aryloxyacetamides

Abstract

The present invention relates to compounds according to general formula (I) which are modulators of SSTR4.

Description

1 GRA 4222-foreign filingAryloxyacetamides

[0001] Priority is claimed of European patent application no. 25 166780.4 that was filed on March 27, 2025.

[0002] The present invention relates to compounds according to general formula (I)(I)which are modulators of SSTR4.

[0003] Somatostatin (SST) is an endogenous peptide that inhibits the secretion of other hormones such as growth hormone, thyroid stimulating hormone, cholecystokinin and insulin (Reichlin, S. “Somatostatin,” V v England Journal of Medicine, (1983) 309, 1495-1501). Somatostatin binds to five different receptor subtypes (SSTR1-5) that are all Gai coupled G-protein coupled receptors (GPCRs) but differ by function and expression. Preclinical data suggest the SSTR4 receptor subtype plays a role in modulating pain, and that agonism of this receptor may be analgesic.

[0004] SSTR4 is expressed in areas associated with pain processing such as dorsal root ganglia (DRG) neurons (Shenoy et. al., “The Somatostatin Receptor-4 Agonist J-2156 Alleviates Mechanical Hypersensitivity in a Rat Model of Breast Cancer Induced Bone Pain,” Frontiers in Pharmacology, (2018) 9(495)) and somatosensory cortical neurons (Kecskes et. al., “Characterization of Neurons Expressing the Novel Analgesic Drug Target Somatostatin Receptor 4 in Mouse and Human Brains,” International Journal of Molecular Sciences, (2020) 21(7788)).

[0005] In DRG neurons, agonism of SSTR4 has been shown to activate G-protein coupled inward rectifying potassium (GIRK) channels and inhibit voltage sensitive calcium currents (Gorham et. al., “Somatostatin 4 receptor activation modulates G-protein coupled inward rectifying potassium channels and voltage stimulated calcium signals in dorsal root ganglion neurons,” European Journal of Pharmacology, (2014) 736: 101-106).

[0006] Additionally, SSTR4 agonism increased a depolarization-activated, non-inactivating K+current (M-cur-rent) and reduced the firing rate of layer V cortical pyramidal neurons (Kecskes et. al., “Characterization of Neurons Expressing the Novel Analgesic Drug Target Somatostatin Receptor 4 in Mouse and Human Brains,” International Journal of Molecular Sciences, (2020) 21(7788)) and hippocampal neurons (Qin et. al., “Somatostatin Receptor Subtype 4 Couples to the M-Current to Regulate Seizures, ”The Journal of Neuroscience,” (2008) 28(14):3567-3576).

[0007] Taken together, these data suggest SSTR4 agonism reduces neuronal excitability via modulation of ion channels and that the development of SSTR4 agonists may be useful as novel analgesics.2 GRA 4222-foreign filing

[0008] Propanamide- and acetamide derivatives with SSTR4 activity are known from e.g. WO 2019 / 169153 and WO 2023 / 187677.

[0009] In addition, A-(2-(het)arylpropan-2-yl) acyl amides with SSTR4 activity are known from e.g. WO 2010 / 059922, WO 2014 / 184275, WO 2015 / 037716, WO 2016 / 075239, WO 2016 / 075240, WO 2021 / 233427, WO 2021 / 233428, WO 2021 / 202781, WO 2022 / 012534, WO 2024 / 102754 and WO 2025 / 027049.

[0010] Miscellaneous chemotypes such as (pseudo-)peptides and heteroaromatic compounds with SSTR4 activity are known from e.g. WO 2005 / 033069, WO 2005 / 033124, WO 2021 / 202775, and WO 2023 / 180125.

[0011] It is an object of the invention to provide novel compounds which are modulators of SSTR4. 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 SSTR4.

[0012] This object has been achieved by the subject-matter of the patent claims.

[0013] A first aspect of the invention relates to a compound according to general formula (I)(I)whereinRl representsH,Ci-4-alkyl or O-Ci-4-alkyl, wherein in each case alkyl is unsubstituted or substituted with one, two, three or four substituents independently of one another selected from F, OH, OCH3, and cyclopropyl;O-C3.6-cycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F, CH3, OH and OCH3,O-(4 to 6-membered heterocycloalkyl) unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3,O-phenyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F, Cl, CH3, OH and OCH3, orO-(5 or 6-membered heteroaryl) unsubstituted or substituted with one, two or three substituents independently of one another selected from F, Cl, CH3, OH and OCH3;Rl' represents H or CH3;or R1 and Rl' together with the carbon atom to which they are attached to form a CTe-cycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3, or a 4 to 6-3 GRA 4222-foreign filingmembered heterocycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3;R2, R3 and R4, in each case independently from one another, represent H, or Ci-4-alkyl unsubstituted or substituted with one, two, three or four substituents independently of one another selected from F, OH and OCH3;R5 representsF or Cl,Ci-4-alkyl unsubstituted or substituted with one, two, three or four substituents independently of one another selected from F, OH, OCH3, and cyclopropyl;C3.6-cycloalkyl, unsubstituted or substituted with one, two or three substituents independently of one another selected from F, CH3and OCH3,4 to 6-membered heterocycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3;R6 represents H, F, Cl or Ci-4-alkyl unsubstituted or substituted with one, two, three or four substituents independently of one another selected from F, OH, and OCH3;or R5 and R6 together with the carbon atom to which they are attached to form a C3.6-cycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F, CH3and OCH3, or a 4 to 6-membered heterocycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3;R7, R8, R9, RIO and Rll, in each case independently from one another, representH,F, Cl, Br or CN,Ci-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, O-Ci-4-alkyl or S-Ci-4-alkyl, wherein in each case alkyl, alkenyl or al- kynyl is unsubstituted or substituted with one, two, three or four substituents independently of one another selected from F, OH, OCH3, and cyclopropyl,C3.6-cycloalkyl or O-C3.6-cycloalkyl, wherein in each case cycloalkyl is unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3,phenyl or O-phenyl, wherein in each case phenyl is unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3;or R7 and R8 or R8 and R9, in each case together with the carbon atoms to which they are attached to, form phenyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3,5 or 6-membered heteroaryl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3,Cs-e-cycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3, or4 GRA 4222-foreign filing5- or 6-membered heterocycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3;X represents CH or N;with the proviso that when R1 represents H or Ci-4-alkyl, or when R1 and Rl' together with the carbon atom to which they are attached to form a C3-6-cycloalkyl, then X represents N; andwith the proviso that when Rl represents O-Ci-4-alkyl, O-C3.6-cycloalkyl, O-(4 to 6-membered heterocycloalkyl), O-phenyl or O-(5 or 6-membered heteroaryl), then X represents CH;Y represents O or S;Z represents CR11 or N;or a physiologically acceptable salt thereof.

[0014] In a preferred embodiment, the compound according to the invention is present in form of the free compound. For the purpose of specification, "free compound" preferably means that the compound according to the 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 as14N or15N solid state NMR, x-ray diffraction, x-ray powder diffraction, IR, Raman, XPS.1H-NMR recorded in solution may also be used to consider the presence of protonation.

[0015] In another preferred embodiment, the compound according to the 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 invention and a physiologically acceptable acid or base including trifluoroacetic acid.

[0016] According to the invention, the compound according to the 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 invention and / or a physiologically acceptable salt thereof with (ii) distinct molecular equivalents of one or more solvents.

[0017] Further, the compound according to the invention may be present in form of the racemate, enantiomers, diastereomers, tautomers or any mixtures thereof.

[0018] The compounds according to the invention may have one or more stereocenters. The person skilled in art knows by looking at a chemical structure whether the depicted compound has one or more stereocenters or not.

[0019] For some compounds according to the invention that have one or more stereocenters and which chemical structures are disclosed in the examples of the present application, the chemical structure includes bold bonds and / or hashed bonds to indicate the relative structural orientation of those substituents connected by the bold bonds and / or hashed bonds to the superior structure. If the bold bonds and / or hashed bonds are depicted in form of a wedge, the absolute stereochemical configuration of the compound is known and thereby indicated. If the bold bonds and / or hashed bonds are depicted as a straight bond (i.e. no wedge), the absolute stereochemical configuration of the compound has not been determined. In that case, the bold bonds and / or hashed bonds merely serve to indicate that this particular compound is present as one enantiomer or one diastereomer (e.g. cis-diastereomer (i.e. mixture of two cis-enantiomers) or trans-diastereomer (i.e. mixture of two trans-enantiomers)). All compounds5 GRA 4222-foreign filingaccording to the invention that have one or more stereocenters but which chemical structures disclosed in the examples of the present application do not include bold bonds and / or hashed bonds, are present as a mixture of the respective stereoisomers.

[0020] The invention also includes isotopic isomers of a compound of the invention, wherein at least one atom of the compound is replaced by an isotope of the respective atom which is different from the naturally predominantly occurring isotope, as well as any mixtures of isotopic isomers of such a compound. Preferred isotopes are2H (deuterium),3H (tritium),13C and14C. Isotopic isomers of a compound of the invention can generally be prepared by conventional procedures known to a person skilled in the art.

[0021] According to the invention, the term "Ci-4-alkyl" preferably means acyclic and preferably saturated hydrocarbon residues, which can be linear (i.e. unbranched) or branched, and which contain 1 to 4 (i.e. 1, 2, 3 or 4) carbon atoms. Preferably, Ci-4-alkyl is saturated.

[0022] 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; more preferably methyl, ethyl, 2-propyl and tert-butyl.

[0023] According to the invention, the term "C2-4-alkenyl" preferably means acyclic and preferably unsaturated hydrocarbon residues, which can be linear (i.e. unbranched) or branched, and which contain 1 to 4 (i.e. 2, 3 or 4) carbon atoms. Preferably, C2-4-alkenyl is unsaturated.

[0024] Preferred C2-4-alkenyl groups are selected from the group consisting of ethenyl, propenyl (-CH2CH=CH2, -CH=CH-CH3, -C(=CH2)-CH3), 1-butenyl, 2-butenyl and 2-methylprop-l-enyl.

[0025] According to the invention, the term "C2-4-alkynyl" preferably means acyclic and preferably unsaturated hydrocarbon residues, which can be linear (i.e. unbranched) or branched, and which contain 1 to 4 (i.e. 2, 3 or 4) carbon atoms. Preferably, C2-4-alkynyl is unsaturated.

[0026] Preferred C2-4-alkynyl groups are selected from the group consisting of ethynyl, propynyl, 1-butynyl and 2-butynyl.

[0027] According to the invention, the terms "C3.6-cycloalkyl" and "C5-6-cycloalkyl" preferably mean monocyclic aliphatic hydrocarbons containing 3, 4, 5 or 6 carbon atoms as ring members and 5 or 6 carbon atoms as ring members, respectively, wherein the hydrocarbons in each case can be saturated or unsaturated (but not aromatic). Preferably, C3.6-cycloalkyl and Cs-e-cycloalkyl are saturated. The C3.6-cycloalkyl and Cs-e-cycloalkyl can be bound to the respective superordinate general structure via any desired and possible ring member of the cycloalkyl group. Preferably, the C3.6-cycloalkyl and Cs-e-cycloalkyl are not condensed with further ring systems and are not bridged.

[0028] Preferred C3.6-cycloalkyl groups are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferred Cs-e-cycloalkyl groups are selected from cyclopentyl and cyclohexyl.

[0029] According to the invention, the term "C4-e-heterocycloalkyl" and "Cs-e-heterocycloalkyl" preferably means monocyclic, heterocycloaliphatic saturated or unsaturated (but not aromatic) residues having 4 to 6, i.e. 4, 5 or 6 ring members, and 5 or 6 ring members, respectively, wherein in each case at least one, if appropriate also two or three ring members, are a heteroatom or a heteroatom group independently one another selected from the group consisting of O, S, S(=O), S(=O)2, N, NH and N(Ci.4-alkyl) such as N(CH3). Preferably, the C4-6-heterocycloalkyl and C5-6-heterocycloalkyl contain only one heteroatom or heteroatom group within the ring. Preferably, C4-e-het-erocycloalkyl and Cs-e-heterocycloalkyl are saturated. The C4-e-heterocycloalkyl and Cs-e-heterocycloalkyl are6 GRA 4222-foreign filingpreferably not condensed with further ring systems and are not bridged. The C4-6-heterocycloalkyl and Cs-e-heter-ocycloalkyl 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, C4-6-heterocycloalkyl and C5-6-heterocycloalkyl are bound to the superordinate general structure via a carbon atom.

[0030] Preferred C4-6-heterocycloalkyl and Cs-e-heterocycloalkyl are selected from the group consisting of oxeta-nyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiopyranyl, tetrahydrothiopy-ranyl 1,1 -dioxide, oxepanyl, piperidinyl, piperidinonyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, 4-methylpiperazi-nyl, morpholinonyl, dioxanyl, piperazinyl, tetrahydropyrrolyl, azepanyl, dioxepanyl, oxazepanyl, diazepanyl, thi-azolidinyl, tetrahydrothiophenyl, tetrahydropyridinyl, dithiolanyl, dihydropyrrolyl, dioxolanyl, dihydropyridinyl, dihydrofuranyl, dihydroisoxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, piperazinyl, N-methylpyridinonyl, pyrazolidinyl and pyranyl; more preferably tetrahydrofuranyl and tetrahydropyranyl.

[0031] According to the invention, the term "5 or 6-membered heteroaryl" preferably refers to a 5 to 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. 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 or 6-membered heteroaryl is bound to the superordinate general structure via a carbon atom of the heterocycle. The 5 or 6-membered heteroaryl is preferably not condensed with a further ring system.

[0032] Preferably, 5 or 6-membered heteroaryl is selected from the group consisting of pyrimidinyl, pyridyl (i.e.2-pyridyl, 3 -pyridyl, 4-pyridyl), pyrazolyl, pyridonyl (pyridinonyl), thienyl (thiophenyl), thiazolyl, pyrazinyl, pyr-idazinyl, isoxazolyl, triazolyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, isothiazolyl, furanyl, thiadiazolyl, N-methylpyridinonyl, tetrazolyl and triazinyl; more preferably pyrimidinyl or pyridyl.

[0033] In a preferred embodiments the compound according to the invention is according to general formula (lb)(lb).

[0034] According to the present invention, R1 representsH,Ci-4-alkyl or O-Ci-4-alkyl, wherein in each case alkyl is unsubstituted or substituted with one, two, three or four substituents independently of one another selected from F, OH, OCH3, and cyclopropyl;O-Cs-e-cycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F, CH3, OH and OCH3,O-(4 to 6-membered heterocycloalkyl) unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3,7 GRA 4222-foreign filingO-phenyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F, Cl, CH3, OH and OCH3, orO-(5 or 6-membered heteroaryl) unsubstituted or substituted with one, two or three substituents independently of one another selected from F, Cl, CH3, OH and OCH3.

[0035] In a preferred embodiment, R1 representsO-Ci-4-alkyl, wherein in each case alkyl is unsubstituted or substituted with one, two, three or four substituents independently of one another selected from F, OH, OCH3, and cyclopropyl;O-C3.6-cycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F, CH3, OH and OCH3,O-(4 to 6-membered heterocycloalkyl) unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3,O-phenyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F, Cl, CH3, OH and OCH3, orO-(5 or 6-membered heteroaryl) unsubstituted or substituted with one, two or three substituents independently of one another selected from F, Cl, CH3, OH and OCH3.

[0036] In another preferred embodiment, R1 representsH,Ci-4-alkyl selected from methyl, ethyl or 2-propyl; or O-Ci.4-alkyl selected from O-methyl, O-ethyl or O-iso- butyl, wherein in each case methyl, ethyl, 2-propyl, O-methyl, O-ethyl or O-isobutyl is unsubstituted or substituted with one, two or three substituents independently of one another selected from F, OH, OCH3, and cyclopropyl;O-(4 to 6-membered heterocycloalkyl) selected from O-tetrahyrdofuranyl or O-tetrahydropyranyl, unsubstituted or substituted with one substituent selected from F and CH3, orO-pyrimidinyl, unsubstituted or substituted with one substituent selected from F, Cl, CH3, OH and OCH3.

[0037] Most preferably, R1 represents O-CH3or O-C2H5.

[0038] According to the present invention, Rl' represents H or CH3; preferably H.

[0039] Further according to the present invention, Rl and Rl' together with the carbon atom to which they are attached can forma C3.6-cycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3, ora 4 to 6-membered heterocycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3.

[0040] In a preferred embodiment, Rl and Rl' together with the carbon atom to which they are attached form8 GRA 4222-foreign filingCs-e-cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein in each case cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is unsubstituted or substituted with one or two substituents independently of one another selected from F and CH3, or4 to 6-membered heterocycloalkyl selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl, wherein in each case oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl is unsubstituted or substituted with one or two substituents independently of one another selected from F and CH3.

[0041] In a preferred embodiment, R1 and Rl' together with the carbon atom to which they are attached to form a cyclopropyl, unsubstituted.

[0042] In yet another preferred embodiment, Rl and Rl' together with the carbon atom to which they are attached to do not form a cycle.

[0043] According to the present invention, R2, R3 and R4, in each case independently from one another, represent H, or Ci-4-alkyl unsubstituted or substituted with one, two, three or four substituents independently of one another selected from F, OH and OCH3. In another preferred embodiment, R2, R3 and R4, in each case independently from one another, represent H, methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, wherein in each case methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl or tert-butyl is unsubstituted or substituted with one, two or three substituents independently of one another selected from F, OH and OCH3.

[0044] In a preferred embodiment, R2, R3 and R4, in each case independently from one another, represent H or CH3

[0045] In another preferred embodiment, at most one of R2, R3 and R4 does not represent H. In still another preferred embodiment, all of R2, R3 and R4 represent H.

[0046] According to the present invention, R5 representsF or Cl,Ci-4-alkyl unsubstituted or substituted with one, two, three or four substituents independently of one another selected from F, OH, OCH3, and cyclopropyl;C3.6-cycloalkyl, unsubstituted or substituted with one, two or three substituents independently of one another selected from F, CH3and OCH3,4 to 6-membered heterocycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3.

[0047] In a preferred embodiment, R5 representsF,Ci-4-alkyl selected from methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl or tert-butyl; wherein in each case methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl or tert-butyl is unsubstituted or substituted with one, two or three substituents independently of one another selected from F, OH, OCH3, and cyclopropyl;9 GRA 4222-foreign filingCs-e-cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; wherein in each case cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is unsubstituted or substituted with one, two or three substituents independently of one another selected from F, CH3and OCH3,4 to 6-membered heterocycloalkyl selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl, wherein in each case oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl is unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3.

[0048] In a preferred embodiment, R5 represents F, Ci-4-alkyl unsubstituted, or C3.6-cycloalkyl unsubstituted. More preferably, R5 represents F, CH3, CH2CH3or cyclopropyl; most preferably CH3or F.

[0049] According to the present invention, R6 represents H, F, Cl or Ci-4-alkyl unsubstituted or substituted with one, two, three or four substituents independently of one another selected from F, OH, and OCH3.

[0050] In a preferred embodiment, R6 represents H, F or Ci.4-alkyl selected from methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl or tert-butyl; wherein in each case methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl or tertbutyl is unsubstituted or substituted with one, two or three substituents independently of one another selected from F, OH, and OCH3.

[0051] In another preferred embodiment, R6 represents H, F or Ci-4-alkyl unsubstituted; more preferably H, F or CH3.

[0052] In a preferred embodiment, R5 and R6 both represent F or both represent CH3; more preferably, both represent CH3.

[0053] Further according to the present invention, R5 and R6 together with the carbon atom to which they are attached to can form a C3.6-cycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F, CH3and OCH3, or a 4 to 6-membered heterocycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3.

[0054] In a preferred embodiment, R5 and R6 together with the carbon atom to which they are attached to form a C3.6-cycloalkyl unsubstituted, or a 5 or 6-membered heterocycloalkyl unsubstituted. More preferably, R5 and R6 together with the carbon atom to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, or tetrahydropyranyl; most preferably cyclobutyl, cyclohexylor tetrahydropyranyl.

[0055] In yet another preferred embodiment, R5 and R6 together with the carbon atom to which they are attached to do not form a cycle.

[0056] According to the present invention, R7, R8, R9, R10 and Rll, in each case independently from one another, representH,F, Cl, Br or CN,Ci-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, O-Ci-4-alkyl or S-Ci-4-alkyl, wherein in each case alkyl, alkenyl or al- kynyl is unsubstituted or substituted with one, two, three or four substituents independently of one another selected from F, OH, OCH3, and cyclopropyl,10 GRA 4222-foreign filingCs-e-cycloalkyl or O-Cke-cycloalkyl. wherein in each case cycloalkyl is unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3,phenyl or O-phenyl, wherein in each case phenyl is unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3.

[0057] In another preferred embodiment, R7, R8, R9, RIO and Rll, in each case independently from one another, representH;F, Cl, Bror CN;Ci-4-alkyl selected from methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl or tert-butyl; wherein in each case methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl or tert-butyl is unsubstituted or substituted with one, two or three substituents independently of one another selected from F, OH, OCH3, and cyclopropyl;C2-4-alkenyl selected from ethenyl, propenyl, 1-butenyl, 2-butenyl and 2-methylprop-l-enyl, wherein in each case ethenyl, propenyl, 1-butenyl, 2-butenyl and 2-methylprop-l-enyl is is unsubstituted or substituted with one, two or three substituents independently of one another selected from F, OH, OCH3, and cyclopropyl; C2-4-alkynyl selected from ethynyl, propynyl, 1-butynyl and 2-butynyl, wherein in each case ethynyl, propynyl, 1-butynyl and 2-butynyl is unsubstituted or substituted with one, two or three substituents independently of one another selected from F, OH, OCH3, and cyclopropyl;O-Ci-4-alkyl selected from O-methyl, O-ethyl, O-(n-propyl), O-(2 -propyl), O-(n-butyl), O-isobutyl or O-(tert- butyl); wherein in each case O-methyl, O-ethyl, O-(n-propyl), O-(2 -propyl), O-(n-butyl), O-isobutyl or O-(tert- butyl) is unsubstituted or substituted with one, two or three substituents independently of one another selected from F, OH, OCH3, and cyclopropyl;S-Ci-4-alkyl selected from S-methyl, S-ethyl, S-(n-propyl), S-(2-propyl), S-(n-butyl), S-isobutyl or S-(tert-bu- tyl); wherein in each case S-methyl, S-ethyl, S-(n-propyl), S-(2 -propyl), S-(n-butyl), S-isobutyl or S-(tert-bu- tyl) is unsubstituted or substituted with one, two or three substituents independently of one another selected from F, OH, OCH3, and cyclopropyl;C3.6-cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; wherein in each case cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3;O-C3.6-cycloalkyl selected from O-cyclopropyl, O-cyclobutyl, O-cyclopentyl or O-cyclohexyl; wherein in each case O-cyclopropyl, O-cyclobutyl, O-cyclopentyl or O-cyclohexyl is unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3;phenyl or O-phenyl, wherein in each case phenyl is unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3.

[0058] In still another preferred embodiment, R7, R8, R9 and R10, in each case independently from one another, represent H, F, Cl, CN, Ci-4-alkyl, O-Ci-4-alkyl, phenyl or O-phenyl, wherein in each case alkyl or phenyl is unsubstituted or substituted with one, two, or three substituents selected from F.11 GRA 4222-foreign filing

[0059] In yet another preferred embodiment, R7, R8, R9 and RIO, in each case independently from one another, represent H, F, Cl, CN, methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, O-methyl, O-ethyl, O-(n-propyl), O-(2 -propyl), O-(n-butyl), O-isobutyl, O-(tert-butyl), phenyl or O-phenyl; wherein in each case methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, O-methyl, O-ethyl, O-(n-propyl), O-(2 -propyl), O-(n-butyl), O-isobutyl, O-(tert-butyl), phenyl or O-phenyl is unsubstituted or substituted with one, two, or three substituents selected from F.

[0060] In another preferred embodiment, at least one of R7, R8, R9 and R10 does not represent H.

[0061] In another preferred embodiment, Rll represents H or F.

[0062] Further according to the invention, R7 and R8 or R8 and R9, in each case together with the carbon atoms to which they are attached to, can formphenyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3,5 or 6-membered heteroaryl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3,Cs-e-cycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3, or5- or 6-membered heterocycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3.

[0063] In a preferred embodiment, R7 and R8 or R8 and R9, in each case together with the carbon atoms to which they are attached to, formphenyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3,5 or 6-membered heteroaryl selected from pyrimidinyl, pyridyl, pyrazolyl, thiazolyl, pyrrolyl or furanyl, wherein in each case pyrimidinyl, pyridyl, pyrazolyl, thiazolyl, pyrrolyl or furanyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3,Cs-e-cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; wherein in each case cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3, or5- or 6-membered heterocycloalkyl selected from tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperi- dinyl, wherein in each case tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl is unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3. In another preferred embodiment, R7 and R8 or R8 and R9, in each case together with the carbon atoms to which they are attached to form phenyl, pyrimidinyl, pyridyl, pyrazolyl, thiazolyl, pyrrolyl or furanyl, wherein in each case phenyl, pyrimidinyl, pyridyl, pyrazolyl, thiazolyl, pyrrolyl or furanyl is unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3. More preferably, R7 and R8 or R8 and R9, in each case together with the carbon atoms to which they are attached to form phenyl or pyridyl, wherein in each case phenyl or pyridyl is unsubstituted or substituted with one, two or three12 GRA 4222-foreign filingsubstituents independently of one another selected from F and CH3. Most preferably, R7 and R8 or R8 and R9, in each case together with the carbon atoms to which they are attached to form phenyl or pyridyl, wherein in each case phenyl or pyridyl is unsubstituted.

[0064] In yet another preferred embodiment, R7 and R8 as well as R8 and R9, in each case together with the carbon atoms to which they are attached to do not form a cycle.

[0065] According to the present invention, X represents CH or N; with the proviso that when R1 represents H or Ci-4-alkyl, or when R1 and Rl' together with the carbon atom to which they are attached to form a C3.6-cycloalkyl. then X represents N; and with the proviso that when Rl represents O-Ci-4-alkyl, O-C3.6-cycloalkyl. O-(4 to 6-membered heterocycloalkyl), O-phenyl or O-(5 or 6-membered heteroaryl), then X represents CH.

[0066] In a preferred embodiment, X represents CH and Rl represents O-Ci-4-alkyl, O-C e-cycloalkyl. O-(4 to 6-membered heterocycloalkyl), O-phenyl or O-(5 or 6-membered heteroaryl); more preferably, O-Ci-4-alkyl and most preferably O-CH3or O-C2H5.

[0067] According to the present invention, Y represents O or S; preferably O.

[0068] Further according to the present invention, Z represents CRH or N; more preferably CH, CF or N.

[0069] In a preferred embodiment, Y represents O and / or Z represents N.

[0070] Preferably, the compound according to the invention is selected from the group consisting of001 2-(3-(tert-butyl)phenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide002 2-(2,4-difluorophenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide003 2-(3-cyanophenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide004 N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methyl-2-(naphthalen-2-yloxy)propanamide005 2-(3-isopropylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide006 2-(3-methoxyphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide007 N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methyl-2-(o-tolyloxy)propanamide008 2-(3-fluorophenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide009 2-(2,3-dichlorophenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide010 N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methyl-2-(m-tolyloxy)propanamideOil 2-(2,3-dimethylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide012 N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methyl-2-(3-(trifluoromethyl)phenoxy)propanamide 013 2-(3-chlorophenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide014 2-(3,5-dimethylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide015 and 016 2-(3,5-dimethylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylbutanamide017 2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-(2,4,5-trifluorophenoxy)acetamide13 GRA 4222-foreign filing2.2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-(3,4,5-trifluorophenoxy)acetamide 2.2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-(2,3,5-trifluorophenoxy)acetamide 2-(3-chloro-4,5-difluorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide 2-(4-chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide2-(2,4-difluoro-3-methylphenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide 2.2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)-2 -phenoxyacetamide2-(3,4-difluoro-5-methylphenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide 2-(3-chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide2.2-difluoro-2-(2-fluoro-3-methylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide 2-(3,5-difluorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide2-(3-chloro-4-fluorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide 2.2-difluoro-2-(3-fluoro-5-methylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide 2.2-difluoro-2-(4-fluoro-3-methylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide 2-(3,5-dimethylphenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide2-(3-chloro-5-fluorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide 2.2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-(m-tolyloxy)acetamide2-(3, 5-dimethylphenoxy)-2,2-difluoro-N-((3S,4S)-3-(2 -methoxy ethoxy )piperidin-4-yl)acetamide formate2-(3,5-dichlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamideN-((3S,4S)-3-(cyclopropylmethoxy)piperidin-4-yl)-2-(3,5-dimethylphenoxy)-2,2-difluoroa- cetamide formate2-(3,5-dimethylphenoxy)-N-((3S,4S)-3-ethoxypiperidin-4-yl)-2,2-difluoroacetamide2.2-difluoro-2-(3-fluoro-5-methylphenoxy)-N-((3S,4S)-3 -(2 -methoxyethoxy )piperidin-4-yl)acet- amideand 040 tran5-2,2-difluoro-2-(3-fluoro-5-methylphenoxy)-N-((3 S*, 4S*)-3-(2 -methoxy etho xy)piperidin- 4-yl)acetamide4-(3,5-dimethylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)tetrahydro-2H-pyran-4-carbox- amide1-(3,5-dimethylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)cyclohexane-l-carboxamide and 044 2-cyclopropyl-2-(3,5-dimethylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide1-(3,5-dimethylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)cyclobutane-l-carboxamide and 047 2-(3-chlorophenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)propanamide14 GRA 4222-foreign filingand 049 2-(3,5-dimethylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)butanamide2-(4-fluoro-3,5-dimethylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-metliylpropanamide 2-(3-chloro-5-fluorophenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide 2-(3-chloro-5-methylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide 2-(3,5-dichlorophenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide 2-((4,6-dimethylpyridin-2-yl)oxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide 2-((4,6-dimethylpyridin-2-yl)oxy)-2-methyl-N-((3S,4S)-3-((2-methylpyrimidin-5-yl)oxy)piperi- din-4-yl)propanamideN-((3S,4S)-3-(2,2-difluoroethoxy)piperidin-4-yl)-2-((4,6-dimethylpyridin-2-yl)oxy)-2- methylpropanamideN-((3S,4S)-3-(difluoromethoxy)piperidin-4-yl)-2-((4,6-dimethylpyridin-2-yl)oxy)-2-methylpro- panamide2-((4,6-dimethylpyridin-2-yl)oxy)-N-((3S,4S)-3-ethoxypiperidin-4-yl)-2-methylpropanamide 2-((3,5-dimethylphenyl)thio)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide 2-(3,5-dimethylphenoxy)-2,2-difluoro-N-((3S,4S)-3-((2-methylpyrimidin-5-yl)oxy)piperidin-4- yl)acetamide2-(3-chloro-2-fluorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide 2,2-difluoro-2-(2-fluoro-5-methylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide 2-(3, 5-dimethylphenoxy)-2,2-difluoro-N-((3S,4S)-3-(2 -hydroxy -2-methylpropoxy )piperidin-4- yl)acetamide2-(3, 5-dimethylphenoxy)-2,2-difluoro-N-((3S,4S)-3-(2 -hydroxy ethoxy )piperidin-4-yl)acetamide 2-(3,5-dimethylphenoxy)-2,2-difluoro-N-((3S,4S)-3-((tetrahydro-2H-pyran-4-yl)oxy)piperidin- 4-yl)acetamide2-(3,5-dimethylphenoxy)-2,2-difluoro-N-((3S,4S)-3-((tetrahydrofuran-3-yl)oxy)piperidin-4- yl)acetamide, stereoisomer- 12-(3,5-dimethylphenoxy)-2,2-difluoro-N-((3S,4S)-3-((tetrahydrofuran-3-yl)oxy)piperidin-4- yl)acetamide, stereoisomer-22-((3,5-dimethylphenyl)thio)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide 2-((4,6-dimethylpyridin-2-yl)thio)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide and 071 2-((4,6-dimethylpyridin-2-yl)oxy)-2-fluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide and 073 2-((4,6-dimethylpyridin-2-yl)oxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)butanamide and 075 2-(3,5-dimethylphenoxy)-2-fluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide15 GRA 4222-foreign filing2-(3,5-dimethylphenoxy)-2,2-difluoro-N-(piperazin-l-yl)acetamide2-(3,5-dimethylphenoxy)-2,2-difluoro-N-(4,7-diazaspiro[2.5]octan-4-yl)acetamide2-(3,5-dimethylphenoxy)-N-((2S,5R)-2,5-dimethylpiperazin-l-yl)-2,2-difluoroacetamide rac-2-(3,5-dimethylphenoxy)-N-((2R*,3S*)-2,3-dimethylpiperazin-l-yl)-2,2-difluoroacetamide 2-(3,5-dimethylphenoxy)-N-((2S,6S)-2,6-dimethylpiperazin-l-yl)-2,2-difluoroacetamide (S)-2-(3,5-dimethylphenoxy)-2,2-difluoro-N-(2-methylpiperazin-l-yl)acetamideme5o-2-(3,5-dimethylphenoxy)-N-(-2,6-dimethylpiperazin-l-yl)-2,2-difluoroacetamide 2-(3,5-dimethylphenoxy)-N-((2S,5S)-2,5-dimethylpiperazin-l-yl)-2,2-difluoroacetamide (S)-2-(3-chloro-5-methylphenoxy)-2,2-difluoro-N-(2-methylpiperazin-l-yl)acetamide(S)-2-(3-chlorophenoxy)-2,2-difluoro-N-(2-methylpiperazin-l-yl)acetamide(R)-2-(3,5-dimethylphenoxy)-2,2-difluoro-N-(2-methylpiperazin-l-yl)acetamide(S)-2-(3 ,5-dimethylphenoxy)-N-(2-ethylpiperazin- 1 -yl)-2,2-difluoroacetamide(S)-N-(2-ethylpiperazin- 1 -yl)-2,2-difluoro-2-(m-tolyloxy)acetamide(R)-2-(3,5-dimethylphenoxy)-2,2-difhioro-N-(2-(methoxymetliyl)piperazin-l-yl)acetamide rac-2-(3,5-dimethylphenoxy)-N-((2R*,3R*)-2,3-dimethylpiperazin-l-yl)-2,2-difluoroacetamide (S)-2-((4,6-dimethylpyridin-2-yl)oxy)-N-(2-ethylpiperazin-l-yl)-2-methylpropanamide (S)-2-((4,6-dimethylpyridin-2-yl)oxy)-2-methyl-N-(2-methylpiperazin-l-yl)propanamide 2-((5-fluoro-4,6-dimethylpyridin-2-yl)oxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpro-panamide2-((3-fluoro-4,6-dimethylpyridin-2-yl)oxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpro-panamide2-((4,6-dimethylpyridin-2-yl)oxy)-2-methyl-N-((3S,4S)-3-(trifluoromethoxy)piperidin-4-yl)pro-panamide(S)-2-((4,6-dimethylpyridin-2-yl)oxy)-N-(2-isopropylpiperazin-l-yl)-2-methylpropanamide 2-((6-chloro-4-methylpyridin-2-yl)oxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropana-mide2-((4-chloro-6-methylpyridin-2-yl)oxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropana-mide2-((4,6-dimethylpyridin-2-yl)oxy)-N-((2S,5S)-2-ethyl-5-methylpiperazin-l-yl)-2-methylpro-panamide2-((4,6-dimethylpyridin-2-yl)oxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide N-((3 S,4S)-3 -methoxypiperidin-4-yl)-2-methyl-2-(naphthalen- 1 -yloxy)propanamide16 GRA 4222-foreign filing102 2-([ 1 , l'-biphenyl] -3 -yloxy)-N-((3 S,4S)-3 -methoxypiperidin-4-yl)-2-methylpropanamide 103 N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methyl-2-(3-phenoxyphenoxy)propanamide104 2-(6-chloro-4-methylpyridin-2-yl)oxy-2,2-difluoro-N-[(3S,4S)-3-methoxypiperidin-4-yl]acetam- ide105 2,2-difluoro-N-[(3S,4S)-3-methoxypiperidin-4-yl]-2-[4-methyl-6-(trifluoromethyl)pyridin-2- yl] oxy acetamide106 2,2-difluoro-2-(3-fluoro-4,6-dimethylpyridin-2-yl)oxy-N-[(3S,4S)-3-methoxypiperidin-4-yl]ac- etamide107 2-(4,6-dimethylpyridin-2-yl)oxy-N-[(3S,4S)-3-ethoxypiperidin-4-yl]-2,2-difluoroacetamide or a physiologically acceptable salt thereof.

[0071] Another aspect of the invention relates to a medicament comprising a compound according to the invention as described above.

[0072] Another aspect of the invention relates to a pharmaceutical dosage form comprising a compound according to the invention. Preferably, the pharmaceutical dosage form comprises a compound according to the 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).

[0073] The pharmaceutical dosage form according to the 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.

[0074] The pharmaceutical dosage form according to the 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 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 invention are administered per kg of the patient's body weight.

[0075] Therefore, another aspect of the invention relates to the pharmaceutical dosage form according to the invention for use in the treatment of pain. Still another aspect of the invention relates to a method of treatment of pain; comprising the administration of a pharmaceutical dosage form according to the invention to a subject in need thereof, preferably a human.17 GRA 4222-foreign filing

[0076] Another aspect of the invention relates to a process for the preparation of the compounds according to the invention. Suitable processes for the synthesis of the compounds according to the invention are known in principle to the person skilled in the art.

[0077] Preferred synthesis routes are described below:

[0078] The compounds according to the invention can be obtained via different synthesis routes. Depending on the synthesis route, different intermediates are prepared and subsequently further reacted. For all amines and carboxylic acids described below it is appreciated that their corresponding salts can be reacted similarly under the appropriate conditions.

[0079] According to a first process, compounds of Formula (I) and (II) may be prepared from compounds of Formulae (V), (IV) or (III) and (V), (VII) or (VI) respectively, as illustrated by Scheme 1.R8 RI Rr(VI)Scheme 1

[0080] PGi is a suitable protecting group, preferably Boc, Cbz or Fmoc. X, Y, Z and R1 - R10 refer to residues as defined above. Rx represents alkyl, cycloalkyl, heterocycloalky, phenyl and heteroaryl.

[0081] The compounds of Formulae (V) and (IV) are reacted in an amide bond forming reaction (b) to yield compounds of Formula (II). Typical reaction conditions comprise, reaction of the amine of Formula (IV) with a carboxylic acid of Formula (V) in the presence of a suitable coupling reagent and a suitable base in a suitable solvent at an appropriate temperature. The compounds of Formula (II) are then deprotected in a reaction (a) to yield compounds of Formula (I). Typical reaction conditions comprise, reaction of the compound of Formula (III) with a suitable reagent such as an acid in a suitable solvent at an appropriate temperature.

[0082] Preparations according to this scheme are exemplified in the preparations described below for examples SC-054, SC-087 and SC-097.

[0083] Alternatively, the compounds of Formulae (V) and (VII) are reacted in an amide bond forming reaction (d) to yield compounds of Formula (VI). Typical reaction conditions comprise, reaction of the amine of Formula (VII) with a carboxylic acid of Formula (V) in the presence of a suitable coupling reagent and a suitable base in a suitable solvent at an appropriate temperature. The compounds of Formula (VI) are then reacted in an alkylation reaction (c). Typical reaction conditions comprise, reaction of the compounds of Formula (VI) with a suitable alkylating reagent in the presence of a suitable base in a suitable solvent at an appropriate temperature. Subsequently, the18 GRA 4222-foreign filingintermediates obtained from reaction (c) are deprotected in a reaction (a) as described above to yield compounds of Formula (II).

[0084] Preparations according to this scheme are exemplified in the preparations described below for examples SC-034, SC-036 and SC-037.

[0085] According to a second process, compounds of Formula (V) may be prepared from compounds of Formulae (IX) and (IIX) or (XI) or (IX) and (X) or XII and (XIII) or (IX) and (XIV) as illustrated by Scheme 2.Scheme 2

[0086] PG3 is a suitable protecting group, preferably OMe or OEt. Y, Z and R5 - RIO refer to residues as defined above. Hal is a suitable halogen or other leaving group, preferably Br (reactions (e) and (f)) or F (reaction (g)).

[0087] The compounds of Formulae (IX) and (IIX) are reacted in a phenol or pyridone O-alkylation reaction (e) to yield compounds of Formula (V). Typical reaction conditions comprise, reaction of the phenol or pyridone of Formula (IX) with an alkylating reagent of Formula (IIX) in the presence of a suitable base in a suitable solvent at an appropriate temperature.

[0088] Preparations according to this scheme are exemplified in the preparations described below for intermediates INT-40, INT-46 and INT-51.

[0089] Alternatively, the compounds of Formulae (IX) and (X) are reacted in a phenol or pyridone O-alkylation reaction (f) to yield compounds of Formula (XI). Typical reaction conditions comprise, reaction of a phenol or pyridone of Formula (IX) with an alkylating reagent of Formula (X) in the presence of a suitable base in a suitable solvent at an appropriate temperature. The compounds of Formula (XI) are then deprotected in a reaction (h) to yield compounds of Formula (V). Typical reaction conditions comprise, reaction of the compound of Formula (XI) with a suitable reagent such as an acid or a base in a suitable solvent at an appropriate temperature.

[0090] Preparations according to this scheme are exemplified in the preparations described below for intermediates INT-64, INT-68 and INT-69.

[0091] Alternatively, the compounds of Formulae (XII) and (XIII) are reacted in a nucleophilic aromatic substitution reaction (g) to yield compounds of Formula (XI). Typical reaction conditions comprise, reaction of an alcohol of Formula (XIII) with an aryl halide of Formula (XII) in the presence of a suitable base in a suitable solvent at an19 GRA 4222-foreign filingappropriate temperature. The compounds of Formula (XI) are then deprotected as described above to yield compounds of Formula (V).

[0092] Preparations according to this scheme are exemplified in the preparation described below for intermediate INT-79.

[0093] Alternatively, the compounds of Formulae (IX) and (XIV) are reacted in a Bargellini type reaction (i) to yield compounds of Formula (V). Typical reaction conditions comprise, reaction of a phenol of Formula (IX) with a ketone of Formula (XIV) in the presence of a suitable base and a suitable reagent such as CHCI3 in a suitable solvent at an appropriate temperature.

[0094] Preparations according to this scheme are exemplified in the preparations described below for intermediates INT-37, INT-38 and INT-39.

[0095] According to a third process, compounds of Formula (XV) and (XVIII) may be prepared from compounds of Formulae (XVII) or (XVI) and (XIX) respectively, as illustrated by Scheme 3.(XIX) (XVIII)Scheme 3

[0096] PGi and PG2are suitable orthogonal protecting groups, preferably Boc, Cbz, PMB, or Fmoc. Alternatively, PG2together with the bound nitrogen may represent an azide moiety. R1 - R4 refer to residues as defined above. Rx represents alkyl, cycloalkyl, heterocycloalky, phenyl and heteroaryl.

[0097] The compounds of Formula (XVII) are reacted in an alkylation reaction (j). Typical reaction conditions comprise, reaction of the compounds of Formula (XVII) with a suitable alkylating reagent in the presence of a suitable base in a suitable solvent at an appropriate temperature. The compounds of Formula (XVI) are then deprotected in a reaction (k) to yield compounds of Formula (XV). Typical reaction conditions comprise, reaction of the compound of Formula (XVI) with such as an acid, base or reductant in a suitable solvent at an appropriate temperature.

[0098] Preparations according to this scheme are exemplified in the preparations described below for intermediates INT-3, INT-15 and INT-22.

[0099] Alternatively, the compounds of Formulae (XIX) are reacted in an amination reaction (1) to yield compounds of Formula (XVIII). Typical reaction conditions comprise, reaction of an amine of Formula (XIX) with a20 GRA 4222-foreign filingsuitable electrophilic amination reagent in the presence of a suitable base in a suitable solvent at an appropriate temperature.

[0100] Preparations according to this scheme are exemplified in the preparations described below for intermediates INT-24, INT-33 and INT-30.

[0101] According to a fourth process, compounds of Formula (XX) may be prepared from compounds of Formulae (IIX) and (XVI) or (IX) and (XXII) or (XXI) as illustrated by Scheme 4.Scheme 4

[0102] PGi and PG2 are suitable orthogonal protecting groups, preferably Boc, Cbz, PMB or Fmoc. Y, Z and R1 -R10 refer to residues as defined above. Rx represents alkyl, cycloalkyl, heterocycloalky, phenyl and heteroaryl. Hal is a suitable halogen or other leaving group, preferably Br.

[0103] The compounds of Formulae (IIX) and (XVI) are reacted in an amide bond forming reaction (0) to yield compounds of Formula (XXII). Typical reaction conditions comprise reaction of the amine of Formula (XVI) with a carboxylic acid of Formula (IIX) in the presence of POCI3 and a suitable base in a suitable solvent at an appropriate temperature. The compounds of Formulae (IX) and (XXII) are reacted in a phenol or pyridone O-alkylation reaction (n) to yield compounds of Formula (XXI). Typical reaction conditions comprise, reaction of the phenol or pyridone of Formula (IX) with an alkylating reagent of Formula (XXII) in the presence of a suitable base in a suitable solvent at an appropriate temperature. The compounds of Formula (XXI) are then deprotected as described above (a) to yield compounds of Formula (XX).

[0104] Preparations according to this scheme are exemplified in the preparations described below for examples SC-100 and SC-104.

[0105] List of Abbreviations:

[0106] Ac: acetyl, amu: atomic mass unit, anhyd.: anhydrous, API: atmospheric pressure ionization, aq.: aqueous, AtaPhos: di-tert-butyl(4-dimethylaminophenyl)phosphine, Boc: tert-butyloxycarbonyl, cAMP: cyclic adenosine monophosphate, Cbz: benzyloxycarbonyl, DAD: diode array detector, DBH: 1, 3 -dibrom-5, 5 -dimethylhydantoin,21 GRA 4222-foreign filingDIPEA: N,N-diisopropylethylamine, DMF: dimethylformamide, DMP: Dess-Martin periodinane, DMSO: dimethyl sulfoxide, dppf: l,l'-bis(diphenylphosphino) ferrocene, dtbpf: l,l'-bis-(di-tert.-butylphosphino)-ferrocen, EC50: half maximal effective concentration, EDC: l-ethyl-3 -(3 -dimethylaminopropyl) carbodiimide, ESI: elec-tropspray ionization, Et: ethyl, EtOAc: ethyl acetate, Ex.: example, Fmoc: fluorenylmethoxycarbonyl, g: gram, h: hour, h: human, Hal: halogen, HATU : hexafluorophosphate azabenzotriazole tetramethyl uronium, HOBt: hydroxybenzotriazole, HPLC: high performance liquid chromatography, Hz: hertz, INT: intermediate, L: liter, LCMS: liquid chromatography mass spectrometry, LDA: lithium diisopropylamide, m: mili, M: molar, m: meter, M: mega, m: multiplet, mCPBA: meta-chloroperoxybenzoic acid, Me: methyl, MHz: megahertz, min: minute, MS: mass spectrometry, Ms: mesyl, MTBE: methyl tert-butyl ether, n: nano, NMR: nuclear magnetic resonance, PE: petrol ether, PG: protecting group, Ph: phenyl, PMB: para-methoxy benzyl, psi: pounds per square inch, R: residue, Rt: retetion time, sat.: saturated, SC: single compound, SCX: Strong Cation Exchanger, SEM: 2-(trimethylsi-lyl)ethoxymethyl , SQD: single quadrupole detector, SSTR: somatostatin receptor, t: tert, T3P: propanepho sphonic acid anhydride

[0107] Methods:

[0108] UPLC-MS / HPLC-MS / SFC / GC methods:

[0109] Method A: Instrument: LCMS / MS API 2000 Applied Biosystems; HPLC: Shimadzu Prominence; Column: XBridge C18 (4.6 x 50 mm, 5 p); Temp: 25 °C; Eluents: A= 10 mM NH4OAc in H2O, B = MeCN; Gradient: 0.0 min 90% A — 1.5 min 70% A — 3.0 min 10% A — 4.0 min 10% A — 5.0 min 90% A; Flow rate: 1.2 mL / min, Detection: UV 220 / 260 nm; Ionization: ESI / API; Mass range: 100 - 800 amu

[0110] Method B: Instmment: LCMS / MS API 2000 Applied Biosystems; HPLC: Shimadzu Prominence; Column: XBridge C18 (4.6 x 50 mm, 5 p); Temp: 25 °C; Eluents: A= 10 mM NH4OAc in H2O, B = MeCN; Gradient: 0.0 min 90% A — > 1.5 min 70% A — > 3.0 min 10% A — > 4.0 min 10% A — > 5.0 min 90% A; Flow rate: 1.0 mL / min, Detection: UV 220 / 260 nm; Ionization: ESI / API; Mass range: 100 - 800 amu

[0111] Method C: Instrument: Waters ACQUITY SQD; HPLC: Waters ACQUITY UPLC; Column: Luna Omega (4.6 x 100 mm, 3 p); Temp: 50 °C; Eluents: A = 0.05% TFA in H2O, B = MeCN; Gradient: 0.0 min 98% A — > 1.0 min 98% A — 5.0 min 50% A —> 9.0 min 5% A — 11.0 min 5% A — 12.0 min 98% A; Flow rate: 1.0 mL / min, Detection: UV 210 - 400 nm; Ionization: ESI / API; Mass range: 100 - 100 amu

[0112] Method D: Instrument: Waters ACQUITY SQD; HPLC: Waters ACQUITY UPLC; Column: Acquity BEH C8 (2.1 x 50 mm, 1.7 p); Temp: 50 °C; Eluents: A = 0.05% HCO2H in H2O, B = MeCN; Gradient: 0.0 min 98% A -> 0.75 min 98% A -► 1.0 min 90% A -> 2.0 min 2% A -► 2.25 min 2% A -> 2.9 min 98% A -► 3.0 min 98% A; Flow rate: 1.5 mL / min, Detection: UV 210 - 400 nm; Ionization: ESI / API; Mass range: 100 - 800 amu

[0113] Method E: Instrument: Waters ACQUITY SQD 2; HPLC: Waters ACQUITY H Class UPLC; Column: Acquity BEH C8 (2.1 x 50 mm, 1.7 p); Temp: 50 °C; Eluents: A = 0.05% HCO2H in H2O, B MeCN; Gradient: 0.0 min 98% A 0.75 min 98% A 1.0 min 90% A -> 2.0 min 2% A -> 2.25 min 2% A -> 2.9 min 98% A 3.0 min 98% A; Flow rate: 1.5 mL / min, Detection: UV 210 - 400 nm; Ionization: ESI / API; Mass range: 100 - 800 amu

[0114] Method F: Instrument: Waters ACQUITY SQD 2; HPLC: Waters ACQUITY H Class UPLC; Column: Acquity BEH C8 (2.1 x 50 mm, 1.7 p); Temp: 50 °C; Eluents: A= 0.05%HC02H inH2O, B = 0.05%HC02H in22 GRA 4222-foreign filingMcCN / FLO 9:1; Gradient: 0.0 min 95% A— > 0.75 min 95% A— > 1.5 min 75% A— > 3.0 min 5% A— > 4.0 min 5% A — > 4.5 min 95% A — > 5.1 min 95% A; Flow rate: 0.8 mL / min, Detection: UV 210 - 400 nm; Ionization: ESI / API; Mass range: 160 - 900 amu

[0115] Method H: Instrument: Waters ACQUITY SQD 2; HPLC: Waters ACQUITY H Class UPLC; Column: XBridge C18 (3.0 x 50 mm, 3.5 g); Temp: 50 °C; Eluents: A = 5 mM NEUOAc in H2O, B = 5 mM NFUOAc in McCN / FLO 9:1; Gradient: 0.0 min 95% A — > 0.75 min 95% A — > 1.0 min 70% A — > 2.0 min 2% A — > 2.5 min 2% A— >2.75 min 95% A— > 3.0 min 95% A; Flow rate: 1.2 mL / min, Detection: UV 210 - 400 nm; Ionization: ESI / API; Mass range: 160 - 900 amu

[0116] Method I: Instrument: Waters ACQUITY SQD 2; HPLC: Waters ACQUITY H Class UPLC; Column: XBridge C18 (3.0 x 50 mm, 3.5 g); Temp: 50 °C; Eluents: A = 5 mM NH4OAC in H2O, B = 5 mM NH4OAC in McCN / FLO 9:1; Gradient: 0.0 min 95% A — > 0.75 min 95% A — > 1.25 min 85% A — > 2.5 min 30% A — > 3.75 min 2% A 4.5 min 95% A — > 5.1 min 95% A; Flow rate: 1.2 mL / min, Detection: UV 220 / 260 nm; Ionization: ESI / API; Mass range: 100 - 900 amu

[0117] Method J: Instrument: Waters ACQUITY SQD 2; HPLC: Waters ACQUITY H Class UPLC; Column: Waters Acquity UPLC BEH C8 (2.1 x 50 mm, 1.7 g); Temp: 45 °C; Eluents: A = 0.05% TFA in H2O, B = 0.05% TFA in MeCN / HzO 9:1; Gradient: 0.0 min 98% A -> 1.2 min 98% A - 2.65 min 5% A — > 3.75 min 5% A - 4.9 min 98% A 5.1 min 98% A; Flow rate: 0.6 mL / min, Detection: UV 200 - 400; Ionization: ESI / API; Mass range: 100 - 900 amu

[0118] Method K: Instrument: Waters ACQUITY SQD 2; HPLC: Waters ACQUITY H Class UPLC; Column: XBridge C18 (3.0 x 50 mm, 3.5 g); Temp: 40 °C; Eluents: A = 5 mM NH4OAC in H2O, B = 5 mM NH4OAC in McCN / FLO 9:1; Gradient: 0.0 min 95% A — > 0.75 min 95% A — > 1.25 min 85% A — > 2.5 min 70% A — > 3.75 min 2% A— > 4.25 min 2% A— >4.5 min 95% A; Flow rate: 1.2 mL / min, Detection: UV 200 -400; Ionization: ESI / API; Mass range: 100 - 900 amu

[0119] Method L: Instrument: UPLC / MS TOF, Agilent 1290 Infinity II; Column: Waters Acquity HSS T3 (2.1 x 50 mm, 1.8 gm); Temp: 60°C; Eluents: A = 0.1%HCO2H inH2O, B = 0.1%HCO2H inMeCN, Gradient: 0.0 min 99% A— > 1.7 min 1%A; Flow rate: 2.0 mL / min, Detection: DAD 224 - 400 nm; Ionization: ESI, Mass range: 100 - 1000 amu.

[0120] Method M: Instrument: UPLC / MS, Waters Acquity; Column: C18 (2.1 x 50 mm, 1.7 gm); Temp: 22°C, Eluents: A = 0.025% NH4OH in H2O, B = MeCN; Gradient: 0.0 min 99% A — > 2.4 min 1% A; Flow rate: 0.75 mL / min, Detection: DAD 245 nm; Ionization: ESI / API, Mass range: 100 - 1000 amu.

[0121] Method N: Instrument: UPLC / MS, Waters Acquity; Column: Phenyl-Hexyl (2.1 x 50 mm, 1.7 gm); Temp: 22°C, Eluents: A = 0.025% NH4OH in H2O, B = MeCN; Gradient: 0.0 min 99% A — > 2.4 min 1% A; Flow rate: 0.75 mL / min, Detection: DAD 245 nm; Ionization: ESI / API, Mass range: 100 - 1000 amu.

[0122] Method O: Instrument: UPLC / MS, Waters Acquity, Column: C18 (2.1 x 50 mm, 1.7 gm); Temp: 80°C; Eluents: A = 0.1%HCO2H inH2O, B = MeCN; Gradient: 0.0 min 99% A— > 1.2 min 1% A; Flow rate: 1.5 mL / min; Detection: DAD 245 nm; Ionization ESI / API, Mass range: 100-1000 amu.23 GRA 4222-foreign filing

[0123] Method P: Instrument: Waters ACQUITY UPC2; Column: (R,R) WHELK-01 (4.6 mm x 150 mm, 5 g); Temp: 35 °C, Pressure: 1450 psi; Eluents: A = CO2, B = 0.3% / -PrNH2inMeOH; Isocratic 75% A; Flow rate: 3.0 mL / min;

[0124] Method Q: Instrument: Waters ACQUITY UPC2; Column: CHIRALCEL OX-H (4.6 mm x 250 mm, 5 g); Temp: 35 °C, Pressure: 1000 psi; Eluents: A = CO2, B = 0.3% / -PrNH2inMeOH; Isocratic 60% A; Flow rate: 3.5 mL / min;

[0125] Method R: Instrument: Waters ACQUITY UPC2; Column: Phenomenex Lux Amylose 2 (3 g); Temp: 40 °C, Pressure: 2000 psi; Eluents: A = CO2, B = 10 mM AmOH in MeOH; Gradient: 0.0 min 95% A —> 14 min 40% A; Flow rate: 1.5 mL / min;

[0126] Method S: Column: CHIRALPAK IG (4.6 x 250 mm. 5 g); Eluent: hexane / CH2C12 / EtOH / i-PrNH260 / 20 / 20 / 0.1; Flow rate: 1 mL / min; Temp: 25 °C

[0127] Method T: Column: CHIRALPAK IG (4.6 x 250 mm. 5 g); Eluent: hexane / EtOH / i-PrNH270 / 30 / 0.1; Flow rate: 1 mL / min; Temp: 35 °C

[0128] Method U: Column: CHIRALPAK AY-H (4.6 x 250 mm. 5 g); Eluent: hexane / EtOH / i-PrNH280 / 20 / 0.1; Flow rate: 1 mL / min; Temp: 25 °C

[0129] Method V:Column: CHIRALPAK IG (4.6 x 250 mm. 5 g); Eluent: hexane / EtOH / i-PrNH280 / 20 / 0.1; Flow rate: 1 mL / min; Temp: 25 °C

[0130] Method W: Instrument: Agilent 6890 GC with 5973N MSD, Column: HP-5MS (30 x 250 gm, 0.25 g); Carrier gas: helium; Flow rate: 1 mL / min; Temp, profile: 2 min 60 °C — > 5 min 100 °C —> 10 min 310 °C —> 4 min 310 °C.

[0131] Synthesis of intermediates:

[0132] Synthesis of INT-1 : tert-butyl (3S,4S)-4-(((benzyloxy)carbonyl)amino)-3-hydroxypiperidine-l-carbox-ylateOH

[0133] To a solution of (3S,4S)-4-amino-3-hydroxypiperidin-l-yl tert-butyl formate (5.0 g, 23.0 mmol) in CH2O2 (20 mL) were added benzyl chloroformate (5.8 g, 69.0 mmol), NaHCOs, (5.8 g, 69.0 mmol) and water (2 mL) at 0° C. Then the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was diluted with water and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with sat. NaCl solution, dried over anhyd. Na2SO i and concentrated under reduced pressure. The crude material was purified by column chromatography (silica, hexane / EtOAc 1:0 - 4:6) to obtain the title compound (7.8 g, 96%). LCMS m / z = 351 [M+H]+; Rt= 3.18 min (Method A).

[0134] Synthesis of INT-2 : tert-butyl (3S,4S)-4-(((benzyloxy)carbonyl)amino)-3-methoxypiperidine-l-carbox-ylate24 GRA 4222-foreign filingoH IxCb^A]L _N_Boc

[0135] To a stirred solution of alcohol INT-1 (7.5 g, 21.3 mmol) in CH2C12(225 mL) was added Ag2O (14.8 g, 64.0 mmol) and iodomethane (16.0 mL, 256 mmol) at room temperature and the mixture was heated to 40° C and stirred for 40 h at that temperature. The mixture was filtered through a pad of celite and concentrated under reduced pressure. The crude material was purified by column chromatography (silica, hexane / acetone 1:0 - 7:3) to afford the title compound (5.0 g, 64%). LCMS m / z = 309 [M+H-56]+; Rt= 3.41 min (Method A).

[0136] Synthesis of INT-3 : tert-butyl (3S,4S)-4-amino-3-methoxypiperidine-l-carboxylate

[0137] To a stirred solution of carbamate INT-2 (8.0 g, 10.9 mmol) in MeOH (250 mL) was added 10%-Pd / C (6.0 g) and the mixture was stirred at room temperature for 2 h under a H2atmosphere (ambient / balloon pressure). The mixture was filtered through a pad of celite and concentrated under reduced pressure. The crude material was purified by column chromatography (silica, CH2Cl2 / MeOH(+ NH3) 1 :0 - 9: 1)) to yield the title compound (4.0 g, 79%).1H NMR (400 MHz, DMSO-de, 100 °C) 83.94 (d, 1H), 3.69 (d, 1H), 3.35 (s, 3H), 2.93-2.87 (m, 1H), 2.78-2.65 (m, 3H), 1.75-1.71 (m, 1H), 1.57 (s, 9H), 1.26-1.14 (m, 1H). LCMS m / z = 231 [M+H]+;Rt= 6.53 min (Method C).

[0138] Synthesis of INT-4 : rac-tert-butyl (3S*,4S*)-4-azido-3-hydroxypiperidine-l-carboxylate

[0139] To a solution of mCPBA (15.5 g, 89.6 mmol) inCH2Cl2(150 mL) was added tert-butyl 3, 6-dihy dropyridine- l(2H)-carboxylate (15.0 g, 81.4 mmol) in CH2C12(75 mL) at 0 °C. The mixture was stirred at room temperature for 16h before it was diluted with 10% aqueous Na2S2O3and the mixture was basified with a sat. Na2CO3solution. The organic layer was separated, dried over anhyd. Na2SOi. filtered and concentrated under reduced pressure. The crude epoxide (15 g, 92%) was used without further purification.

[0140] To a stirred solution of above epoxide (5 g, 25.0 mmol) in a mixture of MeOH (50 mL) and water (50 mL) were added NaN3(3.25 g, 49.9 mmol) and NH4C1 (1.34 g, 25.0 mmol) at room temperature. The mixture was heated to 60 °C and stirred for 18 h at that temperature. The mixture was allowed to cool to room temperature and diluted with EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers was dried over anhyd. Na2SO i. filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (silica, hexane / EtOAc 1 :0 - 7:3 to afford the title compound (2.5 g, 41%). LCMS m / z = 343 [M+H]+; Rt= 2.97 min (Method A).

[0141] Synthesis of INT-5 : tert-butyl (3S,4S)-4-azido-3-hydroxypiperidine-l-carboxylate25 GRA 4222-foreign filing

[0142] To a solution of tert-butyl (3S,4S)-4-amino-3-hydroxypiperidine-l-carboxylate (5.0 g, 23 mmol, 1) in MeOH (63 mL) were added CuSO4-5H2O (0.58 g, 2.3 mmol) and K2CO2(1.6 g, 11 mmol) at room temperature. Imidazol-l-sulfonylazid (5.8 g, 28 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was diluted with H2O and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhyd. Na2SO i and concentrated under reduced pressure. The crude material was purified by column chromatography (silica, hexane / EtOAc 1:0 - 7:3) to obtain the title compound (4.0 g, 71%). 'H NMR (400 MHz, DMSO-de) d 5.57 (m, 1H), 3.91 (m, 1H), 3.81 (m, 1H), 3.39 (m, 1H), 3.25 (m, 1H), 2.75 (m, 1H), 2.56 (m, 1H), 1.82 (m, 1H), 1.38 (s, 9H), 1.22 (m, 1H).

[0143] Synthesis ofINT-6 : rac-tert-butyl (3S*,4S*)-4-azido-3-(2-methoxyethoxy)piperidine-l-carboxylate

[0144] To a stirred solution of alcohol INT-4 (0.7 g, 2.9 mmol,) in DMF (10 mL) was added NaH (60% in mineral oil, 0.17 g , 4.3 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 minutes followed by the addition of 1-bromo-2-methoxyethane (0.4 g, 2.9 mmol) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 3 h before crushed ice was introduced. The mixture was extracted with EtOAc and the organic layers were dried over anhyd. Na2SO4and concentrated under reduced pressure. The crude material was purified by column chromatography (silica, hexane / EtOac 1:0 - 6:4) to afford the title compound (0.8 g, 93%). LCMS m / z = 301 [M+H]+; Rt= 3.57 min (Method A).

[0145] Synthesis ofINT-7 : tert-butyl (3S,4S)-4-azido-3-((2-methylpyrimidin-5-yl)oxy)piperidine-l-carboxylate

[0146] To a solution of alcohol INT-5 (0.3 g, 1.2 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 0.2 g, 4.9 mmol) at room temperature. The mixture was stirred for 20 min before a solution of 5-fluoro-2 -methylpyrimidine (0.21 g, 1.9 mmol) in DMF (2.0 mL) was added and the mixture was stirred at 100 °C for 2 h. The mixture was diluted with H2O (50mL) and extracted with EtOAc (3 x 50 mL). The organic layer was washed with sat. aq. NaCl solution, dried over anhyd. Na2SO i and concentrated under reduced pressure. The crude material was purified by column chromatography (silica, hexane / EtOAc 1 :0 - 1 : 1) to obtain the title compound (0.2 g, 49%). LCMS m / z = 335 [M+H]+; Rt= 3.25 min (Method A).

[0147] Synthesis of INT-8: tert-butyl (3S,4S)-4-azido-3-(2,2-difluoroethoxy)piperidine-l-carboxylate26 GRA 4222-foreign filingFx^F<yN2 / ,.^k-N.Boc

[0148] To a solution of alcohol INT-5 (0.2 g, 0.82 mmol) in THF (10.0 mL) was added NaH (60% in mineral oil, 0.1 g, 1.6 mmol) at 0°C. The mixture was stirred for 20 min before 2,2-difluoroethyl trifluoromethanesulfonate (0.52 g, 2.5 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with sat. aq. NaCl solution, dried over anhyd. Na2SO i. and concentrated under reduced pressure to obtain the title compound (0.2 g, 79%), which was used for the next step without further purification. LCMS m / z = 307 [M+H]+; Rt= 3.67 min (Method A).

[0149] Synthesis of INT-9 : tert-butyl (3S,4S)-4-azido-3-(difluoromethoxy)piperidine-l-carboxylate

[0150] To a solution of alcohol INT-5 (0.25 g, 1.0 mmol) inMeCN (12 mL) was added Cui (0.1 g, 0.51 mmol) and the mixture was heated to 65 °C before 2,2-difluoro-2-(fluorosulfonyl)acetic acid (0.16 mL, 1.5 mmol) was added dropwise. The mixture was stirred at 60 °C for 30 min before it was transferred to a NaHCO, solution and stirred for 30 min at room temperature. The mixture was extracted with MTBE (2 x 50 mL) and the combined organic layers were washed with aqueous LiCI solution, dried over anhyd. Na2SO4and concentrated under reduced pressure. The crude material suspended in MeOH (10 mL) and 0.5 mL NaOMe solution (30% in MeOH) was added. The mixture was stirred for 5 min before water was added and the mixture was extracted with MTBE (3 x 50 ml). The combined organic layers were washed with water, dried over anhyd. Na2SO i and concentrated under reduced pressure. The crude material was purified by column chromatography (silica, hexane / EtOAc 1:0 - 3:7) to obtain the title compound (20 mg, 7%).!H NMR (400 MHz, CDCL) 36.31 (m, 1H), 3.97 (m, 1H), 3.88 (m, 1H), 3.53 (m, 1H), 2.96 (m, 2H), 2.00 (m, 1H), 1.44 (s, 9H), 0.9 (m, 1H).

[0151] Synthesis of INT-10: tert-butyl (3S,4S)-4-azido-3-ethoxypiperidine-l-carboxylate

[0152] To a solution of alcohol INT-5 (0.2 g, 0.83 mmol) in CH2C12(10 mL) was added Ag2O (0.6 g, 2.5 mmol) and iodoethane (0.33 mL, 4.1 mmol) at room temperature. The mixture was heated and stirred at 45°C for 48 h. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (silica, hexane / EtOAc 1:0 - 8:2) to obtain the title compound (0.2 g, 90%). LCMS m / z = 271 [M+H]+; Rt= 3.89 min (Method A).

[0153] Synthesis of INT-11: tert-butyl (3S,4S)-4-azido-3-(2 -hydroxy -2 -methylpropoxy )piperidine-l-carboxylate27 GRA 4222-foreign filing

[0154] To a stirred solution of alcohol INT-5 (0.3 g, 1.2 mmol) in DMF (6.0 mL) was added NaH (60 wt.% in mineral oil, 0.3 g, 3.1 mmol) at room temperature. The mixture was stirred for 20 mins before 2,2-dimethyloxirane (0.89 mL, 9.9 mmol) was added at room temperature. The mixture was heated to 50 °C and stirred for 16 h at that temperature. The mixture was diluted with H2O and extracted with EtOAc (2 x 30 mL). The organic layers were washed with aq. sat. NaCl solution, dried over anhyd. Na2SO i and concentrated under reduced pressure. The cmde material was purified by column chromatography (silica, hexane / acetone 1 :0 - 4: 1) to the title compound (95 mg, 25%). LCMS m / z = 315 [M+H]+; Rt= 3.61 min (Method A).

[0155] Synthesis of INT-12: tert-butyl (3S,4S)-4-azido-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)piperidine-1 -carboxylate, mixture of stereoisomers

[0156] To a stirred solution of alcohol INT-5 (0.5 g, 2.1 mmol) in DMF (8 mL) was added NaH (60 wt.% in mineral oil, 0.12 g , 3.1 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 minutes before 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.43 g, 2.1 mmol) was added at 0 °C. The mixture was stirred at room temperature for 3 h and subsequently ice water was added and the mixture was extracted with EtOAc. The combined organic layers were dried over anhyd. Na2SO4and concentrated under reduced pressure. The crude material was purified by column chromatography (silica, hexane / EtOAc 1:0 - 4:1) to obtain the title compound (0.34 g, 45 %). LCMS m / z = 371 [M+H]+; Rt= 2.18 min (Method H).

[0157] Synthesis of INT-13: tert-butyl (3S,4S)-4-azido-3-((tetrahydro-2H-pyran-4-yl)oxy)piperidine-l-carbox-ylate

[0158] To a stirred solution of alcohol INT-5 (0.47 g, 1.9 mmol) in DMF (15 mL) was added NaH (60 wt.% in mineral oil, 0.19 g, 4.9 mmol) at 0°C and the mixture was stirred for 10 minutes at that temperature before tetra-hydro-2H-pyran-4-yl 4-methylbenzenesulfonate (1.5 g, 5.8 mmol) was added and the mixture was stirred at 80°C for 16 h. The mixture was diluted with H2O and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over anhyd. Na2SO i and concentrated under reduced pressure. The crude material was purified by column chromatography (silica, hexane / acetone 1:0 - 4:1) to afford the title compound (100 mg, 15%). LCMS m / z = 327 [M+H]+; Rt= 3.72 min (Method A).28 GRA 4222-foreign filing

[0159] Synthesis of INT-14: tert-butyl (3 S,4S)-4-azido-3 -((tetrahydrofuran-3 -yl)oxy)piperidine- 1 -carboxylate, mixture of stereoisomers

[0160] To a stirred solution of alcohol INT-5 (0.5 g, 2.1 mmol) inDMF (8 mL) was added NaH (60 wt.% in mineral oil, 0.21 g , 5.1 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 minutes followed by addition of tetrahydro-furan-3-yl methanesulfonate (0.93 g, 6.2 mmol) at 0 °C. The mixture was heated to 70 °C and stirred for 16 h at that temperature. The mixture was allowed to cool to room temperature and ice water was added before it was extracted with EtOAc. The combined organic layers were dried over anhyd. Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography (silica, hexane / EtOAc 1 :0 - 4: 1) to obtain the title compound (0.35 g, 55%). LCMS m / z = 313 [M+H]+; Rt= 1.87 min (Method H).

[0161] Synthesis of INT-15: rac-tert-butyl (3 S*, 4S*)-4-amino-3-(2 -methoxyethoxy )piperidine-l-carboxylate

[0162] To a stirred solution of azide INT-6 (0.8 g, 2.7 mmol) in methanol (20 mL) was added 10%-Pd / C (0.6 g) at room temperature. The mixture was stirred at room temperature under hydrogenated atmosphere (ambient / balloon pressure) for 16 h before it was filtered through pad of celite. The filtrate was concentrated under reduced pressure and the crude title product (0.7 g, 96%) was used in the subsequent reaction without further purification.1H NMR (400 MHz, DMSO-de) d 3.70 - 3.66 (m, 2H), 3.65 - 3.53 (m, 1H), 3.52 - 3.39 (m, 2H), 3.25 (s, 3H), 2.87 - 2.80 (m, 2H), 2.58 (m, 1H), 1.72 - 1.67 (m, 1H), 1.55 (m, 2H), 1.39 (s, 9H), 1.15 - 1.10 (m, 1H).

[0163] The following compounds were prepared in analogy:LC-MS m / z [M+H]+, Rt Intermediate Structure Chemical Name Precursor[min] (Method) tert-butyl (3S,4S)-4-amino- r H3 -((2-methylpy rimidin-5 - 309, 2.24 INT-16H2NINT-7 / , Jx. y l)oxy )piperidine- 1 -carbox(A)Boc ylatetert-butyl (3S,4S)-4-amino- INT-17 3 -(2, 2-difhioroethoxy piperINT-8 281, 1.49 (I) idine- 1 -carboxylateBoc29 GRA 4222-foreign filingFtert-butyl (3S,4S)-4-amino- INT-18 3 -(difluoromethoxy piperiINT-9dine- 1 -carboxylateBoc1H NMR (400 MHz, DMSO-de) 36.78 (m, 1H), 3.95 (m, 1H), 3.63 (m, 2H), 2.93 (m, 1H), 2.71 (m, 1H), 1.74 (m, 2H), 1.39 (s, 9H), 1.19 (m, 1H)tert-butyl (3S,4S)-4-amino- 245, 1.55 INT-19H2N,„ Jx. 3 -ethoxypiperidine- 1 -carINT-10(A) boxylateBoc_V0Htert-butyl (3S,4S)-4-amino- 3-(2-hydroxy-2- 289, 2.62 INT-20 INT-11methylpropoxypiperidine- (A)L Boc 1 -carboxylateXk tert-butyl (3S,4S)-4-amino- < THP3 -(2-((tetrahydro-2H-pyran- CT 345, 1.62 INT-21 2-yl)oxy)ethoxy)piperidine- INT-12(H)L .N. 1 -carboxylate, mixture ofBocstereoisomerstert-butyl (3S,4S)-4-amino- 3 -((tetrahydro-2H-pyran-4- 301, 1.42 INT-22 A. INT-13y l)oxy piperidine- 1 -carbox(H)L _N.Boc ylatetert-butyl (3S,4S)-4-amino- R and 3 -((tetrahy drofuran-3 - 287, 1.92 INT-23 y l)oxy piperidine- 1 -carboxINT-14(H)L _N. ylate, mixture of stereoisoBocmers

[0164] Synthesis of INT-24: tert-butyl (S)-4-amino-3 -methylpiperazine- 1 -carboxylate

[0165] To a solution of NaOH (55 mg, 1.4mmol) in H2O (32 pL) was added tert-butyl (S)-3 -methylpiperazine- 1-carboxylate (500 mg, 2.5 mmol) at 55 °C and the mixture was stirred for 15 min at that temperature. The mixture was cooled to 40°C before a solution of hydroxy lamine-O-sulfonic acid (280 mg, 2.5 mmol) in H2O (175 pL) were added in five portions over 30 minutes. The mixture was stirred for 15 min at 55 °C before more NaOH (55 mg, 1.4 mmol) was added and stirring was continued for 30 min at the same temperature. The mixture was allowed to cool to room temperature and diluted with EtOAc (25 mL) and sat. aq. NaHCOs, solution (10 mL). The layers were30 GRA 4222-foreign filingseparated and the aqueous layer was extracted with EtOAc (25 mL) The combined organic layers were dried over MgSC>4 and concentrated under reduced pressure to afford the title compound (460 mg, 85 %) which was used in the next step without further purification. LCMS m / z = 216 [M+H]+; Rt= 1.45 min (Method M).

[0166] The following compounds were prepared in analogy:? 1z / LC-MS m / z z y— / Y mmM- [M+H]+, Rt Intermediate Structure Chemical Name PrecursorZ / co [min] (Meo 0 thod)tert-butyltert-butyl 4-amino-4,7-dia- 4,7-dia- 228, 0.98 INT-25 ".N,NK zaspiro [2.5] octane-7 -carzaspiro[2.5]L _N. (N)Boc boxylate octane-7- carboxylatetert-butyltert-butyl (2R,5S)-4-amino- (2R,5S)-2,5- 230, 1.02 INT-26 2,5-dimethylpiperazine- 1 - dimethylpi- (N) carboxylate perazine-1- oO carboxylateCD / z meso-tert- ✓ nZm«z— / meso-tert-butyl 4-amino- butyl 3,5-di- H2N t.z 230, 1.08 INT-27 N >z 3 ,5 -dimethylpiperazine- 1 - methylpiper- (M) carboxylate azine-1 -carboxylatetert-butyltert-butyl (R)-4-amino-3- (R)-3- 216, 0.50 INT-28 methylpiperazine- 1 -carboxmethylpiper- (O) ylate azine-1 -carboxylatetert-butyltert-butyl (S)-4-amino-3- (S)-3- 230, 1.00 INT-29 H,N. JLN‘ S ethylpiperazine- 1 -carboxethylpipera- (N)Boc ylate zine-1 -carboxylatetert-butyl(2S,5S)-5- tert-butyl (2S,5S)-4-amino- 144 [M+H- H,M. JL ethyl-2- INT-30 N 5-ethyl-2-methylpiperazine- Boc]+, 9.76 L -N- Boc methylpiper- 1 -carboxylate (W)azine-1 -carboxylate31 GRA 4222-foreign filing

[0167] Synthesis of INT-31: rac-tert-butyl (2S*,3R*)-4-amino-2,3-dimethylpiperazine-l-carboxylate

[0168] To a solution of NaOH (55 mg, 1.4mmol) in H2O (140 pL) was added tert-butyl (S)-3-methylpiperazine-l-carboxylate (250 mg, 1.2 mmol) at 55 °C and the mixture was stirred for 15 min at that temperature. The mixture was cooled to 40 °C before O-(4-Nitrobenzoyl)hydroxylamine (400 mg, 2.2 mmol) was added in five portions over 30 minutes. The mixture was stirred for 15 min at 55 °C before more NaOH (55 mg, 1.4 mmol) was added and stirring was continued for 30 min at the same temperature. The mixture was allowed to cool to room temperature and diluted with EtOAc (25 mL) and sat. aq. NaHCOs, solution (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (25 mL) The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to afford the title compound (171 mg, 64 %) which was used in the next step without further purification. LCMS m / z = 230 [M-H]-; Rt= 1.02 min (Method N).

[0169] The following compounds were prepared in analogy:LC-MS m / z [M+H]+, Rt Intermediate Structure Chemical Name Precursor[min] (Method) tert-butyltert-butyl (3S,5S)-4-amino- (3S,5S)-3,5- H,N. JL 230, 1.08 INT-32 N > 3 ,5 -dimethylpiperazine- 1 - dimethylpi- J - ,NX(N)Boc carboxylate perazine-1- carboxylatetert-butylH2N^ JL tert-butyl (2S,5S)-4-amino- (2S,5S)-2,5- 230, 1.00 INT-33 2,5-dimethylpiperazine- 1 - dimethylpi- Boc (N)carboxylate perazine-1- carboxylatetert-butyl1 (R)-3-(meth- 0. tert-butyl (R)-4-amino-3- oxyme- 246, 0.99 INT-34 H,N. JL (methoxymethyl)piperazine- N thyl)pipera- (N)L -N. 1 -carboxylateBoc zine-1 -carboxylaterac-tert-burac-tert-butyl (2R*,3R*)-4- H2N^N tyl 230, 1.07 INT-35 amino-2, 3 -dimethylpipera(2R*,3R*)- (N)Boc zine- 1 -carboxylate2,3-32 GRA 4222-foreign filingdimethylpiperazine- 1- carboxylatetert-butyltert-butyl (S)-4-amino-3 -iso(S)-3 -iso244, 1.52 INT-36 H2N. JLN' S propylpiperazine- 1 -carboxpropylpiper(M)Boc ylate azine- 1-car- boxylate

[0170] Synthesis of INT-37: rac-2-(3,5-dimethylphenoxy)-2-methylbutanoic acido

[0171] To a solution of 3,5-dimethylphenol (1.0 g, 8.2 mmol) in THF (60 mL) was added NaOH (2.9 g, 73 mmol) and the mixture was stirred for 15 minutes at room temperature before butan-2-one (5.9 g, 81 mmol) was added. The mixture was cooled to 0°C and anhyd. CHC13(2.6 g, 20 mmol) was added dropwise. The mixture was stirred at 0 °C for 2 h and then allowed to warm to room temperature and stirred for 16 h. The mixture was concentrated under reduced pressure and the residue was dissolved inEtOAc (50 mL) and washed with H2O (30 mL). The aqueous layer was acidified to pH ~ 2 with aq. NaHSO i and extracted withEtOAc (3 x 50 mL). The combined organic layers were washed with sat. aq. NaCl solution (30 mL), dried over anhyd. Na2SO i and concentrated under reduced pressure. The crude material was purified by column chromatography (silica, hexane / EtOAc 1:0 - 3 :7) to obtain the title compound (50 mg, 4 %). LCMS m / z = 221 [M-H]-; Rt= 2.44 min (Method B).

[0172] The following compounds were prepared in analogy:LC-MS m / z [M+H]+, Rt Precursor Intermediate Structure Chemical Name[min] (Method) 4-(3 , 5 -dimethylphenoxy )tet- tetrahydro- 251, 1.81 INT-38 AQ- rahydro-2H-pyran-4-carbox- 4H-pyran-4- (D)0 ylic acid oneAQ- 1 -(3 , 5 -dimethylphenoxy )cy- cyclohexa249, 2.11 INT-39clohexane-1 -carboxylic acid none (D)0

[0173] Synthesis of INT-40: 2,2-difluoro-2-(2,4,5-trifluorophenoxy)acetic acid33 GRA 4222-foreign filing

[0174] To a stirred O solution of 2-bromo-2,2-difluoroacetic acid (0.25 g, 1.43 mmol) in dioxane (10 mL) was added 2,3,5-trifluorophenol (0.21 g, 1.43 mmol) and stirred for 5 minutes at 0°C. NaH (60% in mineral oil, 0.12 g, 3.0 mmol) was ad pd 0ed and o the mixture was heated to 100 °C and stirred for 16 h at that temperature. The mixture was acidified with sodium bisu olf V"n’zate solution and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with sat. NaCl solutio o / 71n z (20 mL), dried over anhyd. NaiSO i. filtered and concentrated under reduced opressure. The crude material was purifie Xd by column chromatography (silica, hexane / EtOac 1 :0 - 0: 1) to afford the title compound (0.31 g, 90%). LCMS m / z = 241 [M-H]-; Rt= 1.56 min (Method E).

[0175] The following compounds were prepared in analogy:LC-MS m / z [M-H]; RtIntermediate Structure Chemical Name Precursor[min] (Method)O2,2-difluoro-2-(3,4,5-tri- 3,4,5-tri- INT-41fluorophenoxy)acetic acid fluorophenolNMR (400 MHz, DMSO-de) <57.37 (m, 2H)F2,2-difluoro-2-(2,3,5-tri- 2,3,5-tri241, 2.30 INT-42 r il V X -OHF O fluorophenoxy)acetic acid fluorophenol (F)F OCl2-(3 -chloro-4, 5 -difluorophe- 3 -chloro - 257, 1.82 INT-43 noxy)-2,2-difluoroacetic 4,5-difluoro- F YS vO (E)acid phenol02-(4-chlorophenoxy)-2,2- 4-chlorophe- 221, 1.54 INT-44difluoroacetic acid nol (E)2,4-difluoro- 2-(2,4-difluoro-3- 3- 237, 1.55 INT-45 Y^jT V -OH methylphenoxy)-2,2- methylphe- (D)0 difluoroacetic acidnol2, 2-difluoro-2 -phenoxyace187, 1.17 INT-46 phenoltic acid (D)34 GRA 4222-foreign filing3,4-difluoro- 2-(3,4-difluoro-5- 5- 237, 1.59 INT-47 methylphenoxy)-2,2- methylphe- (D) difluoroacetic acidnol■n -n T|2-(3-chlorophenoxy)-2,2- 3-chlorophe- 221, 1.50 INT-48 7~ \ O -n \ V71difluoroacetic acid nol (E)o o / "H O^^ / Tl _OXo o 2-fluoro-3- 2,2-difluoro-2-(2-fluoro-3 - INT-49 methylphe- methylphenoxy)acetic acidnolNMR (400 MHz, DMSO-de) 37.20 (m, 2H), 7.11 (m, 1H), 2.27 (s, 3H)F2-(3 , 5 -difluorophenoxy )- 3,5-difluoro- INT-50 Jk. V .OH 2,2-difluoroacetic acid phenol0NMR (400 MHz, DMSO-de) 37.27 (m, 1H), 7.07 (m, 2H)Cl OX 2-(3-chloro-4-fluorophe- o 3-chloro-4- 239, 2.38 INT-51 ^ u.°=noxy)-2,2-difluoroacetic YS o V .OHLL / \o011 fluorophenol (A) 0 acid3-fluoro-5- 2,2-difluoro-2-(3-fluoro-5- INT-52 methylphe- methylphenoxy)acetic acidnolNMR (400 MHz, DMSO-de) 37.03 (m, 1H), 6.94 (m, 2H), 2.34 (s, 3H)4-fluoro-3- 2,2-difluoro-2-(4-fluoro-3 - 220, 1.59 INT-53 methylphe- methylphenoxy)acetic acid (D)nol2-(3 , 5 -dimethy Iphenoxy )- 215, 2.47 3,5-dime- f jl V INT-54 Ik OH 2,2-difluoroacetic acid thylphenol ' o (A)oCl2-(3-chloro-5-fluorophe- 3-chloro-5- 239, 1.48 INT-55 noxy)-2,2-difluoroacetic v Jk OH fluorophenol (D)acid02,2-difluoro-2-(m-tol- INT-56 m-cresol Ml Vyloxy)acetic acid0NMR (400 MHz, DMSO-de) 37.31 (m, 1H), 7.11 (m, 1H), 7.02 (m, 2H), 2.32 (s, 3H)35 GRA 4222-foreign filingCl2-(3 , 5 -dichlorophenoxy )- 3,5-dichloro- 255, 1.62 INT-57cr r ^^il 0 V 2,2-difluoroacetic acid phenol (D)0Cl2-(3-chloro-5-methylphe- 3-chloro-5- INT-58 V JC -OH noxy)-2,2-difluoroacetic methylphe- 0° -n acid nol0NMR (400 MHz, DMSO-de) 37. O25 (s, 1H), 7.11 (s, H), 7.06 (s, 1H), 2.33 (s, 3H)XCl2-(3-chloro-2-fluorophe- 3-chloro-2- INT-59 Ar v0yc .OH noxy)-2,2-difluoroacetic11 fluorophenol0 acidNMR (400 MHz, CDCI3) 37.29 (m, 2H), 7.08 (m, 1H)2-fluoro-5- 2,2-difluoro-2-(2-fluoro-5- 219, 1.56 INT-60 methyl- methylphenoxy)acetic acid (E)phenolX 3,5-dime- 00^ ^ >0°== thylben- 2-((3,5-dime- used di(OA ( zenethiol andINT-61 thylphenyl)thio)-2- rectly in 2-bromo-2- methylpropanoic acid next step methylpro- panoic acid2-((3,5-dime- 3,5-dime- 231, 2.64 INT-62 thylphenyl)thio)-2,2- thylben- (A) difluoroacetic acid zenethiol

[0176] Synthesis of INT-63: ethyl 2-((4,6-dimethylpyridin-2-yl)thio)-2,2-difluoroacetateo

[0177] To a mixture of CS2CO3 (470 mg, 1.4 mmol) in DMF (2 mL) was added a solution of 4,6-dimethylpyridine-2-thiol (100 mg, 0.72 mmol) in DMF (2 mL) under nitrogen atmosphere and the mixture was stirred for 5 minutes at room temperature before ethyl 2-bromo-2,2-difluoroacetate (290 mg, 1.4 mmol) was added. The mixture was stirred for 4 h at room temperature before it was diluted with EtOAc (15 mL) and aq. sat. NaHCO3solution (10 mL). The layers were separated, dried over MgSO4and the organic layer was concentrated under reduced pressure. The crude material was purified by preparative HPLC (Puriflash Interchim, column: PHC4 150-212, elution with FLO / MeCN 75:25 - 0 / 1) to afford the title compound (70 mg, 37 %). LCMS m / z = 262 [M-H]-; Rt= 0.69 min (Method O).36 GRA 4222-foreign filing

[0178] Synthesis of INT-64: 2-((4,6-dimethylpyridin-2-yl)thio)-2,2-difluoroacetic acid

[0179] A mixture of NaOH (2 M in H2O, 0.67 mL, 1.3 mmol) and ester INT-63 (70 mg, 0.27 mmol) in EtOH (3 mL) was stirred for 60 minutes at 40°C. The mixture was concentrated under reduced pressure and the residue was diluted with CH2O2 (20 mL) and HO (1 M in H2O, 5 mL). The layers were separated, and the organic layer was concentrated under reduced pressure to afford the title compound which was used in the next step without further purification.

[0180] Synthesis of INT-65: ethyl 2-((4,6-dimethylpyridin-2-yl)oxy)-2-methylpropanoate

[0181] To a mixture of 4,6-dimethylpyridin-2(lH)-one (500 mg, 4.1 mmol) and CS2CO3 (5.3 g, 16 mmol) inDMF (14 mL) was added ethyl 2-bromo-2-methylpropanoate (4 g, 20 mmol) at room temperature and the mixture was heated to 60 °C and stirred for 16 h at the same temperature. The mixture was allowed to cool to room temperature and filtered. The solid residue w 0as washed with EtOAc (50 mL) and the combined organic layers were concentrated under reduced pressure. The crude material was purified by colum chromatography (silica, hexane / EtOAc 19:1)0 —to afford the title compound (520 mg, 54 %). LCMS m / z = 237 [M+H]+; Rt= 1.09 min (Method L). NMR (6000MHz, DMSO-de) <56.62 (s, 1H), 6.39 (s, 1H), 4.03 (q, 2H), 2.21 (s, 3H), 2.20 (s, 3H), 1.54 (s, 6H), 1.05 (t, 3H).

[0182] The following compounds were prepared in analogy:LC-MS m / z [M+H]+, Rt Intermediate Structure Chemical Name Precursor[min] (Method) 6-chloro-4- ethyl 2-((6-chloro-4- methylpyri- 258, 0.78 INT-66 methylpyridin-2-yl)oxy)-2- din-2(lH)- (O) methylpropanoateoneCl 4-chloro-6- ethyl 2-((4-chloro-6- methylpyri- 258, 0.81 INT-67 methylpyridin-2-yl)oxy)-2- din-2(lH)- (O) methylpropanoate0 one

[0183] Synthesis of INT-68: 2-((4,6-dimethylpyridin-2-yl)oxy)-2 -methylpropanoic acid37 GRA 4222-foreign filingo

[0184] To a solution of ester INT-65 (520 mg, 2.2 mmol) in EtOH (22 mL) was added NaOH (2 M in H2O, 2.2OmL, 4.4 mmol) and the mixture was stirred for 4 h at 60 °C. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was suspended in CH2O2 (20 mL) and HC1 (2 M in H2O, 2 mL) was added to adjust the pH 0 to 2 - 3. The layers were separated and the organic layer was concentrated under reduced pressure to yield the title compound (440 mg, 96%) which was used in the next step without further purification. LCMS m / z = 210 [M+H] 0+X; Rt= 0.59 min (Method L). NMR (600 MHz, DMSO-d6) d 6.61 (s, 1H), 6.37 (s, 1H), 2.23 (s, 3H), 2.19 (s, 3H), 1.55 (s, 6H). It is appreciated that isolation of the title compound as either salt or zwitterion could be achieved under the appropriate conditions.

[0185] The following compounds were prepared in analogy:LC-MS m / z [M+H]+, Rt Intermediate Structure Chemical Name Precursor[min] (MeX thod) 02-((6-chloro-4-methylpyri- 230, 0.57 INT-69 0 din-2-yl)oxy)-2 -methylproINT-66(O) panoic acid2-((4-chloro-6-methylpyri- 230, 0.65 INT-70 din-2-yl)oxy)-2 -methylproINT-67(O) panoic acid

[0186] Synthesis of INT-71: rac-2-cyclopropyl-2-(3,5-dimethylphenoxy)acetic acido

[0187] To a stirred solution of 3, 5 -dimethylphenol (1.0 g, 8.19 mmol) in dioxane (40 mL) was added NaH (60% in mineral oil, 0.65 g, 16.4 mmol) and stirred for 15 minutes at room temperature. Rac-ethyl 2-bromo-2-cyclo-propylacetate (1.58 g, 8.19 mmol) was added dropwise and the mixture was heated to 80°C and stirred for 16 hat that temperature. The mixture was diluted with water (30 mL) and extracted withMTBE (30 mL). The aqueous layer was acidified (pH ~ 2) with NaHSO i solution and extracted withEtOAc (50 x 2 mL). The EtOAc layer was washed with sat. NaCl solution (30 mL), dried over anhyd. ISfeSCL and concentrated under reduced pressure. The crude material was purified by column chromatography (silica, hexane / EtOAc 1:0 - 1:1) to afford the title compound (0.76 g, 41%). LCMS m / z = 219 [M-H]’; Rt= 2.28 min (Method B).

[0188] The following compound was prepared in analogy:38 GRA 4222-foreign filingLC-MS m / z [M-H]-, RtIntermediate Structure Chemical Name Precursor[min] (Method) rac-ethyl 2- rac-2-(3,5-dimethylphe- 207, 2.10 INT-72 bromobuta- noxy)butanoic acid (B)0 noate

[0189] Synthesis of INT-73: 5-fluoro-4,6-dimethylpyridin-2(lH)-one

[0190] A mixture of 2, 4-dimethyl-6-oxo-l,6-dihydropyridine-3 -carboxy lie acid (250 mg, 1.5 mmol), selectfluor (690 mg, 1.9 mmol) and LiOAc (300 mg, 4.5 mmol) in 1,2-DCE (7.5 ml) and H2O (1.5 mL) was heated to 70°C under nitrogen atmosphere and stirred for 16 h at that temperature. The mixture was diluted with CH2C12(20 mL) and the layers were separated. The organic layer was concentrated under reduced pressure to yield the title compound which was used in the next step without further purification. LCMS m / z = 142 [M+H]+; Rt= 0.43 min (Method L).

[0191] Synthesis of INT-74: ethyl 2-((5-fluoro-4,6-dimethylpyridin-2-yl)oxy)-2-methylpropanoateo

[0192] To a stirred mixture of CS2CO3 (1.6 g, 4.8 mmol) and crude pyridone INT-73 (170 mg, 1.20 mmol) in DMF (4 mL) was added ethyl 2-bromo-2-methylpropanoate (0.90 mL, 6.0 mmol) under nitrogen atmosphere and the mixture was stirred at 60°C for 4 h. The mixture was allowed to cool to ambient temperature and diluted with EtOAc (20 mL). The precipitate was filtered off and washed with EtOAc (20 mL). The combined organic layers were concentrated under reduced pressure and the crude material was purified by column chromatography (silica, cyclohexane / EtOAc 9:1) to afford the title compound (30 mg, 10%). LCMS m / z = 256 [M+H]+; Rt= 0.79 min (Method O).

[0193] Synthesis of INT-75: 2-((5-fluoro-4,6-dimethylpyridin-2-yl)oxy)-2 -methylpropanoic acid

[0194] To a solution of ester INT-74 (30 mg, 0.12 mmol) in EtOH (1.2 mL) was added NaOH solution (2 M in H2O, 0.12 mL, 0.24 mmol) and the mixture was heated to 60°C and stirred for 2h at that temperature. The mixture was allowed cool to room temperature and stirred for 16 h. The mixture was concentrated under reduced pressure39 GRA 4222-foreign filingto afford the title compound as its sodium carboxylate salt which was used in the next step without further purification. LCMS m / z = 228 [M+H]+; Rt= 0.63 min (Method O).

[0195] Synthesis of INT-76: 2,3-difluoro-4-iodo-6-methylpyridine

[0196] To a solution of 2,3-difluoro-6-methyl-pyridine (500 mg, 3.9 mmol) in THF (10 mL) was added LDA (2 M in THF, 4.6 mmol, 2.3 mL) dropwise at -78 °C and stirred for 1 h at that temperature. A solution of L (1.4 g, 5.4 mmol) in THF (5 mL) was added and the mixture was stirred for 1 h at -78 °C. The mixture was allowed to warm to room temperature, diluted with EtOAc (100 mL) and washed with aq. sat. ^28263 (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were concentrated under reduced pressure and the crude material was purified by column chromatography (silica, cyclohexane / EtOAc 19:1) to afford the title compound (800 mg, 81 %). 'H NMR (600 MHz, DMSO-de) d 7.71 (m, 1H), 2.36 (d, 3H).

[0197] Synthesis of INT-77: methyl 2-((3-fluoro-4-iodo-6-methylpyridin-2-yl)oxy)-2-methylpropanoate

[0198] To a mixture of CS2CO3 (1.5 g, 4.7 mmol) and fluoropyridine INT-76 (600 mg, 2.4 mmol) in DMF (16 mL) was added methyl 2-hydroxy-2-methylpropanoate (0.32 mL, 2.8 mmol) under nitrogen atmosphere. The mixture was heated to 90°C and stirred for 4 h at that temperature before it was allowed to cool to ambient temperature and diluted with EtOAc (50 mL). The precipitate was fdtered and washed with EtOAc (30 mL). The combined organic layers were concentrated under reduced pressure and the crude material was purified by column chromatography (silica, cyclohexane / EtOAc 19: 1) to afford the title compound (140 mg, 17 %). LCMS m / z = 354 [M+H]+; Rt= 1.15 min (Method L).

[0199] Synthesis of INT-78: methyl 2-((3-fluoro-4,6-dimethylpyridin-2-yl)oxy)-2-methylpropanoateo

[0200] To a solution of iodopyridine INT-77 (140 mg, 0.40 mmol) and AtaPhos-PdCL (28 mg, 0.04 mmol) in 1,4-dioxane (4 mL) was added NaOH (2 M in H2O, 0.59 mL, 1.2 mmol) under nitrogen atmosphere. Trimethylboroxine (0.06 mL, 0.44 mol) was added, and the mixture was heated to 60 °C and stirred for 1 h at that temperature. The mixture was allowed to cool to room temperature, was diluted with EtOAc (20 mL) and washed with H2O (10 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by column chromatography (silica, cyclohexane / EtOAc 19: 1) to afford the title compound (60 mg, 63 %). LCMS m / z = 242 [M+H]+; Rt= 0.65 min (Method O).

[0201] Synthesis of INT-79: 2-((3-fluoro-4,6-dimethylpyridin-2-yl)oxy)-2 -methylpropanoic acid40 GRA 4222-foreign filingo

[0202] To a mixture of ester INT-78 (60 mg, 0.25 mmol) in MeOH (2.5 mL) was added NaOH (2 M in H2O, 0.25 mL, 0.50 mmol) at room temperature and the mixture was heated to 60 °C and stirred for 3 h at that temperature. The mixture was allowed to cool to room temperature and stirred for 16 h at that temperature. The mixture was concentrated under reduced pressure and the crude material was suspended in CH2O2 (lOmL) and H2O (1 mL). The aqueous layer was acidified to pH ~ 3 - 4 and the layers were separated. The organic layer was concentrated under reduced pressure to afford the title compound (50 mg, 88 %) which was used in the next step without further purification. LCMS m / z = 228 [M+H]+; Rt= 0.86 min (Method L).

[0203] Synthesis of INT-80: rac-ethyl 2-((4,6-dimethylpyridin-2-yl)oxy)-2-fluoroacetate

[0204] To a solution of 4,6-dimethylpyridin-2(lH)-one (1.0 g, 8.1 mmol) and ethyl 2-bromo-2-fluoroacetate (1.5 g, 8.1 mmol) in MeCN (50 mL) was added CS2CO3 (5.3 g, 16 mmol) at room temperature and and the mixture was stirred at 70 °C for 16 h. The mixture was allowed to cool to room temperature, filtered through pad of celite and was concentrated under reduced pressure. The crude material was purified by column chromatography (silica, hexane / EtOAc 1:0 - 1:1) to afford the title compound (1.5 g, 81%). LCMS m / z = 228 [M+H]+; Rt= 3.55 min (Method A).

[0205] Synthesis of INT-81: rac-2-((4,6-dimethylpyridin-2-yl)oxy)-2 -fluoroacetic acid

[0206] To a solution of ester INT-80 (1.0 g, 4.4 mmol) in a mixture of THF (10 mL), MeOH (10 mL) and H2O (5 mL) was added LiOH-H2O (0.21 g, 8.8 mmol) at room temperature and the mixture was stirred at 50 °C for 2 h. The mixture was allowed to cool to room temperature, concentrated under reduced pressure and the residue was dissolved in H2O (10 mL). The aqueous layer was acidified with HO (1 M in H2O) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhyd. Na2SO4and concentrated under reduced pressure to obtain the title compound (850 mg, 94 %) which was used in the next step without further purification. LCMS m / z = 200 [M+H]+; Rt= 1.77 min (Method A).

[0207] Synthesis of INT-82: rac-ethyl 2-((4,6-dimethylpyridin-2-yl)oxy)butanoate41 GRA 4222-foreign filing

[0208] To a solution of 4,6-dimethylpyridin-2(lH)-one (2.0 g, 16 mmol) and ethyl 2-bromobutanoate (3.2 g, 16 mmol) in MeCN (60 mL) was added CS2CO3 (10.5 g, 32 mmol) at room temperature. The mixture was stirred at 70 °C for 16 h before it was allowed to cool to room temperature and filtered through a pad of celite. The mixture was concentrated under reduced pressure and the crude material was purified by column chromatography (silica, hexane / EtOAc 1:0 - 4:1) to obtain the title compound (1.5 g, 40 %). LCMS m / z = 238 [M+H]+; Rt= 4.14 min (Method A).

[0209] Synthesis of INT-83: rac-2-((4,6-dimethylpyridin-2-yl)oxy)butanoic acid

[0210] To a solution of ester INT-82 (1.0 g, 4.2 mmol) in a mixture of MeCN (10 mL) andH2O (10 mL) was added NaOH (0.34 g, 8.4 mmol) at room temperature. The mixture was stirred at 50 °C for 16 h before it was allowed to cool to room temperature and concentrated under reduced pressure to obtain the title compound (1.5 g, 40 %) which was used in the next step without further purification. LCMS m / z = 210 [M+H]+; Rt= 1.75 min (Method A).

[0211] Synthesis of INT-84: rac-2-(3,5-dimethylphenoxy)-2 -fluoroacetic acid

[0212] To a solution of 3, 5 -dimethylphenol (100 mg, 0.82 mmol) in THF (3.3 mL) was added NaH (69 mg, 1.7 mmol) in portions at 0 °C and the mixture was stirred for 20 min at that temperature before a solution of 2-bromo-2-fluoroacetic acid (128 mg, 0.82 mmol) in THF (1.5 mL) was added. The mixture was allowed to warm to room temperature and was stirred for 30 min before H2O (5 mL) and HO (1 M in H2O, 5 mL) were added. The mixture was extracted with EtOAc (2 x 10 mL) and the layers were separated. The combined organic layers were dried over anhyd. MgSO i and concentrated under reduced pressure to afford the title compound (195 mg, crude) as its sodium carboxylate salt which was used in the next step without further purification.

[0213] Synthesis of INT-85: l-(3,5-dimethylphenoxy)cyclobutane-l-carboxylic acidA / - 0

[0214] To a stirred solution of 3, 5 -dimethylphenol (1.5 g, 12.3 mmol) in dioxane (40 mL) was added NaH (60% in mineral oil, 0.98 g, 24.6 mmol) and stirred for 15 minutes at room temperature. Ethyl 1 -bromocyclobutane- 1-carboxylate (2.6 g, 12.3 mmol) was added dropwise, and the mixture was heated to 90 °C and stirred for 16 at that temperature. The mixture was allowed to cool to room temperature before water (50 mL) was carefully added. The mixture was extracted with EtOAc (30 mL) and the aqueous layer was acidified (pH ~ 2) with cone. HO. The aqueous layer was extracted with EtOAc (50 mL) and the acidic organic extract was washed with sat. NaCl solution (20 mL), dried over anhyd. Na2SO4and concentrated under reduced pressure. The crude was purified by42 GRA 4222-foreign filingcolumn chromatography (silica, hexane / EtOAc 2:1) to the title compound (1.7 g, 63%). LCMS m / z = 219 [M-H]- ; Rt = 1.51 min (Method B).

[0215] Synthesis of INT-179: methyl 2-methyl-2-(naphthalen-l-yloxy)propanoate

[0216] To a stirred solution of naphthalen-l-ol (0.50 g, 3.47 mmol) and methyl 2-hydroxy-2-methylpropanoate (0.82 g, 6.94 mmol) in toluene (8 mL) was added PPh3(1.36 g, 5.20 mmol) and DIAD (1.02 mL, 5.20 mmol) and the reaction mixture was stirred at 110 °C for 16 h. Then, the reaction mixture was diluted with EtOAc (50 mL) and washed with water (10 mL) and sat. NaCl solution (3x10 mL). The organic layer was dried over anhyd. Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography (silica, hex-ane / EtOAc 1:0 - 0:1) to afford the title compound (0.53 g, 62%). LCMS m / z = 245 [M-H]-; Rt= 3.71 min (Method A).

[0217] The following compounds were prepared in analogy:LC-MS m / z [M+H]+, Rt Intermediate Structure Chemical Name Precursors[min] (Method) methyl 2-([l,l'-biphenyl]-3- [l,l'-biphe- 271, 3.78 INT-180yloxy)-2-methylpropanoate nyl]-3-ol (A)methyl 2-methyl-2-(3 -phe3 -phenoxy- 287, 2.08 INT-181noxyphenoxy )propanoate phenol (D)0

[0218] Synthesis of INT-182: 2-methyl-2-(naphthalen-l-yloxy)propanoic acid

[0219] To a solution of INT-179 (0.53 g, 2.17 mmol) in THF:MeOH: water (1:1:1, 9 mL) was added LiOH H2O (0.18 g, 4.35 mmol) and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by addition of NaHSO i solution, and then was diluted with EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhyd. Na2SO i and concentrated under reduced pressure to afford the title compound (0.47 g, 93 %) LCMS m / z = 229 [M-H]-; Rt= 2.01 min (Method E).

[0220] The following compounds were prepared in analogy:43 GRA 4222-foreign filingLC-MS m / z [M+H]+, Rt Intermediate Structure Chemical Name Precursors[min] (Method) 2-( [ 1 , 1 ’-biphenyl] -3 -y loxy )- 255, 2.09 INT-183 INT-1802-methylpropanoic acid (E)2-methyl-2-(3 -pheno xyphe- 273, 2.82 INT-184 INT-181noxy)propanoic acid (F)0

[0221] Synthesis of INT-86: tert-butyl (3S,4S)-4-(2-(4-fluoro-3,5-dimethylphenoxy)-2-methylpropanamido)-3-methoxypiperidine- 1 -carboxylate

[0222] To a mixture of NaH (60% in mineral oil, 48.0 mg, 1.2 mmol) inDMF (1 mL) under nitrogen atmosphere was added 4-fluoro-3,5-dimethyl-phenol (84.0 mg, 0.60 mmol) in DMF (1 mL) at room temperature and the mixture was stirred for 30 minutes. A solution of 2-bromo-2 -methyl-propanoic acid (100 mg, 0.60 mmol) in DMF (1 mL) was added and the mixture was heated to 70 °C and stirred for 4 h at that temperature. The was allowed to cool to room temperature and was diluted with EtOAc (20 mL) and water (5 mL). The layers were separated, and the aqueous layer was acidified with 1 M HO solution (2 mL). The layers were separated, and the acidic organic layer was concentrated under reduced pressure. The crude carboxylic acid (136 mg) was used in the next step without further purification.

[0223] To a stirred solution of above crude carboxylic acid (136 mg, 0.60 mmol) and DIPEA (0.21 mL, 1.20 mmol) in CH2O2 (3 mL) was added T3P (50 wt.% in EtOAc 0.54 mL, 0.90 mmol) under nitrogen and stirred at room temperature for 10 minutes. A solution of amine INT-3 (100 mg, 0.42 mmol) in CH2O2 (3 mL) was added and the mixture was stirred for 1 h before it was diluted with CH2O2 (20 mL) and washed with sat. NaHCCL-solntion (10 mL). The organic layer was concentrated under reduced pressure and the crude material was purified by preparative HPLC (USP-HC4 (150 x 21.2 mm, 5p), elution at ambient temperature with a gradient of A (H2O) / B (MeCN): (60% A — > 0% A) to afford the title compound (25 mg, 10%). LCMS m / z = 439 [M+H]+; Rt= 0.82 min (Method M).

[0224] Synthesis of INT-87: tert-butyl (3S,4S)-4-(2-(3-chloro-5-fluorophenoxy)-2-methylpropanamido)-3-meth-oxypiperidine- 1 -carboxylate44 GRA 4222-foreign filing

[0225] A mixture of NaOH (96.0 mg, 2.40 mmol) and 3-chloro-5-fluorophenol (175 mg, 1.20 mmol) inMEK (4 mL) was stirred at room temperature for 1 h under nitrogen atmosphere. A solution of 2-bromo-2 -methyl-propanoic acid (200 mg, 1.20 mmol) in MEK (2 mL) was added and the mixture was stirred for 2 h. The mixture was diluted with EtOAc (20 mL) and water (1 mL). The layers were separated, and the aqueous layer was acidified with 1 M HO solution (3 mL). The aqueous layer was extracted with EtOAc and the organic layer was concentrated under reduced pressure. The cmde carboxylic acid (200 mg) was used in the next step without further purification.

[0226] To a stirred solution of above crude carboxylic acid (200.0 mg, 0.86 mmol) and DIPEA (0.3 mL, 1.70 mmol) in CH2O2 (5 mL) was added T3P (50 wt.% in EtOAc, 0.77 mL, 1.30 mmol) under nitrogen and stirred at room temperature for 10 minutes. A solution of amine INT-3 (140 mg, 0.60 mmol) in CH2O2 (2 mL) was added and the mixture was stirred for 1 h before it was diluted with CH2O2 (20 mL) and washed with sat. NaHCO,- solution (10 mL). The organic layer was concentrated under reduced pressure and the crude material was.

[0227] The following compounds were prepared in analogy:LC-MS m / z [M+H]+, Rt Intermediate Structure Chemical Name Precursors[min] (Method) 3-chloro-5- tert-butyl (3S,4S)-4-(2-(3- methylphe- Clchloro-5-methylphenoxy)-2- nol (step-1,441, 0.80 INT-88 methy lpropanamido)-3 - reaction atx°^l (M0TK / ''Al )methoxypiperidine- 1 -car50 °C) andBocboxylate INT-3 (step- 2)tert-butyl (3S,4S)-4-(2-(3,5- Cl 3,5-dichloro- dichlorophenoxy)-2- 405 [M+H- phenol (step- INT-89 A yX methy lpropanamido)-3 - 'Bu| , 1.251) and INT-3OBoc methoxypiperidine- 1 -car(L)(stept-2)boxylate

[0228] Synthesis of INT-90: tert-butyl (3S,4S)-4-(2-(3-(tert-butyl)phenoxy)-2-methylpropanamido)-3-methoxy-piperidine- 1 -carboxylate

[0229] To a solution of 2-(3-(tert-butyl)phenoxy)-2 -methylpropanoic acid (0.123 g, 0.52 mmol) in DMF (2 mL) were added DIPEA (0.23 mL, 1.3 mmol) and HATU (0.25 g, 0.65 mmol) at room temperature and the mixture was stirred for 5 minutes. Amine INT-3 (0.1 g, 0.43 mmol) was added, and the mixture was stirred at room45 GRA 4222-foreign filingtemperature for 16 h before it was diluted with EtOAc (50 mL) and washed with water (2 x 20 mL) and sat. NaCl solution (2 x 20 mL). The organic layer was dried over anhyd. NaiSOi. filtered and concentrated under reduced pressure to afford the title compound which was used for next step without further purification. LCMS m / z = 449 [M+H]+; Rt= 2.32 min (Method A).

[0230] The following compounds were prepared in analogy:LC-MS m / z dO "n[M+H]+, Rt Intermediate Structure Chemical Name Precursorszi [min] (Method)> <O- / 2-(2,4- CD O O tert-butyl (3S,4S)-4-(2-(2,4- difluorophe- difluorophenoxy)-2- noxy)-2- 429, 3.54 INT-91 methy lpropanamido)-3 - methylpro- (A) methoxypiperidine- 1 -carpanoic acidboxylateand INT-3N tert-butyl (3S,4S)-4-(2-(3- 2-(3-cyano- cyanophenoxy)-2- phenoxy)-2- 418, 3.37 INT-92 methy lpropanamido)-3 - methylpro- (A) methoxypiperidine- 1 -carpanoic acidBoc boxylate and INT-3tert-butyl (3S,4S)-3-meth- 2-methyl-2- oxy-4-(2-methyl-2-(naph- (naphthalen- 443, 3.97 INT-93 thalen-2-yloxy)pro- 2-yloxy pro(A)O L -N. panamido)piperidine- 1 -carpanoic acidBocboxylate and INT-32-(3-iso- tert-butyl (3S,4S)-4-(2-(3- propylphe- isopropylphenoxy)-2- noxy)-2- 434, 3.82 INT-94 methy lpropanamido)-3 - methylpro- (A) CkV -AO L methoxypiperidine- 1 -carBoc panoic acidboxylateand INT-32-(3-meth- tert-butyl (3S,4S)-3-meth- oxyphe- oxy-4-(2-(3 -metho xyphe- noxy)-2- 423, 3.74 INT-95 noxy)-2-methylpro- methylpro- (A) dkv -AO L panamido)piperidine- 1 -carBoc panoic acidboxylateand INT-346 GRA 4222-foreign filing2-methyl-2- tert-butyl (3S,4S)-3-meth- (o-tol- oxy-4-(2-methyl-2-(o-tol- 407, 2.32 INT-96 OCxM yloxy propaO L yloxypropanamidopiperi- (A)Boc noic acid anddine- 1 -carboxy lateINT-3tert-butyl (3S,4S)-4-(2-(3- 2-(3-fluoro- Ffluorophenoxy)-2- phenoxy)-2- 411, 4.11 INT-97 methy lpropanamido)-3 - methylpro- (A) O L methoxypiperidine- 1 -carpanoic acidBocboxylate and INT-32-(2,3-di- tert-butyl (3S,4S)-4-(2-(2,3- Cl chlorophe- dichlorophenoxy)-2- noxy)-2- 461, 3.77 INT-98 methy lpropanamido)-3 - methylpro- (A) o L methoxypiperidine- 1 -carBoc panoic aciduo boxylate / co and INT-3z —\° ' 2-methyl-2- tert-butyl (3S,4S)-3-meth- (m-tol- ML V IZ « f oxy-4-(2-methyl-2-(m-tol- 407, 3.79 INT-99 yloxy propayloxy)propanamido)piperi- (A) \ o0k. noic acid andBoc dine- 1 -carboxylateINT-3o ~ 2-(2,3-dime- tert-butyl (3S,4S)-4-(2-(2,3- thylphe- dimethylphenoxy)-2- noxy)-2- 421, 3.83 INT-100 methy lpropanamido)-3 - methylpro- (A) methoxypiperidine- 1 -carpanoic acid boxylateand INT-32-methyl-2- tert-butyl (3S,4S)-3-meth- (3-(trifluoro- oxy-4-(2-methyl-2-(3-(tri- methylphe- 461, 4.63 INT-101 X’ v •' fluoromethyl)phenoxy)pro- noxypropa- (A) "A panamido)piperidine- 1 -carBoc noic acid and boxylateINT-3tert-butyl (3S,4S)-4-(2-(3- 2-(3-chloro- Clchlorophenoxy)-2- phenoxy)-2- 427, 3.61 INT-102 cbu^ methy lpropanamido)-3 - methylpro- (A) O ^N. methoxypiperidine- 1 -carpanoic acidBocboxylate and INT-347 GRA 4222-foreign filing2-(3,5-dime- tert-butyl (3S,4S)-4-(2-(3,5- thylphe- dimethylphenoxy)-2- A VA noxy)-2- 421, 3.75 INT-103 methy lpropanamido)-3 - methylpro- (A)0ABoc methoxypiperidine- 1 -carpanoic acidboxylateand INT-3tert-butyl (3S,4S)-4-(2- ((3,5-dimethylphenyl)thio)- INT-61 and 437, 0.83 INT-104 2-methylpropanamido)-3 - INT-3 (O)0Boc methoxypiperidine- 1 -carboxylatetert-butyl (3S,4S)-3-me- thoxy-4-(2-methyl-2-(naph- 6A A. INT-182 and 443, 1.90 INT-185 thalen- 1 -y loxy )propana- INT-3 (A) mido)piperidine- 1 -carboxylatetert-butyl (3S,4S)-4-(2- ([1,1 ’-biphenyl] -3 -yloxy)-2- INT-183 and 469, 3.75 INT-186 methylpropanamido)-3 -meINT-3 (A) thoxypiperidine- 1 -carboxylatetert-butyl (3S,4S)-3-me- thoxy-4-(2-methyl-2-(3 -pheINT-184 and 484, 2.11 INT-187 noxyphenoxy )propana- INT-3 (X) mido)piperidine- 1 -carboxylate

[0231] Synthesis of INT-105: tert-butyl (3S,4S)-4-(2,2-difluoro-2-(2,4,5-trifluorophenoxy)acetamido)-3-methox-ypiperidine- 1 -carboxylate

[0232] To a stirred solution of carboxylic acid INT-40 (0.15 g, 0.62 mmol) in CH2O2 (5.0 mL) were added amine INT-3 (0.17 g, 0.74 mmol), TEA (0.26, 1.86 mmol) and T3P (50 wt.% inEtOAc, 0.6 mL, 0.93 mmol) at 0° C and the mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with EtOAc (50 mL) and washed with water (20 mL) and sat. NaCl solution (20 mL). The organic layer was dried over anhyd. ISfeSCL and concentrated reduced pressure. The crude material was purified by column chromatography (silica, EtOAc / hexane 0:1 - 1:1) to afford the title compound (80 mg, 18%). LCMS m / z = 453 [M+H]+; Rt= 3.14 min (Method F).48 GRA 4222-foreign filing

[0233] The following compounds were prepared in analogy:LC-MS m / z [M+H]+, Rt Intermediate Structure Chemical Name Precursors[min] (Me■n thod) O- tert-butyl (3S,4S)-4-(2-(3,5- O Tl \n - dimethylphenoxy)-2- methylbutanamido)-3 -methINT-37 and 435, 3.88 INT-106 ZIRand S INT- 0 H k > <O- 1 oxypiperidine- 1 -carbox3 (A)Boct ylate, mixture of stereoisocoo o merstert-butyl (3S,4S)-4-(2,2- Fdifluoro-2-(3,4,5-trifluoro- INT-41 and 455, 3.57 INT-107Fn v H f phenoxy )acetamido)-3 - INT-3 (A) oB 00 o o methoxypiperidine- 1 -car£0 £0oc / / boxylate\ / \ / 00J\ J\ \ \~~tert-butyl (3S,4S)-4-(2,2- F xz xz difluoro-2-(2,3,5-trifluoro- ^ u. °= INT-42 and 455, 3.57 INT-108FJ^Xox^^lL00[=phenoxy )acetamido)-3 - 0 “■f.s, f INT-3 (A) ^5 F — O k _ ,NXmethoxypiperidine- 1 -car— Bocboxylatetert-butyl (3S,4S)-4-(2-(2,4- difluoro-3 -methylphenoxy)- INT-45 and 451, 3.54 INT-109 2,2-difluoroacetamido)-3- INT-3 (A) methoxypiperidine- 1 -carboxylatetert-butyl (3S,4S)-4-(2-(3,4- difluoro-5-methylphenoxy)- INT-47 and 451, 3.59 INT-110 2,2-difluoroacetamido)-3- INT-3 (A) methoxypiperidine- 1 -carboxylatetert-butyl (3S,4S)-4-(2,2- difluoro-2-(4-fluoro-3 - INT-53 and 433, 3.73 INT-111 methylphenoxy)acetamido)- INT-3 (A) 3 -methoxypiperidine- 1 -carboxylate49 GRA 4222-foreign filingrac-tert-butyl (3S*,4S*)-4- (2,2-difluoro-2-(3-fluoro-5- methylphenoxy)acetamido)- INT-52 and 477, 3.60 INT-1123 -(2 -methoxy ethoxy )piperi- INT-15 (A) dine-l-carboxylate, trans- racematetert-butyl (3S,4S)-4-(4-(3,5- dimethylphenoxy)tetrahy- INT-38 and 463, 3.51 INT-113 dro-2H-pyran-4-carboxam- INT-3 (A)0Boc ido)-3 -methoxypiperidine- 1 - carboxylatetert-butyl (3S,4S)-4-(l-(3,5- dimethylphenoxy)cyclohex- INT-39 and 461, 4.01 INT-114 ane- 1 -carboxamido)-3 - INT-3 (A) O L -N.Boc methoxypiperidine- 1 -caro o o oCD O CD — / boxylate\ ✓ \ °OJ\ \ '~ tert-butyl (3S,4S)-4-(2-cy- xz IZ* clopropyl-2-(3 , 5 -dime- ^ u°= / o c thy lphenoxy)acetamido)-3 - INT-71 and 433, 3.80 INT-115§ O O “■(: o methoxypiperidine- 1 -carINT-3 (A) o — — boxylate, mixture of stereoisomerstert-butyl (3S,4S)-4-(l-(3,5- dimethylphenoxy)cyclobu- INT-85 and 433, 3.85 INT-116 tane- 1 -carboxamido)-3 - INT-3 (A)0-hLBoc methoxypiperidine- 1 -carboxylatetert-butyl (3S,4S)-4-(2-(3,5- dimethylphenoxy)bu- INT-72 and 421, 3.65 INT-117 tanamido)-3 -methoxypiperi- INT-3R and S Q 1 (A)^s*z*xBoc dine-l-carboxylate, mixtureof stereoisomerstert-butyl (3S,4S)-4-(2-(3,5- dimethylphenoxy)-2,2-diflu- J 1s \ IIK fl F F oroacetamido)-3 -((2-me- INT-54 and 507, 3.50 INT-1180Xkv.. A thylpyrimidin-5- INT-16 (A)0Boc yl)oxy)piperidine- 1 -carboxylate50 GRA 4222-foreign filingtert-butyl (3S,4S)-4-(2-(3- chloro-2-fluorophenoxy)- INT-59 and 453, 3.61 INT-119 2,2-difluoroacetamido)-3- INT-3 (A) methoxypiperidine- 1 -carboxylatetert-butyl (3S,4S)-4-(2,2- O "n o difluoro-2-(2-fluoro-5- O -n INT-60 and 433, 3.57 INT-120 methylphenoxy)acetamido)- 6^ ZIzxF 0 L°“ > < \ z INT-3 (A)-N. 3 -methoxypiperidine- 1 -carBocO—\ • JZ — \ boxylate ° 1 \ / \ ' Z— O 03 / O / O| — co O 03 tert-butyl (3S,4S)-4-(2-(3,5- o X o 82TJdimethylphenoxy)-2,2-diflu- INT-54 and 487, 3.60 INT-121 oroacetamido)-3 -(2 -hydINT-20 (A) roxy-2 -methylpropoxy )pipe- ridine- 1 -carboxylateo oCD tert-butyl (3S,4S)-4-(2-(3,5- / M C dimethylphenoxy)-2,2-diflu- \ ✓ ° z oroacetamido)-3 -(2-((tetra- xz xzINT-54 and 543, 3.82 ^^U_O=^^ U.O=INT-122 hydro-2H-pyran-2- INT-21 (A)O C o y l)oxy )ethoxy)piperidine- 1 - carboxylate, mixture of ste— —reoisomerstert-butyl (3S,4S)-4-(2-(3,5- dimethylphenoxy)-2,2-diflu- oroacetamido)-3 -((tetra- INT-54 and 499, 3.64 INT-123hydro-2H-pyran-4- INT-22 (A) yl)oxy)piperidine- 1 -carboxylatetert-butyl (3S,4S)-4-(2-(3,5- dimethylphenoxy)-2,2-diflu- 1 R and s i QF Foroacetamido)-3 -((tetrahyd- INT-54 and 485, 3.63 INT-124INT-23 rofuran-3-yl)oxy)piperidine- (A) W rS O L .N. Boc 1 -carboxylate, mixture ofstereoisomerstert-butyl (3S,4S)-4-(2- ((3,5-dimethylphenyl)thio)- INT-62 and 445, 3.75 INT-125 2,2-difluoroacetamido)-3- INT-3 (A) methoxypiperidine- 1 -carboxylate51 GRA 4222-foreign filingtert-butyl (3S,4S)-4-(2-((6- chloro-4-methylpyridin-2- INT-69 and 442, 0.69 INT-126 yl)oxy)-2-methylpropana- INT-3 (O)OBoc mido)-3 -methoxypipe ridine- 1 -carboxylatetert-butyl (3S,4S)-4-((2-((4- Clchloro-6-methylpyridin-2- INT-70 and 442, 0.80 INT-127 \f H 1 yl)oxy)-2-methylpro- INT-3 (O) pyl)amino)-3 -methoxypipeBocridine- 1 -carboxylate

[0234] Synthesis of INT-128: tert-butyl (3S,4S)-4-(2-(3-chloro-4,5-difluorophenoxy)-2,2-difluoroacetamido)-3-methoxypiperidine- 1 -carboxylate

[0235] To a stirred solution of carboxylic acid INT-43 (0.23 g, 0.89 mmol) in CH2C12(15 mL) were added DMF (cat. two drops) and oxalyl chloride (0.38 mL, 4.43 mmol) and the mixture was stirred for 1 h before it was concentrated under reduced pressure. The residue was dissolved in CH2C12(6 mL) and TEA (1.24 mL, 8.86 mmol) and amine INT-3 (0.20 g, 0.89 mmol) were added and the mixture was stirred for 16 h at room temperature. The mixture was diluted with CH2C12(30 mL) and washed with H2O (2 x 10 mL) and sat. NaCl solution (10 mL). The organic layer was dried over anhyd. Na2SC>4, fdtered and concentrated under reduced pressure. The crude material was purified by column chromatography (silica, EtOAc / hexane 0:1 - 1:0) to afford the title compound (0.12 g, 27%).1H NMR (400 MHz, DMSO-d6) 39.07 (m, 1H), 7.54 (m, 1H), 7.46 (m, 1H), 4.14 (m, 2H), 3.80 (m, 2H), 3.21 (m, 3H), 3.14 (m, 1H), 2.83 (m, 1H), 1.68 (m, 1H), 1.41 (s, 9H).

[0236] The following compounds were prepared in analogy:LC-MS m / z [M+H]+, Rt Intermediate Structure Chemical Name Precursors[min] (Method) tert-butyl (3S,4S)-4-(2-(4- Ck A XMl V » i chlorophenoxy)-2,2- INT-44 and 435, 2.08 INT-129O k _ ,N%difluoroacetamido)-3 -methINT-3 (A)Bocoxypiperidine- 1 -carboxylatetert-butyl (3S,4S)-4-(2,2- difluoro-2-phenoxyacetam- INT-46 and 401, 3.46 INT-130cow s ido)-3 -methoxypiperidine- 1 - INT-3 (A)Boccarboxylate52 GRA 4222-foreign filingCl tert-butyl (3S,4S)-4-(2-(3- chlorophenoxy)-2,2- INT-48 and 435, 3.63 INT-131 A V H fV M difluoroacetamido)-3 -meth- INT-3 (A)Boc oxypiperidine- 1 -carboxylatetert-butyl (3S,4S)-4-(2,2- difluoro-2-(2-fluoro-3 - INT-49 and 433, 3.58 INT-132 MTFV « r methylphenoxy)acetamido)- INT-3 (A) O k. .N. 3 -methoxypiperidine- 1 -carBocboxylateF tert-butyl (3S,4S)-4-(2-(3,5- difluorophenoxy)-2,2- INT-50 andINT-133 MI v » rdifluoroacetamido)-3 -methINT-3OBoc oxypiperidine- 1 -carboxylate'H NMR (400 MHz, DMSO-de) 39.09 (m, 1H), 7.29 (m, 1H), 7.09 (m, 1H), 4.11 (m, 1H), 3.78 (m, 2H), 3.27 (s, 3H), 3.14 (m, 1H), 2.82 (m, 1H), 1.66 (m, 1H), 1.41 (s, 9H)tert-butyl (3S,4S)-4-(2-(3- Clchloro-4-fluorophenoxy)- INT-51 and 453, 3.42 INT-134FMl V « f 2,2-difluoroacetamido)-3- INT-3 (A) methoxypiperidine- 1 -car° ^'Bocboxylatetert-butyl (3S,4S)-4-(2,2- difluoro-2-(3-fluoro-5- INT-52 andINT-135 MI v H r methylphenoxy)acetamido)- INT-3O k _ ,NXBoc 3 -methoxypiperidine- 1 -carboxylate1H NMR (400 MHz, DMSO-de) 39.03 (m, 1H), 7.05 (m, 1H), 6.93 (m, 1H), 4.10 (m, 2H), 3.78 (m, 2H), 3.28 (s, 3H), 3.16 (m, 1H), 2.81 (m, 1H), 2.34 (s, 3H), 1.65 (m, 1H), 1.41 (s, 9H)tert-butyl (3S,4S)-4-(2-(3,5- dimethylphenoxy)-2,2- INT-54 and 429, 3.64 INT-136 MI v « rK ON / 'M difluoroacetamido)-3 -methINT-3 (A)L .NxBoc oxypiperidine- 1 -carboxylatetert-butyl (3S,4S)-4-(2-(3- Clchloro-5-fluorophenoxy)- INT-55 and 453, 3.62 INT-137 MI v H r 2,2-difluoroacetamido)-3- INT-3 (A) O k _ ,NXmethoxypiperidine- 1 -carBocboxylatetert-butyl (3S,4S)-4-(2,2- difluoro-2-(m-tolyloxy)acet- INT-56 and 415, 3.50 INT-138 A V « famido)-3 -methoxypiperiINT-3 (A) 0 LBoc dine- 1 -carboxylate53 GRA 4222-foreign filingtert-butyl (3S,4S)-4-(2-(3,5- dichlorophenoxy)-2,2- INT-57 and 469, 3.75 INT-139difluoroacetamido)-3 -methINT-3 (A) oxypiperidine- 1 -carboxylatetert-butyl (3S,4S)-4-(2-(3- chloro-5-methylphenoxy)- INT-58 andINT-140 f O V 2,2-difluoroacetamido)-3- INT-3 methoxypiperidine- 1 -carboxylate'H NMR (400 MHz, DMSO-d6) 39.03 (m, 1H), 7.26 (s, 1H), 7.15 (s, 1H), 7.08 (s, 1H), 4.14 (m, 1H), 3.77 (m, 2H), 3.28 (s, 3H), 3.15 (m, 1H), 2.83 (m, 1H), 2.32 (m, 3H), 1.66 (m, 1H), 1.41 (s, 11H)INT-54 andtert-butyltert-butyl (3S,4S)-4-(2-(3,5- (3S,4S)-4- dimethylphenoxy)-2,2-diflu- 413 [M-H]-, INT-141 amino-3-hy- oroacetamido)-3 -hydroxy- 2.79 (B)droxypiperi- / z— piperidine- 1 -carboxylateJ / X \dine-l-car- boxylate^tert-butyl (3S,4S)-4-(2-(3,5- dimethylphenoxy)-2-fluoro-FINT-84 and 411, 0.75 INT-142 1 acetamido)-3 -methoxypipex^k°xS QrN / "rsi INT-3 (O)ridine- 1 -carboxylate, mixture of stereoisomers

[0237] Synthesis of INT-143 and INT-144: tert-butyl (3S,4S)-4-(2-(3-chlorophenoxy)propanamido)-3-methoxy-piperidine-1 -carboxylate, stereoisomer - 2 and tert-butyl (3S,4S)-4-(2-(3-chlorophenoxy)propanamido)-3-meth-oxypiperidine-1 -carboxylate, stereoisomer - 1ci ci

[0238] To a solution of rac-2 -(3 -chloropheno xy)propanoic acid (0.2 g, 1.0 mmol) in DMF (3 mL) were added HATU (0.57 g, 1.50 mmol), EhN (0.4 mL, 3.00 mmol) at 0 °C and the mixture was stirred for 15 minutes. Amine INT-3 (0.28 g, 1.20 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The mixture was partitioned between EtOAc (40 mL) and water (2 x 20 mL) and the oiganic layer was washed with sat. NaCl solution (2 x 20 mL), dried over anhyd. NaaSO i and concentrate under reduced pressure The crude material was purified by column chromatography (silica, EtOAc / hexane 0:1 - 1:0) to afford the title compound (0.21 g, 50%). LCMS m / z = 413 [M+H]+; Rt= 2.23 min (Method A). The mixture of stereoisomers was separated via preparative chiral HPLC (Agilent 1200 series, column: CHIRALPAK IG (250 x 30 mm, 5 p), elution with isocratic hexane / EtOH 85:15 at ambient temperature) to afford the title compounds as separate diastereomers.54 GRA 4222-foreign filing

[0239] INT-143 (stereoisomer - 2, 70 mg, 17 %), Rt= 10.66 min (Method V).

[0240] INT-144 (stereoisomer - 1, 80 mg, 19 %), Rt= 9.42 min (Method V).

[0241] Synthesis of INT-145: tert-butyl (S)-4-(2-(3,5-dimethylphenoxy)-2,2-difluoroacetamido)-3-methylpipera-zine- 1 -carboxylate0ZI / z

[0242] To a stirred solution of carboxylic acid INT-54 (100 mg, 0.46 mmol) in CH2O2 (5 mL) was added T3P (50 / z—wt.% inEtOAc, 0.41 mL, 0.69 mmol) andDI 03P OEA(0.16 ml, 0.92 mmol) at room temperature and the mixture was 0stirred for 30 minutes. A solution of hydrazine INT-24 (99 mg, 0.46 mmol) in CH2C12(1.5ml) was added and the mixture was continued to stir room temperature for Ih. The mixture was concentrated under reduced pressure and the crude material was purified by column chromatography (silica, cyclohexane / EtOAc 1:0 - 1:1) to afford the title compound (34 mg, 18 %). LCMS m / z = 414 [M+H]+; Rt= 0.77 min (Method O).O 0< CD

[0243] The following compounds were pre wpared in analogy:2111111 / LC-MS m / z xz^0= [M+H]+, Rt Intermediate Structure u. / Chemical Name PrecursorsLLJ \O [min] (Method) —tert-butyl (3S,4S)-4-(2- ((4,6-dimethylpyridin-2- F yl)oxy)-2-fluoroacetamido)- INT-81 and 412, 3.38 INT-146 I H 13 -methoxypiperidine- 1 -carINT-3 (A)Rand S O L _N.Boc boxylate, mixture of stereoisomerstert-butyl 4-(2-(3,5-dime- thylphenoxy)-2,2-difluoroa- INT-54 and 426, 0.78 INT-147 r il v v cetamido)-4,7-dia- INT-25 (O)0Boc zaspiro [2.5] octane-7 -carboxylatetert-butyl (2R,5S)-4-(2-(3,5- dimethylphenoxy)-2,2- INT-54 and 428, 0.81 INT-148 difluoroacetamido)-2,5-di- INT-26 (O) methylpiperazine- 1 -carboxylaterac-tert-butyl (2S*,3R*)-4- INT-54 and 428, 0.81 INT-149 (2-(3,5-dimethylphenoxy)- INT-31 (O)2,2-difluoroacetamido)-2,3 -55 GRA 4222-foreign filingdimethylpiperazine- 1 -carboxylatetert-butyl (3S,5S)-4-(2-(3,5- dimethylphenoxy)-2,2- INT-54 and 428, 0.79 INT-150 difluoroacetamido)-3,5-di- INT-32 (0) methylpiperazine- 1 -carboxylateme5o-tert-butyl-4-(2-(3,5-di- z y methylphenoxy)-2,2- INT-54 and 428, 0.79 INT-151 difluoroacetamido)-3,5-di- INT-27 (O) methylpiperazine- 1 -carboxylatetert-butyl (2S,5S)-4-(2-(3,5- dimethylphenoxy)-2,2- r ii v H INT-54 and 428, 1.64 INT-152 N > difluoroacetamido)-2,5-di- INT-33 (N) methylpiperazine- 1 -carboxylate / tert-butyl (S)-4-(2-(3- ^^^> chloro-5-methylphenoxy)- INT-58 and 434, 0.79 INT-153 2,2-difluoroacetamido)-3 - INT-24 (0) — — methylpiperazine- 1 -carboxylatetert-butyl (S)-4-(2-(3-chlo- rophenoxy)-2,2-difluoroa- INT-48 and 420, 0.75 INT-154cetamido)-3-methylpipera- INT-24 (O) zine- 1 -carboxylatetert-butyl (R)-4-(2-(3,5-di- methylphenoxy)-2,2- INT-54 and 414, 0.77 INT-155 difluoroacetamido)-3 - INT-28 (O) methylpiperazine- 1 -carboxylatetert-butyl (S)-4-(2-(3,5-di- methylphenoxy)-2,2- INT-54 and 428, 1.73 INT-156 difluoroacetamido)-3 - INT-29 (M) ethylpiperazine- 1 -carboxylatetert-butyl (S)-4-(2,2- difluoro-2-(m-tolyloxy)acet- INT-56 and 414, 0.77 INT-157 r il v H >amido)-3 -ethylpiperazine- 1 - INT-29 (O) carboxylate56 GRA 4222-foreign filingtert-butyl (R)-4-(2-(3,5-di- methylphenoxy)-2,2- INT-54 and 444, 0.77 INT-158 difluoroacetamido)-3 -(meth- INT-34 (0) oxymethy l)piperazine- 1 -carboxylaterac-tert-butyl (2R*,3R*)-4- (2-(3,5-dimethylphenoxy)- INT-54 and 428, 0.81 INT-159 2,2-difluoroacetamido)-2,3- INT-35 (0) dimethylpiperazine- 1 -carboxylatetert-butyl (S)-4-(2-((4,6-di- methylpyridin-2-yl)oxy)-2- INT-68 and 421, 0.77 INT-160 methy lpropanamido)-3 - INT-29 (0)O L Boc ethylpiperazine- 1 -carboxylateo o u uCD / tert-butyl (S)-4-(2-((4,6-di- y z—H methylpyridin-2-yl)oxy)-2- O^ — INT-68 and 407, 0.73 INT-161 xz xz methy lpropanamido)-3 - INT-24^ (0)0u. Boc methylpiperazine- 1 -carboxo ylate— tert-butyl (3S,4S)-4-(2- ((4,6-dimethylpyridin-2- INT-64 and 446, 0.72 INT-162 I II V H |Xyl)thio)-2,2-difluoroacetam- INT-3 (M) O L -N. Boc ido)-3 -methoxypiperidine- 1 - carboxylatetert-butyl (3S,4S)-4-(2- ((4,6-dimethylpyridin-2- r Tl \ INT-68 and 422, 1.01 INT-163 yl)oxy)-2-methylpro- INT-3 (L)0Boc panamido)-3-methoxypiper- idine- 1 -carboxylatetert-butyl (S)-4-(2-((4,6-di- methylpyridin-2-yl)oxy)-2- INT-68 and 435, 0.81 INT-164 methylpropanamido)-3 -iso- INT-36 (0) o L ^***<Boc propylpiperazine- 1 -carboxylatetert-butyl (2S,5S)-4-(2- ((4,6-dimethylpyridin-2- INT-68 and 435, 3.91 INT-165 yl)oxy)-2-methylpropana- O L INT-30 (A)Boc mido)-5-ethyl-2 -methylpiperazine- 1 -carboxylate57 GRA 4222-foreign filing

[0244] Synthesis of INT-166: tert-butyl (3S,4S)-4-(2-((4,6-dimethylpyridin-2-yl)oxy)-2-methylpropanamido)-3- ((2-methylpyrimidin-5-yl)oxy)piperidine-l-carboxylate

[0245] To a mixture of amine INT-16 (0.16 g, 0.77 mmol) and carboxylate Na-INT-68 (0.53 g, 2.3 mmol) inDMF (5 mL) were added DIPEA (0.4 mL, 2.3 mmol) and T3P (50 wt.% in EtOAc, 2.6 mL, 4.6 mmol) at 0 °C. The mixture was stirred at room temperature for 16 h and subsequently diluted with ice water and the mixture was extracted with EtOAc. The combined organic layers were dried over anhyd. Na2SO4and concentrated under reduced pressure to obtain the title compound (0.2 g, 52%) which was used for the next step without further purification. LCMS m / z = 500 [M+H]+; Rt= 3.43 min (Method A).

[0246] The following compounds were prepared in analogy:LC-MS m / z [M+H]+, Rt Intermediate Structure Chemical Name Precursors[min] (Method) tert-butyl (3S,4S)-3-(2,2-F\xFdifluoroethoxy)-4-(2-((4,6- INT-68 and 472, 3.71 INT-167 A fSV VJA " A i dimethylpyridin-2-yl)oxy)- INT-17 (A)02-methylpropanamido)pi- Bocperidine- 1 -carboxylate1Ftert-butyl (3S,4S)-3-(difluo- romethoxy)-4-(2-((4,6-di- INT-68 and 458, 3.26 INT-168 A rAil X \ ^IUA methylpyridin-2-yl)oxy)-2-0L -hk INT-18 (F)methylpropanamido)piperi- Bocdine- 1 -carboxylatetert-butyl (3S,4S)-4-(2- ((4,6-dimethylpyridin-2- INT-68 and 436, 3.70 INT-169 AAx^iuA yl)oxy)-2-methylpro-0L -hk INT-19 (A)Boc panamido)-3 -ethoxypiperidine- 1 -carboxylatetert-butyl (3S,4S)-4-(2- ((4,6-dimethylpyridin-2- INT-83 and 422, 3.52 INT-170yl)oxy)butanamido)-3 -methINT-3R and S Q 1 (A)xBoc oxypiperidine- 1-58 GRA 4222-foreign filingcarboxylate, mixture of stereoisomerstert-butyl (3S,4S)-4-(2-((5- fluoro-4,6-dimethylpyridin- INT-75 and 440, 0.78 INT-171 2-yl)oxy)-2-methylpro- INT-3 (O) panamido)-3-methoxypiper- ' 0 idine- 1 -carboxylate^^ 0 tert-butyl (3S,4S)-4-(2-((3- ZT fluoro-4,6-dimethylpyridin- INT-79 and 440, 1.13 INT-172 < >0- 2-yl)oxy)-2-methylpro- T \ \- / INT-3 (L)0CDBo Oc panamido)-3-methoxypiper- Oidine- 1 -carboxylateINT-68 andtert-butyl (3S,4S)-4-(2- tert-butyl((4,6-dimethylpyridin-2- (3S,4S)-4- K h \ / 408, 3.3 INT-1730H7 yl)oxy)-2-methylpro- amino-3-hy- AKx / 0yS (A)k. Boc panamido)-3 -hy droxypiperi- droxypiperi- dine- 1 -carboxylate dine-l-car- boxylate

[0247] Synthesis of INT-174: tert-butyl 4-(2-(3,5-dimethylphenoxy)-2,2-difluoroacetamido)piperazine-l-carbox-ylate

[0248] To a stirred solution of carboxylic acid INT-54 (60 mg, 0.28 mmol) in CH2O2 (2.8 mL) and DMF (1 drop) was added oxalyl chloride (0.12 mL, 1.4 mmol) and the mixture was stirred for 1 h at room temperature. The mixture was concentrated in a flow of nitrogen and the residue was dissolved in CH2O2 (2.8 ml) before tert-butyl 4-aminopiperazine-l -carboxylate (56 mg, 0.28 mmol) and TEA (0.12 ml, 0.83 mmol) were added and the mixture was stirred for 1 h at room temperature. The mixture was concentrated under reduced pressure and the crude material was purified by column chromatography (silica, cyclohexane / EtOAc 1 :0 - 1 : l)to afford the title product (61 mg, 55 %). LCMS m / z = 400 [M+H]+; Rt= 0.77 min (Method O).

[0249] Synthesis of INT-175: tert-butyl (3S,4S)-4-(2-(3,5-dimethylphenoxy)-2,2-difluoroacetamido)-3-(2-meth- oxy ethoxy )piperidine- 1 -carboxy late59 GRA 4222-foreign filing

[0250] To a solution of alcohol INT-141 (100 mg, 0.24 mmol) in DMF (4 mL) was added NaH (60% in mineral oil, 18 mg, 0.36 mmol) at 0 °C and the mixture was stirred for 15 min. l-iodo-2 -methoxy ethane (67 mg, 0.36 mmol) was added and the mixture was allowed to warm to room temperature and was stirred for 17 h. Ice cold water was added and the mixture was extracted with EtOAc (50 mL). The organic layer was washed with water (10 mL), sat. NaCl solution (10 mL), dried over anhyd. ISfeSCL and concentrated under reduced pressure. The crude material was purified by preparative HPLC (YMC Triart C18 (250 x 20 mm, 5 p), elution at ambient temperature with a gradient of A (20 mM NH4HCO3 in H2O) / B (MeCN): 0.0 min 80% A — > 3.0 min 70% A — > 20.0 min 20% A — > 20.5 min 0% A) to yield the title compound which was directly used in the subsequent deprotection reaction.

[0251] The following compounds were prepare 0 Od 0 Q in analogy:CQ CO / \ / / z z— ——Intermediate StructureZChemical Name Precursors\0iz xz tert-butyl (3S,4S)-3-(cyclopropyl- INT-141 and (iodo- ^ u_ °=methoxy)-4-(2-(3,5-dimethylphe- INT-176 methyl)cyclopro- 00 noxy)-2,2-difluoroacetamido)piperi- panedine- 1 -carboxylate— —tert-butyl (3S,4S)-4-(2-(3,5-dime- INT-141 and ioINT-177 thylphenoxy)-2,2-difluoroacetamido)- doethane3 -ethoxypiperidine- 1 -carboxylate

[0252] Synthesis of INT-178: tert-butyl (3S,4S)-4-(2-((4,6-dimethylpyridin-2-yl)oxy)-2-methylpropanamido)-3- (((methylthio)carbonothioyl)oxy)piperidine-l-carboxylate

[0253] To a solution of alcohol INT-173 (0.25 g, 0.66 mmol) in DMF (4 mL) was added DBU (0.3 mL, 2.0 mmol) followed by the addition of CS2 (0.2 mL, 3.3 mmol) at 0 °C. The mixture was stirred at room temperature for 4 h before Mel (0.08 mL, 1.3 mmol) was added and stirring was continued at room temperature for 16 h. The mixture was diluted with ice water (100 mL) and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhyd. Na2SO4and concentrated under reduced pressure. The crude60 GRA 4222-foreign filingmaterial was purified by column chromatography (silica, hexane / EtOAc 1:0 - 1:1) to obtain the title compound (0.24 g, 75%). LCMS m / z = 498 [M+H]+; Rt= 3.95 min (Method A).

[0254] Synthesis of INT-188: tert-butyl (3S,4S)-3-methoxy-4-((4-methoxybenzyl)amino)piperidine-l-carbox-ylate

[0255] To a solution of INT-3 (500 mg, 2.17 mmol) and 4-methoxybenzaldehyde (355 mg, 2.6 mmol) inMeOH (50 mL) was added AcOH (0.1 mL) and the mixture was stirred at room temperature for 3 h. The reaction mixture was cooled to 0 °C and NaBH3CN (274 mg, 4.34 mmol) was added portion-wise and stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure, diluted with EtOAc (200 mL), washed with water (50 mL), sat. NH4C1 solution (50 mL) and sat. NaCl solution (50 mL). The organic layer was dried over anhyd. bSO i and concentrated under reduced pressure. The crude material was purified by column chromatography (silica, hexane / EtOAc 4:6 - 1: 1) to afford the title compound (0.49 g, 65%). LC-MS m / z = 351 [M+H]+; Rt = 1.66 o ommin (Method F). / y \ Z ——y ° / —

[0256] The following compounds were prepared in analogy:IZ LC-MS m / z Intermediate Structure Chemical Name Precursors [M+H]+, o 3 Rt[min] \ (Method) tert-butyl (3S,4S)-3-ethoxy-4- INT-193 ((4-methoxybenzyl)amino)piper- INT-192 365, 3.32(A) idine- 1 -carboxylate

[0257] Synthesis of INT-189: tert-butyl (3S,4S)-4-(2-bromo-2,2-difluoro-N-(4-methoxybenzyl)acetamido)-3- methoxypiperidine- 1 -carboxylate

[0258] To a mixture of 2-bromo-2,2-difluoroacetic acid (0.50 g, 2.86 mmol) and INT-188 (500 mg, 1.43 mmol) in pyridine (10 mL) was added POCL (0.66 mL, 7.15 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure, diluted with EtOAc (150 mL), washed with water (50 mL), sat. NaHCO;, (50 mL), sat. NH4C1 solution (50 mL) and sat. NaCl solution (50 mL). The organic layer was dried over anhyd. Na2SO4and concentrated under reduced pressure. The crude material was61 GRA 4222-foreign filingpurified by column chromatography (silica, MeOH / CH2C12 1:99 - 2:98) to afford the title compound (0.550 g, 76%). LC-MS m / z = 507 [M+H]+; Rt = 3.76 min (Method A).

[0259] The following compounds were prepared in analogy:LC-MS m / z Intermediate Structure Chemical Name Precursors [M+H]+,Rt[min] (Method) \ 0tert-butyl (3S,4S)-4-(2-bromo- 2,2-difluoro-N-(4-methoxyben- INT-194 521, 3.9FA INT-193 9 F N» f N— Boc zyl)acetamido)-3 -ethoxypiperi(A) Br O dine- 1 -carboxylate

[0260] Synthesis of INT-190: tert-butyl (3 S,4S)-4-(dibenzylamino)-3 -hydroxypiperidine- 1 -carboxylateBn OH

[0261] To a solution of tert-butyl (3S,4S)-4-amino-3-hydroxypiperidine-l-carboxylate (2.5 g, 11.56 mmol) in ethanol (50 mL) were added Na2COs (2.45 g, 23.12 mmol), Nal (0.35 g, 2.31 mmol) and (bromomethyl)benzene (2.82 mL, 23.7 mmol) at room temperature. The mixture was heated at 80 °C for 16 h. Then, the reaction mixture was concentrated under reduced pressure, diluted with ice water and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with sat. NaCl solution, dried over anhyd. vSOi. filtered and concentrated under reduced pressure. The crude product was triturated with hexane to afford the title compound (3.80 g, 83%). LC-MS m / z = 397 [M+H]+; Rt = 2.17 min (Method A).

[0262] Synthesis of INT-191: tert-butyl (3S,4S)-4-(dibenzylamino)-3-ethoxypiperidine-l-carboxylate

[0263] To a solution of INT-190 (3.8 g, 9.58 mmol) inDMF (70 mL) was added NaH (60% in mineral oil, 0.34 g, 14.38 mmol) portion wise at 0 °C and stirred for 15 min at at 0 °C. Then, ethyl iodide (1.53 mL, 19.17 mmol) was added and reaction mixture was stirred at room temperature for 2h. The reaction mixture was quenched with icewater (50 mL) and extracted with EtOAc (2x 100 mL). The combined organic layers were washed with sat. NaCl solution, dried over anhyd. Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (silica, hexane / EtOAc 1 :0 - 9: 1) to afford the title compound (3.50 g, 86%). LC-MS m / z = 425 [M+H]+; Rt = 2.88 min (Method A).62 GRA 4222-foreign filing

[0264] Synthesis of INT-192: tert-butyl (3S,4S)-4-amino-3-ethoxypiperidine-l-carboxylate

[0265] To a solution of INT- 191 (3.5 g, 8.25 mmol) inMeOH (80 mL) was added 10%Pd-C (50% wet, 1.2 g) and stirred under hydrogen balloon pressure for 16 h at room temperature. After completion, the reaction mixture was filtered through a bed of celite and washed with methanol. The filtrate was concentrated under reduced pressure to afford the title compound (1.70 g, 84%).

[0266] Synthesis of INT-195: tert-butyl (3S,4S)-4-(2-((4,6-dimethylpyridin-2-yl)oxy)-2,2-difluoro-N-(4-methox- ybenzyl)acetamido)-3-methoxypiperidine-l-carboxylate

[0267] A mixture of INT-189 (0.400 g, 0.79 mmol), 4,6-dimethylpyridin-2-ol (0.243 g, 1.97 mmol) and CS2CO3 (0.769 g, 2.37 mmol) in MeCN (40 mL) was heated at 120 °C in a sealed tube for 8 h. The reaction mixture was diluted with EtOAc (300 mL), and washed with water (100 mL). The organic layer was dried over anhyd. Na2SO4and concentrated under reduced pressure. The crude material was directly used in the next synthetic step without further purification. LC-MS m / z = 550 [M+H]+; Rt = 3.58 min (Method F).

[0268] The following compounds were prepared in analogy:LC-MS m / z Example Structure Chemical Name Precursor [M+H]+,Rt[min] (Method) \0 tert-butyl (3S,4S)-4-(2-((6-chloro-4- INT-189 and methylpyridin-2-yl)oxy)-2,2- 6-chloro-4- 570, 4.11 INT-196 1 0 difluoro-N-(4-methoxybenzyl)acet- methylpyri- (A) x l x f l amido)-3 -methoxypiperidine- 1 -carZ / '| | din-2-ol0 LBoc boxylate63 GRA 4222-foreign filing\0 tert-butyl (3S,4S)-4-(2,2-difluoro- INT-189 andN-(4-methoxybenzyl)-2-((4-methyl- 4-methyl-6- 604, 2.43 INT-197 0 6-(trifluoromethyl)pyridin-2- (trifluorome- (F) CF3^NX^O'^U'N / ''|*Z^| yl)oxy)acetamido)-3 -methoxypipethyl)pyridin- ^ ridine- 1 -carboxylate 2-oltert-butyl (3 S,4S)-4-(2,2-difluoro-2- ((3 -fluoro-4,6-dimethylpyridin-2- INT-189 and 568, 3.46 INT-198 yl)oxy)-N-(4-methoxybenzyl)aceta- INT-202 (I) mido)-3 -metho xypiperidine- 1 -carN ° 1 10 L Boc boxylatetert-butyl (3S,4S)-4-(2-((4,6-dime- INT-194 and thylpyridin-2-yl)oxy)-2,2-difluoro- 4,6-dime- 564, 4.20 INT-199 1 Ai ll V 1 N-(4-methoxybenzyl)acetamido)-3- thylpyridin- 1 (A) ethoxypiperidine- 1 -carboxylate 2-ol0Boc

[0269] Synthesis of INT-200: 2-chloro-5-fluoro-4-methylpyridine 1-oxide

[0270] To a solution of 2-chloro-5-fluoro-4-methylpyridine (8.0 g, 54.96 mmol) in CH2O2 (200 mL) was added mCPBA (20.3 g, 82.4 mmol, 70%) and the reaction mixture was heated at 65 °C for 16 h. The reaction mixture was diluted with CH2O2 (200 mL) and washed with water (150 mL). The aqueous layer was extracted with 10% MeOH in CH2O2 (200 mL) and the combined organic layer was dried over anhyd. Na2SC>4, filtered and concentrated under reduced pressure. The cmde material was purified by column chromatography (silica, MeOH / CH2Cl25:95) to afford the title compound (5.0 g, 56%). LC-MS m / z = 162 [M+H]+; Rt = 0.94 min (Method H).

[0271] Synthesis of INT-201: 6-chloro-3-fluoro-4-methylpyridin-2-ol

[0272] To a solution of INT-200 (2 g, 12.4 mmol) inTHF (30 mL) were added TEA (5.18 mL, 37.14 mmol) and TFAA (2.07 mL, 14.9 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction was diluted with EtOAc (200 mL), washed with water (100 mL), sat. NaHCO, solution (100 mL) and sat. NaCl solution (100 mL). The organic layer was dried over anhyd. Na2SC>4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (silica, EtOAc / hexane 15:85) to afford the title compound (0.50 g, 25%). LC-MS m / z = 161 [M+H]+; Rt = 1.28 min (Method H).

[0273] Synthesis of INT-202: 3-fluoro-4,6-dimethylpyridin-2-ol64 GRA 4222-foreign filing

[0274] A solution of INT-201 (500 mg, 3.1 mmol) and IGC'Ch (1.3 g, 9.28 mmol) in 1,4-dioxane (4 mL) and FLO (1 mL) was degassed with N2for 15 min in a sealed tube. Then, trimethylboroxine (2.6 mL, 9.28 mmol, 50% in THF) and (dtbp 0f)PdCl2(202 mg, 0.31 mmol) were added. The reaction mixture was heated at 130 °C for 18 h in a Osealed tube. The mixture was allowed to cool to room temperature, filtered through a celite bed, and washed with EtOAc (100 mL). The filtrate was ZI concentrated under reduced pressure. The crude product was purified by column chromatography (silica, EtOAc / hexane 6:4 - 7:3) to afford the title compound (0.30 g, 69%). LC-MS m / z = 142 [M+H]+; Rt = 1.67 min (Method A). T \ \- X

[0275] Synthesis of products:

[0276] Synthesis of SC-001: 2-(3-(tert-butyl)phenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropana-mide

[0277] To a stirred solution of carbamate INT-90 (0.19 g, 0.42 mmol) in CH2C12(2.0 mL) was added TFA (0.49 mL, 6.4 mmol) at 0 °C and the mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC (YMC Triart C18 (250 x 20 mm, 5 p), elution at ambient temperature with a gradient of A (20 mM NH4HCO3 in H2O) / B (MeCN): 0.0 min 80% A — 3.0 min 55% A —> 25.0 min 15% A — 26.0 min 5% A) to afford the title compound (30 mg, 20%). 'H NMR (400 MHz, DMSO-de) 37.91 (d, 1H), 7.16 (t, 1H), 7.00 (d, 1H), 6.87-6.88 (m, 1H), 6.70 (dd, 1H), 3.58-3.62 (m, 1H), 3.17 (s, 3H), 3.08-3.311 (m, 2H), 2.75-2.78 (m, 1H), 2.32-2.38 (m, 1H), 2.12 (t, 1H), 1.56-1.60 (m, 1H), 1.39-1.40 (singlets, 6H), 1.26-1.32 (m, 1H), 1.23 (s, 9H); LCMS m / z = 349 [M+H]+; Rt= 2.10 min (Method F).

[0278] The following compounds were prepared in analogy:LC-MS Prem / z Example Structure Chemical Name cur[M+H]+, sor Rt[min] (Method) 2-(2,4-difluorophenoxy)-N-((3S,4S)-3-meth- INT- 329, 2.53 SC-002oxypiperidin-4-yl)-2-methylpropanamide 91 (J)65 GRA 4222-foreign filing2-(3-cyanophenoxy)-N-((3S,4S)-3-methoxy- INT- 318, 1.95 SC-003piperidin-4-yl)-2-methylpropanamide 92 (F) T1 J t^V / _r^-n)9nON-((3S,4S)-3-methoxypiperidin-4-yl)-2-me- INT- 343, 2.28 SC-004zx thyl-2-(naphthalen-2-yloxy)propanamide 93 (I) < )o—\f \- X2-(3-isopropylphenoxy)-N-((3S,4S)-3-meth- INT- 335, 2.34 SC-005oxypiperidin-4-yl)-2-methylpropanamide 94 (I)0^02-(3-methoxyphenoxy)-N-((3S,4S)-3-meth- INT- 323, 2.00 SC-006oxypiperidin-4-yl)-2-methylpropanamide 95 (I)0XX\ ✓ ° N-((3S,4S)-3-methoxypiperidin-4-yl)-2-me- INT- 307, 2.10 SC-007 \ / °OCV rS thyl-2-(o-tolyloxy)propanamide 960(I) F oo 2-(3-fluorophenoxy)-N-((3S,4S)-3-methoxy- INT- 311, 1.97 SC-008piperidin-4-yl)-2-methylpropanamide 97c0 (I)0Cl2-(2,3-dichlorophenoxy)-N-((3S,4S)-3- INT- 361, 2.07 SC-009 methoxypiperidin-4-yl)-2-methylpropana- 6c\«„.x 98 (F)0\^NHmideAl K N-((3S,4S)-3-methoxypiperidin-4-yl)-2-me- INT- 307, 2.11 0 v / C 0 H *S 1 1'- n ° “Y \^i thyl-2-(m-tolyloxy)propanamide 99 (I)NH2-(2,3-dimethylphenoxy)-N-((3S,4S)-3- INT- 321, 2.04 SC-011 6C\A.X methoxypiperidin-4-yl)-2-methylpropana- 100 (F)0\^NHmideN-((3S,4S)-3-methoxypiperidin-4-yl)-2-me- INT- 361, 2.64 SC-012 thyl-2-(3-(trifluoromethyl)phenoxy)propana- 101 (J) mide66 GRA 4222-foreign filingCl2-(3-chlorophenoxy)-N-((3S,4S)-3-methox- INT- 327, 2.02 SC-013ypiperidin-4-yl)-2-methylpropanamide 102 (F)0\^NH& 8- 2-(3,5-dimethylphenoxy)-N-((3S,4S)-3- INT- 321, 2.24 SC-014 o o \ / n methoxypiperidin-4-yl)-2-methylpropana- 103 (I) midey y y <°* < <oo** 2-(3,5-dimethylphenoxy)-N-((3S,4S)-3- 335, 2.34 SC-015 TT \ \ \ \ \-- INT- methoxypiperidin-4-yl)-2-methyl- (A), 6.70106RcrS0L^NH butanamide, stereoisomer-2 (U)2-(3,5-dimethylphenoxy)-N-((3S,4S)-3- 335, 2.33INT- SC-016 methoxypiperidin-4-yl)-2-methyl- (A), 5.62106Ror S0II 1 1 butanamide, stereoisomer- 1 (U) The mixture of stereoisomers obtained from the deprotection of INT-106 was resolved by preparative chiral HPLC (Agilent 1200 series; column: CHIRALPAK AY-H (250 x 21 mm, 5 p); elution with isocratic hex- ane / EtOH 90:10 + 0.1% / -PrNH2at ambient temperature) to afford SC-015 (18 mg, 15 %) and SC-016 (29 mg, 24 %).F2,2-difluoro-N-((3S,4S)-3-methoxypiperi- INT- 355, 2.14 SC-017 n v « 8 din-4-yl)-2-(2,4,5-trifluorophenoxy)acetam- 105 (I) F O k^NH ide2,2-difluoro-N-((3S,4S)-3-methoxypiperi- INT- 355, 2.22 SC-018 din-4-yl)-2-(3,4,5-trifluorophenoxy)acetam- 107 (I) ideF2,2-difluoro-N-((3S,4S)-3-methoxypiperi- INT- 355, 2.11 SC-019 r ii v H f din-4-yl)-2-(2,3,5-trifluorophenoxy)acetam-fT 108 (FF ° i OrN'"r ) k^iNH ide2-(3-chloro-4,5-difluorophenoxy)-2,2- INT- 371, 2.34 SC-020 difluoro-N-((3S,4S)-3-methoxypiperidin-4- 128 (I) yl)acetamideCk Y^i v s'H ; 2-(4-chlorophenoxy)-2,2-difluoro-N- INT- 335, 2.07 SC-021 ^oXirN / "A ((3 S,4S)-3 -methoxypiperidin-4-yl)acetamide 129 (F)O k^NH67 GRA 4222-foreign filing2-(2,4-difluoro-3-methylphenoxy)-2,2- INT- 351, 2.20 SC-022 difluoro-N-((3S,4S)-3-methoxypiperidin-4- 109 (I) yl)acetamide■n ■n2,2-difluoro-N-((3S,4S)-3-methoxypiperi- INT- 301, 1,96 SC-023 5 ^~z\ o -n \o O o -n din-4-yl)-2 -phenoxyacetamide 130 (I) / "HZZ zx zx> < o— 2-(3,4-difluoro-5-methylphenoxy)-2,2- \ INT- 351, 2.31 SC-024 y < < >o o*— X difluoro-N-((3S,4S)-3-methoxypiperidin-4- TTT \ \ \ \ \ \--- 110 (I) Z X X yl)acetamideCl2-(3-chlorophenoxy)-2,2-difluoro-N- INT- 335, 2.17 SC-025((3 S,4S)-3 -methoxypiperidin-4-yl)acetamide 131 (I)0k^NH2,2-difluoro-2-(2-fluoro-3-methylphenoxy)- X X INT- 333, 2.15 SC-026 N-((3S,4S)-3-methoxypiperidin-4-yl)aceta- J \ ✓ \ ✓ ° ° J\ J\ \ \~~ 132\ \~ (I) midexz xz \ / °Fo o^^ “■ “■^^lL lLoo==2-(3,5-difluorophenoxy)-2,2-difluoro-N- INT- 337, 2.21 SC-027 r oil ““ v((3 S,4S)-3 -methoxypiperidin-4-yl)acetamide 133 (F) d u_ 0 k^NHu.2-(3-chloro-4-fluorophenoxy)-2,2-difluoro- INT- 353, 2.06 SC-028 N-((3S,4S)-3-methoxypiperidin-4-yl)aceta- 134 (F) mide2,2-difluoro-2-(3-fluoro-5-methylphenoxy)- INT- 333, 2.04 SC-029 N-((3S,4S)-3-methoxypiperidin-4-yl)aceta- 135 (F) mide2,2-difluoro-2-(4-fluoro-3-methylphenoxy)- INT- 333, 2.07 SC-030 N-((3S,4S)-3-methoxypiperidin-4-yl)aceta- 111 (F) mide2-(3,5-dimethylphenoxy)-2,2-difluoro-N- INT- 329, 2.09 SC-031 l il V «Q\((3 S,4S)-3 -methoxypiperidin-4-yl)acetamide 136 (F) 0 k^NH68 GRA 4222-foreign filing2-(3-chloro-5-fluorophenoxy)-2,2-difluoro- INT- 353, 2.30 SC-032 N-((3S,4S)-3-methoxypiperidin-4-yl)aceta- 137 (I) mideo0-' o 2,2-difluoro-N-((3S,4S)-3-methoxypiperi- INT- 315, 2.01 SC-033 ' o din-4-yl)-2-(m-tolyloxy)acetamide 138 (F) zz > < o—\ .0 1X\T \- 2-(3,5-dimethylphenoxy)-2,2-difluoro-N- X INT- 373, 2.12 SC-034 ((3S, 4S)-3-(2 -methoxy ethoxy )piperidin-4- 175 (K) AkvrS yl)acetamide formateo <^NHHCO2H2-(3,5-dichlorophenoxy)-2,2-difluoro-N- INT- 369, 2.11 SC-035((3 S,4S)-3 -methoxypiperidin-4-yl)acetamide 139 (F) zJ\ y \ K Z— K. I~\ / \ ✓ ° ° N-((3S,4S)-3-(cyclopropylmethoxy)piperi- INT- 369, 2.41 SC-036 xz zz din-4-yl)-2-(3,5-dimethylphenoxy)-2,2- j LL 176 (K) difluoroacetamide formateo x O^^ / \ O=o _ / a CMlLo=_ \ / x2-(3,5-dimethylphenoxy)-N-((3S,4S)-3- INT- 343, 2.36 SC-037 u_ (A V HAAoy A ethoxypiperidin-4-yl)-2,2-difluoroacetamide 177 (K)0k^NHCl2,2-difluoro-2-(3-fluoro-5-methylphenoxy)- INT- 349, 2.32 SC-038 A l ^il ° V^Y HN / '.AQ(| N-((3S, 4S)-3-(2 -methoxyethoxy )piperidin- 140 (I) 0 k^NH 4-yl)acetamide0 12,2-difluoro-2-(3-fluoro-5-methylphenoxy)- 377, 2.24 JL ent-1 J INT- SC-039 N-((3S*, 4S*)-3-(2 -methoxy ethoxy )piperi- (A), 7.20PA rAl O v^ «N, 1 i 112din-4-yl)acetamide, tr om-cnantiomcr-l (T) 0 k^NH0 12,2-difluoro-2-(3-fluoro-5-methylphenoxy)- 377, 2.24 ent-2 1 INT- SC-040 N-((3S*, 4S*)-3-(2 -methoxy ethoxy )piperi- (A), 9.10112 A w din-4-yl)acetamide, Zra«5-enantiomer-2 (T)0\xNH69 GRA 4222-foreign filingThe mixture of stereoisomers obtained from the deprotection of INT-112 was resolved by preparative chiral HPLC (Agilent 1200 series; column: CHIRALPAK IG (250 x 30 mm, 5 p); elution with isocratic hexane / EtOH 70:30 at 35 °C) to afford SC-039 (90 mg, 23 %) and SC-040 (70 mg, 18 %).4-(3,5-dimethylphenoxy)-N-((3S,4S)-3- INT- 363, 2.11 SC-041 methoxypiperidin-4-yl)tetrahydro-2H-pyran- 113 (I)0k^NH4-carboxamidel-(3,5-dimethylphenoxy)-N-((3S,4S)-3-me- INT- 361, 2.62 SC-042 thoxypiperidin-4-yl)cyclohexane-l-carboxa- 114 (F)0k^NH mide2-cyclopropyl-2-(3,5-dimethylphenoxy)-N- 333, 2.20INT- SC-043 ((3 S ,4 S)-3 -methoxypiperidin-4-y ^aceta(A), 1.90115Ror S 0 mide, stereoisomer- 1 (P)2-cyclopropyl-2-(3,5-dimethylphenoxy)-N- 333, 2.21INT- SC-044 jik^X ((3 S ,4 S)-3 -methoxypiperidin-4-y ^aceta(A), 2.32115R or S O mide, stereoisomer-2 (P) The mixture of stereoisomers obtained from the deprotection of INT-115 was resolved by preparative SFC (Waters PREP SFC 80; column: (R,R)-Whelk-0 1 (250 x 30 mm, 5 p); elution with isocratic CO2 / 0.2% NH3in MeOH + Z-PrOH 70:30 at 35 °C / 100 bars) to afford SC-043 (53 mg, 24 %) and SC-044 (51 mg, 23 %).l-(3,5-dimethylphenoxy)-N-((3S,4S)-3-me- INT- 333, 2.25 SC-045 jik^X thoxypiperidin-4-yl)cyclobutane-l-carboxa- 116 (I)0k^NH mideCl2-(3-chlorophenoxy)-N-((3S,4S)-3-methox- 313, 2.00INT- SC-046 ypiperidin-4-yl)propanamide, stereoisomer - (F),143R or S O L .NH 2 10.72 (T) Cl2-(3-chlorophenoxy)-N-((3S,4S)-3-methox- 313, 2.02INT- SC-047 ypiperidin-4-yl)propanamide, stereoisomer - (F), 11.98144R or S O k^NH1 (T)2-(3,5-dimethylphenoxy)-N-((3S,4S)-3- 321, 2.22INT- SC-048 methoxypiperidin-4-yl)butanamide, stereoi(A), 1.86117R or SO somer-2 (P)2-(3,5-dimethylphenoxy)-N-((3S,4S)-3- 321, 2.21INT- SC-049 methoxypiperidin-4-yl)butanamide, stereoi(A), 1.61117R or S O k^NH somer-1 (P)70 GRA 4222-foreign filingThe mixture of stereoisomers obtained from the deprotection of INT- 117 was resolved by preparative SFC (Pic Solutions- 175; column: (R,R)-Whelk-0 1 (250 x 30 mm, 5 p); elution with isocratic CO2 / 0.2%NH3inMeOH 80:20 at 35 °C / 100 bars) to afford SC-048 (49 mg, 27 %) and SC-049 (54 mg, 30 %).1 \ II 2-((4,6-dimethylpyridin-2-yl)oxy)-2-methyl- INT- 400, 2.15 SC-055 N-((3S,4S)-3-((2-methylpyrimidin-5- 166 (I)0yl)oxy)piperidin-4-yl)propanamide1H NMR (400 MHz, MeOD) S 8.32 (s, 2H), 6.48 (s, 1H), 6.36 (s, 1H), 4.33-4.27 (m, 1H), 4.03-3.97 (m, 1H), 3.15-3.11 (m, 1H), 2.93-2.90 (m, 1H), 2.65-2.55 (m, 5H), 2.23 (s, 3H), 2.17 (s, 3H), 1.89-1.84 (m, 1H), 1.53 (s, 3H), 1.47-1.39 (m, 4H)F^FN-((3S,4S)-3-(2,2-difluoroethoxy)piperidin- INT- 372, 2.31 SC-056 \ / Hi 4-yl)-2-((4,6-dimethylpyridin-2-yl)oxy)-2- ' N O | | 167 (I)methylpropanamideO k^NH| FN-((3S,4S)-3-(difluoromethoxy)piperidin-4- INT- 358, 2.29 SC-057 II \ / H I yl)-2-((4,6-dimethylpyridin-2-yl)oxy)-2-me- 168 (A) O k^NHthylpropanamide2-((4,6-dimethylpyridin-2-yl)oxy)-N- INT- 336, 2.20 SC-058 ((3S,4S)-3-ethoxypiperidin-4-yl)-2-methyl- 169 AkV rS (I)0 k^NH propanamide'H NMR (400 MHz, DMSO-de) 57.34 (m, 1H), 6.62 (s, 1H), 6.43 (s,lH), 3.52-3.44 (m, 2H), 3.37-3.35 (m, 1H), 3.19-3.13 (m, 1H), 3.03-2.99 (m, 1H), 2.73-2.67 (m, 1H), 2.35-2.29 (m, 2H), 2.22-2.19 (m, 6H), 2.16-2.11 (m, 1H), 1.53-1.51 (m, 7H), 1.14-1.11 (m, 1H), 0.98-0.95 (m, 3H)2-((3,5-dimethylphenyl)thio)-N-((3S,4S)-3- INT- 337, 0.66 SC-059 A V « r methoxypiperidin-4-yl)-2-methylpropana- 104 (L) O k^NHmide1 \ II 2-(3,5-dimethylphenoxy)-2,2-difluoro-N- INT- 407, 2.29 SC-060 r l v « i ((3S,4S)-3-((2-methylpyrimidin-5- 118 (A) ^ yl)oxy)piperidin-4-yl)acetamide'H NMR (400 MHz, DMSO-de) 5 9.06 (m, 1H), 8.39 (s, 2H), 6.85 (s, 1H), 6.74 (s, 2H), 4.41-4.35 (m, 1H), 4.11-4.05 (m, 1H), 3.37-3.33 (m, 1H), 3.06-3.02 (m, 1H), 2.70-2.61 (m, 2H), 2.58 (s, 3H), 2.26 (s, 6H), 1.93- 1.88 (m, 1H), 1.73-1.64 (m, 1H).Cl2-(3-chloro-2-fluorophenoxy)-2,2-difluoro- INT- 353, 2.23 SC-061 fV v H C N-((3S,4S)-3-methoxypiperidin-4-yl)aceta- 119 (I)0k^NH mide71 GRA 4222-foreign filing2,2-difluoro-2-(2-fluoro-5-methylphenoxy)- INT- 333, 2.18 SC-062 N-((3S,4S)-3-methoxypiperidin-4-yl)aceta- 120 (I) F O L ,zNHmide2-(3,5-dimethylphenoxy)-2,2-difluoro-N- INT- 387, 2.28 SC-063ZO o -H ((3S, 4S)-3-(2 -hydroxy -2 -methyl121 (A) propoxy )piperidin-4-yl)acetamideZX zzy— —° 1 \ / > <L°I\ ' z 'T—— \ T 2-(3,5-dimethylphenoxy)-2,2-difluoro-N- / \ X oX INT- 359, 2.17 SC-064 ((3S,4S)-3-(2-hydroxyethoxy)piperidin-4- 122 (A) yl)acetamide1H NMR (400 MHz, DMSO-de) 36.92 (s, 1H), 6.86 (s, 2H), 3.81-3.75 (m, 1H), 3.65-3.54 (m, 4H), 3.42-3.36 (m, 1H), 3.27 (s, 1H), 2.98-2.95 (m, 1H), 2.63-2.57 (m, 1H), 2.46-2.40 (m, 1H), 2.30 (s, 6H), 1.93-1.89 (m, 1H), 1.56-1.47 (m, 1H)1 2-(3,5-dimethylphenoxy)-2,2-difluoro-N- X INT- 399, 2.28 SC-065 or il V « y z— \ X ((3 S,4S)-3 -((tetrahydro-2H-pyran-4- \ 123 (H) \ / °O < - \ / ° NH yl)oxy)piperidin-4-yl)acetamidexz IZ1 u_ / - / u- ^O= Ror s / O 2-(3,5-dimethylphenoxy)-2,2-difluoro-N- 385, 2.29 SC-066 co ULT \ u / \ INT- o ((3S,4S)-3-((tetrahydrofuran-3-yl)oxy)pipe- (A), 5.27 A w 124O ridin-4-yl)acetamide, stereoisomer- 1 (S) - - 2-(3,5-dimethylphenoxy)-2,2-difluoro-N- 385, 2.28INT- SC-067 ((3S,4S)-3-((tetrahydrofuran-3-yl)oxy)pipe- (A), 6.88124ridin-4-yl)acetamide, stereoisomer-2 (S) The mixture of stereoisomers obtained from the deprotection of INT-124 was resolved by preparative chiral HPLC (Agilent 1200 series; column: CHIRALPAK IG (250 x 21 mm, 5 p); elution with isocratic hex- ane / CH2C12 / EtOH 70:15:15 + 0.1% NH3in MeOH at ambient temperature) to afford SC-066 (55 mg, 24 %) and SC-067 (37 mg, 16 %).2-((3,5-dimethylphenyl)thio)-2,2-difluoro- INT- 345, 2.35 SC-068 N-((3S,4S)-3-methoxypiperidin-4-yl)acet- 125 (I) amide2-((4,6-dimethylpyridin-2-yl)oxy)-2-fluoro- 312, 1.90 F 0^ INT- SC-070 1 H 1Jo xk X*^^Nz, N-((3S,4S)-3-methoxypiperidin-4-yl)acet- (I), 2.63 ' NOI I 146 R or S 0 amide, stereoisomer- 1 (Q)72 GRA 4222-foreign filing2-((4,6-dimethylpyridin-2-yl)oxy)-2-fluoro- 312, 1.90INT- SC-071 1 H 1 N-((3S,4S)-3-methoxypiperidin-4-yl)acet- (I), 3.37146RorS O amide, stereoisomer-2 (Q) The mixture of stereoisomers obtained from the deprotection of INT-146 was resolved by preparative SFC (column: CHIRALCEL OX-H (250 x 21 mm, 5 p); elution with isocratic CO2 / 0.2% / -PrNFh in i-PrOH 70:30 at 35 °C / 100 bars) to afford SC-070 (40 mg, 9 %) and SC-071 (50 mg, 11 %).2-((4,6-dimethylpyridin-2-yl)oxy)-N- 322, 2.05INT- SC-072 ((3 S,4S)-3 -methoxypiperidin-4-yl)butana- (I), 2.34170mide, stereoisomer- 1 Ror S 0 (P) 2-((4,6-dimethylpyridin-2-yl)oxy)-N- 322, 2.12INT- SC-073 j6k\A.x ((3 S,4S)-3 -methoxypiperidin-4-yl)butana- (I), 2.61170mide, stereoisomer-2 (P) Ror S 0 k^NHThe mixture of stereoisomers obtained from the deprotection of INT-170 was resolved by preparative SFC (Waters SFC-150; column: (R,R)-Whelk-0 1 (250 x 30 mm, 5 p); elution with isocratic CO2 / 0.2%NH3in MeOH 80:20 at 35 °C / 100 bars) to afford SC-072 (11 mg, 14 %) and SC-073 (13 mg, 17 %). y z—ylllio2-(3,5-dimethylphenoxy)-2-fluoro-N- 311, 0.53 0 Z— ' / / INT- xz xz 1 H ■ SC-074 ((3 S ,4 S)-3 -methoxypiperidin-4-y ^acetam(L), 6.04 >°= 142 u. >°=ide, stereoisomer- 1 (R) RorS O k^NH LL / \O O2-(3,5-dimethylphenoxy)-2-fluoro-N- 311, 0.53 - - F INT- I H ■ SC-075 ((3 S ,4 S)-3 -methoxypiperidin-4-y ^acetam(L), 6.34142ide, stereoisomer-2 Ror S O k^NH (R) The mixture of stereoisomers obtained from the deprotection of INT-142 was resolved by preparative SFC (Waters Absys-SFC-Prep-System; column: Phenomenex Lux Amylose (150 x21.2 mm, 5 p); elution with isocratic COVIO mM AmOH in MeOH 90:10 at 50 °C) to afford SC-074 (3.5 mg, 9 %) and SC-075 (12 mg, 30 %)•2-(3,5-dimethylphenoxy)-2,2-difluoro-N- INT- 300, 0.41 SC-076174 (piperazin- 1 -y l)acetamide (O)2-(3,5-dimethylphenoxy)-2,2-difluoro-N- INT- 326, 0.57 SC-077147 (4,7 -diazaspiro [2.5] octan-4-y l)acetamide (L) XJkV-*) O k^NHINT- 328, 0.43 2-(3,5-dimethylphenoxy)-N-((2S,5R)-2,5-di- SC-078148 methylpiperazin- 1 -yl)-2,2-difluoroacetamide (O)73 GRA 4222-foreign filingrac-2-(3,5-dimethylphenoxy)-N-((2R*,3S*)- INT- 328, 0.44 SC-079 2,3-dimethylpiperazin-l-yl)-2,2-difluoroa- 149 (O) cetamide2-(3,5-dimethylphenoxy)-N-((2S,6S)-2,6-di- INT- 328, 0.61 SC-080 r il o o v H i^^OX1TN'N1 methylpiperazin- 1 -yl)-2,2-difluoroacetamide 150 (L) zx(S)-2-(3,5-dimethylphenoxy)-2,2-difluoro- INT- 314, 0.43 SC-081 &N-(2-methylpiperazin- 1 -yl)acetamide 145 (O) 'H NMR (600 MHz, DMSO-^e) 510.29 (s, 1H), 6.95 (s, 1H), 6.87 (s, 2H), 3.31 (m, 2H), 3.13 (m, 1H), 3.10 - 3.03 (m, 2H), 2.97 (m, 1H), 2.75 (m, 1H), 2.29 (s, 6H), 0.91 (m, 3H)me5o-2-(3,5-dimethylphenoxy)-N-(-2,6-di- INT- 328, 0.59 SC-082methylpiperazin- 1 -yl)-2,2-difluoroacetamide 151 (L) \ zX2.—! •r ii v H tIZ i 2-(3,5-dimethylphenoxy)-N-((2S,5S)-2,5-di- INT- 328, 1.34 SC-083 > ^°O== methylpiperazin- 1 -yl)-2,2-difluoroacetamide 152 (N) LL / 11 / Xo o O O k^NHoC - - -l(S)-2-(3-chloro-5-methylphenoxy)-2,2-diflu- INT- 334, 0.43 SC-084 A IL V HyC N. J 1' 0 N L > oro-N-(2-methylpiperazin- 1 -yl)acetamide 153 (O) O(S)-2-(3-chlorophenoxy)-2,2-difluoro-N-(2- INT- 320, 0.55 SC-085methylpiperazin- 1 -y l)acetamide 154 (L)INT- 314, 0.57 (R)-2-(3,5-dimethylphenoxy)-2,2-difluoro- SC-086N-(2-methylpiperazin- 1 -yl)acetamide 155 (L)(S)-2-(3,5-dimethylphenoxy)-N-(2-ethyl- INT- 328, 0.62 SC-087156 piperazin- 1 -yl)-2,2-difluoroacetamide (L)INT- 314, 0.40 (S)-N-(2-ethylpiperazin- 1 -yl)-2,2-difluoro- r ii v H SC-088157 2-(m-tolyloxy)acetamide (O) W rS74 GRA 4222-foreign filing(R)-2-(3,5-dimethylphenoxy)-2,2-difluoro- INT- 344, 0.43 SC-089 vh°1 N-(2-(methoxymethyl)piperazin- 1 -yl)aceta- 158 (O) O mideo "H \^ z_ rac-2-(3,5-dimethylphenoxy)-N-((2R*,3R*)- INT- 328, 0.44 SC-090 o o 2,3-dimethylpiperazin-l-yl)-2,2-difluoroace- o 159 (O) tamideZIzx& < oT ( \ >o- (S)-2-((4,6-dimethylpyridin-2-yl)oxy)-N-(2- INT- 321, 0.39 SC-091 \T \ \-- X X ethylpiperazin- 1 -yl)-2-methylpropanamide 160 (O)(S)-2-((4,6-dimethylpyridin-2-yl)oxy)-2-me- INT- 307, 0.37 SC-092 thyl-N-(2-methylpiperazin- 1 -yl)propana- 161 (O) mide2-((5-fluoro-4,6-dimethylpyridin-2-yl)oxy)- INT- 340, 0.56 SC-093 Z \ 3:\ ) N-((3S,4S)-3-methoxypiperidin-4-yl)-2- y - 171 (L) z— ' methylpropanamide / / xz xz IZ'H NMR (600 MHz, DMSO lx. -dg) 57.39 (m, 1H), 6.57 (m, 1H), 3.54 (m, 1H), 3.17 (s, 3H), 3.11 - 3.03 (m, 2H), 2.73 (m, 1H), 2.34 (m, o o O 1H), 2.22 (m, 3H), 2.19 (m, 3H), 2.14 (m, 1H), 1.63 - 1.56 (m, 1H), 1.52 (d, 3H), 1.51 (d, 3H), 1.17 (m, 1H)0 — - 2-((3-fluoro-4,6-dimethylpyridin-2-yl)oxy)- INT- 340, 0.60 SC-094 N-((3S,4S)-3-methoxypiperidin-4-yl)-2- AIoV'-A 172 (L)0k^NH methylpropanamide'H NMR (600 MHz, DMSO-^e) 37.40 (d, 1H), 6.69 (d, 1H), 3.54 (m, 1H), 3.19 (s, 3H), 3.11 - 3.03 (m, 2H), 2.77 - 2.68 (m, 1H), 2.38 - 2.29 (m, 1H), 2.21 - 2.14 (m, 6H), 2.17 - 2.10 (m, 1H), 1.63 - 1.55 (m, 1H), 1.57 (s, 3H), 1.54 (s, 3H), 1.20 - 1.09 (m, 1H)(S)-2-((4,6-dimethylpyridin-2-yl)oxy)-N-(2- INT- 335, 0.56 SC-096 isopropylpiperazin-l-yl)-2-methylpropana- 164 (L) mide'H NMR (600 MHz, Chloroform-^ 87.32 (s, 1H), 6.61 (s, 1H), 6.41 (s, 1H), 3.29 - 3.13 (m, 4H), 3.04 (m, 1H), 2.96 (m, 1H), 2.88 (m, 1H), 2.30 (s, 3H), 2.26 (s, 3H), 2.10 (m, 1H), 1.62 (s, 3H), 1.60 (s, 3H), 0.86 (m, 6H)2-((6-chloro-4-methylpyridin-2-yl)oxy)-N- INT- 342, 0.54 SC-097 ((3S,4S)-3-methoxypiperidin-4-yl)-2-me- 126 (L) thylpropanamide75 GRA 4222-foreign filing1H NMR (600 MHz, DMSO-dg) 57.73 (m, 1H), 6.92 (s, 1H), 6.66 (si, 1H), 3.83 (m, 1H), 3.47 - 3.37 (m, 1H), 3.10 (m, 1H), 3.01 (m, 1H), 2.84 - 2.71 (m, 2H), 2.27 (s, 3H), 1.83 (m, 1H), 1.56 (s, 3H), 1.54 (s, 3H), 1.45 (m, 1H)2-((4-chloro-6-methylpyridin-2-yl)oxy)-N- INT- 342, 0.42 SC-098 ((3S,4S)-3-methoxypiperidin-4-yl)-2-me- 0 0 127 (O)thylpropanamidezz zz / Z y— y 2-((4,6-dimethylpyridin-2-yl)oxy)-N- INT- 335, 2.16 SC-099 \ / z— ((2S,5 S)-2-ethyl-5-methylpiperazin- 1 -y 1) -2 - X X 165 (I) methylpropanamide'H NMR (400 MHz, DMSO-dg) 58.19 (s, 1H), 6.63 (s, 1H), 6.41 (s, 1H), 2.86 (m, 1H), 2.66-2.61 (m, 2H), 2.55-2.53 (m, 1H), 2.46-2.42 (m, 2H), 2.23 (s, 3H), 2.20 (s, 3H), 1.52 (s, 6H), 1.29-1.24 (m, 2H), 1.03 (m, 3H), 0.63 (m, 3H)

[0279] Synthesis of SC-095: 2-((4,6-dimethylpyridin-2-yl)oxy)-2-methyl-N-((3S,4S)-3-(trifluoromethoxy)piperi- din-4-yl)propanamide

[0280] To a solution of DBH (0.35 g, 1.2 mmol) in CH2O2 (10 mL) at -78°C was added HF-pyridine (2 mL, 20 mmol) and the reaction mixture was stirred at -78 °C for 1 h before a solution of carbono dithioate INT-178 (0.2 g, 0.4 mmol) in CH2O2 (5mL) was slowly added. The mixture was stirred at -78 °C for 1 h, subsequently allowed to gradually warm to room temperature and stirred for 16 h. Ice water was introduced to the mixture and the pH adjusted to pH ~ 10 with aq. ISfeCCh solution. The mixture was extracted with EtOAc, and the combined organic layers were dried over anhyd. Na2SO4 and concentrated under reduced pressure. The crude material was purified by preparative HPLC (YMC Triart C18 (250 x 21.2 mm, 5 p), elution at ambient temperature with a gradient of A = 20 mM NH4HCO3 in H2O / B = MeCN: 80% A -> 5% A) to yield the title compound (60 mg, 40%).1H NMR (400 MHz, DMSO-t / s) 57.61 (d, 1H), 6.62 (s, 1H), 6.42 (s, 1H), 4.20 - 4.16 (m, 1H), 3.76 - 3.75 (m, 1H), 3.12 - 3.08 (m, 1H), 2.77 -2.74 (m, 1H), 2.50 - 2.33 (m, 3H), 2.21 (s, 3H), 2.20 (s, 3H), 1.51 (s, 6H), 1.35 - 1.31 (m, 1H); LCMS m / z = 376 [M+H]+; Rt= 2.47 min (Method I).

[0281] Synthesis of SC-050: 2-(4-fluoro-3,5-dimethylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methyl- propanamide76 GRA 4222-foreign filing

[0282] To a stirred solution of carbamate INT-86 (25 mg, 0.06 mmol) in CH2O2 (1.5 mL) was added TFA (0.02 mL, 0.29 mmol) at 0 °C and the mixture was stirred for 30 minutes at 30 °C. The mixture was diluted with CH2O2 (10 mL) and washed with sat. NaH CO;, -solution (5 mL). The layers were separated, and the organic layer was concentrated under reduced pressure. The crude material was purified by catch-and-release on a SCX-cartridge (elution with 2 M NH3 in MeOH) to afford the title compound (18.0 mg, 93%).1H NMR (600 MHz, DMSO-cL) 5 8.04 (m, 1H), 6.66 (m, 2H), 3.75 (m, 1H), 3.35 (m, 1H), 3.26 (s, 3H), 2.96 (m, 1H), 2.66 -2.58 (m, 1H), 2.43 (m, 1H), 2.16 (m, 6H), 1.77 - 1.70 (m, 1H), 1.46 (m, 1H), 1.39 (s, 3H), 1.35 (s, 3H); LCMS m / z = 339 [M+H]+; Rt= 0.61 min (Method L).

[0283] The following compounds were prepared in analogy:LC-MS Prem / z ExamStructure Chemical Name cur[M+H]+, plesor Rt [min] (Method) Cl2-(3-chloro-5-fluorophenoxy)-N-((3S,4S)- SC- INT- 345, 0.623-methoxypiperidin-4-yl)-2-methylpro- 051 x X 87 (L)0J\ _J\ \ \-~ panamide\ / \ ✓00Cl xz xz^ ^0= 2-(3-chloro-5-methylphenoxy)-N- SC- >°= INT- 341, 0.65LLX^ ((3 S,4S)-3 -methoxypiperidin-4-yl)-2- 052 0 CO 88 (L)O methylpropanamide— —Cl2-(3,5-dichlorophenoxy)-N-((3S,4S)-3- SC- INT- 361, 0.67 jdjl y a X methoxypiperidin-4-yl)-2-methylpropana- 053 89 (L)0 \XNHmide2-((4,6-dimethylpyridin-2-yl)oxy)-N- SC- INT- 322, 0.46((3 S,4S)-3 -methoxypiperidin-4-yl)-2- 054 163 (L)methylpropanamide'H NMR (600 MHz, DMSO-de) 87.34 (d, 1H), 6.62 (s, 1H), 6.43 (s, 1H), 3.53 (m, 1H), 3.18 (s, 3H), 3.10 - 3.00 (m, 2H), 2.74 - 2.67 (m, 1H), 2.32 (m, 1H), 2.23 (s, 3H), 2.20 (s, 3H), 2.17 - 2.08 (m, 1H), 1.58 (m, 1H), 1.54 (s, 3H), 1.52 (s, 3H), 1.14 (m, 1H)2-((4,6-dimethylpyridin-2-yl)thio)-2,2- SC- INT- 346, 0.46 difluoro-N-((3 S,4S)-3 -methoxypiperidin- 069 162 (L)4-yl)acetamide'H NMR (600 MHz, DMSO-de) 88.92 (d, 1H), 7.31 - 7.27 (m, 1H), 7.12 (m, 1H), 3.54 (m, 1H), 3.25 (s, 3H), 3.15 (m, 1H), 2.81 (m, 1H), 2.42 (s, 3H), 2.37 (m, 1H), 2.29 (m, 3H), 2.13 (m, 1H), 1.59 (m, 1H), 1.37 (m, 1H)77 GRA 4222-foreign filing

[0284] Synthesis of SC-100: 2-((4,6-dimethylpyridin-2-yl)oxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide00

[0285] A solution INT-195 (0.420 g, 0.76 mmol) inTFA (8 mL) was heated at 90 °C for 16 h. The reaction mixture was concentrated, diluted with MeOH (20 mL) and amberlyst A21 resin (250 mg) was added. The mixture was stirred at room temperature for 1 h. Th Oe \ reaction mixture was then filtered, and then washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica, MeOH / CH2Cl23:97-7:93) followed by reverse phase preparative HPLC (YMC Triart C18 (250 x21.2 mm, 5p), elution at ambient temperature with a gradient of A = 20 mM NH4HCO3 in H2O / B = MeCN: 80% A — > 5% A) to afford to afford the title compound (71 mg, 28%). LC-MS m / z = 330 [M+H]+; Rt = 1.80 min (Method F).1H-NMR (400 MHz, DMSO-d6) S 8.87-8.85 (m, 2H), 6.93 (s, 1H), 6.73 (s, 1H), 3.53-3.48 (m, 1H), 3.24-3.16 (m, 5H), 2.81-2.78 (m, 1H), 2.37-2.28 (m, 7H), 2.17-2.07 (m, 1H), 1.64-1.62 (m, 1H), 1.43-1.33 (m, 1H).

[0286] The following compounds were prepared in analogy:LC-MS m / z PrecurExample Structure Chemical Name [M+H]+, sorRt [min] (Method) 2-((6-chloro-4-methylpyridin-2-yl)oxy)- INT- 350, 1.81 SC-104 2,2-difhioro-N-((3 S,4S)-3 -methoxypiper- 196 (F) idin-4-yl)acetamide2,2-difluoro-N-((3S,4S)-3-methoxypipe- r ^il \Fridin-4-yl)-2-((4-methyl-6-(trifluorome- INT- 384, 2.07 SC-105 F^ J^. J.F FN 00 iT 1 1 thyl)pyridin-2-yl)oxy)acetamide 2,2,2- 197 (F) CF3CO2H trifluoroacetate2,2-difluoro-2-((3-fluoro-4,6-dimethyl-F Fpyridin-2-yl)oxy)-N-((3S,4S)-3-me- SC-106 AA^A INT- 348, 2.14 thoxypiperidin-4-yl)acetamide 2,2,2-trif- 198O l^^NH (I) CF3CO2H luoroacetate2-((4,6-dimethylpyridin-2-yl)oxy)-N- INT- 344, 1.84 SC-107 AA-A O^A ((3S,4S)-3-ethoxypiperidin-4-yl)-2,2- 199 (F) k^NH difluoroacetamide78 GRA 4222-foreign filing

[0287] Biological Activity:

[0288] hSSTR4 cAMP assay:

[0289] cAMP accumulation assay using a CHO-K1 human SSTR4 Gi cell line.

[0290] Quantification of intracellular cAMP was performed using the LANCE Ultra cAMP assay kit from Rewity according to the manufacturer’s instructions. CHO-K1 human SSTR4 Gi cell were either seeded in a density of 3K cells per well into a 384 well plate and incubated at 37°C and 5 % CO2 for 18-20 h or a stock of frozen cells were defrosted and seeded in a density of 5K cells per well without any further cultivation directly prior to the assay in a total volume of 5 pL in stimulation buffer. For pre-cultured cells, medium was replaced with 5 pL stimulation buffer before the assay. Cells were then stimulated with forskolin (final concentration 10 pM) and test compound (SSTR4 agonist) in increasing concentrations in duplicates for 30 min at 25 °C. After stimulation, cells were lysed by addition of 10 pL of detection buffer (provided with the kit) and cell lysates were further diluted to ensure final cAMP concentrations fitted well into the dynamic range of the test kit. 10 pL of the diluted lysates were then added to respective wells of an OptiPlate-384 microplate. Thereafter, 5 pL of 4X Eu-cAMP tracer working solution was added, followed by addition of 5 pL of ULight-anti-cAMP working solution. The plate was then incubated for 1 h at 25°C before reading on a TR-FRET microplate instrument. Data were normalized to cAMP high (forskolin only) and low control (forskolin + 100 nM SST14) before fitting to a 4-Paramter logistic function.

[0291] In-vitro functional agonism data (EC50 at hSSTR4) of the exemplified compounds is given in the table below. All data was generated according to the cAMP assay conditions described above in at least duplicate and results are averaged and rounded to two significant figures.hSSTR4 hSSTR4 hSSTR4 Example ECso [pM] Example ECso [pM] Example ECso [pM] SC-001 1.04132 SC-037 0.00026 SC-073 0.04856 SC-002 0.17775 SC-038 0.00013 SC-074 0.00129 SC-003 0.09942 SC-039 0.52992 SC-075 0.29784 SC-004 0.07337 SC-040 0.00259 SC-076 0.01778 SC-005 0.05593 SC-041 0.60510 SC-077 0.02703 SC-006 0.05361 SC-042 0.45959 SC-078 0.00336 SC-007 0.03625 SC-043 0.13772 SC-079 0.02847 SC-008 0.03224 SC-044 0.04954 SC-080 2.21633 SC-009 0.02398 SC-045 0.03025 SC-081 0.00251 SC-010 0.01271 SC-046 0.02715 SC-082 0.64049 SC-011 0.01211 SC-047 0.00725 SC-083 0.00147 SC-012 0.00995 SC-048 0.00544 SC-084 0.00377 SC-013 0.00497 SC-049 0.05383 SC-085 0.02633 SC-014 0.00251 SC-050 0.08057 SC-086 0.02567 SC-015 0.08614 SC-051 0.00588 SC-087 0.00081 SC-016 0.01931 SC-052 0.00512 SC-088 0.00290 SC-017 0.15152 SC-053 0.00127 SC-089 0.00701 SC-018 0.08649 SC-054 0.00066 SC-090 0.0411079 GRA 4222-foreign filingSC-019 0.06521 SC-055 0.00016 SC-091 0.00093 SC-020 0.01430 SC-056 0.00126 SC-092 0.00601 SC-021 0.01053 SC-057 0.00039 SC-093 0.00123 SC-022 0.00838 SC-058 0.00068 SC-094 0.00043 SC-023 0.00743 SC-059 0.00490 SC-095 0.00018 SC-024 0.00290 SC-060 0.00007 SC-096 0.00014 SC-025 0.00232 SC-061 0.01345 SC-097 0.00021 SC-026 0.00369 SC-062 0.01045 SC-098 0.00056 SC-027 0.00210 SC-063 0.00077 SC-099 0.00064 SC-028 0.00171 SC-064 0.00198 SC-100 0.00110 SC-029 0.00020 SC-065 0.00168 SC-101 0.00917 SC-030 0.00159 SC-066 0.00207 SC-102 0.69746 SC-031 0.00022 SC-067 0.00292 SC-103 0.18277 SC-032 0.00047 SC-068 0.00096 SC-104 0.00038 SC-033 0.00044 SC-069 0.02934 SC-105 0.00050 SC-034 0.00035 SC-070 0.05701 SC-106 0.00698 SC-035 0.00035 SC-071 1.01189 SC-107 0.00323 SC-036 0.00028 SC-072 0.07941

Claims

80 GRA 4222-foreign filingPatent claims:

1. A compound according to general formula (I)whereinR1 representsH,Ci-4-alkyl or O-Ci-4-alkyl, wherein in each case alkyl is unsubstituted or substituted with one, two, three or four substituents independently of one another selected from F, OH, OCH3, and cyclopropyl; O-Cs-e-cycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F, CH3, OH and OCH3,O-(4 to 6-membered heterocycloalkyl) unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3,O-phenyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F, Cl, CH3, OH and OCH3, orO-(5 or 6-membered heteroaryl) unsubstituted or substituted with one, two or three substituents independently of one another selected from F, Cl, CH3, OH and OCH3;Rl' represents H or CH3;or Rl and Rl' together with the carbon atom to which they are attached to form a CAe-cycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3, or a 4 to 6-membered heterocycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3;R2, R3 and R4, in each case independently from one another, represent H, or Ci-4-alkyl unsubstituted or substituted with one, two, three or four substituents independently of one another selected from F, OH and OCH3;R5 representsF or Cl,Ci-4-alkyl unsubstituted or substituted with one, two, three or four substituents independently of one another selected from F, OH, OCH3, and cyclopropyl;Cs-e-cycloalkyl, unsubstituted or substituted with one, two or three substituents independently of one another selected from F, CH3and OCH3,4 to 6-membered heterocycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3;R6 represents H, F, Cl or Ci-4-alkyl unsubstituted or substituted with one, two, three or four substituents independently of one another selected from F, OH, and OCH3;81 GRA 4222-foreign filingor R5 and R6 together with the carbon atom to which they are attached to form a Cke-cycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F, CH3and OCH3, or a 4 to 6-membered heterocycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3;R7, R8, R9, RIO and Rll, in each case independently from one another, representH,F, Cl, Br or CN,Ci-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, O-Ci-4-alkyl or S-Ci-4-alkyl, wherein in each case alkyl, alkenyl or alkynyl is unsubstituted or substituted with one, two, three or four substituents independently of one another selected from F, OH, OCH3, and cyclopropyl,C3.6-cycloalkyl or O-C3.6-cycloalkyl, wherein in each case cycloalkyl is unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3, phenyl or O-phenyl, wherein in each case phenyl is unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3;or R7 and R8 or R8 and R9, in each case together with the carbon atoms to which they are attached to, formphenyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3,5 or 6-membered heteroaryl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3,Cs-e-cycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3, or5- or 6-membered heterocycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3;X represents CH or N;with the proviso that when R1 represents H or Ci-4-alkyl, or when R1 and Rl' together with the carbon atom to which they are attached to form a C3.6-cycloalkyl, then X represents N; and with the proviso that when Rl represents O-Ci-4-alkyl, O-C3.6-cycloalkyl, O-(4 to 6-membered heterocycloalkyl), O-phenyl or O-(5 or 6-membered heteroaryl), then X represents CH;Y represents O or S;Z represents CR11 or N;or a physiologically acceptable salt thereof.

2. The compound according to claim 1, wherein Rl representsO-Ci-4-alkyl, wherein in each case alkyl is unsubstituted or substituted with one, two, three or four substituents independently of one another selected from F, OH, OCH3, and cyclopropyl;O-C3.6-cycloalkyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F, CH3, OH and OCH3,82 GRA 4222-foreign filing0-(4 to 6-membered heterocycloalkyl) unsubstituted or substituted with one, two or three substituents independently of one another selected from F and CH3,O-phenyl unsubstituted or substituted with one, two or three substituents independently of one another selected from F, Cl, CH3, OH and OCH3, orO-(5 or 6-membered heteroaryl) unsubstituted or substituted with one, two or three substituents independently of one another selected from F, Cl, CH3, OH and OCH3.

3. The compound according to claim 1, wherein R1 and Rl' together with the carbon atom to which they are attached to form a cyclopropyl, unsubstituted.

4. The compound according to any of the preceding claims, wherein R2, R3 and R4, in each case independently from one another, represent H or CH35. The compound according to any of the preceding claims, wherein at most one of R2, R3 and R4 does not represent H.

6. The compound according to any of the preceding claims, wherein R5 represents F, Ci.4-alkyl unsubstituted, or C3.6-cycloalkyl unsubstituted.

7. The compound according to any of the preceding claims, wherein R6 represents H, F or Ci-4-alkyl unsubstituted.

8. The compound according to any of claims 1 to 5, wherein R5 and R6 together with the carbon atom to which they are attached to form a C3.6-cycloalkyl unsubstituted, or a 5 or 6-membered heterocycloalkyl unsubstituted.

9. The compound according to any of the preceding claims, wherein R7, R8, R9 and RIO, in each case independently from one another, represent H, F, Cl, CN, Ci-4-alkyl, O-Ci-4-alkyl, phenyl or O-phenyl wherein in each case alkyl or phenyl is unsubstituted or substituted with one, two, or three substituents selected from F.

10. The compound according to any of the preceding claims, wherein at least one of R7, R8, R9 and RIO does not represent H.

11. The compound according to any of the preceding claims, wherein R7 and R8, or R8 and R9, in each case together with the carbon atoms to which they are attached, form phenyl or pyridyl, wherein in each case phenyl or pyridyl is unsubstituted.

12. The compound according to any of the preceding claims, wherein Y represents O and / or Z represents N.

13. The compound according to any of the preceding claims, wherein Rll represents H or F.GRA 4222-foreign filing14. The compound according to any of the preceding claims, which is selected from the group consisting of 001 2-(3-(tert-butyl)phenoxy)-N-((3S,4S)-3-methoxypipendin-4-yl)-2-methylpropanamide 002 2-(2,4-difluorophenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide 003 2-(3-cyanophenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide 004 N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methyl-2-(naphthalen-2-yloxy)propanamide 005 2-(3-isopropylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide 006 2-(3-methoxyphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide 007 N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methyl-2-(o-tolyloxy)propanamide008 2-(3-fluorophenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide 009 2-(2,3-dichlorophenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide 010 N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methyl-2-(m-tolyloxy)propanamideOil 2-(2,3-dimethylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide 012 N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methyl-2-(3-(trifluoromethyl)phenoxy)propana- mide013 2-(3-chlorophenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide 014 2-(3,5-dimethylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide 015 and 016 2-(3,5-dimethylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylbutanamide 017 2.2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-(2,4,5-trifluorophenoxy)acetamide 018 2.2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-(3,4,5-trifluorophenoxy)acetamide 019 2.2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-(2,3,5-trifluorophenoxy)acetamide 020 2-(3-chloro-4,5-difluorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acet- amide021 2-(4-chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide 022 2-(2,4-difluoro-3-methylphenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)ac- etamide023 2.2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)-2 -phenoxyacetamide024 2-(3,4-difluoro-5-methylphenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)ac- etamide025 2-(3-chlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide 026 2.2-difluoro-2-(2-fluoro-3-methylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)acetam- ide027 2-(3,5-difluorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide 028 2-(3-chloro-4-fluorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetam- ide029 2.2-difluoro-2-(3-fluoro-5-methylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)acetam- ide030 2.2-difluoro-2-(4-fluoro-3-methylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)acetam- ide031 2-(3,5-dimethylphenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide84 GRA 4222-foreign filing2-(3-chloro-5-fluorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetam- ide2.2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-(m-tolyloxy)acetamide2-(3, 5-dimethylphenoxy)-2,2-difluoro-N-((3S,4S)-3-(2 -methoxy ethoxy )piperidin-4-yl)ac- etamide formate2-(3,5-dichlorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide N-((3S,4S)-3-(cyclopropylmethoxy)piperidin-4-yl)-2-(3,5-dimethylphenoxy)-2,2- difluoroacetamide formate2-(3,5-dimethylphenoxy)-N-((3S,4S)-3-ethoxypiperidin-4-yl)-2,2-difluoroacetamide 2.2-difluoro-2-(3-fluoro-5-methylphenoxy)-N-((3S,4S)-3-(2 -methoxy ethoxy )piperidin-4- yl)acetamideand 040 tran5-2,2-difluoro-2-(3-fluoro-5-methylphenoxy)-N-((3 S*,4S*)-3-(2 -methoxy ethoxy )pi- peridin-4-yl)acetamide4-(3,5-dimethylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)tetrahydro-2H-pyran-4- carboxamide1-(3,5-dimethylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)cyclohexane-l-carbox- amideand 044 2-cyclopropyl-2-(3,5-dimethylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide 1-(3,5-dimethylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)cyclobutane-l-carbox- amideand 047 2-(3-chlorophenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)propanamideand 049 2-(3,5-dimethylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)butanamide2-(4-fluoro-3,5-dimethylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropa- namide2-(3-chloro-5-fluorophenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropana- mide2-(3-chloro-5-methylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropana- mide2-(3,5-dichlorophenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide 2-((4,6-dimethylpyridin-2-yl)oxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpro- panamide2-((4,6-dimethylpyridin-2-yl)oxy)-2-methyl-N-((3S,4S)-3-((2-methylpyrimidin-5- yl)oxy)piperidin-4-yl)propanamideN-((3S,4S)-3-(2,2-difluoroethoxy)piperidin-4-yl)-2-((4,6-dimethylpyridin-2-yl)oxy)-2- methylpropanamideN-((3S,4S)-3-(difluoromethoxy)piperidin-4-yl)-2-((4,6-dimethylpyridin-2-yl)oxy)-2- methylpropanamide2-((4,6-dimethylpyridin-2-yl)oxy)-N-((3S,4S)-3-ethoxypiperidin-4-yl)-2-methylpropana- mide2-((3,5-dimethylphenyl)thio)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methylpropanamide85 GRA 4222-foreign filing2-(3,5-dimethylphenoxy)-2,2-difluoro-N-((3S,4S)-3-((2-methylpyrimidin-5-yl)oxy)piper- idin-4-yl)acetamide2-(3-chloro-2-fluorophenoxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetam- ide2,2-difluoro-2-(2-fluoro-5-methylphenoxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)acetam- ide2-(3, 5-dimethylphenoxy)-2,2-difluoro-N-((3S,4S)-3-(2 -hydroxy -2-methylpropoxy )piperi- din-4-yl)acetamide2-(3, 5-dimethylphenoxy)-2,2-difluoro-N-((3S,4S)-3-(2 -hydroxy ethoxy )piperidin-4-yl)ac- etamide2-(3,5-dimethylphenoxy)-2,2-difluoro-N-((3S,4S)-3-((tetrahydro-2H-pyran-4-yl)oxy)pi- peridin-4-yl)acetamide2-(3,5-dimethylphenoxy)-2,2-difluoro-N-((3S,4S)-3-((tetrahydrofuran-3-yl)oxy)piperi- din-4-yl)acetamide, stereoisomer- 12-(3,5-dimethylphenoxy)-2,2-difluoro-N-((3S,4S)-3-((tetrahydrofuran-3-yl)oxy)piperi- din-4-yl)acetamide, stereoisomer-22-((3,5-dimethylphenyl)thio)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetam- ide2-((4,6-dimethylpyridin-2-yl)thio)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)ac- etamideand 071 2-((4,6-dimethylpyridin-2-yl)oxy)-2-fluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetam- ideand 073 2-((4,6-dimethylpyridin-2-yl)oxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)butanamide and 075 2-(3,5-dimethylphenoxy)-2-fluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acetamide 2-(3,5-dimethylphenoxy)-2,2-difluoro-N-(piperazin-l-yl)acetamide2-(3,5-dimethylphenoxy)-2,2-difluoro-N-(4,7-diazaspiro[2.5]octan-4-yl)acetamide 2-(3,5-dimethylphenoxy)-N-((2S,5R)-2,5-dimethylpiperazin-l-yl)-2,2-difluoroacetamide rac-2-(3,5-dimethylphenoxy)-N-((2R*,3S*)-2,3-dimethylpiperazin-l-yl)-2,2-difluoroa- cetamide2-(3,5-dimethylphenoxy)-N-((2S,6S)-2,6-dimethylpiperazin-l-yl)-2,2-difluoroacetamide (S)-2-(3,5-dimethylphenoxy)-2,2-difluoro-N-(2-methylpiperazin-l-yl)acetamide me5o-2-(3,5-dimethylphenoxy)-N-(-2,6-dimethylpiperazin-l-yl)-2,2-difluoroacetamide 2-(3,5-dimethylphenoxy)-N-((2S,5S)-2,5-dimethylpiperazin-l-yl)-2,2-difluoroacetamide (S)-2-(3-chloro-5-methylphenoxy)-2,2-difluoro-N-(2-methylpiperazin-l-yl)acetamide (S)-2-(3-chlorophenoxy)-2,2-difluoro-N-(2-methylpiperazin-l-yl)acetamide(R)-2-(3,5-dimethylphenoxy)-2,2-difluoro-N-(2-methylpiperazin-l-yl)acetamide (S)-2-(3,5-dimethylphenoxy)-N-(2-ethylpiperazin-l-yl)-2,2-difluoroacetamide(S)-N-(2-ethylpiperazin-l-yl)-2,2-difluoro-2-(m-tolyloxy)acetamide(R)-2-(3,5-dimethylphenoxy)-2,2-difluoro-N-(2-(methoxymethyl)piperazin-l-yl)acetam- ide86 GRA 4222-foreign filing090 rac-2-(3,5-dimethylphenoxy)-N-((2R*,3R*)-2,3-dimethylpiperazin-l-yl)-2,2-difluoroa- cetamide091 (S)-2-((4,6-dimethylpyridin-2-yl)oxy)-N-(2-ethylpiperazin- 1 -yl)-2-methylpropanamide 092 (S)-2-((4,6-dimethylpyridin-2-yl)oxy)-2-methyl-N-(2-methylpiperazin- 1 -yl)propanamide 093 2-((5-fluoro-4,6-dimethylpyridin-2-yl)oxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2- methylpropanamide094 2-((3-fluoro-4,6-dimethylpyridin-2-yl)oxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2- methylpropanamide095 2-((4,6-dimethylpyridin-2-yl)oxy)-2-methyl-N-((3S,4S)-3-(trifluoromethoxy)piperidin-4- yl)propanamide096 (S)-2-((4,6-dimethylpyridin-2-yl)oxy)-N-(2-isopropylpiperazin- 1 -yl)-2 -methylpropanamide097 2-((6-chloro-4-methylpyridin-2-yl)oxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2- methylpropanamide098 2-((4-chloro-6-methylpyridin-2-yl)oxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2- methylpropanamide099 2-((4,6-dimethylpyridin-2-yl)oxy)-N-((2S,5S)-2-ethyl-5-methylpiperazin-l-yl)-2- methylpropanamide100 2-((4,6-dimethylpyridin-2-yl)oxy)-2,2-difluoro-N-((3S,4S)-3-methoxypiperidin-4-yl)acet- amide101 N-((3 S,4S)-3 -methoxypiperidin-4-yl)-2-methyl-2-(naphthalen- 1 -yloxy)propanamide 102 2-([l,r-biphenyl]-3-yloxy)-N-((3S,4S)-3-methoxypiperidin-4-yl)-2 -methylpropanamide 103 N-((3S,4S)-3-methoxypiperidin-4-yl)-2-methyl-2-(3-phenoxyphenoxy)propanamide 104 2-(6-chloro-4-methylpyridin-2-yl)oxy-2,2-difluoro-N-[(3S,4S)-3-methoxypiperidin-4- yl] acetamide105 2,2-difluoro-N-[(3S,4S)-3-methoxypiperidin-4-yl]-2-[4-methyl-6-(trifluoromethyl)pyri- din-2-yl]oxyacetamide106 2,2-difluoro-2-(3-fluoro-4,6-dimethylpyridin-2-yl)oxy-N-[(3S,4S)-3-methoxypiperidin-4- yl] acetamide107 2-(4,6-dimethylpyridin-2-yl)oxy-N-[(3S,4S)-3-ethoxypiperidin-4-yl]-2,2-difluoroacetam- ideor a physiologically acceptable salt thereof.

15. A medicament comprising a compound according to any of the preceding claims.

16. A pharmaceutical dosage form comprising a compound according to any of claims 1 to 14 for use in the treatment of pain.

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