WO2019170904A1 - Pipéridines ou pipéridones substituées par de l'urée et du phényle - Google Patents

Pipéridines ou pipéridones substituées par de l'urée et du phényle Download PDF

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WO2019170904A1
WO2019170904A1 PCT/EP2019/055947 EP2019055947W WO2019170904A1 WO 2019170904 A1 WO2019170904 A1 WO 2019170904A1 EP 2019055947 W EP2019055947 W EP 2019055947W WO 2019170904 A1 WO2019170904 A1 WO 2019170904A1
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methoxyphenyl
urea
alkyl
chlorophenyl
piperidin
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Florian JAKOB
Beatrix Merla
David Rider
Torsten Dunkern
Markus Wagener
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Gruenenthal GmbH
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Gruenenthal GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a compound according to general formula (I)
  • FPR2 which acts as a modulator of FPR2 and can be used in the treatment and/or prophylaxis of disorders which are at least partially mediated by FPR2.
  • FPR2 alias lipoxin A4 receptor, FPRL1, LXA4R, ALXR
  • FPRL1, LXA4R, ALXR G-protein coupled receptor family member that has been shown to mediate calcium mobilization in response to the eicosanoid family member lipoxin A4 (LXA4) and its analogues (Maddox et al., J. Biol. Chem., 1997, 272, 6972-6978).
  • the receptor is widely expressed and has been shown to bind to a large number of different ligands, including endogenous proteins (serum amyloid A) bacterial products (the formyl peptide N- formyl-methionine-leucyl-phenylalanine), other lipid-derivatives (resolvin D1 (RvDl) and its analogues) and peptides, including neuropeptides (Ap42) and HIV (gp41 and gpl20- derived peptides), amongst many others (Chiang et al., Pharmacol. Rev., 2006, 58, 463-487; Fredman and Serhan, Biochem. J., 2011, 437, 185-197; Migeotte et al., Cytokine Growth Factor Rev., 2006, 17, 501-519).
  • endogenous proteins serum amyloid A
  • bacterial products the formyl peptide N- formyl-methionine-leucyl-
  • FPR2-ligands In addition to anti-inflammatory and pro-resolution effects of FPR2-ligands, they have also been demonstrated to have effects on pain mechanisms.
  • LXA4 has been directly shown to alleviate hyperalgesia and bone-cancer -related pain in animal models (Fredman and Serhan, Biochem. J., 2011, 437, 185-197; Hu et al., J. Neuroinflammation. 2012, 9, 278).
  • the FPR2 agonist RvDl has been shown to reduce inflammatory pain, spontaneous pain and post-operative pain and post-surgical pain (Ji et al., Trends Neurosci. 2011, 34, 599-609).
  • FPR2 agonists include, but are not limited to, regulation of inflammation, regulation of hyperalgesia, regulation of proinflammatory mediator production and/or release, regulation of migration and activation of monocytes/macrophages/microglia/astrocytes/dendritic cells and neutrophils, regulation of lymphocyte activation, regulate innalte lymphoid cell activation, proliferation and differentiation, regulation of cytokine production and/or release, regulation of immune reactions, regulation of phagocytosis/efferocytosis, regulation of apoptosis. Further, FPR2 is believed to be involved in the modulation of immune responses, such as those elicited through Graft versus Host Disease (GvHD).
  • GvHD Graft versus Host Disease
  • novel compounds which are modulators, preferably activators of FPR2, and which preferably have advantages over the compounds of the prior art.
  • the novel compounds should in particular be suitable for use in the treatment and/or prophylaxis of disorders or diseases which are at least partially mediated by FPR2.
  • the compounds according to the present invention are highly potent modulators of the FPR2 receptor.
  • the present invention relates to a compound according to general formula (I)
  • X 3 represents N(L-R 4 ) and X 2 represents C3 ⁇ 4 or C(O) and X 4 represent C3 ⁇ 4; or
  • X 3 represents N(L-R 4 ) and X 4 represents C3 ⁇ 4 or C(O) and X 2 represent CH 2 ;
  • n 0, 1 or 2
  • R 1 represents phenyl or 5 or 6-membered heteroaryl
  • R 2 represents O-Ci-e-alkyl, H, F, Cl, Br, CN, Ci -6 -alkyl, C 3-6 -cycloalkyl, CHF 2 , CH 2 F, CF 3 , OH,
  • R 3 represents F, Cl, Br, CHF 2 , CH 2 F, CF 3 , Ci-e-alkyl, C 3-6 -cycloalkyl, O-Ci-e-alkyl, OCHF 2 , OCH 2 F,
  • L represents bond, Ci- 6 -alkylene, C(O), S(0) 2 , C(CH 3 ) 2 ;
  • R 4 represents H, Ci- 6 -alkyl, C 3-6 -cycloalkyl, 3 to 6-membered heterocycloalkyl, aryl, 5 or 6- membered heteroaryl, C(0)NH 2 , C(0)N(H)(Ci -6 -alkyl), C(0)N(Ci -6 -alkyl) 2 , C(0)N(H)(C 3-6 - cycloalkyl), C(0)N(H)(3 to 6-membered heterocycloalkyl), C(0)N(H)(aryl), C(0)N(H)(5 or 6- membered heteroaryl), C(0)N(Ci- 6 -alkyl)(C 3-6 -cycloalkyl), C(0)N(Ci- 6 -alkyl)(3 to 6-membered heterocycloalkyl), C(0)N(Ci- 6 -alkyl)(aryl), C(0)N(Ci- 6 -alkyl)(5 or 6-membered heteroaryl
  • Ci- 6 -alkylene is linear and saturated or unsaturated
  • the compound according to the present invention is present in form of the free compound.
  • free compound preferably means that the compound according to the present invention is not present in form of a salt.
  • Methods to determine whether a chemical substance is present as the free compound or as a salt are known to the skilled artisan such as 14 N or 15 N solid state NMR, x-ray diffraction, x-ray powder diffraction, IR, Raman, XPS. 'H-NMR recorded in solution may also be used to consider the presence of protonation.
  • the compound according to the present invention is present in form of a physiologically acceptable salt.
  • physiologically acceptable salt preferably refers to a salt obtained from a compound according to the present invention and a physiologically acceptable acid or base.
  • the compound according to the present invention may be present in any possible form including solvates, cocrystals and polymorphs.
  • solvate preferably refers to an adduct of (i) a compound according to the present invention and/or a physiologically acceptable salt thereof with (ii) distinct molecular equivalents of one or more solvents.
  • the compound according to the present invention may be present in form of the racemate, enantiomers, diastereomers, tautomers or any mixtures thereof.
  • the compounds according to general formula (I) possess at least two stereogenic carbon atoms and may be stereochemically differentiated according to the relative structural orientation of the phenyl moiety and the urea moiety which are bound to the central nitrogen-containing 6-membered heterocycloalkyl.
  • the term“diastereomer” refers to a compound preferably having a diastereomeric ratio of > 90: 10, more preferably > 92:8, even more preferably > 95:5, most preferably > 98:2 and in particular > 99: 1 or > 99.9: 1.
  • Diastereomers differ from each other with respect to their physical and chemical properties. Methods to determine the diastereomeric ratio (dr) are well known to the person skilled in the art and include, but are not limited to, NMR-methods.
  • the term“enantiomerically pure compound” or“enantiomer” preferably refers to a compound having an enantiomeric excess of > 90 %ee, more preferably > 92 %ee, still more preferably > 95 %ee, most preferably > 98 %ee and in particular > 98 %ee.
  • Methods to determine the enantiomeric excess include, but are not limited to, optical rotary dispersion, circular dichroism, NMR-methods using chiral auxiliaries (“shift reagents”) or separation via chiral HPLC (high performance liquid chromatography, using a chiral stationary phase), chiral GLC (gas-liquid chromatography, using a chiral stationary phase phase) or chiral SFC (supercritical fluid chromatography using a chiral stationary phase).
  • the term“racemic mixture” or“racemate” refers to a mixture (identified by the prefix“rac-trans” or“rac-cis” in the chemical name) of two corresponding enantiomers wherein said corresponding enantiomers are preferably contained in the mixture in a ratio of from 30:70 to 70:30, more preferably 40:60 to 60:40, most preferably 45:55 to 55:45 and in particular 50:50.
  • the term“iso-mix” refers to a mixture (identified by the prefix“iso mix” in the chemical name) of two corresponding diastereomers, wherein said corresponding diastereomers are preferably contained in the mixture in a ratio of from 30:70 to 70:30, more preferably 40:60 to 60:40, most preferably 45:55 to 55:45 and in particular 50:50.
  • Determination of the absolute stereochemical structure is well known to the person skilled in the art and includes, but are not limited to, x-ray diffractometry.
  • the compounds wherein the phenyl and urea moieties which are connected to the central nitrogen-containing 6-membered heterocycloalkyl have a different relative orientation, for instance phenyl moiety up (“bold bond”, / ) and urea moiety down (“hashed bond”, ' ' ) or vice versa, are referred to as the“trans” diastereomer and are identified hereinafter by the prefix“trans” in the chemical name (see general formula trans-II below):
  • trans-ll The trans diastereomer is a racemic mixture of two corresponding enantiomers which are identified via the prefix “entl-trans” and“ent2 -trans” in the chemical name, and which are according to general formulae (Ila) and (lib) shown below:
  • either one of the two enantiomers“entl-trans” (identified by the prefix“entl-trans” in the chemical name) and“ent2-trans” (identified by the prefix“ent2-trans” in the chemical name) is according to general formula (Ila) while the other is according to general formula (lib).
  • one of entl-trans and ent2-trans has to be according to general formula (Ila) and the other one has to be according to general formula (lib).
  • the compounds wherein the phenyl and urea moieties which are connected to the central nitrogen-containing 6-membered heterocycloalkyl have the same relative orientation, for instance both, the phenyl moiety and the urea moiety, up (“bold bond”, / ) or both, the phenyl moiety and the urea moiety, down (“hashed bond”, are referred to as the“cis” diastereomer and are identified hereinafter by the prefix“cis” in the chemical name (see general formula cis-II below):
  • the cis diastereomer is a racemic mixture of two enantiomers which are identified via the prefix“entl-cis” and “ent2-cis” in the chemical name, and which are according to general formulae (He) and (lid) shown below:
  • either one of the terms“diastereomer 1” (identified by the prefix“dial” in the chemical name) and“diastereomer 2” (identified by the prefix“dia2” in the chemical name) refers to the cis diastereomer while the other refers to the trans diastereomer.
  • one of the diastereomers 1 and 2 has to be cis and the other one has to be trans.
  • a chemical formula where the phenyl and the urea moieties are each connected to the central nitrogen-containing 6-membered heterocycloalkyl by“solid bonds” (/ ) shall refer to a mixture of the trans diastereomer and the cis diastereomer, i.e. a mixture of diastereomer 1 and diastereomer 2.
  • the present 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), 13 C and 14 C.
  • Isotopic isomers of a compound of the invention can generally be prepared by conventional procedures known to a person skilled in the art.
  • Ci- 6 -alkyl and Ci-4-alkyl preferably mean acyclic saturated or unsaturated aliphatic (i.e. non-aromatic) hydrocarbon residues, which can be linear (i.e. unbranched) or branched and which can be unsubstituted or mono- or polysubstituted (e.g. di- or trisubstituted), and which contain 1 to 6 (i.e. 1, 2, 3, 4, 5 or 6) and 1 to 4 (i.e. 1, 2, 3 or 4) carbon atoms, respectively.
  • Ci- 6 -alkyl and Ci ⁇ -alkyl are saturated.
  • Ci- 6 -alkyl groups are selected from the group consisting of methyl, ethyl, n-propyl, 2- propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3 -pentyl, 2-methylbutyl, 3-methylbutyl, 3- methylbut-2-yl, 2-methylbut-2-yl, 2,2-dimethylpropyl, n-hexyl, 2-hexyl, 3 -hexyl, 2-methylpentyl, 4-methylpentyl, 4-methylpent-2-yl, 2-methylpent-2-yl, 3,3-dimethylbutyl, 3,3-dimethylbut-2-yl, 3-methylpentyl, 3-methylpent-2- yl and 3-methylpent-3-yl; more preferably methyl, ethyl, n-propyl, 2-propyl, n-
  • Ci- 6 -alkyl groups are selected from Ci ⁇ -alkyl groups.
  • Preferred Ci- 4-alkyl groups are selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec- butyl and tert-butyl.
  • the terms“Ci-6-alkylene” and“Ci- -alkylene” relate to a linear and preferably saturated aliphatic residues which are preferably selected from the group consisting of methylene (- ⁇ 3 ⁇ 4-), ethylene (-CH 2 CH 2 -), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2-) and hexylene (-CH2CH2CH2CH2CH2-); more preferably methylene (-CH 2 -) and ethylene (-CH2CH2-) and most preferably methylene (-CH2-).
  • Ci-6-alkylene is selected from C1- - alkylene.
  • the term“C3-6-cycloalkyl” preferably means cyclic aliphatic hydrocarbons containing 3, 4, 5 or 6 carbon atoms, wherein the hydrocarbons in each case can be saturated or unsaturated (but not aromatic), unsubstituted or mono- or polysubstituted.
  • the C3-6-cycloalkyl group can be bound to the respective superordinate general structure via any desired and possible ring member of the cycloalkyl group.
  • the C3-6-cycloalkyl group can also be condensed with further saturated, (partially) unsaturated, (hetero) cyclic, aromatic or heteroaromatic ring systems, i.e. with cycloalkyl, heterocyclyl, aryl or heteroaryl residues, which in each case can in turn be unsubstituted or mono- or polysubstituted.
  • the C3-6-cycloalkyl group can be singly or multiply bridged such as, for example, in the case of adamantyl, bicyclo[2.2.1]heptyl or bicyclo[2.2.2]octyl.
  • the C3-6-cycloalkyl group is neither condensed with further ring systems nor bridged.
  • C3-6-cycloalkyl groups are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl.
  • Particularly preferred C3-6-cycloalkyl groups are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, most preferably cyclopropyl.
  • the 3 to 6-membered heterocycloalkyl group can also be condensed with further saturated or (partially) unsaturated cycloalkyl or heterocyclyl, aromatic or heteroaromatic ring systems. However, preferably, the 3 to 6-membered heterocycloalkyl group is not condensed with further ring systems.
  • the 3 to 6- membered heterocycloalkyl group can be bound to the superordinate general structure via any desired and possible ring member of the heterocycloaliphatic residue if not indicated otherwise. In a preferred embodiment, the 3 to 6- membered heterocycloalkyl group is bound to the superordinate general structure via a carbon atom.
  • Preferred 3 to 6-membered heterocycloalkyl groups are selected from the group consisting of tetrahydropyranyl, morpholinyl, pyrrolidinyl, 4-methylpiperazinyl, morpholinonyl, azetidinyl, aziridinyl, dithiolanyl, dihydropyrrolyl, dioxanyl, dioxolanyl, dihydropyridinyl, dihydrofuranyl, dihydroisoxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, oxiranyl, oxetanyl, piperazinyl, piperidinyl, pyrazolidinyl, pyranyl, tetrahydropyrrolyl, more preferably tetrahydropyranyl, morpholinyl and pyrrolidinyl.
  • aryl preferably means aromatic hydrocarbons having 6 to 14, i.e. 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring members, preferably having 6 to 10, i.e. 6, 7, 8, 9 or 10 ring members, including phenyls and naphthyls.
  • Each aryl residue can be unsubstituted or mono- or polysubstituted.
  • the aryl can be bound to the superordinate general structure via any desired and possible ring member of the aryl residue.
  • aryl residues can also be condensed with further saturated or (partially) unsaturated cycloalkyl or heterocycloalkyl, aromatic or heteroaromatic ring systems, which can in turn be unsubstituted or mono- or polysubstituted.
  • aryl is condensed with a further ring system.
  • condensed aryl residues are 2H- benzo[b] [ 1 ,4]oxazin-3(4H)-onyl, 1 H-benzo[d]imidazolyl, 2,3 -dihydro- 1 H-indenyl, tetrahydronaphthalenyl, isochroman, 1,3-dihydroisobenzofuranyl, benzodioxolanyl and benzodioxanyl.
  • aryl is selected from the group consisting of phenyl, lH-benzo[d]imidazolyl, 2H-benzo[b][l,4]oxazin-3(4H)-onyl, 2,3 -dihydro- 1H- indenyl, tetrahydronaphthalenyl, isochroman, 1,3-dihydroisobenzofuranyl, 1 -naphthyl, 2-naphthyl, fluorenyl and anthracenyl, each of which can be respectively unsubstituted or mono- or polysubstituted.
  • aryl is not condensed with any further ring system.
  • a particularly preferred aryl is phenyl, unsubstituted or mono- or polysubstituted.
  • the term "5- to 6-membered heteroaryT preferably means 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 selected independently of one another from the group S, N and O and the heteroaryl residue can be unsubstituted or mono- or polysubstituted, if not indicated otherwise.
  • 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 5- to 6-membered heteroaryl is bound to the suprordinate general structure via a carbon atom of the heterocycle.
  • the heteroaryl can also be part of a bi- or polycyclic system having up to 14 ring members, wherein the ring system can be formed with further saturated or (partially) unsaturated cycloalkyl or heterocycloalkyl, aromatic or heteroaromatic ring systems, which can in turn be unsubstituted or mono- or polysubstituted, if not indicated otherwise.
  • the 5- to 6- membered heteroaryl is part of a bi- or polycyclic, preferably bicyclic, system.
  • the 5- to 6-membered heteroaryl is not part of a bi- or polycyclic system.
  • the 5- to 6-membered heteroaryl is selected from the group consisting of pyridyl (i.e. 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, thienyl (thiophenyl), triazolyl, thiadiazolyl, 4,5,6,7-tetrahydro-2H-indazolyl, 2,4,5,6-tetrahydrocyclo- penta[c]pyrazolyl, benzofuranyl, benzoimidazolyl, benzothienyl, benzothiadiazolyl, benzothi
  • Particularly preferred 5- to 6-membered heteroaryl are selected from the group consisting of pyridyl (i.e. 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl, pyridazinyl, thienyl (thiophenyl), oxazolyl and thiazolyl.
  • pyridyl i.e. 2-pyridyl, 3-pyridyl, 4-pyridyl
  • pyrimidinyl pyridazinyl
  • thienyl thiophenyl
  • oxazolyl thiazolyl
  • substituted refers in the sense of the present invention, with respect to the corresponding residues or groups, to the single substitution (monosubstitution) or multiple substitution (polysubstitution), e.g. disubstitution or trisubstitution; more preferably to monosubstitution or disubstitution;
  • the multiple substitution can be carried out using the same or using different substituents.
  • substituted refers in the sense of this invention to the single substitution (monosubstitution) or multiple substitution (disubstitution), of one or two hydrogen atoms each independently of one another by at least one substituent.
  • the disubstitution can be carried out using the same or using different substituents.
  • Ci- 6 -alkyl can e.g. represent ethyl for R 2 and can represent methyl for R 4 .
  • Preferred substituents of Ci- 6 -alkyl, Ci- 6 -alkylene, C3-6-cycloalkyl and 3 to 6- membered heterocycloalkyl are selected from the group consisting of F, Cl, CN, Ci-6-alkyl, CF3, CF2H, CFH2 and OCF3; more preferably F, Cl, CN, Ci-6-alkyl and CF3; most preferably F, CN, CH3, CH2CH3 and CF3; and in particular F.
  • Ci- 6 -alkyl, Ci- 6 -alkylene, C3-6-cycloalkyl and 3 to 6-membered heterocycloalkyl are preferably each independently from one another unsubstituted, mono- di- or trisubstituted, more preferably unsubstituted or monosubstituted or disubstituted with a substituent selected from the group consisting of F, C3 ⁇ 4, CH2CH3, CN and CF3.
  • Ci- 6 -alkylene groups are unsubstituted.
  • aryl, phenyl and 5 or 6-membered heteroaryl in each case independently from one another are unsubstituted or mono- or disubstituted with one or two substituents selected from the group consisting of F, Cl, Br, CN, Ci- 6 -alkyl, CF3, CF2H, CFH2, Ci-4-alkylene-CF3, Ci-4-alkylene-CF2H, Ci-4-alkylene- CFH 2 , C(0)-Ci- 6 -alkyl, C(0)-0H, C(0)-OCi -6 -alkyl, C(0)-N(H)(0H), C(0)-NH 2 , C(0)-N(H)(Ci -6 -alkyl), C(0)- N(Ci- 6 -alkyl) 2 , OH, OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCh, O-Ci-e-alkyl, O-CV,
  • Preferred substituents of aryl, phenyl and 5 or 6-membered heteroaryl are selected from the group consisting of F, Cl, Br, CN, Ci -6 -alkyl, CF 3 , CF 2 H, CFH, OH, OCF 3 , OCF 2 H, OCFH 2 and O-Ci-e-alkyl; more preferably F, Cl, Br, Ci-6-alkyl, CF 3 , OH, OCF 3 and O-Ci-6-alkyl; most preferably Cl, Br, Ci -6 -alkyl and CF 3 and in particular Cl, Br, CH 3 , CH 2 CH 3 and CF 3 .
  • aryl, phenyl and 5 or 6-membered heteroaryl are preferably each independently from one another unsubstituted, mono- or disubstituted, more preferably unsubstituted or monosubstituted with a substituent selected from the group consisting of Cl, Br, Ci-6- alkyl and CF 3 .
  • the compound according to the present invention is according to general formula (Ila) or (lib)
  • the compound according to the present invention is according to general formula (Ila). In still another preferred embodiment, the compound according to the present invention is according to general formula (lib).
  • the compound according to the present invention is according to general formula (He) or (lid)
  • the compound according to the present invention is according to general formula (Ila) or (lib).
  • X 3 represents N(L-R 4 ) and X 2 represents CH 2 or C(O) and X4 represent CH 2 ; or
  • X 3 represents N(L-R 4 ) and X 4 represents CH 2 or C(O) and X 2 represent CH 2
  • X 3 represents N(L-R 4 ) and X 2 represents CH 2 or C(O) and X 4 represent CH 2 .
  • the compound according to the present invention is according to general formula (III)
  • the compound according to the present invention is according to general formula (IV)
  • the compound according to the present invention is according to general formula
  • the compound according to the present invention is according to general formula (III) or (IV).
  • R 1 represents phenyl or 5 or 6-membered heteroaryl, wherein the 5 or 6-membered heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, thienyl (thiophenyl), triazolyl, thiadiazolyl, 4,5,6,7-tetrahydro-2H-indazolyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, benzofuranyl, benzoimidazolyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl, quinazoliny
  • R 1 represents phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiophenyl, thiazolyl or isothiazolyl wherein preferably phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiophenyl, thiazolyl and isothiazolyl in each case independently from one another are unsubstituted or mono- or disubstituted, more preferably unsubstituted or monosubstituted, with one or more substituents selected from the group consisting of F, Cl, Br, CN, unsubstituted Ci- 6 -alkyl, CF3, CF2H, CFH2, C 1-4 - alkylene
  • R 1 represents phenyl, pyridyl, pyrimidinyl, thiophenyl, thiazolyl or isothiazolyl, wherein preferably phenyl, pyridyl, pyrimidinyl, thiophenyl, thiazolyl and isothiazolyl in each case independently from one another are unsubstituted or mono- or disubstituted, more preferably unsubstituted or monosubstituted, with one or more substituents selected from the group consisting of F, Cl, Br, CN, unsubstituted Ci -b-alkyl and CF 3 .
  • R 1 represents phenyl, pyridyl, pyrimidinyl, thiophenyl, thiazolyl or isothiazolyl wherein phenyl, pyridyl, pyrimidinyl, thiophenyl, thiazolyl and isothiazolyl independently from one another are unsubstituted or monosubstituted with one or more substituents selected from the group consisting of Cl, Br, unsubstituted Ci - 6 -alkyl and CF 3 .
  • R 2 represents O-Ci- 6 -alkyl, H, F, Cl, Br, CN, Ci- 6 -alkyl, C3-6-cycloalkyl, CHF2, CH 2 F, CF 3 , OH, OCHF2, OCH2F, OCF 3 , S-Ci-e-alkyl, S(0)-Ci -6 -alkyl, S(0) 2 -Ci- 6 -alkyl, O-Cs-e-cycloalkyl, S-C3- 6-cycloalkyl, S(0)-C 3 -6-cycloalkyl, S(0) 2 -C 3 -6-cycloalkyl, NH 2 , N(H)(Ci -6 -alkyl), N(Ci- 6 -alkyl) 2 , N(H)(C 3 -6- cycloalkyl), N(Ci- 6 -alkyl)(C 3-6 -cycloalkyl),NC(0)(Ci-
  • O-Ci-e-alkyl H, F, Cl, Br, CN, Ci -6 -alkyl, C 3-6 -cycloalkyl, CHF 2 , CH 2 F, CF 3 , OH, OCHF 2 , OCH 2 F, OCF3, S-Ci-e-alkyl, S(0)-Ci- 6 -alkyl, S(0) 2 -Ci- 6 -alkyl, 0-C 3-6 -cycloalkyl, S-C 3-6 -cycloalkyl, S(0)-C 3-6 -cycloalkyl, S(0) 2 -C 3-6 -cycloalkyl, N3 ⁇ 4, N(H)(Ci- 6 -alkyl), N(Ci-6-alkyl)2, N(H)(C3-6-cycloalkyl); more preferably O-Ci- 6 -alkyl H, F, Cl, Br, CN, Ci-e-alkyl, Cs-e-cycloalkyl
  • R 2 represents O-CH 3 , F, Cl, Br, OH, O-CH 2 CH 3 , 0-(CH 2 ) 2 CH 3 , O- CH(CH 3 ) 2 or OCF3.
  • R 3 represents F, Cl, Br, CHF 2 , CH 2 F, CF3, Ci-6-alkyl, C3-6-cycloalkyl, O-C1-6- alkyl, OCHF 2 , OCH 2 F, OCF 3 , S(0)-Ci -6 -alkyl, S(0)-C 3-6 -cycloalkyl, S(0) 2 -Ci- 6 -alkyl or S(0) 2 -C 3-6 -cycloalkyl; more preferably F, Cl, Br, CHF 2 , CH 2 F, CF3, unsubstituted Ci-6-alkyl, unsubstituted C3-6-cycloalkyl, O- (unsubstituted Ci- 6 -alkyl), OCHF2, OCH2F or OCF3; still more preferably F, Cl, Br, CF3, C3 ⁇ 4, CH2CH3, cyclopropyl, OCH3, OCH2CH3 or OCF3; most preferably F, Cl, Br, CH3, Ci6
  • R 3 can be bound to any of the four available carbon atoms of the phenyl ring. Preferably, R 3 occupies the meta position(s) relative to R 2 .
  • n 0, 1 or 2; preferably 0 or 2.
  • R 3 represents F and n represents 2;
  • n 0.
  • the compound according to the present invention is according to general formula (VI) or
  • L represents bond, Ci- 6 -alkylene, C(O), S(0) 2 or C(CH 3 ) 2 .
  • L represents bond, CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 CH 2 , C(0), S(0) 2 or C(CH 3 ) 2 ; more preferably bond, CH 2 , C(O), S(0) 2 or C(CH 3 ) 2 ; most preferably bond, CH 2 or C(O); and in particular bond or CH 2 .
  • R 4 represents H, Ci- 6 -alkyl, C 3-6 -cycloalkyl, 3 to 6-membered heterocycloalkyl, aryl, 5 or 6-membered heteroaryl, C(0)NH 2 , C(0)N(H)(Ci- 6 -alkyl), C(0)N(Ci -6 -alkyl) 2 , C(0)N(H)(C 3-6 -cycloalkyl),
  • aryl and 5 or 6-membered heteroaryl in each case independently from one another are unsubstituted or mono- or disubstituted with one or more substituents selected from the group consisting of F, Cl, Br, CN, Ci-e-alkyl, CF 3 , CF 2 H, CFH 2 , Ci ⁇ -alkylene-CF , Ci- 4 -alkylene-CF 2 H, Ci- 4 -alkylene-CFH 2 , C(0)-Ci -6 -alkyl, C(0)-0H, C(0)-0Ci - 6 -alkyl, C(0)-N(H)(0H), C(0)-NH 2 , C(0)-N(H)(Ci -6 -alkyl), C(0)-N(Ci- 6 -alkyl) 2 , OH, OCF 3 , OCF 2 H, OCFH 2 , OCF 2 Cl, OCFCb, O-Ci- 6 -alkyl, 0-C
  • R 4 represents H, Ci- 6 -alkyl, C3-6-cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 or 6- membered heteroaryl, C(0)NH 2 , C(0)N(H)(Ci- 6 -alkyl), C(0)N(Ci- 6 -alkyl) 2 , C(0)N(H)(C 3-6 -cycloalkyl), C(0)N(H)(3 to 6-membered heterocycloalkyl), C(0)N(H)(phenyl), C(0)N(H)(5 or 6-membered heteroaryl), C(0)N(Ci- 6 -alkyl)(C 3-6 -cycloalkyl), C(0)N(Ci- 6 -alkyl)(3 to 6-membered heterocycloalkyl), C(0)N(C I-6 - alkyl) (phenyl), C(0)N(Ci- 6 -alkyl)(5 or 6-membered heteroaryl,
  • Ci- 6 -alkyl most preferably H, Ci- 6 -alkyl, C3-6-cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 or 6-membered heteroaryl, C(0)NH 2 , C(0)N(H)(Ci- 6 -alkyl), C(0)N(Ci- 6 -alkyl) 2 , C(0)0-(Ci- 6 -alkyl), Ci-e-alkylene-OH or Ci -6 - alkylene-O-Ci- 6 -alkyl; and
  • Ci- 6 -alkyl in particular H, Ci- 6 -alkyl, C3-6-cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 or 6-membered heteroaryl, C(0)NH 2 , C(0)0-(Ci- 6 -alkyl), Ci-e-alkylene-OH or Ci-e-alkylene-O-Ci-e-alkyl.
  • R 4 represents H, Ci- 6 -alkyl, Ci- 6 -alkylene-OH, Ci- 6 -alkylene-0-Ci- 6 -alkyl, 3 to 6- membered cycloalkyl, 3 to 6-membered heterocycloalkyl, C(0)NH 2 , C(0)N(H)(Ci- 6 -alkyl), C(0)N(Ci- 6 -alkyl) 2 , C(0)0-(Ci- 6 -alkyl), 5 or 6-membered heteroaryl, or aryl, preferably phenyl; wherein Ci- 6 -alkyl, Ci- 6 -alkylene, C3- 6 -cycloalkyl and 3 to 6-membered heterocycloalkyl in each case independently from one another are unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, Cl, CN, C1-6- alkyl, CF3, CF2
  • R 4 represents
  • Ci-6-alkyl selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec- butyl, tert-butyl, n-pentyl, 2-pentyl, 3 -pentyl, 2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2- methylbut-2-yl, 2,2-dimethylpropyl and n-hexyl;
  • Ci-6-alkyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, Cl, Br, CN, OH, O-CH3, O-CH2CH3, 0-(CH 2 )2CH 3 , 0-CH(CH 3 )2, S(O)- C3 ⁇ 4, and S(0) 2 -CH 3 ;
  • Ci-6-alkylene-OH selected from the group consisting of CH2OH, CH2CH2OH, (CH2)30H, (CH2)40H, C(H)(OH)-CH 3 , CH 2 C(H)(OH)-CH3, C(CH 3 )2-OH, C(H)(OH)-C(CH 3 ) 2 , and CH 2 C(CH3)2-OH;
  • Ci- 6 -alkylene-0-Ci- 6 -alkyl selected from the group consisting of CH2OCH3, CH2CH2OCH3, (CH2)30CH3, (CH 2 ) 4 OCH3, (CH 2 ) 5 OCH3, and (CH 2 ) 6 0CH 3 ;
  • cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
  • 3 to 6-membered heterocycloalkyl selected from the group consisting of tetrahydropyranyl, morpholinyl, pyrrolidinyl, 4-methylpiperazinyl, morpholinonyl, azetidinyl, aziridinyl, dithiolanyl, dihydropyrrolyl, dioxanyl, dioxolanyl, dihydropyridinyl, dihydrofuranyl, dihydroisoxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, oxiranyl, oxetanyl, piperazinyl, piperidinyl, pyrazolidinyl, pyranyl and tetrahydropyrrolyl;
  • C(0)N(H)(Ci- 6 -alkyl) selected from the group consisting of C(0)N(H)(CH 3 ) and C(0)N(H)(CH 2 CH 3 );
  • C(0)N(Ci- 6 -alkyl) 2 selected from the group consisting of C(0)N(CH 3 ) 2 and 0(0)N( ⁇ 1 ⁇ 4 ⁇ 1 ⁇ 4) 2 ;
  • C(0)0(Ci- 6 -alkyl) selected from the group consisting of C(0)0-CH 3 , C(0)0-CH 2 CH 3 , C(0)0- (CH 2 ) 2 CH 3 , C(0)0-CH(CH 3 ) 2 ;
  • S(0)-Ci- 6 -alkyl selected from the group consisting of S(0)-CH 3 , S(0)-CH 2 CH 3 , S(0)-(CH 2 ) 2 CH 3 , S(O)- CH(CH 3 ) 2 ;
  • S(0) 2 -Ci- 6 -alkyl selected from the group consisting of S(0) 2 -CH 3 , S(0) 2 -CH 2 CH 3 , S(0) 2 -(CH 2 ) 2 CH 3 , S(0) 2 -CH(CH 3 ) 2 ;
  • S(0)-C 3-6 -cycloalkyl selected from the group consisting of S(0)-cyelopropyl, S(0)-cyelobutyl, S(O)- cyclopentyl, S(0)-cyciohexyl;
  • S(0) 2 -C 3-6 -cycloalkyl selected from the group consisting of S(0) 2 -cyclopropyl, S(0) 2 -cyclobutyl, S(0) 2 - cyclopentyl, S(0) 2 -cyclohexyl; or
  • phenyl which is unsubstituted or mono- or disubstituted with one or more substituents selected from the group consisting of F, Cl, Br, CN, OH, 0-CH 3 , or CH 3 ; or
  • 5- or 6-membered heteroaryl selected from the group consisting of pyridyl, pyrimidinyl,
  • pyridazinyl pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, thienyl, triazolyl and thiadiazolyl;
  • 5- or 6-membered heteroaryl is unsubstituted or mono- or disubstituted with one or more substituents selected from the group consisting of F, Cl, Br, CN, OH, 0-CH 3 , or CH 3 .
  • R 4 represents H; methyl, CF 3 , CHF 2 , CH 2 F, ethyl, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CF 2 CH 3 , CHFCH 3 , n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH 2 OH, CH2CH2OH, (CH 2 ) 3 OH, (CH 2 )40H, C(H)(OH)-CH 3 , CH 2 C(H)(OH)-CH 3 , CH 2 C(CH 3 ) 2 OH, CH 2 OCH 3 , CH 2 CH 2 OCH 3 , (CH 2 ) 3 OCH 3 , CH 2 S(0)-CH 3 , CH 2 CH 2 S(0)-CH 3 , (CH 2 ) 3 S(0)-CH 3 , (CH 2 ) 4 S(0)-CH 3 , C(H)(S(0)-CH 3 )
  • L represents bond, C3 ⁇ 4 or C(O);
  • R 4 represents H, Ci- 6 -alkyl, Ci- 6 -alkylene-OH, Ci- 6 -alkylene-0-Ci- 6 -alkyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl, aryl, 5 or 6-membered heteroaryl, C(0)NH 2 , C(0)N(H)(Ci- 6 -alkyl), C(0)N(Ci- 6 -alkyl) 2 , C(0)0-(Ci- 6 -alkyl); S(0)-Ci -6 -alkyl, S(0) 2 -Ci- 6 -alkyl, S(0)-C 3-6 -cycloalkyl, or S (0) 2 -C 3 -6 - cycloalkyl . More preferably,
  • L represents bond, C3 ⁇ 4 or C(O);
  • R 4 represents
  • Ci- 6 -alkyl selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec- butyl, tert-butyl, n-pentyl, 2-pentyl, 3 -pentyl, 2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2- methylbut-2-yl, 2,2-dimethylpropyl and n-hexyl;
  • Ci - 6 -alkyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, Cl, Br, CN, OH, 0-CH 3 , O-CH 2 CH 3 , 0-(CH 2 ) 2 CH 3 , 0-CH(CH 3 ) 2 , S(0)-CH 3 , and S(0) 2 -CH 3 ;
  • Ci- 6 -alkylene-OH selected from the group consisting of CH 2 OH, CH 2 CH 2 OH, (CH 2 ) 3 OH, (CH 2 ) 4 0H, C(H)(OH)-CH 3 , CH 2 C(H)(OH)-CH 3 , C(CH 3 ) 2 -OH, C(H)(OH)-C(CH 3 ) 2 , and CH 2 C(CH 3 ) 2 -OH,
  • Ci- 6 -alkylene-0-Ci- 6 -alkyl selected from the group consisting of CH 2 0CH 3 , CH 2 CH 2 0CH 3 , (CH 2 ) 3 OCH 3 , (CH 2 ) 4 OCH 3 , (CH 2 ) 5 OCH 3 , and (CH 2 ) 6 0CH 3 ,
  • cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
  • 3 to 6-membered heterocycloalkyl selected from the group consisting of tetrahydropyranyl, morpholinyl, pyrrolidinyl, 4-methylpiperazinyl, morpholinonyl, azetidinyl, aziridinyl, dithiolanyl, dihydropyrrolyl, dioxanyl, dioxolanyl, dihydropyridinyl, dihydrofuranyl, dihydroisoxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, oxiranyl, oxetanyl, piperazinyl, piperidinyl, pyrazolidinyl, pyranyl and tetrahydropyrrolyl;
  • C(0)N(H)(Ci- 6 -alkyl) selected from the group consisting of C(0)N(H)(CH 3 ) and C(0)N(H)(CH 2 CH 3 );
  • C(0)N(Ci-6-alkyl) 2 selected from the group consisting of C(0)N(CH 3 ) 2 and C(0)N(CH 2 CH 3 ) 2 ;
  • C(0)0-(Ci- 6 -alkyl) selected from the group consisting of C(0)0-CH 3 , C(0)0-CH 2 CH 3 , C(0)0- (CH 2 ) 2 CH 3 , and C(0)0-CH(CH 3 ) 2 ;
  • S(0)-Ci -6 -alkyl selected from the group consisting of S(0)-C3 ⁇ 4, S(0)-CH 2 CH 3 , S(0)-(CH 2 ) 2 CH 3 , S(O)- CH(CH 3 ) 2 ;
  • S(0) 2 -Ci- 6 -alkyl selected from the group consisting of S(0) 2 -CH 3 , S(0) 2 -CH 2 CH 3 , S(0) 2 -(CH 2 ) 2 CH 3 , and S(0) 2 -CH(CH 3 ) 2 ;
  • S(0)-C 3-6 -cycloalkyl selected from the group consisting of S(0)-cyclopropyl, S(0)-cyclobutyl, S(O)- cyclopentyl, and S(0)-cyclohexyl;
  • S(0) 2 -C 3-6 -cycloalkyl selected from the group consisting of S(0) 2 -cyclopropyl, S(0) 2 -cyclobutyl, S(0) 2 -cyclopentyl, and S(0) 2 -cyclohexyl;
  • phenyl which is unsubstituted or mono- or disubstituted with one or more substituents selected from the group consisting of F, Cl, Br, CN, OH, 0-CH 3 , and CH 3 ; or 5- or 6-membered heteroaryl selected from the group consisting of pyridyl, pyrimidinyl,
  • pyridazinyl pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, thienyl, triazolyl and thiadiazolyl;
  • 5- or 6-membered heteroaryl is unsubstituted or mono- or disubstituted with one or more substituents selected from the group consisting of F, Cl, Br, CN, OH, 0-C3 ⁇ 4, or C3 ⁇ 4.
  • X3 represents N(L-R 4 ) and X2 represents C3 ⁇ 4 or C(O) and X4 represent C3 ⁇ 4;
  • n 0, 1 or 2
  • R 1 represents phenyl, pyridyl, pyrimidinyl, thiophenyl, thiazolyl or isothiazolyl
  • phenyl, pyridyl, pyrimidinyl, thiophenyl, thiazolyl and isothiazolyl independently from one another are unsubstituted or monosubstituted with one or more substituents selected from the group consisting of Cl, Br, unsubstituted Ci-6-alkyl and CF 3 ;
  • R 2 represents O-CH 3 or Cl ;
  • R 3 represents F
  • L represents bond, C3 ⁇ 4 or C(O);
  • R 4 represents
  • Ci-6-alkyl selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec- butyl, tert-butyl, n-pentyl, 2-pentyl, 3 -pentyl, 2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2- methylbut-2-yl, 2,2-dimethylpropyl and n-hexyl;
  • Ci-6-alkyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, Cl, Br, CN, OH, O-CH3, O-CH2CH3, 0-(CH 2 ) 2 CH3, 0-CH(CH 3 ) 2 , S(O)- CH 3 , and S(0) 2 -CH 3 ;
  • Ci-6-alkylene-OH selected from the group consisting of CH2OH, CH2CH2OH, (CH2)30H, (CH2)40H, C(H)(OH)-CH 3 , CH 2 C(H)(OH)-CH 3 , C(CH 3 ) 2 -OH, C(H)(OH)-C(CH 3 ) 2 , and CH 2 C(CH 3 )2-OH,
  • Ci- 6 -alkylene-0-Ci- 6 -alkyl selected from the group consisting of CH2OCH3, CH2CH2OCH3, (CH2)30CH3, (CH 2 ) 4 OCH3, (CH 2 ) 5 OCH 3 , and (CH 2 ) 6 0CH 3 ,
  • cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
  • 3 to 6-membered heterocycloalkyl selected from the group consisting of tetrahydropyranyl, morpholinyl, pyrrolidinyl, 4-methylpiperazinyl, morpholinonyl, azetidinyl, aziridinyl, dithiolanyl, dihydropyrrolyl, dioxanyl, dioxolanyl, dihydropyridinyl, dihydrofuranyl, dihydroisoxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, oxiranyl, oxetanyl, piperazinyl, piperidinyl, pyrazolidinyl, pyranyl and tetrahydropyrrolyl;
  • C(0)N(H)(Ci- 6 -alkyl) selected from the group consisting of C(0)N(H)(CH 3 ) and C(0)N(H)(CH 2 CH 3 );
  • C(0)N(Ci- 6 -alkyl) 2 selected from the group consisting of C(0)N(CH 3 ) 2 and 0(0)N( ⁇ 1 ⁇ 4 ⁇ 1 ⁇ 4) 2 ;
  • C(0)0(Ci- 6 -alkyl) selected from the group consisting of C(0)0-CH 3 , C(0)0-CH 2 CH 3 , C(0)0- (CH 2 )2CH 3 , and C(0)0-CH(CH 3 ) 2 ;
  • S(0)-Ci- 6 -alkyl selected from the group consisting of S(0)-CH 3 , S(0)-CH 2 CH 3 , S(0)-(CH 2 ) 2 CH 3 , and S(0)-CH(CH 3 ) 2 ;
  • S(0) 2 -Ci- 6 -alkyl selected from the group consisting of S(0) 2 -CH 3 , S(0) 2 -CH 2 CH 3 , S(0) 2 -(CH 2 ) 2 CH 3 , and S(0) 2 -CH(CH 3 ) 2 ;
  • S(0)-C 3-6 -cycloalkyl selected from the group consisting of S(0)-cyelopropyl, S(0)-cyelobutyl, S(O)- cyclopentyl, and S(0)-eyclohexyl;
  • S(0) 2 -C 3-6 -cycloalkyl selected from the group consisting of S(0) 2 -cyclopropyl, S(0) 2 -cyclobutyl, S(0) 2 - cyclopentyl, and S(0) 2 -cyclohexyl;
  • phenyl which is unsubstituted or mono- or disubstituted with one or more substituents selected from the group consisting of F, Cl, Br, CN, OH, 0-CH 3 , and CH 3 ; or
  • 5- or 6-membered heteroaryl selected from the group consisting of pyridyl, pyrimidinyl,
  • pyridazinyl pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, thienyl, triazolyl and thiadiazolyl;
  • 5- or 6-membered heteroaryl is unsubstituted or mono- or disubstituted with one or more substituents selected from the group consisting of F, Cl, Br, CN, OH, 0-CH 3 , and CH 3 ; in the form of the free compound or a physiologically acceptable salt thereof.
  • the compound according to the present invention is selected from the group consisting of
  • the compound according to the present invention is a modulator of FPR2, more preferably an agonist of FPR2.
  • the term“modulator of FPR2 (FPR2 modulator)” preferably means that the respective compound exhibits in a target engagement assay an EC50 value on FPR2 of at most 10 mM (10- 1 O 6 mol/L); more preferably at most 1 mM; still more preferably at most 500 nM (10 9 mol/L); yet more preferably at most 300 nM; even more preferably at most 100 nM; most preferably at most 10 nM; and in particular at most 1 nM.
  • a preferred target engagement assay for testing compounds for their potency (EC50) on human FPR2 or FPR1 is described herein below:
  • Cells (hFPRl-Gal5-CHO or hFPR2-Aq-CHO) are suspended in 10 mL of respective complete medium (F12(1X)HAM media; 10% HI-FBS; 0.1 mg/ml Hygromycin B and 0.2 mg/ml Zeocin [for hFPRl only]; 0.4 mg/mL Geneticin and 0.25 mg/ml Zeocin [for hFPR2-Aq only]) and viability is checked using Trypan Blue exclusion. After washing, the cells are plated at 10,000 cells per well in 40 pL complete medium in a 384-well sterile clear bottom black plate and incubated in a 5% CO2 incubator at 37°C for 18 hours.
  • F12(1X)HAM media 10% HI-FBS
  • Hygromycin B 0.1 mg/ml Hygromycin B and 0.2 mg/ml Zeocin [for hFPRl only]
  • Plating media is removed from each well by decanting and gentle tapping before 30 pL of 0.5X Calcium 5 dye solution (0.5X FLIPR Calcium 5 dye (Molecular devices, R8186)); HBSS; 20mM HEPES; 2.5mM Probenecid; 0.025% Pluronic F-127; pH adjusted to 7.4) is added to each well and the plate is then incubated at 37°C for 30 minutes.
  • the plate is equilibrated at room temperature for 10 minutes before placing it in the FLIPR.
  • Compounds are dissolved in DMSO and serially diluted over an 11 point half log (3.16 fold) dilution (2 mM to 20 nM).
  • Compounds are then diluted 1 :50 in assay buffer (HBSS; 20mM HEPES; 2.5mM Probenecid; 0.05% gelatin; 0.1% BSA; pH adjusted to 7.4) just before performing the assay.
  • Compounds are finally added to the respective wells of the cell plate (final assay concentration 10 pM to 100 pM) using the FLIPR (e.g. FLIPR-Tetra, Molecular Devices) and fluorescence readings are captured for 5 minutes.
  • the increase in fluorescence from the basal reading in the presence of the compounds is compared with that of the control wells (wells having no compound) to calculate the activity of the compounds.
  • the EC50 values of the compounds can be determined using e.g. Graph pad Prism software.
  • the compound according to the present invention exhibits in a target engagement assay an EC50 value on FPR2 of at most 1 mM (10 6 mol/L); still more preferably at most 500 nM (10 9 mol/L); yet more preferably at most 300 nM; even more preferably at most 100 nM; most preferably at most 10 nM; and in particular at most 1 nM or at most 100 pM (10 12 mol/L) or at most 10 pM.
  • the compound according to the present invention exhibits in a target engagement assay an EC50 value on FPR2 in the range of from 0.1 nM (10 9 mol/L) to 1000 nM; still more preferably 0.1 nM to 800 nM; yet more preferably 0.1 nM to 500 nM; even more preferably 0.1 nM to 300 nM; most preferably 0.1 nM to 100 nM; and in particular 0.1 nM to 10 nM.
  • the compound according to the present invention exhibits in a target engagement assay an EC50 value on FPR2 in the range of from 1 pM (10 12 mol/L) to 1000 nM; still more preferably 1 pM to 800 nM; yet more preferably 1 pM to 500 nM; even more preferably 1 pM to 300 nM; most preferably 1 pM to 100 nM; and in particular 1 pM to 10 nM.
  • the compound according to the present invention does not activate FPR1.
  • the compound according to the present invention exhibits in a target engagement assay an EC50 value on FPR1 of at least 1 nM (10 9 mol/L); still more preferably at least 500 nM; yet more preferably at least 1 mM (10 6 mol/L); even more preferably at least 100 mM; most preferably at least 500 mM; and in particular at least 1 mM (10 3 mol/L).
  • the compound according to the present invention exhibits a ratio (EC50 on FPR2)/(EC50 on FPR1) in a target engagement assay of >1, more preferably >10, even more preferably >50, still more preferably >100, most preferably >500 and in particular >1000.
  • the compounds according to the present invention are useful as non-peptides modulators of the human FPR2 receptor. More preferably, the compounds according to the present invention are agonists of the human FPR2 receptor.
  • the compounds according to the present invention are preferably useful for the in vivo treatment or prevention of diseases in which participation of FPR2 is implicated.
  • the present invention therefore further relates to a compound according to the present invention for use in the modulation of FPR2 activity.
  • another aspect of the present invention relates to a compound according to the present invention for use in the treatment and/or prophylaxis of a disorder which is mediated at least in part by FPR2, preferably without the activation of FPR1.
  • Still another aspect of the present invention relates to a method of treatment of a disorder which is mediated at least in part by FPR2, preferably without the activation of FPR1 ; comprising the administration of a therapeutically effective amount of a compound according to the present invention to a subject in need thereof, preferably a human.
  • a further aspect of the invention relates to a compound according to the present invention as medicament.
  • the pharmaceutical dosage form comprises a compound according to the present invention and one or more pharmaceutical excipients such as physiologically acceptable carriers, additives and/or auxiliary substances; and optionally one or more further pharmacologically active ingredient.
  • suitable physiologically acceptable carriers, additives and/or auxiliary substances are fillers, solvents, diluents, colorings and/or binders.
  • the pharmaceutical dosage form according to the present invention is preferably for systemic, topical or local administration, preferably for oral administration. Therefore, the pharmaceutical dosage form can be in form of a liquid, semisolid or solid, e.g. in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, films, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, if appropriate pressed into tablets, decanted in capsules or suspended in a liquid, and can also be administered as such.
  • a liquid, semisolid or solid e.g. in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, films, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate
  • the pharmaceutical dosage form according to the present invention is preferably prepared with the aid of conventional means, devices, methods and processes known in the art.
  • the amount of the compound according to the present invention to be administered to the patient may vary and is e.g. dependent on the patient's weight or age and also on the type of administration, the indication and the severity of the disorder.
  • Preferably 0.001 to 100 mg/kg, more preferably 0.05 to 75 mg/kg, most preferably 0.05 to 50 mg of a compound according to the present invention are administered per kg of the patient's body weight.
  • FPR2 is believed to have potential to modify a variety of diseases or disorders in mammals such as humans. These include inflammatory diseases, diabetes, obstructive airway diseases, autoimmune diseases, allergic conditions, rheumatological disorders, HIV-mediated retroviral 5 infections, infectious diseases, sepsis, cardiovascular disorders, fibrotic disorders, neuroinflammation, neurological disorders, pain, prion-mediated diseases, amyloid- mediated disorders, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), inflammatory bowel disease (IBD), ulcerative colitis (UC), rheumatoid arthritis (RA), psoriatic arthritis (PsA), multiple sclerosis (MS). Further, FPR2 is believed to be involved in the modulation of immune responses, such as those elicited through Graft versus Host Disease (GvHD).
  • GvHD Graft versus Host Disease
  • another aspect of the present invention relates to a compound according to the present invention for use in the treatment and/or prophylaxis of a disorder selected from the group consisting of inflammatory diseases, diabetes, obstructive airway diseases, autoimmune diseases, allergic conditions, rheumatological disorders, HIV- mediated retroviral 5 infections, infectious diseases, sepsis, cardiovascular disorders, fibrotic disorders, neuroinflammation, neurological disorders, pain, prion-mediated diseases, amyloid-mediated disorders and Graft versus Host Disease (GvHD).
  • a disorder selected from the group consisting of inflammatory diseases, diabetes, obstructive airway diseases, autoimmune diseases, allergic conditions, rheumatological disorders, HIV- mediated retroviral 5 infections, infectious diseases, sepsis, cardiovascular disorders, fibrotic disorders, neuroinflammation, neurological disorders, pain, prion-mediated diseases, amyloid-mediated disorders and Graft versus Host Disease (GvHD).
  • a disorder selected from the group consisting of inflammatory diseases
  • Still another aspect of the present invention relates to a compound according to the present invention for use in the treatment and/or prophylaxis of a disorder selected from the group consisting of chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), inflammatory bowel disease (IBD), ulcerative colitis (UC), rheumatoid arthritis (RA), psoriatic arthritis (PsA) and multiple sclerosis (MS).
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • IBD inflammatory bowel disease
  • UC ulcerative colitis
  • RA rheumatoid arthritis
  • PsA psoriatic arthritis
  • MS multiple sclerosis
  • a further aspect of the present invention relates to a method of treatment of a disorder selected from the group consisting of inflammatory diseases, diabetes, obstructive airway diseases, autoimmune diseases, allergic conditions, rheumatological disorders, HIV-mediated retroviral 5 infections, infectious diseases, sepsis, cardiovascular disorders, fibrotic disorders, neuroinflammation, neurological disorders, pain, prion-mediated diseases and amyloid-mediated disorders.
  • a disorder selected from the group consisting of inflammatory diseases, diabetes, obstructive airway diseases, autoimmune diseases, allergic conditions, rheumatological disorders, HIV-mediated retroviral 5 infections, infectious diseases, sepsis, cardiovascular disorders, fibrotic disorders, neuroinflammation, neurological disorders, pain, prion-mediated diseases and amyloid-mediated disorders.
  • ACN acetonitrile
  • AcOH acetic acid
  • Boc tert-butyloxycarbonyl
  • Bu butyl
  • Tf triflate
  • dba dibenzylideneacetone
  • DCE dichloroethane
  • DCM dichloromethane
  • DIPEA N,N-diisopropylethylamine
  • DMF N,N-dimethylformamid
  • DMAP 4-(dimethylamino)-pyridine
  • DMS dimethylsulfide
  • DMSO dimethylsulfoxid
  • DPPA Diphenylphosphoryl azide
  • EA ethylacetate
  • EDCI 1 -ethyl-3 -(3- dimethylaminopropyl)carbodiimide
  • Et ethyl
  • E ⁇ 2q diethyl ether
  • EtOAc ethylacetate
  • EtOH ethanol
  • h hour
  • HATU [0-(7
  • LC/MS experiments were performed using a LCMS/MS API 2000 (Applied Biosystem, HPLC: Shimadzu Prominence) or a Waters ACQUITY UPLC system in ESI mode.
  • the compounds according to the present invention were produced in the manner described below.
  • Stepl To a stirred solution of 3-oxo-piperidine-l,4-dicarboxylic acid 1 -tert-butyl ester 4-methyl ester (10.0 g, 37 mmol, 1 eq) in DCM (350 ml) at -78°C was added DIPEA (8.3 ml, 48 mmol, 1.3 eq) drop wise followed by drop wise addition of trifluoromethanesulfonic anhydride (7.4 ml, 44 mmol, 1.2eq) and the reaction mixture was stirred at RT for a period of 2 h. After completion of the reaction (monitored by TLC and LC MS), the reaction mixture was diluted with DCM and washed with aq.
  • reaction mixture was diluted with EA (600 ml) and washed with aq. NaHCCb solution and water. The organic layer was dried over anhyd. Na SC and concentrated under reduced pressure to obtain crude product which was purified by silica gel (100-200 mesh) column chromatography (15% EA/Hexane) to afford 5-(4-methoxy-phenyl)-3,6-dihydro-2H-pyridine-l,4-dicarboxylic acid 1 -tert-butyl ester 4- ethyl ester (8 g, 73% yield) as brown oil.
  • Step3 A stirred solution of 5-(4-methoxy-phenyl)-3,6-dihydro-2H-pyridine-l,4-dicarboxylic acid 1 -tert-butyl ester 4-ethyl ester (8.0 g, 22.0 mmol, 1 eq) in MeOH (200 ml) was degassed with Ar for a period of 15 min followed by the addition of 10% moist Pd-C (2 g) and stirred at RT under 3 ⁇ 4 pressure (450 PSI) for a period of 12 h. After completion of the reaction, it was filtered through celite bed and washed thoroughly with 5% MeOH/ DCM.
  • Step4 To a stirred solution of 3-(4-methoxy-phenyl)-piperidine-l,4-dicarboxylic acid 1 -tert-butyl ester 4-ethyl ester (8.0 g, 22.0 mmol, leq) in EtOH (200 ml) was added 21% NaOEt in EtOH (7.5 ml, 23.14 mmol, 1.05 eq) and refluxed for a period of 16 h. After completion of the reaction, it was concentrated under reduced pressure and diluted with aq. NH 4 CI solution and the organics were extracted with DCM.
  • Step5 To a stirred solution of ira «s-3-(4-methoxy-phenyl)-piperidine-l,4-dicarboxylic acid 1 -tert-butyl ester 4- ethyl ester (7.8 g, 21.5 mmol, leq) in MeOH (300 ml) and H2O (30 ml) was added K 2 CO 3 (11.9 g, 86 mmol, 4.0 eq) and the mixture was refluxed for a period of 16 h. After completion of the reaction, it was concentrated under reduced pressure and diluted with water and extracted with EtOAc. Then the aqueous part was acidified by 1(N) HC1 and extracted with 5% MeOH in DCM.
  • Step6 To a stirred solution of ira «s-3-(4-methoxy-phenyl)-piperidine-l,4-dicarboxylic acid 1 -tert-butyl ester (leq) in toluene (5 ml/ mmol) was added Et3N ( 2.0 eq) followed by the addition of DPP A (2.0 eq) and the reaction mass was refluxed for a period of 4 h. The reaction mixture was cooled to RT and 4-chloro-phenylamine (1.3 eq) was added and the reaction mixture was heated at 120°C for a period of 16 h.
  • Step7 To a stirred solution of ira «s-4-[3-(4-chloro-phenyl)-ureido]-3-(4-methoxy-phenyl)-piperidine-l- carboxylic acid tert-butyl ester (1 eq) in 1, 4-dioxane (2.5 ml/mmol) was added 4M HC1 in dioxane (7.5 ml/mmol) followed by stirring at RT for a period of 2 h. After completion of the reaction (monitored by TLC and LC MS), the reaction mixture was concentrated under reduced pressure to get the crude material which was again basified with saturated aq.
  • Example 2a l-(4-bromophenyl)-3-(3-(4-methoxyphenyl)piperidin-4-yl)urea
  • Stepl To a stirred solution of ira «s-3-(4-methoxy-phenyl)-piperidine-l,4-dicarboxylic acid 1-tert-butyl ester (1 eq) in toluene (5 ml/ mmol) was added Et N ( 2.0 eq) followed by the addition of DPPA (2.0 eq) and the reaction mass was refluxed for a period of 4 h. The reaction was cooled to RT and 4-bromo-phenylamine (1.3 eq) was added and the reaction mixture was heated at 120°C for a period of 16 h. The reaction mass was concentrated in vacuo and diluted with EA (300 ml) and washed with water and brine.
  • Step2 To a stirred solution of ira «s-4-[3-(4-bromo-phenyl)-ureido]-3-(4-methoxy-phenyl)-piperidine-l- carboxylic acid tert-butyl ester (leq) in 1, 4-dioxane (2.5 ml/mmol) was added 4M HCI in dioxane (7.5 ml/mmol) followed by stirring at RT for a period of 2 h. After completion of the reaction (monitored by TLC and LC MS), the reaction mixture was concentrated under reduced pressure to get the crude material which was again basified with saturated aq.
  • Example 3a trans- 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -methylpiperidin-4-yl)urea
  • Example la (leq) in DCE (10 ml/mmol) at 0°C was added Et 3 N (10.0 eq) and stirred for 5 min followed by the addition of HCHO (2eq) and the reaction mixture was again stirred for 30 min at 0°C. Then was added sodium triacetoxy borohydride (4 eq) and stirred at RT for a period of 16 h. After completion of the reaction (monitored by TLC and LC MS), the reaction mixture was diluted with DCM, the organic part was washed with water and brine.
  • Example 4a trans- 1 -(4-bromophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -methylpiperidin-4-yl)urea
  • Example 4a was synthesized starting from Example 2a following Representative procedure for reductive amination described for Example 3a.
  • Example 5 1 -(4-chlorophenyl)-3 -( 1 -(2-methoxyethyl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
  • Example 5a trans- 1 -(4-chlorophenyl)-3 -( 1 -(2-methoxyethyl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
  • Example la 200 mg, 0.50 mmol, leq
  • ACN ACN
  • K 2 CO 3 174 mg, 1.26 mmol, 2.5 eq
  • l-bromo-2-methoxy-ethane 77 mg, 0.55 mmol, 1.1 eq
  • the reaction mixture was stirred at reflux for a period of 16 h.
  • the reaction mixture was concentrated and then diluted with water and extracted with EA (3 x 150 ml), the organic layer was given washed with water and brine. The combined organic layer was dried over anhyd.
  • Stepl To a stirred solution of l-(tert-butyl) 4-ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine- l,4(2H)-dicarboxylate (3.5 g, 8.7 mmol, 1 eq) and 2-fluoro-4-methoxy phenyl boronic acid (1.9 g, 11.29 mmol, 1.3 eq) in THF (75 ml) at RT was added K 2 CO 3 (3.0 g, 21.7 mmol, 2.5 eq) and the reaction mixture was degassed with Ar for a period of 15 minutes followed by the addition of Pd(PPli 3 ) 4 (302 mg, 0.26 mmol, 0.03 eq) and the mixture was stirred under reflux for 16 h.
  • Pd(PPli 3 ) 4 302 mg, 0.26 mmol, 0.03 eq
  • Step2 A stirred solution of l-(tert-butyl) 4-ethyl 5-(2-fluoro-4-methoxyphenyl)-3,6-dihydropyridine-l,4(2H)- dicarboxylate (3.7 g, 9.76 mmol, 1 eq) in MeOH (120 ml) was degassed with Ar for a period of 15 min followed by the addition of 10% moist Pd-C (1.2 g) and stirred at 80°C under H 2 pressure (450 PSI) for a period of 5 days. After completion of the reaction, it was filtered through celite bed and washed thoroughly with 5% MeOH/DCM.
  • Step3 To a stirred solution of l-(tert-butyl) 4-ethyl 3-(2-fluoro-4-methoxyphenyl)piperidine-l,4-dicarboxylate (4.0 g, 10.50 mmol, 1 eq) in EtOH (50 ml) was added 21% NaOEt in EtOH (3.6 ml, 11.02 mmol, 1.05 eq) and the mixture was refluxed for a period of 5 h. After completion of the reaction, it was concentrated under reduced pressure and diluted with aq. NH 4 CI solution and the organics were extracted with DCM.
  • Step4 To a stirred solution of tra «s-l-(tert-butyl) 4-ethyl 3-(2-fluoro-4-methoxyphenyl)piperidine-l,4- dicarboxylate (3.8 g, 9.97 mmol, 1 eq) in EtOH (10 ml) and H O (25 ml) was added KOH (1.67 g, 30 mmol, 3.0 eq) and the mixture was refluxed for a period of 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure and diluted with water and extracted with EtOAc. Then the aq. part was acidified by 1(N) HC1 and extracted with 5% MeOH in DCM.
  • Step5 To a stirred solution of tra «5-l-(tert-butoxycarbonyl)-3-(2-fluoro-4-methoxyphenyl)piperidine-4- carboxylic acid (1.2 g, 3.40 mmol, 1.0 eq) in toluene (25 ml) was added Et N ( 1.0 ml, 6.80 mmol, 2.0 eq) followed by the addition of DPP A (1.5 ml, 6.80 mmol, 2.0 eq) and the reaction mass was refluxed for a period of 4 h.
  • the reaction was cooled to RT and 4-chloro phenylamine (650 mg, 5.0 mmol, 1.5 eq) was added and the reaction mixture was heated at 120°C for a period of 16 h.
  • the reaction mass was concentrated in vacuo and diluted with EA (300 ml) and washed with water and brine. The combined organic layer was dried over anhydr.
  • Step6 Following Representative deprotection of Boc group under acidic conditions (described for Example 43a, Step-2) tra «5-tert-butyl 4-(3 -(4-chlorophenyl)ureido)-3 -(2-fluoro-4-methoxyphenyl)piperidine- 1 -carboxylate was converted to desired tra «5-l-(4-chlorophenyl)-3-(3-(2-fluoro-4-methoxyphenyl)piperidin-4-yl)urea (off white solid, 18% yield).
  • Example 7a l-(4-bromophenyl)-3-(3-(2-fluoro-4-methoxyphenyl)piperidin-4-yl)urea
  • Example 7a was synthesized in analogy to synthesis described for Example 6a.
  • Example 8 l-(4-chlorophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)piperidin-4-yl)urea
  • Stepl To a stirred solution of l-(tert-butyl) 4-ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine- l,4(2H)-dicarboxylate (6.0 g, 14.88 mmol, 1 eq) and 2, 6-difluoro-4-methoxy phenyl boronic acid (3.1 g, 16.37 mmol, 1.1 eq) in THF (150 ml) at RT was added K 2 CO 3 (5.14 g, 37.22 mmol, 2.5 eq) and the reaction mixture was degassed with Ar for a period of 15 minutes followed by the addition of Pd(PPli3)4 (516 mg, 0.44 mmol, 0.03 eq) and the mixture was stirred under reflux for 16 h.
  • K 2 CO 3 5.14 g, 37.22 mmol, 2.5 eq
  • Step2 A stirred solution of l-(tert-butyl) 4-ethyl 5-(2,6-diiluoro-4-methoxyphenyl)-3,6-dihydropyridine-l,4(2H)- dicarboxylate (5.0 g, 12.53 mmol, leq) in MeOH (70 ml) was degassed with Ar for a period of 15 min followed by the addition of 10% moist Pd-C (1.5 g) and stirred at 80°C under 3 ⁇ 4 pressure (450 PSI) for a period of 5 days. After completion of the reaction, it was filtered through celite bed and washed thoroughly with 5% MeOH/DCM.
  • Step3 To a stirred solution of l-(tert-butyl) 4-ethyl 3-(2,6-diiluoro-4-methoxyphenyl)piperidine-l,4- dicarboxylate (5 g, 12.53 mmol, leq) in EtOH (35 ml) was added 21% NaOEt in EtOH (4.0 ml, 13.16 mmol, 1.05 eq) and refluxed for a period of 5 h. After completion of the reaction, it was concentrated under reduced pressure and diluted with aq. NH4CI solution and the organics were extracted with DCM.
  • Step4 To a stirred solution of trans- l-(tert-butyl) 4-ethyl 3-(2,6-difluoro-4-methoxyphenyl)piperidine-l,4- dicarboxylate (5.0 g, 12.53 mmol, leq) in EtOH (10 ml) and H2O (25 ml) was added KOH (2.1 g, 37.59 mmol, 3.0 eq) was refluxed for a period of 16 h. After completion of the reaction, it was concentrated under reduced pressure and diluted with water and extracted with EtOAc. Then the aqueous part was acidified by 1(N) HC1 and extracted with 5% MeOH in DCM. The combined organic layer was dried over anhydr.
  • Step5 To a stirred solution of tra «5-l-(tert-butoxycarbonyl)-3-(2,6-difluoro-4-methoxyphenyl)piperidine-4- carboxylic acid (1.0 g, 2.70 mmol, 1.0 eq) in toluene (50 ml) was added Et3N ( 0.8 ml, 5.40 mmol, 2.0 eq) followed by the addition of DPP A (1.2 ml, 5.40 mmol, 2.0 eq) and the reaction mass was refluxed for a period of 4 h.
  • the reaction was cooled to RT and 4-chloro phenylamine (515 mg, 4.04 mmol, 1.5 eq) was added and the reaction mixture was heated at 120°C for a period of 16 h.
  • the reaction mass was concentrated in vacuo and diluted with EA (250 ml) and washed with water and brine. The combined organic layer was dried over anhydr.
  • Step6 Following Representative deprotection of Boc group under acidic conditions (described for Example 43a, Step-2) tra «5-4-[3-(4-chloro-phenyl)-ureido]-3-(2,6-difluoro-4-methoxy-phenyl)-piperidine-l -carboxylic acid tert-butyl ester was converted to desired tra «5-l-(4-chlorophenyl)-3-(3-(2,6-difluoro-4-methoxyphenyl)piperidin- 4-yl)urea (off white solid, 18% yield).
  • Example 9a l-(4-bromophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)piperidin-4-yl)urea
  • Example 9a was synthesized in analogy to synthesis described for Example 8a.
  • Example 10a l-(4-chlorophenyl)-3-(3-(2-fluoro-4-methoxyphenyl)-l-(2-methoxyethyl)piperidin-4- vDurea
  • Example 10a was synthesized starting from Example 6a following Representative procedure for N-alkylation described in synthesis of Example 5a (yield: 25%).
  • Example 11 1 -(4-bromophenyl)-3 -(3 -(2-fluoro-4-methoxyphenyl)- 1 -(2-methoxyethyl)piperidin-4-yl)urea
  • Example 11a trans- 1 -(4-bromophenyl)-3 -(3 -(2-fluoro-4-methoxyphenyl)- 1 -(2-methoxyethyl)piperidin-4- vDurea
  • Example 11a was synthesized starting from Example 7a following Representative procedure for N-alkylation described in synthesis of Example 5a (yield: 47%).
  • Example 12 l-(4-chlorophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2-methoxyethyl)piperidin-4-yl)urea
  • Example 12a trans- 1 -(4-chlorophenyl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-methoxyethyl)piperidin-4- vDurea
  • Example 12a was synthesized starting from Example 8a following Representative procedure for N-alkylation described in synthesis of Example 5a (yield: 45%).
  • Example 13 l-(4-bromophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2-methoxyethyl)piperidin-4-yl)urea
  • Example 13a trans- 1 -(4-bromophenyl)-3 -(3 -(2.6-difhioro-4-methoxyphenyl)- 1 -(2-methoxyethyl)piperidin-4- vDurea
  • Example 13a was synthesized starting from Example 9a following Representative procedure for N-alkylation described in synthesis of Example 5a (yield: 35%).
  • Example 14 l-(4-chlorophenyl)-3-(l-(cvclopropylmethyl)-3-(2.6-difluoro-4-methoxyphenyl)piperidin-4-yl)urea
  • Example 14a l-(4-chlorophenyl)-3-(l-(cvclopropylmethyl)-3-(2.6-difluoro-4-methoxyphenyl)piperidin-4- vDurea
  • Example 14.1 e3 ⁇ 4t/-tra3 ⁇ 4 ⁇ -l-(4-chlorophenyl)-3-(l-(cvclopropylmethyl)-3-(2.6-difluoro-4- methoxyphenyl)piperidin-4-yl)urea
  • Example 14 2: l-(4-chlorophenyl)-3-(l-(cvclopropylmethyl)-3-(2.6-difluoro-4-
  • Example 14a was synthesized starting from Example 8a following Representative procedure for reductive amination described in synthesis of Example 3a (yield: 55%).
  • chiral SFC Chiralpak AD-H (250 x 4.6 mm)
  • Example 15 l-(4-chlorophenyl)-3-(l -cvclopropyl-3 -(2, 6-difluoro-4-methoxyphenvi)piperidin-4-yl)urea
  • Example 15a trans- 1 -(4-chlorophenyi)-3 -( 1 -cvclopropyl-3 -(2.6-difluoro-4-methoxyphenvi)piperidin-4-yl)urea
  • Example 8a (leq) and cyclopropylboronic acid (2 eq) in DCE (5 ml/mmol) at RT was added Na 2 C0 3 (2 eq) and Cu(OAc) 2 (1 eq) and the reaction mixture was stirred at RT for a period of 24-48 h under oxygen atmosphere.
  • the reaction mixture was diluted with DCM and washed with water and brine.
  • the combined organic layer was dried over anhyd. Na 2 S0 4 and concentrated under reduced pressure.
  • the obtained crude was purified by silica gel (100-200 mesh) column chromatography to obtain the desired compound (yield: 57%).
  • chiral SFC Chiralpak AD-H (250 x 4.6 mm)
  • Example 16 l-(4-chlorophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-methylpiperidin-4-yl)urea
  • Example 16a l-(4-chlorophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-methylpiperidin-4-yl)urea
  • Example 16a was synthesized starting from Example 8a following Representative procedure for reductive amination described in synthesis of Example 3a (yield: 60%).
  • LC-MS: m/z [M+H] + 410.4 (exact mass calc.
  • chiral SFC Chiralpak AD-H (250 x 4.6 mm)
  • Example 17 1 -(4-chlorophenyl)-3 -(3 -(2.6-difluoro-4-methoxyphenyl)- 1 -ethylpiperidin-4-yl)urea
  • Example 17a l-(4-chlorophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-ethylpiperidin-4-yl)urea
  • Example 17a was synthesized starting from Example 8a following Representative procedure for N-alkylation described in synthesis of Example 5a (yield: 65%).
  • chiral SFC Chiralpak AD-H (250 x 4.6 mm)
  • Example 18 l-(4-chlorophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2-hvdroxyethyl)piperidin-4-yl)urea
  • Example 18a l-(4-chlorophenvi)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2-hvdroxyethyl)piperidin-4- vDurea
  • Example 18.1 e3 ⁇ 4t7-tra3 ⁇ 4,y-l-(4-chlorophenvi)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2- hvdroxyethyl)piperidin-4-yl)urea
  • Example 18a was synthesized starting from Example 8a following Representative procedure for N-alkylation described in synthesis of Example 5a (yield: 42%).
  • Example 19 l-(4-chlorophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2.2-difluoroethyl)piperidin-4-yl)urea
  • Example 19a trans- 1 -(4-chlorophenyl)-3 -(3 -(2.6-difluoro-4-methoxyphenyl)- 1 -(2.2-difluoroethyl)piperidin-4- vDurea
  • Example 19.1 e3 ⁇ 4t/-tra3 ⁇ 4 ⁇ -l-(4-chlorophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2.2- difluoroethyl)piperidin-4-yl)urea
  • Example 19a was synthesized starting from Example 8a following Representative procedure for N-alkylation described in synthesis of Example 5a but using CS2CO3 as base instead of K2CO3 (yield: 32%).
  • Example 20 l-(4-chlorophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2-fluoroethyl)piperidin-4-yl)urea
  • Example 20a trans- 1 -(4-chlorophenyi)-3 -(3 -(2.6-difluoro-4-methoxyphenyl)- 1 -(2-fluoroethyl)piperidin-4- vDurea
  • Example 20.1 e3 ⁇ 4t7-tra3 ⁇ 4,y-l-(4-chlorophenvi)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2- fluorOCthyl)piperidin-4-yl)urea
  • Example 20a was synthesized starting from Example 8a following Representative procedure for N-alkylation described in synthesis of Example 5a (yield: 80%).
  • chiral SFC Chiralpak AD-H (250 x 4.6 mm)
  • Example 21 1 -(4-chlorophenvD-3 -( 1 -(2.2-difluoroethyi)-3 -(4-methoxyphenvi)piperidin-4-yl)urea
  • Example 21a l-(4-chlorophenvi)-3-(l-(2.2-difluoroethvi)-3-(4-methoxyphenvi)piperidin-4-yl)urea
  • Example 21.1 e3 ⁇ 4t7-tra3 ⁇ 4,y-l-(4-chlorophenvi)-3-(l-(2.2-difluoroethvi)-3-(4-methoxyphenyl)piperidin-4- vDurea
  • Example 21.2 l-(4-chlorophenyl)-3-(l-(2.2-difluoroethyl)-3-(4-methoxyphenyl)piperidin-4-
  • Example 21a was synthesized starting from Example la following Representative procedure for N-alkylation described in synthesis of Example 5a but using CS2CO3 as base instead of K2CO3 (yield: 24%).
  • chiral HPLC Chiralpak IA (250 x 4.6 mm; Mobile Phase: Hexane/DCM/EtOH: 50/25/25)
  • Example 22 l-(4-chlorophenyl)-3-(l-(2-fluorocthyl)-3-(4-methoxyphenyl)piperidin-4-yl)urea
  • Example 22a trans- 1 -(4-chlorophenyl)-3 -( 1 -(2-fluoroethyl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
  • Example 22.2 ent2-trans- 1 -(4-chlorophenyl)-3 -( 1 -(2-fluoroethyl)-3 -(4-methoxyphenyl)piperidin-4- vDurea
  • Example 22a was synthesized starting from Example la following Representative procedure for N-alkylation described in synthesis of Example 5a but using CS2CO3 as base instead of K2CO3 (yield: 47%).
  • chiral HPLC Chiralpak IA (250 x 4.6 mm; Mobile Phase: Hexane/DCM/EtOH: 50/25/25)
  • Example 23 l-(4-chlorophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2-(methylsulfonyl)ethyl)piperidin-4- vDurea
  • Example 23a l-(4-chlorophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2- (methylsulfonyl)ethyl)piperidin-4-yl)urea
  • Example 23a was synthesized starting from Example 8a following Representative procedure for N-alkylation described in synthesis of Example 5a but using CS2CO3 as base instead of K2CO3 (yield: 47%).
  • Example 24 l-(4-chlorophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-isopropylpiperidin-4-yl)urea
  • Example 24a trans- 1 -(4-chlorophenyl)-3 -(3 -(2.6-difhioro-4-methoxyphenyl)- 1 -isopropylpiperidin-4-yl)urea
  • Example 24a was synthesized starting from Example 8a following Representative procedure for N-alkylation described in synthesis of Example 5a but using CS2CO3 as base instead of K2CO3 (yield: 32%).
  • Example 25 1 -(4-chlorophenyl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-hydro y-2-methylpropyl)piperidin-
  • Example 25a l-(4-chlorophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2-hvdroxy-2- methylpropyl)piperidin-4-yl)urea
  • Example 8a To a stirred solution of Example 8a (150 mg, 0.38 mmol, leq) in EtOH (15 ml) was added 2,2-dimethyl-oxirane (46.5 mg, 0.64 mmol, 1.7 eq) and the mixture was stirred under reflux for a period of 24 h under inert atmosphere.
  • the reaction mixture was rota evaporated and purified by silica gel (100-200 mesh) column chromatography to obtain trans- 1 -(4-chlorophenyl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-hydroxy-2-methylpropyl)piperidin-4- yl)urea (55 mg, 30% yield) as off white solid.
  • Example 26 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-4-yl)piperidin-4-yl)urea
  • Example 26a trans- 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-4-yl)piperidin-4-yl)urea
  • Example la (leq) and Ar-X (1.2 eq) in toluene (10-12 ml/mmol) at RT was added t- BuONa (1.3 eq), Pd 2 (dba)3 (0.05 eq) and BGNAR (0.15 eq) and the reaction mixture was stirred under reflux for a period of 24-48 h under inert atmosphere.
  • the reaction mixture was then diluted with EA and washed with water and brine.
  • the combined organic layer was dried over anhyd. Na 2 SC> 4 and concentrated under reduced pressure.
  • the obtained crude product was purified by silica gel (100-200 mesh) column chromatography to obtain the desired compound as off white solid (8% yield).
  • Example 27 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-3 -yl)piperidin-4-yl)urea
  • Example 27a l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-(pyridin-3-yl)piperidin-4-yl)urea
  • Example 27a was synthesized starting from Example la following Representative procedure for N-arylation ( Pd - catalyzed Buchwald coupling) described in synthesis of Example 26a (yield: 10%).
  • Example 28 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-3 -yl)piperidin-4-yl)urea
  • Example 28a was synthesized starting from Example la following Representative procedure for N-arylation ( Pd - catalyzed Buchwald coupling) described in synthesis of Example 26a (yield: 6%).
  • Example 29 l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-(pyrimidin-5-yl)piperidin-4-yl)urea
  • Example 29a trans- 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyrimidin-5-yl)piperidin-4-yl)urea
  • Example 29a was synthesized starting from Example la following Representative procedure for N-arylation ( Pd - catalyzed Buchwald coupling) described in synthesis of Example 26a (yield: 8%).
  • Example 30 l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-(2-methylpyridin-4-yl)piperidin-4-yl)urea
  • Example 30a trans- 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(2-methylpyridin-4-yl)piperidin-4-yl)urea
  • Example 30a was synthesized starting from Example la following Representative procedure for N-arylation ( Pd - catalyzed Buchwald coupling) described in synthesis of Example 26a (yield: 20%).
  • Example 31 l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-(2-methoxypyridin-4-yl)piperidin-4-yl)urea
  • Example 31a was synthesized starting from Example la following Representative procedure for N-arylation ( Pd - catalyzed Buchwald coupling) described in synthesis of Example 26a (yield: 11%).
  • Example 32 l-(4-chlorophenyl)-3-((3R.4R)-l-(2-fluoropyridin-4-yl)-3-(4-methoxyphenyl)piperidin-4-yl)urea
  • Example 32a l-(4-chlorophenyl)-3-((3R.4R)-l-(2-fluoropyridin-4-yl)-3-(4-methoxyphenyl)piperidin-4- vDurea
  • Example 32a was synthesized starting from Example la following Representative procedure for N-arylation ( Pd - catalyzed Buchwald coupling) described in synthesis of Example 26a (yield: 10%).
  • Example 33 l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-(3-methylpyridin-4-yl)piperidin-4-yl)urea
  • Example 33a trans- 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(3 -methylpyridin-4-yl)piperidin-4-yl)urea
  • Example 33a was synthesized starting from Example la following Representative procedure for N-arylation ( Pd - catalyzed Buchwald coupling) described in synthesis of Example 26a (yield: 15%).
  • Example 34 l-(4-chlorophenyl)-3-(l-(3-fluoropyridin-4-yl)-3-(4-metlioxyplienyl)piperidin-4-yl)urea
  • Example 34a trans- 1 -(4-chlorophenyl)-3 -( 1 -(3 -fluoropyridin-4-yl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
  • Example 34a was synthesized starting from Example la following Representative procedure for N-arylation ( Pd - catalyzed Buchwald coupling) described in synthesis of Example 26a (yield: 11%).
  • Example 35 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenvD- 1 -(pyridazin-4-yl)piperidin-4-yl)urea
  • Example 35a trans- 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenvD- 1 -(pyridazin-4-yl)piperidin-4-yl)urea
  • Example la To a stirred suspension of Example la (1 eq), in DCM (15 ml/mmol) were added corresponding 4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridazine (3 eq), Cu(OAc)2 (2 eq), molecular sieves (100 mg/mmol), TEA (5 eq) and the mixture was stirred at RT for a period of 4-7 days. After completion of the reaction, it was filtered and the residue was washed thoroughly with 5% MeOH-DCM. The combined filtrate was concentrated under reduced pressure and purified by column chromatography (100-200 mesh silica gel) to obtain the desired product (12% yield).
  • Example 36 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyrimidin-4-yl)piperidin-4-yl)urea
  • Example 36a trans- 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenvD- 1 -(pyrimidin-4-yl)piperidin-4-yl)urea
  • Example 36.2 e3 ⁇ 4t2-tra3 ⁇ 4 ⁇ -l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-(pyrimidin-4-yl)piperidin-4- vDurea
  • Example la 200 mg, 0.56 mmol, 1 eq
  • DMSO DMSO
  • K 2 CO 3 155 mg, 1.12 mmol, 2 eq
  • HI salt of 4-iodo-pyrimidine 222 mg, 0.66 mmol, 1.2 eq
  • Cul 11 mg, 0.056 mmol, 0.1 eq
  • L-proline 6.5 mg, 0.056 mmol, 0.1 eq.
  • the reaction mixture was then stirred at 100°C for a period of 18 h. After completion of the reaction, it was diluted with EtOAc (100 ml) and washed with chilled water (3 x 25 ml) and brine.
  • Example 37 l-(4-chlorophenyl)-3-(l-(5-fluoropyrimidin-2-yl)-3-(4-methoxyphenyl)piperidin-4-yl)urea
  • Example la 200 mg, 0.557 mmol, 1 eq
  • DMF DMF
  • CS2CO3 543 mg, 1.67 mmol, 3 eq
  • 2-chloro-5-fluoro-pyrimidine 88.57 mg, 0.68 mmol, 1.2 eq
  • Example 38 l-(4-chlorophenyl)-3-(l-(5-fluoropyridin-2-yl)-3-(4-methoxyphenyl)piperidin-4-yl)urea
  • Stepl To a stirred solution of 3-(4-methoxy-phenyl)-piperidine-l,4-dicarboxylic acid 1 -tert-butyl ester 4-ethyl ester (see Example la) (2.0 g, 5.51 mmol, 1.0 eq) in 1, 4-dioxane (10.0 ml/mmol) was added 4M HCI in dioxane (2.0 ml/mmol) followed by stirring at RT for a period of 4 h.
  • Step2 To a stirred solution of HCI salt of 3-(4-methoxy-phenyl)-piperidine-4-carboxylic acid ethyl ester (700 mg, 1.0 eq, 2.66 mmol) in toluene, tBuONa (511 mg, 2.0 eqv., 5.32 mmol) was added followed by addition of 2- bromo-5-fluoropyridine (562 mg, 1.2 eq, 3.19 mmol). Then BINAP (248.6 mg, 0.15 eq, 0.40 mmol) was added and the mixture was by Ar for 15 min.
  • Step3 To a stirred solution of ethyl l-(5-fluoropyridin-2-yl)-3-(4-methoxyphenyl)piperidine-4-carboxylate (150 mg, 1.0 eq, 0.42 mmol) in EtOH (15 ml), EtONa in EtOH (0.15 ml 2N) was added and the mixture was allowed to heat at 90°C for 6 h. After completion of reaction EtOH was evaporated and the residue was diluted with H 2 0 and the organic components were extracted with EtOAc, dried over anhy.
  • Step4 To a stirred solution of trans-ethyl l-(5-fluoropyridin-2-yl)-3-(4-methoxyphenyl)piperidine-4-carboxylate (150 mg, 1.0 eq, 0.42 mmol) in EtOH, KOH (47 mg, 2.0 eq, 0.84 mmol), MeOH (5 ml), H 2 0 (3 ml) were added and the mixture was heated at 90°C for 16 h. After completion of reaction EtOH was evaporated and the residue was diluted with H 2 0 and organics were extracted with EtOAc. Aqueous layer was acidified by 1 N aq. HC1 and crude product was extracted with 15% MeOH/DCM, dried over anhyd.
  • Step5 To a stirred solution of tra «5-l-(5-fluoropyridin-2-yl)-3-(4-methoxyphenyl)piperidine-4-carboxylic acid (70 mg, 1.0 eqv., 0.21 mmol) in benzene/THF (10 ml, 5:2), TEA (60 m ⁇ , 2.0 eq., 0.42 mmol) was added followed by addition of DPP A (91 m ⁇ , 2.0 eq., 0.41 mmol) and allowed to stir at RT for 4 h. 4-chloroaniline (32 mg, 1.2 eq., 0.25 mmol) was added to it and the mixture was stirred at 90°C for 16 h.
  • Example 39 l-(4-chlorophenyl)-3-(l-(4-fluorophenyl)-3-(4-methoxyphenyl)piperidin-4-yl)urea
  • Example 39a trans- 1 -(4-chlorophenyl)-3 -( 1 -(4-fluorophenyl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
  • Example 39a was synthesized starting from Example la following Representative procedure for N-arylation (Chan Lam coupling) described in synthesis of Example 35a (yield: 21%).
  • Example 40 l-(1.3-bis(4-methoxyphenyl)piperidin-4-yl)-3-(4-chlorophenyl)urea
  • Example 40a trans- 1 -( 1 ,3 -bis(4-methoxyphenyl)piperidin-4-yl)-3 -(4-chlorophenyl)urea
  • Example 40a was synthesized starting from Example la following Representative procedure for N-arylation (Chan Lam coupling) described in synthesis of Example 35a (yield: 25%).
  • Example 41a was synthesized starting from Example la following Representative procedure for N-arylation (Chan Lam coupling) described in synthesis of Example 35a (yield: 10%).
  • Example 42 l-(4-chloro-phenyl)-3-[3-(4-methoxy-phenyl)-l-pyrimidin-2-yl-piperidin-4-yll-urea
  • Example 42a trans- 1 -(4-chloro-phenyl)-3 -[3 -(4-methoxy-phenyl)- 1 -pyrimidin-2-yl-piperidin-4-vH-urea
  • Example 43 l-(3-(4-methoxyphenyl)-l-(pyridin-4-yl)piperidin-4-yl)-3-(3-methylisothiazol-5-yl)urea
  • Stepl To a stirred solution of trans 3-(4-methoxy-phenyl)-piperidine-l,4-dicarboxylic acid 1 -tert-butyl ester (1 eq) in toluene (5 ml/ mmol) was added Et 3 N ( 2.0 eq) followed by the addition of DPPA (2.0 eq) and the reaction mass was refluxed for a period of 4 h. The reaction was cooled to RT and 3-methylisothiazol-5-amine (1.3 eq) was added and the reaction mixture was heated at 120°C for a period of 16 h. The reaction mixture was concentrated in vacuo and diluted with EA (300 ml) and washed with water and brine.
  • Step2 To a stirred solution of tert-butyl 3-(4-methoxyphenyl)-4-(3-(3-methylisothiazol-5-yl)ureido)piperidine-l- carboxylate (leq) in 1, 4-dioxane (2.5 ml/mmol) was added 4M HC1 in dioxane (7.5 ml/mmol) followed by stirring at RT for a period of 2 h. After completion of the reaction (monitored by TLC and LC MS), the reaction mixture was concentrated under reduced pressure and the residue was treated with saturated aq. NaHCCb solution and the organic components were extracted with ethyl acetate. The organic layer was dried over anhyd.
  • Step3 To a stirred solution of l-(3-(4-methoxyphenyl)piperidin-4-yl)-3-(3-methylisothiazol-5-yl)urea (leq) and 4-bromopyridine (1.2 eq) in toluene (10-12 ml/mmol) at RT was added t-BuONa (2 eq), Pd(dba)3 (0.05 eq) and BINAP (0.15 eq) and the reaction mixture was stirred under reflux for a period of 24-48 h under inert atmosphere. The reaction mixture was diluted with EtOAc and washed with water and brine. The combined organic layer was dried over anhyd. Na 3 S0 4 and concentrated under reduced pressure.
  • Example 44a l-(5-chloropyridin-2-yl)-3-(3-(4-methoxyphenyl)piperidin-4-yl)urea
  • Example 44a was synthesized in analogy to synthesis described for Example 43a.
  • Example 45 1 -(4-fluorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-4-yl)piperidin-4-yl)urea
  • Example 45a trans- 1 -(4-fluorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-4-yl)piperidin-4-yl)urea
  • Example 45.1 entl-tmns- 1 -(4-fluorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-4-yl)piperidin-4-yl)urea
  • Example 45.2 l-(4-fluorophenyl)-3-(3-(4-methoxyphenyl)-l-(pyridin-4-yl)piperidin-4-yl)urea
  • Example 45a was synthesized in analogy to synthesis described for Example 43a.
  • Example 46 l-(6-chloropyridin-3-yl)-3-(3-(4-methoxyphenyl)-l-(pyridin-4-yl)piperidin-4-yl)urea
  • Example 46a l-(6-chloropyridin-3-yl)-3-(3-(4-methoxyphenyl)-l-(pyridin-4-yl)piperidin-4-yl)urea
  • Example 46 was synthesized in analogy to synthesis described for Example 43a.
  • Example 47a l-(5-chloropyridin-2-yl)-3-(3-(4-methoxyphenyl)-l-(pyridin-4-yl)piperidin-4-yl)urea
  • Example 47a was synthesized in analogy to synthesis described for Example 43a (step3).
  • Stepl To a cold stirring solution of (4-methoxyphenyl)acetonitrile (20.0 g, 136 mmol, 1 eq) in THF (272 ml) was portion wise added NaH (60%) (10.88 g, 272 mmol, 2 eq). The reaction mixture was then stirred for 30 min at RT. Diethyl carbonate (32.93 ml, 272 mmol, 2 eq) was then drop wise added to the reaction mixture. The reaction mixture was finally stirred for 16 h at RT. The reaction mixture was quenched by addition of ice (100 g).
  • Step2 A solution of ethyl 2-cyano-2-(4-methoxyphenyl)acetate (3.0 g, 13.68 mmol, 1 eq) in EtOH (70 ml), was added cone. HC1 (7 ml). The solution was then deoxygenated by Ar for 10 min. Pd/C (10%, moisture) (0.35 g) was then added to the solution and again deoxygenated by Ar for 10 min. Finally the reaction mixture was set in a PARR shaker apparatus under hydrogen atmosphere at 40 psi for 16 h at RT. The reaction mixture was filtered through celite bed and washed by EtOH (50 ml). The filtrate was concentrated under reduced pressure to get the crude material.
  • Step3 To a cold stirring solution of ethyl 3-amino-2-(4-methoxyphenyl)propanoate hydrochloride (12.0 g, 46.2 mmol, 1 eq) in DCM (250 ml), TEA (25.15 ml, 184.8 mmol, 4 eq) was added at RT. The reaction mixture then stirred for 15 min at 0°C.
  • Step4 Sodium (0.62 g, 27.06 mmol, 1.2 mmol) was dissolved in EtOH (22 ml). This solution was then added to a solution of ethyl 3-((3-ethoxy-2-(4-methoxyphenyl)-3-oxopropyl)amino)-3- oxopropanoate (7.6 g, 46.2 mmol, 1 eq) in toluene (60 ml) at 0°C. The reaction mixture was then stirred for 3 h at reflux condition. The reaction mixture was cooled to RT then all the solvents were evaporated.
  • Step5 A solution of ethyl 5-(4-methoxyphenyl)-2,4-dioxopiperidine-3-carboxylate (1.5 g, 5.15 mmol, 1 eq) in a mixture of acetonitrile and water (10: 1) (33 ml) was stirred at reflux condition for 3 h. The reaction mixture was then cooled to RT and all the solvents were evaporated to get the crude material. Crude product was purified by column chromatography (230-400 mesh silica gel; 5% MeOH/DCM; R f - value-0.45) to afford 5-(4-methoxyphenyl)piperidine-2,4-dione (0.9 g, 80%) as off white solid.
  • Step6 To a stirred solution of 5-(4-methoxyphenyl)piperidine-2,4-dione (1.0 g, 4.26 mmol, 1 eq) in ethanol (30 ml) were added hydroxyl amine hydrochloride (0.476 g, 6.85 mmol, 1.5 eq) and sodium acetate (1.24 g, 9.13 mmol, 2 eq) at RT. The reaction mixture was then stirred for 16 h at RT. After completion of reaction the solvent was evaporated under reduced pressure to get the residue. The residue was then dissolved in DCM (100 ml) and washed by water (2 x 50 ml) followed by brine (50 ml). The organic layer was dried over anhydrous Na 2 SC> 4 , concentrated under reduced pressure to get the 4-(hydroxyimino)-5-(4-methoxyphenyl)piperidin-2-one (1.0 g, 94%) as off white solid.
  • Step7 To a stirred solution of 4-(hydroxyimino)-5-(4-methoxyphenyl)piperidin-2-one (1.0 g, 4.26 mmol, 1 eq) in MeOH (25 ml) was added NiCU 6H 2 0 (2.02 g, 8.53 mmol, 2 eq) at -40°C. The reaction mixture was then stirred for 30 min at same temperature. NaBEE (0.647 g, 17.04 mmol, 1 eq) was then portion wise added to the reaction mixture at -40°C. The reaction mixture was then slowly warm to RT and stirred for 2 h.
  • Boc anhydride (1.39 g, 6.39 mmol, 1.5 eq) was then added to the reaction mixture and stirred for 16 h at RT.
  • the reaction mixture was quenched by addition of ice (20 g). After quenching the reaction mixture was filtered through celite bed and washed by MeOH (30 ml). The filtrate was concentrated under reduced pressure to get the residue.
  • Residue was dissolved in DCM (100 ml) and washed by water (2 x 30 ml) followed by brine (30 ml). The organic layer was dried over anhydrous Na 2 SC> 4 , concentrated under reduced pressure to get the crude material.
  • Step8a To a cold stirring solution of c/s-tert-butyl (5-(4-methoxyphenyl)-2-oxopiperidin-4- yl)carbamate (0.15 g, 0.467 mmol, 1 eq) in DCM (10 ml) was slowly added trifluoro acetic acid (1.5 ml, 18.69 mmol, 40 eq). The reaction mixture was then stirred for 2 h at RT. Evaporate all the solvents and azeotrope by DCM twice the residue was then dissolved in DCM (10 ml) and triethyl amine (0.19 ml, 1.4 mmol, 3 eq) was added to the reaction mixture at 0°C.
  • Step8b To a cold stirring solution of tra «s-tert-butyl (5-(4-methoxyphenyl)-2-oxopiperidin-4- yl)carbamate (0.115 g, 0.358 mmol, 1 eq) in DCM (10 ml) was slowly added trifluoro acetic acid (91.07 ml, 14.33 mmol, 40 eq) at 0°C. The reaction mixture was then stirred for 2 h at RT. Evaporate all the solvents and azeotrope by DCM twice the residue was then dissolved in DCM (10 ml) and triethyl amine (0.146 ml, 1.07 mmol, 3 eq) was added at RT.
  • Example 49.1 c/y-l-(4-chlorophenyl)-3-(5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
  • Example 49.2 l-(4-chlorophenyl)-3-(5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
  • Example 49.1 and Example 49.2 were synthesized in analogy to synthesis described for Example 48.
  • Example 50 l-(4-bromophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
  • Example 50.1 ⁇ i/a/-l-(4-bromophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
  • Example 50.2 c /a2-l-(4-bromophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
  • Stepl To a solution of 2-fluoro-4-methoxyaniline (25 g, 177.3 mmol, 1 eq) in H2O (250 ml), Nal (101.3 g, 531.9 mmol, 3 eq) and HI (100 ml) was added at RT. The reaction was then heated at 90°C. To this heated solution NaNCh (23.7 g, 354.6 mmol, 2 eq) dissolved in 3 ⁇ 40 was added drop wise. The reaction was continued at same temperature for 1 h. After completion of reaction (monitored by TLC) reaction mixture was extracted with EA.
  • Step2 To a solution of 2-fluoro-l-iodo-4-methoxybenzene (25 g, 99.2 mmol, 1 eq) in DMSO (100 ml), CS2CO3 (64.4 g, 198.4 mmol, 2 eq) was added at RT. After degassing the reaction mixture for 15 min, cyano-acetic acid ethyl ester (33.6 g, 297.6 mmol, 3 eq), Cul (7.55 g, 39.68 mmol, 0.4 eq) and L-proline (2.28 g, 19.84 mmol, 0.2 eq) was added at RT.
  • reaction mixture was then continued stirring at 120°C for 16 h. After completion of reaction (monitored by TLC) reaction mixture was diluted with water and extracted with EA. The organic layer was washed with water, brine, dried over Na2S04, filtered and the solvent was evaporated under reduced pressure to get the crude product which was purified by column chromatography to afford ethyl 2-cyano-2-(2-fluoro-4- methoxyphenyl)acetate (7 g, 30%) as brown solid.
  • Step3 A solution of ethyl 2-cyano-2-(2-fluoro-4-methoxyphenyl)acetate (5 g, 21.09 mmol, 1 eq) in EtOH (70 ml), was added cone. HC1 (7 ml). The solution was then deoxygenated by Ar for 10 min. Pd/C (10%, moisture) (0.5 g) was then added to the solution and again deoxygenated by Ar for 10 min. Finally the reaction mixture set in a PARR shaker apparatus under hydrogen atmosphere at 50 psi for 16 at RT. The reaction mixture was filtered through celite bed and washed by EtOH (50 ml).
  • Step4 To a cold stirring solution of ethyl 3-amino-2-(2-fluoro-4-methoxyphenyl)propanoate-HCl (9 g, 37.344 mmol, 1 eq) in DCM (90 ml), TEA (18.1 ml, 130.7 mmol, 3.5 eq) was added. The reaction mixture then stirred for 15 min at 0°C. Ethyl malonylchloride (5.7 g, 48.547 mmol, 1.3 eq) was added drop wise to the reaction mixture at 0°C. The reaction mixture then stirred for 2 h at RT.
  • reaction mixture was diluted with DCM (500 ml) and washed by water (2 x 300 ml) followed by brine (300 ml). The organic layer was dried over anhydrous Na2S04, concentrated under reduced pressure to get the crude product which was purified by column chromatography (230-400 mesh silica gel; 30% EtOAc/hexane; R ⁇ value-0.5) to afford ethyl 3-((3-ethoxy-2-(2-fluoro-4-methoxyphenyl)-3-oxopropyl)amino)-3-oxopropanoate (5 g, 38%) as light brown solid.
  • Step5 Sodium (0.04 g, 1.69 mmol, 1.2 mmol) was dissolved in EtOH (1.5 ml). This solution then added to a solution of ethyl 3-((3-ethoxy-2-(2-fluoro-4-methoxyphenyl)-3-oxopropyl)amino)-3-oxopropanoate (0.5 g, 1.408 mmol, 1 eq) in toluene (10 ml) at 0°C. The reaction mixture then stirred for 3 h at reflux condition. The reaction mixture was cooled to RT then evaporated all the solvents. The residue dissolved in water (20 ml), this aqueous part then washed by EtOAc (40 ml).
  • Step6 A solution of ethyl 5-(2-fluoro-4-methoxyphenyl)-2,4-dioxopiperidine-3-carboxylate (5 g, 16.181 mmol, 1 eq) in a mixture of acetonitrile and water (10: 1) (55 ml) was stirred at reflux condition for 16 h. The reaction mixture was then cooled to RT and the solvent was evaporated to get the crude product which was purified by column chromatography (230-400mesh silica gel; 5% MeOH/DCM; R f ⁇ value-0.45) to afford 5-(2-fluoro-4- methoxyphenyl)piperidine-2,4-dione (2 g, 52%) as off white solid.
  • Step7 To a stirring solution of 5-(2-fluoro-4-methoxyphenyl)piperidine-2,4-dione (2.6 g, 10.97 mmol, 1 eq) in ethanol (90 ml) were added hydroxyl amine hydrochloride (1.14 g, 16.45 mmol, 1.5 eq) and sodium acetate (2.96 g, 21.94 mmol, 2 eq) at RT. The reaction mixture was then stirred for 16 h at RT. The solvent was evaporated and the residue then dissolved in DCM (100 ml) and washed by water (2 x 50 ml) followed by brine (50 ml).
  • Step8 To a stirring solution of 5-(2-fluoro-4-methoxyphenyl)-4-(hydroxyimino)piperidin-2-one (1.25 g, 4.96 mmol, 1 eq) in MeOH (35 ml) was added NiCU-6H 2 0 (2.35 g, 9.88 mmol, 2 eq) at -40°C. The reaction mixture then stirred for 30 min at same temperature. NaBEE (0.753 g, 23.53 mmol, 4 eq) then portion wise added to the reaction mixture at -40°C. The reaction mixture was then slowly warmed to RT and stirred for 2 h.
  • Boc anhydride (1.6 ml, 7.44 mmol, 1.5 eq) was then added to the reaction mixture and stirred for 16 h at RT. The reaction mixture was quenched with ice. After quenching the reaction mixture was filtered through celite bed and washed by MeOH (30 ml). The filtrate was concentrated under reduced pressure to get the residue which was dissolved in DCM (100 ml) and washed by water (2 x 30 ml) followed by brine (30 ml).
  • Step9 To the solution of tert-butyl (5-(2-fluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (0.25 g, 0.739 mmol, 1 eq) in DCM (10 ml), TFA (2.3 ml, 29.585 mmol, 40 eq) was added at 0°C. The reaction mixture was stirred at RT for 3 h. After completion of reaction (monitored by TLC), reaction mixture was evaporated under reduced pressure to get the crude product (0.17 g, 9%), which was used for the next step without further purification.
  • SteplO To the solution of 4-amino-5-(2-fluoro-4-methoxyphenyl)piperidin-2-one (0.1 g, 0.42 mmol, 1 eq) in DCM (7 ml), TEA (0.17 ml, 1.26 mmol, 3 eq) was then added to the reaction mixture at 0°C. l-Bromo-4- isocyanato-benzene (0.083 g, 0.42 mmol, 1 eq) was then added to the reaction mixture and stirred for 16 h at RT.
  • reaction mixture was dissolved in DCM (30 ml) and washed by water (2 x 25 ml) followed by brine (50 ml). The organic layer was dried over anhydrous Na2SC>4, concentrated under reduced pressure to get the crude product which was purified by column chromatography (230-400 mesh silica gel; 5% MeOH/DCM; R f ⁇ value-0.55) followed by prep HPLC to afford pure diasteromerl dial- ⁇ - ⁇ A- bromophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea 50.1 (0.075 g, 41%) and pure diastereomer2 c/za2-l-(4-bromophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea 50.2 (0.03 g, 16%) as white solid.
  • Example 50.2 (dia2): 1H NMR (400 MHz, dmso-d6): d 8.46 (s, 1H), 7.68 (s, 1H), 7.35-7.31 (m, 2H), 7.29-7.25 (m, 3H), 6.80-6.73 (m, 2H), 6.13-6.11 (m, 1H), 4.30 (s, 1H), 3.72 (s, 3H), 3.27-3.17 (m, 3H), 2.58-2.53 (m, 1H), 2.33-2.26 (m, 1H).
  • Example 51.1 ⁇ j/a/-l-(4-chlorophenyl)-3-(5-(2-iluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
  • Example 51.2 ⁇ j/a2-l-(4-chlorophenyl)-3-(5-(2-iluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
  • Example 52 l-(4-bromophenyl)-3-(l-(2-methoxyethyl)-5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
  • Stepl To a cold stirring solution of cA-tert-butyl (5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (for synthesis see Example 48, step7) (0.1 g, 0.312 mmol, 1 eq) in DMF (5 ml), NaH (60%) (0.019 g, 0.468 mmol, 1.5 eq) was added. The reaction mixture was then stirred for 30 min at RT. 2-Bromoethyl methyl ether (0.052 g, 0.375 mmol, 1.2 eq) was then added to the reaction mixture at RT and then stirred for 16 h at RT.
  • reaction mixture was diluted with EtOAc (50 ml) and washed by water (5 x 20 ml) followed by brine (20 ml).
  • the organic layer was dried over anhydrous Na2S04, concentrated under reduced pressure to get the crude product which was purified by column chromatography (230-400 mesh silica gel; 5% MeOH/DCM; R f ⁇ value-0.55) to afford cis-tsrt- butyl (l-(2-methoxyethyl)-5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (0.07 g, 59%) as white solid.
  • Step2 To a cold stirring solution of cA-tert-butyl (l-(2-methoxyethyl)-5-(4-methoxyphenyl)-2-oxopiperidin-4- yl)carbamate (0.15 g, 0.396 mmol, 1 eq) in DCM (10 ml) was slowly added trifluoro acetic acid (1.22 ml, 15.87 mmol, 40 eq). The reaction mixture was then stirred for 2 h at RT. Evaporate all the solvents and azeotrope by DCM twice.
  • Example 52.2 / 3 ⁇ 43 ⁇ 4,?- l-(4-bromophenvi)-3-(l-(2-methoxyethvi)-5-(4-methoxyphenvi)-2-oxopiperidin-4-yl)urea
  • Example 52.2 was synthesized in analogy to synthesis described for Example 52.1 starting from /ra «5-tert-butyl (5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (for synthesis see Example 48).
  • Example 53.1 c «-l-(4-chlorophenyl)-3-(l-(2-methoxyethyl)-5-(4-methoxyphenyl)-2-oxopiperidin-4- yllurea
  • Example 53.1 was synthesized in analogy to synthesis described for Example 52.1.
  • Example 53.2 was synthesized in analogy to synthesis described for Example 52.2.
  • Example 53.2 1H NMR (400 MHz, dmso-d6): d 8.46 (s, 1H), 7.35-7.31 (m, 2H), 7.24-7.20 (m, 4H), 6.89-6.87 (m, 2H), 6.11-6.08 (m, 1H), 4.22-4.19 (m, 1H), 3.71 (s, 3H), 3.58-3.52 (m, 1H), 3.46-3.35 (m, 5H), 3.24 (s, 3H), 3.15-3.08 (m, 1H), 2.66-2.61 (m, 1H), 2.36-2.29 (m, 1H).
  • Example 54 l-(4-bromophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-l-(2-methoxyethyl)-2-oxopiperidin-4-yl)urea
  • Example 54.1 ri/a7-l-(4-bromophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-l-(2-methoxyethyl)-2- oxopiperidin-4-yl)urea
  • Example 54.2 ri/a2-l-(4-bromophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-l-(2-methoxyethyl)-2- oxopiperidin-4-yl)urea
  • Example 54 was synthesized in analogy to synthesis described for Example 52.1. Separation of mixture of diasteomers (54) lead to isolation of Example 54.1 and Example 54.2.
  • Example 54.2 (dia2): 1H NMR (400 MHz, dmso-d6): d 8.48 (s, 1H), 7.35-7.26 (m, 5H), 6.82-6.74 (m, 2H), 6.15- 6.13 (m, 1H), 4.32-4.28 (m, 1H), 3.73 (s, 3H), 3.57-3.51 (m, 1H), 3.46-3.34 (m, 6H), 3.24 (s, 3H), 2.66-2.61 (m, 1H), (s, 1H), 2.42-2.35 (m, 1H).
  • Example 55 l-(4-chlorophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-l-(2-methoxyethyl)-2-oxopiperidin-4-yl)urea
  • Example 55.1 ti/a7-l-(4-chlorophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-l-(2-methoxyethyl)-2- oxopiperidin-4-yl)urea
  • Example 55 was synthesized in analogy to synthesis described for Example 52.1. Separation of mixture of diasteomers (55) lead to isolation of Example 55.1 and Example 55.2.
  • Example 55.1 (dia2): 1H NMR (400 MHz, dmso-d6): d 8.47 (s, 1H), 7.33-7.28 (m, 3H), 7.23-7.20 (m, 2H), 6.82- 6.74 (m, 2H), 6.14-6.12 (m, 1H), 4.25-4.23 (m, 1H), 3.73 (s, 3H), 3.52-3.51 (m, 1H), 3.46-3.45 (m, 2H), 3.43-3.35 (m, 3H), 3.27 (s, 3H), 2.66-2.61 (m, 1H), 2.49-2.40 (m, 2H).
  • Example 56 l-(4-bromophenyl)-3-(5-(2.6-difhtoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
  • Example 56.1 i/a/-l-(4-bromophenyl)-3-(5-(2.6-difhtoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
  • Example 56.2 i/a2-l-(4-bromophenyl)-3-(5-(2.6-difhtoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
  • Stepl To a stirring solution of 4-bromo-3,5-difluoroanisol (5.0 g, 22.42 mmol, 1 eq) in mixture of THF (30 ml) and Et 2 0 (50 ml) was drop wise added n-BuLi (11.21 ml, 22.42 mmol, 1 eq) at -78°C under Ar atmosphere. The reaction mixture was then stirred for 45 min at -78°C. N,N-Dimethylformamide (2.03 ml, 26.45 mmol, 1.18 eq) was then added to the reaction mixture at -78°C. The reaction mixture was finally warmed to RT and stirred for 16 h.
  • reaction mixture was quenched by addition of saturated solution of NH4CI (100 ml).
  • the organic layer was separated and the aqueous layer was extracted with EtOAc (100 ml).
  • the combined organic layer was washed by water (2 x 50 ml) and brine (50 ml).
  • the organic layer was dried over anhydrous Na 2 S04, concentrated under reduced pressure to get the crude material, which was purified by silica gel (230-400 mesh silica gel; 10% EtO Ac/hexane; R f - value-0.5) to afford 2,6-difluoro-4-methoxybenzaldehyde (2.7 g, 70%) as light yellow solid.
  • Step2 To a cold stirring solution of 2,6-difluoro-4-methoxybenzaldehyde (2.3 g, 13.37 mmol, 1 eq) in MeOH (68 ml) was portion wise added NaBFE (0.65 g, 17.11 mmol, 1.28 eq). The reaction mixture was then stirred for 1 h at RT. The reaction mixture was then quenched by addition of ice (10 g). The solvents were evaporated and the residue was dissolved in EtOAc (100 ml) and washed by water (2 x 50 ml) followed by brine (100 ml). The organic layer was dried over anhydrous Na 2 S04, concentrated under reduced pressure to get (2,6-difluoro-4- methoxyphenyl)MeOH (2.2 g, 95%) as off white solid.
  • Step3 To a cold stirring solution of (2,6-difluoro-4-methoxyphenyl)MeOH (0.5 g, 2.87 mmol, 1 eq) in THF (20 ml) was portion wise added ROB 3 ⁇ 4 (1.65 g, 5.74 mmol, 2 eq). The reaction mixture then stirred for 2 h at RT. The reaction mixture was quenched by saturated NaHCCb solution under cooling conditions. The organic layer was separated and aqueous layer was extracted by EtOAc (50 ml). The combined organic layer was washed by water (30 ml) and brine (30 ml).
  • Step4 To a cold stirring solution of 2-(bromomethyl)-l,3-difluoro-5-methoxybenzene (9.5 g, 40.08 mmol, 1 eq) in DMF (38 ml) was slowly added a solution of KCN (3.23 g, 49.7 mmol, 1.24 eq) in water (7.34 ml). The reaction mixture then stirred for 30 min at RT. Water (48 ml) and NaHCCb solution (48 ml) were added to the reaction mixture. The reaction mixture was then extracted by Et 2 0 (2 x 200 ml). The combined organic layer was washed by water (4 x 80 ml) followed by brine (200 ml).
  • Step5 Xylene (10 ml) and NaOEt (11.33 ml, 30.6 mmol, 2 eq) were taken in a round bottle flux and then heated at 50°C. 2-(2,6-difluoro-4-methoxyphenyl)acetonitrile (2.8 g, 15.3 mmol, 1 eq) and diethyl carbonate (3.6 g, 30.6 mmol, 2 eq) were then added to the reaction mixture and stirred for 16 h at 50°C. The reaction mixture was cooled to RT and water (50 ml) was added to it. The reaction mixture was then acidified by 1(N) HC1 solution. The aqueous part was then extracted by EtOAc (2 x 100 ml).
  • Step6 A solution of ethyl 2-cyano-2-(2,6-difluoro-4-methoxyphenyl)acetate (2.5 g, 9.8 mmol, 1 eq) in EtOH (53 ml), was added cone. HC1 (5.3 ml). The solution was then deoxygenated with Ar for 10 min. Pd/C (10%, moisture) (0.25 g) was then added to the solution and again deoxygenated by Ar for 10 min. Finally the reaction mixture set in a PARR shaker apparatus under hydrogen atmosphere at 40 psi for 16 at RT. The reaction mixture was filtered through celite bed and washed by EtOH (50 ml).
  • Step7 To a cold stirring solution of HC1 salt of ethyl 3-amino-2-(2,6-difluoro-4-methoxyphenyl)propanoate (18.7 g, 63.28 mmol, 1 eq) in DCM (340 ml), TEA (25.84 ml, 189.84 mmol, 3 eq) was added.
  • reaction mixture was then stirred for 15 min at 0°C.
  • Ethyl malonylchloride (8.14 ml, 63.28 mmol, 1 eq) was added drop wise to the reaction mixture at 0°C.
  • the reaction mixture then stirred for 2 h at RT.
  • the reaction mixture was diluted with DCM (300 ml) and washed by water (2 x 300 ml) followed by brine (300 ml).
  • Step8 Sodium (0.34 g, 14.745 mmol, 1.1 mmol) was dissolved in EtOH (15 ml). This solution was then added to a solution of ethyl 2-(2,6-difluoro-4-methoxyphenyl)-3 -(3 -ethoxy-3 -oxopropanamido)propanoate (5.0 g, 13.4 mmol, 1 eq) in toluene (45 ml) at 0°C. The reaction mixture was then stirred for 3 h at reflux condition. The reaction mixture was cooled to RT then all the solvents were evaporated.
  • Step9 A solution of ethyl 5-(2,6-difluoro-4-methoxyphenyl)-2,4-dioxopiperidine-3-carboxylate (1.0 g, 3.05 mmol, 1 eq) in a mixture of acetonitrile and water (10: 1) (38 ml) was stirred under reflux for 3 h.
  • reaction mixture was then cooled to RT and the solvents were evaporated to get the crude product which was purified by column chromatography (230-400 mesh silica gel; 5% MeOH/DCM; R f ⁇ value-0.45) to afford 5-(2,6-difluoro-4- methoxyphenyl)piperidine-2,4-dione (0.5 g, 68%) as off white solid.
  • SteplO To a stirring solution of 5-(2,6-difluoro-4-methoxyphenyl)piperidine-2,4-dione (1.0 g, 3.92 mmol, 1 eq) in EtOH (40 ml) were added hydroxyl amine hydrochloride (0.409 g, 5.882 mmol, 1.5 eq) and sodium acetate (1.06 g, 7.84 mmol, 2 eq) at RT. The reaction mixture was then stirred for 16 h at RT. The solvent was evaporated and the residue was then dissolved in DCM (100 ml) and washed by water (2 x 50 ml) followed by brine (50 ml).
  • Stepl 1 To a stirring solution of 5-(2,6-difluoro-4-methoxyphenyl)-4-(hydroxyimino)piperidin-2-one (0.6 g, 2.22 mmol, 1 eq) in MeOH (30 ml) was added NiCU-6H 2 0 (1.054 g, 4.44 mmol, 2 eq) at -40°C. The reaction mixture was then stirred for 30 min at same temperature. NaBEE (0.337 g, 8.88 mmol, 4 eq) was then portion wise added to the reaction mixture at -40°C. The reaction mixture then slowly warm to RT and stirred for 2 h.
  • Boc anhydride (0.726 g, 3.33 mmol, 1.5 eq) was then added to the reaction mixture and stirred for 16 h at RT.
  • the reaction mixture was quenched by addition of ice (20 g). After quenching the reaction mixture was filtered through celite bed and washed by MeOH (30 ml). The filtrate was concentrated under reduced pressure to get the residue which was dissolved in DCM (100 ml) and washed by water (2 x 30 ml) followed by brine (30 ml).
  • Stepl2 To a cold stirring solution of tert-butyl (5-(2,6-difluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (0.125 g, 0.351 mmol, 1 eq) in DCM (10 ml) was slowly added trifluoro acetic acid (1.1 ml, 14.04 mmol, 40 eq). The reaction mixture was then stirred for 2 h at RT. The solvents were evaporated and azeotrope by DCM twice. The residue was then dissolved in DCM (10 ml) and TEA (0.19 ml, 1.4 mmol, 3 eq) was added to the reaction mixture at 0°C.
  • Example 56.1 (dial): 1H NMR (400 MHz, dmso-d6): d 8.43 (s, 1H), 7.77 (s, 1H), 7.33-7.35 (m, 2H), 7.23-7.25 (m, 2H), 6.66-6.68 (m, 2H), 6.55-6.57 (m, 1H), 4.24-4.25 (m, 1H), 3.83-3.88 (m, 1H), 3.73 (s, 3H), 3.60 (s, 1H), 3.37-3.40 (m, 1H), 2.64-2.70 (m, 1H), 2.07-2.12 (m, 1H).
  • Example 56.2 (dia2): 1H NMR (400 MHz, dmso-d6): d 8.44-8.47 (m, 1.23 H), 7.79 (s, 0.52 H), 7.71 (s, 0.98 H), 7.31-7.36 (m, 2.08 H), 7.19-7.28 (m, 2.57 H), 6.80-6.83 (m, 0.51 H), 6.68-6.71 (m, 2.0 H), 6.47-6.49 (m, 0.51 H), 6.14-6.16 (m, 0.91 H), 4.36 (s, 1.10 H), 4.24 (s, 0.55 H), 3.73 (s, 3.46 H), 3.54 (s, 1.12 H), 3.36-3.37 (m, 2.15 H), 3.18 (s, 0.90 H), 2.66 (s, 1.56 H), 2.29-2.36 (m, 1.37 H), 2.08-2.11 (m, 0.66 H).
  • Example 57.1 ti/a /-l-(4-chlorophenvi)-3-(5-(2.6-difluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
  • Example 57.2 ti/a2-l-(4-chlorophenvi)-3-(5-(2.6-difluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
  • Example 57.1 (dial): 1H NMR (400 MHz, dmso-d6): d 8.43 (s, 1H), 7.77 (s, 1H), 7.28-7.30 (m, 2H), 7.21-7.23 (m, 2H), 6.66-6.69 (m, 2H), 6.54-6.56 (m, 1H), 4.24-4.25 (m, 1H), 3.83-3.89 (m, 1H), 3.73 (s, 3H), 3.60 (s, 1H), 3.37-3.40 (m, 1H), 2.64-2.70 (m, 1H), 2.07-2.12 (m, 1H).
  • Example 57.2 (dia2): 1H NMR (400 MHz, dmso-d6): d 8.48 (s, 1H), 7.71-7.79 (m, 1H), 7.21-7.33 (m, 4H), 6.68- 6.83 (m, 2H), 6.49-6.51 (m, 1H), 6.14-6.17 (m, 1H), 4.36 (s, 1H), 4.24 (s, 1H), 3.73 (s, 3H), 3.53 (s, 1H), 3.18 (s, 1H), 2.59-2.66 (m, 1H), 2.29-2.39 (m, 1H), 2.07-2.11 (m, 1H), 1.15-1.18 (m, 5H), 0.74-0.93 (m, 2H).
  • Example 58 l-(4-bromophenyl)-3-(5-(4-methoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea
  • Example 58.1 cis- 1 -(4-bromophenyl)-3-(5-(4-methoxyphenyl)- 1 -methyl-2-oxopiperidin-4- vDurea
  • Example 58.1 was synthesized in analogy to synthesis described for Example 58.2 starting from cA-tert-butyl (5- (4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (for synthesis see Example 48, step7).
  • Example 58.2 trans- 1 -(4-bromophenyl)-3-(5-(4-methoxyphenyl)- 1 -methyl-2-oxopiperidin-4- yl)urea
  • Stepl To a cold stirring solution of /ra «s-tert-butyl (5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (for synthesis see Example 48, step7) (0.31 g, 0.968 mmol, 1 eq) in DMF (10 ml), NaH (60%) (0.058 g, 1.45 mmol, 1.5 eq) was added. The reaction mixture was then stirred for 30 min at RT. Iodomethane (0.165 g, 1.162 mmol, 1.2 eq) was then added to the reaction mixture at 0°C and then stirred for 16 h at RT in a sealed tube.
  • reaction mixture was diluted with EtOAc (100 ml) and washed by water (5 x 30 ml) followed by brine (30 ml).
  • the organic layer was dried over anhydrous Na2S04, concentrated under reduced pressure to get the crude product which was purified by column chromatography (230-400 mesh silica gel; 5% MeOH/DCM; R f ⁇ value-0.55) to afford trans- tert-butyl (5-(4-methoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)carbamate (0.14g, 43%) as off white solid.
  • Step2 To a cold stirring solution of /ra «s-tert-butyl (5-(4-methoxyphenyl)-l-methyl-2-oxopiperidin-4- yl)carbamate (0.07 g, 0.209 mmol, 1 eq) in DCM (10 ml) was slowly added trifluoro acetic acid (0.65 ml, 8.38 mmol, 40 eq). The reaction mixture was then stirred for 2 h at RT. The solvents were evaporated and azeotrope by DCM twice. The residue was then dissolved in DCM (10 ml) and TEA (0.11 ml, 0.807 mmol, 3 eq) was added to the reaction mixture at 0°C.
  • Example 59.1 cis- 1 -(4-chlorophenvi)-3-(5-(4-methoxyphenvD- 1 -methyl-2-oxopiperidin-4-yl)urea
  • Example 59.2 trans- 1 -(4-chlorophenvi)-3-(5-(4-methoxyphenyl)- 1 -methyl-2-oxopiperidin-4-yl)urea
  • Example 59.1 was synthesized in analogy to synthesis described for Example 58.1.
  • Example 59.2 was synthesized in analogy to synthesis described for Example 58.2.
  • Example 60 l-(4-bromophenvi)-3-(5-(2.6-difluoro-4-methoxyphenyl)-l-(2-methoxyethyl)-2-oxopiperidin-4- vDurea
  • Stepl To a cold stirring solution of tert-butyl (5-(2,6-diiluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (for synthesis see Example 56, stepl 1) (0.25 g, 0.702 mmol, 1 eq) in DMF (10 ml), NaH (60%) (0.048 g, 0.468 mmol, 1.7 eq) was added. The reaction mixture was then stirred for 30 min at RT. 2-Bromoethyl methyl ether (0.127 g, 0.913 mmol, 1.3 eq) was then added to the reaction mixture at RT and the mixture was stirred for 16 h at RT.
  • Step2 To a cold stirring solution of tert-butyl (5-(2,6-difluoro-4-methoxyphenyl)-l-(2-methoxyethyl)-2- oxopiperidin-4-yl)carbamate (0.094 g, 0.227 mmol, 1 eq) in DCM (10 ml) was slowly added trifluoro acetic acid (0.71 ml, 9.07 mmol, 40 eq). The reaction mixture was then stirred for 2 h at RT. The solvents were all evaporated and azeotrope by DCM twice.
  • Example 61 l-(4-chlorophenyl)-3-(5-(2.6-difluoro-4-methoxyphenyl)-l-(2-methoxyethyl)-2-oxopiperidin-4- vDurea
  • Example 61 (mixture of diastereomers) was synthesized in analogy to synthesis described for
  • Example 62 l-(4-bromophenyl)-3-(5-(2.6-difluoro-4-methoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea
  • Example 62 (mixture of diastereomers) was synthesized in analogy to synthesis described for
  • Example 58.2. 1H NMR (400 MHz, dmso-d6): d 8.47 (s, 0.18 H), 8.40 (s, 0.82 H), 7.95 (s, 0.11 H), 7.31-7.36 (m, 2.0 H), 7.23- 7.27 (m, 2.06 H), 6.68-6.73 (m, 2.04 H), 6.50-6.53 (m, 0.91 H), 6.17-6.18 (m, 0.22 H), 4.24-4.27 (m, 1.26 H), 3.86-3.91 (m, 0.92 H), 3.74-3.77 (m, 3.89 H), 3.50-3.58 (m, 0.95 H), 2.88-2.91 (m, 2.79 H), 2.66-2.72 (m, 1.24 H), 2.11-2.17 (m, 0.89 H).
  • Example 63 l-(4-chlorophenyl)-3-(5-(2.6-difluoro-4-methoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea
  • Example 63 (mixture of diastereomers) was synthesized in analogy to synthesis described for Example 58.2.
  • Example 64 l-(4-bromophenyl)-3-(5-(2-fluoro-4-mcthoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea
  • Example 64 (mixture of diastereomers) was synthesized in analogy to synthesis described for Example 58.2.
  • Example 65 l-(4-chlorophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea
  • Example 65 (mixture of diastereomers) was synthesized in analogy to synthesis described for Example 58.2.
  • 1H NMR 400 MHz, dmso-d6): d 8.44-8.36 (m, 1H), 7.33-7.29 (m, 3H), 7.24-7.16 (m, 4H), 6.85-6.81 (m, 1H), 6.78-6.72 (m, 2H), 6.43-6.40 (m, 1H), 4.27-4.26 (m, 1H), 3.73-3.71 (m, 4H), 3.66-3.53 (m, 3H), 3.39-3.37 (m, 1H), 2.91 (s, 3H), 2.82 (s, 1H), 2.70-2.64 (m, 1H), 2.19-2.13 (m, 1H).
  • Example 66 l-(5-chloropyridin-2-yl)-3-(3-(2.6-diiluoro-4-metlioxyplienyl)piperidin-4-yl)urea
  • Example 66a l-(5-chloropyridin-2-yl)-3-(3-(2.6-difhtoro-4-methoxyphenyl)piperidin-4- yl)urea
  • Stepl To a stirred solution of ira «.s-3-(2,6-difluoro-4-methoxy-phenyl)-piperidine-l,4-dicarboxyhc acid 1-tert- butyl ester (for synthesis see Example 8a, step4) (300 mg, 0.80 mmol, leq) in toluene (10 ml) was added Et N (0.25 ml, 1.62 mmol, 2.0 eq) followed by the addition of DPP A (0.35 ml, 1.62 mmol, 2.0 eq) and the reaction mass was refluxed for a period of 4 h.
  • reaction mixture was cooled to RT and 5-chloro-pyridin-2-ylamine (123.4 mg, 0.96 mmol, 1.2 eq) was added and the reaction mixture was heated at 120°C for a period of 16 h.
  • the reaction mass was concentrated in vacuo and diluted with EtOAc (150 ml) and washed with water and brine. The combined organic layer was dried over anhydr.
  • Step2 To a stirred solution of desired P3 ⁇ 4 «.s-4-[3-(5-chloro-pyridin-2-yl)-ureido]-3-(2,6-difluoro-4-methoxy- phenyl)-piperidine-l -carboxylic acid tert-butyl ester (200 mg, 0.40 mmol, 1.0 eq) in 1,4-dioxane (2.0 ml) was added 4M HCI in dioxane (2.0 ml) followed by stirring at RT for a period of 2 h.
  • Example 67a ⁇ Ga3 ⁇ 4,?-1-(5-oMoGorn ⁇ hi-2-n ⁇ )-3-(3-(2.6- ⁇ i1EiqGo-4-h ⁇ 6 ⁇ 1iocnr1 ⁇ 6hn1)-1-(2-1TiqGq6 ⁇ 1in ⁇ )rir6G ⁇ h-4- vDurea
  • Example 66a 150 mg, 0.37 mmol, 1 eq
  • ACN 10 ml
  • K 2 CO 3 157 mg, 1.13 mmol, 3.0 eq
  • l-bromo-2-fluoro-ethane 72 mg, 0.56 mmol, 1.5 eq
  • the reaction mixture was stirred under reflux for a period of 16 h.
  • the reaction mixture was concentrated in vacuo, diluted with water and the organic components were extracted with EtOAc. The organic layer was washed with water and brine and dried over anhydr.
  • Example 68 l-(6-chloropyridin-3-yl)-3-(3-(2.6-difluoro-4-methoxyphenyl)piperidin-4-yl)urea
  • Example 68a l-(6-chloropyridin-3-yl)-3-(3-(2.6-difluoro-4-methoxyphenyl)piperidin-4-yl)urea
  • Example 68a was synthesized in analogy to synthesis described for Example 66a (following Representative procedure for urea formation starting from carboxylic acid as described for Example 66a).
  • Example 69 l-(6-chloropyridin-3-yl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2-fluoroethyl)piperidin-4-yl)urea
  • Example 69a l-(6-chloropyridin-3-yl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2-fluoroethyl)piperidin-4- vDurea
  • Example 69a was synthesized in analogy to synthesis described for Example 67a.
  • Example 70 l-(3-(2.6-difluoro-4-methoxyphenyl)piperidin-4-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)urea
  • Example 70a l-(3-(2.6-difluoro-4-methoxyphenyl)piperidin-4-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)urea
  • Example 70a was synthesized in analogy to synthesis described for Example 66a (following Representative procedure for urea formation starting from carboxylic acid as described for Example 66a).
  • Example 71 l-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2-fluoroethyl)piperidin-4-yl)-3-(6- (trifluoromethyl)pyridin-3 -vDurea
  • Example 71a l-(3-(2,6-difluoro-4-methoxyphenyl)-l-(2-fluoroethyl)piperidin-4-yl)-3-(6- (trifluoromethyl)pyridin-3 -vDurea
  • Example 71a was synthesized in analogy to synthesis described for Example 67a.
  • Example 72 l-(3-(2.6-diiluoro-4-methoxyplienyl)piperidin-4-yl)-3-(4-(triiluorometliyl)plienyl)urea
  • Example 72a was synthesized in analogy to synthesis described for Example 66a (following Representative procedure for urea formation starting from carboxylic acid as described for Example 66a).
  • Example 73 1-(3-(2.6- ⁇ 1i ⁇ 0G0-4-h ⁇ 6 ⁇ 1 ⁇ 0cnr1 ⁇ 6hn1)-1-(2- ⁇ 1i ⁇ 0G06 ⁇ 1in1)r ⁇ r6G ⁇ h-4-n1)-3-(4- (triiluoromethvDphenvDurea
  • Example 73a trans- 1 -(3 -(2.6-difhtoro-4-methoxyphenyl)- 1 - vD-S -(4-
  • Example 73a was synthesized in analogy to synthesis described for Example 67a.
  • Example 74 1-(5-o1i1oGo ⁇ 1i ⁇ or1 ⁇ 6h-2-n1)-3-(3-(2.6- ⁇ 1iiqGo-4-h ⁇ 6 ⁇ 1iocnr1 ⁇ 6hn1)-1-(2- ⁇ 1iiqGq6 ⁇ 1in1)r ⁇ r6G ⁇ h-4- vDurea
  • Stepl To a stirred solution of fra «s-3-(2,6-difluoro-4-methoxy-phenyl)-piperidine-l,4-dicarboxylic acid 1-tert- butyl ester (8 g, 5.38 mmol, 1 eq) in ACN (100 ml) at RT was added K 2 CO 3 (8.9 g, 65 mmol, 3 eq) followed by the addition of BnBr (3 ml, 25.9 mmol, 1.2 eq) and the reaction mixture was stirred at reflux for 16 h. After completion of the reaction, it was concentrated under reduced pressure, diluted with water and extracted with EA. The combined organic layer was dried over anhydr.
  • Step2 To a stirred solution of 3-(2,6-difluoro-4-methoxy-phenyl)-piperidine-l,4-dicarboxylic acid 4-benzyl ester 1 -tert-butyl ester (8 g, 17.35 mmol, 1 eq) in 1, 4-dioxane (30 ml) was added 4M HCI in dioxane (15 ml) followed by stirring at RT for a period of 18 h. After completion of the reaction (monitored by TLC and LC MS), the reaction mixture was concentrated under reduced pressure to get the crude material as HCI salt which was diluted with DCM and washed with saturated aqueous NaHCCb solution and brine.
  • Step3 To a stirred solution of 3-(2,6-difluoro-4-methoxy-phenyl)-piperidine-4-carboxylic acid benzyl ester (5.5 g, 15.23 mmol, 1 eq) in ACN (150 ml) at RT was added K2CO3 (6.3 g, 45.7 mmol, 3 eq) followed by the addition of l-bromo-2-fluoro-ethane (1.36 ml, 18.28 mmol, 1.2 eq) and the reaction mixture was stirred at reflux for 16 h. After completion of the reaction, it was concentrated under reduced pressure, diluted with water and extracted with EA. The combined organic layer was dried over anhydr.
  • Step4 A stirred solution of 3-(2,6-difluoro-4-methoxy-phenyl)-l-(2-fluoro-ethyl)-piperidine-4-carboxyhc acid benzyl ester (5.5 g, 13.51 mmol, l eq) in MeOH (100 ml) was degassed with Ar for a period of 15 min followed by the addition of 10% moist Pd-C (2.5 g) and stirred at RT under 3 ⁇ 4 balloon pressure for a period of 18 h. After completion of the reaction, it was filtered through celite bed and washed thoroughly with 5% MeOH/DCM.
  • Step5 To a stirred solution of 3-(2,6-difluoro-4-methoxy-phenyl)-l-(2-fluoro-ethyl)-piperidine-4-carboxylic acid (3.5 g, 11 mmol, leq) in dry DMF (50 ml) were added EDCTHC1 (3.16 g, 16.56 mmol, 1.5 eq) and HOBT (2.2 g, 16.56 mmol, 1.5 eq) in ice-cold condition followed by addition of TEA (3.8 ml, 27.6 mmol, 2.5 eq) and stirred at RT for 15 minutes.
  • EDCTHC1 3.16 g, 16.56 mmol, 1.5 eq
  • HOBT 2.2 g, 16.56 mmol, 1.5 eq
  • Step6 To a stirred solution of 3-(2,6-difluoro-4-methoxy-phenyl)-l-(2-fluoro-ethyl)-piperidine-4-carboxylic acid amide (700 mg, 2.21 mmol, 1 eq) in acetonitrile:water (1: 1) (10.0 ml) was added bis ((trifluoroacetoxy)iodo)benzene (1.4 g, 3.32 mmol, 1.5 eq) at RT and stirred at RT for a period of 18 h.
  • Step7 To a stirred solution of 5-chloro-thiophene-2-carboxylic acid (100 mg, 0.62 mmol, leq) in toluene (5 ml) was added Et 3 N (172 m ⁇ , 1.25 mmol, 2.0 eq) followed by the addition of DPPA (173 m ⁇ , 0.80 mmol, 1.3 eq)) and the reaction mass was refluxed for a period of 4 h.
  • Example 75 l-(5-chlorothiazol-2-yl)-3-(3-(2.6-difluoro-4-methoxyphenyl)piperidin-4-yl)urea
  • Example 75a -(5-chlorothiazol-2-yl)-3-(3-(2.6-difluoro-4-methoxyphenyl)piperidin-4-yl)urea
  • Example 75a was synthesized in analogy to synthesis described for Example 66a (following Representative procedure for urea formation starting from carboxylic acid as described for Example 66a).
  • Example 76 l-(5-chlorothiazol-2-yl)-3-((3R.4R)-3-(2.6-difluoro-4-methoxyphenyl)-l-(2-fluoroethyl)piperidin- 4-yl)urea
  • Example 76a l-(5-chlorothiazol-2-yl)-3-((3R.4R)-3-(2.6-difluoro-4-methoxyphenyl)-l-(2- fluoroethyl)piperidin-4-yl)urea
  • Example 76a was synthesized in analogy to synthesis described for Example 67a.
  • Example 77 l-(2-chlorothiazol-5-yl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2-fluoroethyl)piperidin-4-yl)urea
  • Example 77a l-(2-chlorothiazol-5-yl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2-fluoroethyl)piperidin-4- yl)urea
  • Example 77a was synthesized in analogy to
  • Example 78 l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
  • Example 78a l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
  • Stepl To a stirred solution of KOEt (11.0 g, 130.8 mmol, 1.0 eq) in toluene (170 ml) was added EtOH (30.6 ml, 523.2 mmol, 4.0 eq) drop wise followed by addition of pyrrolidin-2-one (11.0 g, 130.8 mmol, 1.0 eq) under N2 atmosphere at 0°C. A solution of oxalic acid diethyl ester (18 ml, 130.8 mmol, 1.0 eq) was drop wise added to the reaction mixture over 15 min under the same condition. Toluene (70 ml) and EtOAc (27 ml) were added subsequently and the resulting mixture was heated to reflux for 18 h.
  • Step3 To a stirred solution of 6-oxo-5-triiluoromethanesulfonyloxy-l,2,3,6-tetrahydro-pyridine-4-carboxylic acid ethyl ester (1.0 eq), were added K 2 CO 3 (2.5 eq) and required (4-methoxyphenyl)boronic acid (1.2 eq) in toluene- EtOH (1 : 1, 12 ml/mmol). (0.1 eq) was added and degassed with Ar, over a period of 20 min at RT. Resulting mixture was allowed to stir under refluxing condition for another 16 h. Later it was cooled to RT and volatiles were removed under reduced pressure, followed by extraction of organic components with EtOAc.
  • Step4 To a stirred solution of ethyl 5-(4-methoxyphenyl)-6-oxo-l,2,3,6-tetrahydropyridine-4-carboxylate (1 eq) in MeOH (20 ml) was portion wise added Pd-C (moist, 10% w/w, 200 mg) under degassed condition with Ar at RT over a period of 15 min. Resulting mixture was subjected to hydrogenation using Parr-autoclave under 450 psi 3 ⁇ 4 pressure at 90°C for 3 days. After completion of the reaction, it was filtered through celite bed and washed thoroughly with 5% MeOH/DCM (30 ml).
  • Step5 To a stirred solution of ethyl 3-(4-methoxyphenyl)-2-oxopiperidine-4-carboxylate (1 eq) in MeOH/ EtOH/ H O (5:2:5, 20 ml/mmol) was added KOH (2 eq) and the resulting solution was heated to reflux for 12 h. Volatiles were evaporated under reduced pressure and the residue was diluted with water, washed with EtOAc and acidified with 1(N) HC1 at 0°C. Resulting aqueous part was concentrated under reduced pressure to produce a colorless solid mass which was extracted with 10% MeOH/DCM (x3).
  • Step6 To a stirred solution of fra «s-3-(4-methoxyphenyl)-2-oxopiperidine-4-carboxylic acid (1 eq) in benzene/THF (4: 1, 5 ml/mmol) was added Et N (2.0 eq) followed by DPPA (2.0 eq) at RT and the resulting mixture was allowed to stirred for 2 h at the same condition. 4-chloroaniline (1.3 eq) was added and the resulting mixture was again stirred for another 16 h at 70°C. Volatiles were removed under reduced pressure to yield a reddish crude gum. It was then extracted with EtOAc (two times) and the combined organic phase was washed sequentially by water and brine.
  • Example 79a was synthesized in analogy to synthesis described for Example 78a.
  • Example 80 l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea
  • Example 80a trans- 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -methyl-2-oxopiperidin-4-yl)urea
  • Stepl To a stirred solution of ethyl 3-(4-methoxyphenyl)-2-oxopiperidine-4-carboxylate (1.0 eq) in EtOH (18 ml/mmol) was drop wise added NaOEt in EtOH solution (1.0 eq). Resulting mixture was stirred at 80°C for 12 h. After complete conversion of diasteromeric mixture of ethyl 3-(4-methoxyphenyl)-2-oxopiperidine-4-carboxylate in diasteromeric pure trans-ethyl 3-(4-methoxyphenyl)-2-oxopiperidine-4-carboxylate, EtOH was evaporated and a colorless crude mass was obtained.
  • Example 81 1 -(4-chlorophenyl)-3 -(3 -(2-fluoro-4-methoxyphenvi)- 1 -methyl-2-oxopiperidin-4-yl)urea
  • Example 81a was synthesized in analogy to synthesis procedure described for Example 80a.
  • Example 82 l-(4-chlorophenyl)-3-(l-(4-fluorophenyl)-5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
  • Example 82a was synthesized in analogy to synthesis described for Example 84a.
  • Example 83 1 -(4-chlorophenyl)-3-(5-(4-methoxyphenyl)- 1 -(1 -methyl- lH-pyrazol-4-yl)-2-oxopiperidin-4- vDurea
  • Example 83a trans- 1 -(4-chlorophenyl)-3 -(5-(4-methoxyphenyl)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)-2-oxopiperidin- 4-vDurea
  • Example 83.1 entl-tmns- 1 -(4-chlorophenyl)-3-(5-(4-methoxyphenyl)- 1 -(1 -methyl- 1 H-pyrazol-4-yl)-2- oxopiperidin-4-yl)urea
  • Example 83.2 ent2-tmns- 1 -(4-chlorophenyl)-3 -(5-(4-methoxyphenyl)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)-2- oxopiperidin-4-yl)urea
  • Example 83a was synthesized in analogy to synthesis described for Example 84a.
  • Example 84 l-(1.5-bis(4-methoxyphenyl)-2-oxopiperidin-4-yl)-3-(4-chlorophenyl)urea
  • Example 84.1 entl- l-(1.5-bis(4-methoxyphenyl)-2-oxopiperidin-4-yl)-3-(4-chlorophenyl)urea
  • Example 84.2 ent2- l-(1.5-bis(4-methoxyphenyl)-2-oxopiperidin-4-yl)-3-(4-chlorophenyl)urea
  • Stepl A stirred solution of trans- tert-butyl (5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (0.2 g, 0.625 mmol, 1 eq, for synthesis see Example 4)) in dioxane (7 mL), l-iodo-4-methoxy-benzene (0.175 g, 0.75 mmol, 1.5 eq) and K2CO3 (0.258 g, 1.875 mmol, 3 eq) was added at RT. The reaction mixture was degassed with Ar for 30 min.
  • Step2 To a stirred solution of /ra «s-tert-butyl (l,5-bis(4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (0.175 g, 0.41 mmol, 1 eq) in DCM (5 mL), TFA (5 mL) was added at RT. The reaction mixture was stirred at RT for 4 h. After completion of reaction (monitored by TLC) reaction mixture was evaporated under reduce pressure to get the crude product as corresponding TFA salt (0.125 g, 69%) which was azeotrope with toluene and used for the next step without further purification.
  • Step3 To the solution of TFA salt of /ra «s-4-amino-l,5-bis(4-methoxyphenyl)piperidin-2-one (0.175 g, 0.398 mmol, 1 eq) in DCM (10 mL), TEA (0.22 mL, 1.608 mmol, 4 eq) and l-chloro-4-isocyanato-benzene (0.123 g, 0.805 mmol, 2 eq) dissolved in DCM (2 mL) were added and the mixture was stirred at RT for 16 h.

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Abstract

La présente invention concerne un composé selon la formule générale (I) qui agit en tant que modulateur de FPR2 et peut être utilisé dans le traitement et/ou la prophylaxie de troubles qui sont au moins partiellement médiés par FPR2.
PCT/EP2019/055947 2018-03-09 2019-03-11 Pipéridines ou pipéridones substituées par de l'urée et du phényle Ceased WO2019170904A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3789378A1 (fr) * 2019-09-06 2021-03-10 Grünenthal GmbH Pipéridines ou pipéridones substituées par de l'urée et de l'hétéroaryle
US20230348426A1 (en) * 2020-07-09 2023-11-02 Bristol-Myers Squibb Company Oxopyrrolidine fpr2 agonists
WO2025024211A1 (fr) * 2023-07-21 2025-01-30 Eli Lilly And Company Composés de pipéridine ayant une activité d'abaissement de lp(a)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2336105A1 (fr) * 2008-09-19 2011-06-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique contenant de l'azote et son utilisation
WO2015079692A1 (fr) 2013-11-28 2015-06-04 杏林製薬株式会社 Dérivé d'urée ou sel pharmacologiquement acceptable de celui-ci
WO2016189876A1 (fr) * 2015-05-27 2016-12-01 Kyorin Pharmaceutical Co., Ltd. Dérivé de l'urée ou sel pharmacologiquement acceptable de ce dernier
WO2017100390A1 (fr) * 2015-12-10 2017-06-15 Bristol-Myers Squibb Company Agonistes du récepteur 2 du peptide formyle et agonistes du récepteur 1 du peptide formyle à base de pipéridinone

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2336105A1 (fr) * 2008-09-19 2011-06-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique contenant de l'azote et son utilisation
WO2015079692A1 (fr) 2013-11-28 2015-06-04 杏林製薬株式会社 Dérivé d'urée ou sel pharmacologiquement acceptable de celui-ci
EP3075726A1 (fr) * 2013-11-28 2016-10-05 Kyorin Pharmaceutical Co., Ltd. Dérivé d'urée ou sel pharmacologiquement acceptable de celui-ci
WO2016189876A1 (fr) * 2015-05-27 2016-12-01 Kyorin Pharmaceutical Co., Ltd. Dérivé de l'urée ou sel pharmacologiquement acceptable de ce dernier
WO2017100390A1 (fr) * 2015-12-10 2017-06-15 Bristol-Myers Squibb Company Agonistes du récepteur 2 du peptide formyle et agonistes du récepteur 1 du peptide formyle à base de pipéridinone

Non-Patent Citations (16)

* Cited by examiner, † Cited by third party
Title
BARNIG ET AL., SCI. TRANSL. MED., vol. 5, 2013, pages 174ra26
CELIK ET AL., CLIN EXP ALLERGY, vol. 37, 2007, pages 1494 - 1501
CHIANG ET AL., PHARMACOL. REV., vol. 58, 2006, pages 463 - 487
FREDMAN; SERHAN, BIOCHEM. J., vol. 437, 2011, pages 185 - 197
HU ET AL., J. NEUROINFLAMMATION, vol. 9, 2012, pages 278
JI ET AL., TRENDS NEUROSCI., vol. 34, 2011, pages 599 - 609
KARP ET AL., NAT. IMMUNOL., vol. 5, 2004, pages 388 - 392
KIM ET AL., INT. J. CHRON. OBSTRUCT. PULMON. DIS., vol. 11, 2016, pages 1119 - 1128
LEVY ET AL., NAT MED., vol. 8, 2002, pages 1018 - 23
MADDOX ET AL., J. BIOL. CHEM., vol. 272, 1997, pages 6972 - 6978
MIGEOTTE ET AL., CYTOKINE GROWTH FACTOR REV., vol. 17, 2006, pages 501 - 519
NORLING ET AL., JCI INSIGHT, vol. 1, 2016, pages e85922
ROMANO ET AL., EUR J PHARMACOL., vol. 760, 2015, pages 49 - 63
VACHIER I ET AL., J. ALLERGY CLIN. IMMUNOL., vol. 115, 2005, pages 55 - 60
YATOMI ET AL., PHYSIOL. REP., vol. 3, 2015, pages el2628
ZHANG ET AL., INFLAMM. RES., vol. 57, 2008, pages 157 - 162

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3789378A1 (fr) * 2019-09-06 2021-03-10 Grünenthal GmbH Pipéridines ou pipéridones substituées par de l'urée et de l'hétéroaryle
US20230348426A1 (en) * 2020-07-09 2023-11-02 Bristol-Myers Squibb Company Oxopyrrolidine fpr2 agonists
WO2025024211A1 (fr) * 2023-07-21 2025-01-30 Eli Lilly And Company Composés de pipéridine ayant une activité d'abaissement de lp(a)

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