HK1173445A

HK1173445A - Substituted piperidines

Info

Publication number: HK1173445A
Application number: HK13100688.2A
Authority: HK
Inventors: Dirk Heimbach; Susanne Röhrig; Yolanda Cancho Grande; Eckhard Bender; Katja Zimmermann; Anja BUCHMÜLLER; Christoph Gerdes; Mark Jean Gnoth; Kersten Matthias Gericke; Mario Jeske
Original assignee: Bayer Pharma Aktiengesellschaft
Priority date: 2009-05-27
Filing date: 2010-05-19
Publication date: 2013-05-16

Description

Substituted piperidines

The invention relates to novel substituted piperidines, to methods for the production thereof, to the use thereof for the treatment and/or prophylaxis of diseases and to the use thereof for producing medicaments for the treatment and/or prophylaxis of diseases, in particular cardiovascular diseases and tumor diseases.

Thrombocytes (platelets) are important factors in physiological haemostasis and in thromboembolic diseases. In particular in the arterial system, platelets are of central importance in the complex interaction between blood components and the vessel wall. Through the formation of platelet rich thrombi, unwanted platelet activation may lead to thromboembolic diseases and thrombotic complications, with life threatening conditions.

One of the most potent platelet activators is the blood clotting protease thrombin, which forms in damaged vessel walls and which, in addition to fibrin formation, leads to platelet, endothelial and mesenchymal activation (Vu TKH, Hung DT, Wheaton VI, Coughlin SR, Cell 1991, 64, 1057-. In vitro platelet aggregation and in animal models, inhibitors of blood coagulation inhibit platelet aggregation and platelet-rich thrombosis. In humans, arterial thrombosis can be successfully prevented or treated with inhibitors of platelet function and inhibitors of blood coagulation (Bhatt DL, Topol EJ, nat. rev. drug discov.2003, 2, 15-28). Thus, there is a high probability that antagonists of thrombin's platelet action will reduce thrombosis and the occurrence of clinical sequelae such as myocardial infarction and stroke. Other cellular effects of thrombin, such as on endothelial and smooth muscle cells of blood vessels, leukocytes and fibroblasts, may be responsible for inflammatory and proliferative diseases.

At least some of the cellular actions of thrombin are regulated by a class of G protein-coupled Receptors (PARs), the prototype of which is the PAR-1 receptor. PAR-1 is activated by a combination of thrombin and its proteolytic cleavage at the extracellular N-terminus. Proteolytic exposure has a new N-terminus with the amino acid sequence SFLLRN which as an agonist leads to intramolecular receptor activation and intracellular signaling. Peptides derived from tether-ligand sequences can be used as agonists of receptors and, to cause activation and aggregation of platelets. Other proteases, including, for example, cytoplasmic, factor VIIa, factor Xa, trypsin, activated protein C (aPC), tryptase, cathepsin G, protease 3, granzyme A, elastase and matrix metalloproteinase 1(MMP-1), are also capable of activating PAR-1.

In contrast to inhibition of the protease activity of thrombin, which has a direct coagulation inhibitor, blockade of PAR-1 will result in inhibition of platelet activation without reducing the coagulation capacity of the blood (anticoagulation).

Antibodies and other selective PAR-1 antagonists inhibit thrombin-induced aggregation of platelets in vitro at low to moderate thrombin concentrations (Kahn ML, Nakanishi-MatsuiM, Shapiro MJ, Ishihara H, Coughlin SR, J.Clin.invest.1999, 103, 879-. A further thrombin receptor, PAR-4, of possible importance for the pathophysiology of the method of thrombosis is the platelet recognition in humans and animals. PAR-1 antagonists reduce platelet-rich thrombus formation in experimental thrombosis in animals with PAR expression patterns similar to humans (Derian CK, Damiano BP, Addo MF, DarrowAL, D' Andrea MR, Nedelman M, Zhang H-C, Maryanoff BE, Andlade-Gordon P, J.Pharmacol.Exp.Ther.2003, 304, 855-.

In recent years, a large number of substances have been examined for their platelet function-inhibiting effects; however, in practice only a few inhibitors of platelet function have proven useful. Thus, there is a need for drugs that specifically inhibit increased platelet response without significantly increasing the risk of bleeding, and thus reducing the risk of thromboembolic complications.

The action of thrombin, regulated by the receptor PAR-1, affects the progression of the disease during and after Coronary Artery Bypass Graft (CABG) and other surgical procedures and in particular surgical procedures accompanied by extracorporeal circulation (e.g. heart-lung machine). During surgery, bleeding complications may exist due to pre-or intra-operative drug treatment with coagulation-inhibiting and/or platelet-inhibiting substances. For this reason, for example, drug treatment with clopidogrel must be interrupted for several days before CABG. Furthermore, as mentioned, disseminated intravascular coagulation or consumption coagulopathy (DIC) may occur (e.g. during extracorporeal circulation or transfusion due to extensive contact between blood and synthetic surfaces), which in turn can lead to bleeding complications. Subsequently, restenosis of the vein or grafted arterial bypass (which may even create an occlusion) often occurs due to thrombosis, intimal fibrosis, arteriosclerosis, angina pectoris, myocardial infarction, heart failure, arrhythmia, Transient Ischemic Attack (TIA) and/or stroke.

In humans, the receptor PAR-1 is also represented by other cells including, for example, endothelial cells, smooth muscle cells and tumor cells. Malignant neoplastic disease (cancer) has a high incidence and is often associated with a high mortality rate. Current therapy achieves complete symptomatic relief in only a small fraction of patients and is generally associated with severe side effects. There is therefore a high need for more effective and safer treatments. The PAR-1 receptor contributes to cancer development, growth, invasion and metastasis. In addition, PAR-1 expressed on endothelial cells transmits signals that produce angiogenesis, a signal that causes tumors to be approximately 1mm in size ³Larger growth critical processes. Angiogenesis is also implicated in other diseases including, for example, hematopoietic cancer diseases, macular degeneration (which leads to blindness), and diabetic retinopathy, the development or malignancy of inflammatory diseases, such as rheumatoid arthritis and colitisAnd (4) transforming.

Sepsis (or septicemia) is a common disease with high mortality. The initial symptoms of sepsis are generally indeterminate (e.g., fever, decreased general health); however, there may follow systemic activation of the coagulation system ("disseminated intravascular coagulation" or "disseminated coagulopathy" (DIC)) with microthrombosis in various organs and secondary bleeding complications. DIC can also occur independently of sepsis, e.g. during surgery or in connection with tumor diseases.

Sepsis is primarily treated by a strong removal of infectious causes, such as surgical removal of lesions and antibiotic action. Secondly, it consists in the enhanced medical support of temporarily infected organ systems. The treatment of the different stages of the disease has been described, for example, in the following publication (Dellinger et al, Crit Care Med.2004, 32: 858-. There is no proven treatment for DIC.

It is therefore an object of the present invention to provide novel PAR-1 antagonists for the treatment of diseases in humans and animals, such as cardiovascular diseases and thromboembolic diseases, and tumor diseases.

WO 2006/012226, WO 2006/020598, WO 2007/038138, WO2007/130898, WO 2007/101270 and US 2006/0004049 describe structurally similar piperidines as 11- β HSD1 inhibitors for the treatment of, inter alia, diabetes, thromboembolic diseases and stroke.

The present invention provides compounds of the formula

Wherein

A is an oxygen atom or-NR⁴-，

Wherein

R⁴Is hydrogen or C₁-C₃-an alkyl group,

or

R²And R⁴Together with the nitrogen atom to which they are attached form a 4-to 6-membered heterocyclic ring,

wherein the heterocyclic ring may be substituted by 1 to 3 substituents independently selected from halogen, cyano, hydroxy, amino, C₁-C₄-alkyl radical, C₁-C₄-alkoxy and C₁-C₄-a substituent of an alkylamino group,

R₁is a phenyl group, and the phenyl group,

wherein phenyl may be substituted by 1 to 3 substituents independently selected from halogen, monofluoromethyl, difluoromethyl, trifluoromethyl, 1, 1-difluoroethyl, 2, 2, 2-trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, methylsulfonyl, C₁-C₄-alkyl radical, C₁-C₄-alkoxy and C₁-C₄-a substituent of an alkoxycarbonyl group,

R²Is C₁-C₆-alkyl radical, C₃-C₆-cycloalkyl, 4-to 6-membered heterocyclyl, phenyl or 5-or 6-membered heteroaryl,

wherein cycloalkyl, heterocyclyl, phenyl and heteroaryl may be substituted with 1 to 3 substituents independently selected from halogen, cyano, hydroxy, amino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, C₁-C₄-alkyl radical, C₁-C₄-alkoxy radical, C₁-C₆-substituents of alkylamino and phenyl,

wherein phenyl may be substituted with 1 to 3 substituents independently selected from halogen and trifluoromethyl,

and

wherein C is₁-C₆The alkyl group may be substituted by one selected from hydroxyl,trifluoromethyl radical, C₁-C₄-alkoxy radical, C₁-C₄-alkylsulfonyl, C₃-C₆-cycloalkyl and phenyl substituents,

wherein cycloalkyl and phenyl may be substituted by 1 to 3 substituents independently selected from halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, C₁-C₄-alkyl and C₁-C₄-a substituent of an alkoxy group,

R³is C₁-C₆-alkyl radical, C₁-C₆-alkoxy radical, C₁-C₆-alkylamino radical, C₃-C₇Cycloalkyl, 4-to 7-membered heterocyclyl, phenyl, 5-or 6-membered heteroaryl, C₃-C₇-cycloalkyloxy radical, C ₃-C₇Cycloalkylamino, 4-to 7-membered heterocyclylamino, phenylamino or 5-or 6-membered heteroarylamino,

wherein alkyl is C₂-C₆Alkoxy and alkylamino may be substituted by one group chosen from halogen, hydroxy, amino, cyano, C₁-C₄-alkoxy radical, C₁-C₄Alkoxycarbonyl radical, C₃-C₇-cycloalkyl, 4-to 6-membered heterocyclyl, phenyl and 5-or 6-membered heteroaryl,

and

wherein cycloalkyl, heterocyclyl, phenyl, heteroaryl, cycloalkyloxy, cycloalkylamino, heterocyclylamino, phenylamino and heteroarylamino may be substituted with 1 to 3 substituents independently selected from halogen, cyano, oxo, hydroxy, amino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, hydroxycarbonyl, aminocarbonyl, C₁-C₄-alkyl radical, C₁-C₄-alkoxy radical, C₁-C₆-alkylamino radical, C₁-C₄Alkoxycarbonyl radical, C₁-C₄Alkyl ammoniaSubstituted by substituents of the radicals carbonyl and cyclopropyl,

wherein the alkyl group may be substituted with one hydroxy substituent,

and their salts, their solvates and solvates of their salts.

If the compound comprised by formula (I) mentioned below is not also a salt, solvate or solvate of a salt, the compounds according to the invention are compounds of formula (I) and their salts, solvates or solvates of a salt, the compounds of formula (I) comprised by formula (I) mentioned below and their salts and solvates of a salt and the compounds comprised by formula (I) mentioned below as examples and the solvates of their salts, solvates and solvates of a salt.

Depending on their structure, the compounds according to the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The present invention thus includes enantiomers or diastereomers and mixtures of each thereof. From such mixtures of enantiomers and/or diastereomers, the stereoisomerically identical components can be separated in a known manner.

If a compound of the invention can exist in tautomeric forms, the invention includes all tautomeric forms.

In the context of the present invention, preferred salts are physiologically acceptable salts of the compounds of the invention. However, also included are salts which are not suitable per se for pharmaceutical use, but which may be used, for example, for the isolation or purification of the compounds of the invention.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of inorganic acids, carboxylic and sulfonic acids, for example salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.

Physiologically acceptable salts of the compounds of the invention also include salts of customary bases, such as, for example and preferably, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and choline.

In the context of the present invention it is,solvatesAre those forms of the compounds according to the invention which form complexes by complexation with solvent molecules, in solid or liquid form. Hydrates are a particular form of solvates in which the complexation is with water.

In addition, the invention also includes prodrugs of the compounds of the invention. The term "prodrug" includes compounds that may be biologically active or inactive by themselves, but are converted (e.g., by metabolism or hydrolysis) to the compounds of the invention during their residence in the body.

In the context of the present invention, unless otherwise indicated, substituents have the following meanings:

alkyl by itself and in alkoxy, alkylamino, alkylcarbonyl, alkylaminocarbonyl and alkyl Alkyl and alkyl in phenylsulfonyl "Are straight-chain or branched alkyl radicals having from 1 to 6 carbon atoms, such as, and preferably, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl and n-hexyl.

For example and with preference, the reaction mixture is,alkoxy radicalAre methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylamino radicalIs an alkylamino group having one or two (independently selected) alkyl substituents, such as and preferably methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino,n, N-dimethylamino, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-isopropyl-N-propylamino and N-tert-butyl-N-methylamino. C₁-C₄Alkylamino is, for example, a monoalkylamino group having 1 to 4 carbon atoms or a dialkylamino group having in each case 1 to 4 carbon atoms per alkyl substituent.

For example and with preference, the reaction mixture is,alkoxycarbonyl radicalAre methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl and tert-butoxycarbonyl.

Alkyl amino carbonylIs an alkylaminocarbonyl group having one or two (independently selected) alkyl substituents, such as, and preferably, methylaminocarbonyl, ethylaminocarbonyl, N-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-N-propylaminocarbonyl, N-isopropyl-N-N-propylaminocarbonyl and N-tert-butyl-N-methylaminocarbonyl. C ₁-C₄Alkylaminocarbonyl is, for example, a monoalkylaminocarbonyl radical having 1 to 4 carbon atoms or a dialkylaminocarbonyl radical having in each case 1 to 4 carbon atoms per alkyl substituent.

For example and with preference, the reaction mixture is,alkyl sulfonyl radicalAre methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl and tert-butylsulfonyl.

Cycloalkyl radicalsIs a monocyclic cycloalkyl group having typically 3 to 7, preferably 5 or 6, carbon atoms; examples of preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Cycloalkyl oxyIs a monocyclic cycloalkoxy group having typically 3 to 7, preferably 5 or 6, carbon atoms; examples of preferred cycloalkoxy groups are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.

Cycloalkyl aminoIs a monocyclic cycloalkylamino group having typically 3 to 7, preferably 3 or 4, carbon atoms; examples of preferred cycloalkylamino groups are cyclopropylamino, cyclobutylamino, cyclopentylamino and cyclohexylamino.

Heterocyclic radicalIs a compound having 4 to 7 ring atoms and up to 3, preferably up to 2, atoms selected from the group consisting of N, O, S, SO ₂And/or a monocyclic or bicyclic heterocyclic group of hetero groups, wherein the nitrogen atom may also form an N-oxide. Heterocyclyl groups may be saturated or partially unsaturated. Preferably having up to two heteroatoms selected from O, N and S, such as, and preferably, oxetanyl, azetidinyl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, tetrahydrofuryl, tetrahydrothienyl, pyranyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 1, 2, 5, 6-tetrahydropyridin-3-yl, 1, 2, 5, 6-tetrahydropyridin-4-yl, thiopyranyl, morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl, 1-oxothiomorpholin-4-yl, 1, 1-dioxothiomorpholin-4-yl, piperazin-1-yl, piperazin-2-yl.

Heterocyclylamino radicalIs a compound having 4 to 7 ring atoms and up to 2, preferably up to 2, atoms selected from the group consisting of N, O, S, SO₂And/or a monocyclic or bicyclic heterocyclic heterocyclylamino group of a heterogroup, wherein one nitrogen atom may also form an N-oxide. Heterocyclyl groups may be saturated or partially unsaturated. Preferably a 5-or 6-membered monocyclic saturated heterocyclyl radical having up to two heteroatoms selected from O, N and S, such as and preferably oxetanylamino, azetidinylamino, pyrrolidin-2-ylamino, pyrrolidin-3-amino, tetrahydrofurylamino, tetrahydrothienylamino, pyranylamino, piperidin-2-ylamino, piperidin-3-ylamino, piperidin-4-yl-amino, 1, 2, 5, 6-tetrahydropyridin-3-ylamino, 1, 2, 5, 6-tetrahydropyridin-4-ylamino, thiopyranylamino, morpholin-2-ylamino Morpholin-3-ylamino, thiomorpholin-2-ylamino, thiomorpholin-3-ylamino, piperazin-2-ylamino.

Heteroaryl radicalAre aromatic monocyclic radicals having usually 5 or 6 ring atoms and up to 4 heteroatoms from the group consisting of S, O and N, where one nitrogen atom may also form an N-oxide, such as and preferably thienyl, furyl, pyrrolyl, thiazolyl,azolyl radical, isoThe group of azolyl groups,oxadiazolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl.

Heteroaryl aminoIs an aromatic monocyclic heteroarylamino group having typically 5 or 6 ring atoms and up to 4 heteroatoms selected from S, O and N, wherein one nitrogen atom may also form an N-oxide, such as and preferably a thienylamino, furylamino, pyrrolylamino, thiazolylamino,azolylamino, iso(ii) an azolylamino group,oxadiazolylamino, pyrazolylamino, imidazolylamino, pyridylamino, pyrimidylamino, pyridazinylamino, pyrazinylamino.

Halogen elementAre fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

Preference is given to compounds of the formula (I) in which

A is an oxygen atomor-NR⁴-，

Wherein

R⁴Is hydrogen or C₁-C₃-an alkyl group,

or

R²And R ⁴Together with the nitrogen atom to which they are attached form a 4-to 6-membered heterocyclic ring,

R¹is a phenyl group, and the phenyl group,

wherein phenyl is substituted with 1 to 3 substituents independently selected from halogen, trifluoromethyl, 1, 1-difluoroethyl, 2, 2, 2-trifluoroethyl, trifluoromethoxy, C₁-C₄-alkyl radical, C₁-C₄-alkoxy and C₁-C₄-a substituent of an alkoxycarbonyl group,

R²is C₁-C₆-alkyl radical, C₃-C₆-cycloalkyl or 4-to 6-membered heterocyclyl,

wherein cycloalkyl and heterocyclyl may be substituted with 1 to 3 substituents independently selected from halogen, cyano, hydroxy, amino, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methyl, ethyl, methoxy and ethoxy,

and

wherein C is₁-C₆-the alkyl group may be substituted with one substituent selected from the group consisting of hydroxy, trifluoromethyl, methoxy and ethoxy,

R³is C₃-C₇Cycloalkyl, 4-to 7-membered heterocyclyl, phenyl, 5-or 6-membered heteroaryl, C₃-C₇-cycloalkyloxy radical, C₃-C₇Cycloalkylamino, 4-to 7-membered heterocyclylamino, phenylaminoOr a 5-or 6-membered heteroarylamino group,

wherein cycloalkyl, heterocyclyl, phenyl, heteroaryl, cycloalkyloxy, cycloalkylamino, heterocyclylamino, phenylamino and heteroarylamino may be substituted with 1 to 3 substituents independently selected from halogen, cyano, oxo, hydroxy, amino, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, methyl, ethyl, methoxy, ethoxy, dimethylamino, methoxycarbonyl, ethoxycarbonyl, dimethylaminocarbonyl and cyclopropyl,

Wherein methyl and ethyl may be substituted with one hydroxy substituent,

and their salts, their solvates and solvates of their salts.

Preference is also given to compounds of the formula (I), in which

A is an oxygen atom or-NR⁴-，

Wherein

R⁴Is a hydrogen, a methyl or ethyl radical,

or

R²And R⁴Together with the nitrogen atom to which they are attached form azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl,

wherein azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl may be substituted with 1 to 2 substituents independently selected from hydroxy, methyl, ethyl, methoxy and ethoxy,

R¹is a phenyl group, and the phenyl group,

wherein phenyl is substituted with 1 to 2 substituents independently selected from fluoro, trifluoromethyl, 1, 1-difluoroethyl, 2, 2, 2-trifluoroethyl, trifluoromethoxy, methyl, ethyl and methoxy,

R²is methyl, ethyl, propyl, isopropyl, 2-methylpropan-1-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orAn oxetan-3-yl group,

wherein cyclopropyl and cyclobutyl may be substituted by 1 to 2 substituents independently selected from methyl, ethyl, methoxy and ethoxy,

and

wherein methyl and ethyl may be substituted with one substituent selected from the group consisting of hydroxy, trifluoromethyl, methoxy and ethoxy,

R³Is morpholin-4-yl, thiomorpholin-4-yl, 1-oxothiomorpholin-4-yl, 1, 1-dioxothiomorpholin-4-yl, 3-hydroxyazetidin-1-yl, 3-hydroxypyrrolidin-1-yl, 4-cyanopiperidin-1-yl or 4-hydroxypiperidin-1-yl,

and their salts, their solvates and solvates of their salts.

Preference is also given to compounds of the formula (I), in which

A is an oxygen atom or-NR⁴-，

Wherein

R⁴Is a hydrogen, a methyl or ethyl radical,

or

wherein azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl may be substituted with a hydroxy substituent,

R¹is a phenyl group, and the phenyl group,

wherein the phenyl group is substituted with one substituent selected from the group consisting of trifluoromethyl, trifluoromethoxy and ethyl,

R²is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetan-3-yl,

wherein cyclopropyl and cyclobutyl may be substituted by 1 to 2 substituents independently selected from methyl and ethyl,

and

wherein methyl may be substituted with one trifluoromethyl substituent,

and

wherein the ethyl group may be substituted with one substituent selected from the group consisting of a hydroxyl group and a methoxy group,

R³is morpholin-4-yl, thiomorpholin-4-yl or 4-hydroxypiperidin-1-yl,

And their salts, their solvates and solvates of their salts.

Preference is also given to compounds of the formula (I), in which

A is an oxygen atom, and A is an oxygen atom,

R¹is a phenyl group, and the phenyl group,

wherein phenyl is substituted with 1 to 2 substituents independently selected from fluoro, trifluoromethyl, 1, 1-difluoroethyl, 2, 2, 2-trifluoroethyl, trifluoromethoxy and ethyl,

R²is a methyl, ethyl or isopropyl group,

wherein the ethyl group may be substituted with one substituent selected from the group consisting of a hydroxyl group, a methoxy group and an ethoxy group,

R³is 1-oxothiomorpholin-4-yl, 1, 1-dioxothiomorpholin-4-yl, 3-hydroxyazetidin-1-yl, 3-hydroxypyrrolidin-1-yl or 4-hydroxypiperidin-1-yl,

and their salts, their solvates and solvates of their salts.

Preference is also given to compounds of the formula (I), in which

A is an oxygen atom, and A is an oxygen atom,

R¹is a phenyl group, and the phenyl group,

wherein the phenyl group is substituted at the para position relative to the position of attachment to the piperidine ring with a substituent selected from the group consisting of trifluoromethyl, 1, 1-difluoroethyl, 2, 2, 2-trifluoroethyl, trifluoromethoxy, and ethyl,

and

wherein the phenyl group may additionally bear a fluorine substituent in the meta-or ortho-position to the position of attachment to the piperidine ring,

R²is a methyl, ethyl or isopropyl group,

and their salts, their solvates and solvates of their salts.

Preference is also given to compounds of the formula (I), in which

A is an oxygen atom, and A is an oxygen atom,

R¹is a phenyl group, and the phenyl group,

wherein the phenyl group is substituted at the para position relative to the position of attachment to the piperidine ring with a substituent selected from the group consisting of trifluoromethyl, 1, 1-difluoroethyl, 2, 2, 2-trifluoroethyl and trifluoromethoxy,

R²is an ethyl group, and the compound is,

wherein the ethyl group may be substituted with one methoxy substituent,

R³is 1-oxothiomorpholin-4-yl or 1, 1-dioxothiomorpholin-4-yl,

and their salts, their solvates and solvates of their salts.

Also preferred is a compound wherein-R¹And 1, 2, 4-With oxadiazol-5-yl substituents inCompounds of formula (I) which are cis to each other.

Also preferred is where R¹The carbon atom to which it is attached has S configuration and 1, 2, 4-Compounds of formula (I) wherein the carbon atom to which the oxadiazol-5-yl group is attached likewise has the S configuration.

Also preferred are compounds of formula (I) wherein A is an oxygen atom.

Preference is also given to compounds of the formula (I), in which

A is-NR⁴-，

Wherein

R⁴Is a hydrogen, a methyl or ethyl radical,

or

wherein azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl may be substituted with a hydroxy substituent.

Also preferred is where A is-NR⁴A compound of formula (I) wherein R⁴Is hydrogen, methyl or ethyl.

Also preferred is where A is-NR⁴A compound of formula (I) wherein R⁴Is hydrogen.

Also preferred is where R¹A compound of formula (I) which is phenyl, wherein phenyl may be substituted by 1 to 3 substituents independently selected from the group consisting of monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, methylsulfonyl, C₁-C₄-alkyl radical, C₁-C₄-alkoxy and C₁-C₄-substituent substitution of alkoxycarbonyl.

Also preferred is where R¹A compound of formula (I) which is phenyl wherein phenyl is substituted with 1 to 3 substituents independently selected from trifluoromethyl, trifluoromethoxy, C₁-C₄-alkyl radical, C₁-C₄-alkoxy and C₁-C₄-substituent substitution of alkoxycarbonyl.

Also preferred is where R¹A compound of formula (I) which is phenyl, wherein phenyl is substituted with 1 to 2 substituents independently selected from trifluoromethyl, trifluoromethoxy, methyl, ethyl and methoxy.

Preference is also given to the formula R¹A compound of formula (I) which is phenyl, wherein the phenyl group is substituted at the para position relative to the position of attachment to the piperidine ring by a substituent selected from the group consisting of trifluoromethyl, 2, 2, 2-trifluoroethyl, trifluoromethoxy and ethyl.

Also preferred are those of the formula wherein R¹A compound of formula (I) which is phenyl, wherein the phenyl group is substituted at the para position relative to the position of attachment to the piperidine ring by a substituent selected from the group consisting of trifluoromethyl, trifluoromethoxy and ethyl.

Also preferred is where R¹A compound of formula (I) which is phenyl, wherein the phenyl is substituted with one trifluoromethyl substituent in the para position to the position of attachment to the piperidine ring.

Also preferred is where R¹Compounds of formula (I) are phenyl, wherein the phenyl is substituted with one 2, 2, 2-trifluoroethyl substituent in the para position relative to the position of attachment to the piperidine ring.

Preference is also given to compounds of the formula (I), in which

R²Is methyl, ethyl, propyl, isopropyl, 2-methylpropan-1-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or oxetan-3-yl,

and

wherein the methyl and ethyl groups may be substituted with one substituent selected from the group consisting of hydroxy, trifluoromethyl, methoxy and ethoxy.

Preference is also given to compounds of the formula (I), in which

R²Is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetan-3-yl,

and

wherein methyl may be substituted with one trifluoromethyl substituent,

and

wherein the ethyl group may be substituted with one substituent selected from the group consisting of a hydroxyl group and a methoxy group.

Also preferred is where R²A compound of formula (I) which is methyl, ethyl or isopropyl, wherein ethyl may be substituted by one substituent selected from the group consisting of hydroxy, methoxy and ethoxy.

Also preferred is where R²A compound of formula (I) which is ethyl, wherein ethyl may be substituted by one methoxy substituent.

Preference is also given to compounds of the formula (I) in which R³Is morpholin-4-yl, thiomorpholin-4-yl, 1, 1-dioxothiomorpholin-4-yl, 3-hydroxyazetidin-1-yl, 3-hydroxypyrrolidin-1-yl, 4-cyanopiperidin-1-yl or 4-hydroxypiperidin-1-yl.

Preference is also given to compounds of the formula (I) in which R³Is morpholin-4-yl, thiomorpholin-4-yl, 1-oxothiomorpholin-4-yl, 3-hydroxyazetidin-1-yl, 3-hydroxypyrrolidin-1-yl, 4-cyanopiperidin-1-yl or 4-hydroxypiperidin-1-yl.

Preference is also given to compounds of the formula (I) in which R³Is morpholin-4-yl, thiomorpholin-4-yl or 4-hydroxypiperidin-1-yl.

Preference is also given to compounds of the formula (I) in which R³Is oxothiomorpholin-4-yl or 1, 1-dioxoA thiomorpholin-4-yl group.

Preference is also given to compounds of the formula (I) in which R³Is 1, 1-dioxothiomorpholin-4-yl.

The radical definitions specified in the individual radical combinations or preferred radical combinations are not dependent on the individual specified radical combinations and are also replaced by radical definitions of other combinations as desired.

Very particular preference is given to combinations of two or more of the preferred ranges mentioned above.

The invention further provides a process for the preparation of a compound of formula (I), or a salt thereof, a solvate thereof or a solvate of a salt thereof, wherein

[A] A compound of the formula

Wherein

R¹And R³Each as defined above

With a compound of the formula

Wherein

A and R²Each as defined above

Or

[B] A compound of the formula

Wherein

R¹And R³Each as defined above

With a compound of the formula

Wherein

A and R²Each as defined above

Or

[C] A compound of the formula

Wherein

A，R¹And R²Each as defined above

With 0.8 to 1.1 equivalents of m-chloroperbenzoic acid to give a compound of the formula

Wherein

A，R¹And R²Each as defined above

Or

[D] Reacting the compound of formula (Ia) with 2.0 to 3.0 equivalents of m-chloroperbenzoic acid to produce a compound of the formula

Wherein

A，R¹And R²Each as defined above

Or

[E] A compound of the formula

Wherein

A，R¹And R²Each as defined above

With a compound of the formula

Wherein

R³As defined above and

X¹is halogen, preferably bromine or chlorine, or hydroxy or 4-nitrophenoxy,

or

[F] The compound of formula (XV) is reacted in a first stage with 4-nitrophenyl chloroformate and in a second stage with a compound of formula

R³-H(XVI)，

Wherein

R³As defined above.

The compounds of formulae (Ia), (Ib) and (Ic) are a subset of the compounds of formula (I) (Teilmenge).

In the case where A is an oxygen atom, the reaction according to process [ A ] is generally carried out in an inert solvent, optionally in the presence of molecular sieves, optionally in the presence of a base, preferably at a temperature ranging from room temperature to 100 ℃ under standard pressure (Normaldrum).

Inert solvents are, for example, ethers, e.g. diethyl ether, bisAlkanes or tetrahydrofuran, preferably diAn alkane.

The base is, for example, phosphazene P₄Bases, or alkoxides, e.g. sodium methoxide or ethoxide, or other bases, e.g. sodium hydride, preferably phosphazene P ₄A base.

When an alkoxide is used as base, the reaction is carried out in the corresponding alcohol as solvent.

Where A is-NR⁴In case of the following method [ A ]]The reaction is generally carried out in an inert solvent, optionally with an excess of the compound of formula (III), to give the compound of formula (II), optionally in microwaves, preferably at a temperature ranging from 50 ℃ to 200 ℃, at standard pressure to 5 bar.

Inert solvents are, for example, alcohols, such as ethanol or methanol, or other solvents, such as dimethyl sulfoxide, dimethylformamide or N-methylpyrrolidone, preferably ethanol.

The compounds of the formula (III) are known or can be synthesized from suitable starting compounds by known methods.

The reaction according to process [ B ] is generally carried out in an inert solvent, in the presence of a dehydrating agent, optionally in the presence of a base, preferably at a temperature ranging from room temperature to the reflux temperature of the solvent, under standard pressure.

Inert solvents are, for example, halogenated hydrocarbons, such as methylene chloride, chloroform or 1, 2-dichloroethane, ethers, such as bisAlkane, tetrahydrofuranPyran or 1, 2-dimethoxyethane, or other solvents, such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile. It is also possible to use mixtures of solvents. Preferably dimethylformamide or di A mixture of an alkane and dimethylformamide.

Suitable dehydrating agents in this context are, for example, carbodiimides, such as N, N '-diethyl-, N, N' -dipropyl-, N, N '-diisopropyl-, N, N' -dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N '-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N' -propyloxymethyl-polystyrene (PS-carbodiimide), or carbonyl compounds, such as carbonyldiimidazole, or 1, 2-Azole(Oxazolium) compounds, e.g. 2-ethyl-5-phenyl-1, 2-Azole3-sulfate or 2-tert-butyl-5-methyliso-isopropylAzolePerchlorates, or amido compounds, such as 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or bis (2-oxo-3-Oxazolidinyl) phosphoryl chloride or benzotriazolyloxy-tris (dimethyl)Amino group)Hexafluorophosphates, or O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethylureaHexafluorophosphate (HBTU), 2- (2-oxo-1- (2H) -pyridinyl) -1, 1, 3, 3-tetramethylureaTetrafluoroborate (TPTU) or O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylureaHexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-1-yloxytris (dimethylamino) Hexafluorophosphate (BOP), or benzotriazol-1-yloxytris (pyrrolidino)Hexafluorophosphate (PYBOP), or N-hydroxysuccinimide, or mixtures of these with bases.

The base is, for example, an alkali metal carbonate, such as sodium or potassium carbonate, or sodium or potassium bicarbonate, or an organic base, such as a trialkylamine, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preferably diisopropylethylamine.

Preferably, the condensation is carried out with HATU or simply carbonyldiimidazole in the presence of diisopropylethylamine.

The compounds of the formula (V) are known or can be synthesized from suitable starting compounds by known methods.

The reaction is generally carried out in an inert solvent, preferably in the range from room temperature to the reflux temperature of the solvent, under standard pressure according to method [ C ].

Meta-chloroperoxybenzoic acid is preferably used in an amount of 0.9 to 1.0 equivalent.

Inert solvents are, for example, halogenated hydrocarbons, such as methylene chloride, chloroform or 1, 2-dichloroethane. Dichloromethane is preferred.

The reaction according to process [ D ] is generally carried out in an inert solvent, preferably in the range from room temperature to the reflux temperature of the solvent, under standard pressure.

Meta-chloroperoxybenzoic acid is preferably used in an amount of 2.3 to 2.6 equivalents, more preferably in an amount of 2.5 equivalents.

When X is present¹When it is halogen, according to method [ E]The reaction is generally carried out in an inert solvent, optionally in the presence of a base, preferably at a temperature in the range from-30 ℃ to 50 ℃, under standard pressure.

Inert solvents are, for example, tetrahydrofuran, dichloromethane, pyridine, bisAn alkane or dimethylformamide, preferably dichloromethane.

The base is, for example, triethylamine, diisopropylethylamine or N-methylmorpholine, preferably triethylamine or diisopropylethylamine.

When X is present¹When it is hydroxy, according to method [ E]The reaction is generally carried out in an inert solvent, in the presence of a dehydrating agent, optionally in the presence of a base, preferably at a temperature ranging from-30 ℃ to 50 ℃, under standard pressure.

Inert solvents are, for example, halogenated hydrocarbons, such as methylene chloride or chloroform, hydrocarbons, such as benzene, nitromethane, bisAlkane, dimethylformamide or acetonitrile. It is likewise possible to use mixtures of solvents. Particular preference is given to dichloromethane or dimethylformamide.

Suitable dehydrating agents in this context are, for example, carbodiimides, such as N, N '-diethyl-, N, N' -dipropyl-, N, N '-diisopropyl-, N, N' -dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N '-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N' -propyloxymethyl-polystyrene (PS-carbodiimide), or carbonyl compounds, such as carbonyldiimidazole, or 1, 2-AzoleCompounds, for example 2-ethyl-5-phenyl-1, 2-Azole3-sulfate or 2-tert-butyl-5-methyliso-isopropylAzolePerchlorates, or amido compounds, such as 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or bis (2-oxo-3-Oxazolidinyl) phosphoryl chloride or benzotriazolyloxy-tris (dimethylamino)Hexafluorophosphate, orO- (benzotriazol-1-yl) -N, N, N ', N' -tetramethylureaHexafluorophosphate (HBTU), 2- (2-oxo-1- (2H) -pyridinyl) -1, 1, 3, 3-tetramethylureaTetrafluoroborate (TPTU) or O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylureaHexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-1-yloxytris (dimethylamino) Hexafluorophosphate (BOP), or N-hydroxysuccinimide, or mixtures of these with bases.

The base is, for example, an alkali metal carbonate, such as sodium or potassium carbonate, or sodium or potassium bicarbonate, or an organic base, such as a trialkylamine, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

Preferably, the condensation is carried out with HATU or with EDC in the presence of HOBt.

When X is present¹When it is 4-nitrophenoxy, according to process [ E]The reaction is generally carried out in an inert solvent, optionally in the presence of a base, optionally in microwaves, preferably at a temperature in the range from 50 ℃ to 200 ℃ and at a pressure of from standard to 5 bar.

Inert solvents are, for example, N-methylpyrrolidone, bisAlkanes or dimethylformamide, preferably N-methylpyrrolidone.

The compounds of the formula (IX) are known or can be synthesized by known methods from suitable starting compounds.

The first stage reaction according to process [ F ] is generally carried out in an inert solvent in the presence of a base, preferably at a temperature in the range from 0 ℃ to 50 ℃ under standard pressure.

Inert solvents are, for example, halogenated hydrocarbons, such as methylene chloride, chloroform, tetrachloromethane or 1, 2-dichloroethane, preferably methylene chloride.

The base is, for example, an organic base, such as a trialkylamine, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preferably triethylamine.

The reaction according to process [ F ] in the second stage is generally carried out in an inert solvent in the presence of a base, optionally in microwaves, preferably at a temperature in the range from 50 ℃ to 200 ℃ and at a pressure of from standard to 5 bar.

The inert solvent is, for example, dimethyl sulfoxide, dimethylformamide or N-methylpyrrolidone, preferably dimethylformamide.

The base is, for example, an alkali metal carbonate, such as sodium carbonate or potassium carbonate, preferably potassium carbonate.

The compounds of the formula (XVI) are known or can be synthesized from suitable starting compounds by known methods.

The compounds of the formula (II) are known or can be prepared by

Wherein

R¹And R³Each of which is as defined above, each of which is,

reacting with hydrogen chloride solution and sodium nitrite.

The reaction is preferably carried out at a temperature ranging from 0 ℃ to the reflux temperature of the solvent under standard pressure.

The compounds of the formula (VI) are known or can be prepared by reacting the compounds of the formula (IV) with hydroxyguanidine hemisulfate hemihydrate.

The reaction is carried out as described in method [ B ], optionally in the presence of molecular sieves.

Preferably, the condensation is carried out with PYBOP in the presence of diisopropylethylamine and molecular sieves.

The compounds of the formula (IV) are known or can be prepared by

Wherein

R¹And R³Each as defined above and

R⁵is a methyl group or an ethyl group,

reacting with alkali.

The reaction is generally carried out in an inert solvent in the presence of a base, preferably at a temperature ranging from room temperature to the reflux temperature of the solvent, under standard pressure.

Inert solvents are, for example, halogenated hydrocarbons, such as methylene chloride, chloroform, tetrachloromethane or 1, 2-dichloroethane, alcohols, such as methanol or ethanol, ethers, such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, bisAlkanes or tetrahydrofuran, or other solvents, e.g. dimethylformamide, dimethylacetamide, acetonitrile or pyridine, or solventsA mixture, or a mixture of a solvent and water, preferably methanol or a mixture of methanol and an equivalent amount of water, or tetrahydrofuran and water.

The base is, for example, an alkali metal hydroxide, such as sodium hydroxide, lithium hydroxide or potassium hydroxide, or an alkali metal carbonate, such as cesium carbonate, sodium carbonate or potassium carbonate, or an alkoxide, such as potassium tert-butoxide or sodium tert-butoxide, preferably lithium hydroxide or potassium tert-butoxide.

The compounds of the formula (VII) are known or can be prepared by

Wherein

R¹And R⁵Each as defined above

With a compound of the formula

Wherein

R³As defined above and

X¹is halogen, preferably bromine or chlorine, or hydroxy or 4-nitrophenoxy.

When X is present¹When halogen is present, the reaction is generally carried out in an inert solvent, optionally in the presence of a base, preferably at a temperature in the range from-30 ℃ to 50 ℃, under standard pressure.

When X is present¹In the case of hydroxyl groups, the reaction is generally carried out in an inert solvent, in the presence of a dehydrating agent, optionally in the presence of a base, preferably at a temperature ranging from-30 ℃ to 50 ℃, under standard pressure.

Suitable dehydrating agents in this context are, for example, carbodiimides, such as N, N '-diethyl-, N, N' -dipropyl-, N, N '-diisopropyl-, N, N' -dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N '-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N' -propyloxymethyl-polystyrene (PS-carbodiimide), or carbonyl compounds, such as carbonyldiimidazole, or 1, 2-AzoleCompounds, for example 2-ethyl-5-phenyl-1, 2-Azole3-sulfate or 2-tert-butyl-5-methyliso-isopropylAzolePerchlorates, or amido compounds, such as 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or bis (2-oxo-3-Oxazolidinyl) phosphoryl chloride or benzotriazolyloxy-tris (dimethylamino)Hexafluorophosphates, or O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HBTU), 2- (2-oxo-1- (2H) -pyridinyl) -1, 1, 3, 3-tetramethylureaTetrafluoroborate (TPTU) or O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylureaHexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-1-yloxytris (dimethylamino)Hexafluorophosphate (BOP), or N-hydroxysuccinimide, or mixtures of these with bases.

When X is present¹In the case of 4-nitrophenoxy, the reaction is generally carried out in an inert solvent, optionally in the presence of a base, optionally in the presence of microwaves, preferably at a temperature in the range from 50 ℃ to 200 ℃ and at a pressure of from standard to 5 bar.

In other processes, the compound of formula (VII) may be prepared by reacting a compound of formula (VIII) with 4-nitrophenyl chloroformate in a first stage and with a compound of formula

R³-H(X)，

Wherein

R³As defined above.

The first stage reaction is generally carried out in an inert solvent in the presence of a base, preferably at a temperature in the range of 0 ℃ to 50 ℃, under standard pressure.

The reaction of the second stage is generally carried out in an inert solvent in the presence of a base, optionally in microwaves, preferably at a temperature in the range from 50 ℃ to 200 ℃ and at a pressure of standard to 5 bar.

The compounds of the formula (X) are known or can be synthesized from suitable starting compounds by known methods.

The compounds of the formula (VIII) are known or can be prepared by hydrogenation of the compounds of the formula

Wherein

R¹And R⁵Each as defined above.

The hydrogenation is generally carried out in an inert solvent, optionally with the addition of an acid, for example a mineral acid and a carboxylic acid, preferably acetic acid, preferably with a reducing agent at room temperature to the reflux temperature range of the solvent and at a pressure in the range from standard pressure to 100 bar, preferably at standard pressure or at 50 to 80 bar.

Preferred reducing agents are hydrogen with palladium on activated carbon, with rhodium on activated carbon, with ruthenium on activated carbon or mixed catalysts thereof, or hydrogen with palladium on alumina or with rhodium on alumina, or hydrogen with palladium and platinum (IV) oxide on activated carbon, preferably hydrogen with palladium on activated carbon or with rhodium on activated carbon or hydrogen with palladium and platinum (IV) oxide on activated carbon. It is also possible to hydrogenate with hydrogen and platinum (IV) oxide alone under pressure.

Inert solvents are, for example, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or concentrated acetic acid or methanol with addition of concentrated hydrochloric acid, preferably methanol or ethanol or concentrated acetic acid or methanol with addition of concentrated hydrochloric acid.

The compounds of the formula (XI) are known or can be prepared by

Wherein

R⁵As defined above

With a compound of the formula

Wherein

R¹As defined above.

The reaction is generally carried out in an inert solvent, in the presence of a catalyst, optionally in the presence of further reagents, preferably in the range from room temperature to the reflux temperature of the solvent, under standard pressure.

Inert solvents are, for example, ethers, e.g. bisAlkanes, tetrahydrofuran or 1, 2-dimethoxyethane, hydrocarbons, such as benzene, xylene or toluene, or other solvents, such as nitrobenzene, dimethylformamide, dimethylacetamide, dimethylsulfoxide or N-methylpyrrolidone; optionally, a little water is added to these solvents. Preference is given to mixtures of toluene with water or 1, 2-dimethoxyethane, dimethylformamide and water.

The catalyst is, for example, a palladium catalyst which is customary for Suzuki reaction conditions, preferably a catalyst such as dichlorobis (triphenylphosphine) palladium, tetratriphenylphosphine palladium (0), palladium (II) acetate or bis (diphenylphosphinoferrocene) palladium (II) chloride.

Further reagents are, for example, potassium acetate, cesium carbonate, potassium or sodium carbonate, barium hydroxide, potassium tert-butoxide, cesium fluoride, potassium fluoride or potassium phosphate, or mixtures thereof, preferably potassium fluoride or sodium carbonate, or mixtures of potassium fluoride and potassium carbonate.

The compounds of the formulae (XII), (XIII) and (XIV) are known or can be synthesized by known methods from suitable starting compounds.

The compounds of formula (XV) are known or may be prepared by

Wherein

R¹As defined above

With a compound of formula (V) in a first stage and with an acid in a second stage.

The first stage reaction was carried out as described in Process [ B ].

The second stage reaction is generally carried out in an inert solvent, preferably at a temperature in the range of room temperature to 60 ℃, under standard pressure.

Inert solvents are, for example, halogenated hydrocarbons, such as methylene chloride, chloroform, tetrachloromethane or 1, 2-dichloroethane, or ethers, such as tetrahydrofuran or dioxaneAn alkane, preferably dichloromethane.

The base is, for example, trifluoroacetic acid or in bisHydrogen chloride in the alkane, preferably trifluoroacetic acid.

The compounds of the formula (XVII) are known or can be prepared by reacting a compound of the formula (XVIII) with di-tert-butyl dicarboxylate in a first stage and with a base in a second stage.

The first stage reaction is generally carried out in an inert solvent in the presence of a base, preferably at a temperature in the range of from room temperature to 50 ℃, under standard pressure.

The second stage reaction is generally carried out in an inert solvent in the presence of a base, preferably at a temperature ranging from room temperature to the reflux temperature of the solvent, under standard pressure.

Inert solvents are, for example, halogenated hydrocarbons, such as methylene chloride, chloroform, tetrachloromethane or 1, 2-dichloroethane, alcohols, such as methanol or ethanol, ethers, such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, bisAn alkane or tetrahydrofuran, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine, or mixtures of solvents with water, preferably methanol or methanol with an equivalent amount of water, or mixtures of tetrahydrofuran and water.

The preparation of the compounds of formula (I) can be illustrated by the following synthesis scheme.

Scheme (b):

the compounds of the present invention exhibit an unpredictable, useful spectrum of pharmacological and pharmacokinetic effects. They are selective antagonists of the PAR-1 receptor, in particular as inhibitors of platelet aggregation, as inhibitors of endothelial cell activation, as inhibitors of smooth muscle cell proliferation and as inhibitors of tumor growth. For some diseases mentioned, for example cardiovascular diseases with a high risk of thromboembolism, permanent protection of the PAR-1 antagonism is of crucial importance at the same time as simple handling of the medication. The PAR-1 antagonists of the invention exhibit a sustained effect, i.e., an effect lasting at least 16 hours, upon oral administration alone.

They are therefore suitable as medicaments for the treatment and/or prophylaxis of diseases in humans and animals.

The invention further provides the use of a compound of the invention for the treatment and/or prophylaxis of diseases, preferably thromboembolic diseases and/or thromboembolic complications.

"thromboembolic disorders" in the sense of the present invention include in particular diseases such as ST-elevated myocardial infarction (STEMI) and non-ST-elevated myocardial infarction (non-STEMI), stable angina pectoris, unstable angina pectoris, coronary interventions such as angioplasty, reocclusion and restenosis after stent implantation or bypass of the coronary aorta, peripheral arterial occlusive disorders, pulmonary embolism, deep vein thrombosis and renal vein thrombosis, transient ischemic attacks and thrombosis and thromboembolic stroke.

The substance is therefore also suitable for the prevention and treatment of cardiogenic thromboembolisms, such as cerebral ischaemia, stroke and systemic thromboembolism and ischaemia, in patients suffering from acute, intermittent or persistent cardiac arrhythmias, such as atrial fibrillation, and those undergoing cardioversion, and in patients suffering from valvular heart disease or from endovascular objects, such as artificial heart valves, catheters, intra-aortic balloon counterpulsation and pacemaker probes.

Thromboembolic complications are also associated with hemolytic anemia of microangiopathy, extracorporeal circulation, such as hemodialysis, hemofiltration, ventricular assist medical devices and artificial hearts, and artificial heart valves.

Furthermore, the compounds of the invention are also useful for influencing wound healing, for the prophylaxis and/or treatment of vascular diseases and inflammatory diseases in atherosclerotic patients, such as rheumatic diseases of the locomotor system, coronary heart diseases, heart failure, hypertension, inflammatory diseases, such as asthma, COPD, inflammatory lung diseases, glomerulonephritis and inflammatory bowel diseases, and additionally for the prophylaxis and/or treatment of alzheimer's disease, autoimmune diseases, crohn's disease and ulcerative colitis.

In addition, the compounds of the present invention are useful for inhibiting tumor growth and metastasis, microvascular disease, age-related macular degeneration, diabetic retinopathy, diabetic nephropathy and other microvascular disease, and for preventing and treating thromboembolic complications, such as venous thromboembolism, in oncology patients, particularly those undergoing major surgery or chemotherapy or radiation therapy.

The compounds of the invention are additionally suitable for the treatment of cancer. The cancer includes: malignancies (including breast cancer, hepatocellular carcinoma, lung cancer, colorectal cancer, carcinomas of the colon and melanoma), lymphomas (e.g., non-hodgkin's lymphoma and mycosis fungoides), leukemias, sarcomas, mesotheliomas, brain cancers (e.g., glioma), blastomas (e.g., testicular and ovarian cancers), choriocarcinomas, renal cancers, pancreatic cancers, thyroid cancers, head and neck cancers, endometrial cancers, cervical cancers, bladder cancers, gastric cancers and multiple bone marrow cancers.

In addition, PAR-1 expressed on endothelial cells modulates signals leading to vascular growth ("angiogenesis"), a method that enables tumor growth beyond about 1mm³Is important. Induction of angiogenesis among othersDiseases, including rheumatic diseases (e.g., rheumatoid arthritis), pulmonary diseases (e.g., pulmonary fibrosis, pulmonary hypertension, particularly pulmonary hypertension, diseases characterized by pulmonary occlusion), arteriosclerosis, platelet rupture, diabetic retinopathy, and wet macular degeneration.

In addition, the compounds of the invention are suitable for the treatment of sepsis. Sepsis (or septicemia) is a common disease with high mortality. The initial symptoms of sepsis are generally nonspecific (e.g., fever, decreased general health), but later, systemic activation of the coagulation system ("disseminated intravascular coagulation" or "consumptive coagulopathy"; hereinafter, "DIC") may occur, accompanied by the formation of microthrombus and secondary bleeding complications in various organs. In addition, there may be endothelial damage with increased permeability of the catheter and fluid and protein entry into the extravascular space. When the disease is worsening, there may be organ dysfunction or organ failure (e.g. renal failure, liver failure, respiratory failure, defects of the central nervous system and heart/circulation failure) and even multiple organ failure. In principle, this may affect any organ; the most commonly encountered organ dysfunction and organ failure are those of the lung, kidney, cardiovascular system, coagulation system, central nervous system, endocrine glands and liver. Sepsis may be associated with "acute respiratory distress syndrome" (hereinafter ARDS). ARDS may also occur independently of sepsis. "septic shock" occurs with hypotension that must treat and promote further organ damage and is associated with the predictive worsening of the condition.

The pathogens may be bacteria (gram negative and gram positive), fungi, viruses and/or eukaryotes. The site of entry or primary infection may be, for example, pneumonia, infection of the urinary tract or peritonitis. Infection may, but need not, be associated with bacteremia.

Sepsis is defined as the presence of infection and "systemic inflammatory response syndrome" (hereinafter "SIRS"). SIRS occurs during infection, but also in other situations, such as injury, burn, shock, surgery, ischemia, pancreatitis, resuscitation or during tumors. The definition of ACCP/SCCM Consensus Committee of 1992(Crit. Care Med.1992, 20, 864-874) describes the symptoms and measurement parameters (including changes in body temperature, increased heart rate, dyspnea and changes in blood picture) that are required to diagnose "SIRS". The latter (2001) SCCM/ESICM/ACCP/ATS/SIS International separation Definitions conference basically adheres to this standard, but details are fine-tuned (Levy et al, crit. CareMed.2003, 31, 1250-.

DIC and SIRS may occur during sepsis, and as a result of surgery, tumor disease, burns or other injury. In the case of DIC, there is extensive activation of the coagulation system at the surface of damaged endothelial cells, foreign bodies or damaged extravascular tissue. Thus, there is a concomitant hypoxia and subsequent organ dysfunction of the blood clotting in the small ducts of various organs. Side effects are the consumption of coagulation factors (e.g. coagulation factor X, prothrombin, fibrinogen) and platelets, which reduce the coagulation of blood and may lead to a large amount of bleeding.

In addition, the compounds of the invention may also be used to prevent coagulation in vitro, for example for the preservation of blood and plasma products, for cleaning/pre-treatment of catheters and other medical devices and instruments, including extracorporeal circulation, for coating synthetic surfaces of medical devices and instruments used in vivo or in vitro or for biological samples containing platelets.

The invention further provides the use of the compounds of the invention for coating medical instruments and implants, such as catheters, prostheses, stents or artificial heart valves. The compounds of the present invention may be strongly adhered to a surface or, for topical application, released over time from a carrier coating into the immediate environment.

The invention further provides the use of the compounds of the invention for the treatment and/or prophylaxis of diseases, in particular of the above-mentioned diseases.

The invention further provides the use of a compound of the invention for the production of a medicament for the treatment and/or prophylaxis of diseases, in particular of the diseases mentioned above.

The invention further provides methods of treating and/or preventing diseases, in particular the above mentioned diseases, using a therapeutically effective amount of one of the compounds of the invention.

The invention further provides medicaments comprising a compound of the invention and one or more further active ingredients, in particular for the treatment and/or prophylaxis of the abovementioned diseases. Active ingredients suitable for incorporation include, for example and preferably:

calcium channel blockers, e.g. amlodipine besylate (e.g. amlodipine besylate)) Felodipine, diltiazem, verapamil, nifedipine, nitrapyrin methyl ester, nisoldipine and bepridil;

lomerizine;

statins, such as atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin;

cholesterol absorption inhibitors such as ezetimibe and AZD 4121;

cholesteryl ester transfer protein ("CETP") inhibitors, such as tolcept;

low molecular weight heparins, such as dalteparin sodium, adeps sodium, sertoxepin, enoxaparin, heparine sodium, tinzaparin, heparin and nadroparin calcium;

further anticoagulants, such as warfarin, coumarins, fondaparins;

antiarrhythmic agents, such as dofetilide, ibutilide, metoprolol tartrate, propranolol, atenolol, amomoline, dosulepin, pramlinum, procainamide, quinidine, cytisine, ampelodine, lidocaine, mexiletine, metavacaine, emcamide, flecainide, ramatroban, moraxezin, propylamine propiophenone, acebutolol, pindolol, amiodarone, tolfenbromben, butanamide, sotalol, adenosine, atropine and digoxin;

Alpha-adrenergic agonists, such as doxazosin mesylate, terazosin and prazosin;

beta-adrenergic blockers, such as carvedilol, propranolol, timolol, nadolol, atenolol, metoprolol, bisoprolol, nebivolol, betaxolol, acebutolol, and bisoprolol;

aldosterone antagonists such as eplerenone and spironolactone;

angiotensin-converting enzyme inhibitors ("ACE inhibitors"), such as moexipril, quinapril hydrochloride, ramipril, lisinopril, benazepril hydrochloride, enalapril, captopril, spirapril, perindopril, fosinopril, and trandolapril;

angiotensin II receptor blockers ("ARBs"), such as olmesartan medoxomil, candesartan, valsartan, telmisartan, irbesartan, losartan, and eprosartan;

endothelin antagonists such as tezosentan, bosentan and stastasentan-sodium;

inhibitors of neutral endopeptidases, such as candesartan and ecadotril;

phosphodiesterase inhibitors, such as milrinone, theophylline, vinpocetine, EHNA (erythro-9- (2-hydroxy-3-nonyl) adenine), sildenafil, vardenafil and tadalafil;

Fibrinolytic agents such as reteplase, alteplase, and tenecteplase;

GP IIb/IIIa antagonists, such as eptifibatide, abciximab and tirofiban;

direct coagulation inhibitors, such as AZD0837, argatroban, bivalirudin and dabigatran;

indirect blood coagulation inhibitors, such as odipalexine;

direct and indirect factor Xa inhibitors, such as fondaparinux-sodium, apixaban, rizoxaban, rivaroxaban (BAY 59-7939), KFA-1982, DX-9065a, AVE3247, omixaban (XRP0673), AVE6324, SAR377142, idoxuridine, SSR126517, DB-772d, DT-831j, YM-150, 813893, LY517717, and DU-1766;

direct and indirect factor Xa/IIa inhibitors, such as enoxaparin-sodium, AVE5026, SSR128428, SSR128429 and BIBT-986 (tanoji);

a lipoprotein-associated phospholipase a2 ("LpPLA 2") modulator;

diuretics, such as chlorthalidone, ethacrynic acid, furosemide, amiloride, chlorothiazide, hydrochlorothiazide, meclothiazide and benzthiazide;

nitrates, such as isosorbide 5-mononitrate;

thromboxane antagonists such as seratrodast, picotamide and ramatroban;

platelet aggregation inhibitors such as clopidogrel, ticlopidine, cilostazol, aspirin, abciximab, limaprost, efibat and CT-50547;

Cyclooxygenase inhibitors, such as meloxicam, rofecoxib, and celecoxib;

b-type natriuretic peptides, such as nesiritide, ularitide;

NV1FGF modulators, e.g., XRP 0038;

HT1B/5-HT2A antagonists, such as SL 65.0472;

guanylate cyclase activators, such as ataciguat (HMR1766), HMR1069, riociguat and cinaciguat;

e-NOS transcription enhancers, such as AVE9488 and AVE 3085;

antiatherosclerotic substances, such as AGI-1067;

CPU inhibitors such as AZD 9684;

renin inhibitors, such as aliskiren (alikirin) and VNP 489;

inhibitors of adenosine diphosphate-induced platelet aggregation, such as clopidogrel, ticlopidine, prasugrel, AZD6140, ticagrel and enoogrel;

NHE-1 inhibitors, such as AVE4454 and AVE 4890.

Antibiotic therapy: various antibiotic or antifungal drug combinations are suitable when there is planned treatment (before microbiological evaluation is made) or when a specific treatment is made; liquid therapy, such as crystalline or colloidal liquids; vasopressors, such as norepinephrine, dopamine, or vasopressin; myodynamia treatments, such as dobutamine; corticosteroids, such as hydrocortisone, or fludrocortisone; recombinant human activated protein C, Xigris; blood products, such as erythrocyte concentrates, platelet concentrates, erythropoietin or fresh frozen plasma; assisted ventilation, e.g. permissive hypercapnia, low tidal volume, in sepsis-induced Acute Lung Injury (ALI) or acute dyspnea syndrome (ARDS); sedation: such as diazepam, chlordiazepam, midazolam or propofol. Opioid compounds: for example fentanyl, hydromorphone, morphine, pethidine or remifentanil. NSAIDs: such as ketorolac, ibuprofen or antipyretic. Neuromuscular blockade: such as pancuronium bromide; glucose control, e.g., insulin, glucose; renal replacement therapy, such as continuous veno-venous hemofiltration or intermittent hemodialysis. Low-dose dopamine for kidney protection; anticoagulants, for example for thrombosis prevention or for kidney replacement therapy, such as heparin in general, low molecular weight heparin, heparinoids, hirudin, bivalirudin or argatroban; bicarbonate therapy; stress ulcer prevention, such as H2 receptor inhibitors, antacids.

Drugs for proliferative disorders: uracil, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, dibromopropyl piperazine, triethyleneiminotriazine, triethylenethiophosphoramide, malilan, nitrosourea mustard, lomustine, streptozotocin, dacarbazine, methotrexate, 5-fluorouracil, 5-fluorodeoxyuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, vinblastine, vincristine, desacetylvinblastine, disphramycin, actinomycin, daunorubicin, adriamycin, epirubicin, idarubicin, taxol, mithramycin, deoxynikkomycin, mitomycin C, levoasparaginase, interferon, etoposide, 17 alpha-ethynyl estradiol, diethylstilbestrol, testosterone, prednisone, fluorocarbon methyltestosterone, drotalandrone propionate, testolactone, megestrol, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotriarylene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprorelin, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, novabine, anastrozole, letrozole, capecitabine, raloxifene, droloxifene, hexamethylmelamine, oxaliplatin, medroxyprogesterone, medrox Iressa (gefitinib, Zdl839),(capecitabine) is used,(erlotinib), azacitidine (5-azacytidine; 5-azaC), temozolomideGemcitabine (e.g. Gemcitabine(gemcitabine hydrochloride)), or a combination of two or more of the above.

The invention further provides a method for preventing the coagulation of blood in vitro, in particular in a pool of blood or a biological sample comprising platelets, characterized in that an anti-coagulating effective amount of a compound of the invention is added.

The compounds of the invention may act systemically and/or locally. For this purpose, they can be administered in a suitable manner, for example, by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, epidermal, transdermal, conjunctival, otic route or as an implant or stent.

The compounds according to the invention may be administered in a form suitable for these routes of administration.

Suitable administration forms for oral administration are those which act according to the prior art and deliver the compounds according to the invention rapidly and/or in an improved manner and which comprise the compounds according to the invention in crystalline and/or amorphous and/or dissolved form, for example tablets (uncoated or, for example, sugar-coated tablets with enteric coatings or coatings which do not dissolve or delay dissolution and release the compounds according to the invention in a controlled manner), tablets which disintegrate rapidly in the mouth, or films/films, films/lyophilisates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be carried out avoiding absorption steps (e.g., intravenous, intra-arterial, intracardiac, intraspinal or intralumbar) or simultaneously involving absorption (e.g., subcutaneous, intradermal, transdermal or intraabdominal). Administration forms suitable for parenteral administration include preparations for injection and infusions, suspensions, emulsions, lyophilisates or sterile powders in the form of solutions.

Oral administration is preferred.

Suitable for another route of administration are, for example, pharmaceutical forms for inhalation (in particular powder inhalers, nebulizers), nasal drops, solutions, sprays; tablets, films/films or capsules for lingual, sublingual or buccal administration, suppositories, preparations for the ear and eye, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal dosage forms (e.g. patches), emulsions, pastes, foams, dusting powders, implants or stents.

The compounds according to the invention can be converted into the administration forms mentioned. This can be carried out in a manner known per se by mixing with inert, non-toxic, pharmacologically suitable excipients. These excipients include carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (e.g. sodium lauryl sulfate, polyoxyethylene sorbitan oleate), binders (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilizers (e.g. antioxidants, e.g. ascorbic acid), colorants (e.g. inorganic pigments, e.g. iron oxides) and masking flavors and/or flavor enhancers.

The invention further provides medicaments comprising at least one compound of the invention, preferably together with one or more inert, non-toxic, pharmaceutically acceptable excipients, and their use for the above-mentioned purposes.

In the case of parenteral administration, it has generally been found that a dosage of about 5 to 250mg per 24 hours is advantageous for achieving effective results. In the case of oral administration, the dose is about 5 to 100mg every 24 hours.

However, it may be necessary to deviate appropriately from the amounts indicated, in particular with respect to the body weight, the route of administration, the individual response to the active ingredient, the nature of the preparation and the time or interval over which the administration takes place.

Percentages in the following tests and examples are weight percentages unless otherwise indicated; parts are parts by weight. For the solvent ratio of the liquid/liquid solution, the dilution ratio and the concentration data are in each case based on volume. "w/v" means "weight/volume". For example, "10% w/v" means: 100ml of solution or suspension contain 10g of substance.

A)Examples

Abbreviations:

aprex. about

CDI carbonyldiimidazole

d days, doublet (in NMR)

TLC thin layer chromatography

DCI direct chemical ionization (in MS)

dd doublet (in NMR)

DMAP 4-dimethylaminopyridine

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

DPPA Diphenylphosphazidat (Diphenylphosphazidat)

DSC disuccinimidyl carbonate

eq. equivalent

ESI electrospray ionization (in MS)

h hours

HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylureaHexafluorophosphates

HPLC high pressure high performance liquid chromatography

LC-MS liquid chromatography-mass spectrometry combination

LDA lithium diisopropylamide

m multiplet (in NMR)

min for

MS Mass Spectrometry

NMR nuclear magnetic resonance spectrum

PYBOP benzotriazol-1-yloxytris (pyrrolidinyl)

Hexafluorophosphor

Acid salts

q quartet (in NMR)

RP reverse phase (in HPLC)

RT Room temperature

R_tRetention time (in HPLC)

s singlet (in NMR)

t triplet (in NMR)

THF tetrahydrofuran.

HPLC method:

method 1A: the instrument comprises the following steps: HP 1100 with DAD detection; column: kromasil 100RP-18, 60mm × 2.1mm, 3.5 μm; eluent A: 5ml perchloric acid (70%)/l water, eluent B: acetonitrile; gradient: 0min 2% B → 0.5min 2% B → 4.5min 90% B → 6.5min 90% B → 6.7min 2% B → 7.5min 2% B; flow rate: 0.75 ml/min; column temperature: 30 ℃; and (4) UV detection: 210 nm.

LC-MS method:

method 1B:MS instrument type: micromass ZQ; HPLC instrument type: HP 1100 Series; UV DAD; column: phenomenex Gemini 3 mu, 30mm multiplied by 3.0 mm; eluent A: 11 water +0.5ml 50% formic acid, eluent B: 11 acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 2.5min 30% A → 3.0min 5% A → 4.5min 5% A; flow rate: 0.0min 1ml/min, 2.5min/3.0min/4.5min 2 ml/min; oven: 50 ℃; and (4) UV detection: 210 nm.

Method 2B:the instrument comprises the following steps: MicromassQuattro Premier with Waters UPLC Acquity; column: thermo Hypersil GOLD 1.9 μ, 50mm × 1 mm; eluent A: 11 water +0.5ml 50% formic acid, eluent B: 11 acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 0.1min 90% A → 1.5min 10% A → 2.2min 10% A; oven: 50 ℃; flow rate: 0.33 ml/min; and (4) UV detection: 210 nm.

Method 3B:MS instrument type: micromass ZQ; HPLC instrument type: WatersAlliance 2795; column: phenomenex Synergi 2.5. mu.MAX-RP 100A Mercury, 20 mm. times.4 mm; eluent A: 11 water +0.5ml 50% formic acid, eluent B: 11 acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 0.1min 90% A → 3.0min 5% A → 4.0min 5% A → 4.01min 90% A; flow rate: 2 ml/min; oven: 50 ℃; and (4) UV detection: 210 nm.

Method 4B:MS instrument type: waters ZQ; HPLC instrument type: WatersAlliance 2795; column: phenomenex Onyx Monolithic C18, 100 mm. times.3 mm; eluent A: 11 water +0.5ml 50% formic acid, eluent B: 11 acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 2min 65% A → 4.5min 5% A → 6min 5% A; flow rate: 2 ml/min; oven: 40 ℃; and (4) UV detection: 210 nm.

Method 5B:the instrument comprises the following steps: MicromassQuattro Micro MS with HPLC Agilent Series 1100; column: thermo Hypersil GOLD 3 μ 20mm × 4 mm; eluent A: 11 water +0.5ml 50% formic acid, eluent B: 11 acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 100% A → 3.0min 10% A → 4.0min 10% A → 4.01min 100% A → 5.00min 100% A; oven: 50 ℃; flow rate: 2 ml/min; and (4) UV detection: 210 nm.

Method 6B:the instrument comprises the following steps: waters ACQUITY SQD UPLC System; column: WatersAcquity UPLC HSS T31.8 μ 50 × 1 mm; eluent A: 11 water +0.25ml 99% formic acid, eluent B: 11 acetonitrile +0.25ml 99% formic acid; gradient: 0.0min 90% a → 1.2min 5% a → 2.0min 5% a oven: 50 ℃; flow rate: 0.40 ml/min; and (4) UV detection: 210-400 nm.

Method 7B:the instrument comprises the following steps: MicromassQuattro LCZ with HPLC Agilent Series 1100; column: phenomenex Onyx Monolithic C18, 100 mm. times.3 mm. Eluent A: 11 water +0.5ml 50% formic acid, eluent B: 11 acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 2min 65% A → 4.5min 5% A → 6min 5% A; flow rate: 2 ml/min; oven: 40 ℃; and (4) UV detection: 208-400 nm.

Method 8B:the instrument comprises the following steps: MicromassPlatform LCZ with HPLC Agilent Series 1100; column: thermo Hypurity Aquastar 3. mu.50 mm. times.3 mm. Eluent A: 11 water +0.5ml 50% formic acid, eluent B: 11 acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 100% A → 0.2min 100% A → 2.9min 30% A → 3.1min 10% A → 5.5min 10% A; oven: 50 ℃; flow rate: 0.8 ml/min; and (4) UV detection: 210 nm.

Method 9B:the instrument comprises the following steps: waters ACQUITY SQD UPLC System; column: WatersAcquity UPLC HSS T31.8 μ 50mm × 1 mm; eluent A: 11 water +0.25ml 99% formic acid, eluent B: 11BNitrile +0.25ml 99% formic acid; gradient: 0.0min 90% A → 1.2min 5% A → 2.0min 5% A; oven: 50 ℃; flow rate: 0.40 ml/min; and (4) UV detection: 210-400 nm.

Method 10B:MS instrument type: waters ZQ; HPLC instrument type: agilent 1100 Series; UV DAD; column: thermo Hypersil GOLD 3 μ 20mm × 4 mm; eluent A: 11 water +0.5ml 50% formic acid, eluent B: 11 acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 100% a → 3.0min 10% a → 4.0min 10% a, oven: 55 ℃; flow rate: 2 ml/min; and (4) UV detection: 210 nm.

Preparation and separation of diastereomers:

method 1C:phase (1): xborder C18, 5 μm OBD 19 mm. times.150 mm, eluent: acetonitrile/0.1% ammonia solution 55: 45, a first step of; flow rate: 25ml/min, temperature: 28 ℃; and (4) UV detection: 210 nm.

Preparation and separation of enantiomers:

method 1D:phase (1): daicel Chiralpak AD-H, 5 μm 250 mm. times.20 mm; eluent: isopropanol/isohexane 75: 25; flow rate: 12 ml/min; temperature: 45 ℃; and (4) UV detection: 220 nm.

Method 2D:phase (1): daicel Chiralpak AD-H, 5 μm 250 mm. times.20 mm; eluent: isopropanol/isohexane 75: 25; flow rate: 15 ml/min; temperature: 30 ℃; and (4) UV detection: 220 nm.

Method 3D:phase (1): daicel Chiralpak AD-H, 5 μm 250 mm. times.20 mm; eluent: isopropanol/isohexane 70: 30; flow rate: 15 ml/min; temperature: 45 ℃; and (4) UV detection: 220 nm.

Method 4D:phase (1): daicel Chiralpak AD-H, 5 μm 250 mm. times.20 mm; eluent: isopropanol/isohexane 75: 25; flow rate: 15 ml/min; temperature: 45 ℃; and (4) UV detection: 220 nm.

Method 5D:phase (1): daicel Chiralpak IA, 5 μm, 250 mm. times.20mm, eluent: acetonitrile/methanol 70: 30; flow rate: 15ml/min, temperature: 40 ℃; and (4) UV detection: 220 nm.

Method 6D:phase (1): daicel Chiralpak IA, 5 μm, 250 mm. times.20 mm, eluent: acetonitrile/methanol 75: 25; flow rate: 15ml/min, temperature: 40 ℃; and (4) UV detection: 220 nm.

Method 7D:phase (1): daicel Chiralpak IA, 5 μm, 250 mm. times.20 mm, eluent: acetonitrile/methanol 70: 30; flow rate: 15ml/min, temperature: 35 ℃; and (4) UV detection: 220 nm.

Method 8D:phase (1): daicel Chiralpak IA, 5 μm, 250 mm. times.20 mm, eluent: acetonitrile/methanol 70: 30; flow rate: 15ml/min, temperature: 30 ℃; and (4) UV detection: 220 nm.

Method 9D:phase (1): daicel Chiralpak IA, 5 μm, 250 mm. times.20 mm, eluent: acetonitrile/methanol 50: 50; flow rate: 25ml/min, temperature: 25 ℃; and (4) UV detection: 220 nm.

Method 10D:phase (1): daicel Chiralpak IA, 5 μm, 250 mm. times.20 mm, eluent: acetonitrile/methanol 70: 30; flow rate: 15ml/min, temperature: 40 ℃; and (4) UV detection: 220 nm.

Method 11D:phase (1): daicel Chiralpak IA, 5 μm, 250 mm. times.20 mm, eluent: acetonitrile/methanol/tert-butyl methyl ether 25: 50; flow rate: 25ml/min, temperature: 30 ℃; and (4) UV detection: 220 nm.

Analytical separation of enantiomers:

method 1E:phase (1): daicel Chiralpak AD-H, 5 μm 250 mm. times.4.6 mm; eluent: isopropanol/isohexane: 75: 25+ 0.2% trifluoroacetic acid + 1% water; flow rate: 1 ml/min; temperature: 45 ℃; and (4) UV detection: 220 nm.

Method 2E:phase (1): daicel Chiralpak AD-H, 5 μm 250 mm. times.4.6 mm; eluent: ethanol/isohexane: 75: 25+ 0.2% trifluoroacetic acid + 1% water; flow rate: 1 ml/min;temperature: 45 ℃; and (4) UV detection: 220 nm.

Method 3E:phase (1): daicel Chiralpak AD-H, 5 μm 250 mm. times.4.6 mm; eluent: isopropanol/isohexane: 75: 25+ 0.2% trifluoroacetic acid + 1% water; flow rate: 1 ml/min; temperature: 40 ℃; and (4) UV detection: 220 nm.

Method 4E:phase (1): daicel Chiralpak AD-H, 5 μm 250 mm. times.4.6 mm; eluent: isopropanol/isohexane: 70: 30+ 0.2% trifluoroacetic acid + 1% water; flow rate: 1 ml/min; temperature: 45 ℃; and (4) UV detection: 220 nm.

Method 5E:phase (1): daicel Chiralpak AS-H, 5 μm 250mm × 4.6 mm; eluent: isopropanol/isohexane: 75: 25+ 0.2% trifluoroacetic acid + 1% water; flow rate: 0.8 ml/min; temperature: 45 ℃; and (4) UV detection: 220 nm.

Method 6E:phase (1): daicel Chiralpak AD-H, 5 μm 250 mm. times.4.6 mm; eluent: isopropanol/isohexane: 75: 25; flow rate: 1 ml/min; temperature: 45 ℃; and (4) UV detection: 220 nm.

Method 7E:phase (1): daicel Chiralpak IA, 5 μm 250 mm. times.4.6 mm, eluent: acetonitrile/methanol 70: 30; flow rate: 1ml/min, temperature: 40 ℃; and (4) UV detection: 220 nm.

Method 8E:phase (1): daicel Chiralpak IA, 5 μm 250 mm. times.4.6 mm, eluent: acetonitrile/methanol 75: 25; flow rate: 1ml/min, temperature: 25 ℃; and (4) UV detection: 220 nm.

Method 9E:phase (1): daicel Chiralpak IA, 5 μm 250 mm. times.4.6 mm, eluent: acetonitrile/methanol 70: 30; flow rate: 1ml/min, temperature: 25 ℃; and (4) UV detection: 220 nm.

Method 10E:phase (1): daicel Chiralpak IA, 5 μm 250 mm. times.4.6 mm, eluent: acetonitrile/methanol 70: 30; flow rate: 1ml/min, temperature: 30 ℃; and (4) UV detection: 220 nm.

Method 11E:phase (1): daicel Chiralpak IA, 5 μm 250 mm. times.4.6 mm, eluent: acetonitrile/methanol 80: 20; flow rate: 1ml/min, temperature: 25 ℃; and (4) UV detection: 220 nm.

Method 12E:phase (1): daicel Chiralpak IA, 5 μm 250 mm. times.4.6 mm, eluent: acetonitrile/methanol/tert-butyl methyl ether 25: 50; flow rate: 1ml/min, temperature: 30 ℃; and (4) UV detection: 220 nm.

GC-MS method:

method 1F:the instrument comprises the following steps: micromass GCT, GC 6890; column: restek RTX-35, 15 m.times.200. mu.m.times.0.33. mu.m; constant flow rate with helium: 0.88 ml/min; oven: 70 ℃; an inlet: 250 ℃; gradient: 70 ℃, 30 ℃/min → 310 ℃ (hold for 3 min).

The microwave reactor used was Emrys ^TMAn optizer type "single mode" instrument.

Starting compounds

General procedure 1A: suzuki coupling

A mixture of the appropriate bromopyridine in toluene (1.8ml/mmol) was mixed with tetrakis (triphenylphosphine) palladium (0.02 eq), a solution of the appropriate arylboronic acid (1.2 eq) in ethanol (0.5ml/mmol) and a solution of potassium fluoride (2.0 eq) in water (0.2ml/mmol) at RT under argon. The reaction mixture was stirred at reflux for several hours until the conversion was substantially complete. After addition of ethyl acetate and phase separation, the organic phase was washed once with water and once with saturated aqueous sodium chloride solution, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (silica gel 60, eluent: dichloromethane/methanol mixture).

General procedure 2A: hydrogenation of pyridine

A solution of pyridine in ethanol (9ml/mmol) was mixed with palladium on activated carbon (wetted with approximately 50% water, 0.3g/mmol) under argon and the mixture was hydrogenated at 60 ℃ overnight under a 50 bar hydrogen atmosphere. The catalyst was then filtered off through a filter layer and washed repeatedly with ethanol. The combined filtrates were concentrated under reduced pressure.

General procedure 3A: reaction with carbamoyl chloride

A solution of piperidine in dichloromethane (2.5ml/mmol) was mixed drop by drop with N, N-diisopropylethylamine (1.2 eq.) and the appropriate carbamoyl chloride (1.2 eq.) at 0 deg.C under argon. The reaction mixture was stirred at RT. After addition of water and phase separation, the organic phase was washed three times with water and once with saturated aqueous sodium chloride solution, dried (sodium sulfate), filtered and concentrated under reduced pressure.

General procedure 4A: methyl ester hydrolysis/epimerization

To a solution of the appropriate methyl ester (1.0 equiv.) in methanol (35-40ml/mmol) was added potassium tert-butoxide (10 equiv.) at RT. The mixture was stirred at 60 ℃ overnight. If the conversion is incomplete, water (1.0 eq.) is added and the mixture is stirred at 60 ℃ until the conversion is complete. For working up, the methanol is removed under reduced pressure, the residue is mixed with water and the mixture is acidified (pH 1) with a 1N aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure.

General procedure 5A: formation of urea

A solution of nitrophenylcarbamate (1.0 eq) in dimethylformamide (10ml/mmol) is mixed at RT with the appropriate amine (2.0-3.0 eq) and potassium carbonate (1.0 eq) and the mixture is stirred in 15ml portions in a single mode microwave oven (Emrys Optimizer) at 150 ℃ for 0.5-1 h. The reaction solution was filtered and the filtrate was purified by preparative HPLC.

General procedure 6A: methyl ester hydrolysis/epimerization

To a solution of the appropriate methyl ester (1.0 equiv.) in methanol (35-40ml/mmol) was added potassium tert-butoxide (10 equiv.) at RT. The mixture was stirred at 60 ℃ overnight. If the conversion is incomplete, water (1.0 eq.) is added and the mixture is stirred at 60 ℃ until the conversion is complete. For work-up, the methanol was removed under reduced pressure, the residue was mixed with water and the mixture was adjusted to pH 1 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure.

General procedure 7A: hydrogenation of pyridine using a flow hydrogenation apparatus

A solution of pyridine in concentrated acetic acid (approximately 35ml/mmol) was hydrogenated in a flow-type hydrogenation unit ("H-Cube", Budapest, Hungary from Thales Nano) under a hydrogen atmosphere (conditions: 10% Pd/C catalyst, "controlled" mode, 60 bar, 0.5ml/min, 85 ℃ C.). Removal of the solvent on a rotary evaporator yields the corresponding crude product, which is optionally purified by preparative HPLC.

General procedure 8A:oxadiazole formation

A solution of the appropriate piperidine-3-carboxylic acid in dimethylformamide (10-20ml/mmol) was mixed with HATU (1.2 equiv.), N, N-diisopropylethylamine (2.2 equiv.) and the appropriate N' -hydroxyamidine (1.1 equiv.) at RT under argon. The reaction mixture was stirred at RT until the intermediate had completely formed, then further stirred at 120 ℃ until the desired product was formed from the intermediate. The reaction mixture is then purified by preparative HPLC.

Example 1A

5- [4- (trifluoromethyl) phenyl ] pyridine-3-carboxylic acid methyl ester

According to general method 1A, 28g (132mmol) of methyl 5-bromonicotinate and 30g (158mmol, 1.2 equivalents) of 4-trifluoromethylphenylboronic acid are reacted. Yield: 32g (85% of theory)

LC-MS (method 8B): R_t＝2.27min；MS(ESIpos)：m/z＝282[M+H]⁺。

Example 2A

5- [4- (trifluoromethyl) phenyl ] piperidine-3-carboxylic acid methyl ester [ racemic cis/trans isomer mixture ]

According to general method 2A, 32g (112mmol) of methyl 5- [4- (trifluoromethyl) phenyl ] pyridine-3-carboxylate are hydrogenated. Yield: 26g (82% of theory)

LC-MS (method 2B): r_t1.35 and 1.41min (cis/trans isomer); ms (esipos): 288[ M + H ] M/z]⁺。

Example 3A

1- (Morpholin-4-ylcarbonyl) -5- [4- (trifluoromethyl) phenyl ] piperidine-3-carboxylic acid methyl ester [ racemic mixture of cis/trans isomers ]

According to general method 3A, 9.25g (32.2mmol) methyl 5- [4- (trifluoromethyl) phenyl ] piperidine-3-carboxylate and 9.63g (64.7mmol) morpholine-4-carbonyl chloride are reacted. This gave 16.3g of crude product of 76% purity (LC-MS) which was reacted without further purification operations.

LC-MS (method 9B): r_t1.19 and 1.22min (cis/trans isomer); ms (esipos): 401[ M + H ] M/z]⁺。

Example 4A

1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethyl) phenyl ] piperidine-3-carboxylic acid [ racemic cis-isomer ]

According to general method 4A, 22.19g (39.90mmol) of the compound from example 3A and 44.78g (399.0mmol) of potassium tert-butoxide are reacted. This reaction selectively produces the cis isomer. Yield: 18.29g (100% of theory)

LC-MS (method 7B): r_t＝1.95min；MS(ESIpos)：m/z＝387[M+H]⁺。

Example 5A

5- [4- (trifluoromethoxy) phenyl ] pyridine-3-carboxylic acid methyl ester

According to general method 1A, 28g (105mmol) of methyl 5-bromonicotinate and 26g (126mmol, 1.2 equivalents) of 4-trifluoromethoxyphenylboronic acid are reacted. Yield: 14g (41% of theory)

LC-MS (method 1B): r_t＝2.44min；MS(ESIpos)：m/z＝298[M+H]⁺。

Example 6A

5- [4- (trifluoromethoxy) phenyl ] piperidine-3-carboxylic acid methyl ester [ racemic cis/trans isomer mixture ]

According to general method 2A, 14g (45mmol) of methyl 5- [4- (trifluoromethoxy) phenyl ] pyridine-3-carboxylate are hydrogenated. Yield: 8g (59% of theory)

LC-MS (method 1B): r_t1.29min and 1.33min (cis/trans isomers); ms (esipos): 304[ M + H ] M/z]⁺。

Example 7A

5- [4- (trifluoromethoxy) phenyl ] piperidine-1, 3-dicarboxylic acid 3-methyl-1- (4-nitrophenyl) ester [ racemic cis/trans isomer mixture ]

5.32g (26.4mmol) of 4-nitrophenylchloroformate are slowly added to 8.0g (26.4mmol) of methyl 5- (4- (trifluoromethoxy) phenyl) piperidine-3-carboxylate and 5.34g (26.3mmol) of triethylamine in 666ml of dichloromethane at 0 ℃. The mixture was stirred at RT for 2 h. For work-up, the reaction mixture is first washed with saturated aqueous sodium bicarbonate solution and then with water. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1: 2 → 1: 1). Yield: 7.32g (54% of theory)

LC-MS (method 3B): r_t＝2.47min；MS(ESIpos)：m/z＝469[M+H]⁺。

Example 8A

1- (Thiomolin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl ] piperidine-3-carboxylic acid methyl ester [ racemic mixture of cis/trans isomers ]

To 180ml of DMF were added 12.0g (25.1mmol) of 3-methyl-1- (4-nitrophenyl) 5- [4- (trifluoromethoxy) phenyl ] piperidine-1, 3-dicarboxylic acid ester, 7.77g (75.3mmol) of thiomorpholine and 10.4g (75.3mmol) of potassium carbonate and 12 portions were heated at 150 ℃ for 2h in a monomode microwave oven (EmrysOptizer). For work-up, the reaction solutions are combined and filtered, and the residue is purified by preparative HPLC. Yield: 7.88g (73% of theory)

LC-MS (method 9B): r_t1.16 and 1.18min (cis/trans isomers); ms (esipos): m/z 433[ M + H ═]⁺。

Example 9A

1- (Thiomolin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl ] piperidine-3-carboxylic acid [ racemic cis-isomer ]

According to general method 4A, 7.85g (18.2mmol) of the compound from example 8A and 20.4g (182mmol) of potassium tert-butoxide are reacted. This reaction selectively produces the cis isomer. Yield: 7.70g (99% of theory)

LC-MS (method 9B): r_t＝1.04min；MS(ESIpos)：m/z＝419[M+H]⁺。

Example 10A

5- (4-ethylphenyl) pyridine-3-carboxylic acid methyl ester

According to general method 1A, 32g (148mmol) of methyl 5-bromonicotinate and 27g (178mmol, 1.2 equivalents) of 4-ethylphenylboronic acid are reacted. Yield: 24g (64% of theory)

LC-MS (method 3B): r_t＝2.03min；MS(ESIpos)：m/z＝242[M+H]⁺。

Example 11A

5- (4-Ethylphenyl) piperidine-3-carboxylic acid methyl ester [ racemic cis/trans isomer mixture ]

According to general method 2A, 24g (94mmol) of methyl 5- (4-ethylphenyl) pyridine-3-carboxylate were hydrogenated. Yield: 20g (77% of theory)

LC-MS (method 5B): r_t＝1.43min；MS(ESIpos)：m/z＝248[M+H]⁺。

Example 12A

5- (4-Ethylphenyl) piperidine-1, 3-dicarboxylic acid 3-methyl-1- (4-nitrophenyl) ester [ racemic mixture of cis/trans isomers ]

3.0g (12.1mmol) of the compound from example 11A are initially introduced into 30ml of dichloromethane and cooled to 0 ℃ and admixed with 3.4ml (2.4g, 12.1mmol) of triethylamine and 2.4g (12.1mmol) of 4-nitrophenyl chloroformate. The reaction mixture was slowly warmed to RT and stirred at RT for 16 h. The mixture was washed several times with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent dichloromethane → dichloromethane/methanol 100: 2). Yield: 4.7g (83% of theory, 89% pure)

HPLC (method 1A): r_t4.94min and 5.00min (cis/trans isomer); ms (esipos): m/z 413[ M + H ]]⁺。

Example 13A

5- (4-Ethylphenyl) -1- [ (3-hydroxyazetidin-1-yl) carbonyl ] piperidine-3-carboxylic acid methyl ester [ racemic mixture of cis/trans isomers ]

0.3g (0.7mmol) of the compound from example 12A, 0.2g (2.18mmol) of 3-hydroxyazetidine hydrochloride and 0.2g (1.4mmol) of potassium carbonate are initially introduced into 6ml of DMF and reacted for 30min at 150 ℃ in a single-mode microwave oven (Emrys Optimizer). The crude product is purified by preparative HPLC. Yield: 105mg (40% of theory)

LC-MS (method 3B): r_t1.76min and 1.85[ cis/trans isomer [ ]]；MS(ESIpos)：m/z＝361[M+H]⁺。

Example 14A

5- (4-ethylphenyl) -1- [ (3-hydroxyazetidin-1-yl) carbonyl ] piperidine-3-carboxylic acid [ racemic cis-isomer ]

300mg (0.83mmol) of the compound from example 13A are reacted according to general method 4A. This reaction selectively produces the cis isomer. Yield: 250mg (90% of theory)

LC-MS (method 3B): r_t＝1.44min；MS(ESIpos)：m/z＝333[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝12.42(br s，COOH)，7.18-7.13(m，4H)，5.54(br s，OH)，4.39-4.33(m，1H)，4.08-3.97(m，3H)，3.68-3.62(m，3H)，2.78-2.70(m，2H)，2.68-2.54(m，3H)，2.48-2.42(m，1H)，2.08(br d，1H)，1.71(q，1H)，1.15(t，3H)。

Example 15A

5- (4-ethylphenyl) ] pyridine-3-carboxylic acid ethyl ester

According to general method 1A, 29g (126mmol) of ethyl 5-bromonicotinate and 23g (152mmol, 1.2 equivalents) of 4-ethylphenylboronic acid are reacted. Yield: 32g (82% of theory)

LC-MS (method 4B): r_t＝3.80min；MS(ESIpos)：m/z＝256[M+H]⁺。

Example 16A

5- (4-ethylphenyl) ] piperidine-3-carboxylic acid ethyl ester [ racemic cis/trans isomer mixture ]

According to general method 2A, 24g (71mmol) of ethyl 5- (4-ethylphenyl) pyridine-3-carboxylate are hydrogenated. Yield: 15g (81% of theory)

LC-MS (method 5B): r_t1.78min and 1.91min (cis/trans isomers); ms (esipos): m/z 262[ M + H ═]⁺。

Example 17A

5- (4-ethylphenyl) ] piperidine-3-carboxylic acid ethyl ester [ racemic cis-isomer ]

Separation of the diastereomers of 15g of the compound from example 16A according to method 1C gave 2.5g of the cis isomer (example 17A).

LC-MS (method 3B): r_t＝1.02min；MS(ESIpos)：m/z＝262[M+H]⁺。

Example 18A

5- (4-ethylphenyl) ] piperidine-3-carboxylic acid ethyl ester [ racemic trans isomer ]

Separation of the diastereomers of 15g of the compound from example 16A according to method 1C gave 3.0g of the trans isomer (example 18A).

LC-MS (method 3B): r_t＝1.09min；MS(ESIpos)：m/z＝262[M+H]⁺。

Example 19A

5- (4-Ethylphenyl) piperidine-1, 3-dicarboxylic acid 3-ethyl-1- (4-nitrophenyl) ester [ racemic cis-isomer ]

1.93g (9.57mmol) of 4-nitrophenylchloroformate are slowly added to 2.5g (9.57mmol) of ethyl 5- (4-ethylphenyl) piperidine-3-carboxylate, the compound from example 17A, and 1.94g (19.1mmol) of triethylamine in 292ml of dichloromethane at 0 ℃. The mixture was stirred at RT for 2 h. For work-up, the reaction mixture is first washed with saturated aqueous sodium bicarbonate solution and then with water. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC. Yield: 2.66g (64% of theory)

LC-MS (method 2B): r_t＝1.57min；MS(ESIpos)：m/z＝427[M+H]⁺。

Example 20A

5- (4-Ethylphenyl) -1- [ (4-hydroxypiperidin-1-yl) carbonyl ] piperidine-3-carboxylic acid ethyl ester [ racemic cis-isomer ]

To 9ml of DMF 370mg (0.81mmol) of 3-ethyl-1- (4-nitrophenyl) 5- (4-ethylphenyl) piperidine-1, 3-dicarboxylic acid ester, 245mg (2.42mmol) of 4-hydroxypiperidine and 112mg (0.81mmol) of potassium carbonate are added and heated at 150 ℃ for 15min in a monomode microwave oven (Emrys Optimizer). For work-up, the reaction solution was mixed with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC. Yield: 208mg (66% of theory)

LC-MS (method 2B): r_t＝1.23min；MS(ESIpos)：m/z＝389[M+H]⁺。

Example 21A

5- (4-Ethylphenyl) -1- [ (4-hydroxypiperidin-1-yl) carbonyl ] piperidine-3-carboxylic acid [ racemic cis-isomer ]

880mg (2.24mmol) of 5- (4-ethylphenyl) -1- [ (4-hydroxypiperidin-1-yl) carbonyl]Piperidine-3-carboxylic acid ethyl ester dissolved in 15.5ml of diethyl etherA mixture of alkane and 7.7ml water, 215mg (8.97mmol) lithium hydroxide was added and the mixture was stirred at RT overnight. For work-up, the reaction solution is concentrated under reduced pressure, then water is added and the mixture is acidified with 1N hydrochloric acid. The precipitate formed is filtered off, washed and dried under reduced pressure. The filtrate was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The two solids gave an overall yield of 764mg (95% of theory).

LC-MS (method 3B): r_t＝1.49min；MS(ESIpos)：m/z＝361[M+H]⁺。

Example 22A

{3-(3-Amino-1, 2, 4-Oxadiazol-5-yl) -5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl } (morpholin-4-yl) methanone [ racemic cis-isomer]

A solution of 11.9g (30.7mmol) of the carboxylic acid from example 4A in 150ml of DMF under argon is mixed at RT with 19.2g (36.8mmol) of PYBOP and 10.7ml (61.4mmol) of N, N' -diisopropylethylamine. Subsequently, the mixture was stirred at RT for 30min and then the solution was added dropwise over 1.5h to 24.5g (92.1mmol) of hydroxyguanidine hemisulfate hemihydrate, 16.1ml (92.1mmol) of N, N' -diisopropylethylamine anda suspension of molecular sieves. The reaction mixture was stirred at RT for 1h and then filtered through a frit. The residue was washed with 200ml DMF and then the combined organic phases were stirred at 130 ℃ (preheated oil bath) for 1.5 h. Subsequently, the solvent was removed under reduced pressure and the residue was mixed with 300ml of diethyl ether and 300ml of 1N aqueous sodium hydroxide solution and stirred vigorously for 24 h. The solid formed is filtered off, washed with water and diethyl ether and then dried under high vacuum. Yield: 8.80g (66% of theory)

LC-MS (method 2B): r_t＝1.08min；MS(ESIpos)：m/z＝426[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.70(d，2H)，7.56(d，2H)，6.27(s，2H)，3.95(d，1H)，3.63(d，1H)，3.56(d，4H)，3.19(br s，5H)，3.06-2.91(m，3H)，2.29(d，1H)，1.96(q，1H)。

Example 23A

{3- (3-chloro-1, 2, 4-)Oxadiazol-5-yl) -5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl) (morpholin-4-yl) methanone [ racemic cis isomer ]

A solution of 2.59g (37.6mmol) of sodium nitrite in 10ml of water is added dropwise at 0 ℃ to a solution of 8.00g (18.8mmol) of the amine from example 22A in 200ml of concentrated hydrogen chloride solution. After the end of the addition, the mixture was stirred at 0 ℃ for 1h and then at RT for 2 h. The reaction mixture was diluted with 1N aqueous hydrogen chloride solution and extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by preparative HPLC. Yield: 5.83g (70% of theory)

LC-MS (method 6B): r_t＝1.17min；MS(ESIpos)：m/z＝445[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.71(d，2H)，7.57(d，2H)，4.03(d，1H)，3.63(d，1H)，3.57(t，4H)，3.53-3.43(m，1H)，3.21(d，4H)，3.14-2.95(m，3H)，2.35(d，1H)，2.05(q，1H)。

Example 24A

[3- (3-amino-1, 2, 4-)Oxadiazol-5-yl) -5- (4-ethylphenyl) piperidin-1-yl](4-hydroxypiperidin-1-yl) methanone [ racemic cis isomer]

A solution of 2.50g (6.31mmol) of the carboxylic acid from example 21A in 50ml of DMF under argon is mixed at RT with 3.94g (7.57mmol) of PYBOP and 2.20ml (12.6mmol) of N, N' -diisopropylethylamine. Subsequently, the mixture was stirred at RT for 30min and then the solution was added dropwise over 1.5h to 5.04g (18.9mmol) of hydroxyguanidine hemisulfate hemihydrate, 3.30ml (18.9mmol) of N, N' -diisopropylethylamine anda suspension of molecular sieves. The reaction mixture was stirred at RT for 1h and then filtered through a frit. The residue was washed with 50ml DMF and then the combined organic phases were stirred at 130 ℃ (preheated oil bath) for 40 min. Subsequently, the solvent was removed under reduced pressure and the residue was mixed with 30ml of diethyl ether and 30ml of 1N aqueous sodium hydroxide solution and stirred vigorously for 24 h. The organic phase was removed and the aqueous phase was extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 3.00g (77% of theory, 65% purity)

HPLC (method 9B): r_t＝0.89min；MS(ESIpos)：m/z＝400[M+H]⁺。

Example 25A

[3- (3-chloro-1, 2, 4-)Oxadiazol-5-yl) -5- (4-ethylphenyl) piperidin-1-yl](4-hydroxypiperidin-1-yl) -methanone [ racemic cis isomer]

A solution of 332mg (4.81mmol) of sodium nitrite in 1.25ml of water is added dropwise at 0 ℃ to a solution of 1.60g (2.40mmol) of the amine from example 24A having a purity of 60% in 25ml of concentrated hydrogen chloride solution. After the addition was complete, the mixture was stirred at 0 ℃ for 1h and then at RT for 45 min. The reaction mixture was diluted with 1N aqueous hydrogen chloride and extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by preparative HPLC. Yield: 220mg (22% of theory)

HPLC (method 9B): r_t＝1.11min；MS(ESIpos)：m/z＝419[M+H]⁺。

Example 26A

4-nitrophenyl thiomorpholine-4-carboxylate 1, 1-dioxide

17.0g (99.2mmol) of thiomorpholine 1, 1-dioxide hydrochloride are initially taken in 100ml of dichloromethane and, with cooling with an ice bath, mixed with 20.7ml (15.1g, 148.8mmol) of triethylamine. 10.0g (49.6mmol) of 4-nitrophenyl chloroformate are added portionwise. The reaction mixture was stirred at RT for 30 min, mixed with water and ethyl acetate and then filtered. The residue was dried under high vacuum. Yield: 12.4g (83% of theory)

LC-MS (method 6B): r_t＝0.75min；MS(ESIpos)：m/z＝301[M+H]⁺。

Example 27A

4-Nitrophenyl thiomorpholine-4-carboxylate

7.7g (74.4mmol) of thiomorpholine are initially introduced into 100ml of dichloromethane and, with cooling in an ice bath, are mixed with 20.7ml (15.1g, 148.8mmol) of triethylamine. 10.0g (49.6mmol) of 4-nitrophenyl chloroformate are added portionwise. The reaction mixture was stirred at RT for one hour, mixed with water and ethyl acetate. The organic phase is removed, washed with 1N hydrochloric acid and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. Yield: 13.2g (99% of theory)

LC-MS (method 6B): r_t＝0.98min；MS(ESIpos)：m/z＝269[M+H]⁺。

Example 28A

4-Nitrophenyl thiomorpholine-4-carboxylate 1-oxide

13.1g (49.0mmol) of 4-nitrophenyl thiomorpholine-4-carboxylate are initially taken in 135ml of dichloromethane and mixed at 0 ℃ with 7.6g (44.1mmol) of batchwise m-chloroperoxybenzoic acid. The mixture was stirred at RT for two hours, water was added and the organic phase was removed. The organic phase was washed rapidly with saturated aqueous sodium bicarbonate solution, filtered and concentrated under reduced pressure. The crude product is purified by preparative HPLC. Yield: 7.8g (56% of theory)

LC-MS (method 6B): r_t＝0.69min；MS(ESIpos)：m/z＝285[M+H]⁺。

Example 29A

[5- (methoxycarbonyl) pyridin-3-yl ] borate

Under argon, 17.6g (81.4mmol) of methyl 5-bromonicotinate are initially introduced into 375ml of DMF and admixed with 26.9g (105.8mmol) of 4, 4, 4 ', 4 ', 5, 5, 5 ', 5 ' -octamethyl-2, 2 ' -di-1, 3, 2-dioxaborolan, 3.0g (3.6mmol) of tris (dibenzylideneacetone) dipalladium (0), 1.8g (6.5mmol) of tricyclohexylphosphine and 32.0mmol (325.9mmol) of potassium acetate. The reaction mixture was stirred at 100 ℃ for 20 h. Subsequently, the solvent was removed under reduced pressure, the residue was mixed with 40ml of water and 140ml of tert-butyl methyl ether, and the organic phase was removed. The aqueous phase is extracted three times with 80ml of tert-butyl methyl ether each time. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is taken up in 360ml of methanol and mixed with 36ml of concentrated hydrochloric acid. The reaction mixture was heated to reflux for 22h and then stirred at RT for 12 h. About half of the solvent was removed under reduced pressure, and the solution was filtered and further concentrated under reduced pressure. The oily residue is recrystallized twice from acetone and taken up in 10ml of acetone and mixed with 100ml of tert-butyl methyl ether. After 16h, the precipitate formed was removed from the solution. The precipitate was stirred in 50ml of acetone and allowed to stand at RT for 5 weeks, and the solution was removed again. The solutions were combined, concentrated and dissolved in 50ml of tert-butyl-methyl ether. The mixture was allowed to stand at RT for 5 weeks and then the precipitate was removed. The precipitate was washed three times with tert-butyl methyl ether and dried in a drying oven under reduced pressure. Yield: 9.0g (51% of theory)

LC-MS (method 6B): r_t＝0.91min；MS(ESIpos)：m/z＝182[M+H]⁺。

Example 30A

4-bromo-2-fluoro-1-vinylbenzene

10.0g (49.3mmol) of 4-bromo-2-fluorobenzaldehyde are dissolved in 40ml of dichloromethane and 9.6ml (9.7g, 64.0mmol) of 1, 8-diazabicyclo [5.4.0]Dec-7-ene and 19.4g (54.2mmol) of methyltriphenylbromideMix and stir at RT for 3 h. The reaction mixture was purified on silica gel (eluent: dichloromethane). The product fractions were combined, concentrated under reduced pressure and dried under high vacuum. Yield: 4.5g (41% of theory)

GC-MS (method 1F): r_t＝2.95min；MS(ESIpos)：m/z＝201[M+H]⁺。

Example 31A

5- (3-fluoro-4-vinylphenyl) nicotinic acid methyl ester

2.5g (11.2mmol) 4-bromo-2-fluoro-1-vinylbenzene are reacted according to general method 1A with 3.2g (14.5mmol) of [5- (methoxycarbonyl) pyridin-3-yl ] borate. Release of the hydrochloride was obtained by the addition of 1.70g (12.3mmol) of potassium carbonate. Yield: 1.9g (61% of theory)

LC-MS (method 2B): r_t＝1.27min；MS(ESIpos)：m/z＝258[M+H]⁺。

Example 32A

5- (4-Ethyl-3-fluorophenyl) -1-formylpiperidine-3-carboxylic acid methyl ester [ racemic cis/trans isomer mixture ]

1.9g (7.5mmol) methyl 5- (3-fluoro-4-vinylphenyl) nicotinate were reacted according to general method 7A. Yield: 1.6g (72% of theory)

LC-MS (method 6B): r_t1.00min and 1.02min (cis/trans isomers); ms (esipos): 295[ M + H ] M/z ]⁺。

Example 33A

5- (4-Ethyl-3-fluorophenyl) piperidine-3-carboxylic acid methyl ester hydrochloride [ racemic cis/trans isomer mixture ]

1.6g (5.3mmol) of methyl 5- (4-ethyl-3-fluorophenyl) -1-formylpiperidine-3-carboxylate are taken up in 10ml of methanol and heated under reflux with 1ml of water and 0.5ml of concentrated hydrochloric acid for three hours. The reaction mixture was concentrated and dried under reduced pressure. Yield: 1.5g (63% of theory; purity 68%)

LC-MS (method 6B): r_t0.71min and 0.74min (cis/trans isomer); ms (esipos): 266[ M + H ] M/z]⁺。

Example 34A

5- (4-Ethyl-3-fluorophenyl) piperidine-1, 3-dicarboxylic acid 3-methyl-1- (4-nitrophenyl) ester [ racemic cis/trans isomer mixture ]

According to general method 3A, 1.5g (4.8mmol) methyl 5- (4-ethyl-3-fluorophenyl) piperidine-3-carboxylate and 1.3g (6.3mmol) 4-nitrophenyl chloroformate are reacted. Yield: 2.1g (92% of theory)

LC-MS (method 6B): r_t1.30min and 1.32min (cis/trans isomers); ms (esipos): m/z 431[ M + H ]]⁺。

Example 35A

5- (4-Ethyl-3-fluorophenyl) -1- (thiomorpholin-4-ylcarbonyl) piperidine-3-carboxylic acid methyl ester [ racemic mixture of cis/trans isomers ]

According to general method 5A, 2.2g (5.0mmol) of 3-methyl-1- (4-nitrophenyl) 5- (4-ethyl-3-fluorophenyl) piperidine-1, 3-dicarboxylic acid ester and 2.8ml (3.1g, 30.0mmol) of thiomorpholine are reacted. Yield: 1.2g (57% of theory)

LC-MS (method 6B): r_t1.17min and 1.20min (cis/trans isomers); ms (esipos): 395[ M + H ] M/z]⁺。

Example 36A

5- (4-Ethyl-3-fluorophenyl) -1- (thiomorpholin-4-ylcarbonyl) piperidine-3-carboxylic acid [ racemic mixture of cis-isomers ]

According to general method 4A, 1.2g (3.0mmol) of methyl 5- (4-ethyl-3-fluorophenyl) -1- (thiomorpholin-4-ylcarbonyl) piperidine-3-carboxylate are reacted with 3.4g (30.4mmol) of potassium tert-butoxide. Yield: 599mg (50% of theory)

LC-MS (method 6B): r_t＝1.05min；MS(ESIpos)：m/z＝381[M+H]⁺。

Example 37A

5- [4- (difluoromethoxy) phenyl ] nicotinic acid methyl ester

10.0g (44.8mmol)4- (difluoromethoxy) bromobenzene was reacted according to general method 1A with 14.6g (67.3mmol) of [5- (methoxycarbonyl) pyridin-3-yl ] borate. Release of the hydrochloride was obtained by the addition of a further 6.80g (49.3mmol) of potassium carbonate. Yield: 8.6g (67% of theory)

LC-MS (method 2B): r_t＝1.15min；MS(ESIpos)：m/z＝280[M+H]⁺。

Example 38A

5- [4- (Difluoromethoxy) phenyl ] piperidine-3-carboxylic acid methyl ester [ racemic cis/trans isomer mixture ]

A solution of 8.6g (30.9mmol) methyl 5- [4- (difluoromethoxy) phenyl ] nicotinate in concentrated acetic acid (112ml) was mixed with 841mg palladium on carbon (10% palladium) and 1.12g platinum (IV) oxide. This was followed by hydrogenation under hydrogen atmosphere at standard pressure for 24 h. The reaction solution was concentrated under reduced pressure. The residue was taken up in water, acidified with 1N hydrochloric acid (pH ═ 1), extracted with diethyl ether and then basified with saturated aqueous sodium bicarbonate solution (pH > 10) and extracted several times with ethyl acetate. The combined filtrates were dried over sodium sulfate, filtered and concentrated under reduced pressure. Yield: 6.6g (74% of theory)

LC-MS (method 6B): r_t0.65min and 0.66min (cis/trans isomer); ms (esipos): 286[ M + H ] M/z]⁺。

Example 39A

5- [4- (Difluoromethoxy) phenyl ] -1- [ (1, 1-dioxothiomorpholin-4-yl) carbonyl ] piperidine-3-carboxylic acid methyl ester [ cis/trans isomer mixture ]

2.2g (7.7mmol) of methyl 5- [4- (difluoromethoxy) phenyl ] piperidine-3-carboxylate are dissolved in 14ml of N-methyl-2-pyrrolidone and admixed with 4.0ml (3.0g, 23.0mmol) of N, N-diisopropylethylamine and 3.5g (11.5mmol) of 4-nitrophenyl thiomorpholine-4-carboxylate 1, 1-dioxide. The reaction mixture was reacted in a microwave at 180 ℃ for seven minutes. Subsequently, water and ethyl acetate were added, and the aqueous phase was removed and extracted with ethyl acetate several times. The combined organic extracts were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and/or concentrated under reduced pressure. The residue is taken up in diethyl ether and filtered, and the filtrate is purified by preparative HPLC. Yield: 2.0g (51% of theory)

LC-MS (method 6B): r_t0.92min and 0.94min (cis/trans isomer); ms (esipos): m/z 447[ M + H ]]⁺。

Example 40A

5- [4- (difluoromethoxy) phenyl ] -1- [ (1, 1-dioxothiomorpholin-4-yl) carbonyl ] piperidine-3-carboxylic acid [ racemic cis-isomer mixture ]

According to general method 4A, 2.7g (6.1mmol) of methyl 5- [4- (difluoromethoxy) phenyl ] -1- [ (1, 1-dioxothiomorpholin-4-yl) carbonyl ] piperidine-3-carboxylate are reacted with 6.9g (61.3mmol) of potassium tert-butoxide. Yield: 2.1g (77% of theory)

LC-MS (method 6B): r_t＝0.82min；MS(ESIpos)：m/z＝433[M+H]⁺。

Example 41A

5- [4- (Difluoromethoxy) phenyl ] -1- [ (1-oxothiomorpholin-4-yl) carbonyl ] piperidine-3-carboxylic acid methyl ester [ cis/trans isomer mixture ]

2.2g (7.7mmol) of methyl 5- [4- (difluoromethoxy) phenyl ] piperidine-3-carboxylate are dissolved in 14ml of N-methyl-2-pyrrolidone and combined with 4.0ml (3.0g, 23.0mmol) of N, N-diisopropylethylamine and 3.3g (11.5mmol) of 4-nitrophenyl thiomorpholine-4-carboxylate 1-oxide. The reaction mixture was reacted in a microwave at 180 ℃ for seven minutes. Subsequently, water and ethyl acetate were added, and the aqueous phase was removed and extracted with ethyl acetate several times. The combined organic extracts were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. And the residue was purified by preparative HPLC. Yield: 2.2g (59% of theory)

LC-MS (method 6B): r_t0.90min and 0.92min (cis/trans isomer); ms (esipos): m/z 431[ M + H ]]⁺。

Example 42A

5- [4- (difluoromethoxy) phenyl ] -1- [ (1-oxothiomorpholin-4-yl) carbonyl ] piperidine-3-carboxylic acid [ racemic cis-isomer mixture ]

According to general method 4A, 2.7g (6.3mmol) of methyl 5- [4- (difluoromethoxy) phenyl ] -1- [ (1-oxothiomorpholin-4-yl) carbonyl ] piperidine-3-carboxylate are reacted with 7.1g (63.3mmol) of potassium tert-butoxide. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in water and acidified with concentrated hydrochloric acid. The precipitate was filtered off, washed with water and dried under reduced pressure. Yield: 1.1g (34% of theory)

LC-MS (method 6B): r_t＝0.75min；MS(ESIpos)：m/z＝417[M+H]⁺。

Example 43A

Iminocarbamic acid 2-methoxyethyl ester methanesulfonate

A solution of 7.61g (181mmol) of cyanamide in methyl glycol (171ml) was mixed drop by drop with 17.4g (181mmol) of methanesulfonic acid at RT and then stirred for 24 h. The solvent was removed under reduced pressure and the residue was mixed with diethyl ether. Subsequently, the solution was allowed to stand overnight in a refrigerator at about 10 ℃, the solvent was decanted off and the resulting oil was dried under high vacuum. Yield: 33.8g (79% of theory)

¹H NMR(400MHz，DMSO-d₆)：δ＝8.56(br.s.，3H)，6.73(br.s.，1H)，4.43-4.32(m，2H)，3.67-3.56(m，2H)，3.29(s，3H)，2.44(s，3H)。

Example 44A

N' -Hydroxyiminocarbamic acid 2-methoxyethyl ester

A solution of 827mg (11.9mmol) of hydroxylammonium chloride in methanol (76ml) is mixed with 1.29g (23.8mmol) of sodium methoxide at 0 ℃. The mixture was warmed to RT and then 2.00g (7.94mmol, 85% purity) of the mesylate salt from example 43A was added. The mixture was stirred at reflux overnight, the reaction solution was cooled and the solid formed was filtered off. The filtrate was concentrated under reduced pressure, and taken up in ethanol and filtered again. The filtrate is concentrated under reduced pressure and the residue is subsequently purified by column chromatography (silica gel, dichloromethane/methanol 20: 1). Yield: 340mg (29% of theory)

¹H NMR(400MHz，DMSO-d₆)：δ＝8.21(br.s.，1H)，5.38(br.s.，2H)，4.00-3.94(m，2H)，3.54-3.48(m，2H)，3.25(s，3H)。

Example 45A

5- (4-Ethylphenyl) piperidine-1, 3-dicarboxylic acid 3-methyl-1- (4-nitrophenyl) ester [ racemic cis/trans isomer mixture ]

3.0g (12.1mmol) of the compound from example 11A are initially introduced into 30ml of dichloromethane and cooled to 0 ℃ and admixed with 3.4ml (2.4g, 12.1mmol) of triethylamine and 2.4g (12.1mmol) of 4-nitrophenyl chloroformate. The reaction mixture was allowed to warm slowly to RT and stirred at RT for 16 h. The mixture was washed several times with water, dried over sodium sulfate, filtered and dried under reduced pressure. And the residue is purified by column chromatography on silica gel (eluent dichloromethane → dichloromethane/methanol 100: 2). Yield: 4.7g (83% of theory)

LC-MS (method 6B): r_t1.30min and 1.32min (cis/trans isomers); ms (esipos): m/z 413[ M + H ]]⁺。

Example 46A

5- (4-Ethylphenyl) -1- (thiomorpholin-4-ylcarbonyl) piperidine-3-carboxylic acid methyl ester [ racemic cis/trans isomer mixture ]

To 76ml of DMF were added 5.00g (12.1mmol) of the compound from example 45A, 3.57g (36.4mmol) of thiomorpholine and 5.03g (36.4mmol) of potassium carbonate and the mixture was heated in 5 portions in a single-mode microwave oven (Emrys Optizer) at 150 ℃ for 1.5 h. For work-up, the reaction solutions are combined and filtered, and the residue is purified by preparative HPLC. Yield: 3.07g (67% of theory)

LC-MS (method 6B): r_t1.16 and 1.18min (cis/trans isomers); ms (esipos): m/z 377[ M + H ═ M]⁺。

Example 47A

5- (4-Ethylphenyl) -1- (thiomorpholin-4-ylcarbonyl) piperidine-3-carboxylic acid methyl ester [ racemic cis-isomer ]

According to general method 4A, 3.00g (7.97mmol) of the compound from example 46A are reacted with 8.94g (79.7mmol) of potassium tert-butoxide. This reaction selectively produces the cis isomer. Yield: 2.74g (93% of theory)

LC-MS (method 6B): r_t＝1.04min；MS(ESIpos)：m/z＝363[M+H]⁺。

Example 48A

5- [4- (trifluoromethyl) phenyl ] piperidine-1, 3-dicarboxylic acid 3-methyl-1- (4-nitrophenyl) ester [ racemic cis/trans isomer mixture ]

20.0g (69.6mmol) of the compound from example 2A are dissolved in 1.01 g of dichloromethane and mixed with 14.1g (139mmol) of triethylamine at 0 ℃. Subsequently, 14.0g (69.6mmol) of 4-nitrophenyl chlorocarbonate was added dropwise. The reaction mixture was stirred at 0 ℃ for 2h and then at RT for 16 h. For work-up, the mixture was washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. This gave 31.3g of crude product, which was reacted without further purification steps.

LC-MS (method 3B): r_t2.44min and 2.48min (cis/trans isomer); ms (esipos): 453[ M + H ] M/z ]⁺。

Example 49A

1- (Thiomolin-4-ylcarbonyl) -5- [4- (trifluoromethyl) phenyl ] piperidine-3-carboxylic acid methyl ester [ racemic cis/trans isomer mixture ]

To 150ml of DMF are added 10.0g (22.1mmol) of the compound from example 48A, 6.84g (66.3mmol) of thiomorpholine and 9.17g (66.3mmol) of potassium carbonate and divided into 10 portions which are heated at 150 ℃ for 1h in a single-mode microwave oven (Emrys Optimizer). For work-up, the reaction solutions are combined and filtered, and the residue is purified by preparative HPLC. Yield: 5.16g (55% of theory)

LC-MS (method 5B): r_t1.13 and 1.16min (cis/trans isomer); ms (esipos): 417[ M + H ] M/z]⁺。

Example 50A

According to general method 4A, 5.16g (12.4mmol) of the compound from example 49A and 13.9g (124mmol) of potassium tert-butoxide are reacted. This reaction selectively produces the cis isomer. Yield: 4.90g (98% of theory)

LC-MS (method 5B): r_t＝1.04min；MS(ESIpos)：m/z＝403[M+H]⁺。

Example 51A

1-bromo-4- (2, 2, 2-trifluoroethyl) benzene

A solution of 25.0g (100mmol) of 4-bromobenzyl bromide in 1-methyl-2-pyrrolidone (121ml) was mixed at RT with 4.95g (26.0mmol) of copper (I) iodide and 37.5g (195mmol) of methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate. The mixture was heated to 80 ℃ and then stirred overnight. The reaction solution was added to water and extracted with ether, and the organic phase was dried over sodium sulfate. After filtration and concentration of the organic phase in vacuo, the residue is purified by column chromatography (silica gel, cyclohexane/ethyl acetate 20: 1). Yield: 16.1g (67% of theory)

GC-MS (method 1F): r_t＝2.66min；MS(ESIpos)：m/z＝240[M+H]⁺。

Example 52A

5- [4- (2, 2, 2-trifluoroethyl) phenyl ] nicotinic acid methyl ester

A solution of 8.00g (33.5mmol) of the compound from example 51A in toluene (304ml) is mixed under argon at RT with 10.9g (50.2mmol) of the compound from example 29A in ethanol (100ml) and 5.10g (36.8mmol) of potassium carbonate. After stirring for 10min, 3.87g (3.35mmol) tetrakis (triphenylphosphine) palladium and then 5.83g (100mmol) potassium fluoride in water (64ml) were added. The mixture was stirred at reflux for 8h, and the reaction solution was cooled and diluted with ethyl acetate. The reaction solution was washed in water and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (silica gel, dichloromethane/methanol 100: 1 → 80: 1). Yield: 9.20g (69% of theory, purity 75%)

LC-MS (method 6B): r_t＝1.06min；MS(ESIpos)：m/z＝296[M+H]⁺。

Example 53A

5- [4- (2, 2, 2-trifluoroethyl) phenyl ] piperidine-3-carboxylic acid methyl ester [ racemic cis/trans isomer mixture ]

A solution of 9.20g (23.4mmol, 75% purity) of the compound from example 52A in concentrated acetic acid (192ml) was mixed with 1.94g palladium on carbon (10% palladium) and 2.23g platinum (IV) oxide. This was followed by hydrogenation under hydrogen atmosphere at standard pressure for 6h, then 1.00g palladium on carbon (10% palladium) and 2.00g platinum (IV) oxide were added and hydrogenated under hydrogen atmosphere at standard pressure overnight. Subsequently, 1.00g of palladium on carbon (10% palladium) and 3.00g of platinum (IV) oxide were further added, and hydrogenation was further carried out under a hydrogen atmosphere at a standard pressure for 24 hours. The reaction solution was filtered through celite, the filter residue was washed with methanol/water and the combined filtrates were concentrated under reduced pressure. The residue is taken up in dichloromethane and then washed with 1N aqueous sodium carbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. Yield: 6.64g (85% of theory, 90% pure)

LC-MS (method 2B): r_t0.83 and 0.84min [ cis/trans isomer]；MS(ESIpos)：m/z＝302[M+H]⁺。

Example 54A

5- [4- (2, 2, 2-trifluoroethyl) phenyl ] piperidine-1, 3-dicarboxylic acid 3-methyl-1- (4-nitrophenyl) ester [ racemic cis/trans isomer mixture ]

A solution of 6.62g (19.8mmol, 90% purity) of the compound from example 53A in dichloromethane (211ml) was mixed with 9.65ml (7.00g, 69.2mmol) triethylamine and then with 3.99g (19.8mmol) 4-nitrophenyl chloroformate at 0 ℃. The mixture was warmed to RT and stirred for 1 h. The reaction solution was washed with saturated aqueous sodium bicarbonate solution and water, and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 10.3g (91% of theory, 81% pure)

LC-MS (method 2B): r_t1.40 and 1.42min (cis/trans isomer); ms (esipos): 467[ M + H ] M/z]⁺。

Example 55A

1- (Thiomolin-4-ylcarbonyl) -5- [4- (2, 2, 2-trifluoroethyl) phenyl ] piperidine-3-carboxylic acid methyl ester [ racemic cis/trans isomer mixture ]

A solution of 10.3g (17.9mmol, purity 81%) of the compound from example 54A in 1-methyl-2-pyrrolidone (65ml) was mixed with 12.6ml (13.7g, 132mmol) thiomorpholine and 11.5ml (8.56g, 66.2mmol) N, N-diisopropylethylamine and then heated in 5 portions in a monomode microwave oven (Emrys Optimizer) at 150 ℃ for 1 h. For work-up, the reaction solutions were combined and purified directly by preparative HPLC. Yield: 5.63g (71% of theory)

LC-MS (method 6B): r_t1.13 and 1.16min (cis/trans isomer); ms (esipos): m/z 431[ M + H ]]⁺。

Example 56A

1- (Thiomolin-4-ylcarbonyl) -5- [4- (2, 2, 2-trifluoroethyl) phenyl ] piperidine-3-carboxylic acid [ racemic cis-isomer ]

To a solution of 2.97g (6.90mmol) of the compound from example 55A in methanol (83ml) at RT was added 7.74g (69.0mmol) of potassium tert-butoxide. The mixture was stirred at 60 ℃ overnight. For work-up, the methanol was removed under reduced pressure, and the residue was mixed with water and acidified with aqueous 1N hydrochloric acid solution (pH 1). The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 2.61g (76% of theory, 84% purity)

LC-MS (method 6B): r_t＝1.02min；MS(ESIpos)：m/z＝417[M+H]⁺。

Example 57A

1- [ (4-hydroxypiperidin-1-yl) carbonyl ] -5- [4- (2, 2, 2-trifluoroethyl) phenyl ] piperidine-3-carboxylic acid methyl ester [ racemic cis/trans isomer mixture ]

To 14ml of DMF 1.20g (2.57mmol) of the compound from example 54A, 781mg (7.72mmol) of 4-hydroxypiperidine and 533mg (3.86mmol) of potassium carbonate are added and heated at 150 ℃ for 45min in a monomode microwave apparatus (Emrys Optimizer). For work-up, the reaction solutions are combined and filtered, and the residue is purified by preparative HPLC. Yield: 733mg (66% of theory)

LC-MS (method 2B): r_t1.08 and 1.10min (cis/trans isomer); ms (esipos): 429[ M + H ] M/z]⁺。

Example 58A

1- [ (4-hydroxypiperidin-1-yl) carbonyl ] -5- [4- (2, 2, 2-trifluoroethyl) phenyl ] piperidine-3-carboxylic acid [ racemic cis-isomer ]

To a solution of 733mg (1.71mmol) of the compound from example 57A in methanol (32ml) at RT was added 7.74g (17.1mmol) of potassium tert-butoxide. The mixture was stirred at 60 ℃ for 5 h. For work-up, the methanol was removed under reduced pressure, and the residue was mixed with water and acidified with aqueous 1N hydrochloric acid solution (pH 1). The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 735mg (99% of theory)

LC-MS (method 2B): r_t＝0.97min；MS(ESIpos)：m/z＝414[M+H]⁺。

Example 59A

1- (tert-Butoxycarbonyl) -5- [4- (2, 2, 2-trifluoroethyl) phenyl ] piperidine-3-carboxylic acid [ racemic cis/trans isomer mixture ]

1.50g (3.71mmol, purity 75%) of the compound from example 53A in dichloromethane (56ml) are mixed with 0.52ml (375mg, 3.71mmol) triethylamine and 809mg (3.71mmol) di-tert-butyl dicarbonate at RT and stirred for 30 min. Subsequently, the reaction solution was washed with water and saturated aqueous sodium chloride solution, and the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The intermediate thus obtained (1.98g, 85% purity) was taken up in methanol (30ml), mixed at RT with 5.35g (47.7mmol) of potassium tert-butoxide and stirred overnight. For work-up, the methanol was removed under reduced pressure, and the residue was mixed with water and acidified with aqueous 1N hydrochloric acid solution (pH 1). The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 1.54g (75% of theory, purity 75%, 2: 1 cis/trans isomer mixture)

LC-MS (method 6B): r_t1.10 and 1.12min (cis/trans isomer); ms (esipos): m/z 388[ M + H ]]⁺。

Example 60A

3- (3-ethoxy-1, 2, 4-)Oxadiazol-5-yl) -5- [ 3-fluoro-4- (trifluoromethoxy) phenyl]Piperidine [ racemic cis-isomer mixture]

The addition of 387mg (0.50mmol) of 3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [ 3-fluoro-4- (trifluoromethoxy) phenyl]Piperidine-1-carboxylic acid tert-butyl ester and combined with 0.38ml (567mg, 4.97mmol) of trifluoroacetic acid. The reaction mixture was stirred at RT for 16 h, mixed with the same amount of trifluoroacetic acid and stirred at RT for a further 3.5 h. Reaction ofThe mixture was concentrated under reduced pressure, taken up in ethyl acetate and washed twice with saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 195mg (96% of theory)

LC-MS (method 5B): r_t＝1.72min；MS(ESIpos)：m/z＝376[M+H]⁺。

Example 61A

3- (3-ethoxy-1, 2, 4-)Oxadiazol-5-yl) -5- [4- (2, 2, 2-trifluoroethyl) phenyl]Piperidine [ racemic cis isomer]

To a solution of 123mg (0.271mmol) of the compound from example 116 in 8.6ml of dichloromethane at RT was added 0.29ml (432mg, 3.8 mmol) of trifluoroacetic acid and the mixture was stirred overnight. The reaction solution was diluted with dichloromethane and washed with 1N aqueous sodium carbonate solution, and then the organic phase was dried over sodium sulfate. After filtration and removal of the solvent under reduced pressure, 101mg of the title compound were obtained, which was used in the next step without further purification.

LC-MS (method 6B): r_t＝0.81min；MS(ESIpos)：m/z＝356[M+H]⁺。

Example 62A

3- (3-ethoxy-1, 2, 4-)Oxadiazol-5-yl) -5- [4- (2, 2, 2-trifluoroethyl) phenyl]Piperidine-1-carboxylic acid 4-nitrophenyl ester [ racemic cis-isomer ]]

A solution of 52mg (0.14mmol) of the compound from example 61A in dichloromethane (1.6ml) was mixed with 0.07ml (49.7mg, 0.49mmol) triethylamine and then, at 0 ℃ 28mg (0.14mmol) of 4-nitrophenyl chloroformate was added. The mixture was stirred at 0 ℃ for 2h, then warmed to RT and stirred for 1 h. The reaction solution was washed with saturated aqueous sodium bicarbonate solution and water, and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 75.8mg (95% of theory)

LC-MS (method 2B): r_t＝1.48min；MS(ESIpos)：m/z＝521[M+H]⁺。

Example 63A

1-acetyl-5- [4- (2, 2, 2-trifluoroethyl) phenyl ] piperidine-3-carboxylic acid methyl ester [ racemic mixture of cis/trans isomers ]

A solution of 7.00g (23.4mol) of the compound from example 62A in concentrated acetic acid (150ml) was mixed with 3.00g of palladium on carbon (10% palladium) and 5.50g of platinum (IV) oxide and then hydrogenated under an atmosphere of hydrogen at standard pressure until the conversion was complete. The reaction solution was filtered through celite, the filter residue was washed with methanol/water and the combined filtrates were concentrated under reduced pressure. The residue (10.5g) was taken up in dichloromethane (315ml) and then mixed with 18.2ml (13.2g, 131mmol) triethylamine and then with 5.86g (29.1mmol) 4-nitrophenyl chloroformate at 0 ℃. The mixture was stirred at 0 ℃ for 2h, then warmed to RT and stirred overnight. The reaction solution was washed with saturated aqueous sodium bicarbonate and water, the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC and thus the title compound was obtained as a by-product. Yield: 1.32g (14% of theory, 85% purity)

LC-MS (method 2B): r_t1.11 and 1.13min (cis/trans isomer); ms (esipos): 344[ M + H ] M/z]⁺。

Example 64A

1-acetyl-5- [4- (2, 2, 2-trifluoroethyl) phenyl ] piperidine-3-carboxylic acid [ racemic mixture of cis/trans isomers ]

To a solution of 1.32g (3.27mmol) of the compound from example 63A in methanol (73ml) at RT was added 3.67g (32.7mmol) of potassium tert-butoxide. The mixture was stirred at 60 ℃ overnight. For work-up, the methanol was removed under reduced pressure, and the residue was mixed with water and acidified with aqueous 1N hydrochloric acid solution (pH 1). The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 1.19g (99% of theory)

LC-MS (method 2B): r_t＝1.00min；MS(ESIpos)：m/z＝330[M+H]⁺。

Example 65A

3- (3-ethoxy-1, 2, 4-)Oxadiazol-5-yl) -5- [ 3-fluoro-4- (trifluoromethoxy) phenyl]4-nitrophenyl-piperidine-1-carboxylate [ racemic mixture of cis-isomers ]]

195mg (0.48mmol) of 3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [ 3-fluoro-4- (trifluoromethoxy) phenyl]Piperidine, cooled to 0 ℃ and mixed with 0.27ml (193mg, 1.91mmol) triethylamine and 96mg (0.48mmol) 4-nitrophenyl chloroformate. The reaction mixture was stirred at RT for 1 hour, mixed with water and the organic phase removed. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 290mg (94% of theory)

LC-MS (method 6B): r_t＝1.35min；MS(ESIpos)：m/z＝541[M+H]⁺。

Example 66A

3- [3- (2-methoxyethoxy) -1, 2, 4-Diazol-5-yl]-5- [4- (2, 2, 2-trifluoroethyl) phenyl]Piperidine [ racemic cis isomer]

73.0mg (0.171mmol) of the compound from example 117 in ethanol (1.4ml) were mixed with a 6N aqueous hydrogen chloride solution and then stirred at 80 ℃ overnight. The reaction solution was diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 31.5mg (46% of theory) LC-MS (method 6B): rt is 0.79 min; ms (esipos): 386[ M + H ] +, M/z.

Example 67A

3- [3- (2-methoxyethoxy) -1, 2, 4-Diazol-5-yl]-5- [4- (2, 2, 2-trifluoroethyl) phenyl]Piperidine-1-carboxylic acid 4-nitrophenyl ester [ racemic cis-isomer ]]

A solution of 32mg (0.08mmol) of the compound from example 66A in dichloromethane (1.0ml) is mixed with 0.04ml (29mg, 0.29mmol) triethylamine and then, at 0 ℃ 17mg (0.08mmol) of 4-nitrophenyl chloroformate is added. The mixture was stirred at 0 ℃ for 2h, then warmed to RT and stirred for 1 h. The reaction solution was washed with saturated aqueous sodium bicarbonate solution and water, and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 50.5mg (79% of theory, purity 70%)

LC-MS (method 5B): r_t＝2.64min；MS(ESIpos)：m/z＝551[M+H]⁺。

Example 68A

1-bromo-4- (1, 1-difluoroethyl) benzene

A solution of 10.0g (50.2mmol) 4-bromoacetophenone in tetrahydrofuran (20ml) was mixed with 50.0ml (151mmol, 50% in tetrahydrofuran) bis (2-methoxyethyl) aminosulfur trifluoride (Deoxofluor) and 3 drops of methanol, and then stirred under reflux for four days. The reaction mixture was carefully added dropwise to a mixture of saturated aqueous sodium bicarbonate solution and ice (1: 1) and then extracted with diethyl ether. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (silica gel, petroleum ether/dichloromethane 3: 1). Yield: 8.46g (76% of theory)

¹H NMR(400MHz，DMSO-d₆)：δ＝7.70(d，2H)，7.52(d，2H)，1.96(t，3H)。

Example 69A

5- [4- (1, 1-Difluoroethyl) phenyl ] nicotinic acid methyl ester

A solution of 2.98g (13.3mmol) of the compound from example 68A in toluene (25.0ml) in ethanol (8.4ml) and 3.62g (16.7mmol) of the compound from example 29A and 2.03g (14.7mmol) of potassium carbonate are mixed under argon at RT. After stirring for 10min, 1.54g (1.34mmol) tetrakis (triphenylphosphine) palladium and then 2.33g (40.0mmol) potassium fluoride in water (5.8ml) were added. The mixture was stirred at reflux for 8h, and the reaction solution was cooled and diluted with ethyl acetate. The reaction solution was washed in water and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (silica gel, dichloromethane/methanol 100: 1 → 80: 1). Yield: 2.62g (69% of theory, 4: 1 mixture of methyl and ethyl esters)

LC-MS (method 2B): r_t1.20min (methyl ester) and 1.28min (ethyl ester); ms (esipos): 278[ M + H ] M/z]⁺(methyl ester) and 292[ M + H]⁺(Ethyl ester).

Example 70A

5- [4- (1, 1-Difluoroethyl) phenyl ] piperidine-3-carboxylic acid methyl ester [ racemic cis/trans isomer mixture ]

A solution of 2.30g (8.30mmol) of the compound from example 69A in methanol (52ml) and concentrated hydrochloric acid solution (6.5ml) was mixed with 1.05g of palladium on carbon (10% palladium) and 1.92g of platinum (IV) oxide and then hydrogenated under an atmosphere of hydrogen at standard pressure overnight. The reaction solution was filtered through celite, the filter residue was washed with methanol/water and the combined filtrates were concentrated under reduced pressure. The residue is taken up in dichloromethane and then washed with 1N aqueous sodium carbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. Yield: 2.30g (81% of theory, purity 82%)

LC-MS (method 2B): r_t0.80min and 0.81min (cis/trans isomer); ms (esipos): 284[ M + H ] M/z]⁺。

Example 71A

5- [4- (1, 1-Difluoroethyl) phenyl ] piperidine-1, 3-dicarboxylic acid 3-methyl-1- (4-nitrophenyl) ester [ racemic cis/trans isomer mixture ]

A solution of 1.30g (3.78mmol, purity 82%) of the compound from example 70A in dichloromethane (44ml) is mixed with 1.84ml (1.34g, 13.2mmol) triethylamine and then, at 0 ℃ with 762mg (3.78mmol) of 4-nitrophenyl chloroformate. The mixture was warmed to RT and stirred for 2 days. The reaction solution was washed with saturated aqueous sodium bicarbonate solution and water, and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 1.93g (92% of theory, purity 81%, 2: 1 mixture of methyl and ethyl esters)

LC-MS (method 5B): r_t2.58min and 2.61min (methyl ester, cis/trans isomer) and 2.68min and 2.70min (ethyl ester, cis/trans isomer); ms (esipos): 278[ M + H ] M/z]⁺(methyl ester) and 292[ M + H]⁺(Ethyl ester).

Example 72A

5- [4- (1, 1-Difluoroethyl) phenyl ] -1- (thiomorpholin-4-ylcarbonyl) piperidine-3-carboxylic acid methyl ester [ racemic cis/trans isomer mixture ]

A solution of 1.94g (3.50mmol, purity 81%) of the compound from example 71A in 1-methyl-2-pyrrolidone (18ml) was mixed with 1.99ml (2.17g, 21.0mmol) of thiomorpholine and 1.83ml (1.36g, 10.5mmol) of N, N-diisopropylethylamine and then divided into 3 portions which were heated at 150 ℃ for 45min in a monomode microwave oven (Emrys Optizer). For work-up, the reaction solutions were combined and purified directly by preparative HPLC. Yield: 530mg (34% of theory)

LC-MS (method 5B): r_t2.28min and 2.35min (cis/trans isomer); ms (esipos): m/z 413[ M + H ]]⁺。

Example 73A

5- [4- (1, 1-Difluoroethyl) phenyl ] -1- (thiomorpholin-4-ylcarbonyl) piperidine-3-carboxylic acid [ racemic mixture of cis/trans isomers ]

To a solution of 528mg (1.28mmol) of the compound from example 72A in 15ml of methanol at RT is added 1.44g (12.8mmol) of potassium tert-butoxide. The mixture was stirred at 60 ℃ overnight. For work-up, the methanol was removed under reduced pressure, and the residue was mixed with water and acidified with 1N aqueous hydrochloric acid (pH 1). The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 471mg (91% of theory, 2: 1 cis/trans isomer mixture)

LC-MS (method 6B): r_t0.99 and 1.01 min; ms (esipos): m/z 399[ M + H ]]⁺。

Example 74A

4-bromo-2-fluoro-1- (2, 2, 2-trifluoroethyl) benzene

A solution of 10.4g (38.8mmol) 4-bromo-2-fluorobenzyl bromide in 1-methyl-2-pyrrolidone (47ml) was combined at RT with 1.92g (10.1mmol) copper (I) iodide and 14.5g (75.7mmol) methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate. The mixture was heated to 80 ℃ and then stirred overnight. The reaction solution was added to water and extracted with ether, and the organic phase was dried over sodium sulfate. After filtration and concentration of the organic phase under reduced pressure, the residue is purified by column chromatography (silica gel, cyclohexane/ethyl acetate 15: 1). Yield: 7.80g (66% of theory)

GC-MS (method 1F): r_t＝2.42min；MS(ESIpos)：m/z＝258[M+H]⁺。

Example 75A

5- [ 3-fluoro-4- (2, 2, 2-trifluoroethyl) phenyl ] nicotinic acid methyl ester

A solution of 6.78g (23.7mmol) of the compound from example 74A in toluene (339ml) was mixed under argon at RT with 7.74g (35.6mmol) of the compound from example 29A in ethanol (112ml) and 3.61g (26.1mmol) of potassium carbonate. After stirring for 10min, 2.74g (2.37mmol) tetrakis (triphenylphosphine) palladium and then 4.14g (71.2mmol) potassium fluoride in water (71ml) were added. The mixture was stirred at reflux for 8h, and the reaction solution was cooled and diluted with ethyl acetate. The reaction solution was washed in water and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (silica gel, dichloromethane/methanol 150: 1 → 100: 1). The product fractions were concentrated under reduced pressure and the solid obtained was purified by stirring with diethyl ether. Yield: 6.00g (50% of theory, purity 62%)

LC-MS (method 6B): r_t＝1.08min；MS(ESIpos)：m/z＝314[M+H]⁺。

Example 76A

5- [ 3-fluoro-4- (2, 2, 2-trifluoroethyl) phenyl ] piperidine-3-carboxylic acid methyl ester [ racemic mixture of cis/trans isomers ]

A solution of 7.75g (17.1mmol, 69% purity) of the compound from example 75A in methanol (107ml) was mixed with 1.50g of platinum (IV) oxide and concentrated hydrochloric acid solution (13.4 ml). This was followed by hydrogenation under hydrogen atmosphere at 3.5 bar overnight, then 800mg of platinum (IV) oxide were added and hydrogenation again under hydrogen atmosphere at 3.5 bar overnight. Subsequently, 1.00g of platinum (IV) oxide was added, followed by hydrogenation under hydrogen atmosphere at 3.5 bar overnight. The reaction solution was filtered through celite, the filter residue was washed with methanol and the combined filtrates were concentrated under reduced pressure. The residue was taken up in water, then adjusted to pH 9 with 1N aqueous sodium hydroxide solution and subsequently extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. Yield: 6.01g (86% of theory, purity 78%)

LC-MS (method 2B): r_t0.73min and 0.74min (cis/trans isomer); ms (esipos): 320[ M + H ] M/z]⁺。

Example 77A

5- [ 3-fluoro-4- (2, 2, 2-trifluoroethyl) phenyl ] piperidine-1, 3-dicarboxylic acid 3-methyl-1- (4-nitrophenyl) ester [ racemic cis/trans isomer mixture ]

A solution of 4.00g (9.52mmol, purity 76%) of the compound from example 76A in dichloromethane (111ml) was mixed with 4.65ml (3.37g, 33.3mmol) triethylamine and then, at 0 ℃ with 1.92g (9.52mmol) 4-nitrophenyl chloroformate. The mixture was warmed to RT and stirred for 2 h. The reaction solution was washed with saturated aqueous sodium bicarbonate solution and water, and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 5.42g (94% of theory, purity 80%)

LC-MS (method 2B): r_t1.42min and 1.44min (cis/trans isomer); ms (esipos): 485[ M + H ] M/z]⁺。

Example 78A

5- [ 3-fluoro-4- (2, 2, 2-trifluoroethyl) phenyl ] -1- (thiomorpholin-4-ylcarbonyl) piperidine-3-carboxylic acid methyl ester [ racemic cis/trans isomer mixture ]

A solution of 5.85g (9.54mmol, purity 80%) of the compound from example 77A in 1-methyl-2-pyrrolidone (50ml) was mixed with 5.43ml (5.91g, 57.2mmol) of thiomorpholine and 4.99ml (3.70g, 28.6mmol) of N, N-diisopropylethylamine and then divided into 4 portions which were heated at 150 ℃ for 45min in a monomode microwave oven (Emrys Optizer). For work-up, the reaction solutions were combined and purified directly by preparative HPLC. Yield: 4.29g (93% of theory)

LC-MS (method 6B): r_t1.15min and 1.17min (cis/trans isomers); ms (esipos): 449[ M + H ] M/z]⁺。

Example 79A

5- [ 3-fluoro-4- (2, 2, 2-trifluoroethyl) phenyl ] -1- (thiomorpholin-4-ylcarbonyl) piperidine-3-carboxylic acid [ racemic cis-isomer ]

To a solution of 4.29g (9.57mmol) of the compound from example 78A in methanol (190ml) at RT was added 10.7g (112mmol) of potassium tert-butoxide. The mixture was stirred at 60 ℃ overnight. For work-up, the methanol was removed under reduced pressure, and the residue was mixed with water and acidified with 1N aqueous hydrochloric acid (pH 1). The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 3.94g (76% of theory, 80% pure)

LC-MS (method 6B): r_t＝1.04min；MS(ESIpos)：m/z＝435[M+H]⁺。

Example 80A

2- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan

25g (99.8mmol) of 4-bromo-2-fluoro-1- (trifluoromethyl) benzene in 500ml of di (tert-butyl) benzene under argon at RTThe mixture in the alkane was mixed with 27.8g (109.8mmol) of 4, 4, 4 ', 4', 5, 5, 5 ', 5' -octamethyl-2, 2 '-bis-1, 3, 2-dioxaborolan, 2.91g (3.99mmol) of 1, 1' -bis (diphenylphosphino) -ferrocene dichloropalladium (II) dichloromethane complex and with 29.38g (299.4mmol) of potassium acetate. The reaction mixture was stirred for several hours below 100 ℃ until the conversion was substantially complete. The mixture was filtered through celite and mixed with water. After addition of ethyl acetate and phase separation, the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (silica gel-60, eluent: cyclohexane/ethyl acetate 3: 1). This gave 18.22g of a 73% pure (LC-MS) crude product, which was reacted without further purification steps.

¹H NMR(400MHz，DMSO-d₆)：δ＝7.82(dd，1H)，7.67(d，1H)，7.59(d，1H)，1.32(s，12H)。

Example 81A

5- [ 3-fluoro-4- (trifluoromethyl) phenyl ] nicotinic acid methyl ester

According to general method 1A, 18.2g (approx. 62.81mmol) of the compound from example 80A and 5.4g (25.1mmol) of methyl 5-bromonicotinate are reacted. Yield: 7.0g (36% of theory)

LC-MS (method 6B): r_t＝1.11min；MS(ESIpos)：m/z＝300[M+H]⁺。

Example 82A

5- [ 3-fluoro-4- (trifluoromethyl) phenyl ] piperidine-3-carboxylic acid methyl ester acetate (hydroxyacetate) [ racemic mixture of cis/trans isomers ]

According to general method 7A, 7g (23mmol) of the compound from example 81A are hydrogenated. Yield: 8.5g (99% of theory)

LC-MS (method 2B): r_t0.87 and 0.89min (cis/trans isomer); ms (esipos): 306[ M + H-AcOH ] M/z]⁺。

Example 83A

5- [ 3-fluoro-4- (trifluoromethyl) phenyl ] piperidine-1, 3-dicarboxylic acid 3-methyl-1- (4-nitrophenyl) ester [ racemic cis/trans isomer mixture ]

2.3g (6.3mmol) of the compound from example 82A are initially introduced into 83ml of dichloromethane and cooled to 0 ℃ and 3.5ml (2.55g, 25.2mmol) of triethylamine and 1.27g (6.30mmol) of 4-nitrophenyl chloroformate are added. The reaction mixture was allowed to warm slowly to RT and stirred at RT for 1 h. It was washed with water several times, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC. Yield: 651mg (22% of theory)

LC-MS (method 6B): r_t＝1.26min；MS(ESIpos)：m/z＝471[M+H]⁺。

Example 84A

5- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -1- (thiomorpholin-4-ylcarbonyl) piperidine-3-carboxylic acid methyl ester [ racemic cis/trans isomer mixture ]

To 9ml of 1-methyl-2-pyrrolidone 651mg (1.38mmol) of the compound from example 83A, 0.99g (9.69mmol) of thiomorpholine and 0.84ml (0.63g, 4.84mmol) of N, N-diisopropylethylamine were added and heated at 150 ℃ for 1h in a single-mode microwave oven (Emrys Optizer). For working up, the reaction solution is mixed with water. After addition of ethyl acetate and phase separation, the organic phase is washed with 1N aqueous hydrochloric acid, dried (magnesium sulfate), filtered and concentrated under reduced pressure. This gave 550mg of 80% pure (LC-MS) crude product, which was reacted without further purification steps.

LC-MS (method 6B): r_t1.15min and 1.17min (cis/trans isomers); ms (esipos): 435[ M + H ] M/z]⁺。

Example 85A

5- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -1- (thiomorpholin-4-ylcarbonyl) piperidine-3-carboxylic acid [ racemic cis-isomer ]

According to general method 4A, 0.55g (1.01mmol) of the compound from example 84A are reacted with 1.14g (10.1mmol) of potassium tert-butoxide. This gave 455mg of 78% pure (LC-MS) crude product, which was reacted without further purification steps. Yield: 550mg (73% of theory)

LC-MS (method 10B): r_t＝2.28min；MS(ESIpos)：m/z＝421[M+H]⁺。

Example 86A

5- [ 2-fluoro-4- (trifluoromethyl) phenyl ] nicotinic acid methyl ester

According to general method 1A, 5.0g (20.6mmol) of 1-bromo-2-fluoro-4- (trifluoromethyl) benzene and 13.53g (51.44mmol) of methyl 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) nicotinate are reacted. Yield: 3.6g (58% of theory)

LC-MS (method 6B): r_t＝1.13min；MS(ESIpos)：m/z＝300[M+H]⁺。

Example 87A

5- [ 2-fluoro-4- (trifluoromethyl) phenyl ] piperidine-3-carboxylic acid methyl ester [ racemic cis/trans isomer mixture ]

According to general method 7A, 3.6g (12.0mmol) of the compound from example 86A are hydrogenated. Yield: 3.0g (82% of theory)

LC-MS (method 2B): r_t0.85min and 0.87min (cis/trans isomers); ms (esipos): 306[ M + H ] M/z]⁺。

Example 88A

5- [ 2-fluoro-4- (trifluoromethyl) phenyl ] piperidine-1, 3-dicarboxylic acid 3-methyl-1- (4-nitrophenyl) ester [ racemic cis/trans isomer mixture ]

938mg (3.07mmol) of the compound from example 87A were initially introduced into 40ml of dichloromethane and cooled to 0 ℃ and admixed with 1.28ml (0.93g, 9.22mmol) of triethylamine and 0.62g (3.07mmol) of 4-nitrophenyl chloroformate. The reaction mixture was slowly warmed to RT and stirred at RT for 16 h. It was washed with water several times, dried over sodium sulfate, filtered and concentrated under reduced pressure. This gave 1.21g of a crude product of 85% purity (LC-MS) which was reacted without further purification steps.

LC-MS (method 6B): r_t1.28min and 1.30min (cis/trans isomers); ms (esipos): 471[ M + H ] M/z]⁺。

Example 89A

5- [ 2-fluoro-4- (trifluoromethyl) phenyl ] -1- (thiomorpholin-4-ylcarbonyl) piperidine-3-carboxylic acid methyl ester [ racemic cis/trans isomer mixture ]

To 18ml of DMF are added 1.28g (2.73mmol) of the compound from example 88A, 1.41g (13.6mmol) of thiomorpholine and 1.13g (8.18mmol) of potassium carbonate and heated at 150 ℃ for 40 minutes in a single-mode microwave oven (Emrys Optimizer). For work-up, the reaction solution was concentrated by rotary evaporation and the residue was mixed with water. After addition of ethyl acetate and phase separation, the organic phase is washed with 1N aqueous hydrochloric acid, dried (magnesium sulfate), filtered and concentrated under reduced pressure. This gave 946mg of the crude product of 72% purity (LC-MS), which was reacted without further purification steps.

LC-MS (method 2B): r_t1.32 and 1.36min (cis/trans isomer); ms (esipos): 435[ M + H ] M/z]⁺。

Example 90A

5- [ 2-fluoro-4- (trifluoromethyl) phenyl ] -1- (thiomorpholin-4-ylcarbonyl) piperidine-3-carboxylic acid [ racemic cis-isomer ]

According to general method 4A, 945mg (1.56mmol) of the compound from example 89A are reacted with 1.74g (15.5mmol) of potassium tert-butoxide. This gave 762mg of a crude product of 69% purity (LC-MS) which was reacted without further purification steps.

LC-MS (method 2B): r_t＝1.21min；MS(ESIpos)：m/z＝421[M+H]⁺。

Example 91A

5- [ 3-fluoro-4- (trifluoromethoxy) phenyl ] nicotinic acid methyl ester

According to general method 1A, 8.0g (30.9mmol) 4-bromo-2-fluoro-1- (trifluoromethoxy) benzene and 20.13g (77.22mmol) methyl 5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) nicotinate are reacted. Yield: 8.02g (69% of theory)

LC-MS (method 6B): r_t＝1.14min；MS(ESIpos)：m/z＝316[M+H]⁺。

Example 92A

5- [ 3-fluoro-4- (trifluoromethoxy) phenyl ] piperidine-3-carboxylic acid methyl ester [ racemic cis/trans isomer mixture ]

A solution of 5.73g (18.2mmol) of the compound from example 91A in 116ml of ethanol is mixed with 1.11g (0.27mmol) of platinum oxide and hydrogenated with 14.3ml of concentrated hydrochloric acid solution and overnight at RT in a hydrogen atmosphere at 3.5 bar. The catalyst was then filtered off through a filter layer and washed several times with ethanol. The combined filtrates were concentrated under reduced pressure. Yield: 5.95g (100% of theory)

LC-MS (method 5B): r_t1.53min and 1.56min (cis/trans isomer); ms (esipos): 322[ M + H ] M/z]⁺。

Example 93A

5- [ 3-fluoro-4- (trifluoromethoxy) phenyl ] piperidine-1, 3-dicarboxylic acid 3-methyl-1- (4-nitrophenyl) ester [ racemic cis/trans isomer mixture ]

1.74g (5.42mmol) of the compound from example 92A are initially charged in 80ml of dichloromethane and cooled to 0 ℃ and mixed with 1.5ml (1.09g, 10.8mmol) of triethylamine and 1.09g (5.42mmol) of 4-nitrophenyl chloroformate. The reaction mixture was slowly warmed to RT and stirred at RT for 16 h. It was washed with water several times, dried over sodium sulfate, filtered and concentrated under reduced pressure. Yield: 2.4g (87% of theory)

LC-MS (method 5B): r_t2.74 and 2.77min (cis/trans isomers); ms (esipos): 487[ M + H ] M/z]⁺。

Example 94A

5- [ 3-fluoro-4- (trifluoromethoxy) phenyl ] -1- (thiomorpholin-4-ylcarbonyl) piperidine-3-carboxylic acid methyl ester [ racemic cis/trans isomer mixture ]

To 28ml of 1-methyl-2-pyrrolidone 2.40g (4.93mmol) of the compound from example 93A, 3.56g (34.5mmol) of thiomorpholine and 3.0ml (2.32g, 17.3mmol) of N, N-diisopropylethylamine were added and heated in 2 portions in a monomode microwave apparatus (Emrys Optizer) at 150 ℃ for 1 h. For work-up, the reaction solutions were combined and mixed with water. After addition of ethyl acetate and phase separation, the organic phase was washed with saturated aqueous sodium chloride solution, dried (magnesium sulfate), filtered and concentrated under reduced pressure. Yield: 1.97g (89% of theory)

LC-MS (method 2B): r_t1.35 and 1.38min (cis/trans isomer); ms (esipos): 451[ M + H ] M/z]⁺。

Example 95A

5- [ 3-fluoro-4- (trifluoromethoxy) phenyl ] -1- (thiomorpholin-4-ylcarbonyl) piperidine-3-carboxylic acid [ racemic cis-isomer ]

According to general method 4A, 1.95g (4.329mmol) of the compound from example 94A are reacted with 4.86g (43.3mmol) of potassium tert-butoxide. Yield: 1.66g (83% of theory).

LC-MS (method 6B): r_t＝1.07min；MS(ESIpos)：m/z＝437[M+H]⁺。

Example 96A

5- [ 3-fluoro-4- (trifluoromethoxy) phenyl ] piperidine-1, 3-dicarboxylic acid 1-tert-butyl-3-methyl ester [ racemic cis/trans isomer mixture ]

1.02g (3.17mmol) of methyl 5- [ 3-fluoro-4- (trifluoromethoxy) phenyl ] piperidine-3-carboxylate are dissolved in 43ml of dichloromethane and, while cooling in an ice bath, are mixed with 0.88ml (0.64g, 6.34mmol) of triethylamine. 0.69g (3.17mmol) of di-tert-butyl dicarbonate dissolved in 20ml of dichloromethane are added, and after a reaction time of one hour, the mixture is mixed with 50ml of dichloromethane and washed three times with 100ml of water each time. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. Yield: 1.25g (93% of theory)

LC-MS (method 2B): r_t1.51min and 1.53min (cis/trans isomer); ms (esineg): 406[ M-CH ] M/z₃-H]⁺。

Example 97A

1- (1-tert-Butoxycarbonyl) -5- [ 3-fluoro-4- (trifluoromethoxy) phenyl ] piperidine-3-carboxylic acid [ racemic mixture of cis-isomers ]

3.72g (8.82mmol) of 5- [ 3-fluoro-4- (trifluoromethoxy) phenyl ] piperidine-1, 3-dicarboxylic acid 1-tert-butyl-3-methyl ester are dissolved in 65ml of methanol and combined at RT with 9.90g (88.2mmol) of potassium tert-butoxide. After a reaction time of 19 hours, the mixture was concentrated under reduced pressure, taken up in 50ml of water and adjusted to pH 5 with 1N hydrochloric acid. The aqueous phase is extracted three times with 50ml of ethyl acetate each time. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. Yield: 3.11g (85% of theory)

LC-MS (method 5B): r_t＝2.57min；MS(ESIpos)：m/z＝408[M+H]⁺。

Working examples

General procedure 1:oxadiazole formation

A solution of the appropriate piperidine-3-carboxylic acid in dimethylformamide (10-20ml/mmol) is combined with HATU (1.2 equiv.), N, N-diisopropylethylamine (2.2 equiv.) and the appropriate alkyl N' -hydroxyiminocarbamate (1.1 equiv.) at RT under argon. The reaction mixture was stirred at RT until the formation of the intermediate was complete and then further stirred at 120 ℃ until the desired product was formed from the intermediate. The reaction mixture is then purified by preparative HPLC.

General procedure 2: sulfoxide formation

A solution of the appropriate thioether in dichloromethane (40-50ml/mmol) was mixed with m-chloroperoxybenzoic acid (0.9-1.0 eq., 50%) at room temperature and then stirred for 30 min. For work-up, the reaction solution was diluted with dichloromethane and washed with 1N aqueous sodium hydroxide solution. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The compounds are purified by preparative HPLC if desired.

General procedure 3: sulfone formation

A solution of the appropriate thioether in dichloromethane (40-50ml/mmol) was mixed with m-chloroperoxybenzoic acid (2.5 eq., 50%) at room temperature and then stirred for 30 min. For work-up, the reaction solution was diluted with dichloromethane and washed with 1N aqueous sodium hydroxide solution. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The compounds are purified by preparative HPLC if desired.

General procedure 4:oxadiazole formation

The carboxylic acid being soluble in the dicarboxylic acidAlkane/dimethylformamide (3: 1, 1ml/mmol) and heated to 60 ℃. Adding the mixture dissolved in IIAfter addition of an alkane/dimethylformamide (4: 1, 1.6ml/mmol) in N, N' -carbonyldiimidazole (1.5 eq.) the mixture is stirred at 60 ℃ for 3 h. After cooling to RT, the mixture is dissolved in waterAlkyl N' -hydroxyiminocarbamate (1.5 equiv.) in a ratio of 1: 1 alkane/dimethylformamide and stirred at 40 ℃ overnight. Then removing di under reduced pressureAn alkane. The residue dissolved in dimethylformamide was then stirred at 115 ℃ for 1 h. After cooling, the reaction mixture was diluted with water. After extraction with dichloromethane, the organic phase is dried over sodium sulfate and the crude product is purified by preparative HPLC.

Example 1

(3- {3- [ cyclopropyl (methyl) amino group]-1，2，4-Oxadiazol-5-yl } -5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl) (morpholin-4-yl) methanone [ racemic cis isomer]

To 109mg (0.245mmol) of the compound from example 23ATo a solution of oxadiazole in 2.0ml ethanol was added 523mg (7.35mmol) of cyclopropylmethylamine, and the reaction mixture was then stirred in a microwave at 90 ℃ for 12 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC. Yield: 42.0mg (36% of theory)

LC-MS (method 6B): r_t＝1.19min；MS(ESIpos)：m/z＝480[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.70(d，2H)，7.57(d，2H)，3.96(d，1H)，3.62(d，1H)3.56(t, 4H), 3.30-3.23(m, 1H), 3.20(d, 4H), 3.07-2.96(m, 3H), 2.93(s, 3H), 2.29(d, 1H), 1.97(q, 1H), 0.77-0.69(m, 2H), 0.65-0.57(m, 2H); a hidden proton.

Example 2

{3- [3- (isopropylamino) -1, 2, 4-Diazol-5-yl]-5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl } - (morpholin-4-yl) methanone [ racemic cis-isomer]

To 100mg (0.225mmol) of the compound from example 23ATo a solution of oxadiazole in 1.5ml ethanol 266mg (4.50mmol) isopropylamine were added and the reaction mixture was stirred in a microwave at 80 ℃ for 2 h. An additional 266mg (4.50mmol) of isopropylamine are added and the mixture is stirred in the microwave for a further 2h at 80 ℃. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC. Yield: 69.0mg (66% of theory)

LC-MS (method 2B): r_t＝1.29min；MS(ESIpos)：m/z＝468[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.70(d，2H)，7.56(d，2H)，6.75(d，1H)，3.96(d，1H)，3.63(d，1H)，3.59-3.54(m，4H)，3.50(dd，1H)，3.19(t，5H)，3.05-2.94(m，3H)，2.29(d，1H)，1.96(q，1H)，1.13(d，6H)。

Example 3

{3- [3- (isopropylamino) -1, 2, 4-Diazol-5-yl]-5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl } - (morpholin-4-yl) methanone [ enantiomerically pure cis-isomers]

Enantiomeric separation of 53.0mg of the compound from example 2 according to method 1D gave 15.0mg of example 3 (enantiomer 1) and 17.0mg of example 4 (enantiomer 2).

HPLC (method 1E): r _t＝8.96min，＞99.5％ee；

Example 4

HPLC (method 1E): r_t＝23.24min，＞99.5％ee；

Example 5

Morpholin-4-yl {3- [3- (piperidin-1-yl) -1, 2, 4-Diazol-5-yl]-5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl } methanone [ racemic cis isomer]

To 100mg (0.225mmol) of the compound from example 23ATo a solution of oxadiazole in 1.5ml ethanol 195mg (2.25mmol) piperidine was added and then the reaction mixture was stirred in a microwave at 80 ℃ for 2 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC. Yield: 90.0mg (80% of theory)

LC-MS (method 6B): r_t＝1.23min；MS(ESIpos)：m/z＝494[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.70(d，2H)，7.54(d，2H)，3.98(d，1H)，3.64-3.46(m，5H)，3.42(br s，1H)，3.22-3.12(m，3H)，3.07-2.98(m，3H)，2.33(d，1H)，2.24-2.12(m，1H)，1.61-1.49(m, 6H); five hidden protons.

Example 6

{3- [3- (diethylamino) -1, 2, 4-Diazol-5-yl]-5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl } - (morpholin-4-yl) methanone [ enantiomerically pure cis-isomers]

To 100mg (0.225mmol) of the compound from example 23ATo a solution of oxadiazole in 1.5ml ethanol 163mg (2.25mmol) diethylamine were added and the reaction mixture was stirred in a microwave at 80 ℃ for 2 h. A further 163mg (2.25mmol) of diethylamine are added and the mixture is stirred in a microwave for a further 2h at 80 ℃. After a further addition of 704mg (9.63mmol) diethylamine, the mixture is again stirred in a microwave at 80 ℃ for 2 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC. Enantiomeric separation of the racemate obtained according to method 2D 51.8mg gave 25.0mg of example 6 (enantiomer 1) and 24.0mg of example 7 (enantiomer 2).

HPLC (method 2E): r_t8.92min, > 99.0% ee; (enantiomer 1)

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.70(d, 2H), 7.57(d, 2H), 3.96(d, 1H), 3.62(d, 1H), 3.56(br s, 4H), 3.19(br s, 4H), 3.08-2.96(m, 3H), 2.29(d, 1H), 2.04-1.90(m, 1H), 1.09(t, 6H); five hidden protons.

Example 7

HPLC (method 3E): r_t14.64min, > 99.0% ee; (enantiomer 2)

Example 8

{3- [3- (dimethylamino) -1, 2, 4-Diazol-5-yl]-5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl } - (morpholin-4-yl) methanone [ racemic cis-isomer]

To 158mg (0.355mmol) of the compound from example 23ATo a solution of oxadiazole in 2.5ml ethanol was added 2.50ml (19.7mmol, 40% in water) of dimethylamine solution, and then the reaction mixture was stirred in a microwave at 80 ℃ for 1 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC. Yield: 94.0mg (58% of theory)

LC-MS (method 9B): r_t＝1.10min；MS(ESIpos)：m/z＝454[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.70(d，2H)，7.57(d，2H)，3.95(d，1H)，3.61(br s，1H)，3.56(br s，4H)，3.26(br s，1H)，3.19(br s，4H)，3.08-2.97(m，3H)，2.92(s，6H)，2.28(d，1H)，2.04-1.88(m，1H)。

Example 9

{3- [3- (cyclopropylamino) -1, 2, 4-Diazol-5-yl]-5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl } - (morpholin-4-yl) methanone [ racemic cis-isomer]

To a solution of 150mg (0.337mmol) of the compound from example 23ATo a solution of oxadiazole in 1.5ml ethanol 385mg (6.74mmol) cyclopropylamine were added and the reaction mixture was then stirred in a microwave at 80 ℃ for 2 h. An additional 385mg (6.74mmol) of cyclopropylamine are added and the mixture is stirred in the microwave for a further 2h at 80 ℃. This was followed by stirring in a microwave at 90 ℃ for 1 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC. Yield: 95.3mg (61% of theory)

LC-MS (method 5B): r_t＝2.22min；MS(ESIpos)：m/z＝466[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.70(d，2H)，7.56(d，2H)，7.17(d，1H)，3.95(d，1H)，3.62(d，1H)，3.56(br s，4H)，3.27-3.14(m，5H)，3.07-2.92(m，3H)，2.44(dt，1H)，2.29(d，1H)，1.96(q，1H)，0.68-0.58(m，2H)，0.49-0.40(m，6H)。

Example 10

{3- [3- (cyclopropylamino) -1, 2, 4-Diazol-5-yl]-5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl } - (morpholin-4-yl) methanone [ enantiomerically pure cis-isomers]

Enantiomeric separation of 95.3mg of the compound from example 9 according to method 1D gave 36.0mg of example 10 (enantiomer 1) and 17.0mg of example 11 (enantiomer 2).

HPLC (method 3E): r_t＝8.74min，＞99.0％ee；

Example 11

Enantiomeric separation of 95.3mg of the compound from example 9 according to method 1D gave 36.0mg of example 10 (enantiomer 1) and 43.0mg of example 11 (enantiomer 2).

HPLC (method 3E): r_t＝23.26min，＞99.0％ee；

Example 12

(3-{3-[ (1-methylcyclobutyl) amino]-1，2，4-Oxadiazol-5-yl } -5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl) (morpholin-4-yl) methanone [ racemic cis isomer]

To 100mg (0.225mmol) of the compound from example 23ATo a solution of diazole in 1.5ml of ethanol is added 383mg (4.50mmol) of 1-methylcyclobutylamine, and then the reaction mixture is stirred in a microwave for 2h at 80 ℃ and then for 2h at 90 ℃. An additional 383mg (4.50mmol) of 1-methylcyclobutylamine are added and the mixture is stirred in the microwave for a further 6h at 90 ℃ and then for 6h at 100 ℃. Subsequently, an additional 383mg (4.50mmol) of 1-methylcyclobutylamine were added and the mixture was stirred in the microwave for a further 20h at 100 ℃. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC. Yield: 27.2mg (24% of theory)

LC-MS (method 6B): r_t＝1.23min；MS(ESIpos)：m/z＝494[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.71(d，2H)，7.56(d，2H)，7.04(s，1H)，3.96(d，1H)，3.63(d，1H)，3.56(d，4H)，3.27-3.14(m，5H)，3.08-2.90(m，3H)，2.35-2.22(m，3H)，1.96(q，1H)，1.90-1.81(m，2H)，1.79-1.65(m，2H)，1.39(s，3H)。

Example 13

(3- {3- [ (2-methoxyethyl) amino group]-1，2，4-Oxadiazol-5-yl } -5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl) (morpholin-4-yl) methanone [ racemic cis isomer]

To 100mg (0.225mmol) of the compound from example 23ATo a solution of oxadiazole in 3.0ml ethanol was added 25.6mg (0.337mmol) 2-methoxyethylamine, and the reaction mixture was then stirred at 60 ℃ for 3 h. A further 51.2mg (0.674mmol) of 2-methoxyethylamine are added and the mixture is stirred at 60 ℃ for a further 12 h. This was followed by stirring for a further 24h at 80 ℃ and then 45min at 120 ℃. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC. Yield: 15.3mg (12% of theory)

LC-MS (method 2B): r_t＝1.18min；MS(ESIpos)：m/z＝484[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.70(d，2H)，7.56(d，2H)，6.89(t，1H)，3.95(d，1H)，3.62(d，1H)，3.56(t，4H)，3.47-3.40(m，2H)，3.26-3.16(m，10H)，3.06-2.93(m，3H)，2.28(d，1H)，1.95(m，1H)。

Example 14

Morpholin-4-yl {3- [3- (oxetan-3-ylamino) -1, 2, 4-Diazol-5-yl]-5- [4- (trifluoromethyl) phenyl]-piperidin-1-yl } methanone [ racemic cis isomer]

To 100mg (0.225mmol) of the compound from example 23ATo a solution of diazole in 1.5ml of ethanol is added 335mg (4.50mmol) of oxetan-3-amine and the reaction mixture is then stirred for 3 days at 80 ℃. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC. Yield: 59.7mg (55% of theory)

LC-MS (method 9B): r _t＝0.98min；MS(ESIpos)：m/z＝482[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.74-7.66(m，3H)，7.56(d，2H)，4.73(t，2H)，4.60-4.50(m，1H)，4.51-4.45(m，2H)，3.95(d，1H)，3.62(d，1H)，3.59-3.53(m，4H)，3.29-3.16(m，5H)，3.06-2.93(m，3H)，2.29(d，1H)，1.96(q，1H)。

Example 15

(3- {3- [ (3S) -3-Hydroxypyrrolidin-1-yl)]-1，2，4-Oxadiazol-5-yl } -5- [4- (trifluoromethyl) phenyl]-piperidin-1-yl) (morpholin-4-yl) methanone [ racemic cis isomer]

To a solution of 150mg (0.337mmol) of the compound from example 23ATo a solution of oxadiazole in 2.25ml ethanol was added 588mg (6.74mmol) (3S) -pyrrolidin-3-ol, and the reaction mixture was thenStirring in a microwave at 80 ℃ for 2 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC. Yield: 84.9mg (51% of theory)

LC-MS (method 9B): r_t＝0.97min；MS(ESIpos)：m/z＝496[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.70(d，2H)，7.58(d，2H)，4.98(d，1H)，4.35(br s，1H)，3.95(d，1H)，3.62(d，1H)，3.56(br s，4H)，3.44-3.35(m，3H)，3.29-3.14(m，6H)，3.09-2.96(m，3H)，2.28(d，1H)，2.04-1.91(m，2H)，1.90-1.79(m，1H)。

Example 16

(3- {3- [ Ethyl (2-hydroxyethyl) amino group]-1，2，4-Oxadiazol-5-yl } -5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl) (morpholin-4-yl) methanone [ racemic cis isomer]

To a solution of 150mg (0.337mmol) of the compound from example 23ATo a solution of oxadiazole in 2.25ml ethanol was added 601mg (6.74mmol)2- (ethylamino) ethanol, and the reaction mixture was then stirred in a microwave at 80 ℃ for 2 h. A further 601mg (6.74mmol) of 2- (ethylamino) ethanol are added and the mixture is stirred in the microwave at 100 ℃ for a further 7 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC. Yield: 28.3mg (17% of theory)

LC-MS (method 9B): r_t＝1.03min；MS(ESIpos)：m/z＝498[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.70(d，2H)，7.57(d，2H)，3.95(d，1H)，3.62(d，1H)，3.59-3.48(m，6H)，3.28-3.16(m，5H)，3.07-2.95(m，3H)，2.28(d，1H)，1.97(q，1H)，1.09(t，3H)。

Example 17

(3- {3- [ (2-hydroxyethyl) (methyl) amino group ]-1，2，4-Oxadiazol-5-yl } -5- [4- (trifluoromethyl) phenyl]-piperidin-1-yl) (morpholin-4-yl) methanone [ racemic cis isomer]

To a solution of 150mg (0.337mmol) of the compound from example 23ATo a solution of oxadiazole in 2.25ml ethanol was added 507mg (6.74mmol)2- (methylamino) ethanol, and then the reaction mixture was stirred in a microwave at 80 ℃ for 2 h. A further 507mg (6.74mmol) of 2- (methylamino) ethanol are added and the mixture is stirred in the microwave for a further 2h at 80 ℃ and then for 30min at 100 ℃. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC. Yield: 53.7mg (33% of theory)

LC-MS (method 2B): r_t＝1.12min；MS(ESIpos)：m/z＝484[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.70(d，2H)，7.57(d，2H)，4.70(t，1H)，3.95(d，1H)，3.62(d，1H)，3.59-3.51(m，6H)，3.37(t，2H)，3.28-3.15(m，5H)，3.07-2.98(m，3H)，2.96(s，3H)，2.31-2.26(m，1H)，1.97(q，1H)。

Example 18

(3- {3- [ (2-hydroxyethyl) amino group]-1，2，4-Oxadiazol-5-yl } -5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl) (morpholin-4-yl) methanone [ racemic cis isomer]

To a solution of 150mg (0.337mmol) of the compound from example 23ATo a solution of oxadiazole in 2.25ml ethanol was added 412mg (6.74mmol) 2-aminoethanol, and the reaction mixture was then stirred in a microwave at 80 ℃ for 2 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC. Yield: 82.2mg (52% of theory)

LC-MS (method 2B): r_t＝1.06min；MS(ESIpos)：m/z＝470[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.70(d，2H)，7.56(d，2H)，6.76(t，1H)，4.65(t，1H)，3.95(d，1H)，3.62(d，1H)，3.59-3.53(m，4H)，3.49(q，2H)，3.27-3.16(m，5H)，3.12(q，2H)，3.05-2.95(m，3H)，2.28(d，1H)，1.96(q，1H)。

Example 19

(3- {3- [ (2-hydroxyethyl) amino group]-1，2，4-Oxadiazol-5-yl } -5- [4- (tris)Fluoromethyl) phenyl ]Piperidin-1-yl) (morpholin-4-yl) methanone [ enantiomerically pure cis-isomer]

Enantiomeric separation of 82.2mg of the compound from example 18 according to method 3D gave 27.0mg of example 19 (enantiomer 1) and 38.0mg of example 20 (enantiomer 2).

HPLC (method 4E): r_t＝9.34min，＞99.5％ee；

LC-MS (method 9B): r_t＝0.92min；MS(ESIpos)：m/z＝470[M+H]⁺；

Example 20

(3- {3- [ (2-hydroxyethyl) amino group]-1，2，4-Oxadiazol-5-yl } -5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl) (morpholin-4-yl) methanone [ enantiomerically pure cis-isomer]

Enantiomeric separation of 82.2mg of the compound from example 18 according to method 3D gave 36.0mg of example 19 (enantiomer 1) and 43.0mg of example 20 (enantiomer 2).

HPLC (method 4E): r_t＝26.05min，＞99.5％ee；

LC-MS (method 9B): r_t＝0.92min；MS(ESIpos)：m/z＝470[M+H]⁺；

Example 21

{3- [3- (diethylamino) -1, 2, 4-Diazol-5-yl]-5- [4- (4-ethylphenyl) piperidin-1-yl } (4-hydroxypiperidin-1-yl) methanone [ racemic cis isomer]

To 45.0mg (0.098mmol) of the compound from example 25ATo a solution of oxadiazole in 0.61ml ethanol was added 143mg (1.96mmol) diethylamine, and then the reaction mixture was stirred in a microwave at 80 ℃ for 5 h. An additional 143mg (1.96mmol) of diethylamine are added and the mixture is stirred in a microwave for a further 2h at 80 ℃. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC. Yield: 35.6mg (80% of theory)

HPLC (method 9B): r_t＝1.17min；MS(ESIpos)：m/z＝456[M+H]⁺。

Example 22

[3- (4-Ethylphenyl) -5- {3- [ (3R) -3-hydroxypyrrolidin-1-yl group]-1，2，4-Oxadiazol-5-yl } piperidin-1-yl (4-hydroxypiperidin-1-yl) methanone [ racemic cis-isomer]

To 80.0mg (0.191mmol) of from example 25ATo a solution of oxadiazole in 1.20ml ethanol was added 333mg (3.82mmol) (3R) -pyrrolidin-3-ol and the reaction mixture was then stirred in a microwave at 80 ℃ for 2 h. The solvent was removed under reduced pressure, dichloromethane was added and the mixture was washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 64.8mg (70% of theory)

HPLC (method 6B): r_t＝0.93min；MS(ESIpos)：m/z＝470[M+H]⁺。

Example 23

{3- [3- (azetidin-1-yl) -1, 2, 4-Diazol-5-yl]-5- (4-ethylphenyl) piperidin-1-yl } (4-hydroxypiperidin-1-yl) methanone [ racemic cis isomer]

To 80.0mg (0.174mmol) of the compound from example 25ATo a solution of oxadiazole in 1.10ml ethanol was added 198mg (3.48mmol) of azetidine and then the reaction mixture was stirred in a microwave at 80 ℃ for 2 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC. Yield: 46.9mg (61% of theory)

HPLC (method 9B): r_t＝1.04min；MS(ESIpos)：m/z＝440[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.21(d，2H)，7.16(d，2H)，4.66(d，1H)，3.95(dd 4H)，3.88(d，1H)，3.66-3.57(m，1H)，3.55-3.42(m，3H)，3.23(tt，1H)，3.06-2.76(m，5H)，2.57(q，2H)，2.40-2.31(m，2H)，2.22(d，1H)，1.90(q，1H)，1.75-1.65(m，1H)，1.32-1.22(m，2H)，1.16(t，3H)。

Example 24

{3- [3- (2-methoxyethoxy) -1, 2, 4- Diazol-5-yl]-5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl } - (morpholin-4-yl) methanone [ racemic cis-isomer]

684mg (8.99mmol) of ethylene glycol monomethyl ether in 8.00ml of 1, 4-bis at RTAdding into solution in alkaneMolecular sieves and 0.90ml (0.90 mmol; 1M solution in n-hexane) of phosphazene P4 base. Subsequently, 200mg (0.450mmol) in 2.0ml of 1, 4-

IIFrom example 23A in an alkaneDiazole and the reaction mixture stirred at RT for 2 h. The reaction mixture was mixed with water, filtered and extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by preparative HPLC. Yield: 89.8mg (41% of theory).

LC-MS (method 5B): r_t＝2.27min；MS(ESIpos)：m/z＝485[M+H]⁺。

Example 25

{3- [3- (2-methoxyethoxy) -1, 2, 4-Diazol-5-yl]-5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl } - (morpholin-4-yl) methanone [ enantiomerically pure cis-isomers]

Enantiomeric separation of 89.8mg of the compound from example 24 according to method 3D gave 36.0mg of example 25 (enantiomer 1) and 34.0mg of example 26 (enantiomer 2).

HPLC (method 4E): r_t＝9.08min，＞99.5％ee；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.71(d, 2H), 7.57(d, 2H), 4.37(dd, 2H), 3.98(d, 1H), 3.71-3.60(m, 3H), 3.56(t, 4H), 3.20(d, 4H), 3.10-2.94(m, 3H), 2.31(d, 1H), 1.99(q, 1H); four hidden protons.

Example 26

HPLC (method 4E): r_t＝27.36min，＞99.5％ee；

Example 27

Morpholin-4-yl {3- [3- (oxetan-3-yloxy) -1, 2, 4-Diazol-5-yl]-5- [4- (trifluoromethyl) phenyl]-piperidin-1-yl } methanone [ racemic cis isomer]

At RT, 83.3mg (1.12mmol) of 3-hydroxyoxetane in 4.00ml of 1, 4-bisAdding into solution in alkaneMolecular sieves and 0.23ml (0.45 mmol; 2M solution in THF) of phosphazene P4 base. Subsequently, 100mg (0.225mmol) of 1, 4-bis (hydroxymethyl) phosphonium chloride in 2.0ml are addedFrom example 23A in an alkaneDiazole and the reaction mixture stirred at RT for 2 h. The reaction mixture was filtered, diluted with dichloromethane and washed with 1N aqueous hydrogen chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by preparative HPLC. Yield: 18.6mg (17% of theory)

LC-MS (method 2B): r_t＝1.21min；MS(ESIpos)：m/z＝483[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.70(d，2H)，7.57(d，2H)，5.53-5.43(m，1H)，4.86(t，2H)，4.61(dd，2H)，3.98(d，1H)，3.62(d，1H)，3.56(t，4H)，3.41-3.32(m，1H)，3.20(d，4H)，3.09-2.96(m，3H)，2.31(d，1H)，2.06-1.91(m，1H)。

Example 28

Morpholin-4-yl {3- [3- (oxetan-3-yloxy) -1,2，4-diazol-5-yl]-5- [4- (trifluoromethyl) phenyl]-piperidin-1-yl } methanone [ enantiomerically pure cis isomer]

Enantiomeric separation of 54.7mg of the compound from example 27 according to method 4D gave 23.0mg of example 28 (enantiomer 1) and 20.0mg of example 29 (enantiomer 2).

HPLC (method 5E): r_t＝14.49min，＞99.0％ee；

Example 29

Morpholin-4-yl {3- [3- (oxetan-3-yloxy) -1, 2, 4-Diazol-5-yl]-5- [4- (trifluoromethyl) phenyl]-piperidin-1-yl } methanone [ enantiomerically pure cis isomer]

HPLC (method 5E): r_t＝8.81min，＞99.0％ee；

Example 30

{3- (3-ethoxy-1, 2, 4-Diazol-5-yl]-5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl } - (morpholin-4-yl) methanone [ racemic cis-isomer]

To a solution of 150mg (0.337mmol) of the compound from example 23ATo a solution of oxadiazole in 6.25ml ethanol was added 229mg (3.37mmol) sodium ethoxide and then the reaction mixture was stirred at RT for 3 days and at 40 ℃ for 2 days. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC. Yield: 16.8mg (11% of theory)

LC-MS (method 6B): r_t＝1.16min；MS(ESIpos)：m/z＝455[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.71(d，2H)，7.57(d，2H)，4.30(q，2H)，3.97(d，1H)，3.62(d，1H)，3.56(d，4H)，3.20(d，4H)，3.09-2.96(m，3H)，2.31(d，1H)，1.99(q，1H)，1.35(t, 3H); a hidden proton.

Example 31

{3- (3-methoxy-1, 2, 4-Diazol-5-yl]-5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl } - (morpholin-4-yl) methanone [ racemic cis-isomer]

To 100mg (0.225mmol) of the compound from example 23AOxadiazole to a solution of 8.0ml methanol 60.79mg (1.124mmol) of sodium methoxide were added and the reaction mixture was then stirred at reflux for 18 h. The reaction mixture was mixed with water and extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by preparative HPLC. Yield: 32.0mg (31% of theory)

LC-MS (method 9B): r_t＝1.08min；MS(ESIpos)：m/z＝441[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.70(d，2H)，7.57(d，2H)，3.97(s，4H)，3.62(d，1H)，3.56(t，4H)，3.39-3.33(m，1H)，3.20(d，4H)，3.09-2.97(m，3H)，2.31(d，1H)，1.99(q，1H)。

Example 32

Morpholin-4-yl {3- [3- (2, 2, 2-trifluoroethoxy) -1, 2, 4-Diazol-5-yl]-5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl } methanone [ racemic cis isomer]

To a solution of 112mg (1.12mmol) of 2, 2, 2-trifluoroethanol in 4.00ml of 1, 4-bis-ethanol at RTAdding into solution in alkaneMolecular sieves and 0.23ml (0.45 mmol; 2M solution in THF) of phosphazene P4 base. Subsequently, 100mg (0.225mmol) of 1, 4-bis (hydroxymethyl) phosphonium chloride in 2.0ml are addedFrom example 23A in an alkaneDiazole and the reaction mixture stirred at RT for 2 h. The reaction mixture was filtered, diluted with dichloromethane and washed with 1N aqueous hydrogen chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by preparative HPLC. Yield: 12.4mg (11% of theory)

LC-MS (method 9B): r_t＝1.19min；MS(ESIpos)：m/z＝509[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.71(d，2H)，7.57(d，2H)，5.06(q，2H)，4.00(d，1H)，3.62(d，1H)，3.56(t，4H)，3.46-3.35(m，1H)，3.20(d，4H)，3.11-2.97(m，3H)，2.33(d，1H)，2.01(q，1H)。

Example 33

{3- (3-Isopropoxy-1, 2, 4-)Diazol-5-yl]-5- [4- (trifluoromethoxy) phenyl]Piperidin-1-yl } - (thiomorpholin-4-yl) methanone [ racemic cis-isomer]

To a solution of 500mg (1.20mmol) of the carboxylic acid from example 9A in 15.0ml DMF at RT were added 545mg (1.43mmol) HATU and 0.46ml (2.63mmol) N, N' -diisopropylethylamine and the mixture was stirred for 30 min. Subsequently, the mixture was mixed with 565mg (3.56 mmol; 75% purity) of isopropyl N' -hydroxyiminocarbamate [ G.Zinner, G.Nebel, Arch.Pharm.1970, 303, 385-390] and then stirred at RT for 2h and at 120 ℃ for 2 h. The reaction solution was concentrated under reduced pressure and purified directly by preparative HPLC. Yield: 344mg (58% of theory)

LC-MS (method 2B): r_t＝1.48min；MS(ESIpos)：m/z＝501[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.46(d，2H)7.33(d，2H)4.83(sept，1H)3.93(d，1H)3.55(d，1H)3.45(br s，4H)3.32-3.25(m，1H)3.06-2.88(m，3H)2.59(br s，4H)2.29(d，1H)2.02-1.86(m，1H)1.35(d，6H)。

Example 34

[3- (4-ethylphenyl) -5- (3-isopropoxy-1, 2, 4-)Oxadiazol-5-yl) piperidin-1-yl](4-hydroxypiperidin-1-yl) methanone [ racemic cis isomer]

80.0mg (0.222mmol) of the carboxylic acid from example 21A in 0.89ml of DMF and 1.78ml of 1, 4-bisTo the solution in the alkane was added 108mg (0.666mmol) of 1, 1' -carbonyldiimidazole and the mixture was stirred for 3 h. The mixture is then admixed with 52.4mg (0.333 mmol; 75% purity) of isopropyl N' -hydroxyiminocarbamate [ G.Zinner, G.Nebel, Arch.Pharm.1970, 303, 385-390- ]Mix and then stir at RT for 2h and at 120 ℃ for 2 h. The reaction solution was concentrated under reduced pressure and purified directly by preparative HPLC. Yield: 22.6mg (22% of theory)

LC-MS (method 2B): r_t＝1.30min；MS(ESIpos)：m/z＝443[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.21(d，2H)，7.15(d，2H)，4.82(sept，1H)，4.67(d，1H)，3.92(d，1H)，3.66-3.41(m，4H)，3.01-2.77(m，4H)，2.62-2.54(m，4H)，2.26(d，1H)，1.92(q，1H)，1.71(d，2H)，1.35(d，6H)，1.32-1.25(m，2H)，1.16(t，3H)。

Example 35

[3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- (4-ethylphenyl) piperidin-1-yl](3-hydroxyazetidin-1-yl) methanones [ racemic cis-isomer]

To a solution of 80.0mg (0.241mmol) of the carboxylic acid from example 14A in 0.97ml DMF at 60 ℃ and 1.93ml 1, 4-bisTo the solution of the alkane was added 99.8mg (0.615mmol) of 1, 1' -carbonyldiimidazole, and the mixture was stirred for 3 h. Subsequently, the mixture was mixed with 50.1mg (0.481mmol) of N' -hydroxyiminourethane [ G.Zinner, G.Nebel, Arch.pharm.1970, 303, 385-390-]Mix and then stir at RT for 2h and then at 120 ℃ for 2.5 h. The reaction solution was concentrated under reduced pressure and purified directly by preparative HPLC. Yield: 33.1mg (33% of theory)

HPLC (method 6B): r_t＝1.07min；MS(ESIpos)：m/z＝401[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.22(d，2H)，7.16(d，2H)，5.56(d，1H)，4.43-4.35(m，1H)，4.30(q，2H)；4.17-4.04(m，3H)，3.75-3.65(m，3H)，3.25-3.15(m，1H)，3.01-2.72(m，3H)，1.35(t，3H)，1.17(t，3H)。

Example 36

3- (3-ethoxy-1, 2, 4-)Oxadiazol-5-yl) -5- [ 3-fluoro-4- (trifluoromethoxy) phenyl]Piperidine-1-carboxylic acid tert-butyl ester [ racemic cis-isomer mixture]

442mg (1.09mmol) of 1- (tert-butoxycarbonyl) -5- [ 3-fluoro-4- (trifluoromethoxy) phenyl ]-piperidine-3-carboxylic acid in 11.8ml diAlkane and 5.9ml DMF were heated to 60 ℃ and mixed with 264mg (1.63mmol) of 1, 1' -carbonyldiimidazole. The reaction mixture is stirred at this temperature for three hours and then admixed with 170mg (1.63mmol) of N' -hydroxyiminourethane [ G.Zinner, G.Nebel, Arch.pharm.1970, 303, 385-390]And (4) mixing. The mixture was stirred at 50 ℃ for one hour and thereafter at 115 ℃ for nine hours. The reaction mixture was concentrated under reduced pressure, taken up in ethyl acetate and washed three times with water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 387mg (75% of theory, purity 61%)

LC-MS (method 6B): r_t＝1.41min；MS(ESIpos)：m/z＝476[M+H]⁺。

Example 37

{3- (3-Isopropoxy-1, 2, 4-)Diazol-5-yl]-5- [4- (trifluoromethoxy) phenyl]Piperidin-1-yl } - (1-oxothiomorpholin-4-yl) methanone [ racemic cis-isomer]

The compound from example 33 was reacted with 117mg (0.340mmol) of m-chloroperoxybenzoic acid according to general method 2170mg (0.340 mmol). Yield: 44.8mg (26% of theory).

LC-MS (method 5B): r_t＝2.32min；MS(ESIpos)：m/z＝517[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.47(d，2H)，7.33(d，2H)，4.83(dt，1H)，3.97(d，1H)，3.69-3.57(m，3H)，3.56-3.46(m，2H)，3.38-3.33(m，1H)，3.08-2.85(m，5H)，2.75-2.68(m，2H)，2.30(d，1H)，2.03-1.89(m，1H)，1.35(d，6H)。

Example 38

{3- (3-Isopropoxy-1, 2, 4-)Oxadiazol-5-yl) -5- [4- (trifluoromethoxy) phenyl]Piperidin-1-yl } - (1-oxothiomorpholin-4-yl) methanone [ enantiomerically pure cis-isomer ]

The enantiomeric separation of 44.8mg of the racemate from example 37 according to method 4D gave 11.4mg of the title compound from example 38 (enantiomer 1) and 14.4mg of the title compound from example 39 (enantiomer 2).

HPLC (method 6E): r_t＝6.49min，＞99.0％ee；

Example 39

{3- (3-Isopropoxy-1, 2, 4-)Oxadiazol-5-yl) -5- [4- (trifluoromethoxy) phenyl]Piperidin-1-yl } - (1-oxothiomorpholin-4-yl) methanone [ enantiomerically pure cis-isomer]

HPLC (method 6E): r_t＝17.6min，＞99.0％ee；

Example 40

(1, 1-dioxothiomorpholin-4-yl) {3- (3-isopropoxy-1, 2, 4-)Oxadiazol-5-yl) -5- [4- (trifluoromethoxy) phenyl]Piperidin-1-yl ketone [ enantiomerically pure cis-isomers]

3170mg (0.340mmol) of the compound from example 33 are reacted with 293mg (0.340mmol) of m-chloroperbenzoic acid according to the general method. Enantiomeric separation of the racemate according to method 4D gave 50.6mg of the title compound from example 40 (enantiomer 1) and 49.2mg of the title compound from example 41 (enantiomer 2).

HPLC (method 6)E)：R_t＝11.4min，＞99.0％ee；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.47(d, 2H), 7.33(d, 2H), 4.83(dt, 1H), 4.00(d, 1H), 3.73-3.54(m, 5H), 3.17(br.s., 4H), 3.10-2.92(m, 3H), 2.30(d, 1H), 2.02-1.89(m, 1H), 1.35(d, 6H), a hidden proton.

EXAMPLE 41

HPLC (method 6E): r_t＝27.4min，＞99.0％ee；

Example 42

{3- [3- (2-methoxyethoxy) -1, 2, 4-Diazol-5-yl]-5- [4- (trifluoromethoxy) phenyl]Piperidin-1-yl } - (thiomorpholin-4-yl) methanone [ racemic cis-isomer ]

According to general method 1, 300mg (0.717mmol) of the compound from example 9A and 480mg (2.15mmol, purity 60%) of 2-methoxyethyl N' -hydroxyiminocarbamate from example 44A are reacted. Yield: 65mg (17% of theory).

LC-MS (method 2B): r_t＝1.36min；MS(ESIpos)：m/z＝517[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.46(d, 2H), 7.33(d, 2H), 4.40-4.33(m, 2H), 3.93(d, 1H), 3.69-3.63(m, 2H), 3.55(d, 1H), 3.45(br.s., 4H), 3.35(br.s., 1H), 3.06-2.90(m, 3H), 2.59(br.s., 4H), 2.29(d, 1H), 1.95(q, 1H), three hidden protons.

Example 43

{3- [3- (2-methoxyethoxy) -1, 2, 4-Diazol-5-yl]-5- [4- (trifluoromethoxy) phenyl]Piperidin-1-yl } - (1-oxothiomorpholin-4-yl) methanone [ enantiomerically pure cis-isomer]

260.0mg (0.116mmol) of the compound from example 42 are reacted with 36.1mg (0.105mmol) of m-chloroperbenzoic acid according to general method. Enantiomeric separation of the racemate according to method 2D gave 10.0mg of the title compound (enantiomer 1) from example 43.

HPLC (method 6E): r_t＝9.19min，＞99.0％ee；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.47(d, 2H), 7.33(d, 2H), 4.41-4.31(m, 2H), 3.97(d, 1H), 3.71-3.47(m, 7H), 3.11-2.83(m, 5H), 2.77-2.64(m, 2H), 2.30(d, 1H), 2.03-1.87(m, 1H), four hidden protons.

Example 44

{3- [ 3-ethoxy-1, 2, 4-Diazol-5-yl]-5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl } - (thiomorpholin-4-yl) methanone [ racemic cis-isomer]

According to general method 1, 300mg (0.745mmol) of the compound from example 50A and 123mg (1.12mmol) of N' -hydroxyiminourethane [ G.Zinner, G.Nebel, Arch.pharm. (Weinheim)1970, 303, 385-390] are reacted. Yield: 149mg (43% of theory).

LC-MS (method 2B): r_t＝1.40min；MS(ESIpos)：m/z＝471[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.70(d，2H)，7.57(d，2H)，4.30(q，2H)，3.93(d，1H)，3.57(d，1H)，3.45(br.s.，4H)，3.38-3.32(m，1H)，3.08-2.93(m，3H)，2.59(br.s.，4H)，2.31(d，1H)，1.99(q，1H)，1.35(t，3H)。

Example 45

{3- [ 3-ethoxy-1, 2, 4-Diazol-5-yl]-5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl } - (1-oxothiomorpholin-4-yl) methanone [ rac-cis isomer]

265.0mg (0.138mmol) of the compound from example 44 are reacted with 42.9mg (0.124mmol) of m-chloroperbenzoic acid according to general method. Yield: 50.8mg (72% of theory)

LC-MS (method 6B): r_t＝1.02min；MS(ESIpos)：m/z＝487[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.70(d，2H)，7.58(d，2H)，4.30(q，2H)，3.97(d，1H)，3.68-3.48(m，5H)，3.40-3.34(m，1H)，3.10-2.98(m，3H)，2.96-2.84(m，2H)，2.76-2.67(m，2H)，2.31(d，1H)，2.05-1.94(m，1H)，1.35(t，3H)。

Example 46

{3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl } (1-oxothiomorpholin-4-yl) methanone [ enantiomerically pure cis-isomer]

The enantiomeric separation of 42.0mg of the racemate from example 45 according to method 4D gave 18.1mg of the title compound from example 46 (enantiomer 1) and, after purification again by preparative HPLC, 15.6mg of the title compound from example 47 (enantiomer 2).

LC-MS (method 6B): r_t＝1.02min；MS(ESIpos)：m/z＝487[M+H]⁺；

HPLC (method 6E): r_t＝6.88min，＞99.0％ee；

Example 47

Enantiomeric separation of 42.0mg of the racemate from example 45 according to method 4D gave 18.1mg of the title compound from example 46 (enantiomer 1) and, after further purification by preparative HPLC, 15.6mg of the title compound from example 47 (enantiomer 2).

LC-MS (method 6B): r_t＝1.02min；MS(ESIpos)：m/z＝487[M+H]⁺；

HPLC (method 6E): r_t＝23.65min，＞99.0％ee；

Example 48

(1, 1-dioxothiomorpholin-4-yl) {3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl } methanone [ racemic cis isomer]

365.0mg (0.138mmol) of the compound from example 44 are reacted with 119mg (0.345mmol) of m-chloroperoxybenzoic acid according to general method. Yield: 62.3mg (89% of theory)

LC-MS (method 6B): r_t＝1.09min；MS(ESIpos)：m/z＝503[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.71(d，2H)，7.57(d，2H)，4.31(q，2H)，4.01(d，1H)，3.71-3.56(m，5H)，3.39-3.33(m，1H)，3.18(br.s.，4H)，3.12-2.98(m，3H)，2.31(d，1H)，2.05-1.93(m，1H)，1.35(t，3H)。

Example 49

(1, 1-dioxothiomorpholin-4-yl) {3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [4- (trifluoromethyl) phenyl]Piperidin-1-yl ketone [ enantiomerically pure cis-isomers]

Enantiomeric separation of 52.0mg of the racemate from example 48 according to method 4D gave 22.8mg of the title compound from example 49 (enantiomer 1) and 26.6mg of the title compound from example 50 (enantiomer 2).

HPLC (method 6E): r_t＝14.97min，＞99.0％ee；

Example 50

Enantiomeric separation of 52.0mg of the racemate from example 48 according to method 4D gave 22.8mg of the title compound from example 49 (enantiomer 1) and 26.6mg of the title compound from example 50 (enantiomer 1).

HPLC (method 6E): r_t＝56.68min，＞99.0％ee；

Example 51

{3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [4- (trifluoromethoxy) phenyl]Piperidin-1-yl } - (thiomorpholin-4-yl) methanone [ racemic cis-isomer]

According to general method 1, 300mg (0.717mmol) of the compound from example 9A and 235mg (2.15mmol) of N' -hydroxyiminourethane [ G.Zinner, G.Nebel, Arch.pharm. (Weinheim)1970, 303, 385- & 390] are reacted. Yield: 139mg (39% of theory)

LC-MS (method 2B): r_t＝1.42min；MS(ESIpos)：m/z＝487[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.46(d，2H)，7.33(d，2H)，4.30(q，2H)，3.92(d，1H)，3.55(d，1H)，3.48-3.41(m，4H)，3.35(br.s.，1H)，3.05-2.89(m，3H)，2.63-2.57(m，4H)，2.29(d，1H)，1.94(q，1H)，1.35(t，3H)。

Example 52

{3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [4- (trifluoromethoxy) phenyl]Piperidin-1-yl } (1-oxothio-morpholin-4-yl) methanone [ enantiomerically pure cis-isomer]

According to general method 2, 37.1mg (0.123mmol) of the compound from example 51 are reacted with 38.3mg (0.111mmol) of m-chloroperoxybenzoic acid. Enantiomeric separation according to method 4D 37.7mg of the racemate gave 16.1mg of the title compound from example 52 (enantiomer 1) and 16.5mg of the title compound from example 53 (enantiomer 2).

HPLC (method 6E): r_t＝6.44min，＞99.0％ee；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.47(d，2H)，7.33(d，2H)，4.30(q，2H)，3.96(d，1H)，3.68-3.48(m，5H)，3.36(br.s.，1H)，3.07-2.85(m，5H)，2.75-2.68(m，2H)，2.30(d，1H)，1.95(q，1H)，1.35(t，3H)。

Example 53

{3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [4- (tris)Fluoromethoxy) phenyl]Piperidin-1-yl } (1-oxothio-morpholin-4-yl) methanone [ enantiomerically pure cis-isomer]

HPLC (method 6E): r_t＝16.56min，＞99.0％ee；

Example 54

(1, 1-dioxothiomorpholin-4-yl) {3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [4- (trifluoromethoxy) phenyl]Piperidin-1-yl } methanone [ racemic cis isomer]

According to general method 3, 65.0mg (0.134mmol) of the compound from example 51 are reacted with 115mg (0.334mmol) of m-chloroperoxybenzoic acid. Yield: 58.0mg (83% of theory)

LC-MS (method 6B): r_t＝1.13min；MS(ESIpos)：m/z＝519[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.47(d，2H)，7.33(d，2H)，4.30(q，2H)，4.00(d，1H)，3.69-3.57(m，5H)，3.38-3.32(m，1H)，3.18(d，4H)，3.09-2.95(m，3H)，2.29(d，1H)，1.95(q，1H)，135(t，3H)。

Example 55

[3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- (4-ethylphenyl) piperidin-1-yl](Thiomorphin-4-yl) methanone [ racemic cis-isomer]

According to general method 1, 300mg (0.828mmol) of the compound from example 47A and 272mg (2.48mmol) of N' -hydroxyiminourethane [ G.Zinner, G.Nebel, Arch.pharm. (Weinheim)1970, 303, 385- & 390] are reacted. Yield: 130mg (36% of theory)

LC-MS (method 5B): r_t＝2.64min；MS(ESIpos)：m/z＝431[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.22(d, 2H), 7.16(d, 2H), 4.30(q, 2H), 3.93(d, 1H), 3.53(d, 1H), 3.44(br.s., 4H), 3.03-2.79(m, 3H), 2.55-2.62(m, 6H), 2.26(d, 1H), 1.92(q, 1H), 1.35(t, 3H), 1.16(t, 3H), a hidden proton.

Example 56

[3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- (4-ethylphenyl) piperidin-1-yl](1-oxothiomorpholin-4-yl) methanone [ enantiomerically pure cis-isomer]

According to general method 2, 55.0mg (0.128mmol) of the compound from example 55 are reacted with 39.7mg (0.115mmol) of m-chloroperoxybenzoic acid. Enantiomeric separation according to method 4D 50.7mg of the racemate gave 22.1mg of the title compound from example 56 (enantiomer 1) and 21.4mg of the title compound from example 57 (enantiomer 2).

HPLC (method 6E): r_t＝6.07min，＞99.0％ee；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.22(d，2H)，7.16(d，2H)，4.30(q，2H)，3.97(d，1H)，3.68-3.46(m，5H)，3.37-3.31(m，1H)，3.07-2.81(m，5H)，2.76-2.66(m，2H)，2.62-2.55(m，2H)，2.27(d，1H)，1.93(q，1H)，1.35(t，3H)，1.16(t，3H)。

Example 57

HPLC (method 6E): r_t＝8.96min，＞99.0％ee；

Example 58

(1, 1-dioxothiomorpholin-4-yl) [3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- (4-ethylphenyl) piperidin-1-yl]Methanone [ racemic cis isomer]

According to general method 3, 55.0mg (0.128mmol) of the compound from example 55 are reacted with 110mg (0.319mmol) of m-chloroperoxybenzoic acid. Yield: 53.8mg (90% of theory)

LC-MS (method 6B): r_t＝1.13min；MS(ESIpos)：m/z＝463[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.22(d，2H) 7.17(d, 2H), 4.30(q, 2H), 4.00(d, 1H), 3.66-3.56(m, 5H), 3.17(br.s., 4H), 3.09-2.81(m, 3H), 2.61-2.55(m, 2H), 2.26(d, 1H), 1.93(q, 1H), 1.35(t, 3H), 1.16(t, 3H), a hidden proton.

Example 59

{3- (4-ethylphenyl) -5- [3- (2-methoxyethoxy) -1, 2, 4-Diazol-5-yl]Piperidin-1-yl } (thiomorpholin-4-yl) methanone [ racemic cis-isomer]

According to general method 1, 250mg (0.690mmol) of the compound from example 47A and 139mg (1.03mmol) of 2-methoxyethyl N' -hydroxyiminocarbamate from example 44A are reacted. Yield: 96.4mg (29% of theory)

LC-MS (method 6B): r_t＝1.21min；MS(ESIpos)：m/z＝461[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.20(d，2H)，7.16(d，2H)，4.39-4.33(m，2H)，3.93(d，1H)，3.69-3.63(m，2H)，3.53(d，1H)，3.44(br.s.，4H)，3.29(s，3H)，3.03-2.79(m，3H)，2.55-2.62(t，7H)，2.26(d，1H)，1.92(q，1H)，1.16(t，3H)。

Example 60

{3- (4-ethylphenyl) -5- [3- (2-methoxyethoxy) -1, 2, 4-Diazol-5-yl]Piperidin-1-yl } (1-oxothio-morpholin-4-yl) methanone [ enantiomerically pure cis-isomer ]

According to general method 2, 60.0mg (0.122mmol) of the compound from example 59 are reacted with 38.0mg (0.110mmol) of m-chloroperoxybenzoic acid. Enantiomeric separation according to method 7D 33.9mg of the racemate gave 15.6mg of the title compound (enantiomer 1) from example 60 and 13.4mg of the title compound (enantiomer 2) from example 61.

HPLC (method 9E): r_t＝7.29min，＞99.0％ee；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.23(d, 2H), 7.17(d, 2H), 4.40-4.34(m, 2H), 4.01-3.93(m, 1H), 3.69-3.46(m, 7H), 3.29(s, 3H), 3.06-2.82(m, 5H), 2.71(d, 2H), 2.62-2.56(m, 2H), 2.27(d, 1H), 1.93(q, 1H), 1.16(t, 3H), one hidden proton.

Example 61

{3- (4-ethylphenyl) -5- [3- (2-methoxyethoxy) -1, 2, 4-Diazol-5-yl]Piperidin-1-yl } (1-oxothio-morpholin-4-yl) methanone [ enantiomerically pure cis-isomer]

HPLC (method 9E): r_t＝10.26min，＞93.0％ee；

Example 62

(1, 1-dioxothiomorpholin-4-yl) {3- (4-ethylphenyl) -5- [3- (2-methoxyethoxy) -1, 2, 4-Diazol-5-yl]-piperidin-1-yl } methanone [ enantiomerically pure cis isomer]

According to general method 3, 30.0mg (0.061mmol) of the compound from example 59 are reacted with 52.8mg (0.153mmol) of m-chloroperoxybenzoic acid. Enantiomeric separation of 26.3mg of the racemate according to method 7D gave 11.7mg of the title compound from example 62 (enantiomer 1) and 11.8mg of the title compound from example 63 (enantiomer 2).

HPLC (method 9E): r_t＝5.89min，＞99.0％ee；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.23(d，2H)，7.16(d，2H)，4.40-4.33(m，2H)，4.01(d, 1H), 3.69-3.62(m, 3H), 3.60(br.s., 4H), 3.29(s, 3H), 3.17(br.s., 4H), 3.09-2.81(m, 3H), 2.62-2.56(m, 2H), 2.27(d, 1H), 1.93(q, 1H), 1.16(t, 3H), a hidden proton.

Example 63

(1, 1-dioxothiomorpholin-4-yl) {3- (4-ethylphenyl) -5- [3- (2-methoxyethoxy) -1, 2, 4- Diazol-5-yl]-piperidin-1-yl } methanone [ enantiomerically pure cis isomer]

HPLC (method 9E): r_t＝8.90min，＞96.5％ee；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.23(d, 2H), 7.16(d, 2H), 4.40-4.33(m, 2H), 4.01(d, 1H), 3.69-3.62(m, 3H), 3.60(br.s., 4H), 3.29(s, 3H), 3.17(br.s., 4H), 3.09-2.81(m, 3H), 2.62-2.56(m, 2H), 2.27(d, 1H), 1.93(q, 1H), 1.16(t, 3H), a hidden proton.

Example 64

{3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl } - (thiomorpholin-4-yl) methanone [ racemic cis-isomer]

To a solution of 600mg (1.08mmol, purity 75%) of the carboxylic acid from example 56A in 20.0ml of N, N-dimethylformamide are added 657mg (1.73mmol) of HATU and 0.57ml (419mg, 3.24mmol) of N, N-diisopropylethylamine at RT and the mixture is stirred for 30 min. Subsequently, the mixture was mixed with 225mg (1.84mmol, purity 85%) of N' -hydroxyiminourethane [ G.Zinner, G.Nebel, Arch.Pharm.1970, 303, 385-390- ]Mix and then stir at room temperature for 2 h. The reaction solution was purified directly by preparative HPLC. The resulting intermediate was taken up in toluene (68ml), andthe molecular sieves were mixed and stirred under reflux for 2 days. The reaction solution was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC. Yield: 320mg (61% of theory)

LC-MS (method 6B): r_t＝1.17min；MS(ESIpos)：m/z＝485[M+H]⁺。

Example 65

{3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl } (1-oxothio-morpholin-4-yl) methanone [ enantiomerically pure cis-isomer]

According to general method 2, 129mg (0.266mmol) of the compound from example 64 are reacted with 82.7mg (0.240mmol) of m-chloroperoxybenzoic acid. Enantiomeric separation according to method 8D 132mg of the racemate gave 51.0mg of the title compound from example 65 (enantiomer 1) and 53.0mg of the title compound from example 66 (enantiomer 2).

LC-MS (method 6B): r_t＝1.00min；MS(ESIpos)：m/z＝501[M+H]⁺；

HPLC (method 10E): r_t＝5.12min，＞99.0％ee；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.36-7.30(m, 4H), 4.30(q, 2H), 3.97(d, 1H), 3.70-3.46(m, 7H), 3.08-2.85(m, 5H), 2.75-2.67(m, 2H), 2.29(d, 1H), 1.95(q, 1H), 1.35(t, 3H), one hidden proton.

Example 66

{3- (3-ethoxy-1, 2, 4- Oxadiazol-5-yl) -5- [4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl } (1-oxothio-morpholin-4-yl) methanone [ enantiomerically pure cis-isomer]

LC-MS (method 6B): r_t＝1.00min；MS(ESIpos)：m/z＝501[M+H]⁺；

HPLC (method 10E): r_t＝7.27min，＞99.0％ee；

Example 67

(1, 1-dioxothiomorpholin-4-yl) {3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl } methanone [ racemic cis isomer]

72.0mg (0.149mmol) of the compound from example 64 in dichloromethane (6.3ml) are mixed with 128mg (0.371mmol) of m-chloroperoxybenzoic acid at RT and then stirred for 45 min. The reaction solution was diluted with dichloromethane and washed with 1N aqueous sodium hydroxide solution. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 75.3mg (92% of theory)

LC-MS (method 2B): r_t＝1.24min；MS(ESIpos)：m/z＝517[M+H]⁺。

Example 68

(1, 1-dioxothiomorpholin-4-yl) {3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [4- (2, 2, 2-trifluoroethyl) -phenyl]Piperidin-1-yl ketone [ enantiomerically pure cis-isomers]

The enantiomeric separation of 75.3mg of the racemate from example 67 according to method 8D gave 31.4mg of the title compound from example 68 (enantiomer 1) and 31.4mg of the title compound from example 69 (enantiomer 2).

LC-MS (method 2B): r_t＝1.24min；MS(ESIpos)：m/z＝517[M+H]⁺；

HPLC (method 10E): r_t＝4.44min，＞99.0％ee；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.37-7.29(m, 4H), 4.30(q, 2H), 4.01(d, 1H), 3.68-3.56(q, 7H), 3.18(br.s., 4H), 3.09-2.86(m, 3H), 2.29(d, 1H), 1.95(q, 1H), 1.35(t, 3H), one hidden proton.

Example 69

LC-MS (method 2B): r _t＝1.24min；MS(ESIpos)：m/z＝517[M+H]⁺；

HPLC (method 10E): r_t＝6.60min，＞99.0％ee；

Example 70

{3- [3- (2-methoxyethoxy) -1, 2, 4-Diazol-5-yl]-5- [4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl } - (thiomorpholin-4-yl) methanone [ racemic cis-isomer]

To a solution of 300mg (0.783mmol) of the carboxylic acid from example 56A in 10.0ml N, N-dimethylformamide at room temperature were added 329mg (0.864mmol) of HATU and 0.28ml (205g, 1.59mmol) of N, N-diisopropylethylamine and the mixture was stirred for 30 min. The mixture is subsequently mixed with 106mg (0.792mmol) of 2-methoxyethyl N' -hydroxyiminocarbamate from example 44A and stirred at room temperature overnight. The reaction solution was then stirred at 120 ℃ for 2 h. The reaction solution was purified directly by preparative HPLC. Yield: 98.0mg (26% of theory)

LC-MS (method 6B): r_t＝1.16min；MS(ESIpos)：m/z＝515[M+H]⁺；

¹H NMR (400MHz, DMSO-d 6): δ ═ 7.33(s, 4H), 4.37(dd, 2H), 3.93(d, 1H), 3.69-3.52(m, 5H), 3.45(br.s., 4H), 3.04-2.85(m, 3H), 2.59(br.s., 4H), 2.29(d, 1H), 1.94(q, 1H), four hidden protons.

Example 71

{3- [3- (2-methoxyethoxy) -1, 2, 4-Diazol-5-yl]-5- [4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl } - (1-oxothiomorpholin-4-yl) methanone [ racemic cis-isomer]

According to general method 2, 46.7mg (0.091mmol) of the compound from example 70 are reacted with 28.2mg (0.082mmol) of m-chloroperbenzoic acid. Yield: 52.8mg (100% of theory)

LC-MS (method 6B): r_t＝0.96min；MS(ESIpos)：m/z＝531[M+H]⁺。

Example 72

{3- [3- (2-methoxyethoxy) -1, 2, 4-Diazol-5-yl]-5- [4- (2, 2, 2-tris)Fluoroethyl) phenyl]Piperidin-1-yl } - (1-oxothiomorpholin-4-yl) methanone [ racemic cis-isomer]

The enantiomeric separation of 52.8mg of the racemate from example 71 according to method 8D gave 23.6mg of the title compound from example 72 (enantiomer 1) and 21.2mg of the title compound from example 73 (enantiomer 2).

LC-MS (method 6B): r_t＝0.96min；MS(ESIpos)：m/z＝531[M+H]⁺；

HPLC(Method 10E)：R_t＝5.80min，＞99.0％ee；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.33(br.s., 4H), 4.37(br.s., 2H), 4.01-3.93(m, 1H), 3.70-3.46(m, 9H), 3.07-2.85(m, 5H), 2.71(d, 2H), 2.29(d, 1H), 1.95(q, 1H), four hidden protons.

Example 73

{3- [3- (2-methoxyethoxy) -1, 2, 4-Diazol-5-yl]-5- [4- (2, 2, 2-trifluoroethyl) phenyl ]Piperidin-1-yl } - (1-oxothiomorpholin-4-yl) methanone [ racemic cis-isomer]

LC-MS(Method 6B)：R_t＝0.96min；MS(ESIpos)：m/z＝531[M+H]⁺；

HPLC (method 10E): r_t＝8，939min，＞99.0％ee；

Example 74

(1, 1-dioxothiomorpholin-4-yl) {3- [3- (2-methoxyethoxy) -1, 2, 4-Diazol-5-yl]-5- [4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl } methanone [ racemic cis isomer]

According to general method 3, 46.7mg (0.091mmol) of the compound from example 70 are reacted with 78.3mg (0.227mmol) of m-chloroperbenzoic acid. Yield: 41.8mg (82% of theory)

LC-MS (method 6B): r_t＝1.03min；MS(ESIpos)：m/z＝547[M+H]⁺。

Example 75

(1, 1-dioxothiomorpholin-4-yl) {3- [3- (2-methoxyethoxy) -1, 2, 4-Diazol-5-yl]-5- [4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl ketone [ enantiomerically pure cis-isomers]

Enantiomeric separation of the racemate from example 74 according to method 8D 41.8mg gave 18.8mg of the title compound from example 75 (enantiomer 1) and 18.3mg of the title compound from example 76 (enantiomer 2).

LC-MS (method 6B): r_t＝1.03min；MS(ESIpos)：m/z＝547[M+H]⁺；

HPLC (method 10E): r_t＝4.89min，＞99.0％ee；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.33(br.s., 4H), 4.37(br.s., 2H), 4.06-3.94(m, 1H), 3.72-3.54(m, 9H), 3.18(br.s., 4H), 3.10-2.85(m, 3H), 2.29(br.d., 1H), 1.95(q, 1H), four hidden protons.

Example 76

LC-MS (method 6B): r_t＝1.03min；MS(ESIpos)：m/z＝547[M+H]⁺；

HPLC (method 10E): r_t＝7.82min，＞99.0％ee；

Example 77

{3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [ 3-fluoro-4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl } - (thiomorpholin-4-yl) methanone [ racemic cis-isomer]

To a solution of 400mg (0.783mmol, 85% purity) of the carboxylic acid from example 79A in 10.6ml of N, N-dimethylformamide are added 357mg (0.939mmol) of HATU and 0.30ml (1.72mmol) of N, N-diisopropylethylamine at room temperature and the mixture is stirred for 30 min. Subsequently, the mixture was mixed with 118mg (1.02mmol, purity 90%) of N' -hydroxyiminourethane [ G.Zinner, G.Nebel, Arch.Pharm.1970, 303, 385-390] and stirred at room temperature overnight. The reaction solution was diluted with 11ml of N, N-dimethylformamide and then stirred at 140 ℃ for 3 hours. The reaction solution was purified directly by preparative HPLC. Yield: 111mg (28% of theory)

LC-MS (method 2B): r_t＝1.40min；MS(ESIpos)：m/z＝503[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.41(t, 1H), 7.27(d, 1H), 7.20(d, 1H), 4.30(q, 2H), 3.92(d, 1H), 3.67(q, 2H), 3.55(d, 1H), 3.45(br.s., 4H), 3.05-2.90(m, 3H), 2.59(br.s., 4H), 2.29(d, 1H), 2.02-1.88(m, 1H), 1.35(t, 3H), a hidden proton.

Example 78

{3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [ 3-fluoro-4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl } (1-oxothiomorpholin-4-yl) methanone [ racemic cis-isomer]

According to general method 2, 76.0mg (0.151mmol) of the compound from example 77 are reacted with 47.0mg (0.136mmol) of m-chloroperbenzoic acid. Yield: 60.5mg (77% of theory)

LC-MS (method 5B): r_t＝2.16min；MS(ESIpos)：m/z＝519[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.41(t, 1H), 7.28(d, 1H), 7.21(d, 1H), 4.30(q, 2H), 3.96(d, 1H), 3.76-3.45(m, 7H), 3.08-2.83(m, 5H), 2.77-2.68(m, 2H), 2.30(d, 1H), 1.96(q, 1H), 1.35(t, 3H), one hidden proton.

Example 79

{3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [ 3-fluoro-4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl } (1-oxothiomorpholin-4-yl) methanone [ enantiomerically pure cis-isomer]

Enantiomeric separation of 60.5mg of the racemate from example 78 according to method 8D gave 23.0mg of the title compound from example 79 (enantiomer 1) and 24.0mg of the title compound from example 80 (enantiomer 2).

LC-MS (method 5B): r_t＝2.16min；MS(ESIpos)：m/z＝519[M+H]⁺；

HPLC (method 12E): r_t＝4.78min，99.5％ee；

Example 80

LC-MS (method 5B): r_t＝2.16min；MS(ESIpos)：m/z＝519[M+H]⁺；

HPLC (method 12E): r_t＝8.35min，99.4％ee；

Example 81

(1, 1-dioxothiomorpholin-4-yl) {3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [ 3-fluoro-4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl } methanone [ racemic cis isomer ]

According to general method 3, 117mg (0.233mmol) of the compound from example 77 are reacted with 201mg (0.582mmol) of m-chloroperbenzoic acid. Yield: 69.8mg (56% of theory)

LC-MS (method 2B): r_t＝1.25min；MS(ESIpos)：m/z＝535[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.42(t, 1H), 7.28(d, 1H), 7.21(d, 1H), 4.30(q, 2H), 4.00(d, 1H), 3.74-3.54(m, 7H), 3.18(br.s., 4H), 3.09-2.90(m, 3H), 2.29(d, 1H), 1.95(q, 1H), 1.35(t, 3H), one hidden proton.

Example 82

(1, 1-dioxothiomorpholin-4-yl) {3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5[ 3-fluoro-4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl ketone [ enantiomerically pure cis-isomers]

Enantiomeric separation of the racemate from example 81 according to method 10D 142mg gave 54.5mg of the title compound (enantiomer 1) from example 82 and 60.3mg of the title compound (enantiomer 2) from example 83.

LC-MS (method 2B): r_t＝1.25min；MS(ESIpos)：m/z＝535[M+H]⁺；

HPLC (method 9E): r_t＝4.45min，99.0％ee；

Example 83

(1, 1-dioxothiomorpholin-4-yl) {3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [ 3-fluoro-4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl ketone [ enantiomerically pure cis-isomers]

LC-MS (method 2B): r_t＝1.25min；MS(ESIpos)：m/z＝535[M+H]⁺；

HPLC (method 9E): r_t＝7.83min，99.0％ee；

Example 84

{3- [4- (1, 1-difluoroethyl) phenyl]-5- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) piperidin-1-yl } (thiomorpholin-4-yl) methanone [ racemic cis-isomer]

To a solution of 150mg (0.376mmol, 2: 1 cis/trans isomer mixture) of the carboxylic acid from example 73A in 5.2ml of N, N-dimethylformamide are added 172mg (0.452mmol) of HATU and 0.14ml (0.83mmol) of N, N-diisopropylethylamine at RT and the mixture is stirred for 30 min. Subsequently, the mixture was mixed with 43.1mg (0.414mmol) of N' -hydroxyiminourethane [ G.Zinner, G.Nebel, Arch.pharm.1970, 303, 385-390- ]Mix and then stir at room temperature for 2 h. The reaction solution was purified directly by preparative HPLC. The resulting intermediate (118mg) was taken up in toluene (24ml), andthe molecular sieves were mixed and stirred at reflux overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC. Yield: 55.4mg (32% of theory)

LC-MS (method 6B): r_t＝1.19min；MS(ESIpos)：m/z＝467[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.53(d, 2H), 7.44(d, 2H), 4.30(q, 2H), 3.93(d, 1H), 3.55(d, 1H), 3.49-3.40(m, 4H), 3.07-2.91(m, 3H), 2.63-2.56(m, 4H), 2.29(d, 1H), 2.03-1.89(m, 4H), 1.35(t, 3H), one hidden proton.

Example 85

{3- [4- (1, 1-difluoroethyl) phenyl]-5- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) piperidin-1-yl } (1, 1-dioxothiomorpholin-4-yl) methanone [ racemic cis-isomer]

According to general method 3, 50.0mg (0.107mmol) of the compound from example 84 are reacted with 92.5mg (0.268mmol) of m-chloroperbenzoic acid. Yield: 52.5mg (96% of theory)

LC-MS (method 6B): r_t＝1.06min；MS(ESIpos)：m/z＝499[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.53(d, 2H), 7.45(d, 2H), 4.30(q, 2H), 4.00(d, 1H), 3.69-3.55(m, 5H), 3.18(br.s., 4H), 3.11-2.96(m, 3H), 2.34-2.25(m, 1H), 2.03-1.89(m, 4H), 1.35(t, 3H), one hidden proton.

Example 86

{3- [4- (1, 1-difluoroethyl) phenyl]-5- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) piperidin-1-yl } (1, 1-dioxothiomorpholin-4-yl) methanone [ enantiomerically pure cis-isomer]

Enantiomeric separation of 45.0mg of the racemate from example 85 according to method 8D gave 21.0mg of the title compound from example 86 (enantiomer 1) and 21.0mg of the title compound from example 87 (enantiomer 2).

LC-MS (method 6B): r_t＝1.06min；MS(ESIpos)：m/z＝499[M+H]⁺；

HPLC (method 10E): r_t＝5.07min，99.0％ee；

Example 87

LC-MS (method 6B): r_t＝1.06min；MS(ESIpos)：m/z＝499[M+H]⁺；

HPLC (method 10E): r _t＝8.74min，99.0％ee；

Example 88

{3- [4- (1, 1-difluoroethyl) phenyl]-5- [3- (2-methoxyethoxy) -1, 2, 4-Azol-5-yl]Piperidin-1-yl } (1, 1-dioxothiomorpholin-4-yl) methanone [ enantiomerically pure cis-isomer]

To a solution of 157mg (0.394mmol, 2: 1 cis/trans isomer mixture) of the carboxylic acid from example 73A in 5.5ml of N, N-dimethylformamide are added 180mg (0.473mmol) of HATU and 0.15ml (0.87mmol) of N, N-diisopropylethylamine at RT and the mixture is stirred for 30 min. Subsequently, the mixture was mixed with 64.6mg (0.433mmol, purity 90%) of the compound from example 44A and then stirred at room temperature overnight. The reaction solution was purified directly by preparative HPLC. The resulting intermediate (37mg) was taken up in toluene (25ml), andthe molecular sieves were mixed and stirred at reflux overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC. According to general method 3, thus obtained Oxadiazole (15.8mg, 85% of theory) was reacted with 27.5mg (0.080mmol) of m-chloroperoxybenzoic acid. Enantiomeric separation according to method 10D 17.0mg of the racemate gave 5.4mg of the title compound from example 88 (enantiomer 1) and 6.8mg of the title compound from example 89 (enantiomer 2).

LC-MS (method 2B): r_t＝1.17min；MS(ESIpos)：m/z＝529[M+H]⁺；

HPLC (method 7E): r_t＝4.87min，99.0％ee；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.53(d, 2H), 7.45(d, 2H), 4.40-4.34(m, 2H), 4.01(d, 1H), 3.70-3.63(m, 3H), 3.61(br.s., 4H), 3.29(s, 3H), 3.18(br.s., 4H), 3.06(t, 1H), 3.02-2.94(m, 2H), 2.30(d, 1H), 2.03-1.90(m, 4H), one proton hidden

Example 89

Enantiomeric separation of 17.0mg of the racemate from example 88 according to method 10D gave 5.4mg of the title compound from example 88 (enantiomer 1) and 6.8mg of the title compound from example 89 (enantiomer 2).

LC-MS (method 2B): r_t＝1.17min；MS(ESIpos)：m/z＝529[M+H]⁺；

HPLC (method 7E): r_t＝8.54min，99.0％ee；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.53(d, 2H), 7.45(d, 2H), 4.40-4.34(m, 2H), 4.01(d, 1H), 3.70-3.63(m, 3H), 3.61(br.s., 4H), 3.29(s, 3H), 3.18(br.s., 4H), 3.06(t, 1H), 3.02-2.94(m, 2H), 2.30(d, 1H), 2.03-1.90(m, 4H), a hidden proton.

Example 90

{3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl } (4-hydroxy-piperidin-1-yl) methanone [ racemic cis-isomer]

According to general method 1, 150mg (0.362mmol) of the compound from example 58A and 41.5mg (0.398mmol) of N' -hydroxyiminourethane [ G.Zinner, G.Nebel, Arch.Pharm.1970, 303, 385- "390 ] are reacted. Yield: 58.4mg (33% of theory)

LC-MS (method 6B): r_t＝1.07min；MS(ESIpos)：m/z＝483[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆): δ is 7.32(s, 4H), 4.66(d, 1H), 4.30(q, 2H), 3.92(d, 1H), 3.68-3.43(m, 6H), 3.02-2.83(m, 5H), 2.29(d, 1H), 1.93(q, 1H), 1.71(d, 2H), 1.39-1.25(m, 5H), one hidden proton.

Example 91

{3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl } (4-hydroxy-piperidin-1-yl) methanone [ enantiomerically pure cis isomer]

Enantiomeric separation of 58.4mg of the racemate from example 90 according to method 7D gave 20.6mg of the title compound from example 91 (enantiomer 1) and 23.1mg of the title compound from example 92 (enantiomer 2).

LC-MS (method 6B): r_t＝1.05min；MS(ESIpos)：m/z＝483[M+H]⁺；

HPLC (method 9E): r_t＝5.08min，＞99.0％ee；

Example 92

{3- (3-ethoxy-1, 2, 4-oxadiazol-5-yl) -5- [4- (2, 2, 2-trifluoroethyl) phenyl ] piperidin-1-yl } (4-hydroxy-piperidin-1-yl) methanone [ enantiomerically pure cis-isomer ]

LC-MS (method 6B): r_t＝1.05min；MS(ESIpos)：m/z＝483[M+H]⁺；

HPLC (method 9E): r_t＝11.05min，＞99.0％ee；

¹H NMR (400MHz, DMSO-d 6): δ is 7.32(s, 4H), 4.66(d, 1H), 4.30(q, 2H), 3.92(d, 1H), 3.68-3.43(m, 6H), 3.02-2.83(m, 5H), 2.29(d, 1H), 1.93(q, 1H), 1.71(d, 2H), 1.39-1.25(m, 5H), one hidden proton.

Example 93

(4-hydroxypiperidin-1-yl) {3- (3-isopropoxy-1, 2, 4-)Oxadiazol-5-yl) -5- [4- (2, 2, 2-trifluoroethyl) -phenyl]Piperidin-1-yl } methanone [ racemic cis isomer]

According to general method 1, 150mg (0.362mmol) of the compound from example 58A and 62.7mg (0.398mmol, 75% purity) of isopropyl N' -hydroxyiminocarbamate [ G.zinner, G.Nebel, Arch.pharm.1970, 303, 385-390] are reacted. Yield: 41.6mg (23% of theory)

LC-MS (method 6B): r_t＝1.12min；MS(ESIpos)：m/z＝497[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.32(s, 4H), 4.82(quin, 1H), 3.92(d, 1H), 3.69-3.43(m, 6H), 3.03-2.84(m, 5H), 2.29(d, 1H), 1.93(q, 1H), 1.72(d, 2H), 1.39-1.24(m, 9H), one hidden proton.

Example 94

(4-hydroxypiperidin-1-yl) {3- (3-isopropoxy-1, 2, 4-)Oxadiazol-5-yl) -5- [4- (2, 2, 2-trifluoroethyl) -phenyl]Piperidin-1-yl ketone [ enantiomerically pure cis-isomers]

Enantiomeric separation of the racemate from example 93 according to method 7D, 41.6mg, yielded 15.1mg of the title compound from example 94 (enantiomer 1) and 15.9mg of the title compound from example 95 (enantiomer 2).

LC-MS (method 6B): r_t＝1.10min；MS(ESIpos)：m/z＝497[M+H]⁺；

HPLC (method 9E): r_t＝5.05min，＞99.0％ee；

Example 95

LC-MS (method 6B): r_t＝1.10min；MS(ESIpos)：m/z＝497[M+H]⁺；

HPLC (method 9E): r_t＝11.06min，＞99.0％ee；

Example 96

{3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl } (3-hydroxy-azetidin-1-yl) methanone [ enantiomerically pure cis-isomer]

To 3.5ml of DMF were added 110mg (0.211mmol) of the compound from example 67A, 69.3mg (0.633mmol) of 3-hydroxyazetidine hydrochloride and 72.9mg (0.527mmol) of potassium carbonate and heated at 150 ℃ for 20min in a single-mode microwave oven (Emrys Optizer). For work-up, the reaction solutions are combined and filtered, and the residue is purified by preparative HPLC. Enantiomeric separation according to method 8D 47.7mg of the racemate gave 14.7mg of the title compound (enantiomer 1) from example 96 and 17.1mg of the title compound (enantiomer 2) from example 97.

LC-MS (method 10B): r_t＝2.19min；MS(ESIpos)：m/z＝454[M+H]⁺；

HPLC (method 11E): r_t＝4.09min，99.0％ee；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.32(s，4H)，5.57(d，1H)，4.43-4.34(m，1H)，4.30(q，2H)，4.17-4.04(m，3H)，3.78-3.55(m，5H)，3.27-3.16(m，1H)，3.02-2.87(m，2H)，2.87-2.77(m，1H)，2.27(d，1H)，1.96(q，1H)，1.35(t，3H)。

Example 97

{3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl } (3-hydroxy-azetidin-1-yl) methanone [ enantiomerically pure cis-isomer ]

Enantiomeric separation of the racemate from example 96 according to method 8D 47.7mg gave 14.7mg of the title compound from example 96 (enantiomer 1) and 17.1mg of the title compound from example 97 (enantiomer 2).

LC-MS (method 10B): r_t＝2.19min；MS(ESIpos)：m/z＝454[M+H]⁺；

HPLC (method 11E): r_t＝6.68min，96.0％ee；

Example 98

(3-Hydroxyazetidin-1-yl) {3- [3- (2-methoxyethoxy) -1, 2, 4-Diazol-5-yl]-5- [4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl ketone [ enantiomerically pure cis-isomers]

To 2.1ml of DMF 50.5mg (0.064mmol, purity 70%) of the compound from example 67A, 30.2mg (0.275mmol) of 3-hydroxyazetidine hydrochloride and 31.7mg (0.229mmol) of potassium carbonate are added and heated at 150 ℃ for 20min in a single-mode microwave oven (Emrys Optimizer). For work-up, the reaction solutions are combined and filtered, and the residue is purified by preparative HPLC. Enantiomeric separation according to method 8D 100mg of the racemic crude product gave 7.8mg of the title compound from example 98 (enantiomer 1) and 8.0mg of the title compound from example 99 (enantiomer 2).

LC-MS (method 10B): r_t＝2.10min；MS(ESIpos)：m/z＝485[M+H]⁺；

HPLC (method 11E): r_t＝5.07min，＞99.0％ee；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.32(s，4H)，5.57(d，1H)，4.44-4.33(m，3H)，4.18-4.03(m，3H)，3.79-3.56(m，7H)，3.29(s，3H)，3.26-3.17(m，1H)，3.04-2.78(m，3H)，2.27(d，1H)，1.96(q，1H)。

Example 99

(3-Hydroxyazetidin-1-yl) {3- [3- (2-methoxyethoxy) -1, 2, 4- Diazol-5-yl]-5- [4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl ketone [ enantiomerically pure cis-isomers]

Enantiomeric separation of 100mg of the racemic crude product from example 98 according to method 8D gave 7.8mg of the title compound from example 98 (enantiomer 1) and 8.0mg of the title compound from example 99 (enantiomer 2).

LC-MS (method 10B): r_t＝2.09min；MS(ESIpos)：m/z＝485[M+H]⁺；

HPLC (method 11E): r_t＝7.66min，＞98.6％ee；

Example 100

[3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- (4-ethyl-3-fluorophenyl) piperidin-1-yl](Thiomorphin-4-yl) methanone [ racemic cis-isomer]

309mg (0.81mmol) of the compound from example 36A and 169mg (1.62mmol) of ethyl N' -hydroxyiminocarbamate [ G.Zinner, G.Nebel, Arch.Pharm.1970, 303, 385-390] are initially introduced into 3.1ml of DMF and reacted with 463mg (1.22mmol) of HATU and 0.42ml (315mg, 2.44mmol) of N, N-diisopropylethylamine. The mixture was stirred at RT for 15 min; the reaction mixture was partitioned between water and ethyl acetate. The organic phase is washed several times with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was taken up in 3.0ml of DMF and converted for two minutes at 180 ℃ in a microwave (Emrys Optimizer). The reaction mixture was purified by preparative HPLC. Yield: 108mg (30% of theory)

LC-MS (method 2B): r_t＝1.45min；MS(ESIpos)：m/z＝449[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.25(t, 1H), 7.17-7.01(m, 2H), 4.36-4.26(m, 2H), 4.09(q, 2H), 3.97-3.86(m, 1H), 3.58-3.49(m, 1H), 3.47-3.40(m, 3H), 3.29-3.20(m, 1H), 3.05-2.80(m, 3H), 2.64-2.55(m, 5H), 2.26(d, 1H), 1.97-1.81(m, 1H), 1.40-1.28(m, 2H), 1.20-1.08(m, 2H), concealed 2H.

Example 101

(1, 1-dioxothiomorpholin-4-yl) [3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- (4-ethyl-3-fluorophenyl) -piperidin-1-yl]Methanone [ racemic cis isomer]

98mg (0.22mmol) of the compound from example 100 are converted according to general method 3. For work-up, the reaction mixture is passed through a StratoSphere cartridge and washed with dichloromethane, and the eluate is concentrated under reduced pressure. Yield: 99mg (87% of theory)

LC-MS (method 6B): r_t＝1.11min；MS(ESIpos)：m/z＝481[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆): δ 7.29-7.21(m, 1H), 7.16-7.04(m, 2H), 4.30(q, 2H), 4.09(q, 2H), 3.99(d, 1H), 3.63(d, 1H), 3.35-3.22(m, 4H), 3.17(br.s, 1H), 3.12-2.84(m, 3H), 2.62-2.52(m, 5H), 2.34-2.24(m, 1H), 2.01-1.86(m, 1H), 1.40-1.32(m, 2H), 1.26-1.12(m, 2H), a hidden proton.

Example 102

(1, 1-dioxothiomorpholin-4-yl) [3- (3-ethoxy-1, 2, 4- Oxadiazol-5-yl) -5- (4-ethyl-3-fluorophenyl) -piperidin-1-yl]Methanone [ enantiomer pure cis isomer]

Enantiomeric separation of 53.6mg of the racemate from example 101 according to method 10D gave 16mg of the compound from example 102 (enantiomer 1) and 15mg of the compound from example 103 (enantiomer 2).

HPLC (method 7E): r_t＝4.65min，＞99.0％ee；

LC-MS (method 6B): r_t＝1.10min；MS(ESIpos)：m/z＝481[M+H]⁺。

Example 103

(1, 1-dioxothiomorpholin-4-yl) [3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- (4-ethyl-3-fluorophenyl) -piperidin-1-yl]Methanone [ enantiomer pure cis isomer]

HPLC (method 7E): r_t＝6.79min，＞99.0％ee；

LC-MS (method 6B): r_t＝1.10min；MS(ESIpos)：m/z＝481[M+H]⁺。

Example 104

{3- [4- (difluoromethoxy) phenyl]-5- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) piperidin-1-yl } (1, 1-dioxothio-morpholin-4-yl) methanone [ racemic cis-isomer]

226mg (0.52mmol) of DMF are initially taken in 2.0mlThe compound of example 40A and 109mg (1.05mmol) of N' -hydroxyiminourethane [ G.Zinner, G.Nebel, Arch.pharm.1970, 303, 385-390- ]And reacted with 298mg (0.8mmol) of HATU and 0.27ml (203mg, 1.6mmol) of N, N-diisopropylethylamine. The mixture was stirred at RT for 15 min and then the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed repeatedly with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was found to be 5.0mlAbsorbed in an alkane and reacted withAnd (4) mixing the molecular sieves. The mixture was heated to reflux for 16h and the reaction mixture was purified by preparative HPLC. Yield: 86mg (30% of theory)

LC-MS (method 6B): r_t＝0.97min；MS(ESIpos)：m/z＝501[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.42-7.32(m, 2H), 7.15(d, 2H), 4.35-4.26(m, 2H), 4.06-3.96(m, 1H), 3.66-3.53(m, 5H), 3.37-3.27(m, 1H), 3.22-3.14(m, 4H), 3.12-2.88(m, 3H), 2.34-2.23(m, 1H), 2.01-1.88(m, 1H), 1.39-1.30(m, 3H), a hidden proton.

Example 105

{3- [4- (difluoromethoxy) phenyl]-5- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) piperidin-1-yl } (1-oxothio-morpholin-4-yl) methanone [ racemic cis-isomer]

185mg (0.37mmol) of the compound from example 42A and 50mg (0.48mmol) of ethyl N' -hydroxyiminocarbamate [ G.Zinner, G.Nebel, Arch.Pharm.1970, 303, 385-plus 390] are initially introduced into 1.0ml of DMF and reacted with 210mg (0.55mmol) of HATU and 0.19ml (143mg, 1.1mmol) of N, N-diisopropylethylamine. The mixture was stirred at RT for 15 min and then the reaction mixture was partitioned between water and ethyl acetate. The organic phase is washed several times with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 2.0ml of acetic acid and heated under reflux for 1 h. The reaction mixture was purified by preparative HPLC. Yield: 62mg (33% of theory)

LC-MS (method 6B): r_t＝0.94min；MS(ESIpos)：m/z＝485[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.43-7.35(m，2H)，7.15(d，2H)，4.30(q，2H)，4.03-3.91(br.d，1H)，3.68-3.46(m，4H)，3.41-3.35(m，1H)，3.08-2.84(m，4H)，2.71(br.d，2H)，2.57-2.52(m，3H)，2.34-2.23(m，1H)，2.01-1.88(m，1H)，1.35(t，3H)。

Example 106

{3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [ 3-fluoro-4- (trifluoromethyl) phenyl]Piperidin-1-yl } (thiomorpholin-4-yl) methanone [ racemic cis-isomer]

151mg (0.280mmol) of the compound from example 85A and 43mg (0.420mmol) of N' -hydroxyiminourethane [ G.Zinner, G.Nebel, Arch.Pharm.1970, 303, 385- "390 ] are reacted according to general method 4. Yield: 38mg (25% of theory).

LC-MS (method 10B): r_t＝2.66min；MS(ESIpos)：m/z＝489[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.75(t，1H)，7.53(d，1H)，7.39(d，1H)，4.30(q，2H)，3.91(dm，1H)，3.56(d，1H)，3.50-3.40(m，4H)，3.07-2.97(m，3H)，2.62-2.56(m，4H)，2.31(dm，1H)，1.98(q，1H)，1.35(t，3H)。

Example 107

{3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [ 3-fluoro-4- (trifluoromethyl) phenyl]Piperidin-1-yl } (1-oxothiomorpholin-4-yl) methanone [ racemic cis-isomer]

According to general method 2, 19mg (0.040mmol) of the compound from example 106 are reacted. Yield: 12mg (57% of theory).

LC-MS (method 2B): r_t＝1.20min；MS(ESIpos)：m/z＝505[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.75(t，1H)，7.54(d，1H)，7.40(d，1H)，4.30(q，2H)，3.95(dm，1H)，3.66-3.50(m，5H)，3.10-3.02(m，3H)，2.95-2.856(m，2H)，2.75-2.65(m，2H)，2.31(d，1H)，1.99(q，1H)，1.35(t，3H)。

Example 108

(1, 1-dioxothiomorpholin-4-yl) {3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [ 3-fluoro-4- (trifluoromethyl) phenyl]Piperidin-1-yl } methanone [ racemic cis isomer]

According to general method 3, 15mg (0.031mmol) of the compound from example 106 are reacted. Yield: 9mg (51% of theory).

LC-MS (method 2B): r_t＝1.28min；MS(ESIpos)：m/z＝521[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.75(t，1H)，7.54(d，1H)，7.40(d，1H)，4.30(q，2H)，3.99(dm，1H)，3.70-3.55(m，5H)，3.22-3.13(m，3H)，3.10-3.00(m，3H)，2.31(d，1H)，1.99(q，1H)，1.35(t，3H)，1.09(t，1H)。

Example 109

{3- (3-ethoxy-1, 2, 4- Oxadiazol-5-yl) -5- [ 2-fluoro-4- (trifluoromethyl) phenyl]Piperidin-1-yl } - (thiomorpholin-4-yl) methanone [ racemic cis-isomer]

According to general method 4, 254mg (0.405mmol) of the compound from example 90A and 63mg (0.607mmol) of N' -hydroxyiminourethane [ G.Zinner, G.Nebel, Arch.pharm.1970, 303, 385- "390 ] are reacted. Yield: 70mg (35% of theory).

LC-MS (method 6B): r_t＝1.25min；MS(ESIpos)：m/z＝489[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.71-7.66(m，2H)，7.59(d，1H)，4.30(q，2H)，3.93(dm，1H)，3.59(dm，1H)，3.49-3.35(m，5H)，3.24(dm，1H)，3.05-2.93(m，2H)，2.62-2.58(m，4H)，2.29(d，1H)，2.08(q，1H)，1.35(t，3H)。

Example 110

(1, 1-dioxothiomorpholin-4-yl) {3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [ 2-fluoro-4- (trifluoromethyl) phenyl]Piperidin-1-yl } methanone [ racemic cis isomer]

According to general method 3, 58.5mg (0.120mmol) of the compound from example 109 are reacted with 103mg (0.299mmol) of m-chloroperbenzoic acid. Yield: 49.2mg (79% of theory).

LC-MS (method 6B): r_t＝1.12min；MS(ESIpos)：m/z＝521[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆): δ ═ 7.74-7.64(m, 2H), 7.59(d, 1H), 4.31(q, 2H), 4.00(d, 1H), 3.70(d, 1H), 3.61(br.s., 4H), 3.45-3.35(m, 1H), 3.18(br.s., 4H), 3.12-2.95(m, 2H), 2.29(d, 1H), 2.07(q, 1H), 1.35(t, 3H), a hidden proton.

Example 111

(1, 1-dioxothiomorpholin-4-yl) {3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [ 2-fluoro-4- (trifluoromethyl) phenyl ]Piperidin-1-yl ketone [ enantiomerically pure cis-isomers]

Enantiomeric separation of the racemate from example 110 according to method 11D 39.0mg gave 14.0mg of the title compound from example 111 (enantiomer 1) and 15.6mg of the title compound from example 112 (enantiomer 2).

LC-MS (method 6B): r_t＝1.09min；MS(ESIpos)：m/z＝521[M+H]⁺；

HPLC (method 12E): r_t＝4.25min，＞99.0％ee；

Example 112

(1, 1-dioxothiomorpholin-4-yl) {3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [ 2-fluoro-4- (trifluoromethyl) phenyl]Piperidin-1-yl ketone [ enantiomerically pure cis-isomers]

LC-MS (method 6B): r_t＝1.09min；MS(ESIpos)：m/z＝521[M+H]⁺；

HPLC (method 12E): r_t＝6.98min，＞99.0％ee；

Example 113

{3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [ 3-fluoro-4- (trifluoromethoxy) phenyl]Piperidin-1-yl } (3-hydroxyazetidin-1-yl) methanone [ racemic cis-isomer]

145mg (0.23mmol) of the compound from example 65A, 76mg (0.68mmol) of 3-hydroxyazetidine hydrochloride and 62mg (0.45mmol) of potassium carbonate are initially introduced into 4.5ml of DMF and reacted in a microwave at 150 ℃ for 15 minutes. The reaction mixture was purified by preparative HPLC. Yield: 41mg (36% of theory)

LC-MS (method 6B): r_t＝1.09min；MS(ESIpos)：m/z＝475[M+H]⁺；

¹H NMR(400MHz，DMSO-d₆)：δ＝7.57-7.47(m，2H)，7.30-7.24(m，1H)，5.57(d，1H)，4.41-4.35(m，1H)，4.30(q，2H)，4.15-4.05(m，3H)，3.77-3.64(m，3H)，3.25-3.16(m，1H)，3.03-2.87(m，3H)，2.27(br.d，1H)，1.97(q，1H)，1.35(t，3H)。

Example 114

{3- (3-ethoxy-1, 2, 4-Oxadiazol-5-yl) -5- [ 3-fluoro-4- (trifluoromethoxy) phenyl]Piperidin-1-yl } (3-hydroxyazetidin-1-yl) methanones as enantiomerically pure cis-isomers]

The enantiomeric separation of 30mg of the racemate from example 113 according to method 10D gave 12mg of the compound from example 114 (enantiomer 1) and 11mg of the compound from example 115 (enantiomer 2).

HPLC (method 7E): r_t＝3.55min，＞99.0％ee；

LC-MS (method 6B): r_t＝1.09min；MS(ESIpos)：m/z＝475[M+H]⁺。

Example 115

Enantiomeric separation of the racemate from example 113 according to method 10D 117mg yielded 43mg of the compound from example 114 (enantiomer 1) and 38mg of the compound from example 115 (enantiomer 2).

HPLC (method 7E): r_t＝5.64min，＞99.0％ee；

LC-MS (method 6B): r_t＝1.09min；MS(ESIpos)：m/z＝475[M+H]⁺。

Example 116

3- (3-ethoxy-1, 2, 4-)Oxadiazol-5-yl) -5- [4- (2, 2, 2-trifluoroethyl) phenyl]Piperidine-1-carboxylic acid tert-butyl ester [ racemic cis isomer]

To a solution of 459mg (0.889mmol, purity 75%, 2: 1 cis/trans isomer mixture) of the carboxylic acid from example 59A in 19ml of N, N-dimethylformamide are added 541mg (1.42mmol) of HATU and 0.45ml (337mg, 2.61mmol) of N, N-diisopropylethylamine at RT and the mixture is stirred for 30 min. Subsequently, the mixture was admixed with 136mg (1.30mmol) of N' -hydroxyiminoEthyl carbamate [ G.Zinner, G.Nebel, Arch.pharm.1970, 303, 385-390-]Mix and then stir at room temperature overnight. The reaction solution was purified directly by preparative HPLC. The resulting intermediate was taken up in toluene (50ml), andthe molecular sieves were mixed and stirred at reflux overnight. The reaction solution was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC. Yield: 124mg (31% of theory)

LC-MS (method 2B): r_t＝1.52min；MS(ESIpos)：m/z＝400[M-C₄H₈]⁺。

Example 117

1- {3- [3- (2-methoxyethoxy) -1, 2, 4-Diazol-5-yl]-5- [4- (2, 2, 2-trifluoroethyl) phenyl]Piperidin-1-yl } -ethanones [ racemic cis-isomers ]

According to general method 8A, 240mg (0.729mmol) of the compound from example 64A and 108mg (0.802mmol) of 2-methoxyethyl N' -hydroxyiminocarbamate from example 44A are reacted. Yield: 80mg (24% of theory)

LC-MS (method 6B): r_t＝1.03min；MS(ESIpos)：m/z＝428[M+H]⁺。

R)Evaluation of physiological Activity

Abbreviations:

BSA bovine serum albumin

DMEM Dulbecco modified Eagle Medium

EGTA ethylene glycol-bis (2-aminoethyl) -N, N, N ', N' -tetraacetic acid

FCS fetal calf serum

HEPES 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid

[3H] haTRAP tritiated high affinity thrombin receptor activating peptides

PRP platelet rich plasma.

The suitability of the compounds of the invention for the treatment of thromboembolic disorders can be shown in the following test systems:

1.) in vitro testing

A) function of cells in vitro assays

Recombinant cell lines are used to identify antagonists of human protease activated receptor 1(PAR-1) and to quantify the activity of the agents described herein. The cells were originally derived from human embryonic kidney cells (HEK 293; ATCC: American Type Culture Collection, Manassas, VA20108, USA). The test cell line constitutively expresses a modified form of the calpain aequorin which, after recombination with the cofactor coelenterazine, emits light when the concentration of free calcium in the endosomal compartment (component) increases (Rizzuto R, Simpson AW, Brini M, Pozzan T.; Nature 1992, 358, 325-. In addition, the cells stably express endogenous human PAR-1 receptor and endogenous purinergic receptor P2Y 2. The PAR-1 test cells produced, accompanied by the release of intracellular calcium ions, respond to stimulation of endogenous PAR-1 or P2Y2 receptors, which can be quantified with appropriate photometry by fluorescence of the produced aequorin (Milligan G, Marshall F, Rees S, Trends in pharmacological sciences 1996, 17, 235-237).

To test for substance specificity, the effect of endogenous PAR-1 receptor activation was compared to that of endogenous purine P2Y2 receptor activation using the same intracellular signaling pathway.

The test steps are as follows:prior to assay cells were plated in 384-well microtiter plates for two days (48h) in medium (DMEMF12 supplemented with 10% FCS, 2mM glutamine, 20mM HEPES, 1.4mM pyruvate, 0.1mg/ml gentamicin, 0.15% sodium bicarbonate; BioWhittaker Cat. # BE 04-687Q; B-4800Verviers, Belgium) and in cell culture chambers (96% atmospheric humidity, 5% v/v CO)₂And 37 ℃ C. storage. On the day of the experiment, the medium was replaced with tyrode's solution (in mM: 140 sodium chloride, 5 potassium chloride, 1 magnesium chloride, 2 calcium chloride, 20 glucose, 20HEPES) additionally containing coelenterazine (25. mu.M) and glutathione (4mM), and the microtiter plates were then incubated for an additional 3-4 hours. The test substance is then pipetted onto the microtiter plate, 5 minutes after the test substance has been transferred into the wells of the microtiter plate, the plate is transferred into a luminometer and the corresponding EC is added₅₀And measuring the resulting optical signal in a luminometer at once. To distinguish between antagonist substance action and toxic action, endogenous purinergic receptors were immediately subsequently activated with agonist (ATP, final concentration 10 μ M) and the resulting light signal was measured. The results are shown in table a:

Table a:

example No. 2	IC₅₀[nM]
		6	8.7
9	14.3
		16	69.4
33	1.7
		35	35.3
63	20.6
		66	64.5
67	12.0
		69	21.1
80	5.1
		101	6.3

B) PAR-1 receptor binding assays

Platelet membranes were incubated with 12nM [3H ] hatAP and test substance in buffer (50mM TrispH 7.5, 10mM magnesium chloride, 1mM EGTA, 0.1% BSA) at various concentrations for 80min at room temperature. The mixture was then transferred to the filter plate and washed twice with buffer. After addition of scintillation fluid, the radioactivity on the filter was measured in a beta counting tube.

C) platelet aggregation in plasma

To determine platelet aggregation, blood from healthy volunteers of both sexes, who did not receive any drug treatment affecting platelet aggregation for the last ten days, was used. Blood was taken up into monovite (Sarstedt, N ü mbrecht, germany) which contained 3.8% sodium citrate (1 part citrate +9 parts blood) as an anticoagulant. To obtain platelet rich plasma, citrate whole blood was centrifuged at 140g for 20 min.

To determine aggregation, aliquots of platelet rich plasma with increasing concentrations of test substance were incubated at 37 ℃ for 10 min. Subsequently, coagulation was induced by The addition of a thrombin receptor agonist (TRAP6, SFLLRN) to The platelet aggregometer and was determined by nephelometry at 37 ℃ according to Born (Born, G.V.R., Cross M.J., The Aggregation of Blood plants; J.Physiol.1963, 168, 178-one 195). The concentration of SFLLRN that produced the greatest aggregation was determined separately for each donor, as appropriate.

To calculate the inhibitory effect, the maximum increase in light transmission (amplitude of the aggregation curve in%) was determined within 5 minutes after addition of the agonist in the presence and absence of the test substance, and the inhibition was calculated. The inhibition curve was used to calculate the concentration that inhibited aggregation by 50%. The results are shown in table B:

table B:

example No. 2	IC₅₀[nM]
		6	0.67
63	0.24
		66	0.54
69	0.25
		101	0.30

1, d) platelet aggregation in buffer

To determine platelet aggregation, blood from healthy volunteers of both sexes, who did not receive any drug treatment affecting platelet aggregation for the last ten days, was used. Blood was taken up into monovite (Sarstedt, N ü mbrecht, germany) which contained 3.8% sodium citrate (1 part citrate +9 parts blood) as an anticoagulant. To obtain platelet rich plasma, citrate whole blood was centrifuged at 140g for 20 min. One quarter of the volume of ACD buffer (44.8mM sodium citrate, 20.9mM citric acid, 74.1mM glucose and 4mM potassium chloride) was added to the PRP and centrifuged at 1000g for 10 minutes. The platelet pellet was resuspended in wash buffer and centrifuged at 1000g for 10 min. Platelets were resuspended in culture buffer and adjusted to 200000 cells/. mu.l. Before the start of the experiment, calcium chloride and magnesium chloride were added, in each case at a final concentration of 2mM (2M stock solution, dilution 1: 1000). Note that: for ADP-induced coagulation, only calcium chloride was added. The following agonists may be used: TRAP 6-trifluoroacetate, collagen, human α -thrombin and U-46619. For each donor, the concentration of agonist was tested.

The test steps are as follows:96-well microtiter plates were used. The test substances were diluted in DMSO and 2 μ l of each well was started. 178 μ l of platelet suspension was added and the mixture was pre-incubated at room temperature for 10 minutes. 20 μ l of agonist was added and the assay was started immediately in Spectramax, OD405 nm. Kinetics were determined in each of 1 minute 11 assays. Between measurements, the mixture was shaken for 55 seconds.

E) platelet aggregation in plasma depleted of fibrinogen

To determine platelet aggregation, blood from healthy volunteers of both sexes, who did not receive any drug treatment affecting platelet aggregation for the last ten days, was used. Blood was taken up into monovite (Sarstedt, N ü mbrecht, germany) which contained 3.8% sodium citrate (1 part citrate +9 parts blood) as an anticoagulant.

Preparation of fibrinogen-depleted plasma:to obtain low-platelet plasma, citrate whole blood was centrifuged at 140g for 20 min. Low-platelet plasma was mixed with snake venom thrombin (Roche Diagnostic, Germany) in a ratio of 1: 25 and carefully transformed. This was followed by incubation in a water bath at 37 ℃ for 10min, followed by incubation directly on ice for 10 min. The plasma/snake venom thrombin mixture was centrifuged at 1300g for 15min and the supernatant (fibrinogen-depleted plasma) was obtained.

And (3) platelet separation:to obtain platelet rich plasma, citrate whole blood was centrifuged at 140g for 20 min. One quarter of the volume of ACD buffer (44.8mM sodium citrate, 20.9mM citric acid, 74.1mM glucose and 4mM potassium chloride) was added to the PRP and centrifuged at 1300g for 10 minutes. The platelet pellet was resuspended in wash buffer and centrifuged at 1300g for 10 min. Platelets were resuspended and adjusted to 400000 cells/. mu.l in culture buffer and calcium chloride solution was added at a final concentration of 5mM (1/200 dilution).

To determine aggregation, aliquots with increasing concentrations of test substance (98. mu.l fibrinogen-depleted plasma and 80. mu.l platelet suspension) were incubated for 10min at RT. Subsequently, coagulation was induced by The addition of human alpha thrombin in a platelet aggregometer and was determined by nephelometry at 37 ℃ according to Born (Born, G.V.R., Cross M.J., The Aggregation of Blood Platelets; J.Physiol.1963, 168, 178-one 195). The alpha thrombin concentration that gave just the maximum aggregation value was determined for each donor separately.

To calculate the inhibitory effect, the increase in maximum light transmission (amplitude of the aggregation curve in%) was measured over 5 minutes after addition of the agonist in the presence and absence of the test substance, and the inhibition was calculated. The inhibition curve was used to calculate the concentration that inhibited aggregation by 50%.

F) stimulation of washed platelets and analysis in flow cytometry

Separation of washed platelets:human whole blood was obtained from volunteer donors by venipuncture and transferred to monovite (Sarstedt, N ü mbrecht, germany) containing sodium citrate (1 part sodium citrate 3.8% +9 parts whole blood) as anticoagulant. Monovite was centrifuged at 900 rpm and 4 ℃ for 20 minutes (Heraeus Instruments, Germany; Megafuge 1.0 RS). The platelet rich plasma was carefully removed and transferred to a 50ml Falcon tube. ACD buffer (44mM sodium citrate, 20.9mM citric acid, 74.1mM glucose) was then added to the plasma. The volume of ACD buffer corresponds to one quarter of the plasma volume. Platelets were pelleted by centrifugation at 2500rpm for ten minutes at 4 ℃. After this time, the supernatant was carefully decanted off and discarded. The precipitated platelets are first carefully resuspended in one ml of wash buffer (113mM sodium chloride, 4mM disodium hydrogen phosphate, 24mM sodium dihydrogen phosphate, 4mM potassium chloride, 0.2mM ethylene glycol-bis (2-aminoethyl) -N, N' -tetraacetic acid, 0.1% glucose) and then the wash buffer is supplemented to a volume corresponding to the volume of plasma. The washing step was repeated. Platelets were pelleted by another centrifugation at 2500rpm for ten minutes at 4 ℃ and then carefully incubated in one milliliter of culture buffer (134mM sodium chloride pellet, 12mM sodium bicarbonate, 2.9mM potassium chloride, 0.34mM sodium dihydrogen phosphate, 5mM HEPES, 5mM glucose, 2mM calcium chloride and 2mM magnesium chloride) Resuspended and adjusted to a concentration of 300000 platelets per μ l with culture buffer.

Staining and pricking with human alpha-thrombin in the presence or absence of a PAR-1 antagonist Stimulating human platelets:the platelet suspension is preincubated with the substance to be tested or a suitable solvent at 37 ℃ for 10 minutes (Eppendorf, Germany; Thermomixer Comfort). Platelet activation was induced by addition of agonist (0.5. mu.M or 1. mu.M. alpha. -thrombin; Kordia, Netherlands, 3281NIH units/mg; or 30. mu.g/ml thrombin receptor activating peptide (TRAP 6); Bachem, Switzerland) at 37 ℃ and with shaking at 500 rpm. A50. mu.l aliquot was removed at 0, 1, 2.5, 5, 10 and 15 minutes each and transferred into one ml of individually concentrated CellFix^TMSolutions (Becton Dickinson immunocytometric systems, USA). To immobilize the cells, they were incubated in the dark at 4 ℃ for 30 minutes. Platelets were pelleted by centrifugation at 600g for ten minutes at 4 ℃. The supernatant was discarded and platelets were plated on 400. mu.l CellWash^TM(Becton Dickinson immunocytometric systems, USA). A100. mu.l aliquot was transferred to a new FACS tube. Using CellWash^TMMu.l of platelet-identifying antibody and 1. mu.l of activation state-detecting antibody were supplemented to a volume of 100. mu.l. The antibody solution was then added to the platelet suspension and incubated at 4 ℃ for 20 minutes in the dark. After staining, the reaction volume was further increased by adding 400. mu.l CellWash ^TMAnd (4) increasing.

Fluorescein isothiocyanate-conjugated antibodies of human glycoprotein IIb (CD41) (Immunotech Coulter, France; Cat. catalog number 0649) were used for platelet identification. The activation state of platelets can be determined by means of phycoerythrin-conjugated antibodies directed in the direction to the human glycoprotein P-selectin (Immunotech Coulter, France; catalog No. 1759). P-selectin (CD62P) is localized in the alpha-granules of resting platelets. However, with stimulation in vitro or in vivo, it spans the localized (translalized) to the external plasma membrane.

Flow cytometry and data evaluation:samples obtained from BectonFACSCalibur by Dickinson immunocytometry Systems, USA^TMFlow cytometry system instruments, and evaluation and graphical presentation with the aid of CellQuest software, version 3.3(Becton Dickinson Immunocytometry Systems, usa). The extent of platelet activation was determined by the percentage of CD 62P-positive platelets (CD 41-positive case). From each sample 10000 CD 41-positive cases were calculated.

The inhibitory effect of the substance to be tested is calculated by the reduction in platelet activation, which involves activation by an agonist.

1, g) determination of platelet aggregation using parallel plate flow chambers

To determine platelet activation, blood was used from healthy volunteers of both sexes who did not receive any drug treatment affecting platelet aggregation for the last ten days. Blood was taken up into monovite (Sarstedt, N ü mbrecht, germany) which contained 3.8% sodium citrate (1 part citrate +9 parts blood) as an anticoagulant. To obtain platelet rich plasma, citrate whole blood was centrifuged at 140g for 20 min. To the PRP was added a quarter volume of ACD buffer (44.8mM sodium citrate, 20.9mM citric acid, 74.1mM glucose and 4mM potassium chloride) and the mixture was centrifuged at 1000g for 10 min. The platelet pellet was resuspended in wash buffer and centrifuged at 1000g for 10 min. For perfusion studies, a mixture of 40% red blood cells and 60% washed platelets (200000/. mu.l) was prepared and suspended in HEPES-tyrode buffer. Platelet aggregation was determined using parallel plate flow chambers under flow conditions (B.Nieswandt et al, EMBO J.2001, 20, 2120-. Slides were wetted overnight at 4 ℃ with 100. mu.l of a solution of human alpha-thrombin (in Tris buffer) at various concentrations, e.g.10 to 50. mu.g/ml and then blocked with 2% BSA.

Reconstituted blood was passed through a thrombin-wetted slide at a constant flow rate (e.g., 300/second shear rate) for 5 minutes and observed and recorded using a microscope video system. The inhibitory activity of the substances to be tested is determined by the reduced morphology of the platelet aggregate formation. Alternatively, inhibition of platelet activation can be determined by flow cytometry, for example by p-selectin expression (CD62p) (see method 1. f).

1.h) determination of platelet aggregation and activation Using parallel plate flow Chambers (anticoagulant, collagen)

To determine platelet activation under flow conditions, blood from healthy volunteers of both sexes was used, which volunteers had not received any drug treatment affecting platelet aggregation for the last ten days. Blood was taken up into monovite (Sarstedt, N ü mbrecht, Germany). It contained 3.8% sodium citrate (1 part citrate +9 parts blood) as an anticoagulant.

Platelet activation was measured using a parallel plate flow chamber (B.Nieswandt et al, EMBO J.2001, 20, 2120-. Slides were wetted overnight (type I collagen at various concentrations, e.g., 1-10. mu.g/slide) with 20. mu.l of collagen suspension (collagen reagent: Horm, Nycomed) at 4 ℃ and finally blocked with 2% BSA.

To prevent fibrin clot formation, whole citrate-containing blood was mixed with Pefabloc FG (Pentapharm, final concentration 3mM) and passed through a collagen-coated slide (e.g., shear rate of 1000/sec) at constant flow rate for 5 minutes by adding a CaCl2 solution (final Ca + + concentration 5mM) and observed and recorded using a microscope video system. The inhibitory effect of the substances to be tested is determined by the reduced morphology of the platelet aggregate formation. Alternatively, inhibition of platelet activation can be determined by flow cytometry, for example by p-selectin expression (CD62p) (see method 1. f).

I) determination of platelet aggregation and activation Using parallel plate flow Chambers (non-anticoagulated, collagen)

To determine platelet activation under flow conditions, blood from healthy volunteers of both sexes was used, which volunteers had not received any drug treatment affecting platelet aggregation for the last ten days. The hemoaspirate was received in neutral monovite (Sarstedt, N ü mbrecht, germany), which did not contain any anticoagulant and was immediately mixed with Pefabloc FG (pentacharm, final concentration 3mM) to prevent fibrin clot formation. The test substance in DMSO was added simultaneously with Pefablock FG and not further incubated into the parallel plate flow chamber. The determination of platelet activation was carried out by morphometry or flow cytometry in a collagen-coated parallel plate flow cell as described in method 1. h).

2.) in vitro testing

A) platelet aggregation (primate, guinea pig)

Conscious or anesthetized guinea pig or primate test substances are treated orally, intravenously or intraperitoneally in suitable formulations. As a control, other guinea pigs or primates were treated in the same manner with the corresponding vehicle. Depending on the mode of administration, blood from deeply anesthetized animals is obtained by puncturing the heart or aorta for different time periods. Blood was aspirated into monovite (Sarstedt, N ü mbrecht, germany) which contained 3.8% sodium citrate (1 part citrate solution +9 parts blood) as an anticoagulant. To obtain platelet rich plasma, citrate whole blood was centrifuged at 140g for 20 min.

Aggregation was induced in a platelet aggregometer by addition of thrombin receptor agonist (TRAP6, SFLLRN, 50. mu.g/ml; in each experiment, concentration was determined for each animal species) and determined by nephelometry at 37 ℃ according to Born (Born, G.V.R., Cross M.J., The Aggregation of Blood plants; J.Physiol.1963, 168, 178-.

To determine aggregation, the maximum increase in light transmission (amplitude of the aggregation curve in%) was determined within 5 minutes after addition of agonist. The inhibitory effect of the test substance administered in the treated animals was calculated by the decrease in aggregation, based on the average value for the control animals.

In addition to measuring aggregation, inhibition of platelet activation can be measured by flow cytometry, for example by p-selectin expression (CD62p) (see method 1. f).

B) determination of platelet aggregation and activation in parallel plate flow Chambers (primates)

Conscious or anesthetized primates are treated with the test substance orally, intravenously or intraperitoneally in a suitable formulation. As a control, other animals were treated in the same manner with the corresponding vehicle. Depending on the mode of administration, blood was obtained from the animal by venipuncture over different time periods. The blood was transferred to monovite (Sarstedt, N ü mbrecht, germany) which contained 3.8% sodium citrate (1 part citrate solution +9 parts blood) as an anticoagulant. Alternatively, non-anticoagulated blood may be collected with neutral monovites (sarstedt). In both cases, blood was mixed with Pefabloc FG (pentaharmm, final concentration 3mm) to prevent fibrin clot formation.

Whole blood containing citrate was recalcified (recalcify) prior to assay by addition of CaCl2 solution (final Ca + + concentration 5 mM). For the assay, non-anticoagulated blood was added directly to the parallel plate flow chamber. The determination of platelet activation was performed by morphometry or flow cytometry in collagen-coated parallel plate flow chambers as described in method 1. h).

3.) in vivo testing

3.a) thrombosis model

The compounds of the invention can be studied in a suitable animal species in a thrombosis model in which thrombin-induced platelet aggregation is modulated by the PAR-1 receptor. Suitable animal species are guinea pigs and, in particular, primates (cf. Lindahl, A.K., Scarborough, R.M., Naughton, M.A., Harker, L.A., Hanson, S.R., Thromb Haemost1993, 69, 1196; CookJ, Sitko GR, Bednar B, Condra C, Mellott MJ, Feng D-M, Nutt RF, Shager JA, Gould RJ, Connolly TM, Circulation1995, 91, 2961-2971; Kogushi M, Kobayashi H, Matsuoka T, Suzukikis S, Kawahara T, Kaj iwara A, Hishinuma I, circulation.2003, 108 Supliula.17, IV-280; DeriyaanBP, Damido BP, Addre J, Goddle MR J, Gorder J.304, Zoogl Mf, Maradrol J.D.M.304). Alternatively, guinea pigs which have been pretreated with inhibitors of PAR-3 and/or PAR-4 (Leger AJ et al Circulation 2006, 113, 1244-and 1254), or transgenic PAR-3-and/or PAR-4-knocked-down guinea pigs may be used.

B) impaired coagulation and organ dysfunction under disseminated intravascular coagulation conditions (DIC)

The compounds of the invention can be tested in suitable animal species in models of DIC and/or sepsis. Suitable animal species are guinea pigs and in particular primates, and for the study of the effects of endothelium-modulation and mice and rats (cf. Kogushi M, Kobayashi H, Matsuoka T, Suzuki S, Kawahara T, Kai iwara A, Hishinuma I, Circulation2003, 108Suppl.17, IV-280; Derian CK, Damiano BP, Addo MF, Darrow AL, D' Andrea MR, Newan delM, Zhang H-C, Maryanoff BE, Andrad-Gordon P, J.Pharmacol Exp.Ther.2003, 304, 855-; Kaneider NC et AL, Nat munol, 2007, 8, 1303-12; Camer E et AL, Blood, 2006, 107, 3912-21; Riewald M et AL, Biowald 280, 19814). Alternatively, guinea pigs which have been pretreated with inhibitors of PAR-3 and/or PAR-4 (Leger AJ et al Circulation 2006, 113, 1244-and 1254), or transgenic PAR-3-and/or PAR-4-knocked-down guinea pigs may be used.

3.b.1)Thrombin-antithrombin complexes

The thrombin-antithrombin complex (hereinafter referred to as "TAT") is a scale of endogenous formation of thrombin through coagulation activation. TAT was determined by ELISA assay (Enzygnost TATmicro, Dade-Behring). Plasma was obtained from citrated blood by centrifugation. Mu.l TAT sample buffer was added to 50. mu.l plasma, briefly shaken and incubated for 15min at room temperature. The sample was filtered with suction and the wells were washed 3 times with wash buffer (300 μ L/well). Between washing steps, the plate was tapped to remove any residual wash buffer. Conjugate solution (100 μ L) was added and the mixture was incubated at room temperature for 15 min. The sample was filtered with suction and the wells were washed 3 times with wash buffer (300 μ L/well). Chromogenic substrate (100. mu.L/well) was then added, the mixture incubated in the dark at room temperature for 30min, stop solution (100. mu.L/well) was added, and development of the color was measured at 492nm (Safire plate reader).

3.b.2)Parameters of organ dysfunction

Various parameters were determined which allowed conclusions to be drawn in view of the functional limitations of various internal organs due to the administration of LPS, and the therapeutic effect of the test substance to be estimated. Citrate blood or, if appropriate, lithium heparin blood is centrifuged and the plasma is used to determine the parameters. Generally, the following parameters were determined: creatinine, urea, aspartate Aminotransferase (AST), alanine Aminotransferase (ALT), total bilirubin, Lactate Dehydrogenase (LDH), total protein, total albumin, and fibrinogen. This value gives information about renal function, liver function, cardiovascular function and vascular function.

3.b.3)Parameters of inflammation

The extent of the inflammatory response by endotoxin can be shown by the rise in plasma inflammatory mediators, such as interleukins (1, 6, 8 and 10), tumor necrosis factor alpha or monocyte chemoattractant protein-1. ELISA or Luminex systems can be used for this purpose.

3.c) antitumor Activity

The compounds of the invention can be tested in models of cancer, for example in the human breast cancer model in immunocompromised mice (cf. S.Evan-Ram et al, Nature Medicine, 1988, 4, 909-914).

3.d) anti-angiogenic Activity

The compounds of the invention can be tested in vitro and in vivo models of angiogenesis (see: Caunt et al, Journal of Thrombosis and Haemostasis, 2003, 10, 2097-.

E) blood pressure-and pulse-modulating activity

The compounds of the invention can be tested in an in vivo model for their effect on arterial blood pressure and heart rate. For this purpose, rats (e.g. adult rats) were fitted with an implanted radiotelemetry device and used an electronic Data acquisition and storage system (Data Sciences, MN, usa) consisting of a long-term implanted sensor/transmitter device combined with a fluid-filled catheter. The transmitter is implanted in the peritoneal cavity and the sensor catheter is positioned in the descending aorta. The compounds of the invention may be administered (e.g., orally or intravenously). Prior to treatment, mean arterial blood pressure and heart rate were determined for untreated and treated animals and were guaranteed to be in the range of approximately 131-. PAR-1-activating peptide (SFLLRN; e.g. at a dose of 0.1-5mg/kg) is administered intravenously. Blood pressure and heart rate were measured at various time intervals and durations with and without PAR-1-activating peptide and with and without a compound of The invention (see: Cicala C et al, The FASEB Journal, 2001, 15, 1433-5; Stasch JP et al, British Journal of Pharmacology 2002, 135, 344-355).

3.f) thrombosis model

In vivo thrombosis assays further suitable for determining the efficacy of the compounds of the invention are described in Tucker EI, Marzec UM, White TC, Hurst S, Rugonyi S, McCarty OJT, Gailani D, Gruber A, Hanson SR: described in the preservation of vascular graft encapsulation and chromatography-associated chromatography generation by inhibition of factor XI. blood 2009, 113, 936-944.

4.)Determination of solubility

Preparation of the starting solution (original solution):

at least 1.5mg of test substance was accurately weighed into a wide-mouth 10mm spiral V-bottle (from Glastechnik) equipped with a screw cap and a septumGmbH, article No. 8004-WM-H/V15 μ), DMSO is added to a concentration of 50mg/ml and the bottles are spun for 30 minutes.

Preparation of calibration solutions:

the necessary pipetting steps were carried out in 1.2ml 96-well deep-well plates (DWP) by means of a robot handling liquids. The solvent used was an acetonitrile/water 8: 2 mixture.

Preparation of starting solution for calibration solution (stock solution): to 10 μ l of the original solution (concentration 600 μ g/ml) was added 833 μ l of the solvent mixture and the mixture was homogenized. A1: 100 dilution was prepared from each test substance in a separate DWP, and these were homogenized in turn.

Calibration solution 5(600 ng/ml): to 30. mu.l of the stock solution 270. mu.l of the solvent mixture are added and the mixture is homogenized.

Calibration solution 4(60 ng/ml): to 30 μ l of calibration solution 5 270 μ l of the solvent mixture was added and the mixture was homogenized.

Calibration solution 3(12 ng/ml): to 100. mu.l of calibration solution 4, 400. mu.l of the solvent mixture are added and the mixture is homogenized.

Calibration solution 2(1.2 ng/ml): to 30 μ l of calibration solution 3, 270 μ l of the solvent mixture was added and the mixture was homogenized.

Calibration solution 1(0.6 ng/ml): to 150 μ l of calibration solution 2, 150 μ l of the solvent mixture was added and the mixture was homogenized.

Preparation of sample solution:

the necessary pipetting steps were performed in a 1.2ml 96-well DWP by means of a robot handling the liquid. To 10.1. mu.l of the stock solution was added 1000. mu.l of PBS buffer, pH 6.5. (PBS buffer pH 6.5: 61.86g sodium chloride, 39.54g sodium dihydrogen phosphate and 83.35g 1N sodium hydroxide solution weighing into a 1 liter standard bottle and using water to make up for the mark, and the mixture is stirred for about 1 hour, to the 5 liter standard bottle adding 500ml of the solution and using water to make up for the mark, using 1N sodium hydroxide solution pH adjustment to 6.5)

The method comprises the following steps:

the necessary pipetting steps were performed in a 1.2ml 96-well DWP by means of a robot handling the liquid. The sample solution prepared in this way was shaken at 1400rpm and at 20 ℃ for 24 hours using a temperature-variable shaker. From each of these solutions 180. mu.l were collected and transferred into Beckman Polyallemer centrifuge tubes. These solutions were centrifuged at about 223000 Xg for 1 hour. From each sample solution, 100. mu.l of the supernatant was removed and diluted 1: 10 and 1: 1000 with PBS buffer 6.5.

And (3) analysis:

samples were analyzed by HPLC/MS-MS. Test compounds were quantified by a five point calibration curve. The solubility is expressed in mg/l. Analysis sequence: 1) blank (solvent mixture); 2) 0.6ng/ml of calibration solution; 3) calibration solution 1.2 ng/ml; 4) calibration solution 12 ng/ml; 5) calibration solution 60 ng/ml; 6) the calibration solution is 600 ng/ml; 7) blank (solvent mixture); 8) sample solution 1: 1000; 9) sample solution 1: 10.

HPLC/MS-MS method:

HPLC: agilent 1100, dosing pump (G1311A), autosampler CTC HTSPAL, degasser (G1322A) and column oven (G1316A); column: oasis HLB20mm × 2.1mm, 25 μ; temperature: 40 ℃; eluent A: water +0.5ml formic acid/L; eluent B: acetonitrile +0.5ml formic acid/L; flow rate: 2.5 ml/min; the stopping time is 1.5 min; gradient: 0min 95% A, 5% B; gradient: 0-0.5min 5% A, 95% B; 0.5-0.84min 5% A, 95% B; gradient: 0.84-0.85min 95% A, 5% B; 0.85-1.5min 95% A, 5% B. MS/MS: waters Quattro Micro Tandem MS/MS; a Z-Spray API interface; HPLC-MS import separator 1: 20; measured in ESI mode.

5.) determination of pharmacokinetics in vivo

To determine the pharmacokinetics in vivo, the test substances are dissolved in different formulation media (e.g.plasma, ethanol, DMSO, PEG400, etc.) or mixtures of these solubilizers and administered intravenously or orally to mice, rats, dogs or monkeys. Administered intravenously as boles or as infusions. The dosage is in the range of 0.1 to 5 mg/kg. Blood samples were collected through the catheter or as sacrificial plasma over up to 26h at different times. In addition, samples of organs, tissues and urine were obtained. The substance is quantitatively determined in the sample by a calibration sample formed in a particular matrix. Proteins present in the sample are removed by precipitation with acetonitrile or methanol. Subsequently, the samples were subjected to HPLC on 2300HTLC system (pharmaceutical Technologies, Franklin, Mass., USA) or Agilent 1200 (America) Germany) using a reverse-phase column. The HPLC system was coupled by turbo-ion spray coupled to an API 3000 or 4000 triple quadrupole mass spectrometer (Applied Biosystems, Darmstadt, germany). Plasma concentration versus time curves were evaluated using a validated kinetic evaluation procedure.

C)Working examples of pharmaceutical compositions

The substances of the invention can be converted into the following pharmaceutical preparations:

and (3) tablet preparation:

composition (A):

100mg of the compound according to example 1, 50mg of lactose (monohydrate), 50mg of maize starch, 10mg of polyvinylpyrrolidone (PVP 25) (from BASF, Germany) and 2mg of magnesium stearate.

The tablet had a weight of 212mg, a diameter of 8mm and a radius of curvature of 12 mm.

Production:

the mixture of compound of example 1, lactose and starch was granulated with a 5% strength solution (m/m) of PVP in water. The granules were dried and mixed with magnesium stearate for 5 minutes. The mixture is compressed with a conventional tablet press (see above for tablet forms).

Oral suspension:

composition (A):

1000mg of the compound of example 1, 1000mg of ethanol (96%), 400mg of Rhodigel (xanthan gum) (from FMC, USA) and 99g of water.

A single dose of 100mg of a compound of the invention corresponds to 10ml of an oral suspension.

Production:

rhodigel is suspended in ethanol and the compound of example 1 is added to the suspension. Water was added while stirring. The mixture was stirred for about 6h until the Rhodigel had finished swelling.

Solutions that can be taken intravenously:

composition (A):

1mg of the compound of example 1, 15g of polyethylene glycol 400 and 250g of water for injection.

Production:

the compound of example 1 was dissolved along with polyethylene glycol 400 by stirring in water. The solution was sterile filtered (pore diameter 0.22 μm) and formulated under sterile conditions into heat-sterilized infusion bottles. The latter is sealed with an infusion stopper and a roll-pull cover.

Claims

1. A compound of the formula

Wherein

A is an oxygen atom or-NR⁴-，

Wherein

R⁴Is hydrogen or C₁-C₃-an alkyl group,

or

R¹is a phenyl group, and the phenyl group,

wherein cycloalkyl, heterocyclyl, phenyl and heteroaryl may be substituted with 1 to 3 substituents independently selected from halogen, cyano, hydroxy, amino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, C ₁-C₄-alkyl radical, C₁-C₄-alkoxy radical, C₁-C₆-substituents of alkylamino and phenyl,

and

wherein C is₁-C₆The alkyl group may be substituted by one or more groups selected from hydroxy, trifluoromethyl, C₁-C₄-alkoxy radical, C₁-C₄-alkylsulfonyl, C₃-C₆-cycloalkyl and phenyl substituents,

wherein cycloalkyl and phenyl may be substituted by 1 to 3 substituents independently selected from halogen, cyano, monofluoromethyl, bisFluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, C₁-C₄-alkyl and C₁-C₄-a substituent of an alkoxy group,

R³is C₁-C₆-alkyl radical, C₁-C₆-alkoxy radical, C₁-C₆-alkylamino radical, C₃-C₇Cycloalkyl, 4-to 7-membered heterocyclyl, phenyl, 5-or 6-membered heteroaryl, C₃-C₇-cycloalkyloxy radical, C₃-C₇Cycloalkylamino, 4-to 7-membered heterocyclylamino, phenylamino or 5-or 6-membered heteroarylamino,

and

wherein cycloalkyl, heterocyclyl, phenyl, heteroaryl, cycloalkyloxy, cycloalkylamino, heterocyclylamino, phenylamino and heteroarylamino may be substituted with 1 to 3 substituents independently selected from halogen, cyano, oxo, hydroxy, amino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, hydroxycarbonyl, aminocarbonyl, C ₁-C₄-alkyl radical, C₁-C₄-alkoxy radical, C₁-C₆-alkylamino radical, C₁-C₄Alkoxycarbonyl radical, C₁-C₄-substituents of alkylaminocarbonyl and cyclopropyl,

wherein the alkyl group may be substituted with one hydroxy substituent,

or a salt thereof, solvate thereof or solvate of a salt thereof.

2. A compound according to claim 1, characterized in that

A is an oxygen atom, and A is an oxygen atom,

R¹is a phenyl group, and the phenyl group,

wherein phenyl is substituted with 1 to 2 substituents independently selected from the group consisting of fluorine, trifluoromethoxy, 1, 1-difluoroethyl, 2, 2, 2-trifluoroethyl, trifluoromethoxy and ethyl,

R²is a methyl, ethyl or isopropyl group,

or a salt thereof, solvate thereof or solvate of a salt thereof.

3. A compound according to claim 1 or 2, characterized in that

A is an oxygen atom, and A is an oxygen atom,

R¹is a phenyl group, and the phenyl group,

R²Is an ethyl group, and the compound is,

wherein the ethyl group may be substituted with one methoxy substituent,

R³is 1-oxothiomorpholin-4-yl or 1, 1-dioxothiomorpholin-4-yl,

or a salt thereof, solvate thereof or solvate of a salt thereof.

4. A compound according to any one of claims 1 to 3, characterized in that-R¹And 1, 2, 4-The oxadiazol-5-yl substituents are in cis position to each other.

5. A process for the preparation of a compound of formula (I) or one of its salts, its solvate or solvate of its salt according to claim 1, characterized in that

[A] A compound of the formula

Wherein

R¹And R³Each as defined in claim 1

With a compound of the formula

Wherein

A and R²Each as defined in claim 1

Or

[B] A compound of the formula

Wherein

R¹And R³Each as defined in claim 1

With a compound of the formula

Wherein

A and R²Each as defined in claim 1

Or

[C] A compound of the formula

Wherein

A，R¹And R²Each as defined in claim 1

With 0.8 to 1.1 equivalents of m-chloroperoxybenzoic acid to produce the compound of the formula

Wherein

A，R¹And R²Each as defined in claim 1

Or

[D] Reacting the compound of formula (Ia) with 2.0 to 3.0 equivalents of m-chloroperoxybenzoic acid to produce a compound of the formula

Wherein

A，R¹And R²Each as defined in claim 1

Or

[E] A compound of the formula

Wherein

A，R¹And R²Each as defined in claim 1

With a compound of the formula

Wherein

R³As defined in claim 1 and

X¹is halogen, preferably bromine or chlorine, or hydroxyA group or a 4-nitrophenoxy group,

or

R³-H (XVI)，

Wherein

R³As defined in claim 1.

6. Compounds according to any one of claims 1 to 4 for the treatment and/or prophylaxis of diseases.

7. The use of compounds according to any one of claims 1 to 4 for the preparation of medicaments for the treatment and/or prophylaxis of diseases.

8. The use of compounds according to any one of claims 1 to 4 for the preparation of medicaments for the treatment and/or prophylaxis of cardiovascular diseases, thromboembolic diseases and/or tumour diseases.

9. The use of a compound according to any one of claims 1 to 4 for preventing extracorporeal blood coagulation.

10. A medicament comprising a compound according to any one of claims 1 to 4 in association with an inert, non-toxic, pharmaceutically acceptable excipient.

11. A medicament comprising a compound according to any one of claims 1 to 4 in association with a further active ingredient.

12. A medicament according to claim 10 or 11 for the treatment and/or prophylaxis of cardiovascular diseases, thromboembolic diseases and/or tumour diseases.

13. A method for the treatment and/or prophylaxis of thromboembolic disorders in humans and animals using an anticoagulant effective amount of at least one compound according to any one of claims 1 to 4, a medicament according to any one of claims 10 to 12 or a medicament obtained according to claim 7 or 8.

14. Method for preventing extracorporeal blood coagulation, characterized in that an anti-coagulatively effective amount of a compound according to any of claims 1 to 4 is added.