[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2017108203A1 - Novel substituted indoline compounds as phosphodiesterase inhibitors - Google Patents

Novel substituted indoline compounds as phosphodiesterase inhibitors Download PDF

Info

Publication number
WO2017108203A1
WO2017108203A1 PCT/EP2016/025186 EP2016025186W WO2017108203A1 WO 2017108203 A1 WO2017108203 A1 WO 2017108203A1 EP 2016025186 W EP2016025186 W EP 2016025186W WO 2017108203 A1 WO2017108203 A1 WO 2017108203A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
spiro
pyrimidin
cyclopropane
indolin
Prior art date
Application number
PCT/EP2016/025186
Other languages
French (fr)
Inventor
Ingo Konetzki
Florian JAKOB
Markus Wagener
André Welbers
Christian Hesslinger
Original Assignee
Grünenthal GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Grünenthal GmbH filed Critical Grünenthal GmbH
Publication of WO2017108203A1 publication Critical patent/WO2017108203A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to novel substituted indoline 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 phosphodiesterases, 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 observed not only observed with roflumilast and apremilast but also with other PDE4 inhibitors, so the therapeutic range 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 is cAMP-specific and encompasses 4 different subtypes (PDE4A, PDE4B, PDE4C and PDE4D).
  • PDE4A, PDE4B, PDE4C and PDE4D are 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); Progress in Medicinal Chemistry 47 , 37-74; Robichaud, A. et al. (2002)).
  • novel substituted indoline compounds that possess the desired inhibiting and PDE4B-selective properties. These indoline 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; R and R 2 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyi, which is unsubstituted or substituted with one, two, three or four substituents Y;
  • 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;
  • R 3 is -L-R 4 ;
  • R 4 is selected from OH, CN, R 3 , OR 13 , NH 2 , NH(R 13 ) or N(R 3 ) 2 ,
  • Ci-6-alkyl unsubstituted or mono- or polysubstituted
  • Z at each occurcence is independently selected from the group consisting of halogen, OH, CN, SH, N0 2 , d-C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl, (C-
  • NHC(0)NH 2 NHCONH(d-C 6 -alkyl), NHCON(d-C 6 -alkyl) 2 , (d-C 6 -alkylen)NH 2 , (d-C6-alkylen)NH(d-C 6 - alkyl), (d-C 6 -alkylen)N(d-C 6 -alkyl) 2 , (d-C 6 -alkylen)NHCO(d-C 6 -alkyl), (C C 6 -alkylen)NHC0 2 (d-C 6 - alkyl), (C C 6 -alkylen)NHC(0)NH 2 , (C C 6 -alkylen)NHCONH(d-C 6 -alkyl), (d-C 6 -alkylen)NHCON(d-C 6 - alkyl) 2 , NH((d-C6-alkylen)-C0 2 (d-C 6 -alkylen
  • 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.
  • Ci-C6-alkyl is understood to mean branched and unbranched alkyl groups consisting of 1 to 6 carbon atoms.
  • Ci-C6-alkyl radicals are 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 , 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-C6-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 ) 2
  • 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 .
  • -C 6 )-haloalkyl" is understood to be a C-
  • the haloalkyl can be branched or unbranched and optionally mono- or polysubstituted.
  • Preferred (Ci-C6)-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.
  • Preferred (Ci-C6)-haloalkoxy radicals are (Ci-C 3 )-haloalkoxy radicals, in particular OCHF 2 , OCH 2 F, OCF 3 , OCF 2 CH 3 , OCH 2 CH 2 F, OCH 2 CHF 2 and OCH 2 CF 3 .
  • (Ci-C6)-hydroxyalkyl is understood to be a Ci-C6-alkyl in which at least one hydrogen is exchanged for a hydroxyl group.
  • the hydroxyalkyi radicals can be branched or unbranched and optionally mono- or polysubstituted.
  • Preferred (Ci-C6)-hydroxyalkyl radicals are (Ci-C 3 )- hydroxyalkyi 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 .
  • (Ci-C6)-cyanoalkyl is understood to be a Ci-C6-alkyl in which at least one hydrogen is exchanged for a cyano group.
  • the hydroxyalkyi 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.
  • -C 6 )-thioalkyl is understood to mean branched and unbranched thioalkyl groups consisting of 1 to 6 carbon atoms.
  • -C 6 )-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
  • (Ci-C 4 )-thioalkyl radicals are preferred, in particular SCH 3 , SCH 2 CH 3 , SCH 2 CH 2 CH 3 or SCH(CH 3 ) 2 .
  • the term "(d-CeHhiohaloalkyl” is understood to be a (Ci-C6)-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.
  • -C 6 )-thiohaloalkyl radicals are (C-
  • Ci_C 3 -alkylen and “Ci_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.
  • Examples of C 2 -C 6 -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 C 2 -C 6 -alkenyl includes all possible isomers, i.e.
  • 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.
  • the residues may be mono- or bicyclic.
  • 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, wherein 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 )-alkoxy, (Ci-C 6 )-hydroxyalkoxy, C 3 -C 6 -cycloalkyl, NH 2 , NH(Ci-C 6 -alkyl), N(d-C 6 - alkyl)CO(C C 6 -alkyl), NHCO(Ci-C 6 -hydroxyalkyl), N(Ci-C6-alkyl)CO(Ci-C 6 -hydroxyalkyl),N(Ci-C 6 -alkyl)2, NH(d-C 6 -hydroxyalkyl), N(d-C6-alkyl)(d-C6-hydroxyalkyl), NHCO(d-C 6 -alkyl), NH-CONH(d-C 6 -alkyl),
  • substituents may be present either on different or on the same atoms or at different places, and may include identical or different substituents.
  • 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, C 3 -C 6 -cycloalkyl, NH 2 , NH(d-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), CON H 2 , CON H(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-C 6 -alkyl in N(d-C 6 -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(Ci-C6-alkyl) 2 wherein Ci-C6-alkyl may be unsubstituted or substituted by OH , 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 . ithin the scope of the present invention, the symbols
  • the compound of formula (I) is characterized in that each of A, B and C represents CH.
  • the compound of formula (I) is characterized in that R and R 2 together with the carbon atom to which they are attached form a cyclopropyl or a cyclo- butyl, preferably a cyclopropyl, which is unsubstituted or substituted with one, two, three or four substituents Y.
  • the compound of formula (I) is
  • R and R together with the carbon atom to which they are attached form a 3- to 6- membered cycloalkyl, which is unsubstituted or substituted with one or two substituents Y,
  • R and R 2 together with the carbon atom to which they are attached form a unsubstituted 3- to 6-membered cycloalkyl, preferably unsubstituted cyclopropyl or unsubstituted cyclobutyl, more preferably unsubstituted cyclopropyl.
  • the compound of formula (I) is characterized in that G is one of the following groups G1 to G44
  • R 2 is selected H, CH 3 or CH 2 CH 3 ;
  • k at each occurrence is 0, 1 , 2, 3 or 4;
  • Z at each occurcence is independentlyselected 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, (Ci-C6)-cyanoalkyl, Ci-C6-alkoxy, (d-Ce)- thioalkyl, (C C 6 )-haloalkyl, (C C 6 )-thiohaloalkyl, (C C 6 )-haloalkoxy, (d-C 6 -alkylen)-S-(d-C 6 -alkyl), C 3 - C 6 -cycloalkyl, (C 3 -C 6 -cycloalkyl)-(C-
  • Z at each occurcence is independently selected from the group consisting of F, CI, Br, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, CN, d-d-alkyl, d-d-hydroxyalkyl, d-C 6 -alkoxy, C 3 -C 6 -cycloalkyl, 3- to 7- membered heterocycloalkyi, NH 2 , NH(d-C 6 -alkyl), N(Ci-d-alkyl) 2 , NHCO(Ci-d-alkyl), (d-d- alkylen)NH 2 , (d-d-alkylen)NH(d-d-alkyl), (C C 6 -alkylen)N(d-C 6 -alkyl) 2 , (d-C 6 -alkylen)NHCO(d-C 6 - alkyl), NHCONH(C C 6 -alkyl), NH
  • the compound of formula (I) is characterized in that G is one of the groups G1 to G44
  • R 2 is selected 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
  • pyrrolidinyl, said piperidinyl, said aziridinyl, said cyclopropyl, said cyclobutyl, said cyclopentyl and said cyclohexyl is unsubstituted or mono- or polysubstituted with one or more substituents 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 , CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , and NHCOCH 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
  • pyrrolidinyl, said aziridinyl and said cyclopropyl is unsubstituted or mono- or polysubstituted with one or more substituents 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 , and NHCOCH 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 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH(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 ) 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 , NHCOCH3, 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
  • R 3 is -L-R 4 ;
  • R 4 is selected from OH, CN, R 3 , OR 13 , NH 2 , NH(R 13 ) or N(R 3 ) 2 ,
  • C 6 -alkyl) 2 NH(C C 6 -hydroxyalkyl), N(Ci-C 6 -alkyl)(Ci-C 6 -hydroxyalkyl), N(Ci-C 6 -hydroxyalkyl) 2 , NHCO(C C 6 -alkyl), N(d-C 6 -alkyl)CO(d-C 6 -alkyl), NHCO(C C 6 -hydroxyalkyl), N(C C 6 -alkyl)CO- (C C 6 -hydroxyalkyl), CONH 2 , CONH(C C 6 -alkyl), CON(C C 6 -alkyl) 2 , CONH(C C 6 -hydroxyalkyl), CON(Ci-C 6 -alkyl)(Ci-C 6 -hydroxyalkyl), CON(Ci-C 6 -hydroxyalkyl) 2 , C 3 -C 6 -cycloalkyl, and 3- to 7- membered heterocycloalky
  • R 6 is H, (C C 6 -alkyl), (C C 6 )-hydroxyalkyl, (C C 6 )-cyanoalkyl, C 3 -C 6 -cycloalkyl, CO(C C 6 -alkyl) or S0 2 (Ci-C 6 -alkyl); at each occurence m is 0, 1 , 2, 3, 4 or 5, and
  • 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 , d-C 6 -alkyl, d-d-alkoxy, NH 2 , NH(d-C 6 -alkyl), N(d-C 6 -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-d-alkyl) 2 ,
  • the compound of formula (I) is characterized in that
  • R 3 is -L-R 4 , wherein
  • R 4 is selected from OH, CN, C C 6 -alkyl, 0(C C 6 -alkyl), NH 2 , NH(C C 6 -alkyl), N(C C 6 -alkyl) 2 , C 3 -C 6 - cycloalkyl, 3- to 7-membered heterocydoalkyi, 0(C 3 -C 6 -cycloalkyl) or 0(3- to 7-membered heterocydoalkyi),
  • R 4 is selected from one of the following substructures M1 to M120: I
  • the compound according to formula (I) is characterized in that
  • the compound according to formula (I) is characterized in that
  • R 4 is selected from C 3 -C 6 -cycloalkyl or 3- to 7-membered heterocycloalkyi
  • the compound according to formula (I) is characterized in that
  • R 4 is Ci-Ce-alkyl
  • the compound of formula (I) is characterized in that
  • R 4 is selected from C C 6 -alkyl, NH 2 , NH(C C 6 -alkyl), N(C C 6 -alkyl) 2 , C 3 -C 6 -cycloalkyl or 3- to 7- membered heterocycloalkyi,
  • Ci-C6-alkyl is independently unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, Ci-C6-alkoxy, (Ci-C6-alkoxy)-CrC6- alkoxy, (hydroxy)-Ci-C6-alkoxy, C 3 -C 6 -cycloalkyl and 3- to 7-membered heterocycloalkyi;
  • R 4 is selected from one of the above substructures M1 to M120.
  • the compound of formula (I) is characterized in that
  • R 4 is selected from Ci-C6-alkyl
  • Ci-C6-alkyl is independently unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, C-
  • R 4 is selected from Ci-C6-alkyl, C 3 -C 6 -cycloalkyl or 3- to 7-membered heterocycloalkyl,
  • Ci-C6-alkyl is independently unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , OH, Ci-C6-alkoxy, (Ci-C6-alkoxy)-CrC6- alkoxy, (hydroxy)-Ci-C6-alkoxy, C 3 -C 6 -cycloalkyl and 3- to 7-membered heterocycloalkyl;
  • the compound of formula (I) is characterized in that
  • R 4 is selected from Ci-Ce-alkyl, wherein said Ci-C6-alkyl is independently unsubstituted or substituted with OH.
  • 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), (le) or (If),
  • R 4 and G are defined as before.
  • the compound according to general formula (I) is selected from one of the general formula (la), (lb), (lc), (Id), (le) or (If); 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
  • pyrrolidinyl, said aziridinyl and said cyclopropyl is unsubstituted or mono- or polysubstituted with one or more substituents 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 , and NHCOCH 3 , and
  • R 4 is selected from OH, CN, d-C 6 -alkyl, 0(d-C 6 -alkyl), NH 2 , NH(C C 6 -alkyl), N(d-C 6 -alkyl) 2 , C 3 -C 6 - cycloalkyl, 3- to 7-membered heterocycloalkyi, 0(C 3 -C 6 -cycloalkyl) or 0(3- to 7-membered
  • the compound according to general formula (I) is selected from one of the general formula (la), (lb), (Ic), (Id), (le) or (If);
  • 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, CF 3 , CHF 2 ,
  • R 4 is selected from one of the substructures M1 to M120 as defined above.
  • the invention relates to a compound selected from the group consisting of
  • 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), (Id) or (le).
  • 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), (Id) or (le), 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), (Ic), (Id) or (le), 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 eyesand/or gastrointestinal diseases and complaintsand acute and chronic inflammations of and/or inflammatory diseases of the internal organs and/or hyperplastic diseases and/or respiratory or lung diseases associated with elevated mucus production, inflammation and/or obstruction of the respiratory tract and/or diseases of the fibrotic spectrum and/or cancersand/or metabolic diseases and/or cardiovascular diseases and/or 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), (Ic), (Id) or (le), for the use as a medicament for the treatment of inflammatory diseases of the joints, the skin or the eyes, 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), (Ic), (Id) or (le), 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), (Id) or (le), 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), (Id) or (le), 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), (Id) or (le), according to the
  • 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.
  • 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.
  • 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. In the following the present invention is illustrated by way of examples without limiting the invention thereto.
  • APCI atmospheric pressure chemical ionization
  • Mobile phase A 10 mM ammonium acetate in water / Mobile phase B: acetonitrile.
  • Mobile phase A 10 mM ammonium acetate in water / Mobile phase B: acetonitrile.
  • Mobile phase A 0.05% formic acid in water/ Mobile phase B: acetonitrile;
  • n-Butyllithium (2.25 M in hexane, 130 mL, 259.4 mmol) was added drop wise at -40°C to a solution of 6- bromoindolin-2-one (25.0 g, 1 17.9 mmol) and diisopropylamine (36.54 mL, 259.4 mmol) in THF (500 mL). The mixture was stirred for 45 min at that temperature, 1 ,2-dibromoethane (31.0 mL, 353.7 mmol) was added drop wise and stirring was continued for 16 h while the temperature was slowly raised to RT.
  • PdCI 2 (dppf) (67 mg, 0.082 mmol, 0.05 eq) was added to a suspension of 3b) (650 mg, 1.649 mmol, 1 eq), bis(pinacolato)diboron (834 mg, 3.298 mmol, 2 eq) and potassium acetate (243 mg, 2.47 mmol, 1.5 eq) in 1 ,4-dioxane (25 ml) that was kept under Ar.
  • the reaction mixture was stirred for 16 h at 100°C, cooled to RT and filtered through a plug of celite.
  • Example 9 1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)-6'-(isopropylsulfonyl)spiro[cyclopropane-1 ,3'-indoline1
  • Example 10 1 '-(5-(2-Fluorophenyl)pyri '-(isopropylsulfinyl)spiro[cvclopropane-1 ,3'-indolinel
  • Example 1 3-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)sulfonyl) butan- 1-ol
  • Example 12 3-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolin1-6'-yl)sulfinyl) butan- 1-ol
  • Example 13 3-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)sulfonyl) propan-1-ol
  • Example 14 3-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin1-6'-yl)sulfinyl) propan- 1-ol
  • Example 15 2-((1'-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)sulfonyl) ethanol
  • Pd2(dba)3 (4.45g, 4.85 mmol, 0.05 eq) and Xantphos (5.6 g, 9.71 mmol, 0.1 eq) were added to a solution of 5'-bromospiro[cyclopropane-1 ,3'-indolin]-2'-one (23 g, 97.1 mmol, 1 eq), 4-methoxybenzylthiol (18 g, 1 16.5 mmol, 1.2 eq) and DIPEA (36 ml, 204.0 mmol, 2.1 eq) in 1 ,4-dioxane (400 ml) that was stirred under Ar.
  • Example 19 to 21 were prepared analogously to synthesis example 18.
  • Example 20 1 '-(5-(4-Ethylpyridin-2-yl)pyrimidin-2-yl)-N,N-dimethylspiro[cyclopropane-1 ,3'-indolinel-6'- sulfonamide
  • Example 22 1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N-dimethylspiro[cyclopropane-1 ,3'-indolinel-6'- sulfonamide
  • Example 23 1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro[cyclopropane-1 ,3'- indolinel-6'-sulfonamide
  • Example 32 1 '-(5-(6-Ethylpyridin-2-yl)pyrimidin-2-yl)-6'-(ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolinel
  • Example 33 3-((1 '-(5-(4-Cvclopropylpyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)- sulfinyl)propan-1-ol
  • PdCI2(dppf) (204 mg, 0.255 mmol, 0.05 eq) was added to a solution of compound 33e) (2 g, 5.12 mmol, 1 eq), potassium acetate (1.23 g, 12.45 mmol, 2.5 eq) and bis(pinacolato)diboron (2.60 g, 10.23 mmol, 2 eq) in dioxane (20 ml) that was stirred under Ar. The reaction mixture was refluxed for 16 h and then cooled to RT.
  • Example 36 3-((1 '-(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)sulfinyl)- propan-1-ol
  • Synthesis examples 37 to 40 were prepared in analogy to example 33 with the difference that 2.5 equivalents of mCPBA were used in the oxidation step.
  • Example 37 3-((1 '-(5-(4-Cvclopropylpyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-vD- sulfonyl)propan-1-ol
  • Example 38 3-((1 5-(4-Aminopyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)sulfonyl)- propan-1-ol
  • Example 40 3-((1 '-(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)sulfonyl)- propan-1-ol
  • Example 43 1 -(3-(2-(6WEthylsulfonyl)spiro[cvclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)-4-fluorophenyl)- ethanol
  • Example 45 1-(2-(2-(6'-(Ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)pyridin-4-yl)- ethanol
  • Example 47 1-(3-(2-(6'-(Ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)-4-fluorophenyl)- ethanol
  • Example 48 2-(3-(2-(6'-(Ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)-4-fluorophenyl)- propan-2-ol
  • Example 52 (1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin1-6'-yl)(tetrahvdro-2H- Pyran-4-yl)methanol
  • Example 54 1-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)-N-methylcyclo- propanamine
  • Tetrakis(triphenylphosphine)palladium(0) (0.247 g, 0.21 mmol, 0.05 eq) was added to a stirred solution of compound 1 1a (1.7 g, 4.29 mmol, 1 eq) and zinc cyanide (0.502 g, 4.29 mmol, 1 eq) in dioxane (15 ml). The mixture was stirred under Ar at 140°C for 16 h, cooled to RT and poured onto ice water. The precipitating solid was filtered off and dried in vacuo. White solid. Yield: 1.2 g (82%)
  • Example 55 1-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin1-6'-yl)-N,N-dimethyl- cyclopropanamine
  • Example 56 2-((1-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolin1-6'-yl)cyclo- propyl)(methyl)amino)ethanol
  • Ethyl magnesium bromide (5 ml, 14.4 mmol, 6 eq) was slowly added at -78°C to a stirred solution of titanium(IV) isopropoxide (1.43 ml, 4.8 mmol, 2 eq) in THF (15 ml) and the mixture was stirred for 1 h at this temperature.
  • Compound 57a (900 mg, 2.4 mmol, 1 eq) dissolved in THF (10 ml) was slowly added and the reaction mixture was gradually warmed to RT and stirred for 16 h. The reaction mixture was then cooled to 0°C, quenched with aqueous 2N HCI solution, stirred for 10 min. and extracted with EtOAc (2 x 20 ml).
  • Example 58 1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)-6'-(1 -methoxycvclopropyl)spiro[cyclopropane-1 ,3'- indolinel
  • Example 59 6 1-Methoxycvclopropyl)-1 '-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cvclo-propane- 1 ,3'-indolinel
  • Methyl spiro[cyclopropane-1 ,3'-indoline]-6'-carboxylate (2.5 g, 12.31 mmol, 1 eq, compound 50a), 5- bromo-2-chloropyrimidine (2.61g, 13.54 mmol, 1.1 eq) and DIPEA (10 ml, 61.55 mmol, 5 eq) in n-butanol (20 ml) were stirred at 140°C for 16 h in a sealed tube. The reaction mixture was then cooled to RT and the resulting solid was filtered off and dried under vacuum. White solid.
  • Examples 60 and 61 were obtained from the pinacol boronate 59c analogously to synthesis example 59.
  • Example 62 2-(((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)methyl) amino)ethanol
  • Example 63 2-(((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)methyl)- (methvDamino)ethanol
  • Example 64 2-(((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)methyl)- (methyl)amino)-2-methylpropan-1-o
  • Example 65 N-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)methyl)-N- methylacetamide
  • Example 70 3-((1 5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'- indolinl-6'-yl)sulfonyl)propan-1-ol
  • Example 72 3-((1 '-(5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'- indolinl-6'-yl)sulfonyl)propan-1-ol
  • Example 75 3-((1 '-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)sulfonyl)- butan-1-ol
  • Example 76 Ethyl 1 '-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinel-6'- carboxylate
  • Examples 80 to 82 were prepared from 1 '-(5-bromopyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]-6'- sulfonyl chloride in analogy to synthesis example 18.
  • Example 80 N-(2-Hvdroxyethyl)-1 '-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro-
  • Example 83 2-(2-(2-(6'-(Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)pyrimidin-5-yl)pyridin-4- yl)propan-2-amine
  • PdCI 2 (dppf) (0.865 g, 1.061 mmol, 0.05 eq.) was added to a suspension of 1 '-(5-bromopyrimidin-2-yl)-6'- (ethylthio)spiro[cyclopropane-1 ,3'-indoline] 1d (8.0 g, 1.85 mmol, 1 eq.), bis(pinacolato)diboron (8.08 g, 31.83 mmol, 1.5 eq) and potassium acetate (6.23 g, 63.66 mmol, 3.0 eq.) in 1 ,4-dioxane (100 ml) stirred under Ar.
  • Tetrakis(triphenylphosphine)palladium(0) (0.424 g, 0.367 mmol, 0.05 eq.) was added to a solution of 83a (3.0 g, 7.33 mmol, 1 eq.), K 2 C0 3 (2M aqueous solution, 3.0 g, 22.00 mmol, 3 eq.) and 2-(2-bromopyridin- 4-yl)propan-2-amine hydrochloride (1.57g, 7.33 mmol, 1 eq.) in dioxane (30 ml) stirred under Ar. The reaction mixture was then refluxed for 16 h at 100°C, cooled to RT and filtered through a celite pad.
  • Benzyl chloroformate (0.205 ml, 1.44 mmol, 1 eq.) was added at 0°C to a stirred solution of compound 83b (0.6 g, 1.44 mmol, 1 eq.) and DIPEA (0.501 ml, 2.88 mmol, 2 eq.) in THF (30 ml). The reaction mixture was warmed slowly to RT and stirred for another 2 h. The mixture was then diluted with EtOAc and washed with saturated aqueous NaHC0 3 solution and brine. The organic layer was separated, dried over anhydrous Na 2 S0 4 and concentrated.
  • Example 84 2-(2-(2-(6'-(Ethylsulfonyl)spiro[cvclopropane-1 ,3'-indolin1-1 '-yl)Pyrimidin-5-yl)pyridin-4-yl)-N- methylpropan-2-amine
  • the target compound (acetate salt) was derived from 84a in analogy to synthesis example 83.
  • MS: m/z: [M+H] + 464.1.
  • Example 85 1-(2-(2-(6'-(Ethylsulfonyl)spiro[cvclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)pyridin-4-yl)- cyclopropanamine
  • Example 86 1 -(2-(2-(6'-(Ethylsulfonyl)spiro[cvclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)pyridin-4-yl)-N- methylcyclopropanamine
  • Example 87 2-(2-(2-(6'-(Ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)pyridin-4-yl)- propan-2-amine
  • Example 88 2-(2-(2-(6'-(Ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)pyridin-4-yl)-N- methylpropan-2-amine
  • Example 90 1-(2-(2-(6'-(Ethylsulfinyl)spiro[cyclopropane-1,3'-indolinl-1 '-yl)pyrimidin-5-yl)pyridin-4-yl)-N- methylcvclopropanamine
  • Example 92 and 93 2-(6-(2-(6 Ethylsulfinyl)spiro[cvclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)pyridin-2- yl)propan-2-ol (faster and slower elutinq enantiomer)
  • the racemic sulfoxide was prepared from intermediate 3b in analogy to synthesis example 24.
  • the two enantiomers were obtained from this racemate (800 mg) through preparative chiral HPLC.
  • Example 96 N-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin1-6'-yl)-3-hvdroxy- propanamide
  • Example 98 was obtained from the aforementioned alkylation product in analogy to the synthesis protocols for example 96.
  • Example 102 2-(((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)methyl)- amino)-2-methylpropan-1-ol
  • PdCI 2 (dppf) (122 mg, 0.173 mmol) was added at RT to a solution 103c (1.2 g, 3.47 mmol), bis- (pinacolato)diboron (1.76 g, 6.94 mmol) and potassium acetate (1 g, 12.14 mmol) in dry dioxane (30 mL) that was stirred under Ar. The reaction mixture was heated at 90°C for 30 min.
  • Example 104 N-Methyl-N-((1 5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-in vDimethvDacetamide
  • Example 105 2-Methyl-2-(methyl((1 '-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'- indolinl-6'-yl)methyl)amino)propan-

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The invention relates to novel 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 indoline compounds as phosphodiesterase inhibitors
FIELD OF THE INVENTION
The present invention relates to novel substituted indoline 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 phosphodiesterases, 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 observed not only observed with roflumilast and apremilast but also with other PDE4 inhibitors, so the therapeutic range 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); 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. US 2006 / 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 indoline compounds that possess the desired inhibiting and PDE4B-selective properties. These indoline 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 imgf000003_0001
wherein
A, B and C independently represent CH or N; R and R2 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyi, which is unsubstituted or substituted with one, two, three or four substituents Y;
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;
R3 is -L-R4;
L is selected from bond, S(=0), S(=0)2, P(=0)(R4), C(H)(OH) or C(CH3)(OH);
R4 is selected from OH, CN, R 3, OR13, NH2, NH(R13) or N(R 3)2,
wherein each R 3 independently of each other denotes
Ci-6-alkyl, unsubstituted or mono- or polysubstituted;
or
C3.6-cycloalkyl or 3- to 7-membered heterocycloalkyl, in each case unsubstituted or mono- or polysubstituted;
or
C3-6-cycloalkyl or 3- to 7-membered heterocycloalkyl, in each case unsubstituted or mono- or polysubstituted, and in each case connected via a d-C6-alkylen, unsubstituted or mono- or polysubstituted;
Y at each occurrence is independently from one another selected from the group consisting of OH, =0, CN, N02, halogen, C C6-alkyl, C C6-hydroxyalkyl, C C6-alkoxy, S(C C6-alkyl), S(0)(C C6-alkyl), S(0)2(Ci-C6-alkyl), (Ci-C6)-haloalkyl, S(Ci-C6)-haloalkyl, (Ci-C6)-haloalkoxy, (Ci-C6)-cyanoalkyl, C3-C6- cycloalkyl, NH2, NH(d-C6-alkyl), N(d-C6-alkyl)2, NHCO(d-C6-alkyl), NHSO(d-C6-alkyl), NHS(0)2(C1- C6-alkyl), NH(d-C6-alkylen)-CO(d-C6-alkyl), NH(d-C6-alkylen)-SO(d-C6-alkyl), NH(C C6-alkylen)- S02(d-C6-alkyl), NHCONH2, NHCONH(d-C6-alkyl), NH(d-C6-alkylen)-CON(d-C6-alkyl)2, C02H, C02(d-C6-alkyl), CONH2, CONH(d-C6-alkyl) and CON(d-C6-alkyl)2;
Z at each occurcence is independently selected from the group consisting of halogen, OH, CN, SH, N02, d-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, (C-|-C6)-hydroxyalkyl, (d-C6)-cyanoalkyl, d-C6-alkoxy, (d-C6)- thioalkyl, (C C6)-haloalkyl, (d-C6)-thiohaloalkyl, (d-C6)-haloalkoxy, (d-C6-alkylen)-S-(d-C6-alkyl), C3- C6-cycloalkyl, (C3-C6-cycloalkyl)-(d-C3-alkylenyl), 3- to 7-membered heterocycloalkyl, said C3.6-cycloalkyl and said 3- to 7-membered heterocycloalkyl being in each case unsubstituted or mono- or
polysubstituted, NH2, NH(d-C6-alkyl), N(d-C6-alkyl)2, NHCO(d-C6-alkyl), NHC02(d-C6-alkyl),
NHC(0)NH2, NHCONH(d-C6-alkyl), NHCON(d-C6-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), (C C6-alkylen)NHC02(d-C6- alkyl), (C C6-alkylen)NHC(0)NH2, (C C6-alkylen)NHCONH(d-C6-alkyl), (d-C6-alkylen)NHCON(d-C6- alkyl)2, NH((d-C6-alkylen)-C02(d-C6-alkyl), NH(d-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-C6-alkyl)2, NH(d-C6-alkylen)-S(0)2OH, NH(d-C6- alkylen)-S(0)2(C1-C6-alkyl), NH(C1-C6-alkylen)-S(0)20(C1-C6-alkyl), NH(C1-C6-alkylen)-S(0)2NH2, NH(d- C6-alkylen)-S(0)2NH(d-C6-alkyl), C02H, CO(d-C6-alkyl), C02(d-C6-alkyl), 0-CO(d-C6-alkyl), O- C02(d-C6-alkyl), CONH2, CONH(d-C6-alkyl), CON(d-C6-alkyl)2, OCONH(d-C6-alkyl), OCON(d-C6- alkyl)2, OS(0)2(d-C6-alkyl), OS(0)2OH, OS(0)20(d-C6-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(d-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 "Ci-C6-alkyl" is understood to mean branched and unbranched alkyl groups consisting of 1 to 6 carbon atoms. Examples of Ci-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 "Ci-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 "(C-|-C6)-haloalkyl" is understood to be a C-|-C6-alkyl in which at least one hydrogen is exchanged for a halogen atom, preferably for F or CI, particularly preferably for F. The haloalkyl can be branched or unbranched and optionally mono- or polysubstituted. Preferred (Ci-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 (Ci-C6)-haloalkoxy radicals are (Ci-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 hydroxyalkyi radicals can be branched or unbranched and optionally mono- or polysubstituted. Preferred (Ci-C6)-hydroxyalkyl radicals are (Ci-C3)- hydroxyalkyi radicals, in particular CH2OH, CH2CH2OH, CH2CH2CH2OH and CH2CH(OH)CH2OH .
Unless otherwise specified, the term "(Ci-C6)-cyanoalkyl" is understood to be a Ci-C6-alkyl in which at least one hydrogen is exchanged for a cyano group. The hydroxyalkyi 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 "(C-|-C6)-thioalkyl" is understood to mean branched and unbranched thioalkyl groups consisting of 1 to 6 carbon atoms. Examples of (C-|-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 "(d-CeHhiohaloalkyl" is understood to be a (Ci-C6)-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 (C-|-C6)-thiohaloalkyl radicals are (C-|-C3)-thiohaloalkyl radicals, in particular SCHF2, SCH2F, SCF3, SCF2CH3, SCH2CH2F, SCH2CHF2 and SCH2CF3.
In the context of the present invention, the terms "Ci_C3-alkylen" and "Ci_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" is understood to mean heterocycloaliphatic saturated or unsaturated (but not aromatic) residues having 3 to 7, i.e. 3, 4, 5, 6 or 7, 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(C-|.6-alkyl) such as N(CH3), wherein the ring members can be unsubstituted or mono- or polysubstituted. The residues may be mono- or bicyclic. 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, wherein 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)-thiohaloalkyl, (C-|-C6)-haloalkoxy, C3-C6- cycloalkyl, 3- to 7-membered heterocycloalkyl, NH2, NH(C1-C6-alkyl), N(C1-C6-alkyl)2, NH(C1-C6-hydroxy- alkyl), N(Ci-Ce-alkyl)(Ci-Ce-hydiOxyalkyl), N(Ci-Ce- hydroxyalkyl)2, =NH, =N(C1-C6-alkyl), =N(OH), NHCO(C C6-alkyl), N(Ci-Ce-alkyl)CO(Ci-Ce-alkyl), NHCO(Ci-Ce- ydroxyalkyl), N(Ci-Ce-alkyl)CO(Ci-Ce- hydroxyalkyl), NHCOO(Ci-Ce-alkyl), NH-C(0)NH2, NHCONH(Ci-Ce-alkyl), NHCON(CrCe-alkyl)2, NH(C C6-alkylen)-COO(d-d-alkyl), NH(d-d-alkylen)-CONH2, NH(d-d-alkylen)-CONH(d-d-alkyl), NH(C Ce-alkylen)-CON(Ci-Ce-alkyl)2, NHS(0)2OH, NHS(0)2(d-d-alkyl), NHS(0)20(Ci-Ce-alkyl), NHS(0)2NH2, NHS(0)2NH(d-d-alkyl), NHS(0)2N(Ci-Ce-alkyl)2, NH(d-d-alkylen)-S(0)2OH, NH(d-d-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(C C6- alkylen)-S(0)2NH(d-C6-alkyl), C02H, CO(C C6-alkyl), COO(C C6-alkyl), OCO(C C6-alkyl), OCOO(C Ce-alkyl), CONH2, CONH(d-d-alkyl), CON(d-d-alkyl)2, OCONH(d-d-alkyl), OCON(d-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, 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)-alkoxy, (Ci-C6)-hydroxyalkoxy, C3-C6-cycloalkyl, NH2, NH(Ci-C6-alkyl), N(d-C6- alkyl)CO(C C6-alkyl), NHCO(Ci-C6-hydroxyalkyl), N(Ci-C6-alkyl)CO(Ci-C6-hydroxyalkyl),N(Ci-C6-alkyl)2, NH(d-C6-hydroxyalkyl), N(d-C6-alkyl)(d-C6-hydroxyalkyl), NHCO(d-C6-alkyl), NH-CONH(d-C6-alkyl), NHCON(d-C6-alkyl)2, NHS(0)2(C1-C6-alkyl), CONH2, CON H(d-d-alkyl), CON(d-C6-alkyl)2, S(0)(d- C6-alkyl) and S(0)2(d-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, d-d-alkoxy, (Ci-C6)-thioalkyl, (d- C6)-haloalkyl, (Ci-Ce-alkoxyHCi-Ce-alkylenyl), (d-C6-alkoxy)-Ci-C6-alkoxy, (d-C6)-thiohaloalkyl, (Ci-C6)- haloalkoxy, (Ci-C6-thioalkyl)-(Ci-C6-alkylenyl), C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(d-C3-alkylenyl), 3- to 7-membered heterocycloalkyl, (3- to 7-membered heterocycloalkyl)-(C-|-C3-alkylenyl), NH2, NH(d-C6- alkyl), N(C C6-alkyl)2, NHCO(C C6-alkyl), NHCOO(C C6-alkyl), NH-C(0)NH2, NHCONH(C C6-alkyl), NHCON(d-C6-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)N HCON(d-C6-alkyl)2, NH(d-C6-alkylen)-COO(d-C6- alkyl), NH(d-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-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(C C6-alkyl), CON H2, CONH(C C6-alkyl), CON(d-C6-alkyl)2, OCONH(d-C6-alkyl), OCON(d-C6-alkyl)2, OS(0)2(d-C6-alkyl), OS(0)2OH , OS(0)2-(d-C6-alkoxy), OS(0)2NH2, OS(0)2NH(d-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(d-C6-alkyl), and S(0)2N(Ci-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 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 , (Ci-C6)-alkyl, (d-C6)-hydroxyalkyl, (d-C6)-alkoxy, C3-C6-cycloalkyl, NH2, NH(d-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), CON H2, CON H(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-C6-alkyl in N(d-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(Ci-C6-alkyl)2, wherein Ci-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. ithin 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. In another embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that R and R2 together with the carbon atom to which they are attached form a cyclopropyl or a cyclo- butyl, preferably a cyclopropyl, which is unsubstituted or substituted with one, two, three or four substituents Y. In a preferred embodiment of the first aspect of the invention, the compound of formula (I) is
characterized in that R and R together with the carbon atom to which they are attached form a 3- to 6- membered cycloalkyl, which is unsubstituted or substituted with one or two substituents Y,
wherein Y at each occurrence is independently from one another selected from the group consisting of OH, =0, CN, halogen, C C6-alkyl, C C6-hydroxyalkyl, C C6-alkoxy, S(0)(C C6-alkyl), S(0)2(C C6-alkyl), (C C6)-haloalkyl, (C C6)-haloalkoxy, NH2, NH(C C6-alkyl), N(C C6-alkyl)2, NHCO(C C6- alkyl), NHS(0)2(C1-C6-alkyl), CONH2, CONhKd-Ce-alkyl) and
Figure imgf000010_0002
In a preferred embodiment of the first aspect of the invention, the compound of formula (I) is
characterized in that R and R2 together with the carbon atom to which they are attached form a unsubstituted 3- to 6-membered cycloalkyl, preferably unsubstituted cyclopropyl or unsubstituted cyclobutyl, more preferably unsubstituted cyclopropyl.
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 imgf000010_0003
Figure imgf000011_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 is 0, 1 , 2, 3 or 4; and
Z at each occurcence is independentlyselected 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, Ci-C6-alkoxy, (d-Ce)- thioalkyl, (C C6)-haloalkyl, (C C6)-thiohaloalkyl, (C C6)-haloalkoxy, (d-C6-alkylen)-S-(d-C6-alkyl), C3- C6-cycloalkyl, (C3-C6-cycloalkyl)-(C-|-C3-alkylenyl), 3- to 7-membered heterocycloalkyl, said C3.6-cycloalkyl and said 3- to 7-membered heterocycloalkyl, in each case unsubstituted or mono- or polysubstituted, NH2, NH(Ci-Ce-alkyl), N(Ci-Ce-alkyl)2, NHCO(Ci-Ce-alkyl), NHC02(d-C6-alkyl), NHC(0)NH2, NHCONH(d-C6-alkyl), NHCON(d-C6-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), NH(d-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(C1-C6-alkyl), NHS(0)20(C1-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-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-d- alkylen)-S(0)2NH(d-C6-alkyl), C02H, CO(d-d-alkyl), C02(d-d-alkyl), O-CO(d-d-alkyl), 0-C02(d- C6-alkyl), CONH2, CONH(d-d-alkyl), CON(d-C6-alkyl)2, OCONH(d-d-alkyl), OCON(d-d-alkyl)2, OS(0)2(d-C6-alkyl), OS(0)2OH, OS(0)20(C C6-alkyl), OS(0)2NH2, OS(0)2NH(C C6-alkyl), OS(0)2N(d-C6-alkyl)2, S(0)(C C6-alkyl), S(0)2(C C6-alkyl), S(0)2OH, S(0)20(d-C6-alkyl), S(0)2NH2, S(0)2NH(d-d-alkyl), and S(0)2N(d-d-alkyl)2;
Preferably, Z at each occurcence is independently selected from the group consisting of F, CI, Br, CF3, CHF2, CH2F, OCF3, OH, CN, d-d-alkyl, d-d-hydroxyalkyl, d-C6-alkoxy, C3-C6-cycloalkyl, 3- to 7- membered heterocycloalkyi, NH2, NH(d-C6-alkyl), N(Ci-d-alkyl)2, NHCO(Ci-d-alkyl), (d-d- alkylen)NH2, (d-d-alkylen)NH(d-d-alkyl), (C C6-alkylen)N(d-C6-alkyl)2, (d-C6-alkylen)NHCO(d-C6- alkyl), NHCONH(C C6-alkyl), NHCON(C C6-alkyl)2, NHS(0)2(d-C6-alkyl), CONH2, CONH(C C6-alkyl), CON(d-d-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-d-alkyl);
wherein said C3-C6-cycloalkyl and said 3- to 7-membered heterocycloalkyi is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of F, CI,, CN, =0, OH, d-d- alkoxy, (Ci-d-alkoxy Ci-d-alkoxy, (hydroxy)-d-C6-alkoxy, NH2, NH(d-C6-alkyl), N(d-C6-alkyl)2, NH(Ci-d-hydroxyalkyl), N(Ci-C6-alkyl)(d-C6-hydroxyalkyl), N(d-C6-hydroxyalkyl)2, NHCO(d-C6-alkyl), N(d-C6-alkyl)CO(d-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(d-C6-alkyl)(d-C6- hydroxyalkyl), CON(Ci-C6-hydroxyalkyl)2, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyi.
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 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, said piperidinyl, said aziridinyl, said cyclopropyl, said cyclobutyl, said cyclopentyl and said 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 of the first aspect of the invention, the compound of formula (I) is
characterized in that G is select 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, C C4-alkyl, (C C4)-hydroxyalkyl, C C4-alkoxy, C3-C6-cycloalkyl, NH2, NH(d-C4-alkyl), N(d-C4-alkyl)2, NHCO(d-C4-alkyl), (C1-C6-alkylen)NH2, (C1-C6-alkylen)NH(C1-C6- alkyl), (C1-C6-alkylen)N(C1-C6-alkyl)2, (C1-C6-alkylen)NHCO(C1-C6-alkyl), NH-S(0)2(d-C4-alkyl), CONH2, CONH(C 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), S(0)2(Ci-C4-alkyl), pyrrolidinyl, aziridinyl and cyclopropyl,
wherein said pyrrolidinyl, said aziridinyl and said cyclopropyl 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;
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, 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, cycloalkyi or aziridinyl, wherein said cycloalkyi or said aziridinyl 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 imgf000013_0001
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), 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, cycloalkyl or aziridinyl, wherein said cycloalkyl or said aziridinyl 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 another embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that
R3 is -L-R4;
wherein
L is selected from bond, S(=0), S(=0)2, P(=0)(R4), C(H)(OH) or C(CH3)(OH);
and
R4 is selected from OH, CN, R 3, OR13, NH2, NH(R13) or N(R 3)2,
wherein
each R 3 independently of each other
denotes Ci_6-alkyl,
wherein said Ci-C6-alkyl is independently unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, =0, =NH,
Figure imgf000014_0001
=N(OH), OH, d-Ce-alkoxy, (Ci-C6-alkoxy)-Ci-C6-alkoxy, (hydroxy)-Ci-C6-alkoxy, NH2, NH(Ci-C6-alkyl), N(d-
C6-alkyl)2, NH(C C6-hydroxyalkyl), N(Ci-C6-alkyl)(Ci-C6-hydroxyalkyl), N(Ci-C6-hydroxyalkyl)2, NHCO(C C6-alkyl), N(d-C6-alkyl)CO(d-C6-alkyl), NHCO(C C6-hydroxyalkyl), N(C C6-alkyl)CO- (C C6-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;
or
denotes one of the following groups U1 to U8
Figure imgf000014_0002
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 via a Ci_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 V35:
Figure imgf000015_0001
13 does not denote any of the groups V29 to V35, if such group is not connected via a Ci_3-alkylen;
wherein
R6 is H, (C C6-alkyl), (C C6)-hydroxyalkyl, (C C6)-cyanoalkyl, C3-C6-cycloalkyl, CO(C 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, d-C6-alkyl, d-d-alkoxy, NH2, NH(d-C6-alkyl), N(d-C6-alkyl)2, NHCO(d-C6-alkyl), C02H, COO(d-C6-alkyl), CONH2, CONH(d-C6-alkyl) and CON(d-d-alkyl)2,
and wherein said group V1 to V35 may be connected via a d.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.
Preferably, the compound of formula (I) is characterized in that
R3 is -L-R4, wherein
L is selected from bond, S(=0), S(=0)2, P(=0)(R4), C(H)(OH) or C(CH3)(OH)
and
R4 is selected from OH, CN, C C6-alkyl, 0(C C6-alkyl), NH2, NH(C C6-alkyl), N(C C6-alkyl)2, C3-C6- cycloalkyl, 3- to 7-membered heterocydoalkyi, 0(C3-C6-cycloalkyl) or 0(3- to 7-membered heterocydoalkyi),
wherein said Ci-C6-alkyl is independently unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, =0, =NH,
Figure imgf000016_0001
=N(OH), OH, d-d-alkoxy, (d-C6-alkoxy)-Ci-C6-alkoxy, (hydroxy)-d-C6-alkoxy, NH2, NH(d-C6-alkyl), N(d- C6-alkyl)2, NH(C C6-hydroxyalkyl), N(Ci-C6-alkyl)(d-C6-hydroxyalkyl), N(d-C6-hydroxyalkyl)2, NHCO(d-C6-alkyl), N(d-C6-alkyl)CO(d-C6-alkyl), NHCO(d-C6-hydroxyalkyl), N(d-d-alkyl)CO- (d-C6-hydroxyalkyl), CONH2, CONH(C C6-alkyl), CON(C C6-alkyl)2, CONH(C C6-hydroxyalkyl), CON(d-C6-alkyl)(d-C6-hydroxyalkyl), CON(C C6-hydroxyalkyl)2, C3-C6-cycloalkyl and 3- to 7- membered heterocydoalkyi;
and
wherein said C3-C6-cycloalkyl or 3- to 7-membered heterocydoalkyi is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, =0, OH, d-d-alkoxy, (d-C6-alkoxy)-Ci-C6-alkoxy, (hydroxy)-d-C6-alkoxy, NH2, NH(d-C6-alkyl), N(d-C6- alkyl)2, NH(d-C6-hydroxyalkyl), N(Ci-C6-alkyl)(d-C6-hydroxyalkyl), N(d-C6-hydroxyalkyl)2, NHCO(C C6-alkyl), N(d-C6-alkyl)CO(d-C6-alkyl), NHCO(C C6-hydroxyalkyl), N(C C6-alkyl)CO- (d-C6-hydroxyalkyl), CONH2, CONH(C C6-alkyl), CON(C C6-alkyl)2, CONH(C C6-hydroxyalkyl), CON(Ci-C6-alkyl)(Ci-C6-hydroxyalkyl), CON(d-C6-hydroxyalkyl)2, C3-C6-cycloalkyl and 3- to 7- membered heterocydoalkyi.
Preferably,
L is selected from bond, S(=0), S(=0)2, C(H)(OH) or C(CH3)(OH)
and
R4 is selected from one of the following substructures M1 to M120:
Figure imgf000016_0002
Figure imgf000017_0001
Figure imgf000018_0001
I
H I
I
HO^N- Ho^N-
O 0
M116 M117 M118 M119 M120
In a preferred embodiment, the compound according to formula (I) is characterized in that
L is selected from bond
and
R4 is selected from OH, CN, 0(C1-C6-alkyl), 0(C3-C6-cycloalkyl) or 0(3- to 7-membered heterocycloalkyi), wherein said Ci-C6-alkyl is independently unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, =0, Ci-C6-alkoxy, (Ci-C6-alkoxy)-Ci- C6-alkoxy, (hydroxy)-Ci-C6-alkoxy, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyi;
and
wherein said C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyi is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, =0, OH , d-d- alkyl, (C-|-C6)-hydroxyalkyl, C-|-C6-alkoxy, (C-|-C6)-thioalkyl, (C-|-C6)-haloalkyl, (C-|-C6-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(d-C6-hydroxyalkyl)2, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyi.
In another preferred embodiment, the compound according to formula (I) is characterized in that
L is selected from bond
and
R4 is selected from C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyi,
wherein said C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyi is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, =0, OH , d-C6- alkyl, (Ci-C6)-hydroxyalkyl, Ci-C6-alkoxy, (Ci-dMhioalkyl, (Ci-C6)-haloalkyl, (Ci-C6-alkoxy)-Ci-C6-alkoxy, (hydroxy)-Ci-C6-alkoxy, NH2, NH(Ci-C6-alkyl), N(C C6-alkyl)2, NH(Ci-C6-hydroxyalkyl), N(CrC6-alkyl)(Ci- C6-hydroxyalkyl), N(d-C6-hydroxyalkyl)2, NHCO(d-d-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(Ci-C6-hydroxyalkyl), CON(Ci-C6-alkyl)(d-C6-hydroxyalkyl), CON(d-C6-hydroxyalkyl)2, C3-C6- cycloalkyl and 3- to 7-membered heterocycloalkyi.
In another preferred embodiment, the compound according to formula (I) is characterized in that
L is selected from bond
and
R4 is Ci-Ce-alkyl,
wherein said Ci-C6-alkyl is independently unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , =0, OH , Ci-C6-alkoxy, (d-d)- thioalkyl, (d-C6-alkoxy)-d-C6-alkoxy, (hydroxy)-C C6-alkoxy, NH2, NH(C C6-alkyl), N(C C6- alkyl)2, NH(C C6-hydroxyalkyl), N(d-C6-alkyl)(d-C6-hydroxyalkyl), N(C C6-hydroxyalkyl)2, NHCO(d-C6-alkyl), N(d-C6-alkyl)CO(d-C6-alkyl), NHCO(d-C6-hydroxyalkyl), N(C C6- alkyl)CO(Ci-Ce-hydroxyalkyl); CONH2, CONH(Ci-Ce-alkyl), CON(CrCe-alkyl)2, CONH(Ci-Ce- hydroxyalkyl), CON(Ci-C6-alkyl)(Ci-C6-hydroxyalkyl), CON(Ci-C6-hydroxyalkyl)2, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyi;
wherein said C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyi is 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)-Ci-C6-alkoxy, NH2, NH(C C6-alkyl), N(C C6-alkyl)2, NH(C C6-hydroxyalkyl), Nid-Ce-alkylXd-Ce- hydroxyalkyl), N(C-|-C6-hydroxyalkyl)2, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyi.
In another preferred embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that
L is selected from S(=0) or S(=0)2;
and
R4 is selected from C C6-alkyl, NH2, NH(C C6-alkyl), N(C C6-alkyl)2, C3-C6-cycloalkyl or 3- to 7- membered heterocycloalkyi,
wherein said Ci-C6-alkyl is independently unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, Ci-C6-alkoxy, (Ci-C6-alkoxy)-CrC6- alkoxy, (hydroxy)-Ci-C6-alkoxy, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyi;
and
wherein said C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyi is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, =0, OH, C-|-C6- alkyl, (C-|-C6)-hydroxyalkyl, C-|-C6-alkoxy, (C-|-C6)-thioalkyl, (C-|-C6)-haloalkyl, (C-|-C6-alkoxy)-C-|-C6-alkoxy, (hydroxy)-Ci-C6-alkoxy, NH2, NH(Ci-C6-alkyl), N(C C6-alkyl)2, NH(Ci-C6-hydroxyalkyl), N(CrC6-alkyl)(Ci- C6-hydroxyalkyl), N(Ci-C6-hydroxyalkyl)2, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyi.
More preferably,
L is selected from S(=0) or S(=0)2 and
R4 is selected from one of the above substructures M1 to M120.
In another preferred embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that
L is selected from P(=0)(R4);
and
R4 is selected from Ci-C6-alkyl,
wherein said Ci-C6-alkyl is independently unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, C-|-C6-alkoxy, (C-rC6-alkoxy)-C-rC6- alkoxy, (hydroxy)-C-|-C6-alkoxy, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyi.
In yet another preferred embodiment of the first aspect of the invention, the compound of formula (I) characterized in that L is selected from C(H)(OH) or C(CH3)(OH)
and
R4 is selected from Ci-C6-alkyl, C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl,
wherein said Ci-C6-alkyl is independently unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , OH, Ci-C6-alkoxy, (Ci-C6-alkoxy)-CrC6- alkoxy, (hydroxy)-Ci-C6-alkoxy, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyl;
and
wherein said C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, =0, OH, C1-C6- alkyl, (d-C6)-hydroxyalkyl, Ci-C6-alkoxy, (Ci-C6)-thioalkyl, (Ci-C6)-haloalkyl, (Ci-C6-alkoxy)-Ci-C6-alkoxy, (hydroxy)-Ci-C6-alkoxy, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, NH(Ci-C6-hydroxyalkyl), N(Ci-C6-alkyl)(Ci- C6-hydroxyalkyl), N(d-C6-hydroxyalkyl)2, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyl.
In another preferred embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that
L is selected from S(=0), S(=0)2, P(=0)(R4), C(H)(OH) or C(CH3)(OH);
and
R4 is selected from Ci-Ce-alkyl, wherein said Ci-C6-alkyl is independently unsubstituted or substituted with OH.
In yet another preferred 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), (le) or (If),
Figure imgf000021_0001
wherein R4 and G are defined as before.
Preferably,
the compound according to general formula (I) is selected from one of the general formula (la), (lb), (lc), (Id), (le) or (If); 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, CF3, CHF2, CH2F, OCF3, OH, CN, d-C4-alkyl, (Ci-C4)-hydroxyalkyl, d-d-alkoxy, C3-C6- cycloalkyl, NH2, NH(d-d-alkyl), N(d-C4-alkyl)2, NHCO(d-C4-alkyl), (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), NH- S(0)2(d-C4-alkyl), CONH2, CONH(C C6-alkyl), CO-N(C C6-alkyl)2, S(0)2NH2, S(0)2NH(C C6- alkyl), S(0)2N(C C6-alkyl)2, S(0)(C C6-alkyl), S(0)2(C C4-alkyl), pyrrolidinyl, aziridinyl and cyclopropyl,
wherein said pyrrolidinyl, said aziridinyl and said cyclopropyl 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, and
R4 is selected from OH, CN, d-C6-alkyl, 0(d-C6-alkyl), NH2, NH(C C6-alkyl), N(d-C6-alkyl)2, C3-C6- cycloalkyl, 3- to 7-membered heterocycloalkyi, 0(C3-C6-cycloalkyl) or 0(3- to 7-membered
heterocycloalkyi),
wherein said Ci-C6-alkyl is independently unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, =0, =NH , =N(d-C6-alkyl), =N(OH), OH, d-d-alkoxy, (d-C6-alkoxy)-Ci-C6-alkoxy, (hydroxy)-d-C6-alkoxy, NH2, NH(d-C6-alkyl), N(d-C6-alkyl)2, NH(C C6-hydroxyalkyl), N(d-C6-alkyl)(d-C6-hydroxyalkyl), N(C C6-hydroxyalkyl)2, NHCO(C C6-alkyl), N(d-C6-alkyl)CO(d-C6-alkyl), NHCO(C C6-hydroxyalkyl), N(C C6-alkyl)CO(d-C6-hydroxyalkyl), CONH2, CONH(d-C6-alkyl), CON(d-C6-alkyl)2, CONH(d-C6-hydroxyalkyl), CON d-d-alkylXd-d- hydroxyalkyl), CON(Ci-C6-hydroxyalkyl)2, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyi;
and
wherein said C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyi is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, =0, OH, d-d- alkoxy, (d-C6-alkoxy)-Ci-C6-alkoxy, (hydroxy)-d-C6-alkoxy, NH2, NH(C C6-alkyl), N(d-C6-alkyl)2, NH(C C6-hydroxyalkyl), N(d-C6-alkyl)(d-C6-hydroxyalkyl), N(C C6-hydroxyalkyl)2, NHCO(C C6-alkyl), N(d-C6-alkyl)CO(d-C6-alkyl), NHCO(C C6-hydroxyalkyl), N(C C6-alkyl)CO(d-C6-hydroxyalkyl), CONH2, CONH(d-C6-alkyl), CON(d-C6-alkyl)2, CONH(d-C6-hydroxyalkyl), CON d-d-alkylXd-d- hydroxyalkyl), CON(Ci-C6-hydroxyalkyl)2, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyi. More preferably,
the compound according to general formula (I) is selected from one of the general formula (la), (lb), (Ic), (Id), (le) or (If);
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, CF3, CHF2,
CH2F, OCF3, OH , CN, Ci-C4-alkyl, (Ci-C4)-hydroxyalkyl, d-C4-alkoxy, C3-C6-cycloalkyl, NH2, NH(C C4-alkyl), N(d-C4-alkyl)2, NHCO(Ci-C4-alkyl). NH-S(0)2(C1-C4-alkyl), (C1-C6-alkylen)NH2, (Ci-Ce-alkylen)NH(Ci-Ce-alkyl), (C1-C6-alkylen)N(C1-C6-alkyl)2, CONH2, CONH(Ci-Ce-alkyl). CO- N(Ci-Ce-alkyl)2, S(0)2NH2, SiOfeNHid-Ce-alkyl), S(0)2N(Ci-Ce-alkyl)2, S(0)(C Ce-alkyl) and SiOMC C alkyl),
and
R4 is selected from one of the substructures M1 to M120 as defined above.
In yet another preferred embodiment, the invention relates to a compound selected from the group consisting of
1 6'-(Ethylsulfonyl)-1 '-(5-phenylpyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]
2 6'-(lsopropylsulfonyl)-1 '-(5-phenylpyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]
3 6'-(Ethylsulfonyl)-1'-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]
4 6'-(Ethylsulfonyl)-1'-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]
5 1'-(5-(4-Ethylpyridin-2-yl)pyrimidin-2-yl)-6'-(ethylsulfonyl)spiro[cyclopropane-1 ,3'-indoline]
6 6'-(Ethylsulfonyl)-1'-(5-(6-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]
7 6'-(Ethylsulfonyl)-1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]
8 6'-(Ethylsulfinyl)-1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]
9 1'-(5-(2-Fluorophenyl)pyrimidin-2-yl)-6'-(isopropylsulfonyl)spiro[cyclopropane-1 ,3'-indoline]
10 1'-(5-(2-Fluorophenyl)pyrimidin-2-yl)-6'-(isopropylsulfinyl)spiro[cyclopropane-1 ,3'-indoline]
11 3-((1'-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfonyl)butan-1-ol
12 3-((1'-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfinyl)butan-1-ol
13 3-((1'-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfonyl) propan-1-ol
14 3-((1'-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfinyl) propan-1-ol
15 2-((1'-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfonyl) ethanol
16 2-((1'-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfinyl)ethanol
17 6'-(Ethylsulfonyl)-1'-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]
18 N,N-Dimethyl-1'-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]-6'-sulfonamide
N,N-Dimethyl-1'-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]-6'-sulfon- amide
2Q 1^5-(4-Ethylpyridin-2-yl)pyrimidin-2-yl)-N,N-dimethylspiro[cyclopropane-1 ,3'-indoline]-6'-sulfon- amide
2_| N,N-Dimethyl-1'-(5-(6-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]-6'-sulfon- amide
22 1'-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N-dimethylspiro[cyclopropane-1 ,3'-indoline]-6'-sulfonamide
22 1'-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[cyclopropane-1 ,3'- indoline]-6'-sulfonamide
24 6'-(Ethylsulfinyl)-1'-(5-(6-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]
25 6'-(Ethylsulfinyl)-1'-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]
26 1'-(5-(4-Cyclopropylpyridin-2-yl)pyrimidin-2-yl)-6'-(ethylsulfinyl)spiro[cyclopropane-1 ,3'-indoline]
27 1'-(5-(4-Ethylpyridin-2-yl)pyrimidin-2-yl)-6'-(ethylsulfinyl)spiro[cyclopropane-1 ,3'-indoline]
28 2-(2-(6'-(Ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1'-yl)pyrimidin-5-yl)pyridin-4-amine 1 ^5-(6-Ethylpyridin-2-yl)pyrimidin-2-yl)-6'-(ethylsulfinyl)spiro[cyclopropane-1 ,3'-indoline] 1 ^5-(4-Cyclopropylpyridin-2-yl)pyrimidin-2-yl)^
2-(2-(6^Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-am
1 ^5-(6-Ethylpyridin-2-yl)pyrimidin-2-yl)-6^ethylsulfonyl)spiro[cyclopropane-1 ,3'-indoline]
3-((1 '-(5-(4-Cyclopropylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfinyl)- propan-1-ol
3- ((1 '-(5-(4-Aminopyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfinyl)propan- 1 -ol
N-(2-(2-(6^(3-Hydroxypropyl)sulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyri
4- yl)acetamide
3-((1 '-(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfinyl)- propan-1-ol
3-((1 '-(5-(4-Cyclopropylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfonyl)- propan-1-ol
3- ((1 '-(5-(4-Aminopyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfonyl)propan- 1 -ol
N-(2-(2-(6'-((3-Hydroxypropyl)sulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-
4- yl)acetamide
3-((1 '-(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfonyl)- propan-1-ol
1-(2-(2-(6'-(Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-yl)ethanol
2-(2-(2-(6'-(Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2- ol
1- (3-(2-(6'-(Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)-4-fluorophenyl)- ethanol
2- (3-(2-(6'-(Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)-4-fluorophenyl)- propan-2-ol
1-(2-(2-(6'-(Ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-yl)ethanol
2-(2-(2-(6'-(Ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2- ol
1- (3-(2-(6 Ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)-4-fluorophen ethanol
2- (3-(2-(6 Ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)-4-fluorophen propan-2-ol
6^ethylsulfinyl)-1 5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoli 1-(1 5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)propan-1-ol
2-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)butan-2-ol
(1 ^5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)(tetrahydro-2H-pyran^ yl)methanol
1-(1 ^5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cy^
1-(1 ^5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)-N-methyl cyclo- propanamine
1-(1 ^5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cy^
propanamine
2-((1-(1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)cyclopropyl)- (methyl)amino)ethanol 1-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl) cyclopropanol 1 ^5-(2-Fluorophenyl)pyrimidin-2-yl)-6 1-methoxycyclopropyl)spiro[cyclopropane-1 ,3'-indoline]
6 1-Methoxycyclopropyl)-1 ^5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cyclo-propane-1 ,3'- indoline]
6 1-Methoxycyclopropyl)-1 ^5-(pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]
6^1-Methoxycyclopropyl)-1 5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclo-propane-1 ,3'- indoline]
2-(((1^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 '-indolin]-6'-yl)methyl)ami ethanol
2-(((1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3 ndolin]-6'-yl)methyl)(meth amino)ethanol
2-(((1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3 ndolin]-6'-yl)methyl)(meth amino)-2-methylpropan-1-ol
N-((1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)methyl)-N-met^^ acetamide
N-((1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)methyl)-2-h methylacetamide
6'-Ethoxy-1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]
6^Cyclopropylmethoxy)-1 5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline] 3-((1 '^5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)oxy) propan-1-ol
3-((1 ^5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin^ yl)sulfonyl)propan-1-ol
3-((1 ^5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin^ yl)sulfonyl)propan-1-ol
3-((1 ^5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin^ yl)sulfonyl)propan-1-ol
3-((1 ^5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin^ yl)sulfonyl)butan-1-ol
3-((1 ^5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin^ yl)sulfinyl)butan-1-ol
3-((1 ^5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ^'-indolin]-6'-yl)sulfo
1 -ol
ethyl 1 '-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]-6'-carboxylate
2-hydroxyethyl 1 '-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]-6'- carboxylate
1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl dimethylcarbamate 1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl methylcarbamate
N-(2-hydroxyethyl)-1 '-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro- [cyclopropane-1 ,3'-indoline]-6'-sulfonamide
N-(2-Hydroxyethyl)-1 '-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane- 1 ,3'-indoline]-6'-sulfonamide
N-(2-Hydroxyethyl)-1 ^5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]-6'- sulfonamide
2-(2-(2-(6^ethylsulfonyl)spiro[cyclopropane-1 ,3^
amine
2-(2-(2-(6^ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin methylpropan-2-amine
1-(2-(2-(6'-(Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-yl)cyclo-
85
propanamine
1- (2-(2-(6'-(Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-yl)-N- 86
methylcyclopropanamine
2- (2-(2-(64ethylsulfinyl)spiro[cyclopropane-1 ^
87
amine
2-(2-(2-(6^ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridi
88
methylpropan-2-amine
1-(2-(2-(6^ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridi
89
propanamine
1- (2-(2-(6 ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridi
90
cyclopropanamine
2- (6-(2-(6^ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-2^^
91
ol
2-(6-(2-(64ethylsulfinyl)spiro[cyclopropane-1 ^
92
ol (faster eluting enantiomer)
2-(6-(2-(6 ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyri^
93
ol (slower eluting enentioemr)
2-(2-(2-(6'-(methylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-yl)propan- 94
2-ol
2-(2-(2-(6'-(methylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-yl)propan- 95
2-ol
N-(1 ^5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)-3-hydroxypropan- 96
amide
97 N-(1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)-2-hydroxyacetamide
N-(1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)-2-hydroxy-N- 98
methylacetamide
N-(1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)-3-hydroxy-N-
99
methylpropanamide
100 N-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl) methyl)acetamide
N-((1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)methyl)-2-hydroxy- 101
acetamide
2-(((1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyd^
102
methylpropan-1-ol
2-Hydroxy-N-methyl-N-((1 '-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro [cyclopropane-1 ,3 - 103
indolin]-6'-yl)methyl)acetamide
N-methyl-N-((1 ^5-(4-methylpyridin-2-yl)pyrimidm^
methyl)acetamide
2-methyl-2-(methyl((1 ^5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-i
105
yl)methyl)amino)propan-1-ol
2-hydroxy-N-((1 '-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'- 106
indolin]-6'-yl)methyl)-N-methylacetamide
N-((1 ^5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'- 107
yl)methyl)-N-methylacetamide
2-(((1 ^5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'- 108
yl)methyl)(methyl)amino)-2-methylpropan-1-ol 2-(4-Fluoro-3-(2-(6^1-(methylamino)cyclopro
109
yl)phenyl)propan-2-ol
1- (1 '-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)-N-methyl- cyclopropanamine
2- (2-(2-(641-(methylamino)cyclopropyl)spiro[cycto^
pyridin-4-yl)propan-2-ol
N-(1-(1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)cyclopropyl)-N-
112
methylacetamide
N-(1-(1 ^5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)cy^ propyl)-N-methylacetamide
2-(1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopro^
114
amine
2-(1 '-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)-N-methyl- 115
propan-2-amine
2-(2-(2-(6^2-(methylamino)propan-2-yl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin^ pyridin-4-yl)propan-2-ol
2-(2-(2-(6^2-((2-Hydroxyethyl)amino)propan-2-yl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimi 5-yl)pyridin-4-yl)propan-2-ol
2-(2-(2-(6'-(1-((2-Hydroxyethyl)(methyl)amino)cyclopropyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-
118
yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol
2-(2-(2-(6^1-((2-Hydroxyethyl)amino)cyclopropyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimi^ 119
5-yl)pyridin-4-yl)propan-2-ol
2- (2-(2-(6^2-((2-hydroxyethyl)(methyl)amino)propan-2-yl)spiro[cyclopropane-1 '-indolin]-1 '- 120
yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol
1 ^5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N-dimethylspiro[cyclopropane-1 ,3'-indoline]-6'- 121
carboximidamide
(1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)(morpholino)m
122
imine
N-(1 ^5-(4-(2-Hydroxypropan-2-yl)pyridin-2-yl)pyn
123
yl)acetamide
3- hydroxy-N-(1 '-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'- 124
indolin]-6'-yl)propanamide
125 3-hydroxy-N-(1 ^5-(pyridin-2-yl)pyrimidin-2-yl)s^
N-(1 ^5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin] 126
N-methylacetamide
3-Hydroxy-N-(1 '-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro [cyclopropane-1 , 3'-
127
indolin]-6'-yl)-N-methylpropanamide
3-hydroxy-N-methyl-N-(1 ^5-(pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)- 128
propanamide
3-(2-(2-(6'-(Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl) pyridine-4-yl)- 129
azetidin-3-ol
3-(2-(2-(6^ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-yl)aze^ 130
ol
131 1 '-(5-(4-(Azetidin-3-yl)pyridin-2-yl)pyrimidin-2-yl)-6'-(ethylsulfinyl)spiro [cyclopropane-1 ,3'-indoline]
4-(azetidin-3-yl)-2-(2-(6^ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)p
132
1 -oxide
6 Ethylsulfonyl)-1 ^5-(4-(3-methylazetidin-3-yl)pyridin-2-yl)pyrimidin-2-yl)spiro [cyclopropane-
133
1 ,3'-indoline] 6^ethylsulfinyl)-1 5-(4-(3-methylazetidin-3-yl)pyridin-2-yl)pyrimidi ,3'- indoline]
1 ^5-(2-Fluorophenyl)pyrimidin-2-yl)-6'-((tetrahydro-2H-pyran-4-yl)oxy)spiro [cyclopropane-1 ,3 - indoline]
1 ^5-(2-Fluorophenyl)pyrimidin-2-yl)-6'-((tetrahydro-2H-pyran-4-yl)oxy)spiro [cyclopropane-1 ,3 - indoline]
N-Ethyl-1 '-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro [cyclopropane-1 ,3'- indoline]-6'-sulfonamide
1 5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N,N-dimethylspiro[cycto ,3'- indoline]-6'-sulfonamide
1 ^5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[cyclopropan
indoline]-6'-sulfonamide
2-(2-(6'-(ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)isonicotinonitrile
2-(2-(6 ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)ison^
dimethyl(1 ^5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-in
oxide
(1 ^5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'- yl)dimethylphosphine oxide
2,2,2-Trifluoro-1-(1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)ethanol
4-(2,2,2-trifluoro-1-(1 5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin^ yl)ethyl)morpholine 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), (Id) or (le), 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), (Id) or (le), 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), (Id) or (le).
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), (Id) or (le), 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), (Ic), (Id) or (le), 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 eyesand/or gastrointestinal diseases and complaintsand acute and chronic inflammations of and/or inflammatory diseases of the internal organs and/or hyperplastic diseases and/or respiratory or lung diseases associated with elevated mucus production, inflammation and/or obstruction of the respiratory tract and/or diseases of the fibrotic spectrum and/or cancersand/or metabolic diseases and/or cardiovascular diseases and/or 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), (Ic), (Id) or (le), for the use as a medicament for the treatment of inflammatory diseases of the joints, the skin or the eyes, 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), (Ic), (Id) or (le), 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), (Id) or (le), 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), (Id) or (le), 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), (Id) or (le), 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. In the following the present invention is illustrated by way of examples without limiting the invention thereto.
Examples:
Synthesis of compounds according to the invention:
The compounds according to the invention may be prepared according to the following general reaction schemes:
Figure imgf000031_0001
Reaction scheme 02
Figure imgf000031_0002
Figure imgf000032_0001
Figure imgf000032_0002
Figure imgf000032_0003
eaction scheme 05
Figure imgf000032_0004
Reaction scheme 06
Figure imgf000032_0005
(X) eaction scheme 07
Figure imgf000033_0001
(XI) (XXIII)
(XXII)
Reaction scheme 08
Figure imgf000033_0002
Compound (XXIV) corresponds to structure (XXIII) if R is hydrogen.
Reaction scheme 09
Figure imgf000033_0003
Reaction scheme 10 step (iv)
Figure imgf000033_0004
Reaction scheme 1 1
Figure imgf000034_0001
(XXXX) (XXXXI) (XXXXII)
Figure imgf000034_0002
(XXXVII) (XXXXII)
Abbreviations
The following abbreviations are used in the descriptions of the experiments:
APCI = atmospheric pressure chemical ionization; (AtaPhos)2PdCI2 = bis(di-tert-butyl(4-dimethylamino- phenyl)phosphine)dichloropalladium(ll); calc. = calculated; d = day; dba = dibenzylidene-acetone; DCM = DCM; DIPEA = diisopropylethylamine; DMF = Ν,Ν-dimethylformamide; DMSO = dimethylsulfoxide; ES- MS = electrospray mass spectrometry (ES-MS); eq. = equivalent; h = hour; LAH = lithium aluminium hydride; min. = minute(s); EtOAc = ethyl acetate; EtOH = ethanol; mCPBA = m-chloroperoxybenzoic acid; MeOH = methanol; MS = Mass spectrometry; MTBE = methyl-tert-butylether; NMM = N- methylmorpholine; NMP = N-methyl-2-pyrrolidone; PdCI2(dppf) = [1 , 1 '-bis(diphenylphosphino)ferrocene] dichloropalladium(ll) DCM complex; Rt = retention time; RT = room temperature; SFC = supercritical fluid chromatography; TBAF = tetrabutyl ammonium fluoride; TBTU = N,N,N',N'-Tetramethyl-0-(benzotriazol- 1 -yl)uronium tetrafluoroborate; TCCA = trichloroisocyanuric acid; tert = tertiary; TEA: triethylamine; TFA = 2,2,2-trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin layer chromatography; TOFMS = time-of- flight mass spectrometer; Xantphos = 4,5-[bis(diphenylphosphino)]-[9,9-]dimethylxanthene.
The following analytical HPLC methods were used:
Method 1 :
Column: Zorbax Extend C18 (4.6 x 50 mm, 5 μιη); 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 imgf000035_0001
Method 2:
Column: XBridge C18 (4.6 x 50 mm, 5.0 μιη); 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 imgf000035_0002
Method 3:
Column: Zorbax Extend C18 (4.6 x 50 mm, 5 μιη); Instrument: Shimadzu Prominence; Flow rate: 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 imgf000035_0003
Method 4:
Column: Zorbax Extend C18 (4.6 x 50 mm, 5 μιη); Instrument: Shimadzu Prominence; Column temperature: 25°C; Flow rate: 1.0 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:
Time in min % A % B Flow rate in ml/min
0 95 5 1.0
1 95 5 1.0
7.0 50 50 1.0
10.0 10 90 1.0
1 1 .0 10 90 1.0 12.0 95 5 1.0
MS (mass spectrometry) 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.
Method 5:
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/ Mobile phase B: acetonitrile;
Gradient:
Figure imgf000036_0002
MS conditions:
Instrument: ACQUITY SQD Mass Spectrometer from Waters (Single quadruple mass spectrometer) Ionization technique: ESI; Mass range: 100 to 800 Da; Polarity: + Ve.
Figure imgf000036_0001
1a) 6'-Bromospiro[cyclopropane-1 ,3'-indolinl-2'-one
n-Butyllithium (2.25 M in hexane, 130 mL, 259.4 mmol) was added drop wise at -40°C to a solution of 6- bromoindolin-2-one (25.0 g, 1 17.9 mmol) and diisopropylamine (36.54 mL, 259.4 mmol) in THF (500 mL). The mixture was stirred for 45 min at that temperature, 1 ,2-dibromoethane (31.0 mL, 353.7 mmol) was added drop wise and stirring was continued for 16 h while the temperature was slowly raised to RT. The reaction mixture was quenched with 4 N HCI (400 mL) and the aqueous part was separated and extracted with EtOAc (3x 100 mL). The combined organic layers were washed with brine and dried over Na2S04. The solvents were evaporated and the residue was triturated with EtOAc/hexane (1 :4, 200 mL), filtered and washed with EtOAc/hexane (1 :4, 100 mL). Brown solid. Yield: 26.0 g (92%). HPLC (method 1 ): Rt = 2.92 min, m/z [M+H]+ = 240.0 (MW calc. 238.08)
1 b) 6'-(Ethylthio)spiro[cyclopropane-1 ,3'-indolinel
A solution of 1a) (5 g, 21.0 mmol) in THF (50 mL) was added at 0°C to a suspension of KH (30% in mineral oil, 2.8 g, 20.8 mmol) in THF (50 mL). The mixture was stirred for 15 min and then cooled to - 78°C. t-Butyllithium was added drop wise (2.3 M in pentane, 18 mL, 41.4 mmol) and stirring was continued for 15 min. Diethyldisulfide (5.2 mL, 42.0 mmol) was then added at -78°C and the mixture was further stirred at RT for 16 h. The reaction mixture was quenched with saturated NH4CI solution (100 mL) and the aqueous layer was separated and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried over Na2S04 and concentrated under reduced pressure. The remnant was purified by column chromatography [silica gel; EtOAc/hexane = 1 :4]. White solid. Yield: 2.5 g (54%). HPLC (method 2): Rt = 3.12 min, m/z [M+H]+ = 220.2 (MW calc. 219.30) 1 c) 6'-(Ethylthio)spiro[cvclopropane-1 ,3'-indolinel
A solution of 1 b) (0.17 g, 0.77 mmol) in THF (5 mL) was added portion wise at 0°C to a suspension of spiro[cyclopropane-1 ,3'-indolin]-6'-yl(tetrahydro-2H-pyran-4-yl)methanol (0.073 g, 1.94 mmol) in THF (5 mL). The mixture was stirred at 60°C for 1 h, cooled and quenched with 5% aqueous NaOH solution. After stirring for 1 h at RT, the mixture was filtered through a plug of celite. The filter was washed with a blend of MeOH/DCM (1 :4, 3 x 20 mL), the filtrate was evaporated and the remnant was purified by column chromatography [100-200 silica gel; hexane with 2% EtOAc]. Colorless liquid. Yield: 0.056 g (35%). HPLC (method 1 ): Rt = 3.54 min, m/z [M+H]+ = 206.0 (MW calc. 205.32)
1d) 1 '-(5-Bromopyrimidin-2-yl)-6'-(ethylthio)spiro[cyclopropane-1 ,3'-indolinel
NaH (60%, 60 mg, 1.46 mmol) was added to a solution of 1 c) (120 mg, 0.585 mmol) in DMF (3 mL) and the mixture was stirred at 0°C for 10 min. 5-Bromo-2-(methylsulfonyl) pyrimidine (140 mg, 0.585 mmol) was then added and stirring was continued at RT for 16 h. The mixture was diluted with ice cold water and extracted with EtOAc/MTBE (1 :9, 3 x 20 ml). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography [100-200 silica gel; hexane with 2% EtOAc]. Light yellow solid. Yield: 45 mg (21 %). HPLC (method 1 ): Rt = 2.98 min, m/z [M+H]+ = 362.1 (MW calc. 362.29)
1 e) 1 '-(5-Bromopyrimidin-2-yl)-6'-(ethylsulfonyl)spiro[cyclopropane-1 ,3'-indoline1
mCPBA (77%, 0.62 g, 2.76 mmol) in THF (10 mL) was added at 5°C to a solution of compound 1d) (0.50 g, 1.38 mmol) in THF (40 THF) and the resulting mixture was stirred for 3 h at RT. Saturated NaHC03 solution (40 mL) and brine (10 mL) were added and aqueous phase was separated and extracted with THF (2 x 50 mL). The combined organic layers were dried over Na2S04 and evaporated. The remnant was purified by column chromatography [100-200 silica gel; hexane with 2% EtOAc]. Light yellow solid. Yield: 0.25 g (46%). HPLC (method 1 ): Rt = 3.69 min, m/z [M+H]+ = 394.1 (MW calc. 394.29)
1f) 6'-(Ethylsulfonyl)-1 '-(5-phenylpyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline1 (AtaPhos)2PdCI2 (45 mg, 0.06 mmol) was added to a suspension of 1 e) (250 mg, 0.63 mmol), phenylboronic acid (150 mg, 1.27 mmol) and 2 M K2C03 solution (1.3 mL) in t-amyl alcohol (10 mL) that was kept under Ar. The mixture was stirred at 100°C for 1 h, cooled and filtered through a plug of celite. The filter was washed with DCM (2 x 10 mL) and the filtrate was concentrated under reduced pressure. The raw product was purified by column chromatography [100-200 silica gel; EtOAc/hexane 1 :4]. White solid. Yield: 70 mg (28%). HPLC (method 1 ): Rt = 3.79 min, m/z [M+H]+ = 392.3 (MW calc. 391.49) H NMR (400 MHz, DMSO-d6, δ ppm): 9.03 (s, 2H), 8.79 (s, 1 H), 7.78 (d, 2H, J = 7.6 Hz), 7.51 -7.48 (m, 2H), 7.43-7.38 (m, 2H), 7.0 (d, 1 H, J = 7.8 Hz), 4.34 (s, 2H), 3.27-3.21 (m, 2H), 1.29-1.23 (m, 4H), 1.13 (t, 3H, J = 7.3 Hz).
Example 2: 6'-(lsopropylsulfonyl)-1 '-(5-phenylpyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline1
Figure imgf000038_0001
Prepared in analogy to synthesis example 1. White solid. Yield: 75 mg (64%)
HPLC (method 1 ): Rt = 3.93 min, m/z [M+H]+ = 406.1 (MW calc. 405.51 )
H NMR (400 MHz, DMSO-d6, δ ppm): 9.03 (s, 2H), 8.77 (s, 1 H), 7.8-7.78 (m, 2H), 7.51 -7.47 (m, 2H), 7.41-7.37 (m, 2H), 7.06 (d, 1 H, J = 8.0 Hz), 4.34 (s, 2H), 3.38-3.33 (m, 1 H), 1.3 (bs, 2H), 1.23 (bs, 2H), 1.95 (d, 6H, J = 6.7 Hz).
Figure imgf000038_0002
3a) 1 '-(5-Bromopyrimidin-2-yl)-6'-(ethylthio)spiro[cyclopropane-1 ,3'-indoline1
A solution of 6'-(ethylthio)spiro[cyclopropane-1 ,3'-indoline] (3.5 g, 1 eq, 17.07 mmol), 5-bromo-2-chloro- pyrimidine (3.954 g, 1.2 eq, 20.48 mmol) and DIPEA (14.76 ml, 5 eq, 85.36 mmol) in n-butanol (50 ml) was stirred in a sealed tube at 140°C for 20 h. The reaction mixture was cooled to RT and a precipitating solid was filtered off and washed with hexane (2 x 50 ml). Light yellow solid. Yield: 3.2 g (52%)
3b) 1 '-(5-Bromopyrimidin-2-yl)-6'-(ethylsulfonyl)spiro[cyclopropane-1 ,3'-indoline1 mCPBA (3.36 g, 2 eq, 19.34 mmol) was added portion wise to a stirred solution of 3a) (3.5 g, 1 eq, 9.66 mmol) in DCM (100 ml) at 0°C. The reaction mixture was stirred for 3 h at RT, diluted with DCM (100 ml) and successively washed with saturated Na2S03 solution (50 ml), NaHC03 solution (2 x 50 ml) and brine (50 ml). The organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography using [100-200 mesh silica, EtOAc/hexane = 3:2]. White solid. Yield: 3.0 g (79%). MS: m/z: [M+H]+ = 394.2/396.2
3c) 6'-(Ethylsulfonyl)-1 '-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinel
PdCI2(dppf) (67 mg, 0.082 mmol, 0.05 eq) was added to a suspension of 3b) (650 mg, 1.649 mmol, 1 eq), bis(pinacolato)diboron (834 mg, 3.298 mmol, 2 eq) and potassium acetate (243 mg, 2.47 mmol, 1.5 eq) in 1 ,4-dioxane (25 ml) that was kept under Ar. The reaction mixture was stirred for 16 h at 100°C, cooled to RT and filtered through a plug of celite. The solvent was distilled off, 2-bromopyridine (312 mg, 1.979 mmol, 1.2 eq), K2C03 (0.458 mg, 3.298 mmol, 2 eq) and 1 ,4-dioxane (20 ml) were added and the reaction vessel was flushed with Ar. Tetrakis(triphenylphosphine)palladium(0) (95 mg, 0.082 mmol, 0.05 eq) was added and the mixture was stirred for 16 h at 100°C, cooled to RT and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in EtOAc (50 ml) and washed with water (2 x 20 ml) and brine (20 ml). The organic layer was dried over Na2S04 and evaporated. The raw product was further purified by column chromatography [230-400 mesh silica gel; DCM with 5% MeOH]. White solid. Yield: 65 mg (10%). MS: m/z: [M+H]+ = 393.0
H NMR (400 MHz, DMSO-d6, 200°C, δ ppm): 9.34 (s, 2H), 8.82 (s, 1 H), 8.68 (d, J = 4.0 Hz, 1 H), 8.08 (d, J = 7.8 Hz, 1 H), 7.91 (t, J = 7.4 Hz, 1 H), 7.44 (d, J = 7.8 Hz, 1 H), 7.37 (t, J = 6.8 Hz, 1 H), 7.08 (d, J = 7.8 Hz, 1 H,), 4.36 (s, 2H), 3.28-3.23 (m, 2H), 1.29 (d, J = 10.2, 2H), 1.25 (d, J = 10.2, 2H), 1.14 (t, J = 7.3 Hz, 3H). Examples no.'s 4 to 6 were prepared analogously to synthesis example 3.
Figure imgf000039_0001
Whitel solid: Yield: 138 mg. MS: m/z: [M+H]+ = 407.0
H NMR (400 MHz, DMSO-d6, 200°C, δ ppm): 9.32 (s, 2H), 8.82 (d, J = 1.3, 1 H), 8.52 (d, J = 4.9 Hz, 1 H), 7.94 (s, 1 H), 7.44 (dd, J = 6.4 Hz, 1.4 Hz, 1 H), 7.21 (d, J = 4.8 Hz, 1 H), 7.08 (d, J = 7.84 Hz, 1 H), 4.36 (s, 2H), 3.28-3.23 (m, 2H), 2.39 (s, 3H), 1.30 (s, 2H), 1.23 (s, 2H), 1.14 (t, J = 7.3 Hz, 3H).
Example 5: 1 '-(5-(4-ethylpyridin-2-yl)pyrimidin-2-yl)-6'-(ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolinel
Figure imgf000040_0001
White solid. Yield: 68 mg. MS: m/z: [M+H]+ = 420.8
H NMR (400 MHz, DMSO-d6, 200°C, δ ppm): 9.34 (s, 2H), 8.83 (d, J = 1.2 Hz, 1 H), 8.55 (d, J = 4.9 Hz, 1 H), 7.97 (s, 1 H), 7.44 (dd, J = 6.5 Hz, 1.3 Hz, 1 H), 7.24 (d, J = 4.6 Hz, 1 H), 7.08 (d, J = 7.8 Hz, 1 H), 4.36 (s, 2H), 3.23-3.28 (m, 2H), 2.67-2.72 (m, 2H), 1.24-1.31 (m, 7H), 1 .14 (t, J = 7.3 Hz, 1 H).
Figure imgf000040_0002
White solid. Yield: 0.06 g. MS: m/z: [M+H]+ = 406.8
H NMR (400 MHz, DMSO-d6, 200°C, δ ppm): 9.32 (s, 2H), 7.87 (s, 1 H), 7.79 (t, J = 7.6 Hz, 1 H), 7.44 (d, J = 7.8 Hz, 1 H), 7.24 (d, J = 7.5 Hz, 1 H), 7.08 (d, J = 7.8 Hz, 1 H), 4.35 (s, 2H), 3.23-3.29 (m, 2H), 2.55 (s, 3H), 1.31 (s, 2H), 1 .23 (s, 2H), 1.13 (t, J = 7.3 Hz, 3H).
Example 7: 6'-(Ethylsulfonyl)-1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinel
Figure imgf000040_0003
7a) 1 '-(5-Bromopyrimidin-2-yl)-6'-(ethylthio)spiro[cyclopropane-1 ,3'-indolinel
NaH (60%, 1.2 g, 30.48 mmol, 2.5 eq) was added to a stirred solution of 6'-(ethylthio)spiro[cyclopropane- 1 ,3'-indoline] (2.5 g, 12.19 mmol, 1 eq) in DMF (20 ml) at 0°C. The mixture was stirred for 15 min, 5- bromo-2-(methylsulfonyl)pyrimidine (2.9 g, 12.19 mmol, 1 eq) in DMF (5 ml) was added and stirring was continued for 16 h at RT. The reaction was quenched with ice and extracted with EtOAc (2 x 25ml). The combined organic layers were washed with brine (20 ml) and dried over Na2S04. The solvents were removed under vacuum and the remnant was purified by column chromatography [100-200mesh silica gel, hexane/EtOAc = 4:1]. Brown solid. Yield: 2.3 g (52%)
7b) 6'-(Ethylthio)-1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinel
(AtaPhos)2PdCI2 (0.059 g, 0.082 mmol, 0.1 eq) was added to a stirred mixture of compound 7a) (0.3 g, 0.828 mmol, 1 eq), K2C03 (0.343 g, 2.48 mmol, 3 eq) and 2-fluoro phenylboronic acid (0.213 g, 1.65 mmol, 2 eq) in amyl alcohol (15 ml) and water (1.5 ml) that was kept under Ar. The mixture was refluxed for 4 h, then diluted with water (25 ml), and extracted with EtOAc (3 x 25 ml). The combined organic layers were washed with water (15 ml) and brine (15 ml), dried over Na2S04 and concentrated. The remnant was purified by flash column chromatography [100-200 mesh silica gel; hexane/EtOAc = 1 : 1]. White solid. Yield: 0.2 g (64%)
7c) 6'-(Ethylsulfonyl)-1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline1
mCPBA (142 mg, 0.636 mmol, 2 eq) was slowly added at 0°C to a stirred solution of compound 7b) (120 mg, 0.318 mmol, 1 eq) in THF (8 ml). Stirring was continued for 2 h at RT, the mixture was then quenched with saturated NaHC03 solution and extracted with DCM (2 x 15 ml). The combined organic layers were washed with brine (10 ml), dried over Na2S04 and concentrated. The residue was purified by column chromatography [100-200 mesh silica gel; hexane/EtOAc = 3:2]. White solid. Yield: 70 mg (54%). MS: m/z: [M+H]+ = 410.1
H NMR (400 MHz, DMSO-d6, δ ppm): 8.89 (s, 2H), 8.78 (s, 1 H), 7.71 (t, J = 15.2 Hz, 1 H), 7.47 (m, 2H), 7.36 (m, 2H), 7.09 (d, J = 7.8 Hz, 1 H), 4.34 (s, 2H), 3.25 (m, 2H), 1.30 (m, 2H), 1.23 (m, 2H), 1.15 (t, J = 14.6 Hz, 3H).
Figure imgf000041_0001
Oxidation of compound 7b) (120 mg, 0.318 mmol, 1 eq) with mCPBA (57 mg, 0.254 mmol, 0.8 eq) as described under 7c) with the only difference that 0.8 eq of the oxidizing reagent was used. White solid. Yield: 60 mg (48%). MS: m/z: [M+H]+ = 394.2
H NMR (400 MHz, DMSO-d6, δ ppm): 8.86 (s, 2H), 8.58 (s, 1 H), 7.70 (m, 1 H), 7.46 (m, 1 H), 7.36 (m, 2H), 7.17 (d, J = 7.7 Hz, 1 H), 7.01 (d, J = 7.8 Hz, 1 H), 4.31 (s, 2H), 2.97 (m, 1 H), 2.74 (m, 1 H), 1 .24 (m, 2H), 1.17 (m, 2H), 1.08 (t, J = 14.5 Hz, 3H).
Example 9: 1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)-6'-(isopropylsulfonyl)spiro[cyclopropane-1 ,3'-indoline1
Figure imgf000042_0001
Prepared analogously to synthesis example 7. White solid. Yield: 70 mg. MS: m/z: [M+H]+ = 424.2 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.89 (s, 2H), 8.75 (s, 1 H), 7.72 (t, J = 15.9 Hz, 1 H), 7.47 (m, 1 H), 7.41 (m, 3H), 7.09 (d, J = 7.8 Hz, 1 H), 4.34 (s, 2H), 3.37 (m, 1 H), 1 .30 (s, 2H), 1.25 (m, 2H), 1 .19 (d, J = 6.8 Hz, 6H).
Example 10: 1 '-(5-(2-Fluorophenyl)pyri '-(isopropylsulfinyl)spiro[cvclopropane-1 ,3'-indolinel
Figure imgf000042_0002
Prepared analogously to synthesis example 8. White solid. Yield: 70 mg. MS: m/z: [M+H]+ = 408.0 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.83 (s, 2H), 8.56 (s, 1 H), 7.67 (t, J = 14.0 Hz, 1 H), 7.46 (m, 1 H), 7.35 (m, 2H), 7.16 (d, J = 7.6 Hz, 1 H), 6.98 (d, J = 7.6 Hz, 1 H), 4.35 (s, 2H), 2.96 (m, 1 H), 1.24 (s, 2H), 1.17 (d, J = 6.8 Hz, 5H), 1.01 (d, J = 6.6 Hz, 3H).
Example 1 1 : 3-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)sulfonyl) butan- 1-ol
Figure imgf000042_0003
1 1a) 6'-Bromo-1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinel
6'-Bromospiro[cyclopropane-1 ,3'-indoline] (3 g, 13.39 mmol, 1 eq), 2-chloro-5-(2-fluorophenyl) pyrimidine (3.3 g, 16.07 mmol, 1.2 eq) and DIPEA (16.3 ml, 93.73 mmol, 7 eq) in n-butanol (30 ml) were stirred 150°C for 48 h in a sealed tube. The reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc, washed with water (40 ml) and brine (40 ml) and dried over Na2S04. The solvents were distilled off and the remnant was purified by column chromatography [230-400 mesh silica gel; EtOAc/hexane = 1 :9]. White solid. Yield: 1.3 g (25%). MS: m/z: [M+H]+ = 396.0/398.0
1 1 b) 1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)-6'-((4-methoxybenzyl)thio)spiro[cyclopropane-1 ,3'-indolinel Pd2(dba)3 (0.34 g, 0.379 mmol) and Xantphos (0.21 g, 0.379 mmol) were added to a stirred solution of compound 1 1a) (1 .5 g, 3.79 mmol), 4-methoxybenzylthiol (0.795 ml, 5.68 mmol) and DIPEA (1 .64 ml, 9.46 mmol) in 1 ,4-dioxane (30 ml) that was stirred under Ar. The reaction mixture was refluxed for 16 h (TLC indicated the completion of the reaction), cooled to RT and filtered through a plug of celite. The filter was rinsed with EtOAc and the combined organic layers were washed with water (20 ml) and brine (20 ml), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography [230-400 mesh silica gel; EtOAc/hexane = 1 :4]. White solid. Yield: 1.5 g, (86%).
1 1 c) 1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline1-6'-thiol
A solution of compound 1 1 b) (0.5 g, 1.06 mmol, 1 eq), TFA (5 ml) and triethylsilane (1.7 ml, 10.66 mmol, 10 eq) in 1 ,2-dichloroethane (20 ml) was refluxed for 16 h. The volatile parts were removed under vacuum and the residue was purified by column chromatography [100-200 mesh silica gel; EtOAc/hexane = 15:85]. Yield: 0.2 g (54%)
1 1 d) 3-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin1-6'-yl)thio)butan-1 -ol
TEA (0.14 ml, 1.146 mmol, 2 eq) and crotonaldehyde (0.047 ml, 0.573 mmol, 1 eq) were added to a stirred solution of compound 1 1 c) (0.2 g, 0.573 mmol, 1 eq) in EtOH (95%, 6 ml). The mixture was refluxed for 4 h and then cooled to 0°C. Sodium borohydride (0.043 g, 1.146 mmol, 2 eq) was added and stirring was continued for 16 h at RT. The reaction mixture was quenched with 1 N aqueous HCI and extracted with EtOAc (2 x 15 ml). The combined organic layers were washed with brine (10 ml), dried over Na2S04 and concentrated. The residue (0.17 g) was used in the next step without any further purification. MS: m/z: [M+H]+ = 422.0
1 1 e) 3-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolin1-6'-yl)sulfonyl) butan-1-ol mCPBA (105 mg, 0.474 mmol, 2 eq) was slowly added at 0°C to a stirred solution of compound 1 1d) (100 mg, 0.237 mmol, 1 eq) in THF (8 ml). The reaction mixture was stirred for 2 h at RT, then quenched with saturated NaHC03 solution and extracted with DCM (2 x 15 ml). The combined organic layers were washed with brine (10 ml), dried over Na2S04 and concentrated. The residue was purified by column chromatography [100-200mesh silica gel; EtOAc/hexane 2:3]. White solid. Yield: 40 mg (37%). MS: m/z: [M+H]+ = 454.2
H NMR (400 MHz, DMSO-d6, δ ppm): 8.91 (s, 1 H), 8.80 (s, 2H), 7.58 (t, J = 15.4 Hz, 1 H), 7.45 (m, 2H), 7.32 (m, 2H), 6.99 (d, J = 7.9 Hz, 1 H), 4.36 (s, 2H), 3.70 (m, 1 H), 3.60 (m, 1 H), 3.57 (m, 1 H), 2.19 (t, J = 8.7 Hz, 1 H), 1.59 (m, 1 H), 1.30 (t, J = 12.6 Hz, 7H).
Example 12: 3-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolin1-6'-yl)sulfinyl) butan- 1-ol
Figure imgf000044_0001
Compound 1 1 d) (100 mg, 0.237 mmol, 1 eq) was oxidized with 0.9 equivalents mCPBA analogously to procedure 1 1 e). White solid. Yield: 50 mg (48%). MS: m/z: [M+H]+ = 438.1
H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.83 (s, 2H), 8.58 (d, J = 1 1.5 Hz, 1 H), 7.67 (t, J = 14.7 Hz, 1 H), 7.47 (m, 1 H), 7.35 (m, 2H), 7.18 (m, 1 H), 6.98 (d, J = 7.7 Hz, 1 H), 4.33 (s, 2H), 4.26 (m, 1 H), 3.62 (m, 2H), 2.94 (m, 1 H), 1.99 (m, 1 H), 1.59 (m, 1 H), 1.50 (m, 2H), 1.48 (m, 2H), 1.45 (m, 3H).
Example 13: 3-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)sulfonyl) propan-1-ol
Figure imgf000044_0002
13a) 3-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)thio)propan-1-ol Aqueous NaOH solution (20%; 2 ml) followed by 3-bromopropanol (0.15 ml, 1.71 mmol, 1.5 eq) were added to a stirred solution of compound 1 1 c) (0.4 g, 1 .14 mmol, 1 eq) in EtOH (10 ml). The resulting mixture was refluxed for 1 h, cooled and extracted with EtOAc (2 x 25 ml). The combined organic layers were washed with water (10 ml) and brine (10 ml), dried over Na2S04 and concentrated. The residue was purified by column chromatography [100-200 mesh silica gel; EtOAc/hexane 1 :2]. Yield: 0.3 g (64%). MS: m/z: [M+H]+ = 408.2
13b) 3-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolin1-6'-yl)sulfonyl) propan-1-ol Compound 13a) (150 mg, 0.368 mmol, 1 eq) was treated with mCPBA analogously to procedure 1 1 e). White solid. Yield: 55 mg (34%). MS: m/z: [M+H]+ = 440.2
H NMR (400 MHz, DMSO-d6, δ ppm): 8.90 (s, 2H), 8.78 (s, 1 H), 7.72 (t, J = 15.7 Hz, 1 H), 7.45 (m, 4H), 7.09 (d, J = 7.9 Hz, 1 H), 4.63 (t, J = 10.4 Hz, 1 H), 4.34 (s, 2H), 3.42 (d. J = 5.7 Hz, 2H), 3.32 (m, 2H), 1.69 (d, J = 6.7 Hz, 2H), 1 .30 (d, J = 26.9 Hz, 4H).
Example 14: 3-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin1-6'-yl)sulfinyl) propan- 1-ol
Figure imgf000045_0001
mCPBA (0.8 eq) oxidation of compound 13a) (150 mg, 0.368 mmol, 1 eq). White solid. Yield: 65 mg (42%). MS: m/z: [M+H]+ = 424.3
H NMR (400 MHz, DMSO-d6, δ ppm): 8.87 (s, 2H), 8.59 (s, 1H), 7.71 (t, J = 15.0 Hz, 1H), 7.47 (m, 1H), 7.39 (m, 2H), 7.18 (d, J = 7.7 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 4.60 (s, 1H), 4.31 (s, 2H), 3.45 (d, J = 5.7 Hz, 2H), 2.90 (m, 1H), 2.82 (m, 1H), 1.75 (m, 1H), 1.58 (m, 1H), 1.24 (s, 2H), 1.17 (s,2H).
Example 15: 2-((1'-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)sulfonyl) ethanol
Figure imgf000045_0002
Prepared analogously to synthesis example 13. White solid. Yield: 90 mg. MS: m/z: [M+H]+ = 426.2 H NMR (400 MHz, DMSO-d6, δ ppm): 8.90 (s, 2H), 8.78 (s, 1H), 7.72 (t, J = 14.6 Hz, 1H), 7.46 (m, 2H), 7.37 (m, 2H), 7.08 (d, J = 7.9 Hz, 1H), 4.89 (t, J = 10.8 Hz, 1H), 4.34 (s, 2H), 3.71 (m, 2H), 3.42 (m, 2H), 1.30 (d, J = 26.4 Hz, 4H).
Figure imgf000045_0003
Obtained analogously to synthesis example 14. White solid. Yield: 50 mg. MS: m/z: [M+H]+ = 410.1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.87 (s, 2H), 8.61 (s, 1H), 7.70 (t, J = 13.4 Hz, 1H), 7.45 (m, 1H), 7.39 (m, 2H), 7.20 (d, J = 7.4 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 5.06 (s, 1H), 4.31 (s, 2H), 3.82 (m, 1H), 3.67 (m, 1H), 2.95 (s, 2H), 1.24 (m, 2H), 1.17 (s, 2H). xample 17: 6 Ethylsulfonyl)-1 5-(4-methoxypyri^^
Figure imgf000046_0001
17a) 1 5-Bromopyrimidin-2-yl)-6 ethylthio)spiro[cvclopropane-1 ,3'-indolinel
5-Bromo-2-chloropyrimidine (3.954 g, 1.2 eq, 20.48 mmol), 6'-(ethylthio)spiro[cyclopropane-1 ,3'-indoline] (3.5 g, 1 eq, 17.07 mmol) and DIPEA (14.76 ml, 5 eq, 85.36 mmol) in n-butanol (50 ml) were stirred in sealed tube at 140°C for 20 h. The reaction mixture was cooled to RT and an appearing precipitate was filtered off and washed with hexane (2 x 50ml). Light yellow solid. Yield: 3.2 g (52%) 17b) 1 '-(5-Bromopyrimidin-2-yl)-6'-(ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolinel
mCPBA (3.36 g, 2 eq, 19.34 mmol) was added portion wise at 0°C to a stirred solution of 17a) (3.5 g, 1 eq, 9.66 mmol) in DCM (100 ml) and stirring was continued for 3 h at RT. The reaction mixture was diluted with DCM (100 ml) and washed successively with Na2S03 solution (50 ml), NaHC03 solution (2 x 50 ml) and brine (50 ml). The organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure. The remnant was purified by column chromatography [100-200 mesh silica, EtOAc/hexane = 2:3]. White solid. Yield: 3.0 g (79%). MS: m/z: [M+H]+ = 396.2/394.2.
17c) 6'-(Ethylsulfonyl)-1 '-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinel Compound 17b) (580 mg, 1.477 mmol, 1 eq) was converted into a pinacol boronate and then coupled with 2-bromo-4-methoxypyridine (279 mg, 1.477 mmol, 1 eq) analogously to procedure 3c). For the final purification, the raw product was submitted to column chromatography [230-400 mesh silica gel; DCM with 5% MeOH]. White solid. Yield: 70 mg (1 1 %). MS: m/z: [M+H]+ = 422.8
H NMR (400 MHz, DMSO-d6, 20°C, δ ppm): 9.35 (s, 2H), 8.83 (d, J = 1.2 Hz, 1 H), 8.48 (d, J = 5.7 Hz, 1 H), 7.66 (d, J = 2.1 Hz, 1 H), 7.44 (dd, J = 6.5 Hz, 1.3 Hz, 1 H), 7.08 (d, J = 7.8 Hz, 1 H), 6.95 (dd, J = 3.5 Hz, 2.2 Hz, 1 H), 4.36 (s, 2H), 3.92 (s, 3H), 3.28-3.22 (m, 2H), 1.32 (d, J = 7.3, 2H), 1.23 (t, J = 3.5 Hz, 2H), 1.14 (t, J = 7.3 Hz, 3H).
Example 18: N,N-Dimethyl-1 '-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinel-6'- sulfonamide
Figure imgf000047_0001
18a) 5'-((4-Mthoxybenzyl)thio)spiro[cvclopropane-1 ,3'-indolinl-2'-one
Pd2(dba)3 (4.45g, 4.85 mmol, 0.05 eq) and Xantphos (5.6 g, 9.71 mmol, 0.1 eq) were added to a solution of 5'-bromospiro[cyclopropane-1 ,3'-indolin]-2'-one (23 g, 97.1 mmol, 1 eq), 4-methoxybenzylthiol (18 g, 1 16.5 mmol, 1.2 eq) and DIPEA (36 ml, 204.0 mmol, 2.1 eq) in 1 ,4-dioxane (400 ml) that was stirred under Ar. The reaction mixture was refluxed for 16 h, then cooled to RT and filtered through a plug of celite. The filter was rinsed with EtOAc and the filtrate was washed with water (200 ml) and brine (200 ml), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography [230-400 mesh silica gel; EtOAc/hexane = 3:7]. White solid. Yield: 20 g (66%). MS: m/z: [M+H]+ = 312.0
18b) 5'-((4-Methoxybenzyl)thio)spiro[cyclopropane-1 ,3'-indolinel
Compound 18a) (15 g, 48.23 mmol, 1 eq) was added portion wise at 0°C to a suspension of LAH (4.58 g, 120.1 mmol, 2.5 eq) in THF (400 ml). The reaction was stirred at 70°C for 3 h and then quenched with NaOH solution at 0°C. The mixture was filtered and the filtrate was diluted with EtOAc. The organic layer was separated, washed with water (500 ml) and brine (500 ml), and dried over Na2S04. The solvents were removed under vacuum und the residue was purified by column chromatography [100-200 mesh silica gel, EtOAc/hexane = 3:7]. Brown solid. Yield: 14 g (98%). MS: m/z: [M+H]+ = 298.0 18c) 1 '-(5-Bomopyrimidin-2-yl)-5'-((4-methoxybenzyl)thio)spiro[cyclopropane-1 ,3'-indoline1
Compound 18b) (4 g, 13.47 mmol, 1 eq), 5-bromo-2-chloropyrimidine (3.13 g, 16.16 mmol, 1 .2 eq) and DIPEA (16.39 ml, 94.27 mmol, 7 eq) in n-butanol (40 ml) were stirred 120°C for 16 h in a sealed tube. The reaction mixture was cooled to RT and a precipitating solid was filtered off, washed successively with water (100 ml) and hexane (200 ml) and dried in vacuo. Yield: 3.56 g (58%).
18d) 1 '-(5-Bromopyrimidin-2-yl)-N,N-dimethylspiro[cyclopropane-1 ,3'-indoline1-5'-sulfonamide
TCCA (2.01 g, 8.644 mmol, 1 .1 eq) was added to a stirred solution of benzyltrimethylammonium chloride (4.961 g, 26.720 mmol, 3.4 eq) in acetonitrile (90 ml) and stirring was continued for 30 min at RT. A solution of compound 18c) (3.56 g, 7.859 mmol, 1 eq) in acetonitrile (90 ml) cooled to 0°C was added and the mixture was stirred for 5 min, then quenched with 1 M Na2C03 solution and extracted with EtOAc (2 x 150 ml). The combined organic layers were washed with brine (100 ml), dried over Na2S04 and concentrated under reduced pressure.
The sulphonyl chloride thus obtained was dissolved in dry DCM (40 ml) and TEA (5.4 ml, 39.3 mmol, 5 eq) followed by dimethylamine hydrochloride (2.164 g, 26.554 mmol, 3.5 eq) were added at 0°C. The mixture was stirred at RT for 2 h, then diluted with DCM (100 ml), washed with water (50 ml) and brine (50 ml), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography [230-400 mesh silica gel; EtOAc/hexane = 3:7]. White solid. Yield: 3.2 g (97%). MS: m/z: [M+H]+ = 41 1.2
18e) N,N-Dimethyl-1 '-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinel-6'-sulfonamide Compound 18d) (500 mg, 1.225 mmol, 1 eq) was transferred into a pinacol boronate which was then coupled with 2-bromopyridine (232 mg, 1.471 mmol, 1.2 eq) in a Suzuki reaction analogously to procedure 3c). White solid. Yield: 100 mg (20%). MS: m/z: [M+H]+ = 408.3.
H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H), 8.74 (s, 1 H), 8.66 (d, J = 4 Hz, 2H), 8.08 (d, J = 7.8 Hz, 1 H), 7.90 (t, J = 6.9 Hz, 1 H), 7.37 (t, J = 6.6 Hz, 1 H), 7.30 (d, J = 7.4 Hz, 1 H), 7.06 (d, J = 7.8 Hz, 1 H), 4.36 (s, 2H), 2.65 (s, 6H), 1 .23-1.30 (m, 4H).
Example 19 to 21 were prepared analogously to synthesis example 18.
Example 19: N,N-Dimethyl-1 '-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinel-6'- sulfonamide
Figure imgf000048_0001
White solid. Yield: 70 mg. MS: m/z: [M+H]+ = 422.0;
H NMR (400 MHz, DMSO-d6, δ ppm): 9.31 (s, 2H), 8.73 (d, J = 1.0 Hz, 1 H), 8.51 (d, J = 4.9 Hz, 1 H), 7.94 (s, 1 H), 7.29-7.31 (m, 1 H), 7.20 (d, J = 4.8 Hz, 1 H), 7.05 (d, J = 7.8 Hz, 1 H), 4.35 (s, 2H) 2.65 (s, 6H), 2.39 (s, 3H), 1 .17-1.29 (m, 4H).
Example 20: 1 '-(5-(4-Ethylpyridin-2-yl)pyrimidin-2-yl)-N,N-dimethylspiro[cyclopropane-1 ,3'-indolinel-6'- sulfonamide
Figure imgf000048_0002
White solid. Yield: 70 mg. MS: m/z: [M+H]+ = 435.9.0; H NMR (400 MHz, DMSO-c!6, δ ppm): 9.33 (s, 2H), 8.74 (s, 1 H), 8.54 (d, J = 4.9 Hz, 1 H), 7.97 (s, 1 H), 7.30 (d, J = 7.6 Hz, 1 H), 7.24 (d, J = 4.5 Hz, 1 H), 7.06 (d, J = 7.8 Hz, 1 H), 4.36 (s, 2H), 2.64-2.71 (m, 8H), 1.22-1.29 (m, 7H). Example 21 : N,N-Dimethyl-1 5-(6-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indoline1-6'- sulfonamide
Figure imgf000049_0001
White solid. Yield: 90 mg. MS: m/z: [M+H]+ = 422.0
H NMR (400 MHz, DMSO-d6, δ ppm): 9.31 (s, 2H), 8.73 (s, 1 H), 7.86 (d, J = 7.7 Hz, 1 H), 7.78 (t, J = 7.8 Hz, 1 H), 7.3 (d, J = 7.6 Hz, 1 H), 7.23 (d, J = 7.5 Hz, 1 H), 7.06 (d, J = 7.8 Hz, 1 H), 4.35 (s, 2H), 2.64 (s, 6H), 2.54 (s, 3H), 1 .22-1.30 (m, 4H).
Example 22: 1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N-dimethylspiro[cyclopropane-1 ,3'-indolinel-6'- sulfonamide
Figure imgf000049_0002
22a) 1 5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinel-6'-sulfonyl chloride
TCCA (0.109 g, 0.46 mmol, 1.1 eq) was added to a stirred solution of benzyltrimethylammonium chloride (0.265 g, 1.42 mmol, 3.4 eq) in acetonitrile (5 ml), the mixture was stirred for 30 min at RT and then added to compound 1 1 b) (0.2 g, 0.42 mmol, 1 eq) in acetonitrile (5ml) at 0°C. After stirring for 5 min, the mixture was quenched with 1 M Na2C03 solution, stirred for 10 min and extracted with EtOAc (2 x 15 ml). The combined organic layers were washed with brine (10 ml), dried over Na2S04 and concentrated. The residue was purified by column chromatography [230-400 mesh silica gel; EtOAc/hexane = 3:7]. White solid. Yield: 0.05 g (28%). 22b) 1 5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N-dimethylspiro[cyclopropane-1 ,3'-indolinel-6'-sulfonamide TEA (0.2 ml, 1.44 mmol, 3 eq), followed by dimethylamine hydrochloride (78 mg, 0.963 mmol, 2 eq) were added at 0°C to a stirred solution of compound 22a) (200 mg, 0.481 mmol, 1 eq) in DCM (8 ml) and stirring was continued for 2 h. The reaction mixture was diluted with DCM, washed with brine (10 ml), dried over Na2S04 and concentrated. The remnant was purified by column chromatography [230-400 mesh silica gel; EtOAc/hexane = 1 : 1]. White solid. Yield: 100 mg (49%). MS: m/z: [M+H]+ = 425.2 H NMR (400 MHz, DMSO-d6, δ ppm): 8.88 (s, 2H), 8.70 (s, 1 H), 7.71 (t, J = 15.8 Hz, 1 H), 7.47 (m, 1 H), 7.39 (m, 3H), 7.07 (d, J = 7.8 Hz, 1 H), 4.33 (s, 2H), 2.63 (s, 6H), 1.30 (m, 2H), 1.24 (m, 2H).
Example 23: 1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methylspiro[cyclopropane-1 ,3'- indolinel-6'-sulfonamide
Figure imgf000050_0001
Obtained from compound 22a) (200 mg, 0.481 mmol, 1 eq) and 2-methylamino-ethanol (0.077 ml, 0.963 mmol, 2 eq) according to procedure 22b). White solid. Yield: 130 mg (59%). MS: m/z: [M+H]+ = 455.0 H NMR (400 MHz, DMSO-d6, δ ppm): 8.88 (s, 2H), 8.72 (s, 1 H), 7.72 (t, J = 15.6 Hz, 1 H), 7.47 (m, 1 H), 7.39 (m, 3H), 7.04 (d, J = 7.7 Hz, 1 H), 4.78 (t, 10.8 Hz, 1 H), 4.33 (s, 2H), 3.55 (m, 2H), 3.04 (t, J = 1 1.9 Hz, 2H), 2.75 (s, 3H), 1.28 (d, J = 27.4 Hz, 4H).
Figure imgf000050_0002
24a) 1 '-(5-Bromopyrimidin-2-yl)-6'-(ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolinel
mCPBA (1 .35 g, 7.87 mmol, 0.95 eq) was added portion wise at 0°C to a stirred solution of compound 1 d) (3.0 g, 8.28 mmol, 1 .0 eq) in DCM (100 ml). The reaction mixture was stirred for 3 h at RT, then diluted with DCM (100 ml) and washed successively with saturated Na2S03 solution (50 ml), saturated NaHC03 solution (2 x 50 ml) and brine (50 ml). The organic layer was dried over Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography using [100-200 mesh silica, EtOAc/hexane = 2:3]. Light yellow solid. Yield: 2.1 g (67%). MS: m/z: [M+H]+ = 377.9/379.9. 24b) 6'-(Ethylsulfinyl)-1 '-(5-(6-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline1
Compound 24a) (0.567 g, 1.5 mmol, 1 eq) was transferred into a pinacol boronate that was reacted with 2-bromo-6-methyl pyridine (0.310 g, 1.8 mmol, 1 .2 eq) analogously to procedure 3c). White solid. Yield: 0.1 g (17%). MS: m/z: [M+H]+ = 391 .0 H NMR (400 MHz, DMSO-d6, 20°C, δ ppm): 9.29 (s, 2H), 8.61 (s, 1H), 7.84 (d, 1H, J = 7.8 Hz), 7.8 (t, 1H, J = 7.6 Hz), 7.23 (d, 1H, J = 7.4 Hz), 7.17 (dd, 1H, J = 6.4 Hz, 1.3 Hz), 7.00 (d, 1H, J = 7.7 Hz), 4.32 (s, 2H), 2.98-2.94 (m, 1H), 2.78-2.74 (m, 1H,), 2.54 (s, 3H), 1.25-1.17 (m, 4H), 1.07 (t, 3H, J = 7.3). Examples 25 to 29 were prepared analogously to synthesis example 24.
Figure imgf000051_0001
White solid. Yield: 0.15 g. MS: m/z: [M+H]+ = 391.4
H NMR (400 MHz, DMSO-d6, 20°C, δ ppm): 9.29 (s, 2H), 8.61 (s, 1H), 8.52 (d, 1H, J = 5.0 Hz), 7.91 (d, 1H), 7.21-7.16 (m, 2H), 7.00 (d, 1H, J = 7.7 Hz), 4.32 (s, 2H), 2.99-2.94 (m, 1H), 2.78-2.73 (m, 1H), 2.32 (s, 3H), 1.24-1.15 (m,4H), 1.07 (t, 3H, J = 7.3).
Example 26: 1'-(5-(4-Cvclopropylpyridin-2-yl)pyrimidin-2-yl)-6'-(ethylsulfinyl)spiro[cyclopropane-1,3'- indoline!
Figure imgf000051_0002
Obtained from compound 24a) and 2-chloro-4-cyclopropylpyridine. White solid. Yield: 0.42 g. MS: m/z: [M+H]+ = 417.0
H NMR (400 MHz, DMSO-d6, 20°C, δ ppm): 9.3 (s, 2H), 8.61 (s, 1H), 8.45 (d, 1H, J = 4.8 Hz), 7.71 (s, 1H), 7.16 (d, 1H, J = 7.4 Hz), 7.08 (d, 1H, J = 4.3 Hz), 6.99 (d, 1H, J = 7.6 Hz), 4.31 (s, 2H), 2.99-2.94 (m, 1H), 2.78-2.73 (m, 1H), 1.98 (s, 1H), 1.24-1.16 (m, 4H), 1.10-1.05 (m, 5H), 0.95 (s, 2H).
Example 27: 1 5-(4-Ethylpyridin-2-yl)pyrimidin-2-yl)-6'-(ethylsulfinyl)spiro[cyclopropane-1,3'-indolinel
Figure imgf000052_0001
White solid. Yield: 0.18 g. MS: m/z: [M+H]+ = 405.1
H NMR (400 MHz, DMSO-d6, 20°C, δ ppm): 9.31 (s, 2H), 8.61 (s, 1H), 8.54 (d, 1H, J = 4.7 Hz), 7.93 (s, 1H), 7.23 (d, 1H, J = 4.7 Hz), 7.17 (d, 1H, J = 7.4 Hz), 7.00 (d, 1H, J = 7.6 Hz), 4.32 (s, 2H), 2.99-2.94 (m, 1H), 2.78-2.73 (m, 1H), 2.72-2.63 (q, 2H), 1.27-1.24 (m, 5H), 1.17 (s, 1H), 1.07 (t, 3H, J = 7.1 Hz).
Figure imgf000052_0002
White solid. Yield: 0.11 g. MS: m/z: [M+H]+ = 392.0
H NMR (400 MHz, DMSO-d6, 20°C, δ ppm): 9.09 (s, 2H), 8.58 (s, 1H), 8.1 (d, 1H, J = 5.7 Hz), 7.17 (d, 1H, J = 7.7 Hz), 7.00 (d, 2H, J = 7.8 Hz), 6.53-6.48 (m, 3H), 4.31 (s, 2H), 2.99-2.92 (m, 1H), 2.78-2.73 (m, 1H), 1.24-1.17 (m,4H), 1.06 (t, 3H, J = 7.2).
Figure imgf000052_0003
White solid. Yield: 0.05 g. MS: m/z: [M+H]+ = 404.8
H NMR (400 MHz, DMSO-d6, 20°C, δ ppm): 9.31 (s, 2H), 8.61 (s, 1H), 7.85 (d, 1H, J = 7.6 Hz), 7.8 (t, 1H, J = 7.8 Hz), 7.24 (d, 1H, J = 7.4 Hz), 7.17 (d, 1H, J = 7.7 Hz), 7.00 (d, 1H, J = 7.7 Hz), 4.32 (s, 2H), 3.00-2.94 (m, 1H), 2.85-2.73 (m, 3H), 1.3 (t, 3H, J = 7.6 Hz), 1.25-1.17 (m, 4H), 1.07 (t, 3H, J = 7.3 Hz). Example 30: 1 5-(4-Cvclopropylpyridin-2-yl)pyrimidin-2-yl)-6 ethylsulfonyl)spiro[cvclopro indolinel
Figure imgf000053_0001
Prepared from synthesis example 26 via oxidation with mCPBA. White solid. Yield: 0.9 g. MS: m/z: [M+H]+ = 433.4
H NMR (400 MHz, DMSO-d6, 20°C, δ ppm): 9.33 (s, 2H), 8.82 (s, 1 H), 8.46 (d, 1 H, J = 5 Hz), 7.73 (s, 1 H), 7.43 (d, 1 H, J = 7.9 Hz), 7.09 (t, 1 H, J = 7.9 Hz), 4.35 (s, 2H), 3.28-3.22 (m, 2H), 1.98 (s, 1 H), 1.30- 1.22 (m, 4H), 1 .15-1 .09 (m, 5H), 0.96 (s, 2H). Example 31 : 2-(2-(6'-(Ethylsulfonyl)spiro ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)pyridin-4-amine
Figure imgf000053_0002
Prepared from compound 3b) and 4-amino-2-bromo-pyridine analogously to synthesis example 3. White solid. Yield: 75 mg. MS: m/z: [M+H]+ = 407.9
H NMR (400 MHz, DMSO-d6, 20°C, δ ppm): 9.12 (s, 2H), 8.79 (s, 1 H), 8.0 (d, 1 H, J = 5.6 Hz), 7.43 (d, 1 H, J = 7.8 Hz), 7.07 (d, 1 H, J = 7.8 Hz), 7.02 (s, 1 H), 6.49 (d, 1 H, J = 5 Hz), 6.24 (s, 1 H), 4.34 (s, 2H), 3.28-3.22 (q, 2H), 1 .29-1 .22 (m, 4H), 1 .13 (t, 3H, J = 7.3 Hz).
Example 32: 1 '-(5-(6-Ethylpyridin-2-yl)pyrimidin-2-yl)-6'-(ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolinel
Figure imgf000053_0003
Prepared from compound 3b) analogously to synthesis example 3. White solid. Yield: 75 mg. MS: m/z: [M+H]+ = 421.1
H NMR (400 MHz, DMSO-d6, 20°C, δ ppm): 9.33 (s, 2H), 8.82 (s, 1 H), 7.88 (d, 1 H, J = 7.7 Hz), 7.81 (t, 1 H, J = 7.6 Hz), 7.44 (d, 1 H, J = 7.8 Hz), 7.25 (d, 1 H, J = 7.5 Hz), 7.08 (d, 1 H, J = 7.7 Hz), 4.35 (s, 2H), 3.28-3.23 (q, 2H), 2.85-2.79 (m, 2H), 1.32-1 .23 (m, 7H), 1.13 (t, 3H, J = 7.3 Hz).
Example 33: 3-((1 '-(5-(4-Cvclopropylpyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)- sulfinyl)propan-1-ol
Figure imgf000054_0001
33a) 5'-((4-Methoxybenzyl)thio)spiro[cyclopropane-1 ,3'-indolinl-2'-one
Pd2(dba)3 (4.45 g, 4.85 mmol, 0.05 eq) and Xantphos (5.6 g, 9.71 mmol, 0.1 eq) were added to a solution of 5'-bromospiro[cyclopropane-1 ,3'-indolin]-2'-one (23 g, 97.15 mmol, 1 eq), 4-methoxybenzylthiol (18 g, 1 16.5 mmol, 1.2 eq) and DIPEA (36 ml, 204.0 mmol, 2.1 eq) in 1 ,4-dioxane (400 ml) that was stirred under Ar. 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 (200 ml) and brine (200 ml), dried over Na2S04 and concentrated under reduced pressure. The remnant was purified by column chromatography [230-400 mesh silica gel; hexane/EtOAc = 7:3]. White solid. Yield: 20 g (66%). MS: m/z: [M+H]+ = 312.0 33b) 5'-((4-Methoxybenzyl)thio)spiro[cvclopropane-1 ,3'-indolinel
Compound 33a) (15 g, 48.23 mmol, 1 eq) was added portion wise at 0°C to a suspension of LAH (4.58 g, 120.58 mmol, 2.5 eq) in THF (400 ml). The reaction mixture was stirred at 70°C for 3 h and then quenched at 0°C with saturated Na2S04 solution. The mixture was filtered through a sintered funnel and the filtrate was diluted with EtOAc. The organic phase was washed with water (500 ml) and brine (500 ml), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography [hexane/EtOAc = 7:3]. Brown solid. Yield: 14 g (98%). MS: m/z: [M+H]+ = 298.0
33c) 1 '-(5-Bromopyrimidin-2-yl)-5'-((4-methoxybenzyl)thio)spiro[cyclopropane-1 ,3'-indoline1
Compound 33b) (4 g, 13.47 mmol, 1 eq), 5-bromo-2-chloropyrimidine (3.13 g, 16.16 mmol, 1 .2 eq) and DIPEA (16.39 ml, 94.27 mmol, 7 eq) in n-butanol (40 ml) were stirred at 120°C for 16 h in a sealed tube. The reaction mixture was cooled and a precipitate was filtered off, washed with water (100 ml) and hexane (200 ml) and dried in vacuo. Yield: 3.56 g (58%) 33d) 1 5-Bromopyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinel-5'-thiol
A solution of compound 33c) (2 g, 6.73 mmol, 1 eq) in TFA (10 ml) and anisole (4 ml) was stirred at 100°C for 24 h. The reaction mixture was quenched with 10% aqueous NaOH solution and extracted with DCM (3 x 50 ml). The combined organic layers were washed with water (20 ml) and brine (20 ml), dried over Na2S04, filtered and concentrated under reduced pressure. The remnant was purified by column chromatography [100-200 silica gel, hexane with 2% EtOAc]. White solid. Yield: 800 mg (36%)
33e) 3-((1 '-(5-Bromopyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)thio)propan-1-ol
Compound 33d) (300 mg, 0.898 mmol, 1 eq) in ethanol (6 ml) and 20% aqueous NaOH solution (1.5 ml) was stirred for 30 min. 3-Bromo-propan-1-ol (187 mg, 1.347 mmol, 1.5 eq) was added and the reaction mixture was further stirred at 100°C for 24 h, then cooled to RT, neutralized with 6N hydrochloric acid and extracted with DCM/MeOH (95:5; 3 x 25 ml). The combined organic layers were washed with water (25 ml) and brine (25 ml), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography [100-200 silica gel, hexane/EtOAc = 7:3]. White solid. Yield: 200 mg (49%). MS: m/z: [M+H]+ = 392.0/394.0
33f) 3-((1 '-(5-(4-Cvclopropylpyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'- yl)thio)propan-1-ol
PdCI2(dppf) (204 mg, 0.255 mmol, 0.05 eq) was added to a solution of compound 33e) (2 g, 5.12 mmol, 1 eq), potassium acetate (1.23 g, 12.45 mmol, 2.5 eq) and bis(pinacolato)diboron (2.60 g, 10.23 mmol, 2 eq) in dioxane (20 ml) that was stirred under Ar. The reaction mixture was refluxed for 16 h and then cooled to RT. 2M Aqueous K2C03 solution (7 ml), 2-chloro-4-cyclopropylpyridine (1.4 g, 9.150 mmol, 1.8 eq) and (AtaPhos)2PdCI2 (265 mg, 0.374 mmol, 0.07 eq) were added and the reaction mixture was refluxed for further 16 h. The mixture was diluted with water (25 ml) and extracted with EtOAc (3 x 25 ml). The combined organic layers were washed with water (25 ml) and brine (25 ml), dried over anhydrous Na2S04 and evaporated under reduced pressure. The remnant was purified by flash column chromatography [100-200 mesh silica gel; DCM/MeOH = 95:5]. White solid. Yield: 940 mg (43%). MS: m/z: [M+H]+ = 430.9 33g) 3-((1 '-(5-(4-Cvclopropylpyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolin1-6'- yl)sulfinyl)propan-1 -ol
mCPBA (143 mg, 0.662 mmol, 0.95 eq) was slowly added to an ice-cold solution of compound 33f) (300 mg, 0.697 mmol, 1 eq) in DCM (10 ml). Afterwards, the reaction mixture was stirred at RT for 16 h, then quenched with saturated NaHC03 solution and extracted with DCM (25 ml x 3). The combined organic layers were washed with water (2 x 20 ml) and brine (20 ml), dried over anhydrous Na2S04 and evaporated under reduced pressure. The residue was purified by column chromatography [100-200 mesh silica gel; DCM/MeOH = 95:5]. White solid. Yield: 80 mg (26%)
Synthesis examples 34 to 36 were prepared analogously to example 33. Example 34: 3-((1 5-(4-Aminopyridin-2-yl)pyrimidin-2^
propan-1-ol
Figure imgf000056_0001
White solid. Yield: 100 mg. MS: m/z: [M+H]+ = 422.1
H NMR (400 MHz, DMSO-d6, δ ppm): 9.10 (s, 2H), 8.59 (s, 1H), 8.10 (d, J = 5.8 Hz, 1H), 7.18 (d, J = 7.4Hz, 1H), 7.01-6.99 (m, 2H), 6.51 (d, J = 5.4 Hz, 1H), 6.37-6.35 (bs, 2H), 4.61-4.59 (m, 1H), 4.31 (s, 2H), 3.46-3.43 (m, 2H), 2.93-2.91 (m, 1H), 2.83-2.80 (m, 1H), 1.76 (bs, 1H), 1.59 (bs, 1H), 1.24-1.17 (m, 4H) Example 35: N-(2-(2-(6'-((3-Hvdroxypropyl)sulfinyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5- yl)pyridin-4-yl)acetamide
Figure imgf000056_0002
White solid. Yield: 92 mg. MS: m/z: [M+H]+ = 463.9
H NMR (400 MHz, DMSO-d6, δ ppm): 10.45 (s, 1H), 9.14 (s, 2H), 8.60 (s, 1H), 8.52 (d, J = 5.5 Hz, 1H), 8.06 (s, 1H), 7.52 (d, J = 4.6 Hz, 1H), 7.19 (d, J = 7.1 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 4.60 (t, J = 5.2 Hz, 1H), 4.32 (s, 2H), 3.48-3.43 (m, 2H), 2.95-2.91 (m, 1H), 2.83-2.80 (m, 1H), 2.13 (s, 3H), 1.76 (bs, 1H), 1.59 (bs, 1H), 1.25-1.17 (m, 4H)
Example 36: 3-((1 '-(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)sulfinyl)- propan-1-ol
Figure imgf000057_0001
White solid. Yield: 80 mg. MS: m/z: [M+H]+ = 437.1
H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2H), 8.63 (s, 1 H), 8.47 (d, J = 5.3 Hz, 1 H), 7.63 (s, 1 H), 7.18 (d, J = 6.9 Hz, 1 H), 7.00 (d, J = 7.1 Hz, 1 H), 6.94 (bs, 1 H), 4.60 (bs, 1 H), 4.32 (s, 2H), 3.91 (s, 3H), 3.46-3.44 (m, 2H), 2.94 (s, 1 H), 2.79 (s, 1 H), 1.74 (bs, 1 H), 1.59 (bs, 1 H), 1.25-1.17 (m, 4H)
Synthesis examples 37 to 40 were prepared in analogy to example 33 with the difference that 2.5 equivalents of mCPBA were used in the oxidation step. Example 37: 3-((1 '-(5-(4-Cvclopropylpyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-vD- sulfonyl)propan-1-ol
Figure imgf000057_0002
White solid. Yield: 60 mg. MS: m/z: [M+H]+ = 462.7
H NMR (400 MHz, DMSO-d6, δ ppm): 9.34 (s, 2H), 8.82 (s, 1 H), 8.46 (d, J = 5.1 Hz, 1 H), 7.74 (s, 1 H), 7.44 (d, J = 7.8 Hz, 1 H), 7.1-7.07 (m, 2H), 4.62-4.60 (m, 1 H), 4.35 (s, 2H), 3.44-3.39 (m, 2H), 3.28-3.24 (m, 2H), 2.01-1.97 (m, 2H), 1.72-1.68 (m, 2H), 1 .40-1 .29 (m, 2H), 1.12-1.08 (m, 2H), 0.96-0.85 (m, 2H)
Example 38: 3-((1 5-(4-Aminopyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)sulfonyl)- propan-1-ol
Figure imgf000058_0001
White solid. Yield: 56 mg. MS: m/z: [M+H]+ = 438.2
H NMR (400 MHz, DMSO-d6, δ ppm): 9.13 (s, 2H), 8.79 (s, 1 H), 8.09 (d, J = 5.6 Hz, 1 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.07 (d, J = 7.6 Hz, 1 H), 7.03 (s, 1 H), 6.47 (d, J = 3.6 Hz, 1 H), 6.13 (s, 2H), 4.34 (s, 2H), 3.41- 3.16 (m, 6H), 1.68-1.69 (m, 2H), 1 .22-1.14 (m, 4H)
Example 39: N-(2-(2-(6'-((3-Hvdroxypropyl)sulfonyl)spiro[cvclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)- pyridin-4-yl)acetamide
Figure imgf000058_0002
White solid. Yield: 62 mg. MS: m/z: [M+H]+ = 480.1
H NMR (400 MHz, DMSO-d6, δ ppm): 10.43 (s, 1 H), 9.16 (s, 2H), 8.81 (s, 1 H), 8.52 (d, J = 5.3 Hz, 1 H), 8.07 (s, 1 H), 7.53 (d, J = 4.6 Hz, 1 H), 7.44 (d, J = 7.4 Hz, 1 H), 7.08 (d, J = 7.8 Hz, 1 H), 4.61 (t, J = 5.2 Hz, 1 H), 4.35 (s, 2H), 3.43-3.41 (m, 2H), 3.31-3.25 (m, 2H), 2.13 (s, 3H), 1 .70 (bs, 2H), 1.30 (bs, 2H), 1.23 (m, 4H)
Example 40: 3-((1 '-(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)sulfonyl)- propan-1-ol
Figure imgf000058_0003
White solid. Yield: 54 mg. MS: m/z: [M+H]+ = 452.8 H NMR (400 MHz, DMSO-c!6, δ ppm): 9.35 (s, 2H), 8.83 (d, J = 1.2 Hz, 1 H), 8.47 (d, J = 5.6 Hz, 1 H), 7.66 (s, 1 H), 7.44 (d, J = 8.0 Hz, 1 H), 7.08 (d, J = 8.0 Hz, 1 H), 6.96-6.94 (m, 1 H), 4.62 (bs, 1 H), 4.36 (s, 2H), 3.92 (s, 3H), 3.14 (bs, 2H), 3.28-3.24 (m, 2H), 1.70 (bs, 2H), 1.35-1.14 (m, 4H) Example 41 : 1-(2-(2-(6'-(Ethylsulfonyl)spiro[cvclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)pyridin-4-vD- ethanol
Figure imgf000059_0001
Prepared from compound 17b and 1-(2-bromopyridin-4-yl)ethanol analogously to synthesis example 17. Yield: 175 mg. White solid. MS: m/z: [M+H]+ = 437.2
H NMR (400 MHz, DMSO-d6, 20°C, δ ppm): 9.32 (s, 2H), 8.82 (s, 1 H), 8.60 (d, 1 H, J = 4.8 Hz), 7.99 (s, 1 H), 7.43 (d, 1 H, J = 7.8 Hz), 7.36 (d, 1 H, J = 4.5 Hz), 7.08 (d, 1 H, J = 7.8 Hz), 5.46 (d, 1 H, J = 4.2 Hz), 4.79 (t, 1 H, J = 5.2 Hz), 4.35 (s, 2H), 3.28-3.23 (m, 2H), 1.39 (d, 2H, J = 6.4 Hz), 1.3-1 .23 (m, 4H), 1 .13 (t, 3H, J = 7.3 Hz) Example 42: 2-(2-(2-(6'-(Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)pyridin-4-yl)- propan-2-ol
Figure imgf000059_0002
Prepared from compound 17b and 2-(2-bromopyridin-4-yl)propan-2-ol analogously to synthesis example 17. Yield: 305 mg. White solid. MS: m/z: [M+H]+ = 451.3
H NMR (400 MHz, DMSO-d6, 20°C, δ ppm): 9.34 (s, 2H), 8.83 (d, 1 H, J = 0.9 Hz), 8.59 (d, 1 H, J = 5.1 Hz), 8.06 (s, 1 H), 7.47-7.42 (m, 2H), 7.08 (d, 1 H, J = 7.8 Hz), 5.3 (s, 1 H), 4.36 (s, 2H), 3.28-3.23 (m, 2H), 1.49 (s, 6H), 1.3-1.23 (m, 4H), 1.13 (t, 3H, J = 7.3 Hz).
Example 43: 1 -(3-(2-(6WEthylsulfonyl)spiro[cvclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)-4-fluorophenyl)- ethanol
Figure imgf000060_0001
Prepared from compound 17b and 1-(3-bromo-4-fluorophenyl)ethanol analogously to synthesis example 17. Yield: 0.09 g. White solid. MS: m/z: [M+H]+ = 454.1
H NMR (400 MHz, DMSO-d6, 20°C, δ ppm): 8.88 (s, 2H), 8.78 (s, 1 H), 7.6 (d, 1 H, J = 6.6 Hz), 7.43 (d, 1 H, J = 7.5 Hz), 7.3 (t, 1 H, J = 8.7 Hz), 7.08 (d, 1 H, J = 7.8 Hz), 5.25 (d, J = 4.3 Hz), 4.79 (t, J = 5.3 Hz), 4.34 (s, 2H), 3.27-3.22 (m, 2H), 1.37 (d, 2H, J = 6.4 Hz), 1.3-1.23 (m, 4H), 1.13 (t, 3H, J = 7.3 Hz).
Example 44: 2-(3-(2-(6'-(Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)-4-fluorophenyl)- propan-2-ol
Figure imgf000060_0002
Prepared from compound 17b and 2-(3-bromo-4-fluorophenyl)propan-2-ol analogously to synthesis example 17. Yield: 0.07 g. White solid. MS: m/z: [M+H]+ = 468.2
H NMR (400 MHz, DMSO-d6, 20°C, δ ppm): 8.89 (s, 2H), 8.79 (s, 1 H), 7.69 (d, 1 H, J = 7.3 Hz), 7.54 (bs, 1 H), 7.43 (d, 1 H, J = 7.8 Hz), 7.28 (t, 1 H, J = 9.6 Hz), 7.08 (d, 1 H, J = 7.8 Hz), 5.13 (s, 1 H), 4.34 (s, 2H), 3.27-3.22 (m, 2H), 1.47 (s, 6H), 1.3-1.23 (m, 4H), 1.13 (t, 3H, J = 7.2 Hz).
Example 45: 1-(2-(2-(6'-(Ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)pyridin-4-yl)- ethanol
Figure imgf000061_0001
Obtained from compound 24a) and 1-(2-bromopyridin-4-yl)ethanol in an analogous manner as described in synthesis protocol 3c). Yield: 246 mg. White solid. MS: m/z: [M+H]+ = 421.3
H NMR (400 MHz, DMSO-d6, 20°C, δ ppm): 9.29 (s, 2H), 8.6 (t, 2H, J = 5.1 Hz), 7.96 (s, 1 H), 7.36 (d, 1 H, J = 4.9 Hz), 7.17 (d, 1 H, J = 7.8 Hz), 7.00 (d, 1 H, J = 7.7 Hz), 5.45 (d, 1 H, J = 4.4 Hz), 4.8-4.76 (m, 1 H), 4.32 (s, 2H), 2.99-2.92 (m, 1 H), 2.8-2.2.71 (m, 1 H), 1.39 (d, 2H, J = 6.5 Hz), 1.24-1 .17 (m, 4H), 1.07 (t, 3H, J = 7.3 Hz).
Example 46: 2-(2-(2-(6'-(Ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)pyridin-4-yl)- propan-2-ol
Figure imgf000061_0002
Obtained from compound 24a) and 2-(2-bromopyridin-4-yl)propan-2-ol in an analogous manner as described in synthesis protocol 3c). Yield: 0.1 1 g. White solid. MS: m/z: [M+H]+ = 435.2
H NMR (400 MHz, DMSO-d6, 20°C, δ ppm): 9.32 (s, 2H), 8.62 (s, 1 H), 8.59 (d, 1 H, J = 5.0 Hz) 8.04 (s, 1 H), 7.45 (d, 1 H, J = 3.8 Hz), 7.17 (d, 1 H, J = 7.6 Hz), 7.00 (d, 1 H, J = 7.7 Hz), 5.29 (s, 1 H), 4.33 (s, 2H), 2.99-2.94 (m, 1 H), 2.78-2.75 (m, 1 H), 1 .48 (s, 6H), 1.25-1.17 (m, 4H), 1.07 (t, 3H, J = 7.3 Hz).
Example 47: 1-(3-(2-(6'-(Ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)-4-fluorophenyl)- ethanol
Figure imgf000062_0001
Obtained from compound 24a) and 1-(3-bromo-4-fluorophenyl)ethanol in an analogous manner as described in synthesis protocol 3c). Yield: 0.18 g. White solid. MS: m/z: [M+H]+ = 437.8
H NMR (400 MHz, DMSO-d6, 20°C, δ ppm): 8.85 (s, 2H), 8.58 (s, 1 H), 7.59 (d, 1 H, J = 6.1 Hz), 7.41 (d, 1 H, J = 2.6 Hz), 7.3 (t, 1 H, J = 8.6 Hz), 7.16 (d, 1 H, J = 7.7 Hz), 7.0 (d, 1 H, J = 7.7 Hz), 5.26 (d, 1 H, J = 4.2 Hz), 4.78 (t, 1 H, J = 4.7 Hz), 2.99-2.94 (m, 1 H), 2.78-2.72 (m, 1 H), 1.37 (d, 2H, J = 6.3 Hz), 1 .24-1 .17 (m, 4H), 1.06 (t, 3H, J = 7.3 Hz).
Example 48: 2-(3-(2-(6'-(Ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)-4-fluorophenyl)- propan-2-ol
Figure imgf000062_0002
Obtained from compound 24a) and 2-(3-bromo-4-fluorophenyl)propan-2-ol in an analogous manner as described in synthesis protocol 3c). Yield: 0.1 1 g. White solid. MS: m/z: [M+H]+ = 452.0
1 H NMR (400 MHz, DMSO-d6, 20°C, δ ppm): 8.85 (s, 2H), 8.58 (s, 1 H), 7.68 (dd, 1 H, J = 5.7 Hz, 2.0 Hz), 7.54-7.52 (m, 1 H), 7.27 (t, 1 H, J = 8.9 Hz), 7.16 (d, 1 H, J = 7.8 Hz), 7.00 (d, 1 H, J = 7.7 Hz), 5.13 (s, 1 H), 4.31 (s, 2H), 2.99-2.92 (m, 1 H), 2.78-2.2.72 (m, 1 H), 1.47 (s, 6H), 1.24-1.17 (m, 4H), 1.06 (t, 3H, J = 7.3 Hz).
Example 49: 6'-(Ethylsulfinyl)-1 '-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinel
Figure imgf000063_0001
Obtained from compound 24a) and 2-bromo-4-methoxypyridine in an analogous manner as described in synthesis protocol 3c). Yield: 160 mg. White solid. MS: m/z: [M+H]+ = 406.9
H NMR (400 MHz, DMSO-d6, 20°C, δ ppm): 9.32 (s, 2H), 8.62 (d, 1 H, J = 1 .0 Hz), 8.47 (d, 1 H, J = 5.7 Hz), 7.63 (d, 1 H, J = 2.1 Hz), 7.18-7.16 (m, 1 H), 7.00 (d, 1 H, J = 7.8 Hz), 6.96-6.94 (m, 1 H), 4.32 (s, 2H), 3.91 (s, 3H), 2.99-2.94 (m, 1 H), 2.78-2.2.73 (m, 1 H), 1 .24-1 .17 (m, 4H), 1.06 (t, 3H, J = 7.4 Hz).
Figure imgf000063_0002
50a) Methyl spiro[cvclopropane-1 ,3'-indolinel-6'-carboxylate
Pd(OAc)2 (1.5 g, 6.69 mmol) and dppf (3.7 g, 6.69 mmol) were added to a solution of 6'-bromospiro[cyclo- propane-1 ,3'-indoline] (15 g, 66.96 mmol) and TEA (28 mL, 200.88 mmol) in MeOH (100 mL) and DMSO (60 mL) that was kept in an autoclave under N2. The autoclave was then pressurized to 150 psi with carbon monoxide gas. The mixture was stirred at 100°C for 16 h, cooled and filtered through a pad of celite. The filtrate was concentrated and water was added. The precipitate was dissolved in DCM (300 mL) and washed with water (100 mL) and brine (100 mL) and dried over Na2S04. The solvent was removed under reduced pressure and the remnant was purified by flash column chromatography [silica gel; EtOAc/hexane = 1 :4] and then triturated with EtOAc/hexane. Yellow material. Yield: 7.1 g (52%). HPLC (method 1 ): Rt = 3.20 min, m/z [M+H]+ = 204.2 (MW calc. 203.24)
50b) Spiro[cyclopropane-1 ,3'-indolin1-6'-ylmethanol
LAH (0.93 g, 24.63 mmol) was added portion wise at 0°C to a solution of compound 50a) (2.0 g, 9.85 mmol) in THF (200 mL). The reaction mixture was stirred for 2 h at RT, then quenched (0.9 mL water + 0.9 mL 20% NaOH solution + 1.8 mL water) and further stirred for 30 min. The mixture was filtered through a pad of celite and washed with MeOH/DCM (1 :4, 3 x 20 mL). The solvents were removed under reduced pressure and the residue was washed with ether/pentane (20 mL). Yellow solid. Yield: 1.1 g (64%) HPLC (method 1 ): Rt = 2.52 min, m/z [M+H]+ = 175.9 (MW calc. 175.1 )
50c) (1 5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)methanol
Compound 50b) (1.1 g, 6.28 mmol), 2-chloro-5-(2-fluorophenyl)pyrimidine (1.67 g, 7.54 mmol) and and DIPEA (8 mL, 48.5 mmol) in n-butanol (15 mL) were stirred at 100°C for 16 h in a sealed tube. The reaction mixture was cooled and diluted with water. The solvents were evaporated and the residue was purified by column chromatography [silica gel; EtOAc/hexane = 15:85]. Yellow solid. Yield: 1.5 g (68%). HPLC (method 3): Rt = 4.06 min, m/z [M+H]+ = 348.2 (MW calc. 347.1 ) 50d) 1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinel-6'-carbaldehyde
Dess-Martin periodinane reagent (1 .80 g, 4.32 mmol) was added portion wise at 0°C to a solution of compound 50c) (1.0 g, 2.88 mmol) in DCM (100 mL). The reaction mixture was stirred for 1 h at RT, then quenched with saturated NaHC03 solution and extracted in DCM (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04 and concentrated. The remnant was purified by column chromatography [silica gel; DCM/hexane = 4.1]. Yellow solid. Yield: 0.80 g (80%). HPLC (method 3): Rt = 4.5 min, m/z [M+H]+ = 346.2 (MW calc. 345.1 )
50e) 1-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin1-6'-yl)propan-1-ol
3 M Ethyl magnesium chloride in THF (1.7 mL, 5.21 mmoL) was added drop wise at 0°C to a solution of aldehyde 50d) (0.60 g, 1.74 mmol) in THF (30 mL). The reaction mixture was stirred at RT for 2 h, then quenched with saturated NH4CI solution and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04 and concentrated. The remnant was purified by flash column chromatography [silica gel; DCM/hexane = 4.1]. Yellow solid. Yield: 0.25 g (38%). HPLC (method 3): Rt = 10.38 min, m/z [M+H]+ = 376.3 (MW calc. 375.17)
H NMR (400 MHz, DMSO-d6, δ ppm): 8.82 (s, 2H), 8.35 (s, 1 H), 7.69-7.65 (m, 1 H), 7.45-7.31 (m, 3H), 6.88 (d, 1 H, J = 7.3 Hz), 6.73 (d, 1 H, J = 7.5 Hz), 5.1 (d, 1 H, J = 3.8 Hz), 4.43-4.41 (m, 1 H), 4.23 (s, 2H), 1.66-1.59 (m, 2H), 1.22 (bs, 2H), 1.06 (bs, 2H), 0.83 (t, 3H, J = 7.3 Hz).
Figure imgf000064_0001
51a) 1-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin1-6'-yl)propan-1-one
Dess-Martin periodinane reagent (0.67 g, 1.59 mmol) was added portion wise at 0°C to a solution of compound 50 (0.40 g, 1.06 mmol) in DCM (40 mL). The reaction mixture was stirred stirred for 1 h at RT, then quenched with saturated NaHC03 solution and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04 and concentrated. The residue was purified by column chromatography [silica gel; DCM/hexane = 4: 1]. Yellow solid. Yield: 0.420 g. HPLC (method 1 ): Rt = 4.4 min, m/z [M+H]+ = 374.2 (MW calc. 373.16) 51 b) 2-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)butan-2-ol
3 M Methylmagnesium bromide in ether (1.05 mL, 3.15 mmoL) was added drop wise at 0°C to compound 51a) (0.20 g, 0.53 mmol) in THF (30 mL). The reaction mixture was stirred at RT for 16 h, then quenched with saturated NH4CI solution and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04 and concentrated. The remnant was purified by flash column chromatography [silica gel; DCM with 1.5% MeOH]. Yellow solid. Yield: 0.1 1 g (53%). HPLC (method 1 ): Rt = 4.12 min, m/z [M+H]+ = 390.1 (MW calc. 389.19)
H NMR (400 MHz, DMSO-d6, δ ppm): 8.81 (s, 2H), 8.49 (s, 1 H), 7.68 (t, 1 H, J = 7.7 Hz), 7.46-7.31 (m, 3H), 6.96 (d, 1 H, J = 7.7 Hz), 6.71 (d, 1 H, J = 7.8 Hz), 4.76 (s, 1 H), 4.23 (s, 2H), 1.73-1.67 (m, 2H), 1.41 (s, 3H), 1.14 (bs, 2H), 1.06 (bs, 2H), 0.71 (t, 3H, J = 7.2 Hz).
Example 52: (1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin1-6'-yl)(tetrahvdro-2H- Pyran-4-yl)methanol
Figure imgf000065_0001
52a) 6'-(Hvdroxy(tetrahvdro-2H-pyran-4-yl)methyl)spiro[cyclopropane-1 ,3'-indolinl-2'-one
6'-Bromospiro[cyclopropane-1 ,3'-indolin]-2'-one (1.1 g, 4.67 mmol) in dry THF (40 mL) was added drop wise at -30°C to a suspension of KH (30% in mineral oil, 0.61 g, 4.58 mmol) in dry THF (15 mL). The reaction mixture was stirred at this temperature for 20 min and then cooled to -78°C. tert-Butyllithium (2 M in pentane, 5.8 mL, 10.50 mmol) was added and stirring was continued at - 78°C for 30 min. A solution of pyran-4-aldehyde (1.6 g, 14.01 mmol) in dry THF (10 mL) was added via a dropping funnel and the reaction mixture was slowly warmed to RT over 16 h. After quenching with saturated NH4CI solution at 0°C, the mixture was extracted first with EtOAc (3 x 100 mL) and then with DCM/MeOH (98:2, 30 mL). The combined organic layers were dried over Na2S04 and concentrated. The remnant was purified by flash column chromatography [silica; DCM with 5% MeOH]. Brown solid. Yield: 0.43 g (33%). HPLC (method 1 ): Rt = 2.25 min, m/z [M+H]+ = 274.3 (MW calc. 273.33)
52b) Spiro[cvclopropane-1 ,3'-indolin1-6'-yl(tetrahvdro-2H-pyran-4-yl)methanol
To a solution of 52a) (0.43 g, 1.57 mmol) in THF (15 mL) was added LAH (0.21 g, 5.51 mmol) portion wise at 0°C. The reaction mixture was slowly brought to RT and then stirred at 70°C for 1 h. The mixture was quenched 0°C by slow addition of saturated Na2S04 solution, filtered and extracted with EtOAc (3 x 50 ml_). The combined organic layers were dried and evaporated to yield a light brown solid that was used for the next step without purification. Yield: 0.38 g (93%). HPLC (method 1 ): Rt = 2.68 min, m/z [M+H]+ = 260.1 (MW calc. 259.34) 52c) (1 '-(5-Bromopyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)(tetrahydro-2H-pyran-4- vDmethanol
Compound 52b) (0.38 g, 1.47 mmol), 5-bromo-2-chloro-pyrimidine (0.25 g, 1 .32 mmol) and DIPEA (0.78 mL, 4.41 mmol) in n-butanol (7 mL) were stirred at 100°C for 16h. The mixture was cooled to RT and concentrated to half of its volume. The appearing precipitate was filtered off and washed with diethyl ether/hexane (1 :2). White solid. Yield: 0.26 g (42%). HPLC (method 1 ): Rt = 3.70 min, m/z [M+H]+ = 416.1 (MW calc. 416.31 )
52d) (1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)(tetrahvdro-2H-pyran-4- vDmethanol
K2C03 (0.20 g, 1.44 mmol) and (AtaPhos)2PdCI2 (34 mg, 0.048 mmol) were added to a solution of compound 52c) (0.20 g, 0.48 mmol) and 2-fluorophenylboronic acid (0.14 g, 0.96 mmol) in amyl alcohol (15 mL) and water (1.5 mL) that was kept under Ar. The resulting mixture was stirred at 1 10°C for 6 h, then cooled and filtered through a plug of celite. The filtrate was evaporated and the residue purified by flash column chromatography [silica gel; DCM with 1.5% MeOH]. White solid. Yield: 0.16 g (77%). HPLC (method 4): Rt = 9.93 min, m/z [M+H]+ = 432.1 (MW calc. 431.5)
H NMR (400 MHz, DMSO-d6, δ ppm): 8.83 (s, 2H), 8.33 (s, 1 H), 7.68 (t, 1 H, J = 7.9 Hz), 7.46-7.43 (m, 1 H), 7.39-7.32 (m, 2H), 6.86 (d, 1 H, J = 7.6 Hz), 6.76 (d, 1 H, J = 7.6 Hz), 5.19 (d, 1 H, J = 3.9 Hz), 4.24- 4.20 (m, 3H), 3.87 (d, 1 H, J = 7.7 Hz), 3.77 (d, 1 H, J = 9.2 Hz), 3.25-3.12 (m, 2H), 1 .78-1.66 (m, 2H), 1.29-1.07 (m, 7H).
Exampe 53: 1-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)-2-methylpropan- 1-ol
Figure imgf000066_0001
Prepared analogously to synthesis example 52. White solid. Yield: 0.17 g. HPLC (method 3): Rt = 4.70 min, m/z [M+H]+ = 390.0 (MW calc. 389.47)
H NMR (400 MHz, DMSO-d6, δ ppm): 8.82 (s, 2H), 8.33 (s, 1 H), 7.69 (t, 1 H, J = 7.6 Hz), 7.47-7.42 (m, 1 H), 7.38-7.31 (m, 2H), 6.86 (d, 1 H, J = 7.5 Hz), 6.75 (d, 1 H, J = 7.6 Hz), 5.08 (d, 1 H, J = 3.9 Hz), 4.24- 4.18 (m, 3H), 1.85-1.77 (m, 1 H), 1.15 (s, 2H), 1.07 (s, 2H), 0.91 (d, 3H, J = 6.5 Hz), 0.76 (d, 3H, J = 6.6 Hz). Example 54: 1-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)-N-methylcyclo- propanamine
Figure imgf000067_0001
54a) 1 5-(2-Fluorophenyl)pyrimidin-2-yl)spiro^
Tetrakis(triphenylphosphine)palladium(0) (0.247 g, 0.21 mmol, 0.05 eq) was added to a stirred solution of compound 1 1a (1.7 g, 4.29 mmol, 1 eq) and zinc cyanide (0.502 g, 4.29 mmol, 1 eq) in dioxane (15 ml). The mixture was stirred under Ar at 140°C for 16 h, cooled to RT and poured onto ice water. The precipitating solid was filtered off and dried in vacuo. White solid. Yield: 1.2 g (82%)
54b) 1-(1 5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)cyclo-propanamine Ethyl magnesium bromide (5.84 ml, 17.52 mmol, 6 eq) was slowly added at -78°C to a stirred solution of titanium(IV) isopropoxide (1.74 ml, 5.84 mmol, 2 eq) in THF (15 ml) and the mixture was stirred for 1 h at this temperature. Compound 54a (1 g, 2.92 mmol, 1 eq) dissolved in THF (10 ml) was slowly added and stirring was continued for 30 min at -78°C. Boron trifluoride diethyletherate (0.74 ml, 5.84 mmol, 2 eq) was added and the reaction mixture was allowed gradually to warm to RT and stirred for 16 h. The reaction mixture was then quenched at 0°C with 2N HCI solution, stirred for 10 min, basified with 2N NaOH solution and extracted with EtOAc (2 x 40 ml). The organic layers were washed with brine (20 ml), dried over Na2S04 and concentrated. The crude was purified by column chromatography [EtOAc/hexane = 3:1]. Yellow gum. Yield: 0.2g (19%)
54c) tert-Butyl (1-(1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl) cvclo- propyDcarbamate
A solution of compound 54b (0.8 g, 2.15 mmol, 1 eq) and di-tert-butyl dicarbonate (0.9 ml, 3.22 mmol, 1 .5 eq) in toluene (20 ml) was refluxed for 1 h. The solvent was evaporated under reduced pressure and the remnant was purified by column chromatography [EtOAc/hexane = 1 :4]. Yield: 0.45 g (43%). Yellow gum. MS: m/z: [M+H]+ = 473.3
54d) tert-Butyl (1 -(1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin1-6'-yl) cvclo- propyl methyl Carbamate
NaH (57 mg, 1 .43 mmol, 1.5 eq) was added portion wise at 0°C to a stirred solution of compound 54c (0.45 g, 0.953 mmol, 1 eq) in DMF (8 ml). Stirring was continued for 20 min., methyl iodide (0.25 ml, 3.81 mmol, 4 eq) was added and the mixture was further stirred for 1 h. The reaction mixture was quenched with ice and extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with water (2 x 10 ml) and brine (10 ml), dried over Na2S04 and concentrated. The residue was purified by column chromatography [EtOAc/hexane = 1 :4]. Yield: 0.43 g (93%). MS: m/z: [M+H]+ = 486.9
54e) 1-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolin1-6'-yl)-N-methyl cyclo- propanamine
4N HCI (4 mL) was added to a stirred solution of compound 54d (500 mg, 1.02 mmol, 1 eq) in dioxane and stirring was continued for 1 h at RT. The solvent was removed under reduced pressure and the remaining solid was triturated with ether affording the target compound as hydrogen chloride salt. Yellow solid. Yield: 320 mg. MS: m/z: [M+H]+ = 486.9;
H NMR (400 MHz, DMSO-d6, δ ppm): 9.42 (s, 2H), 8.86 (s, 2H), 8.51 (s, 1 H), 7.70 (t, J = 15.1 Hz, 1 H), 7.49 (m, 1 H), 7.39 (m, 1 H), 7.15 (d, J = 7.5 Hz, 1 H), 6.90 (d, J = 7.6 Hz, 1 H), 4.27 (s, 2H), 2.50 (s, 2H), 1.46 (m, 2H), 1.21 (s, 2H), 1.15 (s, 2H). 1.13 (s, 2H)
Example 55: 1-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin1-6'-yl)-N,N-dimethyl- cyclopropanamine
Figure imgf000068_0001
Aqueous formaldehyde solution (0.04 ml, 0.38 mmol, 1.5 eq) was added to a stirred solution of compound 54 (100 mg, 0.25 mmol, 1 eq) in MeOH/DCM (1 : 1 , 6 ml). The mixture was stirred for 30 min., sodium triacetoxyborohydride (82 mg, 0.38 mmol, 1.5 eq) was added and stirring was continued for 16 h at RT. The reaction mixture was quenched with saturated NaHC03 solution and extracted with DCM (2 x 15 ml). The combined organic layers were washed with brine (10 ml), dried over Na2S04 and concentrated. The remnant was purified by column chromatography [EtOAc/hexane = 2:3]. White solid. Yield: 50 mg. MS: m/z: [M+H]+ = 401.1 ;
H NMR (400 MHz, CDCI3, δ ppm): 8.72 (s, 2H), 8.42 (s, 1 H), 7.45 (t, J = 15.0 Hz, 1 H), 7.34 (m, 1 H), 7.22 (m, 1 H), 6.89 (d, J = 7.4 Hz, 1 H), 6.64 (d, J = 7.6 Hz, 1 H), 4.28 (s, 2H), 2.30 (s, 6H), 1 .12 (d, J = 6.0 Hz, 4H), 0.95 (s, 2H), 0.88 (d, J = 13.4 Hz, 2H).
Example 56: 2-((1-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolin1-6'-yl)cyclo- propyl)(methyl)amino)ethanol
Figure imgf000069_0001
NaH (25 mg, 0.62 mmol, 1.2 eq) was added portion wise at 0°C to a stirred solution of compound 54 (200 mg, 0.51 mmol, 1 eq) in THF (10 ml). The mixture was stirred for 20 min., 2-bromoethanol (0.06 ml, 0.77 mmol, 1.5 eq) was added and stirring was continued for 1 h. The reaction mixture was quenched with ice and extracted with EtOAc (2 x 15 ml). The combined organic layers were washed with water (2 x 10 ml) and brine (10 ml), dried over Na2S04 and concentrated. The residue was purified by column chromatography [EtOAc/hexane = 1 : 1]. White solid. Yield: 50 mg. MS: m/z: [M+H]+ = 431 .2;
H NMR (400 MHz, CDCI3, δ ppm): 8.72 (s, 2H), 8.46 (s, 1 H), 7.45 (t, J = 15.2 Hz, 1 H), 7.25 (s, 1 H), 7.22 (m, 2H), 6.91 (d, J = 7.4 Hz, 1 H), 6.64 (d, J = 7.6 Hz, 1 H), 4.28 (s, 2H), 3.55 (d, J = 5.0 Hz, 2H), 2.74 (s, 2H), 2.31 (s, 3H), 1 .16 (d, J = 2.8 Hz, 4H), 0.98 (m, 4H).
Figure imgf000069_0002
57a) Methyl 1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinel-6'-carboxylate
Methyl spiro[cyclopropane-1 ,3'-indoline]-6'-carboxylate 2 (10.0 g, 49.2 mmol, 1 eq, compound 50a), 2- chloro-5-(2-fluorophenyl)pyrimidine (12.2 g, 59.04 mmol, 1.2 eq) and DIPEA (43.0 ml, 246.0 mmol, 5 eq) in n-butanol (100 ml) were stirred at 140°C for 48 h in a sealed tube. The reaction mixture was then cooled to RT and the solid was filtered off and dried under vacuum. White solid. Yield: 10 g (54%). MS: m/z: [M+H]+ = 376.3
57b) 1-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl) cvclopropanol
Ethyl magnesium bromide (5 ml, 14.4 mmol, 6 eq) was slowly added at -78°C to a stirred solution of titanium(IV) isopropoxide (1.43 ml, 4.8 mmol, 2 eq) in THF (15 ml) and the mixture was stirred for 1 h at this temperature. Compound 57a (900 mg, 2.4 mmol, 1 eq) dissolved in THF (10 ml) was slowly added and the reaction mixture was gradually warmed to RT and stirred for 16 h. The reaction mixture was then cooled to 0°C, quenched with aqueous 2N HCI solution, stirred for 10 min. and extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with brine (20 ml), dried over Na2S04 and concentrated. The remnant was purified by column chromatography [EtOAc/hexane = 3:2]. White solid. Yield: 500 mg (50%). MS: m/z: [M+H]+ = 374.0
1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.81 (s, 2H), 8.38 (s, 1 H), 7.69 (t, J = 15.7 Hz, 1 H), 7.45 (m, 1 H), 7.38 (m, 2H), 6.82 (d, J = 7.6 Hz, 1 H), 6.72 (d, J = 7.7 Hz, 1 H), 4.23 (s, 2H), 1.14 (s, 2H), 1.07 (m, 4H), 0.92 (m, 2H).
Example 58: 1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)-6'-(1 -methoxycvclopropyl)spiro[cyclopropane-1 ,3'- indolinel
Figure imgf000070_0001
NaH (80 mg, 2.01 mmol, 1.5 eq) was added portion wise at 0°C to a stirred solution of compound 57 (500 mg, 1.34 mmol, 1 eq) in THF (20 ml). The mixture was stirred for 20 min., methyl iodide (0.34 ml, 5.36 mmol, 4 eq) was added and stirring was continued for 1 h. The reaction mixture was then quenched with ice and extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with water (2 x 10 ml) and brine (10 ml), dried over Na2S04 and concentrated. The residue was purified by column chromatography [EtOAc/hexane = 1 :4]. White solid. Yield: 300 mg (58%). MS: m/z: [M+H]+ = 388.2;
H NMR (400 MHz, DMSO-d6, δ ppm): 8.83 (s, 2H), 8.40 (s, 1 H), 7.69 (t, J = 14 Hz, 1 H), 7.47 (m, 1 H), 7.35 (m, 2H), 6.86 (d, J = 7.6 Hz, 1 H), 6.78 (d, J = 7.6 Hz, 1 H), 4.24 (s, 2H), 3.13 (s, 3H), 1 .22 (s, 2H), 1.07 (m, 4H), 0.92 (m, 2H). Example 59: 6 1-Methoxycvclopropyl)-1 '-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cvclo-propane- 1 ,3'-indolinel
Figure imgf000070_0002
59a) Methyl 1 '-(5-bromopyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinel-6'-carboxylate
Methyl spiro[cyclopropane-1 ,3'-indoline]-6'-carboxylate (2.5 g, 12.31 mmol, 1 eq, compound 50a), 5- bromo-2-chloropyrimidine (2.61g, 13.54 mmol, 1.1 eq) and DIPEA (10 ml, 61.55 mmol, 5 eq) in n-butanol (20 ml) were stirred at 140°C for 16 h in a sealed tube. The reaction mixture was then cooled to RT and the resulting solid was filtered off and dried under vacuum. White solid. Yield: 2.5g (57%) 59b) Methyl 1 '-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'- indoline1-6'-carboxylate
PdCI2(dppf) (0.22 g, 0.277 mmol, 0.05 eq) was added to a solution of compound 59a (2 g, 5.55 mmol, 1 eq), potassium acetate (1 g, 1 1.1 mmol, 2 eq) and bis(pinacolato)diboron (2.81 g, 1 1.1 mmol, 2 eq) in dioxane stirred at RT under Ar. The mixture was 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 (20 ml) and brine (20 ml), dried over Na2S04 and evaporated. The residue was (2 g) was used in the next step without further purification. MS: m/z: [M+H]+ = 408.2
59c) Methyl 1 '-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinel-6'-carboxylate (AtaPhos)2PdCI2 (0.16g, 0.196 mmol, 0.1 eq) was added at RT to a solution of compound 59b (0.8 g, 1.96 mmol, 1 eq), 2-bromo-4-methoxypyridine (0.24 ml, 1.965 mmol, 1 eq) and 10% aqueous K2C03 solution (3 ml) in amyl alcohol (25 ml) stirred under Ar. The mixture was refluxed for 3 h and then filtered through a pad 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 residue was purified by column chromatography [EtOAc/hexane = 3:7]. White solid. Yield: 0.45g (59%).
59d) 1-(1 '-(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl) cvclopropanol Compound 59c (0.55 g, 1.41 mmol) was submitted to a Kulinkovich reaction analogously to procedure 57b. Yellow gum. Yield: 0.17g. MS: m/z: [M+H]+ = 387.4
59e) 6'-(1-Methoxycvclopropyl)-1 '-(5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cvclo-propane-1 ,3'- indolinel
Prepared from compound 59d (200 mg, 0.51 mmol) in analogy to the synthesis protocol of example 58. White solid. Yield: 50 mg. MS: m/z: [M+H]+ = 401.1
H NMR (400 MHz, CDCI3, δ ppm): 9.09 (s, 2H), 8.49 (s, 2H), 7.14 (s, 1 H), 6.98 (d, J = 8.1 Hz, 1 H), 6.77 (d, J = 3.4 Hz, 1 H), 6.67 (d, J = 4.0 Hz, 1 H), 4.3 (s, 2H), 3.91 (s, 3H), 3.26 (s, 3H), 1 .24 (s, 2H), 1.17 (s, 4H), 0.93 (d, J = 8 Hz, 2H).
Examples 60 and 61 were obtained from the pinacol boronate 59c analogously to synthesis example 59. Example 60: 6'-(1-Methoxycvclopropyl)-1 '-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinel
Figure imgf000071_0001
White solid. Yield: 55 mg. MS: m/z: [M+H]+ = 371.2
H NMR (400 MHz, CDCI3, δ ppm): 9.12 (s, 2H), 8.67 (d, J = 3.9 Hz, 1 H), 8.5 (s, 1 H), 7.77 (t, J = 14.9 Hz, 1 H), 7.66 (d, J = 7.7 Hz, 1 H), 7.25 (m, 1 H), 6.98 (d, J = 7.9 Hz, 1 H), 6.67 (d, J = 7.7 Hz, 1 H), 4.3 (s, 2H), 3.26 (s, 3H), 1.24 (s, 2H), 1.19 (d, J = 7.2 Hz, 4H), 1.01 (s, 2H).
Example 61 : 6 1-Methoxycvclopropyl)-1 5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cvclo-propan indolinel
Figure imgf000072_0001
White solid. Yield: 55 mg. MS: m/z: [M+H]+ = 385.2
H NMR (400 MHz, CDCI3, δ ppm): 9.26 (s, 2H), 8.51 (d, J = 4.8 Hz, 1 H), 8.43 (s, 1 H), 7.9 (s, 1 H), 7.19 (d, J = 4.3 Hz, 1 H), 6.88 (d, J = 7.2 Hz, 1 H), 6.78 (d, J = 7.6 Hz, 1 H), 4.26 (s, 2H), 3.15 (s, 3H), 2.38 (s, 3H), 1.16 (s, 2H), 1.12 (s, 2H), 1.08 (s, 2H), 0.93 (s, 2H).
Example 62: 2-(((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)methyl) amino)ethanol
Figure imgf000072_0002
62a) (1 5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)methyl
methanesulfonate
TEA (0.89 mL, 6.33 mmol) and methanesulfonyl chloride (0.25 mL, 3.16 mmol) were added at 0°C to a solution of compound 50c (1.0 g, 2.88 mmol) in DCM (30 mL). The reaction mixture was stirred at RT for 2 h, then poured onto ice-cold water and extracted with DCM (3x 50 mL). The combined organic layers were washed with brine, dried over Na2S04 and concentrated. The remnant was purified by flash column chromatography [silica, EtOAc/hexane = 1 :9]. White solid. Yield: 0.33 g (27%). MS: no ionization. 62b) 2-(((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)methyl)- amino)ethanol K2C03 (0.12 g, 0.85 mmol) and 2-amino-ethanol (0.05 mL, 0.85 mmol) were added at RT to a solution of compound 62a (0.18 g, 0.42 mmol) in acetonitrile (10 mL) and the reaction mixture was stirred at RT for 16 h. The mixture was concentrated, diluted with DCM and washed with saturated NH4CI solution and brine. The organic layer was dried and concentrated and the residue was purified by flash column chromatography [silica, MeOH/DCM = 1 :9]. Colorless solid. Yield: 45 mg (27%); HPLC (method 5): Rt = 1.48 min, m/z [M+H]+ = 391.0 (MW calc. 390.45).
H NMR (400 MHz, DMSO-d6, δ ppm): 8.82 (s, 2 H), 8.35 (s, 1 H), 7.69-7.65 (m, 1 H), 7.47-7.42 (m, 1 H), 7.38-7.32 (m, 2H), 6.94 (d, 1 H, J = 7.6 Hz), 6.77 (d, 1 H, J = 7.6 Hz), 4.55 (s, 1 H), 4.24 (s, 2 H), 3.75 (s, 2H), 3.50-3.48 (m, 2H), 2.64-2.61 (m, 2H), 1.15-1 .1 1 (m, 2H), 1.07 (d, 2H, J = 6.4 Hz).
Example 63: 2-(((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)methyl)- (methvDamino)ethanol
Figure imgf000073_0001
Obtained from compound 50c and 2-methylamino-ethanol analogously to example 62. Colorless solid. Yield: 70 mg. HPLC (method 5): Rt = 1.48 min, m/z [M+H]+ = 405.1 (MW calc. 404.48). H NMR (400 MHz, DMSO-d6, δ ppm): 8.82 (s, 2H), 8.32 (s, 1 H), 7.69-7.66 (m, 1 H), 7.45-7.42 (m, 1 H), 7.38-7.32 (m, 2H), 6.89 (d, 1 H, J = 7.4 Hz), 6.76 (d, 1 H, J = 7.5 Hz), 4.35 (s, 1 H), 4.24 (s, 2H), 3.52-3.48 (m, 4H), 2.44- 2.41 (m, 2H), 2.18 (s, 3H), 1.16-1.07 (m, 4H). Example 64: 2-(((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)methyl)- (methyl)amino)-2-methylpropan-1-o
Figure imgf000073_0002
Prepared from compound 50c and 2-methyl-2-(methylamino)propan-1 -ol analogously to example 62. Colorless solid. Yield: 54 mg. HPLC (method 5): Rt = 1.52 min, m/z [M+H]+ = 433.1 (MW calc. 432.53). H NMR (400 MHz, DMSO-d6, δ ppm): 8.82 (s, 2H), 8.31 (s, 1 H), 7.69-7.65 (m, 1 H), 7.47-7.42 (m, 1 H), 7.38- 7.32 (m, 2H), 6.94 (d, 1 H, J = 7.4 Hz), 6.74 (d, 1 H, J = 7.5 Hz), 4.33 (s, 1 H), 4.23 (s, 2H), 3.55 (s, 2H), 3.39 (d, 2H, J = 4.4 Hz), 2.07 (s, 3H), 1 .15 (s, 2H), 1.09 (s, 8H). Example 65: N-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)methyl)-N- methylacetamide
Figure imgf000074_0001
65a) 1-(1 5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6 I)-N-meth
methanamine
Compound 62a (0.65 g, 1.53 mmol) and MeNH2 (2M in THF, 25 mL) were stirred in a sealed tube at 50°C for 6 h. The reaction mixture was cooled to RT, concentrated and diluted with DCM. The organic layer was washed with saturated NH4CI solution and brine, dried over Na2S04 and evaporated. The raw product was finally purified by flash column chromatography [silica, DCM with 7% MeOH]. Light brown solid. Yield: 0.47 g (85%). HPLC (method 1 ): Rt = 3.31 min, m/z [M+H]+ = 361.2 (MW calc. 360.43).
65b) N-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)methyl)-N-methyl- acetamide
TEA (0.2 mL, 1.53 mmol) and acetyl chloride (0.036 mL, 0.50 mmol) were added at 0°C to a solution of compound 65a (0.20 g, 0.56 mmol) in DCM (10 mL). The reaction mixture was stirred at RT for 3 h, then diluted with DCM and washed with saturated NH4CI solution and brine. The organic phase was dried and concentrated. The residue was purified by flash column chromatography [silica, DCM with 0.5-1.5% MeOH]. Yield: 0.14 g (62%). HPLC (method 5): Rt = 1.82 min, m/z [M+H]+ = 403.1 (MW calc. 402.46). H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.78 (s, 2H), 8.29 (s, 1 H), 7.66-7.62 (m, 1 H), 7.47-7.42 (m, 1 H), 7.35-7.29 (m, 2H), 6.78 (s, 2H), 4.54 (s, 2H), 4.27 (s, 2H), 2.96-2.91 (m, 3H), 2.09 (s, 3H), 1.17-1.09 (m, 4 H).
Example 66: N-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)methyl)-2- hydroxy-N-methylacetamide
Figure imgf000074_0002
TBTU (0.23 g, 0.71 mmol), 4-methylmorpholine (0.13 mL, 1.18 mmol) and compound 65a (0.21 g, 0.59 mol) were added to a solution of hydroxy-acetic acid (45 mg, 0.59 mmol) in dry DMF (5 mL) at 0°C and the reaction mixture was stirred at RT for 16 h. Iced water was added and the mixture was extracted with EtOAc (3x 30 mL). The combined organic layers were washed with saturated NH4CI solution and saturated NaHC03 solution, dried over Na2S04 and evaporated to dryness. The raw product was purified by flash column chromatography [silica; DCM with 0-1.2 % MeOH]. Colorless solid. Yield: 60 mg (24%). HPLC (method 5): Rt = 1.78 min, m/z [M+H]+ = 419.1 (MW calc. 418.16). H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.78 (s, 2H), 8.29 (s, 1 H), 7.66-7.62 (m, 1 H), 7.47-7.42 (m, 1 H), 7.35-7.29 (m, 2H), 6.82- 6.76 (m, 2H), 4.54 (s, 2H), 4.27 (s, 2H), 4.18 (s, 2H), 2.89 (s, 3H), 1.19-1 .08 (m, 4H).
Figure imgf000075_0001
67a) 1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)-6'-methoxyspiro[cyclopropane-1 ,3'-indolinel
A solution of 2-chloro-5-(2-fluoro-phenyl)-pyrimidine (2.5 g, 13.14 mmol), 6'-methoxyspiro [cyclopropane- 1 ,3'-indoline] (2.3 g, 13.14 mmol) and DIPEA (1 1 mL, 63 mmol) in n-butanol (86 mL) was stirred in a sealed tube at 130°C for 16h. The reaction mixture was cooled to RT and the solvent was removed under reduced pressure. The remnant was purified by column chromatography [silica gel; hexane with 2% EtOAc]. White solid. Yield: 2.5 g (55%). HPLC (method 1 ): Rt = 4.36 min, m/z [M+H]+ = 348.2 (MW calc. 347.1 )
67b) 1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-ol
1 N BBr3 in DCM (20 mL, 21.60 mmol) was added drop wise at 0°C to a solution of compound 67a (2.5 g, 7.20 mmol) in DCM (150 mL). The reaction mixture was stirred at RT for 1 h, then quenched with iced water, neutralized with saturated NaHC03 solution and extracted with DCM (3x 100 mL). The combined organic layers were washed with brine, dried and concentrated. The raw product was purified by flash column chromatography [silica; EtOAc/hexane = 1 :9] followed by trituration with ether/pentane. Yellow solid. Yield: 0.4 g (17%). HPLC (method 1 ): Rt = 3.68 min, m/z [M+H]+ = 334.3 (MW calc. 333.36)
67c) 6'-Ethoxy-1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinel
K2C03 (0.16 g, 1 .20 mmol) followed by ethyl iodide (0.07 mL, 0.90 mmol) were added at RT to a solution of compound 67b (0.20 g, 0.60 mmol) in dry DMF (7 mL) and the reaction mixture was stirred at RT for 48 h. Crushed ice was added and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over Na2S04 and evaporated. The residue was purified by flash column chromatography [silica; hexane with 5% EtOAc]. White solid. Yield: 0.15 g (69%). HPLC (method 1 ): Rt = 2.67 min, m/z [M+H]+ = 362.0 (MW calc. 361.41 ). H NMR (400 MHz, DMSO-d6, δ ppm): 8.82 (s, 2H), 8.03 (d, 1 H, J = 1.96 Hz), 7.68-7.64 (m, 1 H), 7.48-7.43 (m, 1 H), 7.38-7.32 (m, 2H), 6.71 (d, 1 H, J = 8.1 Hz), 6.50-6.48 (m, 1 H), 4.22 (s, 2H), 4.03-3.98 (m, 2H), 1 .35-1 .32 (m, 3H), 1.10-1.02 (m, 4H). Example 68: 6'-(Cvclopropylimethoxy)-1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'- indolinel
Figure imgf000076_0001
Compound 67b (0.35 g, 1.05 mmol), (bromomethyl)cyclopropane (0.71 g, 5.25 mmol) and Cs2C03 (0.68 g, 2.10 mmol) in dry DMF (10 mL) were stirred 80°C for 16 h. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by flash column chromatography [silica; EtOAc / hexane = 1 :9]. White solid. Yield: 0.12 g (29%). HPLC (method 1 ): Rt = 2.89 min, m/z [M+H]+ = 388.3 (MW calc. 387.45). H NMR (400 MHz, DMSO-d6, δ ppm): 8.82 (s, 2H), 8.03 (d, 1 H, J = 2.0 Hz), 7.68- 7.64 (m, 1 H), 7.46-7.43 (m, 1 H), 7.39-7.32 (m, 2H), 6.70 (d, 1 H, J = 8.2 Hz), 6.49-6.47 (m, 1 H), 4.22 (s, 2H), 3.80 (d, 2H, J = 6.9 Hz), 1.22 (s, 1 H), 1.10-1.01 (m, 4H), 0.58 (d, 2H, J = 6.4 Hz), 0.33 (d, 2H, J = 3.7 Hz). Example 69: 3-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)oxy) propan-1- ol
Figure imgf000076_0002
Prepared from compound 67b in two steps comprising an alkylation with 2-(3-bromopropoxy)tetrahydro- 2H-pyran and a deprotection of the alcohol utilizing p-toluene sulfonic acid. White solid. Yield: 0.16 g (65%). HPLC (method 5): Rt = 1 .81 min, m/z [M+H]+ = 392.1 (MW calc. 391.1 ). H NMR (400 MHz, DMSO-d6, δ ppm): 8.82 (s, 2H), 8.02 (d, 1 H, J = 1.9 Hz), 7.68-7.64 (m, 1 H), 7.45-7.42 (m, 1 H), 7.38-7.32 (m, 2H), 6.69 (d, 1 H, J = 8.2 Hz), 6.51-6.49 (m, 1 H), 4.54 (t, 1 H, J = 5.0 Hz), 4.2 (s, 2H), 4.02 (t, 2H, J = 6.1 Hz), 3.58-3.54 (m, 2H), 1.88-1.83 (m, 2H), 1 .1 (bs, 2H), 1 .01 (bs, 2H). Example 70: 3-((1 5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'- indolinl-6'-yl)sulfonyl)propan-1-ol
Figure imgf000077_0001
70a) 3-(Spiro[cvclopropane-1 ,3'-indolinl-6'-ylthio)propan-1-ol
Xantphos (1 .29 g, 2.24 mmol) and Pd2(dba)3 (1.0 g, 1.12 mmol) were added to a solution 6'-bromospiro- [cyclopropane-1 ,3'-indoline] (5.0 g, 22.4 mmol), 3-mercapto-propan-1 -ol (2.0 g, 22.4 mmol) and DIPEA (7.4 mL, 44.84 mmol) in dioxane (150 mL) that was stirred under an inert atmosphere. The reaction mixture was stirred at 100°C for 16 h, cooled to RT and filtered through a pad of celite. The fltrate was evaporated and the residue purified by column chromatography [silica; DCM with 0.5-1.0% MeOH]. Yellow gum. Yield: 4 g (75%) HPLC (method 1 ): Rt = 2.89 min, m/z [M+H]+ = 235.8 (MW calc. 235.3) 70b) 6'-((3-((tert-Butyldimethylsilyl)oxy)propyl)thio)spiro[cvclopropane-1 ,3'-indolinel
Imidazole (1.08 g, 15.96 mmol) and TBDMSCI (1.05 g, 7.02 mmol) were added at 0°C to a solution of compound 70a) (1.5 g, 6.38 mmol) in dry DMF (10 mL). The reaction mixture was stirred at RT for 1 h, than quenched with iced water and diluted with MTBE (50 mL). The aqueous phase was extracted with MTBE (2x 30 mL) and the combined organic layers were washed with brine (30 mL) and dried over Na2S04. The solvent was removed in vacuo and the residue was purified by column chromatography [silica; hexane with 5% EtOAc]. Light yellow liquid. Yield: 1 .9 g (86%). HPLC (method 5): Rt = 2.03 min, m/z [M+H]+ = 350.13 (MW calc. 349.61 )
Compound 70b was then reacted with 5-bromo-2-chloropyrimidine (cf procedure 3a). The product of this coupling was submitted to a Suzuki reaction with 2-(2-bromopyridin-4-yl)propan-2-ol (cf procdure 3c) and oxidized (cf procedure 3b). Removal of the protecting group with TBAF provided synthesis example 70. White solid. Yield: 0.13 g. HPLC (method 5): Rt = 1.52 min, m/z [M+H]+ = 481.15 (MW calc. 480.50). H NMR (400 MHz, DMSO-d6, δ ppm): 9.35 (s, 2H), 8.83 (s, 1 H), 8.59 (d, 1 H, J = 4.9 Hz), 8.06 (s, 1 H), 7.47- 7.43 (m, 2H), 7.09 (d, 1 H, J = 7.8 Hz), 5.29 (s, 1 H), 4.62-4.60 (m, 1 H), 4.36 (s, 2H), 3.42-3.40 (m, 2H), 3.28-3.24 (m, 2H), 1.71-1.68 (m, 2H), 1 .49 (s, 6H), 1.31 (s, 2H), 1.23 (s, 2H).
Example 71 : 3-((1 '-(5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'- indolinl-6'-yl)sulfinyl)propan-1-ol
Figure imgf000078_0001
Prepared analogously to synthesis example 70 with the difference that 0.8 equivalents of mCPBA were used in the oxidation step. Light yellow solid. Yield: 0.15 g. HPLC (method 5): Rt = 1.52 min, m/z [M+H]+ = 465.07 (MW calc. 464.58). H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2H), 8.64-8.58 (m, 2H), 8.04 (s, 1 H), 7.46 (d, 1 H, J = 4.6 Hz), 7.19 (d, 1 H, J = 7.7 Hz), 7.01 (d, 1 H, J = 7.7 Hz), 5.29 (s, 1 H), 4.62-4.59 (m, 1 H), 4.33 (s, 2H), 3.48-3.43 (m, 2H), 2.98-2.91 (m, 1 H), 2.84-2.77 (m, 1 H), 1 .79-1.72 (m, 1 H), 1.63- 1.59 (m, 1 H), 1.49 (m, 6H), 1.27 (bs, 2H), 1.17 (bs, 2H).
Example 72: 3-((1 '-(5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'- indolinl-6'-yl)sulfonyl)propan-1-ol
Figure imgf000078_0002
White solid. Yield: 0.05 g. HPLC (method 1 ): Rt = 3.27 min, m/z [M+H]+ = 436.9 (MW calc. 436.53). H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2H), 8.82 (s, 1 H), 8.52 (d, 1 H, J = 4.7 Hz), 7.94 (s, 1 H), 7.45 (d, 1 H, J = 7.7 Hz), 7.21 (d, 1 H, J = 4.1 Hz), 7.09 (d, 1 H, J = 7.7 Hz), 4.62-4.60 (m, 1 H), 4.35 (s, 2H), 3.43-3.41 (m, 2H), 3.28-3.24 (m, 2H), 2.39 (s, 3H), 1.72-1.68 (m, 2H), 1.30 (s, 2H), 1.23 (s, 2H).
Example 73: 3-((1 '-(5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'- indolinl-6'-yl)sulfonyl)butan-1-ol
Figure imgf000079_0001
White solid. Yield: 0.11 g. HPLC (method 5): Rt = 1.55 min, m/z [M+H]+ = 495.14 (MW calc.494.61). H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.29 (s, 2H), 8.83 (s, 1H), 8.59 (d, 1H, J = 5.1 Hz), 8.02 (s, 1H), 7.45-7.40 (m, 2H), 7.05 (d, 1H, J = 7.8 Hz), 4.93 (s, 1H), 4.41 (s, 2H), 4.27-4.25 (m, 1H), 3.58-3.47 (m, 2H), 3.34-3.29 (m, 1H), 2.10-2.06 (m, 1H), 1.53-1.49 (m, 7H), 1.48-1.33 (m, 7H).
Example 74: 3-((1 5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1,3'- indolinl-6'-yl)sulfinyl)butan-1-ol
Figure imgf000079_0002
Light light yellow solid. Yield: 0.12 g. HPLC (method 5): Rt = 1.56 min, m/z [M+H]+ = 479.2 (MW calc. 478.61). H NMR (400 MHz, DMSO-d6, δ ppm): 9.31 (s, 2H), 8.60-8.57 (m, 2H), 8.04 (s, 1H), 7.46 (d, 1H, J = 4.7 Hz), 7.16-7.11 (m, 1H), 7.01 (d, 1H, J = 7.7 Hz), 5.29 (s, 1H), 4.67-4.54 (m, 1H), 4.33 (s, 2H), 3.64-3.41 (m, 2H), 2.90-2.87 (m, 1H), 1.96-1.91 (m, 1H), 1.74 (bs, 1H), 1.48 (s, 6H), 1.25 (s, 2H), 1.17- 1.12 (m, 3H), 0.97 (d, 2H, J = 6.7 Hz).
Example 75: 3-((1 '-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)sulfonyl)- butan-1-ol
Figure imgf000079_0003
White solid. Yield: 95 mg. HPLC (method 5): Rt = 1.62 min, m/z [M+H]+ = 451.1 (MW calc. 450.55). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.27 (s, 2H), 8.82 (s, 1 H), 8.51 (d, 1 H, J = 4.9 Hz), 7.85 (s, 1 H), 7.41-7.39 (m, 1 H), 7.18 (d, 1 H, J = 4.6 Hz), 7.05 (d, 1 H, J = 7.8 Hz), 4.37 (s, 2H), 4.26 (bs, 1 H), 3.58-3.45 (m, 2H), 3.34-6.29 (m, 1 H), 2.41 (s, 3H), 2.08-2.04 (m, 1 H), 1.52-1 .45 (m, 1 H), 1.45-1.24 (m,
7H).
Example 76: Ethyl 1 '-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinel-6'- carboxylate
Figure imgf000080_0001
Synthesized from compound 59a and (2-fluoro-5-methylphenyl)boronic acid in three steps (Suzuki reaction analgously to procedure 1f, ester hydrolysis with lithium hydroixde followed by treatment with ethyl iodide analgously to procedure 67c). White solid. Yield: 0.1 1 g. HPLC (method 1 ): Rt = 4.49 min, m/z [M+H]+ = 403.8 (MW calc. 403.45). H NMR (400 MHz, DMSO-d6, δ ppm): 8.91 (s, 1 H), 8.84 (s, 2H), 7.58-7.48 (m, 2H), 7.25 (d, 2H, J = 8 Hz), 6.94 (d, 1 H, J = 7.8 Hz), 4.34-4.29 (m, 4H), 2.35 (s, 3H), 1 .35- 1.31 (m, 3H), 1 .26 (bs, 2H), 1 .19 (bs, 2H).
Example 77: 2-Hydroxyethyl 1 '-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'- indolinel-6'-carboxylate
Figure imgf000080_0002
Prepared analgously to example 76. White solid. Yield: 0.18 g. HPLC (method 5): Rt = 1.83 min, m/z [M+H]+ = 420.12 (MW calc. 419.45). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.92 (s, 1 H), 8.84 (s, 2H), 7.62-7.60 (m, 1 H), 7.50 (d, 1 H, J = 7.7 Hz), 7.25 (d, 2H, J = 8.3 Hz), 6.95 (d, 1 H, J = 7.8 Hz), 4.93-4.90 (m, 1 H), 4.29-4.27 (m, 4H), 3.73-3.69 (m, 2H), 2.35 (s, 3H) 1.26-1.18 (m, 4H). Example 78: 1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl dimethyl carbamate
Figure imgf000081_0001
K2C03 (0.124 g, 0.9 mmol) and Ν,Ν-dimethylcarbamoyl chloride (0.055 mL, 0.9 mmol) were added to compound 67b (0.2 g, 0.6 mmol) dissolved in acetonitrile (10 mL) and the resulting mixture was stirred at 70-80°C for 16 h. The solvent was distilled off under reduced pressure, EtOAc was added and the mixture was washed with water (2 x 20 mL). The organic phase was dried over Na2S04 and evaporated to dryness. The remnant was purified by column chromatography [100-200 mesh silica; hexane with 0-15% EtOAc]. White solid. Yield: 85 mg (35%). HPLC (method 5): Rt = 1.90 min, m/z [M+H]+ = 405.1 (MW calc. 404.44). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.83 (s, 2H), 8.08 (s, 1 H), 7.68-7.64 (m, 1 H), 7.48-7.43 (m, 1 H), 7.39-7.32 (m, 2H), 6.78 (d, 1 H, J = 8.0 Hz), 6.63 (d, 1 H, J = 8.2 Hz), 4.27 (s, 2H), 3.05 (s, 3H), 2.91 (s, 3H), 1.17 (bs, 2H), 1 .09 (bs, 2H).
Figure imgf000081_0002
Prepared analogously to synthesis example 78. White solid. Yield: 50 mg. HPLC (method 5): Rt = 1 .66 min, m/z [M+H]+ = 391.0 (MW calc. 390.41 ). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.82 (s, 2H), 7.67- 7.62 (m, 2H), 7.52-7.49 (m, 1 H), 7.4-7.33 (m, 2H), 6.74 (d, 1 H, J = 8.0 Hz), 6.67-6.65 (m, 1 H), 6.61-6.58 (m, 1 H), 3.93 (s, 2H), 2.63 (d, 3H, J = 3.8 Hz), 1.05 (bs, 4H).
Examples 80 to 82 were prepared from 1 '-(5-bromopyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]-6'- sulfonyl chloride in analogy to synthesis example 18.
Example 80: N-(2-Hvdroxyethyl)-1 '-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro-
[cyclopropane-1 ,3'-indolinel-6'-sulfonamide
Figure imgf000082_0001
White solid. Yield: 80 mg. HPLC (method 1): Rt = 3.11 min, m/z [M+H]+ = 495.8 (MW calc.495.60). H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H), 8.76 (s, 1H), 8.59 (d, 1H, J = 5.1 Hz), 8.06 (s, 1H), 7.47 (d, 1H, J = 4.8 Hz), 7.32 (d, 1H, J = 7.8 Hz), 7.04 (d, 1H, J = 7.8 Hz), 5.29 (s, 1H), 4.79 (s, 1H), 4.34 (s, 2H), 3.54 (d, 2H, J = 4.8 Hz), 3.04-3.01 (m, 2H), 2.76 (s, 3H), 1.49 (s, 6H), 1.29-1.24 (m, 2H), 1.22-1.19 (m, 2H).
Example 81 : N-(2-Hvdroxyethyl)-1'-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclo- propane-1,3'-indolinel-6'-sulfonami
Figure imgf000082_0002
Yellow solid. Yield: 90 mg. HPLC (method 5): Rt = 1.51 min, m/z [M+H]+ = 482.2 (MW calc.481.57). H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2H), 8.82 (s, 1H), 8.59 (d, 1H, J = 5.1 Hz), 8.05 (s, 1H), 7.53- 7.50 (m, 1H), 7.47 (d, 1H, J = 4.6 Hz), 7.38 (d, 1H, J = 7.8 Hz), 7.02 (d, 1H, J = 7.8 Hz), 5.29 (s, 1H), 4.67-4.64 (m, 1H), 4.34 (s, 2H), 3.41-3.36 (m, 2H), 2.84-2.79 (m, 2H), 1.49 (s, 6H), 1.28 (s, 2H), 1.20 (s,
2H).
Example 82: N-(2-Hvdroxyethyl)-1 5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1,3'- indolinel-6'-sulfonamide
Figure imgf000083_0001
White solid. Yield: 0.1 g. HPLC (method 1 ): Rt = 3.22 min, m/z [M+H]+ = 437.8 (MW calc. 437.52). H NMR (400 MHz, DMSO-d6, δ ppm): 9.29 (s, 2H), 8.80 (s, 1 H), 8.52 (d, 1 H, J = 4.9 Hz), 7.92 (s, 1 H), 7.55- 7.52 (m, 1 H), 7.37-7.35 (m, 1 H), 7.21 (d, 1 H, J = 4.9 Hz), 7.01 (d, 1 H, J = 7.8 Hz), 4.67-4.64 (m, 1 H), 4.33 (s, 2H), 3.41-3.36 (m, 2H), 2.84-2.79 (m, 2H), 2.39 (s, 3H), 1.27 (s, 2H), 1.19 (s, 2H).
Example 83: 2-(2-(2-(6'-(Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)pyrimidin-5-yl)pyridin-4- yl)propan-2-amine
Figure imgf000083_0002
83a) 6 Ethylthio)-1 '-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)spiro[cyclopropane- 1 ,3'-indolinel
PdCI2(dppf) (0.865 g, 1.061 mmol, 0.05 eq.) was added to a suspension of 1 '-(5-bromopyrimidin-2-yl)-6'- (ethylthio)spiro[cyclopropane-1 ,3'-indoline] 1d (8.0 g, 1.85 mmol, 1 eq.), bis(pinacolato)diboron (8.08 g, 31.83 mmol, 1.5 eq) and potassium acetate (6.23 g, 63.66 mmol, 3.0 eq.) in 1 ,4-dioxane (100 ml) stirred under Ar. The reaction mixture was further stirred for 16 h at 100°C, then cooled to RT and filtered through a pad of celite. The filtrate was evaporated under reduced pressure and the remnant was used in the next step without further purification. MS: m/z: [M+H]+ = 410.2
83b) 2-(2-(2-(6 Ethylthio)spiro[cvclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)pyridin-4-yl)propan-2- amine
Tetrakis(triphenylphosphine)palladium(0) (0.424 g, 0.367 mmol, 0.05 eq.) was added to a solution of 83a (3.0 g, 7.33 mmol, 1 eq.), K2C03 (2M aqueous solution, 3.0 g, 22.00 mmol, 3 eq.) and 2-(2-bromopyridin- 4-yl)propan-2-amine hydrochloride (1.57g, 7.33 mmol, 1 eq.) in dioxane (30 ml) stirred under Ar. The reaction mixture was then refluxed for 16 h at 100°C, cooled to RT and filtered through a celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography [100-200 mesh silica gel; DCM with 5% MeOH]. Light yellow gum. Yield: 2.10 (68%). MS: m/z: [M+H]+ = 417.9.
83c) Benzyl (2-(2-(2-(6'-(Ethylthio)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)pyridin-4-yl)- propan-2-yl)carbamate
Benzyl chloroformate (0.205 ml, 1.44 mmol, 1 eq.) was added at 0°C to a stirred solution of compound 83b (0.6 g, 1.44 mmol, 1 eq.) and DIPEA (0.501 ml, 2.88 mmol, 2 eq.) in THF (30 ml). The reaction mixture was warmed slowly to RT and stirred for another 2 h. The mixture was then diluted with EtOAc and washed with saturated aqueous NaHC03 solution and brine. The organic layer was separated, dried over anhydrous Na2S04 and concentrated. The residue was purified by column chromatography [100-200 mesh silica gel; EtOAc/hexane = 1 :3]. Light yellow oil. Yield: 0.41g (52%). MS: m/z: [M+H]+ = 552.3.
83d) Benzyl (2-(2-(2-(6'-(ethylsulfonyl)spiro[cvclopropane-1 ,3'-indolinl-1 '-yl)pyrimidin-5-yl) pyridine-4- yl)propan-2-yl)carbamate
mCPBA (75%, 0.250 g, 1.09 mmol, 2.0 eq.) was added portion wise at 0°C to a stirred solution of 83c (0.3 g, 0.545 mmol, 1 .0 eq.) in THF (20 ml) and the resulting mixture was stirred for 30 min at RT. The reaction mixture was concentrated, diluted with EtOAc (50 ml) and washed with saturated sodium sulphite solution (25 ml), saturated NaHC03 solution (25 ml) and finally brine (25 ml). The organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure. The raw product was purified by column chromatography [100-200 mesh silica gel; DCM with 5% MeOH]. Yield: 0.26 g (38%). MS: m/z: [M+H]+ = 584.1.
83e) 2-(2-(2-(6 Ethylsulfonyl)spiro[cvclopropane-1 ,3'-indolin1-1 '-yl)Pyrimidin-5-yl)pyridin-4-yl)propan-2- amine
Pd/C (10%, 0.045g) was added to a solution of 83d (0.25g, 0.429mmol, 1 eq.) in EtOAc (15 ml) stirred under argon. Hydrogen gas from a balloon was passed into the reaction flask while stirring was continued for 2 h. The reaction mixture was then filtered through a celite pad, the filtrate was concentrated and the residue was purified by preparative HPLC affording the target compound as acetate salt. White solid. MS: m/z: [M+H]+ = 450.1. H NMR (400 MHz, DMSO-d6, δ ppm): 9.37 (s, 2H), 8.84 (s, 1 H), 8.57 (d, J = 5.2 Hz, 1 H), 8.18 (s, 1 H), 7.49 (d, J = 5.2Hz, 1 H), 7.44 (d, J = 8.0 Hz, 1 H), 7.08 (d, J = 8.0 Hz, 1 H), 4.36 (s, 2H), 3.25 (q, J = 7.2 Hz, 2H), 2.02 (s, 3H), 1.89 (s, 3H), 1.42 (s, 6H), 1.31 (s, 2H), 1.23 (s, 2H), 1.14 (t, 3H, J = 7.2Hz).
Example 84: 2-(2-(2-(6'-(Ethylsulfonyl)spiro[cvclopropane-1 ,3'-indolin1-1 '-yl)Pyrimidin-5-yl)pyridin-4-yl)-N- methylpropan-2-amine
Figure imgf000085_0001
84a) Benzyl (2-(2-(2-(6'-(ethylthio)spiro[cvclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)pyridin-4-yl)propan- 2-yl)(methyl)carbamate
NaH (60% in mineral oil, 0.087g, 2.18 mmol, 2 eq.) was added at 0°C to a stirred solution of intermediate 83c (0.6 g, 1.09 mmol, 1 eq.) in DMF (25 ml). The resulting mixture was warmed slowly to RT over 30 min and then cooled again to 0°C. Methyl iodide (1.0 ml, excess) was added at RT and stirring was continued for another 3 h upon warming to RT. The mixture was then diluted with EtOAc (30 ml), washed with cold water (3x25 ml) and brine (20 ml) and dried over anhydrous Na2S04. The solvents were removed under reduced pressure and the residue was purified by column chromatography [100-200 mesh silica gel; hexane with 20% EtOAc]. Yield: 0.42 g (68%). Light yellow solid.
The target compound (acetate salt) was derived from 84a in analogy to synthesis example 83. White solid. Yield: 0.1 g. MS: m/z: [M+H]+ = 464.1. H NMR (400 MHz, DMSO-d6, δ ppm): 9.37 (s, 2H), 8.84 (s, 1 H), 8.59 (d, J = 5.2 Hz, 2H), 8.08 (s, 1 H), 7.44 (d, J = 7.6 Hz, 1 H), 7.40 (d, J = 5.2Hz, 1 H), 7.08 (d, J = 7.6 Hz, 1 H), 4.36 (s, 2H), 3.25 (q, J = 7.2 Hz, 2H), 2.02 (s, 3H), 1.89 (s, 2H), 1.38 (s, 6H), 1 .31 (s, 2H), 1.23 (s, 2H,), 1.14 (t, 3H, J = 7.2 Hz).
Example 85: 1-(2-(2-(6'-(Ethylsulfonyl)spiro[cvclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)pyridin-4-yl)- cyclopropanamine
Figure imgf000085_0002
Prepared from compound 1d and tert-butyl (1-(2-bromopyridin-4-yl)cyclopropyl)carbamate in analogy to example 83. White solid (TFA salt). Yield: 130 mg. MS: m/z: [M+H]+ = 448.1. H NMR (400 MHz, DMSO- d6, δ ppm): 9.37 (s, 2H), 8.85 (d, J = 1 .6 Hz, 1 H), 8.81 (s, 2H), 8.69 (d, J = 5.2 Hz, 1 H), 7.86 (s, 1 H), 7.46 (dd, J = 8.0 Hz, 1.6 Hz, 1 H), 7.31 (d, J = 5.2 Hz, 1 H), 7.10 (d, J = 8.0 Hz, 1 H), 4.36 (s, 2H), 3.25 (q, J = 7.2 Hz, 2H), 1.51 (s, 2H), 1.47 (s, 2H), 1.33 (s, 2H), 1.26 (s, 2H), 1 .10 (t, 3H, J = 7.2 Hz). Example 86: 1 -(2-(2-(6'-(Ethylsulfonyl)spiro[cvclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)pyridin-4-yl)-N- methylcyclopropanamine
Figure imgf000086_0001
Prepared from compound 1 d and tert-butyl (1-(2-bromopyridin-4-yl)cyclopropyl)(methyl)carbamate in analogy to example 83. Yellow solid (TFA salt). Yield: 105 mg. MS: m/z: [M+H]+ = 462.1 . H NMR (400 MHz, DMSO-d6, δ ppm): 9.38 (s, 2H), 8.85 (s, 1 H), 8.74 (d, J = 5.2 Hz, 1 H), 8.05 (s, 1 H), 7.46-7.52 (m, 2H), 7.10 (d, J = 8.0 Hz, 1 H), 4.36 (s, 2H), 3.25 (q, J = 7.2 Hz, 2H), 2.63 (s, 3H), 1.50 (s, 4H), 1.31 (s, 2H), 1.24 (s, 2H), 1 .13 (t, 3H, J = 7.2 Hz).
Example 87: 2-(2-(2-(6'-(Ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)pyridin-4-yl)- propan-2-amine
Figure imgf000086_0002
Prepared from compound 1d and 2-(2-bromopyridin-4-yl)propan-2-amine hydrochloride in analogy to example 83. White solid. Yield: 75 mg (di-acetate salt). MS: m/z: [M+H]+ = 434.1. H NMR (400 MHz, DMSO-d6, 20°C, δ ppm): 9.34 (s, 2H), 8.64 (s, 1 H), 8.56 (d, J = 4.8 Hz, 1 H), 8.16 (s, 2H), 7.48 (d, J = 4.8 Hz, 1 H), 7.17 (d, J = 8.0 Hz, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 4.33 (s, 2H), 2.97 (q, J = 7.2 Hz, 1 H), 2.76 (q, J = 7.2 Hz, 1 H), 1.41 (s, 6H), 1.25 (s, 2H), 1.17 (s, 2H), 1.07 (t, 3H, J = 7.2Hz).
Example 88: 2-(2-(2-(6'-(Ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)pyridin-4-yl)-N- methylpropan-2-amine
Figure imgf000087_0001
Prepared from intermediate 84a in two steps comprising an oxidation with mCPBA and a protecting group removal with BBr3. White solid. Yield: 0.2 g (acetate salt). MS: m/z: [M+H]+ = 448.2. H NMR (400 MHz, DMSO-d6, δ ppm): 9.34 (s, 2H), 8.64 (s, 1H), 8.58 (d, J = 4.8 Hz, 2H), 8.06 (s, 1H), 7.40 (d, J = 4.8Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 4.33 (s, 1H), 2.95 (q, J = 7.2 Hz, 1H), 2.76 (q, J = 7.2 Hz, 1H), 2.02 (s, 3H), 1.89 (s, 4H), 1.38 (s,6H), 1.26 (s, 2H), 1.18 (s,2H), 1.07 (t, J = 7.2Hz, 3H).
Example 89: 1 -(2-(2-(6'-(Ethylsulfinyl)spiro[cvclopropane-1 ,3'-indolinl-1 '-yl)pyrimidin-5-yl)pyridin-4- vDcvclopropanamine
Figure imgf000087_0002
Prepared from compound 1d and tert-butyl (1-(2-bromopyridin-4-yl)cyclopropyl)carbamate in analogy to example 83. Yellow solid (TFA salt). Yield: 110 mg. MS: m/z: [M+H]+ = 432.3. H NMR (400 MHz, DMSO- d6, δ ppm): 9.35 (s, 2H), 8.83 (s, 2H), 8.68 (d, J = 5.2 Hz, 1H), 8.65 (s, 1H), 7.83 (s, 1H), 7.29 (d, J = 5.2 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.33 (s, 2H), 2.97 (q, J = 7.2 Hz, 1H), 2.75 (q, J =7.2 Hz, 1H), 1.56 (s,2H), 1.49 (s,2H), 1.26 (s,2H), 1.18 (s,2H), 1.06 (t, 3H, J = 7.2 Hz).
Example 90: 1-(2-(2-(6'-(Ethylsulfinyl)spiro[cyclopropane-1,3'-indolinl-1 '-yl)pyrimidin-5-yl)pyridin-4-yl)-N- methylcvclopropanamine
Figure imgf000088_0001
Prepared from compound 1 d and tert-butyl (1-(2-bromopyridin-4-yl)cyclopropyl)(methyl)carbamate in analogy to example 83. Yellow solid (TFA salt). Yield: 105 mg. MS: m/z: [M+H]+ = 446.3. H NMR (400 MHz, DMSO-d6, δ ppm): 9.36 (s, 2H), 8.73 (d, J = 5.2 Hz, 1 H), 8.66 (s,1 H), 8.03 (s, 1 H), 7.45 (d, J = 5.2 Hz, 1 H), 7.17 (d, J = 8.0 Hz, 1 H), 7.01 (d, J = 8.0 Hz, 1 H), 4.33 (s, 2H), 2.97 (q, J = 7.2 Hz, 1 H), 2.75 (q, J = 7.2 Hz, 1 H), 2.62 (s, 3H), 1.51-1.50 (m, 4H), 1.25 (s, 2H), 1 .18 (s, 2H), 1.07 (t, 3H, J = 7.2 Hz).
Example 91 : 2-(6-(2-(6'-(Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)pyridin-2- yl)propan-2-ol
Figure imgf000088_0002
Prepared from 3b and 2-(6-chloropyridin-2-yl)propan-2-ol analogously to example 3. Light yellow solid. Yield: 230 mg. HPLC (method 5): Rt = 3.44 min, m/z [M+H]+ = 451.3 (MW calc. 450.55). H NMR (400 MHz, DMSO-d6, δ ppm): 9.37 (s, 2H), 8.82 (s, 1 H), 7.89-7.85 (m, 2H), 7.61 (d, 1 H, J = 6.8 Hz), 7.44 (d, 1 H, J = 7.6 Hz), 7.08 (d, 1 H, J = 7.8 Hz), 5.28 (s, 1 H), 4.35 (s, 2H), 3.28-3.23 (m, 2H), 1.51 (s, 6H), 1.31 (s, 2H), 1.23 (s, 2H), 1.13 (t, 3H, J = 7.2 Hz).
Example 92 and 93: 2-(6-(2-(6 Ethylsulfinyl)spiro[cvclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)pyridin-2- yl)propan-2-ol (faster and slower elutinq enantiomer)
Figure imgf000088_0003
The racemic sulfoxide was prepared from intermediate 3b in analogy to synthesis example 24. The two enantiomers were obtained from this racemate (800 mg) through preparative chiral HPLC.
Faster eluting enantiomer (example 92): Yield = 230 mg. White solid. MS: m/z: [M+H]+ = 434.7 (MW calc. 434.55). Specific optical rotation: [a]589 25 = -163.13° (c. 0.3482, CHCI3). H NMR (400 MHz, DMSO-d6, δ ppm): 9.34 (s, 2H), 8.62 (s, 1 H), 7.87 (s, 2H), 7.61-7.59 (m, 1 H), 7.16 (d, 1 H, J = 7.6 Hz), 7.00 (d, 1 H, J = 7.7 Hz), 5.27 (s, 1 H), 4.32 (s, 2H), 2.99-2.89 (m, 1 H), 2.78-2.73 (bs, 1 H), 1.51 (s, 6H), 1.25 (s, 2H), 1.17 (s, 2H), 1.07 (t, 3H, J = 7.0 Hz). Chiral HPLC: Rt = 7.92 min (column: Chiralpak IA 250 mm x 4.6 mm, 5 μιη, mobile phase: hexane/EtOAc/EtOH /diethylamine = 50/25/25/0.1 ; flow rate = 1.0 ml/min).
Slower eluting enantiomer (example 93): Yield = 170 mg. Brown solid. MS: m/z: [M+H]+ = 435.0 (MW calc. 434.55). Specific optical rotation: [a]589 25 = +151.14° (c. 0.2898, CHCI3). H NMR (400 MHz, DMSO- d6, δ ppm): 9.34 (s, 2H), 8.62 (s, 1 H), 7.87 (s, 2H), 7.61 (m, 1 H), 7.17 (d, 1 H, J = 7.6 Hz), 7.00 (d, 1 H, J = 7.7 Hz), 5.27 (s, 1 H), 4.32 (s, 2H), 2.99-2.94 (m, 1 H), 2.78-2.73 (m, 1 H), 1.51 (s, 6H), 1 .25 (s, 2H), 1.17 (s, 2H), 1.07 (t, 3H, J = 7.0 Hz). Chiral HPLC: Rt = 9.16 min (same conditions as for peak 1 ). Intermediate 1 : 1 '-(5-Bromopyrimidin-2-yl) '-(methylthio)spiro[cyclopropane-1 ,3'-indolinel (lnt-1 )
Figure imgf000089_0001
lnt-1a) 6'-(Methylthio)spiro[cvclopropane-1 ,3'-indolinl-2'-one
6'-Bromospiro[cyclopropane-1 ,3'-indolin]-2'-one (6.0 g, 25.2 mmol) in dry THF (150 mL) was added drop wise at -30°C to a suspension of KH (30% in mineral oil, 3.3 g, 25.2 mmol) in dry THF (60 mL). The mixture was stirred at this temperature for 30 min followed by the addition of t-BuLi (2 M in pentane, 28.9 mL, 57.96 mmol) at -78°C. Stirring was continued for 30 min, then dimethyl disulfide (13.4 mL, 151 .2 mmol) in dry THF (30 mL) was added drop wise at -78°C and the reaction mixture was brought over 16 h to RT. The reaction mixture was quenched under cooling with an ice bath with sat. 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; hexane/EtOAc= 4: 1]. White solid. Yield: 2 g. MS: m/z [M+H]+ = 203.8 (MW calc. 205.28). lnt-1 b) 6'-(Methylthio)spiro[cvclopropane-1 ,3'-indolinel
LAH (0.84 g, 22.16 mmol) was added portion wise at 0°C to a solution of lnt-1a (1.3 g, 6.33 mmol) in THF (50 ml). The reaction mixture was stirred at 80°C for 2 h, cooled and quenched (8.4 mL water, then 8.4 mL 20% NaOH solution, then 16.8 mL water). After stirring for 1 h at RT, the mixture was filtered through a pad of celite, the filter was rinsed with MeOH/DCM (1 :4, 3 x 100 mL) and the filtrate was concentrated under reduced pressure. White solid. Yield: 1.1 g. MS: m/z [M+H]+ = 192.0 (MW calc. 191.29). lnt-1 c) 1 '-(5-Bromopyrimidin-2-yl)-6'-(methylthio)spiro[cyclopropane-1 ,3'-indolinel (lnt-1 ) lnt-1 b (1.6 g, 8.36 mmol), 5-bromo-2-chloro-pyrimidine (3.2 g, 16.72 mmol) and DIPEA (6.9 mL, 41.82 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 precipitating solid was filtered off and washed with ether/hexane. White solid. Yield: 1 .3 g. HPLC (method 1 ): Rt = 2.66 min, m/z [M+H]+ = 350.1 (MW calc. 348.26).
Example 94: 2-(2-(2-(6'-(Methylsulfinyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)pyrimidin-5-yl)pyridin-4- yl)propan-2-ol
Figure imgf000090_0001
Prepared in two steps from lnt-1 analogously to aforementioned protocols (3c and 24a, respectively). Light yellow solid. Yield: 0.1 1 g. HPLC (method 5): Rt = 1.57 min, m/z [M+H]+ = 421.1 (MW calc. 420.53). H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2H), 8.68 (s, 1 H), 8.59 (d, 1 H, J = 4.8 Hz), 8.03 (s, 1 H), 7.46 (d, 1 H, J = 3.8 Hz), 7.22 (d, 1 H, J = 6.4 Hz), 7.01 (d, 1 H, J = 7.6 Hz), 5.29 (bs, 1 H), 4.32 (s, 2H), 2.73 (s, 3H), 1.48 (s, 6H), 1.25 (bs, 2H), 1.17 (bs, 2H). Example 95: 2-(2-(2-(6'-(Methylsulfonyl)spiro[cvclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl) pyridin-4- yl)propan-2-ol
Figure imgf000090_0002
mCPBA (61.3 mg, 0.35 mmol) in THF (30 mL) was added to an ice-cooled solution of example 94 (0.15 g, 0.35 mmol) in THF (30 mL) and the resulting mixture was stirred at RT for 1 h. The mixture was diluted with EtOAc (50 mL) and washed successively with saturated NaHC03 solution (2x 50 mL), saturated sodium bisulfite 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 2% MeOH]. Light yellow solid. Yield: 0.08 g. HPLC (method 1 ): Rt = 3.12 min, m/z [M+H]+ = 437.1 (MW calc. 436.53). H NMR (400 MHz, DMSO-d6, δ ppm): 9.34 (s, 2H), 8.87 (s, 1 H), 8.60 (d, 1 H, J = 4.6 Hz), 8.06 (s, 1 H), 7.50-7.48 (m, 2H), 7.08 (d, 1 H, J = 7.7 Hz), 5.29 (bs, 1 H), 4.35 (s, 2H), 3.19 (s, 3H), 1.49 (s, 6H), 1.30 (bs, 2H), 1.22 (bs, 2H).
Example 96: N-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin1-6'-yl)-3-hvdroxy- propanamide
Figure imgf000091_0001
96a) tert-Butyl spiro[cvclopropane-1 ,3'-indolinl-6'-ylcarbamate
Ν,Ν'-Dimethylcyclohexane 1 ,2-diamine (0.51 g, 3.57 mmol), copper(l) iodide (0.34 g, 1.78 mmol) and K2C03 were added to a solution of 6'-bromospiro[cyclopropane-1 ,3'-indoline] (4.0 g, 17.85 mmol) and tert- butyl carbamate (4.18 g, 35.7 mmol) in 1 ,4-dioxane (250 mL) stirred under Ar. The resulting mixture was heated at 120°C for 16 h in a sealed tube, cooled and filtered through a plug of celite. The filter was rinsed with DCM/MeOH (9:1 , 2 x 50 mL), the filtrate was concentrated and the residue was purified by column chromatography [100-200 mesh silica; EtOAc/hexane = 1 :4]. White solid. Yield: 1.0 g (22%). HPLC (method 1 ): Rt = 3.38 min, m/z [M+H]+ = 261.1 (MW calc. 260.33).
96b) tert-Butyl (1 '-(5-bromopyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolin1-6'-yl)carbamate
Compound 96a (1 .3 g, 5.0 mmol), 5-bromo-2-chloro-pyrimidine (1.16 g, 6.0 mmol) and DIPEA (2.6 mL, 15.0 mmol) in n-butanol (15 mL) were stirred at 120°C for 16 h in a sealed tube. The reaction mixture was concentrated and residue was purified by column chromatography [100-200 mesh silica; hexane/EtOAc= 5:95]. White solid. Yield: 1.2 g (57%). HPLC (method 1 ): Rt = 4.18 min, m/z [M+H]+ = 417.0 (MW calc. 417.30).
96c) tert-butyl (1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin1-6'-yl) carbamate
K2C03 (0.4 g, 2.87 mmol) and (AtaPhos)2PdCI2 (68 mg, 0.09 mmol) were added to a solution of compound 96b (0.4 g, 0.96 mmol) and 2-fluoro-phenylboronic acid (0.144 g, 0.94 mmol) in tert-amyl alcohol (1 .5 mL) and water (1.5 mL) stirred under Ar. The resulting mixture was heated at 90°C for 6 h, then cooled and filtered through a plug of celite. The filtrate was evaporated and the remnant purified by flash column chromatography [silica gel; DCM with 0-0.5% MeOH]. White solid. Yield: 0.4 g (96%). HPLC (method 1 ): Rt = 4.15 min, m/z [M+H]+ = 432.8 (MW calc. 432.49).
96d) 1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolin1-6'-amine
A solution of compound 96c (0.74 g, 1.71 mmol) and TFA (4M in DCM, 17.1 mL) in DCM (20 mL) was stirred for 3 h at RT. The reaction mixture was concentrated, diluted with DCM and washed with saturated K2C03 solution and brine. The organic phase was dried over Na2S04 and evaporated. White solid. Yield: 0.58 g. HPLC (method 1 ): Rt = 3.75 min, m/z [M+H]+ = 332.9 (MW calc. 332.37).
96e) N-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)-3-hvdroxypropan- amide
TBTU (0.34 g, 1.04 mmol), NMM (0.19 mL, 1.74 mmol) and 96d (0.29 g, 0.87 mmol) were added to 3- hydroxypropanic acid (30% in water, 0.26 mL, 0.87 mmol) in DMF (3 mL). The reaction mixture was stirred at RT for 16 h, then quenched with crushed ice and extracted with EtOAc. The combined organic layers were washed with NaHC03 solution (10 mL), NH4CI solution (10 mL) and brine (10 mL) and dried over Na2S04. The solvent was evaporated and the raw product was purified by flash column chromatography [silica; DCM with 0-1 % MeOH]. White solid. Yield: 55 mg. HPLC (method 5): Rt = 1.68 min, m/z [M+H]+ = 405.08 (MW calc. 404.44). H NMR (400 MHz, DMSO-d6, δ ppm): 9.89 (s, 1 H), 8.80 (s, 2H), 8.50 (s, 1 H), 7.69-7.66 (m, 1 H), 7.44-7.34 (m, 4H), 6.73 (d, 1 H, J = 7.9 Hz), 4.65 (bs, 1 H), 4.22 (s, 2H), 3.70 (bs, 2H), 2.46 (s, 2H), 1.13 (bs, 2H), 1.04 (bs, 2H).
Example 97: N-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)-2-hydroxy- acetamide
Figure imgf000092_0001
Prepared from in analogy to example 96. White solid. Yield: 80 mg. HPLC (method 5): Rt = 1.71 min, m/z [M+H]+ = 391.10 (MW calc. 390.41 ). H NMR (400 MHz, DMSO-d6, δ ppm): 9.58 (s, 1 H), 8.80 (s, 2H), 8.58 (s, 1 H), 7.69-7.65 (m, 1 H), 7.44-7.32 (m, 4H), 6.75 (d, 1 H, J = 8.1 Hz), 5.55 (bs, 1 H), 4.23 (s, 2H), 3.99 (d, 2H, J = 5.8 Hz), 1 .14 (bs, 2H), 1 .05 (bs, 2H).
Example 98: N-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)-2-hydroxy-N- methylacetamide
Figure imgf000092_0002
98a) tert-Butyl (1 '-(5-bromopyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)(methyl) carbamate 96b (1.05 g, 2.51 mmol) was added portion wise at 0°C to a suspension of NaH in DMF. The mixture was stirred for 1 h at this temperature, methyl iodide was then added drop wise at 0°C and stirring was continued for 1 h. The reaction mixture was quenched with crushed ice and extracted with MTBE (3x 50 mL). The organic layers were dried over Na2S04 and evaporated. The residue was purified by column chromatography [100-200 mesh silica; hexane with 5% EtOAc]. White solid. Yield: 0.9 g (83%). HPLC (method 1 ): Rt = 4.53 min, m/z [M+H]+ = 433.2 (MW calc. 432.33).
Example 98 was obtained from the aforementioned alkylation product in analogy to the synthesis protocols for example 96. White solid. Yield: 0.12 g. HPLC (method 5): Rt = 1.77 min, m/z [M+H]+ = 405.03 (MW calc. 404.44). H NMR (400 MHz, DMSO-d6, δ ppm): 8.84 (s, 2H), 8.23 (s, 1 H), 7.67-7.63 (m, 1 H), 7.47-7.43 (m, 1 H), 7.38-7.31 (m, 2H), 6.87 (s, 2H), 4.59-4.56 (m, 1 H), 4.28 (s, 2H), 3.77 (bs, 2H), 3.19 (s, 3H), 1.20 (bs, 2H), 1 .14 (bs, 2H).
Example 99: N-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)-3-hydroxy-N- methylpropanamide
Figure imgf000093_0001
Prepared from 98a in analogy to example 96. White solid. Yield: 37 mg. HPLC (method 5): Rt = 1.77 min, m/z [M+H]+ = 419.14 (MW calc. 418.46). H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.81 (s, 2H), 8.25 (s, 1 H), 7.65-7.61 (m, 1 H), 7.45-7.42 (m, 1 H),7.34-7.29 (m, 2H), 6.77 (s, 2H), 4.32 (s, 2H), 4.05 (bs, 1 H), 3.64-3.60 (m, 2H), 3.20 (s, 3H), 2.34-2.31 (m, 2H), 1.21 (bs, 2H), 1.15 (bs, 2H).
Example 100: N-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)methyl)- acetamide
Figure imgf000093_0002
100a) Spiro[cvclopropane-1 ,3'-indolinl-6'-ylmethanol
LAH (18.5 g, 517.2 mmol) was added at 0°C portion wise to a solution of methyl spiro[cyclopropane-1 ,3'- indoline]-6'-carboxylate (30 g, 147.7 mmol) in THF (2.0 L). The reaction mixture was stirred for 2 h and then quenched with water and aqueous NaOH solution. The resulting mixture was filtered through a plug of celite and the filter was rinsed with DCM. The organic layer was separated and evaporated. The product was used in the next step without further purification. Yield: 21 g. HPLC (method 1 ): Rt = 0.29 min, m/z [M+H]+ = 176.0 (MW calc. 175.23).
100b) (1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)methanol
Compound 100a (5.0 g, 28.5 mmol), 2-chloro-5-(2-fluoro-phenyl)-pyrimidine (8.9 g, 42.85 mmol) and DIPEA (29 mL, 171.4 mmol) in n-BuOH (50 mL) were stirred at 90°C for 16 h. The reaction mixture was concentrated and the remnant purified by flash column chromatography [silica; DCM with 0.4% MeOH]. White solid. Yield: 4 g. HPLC (method 1 ): Rt = 3.68 min, m/z [M+H]+ = 348.2 (MW calc. 347.39). 100c) (1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)methyl methane- sulfonate
TEA (5 mL, 36.02 mmol) and methanesulfonyl chloride (2.2 mL, 28.8 mmol) were added to compound 100b (5 g, 14.4 mmol) in DCM (150 mL). The resulting mixture was stirred at RT for 2 h, then poured onto cold water and extracted with DCM (3x 30 mL). The combined organic layers were dried over Na2S04 and evaporated to dryness. The raw product was purified by flash column chromatography [silica; hexane with 10% EtOAc]. White solid. Yield: 2.4 g.
10Od) (1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)methanamine
Compound 100c (1 g, 2.35 mmol) in THF (5 mL) and aqueous ammonia (5 mL) was stirred at 50°C for 6 h. The reaction mixture was cooled and concentrated. DCM (30 mL) was added and the mixture was washed with saturated NH4CI solution and brine. The organic layer was dried over Na2S04, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography [silica; DCM with 5-7% MeOH]. White solid. Yield: 0.40 g. HPLC (method 1 ): Rt = 3.03 m/z [M+H]+ = 346.8 (MW calc. 346.4).
10Oe) N-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl) methyl) acetamide TEA (0.3 mL, 2.6 mmol) and acetyl chloride (0.081g, 1.04 mmol) were added to a solution of compound 100d (0.3 g, 0.86 mmol) in DCM (10 mL) and the resulting mixture was stirred for 3 h at RT. The mixture was washed with saturated NH4CI solution and brine and the organic layer was dried over Na2S04 and evaporated to dryness. The raw product was purified by flash column chromatography [silica; DCM with 0.5-1 .5% MeOH]. White solid. Yield: 0.10 g. HPLC (method 1 ): Rt = 1.74 min, m/z [M+H]+ = 389.1 (MW calc. 388.44). H NMR (400 MHz, DMSO-d6, δ ppm): 8.81 (s, 2H), 8.32 (s, 1 H), 8.28 (s, 1 H), 7.69-7.65 (m, 1 H), 7.45 (d, 1 H, J = 5.7 Hz), 7.38-7.32 (m, 2H), 6.84 (d, 1 H, J = 7.4 Hz), 6.77 (d, 1 H, J =7.6 Hz), 4.23 (s, 4H), 1.86 (s, 3H), 1 .15 (s, 2H), 1.06 (s, 2H).
Example 101 : N-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin1-6'-yl) methyl)-2- hydroxyacetamide
Figure imgf000095_0001
TBTU coupling of compound 100d with 2-hydroxyacetic acid. White solid. Yield: 60 mg. HPLC (method 1 ): Rt = 3.34 min, m/z [M+H]+ = 405.2 (MW calc. 404.44). H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.78 (s, 2H), 8.32 (s, 1 H), 7.76 (s, 1 H), 7.65-7.61 (m, 1 H), 7.43 (s, 1 H), 7.34-7.29 (m, 2H), 6.89 (d, 1 H, J = 7.2 Hz), 6.75 (d, 1 H, J = 7.6 Hz), 5.05 (bs, 1 H), 4.36 (d, 2H, J = 5.6 Hz), 4.26 (s, 2H), 3.89 (d, 2H, J = 5.2 Hz), 1.16 (s, 2H), 1.08 (s, 2H).
Example 102: 2-(((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)methyl)- amino)-2-methylpropan-1-ol
Figure imgf000095_0002
Prepared from 2-amino-2-methylpropan-1-ol and 100c under use of K2C03 as base and acetonitrile as solvent. White solid. Yield: 100 mg. HPLC (method 5): Rt = 1.50 min, m/z [M+H]+ = 419.2 (MW calc. 418.51 ). H NMR (400 MHz, DMSO-d6, δ ppm): 8.81 (s, 2H), 8.32 (s, 1 H), 7.69-7.65 (m, 1 H), 7.45-7.42 (m, 1 H), 7.38-7.31 (m, 2H), 6.94 (d, 1 H, J = 7.6 Hz), 6.74 (d, 1 H, J = 7.6 Hz), 4.55 (bs, 1 H), 4.23 (s, 2H), 3.62 (s, 2H), 3.23 (bs, 2H), 1.53 (bs, 1 H), 1.16-1 .13 (m, 2H), 1.06-1.03 (m, 2H), 1.01 (s, 6H).
Example 103: 2-Hvdroxy-N-methyl-N-((1 '-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro [cvclopropane-1 ,31- indolinl-6'-yl)methyl)acetamide
Figure imgf000095_0003
103a) (1 '-(5-Bromopyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)methanol Spiro[cyclopropane-1 ,3'-indolin]-6'-ylmethanol 100a (5.0 g, 28.5 mmol), 2-chloro-5-bromo-pyrimidine (8.27 g, 42.85 mmol) and DIPEA (29 mL, 171.4 mmol) in n-BuOH (50 mL) were stirred at 90°C for 16 h. The solvent was evaporated and the residue purified by flash column chromatography [silica; DCM with 0.4% MeOH]. White solid. Yield: 4 g (42%). HPLC (method 1 ): Rt = 3.46 min, m/z [M+H]+ = 333.9 (MW calc. 332.20).
103b) (1 '-(5-Bromopyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)methyl methanesulfonate
TEA (1.1 mL, 7.5 mmol) and methanesulfonyl chloride (0.5 mL, 6 mmol) were added to a solution of 103a (1 g, 3 mmol) in DCM (30 mL). The resulting mixture was stirred at RT for 2 h and then poured onto cold water and extracted with DCM (3x 30 mL). The combined organic layers were dried over Na2S04 and evaporated to dryness. The raw product was purified by flash column chromatography (silica; hexane with 10% EtOAc]. White solid. Yield: 0.3 g (25%)
103c) 1-(1 '-(5-Bromopyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)-N-methylmethanamine
Compound 103b (8.8g, 21.6 mmol) was added to MeNH2 in THF (2M, 60 mL) and the resulting mixture was stirred at 50°C for 6 h. The mixture was cooled and concentrated. The residue was diluted with MeOH/DCM (1 :9; 30 mL) and washed with saturated NH4CI solution and brine. The organic layer was dried over Na2S04, the solvents were removed under reduced pressure and the remnant was purified by flash column chromatography [silica; DCM with 5-7% MeOH]. Light brown solid. Yield: 2.2 g (29%). HPLC (method 1 ): Rt = 2.98 min, m/z [M+H]+ = 344.7 (MW calc. 344.06).
103d) N-Methyl-1 -(1 W5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin1-6'-yl)methan- amine
PdCI2(dppf) (122 mg, 0.173 mmol) was added at RT to a solution 103c (1.2 g, 3.47 mmol), bis- (pinacolato)diboron (1.76 g, 6.94 mmol) and potassium acetate (1 g, 12.14 mmol) in dry dioxane (30 mL) that was stirred under Ar. The reaction mixture was heated at 90°C for 30 min. 4-Methyl-2-bromo-pyridine (0.871 g, 5.2 mmol), aqueous K2C03 solution (2M, 7 mL) and tetrakis(triphenylphosphine)palladium(0) (173 mg, 0.173 mmol) were added and the reaction mixture was stirred at 90°C for further 5 h. The mixture was cooled to RT and filtered through a sintered funnel. The filtrate was concentrated and the residue purified by flash column chromatography [silica; DCM with 1.5% MeOH]. White solid. Yield: 1.0 g (80%). HPLC (method 1 ): Rt = 2.84 min, m/z [M+H]+ = 358.2 (MW calc. 357.45).
103e) 2-Hvdroxy-N-methyl-N-((1 '-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro [cyclopropane-1 ,3'-indolin1- 6'-yl)methyl)acetamide
TBTU (0.323 g, 1 mmol), NMM (0.26 mL, 2.1 mmol) and hydroxy-acetic acid (70 mg, 0.92 mmol) were added to a solution of compound 103d (0.3 g, 0.84 mmol) in DMF (10 mL). The resulting mixture was stirred at RT for 16 h, then poured onto ice-cold water, stirred for 15 min and extracted with EtOAc (3x 20 mL). The combined organic layers were washed with saturated NaHC03 solution, saturated NH4CI solution and brine, dried over Na2S04 and concentrated. The raw product was purified by column chromatography [silica; DCM with 1-2% MeOH]. White solid. Yield: 190 mg (54%). HPLC (method 5): Rt = 1.62 min, m/z [M+H]+ = 416.2 (MW calc. 415.49). H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.20 (s, 2H), 8.50-8.51 (m, 1 H), 8.32 (s, 1 H), 7.79 (s, 1 H), 7.16 (d, 1 H, J = 4.4 Hz), 6.78-6.82 (m, 2H), 4.54 (s, 2H), 4.28 (s, 2H), 4.19 (s, 3H), 2.90 (s, 3H), 2.41 (s, 3H), 1.14-1.17 (m, 2H), 1.09-1.12 (m, 2H).
Example 104: N-Methyl-N-((1 5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-in vDimethvDacetamide
Figure imgf000097_0001
Prepared from compound 103d. White solid. Yield: 200 mg. HPLC (method 1 ): Rt = 3.45 min, m/z [M+H]+ = 399.9 (MW calc. 399.4). H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.20 (s, 2H), 8.50-8.51 (m, 1 H), 8.31 (s,1 H), 7.80 (s, 1 H), 7.16 (d, 1 H, J = 4.4 Hz), 6.75-6.81 (m, 2H), 4.54 (s, 2H), 4.28 (s, 2H), 2.92-2.95 (m, 3H), 2.41 (s, 3H), 2.10 (s, 3H), 1.14-1.17 (m, 2H), 1.09-1.12 (m, 2H).
Example 105: 2-Methyl-2-(methyl((1 '-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'- indolinl-6'-yl)methyl)amino)propan-
Figure imgf000097_0002
Prepared from compound 103b and 2-methyl-2-(methylamino)propan-1-ol in analogy to the protocols of example 103. Pale yellow solid. Yield: 60 mg. HPLC (method 5): Rt = 1.43 min, m/z [M+H]+ = 430.1 (MW calc. 429.56). H NMR (400 MHz, DMSO-d6, δ ppm): 9.22 (s, 2H), 8.51 (d, 1 H, J = 5.2 Hz), 8.35 (s, 1 H), 7.87 (s, 1 H), 7.18 (d, 1 H, J = 4.8 Hz ), 6.92 (d, 1 H, J = 7.6 Hz), 6.73 (d, 1 H, J = 7.6 Hz), 4.33 (bs, 1 H), 4.24 (s, 2H), 3.54 (s, 2H), 3.40 (d, 2H, J = 4.8 Hz ), 2.38 (s,3H), 2.06 (s, 3H), 1.16-1.15 (m, 2H), 1 .10-1.06 (m, 8H).
Example 106: 2-Hvdroxy-N-((1 '-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro [cyclo- propane-1 ,3'-indolinl-6'-yl)methyl)-N-methylacetamide
Figure imgf000098_0001
Synthesized in analogy to example 103. White solid. Yield: 80 mg. HPLC (method 1): Rt = 2.98 min, m/z [M+H]+ = 460.1 (MW calc.459.54). H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.21 (s, 2H), 8.56 (d, 1H, J = 4.8 Hz), 8.33 (s, 1H), 7.97 (s, 1H), 7.42 (d, 1H, J = 4.7 Hz), 6.82-6.76 (m, 2H), 4.95 (s, 1H), 4.54 (s, 2H), 4.28 (s, 2H), 4.21 (d, 2H, J = 7.6 Hz), 2.90 (s, 3H), 1.52 (s,6H), 1.18 (s,2H), 1.12-1.09 (m, 2H).
Example 107: N-((1 5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1,3'- indolinl-6'-yl)methyl)-N-methylacetami
Figure imgf000098_0002
Synthesized in analogy to example 104. White solid. Yield: 100 mg. HPLC (method 1): Rt = 3.09 min, m/z [M+H]+ = 444.1 (MW calc.443.54). H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.21 (s, 2H), 8.57 (d, 1H, J = 4.4 Hz), 8.32 (s,1H), 7.97 (s, 1H),7.42 (d, 1H, J = 4.4 Hz), 6.79 (d, 2H, J = 5.9 Hz), 4.95 (s, 1H), 4.53 (s, 2H), 4.28 (s, 2H), 2.95 (s, 3H), 2.09 (s, 3H), 1.52 (s, 6H), 1.17-1.13 (m, 2H), 1.09 (s, 2H). Example 108: 2-(((1'-(5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1,3'- indolinl-6'-yl)methyl)(methyl)amino)-2-methylpropan-1-ol
Figure imgf000098_0003
Synthesized in analogy to example 104. White solid. Yield: 60 mg. HPLC (method 5): Rt = 1.39 min, m/z [M+H]+ = 474.3 (MW calc. 473.61 ). H NMR (400 MHz, DMSO-d6, δ ppm): 9.25 (s, 2H), 8.58 (d, 1 H, J = 4.8 Hz), 8.35 (s, 1 H), 8.01 (s, 1 H), 7.44 (d, 1 H, J = 4.4 Hz), 6.92 (d, 1 H, J = 7.6 Hz), 6.74 (d, 1 H, J = 7.2 Hz), 5.30 (s, 1 H), 4.34 (bs, 1 H), 4.25 (s, 2H), 3.54 (s, 2H), 3.40 (d, 2H, J = 4.7 Hz), 2.06 (s, 3H), 1.48 (s, 6H), 1.22-1.15 (m, 2H), 1 .06 (s, 8H).
Example 109: 2-(4-Fluoro-3-(2-(6'-(1-(methylamino)cvclopropyl)spiro[cvclopropane-1 ,3'-indolinl-1 '- yl)pyrimidin-5-yl)phenyl)propan-2-ol
Figure imgf000099_0001
109a) tert-Butyl 6'-bromospiro[cyclopropane-1 ,3'-indolinel-1 '-carboxylate
6'-Bromospiro[cyclopropane-1 ,3'-indoline] (10.0 g, 44.6 mmol, 1 eq), TEA (10.0 ml, 66.9 mmol, 1.5 eq) and di-tert-butyl dicarbonate (14.5 g, 66.9 mmol, 1.5 eq) in THF (100.0 ml) were stirred at RT for 16 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography [100-200 mesh silica gel; hexane with 5% EtOAc]. White solid. Yield: 13.0 g (90%).
109b) tert-Butyl 6'-cvanospiro[cyclopropane-1 ,3'-indolinel-1 '-carboxylate
Tetrakis(triphenylphosphine)palladium(0) (2.51 g, 2.16 mmol, 0.05 eq) was added at RT to a solution of compound 109a (14.0 g, 43.2 mmol, 1 eq) and zinc cyanide (5.0 g, 43.2 mmol, 1 .0 eq) in DMF (150 ml) stirred under Ar. The reaction mixture was heated at 140°C for 16 h in a sealed tube, then diluted with water (500 ml) and extracted with EtOAc (3x 500 ml). The combined organic layers were washed with water (500 ml) and brine (500 ml), dried over anhydrous Na2S04 and evaporated. The raw product was purified by flash column chromatography [100-200mesh silica gel; hexane/EtOAc = 7:3]. Solid. Yield: 8.0 g (55%). 109c) tert-Butyl 6'-(1-aminocvclopropyl)spiro[cyclopropane-1 ,3'-indolinel-1 '-carboxylate
Ethyl magnesium bromide (9.8 ml, 29.63 mmol, 4 eq) was slowly added at -78°C to a stirred solution of titanium(IV) isopropoxide (4.2 g, 14.81 mmol, 2 eq) in THF (50 ml) and stirring was continued at this temperature for 1 h. Compound 109b (2.0 g, 7.41 mmol, 1 eq) in THF (30 ml) was slowly added and the reaction mixture was stirred for 1 h under warming to RT. The mixture was cooled to -78°C and boron trifluoride diethyl etherate was added. The reaction mixture was stirred for 1 h at RT, then quenched at 0°C with saturated NH4CI, stirred for 10 min and extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine (40 ml), dried over Na2S04 and concentrated. The residue was purified by column chromatography [230-400mesh silica gel, DCM with 1.3% MeOH]. Brown solid. Yield: 1 .37 g (62%).
109d) tert-Butyl 6'-(1-(((benzyloxy)carbonyl)amino)cvclopropyl)spiro[cvclopropane-1 ,3'-indolinel-1 '- carboxylate
DIPEA (20 ml, 109.99 mmol, 3 eq) followed by benzyl chloroformate (8.0 ml, 54.99 mmol, 1 .5 eq) were added at 0°C to compound 109c (1 1 g, 36.67 mmol, 1 eq) in THF (1 10 ml) 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), and dried over Na2S04. The solvent was removed under reduced pressure and the residue was purified by column chromatography [100-200 mesh silica, hexane/EtOAc = 95:5]. White solid. Yield: 14g (88%).
109e) tert-Butyl 6'-(1-(((benzyloxy)carbonyl)(methyl)amino)cvclopropyl)spiro[cvclopropane-1 ,3'-indolinel- 1 '-carboxylate
NaH (1.88 g, 39.04 mmol, 1.5 eq) was added portion wise at 0°C to a stirred solution of compound 109d (1 1.3 g, 26.02 mmol, 1 eq) in DMF (1 10 ml). After stirring for 20 min, methyl iodide (4.9 ml, 78.07 mmol, 3 eq) was added and stirring was continued for 2 h. The reaction mixture was quenched with ice and extracted with EtOAc (3x 200 ml). The organic phase was 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, hexane/EtOAc = 95:5]. Yield: 1 1 .6 g (98%)
109f ) Benzyl methyl(1-(spiro[cvclopropane-1 ,3'-indolin1-6'-yl)cvclopropyl)carbamate
A solution of compound 109e (10 g, 22.29 mmol, 1 eq) in TFA (25 ml) and DCM (100 ml) was stirred at RT for 3 h. The mixture was concentrated at the rotary evaporator and the remnant was washed with diethyl ether and dried. White solid. Yield: 5.7 g (73%).
109g) Benzyl (1 -(1 '-(5-bromopyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolin1-6'-yl)cvclopropyl) (imethyl)- carbamate
Compound 109f (5 g, 1 eq, 14.35 mmol), 5-bromo-2-chloropyrimidine (5.5 g, 2 eq, 28.69 mmol) and DIPEA (17.7 ml, 7 eq, 100.44 mmol) in n-butanol (40 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 through a sintered funnel and washed with hexane (2x 100 ml) and water (100 ml). Light yellow solid. Yield: 4.0 g (55%).
109h) Benzyl methyl(1-(1 '-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)spiro[cvclo- propane-1 ,3'-indolin1-6'-yl)cvclopropyl)carbamate
PdCI2(dppf) (40.8 mg, 0.05 mmol, 0.05 eq) was added to compound 109g (505 mg, 1 mmol, 1 eq), potassium acetate (294 mg, 3.0 mmol, 3 eq) and bis(pinacolato)diboron (508 mg, 2.0 mmol, 2.0 eq) in dioxane (10 ml) stirred under an inert atmosphere and the reaction mixture was refluxed for 16 h. The mixture was evaporated under reduced pressure and the residue was used in the next step without further purification. Yield: 550 mg (99%). 109i) Benzyl (1 -(1 '-(5-(2-fluoro-5-(2-hvdroxypropan-2-yl)phenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'- indolinl-6'-yl)cvclopropyl)(methyl)carbamate
Tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.0166 mmol, 0.05 eq) was added to a suspension of compound 1 19h (0.184 g, 0.333 mmol, 1 eq), 2-(3-bromo-4-fluoro-phenyl)-propan-2-ol (1 17 mg, 0.499 mmol, 1.5 eq) and 20% aqueous K2C03 solution (1 ml) in 1 ,4-dioxane (20 ml) kept under Ar and the reaction mixture was stirred for 16 h at 100°C. The reaction mixture was cooled to RT, filtered through a plug of celite and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 ml) and washed with water (2x 20 ml) and brine (20 ml). The organic layer was dried over anhydrous Na2S04 and concentrated. The raw product was purified by column chromatography [230-400 mesh silica gel; DCM/MeOH = 95/5]. White solid. Yield: 50 mg. MS: m/z: [M+H]+ = 579.0.
109i) 2-(4-Fluoro-3-(2-(6'-(1-(methylamino)cvclopropyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5- yl)phenyl)propan-2-ol
Compound 1 19i (410 mg, 0.709 mmol) in ethanol (30 ml) was hydrogenated with Pd(OH)2 on carbon (Pearlman's catalyst, 20 wt. %, 45 mg) as catalyst under stirring at RT for 1 h. The catalyst was filtered off (Celite), the filter was rinsed with ethanol (100 ml) and the filtrate was evaporated. Purification of the residue by column chromatography [230-400mesh silica, DCM with 2% MeOH] provided the target compound as white solid. Yield: 255 mg (80%). MS: m/z: [M+H]+ = 445.2. H NMR (400 MHz, DMSO-d6, δ ppm): 8.81 (s, 2H), 8.35 (s, 1 H), 7.68-7.66 (m, 1 H), 7.51-7.50 (m, 1 H), 7.26 (t, J = 8.8 Hz, 1 H), 6.93 (d, J = 7.8 Hz, 1 H), 6.73 (d, J = 7.7 Hz, 1 H), 5.12 (s, 1 H), 4.23 (s, 2H), 2.15 (s, 3H), 1 .89 (s, 3H), 1.14-1.06 (m, 4H), 0.88-0.82 (m, 4H).
The examples 1 10 and 1 1 1 were prepared in analogy to synthesis example 109. Example 1 10: 1-(1 '-(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)-N- methylcyclopropanamine
Figure imgf000101_0001
White solid: Yield: 41 1 mg. MS: m/z: [M+H]+ = 400.1. H NMR (400 MHz, DMSO-d6, δ ppm): 9.28 (s, 2H), 8.45 (d, J = 5.6 Hz, 1 H), 8.38 (s, 1 H), 7.61 (s, 1 H), 6.96-6.92 (m, 2H), 6.75 (d, J = 7.5 Hz, 1 H), 4.24 (s, 2H), 3.92 (s, 3H), 2.16 (s, 3H), 1.89 (s, 3H), 1.14-1.06 (m, 4H), 0.88-0.82 (m, 4H).
Example 1 1 1 : 2-(2-(2-(6'-(1-(Methylamino)cvclopropyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5- yl)pyridin-4-yl)propan-2-ol
Figure imgf000102_0001
White solid: Yield: 232 mg. MS: m/z: [M+H]+ = 428.2. H NMR (400 MHz, DMSO-d6, δ ppm): 9.28 (s, 2H), 8.57 (d, J = 4.8 Hz, 1H), 8.39 (s, 1H), 8.03 (s, 1H), 7.44 (d, J = 3.9 Hz, 1H), 6.95 (d, J = 7.7 Hz, 1H), 6.73 (d, J = 7.7 Hz, 1H), 5.28 (s, 1H), 4.25 (s, 2H), 3.26 (s, 1H), 2.17 (s, 3H), 1.49 (s, 6H), 1.15-1.06 (m, 4H), 0.88-0.83 (m, 4H).
Example 112: N-(1-(1 5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1,3'-indolinl-6'-yl)cvclo- propyD-N-methylacetamide
Figure imgf000102_0002
Acetylation of example 54. White solid: Yield: 183 mg. MS: m/z: [M+H]+ = 429.1. H NMR (400 MHz, DMSO-d6, δ ppm): 8.78 (s, 2H), 8.12 (s, 1H), 7.69-7.66 (m, 1H), 7.46-7.43 (m, 1H), 7.38-7.31 (m, 2H), 6.77 (d, J = 7.8 Hz, 1H), 6.55 (d, J = 7.8 Hz, 1H), 4.23 (s, 2H), 2.94 (s, 3H), 1.97 (s, 3H), 1.15 (bs, 3H), 1.26-1.20 (m,1H), 1.15-1.07 (m, 4H). Example 113: N-(1-(1W5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1,3'-indolinl-6'- vDcyclopropyD-N-methylacetamide
Figure imgf000102_0003
Acetylation of example 110. White solid: Yield: 270 mg. MS: m/z: [M+H]+ = 442.4. H NMR (400 MHz, DMSO-d6, δ ppm): 9.21 (s, 2H), 8.46 (s,1H), 8.24 (s, 1H), 7.51 (s, 1H), 6.91 (s, 1H), 6.74 (s, 1H), 6.60 (s, 1H), 4.27 (s, 2H), 3.94 (s, 3H), 3.00 (s, 3H), 2.03 (s, 3H), 1.50-1.41 (m, 4H), 1.16-1.08 (m, 4H). Example 1 14: 2-(1 5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopra^
propan-2-amine
Figure imgf000103_0001
1 14a) 2-(1 5-Bromopyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)propan-2-ol
Compound 59a (0.2 g, 0.56 mmol, 1 eq) in dry THF (5 ml) was added drop wise to a solution of methylmagnesium bromide (0.74 ml, 2.23 mmol, 4 eq., 3M in Et20) in THF (5 ml) stirred at 0°C. The mixture was warmed to RT, stirred for 1 h and then quenched by drop-wise addition of saturated aqueous NH4CI solution under cooling with an ice bath. The mixture was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by column chromatography [100-200 mesh silica gel; hexane/EtOAc = 4:1 ]. White solid. Yield: 0.13 g (65%). MS: m/z: [M+H]+ = 360.0.
1 14b) 2-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)propan-2-ol
Tetrakis(triphenylphosphine)palladium(0) (0.048 g, 0.042 mmol, 0.05 eq) was added at RT to compound 1 14a (0.3 g, 0.835 mmol, 1 eq), 2-fluorophenylboronic acid (0.1 17 g, 0.835 mmol, 1 eq) and K2C03 (1.25 ml, 2M, aqueous) in 1 ,4-dioxane (10 ml) stirred under Ar. The reaction mixture was stirred at 90°C for 16 h, cooled and filtered through a plug of celite. The filtrate was concentrated and the remnant purified by silica gel column chromatography [100-200 mesh silica gel; hexane/EtOAc = 9:1]. White solid. Yield: 0.21 g (67%). MS: m/z: [M+H]+ = 376.4.
1 14c) 6'-(2-Azidopropan-2-yl)-1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline1 Sodium azide (0.073g, 1.1 14 mmol, 2 eq) was added to a stirred solution of compound 1 14b (0.2 g, 0.557 mmol, 1 eq) in DCM (10 ml). The reaction mixture was cooled to 0°C, TFA (0.341 ml, 4.456 mmol, 8 eq) in DCM (3 ml) was added drop wise over 15 min and stirring was continued at 0°C for 1 h. The reaction mixture was then quenched with aqueous ammonia solution (25%) and the organic layer was separated and washed with 10% aqueous K2HP04 solution and brine. The solvent was removed under reduced pressure and the raw product thus obtained (0.18 g) was used in the next step without further purification. MS: m/z: [M+H]+ = 401 .0.
1 14d) 2-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin1-6'-yl)propan-2-amine
Pd/C (10%, 0.223 g, 2.1 mmol, 1 eq) was added to a stirred solution of compound 1 14c (0.840 g, 2.1 mmol, 1 eq) in EtOAc (25 ml). The reaction tube was flushed with H2 gas from a balloon and stirred for 2 h at RT. The mixture was then filtered through plug of celite and the filtrate was evaporated. The raw product (0.61g) was used in the next step without further purification.
1 14e) Benzyl (2-(1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)propan -2- yl Carbamate
DIPEA (0.54 ml, 3.092 mmol, 2 eq) followed by benzyl chloroformate (0.22 ml, 1.546 mmol, 1 eq) was added at 0°C to a stirred solution of compound 1 14d (0.600 g, 1.546 mmol, 1 eq) in THF (20 ml). The reaction mixture was warmed slowly to RT and stirred for another 2 h. The mixture was then diluted with EtOAc, washed with saturated aqueous NaHC03 solution and brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by column chromatography [100-200 mesh silica gel; hexane/EtOAc = 4:1 ]. Light yellow gum. Yield: 0.47 g (57%). MS: m/z: [M+H]+ = 509.4.
1 14f ) Benzyl (2-(1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin1-6'-yl) propan-2-vD- (methyl)carbamate
NaH (60% in mineral oil, 0.074 g, 1.85 mmol, 2 eq) was added at 0°C to a stirred solution of compound 1 14e (0.47 g, 0.925 mmol, 1 eq) in DMF (10 ml). The resulting mixture was warmed to RT over 30 min, methyl iodide (1.0 ml, excess) was added after cooling to 0°C and the mixture was stirred for another 3 h under warming to RT. The reaction mixture was diluted with EtOAc (30 ml), washed with cold water (3x 25 ml) and brine (20 ml) and dried over anhydrous Na2S04. The solvent was evaporated and the residue purified by column chromatography [100-200 mesh silica gel; hexane/EtOAc = 4:1 ]. Light yellow solid. Yield: (0.30 g, 62%). MS: m/z: [M+H]+ = 523.2.
1 14g) 2-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolin1-6'-yl)-N-methyl-propan-2- amine
Compound 1 14f (0.300 g, 0.574 mmol, 1 eq) in EtOAc (15 ml) was hydrogenated for 2 h at RT with Pd/C (10%, 0.061 g, 0.574 mmol, 1 eq) as catalyst and a balloon filled with H2 as hydrogen source. The reaction mixture was then filtered through a plug of celite, the filtrate was concentrated, and the remnant was purified by preparative HPLC affording the target compound as acetate salt. Yield: 0.1 g (39%). MS: m/z: [M+H]+ = 389.1. H NMR (400 MHz, DMSO-d6, δ ppm): 8.82 (s, 2H), 8.51 (s, 1 H), 7.68 (d, J = 7.6 Hz, 1 H), 7.45-7.42 (m, 1 H), 7.38-7.31 (m, 2H), 7.04 (d, J = 8.0 Hz, 1 H), 6.74 (d, J = 8.0 Hz, 1 H), 4.23 (s, 2H), 2.02 (s, 3H), 1 .88 (s, 3H), 1.38 (s, 6H), 1.14-1.09 (m, 2H), 1.08-1.05 (m, 1 H).
Example 1 15: 2-(1 '-(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin1-6'-yl)-N- methylpropan-2-amine
Figure imgf000105_0001
Prepared analogously to synthesis example 1 14. White solid: Yield: 30 mg (acetate salt). MS: m/z: [M+H]+ = 402.2. Example 1 16: 2-(2-(2-(6'-(2-(Methylamino)propan-2-yl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl) pyrimidin-5- yl)pyridin-4-yl)propan-2-ol
Figure imgf000105_0002
Prepared from 1 14a and methyl 2-bromoisonicotinate in analogy to example 1 14. Yield: 0.08 g (39%). MS: m/z: [M+H]+ = 430.3. H NMR (400 MHz, DMSO-d6, δ ppm): 9.27 (s, 2H), 8.58-8.56 (m, 2H), 8.03 (s, 1 H), 7.45 (d, J = 5.2 Hz, 1 H), 7.05 (d, J = 8.0 Hz, 1 H), 6.75 (d, J = 8.0 Hz, 1 H), 5.29 (s, 1 H), 4.26 (s, 2H), 2.03 (s, 3H), 1.49 (s, 6H), 1.38 (s, 6H), 1.15 (s, 2H), 1.07 (s, 2H).
Example 1 17: 2-(2-(2-(6'-(2-((2-Hvdroxyethyl)amino)propan-2-yl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)- pyrimidin-5-yl)pyridin-4-yl)propan-2
Figure imgf000105_0003
Prepared from 1 14a and methyl 2-bromoisonicotinate in analogy to example 1 14. Yield: 0.06 g. MS: m/z: [M+H]+ = 460.3. H NMR (400 MHz, DMSO-d6, δ ppm): 9.27 (s, 2H), 8.59-8.57 (m, 2H), 8.03 (s, 1 H), 7.44 (dd, J1 = 5.2 Hz, J2 = 1.2 Hz, 1 H), 7.05 (d, J = 8.0 Hz, 1 H), 6.75 (d, J = 8.0 Hz, 1 H), 5.30 (s, 1 H), 4.40 (s, 1 H), 4.25 (s, 2H), 3.42 (m, 1 H), 2.34 (m, 2H), 1.48 (s, 6H), 1.40 (s, 6H), 1.16 (s, 2H), 1.07(s, 2H).
Example 1 18: 2-(2-(2-(6W1-((2-Hvdroxyethyl)(methyl)amino)cvclopropyl)spiro[cvclopropane-1 ,3'-indolin1- 1 '-yl)Pyrimidin-5-yl)pyridin-4-yl)prop
Figure imgf000106_0001
Prepared from 109e in analogy to example 109.. White solid. Yield: 45 mg. MS: m/z: [M+H]+ = 472.0. H NMR (400 MHz, DMSO-d6, δ ppm): 9.28 (s, 2H), 8.57 (d, J = 5 Hz, 1 H), 8.40 (s, 1 H), 8.04 (s, 1 H), 7.44 (d, J = 4.7 Hz, 1 H), 6.86 (d, J = 7.1 Hz, 1 H), 6.76 (d, J = 7.6 Hz, 1 H), 5.29 (s, 1 H), 4.26-4.24 (m, 3H), 3.42-3.41 (m, 2H), 2.23 (s, 3H), 1.49 (s, 6H), 1 .17 (s, 2H), 1.07 (s, 2H), 0.89 (s, 2H), 0.77 (s, 2H).
Example 1 19: 2-(2-(2-(6'-(1-((2-Hvdroxyethyl)amino)cvclopropyl)spiro[cvclopropane-1 ,3'-indolinl-1 '-yl)-
Pyrimidin-5-yl)pyridin-4-yl)propan-2
Figure imgf000106_0002
Prepared from 109d in analogy to example 109 (reactions g, h, i, and j followed by an alkylation with ethyl 2-bromoacetate and a LAH reduction as final step). White solid. Yield: 1 10 mg. MS: m/z: [M+H]+ = 458.4. H NMR (400 MHz, DMSO-d6, δ ppm): 9.28 (s, 2H), 8.57 (d, J = 5.2 Hz, 2H), 8.41 (s, 1 H), 8.02 (s, 1 H), 7.44 (d, J = 5.2 Hz, 1 H), 6.93 (d, J = 8.0 Hz, 1 H), 6.73 (d, J = 8.0 Hz, 1 H), 5.29 (s, 1 H), 4.36 (t, J = 5.2 Hz, 1 H), 4.25 (s, 2H), 3.39 (t, J = 5.2 Hz, 2H), 2.52 (m, 2H), 1.49 (s, 6H), 1 .15 (m, 2H), 1.07 (m, 2H), 0.90 (m, 2H), 0.85 (m, 2H).
Example 120: 2-(2-(2-(6'-(2-((2-Hvdroxyethyl)(methyl)amino)propan-2-yl)spiro[cyclopropane-1 ,3'-indolinl-
1 '-yl)Pyrimidin-5-yl)pyridin-4-yl)propan-2-ol
Figure imgf000107_0001
Prepared from 1 14a and methyl 2-bromoisonicotinate in analogy to example 1 14 (reactions b, c, d, e, f, and g, followed an alkylation with (2-bromoethoxy)(tert-butyl)dimethylsilane, a Grignard reaction with methyl magnesium bromide and a deprotection with TBAF). Yield: 0.07 g. MS: m/z: [M+H]+ = 474.4. H NMR (400 MHz, DMSO-d6, δ ppm): 9.27 (s, 2H), 8.63 (s, 1 H), 8.57 (d, J = 5.0 Hz, 1 H), 8.04 (s, 1 H), 7.44 (d, J = 5.0 Hz, 1 H), 7.08 (d, J = 7.6 Hz, 1 H), 6.74 (d, J = 7.6 Hz, 1 H), 5.30 (s, 1 H), 4.26 (s, 2H), 4.18 (m, 1 H), 3.43 (m, 1 H), 2.26 (m, 5H), 1.49 (s, 6H), 1.30 (s, 6H), 1.16 (s, 2H), 1 .07 (s, 2H).
Example 121 : 1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N-dimethylspiro[cvclopropane-1 ,3'-indolinel-6'- carboximidamide
Figure imgf000107_0002
121a) 1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinel-6'-carbonitrile
NaH (60% in oil, 0.4 g, 9.98 mmol) was added at 0°C to tert-butyl 6'-cyanospiro[cyclopropane-1 ,3'- indoline]-1 '-carboxylate 109b (0.85 g, 5.0 mmol) in DMF (17 mL). The mixture was stirred for 30 min at this temperature, 2-chloro-5-(2-fluoro-phenyl)-pyrimidine (1.562 g, 7.49 mmol) was added and stirring was continued at RT for 4 h. The reaction mixture was quenched with crushed ice and extracted with EtOAc (3x 50 mL). The combined organic layers were dried over Na2S04 and evaporated. The remnant was purified by flash column chromatography [silica, hexane with 7% EtOAc]. White solid. Yield: 1.2 g (70%). HPLC (method 1 ): Rt = 4.19 min, m/z [M+H]+ = 343.2 (MW calc. 342.37).
121 b) 1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N-dimethylspiro[cyclopropane-1 ,3'-indolinel-6'- carboximidamide
Dry hydrogen chloride gas was bubbled into a solution of compound 121a (0.25 g, 0.73 mmol) in MeOH (15 mL) for 30 min. The resulting mixture was stirred for 16 h at RT. The solvent was evaporated and the material was suspended in MeOH (25 mL). Dimethylamine (2M in THF, 1.8 mL, 3.74 mmol) was added to the suspension and the mixture was heated at 70°C for 30 min resulting in a clear solution that was further stirred at RT for 24 h. The solvents were distilled off and the residue was submitted for preparative HPLC purification. The solvents of the product containing fractions were evaporated and the raw product was dissolved in DCM/MeOH = 95:5 and washed with saturated NaHC03 solution. The organic phase was dried over Na2S04, the solvents were evaporated and the remaining product was washed with ether. White solid. Yield: 0.1 1 g (39%). HPLC (method 5): Rt = 1.52 min, m/z [M+H]+ = 388.1 (MW calc. 387.45). H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.97 (bs, 1 H), 8.84 (s, 2H), 8.48 (s, 1 H), 7.66-7.62 (m, 1 H), 7.49-7.44 (m, 1 H), 7.36-7.31 (m, 2H), 7.12-7.01 (m, 2H), 4.35 (s, 2H), 3.18 (s, 6H), 1.29 (bs, 2H), 1 .25 (bs, 2H).
Example 122: (1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl) (morpholino)- methanimine
Figure imgf000108_0001
Prepared in analogy example to 121. White solid. Yield: 0.2 g. HPLC (method 1 ): Rt = 3.32 min, m/z [M+H]+ = 430.2 (MW calc. 429.49). H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.82 (s, 2H), 8.39 (s, 1 H), 7.66-7.62 (m, 1 H), 7.45-7.42 (m, 2H), 7.34-7.29 (m, 2H), 6.96 (d, 1 H, J = 7.5 Hz), 6.87 (d, 1 H, J = 7.5 Hz), 4.30 (s, 2H), 3.67 (bs, 4H), 3.35 (bs, 4H), 1 .22 (s, 2H), 1 .15 (s, 2H).
Example 123: N-(1 '-(5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'- indolinl-6'-yl)acetamide
Figure imgf000108_0002
Compound 96b was transferred into a pinacol boronic ester that was coupled with 2-(2-bromopyridin-4- yl)propan-2-ol (protocol 3c), subsequent cleavage of the protecting group with TFA (protocol 96d) and acetylation provided the target compound. Light yellow solid. Yield: 0.07 g. HPLC (method 1 ): Rt = 2.95 min, m/z [M+H]+ = 416.3 (MW calc. 415.49). H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.53 (s, 1 H), 9.19 (s, 2H), 8.57 (t, 2H, J = 4.7 Hz), 7.96 (s, 1 H), 7.42-7.41 (m, 1 H), 7.24 (d, 1 H, J = 7.9 Hz), 6.70 (d, 1 H, J = 8.1 Hz), 4.94 (s, 1 H), 4.27 (s, 2H), 2.50 (s, 3H), 1.52 (s, 6H), 1.14 (s, 2H), 1.06 (s, 2H). Example 124: 3-Hvdroxy-N-(1 W5-(4-(2-hvdroxypropan-2-yl)pyridin-2-ylto^
1 ,3'-indolinl-6'-yl)propanamide
Figure imgf000109_0001
TBTU coupling of 2-(2-(2-(6'-aminospiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-yl)propan- 2-ol (see example 123) with 3-((tert-butyldimethylsilyl)oxy)propanoic acid followed by deprotection with TBAF in THF. Light yellow solid. Yield: 55 mg. HPLC (method 1 ): Rt = 2.83 min, m/z [M+H]+ = 446.3 (MW calc. 445.51 ). H NMR (400 MHz, DMSO-d6, δ ppm): 9.48 (s, 1 H), 9.20 (s, 2H), 8.58-8.57 (m, 2H), 7.97 (s, 1 H), 7.43 (d, 1 H, J = 4.9 Hz), 7.26 (d, 1 H, J = 8.1 Hz), 6.71 (d, 1 H, J = 8 Hz), 4.93 (bs, 1 H), 4.27 (s, 3H), 3.77 (t, 2H, J = 6.3 Hz), 2.53 (s, 2H), 1.52 (s, 6H), 1.14-1.06 (m, 4H).
Example 125: 3-Hvdroxy-N-(1 W5-(pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)- propanamide
Figure imgf000109_0002
Prepared from compound 96b in analogy to example 124. Light yellow solid. Yield: 0.06 g. HPLC (method 1 ): Rt = 2.93 min, m/z [M+H]+ = 387.9 (MW calc. 387.43). H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.51 (s, 1 H), 9.20 (s, 2H), 8.67-8.66 (m, 1 H), 8.54 (s, 1 H), 7.96-7.94 (m, 1 H), 7.87 (t, 1 H, J = 7.8 Hz), 7.34-7.27 (m, 2H), 6.71 (d, 1 H, J = 8.2 Hz), 4.27 (s, 3H), 3.79-3.74 (m, 2H), 2.52 (s, 2H), 1.14-1 .06 (m, 4H). Intermediate 2: tert-Butyl (1 '-(5-bromopyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)(methyl)- carbamate (lnt-2)
Figure imgf000109_0003
r Compound 96b (2 g, 4.79 mmol) was added portion wise at 0°C to a suspension of NaH (230 mg, 5.75 mmol) in DMF (15 mL). The mixture was stirred for 1 h at this temperature, methyl iodide (0.32 mL, 5.27 mmol) was added and stirring was continued for 1 h. The reaction mixture was quenched with crushed ice and extracted with MTBE (3x 50 mL). The combined organic layers were dried over Na2S04, the solvent was evaporated and the residue purified by column chromatography [100-200 mesh silica; hexane/EtOAc = 9: 1]. Light yellow solid. Yield: 1.6 g (77%). HPLC (method 5): Rt = 1.96 min, m/z [M+H]+ = 433.2 (MW calc. 431.33).
Example 126: N-(1 '-(5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'- indolinl-6'-yl)-N-methylacetamide
Figure imgf000110_0001
Prepared from lnt-2 in analogy to example 123. White solid. Yield: 0.02 g. HPLC (method 1 ): Rt = 2.98 min, m/z [M+H]+ = 430.4 (MW calc. 429.51 ). H NMR (400 MHz, DMSO-d6, δ ppm): 9.29 (s, 2H), 8.58 (d, 1 H, J = 4.8 Hz), 8.29 (s, 1 H), 8.00 (s, 1 H), 7.45 (d, 1 H, J = 3.8 Hz), 6.88 (s, 2H), 5.30 (s, 1 H), 4.30 (s, 2H), 3.16 (s, 3H), 1 .81 (s, 3H), 1.48 (s, 6H), 1.21 (s, 2H), 1.13 (s, 2H).
Example 127: 3-Hvdroxy-N-(1 '-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cvclopropane-
Figure imgf000110_0002
Prepared from 2-(2-(2-(6'-(methylamino)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-yl)- propan-2-ol in analogy to example 124. White solid. Yield: 1 15 mg. HPLC (method 1 ): Rt = 2.76 min, m/z [M+H]+ = 460.2 (MW calc. 459.54). H NMR (400 MHz, DMSO-d6, δ ppm): 9.29 (s, 2H), 8.58 (d, 1 H, J = 5.1 Hz), 8.29 (s, 1 H), 8.00 (s, 1 H), 7.45-7.44 (m, 1 H), 6.88 (s, 2H), 5.29 (s, 1 H), 4.41 (t, 1 H, J = 5.2 Hz), 4.31 (s, 2H), 3.59-3.55 (m, 2H), 3.17 (s, 3H), 2.25 (t, 2H, J = 6.2 Hz), 1.48 (s, 6H), 1.21-1.17 (m, 2H), 1.13-1.08 (m, 2H).
Figure imgf000111_0001
vDpropanamide
Figure imgf000111_0002
White solid. Yield: 0.08 g. HPLC (method 5): Rt = 2.96 min, m/z [M+H]+ = 402.0 (MW calc. 401.46). H NMR (400 MHz, DMSO-d6, δ ppm): 9.29 (s, 2H), 8.67 (d, 1 H, J = 3.6 Hz), 8.28 (s, 1 H), 8.02 (d, 1 H, J = 7.7 Hz), 7.89 (t, 1 H, J = 6.8 Hz), 7.36 (t, 1 H, J = 4.9 Hz), 6.88 (s, 2H), 4.41 (bs, 1 H), 4.31 (s, 2H), 3.57- 3.56 (m, 2H), 3.17 (s, 3H), 2.25 (s, 2H), 1.21 (s, 2H), 1 .13 (s, 2H). Example 129: 3-(2-(2-(6'-(Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl) pyridine-4- yl)azetidin-3-ol
Figure imgf000111_0003
Prepared from compound 1 e and tert-butyl 3-(2-chloropyridin-4-yl)-3-hydroxyazetidine-1-carboxylate in analogy to protocol 3c followed by removal of the protecting group with TFA in DCM. White solid. Yield: 105 mg. HPLC (method 1 ): Rt = 1.34 min, m/z [M+H]+ = 448.16 (MW calc. 463.55). H NMR (400 MHz, DMSO-d6, δ ppm): 9.42 (s, 2H), 9.23 (bs, 1 H), 8.85 (s, 2H), 8.73 (d, 1 H, J = 5.0Hz), 8.25 (s, 1 H), 7.52 (d, 1 H, J = 4.4 Hz), 7.46 (d, 1 H, J = 7.7 Hz), 7.10 (d, 1 H, J = 7.8 Hz), 6.98 (bs, 1 H), 4.49 (s, 2H), 4.37 (s, 2H), 4.15 (s, 2H), 3.28-3.22 (m, 2H), 1.31 (s, 2H), 1.24 (s, 2H), 1 .13 (t, 3H, J = 7.3 Hz). Example 130: 3-(2-(2-(6'-(Ethylsulfinyl)spiro[cvclopropane-1 ,3'-indolinl-1'-yl)Pyrimidin-5-yl)pyridin-4-yl)- azetidin-3-ol
Figure imgf000112_0001
Prepared from compound 24a and tert-butyl 3-(2-chloropyridin-4-yl)-3-hydroxyazetidine-1-carboxylate in analogy to protocol 3c followed by removal of the protecting group with hydrogen chloride in dioxane. White solid. Yield: 100 mg. HPLC (method 1 ): Rt = 1.38 min, m/z [M+H]+ = 464.16 (MW calc. 463.55). H NMR (400 MHz, DMSO-d6, δ ppm): 9.39 (s, 2H), 9.22 (bs, 1 H), 8.88 (s, 1 H), 8.73 (d, 1 H, J = 5.0 Hz), 8.66 (s, 1 H), 8.23 (s, 1 H), 7.51 (d, 1 H, J = 4.3 Hz), 7.17 (d, 1 H, J = 7.5 Hz), 7.02-7.00 (m, 2H), 4.48 (s, 2H), 4.34 (s, 2H), 4.15 (s, 2H), 3.00-2.94 (m, 1 H), 2.78-2.66 (m, 1 H), 1.26 (s, 2H), 1.18 (s, 2H), 1 .06 (t, 3H, J = 7.3 Hz). Preparation of tert-Butyl 3-(2-chloropyridin-4-yl)-3-hvdroxyazetidine-1-carboxylate
Figure imgf000112_0002
nBuLi (15 ml, 30.138 mmol) was added drop wise at -78°C to a solution of 2-chloro-4-iodopyridine (6.0 g, 25.1 1 mmol) in THF (100 ml). After stirring for 30 min, tert-butyl 3-oxoazetidine-1-carboxylate (5.15 g, 30.138 mmol) was added at the same temperature. The reaction was stirred for 2 h at RT and then quenched with saturated NH4CI solution (100 ml) and extracted with EtOAc (3x 200 ml). The combined organic layers were washed with water (200 ml) and brine (200 ml), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography [230-400 silica gel, hexane with 0-70% EtOAc]. Gummy liquid. Yield: 5.3 g (74%). HPLC (method 1 ): Rt = 2.88 min, m/z [M-H]+ = 283.0 (MW calc. 284.74).
Example 131 : 1 '-(5-(4-(Azetidin-3-yl)pyridin-2-yl)pyrimidin-2-yl)-6'-(ethylsulfinyl)spiro [cyclopropane- 1 ,3'- indolinel
Figure imgf000113_0001
131a) tert-Butyl 3-(2-(2-(6'-(ethylsulfinyl)spiro[cvclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl) pyridin-4- yl )azetid ine- 1 -carboxylate
tert-Butyl 3-(2-(2-(6^ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyn hydroxyazetidine-1-carboxylate (precursor of example 130, 1.0 g, 1.82 mmol) in MeOH (20 mL) and acetic acid (10 mL) was stirred at RT and in the presence of Pd/C (100 mg) for 16 h under a hydrogen atmosphere at 60 psi. The catalyst was filtered off, the filter was rinsed with EtOH and the filtrate was evaporated. Purification of the residue by column chromatography [230-400 mesh silica gel, DCM with 2% MeOH] provided the target compound as white solid. Yield: 170 mg (18%). HPLC (method 1 ): Rt = 4.39 min, m/z [M-H]+ = 531.67 (MW calc. 532.1 ).
131 b) 1 '-(5-(4-(Azetidin-3-yl)pyridin-2-yl)pyrimidin-2-yl)-6'-(ethylsulfinyl)spiro [cyclopropane-1 ,3'-indolinel TFA (0.6 mL) was added drop wise at 0°C to a suspension compound 131 b (130 mg, 0.245 mmol) in DCM (5 mL). The reaction mixture was stirred at RT for 1 h. The volatile parts were removed under reduced pressure and the residue was diluted with DCM (5 mL) and stirred for 15 min. The precipitate was filtered off and washed first with DCM (10 mL) and then with ether (10 ml). White solid. Yield: 63 mg (48%). HPLC (method 1 ): Rt = 3.61 min, m/z [M+H]+ = 432.4 (MW calc. 431.55). H NMR (400 MHz, DMSO-d6, δ ppm): 9.35 (s, 2H), 9.20 (bs, 1 H), 8.83 (bs, 1 H), 8.73 (d, 1 H, J = 5.0 Hz), 8.45 (s, 1 H), 8.19 (s, 1 H), 7.51 (d, 1 H, J = 4.3 Hz), 6.94 (d, 1 H, J = 7.5 Hz), 6.80 (d, 1 H, J = 7.3 Hz), 4.49-4.47 (m, 2H), 4.27 (s, 2H), 4.14 (s, 2H), 2.97-2.95 (m, 2H), 1.25 (t, 3H, J = 7.2 Hz), 1.18 (s, 2H), 1.09 (s, 2H).
Example 132: 4-(Azetidin-3-yl)-2-(2-(6'-(ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl)- pyridine 1 -oxide
Figure imgf000113_0002
Obtained from 131a via oxidation with mCPBA in THF followed by removal of the BOC protecting group with TFA. Yield: 9 mg. HPLC (method 1): Rt = 2.51 min, m/z [M+H]+ = 448.1 (MW calc.447.55). H NMR (400 MHz, DMSO-d6, δ ppm): 9.30 (s, 2H), 8.70 (d, 1H, J = 4.5 Hz), 8.62 (s, 1H), 8.13 (s, 1H), 7.50 (s, 1H), 7.16 (d, 1H, J = 7.5 Hz), 6.99 (d, 1H, J = 7.2 Hz), 4.46-4.43 (m, 2H), 4.30 (s, 2H), 4.15-4.12 (m, 2H), 3.36-3.35 (m, 1H), 2.95-2.94 (m, 2H), 2.79-2.76 (m, 1H), 1.24 (s,2H), 1.15 (s,2H), 1.10-1.05 (m, 3H).
Example 133: 6'-(Ethylsulfonyl)-1'-(5-(4-(3-methylazetidin-3-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclo- propane-1 ,3'-indolinel
Figure imgf000114_0001
Compound 1e and 4-(1-(tert-butylsulfinyl)-2-methylazetidin-2-yl)-2-chloropyridine were coupled according to protocol 1e. Subsequent removal of the protecting group with hydrogen chloride in dioxane afforded the target compound. Yellow solid. Yield: 50 mg. HPLC (method 1): Rt = 2.78 min, m/z [M+H]+ = 462.2 (MW calc.461.58). H NMR (400 MHz, DMSO-d6, δ ppm): 9.41-9.35 (m, 2H), 9.04 (bs, 1H), 8.85 (s, 1H), 8.77 (d, 1H, J = 5.1 Hz), 8.13 (s, 1H), 7.46 (d, 1H, J = 7.3 Hz), 7.39 (s, 1H), 7.10 (d, 1H, J = 7.6 Hz), 4.50 (s, 3H), 4.20-4.17 (m, 2H), 3.80 (s, 2H), 3.27-3.24 (m, 2H), 3.06-3.03 (m, 1H), 2.66-2.61 (m, 1H), 1.87 (s, 3H), 1.31 (s, 2H), 1.24 (s, 2H), 1.15-1.11 (m, 3H).
Example 134: 6'-(Ethylsulfinyl)-1 '-(5-(4-(3-methylazetidin-3-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cvclo-
Figure imgf000114_0002
Prepared from 1d and 4-(1-(tert-butylsulfinyl)-2-methylazetidin-2-yl)-2-chloropyridine in three steps comprising a Suzuki coupling (procedure 3c), an oxidation towards the sulfone with mCPBA and a removal of the protecting group. White solid. Yield: 80 mg. HPLC (method 1): Rt = 2.64 min, m/z [M+H]+ = 446.2 (MW calc.445.58). H NMR (400 MHz, DMSO-d6, δ ppm): 9.38 (s, 3H), 9.06 (bs, 1H), 8.76 (d, 1H, J = 4.8 Hz), 8.66 (s, 1H), 8.11 (s, 1H), 7.39 (d, 1H, J = 4.6 Hz), 7.18 (d, 1H, J = 8.2 Hz), 7.01 (d, 1H, J = 7.8 Hz), 4.34 (s, 2H), 4.17 (s, 1 H), 3.79 (s, 1 H), 3.05-2.94 (m, 2H), 2.77-2.72 (m, 1 H), 2.60 (m, 1 H), 1.90 (s, 3H), 1.26-1 .18 (m, 4H), 1.06 (t, 3H, J = 7.2 Hz).
Example 135: 1 5-(2-Fluorophenyl)pyrimidin-2-yl)-6 (tetrahvdro-2H-pyran-4-yl)oxy)spiro [cyclopropane- 1 ,3'-indolinel
Figure imgf000115_0001
Prepared from compound 67b and 4-bromotetrahydro-2H-pyran in analogy to procedure 67c. White solid. Yield: 10 mg. MS: m/z: [M+H]+ = 418.1 (MW calc. 417.19).
Figure imgf000115_0002
Prepared from compound 50d and (3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)magnesium bromide. The Grignard reaction (see protocol 50e) was followed by a removal of the tetrahydro-2H-pyran group with p- toluenesulfonic acid in methanol. White solid. Yield: 55 mg. HPLC (method 5): Rt = 1.69 min, m/z [M+H]+ = 406.08 (MW calc. 405.46). H NMR (400 MHz, DMSO-d6, δ ppm): 8.82 (s, 2H), 8.35 (s, 1 H), 7.69-7.65 (m, 1 H), 7.45-7.42 (m, 1 H), 7.38-7.31 (m, 2H), 6.89 (d, 1 H, J = 7.2 Hz), 6.75 (d, 1 H, J = 7.6 Hz), 5.10 (bs, 1 H), 4.50 (bs, 1 H), 4.34 (bs, 1 H), 4.23 (s, 2H), 3.39-3.37 (m, 2H), 1.61-1.38 (m, 4H), 1.15 (bs, 2H), 1.10 (bs, 2H). Examples 137 to 139 were prepared from 1 '-(5-bromopyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]-6'- sulfonyl chloride in analogy to synthesis example 18.
Example 137: N-Ethyl-1 '-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro [cyclopropane- 1 ,3'- indolinel-6'-sulfonamide
Figure imgf000116_0001
White solid. Yield: 0.14 g. HPLC (method 1): Rt = 3.23 min, m/z [M+H]+ = 466.1 (MW calc.465.54). H NMR (400 MHz, DMSO-d6, δ ppm): 9.31 (s, 2H), 8.82 (s, 1H), 8.59 (d, 1H, J = 5.1 Hz), 8.05 (s, 1H), 7.50- 7.46 (m, 2H), 7.37-7.35 (m, 1H), 7.01 (d, 1H, J = 7.8 Hz), 5.29 (s, 1H), 4.34 (s, 2H), 2.84-2.77 (m, 2H), 1.49 (s,6H), 1.29-1.27 (m,2H), 1.24-1.18 (m, 2H), 1.01 (t, 3H, J = 7.2 Hz).
Example 138: 1 5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N,N-dimethylspiro[cyclopropane- 1 ,3'-indolinel-6'-sulfonamide
Figure imgf000116_0002
White solid. Yield: 0.15 g. HPLC (method 1): Rt = 3.36 min, m/z [M+H]+ = 466.4 (MW calc.465.57). H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 2H), 8.75 (d, 1H, J = 0.9 Hz), 8.59 (d, 1H, J = 5.1 Hz), 8.06 (s, 1H), 7.46 (d, 1H, J = 4.9 Hz), 7.31-7.29 (m, 1H), 7.06 (d, 1H, J = 7.8 Hz), 5.29 (s, 1H), 4.35 (s, 2H), 2.64 (s, 6H), 1.49 (s, 6H), 1.31-1.29 (m, 2H), 1.26-1.20 (m, 2H). Example 139: 1 5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro[cyclopropane-1 ,3'- indolinel-6'-sulfonamide
Figure imgf000116_0003
White solid. Yield: 0.19 g. HPLC (method 1 ): Rt = 3.09 min, m/z [M+H]+ = 452.3 (MW calc. 451.54). H NMR (400 MHz, DMSO-d6, δ ppm): 9.32 (s, 2H), 8.81 (s, 1 H), 8.59 (d, 1 H, J = 5.1 Hz), 8.05 (s, 1 H), 7.47 (d, 1 H, J = 4.9 Hz), 7.4-7.33 (m, 2H), 7.03 (d, 1 H, J = 7.8 Hz), 5.30 (s, 1 H), 4.34 (s, 2H), 2.44 (d, 3H, J = 4.9 Hz), 1.49 (s, 6H), 1 .28-1 .24 (m, 2H), 1 .23-1 .20 (m, 2H).
Example 140 and 141 : 2-(2-(6 Ethylsulfinyl)spiro[cvclopropane-1 ,3'-indolinl-1 I)Pyrimidin-5-yl)iso-
Figure imgf000117_0001
The racemic sulfoxide was prepared in two steps from lnt-1 and 2-bromoisonicotinonitrile analogously to aforementioned protocols (3c and 24a, respectively). The single enantiomers were obtained from the racemate via chiral preparative HPLC (column: Chiralpak IA 21 x 250 mm, particle size 5 μιη; mobile phase: hexane/EtOH/DCM/diethylamine = 50/25/25/0.1 ; flow rate: 21 .0 ml/min; detection: UV, 352 nm; run time: 25 min).
Faster eluting enantiomer (example 140): White solid. Yield: 75 mg. Enantiomeric excess: 100% (chiral HPLC). HPLC (method 2): Rt = 1 .77 min., m/z: [M+H]+ = 402.1 (MW calc. 401.49). H NMR (400 MHz, DMSO-d6, δ ppm): 9.34 (s, 2H), 8.90 (d, 1 H, J = 5.0 Hz), 8.61 (s, 1 H), 8.54 (s, 1 H), 7.81-7.79 (m, 1 H), 7.20-7.17 (m, 1 H), 7.01 (d, 1 H, J = 7.8 Hz), 4.32 (s, 2H), 3.00-2.93 (m, 1 H), 2.80-2.73 (m, 1 H), 1.25-1.14 (m, 4H), 1.07 (t, 3H, J = 7.3 Hz). Slower eluting enantiomer (example 141 ): White solid. Yield: 80 mg. Enantiomeric excess: 99.8% (chiral HPLC). HPLC (method 2): Rt = 1 .77 min., m/z: [M+H]+ = 402.1 (MW calc. 401.49). H NMR (400 MHz, DMSO-d6, δ ppm): 9.34 (s, 2H), 8.89 (d, 1 H, J = 5.0 Hz), 8.61 (s, 1 H), 8.54 (s, 1 H), 7.80-7.79 (m, 1 H), 7.19-7.17 (m, 1 H), 7.01 (d, 1 H, J = 7.7 Hz), 4.32 (s, 2H), 3.00-2.94 (m, 1 H), 2.78-2.73 (m, 1 H), 1.26-1.14 (m, 4H), 1.07 (t, 3H, J = 7.3 Hz).
Example 142: 2-(2-(6'-(Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolinl-1 '-yl)Pyrimidin-5-yl) isonicotinonitrile
Figure imgf000118_0001
Prepared from lnt-1 and 2-bromoisonicotinonitrile in two steps (see protocols 3c and 95). White solid. Yield: 75 mg. HPLC (method 1 ): Rt = 3.69 min, m/z [M+H]+ = 418.2 (MW calc. 417.48). H NMR (400 MHz, DMSO-d6, δ ppm): 9.37 (s, 2H), 8.90 (d, 1 H, J = 5.0 Hz), 8.82 (s, 1 H), 8.57 (s, 1 H) 7.82 (d, 1 H, J = 5 Hz), 7.47-7.44 (m, 1 H), 7.09 (d, 1 H, J = 7.8 Hz), 4.35 (s, 2H), 3.28-3.23 (m, 2H), 1 .32-1.21 (m, 4H), 1.14 (t, 3H, J = 7.3 Hz).
Intermediate 3: Dimethyl(spiro[cyclopropan '-indolinl-6'-yl)phosphine oxide (lnt-3)
Figure imgf000118_0002
Xantphos (0.39 g, 0.67 mmol) and Pd(OAc)2 were added to a mixture of 6'-bromospiro[cyclopropane-1 ,3'- indoline] (3.0 g, 13.4 mmol), K3P04 (5.7 g, 26.8 mmol) and dimethyl phosphine oxide (1 .04 g, 13.4 mmol) in dioxane (100 mL) that was stirred at RT under Ar. The reaction mixture was heated at 100°C for 16 h, cooled to RT, and filtered through a plug of celite. The filtrate was concentrated and the residue purified by flash column chromatography [silica; DCM with 3.5% MeOH]. Light yellow solid. Yield: 0.70 g (24%). MS: m/z [M+H]+ = 222.1 (MW calc. 221.24).
Examples 143 and 144 were prepared from lnt-3 in two chemical steps analogously to aforementioned procedures (3a and 3c, respectively). Example 143: Dimethyl(1 5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)- phosphine oxide
Figure imgf000118_0003
White solid. Yield: 18 mg. MS: m/z [M+H]+ = 391.0 (MW calc. 390.42). H NMR (400 MHz, DMSO-d6, δ ppm): 9.27 (s, 2H), 8.76-8.73 (m, 1 H), 8.51 (d, 1 H, J = 4.9 Hz), 7.89 (s, 1 H), 7.32-7.27 (m, 1 H), 7.19 (d, 1 H, J = 4.8 Hz), 6.96-6.93 (m, 1 H), 4.28 (s, 2H), 2.38 (s, 3H), 1.66-1.63 (m, 6H), 1.25-1.14 (m, 4H). Example 144: (1 5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-
6'-yl)dimethylphosphine oxide
Figure imgf000119_0001
White solid. Yield: 16 mg. MS: m/z [M+H]+ = 435.2 (MW calc. 434.47). H NMR (400 MHz, DMSO-d6, δ ppm): 9.30 (s, 2H), 8.78-8.75 (m, 1 H), 8.59 (d, 1 H, J = 5.1 Hz), 8.03 (s, 1 H), 7.46-7.44 (m, 1 H), 7.33-7.28 (m, 1 H), 6.96-6.94 (m, 1 H), 5.29 (s, 1 H), 4.30 (s, 2H), 1.67-1.63 (m, 6H), 1.49 (s, 6H), 1.26-1 .14 (m, 4H).
Example 145: 2,2,2-Trifluoro-1-(1 5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)- ethanol
Figure imgf000119_0002
145a) 1 5-(2-Fluorophenyl)pyrimidin-2-yl)-6'-(2,2,2-trifluoro-1-((trimethylsilyl)oxy)ethyl)spiro
[cyclopropane- 1 ,3'-indolinel
Aldehyde 50d (0.17 g, 0.51 mmol) and trifluoromethyltrimethylsilane (0.2 mL, 1.27 mmol) in dry THF (15 mL) were added at -78°C to a solution of potassium tert-butoxide (0.17 g, 1 .52 mmol) in dry THF (21 mL). The reaction mixture was stirred upon warming to RT over 2 h, then quenched with saturated NH4CI solution and extracted with EtOAc (3x 20 mL). The combined organic layers were washed with brine (30 mL) and dried over Na2S04. The solvent was evaporated and the remnant was used for the next step without any purification. Light yellow liquid. Yield: 0.23 g. HPLC (method 1 ): Rt = 3.04 min, m/z [M+H]+ = 488.2 (MW calc. 487.56).
145b) 2,2,2-Trifluoro-1-(1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)ethanol
TBAF solution (1 M in THF, 1 mL, 1 .03 mmol) was added to compound 145a (0.23 g, 0.47 mmol) in THF (5 mL) at 0°C. The reaction mixture was stirred at RT for 2 h, quenched with saturated 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 raw product was purified by flash column chromatography [silica; hexane/acetone = 4:1] and triturated in DCM/pentane (1 :2). White solid. Yield: 90 mg. HPLC (method 1 ): Rt = 3.89 min, m/z [M+H]+ = 416.2 (MW calc. 415.38). H NMR (400 MHz, DMSO-d6, δ ppm): 8.83 (s, 2H), 8.51 (s, 1 H), 7.7-7.66 (m, 1 H), 7.48-7.46 (m, 1 H), 7.37-7.32 (m, 2H), 7.05 (d, 1 H, J = 7.3 Hz), 6.84 (d, 1 H, J = 7.7 Hz), 6.79 (d, 1 H, J = 5.3 Hz), 5.13-5.09 (m, 1 H), 4.26 (s, 2H), 2.65 (bs, 2H), 1.14 (bs, 2H).
Example 146: 4-(2,2,2-Trifluoro-1-(1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'- vDethvDmorpholine
Figure imgf000120_0001
146a) 2,2,2-Trifluoro-1-(1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cvclopropane-1 ,3'-indolinl-6'-yl)ethyl methanesulfonate
Methanesulfonyl chloride (0.13 mL, 1 .81 mmol) was added to synthesis example 145 (0.5 g, 1.2 mmol) and TEA (0.5 mL, 3.61 mmol) in dry DCM (12 mL) at 0°C. The reaction mixture was stirred at RT for 1 h, quenched with sat. NaHC03 solution and extracted with DCM (3x 20 mL). The combined organic layer was washed with brine (30 mL) and dried over saturated Na2S04. The solvent was removed under reduced pressure and the residue was used for the next step without any purification. White solid. Yield: 0.6 g (50%). HPLC (method 1 ): Rt = 4.07 min, m/z [M+H]+ = 494.1 (MW calc. 493.47). 146b) 4-(2,2,2-Trifluoro-1-(1 5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolinl-6'-yl)- ethvDmorpholine
Compound 146a (0.3 g, 0.61 mmol) and morpholine (1.6 mL, 18.25 mmol) were stirred in a sealed tube at 100°C for 16 h. The reaction mixture was concentrated and the remnant was purified by flash column chromatography [silica; hexane/acetone = 9: 1] followed by preparative HPLC. White solid. Yield: 80 mg (27%). MS: m/z [M+H]+ = 485.1 (MW calc. 484.49). H NMR (400 MHz, DMSO-d6, δ ppm): 8.82 (s, 2H), 8.47 (s, 1 H), 7.70-7.66 (m, 1 H), 7.44-7.38 (m, 1 H), 7.35-7.31 (m, 2H), 6.96 (d, 1 H, J = 7.4 Hz), 6.88 (d, 1 H, J = 7.6 Hz), 4.47-4.42 (m, 1 H), 4.27 (s, 2H), 3.57 (s, 4H), 2.59-2.57 (m, 4H), 1.20 (s, 2H), 1.13 (s, 2H). 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).
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 I given in the tables below (IC50 inhibition of PDE4B):
PDE4B IC50 PDE4B IC50 PDE4B IC50 PDE4B IC50
No. No. No.
[μΜ] (mean) [μΜ] (mean) [μΜ] (mean) [μΜ] (mean)
0,003 21 0,003 42 <0,001 62 0,017
0,005 22 0,008 43 <0,001 63 0,016
0,002 23 0,003 44 <0,001 64 0,027
0,007 24 0,003 45 <0,001 65 0,014
0,001 25 0,001 46 <0,001 66 0,024
0,003 26 0,002 47 <0,001 67 0,122
0,003 27 0,001 48 0,005 68 0,027
0,003 28 <0,001 49 0,001 69 0,015
0,020 29 0,002 50 0,049 70 <0,001
0,006 30 <0,001 51 0,036 71 0,002
0,003 31 <0,001 52 0,026 72 0,001
0,002 32 0,003 53 0,033 73 0,003
<0,001 33 <0,001 54 0,001 74 0,001
0,001 34 <0,001 55 0,024 75 0,003
<0,001 35 <0,001 56 0,004 76 0,032
<0,001 36 <0,001 57 0,071 77 0,030
0,002 37 0,002 58 0,1 18 78 0,075
0,001 39 <0,001 59 0,006 79 0,443
0,004 40 <0,001 60 0,025 80 0,002
0,002 41 <0,001 61 0,017 81 <0,001
PDE4B IC50 PDE4B IC50 PDE4B IC50 PDE4B IC50
No. No. No. No.
[μΜ] (mean) [μΜ] (mean) [μΜ] (mean) [μΜ] (mean)
82 <0,001 102 0,211 122 0,015 142 <0,001
83 0,002 103 0,009 123 0,009 143 0,002
84 0,001 104 0,021 124 0,072 144 0,002
85 0,001 105 0,044 125 0,149 145 0,026
86 0,001 106 0,007 126 0,001 146 0,136
87 0,002 107 0,005 127 0,001
88 0,002 108 0,052 128 0,001
89 <0,001 109 0,036 129 0,002
90 0,001 110 0,002 130 0,002
91 0,006 111 0,004 131 0,020
92 0,023 112 0,199 132 0,003
93 0,003 113 0,161 133 0,003
94 0,001 114 0,031 134 0,003
95 0,001 115 0,023 135 0,626
96 0,258 116 0,003 136 0,009
97 0,091 117 0,003 137 <0,001
98 0,027 118 0,003 138 <0,001
99 0,003 119 0,002 139 0,001
100 0,010 120 0,001 140 <0,001
101 0,082 121 0,089 141 0,001

Claims

Claims
1. A compound according to formula (I)
Figure imgf000124_0001
(I),
wherein
A, B and C independently represent CH or N;
R and R2 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl, which is unsubstituted or substituted with one, two, three or four substituents Y;
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;
R3 is -L-R4;
L is selected from bond, S(=0), S(=0)2, P(=0)(R4), C(H)(OH) or C(CH3)(OH);
R4 is selected from OH, CN, R 3, OR13, NH2, NH(R13) or N(R 3)2,
wherein
each R 3 independently of each other denotes
Ci-6-alkyl, unsubstituted or mono- or polysubstituted;
or
C3-6-cycloalkyl or 3- to 7-membered heterocycloalkyl, in each case unsubstituted or mono- or polysubstituted;
or
C3.6-cycloalkyl or 3- to 7-membered heterocycloalkyl, in each case unsubstituted or mono- or polysubstituted, and in each case connected via a C-|.4-aliphatic group, unsubstituted or mono- or polysubstituted;
Y at each occurrence is independently from one another selected from the group consisting of OH, =0, CN, N02, halogen, Ci-C6-alkyl, Ci-C6-hydroxyalkyl, Ci-d-alkoxy, S(d-C6-alkyl), S(0)(d-C6- alkyl), S(0)2(Ci-C6-alkyl), (Ci-C6)-haloalkyl, S(Ci-C6)-haloalkyl, (Ci-C6)-haloalkoxy, (d-C6)-cyano- alkyl, C3-C6-cycloalkyl, NH2, NH(C C6-alkyl), N(C C6-alkyl)2, NHCO(C C6-alkyl), NHSO(C C6- alkyl), NHS(0)2(C C6-alkyl), NH(d-C6-alkylen)-CO(d-C6-alkyl), NH(d-C6-alkylen)-SO(d-C6-alkyl), NH(d-C6-alkylen)-S02(d-C6-alkyl), NHCONH2, NHCONH(d-C6-alkyl), NH(d-C6-alkylen)-CON(d- C6-alkyl)2, C02H, C02(d-C6-alkyl), CONH2, CONH(d-C6-alkyl) and CON(d-C6-alkyl)2; 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, Ci-C6- alkoxy, (Ci-C6)-thioalkyl, (Ci-C6)- aloalkyl, (Ci-C6)-thiohaloalkyl, (Ci-C6)-haloalkoxy, (d-d-alkylen)- S-(Ci-C6-alkyl), C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C3-alkylenyl), 3- to 7-membered heterocyclo- alkyl, said C3.6-cycloalkyl and said 3- to 7-membered heterocycloalkyl being in each case
unsubstituted or mono- or polysubstituted, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, NHCO(Ci-C6-alkyl), NHC02(C C6-alkyl), NHC(0)NH2, 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, (C1-C6-alkylen)NHCO(C1-C6-alkyl), (C1-C6-alkylen)NHC02(C1-C6-alkyl), (C1-C6-alkylen)NHC(0)NH2, (C1-C6-alkylen)NHCONH(C1-C6- alkyl), (C1-C6-alkylen)NHCON(C1-C6-alkyl)2, NH^Crd-alkylenj-CO^Crd-alkyl), NH(d-d-alkylen)- CONH2, NH(Ci-Ce-alkylen)-CONH(Ci-Ce-alkyl), NH(Ci-Ce-alkylen)-CON(Ci-Ce-alkyl)2> NHS(0)2OH, NHS(0)2(Ci-Ce-alkyl)> NHS(0)20(C C6-alkyl), NHS(0)2NH2, NHS(0)2NH(Ci-Ce-alkyl),
NHS(0)2N(Ci-Ce-alkyl)2, NhKC d-alkylenj-StO^OH, NHid-Ce-alkylen^OMd-Ce-alkyl), NH(C C6-alkylen)-S(0)20(C C6-alkyl), NH(C C6-alkylen)-S(0)2NH2,
Figure imgf000125_0001
alkyl), C02H, CO(C C6-alkyl), C02(d-C6-alkyl), 0-CO(C C6-alkyl), 0-C02(d-C6-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-d-alkyl), OS(0)2N(d-d- alkyl)2, S(0)(d-d-alkyl), S(0)2(d-d-alkyl), S(0)2OH, S(0)20(d-d-alkyl), S(0)2NH2, S(0)2NH(d- C6-alkyl), and S(0)2N(d-d-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 , wherein each of A, B and C represents CH. A compound according to one or more of claims 1 or 2, wherein
R and R2 together with the carbon atom to which they are attached form unsubstituted cyclopropyl or unsubstituted cyclobutyl, preferably unsubstituted cyclopropyl.
A compound according to one or more of claims 1 to 3, wherein G is one of the following groups G1
Figure imgf000125_0002
Figure imgf000126_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 cydohexyl,
wherein said pyrrolidinyl, said piperidinyl, said aziridinyl, said cyclopropyl, said cyclobutyl, said cyclopentyl and said cydohexyl 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 imgf000127_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 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, cycloalkyl or aziridinyl, wherein said cycloalkyl and said aziridinyl 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 one or more of claims 1 to 5, wherein
R3 is -L-R4;
L is selected from bond, S(=0), S(=0)2, P(=0)(R4), C(H)(OH) or C(CH3)(OH)
and
R4 is selected from OH, CN, C C6-alkyl, 0(C C6-alkyl), NH2, NH(C C6-alkyl), N(C C6-alkyl)2, C3- C6-cycloalkyl, 3- to 7-membered heterocycloalkyl, 0(C3-C6-cycloalkyl) or 0(3- to 7-membered heterocycloalkyl),
wherein said Ci-C6-alkyl is independently unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, =0, =NH,
Figure imgf000127_0002
=N(OH), OH, d-Ce-alkoxy, (Ci-C6-alkoxy)-CrC6-alkoxy, (hydroxy)-Ci-C6-alkoxy, NH2, NH(Ci-C6-alkyl), N(d- C6-alkyl)2, NH(C C6-hydroxyalkyl), N(C1-C6-alkyl)(C1-C6-hydroxyalkyl), N(C C6-hydroxyalkyl)2, NHCO(C C6-alkyl), N(C C6-alkyl)CO(d-C6-alkyl), NHCO(C C6-hydroxyalkyl), N(C C6- alkyl)CO(d-C6-hydroxyalkyl), CONH2, CONH(d-C6-alkyl), CON(d-C6-alkyl)2, CONH(C C6- hydroxyalkyl), CON(Ci-C6-alkyl)(d-C6-hydroxyalkyl), CON(d-C6-hydroxyalkyl)2, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyl;
and wherein said C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyi is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, =0, OH, d-Ce-alkoxy, (Ci-C6-alkoxy)-Ci-C6-alkoxy, (hydroxy)-Ci-C6-alkoxy, NH2, NH(Ci-C6-alkyl), N(d-C6- alkyl)2, NH(Ci-C6-hydroxyalkyl), N(Ci-C6-alkyl)(Ci-C6-hydroxyalkyl), N(Ci-C6-hydroxyalkyl)2, NHCO(CrCe-alkyl), N(C Ce-alkyl)CO(Ci-Ce-alkyl)> NHCO(Ci-Ce-hydroxyalkyl), N(d-C6- alkyl)CO(Ci-Ce-hydiOxyalkyl), CONH2, CONH(Ci-Ce-alkyl). CON(Ci-Ce-alkyl)2, CONH(C C6- hydroxyalkyl), CON(C1-C6-alkyl)(C1-C6-hydroxyalkyl), CON(C C6-hydroxyalkyl)2, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyi.
A compound according to one or more of claims 1 to 6,
wherein
L is selected from bond;
and
R4 is selected from OH, CN, 0(C C6-alkyl), 0(C3-C6-cycloalkyl) or 0(3- to 7-membered
heterocycloalkyi),
wherein said Ci-C6-alkyl is independently unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, =0, Ci-C6-alkoxy, (Ci-d- alkoxy)-Ci-C6-alkoxy, (hydroxy)-Ci-C6-alkoxy, C3-C6-cycloalkyl and 3- to 6-membered heterocycloalkyi; and
wherein said C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyi is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, =0, OH, d-C6-alkoxy, (d-d-alkoxy^d-d-alkoxy, (hydroxy)-d-C6-alkoxy, NH2, NH(CrCe-alkyl). N(C C6-alkyl)2, NH(C C6-hydroxyalkyl), N(d-C6-alkyl)(d-C6-hydroxyalkyl), N(d-C6-hydroxyalkyl)2, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyi.
A compound according to one or more of claims 1 to 6,
wherein
L is selected from bond;
and
R4 is C C6-alkyl,
wherein said d-C6-alkyl is independently unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, =0, OH, d-d-alkoxy, (d-d)- thioalkyl, (Ci-C6-alkoxy)-Ci-C6-alkoxy, (hydroxy)-d-C6-alkoxy, NH2, NH(d-C6-alkyl), N(d-C6- alkyl)2, NH(d-C6-hydroxyalkyl), N(Ci-C6-alkyl)(Ci-C6-hydroxyalkyl), N(d-C6-hydroxyalkyl)2, NHCO(d-C6-alkyl), N(d-C6-alkyl)CO(d-C6-alkyl), NHCO(d-C6-hydroxyalkyl), N(d-d- alkyl)CO(d-C6-hydroxyalkyl); CONH2, CONH(d-C6-alkyl), CON(d-C6-alkyl)2, CONH(d-C6- hydroxyalkyl), CON(d-C6-alkyl)(d-C6-hydroxyalkyl), CON(C C6-hydroxyalkyl)2, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyi;
and
wherein said C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyi is 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)-Ci-C6-alkoxy, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, NH(Ci-C6-hydroxyalkyl), N(Ci-C6-alkyl)(Ci-C6-hydroxyalkyl), N(Ci-C6-hydroxyalkyl)2, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyl. 9. A compound according to one or more of claims 1 to 6,
wherein
L is selected from bond;
and
R4 is selected from C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl,
wherein said C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , =0, OH , Ci-C6-alkyl, (Ci-C6)-hydroxyalkyl, Ci-Ce-alkoxy, (Ci-C6)-thioalkyl, (Ci-C6)- haloalkyl, (Ci-C6-alkoxy)-Ci-C6-alkoxy, (hydroxy)-Ci-C6-alkoxy, NH2, NH(Ci-C6-alkyl), N(d-C6- alkyl)2, NH(C C6-hydroxyalkyl), N(d-C6-alkyl)(d-C6-hydroxyalkyl), N(C C6-hydroxyalkyl)2, NHCO(C C6-alkyl), N(d-C6-alkyl)CO(d-C6-alkyl), NHCO(C C6-hydroxyalkyl), N(C C6- alkyl)CO(d-d-hydroxyalkyl), CONH2, CONH(d-C6-alkyl), CON(d-C6-alkyl)2, CON H(d-C6- hydroxyalkyl), CON(d-d-alkyl)(d-C6-hydroxyalkyl), CON(d-C6-hydroxyalkyl)2, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyl.
10. A compound according to one or more of claims 1 to 6,
wherein
L is selected from S(=0) or S(=0)2;
and
R4 is selected from d-d-alkyl, NH2, NH(d-d-alkyl), N(d-C6-alkyl)2, C3-C6-cycloalkyl or 3- to 7- membered heterocycloalkyl,
wherein said d-d-alky! is independently unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , OH , d-d-alkoxy, (d-d- alkoxy)-Ci-C6-alkoxy, (hydroxy )-Ci-C6-alkoxy, C3-C6-cycloalkyl or 3- to 6-membered
heterocycloalkyl; and
wherein said C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , =0, OH , d-d-alkyl, (d-C6)-hydroxyalkyl, Ci-Ce-alkoxy, (d-C6)-thioalkyl, (d-d)- haloalkyl, (d-C6-alkoxy)-Ci-C6-alkoxy, (hydroxy)-d-C6-alkoxy, NH2, NH(d-C6-alkyl), N(d-C6- alkyl)2, NH(d-C6-hydroxyalkyl), N(Ci-C6-alkyl)(d-C6-hydroxyalkyl), N(d-C6-hydroxyalkyl)2, C3- C6-cycloalkyl and 3- to 7-membered heterocycloalkyl.
11. A compound according to one or more of claims 1 to 6,
wherein
L is selected from C(H)(OH) or C(CH3)(OH);
and
R4 is selected from Ci-C6-alkyl, C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein said Ci-C6-alkyl is independently unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, Ci-C6-alkoxy, (CI-CQ- alkoxy)-Ci-C6-alkoxy, (hydroxy)-Ci-C6-alkoxy, C3-C6-cycloalkyl and 3- to 6-membered
heterocycloalkyl; and
wherein said C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, =0, OH, C C6-alkyl, (C C6)-hydroxyalkyl, C C6-alkoxy, (C C6)-thioalkyl, (C C6)- haloalkyl, (d-Ce-alkoxy^d-Ce-alkoxy, (hydroxy)-C C6-alkoxy, NH2, NH(C C6-alkyl), N(C C6- alkyl)2, NH(Ci-C6-hydroxyalkyl), N(Ci-C6-alkyl)(Ci-C6-hydroxyalkyl), N(Ci-C6-hydroxyalkyl)2, C3- C6-cycloalkyl and 3- to 7-membered heterocycloalkyl.
A compound according to one or more of claims 1 to 5, wherein
R3 is -L-R4;
L is selected from bond, S(=0), S(=0)2, P(=0)(R4), C(H)(OH) or C(CH3)(OH)
and
R4 is selected from Ci-C6-alkyl, wherein said Ci-C6-alkyl is independently unsubstituted or substituted with OH .
A compound according to one or more of claims 1 to 1 1 , wherein the compound according to general formula (I) is selected from one of the general formula (la), (lb), (lc), (Id), (le) or (If),
Figure imgf000130_0001
wherein R4 and G are defined as in claim 1 .
14. A compound according to one or more of the preceding claims selected from the group consisting of
1 6'-(Ethylsulfonyl)-1 '-(5-phenylpyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]
2 6'-(isopropylsulfonyl)-1 '-(5-phenylpyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]
3 6'-(Ethylsulfonyl)-1 '-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]
4 6'-(ethylsulfonyl)-1 '-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline] 1 ^5-(4-ethylpyridin-2-yl)pyrimidin-2-yl)-6'-(ethylsulfonyl)spiro[cyclopropane-1 ,3'-indoline] 6 ethylsulfonyl)-1 ^5-(6-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline] 6'-(Ethylsulfonyl)-1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]
6'-(Ethylsulfinyl)-1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]
1 ^5-(2-Fluorophenyl)pyrimidin-2-yl)-6'-(isopropylsulfonyl)spiro[cyclopropane-1 ,3'-indoline] 1 ^5-(2-Fluorophenyl)pyrimidin-2-yl)-6^isopropylsulfinyl)spiro[cyclopropane-1 ,3'-indoline] 3-((1 5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfonyl)butan^ 3-((1 5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfinyl)butan^
3-((1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfonyl) propan-1- ol
3-((1 ^5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfinyl) propan-1 - ol
2-((1 ^5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfonyl) ethanol 2-((1 ^5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfinyl)etha^ 6 Ethylsulfonyl)-1 ^5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoH N,N-Dimethyl-1 '-(5-(pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]-6'-sulfonamide
N,N-Dimethyl-1 5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoli sulfonamide
1 ^5-(4-ethylpyridin-2-yl)pyrimidin-2-yl)-N,N-dimethylspiro[cyclopropane-1 ,3'-indoli
sulfonamide
N,N-dimethyl-1 ^5-(6-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]-6'- sulfonamide
1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N-dimethylspiro[cyclopropane-1 ,3'-indoline]-6'- sulfonamide
1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methylspiro[cyclopropane-1 ,3'- indoline]-6'-sulfonamide
6'-(ethylsulfinyl)-1 '-(5-(6-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline] 6'-(Ethylsulfinyl)-1 '-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline] 1 ^5-(4-Cyclopropylpyridin-2-yl)pyrimidin-2-yl)-6'-(et ylsulfinyl)spiro[cyclopropane-1 ,3'-indoline] 1 ^5-(4-Ethylpyridin-2-yl)pyrimidin-2-yl)-6'-(ethylsulfinyl)spiro[cyclopropane-1 ,3'-indoline] 2-(2-(6^ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-amine 1 ^5-(6-Ethylpyridin-2-yl)pyrimidin-2-yl)-6'-(ethylsulfinyl)spiro[cyclopropane-1 ,3'-indoline] 1 ^5-(4-cyclopropylpyridin-2-yl)pyrimidin-2-yl)-6'-(ethylsulfonyl)spiro[cyclopropane-1 ,3'-indoline] 2-(2-(6^Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-amine 1 '-(5-(6-Ethylpyridin-2-yl)pyrimidin-2-yl)-6'-(ethylsulfonyl)spiro[cyclopropane-1 ,3'-indoline]
3-((1 ^5-(4-Cyclopropylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfinyl)- propan-1 -ol
3- ((1 5-(4-aminopyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfinyl)- propan-1 -ol
N-(2-(2-(6'-((3-hydroxypropyl)sulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-
4- yl)acetamide
3-((1 5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfinyl)- propan-1 -ol
3-((1 ^5-(4-cyclopropylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfonyl)- propan-1 -ol
33--((((11 '-(55--((44--aaminopyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulf^ propan-1 -ol
NN--((22--((22--((66'-(((3-hydroxypropyl)sulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5- yl)pyridin-4-yl)acetamide
4Q 3-((1 5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)sulfo
propan-1 -ol
41 1-(2-(2-(6^Ethylsulfonyl)spiro[cyclopropan^^
Λ 2-(2-(2-(6^Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin^
^ 2-ol
^_ 1-(3-(2-(6^Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)-4-fluorophe ethanol
^ 2-(3-(2-(6^Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)-4-fluorophen propan-2-ol
45 1-(2-(2-(6^Ethylsulfinyl)spiro[cyclopropane-1 ,3'-indo
2-(2-(2-(6^Ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridi
b 2-ol
1-(3-(2-(6^Ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)-4-fluoro ethanol
„ 2-(3-(2-(6^Ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)-4-fluor^
propan-2-ol
49 6 ethylsulfinyl)-1 ^5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]
50 1-(1 ^5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)propan-1-ol
51 2-(1 ^5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)butan-2-ol
22 (1 5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)(tetrahydro-2H
4-yl)methanol
c 1-(1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)-2-methylp
ol
54 1-(1 ^5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)-N-methyl cyclo- propanamine
„ 1-(1 ^5-(2-Fluorophenyl)pyrimidin-2-yl)spiro^
cyclopropanamine
gg 2-((1-(1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)cyclopr^
(methyl)amino)ethanol
57 1-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl) cyclopropanol
58 1 ^5-(2-Fluorophenyl)pyrimidin-2-yl)-6^1-methoxycyclopropyl)spiro[cyclopropane-1 ,3'-indoline gg 6^1-Methoxycyclopropyl)-1 5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cyclo-propane-1 ,3'- indoline]
60 6 1-Methoxycyclopropyl)-1 ^5-(pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]
66'^-(11--MMeettlhoxycyclopropyl)-1 5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclo-propane-1 ,3 - indoline]
g2 22--((((((11 ''--((55--(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'
yl)methyl)amino)ethanol
g_ 2-(((1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'- yl)methyl)(methyl)amino)ethanol
64 2-(((1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'- yl)methyl)(methyl)amino)-2-methylpropan-1-ol
N-((1 5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)methyl)-N methylacetamide
N-((1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)methyl)-2-hydroxy- N-methylacetamide
6'-Ethoxy-1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]
6 Cyclopropylmethoxy)-1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline] 3-((1 5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)oxy) propan-1-ol
3-((1 '-(5-(4-(2-hydroxypropan-2-y )pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'- yl)sulfonyl)propan-1-ol
3-((1 '-(5-(4-(2-hydroxypropan-2-y )pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'- yl)sulfonyl)propan-1-ol
3-((1 '-(5-(4-(2-hydroxypropan-2-y )pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'- yl)sulfonyl)propan-1-ol
3-((1 '-(5-(4-(2-hydroxypropan-2-y )pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'- yl)sulfonyl)butan-1-ol
3-((1 '-(5-(4-(2-hydroxypropan-2-y )pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'- yl)sulfinyl)butan-1-ol
3-(( 1 '-(5-(4-methylpyrid in-2-yl)pyr midin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'- yl)sulfonyl)butan-1-ol
ethyl 1 '-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]-6'- carboxylate
2-hydroxyethyl 1 5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoline]- 6'-carboxylate
1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl dimethylcarbamate 1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl methylcarbamate
N-(2-hydroxyethyl)-1 '-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methylspiro- [cyclopropane-1 ,3'-indoline]-6'-sulfonamide
N-(2-Hydroxyethyl)-1 '-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclo- propane-1 ,3'-indoline]-6'-sulfonamide
N-(2-Hydroxyethyl)-1 5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin 6'-sulfonamide
2-(2-(2-(6'-(ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-yl)propan- 2-amine
2-(2-(2-(6'-(ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-yl)-N- methylpropan-2-amine
1-(2-(2-(6^Ethylsulfonyl)spiro[cycloprop
propanamine
1- (2-(2-(6^Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin
methylcyclopropanamine
2- (2-(2-(6'-(ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-yl)propan- 2-amine
2-(2-(2-(6'-(ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-yl)-N- methylpropan-2-amine
1-(2-(2-(6'-(ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-yl)cyclo- propanamine
1-(2-(2-(6'-(ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-yl)-N- methylcyclopropanamine
2-(6-(2-(6'-(ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-2-yl)propan-
91
2-ol
2-(6-(2-(6'-(ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-2-yl)propan- 92
2-ol (faster eluting enantiomer)
2-(6-(2-(6'-(ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-2-yl)propan- 93
2-ol (slower eluting enentioemr)
2-(2-(2-(6^methylsulfinyl)spiro[cycloprop
94
yl)propan-2-ol
2-(2-(2-(6^methylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-y ^
95
propan-2-ol
N-(1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)-3-hydroxypropan- 96
amide
N-(1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)-2-h
97
acetamide
N-(1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)-2-h
98
methylacetamide
N-(1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)-3-h
99
methylpropanamide
100 N-((1 5-(2-Fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl) methyl)acetamide
N-((1 '-(5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)methyl)-2-hydroxy- 101
acetamide
2-(((1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)meth
102
methylpropan-1-ol
2-Hydroxy-N-methyl-N-((1 ^5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro [cyclopropane-1 ,3'- 103
indolin]-6'-yl)methyl)acetamide
N-methyl-N-((1 ^5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-m
methyl)acetamide
2-methyl-2-(methyl((1 ^5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopr^ ,3'-indolin]-6'-
105
yl)methyl)amino)propan-1-ol
2-hydroxy-N-((1 '-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'- 106
indolin]-6'-yl)methyl)-N-methylacetamide
N-((1 5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'- 107
yl)methyl)-N-methylacetamide
2-(((1 ^5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'- 108
yl)methyl)(methyl)amino)-2-methylpropan-1-ol
2-(4-Fluoro-3-(2-(6 Hmethylamino)cycto
109
pyrimidin-5-yl)phenyl)propan-2-ol
1- (1 ^5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-^
cyclopropanamine
2- (2-(2-(6^1-(methylamino)cyclopropyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrim
pyridin-4-yl)propan-2-ol
N-(1-(1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro^
112
methylacetamide
N-(1-(1 '-(5-(4-Methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)cyclo- 113
propyl)-N-methylacetamide
2-(1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cy^
amine 2-(1 ^5-(4-methoxypyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indoli
115
propan-2-amine
2-(2-(2-(6'-(2-(methylamino)propan-2-yl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)- pyridin-4-yl)propan-2-ol
2-(2-(2-(6 2-((2-Hydroxyethyl)amino)propan-2-yl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)- py rim id i n-5-yl )py rid in-4-y l)propan-2-ol
2-(2-(2-(6^1 -((2-Hydroxyethyl)(methyl)amino)cyclopropyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-
118
yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol
2-(2-(2-(6^1 -((2-Hydroxyethyl)amino)cyclopropyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)- py rim id i n-5-yl )py rid in-4-y l)propan-2-ol
2- (2-(2-(6^2-((2-hydroxyethyl)(methyl)amino)propan-2-yl)spiro[cyclopropane-1 ,3'-indolin]-1 '-
120
yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol
1 ^5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N-dimethylspiro[cyclopropane-1 ,3'-indoline]-6'- 121
carboximidamide
(1 ^5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopro^
122
imine
N-(1 '-(5-(4-(2-Hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'- 123
yl)acetamide
3- hydroxy-N-(1 '-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'- 124
indolin]-6'-yl)propanamide
3-hydroxy-N-(1 ^5-(pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indolin]-6'-yl)propan- 125
amide
N-(1 ^5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrim^
126
yl)-N-methylacetamide
3-Hydroxy-N-(1 '-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro [cyclopropane- 127
1 ,3'-indolin]-6'-yl)-N-methylpropanamide
3-hydroxy-N-methyl-N-(1 ^5-(pyridin-2-yl)pyrim^
128
propanamide
3-(2-(2-(6^Ethylsulfonyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl) pyridine-4-yl)- 129
azetidin-3-ol
3-(2-(2-(6'-(ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)pyridin-4-yl)azetidin- 130
3- ol
1 '-(5-(4-(Azetidin-3-yl)pyridin-2-yl)pyrimidin-2-yl)-6'-(ethylsulfinyl)spiro [cyclopropane-1 ,3'- 131
indoline]
4- (azetidin-3-yl)-2-(2-(6^ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin^
132
yl)pyridine 1 -oxide
6 Ethylsulfonyl)-1 ^5-(4-(3-methylazetidin-3-yl)pyridin-2-yl)pyrimidin-2-yl)spiro [cyclopropane- 133
1 ,3'-indoline]
6^ethylsulfinyl)-1 ^5-(4-(3-methylazetidin-3-yl)pyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropa
134
1 ,3'-indoline]
1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)-6'-((tetrahydro-2H-pyran-4-yl)oxy)spiro [cyclopropane-1 ,3'- 135
indoline]
1 '-(5-(2-Fluorophenyl)pyrimidin-2-yl)-6'-((tetrahydro-2H-pyran-4-yl)oxy)spiro [cyclopropane-1 ,3'- 136
indoline]
N-Ethyl-1 '-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)spiro [cyclopropane- 1 ,3'- 137
indoline]-6'-sulfonamide
1 '-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N,N-dimethylspiro[cyclopropane-1 ,3'- 138
indoline]-6'-sulfonamide 139 1 '"(5"(4-(2-hydroxypropan-2-yl)py^
indoline]-6'-sulfonamide
140 2-(2-(6^ethylsulfinyl)spiro[cyclopropane-1 ,3'-indolin]-1 '-yl)pyrimidin-5-yl)ison
142 2-(2-(6^ethylsulfonyl)spiro[cyclopro
^2 dimethyl(1 ^5-(4-methylpyridin-2-yl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3 - yl)phosphine oxide
144 0^5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)py
yl)dimethylphosphine oxide
2,2,2-Trifluoro-1-(1 ^5-(2-fluorophenyl)pyrimidin-2-yl)s^
yl)ethanol
^„ 4-(2,2,2-trifluoro-1-(1 5-(2-fluorophenyl)pyrimidin-2-yl)spiro[cyclopropane-1 ,3'-indo
yl)ethyl)morpholine
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.
15. Pharmaceutical composition comprising at least one compound as defined in one of claims 1 to 14.
16. 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/EP2016/025186 2015-12-22 2016-12-22 Novel substituted indoline compounds as phosphodiesterase inhibitors WO2017108203A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP15003643.2 2015-12-22
EP15003643 2015-12-22

Publications (1)

Publication Number Publication Date
WO2017108203A1 true WO2017108203A1 (en) 2017-06-29

Family

ID=55068737

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2016/025186 WO2017108203A1 (en) 2015-12-22 2016-12-22 Novel substituted indoline compounds as phosphodiesterase inhibitors

Country Status (3)

Country Link
AR (1) AR107004A1 (en)
TW (1) TW201730183A (en)
WO (1) WO2017108203A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109180648A (en) * 2018-11-02 2019-01-11 郑州大学 7- alkyl-N- pyrimidine indoline-like compound and its synthetic method
WO2020011731A1 (en) * 2018-07-12 2020-01-16 UCB Biopharma SRL Spirocyclic indane analogues as il-17 modulators
CN113292477A (en) * 2021-06-01 2021-08-24 四川大学 Method for synthesizing isoindol-1-ketone analogue through iridium-catalyzed hydrocarbon activation reaction

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1958947A1 (en) * 2007-02-15 2008-08-20 Ranbaxy Laboratories Limited Inhibitors of phosphodiesterase type 4
WO2015018534A1 (en) * 2013-08-09 2015-02-12 Grünenthal GmbH Novel substituted condensed pyrimidine compounds
WO2016008593A1 (en) * 2014-07-16 2016-01-21 Grünenthal GmbH Novel substituted pyrimidine compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1958947A1 (en) * 2007-02-15 2008-08-20 Ranbaxy Laboratories Limited Inhibitors of phosphodiesterase type 4
WO2015018534A1 (en) * 2013-08-09 2015-02-12 Grünenthal GmbH Novel substituted condensed pyrimidine compounds
WO2016008593A1 (en) * 2014-07-16 2016-01-21 Grünenthal GmbH Novel substituted pyrimidine compounds

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020011731A1 (en) * 2018-07-12 2020-01-16 UCB Biopharma SRL Spirocyclic indane analogues as il-17 modulators
US11458124B2 (en) 2018-07-12 2022-10-04 UCBBiopharma Srl Spirocyclic indane analogues as IL-17 modulators
CN109180648A (en) * 2018-11-02 2019-01-11 郑州大学 7- alkyl-N- pyrimidine indoline-like compound and its synthetic method
CN113292477A (en) * 2021-06-01 2021-08-24 四川大学 Method for synthesizing isoindol-1-ketone analogue through iridium-catalyzed hydrocarbon activation reaction

Also Published As

Publication number Publication date
AR107004A1 (en) 2018-03-07
TW201730183A (en) 2017-09-01

Similar Documents

Publication Publication Date Title
AU2019201352B2 (en) Bromodomain inhibitors
US10202360B2 (en) Therapeutic compounds
TW450962B (en) Alpha-substituted pyrimidine-thioalkyl and alkylether compounds
TWI617308B (en) Canine uric acid-3-monooxygenase inhibitor, pharmaceutical composition thereof and use method thereof
WO2018234354A1 (en) Novel substituted 3-indole and 3-indazole compounds as phosphodiesterase inhibitors
AU2011344270A1 (en) Substituted 6,6-fused nitrogenous heterocyclic compounds and uses thereof
AU2022217353B2 (en) Pyridopyrimidinone derivative, preparation method therefor, and use thereof
KR20170117479A (en) Substituted mono- and polyazanaphthalene derivatives and uses thereof
AU2015291477B2 (en) Novel 2,5-substituted pyrimidines as PDE inhibitors
KR20150114575A (en) Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
WO2016008590A1 (en) Novel 2,5-substituted pyrimidines as pde4 inhibitors
EP2964617A1 (en) Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
US9688683B2 (en) Substituted condensed pyrimidine compounds
ES2976515T3 (en) Compounds and compositions for treating conditions associated with APJ receptor activity
WO2008116816A1 (en) Combination of cb2 ligand and paracetamol
JP2022515309A (en) Substituted aryl compounds, their production methods and uses
WO2017108203A1 (en) Novel substituted indoline compounds as phosphodiesterase inhibitors
WO2024173234A1 (en) Inhibitors of parg
WO2017108204A1 (en) Novel substituted spiro-[indoline heterocycloalkane] compounds as phosphodiesterase inhibitors
WO2018234353A1 (en) Novel substituted indole and indazole compounds as phosphodiesterase inhibitors
HK40080347A (en) Bromodomain inhibitors
HK1165197A (en) 5-alkynyl-pyridines
NZ732796A (en) Benzazepine dicarboxamide compounds

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16816202

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16816202

Country of ref document: EP

Kind code of ref document: A1