DE102007057718A1 - New heteroaryl-substituted piperidine compounds are protease-activated receptor antagonists useful for the treatment and/or prophylaxis of e.g. cardiovascular diseases, thromboembolic diseases, tumors, stroke, hypertension and asthma - Google Patents

Abstract

Heteroaryl-substituted piperidine compounds (I) and their salts, solvates or solvate of the salts, are new. Heteroaryl-substituted piperidine compounds of formula (I) and their salts, solvates or solvate of the salts, are new. A : [1,2,4]oxadiazole group of formula (a), thiazole group of formula (b) or (e), [1,3,4]oxadiazole group of formula (c), isoxazole group of formula (d), [1,3,4]thiadiazole group of formula (g) or oxazole group of formula (h); aa : connection with piperidine ring; aaa : connection with R 2>; R 1>phenyl substituted with 1-3 substituents of monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, methylsulfonyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl or 3-6C-cycloalkyl (where 2-4C-alkoxy is substituted by CH 3O or C 2H 5O and the cycloalkyl is substituted by 1-3 substituents of halo or 1-4C-alkyl); R 2>4-6-membered heterocycle, phenyl, 5- or 6-membered heteroaryl (all substituted by 1-3 substituents of halo, CN, amino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, 1-4C-alkyl, 1-4C-alkoxy, 1-6C-alkylamino, 1-4C-alkoxycarbonylamino, 3-6C-cycloalkyl, 4-6 membered heterocycle, phenyl or 5-6 membered heteroaryl, where: alkyl amino is substituted by 1-4C-alkoxy or 1-6C-alkyl amino, 1-4C-alkyl is substituted by halo, OH, amino, aminocarbonyl, 1-4C-alkoxy, 1-6C-alkylamino, 1-4C-alkylthio, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylsulfonyl, 1-4C-alkoxycarbonyl, 1-4C-alkoxycarbonylamino, 3-6C-cycloalkyl, 3-6C-cycloalkylamino, 4-6-membered heterocyclyl, phenyl, phenoxy, 5- or 6-membered heteroaryl or 5- or 6-membered heteroarylthio, and the cycloalkyl, heterocycle, phenyl, phenoxy, heteroaryl or heteroarylthio is substituted by 1-3 substituents of halo, CN, hydroxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, 1-4C-alkyl, 1-4C-alkoxy, 3-6C-cycloalkyl, 4-6-membered heterocycle, phenyl or 5- or 6-membered heteroaryl); and R 3>1-6C-alkyl, 1-6C-alkoxy, 1-6C-alkylamino, 3-7C-cycloalkyl, 4-6-membered heterocycle, phenyl or 5- or 6-membered heteroaryl (where: the alkyl, 2-6C-alkoxy and alkylamino is substituted by OH, amino, CN or 1-4C-alkoxy, and the cycloalkyl, heterocycle, phenol or heteroaryl is substituted by 1-3 substituents of halo, CN, NO 2, oxo, OH, amino, aminomethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, hydroxy carbonyl, amino carbonyl, 1-4C-alkyl, 1-4C-alkoxy, 1-6C-alkyl amino, 1-4C-alkoxy carbonyl or 1-4C-alkyl aminocarbonyl), H, trifluoromethyl, aminomethyl, 1-6C-alkyl, 2-6C-alkenyl, 1-4C-alkoxycarbonyl, 3-6C-cycloalkyl, cyclopentenyl, 1,3-benzodioxolyl or pyridylaminocarbonyl. An independent claim is included for the preparations of (I). [Image] [Image] [Image] ACTIVITY : Cardiovascular-Gen.; Thrombolytic; Cytostatic; Anticoagulant; Hemostatic; Cardiant; Antianginal; Vasotropic; Cerebroprotective; Antiarrhythmic; Muscular-Gen.; Osteopathic; Hypotensive; Antiasthmatic; Nephrotropic; Neuroprotective; Nootropic; Immunosuppressive; Antiinflammatory; Gastrointestinal-Gen.; Antiulcer; Ophthalmological; Antiarthritic; Antirheumatic; Respiratory-Gen.; Antiarteriosclerotic; Antibacterial; Antipyretic; Fungicide; Virucide; Antimicrobial; Uropathic; Vulnerary. MECHANISM OF ACTION : Protease-activated receptor antagonist. The antagonistic activity of (I) was tested in recombinant cell line. The results showed that (I), preferably {3-[3-(2-methoxyethyl)-1,2,4-oxadiazol-5-yl]-5-[3-methyl-4-(trifluoromethoxy)phenyl]piperidin-1-yl}(morpholin-4-yl)methanone exhibited an IC 5 0value of 3.01 nM.

Description

The The invention relates to novel heteroaryl-substituted piperidines, processes for their preparation, their use for treatment and / or prophylaxis of diseases as well as their use for the production of medicines for the treatment and / or prophylaxis of diseases, in particular cardiovascular diseases and tumors.

platelets (Platelets) are an essential factor in both physiological hemostasis (haemostasis) as well thromboembolic disorders. Especially in the arterial system platelets comes of central importance in the complex interaction between blood components and vessel wall too. unwanted Platelet activation can be more platelet-rich Thrombi to thromboembolic disorders and thrombotic complications lead to life-threatening conditions.

One of the most potent platelet activators is the blood coagulation protease thrombin, which is formed on injured blood vessel walls and, in addition to fibrin formation, activates platelets, endothelial cells and mesenchymal cells ( Vu TKH, Hung DT, Wheaton VI, Coughlin SR, Cell 1991, 64, 1057-1068 ). In platelets in vitro and in animal models thrombin inhibitors inhibit platelet aggregation or the formation of platelet-rich thrombi. In humans, arterial thrombosis can be successfully prevented or treated with inhibitors of platelet function as well as thrombin inhibitors ( Bhatt DL, Topol EJ, Nat. Rev. Drug Discov. 2003, 2, 15-28 ). Therefore, platelet thrombin antagonists are highly likely to reduce the formation of thrombi and the onset of clinical consequences such as myocardial infarction and stroke. Further cellular thrombin effects, e.g. Vascular endothelial and smooth muscle cells, leukocytes and fibroblasts, may be responsible for inflammatory and proliferative disorders.

The cellular effects of thrombin are at least partially transmitted a family of G protein-coupled receptors (Protease Activated Receptors, PARs) whose prototype is the PAR-1 receptor. PAR-1 is produced by binding of thrombin and proteolytic cleavage activated its extracellular N-terminus. By the proteolysis becomes a new N-terminus with the amino acid sequence SFLLRN ... exposed as an agonist ("tethered ligand") for intramolecular receptor activation and intracellular transmission Signals leads. Derived from the tethered ligand sequence Peptides can be used as agonists of the receptor and lead to platelets for activation and aggregation. Other proteases are also able to activate PAR-1, hereunder z. Plasmin, factor VIIa, factor Xa, trypsin, activated Protein C (aPC), tryptase, cathepsin G, proteinase 3, granzyme A, Elastase and matrix metalloprotease 1 (MMP-1).

in the In contrast to the inhibition of the protease activity of thrombin with direct thrombin inhibitors should be a blockade of PAR-1 to inhibit platelet activation without reducing coagulability blood (anticoagulation).

Antibodies and other selective PAR-1 antagonists inhibit thrombin-induced aggregation of platelets in vitro at low to moderate thrombin concentrations ( Kahn ML, Nakanishi-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR, J. Clin. Invest. 1999, 103, 879-887 ). Another thrombin receptor of potential importance for the pathophysiology of thrombotic processes, PAR-4, has been identified on human and animal platelets. In experimental thromboses on animals with a human-like PAR expression pattern, PAR-1 antagonists reduce the formation of platelet-rich thrombi ( Derian CK, Damiano BP, Addo MF, Darrow AL, D'Andrea MR, Nedelman M, Zhang HC, Maryanoff BE, Andrade-Gordon P, J. Pharmacol. Exp. Ther. 2003, 304, 855-861 ).

In In recent years, a variety of substances have been found to inhibit their platelet function Effect tested, but in practice, only a few Platelet function inhibitor proven. It therefore exists Need for pharmaceuticals that specifically increase platelet response inhibit without significantly increasing the risk of bleeding and thus reducing the risk of thromboembolic complications.

Effects of thrombin mediated by the receptor PAR-1 have implications for disease progression during and after coronary artery bypass graft (CABG), as well as other operations, and especially extracorporeal circulation (eg, heart lung machine) operations. In the course of the operation, bleeding complications may occur due to pre- or intraoperative medication with anticoagulant and / or platelet-inhibiting substances. For this reason, for example, a medication with clopidogrel must be paused several days before a CABG. Besides, it can be like (eg due to prolonged contact between blood and artificial surfaces when using extracorporeal circulation or in blood transfusions) may lead to the development of disseminated intravascular coagulation or consumption coagulopathy (DIC), which may secondary to bleeding complications. Subsequently, restenosis of the applied venous or arterial bypasses (including occlusion) often occurs due to thrombosis, intimal fibrosis, arteriosclerosis, angina pectoris, myocardial infarction, heart failure, arrhythmias, transient ischemic attack (TIA) and / or stroke.

The receptor PAR-1 is expressed in humans on other cells, including z. Endothelial cells, vascular smooth muscle cells and tumor cells. Malignant tumors (cancer) have a high incidence and are generally associated with high mortality. Current therapies achieve full remission in only a fraction of patients and are typically associated with severe side effects. Therefore, there is a high demand for more effective and safer therapies. The PAR-1 receptor contributes to the development, growth, invasiveness and metastasis of cancer. In addition, PAR-1 expressed on endothelial cells mediates signals that result in vascular growth ("angiogenesis"), a process that is essential for facilitating tumor growth beyond about 1 mm ^3. Angiogenesis also contributes to the onset or exacerbation of other diseases, among them For example, hematopoietic cancers, blindness-related macular degeneration and diabetic retinopathy, inflammatory diseases such as rheumatoid arthritis and colitis.

sepsis (or septicemia) is a common disease with high lethality. Initial symptoms of sepsis are typically nonspecific (eg fever, reduced general condition), however, in the further course it may lead to generalized activation of the coagulation system ("Disseminated Intravascular Coagulation"). or "consumption coagulopathy" (DIC)) with microthrombosis in various organs and secondary bleeding complications. DIC may also occur independently of sepsis, e.g. As in the context of operations or tumors.

The therapy of sepsis consists on the one hand in the consequent elimination of the infectious cause, z. B. by surgical Herdsanierung and Antibinse. On the other hand, it consists in the temporary intensive medical support of the impaired organ systems. Therapies of the various stages of this disease are z. As described in the following publication ( Dellinger et al., Crit. Care Med. 2004, 32, 858-873 ). There are no proven effective therapies for DICs.

A The object of the present invention is therefore new PAR-1 antagonists for the treatment of diseases such. B. cardiovascular diseases and thromboembolic diseases, as well as tumors To provide 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 11-β HSD1 inhibitors used to treat, inter alia, diabetes, thromboembolic disorders and stroke.

in welcher
A für eine Gruppe der Formel

steht,
wobei
# die Anknüpfstelle an den Piperidinring ist,
und
* die Anknüpfstelle an R² ist,
R¹ für Phenyl steht,
wobei Phenyl substituiert sein kann mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Monofluormethyl, Difluormethyl, Trifluormethyl, Monofluormethoxy, Difluormethoxy, Trifluormethoxy, Monofluormethylsulfanyl, Difluormethylsulfanyl, Trifluormethylsulfanyl, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, C₁-C₄-Alkoxycarbonyl und C₃-C₆-Cycloalkyl,
worin C₂-C₄-Alkoxy substituiert sein kann mit einem Substituenten ausgewählt aus der Gruppe bestehend aus Methoxy und Ethoxy,
und
worin Cycloalkyl substituiert sein kann mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen und C₁-C₄-Alkyl,
R² für Wasserstoff, Aminomethyl, C₁-C₆-Alkyl, C₁-C₄-Alkoxycarbonyl, C₃-C₆-Cycloalkyl, 4- bis 6-gliedriges Heterocyclyl, Phenyl, 1,3-Benzodioxolyl oder 5- oder 6-gliedriges Heteroaryl steht,
wobei Cycloalkyl, Heterocyclyl, Phenyl und Heteroaryl substituiert sein können mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen, Cyano, Monofluormethyl, Difluormethyl, Trifluormethyl, Monofluormethoxy, Difluormethoxy, Trifluormethoxy, Monofluormethylsulfanyl, Difluormethylsulfanyl, Trifluormethylsulfanyl, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, C₁-C₆-Alkylamino, C₃-C₆-Cycloalkyl, 4- bis 6-gliedriges Heterocyclyl, Phenyl und 5- oder 6-gliedriges Heteroaryl,
worin Alkylamino substituiert sein kann mit einem Substituenten ausgewählt aus der Gruppe bestehend aus C₁-C₄-Alkoxy und C₁-C₆-Alkylamino,
und
wobei C₁-C₂-Alkyl substituiert sein kann mit einem Substituenten ausgewählt aus der Gruppe bestehend aus C₁-C₄-Alkylsulfonyl, C₁-C₄-Alkoxycarbonylamino, C₃-C₆-Cycloalkyl, 4- bis 6-gliedriges Heterocyclyl, Phenyl, Phenoxy und, 5- oder 6-gliedriges Heteroaryl,
worin Cycloalkyl, Heterocyclyl, Phenyl, Phenoxy und Heteroaryl substituiert sein können mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen, Cyano, Monofluormethyl, Difluormethyl, Trifluormethyl, Monofluormethoxy, Difluormethoxy, Trifluormethoxy, Monofluormethylsulfanyl, Difluormethylsulfanyl, Trifluormethylsulfanyl, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, C₃-C₆-Cycloalkyl, 4- bis 6-gliedriges Heterocyclyl, Phenyl und 5- oder 6-gliedriges Heteroaryl,
R³ für C₁-C₆-Alkyl, C₁-C₆-Alkoxy, C₁-C₆-Alkylamino, C₃-C₇-Cycloalkyl, 4- bis 6-gliedriges Heterocyclyl, Phenyl oder 5- oder 6-gliedriges Heteroaryl steht,
wobei Alkyl, C₂-C₆-Alkoxy und Alkylamino substituiert sein können mit einem Substituenten ausgewählt aus der Gruppe bestehend aus Hydroxy, Cyano und C₁-C₄-Alkoxy,
und
wobei Cycloalkyl, Heterocyclyl, Phenyl und Heteroaryl substituiert sein können mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen, Cyano, Nitro, Oxo, Hydroxy, Amino, Monofluormethyl, Difluormethyl, Trifluormethyl, Monofluormethoxy, Difluormethoxy, Trifluormethoxy, Monofluormethylsulfanyl, Difluormethylsulfanyl, Trifluormethylsulfanyl, Hydroxycarbonyl, Aminocarbonyl, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, C₁-C₆-Alkylamino, C₁-C₄-Alkoxycarbonyl und C₁-C₄-Alkylaminocarbonyl,
und ihre Salze, ihre Solvate und die Solvate ihrer Salze.The invention relates to compounds of the formula

in which
A is a group of the formula

stands,
in which
# is the point of attachment to the piperidine ring,
and
* is the point of attachment to R ² ,
R ^{1 is} phenyl,
wherein phenyl may be substituted with 1 to 3 substituents independently selected from the group consisting of monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, C ₁ -C ₄ -alkyl, C ₁ -C ₄ Alkoxy, C ₁ -C ₄ alkoxycarbonyl and C ₃ -C ₆ cycloalkyl,
in which C ₂ -C ₄ -alkoxy may be substituted by a substituent selected from the group consisting of methoxy and ethoxy,
and
wherein cycloalkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen and C ₁ -C ₄ -alkyl,
R ^{2 is} hydrogen, aminomethyl, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxycarbonyl, C ₃ -C ₆ cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, 1,3-benzodioxolyl or 5- or 6-membered heteroaryl is,
where cycloalkyl, heterocyclyl, phenyl and heteroaryl may be substituted by 1 to 3 substituents, independently selected from the group consisting of halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, C ₁ - C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₆ alkylamino, C ₃ -C ₆ cycloalkyl, 4- to 6-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl,
wherein alkylamino may be substituted by a substituent selected from the group consisting of C ₁ -C ₄ -alkoxy and C ₁ -C ₆ -alkylamino,
and
wherein C ₁ -C ₂ alkyl may be substituted with a substituent selected from the group consisting of C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkoxycarbonylamino, C ₃ -C ₆ cycloalkyl, 4- to 6-membered Heterocyclyl, phenyl, phenoxy and, 5- or 6-membered heteroaryl,
wherein cycloalkyl, heterocyclyl, phenyl, phenoxy and heteroaryl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, C C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₃ -C ₆ -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl,
R ^{3 is} C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylamino, C ₃ -C ₇ -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl or 5- or 6- is a membered heteroaryl,
where alkyl, C ₂ -C ₆ -alkoxy and alkylamino may be substituted by a substituent selected from the group consisting of hydroxy, cyano and C ₁ -C ₄ -alkoxy,
and
wherein cycloalkyl, heterocyclyl, phenyl and heteroaryl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, nitro, oxo, hydroxy, amino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl , Difluoromethylsulfanyl, trifluoromethylsulfanyl, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₆ -alkylamino, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₄ -alkylaminocarbonyl,
and their salts, their solvates, and the solvates of their salts.

invention Compounds are the compounds of the formula (I) and their salts, Solvates and solvates of salts; the compounds encompassed by formula (I) the following formulas and their salts, solvates and solvates the salts as well as those of formula (I), hereinafter referred to as exemplary embodiments mentioned compounds and their salts, solvates and solvates of Salts, as far as those of formula (I), hereinafter not already mentioned salts, solvates and solvates salts.

The Compounds according to the invention can depending on their structure in stereoisomeric forms (Enantiomers, diastereomers) exist. The invention therefore comprises the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers can the stereoisomerically uniform constituents in known Isolate way.

Provided the compounds of the invention in tautomers Forms may include the present invention all tautomeric forms.

When Salts are physiologically acceptable in the context of the present invention Salts of the compounds according to the invention are preferred. Also included are salts that are suitable for pharmaceutical applications themselves are not suitable but for example for the Isolation or purification of the compounds of the invention can be used.

physiological acceptable salts of the compounds of the invention include acid addition salts of mineral acids, Carboxylic acids and sulfonic acids, e.g. B. 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.

physiological acceptable salts of the compounds of the invention Also include salts of conventional bases, such as by way of example and preferably alkali metal salts (eg sodium and potassium salts), Alkaline earth salts (eg calcium and magnesium salts) and ammonium salts, derived from ammonia or organic amines having 1 to 16 C atoms, as exemplified and preferably ethylamine, diethylamine, triethylamine, Ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, Dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, Arginine, lysine, ethylenediamine, N-methylpiperidine and choline.

When Solvates are in the context of the invention, such forms of the invention Compounds referred to in solid or liquid Condition through coordination with solvent molecules to form a complex. Hydrates are a special form of solvates, where coordination takes place with water.

Furthermore For example, the present invention also encompasses prodrugs of the invention Links. The term "prodrugs" includes compounds which themselves may be biologically active or inactive, but during their residence time in the body to inventive Compounds are reacted (for example, metabolically or hydrolytically).

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
Alkyl per se and "Alk" and "alkyl" in alkoxy, alkylamino, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino and alkylsulfonyl are a linear or branched alkyl radical having 1 to 6 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, iso- Propyl, n-butyl, tert-butyl, n-pentyl and n-hexyl.

alkoxy is exemplary and preferably methoxy, ethoxy, n-propoxy, iso -propoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylamino is an alkylamino radical having one or two (independently selected) alkyl substituents, by way of example and by preference methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, N, N-dimethylamino, N, N-diethylamino, N- Ethyl N-methylamino, N-methyl-Nn-propylamino, N-iso-propyl-Nn-propylamino and N-tert-butyl-N-methylamino. C ₁ -C ₄ -alkylamino is, for example, a monoalkylamino radical having 1 to 4 carbon atoms or a dialkylamino radical having in each case 1 to 4 carbon atoms per alkyl substituent.

alkoxycarbonyl is exemplary and preferably methoxycarbonyl, Ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Alkylaminocarbonyl is an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents, by way of example and preferably methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N- Ethyl N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl-Nn-propylaminocarbonyl and N-tert-butyl-N-methylaminocarbonyl. C ₁ -C ₄ -alkylaminocarbonyl is, for example, a monoalkylaminocarbonyl radical having 1 to 4 carbon atoms or a dialkylaminocarbonyl radical having in each case 1 to 4 carbon atoms per alkyl substituent.

alkylcarbonylamino is exemplary and preferably methylcarbonylamino, Ethylcarbonylamino, n-propylcarbonylamino, iso -propylcarbonylamino, n-butylcarbonylamino and tert-butylcarbonylamino.

alkylsulfonyl is exemplary and preferably methylsulfonyl, Ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.

cycloalkyl is a monocyclic cycloalkyl group in the Rule 3 to 7, preferably 5 or 6 carbon atoms, by way of example and preferably cycloalkyl for cycloalkyl, Cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Heterocyclyl is a monocyclic, heterocyclic radical having 5 or 6 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series N, O, S, SO, SO ₂ , wherein a nitrogen atom also form an N-oxide can. The heterocyclyl radicals may be saturated or partially unsaturated. Preferred are 5- or 6-membered monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S, by way of example and preferably pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, tetrahydrofuranyl, 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-tetrahydropyridine-4 yl, thiopyranyl, morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, piperazin-1-yl, piperazin-2-yl.

heteroaryl is an aromatic, monocyclic radical with in the rule 5 or 6 ring atoms and up to 4 heteroatoms from the Row S, O and N, where a nitrogen atom also form an N-oxide may, by way of example and by preference for thienyl, Furyl, Pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, Imidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl.

halogen is fluorine, chlorine, bromine and iodine, preferably for Fluorine and chlorine.

In the formula of the group which can stand for A, the end point of the line next to which a # or a * stands does not stand for a carbon atom or a CH ₂ group but is part of the bond to the atom to which A is bound.

steht,
wobei
# die Anknüpfstelle an den Piperidinring ist,
und
* die Anknüpfstelle an R² ist,
R¹ für Phenyl steht,
wobei Phenyl substituiert ist mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Trifluormethyl, Trifluormethoxy, C₁-C₄-Alkyl und C₁-C₄-Alkoxy,
R² für Wasserstoff, Aminomethyl, C₁-C₄-Alkyl, Methoxycarbonyl, Ethoxycarbonyl, 4- bis 6-gliedriges Heterocyclyl, Phenyl, 1,3-Benzodioxolyl oder 5- oder 6-gliedriges Heteroaryl steht,
wobei Heterocyclyl, Phenyl und Heteroaryl substituiert sein können mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen, Cyano, Trifluormethyl, Trifluormethoxy, Methyl, Ethyl, Methoxy, Ethoxy, Ethylamino und 4- bis 6-gliedriges Heterocyclyl,
worin Ethylamino substituiert sein kann mit einem Substituenten ausgewählt aus der Gruppe bestehend aus Methoxy und Dimethylamino,
und
wobei Methyl substituiert sein kann mit einem Substituenten ausgewählt aus der Gruppe bestehend aus Methylsulfonyl, Ethylsulfonyl, tert-Butoxycarbonylamino, 4- bis 6-gliedriges Heterocyclyl, Phenyl, Phenoxy und 5- oder 6-gliedriges Heteroaryl,
worin Heterocyclyl, Phenyl, Phenoxy und Heteroaryl substituiert sein können mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen, Cyano, Trifluormethyl, Trifluormethoxy, Methyl, Ethyl, Methoxy und Ethoxy,
R³ für C₁-C₆-Alkyl, C₁-C₆-Alkylamino, C₃-C₇-Cycloalkyl, 4- bis 6-gliedriges Heterocyclyl, Phenyl oder 5- oder 6-gliedriges Heteroaryl steht,
wobei Alkylamino substituiert sein kann mit einem Substituenten ausgewählt aus der Gruppe bestehend aus Hydroxy, Methoxy und Ethoxy,
und
wobei Cycloalkyl, Heterocyclyl, Phenyl und Heteroaryl substituiert sein können mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen, Cyano, Oxo, Hydroxy, Amino, Trifluormethyl, Trifluormethoxy, Methyl, Ethyl, Methoxy und Ethoxy,
und ihre Salze, ihre Solvate und die Solvate ihrer Salze.Preference is given to compounds of the formula (I) in which
A is a group of the formula

stands,
in which
# is the point of attachment to the piperidine ring,
and
* is the point of attachment to R ² ,
R ^{1 is} phenyl,
where phenyl is substituted by 1 to 3 substituents independently of one another selected from the group consisting of trifluoromethyl, trifluoromethoxy, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy,
R ^{2 is} hydrogen, aminomethyl, C ₁ -C ₄ -alkyl, methoxycarbonyl, ethoxycarbonyl, 4- to 6-membered heterocyclyl, phenyl, 1,3-benzodioxolyl or 5- or 6-membered heteroaryl,
where heterocyclyl, phenyl and heteroaryl can be substituted by 1 to 3 substituents, independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, ethylamino and 4- to 6-membered heterocyclyl,
wherein ethylamino may be substituted with a substituent selected from the group consisting of methoxy and dimethylamino,
and
where methyl may be substituted by a substituent selected from the group consisting of methylsulfonyl, ethylsulfonyl, tert-butoxycarbonylamino, 4- to 6-membered heterocyclyl, phenyl, phenoxy and 5- or 6-membered heteroaryl,
wherein heterocyclyl, phenyl, phenoxy and heteroaryl may be substituted by 1 to 3 substituents independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy and ethoxy,
R ^{3 is} C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylamino, C ₃ -C ₇ -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl,
wherein alkylamino may be substituted with a substituent selected from the group consisting of hydroxy, methoxy and ethoxy,
and
wherein cycloalkyl, heterocyclyl, phenyl and heteroaryl may be substituted by 1 to 3 substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy and ethoxy,
and their salts, their solvates, and the solvates of their salts.

steht,
wobei
# die Anknüpfstelle an den Piperidinring ist,
und
* die Anknüpfstelle an R² ist,
R¹ für Phenyl steht,
wobei Phenyl substituiert ist mit einem Substituenten ausgewählt aus der Gruppe bestehend aus Trifluormethyl, Trifluormethoxy, Ethyl, Isopropyl und Methoxy,
R² für Wasserstoff, Aminomethyl, Methyl, n-Propyl, tert-Butyl, Methoxycarbonyl, Ethoxycarbonyl, Tetrahydropyridinyl, Phenyl, 1,3-Benzodioxolyl, Thiazolyl, Isoxazolyl, Pyridyl oder Pyrazinyl steht,
wobei Tetrahydropyridinyl, Phenyl, Thiazolyl, Isoxazolyl, Pyridyl und Pyrazinyl substituiert sein können mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen, Trifluormethyl, Trifluormethoxy, Methyl, Ethyl, Methoxy, Ethoxy, Ethylamino und Morpholinyl,
worin Ethylamino substituiert sein kann mit einem Substituenten ausgewählt aus der Gruppe bestehend aus Methoxy und Dimethylamino,
und
wobei Methyl substituiert sein kann mit einem Substituenten ausgewählt aus der Gruppe bestehend aus Methylsulfonyl, tert-Butoxycarbonylamino, Morpholinyl, Phenyl und Phenoxy,
worin Morpholinyl, Phenyl und Phenoxy substituiert sein können mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen, Trifluormethyl, Trifluormethoxy, Methyl, Ethyl, Methoxy und Ethoxy,
R³ für tert-Butyl, N-Methyl-N-ethylamino, Methoxyalkylamino, Cyclopentyl oder Morpholinyl steht,
und ihre Salze, ihre Solvate und die Solvate ihrer Salze.Preference is also given to compounds of the formula (I) in which
A is a group of the formula

stands,
in which
# is the point of attachment to the piperidine ring,
and
* is the point of attachment to R ² ,
R ^{1 is} phenyl,
wherein phenyl is substituted with a substituent selected from the group consisting of trifluoromethyl, trifluoromethoxy, ethyl, isopropyl and methoxy,
R ^{2 is} hydrogen, aminomethyl, methyl, n-propyl, tert-butyl, methoxycarbonyl, ethoxycarbonyl, tetrahydropyridinyl, phenyl, 1,3-benzodioxolyl, thiazolyl, isoxazolyl, pyridyl or pyrazinyl,
wherein tetrahydropyridinyl, phenyl, thiazolyl, isoxazolyl, pyridyl and pyrazinyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, ethylamino and morpholinyl,
wherein ethylamino may be substituted with a substituent selected from the group consisting of methoxy and dimethylamino,
and
wherein methyl may be substituted with a substituent selected from the group consisting of methylsulfonyl, tert-butoxycarbonylamino, morpholinyl, phenyl and phenoxy,
wherein morpholinyl, phenyl and phenoxy may be substituted by 1 to 3 substituents independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy and ethoxy,
R ^{3 is} tert-butyl, N-methyl-N-ethylamino, methoxyalkylamino, cyclopentyl or morpholinyl,
and their salts, their solvates, and the solvates of their salts.

Preference is also given to compounds of the formula (I) in which the substituents -R ¹ and -AR ^{2 are} in the cis position relative to one another.

The in the respective combinations or preferred combinations of Residues in the specified radical definitions become independent of the respective specified combinations of the radicals as desired also replaced by residue definitions of other combinations.

All Particularly preferred are combinations of two or more of above preferred ranges.

in welcher
R¹ und R³ die oben angegebene Bedeutung aufweisen,
mit Verbindungen der Formel

in welcher
R² die oben angegebene Bedeutung aufweist,
umgesetzt werden.The invention further provides a process for the preparation of the compounds of the formula (I), or their salts, their solvates or the solvates of their salts, where compounds of the formula

in which
R ¹ and R ^{3 have} the abovementioned meaning,
with compounds of the formula

in which
R ^{2 has} the meaning indicated above,
be implemented.

The Reaction is generally carried out in inert solvents, in the presence of a dehydrating reagent, optionally in Presence of a base, preferably in a temperature range of room temperature until the reflux of the solvents at normal pressure.

inert Solvents are for example halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or others Solvents such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile. It is also possible to mix to use the solvent. Preferred is dimethylformamide or a mixture of dioxane and dimethylformamide.

When Dehydrating reagents are suitable here, 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-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulphate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or bis- (2-oxo-3-oxazolidinyl) -phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or O- (benzotriazol-1-yl) -N, N, N, N'-tetra-methyluronium hexafluorophosphate (HBTU), 2- (2-oxo-1- (2H) -pyridyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) or O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyl-uronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), or N-hydroxysuccinimide, or mixtures thereof, with Bases.

bases For example, alkali metal carbonates, such as. For example, sodium or potassium carbonate, or bicarbonate, or organic bases such as trialkylamines z. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preferred is diisopropylethylamine.

Preferably the condensation with HATU in the presence of diisopropylethylamine or alternatively only with carbonyldiimidazole.

The Compounds of formula (III) are known or can be after known methods from the corresponding starting compounds synthesize.

in welcher
R¹ und R³ die oben angegebene Bedeutung aufweisen, und
R⁴ für Methyl oder Ethyl steht,
mit einer Base umgesetzt werden.The compounds of formula (II) are known or and can be prepared by reacting compounds of the formula

in which
R ¹ and R ^{3 have} the abovementioned meaning, and
R ^{4 is} methyl or ethyl,
be reacted with a base.

The Reaction is generally carried out in inert solvents, in the presence of a base, preferably in a temperature range of Room temperature until the reflux of the solvents at normal pressure.

inert Solvents are for example halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride or 1,2-dichloroethane, Ethers, such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, Dioxane or tetrahydrofuran, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine, or mixtures of solvents, or mixtures of solvents with water, preferred is a mixture of tetrahydrofuran and water.

bases For example, alkali hydroxides such as sodium, lithium or Potassium hydroxide, or alkali carbonates such as cesium carbonate, Sodium or potassium carbonate, preferably lithium hydroxide.

in welcher
R¹ und R⁴ die oben angegebene Bedeutung aufweisen,
mit Verbindungen der Formel

in welcher
R³ die oben angegebene Bedeutung aufweist,
umgesetzt werden.The compounds of the formula (IV) are known or can be prepared by reacting compounds of the formula

in which
R ¹ and R ^{4 have} the abovementioned meaning,
with compounds of the formula

in which
R ³ has the abovementioned meaning,
be implemented.

The Reaction is generally carried out in inert solvents, optionally in the presence of a base, preferably in a temperature range from -30 ° C to 50 ° C at atmospheric pressure.

inert Solvents are, for example, tetrahydrofuran, methylene chloride, Pyridine, dioxane or dimethylformamide, preferred is methylene chloride.

bases are, for example, triethylamine, diisopropylethylamine or N-methylmorpholine, preferred is triethylamine or diisopropylethylamine.

The Compounds of formula (VI) are known or can be after known methods from the corresponding starting compounds synthesize.

in welcher
R¹ und R⁴ die oben angegebene Bedeutung aufweisen,
hydriert werden.The compounds of formula (V) are known or and can be prepared by reacting compounds of the formula

in which
R ¹ and R ^{4 have} the abovementioned meaning,
be hydrogenated.

The Hydrogenation generally takes place with a reducing agent in inert solvents, optionally with the addition of Acid such as mineral acids and carboxylic acids, preferably acetic acid, preferably in a temperature range from room temperature to the reflux of the solvents and in a pressure range from atmospheric pressure to 100 bar, preferably at 50-80 bar.

When Reducing agent is preferably hydrogen with palladium on activated carbon, with rhodium on activated charcoal, with ruthenium on charcoal or from it mixed catalysts, or hydrogen with palladium on alumina or with rhodium on alumina, hydrogen is preferred 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, preferably methanol or ethanol.

in welcher
R⁴ die oben angegebene Bedeutung aufweist,
mit Verbindungen der Formel

in welcher
R¹ die oben angegebene Bedeutung aufweist,
umgesetzt werden.The compounds of the formula (VII) are known or can be prepared by reacting compounds of the formula

in which
R ^{4 has} the abovementioned meaning,
with compounds of the formula

in which
R ^{1 has} the meaning indicated above,
be implemented.

The Reaction is generally carried out in inert solvents, in the presence of a catalyst, optionally in the presence of a Zusatzreagenzes, preferably in a temperature range of room temperature until the reflux of the solvent at normal pressure.

inert Solvents are, for example, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons such as benzene, xylene or Toluene, or other solvents such as nitrobenzene, dimethylformamide, Dimethylacetamide, dimethyl sulfoxide or N-methylpyrrolidone, optionally a little water is added to these solvents. Prefers is toluene with water or a mixture of 1,2-dimethoxyethane, Dimethylformamide and water.

catalysts are common for example for Suzuki reaction conditions Palladium catalysts, preferably catalysts such. B. Dichlorobis (triphenylphosphine) palladium, tetrakistriphenylphosphine palladium (0), Palladium (II) acetate or bis (diphenylphosphanferrocenyl) palladium (II) chloride.

additional reagents For example, potassium acetate, cesium, potassium or Sodium carbonate, barium hydroxide, potassium tert-butoxide, cesium fluoride, Potassium fluoride or potassium phosphate, preferably potassium fluoride or Sodium.

The Compounds of formulas (VIII) and (IX) are known or are allowed according to known methods from the corresponding starting compounds synthesize.

The preparation of the compounds of the formula (I) can be illustrated by the following synthesis scheme. Scheme 1:

The Compounds of the invention do not show a predictable, valuable pharmacological and pharmacokinetic Spectrum. These are selective antagonists of the PAR-1 receptor, in particular as platelet aggregation inhibitors, as inhibitors Endothelial proliferation and act as an inhibitor of tumor growth.

she are therefore suitable for use as a medicament for treatment and / or prophylaxis of diseases in humans and animals.

Another The present invention is the use of the invention Compounds for the treatment and / or prophylaxis of diseases, preferably of thromboembolic disorders and / or thromboembolic Complications.

To the "thromboembolic diseases" within the meaning of the present Invention include in particular diseases such as myocardial infarction with ST segment increase (STEMI) and without ST segment increase (non-STEMI), stable angina pectoris, unstable angina pectoris, reocclusions and restenosis following coronary interventions such as angioplasty, stenting or aortocoronary bypass, peripheral arterial disease, Pulmonary embolism, deep venous thrombosis and renal venous thrombosis, Transient ischemic attacks as well as thrombotic and thromboembolic stroke.

The Substances are therefore also suitable for prevention and treatment cardiogenic thromboembolism, such as brain ischemia, Stroke and systemic thromboembolism and ischemia, in patients with acute, intermittent or persistent Cardiac arrhythmias, such as atrial fibrillation, and such who undergo cardioversion, and in patients with Heart valve diseases or with intravascular bodies, such as As artificial heart valves, catheters, intra-aorta Balloon counterpulsation and pacemaker probes.

thromboembolic Complications also occur in microangiopathic hemolytic Anemias, extracorporeal blood circuits, such as z. Hemodialysis, hemofiltration, ventricular assist devices and artificial heart, as well as heart valve prostheses.

Furthermore the compounds according to the invention also come for influencing wound healing, for prophylaxis and / or Treatment of atherosclerotic vascular disease and inflammatory diseases such as rheumatic diseases musculoskeletal system, coronary heart disease, heart failure, of hypertension, inflammatory diseases, such as z. Asthma, inflammatory lung disease, glomerulonephritis and inflammatory bowel diseases, about it addition, as well for the prophylaxis and / or treatment of Alzheimer's disease.

In addition, the compounds of the invention for inhibiting tumor growth and metastasis, in microangiopathies, age-related macular degeneration, diabetic retinopathy, diabetic nephropathy and other microvascular diseases and for the prevention and treatment of thromboembolic complications such as venous thromboembolism in tumor patients, ins especially those undergoing major surgery or chemo- or radiotherapy.

Farther the compounds according to the invention are suitable for the treatment of cancer. Cancers include carcinomas (including breast cancer, hepatocellular carcinomas, liver cancer, colorectal cancer, colon cancer and melanoma), Lymphomas (eg non-Hodgkin's lymphomas and mycosis fungoides), leukemias, Sarcomas, mesotheliomas, brain cancers (eg gliomas), germinomas (eg. Testicular cancer and ovarian cancer), choriocarcinomas, kidney cancer, pancreatic cancer, Thyroid cancer, head and neck cancer, endometrial cancer, Cervical cancer, bladder cancer, stomach cancer and multiple myeloma.

In addition, PAR-1 expressed on endothelial cells mediates signals that lead to vascular growth ("angiogenesis"), a process that is essential for facilitating tumor growth beyond about 1 mm ^3. Induction of angiogenesis is also relevant in other diseases, including diseases of the rheumatic type (eg rheumatoid arthritis), pulmonary diseases (eg pulmonary fibrosis, pulmonary arterial hypertension, diseases characterized by pulmonary vascular occlusions), arteriosclerosis, plaque rupture, diabetic retinopathy and wet macular degeneration.

About that In addition, the compounds of the invention suitable for the treatment of sepsis. Sepsis (or septicemia) is a common high mortality disease. Initial symptoms of sepsis are typically nonspecific (eg fever, reduced general condition), later on However, it may cause generalized activation of the coagulation system ("Disseminated Intravascular Coagulation", or "Consumption Coagulopathy", hereinafter referred to as "DIC") with microthrombosis in various Organs and secondary bleeding complications. Furthermore It may cause endothelial damage with elevation vascular permeability and leakage of Liquid and proteins come into the extravasal space. In the further course it can lead to the dysfunction or the failure of a Organs (eg kidney failure, liver failure, respiratory failure, central nervous Deficits and cardiovascular failure) to the multi-organ failure come. This can in principle affect any organ, on most common is organdy dysfunction and failure in the Lung, kidney, cardiovascular system, coagulation system, the central nervous system, endocrine glands and the liver. Sepsis can be associated with an Acute Respiratory Distress Syndrome "(hereafter referred to as ARDS). An ARDS can also occur independently of sepsis. "Septic shock" refers to the occurrence of a treatment subject Lowering blood pressure, which causes further organ damage favored and accompanied by a deterioration in prognosis.

pathogen can bacteria (gram-negative and gram-positive), fungi, Viruses and / or eukaryotes. Entrance gate or primary infection can z. As pneumonia, urinary tract infection, peritonitis. The infection may, but not necessarily, with a Associated with bacteremia.

Sepsis is defined as the presence of an infection and a systemic inflammatory response syndrome (hereafter referred to as "SIRS"). SIRS occurs in the context of infections, but also other conditions such as injuries, burns, shock, surgery, ischemia, pancreatitis, resuscitation or tumors. As defined by the ACCP / SCCM Consensus Conference Committee of 1992 ( Crit. Care Med. 1992, 20, 864-874 ) describes the symptoms required for the diagnosis "SIRS" for diagnosis and measurement parameters (eg altered body temperature, increased heart rate, breathing difficulties and altered blood count). The criteria were essentially retained in the later (2001) SCCM / ESICM / ACCP / ATS / SIS International Sepsis Definition Conference, but refined in details ( Levy et al., Crit. Care Med. 2003, 31, 1250-1256 ).

DIC and SIRS may be due to sepsis, but also as a result surgery, cancer, burns or other injuries occur. At the DIC it comes to the surface of damaged Endothelial cells, foreign body surfaces or injured extravascular tissue for massive activation of the coagulation system. As a result, coagulation occurs in small vessels various organs with hypoxia and subsequent organ dysfunction. Secondarily, coagulation factors are consumed (eg factor X, prothrombin, fibrinogen) and platelets, which reduces the coagulation ability of the blood will and severe bleeding can occur.

The compounds of the invention can also be used ex vivo to prevent coagulation, z. For example, for the preservation of blood and plasma products, for cleaning / pretreatment of catheters and other medical devices and equipment, including extracorporeal circuits, for coating artificial surfaces of in vivo or ex vivo used medical Aids and equipment or biological samples containing platelets.

Another The present invention is the use of the invention Compounds for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another The present invention is the use of the invention Compounds for the manufacture of a medicament for treatment and / or prophylaxis of diseases, in particular those mentioned above Diseases.

Another The subject of the present invention is a method of treatment and / or prophylaxis of diseases, in particular those mentioned above Diseases using a therapeutically effective amount a compound of the invention.

Another object of the present invention are pharmaceutical compositions containing a compound of the invention and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases. As suitable combination active ingredients may be mentioned by way of example and preferably:
Calcium channel blockers, e.g. As amlodipine besilate (e.g., Norvasc ^®.), Felodipine, diltiazem, verapamil, nifedipine, nicardipine, nisoldipine, and bepridil;
Iomerizin;
Statins, z. Atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin;
Cholesterol absorption inhibitors, e.g. Ezetimibe and AZD4121;
Cholesteryl Ester Transfer Protein ("CETP") inhibitors, e.g. B. torcetrapib;
Low Molecular Heparins, e.g. Dalteparin Sodium, Ardeparin, Certoparin, Enoxaparin, Parnaparin, Tinzaparin, Reviparin and Nadroparin;
Other anticoagulants, eg. Warfarin, marcumar, fondaparinux;
Antiarrhythmics, e.g. B. Dofetilide, Ibutilide, Metoprolol, Metoprolol tartrate, Propranolol, Atenolol, Ajmaline, Disopyramide, Prajmaline, Procainamide, Quinidine, Sparteine, Aprindine, Lidocaine, Mexiletine, Tocamide, Encamid, Flecamide, Lorcamide, Moricin, Propafenone, Acebutolol, Pindolol, Amiodarone, Bretylium tosylate, Bunaftin, sotalol, adenosine, atropine and digoxin;
Alpha-adrenergic agonists, e.g. Doxazosin mesylate, terazosone and prazosin;
Beta-adrenergic blockers, e.g. Carvedilol, propranolol, timolol, nadolol, atenolol, metoprolol, bisoprolol, nebivolol, betaxolol, acebutolol and bisoprolol;
Aldosterone antagonists, e.g. Eplerenone and spironolactone;
Angiotensin converting enzyme inhibitors ("ACE inhibitors"), e.g. Moexipril, quinapril hydrochloride, ramipril, lisinopril, benazepril hydrochloride, enalapril, captopril, spirapril, perindopril, fosinopril and trandolapril;
Angiotensin II receptor blockers ("ARBs"), e.g. Olmesartan-medoxomil, candesartan, valsartan, telmisartan, irbesartan, losartan and eprosartan;
Endothelin antagonists, e.g. Tezosentan, bosentan and sitaxsentan sodium;
Neutral endopeptidase inhibitors, e.g. Candoxatril and ecadotril;
Phosphodiesterase inhibitors, e.g. Milrinoone, theophylline, vinpocetine, EHNA (erythro-9- (2-hydroxy-3-nonyl) adenine), sildenafil, vardenafil and tadalafil;
Fibrinolytics, e.g. Reteplase, alteplase and tenecteplase;
GP IIb / IIIa antagonists, e.g. Integrillin, abciximab and tirofiban;
Direct Thrombininhibitoren, z. AZD0837, argatroban and bivalirudin;
Indirect Thrombin Inhibitors, e.g. Eg Odiparcil;
Direct and indirect factor Xa inhibitors, e.g. Fondaparinux sodium, apixaban, razaxaban, rivaroxaban (BAY 59-7939), KFA-1982, DX-9065a, AVE3247, otamixaban (XRP0673), AVE6324, SAR377142, idraparinux, SSR126517, DB-772d, DT-831j, YM -150, 813893, LY517717 and DU-1766 .;
Direct and indirect factor Xa / IIa inhibitors, e.g. Enoxaparin sodium, AVE5026, SSR128428, SSR128429 and BIBI-986 (Tanogitran);
Lipoprotein-associated phospholipase A2 ("LpPLA2") modulators;
Diuretics, eg. Chlorthalidone, ethacrynic acid, furosemide, amiloride, chlorothiazide, hydrochlorothiazide, methylchtothiazide and benzothiazide;
Nitrates, e.g. B. isosorbide-5-mononitrate;
Thromboxane antagonists, e.g. Seratrodast, picotamide and ramatroban;
Platelet aggregation inhibitors, e.g. Clopidogrel, tiklopidine, cilostazol, aspirin, abciximab, limaprost, eptifibatide and CT-50547;
Cyclooxygenase inhibitors, e.g. Meloxicam, rofecoxib and celecoxib;
B-type Natriuretic Peptides, e.g. Nesiritide and Ularitide;
NV1FGF modulators, e.g. Eg XRP0038;
HT1B / 5-HT2A antagonists, e.g. SL65.0472;
Guanylate cyclase activators, e.g. Ataciguat (HMR1766) and HMR1069;
e-NOS transcription enhancers, e.g. AVE9488 and AVE3085;
Anti-atherogenic substances, eg. B. AGI-1067:
CPU inhibitors, e.g. Eg AZD9684;
Renin inhibitors, e.g. Aliskirin and VNP489;
Inhibitors of adenosine diphosphate-induced platelet aggregation, e.g. Clopidogrel, tiklopidine, prasugrel and AZD6140;
NHE-1 inhibitors, e.g. Eg AVE4454 and AVE4890.

antibiotic Therapy: Various antibiotics or antifungal drug combinations come in question, either as a calculated therapy (before the presence of the microbial Findings) or as a specific therapy; Fluid therapy, z. Crystalloids or colloidal liquids; vasopressors, z. Norepinephrines, dopamine or vasopressin; Inntrope Therapy, z. Eg dobutamine; Corticosteroids, e.g. Hydrocortisone, or fludrocortisone; recombinant human activated protein C, Xigris; Blood products, z. B. erythrocyte concentrates, platelet concentrates, erythropin or Fresh Frozen Plasma; Mechanical ventilation in sepsis-induced Acute Lung Injury (ALI) or Acute Respiratory Distress Syndrome (ARDS), e.g. B. Permissive hypercapnia, lower tidal volumes; Sedation: z. As diazepam, lorazepam, midazolam or propofol. opioids: z. Fentanyl, hydromorphone, morphine, meperidine or remifentanil. NSAIDs: z. As ketorolac, ibuprofen or acetaminophen. Neuromuscular Blockade: z. Pancuronium; Glucose control, e.g. Insulin, glucose; Renal replacement procedure, z. B. Continuous veno-venous hemofiltration or intermittent hemodialysis. Dopamine low-dose for renal protection; Anticoagulants, e.g. B. for thrombosis prophylaxis or in kidney replacement procedures, eg. B. unfractionated heparins, low molecular weight heparins, heparinoids, hirudin, bivalirudin or argatroban; Bicarbonate treatment; Stress ulcer prophylaxis, e.g. B. H2 receptor inhibitors, antacids

Drugs in proliferative diseases: uracil, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine , Fludarabine phosphate, pentostatines, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, paclitaxel, mithramycin, deoxycoformycin, mitomycin C, L-asparaginase, interferons, etoposide, teniposide 17.alpha. Ethinyl estradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Tamoxifen, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estranrustine, Medroxyprogesterone acetate, Leuprolide, Flutamide, Toremifene, Goserelin, Cisplatin, Carboplatin, Hydroxyurea, Ams acrine, procarbazine, mitotane, mitoxantrone, levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Oxaliplatin (Eloxatin ^®), Iressa (gefmitib, ZD1839), XELODA ^® (capecitabine), Tarceva ^® (erlotinib), Azacitidine (5-azacytidine; 5-AzaC), Temozolomide (Temodar ^®), gemcitabine (eg, GEMZAR ^® (gemcitabine HCl)), vasostatin, or a combination of two or more of the above.

Another The present invention is a method for preventing the blood coagulation in vitro, especially in blood or biological samples containing platelets by it characterized in that an anticoagulatory effective amount the compound of the invention is added.

The Compounds according to the invention can act systemically and / or locally. For this purpose can they are applied in a suitable manner, such as. Oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

For These routes of administration can be the inventive Compounds are administered in suitable administration forms.

For oral administration are according to the prior art functioning rapidly and / or modified compounds of the invention donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as. As tablets (uncoated or coated tablets, for example, with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound of the invention ren), in the oral cavity rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example, hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

The Parenteral administration can bypass a resorption step happen (eg intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with involvement of absorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Suitable for parenteral administration themselves as application forms u. a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

Prefers is the oral application.

For the other routes of administration are suitable for. B. Inhalation medicines (including powder inhalers, nebulizers), nasal drops, solutions, sprays; lingual, sublingual or buccal tablets to be administered, Films / wafers or capsules, suppositories, ear or eye preparations, Vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic Systems (such as patches), milk, pastes, foams, Scattering powders, implants or stents.

The Compounds according to the invention can converted into the mentioned application forms become. This can be done in a conventional manner by mixing with inert, Non-toxic, pharmaceutically suitable excipients happen. These adjuvants include u. a. excipients (for example, microcrystalline cellulose, lactose, mannitol), Solvents (eg liquid polyethylene glycols), Emulsifiers and dispersing or wetting agents (for example sodium dodecylsulphate, Polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), Stabilizers (eg antioxidants such as ascorbic acid), Dyes (eg inorganic pigments such as iron oxides) and flavor and / or scent remedies.

Another The present invention relates to medicaments which are at least a compound of the invention, preferably together with one or more inert non-toxic, pharmaceutically suitable adjuvant, as well as their use to the previously mentioned purposes.

in the In general, it has proven to be beneficial in parenteral Application amounts of about 5 to 250 mg per 24 hours to achieve to deliver effective results. For oral administration is the Amount about 5 to 100 mg per 24 hours.

Nevertheless it may be necessary, if necessary, of the quantities mentioned to deviate, depending on body weight, Application route, individual behavior towards the Active substance, method of preparation and time or interval, too which the application takes place.

The Percentages in the following tests and examples are provided not stated otherwise, weight percentages; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions each refer to the volume. The indication "w / v" means "weight / volume" (Weight / volume). For example, "10% w / v" means 100 ml Solution or suspension contains 10 g of substance.

A) Examples

Abbreviations:

• approximately

  circa

  CDI

  carbonyldiimidazole

  d

  Day (s), doublet (at NMR)

  DC

  Thin Layer Chromatography

  DCI

  direct chemical Ionization (in MS)

  dd

  Double doublet (at NMR)

  DMAP

  , 4-dimethylaminopyridine

  DMF

  N, N-dimethylformamide

  DMSO

  dimethyl sulfoxide

  d. Th.

  the theory (at yield)

  eq.

  Equivalent (s)

  IT I

  Electrospray ionization (in MS)

  H

  Hour (s)

  HATU

  O- (7-azabenzotriazol-1-yl) -N, N, N, N'-tetramethyluronium hexafluorophosphate

  HPLC

  High pressure, high performance liquid chromatography

  LC-MS

  Liquid chromatography-coupled mass spectroscopy

  LDA

  lithium

  m

  Multiplet (by NMR)

  min

  Minute (s)

  MS

  mass spectroscopy

  NMR

  Nuclear Magnetic Resonance Spectroscopy

  RP

  reverse phase (at HPLC)

  RT

  room temperature

  R _t

  Retention time (at HPLC)

  s

  Singlet (by NMR)

  THF

  tetrahydrofuran

HPLC methods

• Method 1A: Instrument: HP 1100 with DAD Detection; Column: Kromasil 100 RP-18, 60 mm × 2.1 mm, 3.5 m; Eluent A: 5 ml perchloric acid (70%) / l water, eluent 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: 0.75 ml / min; Column temperature: 30 ° C; UV detection: 210 nm.
• Method 2A: Instrument: HP 1100 with DAD Detection; Pillar: Kromasil 100 RP-18, 60 mm × 2.1 mm, 3.5 μm; eluent A: 5 ml perchloric acid (70%) / l water, eluent 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: 0.75 ml / min; Column temperature: 30 ° C; UV detection: 210 nm.
• Method 3A: Instrument: HP 1100 with DAD Detection; Pillar: Kromasil 100 RP-18, 60 mm × 2.1 mm, 3.5 μm; eluent A: 5 ml perchloric acid (70%) / l water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 15 minutes 90% B → 15.2 minutes 2% B → 16 min 2% B; Flow: 0.75 ml / min; Column temperature: 30 ° C; UV detection: 210 nm.
• Method 4A: Phase: Kromasil 100, C18, 5 μm, 250 mm × 4 mm; Eluent: water / acetonitrile 50:50; Flow: 1 ml / min; T: 40 ° C; UV: 210 nm.

LC-MS methods:

• Method 1B: Device Type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Pillar: Phenomenex Gemini 3 μ, 30 mm × 3.0 mm; eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 1 acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.
• Method 2B: Instrument: Micromass QuattroPremier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 μ, 50 mm × 1 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, Eluent B: 1 liter acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A → 0.1 min 90% A → 1.5 min 10% A → 2.2 min 10% A; Oven: 50 ° C; Flow: 0.33 ml / min; UV detection: 210 nm.
• Method 3B: Device Type MS: Micromass ZQ; device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2.5 μ MAX-RP 100A Mercury, 20mm x 4mm; Eluent A: 1 liter of water + 0.5 ml of 50% formic acid, eluent B: 1 liter of acetonitrile + 0.5 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: 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.
• Method 4B: Device Type MS: Waters ZQ; device type HPLC: Waters Alliance 2795; Column: Phenomenex Onyx Monolithic C18, 100 mm × 3 mm; Eluent A: 1 l of water + 0.5 ml of 50% Formic acid, eluent B: 1 liter acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A → 2 min 65% A → 4.5 min 5% A → 6 min 5% A; Flow: 2 ml / min; Oven: 40 ° C; UV detection: 210 nm.
• Method 5B: Instrument: Micromass Quattro Micro MS with HPLC Agilent 1100 series; Column: Thermo Hypersil GOLD 3 μ 20 mm × 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, Eluent B: 1 liter acetonitrile + 0.5 ml 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; Oven: 50 ° C; Flow: 2 ml / min; UV detection: 210 nm.
• Method 6B: Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2.5 μ MAX-RP 100A Mercury 20 mm × 4 mm; Eluent A: 1 liter of water + 0.5 ml 50% formic acid, eluent B: 1 liter acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A → 0.1 min 90% A → 3.0 min 5% A → 4.0 min 5% A → 4.1 min 90% A; Flow: 2 ml / min; Oven: 50 ° C; UV detection: 208-400 nm.
• Method 7B: Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Onyx Mo nolithic C18, 100 mm × 3 mm. Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l 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: 2 ml / min; Oven: 40 ° C; UV detection: 208-400 nm.
• Method 8B: Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Thermo HyPURITY Aquastar 3 μ 50 mm × 2.1 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, Eluent B: 1 liter acetonitrile + 0.5 ml 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; Oven: 50 ° C; Flow: 0.8 ml / min; UV detection: 210 nm.

Preparative diastereomer separation:

• Method 1C: Phase: Kromasil 100 C18, 5 μm 250 mm × 20 mm, eluent: 0.2% aqueous trifluoroacetic acid / acetonitrile 47:53; Flow: 25 ml / min, temperature: 23 ° C; UV detection: 210 nm.
• Method 2C: Phase: Xbrdge C18, 5 μm OBD 19 mm × 150 mm, eluent: acetonitrile / 0.2% trifluoroacetic acid 50:50; Flow: 25 ml / min, temperature: RT; UV detection: 210 nm.
• Method 3C: Phase: Kromasil 100 C18, 5 μm 250 mm × 20 mm, eluent: acetonitrile / 0.2% trifluoroacetic acid 50:50; Flow: 25 ml / min, temperature: RT; UV detection: 210 nm.
• Method 4C: Phase: Kromasil 100 C18, 5 μm 250 mm × 20 mm, eluent: acetonitrile / 0.2% trifluoroacetic acid 57:43; Flow: 25 ml / min, temperature: RT; UV detection: 210 nm.
• Method 5C: Phase: Kromasil 100 C 18, 5 μm 250 mm × 20 mm, eluent: water: acetonitrile 25:75; Flow: 25 ml / min, temperature: 35 ° C; UV detection: 220 nm.
• Method 6C: Phase: Kromasil 100 C18, 5 μm 250 mm × 20 mm, eluent: acetonitrile / water 35:65; Flow: 25 ml / min, temperature: 30 ° C; UV detection: 210 nm.
• Method 7C: Phase: Sunfire C18, 5 μm 150 mm × 19 mm, eluent: water / acetonitrile 50:50; Flow: 25 ml / min, temperature: 24 ° C; UV: 225 nm.
• Method 8C: Phase: Kromasil 100 C18, 5 μm 250 mm × 20 mm, eluent: water / acetonitrile 50:50; Flow: 25 ml / min, temperature: 40 ° C; UV detection: 210 nm.
• Method 9C: Phase: Kromasil 100 C18, 5 μm 250 mm × 20 mm, eluent: water / acetonitrile 35:65; Flow: 25 ml / min, temperature: 30 ° C; UV detection: 210 nm.
• Method 10C: Phase: Sunfire C18, 5 μm 150 mm × 30 mm, eluent: water / acetonitrile 50:50; Flow: 56 ml / min, T: 30 ° C; UV detection: 210 nm.

Preparative enantiomer separation:

• Method 1D: Phase: Daicel Chiralcel OD-H, 5 μm 250 mm × 20 mm, eluent: isopropanol / iso-hexane 40:60; River: 15 ml / min, temperature: 24 ° C; UV detection: 230 nm.
• Method 2D: Phase: Daicel Chiralpak AD-H, 5 μm 250 mm × 20 mm; Eluent: isopropanol / iso-hexane 20:80; River: 20 ml / min; Temperature: 25 ° C; UV detection: 260 nm.
• Method 3D: Phase: Daicel Chiralcel OD-H, 5 μm 250 mm × 20 mm, eluent: ethanol / iso-hexane 30:70; River: 15 ml / min, temperature: 25 ° C; UV detection: 230 nm.
• Method 4D: Phase: Daicel Chiralcel OD-H, 5 μm 250 mm × 20 mm, eluent: isopropanol / iso-hexane 40:60; River: 18 ml / min, temperature: 25 ° C; UV detection: 230 nm.
• Method 5D: Phase: Daicel Chiralpak AD-H, 5 μm 250 mm × 20 mm; Eluent: isopropanol / iso-hexane 50:50; River: 20 ml / min; Temperature: 24 ° C; UV detection: 260 nm.

Analytical separation of enantiomers:

• Method 1E: Phase: Daicel Chiralcel OD-H, 5 μm 250 mm × 4.6 mm, eluent: isopropanol / iso-hexane 50:50; River: 1 ml / min, temperature: 40 ° C; UV detection: 220 nm.
• Method 2E: Phase: Daicel Chiralpak AD-H, 5 μm 250 mm × 4 mm; Eluent: isopropanol / iso-hexane: 20:80; River: 1 ml / min; Temperature: 24 ° C; UV detection: 230 nm.
• Method 3E: Phase: Daicel Chiralcel OD-H, 5 μm 250 mm × 4 mm, eluent: ethanol / iso-hexane 30:70; Flow: 1 ml / min, Temperature: 24 ° C; UV detection: 230 nm.
• Method 4E: Phase: Daicel Chiralpak AD-H, 5 μm 250 mm × 4 mm; Eluent: isopropanol / iso-hexane: 50:50; River: 1 ml / min; Temperature: 24 ° C; UV detection: 230 nm.
• Method 5E: Phase: Daicel Chiralpak AD-H, 5 μm 250 mm × 4 mm; Eluent: isopropanol / iso-hexane: 50:50; River: 1 ml / min; Temperature: 24 ° C; UV detection: 230 nm.

starting compounds

General Method 1A: Suzuki coupling

A Mixture of the corresponding bromopyridine in toluene (1.8 ml / mmol) under argon at RT with tetrakis (triphenylphosphine) palladium (0.02 eq.), With a solution of the corresponding arylboronic acid (1.2 eq.) In ethanol (0.5 ml / mmol) and with a solution from potassium fluoride (2.0 eq.) in water (0.2 ml / mmol). The Reaction mixture will last for several hours until substantially complete Reaction stirred under reflux. To Addition of ethyl acetate and phase separation becomes the organic phase once with water and once with saturated, watery Washed with sodium chloride solution, dried (magnesium sulfate), filtered and concentrated in vacuo. The crude product is purified by flash chromatography (Silica gel 60, eluent: dichloromethane-methanol mixtures).

General Method 2A: Hydrogenation of the pyridine

A Solution of pyridine in ethanol (9 ml / mmol) is treated with palladium on activated charcoal (moistened with approx. 50% water, 0.3 g / mmol) and at 60 ° C overnight in a 50 bar hydrogen atmosphere hydrogenated. Subsequently, the catalyst is over filtered off a filter layer and washed several times with ethanol. The combined filtrates are concentrated in vacuo.

General Method 3A: Reaction with carbamoyl chlorides or carbonyl chlorides

A Solution of the piperidine in dichloromethane (2.5 ml / mmol) under argon at 0 ° C dropwise with N, N-diisopropylethylamine (1.2 eq.) And the corresponding carbamoyl chloride or carbonyl chloride (1.2 eq.). The reaction mixture is stirred at RT. After addition of water and phase separation, the organic phase three times with water and once with saturated, aqueous Washed with sodium chloride solution, dried (sodium sulfate), filtered and concentrated in vacuo.

General Method 4A: saponification

A Solution of the corresponding ester in a mixture of tetrahydrofuran / water (3: 1, 12.5 ml / mmol) is added at RT with lithium hydroxide (2 eq.). The reaction mixture is stirred at 60 ° C and then with aqueous, 1 N hydrochloric acid solution pH 1 provided. After addition of water / ethyl acetate, the aqueous Phase extracted three times with ethyl acetate. The united, organic Phases are dried (sodium sulfate), filtered and in vacuo concentrated.

Example 1A

5- (4-ethylphenyl) pyridin-3-carbonsäuremethylester

According to General Method 1A, 32 g (148 mmol) of methyl 5-bromonicotinate and 27 g (178 mmol, 1.2 eq.) Of 4-ethylphenylboronic acid are reacted. Yield: 24 g (64% of theory)
LC-MS (Method 3B): R _t = 2.03 min; MS (ESIpos): m / z = 242 [M + H] ⁺ .

Example 2A

Methyl 5- (4-ethylphenyl) piperidine-3-carboxylate [racemic cis / trans isomer mixture]

According to General Method 2A, 24 g (94 mmol) of methyl 5- (4-ethylphenyl) pyridine-3-carboxylate are hydrogenated. Yield: 20 g (77% of theory)
LC-MS (Method 5B): R _t = 1.43 min; MS (ESIpos): m / z = 248 [M + H] ⁺ .

Example 3A

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

According to General Method 1A, 29 g (126 mmol) of ethyl 5-bromonicotinate and 23 g (152 mmol, 1.2 eq.) Of 4-ethylphenylboronic acid are reacted. Yield: 32 g (82% of theory)
LC-MS (Method 4B): R _t = 3.80 min; MS (ESIpos): m / z = 256 [M + H] ⁺ .

Example 4A

Ethyl 5- (4-ethylphenyl) piperidine-3-carboxylate [racemic cis / trans isomer mixture]

According to General Method 2A, 24 g (71 mmol) of ethyl 5- (4-ethylphenyl) pyridine-3-carboxylate are hydrogenated. Yield: 15 g (81% of theory)
LC-MS (Method 5B): R _t = 1.78 min and 1.91 min (cis / trans isomers); MS (ESIpos): m / z = 262 [M + H] ⁺ .

Example 5A

Ethyl 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine-3-carboxylate [racemic cis / trans isomer mixture]

According to General Method 3A, 5.2 g (14.0 mmol) of ethyl 5- (4-ethylphenyl) piperidine-3-carboxylate are reacted with 2.1 g (2.1 mmol, 1.2 eq.) Of cyclopentanecarbonyl chloride. Yield: 4.8 g (96% of theory)
LC-MS (Method 4B): R _t = 4.04 min and 4.14 min (cis / trans isomers); MS (ESIpos): m / z = 358 [M + H] ⁺ .

Example 6A

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

According to General Method 4A, 13.8 g (38.6 mmol) of ethyl 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine-3-carboxylate are saponified. Yield: 11.5 g (87% of theory)
LC-MS (Method 1B): R _t = 2.50 min and 2.57 min (cis / trans isomers); MS (ESIpos): m / z = 330 [M + H] ⁺ .

diastereomers of 11.5 g of the cis / trans isomer mixture according to Method 1C 4.1 g of the title compound 7A (cis isomer) and 4.1 g of the trans isomer.

Example 7A

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

• LC-MS (Method 1B): R _t = 2.57 min; MS (ESIpos): m / z = 330 [M + H] ⁺ .

Example 8A

5- [4- (1-methylethyl) phenyl] pyridine-3-carboxylate

4.68 g (20.32 mmol) of ethyl 5-bromonicotinate, 5.00 g (30.49 mmol) of 4- (1-methylethyl) phenylboronic acid, 0.12 g (0.10 mmol) of tetrakis (triphenylphosphine) palladium (0) and 4.31 g (40.65 mmol) of sodium carbonate are dissolved in a Dissolved mixture of 37 ml of 1,2-dimethoxyethane, 10.5 ml of water and 84 ml of dimethylformamide and stirred at 85 ° C for 18 h. For workup, a portion of the dimethylformamide is removed in vacuo, the reaction mixture diluted with water and extracted with dichloromethane. The organic phase is dried over sodium sulfate and the crude product purified by preparative HPLC. Yield: 2.42 g (44% of theory)
LC-MS (Method 6B): R _t = 2.56 min; MS (ESIpos): m / z = 270 [M + H] ⁺ .

Example 9A

Ethyl 5- [4- (1-methylethyl) phenyl] piperidine-3-carboxylate [racemic cis / trans isomer mixture]

2.4 g (8.9 mmol) of ethyl 5- [4- (1-methylethyl) phenyl] pyridine-3-carboxylate are dissolved in 60 ml of ethanol, admixed with 1.33 g of Pd / C (10% strength) and in an autoclave at 60.degree hydrogenated at a hydrogen pressure of 50 bar overnight. The reaction mixture is filtered through silica gel. The resulting solution is concentrated in vacuo. The residue is treated with water, the solution is adjusted to pH 8 with aqueous 1 N sodium hydroxide solution. It is then extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated. Yield: 2.07 g (81% of theory)
LC-MS (Method 1B): R _t = 1.57 min and 2.59 min (cis / trans isomers); MS (ESIpos): m / z = 276 [M + H] ⁺ .

Example 10A

Ethyl 1- (cyclopentylcarbonyl) -5- [4- (1-methylethyl) phenyl] piperidine-3-carboxylate [racemic cis / trans isomer mixture]

1.5 g (5.3 mmol) of ethyl 5- [4- (1-methylethyl) phenyl] piperidine-3-carboxylate are dissolved in 18 ml of dichloromethane and 0.81 g (7.9 mmol) of triethylamine are added at 0 ° C. Subsequently, 1.43 g (10.53 mmol) of cyclopentanecarbonyl chloride are added dropwise. The reaction mixture is stirred for 2 h at RT. For workup, it is washed twice with water. The organic phase is dried over sodium sulfate and concentrated in vacuo. Yield: 2 g (100% of theory)
LC-MS (Method 3B): R _t = 2.56 min and 2.63 min (cis / trans isomers); MS (ESIpos): m / z = 372 [M + H] ⁺ .

Example 11A

1- (cyclopentylcarbonyl) -5- [4- (1-methylethyl) phenyl] piperidine-3-carboxylic acid [racemic cis / trans isomer mixture]

To 2.40 g (6.46 mmol) of ethyl 1- (cyclopentylcarbonyl) -5- [4- (1-methylethyl) phenyl] piperidine-3-carboxylate 50 ml of dioxane, 25 ml of water and 0.63 g (25.84 mmol) of lithium hydroxide are added. The mixture is stirred overnight at RT. to Work-up is removed in vacuo dioxane, the reaction mixture mixed with water and with aqueous 1 N hydrochloric acid solution sour. The mixture is extracted with dichloromethane. The organic phase is dried with sodium sulfate and in vacuo concentrated. Yield: 1.65 g (98% of theory)

diastereomers of 1.65 g of the cis / trans isomer mixture according to Method 2C 553 mg of the title compound 12A (cis isomer) and 638 mg of the trans isomer.

Example 12A

1- (cyclopentylcarbonyl) -5- [4- (1-methylethyl) phenyl] piperidine-3-carboxylic acid [racemic cis isomer]

• LC-MS (Method 1B): R _t = 2.72 min; MS (ESIpos): m / z = 344 [M + H] ⁺ .

Example 13A

5- [4- (trifluoromethyl) phenyl] pyridine-3-carboxylate

6.74 g (29.30 mmol) of ethyl 5-bromonicotinate, 8.35 g (43.94 mmol) of 4-trifluoromethylphenylboronic acid, 0.17 g (0.15 mmol) of tetrakis (triphenylphosphine) palladium (0) and 6.21 g (58.59 mmol) of sodium carbonate are dissolved in a mixture of 75 ml of 1 , 2-dimethoxyethane, 15 ml of water and 184 ml of dimethylformamide and stirred at 85 ° C for 18 h. For workup, a portion of the dimethylformamide is removed in vacuo, the reaction mixture diluted with water and extracted with dichloromethane. The organic phase is dried over sodium sulfate and the crude product is purified by flash chromatography (dichloromethane / acetonitrile 100: 2 → 100: 5). Yield: 6.22 g (72% of theory)
LC-MS (Method 4B): R _t = 3.71 min; MS (ESIpos): m / z = 296 [M + H] ⁺ .

Example 14A

Ethyl 5- [4- (trifluoromethyl) phenyl] -piperidine-3-carboxylate [racemic cis / trans isomer mixture]

5.9 g (19.98 mmol) 5- [4- (trifluoromethyl) phenyl] pyridine-3-carboxylic acid ethyl ester are dissolved in 140 ml of ethanol, treated with 2.98 g of Pd / C (10%) and in an autoclave at 60 ° C in a Hydrogen pressure of 50 bar hydrogenated overnight. The reaction mixture is filtered through silica gel. The resulting solution is concentrated in vacuo. The residue is treated with water, the solution is adjusted to pH 8 with aqueous 1 N sodium hydroxide solution. It is then extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated. Yield: 4.2 g (67% of theory)
LC-MS (Method 4B): R _t = 1.95 min and 2.03 min (cis / trans isomers); MS (ESIpos): m / z = 302 [M + H] ⁺ .

Example 15A

Ethyl 1- (cyclopentylcarbonyl) -5- [4- (trifluoromethyl) phenyl] piperidine-3-carboxylate [racemic cis / trans isomer mixture]

4.2 g (13.5 mmol) of ethyl 5- [4- (trifluoromethyl) phenyl] piperidine-3-carboxylate are dissolved in 33 ml of dichloromethane and 2.04 g (20.2 mmol) of triethylamine are added at 0 ° C. Subsequently, 2.37 g (17.5 mmol) of cyclopentanecarbonyl chloride are added dropwise. The reaction mixture is stirred for 2 h at RT. For workup, it is washed twice with water. The organic phase is dried over sodium sulfate and concentrated in vacuo. Yield: 5.9 g (100% of theory)
LC-MS (Method 7B): R _t = 4.08 min and 4.15 min (cis / trans isomers); MS (ESIpos): m / z = 398 [M + H] ⁺ .

Example 16A

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

To 5.9 g (14.25 mmol) of ethyl 1- (cyclopentylcarbonyl) -5- [4- (trifluoromethyl) phenyl] piperidine-3-carboxylate 99 ml of dioxane, 50 ml of water and 1.37 g (57.0 mmol) of lithium hydroxide where. The mixture is stirred overnight at RT. For work-up, dioxane is removed in vacuo, the reaction mixture mixed with water and with aqueous 1 N hydrochloric acid solution sour. The mixture is extracted with dichloromethane. The organic phase is dried with sodium sulfate and in vacuo concentrated. Yield: 5.3 g (95% of theory)

diastereomers of 5.3 g of the cis / trans isomer mixture according to Method 3C 1525 g of the title compound 17A (cis isomer) and 1949 g of the trans isomer.

Example 17A

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

• HPLC (Method 3C): R _t = 3.66 min (cis isomer).

Example 18A

5- [4- (trifluoromethoxy) phenyl] pyridin-3-carbonsäuremethylester

According to General Method 1A, 23 g (105 mmol) of methyl 5-bromonicotinate and 26 g (126 mmol, 1.2 eq.) Of 4-trifluoromethoxyphenylboronic acid are reacted. Yield: 14 g (41% of theory)
LC-MS (Method 1B): R _t = 2.44 min; MS (ESIpos): m / z = 298 [M + H] ⁺ .

Example 19A

Methyl 5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylate [racemic cis / trans isomer mixture]

According to General Method 2A, 14 g (45 mmol) of methyl 5- [4- (trifluoromethoxy) phenyl] pyridine-3-carboxylate are hydrogenated. Yield: 8 g (59% of theory)
LC-MS (Method 1B): R _t = 1.29 min and 1.33 min (cis / trans isomers); MS (ESIpos): m / z = 304 [M + H] ⁺ .

Example 20A

5- [4- (trifluoromethoxy) phenyl] pyridine-3-carboxylate

3.35 g (14.57 mmol) of ethyl 5-bromonicotinate, 4.50 g (21.85 mmol) of 4- (trifluoromethoxy) phenylboronic acid, 0.84 g (0.73 mmol) of tetrakis (triphenylphosphine) palladium (0) and 3.01 g (29.14 mmol) of sodium carbonate are dissolved in a mixture of Dissolved 38 ml of 1,2-dimethoxyethane, 7.5 ml of water and 91 ml of dimethylformamide and stirred at 85 ° C for 18 h. For workup, a portion of the dimethylformamide is removed in vacuo, the reaction mixture diluted with water and extracted with dichloromethane. The organic phase is dried over sodium sulfate and the crude product is purified by means of flash chromatography (dichloromethane / acetonitrile 100: 0 → 100: 5). Yield: 2.64 g (55% of theory)
LC-MS (Method 4B): R _t = 3.78 min; MS (ESIpos): m / z = 312 [M + H] ⁺ .

Example 21A

Ethyl 5- [4- (trifluoromethoxy) phenyl] -piperidine-3-carboxylate [racemic cis / trans isomer mixture]

2.5 g (7.63 mmol) of 5- [4- (trifluoromethoxy) phenyl] pyridine-3-carboxylic acid ethyl ester are dissolved in 60 ml of ethanol, treated with 1.14 g of Pd / C (10%) and in an autoclave at 60 ° C in a Hydrogen pressure of 50 bar hydrogenated overnight. The reaction mixture is filtered through silica gel. The resulting solution is concentrated in vacuo. The residue is treated with water, the solution is adjusted to pH 8 with aqueous 1 N sodium hydroxide solution. It is then extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated. Yield: 1.76 g (66% of theory)
LC-MS (Method 7B): R _t = 2.47 min and 2.56 min (cis / trans isomers); MS (ESIpos): m / z = 318 [M + H] ⁺ .

Example 22A

Ethyl 1- (cyclopentylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylate [racemic cis / trans isomer mixture]

1.76 g (5.08 mmol) of ethyl 5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylate are dissolved in 12 ml of dichloromethane and 0.77 g (7.62 mmol) of triethylamine are added at 0 ° C. Subsequently, 0.89 g (6.61 mmol) of cyclopentanecarbonyl chloride was added dropwise. The reaction mixture is stirred for 2 h at RT. For workup, it is washed twice with water. The organic phase is dried over sodium sulfate and concentrated in vacuo. Yield: 2.1 g (100% of theory)
LC-MS (Method 7B): R _t = 4.14 min and 4.22 min (cis / trans isomers); MS (ESIpos): m / z = 414 [M + H] ⁺ .

Example 23A

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

To 2.30 g (5.34 mmol) of ethyl 1- (cyclopentylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylate 37 ml of dioxane, 18.5 ml of water and 0.51 g (21.36 mmol) of lithium hydroxide where. The mixture is stirred overnight at RT. For work-up, dioxane is removed in vacuo, the reaction mixture mixed with water and with aqueous 1 N hydrochloric acid solution sour. The mixture is extracted with dichloromethane. The organic phase is dried with sodium sulfate and in vacuo concentrated. Yield: 2.17 g (99% of theory)

diastereomers of 2.17 g of the cis- / trans isomer mixture according to Method 4C 514 mg of the title compound 24A (cis isomer) and 796 mg of the trans isomer.

Example 24A

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

• LC-MS (Method 4B): R _t = 3.51 min; MS (ESIpos): m / z = 386 [M + H] ⁺ .

Example 25A

5- (4-methoxyphenyl) pyridine-3-carboxylate

22.26 g (96.78 mmol) of ethyl 5-bromonicotinate, 25.00 g (164.52 mmol) of 4-methoxyphenylboronic acid, 0.56 g (0.48 mmol) of tetrakis (triphenylphosphine) palladium (0) and 20.51 g (193.55 mmol) of sodium carbonate are dissolved in a mixture of 180 ml of 1 , 2-dimethoxyethane, 50 ml of water and 400 ml of dimethylformamide and stirred at 85 ° C for 18 h. For workup, a portion of the dimethylformamide is removed in vacuo, the reaction mixture diluted with water and extracted with dichloromethane. The organic phase is dried over sodium sulfate and the crude product is purified by means of flash chromatography (dichloromethane / acetonitrile 100: 2 → 100: 5). Yield: 20.18 g (72% of theory)
LC-MS (Method 4B): R _t = 3.21 min; MS (ESIpos): m / z = 258 [M + H] ⁺ .

Example 26A

Ethyl 5- (4-methoxyphenyl) piperidine-3-carboxylate [racemic cis / trans isomer mixture]

18.2 g (70.6 mmol) of ethyl 5- [4- (methoxy) phenyl] pyridine-3-carboxylate are hydrogenated according to General Method 2A. Yield: 18.0 g (100% of theory)
LC-MS (Method 3B): R _t = 0.82 min; MS (ESIpos): m / z = 264 [M + H] ⁺ .

Example 27A

5- (4-Methoxyphenyl) piperidine-1,3-dicarboxylic acid 1-tert-butyl-3-ethyl ester [racemic cis / trans isomer mixture]

5.2 g (17.77 mmol) of ethyl 5- (4-methoxyphenyl) piperidine-3-carboxylate are dissolved in 12 ml of dichloromethane and at room temperature with 3.88 g (17.77 mmol) of di-tert-butyl dicarbonate. The reaction mixture is stirred for 1 h at RT. For work-up is washed twice with water. The organic phase is over sodium sulfate dried and concentrated in vacuo. Yield: 6.8 g (81% of theory)

diastereomers of 6.8 g of the cis / trans isomer mixture according to Method 5C 1998 mg of the title compound 28A (cis isomer) and 3375 mg of the trans isomer.

Example 28A

5- (4-Methoxyphenyl) piperidine-1,3-dicarboxylic acid 1-tert-butyl-3-ethyl ester [racemic cis isomer]

• LC-MS (Method 1B): R _t = 2.93 min; MS (ESIpos): m / z = 364 [M + H] ⁺ .

Example 29A

5- (4-Methoxyphenyl) piperidine-3-carboxylic acid hydrochloride [racemic cis isomer]

1.13 g (3.11 mmol) of 5- (4-methoxyphenyl) piperidine-1,3-dicarboxylic acid 1-tert-butyl-3-ethyl ester are mixed in 40 ml of aqueous 1 N hydrochloric acid solution and concentrated on a rotary evaporator. Yield: 829 mg (98% of theory)
LC-MS (Method 8B): R _t = 2.08 min; MS (ESIpos): m / z = 236 [M + H] ⁺ .

Example 30A

1- (cyclopentylcarbonyl) -5- (4-methoxyphenyl) piperidine-3-carboxylic acid [racemic cis isomer]

0.83 g (3.05 mmol) 5- (4-methoxyphenyl) piperidine-3-carboxylic acid ethyl ester hydrochloride are dissolved in 10 ml of dichloromethane and treated at 0 ° C with 0.77 g (7.62 mmol) of triethylamine. Subsequently, 0.83 g (6.09 mmol) of cyclopentanecarbonyl chloride are added dropwise. The reaction mixture is stirred for 2 h at RT. For workup, it is washed twice with water. The organic phase is dried over sodium sulfate and concentrated in vacuo. The crude product is mixed with 35 ml of dioxane, 17.5 ml of water and 0.29 mg (12.19 mmol) of lithium hydroxide. The mixture is stirred for 1 h at RT. For working up, dioxane is removed in vacuo, the reaction mixture is mixed with water and acidified with aqueous 1 N hydrochloric acid solution. The precipitated solid is filtered off and dried in vacuo. Yield: 0.84 g (75% of theory)
LC-MS (Method 3B): R _t = 1.71 min; MS (ESIpos): m / z = 332 [M + H] ⁺ .

Example 31A

Ethyl 1- (2,2-dimethyl-propanoyl) -5- (4-methoxyphenyl) -piperidine-3-carboxylate [racemic cis / trans isomer mixture]

10.0 g (18.99 mmol) of ethyl 1- (cyclopentylcarbonyl) -5- [4- (methoxy) phenyl] piperidine-3-carboxylate dissolved in 50 ml of dichloromethane and at 0 ° C with 2.88 g (28.48 mmol) of triethylamine are added. Then be 3.00 g (24.68 mmol) of pivaloyl chloride are added dropwise. The Reaction mixture is stirred for 2 h at RT. to Work-up is washed twice with water. The organic phase is dried over sodium sulfate and concentrated in vacuo.

diastereomers of 10 g of the crude product as a cis / trans isomer mixture according to Method 6C gives 2.80 g of the title compound 32A (cis isomer) and 4.61 g of the trans-isomer.

Example 32A

1- (2,2-Dimethylpropanoyl) -5- (4-methoxyphenyl) piperidine-3-carboxylic acid ethyl ester [racemic cis isomer]

• LC-MS (Method 5B): R _t = 2.41 min; MS (ESIpos): m / z = 348 [M + H] ⁺ ,

Example 33A

1- (2,2-Dimethylpropanoyl) -5- (4-methoxyphenyl) piperidine-3-carboxylic acid [racemic cis isomer]

To 2.8 g (14.25 mmol) of ethyl 1- (cyclopentylcarbonyl) -5- [4- (methoxy) phenyl] piperidine-3-carboxylate are added 55 ml of dioxane, 28 ml of water and 0.77 g (32.23 mmol) of lithium hydroxide. The mixture is stirred overnight at RT. For working up, dioxane is removed in vacuo, the reaction mixture is mixed with water and acidified with aqueous 1 N hydrochloric acid solution. The mixture is extracted with dichloromethane. The organic phase is dried with sodium sulfate and concentrated in vacuo. Yield: 2.44 g (95% of theory)
LC-MS (Method 3B): R _t = 1.55 min; MS (ESIpos): m / z = 320 [M + H] ⁺ .

Example 34A

Methyl 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylate [racemic cis / trans isomer mixture]

According to General Method 3A, 6.2 g (22.6 mmol) of methyl 5- (4-ethylphenyl) piperidine-3-carboxylate are reacted with 4.4 g (29.4 mmol, 1.3 eq.) Of morpholine-4-carbonyl chloride. Yield: 7.9 g (97% of theory)
LC-MS (Method 5B): R _t = 2.14 min and 2.22 min (cis / trans isomers); MS (ESIpos): m / z = 361 [M + H] ⁺ .

diastereomers of 7.9 g of the cis / trans isomer mixture according to Method 7C 2.8 g of the title compound 35A (cis isomer) and 3.9 g of the trans isomer.

Example 35A

Methyl 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylate [racemic cis isomer]

• HPLC (Method 4A): R _t = 9.61 min; MS (ESIpos): m / z = 361 [M + H] ⁺ .

Example 36A

Ethyl 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylate [racemic cis / trans isomer mixture]

According to General Method 3A, 10.0 g (36.0 mmol) of ethyl 5- (4-ethylphenyl) piperidine-3-carboxylate are reacted with 7.0 g (46.8 mmol, 1.3 eq.) Of morpholine-4-carbonyl chloride. Yield: 12.0 g (89% of theory)
LC-MS (Method 1B): R _t = 2.38 min and 2.48 min (cis / trans isomers); MS (ESIpos): m / z = 375 [M + H] ⁺ .

diastereomers of 12.0 g of the cis / trans isomer mixture according to method 8C 4.4 g of the title compound 37A (cis isomer) and 5.4 g of the trans isomer.

Example 37A

Ethyl 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylate [racemic cis isomer]

• LC-MS (Method 1B): R _t = 2.48 min; MS (ESIpos): m / z = 375 [M + H] ⁺ .

Example 38A

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

According to General Method 4A, 4.4 g (11.7 mmol) of ethyl 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylate are saponified. Yield: 3.4 g (84% of theory)
LC-MS (Method 1B): R _t = 2.06 min; MS (ESIpos): m / z = 347 [M + H] ⁺ .

Example 39A

Methyl 5- (4-ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidine-3-carboxylate [racemic cis / trans isomer mixture]

According to General Method 3A, 6.7 g (24.1 mmol) of 5- (4-ethylphenyl) piperidine-3-carboxylic acid methyl ester are reacted with 4.2 g (31.4 mmol, 1.3 eq.) Of pyrrolidine-1-carbonyl chloride. Yield: 7.6 g (91% of theory)
LC-MS (Method 3B): R _t = 2.08 min and 2.16 min (cis / trans isomers); MS (ESIpos): m / z = 345 [M + H] ⁺ .

diastereomers of 7.6 g of the cis / trans isomer mixture according to Method 9C 1.6 g of the title compound 40A (cis isomer) and 4.1 g of the trans isomer.

Example 40A

Methyl 5- (4-ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidine-3-carboxylate [racemic cis isomer]

• LC-MS (Method 1B): R _t = 2.55 min; MS (ESIpos): m / z = 345 [M + H] ⁺ .

Example 41A

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

According to General Method 4A, 1.4 g (3.9 mmol) of 5- (4-ethylphenyl) -1- (pyrrolidin-1-ylcarbonyl) piperidine-3-carboxylic acid methyl ester are saponified. Yield: 1.2 g (92% of theory)
LC-MS (Method 2B): R _t = 1.18 min; MS (ESIpos): m / z = 331 [M + H] ⁺ .

Example 42A

Methyl 1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylate [racemic cis / trans isomer mixture]

According to General Method 3A, 8.3 g (26.5 mmol) of 5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid methyl ester are reacted with 5.2 g (34.5 mmol, 1.3 eq.) Of morpholine-4-carbonyl chloride. Yield: 11.0 g (100% of theory)
LC-MS (Method 2B): R _t = 1.21 min and 1.24 min (cis / trans isomers); MS (ESIpos): m / z = 417 [M + H] ⁺ .

diastereomers of 11.0 g of the cis / trans isomer mixture according to Method 10C 4.3 g of the title compound 43A (cis isomer) and 5.0 g of the trans isomer.

Example 43A

Methyl 1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylate [racemic cis isomer]

• LC-MS (Method 3B): R _t = 1.98 min; MS (ESIpos): m / z = 417 [M + H] ⁺ .

Example 44A

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

According to General Method 4A, 4.3 g (10.4 mmol) of methyl 1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylate are saponified. Yield: 4.1 g (98% of theory)
LC-MS (Method 1B): R _t = 2.12 min; MS (ESIpos): m / z = 403 [M + H] ⁺ .

Example 45A

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

Step a): 1- [Ethyl (methyl) carbamoyl] -5- (4-ethylphenyl) piperidine-3-carboxylic acid methyl ester [racemic cis / trans isomer mixture]

According to General Method 3A, 7.0 g (89%, 25.1 mmol) of 5- (4-ethylphenyl) piperidine-3-carboxylic acid methyl ester are reacted with 4.0 g (32.6 mmol, 1.3 eq.) Of ethyl (methyl) carbamoyl chloride. Yield: 8.0 g (96% of theory)
LC-MS (Method 3B): R _t = 2.10 min and 2.18 min (cis / trans isomers); MS (ESIpos): m / z = 333 [M + H] ⁺ .

Step b): 1- [Ethyl (methyl) carbamoyl] -5- (4-ethylphenyl) piperidine-3-carboxylic acid [racemic cis / trans isomer mixture]

According to General Method 4A, 8.0 g (23.2 mmol) of ethyl 1- [ethyl (methyl) carbamoyl] -5- (4-ethylphenyl) piperidine-3-carboxylate are saponified. Yield: 1.2 g (16% of theory)
LC-MS (Method 3B): R _t = 1.79 min and 1.84 min (cis / trans isomers); MS (ESIpos): m / z = 319 [M + H] ⁺ .

Diastereomer separation of 1.2 g of the cis / trans isomer mixture according to Method 9C gives 538 mg of the title compound 45A (cis isomer).
LC-MS (Method 3B): R _t = 1.79 min; MS (ESIpos): m / z = 319 [M + H] ⁺ .

embodiments

General Method 1: Oxadiazole Formation

A Solution of the corresponding piperidine-3-carboxylic acid in dimethylformamide (10 ml / mmol) under argon at RT with HATU (1.2 eq.), N, N-diisopropylethylamine (2.2 eq.) And the corresponding N'-Hydroxyimidamide (1.1 eq.). The reaction mixture is stirred at RT until complete formation of the intermediate, then further stirred at 120 ° C until formation of the desired product from this intermediate. The The reaction mixture is then purified by preparative HPLC purified.

General Method 2: Oxadiazole Formation

The carboxylic acid is dissolved in dioxane / dimethylformamide (3: 1, 1 ml / mmol) and heated to 60.degree. After addition of N, N'-carbonyldiimidazole (1.5 eq.), Dissolved in dioxane / dimethylformamide (4: 1, 1.6 ml / mmol), the mixture is stirred at 60 ° C for 3 h. After cooling to RT, the Carboximidamid, dissolved in dioxane / dimethylformamide 1: 1, added dropwise and stirred at 40 ° C overnight. Thereafter, the dioxane is removed in vacuo. The residue dissolved in dimethylformamide is then stirred for 1 h at 115.degree. The reaction mixture is after cooling, diluted with water. After extraction with dichloromethane, the organic phase is dried over sodium sulphate and the crude product is purified by preparative HPLC.

example 1

1- (cyclopentylcarbonyl) -3- (4-ethylphenyl) -5- (3-phenyl-1,2,4-oxadiazol-5-yl) piperidine [racemic cis isomer]

According to General Method 1, 329 mg (1.0 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine-3-carboxylic acid (Example 7A) and 149 mg (1.1 mmol, 1.1 eq.) Of N'-hydroxybenzenecarboximidamide are reacted , Yield: 235 mg (55% of theory)
HPLC (Method 2A): R _t = 5.64 min; MS (ESIpos): m / z = 430 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 8.01 (d, 2H), 7.63-7.54 (m, 3H), 7.28 (d, 1H), 7.23 (d, 1H), 7.19 (d, 2H), 4.95 (br d, 0.5H), 4.53 (br d, 0.5H), 4.48 (br d, 0.5H), 4.03 (br d, 0.5H), 3.50-3.40 (m, 1H), 3.37- 3.28 (m, 0.5H), 3.27-3.20 (m, 0.5H), 3.19-3.01 (m, 1H), 2.95-2.82 (m, 1H), 2.70-2.68 (m, 1H), 2.58 (q, 2H ), 2.42-2.33 (m, 1H), 2.20-2.02 (m, 1H), 1.90-1.47 (m, 8H), 1.17 (t, 3H).

Enantiomerentrennung of 235 mg of the racemate according to method 1D gives 117 mg of the title compound 2 and 119 mg of the title compound 3.

Example 2

1- (cyclopentylcarbonyl) -3- (4-ethylphenyl) -5- (3-phenyl-1,2,4-oxadiazol-5-yl) piperidine [enantiomerically pure cis isomer]

• HPLC (Method 1E): R _t = 5.25 min,> 99.5% ee; MS (ESIpos): m / z = 430 [M + H] ⁺ .

Example 3

1- (cyclopentylcarbonyl) -3- (4-ethylphenyl) -5- (3-phenyl-1,2,4-oxadiazol-5-yl) piperidine [enantiomerically pure cis isomer]

• HPLC (Method 1E): R _t = 6.98 min,> 99.5% ee; MS (ESIpos): m / z = 430 [M + H] ⁺ .

Example 4

Cis (3,5) -1- (cyclopentylcarbonyl) -3- [4- (1-methylethyl) phenyl] -5- (3-phenyl-1,2,4-oxadiazol-5-yl) piperidine [racemic cis -Isomer]

According to General Method 2, 60 mg (0.18 mmol) of cis- (3,5) -1- (cyclopentylcarbonyl) -5- [4- (1-methylethyl) phenyl] piperidine-3-carboxylic acid (Example 12A) and 36 mg (0.26 mmol, 1.5 eq.) N'-Hydroxybenzencarboximidamid reacted. Yield: 64 mg (83% of theory)
LC-MS (Method 1B): R _t = 3.28 min; MS (ESIpos): m / z = 444 [M + H] ⁺ .

Enantiomerentrennung of 58 mg of the racemate according to Method 2D gives 15 mg of the title compound 5 and 17 mg of the title compound 6.

Example 5

Cis (3,5) -1- (cyclopentylcarbonyl) -3- [4- (1-methylethyl) phenyl] -5- (3-phenyl-1,2,4-oxadiazol-5-yl) piperidine [enantiomerically pure cis -Isomer]

• HPLC (Method 2E): R _t = 7.09 min.

Example 6

Cis (3,5) -1- (cyclopentylcarbonyl) -3- [4- (1-methylethyl) phenyl] -5- (3-phenyl-1,2,4-oxadiazol-5-yl) piperidine [enantiomerically pure cis -Isomer]

• HPLC (Method 2E): R _t = 7.79 min.

Example 7

Cis (3,5) -1- (cyclopentylcarbonyl) -3- (3-phenyl-1,2,4-oxadiazol-5-yl) -5- [4- (trifluoromethyl) phenyl] piperidine [racemic cis isomer ]

According to General Method 2, 150 mg (0.41 mmol) of cis- (3,5) -1- (cyclopentylcarbonyl) -5- [4- (trifluoromethyl) phenyl] piperidine-3-carboxylic acid (Example 17A) and 83 mg (0.61 mmol) are added mmol, 1.5 eq.) of N'-hydroxybenzenecarboximidamide. Yield: 152 mg (80% of theory)
LC-MS (Method 1B): R _t = 3.28 min; MS (ESIpos): m / z = 470 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.05-7.99 (dd, 2H), 7.67-7.54 (t, 2H), 7.86 (m, 5H), 4.96 (br d, 0.5H), 4.57 (br dd, 1H), 4.09 (br d, 0.5H), 3.98 (br d, 2H), 3.19-2.78 (m, 3H), 2.42 (br t, 1H), 2.28-2.10 (m, 1H) , 1.91-1.46 (m, 8H).

Enantiomerentrennung of 142 mg of the racemate according to Method 3D gives 58 mg of the title compound 8 and 58 mg of the title compound 9.

Example 8

Cis (3,5) -1- (cyclopentylcarbonyl) -3- (3-phenyl-1,2,4-oxadiazol-5-yl) -5- [4- (trifluoromethyl) phenyl] piperidine [enantiomerically pure cis isomer ]

• HPLC (Method 3E): R _t = 5.62 min.

Example 9

Cis (3,5) -1- (cyclopentylcarbonyl) -3- (3-phenyl-1,2,4-oxadiazol-5-yl) -5- [4- (trifluoromethyl) phenyl] piperidine [enantiomerically pure cis isomer ]

• HPLC (Method 3E): R _t = 6.16 min.

Example 10

Cis (3,5) -1- (cyclopentylcarbonyl) -3- (3-phenyl-1,2,4-oxadiazol-5-yl) -5- [4- (trifluoromethoxy) phenyl] piperidine [racemic cis isomer ]

According to General Method 2, 60 mg (0.16 mmol) of cis (3,5) -1- (cyclopentylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 24A) and 32 mg (0.23 mmol) are added mmol, 1.5 eq.) of N'-hydroxybenzenecarboximidamide. Yield: 62 mg (83% of theory)
LC-MS (Method 3B): R _t = 3.33 min; MS (ESIpos): m / z = 486 [M + H] ⁺ .

Example 11

Cis (3,5) -1- (2,2-dimethylpropanoyl) -3- (4-methoxyphenyl) -5- (3-phenyl-1,2,4-oxadiazol-5-yl) piperidine [racemic cis] Isomer]

According to General Method 2, 150 mg (0.41 mmol) of cis- (3,5) -1- (2,2-dimethylpropanoyl) -5- (4-methoxyphenyl) piperidine-3-carboxylic acid (Example 33A) and 96 mg ( 0.70 mmol, 1.5 eq.) Of N'-hydroxybenzenecarboximidamide. Yield: 126 mg (64% of theory)
LC-MS (Method 3B): R _t = 2.49 min; MS (ESIpos): m / z = 420 [M + H] ⁺ .

Enantiomerentrennung of 119 mg of the racemate according to method 4D gives 20 mg of the title compound 12 and 17 mg of the title compound 13.

Example 12

Cis (3,5) -1- (2,2-dimethylpropanoyl) -3- (4-methoxyphenyl) -5- (3-phenyl-1,2,4-oxadiazol-5-yl) piperidine [enantiomerically pure cis] Isomer]

• HPLC (Method 4E): R _t = 5.72 min.

Example 13

Cis (3,5) -1- (2,2-dimethylpropanoyl) -3- (4-methoxyphenyl) -5- (3-phenyl-1,2,4-oxadiazol-5-yl) piperidine [enantiomerically pure cis] Isomer]

• HPLC (Method 4E): R _t = 6.42 min.

Example 14

4 - {[3- (4-Ethylphenyl) -5- (3-phenyl-1,2,4-oxadiazol-5-yl) piperidin-1-yl] carbonyl} morpholine [racemic cis isomer]

According to General Method 1, 400 mg (1.16 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarb bonyl) piperidine-3-carboxylic acid (Example 38A) and 173 mg (1.27 mmol, 1.1 eq.) of N'-hydroxybenzenecarboximidamide. Yield: 373 mg (72% of theory)
HPLC (Method 3A): R _t = 4.98 min; MS (ESIpos): m / z = 447 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.01 (d, 2H), 7.63-7.52 (m, 3H), 7.25 (d, 2H), 7.18 (d, 2H), 4.09 (br , 1H), 3.62 (br d, 1H), 3.60-3.54 (m, 4H), 3.53-3.44 (m, 1H), 3.26-3.17 (m, 4H), 3.11 (t, 1H), 2.97 (q, 1H), 2.94-2.85 (m, 1H), 2.58 (q, 2H), 2.38 (br d, 1H), 2.04 (q, 1H), 1.17 (t, 3H).

Enantiomerentrennung of 440 mg of the racemate according to method 5D gives 187 mg of the title compound 15 and 190 mg of the title compound 16.

Example 15

4 - {[3- (4-Ethylphenyl) -5- (3-phenyl-1,2,4-oxadiazol-5-yl) piperidin-1-yl] carbonyl} morpholine [enantiomerically pure cis isomer]

• HPLC (Method 5E): R _t = 7.95 min,> 99.5% ee; MS (ESIpos): m / z = 447 [M + H] ⁺ .

Example 16

4 - {[3- (4-Ethylphenyl) -5- (3-phenyl-1,2,4-oxadiazol-5-yl) piperidin-1-yl] carbonyl} morpholine [enantiomerically pure cis isomer]

• HPLC (Method 5E): R _t = 11.13 min,> 99.5% ee; MS (ESIpos): m / z = 447 [M + H] ⁺ .

Example 17

4 - ({3- (3-phenyl-1,2,4-oxadiazol-5-yl) -5- [4- (trifluoromethoxy) phenyl] piperidin-1-yl} carbonyl) morpholine [racemic cis isomer]

According to General Method 1, 80 mg (0.20 mmol) of 1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 44A) and 30 mg (0.22 mmol, 1.1 eq .) N'-Hydroxybenzencarboximidamid reacted. Yield: 10 mg (10% of theory)
HPLC (Method 2A): R _t = 5.15 min; MS (ESIpos): m / z = 503 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 8.01 (d, 2H), 7.62-7.55 (m, 2H), 7.50 (d, 2H), 7.42 (t, 1H), 7.35 (d, 2H), 4.09 (br d, 1H), 3.64 (br d, 1H), 3.61-3.55 (m, 4H), 3.55-3.46 (m, 1H), 3.25-3.19 (m, 4H), 3.14 (t, 1H), 3.07-2.97 (m, 2H), 2.40 (br d, 1H), 2.07 (q, 1H).

Example 18

4 - ({3- [3- (2-chlorophenyl) -1,2,4-oxadiazol-5-yl] -5- (4-ethylphenyl) piperidin-1-yl} carbonyl) morpholine [racemic cis isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylic acid (Example 38A) and 38 mg (0.22 mmol, 1.1 eq.) 2 -Chloro-N'-hydroxybenzenecarboximidamid reacted. Yield: 49 mg (51% of theory)
HPLC (Method 3A): R _t = 5.01 min; MS (ESIpos): m / z = 481 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.92 (dd, 1H), 7.68 (dd, 1H), 7.61 (dt, 1H), 7.54 (dt, 1H), 7.25 (d, 2H) , 7.18 (d, 2H), 4.10 (br d, 1H), 3.62 (br d, 1H), 3.61-3.54 (m, 4H), 3.58-3.47 (m, 1H), 3.25-3.18 (m, 4H) , 3.11 (t, 1H), 2.97 (q, 1H), 2.95-2.86 (m, 1H), 2.58 (q, 2H), 2.38 (br d, 1H), 2.04 (q, 1H), 1.17 (t, 3H).

Example 19

4 - ({3- [3- (2-chlorophenyl) -1,2,4-oxadiazol-5-yl] -5- [4- (trifluoromethoxy) phenyl] piperidin-1-yl} carbonyl) morpholine [racemic cis -Isomer]

According to General Method 1, 80 mg (0.20 mmol) of 1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 44A) and 38 mg (0.22 mmol, 1.1 eq .) 2-Chloro-N'-hydroxybenzenecarboximidamid reacted. Yield: 56 mg (52% of theory)
HPLC (Method 2A): R _t = 5.17 min; MS (ESIpos): m / z = 537 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.92 (dd, 1H), 7.69 (dd, 1H), 7.61 (dt, 1H), 7.54 (dt, 1H), 7.49 (d, 2H) , 7.34 (d, 2H), 4.09 (br d, 1H), 3.64 (br d, 1H), 3.62-3.48 (m, 5H), 3.26-3.18 (m, 4H), 3.13 (t, 1H), 3.07 -2.97 (m, 2H), 2.42 (br d, 1H), 2.07 (q, 1H).

Example 20

4 - ({3- (4-Ethylphenyl) -5- [3- (2-methylphenyl) -1,2,4-oxadiazol-5-yl] piperidin-1-yl} carbonyl) morpholine [racemic cis isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylic acid (Example 38A) and 33 mg (0.22 mmol, 1.1 eq.) Of N Reacted '-hydroxy-2-methylbenzencarboximidamid. Yield: 62 mg (68% of theory)
HPLC (Method 1A): R _t = 5.12 min; MS (ESIpos): m / z = 461 [M + H] ^+;
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.93 (d, 1H), 7.51-7.44 (m, 1H), 7.43-7.35 (m, 2H), 7.25 (d, 2H), 7.18 ( d, 2H), 4.10 (br d, 1H), 3.62 (br d, 1H), 3.60-3.53 (m, 4H), 3.52-3.44 (m, 1H), 3.25-3.18 (m, 4H), 3.11 ( t, 1H), 2.97 (q, 1H), 2.95-2.86 (m, 1H), 2.58 (q, 2H), 2.56 (s, 3H), 2.38 (br d, 1H), 2.04 (q, 1H), 1.17 (t, 3H).

Example 21

4 - ({3- [3- (2-Methylphenyl) -1,2,4-oxadiazol-5-yl] -5- [4- (trifluoromethoxy) phenyl] piperidin-1-yl} carbonyl) morpholine [racemic cis -Isomer]

According to General Method 1, 80 mg (0.20 mmol) of 1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 44A) and 33 mg (0.22 mmol, 1.1 eq .) N'-hydroxy-2-methylbenzencarboximidamid reacted. Yield: 14 mg (13% of theory)
HPLC (Method 2A): R _t = 5.30 min; MS (ESIpos): m / z = 517 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.92 (dd, 1H), 7.53-7.45 (m, 3H), 7.43-7.33 (m, 4H), 4.09 (br d, 1H), 3.64 (br d, 1H), 3.60-3.55 (m, 4H), 3.54-3.46 (m, 1H), 3.24-3.20 (m, 4H), 3.14 (t, 1H), 3.06-2.99 (m, 2H), 2.42 (br d, 1H), 2.07 (q, 1H).

Example 22

1- (cyclopentylcarbonyl) -3- (4-ethylphenyl) -5- [3- (3-fluorophenyl) -1,2,4-oxadiazol-5-yl] piperidine [racemic cis isomer]

According to General Method 1, 66 mg (0.20 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine-3-carboxylic acid (Example 7A) and 34 mg (0.22 mmol, 1.1 eq.) Of 3-fluoro-N Implemented 'hydroxybenzenecarboximidamide. Yield: 47 mg (53% of theory)
HPLC (Method 2A): R _t = 5.78 min; MS (ESIpos): m / z = 448 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 7.87 (d, 1H), 7.76 (d, 1H), 7.64 (q, 1H), 7.47 (t, 1H), 7.28 (d, 1H) , 7.23 (d, 1H), 7.19 (t, 2H), 4.94 (br d, 0.5H), 4.53 (br d, 0.5H), 4.48 (br d, 0.5H), 4.03 (br d, 0.5H) , 3.50-3.40 (m, 1H), 3.38-3.28 (m, 0.5H), 3.27-3.17 (m, 0.5H), 3.17-3.03 (m, 1H), 2.94-2.83 (m, 1H), 2.81- 2.68 (m, 1H), 2.58 (q, 2H), 2.44-2.34 (m, 1H), 2.19-2.03 (m, 1H), 1.89-1.46 (m, 8H), 1.17 (t, 3H).

Example 23

Cis (3,5) -1- (cyclopentylcarbonyl) -3- [3- (3-fluorophenyl) -1,2,4-oxadiazol-5-yl] -5- [4- (trifluoromethyl) phenyl] piperidine [ racemic cis isomer]

According to General Method 2, 150 mg (0.41 mmol) of cis- (3,5) -1- (cyclopentylcarbonyl) -5- [4- (trifluoromethyl) phenyl] piperidine-3-carboxylic acid (Example 17A) and 93 mg (0.61 mmol) are added mmol, 1.5 eq.) of 3-fluoro-N'-hydroxybenzenecarboximidamide. Yield: 150 mg (76% of theory)
LC-MS (Method 1B): R _t = 3.31 min; MS (ESIpos): m / z = 488 [M + H] ⁺ .

Example 24

Cis (3,5) -1- (cyclopentylcarbonyl) -3- [3- (3-fluorophenyl) -1,2,4-oxadiazol-5-yl] -5- [4- (trifluoromethoxy) phenyl] piperidine [ racemic cis isomer]

According to General Method 2, 70 mg (0.18 mmol) of cis (3,5) -1- (cyclopentylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 24A) and 42 mg (0.27 mmol) are added mmol, 1.5 eq.) of 3-fluoro-N'-hydroxybenzenecarboximidamide. Yield: 70 mg (76% of theory)
LC-MS (Method 1B): R _t = 3.36 min; MS (ESIpos): m / z = 504 [M + H] ⁺ .

Example 25

4 - ({3- (4-Ethylphenyl) -5- [3- (3-fluorophenyl) -1,2,4-oxadiazol-5-yl] piperidin-1-yl) carbonyl) morpholine [racemic cis isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylic acid (Example 38A) and 34 mg (0.22 mmol, 1.1 eq.) 3 -Fluor-N'-hydroxybenzenecarboximidamid implemented. Yield: 55 mg (58% of theory)
HPLC (Method 3A): R _t = 5.06 min; MS (ESIpos): m / z = 465 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.81 (d, 1H), 7.76 (d, 1H), 7.64 (dt, 1H), 7.46 (dt, 1H), 7.24 (d, 2H) , 7.18 (d, 2H), 4.09 (br d, 1H), 3.63 (br d, 1H), 3.62-3.54 (m, 4H), 3.54-3.45 (m, 1H), 3.26- 3.18 (m, 4H) , 3.11 (t, 1H), 2.97 (q, 1H), 2.94-2.84 (m, 1H), 2.58 (q, 2H), 2.38 (br d, 1H), 2.05 (q, 1H), 1.17 (t, 3H).

Example 26

4 - ({3- [3- (3-Fluorophenyl) -1,2,4-oxadiazol-5-yl] -5- [4- (trifluoromethoxy) phenyl] piperidin-1-yl} carbonyl) morpholine [racemic cis -Isomer]

According to General Method 1, 80 mg (0.20 mmol) of 1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 44A) and 34 mg (0.22 mmol, 1.1 eq .) 3-fluoro-N'-hydroxybenzenecarboximidamid reacted. Yield: 71 mg (68% of theory)
HPLC (Method 2A): R _t = 5.21 min; MS (ESIpos): m / z = 521 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.88 (d, 1H), 7.76 (d, 1H), 7.64 (dd, 1H), 7.54-7.44 (m, 3H), 7.34 (d, 2H), 4.09 (br d, 1H), 3.64 (br d, 1H), 3.62-3.53 (m, 4H), 3.56-3.47 (m, 1H), 3.26-3.18 (m, 4H), 3.13 (t, 1H), 3.08-2.97 (m, 2H), 2.41 (br d, 1H), 2.07 (q, 1H).

Example 27

4 - ({3- (4-Ethylphenyl) -5- [3- (3-methylphenyl) -1,2,4-oxadiazol-5-yl] -piperidin-1-yl} carbonyl) morpholine [racemic cis isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylic acid (Example 38A) and 33 mg (0.22 mmol, 1.1 eq.) Of N Reacted '-hydroxy-3-methylbenzencarboximidamid. Yield: 16 mg (18% of theory)
HPLC (Method 1A): R _t = 5.45 min; MS (ESIpos): m / z = 461 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.84 (s, 1H), 7.81 (d, 1H), 7.45 (t, 1H), 7.42 (t, 1H), 7.25 (d, 2H) , 7.18 (d, 2H), 4.09 (br d, 1H), 3.63 (br d, 1H), 3.63-3.53 (m, 4H), 3.53-3.43 (m, 1H), 3.26-3.18 (m, 4H) , 3.11 (t, 1H), 2.97 (q, 1H), 2.94-2.85 (m, 1H), 2.58 (q, 2H), 2.40 (s, 3H), 2.38 (br d, 1H), 2.04 (q, 1H), 1.17 (t, 3H).

Example 28

4 - ({3- (4-Ethylphenyl) -5- [3- (3-methoxyphenyl) -1,2,4-oxadiazol-5-yl] piperidin-1-yl} carbonyl) morpholine [racemic cis isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) -piperidine-3-carboxylic acid (Example 38A) and 37 mg (0.22 mmol, 1.2 eq.) Of N '-Hydroxy-3-methoxybenzencarboximidamid reacted. Yield: 60 mg (63% of theory)
HPLC (Method 1A): R _t = 5.25 min; MS (ESIpos): m / z = 477 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.60 (d, 1H), 7.53-7.46 (m, 2H), 7.25 (d, 2H), 7.21-7.13 (m, 3H), 4.09 ( br d, 1H), 3.84 (s, 3H), 3.62 (br d, 1H), 3.62-3.54 (m, 4H), 3.54-3.43 (m, 1H), 3.24-3.18 (m, 4H), 3.11 ( t, 1H), 2.97 (q, 1H), 2.95-2.85 (m, 1H), 2.58 (q, 2H), 2.37 (br d, 1H), 2.04 (q, 1H), 1.17 (t, 3H).

Example 29

4 - ({3- [3- (3-Chlorophenyl) -1,2,4-oxadiazol-5-yl] -5- (4-ethylphenyl) piperidin-1-yl} carbonyl) morpholine [racemic cis isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylic acid (Example 38A) and 38 mg (0.22 mmol, 1.1 eq.) 3 -Chloro-N'-hydroxybenzenecarboximidamid reacted. Yield: 40 mg (42% of theory)
HPLC (Method 1A): R _t = 5.55 min; MS (ESIpos): m / z = 481 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.03-7.96 (m, 2H), 7.72-7.67 (m, 1H), 7.62 (t, 1H), 7.25 (d, 2H), 7.18 ( d, 2H), 4.09 (br d, 1H), 3.63 (br d, 1H), 3.61-3.54 (m, 4H), 3.55-3.45 (m, 1H), 3.26-3.17 (m, 4H), 3.11 ( t, 1H), 2.97 (q, 1H), 2.95-2.85 (m, 1H), 2.58 (q, 2H), 2.38 (br d, 1H), 2.04 (q, 1H), 1.17 (t, 3H).

Example 30

4 - {[3- (4-Ethylphenyl) -5- {3- [3- (trifluoromethyl) phenyl] -1,2,4-oxadiazol-5-yl} piperidin-1-yl] carbonyl} morpholine [racemic cis -Isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) -piperidine-3-carboxylic acid (Example 38A) and 45 mg (0.22 mmol, 1.1 eq.) Of N '-Hydroxy-3- (trifluoromethyl) benzencarboximidamid reacted. Yield: 60 mg (59% of theory)
HPLC (Method 1A): R _t = 5.59 min; MS (ESIpos): m / z = 515 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.33 (d, 1H), 8.25 (s, 1H), 8.00 (d, 1H), 7.85 (t, 1H), 7.25 (d, 2H) , 7.18 (d, 2H), 4.09 (br d, 1H), 3.62 (br d, 1H), 3.61-3.55 (m, 4H), 3.58-3.47 (m, 1H), 3.26-3.18 (m, 4H) , 3.13 (t, 1H), 2.98 (q, 1H), 2.96-2.86 (m, 1H), 2.58 (q, 2H), 2.38 (br d, 1H), 2.06 (q, 1H), 1.17 (t, 3H).

Example 31

4 - {[3- (4-Ethylphenyl) -5- {3- [3- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl} piperidin-1-yl] carbonyl} morpholine [racemic cis -Isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) -piperidine-3-carboxylic acid (Example 38A) and 48 mg (0.22 mmol, 1.1 eq.) Of N Reacted hydroxy-3- (trifluoromethoxy) benzene carboximidamide. Yield: 68 mg (64% of theory)
HPLC (Method 1A): R _t = 5.65 min; MS (ESIpos): m / z = 531 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.06 (d, 1H), 7.90 (s, 1H), 7.74 (t, 1H), 7.64 (d, 1H), 7.25 (d, 2H) , 7.18 (d, 2H), 4.09 (br d, 1H), 3.62 (br d, 1H), 3.60-3.53 (m, 4H), 3.57-3.46 (m, 1H), 3.25-3.18 (m, 4H) , 3.12 (t, 1H), 2.97 (q, 1H), 2.95-2.84 (m, 1H), 2.58 (q, 2H), 2.37 (br d, 1H), 2.05 (q, 1H), 1.17 (t, 3H).

Example 32

1- (cyclopentylcarbonyl) -3- (4-ethylphenyl) -5- [3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl] piperidine [racemic cis isomer]

According to General Method 1, 66 mg (0.20 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine-3-carboxylic acid (Example 7A) and 34 mg (0.22 mmol, 1.1 eq.) Of 4-fluoro-N Implemented 'hydroxybenzenecarboximidamide. Yield: 45 mg (50% of theory)
HPLC (Method 2A): R _t = 5.71 min; MS (ESIpos): m / z = 448 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 8.07 (dd, 2H), 7.41 (t, 2H), 7.28 (d, 1H), 7.23 (d, 1H), 7.19 (t, 2H) , 4.95 (br d, 0.5H), 4.53 (br d, 0.5H), 4.48 (br d, 0.5H), 4.03 (br d, 0.5H), 3.49-3.40 (m, 1H), 3.37-3.29 ( m, 0.5H), 3.26-3.18 (m, 0.5H), 3.17-3.03 (m, 1H), 2.93-2.83 (m, 1H), 2.80-2.68 (m, 1H), 2.58 (q, 2H), 2.43-2.33 (m, 1H), 2.18-2.03 (m, 1H), 1.88-1.47 (m, 8H), 1.17 (t, 3H).

Example 33

4 - ({3- (4-Ethylphenyl) -5- [3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl] piperidin-1-yl} carbonyl) morpholine [racemic cis isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) -piperidine-3-carboxylic acid (Example 38A) and 34 mg (0.22 mmol, 1.1 eq.) Of 4 -Fluor-N'-hydroxybenzenecarboximidamid implemented. Yield: 56 mg (60% of theory)
HPLC (Method 1A): R _t = 5.31 min; MS (ESIpos): m / z = 465 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.08 (dd, 2H), 7.41 (dd, 2H), 7.24 (d, 2H), 7.18 (d, 2H), 4.09 (br d, 1H ), 3.62 (br d, 1H), 3.61-3.54 (m, 4H), 3.54-3.44 (m, 1H), 3.25-3.18 (m, 4H), 3.11 (t, 1H), 2.97 (q, 1H) , 2.94-2.85 (m, 1H), 2.58 (q, 2H), 2.37 (br d, 1H), 2.03 (q, 1H), 1.17 (t, 3H).

Example 34

4 - ({3- [3- (4-Fluorophenyl) -1,2,4-oxadiazol-5-yl] -5- [4- (trifluoromethoxy) phenyl] piperidin-1-yl} carbonyl) morpholine [racemic cis -Isomer]

According to General Method 1, 80 mg (0.20 mmol) of 1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 44A) and 34 mg (0.22 mmol, 1.1 eq .) Reacted 4-fluoro-N'-hydroxybenzenecarboximidamid. Yield: 55 mg (53% of theory)
HPLC (Method 2A): R _t = 5.18 min; MS (ESIpos): m / z = 521 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.07 (d, 2H), 7.49 (d, 2H), 7.42 (t, 2H), 7.34 (d, 2H), 4.09 (br d, 1H ), 3.64 (br d, 1H), 3.63-3.54 (m, 4H), 3.54-3.45 (m, 1H), 3.26-3.18 (m, 4H), 3.13 (t, 1H), 3.07-2.97 (m, 2H), 2.40 (br d, 1H), 2.06 (q, 1H).

Example 35

4 - ({3- (4-Ethylphenyl) -5- [3- (4-chlorophenyl) -1,2,4-oxadiazol-5-yl] piperidin-1-yl} carbonyl) morpholine [racemic cis isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylic acid (Example 38A) and 38 mg (0.22 mmol, 1.1 eq.) 4 -Chloro-N'-hydroxybenzenecarboximidamid reacted. Yield: 61 mg (64% of theory)
HPLC (Method 2A): R _t = 5.49 min; MS (ESIpos): m / z = 481 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.03 (d, 2H), 7.65 (d, 2H), 7.25 (d, 2H), 7.18 (d, 2H), 4.09 (br d, 1H ), 3.62 (br d, 1H), 3.60-3.54 (m, 4H), 3.53-3.45 (m, 1H), 3.25-3.17 (m, 4H), 3.11 (t, 1H), 2.98 (q, 1H) , 2.95-2.84 (m, 1H), 2.58 (q, 2H), 2.42 (br d, 1H), 2.04 (q, 1H), 1.17 (t, 3H).

Example 36

4 - ({3- [3- (1,3-benzodioxol-5-yl) -1,2,4-oxadiazol-5-yl] -5- (4-ethylphenyl) piperidin-1-yl} carbonyl) morpholine [racemic cis isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) -piperidine-3-carboxylic acid (Example 38A) and 40 mg (0.22 mmol, 1.1 eq.) Of N 'Hydroxy-1,3-benzodioxole-5-carboximidamide reacted. Yield: 55 mg (54% of theory)
HPLC (Method 1A): R _t = 4.63 min; MS (ESIpos): m / z = 491 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.58 (dd, 2H), 7.45 (d, 2H), 7.24 (d, 2H), 7.17 (d, 2H), 7.09 (d, 1H) , 6.14 (s, 2H), 4.08 (br d, 1H), 3.62 (br d, 1H), 3.60-3.53 (m, 4H), 3.51-3.42 (m, 1H), 3.25-3.17 (m, 4H) , 3.09 (t, 1H), 2.95 (q, 1H), 2.93-2.84 (m, 1H), 2.58 (q, 2H), 2.36 (br d, 1H), 2.02 (q, 1H), 1.17 (t, 3H).

Example 37

4 - ({3- [3- (2,4-Difluorophenyl) -1,2,4-oxadiazol-5-yl] -5- (4-ethylphenyl) piperidin-1-yl} carbonyl) morpholine [racemic cis- Isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylic acid (Example 38A) and 38 mg (0.22 mmol, 1.1 eq.) 2 , 4-Difluoro-N'-hydroxybenzenecarboximidamid reacted. Yield: 47 mg (47% of theory)
HPLC (Method 1A): R _t = 5.27 min; MS (ESIpos): m / z = 483 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.10 (dd, 1H), 7.54 (dt, 1H), 7.32 (dt, 1H), 7.24 (d, 2H), 7.18 (d, 2H) , 4.09 (br d, 1H), 3.62 (br d, 1H), 3.61-3.54 (m, 4H), 3.56-3.46 (m, 1H), 3.25-3.17 (m, 4H), 3.11 (t, 1H) , 2.97 (q, 1H), 2.95-2.85 (m, 1H), 2.58 (q, 2H), 2.38 (br d, 1H), 2.03 (q, 1H), 1.17 (t, 3H).

Example 38

4 - ({3- [3- (2,4-Difluorophenyl) -1,2,4-oxadiazol-5-yl] -5- [4- (trifluoromethoxy) phenyl] piperidin-1-yl} carbonyl) morpholine [ racemic cis isomer]

According to General Method 1, 80 mg (0.20 mmol) of 1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 44A) and 38 mg (0.22 mmol, 1.1 eq .) Reacted 2,4-difluoro-N'-hydroxybenzenecarboximidamid. Yield: 52 mg (48% of theory)
HPLC (Method 2A): R _t = 5.12 min; MS (ESIpos): m / z = 539 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.14-8.05 (m, 1H), 7.59-7.46 (m, 3H), 7.38-7.28 (m, 3H), 4.09 (br d, 1H) , 3.64 (br d, 1H), 3.62-3.47 (m, 5H), 3.27-3.17 (m, 4H), 3.13 (t, 1H), 3.08-2.97 (m, 2H), 2.41 (br d, 1H) , 2.06 (q, 1H).

Example 39

4 - ({3- [3- (2,6-Difluorophenyl) -1,2,4-oxadiazol-5-yl] -5- (4-ethylphenyl) piperidin-1-yl} carbonyl) morpholine [racemic cis- Isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylic acid (Example 38A) and 38 mg (0.22 mmol, 1.1 eq.) 2 , 6-difluoro-N'-hydroxybenzenecarboximidamid reacted. Yield: 17 mg (18% of theory)
HPLC (Method 2A): R _t = 5.03 min; MS (ESIpos): m / z = 483 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.80-7.72 (m, 1H), 7.39 (t, 2H), 7.27 (d, 2H), 7.20 (d, 2H), 4.11 (br , 1H), 3.64 (br d, 1H), 3.63-3.53 (m, 5H), 3.29-3.19 (m, 4H), 3.14 (t, 1H), 3.00 (t, 1H), 2.97-2.88 (m, 1H), 2.59 (q, 2H), 2.40 (br d, 1H), 2.07 (q, 1H), 1.19 (t, 3H).

Example 48

4 - ({3- [3- (2,6-Difluorophenyl) -1,2,4-oxadiazol-5-yl] -5- [4- (trifluoromethoxy) phenyl] piperidin-1-yl} carbonyl) morpholine [ racemic cis isomer]

According to General Method 1, 80 mg (0.20 mmol) of 1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 44A) and 38 mg (0.22 mmol, 1.1 eq .) Reacted 2,6-difluoro-N'-hydroxybenzenecarboximidamid. Yield: 42 mg (39% of theory)
HPLC (Method 2A): R _t = 4.98 min; MS (ESIpos): m / z = 539 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.78-7.69 (m, 1H), 7.49 (d, 2H), 7.40-7.32 (m, 4H), 4.09 (br d, 1H), 3.63 (br d, 1H), 3.61-3.52 (m, 5H), 3.27-3.18 (m, 4H), 3.13 (t, 1H), 3.07-2.97 (m, 2H), 2.41 (br d, 1H), 2.07 (q, 1H).

Example 41

4 - ({3- [3- (2,5-dichlorophenyl) -1,2,4-oxadiazol-5-yl] -5- (4-ethylphenyl) piperidin-1-yl} carbonyl) morpholine [racemic cis- Isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) -piperidine-3-carboxylic acid (Example 38A) and 45 mg (0.22 mmol, 1.1 eq.) 2 , 5-dichloro-N'-hydroxybenzenecarboximidamid reacted. Yield: 28 mg (27% of theory)
HPLC (Method 1A): R _t = 5.64 min; MS (ESIpos): m / z = 515 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d _6): δ = 7.97 (d, 1H), 7.77-7.68 (m, 2H), 7.24 (d, 2H), 7.18 (d, 2H), 4:08 (br d , 1H), 3.62 (br d, 1H), 3.61-3.54 (m, 4H), 3.58-3.48 (m, 1H), 3.25-3.17 (m, 4H), 3.11 (t, 1H), 2.97 (q, 1H), 2.95-2.85 (m, 1H), 2.57 (q, 2H), 2.38 (br d, 1H), 2.04 (q, 1H), 1.17 (t, 3H).

Example 42

4 - ({3- [3- (3-Chloro-4-fluorophenyl) -1,2,4-oxadiazol-5-yl] -5- (4-ethylphenyl) piperidin-1-yl} carbonyl) morpholine [racemic cis-isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylic acid (Example 38A) and 41 mg (0.22 mmol, 1.1 eq.) 3 -Chloro-4-fluoro-N'-hydroxybenzenecarboximidamid reacted. Yield: 51 mg (51% of theory)
HPLC (Method 1A): R _t = 5.53 min; MS (ESIpos): m / z = 499 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.15 (dd, 1H), 8.07 (m, 1H), 7.64 (t, 1H), 7.24 (d, 2H), 7.18 (d, 2H) , 4.09 (br d, 1H), 3.63 (br d, 1H), 3.61-3.55 (m, 4H), 3.54-3.45 (m, 1H), 3.25-3.17 (m, 4H), 3.11 (t, 1H) , 2.97 (q, 1H), 2.94-2.85 (m, 1H), 2.58 (q, 2H), 2.41 (br d, 1H), 2.03 (q, 1H), 1.17 (t, 3H).

Example 43

4 - ({3- [3- (3-chloro-4-fluorophenyl) -1,2,4-oxadiazol-5-yl] -5- [4- (trifluoromethoxy) phenyl] piperidin-1-yl} carbonyl) morpholine [racemic cis isomer]

According to General Method 1, 80 mg (0.20 mmol) of 1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 44A) and 41 mg (0.22 mmol, 1.1 eq .) Reacted 3-chloro-4-fluoro-N'-hydroxybenzenecarboximidamid. Yield: 51 mg (46% of theory)
HPLC (Method 2A): R _t = 5.45 min; MS (ESIpos): m / z = 555 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.18-8.12 (m, 1H), 8.07-8.00 (m, 1H), 7.64 (t, 1H), 7.49 (d, 2H), 7.34 ( d, 2H), 4.09 (br d, 1H), 3.64 (br d, 1H), 3.61-3.47 (m, 5H), 3.26-3.18 (m, 4H), 3.13 (t, 1H), 3.08-2.97 ( m, 2H), 2.40 (br d, 1H), 2.07 (q, 1H).

Example 44

2- {5- [1- (Cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-yl] -1,2,4-oxadiazol-3-yl} pyridine [racemic cis isomer]

According to General Method 1, 66 mg (0.20 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine-3-carboxylic acid (Example 7A) and 30 mg (0.22 mmol, 1.1 eq.) Of N'-hydroxypyridine 2-carboximidamide reacted. Yield: 27 mg (30% of theory)
HPLC (Method 2A): R _t = 4.98 min; MS (ESIpos): m / z = 431 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 8.76 (d, 1H), 8.08 (d, 1H), 8.02 (t, 1H), 7.61 (dd, 1H), 7.28 (d, 1H) , 7.24 (d, 1H), 7.19 (t, 2H), 4.96 (br d, 0.5H), 4.54 (br d, 0.5H), 4.49 (br d, 0.5H), 4.03 (br d, 0.5H) , 3.50-3.40 (m, 1H), 3.38-3.30 (m, 0.5H), 3.26-3.18 (m, 0.5H), 3.18-3.03 (m, 1H), 2.94-2.83 (m, 1H), 2.82- 2.67 (m, 1H), 2.58 (q, 2H), 2.44-2.32 (m, 1H), 2.21-2.04 (m, 1H), 1.90-1.45 (m, 8H), 1.17 (t, 3H).

Example 45

3- {5- [1- (Cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-yl] -1,2,4-oxadiazol-3-yl} pyridine [racemic cis isomer]

According to General Method 1, 66 mg (0.20 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine-3-carboxylic acid (Example 7A) and 30 mg (0.22 mmol, 1.1 eq.) Of N'-hydroxypyridine 3-carboximidamide reacted. Yield: 37 mg (43% of theory)
HPLC (Method 2A): R _t = 4.66 min; MS (ESIpos): m / z = 431 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 9.18 (s, 1H), 8.79 (d, 1H), 8.37 (d, 1H), 7.62 (dd, 1H), 7.28 (d, 1H) , 7.24 (d, 1H), 7.19 (t, 2H), 4.96 (br d, 0.5H), 4.53 (br d, 0.5H), 4.49 (br d, 0.5H), 4.03 (br d, 0.5H) , 3.51-3.41 (m, 1H), 3.39-3.32 (m, 0.5H), 3.27-3.19 (m, 0.5H), 3.18-3.02 (m, 1H), 2.97-2.83 (m, 1H), 2.82- 2.68 (m, 1H), 2.58 (q, 2H), 2.43-2.34 (m, 1H), 2.21-2.03 (m, 1H), 1.89-1.47 (m, 8H), 1.17 (t, 3H).

Example 46

3- (5- {cis- (3,5) -1 - {(cyclopentylcarbonyl) -5- [4- (trifluoromethyl) phenyl] piperidin-3-yl} -1,2,4-oxadiazol-3-yl) pyridine [racemic cis isomer]

According to general method 2, 150 mg (0.41 mmol) of cis- (3,5) -1- (cyclopentylcarbonyl) -5- [4- (trifluoromethyl) phenyl] -piperidine-3-carboxylic acid (Example 17A) and 83 mg (0.61 mmol) are added mmol, 1.5 eq.) of N'-hydroxypyridine-3-carboximidamide. Yield: 149 mg (78% of theory)
LC-MS (Method 6B): R _t = 2.51 min; MS (ESIpos): m / z = 471 [M + H] ⁺ .

Example 47

3- (5- {cis- (3,5) - {1- (cyclopentylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidin-3-yl} -1,2,4-oxadiazol-3-yl) pyridine [racemic cis isomer]

According to the general method 2, 70 mg (0.18 mmol) of cis- (3,5) -1- (cyclopentylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 24A) and 41 mg (0.27 mmol) are added mmol, 1.5 eq.) of N'-hydroxypyridine-3-carboximidamide. Yield: 56 mg (63% of theory)
LC-MS (Method 1B): R _t = 2.98 min; MS (ESIpos): m / z = 487 [M + H] ⁺ .

Example 48

4- {5- [1- (Cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-yl] -1,2,4-oxadiazol-3-yl} pyridine [racemic cis isomer]

According to General Method 1, 66 mg (0.20 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine-3-carboxylic acid (Example 7A) and 30 mg (0.22 mmol, 1.1 eq.) Of N'-hydroxypyridine 4-carboximidamide reacted. Yield: 39 mg (45% of theory)
HPLC (Method 2A): R _t = 4.59 min; MS (ESIpos): m / z = 431 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 8.80 (d, 2H), 7.94 (d, 2H), 7.28 (d, 1H), 7.23 (d, 1H), 7.19 (t, 2H) , 4.96 (br d, 0.5H), 4.53 (br d, 0.5H), 4.49 (br d, 0.5H), 4.03 (br d, 0.5H), 3.54-3.40 (m, 1H), 3.40-3.32 ( m, 0.5H), 3.26-3.18 (m, 0.5H), 3.17-3.03 (m, 1H), 2.96-2.82 (m, 1H), 2.81-2.67 (m, 1H), 2.58 (q, 2H), 2.44-2.34 (m, 1H), 2.20-2.03 (m, 1H), 1.89-1.47 (m, 8H), 1.17 (t, 3H).

Example 49

4 - ({3- (3-Pyridin-4-yl-1,2,4-oxadiazol-5-yl) -5- [4- (trifluoromethoxy) phenyl] -piperidin-1-yl} carbonyl) morpholine [racemic cis -Isomer]

According to General Method 1, 80 mg (0.20 mmol) of 1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 44A) and 30 mg (0.22 mmol, 1.1 eq .) N'-hydroxypyridine-4-carboximidamide reacted. Yield: 52 mg (52% of theory)
HPLC (Method 1A): R _t = 4.23 min; MS (ESIpos): m / z = 503 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.81 (d, 2H), 7.95 (d, 2H), 7.49 (d, 2H), 7.34 (d, 2H), 4.10 (br d, 1H ), 3.64 (br d, 1H), 3.61-3.50 (m, 5H), 3.27-3.19 (m, 4H), 3.14 (t, 1H), 3.09-2.98 (m, 2H), 2.41 (br d, 1H ), 2.08 (q, 1H).

Example 50

4 - {[3- (4-Ethylphenyl) -5- (3-pyrazin-2-yl-1,2,4-oxadiazol-5-yl) piperidin-1-yl] carbonyl} morpholine [racemic cis isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) -piperidine-3-carboxylic acid (Example 38A) and 30 mg (0.22 mmol, 1.1 eq.) Of N Reacted hydroxypyrazine-2-carboximidamide. Yield: 45 mg (50% of theory)
HPLC (Method 2A): R _t = 4.52 min; MS (ESIpos): m / z = 449 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 9.27 (s, 1H), 8.90-8.85 (m, 2H), 7.25 (d, 2H), 7.18 (d, 2H), 4.12 (br , 1H), 3.63 (br d, 1H), 3.61-3.50 (m, 5H), 3.26-3.18 (m, 4H), 3.14 (t, 1H), 2.97 (q, 1H), 2.95-2.86 (m, 1H), 2.58 (q, 2H), 2.39 (br d, 1H), 2.07 (q, 1H), 1.17 (t, 3H).

Example 51

4 - ({3- (4-Ethylphenyl) -5- [3- (4-methylpyridin-2-yl) -1,2,4-oxadiazol-5-yl] -piperidin-1-yl} carbonyl) morpholine [racemic cis-isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylic acid (Example 38A) and 33 mg (0.22 mmol, 1.1 eq.) Of N 'Reacted hydroxy-4-methylpyridine-2-carboximidamide. Yield: 35 mg (38% of theory)
HPLC (Method 1A): R _t = 4.49 min; MS (ESIpos): m / z = 462 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.06 (d, 1H), 7.93 (s, 1H), 7.43 (d, 1H), 7.25 (d, 2H), 7.18 (d, 2H) , 4.09 (br d, 1H), 3.62 (br d, 1H), 3.61-3.54 (m, 4H), 3.55-3.46 (m, 1H), 3.27-3.18 (m, 4H), 3.11 (t, 1H) , 2.96 (q, 1H), 2.95-2.85 (m, 1H), 2.58 (q, 2H), 2.43 (s, 3H), 2.38 (br d, 1H), 2.04 (q, 1H), 1.17 (t, 3H).

Example 52

4 - ({3- (4-Ethylphenyl) -5- [3- (6-methylpyridin-2-yl) -1,2,4-oxadiazol-5-yl] -piperidin-1-yl} carbonyl) morpholine [racemic cis-isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylic acid (Example 38A) and 33 mg (0.22 mmol, 1.1 eq.) Of N '-Hydroxy-6-methylpyridine-2-carboximidamide reacted. Yield: 44 mg (47% of theory)
HPLC (Method 1A): R _t = 4.54 min; MS (ESIpos): m / z = 462 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.93-7.85 (m, 2H), 7.51-7.42 (m, 1H), 7.25 (d, 2H), 7.18 (d, 2H), 4.09 ( br d, 1H), 3.63 (br d, 1H), 3.62-3.53 (m, 4H), 3.55-3.45 (m, 1H), 3.25-3.18 (m, 4H), 3.12 (t, 1H), 2.95 ( q, 1H), 2.94-2.83 (m, 1H), 2.57 (q, 2H), 2.37 (br d, 1H), 2.05 (q, 1H), 1.17 (t, 3H).

Example 53

1- (Cyclopentylcarbonyl) -3- (4-ethylphenyl) -5- [3- (2-methyl-1,3-thiazol-4-yl) -1,2,4-oxadiazol-5-yl] piperidine [racemic cis-isomer]

According to General Method 1, 66 mg (0.20 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine-3-carboxylic acid (Example 7A) and 35 mg (0.22 mmol, 1.1 eq.) Of N'-hydroxy- 2-methyl-1,3-thiazole-4-carboximidamide reacted. Yield: 36 mg (40% of theory)
HPLC (Method 2A): R _t = 5.17 min; MS (ESIpos): m / z = 451 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 8.28 (s, 1H), 7.28 (d, 1H), 7.23 (d, 1H), 7.19 (t, 2H), 4.94 (br d, 0.5 H), 4.53 (br d, 0.5H), 4.47 (br d, 0.5H), 4.02 (br d, 0.5H), 3.48-3.37 (m, 1H), 3.35-3.27 (m, 0.5H), 3.25 -3.18 (m, 0.5H), 3.16-3.03 (m, 1H), 2.92-2.82 (m, 1H), 2.79-2.67 (m, 1H), 2.74 (s, 3H), 2.58 (q, 2H), 2.43-2.34 (m, 1H), 2.18-2.02 (m, 1H), 1.88-1.46 (m, 8H), 1.17 (t, 3H).

Example 54

1- (cyclopentylcarbonyl) -3- (4-ethylphenyl) -5- [3- (5-methylisoxazol-3-yl) -1,2,4-oxadiazol-5-yl] piperidine [racemic cis isomer]

According to General Method 1, 66 mg (0.20 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine-3-carboxylic acid (Example 7A) and 31 mg (0.22 mmol, 1.1 eq.) Of N'-hydroxy- 5-methylisoxazole-3-carboximidamide reacted. Yield: 50 mg (58% of theory)
HPLC (Method 1A): R _t = 5.23 min; MS (ESIpos): m / z = 435 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 7.27 (d, 1H), 7.23 (d, 1H), 7.19 (t, 2H), 6.81 (s, 1H), 4.94 (br d, 0.5 H), 4.52 (br d, 0.5H), 4.48 (br d, 0.5H), 4.02 (br d, 0.5H), 3.50-3.40 (m, 1H), 3.40-3.32 (m, 0.5H), 3.25 -3.18 (m, 0.5H), 3.17-3.02 (m, 1H), 2.94-2.81 (m, 1H), 2.80-2.65 (m, 1H), 2.58 (q, 2H), 2.42-2.32 (m, 1H ), 2.19-2.02 (m, 1H), 1.88-1.47 (m, 8H), 1.17 (t, 3H).

Example 55

3- (3-Benzyl-1,2,4-oxadiazol-5-yl) -1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine [racemic cis isomer]

According to General Method 1, 66 mg (0.20 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) -piperidine-3-carboxylic acid (Example 7A) and 33 mg (0.22 mmol, 1.1 eq.) Of N'-hydroxy- Implemented 2-phenylethanimidamide. Yield: 50 mg (56% of theory)
HPLC (Method 1A): R _t = 5.48 min; MS (ESIpos): m / z = 444 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 7.35-7.28 (m, 4H), 7.28-7.22 (m, 2H), 7.21-7.14 (m, 3H), 4.84 (br d, 0.5H ), 4.48 (br d, 0.5H), 4.36 (br d, 0.5H), 4.09 (s, 2H), 3.98 (br d, 0.5H), 3.38-3.29 (m, 1H), 3.22-3.13 (m , 1H), 3.11-3.00 (m, 1H), 2.85-2.73 (m, 1H), 2.72-2.61 (m, 1H), 2.57 (q, 2H), 2.32-2.22 (m, 1H), 2.08-1.92 (m, 1H), 1.84-1.45 (m, 8H), 1.16 (t, 3H).

Example 56

3- (3-Benzyl-1,2,4-oxadiazol-5-yl) -1- (cyclopentylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine [racemic cis isomer]

According to General Method 1, 70 mg (0.18 mmol) of cis- (3,5) -1- (cyclopentylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 24A) and 41 mg (0.27 mmol) mmol, 1.5 eq.) of N'-hydroxy-2-phenylethanimidamide. Yield: 55 mg (61% of theory)
LC-MS (Method 1B): R _t = 3.25 min; MS (ESIpos): m / z = 500 [M + H] ⁺ ;

Example 57

4 - {[3- (3-Benzyl-1,2,4-oxadiazol-5-yl) -5- (4-ethylphenyl) piperidin-1-yl] carbonyl} morpholine [racemic cis isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylic acid (Example 38A) and 33 mg (0.22 mmol, 1.1 eq.) Of N 'Reacted hydroxy-2-phenylethanimidamid. Yield: 43 mg (47% of theory)
HPLC (Method 1A): R _t = 4.85 min; MS (ESIpos): m / z = 461 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.38-7.23 (m, 5H), 7.20 (d, 2H), 7.15 (d, 2H), 4.08 (s, 2H), 3.98 (br , 1H), 3.58 (br d, 1H), 3.58-3.50 (m, 4H), 3.43-3.32 (m, 1H), 3.22-3.13 (m, 4H), 3.00 (t, 1H), 2.91 (q, 1H), 2.89-2.79 (m, 1H), 2.56 (q, 2H), 2.27 (br d, 1H), 1.93 (q, 1H), 1.16 (t, 3H).

Example 58

4 - ({3- (3-Benzyl-1,2,4-oxadiazol-5-yl) -5- [4- (trifluoromethoxy) phenyl] piperidin-1-yl} carbonyl) morpholine [racemic cis isomer]

According to General Method 1, 80 mg (0.20 mmol) of 1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 44A) and 33 mg (0.22 mmol, 1.1 eq .) N'-hydroxy-2-phenylethanimidamid reacted. Yield: 46 mg (44% of theory)
HPLC (Method 1A): R _t = 5.01 min; MS (ESIpos): m / z = 517 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.45 (d, 2H), 7.36-7.22 (m, 7H), 4.08 (s, 2H), 3.97 (br d, 1H), 3.59 (br d, 1H), 3.59-3.51 (m, 4H), 3.43-3.33 (m, 1H), 3.22-3.14 (m, 4H), 3.02 (t, 1H), 3.01-2.91 (m, 2H), 2.29 ( br d, 1H), 1.96 (q, 1H).

Example 59

3- [3- (2-Chlorobenzyl) -1,2,4-oxadiazol-5-yl] -1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine [racemic cis isomer]

According to General Method 1, 66 mg (0.20 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) -piperidine-3-carboxylic acid (Example 7A) and 41 mg (0.22 mmol, 1.1 eq.) Of 2- (2 Chlorophenyl) -N'-hydroxyethanimidamide. Yield: 21 mg (22% of theory)
HPLC (Method 2A): R _t = 5.64 min; MS (ESIpos): m / z = 478 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 7.47 (dd, 1H), 7.42 (dd, 1H), 7.33 (dd, 2H), 7.24 (d, 1H), 7.22-7.13 (m, 3H), 4.83 (br d, 0.5H), 4.48 (br d, 0.5H), 4.37 (br d, 0.5H), 4.21 (s, 2H), 3.98 (br d, 0.5H), 3.38-3.30 ( m, 1H), 3.25-3.14 (m, 1H), 3.13-2.99 (m, 1H), 2.86-2.74 (m, 1H), 2.73-2.62 (m, 1H), 2.57 (q, 2H), 2.32- 2.22 (m, 1H), 2.08-1.92 (m, 1H), 1.84-1.45 (m, 8H), 1.16 (t, 3H).

Example 60

4 - ({3- [3- (2-Chlorobenzyl) -1,2,4-oxadiazol-5-yl] -5- (4-ethylphenyl) piperidin-1-yl} carbonyl) morpholine [racemic cis isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) -piperidine-3-carboxylic acid (Example 38A) and 41 mg (0.22 mmol, 1.1 eq.) 2 - (2-chlorophenyl) -N'-hydroxyethanimidamide reacted. Yield: 10 mg (10% of theory)
LC-MS (Method 2B): R _t = 1.49 min; MS (ESIpos): m / z = 495 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.50-7.44 (m, 1H), 7.45-7.40 (m, 1H), 7.36-7.30 (m, 2H), 7.21 (d, 2H), 7.16 (d, 2H), 4.21 (s, 2H), 3.98 (br d, 1H), 3.58 (br d, 1H), 3.57-3.50 (m, 4H), 3.43-3.33 (m, 1H), 3.22- 3.12 (m, 4H), 3.00 (t, 1H), 2.92 (q, 1H), 2.89-2.79 (m, 1H), 2.56 (q, 2H), 2.27 (br d, 1H), 1.93 (q, 1H ), 1.16 (t, 3H).

Example 61

4 - ({3- (4-Ethylphenyl) -5- [3- (3-methylbenzyl) -1,2,4-oxadiazol-5-yl] -piperidin-1-yl} carbonyl) morpholine [racemic cis isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) -piperidine-3-carboxylic acid (Example 38A) and 36 mg (0.22 mmol, 1.1 eq.) Of N 'Reacted hydroxy-2- (3-methylphenyl) ethanimidamide. Yield: 57 mg (60% of theory)
HPLC (Method 1A): R _t = 5.26 min; MS (ESIpos): m / z = 475 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.25-7.13 (m, 5H), 7.13-7.04 (m, 3H), 4.03 (s, 2H), 3.98 (br d, 1H), 3.57 (br d, 1H), 3.57-3.51 (m, 4H), 3.42-3.33 (m, 1H), 3.21-3.14 (m, 4H), 3.00 (t, 1H), 2.91 (q, 1H), 2.88- 2.79 (m, 1H), 2.57 (q, 2H), 2.28 (s, 3H), 2.25 (br d, 1H), 1.93 (q, 1H), 1.16 (t, 3H).

Example 62

1- (cyclopentylcarbonyl) -3- (4-ethylphenyl) -5- [3- (4-fluorobenzyl) -1,2,4-oxadiazol-5-yl] piperidine [racemic cis isomer]

According to General Method 1, 66 mg (0.20 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine-3-carboxylic acid (Example 7A) and 37 mg (0.22 mmol, 1.1 eq.) Of 2- (4- Fluorophenyl) -N'-hydroxyethanimidamide. Yield: 22 mg (24% of theory)
HPLC (Method 2A): R _t = 5.51 min; MS (ESIpos): m / z = 462 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 7.35 (dd, 2H), 7.24 (d, 1H), 7.22-7.13 (5H), 4.84 (br d, 0.5H), 4.49 (br , 0.5H), 4.37 (br d, 0.5H), 4.09 (s, 2H), 3.98 (br d, 0.5H), 3.38-3.28 (m, 1H), 3.23-3.13 (m, 1H), 3.12- 3.00 (m, 1H), 2.86-2.74 (m, 1H), 2.73-2.62 (m, 1H), 2.57 (q, 2H), 2.32-2.22 (m, 1H), 2.08-1.91 (m, 1H), 1.85-1.44 (m, 8H), 1.16 (t, 3H).

Example 63

4 - ({3- (4-Ethylphenyl) -5- [3- (4-fluorobenzyl) -1,2,4-oxadiazol-5-yl] -piperidin-1-yl} carbonyl) morpholine [racemic cis isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylic acid (Example 38A) and 37 mg (0.22 mmol, 1.1 eq.) 2 - (4-fluorophenyl) -N'-hydroxyethanimidamid reacted. Yield: 44 mg (45% of theory)
HPLC (Method 1A): R _t = 5.14 min; MS (ESIpos): m / z = 479 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.39-7.30 (m, 2H), 7.21 (d, 2H), 7.18-7.10 (m, 4H), 4.09 (s, 2H), 3.98 ( br d, 1H), 3.57 (br d, 1H), 3.57-3.51 (m, 4H), 3.43-3.33 (m, 1H), 3.21-3.13 (m, 4H), 3.00 (t, 1H), 2.92 ( q, 1H), 2.89-2.79 (m, 1H), 2.56 (q, 2H), 2.27 (br d, 1H), 1.92 (q, 1H), 1.16 (t, 3H).

Example 64

4 - ({3- [3- (4-fluorobenzyl) -1,2,4-oxadiazol-5-yl] -5- [4- (trifluoromethoxy) phenyl] piperidin-1-yl} carbonyl) morpholine [racemic cis -Isomer]

According to General Method 1, 80 mg (0.20 mmol) of 1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 44A) and 37 mg (0.22 mmol, 1.1 eq .) Reacted 2- (4-fluorophenyl) -N'-hydroxyethanimidamide. Yield: 61 mg (57% of theory)
HPLC (Method 2A): R _t = 5.02 min; MS (ESIpos): m / z = 535 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.45 (d, 2H), 7.38-7.30 (m, 4H), 7.15 (t, 2H), 4.09 (s, 2H), 3.97 (br , 1H), 3.59 (br d, 1H), 3.59-3.51 (m, 4H), 3.43-3.32 (m, 1H), 3.22-3.15 (m, 4H), 3.02 (t, 1H), 3.00-2.91 ( m, 2H), 2.29 (br d, 1H), 1.96 (q, 1H).

Example 65

4 - ({3- [3- (4-Chlorobenzyl) -1,2,4-oxadiazol-5-yl] -5- (4-ethylphenyl) piperidin-1-yl} carbonyl) morpholine [racemic cis isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) -piperidine-3-carboxylic acid (Example 38A) and 41 mg (0.22 mmol, 1.1 eq.) 2 - (4-chlorophenyl) -N'-hydroxyethanimidamid reacted. Yield: 62 mg (63% of theory)
HPLC (Method 1A): R _t = 5.33 min; MS (ESIpos): m / z = 495 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.39 (d, 2H), 7.33 (d, 2H), 7.21 (d, 2H), 7.16 (d, 2H), 4.10 (s, 2H) , 3.98 (br d, 1H), 3.57 (br d, 1H), 3.57-3.51 (m, 4H), 3.43-3.34 (m, 1H), 3.21-3.14 (m, 4H), 2.99 (t, 1H) , 2.92 (q, 1H), 2.89-2.79 (m, 1H), 2.56 (q, 2H), 2.27 (br d, 1H), 1.93 (q, 1H), 1.16 (t, 3H).

Example 66

4 - ({3- (4-Ethylphenyl) -5- [3- (4-methylbenzyl) -1,2,4-oxadiazol-5-yl] -piperidin-1-yl} carbonyl) morpholine [racemic cis isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) -piperidine-3-carboxylic acid (Example 38A) and 36 mg (0.22 mmol, 1.1 eq.) Of N '-Hydroxy-2- (4-methylphenyl) ethanimidamide implemented. Yield: 57 mg (60% of theory)
HPLC (Method 1A): R _t = 5.31 min; MS (ESIpos): m / z = 475 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.23-7.10 (m, 8H), 4.02 (s, 2H), 3.97 (br d, 1H), 3.57 (br d, 1H), 3.57- 3.50 (m, 4H), 3.42-3.31 (m, 1H), 3.21-3.12 (m, 4H), 2.99 (t, 1H), 2.91 (q, 1H), 2.88-2.79 (m, 1H), 2.56 ( q, 2H), 2.26 (s, 3H), 2.25 (br d, 1H), 1.92 (q, 1H), 1.16 (t, 3H).

Example 67

4 - ({3- [3- (2-Chloro-4-fluorobenzyl) -1,2,4-oxadiazol-5-yl] -5- (4-ethylphenyl) piperidin-1-yl} carbonyl) morpholine [racemic cis-isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) -piperidine-3-carboxylic acid (Example 38A) and 45 mg (0.22 mmol, 1.1 eq.) 2 - (2-chloro-4-fluorophenyl) -N'-hydroxyethanimidamid reacted. Yield: 59 mg (57% of theory)
HPLC (Method 1A): R _t = 5.29 min; MS (ESIpos): m / z = 513 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.53-7.45 (m, 2H), 7.26-7.19 (m, 3H), 7.16 (d, 2H), 4.20 (s, 2H), 3.97 ( br d, 1H), 3.58 (br d, 1H), 3.58-3.51 (m, 4H), 3.43-3.34 (m, 1H), 3.22-3.14 (m, 4H), 3.05-2.89 (m, 2H), 2.89-2.79 (m, 1H), 2.56 (q, 2H), 2.27 (br d, 1H), 1.92 (q, 1H), 1.16 (t, 3H).

Example 68

4 - ({3- (4-Ethylphenyl) -5- [3- (phenoxymethyl) -1,2,4-oxadiazol-5-yl] piperidin-1-yl} carbonyl) morpholine [racemic cis isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) -piperidine-3-carboxylic acid (Example 38A) and 37 mg (0.22 mmol, 1.1 eq.) Of N Reacted hydroxy-2-phenoxyethanimidamid. Yield: 40 mg (42% of theory)
HPLC (Method 1A): R _t = 5.06 min; MS (ESIpos): m / z = 477 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.32 (t, 2H), 7.23 (d, 2H), 7.17 (d, 2H), 7.05 (d, 2H), 6.99 (t, 1H) , 5.26 (s, 2H), 4.02 (br d, 1H), 3.60 (br d, 1H), 3.60-3.52 (m, 4H), 3.50-3.40 (m, 1H), 3.23-3.16 (m, 4H) , 3.06 (t, 1H), 2.93 (q, 1H), 2.91-2.82 (m, 1H), 2.57 (q, 2H), 2.32 (br d, 1H), 1.98 (q, 1H), 1.16 (t, 3H).

Example 69

1- (cyclopentylcarbonyl) -3- (4-ethylphenyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) piperidine [racemic cis isomer]

According to General Method 1, 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 N'-hydroxyethanimidamide are reacted , Yield: 58 mg (79% of theory)
HPLC (Method 2A): R _t = 5.04 min; MS (ESIpos): m / z = 368 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 7.25 (d, 1H), 7.23-7.14 (m, 3H), 4.85 (br d, 0.5H), 4.50 (br d, 0.5H), 4.38 (br d, 0.5H), 3.99 (br d, 0.5H), 3.37-3.28 (m, 1H), 3.23-3.13 (m, 1H), 3.12-3.01 (m, 1H), 2.88-2.74 (m , 1H), 2.73-2.62 (m, 1H), 2.58 (q, 2H), 2.33 (s, 3H), 2.33-2.25 (m, 1H), 2.09-1.94 (m, 1H), 1.86-1.47 (m , 8H), 1.17 (t, 3H).

Example 70

1- (cyclopentylcarbonyl) -3- (4-ethylphenyl) -5- (3-propyl-1,2,4-oxadiazol-5-yl) piperidine [racemic cis isomer]

According to General Method 1, 66 mg (0.20 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine-3-carboxylic acid (Example 7A) and 22 mg (0.22 mmol, 1.1 eq.) Of N'-hydroxybutanimidamide are reacted , Yield: 12 mg (15% of theory)
HPLC (Method 2A): R _t = 5.41 min; MS (ESIpos): m / z = 396 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 7.30-7.13 (m, 4H), 4.85 (br d, 0.5H), 4.50 (br d, 0.5H), 4.38 (br d, 0.5H ), 3.99 (br d, 0.5H), 3.39-3.29 (m, 1H), 3.24-3.14 (m, 1H), 3.14-3.00 (m, 1H), 2.88-2.75 (m, 1H), 2.75-2.62 (m, 1H), 2.67 (t, 2H), 2.57 (q, 2H), 2.34-2.25 (m, 1H), 2.10-1.93 (m, 1H), 1.86-1.45 (m, 8H), 1.73-1.66 (m, 2H), 1.17 (t, 3H), 0.92 (t, 3H).

Example 71

3- (3-tert-Butyl-1,2,4-oxadiazol-5-yl) -1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine [racemic cis isomer]

According to General Method 1, 66 mg (0.20 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) -piperidine-3-carboxylic acid (Example 7A) and 26 mg (0.22 mmol, 1.1 eq.) Of N'-hydroxy- Implemented 2,2-dimethylpropanimidamide. Yield: 49 mg (60% of theory)
HPLC (Method 2A): R _t = 5.63 min; MS (ESIpos): m / z = 410 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 7.26 (d, 1H), 7.24-7.14 (m, 3H), 4.85 (br d, 0.5H), 4.49 (br d, 0.5H), 4.37 (br d, 0.5H), 3.99 (br d, 0.5H), 3.40-3.31 (m, 1H), 3.25-3.16 (m, 1H), 3.14-3.01 (m, 1H), 2.87-2.76 (m , 1H), 2.75-2.67 (m, 1H), 2.58 (q, 2H), 2.33-2.23 (m, 1H), 2.09-1.92 (m, 1H), 1.85-1.44 (m, 8H), 1.31 (s , 9H), 1.17 (t, 3H).

Example 72

cis- (3,5) -3- (3-tert-butyl-1,2,4-oxadiazol-5-yl) -1- (cyclopentylcarbonyl) -5- [4- (1-methylethyl) phenyl] piperidine [racemic cis isomer]

According to General Method 2, 73 mg (0.21 mmol) of cis- (3,5) -1- (cyclopentylcarbonyl) -5- [4- (1-methylethyl) phenyl] piperidine-3-carboxylic acid (Example 12A) and 37 mg (0.32 mmol, 1.5 eq.) Of N'-hydroxy-2,2-dimethylpropanimidamide. Yield: 29 mg (33% of theory)
LC-MS (Method 3B): R _t = 2.88 min; MS (ESIpos): m / z = 424 [M + H] ⁺ .

Example 73

4 - {[3- (3-tert-butyl-1,2,4-oxadiazol-5-yl) -5- (4-ethylphenyl) piperidin-1-yl] carbonyl} morpholine [racemic cis isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylic acid (Example 38A) and 26 mg (0.22 mmol, 1.1 eq.) Of N Reacted '-hydroxy-2,2-dimethylpropanimidamid. Yield: 60 mg (70% of theory)
HPLC (Method 1A): R _t = 4.90 min; MS (ESIpos): m / z = 427 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.22 (d, 2H), 7.16 (d, 2H), 3.99 (br d, 1H), 3.59 (br d, 1H), 3.59-3.50 ( m, 4H), 3.43-3.32 (m, 1H), 3.23-3.13 (m, 4H), 2.99 (q, 2H), 2.92-2.80 (m, 1H), 2.57 (q, 2H), 2.29 (br , 1H), 1.94 (q, 1H), 1.30 (s, 9H), 1.16 (t, 3H).

Example 74

4 - ({3- (3-tert-butyl-1,2,4-oxadiazol-5-yl) -5- [4- (trifluoromethoxy) phenyl] -piperidin-1-yl} carbonyl) -morpholine [racemic cis- Isomer]

According to General Method 1, 80 mg (0.20 mmol) of 1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 44A) and 26 mg (0.22 mmol, 1.1 eq .) N'-hydroxy-2,2-dimethylpropanimidamid reacted. Yield: 68 mg (70% of theory)
HPLC (Method 2A): R _t = 5.08 min; MS (ESIpos): m / z = 483 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.48 (d, 2H), 7.33 (d, 2H), 3.99 (br d, 1H), 3.60 (br d, 1H), 3.59-3.51 ( m, 4H), 3.43-3.33 (m, 1H), 3.23-3.15 (m, 4H), 3.09-2.91 (m, 3H), 2.31 (br d, 1H), 1.96 (q, 1H), 1.30 (s , 9H).

Example 75

Ethyl 5- [1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-yl] -1,2,4-oxadiazole-3-carboxylate [racemic cis isomer]

According to General Method 1, 198 mg (0.60 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine-3-carboxylic acid (Example 7A) and 87 mg (0.66 mmol, 1.1 eq.) Of 2-amino (hydroxyimino ) Ethyl ethanoate implemented. Yield: 73 mg (27% of theory)
HPLC (Method 1A): R _t = 5.28 min; MS (ESIpos): m / z = 426 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 7.30-7.12 (m, 4H), 4.89 (br d, 0.5H), 4.50 (br d, 0.5H), 4.47-4.37 (m, 2.5 H), 4.01 (br d, 0.5H), 3.52-3.32 (m, 1H), 3.20 (t, 1H), 3.14-3.00 (m, 1H), 2.82-2.79 (m, 1H), 2.79-2.63 ( m, 1H), 2.58 (q, 2H), 2.39-2.27 (m, 1H), 2.18-1.99 (m, 1H), 1.89-1.43 (m, 8H), 1.33 (t, 3H), 1.17 (t, 3H).

Example 76

cis- (3,5) -1- (cyclopentylcarbonyl) -3- (4-methoxyphenyl) -5- {3 - [(methylsulfonyl) methyl] -1,2,4-oxadiazol-5-yl} piperidine [racemic cis -Isomer]

According to General Method 2, 100 mg (0.27 mmol) of cis- (3,5) -1- (cyclopentylcarbonyl) -5- (4-methoxyphenyl) -piperidine-3-carboxylic acid (Example 30A) and 63 mg (0.41 mmol, 1.5 eq.) N'-hydroxy-2- (methylsulfonyl) ethanimidamide reacted. Yield: 17 mg (14% of theory)
LC-MS (Method 3B): R _t = 1.88 min; MS (ESIpos): m / z = 448 [M + H] ⁺ .

Example 77

4 - [(3- {3 - [(Methylsulfonyl) methyl] -1,2,4-oxadiazol-5-yl} -5- [4- (trifluoromethoxy) phenyl] piperidin-1-yl) carbonyl] morpholine [racemic cis-isomer]

According to General Method 1, 80 mg (0.20 mmol) of 1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 44A) and 33 mg (0.22 mmol, 1.1 eq .) N'-hydroxy-2- (methylsulfonyl) ethanimidamide reacted. Yield: 50 mg (48% of theory)
HPLC (Method 2A): R _t = 4.37 min; MS (ESIpos): m / z = 519 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.48 (d, 2H), 7.33 (d, 2H), 4.85 (s, 2H), 4.03 (br d, 1H), 3.61 (br d, 1H), 3.60-3.53 (m, 4H), 3.52-3.43 (m, 1H), 3.25-3.18 (m, 4H), 3.17 (s, 3H), 3.07 (t, 1H), 3.03-2.94 (m, 2H), 2.35 (br d, 1H), 2.00 (q, 1H).

Example 78

4 - ({5- [1- (Cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidin-3-yl] -1,2,4-oxadiazol-3-yl} methyl) morpholine [racemic cis isomer]

According to General Method 1, 66 mg (0.20 mmol) of 1- (cyclopentylcarbonyl) -5- (4-ethylphenyl) piperidine-3-carboxylic acid (Example 7A) and 35 mg (0.22 mmol, 1.1 eq.) Of N'-hydroxy- 2-morpholin-4-ylethanimidamid reacted. Yield: 7 mg (8% of theory)
HPLC (Method 2A): R _t = 4.46 min; MS (ESIpos): m / z = 453 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 7.30-7.13 (m, 4H), 4.89 (br d, 0.5H), 4.51 (br d, 0.5H), 4.40 (br d, 0.5H ), 4.01 (br d, 0.5H), 3.43-3.30 (m, 1H), 3.24-3.16 (m, 1H), 3.14-3.00 (m, 1H), 2.90-2.77 (m, 1H), 2.77-2.61 (m, 1H), 2.58 (q, 2H), 2.38-2.27 (m, 1H), 2.11-1.94 (m, 1H), 1.87-1.44 (m, 8H), 1.17 (t, 3H).

Example 79

4 - [(5- {1- (Morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidin-3-yl} -1,2,4-oxadiazol-3-yl) methyl] morpholine [ racemic cis isomer]

According to General Method 1, 80 mg (0.20 mmol) of 1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 44A) and 35 mg (0.22 mmol, 1.1 eq .) N'-hydroxy-2-morpholin-4-ylethanimidamid reacted. Yield: 28 mg (26% of theory)
HPLC (Method 2A): R _t = 4.13 min; MS (ESIpos): m / z = 526 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.47 (d, 2H), 7.33 (d, 2H), 4.00 (br d, 1H), 3.64 (s, 2H), 3.61 (br d, 1H), 3.59-3.52 (m, 4H), 3.47-3.36 (m, 1H), 3.32-3.26 (m, 4H), 3.05 (t, 1H), 3.03-2.93 (m, 2H), 2.32 (br , 1H), 1.98 (q, 1H).

Example 80

4 - ({3- (4-ethylphenyl) -5- [3- (1-methyl-1,2,5,6-tetrahydropyridin-3-yl) -1,2,4-oxadiazol-5-yl] piperidine -1-yl} carbonyl) morpholine [racemic cis isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylic acid (Example 38A) and 34 mg (0.22 mmol, 1.1 eq.) Of N '-Hydroxy-1-methyl-1,2,5,6-tetrahydropyridine-3-carboximidamide [ P. Sauerberg et al. J. Med. 1991, 34, 687-692 ] implemented. Yield: 35 mg (38% of theory)
HPLC (Method 2A): R _t = 4.17 min; MS (ESIpos): m / z = 466 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 7.22 (d, 2H), 7.17 (d, 2H), 6.90-6.84 (m, 1H), 4.01 (br d, 1H), 3.61 (br d, 1H), 3.60-3.53 (m, 4H), 3.44-3.33 (m, 1H), 3.23-3.14 (m, 6H), 3.03 (t, 1H), 2.95 (q, 1H), 2.91-2.82 ( m, 1H), 2.57 (q, 2H), 2.38-2.26 (m, 6H), 1.97 (q, 1H), 1.16 (t, 3H).

Example 81

4 - ({3- [3- (1-methyl-1,2,5,6-tetrahydropyridin-3-yl) -1,2,4-oxadiazol-5-yl] -5- [4- (trifluoromethoxy) phenyl] piperidin-1-yl} carbonyl) morpholine [racemic cis isomer]

According to General Method 1, 80 mg (0.20 mmol) - (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 44A) and 34 mg (0.22 mmol, 1.1 eq. ) N'-hydroxy-1-methyl-1,2,5,6-tetrahydropyridine-3-carboximidamide [ P. Sauerberg et al. J. Med. 1991, 34, 687-692 ] implemented. Yield: 23 mg (22% of theory)
HPLC (Method 2A): R _t = 4.21 min; MS (ESIpos): m / z = 522 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.48 (d, 2H), 7.33 (d, 2H), 6.90-6.84 (m, 1H), 4.01 (br d, 1H), 3.61 (br d, 1H), 3.59-3.53 (m, 4H), 3.46-3.35 (m, 1H), 3.24-3.14 (m, 6H), 3.05 (t, 1H), 3.03-2.93 (m, 2H), 2.38- 2.28 (m, 6H), 1.99 (q, 1H).

Example 82

[({4- (1- (morpholin-4-ylcarbonyl) -5- [trifluoromethoxy) phenyl] piperidin-3-yl} 5- -1,2,4-oxadiazol-3-yl) methyl] -tert.- butylcarbamate [racemic cis isomer]

According to General Method 1, 161 mg (0.40 mmol) of 1- (morpholin-4-ylcarbonyl) -5- {4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 44A) and 83 mg (0.44 mmol, 1.1 eq .) [(2-Amino-2- (hydroxyimino) ethyl] -tert-butylcarbamate.) Yield: 127 mg (57% of theory).
HPLC (Method 2A): R _t = 4.73 min; MS (ESIpos): m / z = 556 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.52-7.44 (m, 3H), 7.33 (d, 2H), 4.23 (d, 1H), 3.99 (br d, 1H), 3.67-3.57 (m, 1H), 3.59-3.53 (m, 4H), 3.46-3.36 (m, 1H), 3.23-3.15 (m, 4H), 3.04 (t, 1H), 3.03-2.93 (m, 2H), 2.31 (br d, 1H), 1.98 (q, 1H), 1.38 (s, 9H).

Example 83

1- (5- {1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidin-3-yl} -1,2,4-oxadiazol-3-yl) methanamine [racemic cis- Isomer]

A solution of 111 mg (0.2 mmol) of [(5- {1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidin-3-yl} -1,2,4-oxadiazole-3 -yl) methyl] tert-butylcarbamate (Example 82) in 3 ml of dichloromethane is reacted at RT with a total of 185 μl (2.4 mmol, 12 eq.) of trifluoroacetic acid and then concentrated in vacuo. The crude product is purified by preparative HPLC (column: Reprosil C18, 10 μm, 250 mm × 30 mm, eluent: acetonitrile / water with 0.1% triethylamine gradient). Yield: 76 mg (83% of theory)
LC-MS (Method 3B): R _t = 1.23 min; MS (ESIpos): m / z = 456 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.47 (d, 2H), 7.33 (d, 2H), 3.99 (br d, 1H), 3.77 (s, 2H), 3.61 (br d, 1H), 3.60-3.52 (m, 4H), 3.45-3.35 (m, 1H), 3.23-3.16 (m, 4H), 3.04 (t, 1H), 3.02-2.93 (m, 2H), 2.32 (br , 1H), 1.98 (q, 1H), 1.98-1.83 (br s, 2H).

Example 84

N-ethyl-3- (4-ethylphenyl) -N-methyl-5- (3-phenyl-1,2,4-oxadiazol-5-yl) piperidine-1-carboxylic acid amide [racemic cis isomer]

According to General Method 1, 64 mg (0.20 mmol) of 1- [ethyl (methyl) carbamoyl] -5- (4-ethylphenyl) piperidine-3-carboxylic acid (Example 45A) and 30 mg (0.22 mmol, 1.1 eq.) Of N 'Reacted hydroxybenzenecarboximidamide. Yield: 12 mg (14% of theory)
HPLC (Method 2A): R _t = 5.36 min; MS (ESIpos): m / z = 419 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.05-8.00 (m, 2H), 7.62-7.53 (m, 3H), 7.24 (d, 2H), 7.18 (d, 2H), 4.01 ( br d, 1H), 3.58-3.46 (m, 2H), 3.17 (q, 2H), 3.06 (t, 1H), 2.95-2.87 (m, 2H), 2.79 (s, 3H), 2.58 (q, 2H ), 2.38 (br d, 1H), 2.03 (q, 1H), 1.17 (t, 3H), 1.08 (t, 3H).

Example 85

N-ethyl-3- (4-ethylphenyl) -5- [3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl] -N-methylpiperidine-1-carboxylic acid amide [racemic cis isomer]

According to General Method 1, 64 mg (0.20 mmol) of 1- [ethyl (methyl) carbamoyl] -5- (4-ethylphenyl) piperidine-3-carboxylic acid (Example 45A) and 34 mg (0.22 mmol, 1.1 eq.) Of 4 -Fluor-N'-hydroxybenzenecarboximidamid implemented. Yield: 46 mg (52% of theory)
HPLC (Method 2A): R _t = 5.40 min; MS (ESIpos): m / z = 437 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 8.12-8.04 (m, 2H), 7.46-7.38 (m, 2H), 7.24 (d, 2H), 7.17 (d, 2H), 4.01 ( br d, 1H), 3.58-3.46 (m, 2H), 3.17 (q, 2H), 3.05 (t, 1H), 2.97-2.85 (m, 2H), 2.79 (s, 3H), 2.57 (q, 2H ), 2.37 (br d, 1H), 2.03 (q, 1H), 1.17 (t, 3H), 1.08 (t, 3H).

Example 86

4 - ({3- [3- (4-Methylphenyl) -1,2,4-oxadiazol-5-yl] -5- [4- (trifluoromethoxy) phenyl] piperidin-1-yl} carbonyl) morpholine [racemic cis -Isomer]

According to General Method 1, 80 mg (0.20 mmol) of 1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 44A) and 33 mg (0.22 mmol, 1.1 eq .) N'-hydroxy-4-methylbenzencarboximidamid reacted. Yield: 68 mg (66% of theory)
HPLC (Method 2A): R _t = 5.25 min; MS (ESIpos): m / z = 517 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.90 (d, 2H), 7.49 (d, 2H), 7.37 (d, 2H), 7.34 (d, 2H), 4.08 (br d, 1H ), 3.64 (br d, 1H), 3.62-3.54 (m, 4H), 3.54-3.44 (m, 1H), 3.27-3.18 (m, 4H), 3.13 (t, 1H), 3.07-2.97 (m, 2H), 2.40 (br d, 1H), 2.39 (s, 3H), 2.06 (q, 1H).

Example 87

3- [3- (2,6-Difluorophenyl) -1,2,4-oxadiazol-5-yl] -N-ethyl-5- (4-ethylphenyl) -N-methylpiperidine-1-carboxylic acid amide [racemic cis isomer ]

According to General Method 1, 64 mg (0.20 mmol) of 1- [ethyl (methyl) carbamoyl] -5- (4-ethylphenyl) piperidine-3-carboxylic acid (Example 45A) and 38 mg (0.22 mmol, 1.1 eq.) 2 , 6-difluoro-N'-hydroxybenzenecarboximidamid reacted. Yield: 23 mg (26% of theory)
HPLC (Method 2A): R _t = 5.18 min; MS (ESIpos): m / z = 455 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.77-7.68 (m, 1H), 7.36 (t, 2H), 7.24 (d, 2H), 7.16 (d, 2H), 4.01 (br , 1H), 3.62-3.50 (m, 2H), 3.17 (q, 2H), 3.05 (t, 1H), 2.97-2.85 (m, 2H), 2.78 (s, 3H), 2.57 (q, 2H), 2.38 (br d, 1H), 2.03 (q, 1H), 1.17 (t, 3H), 1.07 (t, 3H).

Example 88

4 - ({3- [3- (2-chloropyridin-4-yl) -1,2,4-oxadiazol-5-yl] -5- [4- (trifluoromethoxy) phenyl] piperidin-1-yl} carbonyl ) morpholine [racemic cis isomer]

According to General Method 1, 600 mg (1.49 mmol) of 1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 44A) and 281 mg (1.64 mmol, 1.1 eq .) 2-Chloro-N'-hydroxypyridine-4-carboximidamide reacted. Yield: 315 mg (39% of theory)
HPLC (Method 2A): R _t = 4.96 min; MS (ESIpos): m / z = 538 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.65 (dd, 1H), 8.00 (s, 1H), 7.98 (dd, 1H), 7.49 (d, 2H), 7.36 (d, 2H) , 4.10 (br d, 1H), 3.64 (br d, 1H), 3.62-3.50 (m, 5H), 3.27-3.18 (m, 4H), 3.14 (t, 1H), 3.08-2.97 (m, 2H) , 2.41 (br d, 1H), 2.08 (q, 1H).

Example 89

3- [3- (2-Chloropyridin-4-yl) -1,2,4-oxadiazol-5-yl] -N-ethyl-5- (4-ethylphenyl) -N-methylpiperidine-1-carboxylic acid amide [racemic cis -Isomer]

According to General Method 1, 64 mg (0.20 mmol) of 1- [ethyl (methyl) carbamoyl] -5- (4-ethylphenyl) piperidine-3-carboxylic acid (Example 45A) and 38 mg (0.22 mmol, 1.1 eq.) 2 -Chloro-N'-hydroxypyridine-4-carboximidamide reacted. Yield: 13 mg (14% of theory)
HPLC (Method 2A): R _t = 5.22 min; MS (ESIpos): m / z = 454 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.65 (dd, 1H), 8.00 (s, 1H), 7.98 (dd, 1H), 7.24 (d, 2H), 7.18 (d, 2H) , 4.02 (br d, 1H), 3.61-3.50 (m, 2H), 3.17 (q, 2H), 3.06 (t, 1H), 2.98-2.86 (m, 2H), 2.79 (s, 3H), 2.58 ( q, 2H), 2.38 (br d, 1H), 2.05 (q, 1H), 1.17 (t, 3H), 1.08 (t, 3H).

Example 90

4 - ({3- (1,2,4-Oxadiazol-5-yl) -5- [4- (trifluoromethoxy) phenyl] piperidin-1-yl} carbonyl) morpholine [racemic cis isomer]

The title compound is isolated from the reaction of Example 92 with lithium hydroxide in tetrahydrofuran / water at room temperature. Yield: 9 mg (57% of theory)
HPLC (Method 2B): R _t = 1.11 min; MS (ESIpos): m / z = 427 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 12.02-11.82 (br s, 1H), 7.45 (d, 2H), 7.33 (d, 2H), 3.80 (br d, 1H), 3.61- 3.52 (m, 5H), 3.22-3.13 (m, 4H), 2.92-2.77 (m, 3H), 2.71-2.64 (m, 1H), 2.10 (br d, 1H), 1.80 (q, 1H).

Example 91

3- (3-tert-Butyl-1,2,4-oxadiazol-5-yl) -N-ethyl-5- (4-ethylphenyl) -N-methylpiperidine-1-carboxylic acid amide [racemic cis isomer]

According to General Method 1, 64 mg (0.20 mmol) of 1- [ethyl (methyl) carbamoyl] -5- (4-ethylphenyl) piperidine-3-carboxylic acid (Example 45A) and 26 mg (0.22 mmol, 1.1 eq.) Of N Reacted '-hydroxy-2,2-dimethylpropanimidamid. Yield: 52 mg (65% of theory)
HPLC (Method 2A): R _t = 5.30 min; MS (ESIpos): m / z = 399 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.22 (d, 2H), 7.16 (d, 2H), 3.91 (br d, 1H), 3.53 (br d, 1H), 3.43-3.33 ( m, 1H), 3.15 (q, 2H), 3.00-2.80 (m, 3H), 2.76 (s, 3H), 2.57 (q, 2H), 2.29 (br d, 1H), 1.93 (q, 1H), 1.30 (s, 9H), 1.16 (t, 3H), 1.06 (t, 3H).

Example 92

5- {1- (Morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidin-3-yl} -1,2,4-oxadiazole-3-carboxylic acid ethyl ester [racemic cis isomer]

According to General Method 1, 80 mg (0.20 mmol) of 1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidine-3-carboxylic acid (Example 44A) and 29 mg (0.22 mmol, 1.1 eq .) 2-Amino (hydroxyimino) ethanoic acid ethyl ester implemented. Yield: 24 mg (22% of theory)
HPLC (Method 2A): R _t = 4.69 min; MS (ESIpos): m / z = 499 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.48 (d, 2H), 7.34 (d, 2H), 4.41 (q, 2H), 4.03 (br d, 1H), 3.62 (br d, 1H), 3.60-3.47 (m, 5H), 3.25-3.17 (m, 4H), 3.10 (t, 1H), 3.05-2.94 (m, 2H), 2.35 (br d, 1H), 2.03 (q, 1H ), 1.33 (t, 3H).

Example 93

N-ethyl-3- (4-ethylphenyl) -N-methyl-5- [3- (morpholin-4-ylmethyl) -1,2,4-oxadiazol-5-yl] -piperidine-1-carboxylic acid amide [racemic cis- Isomer]

According to General Method 1, 63 mg (0.20 mmol) of 1- [ethyl (methyl) carbamoyl] -5- (4-ethylphenyl) piperidine-3-carboxylic acid (Example 45A) and 35 mg (0.22 mmol, 1.1 eq.) Of N '-Hydroxy-2-morpholin-4-ylethanimidamid implemented. Yield: 5 mg (5% of theory)
HPLC (Method 2A): R _t = 4.24 min; MS (ESIpos): m / z = 442 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.22 (d, 2H), 7.16 (d, 2H), 3.93 (br d, 1H), 3.64 (s, 2H), 3.60-3.50 (m , 5H), 3.47-3.37 (m, 1H), 3.06 (q, 2H), 2.97 (t, 1H), 2.91-2.84 (m, 2H), 2.77 (s, 3H), 2.57 (q, 2H), 2.30 (br d, 1H), 2.00-1.89 (m, 1H), 1.16 (t, 3H), 1.06 (t, 3H).

Example 94

4 - ({3- (4-Ethylphenyl) -5- [3- (5-fluorothiophen-2-yl) -1,2,4-oxadiazol-5-yl] -piperidin-1-yl} carbonyl) morpholine [racemic cis-isomer]

According to General Method 1, 69 mg (0.20 mmol) of 5- (4-ethylphenyl) -1- (morpholin-4-ylcarbonyl) piperidine-3-carboxylic acid (Example 38A) and 35 mg (0.22 mmol, 1.1 eq.) 5 -Fluor-N'-hydroxythiophene-2-carboximidamide implemented. Yield: 51 mg (54% of theory)
HPLC (Method 2A): R _t = 5.11 min; MS (ESIpos): m / z = 471 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.56 (t, 1H), 7.23 (d, 2H), 7.17 (d, 2H), 6.95 (dd, 1H), 4.05 (br d, 1H ), 3.61 (br d, 1H), 3.60-3.52 (m, 4H), 3.51-3.41 (m, 1H), 3.24-3.15 (m, 4H), 3.08 (t, 1H), 2.96 (q, 1H) , 2.93-2.82 (m, 1H), 2.57 (q, 1H), 2.34 (br d, 1H), 2.01 (q, 1H), 1.17 (t, 3H).

Example 95

N- (2-methoxyethyl) -4- (5- {1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidin-3-yl} -1,2,4-oxadiazol-3 -yl) pyridin-2-amine [racemic cis isomer]

According to General Method 3, 69 mg (0.13 mmol) of 4 - ({3- [3- (2-chloropyridin-4-yl) -1,2,4-oxadiazol-5-yl] -5- [4- (4- trifluoromethoxy) phenyl] piperidin-1-yl} carbonyl) morpholine (Example 88) in 1.2 ml of 2-methoxyethylamine. Yield: 31 mg (43% of theory)
HPLC (Method 2A): R _t = 4.28 min; MS (ESIpos): m / z = 577 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.12 (d, 1H), 7.49 (d, 2H), 7.34 (d, 2H), 7.15 (s, 1H), 7.02 (t, 1H) , 6.97 (dd, 1H), 4.08 (br d, 1H), 3.64 (br d, 1H), 3.61-3.54 (m, 4H), 3.54-3.46 (m, 1H), 3.46-3.43 (m, 4H) , 3.27 (s, 3H), 3.25-3.18 (m, 4H), 3.11 (t, 1H), 3.07-2.97 (m, 2H), 2.39 (br d, 1H), 2.05 (q, 1H).

Example 96

4- [4- (5- {1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidin-3-yl} -1,2,4-oxadiazol-3-yl) pyridine 2-yl] morpholine [racemic cis isomer]

According to General Method 3, 69 mg (0.13 mmol) of 4 - ({3- [3- (2-chloropyridin-4-yl) -1,2,4-oxadiazol-5-yl] -5- [4- (4- trifluoromethoxy) phenyl] piperidin-1-yl} carbonyl) morpholine (Example 88) in 0.6 ml of morpholine. Yield: 38 mg (50% of theory)
HPLC (Method 2A): R _t = 4.29 min; MS (ESIpos): m / z = 589 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.31 (d, 1H), 7.49 (d, 2H), 7.34 (d, 2H), 7.28 (s, 1H), 7.20 (dd, 1H) , 4.09 (br d, 1H), 3.76-3.68 (m, 4H), 3.63 (br d, 1H), 3.60-3.54 (m, 4H), 3.54-3.47 (m, 5H), 3.27-3.18 (m, 4H), 3.13 (t, 1H), 3.08-2.97 (m, 2H), 2.39 (br d, 1H), 2.13-2.02 (m, 1H).

Example 97

N, N-dimethyl-N '- [4- (5- {1- (morpholin-4-ylcarbonyl) -5- [4- (trifluoromethoxy) phenyl] piperidin-3-yl} -1,2,4-oxadiazole 3-yl) pyridin-2-yl] ethane-1,2-diamine [racemic cis isomer]

According to General Method 3, 69 mg (0.13 mmol) of 4 - ({3- [3- (2-chloropyridin-4-yl) -1,2,4-oxadiazol-5-yl] -5- [4- (4- trifluoromethoxy) phenyl] piperidin-1-yl} carbonyl) morpholine (Example 88) in 0.6 ml of N, N-dimethyl-diamine. Yield: 8 mg (10% of theory)
HPLC (Method 2A): R _t = 4.09 min; MS (ESIpos): m / z = 590 [M + H] ⁺ ;
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 8.15 (d, 1H), 7.51 (d, 2H), 7.37 (d, 2H), 7.16 (s, 1H), 6.99 (d, 1H) , 6.88 (t, 1H), 4.10 (br d, 1H), 3.65 (br d, 1H), 3.64-3.57 (m, 4H), 3.56-3.48 (m, 1H), 3.39 (q, 2H), 3.28 -3.20 (m, 4H), 3.14 (t, 1H), 3.08-2.98 (m, 2H), 2.48-2.38 (m, 3H), 2.20 (s, 6H), 2.07 (q, 1H).

B) Assessment of physiological efficacy

Abbreviations:

• BSA

  Bovine Serum Albumin

  DMEM

  Dulbecco's Modified Eagle Medium

  EGTA

  Ethylene glycol-glycol-bis- (2-aminoethyl) -N, N, N ', N'-tetra-acetic 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 of the invention for Treatment of thromboembolic disorders can be in the following Assay systems are shown:

1.) In vitro assays

1.a) Cellular, more functional in vitro test

The identification of antagonists of the human Protease Activated Receptor 1 (PAR-1) as well as the quantification of the efficacy of the substances described here is carried out with the aid of a recombinant cell line. The cell is originally derived from a human embryonic kidney cell (HEK293, ATCC: American Type Culture Collection, Manassas, VA 20108, USA). The test cell line constitutively expresses a modified form of the calcium-sensitive photoprotein aequorin which, upon reconstitution with the co-factor coelenterazine, emits light upon increases in the free calcium concentration in the inner mitochondrial compartment ( Rizzuto R, Simpson AW, Brini M, Pozzan T .; Nature 1992, 358, 325-327 ). In addition, the cell stably expresses the endogenous human PAR-1 receptor as well as the endogenous purinergic receptor P2Y2. The resulting PAR-1 test cell responds to stimulation of the endogenous PAR-1 or P2Y2 receptor with an intracellular release of calcium ions, which can be quantified by the resulting aequorin luminescence with a suitable luminometer ( Milligan G, Marshall F, Rees S, Trends in Pharmacological Sciences 1996, 17, 235-237 ).

For the substance specificity test, its effect after activation of the endogenous PAR-1 receptor is compared with the effect after activation of the endogenous purinergic P2Y2 receptor, which uses the same intracellular signaling pathway.

Test Procedure: Cells are incubated for two days (48 hours) prior to testing in culture medium (DMEM F12 supplemented with 10% FCS, 2mM Glutamine, 20mM HEPES, 1.4mM pyruvate, 0.1mg / ml gentamycin, 0.15% Na bicarbonate BioWhittaker Cat. # BE04-687Q; B-4800 Verviers, Belgium) in 384-well microtiter plates and maintained in a cell incubator (96% humidity, 5% v / v CO ₂ , 37 ° C). On the day of the test, the culture medium is treated with a Tyrodel solution (in mM: 140 sodium chloride, 5 potassium chloride, 1 magnesium chloride, 2 calcium chloride, 20 glucose, 20 HEPES) which additionally contains co-factor coelenterazine (25 μM) and glutathione (4 mM), and then incubate the microtiter plate for a further 3-4 hours. Then the test substances are pipetted onto the microtiter plate and 5 minutes after transfer of the test substances into the wells of the microtiter plate, the plate is transferred to the luminometer, a PAR-1 agonist concentration corresponding to EC ₅₀ , and immediately the resulting light signal in the luminometer measured. To distinguish an antagonist substance effect from a toxic effect, the endogenous purinergic receptor with agonist is activated immediately afterwards (ATP, 10 μM final concentration) and the resulting light signal is measured. The results are shown in Table A: TABLE A Example no. IC ₅₀ [nM] 28 28 37 21 38 31 39 6.8 60 10

1.b) PAR-1 receptor binding assay

platelet membranes be with 12 nM [3H] haTRAP and test substance in different concentrations in a buffer (50 mM Tris pH 7.5, 10 mM magnesium chloride, 1 mM EGTA, 0.1% BSA) at room temperature for 80 min. Thereafter, the batch is transferred to a filter plate and washed twice with buffer. After adding scintillation fluid the radioactivity on the filter is in a beta counter measured.

1.c) platelet aggregation in plasma

to Determination of platelet aggregation will be blood from healthy volunteers both sexes, which within the last ten days no had received medications influencing platelet aggregation, used. The blood is used in monovettes (Sarstedt, Nümbrecht, Germany) serving as anticoagulant sodium citrate 3.8% (1 part citrate + 9 parts of blood) included. To obtain platelet-rich Plasma, the citrated whole blood is centrifuged at 140 g for 20 min.

For the aggregation measurements, aliquots of the platelet-rich plasma are incubated with ascending concentrations of test substance at 37 ° C. for 10 min. Subsequently, the aggregation is triggered by addition of a thrombin receptor agonist (TRAP6, SFLLRN) in an aggregometer and determined by the turbidimetric method according to Born ( Born, GVR, Cross MJ, The Aggregation of Blood Platelets; J. Physiol. 1963, 168, 178-195 ) at 37 ° C. The SFLLRN concentration leading to maximum aggregation is determined individually for each donor, if appropriate.

To calculate the inhibitory effect, the maximum increase in light transmission (amplitude of the aggregation curve in%) within 5 minutes after addition of the agonist in the presence and absence of test substance is determined and the inhibition calculated. From the inhibition curves the concentration is calculated, which inhibits the aggregation to 50%. The results are shown in Table B: Table B: Example no. IC ₅₀ [μM] 38 93 39 5.6 60 19.6

1.d) platelet aggregation in buffer

to Determination of platelet aggregation will be blood from healthy volunteers both sexes, which within the last ten days no had received medications influencing platelet aggregation, used. The blood is used in monovettes (Sarstedt, Nümbrecht, Germany) as anticoagulant sodium citrate 3.8% (1 part citrate + 9 parts of blood) included. To obtain platelet-rich Plasma, the citrated whole blood is centrifuged at 140 g for 20 min. To the PRP is added a quarter volume of ACD buffer (44.8 mM sodium citrate, 20.9 mM citric acid, 74.1 mM glucose and 4 mM potassium chloride) added and centrifuged for 10 minutes at 1000 g. The platelet pellet is resuspended with wash buffer and centrifuged for 10 minutes at 1000 g. The platelets are resuspended in incubation buffer and set to 200000 Z / μl. Calcium chloride is added before the start of the experiment and magnesium chloride, final concentration 2 mM each (stock solution 2 M, 1: 1000 dilution). Special feature: with ADP-induced aggregation Only calcium chloride is added. The following agonists can can be used: TRAP6 trifluoroacetate salt, collagen, human α-thrombin and U-46619. The concentration of the agonist becomes each donor tested.

Test procedure: 96-well microtiter plates are used. The test substance is diluted in DMSO and 2 ul per hole presented. 178 μl of platelet suspension are added and 10 Preincubated for minutes at room temperature. 20 μl agonist are added and the measurement in Spectramax, OD 405 nm, immediately started. The kinetics are determined in 11 measurements of 1 minute each. The measurements are shaken for 55 seconds.

1.e) platelet aggregation in fibrinogen-depleted plasma

to Determination of platelet aggregation will be blood from healthy volunteers both sexes, which within the last ten days no had received medications influencing platelet aggregation, used. The blood is used in monovettes (Sarstedt, Nümbrecht, Germany) as anticoagulant sodium citrate 3.8% (1 part citrate + 9 parts of blood) included.

manufacturing of fibrinogen-depleted plasma: For the production of platelet-poor Plasma is the citrated whole blood centrifuged at 140 g for 20 min. The platelet-poor plasma is in the ratio 1:25 with reptilase (Roche Diagnostic, Germany) and carefully inverted. This is followed by 10 min incubation at 37 ° C in a water bath with direct subsequent incubation on ice for 10 min. The Plasma reptilase mixture is centrifuged at 1300 g for 15 min and the supernatant (fibrinogen depleted plasma) becomes won.

Platelet isolation: To obtain platelet-rich plasma is the citrated whole blood centrifuged at 140 g for 20 min. The PRP will become 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) added and centrifuged for 10 minutes at 1300 g. The platelet pellet is resuspended with wash buffer and centrifuged for 10 minutes at 1300 g. The platelets are resuspended and incubated in incubation buffer 400000 Z / μl and calcium chloride solution at a final concentration of 5 mM (1/200 dilution).

For aggregation measurements, aliquots (98 μl fibrinogen-depleted plasma and 80 μl platelet suspension) are incubated with increasing concentrations of test substance at RT for 10 min. Subsequently, the aggregation is triggered by addition of human alpha thrombin in an aggregometer and determined by the turbidimetric method according to Born ( Born, GVR, Cross MJ, The Aggregation of Blood Platelets; J. Physiol. 1963, 168, 178-195 ) at 37 ° C. The alpha thrombin concentration, which just leads to maximum aggregation, is determined individually for each donor.

To calculate the inhibitory effect, the increase in the maximum light transmittance (amplitude of the aggregation curve in%) within 5 minutes after addition of the agonist in presence and Ab the substance is determined and the inhibition calculated. From the inhibition curves the concentration is calculated, which inhibits the aggregation to 50%.

1.f) Stimulation of washed platelets and analysis in flow cytometry

insulation washed platelets: Human whole blood is collected by venipuncture won by volunteer donors and in monovettes (Sarstedt, Nümbrecht, Germany), the as anticoagulant sodium citrate (1 part sodium citrate 3.8% + 9 parts whole blood). The Monovettes are at 900 revolutions per minute and 4 ° C over a period of 20 Centrifuged for minutes (Heraeus Instruments, Germany; Megafuge 1.0RS). The platelet-rich plasma is carefully removed and transferred to a 50 ml Falcon tube. Now the plasma is washed with ACD buffer (44 mM sodium citrate, 20.9 mM Citric acid, 74.1 mM glucose). The volume of ACD buffer corresponds to one quarter of the plasma volume. In ten minutes Centrifugation at 2500 revolutions and 4 ° C will be the Platelets sedimented. Thereafter, the supernatant becomes cautious decanted and discarded. The precipitated platelets be careful with a milliliter wash buffer first (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, N'N'-tetraacetic acid, 0.1% glucose) and then with Wash Buffer to a volume filled up, which corresponds to the amount of plasma. The washing process is carried out a second time. After the platelets through another ten minute centrifugation at 2500 revolutions and 4 ° C, they become cautious in a milliliter incubation buffer (134 mM sodium chloride, 12 mM sodium bicarbonate, 2.9 mM potassium chloride, 0.34 mM sodium dihydrogencarbonate, 5 mM HEPES, 5 mM glucose, 2 mM calcium chloride and 2 mM magnesium chloride) resuspended and incubation buffer to a concentration of 300,000 Platelets per μl.

Staining and stimulation of human platelets with human α-thrombin in the presence or absence of a PAR-1 antagonist: The platelet suspension is preincubated with the substance or solvent to be tested for 10 minutes at 37 ° C. (Eppendorf, Germany; Thermomixer Comfort ). Addition of the agonist (0.5 μM or 1 μM α-thrombin, Kordia, Netherlands, 3281 NIH units / mg or 30 μg / ml thrombin receptor activating peptide (TRAP6), Bachem, Switzerland) at 37 ° and with shaking of 500 Revolutions per minute, the platelet activation is triggered. An aliquot of 50 μl is withdrawn at time points 0, 1, 2.5, 5, 10 and 15 minutes and transferred to one milliliter of single concentrated CellFix ^™ solution (Becton Dickinson Immunocytometry Systems, USA). To fix the cells they are incubated for 30 minutes at 4 ° C in the dark. Ten minutes of centrifugation at 600 g and 4 ° C precipitate the platelets. The supernatant is discarded and the platelets are resuspended in 400 μl CellWash ^™ (Becton Dickinson Immunocytometry Systems, USA). An aliquot of 100 μl is transferred to a new FACS tube. 1 μl of the platelet-identifying antibody and 1 μl of the activation-state detecting antibody are made up to a volume of 100 μl with CellWash ^™ . This antibody solution is then added to the platelet suspension and incubated for 20 minutes at 4 ° C in the dark. Following staining, the batch volume is increased by adding an additional 400 μl of CellWash ^™ .

to Identification of the platelets becomes a fluorescein-isothiocyanate-conjugated Antibodies used against the human glycoprotein IIb (CD41) (Immunotech Coulter, France, Cat No. 0649). With the help of phycoerythrin-conjugated antibody, the against the human glycoprotein P-selectin (Immunotech Coulter, France; Cat. No. 1759), the activation state can be determined determine the platelets. P-selectin (CD62P) is in the α-granules resting platelets isolated. However, after in vitro or in vivo stimulation to the outer plasma membrane translocated.

Flow cytometry and evaluation of the data: The samples are measured in the device FACSCalibur ^™ Flow Cytometry System from Becton Dickinson Immunocytometry Systems, USA, and evaluated and graphically displayed with the aid of the software CellQuest, Version 3.3 (Becton Dickinson Immunocytometry Systems, USA). The level of platelet activation is determined by the percentage of CD62P-positive platelets (CD41-positive events). There are 10,000 CD41 positive events from each sample.

The inhibitory effect of the substances to be tested calculated on the reduction of platelet activation, the refers to activation by the agonist.

1.g) platelet aggregation measurement with the parallel plate flow chamber

To determine platelet aggregation, blood from healthy volunteers of both sexes, who had not received any platelet aggregation-influencing medication within the last ten days, is used. The blood is taken up in monovettes (Sarstedt, Nümbrecht, Germany) containing 3.8% anticoagulant sodium citrate (1 part citrate + 9 parts blood). To obtain platelet-rich plasma, the citrated whole blood is centrifuged at 140 g for 20 min. To the PRP, 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) is added and centrifuged at 1000 g for 10 minutes. The platelet pellet is resuspended with wash buffer and centrifuged for 10 minutes at 1000 g. For the perfusion study, a mixture of 40% erythrocytes and 60% washed platelets (200,000 / μl) is prepared and suspended in HEPES-Tyrode buffer. The measurement of platelet aggregation under flow conditions is carried out by means of the parallel plate flow chamber ( Nieswandt et al., EMBO J. 2001, 20, 2120-2130 ; C. Weeterings, Arterioscler Thromb. Vase. Biol. 2006, 26, 670-675 ; JJ Sixma, Thromb. Res. 1998, 92, 43-46 ). Glass slides are wetted with 100 μl of human α-thrombin solution (dissolved in Tris buffer) overnight at 4 ° C. (α-thrombin in various concentrations, eg 10 to 50 μg / ml) and finally blocked with 2% BSA.

reconstituted But is transited via the thrombin-wetted glass slides Conducted for 5 minutes at a constant flow rate (eg shear rate 300 / second) and observed and recorded by means of a microscope video system. The inhibitory effect of the substances to be tested is morphometrically based on the reduction of platelet aggregation determined. Alternatively, inhibition of platelet activation by flow cytometry, z. B. via p-selectin expression (CD62p) (see Method 1.f).

2.) Ex vivo assay

2.a) platelet aggregation (primates, Guinea pig)

Guinea pig or primates are administered orally, in the awake or anesthetized state, intravenously or intraperitoneally with test substances treated in appropriate formulation. As a control, others will Guinea pigs or primates in identical manner with the corresponding one Vehicle treated. Different according to the type of application For a long time blood from the deep anesthetized animals is being punctured of the heart or the aorta. The blood is in monovettes (Sarstedt, Nümbrecht, Germany) as anticoagulant Sodium citrate 3.8% (1 part citrate solution + 9 parts blood) included. To obtain platelet-rich Plasma, the citrated whole blood is centrifuged at 140 g for 20 min.

The aggregation is triggered by addition of a thrombin receptor agonist (TRAP6, SFLLRN, 50 μg / ml, concentration is determined in each experiment depending on the animal species) in an aggregometer and determined by the turbidimetric method according to Born ( Born, GVR, Cross MJ, The Aggregation of Blood Platelets; J. Physiol. 1963, 168, 178-195 ) at 37 ° C.

to Aggregation measurement will be the maximum increase in light transmission (Amplitude of the aggregation curve in%) within 5 minutes after Addition of agonist determined. The inhibitory effect of the administered Test substances in the treated animals are administered by the Reduction in aggregation, based on the mean of the control animals, calculated.

3.) In vivo assays

3.a) thrombosis models

The compounds according to the invention can be investigated in thrombosis models in suitable animal species in which thrombin-induced platelet aggregation is mediated via the PAR-1 receptor. As animal species guinea pigs and especially primates are suitable (compare: Lindahl, AK, Scarborough, RM, Naughton, MA, Harker, LA, Hanson, SR, Thromb Haemost 1993, 69, 1196 ; Cook JJ, Sitko GR, Bednar B, Condra C, Mellott MJ, Feng DM, Nutt RF, Shager JA, Gould RJ, Connolly ™, Circulation 1995, 91, 2961-2971 ; 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, Nedelman M, Zhang HC, Maryanoff BE, Andrade-Gordon P, J. Pharmacol. Exp. Ther. 2003, 304, 855-861 ). Alternatively guinea pigs pretreated with inhibitors of PAR-3 and / or PAR-4 can be used ( Leger AJ et al., Circulation 2006, 113, 1244-1254 ), or transgenic PAR-3 and / or PAR-4 knockdown guinea pigs.

3.b) coagulation disorder and organ dysfunction Disseminated Intravascular Coagulation (DIC)

The compounds according to the invention can be investigated in models for DIC and / or sepsis in suitable animal species. Guinea pigs and, in particular, primates are suitable as animal species, while mice and rats are also investigated when investigating the endothelium-mediated effects (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, Nedelman M, Zhang HC, Maryanoff BE, Andrade-Gordon P, J. Pharmacol. Exp. Ther. 2003, 304, 855-861 ; Kaneider NC et al., Nat Immunol, 2007, 8, 1303-12 ; Camerer E et al., Blonde, 2006, 107, 3912-21 ; Riewald M et al., J. Biol. Chem., 2005, 280, 19808-14 .). Alternatively guinea pigs pretreated with inhibitors of PAR-3 and / or PAR-4 can be used ( Leger AJ et al., Circulation 2006, 113, 1244-1254 ), or transgenic PAR-3 and / or PAR-4 knockdown guinea pigs.

3.b.1) thrombin-antithrombin complexes

Thrombin-antithrombin complexes (hereinafter referred to as "TAT") are a measure of the endogenous thrombin formed by coagulation activation. DID are determined by an ELISA assay (Enzygnost TAT micro, Dade Behring). From citrated blood is obtained by centrifugation plasma. To 50 μl plasma is added 50 μl TAT sample buffer, shaken briefly and incubated for 15 min at room temperature. The samples are aspirated, and the well 3 times with wash buffer washed (300 μl / well). The plate is between the washes knocked off. Add conjugate solution (100 μl) and incubated for 15 min at room temperature. The samples are sucked off, and the well washed 3 times with wash buffer (300 μl / well). Subsequently, chromogenic susbtrate is added (100 μl / well), Incubated for 30 min in the dark at room temperature, stop solution added (100 μl / well) and color formation at 492 nm measured (sapphire plate reader).

3.b.2) Parameters for organ dysfunction

It different parameters are determined, on the basis of which conclusions on the functional restriction of various internal organs can be pulled by the LPS gift, and the therapeutic Effect of test substances can be estimated. Citrated blood or, if appropriate, lithium heparin blood is centrifuged, and the parameters determined from the plasma. The following parameters will be typically raised: creatinine, urea, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, lactate dehydrogenase (LDH), total protein, total albumin and fibrinogen. The values provide information on the function of the kidney, the liver, the circulation and the vessels.

3.b.3) parameters for inflammation

The Extent of endotoxin-induced inflammatory response can be derived from the rise of inflammatory mediators in the plasma, for. Interleukins (1, 6, 8 and 10), tumor necrosis factor alpha or monocyte chemoattractant protein-1. You can do this ELISAs or the Luminex system.

3.c) antitumor efficacy

The compounds of the invention can be tested in models for cancer, e.g. In the human breast cancer model in immunodeficient mice (see: S. Even-Ram et. al., Nature Medicine, 1988, 4, 909-914 ).

3.d) antiangiogenic activity

The compounds according to the invention can be tested in in vitro and in vivo models for angiogenesis (compare: Caunt et al., Journal of Thrombosis and Haemostasis, 2003, 10, 2097-2102 ; Haralabopoulos et al., Am J Physiol, 1997, C239-C245 ; Tsopanoglou et al., JBC, 1999, 274, 23969-23976 ; Zania et al., JPET, 2006, 318, 246-254 ).

3.e) Blood pressure and heart rate modulating effect

The compounds of the invention can be tested in vivo models for their effect on arterial blood pressure and heart rate. For this purpose, rats (eg Wistar) with implan tiered radio-telemetry units, and an electronic data acquisition and storage system (Data Sciences, MN, USA) consisting of a chronically implantable transducer / transmitter unit in conjunction with a fluid-filled catheter is used. The transmitter is implanted into the peritoneal cavity and the sensor catheter is positioned in the descending aorta. The compounds according to the invention can be administered (for example orally or intravenously). Before treatment, the mean arterial blood pressure and heart rate of the untreated and treated animals are measured and ensured to be in the range of approximately 131-142 mmHg and 279-321 beats / minute. PAR-1 activating peptide (SFLLRN, eg doses between 0.1 and 5 mg / kg) is administered intravenously. Blood pressure and heart rate are measured at different time intervals and with and without PAR-1 activating peptide and with and without one of the compounds according to the invention (compare: Cicala C et al., The Fibers Journal, 2001, 15, 1433-5 ; Stasch JP et al., British Journal of Pharmacology 2002, 135, 344-355 ).

C) embodiments for pharmaceutical compositions

The Substances of the invention can be as follows be converted into pharmaceutical preparations:

Tablet:

Composition:

• 100 mg of the compound of Example 1, 50 mg lactose (monohydrate), 50 mg corn starch, 10 mg polyvinylpyrolidone (PVP 25) (Fa. BASF, Germany) and 2 mg of magnesium stearate.
• Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

production:

The Mixture of the compound of Example 1, lactose and starch with a 5% solution (m / m) of the PVP in water granulated. The granules are dried with magnesium stearate for 5 min. mixed. This mixture comes with a usual Pressed tablet press (format of the tablet see above).

Oral suspension:

Composition:

• 1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg rhodigel (xanthan gum) (FMC, USA) and 99 g water.

one Single dose of 100 mg of the compound of the invention correspond to 10 ml of oral suspension.

production:

The Rhodigel is suspended in ethanol, the compound of the example 1 is added to the suspension. While stirring the addition of the water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.

Intravenous solution:

Composition:

• 1 mg of the compound of Example 1, 15 g of polyethylene glycol 400 and 250 g of water for injections.

production:

The Compound of Example 1 is used together with polyethylene glycol 400 dissolved in the water with stirring. The solution is sterile filtered (pore diameter 0.22 microns) and under aseptic conditions in heat sterilized infusion bottles bottled. These are provided with infusion stoppers and crimp caps locked.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

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Claims (14)

Compound of the formula

in which A is a group of the formula

where # is the point of attachment to the piperidine ring and * is the point of attachment to R ² , R ^{1 is} phenyl, where phenyl may be substituted with 1 to 3 substituents independently selected from the group consisting of monofluoromethyl, difluoromethyl, trifluoromethyl , Monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkoxycarbonyl and C ₃ -C ₆ -cycloalkyl, wherein C ₂ -C _4- alkoxy may be substituted with a substituent selected from the group consisting of methoxy and ethoxy, and wherein cycloalkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen and C ₁ -C ₄ alkyl, R ^{2 is} hydrogen, aminomethyl, C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkoxycarbonyl, C ₃ -C ₆ -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, 1,3-benzodioxolyl or 5- or 6 -lige heteroaryl st eht, wherein cycloalkyl, heterocyclyl, phenyl and heteroaryl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, C C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₆ alkylamino, C ₃ -C ₆ cycloalkyl, 4- to 6-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl, wherein Alkylamino may be substituted with a substituent selected from the group consisting of C ₁ -C ₄ alkoxy and C ₁ -C ₆ alkylamino, and wherein C ₁ -C ₂ alkyl may be substituted by a substituent selected from the group consisting of C ₁ -C ₄ alkylsulfonyl, C ₁ -C ₄ alkoxycarbonylamino, C ₃ -C ₆ cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, phenoxy and 5- or 6-membered heteroaryl, wherein cycloalkyl, heterocyclyl, phenyl , Phenoxy and Heteroaryl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, C ₁ -C ₄ alkyl, C ₁ C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, 4- to 6-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl, R ^{3 is} C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy , C ₁ -C ₆ -alkylamino, C ₃ -C ₇ -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl, wherein alkyl, C ₂ -C ₆ -alkoxy and alkylamino be substituted may be substituted by a substituent selected from the group consisting of hydroxy, cyano and C ₁ -C ₄ alkoxy, and wherein cycloalkyl, heterocyclyl, phenyl and heteroaryl may be substituted by 1 to 3 substituents independently selected from the group consisting of halogen, Cyano, Nitro, Oxo, Hydroxy, amino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, hydroxy-carbonyl, aminocarbonyl, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₆ -alkylamino, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₄ -alkylaminocarbonyl, or one of their salts, their solvates or the solvates their salts. A compound according to claim 1, characterized in that A is a group of the formula

where # is the point of attachment to the piperidine ring and * is the point of attachment to R ² , R ^{1 is} phenyl, wherein phenyl is substituted with 1 to 3 substituents independently selected from the group consisting of trifluoromethyl, trifluoromethoxy, C ₁ C ₄ alkyl and C ₁ -C ₄ alkoxy, R ^{2 is} hydrogen, aminomethyl, C ₁ -C ₄ alkyl, methoxycarbonyl, ethoxycarbonyl, 4- to 6-membered heterocyclyl, phenyl, 1,3-benzodioxolyl or 5 or 6-membered heteroaryl, where heterocyclyl, phenyl and heteroaryl may be substituted by 1 to 3 substituents independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, ethylamino and 4 - to 6-membered heterocyclyl, wherein ethylamino may be substituted with one substituent selected from the group consisting of methoxy and dimethylamino, and wherein methyl may be substituted with one substituent selected from the group consisting of methylsulfonyl, ethylsulfonyl, tert-butoxycarbonylamino, 4- to 6-membered heterocyclyl, phenyl, phenoxy and 5- or 6-membered heteroaryl, in which heterocyclyl, phenyl, phenoxy and heteroaryl may be substituted by 1 to 3 substituents, independently of one another selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy and ethoxy, R ^{3 is} C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylamino, C ₃ -C ₇ -cycloalkyl , 4- to 6-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl, wherein alkylamino may be substituted with a substituent selected from the group consisting of hydroxy, methoxy and ethoxy, and wherein cycloalkyl, heterocyclyl, phenyl and heteroaryl substituted may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy and ethoxy, or one of its salts, its solvates or the solvates of its salts. A compound according to claim 1 or 2, characterized in that A is a group of formula

where # is the point of attachment to the piperidine ring and * is the point of attachment to R ² , R ^{1 is} phenyl, wherein phenyl is substituted with a substituent selected from the group consisting of trifluoromethyl, trifluoromethoxy, ethyl, isopropyl and methoxy, R ^{2 represents} hydrogen, aminomethyl, methyl, n-propyl, tert-butyl, methoxycarbonyl, ethoxycarbonyl, tetrahydropyridinyl, phenyl, 1,3-benzodioxolyl, thiazolyl, isoxazolyl, pyridyl or pyrazinyl, wherein tetrahydropyridinyl, phenyl, thiazolyl, isoxazolyl, pyridyl and Pyrazinyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, trifluoromethyl, Trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, ethylamino and morpholinyl, wherein ethylamino may be substituted with one substituent selected from the group consisting of methoxy and dimethylamino, and wherein methyl may be substituted with one substituent selected from the group consisting of methylsulfonyl, tert -Butoxycarbonylamino, morpholinyl, phenyl and phenoxy, wherein morpholinyl, phenyl and phenoxy may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy and ethoxy, R ^{3 is} tert Butyl, N-methyl-N-ethylamino, methoxyalkylamino, cyclopentyl or morpholinyl, or one of their salts, their solvates or the solvates of their salts. Compound according to one of claims 1 to 3, characterized in that the substituents -R ¹ and -AR ^{2 are} in cis position to each other. Process for the preparation of a compound of the formula (I) or one of its salts, of its solvates or of the solvates of its salts according to Claim 1, characterized in that a compound of the formula

in which R ¹ and R ^{3 have} the meaning given in claim 1, with a compound of the formula

in which R ^{2 has} the meaning given in claim 1, is reacted. A compound according to any one of claims 1 to 4 for the treatment and / or prophylaxis of diseases. Use of a compound according to any one of the claims 1 to 4 for the manufacture of a medicament for the treatment and / or Prophylaxis of diseases. Use of a compound according to any one of the claims 1 to 4 for the manufacture of a medicament for the treatment and / or Prophylaxis of cardiovascular diseases, thromboembolic diseases and / or of tumor diseases. Use of a compound according to any one of the claims 1 to 4 for the prevention of blood coagulation in vitro. Medicament containing a compound after one of claims 1 to 4 in combination with an inert, non-toxic, pharmaceutically suitable excipient. Medicament containing a compound after one of claims 1 to 4 in combination with another Active ingredient. Medicament according to claim 10 or 11 for the treatment and / or prophylaxis of cardiovascular disease, thromboembolic Diseases and / or tumors. Method for the treatment and / or prophylaxis of using thromboembolic diseases in humans and animals an anticoagulatory effective amount of at least one compound one of claims 1 to 4, a medicament according to one of claims 10 to 12 or one of claim 7 or 8 received drug. Method for preventing blood coagulation in in vitro, characterized in that an anticoagulatory effective Amount of a compound according to any one of claims 1 to 4 is added.