HK1170234B

HK1170234B - Substituted piperidines as par-1 antagonists

Info

Publication number: HK1170234B
Application number: HK12110942.4A
Authority: HK
Inventors: Mario Jeske; Dirk Heimbach; Susanne Röhrig; Yolanda Cancho Grande; Dirk Schneider; Ulrich Rester; Eckhard Bender; Mark Meininghaus; Katja Zimmermann; Dmitry Zubov; Anja BUCHMÜLLER; Georges Von Degenfeld; Christoph Gerdes; Michael Gerisch; Mark Jean Gnoth; Kersten Matthias GERICKE
Original assignee: Bayer Intellectual Property Gmbh
Priority date: 2009-03-23
Filing date: 2010-03-12
Publication date: 2015-08-14

Description

Substituted piperidines as PAR-1 antagonists

The present invention relates to novel substituted piperidines, to a process for their preparation, to their use for the treatment and/or prophylaxis of diseases and to their use for the preparation of medicaments for the treatment and/or prophylaxis of diseases, in particular cardiovascular and tumor disorders.

Platelets are an important factor in physiological hemostasis and in thromboembolic diseases. Especially in the arterial system, platelets are of central importance in the complex interaction between blood components and the vessel wall. Undesired platelet activation can lead to life-threatening thromboembolic disorders and thrombotic complications through the formation of platelet-rich thrombi.

One of the most potent platelet activators is the blood coagulation protease thrombin, which is formed on injured blood vessel walls and leads to activation of platelets, endothelial cells and mesenchymal cells in addition to fibrin formation (Vu TKH, Hung DT, Wheaton VI, Coughlin SR, Cell 1991, 64, 1057-. Thrombin inhibitors inhibit platelet aggregation and platelet-rich thrombus formation in vitro in platelets and in animal models. In humans, arterial thrombus formation can be successfully prevented or treated with inhibitors of platelet function and thrombin inhibitors (Bhatt DL, Topol EJ, nat. rev. Drug discov. 2003, 2, 15-28). Thus, it is likely that antagonists of the platelet action of thrombin will reduce the formation of thrombi and the occurrence of clinical sequelae such as myocardial infarction and stroke. Thrombin may cause inflammation and proliferative disorders, for example, on endothelial cells and smooth muscle cells of blood vessels, on leukocytes and on other cellular effects of fibroblasts.

The cellular actions of thrombin are mediated at least sometimes via a family of G protein-coupled receptors (protease activated receptors, PAR), the prototype of which is the PAR-1 receptor. PAR-1 is activated by the binding of thrombin and its proteolytic cleavage at the extracellular N-terminus. This proteolysis exposes a new N-terminus with the amino acid sequence SFLLRN …, which acts as an agonist ("Tethered Ligand") leading to intramolecular receptor activation and transmission of intracellular signals. Peptides derived from tethered ligand sequences can act as agonists of the receptor and act on platelets, leading to activation and aggregation. Other proteases are likewise capable of activating PAR-1, and these include, for example, plasmin, factor VIIa, factor Xa, trypsin, activated protein C (aPC), tryptase, cathepsin G, protease 3, granzyme A, elastase and matrix metalloproteinase 1 (MMP-1).

In contrast to inhibition of the protease activity of thrombin by direct thrombin inhibitors, blockade of PAR-1 will result in inhibition of platelet activation, but not reduction of blood coagulability (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-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR, J. Clin. invest. 1999, 103, 879-. Another thrombin receptor of possible importance for the pathophysiology of the thrombotic process, namely PAR-4, has been identified on human and animal platelets. In experimental thrombosis in animals with PAR expression patterns comparable to humans, PAR-1 antagonists reduce platelet-rich thrombus formation (Derian CK, Damiano BP, Addo MF, Darrow AL, D' Andrea MR, Nedelman M, Zhang H-C, Maryanoff BE, Andrew-Gordon P, J. Pharmacol. exp. Ther. 2003, 304, 855-.

Over the past several years, many substances have been investigated for their platelet function inhibitory effects; however, in practice, only a few inhibitors of platelet function have proven useful. Thus, there remains a need for agents that specifically inhibit increased platelet response, but do not significantly increase the risk of bleeding, and thus reduce the risk of thromboembolic complications.

Thrombin action mediated via the receptor PAR-1 can affect disease progression during and after Coronary Artery Bypass Graft (CABG) and other surgical procedures and particularly those involving extracorporeal circulation (e.g., heart-lung machine). During surgery, there may be bleeding complications due to pre-or intra-operative drug treatment with aggregation inhibiting substances and/or platelet inhibiting substances. For this reason, for example, drug therapy with clopidogrel must be discontinued several days before CABG. Furthermore, as already mentioned (for example due to the extensive contact between blood and artificial surfaces during the use of extracorporeal circulation or blood transfusions), diffuse intravascular coagulopathy or consumption coagulopathy (DIC) can develop, which can subsequently lead to bleeding complications. In further progress, restenosis of the overlapping venous or arterial bypass tube (which may even lead to occlusion) often occurs for the following reasons: thromboembolism, intimal fibrosis, arteriosclerosis, angina pectoris, myocardial infarction, heart failure, arrhythmia, Transient Ischemic Attack (TIA) and/or stroke.

In humans, the receptor PAR-1 may also be expressed in other cells, including, for example, endothelial cells, smooth muscle cells and tumor cells. Malignant neoplastic disease (cancer) has a high incidence and is generally associated with a high mortality rate. Current treatments achieve adequate symptomatic relief in only a small fraction of patients and are typically associated with severe side effects. Therefore, there is a high need for more efficient and safer treatments. The PAR-1 receptor contributes to cancer development, growth, invasion and metastasis. In addition, PAR-1 expressed on endothelial cells mediates signals leading to vascular growth ("angiogenesis"), which is the ability to grow tumors to greater than about 1mm³Is a very critical process. AngiogenesisOther conditions may also be promoted or exacerbated, including, for example, blood cancers, macular degeneration leading to blindness, and diabetic retinopathy, inflammatory conditions such as rheumatoid arthritis and colitis.

Sepsis (or septicemia) is a frequent condition with a high mortality rate. The initial symptoms of sepsis are typically unspecific (e.g., fever, general decline in health); however, with further progression of the disorder, there may be general activation of the coagulation system ("disseminated intravascular coagulation" or "disseminated coagulopathy" (DIC)) and microthrombosis formation and secondary bleeding complications in various organs. DIC may also occur independently of sepsis, for example during surgery or in oncological disorders.

One aspect of the treatment of sepsis is the complete elimination of the infectious cause, e.g., by surgical removal of the lesion and by antibiotic action. On the other hand, it consists in a temporary in-depth medical support of the affected organ system. The treatment of different stages of the disease has been described, for example, in the following publications (Dellinger et al, Crit. Care Med. 2004, 32, 858-873). No effective treatment has been demonstrated for DIC.

It is therefore an object of the present invention to provide novel PAR-1 antagonists which are useful in the treatment of disorders such as cardiovascular diseases and thromboembolic diseases, as well as neoplastic diseases in humans and animals.

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

The present invention provides compounds of the formula

Wherein

A represents a group of the formula

Wherein

# is the point of attachment to the piperidine ring,

is to R²The connection point of (a) is,

R⁴represents hydrogen or C₁-C₃-an alkyl group,

and

R⁵represents hydrogen or C₁-C₃-an alkyl group,

R¹represents a phenyl group, and is represented by,

wherein phenyl can be substituted with 1 to 3 substituents independently selected from: monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, methylsulfonyl, C₁-C₄-alkyl radical, C₁-C₄-alkoxy and C₁-C₄-an alkoxycarbonyl group, a carbonyl group,

R²is represented by C₁-C₆-alkyl radical, C₃-C₆-cycloalkyl, 4-to 6-membered heterocyclyl, phenyl, 2, 2-difluoro-1, 3-benzodioxolyl or 5-or 6-membered heteroaryl,

wherein cycloalkyl, heterocyclyl, phenyl and heteroaryl can be substituted by 1 to 3 substituents which are selected independently of one another from: halogen, cyano, hydroxy, amino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, C₁-C₄-alkyl radical, C₁-C₄-alkoxy radical, C₁-C₆-an alkylamino group and a phenyl group,

wherein phenyl can be substituted with 1 to 3 substituents independently selected from: a halogen and a trifluoromethyl group, and a pharmaceutically acceptable salt thereof,

and

wherein C is₁-C₄-the alkyl group can be substituted with a substituent selected from: c₃-C₆-a cycloalkyl group and a phenyl group,

wherein cycloalkyl and phenyl can be substituted with 1 to 3 substituents independently selected from: halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, C₁-C₄-alkyl and C₁-C₄-an alkoxy group,

R³is represented by C₁-C₆-alkyl radical, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy radical, C₁-C₆-alkylamino radical, C₃-C₇Cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-or 6-membered heteroaryl, C₃-C₇-cycloalkyloxy radical, C₃-C₇Cycloalkylamino, 4-7 membered heterocyclylamino, phenylamino or 5-or 6-membered heteroarylamino,

wherein alkyl is C₂-C₆-alkoxy and alkylamino can be substituted by a substituent selected 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,

wherein alkoxy can be substituted by C₁-C₄-substituted by an alkoxy substituent,

and

wherein cycloalkyl, heterocyclyl, phenyl, heteroaryl, cycloalkyloxy, cycloalkylamino, heterocyclylamino, phenylamino and heteroarylamino can be substituted by 1 to 3 substituents which are independent of one anotherSubstituted with a substituent 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-C₄-an alkylaminocarbonyl group and a cyclopropyl group,

wherein the alkyl group can be substituted with a hydroxy substituent,

and salts, solvates and solvates of salts thereof.

The compounds according to the invention are: the compounds of formula (I) and their salts, solvates and solvates of the salts, the compounds of the following formula, encompassed by formula (I) and their salts, solvates and solvates of the salts, and the compounds encompassed by formula (I) and their salts, solvates and solvates of the salts mentioned below as embodiments, provided that the compounds encompassed by formula (I) mentioned below are not already salts, solvates and solvates of the salts.

Depending on their structure, the compounds according to the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The present invention thus encompasses enantiomers or diastereomers and their respective mixtures. The enantiomerically identical components can be separated off from this mixture of enantiomers and/or diastereomers in a known manner.

When a compound according to the invention may occur in tautomeric forms, the invention encompasses all tautomeric forms.

In the context of the present invention, preferred salts are the physiologically acceptable salts of the compounds according to the invention. However, the invention also covers salts which are not suitable for pharmaceutical use per se, but which can be used, for example, for isolating or purifying the compounds according to the invention.

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

Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, for example and preferably alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms, 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, solvates are those forms of the compounds according to the invention which form complexes by coordination with solvent molecules in the solid or liquid state. Hydrates are a particular form of solvate where coordination with water is achieved.

Furthermore, the present invention also includes prodrugs of the compounds according to the invention. The term "prodrug" includes compounds which may themselves be biologically active or inactive, but which are converted (e.g. by metabolism or hydrolysis) to a compound according to the invention during the in vivo residence time.

In the context of the present invention, unless otherwise indicated, the substituents are as defined below:

alkyl as such and "alkyl" in alkoxy, alkylamino, alkoxycarbonyl, and alkylaminocarbonyl denotes straight or branched chain alkyl groups having 1 to 6 carbon atoms, such as for example and preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl and n-hexyl.

The alkenyl group represents a straight or branched alkenyl group having 2 to 6 carbon atoms. Preference is given to straight-chain or branched alkenyl having 2 to 4, particularly preferably 2 or 3, carbon atoms. The following groups may be mentioned by way of example and preference: vinyl, allyl, n-prop-1-en-1-yl and n-but-2-en-1-yl.

Alkynyl represents straight-chain or branched alkynyl having 2 to 6 carbon atoms. Preference is given to straight-chain or branched alkynyl having 2 to 4, particularly preferably 2 to 3, carbon atoms. The following groups may be mentioned by way of example and preference: ethynyl, n-prop-2-yn-1-yl and n-butyl-3-yn-1-yl.

For example and preferably, alkoxy represents methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.

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

For example and preferably, alkoxycarbonyl denotes methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Alkylaminocarbonyl denotes alkylaminocarbonyl having one or two alkyl substituents, selected independently of one another, such as, and preferably, methylaminocarbonyl, ethylaminocarbonyl, N-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N-diethylaminoAlkylcarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-N-propylaminocarbonyl, N-isopropyl-N-N-propylaminocarbonyl and N-tert-butyl-N-methylaminocarbonyl. C₁-C₄Alkylaminocarbonyl denotes, for example, monoalkylaminocarbonyl having 1 to 4 carbon atoms or dialkylaminocarbonyl having in each case 1 to 4 carbon atoms per alkyl substituent.

Cycloalkyl represents monocyclic cycloalkyl having typically 3 to 7, preferably 5 or 6, carbon atoms; cycloalkyl which may be mentioned by way of example and preferably is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Cycloalkyloxy represents monocyclic cycloalkyloxy having typically 3 to 7, preferably 5 or 6, carbon atoms; cycloalkyloxy which may be mentioned by way of example and preferably is cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.

Cycloalkylamino represents monocyclic cycloalkylamino having typically 3 to 7, preferably 3 or 4, carbon atoms; cycloalkylamino which may be mentioned by way of example and preferably is cyclopropylamino, cyclobutylamino, cyclopentylamino and cyclohexylamino.

Heterocyclyl represents a monocyclic or bicyclic heterocyclyl having 4 to 7 ring atoms and up to 3, preferably up to 2, ring atoms selected from N, O, S, SO₂Wherein the nitrogen atom may also form an N-oxide, and/or a heterogroup (heterologruppe). The heterocyclyl group may be saturated or partially unsaturated. Preference is given to 5-or 6-membered monocyclic saturated heterocyclic radicals having up to two heteroatoms from the group 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, piperazin-1-yl, piperazin-2-yl.

Heterocyclylamino represents a monocyclic or bicyclic heterocycleHeterocyclylamino having 4 to 7 ring atoms and up to 3, preferably up to 2, atoms selected from N, O, S, SO₂Wherein the nitrogen atom may also form an N-oxide. The heterocyclyl group may be saturated or partially unsaturated. Preferred 5-or 6-membered monocyclic saturated heterocyclic groups have up to two heteroatoms selected from O, N and S, such as and preferably oxetanylamino, azetidinylamino, pyrrolidin-2-ylamino, pyrrolidin-3-ylamino, tetrahydrofurylamino, tetrahydrothienylamino, pyranylamino, piperidin-2-ylamino, piperidin-3-ylamino, piperidin-4-ylamino, 1,2,5, 6-tetrahydropyridin-3-ylamino, 1,2,5, 6-tetrahydropyridin-4-ylamino, thiopyranylamino, morpholin-2-ylamino, morpholin-3-ylamino, piperazin-2-ylamino.

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

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

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

In the formulae of the groups which may represent A, the end points of the line segments marked by #, do not represent a carbon atom or CH₂A group is part of the bond of the atom to which a is attached.

Preferred are compounds of formula (I), wherein

A represents a group of the formula

Wherein

# is the point of attachment to the piperidine ring,

is to R²The connection point of (a) is,

R⁴represents hydrogen or C₁-C₃-an alkyl group,

and

R⁵represents hydrogen or C₁-C₃-an alkyl group,

R¹represents a phenyl group, and is represented by,

wherein phenyl is substituted with 1 to 3 substituents independently selected from: trifluoromethyl, trifluoromethoxy, C₁-C₄-alkyl radical, C₁-C₄-alkoxy and C₁-C₄-an alkoxycarbonyl group, a carbonyl group,

wherein cycloalkyl, heterocyclyl, phenyl and heteroaryl can be substituted by 1 to 3 substituents which are selected independently of one another from: halogen, cyano, hydroxy, amino, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy and phenyl,

and

wherein C is₁-C₂-the alkyl group can be substituted by a phenyl substituent,

wherein phenyl can be substituted with 1 to 3 substituents independently selected from: halogen, cyano, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy and ethoxy,

and

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

wherein the methyl and ethyl groups can be substituted with hydroxy substituents,

and salts, solvates and solvates of salts thereof.

Also preferred are compounds of formula (I), wherein

A represents a group of the formula

Wherein

# is the point of attachment to the piperidine ring,

is to R²The connection point of (a) is,

R⁴represents hydrogen or a methyl group,

and

R⁵represents hydrogen or a methyl group,

R¹represents a phenyl group, and is represented by,

wherein phenyl is substituted with 1 to 2 substituents independently selected from: trifluoromethyl, trifluoromethoxy, methyl, ethyl, isopropyl, methoxy and ethoxycarbonyl,

R²represents methyl, ethyl, isopropylA group, tert-butyl, cyclopropyl, cyclopentyl, pyrrolidinyl, piperazinyl, phenyl, 2, 2-difluoro-1, 3-benzodioxolyl, thienyl, thiazolyl or pyridyl,

wherein cyclopentyl, piperazinyl, phenyl, thienyl, thiazolyl and pyridyl can be substituted with 1 to 2 substituents independently selected from: halogen, cyano, hydroxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy and phenyl,

wherein phenyl can be substituted with 1 to 2 substituents independently selected from: a halogen and a trifluoromethyl group, and a pharmaceutically acceptable salt thereof,

and

wherein the methyl group can be substituted with a phenyl substituent,

R³represents methyl, ethyl, isopropyl, tert-butyl, ethoxy, ethylamino, tert-butylamino, N-methyl-N-ethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, morpholin-4-yl, thiomorpholin-4-yl, 1, 1-thiomorpholin-4-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, phenyl, pyrrolyl, furanyl, thiazolyl, pyrazolyl, pyridyl, cyclopentyloxy, cyclohexylamino, phenylamino or pyridylamino,

wherein methyl, ethyl, isopropyl, tert-butyl, ethoxy and ethylamino can be substituted with a substituent selected from the group consisting of: halogen, hydroxy, methoxy, cyclopropyl, phenyl, furyl, thienyl and pyrazolyl,

and

wherein cyclopropyl, cyclobutyl, cyclohexyl, tetrahydrofuryl, morpholin-4-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, phenyl, furanyl, thiazolyl, pyrazolyl, pyridyl, cyclohexylamino and phenylamino can be substituted by 1 to 2 substituents independently selected from: halogen, cyano, oxo, hydroxy, amino, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, methyl, ethyl, methoxy, ethoxy, dimethylamino, methoxycarbonyl, ethoxycarbonyl, dimethylaminocarbonyl and cyclopropyl,

and salts, solvates and solvates of salts thereof.

Also preferred are compounds of formula (I), wherein

A represents a group of the formula

Wherein

# is the point of attachment to the piperidine ring,

is to R²The connection point of (a) is,

R⁴represents hydrogen or a methyl group,

and

R⁵represents hydrogen or a methyl group,

R¹represents a phenyl group, and is represented by,

wherein phenyl is substituted with 1 to 2 substituents independently selected from: trifluoromethyl, trifluoromethoxy, methyl and ethyl,

R²represents methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, phenyl, thienyl or pyridyl,

wherein cyclopentyl, phenyl, thienyl and pyridyl can be substituted with 1 to 2 substituents independently selected from the group consisting of: halogen, cyano, trifluoromethyl, trifluoromethoxy, methyl, methoxy and phenyl,

wherein phenyl can be substituted with 1 to 2 substituents independently selected from: chlorine, fluorine and trifluoromethyl,

and

wherein the methyl group can be substituted with a phenyl substituent,

R³represents morpholin-4-yl, 1, 1-thiomorpholin-4-yl, 3-hydroxyazetidin-1-yl, 3-hydroxypyrrolidin-1-yl, 4-cyanopiperidin-1-yl or 4-hydroxypiperidin-1-yl,

and salts, solvates and solvates of salts thereof.

Also preferred are compounds of formula (I), wherein

A represents a group of the formula

Wherein

# is the point of attachment to the piperidine ring,

is to R²The connection point of (a) is,

R¹represents a phenyl group, and is represented by,

and

wherein the methyl group can be substituted with a phenyl substituent,

and salts, solvates and solvates of salts thereof.

Also preferred are compounds of formula (I) wherein the substituent-R¹and-A-R²Are in-line with each other.

Also preferred are compounds of formula (I), wherein

A represents a group of the formula

Wherein

# is the point of attachment to the piperidine ring,

is to R²The connection point of (a).

Also preferred are compounds of formula (I), wherein

A represents a group of the formula

Wherein

# is the point of attachment to the piperidine ring,

is to R²The connection point of (a).

Also preferred are compounds of formula (I), wherein

A represents a group of the formula

Wherein

# is the point of attachment to the piperidine ring,

is to R²The connection point of (a).

Also preferred are compounds of formula (I), wherein

A represents a group of the formula

Wherein

# is the point of attachment to the piperidine ring,

is to R²The connection point of (a).

Also preferred are compounds of formula (I), wherein

A represents a group of the formula

Wherein

# is the point of attachment to the piperidine ring,

is to R²The connection point of (a).

R⁴Represents hydrogen or a methyl group,

and

R⁵represents hydrogen or methyl.

Also preferred are compounds of formula (I), wherein

A represents a group of the formula

Wherein

# is the point of attachment to the piperidine ring,

is to R²The connection point of (a).

Also preferred are compounds of formula (I) wherein R¹Represents phenyl, wherein the phenyl is substituted in the para position to the point of attachment to the pyridine ring with a substituent selected from the group consisting of trifluoromethyl, trifluoromethoxy and ethyl.

Also preferred are compounds of formula (I) wherein R¹Is phenyl, wherein the phenyl is substituted with an ethyl substituent para to the point of attachment to the piperidine ring.

Also preferred are compounds of formula (I), wherein

and

wherein the methyl group can be substituted with a phenyl substituent.

Also preferred are compounds of formula (I) wherein R²Represents a phenyl group.

Also preferred are compounds of formula (I),wherein R is³Represents morpholin-4-yl, 1, 1-thiomorpholin-4-yl, 3-hydroxyazetidin-1-yl, 3-hydroxypyrrolidin-1-yl, 4-cyanopiperidin-1-yl or 4-hydroxypiperidin-1-yl.

Also preferred are compounds of formula (I) wherein R³Represents morpholin-4-yl.

Also preferred are compounds of formula (I) wherein R³Represents 4-hydroxypiperidin-1-yl.

The radical definitions given individually in the respective combinations or preferred combinations of radicals are independent of the respective given combination of radicals and are also optionally replaced by radical definitions of other combinations.

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

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

[A] A compound of formula (II)

Wherein

A，R¹And R²Having the meaning given above, the use of,

with a compound of the formula

Wherein

R³Have the meanings given above, and

X¹represents halogen, preferably bromine or chlorine, or hydroxyl,

or

[B] Reacting a compound of formula (II) with a compound of formula

Wherein

R^3aIs represented by C₁-C₆-alkyl radical, C₃-C₇-cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-or 6-membered heteroaryl,

wherein alkyl can be substituted with a substituent selected from the group consisting of: 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 and heteroaryl can be substituted by 1 to 3 substituents which are selected independently of one another 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-C₄-an alkylaminocarbonyl group and a cyclopropyl group,

wherein the alkyl group can be substituted with a hydroxy substituent,

to obtain a compound of the formula

Wherein

A，R¹，R²And R^3aHaving the meaning given above, the use of,

or

[C] A compound of the formula

Wherein

R¹And R³Having the meaning given above, the use of,

with a compound of the formula

Wherein

R²Have the meanings given above, and

X²represents halogen, preferably bromine or chlorine, or hydroxyl,

to obtain a compound of the formula

Wherein

R¹、R²And R³Having the meaning given above, the use of,

or

[D] Reacting a compound of formula (V) with a compound of formula

Wherein

R²Having the meaning given above, the use of,

to obtain a compound of the formula

Wherein

R¹、R²And R³Having the meaning given above, the use of,

or

[E] Reacting a compound of formula (V) with a compound of formula

Wherein

R²And R⁵Having the meaning given above, the use of,

to obtain a compound of the formula

Wherein

R¹，R²，R³And R⁵Having the meaning given above, the use of,

or

[F] Reaction of a Compound of formula (Id) with a Compound of formula

Wherein

R⁴Have the meanings given above, and

X³represents halogen, preferably iodine, bromine or chlorine,

to obtain a compound of the formula

Wherein

R¹， R²， R³，R⁴And R⁵Having the meaning given above, the use of,

or

[G] Reacting a compound of formula (V) with a compound of formula

Wherein

R²Have the meanings given above, and

X⁴represents a chlorine or a hydroxyl group, or a salt thereof,

to obtain a compound of the formula

Wherein

R¹、R²And R³Having the meaning given above, the use of,

or

[H] A compound of the formula

Wherein

R¹And R³Having the meaning given above, the use of,

first with disuccinimidyl carbonate and then with a compound of the formula

Wherein

R²Having the meaning given above, the use of,

to obtain a compound of the formula

Wherein

R¹、R²And R³Having the meaning given above.

When X is present²Represents halogen according to method [ A]The reaction of (a) is generally carried out in an inert solvent, optionally also in the presence of a base, preferably at a temperature ranging from-30 ℃ to 50 ℃, under atmospheric pressure.

Inert solvents are, for example, tetrahydrofuran, dichloromethane, pyridine, bisAn alkane or dimethylformamide; tetrahydrofuran is preferred.

A base such as triethylamine, diisopropylethylamine or N-methylmorpholine; preference is given to triethylamine or diisopropylethylamine.

When X is present²When representing a hydroxyl group, according to the method [ A ]]The reaction of (a) 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 atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons, such as methylene chloride or chloroform, hydrocarbons, such as benzene, nitromethane, bisAlkane, dimethylformamide or acetonitrile. Mixtures of solvents may likewise be used. Particularly preferred is dichloromethane or dimethylformamide.

Suitable dehydrating agents 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 such as 2-ethyl-5-phenyl-1, 2-Azole-3-sulfate or 2-tert-butyl-5-methyliso-ylAzolePerchlorates, or amide compounds, e.g. 2-ethylOxy-1-ethoxycarbonyl-1, 2-dihydroquinoline, propanephosphonic anhydride, isobutyl chloroformate, or bis (2-oxo-3-)Oxazolidinyl) phosphoryl chloride or benzotriazolyloxytris (dimethylamino)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 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.

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

The reaction according to process [ B ] is generally carried out in an inert solvent, optionally in the presence of a base, preferably at a temperature ranging from 0 ℃ to 50 ℃ and under atmospheric pressure.

Inert solvents are, for example, tetrahydrofuran, dichloromethane, bisAn alkane or dimethylformamide; tetrahydrofuran is preferred.

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

The reaction according to Process [ C ] is carried out as described for Process [ A ].

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

The reaction according to Process [ D ] is carried out as described for Process [ B ].

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

The reaction according to Process [ E ] is carried out as described for Process [ B ].

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

The reaction according to process [ F ] is generally carried out in an inert solvent, in the presence of a base, optionally in the presence of potassium iodide, preferably at a temperature ranging from room temperature up to reflux of the solvent, at atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons, such as dichloromethane, chloroform or 1, 2-dichloroethane, ethers, such as bisAlkane, tetrahydrofuran or 1, 2-dimethoxyethaneAn alkane, or other solvent such as acetone, dimethylformamide, dimethylacetamide, 2-butanone, or acetonitrile; dimethylformamide is preferred.

The base is, for example, an alkali metal carbonate such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethoxide or potassium tert-butoxide, or an amide such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or an organometallic compound such as butyllithium or phenyllithium, or another base such as sodium hydride, DBU; sodium hydride is preferred.

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

When X is present²When representing halogen, according to method [ G]The reaction of (a) is generally carried out in an inert solvent, optionally in the presence of a base, preferably at a temperature ranging from 0 ℃ to 50 ℃, under atmospheric pressure.

Inert solvents are, for example, tetrahydrofuran, dichloromethane, pyridine, bisAn alkane or dimethylformamide; preferred is dichloromethane.

When X is present²When representing a hydroxyl group, according to method [ G ]]The reaction of (a) is generally carried out in an inert solvent in the presence of 4-dimethylaminopyridine, optionally in the presence of a base, preferably at a temperature ranging from 0 ℃ to 50 ℃, under atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons, such as methylene chloride or chloroform, hydrocarbons, such as benzene, nitromethane, bisAlkane, dimethylformamide or acetonitrile. Mixtures of solvents may likewise be used. Particular preference is given to dichloromethane or dimethylformamide。

Bases are, for example, organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine; diisopropylethylamine is preferred.

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

The reaction according to process [ H ] is generally carried out in an inert solvent, optionally in the presence of a base, preferably at a temperature ranging from 0 ℃ to 50 ℃ under atmospheric pressure.

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

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

Wherein

A，R¹And R²Having the meaning given above.

The hydrogenation generally uses a reducing agent in an inert solvent, optionally with addition of an acid such as a mineral acid and a carboxylic acid, preferably acetic acid, preferably at a temperature ranging from room temperature to reflux of the solvent and a pressure ranging from atmospheric pressure to 100 bar, preferably from 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; preference is given to hydrogen with palladium-on-activated carbon or with rhodium-on-activated carbon.

Inert solvents are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; methanol or ethanol is preferred.

The compounds of the formula (XIII) are known or can be prepared as follows: reacting a compound of the formula

Wherein

A and R²Having the meaning given above, the use of,

with a compound of the formula

Wherein

R¹Having the meaning given above.

The reaction is generally carried out in an inert solvent in the presence of a catalyst, optionally in the presence of additives, preferably at a temperature ranging from room temperature to reflux of the solvent, at atmospheric pressure.

Inert solvents are, for example, ethers, e.g. diAlkane, 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, some water is added to these solvents. Preferred are mixtures of toluene with water or preferably 1, 2-dimethoxyethane, dimethylformamide and water.

Catalysts are, for example, the palladium catalysts customary for Suzuki reaction conditions; preference is given to catalysts such as dichlorobis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium (0), palladium (II) acetate or bis (diphenylphosphinoferryl) palladium (II) chloride.

Additives are, for example, potassium acetate, cesium carbonate, potassium carbonate or sodium carbonate, barium hydroxide, potassium tert-butoxide, cesium fluoride, potassium fluoride or potassium phosphate; preferred are potassium fluoride or sodium carbonate.

The compounds of the formulae (XIV) and (XV) are known or can be synthesized by known methods from the corresponding starting compounds.

A compound of the formula

Wherein

R¹And R²Having the meaning given above, the use of,

are known or can be prepared as follows: reacting a compound of the formula

Wherein

R¹Having the meaning given above, the use of,

with a compound of the formula

Wherein

R²Having the meaning given above.

The reaction is generally carried out as follows: in an inert solvent, in the presence of a catalyst, in the presence of a ligand, optionally in the presence of an additive, the preferred temperature range is from room temperature to reflux of the solvent at atmospheric pressure.

Inert solvents are, for example, ethers, e.g. diAlkane, 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, some water is added to these solvents. Is preferably twoAn alkane.

Catalysts are, for example, the palladium catalysts customarily used for Buchwald-Hartwig cross-coupling; preferred are catalysts such as dichlorobis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium, palladium (II) acetate or bis (diphenylphosphinoferrocenyl) palladium (II) chloride; tris (dibenzylideneacetone) dipalladium is preferred.

The ligand is, for example, 4, 5-bis (diphenylphosphino) -9, 9' -dimethyl-phosphino)Xanthene, 1, 2-bis (diphenylphosphino) ethane, 2,2' -bis (diphenylphosphino) -1,1' -Binaphthyl (BINAP) and 1,1' -bis (diphenylphosphino) ferrocene; preferred is 4, 5-bis (diphenylphosphino) -9, 9' -dimethylTon.

Additives are, for example, potassium acetate, cesium carbonate, potassium carbonate or sodium carbonate, barium hydroxide, potassium tert-butoxide, cesium fluoride, potassium fluoride or potassium phosphate; cesium carbonate is preferred.

The compounds of the formula (XVI) are known or can be synthesized by known methods from the corresponding starting compounds. The compounds of formula (XVI) can also be synthesized from the corresponding starting compounds using the methods described for the reaction of the compound of formula (XIV) with the compound of formula (XV).

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

The compounds of the formula (V) are known or can be prepared by the following methods: reacting a compound of the formula

Wherein

R¹And R³Having the meaning given above, the use of,

with diphenylphosphoryl azide (Diphenylphosphorazidat), and then optionally working up the reaction with addition of an acid.

The reaction is generally carried out as follows: in a solvent, in the presence of a base, optionally in the presence of di-tert-butyl dicarbonate, optionally in the presence of a molecular sieve, the preferred temperature range is from room temperature to reflux of the solvent at atmospheric pressure.

The solvent is, for example, an alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or a mixture of these alcohols with a hydrocarbon such as benzene, xylene or toluene; preferred is a mixture of t-butanol and toluene.

Bases are, for example, organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine; triethylamine is preferred.

Acids are, for example, trifluoroacetic acid in dichloromethane, or concentrated hydrochloric acid.

The compounds of the formula (XVIII) are known or can be prepared by the following methods: reacting a compound of the formula

Wherein

R¹And R³Have the meanings given above, and

R⁶represents a methyl group or an ethyl group,

reacting with alkali.

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

Inert solvents are, for example, halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride or 1, 2-dichloroethane, 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; preferred is a mixture of 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; lithium hydroxide is preferred.

The compounds of formula (XIX) are known or can be prepared by the following methods: reacting a compound of the formula

Wherein

R¹And R⁶Having the meaning given above, the use of,

with a compound of formula (III).

The reaction was carried out as described for method [ A ].

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

Wherein

R¹And R⁶Having the meaning given above.

The hydrogenation is carried out under reaction conditions for the hydrogenation of the compound of formula (XIII).

The compounds of the formula (XXI) are known or can be prepared by the following methods: reacting a compound of the formula

With a compound of formula (XV).

The reaction is carried out under the reaction conditions given for the reaction of the compound of formula (XIV) with the compound of formula (XV).

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

The compounds of the formula (XI) are known or can be prepared by the following methods: reacting a compound of the formula

Wherein

R¹And R³Having the meaning given above, the use of,

with boron tribromide.

The reaction is generally carried out in an inert solvent, preferably at a temperature ranging from-20 ℃ to room temperature, at atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride or 1, 2-dichloroethane; preferred is dichloromethane.

The compounds of the formula (XXIII) are known or can be prepared by the following methods: reacting a compound of the formula

Wherein

R¹Having the meaning given above, the use of,

with a compound of formula (III).

The reaction was carried out as described for method [ A ].

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

Wherein

R¹Having the meaning given above.

The hydrogenation is carried out under the reaction conditions given for the hydrogenation of the compound of formula (XIII).

The compounds of the formula (XXV) are known or can be prepared by the following method: reacting a compound of the formula

With a compound of formula (XV).

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

The free amino group in the compounds of the above process is optionally protected during the reaction by protecting groups known to those skilled in the art; preferred is a tert-butoxycarbonyl protecting group. After the reaction, these protecting groups are removed using reactions known to those skilled in the art; preference is given to reacting with trifluoroacetic acid or concentrated hydrochloric acid.

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

Scheme 1

。

Scheme 2

。

Scheme 3

。

Scheme 4

。

The compounds according to the invention have an unexpectedly useful spectrum of pharmacological and pharmacokinetic activity. They are selective antagonists of the PAR-1 receptor, in particular as inhibitors of platelet aggregation, as inhibitors of endothelial proliferation and as inhibitors of tumor growth.

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

The invention furthermore provides the use of a compound according to the invention for the treatment and/or prophylaxis of disorders, preferably thromboembolic disorders and/or thromboembolic complications.

"thromboembolic disorders" in the sense of the present invention include, in particular, disorders such as myocardial infarction with ST-elevation (STEMI) and myocardial infarction without ST-elevation (non-STEMI), stable angina pectoris, unstable angina pectoris, reocclusion and restenosis after coronary interventions such as angioplasty, stent implantation or aortic coronary bypass surgery, peripheral arterial occlusive diseases, pulmonary embolism, deep vein thrombosis and renal vein thrombosis, temporary ischemic attacks and thrombotic and thromboembolic strokes.

Thus, the substance is also suitable for use in the prevention and treatment of cardiogenic thromboembolic disorders, such as cerebral ischemia, stroke and systemic thromboembolism and ischemia, in patients suffering from acute, intermittent or persistent cardiac arrhythmias, such as atrial fibrillation, and patients undergoing cardioversion, and also in patients suffering from heart valve disorders or from intravascular objects, such as artificial heart valves, catheters, intra-aortic balloon counterpulsation, and pacemaker probes.

In addition, thromboembolic complications are also encountered in the case of hemolytic anemia of microangiopathy, extracorporeal blood circulation such as hemodialysis, hemofiltration, ventricular assist devices and artificial hearts, and artificial heart valves.

Furthermore, the compounds according to the invention are also useful for influencing wound healing; for the prevention and/or treatment of atherosclerotic vascular disorders and inflammatory diseases such as rheumatism of the locomotor system, coronary heart disease, heart failure, hypertension, inflammatory disorders such as asthma, COPD, inflammatory pulmonary disorders, glomerulonephritis and inflammatory bowel disease; and additionally for the prophylaxis and/or treatment of Alzheimer's disease, autoimmune disorders, Crohn's disease and ulcerative colitis.

Furthermore, the compounds according to the invention can be used for inhibiting tumor growth and lesion metastasis formation, for microangiopathy, age-related macular degeneration, diabetic retinopathy, diabetic nephropathy and other microangiopathies, and for the prevention and treatment of thromboembolic complications such as venous thromboembolism, in tumor patients, especially patients undergoing major surgery or chemical or radiation therapy.

The compounds according to the invention are furthermore suitable for the treatment of cancer. Cancers include, inter alia: carcinomas (including breast, hepatocellular, lung, colorectal, colon, and melanoma), lymphomas (e.g., non-Hodgkin's (Hodgkin) lymphoma and mycosis fungoides), leukemias, sarcomas, mesotheliomas, brain cancers (e.g., glioma), germ cell tumors (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 myeloma.

In addition, PAR-1 expressed on endothelial cells mediates signals leading to vascular growth ("angiogenesis"), which for tumor growth is to greater than about 1mm³Is a very critical process. Induction of angiogenesis is also associated with other disorders; these include conditions of the rheumatic type (e.g. rheumatoid arthritis), pulmonary diseases (e.g. pulmonary fibrosis, pulmonary hypertension, especially pulmonary hypertension, conditions characterised by pulmonary obstruction), arteriosclerosis, atherosclerotic plaque rupture, diabetic retinopathy and wet macular degeneration.

In addition, the compounds according to the invention are suitable for the treatment of sepsis. Sepsis (or septicemia) is a frequent condition with a high mortality rate. The initial symptoms of sepsis are typically unspecific (e.g., fever, general decline in health); however, as the disease progresses, there may be general activation of the coagulation system ("disseminated intravascular coagulation" or "consumption coagulopathy", hereinafter "DIC") and there is microthrombosis formation and secondary bleeding complications in various organs. In addition, there may be endothelial damage, combined with increased permeability of the blood vessels and diffusion of fluids and proteins into the extravascular space. As the condition worsens, there may be organ dysfunction or organ failure (e.g., renal failure, liver failure, respiratory failure, shortages of the central nervous system and cardiac/circulatory failure) through to multiple organ failure. In principle, this can affect any organ; organ dysfunction and organ failure most commonly encountered occur in the lungs, kidneys, 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" refers to the development of hypotension requiring treatment, which further contributes to organ damage and is associated with worsening prognosis.

The pathogens may be bacteria (gram negative and gram positive), fungi, viruses and/or eukaryotes. The oral or primary infection may be, for example, pneumonia, urinary tract infection or peritonitis. The 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 can also occur in other states such as trauma, burns, shock, surgery, ischemia, pancreatitis, resuscitation (Reanimation) or tumors. The definition of ACCP/SCCM Consensus Committee (Crit. Care Med. 1992, 20, 864-874) in 1992 describes the symptoms and measured parameters (especially changes in body temperature, increased heart rate, dyspnea and changes in hemograms) that are required to diagnose "SIRS". The latter (2001) SCCM/ESICM/ACCP/ATS/SIS International separation Definitions Conference essentially maintains this standard, but fine-tunes the details (Levy et al, Crit. Care Med. 2003, 31, 1250-.

DIC and SIRS may occur during sepsis, but may also result from surgery, neoplastic disease, burns, or other trauma. For DIC, significant activation of the coagulation system occurs on the surface of injured endothelial cells, on the surface of foreign bodies or on damaged extravascular tissue. Thus, coagulation occurs in small blood vessels of various organs, accompanied by hypoxia and subsequent organ dysfunction. The second is the consumption of coagulation factors (e.g., coagulation factor X, prothrombin, fibrinogen) and platelets, thereby reducing the coagulability of the blood and causing severe bleeding.

In addition, the compounds according to the invention can also be used for preventing coagulation in vitro, for example for preserving blood and plasma products, for cleaning/pre-treating catheters and other medical aids and instruments, including extracorporeal circulation devices, for coating artificial surfaces of medical aids and instruments used in vivo or ex vivo or for platelet-containing biological samples.

The invention furthermore provides for the use of the compounds according to the invention for coating medical devices and implants, such as catheters, prostheses, Stents (Stents) or artificial heart valves. Here, the compounds according to the invention can be firmly attached to the surface or, for local action, released from the carrier coating into the immediate environment over a certain period of time.

The invention furthermore provides the use of the compounds according to the invention for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases.

The invention furthermore provides the use of the compounds according to the invention for the preparation of medicaments for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases.

The invention furthermore provides methods for the treatment and/or prophylaxis of disorders, in particular of the abovementioned disorders, using a therapeutically effective amount of a compound according to the invention.

The invention furthermore provides medicaments comprising a compound according to the invention and one or more further active substances, which are in particular active substances for the treatment and/or prophylaxis of the abovementioned conditions. Suitable active substances include, by way of example and preferably:

calcium channel blockers, e.g. amlodipine besylate (e.g. Norvasc)^®) Felodipine, diltiazem, verapamil, nifedipine, nicardipine, 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, serto heparin, enoxaparin, parnaparin, tinzaparin, heparin and nadroparin;

other anticoagulants, such as warfarin, coumarins, fondaparins;

antiarrhythmic agents, such as dofetilide, ibutilide, metoprolol tartrate, propranolol, amdol, amonal, dapiprodione, pramazone, procainamide, quinidine, sparteine, ampelodine, lidocaine, mexiletine, tolclovir, encam, flecainide, loperamide, ethiozolone, propylamine propiophenone, acebutolol, propranolol, amiodarone, bromotranylamine tosylate, butylamide, mestranidine, 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 sertacontan sodium salt;

neutral endopeptidase inhibitors such as candesartan and ecadotril;

phosphodiesterase inhibitors such as, for example, fenpyrazamine, 3-dimethylxanthine, 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 thrombin inhibitors such as AZD0837, argatroban, bivalirudin and dabigatran etexilate;

indirect thrombin inhibitors, such as β -d-xyloside;

direct and indirect factor Xa inhibitors, for example fondaparinux sodium, apixaban, rizoxaban, rivaroxaban (BAY 59-7939), KFA-1982, DX-9065a, AVE3247, omixaban (XRP0673), AVE6324, SAR377142, epixaparin, 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 (Tanogitran);

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

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

nitrates, such as isosorbide-5-mononitrate;

thromboxane antagonists, such as seratrodast, belococtamine and ramatroban;

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

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

type B natriuretic peptides such as nesiritide and ularitide;

NV1FGF modulators, e.g., XRP 0038;

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

guanylate cyclase activators, such as altreta (HMR1766) and HMR 1069;

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

anti-atherosclerotic substances, such as AGI-1067:

CPU inhibitors such as AZD 9684;

renin inhibitors, such as aliskiren and VNP 489;

adenosine diphosphate-induced platelet aggregation inhibitors such as clopidogrel, ticlopidine, prasugrel and AZD 6140;

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

Antibiotic therapy: combinations of various antibiotics or antifungal drugs are suitable, either according to a calculated therapy (before the microbiological test is performed) or according to a specific therapy; liquid therapy, such as crystalline or colloidal liquids; vasopressors, such as norepinephrine, dopamine, or antidiuretic hormone; therapies that affect muscle contractility, 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; organic assisted ventilation, e.g. licensed hypercapnia, low tidal volume in sepsis-induced Acute Lung Injury (ALI) or acute dyspnea syndrome (ARDS); sedation therapy: such as diazepam, chlordiazepam, midazolam or propiofil (Propofol). Opioid compounds: for example fentanyl, hydromorphone, morphine, pethidine or remifentanil. NSAID: such as ketorolac, ibuprofen or acetaminophen. Neuromuscular blockade: such as pancuronium bromide; glucose control, e.g., insulin, glucose; renal replacement therapy, such as continuous venous-venous hemofiltration or intermittent hemodialysis. Low dose dopamine for kidney protection purposes; anticoagulants, e.g., for thrombosis prevention or for renal replacement therapy, e.g., unfractionated heparin, 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, dibromopropylpiperazine, triethylenemelamine, fosetyl (triethylethiophosphospharamin), busulfan, nitrosurea mustard, lomustine, streptozotocin, dacarbazine, methotrexate, 5-fluorouracil, 5-fluorodeoxyuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, vinblastine, vincristine, desacetylvinorelbine, desacetylvindesine, fludarabine phosphate, etcVinpocetine, bleomycin, actinomycin, daunorubicin, adriamycin, epirubicin, idarubicin, taxol, mithramycin, deoxykojimycin, mitomycin-C, L-asparaginase, interferon, epipodophyllotoxin glucopyranoside, epipodophyllotoxin thiophenoside, 17. alpha-ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluorofluoromethyltestosterone, 2-methyltestosterone propionate, testolactone, megestrol, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, hydroxydehydrocortisol, chlorotriarene, hydroxyprogesterone, famciclesonide, estramustine (Estranrustine), medroxyprogesterone acetate, risperidone, flutamide, toremifene, sex hormone blockers, cisplatin, cis-platinum, cis-diaminocyclobutane carboxylic acid platinum, hydroxyurea, sabcomeline, procarbazine, mitotane, mitoxantrone, levamisole, tenopin, anastrozole, letrozole, capecitabine, Reloxafine, Droloxafine, altretamine, oxaliplatin (Elxatin)^®) Iressa (gefmitib, Zdl839), XELODA^®(Capecitabine), Tarceva^®(erlotinib), azacitidine (5-azacytidine; 5-azaC), temozolomide (Temodar)^®) Gemcitabine (e.g. GEMZAR)^®Gemcitabine hydrochloride), Vasostatin or combinations of two or more thereof.

The invention furthermore provides a method for preventing coagulation in vitro, in particular in platelet-containing stock blood or biological samples, which method is characterized in that an anticoagulation-effective amount of a compound according to the invention is added.

The compounds according to the invention can act systemically and/or locally. For this purpose, they can be administered in a suitable manner, for example: via oral, parenteral route, pulmonary, intranasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic route or as an implant or stent.

The compounds according to the invention can be administered in administration forms suitable for these administration routes.

Suitable for oral administration are administration forms which act according to the prior art and dispense the compounds according to the invention and which contain the compounds of the invention in crystalline and/or amorphous and/or dissolved form, for example tablets (uncoated or coated tablets, for example with a coating which is resistant to gastric juice or has delayed solubility or insolubility and controls the release of the compounds of the invention), tablets which disintegrate rapidly in the mouth, or films/discs (obete), films/lyophilisates, capsules (for example hard or soft gelatin capsules), coated tablets (drage), granules, coarse granules, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration may be carried out bypassing the absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or including the absorption step (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal). Administration forms suitable for parenteral administration are, in particular, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

Oral administration is preferred.

Suitable for other routes of administration are, for example, inhalation pharmaceutical forms (in particular powder inhalants, sprays), nasal drops, solutions or sprays; tongue, sublingual or buccal administration of tablets, films/discs or capsules, suppositories, otic or ocular administration of formulations, vaginal capsules, aqueous suspensions (lotions, ironing compositions), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), emulsions, slurries, foams, dusting powders, implants or stents.

The compounds according to the invention can be converted into the administration forms described. This can be carried out in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable auxiliaries. These auxiliaries include, inter alia, carrier materials (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (e.g. sodium lauryl sulfate, polyoxysorbitan oleate), binders (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilizers (e.g. antioxidants such as, for example, ascorbic acid), colorants (e.g. inorganic pigments such as iron oxides) and aromatics and/or flavors.

The invention further provides medicaments which comprise at least one compound according to the invention, preferably together with one or more inert, non-toxic, pharmaceutically suitable auxiliaries, and the use of these medicaments for the abovementioned purposes.

In the case of parenteral administration, it has generally been found advantageous to administer an amount of about 5-250 mg/24 hours to achieve effective results. In the case of oral administration, the amount is about 5-100 mg/24 hours.

Nevertheless, it is sometimes necessary to deviate from the stated amounts, in particular in relation 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.

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

A) Examples

Abbreviations:

ca. about

CDI carbonyldiimidazole

d days, doublet (in NMR)

DC thin layer chromatography

DCI direct chemical ionization (in MS)

dd doublet (in NMR)

DMAP 4-dimethylaminopyridine

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

DPPA Azidophosphoric acid Diphenyl ester

DSC bis-succinimide carbonate

Of th theoretical value (for yield)

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 multiple linear states (in NMR)

min for

MS mass spectrometry

NMR nuclear magnetic resonance spectroscopy

PYBOP benzotriazol-1-yloxy-tris (pyrrolidinyl)Hexafluorophosphates

q quartet (in NMR)

RP reverse phase (in HPLC)

RT Room temperature

R_tResidence time (in HPLC)

s singlet state (in NMR)

t triplet (in NMR)

THF tetrahydrofuran.

HPLC method:

method 1A Instrument HP 1100 with DAD detection, column Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 μm, mobile phase A: 5 ml perchloric acid (70%)/1 liter water, mobile phase B: acetonitrile, gradient 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 6.5 min 90% B → 6.7 min 2% B → 7.5 min 2% B, flow rate 0.75 ml/min, column temperature: 30 ℃ and 210 nm of UV detection.

Method 2A Instrument HP 1100 with DAD detection, column Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 μm, eluent A5 ml perchloric acid (70%)/1 liter water, mobile phase B acetonitrile, gradient 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 9 min 0% B → 9.2 min 2% B → 10 min 2% B, flow rate 0.75 ml/min, column temperature: 30 ℃ and 210 nm of UV detection.

Method 3A comprises the steps of mixing Kromasil 100, C18, 5 mu m and 250mm x 4 mm, mixing a mobile phase with water/acetonitrile 50:50, mixing a flow rate of 1 ml/min, mixing T with 40 ℃, and mixing UV with 210 nm.

LC-MS method:

method 1B is that MS instrument type is Micromass ZQ, device type HPLC is HP 1100 series, UV DAD, column is Phenomenex Gemini 3 mu, 30 mm x 3.0 mm, mobile phase A is 1L of water + 0.5 mL of 50% formic acid, mobile phase B is 1L of acetonitrile + 0.5 mL of 50% formic acid, gradient is 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A, flow rate is 0.0 min 1 ml/min, 2.5 min/3.0 min/4.5 min 2 ml/min, furnace is 50 ℃ and UV detection is 210 nm.

Method 2B Instrument Micromass Quattro Premier with Waters UPLC Acity, column Thermo Hypersil GOLD 1.9 μm 50mm x 1mm, mobile phase A1 liter of water + 0.5 ml of 50% formic acid, mobile phase B1 liter of acetonitrile + 0.5 ml of 50% formic acid, gradient 0.0 min 90% A → 0.1 min 90% A → 1.5 min 10% A → 2.2 min 10% A, furnace 50 ℃ flow rate 0.33 ml/min, UV detection 210 nm.

Method 3B MS instrument type Micromass ZQ, device type HPLC Waters Alliance 2795, column Phenomenex Synergi 2.5 μm MAX-RP 100A Mercury 20mm x 4 mm, mobile phase A of 1 liter of water + 0.5 ml of 50% formic acid, mobile phase B of 1 liter of acetonitrile + 0.5 ml of 50% formic acid, gradient 0.0 min 90% A → 0.1 min 90% A → 3.0 min 5% A → 4.0 min 5% A → 4.01 min 90% A, flow rate of 2 ml/min, furnace 50 ℃ UV detection 210 nm.

Method 4B MS Instrument type Waters ZQ, HPLC Instrument type Waters Alliance 2795, column Phenomenex Onyx Monoolithic C18, 100 mm x 3 mm, mobile phase A1 liter of water + 0.5 ml of 50% formic acid, mobile phase B1 liter of acetonitrile + 0.5 ml of 50% formic acid, gradient 0.0 min 90% A → 2 min 65% A → 4.5 min 5% A → 6 min 5% A, flow rate 2 ml/min, oven 40 ℃ UV detection 210 nm.

Method 5B Instrument Micromass Quattro Micro MS with HPLC Agilent series 1100, column Thermo Hypersil GOLD 3 μm 20mm x 4 mm, mobile phase A1 liter of water + 0.5 ml of 50% formic acid, mobile phase B1 liter of acetonitrile + 0.5 ml of 50% formic acid, gradient 0.0 min 100% A → 3.0 min 10% A → 4.0 min 10% A → 4.01 min 100% A → 5.00 min 100% A, furnace 50 deg.C, flow rate 2 ml/min, UV detection 210 nm.

Method 6B, instrument Micromass Quattro LCZ with HPLC Agilent series 1100, column Phenomenex Synergi 2.5 μ M MAX-RP 100A Mercury 20mm x 4 mm, mobile phase A of 1L water + 0.5 mL 50% formic acid, mobile phase B of 1L acetonitrile + 0.5 mL 50% formic acid, gradient of 0.0 min 90% A → 0.1 min 90% A → 3.0 min 5% A → 4.0 min 5% A → 4.1 min 90% A, flow rate of 2 ml/min, furnace of 50 ℃, UV detection of 208-.

Method 7B instrument Micromass Quattro LCZ with HPLC Agilent series 1100 column Phenomenex Onyx Monolithic C18, 100 mm x 3 mm, mobile phase A1 liter of water + 0.5 ml of 50% formic acid, mobile phase B1 liter of acetonitrile + 0.5 ml of 50% formic acid, gradient 0.0 min 90% A → 2 min 65% A → 4.5 min 5% A → 6 min 5% A, flow rate 2 ml/min, furnace 40 ℃, UV detection 208-.

Method 8B Instrument, Micromass Platform LCZ with HPLC Agilent series 1100, column Thermo HyPURITY Aquastar 3 μm 50mm x 2.1 mm, mobile phase 1 liter of water + 0.5 ml of 50% formic acid, mobile phase B1 liter of acetonitrile + 0.5 ml of 50% formic acid, gradient 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 5.5 min 10% A, furnace 50 ℃ C., flow rate 0.8 ml/min, UV detection 210 nm.

Method 9B MS instrument Waters ZQ 2000 HPLC instrument Agilent 1100, 2-column loop, autosampler HTC PAL, column YMC-ODS-AQ 50mm x 4.6 mm 3.0 μm, mobile phase A water + 0.1% formic acid, mobile phase B acetonitrile + 0.1% formic acid, gradient 0.0 min 100% A → 0.2 min 95% A → 1.8 min 25% A → 1.9 min 10% A → 2.0 min 5% A → 3.2 min 5% A → 3.21 min 100% A → 3.35 min 100% A, furnace 40 deg.C, flow rate 3.0 ml/min UV detection 210 nm.

Method 10B MS Instrument type Waters ZQ, HPLC Instrument type Agilent 1100 series, UV DAD, column Thermo Hypersil GOLD 3 μm, 20mm x 4 mm, eluent A1 liter of water + 0.5 ml of 50% formic acid, mobile phase B1 liter of acetonitrile + 0.5 ml of 50% formic acid, gradient 0.0 min 100% A → 3.0 min 10% A → 4.0 min 10% A → 4.1 min 100% (flow rate: 2.5 ml/min), furnace 55 deg.C, flow rate: 2 ml/min, UV detection 210 nm.

Method 11B, instrument Waters ACQUITY SQD UPLC System, column Waters ACQUITY UPLC HSS T31.8 μm 50mm x 1mm, mobile phase A1L water + 0.25 mL 99% formic acid, mobile phase B1L acetonitrile + 0.25 mL 99% formic acid, gradient 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A, furnace 50 ℃, flow rate 0.40 ml/min, UV detection 210-.

Non-preparative enantiomeric separations :

Method 1C phase Kromasil 100, C18, 5 μm, 250mm x 20mm, mobile phase 0.2% aqueous trifluoroacetic acid/acetonitrile 47:53, flow rate 25 ml/min, temperature: at 23 deg.C, UV detection is 210 nm.

Method 2C, phase Sunfire C18, 5 mu m 150 mm x 19 mm, mobile phase water/acetonitrile 50:50, flow rate 25 ml/min, temperature: at 24 deg.c, UV detection is 225 nm.

Method 3C, phase Kromasil 100, C18, 5 mu m, 250mm and 20mm, mobile phase water/acetonitrile 50:50, flow rate 25 ml/min, temperature: UV detection at 40 deg.C and 210 nm.

Method 4C, phase Kromasil 100, C18, 5 mu m, 250mm and 20mm, mobile phase water/acetonitrile 35:65, flow rate 25 ml/min, temperature: 30 ℃ and 210 nm of UV detection.

Method 5C, phase Sunfire C18, 5 mu m 150 mm x 30 mm, mobile phase water/acetonitrile 50:50, flow rate 56 ml/min, temperature: 30 ℃ and 210 nm of UV detection.

Method 6C, phase Xbridge C18, 5 mu m OBD 150 mm x 19 mm, mobile phase 0.1% diethylamine solution/acetonitrile 30:70, flow rate 25 ml/min, temperature: 254 nm UV detection at 24 ℃.

Method 7C, phase Sunfire C18, 5 mu m 250mm x 20mm, mobile phase water/acetonitrile 55:45, flow rate 25 ml/min, temperature: 30 ℃ and 210 nm of UV detection.

Method 8C, phase Sunfire C18OBD, 5 mu m 150 mm x 19 mm, mobile phase water/acetonitrile 62:38, flow rate 25 ml/min, temperature: UV detection at 40 deg.C and 210 nm.

Method 9C phase Kromasil 100C, 5 μm 150 mm x 19 mm, mobile phase 0.2% aqueous trifluoroacetic acid/acetonitrile 50:50, flow rate 25 ml/min, temperature: UV detection at 40 deg.C and 210 nm.

Method 10C, phase Xbridge C18, 5 mu m OBD 19 mm x 150 mm, mobile phase 0.1% aqueous ammonia solution/acetonitrile 50:50, flow rate 25 ml/min, temperature: 30 ℃ and 210 nm of UV detection.

Method 11C, phase Xbridge C18, 5μm OBD, 19 mm x 150 mm, mobile phase aqueous ammonia solution/acetonitrile 70:30, flow rate 25 ml/min, temperature: UV detection at 40 deg.C and 210 nm.

Method 12C, phase Xbridge C18, 5μm OBD, 19 mm x 150 mm, mobile phase aqueous ammonia solution/acetonitrile 65:35, flow rate 25 ml/min, temperature: UV detection at 40 deg.C and 210 nm.

Method 13C phase Daisogel SP120-, 10 μm-ODS Bio, 250mm x 20mm, mobile phase 0.1% diethylamine solution/acetonitrile 50:50, flow rate 25 ml/min, temperature: UV detection at 30 deg.C and 240 nm.

Method 14C, phase Xbridge C18, 5 mu m OBD 19 mm x 150 mm, mobile phase 0.1% diethylamine solution/acetonitrile 55:45, flow rate 25 ml/min, temperature: 20 deg.C (RT) and 254 nm UV detection.

Method 15C, phase Xbridge C18, 5 mu m OBD 19 mm x 150 mm, mobile phase 0.2% diethylamine solution/acetonitrile 63:37, flow rate 25 ml/min, temperature: 20 deg.C (RT), and 235 nm for UV detection.

Preparative enantiomeric separation :

Method 1D: phase (1): based on the selection agent poly (N-methacryloyl-L-leucine-I-Chiral silica gel phase of amidocyanogen, 250mm x 20mm, flowPhase (1): isohexane/ethyl acetate 70:30; flow rate: 25 ml/min, temperature: 24 ℃; and (4) UV detection: 260 nm.

Method 2D, phase Daicel Chiralpak AD-H, 5 μm 250mm x 20mm, mobile phase isopropanol/isohexane 30:70, flow rate 20 ml/min, temperature: UV detection at 25 deg.C of 260 nm.

Method 3D, phase Daicel Chiralpak AD-H, 5 μm 250mm x 20mm, mobile phase isopropanol/isohexane 50:50, flow rate 18 ml/min, temperature: UV detection at 25 deg.C of 260 nm.

Method 4D phase-Poly (N-methacryloyl-L-leucine-I) -based selection agentChiral silica gel phase of acylamide, 670 mm x 40 mm, mobile phase isohexane/ethyl acetate 50:50, flow rate 80 ml/min, temperature: UV detection at 24 deg.C of 260 nm.

Method 5D, phase Daicel Chiralcel OD-H, 5 μm 250mm x 20mm, mobile phase isopropanol/isohexane 40:60, flow rate 15 ml/min, temperature: at 24 deg.C, UV detection is 230 nm.

Method 6D, phase Daicel Chiralpak AD-H, 5 μm 250mm x 20mm, mobile phase isopropanol/isohexane 40:60, flow rate 20 ml/min, temperature: UV detection at 24 deg.C of 260 nm.

Method 7D, phase Daicel Chiralcel OD-H, 5 μm 250mm x 20mm, mobile phase isohexane/ethanol 90:10, flow rate 15 ml/min, temperature: at 30 deg.C, UV detection is 220 nm.

Method 8D, phase Daicel Chiralcel AD-H, 5 μm 250mm x 20mm, mobile phase isohexane/ethanol 55:45, flow rate 15 ml/min, temperature: UV detection at 40 deg.C of 220 nm.

Method 9D, phase Daicel Chiralcel AS-H, 5 μm 250mm x 20mm, mobile phase isohexane/2-propanol 75:25, flow rate 15 ml/min, temperature: UV detection at 40 deg.C of 220 nm.

Method 10D, phase Daicel Chiralcel AD-H, 5 μm 250mm x 20mm, mobile phase isohexane/ethanol 50:50, flow rate 15 ml/min, temperature: UV detection at 40 deg.C of 220 nm.

Method 11D, phase Daicel Chiralpak AD-H, 5 μm, 250mm x 20mm, mobile phase isopropanol/isohexane 30:70, flow rate 20 ml/min, temperature: 20 deg.C (RT) and 230 nm for UV detection.

Method 12D, phase Daicel Chiralpak AD-H, 5 μm, 250mm x 20mm, mobile phase isohexane/ethanol 50:50, flow rate 15 ml/min, temperature: UV detection at 40 deg.C of 220 nm.

Method 13D, phases Waters Sunfire C18, 5 μm, 250mm x 20mm, mobile phase A water, mobile phase B acetonitrile, gradient 0.0 min 70% A- > 15 min 10% A- > 15.1 min 70% A- > 20 min 70% A, flow rate 25 ml/min, temperature: 30 ℃ and 210 nm of UV detection.

Method 14D, phase Kromasil 100C 18, 5 μm, 250mm x 20mm, mobile phase water/acetonitrile 62:38, flow rate 25 ml/min, temperature: UV detection at 40 deg.C and 210 nm.

Method 15D, phase Daicel Chiralcel OD-H, 5 μm, 250mm x 20mm, mobile phase isohexane/ethanol 70:30, flow rate 15 ml/min, temperature: UV detection at 40 deg.C of 220 nm.

Method 16D, phase Daicel Chiralpak AD-H, 5 μm, 250mm x 20mm, mobile phase isohexane/ethanol 75:25, flow rate 15 ml/min, temperature: at 25 deg.C, UV detection is 220 nm.

Method 17D, phase Daicel Chiralpak AD-H, 5 μm, 250mm x 20mm, mobile phase isohexane/ethanol 80:20, flow rate 15 ml/min, temperature: at 38 ℃ and with a UV detection wavelength of 220 nm.

Analytical enantiomeric separation :

Method 1E phase-Poly (N-methacryloyl-L-leucine-I) -based selection agentChirality of acylamideSilica gel phase, 250mm x 4.6 mm, mobile phase isohexane/ethyl acetate 50:50, flow rate 1 ml/min, temperature: 265 nm at 20 deg.C and UV detection.

Method 2E, phase Daicel Chiralpak AD-H, 5 μm, 250mm and 4 mm, mobile phase isopropanol/isohexane, flow rate, 1 ml/min, UV detection, 230 nm.

Method 3E phase-Poly (N-methacryloyl-L-leucine-I) -based selection agentChiral silica gel phase of acylamide, 250mm x 4.6 mm, mobile phase isohexane/ethyl acetate 50:50, flow rate 2 ml/min, temperature: 265 nm at 20 deg.C and UV detection.

Method 4E phase Daicel Chiralcel OD-H, 5 μm 250mm x 4 mm, mobile phase isopropanol/isohexane 50:50, flow rate 1 ml/min, temperature: UV detection at 20 deg.C and 230 nm.

Method 5E phase Daicel Chiralcel OD-H, 5 μm 250mm x 4.6 mm, mobile phase isohexane/ethanol 85:15, flow rate 1 ml/min, temperature: UV detection at 40 deg.C of 220 nm.

Method 6E, phase Daicel Chiralcel AD-H, 5 μm 250mm x 4.6 mm, mobile phase isohexane/ethanol 50:50, flow rate 1 ml/min, temperature: UV detection at 40 deg.C of 220 nm.

Method 7E phase Daicel Chiralcel AS-H, 5 μm 250mm x 20mm, mobile phase isohexane/2-propanol 75:25, flow rate 1 ml/min, temperature: UV detection at 40 deg.C of 220 nm.

Method 8E, phase Daicel Chiralcel AD-H, 5 μm 250mm x 4.6 mm, mobile phase isohexane/ethanol 70:30 + 0.2% trifluoroacetic acid + 1% water, flow rate 1 ml/min, temperature: UV detection at 40 deg.C of 220 nm.

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

Starting compounds

General procedure 1A ： Suzuki Coupling of

A mixture of the appropriate bromopyridine in toluene (1.8 ml/mmol) was mixed under argon and at room temperature with tetrakis (triphenylphosphine) palladium (0.02 eq), with a solution of the appropriate arylboronic acid (1.2 eq) in ethanol (0.5 ml/mmol) and with a solution of potassium fluoride (2.0 eq) in water (0.2 ml/mmol). The reaction mixture was stirred under reflux conditions for many hours until essentially complete conversion. 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 was purified by flash chromatography (silica gel 60, mobile phase: dichloromethane/methanol mixture).

General procedure 2A : hydrogenation of pyridine

A solution of pyridine in ethanol (9 ml/mmol) was mixed under argon with palladium on activated charcoal (wetted with about 50% water, 0.3 g/mmol) 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 several times with ethanol. The combined filtrates were concentrated under reduced pressure.

General procedure 3A : by reaction with carbamoyl chlorides or carbonyl chlorides

N, N-diisopropylethylamine (1.2 eq) and the appropriate carbamoyl or carbonyl chloride (1.2 eq) were added dropwise to a solution of piperidine in dichloromethane (2.5 ml/mmol) under argon and at 0 ℃. The reaction mixture was stirred at RT. After addition of water and phase separation, the organic phase is 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 : saponification

Lithium hydroxide (2 equiv.) is added to a solution of the appropriate ester in a mixture of tetrahydrofuran/water (3:1, 12.5 ml/mmol) at room temperature. The reaction mixture was stirred at 60 ℃ and then adjusted to pH 1 using aqueous 1N hydrochloric acid solution. After addition of water/ethyl acetate, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried (sodium sulfate), filtered and concentrated under reduced pressure.

General procedure 5A ： Curtius Decomposition of

Triethylamine (1.7 equivalents), diphenyl azidophosphate (1.1 equivalents) and di-tert-butyl dicarbonate (1.1 equivalents) were added to a solution of the appropriate carboxylic acid in tert-butanol/toluene (1: 1, 8 ml/mmol) under argon and at room temperature. The reaction mixture was stirred at 65 ℃ for 30 min and then at 95 ℃ overnight. After addition of water and phase separation, the organic phase was washed with water and with saturated aqueous sodium chloride solution, dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude product is then purified by flash chromatography (silica gel-60, mobile phase: dichloromethane/methanol mixture). Subsequently, trifluoroacetic acid (10 eq) was added to a solution of the boc-protected amine in dichloromethane (10 ml/mmol) under argon and at room temperature. The reaction mixture was stirred at RT and then concentrated under reduced pressure. The residue was co-evaporated three times with toluene and dichloromethane and used in the next step without further purification.

General procedure 6A : using through-flow (Durchfluss) Hydrogenation device for pyridine

A solution of pyridine in concentrated acetic acid (about 35 mL/mmol) was hydrogenated in a flow-through hydrogenation apparatus ("H-Cube" from Thales Nano, Budapest, Hungary) (conditions: 10% Pd/C catalyst, "control" mode, 60 bar, 0.5 mL/min, 85 ℃). Removal of the solvent on a rotary evaporator gives the corresponding crude product, which is optionally purified by means of preparative HPLC.

General procedure 7A : saponification of methyl esters / Epimerization

Potassium tert-butoxide (10 equiv.) is added to a solution of the appropriate methyl ester (1.0 equiv.) in methanol (35-40 ml/mmol) at room temperature. 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 complete conversion. For work-up, the methanol was removed under reduced pressure, the residue was mixed with water and acidified (pH 1) with aqueous 1N 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 8A : urea formation

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

General procedure 9A : saponification of methyl esters / Epimerization

Potassium tert-butoxide (10 equiv.) is added to a solution of the appropriate methyl ester (1.0 equiv.) in methanol (35-40 ml/mmol) at room temperature. 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 complete conversion. For work-up, methanol was removed under reduced pressure, the residue was mixed with water and the mixture was acidified with 1N hydrochloric acid to pH = 1. The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure.

Examples 1A

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

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

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

Examples 2A

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

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

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

Examples 3A

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

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

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

Examples 4A

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

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

LC-MS (method 5B) R_t= 1.78 min and 1.91 min (cis/trans isomer); MS (ESIpos): M/z = 262 [ M + H =]⁺。

Examples 5A

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

5.2 g (14.0 mmol) of ethyl 5- (4-ethylphenyl) piperidine-3-carboxylate and 2.1 g (2.1 mmol, 1.2 equivalents) of cyclopentanecarboxylic acid chloride were reacted according to general procedure 3A. Yield: 4.8 g (96% of theory).

LC-MS (method 4B): r_t= 4.04 min and 4.14 min (cis/trans isomer); ms (esipos): m/z = 358 [ M + H ]]⁺。

Examples 6A

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

13.8 g (38.6 mmol) of ethyl 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine-3-carboxylate were saponified according to general procedure 4A. Yield: 11.5 g (87% of theory).

LC-MS (method 1B): r_t= 2.50 min and 2.57 min (cis/trans isomer); ms (esipos): m/z = 330 [ M + H [ ]]⁺。

Examples 7A

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

Diastereomeric separation of 11.5 g of the cis/trans isomer mixture of example 6A according to method 1C yields 4.1 g of the title compound 7A (cis isomer) and 4.1 g of the trans isomer.

LC-MS (method 1B) R_t = 2.57 min; MS (ESIpos): m/z = 330 (M+H)⁺。

Examples 8A

1- (Cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-ylamine trifluoroacetate [ racemic cis isomer ]

816 mg (2.48 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine-3-carboxylic acid are subjected to Curtius decomposition according to general procedure 5A. Yield: 730 mg (71% of theory).

LC-MS (method 5B) R_t = 1.68 min; MS (ESIpos): m/z = 301 (M+H)⁺(free base).

Examples 9A

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

6.7 g (24.1 mmol) of methyl 5- (4-ethylphenyl) piperidine-3-carboxylate and 4.2 g (31.4 mmol, 1.3 equivalents) of pyrrolidine-1-carbonyl chloride are reacted according to general procedure 3A. Yield: 7.6 g (91% of theory).

LC-MS (method 3B): r_t= 2.08 min and 2.16 min (cis/trans isomer); ms (esipos): m/z = 345 [ M + H]⁺。

Examples 10A

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

Diastereomeric separation of 7.6 grams of the mixture of cis/trans isomers of example 9A according to method 4C yields 1.6 grams of example 10A (cis isomer) and 4.1 grams of trans isomer.

LC-MS (method 1B) R_t = 2.55 min; MS (ESIpos): m/z = 345 (M+H)⁺。

Examples 11A

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

1.4 g (3.9 mmol) of methyl 5- (4-ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidine-3-carboxylate were saponified according to general procedure 4A. Yield: 1.2 g (92% of theory).

LC-MS (method 2B) R_t = 1.18 min; MS (ESIpos): m/z = 331 (M+H)⁺。

Examples 12A

5- (4-Ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidin-3-amine trifluoroacetate [ racemic cis isomer ]

1.2 g (3.6 mmol) of 5- (4-ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidine-3-carboxylic acid Curtius decomposition was carried out according to general procedure 5A. Yield: 1.2 g (78% of theory).

LC-MS (method 5B) R_t = 1.61 min; MS (ESIpos): m/z = 302 (M+H)⁺(free base).

Examples 13A

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

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

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

Examples 14A

5-bromo-N-phenylpyridine-3-carboxamides

Under argon and at room temperature, 32.4 ml (400 mmol, 2 equiv.) of pyridine, 2.4 g (20 mmol, 0.1 equiv.) of 4-dimethylaminopyridine and a dropwise solution of 44.1 g (200 mmol, 1.0 equiv.) of 5-bromopyridine-3-carbonyl chloride in 200 ml of DMF are added to a solution of 18.6 g (200 mmol) of aniline in 500 ml of tetrahydrofuran. After 3 hours, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water/dichloromethane and the solid was stirred well, filtered off, washed repeatedly with water and dichloromethane and dried under reduced pressure. Yield: 35.7 g (52% of theory). After separation of the mother liquor phases, the organic phase is extracted twice with dichloromethane. The combined organic phases were dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, dichloromethane/methanol 100:1) yielding 11.7 g (18% of theory) of example 14A.

LC-MS (method 6B) R_t = 1.77 min; MS (ESIpos): m/z = 277 (M+H)⁺。

Examples 15A

5- (4-ethylphenyl) -N-phenylpyridine-3-carboxamide

74 g (222 mmol) of 5-bromo-N-phenylpyridine-3-carboxamide and 40g (266 mmol, 1.2 equivalents) of 4-ethylphenylboronic acid are reacted according to general procedure 1A. Yield: 68 g (87% of theory).

LC-MS (method 6B) R_t = 2.26 min; MS (ESIpos): m/z = 303 (M+H)⁺。

Examples 16A

5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide [ racemic cis/trans isomer mixture ]

67 g (218 mmol) of 5- (4-ethylphenyl) -N-phenylpyridine-3-carboxamide are hydrogenated according to general procedure 2A. Yield: 63 g (88% of theory).

Examples 17A

5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide [ racemic cis isomer ]

Diastereomeric separation of 63 grams of the cis/trans isomer mixture (example 16A) according to method 6C yields 25.9 grams of example 17A (cis isomer) and 15.4 grams of the trans isomer.

LC-MS (method 6B) R_t = 1.35 min; MS (ESIpos): m/z = 309 (M+H)⁺。

Examples 18A

1- [ (4-Cyanopiperidin-1-yl) carbonyl ] -5- (4-ethylphenyl) piperidine-3-carboxylic acid methyl ester [ racemic cis/trans isomer mixture ]

3.0 g (6.1 mmol) of the compound from example 65A are reacted according to general method 8A. Yield: 2.1 g (83% of theory).

LC-MS (method 11B): r_t= 1.12 min and 1.14 min (cis/trans isomer); ms (esipos): m/z = 384 [ M + H [ ]]⁺。

Examples 19A

3-bromo-5- (4-ethylphenyl) pyridine

23 g (97 mmol) of 3, 5-dibromopyridine and 18 g (117 mmol, 1.2 equivalents) of 4-ethylphenylboronic acid are reacted according to general procedure 1A. Yield: 17 g (66% of theory).

LC-MS (method 3B) R_t = 2.35 min; MS (ESIpos): m/z = 262 (M+H)⁺。

Examples 20A

[5- (4-ethylphenyl) pyridin-3-yl ] carbamic acid methyl ester

16.8 g (64 mmol) of 3-bromo-5- (4-ethylphenyl) pyridine in 70 ml of bis (ethyl-phenyl) pyridine under argon and at room temperatureThe solution in alkane was added to 555 mg (0.96 mmol, 0.015 eq) of xanthphos (4, 5-bis (diphenylphosphino)) -9, 9' -dimethyl phosphino)Ton), 293 mg (0.32 mmol, 0.005 eq) of tris (dibenzylideneacetone) dipalladium, 29.1 g (89 mmol, 1.4 eq) of cesium carbonate and 5.8 g (77 mmol, 1.2 eq) of methyl carbamate in 100 ml of dipalladiumSuspension in an alkane. The reaction mixture was stirred at 90 ℃ for 20 hours. Since the reaction progresses slowly, 555 mg (0.96 mmol, 0.015 equivalent) of xanthphos and 293 mg (0.32 mmol, 0.005 equivalent) of tris (dibenzylideneacetone) dipalladium are added to the reaction mixture in portions, in total three times, and the mixture is stirred overnight at 90 ℃ in each case. After addition of dichloromethane, the reaction mixture is filtered through kieselguhr and the filtrate is concentrated under reduced pressure. The crude product was stirred with acetonitrile and the remaining residue was repeatedly washed with cold acetonitrile and dried under reduced pressure. Yield: 15 g (90% of theory).

LC-MS (method 5B) R_t = 1.84 min; MS (ESIpos): m/z = 257 (M+H)⁺。

Examples 21A

[5- (4-ethylphenyl) piperidin-3-yl ] carbamic acid methyl ester [ racemic cis/trans isomer mixture ]

A solution of 1.0 g (3.7 mmol) of methyl [5- (4-ethylphenyl) pyridin-3-yl ] carbamate in 100 ml of ethanol and 100 ml of acetic acid was reacted according to general procedure 5A. The solution was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, dichloromethane/methanol 4: 1). Yield: 171 mg (16% of theory).

LC-MS (method 2B) R_t = 0.81 min; MS (ESIpos): m/z = 263 (M+H)⁺。

Examples 22A

3- (4-ethylphenyl) -5-methoxypyridine

5.0 g (27 mmol) of 3-bromo-5-methoxypyridine and 4.8 g (32 mmol, 1.2 equivalents) of 4-ethylphenylboronic acid are reacted according to general procedure 1A. Yield: 3.0 g (53% of theory).

LC-MS (method 1B) R_t = 2.10 min; MS (ESIpos): m/z = 214 (M+H)⁺。

Examples 23A

3- (4-Ethylphenyl) -5-methoxypiperidine [ racemic cis/trans isomer mixture ]

A solution of 1.0 g (4.7 mmol) of 3- (4-ethylphenyl) -5-methoxypyridine in 120 ml of acetic acid was reacted according to general procedure 5A. The solution was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, dichloromethane/methanol gradient). Yield: 880 mg (86% of theory).

LC-MS (method 1B) R_t = 1.10 min; MS (ESIpos): m/z = 220 (M+H)⁺。

Examples 24A

4- { [3- (4-ethylphenyl) -5-methoxypiperidin-1-yl ] carbonyl } morpholine [ racemic cis/trans isomer mixture ]

880 mg (4.0 mmol) of 3- (4-ethylphenyl) -5-methoxypiperidine and 780 mg (5.2 mmol, 1.3 equivalents) of morpholine-4-carbonyl chloride are reacted according to general method 3A. Yield: 896 mg (58% of theory).

LC-MS (method 3B): r_t= 1.81 min and 1.84 min (cis/trans isomer); ms (esipos): m/z = 333 [ M + H ]]⁺。

Examples 25A

5- (4-Ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidin-3-ol [ racemic cis/trans isomer mixture ]

Under argon and at 0 ℃, 4.6 ml of boron tribromide solution (1 molar concentration in dichloromethane, 4.6 mmol, 2 equiv.) are added to a solution of 890 mg (2.3 mmol) of 4- { [3- (4-ethylphenyl) -5-methoxypiperidin-1-yl ] carbonyl } morpholine in 22 ml of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours, then poured onto ice, neutralized with solid sodium bicarbonate, and after addition of water and phase separation, extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was then purified by preparative HPLC (Reprosil C18, water with 0.1% trifluoroacetic acid/acetonitrile gradient). Yield: 314 mg (43% of theory).

LC-MS (method 3B) R_t = 1.50 min; MS (ESIpos): m/z = 319 (M+H)⁺。

Examples 26A

N- {5- [4- (trifluoromethoxy) phenyl ] pyridin-3-yl } benzamide

11.8 g (41.4 mmol) of N- (5-bromopyridin-3-yl) benzamide, 12.8 g (62.1 mmol) of [4- (trifluoromethoxy) phenyl ] boronic acid and 11.4 g (82.7 mmol) of potassium carbonate were dissolved in 70 ml of 1, 2-dimethoxyethane, 21 ml of water and 156 ml of DMF at 50 ℃. The mixture was flushed with argon, 0.24 g (0.2 mmol) of tetrakis (triphenylphosphine) palladium (0) was added and the mixture was stirred at 85 ℃ for 12 h. The reaction mixture was slightly concentrated on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure and the residue was stirred with methyl tert-butyl ether. The solid was filtered off and the filtrate was purified by column chromatography on silica gel (cyclohexane/ethyl acetate 2: 1- > 1: 5). The separated solids and the appropriate fractions from chromatography were combined. Yield: 6.7 g (45% of theory).

LC-MS (method 1B) R_t = 2.47 min; m/z = 359 [M+H]⁺。

Examples 27A

N- {5- [4- (trifluoromethoxy) phenyl ] piperidin-3-yl } benzamide [ racemic cis/trans isomer mixture ]

10.4 g (29.0 mmol) of the compound from example 26A are reacted according to general method 2A. The reaction mixture was purified by column chromatography on silica gel (dichloromethane/methanol 10: 1). Yield: 4.1 g (29% of theory).

LC-MS (method 1B) R_t = 1.50 min; m/z = 365 [M+H]⁺。

Examples 28A

N- {5- [4- (trifluoromethoxy) phenyl ] piperidin-3-yl } benzamide [ racemic cis isomer ]

Diastereomeric separation of 4.1 grams of the cis/trans isomer mixture (example 27A) according to method 10C yields 1.1 grams of example 28A (cis isomer).

LC-MS (method 1B) R_t = 1.56 min; m/z = 365 [M+H]⁺。

Examples 29A

3- [ (Phenylcarbonyl) amino ] -5- [4- (trifluoromethoxy) phenyl ] piperidine-1-carboxylic acid-4-nitrophenyl ester [ racemic cis isomer ]

At 0 ℃, 200 mg (0.55 mmol) of N- {5- [4- (trifluoromethoxy) phenyl ] piperidin-3-yl } benzamide and 153 μ l (1.1 mmol) of triethylamine were initially charged in 17 ml of dichloromethane and 111 mg (0.55 mmol) of 4-nitrophenyl chloroformate were slowly added. The mixture was stirred at 0 ℃ for 2 hours and then warmed to room temperature. Water and saturated aqueous sodium bicarbonate solution were added, and the reaction mixture was extracted. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 254 mg (87% of theory).

LC-MS (method 1B) R_t = 2.88 min; m/z = 530 [M+H]⁺。

Examples 30A

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

2.0 g (5.2 mmol) of the compound from example 18A are reacted according to general method 7A. Yield: 1.8 g (91% of theory).

LC-MS (method 2B) R_t = 1.13 min; MS (ESIpos): m/z = 370 (M+H)⁺。

Examples 31A

N-[5-(3,4- Dimethyl phenyl ) Pyridine compound -3- Base of ] Benzamide derivatives

4.5 g (16.2 mmol) of N- (5-bromopyridin-3-yl) benzamide, 3.0 g (19.5 mmol) of (3, 4-dimethylphenyl) boronic acid and 4.5 g (32.5 mmol) of potassium carbonate are dissolved at 50 ℃ in 59 ml of 1, 2-dimethoxyethane, 19 ml of water and 117 ml of DMF. The mixture was flushed with argon, 0.1 g (0.08 mmol) of tetrakis (triphenylphosphine) palladium (0) was added and the mixture was stirred at 85 ℃ for 12 h. The reaction mixture was slightly concentrated on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase is concentrated and purified by column chromatography on silica gel (dichloromethane/methanol 100:1- > 100: 4). Yield: 3.4 g (68% of theory).

LC-MS (method 2B) R_t = 1.17 min; m/z = 303 [M+H]⁺。

Examples 32A

N-[5-(3,4- Dimethyl phenyl ) Piperidine derivatives -3- Base of ] Benzamide derivatives [ Racemic cis form / Trans isomer mixture ]

A solution of 1.0 g (3.7 mmol) of N- [5- (3, 4-dimethylphenyl) pyridin-3-yl ] benzamide in 120 ml of acetic acid is reacted according to general method 6A. The solution was concentrated under reduced pressure. Yield: 1.85 g

LC-MS (method 2B) R_t = 0.93 min; MS (ESIpos): m/z = 309 (M+H)⁺。

Examples 33A

N-[5-(3,4- Dimethyl phenyl ) Piperidine derivatives -3- Base of ] Benzamide derivatives [ Racemic cis isomer ]

Diastereomeric separation of 3.7 grams of the cis/trans isomer mixture (example 32A) according to method 11C yields 0.8 grams of example 33A (cis isomer).

LC-MS (method 2B) R_t = 0.93 min; m/z = 309 [M+H]⁺。

Examples 34A

[4-({3-(3,4- Dimethyl phenyl )-5-[( Phenyl carbonyl ) Amino group ] Piperidine derivatives -1- Base of } Carbonyl radical ) Tetrahydro-alkanes -2H- Pyrans -4- Base of ] Carbamic acid tert-butyl ester [ Racemic cis isomer ]

75 mg (0.3 mmol) of 4- [ (tert-butoxycarbonyl) amino ] tetrahydro-2H-pyran-4-carboxylic acid together with 110 mg (0.3 mmol) of HATU and 47 mg (0.4 mmol) of 4-dimethylaminopyridine are initially charged in 2 ml of DMF and 60 mg (0.2 mmol) of N- [5- (3, 4-dimethylphenyl) piperidin-3-yl ] benzamide are added. The reaction mixture was stirred at room temperature overnight and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 46 mg (44% of theory).

LC-MS (method 1B) R_t = 2.45 min; m/z = 536 [M+H]⁺。

Examples 35A

[1-({3-(3,4- Dimethyl phenyl )-5-[( Phenyl carbonyl ) Amino group ] Piperidine derivatives -1- Base of } Carbonyl radical ) Cyclobutyl radical ] Carbamic acid tert-butyl ester [ Racemic cis isomer ]

62 mg (0.3 mmol) of 1- [ (tert-butoxycarbonyl) amino ] cyclobutanecarboxylic acid together with 110 mg (0.3 mmol) of HATU and 47 mg (0.4 mmol) of 4-dimethylaminopyridine are initially charged in 2 ml of DMF and 60 mg (0.2 mmol) of N- [ -5- (3, 4-dimethylphenyl) piperidin-3-yl ] benzamide are added. The reaction mixture was stirred overnight and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 54 mg (55% of theory).

LC-MS (method 1B) R_t = 2.61 min; m/z = 505 [M+H]⁺。

Examples 36A

N-{5-[3-( Propane -2- Base of ) Phenyl radical ] Pyridine compound -3- Base of } Benzamide derivatives

1.4 g (4.9 mmol) of N- (5-bromopyridin-3-yl) benzamide, 1.0 g (5.9 mmol) of [3- (1-methylethyl) phenyl ] boronic acid and 1.4 g (9.9 mmol) of potassium carbonate were dissolved in 15 ml of 1, 2-dimethoxyethane, 5 ml of water and 30 ml of DMF at 50 ℃. The mixture was flushed with argon, 29 mg (0.03 mmol) of tetrakis (triphenylphosphine) palladium (0) were added and the mixture was stirred at 85 ℃ for 12 h. The reaction mixture was slightly concentrated on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase is concentrated and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 1.4 g (92% of theory).

LC-MS (method 2B) R_t = 1.27 min; m/z = 317 [M+H]⁺。

Examples 37A

N-{5-[3-( Propane -2- Base of ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis form / Trans isomer mixture ] Trifluoroacetic acid

A solution of 1.43 g (4.52 mmol) of N- {5- [3- (1-methylethyl) phenyl ] pyridin-3-yl } benzamide in 130 ml of ethanol and 30 ml of acetic acid was reacted according to general procedure 2A. The solution was filtered through celite and the filtrate was concentrated under reduced pressure. The product was purified by chromatography. Yield: 0.18 g (8.8% of theory).

LC-MS (method 3B) R_t = 1.20 min; MS (ESIpos): m/z = 323 (M+H)⁺。

Examples 38A

N-[5-(2,3- Dimethyl phenyl ) Pyridine compound -3- Base of ] Benzamide derivatives

3.93 g (13.9 mmol) of N- (5-bromopyridin-3-yl) benzamide, 2.50 g (16.7 mmol) of (2, 3-dimethylphenyl) boronic acid and 3.84 g (27.8 mmol) of potassium carbonate are dissolved at 50 ℃ in 50 ml of 1, 2-dimethoxyethane, 17 ml of water and 100 ml of DMF. The mixture was flushed with argon, 81 mg (0.07 mmol) of tetrakis (triphenylphosphine) palladium (0) was added and the mixture was stirred at 85 ℃ for 12 h. The reaction mixture was slightly concentrated on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase is concentrated under reduced pressure and the residue is stirred with methyl tert-butyl ether, the solid is filtered off and the filtrate is purified by column chromatography on silica gel (cyclohexane/ethyl acetate 2: 1- > 1: 1). The separated solids and the appropriate fractions from chromatography were combined. Yield: 4.2 g (96% of theory).

LC-MS (method 1B) R_t = 2.24 min; m/z = 303 [M+H]⁺。

Examples 39A

N-[5-(2,3- Dimethyl phenyl ) Piperidine derivatives -3- Base of ] Benzamide derivatives [ Racemic cis form / Trans isomer mixture ]

A solution of 550 mg (1.82 mmol) of N- [5- (2, 3-dimethylphenyl) pyridin-3-yl ] benzamide in 150 ml of ethanol is reacted according to general method 5A. The solution was concentrated under reduced pressure. The product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 760 mg (77% of theory, purity 57%).

LC-MS (method 3B) R_t = 1.26 min; MS (ESIpos): m/z = 309 (M+H)⁺。

Examples 40A

N-[5-(2,3- Dimethyl phenyl ) Piperidine derivatives -3- Base of ] Benzamide derivatives [ Racemic cis isomer ]

Diastereomeric separation of 720 mg of the cis/trans isomer mixture (example 39A) according to procedure 12C gave 95 mg of example 40A (the cis isomer).

LC-MS (method 1B) R_t = 1.41 min; m/z = 309 [M+H]⁺。

Examples 41A

4- {5- [ (Phenylcarbonyl) amino ] pyridin-3-yl } benzoic acid ethyl ester

5.14 g (18.2 mmol) of N- (5-bromopyridin-3-yl) benzamide, 5.40 g (27.8 mmol) of 4-ethoxycarbonylphenylboronic acid and 5.03 g (36.4 mmol) of potassium carbonate are dissolved at 50 ℃ in 30 ml of 1, 2-dimethoxyethane, 9 ml of water and 65 ml of DMF. The mixture was flushed with argon, 105 mg (0.09 mmol) of tetrakis (triphenylphosphine) palladium (0) were added and the mixture was stirred at 85 ℃ for 12 h. The reaction mixture was slightly concentrated on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase is concentrated under reduced pressure and the residue is stirred with methyl tert-butyl ether, the solid is filtered off and the filtrate is purified by column chromatography (cyclohexane/ethyl acetate 2: 1- > 1: 1). The separated solids and the appropriate fractions from chromatography were combined. Yield: 4.6 g (60% of theory).

LC-MS (method 1B) R_t = 2.36 min; m/z = 347 [M+H]⁺。

Examples 42A

4- {5- [ (Phenylcarbonyl) amino ] piperidin-3-yl } benzoic acid ethyl ester [ racemic cis/trans isomer mixture ]

17.45 g (50.37 mmol) of ethyl 4- {5- [ (phenylcarbonyl) amino ] pyridin-3-yl } benzoate were reacted according to general procedure 2A. The reaction mixture was purified by column chromatography (dichloromethane/methanol 10: 1). Yield: 10.4 grams (about 75% pure).

LC-MS (method 2B) R_t = 0.85 min; m/z = 353 [M+H]⁺。

Examples 43A

4- {5- [ (Phenylcarbonyl) amino ] piperidin-3-yl } benzoic acid ethyl ester [ racemic cis isomer ]

Diastereomeric separation of 10.3 grams of the cis/trans isomer mixture (example 42A) according to procedure 13C yields 4.2 grams of example 43A (cis isomer).

LC-MS (method 2B) R_t = 0.87 min; m/z = 353 [M+H]⁺。

Examples 44A

N-{5-[3-( Trifluoromethyl radical ) Phenyl radical ] Pyridine compound -3- Base of } Benzamide derivatives

1.95 g (7.02 mmol) of N- (5-bromopyridin-3-yl) benzamide, 2.00 g (10.5 mmol) of [3- (trifluoromethyl) phenyl ] boronic acid and 1.49 g (14.04 mmol) of sodium carbonate are dissolved in 12 ml of 1, 2-dimethoxyethane, 3.5 ml of water and 261 ml of DMF at 50 ℃. The mixture was flushed with argon, 41 mg (0.04 mmol) of tetrakis (triphenylphosphine) palladium (0) was added and the mixture was stirred at 85 ℃ for 12 h. The reaction mixture was slightly concentrated on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography (cyclohexane/ethyl acetate 2: 1). Yield: 860 mg (35% of theory).

LC-MS (method 5B) R_t = 2.26 min; m/z = 343 [M+H]⁺。

Examples 45A

N-{5-[3-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis form / Trans isomer mixture ]

A solution of 840 mg (1.82 mmol) of N- {5- [3- (trifluoromethyl) phenyl ] pyridin-3-yl ] benzamide in 100 ml of glacial acetic acid was reacted according to general procedure 6A. The solution was concentrated under reduced pressure. The product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 700 mg of

LC-MS (method 5B) R_t = 1.55 min; m/z = 349 [M+H]⁺。

Examples 46A

N-{5-[3-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis isomer ]

Diastereomeric separation of 840 mg of the cis/trans isomer mixture (example 45A) according to method 14C yields 176 mg of example 46A (the cis isomer).

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.22 (d, 1H), 7.85 (d, 2H), 7.39-7.63 (m, 7H), 3.88-4.06 (m, 1H), 3.09 (dd, 1H), 2.99 (d, 1H), 2.85-2.95 (m, 1H), 2.37-2.47 (m, 2H), 2.02-2.14 (m, 1H), 1.74 (q, 1H)。

Examples 47A

N-{5-[4-( Trifluoromethyl radical ) Phenyl radical ] Pyridine compound -3- Base of } Benzamide derivatives

11.35 g (40.96 mmol) of N- (5-bromopyridin-3-yl) benzamide, 11.67 g (61.43 mmol) of [4- (trifluoromethyl) phenyl ] boronic acid and 8.68 g (81.91 mmol) of sodium carbonate were dissolved in 68 ml of 1, 2-dimethoxyethane, 21 ml of water and 151 ml of DMF at 50 ℃. The mixture was flushed with argon, 237 mg (0.21 mmol) of tetrakis (triphenylphosphine) palladium (0) were added and the mixture was stirred at 85 ℃ for 12 h. The reaction mixture was slightly concentrated on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography (cyclohexane/ethyl acetate 1: 1). Yield: 10.6 g (76% of theory).

LC-MS (method 5B) R_t = 2.31 min; m/z = 343 [M+H]⁺。

Examples 48A

N-{5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis form / Trans isomer mixture ]

A solution of 1.0 g (2.9 mmol) of N- {5- [4- (trifluoromethyl) phenyl ] pyridin-3-yl ] benzamide in 120 ml of glacial acetic acid is reacted according to general procedure 6A. The solution was concentrated under reduced pressure. The product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 657 mg (50% pure).

LC-MS (method 5B) R_t = 1.69 min; m/z = 349 [M+H]⁺。

Examples 49A

N-{5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis isomer ]

Diastereomeric separation of 2.0 grams of the cis/trans isomer mixture (example 48A) according to method 15C yields 708 mg of example 49A (cis isomer).

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.24 (d, 1H), 7.84 (d, 2H), 7.68 (d, 2H), 7.40-7.56 (m, 5H), 3.93-4.06 (m, 1H), 3.09 (dd, 1H), 2.99 (d, 1H), 2.83-2.94 (m, 1H), 2.37-2.47 (m, 2H), 2.08 (d, 1H), 1.72 (q, 1H)。

Examples 50A

3- [ (Phenylcarbonyl) amino ] -5- [4- (trifluoromethyl) phenyl ] piperidine-1-carboxylic acid-4-nitrophenyl ester [ racemic cis isomer ]

At 0 ℃, 1.5 g (4.3 mmol) of N- {5- [4- (trifluoromethyl) phenyl ] piperidin-3-yl } benzamide and 1.2 ml (1.1 mmol) of triethylamine are initially charged in 131 ml of dichloromethane and 868 mg (4.3 mmol) of 4-nitrophenyl chloroformate is slowly added. The mixture was stirred at 0 ℃ for 2 hours and then warmed to room temperature. Water and saturated aqueous sodium bicarbonate solution were added and the reaction mixture was extracted. The organic phase was concentrated under reduced pressure and purified by column chromatography (cyclohexane/ethyl acetate 1: 2). Yield: 1.95 g (88% of theory).

LC-MS (method 1B) R_t = 2.82 min; m/z = 514 [M+H]⁺。

Examples 51A

[1-({3-[( Phenyl carbonyl ) Amino group ]-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -1- Base of } Carbonyl radical ) Cyclopropyl group ] Carbamic acid tert-butyl ester [ Racemic cis isomer ]

125 mg (0.62 mmol) of 1- [ (tert-butoxycarbonyl) amino ] cyclopropanecarboxylic acid together with 295 mg (0.78 mmol) of HATU and 127 mg (1.03 mmol) of 4-dimethylaminopyridine are initially charged in 8 ml of DMF and 180 mg (0.52 mmol) of N- {5- [4- (trifluoromethyl) phenyl ] piperidin-3-yl } benzamide are added. The reaction mixture was stirred at room temperature overnight and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 179 mg (65% of theory).

Examples 52A

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

28 g (132 mmol) of methyl 5-bromonicotinate and 30 g (158 mmol, 1.2 eq) of 4-trifluoromethylphenylboronic acid were reacted according to general procedure 1A. Yield: 32 g (85% of theory).

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

Examples 53A

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

32 g (112 mmol) of methyl 5- [4- (trifluoromethyl) phenyl ] pyridine-3-carboxylate (example 52A) are hydrogenated according to general method 2A. Yield: 26 g (82% of theory).

LC-MS (method 1B): r_t= 1.35 min and 1.41 min (cis/trans isomer); ms (esipos): m/z = 288 [ M + H [ ]]⁺。

Examples 54A

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

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

LC-MS (method 10B): r_t= 1.19 min and 1.22 min (cis/trans isomer); ms (esipos): m/z = 401 [ M + H [ ]]⁺。

Examples 55A

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

22.19 g (39.90 mmol) of the compound from example 54A and 44.78 g (399.0 mmol) of potassium tert-butoxide are reacted according to general method 7A. Yield: 18.29 g (100% of theory).

LC-MS (method 5B) R_t = 1.95 min; MS (ESIpos): m/z = 387 (M+H)⁺。

Examples 56A

1- { [ 3-amino-5- (4-ethylphenyl) piperidin-1-yl ] carbonyl } piperidine-4-carbonitrile [ racemic cis isomer ]

1.9 g (5.2 mmol) of the compound from example 30A are reacted according to general method 5A. Yield: 0.9 g (49% of theory).

LC-MS (method 11B) R_t = 0.72 min; MS (ESIpos): m/z = 341 (M+H)⁺。

Examples 57A

{ 3-amino-5- [4- (trifluoromethyl) phenyl ] piperidin-1-yl } (morpholin-4-yl) methanone hydrochloride [ racemic cis isomer ]

101 ml of twoA 4N hydrogen chloride solution in an alkane was added to the carbamate from example 172 (9.50 g, 20.1 mmol), and the mixture was then stirred at RT for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was taken up in 1N aqueous hydrogen chloride solution. After washing the aqueous phase with diethyl ether, the aqueous phase was concentrated under reduced pressure. The crude product thus obtained was used further without further purification. Yield: 5.27 g (65% of theory).

LC-MS (method 11B) R_t = 0.71 min; MS (ESIpos): m/z = 358 (M+H)⁺。

Examples 58A

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

20.0 g (69.6 mmol) of the compound from example 53A are dissolved in 1.0 l of dichloromethane and 14.1 g (139 mmol) of triethylamine are added at 0 ℃. 14.0 g (69.6 mmol) of 4-nitrophenyl chloroformate are then added dropwise. The reaction mixture was stirred at 0 ℃ for 2 hours and then at room temperature for 16 hours. For work-up, the mixture was washed with saturated aqueous sodium bicarbonate. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. This gave 31.3 g of crude product, which was reacted without any further purification steps.

LC-MS (method 1B): r_t= 2.44 min and 2.48 min (cis/trans isomer); ms (esipos): m/z = 453 [ M + H]⁺。

Examples 59A

1- (1, 4-dioxa-8-azaspiro [4.5] dec-8-ylcarbonyl) -5- [4- (trifluoromethyl) phenyl ] piperidine-3-carboxylic acid methyl ester [ racemic cis/trans isomer mixture ]

6.00 g (13.3 mmol) of the compound from example 58A, 4.75 g (33.2 mmol) of 8-aza-1, 4-dioxa-spiro [4.5] decane and 1.83 g (13.3 mmol) of potassium carbonate are reacted according to general method 8A. Yield: 5.15 g (81% of theory).

LC-MS (method 11B): r_t= 1.19 min and 1.14 min (cis/trans isomer); ms (esipos): m/z = 457 [ M + H]⁺。

Examples 60A

1- (1, 4-dioxa-8-azaspiro [4.5] dec-8-ylcarbonyl) -5- [4- (trifluoromethyl) phenyl ] piperidine-3-carboxylic acid [ racemic cis isomer ]

5.15 g (11.3 mmol) of the compound from example 59A and 12.7 g (113 mmol) of potassium tert-butoxide are reacted according to general method 7A. Yield: 5.00 g (99% of theory).

LC-MS (method 11B) R_t = 0.99 min; MS (ESIpos): m/z = 443 (M+H)⁺。

Examples 61A

{1-(1,4- Dioxa medicine -8- Azaspiro [4.5] Hair removing device -8- Radical carbonyl )-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Carbamic acid tert-butyl ester [ Racemic cis isomer ]

Activated molecular sieve 4a (about 8.4 g), 1.74 ml triethylamine (12.5 mmol) and 3.15 g (11.4 mmol) diphenyl azidophosphate (diphenylphosphonazidat) were added to the carboxylic acid from example 60A (5.00 g, 10.4 mmol) in t-butanol (189 ml) and the mixture was stirred under reflux conditions overnight. The reaction solution was cooled, and then the molecular sieve was filtered off and washed thoroughly with ethyl acetate. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate. After washing with 2N aqueous hydrogen chloride solution, saturated aqueous sodium bicarbonate solution and water, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was used in the next step without further purification. Yield: 5.32 g (70% of theory, purity 71%).

LC-MS (method 11B) R_t = 1.21 min; MS (ESIpos): m/z = 514 (M+H)⁺。

Examples 62A

{ 3-amino-5- [4- (trifluoromethyl) phenyl ] piperidin-1-yl } (1, 4-dioxa-8-azaspiro [4.5] decan-8-yl) methanone hydrochloride [ racemic cis isomer ]

37 ml in twoA 4N hydrochloric acid solution in an alkane was added to the carbamate from example 61A (5.30 g, 7.33 mmol), and the mixture was then stirred at RT for 1 hour. Is newly added in37 ml of 4N hydrochloric acid solution in an alkane and the mixture is stirred at 60 ℃ for 3 hours. The reaction solution was concentrated under reduced pressure and the residue was taken up in 1N aqueous hydrogen chloride solution. After washing the aqueous phase with diethyl ether, the aqueous phase was concentrated under reduced pressure. The crude product thus obtained was used further without further purification. Yield: 3.20 g (92% of theory).

LC-MS (method 5B) R_t = 1.57 min; MS (ESIpos): m/z = 414 (M+H)⁺。

Examples 63A

N-{1-(1,4- Dioxa medicine -8- Azaspiro [4.5] Hair removing device -8- Radical carbonyl )-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of }- Cyclopentanamide [ Racemic cis isomer ]

177 microliters of triethylamine (1.27 mmol) and 15.5 mg of DMAP (0.127 mmol) were added to a solution of the amine hydrochloride from example 62A (200 mg, 0.422 mmol) in dichloromethane (10 ml), and then 84 mg of cyclopentanecarbonyl chloride (0.633 mmol) was added at 0 ℃. The reaction mixture was warmed to room temperature and stirred overnight. The reaction solution was washed with aqueous 1N hydrogen chloride solution and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (RP18 column; acetonitrile/water gradient). Yield: 112 mg (52% of theory).

LC-MS (method 2B) R_t = 1.28 min; MS (ESIpos): m/z = 510 (M+H)⁺。

Examples 64A

3-chloro-N- {1- (1, 4-dioxa-8-azaspiro [4.5] decan-8-ylcarbonyl) -5- [4- (trifluoromethyl) phenyl ] piperidin-3-yl } benzamide [ racemic cis isomer ]

0.59 ml (3.38 mmol) of N, N '-diisopropylethylamine and 248 mg (1.58 mmol) of 3-chlorobenzoic acid are added to a solution of the compound from example 62A (500 mg, 1.06 mmol) in N, N' -dimethylformamide (18 ml). After addition of 522 mg (1.37 mmol) of HATU, the mixture was stirred at room temperature overnight. The reaction mixture was purified directly by preparative HPLC (RP18 column; acetonitrile/water gradient). Yield: 414 mg (67% of theory).

LC-MS (method 2B) R_t = 1.36 min; MS (ESIpos): m/z = 552 (M+H)⁺。

Examples 65A

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

10.0 g (40.4 mmol) of the compound from example 2A are initially charged in 135 ml of dichloromethane and cooled to 0 ℃ and 11.2 ml (8.2 g, 80.9 mmol) of triethylamine and 8.5 g (40.4 mmol) of 4-nitrophenyl chloroformate are added. The reaction mixture was allowed to warm to room temperature over a2 hour period. For work-up, the mixture was washed twice with water and the organic phase was dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was dried under high vacuum. Yield: 16.5 g (83% of theory).

LC-MS (method 11B) R_t= 1.31 min and1.33 min (cis/trans isomer); MS (ESIpos): M/z = 413 [ M + H;)]⁺。

Examples 66A

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

4.00 g (8.84 mmol) of 3-methyl-1- (4-nitrophenyl) 5- [4- (trifluoromethyl) phenyl ] piperidine-1, 3-dicarboxylic acid ester (example 58A) and 2.92 g (26.5 mmol) of piperidine-4-carbonitrile are reacted according to general procedure 8A. Yield: 3.15 g (77% of theory).

LC-MS (method 1B): r_t= 2.35 min and 2.41 min (cis/trans isomer); ms (esipos): m/z = 424 [ M + H%]⁺。

Examples 67A

1- [ (4-Cyanopiperidin-1-yl) carbonyl ] -5- [4- (trifluoromethyl) phenyl ] piperidine-3-carboxylic acid [ racemic cis isomer ]

2.90 g (6.85 mmol) of methyl 1- [ (4-cyanopiperidin-1-yl) carbonyl ] -5- [4- (trifluoromethyl) phenyl ] piperidine-3-carboxylate (example 66A) are reacted according to general method 9A (reaction time 2 h). Yield: 2.86 g (98% of theory).

LC-MS (method 1B): r_t= 2.15 min；MS (ESIpos)：m/z = 410 (M+H)⁺。

Examples 68A

{1-[(4- Cyanopiperidines -1- Base of ) Carbonyl radical ]-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Carbamic acid tert-butyl ester [ Racemic cis form / Trans isomer mixture ]

18 g of molecular sieve 4a, 3.2 ml (2.3 g, 23 mmol) of triethylamine and 4.6 ml (5.8 g, 21 mmol) of diphenyl azidophosphate (diphenylphosphonazidat) are added to a solution of 7.90 g (19.3 mmol) of the carboxylic acid from example 67A in 350 ml of tert-butanol and the mixture is stirred under reflux overnight. The molecular sieve was then filtered off and washed repeatedly with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with 2N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 8.34 g, 91% pure (82% of theory).

LC-MS (method 11B): r_t= 1.16 min and 1.19 min (cis/trans isomer); ms (esipos): m/z = 481 [ M + H]⁺。

Examples 69A

1- ({ 3-amino-5- [4- (trifluoromethyl) phenyl ] piperidin-1-yl } carbonyl) piperidine-4-carbonitrile hydrochloride [ racemic cis isomer ]

78 ml in twoThe 4N hydrochloric acid solution in alkane was added to 8.30 g (15.7 mmol) of 91% pure carbamate from example 68A and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was taken up in 1N hydrochloric acid. After washing with diethyl ether, the organic phase is concentrated under reduced pressure and the residue is taken up in dichloromethane and extracted repeatedly with 1N hydrochloric acid. The combined aqueous phases are concentrated under reduced pressure and the residue is dried under high vacuum. Yield: 4.93 g (71% of theory).

LC-MS (method 2B) R_t = 0.82 min; MS (ESIpos): m/z = 381 [M+H-HCl]⁺。

Working examples

General procedure 1: Coupling of amides with carboxylic acids

HATU (1.2 eq) and N, N-diisopropylethylamine (3.2 eq) were added to a solution of the appropriate carboxylic acid (1.1 eq) in dimethylformamide (10 ml/mmol) under argon and at room temperature. The reaction mixture was stirred at room temperature for 30 min, and amine (1.0 eq) was added. The reaction mixture was stirred at RT. After addition of water and phase separation, the organic phase was washed with water and with saturated aqueous sodium chloride solution, dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient).

General procedure 2 : amide coupling carbonyl chloride

Under argon and at room temperature, the appropriate phosgene (1.1 eq) and N, N-diisopropylethylamine (3.2 eq) were added dropwise to a solution of the amine (1.0 eq) in tetrahydrofuran (10 ml/mmol). The reaction mixture was stirred at RT. After addition of water and phase separation, the organic phase was washed with water and with saturated aqueous sodium chloride solution, dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient).

General procedure 3 : reaction with carbamoyl chlorides

N, N-diisopropylethylamine (2.5 eq) and the appropriate carbamoyl chloride (1.3 eq) were added dropwise to a solution of the amine (1.0 eq) in tetrahydrofuran (1.25 ml/mmol) under argon and at room temperature. The reaction mixture was stirred at RT. After addition of water and phase separation, the organic phase was washed with water and with saturated aqueous sodium chloride solution, dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient).

General procedure 4 : formation of urea from isocyanates

N, N-diisopropylethylamine (3.2 eq) and the appropriate isocyanate (1.1 eq) were added dropwise to a solution of the amine (1.0 eq) in tetrahydrofuran (10 ml/mmol) under argon and at room temperature. The reaction mixture was stirred at RT. After addition of water and phase separation, the organic phase was washed with water and with saturated aqueous sodium chloride solution, dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient).

General procedure 5 : by reaction with chloroformic acid esters

N, N-diisopropylethylamine (3 equivalents) and the appropriate chloroformate (1.3 equivalents) were added dropwise to a solution of the amine (1.0 equivalent) in tetrahydrofuran (1.25 ml/mmol) under argon and at room temperature. The reaction mixture was stirred at RT. After addition of water and phase separation, the organic phase was washed with water and with saturated aqueous sodium chloride solution, dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient).

General procedure 6 : sulfonamide formation

At room temperature, N' -diisopropylethylamine (2.5 eq) and the appropriate sulfonyl chloride (1.5 eq) were added to a solution of the appropriate amine (1 eq) in dichloromethane (21 ml/mmol). The reaction mixture was stirred at room temperature overnight. For work-up, the dichloromethane was removed under reduced pressure and the residue was purified by preparative HPLC.

General procedure 7 ： Suzuki Reaction of

A solution of tetrakis (triphenylphosphine) palladium (0.02 eq), boric acid (1.2 eq) in ethanol (1 ml/mmol) and potassium fluoride (2.0 eq) in water (1 ml/mmol) was added to a solution of bromide (1.0 eq) in toluene (5 ml/mmol) under argon and at room temperature. The reaction mixture was stirred at reflux. After addition of ethyl acetate and phase separation, the organic phase was washed with water, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient).

General procedure 8 : amide formation

HATU (1.3 equivalents) and N, N '-diisopropylethylamine (3.2 equivalents) were added to a 1.0 equivalent solution of the appropriate amine hydrochloride in N, N' -dimethylformamide at room temperature. Then 1.5 equivalents of the appropriate carboxylic acid are added. The reaction mixture was stirred at room temperature for 16 hours and then purified by preparative HPLC.

Examples 1

1- (cyclopropylcarbonyl) -5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide [ racemic cis isomer ]

68 mg (0.20 mmol) of 5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide (example 17A) and 19 mg (0.22 mmol, 1.1 eq) of cyclopropanecarboxylic acid are reacted according to general method 1. Yield: 38 mg (50% of theory).

HPLC (method 1A) R_t = 4.81 min; MS (ESIpos): m/z = 377 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 10.04 (s, 1H), 7.59 (d, 2H), 7.33-7.12 (m, 6H), 7.04 (t, 1H), 4.61 (br d, 0.5H), 4.52-4.41 (m, 1H), 4.28 (br d, 0.5H), 3.28-3.13 (m, 2H), 2.80-2.69 (m, 1H), 2.65-2.53 (m, 3H), 2.20-1.89 (m, 3H), 1.17 (t, 3H), 0.88-0.65 (m, 4H)。

Examples 2

1- (2, 2-dimethylpropionyl) -5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide [ racemic cis isomer ]

68 mg (0.20 mmol) of 5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide (example 17A) and 22 mg (0.22 mmol, 1.1 eq) of pivalic acid are reacted according to general method 1. Yield: 37 mg (34% of theory).

HPLC(method 2A) R_t = 5.08 min; MS (ESIpos): m/z = 393 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ = 10.03 (s, 1H), 7.59 (d, 2H), 7.29 (t, 2H), 7.23 (d, 2H), 7.18 (d, 2H), 7.04 (t, 1H), 4.51 (br d, 1H), 4.25 (br d, 1H), 3.03-2.88 (m, 2H), 2.71-2.58 (m, 2H), 2.58 (q, 2H), 2.13 (br d, 1H), 1.97 (q, 1H), 1.22 (s, 9H), 1.17 (t, 3H)。

Examples 3

1- (2, 2-dimethylpropionyl) -5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide [ enantiomerically pure cis-isomer ]

Enantiomer separation of 13 mg of the racemate from example 2 according to method 1D gave 5.9 mg of the compound from example 3 (enantiomer 1) and 5.3 mg of the compound from example 4 (enantiomer 2).

LC-MS (method 1E) R_t = 3.17 min; MS (ESIpos): m/z = 393 [M+H]⁺。

Examples 4

LC-MS (method 1E) R_t = 4.65 min; MS (ESIpos): m/z = 393 [M+H]⁺。

Examples 5

1- (Cyclopropylacetyl) -5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide [ racemic cis isomer ]

68 mg (0.20 mmol) of 5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide (example 17A) and 22 mg (0.22 mmol, 1.1 eq) of cyclopropylacetic acid are reacted according to general method 1. Yield: 65 mg (79% of theory).

HPLC (method 1A) R_t = 4.83 min; MS (ESIpos): m/z = 391 [M+H]⁺;

¹H-NMR (500 MHz, DMSO-d₆): δ= 10.02 (s, 0.5H), 9.95 (s, 0.5H), 7.59 (d, 2H), 7.29 (t, 2H), 7.25 (d, 1H), 7.22 (d, 1H), 7.17 (d, 2H), 7.04 (t, 1H), 4.65 (br d, 0.5H), 4.49 (br d, 0.5H), 4.03 (br d, 0.5H), 3.84 (br d, 0.5H), 3.19 (t, 0.5H), 3.10 (t, 0.5H), 2.75-2.53 (m, 3H), 2.58 (q, 2H), 2.40-2.35 (m, 1H), 2.36 (dd, 0.5H), 2.28 (dd, 0.5H), 2.18-2.05 (m, 1H), 2.00-1.86 (m, 1H), 1.17 (t, 3H), 1.03-0.93 (m, 1H), 0.51-0.43 (m, 2H), 0.17-0.09 (m, 2H)。

Examples 6

1- (Cyclopropylacetyl) -5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide [ enantiomerically pure cis-isomer ]

The enantiomer separation of 50mg of the racemate from example 5 according to method 2D gave 18 mg of the compound from example 6 (enantiomer 1) and 18 mg of the compound from example 7 (enantiomer 2).

LC-MS (method 2E) R_t = 6.40 min; MS (ESIpos): m/z = 391 [M+H]⁺。

Examples 7

5- (4-Ethylphenyl) -1- (3-fluoro-2, 2-dimethylpropionyl) -N-phenylpiperidine-3-carboxamide [ racemic cis isomer ]

62 mg (0.20 mmol) of 5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide (example 17A) and 42 mg (0.3 mmol, 1.5 equivalents) of 3-fluoro-2, 2-dimethylpropionyl chloride are reacted according to general method 2. Yield: 68 mg (83% of theory).

HPLC (method 1A) R_t = 4.97 min; MS (ESIpos): m/z = 411 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 10.03 (s, 1H), 7.60 (d, 2H), 7.29 (t, 2H), 7.24 (d, 2H), 7.19 (d, 2H), 7.04 (t, 1H), 4.54-4.43 (m, 2H), 4.40-4.31 (m, 1H), 4.23 (br d, 1H), 3.06-2.90 (m, 2H), 2.73-2.59 (m, 2H), 2.58 (q, 2H), 2.14 (br d, 1H), 1.98 (q, 1H), 1.28 (d, 3H), 1.26 (d, 3H), 1.17 (t, 3H)。

Examples 8

5- (4-Ethylphenyl) -1- (3-methoxypropionyl) -N-phenylpiperidine-3-carboxamide [ racemic cis isomer ]

62 mg (0.18 mmol) of 5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide (example 17A) and 33 mg (0.27 mmol, 1.5 equivalents) of methoxypropionyl chloride are reacted according to general method 2. Yield: 65 mg (91% of theory).

HPLC (method 1A) R_t = 4.64 min; MS (ESIpos): m/z = 395 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 10.04 (s, 0.5H), 10.00 (s, 0.5H), 7.59 (d, 2H), 7.35-7.12 (m, 6H), 7.04 (t, 1H), 4.64 (br d, 0.5H), 4.47 (br d, 0.5H), 4.10 (br d, 0.5H), 3.89 (br d, 0.5H), 3.65-3.50 (m, 2H), 3.27 (s, 3H), 3.18 (t, 0.5H), 3.09 (t, 0.5H), 2.80-2.60 (m, 3H), 2.60-2.50 (m, 3H), 2.19-2.02 (m, 1H), 2.01-1.85 (m, 1H), 1.17 (t, 3H)。

Examples 9

5- (4-ethylphenyl) -N-phenyl-1- (tetrahydro-2H-pyran-4-ylcarbonyl) piperidine-3-carboxamide [ racemic cis isomer ]

62 mg (0.18 mmol) of 5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide (example 17A) and 41 mg (0.27 mmol, 1.5 eq) of tetrahydro-2H-pyran-4-carbonyl chloride are reacted according to general method 2. Yield: 67 mg (88% of theory).

HPLC (method 1A) R_t = 4.64 min; MS (ESIpos): m/z = 421 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 10.05 (s, 0.5H), 10.01 (s, 0.5H), 7.65-7.55 (m, 2H), 7.32-7.23 (m, 3H), 7.23-7.13 (m, 3H), 7.04 (t, 1H), 4.66 (br d, 0.5H), 4.49 (br d, 0.5H), 4.20 (br d, 0.5H), 3.99 (br d, 0.5H), 3.91-3.77 (m, 2H), 3.49-3.33 (m, 2H), 3.24 (t, 0.5H), 3.16 (t, 0.5H), 3.10-2.92 (m, 1H), 2.75-2.53 (m, 5H), 2.20-2.03 (m, 1H), 2.01-1.83 (m, 1H), 1.75-1.45 (m, 4H), 1.17 (t, 3H)。

Examples 10

1- [ (1-Aminocyclopropyl) carbonyl ] -5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide [ racemic cis isomer ]

Step (ii) of a) ： (1-{[3-(4- Ethyl phenyl )-5-( Phenylaminocarbonyl group ) Piperidine derivatives -1- Base of ] Carbonyl radical } Cyclopropyl group ) Carbamic acid tert-butyl ester [ Racemic cis isomer ]

169 mg (0.50 mmol) of 5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide (example 17A) and 111 mg (0.55 mmol, 1.1 eq) of 1- [ (tert-butoxycarbonyl) amino ] cyclopropanecarboxylic acid are reacted according to general method 1. Yield: 119 mg (48% of theory).

HPLC (method 2A) R_t = 4.90 min; MS (ESIpos): m/z = 492 [M+H]⁺。

Step (ii) of b) ： 1-[(1- Amino cyclopropyl group ) Carbonyl radical ]-5-(4- Ethyl phenyl )-N- Phenylpiperidines -3- Carboxamides [ Racemic cis isomer ]

190. mu.l (2.5 mmol, 15 equiv.) of trifluoroacetic acid are added to a solution of 81 mg (0.16 mmol) of tert-butyl (1- { [3- (4-ethylphenyl) -5- (phenylaminocarbonyl) piperidin-1-yl ] carbonyl } cyclopropyl) carbamate in 2 ml of dichloromethane under argon and at room temperature. The reaction mixture was stirred at room temperature for 20 hours, then concentrated under reduced pressure and co-evaporated repeatedly with toluene. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 29 mg (45% of theory).

HPLC (method 1A) R_t = 4.20 min; MS (ESIpos): m/z = 392 [M+H]⁺;

¹H-NMR (500 MHz, DMSO-d₆): δ= 9.99 (s, 1H), 7.60 (d, 2H), 7.29 (t, 2H), 7.24 (d, 2H), 7.18 (d, 2H), 7.04 (t, 1H), 4.54 (br d, 1H), 4.42 (br d, 1H), 3.09-2.79 (m, 2H), 2.80-2.61 (m, 2H), 2.57 (q, 2H), 2.33-2.20 (m, 2H), 2.13 (br d, 1H), 1.94 (q, 1H), 1.17 (t, 3H), 0.94-0.82 (m, 2H), 0.72-0.61 (m, 2H)。

Examples 11

5- (4-Ethylphenyl) -N-phenyl-1- (tetrahydrofuran-2-ylcarbonyl) piperidine-3-carboxamide [ racemic cis isomer ]

68 mg (0.20 mmol) of 5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide (example 17A) and 26 mg (0.22 mmol, 1.1 eq) of tetrahydrofuran-2-carboxylic acid are reacted according to general method 1. Yield: 67 mg (81% of theory).

HPLC (method 1A) R_t = 4.66 min; MS (ESIpos): m/z = 407 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 10.06-9.06 (m, 1H), 7.59 (d, 2H), 7.29 (t, 2H), 7.26-7.20 (m, 2H), 7.20-7.13 (m, 2H), 7.04 (t, 1H), 4.85-4.77 (m, 0.5H), 4.77-4.69 (m, 0.5H), 4.62-4.54 (m, 0.5H), 4.42 (br d, 0.5H), 4.29-4.12 (m, 0.5H), 4.09-3.96 (m, 0.5H), 3.86-3.69 (m, 2H), 3.21 (t, 0.5H), 3.07 (t, 0.5H), 2.82-2.53 (m, 5H), 2.20-1.78 (m, 6H), 1.17 (t, 3H)。

The following example [ racemic cis isomer ] was prepared in a similar manner:

。

examples 38

¹N- Cyclopentyl group -5-(4- Ethyl phenyl ³)-N- Phenylpiperidines -1,3- Dimethylamides [ Racemic cis isomer ]

62 mg (0.20 mmol) of 5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide (example 17A) and 22 mg (0.20 mmol, 1.0 eq) of cyclopentyl isocyanate are reacted according to general method 4. Yield: 70 mg (83% of theory).

HPLC (method 1A) R_t = 4.94 min; MS (ESIpos): m/z = 420 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 10.00 (s, 1H), 7.59 (d, 2H), 7.29 (t, 2H), 7.21 (d, 2H), 7.16 (d, 2H), 7.03 (t, 1H), 6.36 (d, 1H), 4.22 (br d, 1H), 4.08 (br d, 1H), 3.99-3.88 (m, 1H), 2.80 (t, 1H), 2.67 (q, 1H), 2.64-2.58 (m, 2H), 2.57 (q, 2H), 2.07 (br d, 1H), 1.88-1.72 (m, 3H), 1.68-1.55 (m, 2H), 1.52-1.33 (m, 4H), 1.16 (t, 3H)。

Examples 39

¹N- Cyclopropyl group -5-(4- Ethyl phenyl ³)-N- Phenylpiperidines -1,3- Dimethylamides [ Racemic cis isomer ]

62 mg (0.20 mmol) of 5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide (example 17A) and 17 mg (0.20 mmol, 1.0 eq) of cyclopropyl isocyanate are reacted according to general method 4. Yield: 63 mg (80% of theory).

HPLC (method 1A) R_t = 4.63 min; MS (ESIpos): m/z = 392 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 10.00 (s, 1H), 7.59 (d, 2H), 7.29 (t, 2H), 7.21 (d, 2H), 7.16 (d, 2H), 7.03 (t, 1H), 6.68 (d, 1H), 4.16 (br d, 1H), 4.02 (br d, 1H), 2.81 (t, 1H), 2.69 (q, 1H), 2.64-2.52 (m, 3H), 2.57 (q, 2H), 2.07 (br d, 1H), 1.83 (q, 1H), 1.16 (t, 3H), 0.57-0.52 (m, 2H), 0.42-0.35 (m, 2H)。

Examples 40

¹N- Tert-butyl radical -5-(4- Ethyl phenyl ³)-N- Phenylpiperidines -1,3- Dimethylamides [ Racemic cis isomer ]

62 mg (0.20 mmol) of 5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide (example 17A) and 20 mg (0.20 mmol, 1.0 eq) of tert-butyl isocyanate are reacted according to general method 4. Yield: 34 mg (42% of theory).

HPLC (method 1A) R_t = 4.95 min; MS (ESIpos): m/z = 408 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 10.00 (s, 1H), 7.60 (d, 2H), 7.29 (t, 2H), 7.21 (d, 2H), 7.16 (d, 2H), 7.03 (t, 1H), 5.93 (s, 1H), 4.19 (br d, 1H), 4.05 (br d, 1H), 2.77 (t, 1H), 2.70-2.53 (m, 3H), 2.57 (q, 2H), 2.06 (br d, 1H), 1.81 (q, 1H), 1.27 (s, 9H), 1.16 (t, 3H)。

Examples 41

5- (4-Ethylphenyl) -N-phenyl-1- (pyrrolidin-1-ylcarbonyl) piperidine-3-carboxamide [ racemic cis isomer ]

33 mg (0.10 mmol) of 5- (4-ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidine-3-carboxylic acid (example 11A) and 10 mg (0.11 mmol, 1.1 eq) of aniline are reacted according to general procedure 1. Yield: 26 mg (64% of theory).

HPLC (method 1A) R_t = 4.89 min; MS (ESIpos): m/z = 406 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 10.00 (s, 1H), 7.59 (d, 2H), 7.29 (t, 2H), 7.21 (d, 2H), 7.16 (d, 2H), 7.03 (t, 1H), 3.87 (br d, 1H), 3.68 (br d, 1H), 3.31-3.22 (m, 4H), 2.88 (t, 1H), 2.81-2.65 (m, 3H), 2.57 (q, 2H), 2.10 (br d, 1H), 1.87 (q, 1H), 1.81-1.68 (m, 4H), 1.16 (t, 3H)。

Examples 42

5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) -N-phenylpiperidine-3-carboxamide [ racemic cis isomer ]

250 mg (0.74 mmol) of 5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide (example 17A) and 143 mg (0.96 mmol, 1.3 equivalents) of morpholine-4-carbonyl chloride are reacted according to general method 3. Yield: 276 mg (88% of theory).

HPLC (method 1A) R_t = 4.55 min; MS (ESIpos): m/z = 422 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 10.00 (s, 1H), 7.59 (d, 2H), 7.29 (t, 2H), 7.21 (d, 2H), 7.16 (d, 2H), 7.03 (t, 1H), 3.80 (br d, 1H), 3.61 (br d, 1H), 3.60-3.51 (m, 4H), 3.22-3.12 (m, 4H), 2.94 (t, 1H), 2.84 (q, 1H), 2.80-2.66 (m, 2H), 2.57 (q, 2H), 2.10 (br d, 1H), 1.87 (q, 1H), 1.17 (t, 3H)。

Examples 43

5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) -N-phenylpiperidine-3-carboxamide [ enantiomerically pure cis-isomer ]

Separation of 280 mg of the racemate from example 42 according to method 3D enantiomer gave 131 mg of the compound from example 43 (enantiomer 1) and 145 mg of the compound from example 44 (enantiomer 2).

LC-MS (method 2E) R_t = 4.67 min; MS (ESIpos): m/z = 422 [M+H]⁺。

Examples 44

LC-MS (method 2E) R_t = 6.54 min; MS (ESIpos): m/z = 422 [M+H]⁺。

Examples 45

¹N- Ethyl radical -5-(4- Ethyl phenyl ¹)-N- Methyl radical ³-N- Phenylpiperidines -1,3- Dimethylamides [ Racemic cis isomer ]

250 mg (0.74 mmol) of 5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide (example 17A) and 117 mg (0.96 mmol, 1.3 equivalents) of ethyl (methyl) carbamoyl chloride are reacted according to general method 3. Yield: 215 mg (74% of theory).

HPLC (method 1A) R_t = 4.74 min; MS (ESIpos): m/z = 394 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 10.00 (s, 1H), 7.59 (d, 2H), 7.29 (t, 2H), 7.21 (d, 2H), 7.16 (d, 2H), 7.03 (t, 1H), 3.72 (br d, 1H), 3.53 (br d, 1H), 3.21-3.05 (m, 2H), 2.88 (t, 1H), 2.82-2.66 (m, 6H), 2.57 (q, 2H), 2.09 (br d, 1H), 1.86 (q, 1H), 1.16 (t, 3H), 1.06 (t, 3H)。

Examples 46

5- (4-ethylphenyl) -1- [ (4-methylpiperazin-1-yl) carbonyl ] -N-phenylpiperidine-3-carboxamide [ racemic cis isomer ]

250 mg (0.74 mmol) of 5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide (example 17A) and 156 mg (0.96 mmol, 1.3 equivalents) of 4-methylpiperazine-1-carbonyl chloride are reacted according to general method 3. Yield: 213 mg (66% of theory).

HPLC (method 1A) R_t = 3.45 min; MS (ESIpos): m/z = 435 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 10.00 (s, 1H), 7.59 (d, 2H), 7.29 (t, 2H), 7.21 (d, 2H), 7.16 (d, 2H), 7.03 (t, 1H), 3.77 (br d, 1H), 3.58 (br d, 1H), 3.23-3.10 (m, 4H), 2.92 (t, 1H), 2.81 (q, 1H), 2.79-2.66 (m, 2H), 2.57 (q, 2H), 2.09 (br d, 1H), 1.86 (q, 1H), 1.17 (t, 3H)。

Examples 47

5- (4-ethylphenyl) -N-phenyl-1- (piperazin-1-ylcarbonyl) piperidine-3-carboxamide [ racemic cis isomer ]

At room temperature, 13.4 ml (53.5 mmol, 8 eq) of hydrogen chloride in bisA4-molar solution in an alkane was added dropwise to 3.5 g (6.7 mmol) of 4- { [3- (6.7 mmol)4-Ethylphenyl) -5- (phenylaminocarbonyl) piperidin-1-yl]Carbonyl } piperazine-1-carboxylic acid tert-butyl ester (example 50) in 60 ml of bisIn an alkane. The reaction mixture was stirred at room temperature for 20 hours, then concentrated under reduced pressure and reacted with diThe alkane was co-evaporated twice, yielding 3.37 grams of the compound from example 47 as the hydrochloride salt. Using preparative HPLC (Reprosil C18, water/acetonitrile gradient with 0.1% triethylamine), 180 mg of the crude product was further purified to provide the free base (136 mg).

HPLC (method 1A) R_t = 4.18 min; MS (ESIpos): m/z = 421 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 10.00 (s, 1H), 7.60 (d, 2H), 7.29 (t, 2H), 7.21 (d, 2H), 7.17 (d, 2H), 7.03 (t, 1H), 3.77 (br d, 1H), 3.57 (br d, 1H), 3.16-3.03 (m, 4H), 2.90 (t, 1H), 2.85-2.69 (m, 3H), 2.69-2.60 (m, 4H), 2.57 (q, 2H), 2.40-2.30 (m, 1H), 2.10 (br d, 1H), 1.86 (q, 1H), 1.17 (t, 3H)。

Examples 48

1- [ (4-Cyclopropylpiperazin-1-yl) carbonyl ] -5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide [ racemic cis isomer ]

At room temperature, 898 microliters of a 1-molar solution of sodium cyanoborohydride in tetrahydrofuran was added to a solution of 94 milligrams (0.20 mmoles) of 5- (4-ethylphenyl) -N-phenyl-1- (piperazin-1-ylcarbonyl) piperidine-3-carboxamide, 241 microliters (1.20 mmoles, 6 equivalents) of [ (1-ethoxycyclopropyl) oxy ] - (trimethyl) silane, 35 microliters (0.62 mmoles, 3.1 equivalents) of acetic acid, and 115 milligrams of molecular sieve (4 Ǻ) in 1 milliliter of methanol. The reaction mixture was stirred under reflux for 5 hours, then filtered and adjusted to pH 8 using 0.2 molar sodium hydroxide solution. After addition of water/dichloromethane and phase separation, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 60 mg (65% of theory).

HPLC (method 2A) R_t = 4.30 min; MS (ESIpos): m/z = 461 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 10.01 (s, 1H), 7.59 (d, 2H), 7.29 (t, 2H), 7.21 (d, 2H), 7.16 (d, 2H), 7.03 (t, 1H), 3.77 (br d, 1H), 3.58 (br d, 1H), 3.19-3.07 (m, 4H), 2.92 (t, 1H), 2.81 (q, 1H), 2.78-2.65 (m, 2H), 2.57 (q, 2H), 2.09 (br d, 1H), 1.87 (q, 1H), 1.66-1.58 (m, 1H), 1.17 (t, 3H), 0.44-0.38 (m, 2H), 0.33-0.27 (m, 2H)。

The following example [ racemic cis isomer ] was prepared in a similar manner by reductive amination:

。

examples 50

4-{[3-(4- Ethyl phenyl )-5-( Phenylaminocarbonyl group ) Piperidine derivatives -1- Base of ] Carbonyl radical } Piperazine derivatives -1- (iv) Tert-butyl formate [ Racemic cis isomer ]

Under argon and at room temperature, 1.9 g (7.7 mmol) of tert-butyl 4- (chlorocarbonyl) piperazine-1-carboxylate were added to a solution of 2.0 g (5.9 mmol) of 5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide, 144 mg (1.2 mmol, 0.2 eq) of 4-dimethylaminopyridine and 2.1 ml (14.6 mmol, 2.5 eq) of triethylamine in 64 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 17 hours, then water and dichloromethane were added. After phase separation, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 60, dichloromethane/methanol 300:1 → 100:1) which yielded 3.5 g of example 50.

LC-MS (method 1B) R_t = 2.94 min; MS (ESIpos): m/z = 521 [M+H]⁺。

The following example [ racemic cis isomer ] was prepared by general method 3:

。

examples 69

4-({3-[( Phenyl carbonyl ) Amino group ]-5-[4-( Trifluoromethoxy radical ) Phenyl radical ] Piperidine derivatives -1- Base of } Carbonyl radical ) Piperazine derivatives -1- (iv) Tert-butyl formate [ Racemic cis isomer ]

At 0 ℃, 220 mg (0.55 mmol) of N- {5- [4- (trifluoromethoxy) phenyl ] piperidin-3-yl } benzamide was initially charged in 3 ml of dichloromethane and 273 mg (1.10 mmol) of tert-butyl 4- (chlorocarbonyl) piperazine-1-carboxylate and 116 μ l (0.82 mmol) of triethylamine were added. The mixture was slowly warmed to room temperature overnight. Water was added to the reaction mixture, and the reaction mixture was extracted. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 88 mg (28% of theory).

LC-MS (method 1B) R_t = 2.75 min; m/z = 577 [M+H]⁺。

Examples 70 ：

3- (4-Ethylphenyl) -5- (phenylaminocarbonyl) piperidine-1-carboxylic acid-2-methoxyethyl ester [ racemic cis isomer ]

68 mg (0.20 mmol) of 5- (4-ethylphenyl) -N-phenylpiperidine-3-carboxamide (example 17A) and 38 mg (0.22 mmol, 1.1 eq) of 2-methoxyethyl chloroformate are reacted according to general method 5. Yield: 73 mg (89% of theory).

HPLC (method 2A) R_t = 4.67 min; MS (ESIpos): m/z = 411 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 10.04 (s, 1H), 7.59 (d, 2H), 7.29 (t, 2H), 7.22 (d, 2H), 7.17 (d, 2H), 7.04 (t, 1H); 4.27-4.09 (m, 3H), 4.09-3.95 (m, 1H), 3.58-3.49 (m, 2H), 3.27 (s, 3H), 3.05-2.80 (m, 2H), 2.72-2.60 (m, 2H), 2.58 (q, 2H), 2.18-2.06 (m, 1H), 1.88 (q, 1H), 1.17 (t, 3H)。

The following example [ racemic cis isomer ] was prepared in a similar manner:

。

examples 73

1- (Cyclopentylcarbonyl) -5- (4-ethylphenyl) -N- (3-fluorophenyl) piperidine-3-carboxamide [ racemic cis-isomer ]

66 mg (0.20 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine-3-carboxylic acid (example 7A) and 24 mg (0.22 mmol, 1.1 eq) of 3-fluoroaniline are reacted according to general procedure 1. Yield: 38 mg (45% of theory).

HPLC (method 1A) R_t = 5.31 min; MS (ESIpos): m/z = 423 [M+H]⁺;

¹H-NMR (500 MHz, DMSO-d₆): δ= 10.23 (s, 0.5H), 10.19 (s, 0.5H), 7.60 (d, 1H), 7.37-7.28 (m, 2H), 7.25 (d, 1H), 7.24-7.14 (m, 3H), 6.91-6.83 (m, 1H), 4.66 (br d, 0.5H), 4.50 (br d, 0.5H), 4.19 (br d, 0.5H), 3.97 (br d, 0.5H), 3.21 (t, 0.5H), 3.18-3.00 (m, 1.5H), 2.72-2.53 (m, 3H), 2.57 (q, 2H), 2.19-2.08 (m, 1H), 2.02-1.86 (m, 1H), 1.85-1.46 (m, 8H), 1.17 (t, 3H)。

Examples 74

1- (Cyclopentylcarbonyl) -5- (4-ethylphenyl) -N- (3-fluorophenyl) piperidine-3-carboxamide [ enantiomerically pure cis-isomer ]

The enantiomer separation of 36 mg of the racemate from example 73 according to method 4D gave 14 mg of the compound from example 74 (enantiomer 1) and 13 mg of enantiomer 2.

HPLC (method 3E) R_t = 2.26 min; MS (ESIpos): m/z = 423 [M+H]⁺。

Examples 75

1- (Cyclopentylcarbonyl) -5- (4-ethylphenyl) -N- (3-methoxyphenyl) piperidine-3-carboxamide [ racemic cis isomer ]

66 mg (0.20 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine-3-carboxylic acid (example 7A) and 27 mg (0.22 mmol, 1.1 eq) of 3-methoxyaniline are reacted according to general procedure 1. Yield: 52 mg (60% of theory).

HPLC (method 1A) R_t = 5.19 min; MS (ESIpos): m/z = 435 [M+H]⁺;

¹H-NMR (500 MHz, DMSO-d₆): δ= 10.00 (s, 0.5H), 9.96 (s, 0.5H), 7.31 (s, 1H), 7.28-7.11 (m, 6H), 6.62 (d, 1H), 4.65 (br d, 0.5H), 4.50 (br d, 0.5H), 4.17 (br d, 0.5H), 3.97 (br d, 0.5H), 3.21 (t, 0.5H), 3.15-3.00 (m, 1.5H), 2.72-2.53 (m, 3H), 2.57 (q, 2H), 2.17-2.06 (m, 1H), 2.01-1.86 (m, 1H), 1.86-1.46 (m, 8H), 1.17 (t, 3H)。

Examples 76

N-[1-( Cyclopentyl carbonyl group )-5-(4- Ethyl phenyl ) Piperidine derivatives -3- Base of ] Benzamide derivatives [ Racemic cis isomer ]

170 mg (0.41 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-ylamine trifluoroacetate (example 8A) and 50mg (0.41 mmol, 1.0 eq) of benzoic acid are reacted according to general procedure 1. Yield: 58 mg (35% of theory).

HPLC (method 1A) R_t = 4.89 min; MS (ESIpos): m/z = 405 [M+H]⁺;

¹H-NMR (500 MHz, DMSO-d₆): δ= 8.40 (d, 0.6H), 8.36 (d, 0.4H), 7.86 (dd, 2H), 7.53 (t, 1H), 7.47 (t, 2H), 7.27-7.16 (m, 4H), 4.67 (br d, 0.4H), 4.50 (br d, 0.6H), 4.23 (br d, 0.6H), 3.98 (br d, 0.4H), 3.97-3.83 (m, 1H), 3.08-2.99 (m, 1.4H), 2.89 (t, 0.6H), 2.83-2.75 (m, 0.4H), 2.72-2.63 (m, 0.6H), 2.58 (q, 2H), 2.12-2.01 (m, 1.6H), 1.95-1.78 (m, 1.4H), 1.78-1.46 (m, 8H), 1.17 (t, 3H)。

Examples 77

N-[5-(4- Ethyl phenyl )-1-( Pyrrolidine as a therapeutic agent -1- Radical carbonyl ) Piperidine derivatives -3- Base of ] Benzamide derivatives [ Racemic cis isomer ]

125 mg (50%, 0.15 mmol) of 5- (4-ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidin-3-amine trifluoroacetate (example 12A) and 20 mg (0.17 mmol, 1.1 equiv) of benzoic acid are reacted according to general procedure 1. Yield: 35 mg (56% of theory).

HPLC (method 1A) R_t = 4.72 min; MS (ESIpos): m/z = 406 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 8.35 (d, 1H), 7.85 (d, 2H), 7.53 (t, 1H), 7.46 (t, 2H), 7.24-7.14 (m, 4H), 4.07-3.95 (m, 1H), 3.91 (br d, 1H), 3.71 (br d, 1H), 3.33-2.24 (m, 4H), 2.90-2.80 (m, 1H), 2.75-2.60 (m, 2H), 2.57 (q, 2H), 2.08 (br d, 1H), 1.85-1.72 (m, 5H), 1.17 (t, 3H)。

Examples 78

N-[5-(4- Ethyl phenyl )-1-( Pyrrolidine as a therapeutic agent -1- Radical carbonyl ) Piperidine derivatives -3- Base of ]-3- Fluorobenzamides [ Racemic cis isomer ]

83 mg (75% pure, 0.15 mmol) of 5- (4-ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidin-3-amine trifluoroacetate (example 12A) and 23 mg (0.17 mmol, 1.1 equiv) of 3-fluorobenzoic acid are reacted according to general procedure 1. Yield: 41 mg (65% of theory).

HPLC (method 1A) R_t = 4.79 min; MS (ESIpos): m/z = 424 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 8.45 (d, 1H), 7.71 (d, 1H), 7.66 (dd, 1H), 7.52 (dt, 1H), 7.38 (dt, 1H), 7.23-7.14 (m, 4H), 4.06-3.94 (m, 1H), 3.91 (br d, 1H), 3.70 (br d, 1H), 3.32-2.25 (m, 4H), 2.90-2.80 (m, 1H), 2.73-2.60 (m, 2H), 2.57 (q, 2H), 2.08 (br d, 1H), 1.84-1.71 (m, 5H), 1.17 (t, 3H)。

Examples 79

N-[5-(4- Ethyl phenyl )-1-( Pyrrolidine as a therapeutic agent -1- Radical carbonyl ) Piperidine derivatives -3- Base of ]-3- Methoxybenzamides [ Racemic cis isomer ]

83 mg (75% pure, 0.15 mmol) of 5- (4-ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidin-3-ylamine trifluoroacetate (example 12A) and 25 mg (0.17 mmol, 1.1 equiv) of 3-methoxybenzoic acid are reacted according to general procedure 1. Yield: 47 mg (72% of theory).

HPLC (method 2A) R_t = 4.75 min; MS (ESIpos): m/z = 436 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 8.33 (d, 1H), 7.47-7.34 (m, 3H), 7.23-7.14 (m, 4H), 7.09 (dd, 1H), 4.07-3.94 (m, 1H), 3.91 (br d, 1H), 3.80 (s, 3H), 3.71 (br d, 1H), 3.36-2.26 (m, 4H), 2.91-2.80 (m, 1H), 2.65 (t, 2H), 2.57 (q, 2H), 2.09 (br d, 1H), 1.86-1.70 (m, 5H), 1.17 (t, 3H)。

Examples 80

N-[5-(4- Ethyl phenyl )-1-( Pyrrolidine as a therapeutic agent -1- Radical carbonyl ) Piperidine derivatives -3- Base of ]-4- Fluorobenzamides [ Racemic cis isomer ]

125 mg (50%, 0.15 mmol) of 5- (4-ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidin-3-amine trifluoroacetate (example 12A) and 23 mg (0.17 mmol, 1.1 equiv) of 4-fluorobenzoic acid are reacted according to general procedure 1. Yield: 53 mg (83% of theory).

HPLC (method 1A) R_t = 4.78 min; MS (ESIpos): m/z = 424 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 8.37 (d, 1H), 7.93 (dd, 2H), 7.30 (dd, 2H), 7.24-7.14 (m, 4H), 4.06-3.93 (m, 1H), 3.90 (br d, 1H), 3.70 (br d, 1H), 3.32-2.22 (m, 4H), 2.90-2.80 (m, 1H), 2.73-2.60 (m, 2H), 2.57 (q, 2H), 2.08 (br d, 1H), 1.84-1.71 (m, 5H), 1.17 (t, 3H)。

Examples 81

5-chloro-N- [1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-yl ] pyridine-3-carboxamide [ racemic cis isomer ]

65 mg (0.15 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-ylamine trifluoroacetate (example 8A) and 21 mg (0.13 mmol, 0.9 eq) of 5-chloropyridine-3-carboxylic acid are reacted according to general procedure 1. Yield: 39 mg (62% of theory).

HPLC (method 1A) R_t = 4.72 min; MS (ESIpos): m/z = 440 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 8.96 (d, 1H), 8.79 (s, 1H), 8.74 (d, 0.5H), 8.70 (d, 0.5H), 8.33 (d, 1H), 7.27-7.13 (m, 4H), 4.69 (br d, 0.5H), 4.49 (br d, 0.5H), 4.26 (br d, 0.5H), 3.97 (br d, 0.5H), 3.95-3.81 (m, 1H), 3.10-2.97 (m, 1.5H), 2.90 (t, 0.5H), 2.85-2.75 (m, 0.5H), 2.73-2.62 (m, 0.5H), 2.58 (q, 2H), 2.16-1.98 (m, 1.5H), 1.92-1.45 (m, 9.5H), 1.17 (t, 3H)。

Examples 82

5-bromo-N- [1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-yl ] pyridine-2-carboxamide [ racemic cis isomer ]

139 mg (0.34 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-ylamine trifluoroacetate (example 8A) and 68 mg (0.34 mmol, 1.0 eq) of 5-bromopyridine-2-carboxylic acid are reacted according to general procedure 1. Yield: 75 mg (44% of theory).

HPLC (method 2A) R_t = 5.06 min; MS (ESIpos): m/z = 484 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 8.83-8.75 (m, 2H), 8.34-8.23 (m, 1H), 8.02-7.96 (m, 1H), 7.26-7.15 (m, 4H), 4.58 (br d, 0.5H), 4.48 (br d, 0.5H), 4.14 (br d, 0.5H), 4.02-3.85 (m, 1.5H), 3.08-2.93 (m, 2H), 2.84-2.73 (m, 0.5H), 2.71-2.62 (m, 0.5H), 2.57 (q, 2H), 2.13-1.98 (m, 2.5H), 1.87-1.46 (m, 8.5H), 1.17 (t, 3H)。

Examples 83

N-[1-( Cyclopentyl carbonyl group )-5-(4- Ethyl phenyl ) Piperidine derivatives -3- Base of ]-5-[3-( Trifluoromethyl radical ) Phenyl radical ] Pyridine compound -2- Carboxamides [ Racemic cis isomer ]

59 mg (0.12 mmol) of 5-bromo-N- [1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-yl ] pyridine-2-carboxamide (example 82) and 27 mg (0.14 mmol, 1.2 equivalents) of [3- (trifluoromethyl) phenyl ] boronic acid are reacted according to general method 7. Yield: 46 mg (71% of theory).

HPLC (method 2A) R_t = 5.40 min; MS (ESIpos): m/z = 550 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 9.05-9.00 (m, 1H), 8.80 (t, 1H), 8.44-8.37 (m, 1H), 8.19-8.10 (m, 3H), 7.85 (d, 1H), 7.79 (t, 1H), 7.24 (t, 1H), 7.22-7.15 (m, 3H), 4.61 (br d, 0.5H), 4.49 (br d, 0.5H), 4.18 (br d, 0.5H), 4.07-3.91 (m, 1.5H), 3.12-2.96 (m, 2H), 2.87-2.77 (m, 0.5H), 2.72-2.63 (m, 1H), 2.58 (q, 2H), 2.18-2.01 (m, 2.5H), 1.87-1.47 (m, 8H), 1.17 (t, 3H)。

Examples 84

N-[1-( Cyclopentyl carbonyl group )-5-(4- Ethyl phenyl ) Piperidine derivatives -3- Base of ]-5-[3-( Trifluoromethyl radical ) Phenyl radical ] Pyridine compound -2- Carboxamides [ Enantiomerically pure cis-isomers ]

Enantiomer separation of 36 mg of the racemate from example 83 according to method 6D gave 17 mg of the compound from example 84 (enantiomer 1) and 15 mg of the compound from example 85 (enantiomer 2).

HPLC (method 2E) R_t = 6.39 min; MS (ESIpos): m/z = 550 [M+H]⁺。

Examples 85

HPLC (method 2E) R_t = 7.07 min; MS (ESIpos): m/z = 550 [M+H]⁺。

Examples 86

N-[5-(4- Ethyl phenyl )-1-( Pyrrolidine as a therapeutic agent -1- Radical carbonyl ) Piperidine derivatives -3- Base of ]-5-(3- Fluorophenyl group ) Pyridine compound -2- Carboxamides [ Racemic cis isomer ]

62 mg (0.11 mmol) of 5- (4-ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidin-3-amine trifluoroacetate (example 12A) and 27 mg (0.12 mmol, 1.1 equiv) of 5- (3-fluorophenyl) pyridine-2-carboxylic acid are reacted according to general procedure 1. Yield: 31 mg (56% of theory).

HPLC (method 2A) R_t = 5.18 min; MS (ESIpos): m/z = 501 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 8.98 (d, 1H), 8.73 (d, 1H), 8.34 (dd, 1H), 8.12 (d, 1H), 7.76-7.65 (m, 2H), 7.63-7.55 (m, 1H), 7.37-7.28 (m, 1H), 7.21 (d, 2H), 7.17 (d, 2H), 4.13-4.02 (br m, 1H), 3.85 (br d, 1H), 3.70 (br d, 1H), 3.32-3.25 (m, 4H), 2.91-2.81 (m, 1H), 2.77 (t, 1H), 2.72-2.63 (m, 1H), 2.57 (q, 2H), 2.10-1.93 (m, 2H), 1.83-1.71 (m, 4H), 1.17 (t, 3H)。

Examples 87

5-chloro-N- [1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-yl ] thiophene-2-carboxamide [ racemic cis isomer ]

65 mg (0.15 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-ylamine trifluoroacetate (example 8A) and 22 mg (0.13 mmol, 0.9 eq) of 5-chlorothiophene-2-carboxylic acid are reacted according to general procedure 1. Yield: 43 mg (72% of theory).

HPLC (method 2A) R_t = 5.02 min; MS (ESIpos): m/z = 445 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 8.55 (d, 0.6H), 8.50 (d, 0.4H), 7.71 (d, 0.6H), 7.68 (d, 0.4H), 7.26-7.13 (m, 5H), 4.64 (br d, 0.4H), 4.47 (br d, 0.6H), 4.21 (br d, 0.6H), 3.96 (br d, 0.4H), 3.90-3.73 (m, 1H), 3.07-2.97 (m, 1.4H), 2.87 (t, 0.6H), 2.82-2.73 (m, 0.4H), 2.71-2.61 (m, 0.6H), 2.58 (q, 2H), 2.43 (t, 0.6H), 2.11-1.96 (m, 1.4H), 1.91-1.44 (m, 9H), 1.17 (t, 3H)。

Examples 88

N-[1-( Cyclopentyl carbonyl group )-5-(4- Ethyl phenyl ) Piperidine derivatives -3- Base of ]-2,4- Dimethyl group -1,3- Thiazoles -5- Carboxamides [ Racemic cis isomer ]

65 mg (0.15 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-ylamine trifluoroacetate (example 8A) and 21 mg (0.13 mmol, 0.9 eq) of 2, 4-dimethyl-1, 3-thiazole-5-carboxylic acid are reacted according to general procedure 1. Yield: 43 mg (73% of theory).

HPLC (method 1A) R_t = 4.50 min; MS (ESIpos): m/z = 440 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 8.10 (t, 1H), 7.24-7.13 (m, 4H), 4.62 (br d, 0.4H), 4.47 (br d, 0.6H), 4.18 (br d, 0.6H), 3.96 (br d, 0.4H), 3.90-3.74 (m, 1H), 3.08-2.96 (m, 1.4H), 2.89 (t, 0.6H), 2.82-2.73 (m, 0.4H), 2.71-2.62 (m, 0.6H), 2.61 (s, 3H), 2.57 (q, 2H), 2.54 (s, 3H), 2.44 (t, 0.6H), 2.08-1.98 (m, 1.4H), 1.90-1.46 (m, 9H), 1.17 (t, 3H)。

Examples 89

N-[1-( Cyclopentyl carbonyl group )-5-(4- Ethyl phenyl ) Piperidine derivatives -3- Base of ]-2- Phenylacetamides [ Racemic cis isomer ]

57 mg (0.12 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-ylamine trifluoroacetate (example 8A) and 16 mg (0.12 mmol, 1.0 eq) of phenylacetic acid are reacted according to general method 1. Yield: 28 mg (58% of theory).

HPLC (method 2A) R_t = 4.79 min; MS (ESIpos): m/z = 419 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 8.19 (d, 0.6H), 8.12 (d, 0.4H), 7.32-7.12 (m, 9H), 4.56 (br d, 0.5H), 4.44 (br d, 0.5H), 4.15 (br d, 0.5H), 3.92 (br d, 0.5H), 3.68-3.53 (m, 1H), 3.42 (s, 1.2H), 3.40 (s, 0.8H), 3.07-2.88 (m, 2H), 2.75 (t, 1H), 2.57 (q, 2H), 2.32 (t, 0.6H), 2.08-1.96 (m, 1.4H), 1.86-1.44 (m, 8H), 1.17 (t, 3H)。

Examples 90

N-[1-( Cyclopentyl carbonyl group )-5-(4- Ethyl phenyl ) Piperidine derivatives -3- Base of ]-2,2- Dimethylpropionamide [ Racemic cis isomer ]

99 mg (0.20 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-ylamine trifluoroacetate (example 8A) and 20 mg (0.20 mmol, 1.0 eq) of pivalic acid are reacted according to general procedure 1. Yield: 56 mg (73% of theory).

HPLC (method 1A) R_t = 4.81 min; MS (ESIpos): m/z = 385 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 7.33 (t, 1H), 7.23-7.14 (m, 4H), 4.52-4.42 (m, 1H), 4.06 (br d, 0.6H), 3.93 (br d, 0.4H), 3.72-3.60 (m, 1H), 3.05-2.92 (m, 1.4H), 2.77 (t, 0.6H), 2.74-2.65 (m, 0.4H), 2.63-2.53 (m, 2.6H), 2.37 (t, 0.6H), 2.08-1.97 (m, 0.4H), 1.96-1.88 (m, 1H), 1.87-1.45 (m, 9H), 1.16 (t, 3H), 1.10 (s, 5.4H), 1.09 (3.6H)。

Examples 91

1- [5- (4-ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidin-3-yl ] -3-phenylurea [ racemic cis isomer ]

125 mg (50%, 0.15 mmol) of 5- (4-ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidin-3-amine trifluoroacetate (example 12A) and 21 mg (0.18 mmol, 1.2 equivalents) of phenyl isocyanate are reacted according to general procedure 4. Yield: 58 mg (92% of theory).

HPLC (method 1A) R_t = 4.72 min; MS (ESIpos): m/z = 421 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 8.39 (s, 1H), 7.37 (d, 2H), 7.26-7.13 (m, 6H), 6.89 (t, 1H), 6.17 (d, 1H), 3.92 (br d, 1H), 3.72-3.60 (m, 2H), 3.30-3.23 (m, 4H), 2.88-2.77 (m, 1H), 2.66 (q, 1H), 2.57 (q, 2H), 2.52-2.40 (m, 1H), 2.06 (br d, 1H), 1.82-1.70 (m, 4H), 1.56 (q, 1H), 1.17 (t, 3H)。

Examples 92

1- [5- (4-ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidin-3-yl ] -3- (3-methoxyphenyl) urea [ racemic cis isomer ]

83 mg (50%, 0.15 mmol) of 5- (4-ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidin-3-amine trifluoroacetate (example 12A) and 25 mg (0.17 mmol, 1.1 equiv) of 3-methoxyphenyl isocyanate were reacted according to general method 4. Yield: 46 mg (67% of theory).

HPLC (method 2A) R_t = 4.71 min; MS (ESIpos): m/z = 451 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 8.41 (s, 1H), 7.20 (d, 2H), 7.16 (d, 2H), 7.14-7.08 (m, 2H), 6.85 (d, 1H), 6.48 (dd, 1H), 6.16 (d, 1H), 3.91 (br d, 1H), 3.70 (s, 3H), 3.70-3.60 (m, 2H), 3.32-3.25 (m, 4H), 2.87-2.77 (m, 1H), 2.65 (t, 1H), 2.58 (q, 2H), 2.50-2.44 (m, 1H), 2.05 (br d, 1H), 1.80-1.70 (m, 4H), 1.56 (q, 1H), 1.17 (t, 3H)。

Examples 93

1- [5- (4-ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidin-3-yl ] -3- (4-fluorophenyl) urea [ racemic cis isomer ]

83 mg (50%, 0.15 mmol) of 5- (4-ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidin-3-amine trifluoroacetate (example 12A) and 23 mg (0.17 mmol, 1.2 equivalents) of 4-fluorophenyl isocyanate are reacted according to general procedure 4. Yield: 44 mg (67% of theory).

HPLC (method 2A) R_t = 4.73 min; MS (ESIpos): m/z = 439 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 8.43 (s, 1H), 7.42-7.34 (m, 2H), 7.20 (d, 2H), 7.16 (d, 2H), 7.06 (t, 2H), 6.16 (d, 1H), 3.91 (br d, 1H), 3.71-3.60 (m, 2H), 3.32-3.25 (m, 4H), 2.83-2.76 (m, 1H), 2.66 (t, 1H), 2.58 (q, 2H), 2.46 (t, 1H), 2.05 (br d, 1H), 1.81-1.70 (m, 4H), 1.57 (q, 1H), 1.17 (t, 3H)。

The following compound [ racemic cis isomer ] was prepared in a similar manner:

。

examples 95

3- [1- (Cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-yl ] -1-methyl-1-phenylurea [ racemic cis isomer ]

60 mg (0.14 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-ylamine trifluoroacetate (example 8A) and 22 mg (0.14 mmol, 1.0 eq) of methyl (phenyl) carbamoyl chloride are reacted according to general procedure 3. Yield: 37 mg (69% of theory).

HPLC (method 1A) R_t = 4.87 min; MS (ESIpos): m/z = 434 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 7.38 (t, 2H), 7.30-7.24 (m, 2H), 7.21 (t, 1H), 7.18-7.12 (m, 4H), 5.89 (d, 0.5H), 5.85 (d, 0.5H), 4.54 (br d, 0.5H), 4.42 (br d, 0.5H), 4.11 (br d, 0.5H), 3.89 (br d, 0.5H), 3.68-3.53 (m, 1H), 3.16 (s, 1.5H), 3.15 (s, 1.5H), 3.04-2.94 (m, 1H), 2.90 (t, 0.5H), 2.77 (t, 0.5H), 2.73-2.64 (m, 0.5H), 2.56 (q, 2H), 2.43 (t, 0.5H), 2.33 (t, 0.5H), 2.06-1.88 (m, 1.5H), 1.83-1.44 (m, 9H), 1.16 (t, 3H)。

Examples 96

1- [1- (Cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-yl ] -1, 3-dimethyl-3-phenylurea [ racemic cis isomer ]

Under argon and at room temperature, 8 mg of sodium hydride (60% in mineral oil, 0.19 mmol, 2 eq) are added to a solution of 40 mg (0.10 mmol) of 1- [1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-yl ] -3-phenylurea (example 171) in 1 ml of dimethylformamide and the mixture is stirred at room temperature for 30 minutes. To the reaction mixture was added 13 μ l (0.21 mmol, 2.2 equivalents) of methyl iodide and stirred at room temperature for an additional 1.5 hours. After addition of water/dichloromethane and phase separation, the aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 26 mg (61% of theory).

HPLC (method 2A) R_t = 5.03 min; MS (ESIpos): m/z = 448 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 7.34 (d, 2H), 7.28-7.13 (m, 7H), 4.46-4.33 (m, 1H), 3.91-3.78 (m, 2H), 3.16 (t, 1H), 3.08 (s, 3H), 3.05-2.95 (m, 1H), 2.80-2.70 (m, 1H), 2.58 (q, 2H), 1.98-1.84 (m, 2H), 1.83-1.44 (m, 9H), 1.17 (t, 3H)。

Examples 97

1-tert-butyl-3- [1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-yl ] urea [ racemic cis isomer ]

108 mg (0.22 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-ylamine trifluoroacetate (example 7A) and 26 mg (0.26 mmol, 1.2 equivalents) of tert-butyl isocyanate are reacted according to general method 4. Yield: 69 mg (78% of theory).

HPLC (method 2A) R_t = 4.74 min; MS (ESIpos): m/z = 400 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 7.24-7.14 (m, 4H), 5.73 (d, 0.5H), 5.67 (d, 0.5H), 5.66 (s, 0.5H), 5.61 (s, 0.5H), 4.57 (br d, 0.5H), 4.42 (br d, 0.5H), 4.14 (br d, 0.5H), 3.89 (br d, 0.5H), 3.50-3.36 (m, 1H), 3.05-2.94 (m, 1.5H), 2.73-2.61 (m, 1.5H), 2.57 (q, 2H), 2.18 (t, 0.5H), 2.07-1.92 (m, 1.5H), 1.83-1.43 (m, 9H), 1.22 (s, 4.5H), 1.21 (s, 4.5H), 1.16 (t, 3H)。

Examples 98

1- [1- (Cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-yl ] -3-cyclopropylurea [ racemic syn isomer ]

108 mg (0.22 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-ylamine trifluoroacetate (example 7A) and 22 mg (0.26 mmol, 1.2 equivalents) of cyclopropyl isocyanate are reacted according to general procedure 4. Yield: 64 mg (76% of theory).

HPLC (method 2A) R_t = 4.50 min; MS (ESIpos): m/z = 384 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆) δ = 7.24-7.14 (m, 4H), 6.14 (s, 0.6H), 6.12 (s, 0.4H), 5.86 (d, 0.6H), 5.81 (d, 0.4H), 4.56 (br d, 0.4H), 4.42 (br d, 0.6H), 4.15 (br d, 0.6H), 3.90 (br d, 0.4H), 3.56-3.41 (m, 1H), 3.04-2.92 (m, 1.4H), 2.77-2.65 (m, 1H), 2.64-2.52 (m, 0.6H and q, 2H), 2.45-2.35 (m, 1H), 2.26 (t, 0.4H), 2.08-1.91 (m, 1.6H), 1.83-1.43 (m, 0.60H), 3.60-2.52 (m, 1H), 2H) 0.36-0.28 (m, 2H).

Examples 99

N-[1-( Cyclopentyl carbonyl group )-5-(4- Ethyl phenyl ) Piperidine derivatives -3- Base of ] Pyrrolidine as a therapeutic agent -1- Carboxamides [ Racemic cis isomer ]

57 mg (0.12 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-ylamine trifluoroacetate (example 7A) and 20 mg (0.15 mmol, 1.3 equivalents) of pyrrolidine-N-carbonyl chloride are reacted according to general method 3. Yield: 24 mg (52% of theory).

HPLC (method 2A) R_t = 4.60 min; MS (ESIpos): m/z = 398 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 7.23-7.11 (m, 4H), 5.95 (d, 0.6H), 5.91 (d, 0.4H), 4.55 (br d, 0.4H), 4.45 (br d, 0.6H), 4.13 (br d, 0.6H), 3.92 (br d, 0.4H), 3.62-3.49 (m, 1H), 3.26-3.14 (m, 4H), 3.04-2.88 (m, 1.4H), 2.79-2.63 (m, 1H), 2.57 (q, 2H), 2.49-2.40 (m, 0.6H), 2.36-2.28 (m, 0.4H), 2.05-1.92 (m, 1.6H), 1.85-1.73 (m, 5H), 1.73-1.43 (m, 8H), 1.17 (t, 3H)。

Examples 100

1- Benzyl radical -3-[1-( Cyclopentyl carbonyl group )-5-(4- Ethyl phenyl ) Piperidine derivatives -3- Base of ][ Racemic cis isomer ]

108 mg (0.22 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-ylamine trifluoroacetate (example 7A) and 35 mg (0.26 mmol, 1.2 equivalents) of benzyl isocyanate are reacted according to general method 4. Yield: 74 mg (77% of theory).

HPLC (method 1A) R_t = 4.74 min; MS (ESIpos): m/z = 434 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 7.35-7.28 (m, 2H), 7.27-7.19 (m, 3H), 7.19-7.14 (m, 4H), 6.34 (t, 0.6H), 6.29 (t, 0.4H), 6.04 (d, 0.6H), 5.98 (d, 0.4H), 4.60 (br d, 0.4H), 4.43 (br d, 0.6H), 4.26 (dd, 0.6H), 4.23-4.14 (m, 2H), 3.90 (br d, 0.4H), 3.56-3.43 (m, 1H), 3.03-2.94 (m, 1.4H), 2.71 (t, 1H), 2.62-2.55 (m, 0.6H and q, 2H), 2.26 (t, 0.4H), 2.06-1.96 (m, 1.6H), 1.83-1.45 (m, 9H), 1.17 (t, 3H).

Examples 101

N-[5-(4- Ethyl phenyl )-1-( Pyrrolidine as a therapeutic agent -1- Radical carbonyl ) Piperidine derivatives -3- Base of ]-4- Phenylpiperazines -1- Carboxamides [ Racemic cis isomer ]

125 mg (50%, 0.15 mmol) of 5- (4-ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidin-3-ylamine trifluoroacetate (example 12A) and 40 mg (0.18 mmol, 1.2 eq) of 4-phenylpiperazine-1-carbonyl chloride were reacted according to general procedure 3. Yield: 13 mg (18% of theory).

HPLC (method 2A) R_t = 4.37 min; MS (ESIpos): m/z = 490 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 7.22 (t, 2H), 7.19-7.13 (m, 4H), 6.96 (d, 2H), 6.79 (t, 1H), 6.45 (d, 1H), 3.84 (br d, 1H), 3.73-3.61 (m, 2H), 3.48-3.41 (m, 4H), 3.30-3.23 (m, 4H), 3.12-3.04 (m, 4H), 2.83-2.73 (m, 1H), 2.57 (q, 2H), 2.48-2.40 (m, 2H), 1.99 (br d, 1H), 1.80-1.70 (m, 4H), 1.66 (q, 1H), 1.16 (t, 3H)。

Examples 102

[5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidin-3-yl ] carbamic acid methyl ester [ racemic cis isomer ]

170 mg (0.58 mmol) of methyl [5- (4-ethylphenyl) piperidin-3-yl ] carbamate (example 21A) and 113 mg (0.76 mmol, 1.3 eq) of morpholine-4-carbonyl chloride are reacted according to general method 3. Diastereomeric separation of the cis/trans isomer mixture according to method 7C yields 70 mg of the compound from example 102.

LC-MS (method 1B) R_t = 2.13 min; MS (ESIpos): m/z = 376 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆) δ = 7.27 (d, 1H), 7.16 (s, 4H), 3.77 (br d, 1H), 3.62-3.51 (br d, 1H and s, 3H and m, 4H), 3.53-3.22 (m, 1H), 3.19-3.11 (m, 4H), 2.83-2.73 (m, 1H), 2.68 (t, 1H), 2.57 (q, 2H), 2.48 (t, 1H), 1.99 (br d, 1H), 1.54 (q, 1H), 1.16 (t, 3H).

Examples 103

[5- (4-ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidin-3-yl ] carbamic acid phenyl ester [ racemic cis isomer ]

83 mg (0.15 mmol) of 5- (4-ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidin-3-amine trifluoroacetate (example 12A) and 26 mg (0.17 mmol, 1.1 equiv) of phenyl chloroformate are reacted according to general procedure 5. Yield: 25 mg (39% of theory).

HPLC (method 2A) R_t = 4.90 min; MS (ESIpos): m/z = 422 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 7.90 (d, 1H), 7.38 (d, 2H), 7.24-7.14 (m, 5H), 7.11 (d, 2H), 3.92 (br d, 1H), 3.67 (br d, 1H), 3.62-3.32 (m, 1H), 3.30-3.21 (m, 4H), 2.87-2.77 (m, 1H), 2.72-2.61 (m, 2H), 2.57 (q, 2H), 2.09 (br d, 1H), 1.80-1.70 (m, 4H), 1.63 (q, 1H), 1.17 (t, 3H)。

Examples 104

N-[1-( Cyclopentyl carbonyl group )-5-(4- Ethyl phenyl ) Piperidine derivatives -3- Base of ]-1- Phenylmethanesulfonamides [ Racemic cis isomer ]

55 mg (0.12 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-ylamine trifluoroacetate (example 7A) and 21 mg (0.11 mmol, 0.9 eq) of phenylmethanesulfonic acid are reacted according to general procedure 6. Yield: 14 mg (24% of theory).

HPLC (method 2A) R_t = 4.81 min; MS (ESIpos): m/z = 455 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ=7.43-7.33 (m, 5H), 7.21-7.12 (m, 4H), 4.68 (br d, 0.5H), 4.43-4.32 (br d, 0.5H and d, 2H), 4.03 (br d, 0.5H), 3.88 (br d, 0.5H), 3.20-3.02 (m, 1H), 3.01-2.87 (m, 1.5H), 2.76 (t, 0.5H), 2.58 (q, 2H), 2.11-1.99 (m, 1.5H), 1.92-1.82 (m, 0.5H), 1.77-1.47 (m, 9H), 1.17 (t, 3H).

Examples 105

Phenyl 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidin-3-ylcarbamate [ racemic cis isomer ]

Under argon and at room temperature, 184 microliters (1.06 mmol, 3 equivalents) of N, N-diisopropylethylamine and 135 mg (0.53 mmol, 1.5 equivalents) of N, N' -disuccinimidyl carbonate were added to a solution of 112 mg (0.35 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidin-3-ol (example 25A) in 1.7 ml of acetonitrile. The reaction mixture was stirred at room temperature for 3 hours, then 96 microliters (1.06 mmol, 3 equivalents) of aniline and 61 microliters (0.35 mmol, 1.0 equivalent) of N, N-diisopropylethylamine were added at room temperature and the mixture was stirred at room temperature for 1 hour. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 18 mg (12% of theory).

HPLC (method 2A) R_t = 4.75 min; MS (ESIpos): m/z = 438 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 9.71 (s, 1H), 7.47 (d, 2H), 7.28 (t, 2H), 7.23 (d, 2H), 7.17 (d, 2H), 6.99 (t, 1H), 4.78-4.68 (m, 1H), 3.94 (br d, 1H), 3.62-3.53 (m, 5H), 3.23-3.15 (m, 4H), 2.94-2.83 (m, 1H), 2.83-2.70 (m, 2H), 2.58 (q, 2H), 2.25 (br d, 1H), 1.77 (q, 1H), 1.17 (t, 3H)。

Examples 106

N-{1-[(4- Cyanopiperidines -1- Base of ) Carbonyl radical ]-5-[4-( Trifluoromethoxy radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis isomer ]

115 mg (0.22 mmol) of 4-nitrophenyl 3- [ (phenylcarbonyl) amino ] -5- [4- (trifluoromethoxy) phenyl ] piperidine-1-carboxylate were initially charged in 3 ml of DMF and 72 mg (0.65 mmol) of piperidine-4-carbonitrile and 30 mg (0.22 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150 ℃ for 30 minutes. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 53 mg (48% of theory).

LC-MS (method 1B) R_t = 2.43 min; m/z = 501 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.39 (d, 1H), 7.89-7.83 (m, 2H), 7.50-7.55 (m, 1H), 7.49-7.41 (m, 4H), 7.35 (d, 2H), 4.07-3.96 (m, 1H), 3.81 (dd, 1H), 3.64 (d, 1H), 3.43-3.35 (m, 2H), 3.13-2.94 (m, 4H), 2.80-2.61 (m, 2H), 2.12 (d, 1H), 1.93-1.64 (m, 5H)。

Examples 107

N-{1-[(4- Hydroxy piperidines -1- Base of ) Carbonyl radical ]-5-[4-( Trifluoromethoxy radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis isomer ]

550 mg (1.04 mmol) of 4-nitrophenyl 3- [ (phenylcarbonyl) amino ] -5- [4- (trifluoromethoxy) phenyl ] piperidine-1-carboxylate were initially charged in 14 ml of DMF and 315 mg (3.12 mmol) of piperidin-4-ol and 144 mg (1.04 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150 ℃ for 15 minutes. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 430 mg (84% of theory).

LC-MS (method 1B) R_t = 2.19 min; m/z = 492 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.38 (d, 1H), 7.86 (d, 2H), 7.52 (d, 1H), 7.47 (d, 2H), 7.44 (d, 2H), 7.34 (d, 2H), 4.68 (d, 1H), 4.09-3.93 (m, 1H), 3.83-3.74 (m, 1H), 3.66-3.57 (m, 2H), 3.49 (d, 2H), 2.90 (d, 3H), 2.76 (d, 1H), 2.65 (s, 1H), 2.15-2.06 (m, 1H), 1.82-1.69 (m, 3H), 1.33 (d, 2H)。

Examples 108

N-{1-( Morpholine -4- Radical carbonyl )-5-[4-( Trifluoromethoxy radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis isomer ]

At 0 ℃ 100 mg (0.27 mmol) of N- {5- [4- (trifluoromethoxy) phenyl ] piperidin-3-yl } benzamide are initially charged in 1.5 ml of dichloromethane and 82 mg (0.55 mmol) of morpholine-4-carbonyl chloride and 58. mu.l (0.412 mmol) of triethylamine are added. The mixture was slowly warmed to room temperature overnight. Water was added to the reaction mixture, and the reaction mixture was extracted. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 118 mg (90% of theory).

LC-MS (method 3B) R_t = 1.95 min; m/z = 478 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.39 (d, 1H), 7.86 (d, 2H), 7.52 (d, 1H), 7.50-7.41 (m, 4H), 7.35 (d, 2H), 4.08-3.93 (m, 1H), 3.85 (d, 1H), 3.67 (d, 1H), 3.58 (t, 4H), 3.20 (br. s., 4H), 3.05-2.93 (m, 1H), 2.89 (s, 1H), 2.83-2.63 (m, 2H), 2.11 (d, 1H), 1.86-1.74 (m, 1H)。

Examples 109

N-{1-( Morpholine -4- Radical carbonyl )-5-[4-( Trifluoromethoxy radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Enantiomerically pure cis-isomers ]

The enantiomer separation of 117 mg of the racemic cis isomer mixture (example 108) according to method 11D gave 34.8 mg of the compound from example 109 (enantiomer 1).

LC-MS (method 2B) R_t = 1.23 min; m/z = 478 [M+H]⁺。

Examples 110

The enantiomer was separated according to method 11D to give 117 mg of the racemic cis isomer mixture (example 108) to give 29.7 mg of the compound from example 110 (enantiomer 2).

LC-MS (method 2B) R_t = 1.23 min; m/z = 478 [M+H]⁺。

Examples 111

N-(2- Methoxy ethyl radical )-3-[( Phenyl carbonyl ) Amino group ]-5-[4-( Trifluoromethoxy radical ) Phenyl radical ] Piperidine derivatives -1- Carboxamides [ Racemic cis isomer ]

70 mg (0.19 mmol) of N- {5- [4- (trifluoromethoxy) phenyl ] piperidin-3-yl } benzamide are initially charged in 2.5 ml of THF, and 19 mg (0.19 mmol) of 1-isocyanato-2-methoxyethane and 29. mu.l (0.21 mmol) of triethylamine are added. The mixture was stirred at room temperature overnight. The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 32 mg (35% of theory).

LC-MS (method 1B) R_t = 2.32 min; m/z = 466 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.38 (d, 1H), 7.85 (d, 2H), 7.52 (d, 1H), 7.49-7.41 (m, 4H), 7.34 (d, 2H), 6.74-6.66 (m, 1H), 4.21 (dd, 1H), 4.05 (d, 1H), 4.00-3.89 (m, 1H), 3.34 (t, 2H), 3.24 (s, 3H), 3.19 (d, 2H), 2.82 (d, 1H), 2.74-2.56 (m, 2H), 2.10 (d, 1H), 1.73 (q, 1H)。

Examples 112

N- ({3- [ (phenylcarbonyl) amino ] -5- [4- (trifluoromethoxy) phenyl ] piperidin-1-yl } carbonyl) glycine methyl ester [ racemic cis isomer ]

70 mg (0.19 mmol) of N- {5- [4- (trifluoromethoxy) phenyl ] piperidin-3-yl } benzamide are initially charged in 2.5 ml of THF, and 22 mg (0.19 mmol) of methyl N- (oxomethylene) glycinate and 29. mu.l (0.21 mmol) of triethylamine are added. The mixture was stirred at room temperature overnight. The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 76 mg (82% of theory).

LC-MS (method 2B) R_t = 1.20 min; m/z = 480 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.39 (d, 1H), 7.85 (d, 2H), 7.53 (d, 1H), 7.49-7.41 (m, 4H), 7.35 (d, 2H), 7.16 (t, 1H), 4.19 (dd, 1H), 4.07 (d, 1H), 4.02-3.91 (m, 1H), 3.75 (d, 2H), 3.63 (s, 3H), 2.93-2.82 (m, 1H), 2.76 (t, 1H), 2.67 (t, 1H), 2.12 (d, 1H), 1.75 (q, 1H)。

Examples 113

N-{1-[(4- Methyl piperazine -1- Base of ) Carbonyl radical ]-5-[4-( Trifluoromethoxy radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis isomer ]

At 0 ℃, 100 mg (0.27 mmol) of N- {5- [4- (trifluoromethoxy) phenyl ] piperidin-3-yl } benzamide was initially charged in 1.5 ml of dichloromethane and 89 mg (0.55 mmol) of 4-methylpiperazine-1-carbonyl chloride and 58 μ l (0.412 mmol) of triethylamine were added. The mixture was slowly warmed to room temperature overnight. Water was added to the reaction mixture, and the reaction mixture was extracted. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 104 mg (77% of theory).

LC-MS (method 2B) R_t = 1.01 min; m/z = 491 [M+H]⁺;

¹H-NMR (400 MHz, CD₃OD): δ = 7.83 (d, 2H), 7.54 (d, 1H), 7.50-7.40 (m, 4H), 7.26 (d, 2H), 4.21-4.08 (m, 1H), 4.02 (br. s., 1H), 3.87 (br. s., 1H), 3.50 (br. s., 4H), 3.05 (br. s., 4H), 2.91-2.76 (m, 2H), 2.72 (s, 3H), 2.25 (br. s., 1H), 2.01-1.84 (m, 2H), 1.35-1.25 (m, 1H)。

Examples 114

N-{1-( Pyridine compound -4- Radical carbonyl )-5-[4-( Trifluoromethoxy radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis isomer ]

51 mg (0.41 mmol) of pyridine-4-carboxylic acid together with 157 mg (0.41 mmol) of HATU and 67 mg (0.55 mmol) of 4-dimethylaminopyridine are initially charged in 2 ml of DMF and 100 mg (0.27 mmol) of N- {5- [4- (trifluoromethoxy) phenyl ] piperidin-3-yl } benzamide are added. The reaction mixture was stirred at room temperature overnight and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 112 mg (87% of theory).

LC-MS (method 2B) R_t = 1.17 min; m/z = 470 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.69 (dd, 2H), 8.43 (dd, 1H), 7.83 (dd, 2H), 7.60-7.24 (m, 9H), 4.67 (dd, 1H), 4.10 (d, 1H), 3.58 (dd, 1H), 3.19-2.97 (m, 2H), 2.81 (dt, 1H), 2.27-2.11 (m, 1H), 1.92 (q, 1H)。

Examples 115

N-{1-( Pyridine compound -4- Radical carbonyl )-5-[4-( Trifluoromethoxy radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Enantiomerically pure cis-isomers ]

Enantiomer separation of 112 mg of the racemic cis isomer mixture (example 114) according to method 12D gave 37.6 mg of the compound from example 115 (enantiomer 1).

LC-MS (method 3B) R_t = 1.82 min; m/z = 470 [M+H]⁺。

Examples 116

Enantiomer separation of 112 mg of the racemic cis isomer mixture (example 114) according to method 12D gave 33.4 mg of the compound from example 116 (enantiomer 2).

LC-MS (method 3B) R_t = 1.82 min; m/z = 470 [M+H]⁺。

Examples 117

N-{1-[(2R)-2- Methoxy propionyl radical ]-5-[4-( Trifluoromethoxy radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis isomer ]

44 mg (0.41 mmol) of (2R) -2-methoxypropionic acid together with 157 mg (0.41 mmol) of HATU and 67 mg (0.55 mmol) of 4-dimethylaminopyridine are initially charged in 2 ml of DMF and 100 mg (0.27 mmol) of N- {5- [4- (trifluoromethoxy) phenyl ] piperidin-3-yl } benzamide are added. The reaction mixture was stirred at room temperature overnight and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 116 mg (94% of theory).

LC-MS (method 2B) R_t = 1.24 min; m/z = 451 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.63-8.27 (m, 1H), 7.87 (t, 2H), 7.65-7.22 (m, 7H), 4.70-4.43 (m, 1H), 4.40-4.10 (m, 2H), 4.03-3.85 (m, 1H), 3.29-3.20 (m, 3H), 3.12-2.62 (m, 3H), 2.13 (d, 1H), 1.89 (t, 1H), 1.34 (t, 2H), 1.25 (dd, 1H)。

Examples 118

N-[5-(3,4- Dimethyl phenyl )-1-( Morpholine -4- Radical carbonyl ) Piperidine derivatives -3- Base of ] Benzamide derivatives [ Racemic cis isomer ]

At 0 ℃, 60 mg (0.19 mmol) of N-5- (3, 4-dimethylphenyl) piperidin-3-yl } benzamide are initially charged in 1 ml of dichloromethane and 58 mg (0.39 mmol) of morpholine-4-carbonyl chloride and 41 μ l (0.29 mmol) of triethylamine are added. The mixture was slowly warmed to room temperature overnight. Water was added to the reaction mixture, and the reaction mixture was extracted. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 58 mg (71% of theory).

LC-MS (method 3B) R_t = 1.88 min; m/z = 422 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.37 (d, 1H), 7.86 (d, 2H), 7.52 (d, 1H), 7.50-7.42 (m, 2H), 7.09 (d, 1H), 7.06 (s, 1H), 6.99 (d, 1H), 4.05-3.90 (m, 1H), 3.85 (d, 1H), 3.63 (d, 1H), 3.58 (s, 4H), 3.19 (br. s., 4H), 2.79 (d, 1H), 2.75-2.61 (m, 2H), 2.20 (d, 6H), 2.06 (d, 1H), 1.80 (d, 1H)。

Examples 119

N-{1-[(1- Aminocyclobutyl group ) Carbonyl radical ]-5-(3,4- Dimethyl phenyl ) Piperidine derivatives -3- Base of } Benzamide hydrochloride [ Racemic cis isomer ]

55 mg (0.14 mmol) of [1- ({3- (3, 4-dimethylphenyl) -5- [ (phenylcarbonyl) amino group]Piperidin-1-yl } carbonyl) cyclobutyl]Tert-butyl carbamate dissolved in 7 ml of dibutyl carbamateAlkane, 1.5 ml of concentrated hydrochloric acid were added and the mixture was immediately concentrated in a rotary evaporator. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 19 mg (39% of theory).

LC-MS (method 2B) R_t = 0.98 min; m/z = 406 [M+H]⁺。

Examples 120

N-{1-[(4- Aminotetrahydro -2H- Pyrans -4- Base of ) Carbonyl radical ]-5-(3,4- Dimethyl phenyl ) Piperidine derivatives -3- Base of } Benzamide hydrochloride [ Racemic cis isomer ]

33 mg (0.06 mmol) of [4- ({3- (3, 4-dimethylphenyl) -5- [ (phenylcarbonyl) amino]Piperidin-1-yl } carbonyl) tetrahydro-2H-pyran-4-yl]Tert-butyl carbamate was dissolved in 4 ml of diAlkane, 1 ml of concentrated hydrochloric acid was added and the mixture was immediately concentrated in a rotary evaporator. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 15 mg (57% of theory).

LC-MS (method 2B) R_t = 0.97 min; m/z = 436 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.38 (d, 1H), 7.86 (d, 2H), 7.52 (d, 1H), 7.50-7.43 (m, 2H), 7.09 (d, 1H), 7.05 (s, 1H), 6.99 (d, 1H), 4.02-3.86 (m, 1H), 3.77-3.66 (m, 2H), 3.63-3.46 (m, 2H), 2.81-2.58 (m, 3H), 2.20 (d, 7H), 2.08 (d, 6H), 1.85 (q, 1H), 1.61 (br. s., 1H), 1.46 (d, 1H)。

Examples 121

N-{1-( Morpholine -4- Radical carbonyl )-5-[3-( Propane -2- Base of ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis isomer ]

At 0 ℃ 180 mg (0.54 mmol) of N- {5- [3- (1-methylethyl) phenyl ] piperidin-3-yl } benzamide are initially charged in 4 ml of dichloromethane and 162 mg (1.08 mmol) of morpholine-4-carbonyl chloride and 114. mu.l (0.81 mmol) of triethylamine are added. The mixture was slowly warmed to room temperature overnight. Water was added to the reaction mixture, and the reaction mixture was extracted. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 121 mg (51% of theory).

LC-MS (method 3B) R_t = 2.02 min; m/z = 436 [M+H]⁺;

¹H-NMR (500 MHz, DMSO-d ₆): δ = 8.36 (d, 1H), 7.87 (d, 2H), 7.52 (d, 1H), 7.49-7.43 (m, 2H), 7.29-7.23 (m, 1H), 7.16 (s, 1H), 7.11 (dd, 2H), 4.06-3.94 (m, 1H), 3.86 (d, 1H), 3.66 (d, 1H), 3.58 (d, 4H), 3.20 (br. s., 4H), 2.92-2.83 (m, 2H), 2.76 (t, 1H), 2.67 (t, 1H), 2.10 (d, 1H), 1.83 (q, 1H), 1.21 (d, 6H)。

Examples 122

N-[5-(2,3- Dimethyl phenyl )-1-( Morpholine -4- Radical carbonyl ) Piperidine derivatives -3- Base of ] Benzamide derivatives [ Racemic cis isomer ]

At 0 ℃, 80 mg (0.26 mmol) of N- [5- (2, 3-dimethylphenyl) piperidin-3-yl ] benzamide are initially charged in 1.5 ml of dichloromethane and 78 mg (0.52 mmol) of morpholine-4-carbonyl chloride and 55 μ l (0.39 mmol) of triethylamine are added. The mixture was slowly warmed to room temperature overnight. Water was added to the reaction mixture, and the reaction mixture was extracted. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 75 mg (69% of theory).

LC-MS (method 2B) R_t = 1.17 min; m/z = 422 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.38 (d, 1H), 7.87 (d, 2H), 7.55-7.51 (m, 1H), 7.47 (t, 2H), 7.12-6.98 (m, 3H), 4.12-3.96 (m, 1H), 3.85 (dd, 1H), 3.63 (d, 1H), 3.60-3.54 (m, 4H), 3.23-3.16 (m, 4H), 3.17-3.08 (m, 1H), 2.78-2.60 (m, 2H), 2.26 (s, 6H), 2.06-1.95 (m, 1H), 1.88 (q, 1H)。

Examples 123

4- {1- (Morpholin-4-ylcarbonyl) -5- [ (phenylcarbonyl) amino ] piperidin-3-yl } benzoic acid ethyl ester [ racemic cis isomer ]

At 0 ℃ 500 mg (1.42 mmol) of ethyl 4- {5- [ (phenylcarbonyl) amino ] piperidin-3-yl } benzoate are initially charged in 8 ml of dichloromethane and 424 mg (2.84 mmol) of morpholine-4-carbonyl chloride and 300. mu.l (2.13 mmol) of triethylamine are added. The mixture was slowly warmed to room temperature overnight. Water was added to the reaction mixture, and the reaction mixture was extracted. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 551 mg (83% of theory).

LC-MS (method 2B) R_t = 1.12 min; m/z = 466 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.41 (d, 1H), 7.94 (d, 2H), 7.86 (d, 2H), 7.57-7.50 (m, 1H), 7.47 (dd, 4H), 4.31 (q, 2H), 4.09-3.96 (m, 1H), 3.86 (d, 1H), 3.68 (d, 1H), 3.58 (d, 4H), 3.21 (br. s., 4H), 3.08-2.96 (m, 1H), 2.86-2.76 (m, 1H), 2.74-2.64 (m, 1H), 2.13 (d, 1H), 1.83 (q, 1H), 1.32 (t, 3H)。

Examples 124

N-{1-( Morpholine -4- Radical carbonyl )-5-[3-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis isomer ]

At 0 ℃, 165 mg (0.47 mmol) of N- {5- [3- (trifluoromethyl) phenyl ] piperidin-3-yl } benzamide are initially charged in 17 ml of dichloromethane and 71 mg (0.47 mmol) of morpholine-4-carbonyl chloride and 132 μ l (0.95 mmol) of triethylamine are added. The mixture was slowly warmed to room temperature overnight. Water was added to the reaction mixture, and the reaction mixture was extracted. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 202 mg (92% of theory).

LC-MS (method 5B) R_t = 2.19 min; m/z = 462 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.38 (d, 1H), 7.86 (d, 2H), 7.70-7.59 (m, 4H), 7.56-7.50 (m, 1H), 7.50-7.44 (m, 2H), 4.01 (dd, 1H), 3.86 (d, 1H), 3.74-3.52 (m, 5H), 3.21 (br. s., 4H), 3.11-3.02 (m, 1H), 2.84 (t, 1H), 2.75-2.63 (m, 1H), 2.13 (d, 1H), 1.86 (q, 1H)。

Examples 125

N-{1-( Morpholine -4- Radical carbonyl )-5-[3-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Enantiomerically pure cis-isomers ]

The enantiomer separation of 202 mg of the racemic cis isomer mixture (example 124) according to method 13D gave 66 mg of the compound from example 125 (enantiomer 1).

LC-MS (method 1B) R_t = 2.31 min; m/z = 462 [M+H]⁺。

Examples 126

N-{1-( Morpholine -4- Radical carbonyl )-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis isomer ]

At 0 ℃ 705 mg (2.02 mmol) of N- {5- [4- (trifluoromethyl) phenyl ] piperidin-3-yl } benzamide are initially charged in 70 ml of dichloromethane and 321 mg (2.02 mmol) of morpholine-4-carbonyl chloride and 564. mu.l (4.04 mmol) of triethylamine are added. The mixture was slowly warmed to room temperature overnight. Water was added to the reaction mixture, and the reaction mixture was extracted. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 960 mg (100% of theory).

LC-MS (method 1B) R_t = 2.32 min; m/z = 462 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.41 (d, 1H), 7.86 (d, 2H), 7.72 (d, 2H), 7.59-7.50 (m, 3H), 7.47 (t, 2H), 4.10-3.93 (m, 1H), 3.86 (d, 1H), 3.69 (d, 1H), 3.59 (t, 4H), 3.21 (br. s., 4H), 3.10-2.99 (m, 1H), 2.86-2.77 (m, 1H), 2.74-2.65 (m, 1H), 2.13 (d, 1H), 1.83 (q, 1H)。

Examples 127

N-{1-( Morpholine -4- Radical carbonyl )-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Enantiomerically pure cis-isomers ]

The enantiomer separation of 900 mg of the racemic cis isomer mixture (example 126) according to method 14D gave 388 mg of the compound from example 127 (enantiomer 1).

Examples 128

The enantiomer separation of 900 mg of the racemic cis isomer mixture (example 126) according to method 14D gave 361 mg of the compound from example 128 (enantiomer 2).

LC-MS (method 1B) R_t = 2.31 min; m/z = 462 [M+H]⁺。

Examples 129

N-{1-[(4- Hydroxy piperidines -1- Base of ) Carbonyl radical ]-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis isomer ]

80 mg (0.16 mmol) of 4-nitrophenyl 3- [ (phenylcarbonyl) amino ] -5- [4- (trifluoromethyl) phenyl ] piperidine-1-carboxylate were initially charged in 1.7 ml of DMF and 47 mg (0.47 mmol) of piperidin-4-ol and 22 mg (0.16 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150 ℃ for 15 minutes. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 62 mg (83% of theory).

LC-MS (method 3B) R_t = 1.79 min; m/z = 476 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.39 (d, 1H), 7.86 (d, 2H), 7.72 (d, 2H), 7.58-7.50 (m, 3H), 7.50-7.40 (m, 2H), 4.68 (d, 1H), 4.11-3.95 (m, 1H), 3.79 (d, 1H), 3.63 (d, 2H), 3.49 (d, 2H), 3.05 (t, 1H), 2.97-2.85 (m, 2H), 2.78 (t, 1H), 2.73-2.61 (m, 1H), 2.13 (d, 1H), 1.82 (q, 1H), 1.73 (d, 2H), 1.38-1.27 (m, 2H)。

Examples 130

N-{1-[(4- Hydroxy piperidines -1- Base of ) Carbonyl radical ]-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Enantiomerically pure cis-isomers ]

Enantiomer separation of 52 mg of the racemic cis isomer mixture (example 129) according to method 15D gave 19 mg of the compound from example 130 (enantiomer 1).

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.39 (d, 1H), 7.85 (d, 2H), 7.72 (d, 2H), 7.58-7.50 (m, 3H), 7.49-7.35 (m, 2H), 4.68 (d, 1H), 4.11-3.96 (m, 1H), 3.77 (dd, 1H), 3.68-3.58 (m, 2H), 3.54-3.43 (m, 2H), 3.04 (t, 1H), 2.91 (dt, 2H), 2.78 (t, 1H), 2.72-2.62 (m, 1H), 2.21-2.05 (m, 1H), 1.82 (q, 1H), 1.76-1.67 (m, 2H), 1.39-1.26 (m, 2H)。

Examples 131

N-{1-[(4- Hydroxy radicalPiperidine derivatives -1- Base of ) Carbonyl radical ]-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Enantiomerically pure cis-isomers ]

Enantiomer separation of 52 mg of the racemic cis isomer mixture (example 129) according to method 15D gave 20 mg of the compound from example 131 (enantiomer 2).

Examples 132

N-{1-( Thiomorpholine -4- Radical carbonyl )-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis isomer ]

80 mg (0.16 mmol) of 4-nitrophenyl 3- [ (phenylcarbonyl) amino ] -5- [4- (trifluoromethyl) phenyl ] piperidine-1-carboxylate were initially charged in 1.7 ml of DMF and 48 mg (0.47 mmol) of thiomorpholine and 22 mg (0.16 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150 ℃ for 15 minutes. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 45 mg (60% of theory).

LC-MS (method 3B) R_t = 2.10 min; m/z = 478 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.40 (d, 1H), 7.86 (d, 2H), 7.72 (d, 2H), 7.59-7.50 (m, 3H), 7.50-7.43 (m, 2H), 4.09-3.95 (m, 1H), 3.79 (d, 1H), 3.64 (d, 1H), 3.46 (dt, 4H), 3.11-3.00 (m, 1H), 2.80 (t, 1H), 2.74-2.65 (m, 1H), 2.64-2.58 (m, 4H), 2.13 (d, 1H), 1.83 (q, 1H)。

Examples 133

N-(1-{[(2R,5R)-2,5- Dimethyl pyrrolidine -1- Base of ] Carbonyl radical }-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of ) Benzamide derivatives [ Racemic cis isomer ]

80 mg (0.16 mmol) of 4-nitrophenyl 3- [ (phenylcarbonyl) amino ] -5- [4- (trifluoromethyl) phenyl ] piperidine-1-carboxylate were initially charged in 1.7 ml of DMF and 46 mg (0.47 mmol) of (2R,5R) -2, 5-dimethylpyrrolidine and 22 mg (0.16 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150 ℃ for 15 minutes. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 12 mg (15% of theory).

LC-MS (method 2B) R_t = 0.73 min; m/z = 474 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.38 (d, 1H), 7.89-7.81 (m, 2H), 7.71 (d, 2H), 7.59-7.51 (m, 3H), 7.49-7.43 (m, 2H), 4.16-3.93 (m, 3H), 3.92-3.61 (m, 2H), 3.13-2.57 (m, 3H), 2.19-1.99 (m, 2H), 1.92-1.76 (m, 2H), 1.64-1.38 (m, 2H), 1.20 (d, 3H), 1.07 (d, 3H)。

Examples 134

N-{1-[(1,1- Sulphur dioxide oxymorphone (dioxidothiomorpholin)-4- Base of ) Carbonyl radical ]-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of }- Benzamide derivatives [ Racemic cis isomer ]

200 mg (0.39 mmol) of 4-nitrophenyl 3- [ (phenylcarbonyl) amino ] -5- [4- (trifluoromethyl) phenyl ] piperidine-1-carboxylate were initially charged in 4.3 ml of DMF and 158 mg (1.17 mmol) of thiomorpholine 1, 1-dioxide and 54 mg (0.39 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150 ℃ for 15 minutes. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 27 mg (14% of theory).

LC-MS (method 2B) R_t = 1.18 min; m/z = 510 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.42 (d, 1H), 7.86 (d, 2H), 7.73 (d, 2H), 7.58-7.51 (m, 3H), 7.47 (t, 2H), 4.11-3.98 (m, 1H), 3.88 (d, 1H), 3.72 (d, 1H), 3.64 (br. s., 4H), 3.19 (br. s., 4H), 3.08 (t, 1H), 2.91-2.81 (m, 1H), 2.77-2.68 (m, 1H), 2.15 (d, 1H), 1.84 (q, 1H)。

Examples 135

N-(2- Hydroxyethyl group )-3-[( Phenyl carbonyl ) Amino group ]-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -1- Carboxamides [ Racemic cis isomer ]

80 mg (0.16 mmol) of 4-nitrophenyl 3- [ (phenylcarbonyl) amino ] -5- [4- (trifluoromethyl) phenyl ] piperidine-1-carboxylate were initially charged in 1.7 ml of DMF and 29 mg (0.47 mmol) of aminoethanol and 22 mg (0.16 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150 ℃ for 15 minutes. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 10 mg (15% of theory).

LC-MS (method 1B) R_t = 2.12 min; m/z = 436 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.39 (d, 1H), 7.85 (d, 2H), 7.72 (d, 2H), 7.59-7.50 (m, 3H), 7.47 (t, 2H), 6.64 (t, 1H), 4.60 (t, 1H), 4.20 (d, 1H), 4.08 (d, 1H), 4.03-3.91 (m, 1H), 3.40 (q, 2H), 3.11 (q, 2H), 2.96-2.84 (m, 1H), 2.77-2.68 (m, 1H), 2.68-2.58 (m, 1H), 2.10 (br. s., 1H), 1.76 (q, 1H)。

Examples 136

N-{1-[(3- Hydroxy azetidines -1- Base of ) Carbonyl radical ]-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis isomer ]

80 mg (0.16 mmol) of 4-nitrophenyl 3- [ (phenylcarbonyl) amino ] -5- [4- (trifluoromethyl) phenyl ] piperidine-1-carboxylate were initially charged in 1.7 ml of DMF and 51 mg (0.47 mmol) of azetidine-3-ol hydrochloride and 22 mg (0.16 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150 ℃ for 15 minutes. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 44 mg (62% of theory).

LC-MS (method 3B) R_t = 1.74 min; m/z = 448 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.38 (d, 1H), 7.86 (d, 2H), 7.72 (d, 2H), 7.59-7.50 (m, 3H), 7.47 (t, 2H), 5.58 (d, 1H), 4.45-4.35 (m, 1H), 4.18-4.05 (m, 2H), 3.97 (d, 2H), 3.87 (d, 1H), 3.77-3.62 (m, 2H), 2.93 (t, 1H), 2.83-2.62 (m, 2H), 2.10 (d, 1H), 1.84 (q, 1H)。

Examples 137

N-{1-[(4- Cyanopiperidines -1- Base of ) Carbonyl radical ]-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis isomer ]

115 mg (0.22 mmol) of 4-nitrophenyl 3- [ (phenylcarbonyl) amino ] -5- [4- (trifluoromethyl) phenyl ] piperidine-1-carboxylate were initially charged in 2.5 ml of DMF and 74 mg (0.67 mmol) of piperidine-4-carbonitrile and 31 mg (0.22 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150 ℃ for 15 minutes. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 71 mg (65% of theory).

LC-MS (method 1B) R_t = 2.43 min; m/z = 485 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.40 (d, 1H), 7.86 (d, 2H), 7.72 (d, 2H), 7.57-7.51 (m, 3H), 7.47 (t, 2H), 4.09-3.96 (m, 1H), 3.81 (d, 1H), 3.64 (d, 1H), 3.44-3.35 (m, 2H), 3.07 (m, 4H), 2.80 (t, 1H), 2.74-2.62 (m, 1H), 2.12 (br. s., 1H), 1.95-1.63 (m, 5H)。

Examples 138

3- [ (Phenylcarbonyl) amino ] -N- (pyridin-4-yl) -5- [4- (trifluoromethyl) phenyl ] piperidine-1-carboxamide [ racemic cis isomer ]

80 mg (0.23 mmol) of ethyl-N- {5- [4- (trifluoromethyl) phenyl ] piperidin-3-yl } benzamide are initially charged in 2 ml of THF, and 28 mg (0.23 mmol) of 4-isocyanatopyridine and 35. mu.l (0.25 mmol) of triethylamine are added. The mixture was stirred at room temperature overnight. The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 75 mg (70% of theory).

LC-MS (method 1B) R_t = 1.64 min; m/z = 469 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 9.07 (s, 1H), 8.47 (d, 1H), 8.32 (d, 2H), 7.87 (d, 2H), 7.74 (d, 2H), 7.59 (d, 2H), 7.54-7.42 (m, 5H), 4.47-4.22 (m, 2H), 4.16-3.98 (m, 1H), 3.11-2.90 (m, 2H), 2.80 (t, 1H), 2.16 (d, 1H), 1.84 (q, 1H)。

Examples 139

N-(4- Hydroxycyclohexyl )-3-[( Phenyl carbonyl ) Amino group ]-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -1- Carboxamides [ Racemic cis isomer ]

80 mg (0.16 mmol) of 4-nitrophenyl 3- [ (phenylcarbonyl) amino ] -5- [4- (trifluoromethyl) phenyl ] piperidine-1-carboxylate were initially charged in 1.7 ml of DMF and 71 mg (0.47 mmol) of cis-4-aminocyclohexanol hydrochloride and 129 mg (0.94 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150 ℃ for 15 minutes. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 3 mg (4% of theory).

LC-MS (method 1B) R_t = 2.24 min; m/z = 490 [M+H]⁺;

¹H-NMR (500 MHz, CD₃OD): δ = 7.83 (d, 2H), 7.64 (d, 2H), 7.57-7.50 (m, 3H), 7.50-7.44 (m, 2H), 6.39 (d, 1H), 4.25 (dd, 4H), 4.17-4.08 (m, 2H), 3.87 (br. s., 2H), 3.65-3.58 (m, 2H), 3.02-2.94 (m, 2H), 2.84-2.74 (m, 4H), 2.28 (d, 2H), 1.87 (q, 2H)。

Examples 140

N-{1-[(2,6- Dimethyl morpholine -4- Base of ) Carbonyl radical ]-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis isomer ]

80 mg (0.16 mmol) of 4-nitrophenyl 3- [ (phenylcarbonyl) amino ] -5- [4- (trifluoromethyl) phenyl ] piperidine-1-carboxylate were initially charged in 1.7 ml of DMF and 53 mg (0.47 mmol) of (2R,6S) -2, 6-methylmorpholine and 22 mg (0.16 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150 ℃ for 15 minutes. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 49 mg (64% of theory).

LC-MS (method 3B) R_t = 1.80 min; m/z = 490 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.41 (d, 1H), 7.86 (d, 2H), 7.72 (d, 2H), 7.58-7.50 (m, 3H), 7.47 (t, 2H), 4.13-3.94 (m, 1H), 3.83 (d, 1H), 3.67 (d, 1H), 3.59-3.44 (m, 4H), 3.11-3.00 (m, 1H), 2.80 (t, 1H), 2.69 (t, 1H), 2.48-2.42 (m, 2H), 2.13 (d, 1H), 1.86 (q, 1H), 1.12 (d, 3H), 1.08 (d, 3H)。

Examples 141

N-{1-[(3- Oxopiperazines -1- Base of ) Carbonyl radical ]-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis isomer ]

80 mg (0.16 mmol) of 4-nitrophenyl 3- [ (phenylcarbonyl) amino ] -5- [4- (trifluoromethyl) phenyl ] piperidine-1-carboxylate were initially charged in 1.7 ml of DMF and 47 mg (0.47 mmol) of piperazin-2-one and 22 mg (0.16 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150 ℃ for 15 minutes. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 39 mg (52% of theory).

LC-MS (method 3B) R_t = 1.69 min; m/z = 475 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.41 (d, 1H), 7.96 (br. s., 1H), 7.86 (d, 2H), 7.72 (d, 2H), 7.58-7.42 (m, 5H), 4.11-3.98 (m, 1H), 3.85 (d, 1H), 3.76 (s, 2H), 3.70 (d, 1H), 3.46-3.38 (m, 2H), 3.23 (br. s., 2H), 3.07 (t, 1H), 2.85 (t, 1H), 2.78-2.67 (m, 1H), 2.14 (d, 1H), 1.85 (q, 1H)。

Examples 142

3- [ (Phenylcarbonyl) amino ] -N- (tetrahydrofuran-2-ylmethyl) -5- [4- (trifluoromethyl) phenyl ] piperidine-1-carboxamide [ racemic cis isomer ]

80 mg (0.23 mmol) of ethyl-N- {5- [4- (trifluoromethyl) phenyl ] piperidin-3-yl } benzamide are initially charged in 2 ml of THF, and 29 mg (0.23 mmol) of 2- (isocyanatomethyl) tetrahydrofuran and 35. mu.l (0.25 mmol) of triethylamine are added. The mixture was stirred at room temperature overnight. The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 88 mg (81% of theory).

LC-MS (method 1B) R_t = 2.34 min; m/z = 476 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.39 (d, 1H), 7.85 (d, 2H), 7.72 (d, 2H), 7.59-7.44 (m, 5H), 6.72 (q, 1H), 4.20 (d, 1H), 4.11 (d, 1H), 3.96 (br. s., 1H), 3.90-3.81 (m, 1H), 3.79-3.70 (m, 1H), 3.60 (q, 1H), 3.19-3.00 (m, 2H), 2.93-2.83 (m, 1H), 2.79-2.69 (m, 1H), 2.63 (t, 1H), 2.12 (d, 1H), 1.91-1.69 (m, 4H), 1.62-1.48 (m, 1H)。

The following examples were prepared according to the synthesis of example 141:

。

examples 150

1- ({3- [ (phenylcarbonyl) amino ] -5- [4- (trifluoromethyl) phenyl ] piperidin-1-yl } carbonyl) piperidine-4-carboxylic acid [ racemic cis isomer ]

27 mg (0.05 mmol) of methyl 1- ({3- [ (phenylcarbonyl) amino ] -5- [4- (trifluoromethyl) phenyl ] piperidin-1-yl } carbonyl) piperidine-4-carboxylate were initially charged in 0.8 ml each of THF and water, and 4 mg (0.15 mmol) of lithium hydroxide were added. The mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, acidified, and the precipitate was filtered off and dried. Yield: 16 mg (62% of theory).

LC-MS (method 1B) R_t = 2.29 min; m/z = 504 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 12.23 (s, 1H), 8.39 (d, 1H), 7.86 (d, 2H), 7.72 (d, 2H), 7.57-7.50 (m, 3H), 7.49-7.40 (m, 2H), 4.03 (dd, 1H), 3.80 (d, 1H), 3.71-3.52 (m, 3H), 3.10-2.98 (m, 1H), 2.94-2.62 (m, 4H), 2.47-2.35 (m, 1H), 2.11 (br. s., 1H), 1.86-1.77 (m, 3H), 1.49 (d, 2H)。

Examples 151

1- ({3- [ (phenylcarbonyl) amino ] -5- [4- (trifluoromethyl) phenyl ] piperidin-1-yl } carbonyl) piperidine-4-carboxamide [ racemic cis isomer ]

85 mg (0.17 mmol) of 1- ({3- [ (phenylcarbonyl) amino ] -5- [4- (trifluoromethyl) phenyl ] piperidin-1-yl } carbonyl) piperidine-4-carboxylic acid together with 80 mg (0.21 mmol) of HATU and 34 mg (0.28 mmol) of 4-dimethylaminopyridine are initially charged in 1.3 ml of DMF and 11 mg (0.14 mmol) of ammonium acetate are added. The reaction mixture was stirred at room temperature overnight and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 46 mg (53% of theory).

LC-MS (method 3B) R_t = 1.72 min; m/z = 503 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.40 (d, 1H), 7.86 (d, 2H), 7.72 (d, 2H), 7.59-7.51 (m, 3H), 7.51-7.41 (m, 2H), 7.27 (s, 1H), 6.77 (s, 1H), 4.02 (d, 1H), 3.80 (d, 1H), 3.65 (br. s., 3H), 3.11-2.97 (m, 1H), 2.84-2.64 (m, 4H), 2.32-2.21 (m, 1H), 2.12 (br. s., 1H), 1.82 (q, 1H), 1.68 (br. s., 2H), 1.49 (br. s., 2H)。

Examples 152

N,N- Dimethyl group -1-({3-[( Phenyl carbonyl ) Amino group ]-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -1- Base of } Carbonyl radical ) Piperidine derivatives -4- Carboxamides [ Racemic cis isomer ]

85 mg (0.17 mmol) of 1- ({3- [ (phenylcarbonyl) amino ] -5- [4- (trifluoromethyl) phenyl ] piperidin-1-yl } carbonyl) piperidine-4-carboxylic acid together with 80 mg (0.21 mmol) of HATU and 34 mg (0.28 mmol) of 4-dimethylaminopyridine are initially charged in 1.3 ml of DMF and 6 mg (0.14 mmol) of N-methyl-methylamine are added. The reaction mixture was stirred at room temperature overnight and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 62 mg (69% of theory).

LC-MS (method 3B) R_t = 1.86 min; m/z = 531 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.40 (d, 1H), 7.85 (d, 2H), 7.72 (d, 2H), 7.58-7.42 (m, 5H), 4.10-3.99 (m, 1H), 3.78 (br. s., 1H), 3.72-3.59 (m, 3H), 3.09-2.98 (m, 4H), 2.90-2.75 (m, 7H), 2.73-2.63 (m, 1H), 2.12 (d, 1H), 1.82 (q, 1H), 1.61 (br. s., 2H), 1.48 (d, 2H)。

Examples 153

N-{1-[(1- Cyanocyclopropyl group ) Carbonyl radical ]-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis isomer ]

31 mg (0.28 mmol) of 1-cyanocyclopropanecarboxylic acid together with 131 mg (0.34 mmol) of HATU and 56 mg (0.46 mmol) of 4-dimethylaminopyridine are initially charged in 2 ml of DMF and 80 mg (0.23 mmol) of N- {5- [4- (trifluoromethyl) phenyl ] piperidin-3-yl } benzamide are added. The reaction mixture was stirred at room temperature overnight and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 73 mg (72% of theory).

LC-MS (method 2B) R_t = 1.25 min; m/z = 442 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.50 (d, 1H), 7.88 (d, 2H), 7.76 (d, 2H), 7.65-7.43 (m, 5H), 4.53 (d, 1H), 4.31 (d, 1H), 4.05 (br. s., 1H), 3.26-3.09 (m, 2H), 2.18 (d, 1H), 1.97 (q, 1H), 1.64 (d, 5H)。

Examples 154

N-{1-[(3- Methyl pyridine -4- Base of ) Carbonyl radical ]-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Benzamide derivatives [ Racemic cis isomer ]

38 mg (0.28 mmol) of 3-methylpyridine-4-carboxylic acid together with 131 mg (0.34 mmol) of HATU and 56 mg (0.46 mmol) of 4-dimethylaminopyridine are initially charged in 2 ml of DMF and 80 mg (0.23 mmol) of N- {5- [4- (trifluoromethyl) phenyl ] piperidin-3-yl } benzamide are added. The reaction mixture was stirred at room temperature overnight and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 65 mg (59% of theory).

LC-MS (method 1B) R_t = 2.14 min; m/z = 468 [M+H]⁺。

Examples 155

N-{1-[(4- Cyanopiperidines -1- Base of ) Carbonyl radical ]-5-(4- Ethyl phenyl ) Piperidine derivatives -3- Base of } Pyridine compound -4- Carboxamides [ Racemic cis isomer ]

70 mg (0.21 mmol) of the compound from example 56A are reacted with 28 mg (0.23 mmol) of isonicotinic acid according to general procedure 1. In contrast to general procedure 1, isonicotinic acid, HATU and N, N-diisopropylamine were added once more. After a total of two days of reaction time, the mixture was worked up as described in general method 1. Yield: 42 mg (46% of theory).

HPLC (method 2A) R_t = 3.94 min; m/z = 446 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ = 8.72 (d, 2H), 8.67 (d, 1H), 7.76 (d, 2H), 7.21-7.19 (m, 3H), 4.05-3.95 (m, 1H), 3.80 (br d, 1H), 3.60 (br d, 1H), 3.37 (q, 2H), 3.12-3.02 (m, 3H), 2.90-2.82 (m, 1H), 2.77-2.60 (m, 3H), 2.37 (q, 2H), 2.08 (br d, 1H), 1.92-1.85 (m, 2H), 1.77 (q, 1H), 1.72-1.62 (m, 2H), 1.17 (t, 3H)。

Examples 156

N-{1-[(4- Cyanopiperidines -1- Base of ) Carbonyl radical ]-5-(4- Ethyl phenyl ) Piperidine derivatives -3- Base of }-3- Methoxybenzamides [ Racemic cis isomer ]

70 mg (0.21 mmol) of the compound from example 56A are reacted with 39 mg (0.23 mmol) of 3-methoxybenzoyl chloride in dichloromethane according to general method 2. Yield: 87 mg (89% of theory).

HPLC (method 2A) R_t = 4.48 min; m/z = 475 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.34 (d, 1H), 7.47-7.42 (m, 1H), 7.42-7.34 (m, 2H), 7.23-7.15 (m, 4H), 7.09 (dd, 1H), 4.05 – 3.92 (m, 1H), 3.83-3.75 (m, 1H), 3.80 (s, 3H), 3.62 (br d, 1H), 3.38 (br d, 2H), 3.13-3.01 (m, 3H), 2.91-2.81 (m, 1H), 2.71 (s, 2H), 2.58 (q, 2H), 2.07 (br d, 1H), 1.93-1.84 (m, 2H), 1.78 (q, 1H), 1.74-1.63 (m, 2H), 1.17 (t, 3H)。

Examples 157

N-{1-[(4- Cyanopiperidines -1- Base of ) Carbonyl radical ]-5-(4- Ethyl phenyl ) Piperidine derivatives -3- Base of }-3- Fluorobenzamides [ Racemic cis isomer ]

70 mg (0.21 mmol) of the compound from example 56A are reacted with 36 mg (0.23 mmol) of 3-fluorobenzoyl chloride in dichloromethane according to general method 2. Yield: 62 mg (66% of theory).

HPLC (method 2A) R_t = 4.49 min; m/z = 463 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.46 (d, 1H), 7.74-7.64 (m, 2H), 7.53 (td, 1H), 7.42-7.36 (m, 1H), 7.22-7.15 (m, 4H), 3.99 (td, 1H), 3.83-3.76 (m, 1H), 3.60 (br d, 1H), 3.42-3.33 (m, 2H), 3.12-3.01 (m, 3H), 2.91-2.82 (m, 1H), 2.72-2.69 (m, 2H), 2.56 (q, 2H), 2.07 (br d, 1H), 1.92-1.63 (m, 5H), 1.17 (t, 3H)。

Examples 158

N-{1-[(4- Cyanopiperidines -1- Base of ) Carbonyl radical ]-5-(4- Ethyl phenyl ) Piperidine derivatives -3- Base of }-3- Methylbenzamide [ Racemic cis isomer ]

70 mg (0.21 mmol) of the compound from example 56A are reacted with 35 mg (0.23 mmol) of 3-methylbenzoyl chloride in dichloromethane according to general method 2. Yield: 85 mg (91% of theory).

HPLC (method 2A) R_t = 4.56 min; m/z = 459 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d ₆): δ = 8.32 (d, 1H), 7.79-7.50 (m, 2H), 7.37-7.32 (m, 2H), 7.23-7.14 (m, 4H), 3.98 (dd, 1H), 3.83-3.76 (m, 1H), 3.61 (br d, 1H), 3.42-3.34 (m, 2H), 3.12-3.01 (m, 3H), 2.90-2.82 (m, 1H), 2.71-2.68 (m, 2H), 2.58 (q, 2H), 2.07 (br d, 1H), 1.92-1.63 (m, 5H), 1.17 (t, 3H)。

Examples 159

3-cyano-N- {1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethyl) phenyl ] piperidin-3-yl } benzamide [ racemic cis isomer ]

200 mg (0.508 mmol) of the amine [ racemic cis isomer ] from example 57A and 112 mg (0.762 mmol) of 3-cyanobenzoic acid are reacted according to general method 8. Yield: 206 mg (80% of theory).

LC-MS (method 2B) R_t = 1.18 min; MS (ESIpos): m/z = 487 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆): δ = 8.63 (d, 1H), 8.30 (s, 1H), 8.17 (d, 1H), 8.02 (d, 1H), 7.63-7.79 (m, 3H), 7.55 (d, 2H), 3.94-4.10 (m, 1H), 3.87 (d, 1H), 3.68 (d, 1H), 3.59 (br. s., 4H), 3.21 (br. s., 4H), 3.06 (t, 1H), 2.79-2.89 (m, 1H), 2.70 (t, 1H), 2.16 (d, 1H), 1.81 (q, 1H)。

The following compounds [ racemic cis isomers ] were prepared in a similar manner:

。

examples 166

N-{1-( Morpholine -4- Radical carbonyl )-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Cyclopentanamide [ Racemic cis isomer ]

212 microliters of triethylamine (1.52 mmol) and 18.6 mg of DMAP (0.152 mmol) were added to a solution of the compound from example 57A (200 mg, 0.508 mmol) in dichloromethane (12 ml), followed by the addition of 93 microliters of cyclopentanecarbonyl chloride (0.762 mmol) at 0 ℃. The reaction mixture was warmed to room temperature and stirred overnight. The reaction solution was washed with aqueous 1N hydrochloric acid and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (RP18 column; acetonitrile/water gradient). Yield: 133 mg (57% of theory).

LC-MS (method 5B) R_t = 2.17 min; MS (ESIpos): m/z = 454 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ = 7.80 (d, 1H), 7.70 (d, 2H), 7.52 (d, 2H), 3.74 (d, 2H), 3.63 (d, 1H), 3.56 (br. s., 4H), 3.17 (br. s., 4H), 2.97 (br. s., 1H), 2.84-2.73 (m, 1H), 2.02 (d, 1H), 1.78-1.66 (m, 2H), 1.54-1.66 (m, 5H), 1.48 (br. s., 2H)。

Examples 167

2, 2-dimethyl-N- {1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethyl) phenyl ] piperidin-3-yl } propanamide [ racemic cis isomer ]

212 microliters of triethylamine (1.52 mmol) and 18.6 mg of DMAP (0.152 mmol) were added to a solution of the compound from example 57A (200 mg, 0.508 mmol) in dichloromethane (12 ml) followed by the addition of 94 microliters of pivaloyl chloride (0.76 mmol) at 0 ℃. The reaction mixture was warmed to room temperature and stirred overnight. The reaction solution was washed with aqueous 1N hydrochloric acid and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (RP18 column; acetonitrile/water gradient). Yield: 154 mg (68% of theory).

LC-MS (method 5B) R_t = 2.17 min; MS (ESIpos): m/z = 442 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ = 7.70 (d, 2H), 7.52 (d, 2H), 7.31 (d, 1H), 3.85-3.72 (m, 1H), 3.71-3.61 (m, 2H), 3.56 (d, 4H), 3.18 (br. s., 4H), 3.04-2.92 (m, 1H), 2.76 (t, 1H), 1.97 (d, 1H), 1.73 (q, 1H), 1.09 (s, 9H)。

Examples 168

2-methyl-N- {1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethyl) phenyl ] piperidin-3-yl } propanamide [ racemic cis isomer ]

212 microliters of triethylamine (1.52 mmol) and 18.6 milligrams of DMAP (0.152 mmol) were added to a solution of the compound from example 57A (200 mg, 0.508 mmol) in dichloromethane (12 ml) followed by the addition of 80 microliters of isobutyryl chloride (0.76 mmol) at 0 ℃. The reaction mixture was warmed to room temperature and stirred overnight. The reaction solution was washed with aqueous 1N hydrochloric acid and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (RP18 column; acetonitrile/water gradient). Yield: 142 mg (65% of theory).

LC-MS (method 5B) R_t = 2.03 min; MS (ESIpos): m/z = 428 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ = 7.76 (d, 1H), 7.70 (d, 2H), 7.52 (d, 2H), 3.74 (d, 2H), 3.63 (d, 1H), 3.56 (t, 4H), 3.18 (d, 4H), 2.92-3.03 (m, 1H), 2.74-2.84 (m, 1H), 2.29-2.39 (m, 1H), 2.01 (d, 1H), 1.60 (q, 1H), 1.00 (t, 7H)。

Examples 169

3-chloro-N- {1- [ (4-hydroxypiperidin-1-yl) carbonyl ] -5- [4- (trifluoromethyl) phenyl ] piperidin-3-yl } benzamide [ racemic cis isomer ]

7.2 mg of sodium borohydride (0.19 mmol) were added at 0 ℃ to a solution of the ketone from example 174 (60 mg, 0.118 mmol) in methanol (2.4 ml). The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, taken up in water and extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 52 mg (85% of theory).

LC-MS (method 2B) R_t = 1.24 min; MS (ESIpos): m/z = 510 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆) δ = 8.52 (d, 1H), 7.91 (s, 1H), 7.82 (d, 1H), 7.72 (d, 2H), 7.58-7.64 (m, 1H), 7.48-7.57 (m, 3H), 4.68 (d, 1H), 3.96-4.09 (m, 1H), 3.78 (d, 1H), 3.62 (d, 2H), 3.44-3.54 (m, 2H), 2.97-3.09 (m, 1H), 2.86-2.96 (m, 2H), 2.74-2.84 (m, 1H), 2.63-2.73 (m, 1H), 2.13 (d, 1H), 1.66-1.88 (m, 3H), 1.32 (q, 2H)。

Examples 170

N-{1-[(4- Hydroxy piperidines -1- Base of ) Carbonyl radical ]-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Cyclopentanamide [ Racemic cis isomer ]

At 0 ℃, 6.8 mg of sodium borohydride (0.18 mmol) was added to a solution of the ketone from example 173 (52.6 mg, 0.113 mmol) in methanol (3.0 ml). The reaction mixture was warmed to room temperature and stirred for 2.5 hours. The reaction solution was concentrated under reduced pressure, taken up in water and extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 46.6 mg (91% of theory).

LC-MS (method 2B) R_t = 1.16 min; MS (ESIpos): m/z = 468 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ = 7.78 (d, 1H), 7.70 (d, 2H), 7.51 (d, 2H), 4.67 (d, 1H), 3.64-3.81 (m, 2H), 3.53-3.64 (m, 2H), 3.46 (d, 2H), 2.81-3.04 (m, 3H), 2.69-2.79 (m, 1H), 2.01 (d, 1H), 1.71 (d, 4H), 1.55-1.66 (m, 5H), 1.43-1.54 (m, 2H), 1.23-1.35 (m, 2H)。

Examples 171

1- [1- (Cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-yl ] -3-phenylurea [ racemic cis-isomer ]

108 mg (0.22 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-ylamine trifluoroacetate (example 8A) and 31 mg (0.26 mmol, 1.2 equivalents) of phenyl isocyanate are reacted according to general method 4. Yield: 72 mg (79% of theory).

HPLC (method 1) R_t = 4.79 min; MS (ESIpos): m/z = 420 [M+H]⁺;

¹H-NMR (500 MHz, DMSO-d₆): δ= 8.45 (s, 0.6H), 8.41 (s, 0.4H), 7.38 (d, 2H), 7.28-7.13 (m, 6H), 6.95-6.87 (m, 1H), 6.25 (d, 0.6H), 6.19 (d, 0.4H), 4.66 (br d, 0.4H), 4.45 (br d, 0.6H), 4.22 (br d, 0.6H), 3.93 (br d, 0.4H), 3.66-3.49 (m, 1H), 3.08-2.97 (m, 1.4H), 2.83-2.72 (m, 1H), 2.69-2.61 (m, 0.6H), 2.58 (q, 2H), 2.33 (t, 0.6H), 2.10-2.00 (m, 1.4H), 1.85-1.44 (m, 9H), 1.17 (t, 3H)。

Examples 172

{1-( Morpholine -4- Radical carbonyl )-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Carbamic acid tert-butyl ester [ Racemic cis isomer ]

Activated molecular sieve 4a (about 10 g), 2.16 ml (15.5 mmol) triethylamine and 3.92 g (14.2 mmol) diphenyl azidophosphate (diphenylphosphonazidat) were added to the carboxylic acid from example 55A (5.00 g, 12.9 mmol) in t-butanol (235 ml) and the mixture was stirred under reflux conditions overnight. The reaction solution was cooled, and then the molecular sieve was filtered off and washed thoroughly with ethyl acetate. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate. After washing with 2N aqueous hydrogen chloride solution, saturated aqueous sodium bicarbonate solution and water, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was used in the next step without further purification. Yield: 5.53 g (89% of theory).

LC-MS (method 11B) R_t = 1.15 min; MS (ESIpos): m/z = 458 [M+H]⁺。

Examples 173

N-{1-[(4- Oxopiperidine -1- Base of ) Carbonyl radical ]-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Cyclopentanamide [ Racemic cis isomer ]

14.3 mg of pyridineP-toluenesulfonate salt (0.057 mmol) was added to a solution of the acetal from example 63A (97.2 mg, 0.191 mmol) in 5.5 ml of acetone/water (10: 1) and the mixture was stirred under reflux overnight. Another 14.3 mg of pyridine was addedP-toluenesulfonate (0.057 mmol) and the mixture was stirred under reflux for another night. The mixture was then cooled and the precipitate formed was filtered off. Yield: 66.2 mg (74% of theory).

LC-MS (method 11B) R_t = 1.05 min; MS (ESIpos): m/z = 466 [M+H]⁺。

Examples 174

3-chloro-N- {1- [ (4-oxopiperidin-1-yl) carbonyl ] -5- [4- (trifluoromethyl) phenyl ] piperidin-3-yl } benzamide [ racemic cis isomer ]

54.6 mg of pyridineP-toluenesulfonate (0.217 mmol) was added to a solution of the acetal from example 64A (400 mg, 0.725 mmol) in 15 ml of acetone/water (10: 1) and the mixture was stirred under reflux for 3 days, after 24 h and 48 h another 54.6 mg of pyridine was addedP-toluenesulfonate salt (0.217 mmol). The solvent was then removed under reduced pressure and the residue was taken up in water and the mixture was extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yield: 363 mg (of theory)92%)。

LC-MS (method 11B) R_t = 1.12 min; MS (ESIpos): m/z = 508 [M+H]⁺。

Examples 175

N-{1-[(4- Cyanopiperidines -1- Base of ) Carbonyl radical ]-5-(4- Ethyl phenyl ) Piperidine derivatives -3- Base of } Cyclopentanamide [ Racemic cis isomer ]

At 0 ℃, 80 mg (0.24 mmol) of the compound from example 56A was initially charged in 2.5 ml of dichloromethane, 49 μ l (36 mg, 1.5 equivalents) of triethylamine and 58 μ l (64 mg, 0.47 mmol) of cyclopentanecarboxylic acid chloride were added. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for another 16 hours. The mixture was then washed twice with water and the organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was taken up in methanol/DMF and the residue was isolated and the filtrate was purified by preparative HPLC (RP18 column; acetonitrile/water gradient). The residue and the product-containing fractions were combined. Yield: 94 mg (91% of theory).

LC-MS (method 5B) R_t = 2.31 min; MS (ESIpos): m/z = 437 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ= 7.51 (d, NH), 7.36-6.98 (m, 4H), 3.70 (d, 2H), 3.56 (d, 1H), 3.04 (t, 4H), 2.86-2.72 (m, 1H), 2.72-2.60 (m, 2H), 2.55 (q, 2H), 1.97 (d, 1H), 1.86 (d, 2H), 1.79-1.43 (m, 12H), 1.16 (t, 3H)。

Examples 176

N-{1-[(4- Hydroxy piperidines -1- Base of ) Carbonyl radical ]-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Cyclopentanamide [ Enantiomerically pure cis-isomers ]

Enantiomer separation of 48.6 mg of the racemate from example 170 according to method 16D gave 14 mg of the compound from example 176 (enantiomer 1) and 16 mg of the compound from example 177 (enantiomer 2).

HPLC (method 8E) R_t = 4.50 min, >99.0% ee;

LC-MS (method 11B) R_t = 1.00 min; MS (ESIpos): m/z = 468 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆): δ = 7.78 (d, 1H), 7.70 (d, 2H), 7.51 (d, 2H), 4.67 (d, 1H), 3.82-3.53 (m, 4H), 3.46 (d, 2H), 3.05-2.81 (m, 3H), 2.80-2.69 (m, 1H), 2.01 (d, 1H), 1.81-1.41 (m, 12H), 1.37-1.19 (m, 2H)。

Examples 177

HPLC (method 8E) R_t = 5.14 min, >95.0% ee;

LC-MS (method 11B) R_t= 1.00 min; MS (ESIpos): m/z = 468 [M+H]⁺;

Examples 178

N-{1-[(4- Cyanopiperidines -1- Base of ) Carbonyl radical ]-5-[4-( Trifluoromethyl radical ) Phenyl radical ] Piperidine derivatives -3- Base of } Cyclopentanamide [ Enantiomerically pure cis-isomers ]

At 0 ℃, 90 mg (0.21 mmol) of the compound from example 69A was initially charged in 5.0 ml of dichloromethane and 86 μ l (62 mg, 0.62 mmol) of triethylamine, 37 μ l (41 mg, 0.31 mmol) of cyclopentanecarbonyl chloride and 7.5 mg (0.062 mmol) of 4- (dimethylamino) pyridine were added. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for another 16 hours. The mixture was washed with 1N hydrochloric acid and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (RP18 column; acetonitrile/water gradient). Yield: 74.8 mg (77% of theory). Enantiomer separation of 74.8 mg of the racemate according to method 17D gave 27 mg of the compound from example 178 (enantiomer 1) and 28 mg of the compound from example 179 (enantiomer 2).

HPLC (method 8E) R_t = 5.96 min, >99.0% ee;

LC-MS (method 11B) R_t = 1.11 min; MS (ESIpos): m/z = 477 [M+H]⁺;

¹H-NMR (400 MHz, DMSO-d₆) δ = 7.80 (d, 1H), 7.70 (d, 2H), 7.52 (d, 2H), 3.80-3.65 (m, 2H), 3.60 (d, 1H), 3.14-2.90 (m, 4H), 2.85-2.72 (m, 1H), 2.01 (d, 1H), 1.85 (br. s, 2H), 1.77-1.39 (m, 16H), 4H is masked.

Examples 179

Enantiomer separation of 74.8 mg of the racemate from example 178 according to method 17D gave 27 mg of the compound from example 178 (enantiomer 1) and 28 mg of the compound from example 179 (enantiomer 2).

HPLC (method 8E) R_t = 6.68 min, >98.0% ee;

LC-MS (method 11B) R_t = 1.11 min; MS (ESIpos): m/z = 477 [M+H]⁺;

B) Evaluation of physiological efficacy

Abbreviations:

BSA bovine serum albumin

DMEM Dulbecco's 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 peptide

PRP platelet rich plasma.

The suitability of the compounds according to the invention for the treatment of thromboembolic disorders can be demonstrated by using the following analytical system:

1.) in vitro analysis

A) in vitro testing of cell function

Identification of agonists of human protease activated receptor 1(PAR-1) by means of recombinant cell lines and quantitative analysis of the activity of the substances described herein. The cells were originally derived from human embryonic kidney cells (HEK293; ATCC: American Type Culture Collection, Manassas, VA 20108, USA). The test cell lines constructively expressed a modified form of the calcium-sensitive photoprotein aequorin, which luminesces upon reconstitution with the cofactor coelenterazine when the concentration of free calcium in the internal mitochondrial chamber is increased (Rizzuto R, Simpson AW, Brini M, Pozzan T.; Nature 1992, 358, 325-. In addition, the cells stably express the endogenous human PAR-1 receptor and the endogenous purinergic receptor P2Y 2. The resulting intracellular release of calcium ions from PAR-1 test cells in response to stimulation of endogenous PAR-1 or P2Y2 receptors can be qualitatively analyzed by the resulting fluorescence of aequorin using a suitable luminometer (Milligan G, Marshall F, Rees S, Trends in pharmaceutical Sciences 1996, 17, 235-237).

To test substance specificity, the effect following activation of the endogenous PAR-1 receptor was compared with the effect following activation of the endogenous purinergic P2Y2 receptor using the same intracellular signaling pathway.

Test procedure:two days (48 hours) before the assay, the cells were incubated in culture medium (DMEM F12, supplemented with 10% FCS, 2 mM glutamine,10mM HEPES, 1.4 mM pyruvate, 0.1 mg/ml gentamicin, 0.15% sodium bicarbonate; # BE04-687Q from BioWhittaker Cat.; b-4800 Verviers, Belgium) cells were seeded in 384-well microtiter plates and maintained in cell culture incubator (96% humidity, 5% v/v CO)₂37 ℃ C.). On the day of the assay, the culture medium was replaced with Tyrode solution (in mM: 140 sodium chloride, 5 potassium chloride, 1 magnesium chloride, 2 calcium chloride, 20 glucose, 20 HEPES) additionally containing the co-factors coelenterazine (25. mu.M) and glutathione (4 mM), and then incubated on the microtiter plates for an additional 3-4 hours. The test substance is then pipetted onto the microtiter plate and 5 minutes after the test substance is transferred into the wells of the microtiter plate the plate is transferred into the luminometer, adding the test substance to the EC₅₀The corresponding PAR-1 agonist concentration and immediately measuring the resulting optical signal in a luminometer. To distinguish the antagonist substance effect from the toxic effect, the endogenous purinergic receptors were then immediately activated with agonist (ATP, final concentration 10 μ M) and the resulting optical signal was measured. The results are shown in Table A:

watch (A) A ：

。

B) PAR-1 receptor binding assay

Platelet membranes were incubated with 12 nM [3H ] hatAP and varying concentrations of test substance in buffer (50 mM Tris pH 7.5, 10mM magnesium chloride, 1mM EGTA, 0.1% BSA) for 80 minutes at room temperature. The mixture was then transferred onto the filter plate and washed twice with buffer. After addition of scintillation fluid, the radioactivity on the filter was measured in beta counting tubes.

C) platelet aggregation in plasma

Platelet aggregation was determined using blood from healthy male and female subjects who did not receive any platelet aggregation affecting type of drug treatment for the last ten days. The blood was inhaled into monovitenten (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, whole citrate-containing blood was centrifuged at 140g for 20 minutes.

For the aggregation measurement, aliquots of platelet rich plasma were incubated with increasing concentrations of the test substance at 37 ℃ for 10 minutes. The coagulation was then triggered by The addition of a thrombin receptor agonist (TRAP6, SFLLRN) to The coagulometer and was determined at 37 ℃ by using a nephelometry according to Born (Born, G.V.R., Cross M.J., The Aggregation of Blood plants; J. Physiol.1963, 168, 178-195). The concentration of SFLLRN which resulted in the highest aggregation rate was determined individually for each donor, as appropriate.

To calculate the inhibitory effect, the maximum increase in light transmittance (amplitude of the aggregation curve,%) was measured in the presence and absence of the test substance within 5 minutes after the addition of the agonist, and the inhibition rate was calculated. The inhibition curve was used to calculate the concentration at which the agglomeration was 50% inhibited.

1.d) platelet aggregation in buffer

Platelet aggregation was determined using blood from healthy male and female subjects who did not receive any platelet aggregation affecting type of drug treatment for the last ten days. The blood was inhaled into monovitenten (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, whole citrate-containing blood was centrifuged at 140g for 20 minutes. One quarter of the volume of ACD buffer (44.8 mM sodium citrate, 20.9 mM citric acid, 74.1 mM glucose and 4 mM potassium chloride) was added to the PRP, followed by centrifugation at 1000g for 10 minutes. The platelet pellets were resuspended in wash buffer and centrifuged at 1000g for 10 min. The platelets were resuspended in culture buffer and adjusted to 200000 cells/. mu.l. Before the start of the test, calcium chloride and magnesium chloride were added, in each case at a final concentration of 2 mM (2M stock solution, dilution ratio 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. The concentration of agonist was determined for each donor.

Test procedure:96-well microtiter plates were used. The test substances were diluted in DMSO and pre-loaded at 2. mu.l per well. 178 μ l of platelet suspension was added, followed by preincubation at room temperature for 10 minutes. 20 μ l of agonist was added and measurement in Spectramax, OD 405 nm was started immediately. Kinetics were determined in 11 measurements for 1 minute each. Oscillate for 55 seconds in the middle of the measurement.

E) platelet aggregation in fibrinogen-poor plasma

Platelet aggregation was determined using blood from healthy male and female subjects who did not receive any platelet aggregation affecting type of drug treatment for the last ten days. The blood was inhaled into monovitenten (Sarstedt, N ü mbrecht, germany) which contained 3.8% sodium citrate (1 part citrate + 9 parts blood) as an anticoagulant.

Preparation of fibrinogen-poor plasma:to obtain platelet-low plasma, whole blood containing citrate was centrifuged at 140g for 20 minutes. Platelet-poor plasma was mixed with snake venom thrombin (Roche Diagnostic, Germany) in a ratio of 1:25 and then carefully inverted. This was followed by a 10 minute incubation in a water bath at 37 ℃ followed directly by a 10 minute incubation on ice. The plasma/snake venom thrombin mixture was centrifuged at 1300g for 15 minutes to obtain the supernatant (fibrinogen depleted plasma).

Platelet isolation:to obtain platelet rich plasma, whole citrate-containing blood was centrifuged at 140g for 20 minutes. One quarter of the volume of ACD buffer (44.8 mM sodium citrate, 20.9 mM citric acid, 74.1 mM glucose and 4 mM potassium chloride) was added to the PRP, which was then centrifuged at 1300g for 10 minutes. Resuspending the platelet pelletFloat in washing buffer and centrifuge at 1300g for 10 min. The platelets were resuspended in culture buffer and adjusted to 400000 cells/. mu.l, then calcium chloride solution was added to a final concentration of 5 mM (dilution ratio 1/200).

For the agglutination measurements, aliquots with increasing concentrations of the test substance (98. mu.l of fibrinogen-depleted plasma and 80. mu.l of platelet suspension) were incubated at room temperature for 10 minutes. The coagulation was then triggered by The addition of human alpha thrombin in a coagulometer and was determined using a nephelometry according to Born (Born, G.V.R., Cross M.J., The Aggregation of Blood plates, J. physiol.1963, 168, 178-. The concentration of alpha thrombin was determined for each donor just enough to cause the highest aggregation rate.

To calculate the inhibitory activity, the increase in maximum light transmittance (amplitude of the aggregation curve,%) was measured in the presence and absence of test substance within 5 minutes after the addition of the agonist, and the inhibition rate was calculated. The concentration at which the aggregation was inhibited by 50% was calculated from the inhibition curve.

F) stimulation of washed platelets and analysis in flow cytometry

Isolation of washed platelets:human whole blood was obtained from volunteer donors by venipuncture and transferred to monovitenten (Sarstedt, N ü mbrecht, germany) containing sodium citrate as anticoagulant (1 part sodium citrate 3.8% + 9 parts whole blood). The Monovitenten was centrifuged at 900 rpm and 4 ℃ for 20 minutes (Heraeus Instruments, Germany; Megafuge 1.0 RS). Platelet rich plasma was carefully removed and transferred to a 50 ml Falcon tube. ACD buffer (44 mM sodium citrate, 20.9 mM citric acid, 74.1 mM glucose) was then added to the plasma. The volume of ACD buffer corresponds to one quarter of the plasma volume. The platelets were sedimented by centrifugation at 2500 rpm for ten minutes at 4 ℃. The supernatant was then carefully decanted and discarded. The precipitated platelets were initially resuspended carefully in 1 ml of wash buffer (113 mM sodium chloride, 4 mM disodium hydrogen phosphate)24 mM sodium dihydrogen phosphate, 4 mM potassium chloride, 0.2 mM ethylene glycol-bis (2-aminoethyl) -N, N' -tetraacetic acid, 0.1% glucose), and then supplemented with a washing buffer to a volume corresponding to the volume of the plasma amount. The washing procedure was carried out twice. The platelets were pelleted by re-centrifugation at 2500 rpm for ten minutes at 4 ℃ and then carefully resuspended in 1 ml of culture buffer (134 mM sodium chloride, 12 mM sodium bicarbonate, 2.9 mM potassium chloride, 0.34 mM sodium bicarbonate, 5 mM HEPES, 5 mM glucose, 2 mM calcium chloride and 2 mM magnesium chloride) and adjusted to a concentration of 300000 platelets/. mu.l with culture buffer.

In that PAR-1 Human alpha for human platelets in the Presence or absence of an antagonist - Thrombin staining and stimulation:the platelet suspension is preincubated with the substance to be tested or a suitable solvent for 10 minutes at 37 ℃ (Eppendorf, Germany; Thermomixer Comfort). Platelet activation was triggered by addition of agonist (0.5 μ M or 1 μ M α -thrombin; Kordia, Netherlands, 3281 NIH units/mg; or 30 μ g/ml peptide for thrombin receptor activation (TRAP 6); Bachem, Switzerland) at 37 deg.C and shaking at 500 rpm. At time points 0, 1, 2.5, 5, 10 and 15 minutes, in each case 50. mu.l aliquots were removed and transferred to 1 ml single concentrated CellFix^TMIn solution (Becton Dickinson immunocytometer Systems, USA). To fix the cells, they were incubated in the dark at 4 ℃ for 30 minutes. Platelets were precipitated by centrifugation at 600 g and 4 ℃ for ten minutes. The supernatant was discarded and the platelets resuspended in 400. mu.l of CellWash^TM(Becton Dickinson Immunocytometry Systems, USA). 100 μ l aliquots were transferred to new FACS tubes. 1. mu.l of the platelet-identifying antibody and 1. mu.l of the activation state-detecting antibody CellWash^TMMake up 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, an additional 400. mu.l of CellWash was passed^TMTo increase the volume of the mixture.

Fluorescein isothiocyanate conjugated antibodies (Immunotech Coulter, france; cat. No.0649) directed against human glycoprotein IIb (CD41) were used to identify platelets. The activation state of platelets can be determined with the aid of phycoerythrin-conjugated antibodies against the human glycoprotein P-selectin (Immunotech Coulter, France; Cat. No. 1759). P-selectin (CD62P) is localized in the alpha-particles of resting platelets. However, after in vitro or in vivo stimulation, it is translocated to the external plasma membrane.

Flow cytometry and data evaluation:FACSCalibur available from Becton Dickinson immunocytometer Systems, USA^TMSamples were measured in a flow cytometer system instrument and evaluated and graphed with the aid of CellQuest software version 3.3 (Becton Dickinson Immunocytometry Systems, USA). The percentage of CD62P positive platelets (CD 41-positive events) was used to determine the extent of platelet activation. 10000 CD 41-positive events were counted from each sample.

The inhibitory activity of the test substance is calculated using the decrease in platelet activation, which is called activation by an agonist.

1.g) measurement of platelet aggregation using parallel plate flow chamber

Platelet aggregation was determined using blood from healthy male and female subjects who did not receive any platelet aggregation affecting type of drug treatment for the last ten days. The blood was inhaled into monovitenten (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, whole citrate-containing blood was centrifuged at 140g for 20 minutes. One quarter of the volume of ACD buffer (44.8 mM sodium citrate, 20.9 mM citric acid, 74.1 mM glucose and 4 mM potassium chloride) was added to the PRP, followed by centrifugation at 1000g for 10 minutes. The platelet pellets were 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/μ l) was prepared and then suspended in HEPES-Tyrode buffer. Platelet aggregation under flow conditions was measured using a parallel plate flow chamber (B. Nieswandt et al, EMBO J. 2001, 20, 2120-. Slides were wetted overnight (various concentrations of α -thrombin, e.g., 10-50 μ g/ml) with 100 μ l of human α -thrombin solution (in Tris-buffer) at 4 ℃ and then blocked with 2% BSA.

Reconstituted blood was passed over a thrombin-wetted slide at a constant flow rate (e.g., 300/sec shear rate) for 5 minutes, then observed and recorded by using a microscope video system. The inhibitory activity of the substances to be tested is determined morphologically by the reduction of platelet aggregate formation. Alternatively, inhibition of platelet activation can be determined by flow cytometry, e.g., via p-selectin expression (CD62p) (see method 1. f).

2.) In vitro analysis

A) platelet aggregation (primate, guinea pig)

Guinea pigs or primates in the conscious or anesthetized state are administered with the test substances in suitable formulations by the oral, intravenous or intraperitoneal route. As a control, other guinea pigs or primates were treated in the same manner with the corresponding vehicle. After different periods of time depending on the mode of administration, blood from deeply anesthetized animals was obtained by puncturing the heart or aorta. The blood was inhaled into monovitenten (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, whole citrate-containing blood was centrifuged at 140g for 20 minutes.

Coagulation was triggered by addition of a thrombin receptor agonist (TRAP6, SFLLRN, 50. mu.g/ml; in each experiment, concentrations were determined for each animal species) in a coagulometer and was determined at 37 ℃ by using a nephelometry according to Born (Born, G.V.R., Cross M.J., The agglutination of Blood plants; J. Physiol.1963, 168, 178-one 195).

To measure aggregation, the maximum increase in light transmission (amplitude of the aggregation curve,%) was determined within 5 minutes after addition of agonist. The inhibitory activity of the test substance administered in the treated animals was calculated using the decrease in aggregation, based on the mean values of the control animals.

3.) In vivo assays

3.a) thrombosis model

The compounds according to the invention can be studied in a model of thrombosis in a suitable animal species, in which thrombin-induced platelet aggregation is mediated via the PAR-1 receptor. Suitable animal species are guinea pigs and in particular primates (compare: Lindahl, A.K., Scarborough, R.M., Naughton, M.A., Harker, L.A., Hanson, S.R., Thromb Haemost 1993, 69, 1196; Cook JJ, Sitko GR, Bednar B, Condra C, Mellott MJ, Feng D-M, Nutt RF, Shager JA, Gould RJ, Connolly TM, Circulation 1995, 91, 2961-2971; Kogushi M, Kobayashi H, Matsuoka T, Suzuki S, Kawahara T, Kajiwara A, Hishinuma I, Circulation support 17, IV-280; Dermaribp, Damoano BP, Andoro J, Addre J, Gordol J Mf J, Gordol J, J-D, Gordol J-D304, 855-861). 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-knock-out (knock down) guinea pigs may be used.

B) blood coagulation disturbance and organ dysfunction in Disseminated Intravascular Coagulation (DIC)

The compounds according to the invention can be studied in models of DIC and/or sepsis in suitable animal species. Suitable animal species are guinea pigs and in particular primates, and for the study of endothelial-mediated effects mice and rats are also used (compare: Kogushi M, Kobayashi H, Matsuoka T, Suzuki S, Kawahara T, Kajiwara A, Hishinuma I, Circulation 2003, 108 Suppl.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, 855-861; Kaneider NC et AL, Nat mulol, 2007, 8, 1303-12; Camer E et AL, Blood, 107, 3912-21; Riewam et AL, Riewald J. Biol. 10, 19808, 14). 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-knock-out guinea pigs may be used.

3.b.1) Thrombin - Antithrombin complexes

The thrombin-antithrombin complex (hereinafter "TAT") is a measure of the formation of thrombin endogenously activated by blood coagulation. TAT is determined via ELISA analysis (Enzygnost TAT micro, Dade-Behring). Plasma was obtained from citrated blood by centrifugation. Mu.l of TAT sample buffer was added to 50. mu.l of plasma, followed by brief shaking and incubation of the mixture at room temperature for 15 minutes. The sample was suction filtered and the wells were washed three times with wash buffer (300. mu.l/well). In the middle of these washing processes, the plate is tapped. Conjugate solution (100. mu.l) was added and the samples were incubated at room temperature for 15 minutes. Samples were aspirated and wells were washed three times with wash buffer (300. mu.l/well). Then, a chromogenic substrate (100. mu.l/well) was added, incubated at room temperature for 30 minutes in the dark, a stop solution (100. mu.l/well) was added, and the color formation at 492 nm was measured (Saphire Plate reader).

3.b.2) Parameters of organ dysfunction

Various parameters were determined, from which conclusions can be drawn on the functional limitations of various internal organs caused by the administration of LPS, and the therapeutic effect of the test substances can be evaluated. Citrate blood or optionally lithium heparin blood is centrifuged and the parameters are determined from the plasma. Typically, the following parameters are proposed: creatinine, urea, aspartate Aminotransferase (AST), alanine Aminotransferase (ALT), total bilirubin, Lactate Dehydrogenase (LDH), total protein, total albumin, and fibrinogen. These values give indices on renal function, hepatic function, circulatory function and vascular function.

3.b.2) Parameters of inflammation

The extent of the inflammatory response triggered by endotoxin can be demonstrated by an increase in inflammation mediators such as interleukins (1, 6, 8 and 10), tumor necrosis factor alpha or monocyte chemoattractant protein-1 in plasma. ELISA or Luminex systems can be used for this purpose.

3.c) antitumor Activity

The compounds according to the invention can be tested in cancer models, for example in human breast cancer models in immunodeficient mice. (comparison: S, Even-Ram et al, Nature Medicine, 1988, 4, 909-914).

3.d) anti-angiogenic Activity

The compounds according to the invention can be tested in vitro and in vivo models of angiogenesis (comparison: Caunt et al, Journal of Thrombosis and Haemostasis, 2003, 10, 2097-.

E) blood pressure and Heart Rate regulating Activity

The compounds according to 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. Wistar) are provided with implantable radiotelemetry devices and use an electronic Data acquisition and storage system (Data Sciences, MN, USA) consisting of a long-term implantable sensor/transmitter device and a liquid-filled catheter. The transmitter is implanted in the peritoneal cavity and the probe catheter is located in the descending aorta. The compounds according to the invention can be administered (e.g. orally or intravenously). Before treatment, the mean arterial blood pressure and heart rate were measured for untreated and treated animals and were ensured to be within the range of about 131-. PAR-1 activating peptide (SFLLRN; e.g., at a dose of between 0.1-5 mg/kg) is administered intravenously. Blood pressure and heart rate were measured at various time intervals and time spans with and without PAR-1-activating peptides and with and without compounds according to The invention (compare: Cicala C et al, The FASEB Journal, 2001, 15, 1433-5; Stasch JP et al, British Journal of Pharmacology 2002, 135, 344-.

4.) Determination of solubility

Starting solution ( The original solution ) The preparation of (1):

at least 1.5 mg of the test substance are weighed out accurately into a wide-mouthed 10 mm-threaded V-vial (Glastechnik Gr ä fenroda GmbH, art. number 8004-WM-H/V15 μ) with a fitted screw cap and septum, DMSO is added to a concentration of 50mg/ml and the V-vial is vortexed for 30 minutes.

Preparation of calibration solutions:

the required pipette transfer steps were carried out in a 1.2 ml 96-Deep Well Plate (DWP) by means of a liquid handling robot. The solvent used was an acetonitrile/water 8:2 mixture.

Preparation of starting solution (stock solution) of calibration solution: mu.l of the solvent mixture was added to 10. mu.l of the original solution (concentration = 600. mu.g/ml) and then homogenized. A 1:100 dilution in individual DWPs was prepared from each test substance, and these were subsequently homogenized.

Calibration solution 5 (600 ng/ml): 270. mu.l of the solvent mixture are added to 30. mu.l of the stock solution and then homogenized.

Calibration solution 4 (60 ng/ml): 270. mu.l of the solvent mixture were added to 30. mu.l of the calibration solution 5, followed by homogenization.

Calibration solution 3 (12 ng/ml): 400. mu.l of the solvent mixture are added to 100. mu.l of the calibration solution 4 and then homogenized.

Calibration solution 2 (1.2 ng/ml): 270. mu.l of the solvent mixture was added to 30. mu.l of the calibration solution 3, followed by homogenization.

Calibration solution 1 (0.6 ng/ml): 150 μ l of the solvent mixture was added to 150 μ l of the calibration solution 2, followed by homogenization.

Preparation of sample solution:

the required pipette transfer steps were performed in a 1.2 ml 96-well DWP by means of a liquid handling robot. To 10.1. mu.l of this stock solution was added 1000. mu.l of PBS buffer, pH 6.5. (PBS buffer pH 6.5: 61.86 g sodium chloride, 39.54 g sodium dihydrogen phosphate and 83.35 g 1N sodium hydroxide aqueous solution were weighed into a 1-liter volumetric flask, then filled with water, and stirred for about 1 hour, 500 ml of this solution was added to the 5-liter volumetric flask, then filled with water, pH was adjusted to 6.5 using 1N sodium hydroxide aqueous solution.)

The procedure is as follows:

the required pipette transfer steps were performed in a 1.2 ml 96-well DWP by means of a liquid handling robot. The sample solution prepared in this manner was shaken at 1400 rpm and at 20 ℃ for 24 hours by using a variable temperature shaker. In each case 180. mu.l of these solutions were removed and transferred to Beckman Polyallemer centrifuge tubes. These solutions were centrifuged at about 223000 Xg for 1 hour. Mu.l of the supernatant was separated from each sample solution and then diluted 1:10 and 1:1000 with PBS buffer 6.5.

And (3) analysis:

samples were analyzed by HPLC/MS-MS. Quantitative analysis of test compounds was performed by a five-point calibration curve. The solubility is expressed in mg/l. Analyzing the sequence: 1) blank (solvent mixture); 2) 0.6 ng/ml of correction solution; 3) correcting the solution to 1.2 ng/ml; 4) correcting the solution to 12 ng/ml; 5) 60 ng/ml of correction solution; 6) correcting the solution by 600 ng/ml; 7) blank (solvent mixture); 8) 1:1000 of sample solution; 9) sample solution 1: 10.

HPLC/MS-MS The method comprises the following steps:

HPLC: agilent 1100, quat. pump (G1311A), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); column: oasis HLB 20mm × 2.1 mm, 25 μ; temperature: 40 ℃; eluent A: water + 0.5 ml formic acid/L; eluent B: acetonitrile + 0.5 ml formic acid/L; flow rate: 2.5 ml/min; the stop time was 1.5 minutes; gradient: 0 min 95% A, 5% B; slow lifting sequence: 0-0.5 min 5% A, 95% B; 0.5-0.84 min 5% A, 95% B; slow lifting sequence: 0.84-0.85 min 95% A, 5% B; 0.85-1.5 min 95% A, 5% B.

MS/MS: waters Quattro Micro Tandem MS/MS; Z-Spray API-Interface; HPLC-MS inlet splitter 1: 20; measurement in ESI mode.

C) Working examples of pharmaceutical compositions

The substances of the invention can be converted into pharmaceutical preparations in the following manner:

and (3) tablet preparation:

consists of the following components:

100 mg of the compound according to example 1, 50mg of lactose (monohydrate), 50mg of maize starch, 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Germany) and 2 mg of magnesium stearate.

The tablet weight was 212 mg. The diameter is 8 mm, and the curvature radius is 12 mm.

Production:

the mixture of compound, lactose and starch of example 1 was granulated with a 5% solution (m/m) of PVP in water. After drying, the granules were then mixed with magnesium stearate for 5 minutes. The mixture is compressed using a conventional tablet press (see above for tablet forms).

Oral suspension:

consists of the following components:

1000 mg of the compound of example 1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum) (FMC, USA) and 99 g of water.

A single dose of 100 mg of a compound according to the invention corresponds to 10 ml of an oral suspension.

Production:

rhodigel was suspended in ethanol and the compound of example 1 was then added to the suspension. Water was added while stirring. Stirring for about 6 hours until the Rhodigel has finished swelling.

Solutions capable of intravenous administration:

consists of the following components:

1 mg of the compound of example 1, 15 g of polyethylene glycol 400 and 250 g of water for injection.

Production:

the compound of example 1 was dissolved in water with polyethylene glycol 400 by stirring. The solution was sterilized by filtration (pore diameter: 0.22 μm) and filled into a heat-sterilized infusion bottle under aseptic conditions. The latter is closed with a pouring stopper and a crimp cap.

Claims

1.A compound of the formula

It is characterized in that

A represents a group of the formula

Wherein

# is the point of attachment to the piperidine ring,

is to R²The connection point of (a) is,

R⁴represents hydrogen or a methyl group,

and

R⁵represents hydrogen or a methyl group,

R¹represents a phenyl group, and is represented by,

R²represents methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, pyrrolidinyl, piperazinyl, phenyl, 2, 2-difluoro-1, 3-benzodioxolyl, thienyl, thiazolyl or pyridyl,

and

wherein the methyl group can be substituted with a phenyl substituent,

and

or a salt thereof.

2.A compound according to claim 1, characterized in that

A represents a group of the formula

Wherein

# is the point of attachment to the piperidine ring,

is to R²The connection point of (a) is,

R¹represents a phenyl group, and is represented by,

and

wherein the methyl group can be substituted with a phenyl substituent,

or a salt thereof.

3. Compound according to any one of claims 1 to 2, characterized in that the substituent-R¹and-A-R²Are in-line with each other.

4. Process for the preparation of a compound of formula (I) or a salt thereof according to claim 1, characterized in that

[A] A compound of the formula

Wherein

A，R¹And R²Having the meaning given in claim 1,

with a compound of the formula

Wherein

R³Have the meanings given in claim 1, and

X¹represents a halogen, or a hydroxyl group,

or

[B] Reacting a compound of formula (II) with a compound of formula

Wherein

R^3aRepresents ethyl, tert-butyl, cyclohexyl, phenyl, or pyridyl,

wherein ethyl and tert-butyl can be substituted with a substituent selected from the group consisting of: halogen, hydroxy, methoxy, cyclopropyl, phenyl, furyl, thienyl and pyrazolyl,

and

wherein cyclohexyl, phenyl and pyridyl can be substituted with 1 to 2 substituents independently selected from the group consisting of: halogen, cyano, oxo, hydroxy, amino, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxycarbonyl, aminocarbonyl, methyl, ethyl, methoxy, ethoxy, dimethylamino, methoxycarbonyl, ethoxycarbonyl, dimethylaminocarbonyl and cyclopropyl,

wherein the ethyl group can be substituted with a hydroxy substituent,

to obtain a compound of the formula

Wherein

A，R¹And R²Has the meaning given in claim 1, R^3aAs defined above, the above-mentioned,

or

[C] A compound of the formula

Wherein

R¹And R³Having the meaning given in claim 1,

with a compound of the formula

Wherein

R²Have the meanings given in claim 1, and

X²represents a halogen, or a hydroxyl group,

to obtain a compound of the formula

Wherein

R¹、R²And R³Having the meaning given in claim 1,

or

[D] Reacting a compound of formula (V) with a compound of formula

Wherein

R²Having the meaning given in claim 1,

to obtain a compound of the formula

Wherein

R¹、R²And R³Having the meaning given in claim 1,

or

[E] Reacting a compound of formula (V) with a compound of formula

Wherein

R²And R⁵Having the meaning given in claim 1,

to obtain a compound of the formula

Wherein

R¹，R²，R³And R⁵Having the meaning given in claim 1,

or

[F] Reaction of a Compound of formula (Id) with a Compound of formula

R⁴-X³ (IX)

Wherein

R⁴Have the meanings given in claim 1, and

X³represents a halogen, and is characterized in that,

to obtain a compound of the formula

Wherein

R¹，R²，R³，R⁴And R⁵Having the meaning given in claim 1,

or

[G] Reacting a compound of formula (V) with a compound of formula

Wherein

R²Have the meanings given in claim 1, and

X⁴represents a chlorine or a hydroxyl group, or a salt thereof,

to obtain a compound of the formula

Wherein

R¹、R²And R³Having the meaning given in claim 1,

or

[H] A compound of the formula

Wherein

R¹And R³Having the meaning given in claim 1,

first with disuccinimidyl carbonate and then with a compound of the formula

H₂N-R² (XII)，

Wherein

R²Having the meaning given in claim 1,

to obtain a compound of the formula

Wherein

R¹、R²And R³Have the meaning given in claim 1.

5. The method of claim 4, wherein X¹Represents bromine or chlorine.

6. The method of claim 4, wherein X²Represents bromine or chlorine.

7. The method of claim 4, wherein X³Represents iodine, bromine or chlorine.

8. The use of a compound according to any one of claims 1 to 3 for the preparation of a medicament for the treatment and/or prophylaxis of cardiovascular disorders, thromboembolic disorders, and/or oncological disorders.

9. A medicament comprising a compound according to any one of claims 1 to 3 in combination with inert, non-toxic, pharmaceutically suitable auxiliaries.

10. A medicament comprising a compound according to any one of claims 1 to 3 in combination with a further active substance.

11. Medicament according to claim 9 or 10 for the treatment and/or prevention of cardiovascular disorders, thromboembolic disorders, and/or oncological disorders.