemented with 500 μΜ IBMX. The fluorescence donor (Europium chelate-labeled cAMP) and the fluorescence acceptor (anti- cAMP antibody labeled with the ULight™ dye) were then added together with 500 μΜ IBMX to a 10 μΙ aliquot. After 60 min, the fluorescence transfer corresponding to the amount of residual cAMP was measured at Aex = 337 nm, Aem = 620 nm and Aem = 665 nm using a microplate reader (PHERAstar, BMG). The enzyme activity was determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio) multiplied by 10000. The results were expressed as percent inhibition of the control enzyme activity. IC50 values (IC50 = concentration causing a half-maximal inhibition of control specific activity) were derived from dose response measurements with ten different concentrations (n = 3; N = 1- 3).
Several compounds according to the invention are tested in the above-described assay. The results are given in the tables below (IC50 inhibition of PDE4B of Examples Nos.):
PDE4B IC50 PDE4B IC50 PDE4B IC50 PDE4B IC50
No. No. No. No.
[μΜ] (mean) [μΜ] (mean) [μΜ] (mean) [μΜ] (mean)
1 0,001 26 0,010 51 0,004 76 <0,001
2 0,002 27 0,002 52 0,001 77 0,001
3 0,004 28 0,001 53 0,001 78 0,001
4 0,001 29 0,003 54 <0,001 79 0,007
5 0,004 30 0,013 55 <0,001 80 0,001
6 0,019 31 0,001 56 0,012 81 0,002
7 <0,001 32 <0,001 57 0,004 82 0,002
8 0,010 33 <0,001 58 <0,001 83 0,002
9 0,004 34 0,019 59 0,001 84 0,003
10 0,017 35 0,001 60 0,002 85 0,012
1 1 0,002 36 0,007 61 0,001 86 0,008
12 0,002 37 0,004 62 0,012 87 0,017
13 0,023 38 <0,001 63 0,002 88 0,003
14 0,002 39 0,004 64 0,025 89 0,005
15 0,002 40 0,003 65 0,005 90 0,001
16 0,015 41 0,008 66 0,002 91 0,002
17 0,006 42 0,004 67 0,002 92 0,001
18 0,060 43 0,005 68 0,005 93 0,001
19 0,019 44 0,002 69 0,025 94 0,007
20 0,004 45 0,003 70 0,001 95 0,002
21 0,001 46 0,002 71 <0,001 96 0,006
22 0,007 47 0,01 1 72 0,001 97 0,006 0,007 48 0,006 73 0,002 98 0,012
0,017 49 0,005 74 0,003 99 0,005
<0,001 50 0,008 75 0,001 100 0,002
PDE4B IC50 PDE4B IC50 PDE4B IC50 PDE4B IC50
No. No. No.
[μΜ] (mean) [μΜ] (mean) [μΜ] (mean) [μΜ] (mean)
0,001 126 0,133 151 0,001 176 0,005
0,001 127 0,001 152 0,002 177 0,006
0,005 128 0,001 153 0,037 178 0,589
0,002 129 0,033 154 <0,001 179 0,020
0,042 130 0,006 155 0,004 180 0,01 1
0,027 131 0,057 156 <0,001 181 0,004
0,439 132 0,009 157 0,001 182 0,051
0,028 133 0,003 158 <0,001 183
0, 182 134 0,096 159 0,010 184 0,005
0,006 135 0,012 160 0,002 185 <0,001
0,003 136 0,014 161 0,062 186 0,003
0,014 137 0,038 162 0,002 187 0,001
0,008 138 0,159 163 0,022 188 0,053
0,007 139 0,052 164 0,107 189 0,01 1
0,007 140 0,719 165 0,006 190 <0,001
0,006 141 0,044 166 0,013 191 <0,001
0,003 142 0,012 167 0,126 192
0,005 143 0,005 168 0,016 193
0,001 144 0,1 18 169 0,007
0,001 145 0,167 170 0,002
<0,001 146 0,005 171 0,001
0,010 147 0,008 172 <0,001
<0,001 148 0,014 173 <0,001
<0,001 149 0,031 174 0,002
0,24 150 0,014 175 0,008

Claims

Claims
1. A compound of formula (I)
Figure imgf000151_0001
wherein
A, B and C independently represent CH or N;
m is 0, 1 , 2 or 3 and n is 0, 1 , 2 or 3, whith the proviso that the sum (m + n) is 2, 3 or 4;
L is selected from the group consisting of C(=0)NR2,S(=0), S(=0)2, S(=0)2NR2, P(=0)(R2), O or bond;
R is selected from
C-i-6-alkyl, unsubstituted or mono- or polysubstituted;
or
C3-6-cycloalkyl or 3- to 7-membered heterocycloalkyi, in each case unsubstituted or mono- or polysubstituted;
R2 is selected from H or C-|-C6-alkyl, unsubstituted or mono- or polysubstituted;
or
R and R2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyi,
wherein said 3- to 12-membered heterocycloalkyi may contain one or two additional heteroatoms selected from the group consisting of O, S and N and may be mono- or bicyclic and
wherein said 3- to 12-membered heterocycloalkyi is unsubstituted or mono- or polysubstituted; G represents a phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or said 5- or 6- membered heteroaryl is unsubstituted or substituted with one, two, three or four substituents Z; wherein
Z at each occurcence is independently selected from the group consisting of halogen, OH, CN, SH, N02, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-cyanoalkyl, d-d- alkoxy, (Ci-C6)-thioalkyl, (Ci-C6)-haloalkyl, (Ci-C6-alkoxy)-(Ci-C6-alkylenyl), (Ci-C6-alkoxy)-Ci-C6- alkoxy, (Ci-C6)-thiohaloalkyl, (Ci-C6)-haloalkoxy, (Ci-C6-thioalkyl)-(Ci-C6-alkylenyl), C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(C-|-C3-alkylenyl), 3- to 7-membered heterocycloalkyi, (3- to 7-membered heterocycloalkyl)-(C-|-C3-alkylenyl), said C3.6-cycloalkyl and said 3- to 7-membered heterocycloalkyi being in each case unsubstituted or mono- or polysubstituted, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, NHCO(d-d-alkyl), NHC02(d-d-alkyl), NHC(0)NH2, NHCONH(d-d-alkyl), NHCON(d-d-alkyl)2, (d-C6-alkylen)NH2, (d-C6-alkylen)NH(d-C6-alkyl), (d-C6-alkylen)N(d-C6-alkyl)2, (d-C6- alkylen)NHCO(d-C6-alkyl), (d-C6-alkylen)NHC02(d-C6-alkyl), (d-C6-alkylen)NHC(0)NH2, (d-C6- alkylen)NHCONH(d-C6-alkyl), (d-C6-alkylen)NHCON(d-C6-alkyl)2, NH((d-C6-alkylen)-C02(d-C6- alkyl), NHid-Ce-alkylenJ-CONHz, NHiCi-Ce-alkylenJ-CONHiCrC^alkyl), NH(CrCe-alkylen)- 0)2OH, NHS(0)2(CrC6-alkyl), NHS(0)20(C1-C6-alkyl), NHS(0)2NH2,
Figure imgf000152_0001
NHS(0)2N(C C6-alkyl)2, NHiCi-Ce-alkylenJ-SiOfeOH, NH(Ci-Ce-alkylen)- SiOMCi-Ce-alkyl), NHtC Ce-alkylen^O^CKC Ce-alkyl), NH(C C6-alkylen)-S(0)2NH2, NH(C Ce-
Figure imgf000152_0002
C02H, CO(Ci-Ce-alkyl), C02(Ci-Ce-alkyl), 0-CO(Ci-Ce-alkyl), O- C02(Ci-Ce-alkyl), CONH2, CONH(Ci-Ce-alkyl), CONiCi-Ce-alkylfc, OCONH(Ci-Ce-alkyl), OCON(C C6-alkyl)2, OS(0)2(C C6-alkyl), OS(0)2OH, OS(0)20(C C6-alkyl), OS(0)2NH2, OS(0)2NH(C C6- alkyl), OS(0)2N(C C6-alkyl)2, S(0)(C C6-alkyl), S(0)2(C C6-alkyl), S(0)2OH, S(0)20(C C6-alkyl), S(0)2NH2,
Figure imgf000152_0003
and S(0)2N(Ci-Ce-alkyl)2;
optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a physiologically acceptable solvate thereof.
A compound according to claim 1 , characterized in that each of A, B and C represents CH.
A compound according to one or more of claims 1 or 2, characterized in that m is 1 and n is 1 or m is 1 and n is 2 or m is 2 and n is 2, preferably m is 1 and n is 1.
A compound according to one or more of claims 1 to 3, wherein G is one of the following groups G1
Figure imgf000152_0004
Figure imgf000153_0001
in which the site marked with an asterisk (*) indicates the binding site, which is bonded to the pyrimidine ring;
R 2 is selected H, CH3 or CH2CH3;
k at each occurrence 0, 1 , 2, 3 or 4; and
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3), CH(CH3)NH(CH3), CH2N(CH3)2, CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN, SOCH3, S02CH3, SOCH2CH3, S02CH2CH3, S02NH2, pyrrolidinyl, piperidinyl, aziridinyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,
wherein said pyrrolidinyl, piperidinyl, aziridinyl, oxetanyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, and NHCOCH3. A compound according to one or more of claims 1 to 4, wherein G is one of the following groups G45 or G2
Figure imgf000154_0001
G45
in which the site marked with an asterisk (*) indicates the binding site, which is bonded to the pyrimidine ring;
k at each occurrence 0, 1 or 2; and
ZA is H or F;
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3), CH(CH3)NH(CH3), CH2N(CH3)2, CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN, SOCH3,S02CH3, cyclopropyl, cyclobutyl, 3-oxetanyl, 2-aziridinyl, 3- aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl, wherein said cyclopropyl, cyclobutyl, 3- oxetanyl, 2-aziridinyl, 3-aziridinyl, 1 -pyrrolidinyl, 1-piperidinyl and 1-morpholinyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, CI, CN, CF3, OCF3, OH, OCH3, CH3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), N(CH3)2 and NHCOCH3.
A compound according to any of claims 1 to 5, characterized in that
L is selected from C(=0)NR2, S(=0), S(=0)2 , P(=0)(R2), S(=0)2NR2 or bond
A compound according to any of claims 1 to 6, characterized in that
L is selected from C(=0)NR2, S(=0), S(=0)2, S(=0)2NR2 or bond; and
R is selected from Ci-C6-alkyl, C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl,
wherein said Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, =0, =NH, NH2, NH(Ci-C6- alkyl), N(Ci-C6-alkyl)2, Ci-C6-alkoxy, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyl; and
wherein said 3- to 7-membered heterocycloalkyl may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
wherein said C3-C6-cycloalkyl and said 3- to 7-membered heterocycloalkyl is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, =0, NH2, NH(d-C6-alkyl), N(Ci-C6-alkyl)2, Ci-C6-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-Ce)-haloalkyl and Ci-C6-alkoxy; and
R2 is selected from H or Ci-C6-alkyl
wherein said Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, OH, Ci-C6-alkoxy, and C3-C6- cycloalkyl;
or
R and R2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyi,
wherein said 3- to 12-membered heterocycloalkyi may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
wherein said 3- to 12-membered heterocycloalkyi is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, =0, NH2, NH(CrC6-alkyl), N(Ci-C6-alkyl)2, Ci-C6-alkyl, (Ci-C6)-hydroxyalkyl, (d-C6)-haloalkyl and C C6- alkoxy.
A compound according to any of claims 1 to 7, characterized in that
L is C(=0)NR2 and
R is selected from one of the following substructures M1 to M76:
Figure imgf000155_0001
Figure imgf000156_0001
an
R2 is selected from H or CH3.
A compound according to any of claims 1 to 7, characterized in that
L is C(=0)NR2 and
R and R2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyl, herein said 3- to 12-membered heterocycloalkyi denotes one of the following groups Q1 to Q34:
Figure imgf000157_0001
in which the site marked with an asterisk (*) indicates the binding site, which is bonded to the carbonyl group of L;
R5 is selected from the group consisting of H, C-i-Ce-alkyl, (Ci-C6)-hydroxyalkyl, (d-C6)-cyanoalkyl, C3-C6-cycloalkyl, CO(Ci-C6-alkyl) and S02-(Ci-C6)-alkyl;
at each occurrence p is 0, 1 , 2, 3, 4 or 5; and
X6 at each occurrence is independently selected from the group consisting of OH, =0, CN, F, CI, Br, CF3, CHF2, CH2F, OCF3, C-i-Ce-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-cyanoalkyl, (d-C6)-alkoxy, (C3- C6)-cycloalkyl, NH2, NH(C C6-alkyl), N(d-C6-alkyl)2, NHCO(d-C6-alkyl), C02H, CO(d-C6-alkyl), COO(d-C6-alkyl), CONH2, CONH(d-C6-alkyl) and CON(d-C6-alkyl)2.
10. A compound according to any of claims 1 to 7, characterized in that
L is S(=0) or S(=0)2 and
R is selected from OH, CN, d-d-alkyl, NH2, NH(d-d-alkyl), N(d-C6-alkyl)2, C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyi,
wherein said d-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH , NH2, d-d-alkoxy, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyi;
and
wherein said 3- to 7-membered heterocycloalkyi may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
wherein said 3- to 7-membered heterocycloalkyi is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , OH, =0, NH2, d-C6-alkyl, (d-C6)-hydroxyalkyl, (Ci-C6)-haloalkyl and d-d-alkoxy.
1 1 . A compound according to any of claims 1 to 7, characterized in that
L is S(=0) or S(=0)2 and
R is selected from one of the substructures M1 to M76 according to claim 8.
12. A compound according to claim 1 , wherein the compound according to general formula (I) is selected from one of the general formula (la), (lb), (lc) or (Id),
Figure imgf000158_0001
wherein R , R2 and G are defined as in any of the preceeding claims.
13. A compound according to claim 12, wherein the compound according to the general formula (la), (lb), (lc), (Id) or (le) is characterized in that G is selected from G1 or G2, wherein
k at each occurrence is 0, 1 , 2 or 3;
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3),
NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2,
CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, S02CH3, cyclopropyl and cyclobutyl;
and wherein R and R2 are defined as in any of the preceeding claims.
A compound according to one or more of the preceding claims selected from the group consisting of
1 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-N,N-dimethylspiro[indoline-3,3'-oxetane]-6-carboxamide
2 (1 -(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)methanone
N-(2-Amino-2-oxoethyl)-1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-N-methylspiro[indoline-
3
3,3'-oxetane]-6-carboxamide
4 morpholino(1-(5-phenylpyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)methanone
N-(2-amino-2-oxoethyl)-1-(5-(2-fluoro-5-methoxyphenyl)pyrimidin-2-yl)-N-methylspiro[indoline- 5
3,3'-oxetane]-6-carboxamide
N-(2-amino-2-oxoethyl)-N-methyl-1 -(5-phenylpyrimidin-2-yl)spiro[indoline-3,3'-oxetane]-6- carboxamide
N-(2-amino-2-oxoethyl)-1-(5-(5-ethyl-2-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[indoline-
7
3,3'-oxetane]-6-carboxamide
8 morpholino(1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)methanone
(1 -(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6- 9
yl)(morpholino)methanone
(1 -(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)-
10
methanone
N-(2-amino-2-oxoethyl)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[indoline-3,3'- oxetane]-6-carboxamide
N-(2-amino-2-oxoethyl)-1-(5-(5-ethoxy-2-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[indoline-
2
3,3'-oxetane]-6-carboxamide
N-(2-amino-2-oxoethyl)-N-methyl-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]- 3
6-carboxamide
morpholino(1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)- 4
methanone
(1 -(5-(2-fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)- 5
(morpholino)methanone
1-(5-(2-fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro- 6
[indoline-3,3'-oxetane]-6-carboxamide
N-(2-hydroxyethyl)-N-methyl-1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)spiro[indoline-3,3'- oxetane]-6-carboxamide
18 (1 -(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(pyrrolidin-1-yl)methanone
19 (1 -(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(piperazin-1-yl)methanone
20 1-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3'-oxetane]- 6-carboxamide
(1 S,4S)-2,5-diazabicyclo[2 .1]heptan-2-yl(1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[ind 3,3'-oxetan]-6-yl)methanone
(1 -(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(piperazi methanone
(1 -(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(pyrroli^
methanone
N-(2-hydroxyethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3^'- oxetane]-6-carboxamide
(1 S,4S)-2,5-diazabicyclo[2 .1]heptan-2-yl(1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro- [indoline-3,3'-oxetan]-6-yl)methanone
N-(2-amino-2-oxoethyl)-1-(5-(3-cyclopropylphenyl)pyrimidin-2-yl)-N-methylspiro[indoline-3,3'- oxetane]-6-carboxamide
N-(2-Amino-2-oxoethyl)-N-methyl-1-(5-(m-tolyl)pyrimidin-2-yl)spiro[indoline-3^'-oxetane]-6- carboxamide
(S)-N-(2-amino-2-oxoethyl)-1 -(5-(2-fluoro-5-(1-hydroxyethyl)phenyl)pyrimidin-2-yl)-N-meth spiro[indoline-3,3'-oxetane]-6-carboxamide
(R)-N-(2-amino-2-oxoethyl)-1-(5-(2-fluoro-5-(1-hydroxyethyl)phenyl)pyrimidin-2-yl)-N-methyl- spiro[indoline-3,3'-oxetane]-6-carboxamide
N-(2-amino-2-oxoethyl)-1-(5-(2-fluoro-5-(2-hydroxypropan-2-yl)phenyl)pyrimidin-2-yl)-N- methylspiro[indoline-3,3'-oxetane]-6-carboxamide
Morpholino(1-(5-(m-tolyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)methanone
(1 -(5-(2-fluoro-5-methoxyphenyl)pyrimidin-2-yl)spiro[indoline-3^'-oxetan]-6-yl)(morpholino)- methanone
(1 -(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)- methanone
(1 -(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(pyrrolidin-1-yl)methan
(1 -(5-(4-cyclopropylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(pyrrolidin-1-y methanone
(1 -(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(pyrrolidin-1-yl)- methanone
(1 -(5-(3-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)methanone (1 -(5-(4-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)methanone (1 -(5-(2,5-difluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)methanone
(1 -(5-(2,3-Difluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino) methanone
(1 -(5-(3,5-Difluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino) methanone
1-(5-(3-Fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3'-oxetane]- 6-carboxamide
1-(5-(4-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3'-oxetane]-6- carboxamide
1-(5-(2,5-difluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3'- oxetane]-6-carboxamide
1-(5-(2,3-difluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3'- oxetane]-6-carboxamide
1-(5-(3,5-difluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3'- oxetane]-6-carboxamide
N-(2-amino-2-oxoethyl)-1-(5-(3-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[indoline-^ oxetane]-6-carboxamide
N-(2-amino-2-oxoethyl)-1-(5-(4-fluorophenyl)pyrimidin-2-yl)-N-methylspiro[indoline-3 oxetane]-6-carboxamide
N-(2-amino-2-oxoethyl)-1-(5-(2,5-difluorophenyl)pyrimidin-2-yl)-N-methylspiro[indoli^ oxetane]-6-carboxamide
N-(2-Amino-2-oxoethyl)-1-(5-(2,3-difluorophenyl)pyrimidin-2-yl)-N-methylspiro [indoline-3,3'- oxetane]-6-carboxamide
N-(2-Amino-2-oxoethyl)-1-(5-(3,5-difluorophenyl)pyrimidin-2-yl)-N-methylspiro [indoline-3,3'- oxetane]-6-carboxamide
6-(Ethylsulfinyl)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]
6-(Ethylsulfonyl)-1-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]
6-(ethylsulfinyl)-1-(5-(2-fluoro-5-methylphe^
6-(Ethylsulfonyl)-1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane] 6-(ethylsulfinyl)-1-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3^'-oxetan 6-(Ethylsulfonyl)-1-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan 1-(5-(4-cyclopropylpyridin-2-yl)pyrimidin^
1-(5-(4-cyclopropylpyridin-2-yl)pyrimidin-2-yl)-6-(ethylsulfonyl)spiro[indoline-3^'-oxetan
1-(5-(4-ethylpyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,^ oxetane]-6-carboxamide
1-(5-(4-cyclopropylpyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoli oxetane]-6-carboxamide
N-(2-hydroxyethyl)-1-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[indolin oxetane]-6-carboxamide
1 - (5-(4-ethoxy py rid i n-2-y l)py rim id i n-2-y I )-^
oxetane]-6-carboxamide
N-(2-hydroxyethyl)-N-methyl-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'^^ carboxamide
N-(2-hydroxyethyl)-N-methyl-1-(5-(4-(trifluoromethyl)pyridin-2-yl)pyrimidin^
3,3'-oxetane]-6-carboxamide
N-(2-hydroxyethyl)-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N- methylspiro[indoline-3,3'-oxetane]-6-carboxamide
(1 -(5-(4-(2-Hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan^ (pyrrolidin-l-yl)methanone
( 1 -(5-(4-ethoxy py rid i n-2-yl )py ri m id in-2-y l)spi
methanone
pyrrolidin-1-yl(1 -(5-(4-(trifluoromethyl)pyridin-2-yl)pyrimidin-2-yl)spiro
yl)methanone
(1 -(5-(4-ethylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(pyrrolidi yl)methanone
(S)- or (R)-1-(3-(2-(6-(ethylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)-4- fluorophenyl)ethanol
(R)- or (S)-1-(3-(2-(6-(ethylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)-4- fluorophenyl)ethanol
2- (3-(2-(6-(ethylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)-4-fluorophen 2-ol
2-(3-(2-(6-(ethylsulfinyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)-4-fl^
74
ol
75 2-(2-(2-(6-(Ethylsulfonyl)spiro[indoline-3^'-oxetan]-1-yl)pyrimidin-5-yl)pyridin-4-yl)p
76 2-(2-(2-(6-(Ethylsulfinyl)spiro[indoline-3^'-oxetan]-1-yl)pyrimidin-5-yl)pyridin-4-^
(S)- or (R)-1-(2-(2-(6-(ethylsulfonyl)spiro[indo
77
ethanol
(R)- or (S)-1-(2-(2-(6-(ethylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)pyridi 78
ethanol
N-(2-hydroxyethyl)-N-methyl-1-(5-phenylpyn
79
carboxamide
N-(2-Hydroxyethyl)-N-methyl-1-(5-(m-tolyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxeta -6- 80
carboxamide
1-(5-(3-cyclopropylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indolin
81
oxetane]-6-carboxamide
N-(2-hydroxyethyl)-1-(5-(3-methoxyphenyl)pyrimidin-2-yl)-N-methylspiro[indolin
82
oxetane]-6-carboxamide
1-(5-(3-ethoxyphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indolin
83
6-carboxamide
1-(5-(3-chlorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indolin
84
carboxamide
N-(2-hydroxyethyl)-N-methyl-1-(5-(3-(trifluoromethoxy)phenyl)pyrimidin-2-yl)spiro
85
oxetane]-6-carboxamide
1-(5-(3-aminophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoli
86
carboxamide
N-(2-hydroxyethyl)-N-methyl-1-(5-(3-(pyrrolidin-1-yl)phenyl)pyrimidin-2-yl)spiro[indoli
87
oxetane]-6-carboxamide
N-(2-hydroxyethyl)-1-(5-(3-(1-hydroxyethyl)phenyl)pyrimidin-2-yl)-N-methylspiro[indoline-3,^ 88
oxetane]-6-carboxamide
1-(5-(3,4-difluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3'- 89
oxetane]-6-carboxamide
1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3 90
oxetane]-6-carboxamide
1-(5-(5-cyclopropyl-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline- 91
3,3'-oxetane]-6-carboxamide
1-(5-(2-fluoro-5-methoxyphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3 92
oxetane]-6-carboxamide
1-(5-(5-ethoxy-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3^ 93
oxetane]-6-carboxamide
1-(5-(2-fluoro-5-(trifluoromethoxy)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N- 94
methylspiro[indoline-3,3'-oxetane]-6-carboxamide
1-(5-(5-amino-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3^ - 95
oxetane]-6-carboxamide
1-(5-(5-(ethylamino)-2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indol^ 96
3,3'-oxetane]-6-carboxamide
1-(5-(3-(ethylamino)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3 97
oxetane]-6-carboxamide pyrrolidin-1-yl(1 -(5-(4-(trifluoromethyl)pyridin-2-yl)pyrimidin-2-yl)spiro[indoli
yl)methanone
2-(2-(2-(6-(methylsulfinyl)spiro[indoline-3^'-oxetan]-1-yl)pyrimidin-5-yl)pyrid
2-(2-(2-(6-(methylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)pyridin^
ol
1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-N,N-dimethylspiro[indoline-3,3'-oxet^ sulfonamide
1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoH
102
oxetane]-6-sulfonamide
N,N-dimethyl-1 -(5-(4-methylpyridin-2-yl)pyn
103
sulfonamide
N-(2-hydroxyethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'- oxetane]-6-sulfonamide
N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-N-(oxetan-3-ylmethyl)spiro[indoline-3,3'-
105
oxetane]-6-carboxamide
N-(cyclopropylmethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'- 106
oxetane]-6-carboxamide
N-((3,3-difluorocyclobutyl)methyl)-N-methyl-1 -(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro- 107
[indoline-3,3'-oxetane]-6-carboxamide
108 6-(Ethylsulfinyl)-1 -(5-(pyridazin-3-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]
109 6-(ethylsulfonyl)-1-(5-(pyridazin-3-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]
110 2-(3-(2-(6-(ethylsulfinyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)phenyl)propan-2-ol
111 2-(3-(2-(6-(ethylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)phenyl)propan-2-ol
112 6-(ethylsulfinyl)-1-(5-(5-methylpyridazin-3-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]
113 6-(ethylsulfonyl)-1-(5-(5-methylpyridazin-3-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]
2-(6-(2-(6-(Ethylsulfinyl)spiro[indoline-3^'-oxetan]-1-yl)pyrimidin-5-yl)pyridazin-4-yl)propan-2- ol
2-(6-(2-(6-(ethylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)pyridazin-4-yl)propan-2- ol
116 2-((1-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)sulfinyl) ethanol
117 2-((1-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)sulfonyl)ethanol
2-(2-(2-(6-((2-Hydroxyethyl)sulfinyl)spiro[indoline-3^'-oxetan]-1-yl)pyrimidin-5-yl)pyridin-4-yl)^
118
propan-2-ol
2- (2-(2-(6-((2-Hydroxyethyl)sulfonyl)spiro[indoline-3^'-oxetan]-1-yl)pyrimidin-5-yl)pyridin-4-yl)-
119
propan-2-ol
3- ((1-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl) sulfinyl)propan-1-
120
ol
3-((1-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl) sulfonyl)propan-1-
121
ol
3-((1-(5-(4-(2-Hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)-
122
sulfinyl)propan-1-ol
3-((1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)-
124
sulfonyl)propan-1-ol
(1 -(5-(6-hydroxypyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)-
125
methanone
126 (1 -(5-(3-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)- methanone
(1 -(5-(2-fluoro-3-hydroxyphenyl)pyrim^
127
methanone
(1 -(5-(3-amino-2-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3^'-oxetan]-6-yl)(m
128
methanone
129 (1 -(6-methyl-[4,5'-bipyrimidin]-2'-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)methanone
(1 -(5-(2-fluoro-6-hydroxyphenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)- 130
methanone
(1 -(5-(2-amino-6-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)-
131
methanone
(1 -(5-(6-aminopyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)- 132
methanone
(1 -(5-(2-fluoro-3-methylphenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)- 133
methanone
(1 -(5-(2-fluoro-6-methylphenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)- 134
methanone
135 (1 -(4-methyl-[2,5'-bipyrimidin]-2'-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)methanone
136 (1 -(4,6-dimethyl-[2,5'-bipyrimidin]-2'-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)methanone
1-([2,5'-bipyrimidin]-2'-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3'-oxetane]-6-
137
carboxamide
N-(2-hydroxyethyl)-N-methyl-1-(5-(pyrazin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]-6- 138
carboxamide
N-(2-Hydroxyethyl)-N-methyl-1 -(5-(6-methylpyridin-2-yl)pyrimidin-2-yl)spiro [indoline-3,3'- 139
oxetane]-6-carboxamide
N-(2-hydroxyethyl)-1-(5-(6-hydroxypyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[indoline-3,3'- 140
oxetane]-6-carboxamide
N-(2-hydroxyethyl)-1-(5-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro- 141
[indoline-3,3'-oxetane]-6-carboxamide
(1 -(5-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)- 142
(morpholino)methanone
(1 -(5-(6-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)(morpholino)- 143
methanone
N-((3-hydroxyoxetan-3-yl)methyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro- 144
[indoline-3,3'-oxetane]-6-carboxamide
N-((1-hydroxycyclopropyl)methyl)-N-methyl-1 -(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro- 145
[indoline-3,3'-oxetane]-6-carboxamide
1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N,N-dimethylspiro[indoline-3,3'- 146
oxetane]-6-carboxamide
1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[indoline-3,3'-oxetane]- 147
6-carboxamide
148 N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]-6-carboxamide
N-(2-hydroxyethyl)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetane]-6- 149
carboxamide
N-(2-hydroxyethyl)-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-
150
oxetane]-6-carboxamide
1-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)spiro[indoline-3,3'-oxetane]-6- 151
carboxamide (1 -(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[indolin
152
(morpholino)methanone
1-(5-(2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)spiro[indoline-3,3'-oxetane]-6- 153
carboxamide
N-(2-Hydroxyethyl)-1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro- 154
[indoline-3,3'-oxetane]-6-sulfonamide
N-(2-hyd roxyethyl )- 1 -(5-(4-(2-hyd roxypropan-2^
155
oxetane]-6-sulfonamide
N-(2-hydroxyethyl)-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline
156
sulfonamide
157 N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimi
1-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[indol^
158
6-sulfonamide
159 6-(ethylsulfinyl)-1 -(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indolm
161 6-(ethylsulfinyl)-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxete
163 6-(ethylsulfonyl)-1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan
164 2-(6-(2-(6-(Ethylsulfinyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)pyridi^
166 2-(6-(2-(6-(Ethylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)pyridm
167 2-((1-(5-(Pyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)sulfin
169 2-((1-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[indoH^
2-(2-(2-(6-(Ethylsulfinyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)pyrid
170
amine
2-(2-(2-(6-(ethylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2- amine
172 2-(2-(6-(ethylsulfinyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)isonicotinamide
173 2-(2-(6-(ethylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)isonicotinamide
174 2-(2-(6-(morpholine-4-carbonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)isonicotinamide
1-(5-(4-carbamoylpyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3'-
175
oxetane]-6-carboxamide
176 2-(2-(6-(morpholine-4-carbonyl)spiro[indoline-3,3'-oxetan]-1 -yl)pyrimidin-5-yl)isonicotinonitril^
1-(5-(4-cyanopyridin-2-yl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[indoline-3,3'- 177
oxetane]-6-carboxamide
N-(2-Hydroxyethyl)-N-methyl-1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-2 3 5 6'-tetrahydro-
178
spiro[indoline-3,4'-pyran]-6-carboxamide
2-(4-Fluoro-3-(2-(6-(1 -(methylamino)cyclopropyl)spiro[indoline-3,3'-oxetan]-1-yl) pyrimidin-5- 179
yl)phenyl)propan-2-ol
1-(1 -(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)-N-methylcyclopropan- 180
amine
1-(1 -(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)-N-methylcyclo- 181
propanamine
1- (1 -(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)-N-methylcyclo- 182
propanamine
2- (2-(2-(6-(1-(Methylamino)cyclopropyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)pyridin-4- 183
yl)propan-2-ol
N-methyl-1-(1-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)cyclo- 184
propanamine N-ethyl-1 -(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)sp^
sulfonamide
1-(5-(4-(2-aminopropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[indoline-3,3'-oxetane]-6- sulfonamide
.jg-. 1-(5-(4-(2-aminopropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N,N-dimethylspiro[indoline-3,^
oxetane]-6-sulfonamide
^gg N-(2-Hydroxyethyl)-N-methyl-1 5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-4,5-dihydro-2H-spiro [furan-3,3'-indoline]-6'-carboxamide
189 2-(2-(6-(ethylsulfinyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)isonicotinonitrH
191 2-(2-(6-(Ethylsulfonyl)spiro[indoline-3,3'-oxetan]-1-yl)pyrimidin-5-yl)isonicotinonitrile
192 (1 -(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl)dimethyl- phosphine oxide
193 (1 -(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[indoline-3,3'-oxetan]-6-yl) dimethylphosphine oxide optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a physiologically acceptable solvate thereof.
Pharmaceutical composition comprising at least one compound as defined in one of claims 1 to 14.
A compound as defined in one of claims 1 to 14 in the presented form or in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a physiologically acceptable solvate thereof, for use as a medicament for the treatment of conditions or diseases that can be treated by inhibition of the PDE4 enzyme,
wherein the conditions or diseases that can be treated by inhibition of the PDE4 enzyme are selected from the following group: inflammatory diseases of the joints, skin and eyes, gastrointestinal diseases and complaints, inflammatory diseases of the internal organs; hyperplastic diseases, respiratory or lung diseases associated with elevated mucus production, inflammation and/or obstruction of the respiratory tract, diseases of the fibrotic spectrum, cancers, metabolic diseases, psychological disorders, and diseases of the peripheral or central nervous system.
PCT/EP2016/025187 2015-12-22 2016-12-22 Novel substituted spiro-[indoline heterocycloalkane] compounds as phosphodiesterase inhibitors WO2017108204A1 (en)

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US20140235612A1 (en) * 2013-02-19 2014-08-21 Pfizer Inc. Azabenzimidazole Compounds
WO2014170020A1 (en) * 2013-04-16 2014-10-23 Grünenthal GmbH Substituted condensed pyrimidine compounds
WO2016008593A1 (en) * 2014-07-16 2016-01-21 Grünenthal GmbH Novel substituted pyrimidine compounds

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US20140235612A1 (en) * 2013-02-19 2014-08-21 Pfizer Inc. Azabenzimidazole Compounds
WO2014170020A1 (en) * 2013-04-16 2014-10-23 Grünenthal GmbH Substituted condensed pyrimidine compounds
WO2016008593A1 (en) * 2014-07-16 2016-01-21 Grünenthal GmbH Novel substituted pyrimidine compounds

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114031558A (en) * 2021-12-14 2022-02-11 无锡捷化医药科技有限公司 Preparation method of 1- (6-chloropyridazin-4-yl) ethyl-1-ketone

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