EP3004086A1

EP3004086A1 - Substituted benzoxazoles

Info

Publication number: EP3004086A1
Application number: EP14727212.4A
Authority: EP
Inventors: Swen Allerheiligen; Anja BUCHMÜLLER; Karen Engel; Christoph Gerdes; Kersten Matthias Gericke; Michael Gerisch; Stefan Heitmeier; Alexander Hillisch; Tom KINZEL; Phlip LIENAU; Bernd Riedl; Susanne Röhrig; Martina Victoria Schmidt; Julia Strassburger; Adrian Tersteegen
Original assignee: Bayer Pharma AG
Current assignee: Bayer Pharma AG
Priority date: 2013-06-03
Filing date: 2014-05-30
Publication date: 2016-04-13
Also published as: CA2913958A1; JP2016520110A; CN105431428A; US20160108027A1; WO2014195230A1

Abstract

The invention relates to substituted benzoxazoles of formula (1) where R¹ stands for a group of formula, and a method for preparing same and their use in the production of drugs for the treatment and/or prevention of diseases, in particular cardiovascular diseases, preferably thrombotic or thromboembolic diseases.

Description

Substituted benzoxazoles

The invention relates to substituted benzoxazoles and processes for their preparation and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular cardiovascular diseases, preferably of thrombotic or thromboembolic diseases.

Blood clotting is a protective mechanism of the organism that can quickly and reliably "seal" defects in the vessel wall, thus preventing or minimizing blood loss, and bleeding after vascular injury is essentially through the coagulation system, which involves an enzymatic cascade It involves numerous clotting factors, each of which, once activated, converts the next inactive precursor to its active form, transforming the soluble fibrinogen into the insoluble fibrin at the end of the cascade Traditionally, one differentiates between the intrinsic and the extrinsic system in blood coagulation, which culminate in a concluding common reaction pathway, where factors Xa and IIa (thrombin) play key roles: Factor Xa bundles the signals of the two coagulation pathways because it is formed by Factor VIIa / Tissue Factor (extrinsic pathway) as well as the Tenase complex (intrinsic pathway) by reaction of Factor X. The activated serine protease Xa cleaves prothrombin to thrombin, which transmits the cascade impulses to the coagulation status of the blood via a series of reactions: Thrombin splits fibrinogen directly into fibrin. It activates the factor ΧΠΙ to factor XIIIa necessary for the stabilization of the fibrin clot. In addition, thrombin is a potent trigger of platelet aggregation (via PAR-1 activation), which also makes a significant contribution to hemostasis. By activating TAFI (thrombin-activatable fibrinolysis inhibitor) to TAFIa thrombin inhibits the dissolution of the clot in the complex with thrombomodulin. Activation of factors V and Vin leads to the potentiation of thrombin production and thus to the enhancement of the coagulation reaction.

In addition to thrombin, which is freely present in the blood, bound forms are also known: During the formation of a fibrin clot, thrombin and prothrombinase (factor Xa in the complex) are bound to the fibrin skeleton. These enzyme molecules continue to have activity and can not be inhibited by the body's anti-thrombin III. Clots thus have a general procoagulant potential in this way.

In addition, thrombin is involved, in particular via the activation of PAR-1 receptors on endothelial cells, also in inflammatory processes which interact with the Coagulation system speeds up both processes.

An uncontrolled activation of the coagulation system or a defective inhibition of the activation processes can cause the formation of local thromboses or embolisms in vessels (arteries, veins, lymphatics) or cardiac cavities. In addition, systemic hypercoagulability can lead to system-wide thrombus formation and eventually to consumption coagulopathy in the context of disseminated intravascular coagulation. Thromboembolic complications also occur in microangiopathic hemolytic anemias, extracorporeal blood circuits such as hemodialysis, and heart valve prostheses and stents. In the course of many cardiovascular and metabolic diseases systemic factors, such as hyperlipidemia, diabetes or smoking, as a result of blood flow changes with stasis, such as in atrial fibrillation, or due to pathological vascular wall changes, eg endothelial dysfunction or atherosclerosis, lead to an increased tendency of coagulation and platelet activation, which can lead to thromboembolic disorders and thrombotic complications with life-threatening conditions through the formation of fibrin and platelet-rich thrombi. Thromboembolic disease remains among the most common causes of morbidity and mortality in most industrialized countries [Heart Disease: A Textbook of Cardiovascular Medicine, Eugene Braunwald, 5th Ed., 1997, WB Saunders Company, Philadelphia]. The anticoagulants known from the prior art, ie substances for the inhibition or prevention of blood clotting, have various disadvantages. In the therapy and prophylaxis of thromboembolic diseases, on the one hand heparin is used, which is administered parenterally or subcutaneously. Due to more favorable pharmacokinetic properties, although increasingly low molecular weight heparin is nowadays increasingly preferred; However, this also the known disadvantages described below can not be avoided, which consist in the therapy with heparin. Thus, heparin is orally ineffective and has only a comparatively low half-life. In addition, there is a high risk of bleeding, in particular cerebral hemorrhage and bleeding in the gastrointestinal tract can occur, and it can lead to thrombocytopenia, Alopecia medicomentosa or osteoporosis [Pschyrembel, Clinical Dictionary, 257th edition, 1994, Walter de Gruyter Verlag, page 610, keyword "heparin "Römpp Lexicon Chemistry, Version 1.5, 1998, Georg Thieme Verlag Stuttgart, keyword" heparin "]. Although low molecular weight heparins are less likely to develop heparin-induced thrombocytopenia, they are also only subcutaneous to apply. This also applies to fondaparinux, a synthetically produced, selective factor Xa inhibitor with a long half-life.

A second class of anticoagulants are the vitamin K antagonists. These include, for example, 1,3-indandiones, but especially compounds such as warfarin, phenprocoumon, dicumarol and other coumarin derivatives, which are unsuitable for the synthesis of various products of certain vitamin K-dependent coagulation factors in the liver. Due to the mechanism of action, the effect is only very slow (latency until the onset of action 36 to 48 hours). Although the compounds can be administered orally, due to the high risk of bleeding and the narrow therapeutic index, a complex individual adjustment and observation of the patient is necessary [J. Hirsh, J. Dalen, D.R. Anderson et al., "Oral anticoagulants: Mechanism of action, clinical effectiveness, and optimal therapeutic rank" Chest 2001, 119, 8S-21S, J. Ansell, J.Hirsh, J.Dalen et al., "Managing oral anticoagulant therapy "Chest 2001, 119, 22S-38S; P.S. Wells, A.M. Holbrook, N.R. Crowther et al, "Interactions of warfarin with drugs and food" Ann Intern Med, 1994, 121, 676-683.] In addition, other side effects such as gastrointestinal disorders, hair loss and skin necrosis are described.

Recent approaches to oral anticoagulants are at various stages of clinical testing or use, but have also shown disadvantages, such as: Highly variable bioavailability, liver damage and bleeding complications, especially in patients with kidney damage.

In the case of antithrombotic drugs, the therapeutic range is important: The distance between the therapeutically effective dose for anticoagulation and the dose at which bleeding can occur should be as large as possible so that maximum therapeutic efficacy is achieved with minimal risk profile. In particular, under therapeutic conditions with already existing thrombi, it may be advantageous to inhibit the factor IIa present in the thrombus and thus to promote rapid thrombus degradation. In various in-vitro and in-vivo models with, for example, argatroban or hirudin as Flla inhibitors, the beneficial effect of FIIa inhibition on already existing thrombus alone or in the presence of tissue-type plamogen activator (tPA) was worked out.

An object of the present invention is therefore to provide novel compounds as thrombin inhibitors for the treatment of cardiovascular diseases, in particular of thrombotic or thromboembolic diseases, in humans and animals, which have a broad therapeutic range and show good pharmacokinetic behavior.

WO 98/37075 describes, inter alia, benzoxazole derivatives with an amidinobenzylamino substituent as thrombin inhibitors. Amidino-substituted thrombin inhibitors have a short half-life and low oral bioavailability. As such, the compounds are only suitable for parenteral use and must be used as prodrugs when given orally (A. Casimiro-Garcia, DA Dudley, RJ Heemstra, KJ Filipski, CF Bigge, JJ Edmunds, Expert Opin. Ther. 16 (2), 119-145).

WO 2007/140982 describes the use of benzoxazoles as thrombin inhibitors. EP-A 0 535 521 describes the use of benzoxazoles as leukotriene biosynthesis inhibitors for the treatment of inflammatory diseases.

The invention relates to compounds of the formula

in which

R is a group of the formula

where * is the point of attachment to the carbonyl group,

X represents an oxygen atom, a sulfur atom or CH-R ⁶ , where is hydrogen or hydroxy,

R ^{2 is} hydrogen, aminocarbonyl, C ¹ -C 6 -alkyl, C 3 -C 6 -cycloalkyl or phenyl, in which alkyl and cycloalkyl may be substituted by a substituent selected from the group consisting of hydroxy, methoxy, cyano, hydroxycarbonyl, aminocarbonyl, methylsulfonyl, Difluoromethoxy, trifluoromethoxy and cyclopropyl, in which cyclopropyl may itself be substituted by a hydroxy substituent, or in which alkyl and cycloalkyl may be substituted by from 1 to 3 fluoro substituents,

R ^{3 is} hydrogen or GC ₄ - alkyl, or

R ² and R ³ together with the carbon atom to which they are attached form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring, in which the cyclobutyl ring and cyclopentyl ring may be substituted by a hydroxy substituent,

R ^{4 is} hydrogen or GC ₆ - alkyl, wherein alkyl may be substituted with a hydroxy substituent, or wherein alkyl may be substituted with 1 to 3 fluorine substituents, R ^{5 is} C 1 -C ₄ alkyl, or

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring, wherein the cyclobutyl ring and cyclopentyl ring may be substituted with a hydroxy substituent,

R ^{7 is} hydrogen or C ₁ -C ₆ -alkyl in which alkyl may be substituted by a substituent selected from the group consisting of cyano, hydroxy and methoxy, or in which alkyl may be substituted by 1 to 3 substituents fluoro,

R ^{8 is} hydrogen,

R ^{9 is} hydrogen or Ci-Cö-alkyl, wherein alkyl may be substituted with a substituent selected from

A group consisting of hydroxy, cyano and aminocarbonyl, or wherein alkyl may be substituted by 1 to 3 substituents fluoro, R ^{10 is} hydrogen, R ^{11 is} Ci-C ₄ alkyl, wherein alkyl may be substituted with a substituent hydroxy, R ^{12 is} hydrogen or C 1 -C ₄ -alkyl, or

R ¹¹ and R ¹² together with the carbon atom to which they are attached form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring, in which the cyclobutyl ring and cyclopentyl ring may be substituted by a hydroxy substituent,

R ^{13 is} methyl, ethyl, (3-fluoroazetidin-1-yl) carbonyl, (3,3-difluoroazetidin-1-yl) carbonyl or morpholin-4-ylcarbonyl, wherein methyl and ethyl are substituted with a substituent selected from the group consisting of cyano and hydroxy,

R 14 is hydrogen, methoxy, ethoxy or cyclopropyloxy, where methoxy and ethoxy may be substituted by from 1 to 3 substituents selected from the group consisting of deuterium and fluoro,

R 15 is hydrogen or methyl, and

R 16 is hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts. Compounds of the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, as well as the compounds of formula (I), hereinafter referred to as embodiment (e) and their salts, solvates and solvates of the salts, as far as the compounds of formula (I) mentioned below are not already salts, solvates and solvates of the salts. The compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in atropisomers). The present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.

If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms. The present invention also includes all suitable isotopic variants of the compounds of the invention. An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature. Examples of isotopes used in a compound of the invention can be incorporated are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (deuterium), ³ H (tritium), ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ 0, ¹⁸ 0, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ I. Certain isotopic variants of a compound of the invention such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, to study the mechanism of action or drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with ³ H or ¹⁴ C isotopes are particularly suitable for this purpose. Moreover, the incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.

Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included are salts which are not suitable for pharmaceutical applications themselves but can be used, for example, for the isolation or purification of the compounds according to the invention.

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

Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms. Atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and choline. Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. In addition, the present invention also includes prodrugs of the compounds of the invention. The term "prodrugs" includes compounds which may themselves be biologically active or inactive, but during their residence time in the body are converted to compounds of the invention (for example metabolically or hydrolytically).

For the purposes of the present invention, the term "treatment" or "treating" includes inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, suppressing, restraining or curing a disease, a disease, a disease, an injury or a medical condition , the unfolding, the course or progression of such conditions and / or the symptoms of such conditions. The term "therapy" is understood to be synonymous with the term "treatment". The terms "prevention", "prophylaxis" or "prevention" are used interchangeably in the context of the present invention and denote the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a Progression of such conditions and / or to get, experience, suffer or have the symptoms of such conditions. The treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:

Alkyl is a linear or branched alkyl radical having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl Butyl, n-pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3- Dimethylbutyl, 1-ethylbutyl and 2-ethylbutyl.

Cycloalkyl represents a monocyclic cycloalkyl group having 3 to 6 carbon atoms, by way of example and preferably cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Denη the formulas of the group, which may stand for R ¹ , is the end point of the line, next to each a * is not a carbon atom or a CEh group but is part of the bond to the atom to which R ^{1 is} attached ,

Preference is given to compounds of the formula (I) in which, for a group of the formula

where * is the point of attachment to the carbonyl group, X is an oxygen atom or CH-R ⁶ , where

R ^{6 is} hydrogen,

R ^{2 is} hydrogen, GC ₄ alkyl or C ₃ -C ₆ cycloalkyl, wherein alkyl and cycloalkyl may be substituted with a substituent selected from the group consisting of hydroxy, methoxy, hydroxycarbonyl, difluoromethoxy and cyclopropyl, in which cyclopropyl in turn be substituted may be substituted with one hydroxy substituent, or wherein alkyl may be substituted with from 1 to 3 fluorine substituents, R ^{3 is} hydrogen or GC ₄ alkyl, or R ² and R ³ together with the carbon atom to which they are attached form a cyclobutyl ring, wherein the cyclobutyl ring may be substituted with a hydroxy, R ^{4 is} hydrogen or GC ₄ alkyl, wherein alkyl may be substituted with a hydroxy substituent,

R ^{5 is} C 1 -C ₄ -alkyl,

R ^{7 is} C 1 -C ₄ -alkyl, in which alkyl may be substituted by a methoxy substituent, R ^{8 is} hydrogen,

R ^{9 is} C 1 -C ₄ -alkyl, in which alkyl may be substituted by a substituent selected from the group consisting of cyano and aminocarbonyl,

R ^{10 is} hydrogen, R ^{11 is} C 1 -C ₄ -alkyl,

R ^{12 is} hydrogen or Ci-C - alkyl, or

R ¹¹ and R ¹² together with the carbon atom to which they are attached form a cyclopropyl ring, R ^{13 is} methyl, ethyl, (3-fluoroazetidin-1-yl) carbonyl, (3,3-difluoroazetidin-1-yl) carbonyl or morpholin-4-ylcarbonyl wherein methyl and ethyl are substituted by a substituent selected from the group consisting of cyano and hydroxy,

R ^{14 is} hydrogen, ethoxy or cyclopropyloxy, wherein ethoxy may be substituted with 1 to 3 substituents selected from the group consisting of deuterium and fluorine,

R ^{15 is} hydrogen or methyl, and R ^{16 is} hydrogen or methyl, and their salts, their solvates and the solvates of their salts. Preference is also given to compounds of the formula (I) in which R ^{1 is} a group of the formula

where * is the point of attachment to the carbonyl group,

X is an oxygen atom,

R ^{2 is} C ¹ -C 4 alkyl or cyclobutyl, wherein alkyl may be substituted with one substituent selected from the group consisting of hydroxy and methoxy, or wherein alkyl may be substituted with 1 to 3 substituents fluoro, and wherein cyclobutyl is substituted with one Substituents hydroxy, R ^{3 is} hydrogen or methyl,

R ^{4 is} hydrogen or methyl, and

R ^{5 is} methyl, or

R ^{2 is} methyl or ethyl, wherein methyl or ethyl may be substituted with 1 to 3 substituents fluoro, R ^{3 is} hydrogen or methyl, R ^{4 is} GC ₄ alkyl, wherein alkyl is substituted with a hydroxy substituent, and

R ^{5 is} methyl, or

R ² and R ³ together with the carbon atom to which they are attached form a cyclobutyl ring in which the cyclobutyl ring is substituted by a hydroxy substituent, R ^{4 is} hydrogen or methyl, and

R ^{5 is} methyl,

R ^{7 is} methyl or ethyl, in which methyl and ethyl may be substituted by a methoxy substituent,

R ^{8 is} hydrogen,

R ^{9 is} methyl or ethyl, in which methyl and ethyl may be substituted by a substituent selected from the group consisting of cyano and aminocarbonyl, R ^{10 is} hydrogen, R ^{11 is} methyl, R ^{12 is} hydrogen, or R ¹¹ and R ^{12 taken} together with the carbon atom to which they are attached

Form cyclopropyl ring,

R ^{13 is} methyl, in which methyl is substituted by a hydroxy substituent,

R ^{14 is} ethoxy or cyclopropyloxy, wherein ethoxy may be substituted with 1 to 3 substituents selected from

Group consisting of deuterium and fluorine,

R ^{15 is} hydrogen, and

R ^{16 is} hydrogen or methyl, and their salts, their solvates and the solvates of their salts.

Preference is also given to compounds of the formula (II) in which R ^{1 is} a group of the formula

where * is the point of attachment to the carbonyl group, X is an oxygen atom, R ^{2 is} C 1 -C ₄ -alkyl or cyclobutyl, wherein alkyl is substituted with a hydroxy substituent, and wherein cyclobutyl is substituted with a hydroxy, R ^{3 is} hydrogen,

R ^{4 is} hydrogen or methyl, and

R ^{5 is} methyl, or R ^{2 is} methyl, wherein methyl may be substituted with 1 to 2 substituents fluoro, R ^{3 is} hydrogen or methyl, R ^{4 is} Ci-C ₄ alkyl, wherein alkyl is substituted with one Substituents hydroxy, and

R ^{5 is} methyl, or

^R: and R ³ together with the carbon atom to which they are attached form a cyclobutyl ring, wherein the cyclobutyl ring is substituted with a substituent hydroxy,

R ^{4 is} hydrogen, and

R ^{5 is} methyl, R ^{7 is} methyl,

R ^{8 is} hydrogen,

R ^{9 is} methyl or ethyl, in which methyl may be substituted by a cyano substituent, R ^{10 is} hydrogen,

R ^{11 is} methyl, R ^{12 is} hydrogen, or

R ¹¹ and R ¹² together with the carbon atom to which they are attached form a cyclopropyl ring,

R ^{13 is} methyl, in which methyl is substituted by a hydroxy substituent,

R ^{14 is} ethoxy or cyclopropyloxy, wherein ethoxy may be substituted by 1 to 3 substituents selected from the group consisting of deuterium and fluoro,

R ^{15 is} hydrogen, and

R ^{16 is} hydrogen or methyl, and their salts, their solvates and the solvates of their salts. Preference is also given to compounds of the formula (I) in which R ^{1 is} a group of the formula where * is the point of attachment to the carbonyl group, X is an oxygen atom, a sulfur atom or CH-R ⁶ , where

R ^{6 is} hydrogen or hydroxy,

R ^{3 is} hydrogen or C 1 -C 4 -alkyl, or

R ^{4 is} hydrogen or C 1 -C ⁶ -alkyl, wherein alkyl may be substituted with a substituent hydroxy, or wherein alkyl may be substituted with 1 to 3 substituents fluoro, R ^{5 is} Ci-C ₄ alkyl, or

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring wherein the cyclobutyl ring and cyclopentyl ring may be substituted with a hydroxy, R ⁷ substituent for hydrogen or Ci-Ce-alkyl, wherein alkyl may be substituted with a substituent selected from the group consisting of cyano, hydroxy and methoxy, or wherein alkyl may be substituted with 1 to 3 substituents fluorine, R ^{8 is} hydrogen, and

R ^{16 is} hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts. Preference is also given to compounds of the formula (I) in which R ^{1 is} a group of the formula

where * is the point of attachment to the carbonyl group, X is an oxygen atom or CH-R ⁶ , where R ^{6 is} hydrogen,

R ^{2 is} hydrogen, GC ₄ alkyl or C ₃ -C ₆ cycloalkyl, wherein alkyl and cycloalkyl may be substituted with a substituent selected from the group consisting of hydroxy, methoxy, hydroxycarbonyl, difluoromethoxy and cyclopropyl, in which cyclopropyl in turn be substituted can with one

Substituents hydroxy, or wherein alkyl may be substituted with 1 to 3 substituents fluorine, R ^{3 is} hydrogen or GC ₄ - alkyl, or

R ² and R ³ together with the carbon atom to which they are attached form a cyclobutyl ring, wherein the cyclobutyl ring may be substituted with a hydroxy, R ^{4 is} hydrogen or GC ₄ alkyl, wherein alkyl may be substituted with a substituent hydroxy, R ^{5 is} C 1 -C ₄ -alkyl, R ^{7 is} C 1 -C ₄ -alkyl, in which alkyl may be substituted by a substituent methoxy, R ^{8 is} hydrogen, and

R ^{16 is} hydrogen or methyl, and their salts, their solvates and the solvates of their salts. Preference is also given to compounds of the formula (I) in which R ^{1 is} a group of the formula

where * is the point of attachment to the carbonyl group, X is an oxygen atom,

R ^{2 is} C i -C ₄ alkyl or cyclobutyl, wherein alkyl may be substituted with one substituent selected from the group consisting of hydroxy and methoxy, or wherein alkyl may be substituted with 1 to 3 substituents fluoro, and wherein cyclobutyl is substituted with a substituent hydroxy, R ^{3 is} hydrogen or methyl, R ^{4 is} hydrogen or methyl, and R ^{5 is} methyl, or

R ^{2 is} methyl or ethyl, in which methyl or ethyl may be substituted by 1 to 3 substituents fluorine, R ^{3 is} hydrogen or methyl,

R ^{4 is} C 1 -C ₄ -alkyl, wherein alkyl is substituted with a hydroxy substituent, and

R ^{5 is} methyl, or

R ² and R ³ together with the carbon atom to which they are attached form a cyclobutyl ring in which the cyclobutyl ring is substituted by a hydroxy substituent,

R ^{4 is} hydrogen or methyl, and

R ^{5 is} methyl,

R ^{7 is} methyl or ethyl, wherein methyl and ethyl may be substituted by a methoxy substituent, R ^{s is} hydrogen, and

R ^{16 is} hydrogen or methyl, and their salts, their solvates and the solvates of their salts. Preference is also given to compounds of the formula (I) in which

R ^{1 is} a group of the formula

stands,

where * is the point of attachment to the carbonyl group,

X is an oxygen atom,

R ^{2 is} C ¹ -C ₄ -alkyl or cyclobutyl,

wherein alkyl is substituted with a hydroxy substituent, and

wherein cyclobutyl is substituted with a hydroxy substituent,

R ^{3 is} hydrogen,

R ^{4 is} hydrogen or methyl,

and

R ^{5 is} methyl,

or

R ^{2 is} methyl,

wherein methyl may be substituted with 1 to 2 substituents fluorine,

R ^{3 is} hydrogen or methyl,

R ^{4 is} C 1 -C ₄ -alkyl,

wherein alkyl is substituted with a hydroxy substituent, and

R ^{5 is} methyl, or

R ^{4 is} hydrogen, and

R ^{5 is} methyl, R ^{7 is} methyl,

R ^{8 is} hydrogen, and

where * is the point of attachment to the carbonyl group,

R ^{3 is} hydrogen or GC ₄ - alkyl, or

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring, wherein the cyclobutyl ring and cyclopentyl ring may be substituted with a hydroxy substituent, and

R ^{16 is} hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts.

Preference is also given to compounds of the formula (I) in which R ^{1 is} a group of the formula

R ^{6 is} hydrogen,

R ^{2 is} hydrogen, GC ₄ alkyl or C ₃ -C ₆ cycloalkyl, wherein alkyl and cycloalkyl may be substituted with a substituent selected from the group consisting of hydroxy, methoxy, hydroxycarbonyl, difluoromethoxy and cyclopropyl, in which cyclopropyl in turn be substituted may be substituted with a hydroxy substituent, or wherein alkyl may be substituted with from 1 to 3 fluoro substituents, hydrogen or GC is t-alkyl, or

R ² and R ³ together with the carbon atom to which they are attached form a cyclobutyl ring in which the cyclobutyl ring may be substituted by a hydroxy substituent,

R ^{4 is} hydrogen or GC ₄ -alkyl, in which alkyl may be substituted by a hydroxy substituent,

R ^{5 is} C 1 -C ₄ -alkyl, and R ^{16 is} hydrogen or methyl, and their salts, their solvates and the solvates of their salts. Preference is also given to compounds of the formula (I) in which R ^{1 is} a group of the formula

where * is the point of attachment to the carbonyl group,

X is an oxygen atom,

R ^{2 is} C ¹ -C ₄ -alkyl or cyclobutyl, wherein alkyl may be substituted with one substituent selected from the group consisting of hydroxy and methoxy, or wherein alkyl may be substituted with 1 to 3 substituents fluorine, and wherein cyclobutyl is substituted with a hydroxy substituent, R ^{3 is} hydrogen or methyl, R ^{4 is} hydrogen or methyl, and

R ^{5 is} methyl, or

R ^{2 is} methyl or ethyl, in which methyl or ethyl may be substituted by 1 to 3 substituents fluoro,

R ^{3 is} hydrogen or methyl, R ^{4 is} C ¹ -C ₄ -alkyl wherein alkyl is substituted with one hydroxy substituent and R ^{5 is} methyl, or

R ^{5 is} methyl, and R ^{16 is} hydrogen or methyl,

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

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

R ^{1 is} a group of the formula

stands,

where * is the point of attachment to the carbonyl group,

X is an oxygen atom,

R ^{2 is} G-Ci-alkyl or cyclobutyl,

wherein alkyl is substituted with a hydroxy substituent, and

wherein cyclobutyl is substituted by a hydroxy substituent, R ^{3 is} hydrogen,

R ^{4 is} hydrogen or methyl,

and

R ^{5 is} methyl,

or

R ^{2 is} methyl,

in which methyl may be substituted by 1 to 2 substituents fluorine, R ^{3 is} hydrogen or methyl, R ^{4 is} C 1 -C ₄ -alkyl, wherein alkyl is substituted with a hydroxy substituent, and

R ^{5 is} methyl, or

R ^: and R ³ together with the carbon atom to which they are attached form a cyclobutyl ring in which the cyclobutyl ring is substituted by a hydroxy substituent, R ^{4 is} hydrogen, and

R ^{5 is} methyl, and

where * is the point of attachment to the carbonyl group, X is an oxygen atom, R ^{2 is} C 1 -C ₄ -alkyl or cyclobutyl,

wherein alkyl is substituted with a hydroxy substituent, and

wherein cyclobutyl is substituted by a hydroxy substituent, R ^{3 is} hydrogen,

R ^{4 is} hydrogen or methyl,

and

R ^{5 is} methyl,

and

R ^{16 is} hydrogen or methyl,

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

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

R ^{1 is} a group of the formula

stands,

where * is the point of attachment to the carbonyl group,

X is an oxygen atom,

R ^{2 is} methyl,

R ^{5 is} methyl, and

R ^{16 is} hydrogen or methyl, and their salts, their solvates and the solvates of their salts. Preference is also given to compounds of the formula (II) in which R ^{1 is} a group of the formula

where * is the point of attachment to the carbonyl group, X is an oxygen atom,

R ^{4 is} hydrogen, and

R ^{5 is} methyl, and R ^{16 is} hydrogen or methyl, and their salts, their solvates and the solvates of their salts. Preference is also given to compounds of the formula (I) in which R ^{1 is} a group of the formula

where * is the point of attachment to the carbonyl group,

R ^{7 is} hydrogen or GC ₆ -alkyl in which alkyl may be substituted by a substituent selected from the group consisting of cyano, hydroxy and methoxy, or wherein alkyl may be substituted by 1 to 3 substituents fluoro, R ^{8 is} hydrogen, and R ^{16 is} hydrogen, methyl or fluoromethyl, and their salts, their solvates and the solvates of their salts. Preference is also given to compounds of the formula (I) in which R ^{1 is} a group of the formula where * is the point of attachment to the carbonyl group, R ^{7 is} C 1 -C ₄ -alkyl, in which alkyl may be substituted by a substituent methoxy,

R ^{8 is} hydrogen, and

where * is the point of attachment to the carbonyl group, X is an oxygen atom,

R ^{7 is} methyl or ethyl, in which methyl and ethyl may be substituted by a methoxy substituent, R ^{8 is} hydrogen, and

R ^{16 is} hydrogen or methyl,

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

stands,

where * is the point of attachment to the carbonyl group,

R ^{7 is} methyl,

R ^{8 is} hydrogen,

and

R ^{16 is} hydrogen or methyl,

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

stands, where * is the point of attachment to the carbonyl group,

R ^{9 is} hydrogen or C 1 -C ⁶ -alkyl, in which alkyl may be substituted by a substituent selected from the group consisting of hydroxy, cyano and aminocarbonyl, or in which alkyl may be substituted by 1 to 3 substituents fluoro,

R ^{10 is} hydrogen,

R ^{11 is} C 1 -C ₄ -alkyl, in which alkyl may be substituted by one hydroxy, R ^{12 is} hydrogen or C 1 -C ₄ -alkyl, or

R ¹¹ and R ^{12 taken} together with the carbon atom to which they are attached form a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring, wherein the cyclobutyl ring and cyclopentyl ring may be substituted with a hydroxy substituent, and

where * is the point of attachment to the carbonyl group,

R ^{9 is} Ci-Gi-alkyl, wherein alkyl may be substituted with a substituent selected from the group consisting of cyano and aminocarbonyl,

R ^{10 is} hydrogen,

R ^{11 is} C 1 -C ₄ -alkyl,

R ^{12 is} hydrogen or GC ₄ alkyl, or R ¹¹ and R ¹² together with the carbon atom to which they are attached are

Form cyclopropyl ring, and

where * is the point of attachment to the carbonyl group, R ^{9 is} methyl or ethyl, wherein methyl and ethyl may be substituted with a substituent selected from the group consisting of cyano and aminocarbonyl,

R ^{10 is} hydrogen,

R ^{11 is} methyl, R ^{12 is} hydrogen, or

R ¹¹ and R ¹² together with the carbon atom to which they are attached form a cyclopropyl ring, and R ^{16 represents} hydrogen or methyl, and their salts, their solvates and the solvates of their salts. Preference is also given to compounds of the formula (I) in which R ^{1 is} a group of the formula

where * is the point of attachment to the carbonyl group,

R ^{9 is} methyl or ethyl, in which methyl may be substituted by a cyano substituent,

R ^{10 is} hydrogen, R ^{11 is} methyl,

R ^{12 is} hydrogen, or

where * is the point of attachment to the carbonyl group,

R ^{13 is} methyl, ethyl, (3-fluoroazetidin-1-yl) carbonyl, (3,3-difluoro-azetidin-1-yl) carbonyl or morpholin-4-ylcarbonyl wherein methyl and ethyl are substituted with one substituent selected from Group consisting of cyano and hydroxy,

R ^{14 is} hydrogen, methoxy, ethoxy or cyclopropyloxy, where methoxy and ethoxy may be substituted by from 1 to 3 substituents selected from the group consisting of deuterium and fluoro,

R ^{15 is} hydrogen or methyl, and

where * is the point of attachment to the carbonyl group,

R ^{14 is} hydrogen, ethoxy or cyclopropyloxy, where ethoxy may be substituted by 1 to 3 substituents selected from the group consisting of deuterium and fluorine,

R ^{15 is} hydrogen or methyl, and

where the point of attachment to the carbonyl group is,

R 13 is methyl, in which methyl is substituted by a hydroxy substituent,

R 14 is ethoxy or cyclopropyloxy, where ethoxy may be substituted by 1 to 3 substituents selected from deuterium and fluoro group,

R is hydrogen, and

Preference is also given to compounds of the formula (I) in which R ^{16 is} hydrogen. Preference is also given to compounds of the formula (I) in which R ^{16 is} methyl. Preference is also given to compounds which have the formula (Ia)

wherein R ¹ and R ^{15 are} as defined above. It is also preferable

(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [(5R) -2- (2-hydroxyethyl) -2,5- dimethylmorpholin-4-yl] methanone [enantiomerically pure isomer] or (2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (2-hydroxypropan-2-yl) -2-methylmorpholine. 4-yl] methanone [enantiomerically pure isomer 2] or

7 - [(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -6-ethyl-4,7-diazaspiro [2.5 ] octan-5-one [enantiomerically pure isomer 1] or

{1 - [(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -5,5-dimethyl-3-oxopiperazine 2-yl} acetonitrile [enantiomerically pure isomer 2] or (2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (1 - hydroxyethyl) -2,2-dimethylmorpholin-4-yl] methanone [enantiomerically pure isomer 1] or one of the salts, the solvates or the solvates of the salts of these compounds.

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 the compounds of the formula

in which

R has the meaning given above, with compounds of the formula

R-- H (ΙΠ), in which R ^{1 has} the meaning given above, be reacted with Dehydratisierungsreagenzien.

The reaction is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from 0 ° C. to room temperature at atmospheric pressure. Suitable dehydrating reagents for this purpose are, for example, carbodiimides, such as e.g. JV, iV'-diethyl, A ^ W-dipropyl, A ^ W-diisopropyl, A ^ A ^ '- dicyclohexylcarbodiimide, N - ^ - Dimefhylamino- isopropy ^ -N'-ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), 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-methylisoxazolium 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 0- (benzotriazol-1-yl) -A ^^ A ^ '' - tetra-methyluronium hexafluorophosphate (HBTU), 2 - (2-oxo-l- (2H) -pyridyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), (benzotriazol-1-yloxy) bis-dimethylamino-methylium-fluoroborate (TBTU) or (^ - (T-azabenzotriazole) ly ^ -A ^^ A ^^ tetramet Hyluronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), or mixtures thereof, with bases. Preferably, the condensation is carried out with HATU or ^ - (S-dimethylaminoisopropyl) - ^ '- ethylcarbodiimide hydrochloride (EDC).

Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines, e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, preferred is diisopropylethylamine or 4-dimethylaminopyridine. Preference is given to the combination of HATU and diisopropylethylamine or N-α-dimethylamino-isopropyl-N'-ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine.

Inert solvents are, for example, halogenated hydrocarbons, such as dichloromethane or trichloromethane, hydrocarbons, such as benzene, or other solvents, such as nitromethane, dioxane, dimethylformamide, dimethyl sulfoxide or acetonitrile, or mixtures of the solvents, dimethylformamide being preferred. The compounds of the formula (ΙΠ) are known, can be synthesized by known processes from the corresponding starting compounds or can be prepared analogously to the processes described in the Examples section.

The compound of the formula (II) is known or can be prepared by reacting the compounds of the formula

in which

R has the meaning given above, and

R ^{17 is} methyl or ethyl, are reacted with a base.

The reaction is generally carried out in inert solvents, preferably in a temperature range from 0 ° C to room temperature at atmospheric pressure.

Bases are, for example, alkali metal hydroxides such as sodium, lithium or potassium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, sodium hydroxide is preferred.

Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile or pyridine, or mixtures of solvents, dioxane is preferred.

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

R 17 is methyl or ethyl, with compounds of the formula

in which

R has the meaning given above, be reacted in the presence of a base.

The reaction is generally carried out in inert solvents, preferably in a temperature range from room temperature to the reflux of the solvent at atmospheric pressure.

The compounds of the formulas (V) and (VI) are known, can be synthesized by known processes from the corresponding starting compounds or can be prepared analogously to the processes described in the Examples section.

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

The compounds of the invention show an unpredictable, valuable pharmacological activity spectrum and a good pharmacokinetic behavior. These are compounds which influence the proteolytic activity of the serine protease thrombin. The compounds of this invention inhibit thrombin-catalyzed enzymatic cleavage of substrates that play an essential role in the activation of blood clotting, platelet aggregation (via platelet PAR-1 activation), and thrombin-induced inflammatory, fibrosis, and angiogenesis Take processes. They are therefore suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.

Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular cardiovascular diseases, preferably thrombotic or thromboembolic diseases and / or thrombotic or thromboembolic complications.

As a key enzyme at the end of the coagulation cascade, thrombin translates the impulses from the cascade into the coagulation status of the blood via a series of reactions. The conversion of fibrinogen to insoluble fibrin leads to fibrin clot formation, which is stabilized by the factor XHIa, which is also activated by thrombin. By activating TAFI (thrombin-activatable fibrinolysis inhibitor) to TAFIa thrombin inhibits the dissolution of the clot in the complex with thrombomodulin. Activation of the factors V and Vin leads to the potentiation of thrombin production and thus to the enhancement of the Clotting reaction. In addition, thrombin is a potent trigger of platelet aggregation (via PAR-1 activation), which also makes a significant contribution to hemostasis.

Therefore, the compounds of the invention are suitable for the treatment and / or prophylaxis of diseases or complications that may arise or arise due to clot formation.

For the purposes of the present invention, "thrombotic or thromboembolic diseases" include diseases which occur both in the arterial and in the venous vascular bed and can be treated with the compounds according to the invention, in particular diseases in the coronary arteries of the heart, such as acute coronary syndrome ( ACS), heart attack with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI), stable angina pectoris, unstable angina pectoris, reocclusions and restenosis after coronary interventions such as angioplasty, stent implantation or aortocoronary bypass, but also thrombotic or thromboembolic disorders in other vessels leading to peripheral arterial occlusive diseases, pulmonary embolism, venous thromboembolism, venous thrombosis, especially in deep leg veins and renal veins, transient ischemic attacks as well as thrombotic stroke and thromboembolic stroke s.

The stimulation of the coagulation system can be done by various causes or comorbidities. Among other things, in the context of surgical interventions, immobility, bed-rest, infections or cancer or cancer therapy, the coagulation system can be strongly stimulated and there are thrombotic complications, especially venous thrombosis. The compounds according to the invention are therefore suitable for thrombosis prophylaxis in the context of surgical interventions in patients who have a cancer. The compounds according to the invention are therefore also suitable for thrombosis prophylaxis in patients with an activated coagulation system, for example under the stimulation situations described.

The compounds of the invention are therefore also useful in the prevention and treatment of cardiogenic thromboembolism, such as brain ischemia, stroke and systemic thromboembolism and ischaemia, in patients with acute, intermittent or persistent cardiac arrhythmias, such as atrial fibrillation, and those undergoing cardioversion , in patients with valvular heart disease or with artificial heart valves. Thromboembolic complications also occur in microangiopathic hemolytic anemias, extracorporeal blood circuits such as hemodialysis, and heart valve prostheses.

In addition, the compounds according to the invention come into consideration in particular for the treatment of diseases in which the clot already exists, since, in particular, thrombin which is incorporated in the clot contributes to clot stability. Since the inhibition of these thrombin molecules accelerates clot degradation, the compounds of the invention can be used to treat existing clots. These clots can arise in the entire vascular system and lead to serious complications in various organs, in particular by ischemia, inflammatory reactions or embolization, such as myocardial infarction or cerebral infarction, but also pulmonary embolism or postthrombotic syndrome, especially after deep vein thrombosis. The compounds according to the invention are therefore also suitable for the treatment of venous and arterial occlusions of the eye vessels which are caused by clots, for example age-related macular degeneration. Due to the observed synergistic effects with ly therapeutic principles such as the tissue plasminogen activator (tPA), the compounds for adjuvant use in a thrombolytic therapy.

In addition, the compounds according to the invention are suitable for the treatment and / or prophylaxis of diseases in which micro-clot formations or fibrin deposits in cerebral vessels occur which can lead to dementias such as, for example, vascular dementia or Alzheimer's disease. In this case, the clot can contribute to the disease both via occlusions and via the binding of further disease-relevant factors.

In addition, the compounds according to the invention are particularly suitable for the treatment and / or prophylaxis of diseases in which not only the procoagulant but also the proinflammatory component of the thrombin action plays an essential role. In particular, the mutual reinforcement of coagulation and inflammation can be prevented by the compounds according to the invention and therefore the probability of a thrombotic complication can be decisively reduced. Here, inter alia, the treatment and / or prophylaxis in the context of atherosclerotic vascular diseases, inflammation in the context of rheumatic diseases of the musculoskeletal system, inflammatory diseases of the lung, such as pulmonary fibrosis, inflammatory diseases of the kidney, such as glomerulonephritis, inflammatory diseases of the intestine, such as Crohn's disease or ulcerative colitis, or diseases that occur in the May be present in the context of a diabetic underlying disease, such as diabetic retinopathy or nephropathy.

In addition, the compounds of the present invention can be used to inhibit tumor growth and metastasis, and to prevent and / or treat thromboembolic complications such as venous thromboembolism in tumor patients, particularly those undergoing major surgery or chemotherapy or radiotherapy.

In addition, the compounds according to the invention are also suitable for the prophylaxis and / or treatment of pulmonary hypertension. The term "pulmonary hypertension" in the context of the present invention includes pulmonary arterial hypertension, pulmonary hypertension in diseases of the left heart, pulmonary hypertension in lung disease and / or hypoxia and pulmonary hypertension due to chronic thromboembolism (CTEPH).

"Pulmonary Arterial Hypertension" includes Idiopathic Pulmonary Arterial Hypertension (IPAH, formerly referred to as Primary Pulmonary Hypertension), Familial Pulmonary Arterial Hypertension (FPAH), and Associated Pulmonary Arterial Hypertension (APAH), which is associated with collagenosis. congenital systemic pulmonary shunt veins, portal hypertension, HIV infections, the use of certain drugs and medications, with other diseases (thyroid diseases, glycogen storage diseases, Gaucher disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy), with diseases with a significant venous / capillary involvement such as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, as well as persistent pulmonary hypertension of newborns.

Pulmonary hypertension in left heart disease includes left atrial or ventricular disease and mitral or aortic valve failure.

Pulmonary hypertension in lung disease and / or hypoxia includes chronic obstructive pulmonary disease, interstitial lung disease, sleep apnea syndrome, alveolar hypoventilation, chronic altitude sickness, and plant-related malformations.

Pulmonary hypertension due to chronic thromboembolism (CTEPH) includes thromboembolic occlusion of proximal pulmonary arteries, thromboembolic occlusion of distal pulmonary arteries, and non-thrombotic pulmonary embolisms (tumor, parasites, foreign bodies). Another object of the present invention is the use of the compounds of the invention for the preparation of medicaments for the treatment and / or prophylaxis of pulmonary hypertension in sarcoidosis, histiocytosis X and Lymphangiomatosis.

In addition, the substances according to the invention are also suitable for the treatment of pulmonary and hepatic fibroses.

In addition, the compounds according to the invention also come for the treatment and / or prophylaxis of disseminated intravascular coagulation in the context of an infectious disease, and / or of Systemic Inflammatory Syndrome (SIRS), septic organ dysfunction, septic organ failure and Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury (ALI), Septic shock and / or septic organ failure.

In the course of an infection, there may be 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. In addition, endothelial damage can result in increased vascular permeability and leakage of fluid and proteins into the extravasal space. Subsequently, organ failure (e.g., renal failure, liver failure, respiratory failure, CNS deficits and cardiovascular failure) or multiple organ failure may occur.

In DIC, the surface of damaged endothelial cells, foreign body surfaces or extravasated extravascular tissue causes massive activation of the coagulation system. As a result, coagulation occurs in small vessels of various organs with hypoxia and subsequent organ dysfunction. Secondarily, coagulation factors (eg Factor X, prothrombin and fibrinogen) and platelets are consumed, reducing the blood's ability to coagulate and causing severe bleeding. The compounds according to the invention are particularly suitable for the treatment and / or prophylaxis of acute coronary syndrome (ACS), venous thromboembolism, venous thrombosis, in particular in deep leg veins and renal veins, pulmonary embolisms, stroke and / or thrombosis prophylaxis in the context of surgical interventions, in particular in the context surgical intervention in patients who have cancer. Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases. Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using a therapeutically effective amount of a compound of the invention.

Another object of the present invention are the compounds of the invention for use in a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using a therapeutically effective amount of 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 addition, the compounds of the invention may also be used to prevent coagulation ex vivo, e.g. to protect organs to be transplanted from organ damage caused by clot formation and to protect the organ recipient from thromboemboli from the transplanted organ, to preserve blood and plasma products, to clean / pretreat catheters and other medical devices and equipment, to coat artificial surfaces of medical devices and equipment used in vivo or ex vivo, or biological samples that may contain factor IIa.

Another object of the present invention is a method for preventing blood coagulation in vitro, especially in blood or biological samples that might contain factor IIa, which is characterized in that an anticoagulatory effective amount of the compound of the invention is added. 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:

• lipid-lowering agents, in particular HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors such as, for example, lovastatin (Mevacor), simvastatin (Zocor), pravastatin

(Pravachol), fluvastatin (Lescol) and atorvastatin (Lipitor); Coronary / vasodilators, in particular ACE (angiotensin converting enzyme) inhibitors such as captopril, lisinopril, enalapril, ramipril, cilazapril, benazepril, fosinopril, quinapril and perindopril, or AII (angiotensin ID receptor antagonists such as embusartan, Losartan, valsartan, irbesartan, candesartan, eprosartan and temisarta, or beta-adrenoceptor antagonists such as carvedilol, alprenolol, bisoprolol, acebutolol, atenolol, betaxolol, carteolol, metoprolol, nadolol, penbutolol, pindolol, propranolol and timolol, or alpha- 1 Adrenoceptor antagonists such as prazosin, bunazosin, doxazosin and terazosin, or diuretics such as hydrochlorothiazide, furosemide, bumetanide, piretanide, torasemide, amiloride and dihydralazine, or calcium channel blockers such as verapamil and diltiazem, or dihydropyridine derivatives such as nifedipine ( Adalat) and nitrendipine (Bayotensin), or nitro preparations such as b For example, isosorbide-5-mononitrate, isosorbide dinitrate, and glycerol trinitrate, or substances that cause an increase in cyclic guanosine monophosphate (cGMP), such as soluble guanylate cyclase stimulants, such as riociguat;

Plasminogen activators (thrombolytics / fibrinolytics) and thrombolysis / fibrinolysis-enhancing compounds such as inhibitors of plasminogen activator inhibitor (PAI inhibitors) or inhibitors of thrombin-activated fibrinolysis inhibitor (TAFI inhibitors) such as tissue plasminogen activator ( t-PA, such as Actilyse ^®), streptokinase, reteplase and urokinase;

Anticoagulant substances (anticoagulants) such as heparin (UFH), low molecular weight heparin (LMWH) such as tinzaparin, certoparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, danaparoid, semuloparin (AVE 5026), adomiparin (M118) and EP-42675 / ORG42675; Direct thrombin inhibitors (DTI) such as Pradaxa (Dabigatran), Atecegatran (AZD-0837), DP-4088, SSR-182289 A, argatroban, bivalirudin and Tanogitran (BIBT-986 and prodrug BIBT-1011), hirudin;

Direct factor Xa inhibitors such as rivaroxaban, apixaban, edoxaban (DU-176b), betrixaban (PRT-54021), R-1663, darexaban (YM-150), otamixaban (FXV-673 / RPR-130673), letaxaban ( TAK-442), razaxaban (DPC-906), DX-9065a, LY-517717, idraparinux and fondaparinux;

• platelet aggregation-inhibiting substances (platelet aggregation inhibitors, antiplatelet agents) such as acetylsalicylic acid (such as aspirin), Ticlopidine (Ticlid), Clopidogrel (Plavix), Prasugrel, Ticagrelor, Cangrelor, Elinogrel, Vorapaxar;

Fibrinogen receptor antagonists (glycoprotein Hb / nia antagonists) such as abciximab, eptifibatide, tirofiban, lamifiban, lefradafiban and fradafiban; Recombinant human activated protein C such as Xigris;

• as well as antiarrhythmic drugs.

The present invention further relates to the combination of a compound of this invention with 5-chloro-A ^r - ({(5 _l ^R S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] - l, 3-oxazolidin-5-yl} -methyl) -2-thiophenecarboxamide (rivaroxaban) [WO 01/47919] having the structural formula

The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent. For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For the 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. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), orally 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 be done bypassing a resorption step (eg intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with the involvement of a Absorption (eg intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). For parenteral administration, suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders. The oral application is preferred.

For the other routes of administration are suitable, for example Inhalation medicines (including powder inhalers, nebulizers), nasal drops, solutions, sprays; lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic 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 be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecylsulfate, 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 odoriferous.

Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention, preferably together with one or more inert non-toxic, pharmaceutically suitable excipient, as well as their use for the purposes mentioned above. In general, it has been found to be beneficial to administer amounts of about 5 to 250 mg per 24 hours when administered parenterally to achieve effective results. When administered orally, the amount is about 5 to 500 mg per 24 hours.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. The percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume. The term "w / v" means "weight / volume". Thus, for example, "10% w / v" means: 100 ml of solution or suspension contains 10 g of substance.

A) Examples

Abbreviations: br. d. broad doublet (in NMR)

br. m. wide multiple "(by NMR)

br. s. broad singlet (by NMR)

about circa

d day (s), doublet (by NMR)

TLC thin layer chromatography

DCI direct chemical ionization (in MS)

dd double doublet (by NMR)

DMAP 4-dimethylaminopyridine

DMF A ^ N-dimethylformamide

DMSO dimethyl sulfoxide

dt double triplet (by NMR)

d. Th. Of theory (at yield)

EDCI N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide ESI electrospray ionization (in MS)

GC-MS gas chromatography-coupled mass spectroscopy h hour (s)

HATU (^ - (T-Azabenzotriazol-1-yl-^ ^ A ^^ tetramethyluronium hexafluorophosphate

HPLC high pressure, high performance liquid chromatography

LC-MS Liquid Chromatography-Coupled Mass Spectroscopy in Moles (by NMR)

M molar

m _c centered multiple «(by NMR)

min minute (s)

MS mass spectroscopy

prep. Preparative (on HPLC)

N normal

NMR nuclear magnetic resonance spectroscopy

q quartet (by NMR)

quant. quantitatively

quin quintet (by NMR)

RP reverse phase (on HPLC) RT room temperature

Retention time (on HPLC)

s singlet (by NMR)

t triplet (by NMR)

TFA trifluoroacetic acid

THF tetrahydrofuran

UV ultraviolet

UPLC ultrahigh-pressure, ultra-performance liquid chromatography

LC-MS methods:

Method 1A: Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μ 50 x 1 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A -> 1.2 min 5% A -> 2.0 min 5% A; Oven: 50 ° C; Flow: 0.40 ml / min; UV detection: 208-400 nm.

Method 2A: Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μ 30 x 2 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A -> 1.2 min 5% A -> 2.0 min 5% A; Oven: 50 ° C; Flow: 0.60 ml / min; UV detection: 208-400 nm.

Method 3A: Instrument: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 μ 50 x 1 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 97% A -> 0.5 min 97% A -> 3.2 min 5% A -> 4.0 min 5% A; Oven: 50 ° C; Flow: 0.3 ml / min; UV detection: 210 nm. Method 4A: Instrument MS: Waters (Micromass) Quattro Micro; Instrument HPLC: Agilent 1 100 series; Column: YMC-Triart C18 3 μ 50 x 3 mm; Eluent A: 1 l of water + 0.01 mol of ammonium carbonate, eluent B: 1 l of acetonitrile; Gradient: 0.0 min 100% A-> 2.75 min 5% A-> 4.5 min 5% A; Oven: 40 ° C; Flow: 1.25 ml / min; UV detection: 210 nm.

Method 5A: Instrument MS: Waters (Micromass) QM; Instrument HPLC: Agilent 1100 series; Column: Agient ZORBAX Extend-C18 3.0 x 50mm 3.5-micron; Eluent A: 1 l of water + 0.01 mol of ammonium carbonate, eluent B: 1 l of acetonitrile; Gradient: 0.0 min 98% A-> 0.2 min 98% A-> 3.0 min 5% A ^ 4.5 min 5% A; Oven: 40 ° C; Flow: 1.75 ml / min; UV detection: 210 nm.

Method 6A: Instrument MS: Waters (Micromass) ZQ; Instrument HPLC: Agilent 1100 series; Column: Agient ZORBAX Extend-C18 3.0 x 50mm 3.5-micron; Eluent A: 1 liter of water + 0.01 mol Ammonium carbonate, eluent B: 1: 1 acetonitrile; Gradient: 0.0 min 98% A-> 0.2 min 98% A-> 3.0 min 5% A ^ 4.5 min 5% A; Oven: 40 ° C; Flow: 1.75 ml / min; UV detection: 210 nm.

Method 7A: Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μ 50 x 1 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 95% A -> 6.0 min 5% A-> 7.5 min 5% A; Oven: 50 ° C; Flow: 0.35 ml / min; UV detection: 210 - 400 nm.

GC-MS methods:

Method 1B: Instrument: Thermo DFS, Trace GC Ultra; Column: Restek RTX-35, 15 m x 200 μιη x 0.33 μηι; constant flow with helium: 1.20 ml / min; Oven: 60 ° C; Met: 220 ° C; Gradient: 60 ° C, 30 ° C / min -> 300 ° C (hold for 3.33 min).

Method 2B: Instrument: Micromass GCT, GC6890; Column: Restek RTX-35, 15 m x 200 μιη x 0.33 μηι; constant flow with helium: 0.88 ml / min; Oven: 70 ° C; Met: 250 ° C; Gradient: 70 ° C, 30 ° C / min -> 310 ° C (hold for 3 min).

MS Methods: Method IC: Instrument: Thermo Fisher-Scientific DSQ; chemical ionization; Reactant gas NH ₃ ; Source temperature: 200 ° C; Ionization energy 70eV.

Method 2C: Instrumeit: Waters ZQ 2000; Electrospray ionization; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; 25% A, 75% B; Flow: 0.25 ml / min. Preparative enantiomeric Z diastereomer separation on chiral phase:

Method 1D: Phase: Daicel Chiralpak AZ-H, 5 μιη 250 mm x 30 mm, eluent: iso-hexane / ethanol 50:50; Flow: 40 ml / min; Temperature: 20 ° C; UV detection: 220 nm.

Method 2D: Phase: Daicel Chiralpak AZ-H, 5 μιη 250 mm x 30 mm, eluent: iso-hexane / ethanol 50:50; Flow: 40 ml / min, temperature: 25 ° C; UV detection: 220 nm. Method 3D: Phase: Daicel Chiralpak AD-H SFC, 10 μιη 250 mm × 20 mm, eluent: carbon dioxide / ethanol 70:30; Flow: 100 ml / min, makeup flow rate: 30 ml / min, baking pressure: 80 bar; Temperature: 40 ° C; UV detection: 220 nm.

Method 4P: Phase: Daicel Chiralpak AD-H, 5 μιη 250 mm x 20 mm, eluent: iso-hexane / isopropanol 70:30; Flow: 20 ml / min; Temperature: 25 ° C; UV detection: 230 nm. Method 5D: Phase: Daicel Chiralpak AZ-H, 5 μm 250 mm × 30 mm, eluent: isohexane / ethanol 90:10; Flow: 40 ml / min; Temperature: 25 ° C; UV detection: 220 nm.

Method 6D: Phase: Daicel Chiralpak AY-H, 5 μιη 250 mm x 20 mm, eluent: iso-hexane / ethanol 90:10; Flow: 40 ml / min; Temperature: 40 ° C; UV detection: 220 nm. Method 7D: Phase: Daicel Chiralpak AS-H, 5 μιη 250 mm × 20 mm, eluent: isohexane / ethanol 70:30; Flow: 20 ml / min; Temperature: 25 ° C; UV detection: 230 nm.

Method 8D: Phase: Daicel Chiralpak AZ-H, 5 μιη 250 mm x 30 mm, eluent: iso-hexane / ethanol 50:50; Flow: 20 ml / min; Temperature: 25 ° C; UV detection: 220 nm.

Method 9D: Phase: Daicel Chiralpak OZ-H, 5 μιη 250 mm x 20 mm, eluent: iso-hexane / ethanol 50:50; Flow: 15 ml / min; Temperature: 30 ° C; UV detection: 220 nm.

Method 10D: Phase: Daicel Chiralpak OD-H, 5 μιη 250 mm × 20 mm, eluent: iso-hexane / ethanol 60:40; Flow: 20 ml / min; Temperature: 22 ° C; UV detection: 230 nm.

Method HD: Phase: Daicel Chiralpak AD-H SFC, 10 μιη 250 mm x 20 mm, eluent: carbon dioxide / methanol 70:30; Flow: 100 ml / min, makeup flow rate: 30 ml / min, baking pressure: 80 bar; Temperature: 40 ° C; UV detection: 210 nm.

Method 12D: Phase: Daicel Chiralcel AD-H, 5 μιη 250 mm x 20 mm; Eluent: iso-hexane / ethanol 50:50 + 0.2% diethylamine; Flow: 20 ml / min; Temperature: 20 ° C; UV detection: 220 nm.

Method 13D: Phase: Daicel Chiralcel AD-H, 5 μιη 250 mm x 20 mm; Eluent: iso-hexane / in-propanol 50:50 + 0.2% diethylamine; Flow: 20 ml / min; Temperature: 20 ° C; UV detection: 230 nm. Method 14D: Phase: Daicel Chiralpak OD-H, 5 μm 250 mm × 20 mm, eluent: isohexane / isopropanol 50:50; Flow: 20 ml / min; Temperature: 25 ° C; UV detection: 230 nm.

Method 15D: Phase: Daicel Chiralpak IC, 5 μιη 250 mm x 20 mm, eluent: ieri-butyl methyl ether / methanol 50:50; Flow: 20 ml / min; Temperature: 25 ° C; UV detection: 220 nm.

Method 16D: Phase: Daicel Chiralpak AY-H, 5 μιη 250 mm x 20 mm, eluent: iso-hexane / ethanol 50:50; Flow: 20 ml / min; Temperature: 20 ° C; UV detection: 230 nm.

Method 17D: Phase: Daicel Chiralpak AS-H, 5 μιη 250 mm x 20 mm, eluent: iso-hexane / ethanol 90:10; Flow: 20 ml / min; Temperature: 25 ° C; UV detection: 220 nm. Method 18D: Phase: Daicel Chiralcel AZ-H, 5 μηι 250 mm x 40 mm; Eluent: iso-hexane / ethanol 90: 10 + 0.2% diethylamine; Flow: 35 ml / min; Temperature: 25 ° C; UV detection: 230 nm.

Method 19D: Phase: Daicel IA, 5 μιη 250 mm x 40 mm; Eluent: ferric butyl methyl ether / methanol 50:50; Flow: 20 ml / min; Temperature: 25 ° C; UV detection: 230 nm. Method 20D: Phase: Daicel Chiralcel AD-H, 5 μιη 250 mm x 20 mm; Eluent: iso-hexane / in-propanol 60:40 + 0.2% diethylamine; Flow: 20 ml / min; Temperature: 20 ° C; UV detection: 220 nm.

Method 21D: Phase: Daicel Chiralpak IC, 5 μιη 250 mm x 20 mm, eluent: ieri-butyl methyl ether / methanol / acetonitrile 50:25:25; Flow: 15 ml / min; Temperature: 35 ° C; UV detection: 220 nm.

Method 22D: Phase: Daicel Chiralcel AZ-H, 5 μιη 250 mm x 40 mm; Eluent: iso-hexane / ethanol 90: 10 + 0.2% diethylamine; Flow: 15 ml / min; Temperature: 30 ° C; UV detection: 220 nm.

Method 23D: Phase: Daicel Chiralcel AD-H, 5 μιη 250 mm x 20 mm; Eluent: iso-hexane / in-propanol 50:50; Flow: 20 ml / min; Temperature: 40 ° C; UV detection: 210 nm.

Method 24D: Phase: Daicel Chiralpak IC, 5 μιη 250 mm × 20 mm, eluent: acetonitrile / methanol 30:70; Flow: 30 ml / min; Temperature: 25 ° C; UV detection: 220 nm. Method 25D: Phase: Daicel Chiralpak OD-H, 5 μιη 250 mm × 20 mm, eluent: iso-hexane / ethanol 50:50; Flow: 20 ml / min, temperature: 20 ° C; UV detection: 220 nm.

Method 26D: Phase: Daicel Chiralpak AS-H, 5 μιη 250 mm × 20 mm, eluent: isohexane / ethanol 70:30 + 0.2% diethylamine; Flow: 20 ml / min; Temperature: 20 ° C; UV detection: 220 nm.

Method 27D: Phase: Daicel Chiralpak AD-H SFC, 5 μιη 250 mm x 30 mm, eluent: carbon dioxide / methanol 80:20; Flow: 100 ml / min, step gradient after 3 min for 1.5 min carbon dioxide / methanol 70:30; Makeup flow rate: 30 ml / min, baking pressure: 120 bar; Temperature: 40 ° C; UV detection: 210 nm.

Method 28D: Phase: Daicel Chiralpak AD-H, 5 μιη 250 mm x 20 mm, eluent: iso-hexane / ethanol 30:70; Flow: 20 ml / min, temperature: 40 ° C; UV detection: 210 nm. Method 29D: Phase: Daicel Chiralcel AD-H, 5 μιη 250 mm x 20 mm; Eluent: iso-hexane / ethanol 50:50; Flow: 20 ml / min; Temperature: 40 ° C; UV detection: 210 nm.

Method 30D: Phase: Daicel Chiralpak AS-H, 5 μιη 250 mm x 20 mm, eluent: iso-hexane / ethanol 50:50; Flow: 20 ml / min, temperature: 35 ° C; UV detection: 230 nm. Method 31D: Phase: Daicel Chiralcel AD-H, 5 μηι 250 mm x 20 mm; Eluent: iso-hexane / ώσ-propanol 50:50; Flow: 20 ml / min; Temperature: 25 ° C; UV detection: 230 nm.

Method 32D: Phase: Daicel Chiralpak OD-H, 5 μηι 250 mm x 20 mm, eluent: iso-hexane / w-propanol 80:20; Flow: 20 ml / min, temperature: 25 ° C; UV detection: 220 nm. Method 33D: Phase: Daicel Chiralpak AY-H, 5 μm 250 mm × 20 mm, eluent: isohexane / w / propanol 50:50 + 0.2% diethylamine; Flow: 15 ml / min, temperature: 40 ° C; UV detection: 220 nm.

Method 34D: Phase: Daicel Chiralcel AD-H, 5 μιη 250 mm x 20 mm; Eluent: iso-hexane / ώσ-propanol 50:50; Flow: 20 ml / min; Temperature: 20 ° C; UV detection: 220 nm.

Method 35D: Phase: Daicel Chiralpak OZ-H, 5 μιη 250 mm x 20 mm, eluent: iso-hexane / ethanol 50:50; Flow: 20 ml / min, temperature: 25 ° C; UV detection: 220 nm.

Method 36D: Phase: Daicel Chiralcel AD-H, 5 μηι 250 mm x 20 mm; Eluent: ethanol + 0.2% acetic acid / acetonitrile + 0.2% acetic acid 90:10; Flow: 20 ml / min; Temperature: 25 ° C; UV detection: 230 nm.

Method 37D: Phase: Daicel Chiralpak ID, 5 μιη 250 mm × 20 mm, eluent: ieri-butyl methyl ether / methanol 70:30; Flow: 20 ml / min, temperature: 25 ° C; UV detection: 230 nm.

Method 38D: Phase: Daicel Chiralcel AZ-H, 5 μιη 250 mm x 20 mm; Eluent: iso-hexane / n-propanol 50:50 + 0.2% diethylamine; Flow: 20 ml / min; Temperature: 45 ° C; UV detection: 220 nm.

Method 39D: Phase: Daicel Chiralpak ID, 5 μιη 250 mm x 20 mm, eluent: ieri-butyl methyl ether / methanol 70:30; Flow: 20 ml / min, temperature: 20 ° C; UV detection: 230 nm. Method 40D: Phase: Daicel Chiralcel AZ-H, 5 μm 250 mm × 40 mm; Eluent: ethanol; Flow: 13 ml / min; Temperature: 45 ° C; UV detection: 220 nm.

Method 41D: Phase: Daicel Chiralcel AD-H, 5 μιη 250 mm x 20 mm; Eluent: iso-hexane / n-propanol 50:50 + 0.2% diethylamine; Flow: 20 ml / min; Temperature: 25 ° C; UV detection: 220 nm.

Method 42D: Phase: Daicel Chiralpak OZ-H, 5 μηι 250 mm x 20 mm, eluent: isohexane ethanol 30:70 + 0.2% diethylamine; Flow: 15 ml / min, temperature: 40 ° C; UV detection: 220 nm.

Method 43D: Phase: Daicel Chiralcel OD-H, 5 μιη 250 mm x 40 mm; Eluent: iso-hexane / in-propanol 90: 10 + 0.2% diethylamine; Flow: 20 ml / min; Temperature: 25 ° C; UV detection: 220 nm. Method 44D: Phase: Daicel Chiralcel AZ-H, 5 μηι 250 mm x 40 mm; Eluent: iso-hexane / ethanol 80:20 + 0.2% diethylamine; Flow: 20 ml / min; Temperature: 25 ° C; UV detection: 220 nm.

Method 45D: Phase: Daicel Chiralpak AZ-H, 5 μιη 250 mm x 20 mm, eluent: iso-hexane / ethanol 70:30; Flow: 20 ml / min, temperature: 40 ° C; UV detection: 220 nm. Method 46D: Phase: Daicel Chiralpak OZ-H, 5 μm 250 mm × 20 mm, eluent: isohexane / ethanol 25:75; Flow: 15 ml / min, temperature: 40 ° C; UV detection: 220 nm.

Method 47D: Phase: Daicel Chiralpak IC, 5 μιη 250 mm x 20 mm, eluent: ieri-butyl methyl ether / methanol 50:50; Flow: 20 ml / min, temperature: 30 ° C; UV detection: 220 nm.

Method 48D: Phase: Daicel IA, 5 μιη 250 mm x 40 mm; Eluent: ieri-butyl methyl ether / methanol 50:50; Flow: 20 ml / min; Temperature: 30 ° C; UV detection: 220 nm.

Method 49D: Phase: Daicel Chiralpak AS-H, 5 μm, 250 mm × 20 mm, eluent: 50% iso-hexane, 50% ethanol; Flow: 20 ml / min; Temperature: 25 ° C; Detection: 220 nm.

Method 50D: Phase: Daicel Chiralpak IC, 5 μηι, 250 mm x 20 mm, eluent: 50% iso-hexane, 50% ethanol; Flow: 15 ml / min; Temperature: 40 ° C; Detection: 220 nm. Method 51D: Phase: Daicel Chiralpak OD-H, 5 μm, 250 mm × 4 mm, eluent: 95% isohexane, 5% ethanol + 1% diethylamine; Flow: 20 ml / min; Temperature: 40 ° C; Detection: 220 nm.

Method 52D: Phase: Daicel Chiralpak AZ-H, 5 μm, 250 mm x 30 mm, eluent: 10% iso-hexane, 90% ethanol + 0.2% diethylamine; Flow: 40 ml / min; Temperature: 20 ° C; Detection: 220 nm.

Method 53D: Phase: Daicel Chiralpak OD-H, 5 μm, 250 mm × 20 mm, eluent: 95% iso-hexane, 5% ethanol; Flow: 20 ml / min; Temperature: 40 ° C; Detection: 220 nm.

Method 54D: Phase: Daicel Chiralpak IC, 5 μm, 250 mm × 20 mm, eluent: 70% acetonitrile, 30% methanol with 0.2% diethylamine; Flow: 15 ml / min; Temperature: 45 ° C; Detection: 220 nm.

Method 55D: Phase: Daicel Chiralpak OD-H, 5 μm, 250 mm × 20 mm, eluent: 70% iso-hexane, 30% ethanol with 2% diethylamine; Flow: 20 ml / min; Temperature: 25 ° C; Detection: 220 nm. Method 56D: Phase: Daicel Chiralpak OD-H, 5 μm, 250 mm × 20 mm, eluent: 50% isohexane, 50% ethanol with 0.2% diethylamine; Flow: 15 ml / min; Temperature: 40 ° C; Detection: 220 nm.

Method 57D: Phase: Daicel Chiralpak OD-H, 5 μm, 250 mm × 20 mm, eluent: 50% iso-hexane, 50% ethanol; Flow: 20 ml / min; Temperature: 25 ° C; Detection: 220 nm. Method 58D: Phase: Daicel Chiracel OZ-H, 5 μηι, 250 mm x 20 mm, eluent: 50% iso-hexane, 50% iso-ethanol; Flow: 15 ml / min; Temperature: 40 ° C; Detection: 220 nm.

Method 59D: Phase: Daicel Chiralpak IC-H, 5 μm, 250 mm × 20 mm, eluent: 50% tert-butyl methyl ether, 50% methanol; Flow: 20 ml / min; Temperature: 25 ° C; Detection: 220 nm. Method 60D: Phase: Daicel Chiracel OD-H, 5 μm, 250 mm × 20 mm, eluent: 70% iso-hexane, 30% isopropanol; Flow: 20 ml / min, temperature: 25 ° C; Detection: 220 nm.

Analytical Enantiomeric ZDiastereomer Separation on Chiral Phase:

Method IE: Phase: Daicel Chiralcel OZ-H, 5 μιη 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 50:50; Flow: 1 ml / min; Temperature: 30 ° C; UV detection: 220 nm. Method 2E: Phase: Daicel Chiralcel AZ-H, 5 μιη 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 50:50; Flow: 1 ml / min; Temperature: 30 ° C; UV detection: 220 nm.

Method 3E: Phase: Daicel Chiralpak AD-H SFC, 5 μιη 250 mm x 4.6 mm; Eluent: carbon dioxide / ethanol 70:30; Flow: 3 ml / min; Temperature: 30 ° C; UV detection: 220 nm.

Method 4E: Phase: Daicel Chiralpak AD-H, 5 μιη 250 mm x 4.6 mm, eluent: iso-hexane / isopropanol 50:50; Flow: 1 ml / min; Temperature: 30 ° C; UV detection: 220 nm.

Method 5E: Phase: LUX amylose-2, 5 μιη 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 90:10; Flow: 1 ml / min; Temperature: 30 ° C; UV detection: 220 nm.

Method 6E: Phase: Daicel Chiralpak AS-H, 5 μιη 250 mm x 4.6 mm, eluent: iso-hexane / isopropanol 50:50; Flow: 1 ml / min; Temperature: 30 ° C; UV detection: 220 nm. Method 7E: Phase: Daicel Chiralcel OD-H, 5 μιη 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 80:20 + 0.2% diethylamine; Flow: 1 ml / min; Temperature: 40 ° C; UV detection: 220 nm.

Method 8E: Phase: Daicel Chiralpak AD-H, 5 μιη 250 mm x 4.6 mm, eluent: iso-hexane / ethanol 50:50; Flow: 1 ml / min; Temperature: 30 ° C; UV detection: 220 nm.

Method 9E: Phase: Daicel Chiralcel OZ-H, 5 μιη 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 50:50; Flow: 1 ml / min; Temperature: 40 ° C; UV detection: 220 nm.

Method 10E: Phase: Daicel Chiralcel OD-H, 5 μηι 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 50:50; Flow: 1 ml / min; Temperature: 30 ° C; UV detection: 220 nm. Method 11E: Phase: Daicel Chiralpak AD-H SFC, 5 μηι 250 mm x 4.6 mm; Eluent: carbon dioxide / ethanol 70:30; Flow: 4 ml / min; Temperature: 30 ° C; UV detection: 220 nm.

Method 12E: Phase: Daicel Chiralcel AD-H, 5 μηι 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 50:50 + 0.2% diethylamine; Flow: 1 ml / min; Temperature: 40 ° C; UV detection: 220 nm. Method 13E: Phase: Daicel Chiralpak OD-H, 5 μιη 250 mm × 4.6 mm, eluent: iso-hexane / isopropanol 50:50; Flow: 1 ml / min; Temperature: 25 ° C; UV detection: 220 nm.

Method 14E: Phase: Daicel Chiralpak IC, 5 μηι 250 mm x 4.6 mm, eluent: ieri-butyl methyl ether / methanol 50:50; Flow: 1 ml / min; Temperature: 30 ° C; UV detection: 220 nm.

Method 15E: Phase: Daicel Chiralpak AY-H, 5 μιη 250 mm x 4.6 mm, eluent: iso-hexane / ethanol 50:50; Flow: 1 ml / min; Temperature: 45 ° C; UV detection: 220 nm.

Method 16E: Phase: Daicel Chiralcel AZ-H, 5 μιη 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 90:10; Flow: 1 ml / min; Temperature: 30 ° C; UV detection: 220 nm.

Method 17E: Phase: Daicel Chiralpak AS-H, 5 μιη 250 mm x 4.6 mm, eluent: iso-hexane / ethanol 90:10; Flow: 1 ml / min; Temperature: 30 ° C; UV detection: 220 nm. Method 18E: Phase: Daicel Chiralcel AZ-H, 5 μιη 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 90: 10 + 0.2% diethylamine; Flow: 1 ml / min; Temperature: 40 ° C; UV detection: 230 nm.

Method 19E: Phase: Daicel IA, 5 μιη 250 mm x 4.6 mm; Eluent: ieri-butyl methyl ether / methanol 50:50; Flow: 1 ml / min; Temperature: 30 ° C; UV detection: 220 nm.

Method 20E: Phase: Daicel Chiralcel AD-H, 5 μηι 250 mm x 4.6 mm; Eluent: iso-hexane / in-propanol 50:50 + 0.2% diethylamine; Flow: 1 ml / min; Temperature: 40 ° C; UV detection: 220 nm.

Method 2 IE: Phase: Daicel Chiralpak IC, 5 μm 250 mm × 4.6 mm, eluent: ieri-butyl methyl ether / methanol 50:50; Flow: 1 ml / min; Temperature: 40 ° C; UV detection: 220 nm.

Method 22E: Phase: Daicel Chiralpak IC, 5 μιη 250 mm x 4.6 mm, eluent: acetonitrile / methanol 30:70; Flow: 1 ml / min; Temperature: 30 ° C; UV detection: 220 nm.

Method 23E: Phase: Daicel Chiralcel OD-H, 5 μηι 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 80:20; Flow: 1 ml / min; Temperature: 40 ° C; UV detection: 220 nm.

Method 24E: Phase: Daicel Chiralcel OZ-H, 5 μιη 250 mm x 4.6 mm; Eluent: iso-hexane / ethanol 50:50; Flow: 1 ml / min; Temperature: 30 ° C; UV detection: 220 nm. Method 25E: Phase: Daicel Chiralpak AD-H SFC, 5 μιη 250 mm x 4.6 mm; Eluent: carbon dioxide / methanol 70:30; Flow: 3 ml / min; Temperature: 30 ° C; UV detection: 220 nm.

Method 26E: Phase: Daicel Chiralpak AD-H, 5 μιη 250 mm x 4.6 mm, eluent: iso-hexane / ethanol 30:70; Flow: 1 ml / min, temperature: 40 ° C; UV detection: 220 nm. Method 27E: Phase: Daicel Chiralpak AD-H, 5 μm 250 mm × 4.6 mm, eluent: isohexane / ethanol 50:50; Flow: 1 ml / min, temperature: 40 ° C; UV detection: 220 nm.

Method 28E: Phase: Daicel Chiralpak AS-H, 5 μιη 250 mm x 4.6 mm, eluent: iso-hexane / ώσ-propanol 50:50; Flow: 1 ml / min, temperature: 40 ° C; UV detection: 220 nm.

Method 29E: Phase: Daicel Chiralpak OD-H, 5 μιη 250 mm x 4.6 mm, eluent: iso-hexane where propanol 80:20; Flow: 1 ml / min, temperature: 30 ° C; UV detection: 220 nm.

Method 30E: Phase: Daicel Chiralpak AY-H, 5 μηι 250 mm x 4.6 mm, eluent: iso-hexane wo- Propanol 50:50; Flow: 1 ml / min, temperature: 40 ° C; UV detection: 220 nm.

Method 3 IE: Phase: Daicel Chiralpak AD-H, 5 μιη 250 mm x 4.6 mm, eluent: iso-hexane / ώσ-propanol 50:50; Flow: 1 ml / min, temperature: 25 ° C; UV detection: 230 nm. Method 32E: Phase: Daicel Chiralcel AD-H, 5 μιη 250 mm x 4.6 mm; Eluent: ethanol + 0.2% acetic acid / acetonitrile + 0.2% acetic acid 90:10; Flow: 1 ml / min; Temperature: 25 ° C; UV detection: 230 nm.

Method 33E: Phase: Daicel Chiralpak ID, 5 μιη 250 mm × 4 mm, eluent: ieri-butyl methyl ether / methanol 70:30; Flow: 1 ml / min, temperature: 40 ° C; UV detection: 220 nm. Method 34E: Phase: Daicel Chiralcel AZ-H, 5 μιη 250 mm x 4.6 mm; Eluent: iso-hexane / in-propanol 50:50 + 0.2% diethylamine; Flow: 1 ml / min; Temperature: 45 ° C; UV detection: 220 nm.

Method 35E: Phase: Daicel Chiralpak ID, 5 μιη 250 mm × 4 mm, eluent: ieri-butyl methyl ether / methanol 70:30; Flow: 1 ml / min, temperature: 30 ° C; UV detection: 220 nm.

Method 36E: Phase: Daicel Chiralcel AZ-H, 5 μιη 250 mm x 4.6 mm; Eluent: ethanol; Flow: 1 ml / min; Temperature: 45 ° C; UV detection: 220 nm.

Method 37E: Phase: Daicel Chiralpak OZ-H, 5 μιη 250 mm x 4.6 mm, eluent: isohexane / ethanol 30:70 + 0.2% diethylamine; Flow: 1 ml / min, temperature: 40 ° C; UV detection: 230 nm. Method 38E: Phase: Daicel Chiralcel OD-H, 5 μηι 250 mm x 4.6 mm; Eluent: iso-hexane / in-propanol 90: 10 + 0.2% diethylamine; Flow: 1 ml / min; Temperature: 25 ° C; UV detection: 220 nm.

Method 39E: Phase: Daicel Chiralpak AZ-H, 5 μιη 250 mm x 4.6 mm, eluent: iso-hexane / ethanol 70:30; Flow: 1 ml / min, temperature: 30 ° C; UV detection: 220 nm. Method 40E: Phase: Daicel Chiralpak OZ-H, 5 μιη 250 mm × 4.6 mm, eluent: iso-hexane / ethanol 25:75; Flow: 1 ml / min, temperature: 40 ° C; UV detection: 220 nm.

Method 4 IE: Phase: Daicel Chiralpak OZ-H, 5 μιη 250 mm x 4.6 mm, eluent: iso-hexane / ethanol 20:80; Flow: 1 ml / min, temperature: 40 ° C; UV detection: 220 nm.

Method 42E: Phase: Daicel Chiralpak AS-H, 5 μm, 250 mm × 4.6 mm, eluent: 50% iso-hexane, 50% ethanol; Flow: 1 ml / min; Temperature: 25 ° C; Detection: 220 nm.

Method 43E: Phase: Daicel Chiralpak IC, 5 μηι, 250 mm x 4.6 mm, eluent: 50% iso-hexane, 50% ethanol; Flow: 1 ml / min; Temperature: 40 ° C; Detection: 220 nm.

Method 44E: Phase: Daicel Chiralpak AS-H, 5 μηι, 250 mm x 4.6 mm, eluent: 30% iso-hexane, 70% ethanol; Flow: 1 ml / min; Temperature: 30 ° C; Detection: 220 nm. Method 45 E: Phase: Daicel Chiralpak OD-H, 5 μm, 250 mm × 4.6 mm, eluent: 95% iso-hexane, 5% ethanol; Flow: 1 ml / min; Temperature: 30 ° C; Detection: 220 nm.

Method 46E: Phase: Daicel Chiralpak IC, 5 μm, 250 mm × 4.6 mm, eluent: ethanol + 0.2% diethylamine; Flow: 1 ml / min; Temperature: 45 ° C; Detection: 235 nm.

Method 47E: Phase: Daicel Chiralpak OD-H, 5 μm, 250 mm × 4 mm, eluent: 50% iso-hexane, 50% ethanol + 0.2% diethylamine; Flow: 1 ml / min; Temperature: 40 ° C, detection: 220 nm.

Method 48E: Phase: Daicel Chiralpak OD-H, 5 μm, 250 mm × 4 mm, eluent: 50% iso-hexane, 50% ethanol + 0.2% diethylamine; Flow: 1 ml / min; Temperature: 40 ° C; Detection: 220 nm.

Method 49E: Phase: Daicel Chiralpak OD-H, 5 μηι, 250 mm x 4.6 mm, eluent: 50% iso-hexane, 50% ethanol; Flow: 1 ml / min; Temperature: 30 ° C; Detection: 220 nm. Method 50E: Phase: Daicel Chiralpak OZ-H, 5 μιη, 250 mm x 4.6 mm, eluent: 60% iso-hexane, 40% ethanol; Flow: 1 ml / min; Temperature: 30 ° C; Detection: 220 nm.

Method 5 IU: Phase: Daicel Chiralpak IC-H, 5 μm, 250 mm × 4.6 mm, eluent: 50% tert-butyl methyl ether, 50% methanol; Flow: 1 ml / min; Temperature: 30 ° C; Detection: 220 nm. Method 52E: Phase: Daicel Chiralpak OD-H, 5 μηι, 250 mm x 4.6 mm, eluent: 70% iso-hexane, 30% iso-propanol, flow: 1 ml / min; Temperature: 30 ° C; Detection: 220 nm.

Preparative cleaning:

Method 1F: Phase: Sunfire C-18, 5 μηι 250 mm x 20 mm, eluent: water / acetonitrile gradient 80: 20-> 5:95, flow: 23.75 ml / min + constant addition of 2% formic acid; Flow: 1.25 ml / min; UV detection: 210 nm.

Method 2F: Phase: Sunfire C-18, 5 μιη 250 mm x 20 mm, eluent: water / acetonitrile 30:70; Flow: 25 ml / min; Temperature: 24 ° C; UV detection: 210 nm.

Method 3F: Phase: Sunfire C-18, 5 μιη 250 mm x 20 mm, eluent: water / methanol / 1% ammonia in water 32: 60: 8; Flow: 25 ml / min; Temperature: 25 ° C; UV detection: 210 nm.

Method 4F: Phase: Shield C-18, 5 μιη 100 mm x 190 mm, water / methanol / 1% trifluoroacetic acid in water 48:40:12; Flow: 23.8 ml / min; Temperature: 40 ° C; UV detection: 210 nm.

Method 5F: Phase: Shield C-18.5 μιη 100 mm x 190 mm, water / acetonitrile Gradient 90: 10 → 5:95; Flow: 25 ml / min; Temperature: 23 ° C; UV detection: 210 nm. Method 6F: Phase: X-Bridge C-18.5 μιη 150 mm x 19 mm, eluent: water / acetonitrile gradient 95: 5-> 5:95, flow: 23.75 ml / min + constant Addition of 2% ammonia in water; Flow: 1.25 ml / min; Temperature: 23 ° C; UV detection: 210 nm.

Method 7F: Phase: Daiso C-18 Bio, 10 μιη 300 mm x 100 mm, eluent: water, 0.1% TFA / acetonitrile isocratic 20:80; Flow: 250 ml / min; Temperature: 20 ° C; UV detection: 210 nm. Method 8F: Phase: Kromasil 100 C18, 5 μm, 250 mm × 20 mm, eluent: 24% water, 70% methanol; Flow: 23.75 ml / min, addition of 6% 1% trifluoroacetic acid with 1.25 ml / min flow; Temperature: 40 ° C; Detection: 210 nm.

Preparative diastereomer separation on achiral phase:

Method IG: Phase: Sunfire C-18.5 μιη 250 mm x 20 mm, eluent: water / methanol 60:40, flow: 60 ml / min, temperature: 23 ° C, UV detection: 210 nm.

Method 2G: Phase: Sunfire C18, 5 μηι, 150 mm x 19 mm, eluent: 60% water, 40% methanol; from 10.00 min 23% water, 77% methanol, from 10.10 min 60% water, 40% methanol; Flow: 23.75 ml / min, addition of 0.1% 2% formic acid with 1.25 ml / min flow; Temperature: 25 ° C; Detection: 220 nm. Method 3G: Phase: Sunfire C18, 5 μηι, 250 mm x 20 mm, eluent: 65% water, 35% acetonitrile; Flow: 23.75 ml / min, addition of 0.1% 2% trifluoroacetic acid with 1.25 ml / min flow; Temperature: 23 ° C; Detection: 210 nm.

Microwave A single-mode Biotage Initiator Microwave Synthesizer was used as the microwave reactor.

When purifying compounds of the invention by preparative HPLC by the methods described above, in which the eluants contain additives such as trifluoroacetic acid, formic acid or ammonia, the compounds of the invention may be in salt form, for example as trifluoroacetate, formate or ammonium salt, if the Compounds according to the invention contain a sufficiently basic or acidic functionality. Such a salt can be converted into the corresponding free base or acid by various methods known to those skilled in the art. In the synthesis intermediates and embodiments of the invention described below, when a compound is listed in the form of a salt of the corresponding base-related acid, the exact stoichiometric composition of such a salt is as obtained by the particular method of preparation and / or purification was not known, as a rule. Therefore, unless otherwise specified, name and structural formula additives such as "hydrochloride", "trifluoroacetate", "sodium salt" or "x HCl", "x CF 3 COOH", "x Na ⁺ " are not stoichiometric for such salts but solely descriptive of the contained salt-forming components.

The same applies mutatis mutandis to the case where synthesis intermediates or embodiments or salts thereof according to the described preparation and / or purification processes in the form of solvates, such as hydrates, were obtained, the stoichiometric composition (if defined type) is not known. starting compounds

Example 1A

7-Methoxy-2-thioxo-2,3-dihydro-l, 3-benzoxazol-5-carbonsäuremethylester

20.0 g (101 mmol) of 3-amino-4-hydroxy-5-methoxybenzoic acid methyl ester and 17.9 g (112 mmol) of potassium O-ethyldithiocarbonate were dissolved in pyridine (400 ml) and stirred under reflux for 3 h (analogous to Lit .: R. Lok et al., / Org. Chem. 1996, 61, 3289-3297). The reaction mixture was then cooled and added to a mixture of ice (600 g) and concentrated hydrochloric acid (60 ml). The resulting solid was filtered off in vacuo and washed with water (5 x 200 ml). The solid was first dried at 50 ° C / 40 mbar and then under high vacuum. Yield: 23.3 g (96% of theory).

LC-MS (Method 1A): R _t = 0.79 min; MS (ESIpos): m / z = 240 [M + H] ⁺ ;

^: H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 14.1 (br, s, 1H), 7.45 (d, 1H), 7.32 (d, 1H), 4.00 (s, 3H), 3.88 (s, 3H). Example 2A

2-chloro-7-methoxy-l, 3-benzoxazol-5-carbonsäuremethylester

150 g (627 mmol) of methyl 7-methoxy-2-thioxo-2,3-dihydro-1,3-benzoxazole-5-carboxylate were suspended in thionyl chloride (450 ml), with catalytic amounts of / V, / V- Dimethylformamide (1.0 ml) and then stirred for 3 h (analogously to R. Lok et al., J. Org. Chem. 1996, 61, 3289-3297). Re-added / V, / V-dimethylformamide (1.0 mL) and until to the end of gas evolution (about 4 h) at 70 ° C stirred. The reaction solution was concentrated in vacuo and the residue was coevaporated to completely remove the thionyl chloride with dichloromethane (3 x 200 ml). The solid was dried under high vacuum and then purified by column chromatography on silica gel (dichloromethane). Alternatively, the crude product can be used directly. Yield: 125.6 g (82% of theory).

LC-MS (Method 1A): R _t = 1.00 min; MS (ESIpos): m / z = 242 [M + H] ⁺ ;

^H-NMR (400 MHz, CDC1 _3): δ [ppm] = 7.99 (d, 1H), 7.62 (d, 1H), 4:07 (s, 3H), 3.96 (s, 3H).

Example 3A

2- {[(4-Chloro-2-yl) -methyl] -amino} -7-methoxy-1,3-benzo-azole-5-carboxylic acid methyl ester

25.5 g (93.9 mmol, purity: 90%) of methyl 2-chloro-7-methoxy-1,3-benzoxazole-5-carboxylate and 20.2 g (93.9 mmol) of 1- (4-chloropyridin-2-yl) Methanamine dihydrochloride in 1,4-dioxane (700 ml) at RT with 72.8 g (98.2 ml, 563 mmol) / V, / V-diisopropylethylamine and then stirred for 8 h at 80 ° C. The reaction solution was concentrated in vacuo, the residue taken up in ethyl acetate and washed with 0.5 M aqueous hydrogen chloride solution. The organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solid was stirred with a little acetonitrile, filtered in vacuo and dried under high vacuum. Yield: 24.8 g (75% of theory).

LC-MS (Method 1A): R _t = 0.94 min; MS (ESIpos): m / z = 348 [M + H] ⁺ . Example 4A

2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid

There were introduced 3.47 g (9.98 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-l, 3-benzoxazole-5-carboxylic acid methyl ester in 1,4-dioxane (200 ml) and then treated with 2N aqueous sodium hydroxide solution (100 ml). It was stirred for 16 h at RT and then in vacuo, the 1,4-dioxane largely removed. The residue was diluted with water (200 ml) and then adjusted to pH = 5 with concentrated hydrogen chloride solution. The precipitated solid was filtered off in vacuo, washed with water and dried under high vacuum. Yield: 2.47 g (75% of theory).

LC-MS (Method 3A): R _t = 1.72 min; MS (ESIpos): m / z = 334 [M + H] ⁺ . Example 5A

Methyl 2- {[1- (4-chloropyridin-2-yl) ethyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylate [racemate]

13.3 g (47.9 mmol, purity: 87%) of methyl 2-chloro-7-methoxy-1,3-benzoxazole-5-carboxylate and 7.50 g (157 mmol) of 1- (4-chloropyridin-2-yl) ethanamine [racemate, Lit .: V. Gotor et al, Adv. Synth. Catal. 2007, 349, 1481-1488] in tetrahydrofuran (650 ml) at RT with 18.6 g (25.0 ml, 129 mmol) / V, / V-diisopropylethylamine and then stirred overnight. The reaction solution was concentrated in vacuo, the residue taken up in ethyl acetate and the resulting solid was filtered off in vacuo. The filtrate was washed with 0.5 M aqueous hydrogen chloride solution, the organic phases dried over sodium sulfate, filtered and concentrated in vacuo. The solids were combined and dried under high vacuum. Yield: 20.5 g (100% of theory, purity: 90%). LC-MS (Method 1A): R _t = 0.94 min; MS (ESIpos): m / z = 362 [M + H] ⁺ . Example 6A

2- {[1- (4-Chloropyridin-2-yl) ethyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid [racemate]

There were 20.5 g (51.0 mmol, purity: 90%) of 2- {[1- (4-chloropyridin-2-yl) ethyl] amino} -7-methoxy-l, 3-benzoxazole-5-carboxylic acid methyl ester [racemate] in Submitted 1,4-dioxane (550 ml) and then with 2 N aqueous sodium hydroxide solution (275 ml). It was stirred for 5 h at 55 ° C and then the vacuum largely removed the 1,4-dioxane. The residue was adjusted to pH = 5 with 2 N hydrogen chloride solution, the precipitated solid was filtered off in vacuo and dried under high vacuum. Yield: 14.1 g (62% of theory, purity: 79%).

LC-MS (Method 3A): R _t = 1.85 min; MS (ESIpos): m / z = 348 [M + H] ⁺ . Example 7A l-Benzyl-2-ethyl- (4R) -4-ethoxypyrrolidine-1,2-dicarboxylate [mixture of diastereomers, 2 isomers]

10.0 g (37.7 mmol) of (4R) -1 - [(benzyloxy) carbonyl] -4-hydroxy-L-proline in N, N-dimethylformamide (110 ml) were initially charged under argon and 0.96 g (0.9 g) at 0.degree. 49.0 mmol, 60% suspension in paraffin oil) of sodium hydride. The reaction mixture was stirred for 30 min and then admixed with 7.54 ml (14.7 g, 94.2 mmol) of iodoethane. It was on RT and then cooled again to 0 ° C and treated with another 1.96 g (49.0 mmol, 60 ige suspension in paraffin oil) of sodium hydride and stirred for 30 min. An additional 7.54 ml (14.7 g, 94.2 mmol) of iodoethane was added, warmed to RT and stirred overnight. The reaction mixture was cautiously mixed with water and then extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 14.8 g (94% of theory, purity: 77%).

LC-MS (Method 1A): R _t = 1.06 min; MS (ESIpos): m / z = 322 [M + H] ⁺ .

Example 8A

Benzyl- (4R) -4-ethoxy-2- (hydroxymethyl) pyrrolidine-1-carboxylate [mixture of diastereomers, isomers]

13.5 g (32.6 mmol, purity: 77%) of 1-benzyl-2-ethyl- (4R) -4-ethoxypyrrolidine-1,2-dicarboxylate [diastereomer mixture, 2 isomers] were initially charged under argon in tetrahydrofuran (150 ml) and at 0 ° C with 817 mg (37.5 mmol) of lithium borohydride. The reaction mixture was warmed to RT and then stirred overnight. The reaction mixture was cautiously added with water (100 ml), adjusted to pH = 1 with 2N aqueous hydrogen chloride solution and then extracted with ethyl acetate. The organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative RP-HPLC (acetonitrile / water). Yield: 4.78 g (52% of theory, diastereomeric ratio: about 2: 1).

LC-MS (Method 1A): R _t = 0.81 min (Diastereomer 1), R _t = 0.83 min (Diastereomer 2);

MS (ESIpos): m / z = 280 [M + H] ⁺ .

Example 9A [(4R) -4-ethoxypyrrolidin-2-yl] methanol [mixture of diastereomers, 2 isomers]

2.00 g (7.16 mmol) of benzyl- (4R) -4-ethoxy-2- (hydroxymethyl) pyrrolidine-1-carboxylate [diastereomer mixture, 2 isomers] in methanol (46.3 ml) were initially charged under argon with 221 mg of palladium on carbon (10 ig) and 111 mg of platinum (IV) oxide and then stirred under hydrogen atmosphere under atmospheric pressure until the end of the hydrogen uptake. The reaction solution was filtered through kieselguhr, washed with methanol and concentrated in vacuo. Yield: 1.17 g (quant.).

MS (Method 2C): m / z = 146 [M + H] ⁺ ;

^: H-NMR (400 MHz, DMSO δ [ppm] = 4.04-2.67 (m, 10H), 2.10-1.30 (m, 2H), 1.22-0.97 (m, 3H).

Example 10A

1-Benzyl-2-methyl- (4R) -4- (2,2-difluoroethoxy) pyrrolidine-1,2-dicarboxylate

[Mixture of diastereomers, 2 isomers]

There were 8.20 g (24.7 mmol, purity: 84%) of 1-benzyl-2-methyl- (4R) -4-hydroxypyrrolidine-1, 2-dicarboxylate and 5.81 g (27.1 mmol) of 2,2-Difluorethyltrifluormefhansulfonat in N, N - Introduced dimethylformamide (200 ml) under argon and treated at 0 ° C with 1.28 g (32.1 mmol, 60% suspension in paraffin oil) of sodium hydride. The mixture was allowed to warm to rt and stirred for 1 h. The reaction mixture was concentrated in vacuo, the residue taken up in dichloromethane and then washed with water and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and in vacuo concentrated. The crude product was purified by preparative RP-HPLC (acetonitrile / water). Yield: 6.55 g (69% of theory, purity: 90%, diastereomeric ratio: about 5: 4).

LC-MS (Method 2A): R _t = 0.98 min (enantiomerically pure isomer 1), R _t = 0.99 min (enantiomerically pure isomer 2); MS (ESIpos): m / z = 344 [M + H] ⁺ .

Example IIA

Benzyl (4R) -4- (2,2-difluoroethoxy) -2- (hydroxymethyl) pyrrolidine-l-carboxylate

[Mixture of diastereomers, 2 isomers]

There were 6.50 g (17.0 mmol, purity: 90%) of 1-benzyl-2-methyl- (4R) -4- (2,2-difluoro-phenoxy) -pyrrolidine-l, 2-dicarboxylate [diastereomer mixture, 2 isomers] in tetrahydrofuran (200 ml) and treated at 0 ° C with 1.11 g (51.1 mmol) of lithium borohydride. The reaction mixture was warmed to RT and then stirred overnight. The reaction mixture was added cautiously with water (50 ml) and the tetrahydrofuran was removed in vacuo. The residue was taken up in dichloromethane and washed with 1 M sodium carbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative RP-HPLC (acetonitrile / water). Yield: 4.25 g (79% of theory, diastereomer ratio: about 1: 1).

LC-MS (Method 2A): R _t = 0.87 min (enantiomerically pure isomer 1), R _t = 0.88 min (enantiomerically pure isomer 2);

MS (ESIpos): m / z = 316 [M + H] Example 12A

Benzyl- (4R) -4- (2,2-difluoroethoxy) -2- (hydroxymethyl) pyrrolidine-1-carboxylate [enantiomerically pure isomer 1]

Diastereomer separation on chiral phase of 1.06 g of the compound from Example I IA according to Method 27D gave 447 mg of Example 12A (enantiomerically pure isomer 1) and 510 mg of Example 13A (enantiomerically pure isomer 2).

HPLC (Method 25E): R _t = 1.90 min,> 99.0 g;

LC-MS (Method 2A): R _t = 0.88 min; MS (ESIpos): m / z = 316 [M + H] ⁺ . Example 13A

Benzyl- (4R) -4- (2,2-difluoroethoxy) -2- (hydroxymethyl) pyrrolidine-1-carboxylate [enantiomerically pure isomer 2]

Diastereomer separation on chiral phase of 1.06 g of the compound from Example I IA according to Method 27D gave 447 mg of Example 12A (enantiomerically pure isomer 1) and 510 mg of Example 13A (enantiomerically pure isomer 2). HPLC (Method 25E): R _t = 2.97 min,> 99.0 g;

LC-MS (Method 2A): R _t = 0.87 min; MS (ESIpos): m / z = 316 [M + H] ⁺ .

Example 14A

[(4R) -4- (2,2-Difluoroethoxy) pyrrolidin-2-yl] mefhanol [enantiomerically pure isomer 2]

510 mg (1.62 mmol) of benzyl- (4R) -4- (2,2-difluoroethoxy) -2- (hydroxymethyl) pyrrolidine-1-carboxylate [enantiomerically pure isomer 2, Example 13A] in methanol (10.4 ml) were initially charged, under argon with 52.0 mg palladium on carbon (10 ig) and stirred under hydrogen atmosphere at atmospheric pressure until the end of hydrogen uptake. The reaction solution was filtered through kieselguhr, washed with methanol and concentrated in vacuo. Yield: 299 mg (quant.).

MS (Method 2C): m / z = 182 [M + H] ⁺ . Example 15A

1-benzyl-2-methyl- (4R) -4 - [(1, 1 - ² H ₂₎ ethyloxy] pyrrolidin-1, 2-dicarboxylate

[Mixture of diastereomers, 2 isomers]

There were added 6.29 g (22.5 mmol) of 1-benzyl-2-methyl- (4R) -4-hydroxypyrrolidine-1,2-dicarboxylate in / VN-dimethylformamide (100 ml) under argon at 0 ° C with 1.35 g (33.8 mmol , 60 ige suspension in paraffin oil) sodium hydride. It was stirred for 30 min, with 5.00g (9:37 ml, 45.1 mmol) l-bromo (2,2- ² H ₂₎ and propane 832 mg (2.25 mmol) of tetra-w-butylammonium iodide warmed to RT and stirred for 3 h. The reaction mixture was cautiously mixed with water and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 5.07 g (60% of theory, purity: 83%, diastereomer ratio: about 4: 5).

LC-MS (Method 1A): R _t = 0.98 min (enantiomerically pure isomer 1), R _t = 0.99 min (enantiomerically pure isomer 2);

MS (ESIpos): m / z = 310 [M + H] ⁺ . Example 16A

Benzyl (4R) -4- [(1.1 to ² H ₂₎ ethyloxy] -2- (hydroxymethyl) pyrrolidin-1-carboxylate

[Mixture of diastereomers, 2 isomers]

It was 4.00 g (10.8 mmol, purity: 83%) of 1-benzyl-2-methyl- (4R) -4 - [(l, l- ² H ₂ ) ethyloxy] pyrrolidin-l, 2-dicarboxylate [Diastereomerengemisch, 2 Isomers] in tetrahydrofuran (26.0 ml) and treated at 0 ° C with 270 mg (12.4 mmol) of lithium borohydride. The reaction mixture was warmed to RT and then stirred overnight. Then water was cautiously added and then made acidic with 2N aqueous hydrogen chloride solution. The aqueous phase was extracted several times with ethyl acetate and the collected organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 1.01 g (29% of theory, purity: 88%, diastereomer ratio: about 1: 1).

LC-MS (Method 1A): R _t = 0.81 min (enantiomerically pure isomer 1), R _t = 0.84 min (enantiomerically pure isomer 2); MS (ESIpos): m / z = 282 [M + H] ⁺ .

Example 17A

{(4R) -4 - [(l, l- ² H ² ) ethyloxy] pyrrolidin-2-yl} methanol [mixture of diastereomers, 2 isomers]

There were 1.00 g (3.55 mmol) of benzyl- (4R) -4 - [(1,1-H ² ) ethyloxy] -2- (hydroxymethyl) pyrrolidine-1-carboxylate [mixture of diastereomers, 2 isomers] in methanol (23.0 ml). initially charged under argon with 110 mg of palladium on carbon (10 ig) and 55.0 mg of platinum (IV) oxide and then stirred under hydrogen atmosphere at atmospheric pressure until the end of the hydrogen uptake. The reaction solution was filtered through kieselguhr, washed with methanol and concentrated in vacuo. Yield: 576 mg (quant.).

MS (Method 2C): m / z = 148 [M + H] ⁺ .

Example 19A

Benzyl (4R) -2- (cyanomethyl) -4 - [(l, l ² H ₂₎ ethyloxy] pyrrolidine-l-carboxylate

[Mixture of diastereomers, 2 isomers]

There was added under argon 2.90 g (10.3 mmol) of benzyl (4R) -4 - [(l, l ² H ₂₎ ethyloxy] -2- (hydroxymethyl) pyrrolidine-l -carboxylate [mixture of diastereomers, 2 isomers] in dichloromethane ( 100 ml) and treated at 0 ° C with 3.54 g (2.39 ml, 30.9 mmol) of methanesulfonyl chloride and 3.13 g (4.31 ml, 30.9 mmol) of triethylamine. The reaction mixture was warmed to RT and then stirred for 2 h. The reaction mixture was cautiously treated with water, the phases were separated and the aqueous phase extracted with dichloromethane. The collected organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (2.40 g) was dissolved in A ^ N-dimethylformamide (10 ml) under argon at RT to a 0.5 N solution of lithium cyanide in A ^ N-dimethylformamide (20 ml, 10 mmol). The reaction mixture was first stirred at RT overnight, then stirred at 60 ° C. for a further night and then at 80 ° C. for 2 d. The reaction solution was concentrated in vacuo and the residue was taken up in ethyl acetate and water. After separation of the phases, the aqueous phase was extracted twice with ethyl acetate. The collected organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by means of two preparative RP-HPLC (acetonitrile / water + 0.1% formic acid). Yield: 430 mg (14% of theory over two stages).

LC-MS (Method 1A): R _t = 0.96 min; MS (ESIpos): m / z = 291 [M + H] ⁺ . Example 20A {(4R) -4- [(1, 1 - ² H ₂₎ ethyloxy] pyrrolidin-2-yl} acetonitrile [mixture of diastereomers, isomers 2]

There were 430 mg (1.48 mmol) of benzyl (4R) -2- (cyanomethyl) -4 - [(l, l- ² H ₂ ) ethyloxy] pyrrolidine-l-carboxylate [diastereomer mixture, 2 isomers] in ethanol (50 ml ), added under argon with 26 mg of palladium on carbon (10%) and then stirred under hydrogen atmosphere under atmospheric pressure overnight. The reaction solution was filtered, washed with ethanol and concentrated in vacuo. The crude product was used directly in Example 9. Yield: 234 mg (quant.).

Example 21A

1-Benzyl-2-methyl- (2S, 4R) -4- (1-ethoxyethoxy) pyrrolidine-1,2-dicarboxylate

[Mixture of diastereomers, 2 isomers]

There were charged 5.00 g (17.9 mmol) of 1-benzyl-2-methyl- (2S, 4R) -4-hydroxypyrrolidine-1,2-dicarboxylate [enantiomerically pure isomer] in ethyl vinyl ether (32.4 ml) and at 0 ° C with 12.0 mg (8.1 μΐ, 0.11 mmol) of trifluoroacetic acid. The reaction mixture was warmed to RT and stirred for 4 d. The reaction mixture was then treated with solid sodium hydrogen carbonate (800 mg) and stirred for 1 h. Subsequently, the reaction mixture was filtered and concentrated in vacuo at 40 to 50 ° C. The crude product was used without further purification in the next step. Yield: 6.20 g (93% of theory).

LC-MS (Method 2A): R _t = 1.05 min; MS (ESIpos): m / z = 352 [M + H] ⁺ ; Ή-NMR (400 MHz, DMSO δ [ppm] = 7.42-7.22 (m, 5H), 5.17-4.90 (m, 2H), 4.79-4.69 (m, 1H), 4.40-4.23 (m, 2H), 3.69 -3.30 (m, 7H), 2.30 (m _c, 1H), 2:04 (m _c, 1H), 1.18 (m _c, 3H), 1:12 to 1:05 (m, 3H).

Example 22A

1-Benzyl-2-methyl- (2S, 4R) -4- (vinyloxy) pyrrolidine-1,2-dicarboxylate [enantiomerically pure isomer]

There were 20 g (17.3 mmol, purity: 30%) of 1-benzyl-2-methyl- (2S, 4R) -4- (1-ethoxyethoxy) pyrrolidine-1,2-dicarboxylate [diastereomer mixture, 2 isomers] under argon in dichloromethane (60 ml) and treated at 0 ° C with 1.82 g (2.51 ml, 18.0 mmol) of triethylamine and 3.93 g (3.21 ml, 17.7 mmol) Trimethylsilyltrifluormethansulfonat added dropwise. The reaction mixture was warmed to RT and stirred for 3.5 h. It was then cooled again to 0 ° C and another 1.82 g (2.51 ml, 18.0 mmol) of triethylamine and 3.93 g (3.21 ml, 17.7 mmol) of trimethylsilyl trifluoromefansulfonate were added. The reaction solution was warmed to RT and stirred for 2 d. It was then cooled again to 0 ° C. and a further 1.82 g (2.51 ml, 18.0 mmol) of triethylamine and 3.93 g (3.21 ml, 17.7 mmol) of trimethylsilyltrifluoromethanesulfonate were added. The reaction solution was warmed to RT and stirred overnight. The reaction mixture was then added with 1 N aqueous sodium hydroxide solution (60 ml), diluted with water and extracted. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (cyclohexane / ethyl acetate 3: 1). Yield: 2.48 g (42% of theory, purity: 90%).

LC-MS (Method 1A): R _t = 0.98 min; MS (ESIpos): m / z = 306 [M + H] ⁺ .

Example 23A

1-Benzyl-2-methyl- (2S, 4R) -4- (cyclopropyloxy) pyrrolidine-1,2-dicarboxylate [enantiomerically pure isomer]

There were 13.4 ml (13.4 mmol) of an I M diethylzinc solution in hexane under argon in dichloromethane (70 ml) and then treated at 0 ° C with 3.53 g (1.06 ml, 13.2 mmol) of diiodomethane in dichloromethane (14 ml) added dropwise. After 30 minutes, 1.88 g (5.36 mmol, purity: 87%) of 1-benzyl-2-methyl- (2S, 4R) -4- (vinyloxy) pyrrolidine-1,2-dicarboxylate [enantiomerically pure isomer] in dichloromethane (21 ml ), the reaction mixture was warmed to RT and stirred overnight. The reaction was stopped by adding saturated aqueous ammonium chloride solution, the phase was separated and the aqueous phase extracted with ethyl acetate. The collected organic phases were washed with saturated aqueous sodium carbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative RP-HPLC (acetonitrile / water). Yield: 1.09 g (59% of theory).

LC-MS (Method 2A): R _t = 1.03 min; MS (ESIpos): m / z = 320 [M + H] ⁺ . Example 24A

Mefhyl- (4R) -4- (cyclopropyloxy) -L-proline [enantiomerically pure isomer]

1.09 g (3.21 mmol) of 1-benzyl-2-methyl- (25 ', 4R) -4- (cyclopropyloxy) -pyrrolidine-1, 2-dicarboxylate [enantiomerically pure isomer] in methanol (20.6 ml) were initially charged under argon 103 mg of palladium on carbon (10 ig) and then stirred under hydrogen atmosphere under atmospheric pressure for 4 h. The reaction solution was filtered through kieselguhr, washed with methanol and concentrated in vacuo. Yield: 630 mg (100% of theory).

MS (Method 2C): m / z = 186 [M + H] ⁺ . Example 25A

Methyl (4R) -1 - [(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -4- (cyclopropyloxy) -L-proline [enantiomerically pure isomer]

There were added 1.20 g (2.91 mmol, purity: 81%) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 630 mg (3.20 mmol ) Methyl (4R) -4- (cyclopropyloxy) -L-proline [enantiomerically pure isomer] in A ^ N-dimethylformamide (24.2 ml) and treated with 1.51 g (2.03 ml, 11.6 mmol) / V, / V-diisopropylethylamine , Subsequently, 1.33 g (3.49 mmol) of HATU was added at RT and stirred for 2 h. The reaction solution was concentrated under reduced pressure and then purified directly by preparative RP-HPLC (acetonitrile / water) without further work-up. Yield: 748 mg (12% of theory, purity: 24%).

LC-MS (Method 1A): R _t = 0.92 min; MS (ESIpos): m / z = 501 [M + H] ⁺ . Example 26A

(4R) - 1 - [(2- {[(4-Chloro-pyridin-2-yl) -methy 1] -amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -4- (cyclopropyloxy) - L-proline [enantiomerically pure isomer]

There were 749 mg (0.366 mmol, purity: 24%) of methyl (4R) -1 - [(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole -5-yl) carbonyl] -4- (cyclopropyloxy) -L-prolinate

[enantiomerically pure isomer] in tetrahydrofuran / water (3: 1, 12.0 ml), treated with 35.1 mg (1.46 mmol) of lithium hydroxide and stirred at RT for 1 h. Subsequently, the reaction solution was acidified with 1N aqueous hydrogen chloride solution and extracted with ethyl acetate. The collected organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 878 mg (quant., Purity: 26%).

LC-MS (Method 2A): R _t = 0.79 min; MS (ESIpos): m / z = 487 [M + H] ⁺ . Example 27 A

Benzyl- (2 S _l ', 4R) -4- (cyclopropyloxy) -2- (hydroxymethyl) pyrrolidine-l-carboxylate

[enantiomerically pure isomer]

1.35 g (4.23 mmol) of 1-benzyl-2-methyl- (2 _{l of} S ', 4R) -4- (cyclopropyloxy) -pyrrolidine-l, 2-dicarboxylate [enantiomerically pure isomer] in tetrahydrofuran (20.0 ml) were initially charged and added 0 ° C with 106 mg (4.87 mmol) of lithium borohydride. The reaction mixture was warmed to RT and then stirred overnight. The reaction mixture was cautiously treated with water (200 ml) and then acidified with 2N aqueous hydrogen chloride solution. The aqueous phase was extracted several times with ethyl acetate and the collected organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative RP-HPLC (acetonitrile / water). Yield: 1.09 g (59% of theory).

LC-MS (Method 2A): R _t = 0.89 min; MS (ESIpos): m / z = 292 [M + H] ⁺ ;

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.42-7.27 (m, 5H), 5.10 (d, 1H), 5.03 (d, 1H), 4.76 (br, s, 1H) , 4.16 (br., 1H), 3.81 (br, s, 1H), 3.61-3.36 (m, 4H), 3.28-3.19 (m, 1H), 2.13-1.92 (m, 2H), 0.51- 0.36 (m, 4H).

Example 28A

[(2S, 4R) -4- (Cyclopropyloxy) pyrrolidin-2-yl] methanol [enantiomerically pure isomer]

690 mg (2.37 mmol) of benzyl- (2S, 4R) -4- (cyclopropyloxy) -2- (hydroxymethyl) pyrrolidine-1-carboxylate [enantiomerically pure isomer] in methanol (20.0 ml) were initially charged under argon with 91 mg of palladium on carbon (10%) and then stirred under hydrogen atmosphere under atmospheric pressure overnight. The reaction solution was filtered through kieselguhr, washed with methanol and concentrated in vacuo. Yield: 383 mg (98% of theory).

MS (Method 2C): m / z = 158 [M + H] ⁺ . Example 29A 1-Benzyl-2-methyl-2-methylpyrrolidine-1,2-dicarboxylate [enantiomerically pure isomer 2]

There were 2.75 g (10.5 mmol) of 1-benzyl-2-methyl-pyrrolidine l, 2-dicarboxylate [racemate] in tetrahydrofuran (24 ml) and under argon at -78 ° C with 15.7 ml (15.7 mmol) 1 M Lithiumhexamethyldisilazid solution in tetrahydrofuran and then the reaction mixture was stirred for 30 min. Subsequently, at -78 ° C., 2.37 g (1.04 ml, 16.7 mmol) of iodomethane were added, the reaction mixture was warmed to RT and stirred overnight. The reaction solution was then concentrated under reduced pressure, the residue was combined with water and extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was separated on a chiral phase according to Method 32D into the enantiomers. The target compound corresponded to the later eluting enantiomerically pure isomer 2. Yield: 942 mg (32% of theory, enantiomerically pure isomer 2).

HPLC (Method 29E): R _t = 7.26 min,> 99.9% ee;

LC-MS (Method 2A): R _t = 1.04 min; MS (ESIpos): m / z = 278 [M + H] ⁺ .

The target compound is described as a racemate in the Zhu patent, Gui-Dong et al., US 20060229289, 2006, but with sodium hexamethyldisilazide solution.

Example 30A

Methyl 2-methylprolinate [enantiomerically pure isomer]

There were 11.6 g (41.8 mmol) of 1-benzyl-2-methyl-2-methylpyrrolidin-l, 2-dicarboxylate [enantiomerically pure isomer 2, Example 29 A] in methanol (270 ml) submitted under argon with 1.34 g of palladium on carbon (10%) and then stirred under hydrogen atmosphere under atmospheric pressure until the end of the hydrogen uptake. The reaction solution was filtered through kieselguhr, washed with methanol and concentrated in vacuo. Yield: 5.05 g (84% of theory). MS (Method 2C): m / z = 144 [M + H] ⁺ ;

Rotation: [a] = 2.59 ° (c = 0.45, chloroform). Example 31A

Methyl 1 - [(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -2-methylprolinate [enantiomerically pure isomer]

There were added 300 mg (0.899 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 193 mg (1.35 mmol) of methyl 2- Methylprolinat [enantiomerically pure isomer] in A ^ N-dimethylformamide (4.50 ml) and treated with 349 mg (470 μΐ, 2.70 mmol) of N, N-diisopropylethylamine. Subsequently, 615 mg (1.62 mmol) of HATU were added at RT and stirred for 14 h. The reaction solution was concentrated under reduced pressure and then purified directly by preparative RP-HPLC (acetonitrile / water) without further work-up. Yield: 213 mg (51% of theory).

LC-MS (Method 2A): R _t = 0.90 min; MS (ESIpos): m / z = 459 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.71 (t, 1H), 8.52 (d, 1H), 7.53 (d, 1H), 7.46 (dd, 1H), 6.94 (i.e. , 1H), 6.76 (s, 1H), 4.63 (d, 2H), 3.92 (s, 3H), 3.67-3.58 (m, 4H), 3.51-3.42 (m, 1H), 2.14- 2.05 (m, 1H ), 1.97-1.81 (m, 3H), 1.57 (s, 3H).

Example 32A

1 - [(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -2-methylproline [enantiomerically pure isomer]

There were added 213 mg (0.464 mmol) of methyl 1 - [(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -2 -methylprolinate [enantiomerically pure isomer] in tetrahydrofuran / water (3: 1, 12 ml), treated with 13.3 mg (0.557 mmol) of lithium hydroxide and stirred at 70 ° C overnight. Subsequently, the reaction solution was concentrated in vacuo, mixed with water and neutralized with 1 N aqueous hydrogen chloride solution. The reaction mixture was extracted with ethyl acetate and the aqueous phase was then concentrated in vacuo. The crude product was used without further purification in the next step (saline). Yield: 288 mg (100% of theory, purity: 71%).

LC-MS (Method 3A): R _t = 1.84 min; MS (ESIpos): m / z = 445 [M + H] ⁺ . Example 33A

/ V-Benzyl-2-chloro / V- (1,3-dihydroxy-2-methylpropan-2-yl) propanamide [racemate]

There were 10.7 g (54.8 mmol) of 2- (benzylamino) -2-methylpropane-1,3-diol [Lit .: J. Cossy et al., J. Org. Chem. 2012, 77, 6087-6099] in dichloromethane (400 ml), cooled to 0 ° C and treated with 8.32 g (11.5 ml, 82.2 mmol) of triethylamine. Subsequently, 8.35 g (6.52 ml, 65.8 mmol) of 2-chloropropionyl chloride [racemate] were added dropwise. After stirring for 30 minutes, a further 5.57 g (3.70 ml, 37.3 mmol) of 2-chloropropionyl chloride [racemate] were added dropwise and then the reaction solution was warmed to RT. The reaction solution was concentrated in vacuo, the residue taken up in 1 N aqueous hydrogen chloride solution and extracted several times with dichloromethane. The organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 15.6 g (99% of theory).

LC-MS (Method 1A): R _t = 0.58 min; MS (ESIpos): m / z = 286 [M + H] ⁺ .

Example 34A 4-Benzyl-5- (hydroxymethyl) -2,5-dimethylmorpholin-3-one [mixture of diastereomers, 4 isomers]

There were 15.6 g (54.8 mmol) A ^{r-benzyl-2-chloro-A} ^r - (l, 3-dihydroxy-2-methylpropan-2- yl) propanamide [racemate] (300 ml) were charged in isopropanol at 0 ° C cooled and treated with 24.6 g (219 mmol) of potassium ieri-butoxide in one portion. It was stirred overnight, allowing to warm to rt. Zw-propanol was largely removed in vacuo, the residue taken up in 2 N aqueous hydrogen chloride solution (300 ml) and extracted several times with dichloromethane. The organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 15.2 g (96% of theory, purity: 86%, diastereomer ratio about 1: 1). LC-MS (Method 1A): R _t = 0.72 min (diastereomer 1, 2 isomers), R _t = 0.74 min (diastereomer 2, 2 isomers); MS (ESIpos): m / z = 250 [M + H] ⁺ .

Example 35A

(4-Benzyl-3,6-dimethylmorpholin-3-yl) methanol [mixture of diastereomers, 4 isomers]

15.6 g (62.6 mmol) of 4-benzyl-5- (hydroxymethyl) -2,5-dimethylmorpholin-3-one [mixture of diastereomers, 4 isomers] in tetrahydrofuran (300 ml) were initially charged under argon with 93.9 ml (188 mmol). 2 M borane-dimethyl sulfide complex solution in tetrahydrofuran and then the reaction mixture stirred for 3 h under reflux. Subsequently, the batch was cooled to RT, carefully mixed with methanol (150 ml) and then stirred for 4 h under reflux. It was then completely concentrated under reduced pressure and the residue was purified by preparative RP-HPLC (acetonitrile / water). Yield: 6.53 g (44% of theory).

LC-MS (Method 4A): R _t = 0.28 min; MS (ESIpos): m / z = 236 [M + H] ⁺ . Example 36A

(4-Benzyl-3,6-dimethylmorpholin-3-yl) methanol [enantiomerically pure isomer 1]

Enantiomer separation on a chiral phase of 6.53 g of the compound from Example 35A according to Method 18D and subsequent purification by preparative RP-HPLC (acetonitrile / water) gave 1.12 g of Example 36 A (enantiomerically pure isomer 1), 1.23 g of Example 37 A (enantiomerically pure isomer 2), 441 mg of Example 38A (enantiomerically pure isomer 3) and 457 mg of Example 39A (enantiomerically pure isomer 4).

HPLC (Method 18E): R _t = 5.13 min,> 99.0 ee; LC-MS (Method 4A): R _t = 2.56 min; MS (ESIpos): m / z = 236 [M + H] ⁺ .

Example 37A

(4-Benzyl-3,6-dimethylmorpholin-3-yl) methanol [enantiomerically pure isomer 2]

HPLC (Method 18E): R _t = 5.73 min,> 99.0 ee; LC-MS (Method 4A): R _t = 2.52 min; MS (ESIpos): m / z = 236 [M + H] ⁺ .

Example 38A

(4-Benzyl-3,6-dimethylmorpholin-3-yl) methanol [enantiomerically pure isomer 3]

Enantiomer separation on a chiral phase of 6.53 g of the compound from Example 35A according to Method 18D and subsequent purification by preparative RP-HPLC (acetonitrile / water) gave 1.12 g of Example 36 A (enantiomerically pure isomer 1), 1.23 g of Example 37 A (enantiomerically pure isomer 2) , 441 mg of Example 38A (enantiomerically pure isomer 3) and 457 mg of Example 39A (enantiomerically pure isomer 4). HPLC (Method 18E): R _t = 6.57 min,> 99.0 ee;

LC-MS (Method 4A): R _t = 2.60 min; MS (ESIpos): m / z = 236 [M + H] ⁺ .

Example 39A

(4-Benzyl-3,6-dimethylmorpholin-3-yl) methanol [enantiomerically pure isomer 4]

Enantiomer separation on a chiral phase of 6.53 g of the compound from Example 35A according to Method 18D and subsequent purification by preparative RP-HPLC (acetonitrile / water) gave 1.12 g of Example 36 A (enantiomerically pure isomer 1), 1.23 g of Example 37 A (enantiomerically pure isomer 2), 441 mg of Example 38A (enantiomerically pure isomer 3) and 457 mg of Example 39A (enantiomerically pure isomer 4). HPLC (Method 18E): R _t = 6.92 min,> 99.0 ee;

LC-MS (Method 4A): R _t = 2.61 min; MS (ESIpos): m / z = 236 [M + H] ⁺ .

Example 40A

(3,6-Dimethylmorpholin-3-yl) methanol [enantiomerically pure isomer 1]

1.12 g (4.76 mmol) of (4-benzyl-3,6-dimethylmorpholin-3-yl) methanol [enantiomerically pure isomer 1, Example 36 A] in ethanol (120 ml) were initially charged under argon with 112 mg of palladium on carbon ( 10 ig) and 112 mg of palladium hydroxide on carbon (20%) and then stirred overnight under a hydrogen atmosphere under atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue washed with methanol. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 651 mg (94% of theory).

Ή NMR (400 MHz, DMSO-ife): δ [ppm] = 4.44 (br, s, 1H), 3.56 (d, 1H), 3.40 (d, 2H), 3.36-3.22 (m, 2H), 3.06 (d, 1H), 1.98 (see also, 1H), 0.99 (d, 3H), 0.77 (s, 3H), one proton not visible. Example 41A

(3,6-Dimethylmorpholin-3-yl) methanol [enantiomerically pure isomer 4]

457 mg (1.94 mmol) of (4-benzyl-3,6-dimethylmorpholin-3-yl) methanol [enantiomerically pure isomer 4, Example 39 A] in ethanol (50 ml) were initially charged under argon with 46 mg of palladium on carbon ( 10%) and 46 mg of palladium hydroxide on carbon (20%) and then stirred overnight under a hydrogen atmosphere under atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue washed with methanol. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 280 mg (99% of theory). Ή NMR (400 MHz, DMSO- e): δ [ppm] = 4.62 (br, s, 1H), 3.40 (d, 1H), 3.30-3.18 (m, 2H), 3.11 (br. 2H), 2.58-2.55 (m, 1H), 1.81 (m _c , 1H), 1.05-0.96 (m, 6H), one proton not visible.

Example 42A

A ^{r-benzyl-2-chloro-A} ^r - (l, 3-dihydroxypropane-2-yl) propanamide [racemate]

There were 60.5 g (334 mmol) of 2- (benzylamino) propane-l, 3-diol [Lit .: W. Lacote et al., Org. Lett. 2011, 13, 5990-5993] in w-propanol (0.93 1), cooled to 0 ° C and treated with 50.7 g (69.8 ml, 501 mmol) of triethylamine. Subsequently, 50.9 g (38.9 ml, 401 mmol) of 2-chloropropionyl chloride [racemate] were added dropwise. The reaction solution was allowed to warm to rt and then concentrated in vacuo. The residue was treated with 0.5 N aqueous hydrogen chloride solution and extracted with dichloromethane. The organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 91.7 g (94% of theory).

LC-MS (Method 1A): R _t = 0.71 min; MS (ESIpos): m / z = 272 [M + H] ⁺ . Example 43A

4-Benzyl-5- (hydroxymethyl) -2-methylmorpholin-3-one [mixture of diastereomers, 4 isomers]

There were 81.3 g (272 mmol, purity: 91%) / V-benzyl-2-chloro- / V- (l, 3-dihydroxypropan-2-yl) propanamide [racemate] presented in w-propanol (600 ml), cooled to 0 ° C and treated with 91.6 g (817 mmol) of potassium ieri-butoxide. The reaction solution was allowed to warm to rt and Stirred overnight at RT. Λο-Propanol was largely removed in vacuo and the residue taken up in dichloromethane. It was washed with water, the organic phase dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 61.7 g (96% of theory, diastereomer ratio about 7: 3).

LC-MS (Method 2A): R _t = 0.61 min (diastereomer 1, 2 isomers), R _t = 0.62 min (diastereomer 2, 2 isomers);

MS (ESIpos): m / z = 236 [M + H] ⁺ . Example 44A

4-Benzyl-5 - ({[ieri-butyl (dimethyl) silyl] oxy} methyl) -2-methylmorpholine-3- [mixture of diastereomers, 4 isomers]

21.5 g (91.4 mmol) of 4-benzyl-5- (hydroxymethyl) -2-methylmorpholin-3-one [diastereomer mixture, 4 isomers] in / V, / V-dimethylformamide (126 ml) were initially charged at RT with 12.4 g (183 mmol) of imidazole and then 14.5 g (96.0 mmol) of ieri-Butyldimethylsilylchlorid added. It was stirred for 2 h and then the solvent was largely removed in vacuo. The residue was taken up in ethyl acetate / water and the organic phase was washed with water, 0.4 N aqueous hydrogen chloride solution, saturated aqueous sodium bicarbonate solution and water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 31.2 g (97% of theory, diastereomer ratio about 7: 3).

LC-MS (Method 1A): R _t = 1.41 min; MS (ESIpos): m / z = 350 [M + H] ⁺ ;

^: H-NMR (400 MHz, DMSO δ [ppm] = 7.38-7.18 (m, 5H), 5.00 (d, 0.3H), 4.95 (d, 0.7H), 4.32-4.19 (m, 2H), 3.92- 3.85 (m, 1H), 3.75-3.62 (m, 3H), 3.32-3.26 (m, 0.3H), 3.19-3.13 (m, 0.7H), 1.35 (d, 0.9H), 1.32 (d, 2.1 H), 0.84-0.80 (m, 9H), 0.04-0.03 (m, 6H). Example 45A

2-allyl-4-benzyl-5 - ({[iper] butyl (dimethyl) silyl] ^

[Mixture of diastereomers, 4 isomers]

30.6 g (87.5 mmol) of 4-benzyl-5 - ({[ieri-butyl (dimethyl) silyl] oxy} methyl) -2-methylmorpholin-3-one [diastereomer mixture, 4 isomers] in tetrahydrofuran (1.13 l) were initially charged , Under argon at -78 ° C with 123 ml (123 mmol) 1 M Lithiumhexamethyldisilazid solution in tetrahydrofuran and then the reaction mixture was stirred for 15 min. Subsequently, 17.6 g (9.61 ml, 105 mmol) of allyl iodide were added at -78 ° C., the reaction mixture was warmed to RT and stirred overnight. The reaction was stopped by adding saturated aqueous ammonium chloride solution, and then the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 36.6 g (100% of theory).

LC-MS (Method 1A): R _t = 1.53 min; MS (ESIpos): m / z = 390 [M + H] ⁺ . Example 46A

[4-Benzyl-5 - ({[ieri-butyl (dimethyl) silyl] oxy} methyl) -2-methyl-3-oxomorpholin-2-yl] acetaldehyde [mixture of diastereomers, 4 isomers]

There were 1.80 g (4.62 mmol) of 2-allyl-4-benzyl-5 - ({[ieri-butyl (dimethyl) silyl] oxy} methyl) -2-methylmorpholin-3-οη [mixture of diastereomers, 4 isomers] in tetrahydrofuran ( 100 ml) and water (60 ml) and treated at 0 ° C with 1.16 ml (0.427 mmol) 2.5 osmium oxytroxide solution in ieri-butanol and 2.96 g (13.9 mmol) of sodium periodate. It was then warmed to RT and stirred for 20 h. The reaction solution was filtered through kieselguhr and the filter residue was washed with ethyl acetate. After separation of the phases, the organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 2.02 g (87% of theory, purity: 78%).

LC-MS (Method 2A): R _t = 1.42 min; MS (ESIpos): m / z = 392 [M + H] ⁺ .

Example 47A

4-Benzyl-5 - ({[ieri-butyl (dimethyl) silyl] oxy} methyl) -2- (2-hydroxyethyl) -2-methylmorpholin-3-one [mixture of diastereomers, 4 isomers]

There were 22.2 g (32.5 mmol, purity: 57%) of [4-benzyl-5 - ({[ferric butyl (dimethyl) silyl] oxy} -methyl) -2-methyl-3-oxomorpholin-2-yl] acetaldehyde [Diastereomer mixture, 4 isomers] in methanol (242 ml) and treated at 0 ° C with 1.84 g (48.7 mmol) of sodium borohydride. It was then warmed to RT and stirred for 30 min. The reaction solution was mixed with water, the methanol was largely removed in vacuo and the residue extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 22.8 g (quant., Purity: 62%).

LC-MS (Method 1A): R _t = 1.28 min; MS (ESIpos): m / z = 394 [M + H] ⁺ .

Example 48A

4-Benzyl-5 - ({[iperi-butyl (dimethyl) silyl] oxy} methyl) -2- (2- {[iperi-butyl (diphenyl) silyl] oxy} ethyl) -2-methylmorpholin-3-one [ Diastereomeric mixture, 4 isomers]

There were 15.0 g (38.1 mmol) of 4-benzyl-5 - ({[ieri-butyl (dimethyl) silyl] oxy} methyl) -2- (2-hydroxyethyl) -2-methylmorpholin-3-one [diastereomer mixture, 4 isomers ], 7.73 g (114 mmol) of imidazole and 4- (dimethylamino) pyridine (6 mg) in / V, / V-dimethylformamide (52.8 ml) and treated at 0 ° C with 15.7 g (57.2 mmol) ieri-Butyldiphenylsilylchlorid , The mixture was stirred for 60 h while warming to RT. Subsequently, the solvent was largely removed in vacuo, the residue taken up in ethyl acetate / water and the organic phase washed with water and saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by flash chromatography on silica gel (cyclohexane / ethyl acetate 9: 1). Yield: 15.6 g (49% of theory, purity: 50%).

LC-MS (Method 7A): R _t = 6.96 min; MS (ESIpos): m / z = 633 [M + H] ⁺ . Example 49A

4-Benzyl-2- (2- {[iper] butyl (diphenyl) silyl] oxy} ethyl) -5- (hydroxymethyl) -2-methylmorph

[Mixture of diastereomers, 4 isomers]

There were obtained 15.6 g (12.3 mmol, crude product) of 4-benzyl-5 - ({[ieri-butyl (dimethyl) silyl] oxy} methyl) -2- (2- {[ieri-butyl (diphenyl) silyl] oxy} ethyl ) -2-methylmorpholin-3-one [mixture of diastereomers, 4 isomers] in concentrated acetic acid, tetrahydrofuran and water (250 ml, 3: 1: 1) and stirred at RT overnight. Subsequently, the reaction solution was diluted with ethyl acetate, washed three times with water, once with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product obtained was purified by flash chromatography on silica gel (cyclohexane / ethyl acetate 7: 3 - 1: 1). Yield: 2.55 g (40% of theory).

LC-MS (Method 1A): R _t = 1.43 min; MS (ESIpos): m / z = 518 [M + H] ⁺ . Example 50A

4-Benzyl-5- (fluoromethyl) -2- (2-hydroxyethyl) -2-methylmorpholin-3-one [mixture of diastereomers, 4 isomers]

There were 2.00 g (3.86 mmol) of 4-benzyl-2- (2- {[ieri-butyl (diphenyl) silyl] oxy} ethyl) -5- (hydroxymethyl) -2-methylmorpholin-3-one [diastereomer mixture, 4 isomers ] in tetrahydrofuran (40.0 ml) and slowly added at RT with 20.0 ml (46.5 mmol) of bis (2-methoxyethyl) amino sulfur trifluoride (deoxofluor, 50% solution in tetrahydrofuran). Subsequently, 1 drop of methanol was added and then stirred for 2 h at RT and then for 2 h under reflux. The reaction solution was then carefully added dropwise into saturated aqueous sodium bicarbonate solution, the phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was taken up in tetrahydrofuran (40.0 ml) and admixed with 15.5 ml (15.5 mmol) of tetra-w-butylammonium fluoride solution (1.0 M in tetrahydrofuran). It was stirred overnight at RT and then the reaction solution was concentrated in vacuo. The residue was taken up in dichloromethane, washed with water and then the organic phase dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 2.74 g (74% of theory, purity: 29%).

LC-MS (Method 1A): R _t = 0.76 min; MS (ESIpos): m / z = 282 [M + H] ⁺ .

Example 51A

2- [4-Benzyl-5- (fluoromethyl) -2-methylmorpholin-2-yl] ethanol [mixture of diastereomers, 4 isomers]

There were 2.74 g (2.87 mmol, purity: 29%) of 4-benzyl-5- (fluoromethyl) -2- (2-hydroxyethyl) -2-methylmorpholin-3-one [diastereomer mixture, 4 isomers] in tetrahydrofuran (29.1 ml). submitted under argon with 5.74 ml (11.5 mmol) 2 M borane-dimethyl sulfide complex solution in tetrahydrofuran and then the reaction mixture stirred for 3 h under reflux. Subsequently, the batch was cooled to 0 ° C, cautiously treated with methanol (7.5 ml) and then stirred for 30 min under reflux. The mixture was then concentrated completely under reduced pressure and the residue was purified directly by preparative RP-HPLC (acetonitrile / water, isocratic). Yield: 769 mg (97% of theory, diastereomer ratio about 3: 2). LC-MS (Method 1A :): R _t = 0.63 min (diastereomer 1, 2 isomers), R _t = 0.65 min (diastereomer 2, 2 isomers).

MS (ESIpos): m / z = 268 [M + H] ⁺ . Example 52A

2- [5- (fluoromethyl) -2-methylmorpholin-2-yl] ethanol [mixture of diastereomers, 4 isomers]

769 mg (2.80 mmol) of 2- [4-benzyl-5- (fluoromethyl) -2-methylmorpholin-2-yl] ethanol [diastereomer mixture, 4 isomers] in ethanol (41.8 ml) were initially charged under argon with 154 mg of palladium on carbon (10%) and 77.0 mg of palladium hydroxide on carbon (20%) and then stirred for 4 h under a hydrogen atmosphere under atmospheric pressure. The Reaction solution was filtered through kieselguhr and the filter residue washed with ethanol. It was concentrated in vacuo, coevaporated several times with dichloromethane and then the product was dried under high vacuum. Yield: 521 mg (99% of theory).

MS (Method IC): m / z = 178 [M + H] ⁺ . Example 53A

4-Benzyl-5 - ({[ieri-butyl (dimethyl) silyl] oxy} methyl) -2- (2-hydroxypropyl) -2-methylmorpholin-3-one [mixture of diastereomers, 8 isomers]

There were 10.0 g (17.9 mmol, purity: 70%) of [4-benzyl-5 - ({[ieri-butyl (dimethyl) silyl] oxy} methyl) -2-methyl-3-oxomorpholin-2-yl] acetaldehyde [Diastereomer mixture, 4 isomers] in tetrahydrofuran (75.4 ml) and treated at -78 ° C with 26.8 ml (26.8 mmol) 1 M methylmagnesium bromide solution in tetrahydrofuran. The mixture was stirred for 15 min at -78 ° C and then warmed to RT. Subsequently, the reaction solution was added carefully with saturated aqueous ammonium chloride solution, the tetrahydrofuran was largely removed in vacuo and the residue taken up in dichloromethane. After separation of the phases, the organic phase was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 9.65 g of crude product.

LC-MS (Method 1A): R _t = 1.25 min (diastereomer 1, 2 isomers), R _t = 1.27 min (diastereomer 2, 2 isomers), 1.39 (diastereomer 3, 2 isomers), one diastereoisomer, 2 isomers obscured.

MS (ESIpos): m / z = 408 [M + H] ⁺ . Example 54A

4-Benzyl-5 - ({[tertiarybutyl (dimethyl) silyl] oxy} methyl ^

2-methylmorpholin-3-one [mixture of diastereomers, 8 isomers]

There were 9.65 g (22.0 mmol) of 4-benzyl-5 - ({[ferric-butyl (dimethyl) silyl] oxy} methyl) -2- (2-hydroxypropyl) -2-methylmorpholin-3-one [diastereomer mixture, 8 isomers ], 3.00 g (44.0 mmol) of imidazole and 134 mg (1.10 mmol) of 4- (dimethylamino) pyridine in dichloromethane (500 ml) and treated at 0 ° C with 6.66 g (6.30 ml, 24.2 mmol) ieri-Butyldiphenylsilylchlorid. The mixture was stirred for 48 h while warming to RT. It was warmed to 40 ° C and stirred for a further 24 h. After addition of a further 1.06 g (1.00 ml, 4.06 mmol) of ieri-Butyldiphenylsilylchlorid was stirred until complete conversion at 40 ° C. Subsequently, the reaction solution was diluted with dichloromethane and the organic phase was washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 17.2 g of crude product.

LC-MS (Method 1A): R _t = 1.82 min (diastereomer 1, 2 isomers + diastereomer 2, 2 isomers), Rt = 1.87 min (diastereomer 3, 2 isomers + diastereomer 4, 2 isomers);

MS (ESIpos): m / z = 647 [M + H] Example 55A

4-Benzyl-2- (2- {[iper] butyl (diphenyl) silyl] oxy} propyl) -5- (hydroxymethyl) -2-methylmorph

[Mixture of diastereomers, 8 isomers]

There were 17.2 g (6.12 mmol, crude product) of 4-benzyl-5 - ({[ferric butyl (dimethyl) silyl] oxy} methyl) -2- (2- {[ieri-butyl (diphenyl) silyl] oxy} propyl ) -2-methylmorpholin-3-one [mixture of diastereomers, 8 isomers] in concentrated acetic acid (111 ml), tetrahydrofuran (36.0 ml) and water (36.0 ml) and stirred for 5 d at RT. Subsequently, the reaction solution was diluted with ethyl acetate, washed once with water, three times with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by flash chromatography on silica gel (cyclohexane / ethyl acetate 20: 1 - 1: 1). Yield: 2.22 g (68% of theory).

LC-MS (Method 1A): R _t = 1.50 min; MS (ESIpos): m / z = 532 [M + H] ⁺ . Example 56A

4-Benzyl-2- (2- {[ieri-butyl (diphenyl) silyl] oxy} propyl) -5- (fluoromethyl) -2-methylmorpholin-3-one [mixture of diastereomers, 8 isomers]

There were 2.10 g (3.95 mmol) of 4-benzyl-2- (2- {[ieri-butyl (diphenyl) silyl] oxy} propyl) -5- (hydroxymethyl) -2-methylmorpholin-3-one [diastereomer mixture, 8 isomers ] in tetrahydrofuran (105 ml) and slowly added at RT with 11.7 ml (27.1 mmol) of bis (2-methoxyethyl) amino sulfur trifluoride (deoxofluor, 50% solution in tetrahydrofuran). Subsequently, 2 drops of ethanol were added and then stirred for 5 h under reflux. The reaction solution was then carefully added dropwise into saturated aqueous sodium bicarbonate solution, the phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 3.73 g (quant., Purity: 82%).

LC-MS (Method 1A): R _t = 1.63 min; MS (ESIpos): m / z = 534 [M + H] ⁺ .

Example 57A

4-Benzyl-5- (fluoromethyl) -2- (2-hydroxypropyl) -2-methylmorpholin-3-one [mixture of diastereomers, 8 isomers]

There was added 3.70 g (5.68 mmol, purity: 82%) of 4-benzyl-2- (2- {[ieri-butyl (diphenyl) silyl] oxy} propyl) -5- (fluoromethyl) -2-methylmorpholine-3- initially charged with [diastereomer mixture, 8 isomers] in tetrahydrofuran (124 ml) and at RT with 19.7 ml (19.7 mmol) of tetra-w-butylammonium fluoride solution (1.0 M in tetrahydrofuran). It was stirred overnight at RT and then the reaction solution was concentrated in vacuo. The residue was taken up in dichloromethane, washed with water and then the organic phase dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was then purified by preparative RP-HPLC (acetonitrile / water). Yield: 728 mg (43% of theory).

LC-MS (Method 1A): R _t = 0.85 min (diastereomer 1 + diastereomer 2), R _t = 0.86 min (diastereomer 3 + diastereomer 4);

MS (ESIpos): m / z = 296 [M + H] ⁺ .

Example 58A 1- [4-Benzyl-5- (fluoromethyl) -2-methylmorpholin-2-yl] -propan-2-ol Trifluoroacetate [diastereomer 1, 2 isomers + diastereomer 2, 2 isomers + diastereomer 3, 2 isomers + diastereomer 4 , 2 isomers]

728 mg (2.46 mmol) of 4-benzyl-5- (fluoromethyl) -2- (2-hydroxypropyl) -2-methylmorpholin-3-one [diastereomer mixture, 8 isomers] in tetrahydrofuran (24.2 ml) were initially charged under argon 4.93 ml (9.86 mmol) of 2 M borane-dimethyl sulfide complex solution in tetrahydrofuran are added and then the reaction mixture is stirred for 2 h under reflux. Subsequently, the mixture was added carefully at 0 ° C with methanol (10 ml) and stirred for 30 min under reflux. It was then completely concentrated under reduced pressure and the residue was purified by preparative RP-HPLC (acetonitrile / water). The isomer mixture (262 mg) was then separated on the achiral phase according to method 3G into the four diastereomers. Yield: 15.2 mg (2% of theory, diastereomer 1, 2 isomers); 166 mg (23% of theory, diastereomer 2, 2 isomers), 44.7 mg (6% of theory, diastereomer 3, 2 isomers), 92.5 mg (13% of theory, diastereomer 4, 2 isomers).

LC-MS (Method 1A :): R _t = 0.68 min (diastereomer 1, 2 isomers), R _t = 0.69 min (diastereomer 2, 2 isomers), R _t = 0.73 min (diastereomer 3, 2 isomers), R _t = 0.68 min (diastereomer 4, 2 isomers). MS (ESIpos): m / z = 282 [M + H-TFA] ⁺ .

Example 59A 1- [5- (fluoromethyl) -2-methylmorpholin-2-yl] propan-2-ol Trifluoroacetate [diastereomer 2,

2 isomers]

There were 166 mg (0.421 mmol) of 1- [4-benzyl-5- (fluoromethyl) -2-methylmorpholin-2-yl] propan-2-ol trifluoroacetate [diastereomer 2, 2 isomers, Example 58A] in ethanol (4.23 ml ), added under argon with 17.0 mg of palladium on carbon (10%) and 8.0 mg of palladium hydroxide on carbon (20%) and then stirred overnight under a hydrogen atmosphere under atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue washed with ethanol. It was concentrated in vacuo and then the product was dried under high vacuum. Yield: 126 mg (98% of theory).

GC-MS (Method 2B): R _t = 3.97 min.

Example 60A

/ V-Benzyl-2-chloro- / V - [(2R) -l-hydroxypropan-2-yl] propanamide [mixture of diastereomers, 2 isomers]

16.4 g (99.3 mmol) of (2R) -2- (benzylamino) propan-1-ol [Lit .: TJ Tewson et al., Synthesis 2002, 6, 766-770] in w-propanol (500 ml) were initially charged , cooled to 0 ° C and treated with 20.1 g (27.7 ml, 199 mmol) of triethylamine. Subsequently, 13.9 g (10.8 ml, 109 mmol) of 2-chloropropionyl chloride [racemate] were added dropwise, the reaction solution was allowed to warm to RT, stirred overnight and then concentrated in vacuo. The residue was treated with 0.5 N aqueous hydrogen chloride solution and extracted with ethyl acetate. The organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 24.3 g (88% of theory, purity: 92%, diastereomer ratio about 1: 1).

LC-MS (Method 1A): R _t = 0.80 min (diastereomer 1), R _t = 0.84 min (diastereomer 2);

MS (ESIpos): m / z = 256 [M + H] ⁺ .

Example 61 A

(5R) -4-Benzyl-2,5-dimethylmorpholin-3-one [mixture of diastereomers, 2 isomers]

There were 30.0 g (109 mmol, purity: 93%) / V-benzyl-2-chloro- / V - [(2R) -l-hydroxypropan-2-yl] propanamide [diastereomer mixture, 2 isomers] in w-propanol ( 588 ml), cooled to 0 ° C and treated with 49.0 g (436 mmol) of potassium ieri-butoxide. The reaction solution was allowed to warm to rt and stirred overnight. Zso-propanol was largely removed in vacuo and the residue taken up in water. It was extracted with ethyl acetate, the organic phases dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 22.8 g (93% of theory). LC-MS (Method 1A): R _t = 0.85 min; MS (ESIpos): m / z = 220 [M + H] ⁺ . Example 62A

(5R) -2-allyl-4-benzyl-2,5-dimethylmorpholin-3-one [mixture of diastereomers, 2 isomers]

There were 22.8 g (104 mmol) of (5R) -4-benzyl-2,5-dimethylmorpholin-3-one [diastereomer mixture, 2 isomers] in tetrahydrofuran (1.34 1) submitted under argon at -78 ° C with 146 ml ( 146 mmol) 1 M lithium hexamethyldisilazide solution in tetrahydrofuran and stirred for 15 min. Subsequently, 21.0 g (11.4 ml, 125 mmol) of allyl iodide were added at -78 ° C, the reaction mixture was allowed to warm to RT and stirred for 3 h. The reaction was stopped by adding saturated aqueous ammonium chloride solution and then extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 27.5 g (77% of theory, purity: 75%). LC-MS (Method 1A): R _t = 0.99 min; MS (ESIpos): m / z = 260 [M + H] ⁺ .

Example 63A

[(5R) -4-Benzyl-2,5-dimethyl-3-oxomorpholin-2-yl] acetaldehyde [mixture of diastereomers, 2 isomers]

There were 27.4 g (79.9 mmol, purity: 75%) of (5R) -2-allyl-4-benzyl-2,5-dimethylmorpholin-3-one [diastereomer mixture, 2 isomers] in tetrahydrofuran (620 ml) and water (370 ml) and treated at 0 ° C with 4.35 ml (1.60 mmol) 2.5% osmium tetroxide solution in ieri-butanol and 51.2 g (240 mmol) of sodium periodate. The reaction solution was allowed to warm to rt and stirred overnight. The reaction solution was filtered through kieselguhr and the filter residue was washed with tetrahydrofuran. The reaction solution was taken up in ethyl acetate and diluted with water. After separation of the phases, the organic phase was washed with 1 N aqueous sodium sulfite solution (2 × 400 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 23.6 g of crude product.

LC-MS (Method 1A): R _t = 0.81 min (enantiomerically pure isomer 1), R _t = 0.84 min (enantiomerically pure isomer 2);

MS (ESIpos): m / z = 262 [M + H] ⁺ . Example 64A

(5R) -4-Benzyl-2- (2-hydroxyethyl) -2,5-dimethylmorpholin-3-one [diastereomer mixture, 2

isomers]

There were 7.00 g (about 26.8 mmol, crude product) [(5R) -4-benzyl-2,5-dimethyl-3-oxomorpholin-2-yl] acetaldehyde [diastereomer mixture, 2 isomers] in methanol (200 ml) and at 0 ° C with 3.04 g (80.4 mmol) of sodium borohydride. The reaction solution was allowed to warm to rt and stirred for 30 min. The reaction solution was mixed with water, the methanol was largely removed in vacuo and the residue extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative RP-HPLC (acetonitrile / water). Yield: 6.82 g (70% of theory, purity: 73%).

LC-MS (Method 1A): R _t = 0.71 min; MS (ESIpos): m / z = 264 [M + H] ⁺ . Example 65A

2 - [(5R) -4-Benzyl-2,5-dimethylmorpholin-2-yl] ethanol [enantiomerically pure isomer 1 + enantiomerically pure isomer 2]

There were obtained 6.80 g (18.9 mmol, purity: 73%) of (5R) -4-benzyl-2- (2-hydroxyethyl) -2,5-dimethyl-morpholin-3-one [mixture of diastereomers, 2 isomers] in tetrahydrofuran (191 ml), added under argon with 37.7 ml (75.4 mmol) of 2 M borane-dimethyl sulfide complex solution in tetrahydrofuran and stirred for 2 h under reflux. The mixture was subsequently cooled to 0 ° C., cautiously mixed with methanol (37 ml) and stirred at reflux for 30 minutes. It was completely concentrated under reduced pressure, and the residue was taken up in acetonitrile and subjected directly to purification and diastereomer separation by preparative RP-HPLC (acetonitrile / water, isocratic). Enantiomerically pure isomer 1 was eluted as a first compound. Yield: 1.34 g (28% of theory, enantiomerically pure isomer 1). Enantiomerically pure isomer 2 was eluted as a second compound. Yield: 2.28 g (47% of theory, enantiomerically pure isomer 2).

Enantiomerically pure isomer 1: LC-MS (Method 4A): R _t = 2.55 min; MS (ESIpos): m / z = 250 [M + H] ⁺ ; Enantiomerically pure isomer 2:

LC-MS (Method 4A): R _t = 2.64 min; MS (ESIpos): m / z = 250 [M + H] ⁺ .

Example 66A

2 - [(5R) -2,5-dimethylmorpholin-2-yl] ethanol [enantiomerically pure isomer]

There were 2.25 g (9.02 mmol) of 2 - [(5R) -4-benzyl-2,5-dimethylmorpholin-2-yl] efhanol

[enantiomerically pure isomer 2, Example 65A] in ethanol (90.7 ml), added under argon with 227 mg of palladium on carbon (10 ig) and 113 mg of palladium hydroxide on carbon (20%) and stirred overnight under a hydrogen atmosphere under atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue was washed with ethanol. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 1.46 g (quant.).

MS (Method IC): m / z = 160 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-de): δ [ppm] = 4.21 (t, 1H), 3.53-3.44 (d, 2H), 3.34 (dd, 1H), 3.14 (t, 1H), 2.65- 2.52 (m, 3H), 2.07 (br, s, 1H), 1.52 (td, 2H), 1.18 (s, 3H), 0.85 (d, 3H). Example 67A

(5R) -4-Benzyl-2- (2-hydroxypropyl) -2,5-dimethylmorpholin-3-one [mixture of diastereomers,

There were 16.8 g (about 64.3 mmol, crude product) of [(5R) -4-benzyl-2,5-dimethyl-3-oxomorpholin-2-yl] acetaldehyde [Example 63A, mixture of diastereomers, 2 isomers] in tetrahydrofuran (275 ml ) and treated at -78 ° C with 77.2 ml (77.2 mmol) 1 M methylmagnesium bromide solution in tetrahydrofuran. The mixture was stirred for 15 min at -78 ° C and then allowed to warm the reaction solution to RT. Subsequently, the reaction solution was added carefully with saturated aqueous ammonium chloride solution (400 ml), the tetrahydrofuran was largely removed in vacuo and the residue taken up in dichloromethane. After separation of the phases, the organic phase was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 16.2 g of crude product.

LC-MS (Method 1A): R _t = 0.78, 0.80 min; MS (ESIpos): m / z = 278 [M + H] ⁺ .

Example 68A l - [(5R) -4-Benzyl-2,5-dimethylmorpholin-2-yl] propan-2-ol [enantiomerically pure isomer 1 + enantiomerically pure isomer 2 + enantiomerically pure isomer 3 + enantiomerically pure isomer 4]

16.2 g (about 39.1 mmol, crude product) of (5R) -4-benzyl-2- (2-hydroxypropyl) -2,5-dimethylmorpholin-3-one [diastereomer mixture, 4 isomers] in tetrahydrofuran (397 ml) were initially charged , Under argon with 78.3 ml (157 mmol) of 2 M borane-dimethyl sulfide complex solution in tetrahydrofuran and stirred for 2 h under reflux. Subsequently, the batch was cooled to 0 ° C, cautiously with methanol (80 ml) and stirred for 30 min under reflux. The mixture was then concentrated completely in vacuo, and the residue was taken up in acetonitrile and subjected directly to purification and diastereomer separation by preparative RP-HPLC (acetonitrile / water, isocratic). The target compound eluted as the third component. Yield: target Compound: 3.11 g (29% of theory, enantiomerically pure isomer 3); enantiomerically pure isomer 1: 2.12 g (20% of theory); enantiomerically pure isomer 2: 506 mg (5% of theory); enantiomerically pure isomer 4: 1.72 g (16% of theory). Enantiomerically pure isomer 3:

LC-MS (Method 1A): R _t = 0.39 min; MS (ESIpos): m / z = 264 [M + H] ⁺ ;

^H-NMR (400 MHz, DMSO-de): δ [ppm] = 7:34 to 7:18 (m, 5H), 4.10 (d, IH), 3.96 (d, IH), 3.79 (m _c, IH), 3:48 (dd, IH), 3:36 (m _c, IH), 3:04 (d, IH) 2.46 (d, IH), 2.28 (m _c, IH), 1.88 (d, IH) 1.44 (dd, IH), 1.36 (dd, IH), 1.23 (s, 3H), 1.01 (d, 3H), 0.98 (d, 3H).

Enantiomerically pure isomer 1:

LC-MS (Method 1A): R _t = 0.43 min; MS (ESIpos): m / z = 264 [M + H] ⁺ ;

Ή-NMR (400 MHz, DMSO-ife): δ [ppm] = 7:33 to 7:18 (m, 5H), 4.16 (d, IH), 3.90 (d, IH), 3.76 (m _c, IH), 3:50 ( dd, IH), 3.26 (dd, IH), 3.10 (d, IH), 2:43 (d, IH), 2:32 (m _c, IH), 2.10 (dd, IH), 1.84 (d, IH), 1.27 ( dd, IH), 1.09-1.06 (m, 6H), 0.98 (d, 3H).

Enantiomerically pure isomer 2:

LC-MS (Method 1A): R _t = 0.45 min; MS (ESIpos): m / z = 264 [M + H] ⁺ ;

^H-NMR (400 MHz, DMSO-ife): δ [ppm] = 7:32 to 7:20 (m, 5H), 4.11 (d, IH), 3.92 (d, IH), 3:57 (m _c, IH), 3.51, (dd, IH), 3:41 (dd, IH), 3:06 (d, IH), 2:47 (d, IH), 2:34 (m _c, IH), 1.85-1.74 (m, 2H), 1:59 (dd, IH) , 1.06 (s, 3H), 1.03-0.97 (t, 6H).

Enantiomerically pure isomer 4:

LC-MS (Method 1A): R _t = 0.44 min; MS (ESIpos): m / z = 264 [M + H] ⁺ ;

^: H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.49 (s, 5H), 4.69 (d, IH), 4.28-4.15 (m, 2H), 3.86- 3.73 (m, 3H) , 3.63 (t, IH), 3.32 (t, IH), 3.21 (brs, IH), 2.84 (d, IH), 1.52-1.38 (m, 4H), 1.28 (s, 3H), 1.01 ( d, 3H).

Example 69A

1 - [(5R) -2,5-dimethylmorpholin-2-yl] propan-2-ol [enantiomerically pure isomer]

3.10 g (11.8 mmol) of l - [(5R) -4-benzyl-2,5-dimethylmorpholin-2-yl] propan-2-ol [Example 68A, enantiomerically pure isomer 3] in ethanol (118 ml) were initially charged, under argon with 296 mg of palladium on carbon (10 ig) and 148 mg of palladium hydroxide on carbon (20%) and then stirred overnight under a hydrogen atmosphere under atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue was washed with hot ethanol (100 ml). It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 2.06 g (quant.).

GC-MS (Method 1B): R _t = 3.86 min; MS (EIpos): m / z = 173 [M] ⁺ ;

^: H-NMR (400 MHz, DMSO-de): δ [ppm] = 4.20 (d, 1H), 3.87 (br, s, 1H), 3.35 (dd, 1H), 3.16 (t, 1H), 2.67 -2.53 (m, 3H), 2.05 (br, s, 1H), 1.44 (dd, 1H), 1.36 (dd, 1H), 1.23 (s, 3H), 1.04 (d, 3H), 0.85 (d, 3H).

Example 70A

/ V-Benzyl-2-chloro / V - [(2R) -l-hydroxy-butan-2-yl] -propanamide [mixture of diastereomers, 2 isomers]

39.24 g (219 mmol) of (2R) -2- (benzylamino) butan-1-ol [Lit .: P. Deniz et al., Tetrahedron 2011, 67, 6227-6232] in ω-propanol (500 ml). initially charged and mixed with 46.5 g (64.0 ml, 459 mmol) of triethylamine. Subsequently, 30.5 g (23.4 ml, 109 mmol) of 2-chloropropionyl chloride [racemate] were added dropwise and the reaction solution was stirred for 4 h at RT. It was then concentrated in vacuo, the residue was treated with water and extracted with dichloromethane. The organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 49.0 g (83% of theory, diastereomer ratio about 1: 1).

LC-MS (Method 1A): R _t = 0.86 min (enantiomerically pure isomer 1), R _t = 0.88 min (enantiomerically pure isomer 2); MS (ESIpos): m / z = 270 [M + H] ⁺ . Example 71 A

(5R) -4-Benzyl-5-ethyl-2-methylmorpholin-3-one [mixture of diastereomers, 2 isomers]

There were 25.0 g (92.7 mmol) A ^{r-benzyl-2-chloro-A} ^r - [(2R) -l-hydroxybutane-2-yl] propanamide [mixture of diastereomers, 2 isomers] in wo-propanol (400 ml) were charged, cooled to 0 ° C and then mixed with 34.3 g (306 mmol) of potassium ieri-butoxide in one portion. It was warmed slowly to RT and stirred overnight. The where-propanol was largely removed in vacuo and the residue taken up in ethyl acetate. The organic phase was washed twice with water, once with 1N aqueous hydrogen chloride solution and once with saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 19.5 g (90% of theory).

LC-MS (Method 1A): R _t = 0.93 min; MS (ESIpos): m / z = 234 [M + H] ⁺ .

Example 72A (5R) -2-Allyl-4-benzyl-5-ethyl-2-methylmorpholin-3-one [mixture of diastereomers, 2 isomers]

17.5 g (75.0 mmol) of (5R) -4-benzyl-5-ethyl-2-methylmorpholin-3-one [diastereomer mixture, 2 isomers] in tetrahydrofuran (320 ml) were initially charged under argon at -78 ° C. with 82.5 ml (82.5 mmol) 1 M lithium hexamethyldisilazide solution in tetrahydrofuran added and stirred for 30 min. Subsequently, at -78 ° C., 10.9 g (7.79 ml, 90.0 mmol) of allyl bromide in tetrahydrofuran (20 ml) were added dropwise. The reaction mixture was allowed to warm to rt and stirred overnight. The reaction was stopped by adding water and then extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (cyclohexane / ethyl acetate gradient). Yield: 13.5 g (65% of theory).

LC-MS (Method 1A): R _t = 1.11 min; MS (ESIpos): m / z = 274 [M + H] ⁺ .

Example 73A [(5R) -4-Benzyl-5-ethyl-2-methyl-3-oxomorpholin-2-yl] acetaldehyde [mixture of diastereomers,

2 isomers]

There were initially charged 10.5 g (38.4 mmol) of (5R) -2-allyl-4-benzyl-5-ethyl-2-methylmorpholin-3-one [mixture of diastereomers, 2 isomers] in methanol (300 ml) and then at -78 ° C ozone-containing oxygen introduced into the solution for 30 min (ozone generator LAB2B Triogen / Degremont Technologies Ltd., ozone concentration: about 30-50 mg / 1). Subsequently, pure oxygen was introduced into the reaction solution for a few minutes to remove excess ozone. 23.9 g (28.2 ml, 384 mmol) of dimethyl sulfide were added to the reaction solution at -78 ° C., and the mixture was stirred overnight and allowed to warm to RT. The reaction solution was concentrated in vacuo, the residue taken up in ethyl acetate and washed with water, 1 N aqueous hydrogen chloride solution and saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 10.1 g of crude product.

LC-MS (Method 1A): R _t = 0.90 min; MS (ESIpos): m / z = 276 [M + H] ⁺ . Example 74A

(5R) -4-Benzyl-5-ethyl-2- (2-hydroxyethyl) -2-methylmorpholin-3-one [mixture of diastereomers,

2 isomers]

There were 9.80 g (about 35.6 mmol, crude product) of [(5R) -4-benzyl-5-ethyl-2-methyl-3-oxomorpholin-2-yl] acetaldehyde [mixture of diastereomers, 2 isomers] in methanol (100 ml). initially charged and mixed at 0 ° C with 1.41 g (37.4 mmol) of sodium borohydride. Then allowed to warm to RT and stirred for 30 min. The reaction solution was added with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (cyclohexane / ethyl acetate gradient). Yield: 9.79 g (99% of theory).

LC-MS (Method 1A): R _t = 0.79 min; MS (ESIpos): m / z = 278 [M + H] ⁺ .

Example 75A

2 - [(5R) -4-Benzyl-5-ethyl-2-methylmorpholin-2-yl] ethanol [mixture of diastereomers, 2 isomers]

There were 9.79 g (35.3 mmol) of (5R) -4-benzyl-5-ethyl-2- (2-hydroxyethyl) -2-methylmorpholin-3-one [diastereomer mixture, 2 isomers] in tetrahydrofuran (180 ml) submitted under Argon with Added 106 ml (212 mmol) of 2 M borane-dimethyl sulfide complex solution in tetrahydrofuran and stirred overnight at RT. Ethanol was added until gas evolution ceased and stirred at reflux for 30 min. It was then completely concentrated in vacuo, the residue taken up in acetonitrile and purified directly by flash chromatography on silica gel (cyclohexane / Essigsäureefhylester gradient). Yield: 8.60 g (92% of theory, diastereomer ratio about 2: 1).

LC-MS (Method 2A): R _t = 0.46 min (enantiomerically pure isomer 1), R _t = 0.49 min (enantiomerically pure isomer 2);

MS (ESIpos): m / z = 274 [M + H] ⁺ . Example 76A

2 - [(5R) -5-ethyl-2-methylmorpholin-2-yl] ethanol [mixture of diastereomers, 2 isomers]

There were initially charged 4.00 g (15.2 mmol) of 2 - [(5R) -4-benzyl-5-ethyl-2-methylmorpholin-2-yl] ethanol [diastereomer mixture, 2 isomers] in ethanol (150 ml) under argon with 400 Mg palladium on carbon (10%) and 200 mg of palladium hydroxide on carbon (20%) and stirred for 40 h under a hydrogen atmosphere at atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue washed with ethanol. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 2.55 g (90% of theory).

MS (Method IC): m / z = 174 [M + H] ⁺ . Example 77A

4-Benzyl-5- (methoxymethyl) -2-methylmorpholin-3-one [mixture of diastereomers, 4 isomers]

There were 15.0 g (63.8 mmol) of 4-benzyl-5- (hydroxymethyl) -2-methylmorpholin-3-one [diastereomer mixture, 4 isomers] in A ^ N-dimethylformamide (600 ml) and charged with 5.10 g (128 mmol, 60% suspension in paraffin oil) of sodium hydride and 22.6 g (9.92 ml, 159 mmol) of iodomethane. It was stirred for 2 h and then the reaction was stopped by the slow addition of water (30 ml). It was concentrated in vacuo, the residue taken up in water and extracted several times with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was taken up in toluene and washed with water and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative RP-HPLC (acetonitrile / water). Yield: 16.7 g (96% of theory).

LC-MS (Method 1A): R _t = 0.82 min; MS (ESIpos): m / z = 250 [M + H] ⁺ . Example 78A 2-Allyl-4-benzyl-5- (methoxymethyl) -2-methylmorpholin-3-one [mixture of diastereomers, 4 isomers]

There were initially charged 4.00 g (15.5 mmol) of 4-benzyl-5- (methoxymethyl) -2-methylmorpholin-3-one [diastereomer mixture, 4 isomers] in tetrahydrofuran (200 ml) under argon at -78 ° C. with 21.7 ml ( 21.7 mmol) in lithium hexamethyldisilazide solution in tetrahydrofuran and then stirred the reaction mixture for 15 min. Subsequently, at -78 ° C., 3.12 g (1.70 ml, 18.6 mmol) of allyl iodide were added, the reaction mixture was warmed to RT and stirred overnight. The reaction was stopped by adding saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 5.26 g (99% of theory, purity: 84%).

LC-MS (Method 1A): R _t = 1.04 min; MS (ESIpos): m / z = 290 [M + H] ⁺ .

Example 79A [4-Benzyl-5- (methoxymethyl) -2-methyl-3-oxomorpholin-2-yl] acetaldehyde

[Mixture of diastereomers, 4 isomers]

There was added 5.26 g (15.4 mmol, purity: 84%) of 2-allyl-4-benzyl-5- (methoxymethyl) -2-methylmorpholin-3-one [diastereomer mixture, 4 isomers] in tetrahydrofuran (333 ml) and water (199 ml) and treated at 0 ° C with 3.87 ml (1.42 mmol) 2.5% osmium tetroxide solution in ieri-butanol and 9.88 g (46.2 mmol) of sodium periodate. It was then warmed to RT and stirred for 20 h. The reaction solution was filtered through kieselguhr and the tetrahydrofuran was removed in vacuo. The aqueous phase was extracted with ethyl acetate and the organic phase was washed with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 5.06 g (91% of theory, purity: 81%).

LC-MS (Method 1A): R _t = 0.85 min (diastereomer 1, 2 isomers), R _t = 0.88 min (diastereomer 2, 2 isomers); MS (ESIpos): m / z = 292 [M + H] ⁺ . Example 80A

4-Benzyl-2- (2-hydroxyethyl) -5- (methoxymethyl) -2-methylmorpholine-3-one

[Mixture of diastereomers, 4 isomers]

5.00 g (13.7 mmol, purity: 80%) of [4-benzyl-5- (methoxymethyl) -2-methyl-3-oxomorpholin-2-yl] acetaldehyde [diastereomer mixture, 4 isomers] in methanol (102 ml) were initially charged and at 0 ° C with 1.56 g (41.2 mmol) of sodium borohydride. It was then warmed to RT and stirred for 30 min. The reaction solution was added with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 4.84 g (65% of theory, purity: 54%).

LC-MS (Method 2A): R _t = 0.74 min (diastereomer 1, 2 isomers), R _t = 0.75 min (diastereomer 2, 2 isomers);

MS (ESIpos): m / z = 294 [M + H] ⁺ . Example 81A

2- [4-Benzyl-5- (methoxymethyl) -2-methylmorpholin-2-yl] ethanol [mixture of diastereomers, 4 isomers]

There were 4.84 g (18.9 mmol, purity: 54%) of 4-benzyl-2- (2-hydroxyethyl) -5- (methoxy-methyl) -2-methylmorpholin-3-one [diastereomer mixture, 4 isomers] in tetrahydrofuran (88 ml). initially charged under argon with 44.6 ml (89.2 mmol) of 2 M borane-dimethyl sulfide complex solution in tetrahydrofuran and stirred for 1 h under reflux. Subsequently, the batch was cooled to RT, cautiously treated with ethanol (40 ml) and stirred for 1 h under reflux. The mixture was then concentrated completely in vacuo, and the residue was taken up in acetonitrile and purified by preparative RP-HPLC (acetonitrile / water, isocratic). Yield: 2.65 g (quant., Diastereomer ratio about 3: 2). LC-MS (Method 1A): R _t = 0.49 min (diastereomer 1, 2 isomers), R _t = 0.53 min (diastereomer 2, 2 isomers);

MS (ESIpos): m / z = 280 [M + H] ⁺ . Example 82A

2- [5- (methoxymethyl) -2-methylmorpholin-2-yl] ethanol [mixture of diastereomers, 4 isomers]

2.65 g (9.49 mmol) of 2- [4-benzyl-5- (methoxymethyl) -2-methylmorpholin-2-yl] ethanol [diastereomer mixture, 4 isomers] in ethanol (37.9 ml) were initially charged under argon with 250 mg of palladium on carbon (10%) and 125 mg of palladium hydroxide on carbon (20%) and stirred for 20 h under a hydrogen atmosphere at atmospheric pressure. The reaction solution was over Diatomaceous earth filtered and the filter residue washed with methanol. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 1.75 g (92% of theory).

MS (Method 2C): m / z = 190 [M + H] ⁺ .

Example 83A / V-Benzyl-2-chloro / V- (1-hydroxy-2-methylpropan-2-yl) propanamide [racemate]

20.0 g (106 mmol) of 2- (benzylamino) -2-methylpropan-1-ol [Lit .: M. Le Hyaric et al., Chem. Biol. Drug Des. 2011, 78 876-880] in w-propanol (350 ml), cooled to 0 ° C and treated with 22.6 g (31.1 ml, 223 mmol) of triethylamine. Subsequently, 15.6 g (12.2 ml, 123 mmol) of 2-chloropropionyl chloride [racemate] were added dropwise. After stirring for 30 minutes, a further 7.09 g (5.55 ml, 55.9 mmol) of 2-chloropropionyl chloride [racemate] were added dropwise and the reaction solution was allowed to warm to RT. The reaction solution was concentrated in vacuo, the residue taken up in ethyl acetate (700 ml) and washed with water (400 ml). The organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 37.1 g (quant.).

LC-MS (Method 1A): R _t = 0.95 min; MS (ESIpos): m / z = 270 [M + H] ⁺ . Example 84A

4-Benzyl-2,5,5-trimethylmorpholin-3-one [racemate]

There were 37.1 g (72.9 mmol, purity: 53%) A ^{r-benzyl-2-chloro-A} ^r - (l-hydroxy-2-methylpropan-2- yl) propanamide [racemate] in wo-propanol (500 ml) cooled to 0 ° C and mixed with 24.5 g (219 mmol) of potassium ieri-butoxide in one portion. It was stirred for 1 h at 0 ° C and then the isopropanol largely removed in vacuo. The residue was taken up in dichloromethane and washed with 1 N aqueous hydrogen chloride solution (400 ml). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 23.2 g (quant.).

LC-MS (Method 1A): R _t = 0.91 min; MS (ESIpos): m / z = 234 [M + H] ⁺ .

Example 85A 2-Allyl-4-benzyl-2,5,5-trimethylmorpholin-3-one [racemate]

21.58 g (92.1 mmol) of 4-benzyl-2,5,5-trimethylmorpholin-3-one [racemate] in tetrahydrofuran (1.19 l) were initially charged under argon at -78 ° C. with 129 ml (129 mmol) of IM lithium hexamethyldisilazide Added solution in tetrahydrofuran and stirred for 15 min. Subsequently, at -78 ° C., 23.2 g (12.6 ml, 138 mmol) of allyl iodide were added, the reaction mixture was warmed to RT and stirred overnight. It was again cooled to -78 ° C, treated with 92.1 ml (92.1 mmol) 1 M lithium hexamethyldisilazide solution in tetrahydrofuran and then the reaction mixture was stirred for 30 min. Then another 15.5 g (8.42 ml, 92.1 mmol) of allyl iodide were added and warmed to RT. The reaction was stopped by adding saturated aqueous ammonium chloride solution and then extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 23.4 g (93% of theory). LC-MS (Method 1A): R _t = 1.09 min; MS (ESIpos): m / z = 274 [M + H] Example 86A

(4-Benzyl-2,5,5-trimethyl-3-oxomorpholin-2-yl) acetaldehyde [racemate]

23.6 g (73.4 mmol) of (2-allyl-4-benzyl-2,5,5-trimethylmorpholin-3-one [racemate] in tetrahydrofuran (570 ml) and water (340 ml) at 0 ° C. with 4.00 ml 47.1 g (220 mmol) of sodium periodate were then allowed to warm to RT and stirred overnight, the reaction solution was filtered through kieselguhr and the filter residue was washed with tetrahydrofuran After separation of the phases, the organic phase was washed with 1 N aqueous sodium sulfite solution (2 × 800 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure, the crude product was purified in the next stage without further purification Yield: 19.8 g of crude product.

LC-MS (Method 1A): R _t = 0.93 min; MS (ESIpos): m / z = 276 [M + H] ⁺ .

Example 87A 4-Benzyl-2- (2-hydroxyethyl) -2,5,5-trimethylmorpholin-3-one [racemate]

There were 6.50 g (about 23.6 mmol, crude product) (4-benzyl-2,5,5-trimethyl-3-oxomorpholin-2-yl) acetaldehyde [racemate] in methanol (176 ml) at 0 ° C with 2.68 g (70.8 mmol) of sodium borohydride. Then allowed to warm to RT and stirred for 30 min. The reaction solution was mixed with water, methanol was largely removed in vacuo and the residue extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative RP-HPLC (acetonitrile / water). Yield: 5.89 g (62% of theory, purity: 69%).

LC-MS (Method 4A): R _t = 2.31 min; MS (ESIpos): m / z = 278 [M + H] ⁺ .

Example 88A 2- (4-Benzyl-2,5,5-trimethylmorpholin-2-yl) ethanol [racemate]

5.85 g (21.1 mmol) of 4-benzyl-2- (2-hydroxyethyl) -2,5,5-trimethylmorpholin-3-one [racemate] in tetrahydrofuran (210 ml) were initially charged, under argon with 42.2 ml (84.4 mmol ) 2 M borane-dimethyl sulfide complex solution in tetrahydrofuran and stirred for 2 h under reflux. Subsequently, the mixture was cooled to 0 ° C, carefully added with methanol (45 ml) and stirred for 30 min under reflux to destroy any Borkomplexe. It was then completely concentrated in vacuo, the residue taken up in acetonitrile and purified directly by preparative RP-HPLC (acetonitrile / water). Yield: 3.10 g (55% of theory).

LC-MS (Method 4A): R _t = 2.82 min; MS (ESIpos): m / z = 264 [M + H] ⁺ . Example 89A

2- (2,5,5-trimethylmorpholin-2-yl) ethanol [racemate]

There were 3.00 g (11.4 mmol) of 2- (4-benzyl-2,5,5-trimethylmorpholin-2-yl) ethanol [racemate] in ethanol (115 ml) submitted, under argon with 286 mg of palladium on carbon (10 ig ) and 143 mg of palladium hydroxide on carbon (20%) and stirred overnight under a hydrogen atmosphere at atmospheric pressure. Subsequently, a further 286 mg of palladium on carbon (10%) and 143 mg of palladium hydroxide on carbon (20% strength) were added and again stirred overnight under a hydrogen atmosphere at atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue washed with ethanol. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 2.06 g (quant.). MS (Method IC): m / z = 174 [M + H] ⁺ .

Example 90A

4-Benzyl-2- (2-hydroxypropyl) -2,5,5-trimethylmorpholin-3-one [mixture of diastereomers, 4 isomers]

It 6.50 g (about 23.6 mmol, crude product) (4-benzyl-2,5,5-trimethyl-3-oxomorpholin-2-yl) acetaldehyde [racemate] in tetrahydrofuran (101 ml) and at -78 ° C. Slowly added 28.3 ml (28.3 mmol) of methylmagnesium bromide (2 M solution in tetrahydrofuran). It was stirred for 15 min at -78 ° C before being allowed to warm to rt. The reaction was stopped by adding saturated aqueous ammonium chloride solution (about 70 ml) and the tetrahydrofuran was removed in vacuo. The residue was taken up in dichloromethane and washed with water. The organic phase was over sodium sulfate dried, filtered and concentrated in vacuo. The crude product was used without further purification of the next step. Yield: 6.17 g (54% of theory).

LC-MS (Method 4A): R _t = 2.46 min; MS (ESIpos): m / z = 292 [M + H] ⁺ .

Example 91A

2- (4-Benzyl-2,5,5-trimethylmorpholin-2-yl) -propan-2-ol [diastereomer 1, 2 isomers diastereomer 2, 2 isomers]

6.15 g (21.1 mmol) of 4-benzyl-2- (2-hydroxypropyl) -2,5,5-trimethylmorpholin-3-one [diastereomer mixture, 4 isomers] in tetrahydrofuran (210 ml) were initially charged under argon with 42.2 ml (84.4 mmol) 2 M borane-dimethyl sulfide complex solution in tetrahydrofuran and stirred for 2 h under reflux. Subsequently, the batch was cooled to 0 ° C, cautiously mixed with methanol (45 ml) and stirred for 30 min under reflux. It was then concentrated completely in vacuo, the residue was taken up in acetonitrile and subjected directly to purification and diastereomer separation by preparative RP-HPLC (acetonitrile / water, isocratic). A mixed fraction (1.10 g) was reconditioned on achiral phase according to method 3F. Yield: 1.74 g (29% of theory, diastereomer 1, 2 isomers) and 434 mg (26% of theory, diastereomer 2, 2 isomers).

Diastereomer 1, 2 isomers:

LC-MS (Method 4A): R _t = 3.06 min; MS (ESIpos): m / z = 279 [M + H] ⁺ . Diastereomer 2, 2 isomers:

LC-MS (Method 4A): R _t = 3.18 min; MS (ESIpos): m / z = 279 [M + H] ⁺ . Example 92A 1- (2,5,5-trimethylmorpholin-2-yl) propan-2-ol [diastereomer 1, 2 isomers]

There were initially charged 3.00 g (11.4 mmol) of 2- (4-benzyl-2,5,5-trimethylmorpholin-2-yl) -propan-2-ol [diastereomer 1, 2 isomers, Example 91A] in ethanol (54.0 ml), under argon with 135 mg of palladium on carbon (10 ig) and 67.0 mg of palladium hydroxide on carbon (20%) and then stirred overnight under a hydrogen atmosphere at atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue washed with ethanol. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 1.09 g (quant.).

MS (method IC): m / z = 188 [M + H] ⁺ .

Example 93A

4-Benzyl-6-methyl-5-oxomorpholine-3-carboxylic acid [mixture of diastereomers, 4 isomers]

20.0 g (85.0 mmol) of 4-benzyl-5- (hydroxymethyl) -2-methylmorpholin-3-one [diastereomer mixture, 4 isomers] in acetonitrile (1.50 l) were initially charged, and 42.6 g (187 mmol) of periodic acid were added at RT and stirred for 15 min. It was then cooled to 0 ° C and treated with 733 mg (3.40 mmol) of pyridinium chlorochromate in acetonitrile (30 ml). It was stirred for 2 h at 0 ° C and then the reaction solution was concentrated to about 50 ml in vacuo. It was mixed with water (1.00 1) and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 21.4 g (60% of theory, purity: 60%).

LC-MS (Method 1A): R _t = 0.65 min; MS (ESIpos): m / z = 250 [M + H] ⁺ .

Example 94A 4-Benzyl-6-methyl-5-oxomorpholine-3-carboxylic acid methyl ester [mixture of diastereomers, 4 isomers]

21.3 g (crude product) of 4-benzyl-6-methyl-5-oxomorpholine-3-carboxylic acid [diastereomer mixture, 4 isomers] in methanol (500 ml) were cooled to 0 ° C. and 12.5 ml (171 mmol) of thionyl chloride were added slowly , It was stirred for 2 h under reflux and then concentrated completely in vacuo. The crude product was used without further purification in the next step. Yield: 19.8 g (88% of theory, crude product).

LC-MS (Method 1A): R _t = 0.80 min; MS (ESIpos): m / z = 264 [M + H] ⁺ .

Example 95A 4-Benzyl-5- (2-hydroxypropan-2-yl) -2-methylmorpholin-3-one [racemate]

4.00 g (approx. 15.2 mmol, crude product) of 4-benzyl-6-methyl-5-oxomorpholine-3-carboxylic acid methyl ester [diastereomer mixture, 4 isomers] in tetrahydrofuran (55.8 ml) were initially charged at -78 ° C. with 53.2 ml ( 53.2 mmol) of 1M methylmagnesium bromide solution in tetrahydrofuran. It was stirred for 15 min at -78 ° C before being allowed to warm to rt. Subsequently, the reaction solution was added carefully with saturated aqueous ammonium chloride solution (70 ml), the tetrahydrofuran was largely removed in vacuo and the residue taken up in dichloromethane. After separation of the phases, the organic phase was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative RP-HPLC (acetonitrile / water). Yield: 968 mg (24% of theory); on this or one of the previous stages, complete epimerization to one of the two possible diastereomers took place.

LC-MS (Method 4A): R _t = 0.79 min; MS (ESIpos): m / z = 264 [M + H] ⁺ .

Example 96A 2- (4-Benzyl-6-methylmorpholin-3-yl) propan-2-ol [racemate]

967 mg (3.67 mmol) of 4-benzyl-5- (2-hydroxypropan-2-yl) -2-methylmorpholin-3-one [racemate] in tetrahydrofuran (36.1 ml) were initially charged under argon with 7.34 ml (14.7 mmol ) 2 M borane-dimethyl sulfide complex solution in tetrahydrofuran and stirred for 2 h under reflux. Subsequently, the batch was cooled to 0 ° C, cautiously treated with methanol (10 ml) and stirred for 30 min under reflux. It was then completely concentrated in vacuo, the residue taken up in acetonitrile and purified directly by preparative RP-HPLC (acetonitrile / water). Yield: 433 mg (47% of theory).

LC-MS (Method 1A): R _t = 0.44 min; MS (ESIpos): m / z = 250 [M + H] ⁺ . Example 97A

2- (4-Benzyl-6-methylmorpholin-3-yl) propan-2-ol [enantiomerically pure isomer 1]

Enantiomer separation on chiral phase of 433 mg of the compound from Example 96A according to Method 22D gave 179 mg of Example 97A (enantiomerically pure isomer 1) and 183 mg of Example 98A (enantiomerically pure isomer 2). HPLC (Method 18E): R _t = 5.50 min, 99.0% ee;

LC-MS (Method 1A): R _t = 0.43 min; MS (ESIpos): m / z = 250 [M + H] ⁺ .

Example 98A

2- (4-Benzyl-6-methylmorpholin-3-yl) propan-2-ol [enantiomerically pure isomer 2]

Enantiomer separation on chiral phase of 433 mg of the compound from Example 96A according to Method 22D gave 179 mg of Example 97A (enantiomerically pure isomer 1) and 183 mg of Example 98A (enantiomerically pure isomer 2).

HPLC (Method 18E): R _t = 6.88 min, 99.0% ee;

LC-MS (Method 1A): R _t = 0.44 min; MS (ESIpos): m / z = 250 [M + H] ⁺ . Example 99A

2- (6-Methylmorpholin-3-yl) propan-2-ol [enantiomerically pure isomer 1]

179 mg (0.718 mmol) of 2- (4-benzyl-6-methylmorpholin-3-yl) propan-2-ol [enantiomerically pure isomer 1, Example 97 A] in ethanol (7.22 ml) were initially charged under argon 20.9 mg of palladium on carbon (10%) and 10.5 mg of palladium hydroxide on carbon (20%) and then stirred overnight under a hydrogen atmosphere at atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue washed with ethanol. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 94.4 mg (82% of theory).

MS (Method IC): m / z = 160 [M + H] ⁺ .

Example 100A 2- (6-Methylmorpholin-3-yl) propan-2-ol [enantiomerically pure isomer 2]

182 mg (0.730 mmol) of 2- (4-benzyl-6-methylmorpholin-3-yl) -propan-2-ol [enantiomerically pure isomer 2, Example 98A] in ethanol (7.22 ml) were initially charged under argon with 21.3 mg of palladium on charcoal (10%) and 10.6 mg of palladium hydroxide on carbon (20%) and then stirred overnight under a hydrogen atmosphere at atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue washed with ethanol. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 118 mg (quant.).

MS (Method IC): m / z = 160 [M + H] ⁺ .

Example 101A 2-Methyl-2- {[()) -phenylmethylene] amino} propane-1,3-diol

183 g (947 mmol) of 2-amino-2-methylpropane-1,3-diol were suspended in ethyl acetate (200 ml), and under ice-cooling, 103 g (98.6 ml, 970 mmol) of benzaldehyde were added dropwise. Then allowed to warm to RT stirred for 2 h. It was concentrated at 70 ° C in vacuo and the residue used without further purification in the next stage. Yield: 183 g (99% of theory).

Example 102A

2- (benzylamino) -2-methylpropane-l, 3-diol

100 g (951 mmol) of 2-methyl-2- {[(£ ^' ) -phenylmethylene] amino} propane-1,3-diol [Lit .: B. Anxionnat et al., /. Org. Chem. 2012, 77, 6087-6099] presented in ethanol (1.00 1) and at 0 ° C in portions with 71.6 g (1.89 mol) of sodium borohydride added (strong gas evolution). The mixture was allowed to warm to RT and stirred overnight. It was then concentrated under reduced pressure and the residue was taken up in water (700 ml). It was adjusted to about pH = 1 with concentrated aqueous hydrogen chloride solution and extracted with dichloromethane. The aqueous phase was brought to about pH = 10 with 50% aqueous sodium hydroxide solution and then extracted several times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Yield: 151 g (79% of theory). LC-MS (Method 4A): R _t = 1.86 min; MS (ESIpos): m / z = 196 [M + H] Example 103A

A ^{r-benzyl-2-chloro-A} ^r - (l, 3-dihydroxy-2-methylpropan-2-yl) propanamide [racemate]

10.7 g (54.8 mmol) of 2- (benzylamino) -2-methylpropane-1,3-diol in dichloromethane (400 ml) were initially charged, cooled to 0 ° C. and admixed with 8.32 g (11.5 ml, 82.2 mmol) of triethylamine. Subsequently, first 8.35 g (6.52 ml, 65.8 mmol) of 2-chloropropionyl chloride [racemate] and then a further 5.57 g (4.35 ml, 49.3 mmol) of 2-chloropropionyl chloride [racemate] were added dropwise. After stirring for 10 minutes, the reaction solution was concentrated in vacuo, the residue taken up in 1 N aqueous hydrogen chloride solution and extracted several times with dichloromethane. The collected organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 15.6 g (99% of theory).

Example 104A

4-Benzyl-5- (hydroxymethyl) -2,5-dimethylmorpholin-3-one [mixture of diastereomers, 4 isomers]

There were 15.6 g (54.8 mmol) A ^{r-benzyl-2-chloro-A} ^r - (l, 3-dihydroxy-2-methylpropan-2- yl) propanamide [racemate] (300 ml) were charged in isopropanol at 0 ° C cooled and treated with 24.6 g (219 mmol) of potassium ieri-butoxide in one portion. It was stirred overnight, allowing to warm to rt. Zw-propanol was largely removed in vacuo, the residue taken up in 2 N aqueous hydrogen chloride solution (300 ml) and extracted several times with dichloromethane. The organic phases were dried over sodium sulfate, filtered and in vacuo concentrated. The crude product was used without further purification in the next step. Yield: 15.2 g (96% of theory, purity: 86%, diastereomer ratio about 1: 1).

LC-MS (Method 1A): R _t = 0.72 min (diastereomer 1, 2 isomers), R _t = 0.74 min (diastereomer 2, 2 isomers); MS (ESIpos): m / z = 250 [M + H] ⁺ .

Example 105A

4-Benzyl-5 - ({[iperi-butyl (dimethyl) silyl] oxy} methyl) -2,5-dimethylmorpholine-3-one

[Mixture of diastereomers, 4 isomers]

There were 20.0 g (80.2 mmol) of 4-benzyl-5- (hydroxymethyl) -2,5-dimethylmorpholin-3-one [diastereomer mixture, 4 isomers] in / V, / V-dimethylformamide (132 ml) and at RT with 10.9 g (160 mmol) of imidazole are added. Subsequently, 12.7 g (84.2 mmol) of tert-butyldimethylsilyl chloride were added and the mixture was stirred overnight. The reaction solution was concentrated in vacuo, taken up in ethyl acetate, washed several times with water, once with 0.4 N aqueous hydrogen chloride solution, once with saturated aqueous sodium bicarbonate solution and again with water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. Yield: 27.9 g (93% of theory, diastereomer ratio: about 1: 1).

LC-MS (Method 1A): R _t = 1.45 min (diastereomer 1, 2 isomers), R _t = 1.47 min (diastereomer 2, 2 isomers);

MS (ESIpos): m / z = 364 [M + H] ⁺ .

Example 106A

4-Benzyl-5 - ({[ieri-butyl (dimethyl) silyl] oxy} methyl) -2,2,5-trimethylmorpholin-3-one [racemate]

There were 27.9 g (76.7 mmol) of 4-benzyl-5 - ({[ieri-butyl (dimethyl) silyl] oxy} methyl) -2,5-dimethylmorpholin-3-οη [diastereomer mixture, 4 isomers] in tetrahydrofuran (959 ml ) and treated dropwise at -78 ° C with 59.7 ml (107 mmol) of lithium diisopropylamide solution (2.0 M in tetrahydrofuran / w-heptane / Efhyibenzol). It was stirred for 15 min and then treated with 13.1 g (5.73 ml, 92.1 mmol) of iodomethane. The mixture was allowed to warm to rt and stirred for 2 h. It was mixed with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 31.9 g (59% of theory, purity: 54%).

LC-MS (Method 1A): R _t = 1.49 min; MS (ESIpos): m / z = 378 [M + H] ⁺ . Example 107A

4-Benzyl-5- (hydroxymethyl) -2,2,5-trimethylmorpholin-3-one [racemate]

There was obtained 31.8 g (45.5 mmol, purity: 54%) of 4-benzyl-5 - ({[ieri-butyl (dimethyl) silyl] oxy} -methyl) -2,2,5-trimethylmorpholin-3-one [racemate]. in tetrahydrofuran (991 ml) and treated at RT with 158 ml (158 mmol) of tetra-w-butylammonium fluoride solution (1.0 M in tetrahydrofuran). It was stirred overnight at RT and then the reaction solution was concentrated in vacuo. The residue was taken up in dichloromethane and washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The Crude product was then purified by preparative RP-HPLC (acetonitrile / water). Yield: 15.2 g (91% of theory, purity: 72%).

LC-MS (Method 1A): R _t = 0.79 min; MS (ESIpos): m / z = 264 [M + H] ⁺ . Example 108A (4-Benzyl-3,6,6-trimethylmorpholin-3-yl) methanol [racemate]

3.00 g (11.4 mmol) of 4-benzyl-5- (hydroxymethyl) -2,2,5-trimethylmorpholin-3-one [racemate] in tetrahydrofuran (112 ml) were initially charged, under argon with 22.8 ml (45.6 mmol) of 2 M borane-dimethyl sulfide complex solution in tetrahydrofuran and stirred for 2 h under reflux. Subsequently, the batch was cooled to 0 ° C and carefully added with methanol (26 ml). It was stirred for 30 min under reflux and then completely concentrated in vacuo. The crude product was purified by preparative RP-HPLC (acetonitrile / water). Yield: 1.74 g (58% of theory).

LC-MS (Method 1A): R _t = 0.46 min; MS (ESIpos): m / z = 250 [M + H] ⁺ . Example 109A

(3,6,6-Trimethylmorpholin-3-yl) methanol [racemate]

There were 1.74 g (6.98 mmol) of 2 (4-benzyl-3,6,6-trimethylmorpholin-3-yl) methanol [racemate] in ethanol (70.1 ml) and under argon with 200 mg of palladium on carbon (10% ) and 100 mg of palladium hydroxide on carbon (20%) and then submerged overnight Hydrogen atmosphere stirred at atmospheric pressure. The reaction solution was filtered through kieselg and concentrated in vacuo. Yield: 1.16 g (quant.).

MS (Method IC): m / z = 160 [M + H] ⁺ .

Example 110A

There were 15.0 g (63.8 mmol) of 4-benzyl-5- (hydroxymethyl) -2-methylmorpholin-3-one [diastereomer mixture, 4 isomers] in / V, / V-dimethylformamide (600 ml) and charged with 5.10 g (128 mmol, 60% suspension in paraffin oil) of sodium hydride and 22.6 g (9.92 ml, 159 mmol) of iodomethane. It was stirred for 2 h and then the reaction was stopped by the slow addition of water (30 ml). It was concentrated in vacuo, the residue taken up in water and extracted several times with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was taken up in toluene and washed with water and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative RP-HPLC (acetonitrile / water). Yield: 16.7 g (96% of theory).

LC-MS (Method 1A): R _t = 0.82 min; MS (ESIpos): m / z = 250 [M + H] ⁺ .

Example IIIA 5- (Methoxymethyl) -2,2-dimethyl-4- (1-phenylethyl) morpholin-3-one [mixture of diastereomers, 4 isomers]

There were 8.30 g (30.5 mmol) of 4-benzyl-5- (methoxymethyl) -2-methylmorpholin-3-one [diastereomer mixture, 4 isomers] in tetrahydrofuran (381 ml) and at -78 ° C with 21.3 ml (42.7 mmol ) Lithium diisopropylamide solution (1.8 M in tetrahydrofuran / M-heptane / ethylbenzene). After 15 minutes, 5.19 g (2.28 ml, 36.6 mmol) of iodomethane were added at -78 ° C. The mixture was stirred for 2 h while warming to RT. Subsequently, the reaction mixture was admixed with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The collected organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative RP-HPLC (acetonitrile / water). Yield: 3.68 g (43% of theory).

LC-MS (Method 1A): R _t = 0.97 min; MS (ESIpos): m / z = 278 [M + H] ⁺ . Example 112A

5- (methoxymethyl) -2,2-dimethyl-4- (1-phenylethyl) morpholine [mixture of diastereomers, 4 isomers]

3.60 g (13.0 mmol) of 5- (methoxymethyl) -2,2-dimethyl-4- (1-phenylethyl) morpholin-3-one [diastereomer mixture, 4 isomers] in tetrahydrofuran (128 ml) were initially charged under argon with 26.0 ml (51.9 mmol) 2 M borane-dimethyl sulfide complex solution in tetrahydrofuran and then the reaction mixture stirred for 2 h under reflux. Subsequently, the batch was cooled to 0 ° C, carefully mixed with methanol (70 ml) and then stirred for 30 min under reflux. It was then completely concentrated in vacuo, the residue in Acetonitrile and purified directly by preparative RP-HPLC (acetonitrile / water, isocratic). Yield: 2.65 g (73% of theory).

LC-MS (Method 5A): R _t = 0.74 min; MS (ESIpos): m / z = 264 [M + H] ⁺ .

Example 113A 5- (Methoxymethyl) -2,2-dimethylmorpholine [racemate]

2.65 g (10.1 mmol) of 5- (methoxymethyl) -2,2-dimethyl-4- (1-phenylethyl) morpholine [diastereomer mixture, 4 isomers] in ethanol (80.7 ml) were initially charged under argon with 283 mg of palladium on carbon (10%) and 139 mg of palladium hydroxide on carbon (20%) and then stirred overnight under a hydrogen atmosphere under atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue washed with ethanol. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 1.43 g (89% of theory).

GC-MS (Method 2B): R _t = 2.62 min; MS (EIpos): m / z = 160 [M] ⁺ . Example 114A

4-Benzyl-5 - ({[ieri-butyl (dimethyl) silyl] oxy} methyl) -2,2-dimethylmorpholin-3-one [racemate]

17.0 g (70.7 mmol) of 4-benzyl-5 - ({[ieri-butyl (dimethyl) silyl] oxy} methyl) -2-methylmorpholin-3-one [diastereomer mixture, 4 isomers] in tetrahydrofuran (340 ml) were initially charged and at -78 ° C with 32.4 ml (58.4 mmol) of lithium diisopropylamide solution (1.8 M in Tetrahydrofuran / w-heptane / efhylbenzene). It was slowly warmed to 0 ° C and then treated with 8.97 g (3.94 ml, 63.2 mmol) of iodomethane. After 1.5 h, the mixture was recooled to -78 ° C. and 5.40 ml (9.73 mmol) of lithium diisopropylamide solution (1.8 M in tetrahydrofuran / n-heptane / ethylbenzene) were added. It was then warmed to 0 ° C and treated with 2.07 g (0.91 ml, 14.6 mmol) of iodomethane. After 1 h, the reaction solution was added with cooling with water, tetrahydrofuran removed in vacuo, the residue taken up in ethyl acetate and then washed with water and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 19.8 g (98% of theory, purity: 88%).

LC-MS (Method 1A): R _t = 1.45 min; MS (ESIpos): m / z = 364 [M + H] ⁺ .

Example 115A

4-Benzyl-5- (hydroxymethyl) -2,2-dimethylmorpholin-3-one [racemate]

There were 18.1 g (43.8 mmol, purity: 88%) of 4-benzyl-5 - ({[ieri-butyl (dimethyl) silyl] oxy} methyl) -2,2-dimethylmorpholin-3-one [racemate] in tetrahydrofuran ( 329 ml), at RT with 110 ml (110 mmol) of tetra-w-butylammonium fluoride solution (1.0 M in tetrahydrofuran) and stirred overnight. Then the reaction solution was concentrated in vacuo, the residue taken up in ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (dichloromethane, dichloromethane / methanol 100: 3). Yield: 9.99 g (89% of theory).

LC-MS (Method 1A): R _t = 0.73 min; MS (ESIpos): m / z = 250 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-ife): δ [ppm] = 7.43-7.35 (m, 2H), 7.34-7.21 (m, 3H), 5.09-4.98 (m 2H), 4.23 (d, 1H) , 3.90-3.75 (m, 2H), 3.65-3.55 (m, 2H), 3.15 (br. T., 1H), 1.42 (s, 3H), 1.39 (s 3H). Example 116A

4-Benzyl-5- (fluoromethyl) -2,2-dimethylmorpholin-3-one [racemate]

2.00 g (8.02 mmol) of 4-benzyl-5- (hydroxymethyl) -2,2-dimethylmorpholin-3-one [racemate] in tetrahydrofuran (40.1 ml) were initially charged at RT with 8.09 ml (18.8 mmol) of bis ( 2-methoxyethyl) amino sulfur trifluoride (deoxofluor, 50% solution in tetrahydrofuran). Subsequently, 2 drops of ethanol were added and then stirred for 5 h under reflux. The reaction solution was carefully added dropwise into saturated aqueous sodium bicarbonate solution, the phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 2.15 g (87% of theory, purity: 81%).

LC-MS (Method 1A): R _t = 0.91 min; MS (ESIpos): m / z = 252 [M + H] ⁺ .

Example 117A 4-Benzyl-5- (fluoromethyl) -2,2-dimethylmorpholine [racemate]

2.15 g (8.56 mmol) of 4-benzyl-5- (fluoromethyl) -2,2-dimethylmorpholin-3-one [racemate] in tetrahydrofuran (84.2 ml) were initially charged under argon with 17.1 ml (34.2 mmol) of 2M borane - Added dimethyl sulfide complex solution in tetrahydrofuran and stirred under reflux for 2 h. Subsequently, the batch was cooled to 0 ° C, carefully mixed with methanol (10 ml) and Stirred under reflux for 30 min. The mixture was then concentrated completely in vacuo, and the residue was taken up in acetonitrile and purified by preparative RP-HPLC (acetonitrile / water, isocratic). Yield: 1.03 g (43% of theory, purity: 86%).

LC-MS (Method 1A): R _t = 0.85 min; MS (ESIpos): m / z = 238 [M + H] ⁺ . Example 118A

5- (fluoromethyl) -2,2-dimethylmorpholine [racemate]

1.00 g (4.21 mmol) of 4-benzyl-5- (fluoromethyl) -2,2-dimethylmorpholine [racemate] in ethanol (33.8 ml) were initially charged under argon with 99 mg of palladium on carbon (10%) and 50 mg Palladium hydroxide on carbon (20%) and then stirred overnight under a hydrogen atmosphere at atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue washed with ethanol. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 192 g (31% of theory).

GC-MS (Method 2B): R _t = 1.98 min. Example 119A

4-Benzyl-2,5,5-trimethylmorpholine [racemate]

5.10 g (20.3 mmol) of 4-benzyl-2,5,5-trimethylmorpholin-3-one [racemate] in tetrahydrofuran (200 ml) were initially charged under argon with 30.5 ml (61.0 mmol) of 2M borane-dimethyl sulfide complex Added solution in tetrahydrofuran and stirred for 2 h under reflux. The mixture was then cooled to 0 ° C, cautiously added with ethanol (150 ml) and for 2 h under Reflux stirred. It was then concentrated under reduced pressure and the residue was purified by preparative RP-HPLC (acetonitrile / water, isocratic). Yield: 2.42 g (53% of theory).

LC-MS (Method 4A): R _t = 3.04 min; MS (ESIpos): m / z = 236 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.34-7.17 (m, 5H), 3.96 (d, 1H), 3.50-3.36 (m, 2H), 3.25 (d, 1H) , 2.92 (d, 1H), 2.26 (dd, 1H), 2:04 (m _c, 1H), 1:04 (d, 6H), 0.98 (d, 3H).

Example 120A

2,5,5-trimethylmorpholine [racemate]

2.40 g (8.29 mmol) of 4-benzyl-2,5,5-trimethylmorpholine [racemate] in methanol (80 ml) were initially charged under argon with 240 mg of palladium on carbon (10%) and 120 mg of palladium hydroxide on carbon ( 20%) and then stirred overnight under a hydrogen atmosphere at atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue washed with methanol. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 1.12 g (79% of theory). ^H-NMR (400 MHz, DMSO-d _6): δ [ppm] = 3:37 (d, 1H), 3.27 (m _c, 1H), 3.17 (s, 1H), 3:09 (dd, 1H), 1.78 ( br., 1H), 1.08 (s, 3H), 1.01 (d, 3H), 0.87 (s, 3H), one proton not visible.

Example 121A

Methyl [3- (benzyloxy) cyclobutylidene] [(ieri-butoxycarbonyl) amino] acetate

928 mg (3.12 mmol) of methyl [(tert-butoxycarbonyl) amino] (dimethoxyphosphoryl) acetate [racemate] and 500 mg (2.84 mmol) of 3- (benzyloxy) cyclobutanone [K. Ogura, G. Tsuchihashi et al., Bull. Chem. Soc. Jpn. 1984, 57, 1637-1642] in dichloromethane (50 ml), at RT with 605 mg (0.590 ml, 3.97) l, 8-diazabicyclo [5.4.0] undec-7-ene and then stirred overnight. The reaction solution was concentrated in vacuo and the residue taken up in ethyl acetate. The organic phase was washed with water, 0.5 N aqueous hydrogen chloride solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative RP-HPLC (acetonitrile / water). Yield: 651 mg (60% of theory).

LC-MS (Method 1A): R _t = 1.15 min; MS (ESIpos): m / z = 348 [M + H] ⁺ ;

^: H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.11 (br. S., 1H), 7.41-7.25 (m, 5H), 4.42 (s, 2H), 4.13 (quin, 1H ), 3.63 (s, 3H), 3.25 (br, d, 1H), 2.99 (br, d, 1H), 2.85 (br, d, 1H), 2.65 (m, 1H), 1.37 (s, 9H). Example 122A

Methyl [3- (benzyloxy) cyclobutyl] [(feri-butoxycarbonyl) amino] acetate [cis and trans isomer mixture, 4 isomers]

650 mg (1.87 mmol) of methyl [3- (benzyloxy) cyclobutylidene] [(ieri-butoxycarbonyl) -amino] acetate and 455 mg (18.7 mmol) of magnesium turnings in methanol (50 ml) were initially charged and stirred at RT for 3 h in the ultrasonic bath [Elma, Transsonic T 780] implemented. The reaction solution was mixed with half-saturated aqueous ammonium chloride solution and extracted several times with dichloromethane. The organic phases were dried over sodium sulfate, filtered and in vacuo concentrated. The crude product was used without further purification in the next step. Yield: 630 mg (96% of theory).

LC-MS (Method 1A): R _t = 1.16 min; MS (ESIpos): m / z = 350 [M + H] ⁺ , 250 [M + H-COOC (CH ₃ ) ₃ ]; ^: H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.39-7.20 (m, 6H), 4.34 (s, 2H), 4.07 (quin, 0.3H), 3.99-3.73 (m, 1.7 H), 3.60 (s, 3H), 2.34-1.94 (m, 3.5H), 1.74-1.59 (m, 1.5H), 1.45-1.27 (m, 9H).

Example 123A ieri-butyl {1- [3- (benzyloxy) cyclobutyl] -2-hydroxyethyl} carbamate [cis and trans isomer mixture, 4 isomers]

There were 620 mg (1.77 mmol) of methyl [3- (benzyloxy) cyclobutyl] [(tert-butoxycarbonyl) amino] - acetate [cis and iraws isomer mixture, 4 isomers] in tetrahydrofuran (6.0 ml) and at 0 ° C mixed with 4.44 ml (8.87 mmol) of 2 M lithium borohydride solution in tetrahydrofuran. The mixture was then stirred for 4 h while allowing to warm to RT. The reaction was stopped by adding ethyl acetate (50.0 ml) and the reaction solution was then washed with 0.5 N aqueous hydrogen chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 560 mg (96% of theory).

LC-MS (Method 1A): R _t = 0.99 min; MS (ESIpos): m / z = 322 [M + H] ⁺ , 222 [M + H-Boc];

^: H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.47-7.15 (m, 5H), 6.65-6.41 (m, 1H), 4.46 (br. 0.5H), 4.33 (s, 2H ), 3.88-3.70 (m, 0.7H), 3.67-3.09 (m, 3.8H), 2.36-1.78 (m, 3.5H), 1.74-1.48 (1.5H), 1.38 (s, 9H). Example 124A

2-Amino-2- [3- (benzyloxy) cyclobutyl] ethanol trifluoroacetate [cis and iraws isomer mixture, 4 isomers]

560 mg (1.74 mmol) of feri-butyl {1- [3- (benzyloxy) cyclobutyl] -2-hydroxyethyl} carbamate [cis and iraws isomer mixture, 4 isomers] in dichloromethane (8.0 ml) were initially charged at RT added with 1.0 ml (12.9 mmol) of trifluoroacetic acid and stirred for 2 h. Then, the reaction solution was completely concentrated in vacuo and excess trifluoroacetic acid was removed by multiple coevaporation with dichloromethane. The crude product was used without further purification in the next step. Yield: 580 mg (95% of theory).

LC-MS (Method 4A): R _t = 2.10 min; MS (ESIpos): m / z = 222 [M + H-TFA] ⁺ .

Example 125A

N- {1- [3- (benzyloxy) cyclobutyl] -2-hydroxyethyl} -2-chloropropanamide [mixture of diastereomers, 8 isomers]

580 mg (1.73 mmol) of 2-amino-2- [3- (benzyloxy) cyclobutyl] ethanol trifluoroacetate [cis- and iraws isomer mixture, 4 isomers] in w-propanol (15 ml) were initially charged, cooled to 0 ° C and treated with 700 mg (960 μΐ, 6.92 mmol) of triethylamine. Subsequently, 242 mg (190 μΐ, 1.90 mmol) of 2-chloropropionyl chloride [racemate] were added dropwise, stirred for 1 h at 0 ° C and then concentrated completely in vacuo. The residue was treated with 0.5 N aqueous hydrogen chloride solution (50 ml) and extracted several times with dichloromethane. The organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 638 mg (91% of theory, purity: 77%). LC-MS (Method 4A): R _t = 2.36 min; MS (ESIpos): m / z = 312 [M + H] ⁺ . Example 126A

5- [3- (Benzyloxy) cyclobutyl] -2-methylmorpholin-3-one [mixture of diastereomers, 8 isomers]

1.15 g (3.69 mmol) of N- {1- [3- (benzyloxy) cyclobutyl] -2-hydroxyethyl} -2-chloropropanamide [diastereomer mixture, 8 isomers] in ω-propanol (30.0 ml) were initially charged to 0 Cooled ° C and then 1.66 g (14.8 mmol) of potassium ieri-butoxide added in one portion. It was allowed to come to RT and then stirred at 50 ° C for 1 h. The where-propanol was largely removed in vacuo and the residue taken up in ethyl acetate. The organic phase was washed with 1N aqueous hydrogen chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative RP-HPLC (acetonitrile / water). Yield: 953 mg (93% of theory).

LC-MS (Method 1A): R _t = 0.88 min; MS (ESIpos): m / z = 276 [M + H] ⁺ ;

Ή NMR (400 MHz, CDCL): δ [ppm] = 7.43-7.27 (m, 5H), 6.40 (br, s, 0.16H), 6.24 (br, s, 0.38H), 6.12-5.94 ( m, 0.46H), 4.41 (s, 2H), 4.24-4.05 (m, 1.25H), 4.03-3.86 (m, 1.25H), 3.82-3.51 (m, 1.5H), 3.31-3.21 (m, 1H ), 2.54-1.57 (m, 5H), 1.48-1.41 (m, 3H). Example 127A

5- [3- (Benzyloxy) cyclobutyl] -2-methylmorpholine [mixture of diastereomers, 8 isomers]

953 mg (3.46 mmol) of 5- [3- (benzyloxy) cyclobutyl] -2-methylmorpholin-3-one [diastereomer mixture, 8 isomers] in tetrahydrofuran (10 ml) were initially charged under argon with 6.92 ml (13.8 mmol) of 2 M borane-dimethyl sulfide complex solution in tetrahydrofuran and stirred under reflux for 3 h. Subsequently, the reaction solution was carefully added dropwise in ethanol (50.0 ml) and stirred under reflux for 8 h. It was then concentrated under reduced pressure, and the residue was taken up in acetonitrile and purified by preparative RP-HPLC (acetonitrile / water). Yield: 780 mg (84% of theory).

LC-MS (Method 1A): R _t = 0.57, 0.60 min; MS (ESIpos): m / z = 262 [M + H] ⁺ ;

Ή-NMR (400 MHz, DMSO-): δ [ppm] = 7.39-7.24 (m, 5H), 4.37-4.31 (m, 2H), 4.11-3.98 (m, 0.3H), 3.92-3.78 (m , 0.7H), 3.72-3.54 (m, 0.5H), 3.50-3.40 (m, 1.5H), 2.94-2.70 (m, 1H), 2.61 (td, 0.3H), 2.48-1.82 (m, 5.7H ), 1.73-1.40 (m, 2H), 1.06-0.94 (m, 3H), one proton obscured. Example 128A

Benzyl-5- [3- (benzyloxy) cyclobutyl] -2-methylmorpholine-4-carboxylate [mixture of diastereomers, 4 isomers]

There were initially charged 900 mg (3.44 mmol) of 5- [3- (benzyloxy) cyclobutyl] -2-methylmorpholine [mixture of diastereomers, 8 isomers] and 890 mg (1.20 ml, 6.89 mmol) of α-diisopropylethylamine in dichloromethane (45.0 ml) 0 ° C with 881 mg (0.74 ml, 5.17 mmol) of benzyl chloroformate was added dropwise and stirred overnight while allowing to warm to RT. The reaction solution was concentrated in vacuo and the residue taken up in acetonitrile. Purification and diastereomer separation by RP-HPLC on achiral phase (acetonitrile / water) gave 537 mg (36% of theory) of the target compound of Example 128 A (mixture of diastereomers, 4 isomers) and 588 mg (43% of theory) of the target compound of Example 129A (mixture of diastereomers, 4 isomers).

LC-MS (Method 1A): R _t = 1.26 min; MS (ESIpos): m / z = 396 [M + H] ⁺ ;

^: H-NMR (400 MHz, DMSO δ [ppm] = 7.41-7.24 (m, 10H), 5.22-5.01 (m, 2H), 4.33-4.26 (m, 2H), 4.09-3.66 (m, 4H), 3.51 (d, 1H), 3.29-3.10 (m, 2H), 2.82 (br, s, 0.3H), 2.48-1.79 (m, 3.3H), 1.69-1.52 (m, 1.4H), 1.14-1.07 (m, 3H) Example 129A

LC-MS (Method 1A): R _t = 1.29 min; MS (ESIpos): m / z = 396 [M + H] ⁺ ;

^: H-NMR (400 MHz, DMSO-ώ): δ [ppm] = 7.44-7.22 (m, 10H), 5.20-4.98 (m, 2H), 4.36-4.20 (m, 2H), 4.14-3.34 (m , 6H), 2.88-2.57 (m, 1.5H), 2.44-1.53 (m, 4.5H), 1.10-1.03 (m, 3H).

Example 130A 3- (6-Methylmorpholin-3-yl) cyclobutanol [mixture of diastereomers, 4 isomers]

HO 580 mg (1.47 mmol) of benzyl 5- [3- (benzyloxy) cyclobutyl] -2-methylmorpholine-4-carboxylate [Example 129A, mixture of diastereomers, 4 isomers] in ethanol (100 ml) were initially charged under argon with 58 mg Palladium on carbon (10 ig) and 58 mg of palladium hydroxide on carbon (20%) and then stirred overnight under a hydrogen atmosphere under atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue was washed with ethanol. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 245 mg (97% of theory).

GC-MS (Method 1B): R _t = 4.60, 4.67 min; MS (EIpos): m / z = 171 [M] ⁺ ;

^: H NMR (400 MHz, DMSO-ife): δ [ppm] = 4.94-4.84 (m, 1H), 4.16-4.05 (d, 0.6H), 3.93-3.82 (m, 0.7H), 3.55-3.40 (m, 3.3H), 3.19-3.14 (m, 0.7H), 3.17 (d, 1H), 2.47-1.76 (m, 6H), 1.58-1.28 (m, 1.5H), 1.08-0.94 (m, 3.5 H).

Example 131A

[l-Amino-3- (benzyloxy) cyclobutyl] methanol [diastereomeric mixture, 2 isomers, cis / trans ca.

4: 1]

I) There were 5.00 g (20.3 mmol) of 2- (benzyloxy) -5,7-diazaspiro [3.4] octane-6,8-dione [diastereomer mixture, 2 isomers, cis / trans ca. 4: 1; TM Shoup, MM Goodman, J. Labeled. Cpd. Radio Pharm. 1999, 42, 215-225; US2006 / 292073 Al] in water (100 ml) and treated with 32.0 g (102 mmol) of barium hydroxide octahydrate. The suspension was stirred in seven portions in the microwave (Biotage Synthesizer) for 1.5 h at 140 ° C. The suspensions were combined and adjusted to a pH of about 4 with 6 N aqueous sulfuric acid solution. The precipitated solid was filtered off in vacuo, the filtrate was then concentrated in vacuo and the resulting solid dried under high vacuum. 6.2 g of crude product were obtained. Π) 21.3 g (24.9 ml, 196 mmol) of chlorotrimethylsilane were added dropwise to 49.1 ml of 2 M lithium borohydride solution in tetrahydrofuran (98.2 mmol). The resulting suspension was cooled to 0 ° C and then treated portionwise with 5.43 g of the crude product of I). It was then warmed to RT and then stirred at RT overnight. The reaction became by dropwise addition of methanol (15 ml) and the reaction solution was subsequently concentrated in vacuo. The residue was taken up in ethyl acetate and washed with 2 N aqueous sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate, the combined organic phases dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 3.76 g (crude product).

LC-MS (Method 4A): R _t = 2.10 min; MS (ESIpos): m / z = 208 [M + H] ⁺ ;

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.39-7.22 (m, 5H), 4.66 (br, s, 1H), 4.32 (s, 2H), 4.15 (quin, 0.2H ), 3.70 (quin, 0.8H), 3.22-3.14 (m, 2H), 2.34-2.26 (m, 2H), 1.91-1.74 (m, 2H), 1.72-1.61 (m, 2H).

Example 132A ieri-butyl [3- (benzyloxy) -1- (hydroxymethyl) cyclobutyl] carbamate [enantiomerically pure cis and trans isomers]

3.76 g (18.1 mmol) of [l-amino-3- (benzyloxy) cyclobutyl] methanol [diastereomer mixture, 2 isomers cisltrans ca. 4: 1] in dichloromethane (150 ml) were initially charged at room temperature with 4.36 g (20.0 mmol) of di-ieri-butyldicarbonate and 3.86 g (5.31 ml, 38.1 mmol) of triethylamine and stirred at RT overnight. It was then washed with 0.5 N aqueous hydrogen chloride solution, saturated aqueous sodium bicarbonate solution and water, the organic phase dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (6.4 g) was purified by preparative RP-HPLC (method IG) and separated into the diastereomers. The faster eluting major diastereomer was the cw isomer and the slower eluting minor diastereomer was the trans-lsomei. Yield: 3.45 g (61% of theory, enantiomerically pure cis isomer); 690 mg (12% of theory, enantiomerically pure iraws isomer). enantiopure cw diastereomer: LC-MS (Method 1A): R _t = 2.00 min; MS (ESIpos): m / z = 308 [M + H] ⁺ ; enantiomerically pure iraws diastereomer:

LC-MS (Method 1A): R _t = 2.02 min; MS (ESIpos): m / z = 308 [M + H] ⁺ . Example 133A [ds-1-Amino-3- (benzyloxy) cyclobutyl] mefhanol hydrochloride [enantiomerically pure cw isomer] xHCl

3.45 g (11.2 mmol) of tert-butyl [cw-3- (benzyloxy) -l- (hydroxymethyl) cyclobutyl] carbamate [enantiomerically pure cw isomer from Example 132A] in 1,4-dioxane (30 ml) were initially charged , At RT with 11.2 ml of 4 N hydrogen chloride solution in 1,4-dioxane / water and stirred for 20 h at RT. It was then concentrated under reduced pressure and the residue was dried under high vacuum. The crude product was used without further purification in the next step. Yield: 2.81 g (quant.).

LC-MS (Method 1A): R _t = 0.40 min; MS (ESIpos): m / z = 208 [M + H-HC1] ⁺ ;

^: H NMR (400 MHz, DMSO-ife): δ [ppm] = 8.24 (br, s, 3H), 7.43-7.25 (m, 5H), 5.54 (br, s, 1H), 4.39 (s , 2H), 3.90 (quin, 1H), 3.46 (br d, 2H), 2.42 (m _c , 2H), 2.12 (m _c , 2H).

Example 134A

/ V- [cw-3- (benzyloxy) -1- (hydroxymethyl) cyclobutyl] -2-chloropropanamide [racemate]

H

2.81 g (11.5 mmol) of [ds-1-amino-3- (benzyloxy) cyclobutyl] mefhanol hydrochloride [enantiomerically pure cw isomer] in w-propanol (70.0 ml) were initially charged, cooled to 0 ° C. and treated with 4.67 g ( 6.43 ml, 46.1 mmol) of triethylamine. Subsequently, 1.61 g (1.26 ml, 12.7 mmol) of 2-chloropropionyl chloride [racemate] were added dropwise. The reaction solution was allowed to warm to RT, stirred for 1 h, and then the reaction solution was concentrated in vacuo. The residue was taken up in dichloromethane and washed with 1N aqueous hydrogen chloride solution. The organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 3.38 g (97% of theory). LC-MS (Method 1A): R _t = 0.85 min; MS (ESIpos): m / z = 298 [M + H] ⁺ .

Example 135A ds-2- (Benzyloxy) -7-methyl-8-oxa-5-azaspiro [3.5] nonan-6-one [racemate]

There were 3.38 g (11.4 mmol) / V [cw-3- (benzyloxy) -1- (hydroxymethyl) cyclobutyl] -2-chloropropanamid [racemate] in w-propanol (250 ml) presented, cooled to 0 ° C and with 3.82 g (34.1 mmol) of potassium ieri-butoxide in one portion. The mixture was allowed to warm to RT and stirred at 50 ° C for 1 h. Then, where-propanol was largely removed in vacuo and the residue taken up in dichloromethane. The organic phase was washed with 1N aqueous hydrogen chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative RP-HPLC (acetonitrile / water). Yield: 2.96 g (99% of theory).

LC-MS (Method 1A): R _t = 0.86 min; MS (ESIpos): m / z = 262 [M + H] ⁺ .

Example 136A cw-2- (Benzyloxy) -7-methyl-8-oxa-5-azaspiro [3.5] nonane [racemate]

2.96 g (11.3 mmol) of cw-2- (benzyloxy) -7-methyl-8-oxa-5-azaspiro [3.5] nonan-6-one [racemate] in tetrahydrofuran (200 ml) were initially charged, under argon with 22.7 ml (45.3 mmol) 2 M borane-dimethyl sulfide complex solution in tetrahydrofuran and stirred for 2 h under reflux. Subsequently, the reaction solution was cooled to 0 ° C, it was carefully added dropwise methanol (100 ml) and stirred for 12 h at reflux. It was then completely concentrated in vacuo, the residue taken up in acetonitrile and purified directly by preparative RP-HPLC (acetonitrile / water). Yield: 2.80 g (91% of theory).

LC-MS (Method 1A): R _t = 0.61 min; MS (ESIpos): m / z = 248 [M + H] ⁺ . Example 137A ieri-butyl-cw-2- (benzyloxy) -7-methyl-8-oxa-5-azaspiro [3.5] nonane-5-carboxylate [racemate]

2.80 g (11.3 mmol) of cw-2- (benzyloxy) -7-methyl-8-oxa-5-azaspiro [3.5] nonane [racemate] in dichloromethane (150 ml) were initially charged at RT with 3.71 g (17.0 mmol ) Di-ieri-butyldicarbonate and 5.73 g (7.89 ml, 56.6 mmol) of triethylamine and stirred overnight at RT. The reaction solution was washed with 0.5N aqueous hydrogen chloride solution, saturated aqueous sodium hydrogencarbonate solution and water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. Yield: 3.33 g (84% of theory).

LC-MS (Method 1A): R _t = 1.28 min; MS (ESIpos): m / z = 348 [M + H] ⁺ . Example 138A ieri-butyl-cw-2- (benzyloxy) -7-methyl-8-oxa-5-azaspiro [3.5] nonane-5-carboxylate

[enantiomerically pure isomer 1]

Enantiomer separation of 3.33 g of the compound from Example 137A (Method 5D) gave 1.06 g of the compound from Example 138A [enantiomerically pure isomer 1].

HPLC (Method 11E): R _t = 5.06 min, 99.9% ee;

LC-MS (Method 1A): R _t = 1.30 min; MS (ESIpos): m / z = 348 [M + H] ⁺ ;

Ή-NMR (400 MHz, DMSO-ife): δ [ppm] = 7:40 to 7:23 (m, 5H), 4:37 (m _c, 2H), 3.79 (quin, IH), 3.62 (dd, IH), 3.49- 3:33 (m, 3H), 2.69-2.56 (m, 2H), 2:43 (dd, IH), 2:32 to 2:23 (m, IH), 1.78 (m _c, IH), 1:38 (s, 9H), 1:01 (d , 3H).

Example 139A cw-2- (Benzyloxy) -7-methyl-8-oxa-5-azaspiro [3.5] nonane hydrochloride [enantiomerically pure isomer 1]

1.06 g (3.06 mmol) of iperi-butyl-cw-2- (benzyloxy) -7-methyl-8-oxa-5-azaspiro [3.5] nonane-5-carboxylate [enantiomerically pure isomer 1 from Example 138A] in FIG. 1, 4-dioxane (30 ml) submitted and at RT with 10.0 ml of 4 N hydrogen chloride solution in 1,4-dioxane. It was stirred overnight at RT, then concentrated in vacuo and the product was dried under high vacuum. Yield: 1.04 g (quant.).

LC-MS (Method 1A): R _t = 0.48 min; MS (ESIpos): m / z = 248 [M + H-HC1] ⁺ . Example 140A cw-7-methyl-8-oxa-5-azaspiro [3.5] nonan-2-ol hydrochloride [enantiomerically pure isomer 1]

1.03 g (3.66 mmol) of cw-2- (benzyloxy) -7-methyl-8-oxa-5-azaspiro [3.5] nonane hydrochloride [enantiomerically pure isomer 1 from Example 139A] in methanol (36.7 ml) and 3.34 ml of 2 N aqueous hydrogen chloride solution, under argon with 119 mg of palladium on carbon (10 ig) and 59.7 mg of palladium hydroxide on carbon (20%) and then stirred overnight under a hydrogen atmosphere under atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue washed with methanol. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 785 mg (99% of theory). MS (Method IC): m / z = 158 [M + H-HC1] ⁺ ;

^: H NMR (400 MHz, DMSO-ife): δ [ppm] = 9.84 (br, s, 1H), 9.57 (br, s, 1H), 3.78-3.60 (m, 4H), 3.11 (i.e. , 1H), 2.27-2.18 (m, 1H), 2.13-2.00 (m, 2H), 1.09 (d, 3H), three protons obscured.

Example 141A

4-Benzyl-2- [2- (benzyloxy) ethyl] -5 - ({[ieri-butyl (dimethyl) silyl] oxy} methyl) -2-methylmorpholine-3-one [mixture of diastereomers, 4 isomers]

20.5 g (31.3 mmol, purity: 60%) of 4-benzyl-5 - ({[feri-butyl (dimethyl) silyl] oxy} -methyl) -2- (2-hydroxyethyl) -2-methylmorpholine-3- on [mixture of diastereomers, 4 isomers] in N, N-dimethylformamide (205 ml) under argon and treated at 0 ° C with 1.12 g (46.9 mmol, 60% suspension in paraffin oil) of sodium hydride. Subsequently, 4.09 ml (5.88 g, 34.4 mmol) of benzyl bromide were added dropwise and the mixture was stirred at RT overnight. A further 560 mg (23.4 mmol, 60% suspension in paraffin oil) of sodium hydride, 2.04 ml (2.96 g, 17.2 mmol) of benzyl bromide and catalytic amounts of tetra-n-butylammonium iodide (about 50 mg) were added and the reaction continued for 2 h RT stirred. The mixture was then stirred for 1 h at 50 ° C, again 560 mg (23.4 mmol, 60% suspension in paraffin oil) sodium hydride was added and stirred for 1 h at 50 ° C. The reaction mixture was concentrated in vacuo, the residue taken up in ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative RP-HPLC (acetonitrile / water). Yield: 7.19 g (44% of theory). LC-MS (Method 1A): R _t = 1.58 min; MS (ESIpos): m / z = 484 [M + H] ⁺ .

Example 142A

4-Benzyl-2- [2- (benzyloxy) ethyl] -5- (hydroxymethyl) -2-methylmorpholine-3-one

[Mixture of diastereomers, 4 isomers]

There were obtained 7.19 g (13.7 mmol) of 4-benzyl-2- [2- (benzyloxy) ethyl] -5- ({[ieri-butyl (dimethyl) silyl] oxy} methyl) -2-methylmorpholin-3-one [ Diastereomer mixture, 4 isomers] in tetrahydrofuran (100 ml) and at RT with 34.3 ml (34.3 mmol) of tetra-w-butylammonium fluoride solution (1.0 M in tetrahydrofuran). It was stirred for 4 h at RT and then the reaction solution was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, the organic phase dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was then purified by preparative RP-HPLC (acetonitrile / water). Yield: 4.83 g (93% of theory). LC-MS (Method 1A): R _t = 0.99 min; MS (ESIpos): m / z = 370 [M + H] ⁺ .

Example 143A

4-Benzyl-6- [2- (benzyloxy) ethyl] -6-methyl-5-oxo-morpholine-3-carbaldehyde

[Mixture of diastereomers, 4 isomers]

To 4.09 g (2.81 mL, 32.2 mmol) of oxalic acid dichloromethane in dichloromethane (8.0 mL) at -78 ° C was added 4.40 g (4.00 mL, 56.3 mmol) of slow dimethylsulfoxide in dichloromethane (4.0 mL). Subsequently, 3.66 g (9.71 mmol) of 4-benzyl-2- [2- (benzyloxy) ethyl] -5- (hydroxymethyl) -2-methylmorpholin-3-one [diastereomer mixture, 4 isomers] in dichloromethane (8.0 ml) were added. The cold reaction mixture was slowly treated with 10.8 g (14.9 ml, 107 mmol) of triethylamine, the reaction mixture was allowed to warm to rt and stirred overnight. The reaction mixture was poured into water, after phase separation, the organic phase washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (cyclohexane / ethyl acetate 2: 1). Yield: 3.54 g (86% of theory, purity: 86%).

LC-MS (Method 1A :): R _t = 0.94 min (hydrate), R _t = 1.11 min (aldehyde) MS (ESIpos): m / z = 368 [M + H] ⁺ .

Example 144A

4-Benzyl-2- [2- (benzyloxy) ethyl] -5- (difluoromethyl) -2-methylmorpholine-3-one

[Mixture of diastereomers, 4 isomers]

There were initially charged 3.18 g (8.65 mmol) of 4-benzyl-6- [2- (benzyloxy) ethyl] -6-methyl-5-oxomorpholine-3-carbaldehyde [diastereomer mixture, 4 isomers] in dichloromethane (127 ml) and at RT Slowly added to 8.0 ml (18.6 mmol) of bis (2-methoxyethyl) amino sulfur trifluoride (deoxofluor, 50% solution in tetrahydrofuran). Subsequently, 1 drop of methanol was added and then stirred at RT overnight. An additional 8.0 ml (18.6 mmol) of bis (2-methoxyethyl) amino-sulfur trifluoride (deoxofluor, 50% solution in tetrahydrofuran) was added and the mixture was stirred at RT for 48 h. The reaction solution was carefully added dropwise into saturated aqueous sodium bicarbonate solution, the phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was added without further purification used the next stage. Yield: 4.29 g (91% of theory, purity: 71%, diastereomer ratio about 2: 1).

LC-MS (Method 1A :): R _t = 1.22 min (diastereomer 1, 2 isomers), R _t = 1.24 min (diastereomer 2, 2 isomers). MS (ESIpos): m / z = 390 [M + H] ⁺ .

Example 145A

4-Benzyl-2- [2- (benzyloxy) ethyl] -5- (difluoromethyl) -2-methylmorpholine [diastereomer 1, 2 isomers + diastereomer 2, 2 isomers]

There were obtained 4.29 g (7.90 mmol, purity: 71%) of 4-benzyl-2- [2- (benzyloxy) ethyl] -5- (difluoromethyl) -2-methylmorpholin-3-one [mixture of diastereomers, 4 isomers] in tetrahydrofuran ( 80.0 ml), added under argon with 15.8 ml (31.6 mmol) of 2 M borane-dimethyl sulfide complex solution in tetrahydrofuran and stirred for 3 h under reflux. Subsequently, a further 6.0 ml (12.0 mmol) of 2 M borane-dimethyl sulfide complex solution in tetrahydrofuran were added and the mixture was stirred at reflux for 1 h. Then, methanol was added cautiously (40 ml) and stirred for 30 minutes under reflux. It was completely concentrated in vacuo, the residue was purified on an achiral phase by Method 2G and separated into the two diastereomers. Yield: 514 mg (17% of theory, diastereomer 1, 2 isomers, minor isomers); 935 mg (31% of theory, diastereomer 2, 2 isomers, main isomers). LC-MS (Method 1A :): R _t = 1.43 min (diastereomer 1, 2 isomers, minor isomers), R _t = 1.43 min (diastereomer 2, 2 isomers, major isomers); MS (ESIpos): m / z = 376 [M + H] ⁺ . Ή-NMR (400 MHz, DMSO- e): δ [ppm] = 7.38-7.20 (m, 10H), 6.65 (dt, 1H), 4.37 (s, 2H), 3.83 (br. T., 2H), 3.70-3.59 (m, 2H), 3:39 (t, 2H), 2.82 (m _c, 1H), 2.19 (d, 1H), 2:03 (dt, 1H), 1.66 (dt, 1H), 1:09 (s, 3H ), 1 proton obscured, (minor isomers).

Ή-NMR (400 MHz, DMSO δ [ppm] = 7.40-7.16 (m, 10H), 6.43 (dt, 1H), 4.37 (s, 2H), 3.90- 3.80 (m, 2H), 3.73-3.59 (m , 2H), 3:42 (t, 2H), 2.82 (m _c, 1H), 2.60 (d, 1H), 2.11, (d, 1H), 1.89 (dt, 1H), 1.69 (dt, 1H), 1.13 (s , 3H), (main isomers).

Example 146A

2- [5- (difluoromethyl) -2-methylmorpholin-2-yl] ethanol [diastereomer 1, 2 isomers]

510 mg (1.36 mmol) of 4-benzyl-2- [2- (benzyloxy) ethyl] -5- (difluoromethyl) -2-methylmorpholine [diastereomer 1, 2 isomers, minor isomers, Example 145A] in ethanol (63.8 ml). initially charged under argon with 130 mg of palladium on carbon (10 ig) and 65.0 mg of palladium hydroxide on carbon (20 ig) and then stirred overnight under a hydrogen atmosphere at atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue was washed with ethanol. It was concentrated in vacuo and then the product was dried under high vacuum. Yield: 281 mg (99% of theory).

MS (Method IC): m / z = 196 [M + H] ⁺ .

^: H NMR (400 MHz, DMSO δ [ppm] = 5.91 (dt, 1H), 4.28 (t, 1H), 3.61-3.40 (m, 4H), 2.87 (br, s, 1H), 2.67-2.58 (m, 1H), 1.71-1.61 (m, 1H), 1.60-1.50 (m, 1H), 1.18 (s, 3H), 2 protons occluded.

Example 147A

/ V-Benzyl-2-chloro- / V- (1,4-dihydroxybutan-2-yl) propanamide [mixture of diastereomers, 4 isomers]

There were 20.6 g (106 mmol) of 2- (benzylamino) butane-l, 4-diol [racemate] [Lit .: BL Feringa, B. de Lange, Heterocycles 1988, 27, 1197-1205] in w-propanol (500 ml), cooled to 0 ° C and treated with 21.4 g (29.4 ml, 211 mmol) of triethylamine. Subsequently, 16.1 g (12.6 ml, 127 mmol) of 2-chloropropionyl chloride [racemate] were added dropwise. After stirring for 30 minutes, a further 10.4 g (8.37 ml, 84.4 mmol) of 2-chloropropionyl chloride [racemate] were added dropwise and the reaction solution was allowed to warm to RT and then concentrated in vacuo. The residue was taken up in ethyl acetate (500 ml) and washed with 0.5 N aqueous hydrogen chloride solution (400 ml). The aqueous phase was extracted several times with ethyl acetate. The organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 37.5 g (78% of theory, purity: 63%, diastereomer ratio about 2: 1).

LC-MS (Method 1A): R _t = 0.71 min (diastereomer 1, 2 isomers), R _t = 0.72 min (diastereomer 2, 2 isomers); MS (ESIpos): m / z = 286 [M + H] ⁺ .

Example 148A

4-Benzyl-5- (2-hydroxyethyl) -2-methylmorpholin-3-one [mixture of diastereomers, 4 isomers]

There were 37.5 g (82.5 mmol, purity: 63%) A ^r -Benzyl-2-chloro- / V- (l, 4-dihydroxybutan-2-yl) propanamide [diastereomer mixture, 4 isomers] in w-propanol (500 ml ) and cooled to 0 ° C. Then, 73.5 g (655 mmol) of potassium ieri-butoxide was added in one portion and it was stirred for 1 h at 0 ° C. Zso-propanol was largely removed in vacuo, the The residue was taken up in ethyl acetate and washed with 1 N aqueous hydrogen chloride solution (400 ml). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 28.8 g (quant., Purity: 82%, diastereomer ratio about 2.5: 1). LC-MS (method 7A :): R _t = 1.42 min (diastereomer 1, 2 isomers), R _t = 1.46 min (diastereomer 2, 2 isomers);

MS (ESIpos): m / z = 250 [M + H] ⁺ . Example 149A

2- (4-Benzyl-6-methylmorpholin-3-yl) ethanol [mixture of diastereomers, 4 isomers]

28.8 g (94.7 mmol, purity: 82%) of 4-benzyl-5- (2-hydroxyethyl) -2-methylmorpholine-3-one [diastereomer mixture, 4 isomers] in tetrahydrofuran (800 ml) were initially charged under argon with 231 ml (462 mmol) 2 M borane-dimethyl sulfide complex solution in tetrahydrofuran and then stirred under reflux for 2 h. Subsequently, the batch was cooled to 0 ° C, carefully mixed with methanol (220 ml) and stirred for 30 min under reflux. It was then completely concentrated in vacuo. Yield: 19.2 g (crude product).

LC-MS (Method 1A :): R _t = 0.26 min (diastereomer 1, 2 isomers), R _t = 0.28 min (diastereomer 2, 2 isomers).

MS (ESIpos): m / z = 236 [M + H] ⁺ . Example 150A

(4-Benzyl-6-methylmorpholin-3-yl) acetaldehyde [mixture of diastereomers, 4 isomers]

64.7 g (44.5 ml, 510 mmol) of oxalyl chloride in dichloromethane (340 ml) were initially charged and then at -78 ° C. 79.7 g (72.4 ml, 1.02 mol) of dimethyl sulfoxide in dichloromethane (60 ml) were added slowly. Subsequently, 12.0 g (about 51.0 mmol, crude product) of 2- (4-benzyl-6-methylmorpholin-3-yl) ethanol [diastereomer mixture, 4 isomers] in dichloromethane (60 ml) was added and the reaction mixture for 1 h at -78 ° C stirred. The cold reaction mixture was subsequently treated with 155 g (213 ml, 1.53 mol) of triethylamine over 20 min and the reaction mixture was allowed to warm to rt. The reaction mixture was poured into water and, after phase separation, the organic phase was washed with water. It was then dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was then purified by flash chromatography on silica gel (cyclohexane / ethyl acetate 10: 1 - 1: 1). Yield: 7.14 g (48% of theory, purity: 80%).

LC-MS (method 4A :): R _t = 2.57 min; MS (ESIpos): m / z = 234 [M + H] ⁺ . Example 151A 1- (4-Benzyl-6-methylmorpholin-3-yl) propan-2-ol [mixture of diastereomers, 8 isomers]

2.30 g (9.86 mmol) of (4-benzyl-6-methylmorpholin-3-yl) acetaldehyde [diastereomer mixture, 4 isomers] in tetrahydrofuran (42.2 ml) were initially charged at -78 ° C. with 11.8 ml (11.8 mmol) of 1M Methylmagnesiumbromid solution in tetrahydrofuran. It was stirred for 15 min at -78 ° C before being allowed to warm to rt. The reaction solution was cautiously treated with saturated aqueous ammonium chloride solution (70 ml), tetrahydrofuran was largely removed in vacuo and the residue taken up in dichloromethane. After separation of the Phases, the organic phase was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 1.94 g of crude product.

LC-MS (method 4A :): R _t = 2.34 min (diastereomer 1, 2 isomers), R _t = 2.40 min (diastereomer 2, 2 isomers), R _t = 2.47 min (diastereomer 3, 2 isomers); Diastereomer 4, 2 isomers obscured;

MS (ESIpos): m / z = 250 [M + H] ⁺ .

Example 152A 1- (4-Benzyl-6-methylmorpholin-3-yl) acetone [mixture of diastereomers, 4 isomers]

To 9.67 g (6.65 ml, 76.2 mmol) of oxalic acid dichloromethane in dichloromethane (50 ml) was added slowly at -78 ° C 11.9 g (10.8 ml, 152 mmol) of dimethyl sulfoxide in dichloromethane (9.0 ml). Subsequently, 1.90 g (about 7.62 mmol, crude product) of 1- (4-benzyl-6-methylmorpholin-3-yl) propan-2-ol [diastereomer mixture, 8 isomers] in dichloromethane (9.0 ml) was added and the reaction mixture for 1 h stirred at -78 ° C. The cold reaction mixture was subsequently admixed with 23.1 g (31.9 ml, 229 mmol) of triethylamine over the course of 20 minutes, and the reaction mixture was then allowed to warm to RT. The reaction mixture was poured into water and, after phase separation, the organic phase was washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative RP-HPLC (acetonitrile / water). Yield: 544 mg (28% of theory, diastereomer ratio: about 1: 1).

LC-MS (Method 1A :): R _t = 0.45 min (diastereomer 1, 2 isomers), R _t = 0.47 min (diastereomer 2, 2 isomers)

MS (ESIpos): m / z = 248 [M + H] Example 153A 1- (4-Benzyl-6-methylmorpholin-3-yl) -2-methylpropan-2-ol [diastereomer 1, 2 isomers + diastereomer 2, 2 isomers]

544 mg (2.20 mmol) of 1- (4-benzyl-6-methylmorpholin-3-yl) acetone [diastereomer mixture, 4 isomers] in tetrahydrofuran (9.42 ml) were initially charged at -78 ° C. with 2.86 ml (2.86 mmol). 1 M methylmagnesium bromide solution in tetrahydrofuran was added. The mixture was stirred for 15 min at -78 ° C and then allowed to come to RT. Subsequently, the reaction solution was added carefully with saturated aqueous ammonium chloride solution (70 ml), the tetrahydrofuran was largely removed in vacuo and the residue taken up in dichloromethane. After separation of the phases, the organic phase was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative RP-HPLC (acetonitrile / water, isocratic) and separated into the two diastereomers. Yield: 109 mg (19% of theory, diastereomer 1, 2 isomers), 109 mg (19% of theory, diastereomer 2, 2 isomers).

LC-MS (Method 1A :): R _t = 0.49 min (diastereomer 1, 2 isomers), R _t = 0.54 min (diastereomer 2, 2 isomers); MS (ESIpos): m / z = 264 [M + H] ⁺ .

Example 154A

2-methyl-1- (6-methylmorpholin-3-yl) propan-2-ol [diastereomer 2, 2 isomers]

110 mg (0.416 mmol) of 1- (4-benzyl-6-methylmorpholin-3-yl) -2-methylpropan-2-ol [diastereomer 2, 2 isomers, Example 153A] in ethanol (4.2 ml) were initially charged Argon with 10.4 mg of palladium on carbon (10%) and 5.2 mg of palladium hydroxide on carbon (20%) and then stirred overnight under a hydrogen atmosphere at atmospheric pressure. The Reaction solution was filtered through kieselguhr and the filter residue washed with ethanol. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 74.4 mg (quant.).

MS (Method IC): m / z = 174 [M + H] ⁺ . Example 155A

/ V-Benzyl-2-chloro / V - [(2R) -l, 4-dihydroxybutan-2-yl] propanamide [mixture of diastereomers, 2 isomers]

There were 45.1 g (55.3 mmol, purity: 72%) of (2R) -2- (benzylamino) butane-l, 4-diol [B. L. Feringa, Tetrahedron 1989, 45, 6799-6818] in w-propanol (239 ml), cooled to 0 ° C and treated with 11.2 g (15.4 ml, 111 mmol) of triethylamine. Subsequently, 10.5 g (8.23 ml, 83.0 mmol) of 2-chloropropionyl chloride [racemate] were added dropwise. After stirring for 10 minutes, the reaction solution was concentrated in vacuo, the residue taken up in ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 21.4 g (quant., Purity: 82%, diastereomer ratio about 3: 2).

LC-MS (Method 1A): R _t = 0.65 min (enantiomerically pure isomer 1), R _t = 0.67 min (enantiomerically pure isomer 2);

MS (ESIpos): m / z = 286 [M + H] ⁺ . Example 156A

(5R) -4-Benzyl-5- (2-hydroxyethyl) -2-methylmorpholin-3-one [mixture of diastereomers, 2 isomers]

There were 21.4 g (62.1 mmol, purity: 82%) of N-benzyl-2-chloro-N - [(2R) -l, 4-dihydroxybutan-2-yl] propanamide [diastereomer mixture, 2 isomers] in w-propanol ( 335 ml), cooled to 0 ° C and then combined with 27.9 g (249 mmol) of potassium ieri-butoxide in one portion. It was stirred overnight, allowing the reaction to warm to rt. Λο-Propanol was largely removed in vacuo, the residue taken up in water (300 ml) and extracted with ethyl acetate. The organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 13.3 g (69% of theory, purity: 81%, diastereomer ratio about 3: 2). LC-MS (Method 7 A): R _t = 3.23 min (enantiomerically pure isomer 1), R _t = 3.34 min (enantiomerically pure isomer 2);

MS (ESIpos): m / z = 250 [M + H] ⁺ .

Example 157A

(5R) -4-Benzyl-5- (2- {[ieri-butyl (dimethyl) silyl] oxy} ethyl) -2-methylmorpholin-3-one

[Mixture of diastereomers, 2 isomers]

There were 13.3 g (43.3 mmol) of (5R) -4-benzyl-5- (2-hydroxyethyl) -2-methylmorpholin-3-one [diastereomer mixture, 2 isomers] in / VN-dimethylformamide (60.0 ml) and at RT with 8.85 g (130 mmol) of imidazole added. Subsequently, at 0 ° C., 9.80 g (65.0 mmol) of tert-butyldimethylsilyl chloride were added and the mixture was stirred overnight while the reaction solution was allowed to warm to RT. The mixture was subsequently concentrated in vacuo, taken up in ethyl acetate and washed several times with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was then purified by chromatography on silica gel (cyclohexane / ethyl acetate 6: 1, then cyclohexane / ethyl acetate 5: 1). Yield: 8.03 g (49% of theory, diastereomer ratio: about 2.3: 1). LC-MS (Method 1A): R _t = 1.41 min; MS (ESIpos): m / z = 364 [M + H] ⁺ ;

^: H-NMR (400 MHz, DMSO δ [ppm] = 7.40-7.18 (m, 5H), 5.12-5.03 (m, 1H), 4.33-4.21 (m, 1H), 4.14 (d, 0.3H), 4.05 (m, 0.7H), 3.95-3.84 (m, 1H), 3.74-3.56 (m, 3H), 3.39 (dd, 0.3H), 3.28 (d, 0.7H), 1.98-1.70 (m, 2H), 1.39 (d, 0.9H), 1.35 (d, 2.1H), 0.82 (s, 9H), 0.02 (s, 1.8H), 0.00 (s, 4.2H) Example 158A

(5R) -4-Benzyl-5- (2- {[ieri-butyl (dimethyl) silyl] oxy} ethyl) -2,2-dimethylmorpholin-3-one

[enantiomerically pure isomer]

There were 7.00 g (18.6 mmol) of (5R) -4-benzyl-5- (2- {[ieri-butyl (dimethyl) silyl] oxy} ethyl) -2-methylmorpholin-3-οη [diastereomer mixture, 2 isomers] in Submitted tetrahydrofuran (233 ml) and treated dropwise at -78 ° C with 13.0 ml (26.1 mmol) of lithium diisopropylamide solution (2.0 M in tetrahydrofuran / w-heptane / Efhylbenzol). It was stirred for 15 min and then admixed with 3.17 g (1.39 ml, 22.4 mmol) of iodomethane. The reaction solution was allowed to warm to RT and stirred for 2 h. The reaction was stopped by adding saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 8.36 g (70% of theory, purity: 59%).

LC-MS (Method 1A): R _t = 1.47 min; MS (ESIpos): m / z = 378 [M + H] ⁺ . Example 159A

(5R) -4-Benzyl-5- (2- {[iper] butyl (dimethyl) silyl] oxy} ethyl) -2,2-dimethylmorpholine

[enantiomerically pure isomer]

8.36 g (13.1 mmol, purity: 59%) of (5R) -4-benzyl-5- (2- {[ieri-butyl (dimethyl) silyl] oxy} ethyl) -2,2-dimethylmorpholine-3- on [enantiomerically pure isomer] in tetrahydrofuran (133 ml), added under argon with 26.2 ml (52.3 mmol) 2 M borane-dimethyl sulfide complex solution in tetrahydrofuran and stirred under reflux for 4 h. It was then cooled to 0 ° C, cautiously with methanol (30 ml), stirred for 30 min under reflux and then concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 8.39 g (96% of theory, purity: 55%).

LC-MS (Method 1A): R _t = 1.15 min; MS (ESIpos): m / z = 364 [M + H] ⁺ . Example 160A

2 - [(3R) -4-Benzyl-6,6-dimethylmorpholin-3-yl] ethanol [mixture of enantiomers, 2 isomers]

There were obtained 7.39 g (11.2 mmol, purity: 55%) of (5R) -4-benzyl-5- (2- {[ieri-butyl (dimethyl) silyl] oxy} ethyl) -2,2-dimethylmorpholine [enantiomerically pure isomer ] in tetrahydrofuran (148 ml) and at RT with 30.5 ml (30.5 mmol) of tetra-w-butylammonium fluoride solution (1.0 M in tetrahydrofuran). It was stirred for 1 h at RT and then concentrated in vacuo. The residue was purified by preparative RP-HPLC (acetonitrile / water, isocratic). Yield: 1.97 g (38% of theory, enantiomeric ratio: about 85:15); at this stage, a proportionate isomerization of the stereocenter was found on one of the previous precursors.

HPLC (method 7E): R _t = 4.41 min, 85:15 R: S enantiomer ratio;

LC-MS (Method 1A): R _t = 0.35 min; MS (ESIpos): m / z = 250 [M + H] ⁺ ; Ή-NMR (400 MHz, DMSO-d _6): δ [ppm] = 7.31 (d, 4H), 7.22 (m _c, IH), 4.45 (t, IH), 3.93 (d, IH), 3.60 (dd , IH), 3.54-3.40 (m, 3H), 3.10 (d, IH), 2.40-2.29 (m, 2H), 1.85 (d, IH), 1.79-1.69 (m, IH), 1.59 (m _c , IH), 1.14 (s, 3H), 1.04 (s, 3H).

Example 161A

2 - [(3R) -6,6-Dimethylmorpholin-3-yl] ethanol [mixture of enantiomers, 2 isomers]

1.00 g (4.01 mmol) of 2 - [(3R) -4-benzyl-6,6-dimethylmorpholin-3-yl] ethanol [enantiomer mixture, enantiomer ratio: about 85:15] in ethanol (40.0 ml) were initially charged, under argon with 150 mg of palladium on carbon (10%) and 150 mg of palladium hydroxide on carbon (20%) and then stirred for 4 h under a hydrogen atmosphere under atmospheric pressure. The reaction solution was filtered through kieselguhr and concentrated in vacuo. Yield: 680 mg (quant.).

GC-MS (Method 2B): R _t = 3.71 min; MS (EIpos): m / z = 159 [M] ⁺ ;

^: H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm] = 4.32 (br.s .., IH), 3.46 (t, 2H), 3.38 (dd, IH), 3.21 (t, IH), 2.64-2.54 (m, 2H), 2.47-2.42 (m, IH), 1.36 (m _c , 2H), 1.18 (s, 3H), 1.02 (s, 3H), one proton obscured.

Example 162A

4-Benzyl-5 - [(difluoromethoxy) methyl] -2-methylmorpholin-3-one [mixture of diastereomers, 4 isomers]

4.03 g (17.1 mmol) of 4-benzyl-5- (hydroxymethyl) -2-methylmorpholin-3-one [diastereomer mixture, 4 isomers] in acetonitrile (80 ml) were initially charged and then the solution was degassed by passing in argon for 5 min , Subsequently, 652 mg (3.43 mmol) of copper (I) iodide were added and the reaction mixture was heated to 55 ° C. Subsequently, a solution of 5.49 g (3.19 ml, 30.8 mmol) of difluoro (fluorosulfonyl) acetic acid in degassed acetonitrile (10 ml) was added dropwise within 30 min and stirred for 3 h at 55 ° C. The reaction solution was concentrated in vacuo, the residue was combined with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was then purified by preparative RP-HPLC (acetonitrile / water, isocratic). Yield: 3.15 g (64% of theory).

LC-MS (Method 1A): R _t = 0.92 min; MS (ESIpos): m / z = 286 [M + H] ⁺ .

Example 163A

2-Allyl-4-benzyl-5 - [(difluoromethoxy) methyl] -2-methylmorpholin-3-one [mixture of diastereomers, 4 isomers]

There were 8.30 g (29.1 mmol) of 4-benzyl-5 - [(difluoromethoxy) methyl] -2-methylmorpholin-3-one [diastereomer mixture, 4 isomers] in tetrahydrofuran (364 ml), under argon at -78 ° C with 69.8 ml (69.8 mmol) of 1 M lithium hexamethyldisilazide solution in tetrahydrofuran are added and then the reaction mixture is stirred for 15 min. Subsequently, 14.7 g (7.98 ml, 87.3 mmol) of allyl iodide was added dropwise at -78 ° C, the reaction mixture was warmed to RT and stirred overnight. The reaction was stopped by adding saturated aqueous ammonium chloride solution and then extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 9.92 g (94% of theory).

LC-MS (Method 1A): R _t = 1.09 min; MS (ESIpos): m / z = 326 [M + H] ⁺ .

Example 164A

{4-Benzyl-5- [(1,1-difluoroethoxy) methyl] -2-methyl-3-oxomorpholin-2-yl-Jacetaldehyde

[Mixture of diastereomers, 4 isomers]

There were 10.5 g (30.9 mmol) of 2-allyl-4-benzyl-5 - [(difluoromethoxy) methyl] -2-methylmorpholine-3-one (mixture of diastereomers, 4 isomers) in tetrahydrofuran (250 ml) and water (150 ml). initially charged at 0 ° C with 1.68 ml (0.618 mmol) of 2.5% osmium tetroxide solution in ieri-butanol and 19.8 g (92.6 mmol) of sodium periodate. It was then warmed to RT and stirred overnight. The reaction solution was filtered through kieselguhr and the filter residue washed with tetrahydrofuran. The reaction solution was taken up in ethyl acetate and diluted with water. After separation of the phases, the organic phase was washed with 1 N aqueous sodium sulfite solution (2 × 800 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 9.30 g of crude product.

LC-MS (Method 1A): R _t = 0.96 min; MS (ESIpos): m / z = 328 [M + H] ⁺ . Example 165A

4-Benzyl-5 - [(difluoromethoxy) methyl] -2- (2-hydroxyethyl) -2-methylmorpholin-3-one

[Mixture of diastereomers, 4 isomers]

There were 3.00 g (about 5.96 mmol, crude product) of {4-benzyl-5 - [(1, 1-difluoroethoxy) methyl] -2-methyl-3-oxomorpholin-2-yl} acetaldehyde [diastereomer mixture, 4 isomers] in Submitted methanol (44.4 ml) and treated at 0 ° C with 676 mg (17.9 mmol) of sodium borohydride. It was then warmed to RT and stirred for 30 min. The reaction solution was added with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 2.66 g (83% of theory, purity: 61%).

LC-MS (Method 1A :): R _t = 0.83 min (diastereomer 1, 2 isomers), R _t = 0.85 min (diastereomer 2, 2 isomers).

MS (ESIpos): m / z = 330 [M + H] ⁺ .

Example 166A

2- {4-Benzyl-5 - [(difluoromethoxy) methyl] -2-methylmorpholin-2-yl, Jethanoi [enantiomerically pure

Isomer 2]

There were 2.66 g (4.96 mmol, purity: 61%) of 4-benzyl-5 - [(difluoromethoxy) methyl] -2- (2-hydroxyethyl) -2-methylmorpholin-3-one [mixture of diastereomers, 4 isomers] in tetrahydrofuran ( 50 ml), under argon with 9.91 ml (19.8 mmol) 2 M borane-dimethylsulfide complex Solution in tetrahydrofuran and then the reaction mixture stirred for 2 h under reflux. Subsequently, the batch was cooled to 0 ° C, cautiously mixed with methanol (45 ml) and then stirred for 30 min under reflux. It was then completely concentrated in vacuo, the residue taken up in acetonitrile and purified directly by preparative RP-HPLC (acetonitrile / water). The isomer mixture was separated on chiral phase according to Method 43D and 44D. Yield: 316 mg (19% of theory, enantiomerically pure isomer 2).

HPLC (Method 37E): R _t = 8.60 min,> 99.0% ee;

LC-MS (Method 1A): R _t = 0.80 min; MS (ESIpos): m / z = 316 [M + H] ⁺ ; ^H-NMR (400 MHz, DMSO-ife): δ [ppm] = 7.32 (d, 1H), 7.24 (m _c, 1H), 6.67 (t, 1H), 4.22 (t, 1H), 4:06 (dd , 1H), 3.96 (dd, 1H), 3.90 (d, 1H), 3.69 (dd, 1H), 3.54 (dd, 1H), 3.47-3.32 (m, 3H), 2.63-2.55 (m, 1H), 2:36 (d, 1H), 2:04 (d, 1H), 1.80 (m _c, 1H), 1:49 (m _c, 1H), 1.12 (s, 3H).

Example 167A

2- {5 - [(Difluoromethoxy) methyl] -2-methylmorpholin-2-yl} ethanol [enantiomerically pure isomer 2]

There were introduced 310 mg (0.983 mmol) 2- {4-benzyl-5 - [(difluoromethoxy) methyl] -2-methylmorpholin-2-yljethanol [enantiomerically pure isomer 2] in ethanol (20.0 ml), under argon with 50 mg of palladium on carbon (10%) and 25 mg of palladium hydroxide on carbon (20%) and then stirred overnight under a hydrogen atmosphere under atmospheric pressure. The reaction solution was filtered through kieselguhr and concentrated in vacuo. Yield: 198 mg (85% of theory).

MS (Method IC): m / z = 226 [M] ⁺ ; Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 6.66 (t, 1H), 4.25 (t, 1H), 3.71 (dd, 2H), 3.53-3.43 (m, 3H), 2.84- 2.74 (m, 1H), 2.60 (d, 1H), 2.29 (br., 1H), 1.57 (m _c , 2H), 1.18 (s, 3H), two protons concealed.

Example 168A 2-Allyl-4-benzyl-2-methylmorpholin-3-one [racemate]

There were 20.0 g (97.4 mmol) of 4-benzyl-2-methylmorpholin-3-one [racemate] [R. Perrone et al., Synthesis 1976, 9, 598-600] in tetrahydrofuran (500 ml), under argon at -78 ° C with 136 ml (136 mmol) 1 M Lithiumhexamethyldisilazid solution in tetrahydrofuran and then the reaction mixture for 15 stirred for a few minutes. Subsequently, at -78 ° C., 19.6 g (10.7 ml, 117 mmol) of allyl iodide were added, the reaction mixture was warmed to RT and stirred overnight. The mixture was subsequently cooled to 0 ° C., admixed again with 68 ml (68 mmol) of 1 M lithium hexamethyldisilazide solution in tetrahydrofuran and 9.80 g (5.35 ml, 56.5 mmol) and stirred at RT for 3 h. The reaction was started by adding saturated aqueous ammonium chloride Solution and then extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 25.8 g (73% of theory, purity: 67%).

LC-MS (Method 1A): R _t = 0.97 min; MS (ESIpos): m / z = 246 [M + H] ⁺ . Example 169A

(4-Benzyl-2-methyl-3-oxomorpholin-2-yl) acetaldehyde [racemate]

There were charged 6.40 g (26.1 mmol) of 2-allyl-4-benzyl-2-methylmorpholin-3-one [racemate] in tetrahydrofuran (400 ml) and water (250 ml) and at 0 ° C with 6.55 ml (2.41 mmol ) 2.5 g Osmiumtetroxid solution in ieri-butanol and 16.7 g (78.3 mmol) of sodium periodate added. It was then warmed to RT and stirred for 20 h. The reaction solution was filtered through kieselguhr and the filter residue washed with tetrahydrofuran. The reaction solution was taken up in ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 6.99 g of crude product.

LC-MS (Method 1A): R _t = 0.78 min; MS (ESIpos): m / z = 248 [M + H] ⁺ .

Example 170A

4-Benzyl-2- (2-hydroxyethyl) -2-methylmorpholin-3-one [racemate]

There were 6.99 g (about 28.3 mmol, crude product) (4-benzyl-2-methyl-3-oxomorpholin-2-yl) acetaldehyde [racemate] in methanol (120 ml) and at 0 ° C with 3.04 g (80.4 mmol) sodium borohydride. It was then warmed to RT and stirred for 30 min. The reaction solution was mixed with water, the methanol was largely removed in vacuo and the residue is extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 5.80 g (82% of theory, crude product).

LC-MS (Method 2A): R _t = 0.67 min; MS (ESIpos): m / z = 250 [M + H] ⁺ . Example 171A

2- (4-Benzyl-2-methylmorpholin-2-yl) ethanol [racemate]

5.80 g (about 23.3 mmol, crude product) of 4-benzyl-2- (2-hydroxyethyl) -2-methylmorpholin-3-one [racemate] in tetrahydrofuran (230 ml) were initially charged, under argon with 116 ml (233 mmol ) 2M borane-dimethyl sulfide complex solution in tetrahydrofuran and then the reaction mixture was stirred for 1 h under reflux. Subsequently, the batch was cooled to RT, carefully mixed with ethanol (90 ml) and then stirred for 1 h under reflux. It was then completely concentrated in vacuo, the residue taken up in acetonitrile and purified directly by preparative RP-HPLC (acetonitrile, water, isocratic). Yield: 4.58 g (83% of theory).

LC-MS (Method 4A): R _t = 2.42 min; MS (ESIpos): m / z = 236 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.36-7.21 (m, 5H), 4.27 (t, 1H), 3.59 (t, 2H), 3.48-3.39 (m, 4H) , 2.29 (br. D., 2H), 2.18 (d, 1H), 2.09 (d, 1H), 1.91 (dt, 1H), 1.56 (dt, 1H), 1.13 (s, 3H).

Example 172A 2- (2-Methylmorpholin-2-yl) ethanol [racemate]

4.65 g (19.8 mmol) of 2- (4-benzyl-2-methylmorpholin-2-yl) ethanol [racemate] in ethanol (200 ml) were initially charged under argon with 465 mg palladium on charcoal (10%) and 235 mg Palladium hydroxide on carbon (20%) and then stirred for 36 h under a hydrogen atmosphere under atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue washed with methanol. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 2.66 g (90% of theory).

MS (Method 2C): m / z = 146 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-ife): δ [ppm] = 3.53-3.38 (m, 4H), 2.58 (dd, 1H), 2.52 (d, 1H), 2.43 (d, 1H), 1.84 ( dt, 1H), 1.55 (dt, 1H), 1.09 (s, 3H), two protons not visible.

Example 173A

Benzyl 2- (2-hydroxyethyl) -2-methylmorpholine-4-carboxylate [racemate]

1.85 g (12.7 mmol) of 2- (2-methylmorpholin-2-yl) ethanol [racemate] in dichloromethane (25.5 ml) were initially charged at 0.degree. C. with 2.13 g (2.93 ml, 21.0 mmol) of triethylamine followed by dropwise addition 3.57 g (3.00 ml, 21.0 mmol) of benzyl chloroformate were added. The reaction solution was warmed to RT and stirred overnight. The reaction solution was diluted with dichloromethane and washed once each with 1 N aqueous hydrogen chloride solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was in Acetonitrile and purified directly by preparative RP-HPLC (acetonitrile / water). Yield: 2.61 g (73% of theory).

LC-MS (Method 1A): R _t = 0.83 min; MS (ESIpos): m / z = 280 [M + H] ⁺ . Example 174A Benzyl 2-methyl-2- (2-oxoethyl) morpholine-4-carboxylate [racemate]

3.61 g (2.48 ml, 28.5 mmol) of oxalyl chloride in dichloromethane (63 ml) were initially charged and then 2.15 g (1.95 ml, 27.5 mmol) of dimethylsulfoxide in dichloromethane (11 ml) were slowly added at -78 ° C. After 30 minutes, 2.65 g (9.49 mmol) of benzyl 2- (2-hydroxyethyl) -2-methylmorpholine-4-carboxylate [racemate] in dichloromethane (11 ml) was added. The cold reaction mixture was treated slowly after 30 minutes (20 min) with 5.76 g (7.93 ml, 56.9 mmol) of triethylamine and then the reaction mixture was warmed to RT and stirred overnight. The reaction mixture was poured into water and, after phase separation, the organic phase was washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product obtained was purified by flash chromatography on silica gel (cyclohexane / ethyl acetate 10: 1 - 1: 1). Yield: 2.99 g (96% of theory, purity: 85%).

LC-MS (Method 1A): R _t = 0.90 min; MS (ESIpos): m / z = 278 [M + H] ⁺ .

Example 175A Benzyl 2- (2-hydroxypropyl) -2-methylmorpholine-4-carboxylate [enantiomerically pure isomer 2]

2.99 g (9.16 mmol, purity: 85%) of benzyl 2-methyl-2- (2-oxo-ethyl) -morpholine-4-carboxylate [racemate] in tetrahydrofuran (39.2 ml) were initially charged at -78 ° C. with 11.0 ml (11.0 mmol) 1M methylmagnesium bromide solution in tetrahydrofuran. The mixture was stirred for 15 min at -78 ° C and then warmed to RT. Then, the reaction solution was added carefully with saturated aqueous ammonium chloride solution (70 ml), the tetrahydrofuran was largely removed in vacuo and the residue taken up in dichloromethane. After separation of the phases, the organic phase was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was taken up in acetonitrile and purified directly by preparative RP-HPLC (acetonitrile / water). The isomer mixture was repeatedly separated on a chiral phase according to Method 45D. Yield: 362 mg (14% of theory, enantiomerically pure isomer 2).

HPLC (Method 39E): R _t = 6.84 min,> 95% ee;

LC-MS (Method 1A): R _t = 0.91 min; MS (ESIpos): m / z = 294 [M + H] ⁺ . Example 177A 1- (2-Methylmorpholin-2-yl) propan-2-ol [enantiomerically pure isomer 2]

362 mg (1.23 mmol) of benzyl 2- (2-hydroxypropyl) -2-methylmorpholine-4-carboxylate [enantiomerically pure isomer 2] in ethanol (12.4 ml) were initially charged, under argon, with 36.0 mg of palladium on carbon (10% strength by weight) and 18.0 mg of palladium hydroxide on carbon (20%) and then stirred overnight under a hydrogen atmosphere under atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue washed with ethanol. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 198 mg (100% of theory).

MS (Method 2C): m / z = 160 [M + H] ⁺ . Example 178A

[4-Benzyl-6,6-dimethylmorpholin-3-yl] acetaldehyde [enantiomeric mixture, 2 isomers]

800 mg (550 μΐ, 6.30 mmol) of oxalic acid dichloride in dichloromethane (20 ml) were initially charged and then, at -78 ° C., 861 mg (782 μΐ, 11.0 mmol) of dimethyl sulfoxide in dichloromethane (5.0 ml) were slowly added. Subsequently, 947 mg (3.80 mmol) of 2 - [(3R) -4-benzyl-6,6-dimethylmorpholin-3-yl] ethanol [enantiomeric mixture, 2 isomers] in dichloromethane (6.0 ml) were added and the reaction mixture was added for 1 h -78 ° C stirred. The cold reaction mixture was subsequently treated with 2.11 g (2.91 ml, 20.9 mmol) of triethylamine over the course of 20 minutes, and then the reaction mixture was warmed to RT. The reaction mixture was poured into water and, after phase separation, the organic phase was washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was then purified by flash chromatography on silica gel (cyclohexane / ethyl acetate 10: 1). Yield: 860 mg (91% of theory); proportional isomerization.

LC-MS (Method 1A :): R _t = 0.49 min; MS (ESIpos): m / z = 249 [M + H] ⁺ ; ^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 9.78 (t, 1H), 7.37-7.16 (m, 5H), 3.81 (d, 1H), 3.67 (dd, 1H), 3.52 (dd, 1H), 3.16 (d, 1H), 2.89-2.80 (m, 1H), 2.72-2.64 (m, 2H), 2.32 (d, 1H), 1.92 (d, 1H), 1.13 (s, 3H ), 1.08 (s, 3H).

Example 179A 1- [4-Benzyl-6,6-dimethylmorpholin-3-yl] -propan-2-ol [mixture of diastereomers, 4 isomers]

860 mg (3.48 mmol) of [4-benzyl-6,6-dimethylmorpholin-3-yl] acetaldehyde [enantiomer mixture, 2 isomers] in tetrahydrofuran (14.9 ml) were initially charged at -78 ° C. with 4.17 ml (4.17 mmol) 1 M methylmagnesium bromide solution in tetrahydrofuran was added. The mixture was stirred for 15 min at -78 ° C and then warmed to RT. Subsequently, the reaction solution was added carefully with saturated aqueous ammonium chloride solution (50 ml), the tetrahydrofuran was largely removed in vacuo and the residue taken up in dichloromethane. After separation of the phases, the organic phase was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified directly by preparative RP-HPLC (acetonitrile / water, isocratic). Yield: 571 mg (62% of theory, diastereomer ratio about 1: 1).

LC-MS (Method 1A :): R _t = 0.47 min (diastereomer 1, 2 isomers), R _t = 0.50 min (diastereomer 2, 2 isomers).

MS (ESIpos): m / z = 264 [M + H] ⁺ . Example 180A 1- [6,6-dimethylmorpholin-3-yl] propan-2-ol [mixture of diastereomers, 4 isomers]

565 mg (2.15 mmol) of 1- [4-benzyl-6,6-dimethylmorpholin-3-yl] -propan-2-ol [diastereomer mixture, 4 isomers] in ethanol (21.6 ml) were initially charged under argon with 53.9 mg of palladium on carbon (10%) and 27.0 mg of palladium hydroxide on carbon (20%) and then stirred overnight under a hydrogen atmosphere under atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue with ethanol rewashed. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 366 mg (98% of theory).

MS (Method 2C): m / z = 174 [M + H] ⁺ .

Example 181A A ^{r-benzyl-2-chloro-} / V - [(2 _l ^r S) -l, 4-dihydroxybutane-2-yl] propanamide [mixture of diastereomers, isomers 2]

There were 45.1 g (199 mmol, purity: 86%) of (2S) -2- (benzylamino) butane-l, 4-diol [F. Horiuchi, M. Matsui, Agr. Biol. 1973, 37, 1713-1716] in w-propanol (1.00 1), cooled to 0 ° C and treated with 40.2 g (55.4 ml, 397 mmol) of triethylamine. Subsequently, 37.8 g (29.6 ml, 298 mmol) of 2-chloropropionyl chloride [racemate] were added dropwise. After stirring for 30 minutes, a further 18.9 g (14.8 ml, 149 mmol) of 2-chloropropionyl chloride [racemate] were added dropwise and the reaction solution was allowed to warm to RT and then concentrated in vacuo. The residue was taken up in ethyl acetate (1.00 l) and washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 71.8 g (quant., Purity: 82%, diastereomeric ratio about 1: 1).

LC-MS (Method 1A): R _t = 0.65 min (enantiomerically pure isomer 1), R _t = 0.67 min (enantiomerically pure isomer 2); MS (ESIpos): m / z = 286 [M + H] ⁺ .

Example 182A

(5S) -4-Benzyl-5- (2-hydroxyethyl) -2-methylmorpholin-3-one [mixture of diastereomers, 2 isomers]

There were 71.8 g (206 mmol, purity: 82%) / V-benzyl-2-chloro- / V - [(2S) -l, 4-dihydroxybutan-2-yl] propanamide [diastereomer mixture, 2 isomers] in wo- Propanol (1.30 1) and cooled to 0 ° C. Then 92.4 g (824 mmol) of potassium ieri-butoxide were added in one portion, stirred at 0 ° C for 30 min. The reaction solution was allowed to warm to rt and wo-propanol removed in vacuo. The residue was taken up in ethyl acetate (500 ml). Water (600 ml) was added, the mixture was extracted, and after phase separation the aqueous phase was extracted with ethyl acetate (2 × 300 ml). The organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 58.6 g (quant., Purity: 90%, diastereomer ratio about 3: 2).

LC-MS (Method 3 A): R _t = 1.51 min (enantiomerically pure isomer 1), R _t = 1.53 min (enantiomerically pure isomer 2);

MS (ESIpos): m / z = 250 [M + H] ⁺ . Example 183A

2 - [(3S) -4-Benzyl-6-methylmorpholin-3-yl] efhanol [enantiomerically pure isomer]

There were 30.0 g (108 mmol) of (5 ^ -4-benzyl-5- (2-hydroxyethyl) -2-methylmorpholin-3-one [diastereomer mixture, 2 isomers] in tetrahydrofuran (1.10 1) submitted, under argon with 217 ml (433 mmol) 2 M borane-dimethylsulfide complex solution in tetrahydrofuran and stirred under reflux for 2 h Subsequently, the mixture was cooled to 0 ° C, cautiously with methanol (200 ml) and stirred under reflux for 30 min in a vacuum completely concentrated, the residue was taken up in acetonitrile and subjected to purification and diastereomer separation by preparative RP-HPLC (acetonitrile / water, isocratic). The target compound eluted as a second component (enantiomerically pure isomer 2). Yield: enantiomerically pure isomer 2: 12.1 g (47% of theory); Enantiomerically pure isomer 1: 6.23 g (24% of theory).

Enantiomerically pure isomer 2:

LC-MS (Method 4A): R _t = 2.33 min; MS (ESIpos): m / z = 236 [M + H] ⁺ ;

Ή-NMR (400 MHz, DMSO δ [ppm] = 7.36-7.18 (m, 5H), 4.42 (t, 1H), 3.69-3.35 (m, 7H), 2.65-2.56 (m, 1H), 2.36-2.29 (m, 1H), 2.26-2.16 (m, 1H), 1.81-1.65 (m, 2H), 1.00 (d, 3H) Enantiomerically pure isomer 1:

LC-MS (Method 4A): R _t = 2.23 min; MS (ESIpos): m / z = 236 [M + H] ⁺ ;

^: H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.37-7.19 (m, 5H), 4.49 (t, 1H), 4.10 (d, 1H), 3.76 (dd, 1H), 3.58 -3.38 (m, 3H), 3:33 to 3:20 (m, 1H), 2.95 (d, 1H), 2.27 (m _c, 1H), 1.80 (m _c, 1H), 1.68 (dd, 1H), 1:48 (mc , 1H), 0.94 (d, 3H). Example 184A

(4-Benzyl-6-methylmorpholin-3-yl) acetaldehyde [mixture of diastereomers, 2 isomers]

2.24 g (1.54 ml, 17.6 mmol) of oxalyl chloride in dichloromethane (70.5 ml) were initially charged and then 2.41 g (2.19 ml, 30.8 mmol) of dimethyl sulfoxide in dichloromethane (12.5 ml) were slowly added at -78 ° C. Subsequently, 2.50 g (10.6 mmol) of 2 - [(3S) -4-benzyl-6-methylmorpholin-3-yl] ethanol [enantiomerically pure diastereomer] in dichloromethane (12.5 ml) were added. The cold reaction mixture was then slowly (20 min) with 5.91 g (8.14 ml, 58.4 mmol) of triethylamine and then the reaction mixture was heated to RT and stirred overnight. The reaction mixture was poured into water and, after phase separation, the organic phase was washed with water. The organic phase was over Dried sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by flash chromatography on silica gel (cyclohexane / ethyl acetate 10: 1 - 1: 1). Yield: 2.23 g (89% of theory); proportional isomerization.

LC-MS (Method 4A :): R _t = 2.58 min (enantiomerically pure isomer 1), R _t = 2.60 min (enantiomerically pure isomer 2)

MS (ESIpos): m / z = 234 [M + H] ⁺ .

Example 185A 1- (4-Benzyl-6-methylmorpholin-3-yl) propan-2-ol [mixture of diastereomers, 2 isomers]

2.20 g (9.43 mmol) of (4-benzyl-6-methylmorpholin-3-yl) acetaldehyde [diastereomer mixture, 2 isomers] in tetrahydrofuran (40.4 ml) were initially charged at -78 ° C. with 11.3 ml (11.3 mmol) of 1M Methylmagnesiumbromid solution in tetrahydrofuran. The mixture was stirred for 15 min at -78 ° C and then warmed to RT. Subsequently, the reaction solution was added carefully with saturated aqueous ammonium chloride solution (70 ml), the tetrahydrofuran was largely removed in vacuo and the residue taken up in dichloromethane. After separation of the phases, the organic phase was washed with water, dried over sodium sulfate, filtered, concentrated in vacuo and subjected directly to purification and diastereomer separation by preparative RP-HPLC (acetonitrile / water, isocratic). The target compound eluted as a diastereomer mixture (2 isomers) as a third component. Yield: target Compound: 627 mg (25% of theory, 2 isomers, diastereomer 3 + 4); Diastereomer 1: 476 mg (20% of theory); Diastereomer 2: 424 mg (17% of theory).

Diastereomer 3 + 4 (2 isomers, target compound):

LC-MS (Method 4A): R _t = 2.46 min; MS (ESIpos): m / z = 250 [M + H] ⁺ ; Diastereomer 1: LC-MS (Method 4A): R _t = 2.32 min; MS (ESIpos): m / z = 250 [M + H] ⁺ ; Diastereomer 2:

LC-MS (Method 4A): R _t = 2.39 min; MS (ESIpos): m / z = 250 [M + H] ⁺ .

Example 186A 1- (6-Methylmorpholin-3-yl) propan-2-ol [mixture of diastereomers, 2 isomers]

627 mg (2.51 mmol) of 1- (4-benzyl-6-methylmorpholin-3-yl) -propan-2-ol [diastereomer mixture, 2 isomers, diastereomer 3 + 4, Example 186A] in ethanol (25.3 ml) were initially charged. Under argon with 63.2 mg of palladium on carbon (10 ig) and 31.6 mg of palladium hydroxide on carbon (20%) and then stirred overnight under a hydrogen atmosphere under atmospheric pressure. An additional 63.2 mg of palladium on charcoal (10%) and 31.6 mg of palladium hydroxide on carbon (20% strength) were added and again stirred overnight under a hydrogen atmosphere under normal pressure. The reaction solution was filtered through kieselguhr and the filter residue washed with ethanol. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 411 mg (quant.). MS (Method IC): m / z = 160 [M + H] ⁺ .

Example 187A

/ V-Benzyl- / V - [(2R, 3R) -3- {[ieri-butyl (dimethyl) silyl] oxy} -l-hydroxybutan-2-yl] -2-chloropropanamide [mixture of diastereomers, 2 isomers]

4.10 g (13.3 mmol) of (2R, 3R) -2- (benzylamino) -3- [[tert-butyl (dimethyl) silyl] oxy} butan-1-ol [Lit .: D. Tanner et al., /. Org. Chem. 1997, 62, 7364-7375] in w-propanol (36.9 ml), cooled to 0 ° C and treated with 2.01 g (2.77 ml, 19.9 mmol) of triethylamine. Subsequently, 2.02 g (1.54 ml, 15.9 mmol) of 2-chloropropionyl chloride [racemate] were added dropwise, warmed to RT and stirred for 3 h. The reaction solution was concentrated in vacuo, the residue taken up in 0.5 N aqueous hydrogen chloride solution and extracted several times with dichloromethane. The organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 5.45 g (76% of theory, purity: 74%).

LC-MS (Method 1A :): R _t = 1.38 min (enantiomerically pure isomer 1), R _t = 1.41 min (enantiomerically pure isomer 2)

MS (ESIpos): m / z = 400 [M + H] ⁺ . Example 188A

(5R) -4-Benzyl-5- [(IR) -1 - {[ieri-butyl (dimethyl) silyl] oxy} ethyl] -2-methylmorpholin-3-one

[Mixture of diastereomers, 2 isomers]

There was added 5.45 g (206 mmol, 74% pure) of N-benzyl-N - [(2R, 3R) -3- [[tert-butyl (dimethyl) silyl] oxy} -l-hydroxybutan-2-yl] - 2-chloropropanamide [diastereomer mixture, 2 isomers] in w-propanol (25.9 ml) submitted, cooled to 0 ° C and then 3.42 g (30.5 mmol) of potassium ieri-butoxide added in one portion. It was warmed to RT and stirred for 1 h. The where-propanol was largely removed in vacuo and the residue was treated with 1 N aqueous hydrogen chloride solution. It was extracted with dichloromethane, the organic phases dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 4.88 g, (99% of theory, purity: 75%, diastereomer ratio about 1: 2).

LC-MS (Method 1A): R _t = 1.46 min (enantiomerically pure isomer 1), R _t = 1.47 min (enantiomerically pure isomer 2); MS (ESIpos): m / z = 364 [M + H] ⁺ . Example 189A

(5R) -4-Benzyl-5- [(IR) -1-hydroxyethyl] -2-methylmorpholin-3-one [mixture of diastereomers, 2 isomers]

There were added 4.55 g (9.41 mmol, purity: 75%) of (5R) -4-benzyl-5 - [(1R) -l- [[ieri-butyl (dimethyl) silyl] oxy} ethyl] -2-methylmorpholine. 3-on [diastereomer mixture, 2 isomers] in tetrahydrofuran (47.5 ml) and at RT with 23.5 ml (23.5 mmol) of tetra-w-butylammonium fluoride solution (1.0 M in tetrahydrofuran). It was stirred for 2 h at RT and then the reaction solution was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water and then the organic phase dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was then purified by flash chromatography on silica gel (dichloromethane, dichloromethane / methanol 50: 1). Yield: 2.29 g (81% of theory, purity: 83%).

LC-MS (Method 1A): R _t = 0.73 min; MS (ESIpos): m / z = 250 [M + H] ⁺ . Example 190A

(1R) -1 - [(3R) -4-Benzyl-6-methylmorpholin-3-yl] ethanol [mixture of diastereomers, 2 isomers]

There were 2.29 g (9.19 mmol) of (5R) -4-benzyl-5 - [(lR) -l-hydroxyethyl] -2-methylmorpholin-3-one [diastereomer mixture, 2 isomers] in tetrahydrofuran (90.4 ml) submitted under Argon with 18.4 ml (36.4 mmol) 2 M borane-dimethyl sulfide complex solution in tetrahydrofuran and then the reaction mixture stirred for 2 h under reflux. Subsequently, the Cooled to 0 ° C approach, mixed carefully with methanol (50 ml) and then stirred for 30 min under reflux. It was then completely concentrated in vacuo, the residue taken up in acetonitrile and purified directly by preparative RP-HPLC (acetonitrile / water). Both isomers were isolated, but then rejoined. Yield: 891 mg (41% of theory).

LC-MS (Method 5A): R _t = 2.05 min (enantiomerically pure isomer 1), R _t = 2.20 min (enantiomerically pure isomer 2);

MS (ESIpos): m / z = 236 [M + H] ⁺ .

Example 191A (1R) -l - [(3R) -6-Methylmorpholin-3-yl] ethanol [mixture of diastereomers, 2 isomers]

891 mg (3.79 mmol) of (1R) -l - [(3R) -4-benzyl-6-methylmorpholin-3-yl] ethanol [diastereomer mixture, 2 isomers] in ethanol (30.4 ml) were initially charged under argon with 90.0 mg of palladium on carbon (10%) and 45.0 mg of palladium hydroxide on carbon (20%) and then stirred overnight under a hydrogen atmosphere under atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue washed with ethanol. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 599 mg (quant.).

MS (Method 5A): m / z = 146 [M + H] ⁺ . Example 192A

4-Benzyl-3,6,6-trimethyl-5-oxomorpholine-3-carbaldehyde [racemate]

17.6 g (12.1 ml, 139 mmol) of oxalyl chloride in dichloromethane (324 ml) were initially charged and then 10.5 g (9.54 ml, 134 mmol) of dimethyl sulfoxide in dichloromethane (58 ml) were slowly added at -78 ° C. Subsequently, 12.2 g (46.3 mmol) of 4-benzyl-5- (hydroxymethyl) -2,2,5-trimethylmorpholin-3-one [racemate] in dichloromethane (58 ml) were added followed by stirring for 30 min. The cold reaction mixture was then slowly (20 min) with 28.1 g (38.7 ml, 278 mmol) of triethylamine and then the reaction mixture was heated to RT and stirred overnight. The reaction mixture was poured into water and, after phase separation, the organic phase was washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product obtained was purified by flash chromatography on silica gel (cyclohexane / ethyl acetate 10: 1 - 2: 1). Yield: 9.00 g (57% of theory, purity: 76%).

LC-MS (Method 1A :): R _t = 0.88 min; MS (ESIpos): m / z = 262 [M + H] ⁺ .

Example 193A 4-Benzyl-5- (1-hydroxyethyl) -2,2,5-trimethylmorpholin-3-one [mixture of diastereomers, 4 isomers]

There were charged 9.00 g (26.4 mmol, purity: 76%) of 4-benzyl-3,6,6-trimethyl-5-oxomorpholine-3-carbaldehyde [racemate] in tetrahydrofuran (107 ml) and at -78 ° C with 39.6 ml (39.6 mmol) of 1M methylmagnesium bromide solution in tetrahydrofuran. The mixture was stirred for 15 min at -78 ° C and then warmed to RT. Subsequently, the reaction solution was added cautiously with saturated aqueous ammonium chloride solution (70 ml), the tetrahydrofuran largely removed in vacuo and the residue taken up in dichloromethane. After separation of the phases, the organic phase was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used without further purification in the next step. Yield: 9.00 g (94% of theory, purity: 74%). LC-MS (Method 1A): R _t = 0.83 min; MS (ESIpos): m / z = 278 [M + H] ⁺ .

Example 194A 1- (4-Benzyl-3,6,6-trimethylmorpholin-3-yl) ethanol [diastereomer, 2 isomers]

9.33 g (33.6 mmol) of 4-benzyl-5- (1-hydroxyethyl) -2,2,5-trimethylmorpholin-3-one [diastereomer mixture, 4 isomers] in tetrahydrofuran (331 ml) were initially charged under argon with 67.3 ml (135 mmol) 2 M borane-dimethyl sulfide complex solution in tetrahydrofuran and then the reaction mixture stirred for 2 h under reflux. Subsequently, the batch was cooled to 0 ° C, carefully mixed with methanol (78 ml) and then stirred for 30 min under reflux. The mixture was then concentrated completely in vacuo, and the residue was taken up in acetonitrile and subjected directly to purification and diastereomer separation by preparative RP-HPLC (acetonitrile / water, isocratic). The target compound eluted as a second component. Yield: target Compound: 832 mg (9% of theory, diastereomer 2, 2 isomers); Minor isomer: 3.30 g (37% of theory, diastereomer 1, 2 isomers).

Diastereomer 2, 2 isomers (target compound): LC-MS (Method 1A): R _t = 0.58 min; MS (ESIpos): m / z = 264 [M + H] ⁺ ;

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.39-7.15 (m, 5H), 4.49 (d, 1H), 4.17 (d, 1H), 3.79- 3.65 (m, 2H), 3.18-3.07 (m, 2H), 2.23-2.13 (m, 2H), 1.17-1.13 (m, 6H), 1.02 (d, 6H).

Diastereomer 1, 2 isomers:

LC-MS (Method 1A): R _t = 0.63 min; MS (ESIpos): m / z = 264 [M + H] ⁺ ; Ή-NMR (400 MHz, DMSO-ife): δ [ppm] = 7.36-7.15 (m, 5H), 4.58 (d, 1H), 4.07 (quin, 1H), 3.80 (d, 1H), 3.63 (i.e. , 1H), 3.32-3.24 (m, 2H), 2.20 (m, 1H), 2.12 (d, 1H), 1.19 (d, 3H), 1.14 (s, 3H), 1.08 (s, 3H), 1.02 ( s, 3H).

Example 195A 1- (3,6,6-trimethylmorpholin-3-yl) ethanol [diastereomer 2, 2 isomers]

832 mg (3.16 mmol) of 1- (4-benzyl-3,6,6-trimethylmorpholin-3-yl) ethanol [racemate] in ethanol (31.8 ml) were initially charged under argon with 91.0 mg of palladium on carbon (10%). ig) and 45.0 mg of palladium hydroxide on carbon (20%) and then stirred overnight under a hydrogen atmosphere under atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue washed with ethanol. It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 549 mg (100% of theory).

MS (Method 6A): m / z = 174 [M + H] ⁺ .

Example 196A 2-chloro-A ^L (1,4-dihydroxybutan-2-yl) propanamide [diastereomeric mixture, 4 isomers]

There were 5.50 g (52.3 mmol) of 2-aminobutane-l, 4-diol [racemate] [Lit .: AS Jogalekar et al., WO 2008151304, 2008] in w-propanol (184 ml) and 5.29 g (7.29 ml, 52.3 mmol) of triethylamine. Subsequently, 7.31 g (5.59 ml, 57.5 mmol) of 2-chloropropionyl chloride [racemate] were added dropwise and the mixture was stirred at RT overnight. The reaction solution was concentrated in vacuo and the resulting crude product used directly in the next step.

MS (Method 1B): m / z = 195 [M + H] Example 197A

5- (2-hydroxyethyl) -2-methylmorpholin-3-one [mixture of diastereomers, 4 isomers]

There were 10.2 g (about 52.3 mmol, crude product) of 2-chloro-A ^L (l, 4-dihydroxybutan-2-yl) propanamide [diastereomer mixture, 4 isomers] in w-propanol (221 ml) presented, to 0 ° C. cooled and then added 29.3 g (261 mmol) of potassium ieri-butoxide in one portion. It was warmed to RT and stirred for 60 h. The reaction solution was concentrated in vacuo and the resulting crude product used directly in the next step.

LC-MS (Method 3A): R _t = 0.34 min; MS (ESIpos): m / z = 160 [M + H] ⁺ . Example 198A

5- (2- {[ieri-butyl (diphenyl) silyl] oxy} ethyl) -2-methylmorpholin-3-one [diastereomer, 2 isomers]

There were 3.93 g (about 24.7 mmol, crude product) of 5- (2-hydroxyethyl) -2-methylmorpholin-3-one [diastereomer mixture, 4 isomers] in / V, / V-dimethylformamide (50 ml) and then at 0 ° C. with 5.05 g (74.1 mmol) of imidazole and 10.2 g (37.1 mmol) of tert-butyldiphenylsilyl chloride. The mixture was stirred for 24 h while warming to RT. Subsequently, the reaction solution was treated with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by preparative RP-HPLC (acetonitrile / water) to obtain only the main diastereomer. Yield: 2.05 g (20% of theory).

LC-MS (Method 1A): R _t = 1.31 min; MS (ESIpos): m / z = 398 [M + H] ⁺ . Example 199A

5- (2- {[ieri-butyl (diphenyl) silyl] oxy} ethyl) -2-methylmorpholine [diastereomer, 2 isomers]

1.20 g (3.02 mmol) of 5- (2- {[ieri-butyl (diphenyl) silyl] oxy} ethyl) -2-methylmorpholine-3-one [diastereomer, 2 isomers] in tetrahydrofuran (70.6 ml) were initially charged 7.55 ml (15.1 mmol) of 2 M borane-dimethylsulfide complex solution in tetrahydrofuran are added and then the reaction mixture is stirred at RT for 60 h. Subsequently, the batch was completely concentrated in vacuo, the residue taken up in ethanol stirred overnight under reflux. Subsequently, the batch was completely concentrated under reduced pressure and the crude product obtained was used directly in the next step. Yield: 1.22 g (quant.).

LC-MS (Method 1A): R _t = 1.08 min; MS (ESIpos): m / z = 383 [M + H] ⁺ .

Example 200A

[5- (2- {[ieri-butyl (diphenyl) silyl] oxy} ethyl) -2-methylmorpholin-4-yl] (2- {[(4-chloropyridin-2-yl) methyl] amino} -7- methoxy-1,3-benzoxazol-5-yl) methanone [diastereomer, 2 isomers]

There were added 600 mg (1.80 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 759 mg (1.98 mmol) of 5- (2 - {[ieri-butyl (diphenyl) silyl] oxy} ethyl) -2-methylmorpholine [racemate] in / V, / V-dimethylformamide (4.90 ml) and with 744 mg (1.00 ml, 5.75 mmol) / VN-diisopropylethylamine added. Subsequently, at RT 820 mg (2.16 mmol) HATU was added and stirred for 1 h. The reaction solution was then purified without further work-up directly by means of preparative RP-HPLC (acetonitrile / water + 0.1% formic acid). Yield: 845 mg (67% of theory).

LC-MS (Method 3A): R _t = 2.94 min; MS (ESIpos): m / z = 699 [M + H] ⁺ . Example 201A ieri-butyl 2- {[(1-methoxy-1-oxobutan-2-yl) amino] methyl} azetidine-1-carboxylate

[Mixture of diastereomers, 4 isomers]

1.80 g (9.66 mmol) of ieri-butyl-2- (aminomethyl) azetidine-1-carboxylate [racemate] were dissolved in 25 ml of dichloromethane, with 1.62 ml (1.17 g, 11.6 mmol) of triethylamine and 1.11 ml (1.75 g, 9.66 mmol ) Methyl 2-bromobutanoate [racemate] and stirred overnight at reflux. Then, 1.35 ml (0.98 g, 9.66 mmol) of triethylamine and 0.89 ml (1.40 g, 7.73 mmol) of methyl 2-bromobutanoate [racemate] were added and the mixture was stirred under reflux overnight. After cooling to room temperature, water was added and the phases were separated. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and then freed from the solvent in vacuo. This gave 2.64 g (83% of theory, purity: 87%) of the desired product.

LC-MS (Method 6A): R _t = 2.16 min (diastereomer 1, 2 isomers), R _t = 2.22 min (diastereomer 2, 2 isomers);

MS (ESIpos): m / z = 287 [M + H] ⁺

Example 202A ieri-butyl-2- ({[(benzyloxy) carbonyl] (1-methoxy-1-oxobutan-2-yl) amino} methyl) azetidine-1-carboxylate [mixture of diastereomers, 4 isomers]

To 3.75 g (8.77 mmol) of ieri-butyl-2- {[(1-methoxy-1-oxobutan-2-yl) amino] methyl} azetidine-1-carboxylate [diastereomer mixture, 4 isomers] in 100 ml of THF at 0 ° C slowly added dropwise a solution of 1.88 ml (2.25 g, 13.2 mmol) of benzyl chlorocarbonate in 7 ml of toluene. Then a solution of 2.20 ml (1.59 g, 15.8 mmol) of triethylamine in 10 ml of THF was slowly added dropwise and stirred overnight at room temperature. It was concentrated under reduced pressure and the residue was combined with water and ethyl acetate. After separation of the phases, the aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution. It was dried over sodium sulfate, filtered, the filtrate concentrated in vacuo and the residue dried under high vacuum. Then, the residue was added with cyclohexane and ethyl acetate and purified by silica gel chromatography (cyclohexane / ethyl acetate 10: 3). This gave 2.31 g (38% of theory, purity: 62%) of the desired product. Example 203A

Methyl 2- {(azetidin-2-ylmethyl) [(benzyloxy) carbonyl] amino} butanoate trifluoroacetate [mixture of diastereomers, 4 isomers]

x CF ₃ C0 ₂ H To 2.31 g (3.41 mmol, purity: 62%) of ieri-butyl 2 - ({[(benzyloxy) carbonyl] (1-methoxy-1-oxobutan-2-yl) amino} methyl) azetidine-1-carboxylate [mixture of diastereomers , 4 isomers] in 45 ml of dichloromethane 2.62 ml (3.88 g, 34.1 mmol) of trifluoroacetic acid were added and it was stirred overnight at room temperature. It was then concentrated in vacuo, the residue was treated with dichloromethane and water and the phases were separated. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were washed with saturated aqueous sodium chloride solution. After drying over sodium sulfate, the mixture was concentrated under reduced pressure and the residue was dried under high vacuum. 1.41 g (28% of theory, purity: 29%) of the desired product were obtained. LC-MS (Method 1A): R _t = 0.72 min; MS (ESIpos): m / z = 320 [M + H-TFA] ⁺

Example 204A

Benzyl 3-ethyl-2-oxo-1,4-diazabicyclo [4.2.0] octane-4-carboxylate [mixture of diastereomers, 4 isomers]

1.41 g (0.94 mmol, purity: 29%) of methyl -2- {(azetidin-2-ylmethyl) [(benzyloxy) carbonyl] -amino-jbutanoate trifluoroacetate [diastereomer mixture, 4 isomers] in 30 ml of methanol were mixed with 0.65 g (4.71 mmol ) Potassium carbonate was added and it was stirred overnight at room temperature. It was then concentrated under reduced pressure, the residue was combined with water and ethyl acetate and the phases were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution. After drying over sodium sulfate, the mixture was concentrated under reduced pressure and the residue was dried under high vacuum. The residue was dissolved in methanol and water and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient). 383 mg (quant.) Of the desired product were obtained. LC-MS (Method 1A): R _t = 0.89 min; MS (ESIpos): m / z = 289 [M + H] Example 205A

3-ethyl-1,4-diazabicyclo [4.2.0] octan-2-one [mixture of diastereomers, 4 isomers]

383 mg (0.78 mmol, purity: 60%) of benzyl 3-ethyl-2-oxo-1,4-diazabicyclo [4.2.0] octane-4-carboxylate [mixture of diastereomers, 4 isomers, Example 204A] in 30 ml of methanol were added under argon with 424 mg (0.39 mmol) of 10% palladium on activated carbon and hydrogenated for 4 h at RT and atmospheric pressure. It was then filtered, the filtrate concentrated in vacuo and the residue dried under high vacuum. 74.8 mg (61% of theory) of the desired product were obtained.

MS (Method IC): m / z = 155 [M + H] ⁺ Example 206A ieri-butyl-2- {[(1,3-dimethoxy-1-oxopropan-2-yl) -amino] -methyl} -azetidine-1 - carboxylate

[Mixture of diastereomers, 4 isomers]

3.00 g (16.1 mmol) of ieri-butyl-2- (aminomethyl) azetidine-1-carboxylate [racemate] were dissolved in 40 ml of dichloromethane, with 2.69 ml (1.96 g, 19.3 mmol) of triethylamine and 3.17 g (16.1 mmol) of methyl 2-bromo-3-methoxypropanoate [racemate] and stirred overnight at room temperature. 1.12 ml (0.82 g, 8.05 mmol) of triethylamine and 0.90 g (4.59 mmol) of methyl 2-bromo-3-methoxypropanoate [racemate] were added and the mixture was stirred at reflux overnight. Then 2.69 ml (1.96 g, 19.3 mmol) of triethylamine and 3.17 g (16.1 mmol) of methyl 2-bromo-3-methoxypropanoate [racemate] were added and stirred overnight under reflux. To After cooling, the precipitate was filtered off, the filtrate was mixed with water and the phases were separated. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were washed with saturated aqueous sodium chloride solution. After drying over sodium sulfate, the solvent was removed in vacuo and the residue was dried under high vacuum. This gave 6.89 g (94% of theory, purity: 67%) of the desired product.

LC-MS (Method 6 A): 1.91 min (diastereomer 1, 2 isomers), R _t = 1.96 min (diastereomer 2, 2 isomers);

MS (ESIpos): m / z = 303 [M + H] ⁺ Example 207A

Methyl- / V- (azetidin-2-ylmethyl) -N- [(benzyloxy) carbonyl] -O-methylserinate trifluoroacetate [mixture of diastereomers, 4 isomers]

To 6.89 g (15.26 mmol, purity: 67%) of ieri-butyl-2- {[(1,3-dimethoxy-1-oxopropan-2-yl) -amino] -methyl} azetidine-1-carboxylate [mixture of diastereomers, 4 isomers] in 150 ml of dichloromethane was added 17.6 ml (25.9 g, 227 mmol) of trifluoroacetic acid and stirred at room temperature overnight. After addition of 8.8 ml (12.9 g, 113 mmol) of triflouretic acid was stirred overnight at room temperature, then concentrated in vacuo and the residue dissolved in dichloromethane. It was concentrated in vacuo, the residue obtained redissolved in dichloromethane and then freed from the solvent in vacuo. After drying in a high vacuum, the resulting crude product without purification was further used in Example 208A.

Example 208A

3- (methoxymethyl) -1,4-diazabicyclo [4.2.0] octan-2-one [mixture of diastereomers, 4 isomers]

10.9 g (20.6 mmol, purity: 60%) of methyl N- (azetidin-2-ylmethyl) -N - [(benzyloxy) carbonyl] -0-methylserinate Trifluoroacetate [diastereomer mixture, 4 isomers] in 150 ml of methanol were mixed with 11.4 g (82.7 mmol) of potassium carbonate and it was stirred overnight at room temperature. It was then concentrated under reduced pressure and the residue was dried under high vacuum. This gave 22.5 g of crude product which was used without further purification in Example 209A.

MS (Method IC): m / z = 171 [M + H] ⁺ Example 209A Benzyl-3- (methoxymethyl) -2-oxo-1,4-diazabicyclo [4.2.0] octane-4-carboxylate

[Mixture of diastereomers, 4 isomers]

To 22.48 g (19.8 mmol, purity: 19%) of 3- (methoxymethyl) -1,4-diazabicyclo [4.2.0] octan-2-one [mixture of diastereomers, 4 isomers] in 200 ml of THF was dissolved at 0 ° C of 2.82 ml (3.38 g, 19.8 mmol) of benzyl chlorocarbonate in 6.5 ml of toluene. Then a solution of 3.13 ml (2.41 g, 23.8 mmol) of triethylamine in 10 ml of THF was slowly added dropwise and it was stirred overnight at room temperature. It was then cooled to 0 ° C and first a solution of 1.69 ml (2.03 g, 11.9 mmol) of benzyl chlorocarbonate in 4 ml of toluene and then slowly added dropwise a solution of 1.93 ml (1.40 g, 13.9 mmol) of triethylamine in 10 ml of THF and overnight stirred at room temperature. After filtration, the filtrate was concentrated in vacuo and then with Water and ethyl acetate are added. After separation of the phases, the aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution. It was dried over sodium sulfate, filtered, the filtrate concentrated in vacuo and the residue dried under high vacuum. The residue was dissolved in acetonitrile and water and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient). 1.08 g (18% of theory) of the desired product were obtained.

LC-MS (Method 1A): R _t = 0.83 min; MS (ESIpos): m / z = 305 [M + H] ⁺ Example 210A Benzyl-3- (methoxymethyl) -2-oxo-1,4-diazabicyclo [4.2.0] octane-4-carboxylate [enantiomerically pure isomer 3]

1.08 g of benzyl-3- (methoxymethyl) -2-oxo-1,4-diazabicyclo [4.2.0] octane-4-carboxylate [diastereomer mixture] (Example 209 A) were separated into the enantiomers on a chiral phase [Method 49D ].

Yield enantiomerically pure isomer 3: 266.5 mg (99.8% ee) enantiomerically pure isomer 3: R _t = 9.74 min [Method 42E]. LC-MS (Method 1A): R _t = 0.79 min; MS (ESIpos): m / z = 305 [M + H] ⁺ Example 211A

3- (Methoxymethyl) -1,1,4-diazabicyclo [4.2.0] octan-2-one [enantiomerically pure isomer 3]

266.5 mg of benzyl 3- (methoxymethyl) -2-oxo-1,4-diazabicyclo [4.2.0] octane-4-carboxylate [enantiomerically pure isomer 3, Example 210A] in 25 ml of methanol were added under argon to 465 mg (0.44 mmol 10) palladium on charcoal and hydrogenated overnight at RT and atmospheric pressure. It was then filtered, the filtrate concentrated in vacuo and the residue dried under high vacuum. 138 mg (92% of theory) of the desired product were obtained.

MS (Method IC): m / z = 171 [M + H] ⁺

Example 212A ieri-butyl-2- [(benzylamino) methyl] azetidine-1-carboxylate [racemate]

10.0 g (53.7 mmol) of ieri-butyl-2- (aminomethyl) azetidine-1-carboxylate and 2.03 g (37.8 mmol) of benzaldehyde in 100 ml of methanol were refluxed for 2.5 h. It was then cooled to 0 ° C and slowly added at this temperature within 15 min sodium borohydride. It was stirred overnight at RT. It was then concentrated under reduced pressure, the residue was combined with dichloromethane and water, the phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. The resulting residue was washed with dichloromethane and purified by silica gel chromatography (dichloromethane, then dichloromethane: methanol = 100: 4). Yield: 7.43 g (50% of theory).

LC-MS (Method 6A): R _t = 2.41 min; MS (ESIpos): m / z = 277 [M + H] ^+. Example 213A ieri-butyl-2- {[benzyl (1-methoxy-1-oxopropan-2-yl) amino] methyl} azetidine-1-carboxylate

[Mixture of diastereomers, 4 isomers]

There were dissolved 2.50 g (9.05 mmol) of ieri-butyl-2 - [(benzylamino) methyl] azetidine-1-carboxylate [racemate] in dichloromethane (150 ml) with 5.55 ml (4.03 g, 39.8 mmol) of triethylamine and 3.04 ml (4.53 g, 27.1 mmol) 2-bromopropionic acid methyl ester [racemate] and stirred overnight at RT. Then, 5.55 ml (4.03 g, 39.8 mmol) of triethylamine and 3.04 ml (4.53 g, 27.1 mmol) of methyl 2-bromopropanoate [racemate] were added and the mixture was stirred overnight at 40.degree. Subsequently, 5.55 ml (4.03 g, 39.8 mmol) of triethylamine and 3.04 ml (4.53 g, 27.1 mmol) of 2-bromopropanoic acid methyl ester [racemate] were added again and the mixture was stirred overnight at 40.degree. After cooling to room temperature, it was diluted with water and dichloromethane and the phases were separated. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and then freed from the solvent in vacuo. The resulting crude product was purified by silica gel chromatography (dichloromethane, then dichloromefham methanol = 100: 1). Yield: 3.22 g (94% of theory).

LC-MS (Method 1A): R _t = 1.00 min (diastereomer 1), R _t = 1.13 min (diastereomer 2);

MS (ESIpos): m / z = 363 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO δ [ppm] = 7.35-7.28 (m, 4H), 7.27-7.20 (m, 1H), 4.18-3.98 (m, 1H), 3.85-3.73 (m, 1H), 3.71-3.51 (m, 6H), 3.51-3.38 (m, 1H), 3.04-2.88 (m, 1H), 2.85-2.69 (m, 1H), 2.15-1.96 (m, 1H), 1.93-1.65 (m, 1H), 1.34 (d, 9H), 1.26-1.15 (m, 3H). Example 214A

Methyl A ^r - (azetidin-2-ylmethyl) -N-benzyl alaninate hydrochloride [mixture of diastereomers, 4 isomers]

3.2 g (8.5 mmol) of ieri-butyl-2- {[benzyl (1-methoxy-1-oxopropan-2-yl) -amino] -methyl} -azetidine-1-carboxylate [mixture of diastereomers, 4 isomers] in dioxane (74 ml) were added 14.9 ml (59.7 mmol) of 4 N hydrogen chloride solution in 1,4-dioxane and stirred overnight at room temperature. Subsequently, 14 ml (59.7 mmol) of 4 N hydrogen chloride solution in 1,4-dioxane were added again and the mixture was stirred at RT overnight. It was then concentrated under reduced pressure and the product was dried under high vacuum. Yield: 3.13 g (98% of theory, purity: 80%).

LC-MS (Method 1A): R _t = 0.68 min (diastereomer 1, 2 isomers), R _t = 0.70 min (diastereomer 2, 2 isomers);

MS (ESIpos): m / z = 263 [M + H-HC1] ⁺ . Example 215A

4-Benzyl-3-methyl-1,4-diazabicyclo [4.2.0] octan-2-one [enantiomerically pure isomer 3]

21.8 g (51.0 mmol, purity: 70%) of methyl / V- (azetidin-2-ylmethyl) - / V-benzylalaninate [diastereomer mixture, 4 isomers] in methanol (562 ml) were initially charged, with 28.2 g (204 mmol ) Potassium carbonate and then stirred for 2.5 d at RT. The reaction solution became filtered and at 20 ° C, the solvent was largely removed in vacuo. The residue was taken up in water and extracted several times with dichloromethane and chloroform / 2-propanol (7: 3). The collected organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (12.1 g) was separated by method 7D into the corresponding isomers. The target compound eluted as the third component. Yield: 2.47 g (21% of theory).

HPLC (Method 6E): R _t = 7.49 min, 99.0% ee;

LC-MS (Method 1A): R _t = 0.50 min; MS (ESIpos): m / z = 231 [M + H] ⁺ . Example 216A 3-Methyl-1,4-diazabicyclo [4.2.0] octan-2-one [enantiomerically pure isomer 3]

There were 2.40 g (10.4 mmol) of 4-benzyl-3-methyl-l, 4-diazabicyclo [4.2.0] octan-2-one [enantiomerically pure isomer 3] in ethanol (85 ml) and under argon with 250 mg of palladium on carbon (10%) and 130 mg of palladium hydroxide on carbon (20%) and then stirred overnight under a hydrogen atmosphere under atmospheric pressure. The reaction solution was filtered through kieselguhr and the filter residue was washed with hot ethanol (100 ml). It was concentrated under reduced pressure and the product was dried under high vacuum. Yield: 1.56 g (quant.).

GC-MS (Method 2B): R _t = 4.50 min; MS (EIpos): m / z = 140 [M] ⁺ ; MS (Method IC): m / z = 141 [M + H] ⁺ ;

^H-NMR (400 MHz, DMSO-d _6): δ [ppm] = 4:59 (m _c, 1H), 4.09-3.89 (m, 2H), 3.27 (q, 1H), 2.95 (dd, 1H), 2.58-2.53 (m, 2H), 2.33-2.04 (m, 2H), 1.12 (d, 3H).

Example 217A ieri-butyl-4-benzyl-5-oxo-4,7-diazaspiro [2.5] octane-7-carboxylate

2.47 g (61.9 mmol) of sodium hydride were added in portions to 2.50 g (8.84 mmol) of ieri-butyl-5-oxo-4,7-diazaspiro [2.5] octane-7-carboxylate in 80 ml of THF at 0 ° C. under argon was stirred at 0 ° C for 30 min. Then 1.26 ml (1.81 g, 10.6 mmol) of benzyl bromide were added dropwise and it was stirred overnight at room temperature. It was then cooled to 0 ° C, treated with 1.24 g (30.9 mmol) of sodium hydride and stirred at 0 ° C for 30 min. 0.63 ml (0.91 g, 5.3 mmol) of benzyl bromide were added dropwise and it was stirred overnight at room temperature. Subsequently, at 0 ° C, first with ethanol and then with water and ethyl acetate. After separation of the phases, the aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was dried under high vacuum and purified by silica gel chromatography (cyclohexane / ethyl acetate 10: 1) and then by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient). 1.98 g (71 d.s.) of the desired product were obtained. LC-MS (Method 1A): R _t = 1.09 min; MS (ESIpos): m / z = 317 [M + H] ⁺

^: H NMR (400 MHz, DMSO-de): δ [ppm] = 7.38-7.14 (m, 5H), 4.41 (s, 2H), 4.16 (br, s, 2H), 1.40 (br. , 9H), 0.98-0.89 (m, 2H), 0.79-0.72 (m, 2H).

Example 218A ieri-butyl-4-benzyl-6-methyl-5-oxo-4,7-diazaspiro [2.5] octane-7-carboxylate [racemate]

At -78 ° C, under argon, to 1.20 g (3.79 mmol) of ieri-butyl-4-benzyl-5-oxo-4,7-diazaspiro [2.5] octane-7-carboxylate in 48 ml of THF was added 11.38 ml (11.38 mmol). a 1 M lithium hexamethyldisilazide solution in THF was added dropwise and it was stirred for 30 min at -78 ° C. Then, 0.47 ml (7.59 mmol) of methyl iodide was added dropwise, and it was stirred for 1.5 hours. Subsequently, at 0 ° C first with saturated aqueous ammonium chloride solution and then treated with ethyl acetate. After separation of the phases, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo, the residue dried under high vacuum, dissolved in acetonitrile and water and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient). This gave 0.54 g (41% of theory) of the desired product.

Example 219A ieri-butyl-6-methyl-5-oxo-4,7-diazaspiro [2.5] octane-7-carboxylate [racemate]

At -78 ° C., 10 ml (7.70 g, 452 mmol) of ammonia were admixed with 107 mg (15.5 mmol) of lithium and stirred for a few minutes. Then 540 mg (1.55 mmol) of ieri-butyl-4-benzyl-6-methyl-5-oxo-4,7-diazaspiro [2.5] octane-7-carboxylate [racemate] in 5 ml of THF were added dropwise, slowly warmed to room temperature and then stirred overnight at room temperature. Subsequently, at 0 ° C first with saturated aqueous ammonium chloride solution and then treated with ethyl acetate. After separation of the phases, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo and the residue was dried under high vacuum. This gave 353 mg of the crude product, which was used without further purification.

MS (Method IC): m / z = 241 [M + H] ⁺ .

Example 220A

6-Methyl-4,7-diazaspiro [2.5] octan-5-one trifluoroacetate [racemate]

To 331 mg (1.38 mmol) of iperi-butyl-6-methyl-5-oxo-4,7-diazaspiro [2.5] octane-7-carboxylate [racemate] in 10 ml of dichloromethane was added 1.06 ml (1.57 g, 13.8 mmol) of trifluoroacetic acid was added and it was stirred for 2 h at room temperature. It was then concentrated in vacuo and the residue was dissolved in dichloromethane. It was concentrated in vacuo and the residue obtained was redissolved in dichloromethane, freed from solvent in vacuo and dried under high vacuum. The resulting crude product (605 mg) was used further without purification.

MS (Method IC): m / z = 141 [M + H] ⁺ .

Example 221A

Butyl 4-benzyl-6-ethyl-5-oxo-4,7-diazaspiro [2.5] octane-7-carboxylate [racemate]

At -78 ° C., under argon, to 600 mg (1.89 mmol) of ieri-butyl-4-benzyl-5-oxo-4,7-diazaspiro [2.5] octane-7-carboxylate in 24 ml of THF was added 5.69 ml (5.69 mmol). a 1 M lithium hexamethyldisilazide solution in THF was added dropwise and it was stirred for 30 min at -78 ° C. Then 491 μΐ (675 mg, 3.79 mmol) of ethyl trifluoromethanesulfonate were added dropwise and the mixture was stirred for 2 h. Subsequently, at 0 ° C first with saturated aqueous ammonium chloride solution and then treated with ethyl acetate. After separation of the phases, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution and then over sodium sulfate dried. After filtration, the filtrate was concentrated in vacuo and the residue was dried under high vacuum. 684 mg (97% of theory, purity: 93%) of the desired product were obtained.

Example 222A

Butyl 6-ethyl-5-oxo-4,7-diazaspiro [2.5] octane-7-carboxylate [racemate]

At -78 ° C., 13 ml of ammonia were admixed with 128 mg (18.4 mmol) of lithium and stirred for 10 minutes. Then 684 mg (1.84 mmol, purity: 93%) of ieri-butyl-4-benzyl-6-ethyl-5-oxo-4,7-diazaspiro [2.5] octane-7-carboxylate [racemate] in 3 ml of THF were added dropwise , warmed slowly to room temperature and then stirred overnight at room temperature. Subsequently, at 0 ° C first with saturated aqueous ammonium chloride solution and then treated with water and ethyl acetate. After separation of the phases, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo and the residue was dried under high vacuum. 325 mg of the crude product were obtained, which was used without further purification.

MS (Method IC): m / z = 255 [M + H] ⁺ Example 223A

6-ethyl-4,7-diazaspiro [2.5] octan-5-one trifluoroacetate [racemate]

To 325 mg (1.28 mmol) of iperi-butyl-6-ethyl-5-oxo-4,7-diazaspiro [2.5] octane-7-carboxylate [racemate] in 12 ml of dichloromethane were added 0.985 ml (1.46 g, 12.8 mmol) of trifluoroacetic acid was added and it was stirred overnight at room temperature. It was then concentrated under reduced pressure and the residue was dried under high vacuum. The crude product obtained (534 mg) was used without purification.

MS (Method IC): m / z = 155 [M + H] ⁺

Example 224A

Benzyl 6-ethyl-5-oxo-4,7-diazaspiro [2.5] octane-7-carboxylate [racemate]

To 1.33 g (2.37 mmol, purity: 75%) of 6-ethyl-4,7-diazaspiro [2.5] octan-5-one trifluoroacetate [racemate] in 19 ml of THF at 0 ° C was added a solution of 0.34 ml (0.40 g , 2.37 mmol) of benzyl chlorocarbonate in 0.7 ml of toluene. Then a solution of 0.39 ml (0.28 g, 2.84 mmol) of triethylamine in 10 ml of THF was slowly added dropwise, stirred overnight at room temperature and then treated with water and ethyl acetate. After separation of the phases, the aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution. It was dried over sodium sulfate, filtered, the filtrate concentrated in vacuo, the residue dried under high vacuum, dissolved in methanol and water and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient). 120 mg (18% of theory) of the desired product were obtained.

MS (method IC): m / z = 289 [M + H] ⁺

Example 225A

6-Ethyl-4,7-diazaspiro [2.5] octan-5-one [racemate]

124 mg of benzyl 6-ethyl-5-oxo-4,7-diazaspiro [2.5] octane-7-carboxylate [racemate, Example 224A] in 8 ml of methanol was added under argon with 224 mg (0.21 mmol) 10% palladium on charcoal added and hydrogenated for 4 h at RT and atmospheric pressure. It was then filtered, the filtrate concentrated in vacuo and the residue dried under high vacuum. 63 mg (96% of theory) of the desired product were obtained.

Example 226A

[(ieri-butoxycarbonyl) {2- [methoxy (methyl) amino] -2-oxoethyl} amino

At 0 ° C, 35 g (150 mmol) of 2,2 '- [(feri-butoxycarbonyl) imino] diacetic acid in,, V,., V-dimethylformamide (250 ml) in portions with 33.9 g (177 mmol) of N-ethyl -N '- (3-dimethylaminopropyl) carbodiimide hydrochloride and stirred for 1 h at room temperature. It was cooled to 0 ° C and at 0 ° C to 5 ° C, a solution of 17.3 g (177 mmol) Ν, Ο-dimethylhydroxylamine hydrochloride and 22.8 g (30.8 ml, 177 mmol) of NN-diisopropyl-ethylamine in 150 ml of dimethylformamide dropwise. It was stirred overnight at room temperature. It was then added to a mixture of ice and aqueous 1 M hydrogen chloride solution and then treated with ethyl acetate. After separation of the phases, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were washed twice with aqueous 1 M hydrogen chloride solution and once with saturated aqueous sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo and the residue was dried under high vacuum. The residue was mixed with diethyl ether and treated in an ultrasonic bath for 20 min. The resulting solid was filtered off and dried under high vacuum. 27.8 g (64% of theory) of the desired product were obtained. LC-MS (Method 1A): R _t = 0.64 min; MS (ESIpos): m / z = 277 [M + H] ⁺

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 12.62 (br.s .., 1H), 4.19-4.11 (m, 2H), 3.88 (d, 2H), 3.68 (d, 3H), 3.10 (d, 3H), 1.35 (d, 9H).

Example 227A N- (ieri-butoxycarbonyl) -N- (2-oxopropyl) glycine

75.2 ml (26.9 g, 225 mmol) of a 3 molar solution of methylmagnesium bromide in diethyl ether were slowly added at 0 ° C. to 13 g (45 mmol) of [(ieri-butoxycarbonyl) {2- [methoxy (methyl) amino] -2- oxoethyl} amino] acetic acid in 260 ml of THF. It was stirred for 2 h at room temperature. Then 78 ml of saturated aqueous ammonium chloride solution and 78 ml of water were added dropwise at 0 ° C and allowed to slowly warm to room temperature. Diethyl ether was added and, after separation of the phases, the organic phase was washed with 1 N aqueous sodium hydroxide solution. The aqueous phase was cooled to 0 ° C, made acidic with concentrated hydrogen chloride solution and diluted with diethyl ether. The phases were separated and the aqueous phase washed twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo and the residue was dried under high vacuum. This gave 8.85 g (64% of theory, purity: 75%) of the crude product, which was used without purification. Example 228A ieri-butyl-4-benzyl-3-methyl-5-oxopiperazine-1-carboxylate [racemate]

i) N- [2- (benzylamino) propyl] -N- (feri-butoxycarbonyl) glycine

8.8 g (25 mmol, purity: 67%) of N- (ieri-butoxycarbonyl) -N- (2-oxopropyl) glycine in 160 ml of 1,2-dichloroethane were mixed with 1.76 g (1.81 ml, 16.5 mmol) of benzylamine, 1.53 g (1.46 ml, 25 mmol) of concentrated acetic acid and 7.02 g (16.6 mmol) of sodium triacetoxyborohydride were added and it was stirred overnight at room temperature. It was then concentrated in vacuo.

LC-MS (Method 1A): R _t = 0.71 min; MS (ESIpos): m / z = 323 [M + H] ⁺ ii) ieri-butyl-4-benzyl-3-methyl-5-oxopiperazine-1-carboxylate

The crude product N- [2- (benzylamino) propyl] -N- (ieri-butoxycarbonyl) glycine from i) was dissolved in 132 ml of DMF and mixed with 4.88 g (25 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide- added hydrochloride. It was stirred overnight at room temperature, treated with 2.44 g (12.7 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimidhydrochlorid and stirred again overnight. It was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo, the residue was dried under high vacuum and purified by silica gel chromatography (dichloromethane, then dichloromethane / methanol 100: 2). This gave 6.64 g (79% of theory) of the desired product.

LC-MS (Method 1A): R _t = 1.02 min; MS (ESIpos): m / z = 305 [M + H] ⁺

Example 229A ieri-butyl-4-benzyl-2-ethyl-5-methyl-3-oxopiperazine-1-carboxylate [mixture of diastereomers, 4 isomers]

5.91 ml (5.91 mmol) of a 1 M lithium hexamethyldisilazide solution in THF were added at -78 ° C. under argon to 600 mg (1.97 mmol) of ieri-butyl-4-benzyl-3-methyl-5-oxopiperazine-1-carboxylate [racemate ] was added dropwise in 24 ml of THF and stirred at -78 ° C for 30 min. Then, 0.51 ml (3.94 mmol) of ethyl trifluoromethanesulfonate was added dropwise, and it was stirred for 2 hours. It was then poured into saturated aqueous ammonium chloride solution and treated with ethyl acetate. After separation of the phases, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo and the residue was dried under high vacuum. 821 mg (87% of theory, purity: 70%) of the desired crude product were obtained.

LC-MS (Method 1A): R _t = 1.18 min; MS (ESIpos): m / z = 333 [M + H] ⁺

Example 230A ieri-butyl-2-ethyl-5-methyl-3-oxopiperazine-1-carboxylate [mixture of diastereomers, 4 isomers]

At -78 ° C., 18 ml of ammonia were admixed with 120 mg (17.3 mmol) of lithium and stirred for a few minutes. Then 821 mg (1.72 mmol) of ieri-butyl-4-benzyl-2-ethyl-5-methyl-3-oxopiperazine-1-carboxylate [diastereomer mixture, 4 isomers, Example 229 A] in 6 ml of THF were added dropwise, slowly to room temperature heated and stirred overnight at room temperature. Subsequently, first with saturated aqueous ammonium chloride solution and then with ethyl acetate. After separation of the phases, the aqueous phase was washed twice with ethyl acetate extracted, the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo and the residue was dried under high vacuum. 240 mg of the crude product were obtained, which was used without further purification. MS (Method IC): m / z = 243 [M + H] ⁺

Example 231A

3-Ethyl-6-methylpiperazin-2-one trifluoroacetate [mixture of diastereomers, 4 isomers]

To 657 mg (2.71 mmol) of iperi-butyl-2-ethyl-5-methyl-3-oxopiperazine-1-carboxylate [diastereomer mixture, 4 isomers, Example 230A] in 22 ml of dichloromethane was added 1.46 ml (2.16 g, 18.9 mmol) of trifluoroacetic acid and stirred overnight at room temperature. It was then concentrated in vacuo and the residue was dissolved in dichloromethane. It was concentrated in vacuo, the residue obtained redissolved in dichloromethane, then freed from solvent in vacuo and dried under high vacuum. The crude product obtained (1.00 g) was used without purification.

MS (Method IC): m / z = 142 [M + H] ⁺

Example 232A

Benzyl 2-ethyl-5-methyl-3-oxopiperazine-1-carboxylate [mixture of diastereomers, 4 isomers]

To 1.55 g (2.18 mmol, purity: 20%) of 3-ethyl-6-methylpiperazin-2-one trifluoroacetate [diastereomer mixture, 4 isomers] in 1 ml THF at 0 ° C a solution of 0.31 ml (0.37 g, 2.18 mmol ) Benzylchlorocarbonat added dropwise in 1.2 ml of toluene. Then a solution of 0.36 ml (0.26 g, 2.62 mmol) of triethylamine in 0.5 ml of THF was slowly added dropwise, stirred overnight at room temperature and then treated with water and ethyl acetate. After separation of the phases, the aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution. It was dried over sodium sulfate, filtered, the filtrate concentrated in vacuo and the residue dried under high vacuum, dissolved in methanol and water and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient). 84 mg (14% of theory) of the desired product were obtained.

LC-MS (Method 1A): R _t = 0.83 min; MS (ESIpos): m / z = 277 [M + H] ⁺ Example 233A

3-ethyl-6-methylpiperazin-2-one [mixture of diastereomers, 4 isomers]

84 mg of benzyl 2-ethyl-5-methyl-3-oxopiperazine-l-carboxylate [diastereomer mixture, 4 isomers, Example 232A] in 10 ml of methanol was added under argon with 97 mg (0.09 mmol) of 10% palladium on activated charcoal and Hydrogenated at RT and normal pressure for 4 h. It was then filtered, the filtrate concentrated in vacuo and the residue dried under high vacuum. 41 mg (95% of theory) of the desired product were obtained.

MS (Method IC): m / z = 143 [M + H] ⁺

Example 234A

Benzyl 2-ethyl-5-methyl-3-oxopiperazine-1-carboxylate [enantiomerically pure isomer 3]

The diastereomeric mixture from Example 232A was separated into the enantiomers on a chiral phase [Method 50D]. Yield enantiomerically pure isomer 3: 50 mg (99% ee) enantiomerically pure isomer 3: R _t = 6.72 min [Method 43E]. LC-MS (Method 1A): R _t = 0.87 min; MS (ESIpos): m / z = 277 [M + H] ⁺

Example 235A

3-ethyl-6-methylpiperazin-2-one [enantiomerically pure isomer 3]

50 mg of benzyl 2-ethyl-5-methyl-3-oxopiperazine-1-carboxylate [enantiomerically pure isomer 3, Example 234A] in 7 ml of ethanol was added under argon with 96 mg (0.09 mmol) of 10% palladium on activated charcoal and Hydrogenated at RT and normal pressure overnight. It was then filtered, the filtrate concentrated in vacuo and the residue dried under high vacuum. 28 mg (quant.) Of the desired crude product were obtained.

MS (Method IC): m / z = 143 [M + H] ⁺ Example 236A

2- (5,5-Dimethyl-3-oxopiperazin-2-yl) acetamide [racemate]

7.06 ml (6.0 g, 68 mmol) of 2-methylpropane-1,2-diamine in 150 ml of ethanol was stirred at room temperature with 6.60 g (68 mmol) of 1: 1 pyrrole-2,5-dione and allowed to stand at room temperature for 1 h touched. It was then concentrated under reduced pressure and the residue was dried under high vacuum. This gave 12.3 g (97% of theory) of the desired product.

LC-MS (Method 5A): R _t = 0.26 min; MS (ESIpos): m / z = 186 [M + H] ⁺

Example 237A

Ethyl (5-methylpyridin-2-yl) acetate

179 ml (287 mmol) of a 1.6 molar solution of w-butyllithium in hexane were added at -50 ° C. to 40.2 ml (29.1 g, 287 mmol) / V, / V-diisopropylethylamine and 14.0 ml (10.8 g, 92.8 mmol). Added dropwise 115, Ν, Ν, Ν- tetramethylethylenediamine in 115 ml of THF and it was stirred at -50 ° C for 1 h. Then 15.1 ml (14.0 g, 130 mmol) of 2,5-dimethylpyridine were added dropwise and stirred at 0 ° C for 1 h. At -78 ° C 12.5 ml (14.2 g, 131 mmol) of ethyl chlorocarbonate were added dropwise and it was stirred overnight at room temperature. Then, at 0 ° C., first 40 ml of saturated aqueous ammonium chloride solution and then 30 ml of saturated aqueous sodium chloride solution were added dropwise. At room temperature, ethyl acetate was added, the phases were separated, the aqueous phase extracted twice with ethyl acetate, the combined organic phases washed with saturated aqueous sodium chloride solution and over Dried sodium sulfate. After filtration, the filtrate was concentrated in vacuo, the residue was dried under high vacuum, dissolved in cyclohexane / ethyl acetate and purified by silica gel chromatography (cyclohexane / ethyl acetate 10: 1 - 10: 5). 6.12 g (26% of theory) of the desired product were obtained. LC-MS (Method 1A): R _t = 0.83 min; MS (ESIpos): m / z = 180 [M + H] ⁺

Example 238A

Ethyl (5-methylpiperidin-2-yl) acetate hydrochloride [mixture of diastereomers, 4 isomers]

Under argon, 2.56 g (13.9 mmol) of ethyl (5-methylpyridin-2-yl) acetate (Example 237 A) in 66 ml of acetic acid with 51 mg (0.21 mmol) of platinum (IV) oxide hydrate and overnight at room temperature and atmospheric pressure hydrogenated. It was then filtered through silica gel, the filtrate was concentrated in vacuo and the residue was treated with 100 ml of 1N aqueous hydrogen chloride solution. The mixture was concentrated in vacuo and the residue was dried under high vacuum. This gave 2.44 g (78% of theory) of the desired product. MS (Method IC): m / z = 223 [M + H] ⁺

Example 239A

2- (5-methylpiperidin-2-yl) ethanol [mixture of diastereomers, 4 isomers]

2.71 ml (2.71 mmol) of a 1.0 M lithium aluminum hydride solution in THF were added dropwise at 0 ° C. to 400 mg (1.80 mmol) of ethyl (5-methylpiperidin-2-yl) acetate hydrochloride [diastereomer mixture, 4 isomers] in 16 ml of THF and it was stirred at room temperature overnight. At 0 ° C, 1.44 ml (1.44 mmol) of a 1.0 molar lithium aluminum hydride solution in THF was added dropwise and it was stirred overnight at room temperature. At 0 ° C., 144 μl of water, 156 μl of 3 M aqueous sodium hydroxide solution and again 372 μl of water were added and the resulting precipitate was filtered off. The filtrate was concentrated in vacuo and the residue was dried under high vacuum. 275 mg (quant.) Of the desired product were obtained. MS (Method IC): m / z = 144 [M + H] ⁺ Example 240A

Ethyl {1 - [(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -5-methylpiperidin-2-yl} acetate [mixture of diastereomers, 4 isomers]

500 mg (1.49 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid in / V, / V-dimethylformamide (15 ml) with 1.36 g (1.82 ml, 10.5 mmol) of N, N-diisopropylethylamine and 398 mg (1.79 mmol) of ethyl (5-methylpiperidin-2-yl) acetate [diastereomer mixture, 4 isomers]. Then 684 mg (1.79 mmol) of HATU were added at 0 ° C and it was stirred for 2 h at room temperature. Then, 199 mg (0.899 mmol) of ethyl (5-methylpiperidin-2-yl) acetate [diastereomer mixture, 4 isomers] were added and stirred at room temperature for 1 h. It was mixed with water and purified by preparative HPLC (acetonitrile / water). 110 mg (15% of theory) of the target compound were obtained as mixture of diastereomers.

LC-MS (Method 1A): R _t = 0.98 min (diastereomer 1, 2 isomers), R _t = 1.00 min (diastereomer 2, 2 isomers); MS (ESIpos): m / z = 501 [M + H] ⁺

Example 241A

Ethyl (5-methylpiperidin-2-yl) acetate acetate [mixture of diastereomers, 4 isomers]

Under argon, 6.12 g (34.1 mmol) of ethyl (5-methylpyridin-2-yl) acetate Example 237 A in 250 ml of acetic acid with 251 mg (1.02 mmol) of platinum (IV) oxide and 1.09 g (1.02 mmol) 10 palladium on activated charcoal and it was hydrogenated overnight at room temperature and atmospheric pressure. 125 mg (0.51 mmol) of platinum (IV) oxide hydrate and 545 mg (0.51 mmol) of 10% palladium on activated charcoal were added and hydrogenation was carried out overnight at room temperature and normal pressure. The mixture was then filtered through silica gel, the filtrate was treated with 125 mg (0.51 mmol) of platinum (IV) oxide hydrate and 545 mg (0.51 mmol) of 10% palladium on activated charcoal and hydrogenated overnight at room temperature and normal pressure. It was filtered through silica gel, the filtrate concentrated in vacuo and the residue dried under high vacuum. 12.4 g of the desired crude product were obtained. GC-MS (Method 2B): R _t = 3.69 min; MS (ESIpos): m / z = 185 [M + H] ⁺

Example 242A ieri-butyl-2- (2-ethoxy-2-oxoethyl) -5-methylpiperidine-1-carboxylate [mixture of diastereomers,

4 isomers]

3.00 g (12.2 mmol) of ethyl (5-methylpiperidin-2-yl) acetate acetate [diastereomer mixture, 4 isomers, Example 241A] in 120 ml of dichloromethane were mixed with 5.96 ml (4.33 g, 42.8 mmol) of triethylamine and 4.00 g (18.3 mmol ) Di-tert-butyl dicarbonate. It was stirred overnight at room temperature and then allowed to stand at room temperature for 5 d. The mixture was then concentrated under reduced pressure, the residue was combined with ethyl acetate and water, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo and the residue was dried under high vacuum. This gave 2.11 g (39% of theory, purity: 64%) of the desired product.

LC-MS (Method 4A): R _t = 3.09 min; MS (ESIpos): m / z = 285 [M + H] ⁺ Example 243A ieri-butyl-2- [(1-hydroxycyclopropyl) methyl] -5-methylpiperidine-1-carboxylate

[Mixture of diastereomers, 4 isomers]

Under argon, 1.50 g (3.36 mmol, purity: 64%) of ieri-butyl-2- (2-ethoxy-2-oxoethyl) -5-methylpiperidine-1-carboxylate [diastereomer mixture, 4 isomers, Example 242A] in 10.8 ml of diethyl ether with 99 μΐ (96 mg, 0.34 mmol) of titanium (IV) tetrapropane-2-olate. Then were 2.37 ml (7.13 mmol) of 3M ethylmagnesium bromide solution in diethyl ether were slowly added dropwise and the mixture was stirred at room temperature overnight. Then, 10 ml of diethyl ether were added, followed by dropwise addition with cooling 99 .mu.l (96 mg, 0.34 mmol) of titanium (IV) tetrapropan-2-olate and 2.37 ml (7.13 mmol) of 3M ethylmagnesium bromide solution in diethyl ether. It was stirred for 2 h at room temperature and then added to cooled 10% aqueous sulfuric acid. After addition of diethyl ether, the phases were separated and the aqueous phase washed twice with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo and the residue was dried under high vacuum. 930 mg (quant.) Of the desired product were obtained.

MS (Method IC): m / z = 270 [M + H] ⁺

Example 244A l - [(5-methylpiperidin-2-yl) methyl] cyclopropanol trifluoroacetate [mixture of diastereomers, 4 isomers]

To 927 mg (3.44 mmol) of iperi-butyl 2 - [(1-hydroxycyclopropyl) methyl] -5-methylpiperidine-1-carboxylate [diastereomer mixture, 4 isomers, Example 243A] in 35 ml of dichloromethane was added 2.65 ml (3.92 g, 34.4%) mmol) of triflouretic acid and stirred overnight at room temperature. It was then concentrated in vacuo and dried under high vacuum. The crude product obtained (1.45 g) was used further without purification.

MS (Method IC): m / z = 170 [M + H-TFA] ⁺

Example 245A

Methyl-5-methylpyridine-2-carboxylate

To 3.00 g (21.9 mmol) of 5-methylpyridine-2-carboxylic acid in 40 ml of methanol was added dropwise 15 ml (60 mmol) of 4 M hydrogen chloride solution in dioxane, and it was stirred at room temperature overnight. Then, 10 ml (40 mmol) of 4 M hydrogen chloride solution in dioxane were added dropwise and it was stirred first at room temperature overnight and then at 70 ° C overnight. It was mixed with methanol and another 20 ml (80 mmol) of 4 M hydrogen chloride solution in dioxane and it was stirred overnight at reflux. It was then concentrated under reduced pressure and the residue was combined with water and dichloromethane. After phase separation, the aqueous phase was washed twice more with dichloromethane, the combined organic phases were washed with sodium chloride solution and then dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo and the residue was dried under high vacuum. This gave 2.08 g (59% of theory) of the desired product.

LC-MS (Method 1A): R _t = 0.55 min; MS (ESIpos): m / z = 152 [M + H] ⁺

Example 246A Methyl 5-methylpiperidine-2-carboxylate acetate [mixture of diastereomers, 4 isomers]

Under argon, 2.08 g (13.1 mmol) of methyl 5-methylpyridine-2-carboxylate (Example 245 A) in 90 ml of acetic acid with 96 mg (0.39 mmol) of platinum (IV) oxide and 417 mg (0.39 mmol) of 10% palladium on activated charcoal and hydrogenated overnight at room temperature and atmospheric pressure. Then 48 mg (0.20 mmol) of platinum (IV) oxide hydrate and 208 mg (0.20 mmol) of 10% palladium on activated charcoal were added and the mixture was hydrogenated overnight at room temperature and normal pressure. It was filtered through silica gel, the filtrate concentrated in vacuo and the residue dried under high vacuum. This gave 3.10 g of the desired crude product. LC-MS (Method 2B): R _t = 2.94 min; MS (ESIpos): m / z = 158 [M + H] ⁺ Example 247A 1-ieri-butyl-2-methyl-5-methylpiperidine-1,2-dicarboxylate [mixture of diastereomers, 4 isomers]

1.50 g (6.90 mmol) of methyl 5-methylpiperidine-2-carboxylate acetate [diastereomer mixture, 4 isomers, Example 246A] in 70 ml of dichloromethane were mixed with 4.81 ml (3.49 g, 34.5 mmol) of triethylamine and 3.01 g (13.8 mmol) of ieri-butyldicarbonate added. It was stirred overnight at room temperature. The mixture was then concentrated under reduced pressure, the residue was combined with ethyl acetate and water, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo and the residue was dried under high vacuum. This gave 1.43 g (39% of theory, purity: 62%) of the desired product.

LC-MS (Method 4A): R _t = 2.948 min (diastereomer 1, 2 isomers), R _t = 2.99 min (diastereomer 2, 2 isomers);

MS (ESIpos): m / z = 158 [M-Boc + H] ⁺

Example 248A ieri-butyl 2- (1-hydroxycyclopropyl) -5-methylpiperidine-1-carboxylate [mixture of diastereomers, 4 isomers]

Under argon, 1.00 g (3.39 mmol, purity: 62%) of l-ieri-butyl-2-methyl-5-methylpiperidine-1,2-dicarboxylate (diastereomer mixture, 4 isomers, Example 247 A) in 12.5 ml of diethyl ether with 115 μΐ (110 mg, 0.389 mmol) of titanium (IV) tetrapropan-2-olate. Then 2.75 ml (8.25 mmol) of 3 molar solution of ethylmagnesium bromide in diethyl ether were slowly added dropwise and the mixture was stirred at room temperature overnight. It was mixed with 10 ml of diethyl ether and then added dropwise with cooling 115 μΐ (110 mg, 0.389 mmol) of titanium (IV) tetrapropan-2-olate and 2.75 ml (8.25 mmol) of 3 M ethylmagnesium bromide solution in diethyl ether. It was stirred for 2 h at room temperature and then added to cooled 10% aqueous sulfuric acid. After addition of diethyl ether, the phases were separated and the aqueous phase washed twice with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo and the residue was dried under high vacuum. 410 mg (41 d.s.) of the desired product were obtained.

MS (Method IC): m / z = 256 [M + H] ⁺ Example 249A 1- (5-methylpiperidin-2-yl) cyclopropanol trifluoroacetate [mixture of diastereomers, 4 isomers]

To 410 mg (1.06 mmol) of iperi-butyl-2- (1-hydroxycyclopropyl) -5-methylpiperidine-1-carboxylate [diastereomeric mixture, 4 isomers, Example 248A] in 16 ml of dichloromethane was added 1.24 ml (1.83 g, 16.1 mmol) of trifluoroacetic acid and stirred overnight at room temperature. It was then concentrated in vacuo and dried under high vacuum. The resulting crude product (645 mg) was used without purification.

MS (Method IC): m / z = 156 [M + H-TFA] ⁺

Example 250A 2- (5-Methyl-3-oxopiperazin-2-yl) acetamide [mixture of diastereomers, 4 isomers]

5.74 ml (5.0 g, 67 mmol) of propan-1,2-diamine in 160 ml of ethanol were admixed at room temperature with 6.55 g (67 mmol) of 1-pyrrole-2,5-dione and it was stirred overnight at room temperature , It was then concentrated under reduced pressure and the residue was dried under high vacuum. This gave 12.6 g of the desired crude product.

MS (method IC): m / z = 172 [M + H] ⁺

Example 251A

2- {1 - [(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -5-methyl-3-oxopiperazine 2-yl} acetamide [mixture of diastereomers, 4 isomers]

2.42 g (7.25 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid in / V, / V-dimethylformamide (70 ml) with 2.06 g (2.78 ml, 15.9 mmol) of N, N-diisopropylethylamine, 3.31 g (8.70 mmol) of HATU and 1.49 g (8.70 mmol) of 2- (5-methyl-3-oxopiperazin-2-yl) acetamide [mixture of diastereomers, 4 Isomers] was added and it was stirred for 2.5 h at room temperature. After addition of dichloromethane and water, the phases were separated and the aqueous phase washed twice with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo and the residue was dried under high vacuum. The residue was combined with methanol and water and purified by preparative HPLC (acetonitrile / water). 480 mg (14% of theory) of the target compound were obtained. The aqueous phase from the extraction was also concentrated in vacuo and the residue is combined with methanol and water and purified by preparative HPLC (acetonitrile / water). 850 mg (24% of theory) of the target compound were again obtained.

LC-MS (Method 1A): R _t = 0.63 min; MS (ESIpos): m / z = 487 [M + H] ⁺

Example 252A 4-Benzyl-5 - ({[(2,2-dimethylpropyl) (dimethyl) silyl] oxy} methyl) -2,2-dimethylmorpholin-3-one [racemate]

32.4 mL (58.4 mmol) of 1.8 M lithium diisopropylamide solution in THF / heptane was added at -78 ° C under argon to 17.0 g (48.6 mmol) of 4-benzyl-5 - ({[ieri-butyl (dimethyl) silyl] oxy} methyl) -2-methylmorpholin-3-one [diastereomer mixture, 4 isomers] in 340 ml of THF was added dropwise. The mixture was warmed to 0 ° C. in the course of 20 min, admixed with 3.94 ml (8.97 g, 63.2 mmol) of methyl iodide and stirred for 1.5 h. It was cooled to -78 ° C, with 5.40 ml (9.72 mmol) of 1.8-M lithium diisopropylamide solution in THF / heptane, heated to 0 ° C within 20 min and treated with 0.91 ml (2.07 g, 14.6 mmol) of methyl iodide , The mixture was stirred for 1 h at room temperature and then treated cautiously with ice cooling with water. It was then concentrated in vacuo, the residue treated with ethyl acetate, washed with water and saturated aqueous sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo and the residue was dried under high vacuum. This gave 19.8% (98% of theory) of the desired crude product. LC-MS (Method 1A): R _t = 1.45 min; MS (ESIpos): m / z = 364 [M + H] ⁺

Example 253A

4-Benzyl-5- (hydroxymethyl) -2,2-dimethylmorpholin-3-one [racemate]

18.1 g (43.8 mmol) of 4-benzyl-5 - ({[(2,2-dimethylpropyl) (dimethyl) silyl] oxy} methyl) -2,2-dimethylmorpholin-3-one [racemate] in 330 ml of THF were added At room temperature with 109.5 ml (109.5 mmol) of a 1 M tetra-w-butylammonium fluoride solution in THF and stirred overnight. It was concentrated in vacuo, the residue treated with ethyl acetate and washed with water. After separation of the phases, the organic phase was dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (dichloromethane-dichloromethane / methanol 100: 3). This gave 9.99 g (89% of theory) of the desired product. LC-MS (Method 1A): R _t = 0.73 min; MS (ESIpos): m / z = 250 [M + H] ⁺

^: H-NMR (400 MHz, DMSO-de): δ [ppm] = 7.43-7.20 (m, 5H), 5.11-4.92 (m, 2H), 4.23 (d, 1H), 3.93-3.71 (m, 2H ), 3.66-3.54 (m, 2H), 3.18-3.10 (m, 1H), 1.42 (s, 3H), 1.39 (s, 3H).

Example 254A

4-Benzyl-6,6-dimethyl-5-oxomorpholine-3-carboxylic acid [racemate]

19.5 g (43.8 mmol) of 4-benzyl-5- (hydroxymethyl) -2,2-dimethylmorpholin-3-one [racemate] in 1200 ml of acetonitrile were admixed at room temperature with 37.65 g (165 mmol) of periodic acid and stirred for 15 min. Then, at 0 ° C., 647 mg (3.00 mmol) of pyridinium chlorochromate in 45 ml of acetonitrile were added and the mixture was stirred at 0 ° C. for 2 h. It was concentrated in vacuo, the residue was then treated with water and washed with ethyl acetate. After separation of the phases, the organic phase was dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo and the residue was dried under high vacuum. This gave 18.4 g (56% of theory, purity: 60%) of the desired crude product. LC-MS (Method 1A): R _t = 0.69 min; MS (ESIpos): m / z = 264 [M + H] ⁺

Example 255A

Methyl 4-benzyl-6,6-dimethyl-5-oxomorpholine-3-carboxylate [racemate]

To 18.5 g (70.4 mmol, purity: 60%) of 4-benzyl-6,6-dimethyl-5-oxomorpholine-3-carboxylic acid [racemate] in 232 ml of methanol at 0 ° C slowly 12.2 ml (16.7 g, 141 mmol ) Thionyldichlorid added dropwise. The mixture was then heated to reflux for 2 h with stirring. It was concentrated under reduced pressure and the residue was dried under high vacuum. This gave 18.4 g (80% of theory, purity: 85%) of the desired crude product. LC-MS (Method 1A): R _t = 0.87 min; MS (ESIpos): m / z = 278 [M + H] ⁺

Example 256A

4-Benzyl-5- (2-hydroxypropan-2-yl) -2,2-dimethylmorpholin-3-one [racemate]

To 9.1 g (27.9 mmol, purity: 85%) of methyl 4-benzyl-6,6-dimethyl-5-oxomorpholine-3-carboxylate [racemate] in 507 ml of THF were added slowly at 0 ° C. 32.5 ml (97.6 mmol) 3 M methylmagnesium bromide solution in diethyl ether added dropwise. The mixture was then stirred at 0 ° C. for 1 h and then at room temperature overnight. At 0 ° C., 16.7 ml (50.2 mmol) of 3M methylmagnesium bromide solution in diethyl ether were added and the mixture was stirred at room temperature overnight. Then, at 0 ° C., saturated aqueous ammonium chloride solution was added and the mixture was freed from THF in vacuo. The residue was added with dichloromethane and water, which Separate phases and the organic phase washed twice with water. Subsequently, the aqueous phase was washed with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo, the residue dried under high vacuum and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient). This gave 3.36 g (43% of theory) of the desired product.

LC-MS (Method 1A): R _t = 0.85 min; MS (ESIpos): m / z = 278 [M + H] ⁺

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.41-6.99 (m, 5H), 5.35-5.06 (m, 1H), 4.76 (s, 1H), 4.52 (d, 1H), 4.25-3.95 (m, 1H), 3.89-3.57 (m, 1H), 3.12-2.97 (m, 1H), 1.38-1.33 (m, 6H), 1.28-1.23 (m, 3H), 1.20 (s, 3H ).

Example 257A

2- (4-Benzyl-6,6-dimethylmorpholin-3-yl) propan-2-ol [racemate]

To 3.36 g (11.8 mmol) of 4-benzyl-5- (2-hydroxypropan-2-yl) -2,2-dimethylmorpholin-3-one [racemate] in 421 ml of methanol was slowly added 59.3 ml (118 mmol) of 2 M dimethyl sulfide borane complex solution in THF added dropwise. It was stirred overnight at room temperature and then under reflux for 7 h. Subsequently, 300 ml of methanol were slowly added at room temperature and it was heated with stirring for 4 h to reflux. It was then concentrated, the residue was dried under high vacuum and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient). 1.51 g (48% of theory) of the desired product were obtained.

LC-MS (Method 1A): R _t = 0.58 min; MS (ESIpos): m / z = 264 [M + H]

^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.40-7.15 (m, 5H), 5.04 (d, 1H), 4.59 (s, 1H), 3.56 (dd, 1H), 3.41 (t, 1H), 3.02-2.89 (m, 1H), 2.41-2.26 (m, 2H), 1.83 (d, 1H), 1.24 (s, 3H), 1.15 (s, 3H), 1.09 (s, 3H ), 0.96 (s, 3H). Example 258A

2- (4-Benzyl-6,6-dimethylmorpholin-3-yl) propan-2-ol [enantiomerically pure isomer 1]

1.51 g of 2- (4-benzyl-6,6-dimethylmorpholin-3-yl) -propan-2-ol [racemate, Example 257A] were separated into the enantiomers on a chiral phase [Method 51D].

Yield enantiomerically pure isomer 1: 448 mg (100% ee) enantiomerically pure isomer 1: R _t = 5.40 min [Method 44E].

LC-MS (Method 1A): R _t = 0.66 min; MS (ESIpos): m / z = 264 [M + H] ⁺

^H-NMR (400 MHz, DMSO-d _6): δ [ppm] = 7:39 to 7:11 (m, 5H), 5:04 (d, 1H), 4:59 (s, 1H), 3:56 (dd, 1H), 3:46 -3.35 (m, 1H), 3.30 (s, 1H), 2.96 (d, 1H), 2.40-2.26 (m, 2H), 1.24 (s, 3H), 1.15 (s, 3H), 1.09 (s, 3H ), 0.96 (s, 3H).

Example 259A

2- (6,6-Dimethylmorpholin-3-yl) propan-2-ol [enantiomerically pure isomer 1]

477 mg (1.81 mmol) of 2- (4-benzyl-6,6-dimethylmorpholin-3-yl) propan-2-ol] [enantiomerically pure isomer 1] in 20 ml of ethanol were dissolved under argon with 60 mg (0.56 mmol) 10%. iges palladium on activated carbon and 30 mg (0.21 mmol) of palladium (II) hydroxide and hydrogenated overnight at RT and atmospheric pressure. It was then filtered through silica gel, the filtrate concentrated in vacuo and the residue dried in a high vacuum. 307 mg (98% of theory) of the desired product were obtained.

MS (Method IC): m / z = 174 [M + H] ⁺

^: H-NMR (400 MHz, DMSO-ife): δ [ppm] = 4.41-4.23 (m, 1H), 3.50-3.26 (m, 3H), 2.72-2.60 (m, 1H), 2.37 (dd, 1H ), 1.18 (s, 3H), 1.10-0.97 (m, 9H).

Example 260A

4-Benzyl-5- (1-hydroxycyclopropyl) -2,2-dimethylmorpholin-3-one [racemate]

To 9.1 g (27.9 mmol, purity: 85%) of methyl 4-benzyl-6,6-dimethyl-5-oxomorpholine-3-carboxylate [racemate] in 350 ml of diethyl ether were added slowly at room temperature 0.83 ml (0.79 g, 2.79 mmol ) Titanium (iV) tetrapropan-2-olate and then 19.7 ml (59.1 mmol) 3 M Efhylmagnesium- bromide solution in diethyl ether added dropwise. It was stirred overnight at room temperature and then 0.83 ml (0.79 g, 2.79 mmol) of titanium (IV) tetrapropan-2-olate and 19.7 ml (59.1 mmol) of 3M ethylmagnesium bromide solution in diethyl ether were slowly added dropwise and the mixture was stirred overnight. Then, 0.21 ml (0.19 g, 0.69 mmol) of titanium (IV) tetrapropan-2-olate and 4.92 ml (14.7 mmol) of 3M ethylmagnesium bromide solution in diethyl ether were slowly added dropwise and the mixture was stirred at room temperature for 4 h. It was added to cooled 10% aqueous sulfuric acid and diluted with diethyl ether. The phases were separated, the aqueous phase washed twice with diethyl ether, the combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo, the residue dried under high vacuum and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient). This gave 1.67 g (20% of theory) of the desired product.

LC-MS (Method 1A): R _t = 0.81 min; MS (ESIpos): m / z = 276 [M + H] Ή NMR (400 MHz, DMSO- e): δ [ppm] = 7.42-7.07 (m, 5H), 5.48 (s, IH), 5.38 (d, IH), 4.29-4.13 (m, IH), 4.08 3.94 (m, IH), 3.83 (dd, IH), 2.79 (dd, IH), 1.47-1.25 (m, 6H), 0.80-0.66 (m, IH), 0.62-0.45 (m, IH), 0.42 -0.21 (m, 2H).

Example 261A 1 - (4-Benzyl-6,6-dimethylmorpholin-3-yl) cyclopropanol [racemate]

To 1.57 g (5.36 mmol) of 4-benzyl-5- (1-hydroxycyclopropyl) -2,2-dimethylmorpholin-3-one [racemate] in 300 ml of methanol was added slowly at room temperature 26.8 ml (53.6 mmol) of 2M dimethylsulfide borane complex. Solution dripped in THF. It was stirred overnight at room temperature and then under reflux for 2 h. Subsequently, 300 ml of methanol were slowly added at room temperature and it was heated to reflux for 4 h. It was then concentrated and the residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient). 1.08 g (77% of theory) of the desired product were obtained.

LC-MS (Method 1A): R _t = 0.49 min; MS (ESIpos): m / z = 262 [M + H] ⁺ ^: H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.47-7.15 (m, 5H), 4.96 (s, IH) , 4.68 (d, IH), 3.91 (t, IH), 3.53 (dd, IH), 2.80 (d, IH), 2.32 (d, IH), 1.70 (d, IH), 1.53 (dd, IH), 1.26-1.14 (m, 3H), 0.95 (s, 3H), 0.82-0.70 (m, IH), 0.58-0.45 (m, 2H), 0.40-0.30 (m, IH)

Example 262A 1- (4-Benzyl-6,6-dimethylmorpholin-3-yl) cyclopropanol [enantiomerically pure isomer 1]

1.08 g of 1- (4-benzyl-6,6-dimethylmorpholin-3-yl) cyclopropanol [racemate, Example 261 A] were separated into the enantiomers on a chiral phase [Method 52D].

Yield enantiomerically pure isomer 1: 340 mg (100% ee) enantiomerically pure isomer 1: R _t = 4.53 min [Method 44E]. LC-MS (Method 1A): R _t = 0.55 min; MS (ESIpos): m / z = 262 [M + H] ⁺

^H-NMR (400 MHz, DMSO-d _6): δ [ppm] = 7:47 to 7:15 (m, 5H), 4.96 (s, 1H), 4.68 (d, 1H), 3.91 (dd, 1H), 3:53 (dd, 1H), 2.80 (d, 1H), 2.32 (d, 1H), 1.70 (d, 1H), 1.53 (dd, 1H), 1.26-1.14 (m, 3H), 0.95 (s, 3H), 0.82-0.70 (m, 1H), 0.58-0.45 (m, 2H), 0.40-0.30 (m, 1H).

Example 263A 1- (6,6-Dimethylmorpholin-3-yl) cyclopropanol [enantiomerically pure isomer 1]

339 mg (1.29 mmol) of 1- (4-benzyl-6,6-dimethylmorpholin-3-yl) cyclopropanol [enantiomerically pure isomer 1] in 15 ml of ethanol were dissolved under argon with 43 mg (0.40 mmol) of 10% palladium on activated charcoal and 21 mg (0.15 mmol) of palladium (II) hydroxide added and hydrogenated overnight at RT and atmospheric pressure. It was then filtered through silica gel, the filtrate concentrated in vacuo and the residue dried under high vacuum. 217 mg (98% of theory) of the desired product were obtained.

MS (Method IC): m / z = 172 [M + H] ⁺ Example 264A 4-Benzyl-6,6-dimethyl-5-oxomorpholine-3-carbaldehyde [racemate]

To 1.67 ml (2.43 g, 19 mmol) Ethandioyldichlorid in 195 ml of dichloromethane was slowly added dropwise at -50 ° C, a solution of 2.42 ml (2.67 g, 34.2 mmol) DMSO in 35 ml of dichloromethane and it was 10 min at -50 ° C. touched. Then, a solution of 3.48 g (13.7 mmol) of 4-benzyl-5- (hydroxymethyl) -2,2-dimethylmorpholin-3-one [racemate] in 45 ml of dichloromethane was slowly added dropwise and it was stirred at -50 ° C for 10 min , At -78 ° C., a solution of 9.53 ml (6.92 g, 68.3 mmol) of triethylamine in 25 ml of dichloromethane was added dropwise. The mixture was stirred for 2 h at -78 ° C and allowed to warm slowly to room temperature. Saturated aqueous sodium bicarbonate solution and dichloromethane were added and the phases were separated. The aqueous phase was washed twice with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo and the residue was dried under high vacuum. This gave 3.86 g (purity: 47%) of the desired crude product. LC-MS (Method 1A): R _t = 0.84 min; MS (ESIpos): m / z = 248 [M + H] ⁺ Example 265A

4-Benzyl-5- (1-hydroxyethyl) -2,2-dimethylmorpholin-3-one [mixture of diastereomers, 4 isomers]

To 3.86 g (15.6 mmol) of 4-benzyl-6,6-dimethyl-5-oxomorpholine-3-carbaldehyde [racemate] in 50 ml of THF at 0 ° C slowly 15.6 ml (46.8 mmol) of 3 M methylmagnesium iodide solution in diethyl ether dropped and stirred at room temperature for 1.5 h. It was mixed with saturated aqueous ammonium chloride solution and freed from the THF in vacuo. The residue was added with dichloromethane and water, and the phases were separated. The organic phase was washed with water and dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo and the residue was dried under high vacuum. This gave 3.65 g (82% of theory, purity: 92%) of the desired product.

LC-MS (Method 1A): R _t = 0.80 min; MS (ESIpos): m / z = 264 [M + H] ⁺ ^: H-NMR (400 MHz, DMSO-ife): δ [ppm] = 7.40-7.12 (m, 5H), 5.17-4.91 (m, 2H , 4.31-4.20 (m, 1H), 4.10-3.95 (m, 1H), 3.89-3.66 (m, 2H), 3.09-2.93 (m, 1H), 1.41-1.27 (m, 6H), 1.11 (i.e. , 3H).

Example 266A 1- (4-Benzyl-6,6-dimethylmorpholin-3-yl) ethanol [mixture of diastereomers, 4 isomers]

To 3.65 g (12.9 mmol, purity: 92%) of 4-benzyl-5- (1-hydroxyethyl) -2,2-dimethylmorpholin-3-one [diastereomer mixture, 4 isomers] in 400 ml of methanol was slowly added 64.5 ml ( 129 mmol) 2 M dimethyl sulfide borane complex solution in THF was added dropwise. It was stirred overnight at room temperature and then under reflux for 2 h. Subsequently, 400 ml of methanol were slowly added at room temperature and then heated to reflux for 4 h. After concentration, the residue was purified by silica gel chromatography (dichloromethane / methanol 100: 2 - 100: 3). This gave 2.11 g (65% of theory) of the desired product.

LC-MS (Method 1A): R _t = 0.50 min; MS (ESIpos): m / z = 250 [M + H] ⁺

Example 267A 1- (4-Benzyl-6,6-dimethylmorpholin-3-yl) ethanol [enantiomerically pure isomer 2]

2.11 g of 1- (4-benzyl-6,6-dimethylmorpholin-3-yl) ethanol [mixture of diastereomers, 4 isomers, Example 266A] were separated into the enantiomers on a chiral phase [Method 53D].

Yield enantiomerically pure isomer 2: 577 mg (100% ee) enantiomerically pure isomer 2: R _t = 6.55 min [Method 45E]. LC-MS (Method 1A): R _t = 0.52 min; MS (ESIpos): m / z = 250 [M + H] ⁺

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.40-7.16 (m, 5H), 4.66 (d, 1H), 4.31-4.19 (m, 1H), 4.05 (d, 1H), 3.72-3.48 (m, 2H), 3.00 (d, 1H), 2.40-2.23 (m, 2H), 1.79 (d, 1H), 1.20-1.06 (m, 6H), 0.98 (s, 3H).

Example 268A 1- (4-Benzyl-6,6-dimethylmorpholin-3-yl) ethanol [enantiomerically pure isomer 1]

Yield enantiomerically pure isomer 1: 65 mg (100% ee) enantiomerically pure isomer 1: R _t = 5.75 min [Method 45E].

LC-MS (Method 1A): R _t = 0.50 min; MS (ESIpos): m / z = 250 [M + H] ⁺

^: H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.41-7.17 (m, 5H), 4.63 (d, 1H), 4.48 (d, 1H), 3.91- 3.80 (m, 1H) , 3.57-3.43 (m, 2H), 2.96 (d, 1H), 2.40-2.20 (m, 2H), 1.79 (d, 1H), 1.22-1.09 (m, 6H), 1.01-0.90 (m, 3H) , Example 269A 1- (6,6-dimethylmorpholin-3-yl) ethanol [enantiomerically pure isomer 2]

575 mg (2.31 mmol) of 1- (4-benzyl-6,6-dimethylmorpholin-3-yl) ethanol [enantiomerically pure isomer 2] in 26 ml of ethanol under argon with 76 mg (0.71 mmol) of 10% palladium on charcoal and 38 mg (0.27 mmol) of palladium (II) hydroxide added and hydrogenated overnight at RT and atmospheric pressure. It was then filtered through silica gel, the filtrate concentrated in vacuo and the residue dried under high vacuum. 217 mg (98% of theory) of the desired product were obtained.

MS (Method IC): m / z = 160 [M + H] ⁺

^: H-NMR (400 MHz, DMSO-ife): δ [ppm] = 6.93-6.58 (m, 1H), 4.70-4.48 (m, 2H), 4.43-4.31 (m, 1H), 2.64 (d, 2H ), 2.33 (ddd, 2H), 1.36 (s, 3H), 1.25-1.12 (m, 6H).

Example 270A 1- (6,6-dimethylmorpholin-3-yl) ethanol [enantiomerically pure isomer 1]

64 mg (0.26 mmol) of 1- (4-benzyl-6,6-dimethylmorpholin-3-yl) ethanol [enantiomerically pure isomer 1] in 10 ml of ethanol under argon with 8.6 mg (0.07 mmol) of 10% palladium on charcoal and 4.3 mg (0.03 mmol) of palladium (II) hydroxide added and hydrogenated overnight at room temperature and atmospheric pressure. It was then filtered through silica gel, the filtrate concentrated in vacuo and the residue dried under high vacuum. 41 mg (100% of theory) of the desired product were obtained. MS (Method IC): m / z = 160 [M + H] Exemplary embodiments Example 1

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [(4R) -4-efhoxy-2- (hydroxymethyl) pyrrolidine-1 -yl] methanone [mixture of diastereomers, 2 isomers]

There were 120 mg (0.291 mmol, purity: 81%) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-l, 3-benzoxazole-5-carboxylic acid and 63.4 mg (0.437 mmol ) [(4R) -4-ethoxypyrrolidin-2-yl] methanol [diastereomeric mixture, 2 isomers] in A ^ N-dimethylformamide (1.34 ml) and 132 mg (178 μΐ, 0.510 mmol) /V ,.V-diisopropylethylamine added. Then 133 mg (0.350 mmol) of HATU were added at RT and stirred for 1 h. The reaction solution was then purified without further work-up directly by preparative RP-HPLC (acetonitrile / water). Yield: 87.4 mg (63% of theory).

LC-MS (Method 2A): R _t = 0.76 min (enantiomerically pure isomer 1), R _t = 0.78 min (enantiomerically pure isomer 2); MS (ESIpos): m / z = 461 [M + H] ⁺ .

Example 2

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [(4R) -4-ethoxy-2- (hydroxymethyl) -pyrrolidine-1 -yl] methanone [enantiomerically pure isomer 1]

Diastereomer separation on chiral phase of 83.0 mg of the compound from Example 1 according to Method 28D gave 46.0 mg of Example 2 (enantiomerically pure isomer 1) and 21.0 mg of Example 3 (enantiomerically pure isomer 2).

HPLC (Method 26E): R _t = 5.10 min,> 99.9 ee; LC-MS (Method 1A): R _t = 0.80 min; MS (ESIpos): m / z = 461 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.70 (t, IH), 8.52 (d, IH), 7.53 (d, IH), 7.46 (dd, IH), 6.98 (s , IH), 6.84 (s, IH), 4.77 (t, IH), 4.63 (d, 2H), 4.20 (br, s, IH), 3.95 (br, s, IH), 3.92 (s, 3H ), 3.71-3.62 (m, IH), 3.59-3.48 (m, 2H), 3.25-3.16 (m, IH), 2.02 (d, 2H), 1.00 (t, 3H), two protons obscured. Example 3

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [(4R) -4-ethoxy-2- (hydroxymethyl) -pyrrolidine-1 -yl] methanone [enantiomerically pure isomer 2]

HPLC (Method 26E): R _t = 10.9 min,> 99.9 ee;

LC-MS (Method 1A): R _t = 0.82 min; MS (ESIpos): m / z = 461 [M + H] ⁺ ;

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.69 (t, IH), 8.52 (d, IH), 7.53 (d, IH), 7.45 (dd, IH), 6.96 (s, IH), 6.81 (s, IH), 4.80 (brs, IH), 4.63 (d, 2H), 4.23-4.06 (m, IH), 3.91 (s, 4H), 3.58 (br. 2H), 2.25-1.88 (m, 2H), 1.06 (br., 3H), four protons obscured. Example 4

(2- {[1- (4-Chloro-2-yl) ethyl] am

(hydroxymethyl) pyrrolidin-1-yl] methanone [mixture of diastereomers, 2 isomers]

There were 200 mg (0.454 mmol, purity: 79%) of 2- {[1- (4-chloropyridin-2-yl) ethyl] amino} -7-methoxy-l, 3-benzoxazole-5-carboxylic acid [racemate] and 99.0 mg (0.682 mmol) of [(4R) -4-ethoxypyrrolidin-2-yl] methanol [diastereomer mixture, 2 isomers] in A ^ / V-dimethylformamide (2.09 ml) are initially charged with 206 mg (277 μl, 1.59 mmol) / VN-Diisopropylefhylamin added. Subsequently, 207 mg (0.545 mmol) of HATU were added at RT and the mixture was stirred for 1 h. The reaction solution was then purified without further workup directly by preparative RP-HPLC (acetonitrile / water). Yield: 141 mg (65% of theory).

LC-MS (Method 1A): R _t = 0.85 min (enantiomerically pure isomer 1), R _t = 0.87 min (enantiomerically pure isomer 2);

MS (ESIpos): m / z = 475 [M + H] ⁺ ; LC-MS (Method 2A): R _t = 0.82 min; MS (ESIpos): m / z = 475 [M + H] ⁺ .

Example 5

(2- {[1- (4-Chloropyridin-2-yl) ethyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [(4R) -4-ethoxy-2- (hydroxymethyl) pyrrolidine -l-yl] methanone [enantiomerically pure isomer 1]

Chiral phase diastereomer separation of 137 mg of the compound of Example 4 according to Method 29D gave 46.0 mg of Example 5 (enantiomerically pure isomer 1) and 48.0 mg of Example 6 (enantiomerically pure isomer 2); only the two isomers of the main pyrrolidine isomer of Example 4 could be isolated. HPLC (Method 27E): R _t = 6.39 min,> 99.9 ee;

LC-MS (Method 1A): R _t = 0.85 min; MS (ESIpos): m / z = 475 [M + H] ⁺ ;

^: H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.68 (d, 1H), 8.52 (d, 1H), 7.58 (d, 1H), 7.44 (dd, 1H), 6.97 (s , 1H), 6.82 (s, 1H), 4.98 (quin, 1H), 4.76 (t, 1H), 4.19 (br, s, 1H), 3.95 (br, s, 1H), 3.91 (s, 3H ), 3.72-3.60 (m, 1H), 3.58-3.45 (m, 2H), 3.25-3.12 (m, 1H), 2.01 (br, d, 2H), 1.52 (d, 3H), 0.99 (t, 3H), two protons obscured.

Example 6

Chiral phase diastereomer separation of 137 mg of the compound of Example 4 according to Method 29D gave 46.0 mg of Example 5 (enantiomerically pure isomer 1) and 48.0 mg of Example 6 (enantiomerically pure isomer 2); only the two isomers of the main pyrrolidine isomer of Example 4 could be isolated.

HPLC (Method 27E): R _t = 8.23 min,> 97 ee;

LC-MS (Method 1A): R _t = 0.85 min; MS (ESIpos): m / z = 475 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-de): δ [ppm] = 8.69 (d, 1H), 8.53 (d, 1H), 7.58 (d, 1H), 7.44 (dd, 1H), 6.96 (s, 1H), 6.82 (s, 1H), 4.99 (quin, 1H), 4.81-4.69 (m, 1H), 4.19 (br, s, 1H), 3.99-3.85 (m, 4H), 3.70-3.60 (m , 1H), 3.56-3.48 (d, 2H), 3.24-3.13 (m, 1H), 2.01 (br, d, 2H), 1.51 (d, 3H), 0.99 (t, 3H), two protons concealed. Example 7

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [(4R) -4- (2,2-difluoroethoxy) -2- (hydroxymethyl) pyrrolidin-1-yl] methanone [enantiomerically pure isomer 2]

There were 80.0 mg (0.194 mmol, purity: 81%) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-l, 3-benzoxazole-5-carboxylic acid and 38.7 mg (0.214 mmol ) [(4R) -4- (2,2-Difluoroethoxy) pyrrolidin-2-yl] methanol [enantiomerically pure isomer 2] in A ^ N-Dimefhylformamid (0.84 ml) and with 55.2 mg (74 μΐ, 0.427 mmol) A ^ N-diisopropylethylamine added. 88.6 mg (0.233 mmol) of HATU were subsequently added at RT and the mixture was stirred overnight. The reaction solution was then purified without further workup directly by preparative RP-HPLC (acetonitrile / water). Yield: 46.1 mg (47% of theory).

Ή NMR (400 MHz, DMSO-ife): δ [ppm] = 8.69 (t, 1H), 8.52 (d, 1H), 7.53 (s, 1H), 7.45 (dd, 1H), 6.99 (s, 1H ), 6.84 (s, 1H), 6.03 (tt, 1H), 4.78 (t, 1H), 4.63 (d, 2H), 4.21 (br, s, 1H), 4.09 (br, s, 1H), 3.92 (s, 3H), 3.76-3.36 (m, 6H), 2.12-2.01 (m, 2H). Example 8

(2- {[1 - (4-chloropyridin-2-yl) ethyl] amino} -7-methoxy-1, 3-benzoxazol-5-yl) [(4R) -4- ^[(1,1-2 H2 ) ethyloxy] -2- (hydroxymethyl) pyrrolidin-1-yl] methanone [enantiomerically pure isomer 2]

Diastereomer separation on achiral phases of 247 mg of the compound from Example 97 according to Method 2F and further diastereomer separation on a chiral phase according to Method 29D gave 30.0 mg of Example 8 (enantiomerically pure isomer 2).

HPLC (Method 27E): R _t = 10.1 min,> 99.9 ee; LC-MS (Method 1A): R _t = 0.86 min; MS (ESIpos): m / z = 477 [M + H] ⁺ ;

^: H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.69 (d, 1H), 8.53 (d, 1H), 7.58 (s, 1H), 7.44 (dd, 1H), 6.96 (s , 1H), 6.82 (s, 1H), 4.99 (quin, 1H), 4.77 (br, s, 1H), 4.19 (br, s, 1H), 3.99-3.85 (m, 4H), 3.74-3.59 (m, 1H), 3.53 (d, 2H), 2.01 (d, 2H), 1.51 (d, 3H), 0.98 (s, 3H), one proton concealed.

Example 9 {(4R) -1 - [(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -4- [( 1, 1 - ² H ₂ ) ethyloxy] pyrrolidin-2-yl} acetonitrile [enantiomerically pure isomer]

200 mg (0.599 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 85.1 mg (0.545 mmol) of {(4R) 4 - [(l, l- ² H ² ) ethyloxy] pyrrolidin-2-yl} acetonitrile [mixture of diastereomers, 2 isomers] in A 1 N-dimethylformamide (2.51 ml) and 246 mg (332 μΐ, 1.91 mmol) / V, / V-diisopropylethylamine added. Subsequently, 249 mg (0.654 mmol) of HATU were added at RT and the mixture was stirred overnight. The reaction solution was then purified without further workup directly by preparative RP-HPLC (acetonitrile / water). The crude product was then further purified by Method 30D and again by preparative RP-HPLC (acetonitrile / water). Yield: 15.5 mg (5% of theory), only one isomer could be isolated.

HPLC (Method 28E): R _t = 16.8 min,> 99.9 ee;

LC-MS (Method 2A): R _t = 0.91 min; MS (ESIpos): m / z = 472 [M + H] ⁺ ; Ή NMR (400 MHz, DMSO- e): δ [ppm] = 8.75 (t, 1H), 8.52 (d, 1H), 7.53 (d, 1H), 7.46 (dd, 1H), 6.97 (s, 1H ), 6.84 (s, 1H), 4.63 (d, 2H), 4.28 (m 1H), 4.02 (br, s, 1H), 3.93 (s, 3H), 3.69 (dd, 1H), 3.40 (d, 1H), 3.10 (dd, 1H), 2.98 (d, 1H), 2.34-2.23 (m, 1H), 1.90 (m 1H), 0.99 (m, 3H).

Example 10 (2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) {(2 _L S ', 4R) -4- (cyclopropyloxy) -2 - [(3,3-difluorazetidin-l-yl) carbonyl] pyrrolidin-l-yl} methanone

[enantiomerically pure isomer]

292 mg (crude product, purity: 26%) of (4R) -1 - [(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5- yl) carbonyl] -4- (cyclopropyloxy) -L-proline

[enantiomerically pure isomer, Example 26A] and 85.6 mg (0.661 mmol) of 3,3-difluoroazetidine hydrochloride in A ^ N-Dimefhylformamid presented (4.90 ml) and treated with 311 mg (419 μΐ, 2.40 mmol) of NN-diisopropylethylamine. Then 274 mg (0.721 mmol) of HATU were added at RT and stirred for 2 h. The reaction solution was first purified without further workup directly by preparative RP-HPLC (acetonitrile / water) and then again by method 3F. Yield: 33.8 mg (9% of theory).

LC-MS (Method 1A): R _t = 0.86 min; MS (ESIpos): m / z = 562 [M + H] ⁺ ;

^: H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.73 (t, 1H), 8.52 (d, 1H), 7.53 (d, 1H), 7.46 (dd, 1H), 7.00 (i.e. , 1H), 6.84 (d, 1H), 4.96 (m _c, 1H), 4.75 (m _c, 1H), 4.64 (d, 2H), 4:48 to 4:23 (m, 3H), 4.19 (br. s., 1H), 3.93 (m, 3H), 3.82 (dd, 1H), 3.55 (d, 1H), 3.24-3.13 (m, 1H), 2.38-2.29 (m, 1H), 2.02 (m _c , 1H), 0.59-0.29 (m, 4H). Example 11

(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) {(2S, 4R) -4- (cyclopropyloxy) -2 - [( 3-fluoroazetidin-1-yl) carbonyl] pyrrolidin-1-yl} methanone [enantiomerically pure isomer]

[enantiomerically pure isomer, Example 26A] and 73.7 mg (0.661 mmol) of 3-fluoroazetidine hydrochloride in A ^ N-Dimefhylformamid presented (4.90 ml) and treated with 311 mg (419 μΐ, 2.40 mmol) of NN-diisopropylethylamine. Then 274 mg (0.721 mmol) of HATU were added at RT and stirred for 2 h. The reaction solution was first purified without further workup directly by preparative RP-HPLC (acetonitrile / water) and then again by method 3F. Yield: 26.4 mg (8% of theory).

LC-MS (Method 1A): R _t = 0.80 min; MS (ESIpos): m / z = 544 [M + H] ⁺ ; ^: H NMR (400 MHz, DMSO δ [ppm] = 8.73 (t, IH), 8.52 (d, IH), 7.53 (s, IH), 7.46 (dd, IH), 6.99 (s, IH), 6.83 (d, IH), 5.61-5.29 (m, IH), 4.92-4.07 (m, 7H), 3.98-3.88 (m, 4H), 3.79 (d, IH), 3.54 (d, IH), 3.20 (br , s., IH), 2.35-2.22 (m, IH), 1.99 (d, IH), 0.57-0.27 (m, 4H).

Example 12

(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [(2S, 4R) -4- (cyclopropyloxy) -2- (hydroxymethyl ) pyrrolidin-1-yl] methanone [enantiomerically pure isomer]

There were added 60.0 mg (0.146 mmol, purity: 81%) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 26.5 mg (0.160 mmol ) [(2S, 4R) -4- (Cyclopropyloxy) pyrrolidin-2-yl] methanol [enantiomerically pure isomer] in

(1.20 ml) and admixed with 75 mg (101 μΐ, 0.58 mmol) /V ,.V-diisopropylethylamine. 66 mg (0.18 mmol) of HATU were then added at RT and the mixture was stirred overnight. The reaction solution was then purified without further workup directly by preparative RP-HPLC (acetonitrile / water). Yield: 27.0 mg (37% of theory).

LC-MS (Method 1A): R _t = 0.78 min; MS (ESIpos): m / z = 473 [M + H] ⁺ ; ^: H NMR (400 MHz, DMSO-de): δ [ppm] = 8.69 (t, 1H), 8.52 (d, 1H), 7.53 (s, 1H), 7.45 (dd, 1H), 7.00 (s, 1H), 6.86 (s, 1H), 4.77 (t, 1H), 4.63 (d, 2H), 4.18 (br, s, 1H), 4.06 (br, s, 1H), 3.92 (s, 3H) , 3.73-3.41 (m, 4H), 3:09 (m _c., 1H), 2:07 to 2:03 (m, 2H), 0:47 to 0:23 (m, 4H).

Example 13

(2- {[1- (4-Chloropyridin-2-yl) ethyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [(2 _L S ', 4R) -4- (cyclopropyloxy) -2- (hydroxymethyl) pyrrolidin-1-yl] methanone [mixture of diastereomers, isomers]

There were 150 mg (0.341 mmol, purity: 79%) of 2- {[1- (4-chloropyridin-2-yl) ethyl] amino} -7-methoxy-l, 3-benzoxazole-5-carboxylic acid [racemate] and 62.0 mg (0.375 mmol) of [(2S, 4R) -4- (cyclopropyloxy) pyrrolidin-2-yl] methanol [enantiomerically pure isomer] in / V, / V-dimethylformamide (1.48 ml) are initially charged with 96.9 mg (131 l, 0.750 mmol) / VN-diisopropylethylamine. Subsequently, 155 mg (0.409 mmol) of HATU were added at RT and stirred for 2 h. The reaction solution was then purified without further workup directly by preparative RP-HPLC (acetonitrile / water). Yield: 70 mg (41% of theory).

LC-MS (Method 1A): R _t = 0.88 min; MS (ESIpos): m / z = 487 [M + H] ⁺ . Example 14

(2- {[1- (4-Chloropyridin-2-yl) ethyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [(2 _L S ', 4R) -4- (cyclopropyloxy) -2- (hydroxymethyl) pyrrolidin-1-yl] methanone [enantiomerically pure isomer 1]

Chiral phase diastereomer separation of 55.5 mg of the compound of Example 13 according to Method 31D gave 16.3 mg of Example 14 (enantiomerically pure isomer 1) and 18.3 mg of Example 15 (enantiomerically pure isomer 2).

HPLC (Method 4E): R _t = 5.81 min,> 99.0% ee;

LC-MS (Method 2A): R _t = 0.85 min; MS (ESIpos): m / z = 487 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.68 (d, 1H), 8.52 (d, 1H), 7.57 (d, 1H), 7.43 (dd, 1H), 6.99 (s , 1H), 6.84 (s, 1H), 4.98 (quin., 1H), 4.76 (t, 1H), 4.17 (br. S., 1H), 4.06 (br. S., 1H), 3.91 (s, 3H), 3.75-3.38 (m, 4H), 3.09 (br, s, 1H), 2.05 (d, 2H), 1.52 (d, 3H), 0.43-0.22 (m, 4H).

Example 15

(2- {[1- (4-Chloropyridin-2-yl) ethyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [(2 _L S ', 4R) -4- (cyclopropyloxy) -2- (hydroxymethyl) pyrrolidin-1-yl] methanone [enantiomerically pure isomer 2]

Chiral phase diastereomer separation of 55.5 mg of the compound of Example 13 according to Method 31D gave 16.3 mg of Example 14 (enantiomerically pure isomer 1) and 18.3 mg of Example 15 (enantiomerically pure isomer 2). HPLC (Method 4E): R _t = 7.08 min,> 99.0 ee;

LC-MS (Method 2A): R _t = 0.85 min; MS (ESIpos): m / z = 487 [M + H] ⁺ ;

^: H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.69 (d, 1H), 8.53 (d, 1H), 7.58 (d, 1H), 7.44 (dd, 1H), 6.97 (s , 1H), 6.84 (s, 1H), 4.99 (quin., 1H), 4.77 (t, 1H), 4.17 (br. S., 1H), 4.04 (br. S., 1H), 3.91 (s, 4H), 3.76-3.38 (m, 4H), 3.08 (br, s, 1H), 2.05 (d, 2H), 1.51 (d, 3H), 0.44-0.22 (m, 4H). Example 16

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) {2 - [(3,3-difluoroacetyl-1-yl) carbonyl] -2-methylpyrrolidin-1-yl-ylmethanone [enantiomerically pure isomer]

There were obtained 96.0 mg (crude product, purity: 71%) of l - [(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl]. 2-methylproline [enantiomerically pure isomer] and 22.0 mg (0.170 mmol) of 3,3-difluorazedidine hydrochloride in A ^ N-dimethylformamide (2.36 ml) and treated with 79.9 mg (108 μΐ, 618 mmol) / VN-diisopropylethylamine. 70.5 mg (0.186 mmol) of HATU were subsequently added at RT and the mixture was stirred overnight. The reaction solution became without further workup directly purified by preparative RP-HPLC (acetonitrile / water). Yield: 43.2 mg (53% of theory).

LC-MS (Method 3A): R _t = 1.95 min; MS (ESIpos): m / z = 520 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.74 (t, 1H), 8.52 (d, 1H), 7.52 (d, 1H), 7.45 (dd, 1H), 7.07 (i.e. , 1H), 6.80 (d, 1H), 4.63 (d, 2H), 4.35 (q, 2H), 3.93 (s, 3H), 3.73-3.60 (m, 1H), 3.58-3.48 (m, 1H), 2.19-2.08 (m, 1H), 1.97-1.78 (m, 3H), 1.53 (s, 3H), two protons obscured.

Example 17

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) {2- [(3-fluoroacetyl-1-yl) carbonyl] -2 -methylpyrrolidin-1-yl} methanone [enantiomerically pure isomer]

There were obtained 96.0 mg (crude product, purity: 71%) of l - [(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl]. 2-Methylproline [enantiomerically pure isomer] and 19.0 mg (0.170 mmol) of 3-fluorazedidine hydrochloride in A ^ N-dimethylformamide (1.29 ml) and treated with 79.9 mg (108 μΐ, 618 mmol) / V, / V-diisopropylethylamine. 70.5 mg (0.186 mmol) of HATU were subsequently added at RT and the mixture was stirred overnight. The reaction solution was purified directly by preparative RP-HPLC (acetonitrile / water) without further work-up. Yield: 34.7 mg (44% of theory).

LC-MS (Method 1A): R _t = 0.82 min; MS (ESIpos): m / z = 502 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.73 (t, 1H), 8.52 (d, 1H), 7.52 (d, 1H), 7.45 (dd, 1H), 7.05 (i.e. , 1H), 6.80 (d, 1H), 5.37 (dm _c , 1H), 4.63 (d, 2H), 4.42-3.85 (m, 7H), 3.68-3.58 (m, 1H), 3.57-3.49 (m, 1H), 2.15-2.04 (m, 1H), 1.98-1.80 (m, 3H), 1.51 (s, 3H). Example 18

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [2-methyl-2- (morpholin-4-ylcarbonyl) -pyrrolidine-1 -yl] methanone [enantiomerically pure isomer]

There were obtained 96.0 mg (crude product, purity: 71%) of l - [(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl]. 2-methylproline [enantiomerically pure isomer] and 14.8 mg (0.170 mmol) of morpholine in A ^ / V-Dimefhylformamid (2.36 ml) and treated with 79.9 mg (108 μΐ, 618 mmol) /V ,.V-Diisopropylethylamin added. 70.5 mg (0.186 mmol) of HATU were subsequently added at RT and the mixture was stirred overnight. The reaction solution was purified directly by preparative RP-HPLC (acetonitrile / water) without further work-up. Yield: 41.9 mg (52% of theory).

LC-MS (Method 1A): R _t = 0.82 min; MS (ESIpos): m / z = 513 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.72 (t, 1H), 8.52 (d, 1H), 7.52 (d, 1H), 7.45 (dd, 1H), 6.97 (i.e. , 1H), 6.71 (d, 1H), 4.62 (d, 2H), 3.92 (s, 3H), 3.81-3.67 (m, 1H), 3.61-3.37 (m, 9H), 2.19- 1.73 (m, 4H ), 1.52 (s, 3H).

Example 19

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (hydroxymethyl) -2,5-dimethylmorpholin-4-yl] methanone [enantiomerically pure isomer 1]

There were added 60.0 mg (0.169 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 29.4 mg (0.203 mmol) (3.6 -Dimethylmorpholin-3-yl) methanol [enantiomerically pure isomer 1, Example 40A] in A ^ N-Dimefhylformamid initially charged (0.78 ml) and treated with 76.4 mg (103 μΐ, 0.591 mmol) / VN-diisopropylethylamine. 77.1 mg (0.203 mmol) of HATU were then added at RT and the mixture was stirred overnight. The reaction solution was then purified without further work-up directly by preparative RP-HPLC (acetonitrile / water). Yield: 22.2 mg (28% of theory).

LC-MS (Method 1A): R _t = 0.83 min; MS (ESIpos): m / z = 461 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-de): δ [ppm] = 8.69 (t, IH), 8.51 (d, IH), 7.52 (d, IH), 7.45 (dd, IH), 6.86 (d, IH), 6.71 (d, IH), 4.87 (t, IH), 4.62 (d, 2H), 3.94-3.85 (m, 4H), 3.81-3.64 (m, 3H), 3.38 (dd, IH), 3.21 (d, IH), 2.87 (dd, IH), 1.34 (s, 3H), 0.97 (d, 3H).

Example 20

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (hydroxymethyl) -2,5-dimethylmorpholin-4-yl] methanone [enantiomerically pure isomer 4]

There were added 60.0 mg (0.169 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 29.4 mg (0.203 mmol) (3.6 -Dimethylmorpholin-3-yl) methanol [enantiomerically pure isomer 4, Example 41A] in / V, / V-dimethylformamide (0.78 ml) and treated with 76.4 mg (103 μΐ, 0.591 mmol) / VN-diisopropylethylamine. 77.1 mg (0.203 mmol) of HATU were then added at RT and the mixture was stirred overnight. The reaction solution was then purified without further work-up directly by preparative RP-HPLC (acetonitrile / water). Yield: 28.1 mg (36% of theory).

LC-MS (Method 1A): R _t = 0.87 min; MS (ESIpos): m / z = 461 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.70 (t, IH), 8.52 (d, IH), 7.52 (d, IH), 7.46 (dd, IH), 6.86 (i.e. , IH), 6.71 (s, IH), 4.81 (t, IH), 4.63 (d, 2H), 3.91 (s, 3H), 3.79 (d, 2H), 3.65 (d, 2H), 3.53 (d, IH), 2.91 (dd, IH), 1.32 (s, 3H), 0.98 (d, 3H), one proton obscured. Example 21

(2- {[(4-Chloro-pyridin-2-yl) methyl] -amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (fluoro-ethyl) -2- (2-hydroxyethyl) -2- methylmorpholin-4-yl] methanone [mixture of diastereomers, 4 isomers]

H

There were added 200 mg (0.563 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 120 mg (0.676 mmol) of 2- [5 - (Fluoromethyl) -2-methylmorpholin-2-yl] ethanol [diastereomer mixture, 4 isomers] in A ^ N-Dimefhylformamid (2.67 ml) and treated with 255 mg (343 μΐ, 1.97 mmol) /V ,.V-Diisopropylethylamin added , Subsequently, 257 mg (0.676 mmol) of HATU were added at RT and the mixture was stirred overnight. The reaction solution was then purified without further work-up directly by preparative RP-HPLC (acetonitrile / water). Yield: 138 mg (49% of theory).

LC-MS (Method 1A): R _t = 0.80 min; MS (ESIpos): m / z = 493 [M + H] ⁺ . Example 22

(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (fluoromethyl) -2- (2-hydroxypropyl) -2- methylmorpholin-4-yl] methanone [racemate]

H

There were obtained 92.1 mg (0.276 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 101 mg (0.331 mmol) of 1- [5 - (Fluoromethyl) -2-methylmorpholin-2-yl] propan-2-ol trifluoroacetate [racemate] in / V, / V-dimethylformamide (1.27 ml) and charged with 125 mg (168 μΐ, 0.965 mmol) /V ,.V-diisopropylethylamine were added. Subsequently, at RT

Added 126 mg (0.331 mmol) HATU and stirred overnight. The reaction solution was then purified without further work-up directly by preparative RP-HPLC (acetonitrile / water). Yield: 57.6 mg (41% of theory). LC-MS (Method 1A): R _t = 0.84 min; MS (ESIpos): m / z = 507 [M + H] ⁺ .

Example 23

(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (fluoromethyl) -2- (2-hydroxypropyl) -2- methylmorpholin-4-yl] methanone [enantiomerically pure isomer 1]

H

Enantiomer separation on a chiral phase of 52 mg of the compound from Example 22 according to Method 33D gave 19.6 mg of Example 23 (enantiomerically pure isomer 1).

HPLC (Method 30E): R _t = 9.64 min,> 99.0% ee;

LC-MS (Method 1A): R _t = 0.84 min; MS (ESIpos): m / z = 507 [M + H] ⁺ . Example 24 (2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [(5R) -2- (2-hydroxyethyl) -2, 5-dimethylmorpholin-4-yl] methanone [enantiomerically pure isomer]

Cl 100 mg (0.282 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 53.8 mg (0.338 mmol) of 2 - [( 5R) -2,5-dimethylmorpholin-2-yl] efhanol [enantiomerically pure isomer] in A ^ N-Dimefhylformamid (1.30 ml) and treated with 127 mg (172 μΐ, 0.986 mmol) /V ,.V-Diisopropylethylamin added. Subsequently, 129 mg (0.338 mmol) of HATU were added at RT and stirred overnight. The reaction solution was then purified without further work-up directly by preparative RP-HPLC (acetonitrile / water). Yield: 96.6 mg (72% of theory).

LC-MS (Method 1A): R _t = 0.77 min; MS (ESIpos): m / z = 475 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-de): δ [ppm] = 8.69 (t, 1H), 8.52 (d, 1H), 7.53 (d, 1H), 7.45 (dd, 1H), 6.82 (s, 1H), 6.67 (s, 1H), 4.63 (d, 2H), 4.30 (t, 1H), 3.92 (s, 3H), 3.74 (dd, 1H), 3.38 (br, s, 2H), 2.96 ( br., 1H), 2.02 (m _c , 1H), 1.45 (br., 1H), 1.22 (d, 3H), 1.08 (br, s, 3H), three protons obscured.

Example 25

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [(5R) -2- (2-hydroxypropyl) -2,5- dimethylmorpholin-4-yl] methanone [enantiomerically pure isomer]

80.0 mg (0.225 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 46.8 mg (0.270 mmol) of l - [( 5R) -2,5-dimethylmorpholin-2-yl] propan-2-ol [enantiomerically pure isomer] in / V, / V-dimethylformamide (1.27 ml) and treated with 102 mg (137 μΐ, 0.789 mmol) / V, / V-diisopropylethylamine added. Subsequently, at RT, 103 mg (0.270 mmol) of HATU were added and the mixture was stirred overnight. The reaction solution was then purified without further workup directly by preparative RP-HPLC (acetonitrile / water). Yield: 80.5 mg (71% of theory).

LC-MS (Method 1A): R _t = 0.82 min; MS (ESIpos): m / z = 489 [M + H] ⁺ ; Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.68 (t, 1H), 8.51 (d, 1H), 7.52 (d, 1H), 7.45 (dd, 1H), 6.81 (s, 1H), 6.66 (d, 1H), 4.63 (d, 2H), 4.23 (d, 1H), 3.92 (s, 3H), 3.78-3.67 (m, 2H), 3.29 (br, s, 1H), 2.96 (br d, 1H), 1.91 (dd, 1H), 1.35-1.25 (m, 1H), 1.21 (d, 3H), 1.16 (br, s, 3H), 1.10 (d, 3H), a proton obscured. Example 26

(2- {[1- (4-chloropyridin-2-yl) ethyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [(5R) -2- (2-hydroxypropyl) -2, 5-dimethylmorpholin-4-yl] methanone [mixture of diastereomers, 2 isomers]

H

There were 120 mg (0.276 mmol, purity: 80%) of 2- {[1- (4-chloropyridin-2-yl) ethyl] amino} -7-methoxy-l, 3-benzoxazole-5-carboxylic acid [racemate] and 57.4 mg (0.331 mmol) of l - [(5R) -2,5-dimethylmorpholin-2-yl] propan-2-ol [enantiomerically pure isomer] in A ^ N-dimethylformamide (1.27 ml) are initially charged with 125 mg (168 μΐ , 0.966 mmol) /V ,.V- diisopropylethylamine. Then 126 mg (0.331 mmol) of HATU were added at RT and stirred overnight. The reaction solution was then purified without further workup directly by preparative RP-HPLC (acetonitrile / water) and then purified by method 4F. Yield: 30.2 mg (19% of theory).

LC-MS (Method 1A): R _t = 0.89 min; MS (ESIpos): m / z = 503 [M + H] ⁺ . Example 27

(2- {[1- (4-chloropyridin-2-yl) ethyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [(5R) -2- (2-hydroxypropyl) -2, 5-dimethylmorpholin-4-yl] methanone [enantiomerically pure isomer 2] H

Diastereomer separation on a chiral phase of 25 mg of the compound from Example 26 according to Method 34D and further purification according to Method 5F gave 5.3 mg of Example 27 (enantiomerically pure isomer 2). HPLC (Method 31E): R _t = 8.00 min,> 99.0 ee;

LC-MS (Method 1A): R _t = 0.91 min; MS (ESIpos): m / z = 503 [M + H] ⁺ ;

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.70 (d, 1H), 8.52 (d, 1H), 7.57 (d, 1H), 7.44 (dd, 1H), 6.78 (s, 1H), 6.65 (s, 1H), 4.98 (quin, 1H), 3.91 (s, 3H), 3.78-3.63 (m, 2H), 2.95 (br, s, 1H), 1.91 (dd, 1H), 1.51 (d, 3H), 1.35-1.12 (m, 7H), 1.09 (d, 3H), four protons obscured.

Example 28

(2- {[1- (4-Chloropyridin-2-yl) ethyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [(5R) -5-ethyl-2- (2-hydroxyethyl ) -2-methylmorpholin-4-yl] methanone [mixture of diastereomers, 2 isomers]

200 mg (0.599 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 145 mg (0.840 mmol) of 2 - [( 5R) -5-ethyl-2-methylmorpholin-2-yl] ethanol [diastereomeric mixture, 2 isomers] in / V, / V-dimethylformamide (2.76 ml) and containing 271 mg (365 μΐ, 2.10 mmol) / V, / V-diisopropylethylamine added. 273 mg (0.719 mmol) of HATU were then added at RT and the mixture was stirred overnight. The reaction solution became subsequently purified without further work-up directly by means of preparative RP-HPLC (acetonitrile / water). Yield: 196 mg (64% of theory).

LC-MS (Method 1A): R _t = 0.83 min (enantiomerically pure isomer 1), R _t = 0.85 min (enantiomerically pure isomer 2); MS (ESIpos): m / z = 489 [M + H] ⁺ .

Example 29

(2- {[1- (4-Chloropyridin-2-yl) ethyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [(5R) -5-ethyl-2- (2-hydroxyethyl ) -2-methylmorpholin-4-yl] methanone [enantiomerically pure isomer 1]

Diastereomer separation on a chiral phase of 195 mg of the compound from Example 28 according to Method 35D and further purification by means of preparative RP-HPLC (acetonitrile / water) gave 21 mg of Example 29 (enantiomerically pure isomer 1).

HPLC (Method IE): R _t = 9.78 min,> 99.9% ee;

LC-MS (Method 1A): R _t = 0.79 min; MS (ESIpos): m / z = 489 [M + H] ⁺ ;

^: H-NMR (400 MHz, DMSO-de): δ [ppm] = 8.72 (t, 1H), 8.52 (d, 1H), 7.53 (d, 1H), 7.46 (dd, 1H), 6.81 (br. s., 1H), 6.65 (s, 1H), 4.63 (d, 2H), 4.33 (br, s, 1H), 3.91 (s, 3H), 3.82 (d, 1H), 3.49 (see p. , 3H), 1.79 (m _c , 1H), 1.60 (br, s, 3H), 1.13 (br, s, 3H), 0.83 (br, s, 3H), three protons obscured.

Example 30

((2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [2- (2-hydroxyethyl) -5- (methoxymethyl) -2 -methylmorpholin-4-yl] methanone [mixture of diastereomers, 4 isomers] H

300 mg (0.899 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 221 mg (1.17 mmol) of 2- [5 - (methoxymethyl) -2-methylmorpholin-2-yl] ethanol [mixture of diastereomers, 4 isomers] in (4.14 ml) and treated with 407 mg (548 μΐ, 3.15 mmol) /V ,.V- diisopropylethylamine. 410 mg (1.08 mmol) of HATU were then added at RT and stirred overnight. The reaction solution was then purified without further work-up directly by preparative RP-HPLC (acetonitrile / water). Yield: 277 mg (61% of theory).

LC-MS (Method 1A): R _t = 0.80 min; MS (ESIpos): m / z = 505 [M + H] ⁺ . Example 31

((2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [2- (2-hydroxyethyl) -5- (methoxymethyl) -2 -methylmorpholin-4-yl] methanone [enantiomerically pure isomer 1]

H

Diastereomer separation on a chiral phase of 270 mg of the compound from Example 30 according to Method 36D gave 21 mg of Example 31 (enantiomerically pure isomer 1).

HPLC (Method 32E): R _t = 4.68 min,> 99.9% ee;

LC-MS (Method 1A): R _t = 0.73 min; MS (ESIpos): m / z = 505 [M + H] ⁺ . Example 32

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [2- (2-hydroxyethyl) -2,5,5-trimethylmorpholine. 4-yl] methanone [racemate]

H

120 mg (0.338 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 70.2 mg (0.406 mmol) of 2- (2 , 5,5-trimethylmorpholin-2-yl) ethanol [racemate] [racemate] in A ^ N-dimethylformamide (1.56 ml) and treated with 153 mg (206 μΐ, 1.18 mmol) / VN-diisopropylethylamine. Subsequently 154 mg (0.406 mmol) of HATU were added at RT and stirred overnight. The reaction solution was then purified without further work-up directly by preparative RP-HPLC (acetonitrile / water). Yield: 60.6 mg (34% of theory).

LC-MS (Method 1A): R _t = 0.85 min; MS (ESIpos): m / z = 489 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.66 (t, IH), 8.51 (d, IH), 7.53 (d, IH), 7.45 (dd, IH), 6.75 (i.e. , IH), 6.61 (d, IH), 4.63 (d, 2H), 4.26 (t, IH), 3.90 (s, 3H), 3.45-3.34 (s, 4H), 3.22 (d, IH), 3.12 ( d, IH), (1.74 m _c, IH), 1:54 to 1:37 (m, 7H) 1.08 (s, 3H).

Example 33

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [2- (2-hydroxyethyl) -2,5,5-trimethylmorpholine. 4-yl] methanone [enantiomerically pure isomer 2]

H

l Enantiomer separation on a chiral phase of 55.0 mg of the compound from Example 32 according to Method 37D gave 24.4 mg of Example 33 (enantiomerically pure isomer 2).

HPLC (Method 33E): R _t = 6.74 min,> 99.0 ee;

LC-MS (Method 1A): R _t = 0.81 min; MS (ESIpos): m / z = 489 [M + H] ⁺ ; ^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.66 (t, IH), 8.51 (d, IH), 7.53 (d, IH), 7.45 (dd, IH), 6.75 (i.e. , IH), 6.61 (d, IH), 4.63 (d, 2H), 4.29 (t, IH), 3.90 (s, 3H), 3.45-3.34 (s, 4H), 3.22 (d, IH), 3.12 ( d, IH), (1.74 m _c, IH), 1:54 to 1:37 (m, 7H) 1.08 (s, 3H).

Example 34

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [2- (2-hydroxypropyl) -2,5,5-trimethylmorpholine. 4-yl] methanone [racemate]

H

120 mg (0.338 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 76.0 mg (0.406 mmol) of 1- [6 , 6-Dimethylmorpholin-3-yl] propan-2-ol [diastereomer mixture, 4 isomers] in / V, / V-dimethylformamide (1.56 ml) and with

153 mg (206 μΐ, 1.18 mmol) / VN-diisopropylethylamine were added. Subsequently, at RT

Added 154 mg (0.406 mmol) HATU and stirred overnight. The reaction solution was then purified without further workup directly by preparative RP-HPLC (acetonitrile / water). Yield: 53.9 mg (31% of theory).

LC-MS (Method 1A): R _t = 0.91 min; MS (ESIpos): m / z = 503 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.64 (t, IH), 8.51 (d, IH), 7.53 (d, IH), 7.45 (dd, IH), 6.74 (i.e. , IH), 6.61 (d, IH), 4.62 (d, 2H), 4.13 (d, IH), 3.90 (s, 3H), 3.71 (br. s., IH), 3:40 (m _c, 2H); 3.22 (mc, 2H), 1.68-1.32 (m, 8H), 1.16 (s, 3H), 1.03 (d, 3H). Example 35

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [2- (2-hydroxypropyl) -2,5,5-trimethylmorpholine. 4-yl] methanone [enantiomerically pure isomer 1]

H

Enantiomer separation on a chiral phase of 48.0 mg of the compound from Example 34 according to Method 31D gave 24.4 mg of Example 35 (enantiomerically pure isomer 1).

HPLC (Method 4E): R _t = 5.96 min,> 99.9 ee;

LC-MS (Method 1A): R _t = 0.91 min; MS (ESIpos): m / z = 503 [M + H] ⁺ ;

^: H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.67 (t, 1H), 8.51 (d, 1H), 7.53 (d, 1H), 7.45 (dd, 1H), 6.74 (i.e. , 1H), 6.61 (d, 1H), 4.62 (d, 2H), 4.15 (d, 1H), 3.90 (s, 3H), 3.71 (br, s, 1H), 3.40 (m _c , 2H), 3.22 (m _c, 2H), 1.68-1.32 (m, 8H), 1.16 (s, 3H), 1:03 (d, 3H).

Example 36

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (2-hydroxypropan-2-yl) -2-methylmorpholine. 4-yl] methanone [enantiomerically pure isomer 1]

87.3 mg (0.246 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 47.0 mg (0.295 mmol) of 2- (6 -Methylmorpholin-3-yl) propan-2-ol [enantiomerically pure isomer 1, Example 99 A] in / V, / V-dimethylformamide (1.13 ml) and presented with 111 mg (150 μΐ, 0.861 mmol) /V ,.V- diisopropylethylamine. Then 112 mg (0.295 mmol) of HATU were added at RT and stirred overnight. The reaction solution was then purified without further work-up directly by preparative RP-HPLC (acetonitrile / water). Yield: 88.4 mg (73% of theory). LC-MS (Method 1A): R _t = 0.81 min; MS (ESIpos): m / z = 475 [M + H] ⁺ .

Example 37

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (2-hydroxypropan-2-yl) -2-methylmorpholine. 4-yl] methanone [enantiomerically pure isomer 2]

108 mg (0.304 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 58.0 mg (0.364 mmol) of 2- (6 -Methylmorpholin-3-yl) propan-2-ol [enantiomerically pure isomer 2, Example 100A] in / V, / V-dimethylformamide (1.40 ml) and with 137 mg (185 μΐ, 1.06 mmol) / V, / V- Diisopropylethylamine added. Subsequently 139 mg (0.364 mmol) of HATU were added at RT and the mixture was stirred overnight. The reaction solution was then purified without further work-up directly by preparative RP-HPLC (acetonitrile / water). Yield: 94.6 mg (65% of theory).

LC-MS (Method 1A): R _t = 0.81 min; MS (ESIpos): m / z = 475 [M + H] ⁺ .

Example 38

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (hydroxymethyl) -2,2,5-trimethylmorpholine-4- yl] methanone [racemate]

There were added 150 mg (0.449 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 85.9 mg (0.539 mmol) (3.6 , 6-trimethylmorpholin-3-yl) methanol [racemate] in A ^ N-dimethylformamide (2.07 ml) and admixed with 203 mg (274 μΐ, 1.57 mmol) /V ,.V-diisopropylethylamine. 205 mg (0.539 mmol) of HATU were subsequently added at RT and the mixture was stirred overnight. The reaction solution was then purified without further work-up directly by preparative RP-HPLC (acetonitrile / water). Yield: 45.0 mg (21% of theory).

LC-MS (Method 1A): R _t = 0.88 min; MS (ESIpos): m / z = 475 [M + H] ⁺ . Example 39

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (hydroxymethyl) -2,2,5-trimethylmorpholine-4- yl] methanone [enantiomerically pure isomer 1]

Enantiomer separation on chiral phase of 64.9 mg of the compound from Example 38 according to Method 38D gave 27.0 mg of Example 39 (enantiomerically pure isomer 1) and 23.0 mg of Example 40 (enantiomerically pure isomer 2).

HPLC (Method 34E): R _t = 10.9 min,> 99.0% ee;

LC-MS (Method 1A): R _t = 0.83 min; MS (ESIpos): m / z = 475 [M + H] ⁺ . Example 40

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (hydroxymethyl) -2,2,5-trimethylmorpholine-4- yl] methanone [enantiomerically pure isomer 2]

HPLC (Method 34E): R _t = 13.6 min,> 99.0 ee;

LC-MS (Method 1A): R _t = 0.83 min; MS (ESIpos): m / z = 475 [M + H] ⁺ . Example 41

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (methoxymethyl) -2,2-dimethylmorpholin-4-yl] methanone [racemate]

120 mg (0.360 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 68.7 mg (0.431 mmol) of 5- (methoxymethyl ) -2,2-dimethylmorpholine [racemate] in / V, / V-dimethylformamide (1.66 ml) and admixed with 163 mg (219 μΐ, 1.26 mmol) / V, / V-diisopropylethylamine. Subsequently, 164 mg (0.431 mmol) of HATU were added at RT and the mixture was stirred overnight. The reaction solution was then without further Work-up directly purified by preparative RP-HPLC (acetonitrile / water). Yield: 146 mg (84% of theory).

LC-MS (Method 1A): R _t = 0.90 min; MS (ESIpos): m / z = 475 [M + H] ⁺ ;

^H-NMR (400 MHz, DMSO-d _6): δ [ppm] = 8.71 (t, 1H), 8:52 (d, 1H), 7:52 (d, 1H), 7:46 (dd, 1H), 6.86 (br , 1H), 6.72 (br, s, 1H), 4.63 (d, 2H), 3.91 (s, 3H), 3.78 (dd, 1H), 3.65-3.12 (m, 32H), 1.26-0.94 (m, 6H), nine protons greatly widened and obscured by water signal.

Example 42

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (fluoromethyl) -2,2-dimethylmorpholin-4-yl] methanone [racemate]

There were 80.0 mg (0.240 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-l, 3-benzoxazole-5-carboxylic acid and 42.3 mg (0.288 mmol) of 5- (fluoromethyl ) -2,2-dimethylmorpholine [racemate] in A ^ N-dimethylformamide (1.10 ml) and admixed with 108 mg (146 μΐ, 0.839 mmol) / VN-diisopropylethylamine. 109 mg (0.288 mmol) of HATU were then added at RT and the mixture was stirred overnight. The reaction solution was then purified without further work-up directly by preparative RP-HPLC (acetonitrile / water). Yield: 54.8 mg (45% of theory).

LC-MS (Method 1A): R _t = 1.94 min; MS (ESIpos): m / z = 462 [M + H] ⁺ ;

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.72 (t, 1H), 8.52 (d, 1H), 7.52 (d, 1H), 7.45 (dd, 1H), 6.85 (br. s., 1H), 6.68 (s, 1H), 4.83-4.57 (m, 4H), 3.91 (s, 3H), 3.88-3.80 (m, 1H), 1.17 (bp s, 6H), four protons obscured or greatly widened.

Example 43

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (fluoromethyl) -2,2-dimethylmorpholin-4-yl] methanone [enantiomerically pure isomer 1]

Enantiomer separation on chiral phase of 50 mg of the compound of Example 42 according to Method 39D gave 16.4 mg of Example 43 (enantiomerically pure isomer 1).

HPLC (Method 35E): R _t = 5.31 min,> 99.0 ee; LC-MS (Method 1A): R _t = 0.91 min; MS (ESIpos): m / z = 463 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-de): δ [ppm] = 8.72 (t, 1H), 8.52 (d, 1H), 7.52 (d, 1H), 7.45 (dd, 1H), 6.85 (br. s., 1H), 6.68 (s, 1H), 4.83-4.57 (m, 4H), 3.91 (s, 3H), 3.88-3.80 (m, 1H), 1.17 (bp s, 6H), four protons concealed broadened.

Example 44 (2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) (2,5,5-trimethylmorpholin-4-yl) methanone [ racemate]

150 mg (0.422 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 65.5 mg (0.507 mmol) of 2,5, 5-trimethylmorpholine [racemate] in / V, / V-dimethylformamide (2.01 ml) and treated with 191 mg (258 μΐ, 0.507 mmol) of N, N-diisopropylethylamine. Subsequently, 193 mg (0.507 mmol) of HATU were added at RT and stirred for 1 h. The reaction solution was then purified without further work-up directly by preparative RP-HPLC (acetonitrile / water). Yield: 126 mg (67% of theory).

LC-MS (Method 1A): R _t = 0.95 min; MS (ESIpos): m / z = 445 [M + H] ⁺ ; Ή NMR (400 MHz, DMSO- e): δ [ppm] = 8.68 (t, 1H), 8.51 (d, 1H), 7.52 (d, 1H), 7.45 (dd, 1H), 6.88 (d, 1H ), 6.73 (d, 1H), 4.63 (d, 2H), 3.91 (s, 3H), 3.69 (m 1H), 3.48 (m _c , 1H), 3.43-3.34 (m, 2H), 2.80 (dd, 1H), 1.40 (s, 3H), 1.36 (s, 3H), 0.99 (d, 3H).

Example 45 (2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) (2,5,5-trimethylmorpholin-4-yl) methanone [ enantiomerically pure isomer 1]

Enantiomer separation on a chiral phase of 118 mg of the compound from Example 44 according to Method 40D gave 53.4 mg of Example 45 (enantiomerically pure isomer 1). HPLC (Method 36E): R _t = 8.18 min,> 99.9 ee;

LC-MS (Method 1A): R _t = 0.95 min; MS (ESIpos): m / z = 445 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-de): δ [ppm] = 8.68 (t, 1H), 8.51 (d, 1H), 7.52 (d, 1H), 7.45 (dd, 1H), 6.88 (d, 1H), 6.73 (d, 1H), 4.62 (d, 2H), 3.91 (s, 3H), 3.69 (m _c, 1H), 3:48 (d, 1H), 3:42 to 3:34 (m, 2H), 2.80 ( dd, 1H), 1.40 (s, 3H), 1.36 (s, 3H), 0.99 (d, 3H). Example 46

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (3-hydroxycyclobutyl) -2-methylmorpholin-4-yl] methanone [mixture of diastereomers, 4 isomers]

There were added 100 mg (0.282 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 57.9 mg (0.338 mmol) of 3- (6 -Methylmorpholin-3-yl) cyclobutanol [diastereomer mixture, 4 isomers] in A ^ N-dimethylformamide (1.30 ml) and treated with 127 mg (172 μΐ, 0.986 mmol) /V ,.V-Diisopropylethylamin added. Subsequently, 129 mg (0.338 mmol) of HATU were added at RT and stirred overnight. The reaction solution was then purified without further work-up directly by preparative RP-HPLC (acetonitrile / water). Yield: 91.8 mg (67% of theory).

LC-MS (Method 1A): R _t = 0.78 min (diastereomer 1, 2 isomers), R _t = 0.79 min (diastereomer 2, 2 isomers); MS (ESIpos): m / z = 487 [M + H] ⁺ .

Example 47

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (3-hydroxycyclobutyl) -2-methylmorpholin-4-yl] methanone [diastereomer 1, 2 isomers]

Diastereomer separation on achiral phase of 86.0 mg of the compound from Example 46 according to Method 1F gave 18.1 mg of Example 47 (diastereomer 1, 2 isomers) and 49.3 mg of Example 48 (diastereomer 2, 2 isomers).

LC-MS (Method 1A): R _t = 0.81 min (diastereomer 1, 2 isomers), MS (ESIpos): m / z = 487 [M + H] ⁺ . Example 48

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (3-hydroxycyclobutyl) -2-methylmorpholin-4-yl] methanone [diastereomer 2, 2 isomers]

Diastereomer separation on achiral phase of 86.0 mg of the compound from Example 46 according to Method 1F gave 18.1 mg of Example 47 (diastereomer 1, 2 isomers) and 49.3 mg of Example 48 (diastereomer 2, 2 isomers). LC-MS (Method 1A): R _t = 0.82 min (diastereomer 2,, 2 isomers), MS (ESIpos): m / z = 487 [M + H] ⁺ .

Example 49

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (3-hydroxycyclobutyl) -2-methylmorpholin-4-yl] methanone [enantiomerically pure isomer 1]

Enantiomer separation on a chiral phase of 15.0 mg of the compound from Example 47 according to Method 41D gave 6.2 mg of Example 49 (enantiomerically pure isomer 1) and 7.2 mg of Example 50 (enantiomerically pure isomer 2).

HPLC (method 20E): R _t = 6.63 min,> 99.9 ee; LC-MS (Method 1A): R _t = 0.81 min; MS (ESIpos): m / z = 487 [M + H] ⁺ . Example 50

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (3-hydroxycyclobutyl) -2-methylmorpholin-4-yl] methanone [enantiomerically pure isomer 2]

HPLC (Method 20E): R _t = 15.9 min,> 99.9 ee;

LC-MS (Method 1A): R _t = 0.81 min; MS (ESIpos): m / z = 487 [M + H] ⁺ . Example 51

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (3-hydroxycyclobutyl) -2-methylmorpholin-4-yl] methanone [enantiomerically pure isomer 3]

Enantiomer separation on chiral phase of 45.0 mg of the compound from Example 48 according to Method 42D gave 14.2 mg of Example 51 (enantiomerically pure isomer 3) and 19.8 mg of Example 52 (enantiomerically pure isomer 4). HPLC (Method 27E): R _t = 5.23 min,> 99.9 ee;

LC-MS (Method 1A): R _t = 0.78 min; MS (ESIpos): m / z = 487 [M + H] ⁺ .

Example 52

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (3-hydroxycyclobutyl) -2-methylmorpholin-4-yl] methanone [enantiomerically pure isomer 4]

Enantiomer separation on chiral phase of 45.0 mg of the compound from Example 48 according to Method 42D gave 14.2 mg of Example 51 (enantiomerically pure isomer 3) and 19.8 mg of Example 52 (enantiomerically pure isomer 4).

HPLC (Method 27E): R _t = 10.4 min,> 99.9 ee;

LC-MS (Method 1A): R _t = 0.78 min; MS (ESIpos): m / z = 487 [M + H] ⁺ .

Example 53

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) (2-hydroxy-7-methyl-8-oxa-5-azaspiro [ 3.5] non-5-yl) methanone [enantiomerically pure cw isomer 1]

There were added 60.0 mg (0.169 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 39.3 mg (0.203 mmol) of cw-7. Methyl 8-oxa-5-azaspiro [3.5] nonan-2-ol hydrochloride [enantiomerically pure isomer 1] in A ^ N-Dimefhylformamid (0.78 ml) and charged with 76.4 mg (103 μΐ, 0.591 mmol) /V ,. -Diisopropylethylamin added. 77.1 mg (0.203 mmol) of HATU were then added at RT and the mixture was stirred for 1 h. Subsequently, another 39.3 mg (0.203 mmol) of cw-7-methyl-8-oxa-5-azaspiro [3.5] nonan-2-ol hydrochloride [enantiomerically pure isomer 1] and 76.4 mg (103 μΐ, 0.591 mmol) / V ,. Added V-diisopropylethylamine and stirred at RT for 1 h. The reaction solution was then purified without further work-up directly by preparative RP-HPLC (acetonitrile / water). Yield: 49.0 mg (60% of theory).

LC-MS (Method 1A): R _t = 0.76; MS (ESIpos): m / z = 473 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.71 (t, 1H), 8.52 (d, 1H), 7.53 (d, 1H), 7.46 (dd, 1H), 6.92 (i.e. , 1H), 6.79 (d, 1H), 5.09 (d, 1H), 4.63 (d, 2H), 3.93 (s, 3H), 3.86 (q, 1H), 3.62 (dd, 1H), 3.49 (d, 2H), 2.91 (dd, 1H), 2.69 (m _c, 1H), 2:39 to 2:28 (m, 1H), 2:21 to 2:12 (m, 1H), 1.85 (t, 1H), 0.91 (d, 3H); a proton obscured.

Example 54

(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (difluoromethyl) -2- (2-hydroxyethyl) -2- methylmorpholin-4-yl] methanone [racemate]

H

There were added 100 mg (0.282 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 70.2 mg (0.338 mmol) of 2- [5 - (Difluoromethyl) -2-methylmorpholin-2-yl] ethanol [diastereomer 1, 2 isomers] in / V, / V-dimethylformamide (1.34 ml) and with 127 mg (171 μΐ, 0.986 mmol) / V, / V -Diisopropylethylamin added. Subsequently, 129 mg (0.338 mmol) of HATU were added at RT and stirred overnight. The reaction solution was then purified without further workup directly by preparative RP-HPLC (acetonitrile / water) and then purified by method 6F. Yield: 5.4 mg (3% of theory). LC-MS (Method 1A): R _t = 0.85 min; MS (ESIpos): m / z = 511 [M + H] ⁺ . Example 55

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (2-hydroxy-2-methylpropyl) -2-methylmorpholine. 4-yl] methanone [racemate]

There were 63.2 mg (0.178 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 37.0 mg (0.214 mmol) of 2-methyl l- (6-methylmorpholin-3-yl) propan-2-ol [diastereomer 2, 2 isomers] in / V, / V-dimethylformamide (0.82 ml) and 80.5 mg (108 μΐ, 0.623 mmol) / V, / V-diisopropylethylamine added. 81.2 mg (0.214 mmol) of HATU were then added at RT and the mixture was stirred overnight. The reaction solution was then purified without further work-up directly by preparative RP-HPLC (acetonitrile / water). Yield: 66.4 mg (76% of theory).

LC-MS (Method 1A): R _t = 0.86 min; MS (ESIpos): m / z = 489 [M + H] ⁺ .

Example 56 (2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (2-hydroxy-2-methylpropyl) -2- methylmorpholin-4-yl] methanone [enantiomerically pure isomer 1]

Enantiomer separation on chiral phase of 60.0 mg of the compound from Example 55 according to Method 23D gave 28.0 mg of Example 56 (enantiomerically pure isomer 1) and 29.0 mg of Example 57 (enantiomerically pure isomer 2).

HPLC (Method 31E): R _t = 7.06 min,> 99.9 ee; LC-MS (Method 1A): R _t = 0.83 min; MS (ESIpos): m / z = 489 [M + H] ⁺ .

Example 57

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (2-hydroxy-2-methylpropyl) -2-methylmorpholine. 4-yl] methanone [enantiomerically pure isomer 2]

HPLC (Method 31E): R _t = 9.33 min,> 99.9 ee;

LC-MS (Method 1A): R _t = 0.83 min; MS (ESIpos): m / z = 489 [M + H] ⁺ . Example 58

(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [(5R) -5- (2-hydroxyethyl) -2,2- dimethylmorpholin-4-yl] methanone [mixture of enantiomers, 2 isomers]

70.0 mg (0.210 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 41.1 mg (0.252 mmol) of 2 - [( 3R) -6,6-dimethylmorpholin-3-yl] efhanol [enantiomeric mixture, 2 isomers, enantiomeric ratio: ca. 85: 15] in A ^ N-dimethylformamide (1.00 ml) and 94.9 mg (128 μΐ, 0.734 mmol) /V, .V- diisopropylethylamine. 95.7 mg (0.252 mmol) of HATU were subsequently added at RT and the mixture was stirred for 1 h. The reaction solution was then purified without further work-up directly by means of preparative RP-HPLC (acetonitrile / water). Yield: 64.0 mg (61% of theory, mixture of enantiomers, 2 isomers, enantiomeric ratio: about 85:15).

LC-MS (Method 1A): R _t = 0.79 min; MS (ESIpos): m / z = 475 [M + H] ⁺ ;

^: H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm] = 8.66 (br.s .., 1H), 8.51 (d, 1H), 7.52 (d, 1H), 7.45 (dd, 1H), 6.82 (br, s, 1H), 6.67 (s, 1H), 4.63 (s, 2H), 4.37 (br, s, 1H), 3.91 (s, 3H), 3.79 (dd, 1H), 3.51- 3.34 (m, 3H), 1.99-1.76 (m, 2H), 1.27-0.96 (m, 6H), three protons strongly broadened or obscured.

Example 59 (2- {[1- (4-chloropyridin-2-yl) ethyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [(5R) -5- (2-hydroxyethyl) - 2,2-dimethylmorpholin-4-yl] methanone [mixture of diastereomers, 4 isomers]

There were 70.0 mg (0.159 mmol, purity: 79%) of 2- {[1- (4-chloropyridin-2-yl) ethyl] amino} -7-methoxy-l, 3-benzoxazole-5-carboxylic acid [racemate] and 30.4 mg (0.191 mmol) of 2 - [(3R) -6,6- Dimethylmorpholin-3-yl] ethanol [enantiomer mixture, 2 isomers, enantiomeric ratio: about 85: 15] in N, / V-Dimefhylformamid (0.73 ml) and charged with 71.9 mg (97 μΐ, 0.557 mmol) of N, N-diisopropylethylamine added. 72.6 mg (0.191 mmol) of HATU were subsequently added at RT and the mixture was stirred for 1 h. The reaction solution was then purified directly by preparative RP-HPLC (acetonitrile / water) and Method F without further work-up. Yield: 44.0 mg (51% of theory, diastereomer mixture, 4 isomers, about 91: 9 diastereomer ratio).

LC-MS (Method 1A): R _t = 0.75 min; 0.84 min; MS (ESIpos): m / z = 489 [M + H] ⁺ . Example 60 (2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) {5-

[(difluoromethoxy) methyl] -2- (2-hydroxyethyl) -2-methylmorpholin-4-yl} methanone

[enantiomerically pure isomer]

There were added 50.0 mg (0.141 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 38.1 mg (0.169 mmol) of 2- {5 [(Difluoromethoxy) methyl] -2-methylmorpholin-2-yl] -ethanoi [enantiomerically pure isomer] in / V, / V-dimethylformamide (0.671 ml) and treated with 63.7 mg (85.9 μΐ, 0.493 mmol) / V, / V- Diisopropylethylamine added. 64.3 mg (0.169 mmol) of HATU were subsequently added at RT and the mixture was stirred overnight. The reaction solution was then purified without further workup directly by preparative RP-HPLC (acetonitrile / water). Yield: 18.6 mg (23% of theory).

LC-MS (Method 1A): R _t = 0.87 min; MS (ESIpos): m / z = 541 [M + H] ⁺ . Example 61

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [2- (2-hydroxypropyl) -2-methylmorpholin-4-yl] methanone [enantiomerically pure isomer]

H

80.0 mg (0.225 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 43.1 mg (0.270 mmol) of 1- (2 -Methylmorpholin-2-yl) propan-2-ol [enantiomerically pure isomer] in A ^ N-Dimefhylformamid (1.04 ml) and charged with 102 mg (137 μΐ, 0.789 mmol) /V ,.V-Diisopropylethylamin added. Subsequently, at RT, 103 mg (0.270 mmol) of HATU were added and the mixture was stirred overnight. The reaction solution was then purified without further work-up directly by preparative RP-HPLC (acetonitrile / water). Yield: 81.5 mg (76% of theory).

LC-MS (Method 1A): R _t = 0.78 min; MS (ESIpos): m / z = 475 [M + H] ⁺ ;

^: H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.71 (t, 1H), 8.52 (d, 1H), 7.52 (d, 1H), 7.46 (dd, 1H), 6.85 (br , 1H), 6.71 (s, 1H), 4.63 (d, 2H), 4.40-4.14 (br, m, 1H), 3.91 (s, 3H), 3.86-3.45 (br, m, 4H ), 3.18 (d, 1H), 1.68-0.93 (m, 8H), two protons obscured.

Example 62

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (2-hydroxypropyl) -2,2-dimethylmorpholine-4- yl] methanone [enantiomerically pure isomer 1]

125 mg (0.376 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 78.1 mg (0.451 mmol) of 1- [6 , 6-Dimethylmorpholin-3-yl] propan-2-ol [diastereomer mixture, 4 isomers] in A ^ N-Dimefhylformamid (1.79 ml) and treated with 170 mg (229 μΐ, 1.32 mmol) of AyV-diisopropylethylamine. Subsequently, 171 mg (0.451 mmol) of HATU were added at RT and stirred for 1 h. The reaction solution was then purified without further workup directly by preparative RP-HPLC (acetonitrile / water) and separated into the two diastereomers. Yield: 82.9 mg (45% of theory, diastereomer 1), 73.1 mg (39% of theory, diastereomer 2). Enantiomer separation on chiral phase of 73.1 mg of diastereomer 1 according to Method 46D gave 31.0 mg of Example 62 (enantiomerically pure isomer 1) and 44.0 mg of Example 63 (enantiomerically pure isomer 2).

HPLC (Method 40E): R _t = 4.78 min,> 99.0% ee;

LC-MS (Method 1A): R _t = 0.85 min; MS (ESIpos): m / z = 489 [M + H] ⁺ .

Example 63

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (2-hydroxypropyl) -2,2-dimethylmorpholine-4- yl] methanone [enantiomerically pure isomer 2]

125 mg (0.376 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 78.1 mg (0.451 mmol) of 1- [6 , 6-Dimethylmorpholin-3-yl] propan-2-ol [diastereomer mixture, 4 isomers] in / V, / V-dimethylformamide (1.79 ml) and treated with 170 mg (229 μΐ, 1.32 mmol) / VN-diisopropylethylamine. Subsequently, 171 mg (0.451 mmol) of HATU were added at RT and stirred for 1 h. The reaction solution was then purified without further workup directly by preparative RP-HPLC (acetonitrile / water) and separated into the two diastereomers. Yield: 82.9 mg (45% of theory, diastereomer 1), 73.1 mg (39% of theory, diastereomer 2). Enantiomer separation on chiral phase of 73.1 mg of diastereomer 1 according to Method 46D gave 31.0 mg of Example 62 (enantiomerically pure isomer 1) and 44.0 mg of Example 63 (enantiomerically pure isomer 2). HPLC (Method 40E): R _t = 6.32 min,> 99.0% ee;

LC-MS (Method 1A): R _t = 0.82 min; MS (ESIpos): m / z = 489 [M + H] ⁺ .

Example 64

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (2-hydroxypropyl) -2,2-dimethylmorpholine-4- yl] methanone [enantiomerically pure isomer 3]

125 mg (0.376 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 78.1 mg (0.451 mmol) of 1- [6 , 6-Dimethylmorpholin-3-yl] propan-2-ol [diastereomer mixture, 4 isomers] in / V, / V-dimethylformamide (1.79 ml) and charged with

170 mg (229 μΐ, 1.32 mmol) / VN-diisopropylethylamine were added. Subsequently, at RT

Added 171 mg (0.451 mmol) HATU and stirred for 1 h. The reaction solution was then purified without further workup directly by preparative RP-HPLC (acetonitrile / water) and separated into the two diastereomers. Yield: 82.9 mg (45% of theory, diastereomer 1), 73.1 mg (39% of theory, diastereomer 2). Enantiomer separation on chiral phase of 73.0 mg of diastereomer 2 according to Method 46D gave 18.5 mg of Example 64 (enantiomerically pure isomer 3) and 24.0 mg of Example 65 (enantiomerically pure isomer 4).

HPLC (Method 41E): R _t = 5.13 min,> 99.0% ee;

LC-MS (Method 1A): R _t = 0.84 min; MS (ESIpos): m / z = 488 [M + H] ⁺ .

Example 65

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (2-hydroxypropyl) -2,2-dimethylmorpholine-4- yl] methanone [enantiomerically pure isomer 4]

125 mg (0.376 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 78.1 mg (0.451 mmol) of 1- [6 , 6-Dimethylmorpholin-3-yl] propan-2-ol [diastereomer mixture, 4 isomers] in A ^ N-Dimefhylformamid (1.79 ml) and treated with 170 mg (229 μΐ, 1.32 mmol) of AyV-diisopropylethylamine. Subsequently, 171 mg (0.451 mmol) of HATU were added at RT and stirred for 1 h. The reaction solution was then purified without further workup directly by preparative RP-HPLC (acetonitrile / water) and separated into the two diastereomers. Yield: 82.9 mg (45% of theory, diastereomer 1), 73.1 mg (39% of theory, diastereomer 2). Enantiomer separation on chiral phase of 73.0 mg of diastereomer 2 according to Method 46D gave 18.5 mg of Example 64 (enantiomerically pure isomer 3) and 24.0 mg of Example 65 (enantiomerically pure isomer 4).

HPLC (Method 41E): R _t = 5.13 min,> 99.0% ee;

LC-MS (Method 1A): R _t = 0.84 min; MS (ESIpos): m / z = 489 [M + H] ⁺ .

Example 66 (2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (2-hydroxypropyl) -2-methylmorpholine-4 yl] methanone [enantiomerically pure isomer 1]

150 mg (0.422 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 80.7 mg (0.406 mmol) of 1- (6 -methyl-3-yl) propan-2-ol [Diastereomer mixture, 2 isomers] in A ^ N-Dimefhylformamid (2.01 ml) and treated with 191 mg (258μ1, 1.48 mmol) / VN-Diisopropylefhylamin added. Subsequently, at RT, 193 mg (0.507 mmol) of HATU were added and the mixture was stirred overnight. The reaction solution was then purified without further work-up directly by preparative RP-HPLC (acetonitrile / water). Diastereomer separation on chiral phase of 100 mg according to Method 47D gave 44.4 mg of Example 66 (enantiomerically pure isomer 1) and 43.1 mg of Example 67 (enantiomerically pure isomer 2).

HPLC (Method 14E): R _t = 4.19 min,> 99.0 ee;

LC-MS (Method 1A): R _t = 0.79 min; MS (ESIpos): m / z = 475 [M + H] ⁺ . Example 67

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (2-hydroxypropyl) -2-methylmorpholin-4-yl] methanone [enantiomerically pure isomer 2]

150 mg (0.422 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 80.7 mg (0.406 mmol) of 1- (6 -Methylmorpholin-3-yl) propan-2-ol [diastereomer mixture, 2 isomers] in / V, / V-dimethylformamide (2.01 ml) and treated with 191 mg (258μ1, 1.48 mmol) / VN-diisopropylethylamine. Subsequently, at RT, 193 mg (0.507 mmol) of HATU were added and the mixture was stirred overnight. The reaction solution was then purified without further workup directly by preparative RP-HPLC (acetonitrile / water). Diastereomer separation on a chiral phase of 100 mg according to Method 47D gave 44.4 mg of Example 66 (enantiomerically pure isomer 1) and 43.1 mg of Example 67 (enantiomerically pure isomer 2).

HPLC (Method 14E): R _t = 5.87 min,> 99.0 ee;

LC-MS (Method 1A): R _t = 0.82 min; MS (ESIpos): m / z = 475 [M + H] ⁺ . Example 68

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) {(5R) -5- [(IR) -1-hydroxyethyl] - 2-methylmorpholin-4-yl} methanone [mixture of diastereomers, 2 isomers]

120 mg (0.360 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 62.7 mg (0.431 mmol) of (1R) - l - [(3R) -6-methylmorpholin-3-yl] ethanol [mixture of diastereomers, 2 isomers] in (1.66 ml) and admixed with 163 mg (219 μΐ, 1.26 mmol) /V ,.V- diisopropylethylamine. Subsequently, 164 mg (0.431 mmol) of HATU were added at RT and the mixture was stirred overnight. The reaction solution was then purified without further work-up directly by preparative RP-HPLC (acetonitrile / water). Yield: 112 mg (67% of theory).

LC-MS (method 7A :): R _t = 0.79 min (diastereomer 1), R _t = 0.80 min (diastereomer 2); MS (ESIpos): m / z = 461 [M + H] ⁺ . Example 69 (2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (1-hydroxyethyl) -2,2,5- trimethylmorpholin-4-yl] methanone [mixture of diastereomers, 2 isomers]

120 mg (0.360 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid and 74.8 mg (0.431 mmol) of 1- (3 , 6,6-Trimethylmorpholin-3-yl) ethanol [diastereomer 2, 2 isomers] in / V, / V-dimethylformamide (1.66 ml) and charged with 163 mg (219 μΐ, 1.26 mmol) /V ,.V- diisopropylethylamine. Subsequently, 164 mg (0.431 mmol) of HATU were added at RT and the mixture was stirred overnight. The reaction solution was then purified without further work-up directly by preparative RP-HPLC (acetonitrile / water). Yield: 13 mg (7% of theory). LC-MS (Method 1A :): R _t = 0.79 min; MS (ESIpos): m / z = 489 [M + H] ⁺ ;

^H-NMR (400 MHz, DMSO-d _6): δ [ppm] = 8.67 (t, IH), 8:52 (d, IH), 7:53 (d, IH), 7:46 (dd, IH), 6.77 (d , IH), 6.63 (d, IH), 5.08 (d, IH), 4.62 (d, 2H), 4.41 (quin, IH), 3.98 (d, IH), 3.89 (s, 3H), 3.67-3.44 ( m, IH), 3.25 (d, IH), 3.09 (d, IH), 1.56 (s, 3H), 1.10 (s, 3H), 1.06 (d, 3H), 0.98 (s, 3H).

Example 70 (2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (2-hydroxyethyl) -2-methylmorpholine-4- yl] methanone [racemate]

There were 840 mg (1.20 mmol) of [5- (2- {[tert-butyl (diphenyl) silyl] oxy} ethyl) -2-methylmorpholin-4-yl] (2- {[(4-chloropyridin-2-yl ) methyl] amino} -7-methoxy-l, 3-benzoxazol-5-yl) methanone [racemate] in tetrahydrofuran (25.2 ml), at RT with 628 mg (2.40 mmol) of tetra-w-butylammonium fluoride and for 30 stirred for a few minutes. The reaction solution was then concentrated under reduced pressure and the residue was purified directly by preparative RP-HPLC (acetonitrile / water). Yield: 525 mg (91% of theory).

LC-MS (Method 2A): R _t = 0.73 min; MS (ESIpos): m / z = 461 [M + H] ⁺ . Example 71

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (2-hydroxyethyl) -2-methylmorpholin-4-yl] methanone [enantiomerically pure isomer 1]

Enantiomer separation on a chiral phase of 512 mg of the compound from Example 70 according to Method 48D after repeated purification by preparative RP-HPLC (acetonitrile / water) gave 178 mg of Example 71 (enantiomerically pure isomer 1) and 168 mg of Example 72 (enantiomerically pure isomer 2) ,

HPLC (Method 19E): R _t = 4.65 min,> 99.0 ee;

LC-MS (Method 2A): R _t = 0.74 min; MS (ESIpos): m / z = 461 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.70 (d, 1H), 8.52 (d, 1H), 7.53 (d, 1H), 7.46 (dd, 1H), 6.85 (i.e. , 1H), 6.71 (br, s, 1H), 4.63 (d, 2H), 4.52 (br, s, 1H), 4.19 (d, 1H), 3.92 (s, 3H), 3.84-3.37 (m , 5H), 3.09-2.59 (m, 1H), 2.03-1.71 (m, 2H), 1.23-0.91 (m, 3H), one proton obscured.

Example 72

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (2-hydroxyethyl) -2-methylmorpholin-4-yl] methanone [enantiomerically pure isomer 2]

Enantiomer separation on a chiral phase of 512 mg of the compound from Example 70 according to Method 48D after repeated purification by preparative RP-HPLC (acetonitrile / water) gave 178 mg of Example 71 (enantiomerically pure isomer 1) and 168 mg of Example 72 (enantiomerically pure isomer 2) , HPLC (Method 19E): R _t = 6.21 min,> 99.0 ee;

LC-MS (Method 2A): R _t = 0.74 min; MS (ESIpos): m / z = 461 [M + H] ⁺ ;

^: H NMR (400 MHz, DMSO-de): δ [ppm] = 8.70 (d, IH), 8.52 (d, IH), 7.52 (d, IH), 7.45 (dd, IH), 6.84 (br. , IH), 6.70 (brs, IH), 4.62 (d, 2H), 4.56-4.14 (m, 2H), 3.91 (s, 3H), 3.84-3.37 (m, 5H), 3.07- 2.60 (m, IH), 2.01-1.75 (m, 2H), 1.21-0.87 (m, 3H), one proton obscured.

Example 73

4 - [(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -3-ethyl-1,4-diazabicyclo [4.2 .0] octan-2-one [mixture of diastereomers, 4 isomers]

92.7 mg (0.278 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid in / V, / V-dimethylformamide (2.8 ml) with 60 mg (0.39 mmol) of 3-ethyl-1,4-diazabicyclo [4.2.0] octan-2-one [mixture of diastereomers, 4 isomers], 23.8 mg (0.19 mmol) of 4-dimethylaminopyridine and 95.9 mg (0.500 mmol ) N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide was added and it was stirred for 1.5 h at room temperature. Then acetonitrile and water were added and purified by preparative HPLC (acetonitrile / water). 62.8 mg (48% of theory) of the target compound were obtained.

LC-MS (Method 1A): R _t = 0.84 min; MS (ESIpos): m / z = 471 [M + H] ⁺

^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.71 (t, IH), 8.52 (d, IH), 7.52 (s, IH), 7.46 (d, IH), 6.92-6.86 (m, IH), 6.77-6.70 (m, IH), 4.63 (d, 3H), 4.17-4.00 (m, IH), 3.98-3.87 (m, 4H), 3.71 (dd, IH), 3.02-2.90 (m, IH), 2.08-2.00 (m, IH), 1.71-1.42 (m, IH), 0.97 (t, IH), 0.84 (br, s, 3H); 2 H probably hidden under DMSO signal.

Example 74

4 - [(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -3- (methoxymethyl) -1,4-diazabicyclo [4.2.0] octan-2-one [enantiomerically pure isomer 3]

96 mg (0.29 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid in A ^ N-dimethylformamide (2.9 ml) were treated with 69 mg (0.40 mmol) 3- (methoxymethyl) -1,4-diazabicyclo [4.2.0] octan-2-one [enantiomerically pure isomer 3], 24 mg (0.20 mmol) 4-dimethylaminopyridine and 99 mg (0.52 mmol) N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide was added and it was stirred for 1 h at room temperature. Then acetonitrile and water were added and purified by preparative HPLC (acetonitrile / water). 56.7 mg (40% of theory) of the target compound were obtained.

LC-MS (Method 1A): R _t = 0.74 min; MS (ESIpos): m / z = 486 [M + H] ⁺ ^: H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.72 (t, 1H), 8.52 (d, 1H), 7.52 (s, 2H), 6.90 (s, 1H), 6.77 (s, 1H), 4.69-4.51 (m, 3H), 4.40 (br, s, 1H), 4.12-3.98 (m, 1H), 3.96- 3.86 (m, 4H), 3.74-3.54 (m, 3H), 3.41 (t, 1H), 2.89-2.73 (s, 1H), 2.45-2.37 (m, 1H), 2.14-1.98 (m, 2H); 1 H probably hidden under DMSO signal.

Example 75 4 - [(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -3-methyl-1,4-diazabicyclo [4.2.0] octan-2-one [enantiomerically pure isomer 1]

88 mg (0.27 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid in A ^ N-dimethylformamide (2 ml) were treated with 120 mg (162 μΐ, 0.929 mmol) of N, N-diisopropylethylamine, 121 mg (0.32 mmol) of HATU and 74 mg (0.53 mmol) of methyl 1,4 diazabicyclo [4.2.0] octan-2-one [diastereomer mixture, 4 isomers] and stirred at room temperature for 2.5 h. It was then purified by preparative HPLC (acetonitrile / water). 41 mg (33% of theory) of the target compound were obtained as a mixture of diastereomers, 4 isomers.

LC-MS (Method 1A): R _t = 0.75 min; MS (ESIpos): m / z = 456 [M + H] ⁺ ^: H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.78-8.66 (m, 1H), 8.52 (d, 1H) , 7.58-7.42 (m, 2H), 6.92-6.83 (m, 1H), 6.79-6.72 (m, 1H), 4.63 (d, 4H), 4.23 (d, 1H), 4.11-3.85 (m, 6H) , 3.79-3.65 (m, 1H), 2.08 (d, 1H), 1.44-1.32 (m, 3H).

The diastereomeric mixture was separated into the enantiomers on a chiral phase [Method 54D]. enantiomerically pure isomer 1: Yield: 7 mg (99% ee) enantiomerically pure isomer 1: R _t = 10.86 min [Method 46E].

LC-MS (Method 1A): R _t = 0.73 min; MS (ESIpos): m / z = 456 [M + H] ⁺

^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.72 (t, 1H), 8.52 (d, 1H), 7.52 (s, 1H), 7.44-7.40 (m, 1H), 6.87 (s, 1H), 6.72 (s, 1H), 4.77-4.56 (m, 4H), 4.12-3.97 (m, 2H), 3.96-3.93 (m, 1H), 3.92 (s, 3H), 3.74-3.63 (m, 1H), 2.31-2.11 (m, 1H), 1.44-1.30 (m, 3H). Example 76

7 - [(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -6-methyl-4,7-diazaspiro [2.5 ] octan-5-one [racemate]

221 mg (0.662 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid in / V, / V-dimethylformamide (6 ml) with 130 mg (0.927 mmol) of 6-methyl-4,7-diazaspiro [2.5] octan-5-one trifluoroacetate [racemate], 57 mg (0.46 mmol) of 4-dimethylaminopyridine and 228 mg (1.19 mmol) of N- [3] (Dimethylamino) propyl] -N'-ethylcarbodiimid and it was stirred for 1 h at room temperature. Then acetonitrile and water were added and purified by preparative HPLC (acetonitrile / water). 174 mg (58% of theory) of the target compound were obtained as racemate.

LC-MS (Method 1A): R _t = 0.78 min; MS (ESIpos): m / z = 455 [M + H] ⁺

^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.72 (t, IH), 8.51 (d, IH), 8.15 (s, IH), 7.52 (s, IH), 7.45 (dd , IH), 6.84 (s, IH), 6.70 (s, IH), 4.63 (d, 2H), 3 ^ 92 (s, 3H), 1.43 (d, 3H), 0.84-0.50 (m, 4H); 3 H probably hidden under DMSO signal.

Example 77

7 - [(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -6-methyl-4,7-diazaspiro [2.5 ] octan-5-one [enantiomerically pure isomer 1]

The racemate of Example 76 was separated into the enantiomers on a chiral phase [Method 55D]. Enantiomerically pure isomer 1: Yield: 79 mg (100% ee) enantiomerically pure isomer 1: R _t = 4.48 min [Method 47E].

LC-MS (Method 1A): R _t = 0.77 min; MS (ESIpos): m / z = 455 [M + H] ⁺

^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.72 (t, IH), 8.52 (d, IH), 8.15 (s, IH), 7.53 (s, 2H), 6.84 (s , IH), 6.71 (s, IH), 4.63 (d, 2H), 3.92 (s, 3H), 1.51-1.35 (m, 4H), 0.90-0.54 (m, 4H); 2 H probably hidden under DMSO signal.

Example 78

7 - [(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -6-ethyl-4,7-diazaspiro [2.5 ] octan-5-one [racemate]

92 mg (0.28 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid in A ^ N-dimethylformamide (2.8 ml) were treated with 60 mg (0.39 mmol) of 6-ethyl-4,7-diazaspiro [2.5] octan-5-one [racemate], 24 mg (0.19 mmol) of 4-dimethylaminopyridine and 96 mg (0.50 mmol) of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide and it was stirred for 1.5 h at room temperature. Then acetonitrile and water were added and purified by preparative HPLC (acetonitrile / water). 50 mg (38% of theory) of the target compound were obtained as racemate.

LC-MS (Method 1A): R _t = 0.83 min; MS (ESIpos): m / z = 470 [M + H] ^: H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.73 (t, 1H), 8.52 (d, 1H), 8.10 ( s, 1H), 7.58-7.39 (m, 2H), 6.85 (br, s, 1H), 6.70 (s, 1H), 4.87-4.58 (m, 3H), 3.92 (s, 3H), 3.78- 3.68 (m, 1H), 3.01-2.89 (m, 1H), 2.02-1.83 (m, 2H), 0.97 (t, 3H), 0.77-0.45 (m, 3H), 0.29 (br, s, 1H) ,

Example 79

7 - [(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -6-ethyl-4,7-diazaspiro [2.5 ] octan-5-one [enantiomerically pure isomer 1]

50 mg of 7 - [(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -6-ethyl-4,7-diazaspiro [2.5] octan-5-one [racemate] Example 78 was separated into the enantiomers on a chiral phase [Method 56D]. enantiomerically pure isomer 1: Yield: 21 mg (100% ee) enantiomerically pure isomer 1: R _t = 4.20 min [method 48E].

LC-MS (Method 1A): R _t = 0.81 min; MS (ESIpos): m / z = 470 [M + H] ⁺

^: H NMR (400 MHz, DMSO-de): δ [ppm] = 8.73 (t, IH), 8.51 (d, IH), 8.09 (s, IH), 7.52 (s, IH), 7.48-7.42 ( m, IH), 6.84 (brs, IH), 6.70 (s, IH), 4.88-4.72 (m, IH), 4.62 (d, 2H), 3.92 (s, 3H), 3.78-3.67 (m , IH), 3.18-3.09 (m, IH), 1.98-1.82 (m, 2H), 1.05-0.52 (m, 6H), 0.29 (br, s, IH).

Example 80

4 - [(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -3-ethyl-6-methylpiperazin-2-one [Diastereomer 2, 2 isomers]

63.7 mg (0.191 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid in A ^ N-dimethylformamide (2 ml) were treated with 86 mg (116 μΐ, 0.67 mmol) of N, N-diisopropylethylamine, 87 mg (0.23 mmol) of HATU and 54 mg (0.38 mmol) of 3-ethyl-6-methylpiperazin-2-one [diastereomer mixture, 4 isomers] were added to give 2.5 h stirred at room temperature. It was then concentrated under reduced pressure, the residue was dissolved in methanol and water and purified by preparative HPLC (acetonitrile / water). This gave 45 mg (51 d.th.) of the target compound as a mixture of diastereomers, 4 isomers.

LC-MS (Method 1A): R _t = 0.74 min (diastereomer 1, 2 isomers), R _t = 0.77 min (diastereomer 2, 2 isomers);

MS (ESIpos): m / z = 458 [M + H] ⁺ The diastereomer mixture, 4 isomers were separated into the diastereomers 1, 2 isomers and diastereomer 2, 2 isomers [Method 2G].

Diastereomer 2, 2 isomers: R _t = 9.1 min

Diastereomer 2, 2 isomers: Yield: 16 mg LC-MS (Method 1A): R _t = 0.77 min; MS (ESIpos): m / z = 458 [M + H] ⁺

^: H NMR (400 MHz, DMSO-ife): δ [ppm] = 8.72 (t, 1H), 8.52 (d, 1H), 7.99 (br, s, 1H), 7.53 (s, 1H), 7.48 -7.43 (m, 1H), 6.88 (br, s, 1H), 6.73 (s, 1H), 4.73 (br, s, 1H), 4.63 (d, 2H), 3.92 (s, 3H), 3.67 -3.40 (m, 2H), 3.03-2.93 (m, 1H), 1.97-1.72 (m, 2H), 0.93 (br, s, 6H). Example 81

4 - [(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -3-ethyl-6-methylpiperazin-2-one [enantiomerically pure isomer 3]

47.3 mg (0.142 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid in / V, / V-dimethylformamide (1.4 ml) with 28.2 mg (0.19 mmol) of 3-ethyl-6-methylpiperazin-2-one [enantiomerically pure isomer 3], 12 mg (0.10 mmol) of 4-dimethylaminopyridine and 48 mg (0.25 mmol) of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimid added and it was stirred for 1 h at room temperature. Then methanol and water were added and purified by preparative HPLC (acetonitrile / water). 12 mg (18% of theory) of the target compound were obtained.

LC-MS (Method 1A): R _t = 0.80 min; MS (ESIpos): m / z = 458 [M + H] ⁺

^: H-NMR (400 MHz, DMSO-ife): δ [ppm] = 8.73 (br, s, 1H), 8.52 (d, 1H), 7.99 (br, s, 1H), 7.53 (s, 1H ), 7.46 (dd, 1H), 6.88 (br, s, 1H), 6.73 (s, 1H), 4.78-4.67 m, 1H), 4.62 (br, s, 2H), 3.92 (s, 3H) , 3.74-3.41 (m, 2H), 3.04-2.91 (m, 1H), 1.96-1.73 (m, 2H), 1.05-0.83 (m, 6H). Example 82

2- {1 - [(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -5,5-dimethyl-3- oxopiperazin-2-yl} acetamide [racemate]

1.44 g (4.06 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid in A ^ N-dimethylformamide (18 ml) were treated with 1.15 g g (1.55 ml, 8.92 mmol) of N, N-diisopropylethylamine and 1.85 g (4.87 mmol) of HATU and 902 mg (4.87 mmol) of 2- (5,5-dimethyl-3-oxopiperazin-2-yl) acetamide [racemate] and it was stirred for 3 h at room temperature. It was then concentrated under reduced pressure and the residue was purified by preparative HPLC (acetonitrile / water). 390 mg (19% of theory) of the target compound were obtained.

LC-MS (Method 1A): R _t = 0.66 min; MS (ESIpos): m / z = 501 [M + H] ⁺

Example 83 {1- [(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -5,5-dimethyl-3- oxopiperazin-2-yl} acetonitrile [racemate]

1.44 g (4.06 mmol) of 2- {1 - [(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -5, 5-dimethyl-3-oxopiperazin-2-yl} acetamide [racemate] in THF (8 ml) were admixed with 288 mg (295 μΐ, 3.64 mmol) of pyridine and 764 mg (514 μΐ, 3.64 mmol) of trifluoroacetic anhydride and it became 2 h stirred at room temperature. It was then added to water, treated with methanol and purified by preparative HPLC (acetonitrile / water). 150 mg (33% of theory) of the target compound were obtained as racemate.

LC-MS (Method 1A): R _t = 0.76 min; MS (ESIpos): m / z = 483 [M + H] ⁺ Example 84

{1- [(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-13-benzoxazol-5-yl) carbonyl] -5,5-dimethyl-3-oxopiperazine-2- yl} acetonitrile [enantiomerically pure isomer 2]

The racemate of Example 83 was separated into the enantiomers on a chiral phase [Method 57D]. enantiomerically pure isomer 2: Yield: 23 mg (97% ee) enantiomerically pure isomer 2: R _t = 6.33 min [Method 49E].

LC-MS (Method 1A): R _t = 0.76 min; MS (ESIpos): m / z = 483 [M + H] ⁺

^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.74 (t, 1H), 8.52 (d, 1H), 8.41 (s, 1H), 7.53 (d, 1H), 7.45 (dd , 1H), 6.89 (s, 1H), 6.76 (s, 1H), 5.75 (s, 1H), 4.63 (d, 2H), 3.92 (s, 3H), 3.44-3.34 (m, 1H), 3.27- 3.18 (m, 1H), 3.15-3.01 (m, 1H), 1.07 (d, 6H); 1 H probably hidden under DMSO signal.

Example 85

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [2- (2-hydroxyethyl) -5-methylpiperidin-1-yl] methanone [diastereomer 2, 2 isomers]

126 mg (0.378 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid in A ^ N-dimethylformamide (1.9 ml) were treated with 195 mg (264 μΐ, 1.51 mmol) of N, N-diisopropylethylamine and 74.5 mg (0.416 mmol) of 2- (5-methylpiperidin-2-yl) ethanol [diastereomer mixture, 4 isomers]. Then, at 0 ° C, 172 mg (0.454 mmol) of HATU were added and stirred at room temperature for 4 h. It was mixed with water and purified by preparative HPLC (acetonitrile / water). This gave 61 mg (18% of theory) of the target compound as a mixture of diastereomers.

LC-MS (Method 1A): R _t = 0.88 min (diastereomer 1, 2 isomers), R _t = 0.89 min (diastereomer 2, 2 isomers); MS (ESIpos): m / z = 459 [M + H] ⁺

The mixture of diastereomers was separated [Method 3G].

Diastereomer 2, 2 isomers: R _t = 7.1 min

Diastereomer 2, 2 isomers: Yield: 2 mg

LC-MS (Method 1A): R _t = 0.91 min; MS (ESIpos): m / z = 459 [M + H] ⁺ Example 86

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [2- (2-hydroxy-2-methylpropyl) -5-methylpiperidine. l-yl] methanone [diastereomer 1, 2 isomers]

At 0 ° C, to 110 mg (0.22 mmol) of ethyl {1 - [(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl ) Carbonyl] -5-methylpiperidin-2-yl} acetate [diastereomer mixture, 4 isomers] in 2.44 ml of THF 256 μΐ (0.768 mmol) of a 3 M solution of methylmagnesium bromide in diethyl ether was added dropwise and it was 15 min at 0 ° C and then Stirred at room temperature overnight. Subsequently, it was mixed carefully with saturated aqueous ammonium chloride solution and concentrated in vacuo to half. It was mixed with water and dichloromethane and the phases separated. The organic phase was washed twice with water and then dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo and the residue was purified by preparative HPLC (acetonitrile / water). This gave 67 mg (62% of theory) of the target compound as a mixture of diastereomers, 4 isomers. LC-MS (Method 1A): R _t = 0.96 min (diastereomer 1, 2 isomers), R _t = 0.99 min (diastereomer 2, 2 isomers);

MS (ESIpos): m / z = 487 [M + H] ⁺

The diastereomer mixture was separated [Method 60D]. Diastereomer 1, 2 Isomers: R _t = 7.1 min Diastereomer 1, 2 Isomers: Yield: 17 mg

Diastereomer 1, 2 isomers: R _t = 6.42 min [Method 52E].

LC-MS (Method 1A): R _t = 0.93 min; MS (ESIpos): m / z = 487 [M + H] ⁺

^: H NMR (500 MHz, DMSO δ [ppm] = 8.64 (d, 1H), 8.51 (d, 1H), 7.52 (s, 1H), 7.47-7.41 (m, 1H), 6.83-6.72 (m, 1H), 6.71-6.57 (m, 1H), 4.89 (br, s, 1H), 4.62 (d, 2H), 4.30-4.15 (m, 1H), 3.90 (s, 3H), 2.79 (t, 1H ), 1.97-1.21 (m, 6H), 1.19-1.10 (m, 4H), 1.09-0.64 (m, 6H).

Example 87

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) {2- [(1-hydroxycyclopropyl) methyl] -5-methylpiperidine-1 -yl} methanone [mixture of diastereomers,

4 isomers]

188 mg (0.565 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid in A ^ N-dimethylformamide (5.5 ml) were treated with 365 mg (492 μΐ, 2.82 mmol) of N, N-diisopropylethylamine, 257 mg (0.678 mmol) of HATU and 320 mg (1.13 mmol) of l - [(5-methyl) piperidin-2-yl) methyl] cyclopropanol [mixture of diastereomers, 4 isomers]. The mixture was stirred at room temperature for 2 h and purified by preparative HPLC (acetonitrile / water). 56 mg (18% of theory) of the target compound were obtained as a mixture of diastereomers, 4 isomers.

LC-MS (Method 1A): R _t = 1.04 min; MS (ESIpos): m / z = 485 [M + H] ⁺ ^: H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.67 (t, IH), 8.51 (d, IH), 7.52 (s, IH), 7.46-7.40 (m, IH), 6.83-6.56 (m, 2H), 5.15-5.03 (m, IH), 4.63 (d, 2H), 3.96-3.81 (m, 3H), 2.86 -2.59 (m, 2H), 1.96-1.08 (m, 8H), 0.97-0.65 (m, 6H), 0.61-0.24 (m, IH).

Example 88

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) {2- [(1-hydroxycyclopropyl) methyl] -5-methylpiperidine-1 -yl} methanone [enantiomerically pure isomer 2]

The diastereomer mixture from example 87 was separated [method 8F]. Enantiomerically pure isomer 2: Yield: 18 mg

LC-MS (Method 7A): R _t = 3.06 min; MS (ESIpos): m / z = 485 [M + H] ⁺ Example 89

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [2- (1-hydroxycyclopropyl) -5-methyl-piperidin-1-yl] methanone [diastereomer 1, 2 isomers]

198 mg (0.594 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid in A ^ N-dimemylformamide (6.5 ml) were treated with 384 mg (518 μΐ, 2.97 mmol) of N, N-diisopropylethylamine, 271 mg (0.713 mmol) of HATU and 320 mg (1.19 mmol) of 1- (5-methylpiperidin-2-yl) cyclopropanol trifluoroacetate [diastereomer mixture, 4 isomers]. The mixture was stirred at room temperature for 2 h and purified by preparative HPLC (acetonitrile / water). 45 mg (15% of theory) of diastereomer 1, 2 isomers were obtained.

LC-MS (Method 1A): R _t = 0.93 min; MS (ESIpos): m / z = 471 [M + H] ⁺

^: H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.66 (t, 1H), 8.52 (d, 1H), 7.53 (s, 1H), 7.47-7.39 (m, 1H), 7.33 -7.18 (m, 1H), 6.83 (br, s, 1H), 6.67 (s, 1H), 5.40 (s, 1H), 4.63 (d, 2H), 3.95-3.86 (m, 3H), 1.93- 1.87 (m, 1H), 1.78-1.41 (m, 4H), 1.07-0.45 (m, 8H); 2 H probably covered by DMSO signal.

Example 90

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [2- (1-hydroxycyclopropyl) -5-methyl-piperidin-1-yl] methanone [diastereomer 2, 2 isomers]

198 mg (0.594 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid in A ^ N-dimethylformamide (6.5 ml) were treated with 384 mg (518 μΐ, 2.97 mmol) of N, N-diisopropylethylamine, 271 mg (0.713 mmol) of HATU and 320 mg (1.19 mmol) of 1- (5-methylpiperidin-2-yl) cyclopropanol trifluoroacetate [diastereomer mixture, 4 isomers]. The mixture was stirred at room temperature for 2 h and purified by preparative HPLC (acetonitrile / water). 45 mg (15% of theory) of diastereomer 2, 2 isomers were obtained.

LC-MS (Method 1A): R _t = 1.06 min; MS (ESIpos): m / z = 471 [M + H] ⁺

^: H NMR (400 MHz, DMSO δ [ppm] = 8.74-8.63 (m, 1H), 8.51 (d, 1H), 7.53 (br, s, 1H), 7.48-7.41 (m, 1H), 7.33 -7.21 (m, 1H), 6.88-6.55 (m, 2H), 5.30-5.15 (m, 1H), 4.63 (d, 2H), 3.96-3.86 (m, 3H), 3.77-3.42 (m, 1H) , 1.98-1.48 (m, 4H), 1.09-0.62 (m, 8H); 2 H probably masked by DMSO signal. Example 91

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [2- (1-hydroxycyclopropyl) -5-methyl-piperidin-1-yl] methanone [enantiomerically pure isomer 2]

(2- {[(4-Chloro-pyridin-2-yl) -methyl] -amino} -7-methoxy-1,3-benzoxazol-5-yl) [2- (1-hydroxycyclopropyl) -5-methyl-piperidine-1-one] yl] methanone [diastereomer 1, 2 isomers] Example 89 was separated on a chiral phase [Method 58D]. enantiomerically pure isomer 2: yield: 14 mg enantiomerically pure isomer 2: R _t = 9.26 min [method 50 E]. LC-MS (Method 1A): R _t = 0.93 min; MS (ESIpos): m / z = 471 [M + H] ⁺

Ή NMR (400 MHz, DMSO- e): δ [ppm] = 8.69 (t, IH), 8.52 (d, IH), 7.53 (s, IH), 7.47-7.39 (m, IH), 6.88-6.78 (m, IH), 6.67 (s, IH), 5.42 (s, IH), 4.63 (d, 2H), 4.07 (br, s, IH), 3.94-3.85 (m, 3H), 3.58-3.50 ( m, 2H), 2.10-1.19 (m, 6H), 0.97-0.40 (m, 6H).

Example 92 {1- [(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -5-methyl-3-oxopiperazine 2-yl} acetonitrile [enantiomerically pure isomer 4]

850 mg (1.77 mmol) of 2- {1 - [(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -5- Methyl-3-oxopiperazin-2-yl} acetamide [diastereomer mixture, 4 isomers] in THF (17 ml) were treated with 609 mg (623 μΐ, 7.70 mmol) of pyridine and 1.62 g (1.08 ml, 7.70 mmol) of trifluoroacetic anhydride and it was Stirred for 1 h at room temperature. It was then added carefully to ice-water, combined with dichloromethane, the phases were separated and the aqueous phase was washed twice with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo, the residue treated with acetonitrile and water and purified by silica gel chromatography (dichloromethane / methanol 100: 3 - 100: 7). 336 mg (42% of theory) of the target compound were obtained as a mixture of diastereomers, 4 isomers.

LC-MS (Method 1A): R _t = 0.72 min; MS (ESIpos): m / z = 469 [M + H] ⁺

The diastereomer mixture was separated into the enantiomers on a chiral phase [Method 59D]. enantiomerically pure isomer 4: Yield: 18 mg (97% ee) enantiomerically pure isomer 4: R _t = 5.86 min [Method 51E].

LC-MS (Method 1A): R _t = 0.73 min; MS (ESIpos): m / z = 469 [M + H] ⁺

^: H NMR (400 MHz, DMSO-de): δ [ppm] = 8.73 (t, 1H), 8.52 (d, 1H), 8.40 (s, 1H), 7.53 (s, 1H), 7.45 (dd, 1H), 6.96-6.87 (m, 1H), 6.83-6.67 (m, 1H), 4.63 (d, 2H), 3.92 (s, 3H), 3.61-3.54 (m, 1H), 3.24-3.03 (m, 3H), 1.00 (brs, 3H); 2 H probably hidden under DMSO signal. Example 93

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (2-hydroxypropan-2-yl) -2,2- dimethylmorpholin-4-yl] methanone [enantiomerically pure isomer 1]

96 mg (0.29 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid (3.0 ml) were treated with 130 mg (176 μΐ, 1.01 mmol) of N, N-diisopropylethylamine, 131 mg (0.35 mmol) of HATU and 2- (6,6-dimethylmorpholin-3-yl) propan-2-ol [enantiomerically pure isomer 1, Example 259A] and stirred for 4.5 h at room temperature. Then 56.5 mg (75 μM, 0.43 mmol) / V, V-diisopropylethylamine, 655 mg (1.75 mmol) HATU and 50 mg (0.288 mmol) 2- (6,6-dimethylmorpholin-3-yl) propan-2-one were added. ol [enantiomerically pure isomer 1, Example 259 A] was added and stirred for 2 h at room temperature. It was concentrated under reduced pressure and the residue was purified by preparative HPLC (acetonitrile / water). 8 mg (6% of theory) of the target compound were obtained. LC-MS (Method 1A): R _t = 0.83 min; MS (ESIpos): m / z = 489 [M + H] ⁺

Example 94

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (1-hydroxycyclopropyl) -2,2-dimethylmorpholine-4- yl] methanone [enantiomerically pure isomer 1]

105 mg (0.315 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid in A ^ N-dimethylformamide (3.3 ml) were washed with 143 mg (192 μΐ, 1.10 mmol) of N, N-diisopropylethylamine, 144 mg (0.378 mmol) of HATU and 108 mg (0.631 mmol) of 1- (6,6-dimethylmorpholin-3-yl) cyclopropanol [enantiomerically pure isomer 1, Example 263 A ] and it was stirred for 3 h at room temperature. It was then concentrated under reduced pressure and the residue was purified by preparative HPLC (acetonitrile / water). 55 mg (36% of theory) of the target compound were obtained.

LC-MS (Method 1A): R _t = 0.83 min; MS (ESIpos): m / z = 487 [M + H] ⁺

^: H NMR (400 MHz, DMSO-ife): δ [ppm] = 8.69 (t, 1H), 8.52 (d, 1H), 7.52 (s, 1H), 7.46 (dd, 1H), 6.96 (s, 1H), 6.77 (s, 1H), 5.76 (s, 1H), 5.52 (s, 1H), 4.62 (d, 2H), 3.91 (s, 4H), 3.75 (dd, 1H), 1.31-0.75 (m , 8H), 0.69-0.41 (m, 2H); 2 H probably hidden under DMSO signal. Example 95

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (1-hydroxyethyl) -2,2-dimethylmorpholine-4- yl] methanone [enantiomerically pure isomer 1]

44 mg (0.13 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid (1 ml) were admixed with 58 mg (78 μΐ, 0.45 mmol) of N, N-diisopropylethylamine, 58 mg (0.15 mmol) of HATU and 41 mg (0.26 mmol) of 1- (6,6-dimethylmorpholin-3-yl) ethanol. Enantiomerically pure isomer 1, Example 270A] and stirred for 2 h at room temperature. It was concentrated under reduced pressure and the residue was purified by preparative HPLC (acetonitrile / water). 18 mg (29% of theory) of the target compound were obtained.

LC-MS (Method 1A): R _t = 0.78 min; MS (ESIpos): m / z = 475 [M + H] ⁺

^: H-NMR (400 MHz, DMSO-ife): δ [ppm] = 8.73 (br.s .., IH), 8.52 (d, IH), 7.52 (s, IH), 7.46 (dd, IH), 6.90 -6.58 (m, 2H), 5.76 (s, IH), 4.99-4.78 (m, IH), 4.63 (d, 2H), 4.17-3.98 (m, 2H), 3.97-3.87 (m, 4H), 3.86 -3.58 (m, IH), 3.22-2.97 (m, 2H), 1.32-0.84 (m, 9H).

Example 96

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (1-hydroxyethyl) -2,2-dimethylmorpholine-4- yl] methanone [enantiomerically pure isomer 2]

105 mg (0.31 mmol) of 2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazole-5- carboxylic acid in A ^ N-dimethylformamide (3 ml) were treated with 142 mg (191 μΐ, 1.11 mmol) of N, N-diisopropylethylamine, 143 mg (0.38 mmol) of HATU and 100 mg (0.628 mmol) of 1- (6,6-dimethylmorpholine 3-yl) ethanol [enantiomerically pure isomer 2, Example 269A] and stirred at room temperature for 3 h. It was concentrated under reduced pressure and the residue was purified by preparative HPLC (acetonitrile / water). 50 mg (32% of theory) of the target compound were obtained.

LC-MS (Method 1A): R _t = 0.80 min; MS (ESIpos): m / z = 475 [M + H] ⁺

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 8.67 (brs., IH), 8.52 (d, IH), 7.53 (d, IH), 7.45 (dd, IH), 7.05 -6.72 (m, 2H), 5.16-4.94 (m, IH), 4.62 (d, 2H), 4.21-4.02 (m, 2H), 3.90 (s, 3H), 3.79-3.52 (m, 2H), 1.28 -0.86 (m, 9H); 2 H probably hidden under DMSO signal.

Example 97

(2- {[l- (4-chloropyridin-2-yl) ethyl] amino} -7-methoxy-l, 3-benzoxazol-5-yl) [(4R) -4 - [(l, ^l-2 H ₂ ) ethyloxy] -2- (hydroxymethyl) pyrrolidin-1-yl] methanone [mixture of diastereomers, 4 isomers]

300 mg (0.682 mmol, purity: 79%) of 2- {[1- (4-chloropyridin-2-yl) ethyl] amino} -7-methoxy-1,3-benzoxazole-5-carboxylic acid [racemate] and 120 mg (0.818 mmol) of {(4R) -4 - [(l, l- ² H ₂ ) ethyloxy] pyrrolidin-2-yl} methanol [diastereomer mixture, 2 isomers] in N, N-dimethylformamide (3.14 ml) 308 mg (415 μΐ, 2.39 mmol) of N, N-diisopropylethylamine were then added at RT 311 mg (0.818 mmol) of HATU and stirred for 1 h The reaction solution was then without further work-up directly by preparative RP-HPLC ( Acetonitrile / water) Yield: 247 mg (76% of theory).

LC-MS (Method 1A): R _t = 0.84 min (enantiomerically pure isomer 1), R _t = 0.85 min (enantiomerically pure isomer 2); R _t = 0.87 min (enantiomerically pure isomer 3); enantiomerically pure isomer 4 concealed.

MS (ESIpos): m / z = 477 [M + H] ⁺ . B) Assessment of physiological efficacy

The suitability of the compounds according to the invention for the treatment of thromboembolic disorders can be demonstrated in the following assay systems: a) Test descriptions (in vitro) a.l) Measurement of thrombin inhibition in buffer

To determine the thrombin inhibition of the substances listed above, a biochemical test system is constructed in which the reaction of a thrombin substrate is used to determine the enzymatic activity of human thrombin. Thrombin separates from the peptic substrate aminomethylcoumarin, which is measured fluorescently. The determinations are carried out in microtiter plates.

Substances to be tested are dissolved in dimethylsulfoxide at various concentrations and incubated with human thrombin (0.06 nmol / l dissolved in 50 mmol / l Tris buffer [C, C, C-tris (hydroxymethyl) -aminomethane], 100 mmol / l sodium chloride for 15 min , 0.1% BSA [bovine serum albumin], pH 7.4) at 22 ° C. Subsequently, the substrate (5 μηιοΐ / ΐ Boc-Asp (OBzl) - Pro-Arg-AMC from Bachem) is added. After incubation for 30 min, the sample is excited at a wavelength of 360 nm and the emission is measured at 460 nm. The measured emissions of the test mixtures with test substance are compared with the test mixtures without test substance (excluding dimethylsulfoxide instead of test substance in dimethyl sulfoxide) and ICso values are calculated from the concentration-activity relationships. Representative activity data from this test are listed in Table 1 below (in part as averages from individual determinations):

Table 1

Example no. ICso [nM] Example No., ICso [nM]

1 15 2 6.2

3 330 4 39

5 2800 6 15

7 37 8 2600

9 9.7 10 31

11 31 12 4.4 Example no. ICso [nM] Example no. ICso [nM]

13 21 14 550

15 6.4 16 30

17 33 18 17

19 34 20 36

21 10 22 1.7

23 0.8 24 2.5

25 1.0 26 6.2

27 2.1 28 3.2

29 1.9 30 25

31 11 32 12

33 7.2 34 7.3

35 5.0 36 39

37 37 38 13

39 11 40 18

41 50 42 27

43 18 44 32

45 24 46 14

47 11 48 11

49 24 50 12

51 8.0 52 28

53 36 54 11

55 21 56 25

57 20 58 17

59 60 60 5.2

61 24 62 68

63 11 64 44 Example no. ICso [nM] Example No., ICso [nM]

65 24 66 28

67 16 68 59

69 17 70 38

71 97 72 29

73 51 74 32

75 32 76 19

77 14 78 13

79 4.5 80 16

81 12 82 170

83 36 84 11

85 17 87 5.3

88 6.6 89 17

90 28 91 13

92 96 93 8.8

94 18 95 6.8

96 41 97 17

a.2) Determination of selectivity

To demonstrate the selectivity of the substances with respect to thrombin inhibition, the test substances are tested for their inhibition of other human serine proteases, such as factor Xa, factor XIIa, factor XIa, trypsin and plasmin. To determine the enzymatic activity of factor Xa (1.3 nmol / l of Kordia), factor Xlla (10 nmol / l of Kordia), factor XIa (0.4 nmol / l of Kordia), trypsin (83 mU / ml of Sigma) and plasmin (0.1 μg / ml of Kordia) these enzymes are dissolved (50 mmol / l Tris buffer [C, C, C-tris (hydroxymethyl) -aminomethane], 100 mmol / l sodium chloride, 0.1% BSA [bovine serum albumin], 5 mmol / l calcium chloride, pH 7.4) and incubated for 15 min with test substance in various concentrations in dimethylsulfoxide and with dimethyl sulfoxide without test substance. Subsequently, the enzymatic reaction is started by adding the appropriate substrates (5 μηιοΐ / ΐ Boc-Ile-Glu-Gly-Arg-AMC of Bachem for FXa, 5 μιηοΐ / ΐ H-Pro-Phe-Arg-AMC of Bachem for factor Xüa, 5 μηιοΐ / ΐ Boc-Πε-Glu-Gly-Arg-AMC of Bachem for trypsin, 5 μηιοΐ / ΐ Boc-Glu (OBzl) -Ala-Arg-AMC from Bachem for factor XIa, 50 μηιοΐ / ΐ MeOSuc-Ala-Phe-Lys-AMC from Bachem for plasmin). After an incubation period of 30 min at 22 ° C, the fluorescence is measured (excitation: 360 nm, emission: 460 nm). The measured emissions of the test mixtures with test substance are compared with the test mixtures without test substance (excluding dimethylsulfoxide instead of test substance in dimethyl sulfoxide) and ICso values are calculated from the concentration-activity relationships. a.3) Determination of the thrombin-inhibitory effect of the potential inhibitors in plasma samples

To determine the inhibition of thrombin in plasma samples, prothrombinase present in the plasma is activated by ecarin. Subsequently, the thrombin activity or its inhibition by potential inhibitors by the addition of a substrate is measured fluorescently.

The substances to be tested are dissolved in different concentrations in dimethyl sulfoxide and diluted with water. In white 96-well flat bottom plates are 20 μΐ substance dilution with 20 μΐ ecarin solution (Ecarin reagent, Sigma E-0504, final concentration 20 mU per batch) in Ca buffer (200 mM Hepes + 560 mM sodium chloride + 10 mM calcium chloride + 0.4% PEG) or mixed with 20 μl Ca buffer (as unstimulated control). Furthermore, 20 μΐ fluorogenic thrombin substrate (Bachem 1-1120, final concentration 50 μηιοΐ / ΐ) and 20 μΐ citrated plasma (Octapharma) are added and well homogenized. The plate is measured in the SpectraFluorplus Reader with an excitation filter 360 nm and emission filter 465 nm for 20 minutes every minute. The IC 50 value is determined when approx. 70% of the maximum signal is reached (approx. 12 min). Representative activity data from this test are listed in Table 2 below (in part as averages from individual determinations):

Table 2

Example no. ICso [nM] Example No., ICso [nM]

1 25 2 19

4 66 7 70

9 13 10 39

11 101 12 8.9 Example no. ICso [nM] Example No., ICso [nM]

13 31 15 21

16 36 17 52

18 27 19 53

20 66 21 55

22 11 23 6.5

24 12 25 6.8

26 44 27 7.6

28 17 29 8.8

30 65 31 34

32 36 33 14

34 37 35 71

36 57 37 44

38 22 39 40

40 33 41 50

42 34 43 17

45 41 46 23

47 24 48 16

49 53 50 28

51 17 52 34

53 49 54 35

55 33 56 57

57 30 58 27

59 90 60 24

61 100 62 107

63 20 65 61

67 38 68 72 Example no. ICso [nM] Example No., ICso [nM]

69 27 70 74

72 37 73 50

74 56 75 48

76 36 77 23

78 19 79 14

80 16 81 32

83 62 84 21

85 47 87 27

89 35 90 94

91 24 92 148

93 17 94 28

95 13 96 43

97 27

a.4) thrombin generation assay (thrombogram)

The effect of the test substances on the thrombinogram (thrombin generation assay according to Hemker) is determined in vitro in human plasma (Octaplas® from Octapharma). In Hemker thrombin generation assay, the activity of thrombin in clotting plasma is determined by measuring the fluorescent cleavage products of substrate 1-1140 (Z-Gly-Gly-Arg-AMC, Bachem). To start the coagulation reaction reagents of the company Thrombinoscope are used (PPP reagent: 30 pM recombinant tissue factor, 24 μΜ phospholipids in HEPES). The reaction is carried out in the presence of varying concentrations of test substance or the corresponding solvent. In addition, a Thrombin calibrator from the company Thrombinoscope is used, whose amidolytic activity is required for calculating the thrombin activity in a plasma sample.

The test is carried out according to the manufacturer (Thrombionsocpe BV): 4 μΐ of the test substance or the solvent, 76 μΐ plasma and 20 μΐ PPP reagent or thrombin calibrator are incubated for 5 min at 37 ° C. After addition of 20 μM 2.5 mM thrombin substrate in 20 mM Hepes, 60 mg / ml BSA, 102 mM calcium chloride, the thrombin generation is over 120 measured every 20 seconds. The measurement is carried out with a fluorometer (Fluoroskan Ascent) from Thermo Electron, which is equipped with a 390/460 nM filter pair and a dispenser. By using the "thrombinoscope software", the thrombogram is calculated and graphically displayed and the following parameters are calculated: lag time, time to peak, peak, ETP (endogenous thrombin potential) and start tail a.5) Determination of the anticoagulant effect

The anticoagulant activity of the test substances is determined in vitro in human, rabbit and rat plasma. For this purpose, blood is removed using a 0.11 molar sodium citrate solution as a template in a mixing ratio of sodium citrate / blood 1/9. The blood is mixed well immediately after collection and centrifuged for 15 minutes at approximately 4000 g. The supernatant is pipetted off.

The prothrombin time (PT, synonyms: thromboplastin time, quick test) is determined in the presence of varying concentrations of test substance or the corresponding solvent with a commercially available test kit (Neoplastin® from Boehringer Mannheim or Hemoliance® RecombiPlastin from Instrumentation Laboratory). The test compounds are incubated for 3 minutes at 37 ° C with the plasma. Subsequently, coagulation is triggered by the addition of thromboplastin and the time of coagulation is determined. The concentration of test substance is determined which causes a doubling of the prothrombin time. Representative activity data from this test are listed in Table 3 below (in part as averages from individual determinations):

Table 3

Example no. ICso ΙμΜ Ι Example No., ICso | μΜ!

2 2.79 6 6.2

9 2.74 12 0.93

15 3.38 16 3.84

18 2.45 20 5.75

21 5.65 24 1.14

25 0.93 26 4.58

27 2.19 29 1.0

30 5.8 31 2.79 Example no. ICso ΙμΜ Ι Example No., ICso | μΜ!

32 3.28 33 2.95

34 6.04 37 3.48

38 3.81 45 5.27

47 3.23 48 2.49

51 2.11 52 4.24

58 2.85 60 2.55

63 2.36 65 5.18

67 3.95 69 5.05

72 4.73 75 4.15

77 2.83 78 2.63

79 1.24 80 3.27

81 2.46 84 2.55

85 4.26 93 2.07

94 2.93 95 1.61

97 5.49

The thrombin time (TT) is determined in the presence of varying concentrations of test substance or the corresponding solvent with a commercially available test kit (Thrombin Reagent from Roche). The test compounds are incubated for 3 minutes at 37 ° C with the plasma. Subsequently, coagulation is triggered by the addition of the thrombin reagent and the time of coagulation is determined. The concentration of test substance is determined which causes a doubling of the thrombin time.

The activated partial thromboplastin time (APTT) is determined in the presence of varying concentrations of test substance or the corresponding solvent with a commercially available test kit (PTT Reagent from Roche). The test compounds are incubated for 3 minutes at 37 ° C with the plasma and the PTT reagent (cephalin, kaolin). Subsequently, coagulation is triggered by the addition of 25 mM calcium chloride and the time of coagulation is determined. The concentration of test substance is determined which causes a doubling of the APTT. a.6) thromboelastography (thromboelastogram)

The thromboelastography is performed with the help of the thromboelastograph ROTEM from Pentapharm and the associated accessories cup and pin. The measurement is in whole blood, which is previously taken in sodium citrate monovettes Sarstedt. The blood is kept in the monovettes using a shaker in motion and at 37 ° C for 30 min. pre-incubated.

A 2 molar stock solution of calcium chloride in water is prepared. This is diluted 1:10 with an aqueous 0.9% sodium chloride solution. To measure this 20 μΐ 200 mM calcium chloride solution are placed in the cups (final concentration of calcium chloride 12.5 mM). Add 3.2 μΐ of substance or solvent. The measurement is started by adding 300 μΐ of whole blood. After the addition, pipette up and down briefly with the pipette tip without creating any air bubbles. The measurement takes place over 2.5 hours or is stopped at the beginning of fibrinolysis. The following parameters are determined for evaluation: CT (clotting time / [sec.]), CFT (clotting formation time / [sec.]), MCF (maximum clot firmness / [mm]) and the alpha angle [°]. The measuring points are recorded every 3 seconds and displayed graphically over the y-axis as MCF [mm] and on the x-axis as time [sec]. a.7) Inhibition of thrombus-bound coagulation factors thrombin

Blood clots that form either before starting therapy with anticoagulants, during therapy breaks or despite therapy, contain large amounts of coagulation factors, which may promote progressive thrombus formation. These coagulation factors are tightly bound to the thrombus and can not be washed out. In certain clinical situations, this may pose a risk for the patient. In the experiments listed below, both thrombin and FXa with biological (procoagulant) activity can be detected in human thrombi. Thrombi formed in vitro

Thrombi are formed in vitro from human plasma and assayed for activity of the bound coagulation factors thrombin and FXa. For this, 300 μl of plasma are mixed with 30 μl of lipid vesicles and 30 μl of an aqueous calcium chloride solution in a 48 MTP plate and incubated for 30 minutes. This and the following steps are performed at 37 ° C and under constant agitation (300 rpm). The thrombi formed are transferred to a new 48 MTP plate and washed in 0.9% sodium chloride solution twice for 10 min, blotting the thrombus between the washes on filter paper. The thrombus is in Buffer B was transferred (Owens veronal buffer, 1% BSA) and incubated for 15 min, blotted onto filter paper and incubated in test substance at different concentrations in buffer B for 30 min. Subsequently, the clots are washed twice as described above. The thrombi are blotted and transferred into buffer D: (240 μΐ Owren's veronal buffer, 1% BSA and 15.6 mM calcium chloride) and incubated with or without 0.6 μΜ prothrombin for 45 min. The reaction is stopped by 75 μL of 1% EDTA solution. Thrombin is separately in the thrombus in buffer A (7.5 mM Na ₂ EDTAx2H ₂ 0, 175 mM sodium chloride, 1% BSA, pH 8.4) or in the supernatant from the last step was measured. For this purpose, the under a. l) used thrombin substrate in the final concentration 50 μΜ used, and the resulting fluorescence measured in fluorescence plate reader (360 / 465nm). a.8) Influence of Thrombin Inhibitors on Thrombolysis in Platelet-poor Plasma

The effect of the test substances on in vitro thrombolysis in platelet-poor plasma is tested in the presence of tissue plasminogen activator (tPA). For this purpose, a clot is initially formed under control by means of turbidity measurement (UV absorption at 405 nm) in a microtiter plate in human plasma with the addition of tissue factor (tissue factor), the dissolution of which is adjusted by simultaneous administration of tissue plasminogen activator (tPA) within a specific time window becomes. Simultaneous addition of different amounts of the test substance can lead to a shortening of the thrombolytic time (time between the maximum turbidity and the re-achievement of the baseline). In a 384-well microtiter plate, 63 μM human plasma (German Red Cross equivalent to 90% plasma in test) with 0.7 μM of an ethanol / water mixture (1: 1) containing different concentrations of the test substances, 1.7 μM of a solution of human thrombomodulin (final concentration 10 nM) and 1.7 μΐ _^ of a solution of human tissue-type plasminogen activator (Actilyse®, final concentration 3 nM) was added. The coagulation by the addition of 3.5 μΐ _^ a tissue factor-containing solution (RecombiPlastin 2G in a l: 100 dilution in 0.2 M calcium chloride solution) was started at 37 ° C. Thereafter, the turbidity measurement (UV absorbance measurement at 405 nm) is started immediately at minute intervals. The thrombolysis time is calculated as the time between the maximum absorption and the baseline recovery. b) Determination of the antithrombotic effect (in vivo) bl) Arteriovenous shunt and bleeding model (combi model rat)

Sober male rats (strain: HSD CPB: WU) weighing 300-350 g anesthetized with Inactin (150 - 180 mg kg). Thrombus formation is induced in an arteriovenous shunt by the method of Christopher N. Berry et al., Br. J. Pharmacol. (1994), 113, 1209-1214. For this purpose, the left jugular vein and the right carotid artery are dissected free. An extracorporeal shunt is placed between the two vessels by means of a 10 cm long polyethylene tube (PE 60). This polyethylene tube is centered in another 3 cm polyethylene tube (PE 160), which includes a roughened and looped nylon thread to create a thrombogenic surface. The extracorporeal circuit is maintained for 15 minutes. Then the shunt is removed and the nylon thread with the thrombus weighed immediately. The net weight of the nylon thread was determined before the start of the test.

To determine the bleeding time, immediately after opening the shunt circuit, the tail tip of the rats is catered for 3 mm with a razor blade. The tail is placed in 37 ° C tempered saline and the bleeding from the cut wound observed over 15 minutes. The time to stop the bleeding for at least 30 seconds (initial bleeding time), the total bleeding time within 15 minutes (cumulative bleeding time) and the amount of blood loss via the photometric determination of the collected hemoglobin are determined.

The test substances are administered either intravenously via the contralateral jugular vein as a single bolus or as a bolus followed by continuous infusion or orally by means of a gavage, prior to application of the extracorporeal circuit and tail tip incision. b.2) Iron (II) Chloride Damage and Bleeding Model (Combi Model II, Rat)

Male rats (strain: HsdRCCHan: Wist) weighing 300g-325g are anesthetized with Inactin (180 mg / kg) intraperitoneally. Thrombus formation is triggered by iron (II) chloride in the carotid artery. For this purpose, the right carotid artery is dissected free. Then a flow probe is connected and blood flow is recorded for 10 minutes. Thereafter, artery and environment are drained. Parafilm (10 x 8 mm) and filter paper (10 x 6 mm kinked) are placed under the carotid artery and treated with 20μl iron (II) chloride solution (ferrous chloride tetrahydrate Reagent Plus 99%, Sigma, 5% Solution in water is prepared). A small piece of filter paper is placed on top of the carotid artery and also wetted with iron (II) chloride solution. The carotid artery is covered with a damp swab and left for 5 minutes. Thereafter, parafilm and filter paper are removed and the artery rinsed with physiological sodium chloride solution. Reassemble the flowhead and record blood flow for 30 minutes. Thereafter, the measurement is stopped and the free-prepared Piece of A. carotid clamped with vascular clamps and excised. The thrombus in the vessel is removed from the vessel using tweezers and weighed immediately.

To determine the bleeding time, the tail tip of the rat is catered for by a razor blade after damage and re-attachment of the flow measuring head by 3 mm. The tail is placed in 37 ° C tempered water and the bleeding from the cut wound observed over 15 minutes. The time to stop the bleeding for at least 30 seconds (initial bleeding time), the total bleeding time within 15 minutes (cumulative bleeding time) and the amount of blood loss via the photometric determination of the collected hemoglobin are determined. The test substances are given either intravenously via the jugular vein as a single bolus directly before the start of the experiment or as a bolus (before the start) with subsequent continuous infusion. b.3) Rabbit Venous Reperfusion and Hemorrhage Model (Combi Model Rabbit)

Male New Zealand rabbits weighing 2.8 - 3.4 kg are anesthetized with an intramuscular ketamine / Rompun bolus injection. Subsequently, the animal is shaved at the necessary sites for the operation. Via an indwelling cannula, a continuous anesthetic infusion (ketamine / rompun) is administered via the left ear vein. The right and left femoral veins and the right femoral artery are catheterized with a polyethylene tube (PE50). Subsequently, the jugular vein is gently dissected free, so that the vessel is as little as possible strained and damaged and no more fat is on the vessel. By means of a suitable flow measuring system (Powerlab, Transonic TS420 incl. Flow measuring head), the flow is recorded in the jugular vein (Lab Chart Software). 1.4 ml of citrated blood are taken twice from the rabbit before starting the experiment from the femoral artery and the basal bleeding time is determined at the ear margin. Once the flow in the jugular vein has been constant for 10 min (complete regeneration of the vessel after preparation), the vein is clamped with small vascular clamps 2 cm long. In a Petri dish, the previously taken citrated blood (300 μΐ) is mixed with calcium chloride (0.25 M, 90 μΐ) and thrombin (25 U / ml, 60 μΐ). 180 μΐ of the blood / calcium chloride / thrombin mixture are rapidly drawn up with a 1 ml syringe and injected through a 27G cannula into the clamped vessel segment. The puncture site is clamped with tweezers for one minute to prevent blood from escaping. Two minutes after injection of the thrombus, the test substance is applied as a bolus and infused through the left venous femoral catheter and connected. 14 minutes after thrombus injection tissue plasminogen activator is connected as a bolus and infusion (Actilyse®, 20 μg / kg bolus & 150 μg / kg / h infusion) to the right femoral vein. 15 minutes after thrombus injection, the stasis is opened and the Flow sensor connected. The blood flow in the vessel is taken up for 120 minutes while the vessel is kept moist with warm 0.9% aqueous sodium chloride solution. After 105 minutes of reperfusion, the ear bleeding time is again determined. At the end of the experiment, after 120 minutes of reperfusion, 1.4 ml of citrated blood is taken, the animal is killed painlessly by 1.5 ml T61 bolus injection and the thrombus weight in the jugular vein is determined. The blood taken before and after the experiment is used for plasma collection and ex vivo coagulation time determination.

The area under the blood flow-time curve is calculated (AUC) and related to the maximum achievable area calculated from pre-trial blood flow and time (120 min). The area obtained exclusively with tissue plasminogen activator is subtracted from the area achieved with the respective substance or dosage. The resulting area is considered as a measure of the improvement in reperfusion by the substance to be tested. c) Determination of pharmacokinetics c.l) Pharmacokinetics after intravenous administration of the test substance

Male Wistar rats are anesthetized and a catheter is placed in the jugular vein. The next day, a defined dose of the test substance is administered as a solution by tail vein injection. Blood samples are collected by the catheter over a period of 7 hours (9 times). Female beagle dogs are administered a defined dose of the test substance as a solution via the cephalic vein as a 15 min infusion. Blood samples are collected using a catheter in the cephalic vein over a period of 7 hours (12 times).

The blood is centrifuged in heparin vessels. The plasma sample is mixed with acetonitrile for protein precipitation and centrifuged. The test substance in the supernatant is quantified by LC / MS-MS. The determined plasma concentrations of the test substance are used to calculate the pharmacokinetic parameters such as AUC (area under the plasma concentration-time curve), V _ss (distribution volume), C _ma x (highest concentration of the test substance in the plasma after administration), tm (half-life) and CL (total clearance of the test substance from the plasma) used. For the calculation of the blood clearance, the blood-plasma distribution is determined by incubation of the test substance in blood. After separation of the plasma by centrifugation, the concentration of the test substance in the plasma is determined by LC / MS-MS. c.2) Pharmacokinetics after peroral administration of the test substance Male Wistar rats are anesthetized and a catheter is placed in the jugular vein. The next day, a defined dose of the test substance is administered perorally. Blood samples are collected by the catheter over a period of 24 hours (9 times). Female beagle dogs are given a defined dose of the test substance orally. Blood samples are collected using a catheter in the cephalic vein over a period of 24 hours (9 times).

The blood is centrifuged in heparin vessels. The plasma sample is mixed with acetonitrile for protein precipitation and centrifuged. The test substance in the supernatant is quantified by LC / MS-MS. The determined plasma concentrations of the test substance are used to calculate the pharmacokinetic parameters such as AUC (area under the plasma concentration-time curve), Cmax (highest concentration of the test substance in the plasma after administration), tm (half-life) and F (bioavailability). c.3) Caco-2 Permeability Assay The in vitro permeability of the test substance to a Caco-2 cell monolayer is determined by an established in vitro prediction system for permeability through the gastrointestinal tract [1]. Caco-2 cells (ACC No. 169, DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig) are seeded on 24 well plates and cultured for 14 to 16 days. The test substance is dissolved in DMSO and diluted to a concentration of 2 μΜ in transport buffer (HBSS, Hanks Buffered Salt Solution, Gibco / Invitrogen supplemented with glucose (final concentration 19.9 mM) and HEPES (final concentration 9.8 mM)). To determine the apical to basolateral permeability (P _app AB), the test substance is added to the apical side and transport buffer to the basolateral side of the cell monolayer. To determine the basolateral to apical permeability (P _app BA), the test substance is added to the basolateral side and transport buffer of the apical side of the cell monolayer. Samples from the donor compartment are taken at the beginning of the experiment to determine the mass balance. After an incubation period of 2 hours at 37 ° C, samples were taken from both compartments. Samples are quantified by LC / MS-MS and the permeation coefficients are calculated. The permeability of Lucifer Yellow is determined for each cell monolayer to ensure the integrity of the cell monolayer. The permeability of atenolol (low permeability marker) and sulfasalazine (active excretion marker) is co-determined in each cell batch for quality control of the cells. Literature: Artursson, P. and Karlsson, J. (1991). Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem. Biophys.175 (3), 880-885. c.4) In vitro clearance Determination with hepatocytes Incubations with fresh primary hepatocytes are performed at 37 ° C in a total volume of 1.5 ml with a modified Janus ^® robot (Perkin Elmer) with shaking. The incubations typically contain 1 million live liver cells / ml, ~ 1 μΜ substrate and 0.05 M potassium phosphate buffer (pH = 7.4). The final ACN concentration in the incubation is <1%.

Aliquots of 125 μΐ are taken from the incubations after 2, 10, 20, 30, 50, 70 and 90 minutes and transferred to 96-well filter plates (0.45 μηι Low-Binding Hydrophilic PTFE, Millipore: MultiScreen Solvinert). These each contain 250 μΐ ACN to stop the reaction. After centrifugation, the filtrates are analyzed with MS / MS (usually API 3000).

The in vitro clearances are calculated from the half-lives of the substance degradation using the following equations:>CL'intrinsk [ml / (min kg)] = (0.693 / in vitro tl / 2 [min]) · (liver weight [g liver kg body weight ]) · (Cell count [1.1 × ^10Λ 8] / liver weight [g]) / (cell count [1 × ^10Λ 6] / incubation volume [ml])

CL _b i _ood is calculated without consideration of the free fraction ("nonrestricted well stirred model") according to the following equation. > CLbiood well-stirred [L / (h-kg)] = (Q _H [L / (h-kg)] -CL ' _intrinsic [L / (h-kg)]) / (Q _H [L / (h -kg)] +

CL intrinsic [L / (h-kg)])

The species-specific extrapolation factors to be calculated are summarized in the following Table 4:

Table 4

Fmax values indicating the maximum possible bioavailability - related to hepatic extraction - are calculated as follows: F _max well-stirred [%] = (L- (CL _mo od well-stirred [L / (h-kg)] / Q _H [L / (h-kg)])) · 100 c.5) CYP inhibition test

Inhibitory properties of an active substance on the cytochrome P450 (CYP) of the human organism can have massive clinical effects (drug interactions), as a major part of the prescribed drugs are degraded (metabolised) by these enzymes. In particular, the CYP isoenzymes of the 1A and 2C family, CYP2D6, and with a share of almost 50% CYP3A4 are involved in this process. In order to exclude or minimize these possible drug interactions (Drug Interactions, DDI), the ability of substances to inhibit CYP1A2, CYP2C8, CYP2C9, CYP2D6 and CYP3A4 in humans, with human liver microsomes (pool of different individuals) is examined , This is done by measuring CYP isoform-specific metabolites formed from standard substrates such as phenacetin, amodiaquine, diclofenac, dextromethorphan, midazolam and testosterone. The inhibition effects are investigated at six different concentrations of the test compounds (1.5, 3.1, 6.3, 12.5, 25 and 50 μΜ as maximum concentration or 0.6, 1.3, 2.5, 5, 10 and 20 μΜ as maximum concentration), with the extent of CYP isoform-specific metabolite formation the standard substrates in the absence of the test compounds and calculated the corresponding ICso values. CYP isoform-specific standard inhibitors such as furafylline, montelukast, sulfaphenazole, fluoxetine and ketoconazole serve as controls of the results obtained. In order to obtain evidence of possible mechanism-based inhibitors (MBI) on CYP3A4, before the addition of midazolam or testosterone as Standard substrates for CYP3A4 the human liver microsomes incubated for 30 minutes in the presence of the inhibitor to be examined. A reduction in the IC 50 value obtained compared to the batch without preincubation serves as an indication of a mechanism-based inhibition. The positive control is mibefradil. Procedure: The incubations of the standard substrates with human liver microsomes (14-100 μg / ml) in the presence of the test compound (as a potential inhibitor) are carried out at 37 ° C. in 96-well plates on a workstation (Tecan, Genesis, Hamiltion, MICROLAB STARLET). The incubation times are 10-15 minutes. The test compounds are preferably dissolved in acetonitrile (1.0, 2.0 or 2.5, 5.0 mM stock solution). The 96-well plates are prepared by sequentially adding a stock solution of NADP +, EDTA, glucose-6-phosphate and glucose-6-phosphate dehydrogenase in phosphate buffer (pH 7.4), the test compound, and a solution of standard substrate and human liver microsomes in phosphate Buffer (pH 7.4). The total volume is 200 μΐ. The 96-well plate also contains the corresponding control incubations with and without standard inhibitor. The incubations are stopped after the respective incubation period by adding 100 .mu.l of acetonitrile, which is a suitable internal standard. Precipitated proteins are separated by centrifugation (3000 rpm, 10 minutes, 10 ° C). The resulting supernatants of the respective plates are combined on a plate and analyzed by LC-MS / MS. From the obtained measurement data, the IC 50 values are generated and used to evaluate the inhibitory potential of the test compound. c.6) Cellular viiro assay for determining the induction of drug-degrading cytochrome enzymes (CYPs) in human primary hepatocytes

Enzyme induction is an undesirable property of a drug that calls into question a broad and safe applicability of the drug. The consequence of enzyme induction is an accelerated degradation (metabolization) of drugs in the liver. The combined use of an enzyme inducer and other medications such as immunosuppressants, coagulants or contraceptives can lead to a total inefficacy of the drug.

The aim of the study is to find substances that do not have this undesirable drug interaction. The identification of enzyme inducers takes place with the aid of primary hepatocytes of humans in long-term culture. To cultivate the cells, hepatocytes are plated out on a collagen I layer (density of 100,000 cells / cm ² ) and the grown cells are then overlaid with a second collagen layer (sandwich technique). (Kern A, Bader A, Pichlmayr R, and Sewing KF, Biochem PharmacoL, 54, 761-772 (1997). In order to obtain the influence of the test substances on the regulation of the liver enzymes, the hepatocytes are incubated in the long-term culture for several days with the active ingredients.

Test procedure: The cells are treated with the test substances after a two-day regeneration phase in Williams Medium E, 10% FCS, prednisolone, insulin, glucagon and L-glutamine, penicillin and streptomycin. For this purpose, stock solutions of the active compounds are prepared at a concentration of 1 mg / ml in acetonitrile or methanol and pipetted in 8 dilution steps (1: 3) in cell culture medium to the cell cultures and in a cell incubator (96% humidity, 5% v / v carbon dioxide, 37 ° C) for about 5 days. The cell culture medium is changed daily. After this incubation period, the cell cultures are incubated with cytochrome P450 (CYP) -specific substrates to determine the activity of the liver enzymes CYP1A2, CYP3A4, CYP2B6 and CYP2C19. Stopped samples are either analyzed directly or stored at -20 ° C until analysis.

For this purpose, the media of the cell cultures are chromatographed with suitable C18-reversed-phase columns and variable mixtures of acetonitrile and 10 mM ammonium formate (HPLC-MS / MS).

The mass spectrometric data are used to quantify the substrate turnover and, derived therefrom, to calculate the liver enzyme activities. Agents with unfavorable properties on the regulation of liver enzymes are not pursued.

C) Exemplary embodiments of pharmaceutical compositions

The substances according to the invention can be converted into pharmaceutical preparations as follows:

Tablet:

Composition: 100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50 mg of corn starch, 10 mg of polyvinylpyrrolidone (PVP 25) (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 is granulated with a 5% solution (m / m) of the PVP in water. The granules, after drying with the magnesium stearate for 5 min. mixed. This mixture is compressed with a conventional tablet press (for the tablet format see above).

Oral suspension:

Composition:

1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of rhodigel (xanthan gum) (FMC, USA) and 99 g of water. A single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.

production:

The rhodigel is suspended in ethanol, the compound of Example 1 is added to the suspension. While stirring, the addition of water. Until the swelling of the Rhodigels swirling is about 6 h stirred.

Intravenous solution:

Composition:

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

production:

The compound of Example 1 is dissolved together with polyethylene glycol 400 in the water with stirring. The solution is sterile filtered (pore diameter 0.22 μηι) and filled under aseptic conditions in heat sterilized infusion bottles. These are closed with infusion stoppers and crimp caps.

Claims

claims

Compound of the formula

in which for a group of the formula

where * is the point of attachment to the carbonyl group,

X represents an oxygen atom, a sulfur atom or CH-R ⁶ , wherein

R is hydrogen or hydroxy,

R ^{2 is} hydrogen, aminocarbonyl, C ¹ -C 6 -alkyl, C 3 -C 6 -cycloalkyl or phenyl, in which alkyl and cycloalkyl may be substituted by a substituent selected from the group consisting of hydroxy, methoxy, cyano, hydroxycarbonyl, aminocarbonyl, methylsulfonyl, Difluoromethoxy, trifluoromethoxy and cyclopropyl, in which cyclopropyl may in turn be substituted by a hydroxy substituent, or in which alkyl and cycloalkyl can be substituted by 1 to 3 substituents fluorine,

R ^{3 is} hydrogen or C 1 -C ₄ -alkyl, or

R ^{4 is} hydrogen or C 1 -C 6 -alkyl in which alkyl may be substituted by one hydroxy substituent or in which alkyl may be substituted by from 1 to 3 fluoro substituents, R ^{5 is} C 1 -C ₄ alkyl, or

R ^{7 is} hydrogen or C 1 -C ⁶ -alkyl, in which alkyl may be substituted by a substituent selected from the group consisting of cyano, hydroxy and methoxy, or in which alkyl may be substituted by 1 to 3 substituents fluorine, represents hydrogen, R ^{9 is} hydrogen or Ci-Cö-alkyl, wherein alkyl may be substituted with a substituent selected from the group consisting of hydroxy, cyano and aminocarbonyl, or wherein alkyl may be substituted with 1 to 3 substituents fluorine, R ^{10 is} hydrogen R ^{11 is} C 1 -C ₄ -alkyl, in which alkyl may be substituted by one hydroxy, R ^{12 is} hydrogen or C 1 -C ₄ -alkyl, or

R ^{15 is} hydrogen or methyl,

is hydrogen, methyl or fluoromethyl, or one of its salts, its solvates or the solvates of its salts. 2. A compound according to claim 1, characterized in that R ^{1 is} a group of the formula

R ^{6 is} hydrogen,

R ^{2 is} hydrogen, Ci-C ₄ alkyl or Cs-Ce-cycloalkyl, wherein alkyl and cycloalkyl may be substituted with a substituent selected from the group consisting of hydroxy, methoxy, hydroxycarbonyl, difluoromethoxy and cyclopropyl, in which cyclopropyl be substituted in turn may be substituted with one hydroxy substituent or wherein alkyl may be substituted with from 1 to 3 fluoro substituents, R ^{3 is} hydrogen or C 1 -C 6 alkyl, or

R ² and R ³ together with the carbon atom to which they are attached form a cyclobutyl ring, wherein the cyclobutyl ring may be substituted with a hydroxy substituent,

R ^{4 is} hydrogen or C 1 -C ₄ -alkyl, in which alkyl may be substituted by a hydroxy substituent, R ^{5 is} C 1 -C ₄ -alkyl, R ^{7 is} C 1 -C ₄ -alkyl, in which alkyl may be substituted with a substituent methoxy,

R ^{8 is} hydrogen,

R ^{9 is} C 1 -C 4 -alkyl, in which alkyl may be substituted by a substituent selected from the group consisting of cyano and aminocarbonyl,

R ^{10 is} hydrogen,

R ^{11 is} C 1 -C ₄ -alkyl,

R ^{12 is} hydrogen or C 1 -C ₄ -alkyl, or

R ^{15 is} hydrogen or methyl, and

R ^{16 is} hydrogen or methyl,

or one of its salts, its solvates or the solvates of its salts.

3. A compound according to any one of claims 1 or 2, characterized in that

R ^{1 is} a group of the formula

stands,

where * is the point of attachment to the carbonyl group,

X is an oxygen atom,

R ^{2 is} C ¹ -C ⁴ -alkyl or cyclobutyl,

wherein alkyl is substituted with a hydroxy substituent, and

wherein cyclobutyl is substituted by a hydroxy substituent, R ^{3 is} hydrogen,

R ^{4 is} hydrogen or methyl,

and

R ^{5 is} methyl,

or

R ^{2 is} methyl,

wherein methyl may be substituted with 1 to 2 substituents fluorine, R ^{3 is} hydrogen or methyl, R ^{4 is} C 1 -C ₄ -alkyl, wherein alkyl is substituted with a hydroxy substituent, and

R ^{5 is} methyl, or

R ^{4 is} hydrogen, and

R ^{5 is} methyl,

R ^{7 is} methyl,

R ^{8 is} hydrogen,

R ^{9 is} methyl or ethyl, wherein methyl may be substituted with a cyano substituent, R ^{10 is} hydrogen, R ^{u is} methyl, R ^{12 is} hydrogen, or

R ^{13 is} methyl, wherein methyl is substituted with a hydroxy substituent,

R ^{14 is} ethoxy or cyclopropyloxy, wherein ethoxy may be substituted with 1 to 3 substituents selected from the group consisting of deuterium and fluorine, R ^{15 is} hydrogen, and

R ^{16 is} hydrogen or methyl, or one of their salts, their solvates or the solvates of their salts. 4. A compound according to any one of claims 1 to 3, characterized in that R ^{1 is} a group of formula

where * is the point of attachment to the carbonyl group,

X is an oxygen atom,

R ^{2 is} C 1 -C ₄ -alkyl or cyclobutyl, in which alkyl is substituted by one hydroxy substituent, and wherein cyclobutyl is substituted by one hydroxy, R ^{3 is} hydrogen, R ^{4 is} hydrogen or methyl, and

R ^{5 is} methyl, or

R ^{2 is} methyl, wherein methyl may be substituted with 1 to 2 substituents fluoro, R ^{3 is} hydrogen or methyl, R ^{4 is} Ci-Gi-alkyl, wherein alkyl is substituted with a hydroxy substituent, and

R ^{5 is} methyl, or

R ^{4 is} hydrogen, and

R ^{5 is} methyl,

R ^{7 is} methyl,

R ^{8 is} hydrogen,

is hydrogen or methyl, one of its salts, its solvates or the solvates of its salts.

5. A compound according to any one of claims 1 to 4, characterized in that R ^{1 is} a group of formula

stands,

where * is the point of attachment to the carbonyl group,

X is an oxygen atom,

R ^{2 is} C 1 -C ₄ -alkyl or cyclobutyl,

wherein alkyl is substituted with a hydroxy substituent, and

wherein cyclobutyl is substituted with a hydroxy substituent,

R ^{3 is} hydrogen,

R ^{4 is} hydrogen or methyl,

and

R ^{5 is} methyl,

or

R ^{2 is} methyl,

wherein methyl may be substituted with 1 to 2 substituents fluorine,

R ^{3 is} hydrogen or methyl,

R ^{4 is} C 1 -C ₄ -alkyl,

wherein alkyl is substituted with a hydroxy substituent, and is methyl, or

R ^{4 is} hydrogen, and

R ^{5 is} methyl, and

R ^{16 is} hydrogen or methyl, or one of their salts, their solvates or the solvates of their salts.

A compound according to claim 1, characterized in that the compound

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [(5R) -2- (2-hydroxyethyl) -2,5- dimethylmorpholin-4-yl] methanone [enantiomerically pure isomer] or

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (2-hydroxypropan-2-yl) -2-methylmorpholine. 4-yl] methanone [enantiomerically pure isomer 2] or

{1 - [(2- {[(4-chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) carbonyl] -5,5-dimethyl-3-oxopiperazine 2-yl} acetonitrile [enantiomerically pure isomer 2] or

(2- {[(4-Chloropyridin-2-yl) methyl] amino} -7-methoxy-1,3-benzoxazol-5-yl) [5- (1-hydroxyethyl) -2,2-dimethylmorpholine-4- yl] methanone [enantiomerically pure isomer 1] or one of the salts, the solvates or the solvates of the salts of these compounds.

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 ^{16 has} the meaning given in claim 1, with a compound of the formula

R-H (ΙΠ), in which

R ^{1 has} the meaning given in claim 1, is reacted with Dehydratisierungsreagenzien.

8. A compound according to any one of claims 1 to 6 for the treatment and / or prophylaxis of diseases. 9. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment and / or prophylaxis of diseases. 10. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment and / or prophylaxis of thromboembolic disorders. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment and / or prophylaxis of acute coronary syndrome (ACS), venous thromboembolism, venous thrombosis, especially in deep leg veins and renal veins, pulmonary embolism, stroke and / or thrombosis prophylaxis in the context of surgical interventions, in particular in the context of surgical interventions in patients who have cancer.

A medicament containing a compound according to any one of claims 1 to 6 in combination with an inert, non-toxic, pharmaceutically suitable excipient.

Medicament according to claim 12 for the treatment and / or prophylaxis of thromboembolic diseases.

A method for combating thromboembolic disorders in humans and animals by administering a therapeutically effective amount of at least one compound of any one of claims 1 to 6, a drug of claim 12 or a pharmaceutical composition of claim 9, 10 or 11.