WO2019170904A1 - Piperidines or piperidones substituted with urea and phenyl - Google Patents

Piperidines or piperidones substituted with urea and phenyl Download PDF

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Publication number
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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Prior art keywords
methoxyphenyl
urea
alkyl
chlorophenyl
piperidin
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PCT/EP2019/055947
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French (fr)
Inventor
Florian JAKOB
Beatrix Merla
David Rider
Torsten Dunkern
Markus Wagener
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Grünenthal GmbH
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Publication of WO2019170904A1 publication Critical patent/WO2019170904A1/en

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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

The present invention relates to a compound according to general formula (I) 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.

Description

Piperidines or piperidones substituted with urea and phenyl
The present invention relates to a compound according to general formula (I)
Figure imgf000002_0001
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) is a 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).
Wide ranging anti-inflammatory and pro-resolving effects of FPR2 ligands have been shown in pre-clinical models. For example, in vivo activities for LXA4, or derivatives, or stable analogues, and RvDl, or derivatives, or stable analogues have been demonstrated in arthritis, asthma, cardiovascular diseases, chronic obstructive pulmonary disease (COPD) colitis, corneal injury, cystic fibrosis, dermal inflammation, fibrosis of the lung and kidney, glomerulonephritis, graft versus host disease (GvHD), inflammatory pain, ischemia / reperfusion injury, periodontitis, peritonitis, post-operative pain, pancreatitis, retinopathy and sepsis (Fredman and Serhan, Biochem. J., 2011, 437, 185-197; Romano et al., Eur J Pharmacol. 2015, 760, 49-63; Yatomi et al., Physiol. Rep., 2015, 3, pii, el2628). It has been demonstrated that the FPR2 agonist 17-R-RvDl is able to reduce the severity of arthritis in the K/BxN serum transfer model of arthritis (Norling et al., JCI Insight, 2016, 1, e85922) and the stable agonist BML-111 has similar actions in the collagen-induced arthritis model (Zhang et al., Inflamm. Res., 2008, 57, 157- 162). The potential use of FPR2 modulators in lung diseases has been well documented. In terms of asthma, it has been demonstrated that the addition of LXA4 or RvDl, or their stable analogues, are able to improve asthmatic symptoms in animal models (Bamig et al., Sci. Transl. Med., 2013, 5, 174ra26; Levy et al., Nat Med. 2002, 8, 1018-23). It has also been demonstrated that in severe asthma patients there are reduced levels of LXA4 (Celik et al., Clin Exp Allergy, 2007, 37, 1494-1501). Similar reductions in pulmonary LXA4 levels were seen in patients with COPD (Vachier I et al,. J. Allergy Clin. Immunol., 2005, 115, 55-60) and cystic fibrosis (Karp et al., Nat. Immunol. 2004, 5, 388-392). RvDl attenuated smoking-induced emphysema in vivo (Kim et al., Int. J. Chron. Obstruct. Pulmon. Dis., 2016, 11 1119-1128) and 17-R-RvDl attenuates pulmonary fibrosis by inhibiting neutrophilic inflammation and promoting pulmonary restoration (Yatomi et al., Physiol. Rep., 2015, 3, pii, el2628).
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). Furthermore, 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).
The biological properties of 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).
Compounds which are active as modulators of FPR2 are also known from WO 2015/079692.
It was an object of the present invention to provide 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.
This object has been achieved by the subject-matter of the patent claims.
It was surprisingly found that 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)
Figure imgf000003_0001
wherein
X3 represents N(L-R4) and X2 represents C¾ or C(O) and X4 represent C¾; or
X3 represents N(L-R4) and X4 represents C¾ or C(O) and X2 represent CH2; and
n represents 0, 1 or 2
R1 represents phenyl or 5 or 6-membered heteroaryl,
R2 represents O-Ci-e-alkyl, H, F, Cl, Br, CN, Ci-6-alkyl, C3-6-cycloalkyl, CHF2, CH2F, CF3, OH,
OCHF2, OCH2F, OCF3, S-Ci-e-alkyl, S(0)-Ci-6-alkyl, S(0)2-Ci-6-alkyl, 0-C3-6-cycloalkyl, S-C3- 6-cycloalkyl, S(0)-C3-6-cycloalkyl, S(0)2-C3-6-cycloalkyl, NH2, N(H)(Ci-6-alkyl), N(Ci-6-alkyl)2, N(H)(C3-6-cycloalkyl), N(Ci-6-alkyl)(C3-6-cycloalkyl),NC(0)(Ci-6-alkyl), NC(0)(C3-6- cycloalkyl), NC(0)(3 to 6-membered heterocycloalkyl);
R3 represents F, Cl, Br, CHF2, CH2F, CF3, Ci-e-alkyl, C3-6-cycloalkyl, O-Ci-e-alkyl, OCHF2, OCH2F,
OCF3, S(0)-Ci-6-alkyl, S(0)-C3-6-cycloalkyl, S(0)2-Ci-6-alkyl, S(0)2-C3-6-cycloalkyl;
L represents bond, Ci-6-alkylene, C(O), S(0)2, C(CH3)2; and
R4 represents H, Ci-6-alkyl, C3-6-cycloalkyl, 3 to 6-membered heterocycloalkyl, aryl, 5 or 6- membered heteroaryl, C(0)NH2, C(0)N(H)(Ci-6-alkyl), C(0)N(Ci-6-alkyl)2, C(0)N(H)(C3-6- 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)(C3-6-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), C(0)N(C3-6-cycloalkyl)(C3-6-cycloalkyl), C(0)N(C3-6-cycloalkyl)(3 to 6-membered heterocycloalkyl), C(0)N(C3-6-cycloalkyl)(aryl), C(0)N(C3-6-cycloalkyl)(5 or 6-membered heteroaryl), C(0)0-(Ci-6-alkyl), C(0)0-(C3-6-cycloalkyl), C(0)0-(3 to 6-membered heterocycloalkyl), C(0)0-(aryl), C(0)0-(5 or 6-membered heteroaryl), S(0)-Ci-6-alkyl, S(0)2- Ci-6-alkyl, S(0)-C3-6-cycloalkyl, S(0)2-C3-6-cycloalkyl, Ci-6-alkylene-OH, Ci-6-alkylene-0-Ci-6- alkyl, Ci-6-alkylene-C3-6-cycloalkyl, Ci-6-alkylene-3 to 6-membered heterocycloalkyl, Ci-6- alkylene-aryl, Ci-6-alkylene-5 or 6-membered heteroaryl; wherein Ci-6-alkyl in each case independently from one another is linear or branched, saturated or unsaturated;
wherein Ci-6-alkylene is linear and saturated or unsaturated;
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, Ci-6-alkyl, CF3, CF2H, CFH2, CF2C1, CFC12, C(0)-Ci-6- alkyl, C(0)-0H, C(0)-OCi-6-alkyl, C(0)-NH2, C(0)-N(H)(Ci-6-alkyl), C(0)-N(Ci-6-alkyl)2, OH, =0, OCF3, OCF2H, OCFH2, OCF2Cl, OCFCl2, O-Ci-e-alkyl, 0-C(0)-Ci-6-alkyl, 0-C(0)-0-Ci-6-alkyl, O-(CO)- N(H)(CI-6 - alkyl) , 0-C(0)-N(Ci-6-alkyl)2, 0-S(0)2-NH2, 0-S(0)2-N(H)(Ci-6-alkyl), 0-S(0)2-N(Ci-6- alkyl)2, NH2, N(H)(Ci-6-alkyl), N(Ci-6-alkyl)2, N(H)-C(0)-Ci-6-alkyl, N(H)-C(0)-0-Ci-6-alkyl, N(H)- C(0)-NH2, N(H)-C(0)-N(H)(Ci-6-alkyl), N(H)-C(0)-N(Ci-6-alkyl)2, N(Ci-6-alkyl)-C(0)-Ci-6-alkyl, N(Ci_ 6-alkyl)-C(0)-0-Ci-6-alkyl, N(Ci-6-alkyl)-C(0)-NH2, N(Ci-6-alkyl)-C(0)-N(H)(Ci-6-alkyl), N(Ci-6-alkyl)- C(0)-N(Ci-6-alkyl)2, N(H)-S(0)20H, N(H)-S(0)2-Ci-6-alkyl, N(H)-S(0)2-0-Ci-6-alkyl, N(H)-S(0)2-NH2, N(H)-S(0)2-N(H)(Ci-6-alkyl), N(H)-S(0)2N(Ci-6-alkyl)2, N(Ci-6-alkyl)-S(0)2-0H, N(Ci-6-alkyl)-S(0)2-Ci- 6-alkyl, N(Ci-6-alkyl)-S(0)2-0-Ci-6-alkyl, N(Ci-6-alkyl)-S(0)2-NH2, N(Ci-6-alkyl)-S(0)2-N(H)(Ci-6-alkyl), N(Ci-6-alkyl)-S(0)2-N(Ci-6-alkyl)2, SCF3, SCF2H, SCFH2, S-Ci-e-alkyl, S(0)-Ci-6-alkyl, S(0)2-Ci-6-alkyl, S(0)2-0H, S(0)2-0-Ci-6-alkyl, S(0)2-NH2, S(0)2-N(H)(Ci-6-alkyl), S(0)2-N(Ci-6-alkyl)2, C3-6-cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 or 6-membered heteroaryl, 0-C3-6-cycloalkyl, 0(3 to 6- membered heterocycloalkyl), O-phenyl, 0(5 or 6-membered heteroaryl), C(0)-C3-6-cycloalkyl, C(0)-(3 to 6-membered heterocycloalkyl), C(0)-phenyl, C(0)-(5 or 6-membered heteroaryl), S(0)2-(C3-6-cycloalkyl), S(0)2-(3 to 6-membered heterocycloalkyl) and S(0)2-phenyl or S(0)2-(5 or 6-membered heteroaryl); wherein aryl, phenyl 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-6-alkyl, CF3, CF2H, CFH2, Ci-4-alkylene-CF3, Ci^-alkylene-CFzH, Ci-4-alkylene-CFH2, C(0)-Ci-6-alkyl, C(0)-0H, C(0)-0Ci-6-alkyl, C(0)-N(H)(0H), C(0)-NH2, C(0)-N(H)(Ci-6-alkyl), C(O)- N(Ci-6-alkyl)2, OH, OCF3, OCF2H, OCFH2, OCF2Cl, OCFCb, O-Ci-e-alkyl, O-Cs-e-cycloalkyl, 0-(3 to 6- membered heterocycloalkyl), NH2, N(H)(Ci-6-alkyl), N(Ci-6-alkyl)2, N(H)-C(0)-Ci-6-alkyl, N(C 1-6 -alkyl) - C(0)-Ci-6-alkyl, N(H)-C(0)-NH2, N(H)-C(0)-N(H)(Ci-6-alkyl), N(H)-C(0)-N(Ci-6-alkyl)2, N(Ci-6-alkyl)- C(0)-N(H)(CI-6 - alkyl) , N(Ci-6-alkyl)-C(0)-N(Ci-6-alkyl)2, N(H)-S(0)2-Ci-6-alkyl, SCF3, S-Ci-e-alkyl, S(0)-Ci-6-alkyl, S(0)2-Ci-6-alkyl, S(0)2-NH2, S(0)2-N(H)(CI-6- alkyl), S(0)2-N(Ci-6-alkyl)2, C3-6- cycloalkyl, Ci-4-alkylene-C3-6-cycloalkyl, 3 to 6-membered heterocycloalkyl, Ci-4-alkylene-(3 to 6- membered heterocycloalkyl), phenyl and 5 or 6-membered heteroaryl; in the form of the free compound or a physiologically acceptable salt thereof.
In a preferred embodiment, the compound according to the present invention is present in form of the free compound. For the purpose of specification, "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 14N or 15N 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.
In another preferred embodiment, the compound according to the present invention is present in form of a physiologically acceptable salt. For the purposes of this specification, the term“physiologically acceptable salt” preferably refers to a salt obtained from a compound according to the present invention and a physiologically acceptable acid or base.
According to the present invention, the compound according to the present invention may be present in any possible form including solvates, cocrystals and polymorphs. For the purposes of this specification, the term "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.
Further, 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. In the sense of the present invention, 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.
In the sense of the present invention, 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 are well known to the person skilled in the art and 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).
Further in the sense of the present invention, 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.
Further in the sense of the present invention, 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.
In the sense of the present invention, 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):
Figure imgf000006_0001
(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:
Figure imgf000007_0001
In the following, 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). For the purpose of clarification, 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).
Further in the sense of the present invention, 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”,
Figure imgf000007_0002
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):
Figure imgf000007_0003
(cis-II)
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:
Figure imgf000007_0004
(lie) (lid) In the following, either one of the two enantiomers“entl-cis” (identified by the prefix“entl-cis” in the chemical name) and“ent2-cis” (identified by the prefix“ent2-cis” in the chemical name) is according to general formula (He) while the other is according to general formula (lid). For the purpose of clarification, one of entl-cis and ent2-cis has to be according to general formula (He) and the other one has to be according to general formula (lid).
In the following, 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. For the purpose of clarification, one of the diastereomers 1 and 2 has to be cis and the other one has to be trans.
In the sense of the present invention, 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 2H (deuterium), 3H (tritium), 13C and 14C. Isotopic isomers of a compound of the invention can generally be prepared by conventional procedures known to a person skilled in the art.
According to the present invention, the terms "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. Preferably, Ci-6-alkyl and Ci^-alkyl are saturated. Preferred 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-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. Particularly preferred 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.
Further according to the present invention, 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 (-<¾-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-) and hexylene (-CH2CH2CH2CH2CH2CH2-); more preferably methylene (-CH2-) and ethylene (-CH2CH2-) and most preferably methylene (-CH2-). Preferably, Ci-6-alkylene is selected from C1- - alkylene. Still further according to the present invention, 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. Further, 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. However, preferably, the C3-6-cycloalkyl group is neither condensed with further ring systems nor bridged.
Preferred 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.
According to the present invention, the term "3 to 6-membered heterocycloalkyl” preferably means heterocycloaliphatic saturated or unsaturated (but not aromatic) residues having 3 to 6, i.e. 3, 4, 5 or 6 ring members, wherein in each case at least one, if appropriate also two or three carbon atoms are replaced by a heteroatom or a heteroatom group each selected independently of one another from the group consisting of O, S, S(=0), S(=0)2, N, NH and N(Ci-4-alkyl) such as N(C¾), wherein the carbon atoms of the ring can be unsubstituted or mono- or polysubstituted. 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.
According to the present invention, the term "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. The 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. In a preferred embodiment, aryl is condensed with a further ring system. Examples of 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. Preferably, 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. In another preferred embodiment, aryl is not condensed with any further ring system. A particularly preferred aryl is phenyl, unsubstituted or mono- or polysubstituted.
According to the present invention, 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. In the case of substitution on the heteroaryl, 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. Preferably, 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. In a preferred embodiment, the 5- to 6- membered heteroaryl is part of a bi- or polycyclic, preferably bicyclic, system. In another preferred embodiment, the 5- to 6-membered heteroaryl is not part of a bi- or polycyclic system. Preferably, 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, benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl, quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, isoquinolinyl, naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl, phenothiazinyl, phthalazinyl, purinyl, phenazinyl, tetrazolyl and triazinyl. 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.
In connection with the terms“Ci-6-alkyl”,“Ci^-alkyl”,“C3-6-cycloalkyl”,“3 to 6-membered heterocycloalkyl” and “Ci-6-alkylene”, the term "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;
of one or more hydrogen atoms each independently of one another by at least one substituent. In case of a multiple substitution, i.e. in case of polysubstituted residues, such as di- or trisubstituted residues, these residues may be polysubstituted either on different or on the same atoms, for example trisubstituted on the same carbon atom, as in the case of CF3, CH2CF3 or disubstituted as in the case of 1,1-difluorocyclohexyl, or at various points, as in the case of CH(OH)-CH=CH-CHCl2 or l-chloro-3-fluorocyclohexyl. The multiple substitution can be carried out using the same or using different substituents. In relation to the terms“phenyl”, "aryl” and“5- to 6-membered heteroaryl”, the term "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.
If a residue occurs multiply within a molecule, then this residue can have respectively different meanings for various substituents: if, for example, both R2 and R4 denote Ci-6-alkyl, then Ci-6-alkyl can e.g. represent ethyl for R2 and can represent methyl for R4.
According to the present invention, 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, Ci-6-alkyl, CF3, CF2H, CFFh, CF2CI, CFCh, C(0)-Ci-6-alkyl, C(0)-0H, C(0)-OCi-6-alkyl, C(0)-NH2, C(0)-N(H)(Ci-6-alkyl), C(0)-N(Ci-6-alkyl)2, OH, =0, OCF3, OCF2H, OCFH2, OCF2CI, OCFCh, O-Ci-e-alkyl, 0-C(0)-Ci-6-alkyl, 0-C(0)-0-Ci-6-alkyl, O- (CO)-N(H)(CI-6 - alkyl) , 0-C(0)-N(Ci-6-alkyl)2, 0-S(0)2-NH2, 0-S(0)2-N(H)(Ci-6-alkyl), 0-S(0)2-N(Ci-6-alkyl)2, NH2, N(H)(CI-6 - alkyl) , N(Ci-6-alkyl)2, N(H)-C(0)-Ci-6-alkyl, N(H)-C(0)-0-Ci-6-alkyl, N(H)-C(0)-NH2, N(H)- C(0)-N(H)(CI-6 - alkyl) , N(H)-C(0)-N(Ci-6-alkyl)2, N(Ci-6-alkyl)-C(0)-Ci-6-alkyl, N(Ci-6-alkyl)-C(0)-0-Ci-6- alkyl, N(Ci-6-alkyl)-C(0)-NH2, N(Ci-6-alkyl)-C(0)-N(H)(Ci-6-alkyl), N(Ci-6-alkyl)-C(0)-N(Ci-6-alkyl)2, N(H)- S(0)20H, N(H)-S(0)2-Ci-6-alkyl, N(H)-S(0)2-0-Ci-6-alkyl, N(H)-S(0)2-NH2, N(H)-S(0)2-N(H)(Ci-6-alkyl), N(H)-S(0)2N(CI-6 - alkyl)2 , N(Ci-6-alkyl)-S(0)2-0H, N(Ci-6-alkyl)-S(0)2-Ci-6-alkyl, N(Ci-6-alkyl)-S(0)2-0-Ci-6- alkyl, N(Ci-6-alkyl)-S(0)2-NH2, N(Ci-6-alkyl)-S(0)2-N(H)(Ci-6-alkyl), N(Ci-6-alkyl)-S(0)2-N(Ci-6-alkyl)2, SCF3, SCF2H, SCFH2, S-Ci-e-alkyl, S(0)-Ci-6-alkyl, S(0)2-Ci-6-alkyl, S(0)2-0H, S(0)2-0-Ci-6-alkyl, S(0)2-NH2, S(0)2- N(H)(Ci-6-alkyl), S(0)2-N(Ci-6-alkyl)2, C3-6-cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 or 6- membered heteroaryl, 0-C3-6-cycloalkyl, 0-(3 to 6-membered heterocycloalkyl), O-phenyl, 0-(5 or 6-membered heteroaryl), C(0)-C3-6-cycloalkyl, C(0)-(3 to 6-membered heterocycloalkyl), C(0)-phenyl, C(0)-(5 or 6- membered heteroaryl), S(0)2-(C3-6-cycloalkyl), S(0)2-(3 to 6-membered heterocycloalkyl), S(0)2-phenyl and S(0)2-(5 or 6-membered heteroaryl). 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. According to this embodiment, 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, C¾, CH2CH3, CN and CF3. Preferably, Ci-6-alkylene groups are unsubstituted.
According to the present invention, 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- CFH2, C(0)-Ci-6-alkyl, C(0)-0H, C(0)-OCi-6-alkyl, C(0)-N(H)(0H), C(0)-NH2, C(0)-N(H)(Ci-6-alkyl), C(0)- N(Ci-6-alkyl)2, OH, OCF3, OCF2H, OCFH2, OCF2Cl, OCFCh, O-Ci-e-alkyl, O-CV, -cycloalkyl, 0-(3 to 6- membered heterocycloalkyl), N¾, N(H)(Ci-6-alkyl), N(Ci-6-alkyl)2, N(H)-C(0)-Ci-6-alkyl, N(Ci-6-alkyl)-C(0)- Ci-e-alkyl, N(H)-C(0)-NH2, N(H)-C(0)-N(H)(Ci-6-alkyl), N(H)-C(0)-N(Ci-6-alkyl)2, N(Ci-6-alkyl)-C(0)- N(H)(CI-6 - alkyl) , N(Ci-6-alkyl)-C(0)-N(Ci-6-alkyl)2, N(H)-S(0)2-Ci-6-alkyl, SCF3, S-Ci-6-alkyl, S(0)-Ci-6-alkyl, S(0)2-Ci-6-alkyl, S(0)2-NH2, S(0)2-N(H)(Ci-6-alkyl), S(0)2-N(Ci-6-alkyl)2, C3-6-cycloalkyl, Ci-4-alkylene-C3-6- cycloalkyl, 3 to 6-membered heterocycloalkyl, Ci^-alkylene-^ to 6-membered heterocycloalkyl), phenyl or 5 or 6-membered heteroaryl. 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, CF3, CF2H, CFH, OH, OCF3, OCF2H, OCFH2 and O-Ci-e-alkyl; more preferably F, Cl, Br, Ci-6-alkyl, CF3, OH, OCF3 and O-Ci-6-alkyl; most preferably Cl, Br, Ci -6 -alkyl and CF3 and in particular Cl, Br, CH3, CH2CH3 and CF3. According to this embodiment, 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 CF3.
In a preferred embodiment the compound according to the present invention is according to general formula (Ila) or (lib)
Figure imgf000012_0001
In another preferred embodiment, 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).
In a further preferred embodiment, the compound according to the present invention is according to general formula (He) or (lid)
Figure imgf000012_0002
In a particularly preferred embodiment, the compound according to the present invention is according to general formula (Ila) or (lib).
According to the present invention,
X3 represents N(L-R4) and X2 represents CH2 or C(O) and X4 represent CH2; or
X3 represents N(L-R4) and X4 represents CH2 or C(O) and X2 represent CH2
Preferably, X3 represents N(L-R4) and X2 represents CH2 or C(O) and X4 represent CH2. In a preferred embodiment, the compound according to the present invention is according to general formula (III)
Figure imgf000013_0001
In another preferred embodiment, the compound according to the present invention is according to general formula (IV)
Figure imgf000013_0002
In another preferred embodiment, the compound according to the present invention is according to general formula
(V):
Figure imgf000013_0003
In a particularly preferred embodiment, the compound according to the present invention is according to general formula (III) or (IV).
In a preferred embodiment, R1 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, quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, isoquinolinyl, naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl, phenothiazinyl, phthalazinyl, purinyl, phenazinyl, tetrazolyl and triazinyl. According to this embodiment, preferably phenyl, 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, quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, isoquinolinyl, naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl, phenothiazinyl, phthalazinyl, purinyl, phenazinyl, tetrazolyl and triazinyl in each case independently from one another are unsubstituted or mono- or disubstituted, more preferably unsubstituted or monosubstituted, with one or two substituents selected from the group consisting of F, Cl, Br, CN, Ci-6-alkyl, CF3, CF2H, CFFh, Ci-4-alkylene-CF3, Ci-4-alkylene-CF2H, C1-4- alkylene-CFHz, C(0)-Ci-6-alkyl, C(0)-0H, C(0)-0Ci-6-alkyl, C(0)-N(H)(0H), C(0)-NH2, C(0)-N(H)(Ci-6- alkyl), C(0)-N(Ci-6-alkyl)2, OH, OCF3, OCF2H, OCFH2, OCF2Cl, OCFCI2, O-Cu, -alkyl, O-Cs-e-cycloalkyl, 0-(3 to 6-membered heterocycloalkyl), NH2, N(H)(Ci-6-alkyl), N(Ci-6-alkyl)2, N(H)-C(0)-Ci-6-alkyl, N(C 1-6- alkyl) - C(0)-Ci-6-alkyl, N(H)-C(0)-NH2, N(H)-C(0)-N(H)(Ci-6-alkyl), N(H)-C(0)-N(Ci-6-alkyl)2, N(Ci-6-alkyl)-C(0)- N(H)(C 1 -6 - alkyl) , N(Ci-6-alkyl)-C(0)-N(Ci-6-alkyl)2, N(H)-S(0)2-Ci-6-alkyl, SCF3, S-Ci-6-alkyl, S(0)-Ci-6-alkyl, S(0)2-Ci-6-alkyl, S(0)2-NH2, S(0)2-N(H)(Ci-6-alkyl), S(0)2-N(Ci-6-alkyl)2, Cs-e-cycloalkyl, C1.4-alkylene-C3.6- cycloalkyl, 3 to 6-membered heterocycloalkyl, Ci-4-alkylene-(3 to 6-membered heterocycloalkyl), phenyl or 5 or 6-membered heteroaryl; more preferably F, Cl, Br, CN, unsubstituted Ci-6-alkyl, CF3, CF2H, CFH2, Ci-4-alkylene- CF3, Ci-4-alkylene-CF2H, Ci-4-alkylene-CFH2, OCF3, OCF2H, OCFH2 and 0-(unsubstituted Ci-6-alkyl); still more preferably F, Cl, Br, CN, unsubstituted Ci-6-alkyl, CF3, CF2H, CFH2, OCF3, OCF2H, OCFH2 and 0-(unsubstituted Ci-6-alkyl); most preferably F, Cl, Br, CN, unsubstituted Ci-6-alkyl and CF3; and in particular Cl, Br, C¾ and CF3.
Preferably, R1 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, C1-4- alkylene-CF3, Ci-4-alkylene-CF2H, Ci-4-alkylene-CFH2, OCF3, OCF2H, OCFH2 and O- (unsubstituted Ci-6-alkyl); more preferably R1 represents phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, thiazolyl or isothiazolyl, wherein preferably phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, thiazolyl and isothiazolyl in each case independently from one another are unsubstituted or mono- or polysubstituted, 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, OCF3, OCF2H, OCFH2 and 0-(unsubstituted Ci-6-alkyl); and
most preferably R1 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 CF3.
In a preferred embodiment, R1 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 CF3.
According to the present invention, R2 represents O-Ci-6-alkyl, H, F, Cl, Br, CN, Ci-6-alkyl, C3-6-cycloalkyl, CHF2, CH2F, CF3, OH, OCHF2, OCH2F, OCF3, 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)-C3-6-cycloalkyl, S(0)2-C3-6-cycloalkyl, NH2, N(H)(Ci-6-alkyl), N(Ci-6-alkyl)2, N(H)(C3-6- cycloalkyl), N(Ci-6-alkyl)(C3-6-cycloalkyl),NC(0)(Ci-6-alkyl), NC(0)(C3-6-cycloalkyl), NC(0)(3 to 6-membered heterocycloalkyl) ;
preferably O-Ci-e-alkyl, H, F, Cl, Br, CN, Ci-6-alkyl, C3-6-cycloalkyl, CHF2, CH2F, CF3, OH, OCHF2, OCH2F, OCF3, S-Ci-e-alkyl, S(0)-Ci-6-alkyl, S(0)2-Ci-6-alkyl, 0-C3-6-cycloalkyl, S-C3-6-cycloalkyl, S(0)-C3-6-cycloalkyl, S(0)2-C3-6-cycloalkyl, N¾, 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, CHF2, CH2F, CF3, OH, OCHF2, OCH2F or OCF3; even more preferably O-Ci-e-alkyl, F, Cl, Br, CN, Ci-e-alkyl, C3-6-cycloalkyl, CHF2, CH2F, CF3, OH, OCHF2, OCH2F or OCF3; still more preferably 0-(unsubstituted Ci-6-alkyl), F, Cl, Br, CN, unsubstituted Ci-6-alkyl, unsubstituted C3- 6-cycloalkyl, CHF2, CH2F, CF3, OH, OCHF2, OCH2F or OCF3 ; yet more preferably O-CH3, O-CH2CH3, O- CH2CH2CH3, 0-CH(CH3)2, F, Cl, Br, CN, C¾, CH2CH3, CH2CH2CH3, CH(CH3)2„ CF3 or OCF3; most preferably O-CH3, F, Cl, Br, CF3 or OCF3; and in particular O-CH3 or Cl.
In a particularly preferred embodiment, R2 represents O-CH3, F, Cl, Br, OH, O-CH2CH3, 0-(CH2)2CH3, O- CH(CH3)2 or OCF3.
According to the present invention, R3 represents F, Cl, Br, CHF2, CH2F, CF3, Ci-6-alkyl, C3-6-cycloalkyl, O-C1-6- alkyl, OCHF2, OCH2F, OCF3, S(0)-Ci-6-alkyl, S(0)-C3-6-cycloalkyl, S(0)2-Ci-6-alkyl or S(0)2-C3-6-cycloalkyl; more preferably F, Cl, Br, CHF2, CH2F, 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, C¾, CH2CH3, cyclopropyl, OCH3, OCH2CH3 or OCF3; most preferably F, Cl, Br or CF3; and in particular F.
R3 can be bound to any of the four available carbon atoms of the phenyl ring. Preferably, R3 occupies the meta position(s) relative to R2.
According to the present invention, n represents 0, 1 or 2; preferably 0 or 2.
In a preferred embodiment,
R3 represents F and n represents 2; or
n represents 0.
Particularly preferably, the compound according to the present invention is according to general formula (VI) or
(VII)
Figure imgf000016_0001
According to the present invention, L represents bond, Ci-6-alkylene, C(O), S(0)2 or C(CH3)2.
Preferably, L represents bond, CH2, CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH2CH2CH2CH2CH2, CH2CH2CH2CH2CH2CH2, C(0), S(0)2 or C(CH3)2; more preferably bond, CH2, C(O), S(0)2 or C(CH3)2; most preferably bond, CH2 or C(O); and in particular bond or CH2.
Further according to the present invention,
R4 represents H, Ci-6-alkyl, C3-6-cycloalkyl, 3 to 6-membered heterocycloalkyl, aryl, 5 or 6-membered heteroaryl, C(0)NH2, C(0)N(H)(Ci-6-alkyl), C(0)N(Ci-6-alkyl)2, C(0)N(H)(C3-6-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)(C3-6-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), C(0)N(C3-6-cycloalkyl)(C3. 6-cycloalkyl), C(0)N(C3-6-cycloalkyl)(3 to 6-membered heterocycloalkyl), C(0)N(C3-6- cycloalkyl)(aryl), C(0)N(C3-6-cycloalkyl)(5 or 6-membered heteroaryl), C(0)0-(Ci-6-alkyl), C(0)0- (C3.6-cycloalkyl), C(0)0-(3 to 6-membered heterocycloalkyl), C(0)0-(aryl), C(0)0-(5 or 6-membered heteroaryl), S(0)-Ci-6-alkyl, S(0)2-Ci-6-alkyl, S(0)-C3-6-cycloalkyl, S(0)2-C3-6-cycloalkyl, Ci-6- alkylene-OH, Ci-6-alkylene-0-Ci-6-alkyl, Ci-6-alkylene-C3-6-cycloalkyl, Ci-6-alkylene-3 to 6-membered heterocycloalkyl, Ci-6-alkylene-aryl, Ci-6-alkylene-5 or 6-membered heteroaryl;
wherein preferably
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, Ci-e-alkyl, CF3, CF2H, CFH2, CF2C1, CFC12, C(0)-Ci-6-alkyl, C(0)-0H, C(0)-0Ci-6-alkyl, C(0)-NH2, C(0)-N(H)(Ci-6-alkyl), C(0)-N(Ci-6-alkyl)2, OH, =0, OCF3, OCF2H, OCFH2, OCF2Cl, OCFCh, O-Ci-6-alkyl, 0-C(0)-Ci-6-alkyl, 0-C(0)-0-Ci-6-alkyl, 0-(C0)-N(H)(Ci-6- alkyl), 0-C(0)-N(Ci-6-alkyl)2, 0-S(0)2-NH2, 0-S(0)2-N(H)(Ci-6-alkyl), 0-S(0)2-N(Ci-6-alkyl)2, NH2, N(H)(CI-6 - alkyl) , N(Ci-6-alkyl)2, N(H)-C(0)-Ci-6-alkyl, N(H)-C(0)-0-Ci-6-alkyl, N(H)-C(0)-NH2, N(H)- C(0)-N(H)(CI-6 - alkyl) , N(H)-C(0)-N(Ci-6-alkyl)2, N(Ci-6-alkyl)-C(0)-Ci-6-alkyl, N(Ci-6-alkyl)-C(0)-0- Ci-e-alkyl, N(Ci-6-alkyl)-C(0)-NH2, N(Ci-6-alkyl)-C(0)-N(H)(Ci-6-alkyl), N(Ci-6-alkyl)-C(0)-N(Ci-6- alkyl)2, N(H)-S(0)20H, N(H)-S(0)2-Ci-6-alkyl, N(H)-S(0)2-0-Ci-6-alkyl, N(H)-S(0)2-NH2, N(H)-S(0)2- N(H)(CI-6 - alkyl) , N(H)-S(0)2N(Ci-6-alkyl)2, N(Ci-6-alkyl)-S(0)2-0H, N(Ci-6-alkyl)-S(0)2-Ci-6-alkyl, N(Ci-6-alkyl)-S(0)2-0-Ci-6-alkyl, N(Ci-6-alkyl)-S(0)2-NH2, N(Ci-6-alkyl)-S(0)2-N(H)(Ci-6-alkyl), N(CI-6- alkyl)-S(0)2-N(Ci-6-alkyl)2, SCF3, SCF2H, SCFH2, S-Ci-6-alkyl, S(0)-Ci-6-alkyl, S(0)2-Ci-6-alkyl, S(0)2- OH, S(0)2-0-Ci-6-alkyl, S(0)2-NH2, S(0)2-N(H)(Ci-6-alkyl), S(0)2-N(Ci-6-alkyl)2, C3-6-cycloalkyl, 3 to 6- membered heterocycloalkyl, phenyl, 5 or 6-membered heteroaryl, 0-C3-6-cycloalkyl, 0-(3 to 6-membered heterocycloalkyl), O-phenyl, 0-(5 or 6-membered heteroaryl), C(0)-C3-6-cycloalkyl, C(0)-(3 to 6- membered heterocycloalkyl), C(0)-phenyl, C(0)-(5 or 6-membered heteroaryl), S(0)2-(C3-6-cycloalkyl), S(0)2-(3 to 6-membered heterocycloalkyl), S(0)2-phenyl and S(0)2-(5 or 6-membered heteroaryl); more preferably F, Cl, CN, Ci-6-alkyl, CF3, CF2H, CFH2; OCF3, S(0)-Ci-6-alkyl, and S(0)2-Ci-6-alkyl; still more preferably F, Cl, CN, Ci-e-alkyl, CF3, and S(0)2-Ci-6-alkyl; most preferably F, CN, CH3, CH2CH3, CF3, and S(0)2-C]¾; and in particular F and S(0)2-C]¾;
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, CF3, CF2H, CFH2, Ci^-alkylene-CF , Ci-4-alkylene-CF2H, Ci-4-alkylene-CFH2, C(0)-Ci-6-alkyl, C(0)-0H, C(0)-0Ci -6-alkyl, C(0)-N(H)(0H), C(0)-NH2, C(0)-N(H)(Ci-6-alkyl), C(0)-N(Ci-6-alkyl)2, OH, OCF3, OCF2H, OCFH2, OCF2Cl, OCFCb, O-Ci-6-alkyl, 0-C3-6-cycloalkyl, 0-(3 to 6-membered heterocycloalkyl), NH2, N(H)(Ci-6-alkyl), N(Ci-6-alkyl)2, N(H)-C(0)-Ci-6-alkyl, N(Ci-6-alkyl)-C(0)-Ci-6- alkyl, N(H)-C(0)-NH2, N(H)-C(0)-N(H)(Ci-6-alkyl), N(H)-C(0)-N(Ci-6-alkyl)2, N(Ci-6-alkyl)-C(0)- N(H)(C i -6 - alkyl) , N(Ci-6-alkyl)-C(0)-N(Ci-6-alkyl)2, N(H)-S(0)2-Ci-6-alkyl, SCF3, S-Ci-e-alkyl, S(0)-Ci-6- alkyl, S(0)2-Ci-6-alkyl, S(0)2-NH2, S(0)2-N(H)(Ci-6-alkyl), S(0)2-N(Ci-6-alkyl)2, Cs-e-cycloalkyl, CM- alkylene-C3-6-cycloalkyl, 3 to 6-membered heterocycloalkyl, Ci^-alkylene-(3 to 6-membered heterocycloalkyl), phenyl and 5 or 6-membered heteroaryl; more preferably F, Cl, CN, Ci-6-alkyl, O-Ci-6- alkyl, CF3, CF2H, CFH2 and OCF3; still more preferably F, Cl, CN, Ci-6-alkyl, O-Ci-6-alkyl, and CF3; most preferably F, CN, C¾, O-CH3, and CF3; and in particular F, C¾, and O-CH3.
Preferably, R4 represents H, Ci-6-alkyl, C3-6-cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 or 6- membered heteroaryl, C(0)NH2, C(0)N(H)(Ci-6-alkyl), C(0)N(Ci-6-alkyl)2, C(0)N(H)(C3-6-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)(C3-6-cycloalkyl), C(0)N(Ci-6-alkyl)(3 to 6-membered heterocycloalkyl), C(0)N(CI-6- alkyl) (phenyl), C(0)N(Ci-6-alkyl)(5 or 6-membered heteroaryl), C(0)N(C3-6-cycloalkyl)(C3-6-cycloalkyl), C(0)N(C3-6-cycloalkyl)(3 to 6-membered heterocycloalkyl), C(0)N(C3-6-cycloalkyl)(phenyl), C(0)N(C3-6- cycloalkyl)(5 or 6-membered heteroaryl), C(0)0-(Ci-6-alkyl), C(0)0-(C3-6-cycloalkyl), C(0)0-(3 to 6-membered heterocycloalkyl), C(0)0-(phenyl), C(0)0-(5 or 6-membered heteroaryl), S(0)-Ci-6-alkyl, S(0)2-Ci-6-alkyl, S(O)- C3-6-cycloalkyl, S(0)2-C3-6-cycloalkyl, Ci-6-alkylene-OH, Ci-6-alkylene-0-Ci-6-alkyl, Ci-6-alkylene-C3-6- cycloalkyl, Ci-6-alkylene-3 to 6-membered heterocycloalkyl, Ci-6-alkylene-phenyl, Ci-6-alkylene-5 or 6-membered heteroaryl;
more preferably H, Ci-6-alkyl, C3-6-cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 or 6-membered heteroaryl, C(0)NH2, C(0)N(H)(Ci-6-alkyl), C(0)N(Ci-6-alkyl)2, C(0)N(H)(C3-6-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)0-(Ci-6-alkyl), C(0)0-(C3-6-cycloalkyl), C(0)0-(3 to 6-membered heterocycloalkyl), S(0)-Ci-6-alkyl, S(0)2-Ci-6-alkyl, Ci-6- alkylene-OH, Ci-6-alkylene-0-Ci-6-alkyl, Ci-6-alkylene-C3-6-cycloalkyl, Ci-6-alkylene-3 to 6-membered heterocycloalkyl, Ci-6-alkylene-phenyl, Ci-6-alkylene-5 or 6-membered heteroaryl;
still more preferably H, Ci-6-alkyl, C3-6-cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 or 6-membered heteroaryl, C(0)NH2, C(0)N(H)(Ci-6-alkyl), C(0)N(Ci-6-alkyl)2, C(0)N(H)(C3-6-cycloalkyl), C(0)N(H)(3 to 6- membered heterocycloalkyl), C(0)0-(Ci-6-alkyl), C(0)0-(C3-6-cycloalkyl), C(0)0-(3 to 6-membered heterocycloalkyl), Ci-6-alkylene-OH, Ci-6-alkylene-0-Ci-6-alkyl, Ci-6-alkylene-C3-6-cycloalkyl, Ci-6-alkylene-3 to 6-membered heterocycloalkyl, Ci-6-alkylene-phenyl;
most preferably H, Ci-6-alkyl, C3-6-cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 or 6-membered heteroaryl, C(0)NH2, 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
in particular H, Ci-6-alkyl, C3-6-cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 or 6-membered heteroaryl, C(0)NH2, C(0)0-(Ci-6-alkyl), Ci-e-alkylene-OH or Ci-e-alkylene-O-Ci-e-alkyl.
In a preferred embodiment, R4 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)NH2, 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, CF2H, CFFh and OCF3; and wherein phenyl 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, CN, Ci-e-alkyl, O-Ci-e-alkyl, CF3, CF2H, CFH2 and OCF3.
In another preferred embodiment, R4 represents
H;
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;
wherein 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-(CH2)2CH3, 0-CH(CH3)2, S(O)- C¾, and S(0)2-CH3;
Ci-6-alkylene-OH selected from the group consisting of CH2OH, CH2CH2OH, (CH2)30H, (CH2)40H, C(H)(OH)-CH3, CH2C(H)(OH)-CH3, C(CH3)2-OH, C(H)(OH)-C(CH3)2, and CH2C(CH3)2-OH;
Ci-6-alkylene-0-Ci-6-alkyl selected from the group consisting of CH2OCH3, CH2CH2OCH3, (CH2)30CH3, (CH2)4OCH3, (CH2)5OCH3, and (CH2)60CH3;
3 to 6-membered 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)NH2;
C(0)N(H)(Ci-6-alkyl) selected from the group consisting of C(0)N(H)(CH3) and C(0)N(H)(CH2CH3); C(0)N(Ci-6-alkyl)2 selected from the group consisting of C(0)N(CH3)2 and 0(0)N(ϋ¼ϋ¼)2;
C(0)0(Ci-6-alkyl) selected from the group consisting of C(0)0-CH3, C(0)0-CH2CH3, C(0)0- (CH2)2CH3, C(0)0-CH(CH3)2;
S(0)-Ci-6-alkyl selected from the group consisting of S(0)-CH3, S(0)-CH2CH3, S(0)-(CH2)2CH3, S(O)- CH(CH3)2;
S(0)2-Ci-6-alkyl selected from the group consisting of S(0)2-CH3, S(0)2-CH2CH3, S(0)2-(CH2)2CH3, S(0)2-CH(CH3)2;
S(0)-C3-6-cycloalkyl selected from the group consisting of S(0)-cyelopropyl, S(0)-cyelobutyl, S(O)- cyclopentyl, S(0)-cyciohexyl;
S(0)2-C3-6-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-CH3, or CH3; 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;
wherein said 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-CH3, or CH3.
More preferably, R4 represents H; methyl, CF3, CHF2, CH2F, ethyl, CH2CF3, CH2CHF2, CH2CH2F, CF2CH3, CHFCH3, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CH2OH, CH2CH2OH, (CH2)3OH, (CH2)40H, C(H)(OH)-CH3, CH2C(H)(OH)-CH3, CH2C(CH3)2OH, CH2OCH3, CH2CH2OCH3, (CH2)3OCH3, CH2S(0)-CH3, CH2CH2S(0)-CH3, (CH2)3S(0)-CH3, (CH2)4S(0)-CH3, C(H)(S(0)-CH3)-CH3, CH2C(H)(S(0)-CH3)-CH3,
CH2C(CH3)2S(0)-CH3, CH2S(0)2-CH3, CH2CH2S(0)2-CH3, (CH2)3S(0)2-CH3, (CH2)4S(0)2-CH3, C(H)(S(0)2- CH3)-CH3, CH2C(H)(S(0)2-CH3)-CH3, CH2C(CH3)2S(0)2-CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, dioxanyl, oxiranyl, piperazinyl, piperidinyl, pyrazolidinyl, pyranyl, C(0)NH2, C(0)0-CH3, C(0)0-CH2CH3, C(0)0-(CH2)2CH3, S(0)-CH3, S(0)-CH2CH3, S(0)2-CH3, S(0)2- CH2CH3, phenyl, fluorophenyl, chlorophenyl, bromophenyl, methoxyphenyl, methylphenyl, pyridyl, methoxypyridyl, fluoropyridyl, methylpyridyl, pyrimidinyl, methoxypyrimidinyl, fluoropyrimidinyl, methylpyrimidinyl, pyridazinyl, methoxypyridazinyl, fluoropyridazinyl, methylpyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, thienyl, triazolyl or thiadiazolyl.
In a preferred embodiment,
L represents bond, C¾ or C(O); and/or
R4 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)NH2, 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)-C3-6-cycloalkyl, or S (0)2 -C3 -6 - cycloalkyl . More preferably,
L represents bond, C¾ or C(O); and
R4 represents
H;
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;
wherein 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-CH3, O-CH2CH3, 0-(CH2)2CH3, 0-CH(CH3)2, S(0)-CH3, and S(0)2-CH3;
Ci-6-alkylene-OH selected from the group consisting of CH2OH, CH2CH2OH, (CH2)3OH, (CH2)40H, C(H)(OH)-CH3, CH2C(H)(OH)-CH3, C(CH3)2-OH, C(H)(OH)-C(CH3)2, and CH2C(CH3)2-OH,
Ci-6-alkylene-0-Ci-6-alkyl selected from the group consisting of CH20CH3, CH2CH20CH3, (CH2)3OCH3, (CH2)4OCH3, (CH2)5OCH3, and (CH2)60CH3,
3 to 6-membered 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)NH2,
C(0)N(H)(Ci-6-alkyl) selected from the group consisting of C(0)N(H)(CH3) and C(0)N(H)(CH2CH3);
C(0)N(Ci-6-alkyl)2 selected from the group consisting of C(0)N(CH3)2 and C(0)N(CH2CH3)2;
C(0)0-(Ci-6-alkyl) selected from the group consisting of C(0)0-CH3, C(0)0-CH2CH3, C(0)0- (CH2)2CH3, and C(0)0-CH(CH3)2;
S(0)-Ci-6-alkyl selected from the group consisting of S(0)-C¾, S(0)-CH2CH3, S(0)-(CH2)2CH3, S(O)- CH(CH3)2;
S(0)2-Ci-6-alkyl selected from the group consisting of S(0)2-CH3, S(0)2-CH2CH3, S(0)2-(CH2)2CH3, and S(0)2-CH(CH3)2;
S(0)-C3-6-cycloalkyl selected from the group consisting of S(0)-cyclopropyl, S(0)-cyclobutyl, S(O)- cyclopentyl, and S(0)-cyclohexyl;
S(0)2-C3-6-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-CH3, and CH3; 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;
wherein said 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-C¾, or C¾.
In a particularly preferred embodiment,
X3 represents N(L-R4) and X2 represents C¾ or C(O) and X4 represent C¾;
and
n represents 0, 1 or 2
R1 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 CF3;
R2 represents O-CH3 or Cl ;
R3 represents F;
L represents bond, C¾ or C(O); and
R4 represents
H;
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;
wherein 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-(CH2)2CH3, 0-CH(CH3)2, S(O)- CH3, and S(0)2-CH3;
Ci-6-alkylene-OH selected from the group consisting of CH2OH, CH2CH2OH, (CH2)30H, (CH2)40H, C(H)(OH)-CH3, CH2C(H)(OH)-CH3, C(CH3)2-OH, C(H)(OH)-C(CH3)2, and CH2C(CH3)2-OH,
Ci-6-alkylene-0-Ci-6-alkyl selected from the group consisting of CH2OCH3, CH2CH2OCH3, (CH2)30CH3, (CH2)4OCH3, (CH2)5OCH3, and (CH2)60CH3,
3 to 6-membered 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)NH2,
C(0)N(H)(Ci-6-alkyl) selected from the group consisting of C(0)N(H)(CH3) and C(0)N(H)(CH2CH3); C(0)N(Ci-6-alkyl)2 selected from the group consisting of C(0)N(CH3)2 and 0(0)N(ϋ¼ϋ¼)2;
C(0)0(Ci-6-alkyl) selected from the group consisting of C(0)0-CH3, C(0)0-CH2CH3, C(0)0- (CH2)2CH3, and C(0)0-CH(CH3)2;
S(0)-Ci-6-alkyl selected from the group consisting of S(0)-CH3, S(0)-CH2CH3, S(0)-(CH2)2CH3, and S(0)-CH(CH3)2;
S(0)2-Ci-6-alkyl selected from the group consisting of S(0)2-CH3, S(0)2-CH2CH3, S(0)2-(CH2)2CH3, and S(0)2-CH(CH3)2;
S(0)-C3-6-cycloalkyl selected from the group consisting of S(0)-cyelopropyl, S(0)-cyelobutyl, S(O)- cyclopentyl, and S(0)-eyclohexyl;
S(0)2-C3-6-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-CH3, and CH3; 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;
wherein said 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-CH3, and CH3; in the form of the free compound or a physiologically acceptable salt thereof.
In a preferred embodiment, the compound according to the present invention is selected from the group consisting of
1 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)piperidin-4-yl)urea
2 1 -(4-bromophenyl)-3 -(3 -(4-methoxyphenyl)piperidin-4-yl)urea
3 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -methylpiperidin-4-yl)urea
4 1 -(4-bromophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -methylpiperidin-4-yl)urea
5 1 -(4-chlorophenyl)-3 -( 1 -(2-methoxyethyl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
6 1 -(4-chlorophenyl)-3 -(3 -(2-fiuoro-4-methoxyphenyl)piperidin-4-yl)urea
7 1 -(4-bromophenyl)-3 -(3 -(2-fluoro-4-methoxyphenyl)piperidin-4-yl)urea
8 1 -(4-chlorophenyl)-3 -(3 -(2,6-difiuoro-4-methoxyphenyl)piperidin-4-yl)urea
9 1 -(4-bromophenyl)-3 -(3 -(2,6-difiuoro-4-methoxyphenyl)piperidin-4-yl)urea
10 1 -(4-chlorophenyl)-3 -(3 -(2-fluoro-4-methoxyphenyl)- 1 -(2-methoxyethyl)piperidin-4-yl)urea
11 1 -(4-bromophenyl)-3 -(3 -(2-fluoro-4-methoxyphenyl)- 1 -(2-methoxyethyl)piperidin-4-yl)urea
12 1 -(4-chlorophenyl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-methoxyethyl)piperidin-4-yl)urea
13 1 -(4-bromophenyl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-methoxyethyl)piperidin-4-yl)urea
14 1 -(4-chlorophenyl)-3 -( 1 -(cyclopropylmethyl)-3 -(2,6-difiuoro-4-methoxyphenyl)piperidin-4-yl)urea
15 1 -(4-chlorophenyl)-3 -( 1 -cyclopropyl-3 -(2, 6-difiuoro-4-methoxyphenyl)piperidin-4-yl)urea 1 -(4-chlorophenyl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -methylpiperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -ethylpiperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-hydroxyethyl)piperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2,2-difluoroethyl)piperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-fluoroethyl)piperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -( 1 -(2,2-difluoroethyl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -( 1 -(2-fluoroethyl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-(methylsulfbnyl)ethyl)piperidin-4- yl)urea
1 -(4-chlorophenyl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -isopropylpiperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-hydroxy-2-methylpropyl)piperidin-4- yl)urea
1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-4-yl)piperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-3 -yl)piperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-3 -yl)piperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyrimidin-5-yl)piperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(2-methylpyridin-4-yl)piperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(2-methoxypyridin-4-yl)piperidin-4-yl)urea 1 -(4-chlorophenyl)-3 -((3R,4R)- 1 -(2-fluoropyridin-4-yl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(3 -methylpyridin-4-yl)piperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -( 1 -(3 -fluoropyridin-4-yl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridazin-4-yl)piperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyrimidin-4-yl)piperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -( 1 -(5-fluoropyrimidin-2-yl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea 1 -(4-chlorophenyl)-3 -( 1 -(5-fluoropyridin-2-yl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -( 1 -(4-fluorophenyl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
1 -( 1 ,3 -bis(4-methoxyphenyl)piperidin-4-yl)-3 -(4-chlorophenyl)urea
1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -phenylpiperidin-4-yl)urea
l-(4-chloro-phenyl)-3-[3-(4-methoxy-phenyl)-l-pyrimidin-2-yl-piperidin-4-yl]-urea
l-(3-(4-methoxyphenyl)-l-(pyridin-4-yl)piperidin-4-yl)-3-(3-methylisothiazol-5-yl)urea l-(5-chloropyridin-2-yl)-3-(3-(4-methoxyphenyl)piperidin-4-yl)urea
1 -(4-fluorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-4-yl)piperidin-4-yl)urea
1 -(6-chloropyridin-3 -yl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-4-yl)piperidin-4-yl)urea
1 -(5-chloropyridin-2-yl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-4-yl)piperidin-4-yl)urea
l-(4-bromophenyl)-3-(5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
l-(4-chlorophenyl)-3-(5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
l-(4-bromophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
l-(4-chlorophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
l-(4-bromophenyl)-3-(l-(2-methoxyethyl)-5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea l-(4-chlorophenyl)-3-(l-(2-methoxyethyl)-5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea l-(4-bromophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-l-(2-methoxyethyl)-2-oxopiperidin-4-yl)urea l-(4-chlorophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-l-(2-methoxyethyl)-2-oxopiperidin-4-yl)urea l-(4-bromophenyl)-3-(5-(2,6-difluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
l-(4-chlorophenyl)-3-(5-(2,6-difluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
l-(4-bromophenyl)-3-(5-(4-methoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea
l-(4-chlorophenyl)-3-(5-(4-methoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea
l-(4-bromophenyl)-3-(5-(2,6-difluoro-4-methoxyphenyl)-l-(2-methoxyethyl)-2-oxopiperidin-4-yl)urea l-(4-chlorophenyl)-3-(5-(2,6-difluoro-4-methoxyphenyl)-l-(2-methoxyethyl)-2-oxopiperidin-4-yl)urea l-(4-bromophenyl)-3-(5-(2,6-difluoro-4-methoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea l-(4-chlorophenyl)-3-(5-(2,6-difluoro-4-methoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea l-(4-bromophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea
l-(4-chlorophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea
l-(5-chloropyridin-2-yl)-3-(3-(2,6-difluoro-4-methoxyphenyl)piperidin-4-yl)urea
1 -(5-chloropyridin-2-yl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-fluoroethyl)piperidin-4-yl)urea
1 -(6-chloropyridin-3 -yl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)piperidin-4-yl)urea
1 -(6-chloropyridin-3 -yl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-fluoroethyl)piperidin-4-yl)urea
1 -(3 -(2,6-difluoro-4-methoxyphenyl)piperidin-4-yl)-3 -(6-(trifluoromethyl)pyridin-3 -yl)urea
1 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-fluoroethyl)piperidin-4-yl)-3 -(6-(trifluoromethyl)pyridin-3- yl)urea
1 -(3 -(2,6-difluoro-4-methoxyphenyl)piperidin-4-yl)-3 -(4-(trifluoromethyl)phenyl)urea
1 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-fluoroethyl)piperidin-4-yl)-3 -(4- (trifluoromethyl)phenyl)urea
1 -(5-chlorothiophen-2-yl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-fluoroethyl)piperidin-4-yl)urea l-(5-chlorothiazol-2-yl)-3-(3-(2,6-difluoro-4-methoxyphenyl)piperidin-4-yl)urea
1 -(5-chlorothiazol-2-yl)-3 -((3R,4R)-3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-fluoroethyl)piperidin-4- yl)urea
1 -(2-chlorothiazol-5-yl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-fluoroethyl)piperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -(3 -(2-fluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -methyl-2-oxopiperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -(3 -(2-fluoro-4-methoxyphenyl)- 1 -methyl-2-oxopiperidin-4-yl)urea
l-(4-chlorophenyl)-3-[l-(4-fluorophenyl)-5-(4-methoxyphenyl)-2-oxo-4-piperidyl]urea
l-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)-l-(l-methylpyrazol-4-yl)-2-oxo-4-piperidyl]urea
1 -[ 1 ,5-bis(4-methoxyphenyl)-2-oxo-4-piperidyl]-3-(4-chlorophenyl)urea
l-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)-2-oxo-l-pyridazin-3-yl-4-piperidyl]urea
l-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)-l-(6-methyl-2-pyridyl)-2-oxo-4-piperidyl]urea l-(4-chlorophenyl)-3-[l-[(5-chloro-2-thienyl)methyl]-3-(4-methoxyphenyl)-4-piperidyl]urea
1 -(4-chlorophenyl)-3 -[3 -(4-methoxyphenyl)- 1 -(3 -pyridyhnethyl)-4-piperidyl]urea
1 -(4-chlorophenyl)-3 -[3 -(4-methoxyphenyl)- 1 -(pyrimidin-2-ylmethyl)-4-piperidyl]urea
l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-[(5-methylisoxazol-3-yl)methyl]-4-piperidyl]urea l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-[(5-(trifluoromethyl)isoxazol-3-yl)methyl]piperidin-4- yljurea
l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-[(3-methylisoxazol-5-yl)methyl]-4-piperidyl]urea 93 1 -(4-chlorophenyl)-3-[3-(4-methoxyphenyl)- 1 -[(5-methyl- 1, 2, 4-oxadiazol-3-yl)methyl]-4- piperidyl]urea
94 l-(4-chlorophenyl)-3-[3-(4-chlorophenyl)-l-[(5-methylisothiazol-3-yl)methyl]-4-piperidyl]urea
95 l-[l-(2,2-difluoroethyl)-3-(4-methoxyphenyl)-4-piperidyl]-3-(3-methylisothiazol-5-yl)urea
96 1 -(4-chlorophenyl)-3 -[3 -(4-methoxyphenyl)- 1 -(pyridine-3 -carbonyl)-4-piperidyl]urea
97 1 -(4-chlorophenyl)-3 -[ 1 -(4-iluorobenzoyl)-3 -(4-methoxyphenyl)-4-piperidyl]urea
98 l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-(5-methylisoxazole-3-carbonyl)-4-piperidyl]urea
99 l-(4-chlorophenyl)-3-[l-(5-chlorothiophene-2-carbonyl)-3-(4-methoxyphenyl)-4-piperidyl]urea
100 l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-[(4-methylpyrimidin-2-yl)methyl]-4-piperidyl]urea
101 l-[3-(4-methoxyphenyl)-l-[(4-methylpyrimidin-2-yl)methyl]-4-piperidyl]-3-(3-methylisothiazol-5- yl)urea
102 l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-[(5-methylpyrimidin-2-yl)methyl]-4-piperidyl]urea
103 l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-[(4-methoxypyrimidin-2-yl)methyl]-4-piperidyl]urea
104 l-[3-(4-methoxyphenyl)-l-[(5-methoxypyrimidin-2-yl)methyl]-4-piperidyl]-3-(3-methylisothiazol-5- yl)urea
107 l-(4-iluorophenyl)-3-[5-(4-methoxyphenyl)-2-oxo-l-(2-pyridylmethyl)-4-piperidyl]urea
108 l-(4-fluorophenyl)-3-[5-(4-methoxyphenyl)-2-oxo-l-(4-pyridylmethyl)-4-piperidyl]urea
109 l-[3-(4-methoxyphenyl)-l-(4-pyridyl)-4-piperidyl]-3-(3-methylisothiazol-5-yl)urea
110 l-[3-(4-methoxyphenyl)-l-pyridazin-4-yl-4-piperidyl]-3-(3-methylisothiazol-5-yl)urea
111 l-[3-(4-methoxyphenyl)-l-(2-methyl-4-pyridyl)-4-piperidyl]-3-(3-methylisothiazol-5-yl)urea
112 l-[l-(4-iluorophenyl)-3-(4-methoxyphenyl)-4-piperidyl]-3-(3-methylisothiazol-5-yl)urea
113 l-[l-[(5-chloro-2-thienyl)methyl]-3-(4-methoxyphenyl)-4-piperidyl]-3-(3-methylisothiazol-5-yl)urea
114 l-[3-(4-methoxyphenyl)-l-(3-pyridylmethyl)-4-piperidyl]-3-(3-methylisothiazol-5-yl)urea
115 l-[3-(4-methoxyphenyl)-l-[(l-methylpyrazol-4-yl)methyl]-4-piperidyl]-3-(3-methylisothiazol-5- yl)urea
116 l-[3-(4-methoxyphenyl)-l-(pyrimidin-2-ylmethyl)-4-piperidyl]-3-(3-methylisothiazol-5-yl)urea
117 l-[3-(4-methoxyphenyl)-l-[(5-methylisoxazol-3-yl)methyl]-4-piperidyl]-3-(3-methylisothiazol-5- yl)urea
118 l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-[[2-(trifluoromethyl)-3-pyridyl]methyl]-4- piperidyl]urea
119 l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-[[4-(trifluoromethyl)-3-pyridyl]methyl]-4- piperidyl]urea
120 l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-[(5-methyl-3-pyridyl)methyl]-4-piperidyl]urea
121 l-(4-chlorophenyl)-3-[l-[(5-chloro-3-pyridyl)methyl]-3-(4-methoxyphenyl)-4-piperidyl]urea
122 l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-[(6-methyl-3-pyridyl)methyl]-4-piperidyl]urea
123 1 -(4-chlorophenyl)-3 -[3 -(4-methoxyphenyl)- 1 -(tetrahydropyran-4-ylmethyl)-4-piperidyl]urea
124 1 -(4-chlorophenyl)-3 -[ 1 -(2,2-difluoropropanoyl)-3 -(4-methoxyphenyl)-4-piperidyl]urea in the form of the free compound or a physiologically acceptable salt thereof.
In a preferred embodiment, the compound according to the present invention is a modulator of FPR2, more preferably an agonist of FPR2. In the sense of the present invention, 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. 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. For the assay 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.
In a preferred embodiment, 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.
In a preferred embodiment, 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. In another preferred embodiment, 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.
In a preferred embodiment, the compound according to the present invention does not activate FPR1. According to this embodiment, 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). Preferably, 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.
Preferably, 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.
Therefore, 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.
Therefore, 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.
Another aspect of the present invention relates to a pharmaceutical dosage form comprising a compound according to the present invention. Preferably, 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. Examples of suitable physiologically acceptable carriers, additives and/or auxiliary substances are fillers, solvents, diluents, colorings and/or binders. These substances are known to the person skilled in the art (see H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, Editio Cantor Aulendoff).
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.
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).
Therefore, 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).
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).
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.
EXAMPLES
Abbreviations:
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; EΪ2q = diethyl ether; EtOAc = ethylacetate; EtOH = ethanol; h = hour; HATU = [0-(7-Azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium-hexafluorphosphate]; HOBT = hydroxybenzotriazole, MeOH = methanol; min = minute; Rt = retention time; RT = room temperature; TEA = triethylamine; tert = tertiary; THF = tetrahydrofuran; Xantphos = 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene.
Representative methods:
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. LC was run in three set ups: 1) Zorbax Extend (C18 4.6 X 50 mm, 5 micron) with a gradient of A: Buffer 10 mM Ammonium Acetate in water and B: Acetonitrile at a flow rate of 1.2 ml/min or 1.5 ml/min (T=25°C); 2) Xbridge( Cl 8 4.6 X 50 mm, 5 micron) with a gradient of A: Buffer 10 mM Ammonium Acetate in water and B: Acetonitrile with a flow rate of 1.2 ml/min (T=25°C); 3) Epic C18 ( 4.6 X 50 mm, 5 micron) with a gradient of A: 10 mM Ammonium Acetate in water and B: Acetonitrile at a flow rate of 1.2 ml/min (T=25°C). UPLC was run in one set up: YMC (Column length: 33 mm; Internal diameter of column: 2.1 mm; Particle Size: 3 micron) with a gradient of A: 0.05% Formic acid in water with a flow rate of 1.5 ml/min (T=50°C).
The names of the compounds exemplified in this patent were generated using ChemDraw Ultra 16.0. This is a chemical-name-generating program that assigns chemical names to drawn structures at the press of a button.
The compounds according to the present invention were produced in the manner described below.
Example 1: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)piperidin-4-yl)urea
Example la: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)piperidin-4-yl)urea
Example 1.1: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)piperidin-4-yl)urea
Figure imgf000029_0001
Figure imgf000029_0002
Figure imgf000029_0003
Figure imgf000030_0001
1-1 1.2
ent-1 ent-2
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. NaHCCb solution and water. The organic layer was dried over anhyd. Na2SC>4 and concentrated under reduced pressure to obtain crude product which was purified by silica gel (100- 200 mesh) column chromatography (5% EA/Hexane) to afford 1 -(tert-butyl) 4-ethyl 5-
(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-l,4(2H)-dicarboxylate (12 g, 83% yield) as brown oil. Step2: To a stirred solution of 1 -(tert-butyl) 4-ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine- l,4(2H)-dicarboxylate (12.0 g, 30 mmol, 1 eq) and 4-methoxy phenyl boronic acid (5.0 g, 32.75 mmol, 1.1 eq) in THF (300 ml) at RT was added K2CO3 (10.28 g, 48 mmol, 1.3 eq) and the reaction mixture was degassed with Ar for a period of 15 min followed by the addition of Pd(PPli and stirred under reflux for 16 h. After completion of the reaction (monitored by TLC and LC MS), the 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 ¾ 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. The solvent was evaporated to get the desired 3-(4-methoxy-phenyl)-piperidine-l,4-dicarboxylic acid 1- tert-butyl ester 4-ethyl ester (8 g, 100% crude yield) as yellow sticky solid.
LC-MS: m/z [M+H]+ = 364.10 (exact mass calc. = 363.20).
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. NH4CI solution and the organics were extracted with DCM. The solvent was evaporated to get the desired ira«s-3-(4-methoxy-phenyl)-piperidine-l,4-dicarboxylic acid 1 -tert-butyl ester 4-ethyl ester (7.8 g, 97% crude yield) as yellow sticky solid. LC-MS: m/z [M+H]+ = 364.3 (exact mass calc. = 363.20).
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 K2CO3 (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. The combined organic layer was dried over anhyd. Na2S04 and concentrated to get the desired ira«s-3-(4-methoxy-phenyl)-piperidine-l,4-dicarboxylic acid 1 -tert-butyl ester (6.0 g, 83% crude yield) as yellow solid. LC-MS: m/z [M-H]+ = 334.0 (exact mass calc. = 335.17).
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. 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 anhyd. Na2SC>4 and concentrated under reduced pressure to get the crude product which was purified by silica gel (100-200 mesh) column chromatography (25% EA in Hexane) to obtain desired ira«s-4-[3-(4-chloro/bromo- phenyl)-ureido]-3-(4-methoxy-phenyl)-piperidine-l-carboxylic acid tert-butyl ester as yellowish solid (56% yield). LC-MS: m/z [M+H]+ = 460.1 (exact mass calc. = 459.19).
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. NaHCCb solution and extracted with EtOAc and the organic layer was dried over anhyd. Na2S04 and concentrated to get the crude material which was purified by triturating with pentane and diethyl ether to get the desired ira«s-l-(4-chloro-phenyl)-3-[3-(4-methoxy-phenyl)-piperidin-4-yl]-urea (86% yield). LC-M: m/z [M+H]+ = 360.2 (exact mass calc. = 359.14).
¾ NMR (400 MHz, DMSO-<¾) d 8.27 (s, 1 H), 7.30 (d, J= 8 Hz, 2 H), 7.19 (d, J= 8 Hz, 2 H), 7.14 (d, J= 8 Hz, 2 H), 6.82 (d, J = 8 Hz, 2 H), 5.90 (d, J= 8 Hz, 1 H), 3.80-3.73 (m, 1 H), 3.69 (s, 3 H), 2.97-2.88 (m, 2 H), 2.61- 2.55 (m, 1 H), 2.50 (s, 2 H), 2.47-2.32 (m, 1 H), 1.96 (d, J= 8 Hz, 1 H), 1.33-1.27 (m, 1 H).
The racemic Example la was subjected to chiral separation by chiral SFC (Chiralpak AD-H (250 x 4.6 mm) to render both the enantiomers as Example 1.1 (first eluting enantiomer; RT=3.9 min; Solvent: 0.5% iPr-Amine in MeOH) and Example 1.2 (second eluting enantiomer; RT= 5.1 min; Solvent: 0.5% iPr-Amine in MeOH).
Example 2: l-(4-bromophenyl)-3-(3-(4-methoxyphenyl)piperidin-4-yl)urea
Example 2a: l-(4-bromophenyl)-3-(3-(4-methoxyphenyl)piperidin-4-yl)urea
Figure imgf000032_0001
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. The combined organic layer was dried over anhyd. Na2SC>4 and concentrated under reduced pressure to get the crude product which was purified by silica gel (100-200 mesh) column chromatography (25% EA in Hexane) to obtain desired ira«s-4-[3-(4-chloro/bromo- phenyl)-ureido]-3-(4-methoxy-phenyl)-piperidine-l-carboxylic acid tert-butyl ester as yellowish solid (55% yield). LC-MS: m/z [M+H]+ = 504.8 (exact mass calc. = 503.14).
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. NaHCCb solution and extracted with EtOAc and the organic layer was dried over anhyd. Na SC and concentrated to get the crude material which was purified by triturating with pentane and diethyl ether to get the desired ira«s-l-(4-bromo-phenyl)-3-[3-(4-methoxy-phenyl)-piperidin-4-yl]-urea (10% yield). LC-MS: m/z [M+H]+ = 404.2 (exact mass calc. = 403.09).
'H NMR (400 MHz, DMSO-<¾) d 8.27 (s, 1 H), 7.31 (d, J= 8 Hz, 2 H), 7.24 (d, J= 8 Hz, 2 H), 7.14 (d, J= 8 Hz, 2 H), 6.82 (d, J = 8 Hz, 2 H), 5.91 (d, J= 8 Hz, 1 H), 3.80-3.75 (m, 1 H), 3.68 (s, 3 H), 2.96-2.88 (m, 2 H), 2.66- 2.57 (m, 1 H), 2.51-2.46 (m, 2 H), 1.95 (d, J= 8 Hz, 1 H), 1.32-1.24 (m, 1 H).
Example 3: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-methylpiperidin-4-yl)urea
Example 3a: trans- 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -methylpiperidin-4-yl)urea
Figure imgf000032_0002
Representative procedure for reductive amination:
To a stirred solution of Example la (leq) in DCE (10 ml/mmol) at 0°C was added Et3N (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. The combined organic layer was dried over Na S and concentrated under reduced pressure to get the crude material which was purified by silica gel (100-200 mesh) column chromatography (70% EA in Hexane) to obtain desired ira«s-l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-methylpiperidin-4-yl)urea (35% yield). LC-MS: m/z [M+H]+ = 374.2 (exact mass calc. = 373.16).
¾ NMR (400 MHz, DMSO-c ) d 8.30 (s, 1 H), 7.30 (d , J= 8 Hz, 2 H), 7.20-7.16 (m, 4 H), 6.83 (d, J= 8 Hz, 2 H), 5.91 (d, J= 8 Hz, 1 H), 3.69 (s, 4 H), 2.81-2.67 (m, 3 H), 2.16 (s, 3 H), 2.03-1.91 (m, 3 H), 1.49-1.45 (m, 1 H).
Example 4: l-(4-bromophenyl)-3-(3-(4-methoxyphenyl)-l-methylpiperidin-4-yl)urea
Example 4a: trans- 1 -(4-bromophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -methylpiperidin-4-yl)urea
Figure imgf000033_0001
Example 4a was synthesized starting from Example 2a following Representative procedure for reductive amination described for Example 3a.
Physical property: Off White solid; Yield: 12%.
LC-MS: m/z [M+H]+ = 418.2 (exact mass calc. = 417.11).
'H NMR (400 MHz, DMSO-<¾) d 8.30 (s, 1 H), 7.31 (d, J= 8 Hz, 2 H), 7.24 (d, J= 8 Hz, 2 H), 7.17 (d, J= 8 Hz, 2 H), 6.83 (d, J = 8 Hz, 2 H), 5.91 (d, J= 8 Hz, 1 H), 3.69 (s, 4 H), 2.78-2.66 (m, 3 H), 2.16 (s, 3 H), 2.03-1.97 (m, 3 H), 1.48-1.23 (m, 1 H).
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
Figure imgf000033_0002
Representative procedure for N-alkylation:
To a stirred solution of Example la (200 mg, 0.50 mmol, leq) in ACN (5 ml) at 0°C was added K2CO3 (174 mg, 1.26 mmol, 2.5 eq) followed by the addition of l-bromo-2-methoxy-ethane (77 mg, 0.55 mmol, 1.1 eq) and the reaction mixture was stirred at reflux for a period of 16 h. After completion of the reaction (monitored by TLC and LC MS), 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. Na SC and concentrated to get the crude material which was purified by normal silica gel (100-200 mesh) column chromatography (2% MeOH/DCM) to obtain desired ira«s-l-(4-chloro-phenyl)-3-[l-(2-methoxy-ethyl)-3-(4- methoxy-phenyl)-piperidin-4-yl]-urea (75 mg, 36%) as off white solid. LC-MS: m/z [M+H]+ = 418.2 (exact mass calc. = 417.18).
¾ NMR (400 MHz, DMSO-<¾) d 8.32 (s, 1 H), 7.29 (d, J= 8 Hz, 2 H), 7.20-7.16 (m, 4 H), 6.83 (d, J= 8 Hz, 2 H), 5.89 (d, J = 8 Hz, 1 H), 3.69 (s, 4 H), 3.42-3.39 (m, 2 H), 3.21 (s, 3 H), 2.91-2.89 (m, 1 H), 2.87-2.72 (m, 1 H), 2.70-2.66 (m, 1 H), 2.50-2.46 (m, 2 H), 2.12-2.05 (m, 3 H), 1.56-1.40 (m, 1 H).
Example 6: l-(4-chlorophenyl)-3-(3-(2-fluoro-4-methoxyphenyl)piperidin-4-yl)urea
Figure imgf000034_0001
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 K2CO3 (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(PPli3)4 (302 mg, 0.26 mmol, 0.03 eq) and the mixture was stirred under reflux for 16 h. After completion of the reaction (monitored by TLC and LC-MS), the reaction mixture was diluted with EA (200 ml) and washed with aq. NaHCCb solution and water. The organic layer was dried over anhydr. Na2S04 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 l-(tert-butyl) 4-ethyl 5-(2-fluoro-4-methoxyphenyl)-3,6-dihydropyridine-l,4(2H)-dicarboxylate (1.5 g, 45% yield) as brown oil. LC- MS: m/z [M+H]+ = 380.3 (exact mass calc. = 379.18).
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 H2 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. The solvent was evaporated to get the desired l-(tert-butyl) 4-ethyl 3-(2-fluoro-4-methoxyphenyl)piperidine-l,4- dicarboxylate (3.7 g, 99% crude yield) as yellow sticky solid. LC-MS: m/z [M+H]+ = 382.2 (exact mass calc. = 381.20).
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. NH4CI solution and the organics were extracted with DCM. The solvent was evaporated to get the desired trans- l-(tert-butyl) 4-ethyl 3-(2-fluoro-4-methoxyphenyl)piperidine-l,4- dicarboxylate (3.8 g, 100% crude yield) as yellow sticky solid.
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. The combined organic layer was dried over anhydr. Na SC and concentrated to get the desired tra«s-l-(tert-butoxycarbonyl)-3-(2-fluoro-4- methoxyphenyl)piperidine-4-carboxylic acid (2.5 g, 72% crude yield) as yellow solid. LC-MS: m/z [M-H]+ = 351.9 (exact mass calc. = 353.16).
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. Na SC and concentrated under reduced pressure to get the crude product which was purified by silica gel (100-200 mesh) column chromatography (25% EA in Hexane) to obtain desired trans-lerl-bxxlyl 4-(3-(4-chlorophenyl)ureido)-3- (2-fluoro-4-methoxyphenyl)piperidine-l-carboxylate (1.0 g, 61% yield) as yellowish solid. LC-MS: m/z [M-H]+ = 478.3 (exact mass calc. = 477.18).
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). LC-MS: m/z [M+H]+ = 378.1 (exact mass calc. = 377.13).
'H NMR (400 MHz, DMSO-c ) d (s, 1H), 8.30 (s, 1H), 7.31-7.18 (m, 6H), 6.75-6.72 (m, 2H), 5.98-5.96 (m, 1 H), 3.92-3.90 (m, 1H), 3.71 (s, 3H), 3.00-2.88 (m, 2H), 2.87-2.81 (m, 1H), 2.64-2.53 (m, 2H), 1.96 (d, J = 12 Hz, 1 H), 1.39-1.34 (m, 1H), (m, 1H).
Example 7: l-(4-bromophenyl)-3-(3-(2-fluoro-4-methoxyphenyl)piperidin-4-yl)urea
Example 7a: l-(4-bromophenyl)-3-(3-(2-fluoro-4-methoxyphenyl)piperidin-4-yl)urea
Figure imgf000035_0001
Figure imgf000035_0002
Starting from tra«5-l-(tert-butoxycarbonyl)-3-(2-fluoro-4-methoxyphenyl)piperidine-4-carboxylic acid, Example 7a was synthesized in analogy to synthesis described for Example 6a. LC-MS: m/z [M+H]+ = 422.1 (exact mass calc. = 421.08). ¾ NMR (400 MHz, DMSO-<¾) d 8.29 (s, 1H), 7.33-7.19 (m, 5H), 6.74-6.70 (m, 2H), 5.95 (d, J= 9 Hz, 1H), 3.94- 3.82 (m, 1H), 3.32 (s, 3H), 2.97-2.88 (m, 2H), 2.81-2.76 (m, 1H), 2.66-2.61 (m, 1H), 1.94 (d , J= 12 Hz, 1H), 1.36- 1.28 (m, 1H).
Example 8: l-(4-chlorophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)piperidin-4-yl)urea
Figure imgf000036_0001
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 K2CO3 (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. After completion of the reaction (monitored by TLC and LC MS), the reaction mixture was diluted with EA (200 ml) and washed with aq. NaHCCb solution and water. The organic layer was dried over anhydr. Na2SC>4 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 l-(tert- butyl) 4-ethyl 5-(2,6-diiluoro-4-methoxyphenyl)-3,6-dihydropyridine-l,4(2H)-dicarboxylate (1.5 g, 84 % yield) as brown oil. LC-MS: m/z [M+H]+ = 398.0 (exact mass calc. = 397.17).
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 ¾ 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. The solvent was evaporated to get the desired l-(tert-butyl) 4-ethyl 3-(2,6-diiluoro-4-methoxyphenyl)piperidine- 1,4-dicarboxylate (5.0 g, 90% crude yield) as yellow sticky solid. LC-MS: m/z [M+H]+ = 399.9 (exact mass calc. = 399.19).
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. The solvent was evaporated to get the desired tra«5-l-(tert-butyl) 4-ethyl 3-(2,6-diiluoro-4-methoxyphenyl)piperidine-l,4-dicarboxylate (5.0 g, 100% crude yield) as yellow sticky solid. LC-MS: m/z [M+H]+ = 400.0 (exact mass calc. = 399.19). 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. Na2S04 and concentrated to get the desired tra«5-l-(tert-butoxycarbonyl)-3-(2,6-difluoro-4-methoxyphenyl)piperidine-4-carboxylic acid (4.0 g, 86% crude yield) as yellow solid. LC-MS: m/z [M-H]+ = 370.0 (exact mass calc. = 371.15).
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. Na2SC>4 and concentrated under reduced pressure to get the crude product which was purified by silica gel (100-200 mesh) column chromatography (25% EA in Hexane) to obtain desired ira«s-4-[3-(4-chloro-phenyl)-ureido]-3-(2,6- difluoro-4-methoxy-phenyl)-piperidine-l -carboxylic acid tert-butyl ester (700 mg, 52% yield) as yellowish solid. LC-MS: m/z [M-H]+ = 496.1 (exact mass calc. = 495.17).
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). LC-MS: m/z [M+H]+ = 396.3 (exact mass calc. = 395.12).
¾ NMR (400 MHz, DMSO-c ) d 8.30 (s, 1 H), 7.26 (d, J = 8 Hz, 2 H), 7.18 (d, J = 8 Hz, 2 H), 6.63 (d, J = 11 Hz, 2 H), (, H), 5.93 (d, J = 8 Hz, 1 H), 4.04 (br m, 1 H), 3.71 (s, 3 H), 2.99-2.82 (m, 4 H), 2.49-2.46 (m, 1 H), 1.91 (d, J= 10 Hz, 1 H), 1.29-1.23 (m, 1 H).
Example 9: l-(4-bromophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)piperidin-4-yl)urea
Example 9a: l-(4-bromophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)piperidin-4-yl)urea
Figure imgf000037_0001
Starting from trans- 1 -(tert-butoxycarbonyl)-3 -(2,6-difluoro-4-methoxyphenyl)piperidine-4-carboxylic acid, Example 9a was synthesized in analogy to synthesis described for Example 8a. LC-MS: m/z [M+H]+ = 440.0 (exact mass calc. = 439.07).
¾ NMR (400 MHz, DMSO-c ) d 8.32 (s, 1 H), 7.31 (d, J = 9 Hz, 2 H), 7.21 (d, J = 9 Hz, 2 H), 6.62 (d, J = 11 Hz, 2 H), 5.94 (d, J = 9 Hz, 1 H), 4.08-4.01 (m, 1 H), 3.72 (s, 3 H), 2.98-2.95 (m, 1 H), 2.88-2.82 (m, 3 H), 2.57- 2.50 (m, 1 H), 1.91 (d, J= 11 Hz, 1 H), 1.31-1.23 (m, 1 H). Example 10: l-(4-chlorophenyl)-3-(3-(2-fluoro-4-methoxyphenyl)-l-(2-methoxyethyl)piperidin-4-yl)urea
Example 10a: l-(4-chlorophenyl)-3-(3-(2-fluoro-4-methoxyphenyl)-l-(2-methoxyethyl)piperidin-4- vDurea
Figure imgf000038_0001
Example 10a was synthesized starting from Example 6a following Representative procedure for N-alkylation described in synthesis of Example 5a (yield: 25%). LC-MS: m/z [M+H]+ = 436.3 (exact mass calc. = 435.17). 1H NMR (400 MHz, DMSO-d6) d 8.33 (s, 1 H), 7.31-7.18 (m, 5 H), 6.76-6.70 (m, 2 H), 5.96-5.94 (d, J = 8 Hz, 1 H), 3.83-3.80 (m, 1 H), 3.71 (s, 3 H), 3.42-3.39 (m, 2 H), 3.23-2.21 (m, 3 H), 2.99-2.91 (m, 2 H), 2.84 (d, J = 10 Hz, 1 H), 2.50-2.49 (m, 1 H), 2.16-2.05 (m, 2 H), 1.97-1.95 (m, 1 H), 1.53-1.47 (m, 1 H).
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
Figure imgf000038_0002
Example 11a was synthesized starting from Example 7a following Representative procedure for N-alkylation described in synthesis of Example 5a (yield: 47%). LC-MS: m/z [M+H]+ = 480.0 (exact mass calc. = 479.12).
1H NMR (400 MHz, DMSO-d6) d 8.34 (s, 1 H), 7.32 (d, J = 8 Hz, 2 H), 7.26-7.22 (m, 3 H), 6.76-6.70 (m, 2 H), 5.95 (d, J = 8 Hz, 1 H), 3.83-3.80 (m, 1 H), 3.71 (s, 3 H), 3.42-3.39 (m, 2 H), 3.21 (s, 3 H), 2.99-2.91 (m, 2 H), 2.85-2.82 (m, 1 H), 2.50-2.49 (m, 1 H), 2.16-2.05 (m, 2 H), 1.98-1.94 (m, 1 H), 1.50-1.47 (m, 1 H).
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
Figure imgf000039_0001
Example 12a was synthesized starting from Example 8a following Representative procedure for N-alkylation described in synthesis of Example 5a (yield: 45%). LC-MS: m/z [M+H]+ = 453.8 (exact mass calc. = 453.16).
1H NMR (400 MHz, DMSO-d6) d 8.34 (s, 1 H), 7.27 (d, J = 8 Hz, 2 H), 7.18 (d, J = 8 Hz, 2 H), 6.65 (d, J = 8 Hz, 2 H), 5.95 (d, J = 8 Hz, 1 H), 3.98-3.96 (m, 1 H), 3.72 (s, 3 H), 3.43-3.40 (m, 2 H), 3.22 (s, 3 H), 3.05-3.00 (m, 1 H), 2.94 (d, J = 8 Hz, 1 H), 2.83 (d, J = 8 Hz, 1 H), 2.41-2.32 (m, 1 H), 2.13-2.08 (m, 1 H), 1.94-1.92 (m, 1 H), 1.46-1.44 (m, 1 H).
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
Figure imgf000039_0002
Example 13a was synthesized starting from Example 9a following Representative procedure for N-alkylation described in synthesis of Example 5a (yield: 35%). LC-MS: m/z [M+H]+ = 498.3 (exact mass calc. = 497.11). 'H NMR (400 MHz, DMSO-<¾) d 8.34 (s, 1 H), 7.31 (d, J= 8 Hz, 2 H), 7.22 (d, J= 8 Hz, 2 H), 6.65 (d, J= 8 Hz, 2 H), 5.95 (d, J= 8 Hz, 1 H), 3.98-3.96 (m, 1 H), 3.72 (s, 3 H), 3.42-3.40 (m, 2 H), 3.21 (s, 3 H), 3.05-3.00 (m, 1 H), 2.95-2.92 (m, 1 H), 2.84-2.82 (m, 1 H), 2.41-2.32 (m, 1 H), 2.13-2.08 (m, 1 H), 1.94-1.91 (m, 1 H), 1.46-1.43 (m, 1 H).
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: e¾t/-tra¾^-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-
Figure imgf000039_0003
methoxyphenyl)piperidin-4-yl)urea
Figure imgf000040_0001
Example 14a was synthesized starting from Example 8a following Representative procedure for reductive amination described in synthesis of Example 3a (yield: 55%). LC-MS: m/z [M+H]+ = 449.8 (exact mass calc. = 449.17).
¾ NMR (400 MHz, DMSO-t¾) d 8.36 (s, 1 H), 7.27 (d, J= 8 Hz, 2 H), 7.19 (d, J= 8 Hz, 2 H), 6.65 (d, J= 8 Hz, 2 H), 5.96 (d, J= 8 Hz, 1 H), 4.05-3.94 (br s, 1 H), 3.72 (s, 3 H), 3.04-3.02 (m, 2 H), 2.93-2.90 (m, 1 H), 2.36-2.31 (m, 1 H), 2.21 (d, J= 8 Hz, 2 H), 2.09-2.03 (m, 1 H), 1.97-1.93 (m, 1 H), 1.46 (d, J= 8 Hz, 1 H), 0.84-0.76 (br s, 1 H), 0.43 (d, J= 8 Hz, 2 H), 0.04 (s, 2 H).
The racemic Example 14a was subjected to chiral separation by chiral SFC (Chiralpak AD-H (250 x 4.6 mm) to render both the enantiomers as Example 14.1 (first eluting enantiomer; RT=3.6 min; Solvent: 0.5% iPr- Amine in MeOH) and Example 14.2 (second eluting enantiomer; RT= 7.0 min; Solvent: 0.5% iPr-Amine in MeOH).
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 15.1: entl-trans- l-(4-chlorophenyi)-3-(l -cvclopropyl-3 -(2, 6-difluoro-4- methoxyphenyl)piperidin-4-yl)urea
Example 15.2: ent2-trans- l-(4-chlorophenyi)-3-(l -cvclopropyl-3 -(2, 6-difluoro-4- methoxyphenyl)piperidin-4-yl)urea
Figure imgf000040_0002
Figure imgf000041_0003
Representative procedure for Chan-Lam coupling
To a stirred solution of Example 8a (leq) and cyclopropylboronic acid (2 eq) in DCE (5 ml/mmol) at RT was added Na2C03 (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. Na2S04 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%). LC- MS: m/z [M+H]+ = 436.3 (exact mass calc. = 435.15).
¾ NMR (400 MHz, DMSO-<¾) d 8.35 (s, 1 H), 7.27 (d , J= 8 Hz, 2 H), 7.18 (d, J= 8 Hz, 2 H), 6.65 (d, J= 8 Hz, 2 H), 5.91 (d, J= 8 Hz, 1 H), 4.01-3.98 (m, 1 H), 3.72 (s, 3 H), 2.99-2.93 (m, 2 H), 2.88-2.89 (m, 1 H), 2.60-2.54 (m, 1 H), 2.32-2.28 (m, 1 H), 1.93 (d, J= 8 Hz, 1 H), 1.67-1.65 (m, 1 H), 1.41-1.38 (m, 1 H), 0.42-0.40 (m, 2 H), 0.30-0.29 (m, 2 H).
The racemic Example 15a was subjected to chiral separation by chiral SFC (Chiralpak AD-H (250 x 4.6 mm) to render both the enantiomers as Example 15.1 (first eluting enantiomer; RT=3.72 min; Solvent: 0.5% iPr-Amine in MeOH) and Example 15.2 (second eluting enantiomer; RT= 5.7 min; Solvent: 0.5% iPr-Amine in MeOH).
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 16.1: e¾t7-tra¾,y-l-(4-chlorophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-methylpiperidin-
4-vDurea
Example 16.2: l-(4-chlorophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-methylpiperidin-
Figure imgf000041_0001
4-vDurea
Figure imgf000041_0002
16.1 16.2
ent1 ent2 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. =
Figure imgf000042_0001
8.32 (s, 1 H), 7.27 (d, J = 9 Hz, 2 H), 7.18 (d, J = 8 Hz, 2 H), 6.65 (d, J = 12 Hz, 2 H), 5.96 (d , J= 8 Hz, 1 H), 3.97-3.94 (m, 1 H), 3.72 (s, 3 H), 3.15-3.05 (m, 1 H), 2.83-2.80 (m, 1 H), 2.32- 2.30 (m, 1 H), 2.18 (s, 3 H), 2.04-1.92 (m, 2 H), 1.48-1.45 (m, 1 H).
The racemic Example 16a was subjected to chiral separation by chiral SFC (Chiralpak AD-H (250 x 4.6 mm) to render both the enantiomers as Example 15.1 (first eluting enantiomer; RT= 3.5 min; Solvent: 0.5% iPr-Amine in MeOH) and Example 15.2 (second eluting enantiomer; RT= 5.3 min; Solvent: 0.5% iPr-Amine in MeOH).
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 17.1: entl-trans- 1 -(4-chlorophenyl)-3 -(3 -(2.6-difluoro-4-methoxyphenyl)- 1 -ethylpiperidin-4- vDurea
Example 17.2: l-(4-chlorophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-ethylpiperidin-4-
Figure imgf000042_0002
yfiurea
Figure imgf000042_0003
Figure imgf000042_0004
17.1 17.2
ent1 ent2
Example 17a was synthesized starting from Example 8a following Representative procedure for N-alkylation described in synthesis of Example 5a (yield: 65%). LC-MS: m/z [M+H]+ = 424.2 (exact mass calc. = 423.15). ¾ NMR (400 MHz, DMSO-c ) d 8.34 (s, 1 H), 7.27 (d, J = 8 Hz, 2 H), 7.18 (d, J = 8 Hz, 2 H), 6.65 (d, J = 12 Hz, 2 H), 5.95 (d, J = 8 Hz, 1 H), 4.05-3.95 (m, 2 H), 3.72 (s, 3 H), 3.17-3.01 (m, 1 H), 2.96-2.91 (m, 1 H), 2.79- 2.76 (m, 1 H), 2.37-2.27 (m, 3 H), 1.98-1.96 (m, 2 H), 1.55-1.45 (m, 1 H), 1.00-0.96 (m, 3 H).
The racemic Example 17a was subjected to chiral separation by chiral SFC (Chiralpak AD-H (250 x 4.6 mm) to render both the enantiomers as Example 17.1 (first eluting enantiomer; RT=3.3 min; Solvent: 0.5% iPr-Amine in MeOH) and Example 17.2 (second eluting enantiomer; RT= 5.1 min; Solvent: 0.5% iPr-Amine in MeOH).
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: e¾t7-tra¾,y-l-(4-chlorophenvi)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2- hvdroxyethyl)piperidin-4-yl)urea
Example 18.2: l-(4-chlorophenvi)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2-
Figure imgf000043_0001
hvdroxyethyl)piperidin-4-yl)urea
Figure imgf000043_0002
18.1 18.2
ent1 ent2
Example 18a was synthesized starting from Example 8a following Representative procedure for N-alkylation described in synthesis of Example 5a (yield: 42%). LC-MS: m/z [M+H]+ = 440.2 (exact mass calc. = 439.15). ¾ NMR (400 MHz, DMSO-c ff) d 8.34 (s, 1 H), 7.27 (d, J = 8 Hz, 2 H), 7.18 (d, J = 8 Hz, 2 H), 6.65 (d, J = 12 Hz, 2 H), 5.94 (d , J= 6 Hz, 1 H), 4.41-4.36 (m, 1 H), 4.02-3.98 (m, 1 H), 3.72 (s, 3 H), 3.49-3.47 (m, 2 H), 3.14- 3.09 (m, 1 H), 2.97-2.90 (m, 1 H), 2.88-2.85 (m, 1 H), 2.43-2.38 (m, 3 H), 2.19-2.11 (m, 1 H), 1.92-1.91 (m, 1 H), 1.51-1.42 (m, 1 H).
The racemic Example 18a was subjected to chiral separation by chiral SFC (Chiralpak AD-H (250 x 4.6 mm) to render both the enantiomers as Example 18.1 (first eluting enantiomer; RT=3.1 min; Solvent: 0.5% iPr- Amine in MeOH) and Example 18.2 (second eluting enantiomer; RT= 4.2 min; Solvent: 0.5% iPr-Amine in MeOH).
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: e¾t/-tra¾^-l-(4-chlorophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2.2- difluoroethyl)piperidin-4-yl)urea
Example 19.2: l-(4-chlorophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2.2-
Figure imgf000043_0003
difluoroethyl)piperidin-4-yl)urea
Figure imgf000044_0001
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%). LC-MS: m/z [M+H]+ = 459.9 (exact mass calc. = 459.13).
1H NMR (400 MHz, DMSO-d6) d 8.36 (1, H), 7.27 (d, J = 9 Hz, 2 H), 7.19 (d, J = 9 Hz, 2 H), 6.65 (d, J = 11 Hz, 2 H), 6.30-5.98 (m, 1 H), 5.96 (d, J = 9 Hz, 1 H), 4.05-3.92 (m, 1 H), 3.72 (s, 3 H), 3.08-3.01 (m, 1 H), 3.03-3.01 (m, 1 H), 2.93-2.87 (m, 1 H), 2.81-2.71 (m, 2 H), 2.62-2.54 (m, 1 H), 2.39-2.26 (m, 1 H), 1.97-1.91 (m, 1 H), 1.56- 1.41 (m, 1 H).
The racemic Example 19a was subjected to chiral separation by chiral HPLC (Chiralpak IA (250 x 4.6 mm); Mobile phase: Hexane/DCM/EtOH: 70/15/15) to render both the enantiomers as Example 19.1 (first eluting enantiomer; RT= 5.6 min) and Example 19.2 (second eluting enantiomer; RT= 6.1 min).
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: e¾t7-tra¾,y-l-(4-chlorophenvi)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2- fluorOCthyl)piperidin-4-yl)urea
Example 20.2: l-(4-chlorophenvi)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2-
Figure imgf000044_0002
fluorOCthyl)piperidin-4-yl)urea
Figure imgf000044_0003
Figure imgf000045_0003
Example 20a was synthesized starting from Example 8a following Representative procedure for N-alkylation described in synthesis of Example 5a (yield: 80%). LC-MS: m/z [M+H]+ = 442.2 (exact mass calc. = 441.14). ¾ NMR (400 MHz, DMSO-c ff) d 8.34 (s, 1 H), 7.27 (d, J = 9 Hz, 2 H), 7.19 (d, J = 9 Hz, 2 H), 6.65 (d, J = 11 Hz, 2 H), 5.96 (d, J= 9 Hz, 1 H), 4.58 (t, J= 5 Hz, 1 H), 4.46 (t, J= 5 Hz, 1 H), 4.03-3.97 (m, 1 H), 3.72 (s, 3 H), 3.08-3.02 (m, 1 H), 2.96 (d, J= 11 Hz, 1 H), 2.86 (d, J= 9 Hz, 1 H), 2.69 (t, J= 5 Hz, 1 H), 2.62 (t, J= 5 Hz, 1 H), 2.50-2.43 (m, 1 H), 2.17 (t , J= 12 Hz, 1 H), 1.95 (d , J= 10 Hz, 1 H), 1.49-1.45 (m, 1 H).
The racemic Example 20a was subjected to chiral separation by chiral SFC (Chiralpak AD-H (250 x 4.6 mm) to render both the enantiomers as Example 20.1 (first eluting enantiomer; RT=4.4 min; Solvent: 0.5% iPr- Amine in MeOH) and Example 20.2 (second eluting enantiomer; RT= 7.1 min; Solvent: 0.5% iPr-Amine in MeOH).
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: e¾t7-tra¾,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-
Figure imgf000045_0001
vDurea
Figure imgf000045_0002
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%). LC-MS: m/z [M+H]+ = 424.2 (exact mass calc. = 423.15). ¾ NMR (400 MHz, DMSO-c¾) d 8.34 (s, 1 H), 7.29 (d, J= 9 Hz, 2 H), 7.20-7.17 (m, 4 H), 6.84 (d, J= 9 Hz, 2 H), 6.27-5.99 (m, 2 H), 5.90 (d, J= 8 Hz, 1 H), 3.72 (s, 3 H), 2.96-2.84 (m, 2 H), 2.79-2.72 (m, 3 H), 2.41-2.21 (m, 2 H), 1.99-1.96 (m, 1 H), 1.46-1.42 (m, 1 H).
The racemic Example 21a was subjected to chiral separation by chiral HPLC (Chiralpak IA (250 x 4.6 mm; Mobile Phase: Hexane/DCM/EtOH: 50/25/25) to render both the enantiomers as Example 21.1 (first eluting enantiomer; RT=3.7 min) and Example 21.2 (second eluting enantiomer; RT= 5.3 min).
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 22.1: entl-trans- 1 -(4-chlorophenyl)-3 -( 1 -(2-fluoroethyl)-3 -(4-methoxyphenyl)piperidin-4- vDurea
Example 22.2: ent2-trans- 1 -(4-chlorophenyl)-3 -( 1 -(2-fluoroethyl)-3 -(4-methoxyphenyl)piperidin-4- vDurea
Figure imgf000046_0001
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%). LC-MS: m/z [M+H]+ = 406.2 (exact mass calc. = 405.16).
¾ NMR (400 MHz, DMSO-c¾) d 8.32 (s, 1 H), 7.30 (d, J= 9 Hz, 2 H), 7.21-7.18 (m, 4 H), 6.84 (d, J= 8 Hz, 2 H), 5.90 (d, J= 8 Hz, 1 H), 4.57 (t , J= 5 Hz, 1 H), 4.45 (t , J= 5 Hz, 1 H), 3.70 (s, 3 H), 2.93 (d, J= 12 Hz, 1 H), 2.86 (d ,J= 10 Hz, 1 H), 2.71-2.64 (m, 2 H), 2.61-2.54 (m, 1 H), 2.23-2.08 (m, 2 H), 2.0 (d , J= 11 Hz, 1 H), 1.51- 1.46 (m, 2 H).
The racemic Example 22a was subjected to chiral separation by chiral HPLC (Chiralpak IA (250 x 4.6 mm; Mobile Phase: Hexane/DCM/EtOH: 50/25/25) to render both the enantiomers as Example 22.1 (first eluting enantiomer; RT= 4.0 min) and Example 22.2 (second eluting enantiomer; RT= 5.4 min).
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
Figure imgf000047_0001
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%). LC-MS: m/z [M+H]+ = 502.2 (exact mass calc. = 501.13).
¾ NMR (400 MHz, DMSO-c ) d 8.34 (s, 1 H), 7.27 (d, J = 9 Hz, 2 H), 7.19 (d, J = 9 Hz, 2 H), 6.65 (d, J = 11 Hz, 2 H), 5.97 (d, J = 9 Hz, 1 H), 4.05-3.96 (m, 1 H), 3.72 (s, 3 H), 3.34-3.30 (m, 3 H), 3.06-2.92 (m, 5 H), 2.72- 2.68 (m, 1 H), 2.76-2.72 (m, 2 H), 2.41-2.31 (m, 1 H), 2.19-2.14 (m, 1 H), 1.96 (d, J= 10 Hz, 1 H), 1.48-1.45 (m, 1 H).
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
Figure imgf000047_0002
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%). LC-MS: m/z [M+H]+ = 438.2 (exact mass calc. = 437.17).
¾ NMR (400 MHz, DMSO-c ) d 8.34 (s, 1 H), 7.27 (d, J = 9 Hz, 2 H), 7.19 (d, J = 9 Hz, 2 H), 6.65 (d, J = 11 Hz, 2 H), 5.93 (d, J= 9 Hz, 1 H), 4.03-3.92 (br s, 1 H), 3.72 (s, 3 H), 3.05-2.97 (m, 1 H), 2.83 (d, J= 10 Hz, 1 H), 2.76-2.72 (m, 2 H), 2.92-2.73 (m, 1 H), 1.97 (d, J= 11 Hz, 1 H), 1.40 (d, J= 13 Hz, 1 H), 9.58 (d, J= 5 Hz, 6 H).
Example 25: 1 -(4-chlorophenyl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-hydro y-2-methylpropyl)piperidin-
4-yl)urea
Example 25a: l-(4-chlorophenyl)-3-(3-(2.6-difluoro-4-methoxyphenyl)-l-(2-hvdroxy-2- methylpropyl)piperidin-4-yl)urea
Figure imgf000048_0001
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. LC-MS: m/z [M+H]+ = 468.2 (exact mass calc. = 467.18).
¾ NMR (400 MHz, DMSO-c ff) d 8.34 (s, 1 H), 7.27 (d, J = 9 Hz, 2 H), 7.19 (d, J = 9 Hz, 2 H), 6.64 (d, J = 11 Hz, 2 H), 5.92 (d, J= 9 Hz, 1 H), 4.06 (s, 1 H), 3.97-3.94 (m, 1 H), 3.71 (s, 3 H), 3.08-2.92 (m, 3 H), 2.29-2.23 (m, 3 H), 1.89 (d, J= 9 Hz, 1 H), 1.50-1.48 (m, 1 H), 1.08 (s, 6 H).
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
Figure imgf000048_0002
Representative procedure for N-arylation (Pd-catalyzed Buchwald coupling)
To a stirred solution of Example la (leq) and Ar-X (1.2 eq) in toluene (10-12 ml/mmol) at RT was added t- BuONa (1.3 eq), Pd2(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. Na2SC>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). LC-MS: m/z [M+H]+ = 437.2 (exact mass calc. = 436.17).
¾ NMR (400 MHz, DMSO-c ) d 8.32 (d, 2 H), 7.96 (d, J= 4 Hz, 1 H), 7.34-7.30 (m, 3 H), 7.26 (d, J= 8 Hz, 2 H), 7.20 (d, J= 9 Hz, 3 H), 6.87 (d, J= 8 Hz, 2 H), 5.99 (d, J= 8 Hz, 1 H), 4.00-3.97 (m, 1 H), 3.86 (d, J= 13 Hz, 1 H), 3.73-3.71 (m, 4 H), 3.02-2.91 (m, 1 H), 2.89-2.84 (m, 1 H), 2.81-2.76 (m, 1 H), 2.08 (d, J = 11 Hz, 1 H), 1.57-1.55 (m, 1 H).
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
Figure imgf000049_0001
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%). LC-MS: m/z [M+H]+ = 437.2 (exact mass calc. = 436.17).
¾ NMR (400 MHz, DMSO-<&) d 8.33 (s, 1 H), 8.150 (d, J= 6 Hz, 2 H), 7.32-7.25 (m, 4 H), 7.19 (d, J= 9 Hz, 2 H), 6.90-6.86 (m, 4 H), 5.98 (d, J= 8 Hz, 1 H), 4.10-4.02 (m, 2 H), 3.88 (d, J= 12 Hz, 1 H), 3.72 (s, 3 H), 3.14- 3.00 (m, 2 H), 2.72-2.66 (m, 1 H), 2.05 (d, J= 10 Hz, 1 H), 1.50-1.49 (m, 1 H).
Example 28: 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-3 -yl)piperidin-4-yl)urea
-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-(pyridin-3-yl)piperidin-4-yl)urea
Figure imgf000049_0002
Figure imgf000049_0003
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%). LC-MS: m/z [M+H]+ = 437.2 (exact mass calc. = 436.17).
1H NMR (400 MHz, DMSO-c/ff) 5 8.31 (s, 1 H), 8.10 (d, J= 4 Hz, 1 H), 7.51 (t, /= 7 Hz, 1 H), 7.31 (d, /= 9 Hz, 2 H), 7.24 (d, J= 8 Hz, 2 H), 7.19 (d, J= 9 Hz, 2 H), 6.89-6.85 (m, 3 H), 6.62-6.59 (m, 1 H), 5.96 (d, J= 8 Hz, 1 H), 4.33 (t, J= 13 Hz, 2 H), 4.04 (d, J= 12 Hz, 1 H), (, H), 3.71 (s, 3 H), 3.01 (t , J= 13 Hz, 1 H), 2.90 (t , J= 12 Hz, 1 H), 2.69-2.63 (m, 1 H), 2.05 (d, J= 13 Hz, 1 H), 1.44-1.41 (m, 1 H).
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
Figure imgf000049_0004
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%). LC-MS: m/z [M+H]+ = 438.2 (exact mass calc. = 437.16). ¾ NMR (400 MHz, DMSO-c ) d 8.55 (s, 1 H), (, H), 8.51 (s, 2 H), 8.35 (s, 1 H), 7.32-7.26 (m, 4 H), 7.20 (d, J = 9 Hz, 2 H), 6.87 (d, J= 9 Hz, 2 H), 5.98 (d, J= 8 Hz, 1 H), 4.02-3.93 (m, 2 H), 3.83 (d, J= 11 Hz, 1 H), 3.71 (s, 3 H), 3.04 (t , J= 13 Hz, 1 H), 2.96 (t , J= 12 Hz, 1 H), 2.82-2.78 (m, 1 H), 2.08 (d , J= 10 Hz, 1 H), 1.58-1.55 (m, 1 H).
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
Figure imgf000050_0001
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%). LC-MS: m/z [M+H]+ = 451.3 (exact mass calc. = 450.18).
¾ NMR (400 MHz, DMSO-<¾) d 8.33 (s, 1 H), 8.02 (d, J= 6 Hz, 1 H), 7.32-7.18 (m, 6 H), 6.88 (d, J= 8 Hz, 2 H), 6.73 (s, 1 H), 6.68-6.67 (m, 1 H), 5.97 (d, J= 8 Hz, 1 H), 4.05-3.99 (m, 2 H), 3.85 (d, J= 13 Hz, 1 H), 3.69 (s, 3 H), 3.10-2.96 (m, 2 H), 2.71-2.66 (m, 1 H), 2.32 (s, 3 H), 2.05 (d, J= 11 Hz, 1 H), 1.47-1.44 (m, 1 H).
Example 31: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-(2-methoxypyridin-4-yl)piperidin-4-yl)urea
hlorophenyl)-3-(3-(4-methoxyphenyl)-l-(2-methoxypyridin-4-yl)piperidin-4-yl)urea
Figure imgf000050_0002
Figure imgf000050_0003
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%). LC-MS: m/z [M+H]+ = 467.1 (exact mass calc. = 466.18).
¾ NMR (400 MHz, DMSO-<¾) d 8.32 (s, 1 H), 7.89 (d, J= 6 Hz, 1 H), 7.30 (d, J= 9 Hz, 2 H), 7.24 (d, J= 8 Hz, 2 H), 7.19 (d, J= 9 Hz, 2 H), 6.87 (d, J= 8 Hz, 2 H), 6.57 (d, J= 5 Hz, 1 H), 6.12 (s, 1 H), 6.96 (d, J= 8 Hz, 1 H), 4.05-4.02 (m, 1 H), 3.98-3.94 (m, 1 H), 3.81-3.76 (m, 1 H), 3.76 (s, 3 H), 3.71 (s, 3 H), 3.10-2.97 (m, 2 H), 2.70-2.67 (m, 1 H), 2.03-1.99 (m, 1 H), 1.46-1.44 (m, 1 H).
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
Figure imgf000051_0001
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%).
LC-MS: m/z [M+H]+ = 455.0 (exact mass calc. = 454.16).
¾ NMR (400 MHz, DMSO-c ) d 8.34 (s, 1 H), 7.79 (d, J= 6 Hz, 1 H), 7.31-7.25 (m, 4 H), (, H), 7.19 (d, J= 9
Hz, 2 H), 6.88 (d, /= 9 Hz, 2 H), 6.81 (d, J= 6 Hz, 1 H), (, H), 6.50 (s, 1 H), (, H), 5.96 (d, J= 8 Hz, 1 H), 4.06- 4.02 (m, 2 H), 3.88 (d, J= 13 Hz, 1 H), 3.69 (s, 3 H), 3.18-3.05 (m, 2 H), 2.71-2.66 (m, 1 H), 2.07-2.03 (m, 1 H), 1.47-1.44 (m, 1 H).
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
Figure imgf000051_0002
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%).
LC-MS: m/z [M+H]+ = 451.2 (exact mass calc. = 450.18).
¾ NMR (400 MHz, DMSO-c ) d 8.38 (s, 1 H), 8.20 (s, 2 H), 7.32 (d, J= 9 Hz, 2 H), 7.27-7.19 (m, 2 H), 7.26-
7.23 (m, 2 H), 6.88-6.86 (m, 3 H), 6.01 (d, J= 8 Hz, 1 H), 3.97-3.94 (m, 1 H), 3.70 (s, 3 H), 3.36 (s, 1 H), 3.22 (d, J= 11 Hz, 1 H), 2.92-2.81 (m, 3 H), 2.22 (s, 3 H), 2.14 (d, J= 10 Hz, 1 H), 1.66-1.63 (m, 1 H).
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
Figure imgf000051_0003
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%).
LC-MS: m/z [M+H]+ = 454.8 (exact mass calc. = 454.16). 1H NMR (400 MHz, DMSO-d6) d 8.38 (s, 1 H), 8.24 (d, J = 6 Hz, 1 H), 8.11 (d, 1 H), 7.31 (d, J = 9 Hz, 2 H), 7.25 (d, J = 9 Hz, 2 H), 7.20 (d, J = 9 Hz, 2 H), 7.01-6.98 (m, 1 H), 6.87 (d, J = 9 Hz, 2 H), 6.01 (d, J = 8 Hz, 1 H), 4.04-4.02 (m, 1 H), 3.82-3.79 (m, 1 H), 3.71 (s, 3 H), 3.70-3.62 (m, 1 H), 3.21-3.16 (m, 1 H), 3.12-3.08 (m, 1 H), 2.87-2.84 (m, 1 H), 2.10 (d, J = 13 Hz, 1 H), 1.62-1.57 (m, 1 H).
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
Figure imgf000052_0001
Representative procedure for N-arylation (Chan Lam coupling)
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).
LC-MS: m/z [M+H]+ = 437.8 (exact mass calc. = 437.16).
¾ NMR (400 MHz, DMSO-c/ff) d 8.99 (d, J= 3 Hz, 1 H), 8.60 (d, J= 6 Hz, 1 H), 8.36 (s, 1 H), 7.32-7.24 (m, 4 H), 7.19 (d, J= 9 Hz, 2 H), 6.99-6.97 (m, 1 H), 6.88 (d, J= 9 Hz, 2 H), 5.96 (d, J= 8 Hz, 1 H), 4.15-4.09 (m, 2 H), 4.04-3.96 (m, 1 H), 3.70 (s, 3 H), 3.18-3.05 (m, 2 H), 2.74-2.66 (m, 1 H), 2.08-2.06 (m, 1 H), 1.51-1.45 (m, 1 H).
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 36.1 : entl -trans- 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyrimidin-4-yl)piperidin-4- vDurea
Example 36.2: e¾t2-tra¾^-l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-(pyrimidin-4-yl)piperidin-4- vDurea
Figure imgf000053_0001
To a stirred suspension of Example la (200 mg, 0.56 mmol, 1 eq), in DMSO (15 ml) was added K2CO3 (155 mg, 1.12 mmol, 2 eq) followed by the addition of HI salt of 4-iodo-pyrimidine (222 mg, 0.66 mmol, 1.2 eq), Cul (11 mg, 0.056 mmol, 0.1 eq) and 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. The organic part was dried over anhyd. Na2S04, filtered and concentrated under reduced pressure. The crude product was then purified by column chromatography (100-200 mesh silica gel, 3-5% MeOH in DCM as eluent) to obtain the desired fra«s-l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l- (pyrimidin-4-yl)piperidin-4-yl)urea (85 mg, 35% yield) as off white solid.
LC MS: m/z [M+H]+ = 438.1 (exact mass calc. = 437.16).
¾ NMR (400 MHz, DMSO-*) d 8.50 (s, 1 H), 8.36 (s, 1 H), 8.18 (br s, 1 H), 7.30 (d, J= 8 Hz, 2 H), 7.25 (d, J = 8 Hz, 2 H), 7.20 (d, J= 8 Hz, 2 H), 6.90-6.88 (m, 3 H), 5.95 (d, J= 8 Hz, 1 H), 4.48-4.32 (br m, 2 H), 4.10-4.08 (m, 1 H), 3.72 (s, 3 H), 3.14-3.08 (m, 1 H), 3.04-2.98 (m, 1 H), 2.68-2.58 (m, 1 H), 2.08-2.07 (m, 1 H), 1.41-1.36 (m, 1 H).
Racemic mixture Example 36a was separated by preparative chiral HPLC to afford both the enantiomers as Example 36.1 (first eluting enantiomer: RT=5.2min) and Example 36.2 (second eluting enantiomer: RT=6.8min) (Chiralpak IG (4.6 x 250 mm), solvent: Hexane/EtOH/EA 50/25/25).
Example 37: l-(4-chlorophenyl)-3-(l-(5-fluoropyrimidin-2-yl)-3-(4-methoxyphenyl)piperidin-4-yl)urea
enyl)piperidin-4-yl)urea
Figure imgf000053_0002
To a stirred suspension of Example la (200 mg, 0.557 mmol, 1 eq) in DMF (15 ml) was added CS2CO3 (543 mg, 1.67 mmol, 3 eq) followed by the addition 2-chloro-5-fluoro-pyrimidine (88.57 mg, 0.68 mmol, 1.2 eq) and the mixture was stirred at RT for a period of 3 h. After completion of the reaction, it was diluted with water and extracted with EtOAc (3 x 150 ml), washed thoroughly with water (50 ml) and brine (50 ml). The combined organic layer was dried over anhyd. Na2S04, filtered, rota evaporated and purified by column chromatography (100-200 mesh silica gel) eluting with 2% MeOH-DCM to obtain /ra«s-l-(4-chlorophenyl)-3-(l-(5- fluoropyrimidin-2-yl)-3-(4-methoxyphenyl)piperidin-4-yl)urea (100 mg, 40%) as off white solid.
LC-MS: m/z [M+H]+ = 456.0 (exact mass calc. = 455.15).
'H NMR (400 MHz, DMSO-c ) d 8.45 (s, 2 H), 8.34 (s, 1 H), 7.31 (d, J= 9 Hz, 2 H), 7.24-7.18 (m, 4 H), 6.88 (d, J= 8 Hz, 2 H), 5.93 (d, J= 8 Hz, 1 H), 4.65 (d, J= 13 Hz, 1 H), 4.56 (d, J= 11 Hz, 1 H), 4.08-4.05 (m, 1 H), 3.71 (s, 3 H), 3.12-3.06 (m, 1 H), 3.02-2.96 (m, 1 H), 2.67-2.64 (m, 1 H), 2.07 (d, J= 10 Hz, 1 H), 1.42-1.39 (m, 1 H).
Example 38: l-(4-chlorophenyl)-3-(l-(5-fluoropyridin-2-yl)-3-(4-methoxyphenyl)piperidin-4-yl)urea
Exam a
Figure imgf000054_0002
Figure imgf000054_0001
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. 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. The organic layer was dried over anhyd. Na2S04 and concentrated under reduced pressure to obtain HCI salt of 3-(4-methoxy- phenyl)-piperidine-4-carboxylic acid ethyl ester (1.3 g, 90%) as off white solid. LCMS: m/z [M+H]+ = 264.0 (exact mass calc. = 263.15).
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. Then Pd2dba3 (121.7 mg, 0.05 eq, 0.13 mmol) was added and the mixture was refluxed for 16 h. After completion of reaction toluene was evaporated and the residue was diluted with H20 and organics were extracted with EtOAc, dried over anhy. Na2S04 and the solvent was evaporated to obtain the crude product which was purified by silica gel column chromatography with 100-200 mesh size using 10-20% EA/Hexane as an eluent to obtain ethyl l-(5-fluoropyridin-2-yl)-3-(4-methoxyphenyl)piperidine-4-carboxylate (250 mg, 26%) as off-white solid. LCMS: m/z [M+H]+ = 358.8 (exact mass calc. = 358.17).
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 H20 and the organic components were extracted with EtOAc, dried over anhy. Na2SC>4 and concentrated under reduced pressure to obtain trans-Q†hy\ l-(5-fluoropyridin-2-yl)-3-(4-methoxyphenyl)piperidine-4-carboxylate (500 mg, 97%) as crude product (red sticky solid) which was used for next step. LCMS: m/z [M+H]+ = 358.7 (exact mass calc. = 358.17).
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), H20 (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 H20 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. Na2SC>4 and the solvent was evaporated to obtain tra«5-l-(5-fluoropyridin-2-yl)-3-(4-methoxyphenyl)piperidine-4-carboxylic acid (51% yield) which was used for next step without further purification. LCMS: m/z [M-H]+ = 329.3 (exact mass calc. = 330.14).
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 mΐ, 2.0 eq., 0.42 mmol) was added followed by addition of DPP A (91 mΐ, 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. After completion of reaction, benzene/THF was evaporated and the residue was diluted with H20 and extracted with 5 % MeOH/DCM. Organic layer was dried over anhyd. Na2S04 and the solvent was evaporated to obtain the crude product which was first purified by column chromatography (100-200 mesh silica gel) and second by preparative TLC to obtain trans- 1- (4-chlorophenyl)-3-(l-(5-fluoropyridin-2-yl)-3-(4-methoxyphenyl)piperidin-4-yl)urea (10 mg, 10%) as off-white solid. LCMS: m/z [M+H]+ = 455.0 (exact mass calc. = 454.16).
¾ NMR (400 MHz, DMSO-<¾) d 8.32 (s, 1 H), 8.08 (d, J = 3 Hz, 1 H), 7.61-7.46 (m, 1 H), 7.31 (d, J = 9 Hz, 2 H), 7.25-7.18 (m, 4 H), 6.94-6.90 (m, 1 H), 6.87 (d, J = 9 Hz, 2 H), 5.96 (d, J = 8 Hz, 1 H), 4.31-4.21 (m, 2 H), 4.08-4.01 (m, 1 H), 3.71 (s, 3 H), 3.15-3.08 (m, 1 H), 2.94-2.89 (m, 1 H), 2.69-2.65 (m, 1 H), 2.06-2.03 (m, 1 H), 1.48-1.33 (m, 1 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
Figure imgf000055_0001
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%). LC-MS: m/z [M+H]+ = 454.0 (exact mass calc. = 453.16).
'H NMR (400 MHz, DMSO-<¾) d 8.33 (s, 1 H), 7.31 (d , J= 9 Hz, 2 H), 7.25 (d, J= 9 Hz, 2 H), 7.20 (d, J= 9 Hz, 2 H), 7.04-6.94 (m, 4 H), 6.87 (d, J= 9 Hz, 2 H), 5.99 (d, J= 8 Hz, 1 H), 3.94-3.92 (m, 1 H), 3.71 (s, 3 H), 3.69- 3.66 (m, 1 H), 3.56 (d, J= 9 Hz, 1 H), 2.91-2.78 (m, 3 H), 2.08 (d, J= 9 Hz, 1 H), 1.60-1.56 (m, 1 H).
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
Figure imgf000056_0001
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%). LC-MS: m/z [M+H]+ = 466.1 (exact mass calc. = 465.18).
¾ NMR (400 MHz, DMSO-c ) d 8.34 (s, 1 H), 7.31 (d, J= 9 Hz, 2 H), 7.26-7.19 (m, 4 H), 6.91-6.85 (m, 4 H), 6.79 (d, J= 9 Hz, 2 H), 5.99 (d, J= 8 Hz, 1 H), 3.91-3.88 (m, 1 H), 3.70 (s, 3 H), 3.67 (s, 3 H), 3.58 (d, J= 13 Hz, 1 H), 3.47 (d, J= 11 Hz, 1 H), 2.83-2.78 (m, 2 H), 2.74-2.68 (m, 1 H), 2.09 (d, J= 13 Hz, 1 H), 1.59 (d, J= 9 Hz, 1 H).
Example 41: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-phenylpiperidin-4-yl)urea
-yl)urea
Figure imgf000056_0002
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%). LC-MS: m/z [M+H]+ = 436.2 (exact mass calc. = 435.17).
¾ NMR (400 MHz, DMSO-<¾) d 8.84 (s, 1 H), 7.33 (d, J= 4 Hz, 2 H), 7.26 (d, J= 9 Hz, 2 H), 7.21-7.18 (m, 4 H), 6.94 (d, J= 8 Hz, 2 H), 6.87 (d, J= 9 Hz, 2 H), 6.74 (t, J= 7 Hz, 1 H), (, H), 6.00 (d, J= 8 Hz, 1 H), 4.07- 4.01 (m, 1 H), 3.79 (d, J= 12 Hz, 1 H), 3.71 (s, 3 H), 3.65 (d, J= 10 Hz, 1 H), 2.95-2.86 (m, 1 H), 2.83-2.76 (m, 2 H), 2.08 (d, J= 9 Hz, 1 H), 1.60-1.52 (m, 1 H).
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
Figure imgf000057_0001
Representative procedure for nucleophilic aromatic substitution (SsAr)
To a stirred solution of fra«.s-l-(4-chloro-phenyl)-3-[3-(4-methoxy-phenyl)-piperidin-4-yl]-urea (200 mg, 0.56 mmol, 1 eq) and 2-chloro-pyrimidine (70 mg, 0.62 mmol, l . leq) in n BuOH (5 ml) at RT was added DIPEA (0.7 ml, 3.9 mmol, 7 eq) and the reaction mixture was stirred at 140°C for a period of 48 h in a sealed vessel. The reaction mixture was diluted with 5% MeOH in DCM and washed with water and brine. The combined organic layer was dried over anhyd. Na2SC>4 and concentrated under reduced pressure. The obtained crude product was purified by silica gel (100-200 mesh) column chromatography to obtain fra«s-l-(4-chloro-phenyl)-3-[3-(4- methoxy-phenyl)-l-pyrimidin-2-yl-piperidin-4-yl]-urea (50 mg, 18%) as off white solid. LC-MS: m/z [M+H]+ = 438.40 (exact mass calc. = 437.16).
'H NMR (400 MHz, DMSO-<&) d 8.36 (d, J= 5 Hz, 3 H), 7.31 (d, J= 9 Hz, 2 H), 7.24-7.18 (m, 4 H), 6.88 (d, J = 9 Hz, 2 H), 6.62 (t , J= 5 Hz, 1 H), 5.95 (d, J= 8 Hz, 1 H), 4.75 (d, J= 12 Hz, 1 H), 4.66 (d , J= 11 Hz, 1 H), 4.08- 4.06 (m, 1 H), 3.72 (s, 3 H), 3.06 (t , J = 12 Hz, 1 H), 2.99-2.92 (m, 1 H), 2.66-2.53 (m, 1 H), (, H), 2.07 (d , J = 11 Hz, 1 H), 1.51-1.39 (m, 1 H).
Example 43: l-(3-(4-methoxyphenyl)-l-(pyridin-4-yl)piperidin-4-yl)-3-(3-methylisothiazol-5-yl)urea
-yl)-3-(3-methylisothiazol-5-yl)urea
Figure imgf000057_0002
Representative procedure for Curtius rearrangement
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 Et3N ( 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. The combined organic layer was dried over anhyd. Na3S04 and concentrated under reduced pressure to get the crude product which was purified by silica gel (100-200 mesh) column chromatography (25% EA in Hexane) to obtain desired product as yellowish solid (56% yield). LC-MS: m/z [M+H]+ = 447.2 (exact mass calc. = 446.20).
Representative deprotection of Boc group under acidic conditions
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. Na3S04 and concentrated in vacuo to get the crude material which was purified by triturating with pentane and diethyl ether to get the desired product (98% yield). LC-MS: m/z [M+H]+ = 347.2 (exact mass calc. = 346.15).
Representative procedure for N-arylation (Pd-catalyzed Buchwald coupling II)
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. Na3S04 and concentrated under reduced pressure. The obtained crude was purified by silica gel (100-200 mesh) column chromatography to obtain the desired ira«s-l-(3-(4-rnethoxyphenyl)-l-(pyridin-4- yl)piperidin-4-yl)-3-(3-methylisothiazol-5-yl)urea as off-white solid (7% yield). LC-MS: m/z [M+H]+ = 424.2 (exact mass calc. = 423.17).
¾ NMR (400 MHz, DMSO-<¾) d 9.91 (s, 1 H), 8.15 (d, J = 6 Hz, 2 H), 7.24 (d, J = 9 Hz, 2 H), 6.88-6.83 (m, 4 H), 6.51-6.50 (m, 1 H), 6.38 (s, 1 H), 4.06 (d, J = 10 Hz, 2 H), 3.90 (m, 1 H), 3.70 (s, 3 H), 3.19-3.05 (m, 2 H), 2.81-2.72 (m, 1 H), 2.19 (s, 3 H), 2.08-2.01 (m, 1 H), 1.56-1.42 (m, 1 H).
Example 44: l-(5-chloropyridin-2-yl)-3-(3-(4-methoxyphenyl)piperidin-4-yl)urea
Example 44a: l-(5-chloropyridin-2-yl)-3-(3-(4-methoxyphenyl)piperidin-4-yl)urea
Figure imgf000058_0001
Example 44a was synthesized in analogy to synthesis described for Example 43a.
Physical property: Off white solid. LC-MS: m/z [M+H]+ = 360.0 (exact mass calc. = 359.14).
¾ NMR (400 MHz, DMSO-<¾) d 8.58 (s, 1 H), 7.30 (d, J = 9 Hz, 2 H), 7.20-7.16 (m, 4 H), 6.84 (d, J = 9 Hz, 2 H), 6.23 (d, J = 8 Hz, 1 H), 3.88-3.85 (m, 1 H), 3.76 (s, 3 H), 3.18-3.16 (m, 1 H), 2.98-2.96 (m, 1 H), 2.78-2.60 (m, 3 H), 2.07-2.01 (m, 1 H), 1.47-1.38 (m, 1 H).
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
Figure imgf000059_0001
Figure imgf000059_0002
Example 45a was synthesized in analogy to synthesis described for Example 43a.
Physical property: Off white solid (13% yield in step3).
LC-MS: m/z [M+H]+ = 421.0 (exact mass calc. = 420.20).
¾ NMR (400 MHz, DMSO-c ) d 8.21 (s, 1 H), 8.15 (d , J= 6 Hz, 2 H), 7.29-7.25 (m, 4 H), 7.01-6.97 (m, 2 H), 6.89-6.85 (m, 4 H), 5.91 (d, J= 8 Hz, 2 H), 4.05-4.02 (m, 2 H), 3.87 (d, J= 14 Hz, 1 H), 3.71 (s, 3 H), 3.13-2.99 (m, 2 H), 2.71-2.66 (m, 1 H), 2.05 (s, 3 H), 2.08-2.01 (d, J= 10 Hz, 1 H), 1.46-1.44 (m, 1 H).
Racemic mixture Example 45a was separated by preparative chiral HPLC to afford both the enantiomers as Example 45.1 (first eluting enantiomer: RT=9.1min) and Example 45.2 (second eluting enantiomer: RT=10.2min) (Chiralpak ID (4.6 x 250 mm), solvent: Hexane/EtOH/EA/iPr-Amine 75/15/15/0.1).
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
Figure imgf000059_0003
Figure imgf000060_0001
46a
Example 46 was synthesized in analogy to synthesis described for Example 43a.
Physical property: Off white solid (7% yield in step3). LC-MS: m/z [M+H]+ = 438.3 (exact mass calc. = 437.16). ¾ NMR (400 MHz, DMSO-c¾) d 8.57 (s, 1 H), 8.28 (d, J= 3 Hz, 1 H), 8.16 (d, J= 6 Hz, 2 H), 7.83-7.80 (m, 1 H), 7.32-7.26 (m, 3 H), 6.92-6.88 (m, 4 H), 6.19 (d, J= 9 Hz, 1 H), 4.10-4.06 (m, 2 H), 3.91 (d, J= 14 Hz, 1 H), 3.71 (s, 3 H), 3.15-3.05 (m, 2 H), 2.78-2.62 (m, 1 H), 2.06 (d, J= 13 Hz, 1 H), 1.51-1.45 (m, 1 H).
Example 47: l-(5-chloropyridin-2-yl)-3-(3-(4-methoxyphenyl)-l-(pyridin-4-yl)piperidin-4-yl)urea
Example 47a: l-(5-chloropyridin-2-yl)-3-(3-(4-methoxyphenyl)-l-(pyridin-4-yl)piperidin-4-yl)urea
Figure imgf000060_0002
47a
Example 47a was synthesized in analogy to synthesis described for Example 43a (step3).
Physical property: Off white solid (12% yield). LC-MS: m/z [M+H]+ = 438.1 (exact mass calc. = 437.16).
¾ NMR (400 MHz, DMSO-c ) 9.05 (s, 1 H), 8.15 (m, 3 H), 7.73-7.70 (m, 1 H), 7.52-7.50 (m, 1 H), 7.40 (d, J = 8.8 Hz, 1 H), 7.28 (d, J= 8.4 Hz, 2 H), 6.87-6.86 (m, 4 H), 4.08-4.02 (m, 2 H), 3.89 (d, J= 13.3 Hz, 1 H), 3.70 (s, 3 H), 3.16-3.07 (m, 2 H), 2.70-2.64 (m, 1 H), 2.13 (d, J= 10 Hz, 1 H), 1.45-1.42 (m, 1 H).
Example 48: l-(4-bromophenyl)-3-(5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
Example 48.1: c/y-l-(4-bromophenyl)-3-(5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
Figure imgf000060_0003
Figure imgf000061_0001
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). The reaction mixture was diluted with EtOAc (500 ml) and washed by water (2 x 100 ml) followed by brine (100 ml). The organic layer was dried over anhydrous Na2S04, concentrated under reduced pressure to get the crude material. Crude product was purified by column chromatography (230-400mesh silica gel; 10% EtOAc/hexane; R^value-0.4) to afford ethyl 2-cyano-2-(4-methoxyphenyl)acetate (13.0 g, 44%) as light yellow solid.
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. Crude material was stirred with EtOAc and precipitate was formed which was collected by filtration to get the ethyl 3-amino-2- (4-methoxyphenyl)propanoate hydrochloride (1.8 g, 51%) as off white solid. 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. Ethyl malonyl chloride (10.433 g, 69.3 mmol, 1.5 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 100 ml) followed by brine (100 ml). The organic layer was dried over anhydrous Na2SC>4, concentrated under reduced pressure to get the crude material. Crude product was purified by column chromatography (230- 400mesh silica gel; 30% EtOAc/hexane; R^value-0.5) to afford ethyl 3-((3-ethoxy-2-(4- methoxyphenyl)-3-oxopropyl)amino)-3-oxopropanoate (7.6 g, 49%) as light brown solid.
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. The residue was dissolved in water (200 ml), the aqueous part was washed by EtOAc (100 ml). The aqueous part was then acidified by 2(N) HC1 solution and extracted by EtOAc (2 x 150 ml). The combined organic layer was washed by water (100 ml) followed by brine (100 ml). The organic layer was dried over anhydrous Na2S04, concentrated under reduced pressure to get the crude material. Crude product was purified by column chromatography (230-400 mesh silica gel; 5% MeOH/DCM; R^ value-0.5) to afford ethyl 5-(4-methoxyphenyl)-2,4-dioxopiperidine-3-carboxylate (1.7 g, 26%) as light yellow solid.
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; Rf- 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 Na2SC>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 6H20 (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 Na2SC>4, concentrated under reduced pressure to get the crude material. Crude product was purified by column chromatography (230-400 mesh silica gel; 5% MeOH/DCM; Rf^ value-0.5) to afford c/s-tert-butyl (5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (0.3 g, 22%) as white solid and tra«5-tert-butyl (5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (0.15 g, 11%) as white solid, which was confirmed by 2-D NMR experiments.
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. 4-Bromophenyl isocyanate (0.092 g, 0.467 mmol, 1 eq) was then added to the reaction mixture and stirred for 16 h at RT. The reaction mixture was dissolved in DCM (50 ml) and washed by water (2 x 20 ml) followed by brine (20 ml). The organic layer was dried over anhydrous Na2SC>4, concentrated under reduced pressure to get the crude material. Crude product was purified by column chromatography (230-400 mesh silica gel; 5% MeOH/DCM; Rf^value-0.55) to afford c/s-l-(4-bromophenyl)-3-(5-(4-methoxyphenyl)-2- oxopiperidin-4-yl)urea 48.1 (0.085 g, 44%) as white solid.
Example 48.1: 1H NMR (400 MHz, dmso-d6): d 8.47 (s, 1H), 7.76 (s, 1H), 7.37-7.35 (m, 2H), 7.31- 7.28 (m, 2H), 7.21-7.19 (m, 2H), 6.88-6.86 (m, 2H), 6.37 (d, J=8.8 Hz, 1H), 4.25-4.22 (m, 1H), 3.70 (s, 3H), 3.47-3.45 (m, 2H), 3.31-3.29 (m, 1H), 2.59-2.58 (m, 1H), 2.13-2.08 (m, 1H).
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. To this solution 4-bromophenyl isocyanate (0.066 g, 0.358 mmol, 1 eq) was added to the reaction mixture and stirred for 16 h at RT. The reaction mixture was diluted with DCM (50 ml) and washed by water (2 x 20 ml) followed by brine (20 ml). The organic layer was dried over anhydrous Na2SC>4, concentrated under reduced pressure to get the crude material. Crude product was purified by column chromatography (230- 400mesh silica gel; 5% MeOH/DCM; Rf^value-0.55) to afford tra«s-l-(4-bromophenyl)-3-(5-(4- methoxyphenyl)-2-oxopiperidin-4-yl)urea 48.2 (0.062 g, 41%) as white solid.
Example 48.2: 1H NMR (400 MHz, dmso-d6): d 8.43 (s, 1H), 7.66 (s, 1H), 7.34-7.32 (m, 2H), 7.27-7.22 (m, 4H), 6.88-6.85 (m, 2H), 6.09 (d, J=8 Hz, 1H), 4.20 (bs, 1H), 3.70 (s, 3H), 3.22-3.20 (m, 2H), 3.02- 3.01 (m, 1H), 2.58-2.56 (m, 1H), 2.27-2.20 (m, 1H).
Example 49: l-(4-chlorophenyl)-3-(5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
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
Figure imgf000063_0001
Figure imgf000064_0001
Example 49.1 and Example 49.2 were synthesized in analogy to synthesis described for Example 48. Example 49.1: White solid (28% yield); 1H NMR (400 MHz, dmso-d6): d 8.47 (s, 1H), 7.76 (s, 1H), 7.36-7.33 (m, 2H), 7.25-7.19 (m, 4H), 6.88-6.86 (m, 2H), 6.37 (d, J=8.4 Hz, 1H), 4.25-4.23 (m, 1H), 3.70 (s, 3H), 3.47-3.46 (m, 2H), 3.30 (s, 1H), 2.59-2.54 (m, 1H), 2.13-2.08 (m, 1H).
Example 49.2: White solid (41% yield); 1H NMR (400 MHz, dmso-d6): d 8.43 (s, 1H), 7.66 (s, 1H), 7.32-7.30 (m, 2H), 7.24-7.20 (m, 4H), 6.88-6.86 (m, 2H), 6.08 (d, J=8 Hz, 1H), 4.20-4.18 (m, 1H), 3.70 (s, 3H), 3.29-3.18 (m, 2H), 3.05-2.99 (m, 1H), 2.58-2.52 (m, 1H), 2.27-2.20 (m, 1H).
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
Figure imgf000064_0002
Figure imgf000065_0001
2)
50.1 50 2
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 ¾0 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. The organic layer was washed with water, brine, dried over Na2SC>4, filtered and the solvent was evaporated under reduced pressure to get the crude product which was purified by column chromatography to afford 2-fluoro-l- iodo-4-methoxybenzene (34 g, 76%) as brown gum.
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. The 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). The filtrate was concentrated under reduced pressure to get the crude product which was washed with hexane and EA to afford ethyl 3-amino-2-(2-fluoro-4- methoxyphenyl)propanoate-HCl (4 g, 79%) as off white solid.
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. After completion of reaction (monitored by TLC), 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). The aqueous part then acidified by 2(N) HC1 solution and extracted by EtOAc (2 x 50 ml). The combined organic layer was washed by water (50 ml) followed by brine (50 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; Rf^value-0.5) to afford ethyl 5- (2-fluoro-4-methoxyphenyl)-2,4-dioxopiperidine-3-carboxylate (0.3 g, 69%) as light yellow solid.
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; Rf^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). The organic layer was dried over anhydrous Na2SC>4, concentrated under reduced pressure to get 5-(2-fluoro-4- methoxyphenyl)-4-(hydroxyimino)piperidin-2-one (1.2 g, 43%) which was used for the next step without further purification.
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-6H20 (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). 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; Rf^value-0.5) to afford tert-butyl (5-(2-fluoro-4- methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (0.7 g, 42%) as white solid.
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. After completion of the reaction (monitored by TLC), 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; Rf^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 50.1 (dial): 1H NMR (400 MHz, dmso-d6): d 8.40 (s, 1H), 7.80 (s, 1H), 7.36-7.34 (m, 2H), 7.28-7.25 (m, 2H), 7.23 (t, J=8.4 Hz, 1H), 6.83-6.80 (m, 1H), 6.73-6.70 (m, 1H), 6.47 (d, J=8.8 Hz, 1H), 4.26-4.24 (m, 1H), 3.72 (s, 3H), 3.53-3.51 (m, 2H), 3.41-3.39 (m, 1H), 2.65-2.59 (m, 1H), 2.12-2.06 (m, 1H).
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: l-(4-chlorophenyl)-3-(5-(2-fluoro-4-methoxyphenvi)-2-oxopiperidin-4-yl)urea
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
Figure imgf000067_0002
Figure imgf000067_0001
diasteroisomer 1 (dial) diasteroisomer 2 (dia2)
61.1 51.2
To the solution of 4-amino-5-(2-iluoro-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. 4-Chlorophenyl isocyanate (0.064 g, 0.42 mmol, 1 eq) was then added to the reaction mixture and stirred for 16 h at RT. After completion of the reaction (monitored by TLC), 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; Rf^value-0.55) followed by prep HPLC to afford pure diasteomerl c /a/-l-(4-chlorophenyl)-3-(5- (2-fluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea 51.1 (0.057 g, 35%) and pure diasteromer2 clia2- 1-(4- chlorophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea 51.2 (0.035 g, 21%) as white solid. Example 51.1 (dial): 1H NMR (400 MHz, dmso-d6): d 8.41 (s, 1H), 7.80 (s, 1H), 7.33-7.31 (m, 2H), 7.24-7.19 (m, 3H), 6.83-6.80 (m, 1H), 6.73-6.71 (m, 1H), 6.47 (d, J=9.2 Hz, 1H), 4.26-4.24 (m, 1H), 3.72 (s, 3H), 3.54-3.49 (m, 2H), 3.43-3.39 (m, 1H), 2.65-2.59 (m, 1H), 2.12-2.06 (m, 1H).
Example 51.2 (dial): 1H NMR (400 MHz, dmso-d6): d 8.47 (s, 1H), 7.68 (s, 1H), 7.33-7.27 (m, 3H), 7.22-7.20 (m, 2H), 6.80-6.73 (m, 2H), 6.13 (d, J=8.4 Hz, 1H), 4.26-4.25 (m, 1H), 3.72 (s, 3H), 3.29-3.17 (m, 3H), 2.58-2.52 (m, 1H), 2.33-2.26 (m, 1H).
Example 52: l-(4-bromophenyl)-3-(l-(2-methoxyethyl)-5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
Example 52.1: cA-l-(4-bromophenyl)-3-(l-(2-methoxyethyl)-5-(4-methoxyphenyl)-2-oxopiperidin-4- vDurea
Figure imgf000068_0001
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. The 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; Rf^ 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. The residue was then dissolved in DCM (10 ml) and TEA (0.16 ml, 1.19 mmol, 3 eq) was then added to the reaction mixture at 0°C. 4-Bromophenyl isocyanate (0.078 g, 0.396 mmol, 1 eq) was then added to the reaction mixture and stirred for 16 h at RT. The reaction mixture was dissolved in DCM (50 ml) and washed by water (2 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; Rf^value-0.55) to afford cA-l-(4-bromophenyl)-3-(l-(2-methoxyethyl)-5-(4- methoxyphenyl)-2-oxopiperidin-4-yl)urea (0.105 g, 60%) as white solid.
1H NMR (400 MHz, dmso-d6): d 8.59 (s, 1H), 7.38-7.36 (m, 2H), 7.32-7.30 (m, 2H), 7.21-7.19 (m, 2H), 6.90- 6.88 (m, 2H), 6.29-6.27 (m, 1H), 4.24-4.23 (m, 1H), 3.72 (m, 3H), 3.69-3.65 (m, 2H), 3.62-3.56 (m, 1H), 3.53- 3.44 (m, 3H), 3.41-3.40 (m, 1H), 3.27 (s, 3H), 2.62-2.57 (m, 1H), 2.18-2.12 (m, 1H).
Example 52.2: / ¾¾,?- l-(4-bromophenvi)-3-(l-(2-methoxyethvi)-5-(4-methoxyphenvi)-2-oxopiperidin-4-yl)urea
Figure imgf000068_0002
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).
1H NMR (400 MHz, dmso-d6): d 8.46 (s, 1H), 7.35-7.22 (m, 6H), 6.89-6.87 (m, 2H), 6.11-6.09 (m, 1H), 4.20 (s, 1H), 3.71 (s, 3H), 3.57-3.52 (m, 1H), 3.46-3.37 (m, 5H), 3.24 (s, 3H), 3.15-3.11 (m, 1H), 2.66-2.61 (m, 1H), 2.36- 2.29 (m, 1H). Example 53: l-(4-chlorophenyl)-3-(l-(2-methoxyethyl)-5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
Example 53.1: c«-l-(4-chlorophenyl)-3-(l-(2-methoxyethyl)-5-(4-methoxyphenyl)-2-oxopiperidin-4- yllurea
Example 53.2: fra¾,y-l-(4-chlorophenyl)-3-(l-(2-methoxyethyl)-5-(4-methoxyphenyl)-2-oxopiperidin-4- yl)urea
Figure imgf000069_0001
Example 53.1 was synthesized in analogy to synthesis described for Example 52.1.
Example 53.1: 1H NMR (400 MHz, dmso-d6): d 8.54 (s, 1H), 7.37-7.35 (m, 2H), 7.25-7.18 (m, 4H), 6.90-6.88 (m, 2H), 6.25 (d, J=8.4 Hz, 1H), 4.24-4.23 (m, 1H), 3.71 (s, 3H), 3.69-3.60 (m, 3H), 3.59-3.50 (m, 3H), 3.49-3.43 (m, 1H), 3.26 (s, 3H), 2.62-2.56 (m, 1H), 2.18-2.12 (m, 1H).
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
Figure imgf000069_0002
Figure imgf000069_0003
54.1 54.2
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 54.1 (dial): 1H NMR (400 MHz, dmso-d6): d 8.44 (s, 1H), 7.37-7.35 (m, 2H), 7.29-7.27 (m, 2H), 7.24- 7.20 (m, 1H), 6.84-6.81 (m, 1H), 6.75-6.73 (m, 1H), 6.33 (d, J=8.4 Hz, 1H), 4.27-4.25 (m, 1H), 3.73 (s, 3H), 3.65 (s, 3H), 3.58-3.47 (m, 4H), 3.26 (s, 3H), 2.67-2.61 (m, 1H), 2.17-2.11 (m, 1H).
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 55.1: ti/a2-l-(4-chlorophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-l-(2-methoxyethyl)-2- oxopiperidin-4-yl)urea
Figure imgf000070_0001
55.1 55.2
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 (dial): 1H NMR (400 MHz, dmso-d6): d 8.45 (s, 1H), 7.35-7.32 (m, 2H), 7.24-7.20 (m, 3H), 6.84- 6.81 (m, 1H), 6.75-6.73 (m, 1H), 6.33 (d, J=8.4 Hz, 1H), 4.27-4.25 (m, 1H), 3.73 (s, 3H), 3.65 (s, 3H), 3.54-3.50 (m, 4H), 3.26 (s, 3H), 2.67-2.61 (m, 1H), 2.17-2.11 (m, 1H).
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
Figure imgf000071_0001
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 Et20 (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. The 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 Na2S04, concentrated under reduced pressure to get the crude material, which was purified by silica gel (230-400 mesh silica gel; 10% EtO Ac/hexane; Rf- 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 Na2S04, 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 ROB¾ (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). The organic layer was dried over anhydrous Na2SC>4, 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^ value-0.5) to afford 2-(bromomethyl)-l,3-difluoro-5-methoxybenzene (0.45 g, 66%) as color less liquid.
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 Et20 (2 x 200 ml). The combined organic layer was washed by water (4 x 80 ml) followed by brine (200 ml). The organic layer was dried over anhydrous Na2SC>4, concentrated under reduced pressure to get the crude material, which was purified by silica gel (230-400 mesh silica gel; 10% EtOAc/hexane; R^value-0.4) to afford 2-(2,6-difluoro-4-methoxyphenyl)acetonitrile (3.5 g, 48%) as color less liquid.
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). The combined organic layer was washed by water (2 x 50 ml) followed by brine (50 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; 10% EtOAc/hexane; R^value-0.4) to afford ethyl 2-cyano-2-(2,6-difluoro-4-methoxyphenyl)acetate (2.5 g, 64%) as color less liquid.
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). The filtrate was concentrated under reduced pressure to get the crude product which was then stirred with EtOAc and a precipitate was formed which was collected by filtration to get HC1 salt of ethyl 3-amino-2-(2,6-difluoro-4-methoxyphenyl)propanoate (1.5 g, 52%) as off white solid. 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. The 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). The organic layer was dried over anhydrous Na2S04, concentrated under reduced pressure to get the crude product which was purified by column chromatography (230-400mesh silica gel; 30% EtOAc/hexane; R^value-0.5) to afford ethyl 2-(2,6-difluoro-4- methoxyphenyl)-3 -(3 -ethoxy-3 -oxopropanamido)propanoate (11.0 g, 47%) as light brown solid.
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. The residue was dissolved in water (100 ml), this aqueous part was then washed by EtOAc (100 ml). The aqueous part was acidified by 2(N) HC1 solution and extracted by EtOAc (2 x 100 ml). The combined organic layer was washed by water (100 ml) followed by brine (100 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; Rf- value-0.5) to afford ethyl 5-(2,6-difluoro-4-methoxyphenyl)-2,4-dioxopiperidine-3-carboxylate (1.0 g, 23%) as off white solid.
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. The 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; Rf^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). The organic layer was dried over anhydrous Na2S04, concentrated under reduced pressure to get 5-(2,6-difluoro- 4-methoxyphenyl)-4-(hydroxyimino)piperidin-2-one (1.0 g, 94%) as off white solid.
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-6H20 (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). 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; Rf^ value-0.5) to afford tert-butyl (5-(2,6- difluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (0.3 g, 36%) as white solid.
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. 4-Bromophenyl isocyanate (0.069 g, 0.351 mmol, 1 eq) then added to the reaction mixture and stirred for 16 h at RT. The reaction mixture was dissolved in DCM (50 ml) and washed by water (2 x 20 ml) followed by brine (20 ml). The organic layer 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; Rf^ value-0.55) followed by prep HPLC to afford pure diasteromerl c /a/-l-(4-bromophenyl)-3-(5- (2,6-difluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea (0.072 g, 45%) and pure diastereomer2 clia2- 1-(4- bromophenyl)-3-(5-(2,6-difluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea (0.012 g, 8%) as white solids. 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: l-(4-chlorophenvi)-3-(5-(2.6-difluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
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
Figure imgf000074_0001
To a cold stirring solution of tert-butyl (5-(2,6-diiluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (0.125 g, 0.351 mmol, 1 eq) in DCM (10 ml) was slowly added triiluoro 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. 4-Chlorophenyl isocyanate (0.054 g, 0.351 mmol, 1 eq) was then added to the reaction mixture and stirred for 16 h at RT. The reaction mixture was dissolved in DCM (50 ml) and washed by water (2 x 20 ml) followed by brine (20 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; Rf- value-0.55) followed by prep HPLC to afford compound pure diasteomerl c//a/-l-(4-chlorophenyl)-3-(5-(2,6- difluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea (0.065 g, 45%) and diasteomer2 c//a2-l-(4-chlorophenyl)-3- (5-(2,6-difluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea (0.01 g, 7%) as white solids.
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
Figure imgf000075_0001
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).
1H NMR (400 MHz, dmso-d6): d 8.45 (s, 1H), 7.37-7.35 (m, 2H), 7.31-7.29 (m, 2H), 7.20-7.18 (m, 2H), 6.90- 6.87 (m, 2H), 6.36 (d, J=8.8 Hz, 1H), 4.26-4.25 (m, 1H), 3.71 (s, 3H), 3.60-3.55 (m, 2H), 3.41 (s, 1H), 2.91 (s, 3H), 2.60-2.59 (m, 1H), 2.20-2.14 (m, 1H).
Example 58.2: trans- 1 -(4-bromophenyl)-3-(5-(4-methoxyphenyl)- 1 -methyl-2-oxopiperidin-4- yl)urea
Figure imgf000075_0002
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. The 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; Rf^ 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. 4-Bromophenyl isocyanate (0.042 g, 0.209 mmol, 1 eq) was then added to the reaction mixture and stirred for 16 h at RT. The reaction mixture was dissolved in DCM (50 ml) and washed by water (2 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 (230-400mesh silica gel; 5% MeOH/DCM; Rf^value-0.55) to afford /ra«s-l-(4-bromophenyl)-3-(5-(4-methoxyphenyl)-l-methyl-2- oxopiperidin-4-yl)urea (0.059 g, 65%) as white solid. 1H NMR (400 MHz, dmso-d6): d 8.43 (s, 1H), 7.34-7.32 (m, 2H), 7.27-7.22 (m, 4H), 6.89-6.87 (m, 2H), 6.09 (d, J=8 Hz, 1H), 4.24-4.21 (m, 1H), 3.70 (s, 3H), 3.393.36 (m, 1H), 3.30-3.28 (m, 1H), 3.18-3.12 (m, 1H), 2.81 (s, 3H), 2.64-2.58 (m, 1H), 2.34-2.27 (m, 1H).
Example 59: l-(4-chlorophenyl)-3-(5-(4-methoxyphenvi)-l-methyl-2-oxopiperidin-4-yl)urea
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
Figure imgf000076_0001
Example 59.1 was synthesized in analogy to synthesis described for Example 58.1.
Example 59.1: 1H NMR (400 MHz, dmso-d6): d 8.48 (s, 1H), 7.37-7.34 (m, 2H), 7.25-7.23 (m, 2H), 7.20-7.18 (m, 2H), 6.90-6.87 (m, 2H), 6.38 (d, 1H, J=8.4 Hz), 4.27-4.24 (m, 1H), 3.71 (s, 3H), 3.60-3.56 (m, 2H), 3.43-3.41 (m, 1H), 2.91 (s, 3H), 2.64-2.59 (m, 1H), 2.20-2.14 (m, 1H).
Example 59.2 was synthesized in analogy to synthesis described for Example 58.2.
Example 59.2: 1H NMR (400 MHz, dmso-d6): d 8.43 (s, 1H), 7.32-7.30 (m, 2H), 7.24-7.19 (m, 4H), 6.89-6.87 (m, 2H), 6.09 (d, J=8 Hz, 1H), 4.24-4.21 (m, 1H), 3.70 (s, 3H), 3.36 (s, 1H), 3.29 (s, 1H), 3.18-3.12 (m, 1H), 2.81 (s, 3H), 2.64-2.58 (m, 1H), 2.34-2.27 (m, 1H).
Example 60: l-(4-bromophenvi)-3-(5-(2.6-difluoro-4-methoxyphenyl)-l-(2-methoxyethyl)-2-oxopiperidin-4- vDurea
Figure imgf000076_0002
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. The reaction mixture was diluted with EtOAc (80 ml) and washed by water (5 x 30 ml) followed by brine (30 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 (230-400mesh silica gel; 5% MeOH/DCM; Rf^value-0.55) to afford tert-butyl (5-(2,6-difluoro-4-methoxyphenyl)-l-(2-methoxyethyl)-2-oxopiperidin-4-yl)carbamate (0.188 g, 65%) as white solid. 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. The residue was then dissolved in DCM (10 ml) and TEA (0.092 ml, 0.68 mmol, 3 eq) was then added to the reaction mixture at 0°C. 4-Bromophenyl isocyanate (0.045 g, 0.227 mmol, 1 eq) was then added to the reaction mixture and stirred for 16 h at RT. The reaction mixture was dissolved in DCM (50 ml) and washed by water (2 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; Rf^value-0.55) to afford l-(4-bromophenyl)-3-(5-(2,6-difluoro-4- methoxyphenyl)-l-(2-methoxyethyl)-2-oxopiperidin-4-yl)urea (white solid, 0.038 g, 33%) as mixture of diastereomers.
1H NMR (400 MHz, dmso-d6): d 8.49 (s, 0.17 H), 8.44 (s, 0.83 H), 7.32-7.36 (m, 2.0 H), 7.24-7.26
(m, 1.94 H), 6.68-6.71 (m, 1.96 H), 6.41-6.43 (m, 0.88 H), 6.15-6.16 (m, 0.20 H), 4.24-4.26 (m, 1.19
H), 3.90-3.95 (m, 0.98 H), 3.74 (s, 3.79 H), 3.56-3.65 (m, 1.77 H), 3.46-3.49 (m, 2.27 H), 3.39-3.40
(m, 1.27 H), 3.24-3.25 (m, 2.97 H), 2.67-2.73 (m, 1.12 H), 2.15-2.21 (m, 1.04 H).
Example 61: l-(4-chlorophenyl)-3-(5-(2.6-difluoro-4-methoxyphenyl)-l-(2-methoxyethyl)-2-oxopiperidin-4- vDurea
Figure imgf000077_0001
Example 61 (mixture of diastereomers) was synthesized in analogy to synthesis described for
Example 59.
1H NMR (400 MHz, dmso-d6): d 8.48 (s, 0.18 H), 8.43 (s, 0.85 H), 7.29-7.31 (m, 2.0 H), 7.19-7.23 (m, 1.94 H), 6.68-6.73 (m, 1.98 H), 6.40-6.42 (m, 0.91 H), 6.15-6.16 (m, 0.21 H), 4.25-4.28 (m, 1.17 H), 3.90-3.95 (m, 0.85H), 3.74 (s, 3.89 H), 3.60-3.69 (m, 1.91 H), 3.46-3.49 (m, 2.31 H), 3.39-3.44 (m, 1.22 H), 3.23-3.25 (m, 2.90 H), 2.67- 2.73 (m, 1.09 H), 2.15-2.21 (m, 0.95 H).
Example 62: l-(4-bromophenyl)-3-(5-(2.6-difluoro-4-methoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea
Figure imgf000077_0002
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
Figure imgf000078_0001
Example 63 (mixture of diastereomers) was synthesized in analogy to synthesis described for Example 58.2.
1H NMR (400 MHz, dmso-d6): d 8.45 (s, 0.21 H), 8.37 (s, 0.92 H), 7.28-7.32 (m, 2.0 H), 7.19-7.24 (m, 1.98 H), 6.68-6.73 (m, 2.06 H), 6.48-6.50 (m, 0.88 H), 6.15-6.16 (m, 0.24 H), 4.24-4.26 (m, 1.3 H), 3.85-3.91 (m, 0.97 H), 3.74 (s, 3.82 H), 3.51-3.58 (m, 1.09 H), 2.88-2.91 (m, 2.56 H), 2.66-2.72 (m, 1.17 H), 2.11-2.17 (m, 1.04 H).
Example 64: l-(4-bromophenyl)-3-(5-(2-fluoro-4-mcthoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea
Figure imgf000078_0002
Example 64 (mixture of diastereomers) was synthesized in analogy to synthesis described for Example 58.2.
1H NMR (400 MHz, dmso-d6): d 8.51-8.49 (m, 1H), 7.36-7.32 (m, 3H), 7.29-7.26 (m, 3H), 7.21-7.17 (m, 1H), 6.84-6.72 (m, 3H), 6.54 (d, J=8.8 Hz, 1H), 6.20 (d, J=8.4 Hz, 1H), 4.32-4.26 (m, 2H), 3.73-3.71 (m, 4H), 3.68- 3.60 (m, 2H), 3.56-3.52 (m, 1H), 3.41-3.37 (m, 1H), 2.91 (s, 3H), 2.81 (s, 1H), 2.69-2.57 (m, 2H), 2.40-2.32 (m, 1H), 2.19-2.13 (m, 1H).
Example 65: l-(4-chlorophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea
Figure imgf000078_0003
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
Figure imgf000079_0001
p
Representative procedure for urea formation starting from carboxylic acid
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. The 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. Na2SC>4 and concentrated under reduced pressure to get the crude product which was purified by silica gel (100-200 mesh) column chromatography (25% EtOAc in Hexane) to obtain desired fra«5-4-[3-(5-chloro-pyridin-2-yl)-ureido]-3-(2,6-difluoro-4-methoxy-phenyl)-piperidine-l -carboxylic acid tert-butyl ester (200 mg, 50% yield) as yellowish solid.
Step2: To a stirred solution of desired P¾«.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. 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 basified with saturated aq. NaHCCb solution and extracted with ethyl acetate and the organic layer was dried over anhydr. Na SC and concentrated to get the desired trans- l-(5-chloro-pyridin-2-yl)-3-[3-(2,6- difluoro-4-methoxy-phenyl)-piperidin-4-yl]-urea (200 mg, crude) as off white solid. LC-MS: m/z [M+H]+ = 397.4 (exact mass calc. = 396.12).
Example 67: 1-
Figure imgf000079_0002
Example 67a: ^Ga¾,?-1-(5-oMoGornήάhi-2-nί)-3-(3-(2.6-άi1EiqGo-4-hΐ6ΐ1iocnr1ΐ6hn1)-1-(2-1TiqGq6ΐ1inί)rir6Gίάίh-4- vDurea
Figure imgf000080_0001
To a stirred solution of Example 66a (150 mg, 0.37 mmol, 1 eq) in ACN (10 ml) at RT was added K2CO3 (157 mg, 1.13 mmol, 3.0 eq) followed by the addition of l-bromo-2-fluoro-ethane (72 mg, 0.56 mmol, 1.5 eq) and the reaction mixture was stirred under reflux for a period of 16 h. After completion of the reaction (monitored by TLC and LC MS), 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. Na2S04 and concentrated under reduced pressure to obtain the crude material which was purified by silica gel (100-200 mesh) column chromatography (2% MeOH/DCM) to afford ira«s-l-(5-chloro-pyridin-2-yl)-3-[3-(2,6-difluoro-4- methoxy-phenyl)-l-(2-fluoro-ethyl)-piperidin-4-yl]-urea (25 mg, 15%) as off white solid. LC-MS: m/z [M+H]+ = 443.2 (exact mass calc. = 442.14).
'H NMR (400 MHz, DMSO-<¾) d 9.06 (s, 1 H), 8.12 (s, 1 H), 7.73-7.70 (m, 1 H), 7.52 (d, J= 7 Hz, 1 H), 7.38 (d, J = 9 Hz, 1 H), 6.66 (d, J = 11 Hz, 2 H), 4.58 (t, J = 5 Hz, 1 H), 4.46 (t, J = 5 Hz, 1 H), 4.00-3.97 (m, 1 H), 3.70 (s, 3 H), 3.12-3.05 (m, 1 H), 2.96 (d, J= 11 Hz, 1 H), 2.70 (t, J = 5 Hz, 1 H), 2.63 (t, J = 5 Hz, 1 H), 2.19 (t, J = 12 Hz, 1 H), 2.04 (d , J= 12 Hz, 1 H), 1.47 (d , J= 12 Hz, 1 H).
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
Figure imgf000080_0002
Figure imgf000080_0003
p
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).
Physical property: Off white solid; Yield: 56% over 2 steps. LC-MS: m/z [M+H]+ = 397.1 (exact mass calc. = 396.12).
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
Figure imgf000081_0001
Example 69a was synthesized in analogy to synthesis described for Example 67a.
¾ NMR (400 MHz, DMSO-<¾) d 8.56 (s, 1 H), 8.25 (d, J= 3 Hz, 1 H), 7.80-7.78 (m, 1 H), 7.29 (d, J= 9 Hz, 1 H), 6.67-6.62 (m, 2 H), 6.17 (d, J= 9 Hz, 1 H), 4.58 (t, J= 5 Hz, 1 H), 4.46 (t , J= 5 Hz, 1 H), 4.02-3.98 (m, 1 H), 3.72 (s, 3 H), 3.10-3.05 (m, 1 H), 2.97 (d, J= 11 Hz, 1 H), 2.87 (d, J= 10 Hz, 1 H), 2.69 (t, J= 5 Hz, 1 H), 2.62 (t , J= 5 Hz, 1 H), 2.49-2.41 (m, 1 H), 2.18 (t , J= 11 Hz, 1 H), 1.95 (d, J= 10 Hz, 1 H), 1.53-1.50 (m, 1 H).
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
Figure imgf000081_0002
Figure imgf000081_0003
step-1
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).
Physical property: Off white solid; Yield: 48% over 2 steps. LC-MS: m/z [M+H]+ = 431.2 (exact mass calc. = 430.14).
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
Figure imgf000081_0004
Example 71a was synthesized in analogy to synthesis described for Example 67a. LC-MS: m/z [M+H]+ = 477.2 (exact mass calc. = 476.16). ¾ NMR (400 MHz, DMSO-<¾) d 8.87 (s, 1 H), 8.52 (d, J= 2 Hz, 1 H), 8.01 (d, J= 8 Hz, 1 H), 7.68 (d, J= 9 Hz, 1 H), 6.66 (d , J= 11 Hz, 2 H), 6.30 (d, J= 9 Hz, 1 H), 4.58 (t, J= 5 Hz, 1 H), 4.46 (t, J= 5 Hz, 1 H), 4.04-4.01 (m, 1 H), 3.72 (s, 3 H), 3.12-3.07 (m, 1 H), 2.97 (d, J= 11 Hz, 1 H), 2.87 (d, J= 10 Hz, 1 H), 2.70 (t , J= 5 Hz, 1 H), 2.62 (t, J= 5 Hz, 1 H), 2.44-2.42 (m, 1 H), 2.18 (t , J= 13 Hz, 1 H), 1.97 (d, J= 11 Hz, 1 H), 1.57-1.48 (m, 1 H).
Example 72: l-(3-(2.6-diiluoro-4-methoxyplienyl)piperidin-4-yl)-3-(4-(triiluorometliyl)plienyl)urea
a
Figure imgf000082_0001
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).
Physical property: Off white solid; Yield: 52% over 2 steps. LC-MS: m/z [M+H]+ = 430.2 (exact mass calc. = 429.15).
Example 73: 1-(3-(2.6-άίί1iΐ0G0-4-hΐ6ΐ1ΐ0cnr1ΐ6hn1)-1-(2-ί1iΐ0G06ΐ1in1)rίr6Gίάίh-4-n1)-3-(4- (triiluoromethvDphenvDurea
Example 73a: trans- 1 -(3 -(2.6-difhtoro-4-methoxyphenyl)- 1 - vD-S -(4-
Figure imgf000082_0002
(trifluoromethvDphenvDurea
Figure imgf000082_0003
Example 73a was synthesized in analogy to synthesis described for Example 67a. LC-MS: m/z [M+H]+ = 476.3 (exact mass calc. = 475.17).
¾ NMR (400 MHz, DMSO-c ) d 8.64 (s, 1 H), 7.50 (d, J = 9 Hz, 2 H), 7.44 (d, J = 9 Hz, 2 H), 6.66 (d, J = 11 Hz, 2 H), 6.10 (d, J= 9 Hz, 1 H), 4.58 (t, J= 5 Hz, 1 H), 4.46 (t, J= 5 Hz, 1 H), 4.02-4.00 (m, 1 H), 3.72 (s, 3 H), 3.09-3.04 (m, 1 H), 2.97 (d, J= 11 Hz, 1 H), 2.87 (d, J= 10 Hz, 1 H), 2.71-2.68 (m, 1 H), 2.62 (t, J= 5 Hz, 1 H), 2.45-2.42 (m, 1 H), 2.18 (t, J= 12 Hz, 1 H), 1.98-1.95 (m, 1 H), 1.51-1.49 (m, 1 H).
Example 74: 1-(5-o1i1oGoΐ1iίor1ΐ6h-2-n1)-3-(3-(2.6-άίί1iiqGo-4-hΐ6ΐ1iocnr1ΐ6hn1)-1-(2-ί1iiqGq6ΐ1in1)rίr6Gίάίh-4- vDurea
Example 74a 2-n1)-3-(3-(2.6-άίί1iiqGq-4-hΐ6ΐ1iocnr1ΐ6hn1)-1-(2-ί1iiqGq6ΐ1in1)rίr6Gίάίh-
Figure imgf000082_0004
4-yl)urea
Figure imgf000083_0001
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 K2CO3 (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. Na2SC>4, filtered and concentrated to get the crude product which was purified by silica gel (100-200 mesh) column chromatography (10-15% EA in Hexane) to afford 3- (2,6-difluoro-4-methoxy-phenyl)-piperidine-l,4-dicarboxylic acid 4-benzyl ester 1 -tert-butyl ester (8 g, 80%) as off white solid.
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. The organic layer was dried over anhyd. Na2SC>4 and concentrated under reduced pressure to obtain 3-(2,6-difluoro-4-methoxy-phenyl)-piperidine-4- carboxylic acid benzyl ester (5.5 g, 88%) as white solid. LC-MS: m/z [M+H]+ = 362.2 (exact mass calc. = 361.15). 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. Na2SC>4, filtered and concentrated to get the crude product which was purified by silica gel (100-200 mesh) column chromatography (15-20% EA in Hexane) to afford 3- (2,6-difluoro-4-methoxy-phenyl)-l-(2-fluoro-ethyl)-piperidine-4-carboxylic acid benzyl ester (5.5 g, 88%) as grey solid. LC-MS: m/z [M+H]+ = 408.0 (exact mass calc. = 407.17). 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 ¾ 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. The solvent was evaporated to get the desired 3-(2,6-difluoro-4-methoxy-phenyl)-l-(2-fluoro-ethyl)-piperidine-4- carboxylic acid (3.5 g, 81% crude yield) as brown solid. LC-MS: m/z [M-H]+ = 315.8 (exact mass calc. = 317.12). 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. Then NEb in MeOH (7M, 2.36 ml, 16.5 mmol, 1.5 eq) was added and stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc and washed with ice-cold water and brine. The organic layer was dried over anhydr. Na2S04 and concentrated under reduced pressure to obtain crude product which was purified by silica gel (100-200 mesh) column chromatography (5% MeOH/DCM) to afford 3-(2,6-difluoro-4-methoxy-phenyl)-l-(2-fluoro-ethyl)-piperidine-4-carboxylic acid amide (1.7 g, 49% yield) as yellowish sticky solid. LC-MS: m/z [M+H]+ = 317.2 (exact mass calc. = 316.14).
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. 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 diluted with EtOAc and washed with ice-cold water and brine. The organic layer was dried over anhydr. Na2S04 and concentrated under reduced pressure to obtain crude product which was purified by silica gel (100-200 mesh) column chromatography (5% MeOH/DCM) to afford 3-(2,6- difluoro-4-methoxy-phenyl)-l-(2-fluoro-ethyl)-piperidin-4-ylamine (600 mg, 94% yield) as yellowish sticky solid. LC-MS: m/z [M+H]+ = 289.0 (exact mass calc. = 288.18).
Step7: To a stirred solution of 5-chloro-thiophene-2-carboxylic acid (100 mg, 0.62 mmol, leq) in toluene (5 ml) was added Et3N (172 mΐ, 1.25 mmol, 2.0 eq) followed by the addition of DPPA (173 mΐ, 0.80 mmol, 1.3 eq)) and the reaction mass was refluxed for a period of 4 h. The reaction was cooled to RT and 3-(2,6-difluoro-4-methoxy- phenyl)-l-(2-fluoro-ethyl)-piperidin-4-ylamine (177 mg, 0.62 mmol, leq) 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 (300 ml) and washed with water and brine. The combined organic layer was dried over anhydr. Na2S04 and concentrated under reduced pressure to get the crude product which was purified by silica gel (100-200 mesh) column chromatography (5% MeOH/DCM) followed by further prep TLC plate purification to afford tri s- 1- (5 -chloro- thiophen-2-yl)-3-[3-(2,6-difluoro-4-methoxy-phenyl)-l-(2-fluoro-ethyl)-piperidin-4-yl]-urea (35 mg, 12%) as off white solid. LC-MS: m/z [M+H]+ = 447.7 (exact mass calc. = 442.14).
¾ NMR (400 MHz, DMSO-c/ff) d 9.37 (s, 1 H), 6.67-6.64 (m, 3 H), 6.17-6.12 (m, 2 H), 4.58 (s, 1 H), 4.50 (s, 1 H), 4.01-3.95 (m, 1 H), 3.72 (s, 3 H), 3.15-2.95 (m, 1 H), 2.95-2.84 (m, 2 H), 2.69 (s, 1 H), 2.61 (s, 1 H), 2.20- 2.14 (m, 1 H), 1.91 (d, /= 12 Hz, 1 H), 1.52 (d, /= 10 Hz, 1 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
Figure imgf000085_0001
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).
Physical property: Off white solid; Yield: 47% over 2 steps.
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
Figure imgf000085_0002
Example 76a was synthesized in analogy to synthesis described for Example 67a. LC-MS: m/z [M+H]+ = 449.1 (exact mass calc. = 448.09).
¾ NMR (400 MHz, DMSO-c ) d 10.25 (s, 1 H), 7.26 (s, 1 H), 6.67 (d, J= 11 Hz, 2 H), 6.35 (d, J= 8 Hz, 1 H), 4.58 (t, J= 5 Hz, 1 H), 4.46 (t, J= 4 Hz, 1 H), 4.01-3.96 (m, 1 H), 3.72 (s, 3 H), 3.10-3.04 (m, 1 H), 2.96 (d , J = 12 Hz, 1 H), 2.87 (d , J= 9 Hz, 1 H), 2.71-2.68 (m, 1 H), 2.62 (t , J= 5 Hz, 1 H), 2.50-2.47 (m, 1 H), 2.18 (t , J= 12 Hz, 1 H), 1.95 (d, J= 10 Hz, 1 H), 1.54-1.51 (m, 1 H).
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
Figure imgf000085_0003
Starting from fra«s-3-(2,6-difluoro-4-methoxyphenyl)-l-(2-fluoroethyl)piperidin-4-amine (for synthesis see Example 74a, step6) and 2-chlorothiazole-5-carboxylic acid, Example 77a was synthesized in analogy to
Example 74a. Physical property: Off white solid; Yield: 15%
LC-MS: m/z [M+H]+ = 449.0 (exact mass calc. = 448.09).
¾ NMR (400 MHz, DMSO-c/ff) d 9.63 (s, 1 H), 7.00 (s, 1 H), 6.65 (d, J= 11 Hz, 2 H), 6.46 (d, J= 8 Hz, 1 H), 4.58 (t , J= 5 Hz, 1 H), 4.46 (t , J= 5 Hz, 1 H), 3.97 (d, J= 13 Hz, 1 H), 3.72 (s, 3 H), 3.14-3.08 (m, 1 H), 2.96 (d, J= 11 Hz, 1 H), 2.86 (d, /= 10 Hz, 1 H), 2.69 (t, J= 5 Hz, 1 H), 2.62 (t, J= 5 Hz, 1 H), 2.47-2.39 (m, 1 H), 2.16 (t , J= 12 Hz, 1 H), 1.90 (d, / = 9 Hz, 1 H), 1.56 (d, J= 9 Hz, 1 H).
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
Figure imgf000086_0001
Figure imgf000086_0002
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. The mixture was allowed to cool to RT and quenched with drop wise addition of aq HC1 (6 (M)) until acidified under ice cooled condition. Volatiles were evaporated under reduced pressure and the obtained yellowish crude product was dissolved in DCM (400 ml). Obtained organic part was washed sequentially with water (100 ml) and brine (100 ml), dried overNa2S04, filtered and concentrated under reduced pressure to leave a crude yellowish mass. Purification by recrystallization with EtOAc rendered 5-hydroxy-6-oxo-l,2,3,6-tetrahydro-pyridine-4-carboxylic acid ethyl ester (11.0 g, crude) as yellowish solid. It was used as such without further purification. LCMS: Exact Mass: 185.07, [M+H]+ = 186.2. Step2: To a stirred solution 5-hydroxy-6-oxo-l,2,3,6-tetrahydro-pyridine-4-carboxylic acid ethyl ester (11.0 g, 59.45 mmol, 1.0 eq) in DCM (200 ml) at -78°C was added DIPEA (13 ml, 71.35 mmol, 1.3 eq) followed by addition of triflic anhydride (12 ml, 71.35 mmol, 1.2 eq) under N2 atmosphere. Resulting mixture was stirred for 2 h at the same condition. It was quenched with water under ice cooled condition and diluted with DCM (200 ml). Obtained organic part was washed sequentially with water (100 ml) and brine (100 ml), dried overNa2S04, filtered and concentrated under reduced pressure to leave a crude yellowish mass. Purification by column chromatography using 100-200 mesh silica gel and 0 to 30 % EtOAc/hexane as gradient yielded 6-oxo-5- trifluoromethanesulfonyloxy-l,2,3,6-tetrahydro-pyridine-4-carboxylic acid ethyl ester (8.5 g, 20 % yield, over two steps) as colorless solid.
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 K2CO3 (2.5 eq) and required (4-methoxyphenyl)boronic acid (1.2 eq) in toluene- EtOH (1 : 1, 12 ml/mmol).
Figure imgf000087_0001
(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. The combined organic layer was washed with water and brine, dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. Resulting yellowish crude product was purified by chromatography on 100-200 mesh silica gel using 0 to 30% EtOAc/ hexane as gradient to provide pure ethyl 5-(4-methoxyphenyl)-6-oxo-l,2,3,6-tetrahydropyridine- 4-carboxylate (74% yield) as off-white solid. LCMS: Exact Mass: 275.12; [M+H]+ = 275.9.
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 ¾ 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). Filtrate was evaporated to render the desired ethyl 3-(4- methoxyphenyl)-2-oxopiperidine-4-carboxylate (75% yield) as colorless gum. LCMS: Exact Mass: 277.13; [M+H]+ = 277.
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). Combined organic extract was concentrated under reduced pressure to furnish fra«s-3-(4-methoxyphenyl)-2-oxopiperidine-4-carboxylic acid (39% yield) as colorless solid. It was washed several times with diethyl ether and used for the next step without further purification. LCMS: Exact Mass: 249.10; [M-H]+ = 247.9.
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. The combined organic phase was dried over Na S , filtered and the solvent was evaporated under reduced pressure to furnish the crude product as yellowish gummy solid. It was then purified by column chromatography using 100-200 silica gel and 0-10% MeOH /DCM as gradient to yield trans-\-{A- chlorophenyl)-3-(3-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea (14% yield) as off white solid. LCMS: Exact Mass: 373.12; [M+H]+ = 374.1.
¾ NMR (400 MHz, DMSO-c/ff) 8.81 (s, 1 H), 7.77 (s, 1 H), 7.37-7.33 (m, 2 H), 7.25-7.20 (m, 2 H), 7.12 (d, J = 8.8 Hz, 2 H), 6.84 (d, J= 8.4 Hz, 2 H), 6.67 (d, J= 6.0 Hz, 1 H), 3.95-3.93 (m, 1 H), 3.72 (s, 3 H), 3.44-3.42 (m, 1 H), 3.32-3.26 (m, 2 H), 1.99-1.96 (m, 1 H), 1.69-1.66 (m, 1 H). Example 79: l-(4-chlorophenyl)-3-(3-(2-fluoro-4-mcthoxyphenyl)-2-oxopiperidin-4-yl)urea
lorophenyl)-3-(3-(2-fluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
Pd-C / H
Step-2
Figure imgf000088_0001
Figure imgf000088_0002
Figure imgf000088_0003
Figure imgf000088_0004
Example 79a was synthesized in analogy to synthesis described for Example 78a.
LCMS: Exact Mass: 391.11; [M+H]+ = 392.0.
'H NMR (400 MHz, DMSO-c ) 8.49 (s, 1 H), 7.76 (d , J= 2.4 Hz, 1 H), 7.30 (d, J= 9.2 Hz, 2 H), 7.20 (d, J= 9.2 Hz, 2 H), 7.13 (t , J= 8.4 Hz, 1 H), 6.75-6.67 (m, 2 H), 6.21 (d, J= 8.4 Hz, 1 H), 4.04-4.01 (m, 1 H), 3.72 (s, 3 H), 3.51-3.50 (m, 1 H), 3.31-3.25 (m, 1 H), 3.24-3.20 (m, 1 H), 2.06-2.02 (m, 1 H), 1.79-1.76 (m, 1 H).
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
Figure imgf000088_0005
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. Later it was dissolved in THF (6 ml/mmol), followed by portion wise addition of NaH (1.5 eq) at 0 °C. Resulting solution was stirred for another 30 min and Mel (1.0 eq) was added drop wise at the same condition. Stirring was continued for another 16 h at RT. After completion of the starting material LiOH H20 (5.0 eq) and water (1 ml/mmol) were added under ice cooled condition. Resulting mixture was stirred for another 18 h at RT. Volatiles were evaporated under reduced pressure and the residue was diluted with water, washed with EtOAc, acidified with 1(N) HC1 and finally extracted with 10% MeOH/DCM. Organic layer was dried over Na2S04 and concentrated to get crude /ra«s-3-(4-methoxyphenyl)-l-methyl-2-oxopiperidine-4- carboxylic acid. It was used as such without further purification.
LCMS: Exact Mass: 263.12; [M+H]+ = 264.3. Step2: /ra«s-3-(4-methoxyphenyl)-l-methyl-2-oxopiperidine-4-carboxylic acid was converted to desired trans-1- (4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -methyl-2-oxopiperidin-4-yl)urea following Step-6 procedure described for synthesis of Example 78a.
Physical appearance: off white solid; Yield: 5%.
LCMS: Exact Mass: 387.13; [M+H]+ = 387.8.
¾ NMR (400 MHz, DMSO-c¾) 8.48 (s, 1 H), 7.35 (d , J= 8.8 Hz, 2 H), 7.21 (d, J= 8.8 Hz, 2 H), 7.09 (d, J= 8.8 Hz, 2 H), 6.85 (d, J= 8.4 Hz, 2 H), 3.97-3.95 (m, 1 H), 3.71 (s, 3 H), 3.51-3.44 (m, 2 H), 2.89 (s, 3 H), 2.02-1.90 (m, 1 H), 1.78-1.70 (m, 1 H).
Example 81: 1 -(4-chlorophenyl)-3 -(3 -(2-fluoro-4-methoxyphenvi)- 1 -methyl-2-oxopiperidin-4-yl)urea
Figure imgf000089_0001
Example 81a was synthesized in analogy to synthesis procedure described for Example 80a.
Physical appearance: off white solid; Yield: 13% (Step-2).
LCMS: Exact Mass: 405.13; [M+H]+ = 406.2.
¾ NMR (400 MHz, DMSO-c/ff) 8.48 (s, 1 H), 7.30 (d, J= 8.8 Hz, 2 H), 7.21 (d, J= 8.8 Hz, 2 H), 7.13-7.08 (m, 1 H), 6.74-6.67 (m, 2 H), 6.25 (d, J = 8.0 Hz, 1 H), 4.05-4.03 (m, 1 H), 3.73 (s, 3 H), 3.61-3.58 (m, 1 H), 3.47- 3.38 (m, 1 H), 2.86 (s, 3 H), 2.10-2.07 (m, 1 H), 1.89-1.85 (m, 1 H).
Example 82: l-(4-chlorophenyl)-3-(l-(4-fluorophenyl)-5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
yl)urea
Figure imgf000089_0002
Starting from /ra«s-tert-butyl (5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (for synthesis see Example 48) Example 82a was synthesized in analogy to synthesis described for Example 84a.
1H NMR (400 MHz, dmso-d6): d 8.47 (s, 1H), 7.32-7.38 (m, 4H), 7.29 (d, J = 8.4 Hz, 2H), 7.18-7.23 (m, 4H), 6.89 (d, J = 8.4 Hz, 2H), 6.18 (d, J = 7.6 Hz, 1H), 4.43 (m, 1H), 3.83 (t, J = 10.8 Hz, 1H), 3.70 (s, 3H), 3.51 (q, J = 7.2 Hz & 4.8, 1H), 2.81 (q, J = 5.2 Hz & 11.6 Hz, 1H), 2.57 (s, 1H). 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
Figure imgf000090_0001
Starting from trans- tert-butyl (5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (for synthesis see Example 48) Example 83a was synthesized in analogy to synthesis described for Example 84a. Example 83a (racemic mixture) was separated by chiral preparative HPLC to afford first eluting enantiomer Example 83.1 (RT=11 4min) and second eluting enantiomer Example 83.2 (RT=13.2min) (Chiralpak IC (4.6 x 250 mm); Mobile phase: EtOH: 100).
1H NMR (400 MHz, dmso-d6, T=100°C): d 8.57 (s, 1H), 8.00 (s, 1H), 7.61 (s, 1H), 7.28-7.34 (m, 4H), 7.21 (d, J = 9.2 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.26 (d, J = 7.2 Hz, 1H), 4.34 (bs, 1H), 3.78 (s, 3H), 3.72 (s, 5H).
Example 84: l-(1.5-bis(4-methoxyphenyl)-2-oxopiperidin-4-yl)-3-(4-chlorophenyl)urea
Example 84a 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
Figure imgf000090_0002
Example 84.2: ent2- l-(1.5-bis(4-methoxyphenyl)-2-oxopiperidin-4-yl)-3-(4-chlorophenyl)urea
Figure imgf000090_0003
Figure imgf000091_0001
. 84.2
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. After that Cul (0.024 g, 0.125 mmol, 0.2 eq) and trans-N, N-dimethylcyclohexayl-1, 2-diamine (0.035 g, 0.25 mmol, 0.4 eq) were added and the reaction mixture was stirred at 120°C for 16 h in a sealed tube. After completion of the reaction (monitored by TLC, TLC system 5% methanol in DCM, Rf-0.4), the reaction mixture was filtered through celite bed and the solvent was evaporated under reduced pressure to get the crude product which was purified by column chromatography (230-400 mesh silica gel; 0 to 2% MeOH in DCM) to afford trans- tert-butyl (l,5-bis(4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (0.175 g, 66%) as brown solid.
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. After completion of reaction (monitored by TLC), reaction mixture was evaporated under reduced pressure to get the crude product which was initially purified by column chromatography to afford fraw,s-l-(l,5-bis(4- methoxyphenyl)-2-oxopiperidin-4-yl)-3-(4-chlorophenyl)urea as racemic mixture which was separated by chiral preparative HPLC to afford both the enantiomers as Example 84.1 (0.05 g, 26%, first eluting enantiomer: RT=18.7 min;) and Example 84.2 (0.06 g, 31%, second eluting enantiomer: RT=23.2 min) (Chiralpak IA (4.6 x 250 mm), solvent: Hexane/EA/EtOH/iPr-Amine 70/15/15/0.1). 1H NMR (400 MHz, dmso-d6): d 8.47 (s, 1H), 7.34 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 7.21-7.24 (m, 4H), 6.87-6.93 (m, 4H), 6.18 (d, J = 8.0 Hz, 1H), 4.39-4.41 (m, 1H), 3.78 (t, J = 11.2 Hz, 1H), 3.74 (s, 3H), 3.70 (s, 3H), 3.50 (q, J = 5.6 Hz & 6.8, 1H), 3.31 (s, 1H), 2.76-2.81 (m, 1H), 2.49 (s, 1H).
Exampe 85: l-(4-chlorophenyl)-3-(5-(4-methoxyphenyl)-2-oxo-l-(pyridazin-3-yl)piperidin-4-yl)urea
Exampe idazin-3-yl)piperidin-4-yl)urea
Figure imgf000092_0001
Figure imgf000092_0002
Starting from trans- tert-butyl (5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (for synthesis see Example 84) Example 85a was synthesized in analogy to synthesis described for Example 84a.
1H NMR (400 MHz, dmso-d6, T=100°C): d 9.02 (d, J = 4.4 Hz, 1H), 8.49 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.69 (q, J = 4.0 Hz & 4.8 Hz, 1H), 7.33 (t, J = 8.8 Hz, 4H), 7.23 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 6.26 (d, J = 8.0 Hz, 1H), 4.54 (bs, 1H), 4.16 (t, J = 4.8 Hz, 1H), 4.01 (d, J = 11.6 Hz, 1H), 3.72 (s, 3H), 3.33 (s, 1H), 2.99 (q, J = 11.2 Hz & 6.0 Hz, 1H), 2.70 (q, J = 8.0 Hz & 9.2 Hz, 1H).
Exampe 86: l-(4-chlorophenyl)-3-(5-(4-methoxyphenyl)-l-(6-methylpyridin-2-yl)-2-oxopiperidin-4-yl)urea Exampe 86a: c«-l-(4-chlorophenyl)-3-(5-(4-methoxyphenyl)-l-(6-methylpyridin-2-yl)-2-oxopiperidin-4-yl)urea
Exampe 86.1: _ entl-cis- 1 -(4-chlorophenyl)-3-(5-(4-methoxyphenyl)- 1 -(6-methylpyridin-2-yl)-2- oxopiperidin-4-yl)urea
Exampe 86.2: _ ent2-cis- 1 -(4-chlorophenyl)-3-(5-(4-methoxyphenyl)- 1 -(6-methylpyridin-2-yl)-2- oxopiperidin-4-yl)urea
Figure imgf000093_0001
Stepl : A stirred solution of cA-tert-butyl (5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (0.25 g, 0.781 mmol, 1 eq, for synthesis see Example 48) in dioxane (8 mL), 2-chloro-6-methyl-pyridine (0.119 g, 0.937 mmol, 1.2 eq) and CS2CO3 (0.507 g, 1.562 mmol, 2 eq) was added at RT. The reaction mixture was degassed with Ar for 30 min. After that Pd2(dba)3 (0.035 g, 0.039 mmol, 0.05 eq) and Xantphos (0.027 g, 0.046 mmol, 0.06 eq) were added and the reaction was stirred at 120°C for 16 h in sealed tube. After completion of the reaction, (monitored by TLC, TLC system 5% methanol in DCM, Rf-0.4), the reaction mixture was filtered through celite bed and the solvent was evaporated under reduced pressure to get the crude product which was purified by column chromatography (230-400 mesh silica gel; 0 to 2% MeOH in DCM) to afford cA-tert-butyl (5-(4-methoxyphenyl)- l-(6-methylpyridin-2-yl)-2-oxopiperidin-4-yl)carbamate (0.15 g, 47%) as brown solid.
Step2: To a stirred solution of cA-tert-butyl (5-(4-methoxyphenyl)-l-(6-methylpyridin-2-yl)-2-oxopiperidin-4- yl)carbamate (0.28 g, 0.681 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 (0.2 g, 69%) which was azeotrope with toluene and used for the next step without further purification.
Step3: To the solution of TFA salt of cA-4-amino-5-(4-methoxyphenyl)-l-(6-methylpyridin-2-yl)piperidin-2-one (0.35 g, 0.82 mmol, 1 eq) in DCM (10 mL), TEA (0.47 mL, 3.37 mmol, 3 eq) and l-chloro-4-isocyanato-benzene (0.26 g, 1.688 mmol, 1.5 eq) dissolved in DCM (2 mL) was added at RT and the reaction mixture was stirred at RT for 16 h. After completion of reaction (monitored by TLC), reaction mixture was evaporated under reduced pressure to get the crude product which was initially purified by column chromatography followed to afford Example 86. Separation of racemic Example 86a by chiral preparative HPLC to afford Example 86.1 (0.075 g, 20%, first eluting enantiomer: RT=5.5min) and Example 86.2 (0.08 g, 21%, second eluting enantiomer: RT=6.1) (Chiralpak IA (4.6 x 250 mm), solvent: Hexane/EA/EtOH 50/25/25) as white solids.
Example 87: l-(4-chlorophenyl)-3-(l-((5-chlorothiophen-2-yl)methyl)-3-(4-methoxyphenyl)piperidin-4-yl)urea
Example 87a l-(4-chlorophenyl)-3-(l-((5-chlorothiophen-2-yl)methyl)-3-(4-methoxyphenyl)piperidin-4- vDurea Example _ 87.1: _ e¾t/-tra¾^-l-(4-chlorophenyl)-3-(l-((5-chlorothiophen-2-yl)methyl)-3-(4- methoxyphenyl)piperidin-4-yl)urea
Example _ 87.2: _ l-(4-chlorophenyl)-3-(l-((5-chlorothiophen-2-yl)methyl)-3-(4-
Figure imgf000094_0001
methoxyphenyl)piperidin-4-yl)urea
Figure imgf000094_0002
Stepl: To the solution of trans- tert-butyl 4-(3-(4-chlorophenyl)ureido)-3-(4-methoxyphenyl)piperidine-l- carboxylate (4.9 g, 10.656 mmol, 1 eq, for synthesis see Example 1) in DCM (20 mL), TFA (20 mL) was added drop wise at 0°C. The reaction mixture was allowed to stir at RT for 2 h. After completion of reaction (checked by TLC) DCM and excess of TFA was removed under reduced pressure to get crude product which was washed with diethyl ether and dried under reduced pressure to get trans- l-(4-chlorophenyl)-3-(3-(4- methoxyphenyl)piperidin-4-yl)urea (4.2 g) as TFA salt.
Step2: To the stirring solution of TFA salt of ira«s-l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)piperidin-4-yl)urea (0.7 g, 1.945 mmol, 1 eq) in acetonitrile (10 mL), K2CO3 (1.34 g, 9.695 mmol, 5 eq) was added at 0°C and allowed to stir for 10 min, then 2-chloro-5-chloromethyl-thiophene (0.487 g, 2.915 mmol, 1.5 eq) was added and again allowed to stir for 24 h. Then water was added and the mixture was extracted with EtOAc (3 x 100 mL). EtOAc part was collected, dried over Na2S04 and evaporated to dryness to get crude product which was purified by column chromatography to get Example 87a. Racemic Example 87a was separated by chiral preparative HPLC to afford compound Example 87.1 (0.057 g, 6%, first eluting enantiomer: RT=5.6min) and Example 87.2 (0.046 g, 5%, second eluting enantiomer: RT=6.8min) (Chiralpak IG (4.6 x 250 mm), solvent: Hexane/EA/EtOH/ iPr- Amine 70/15/15/0.1).
'H NMR (400 MHz, DMSO- d6): d 8.33 (s, 1H), 7.29 (d, J= 8.8 Hz, 2H), 7.17 (t , J= 8.8 Hz, 4H), 6.92 (d, J= 3.6 Hz, 1H), 6.82 (d, J = 8.2 Hz, 3H), 5.91 (d, J = 8.2 Hz, 1H), 3.72-3.75 (m, 1H), 3.68 (s, 3H), 3.64 (s, 2H), 2.81- 2.92 (m, 2H), 2.66-2.73 (m, 1H), 1.90-2.19 (m, 3H), 1.43-1.48 (m, 1H).
Example 88: 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-3 -vhnethyl)piperidin-4-yl)urea
Example 88a l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-(pyridin-3-ylmethyl)piperidin-4-yl)urea
Example 88.1: entl-trans- 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-3 -ylmethyl)piperidin-4- vDurea Example 88.2: ent2-trans- 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-3 -ylmethyl)piperidin-4- yl)urea
Figure imgf000095_0001
To the stirring solution of TFA salt of ira«s-l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)piperidin-4-yl)urea (0.3 g, 0.833 mmol, 1 eq, for synthesis see Example 87a) in acetonitrile (10 mL), K2CO3 (0.576 g, 4.167 mmol, 5 eq) was added at 0°C and allowed to stir for 10 min, then bromomethyl-pyridine (0.316 g, 1.249 mmol, 1.5 eq) was added and again allowed to stir for 24 h. Then water was added and the mixture was extracted with EtOAc (3 x 100 mL). EtOAc part was collected, dried over Na2S04 and evaporated to dryness to get crude product which was purified by column chromatography to get Example 87a. Racemic Example 88a was separated by chiral preparative HPLC to afford compound Example 88.1 (0.057 g, 6%, first eluting enantiomer: RT=5.1min) and Example 88.2 (0.046 g, 5%, second eluting enantiomer: RT=6.8min) (Chiralpak IG (4.6 x 250 mm), solvent: Hexane/EA/EtOH 50/25/25).
¾ NMR (400 MHz, DMSO- d6): d 8.44-8.46 (m, 2H), 8.35 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.33-7.36 (m, 1H), 7.29 (d , J= 8.9 Hz, 2H), 7.14-7.20 (m, 4H), 6.82 (d, J= 8.5 Hz, 2H), 5.92 (d, J= 8.2 Hz, 1H), 3.72-3.75 (m, 1H), 3.68 (s, 3H), 3.52 (s, 2H), 2.67-2.85 (m, 3H), 1.98-2.17 (m, 3H), 1.46-1.49 (m, 1H).
Example 89: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-(pyrimidin-2-ylmethyl)piperidin-4-yl)urea
Example 89: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-(pyrimidin-2-ylmethyl)piperidin-4-yl)urea
Example _ 89.1: _ entl-trans- 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyrimidin-2- ylmethyl)piperidin-4-yl)urea
Example _ 89.2: _ ent2-trans- 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyrimidin-2- ylmethyl)piperidin-4-yl)urea
Figure imgf000096_0001
Starting from 2-(bromomethyl)pyrimidine, Example 89a was synthesized in analogy to synthesis described for Example 88a. Racemic Example 89a was separated by chiral preparative HPLC to afford compound Example 89.1 (0.038 g, 6%, first eluting enantiomer: RT=4.9min) and Example 89.2 (0.037 g, 6%, second eluting enantiomer: RT=7.4min) (Chiralpak ID (4.6 x 250 mm), solvent: Hexane/EA/EtOH/ 50/25/25).
'H NMR (400 MHz, DMSO- *-100°C): d 8.74 (d, J= 4.8 Hz, 2H), 8.08 (s, 1H), 7.27-7.34 (m, 3H), 7.15-7.18 (m, 4H), 6.83 (d, J= 8.6 Hz, 2H), 5.72 (d, J= 8.2 Hz, 1H), 3.71-3.78 (m, 6H), 3.0-3.10 (m, 2H), 2.71-2.79 (m, 1H), 2.30-2.43 (m, 2H), 2.01-2.03 (m, 1H), 1.54-1.58 (m, 1H).
Example 90: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((5-methylisoxazol-3-yl)methyl)piperidin-4-yl)urea Example 90a l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((5-methylisoxazol-3-yl)methyl)piperidin-4- vDurea
Example _ 90.1: _ e¾t/-tra¾^-l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((5-methylisoxazol-3- yl)methyl)piperidin-4-yl)urea
Example _ 90.2: _ l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((5-methylisoxazol-3-
Figure imgf000096_0002
yl)methyl)piperidin-4-yl)urea
Figure imgf000096_0003
Starting from 3-(bromomethyl)-5-methylisoxazole, Example 90a was synthesized in analogy to synthesis described for Example 88a. Racemic Example 90a was separated by chiral preparative HPLC to afford compound Example 90.1 (0.13 g, 20%, first eluting enantiomer: RT=4.7min) and Example 90.2 (0.106 g, 17%, second eluting enantiomer: RT=5.3min) (Chiralpak ID (4.6 x 250 mm), solvent: Hexane/EA/EtOH 50/25/25).
Example 91: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((5-(trifluoromethyl)isoxazol-3-yl)methyl)piperidin-
4-vDurea
Example _ 91a: _ l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((5-(trifluoromethyl)isoxazol-3-
Figure imgf000097_0001
yl)methyl)piperidin-4-yl)urea
Example 91.1: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((5-(trifluororncthyl)isoxazol-3-
Figure imgf000097_0002
yl)methyl)piperidin-4-yl)urea
Example 91.2: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((5-(trifluoromethyl)isoxazol-3-
Figure imgf000097_0003
yl)methyl)piperidin-4-yl)urea
Figure imgf000097_0004
To the stirring solution of (5-trifluoromethyl-isoxazol-3-yl)-methanol (0.275 g, 1.646 mmol, 1 eq) in DCM (10 mL), DMAP (0.04 g, 0.329 mmol, 0.2 eq) and TEA (0.45 mL, 3.292 mmol, 2 eq) were added at RT and the mixture was allowed to stir for lO min. After that tosylchlorid (0.314 g, 1.646 mmol, 1 eq) was added at RT and the reaction mixture was continued stirring at the same temperature for 3 h. Then TFA salt of trans- l-(4-chlorophenyl)-3-(3- (4-methoxyphenyl)piperidin-4-yl)urea (0.709 g, 1.975 mmol, 1.2 eq) and K2CO3 (0.568 g, 4.115 mmol, 2.5 eq) were added at RT and the mixture was stirred for 16 h. After completion of reaction (monitored by TLC), reaction mixture was filtered through sintered and filtrate was evaporated under reduced pressure to get the crude product which was purified by column chromatography to afford Example 91a. Racemic Example 91a was separated by chiral preparative HPLC to afford Example 91.1 (0.075 g, 9%, first eluting enantiomer: RT=5.0min) and Example 91.2 (0.1 g, 12%, second eluting enantiomer: RT=7.0min) (Chiralpak IA (4.6 x 250 mm), solvent: Hexane/DCM/EtOH 70/15/15).
¾ NMR (400 MHz, DMSO- d6): d 8.33 (s, 1H), 7.42 (s, 1H), 7.29 (d, J = 8.9 Hz, 2H), 7.18 (t , J = 8.6 Hz, 4H), 6.83 (d , J= 8.5 Hz, 2H), 5.92 (d, J= 8.1 Hz, 1H), 3.69-3.70 (m, 6H), 2.66-2.87 (m, 3H), 2.16-2.32 (m, 2H), 1.99- 2.02 (m, 1H), 1.40-1.60 (m, 1H).
Example 92: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((3-methylisoxazol-5-yl)methyl)piperidin-4-yl)urea
Example 92a: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((3-methylisoxazol-5-yl)methyl)piperidin-4- vDurea Example _ 92.1: _ e¾t/-tra¾^-l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((3-methylisoxazol-5- yl)methyl)piperidin-4-yl)urea
Example _ 92.2: _ l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((3-methylisoxazol-5-
Figure imgf000098_0001
yl)methyl)piperidin-4-yl)urea
Figure imgf000098_0002
Starting from 5-(bromomethyl)-3-methylisoxazole, Example 92a was synthesized in analogy to synthesis described for Example 88a. Racemic Example 92a was separated by chiral preparative HPLC to afford Example 92.1 (0.095 g, 17%, first eluting enantiomer: RT=3.9min) and Example 92.2 (0.05 g, 10%, second eluting enantiomer: RT=4.4min) (Chiralpak ID (4.6 x 250 mm), solvent: Hexane/EA/EtOH/ 50/25/25).
¾ NMR (400 MHz, DMSO- d6): d 8.32 (s, 1H), 7.29 (d, J= 8.7 Hz, 2H), 7.15-7.20 (m, 4H), 6.83 (d, J= 8.4 Hz, 2H), 6.24 (s, 1H), 5.91 (d, J= 8.1 Hz, 1H), 3.64-3.73 (m, 6H), 2.66-2.88 (m, 3H), 2.19-2.30 (m, 4H), 2.11 (t , J = 11.0 Hz, 1H), 2.0 (d, J= 11.3 Hz, 1H), 1.46-1.51 (m, 1H).
Example 93: 1 -(4-chlorophenvi)-3-(3-(4-methoxyphenvi)- 1 -((5-methyl- 1.2.4-oxadiazol-3-yl)methyl)piperidin-4- vDurea
Example _ 93a: _ transA -(4-chlorophenvi)-3-(3-(4-methoxyphenvi)- 1 -((5-methyl- 1.2,4-oxadiazol-3- yl)methyl)piperidin-4-yl)urea
Example 93.1: entl-trans- 1 -(4-chlorophenyl)-3-(3-(4-methoxyphenvi)- 1 -((5-methyl- 1 ,2,4-oxadiazol-3- yl)methyl)piperidin-4-yl)urea
Example 93.2: ent2-trans- 1 -(4-chlorophenyl)-3-(3-(4-methoxyphenvi)- 1 -((5-methyl- 1 ,2,4-oxadiazol-3- yl)methyl)piperidin-4-yl)urea
Figure imgf000098_0003
Starting from 3-(chloromethyl)-5-methyl-l,2,4-oxadiazole, Example 93a was synthesized in analogy to synthesis described for Example 88a. Racemic Example 93a was separated by chiral preparative HPLC to afford compound Example 93.1 (0.085 g, 19%, first eluting enantiomer: RT=3.9min) and Example 93.2 (0.09 g, 20%, second eluting enantiomer: RT=4.4min) (Chiralpak IA (4.6 x 250 mm), solvent: Hexane/DCM/EtOH/ 50/25/25).
¾ NMR (400 MHz, DMSO- *-100°C): d 8.09 (s, 1H), 7.28 (d, J = 8.7 Hz, 2H), 7.15-7.19 (m, 4H), 6.84 (d, J = 8.3 Hz, 2H), 5.74 (d, J= 8.0 Hz, 1H), 3.67-3.78 (m, 6H), 2.74-2.96 (m, 3H), 2.55 (s, 3H), 2.27-2.40 (m, 2H), 2.03 (d , J= 11.9 Hz, 1H), 1.51-1.59 (m, 1H).
Example 94: l-(4-chlorophenvi)-3-(3-(4-methoxyphenvi)-l-((5-methylisothiazol-3-yl)methyl)piperidin-4- vDurea
Example 94a l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((5-methylisothiazol-3-yl)methyl)piperidin-
4-yl)urea
Example 94.1: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((5-methylisothiazol-3-
Figure imgf000099_0001
vDmethyl)piperidin-4-yl)urea
Example 94.2: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((5-methylisothiazol-3-
Figure imgf000099_0002
vDmethyl)piperidin-4-yl)urea
Figure imgf000099_0003
Starting from 3-(chloromethyl)-5-methyl-l,2,4-oxadiazole, Example 94a was synthesized in analogy to synthesis described for Example 88a. Racemic Example 94a was separated by chiral preparative HPLC to afford Example 94.1 (43 mg, 9%, first eluting enantiomer: RT=3.8min) and Example 94.2 (36 mg, 8%, second eluting enantiomer: RT=4.7min) (Chiralpak IA (4.6 x 250 mm), solvent: Hexane/DCM/EtOH/ 50/25/25).
¾ NMR (400 MHz, DMSO- d6): d 8.33 (s, 1H), 7.27-7.33 (m, 6H), 7.19 (d, J= 8.6 Hz, 2H), 7.06 (s, 1H), 5.99 (d, J = 8.3 Hz, 1H), 3.74-3.77 (m, 1H), 3.57 (s, 2H), 2.79-2.81 (m, 3H), 2.54 (s, 3H), 2.12-2.22 (m, 2H), 1.95-1.97 (m, 1H), 1.49-1.51 (m, 1H).
Example 95: l-(l-(2.2-difluoroethyl)-3-(4-methoxyphenyl)piperidin-4-yl)-3-(3-methylisothiazol-5-yl)urea
Example 95a l-(l-(2.2-difluoroethyl)-3-(4-methoxyphenyl)piperidin-4-yl)-3-(3-methylisothiazol-5-
Figure imgf000099_0004
vDurea
Example _ 95.1: _ entl-trans- 1 -( 1 -(2.2-difluoroethyl)-3 -(4-rnethoxyphenyl)piperidin-4-vD-3 -(3 - methylisothiazol-5-vDurea Example _ 95.2: _ ent2-trans- 1 -( 1 -(2,2-difluoroethyl)-3 -(4-methoxyphenyl)piperidin-4-yl)-3 -(3 - methylisothiazol-5-yl)urea
Figure imgf000100_0001
p . .
Stepl : To the solution of trans- tert-butyl 3-(4-methoxyphenyl)-4-(3-(3-methylisothiazol-5-yl)ureido)piperidine- 1-carboxylate (0.54 g, 1.209 mmol, 1 eq, for synthesis see Example 43) in DCM (10 mL), TFA (1 mL) was added drop wise at 0°C. The reaction mixture was allowed to stir at RT for 2 h. After completion of reaction (checked by TLC) DCM and excess TFA were removed under reduced pressure to get crude product which was washed with diethyl ether and dried under reduced pressure to get tra«s-l-(3-(4-methoxyphenyl)piperidin-4-yl)-3-(3- methylisothiazol-5-yl)urea (0.54 g) as TFA salt.
Step2: To the stirring solution of TFA salt of tra«s-l-(3-(4-methoxyphenyl)piperidin-4-yl)-3-(3-methylisothiazol- 5-yl)urea (0.4 g, 1.154 mmol, 1 eq) in acetonitrile (30 mL), K2CO3 (0.797 g, 5.77 mmol, 5 eq) was added at 0°C and the mixture was allowed to stir for 10 min, then 2,2-difluoroethyl trifluoromethanesulfonate (0.266 g, 1.3854 mmol, 1.2 eq) was added and again allowed to stir for 24 h. After completion of reaction water was added, the mixture was extracted with EtOAc (3 x 100 mL). EtOAc part was collected, dried over Na2SC>4 and the solvent was evaporated to dryness to get crude product, which was purified by column chromatography to afford Example 95. Racemic Example 95a was separated by chiral preparative HPLC to afford Example 95.1 (0.09 g, 19%, first eluting enantiomer: RT=3.4min) and Example 95.2 (0.12 g, 25%, second eluting enantiomer: RT=8.8min) (Chiralpak IA (4.6 x 250 mm), solvent: Hexane/DCM/EtOH/ 50/25/25).
'H NMR (400 MHz, DMSO- d6): d 9.87 (s, 1H), 7.16 (d, J= 8.4 Hz, 2H), 6.83 (d, J= 8.4 Hz, 2H), 6.38-6.50 (m, 2H), 5.99-6.28 (m, 1H), 3.70-3.76 (m, 1H), 3.68 (s, 3H), 2.70-2.96 (m, 5H), 2.27-2.38 (m, 2H), 2.19 (s, 3H), 1.93- 1.96 (m, 1H), 1.49-1.57 (m, 1H).
Example 96: 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -nicotinoylpiperidin-4-yl)urea
Example 96a: trans- 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -nicotinoylpiperidin-4-yl)urea
Example 96.1: e¾t/-tra¾^-l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-nicotinoylpiperidin-4-yl)urea Example 96.2: ent2-trans- 1 -(4-chlorophenyi)-3 -(3 -(4-methoxyphenyl)- 1 -nicotinoylpiperidin-4-yl)urea
Figure imgf000101_0001
To a stirred solution of nicotinoyl chloride (0.099 g, 0.556 mmol, 2 eq) in DCM (5 mL) was added DIPEA (0.25 mL, 1.39 mmol, 5.0 eq) and Example la (0.1 g, 0.278 mmol, 1 eq) at RT. The reaction mixture was stirred for 16 h at RT. After completion of the reaction (monitored by TLC, TLC system 5% MeOH-DCM, Rf-0.4) reaction mixture was evaporated to dryness to get crude product, which was purified by column chromatography to afford Example 96a. Racemic Example 96a was separated by chiral preparative HPLC to afford Example 96.1 (0.022 g, 17%, first eluting enantiomer: RT=4.9min) and Example 96.2 (0.042 g, 33%, second eluting enantiomer: RT=5.9min) (Chiralpak IG (4.6 x 250 mm), solvent: Hexane/DCM/iPr-Amine 80/20/0.1).
¾ NMR (400 MHz, DMSO- d6): d 8.63 (s, 1H), 8.19 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.45 (q, J = 4.8 Hz & 2.8 Hz, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.16-7.20 (m, 4H), 6.85 (d, J = 8.4 Hz, 2H), 5.84 (d, J = 8.0 Hz, 1H), 4.02-4.21 (m, 3H), 3.72 (s, 3H), 3.07-3.22 (m, 2H), 2.74-2.80 (m, 1H), 1.98-2.12 (m, 1H), 1.53-1.58 (m, 1H).
Example 97 : 1 -(4-chlorophenyl)-3 -( 1 -(4-fluorobenzoyl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
Example 97a: trans- 1 -(4-chlorophenyl)-3 -( 1 -(4-fluorobenzoyl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
Example 97.1: e¾t/-tra¾^-l-(4-chlorophenyl)-3-(l-(4-fluorobenzoyl)-3-(4-methoxyphenyl)piperidin-4- vDurea
Example 97.2: ent2-tmns- 1 -(4-chlorophenyl)-3 -( 1 -(4-fluorobenzoyl)-3 -(4-methoxyphenyl)piperidin-4- vDurea
Figure imgf000101_0002
To a stirred solution of 4-fluoro-benzoic acid (0.281 g, 2.00 mmol, 1.2 eq) in DMF (10 mL) was added HATU (1.27 g, 3.334 mmol, 2.0 eq), DIPEA (1.5 mL, 8.335 mmol, 5.0 eq) and the mixture was stirred at RT for 10 min followed by addition of a solution of Example la (0.6 g, 1.667 mmol, 1.0 eq). The reaction mixture was stirred for 16 h at RT. After completion of the reaction (monitored by TLC, TLC system 5% MeOH-DCM, Rf-0.4) reaction mixture was poured into cold water and extracted with EtOAc (2 x 100 mL). The organic layer was washed with water (2 x 50 mL) and brine (2 x 50 mL), dried over Na2SC>4 and evaporated to dryness to get crude product, which was purified by column chromatography to afford Example 97a. Racemic Example 97a was separated by chiral preparative to afford Example 97.1 (0.035 g, 4%, first eluting enantiomer: RT=5.3min) and Example 97.2 (0.035 g, 4%, second eluting enantiomer: RT=6.4min) HPLC (Chiralpak IC (4.6 x 250 mm), solvent: Hexane/DCM/EtOH 70/15/15).
¾ NMR (400 MHz, DMSO- d6): d 8.16 (s, 1H), 7.49 (q, J = 5.2 Hz & 2.8 Hz, 1H), 7.16-7.30 (m, 8H), 6.85 (d, J = 8.8 Hz, 2H), 5.81 (d, J = 7.6 Hz, 1H), 4.01-4.09 (m, 3H), 3.72 (s, 3H), 3.02-3.15 (m, 2H), 2.73 (t, J = 6.0 Hz, 1H), 2.08 (d, J = 12.8 Hz, 1H), 1.50-1.53 (m, 1H).
Example 98: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-(5-methylisoxazole-3-carbonyl)piperidin-4-yl)urea Example 98a: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-(5-methylisoxazole-3-carbonyl)piperidin-4- vDurea
Example _ 98.1: _ e¾t/-tra¾^-l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-(5-methylisoxazole-3- carbonyl)piperidin-4-yl)urea
Example _ 98.2: _ ent2-trans- 1 -(4-chlorophenyl)-3-(3-(4-methoxyphenyl)- 1 -(5-methylisoxazole-3- carbonyl)piperidin-4-yl)urea
Figure imgf000102_0001
Starting from 5-methylisoxazole-3-carboxylic acid and Example la, Example 98a was synthesized in analogy to synthesis described for Example 97. Racemic Example 98a was separated by chiral HPLC to afford Example 98.1 (0.08 g, 15%, first eluting enantiomer: RT=6.5min) and Example 98.2 (0.085 g, 16%, second eluting enantiomer: RT=7.9min) (Chiralpak IC (4.6 x 250 mm), solvent: Hexane/DCM/EtOH 70/15/15).
¾ NMR (400 MHz, DMSO- d6): d 8.12 (s, 1H), 7.16-30 (m, 6H), 6.87 (d, J = 7.6 Hz, 2H), 6.39 (s, 1H), 5.84 (d, J = 8.0 Hz, 1H), 4.45-4.55 (bs, 1H), 4.06-4.09 (bs, 2H), 3.73 (s, 3H), 3.23 (bs, 2H), 2.74 (t, J = 8.0 Hz, 1H), 2.45 (s, 3H), 2.12 (bs, 1H), 1.50-1.56 (m, 1H). Example 99: l-(4-chlorophenyl)-3-(l-(5-chlorothiophene-2-carbonyl)-3-(4-methoxyphenyl)piperidin-4-yl)urea Example 99a: l-(4-chlorophenyl)-3-(l-(5-chlorothiophene-2-carbonyl)-3-(4-methoxyphenyl)piperidin-4- vDurea
Example _ 99.1: _ entl-trans- 1 -(4-chlorophenyi)-3 -( 1 -(5-chlorothiophene-2-carbonyi)-3 -(4- methoxyphenyl)piperidin-4-yl)urea
Example _ 99.2: _ (4-chlorophenvi)-3-(l-(5-chlorothiophene-2-carbonvi)-3-(4-
Figure imgf000103_0001
methoxyphenyl)piperidin-4-yl)urea
Figure imgf000103_0002
Starting from 5-chlorothiophene-2-carboxylic acid and Example la, Example 99a was synthesized in analogy to synthesis described for Example 97a. Racemic Example 99a was separated by chiral HPLC to afford Example 98.1 (0.09 g, 16%, first eluting enantiomer: RT=5.7min) and Example 98.2 (0.08 g, 14%, second eluting enantiomer: RT=7.0min) (Chiralpak IC (4.6 x 250 mm), solvent: Hexane/DCM/EtOH 70/15/15).
Example 100: l-(4-chlorophenyl)-3-(3-(4-methoxyphenvi)-l-((4-methylpyrimidin-2-yl)methyl)piperidin-4- vDurea
Example 100a: (4-chlorophenvi)-3-(3-(4-methoxyphenyl)-l-((4-methylpyrimidin-2-yl)methyl)piperidin-
4-vDurea
Example 100.1: (4-chlorophenvi)-3-(3-(4-methoxyphenvi)-l-((4-methylpyrimidin-2-
Figure imgf000103_0003
yl)methyl)piperidin-4-yl)urea
Example 100.2: (4-chlorophenvi)-3-(3-(4-methoxyphenvi)-l-((4-methylpyrimidin-2-
Figure imgf000103_0004
yl)methyl)piperidin-4-yl)urea
Figure imgf000104_0001
Starting from (4-methylpyrimidin-2-yl)methanol and Example la, Example 100a was synthesized in analogy to synthesis described for Example 91a. Racemic Example 100a was separated by chiral HPLC to afford Example 100.1 (0.045 g, 6%, first eluting enantiomer: RT=4.4min) and Example 100.2 (0.042 g, 6%, second eluting enantiomer: RT=12.7min) (Chiralpak IG (4.6 x 250 mm), solvent: Hexane/EA/EtOH/iPr-Amine 50/25/25/0.1).
¾ NMR (400 MHz, DMSO- d6): d 8.59 (d, J = 5.2 Hz, 1H), 8.34 (s, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 4.8 Hz, 1H), 7.14-7.20 (m, 4H), 6.82 (d, J = 8.4 Hz, 2H), 5.92 (d, J = 7.2 Hz, 1H), 3.65-3.73 (m, 6H), 2.84-2.94 (m, 2H), 2.68-2.73 (m, 1H), 2.43 (s, 3H), 2.17-2.32 (m, 2H), 1.97 (d, J = 10.8 Hz, 1H), 1.45-1.51 (m, 1H).
Example _ 101: _ l-(3-(4-methoxyphenyl)-l-((4-methylpyrimidin-2-yl)methyl)piperidin-4-yl)-3-(3- methylisothiazol-5-yl)urea
Example 101a: l-(3-(4-methoxyphenyl)-l-((4-methylpyrimidin-2-yl)methyl)piperidin-4-yl)-3-(3-
Figure imgf000104_0002
methylisothiazol-5-yl)urea
Example 101.1: e¾t7-tra¾,y-l-(3-(4-methoxyphenyl)-l-((4-methylpyrimidin-2-yl)methyl)piperidin-4-yl)-
3-(3-methylisothiazol-5-yl)urea
Example 101.2: ent2-trans- 1 -(3-(4-methoxyphenyl)- 1 -((4-methylpyrimidin-2-yl)methyl)piperidin-4-yl)-
3-(3-methylisothiazol-5-yl)urea
Figure imgf000104_0003
Starting from (4-methylpyrimidin-2-yl)methanol and trans-l-(3-(4-methoxyphenyl)piperidin-4-yl)-3-(3- methylisothiazol-5-yl)urea (for synthesis see Example 95a), Example 101a was synthesized in analogy to synthesis described for Example 91a. Racemic Example 101a was separated by chiral HPLC to afford Example 101.1 (0.035 g, 5%, first eluting enantiomer: RT=4.5min) and Example 101.2 (0.04 g, 5%, second eluting enantiomer: RT=6.6min) (Chiralpak IG (4.6 x 250 mm), solvent: Hexane/EA/EtOH/iPr-Amine 50/25/25/0.1).
¾ NMR (400 MHz, DMSO- d6): d 9.91 (s, 1H), 8.58 (d, J = 4.8 Hz, 1H), 7.25 (d, J = 5.2 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 2H), 6.46 (bs, 1H), 6.37 (s, 1H), 3.66-3.68 (m, 6H), 2.93 (d, J = 10.8 Hz, 1H), 2.85 (d, J = 11.2 Hz, 1H), 2.78 (t, J = 10.8 Hz, 1H), 2.43 (s, 3H), 2.23-2.32 (m, 1H), 2.18 (s, 4H), 1.94 (d, J = 10.8 Hz, 1H), 1.53 (d, J = 8.4 Hz, 1H).
Example 102: l-(4-chlorophenyl)-3-(3-(4-methoxyphenvi)-l-((5-methylpyrimidin-2-yl)methyl)piperidin-4- vDurea
Example 102a: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((5-methylpyrimidin-2-yl)methyl)piperidin-
4-vDurea
Example 102.1: l-(4-chlorophenvi)-3-(3-(4-methoxyphenvi)-l-((5-methylpyrimidin-2-
Figure imgf000105_0001
yl)methyl)piperidin-4-yl)urea
Example 102.2: l-(4-chlorophenyl)-3-(3-(4-methoxyphenvi)-l-((5-methylpyrimidin-2-
Figure imgf000105_0002
yl)methyl)piperidin-4-yl)urea
Figure imgf000105_0003
Starting from (5-methylpyrimidin-2-yl)methanol and Example la, Example 102a was synthesized in analogy to synthesis described for Example 103. Racemic Example 102a was separated by chiral HPLC to afford Example 102.1 (0.055 g, 9%, first eluting enantiomer: RT=7.1min) and Example 102.2 (0.071 g, 11%, second eluting enantiomer: RT=1 lmin) (Chiralpak IG (4.6 x 250 mm), solvent: iPrOH/iPr-Amine 100/0.1).
¾ NMR (400 MHz, DMSO- d6): d 8.59 (s, 2H), 8.31 (s, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.13-7.19 (m, 1H), 6.82 (d, J = 8.4 Hz, 2H), 5.90 (d, J = 8.0 Hz, 1H), 3.67-3.74 (m, 6H), 2.83-2.93 (m, 2H), 2.66-2.72 (m, 1H), 2.27-2.30 (m, 1H), 2.24 (s, 3H), 2.15-2.20 (m, 1H), 1.97 (d, J = 10.0 Hz, 1H), 1.42-1.50 (m, 1H).
Example 103: l-(4-chlorophenyl)-3-(3-(4-methoxyphenvi)-l-((4-methoxypyrimidin-2-yl)methyl)piperidin-4- vDurea
Example _ 103a: _ trans- 1 -(4-chlorophenyi)-3 -(3 -(4-methoxyphenyl)- 1 -((4-methoxypyrimidin-2- yl)methyl)piperidin-4-yl)urea Example 103.1: e¾t7-tra¾,y-l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((4-methoxypyrimidin-2- yl)methyl)piperidin-4-yl)urea
Example 103.2: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((4-methoxypyrimidin-2-
Figure imgf000106_0001
yl)methyl)piperidin-4-yl)urea
Figure imgf000106_0002
To a stirred solution of (4-methoxypyrimidin-2-yl)methanol (0.4 g, 2.842 mmol, 1 eq) in DCM (10 mL) was added Et3N (1.2 mL, 8.526 mmol, 3 eq), >-toluenesulfonyl chloride (0.652 g, 3.421 mmol, 1 eq) and DMAP (catalytic amount) and the mixture was stirred at RT. After completion of the reaction (monitored by TLC, TLC system 5% MeOH-DCM, Rf-0.7), Example la (0.716 g, 1.989 mmol, 0.7 eq), K2C03 (0.784 g, 5.684 mmol, 2 eq) and Nal (catalytic amount) was added and the mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC, TLC system 5% MeOH-DCM, Rf-0.4) it was diluted with water (25 mL) and extracted with 10%MeOH-DCM (2 x 25 mL), dried over anhyd. Na2SC>4, concentrated in vacuo, purified by column chromatography (230-400 mesh silica gel; 2% MeOH-DCM) to afford Example 103a. Racemic Example 103a was separated by chiral HPLC to afford Example 103.1 (0.088 g, 9.2%, first eluting enantiomer: RT=4.5min) and Example 103.2 (0.068 g, 7%, second eluting enantiomer: RT=11.5min) (Chiralpak IG (4.6 x 250 mm), solvent: Hexane/DCM/EtOH 60/20/20).
JH NMR (400 MHz, DMSO- d6): d 8.44 (d, J = 5.6 Hz, 1H), 8.35 (s, 1H), 7.30 (d, J = 8.8 Hz, 2H), 7.16-7.20 (m, 4H), 6.79-6.83 (m, 3H), 5.95 (d, J = 8.0 Hz, 1H), 3.90 (s, 1H), 3.65-3.74 (m, 6H), 2.90-2.97 (m, 2H), 2.67-2.75 (m, 1H), 2.23-2.37 (m, 2H), 1.97 (d, J = 10.0 Hz, 1H), 1.45-1.53 (m, 1H).
Example _ 104: _ l-(-3-(4-methoxyphenyl)-l-((5-methoxypyrimidin-2-yl)methyl)piperidin-4-yl)-3-(3- methylisothiazol-5-yl)urea
Example 104a: l-(-3-(4-methoxyphenyl)-l-((5-methoxypyrimidin-2-yl)methyl)piperidin-4-yl)-3-(3-
Figure imgf000106_0003
methylisothiazol-5-yl)urea
Example 104.1: e¾t7-tra¾,y-l-(-3-(4-methoxyphenyl)-l-((5-methoxypyrimidin-2-yl)methyl)piperidin-4- yl)-3-(3-methylisothiazol-5-yl)urea
Example 104.2: ent2-trans- 1 -(-3-(4-methoxyphenyl)- 1 -((5-methoxypyrimidin-2-yl)methyl)piperidin-4- vD-3-(3-methylisothiazol-5-vDurea
Figure imgf000107_0001
Starting from (5-methoxypyrimidin-2-yl)methanol and fraw,s-l-(3-(4-methoxyphenyl)piperidin-4-yl)-3-(3- methylisothiazol-5-yl)urea (for synthesis see Example 95a), Example 104a was synthesized in analogy to synthesis described for Example 103a. Racemic Example 104a was separated by chiral HPLC to afford Example 104.1 (0.076 g, 8%, first eluting enantiomer: RT=2.0min) and Example 104.2 (0.068 g, 7%, second eluting enantiomer: RT=5.1min) (Chiralpak IG (4.6 x 250 mm), solvent: ACN/MeOH/iPr-Amine 50/50/0.1).
¾ NMR (400 MHz, DMSO- d6): d 9.85 (s, 1H), 8.45 (d, J = 5.6 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 6.82 (d, J = 7.6 Hz, 2H), 6.38-6.45 (m, 2H), 3.90 (s, 3H), 3.68 (s, 6H), 2.90-2.96 (m, 2H), 2.81 (m, 1H), 2.27-2.35 (m, 2H), 2.19 (s, 3H), 1.96 (d, J = 9.6 Hz, 1H), 1.54-1.57 (m, 1H).
Example 105: l-(4-fluorophenvi)-3-(5-(4-methoxyphenvi)-2-oxo-l-(pyridin-2-ylmethyl)piperidin-4-yl)urea
Example 105a: cA-l-(4-fluorophenvi)-3-(5-(4-mcthoxyphenvi)-2-oxo-l-(pyridin-2-ylmethyl)piperidin-4-yl)urea
Figure imgf000107_0002
Stepl : To a stirred solution of cA-tert-butyl (5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate (0.15 g, 0.47 mmol, 1 eq, for synthesis see Example 48) in DMF (8 mL), NaH (0.028 g, 0.7 mmol, 1.5 eq) was added at RT. The reaction mixture was stirred at RT for 30 min. To the solution of 2-bromomethyl-pyridine hydrobromide salt (0.155 g, 0.611 mmol, 1.3 eq) in DMF (2 mL), TEA (1 mL) was added to make the salt free. This solution was then added to the previous solution of cA-tert-butyl (5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)carbamate drop wise at 0°C. The reaction mixture was then continued stirring at RT for 16 h. After completion of the reaction (monitored by TLC), reaction mixture was quenched with ice and extracted with EA. The organic layer was washed with water, brine, dried over Na2SC>4, filtered and the solvent was evaporated under reduced pressure to get the crude product which was purified by column chromatography to afford desired cA-tert-butyl (5-(4- methoxyphenyl)-2-oxo-l-(pyridin-2-ylmethyl)piperidin-4-yl)carbamate (0.04 g, 21%) as brown solid.
Step2: To a stirred solution of cA-tert-butyl (5-(4-methoxyphenyl)-2-oxo-l-(pyridin-2-ylmethyl)piperidin-4- yl)carbamate (0.03 g, 0.073 mmol, 1 eq) in DCM (3 mL), TFA (2 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 (0.021 g, 67.7%) which was azeotrope with toluene and used for the next step without further purification.
Step3: To the solution of TFA salt of cA-4-amino-5-(4-methoxyphenyl)-l-(pyridin-2-ylmethyl)piperidin-2-one (0.03 g, 0.0705 mmol, 1 eq) in DCM (5 mL), TEA (0.03 mL, 0.219 mmol, 2.97 eq) and l-fluoro-4-isocyanato- benzene (0.01 mL, 0.11 mmol, 1.49 eq) dissolved in DCM (1 mL) was added at RT and the reaction mixture was stirred at RT for 16 h. After completion of reaction (monitored by TLC), reaction mixture was evaporated under reduced pressure to get the product which was initially purified by column chromatography to afford Example 105a (0.02 g, 63%) as white solid.
¾ NMR (400 MHz, DMSO- d6): d 8.54 (d, J= 4.4 Hz, 1H), 8.42 (s, 1H), 7.78 (t, J = 6.9 Hz, 1H), 7.27-7.36 (m, 4H), 7.19 (d, J= 8.5 Hz, 2H), 7.04 (t , J= 8.9 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.25 (d, J= 7.9 Hz, 1H), 4.85 (d, J= 15.6 Hz, 1H), 4.52 (d, J= 15.5 Hz, 1H), 4.25-4.30 (m, 1H), 3.70 (s, 3H), 3.67-3.68 (m, 1H), 3.45-3.50 (m, 1H), 3.05-3.10 (m, 1H), 2.66-2.75 (m, 1H), 2.26-2.32 (m, 1H).
Example 105b: l-(4-fluorophenyl)-3-(5-(4-methoxyphenyl)-2-oxo-l-(pyridin-3-ylmethyl)piperidin-4-
Figure imgf000108_0001
vDurea
Figure imgf000108_0002
Starting from 3-(bromomethyl)pyridine hydrobromide salt and trans- tert-butyl (5-(4-methoxyphenyl)-2- oxopiperidin-4-yl)carbamate (for synthesis see Example 48), Example 105b was synthesized in analogy to synthesis described for Example 105a.
¾ NMR (400 MHz, DMSO- d6): d 8.47-8.50 (m, 2H), 8.33 (s, 1H), 7.69 (d, J= 7.8 Hz, 1H), 7.35-7.38 (m, 1H), 7.26-7.29 (m, 2H), 7.19 (d, J= 8.5 Hz, 2H), 7.0 (t, J= 8.8 Hz, 2H), 6.85 (d, J= 8.5 Hz, 2H), 5.98 (d, J= 8.0 Hz, 1H), 4.50-4.55 (m, 2H), 4.25-4.30 (m, 1H), 3.69 (m, 3H), 3.14-3.17 (m, 1H), 2.76 (dd, J= 5.4, 17.0 Hz, 1H), 2.40- 2.44 (m, 1H).
Example 107: l-(4-fluorophenyl)-3-(5-(4-methoxyphenyl)-2-oxo-l-(pyridin-2-ylmethyl)piperidin-4-yl)urea
Example 107a: trans- 1 -(4-fluorophenyl)-3-(5-(4-methoxyphenyl)-2-oxo- 1 -(pyridin-2-vhnethyl)piperidin-4- yl)urea
Figure imgf000109_0001
(trans-isomer)
Figure imgf000109_0002
Starting from 2-(bromomethyl)pyridine hydrobromide salt and trans- tert-butyl (5-(4-methoxyphenyl)-2- oxopiperidin-4-yl)carbamate (for synthesis see Example 48), Example 107a was synthesized in analogy to synthesis described for Example 105.
¾ NMR (400 MHz, DMSO- d6): d 8.52 (d, J= 3.9 Hz, 1H), 8.35 (s, 1H), 7.77 (t, J= 7.6 Hz, 1H), 7.27-7.31 (m, 4H), 7.21 (d, / = 8.4 Hz, 2H), 7.01 (t, /= 8.8 Hz, 2H), 6.85 (d, J= 8.5 Hz, 2H), 6.02 (d, J= 7.8 Hz, 1H), 4.60 (q, J= 14.5 Hz, 2H), 4.27-4.29 (m, 1H), 3.69 (s, 3H), 3.35-3.45 (m, 2H), 3.19-3.23 (m, 1H), 2.71-2.77 (m, 1H), 2.41- 2.45 (m, 1H).
Example 108: l-(4-fluorophenyl)-3-(5-(4-methoxyphenyl)-2-oxo-l-(pyridin-4-ylmethyl)piperidin-4-yl)urea
Example 108a: trans- 1 -(4-fluorophenyl)-3-(5-(4-methoxyphenyl)-2-oxo- 1 -(pyridin-4-vhnethyl)piperidin-4- vDurea
Figure imgf000110_0001
Figure imgf000110_0003
Starting from 4-(chloromethyl)pyridine hydrochloride salt and trans- tert-butyl (5-(4-methoxyphenyl)-2- oxopiperidin-4-yl)carbamate (for synthesis see Example 48), Example 108a was synthesized in analogy to synthesis described for Example 105.
'H NMR (400 MHz, DMSO- d6): d 8.52 (d, J= 5.8 Hz, 2H), 8.34 (s, 1H), 7.26-7.30 (m, 4H), 7.21 (d, J= 8.5 Hz, 2H), 7.01 (t , J= 8.8 Hz, 2H), 6.85 (d, J= 8.6 Hz, 2H), 5.99 (d, J= 8.0 Hz, 1H), 4.54 (q, J= 16.08 Hz, 2H), 4.30- 4.32 (m, 1H), 3.69 (s, 3H), 3.36-3.38 (m, 1H), 3.19-3.28 (m, 2H), 2.79 (dd, J = 5.5, 17.1 Hz, 1H), 2.44-2.46 (m, 1H).
Example 109: l-(3-(4-methoxyphenyl)-l-(pyridin-4-yl)piperidin-4-yl)-3-(3-methylisothiazol-5-yl)urea
Example 109a l-(3-(4-methoxyphenyl)-l-(pyridin-4-yl)piperidin-4-yl)-3-(3-methylisothiazol-5-yl)urea
Example _ 109.1; _ entl-tmns- 1 -(3 -(4-methoxyphenyl)- 1 -(pyridin-4-yl)piperidin-4-yl)-3 -(3 - methylisothiazol-5-yl)urea
Example _ 109.2; _ l-(3-(4-methoxyphenyl)-l-(pyridin-4-yl)piperidin-4-yl)-3-(3-
Figure imgf000110_0002
methylisothiazol-5-yl)urea
Figure imgf000111_0001
Example 109a Example 109.1 Example 109.2
Step-1 : To a stirred solution of ira«s-3-(4-methoxy-phenyl)-4-[3-(3-methyl-isothiazol-5-yl)-ureido]-piperidine-l- carboxylic acid tert-butyl ester (2.7 g, 6.05 mmol, 1 eq, for synthesis see Example 95) in 1, 4-dioxane (10.0 mL) was added 4M HCI in dioxane (10.0 mL) followed by stirring at RT for a period of 4 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 of ira«s-l-[3-(4-methoxy-phenyl)-piperidin-4-yl]-3-(3-methyl-isothiazol-5-yl)-urea (2 g, 86% crude yield) as off white solid.
Step2: To a stirred solution of HCI salt of ira«s-l-[3-(4-methoxy-phenyl)-piperidin-4-yl]-3-(3-methyl-isothiazol- 5-yl)-urea (500 mg, 1.31 mmol, 1 eq) and 4-bromo-pyridine (305 mg, 1.56 mmol, 1.2 eq) in toluene (25 mL) at RT was added t-BuONa (502 mg, 5.22 mmol, 4 eq), Pd (dba (60 mg, 0.065 mmol, 0.05 eq) and BINAP (122 mg, 0.20 mmol, 0.15 eq) and the reaction mixture was stirred under reflux for a period of 16 h under inert atmosphere. The reaction mixture was diluted with 10% MeOH in DCM and washed with water and brine. The combined organic layer was dried over anhyd. Na2SC>4 and concentrated under reduced pressure. The obtained crude product was purified by silica gel (100-200 mesh) column chromatography, 3% MeOH in DCM was the eluent to obtain the desired trans-l-[3-(4-methoxy-phenyl)-3,4,5,6-tetrahydro-2H-[l,4']bipyridinyl-4-yl]-3-(3-methyl-isothiazol- 5-yl)-urea (135 mg, 20%) as off white solid. 135 mg of racemic Example 109a was separated by preparative chiral HPLC to afford both the enantiomers as Example 109.1 (35 mg, first eluting enantiomer: RT=l l .lmin) and Example 109.2 (20 mg, second eluting enantiomer: RT=11.8min) (Chiralpak IC (4.6 x 250 mm), solvent: MeOH/iPr-Amine 100/0.1).
¾ NMR (400 MHz, DMSO-<¾) d 9.90 (s, 1 H), 8.14 (d, J = 6 Hz, 2 H), 7.24 (d, J = 8 Hz, 2 H), 6.88-6.83 (m, 4 H), 6.52-6.42 (m, 1 H), 6.38 (s, 1 H), 4.08-4.02 (m, 2 H), 3.86 (d, J= 12 Hz, 1 H), 3.71 (s, 3 H), 3.17-3.00 (m, 2 H), 2.78-2.72 (m, 1 H), 2.19 (s, 3 H), 2.00 (d, J= 8 Hz, 1 H), 1.52-1.48 (m, 1 H).
Example 110: l-(3-(4-methoxyphenvi)-l-(pyridazin-4-yl)piperidin-4-yl)-3-(3-methylisothiazol-5-yl)urea
Example 110a: l-(3-(4-methoxyphenvi)-l-(pyridazin-4-yl)piperidin-4-yl)-3-(3-methylisothiazol-5-yl)urea Example _ 110.1: entl -trans- 1 -(3 -(4-methoxyphenvD- 1 -(pyridazin-4-yl)piperidin-4-yl)-3 -(3 - methylisothiazol-5-yl)urea
Example _ 110.2: _ l-(3-(4-methoxyphenvi)-l-(pyridazin-4-yl)piperidin-4-yl)-3-(3-
Figure imgf000112_0001
methylisothiazol-5-yl)urea
Figure imgf000112_0002
Example 110a Example 110.1 Example 110.2
Starting from 4-bromopyridazine (HCI salt) and HCI salt of ira«s-l-[3-(4-methoxy-phenyl)-piperidin-4-yl]-3-(3- methyl-isothiazol-5-yl)-urea Example 110a was synthesized in analogy to synthesis described for Example 109. Racemic Example 110a was separated by preparative chiral HPLC to afford both the enantiomers as Example 110.1 (20 mg, first eluting enantiomer: RT=16.1min) and Example 110.2 (10 mg, second eluting enantiomer: RT=17.1min) (Chiralpak IB (4.6 x 250 mm), solvent: MeOH/iPr-Amine 100/0.1).
¾ NMR (400 MHz, DMSO-c¾) d 9.93 (s, 1 H), 8.99 (d, J= 3 Hz, 1 H), 8.61 (d, J= 6 Hz, 1 H), 7.25 (d, J= 8 Hz, 2 H), 7.00-6.98 (m, 1 H), 6.87 (d, J= 9 Hz, 2 H), 6.45 (d, J= 1 Hz, 1 H), 6.38 (s, 1 H), 4.17-4.06 (m, 2 H), 3.98 (d, J= 12 Hz, 1 H), 3.71 (s, 3 H), 3.19-3.07 (m, 2 H), 2.80-2.75 (m, 1 H), 2.19 (s, 3 H), 2.03 (d , J= 10 Hz, 1 H), 1.54-1.50 (m, 1 H).
Example 111: 1 -(3 -(4-methoxyphenvD- 1 -(2-methylpyridin-4-yl)piperidin-4-yl)-3 -(3 -methylisothiazol-5-yl)urea
Example 111a: trans- 1 -(3 -(4-methoxyphenvi)- 1 -(2-methylpyridin-4-yl)piperidin-4-yl)-3 -(3 -methylisothiazol-5- vDurea
Example 111.1: entl -trans- 1 -(3 -(4-methoxyphenvi)- 1 -(2-methylpyridin-4-yl)piperidin-4-yl)-3 -(3 - methylisothiazol-5-yl)urea
Example 111.2: l-(3-(4-methoxyphenyl)-l-(2-methylpyridin-4-yl)piperidin-4-yl)-3-(3-
Figure imgf000112_0003
methylisothiazol-5-yl)urea
Figure imgf000113_0001
Example 111a Example 111.1 Example 111.2
Starting from 4-bromo-2-methylpyridine and HC1 salt of ira«s-l-[3-(4-methoxy-phenyl)-piperidin-4-yl]-3-(3- methyl-isothiazol-5-yl)-urea Example 111a was synthesized in analogy to synthesis described for Example 109a. Racemic Example 111a was separated by preparative chiral HPLC to afford both the enantiomers as Example 111.1 (35 mg, first eluting enantiomer: RT=5.5min) and Example 111.2 (25 mg, second eluting enantiomer: RT=5.8min) (Chiralpak IB (4.6 x 250 mm), solvent: MeOH/iPr-Amine 100/0.1).
¾ NMR (400 MHz, DMSO-c ff) d 10.05 (s, 1 H), 8.02 (d, J= 6 Hz, 1 H), 7.23 (d, J= 8 Hz, 2 H), 6.86 (d, J= 8 Hz, 2 H), 6.72 (s, 1 H), 6.67-6.65 (m, 1 H), 6.62-6.59 (m, 1 H), 6.38 (s, 1 H), 4.02-3.99 (m, 2 H), 3.84 (d, J= 14 Hz, 1 H), 3.71 (s, 3 H), 3.08-2.92 (m, 2 H), 2.79-2.71 (m, 1 H), 2.31 (s, 3 H), 2.19 (s, 3 H), 2.00 (d, J= 11 Hz, 1 H), 1.85 (s, 1 H).
Example 112: l-(l-(4-fluorophenvi)-3-(4-methoxyphenvi)piperidin-4-yl)-3-(3-methylisothiazol-5-yl)urea
Example 112a: trans- 1 -(1 -(4-fluorophenyi)-3 -(4-methoxyphenyl)piperidin-4-yl)-3 -(3 -methylisothiazol-5-yl)urea
Example _ 112.1: _ entl -trans- 1 -(1 -(4-fluorophenyi)-3 -(4-methoxyphenyl)piperidin-4-yl)-3 -(3 - methylisothiazol-5-yl)urea
Example _ 112.2: _ ent2 -trans- 1 -(1 -(4-fluorophenyi)-3 -(4-methoxyphenyl)piperidin-4-yl)-3 -(3 - methylisothiazol-5-yl)urea
Figure imgf000114_0001
Example 112a Example 112.1 Example 112.2
To a stirred suspension of ira«s-l-[3-(4-methoxy-phenyl)-piperidin-4-yl]-3-(3-methyl-isothiazol-5-yl)-urea (500 mg, 1.30 mmol, 1 eq), 4-fluoro phenyl boronic acid (550 mg, 3.92 mmol, 3 eq) was added molecular sieves (4A, 150 mg), TEA (0.92 mL, 6.53 mmol, 5 eq) in DCM (30 mL) and the mixture was stirred at RT under oxygen for a period of 24 h. After completion of the reaction, it was filtered through celite bed and washed thoroughly with 5% MeOH-DCM, the organic layer was rota evaporated to get the crude product which was purified by silica gel (100-200 mesh) column chromatography using 3% MeOH in DCM as the eluent to obtain Example 112 (180 mg, 31%) as off white solid. Racemic mixture Example 112 was separated by preparative chiral HPLC to afford both the enantiomers as Example 112.1 (47 mg, first eluting enantiomer: RT=4.1min) and Example 112.2 (45 mg, second eluting enantiomer: RT=4.8min) (Chiralpak IC (4.6 x 250 mm), solvent: Hexane/DCM/EtOH 50/25/25).
¾ NMR (400 MHz, DMSO-<¾) d 9.88 (s, 1 H), 7.23 (d, J= 9 Hz, 2 H), 7.04-6.94 (m, 4 H), 6.85 (d, J= 9 Hz, 2 H), 6.51-6.48 (m, 1 H), 6.39 (s, 1 H), 3.94-3.71 (m, 1 H), 3.70 (s, 1 H), 3.69 (s, 3 H), 3.57 (d, J = 11 Hz, 1 H), 2.92-2.77 (m, 3 H), 2.19 (s, 3 H), 2.03 (d, J= 9 Hz, 1 H), 1.65-1.62 (m, 1 H).
Example 113: l-(l-((5-chlorothiophen-2-yl)methyl)-3-(4-methoxyphenvi)piperidin-4-yl)-3-(3-methylisothiazol-
5 -vDurea
Example _ 113a: l-(l-((5-chlorothiophen-2-yl)methyl)-3-(4-methoxyphenyl)piperidin-4-yl)-3-(3-
Figure imgf000114_0002
methylisothiazol-5-yl)urea
Example 113.1: l-(l-((5-chlorothiophen-2-yl)methyl)-3-(4-methoxyphenyl)piperidin-4-yl)-3-
Figure imgf000114_0003
( 3 -methylisothiazol-5 -vDurea
Example 113.2: e¾t2-tra¾,y-l-(l-((5-chlorothiophen-2-vDmethvD-3-(4-methoxyphenvDpiperidin-4-vD-3-
( 3 -methylisothiazol-5 -vDurea
Figure imgf000115_0001
To a stirred solution of HCI salt of ira«.s-l-[3-(4-methoxy-phenyl)-piperidin-4-yl]-3-(3-methyl-isothiazol-5-yl)- urea (300 mg , 0.78 mmol, 1 eq, for synthesis see Example 43) and 2-chloro-5-chloromethyl-thiophene (131 mg, 0.78 mmol, 1.0 eq) in acetonitrile (20 mL) was added CS2CO3 (765 mg, 2.35 mmol, 3.0 eq) and the reaction mixture was allowed to stir at 70°C for 18 h. After completion of the reaction, acetonitrile was evaporated, mixture was diluted with water and the organics were extracted with 10% MeOH/ DCM. The organic layer was dried over anhyd. Na SC> , filtered and rota evaporated to get the crude material which was purified by column chromatography to obtain Example 113a (185 mg, 50%) as off white solid. The enantiomers were separated by prep chiral SFC to obtain the enantiomers as Example 113.1 (59 mg, first eluting enantiomer: RT=4.6min) and Example 113.2 (69 mg second eluting enantiomer: RT=5.6min) (chiral SFC column (R,R)-WHELK-01).
1H NMR (400 MHz, DMSO-d6) d 9.88 (s, 1 H), 7.15 (d, J = 8 Hz, 2 H), 6.92 (s, 1 H), (, H), 6.81 (d, J = 8 Hz, 3 H), 6.38 (s, 2 H), 3.74 (s, 1 H), 3.72 (s, 3 H), 3.68 (s, 2 H), 2.91 (d, J = 12 Hz, 1 H), 2.84-2.78 (m, 2 H), 2.19 (s,
3 H), 2.12-1.99 (m, 1 H), 1.97 (d, J = 11 Hz, 1 H), 1.55-1.52 (m, 1 H).
Example 114: 1 -(3 -(4-methoxyphenvi)- 1 -(pyridin-3 -ylmethyl)piperidin-4-yl)-3 -(3 -methylisothiazol-5-yl)urea
Example 114a: trans- 1 -(3 -(4-methoxyphenvi)- 1 -(pyridin-3 -vhnethyl)piperidin-4-yl)-3 -(3 -methylisothiazol-5- vDurea
Example 114.1: _ entl -trans- 1 -(3 -(4-methoxyphenvi)- 1 -(pyridin-3 -vhnethyl)piperidin-4-yl)-3 -(3 - methylisothiazol-5-yl)urea
Example 114.2: _ ent2-trans- 1 -(3 -(4-methoxyphenvi)- 1 -(pyridin-3 -vhnethyl)piperidin-4-yl)-3 -(3 - methylisothiazol-5-yl)urea
Figure imgf000116_0001
Example 114a Example 114.1 Example 114.2
To a stirred solution of HCI salt of ira«.s-l-[3-(4-methoxy-phenyl)-piperidin-4-yl]-3-(3-methyl-isothiazol-5-yl)- urea (300 mg , 0.78 mmol, 1 eq, for synthesis see Example 43) in DCE (20 mL) was added TEA (1.1 mL, 7.84 mmol, 10.0 eq) and the reaction mixture was allowed to stir at 0°C for 5 to 10 min followed by the addition of pyridine-3 -carbaldehyde (168 mg , 1.56 mmol , 2.0 eq) and stirred at 0°C for another 30 min. After that, sodium triacetoxy borohydride (665 mg, 3.13 mmol, 4.0 eq) was added to this mixture and continued stirring at RT for 16 h. After completion of the reaction, the reaction mixture was diluted with water and the organic component was extracted with 10% MeOH/ DCM. The organic layer was dried over anhyd. Na SC> , filtered and concentrated under reduced pressure to get crude product which was purified by silica gel (100-200 mesh) column chromatography to obtain Example 114a (170 mg, 50%) as off white solid. The enantiomers were separated by prep chiral HPLC to obtain Example 114.1 (47 mg, first eluting enantiomer: RT=l l. lmin) and Example 114.2 (50 mg, second eluting enantiomer: RT=14.5min) (Chiralpak IC (4.6 x 250 mm), solvent: Hexane/DCM/EtOH/iPr- Amine 70/15/15/0.1).
¾ NMR (400 MHz, DMSO-<¾) d 9.86 (s, 1 H), 8.47 (d , J= 14 Hz, 2 H), 7.70 (d, /= 8 Hz, 1 H), 7.34 (br s, 1 H), 7.14 (d , J= 8 Hz, 2 H), 6.81 (d, J= 8 Hz, 2 H), 6.38 (s, 2 H), 3.73-3.71 (m, 1 H), 3.67 (s, 3 H), 3.53 (s, 2 H), 2.86- 2.84 (m, 3 H), 2.18-2.08 (m, 5 H), 1.97 (d, J= 11 Hz, 1 H), 1.55-1.53 (m, 1 H).
Example _ 115: _ 1 -(3 -(4-methoxyphenvi)- 1 -(( 1 -methyl- 1 H-pyrazol-3 -yl)methyl)piperidin-4-yl)-3 -(3 - methylisothiazol-5-yl)urea
Example 115a: trans- 1 -(3 -(4-methoxyphenvi)- 1 -(( 1 -methyl- 1 H-pyrazol-3 -yl)methyl)piperidin-4-yl)-3 -(3 - methylisothiazol-5-yl)urea
Example 115.1: entl -trans- 1 -(3 -(4-methoxyphenvi)- 1 -(( 1 -methyl- 1 H-pyrazol-3 -yl)methyl)piperidin-4- vD-3-(3-methylisothiazol-5-vDurea
Example 115.2: ent2-trans- 1 -(3 -(4-methoxyphenvi)- 1 -(( 1 -methyl- 1 H-pyrazol-3 -yl)methyl)piperidin-4- vD-3-(3-methylisothiazol-5-vDurea
Figure imgf000117_0001
Starting from 1 -methyl- lH-pyrazole-3-carbaldehyde Example 115a was synthesized in analogy to synthesis described for Example 114. Racemic Example 115a was separated by preparative chiral HPLC to afford Example 115.1 (39 mg, first eluting enantiomer: RT=9.4min) and Example 115.2 (42 mg, second eluting enantiomer: RT=11.3min) (Chiralpak IC (4.6 x 250 mm), solvent: Hexane/DCM/EtOH/iPr-Amine 70/15/15/0.1).
¾ NMR (400 MHz, DMSO-<¾) d 9.83 (s, 1 H), 7.53 (s, 1 H), 7.27 (s, 1 H), 7.13 (d, J= 8 Hz, 2 H), 6.81 (d, J= 8 Hz, 2 H), 6.38 (s, 2 H), 3.71 (s, 3 H), 3.68 (s, 4 H), 3.32 (s, 2 H), 2.91-2.89 (m, 1 H), 2.86-2.66 (m, 2 H), 2.18 (s, 3 H), 1.98-1.90 (m, 3 H), 1.54-1.46 (m, 1 H).
Example 116: l-(3-(4-methoxyphenvi)-l-(pyrimidin-2-vhnethyl)piperidin-4-yl)-3-(3-methylisothiazol-5-yl)urea
Example 116a l-(3-(4-methoxyphenvi)-l-(pyrimidin-2-vhnethyl)piperidin-4-yl)-3-(3-methylisothiazol-5- vDurea
Example 116.1: e¾^/-^ra¾^-l-(3-(4-methoxyphenyl)-l-(pyrimidin-2-ylmethyl)piperidin-4-yl)-3-(3- methylisothiazol-5-yl)urea
Example 116.2: ent2-trans- 1 -(3 -(4-methoxyphenyl)- 1 -(pyrimidin-2-vhnethyl)piperidin-4-yl)-3 -(3 - methylisothiazol-5-yl)urea
Figure imgf000117_0002
To a stirred solution of HCI salt of ira«s-l-[3-(4-methoxy-phenyl)-piperidin-4-yl]-3-(3-methyl-isothiazol-5-yl)- urea (400 mg , 1.04 mmol, 1 eq, for synthesis see Example 43) and 2-chloromethyl-pyrimidine (131.7 mg, 1.25 mmol, 1.2 eq) in acetonitrile (25 mL) was added CS2CO3 (1.52 g, 4.7 mmol, 4.5 eq) and the reaction mixture was allowed to stir at 80°C for 18 h. After completion of the reaction, acetonitrile was evaporated, diluted with water and extracted with 10% MeOH/DCM. The organic layer was dried over anhyd. Na2S04, filtered and rota evaporated to get the crude material which was purified by column chromatography to obtain Example 116a (110 mg, yield 25%) as off white solid. The enantiomers were separated by preparative chiral HPLC to obtain Example 116.1 (39 mg, first eluting enantiomer: RT=4.9min) and Example 116.2 (39 mg, second eluting enantiomer: RT=5.7min) (Chiralpak IG (4.6 x 250 mm), solvent: Hexane/DCM/EtOH 50/25/25).
¾ NMR (400 MHz, DMSO-c ) d 9.82 (s, 1 H), 8.76 (d, J= 5 Hz, 2 H), 7.38 (t, J= 5 Hz, 1 H), 7.14 (d, J= 8 Hz, 2 H), 6.81 (d, J = 8 Hz, 2 H), 6.38 (s, 2 H), 3.72 (s, 3 H), 3.68 (s, 3 H), 2.95 (d, J = 12 Hz, 1 H), 2.87 (d, J = 11 Hz, 1 H), 2.78 (t, J = 11 Hz, 1 H), 2.31 (d, J = 10 Hz, 2 H), 2.19 (s, 3 H), 1.95 (d, J = 10 Hz, 1 H), 1.58-1.50 (m, 1 H).
Example 117: l-(3-(4-methoxyphenyl)-l-((5-methylisoxazol-3-yl)methyl)piperidin-4-yl)-3-(3-methylisothiazol- 5-yl)urea
Example _ 117a: _ l-(3-(4-methoxyphenyl)-l-((5-methylisoxazol-3-yl)methyl)piperidin-4-yl)-3-(3-
Figure imgf000118_0001
methylisothiazol-5-yl)urea
Example 117.1: e¾t/-tra¾^-l-(3-(4-methoxyphenyl)-l-((5-methylisoxazol-3-yl)methyl)piperidin-4-yl)-3- ( 3 -methylisothiazol-5 -yllurea
Example 117.2: l-(3-(4-methoxyphenyl)-l-((5-methylisoxazol-3-yl)methyl)piperidin-4-yl)-3-
Figure imgf000118_0002
( 3 -methylisothiazol-5 -yllurea
Figure imgf000118_0003
Example 117a Example 117.1 Example 117.2
To a stirred solution of HCI salt of trans-l-[3-(4-methoxy-phenyl)-piperidin-4-yl]-3-(3-methyl-isothiazol-5-yl)- urea (400 mg , 1.04 mmol, 1 eq, for synthesis see Example 43) and 3-bromomethyl-5-methyl-isoxazole (221 mg, 1.25 mmol, 1.2 eq) in acetonitrile (25 mL) was added K2CO3 (649 mg, 4.7 mmol, 4.5 eq) and the reaction mixture was allowed to stir at 70°C for 18 h. After completion of the reaction, acetonitrile was evaporated, diluted with water and extracted with 10% MeOH/DCM. The organic layer was dried over anhyd. Na2SC>4, filtered and rota evaporated to get the crude material, which was purified by column chromatography to obtain Example 117a (150 mg, 32%) as off white solid. The enantiomers were separated by preparative chiral HPLC to obtain Example 117.1 (47 mg, first eluting enantiomer: RT=8.1min) and Example 117.2 (41 mg, second eluting enantiomer: RT=9.6min) (Chiralpak IC (4.6 x 250 mm), solvent: Hexane/DCM/EtOH 50/25/25).
¾ NMR (400 MHz, DMSO-t¾) d 9.84 (s, 1 H), 7.14 (d, J= 8 Hz, 2 H), 6.82 (d, J= 8 Hz, 2 H), 6.38 (s, 2 H), 6.16 (s, 1 H), 3.68 (s, 4 H), 3.51 (s, 2 H), 2.86-2.77 (m, 3 H), 2.37 (s, 3 H), 2.19-2.07 (m, 5 H), 1.96 (d, J= 9 Hz,
1 H), 1.57-1.51 (m, 1 H). Example 118: l-(4-chlorophenyl)-3-(3-(4-methoxyphenvi)-l-((2-(trifluoromethyl)pyridin-3-yl)methyl)piperidin- 4-vDurea
Example _ 118a: _ trans- 1 -(4-chlorophenyi)-3 -(3 -(4-methoxyphenvD- 1 -((2-(frifluoromethyl)pyridin-3 - yl)methyl)piperidin-4-yl)urea
Example 118.1 : entl -trans- 1 -(4-chlorophenyi)-3 -(3 -(4-methoxyphenvD- 1 -((2-(frifluoromethyl)pyridin-3 - yl)methyl)piperidin-4-yl)urea
Example 118.2: l-(4-chlorophenvi)-3-(3-(4-methoxyphenvi)-l-((2-(trifluoromethyl)pyridin-3-
Figure imgf000119_0001
yl)methyl)piperidin-4-yl)urea
Figure imgf000119_0002
Starting from TFA salt of ira«s-l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)piperidin-4-yl)urea (for synthesis see Example 87) and (2-(trifluoromethyl)pyridin-3-yl)metanol, Example 118a was synthesized in analogy to synthesis described for Example 91. Enantiomers were separated by preparative chiral HPLC to obtain Example 118.1 (35 mg, first eluting enantiomer: RT=5.3min) and Example 118.2 (27 mg, second eluting enantiomer: RT=6.9min) (Chiralpak IA (4.6 x 250 mm), solvent: Hexane/EtOH 75/25).
¾ NMR (400 MHz, DMSO- d6): d 8.61 (d, J = 4.0 Hz, 1H), 8.34 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.70-7.73 (m, 1H), 7.30 (d, J = 8.8 Hz, 2H), 7.15-7.24 (m, 4H), 6.82 (d, J = 8.8 Hz, 2H), 5.95 (d, J = 8.0 Hz, 1H), 3.72-3.78 (m, 1H), 3.68 (s, 5H), 2.66-2.82 (m, 3H), 2.15-2.32 (m, 2H), 2.01 (d, J = 10.0 Hz, 1H), 1.49-1.54 (m, 1H).
Example 119: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((4-(trifluoromethyl)pyridin-3-yl)methyl)piperidin- 4-yl)urea
Example _ 119a: _ trans- 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenvD- 1 -((4-(trifluoromethyl)pyridin-3 - yl)methyl)piperidin-4-yl)urea
Example 119.1: entl -trans- 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenvD- 1 -((4-(trifluoromethyl)pyridin-3 - yl)methyl)piperidin-4-yl)urea
Example 119.2: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((4-(trifluoromethyl)pyridin-3-
Figure imgf000119_0003
yl)methyl)piperidin-4-yl)urea
Figure imgf000120_0001
Starting from TFA salt of ira«s-l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)piperidin-4-yl)urea (for synthesis see Example 87) and (4-(trifluoromethyl)pyridin-3-yl)methanol, Example 119a was synthesized in analogy to synthesis described for Example 91. Enantiomers were separated by preparative chiral HPLC to obtain Example
119.1 (65 mg) and Example 119.2 (65 mg).
¾ NMR (400 MHz, DMSO- d6): d 8.95 (s, 1H), 8.72 (s, 1H), 8.36 (s, 1H), 7.68 (s, 1H), 7.30 (d, J = 8.8 Hz, 2H), 7.15-7.20 (m, 4H), 6.82 (d, J = 8.4 Hz, 2H), 5.96 (d, J = 8.4 Hz, 1H), 3.75 (bs, 1H), 3.68 (s, 5H), 2.82 (d, J = 9.6 Hz, 1H), 2.66-2.75 (m, 2H), 2.17-2.28 (m, 2H), 2.00 (d, J = 11.2 Hz, 1H), 1.48-1.54 (m, 1H).
Example 120: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((5-methylpyridin-3-yl)methyl)piperidin-4-yl)urea Example 120a: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((5-methylpyridin-3-yl)methyl)piperidin-4- vDurea
Example _ 120.1: _ e¾t/-tra¾^-l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((5-methylpyridin-3- yl)methyl)piperidin-4-yl)urea
Example _ 120.2: _ ent2-tmns-\-(A- chlorophenyl) - 3 - (3 - (4-methoxyphenyl) - 1 - ((5 -methylp yridin- 3 - yl)methyl)piperidin-4-yl)urea
Figure imgf000120_0002
Starting from TFA salt of ira«s-l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)piperidin-4-yl)urea (for synthesis see Example 87) and (5-methylpyridin-3-yl)methanol, Example 120a was synthesized in analogy to synthesis described for Example 91. Enantiomers were separated by preparative chiral HPLC to obtain Example 120.1 (60 mg) and Example 120.2 (65 mg).
¾ NMR (400 MHz, DMSO- d6): d 8.28-8.34 (m, 3H), 7.50 (s, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.14-7.20 (m, 4H), 6.82 (d, J = 8.4 Hz, 2H), 5.90 (d, J = 8.0 Hz, 1H), 3.68-3.74 (m, 4H), 3.47 (s, 2H), 2.83 (d, J = 11.2 Hz, 1H), 2.68- 2.77 (m, 2H), 2.28 (s, 3H), 1.98-2.16 (m, 3H), 1.46-1.49 (m, 1H).
Example 121: l-(4-chlorophenyl)-3-(l-((5-chloropyridin-3-yl)methyl)-3-(4-methoxyphenyl)piperidin-4-yl)urea
Example 121a l-(4-chlorophenyl)-3-(l-((5-chloropyridin-3-yl)methyl)-3-(4-methoxyphenyl)piperidin-4- vDurea
Example _ 121.1: _ e¾t7-tra¾,y-l-(4-chlorophenyl)-3-(l-((5-chloropyridin-3-yl)methyl)-3-(4- methoxyphenyl)piperidin-4-yl)urea
Example _ 121.2: _ e¾t7-tra¾,y-l-(4-chlorophenyl)-3-(l-((5-chloropyridin-3-yl)methyl)-3-(4- methoxyphenyl)piperidin-4-yl)urea
Figure imgf000121_0002
Starting from TFA salt of tra«s-l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)piperidin-4-yl)urea (for synthesis see Example 87) and (5-chloropyridin-3-yl)methanol, Example 121a was synthesized in analogy to synthesis described for Example 91. Enantiomers were separated by preparative chiral HPLC to obtain Example 121.1 (58 mg, first eluting enantiomer) and Example 121.2 (55 mg, second eluting enantiomer).
¾ NMR (400 MHz, DMSO- d6): d 8.51 (s, 1H), 8.46 (s, 1H), 8.35 (s, 1H), 7.84 (s, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.15-7.20 (m, 4H), 6.82 (d, J = 8.4 Hz, 2H), 5.90 (d, J = 8.4 Hz, 1H), 3.74 (m, 1H), 3.68 (s, 3H), 3.55 (s, 2H), 2.83 (d, J = 11.2 Hz, 1H), 2.69-2.77 (m, 2H), 2.07-2.20 (m, 2H), 2.00 (d, J = 11.2 Hz, 1H), 1.46-1.52 (m, 1H).
Example 122: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((6-methylpyridin-3-yl)methyl)piperidin-4-yl)urea
Example 122a l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((6-methylpyridin-3-yl)methyl)piperidin-4- vDurea
Example _ 122.1: _ entl -trans- 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenvD- 1 -((6-methylpyridin-3 - vDmcthyl)piperidin-4-yl)urea
Example _ 122.2: _ l-(4-chlorophenyD-3-(3-(4-methoxyphenvD-l-((6-methylpyridin-3-
Figure imgf000121_0001
yl)methyl)piperidin-4-yl)urea
Figure imgf000122_0003
Starting from TFA salt of ira«s-l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)piperidin-4-yl)urea (for synthesis see Example 87) and (6-methylpyridin-3-yl)methanol, Example 122 was synthesized in analogy to synthesis described for Example 91. Enantiomers were separated by preparative chiral HPLC to obtain Example 122.1 (37 mg, first eluting enantiomer) and Example 122.2 (53 mg, second eluting enantiomer).
¾ NMR (400 MHz, DMSO- d6): d 8.33 (s, 2H), 7.56 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.14-7.20 (m, 5H), 6.81 (d, J = 8.4 Hz, 2H), 5.90 (d, J = 8.0 Hz, 1H), 3.68-3.73 (m, 4H), 3.46 (s, 2H), 2.82 (d, J = 10.4 Hz, 1H), 2.66-2.75 (m, 2H), 2.32 (s, 3H), 2.09-2.14 (m, 1H), 1.98-2.06 (m, 2H), 1.44-1.47 (m, 1H).
Example 123: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((tetrahvdro-2H-pyran-4-yl)methyl)piperidin-4- vDurea
Example _ 123a: _ trans- 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -((tetrahvdro-2H-pyran-4- yl)methyl)piperidin-4-yl)urea
Example 123.1: e¾t/-tra¾^-l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((tetrahvdro-2H-pyran-4- yl)methyl)piperidin-4-yl)urea
Example 123.2: l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)-l-((tetrahvdro-2H-pyran-4-
Figure imgf000122_0001
yl)methyl)piperidin-4-yl)urea
Figure imgf000122_0002
Starting from TFA salt of ira«s-l-(4-chlorophenyl)-3-(3-(4-methoxyphenyl)piperidin-4-yl)urea (for synthesis see Example 87) and 4-(bromomethyl)tetrahydro-2H-pyran, Example 123a was synthesized in analogy to synthesis described for Example 88. Enantiomers were separated by preparative chiral HPLC to obtain Example 123.1 (85 mg) and Example 123.2 (90 mg).
¾ NMR (400 MHz, DMSO- d6): d 8.33 (s, 1H), 7.30 (d, J = 8.8 Hz, 2H), 7.17-7.20 (m, 4H), 6.83 (d, J = 8.4 Hz, 2H), 5.89 (d, J = 8.4 Hz, 1H), 3.80 (d, J = 11.2 Hz, 2H), 3.69-3.72 (bs, 4H), 3.23-3.32 (m, 2H), 2.86 (d, J = 10.8 Hz, 1H), 2.78 (d, J = 10.4 Hz, 1H), 2.67 (t, J = 9.6 Hz, 1H), 2.13 (d, J = 6.8 Hz, 2H), 1.94-2.02 (m, 3H), 1.70 (bs, 1H), 1.58 (d, J = 12.8 Hz, 2H), 1.45 (d, J = 9.2 Hz, 1H), 1.08-1.13 (m, 2H).
Example 124: l-(4-chlorophenyl)-3-(l-(2.2-difluoropropanoyl)-3-(4-methoxyphenyl)piperidin-4-yl)urea
Example 124a: trans- 1 -(4-chlorophenyl)-3 -( 1 -(2.2-difluoropropanoyl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
Example _ 124.1: _ l-(4-chlorophenyl)-3-(l-(2.2-difluoropropanoyl)-3-(4-
Figure imgf000123_0001
methoxyphenyl)piperidin-4-yl)urea
Example _ 124.2: _ ent2-trans- 1 -(4-chlorophenyl)-3 -( 1 -(2,2-difluoropropanoyl)-3 -(4- methoxyphenyl)piperidin-4-yl)urea
Figure imgf000123_0002
Starting from 2,2-Difluoro-propionic acid and Example la, Example 124a was synthesized in analogy to synthesis described for Example 97. Enantiomers were separated by preparative chiral HPLC to obtain Example 124.1 (0.06 g) and Example 124.2 (0.05 g).
¾ NMR (400 MHz, DMSO- d6): d 8.39 (s, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.18-7.24 (m, 4H), 6.88 (d, J = 6.0 Hz, 2H), 5.96-5.99 (m, 1H), 4.24-4.44 (m, 1H), 4.05-4.12 (m, 2H), 3.71 (s, 3H), 3.36 (m, 1H), 3.27 (m, 1H), 2.91-2.97 (m, 1H), 2.65-2.67 (m, 1H), 2.08-2.11 (m, 1H), 1.75-1.87 (m, 3H), 1.42 (m, 1H).
Biological activity of the compounds according to the invention:
Assay method for measuring agonistic activity of compounds in hFPRl-Ga!5-CHO and hFPR2-Aq-CHO cell
Cryo-vial containing 6xl06 cells (hFPRl-Gal5-CHO or hFPR2-Aq-CHO) was thawed in a 37°C water bath. Cells were suspended in 10ml of respective complete growth media (F12(1X)HAM media (Gibco; Cat#11765); 10% HI-FBS (Gibco; Cat#10082); 0.1 mg/ml Hygromycin B (Invitrogen; Cat# 10687-010) [for hFPRl only]; 0.2 mg/ml Zeocin (Invitrogen; Cat#R25001) [for hFPRl only]; 0.4 mg/ml Geneticin (Gibco; Cat#10131) [for hFPR2-Aq only]; 0.25 mg/ml Zeocin (Invitrogen; Cat#R25001) [for hFPR2-Aq only]) in a 15ml centrifuge tube. The cell viability was checked with the help of Trypan Blue dye. Upon washing the cells, those were plated in a 384-well sterile clear bottom black plate (Greiner Bioone Cat# 781091) so that, each well contained 10,000 cells in 40m1 complete growth media. The plate was incubated in a 5% CO2 incubator at 37°C for 18 hours.
Before assay on the next day, the cell plating media was removed from each well of the plate by decanting and gentle tapping. 30m1 of 0.5X Calcium 5 dye solution (0.5X FLIPR Calcium 5 dye (Molecular devices Cat# R8186); HBSS (Invitrogen; Cat#14025); 20mM HEPES (Sigma; Cat#H0887); 2.5mM Probenecid (Sigma; Cat#P8761); 0.025% Pluronic F-127 (Sigma; Cat#P2443); pH adjusted to 7.4) was added to each well. The plate was then incubated at 37°C for 30 minutes. Following which the plate was equilibrated at room temperature for 10 minutes before placing it in a 384 well FLIPR for assay. Compounds were dissolved in DMSO and serially diluted following 11 point half log (3.16 fold) dilution with a starting concentration of 2mM (Final assay concentration 10mM). Aliquots of above mentioned each dilution was mixed with assay buffer (HBSS (Invitrogen; Cat#14025); 20mM HEPES (Sigma; Cat#H0887); 2.5mM Probenecid (Sigma; Cat#P8761); 0.05% gelatin (Sigma; Cat#G1890); 0.1% BSA (Sigma; Cat#A3059); pH adjusted to 7.4) just before performing the assay. Compounds were added to the respective wells of the assay ready cell plate with the help of the FLIPR (FLIPR Tetra) and fluorescence readings were captured for 5 minutes to measure any agonistic response of the compounds. The increase in fluorescence readings from the basal reading in presence of the compounds were compared with that of the control wells (wells having no compound) to calculate the agonistic activity of the compounds. The EC50 values of the compounds were determined using the Graph pad Prism software. The results are summarized in Table 1 below.
Table 1 :
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000125_0002
Figure imgf000126_0001

Claims

1. A compound according to general formula (I)
Figure imgf000127_0001
wherein
X3 represents N(L-R4) and X2 represents CH2 or C(O) and X4 represent CH2; or
X3 represents N(L-R4) and X4 represents CH2 or C(O) and X2 represent CH2; and
n represents 0, 1 or 2
R1 represents phenyl or 5 or 6-membered heteroaryl,
R2 represents O-Ci-e-alkyl, H, F, Cl, Br, CN, Ci-6-alkyl, C3-6-cycloalkyl, CHF2, CH2F, CF3, OH,
OCHF2, OCH2F, OCF3, S-Ci-e-alkyl, S(0)-Ci-6-alkyl, S(0)2-Ci-6-alkyl, 0-C3-6-cycloalkyl, S-C3- 6-cycloalkyl, S(0)-C3-6-cycloalkyl, S(0)2-C3-6-cycloalkyl, NH2, N(H)(Ci-6-alkyl), N(Ci-6-alkyl)2, N(H)(C3-6-cycloalkyl), N(Ci-6-alkyl)(C3-6-cycloalkyl),NC(0)(Ci-6-alkyl), NC(0)(C3-6- cycloalkyl), NC(0)(3 to 6-membered heterocycloalkyl);
R3 represents F, Cl, Br, CHF2, CH2F, CF3, Ci-e-alkyl, C3-6-cycloalkyl, O-Ci-e-alkyl, OCHF2, OCH2F,
OCF3, S(0)-Ci-6-alkyl, S(0)-C3-6-cycloalkyl, S(0)2-Ci-6-alkyl, S(0)2-C3-6-cycloalkyl;
L represents bond, Ci-6-alkylene, C(O), S(0)2, C(CH3)2; and
R4 represents H, Ci-6-alkyl, C3-6-cycloalkyl, 3 to 6-membered heterocycloalkyl, aryl, 5 or 6- membered heteroaryl, C(0)NH2, C(0)N(H)(Ci-6-alkyl), C(0)N(Ci-6-alkyl)2, C(0)N(H)(C3-6- 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)(C3-6-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), C(0)N(C3-6-cycloalkyl)(C3-6-cycloalkyl), C(0)N(C3-6-cycloalkyl)(3 to 6-membered heterocycloalkyl), C(0)N(C3-6-cycloalkyl)(aryl), C(0)N(C3-6-cycloalkyl)(5 or 6-membered heteroaryl), C(0)0-(Ci-6-alkyl), C(0)0-(C3-6-cycloalkyl), C(0)0-(3 to 6-membered heterocycloalkyl), C(0)0-(aryl), C(0)0-(5 or 6-membered heteroaryl), S(0)-Ci-6-alkyl, S(0)2- Ci-6-alkyl, S(0)-C3-6-cycloalkyl, S(0)2-C3-6-cycloalkyl, Ci-6-alkylene-OH, Ci-6-alkylene-0-Ci-6- alkyl, Ci-6-alkylene-C3-6-cycloalkyl, Ci-6-alkylene-3 to 6-membered heterocycloalkyl, Ci-6- alkylene-aryl, Ci-6-alkylene-5 or 6-membered heteroaryl; wherein Ci-6-alkyl in each case independently from one another is linear or branched, saturated or unsaturated; wherein Ci-6-alkylene is linear and saturated or unsaturated;
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, Ci-6-alkyl, CF3, CF2H, CFH2, CF2C1, CFC12, C(0)-Ci-6- alkyl, C(0)-0H, C(0)-0Ci-6-alkyl, C(0)-NH2, C(0)-N(H)(Ci-6-alkyl), C(0)-N(Ci-6-alkyl)2, OH, =0, OCF3, OCF2H, OCFH2, OCF2Cl, OCFCl2, O-Ci-e-alkyl, 0-C(0)-Ci-6-alkyl, 0-C(0)-0-Ci-6-alkyl, O-(CO)- N(H)(CI-6 - alkyl) , 0-C(0)-N(Ci-6-alkyl)2, 0-S(0)2-NH2, 0-S(0)2-N(H)(Ci-6-alkyl), 0-S(0)2-N(Ci-6- alkyl)2, NH2, N(H)(Ci-6-alkyl), N(Ci-6-alkyl)2, N(H)-C(0)-Ci-6-alkyl, N(H)-C(0)-0-Ci-6-alkyl, N(H)-
C(0)-NH2, N(H)-C(0)-N(H)(Ci-6-alkyl), N(H)-C(0)-N(Ci-6-alkyl)2, N(Ci-6-alkyl)-C(0)-Ci-6-alkyl, N(Ci_ 6-alkyl)-C(0)-0-Ci-6-alkyl, N(Ci-6-alkyl)-C(0)-NH2, N(Ci-6-alkyl)-C(0)-N(H)(Ci-6-alkyl), N(Ci-6-alkyl)-
C(0)-N(Ci-6-alkyl)2, N(H)-S(0)20H, N(H)-S(0)2-Ci-6-alkyl, N(H)-S(0)2-0-Ci-6-alkyl, N(H)-S(0)2-NH2, N(H)-S(0)2-N(H)(Ci-6-alkyl), N(H)-S(0)2N(Ci-6-alkyl)2, N(Ci-6-alkyl)-S(0)2-0H, N(Ci-6-alkyl)-S(0)2-Ci- 6-alkyl, N(Ci-6-alkyl)-S(0)2-0-Ci-6-alkyl, N(Ci-6-alkyl)-S(0)2-NH2, N(Ci-6-alkyl)-S(0)2-N(H)(Ci-6-alkyl), N(Ci-6-alkyl)-S(0)2-N(Ci-6-alkyl)2, SCF3, SCF2H, SCFH2, S-Ci-e-alkyl, S(0)-Ci-6-alkyl, S(0)2-Ci-6-alkyl, S(0)2-0H, S(0)2-0-Ci-6-alkyl, S(0)2-NH2, S(0)2-N(H)(Ci-6-alkyl), S(0)2-N(Ci-6-alkyl)2, Cs-e-cycloalkyl,
3 to 6-membered heterocycloalkyl, phenyl, 5 or 6-membered heteroaryl, 0-C3-6-cycloalkyl, 0(3 to 6- membered heterocycloalkyl), O-phenyl, 0(5 or 6-membered heteroaryl), C(0)-C3-6-cycloalkyl, C(0)-(3 to 6-membered heterocycloalkyl), C(0)-phenyl, C(0)-(5 or 6-membered heteroaryl), S(0)2-(C3-6-cycloalkyl), S(0)2-(3 to 6-membered heterocycloalkyl) and S(0)2-phenyl or S(0)2-(5 or 6-membered heteroaryl); wherein aryl, phenyl 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-6-alkyl, CF3, CF2H, CFH2, Ci^-alkylene-CF , Ci-4-alkylene-CF2H, Ci-4-alkylene-CFH2, C(0)-Ci-6-alkyl, C(0)-0H, C(0)-0Ci-6-alkyl, C(0)-N(H)(0H), C(0)-NH2, C(0)-N(H)(Ci-6-alkyl), C(O)- N(Ci-6-alkyl)2, OH, OCF3, OCF2H, OCFH2, OCF2Cl, OCFCl2, O-Ci-e-alkyl, O-Cs-e-cycloalkyl, 0-(3 to 6- membered heterocycloalkyl), NH2, N(H)(Ci-6-alkyl), N(Ci-6-alkyl)2, N(H)-C(0)-Ci-6-alkyl, N(Ci-6-alkyl)- C(0)-Ci-6-alkyl, N(H)-C(0)-NH2, N(H)-C(0)-N(H)(Ci-6-alkyl), N(H)-C(0)-N(Ci-6-alkyl)2, N(Ci-6-alkyl)- C(0)-N(H)(CI-6 - alkyl) , N(Ci-6-alkyl)-C(0)-N(Ci-6-alkyl)2, N(H)-S(0)2-Ci-6-alkyl, SCF3, S-Ci-e-alkyl, S(0)-Ci-6-alkyl, S(0)2-Ci-6-alkyl, S(0)2-NH2, S(0)2-N(H)(Ci-6- alkyl), S(0)2-N(Ci-6-alkyl)2, C3-6- cycloalkyl, Ci-4-alkylene-C3-6-cycloalkyl, 3 to 6-membered heterocycloalkyl, Ci-4-alkylene-(3 to 6- membered heterocycloalkyl), phenyl and 5 or 6-membered heteroaryl; in the form of the free compound or a physiologically acceptable salt thereof.
2. The compound according to claim 1, which is according to general formula (Ila) or (lib)
Figure imgf000128_0001
3. The compound according to claim 1 which is according to general formula (III)
Figure imgf000129_0001
4. The compound according to claim 1 which is according to general formula (IV)
Figure imgf000129_0002
5. The compound according to claim 1 which is according to general formula (V)
Figure imgf000129_0003
6. The compound according to any of the preceding claims, wherein R1 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, quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, isoquinolinyl, naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl, phenothiazinyl, phthalazinyl, purinyl, phenazinyl, tetrazolyl and triazinyl.
7. The compound according to any of the preceding claims, wherein R2 represents O-CH3, F, Cl, Br, OH, O- CH2CH3, 0-(CH2)2CH3, 0-CH(CH3)2 or OCF3.
8. The compound according to any of the preceding claims, wherein
R3 represents F and n represents 2; or
n represents 0.
9. The compound according to any of the preceding claims, wherein
L represents bond, CH2 or C(O); and/or
R4 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)NH2, 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)-C3-6- cycloalkyl, or S(0)2-C3-6-cycloalkyl.
10. The compound according to any of the preceding claims, wherein
X3 represents N(L-R4) and X2 represents CH2 or C(O) and X4 represent CH2; and
n represents 0, 1 or 2
R1 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 CF3;
R2 represents O-CH3 or Cl ;
R3 represents F;
L represents bond, CH2 or C(O); and
R4 represents
H;
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;
wherein C 1-6 -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, 0-CH2CH3, 0-(CH2)2CH3, 0-CH(CH3)2, S(0)-CH3, and S(0)2-CH3;
Ci-6-alkylene-OH selected from the group consisting of CH2OH, CH2CH2OH, (CH2)30H, (CH2)4OH, C(H)(OH)-CH3, CH2C(H)(OH)-CH3, C(CH3)2-OH, C(H)(OH)-C(CH3)2, and
CH2C(CH3)2-OH,
Ci-6-alkylene-0-Ci-6-alkyl selected from the group consisting of CH2OCH3, CH2CH2OCH3, (CH2)3OCH3, (CH2)4OCH3, (CH2)5OCH3, and (CH2)6OCH3,
3 to 6-membered 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)NH2,
C(0)N(H)(Ci-6-alkyl) selected from the group consisting of C(0)N(H)(CH3) and C(0)N(H)(CH2CH3);
C(0)N(Ci-6-alkyl)2 selected from the group consisting of C(0)N(CH3)2 and C(0)N(CH2CH3)2;
C(0)0-(Ci-6-alkyl) selected from the group consisting of C(0)0-CH3, C(0)0-CH2CH3, C(0)0- (CH2)2CH3, and C(0)0-CH(CH3)2;
S(0)-Ci-6-alkyl selected from the group consisting of S(0)-CH3, S(0)-CH2CH3, S(0)-(CH2)2CH3, and S(0)-CH(CH3)2;
S(0)2-Ci-6-alkyl selected from the group consisting of S(0)2-CH3, S(0)2-CH2CH3, S(0)2- (CH2)2CH3, and S(0)2-CH(CH3)2;
S(0)-C3-6-cycloalkyl selected from the group consisting of S(0)-cyelopropyl, S(0)-cyelobutyl, S(0)-cyelopentyl, and S(0)-cyelohexyl;
S(0)2-C3-6-cycloalkyl selected from the group consisting of S(0)2-cyelopropyl, S(0)2-cyelobutyl, S(0)2-cyelopentyl, and S(0)2-cyelohexyl;
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-CH3, and CH3; 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;
wherein said 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-CH3, and CH3; in the form of the free compound or a physiologically acceptable salt thereof.
11. The compound according to any of claims 1 and 6 to 9 which is according to general formula (VI) or (VII)
Figure imgf000131_0001
12. The compound according to any of the preceding claims which is selected from the group consisting of
1 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)piperidin-4-yl)urea
2 1 -(4-bromophenyl)-3 -(3 -(4-methoxyphenyl)piperidin-4-yl)urea
3 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -methylpiperidin-4-yl)urea
4 1 -(4-bromophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -methylpiperidin-4-yl)urea
5 1 -(4-chlorophenyl)-3 -( 1 -(2-methoxyethyl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
6 1 -(4-chlorophenyl)-3 -(3 -(2-fluoro-4-methoxyphenyl)piperidin-4-yl)urea
7 1 -(4-bromophenyl)-3 -(3 -(2-iluoro-4-methoxyphenyl)piperidin-4-yl)urea
8 1 -(4-chlorophenyl)-3 -(3 -(2,6-difhioro-4-methoxyphenyl)piperidin-4-yl)urea
9 1 -(4-bromophenyl)-3 -(3 -(2,6-diiluoro-4-methoxyphenyl)piperidin-4-yl)urea
10 1 -(4-chlorophenyl)-3 -(3 -(2-fluoro-4-methoxyphenyl)- 1 -(2-methoxyethyl)piperidin-4-yl)urea
11 1 -(4-bromophenyl)-3 -(3 -(2-fluoro-4-methoxyphenyl)- 1 -(2-methoxyethyl)piperidin-4-yl)urea
12 1 -(4-chlorophenyl)-3 -(3 -(2,6-difhioro-4-methoxyphenyl)- 1 -(2-methoxyethyl)piperidin-4-yl)urea
13 1 -(4-bromophenyl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-methoxyethyl)piperidin-4-yl)urea
14 1 -(4-chlorophenyl)-3 -( 1 -(cyclopropyhnethyl)-3 -(2,6-difluoro-4-methoxyphenyl)piperidin-4- yl)urea
15 1 -(4-chlorophenyl)-3 -( 1 -cyclopropyl-3 -(2, 6-diiluoro-4-methoxyphenyl)piperidin-4-yl)urea
16 1 -(4-chlorophenyl)-3 -(3 -(2,6-difhioro-4-methoxyphenyl)- 1 -methylpiperidin-4-yl)urea
17 1 -(4-chlorophenyl)-3 -(3 -(2,6-difhioro-4-methoxyphenyl)- 1 -ethylpiperidin-4-yl)urea
18 1 -(4-chlorophenyl)-3 -(3 -(2,6-difhioro-4-methoxyphenyl)- 1 -(2-hydroxyethyl)piperidin-4-yl)urea
19 1 -(4-chlorophenyl)-3 -(3 -(2,6-difhioro-4-methoxyphenyl)- 1 -(2,2-diiluoroethyl)piperidin-4-yl)urea
20 1 -(4-chlorophenyl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-fluoroethyl)piperidin-4-yl)urea
21 1 -(4-chlorophenyl)-3 -( 1 -(2,2-diiluoroethyl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
22 1 -(4-chlorophenyl)-3 -( 1 -(2-fluoroethyl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
23 1 -(4-chlorophenyl)-3 -(3 -(2,6-difhioro-4-methoxyphenyl)- 1 -(2-(methylsulfonyl)ethyl)piperidin-4- yl)urea
24 1 -(4-chlorophenyl)-3 -(3 -(2,6-difhioro-4-methoxyphenyl)- 1 -isopropylpiperidin-4-yl)urea
25 1 -(4-chlorophenyl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-hydroxy-2- methylpropyl)piperidin-4-yl)urea
26 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-4-yl)piperidin-4-yl)urea
27 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-3 -yl)piperidin-4-yl)urea
28 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-3 -yl)piperidin-4-yl)urea
29 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyrimidin-5-yl)piperidin-4-yl)urea
30 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(2-methylpyridin-4-yl)piperidin-4-yl)urea
31 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(2-methoxypyridin-4-yl)piperidin-4-yl)urea
32 1 -(4-chlorophenyl)-3 -((3R,4R)- 1 -(2-fluoropyridin-4-yl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
33 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(3 -methylpyridin-4-yl)piperidin-4-yl)urea
34 1 -(4-chlorophenyl)-3 -( 1 -(3 -fluoropyridin-4-yl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
35 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridazin-4-yl)piperidin-4-yl)urea
36 1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyrimidin-4-yl)piperidin-4-yl)urea 1 -(4-chlorophenyl)-3 -( 1 -(5-fluoropyrimidin-2-yl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -( 1 -(5-fluoropyridin-2-yl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -( 1 -(4-fluorophenyl)-3 -(4-methoxyphenyl)piperidin-4-yl)urea
1 -( 1 ,3 -bis(4-methoxyphenyl)piperidin-4-yl)-3 -(4-chlorophenyl)urea
1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -phenylpiperidin-4-yl)urea
l-(4-chloro-phenyl)-3-[3-(4-methoxy-phenyl)-l-pyrimidin-2-yl-piperidin-4-yl]-urea l-(3-(4-methoxyphenyl)-l-(pyridin-4-yl)piperidin-4-yl)-3-(3-methylisothiazol-5-yl)urea l-(5-chloropyridin-2-yl)-3-(3-(4-methoxyphenyl)piperidin-4-yl)urea
1 -(4-fluorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-4-yl)piperidin-4-yl)urea
1 -(6-chloropyridin-3 -yl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-4-yl)piperidin-4-yl)urea
1 -(5-chloropyridin-2-yl)-3 -(3 -(4-methoxyphenyl)- 1 -(pyridin-4-yl)piperidin-4-yl)urea l-(4-bromophenyl)-3-(5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
l-(4-chlorophenyl)-3-(5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
l-(4-bromophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
l-(4-chlorophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
l-(4-bromophenyl)-3-(l-(2-methoxyethyl)-5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea l-(4-chlorophenyl)-3-(l-(2-methoxyethyl)-5-(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea l-(4-bromophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-l-(2-methoxyethyl)-2-oxopiperidin-4- yl)urea
l-(4-chlorophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-l-(2-methoxyethyl)-2-oxopiperidin-4- yl)urea
l-(4-bromophenyl)-3-(5-(2,6-difluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea l-(4-chlorophenyl)-3-(5-(2,6-difluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea l-(4-bromophenyl)-3-(5-(4-methoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea
l-(4-chlorophenyl)-3-(5-(4-methoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea
l-(4-bromophenyl)-3-(5-(2,6-difluoro-4-methoxyphenyl)-l-(2-methoxyethyl)-2-oxopiperidin-4- yl)urea
l-(4-chlorophenyl)-3-(5-(2,6-difluoro-4-methoxyphenyl)-l-(2-methoxyethyl)-2-oxopiperidin-4- yl)urea
l-(4-bromophenyl)-3-(5-(2,6-difluoro-4-methoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea l-(4-chlorophenyl)-3-(5-(2,6-difluoro-4-methoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea l-(4-bromophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea l-(4-chlorophenyl)-3-(5-(2-fluoro-4-methoxyphenyl)-l-methyl-2-oxopiperidin-4-yl)urea l-(5-chloropyridin-2-yl)-3-(3-(2,6-difluoro-4-methoxyphenyl)piperidin-4-yl)urea
1 -(5-chloropyridin-2-yl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-fluoroethyl)piperidin-4- yl)urea
1 -(6-chloropyridin-3 -yl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)piperidin-4-yl)urea
1 -(6-chloropyridin-3 -yl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-fluoroethyl)piperidin-4- yl)urea
1 -(3 -(2,6-difluoro-4-methoxyphenyl)piperidin-4-yl)-3 -(6-(trifluoromethyl)pyridin-3 -yl)urea
1 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-fluoroethyl)piperidin-4-yl)-3 -(6- (trifluoromethyl)pyridin-3 -yl)urea
1 -(3 -(2,6-difluoro-4-methoxyphenyl)piperidin-4-yl)-3 -(4-(trifluoromethyl)phenyl)urea 1 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-fluoroethyl)piperidin-4-yl)-3 -(4- (trifluoromethyl)phenyl)urea
1 -(5-chlorothiophen-2-yl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-fluoroethyl)piperidin-4- yl)urea
l-(5-chlorothiazol-2-yl)-3-(3-(2,6-difluoro-4-methoxyphenyl)piperidin-4-yl)urea
l-(5-chlorothiazol-2-yl)-3-((3R,4R)-3-(2,6-difluoro-4-methoxyphenyl)-l-(2- fluoroethyl)piperidin-4-yl)urea
1 -(2-chlorothiazol-5-yl)-3 -(3 -(2,6-difluoro-4-methoxyphenyl)- 1 -(2-fluoroethyl)piperidin-4- yl)urea
1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -(3 -(2-fluoro-4-methoxyphenyl)-2-oxopiperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -(3 -(4-methoxyphenyl)- 1 -methyl-2-oxopiperidin-4-yl)urea
1 -(4-chlorophenyl)-3 -(3 -(2-fluoro-4-methoxyphenyl)- 1 -methyl-2-oxopiperidin-4-yl)urea l-(4-chlorophenyl)-3-[l-(4-fluorophenyl)-5-(4-methoxyphenyl)-2-oxo-4-piperidyl]urea l-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)-l-(l-methylpyrazol-4-yl)-2-oxo-4-piperidyl]urea
1 -[ 1 ,5-bis(4-methoxyphenyl)-2-oxo-4-piperidyl]-3-(4-chlorophenyl)urea
l-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)-2-oxo-l-pyridazin-3-yl-4-piperidyl]urea l-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)-l-(6-methyl-2-pyridyl)-2-oxo-4-piperidyl]urea l-(4-chlorophenyl)-3-[l-[(5-chloro-2-thienyl)methyl]-3-(4-methoxyphenyl)-4-piperidyl]urea
1 -(4-chlorophenyl)-3 -[3 -(4-methoxyphenyl)- 1 -(3 -pyridylmethyl)-4-piperidyl]urea
1 -(4-chlorophenyl)-3 -[3 -(4-methoxyphenyl)- 1 -(pyrimidin-2-ylmethyl)-4-piperidyl]urea l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-[(5-methylisoxazol-3-yl)methyl]-4-piperidyl]urea l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-[(5-(trifluoromethyl)isoxazol-3- yl)methyl]piperidin-4-yl]urea
l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-[(3-methylisoxazol-5-yl)methyl]-4-piperidyl]urea 1 -(4-chlorophenyl)-3-[3-(4-methoxyphenyl)- 1 -[(5-methyl- 1,2, 4-oxadi azol-3-yl)methyl]-4- piperidyljurea
l-(4-chlorophenyl)-3-[3-(4-chlorophenyl)-l-[(5-methylisothiazol-3-yl)methyl]-4-piperidyl]urea l-[l-(2,2-difluoroethyl)-3-(4-methoxyphenyl)-4-piperidyl]-3-(3-methylisothiazol-5-yl)urea 1 -(4-chlorophenyl)-3 -[3 -(4-methoxyphenyl)- 1 -(pyridine-3 -carbonyl)-4-piperidyl]urea
1 -(4-chlorophenyl)-3 -[ 1 -(4-fluorobenzoyl)-3 -(4-methoxyphenyl)-4-piperidyl]urea
l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-(5-methylisoxazole-3-carbonyl)-4-piperidyl]urea l-(4-chlorophenyl)-3-[l-(5-chlorothiophene-2-carbonyl)-3-(4-methoxyphenyl)-4-piperidyl]urea l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-[(4-methylpyrimidin-2-yl)methyl]-4- piperidyljurea
l-[3-(4-methoxyphenyl)-l-[(4-methylpyrimidin-2-yl)methyl]-4-piperidyl]-3-(3-methylisothiazol-
5-yl)urea
l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-[(5-methylpyrimidin-2-yl)methyl]-4- piperidyljurea
l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-[(4-methoxypyrimidin-2-yl)methyl]-4- piperidyljurea 104 l-[3-(4-methoxyphenyl)-l-[(5-methoxypyrimidin-2-yl)methyl]-4-piperidyl]-3-(3- methylisothiazol-5-yl)urea
107 l-(4-fluorophenyl)-3-[5-(4-methoxyphenyl)-2-oxo-l-(2-pyridylmethyl)-4-piperidyl]urea
108 l-(4-fluorophenyl)-3-[5-(4-methoxyphenyl)-2-oxo-l-(4-pyridylmethyl)-4-piperidyl]urea
109 l-[3-(4-methoxyphenyl)-l-(4-pyridyl)-4-piperidyl]-3-(3-methylisothiazol-5-yl)urea
110 l-[3-(4-methoxyphenyl)-l-pyridazin-4-yl-4-piperidyl]-3-(3-methylisothiazol-5-yl)urea
111 l-[3-(4-methoxyphenyl)-l-(2-methyl-4-pyridyl)-4-piperidyl]-3-(3-methylisothiazol-5-yl)urea
112 l-[l-(4-fluorophenyl)-3-(4-methoxyphenyl)-4-piperidyl]-3-(3-methylisothiazol-5-yl)urea
113 l-[l-[(5-chloro-2-thienyl)methyl]-3-(4-methoxyphenyl)-4-piperidyl]-3-(3-methylisothiazol-5- yl)urea
114 l-[3-(4-methoxyphenyl)-l-(3-pyridylmethyl)-4-piperidyl]-3-(3-methylisothiazol-5-yl)urea
115 l-[3-(4-methoxyphenyl)-l-[(l-methylpyrazol-4-yl)methyl]-4-piperidyl]-3-(3-methylisothiazol-5- yl)urea
116 l-[3-(4-methoxyphenyl)-l-(pyrimidin-2-ylmethyl)-4-piperidyl]-3-(3-methylisothiazol-5-yl)urea
117 l-[3-(4-methoxyphenyl)-l-[(5-methylisoxazol-3-yl)methyl]-4-piperidyl]-3-(3-methylisothiazol-5- yl)urea
118 l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-[[2-(trifluoromethyl)-3-pyridyl]methyl]-4- piperidyl]urea
119 l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-[[4-(trifluoromethyl)-3-pyridyl]methyl]-4- piperidyl]urea
120 l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-[(5-methyl-3-pyridyl)methyl]-4-piperidyl]urea
121 l-(4-chlorophenyl)-3-[l-[(5-chloro-3-pyridyl)methyl]-3-(4-methoxyphenyl)-4-piperidyl]urea
122 l-(4-chlorophenyl)-3-[3-(4-methoxyphenyl)-l-[(6-methyl-3-pyridyl)methyl]-4-piperidyl]urea
123 1 -(4-chlorophenyl)-3 -[3 -(4-methoxyphenyl)- 1 -(tetrahydropyran-4-ylmethyl)-4-piperidyl]urea
124 1 -(4-chlorophenyl)-3 -[ 1 -(2,2-difluoropropanoyl)-3 -(4-methoxyphenyl)-4-piperidyl]urea in the form of the free compound or a physiologically acceptable salt thereof.
13. A pharmaceutical dosage form comprising a compound according to any of claims 1 to 12.
14. A compound according to any of claims 1 to 12 for use in the treatment and/or prophylaxis of a disorder which is mediated at least in part by FPR2.
15. The compound according to claim 14 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).
PCT/EP2019/055947 2018-03-09 2019-03-11 Piperidines or piperidones substituted with urea and phenyl WO2019170904A1 (en)

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