EP3049403A1 - Substituted phenylalanine derivatives - Google Patents

Abstract

The invention relates to substituted phenylalanine derivatives and to methods for the production thereof, in addition to the use of said derivatives for producing medicaments for the treatment and/or prophylaxis of diseases, in particular cardiovascular diseases and/or perioperative heavy blood loss.

Description

 Substituted phenylalanine derivatives

The invention relates to substituted phenylalanine derivatives 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 and / or perioperative severe blood loss.

Blood clotting is a protective mechanism of the organism that can rapidly and reliably "seal" defects in the blood vessel wall, thus preventing or minimizing blood loss, and hemostasis following vascular injury is essentially through the coagulation system, where an enzymatic cascade becomes more complex 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 final common pathway, where factors Xa and IIa (thrombin) play key roles: Factor Xa bundles the signals of the two ger because it is produced both by Factor VIIa / Tissue Factor (extrinsic pathway) and 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.

In recent years, the traditional theory of the two separate areas of the coagulation cascade (extrinsic or intrinsic pathway) has been modified based on new findings: in these models, coagulation is initiated by binding of activated factor VIIa to tissue factor (TF). The resulting complex activates factor X, which in turn leads to thrombin generation with subsequent production of fibrin and platelet activation (via PAR-1) as hemorrhagic end-products of hemostasis. Compared to the subsequent amplification / propagation phase, the rate of thrombin production is small and limited by the appearance of TFPI as an inhibitor of the TF-FVIIa-FX complex. A key component of the transition from initiation to amplification and propagation of coagulation is factor XIa. Thrombin activated in positive feedback loops in addition to Factor V and Factor VIII and Factor XI to Factor XIa, which converts Factor IX to Factor IXa and on the thus generated Factor IXa / Factor VIIIa complex quickly larger amounts of Factor Xa produced. This triggers the production of large amounts of thrombin, which leads to strong thrombus growth and stabilizes the thrombus.

The formation of a thrombus or a blood clot is counter-regulated by the fibrinolysis. Upon activation of plasminogen by tissue plasminogen activator (tPA), the active serine protease, plasmin, cleaves polymerized fibrin and thus degrades the thrombus. This process is called fibrinolysis - with plasmin as the key enzyme.

Uncontrolled activation of the coagulation system or defective inhibition of the activation processes can cause the formation of local thromboses or emboli in vessels (arteries, veins, lymphatics) or cardiac cavities. This can lead to serious thrombotic or thromboembolic disorders. In addition, systemic hypercoagulability can lead to consumption coagulopathy in the context of disseminated intravascular coagulation.

In the course of many cardiovascular and metabolic diseases, systemic factors, e.g. Hyperlipidemia, diabetes or smoking, due to blood flow changes with stasis, e.g. in atrial fibrillation, or as a result of pathological vascular wall changes, e.g. endothelial dysfunction or atherosclerosis, to an increased tendency of coagulation and platelet activation. This undesirable and excessive hemostasis can lead to thromboembolic diseases and thrombotic complications with life-threatening conditions by the formation of fibrin and platelet-rich thrombi.

Thromboembolic disorders are the most common cause of morbidity and mortality in most industrialized countries [Heart Disease: A Textbook of Cardiovascular Medicine, Eugene Braunwald, 5th Ed., 1997, W.B. Saunders Company, Philadelphia].

The anticoagulants known in the art, i. Substances for the inhibition or prevention of blood clotting have various, often serious disadvantages. An efficient method of treatment or prophylaxis of thrombotic or thromboembolic diseases therefore proves to be very difficult and unsatisfactory in practice.

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, the known disadvantages described below can not thereby also be avoided 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 hemorrhages 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 have a lower probability of developing heparin-induced thrombocytopenia, they can only be administered subcutaneously. 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. Crow et al., Interactions of warfarin with drugs and food, Ann.Med.Med.Med., 1994, 121, 676-683.] Other side effects such as gastrointestinal disturbances, hair loss, and cutaneous necrosis have also been described and more recent approaches to oral anticoagulants have been reported However, in various phases of clinical trials or in clinical use, have also shown disadvantages, such as highly variable bioavailability, liver damage and bleeding complications.

In the case of antithrombotic drugs, the therapeutic range is of central importance: 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 a minimal risk profile.

In various in vivo models with, for example, antibodies as factor XIa inhibitors, but also in factor XIa knock-out models, the anti-thrombotic effect was demonstrated with little / no prolongation of bleeding time or increase in blood volume. In clinical trials Increased factor XIa levels were associated with an increased event rate. In contrast, Factor XI deficiency (hemophilia C), unlike Factor Villa or Factor EXa (Hemophilia A and B, respectively), did not result in spontaneous bleeding and only occurred during surgery and trauma. Instead, it showed protection against certain thromboembolic events.

In hyperfibrinolytic conditions, there is no sufficient wound closure resulting in severe, sometimes life-threatening bleeding. These bleedings can be stopped by inhibiting fibrinolysis with antifibrinolytic agents, which reduces plasmin activity. Corresponding effects could be demonstrated with the plasminogen inhibitor tranexamic acid in various clinical studies.

It is therefore an object of the present invention to provide novel compounds for the treatment and / or prophylaxis of cardiovascular diseases and / or perioperative severe blood loss in humans and animals having a wide therapeutic range.

W089 / 11852 describes inter alia substituted phenylalanine derivatives for the treatment of pancreatitis and WO 2007/070816 describes substituted thiophene derivatives as factor XIa inhibitors.

The invention relates to compounds of the formula

in which

R ^{1 is} a group of the formula

where # is the point of attachment to the nitrogen atom,

R ^{6 is} 5-membered heteroaryl, wherein heteroaryl may be substituted with one substituent selected from the group consisting of oxo, chloro, cyano, hydroxy and C ₁ -C ₃ -alkyl, wherein alkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of hydroxy, amino, hydroxycarbonyl and methoxy, or wherein alkyl may be substituted with 1 to 7 fluorine substituents, or wherein alkyl is substituted with one substituent selected from the group consisting of hydroxy, amino, hydroxycarbonyl and methoxy and wherein Alkyl is additionally substituted by 1 to 6 substituents fluorine, R ^{7 is} hydrogen, fluorine or chlorine,

R ⁸ and R ⁹ together with the carbon atoms to which they are attached form a 5-membered heterocycle, it being possible for the heterocycle to be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, chloro, cyano, hydroxy, and Ci C ₃ alkyl, pyrazolyl and pyridyl, wherein alkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of hydroxy, amino, hydroxycarbonyl and methoxy, or wherein alkyl may be substituted with 1 to 7 substituents fluoro, or wherein alkyl is substituted with a substituent selected from the group consisting of hydroxy, amino, hydroxycarbonyl and methoxy and wherein alkyl is additionally substituted with 1 to 6 substituents fluoro,

R is hydrogen, fluorine or chlorine, is a group of the formula

where * is the point of attachment to the phenyl ring,

R ^{4 is} hydrogen, hydroxyl, amino, C ₁ -C 4 -alkoxy, C ₁ -C ₃ -alkylamino, C ₁ -C 4 -alkylcarbonylamino, C ₃ -C 6 -cycloalkylamino or a 5- or 6-membered heterocyclyl bonded via a nitrogen atom, wherein alkoxy may be substituted with 1 to 2 substituents independently selected from the group consisting of amino and C ₁ -C 3 alkylamino, and wherein heterocyclyl may be substituted with 1 to 2 substituents independently selected from the group consisting of oxo, fluoro, Hydroxy, amino, hydroxycarbonyl, C 1 -C ₄ -alkyl, C ₁ -C ₃ -alkylamino, difluoromethyl, trifluoromethyl, 2,2,2-trifluoro-1-yl, C ₁ -C ₄ -alkoxycarbonyl, aminocarbonyl and C ₁ -C ₃ -alkylaminocarbonyl,

R ^{5 is} hydrogen, hydroxy, C 1 -C ₄ -alkyl, methoxy, trifluoromethyl or benzyloxy,

R ¹¹ is hydrogen, amino, Ci-C ₄ alkoxy, _{Ci-C3-alkylamino,} Ci-C ₄ alkoxycarbonyl, Ci-C ₃ alkylsulfonyl, -S (0) ₂ NR ¹³ R ^14, or a pyridinyloxy Nitrogen atom bound 5- or 6-membered heterocyclyl, wherein alkoxy may be substituted with 1 to 2 substituents independently selected from the group consisting of amino and C1-C3 alkylamino, and wherein alkylamino may be substituted with a 5- or 6-membered heterocyclyl bonded via a nitrogen atom, and heterocyclyl substituted may be with 1 to 2 substituents independently selected from the group consisting of oxo, fluoro, hydroxy, amino, hydroxycarbonyl, Ci-Gt-alkyl, Ci-C3-alkylamino, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroeth-l -yl, Ci-C t-alkoxycarbonyl, aminocarbonyl and Ci-C3-alkylaminocarbonyl, and wherein

R ^{13 is} hydrogen, C ¹ -C 3 -alkyl, C 3 -C 6 -cycloalkyl, benzyl or a 4 to 8-membered heterocyclyl bonded via a carbon atom,

R ^{14 is} hydrogen or Ci-Cs-alkyl, or

R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, wherein the heterocycle may be substituted with 1 to 2 substituents independently selected from the group consisting of oxo, fluoro, hydroxy, amino , Hydroxycarbonyl, C ₁ -C 4 -alkyl, C ₁ -C ₃ -alkylamino, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroeth-1-yl, C ₁ -C 4 -alkoxycarbonyl, aminocarbonyl and C ₁ -C ₃ -alkylaminocarbonyl, for hydrogen, Is fluorine, chlorine, hydroxyl, C 1 -C 4 -alkyl, methoxy or trifluoromethyl, is hydrogen, amino, C 1 -C 4 -alkoxy, C 1 -C 3 -alkylamino, C 1 -C 4 -alkoxycarbonyl, C 1 -C 3 -alkylsulfonyl, -S (O) 2NR ¹⁷ R ¹⁸ , pyridinyloxy or 5 or 6 bonded via a nitrogen atom heterocyclyl, wherein alkoxy may be substituted with 1 to 2 substituents independently selected from the group consisting of amino and C ₁ -C 3 alkylamino, and wherein alkylamino may be substituted with a 5- or 6-membered linked via a nitrogen atom Heterocyclyl, and where heterocyclyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, fluoro, hydroxy, amino, hydroxycarbonyl, C 1 -C 4 -alkyl, C 1 -C 3 -alkylamino, difluoromethyl, trifluoromethyl, 2, 2,2-trifluoroeth-1-yl, Ci-C t -alkoxycarbonyl, aminocarbonyl and Ci-C3-alkylaminocarbonyl, and wherein

R ^{17 is} hydrogen, C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl, benzyl or a 4 to 8-membered heterocyclyl bonded via a carbon atom,

R ^{18 is} hydrogen or C ₁ -C ₃ -alkyl, or

R ¹⁷ and R ¹⁸ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, wherein the heterocycle may be substituted with 1 to 2 substituents independently selected from the group consisting of oxo, fluoro, hydroxy, amino , Hydroxycarbonyl, C ₁ -C 4 -alkyl, C ₁ -C ₃ -alkylamino, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroeth-1-yl, C ₁ -C 4 -alkoxycarbonyl, aminocarbonyl and C ₁ -C 3 -alkylaminocarbonyl, R ^{16 is} hydrogen, fluorine, chlorine, C 1 -C ⁴ -alkyl, methoxy or trifluoromethyl,

R ^{3 is} hydrogen, fluorine, chlorine, methyl or methoxy, 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 those 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.

Depending on their structure, the compounds of the invention may exist in different stereoisomeric forms, 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 according to 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 which can be incorporated into a compound of the invention 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 C1, 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, for the study of 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. In addition, the incorporation of isotopes, such as For example, of deuterium, lead to certain therapeutic benefits as a result of greater metabolic stability of the compound, such as an extension of the half-life in the body or a reduction of 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 1 to 16 carbon atoms, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and choline.

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 themselves are biologically active or inactive may, however, be converted into compounds of the invention during their residence time in the body (for example metabolically or hydrolytically).

The following two representations (A) and (B) of a 1,4-disubstituted cyclohexyl derivative are equivalent to each other and are synonymous and, in both cases, descriptive of a trans-1,4-disubstituted cyclohexyl derivative.

 (A) (B)

This applies in particular to the structural element of the tranexamic acid amide, for example N - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl and iraws-4- (aminomethyl) cyclohexyl] carbonyl}. In the present invention, the illustration (A) is used.

The following three tautomeric representations (C), (D) and (E) of a triazole derivative are equivalent to each other and synonymous and, in all cases, descriptive of a 1,4-disubstituted triazole derivative.

 (C) (D) (E)

This applies in particular to the following structural elements: l / il, 2,4-triazol-3-yl, l / il, 2,4-triazol-5-yl, 4 / il, 2,4-triazol-3-yl and 4H -l, 2,4-triazol-5-yl. Y ¹ and Y ² are different substituents.

The following two tautomeric representations (F) and (G) of a tetrazole derivative are equivalent to each other and synonymous and, in all cases, descriptive of a tetrazole derivative.

(F) (G) This applies in particular to the following structural elements: l / i-tetrazol-5-yl and 2 / i-tetrazol-5-yl. Y ³ is the remaining part of the compound.

The compounds of the formula of the invention

as well as all L-phenylalanine intermediates are described on the in the formula above with a "~" labeled stereocenter as (S) configuration, since L-phenylalanine derivatives are introduced as central building blocks in the synthesis For example, coupling of the L-phenylalanine intermediate with the amine H ₂ NR ^{1 may result} in partial epimerization at the "~" labeled stereocenter. Thus, a mixture of the compounds according to the invention of (S) -enantiomer and (R) -enantiomer can be formed. The main component is the respectively depicted (S) -enantiomer. The mixtures of (S) -enantiomer and (R) -enantiomer can be separated into their enantiomers by methods known to those skilled in the art, for example by chromatography on a chiral phase. The enantiomers can be separated either directly after the coupling of the L-phenylalanine intermediates with the amine H ₂ NR ¹ or at a later intermediate of the synthesis or else the compounds according to the invention. Preferably, the separation of the enantiomers is directly after the coupling of the L-phenylalanine intermediates with the amine H ₂ NR ¹ . 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 synonymously in the context of the present invention and designate the avoidance or reduction of the risk To get, to experience, to suffer or to have a disease, a disease, a disease, an injury or a health disorder, a development or progression of such conditions and / or the symptoms of such conditions.

The treatment or 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 4 carbon atoms, preferably 1 to 3 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, iso-propyl, 2-methyl-prop-1-yl, n-butyl and tert-butyl.

Alkoxy represents a linear or branched alkoxy radical having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, by way of example and preferably methoxy, ethoxy, n-propoxy, iso-propoxy, 2-methyl-prop-l-oxy, n-butoxy and ieri-butoxy.

Alkylamino represents an amino group having one or two independently selected identical or different linear or branched alkyl radicals, each having 1 to 3 carbon atoms, by way of example and preferably methylamino, ethylamino, n-propylamino, iso-propylamino, A ^ N- Dimethylamino, A ^ N-Diemylamino, N-ethyl-N-memylamino, N-Met yl-nn-propylamino, N-iso-propyl-Nn-propylamino and A ^ N-diisopropylamino. C 1 -C 3 -alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having in each case 1 to 3 carbon atoms per alkyl radical.

Alkylsulfonyl represents a sulfonyl group having a linear or branched alkyl group having 1 to 3 carbon atoms, by way of example and preferably methylsulfonyl, ethylsulfonyl, n-propylsulfonyl and iso-propylsulfonyl.

Alkoxycarbonyl is a linear or branched alkoxy radical which is bonded via a carbonyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, by way of example and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl and tert-butylcarbonyl. butoxycarbonyl.

Alkylaminocarbonyl is an amino group having one or two independently selected identical or different straight-chain or branched alkyl substituents, each having 1 to 3 carbon atoms, and which is bonded via a carbonyl group, by way of example and preferably methylaminocarbonyl, ethylaminocarbonyl, n- Propylaminocarbonyl, iso-propylaminocarbonyl, A ^ N-dimemylaminocarbonyl, JV, JV-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-iso-propyl-Nn-propylaminocarbonyl and A ^ N-diisopropylaminocarbonyl. C 1 -C 3 -alkylaminocarbonyl is, for example, a monoalkylaminocarbonyl radical having 1 to 3 carbon atoms or a dialkylaminocarbonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.

Cycloalkyl represents a monocyclic cycloalkyl group having 3 to 6 carbon atoms, by way of example and preferably cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

4 to 8-membered heterocyclyl bonded via a carbon atom in the definition of the radicals R ¹³ and R ¹⁷ is a saturated or partially unsaturated monocyclic or bicyclic radical which is bonded via a carbon atom having 4 to 8 ring atoms, preferably 5 or 6 Ring atoms, and up to 3 heteroatoms and / or hetero groups, preferably 1 or 2 heteroatoms and / or hetero groups, from the series S, O, N, SO and SO ₂ , wherein a nitrogen atom can also form an N-oxide, by way of example and preferably for azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, 3-azabicyclo [3.1.0] hex-6-yl, 8-azabicyclo [3.2.1] octane

3-yl and azepanyl, more preferably piperidinyl.

4- to 7-membered heterocycle in the definition of the radicals R ¹³ and R ¹⁴ and R ¹⁷ and R ¹⁸ is a saturated or partially unsaturated monocyclic or bicyclic radical having 4 to 7 ring atoms, preferably 5 or 6 ring atoms, and up to 3 Heteroatoms and / or hetero groups, preferably 1 or 2 heteroatoms and / or hetero groups, from the series S, O, N, SO and SO ₂ , wherein a nitrogen atom can also form an N-oxide, by way of example and preferably azetidinyl, pyrrolidinyl, morpholinyl , Thiomorpholinyl, piperidinyl, piperazinyl, 3-azabicyclo [3.1.0] hex-6-yl, 8-azabicyclo [3.2.1] oct-3-yl and azepanyl, most preferably morpholinyl and piperazinyl. 5-membered heteroaryl in the definition of the radical R ⁶ is an aromatic monocyclic radical having 5 ring atoms and up to 4 heteroatoms and / or hetero groups from the series S, O, N, SO and SO ₂ , where a nitrogen atom is also an N- May exemplify and preferably for thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl, more preferably oxadiazolyl, pyrazolyl, triazolyl and tetrazolyl. 5-membered heterocycle in the definition of the radicals R ⁸ and R ⁹ is a saturated, partially unsaturated or aromatic monocyclic radical having 5 ring atoms and up to 2 heteroatoms and / or hetero groups from the series S, O, N, SO and SO ₂ where a nitrogen atom can also form an N-oxide. This 5-membered heterocycle is together with the phenyl ring to which it is attached exemplarily and preferably 2,3-dihydro-1-benzothiophene-5-yl, 1,3-dihydro-2-benzothiophene-5-yl, 2,3-dihydro-1-benzofuran -5-yl, 1,3-dihydro-2-benzofuran-5-yl, indolin-5-yl, isoindolin-5-yl, 2,3-dihydro-1 / i-indazol-5-yl, 2,3 - Dihydro-l / i-benzimidazol-5-yl, l, 3-dihydro-2, l-benzoxazol-5-yl, 2,3-dihydro-l, 3-benzoxazol-5-yl, l, 3-dihydro -2,1-benzothiazol-5-yl, 2,3-dihydro-1,3-benzothiazol-5-yl, l / i-benzimidazol-5-yl, l / i-indazol-5-yl, l, 2 Benzoxazol-5-yl, indol-5-yl, isoindol-5-yl, benzofuran-5-yl, benzothiophene

5-yl, 2,3-dihydro-1-benzothiophene-6-yl, 1, 3-dihydro-2-benzothiophene-6-yl, 2,3-dihydro-1-benzofuran-6-yl, 1, 3 Dihydro-2-benzofuran-6-yl, indolin-6-yl, isoindolin-6-yl, 2,3-dihydro-1-i-indazol-6-yl, 2,3-dihydro-1 / i-benzimidazole 6-yl, l, 3-dihydro-2, 1-benzoxazol-6-yl, 2,3-dihydro-l, 3-benzoxazol-6-yl, l, 3-dihydro-2, l-benzothiazole-6 yl, 2,3-dihydro-l, 3-benzothiazol-6-yl, IH-benzimidazol-6-yl, l / i-indazol-6-yl, l, 2-benzoxazol-6-yl, indole-6 yl, isoindol-6-yl, benzofuran-6-yl and benzothiophene-6-yl, more preferably 2,3-dihydro-l / i-indazol-6-yl, 1 / i-benzimidazole

6-yl and l / i-indazol-6-yl, most preferably 2,3-dihydro-l / i-indazol-6-yl and 1 / hndazol-6-yl. Heterocycle in the definition of the radicals R ⁴ , R ¹¹ and R ¹⁵ is a saturated or partially unsaturated monocyclic radical which is bonded via a nitrogen atom having 5 or 6 ring atoms, and up to 3 heteroatoms and / or hetero groups, preferably 1 or 2 heteroatoms and / or hetero groups, from the series S, O, N, SO and SO ₂ , where a nitrogen atom can also form an N-oxide, by way of example and preferably pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl and piperazinyl, more preferably morpholinyl and piperazinyl.

Denη the formulas of the group, which may stand for R ¹ , is the end point of the line, next to each of a #, not a carbon atom or a CEE group but is part of the bond to the atom to which R ^{1 is} attached , Denη the formulas of the group, which may stand for R ² , is the end point of the line, next to each a * is not a carbon atom or a CEE group but is part of the bond to the atom to which R ^{2 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 nitrogen atom,

R is 5-membered heteroaryl, wherein heteroaryl may be substituted with one substituent selected from the group consisting of oxo, chloro and C ₁ -C ₃ -alkyl, wherein alkyl may be substituted with 1 to 2 substituents independently selected from the group from hydroxycarbonyl and methoxy, or wherein alkyl may be substituted with 1 to 7 substituents fluorine, or wherein alkyl is substituted with a substituent hydroxycarbonyl and wherein alkyl is additionally substituted with 1 to 6 substituents fluoro,

R ^{7 is} hydrogen or fluorine,

R ⁸ and R ⁹ together with the carbon atoms to which they are attached form a 5-membered heterocycle, it being possible for the heterocycle to be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, chloro, hydroxy, Ci-C ₃ alkyl, pyrazolyl and pyridyl, wherein alkyl may be substituted with 1 to 2 substituents independently selected from the group consisting of hydroxycarbonyl and methoxy, or wherein alkyl may be substituted with 1 to 7 substituents fluorine, or wherein alkyl is substituted with a substituent hydroxycarbonyl and wherein alkyl is additionally substituted with 1 to 6 substituents fluoro,

R is hydrogen or fluorine, a group of the formula

where * is the point of attachment to the phenyl ring, R ^{4 is} hydrogen, hydroxy, amino, C 1 -C 3 -alkylamino, C 1 -C 4 -alkylcarbonylamino,

C3-C6-cycloalkylamino or via a nitrogen atom bonded 5- or 6-membered heterocyclyl, wherein heterocyclyl may be substituted by 1 to 2 substituents independently selected from the group consisting of Ci-C t-alkyl, R ^{5 is} hydrogen, hydroxy , Methyl, ethyl, methoxy, trifluoromethyl or

Benzyloxy stands,

R ¹¹ is hydrogen, amino, Ci-C t-alkoxy, Ci-C3-alkylamino, Ci-C t-alkoxycarbonyl, Ci-C3-alkylsulfonyl, -S (0) ₂ NR ¹³ R ^14, Pyridinyloxy or bound via a nitrogen atom 5- or 6-membered heterocyclyl, wherein alkoxy may be substituted with 1 to 2 substituents independently selected from the group consisting of amino and C ₁ -C 3 alkylamino, and wherein alkylamino may be substituted with a 5- or 6-membered heterocyclyl bonded via a nitrogen atom, and wherein heterocyclyl may be substituted with 1 to 2 substituents independently selected from the group consisting of Ci-C t-alkyl, and wherein

R ^{13 is} hydrogen, C ₁ -C ₃ -alkyl, C ₃ -C 6 -cycloalkyl, benzyl or a 4 to 8-membered heterocyclyl bonded via a carbon atom,

R ^{14 is} hydrogen, methyl or ethyl, or

R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, wherein the heterocycle may be substituted by 1 to 2 substituents independently selected from the group consisting of C ₁ -C 4 -alkyl, represents hydrogen, chlorine, hydroxyl, methyl, ethyl, methoxy or trifluoromethyl, hydrogen, amino, C ₁ -C 4 -alkoxy, C ₁ -C ₃ -alkylamino, C ₁ -C 4 -alkoxycarbonyl, C ₁ -C ₃ -alkylsulfonyl, S (O) ₂ NR ¹⁷ R ¹⁸ , pyridinyloxy or a 5- or 6-membered heterocyclyl bonded via a nitrogen atom, where alkoxy may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of amino and C ₁ -C 3 Alkylamino, and wherein alkylamino may be substituted by a 5- or 6-membered heterocyclyl bonded via a nitrogen atom, and wherein heterocyclyl may be substituted with 1 to 2 substituents independently selected from the group consisting of Ci-C t-alkyl, and wherein

R ^{17 is} hydrogen, C ₁ -C ₃ -alkyl, C ₃ -C 6 -cycloalkyl, benzyl or a 4 to 8-membered heterocyclyl bonded via a carbon atom,

R ^{18 is} hydrogen, methyl or ethyl, or

R ¹⁷ and R ¹⁸ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, wherein the heterocycle may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of C ₁ -C 4 -

alkyl,

R 16 is hydrogen, fluorine, chlorine, methyl, ethyl, methoxy or trifluoromethyl,

R ^{3 is} hydrogen, fluorine, methyl or methoxy, and their salts, their solvates and the solvates of their salts.

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

R is a group of the formula

where # is the point of attachment to the nitrogen atom, represents 5-membered heteroaryl, where heteroaryl may be substituted by a substituent selected from the group consisting of oxo and chlorine,

R ^{7 is} hydrogen or fluorine,

R ⁸ and R ⁹ together with the carbon atoms to which they are attached form a 5-membered heterocycle, where the heterocycle may be substituted by 1 to 2 substituents Oxo, R ^{10 is} hydrogen, a group of the formula

where * is the point of attachment to the phenyl ring,

R ^{4 is} amino, C ₁ -C ₃ -alkylamino or a 5- or 6-membered heterocyclyl bonded via a nitrogen atom, it being possible for heterocyclyl to be substituted by 1 to 2 substituents of methyl,

R ^{5 is} hydrogen, hydroxy, methyl, methoxy or benzyloxy,

R ¹¹ is hydrogen, amino, Ci-C t-alkoxy, _{Ci-C3-alkylamino,} Ci-C t-alkoxycarbonyl, Ci-C ₃ alkylsulfonyl, -S (0) ₂ NR ¹³ R ^14, or a pyridinyloxy Nitrogen atom bonded 5- or 6-membered heterocyclyl, wherein alkoxy may be substituted with a substituent Ci-C3-alkylamino, and wherein alkylamino may be substituted with a 5- or 6-membered heterocyclyl bonded via a nitrogen atom, and wherein heterocyclyl may be substituted with 1 to 2 substituents methyl, and wherein

R ^{13 is} a 4- to 8-membered heterocyclyl bonded via a carbon atom,

R ^{14 is} hydrogen, or

R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, wherein the heterocycle may be substituted by 1 to 2 substituents methyl, R ^{12 is} hydrogen, hydroxy, methyl or trifluoromethyl,

R ^{15 represents} hydrogen, C 1 -C 4 -alkoxy or a 5- or 6-membered heterocyclyl bonded via a nitrogen atom, it being possible for heterocyclyl to be substituted by 1 to 2 substituents methyl, R ^{16 represents} hydrogen, R ^{3 represents} hydrogen or fluorine, and their salts, their solvates, and the solvates of their salts. Compounds of the formula (I) in which R ¹ is a group of the formula are preferred where # is the point of attachment to the nitrogen atom,

R ^{6 is} oxadiazolyl, pyrazolyl, triazolyl or tetrazolyl, where oxadiazolyl, pyrazolyl and triazolyl may be substituted by a substituent selected from the group consisting of oxo and chlorine,

R ^{7 is} hydrogen or fluorine,

is 2,3-dihydro-l / i-indazol-6-yl or l / hndazol-6-yl, wherein 2,3-dihydro-l / i-indazol-6-yl and l / hndazol-6-yl may be substituted with a substituent oxo, for a group of the formula

where * is the point of attachment to the phenyl ring,

R ^{4 is} amino, C 1 -C 3 -alkylamino or heterocyclyl bonded via a nitrogen atom selected from the group consisting of morpholinyl and piperazinyl, where morpholinyl and piperazinyl may be substituted by 1 to 2 substituents of methyl, represents hydrogen, hydroxyl, methyl, methoxy or benzyloxy, hydrogen, amino, C 1 -C 4 -alkoxy, C 1 -C 3 -alkylamino, C 1 -C 4 -alkoxycarbonyl, C 1 -C 3 -alkylsulfonyl, -S (O) 2NR ¹³ R ¹⁴ , pyridinyloxy or heterocyclyl bonded via a nitrogen atom selected from the group consisting of morphohnyl and piperazinyl, where alkoxy may be substituted by a substituent C 1 -C 3 -alkylamino, and wherein alkylamino may be substituted by a heterocyclyl bonded via a nitrogen atom selected from the group consisting of morphohnyl and piperazinyl, and wherein morphohnyl and piperazinyl may be substituted with 1 to 2 substituents methyl, and wherein

R ^{13 is} piperidinyl bound via a carbon atom,

R ^{14 is} hydrogen, or

R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a morpholinyl or piperazinyl in which morpholinyl and piperazinyl may be substituted by 1 to 2 substituents methyl, hydrogen, hydroxy, methyl or trifluoromethyl, hydrogen, Ci-Gt Alkoxy or heterocyclyl bonded via a nitrogen atom selected from the group consisting of morpholinyl and piperazinyl, where morpholinyl and piperazinyl can be substituted by 1 to 2 substituents methyl,

R ^{16 is} hydrogen,

R ^{3 is} hydrogen or fluorine, 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 nitrogen atom,

R ^{6 is} oxadiazolyl, pyrazolyl, triazolyl or tetrazolyl, wherein oxadiazolyl, pyrazolyl and triazolyl may be substituted with one substituent selected from the group consisting of oxo and chlorine, and R ^{7 is} hydrogen or fluorine.

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

R ^{1 is} 2,3-dihydro-l / i-indazol-6-yl or l / hndazol-6-yl, wherein 2,3-dihydro-l / i-indazol-6-yl and l / hndazole-6 -yl may be substituted with a substituent oxo. Preference is also given to compounds of the formula (I) in which

R ^{2 is} a group of the formula where * is the point of attachment to the phenyl ring,

R ^{4 is} amino, C 1 -C 3 -alkylamino or heterocyclyl bonded via a nitrogen atom selected from the group consisting of morphohnyl and

Piperazinyl, wherein morphohnyl and piperazinyl may be substituted with 1 to 2 substituents methyl, and R ^{5 is} hydrogen, hydroxy, methyl, methoxy or benzyloxy.

Preference is also given to compounds of the formula (I) in which R ^{2 is} a group of the formula

is, the point of attachment to the phenyl ring, is hydrogen, amino, Ci-C t-alkoxy, Ci-C3-alkylamino, Ci-C t-alkoxycarbonyl, Ci-C3-alkylsulfonyl, -S (0) ₂ NR ¹³ R ¹⁴ , Pyridinyloxy or heterocyclyl bonded via a nitrogen atom selected from the group consisting of morphohnyl and piperazinyl, where alkoxy may be substituted by a substituent C 1 -C 3 -alkylamino, and wherein alkylamino may be substituted with a heterocyclyl bonded via a nitrogen atom selected from the group consisting of morphohnyl and piperazinyl, and wherein morphohnyl and piperazinyl may be substituted with 1 to 2 substituents methyl, and wherein

R ^{13 is} piperidinyl bound via a carbon atom,

R ^{14 is} hydrogen, or

R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a morpholinyl or piperazinyl, where morpholinyl and piperazinyl may be substituted by 1 to 2 substituents methyl, and

R ^{12 is} hydrogen, hydroxy, methyl or trifluoromethyl. Preference is also given to compounds of the formula (I) in which R ^{2 is} a group of the formula

stands, where * is the point of attachment to the phenyl ring,

R is hydrogen, Ci-Gt-alkoxy or heterocyclyl bonded via a nitrogen atom selected from the group consisting of morpholinyl and piperazinyl, where morpholinyl and piperazinyl may be substituted by 1 to 2 substituents methyl, and

R ^{16 is} hydrogen.

Preference is also given to compounds of the formula (I) in which R ^{3 is} hydrogen or fluorine.

The residue definitions given in detail in the respective combinations or preferred combinations of residues are also replaced by residue definitions of other combinations, regardless of the particular combinations of the residues indicated.

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

The invention further provides a process for the preparation of 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 ¹ , R ² and R ^{3 have} the abovementioned meaning, are reacted with an acid. The reaction is generally carried out in inert solvents, preferably in a temperature range from room temperature to 60 ° C at atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane, or ethers such as tetrahydrofuran or dioxane, dioxane is preferred.

Acids are for example trifluoroacetic acid or hydrogen chloride in dioxane, preferred is hydrogen chloride in dioxane.

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

[A] Compounds of the formula

in which

R ¹ and R ^{3 have} the abovementioned meaning, and

Q ^{1 is} -B (OH) 2, a boronic acid ester, preferably boronic acid pinacol ester, or

 stands, with compounds of the formula

X ¹ R ² (IV), in which

R ^{2 has} the meaning given above, and

X is bromine or iodine, are reacted under Suzuki coupling conditions, or

[B] Compounds of the formula

in which R ¹ and R ^{3 have} the abovementioned meaning, and X ^{2 is} bromine or iodine, with compounds of the formula

Q ² - R ² (VI), in which R ^{2 has} the meaning given above, and

Q ^{2 is} -B (OH) 2, a boronic acid ester, preferably boronic acid pinacol ester, or -BF ₃ , are reacted under Suzuki coupling conditions, or [C] compounds of the formula

in which

R ² and R ^{3 have} the abovementioned meaning, with compounds of the formula H ₂ N-R ₍ vni), in which

R ^{1 has} the meaning given above, be reacted in the presence of dehydrating reagents.

The reaction according to process [A] is generally carried out in inert solvents, in the presence of a catalyst, optionally in the presence of an additional reagent, optionally in a microwave, preferably in a temperature range from room temperature to 150 ° C at atmospheric pressure to 3 bar.

Catalysts are for example customary for Suzuki reaction conditions palladium catalysts, preferred are catalysts such as dichlorobis (triphenylphosphine) palladium, tetrakistriphenylphosphinepalladium (O), palladium (II) acetate / triscyclohexylphosphine, tris (dibenzylideneacetone) dipalladium, bis (diphenylphosphanferrocenyl) palladium - (II) chloride, l, 3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene (1,4-naphthoquinone) palladium dimer, allyl (chloro) - (1,3-dimesityl-l, 3-dihydro -2H-imidazol-2-ylidene) palladium, palladium (II) acetate / dicyclohexyl- (2 ', 4', 6'-triisopropyl-biphenyl-2-yl) -phosphine, [1,1-bis (diphenylphosphino) ferrocene] - palladium (II) chloride monodichloromethane adduct or XPhos precatalyst [(2'-aminobiphenyl-2-yl) (chloro) palladium dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (1: 1)], preferred is tetrakistriphenylphosphine palladium (O), [1,1-bis (diphenylphosphino) ferrocene] - palladium (II) chloride monodichloromethane adduct or XPhos precatalyst [(2'-aminobiphenyl-2-yl) (chloro) palladium-dicyclohexyl (2 ', 4', 6'-triisopropylbiphenyl-2-yl) phosphine (1: 1 )].

Additional reagents are for example potassium acetate, cesium, potassium or sodium carbonate, potassium tert-butoxide, cesium fluoride or potassium phosphate, which may be present in aqueous solution, preference is given to additional reagents such as potassium acetate or a mixture of potassium acetate and sodium carbonate.

Inert solvents are, for example, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons, such as benzene, xylene or toluene, or carboxamides, such as dimethylformamide or dimethylacetamide, alkylsulfoxides, such as dimethylsulfoxide, or N-methylpyrrolidone or acetonitrile, or mixtures of the solvents with alcohols, such as methanol or ethanol and / or water, preferred is toluene, dimethylformamide or dimethyl sulfoxide.

The compounds of the formula (IV) 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 reaction according to method [B] is carried out as described for method [A].

The compounds of the formula (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 reaction according to process [C] is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from 0 ° C to reflux of the solvent at atmospheric pressure.

Carbodiimides such as Ν, Ν'-diethyl, A ^ A ^ '- dipropyl, A ^ A ^' - diisopropyl-, A ^ W-Dicyclohexylcarbodiimid, N - ^ - Dimefhylamino- isopropy ^ - are suitable as dehydrating reagents such as 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-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanophosphonic anhydride, or isobutyl chloroformate, or bis- (2-oxo-3-oxazolidinyl) -phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or 0- (benzotriazol-1-yl) - (-) tetra-methyluronium hexafluorophosphate (HBTU), 2- (2-oxo-l- (2H) -pyridyl) -1,3,3-tetramethyluronium tetrafluoroborate (TPTU), (benzotriazol-1-yloxy) bi sdimethylamino- methylium fluoroborate (TBTU) or (^ - (T-azabenzotriazole-1-yl) -AB ^ a-tetramethyl-uronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-1-yloxy-tris (dimethylamino ) phosphonium hexafluorophosphate (BOP), or ethylhydroxy (hydroxyimino) acetate (Oxyma), or (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), or N - [( Dimethylamino) (3 / i- [l, 23] triazolo [4,5-b] pyridin-3-yloxy) methylidene] -N-methylmethanaminium hexa

or 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide (T3P), or mixtures thereof, preference is given to N - [(dimethylamino) (3 / i- [l, 2,3] triazolo [4,5-b] pyridin-3-yloxy) methylidene] - N -methylmethane-aminium hexafluorophosphate or 2,4,6-tripropyl-1, 3,5,2, 4,6-trioxatri- phosphinane-2,4,6-trioxide (T3P).

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. Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, or other solvents such as nitromethane, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile or pyridine, or mixtures of the solvents, preferably tetrahydrofuran or dimethylformamide or a mixture of dimethylformamide and pyridine. The compounds of the formula (VIII) 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 compounds of formula (III) are known or may be prepared by reacting compounds of formula (V) with 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi -l, 3,2-dioxaborolane.

The reaction is generally carried out in inert solvents, in the presence of a catalyst, optionally in the presence of an additional reagent, optionally in a microwave, preferably in a temperature range from room temperature to 150 ° C at atmospheric pressure to 3 bar. Hydroylation in an acidic medium gives the corresponding boronic acids. Working up with potassium hydrogen difluoride solution (KHF 2 solution) gives the corresponding trifluoroborates. Catalysts are, for example, customary for the borylation of aryl halides palladium catalysts, preferred are catalysts such as dichlorobis (triphenylphosphine) palladium,

Tetrakistriphenylphosphinepalladium (O), palladium (II) acetate / triscyclohexylphosphine,

Tris (dibenzylideneacetone) dipalladium, bis (diphenylphosphineferrocenyl) palladium (II) chloride, 1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene (1,4-naphthoquinone) palladium dimer, allyl (chloro) - (1,3-dimesityl-l, 3-dihydro-2H-imidazol-2-ylidene) palladium, palladium (II) acetate / dicyclohexyl

(2 ', 4', 6'-triisopropyl-biphenyl-2-yl) -phosphine, [1,1-bis (diphenylphosphino) ferrocene] -palladium (II) chloride monodichloromethane adduct or XPhos precatalyst [(2 '-Aminobiphenyl-2-yl) (chloro) palladium-dicyclohexyl (2', 4 ', 6'-triisopropylbiphenyl-2-yl) phosphine (1: 1)], preferred are tetrakistriphenylphosphine palladium (O) and [l, l-bis (diphenylphosphino) ferrocene] palladium (II) chloride.

Additional reagents are for example potassium acetate, cesium, potassium or sodium carbonate, potassium or sodium tert-butoxide, cesium fluoride, potassium phosphate or potassium phenoxide, preferably potassium acetate. Inert solvents are, for example, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons, such as benzene, xylene or toluene, or carboxamides, such as dimethylformamide or dimethylacetamide, alkylsulfoxides, such as dimethylsulfoxide, or N-methylpyrrolidone or acetonitrile; preference is given to dioxane, dimethylformamide or dimethylsulfoxide. Literature: K.L. Billingslay, T.E. Barde, S.L Buchwald, Angew. Chem. 2007, 119, 5455 or T.Graening, News from Chemistry, Jan 2009, 57, 34.

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

in which R ^{3 has} the abovementioned meaning, and X ^{2 is} bromine or iodine, are reacted with compounds of formula (VIII) in the presence of dehydrating reagents. The reaction is carried out as described for method [C].

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

in which

R ² and R ^{3 have} the abovementioned meaning, and

X ^{3 is} methyl or ethyl, are reacted with 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.

Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane, alcohols such as methanol or ethanol, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, or other solvents such as dimethylformamide , Dimethylacetamide, Acetonitrile or pyridine, or mixtures of solvents, or mixtures of solvent with water, preferred is a mixture of tetrahydrofuran and water.

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, or alcoholates such as potassium or sodium tert-butoxide, preferably sodium hydroxide or lithium hydroxide.

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

in which R ^{3 has} the abovementioned meaning, X ^{3 is} methyl or ethyl, and X ^{4 is} bromine or iodine, are reacted with compounds of formula (VI) under Suzuki coupling conditions.

The reaction is carried out as described for method [A]. The compounds of the formula (XI) 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 proteases FXIa and kallikrein and optionally plasmin. The compounds of the present invention inhibit the enzymatic cleavage of substrates which play an essential role in the activation of the blood coagulation cascade and the aggregation of platelets. If the compounds according to the invention inhibit plasmin activity, inhibition of fibrinolysis occurs. 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. For the purposes of the present invention, "thromboembolic disorders" include in particular diseases 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 restenoses after coronary interventions such as angioplasty, stent implantation or aortocoronary bypass, peripheral arterial occlusive diseases, pulmonary embolism, venous thrombosis, especially in deep leg veins and renal veins, transient ischemic attacks and thrombotic and thromboembolic stroke.

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. In addition, the compounds according to the invention are suitable for the treatment and prevention of disseminated intravascular coagulation (DIC), which occur, inter alia, in the context of sepsis, but also as a result of operations, tumor diseases, burns or other injuries and can lead to severe organ damage through microthromboses. 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 also have an influence on wound healing, for the prophylaxis and / or treatment of atherosclerotic vascular diseases and inflammatory diseases such as rheumatic disorders of the musculoskeletal system, coronary heart diseases, cardiac insufficiency, hypertension, inflammatory diseases such as asthma, inflammatory lung diseases, Glomerulonephritis and inflammatory bowel diseases, such as Crohn's disease or ulcerative colitis, or acute renal failure into consideration, moreover, also for the prophylaxis and / or treatment of dementia diseases such. B. Alzheimer's disease. In addition, the compounds of the present invention can inhibit tumor growth and metastasis, microangiopathies, age-related macular degeneration, diabetic retinopathy, diabetic nephropathy and other microvascular diseases, and for the prevention and treatment of thromboembolic complications such as venous thromboembolism. in tumor patients, especially those undergoing major surgery or chemo- 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" covers certain forms of pulmonary hypertension as defined, for example, by the World Health Organization (WHO), such as pulmonary arterial hypertension, pulmonary hypertension in diseases of the left heart, pulmonary hypertension in pulmonary 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 (AP AH) associated with collagenosis, congenital systemic pulmonary shunt veins, portal hypertension, HIV infections, use of certain drugs and medications, other diseases (thyroid disease, glycogen storage disorders, Gaucher disease, here medical telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy), with diseases with 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 infectious disease and / or systemic inflammatory syndrome (SIRS), septic organ dysfunction, septic organ failure and multi-organ failure, 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. This can be prevented by the compounds of the invention. Secondarily, coagulation factors (e.g., Factor X, prothrombin, and fibrinogen) and platelets are consumed, which lowers the blood's ability to coagulate and cause severe bleeding.

In addition, the compounds according to the invention are also suitable for the prophylaxis and / or treatment of hyperfibrinolysis. Prophylaxis and / or treatment can reduce or eliminate severe perioperative blood loss. Strong bleeding occurs in severe surgery, such as. Coronary artery bypass graft surgery, transplantation or hysterectomy, as well as trauma, haemorrhagic shock, or postpartum hemorrhage. In the above-mentioned indications, perioperative use of extracorporeal circulation systems or filter systems, such as, for example, heart lung machine, hemofiltration, hemodialysis, extracorporeal membrane oxygenation or ventricular support system, such as artificial heart, may occur. This also requires anticoagulation, to which the compounds of the invention can also be used. The compounds according to the invention are also suitable for anticoagulation during the renal replacement procedure, for example in continuous veno-venous hemofiltration or intermittent hemodialysis.

In addition, the compounds according to the invention can also be used for the prevention of coagulation ex vivo, e.g. for the preservation of blood and plasma products, for the cleaning / pretreatment of catheters and other medical devices and equipment, for the coating of artificial surfaces of in vivo or ex vivo used medical devices and devices or for biological samples which might contain Factor XIa.

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.

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 XIa, 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 lovastatin (Mevacor), simvastatin (Zocor), pravastatin (pravachol), fluvastatin (Lescol) and atorvastatin (Lipitor);

Coronary / vasodilators, particularly ACE (angiotensin converting enzyme) inhibitors such as captopril, lisinopril, enalapril, ramipril, cilazapril, benazepril, fosinopril, quinapril and perindopril, or AII (angiotensin II) 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 for example, isosorbide-5-mononitrate, isosorbide dinitrate, and glyceryl trinitrate, or substances which 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 the plasminogen activator inhibitor (PAI inhibitors) or inhibitors of the thrombin-activated fibrinolysis inhibitor (TAFI inhibitors) such as, for example, tissue plasminogen activator ( t-PA), 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 (Ml 18) and EP-42675 / ORG42675; direct thrombin inhibitors (DTI) such as Pradaxa (Dabigatran), Atecegatran (AZD-0837), DP-4088 and 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, Tanogitran (BIBT-986, prodrug: BIBT-1011), Idraparinux and Fondaparinux;

Antiplatelet agents (platelet aggregation inhibitors, platelet aggregation inhibitors) such as, for example, aspirin, ticlopidine (ticlid), clopidogrel (plavix), prasugrel, ticagrelor, cangrelor, elinogrel,

Vorapaxar;

Fibrinogen receptor antagonists (glycoprotein Iib / IIIa antagonists) such as abciximab, eptifibatide, tirofiban, lamifiban, lefradafiban and fradafiban;

• as well as antiarrhythmics; · Various antibiotics or antifungal drugs, either as a calculated therapy (before the presence of the microbial condition) or as a specific therapy;

Vasopressors such as norepinephrine, dopamine and vasopressin;

Inotropic therapy such as dobutamine;

Corticosteroids such as hydrocortisone and fludrocortisone; Recombinant human activated protein C such as Xigris;

• blood products such as red blood cell concentrates, platelet concentrates,

 Erythropietin and Fresh Frozen Plasma.

"Combinations" within the meaning of the invention not only pharmaceutical forms containing all components (so-called. Fixed combinations) and combination packs containing the components separated from each other, understood, but also simultaneously or temporally staggered applied components, if they are for prophylaxis and It is also possible to combine two or more active substances, ie two or more combinations.

The compounds according to the invention can act systemically and / or locally. For this purpose, they can be applied in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically 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.

Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

Preference is given to parenteral administration.

For other routes of administration are, 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 excipients include excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitol oleate), 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: bs / br. s. broad singlet (by NMR)

bd wide doublet (by NMR)

cat. catalytic

 CI chemical ionization (in MS)

dd doublet of doublet (by NMR)

 DMF dimethylformamide

 DMSO dimethyl sulfoxide

dt doublet from triplet (by NMR)

d. Th. Of theory (at yield)

 EI electron impact ionization (in MS)

eq. Equivalent (s)

ESI electrospray ionization (in MS)

h hour (s)

HATU 0- (7-azabenzotriazol-l-yl) -A ^r, A ^r, A ⁱ ', A ^i' -tetramethyl-uronium hexafluorophosphate

 HPLC high pressure, high performance liquid chromatography

LC-MS liquid chromatography-coupled mass spectrometry m multiple (in NMR)

 M molar

min minute (s)

 MS mass spectrometry

 N normal

 NMR nuclear magnetic resonance spectrometry

q quartet (by NMR)

quant. quantitatively

quint quintet (by NMR)

 RT room temperature

 Retention time (on HPLC)

s singlet (by NMR)

 TFA trifluoroacetic acid

THF tetrahydrofuran

UV ultraviolet spectrometry HPLC and LC / MS methods:

Method 1 (LC-MS): Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8μ 50mm x 1mm; 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: 210 - 400 nm.

Method 2 (LC-MS): Instrument: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 μ 50 mm 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 3 (LC-MS): Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μ 30 mm 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 Furnace: 50 ° C; Flow: 0.60 ml / min; UV detection: 208-400 nm. Method 4 (LC-MS): Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 μ 50 mm x 2.1 mm; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow: 0.8 ml / min; Temperature: 60 ° C; Injection: 2 μΐ; DAD scan: 210-400 nm; ELSD.

Method 5 (LC-MS): Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH Cl 8 1.7 μ 50 mm x 2.1 mm; Eluent A: water + 0.2% ammonia, eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow: 0.8 ml / min; Temperature: 60 ° C; Injection: 2 μΐ; DAD scan: 210-400 nm; ELSD.

Method 6 (HPLC): System: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; Column: Chromatorex C-18 125 mm × 30 mm, eluent A: 0.1% formic acid in water, eluent B: acetonitrile, gradient: A 95% / B 5% -> A 55% / B 45%; Flow: 150 ml / min; UV detection: 254 nm.

Method 7 (HPLC): System: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; Column: Chromatorex C-18 125 mm × 30 mm, eluent A: 0.1% formic acid in water, eluent B: acetonitrile; Gradient: A 90% / B 10% -> A 50% / B 50%; Flow: 150 ml / min; UV detection: 254 nm.

Method 8 (HPLC): System: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; Column: Chromatorex C-18 125 mm × 30 mm, eluent A: 0.1% formic acid in water, eluent B: acetonitrile; Gradient: A 85% / B 15% -> A 45% / B 55%; Flow: 150 ml / min; UV detection: 254 nm.

Method 9 (HPLC): System: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; Column: Chromatorex C-18 125 mm × 30 mm, eluent A: 0.1% formic acid in water, eluent B: acetonitrile; Gradient: A 80% / B 20% -> A 40% / B 60%; Flow: 150 ml / min; UV detection: 254 nm.

Method 10 (HPLC): Instrument: Waters autopurification system SQD; Column: Waters XBrigde C18 5μ 100 mm x 30 mm; Eluent A: water + 0.1% formic acid (99%), eluent B: acetonitrile; Gradient: 0-8.0 min 1-100% B, 8.0-10.0 min 100% B; Flow 50.0 ml / min; Temperature: RT; Injection: 2500 μΐ; DAD scan: 210-400 nm.

Method 11 (HPLC): Instrument: Waters autopurification system SQD; Column: Waters XBrigde C18 5μ 100 mm x 30 mm; Eluent A: water + 0.2% ammonia (32%), eluent B: acetonitrile; Gradient: 0-8.0 min 1-100% B, 8.0-10.0 min 100% B; Flow 50.0 ml / min; Temperature: RT; Injection: 2500 μΐ; DAD scan: 210-400 nm.

Method 12 (LC-MS): Instrument MS: Waters (Micromass) QM; Instrument HPLC: Agilent 1100 series; Column: Agient ZORBAX Extend-C18 3.0mm 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 13 (LC-MS): Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μ 50 mm 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.

Method 14 (LC-MS): Instrument MS: Waters (Micromass) Quattro Micro; Instrument HPLC: Agilent 1100 series; Column: YMC-Triart C18 3 μ 50 mm 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 10 0% A-> 2.75 min 5% A-> 4.5 min 5% A; Oven: 40 ° C; Flow: 1.25 ml / min; UV detection: 210 nm.

Method 15 (HPLC): System: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; Column: Chromatorex C-18 125 mm x 30 mm; Eluent A: 0.1% formic acid in water, eluent B: acetonitrile, gradient: A 60% / B 40% -> A 20% / B 80%; Flow: 150 ml / min; UV detection: 254 nm. Method 16 (HPLC): Isolera: Cartridge SNAP 100 g, n-hexane / ethyl acetate 90% / 10% to 100% ethyl acetate in 30 min, then 100% ethyl acetate to 85 min; Flow: 40 ml / min; UV detection: 254 nm.

Microwave: The microwave reactor used was a Biotage ™ initiator.

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. Weaker salts can be converted to the corresponding chlorides by addition of some hydrochloride. 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 that 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.

If the starting compounds and examples contain an L-phenylalanine derivative as the central building block, the corresponding stereocenter is described as (S) -configuration. Unless otherwise stated, it was not examined whether in individual cases in the coupling of the L-phenylalanine intermediate with the amine H ₂ NR ¹ partial epimerization of the stereocenter took place. Thus, a mixture of the compounds of (S) -enantiomer and (R) -enantiomer according to the invention may be present. The main component is the respectively depicted (S) -enantiomer. starting compounds

Example 1A

Methyl-N - [(ω-α-4- {[(ω-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4-iodo-L-phenylalaninate

Methyl 4-iodo-L-phenylalaninate hydrochloride (5.7g, 16.7mmol), 5α- {[(4-i-butoxycarbonyl) -amino] -methyl} -cyclohexanecarboxylic acid (4.4g, 16.7mmol) and N, N- Diisopropylethylamine (11.7 mL, 67 mmol) was suspended in 90 mL of ethyl acetate. The solution was cooled to 0 ° C. Subsequently, 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide (50% in ethyl acetate, 26.6 g, 42 mmol) was added dropwise, 30 min at 0 ° C and stirred overnight at RT. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic phases were washed once with saturated aqueous ammonium chloride solution and once with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered off and concentrated to dryness. The residue was recrystallized from acetonitrile. This gave 5.6 g (73% of theory) of the title compound.

^: H-NMR (300 MHz, DMSO-de): δ = ppm 0.68-0.86 (m, 2H), 1.02-1.27 (m, 3H), 1.33 (s, 9H), 1.45- 1.55 (m, 1 H), 1.62 (m, 3 H), 1.92 - 2.04 (m, 1 H), 2.70 (t, 2 H), 2.79 (dd, 1 H), 2.94 (dd, 1 H), 3.56 (s, 3 H), 4.27-4.44 (m, 1H), 6.69-6.79 (m, 1H), 6.98 (d, 2H), 7.59 (d, 2H), 8.10 (d, 1H). LC-MS (Method 4): R _t = 1.32 min; MS (ESIpos): m / z = 545.2 [M + H] ⁺ .

Example 2A

^~ N - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4-iodo-L-phenylalanine

Methyl 4-iodo-N- [(trans - {{(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -L-phenylalaninate (3.8 g, 7.0 mmol) was dissolved in 55 mL of tetrahydrofuran, to 0 ° C cooled and treated with 5.3 ml of 2N aqueous sodium hydroxide solution. It was allowed to come to RT and stirred overnight at RT. Subsequently, the tetrahydrofuran was removed and the aqueous phase washed twice with ieri-butylmethyl ether. The aqueous phase was then adjusted to pH 3 with 1N hydrochloric acid and the precipitated solid was filtered off with suction. The aqueous phase was extracted three times with dichloromethane and the organic phase was concentrated. The residue from the organic phase was combined with the solid and dried under high vacuum. 3.8 g (100% of theory) of the title compound were obtained.

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.72-0.85 (m, 2H), 1.08-1.27 (m, 3H), 1.33 (s, 9H), 1.63 (m, 4 H), 1.87 - 1.96 (m, 1H), 2.70 (t, 2H), 2.83 (dd, 1H), 2.95 (dd, 1H), 3.83 (m, 1H), 6.69 - 6.75 (m , 1H), 6.84 (d, 2H), 6.93 (d, 1H), 7.47 (d, 2H).

LC-MS (Method 4): R _t = 1.20 min; MS (ESIpos): m / z = 531.1 [M + H] ⁺ . Example 3A

^~ N-alpha - [(trans - - {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -N- [4- (3-chloro-4-yl, 2,4-triazole-5 yl) phenyl] -4-iodo-L-phenylalanine amide

Cl N - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4-iodo-L-phenylalanine (2.4 g, 4.5 mmol), 4- (1/3-chlorotriazole) 5-yl) aniline (70%, 1.4 g, 5.0 mmol) and triethylamine (1.6 ml, 11 mmol) were suspended in 44 ml of ethyl acetate and treated with 2,4,6-tripropyl-l, 3,5,2,4 6-trioxatriphosphinane-2,4,6-trioxide (50% in ethyl acetate, 5.3 ml, 9.0 mmol). It was then refluxed for 2 h and stirred for a further 24 h at RT. The reaction mixture was mixed with water and the precipitated solid was filtered off, washed with a little ethyl acetate and water and dried under high vacuum. 2.5 g (78% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.78 (m, 2H), 1.05-1.27 (m, 4H), 1.33 (s, 9H), 1.48 - 1.55 (m, 1H ), 1.64 (m, 3H), 2.00 - 2.10 (m, 1H), 2.71 (t, 2H), 2.79 (dd, 1H), 2.95 (dd, 1H), 4.55 - 4.65 (m, 1 H), 6.68 - 6.77 (m, 1H), 7.07 (d, 2H), 7.60 (d, 2H), 7.70 (d, 2H), 7.86 (d, 2H), 8.06 (d, 1H), 10.33 (s, 1H).

LC-MS (Method 4): R _t = 1.31 min; MS (ESIpos): m / z = 707.3 [M + H] ⁺ . Example 4A 4-Bromo-Na / j / ia - [(1α-ε-4- {[(feri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -N- [4- (3-chloro-4 / il, 2,4-triazol-5-yl) phenyl] -L-phenylalanine amide

4-Bromo-N - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -L-phenylalanine (6.3 g, 13 mmol), 4- (l / i-3) Chlorotriazol-5-yl) aniline (2.8 g, 14.3 mmol) and N, N-diisopropylamine (6.8 mL, 39 mmol) were suspended in 130 mL of ethyl acetate and treated with 2,4,6-tripropyl-1,3,5, 2 , 4, 6-trioxatriphosphinane-2,4,6-trioxide (50% in ethyl acetate, 21 g, 32.6 mmol). It was then refluxed for 3 h. The reaction mixture was mixed with water and the phases were separated. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography via Isolera (method 16) and HPLC (method 11, 40-70% B). 1.8 g (23% of theory) of the title compound were obtained.

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.71-0.86 (m, 2H), 1.03-1.26 (m, 3H), 1.33 (s, 9H), 1.48-1.55 (m , 1H), 1.58 - 1.69 (m, 3H), 2.02 - 2.10 (m, 1H), 2.68 - 2.74 (m, 2H), 2.81 (dd, 1H), 2.98 (dd, 1H) , 4.50 - 4.68 (m, 1H), 6.67 - 6.76 (m, 1H), 7.22 (d, 2H), 7.44 (d, 2H), 7.71 (d, 2H), 7.86 (d, 2 H), 8.07 (d, 1H), 10.33 (s, 1H).

LC-MS (Method 4): R _t = 1.28 min; MS (ES Ineg): m / z = 659.4 [MH] \ Example 5A

NaI / ia - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4-iodo-N- (3, 2,3-dihydro-1 / i-indazole -6-yl) -L-phenylalaninamide

^~ N - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4-iodo-L-phenylalanine (1.91 g, 3.6 mmol), 6-amino-1,2-dihydroxy 3 # -indazol-3-one (0.55 g, 3.60 mmol) and N, N-diisopropylamine (1.9 ml, 10.8 mmol) were suspended in 23 ml of ethyl acetate and treated with 2,4,6-tripropyl-l, 3.5, 2,4,6-trioxatriphosphinane-2,4,6-trioxide (50% in ethyl acetate, 5.73 g, 9.0 mmol). It was then refluxed for 3 h, further 6-amino-l, 2-dihydro-3 / i-indazol-3-one (0.14 g, 0.90 mmol), N, N-diisopropylamine (0.47 ml, 2.70 mmol) and 2.4 , 6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide (50% in ethyl acetate, 1.43 g, 2.25 mmol) was added and refluxed for a further 3 h. Water was added to the reaction mixture, the phases were separated and the aqueous phase was extracted three times with ethyl acetate. The solid precipitated in both phases was filtered off with suction and dried under high vacuum. 1.35 g (57% of theory) of the title compound were obtained.

^: H-NMR (300 MHz, DMSO-de): δ = ppm 0.66-0.91 (m, 2H), 1.01-1.25 (m, 4H), 1.33 (s, 9H), 1.44-1.54 (m, 1 H), 1.62 (m, 3 H), 1.98 - 2.10 (m, 1 H), 2.66 - 2.80 (m, 3 H), 2.92 (dd, 1 H), 4.49 - 4.61 (m, 1H), 6.70-6.76 (m, 1H), 6.79 (d, 1H), 6.94 (dd, 1H), 7.05 (d, 2H), 7.38 (d, 1H), 7.59 (d, 2H), 8.00 (d, 1H), 9.91 (s, 1H), 10.46 (s, 1H), 10.51 (s, 1H).

LC-MS (Method 4): R _t = 1.15 min; MS (ESIpos): m / z = 662.1 [M + H] ⁺ .

Example 6A Methyl 4-bromo-N - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -L-phenylalaninate

A solution of methyl 4-bromo-L-phenylalaninate (250 g, 874 mmol) and trans-4- {[(tert-butoxycarbonyl) amino] methyl-2-cyclohexanecarboxylic acid (225 g, 874 mmol) in ethyl acetate (5012 mL) was added N, N-diisopropylethylamine (381 mL, 2186 mmol). The suspension was added dropwise with a 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide solution (50% in dimethylformamide, 766 ml, 1312 mmol) and then stirred for 3 h at RT. The reaction mixture was stirred into water and extracted three times with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution. It was dried over sodium sulfate and the solvent removed. 420 g (97% of theory) of the title compound were obtained.

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.68-0.92 (m, 2H), 1.04-1.32 (m, 4H), 1.37 (s, 9H), 1.48-1.73 (m , 4H), 2.03 (m, 1H), 2.74 (m, 2H), 2.78 - 2.90 (m, 1H), 2.94 - 3.05 (m, 1H), 4.36 - 4.50 (m, 1H) , 6.72 - 6.85 (m, 1H), 7.17 (d, 2H), 7.46 (d, 2H), 8.15 (d, 1H).

LC-MS (Method 1): R _t = 1.14 min; MS (ESIpos): m / z = 497 [M + H] ⁺ .

Example 7A

Methyl 4-bromo-N - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -DL-phenylalaninate

5.00 g (20.48 mmol) of 4-bromo-DL-phenylalanine were dissolved in 50 ml of methanol and slowly added at 0 ° C with 4.5 ml (61.45 mmol) of thionyl chloride. The reaction mixture was stirred at RT for 16 h and then the solvent was removed on a rotary evaporator. The crude product was washed with diethyl ether and the solid dried under high vacuum. 5.02 g (95% of theory) of DL-methyl-4-bromophenylalaninate were obtained.

LC-MS (Method 1): R _t = 0.51 min; MS (ESIpos): m / z = 258 [M + H] ⁺ .

2.50 g (9.69 mmol) of DL-methyl-4-bromophenylalaninate, 2.49 g (9.69 mmol) of trans4-{[(tert-butoxycarbonyl) amino] methyl} cyclohexanecarboxylic acid and 4.22 ml (24.21 mmol) of N, N-diisopropylethylamine were dissolved in 48 ml of ethyl acetate suspended and cooled to 0 ° C. The suspension was slowly mixed with 8.5 ml (14.53 mmol) 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide solution (50% in dimethylformamide) and Stirred under reflux for 3 h and at RT for 16 h. The reaction mixture was added to water, the phases were separated and the aqueous phase extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. This gave 3.29 g (68% of theory) of the title compound.

LC-MS (Method 1): R _t = 1.11 min; MS (ESIpos): m / z = 497 [M + H] ⁺ . Example 8A

4-Bromo-N - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -L-phenylalanine

A solution of methyl 4-bromo-N - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -L-phenylalaninate in tetrahydrofuran (3000 ml) was treated with a solution of Lithium hydroxide (72 g, 3015 mmol) in water (600 ml) was added. The suspension was stirred at RT for 16 h. The reaction mixture was acidified with 1N hydrochloric acid solution and treated with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent removed. This gave 284 g (97% of theory) of the title compound.

'H-NMR (400 MHz, DMSO-ife): δ = ppm 0.71-0.90 (m, 2H), 1.22 (d, 4H), 1.37 (s, 9H), 1.45- 1.73 (m, 5H ), 2.03 (m, 1H), 2.67 - 2.88 (m, 3H), 2.95 - 3.09 (m, 1H), 4.38 (m, 1H), 6.77 (s, 1H), 7.17 (d, 2H), 7.46 (d, 2H), 7.99 (d, 1H), 12.65 (br. S, 1H).

LC-MS (Method 1): R _t = 1.03 min; MS (ES Ineg): m / z = 481

Example 9A

4-Bromo-N - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -DL-phenylalanine

A solution of 1.60 g (3.22 mmol) of methyl 4-bromo-N- [(trans - {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -DL-phenylalaninate in 60 ml of tetrahydrofuran was added 1.35 g (32.17 mmol) of lithium hydroxide dissolved in 20 ml of water. The reaction mixture was stirred for 16 h at RT, then acidified with 1N hydrochloric acid solution and washed with Ethyl acetate added. The phases were separated and the organic phase washed with water and saturated aqueous sodium chloride solution and dried over sodium sulfate. The solvent was removed on a rotary evaporator and the residue was stirred with a little acetonitrile, filtered off and dried under high vacuum. 1.34 g (86% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.03 min; MS (ESIneg): m / z = 481 [MH] \

Example 10A

4-Bromo-Na / j / ia - [(α-α-4- {[(ferric-butoxycarbonyl) -amino] -methyl-cyclohexyl-carbonyl] -N- [4- (2H-tetrazol-5-yl) -phenyl] -L-phenylalanine amide

A solution of 4-bromo-N - [(1α-ε-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -L-phenylalanine (11 g, 22 mmol) and 4- (2 / i -Tetrazol-5-yl) aniline (4 g, 24 mmol) in dimethylformamide (161 mL) was added N, N -diisopropylethylamine (9.6 mL, 55 mmol). The suspension was added dropwise at 0 ° C with a 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphinan- 2,4,6-trioxide solution (50% in dimethylformamide, 16.9 g, 27 mmol) and then stirred at RT for 16 h. The reaction mixture was stirred into ethyl acetate (13,000 ml) and extracted three times with water (1570 ml each). The organic phase was dried with sodium sulfate and the solvent removed. The crude product was stirred with acetonitrile and filtered with suction. 11.4 g (78% of theory) of the title compound were obtained. Ή NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.67-0.90 (m, 2H), 1.24 (m, 4H), 1.37 (s, 9H), 1.51-1.74 (m, 4H ), 2.02 - 2.17 (m, 1H), 2.71 - 2.79 (m, 2H), 2.79 - 2.89 (m, 1H), 2.99 - 3.06 (m, 1H), 3.06 - 3.16 (m, 1H ), 3.51 - 3.67 (m, 1H), 4.55 - 4.74 (m, 1H), 6.01 - 6.02 (m, 1H), 6.69 - 6.84 (m, 1H), 7.21 - 7.32 (m, 2H ), 7.43-7.55 (m, 2H), 7.64-7.76 (m, 2H), 7.88-7.99 (m, 2H), 8.03- 8.14 (m, 1H), 10.25 (s, 1H). LC-MS (Method 1): R _t = 1.07 min; MS (ES Ineg): m / z = 624 [MH] \ Example IIA

4-Bromo-Na / j / ia - [(α-α-4- {[(ferric-butoxycarbonyl) -amino] -methyl-cyclohexyl-carbonyl] -N- [4- (2H-tetrazol-5-yl) -phenyl] -DL-phenylalanine amide

100 mg (0.21 mmol) of 4-bromo-N - [(α-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -DL-phenylalanine and 37 mg (0.23 mmol) of 4- ( 2 / i-tetrazol-5-yl) aniline in 1.5 ml of dimethylformamide were admixed with 0.09 ml (0.52 mmol) Ν, Ν-diisopropylethylamine. The reaction mixture was stirred at 0 ° C. with 0.15 ml (0.25 mmol) of 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide solution (50% in dimethylformamide ) and stirred at RT for 16 h. The reaction mixture was stirred into ethyl acetate and washed three times with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, the solvent was removed on a rotary evaporator and the crude product was stirred with acetonitrile and then dried under high vacuum. 64 mg (49% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.03 min; MS (ES Ineg): m / z = 481 [MH] \ Example 12A

4-Bromo-Na / j / ia - [(1α'-4- {[(feri-butoxycarbonyl) amino] -methyl} cyclohexyl) -carbonyl] -N- [3-fluoro-4- (2-i-tetrazole) 5-yl) phenyl] -L-phenylalanine amide

4-Bromo-N - [(1α-i-4- {[(4-butoxy carbonyl) amino] methyl} cyclohexyl) carbonyl] -L-phenylalanine 10 g, 20.7 mmol), 3-fluoro-4- (2-metrazole -5-yl) aniline (4 g, 22.8 mmol) and N, N-diisopropylethylamine (11 mL, 62 mmol) were suspended in 210 mL of ethyl acetate and treated with 2,4,6-tripropyl-l, 3,5,2, 4,6-trioxatriphosphinane-2,4,6-trioxide (50% in ethyl acetate, 33 g, 52 mmol). The mixture was then refluxed for 2 h, stirred at RT for 48 h and refluxed for a further 3 h. There was added 3-fluoro-4- (2-i-tetrazol-5-yl) aniline (741 mg, 4.1 mmol). The reaction mixture was refluxed for 4 h, water was added and the precipitated solid was filtered off with suction, washed with a little ethyl acetate and water and dried under high vacuum. This gave 3.9 g (30% of theory) of the title compound.

^: H NMR (300 MHz, DMSO-d ₆ ): δ = ppm 0.81 (m, 2H), 1.07-1.30 (m, 4H), 1.36 (s, 9H), 1.50-1.73 (m, 4 H), 2.01 - 2.15 (m, 1H), 2.74 (m, 2H), 2.87 (dd, 1H), 3.00 (dd, 1H), 4.55 - 4.70 (m, 1H), 6.68 - 6.80 (m, 1H), 7.24 (d, 2H), 7.42 - 7.51 (m, 3H), 7.83 (dd, 1H), 8.00 (t, 1H), 8.15 (d, 1H), 10.61 (s, 1H). LC-MS (Method 4): R _t = 1.23 min; MS (ES Ineg): m / z = 644.3 [MH] \ Example 13A

NaI / ia - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl) -N- [4- (1-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide

4-bromo-Na // j / ia - [(4- {iraws

tetrazol-5-yl) phenyl] -L-phenylalanine amide (4.1 g, 6.5 mmol) and bis (pinacolacto) diborane (2.5 g, 9.8 mmol) were dissolved in 41 mL dimethyl sulfoxide, vented with argon and overlaid. The reaction mixture was admixed with l, r-bis (diphenylphosphine) ferrocenedichloropalladium (II) (267 mg, 0.16 mmol) and potassium acetate (1.9 g, 19.6 mmol) and microwave at 110 ° C. for 24 h and at 150 ° C. for 30 min (Biotage initiator) stirred and then reacted further as the crude product.

LC-MS (Method 4): R _t = 1.33 min; MS (ESIpos): m / z = 674.6 [M + H] ⁺ . Example 14A

4-Bromo-Na / j / ia - [(1α'-4- {[(feri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) carbonyl] -N- (3-oxo-2,3-dihydro-1 / i -indazol-6-yl) -L-phenylalanine amide

A solution of 4-bromo-N - [(1α-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -L-phenylalanine (1500 mg, 3 mmol) and 6-amino-1, 2-Dihydro-3 / i-indazol-3-one (555 mg, 24 mmol) in ethyl acetate (21 mL) was added N, N -diisopropylethylamine (1.4 mL, 7.8 mmol). The suspension was treated with a 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide Solution (50% in dimethylformamide, 2.2 ml, 3.7 mmol) and treated with dimethylformamide until dissolved and then stirred for 16 h at RT. The reaction mixture was stirred into ethyl acetate, washed twice with water and once with aqueous sodium chloride solution. The organic phase was dried with sodium sulfate and the solvent removed. The crude product was stirred with acetonitrile and filtered with suction. The residue was separated twice by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% TFA). The crude product was stirred with methanol and filtered with suction. 202 mg (11% of theory) of the title compound were obtained.

^: H-NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.69-0.89 (m, 2H), 1.04-1.29 (m, 3H), 1.37 (s, 9H), 1.67 (m, 4 H), 2.04 - 2.17 (m, 1H), 2.75 (m, 3H), 2.94 - 3.07 (m, 1H), 4.54 - 4.75 (m, 1H), 6.68 - 6.83 (m, 1H) , 7.96 (d, 1H) , 11.08 (brs s, 1 H).

LC-MS (Method 1): R _t = 1.00 min; MS (ESIpos): m / z = 614 [M + H] ⁺ . Example 15A 4-Biom N-alpha - [(trans-4- {[(ferric-butoxycarbonyl) -amino] -methyl} cyclohexyl) -carbonyl] -N- [4- (5-oxo-4,5-dihydro-1, 2,4-oxadiazol-3-yl) phenyl] -L-phenylalaninamide

A solution of 4-bromo-N - [(1α-ε-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -L-phenylalanine (1000 mg, 2 mmol) and 3- (4-aminophenyl ) -4,5-dihydro-l, 2,4-oxadiazol-5-one (403 mg, 2 mmol) in dimethylformamide (15 mL) was added N, N -diisopropylethylamine (0.9 mL, 5 mmol). The suspension was treated with a 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphinane-2, 4,6-trioxide solution (50% in dimethylformamide, 1580 mg, 5 mmol) and until added to the solution with dimethylformamide and then stirred for 16 h at RT. The reaction mixture was stirred into ethyl acetate (1200 ml), washed with water (150 ml) and once with aqueous sodium chloride solution. The organic phase was dried with sodium sulfate and the solvent is removed. The crude product was stirred with acetonitrile and filtered with suction. 540 mg (38% of theory, 94% purity) of the title compound were obtained.

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.68-0.98 (m, 2H), 1.05-1.31 (m, 4H), 1.39 (s, 9H), 1.46-1.76 (m , 4H), 1.98 - 2.15 (m, 1H), 2.65 - 3.07 (m, 4H), 4.56 - 4.71 (m, 1H), 6.71 - 6.83 (m, 1H), 7.25 (d, 2 H), 7.47 (d, 2H), 7.72-7.84 (m, 4H), 8.10-8.20 (m, 1H), 10.45 (s, 1H), 12.86 (br s, 1H).

LC-MS (Method 1): R _t = 1.12 min; MS (ES Ineg): m / z = 640 [MH] \ Example 16A

4-Bromo-N-a / j / ia - [(ω-α-4- {[(ferric-butoxycarbonyl) -amino] -methyl-cyclohexyl) -carbonyl] -Ν-1 / ί-indazol-6-yl-L-phenylalanine-amide

A solution of 4-bromo-N - [(1α-ε-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -L-phenylalanine (2000 mg, 4 mmol) and 6-aminoindazole (606 mg , 5 mmol) in dimethylformamide (30 ml) was added N, N-diisopropylethylamine (1.8 ml, 10 mmol). The suspension was treated with a 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide solution (50% in dimethylformamide, 3.2 mg, 5 mmol) and until added to the solution with dimethylformamide and then stirred for 16 h at RT. The reaction mixture was stirred into ethyl acetate (2500 ml), washed three times with water (300 ml) and once with aqueous sodium chloride solution. The organic phase was dried with sodium sulfate and the solvent removed. The crude product was stirred with acetonitrile and filtered with suction. 1400 mg (54% of theory) of the title compound were obtained.

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.68-0.98 (m, 2H), 1.05-1.31 (m, 4H), 1.39 (s, 9H), 1.46-1.76 (m , 4H), 1.98 - 2.15 (m, 1H), 2.65 - 3.07 (m, 4H), 4.56 - 4.71 (m, 1H), 6.71 - 6.83 (m, 1H), 7.25 (d, 2 H), 7.47 (d, 2H), 7.72-7.84 (m, 4H), 8.10-8.20 (m, 1H), 10.45 (s, 1H), 12.86 (br s, 1H). LC-MS (Method 1): R _t = 1.09 min; MS (ESIpos): m / z = 598 [M + H] ⁺ . Example 17A

Ethyl 5- {4- [(2S) -2- {[(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} 3-oxo-3- {[4- (2 / i-tetrazol-5-yl) phenyl] amino} propyl] phenyl} -6-methylpyridine-2-carboxylate trifluoroacetate

A solution of 102.8 mg (0.45 mmol) of 5-bromo-6-methylpyridine-2-carboxylic acid methyl ester and 121.6 mg (0.48 mmol) of bis (pinacolato) diborane in 2.5 ml of toluene were treated with 93.9 mg (0.96 mmol) of potassium acetate and 5 min with Argon degassed. 13.0 mg (0.02 mmol) of [1,1-bis (diphenylphosphine) ferrocene] dichloropalladium dichloromethane complex was added and the mixture was stirred for 3 h at 120 ° C in a preheated oil bath. The mixture was concentrated and the residue was taken up in 2.5 ml of 1,2-dimethoxyethane and 1 ml of ethanol. There were 200 mg (0.32 mmol) 4-biome N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -N- [4- (2 / i-tetrazole -5-yl) phenyl] -L-phenylalanine amide, 13.0 mg (0.02 mmol) of [1, 1-bis (diphenylphosphine) ferrocene] dichloropalladium dichloromethane complex and 0.36 ml (0.72 mmol) of 2M sodium carbonate solution in water added and stirred overnight at reflux. The reaction mixture was mixed with a little dimethylformamide, water and acetonitrile, filtered and the filtrate was separated by preparative HPLC (eluent: acetonitrile / water with 0.1% TFA (gradient)). The vials containing product were concentrated and dried under high vacuum. The residue was recrystallized from a little methanol, filtered off with suction, and after-dried again in a high vacuum. 33 mg (14% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.04 min; MS (ESIpos): m / z = 711 [M + H-TFA] ⁺ . Example 18A ieri-butyl-5- (4-aminophenyl) -3-oxo-2,3-dihydro-l / i-pyrazole-1-carboxylate

2.50 g (12.19 mmol) of 5- (4-nitrophenyl) -1,2-dihydro-3 / pyrazol-3-one were initially charged in 50 ml of dichloromethane, with 1.7 ml (12.19 mmol) of triethylamine and 2.66 g (12.19 mmol ) Oi tert-butyl dicarbonate and the reaction mixture stirred for 4 h at RT. Water was added and extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and the solvent removed. The residue was separated by column chromatography on silica gel (dichloromethane / methanol 200: 1 → 100: 1). The product-containing fractions were concentrated and the residue was dissolved in 100 ml of ethanol. 253 mg of palladium on charcoal (10%) was added. The suspension was hydrogenated for 2 h at RT under normal hydrogen pressure, then filtered through a paper filter and washed with a little ethanol. The filtrate was concentrated and dried. This gave 1.99 g (53% of theory, 90% purity) of the title compound over 2 stages. LC-MS (Method 1): R _t = 2.06 min; MS (ESIpos): m / z = 276 [M + H] ⁺ .

Example 19A ieri-butyl-5- [4 - ({4-bromo-N - [(1α-ε-4- {[(feri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -L-phenylalanyl} amino) phenyl ] -3-oxo-2,3-dihydro-1 / pyrazole-1-carboxylate

A solution of 134 mg (0.28 mmol) 4-bromo-N - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -L-phenylalanine and 101 mg (0.33 mmol, 90% purity) ieri-butyl-5- (4-aminophenyl) -3-oxo-2,3-dihydro-l / i-pyrazole-1-carboxylate (949 mg, 3.7 mmol) in 2 ml of ethyl acetate was mixed with 0.12 ml (0.69 mmol) Ν, Ν-diisopropylethylamine. The suspension was treated with a 0.19 ml (0.33 mmol) 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide solution (50% in dimethylformamide) and until added to the solution with dimethylformamide and then stirred for 16 h at RT. The reaction mixture was stirred into ethyl acetate, washed three times with water and once with aqueous sodium chloride solution. The organic phase was dried over sodium sulfate and the solvent removed. The crude product was dissolved in a little methanol and separated by preparative HPLC (eluent: acetonitrile / water with 0.1% TFA (gradient)). 134 mg (64% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.73-0.91 (m, 2H), 1.06-1.32 (m, 3H), 1.37 (s, 9H), 1.45-1.59 (m, 10 H), 1.60 - 1.73 (m, 3H), 2.03 - 2.14 (m, 1H), 2.70 - 2.78 (m, 2H), 2.79 - 2.89 (m, 1H), 2.96 - 3.07 (m, 1H), 4.59 - 4.69 (m, 1H), 6.48 (s, 1H), 6.74 - 6.83 (m, 1H), 7.25 (d, 2H), 7.48 (d, 2H), 7.62 - 7.73 (m, 4H), 8.13 (d, 1H), 10.27 (s, 1H), 12.95 (s, 1H).

LC-MS (Method 1): R _t = 1.26 min; MS (ESIneg): m / z = 738 [MH] \

Example 20A

Methyl (2 Z) -3- (4-bromo-3-fluorophenyl) -2 - [(ieri-butoxycarbonyl) amino] acrylate

Methyl - [(ieri-butoxycarbonyl) amino] (dimethoxyphosphoryl) acetate (1.46 g, 4.93 mmol) was placed under argon atmosphere in dichloromethane (ca 30 ml), with 1,8-diazabicyclo (5.4.0) undec-7-ene (0.82 g, 5.42 mmol) and stirred for 10 min at RT. A solution of 4-bromo-3-methoxybenzaldehyde (1.00 g, 23 mmol) in dichloromethane (6.5 ml) was added and stirred at RT for 90 min. Ethyl acetate was added to the reaction mixture and the solution was adjusted to pH 4 with 1N hydrochloric acid solution. The phases were separated and the aqueous phase extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent was removed. The crude product was applied to silica gel and purified by column chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 10: 1-> 5: 1) and the solvent was removed. 1.19 g (64% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO δ = ppm 1.39 (s, 9H), 3.74 (s, 3H), 7.1 (br, s, 1H), 7.43 (d, 1H), 7.63 (d, 1 H), 7.77 (t, 1 H), 8.9 (brs s, 1 H).

LC-MS (Method 2): R _t = 2.44 min; MS (ES Ineg): m / z = 372 [MH] \ Example 21A Methyl 4-bromo-N- (ieri-butoxycarbonyl) -3-fluoro-L-phenylalaninate

Methyl (2Z) -3- (4-bromo-3-fluorophenyl) -2 - [(ieri-butoxycarbonyl) amino] acrylate (1.19 g, 3.17 mmol) was initially charged in ethanol (34 ml), the mixture degassed with argon , with (+) - l, 2-bis ((2S, 5S) -2,5-diethylphospholano) benzene (cyclooctadiene) rhodium (I) trifluoromethanesulfonic acid (49 mg, 0.06 mmol) and 48 h at RT under hydrogen atmosphere (3 bar) stirred. The reaction mixture was filtered through silica gel, washed with ethanol and concentrated to dryness. 1.11 g (93% of theory) of the title compound were obtained. α-D = -0.014 ° (23 ° C, c = 0.505 g / 100 ml)

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 1.22-1.35 (m, 9H), 2.78-2.88 (m, 1H), 2.99-3.07 (m, 1H), 3.63 (s , 3H), 4.16 - 4.27 (m, 1H), 7.02 - 7.09 (m, 1H), 7.25 - 7.38 (m, 2H), 7.61 (t, 1H).

LC-MS (Method 1): R _t = 1.17 min; MS (ESIpos): m / z = 376 [M + H] ⁺ .

Example 22A Methyl-4-bromo-3-fluoro-L-phenylalaninate hydrochloride

A solution of methyl 4-bromo-N- (ieri-butoxycarbonyl) -3-fluoro-L-phenylalaninate (1.05 g, 2.78 mmol) in 1,4-dioxane (20 mL) was treated with 10.4 mL (41.7 mmol) 4M Hydrogen chloride in 1,4-dioxane and stirred overnight at RT. The precipitate was filtered off, washed with a little acetonitrile and dried under high vacuum. 0.57 g (66% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.54 min; MS (ESIpos): m / z = 276 [M + H-HC1] \

Example 23A

4-Bromo-N - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -3-fluoro-L-phenylalanine

A solution of methyl 4-bromo-3-fluoro-L-phenylalaninate hydrochloride (569mg, 1.82mmol) and α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexanecarboxylic acid (562mg, 2.19mmol ) in ethyl acetate (15 ml) was added N, N -diisopropylethylamine (0.79 ml, 4.55 mmol). The reaction mixture was treated with a 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphinane-2, 4,6-trioxide solution (50% in dimethylformamide, 1.0 ml, 2.19 mmol) and bis added to the precipitate with dimethylformamide and then stirred for 16 h at RT. The reaction mixture was stirred into ethyl acetate, washed four times with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate and the solvent removed. The residue was acetonitrile stirred hot, filtered off with suction and dried under high vacuum. The resulting solid was dissolved in 28 ml of tetrahydrofuran and treated with a solution of lithium hydroxide monohydrate (472 mg, 11.25 mmol) in water (8 ml). The suspension was stirred at RT for 16 h. The reaction mixture was acidified with 1N hydrochloric acid solution and treated with ethyl acetate. The phases were separated, the organic phase washed with water and with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent removed. The residue was recrystallized with a little diethyl ether and then dried under high vacuum. 1048 mg (quant.) Of the slightly contaminated title compound was obtained over two stages. Ή-NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.71-0.94 (m, 2H), 1.05-1.31 (m, 3H), 1.37 (s, 9H), 1.47- 1.56 (m, 1 H), 1.60 - 1.74 (m, 3H), 1.81 - 1.92 (m, 1H), 1.95 - 2.15 (m, 1H), 2.69 - 2.79 (m, 2H), 2.78 - 2.79 (m, 1 H), 2.80 - 2.90 (m, 1H), 3.01 - 3.10 (m, 1H), 3.13 - 3.19 (m, 1H), 4.36 - 4.46 (m, 1H), 6.74 - 6.84 (m, 1H), 6.97 - 7.06 (m, 1H), 7.19 - 7.26 (m, 1H), 7.26 - 7.27 (m, 1H), 7.55 - 7.64 (m, 1H), 7.97 - 8.06 (m, 1 H), 12.0 (brs s, 1 H), 12.7 (brs s, 1 H). LC-MS (Method 1): R _t = 1.05 min; MS (ESIneg): m / z = 499 [MH] \

Example 24A

4-Bromo-Na / j / ia - [(1α'-4- {[(feri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -3-fluoro-N- [4- (2-i-tetrazole) 5-yl) phenyl] -L-phenylalaninamide

A solution of 4-bromo-N - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -3-fluoro-L-phenylalanine (1.05 g, 2.09 mmol) and 4- (2 / i-Tetrazol-5-yl) aniline (404 mg, 2.51 mmol) in ethyl acetate (16 ml) was added N, N -diisopropylethylamine (0.91 ml, 5.23 mmol) and stirred at RT for a few minutes. The reaction mixture was treated with a 2,4,6-tripropyl-1,3,5,4,4,6-trioxatriphosphinane-2,4,6-trioxide solution (50% in dimethylformamide, 1.5 ml, 2.51 mmol) and then stirred for 16 h at RT. The reaction mixture was stirred into ethyl acetate, washed three times with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate and the solvent removed. 1.12 g (72% of theory, 87% purity) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.74-0.93 (m, 2H), 1.07-1.31 (m, 3H), 1.37 (s, 9H), 1.49-1.59 (m, 1 H), 1.61 - 1.73 (m, 3H), 2.04 - 2.14 (m, 1H), 2.70 - 2.78 (m, 2H), 2.83 - 2.93 (m, 1H), 3.01 - 3.10 (m, 1 H), 4.62 - 4.72 (m, 1H), 6.74 - 6.83 (m, 1H), 7.06 - 7.14 (m, 1H), 7.27 - 7.33 (m, 1H), 7.59 - 7.66 (m, 1H), 7.80 (d, 2H), 8.00 (d, 2H), 8.14 - 8.21 (m, 1H), 10.44 (s, 1H), 16.7 (brs s, 1H).

LC-MS (Method 1): R _t = 1.10 min; MS (ESIneg): m / z = 642 [MH] \

Example 25A ieri-butyl-4- {[(5-bromopyridin-3-yl) sulfonyl] amino} piperidine-1-carboxylate

5-Bromopyridine-3-sulfonyl chloride (1.0 g, 3.9 mmol) was dissolved in 20 ml of dichloromethane, cooled to 0 ° C and washed with N, N-diisopropylamine (1.7 ml, 9.7 mmol) and fer-butyl-4-aminopiperidine-1 - Carboxylate (1.2 g, 5.8 mmol). The reaction mixture was allowed to come to RT and stirred for 2 h. It was then concentrated and purified by HPLC (Method 9). 1.0 g (62% of theory) of the title compound was obtained.

^: H NMR (300 MHz, DMSO-de): δ = ppm 1.09-1.25 (m, 2H), 1.33 (s, 9H), 1.47-1.58 (m, 2H), 2.71-2.83 (m, 2H), 3.20 - 3.27 (m, 1H), 3.63 - 3.74 (m, 2H), 8.07 - 8.12 (m, 1H), 8.36 (t, 1H), 8.91 (d, 1H), 8.95 (d, 1 H).

LC-MS (method 1): R _t = 1.19 min; MS (ES Ineg): m / z = 420 [MH] ^" . Example 26A

N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [2- (morpholin-4-yl) pyrimidin-5-yl] -N- [4 - (1 / i-tetrazol-5-yl) phenyl 1] -L-phenylalanine amide formate

4-Bromo-Na / j / ia - [(iraws-4- {[(fer ^ buto

tetrazol-5-yl) phenyl] -L-phenylalanine amide (150mg, 0.24mmol) and 4- [5- (4,4,5,5-tetramethyl-, 3,2-dioxaborolan-2-yl) pyrimidine 2-yl] morpholine (107 mg, 0.36 mmol) was dissolved in dimethylsulfoxide (2 ml) and treated with tetrakis (triphenylphosphine) palladium (0) (28 mg, 24 μηιοΐ), sodium carbonate (76 mg, 0.72 mmol) and water (0.36 ml, 20 mmol). The reaction mixture was stirred for 120 min at 110 ° C. in the microwave (Biotage Initiator), cooled, filtered and purified by chromatography via HPLC (Method 9). 28 mg (18% of Th.) Of the title compound were obtained.

LC-MS (Method 4): R _t = 1.19 min; MS (ESIpos): m / z = 711 [M + H-HCOOH] ⁺ . Example 27A N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- {5- [(4-methylpiperazin-1-yl) sulfonyl] pyridin-3-yl } -N- [4- (1-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide formate

H-C - N N - S = 0

^N - 'ox HCOOH

4-Bromo-Na / j / ia - [(1α-ε-4- {[(ferric-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbon ^ -N- [4- (1-tetrazol-5-yl) -phenyl ] -L-phenylalanine amide (150 mg, 0.24 mmol) and 1-methyl-4- {[5- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) pyridine-3] yl] sulfonyl} piperazine (132 mg, 0.36 mmol) were dissolved in dimethylsulfoxide (2 ml) and treated with tetrakis (triphenylphosphine) palladium (0) (28 mg, 24 μηιοΐ), sodium carbonate (76 mg, 0.72 mmol) and water (0.36 ml, 20 mmol). The reaction mixture was stirred for 120 minutes at 110 ° C. in the microwave (Biotage Initiator), cooled, filtered and purified by chromatography via HPLC (Method 11). 111 mg (59% of Th.) Of the title compound were obtained. LC-MS (Method 5): R _t = 0.81 min; MS (ESIpos): m / z = 787.5 [M + H-HCOOH] ⁺ .

Example 28A

^~ N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (2-chloropyridin-3-yl) -N- [4- (1-i-tetrazole -5-yl) phenyl] -L-phenylalanine amide formate

4-Bromo-Na / i / ia - [(i-i-4- {[(fero-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl-4- [4- (1-y-tetrazol-5-yl) -phenyl ] -L-phenylalanine amide (150 mg, 0.24 mmol) and 2-chloro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (86 mg, 0.36 mmol) were dissolved in dimethyl sulfoxide (2 ml) and treated with tetrakis (triphenylphosphine) palladium (0) (28 mg, 24 μηιοΐ), sodium carbonate (76 mg, 0.72 mmol) and water (0.36 ml, 20 mmol). The reaction mixture was stirred for 120 minutes at 110 ° C. in the microwave (Biotage Initiator), cooled, filtered and purified by chromatography via HPLC (Method 10). 31 mg (20% of Th.) Of the title compound were obtained.

LC-MS (Method 4): R _t = 1.19 min; MS (ESIpos): m / z = 659.5 [M + H-HCOOH] ⁺ . Example 29A

N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [6- (dimethylamino) pyridin-3-yl] -N- [4- (1 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide formate

4-Bromo-Na / j / ia - [(ω-α-4- {[(ferric-butoxycarbonyl) -amino] -methyl-cyclohexyl-carbonyl] -N- [4- (l-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide (46 mg, 0.07 mmol) and [6- (dimethylamino) pyridin-3-yljboronic acid (13 mg, 0.08 mmol) were dissolved in dimethylsulfoxide (0.7 ml) and treated with 1,1'-bis (diphenylphosphine ) ferrocenedichloropalladium (II) (6 mg, 7 μηιοΐ), sodium carbonate (23 mg, 0.22 mmol) and water (0.11 ml, 6.3 mmol) were added. The reaction mixture was stirred for 60 minutes at 110 ° C. in the microwave (Biotage Initiator), cooled, filtered and purified by chromatography via HPLC (Method 8). 3 mg (7% of th.) Of the title compound were obtained.

LC-MS (Method 4): R _t = 0.90 min; MS (ESIpos): m / z = 668.2 [M + H-HCOOH] ⁺ . Example 30A

^~ N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- {6- [3- (dimethylamino) propoxy] pyridin-3-yl} -N- [ 4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide and 18.4 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) were taken up in 1.5 ml of 1,2-dimethoxyethane and stirred at RT for 10 min. To the reaction mixture was added a solution of 146 mg (0.48 mmol) of N, N-dimethyl-3- {[5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2 - Yl] oxy} propan-l-amine dropped in 0.50 ml of ethanol. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, it was stirred at reflux for 3 hours. The reaction mixture was admixed with 1N aqueous hydrochloric acid, the salts were filtered off and the filtrate was separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). This gave 120 mg of a mixture of the title compound and the corresponding deprotected amine, which was used directly in the next step.

LC-MS (Method 1): R _t = 0.81 min; MS (ESfneg): m / z = 724 [MH-TFA] ^" .

Example 31A

^~ N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [6- (morpholin-4-yl) pyridin-3-yl] -N- [4 - (2 / i-tetrazol-5-yl) phenyl] -L-phenylalaninamide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide and 18.4 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) were taken up in 1.5 ml of 1,2-dimethoxyethane and stirred at RT for 10 min. To the reaction mixture was added a solution of 139 mg (0.48 mmol) of 4- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl] morpholine in 0.50 ml Ethanol dripped. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, the mixture was stirred at reflux for 3 h and at RT for 16 h. The reaction mixture was treated with 1N aqueous hydrochloric acid, the phases were separated and the aqueous phase was extracted three times with ethyl acetate. The aqueous phases were concentrated and the residue was stirred with methanol / DMSO. The filtrate was separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). This gave 69 mg of a mixture of the title compound and the corresponding deprotected amine, which was used directly in the next step. LC-MS (Method 1): R _t = 0.93 min; MS (ESfneg): m / z = 708 [MH-TFA]. ^" Example 32A

Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -N- [4- (5-oxo-4,5-dihydro-1,2) 4-oxadiazol-3-yl) phenyl] -4-pyridin-4-yl-L-phenylalanine amide

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(α-α-4- {[(ferric-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (5- oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) phenyl] -L-phenylalanine amide and 18.4 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) were added under argon in 1.4 ml of 1.2 - Dimethoxyethane and stirred for 10 min at RT. A solution of 57 mg (0.48 mmol) of pyridine-4-boronic acid in 0.54 ml of ethanol was added dropwise to the reaction mixture and the mixture was stirred at RT for a further 10 min. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, it was stirred at RT for 5 min and under reflux for 3 h. The reaction mixture was mixed with a little methanol, filtered through a Millipore syringe filter and separated by preparative HPLC (mobile phase: acetonitrile / water gradient). 40 mg (39% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.83 min; MS (ESIneg): m / z = 639 [MH] \

Example 33A

^~ N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- {6- [(2 → 5,6)} - 2,6-dimethylmorpholine-4 yl] pyridin-3-yl} - N - [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide and 18.4 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) were taken up in 1.5 ml of 1,2-dimethoxyethane and stirred at RT for 10 min. To the reaction mixture was added a solution of 152 mg (0.48 mmol) (2R ₁ S ^, 6S ^, R) -2,6-dimethyl-4- [5- (4,4,5,5-tetramethyl-1, 3 , 2-dioxaborolan-2-yl) pyridin-2-yl] morpholine in 0.50 ml of ethanol. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, it was stirred at reflux for 3 hours. The reaction mixture was admixed with 1N aqueous hydrochloric acid, the salts were filtered off and the filtrate was separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). The product-containing fractions were mixed with a few drops of 4N hydrochloric acid, concentrated and the residue was dried under high vacuum. This gave 104 mg of a mixture of the title compound and the corresponding deprotected amine, which was used directly in the next step.

LC-MS (Method 1): R _t = 1.09 min; MS (ES Ineg): m / z = 736 [MH-TFA]. ^" Example 34A

Na / j / ia - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (5-chloropyridin-3-yl) -N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide and 18.4 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) were taken up in 1.5 ml of 1,2-dimethoxyethane and stirred at RT for 10 min. A solution of 75 mg (0.48 mmol) of (5-chloropyridin-3-yl) boronic acid in 0.50 ml of ethanol was added dropwise to the reaction mixture. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, it was stirred at reflux for 3 hours. The reaction mixture was admixed with 1N aqueous hydrochloric acid, the salts were filtered off and the filtrate was separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). 93 mg (88% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.13 min; MS (ES Ineg): m / z = 657 [MH-TFA] ^" .

Example 35A

N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4-pyridin-4-yl-N- [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

400 mg (0.64 mmol) 4-bromo-Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide and 74 mg (0.06 mmol) of tetrakis (triphenylphosphine) palladium (0) were taken up in 6 ml of 1,2-dimethoxyethane and stirred at RT for 10 min. To the reaction mixture was added dropwise a solution of 235 mg (1.92 mmol) of pyridine-4-boronic acid in 3 ml of ethanol. After the addition of 5 ml of 2N aqueous sodium carbonate solution was stirred at reflux for 3 h and 2.4 d at RT. The reaction mixture was admixed with 1N aqueous hydrochloric acid, the salts were filtered off and the filtrate was separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). 313 mg (64% of theory) of the title compound were obtained. LC-MS (method 1): R _t = 0.82 min; MS (ES Ineg): m / z = 623 [MH-TFA] ^" .

Example 36A

N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (4-chloropyridin-3-yl) -N- [4- (2-i-tetrazole) 5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide and 18.4 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) were taken up in 1.5 ml of 1,2-dimethoxyethane and stirred at RT for 10 min. A solution of 92 mg (0.48 mmol) of (4-chloropyridin-3-yl) boronic acid in 0.50 ml of ethanol was added dropwise to the reaction mixture. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, it was stirred at reflux for 3 hours. The reaction mixture was admixed with 1N aqueous hydrochloric acid, the salts were filtered off and the filtrate was separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). 83 mg (65% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.03 min; MS (ES Ineg): m / z = 657 [MH-TFA] ^" . Example 37A

Na / j / ia - [(i-i-4- {[(ω-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -4- (2-methylpyridin-3-yl) -N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide and 18.4 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) were taken up in 1.5 ml of 1,2-dimethoxyethane and stirred at RT for 10 min. To the reaction mixture, a solution of 66 mg (0.48 mmol) of (2-methylpyridin-3-yl) boronic acid in 0.50 ml of ethanol was added dropwise. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, it was stirred at reflux for 3 hours. The reaction mixture was admixed with 1N aqueous hydrochloric acid, the salts were filtered off and the filtrate was separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). 63 mg of a mixture of the title compound and the corresponding deprotected amine were obtained, which was used directly in the next step. LC-MS (Method 1): R _t = 0.77 min; MS (ES Ineg): m / z = 637 [MH-TFA] ^" .

Example 38A

Na / j / ia - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -N- [4- (5-oxo-4,5-dihydro-1, 2, 4-oxadiazol-3-yl) phenyl] -4-pyridin-3-yl-L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (5-oxo -4,5-dihydro-l, 2,4-oxadiazol-3-yl) phenyl] -L-phenylalanine amide and 18 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) were dissolved under argon in 1.4 ml of 1,2- Dimethoxyethane and stirred for 10 min at RT. A solution of 57 mg (0.47 mmol) of pyridine-3-boronic acid in 0.54 ml of ethanol was added dropwise to the reaction mixture and the mixture was stirred at RT for a further 10 min. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, the mixture was stirred at RT for 5 min and under reflux for 3 h. The reaction mixture was mixed with a little methanol, filtered through a Milhspornes syringe filter and separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). 78 mg (75% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.92 min; MS (ESIneg):. M / z = 639 [MH-TFA] ^"Example 39A

Na / j / ia - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (3-chloropyridin-4-yl) -N- [4- (2 / f-tetrazol-5-yl) phenyl] -L-phenylalaninamide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide and 18.4 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) were taken up in 1.5 ml of 1,2-dimethoxyethane and stirred at RT for 10 min. To the reaction mixture was added dropwise a solution of 75 mg (0.48 mmol) of 3-chloro-4-pyridinboronic acid in 0.50 ml of ethanol. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, the mixture was stirred at reflux for 3 h and at RT for 16 h. The reaction mixture was admixed with 1N aqueous hydrochloric acid, the salts were filtered off and the filtrate was separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). 74 mg (56% of theory, 94% purity) of the title compound were obtained. LC-MS (Method 1): R _t = 1.02 min; MS (ES Ineg): m / z = 657 [MH-TFA] ^" .

Example 40A

N-a / j / ia - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (6- {2-)

(morpholin-4-yl) ethyl] amino} pyridin-3-yl) -N- [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide

trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide and 18 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) were taken up under argon in 1.4 ml of 1,2-dimethoxyethane and stirred at RT for 10 min. To the reaction mixture was added a solution of 160 mg (0.47 mmol) of N- [2- (morpholin-4-yl) ethyl] -5- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-one). yl) pyridine-2-amine in 0.54 ml of ethanol was added dropwise and stirred for a further 10 min at RT. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, it was stirred at RT for 5 min and under reflux for 3 h. The reaction mixture was mixed with a little methanol over a millipore syringe filter filtered and separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). 134 mg (94% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.80 min; MS (ES Ineg): m / z = 751 [MH-TFA] ^" .

Example 41 A NaI / ia - [(ira «A-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (6-hydroxypyridin-3-yl) -N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide and 18.4 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) were taken up in 1.5 ml of 1,2-dimethoxyethane and stirred at RT for 10 min. To the reaction mixture was added dropwise a solution of 110 mg (0.48 mmol) of [6- (benzyloxy) pyridin-3-yl] boronic acid in 0.50 ml of ethanol. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, it was stirred at reflux for 3 hours. The reaction mixture was admixed with 1N aqueous hydrochloric acid, the salts were filtered off and the filtrate was separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). The intermediate mixture obtained was dissolved in 70 ml of methanol and 30 ml of dichloromethane, and 20 mg (0.02 mmol) of palladium on activated carbon (10%) were added. The suspension was hydrogenated at RT under hydrogen normal pressure for 2.5 h and then filtered through kieselguhr. The filtrate was concentrated and the residue was separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). 25 mg (21% of theory) of the title compound were obtained over 2 stages.

LC-MS (Method 1): R _t = 0.87 min; MS (ES Ineg): m / z = 639 [MH-TFA] ^" . Example 42A

N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] - N - [4- (2-i-tetrazol-5-yl) phenyl] -4- [6- (trifluoromethyl) pyridin-3-yl] -L-phenylalaninamide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide and 18 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) were taken up under argon in 1.4 ml of 1,2-dimethoxyethane and stirred at RT for 10 min. A solution of 91 mg (0.48 mmol) of [6- (trifluoromethyl) pyridin-3-yl] boronic acid in 0.54 ml of ethanol was added dropwise to the reaction mixture and the mixture was stirred at RT for a further 10 min. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, it was stirred at RT for 5 min and under reflux for 3 h. The reaction mixture was mixed with a little methanol, filtered through a Millipore syringe filter and separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). 64 mg (49% of theory) of the title compound were obtained. LC-MS (Method 1): R _t = 1.11 min; MS (ES Ineg): m / z = 691 [MH-TFA] ^" .

Example 43A

^~ N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- {6- [3-

(dimethylamino) propoxy] pyridin-3-yl} - N - [4- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) phenyl] -L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(α-α-4- {[(ferric-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (5- oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) phenyl] -L-phenylalanine amide and 18 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) were dissolved under argon in 1.4 ml of 1.2 - Dimethoxyethane and stirred for 10 min at RT. To the reaction mixture was added a solution of 143 mg (0.48 mmol) of N, N-dimethyl-3- {[5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2 -yl] oxy} propan-1-amine was added dropwise in 0.54 ml of ethanol and stirred at RT for a further 10 min. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, it was stirred at RT for 5 min and under reflux for 3 h. The reaction mixture was mixed with a little methanol, filtered through a Millipore syringe filter and separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). 96 mg (71% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.80 min; MS (ESfneg): m / z = 740 [MH-TFA] ^" .

Example 44A NaI / ia - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (3-methoxypyridin-4-yl) -N- [4- ( 2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide and 18.4 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) were taken up in 1.5 ml of 1,2-dimethoxyethane and stirred at RT for 10 min. A solution of 73 mg (0.48 mmol) of (3-methoxypyridin-4-yl) boronic acid in 0.50 ml of ethanol was added dropwise to the reaction mixture. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, the mixture was stirred at reflux for 3 h and at RT for 16 h. The reaction mixture was separated directly by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). This gave 78 mg of a mixture of the title compound and the partially deprotected title compound, which was used directly in the next step.

LC-MS (Method 1): R _t = 0.87 min; MS (ES Ineg): m / z = 653 [MH-TFA]. ^" Example 45A

N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (6-methoxy-2-methylpyridin-3-yl) -N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide, 18.4 mg (0.02 mmol) tetrakis (triphenylphosphine) palladium (0) and 67 mg (0.40 mmol) 2-methyl-6-methoxypyridine-3-boronic acid were dissolved in 1.5 ml 1,2-dimethoxyethane and 0.50 ml of ethanol. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, it was stirred at reflux for 3 hours. The salts were filtered off from the reaction mixture and the filtrate was separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). This gave 89 mg of a mixture of the title compound and the partially deprotected title compound, which was used directly in the next step. LC-MS (Method 1): R _t = 1.10 min; MS (ESfneg): m / z = 667 [MH-TFA] ^" .

Example 46A

4- [4- (Benzyloxy) -2- (dimethylamino) -pyrimidin-5-yl] -Na / j / ia - [(ω-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl ] -N- [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide, 18.4 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) and 109 mg (0.40 mmol) of [4- (benzyloxy) -2- (dimethylamino) pyrimidine-5 -yl] boronic acid were taken up in 1.5 ml of 1,2-dimethoxyethane and 0.50 ml of ethanol. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, it was stirred at reflux for 3 hours. The salts were filtered off from the reaction mixture and the filtrate was separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). 114 mg (76% of theory) of the title compound were obtained. LC-MS (Method 1): R _t = 1.09 min; MS (ES Ineg): m / z = 773 [MH-TFA]. ^" Example 47A

NaI / ia - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (3-methylpyridin-4-yl) -N- (3-oxo -2,3-dihydro-l / i-indazol-6-yl) -L-phenylalaninamide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- (3-oxo-2, 3-dihydro-l / i-indazol-6-yl) -L-phenylalanine amide and 27 mg (0.03 mmol) of l, -bis (diphenylphosphine) ferrocenepalladium (II) chloride were taken up under argon in 1.4 ml of 1,2-dimethoxyethane and Stirred for a few minutes at RT. A solution of 67 mg (0.49 mmol) of 3-methylpyridine-4-boronic acid in 0.54 ml of ethanol was added dropwise to the reaction mixture and the mixture was stirred a further few minutes at RT. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution was stirred for 5 min at RT and irradiated for 1 h at 120 ° C in the microwave. The reaction mixture was mixed with a little methanol, filtered through kieselguhr and a Millipore syringe filter and separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). This gave 70 mg of a mixture of the title compound and the partially deprotected title compound, which was used directly in the next step.

LC-MS (Method 1): R _t = 0.71 min; MS (ES Ineg): m / z = 625 [MH-TFA]. ^" Example 48A ^~ N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [6 - (morpholin-4-yl) pyridin-3-yl] -N- (3-oxo-2,3-dihydro-1 / i-indazol-6-yl) -L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- (3-oxo-2, 3-dihydro-l / i-indazol-6-yl) -L-phenylalanine amide and 27 mg (0.03 mmol) of l, -bis (diphenylphosphine) ferrocenepalladium (II) chloride were taken up under argon in 1.4 ml of 1,2-dimethoxyethane and Stirred for a few minutes at RT. To the reaction mixture was added a solution of 142 mg (0.49 mmol) of 4- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl] morpholine in 0.54 ml Ethanol added dropwise and stirred for a few minutes at RT. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution was stirred for 5 min at RT and irradiated for 1 h at 120 ° C in the microwave. The reaction mixture was mixed with a little methanol, filtered through kieselguhr and a Millipore syringe filter and separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). This gave 92 mg of a mixture of the title compound and the partially deprotected title compound, which was used directly in the next step.

LC-MS (Method 2): R _t = 1.88 min; MS (ES Ineg): m / z = 696 [MH-TFA]. ^" Example 49A

^~ N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [2- (dimethylamino) pyrimidin-5-yl] -N- [4- ( 2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i tetrazole-5-yl) phenyl] -L-phenylalanine amide, 18.4 mg (0.02 mmol) tetrakis (triphenylphosphine) palladium (0) and 67 mg (0.40 mmol) of [2- (dimethylamino) pyrimidin-5-yl] boronic acid were added in 1.5 ml of 1,2-dimethoxyethane and 0.50 ml of ethanol were added. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, it was stirred at reflux for 3 hours. The salts were filtered off from the reaction mixture and the filtrate was separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). This gave 73 mg (58% of theory) of the title compound. LC-MS (Method 1): R _t = 1.06 min; MS (ES Ineg): m / z = 667 [MH-TFA] ^" .

Example 50A

4- (2-Aniynopyridin-3-yl) -Na / j / ia - [(1α-5-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) -carbonyl] -N- [4- (2 / f-tetrazol-5-yl) phenyl] -L-phenylalaninamide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i tetrazol-5-yl) phenyl] -L-phenylalanine amide, 18.4 mg (0.02 mmol) tetrakis (triphenylphosphine) palladium (0) and 128 mg (0.40 mmol) ieri-butyl [3- (4,4,5,5 - tetramethyl-l, 3,2-dioxaborolan-2-yl) pyridin-2-yl] carbamate were taken up in 1.5 ml of 1,2-dimethoxyethane and 0.50 ml of ethanol. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, the mixture was stirred at reflux for 3 h and at RT for 16 h. The salts were filtered off from the reaction mixture and the filtrate was separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). This gave 64 mg of a mixture of the title compound and the partially deprotected title compound, which was used directly in the next step.

LC-MS (Method 1): R _t = 0.74 min; MS (ES Ineg): m / z = 638 [MH-TFA] ^" .

Example 51 A

N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (2-methylpyridin-3-yl) -N- (3-oxo-2,3 dihydro-l / i-indazol-6-yl) -L-phenylalaninamide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- (3-oxo-2, 3-dihydro-l / i-indazol-6-yl) -L-phenylalanine amide and 27 mg (0.03 mmol) of l, -bis (diphenylphosphine) ferrocenepalladium (II) chloride were taken up under argon in 1.4 ml of 1,2-dimethoxyethane and Stirred for a few minutes at RT. A solution of 67 mg (0.49 mmol) of 2-methylpyridine-3-boronic acid in 0.54 ml of ethanol was added dropwise to the reaction mixture and the mixture was stirred a further few minutes at RT. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution was stirred for 5 min at RT and irradiated for 1 h at 120 ° C in the microwave. The reaction mixture was mixed with a little methanol, filtered through kieselguhr and a Millipore syringe filter and separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). 55 mg of a mixture were obtained the title compound and the partially deprotected title compound which was used directly in the next step.

LC-MS (Method 1): R _t = 0.70 min; MS (ES Ineg): m / z = 625 [MH-TFA]. ^" Example 52A N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -N-1 / i -indazol-6-yl-4- (6-methoxy-2-methylpyridin-3-yl) -L-phenylalanine amide trifluoroacetate

100 mg (0.17 mmol) 4-bromo-Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -Nl / i-indazol-6-yl L-phenylalanine amide, 12.2 mg (0.02 mmol) of 1,1'-bis (diphenylphosphine) ferrocenepalladium (II) chloride and 70 mg (0.42 mmol) of (6-methoxy-2-methylpyridin-3-yl) boronic acid were dissolved in 1.5 ml 1,2-dimethoxyethane and 0.50 ml of ethanol. After addition of 1.2 ml of 2N aqueous sodium carbonate solution, the reaction mixture was irradiated for 1 h at 120 ° C. in the microwave, then filtered through kieselguhr and the filtrate was separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). , 90 mg (69% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.11 min; MS (ES Ineg): m / z = 639 [MH-TFA]. ^" Example 53A

N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [4-methyl-6- (morpholin-4-yl) pyridin-3-yl] -N - [4- (2 # -tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide, 18.4 mg (0.02 mmol) tetrakis (triphenylphosphine) palladium (0) and 121 mg (0.40 mmol) 4- [4-methyl-5- (4,4,5 5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl] morpholine were taken up in 1.5 ml of 1,2-dimethoxyethane and 0.50 ml of ethanol. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, it was stirred at reflux for 3 hours. The salts were filtered off from the reaction mixture and the filtrate was separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). This gave 45 mg of a mixture of the title compound and the partially deprotected title compound, which was used directly in the next step.

LC-MS (Method 1): R _t = 0.89 min; MS (ESfneg): m / z = 722 [MH-TFA] ^" .

Example 54A

N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (6-methoxy-2-methylpyridin-3-yl) -N- (3-oxo-2 , 3-dihydro-l / i-indazol-6-yl) -L-phenylalaninamide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- (3-oxo-2, 3-dihydro-l / i-indazol-6-yl) -L-phenylalanine amide and 27 mg (0.03 mmol) of l, -bis (diphenylphosphine) ferrocenepalladium (II) chloride were taken up under argon in 1.4 ml of 1,2-dimethoxyethane and Stirred for a few minutes at RT. A solution of 82 mg (0.49 mmol) of 2-methyl-6-methoxypyridine-3-boronic acid in 0.54 ml of ethanol was added dropwise to the reaction mixture and the mixture was stirred a further few minutes at RT. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution was stirred for 5 min at RT and irradiated for 1 h at 120 ° C in the microwave. The reaction mixture was mixed with a little methanol, filtered through kieselguhr and a Millipore syringe filter and separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). 81 mg (61% of theory, 94% purity) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.01 min; MS (ES Ineg): m / z = 655 [MH-TFA]. ^" Example 55A

Na / j / ia - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [4-methoxy-2- (4-methylpiperazin-1-yl) pyrimidine 5-yl] - N - [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i tetrazol-5-yl) phenyl] -L-phenylalanine amide, 18.4 mg (0.02 mmol) tetrakis (triphenylphosphine) palladium (0) and 133 mg (0.40 mmol) 4-methoxy-2- (4-methylpiperazin-1-yl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine was taken up in 1.5 ml of 1,2-dimethoxyethane and 0.50 ml of ethanol. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, it was stirred at reflux for 3 hours. From the reaction mixture the salts were filtered off and the filtrate was separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). This gave 126 mg of a mixture of the title compound and the partially deprotected title compound, which was used directly in the next step. LC-MS (Method 1): R _t = 0.81 min; MS (ES Ineg): m / z = 752 [MH-TFA] ^" .

Example 56A

NaI / ia - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [6- (pyridin-3-yloxy) pyridin-3-yl] -N - [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i tetrazol-5-yl) phenyl] -L-phenylalanine amide, 18.4 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) and 86 mg (0.40 mmol) of [6- (pyridin-3-yloxy) pyridin-3-yl Boronic acid was taken up in 1.5 ml of 1,2-dimethoxyethane and 0.50 ml of ethanol. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, it was stirred at reflux for 3 hours. The salts were filtered off from the reaction mixture and the filtrate was separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). This gave 105 mg of a mixture of the title compound and the partially deprotected title compound, which was used directly in the next step.

LC-MS (Method 1): R _t = 1.01 min; MS (ES Ineg): m / z = 716 [MH-TFA]. ^" Example 57A ieri-butyl-4- (4- {4 - [(2 _L s ^, ) -2- {[(ira-A-4] {[(ieri-butoxycarbonyl) amino] methyl] cyclohexyl) carbonyl] -amino] -3-oxo-3- {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propyl] -phenyl} -pyridine 2-yl) piperazine-1-carboxylate trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide, 18.4 mg (0.02 mmol) tetrakis (triphenylphosphine) palladium (0) and 124 mg (0.32 mmol) urei-butyl-4- [4- (4.4.5 5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl] -piperazine-1-carboxylate were taken up in 1.5 ml of 1,2-dimethoxyethane and 0.50 ml of ethanol. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution was stirred at reflux for 5 h. The salts were filtered off from the reaction mixture and the filtrate was separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). The product-containing fractions were freed of acetonitrile on a rotary evaporator and the residue was dried on a lyophilizer. This gave 74 mg of a mixture of the title compound and the partially deprotected title compound, which was used directly in the next step.

LC-MS (Method 1): R _t = 1.01 min; MS (ES Ineg): m / z = 807 [MH-TFA] ^" .

Example 58A ^~ N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [6- (morpholin-4-yl) pyridin-3-yl] -N- [4- (5-oxo-2,5-dihydro-1-pyrazol-3-yl) phenyl] -L-phenylalanine amide trifluoroacetate

123 mg (0.17 mmol) of ieri-butyl-5- [4 - ({4-bromo-N - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -L- phenylalanyl} amino) phenyl] -3-oxo-2,3-dihydro-l / i-pyrazole-1-carboxylate and 27 mg (0.03 mmol) of l, -bis (diphenylphosphine) ferrocenepalladium (II) chloride were added under argon in 1.8 ml of 1,2-dimethoxyethane and stirred for a few minutes at RT. To the reaction mixture was added a solution of 145 mg (0.50 mmol) of 4- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl] morpholine in 0.66 ml Ethanol added dropwise and stirred for a few minutes at RT. After the addition of 1.5 ml of 2N aqueous sodium carbonate solution was stirred for 5 min at RT and irradiated for 1 h at 120 ° C in the microwave. The reaction mixture was mixed with a little methanol, filtered through kieselguhr and a Millipore syringe filter and separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). This gave 99 mg of a mixture of the title compound and the partially deprotected title compound, which was used directly in the next step.

LC-MS (Method 1): R _t = 0.87 min; MS (ES Ineg): m / z = 722 [MH-TFA]. ^" Example 59A

^~ N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [2- (morpholin-4-yl) pyridin-4-yl] -N- [4 - (2 / i-tetrazol-5-yl) phenyl] -L-phenylalaninamide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide, 18.4 mg (0.02 mmol) tetrakis (triphenylphosphine) palladium (0) and 93 mg (0.32 mmol) 4- [4- (4,4,5,5-tetramethyl -l, 3,2-dioxaborolan-2-yl) pyridin-2-yl] morpholine were taken up in 1.5 ml of 1,2-dimethoxyethane and 0.50 ml of ethanol. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, the mixture was stirred at reflux for 4 h and at RT for 7 d. The salts were filtered off from the reaction mixture and the filtrate was separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). This gave 85 mg of a mixture of the title compound and the partially deprotected title compound, which was used directly in the next step.

LC-MS (Method 1): R _t = 0.87 min; MS (ESfneg): m / z = 708 [MH-TFA] ^" .

Example 60A

N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [2- (morpholin-4-yl) pyridin-4-yl] -N- (3 oxo-23-dihydro-l / i-indazol-6-yl) -L-phenylalaninamide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- (3-oxo-2, 3-dihydro-l / i-indazol-6-yl) -L-phenylalanine amide, 12 mg (0.02 mmol) of 1-bis (diphenylphosphine) ferrocene palladium (II) chloride and 94 mg (0.33 mmol) of 4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine -2-yl] morpholine were taken up in 1.5 ml of 1,2-dimethoxyethane and 0.50 ml of ethanol. After addition of 1.2 ml of 2N aqueous sodium carbonate solution, the reaction mixture was irradiated for 1 h at 120 ° C in the microwave, then filtered through kieselguhr and the filtrate separated by preparative HPLC (eluent: acetonitrile / water gradient, 0.1% trifluoroacetic acid) , This gave 85 mg of a mixture of the title compound and the partially deprotected title compound, which was used directly in the next step.

LC-MS (Method 1): R _t = 0.60 min; MS (ES Ineg): m / z = 696 [MH-TFA]. ^" Example 61A

N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (2-methoxypyridin-3-yl) -N- [4- (2-i-tetrazole) 5-yl) phenyl] -L-phenylalanine amide

250 mg (0.40 mmol) 4-bromo-Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide and 46 mg (0.04 mmol) of tetrakis (triphenylphosphine) palladium (0) were taken up under argon in 3.6 ml of 1,2-dimethoxyethane and stirred at RT for 10 min. To the reaction mixture was added dropwise a solution of 281 mg (1.20 mmol) of 2-methoxy-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine in 1.35 ml of ethanol and a further 10 stirred at RT for min. After the addition of 3 ml of 2N aqueous sodium carbonate solution, the mixture was stirred at RT for 5 min and under reflux for 3 h. The reaction mixture was dissolved in a little methanol / acetonitrile, filtered through a Millipore syringe filter and separated by preparative HPLC (eluent: acetonitrile / water gradient). 217 mg (82% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.07 min; MS (ES Ineg): m / z = 653 Example 62A

Na / j / ia - [(i-i-4- {[(ω-butoxycarbonyl) amino] -methyl} cyclohexyl) -carbonyl] -4- (6-methoxypyridin-3-yl) -N- [4- ( 2 / i-tetrazol-5-yl) phenyl] -L-phenylalaninamide

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide and 18 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) were taken up under argon in 1.4 ml of 1,2-dimethoxyethane and stirred at RT for 10 min. A solution of 73 mg (0.48 mmol) of 2-methoxypyridine-5-boronic acid in 0.5 ml of ethanol was added dropwise to the reaction mixture and the mixture was stirred at RT for a further 10 min. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, it was stirred at RT for 5 min and under reflux for 3 h. The reaction mixture was treated with 0.5N aqueous hydrochloric acid solution, the phases were separated and the aqueous phase extracted three times with Essigsäueethylester. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent was removed on a rotary evaporator. The residue was dissolved in a little methanol, filtered through a Millipore syringe filter and separated by preparative HPLC (eluent: acetonitrile / water gradient). 43 mg (41% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.05 min; MS (ESIneg): m / z = 653 [MH] \

Example 63A NaI / ia - [(α-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [5- (methylsulfonyl) pyridin-3-yl] -N - [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide and 18 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) were taken up in 1.5 ml of 1,2-dimethoxyethane under argon and stirred at RT for 10 min. A solution of 96 mg (0.48 mmol) of [5- (methylsulfonyl) pyridin-3-yl] boronic acid in 0.5 ml of ethanol was added dropwise to the reaction mixture. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution was stirred at 100 ° C for 3 h. The reaction mixture was added with 1N aqueous hydrochloric acid solution and filtered from the salts. The filtrate was separated by preparative HPLC (eluent: acetonitrile / water gradient, 0.1% trifluoroacetic acid). 103 mg (51% of theory, 64% purity) of the title compound were obtained.

LC-MS (Method 13): R _t = 2.83 min; MS (ES Ineg): m / z = 701 [MH-TFA] ^" .

Example 64A

N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [4-hydroxy-2- (piperidin-1-yl) pyrimidin-5-yl] -N - [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

H 100 mg (0.11 mmol) of 4- [4- (benzyloxy) -2- (piperidin-1-yl) -pyrimidin-5-yl] -Na / j / ia - [(ira "λ-4- {[(ferric acid) butoxycarbonyl) amino] methyl 1} cyclohexyl) carbonyl 1] -N- [4- (2-i-tetrazol-5-yl) -phenyl] -L-phenylalanine amide trifluoroacetate and 35 mg of palladium 10% on charcoal were added under argon taken up in 45 ml of methanol and hydrogenated at RT under hydrogen normal pressure for 3 h. The reaction mixture was filtered through a Milhspornes syringe filter and concentrated on a rotary evaporator. The residue was taken up in a little methanol and dimethyl sulfoxide and separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). 54 mg (54% of theory, 91% purity) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.95 min; MS (ES Ineg): m / z = 723 [MH-TFA]. ^" Example 65A ieri-butyl-4- (5- {4 - [(2 _L s ^r ) -2- {[(ira-A-4] {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -amino} -3-oxo-3- {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propyl] -phenyl} - 4-methylpyridin-2-yl) -piperazine-1-carboxylate trifluoroacetate

150 mg (0.24 mmol) 4-bromo-Na / j / ia - [(1α-ε-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide, 193 mg (0.48 mmol) of ieri-butyl-4- [4-methyl-5- (4,4,5,5-tetramethyl-1, 3.2 dioxaborolan-2-yl) pyridin-2-yl] piperazine-1-carboxylate and 18 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) were taken up in 2 ml of 1,2-dimethoxyethane and 1 ml of ethanol. After the addition of 1.5 ml of 2N aqueous sodium carbonate solution, the mixture was stirred at 100 ° C. for 4 h and at RT for 16 h. The reaction mixture was filtered from the salts. The filtrate was separated by preparative HPLC (eluent: acetonitrile / water gradient, 0.1% trifluoroacetic acid). This gave 153 mg of a mixture of the title compound and the partially deprotected title compound, which was used directly in the next step. LC-MS (Method 1): R _t = 1.06 min; MS (ES Ineg): m / z = 821 [MH-TFA] ^" .

Example 66A

N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (2-efhoxypyridin-3-yl) -N- [4- (2-i-tetrazole) 5-yl) phenyl] -L-phenylalanine amide

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide and 18 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) were taken up under argon in 1.4 ml of 1,2-dimethoxyethane and stirred at RT for 10 min. A solution of 80 mg (0.48 mmol) of 2-ethoxypyridine-3-boronic acid in 0.5 ml of ethanol was added dropwise to the reaction mixture and the mixture was stirred at RT for a further 10 min. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, it was stirred at RT for 5 min and under reflux for 3 h. The reaction mixture was treated with 0.5N aqueous hydrochloric acid solution, the phases were separated and the aqueous phase extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and the solvent was removed on a rotary evaporator. The residue was dissolved in a little methanol, filtered through a Millipore syringe filter and separated by preparative HPLC (eluent: acetonitrile / water gradient). The product-containing fractions were concentrated and the residue was stirred with a little acetonitrile. 31 mg (28% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.11 min; MS (ES Ineg): m / z = 667 Example 67A

N-a / j / ia - [(i-i-4- {[(tert-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [3-cM

(morpholin-4-yl) pyridin-4-yl] - N - [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide, 104 mg (0.32 mmol) of 4- [3-chloro-4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) yl) pyridin-2-yl] morpholine and 12 mg (0.02 mmol) of 1-bis (diphenylphosphine) ferrocenepalladium (II) chloride were stirred in 1.5 ml of 1,2-dimethoxyethane and 0.5 ml of ethanol. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution was stirred at 100 ° C for 4 h. The reaction mixture was filtered. The filtrate was again filtered through a Millipores syringe filter and separated by preparative HPLC (eluent: acetonitrile / water gradient, 0.1% trifluoroacetic acid). This gave 74 mg of a mixture of the title compound and the partially deprotected title compound, which was used directly in the next step. LC-MS (Method 1): R _t = 1.07 min; MS (ES Ineg): m / z = 742 [MH-TFA] ^" .

Example 68A

Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -3-fluoro-4- [6- (morpholin-4-yl) pyridine-3-yl] yl] - N - [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -3-fluoro-N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide and 18 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) were taken up under argon in 1.5 ml of 1,2-dimethoxyethane and stirred at RT for 10 min , To the reaction mixture was added a solution of 135 mg (0.47 mmol) of 4- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl] morpholine in 0.5 ml Ethanol was added dropwise and stirred for a further 10 min at RT. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, it was stirred at RT for 5 min and under reflux for 3 h. The reaction mixture was mixed with a little methanol, filtered through a Millipore syringe filter and separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). 80 mg (57% of theory, 93% purity) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.98 min; MS (ES Ineg): m / z = 726 [MH-TFA]. ^" Example 69A N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- {6- [3- (dimethylamino) propoxy] pyridin-3-yl} -3-fluoro-N- [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -3-fluoro-N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide and 18 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0) were taken up under argon in 1.5 ml of 1,2-dimethoxyethane and stirred at RT for 10 min , A solution of 143 mg (0.47 mmol) of 2- (3-N, N-dimethylaminopropoxy) pyridine-5-boronic acid pinacol ester in 0.5 ml of ethanol was added dropwise to the reaction mixture and the mixture was stirred at RT for a further 10 min. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution, it was stirred at RT for 5 min and under reflux for 3 h. The reaction mixture was mixed with a little water, filtered through a Millipores syringe filter and separated by preparative HPLC (mobile phase: acetonitrile / water gradient, 0.1% trifluoroacetic acid). This gave 74 mg of a mixture of the title compound and the partially deprotected title compound, which was used directly in the next step.

LC-MS (Method 2): R _t = 1.92 min; MS (ES Ineg): m / z = 742 [MH-TFA]. ^" Example 70A

Na / j / ia - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [3-fluoro-2- (morpholin-4-yl) pyridine-4- yl] - N - [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

100 mg (0.16 mmol) of 4-bromo-Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) carbonyl] -N- [4- (1 / i tetrazol-5-yl) phenyl] -L-phenylalanine amide, 98 mg (0.32 mmol) of 4- [3-fluoro-4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) yl) pyridin-2-yl] morpholine and 12 mg (0.02 mmol) of 1-bis (diphenylphosphine) ferrocenepalladium (II) chloride were taken up in 1.5 ml of 1,2-dimethoxyethane and 0.5 ml of ethanol. After the addition of 1.2 ml of 2N aqueous sodium carbonate solution was stirred at 100 ° C for 4 h. The reaction mixture was filtered from the salts. The filtrate was filtered through a Millipore syringe filter and separated by preparative HPLC (eluent: acetonitrile / water gradient, 0.1% trifluoroacetic acid). This gave 60 mg of a mixture of the title compound and the partially deprotected title compound, which was used directly in the next step.

LC-MS (Method 1): R _t = 1.05 min; MS (ES Ineg): m / z = 726 [MH-TFA] ^" .

Example 71 A ieri-butyl-4- (5- {4 - [(2 _l ^r S) -2- {[(ira "Ä-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) - carbonyl] amino} -3- {[3-fluoro-4- (2 / i-tetrazol-5-yl) phenyl] amino} -3-oxopropyl] phenyl} -4-methylpyridin-2-yl) piperazine-1-carboxylate

To a solution of 150 mg (0.23 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} cyclohexyl) -carbonyl] -N- [3 fluoro-4- (2-i-tetrazol-5-yl) -phenyl] -L-phenylalanine amide and 148.2 mg (0.35 mmol) of iperi-butyl-4- [4-methyl-5- (4,4,5,5-) tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl] -piperazine-1-carboxylate in 2 ml of DMSO were added 26.9 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0), 74.0 mg (0.7 mmol ) Sodium carbonate and 0.35 ml (19.5 mmol) of water. The mixture was microwave-treated at 110 ° C for 90 minutes. The batch was filtered and purified by preparative HPLC (Method 11). 82 mg (42% of theory) of the title compound were obtained. LC-MS (Method 5): R _t = 1.01 min; MS (ESIpos): m / z = 841.6 [M + H] ⁺ .

Example 72A ieri-butyl-4- (5- {4 - [(2 _l ^r S) -2- {[(ira "Ä-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) - carbonyl] amino } -3- {[4- (3-chloro-4-yl, 2,4-triazol-5-yl) -phenyl] -amino} -3-oxopropyl] -phenyl} -4-methyl-pyridin-2-yl) -piperazine-1 carboxylate

A solution of 150 mg (0.23 mmol) 4-bromo-Na / j / ia - [(1α-ε-4- {[(fer-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (3 -chloro-4 / il, 2,4-triazol-5-yl) -phenyl] -L-phenylalanine amide and 144.7 mg (0.34 mmol) of ieri-butyl-4- [4-methyl-5- (4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl] -piperazine-1-carboxylate in 2 ml of DMSO was treated with 26.3 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (0), 72.3 mg (0.68 mmol) of sodium carbonate and 0.34 ml (19.0 mmol) of water. The mixture was microwave-treated at 110 ° C for 90 minutes. It became 1 eq. ieri-butyl-4- [4-methyl-5- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) pyridin-2-yl] -piperazine-1-carboxylate and 0.1 eq , Added tetrakis (triphenylphosphine) palladium (0) and in the microwave for 1 h at 110 ° C. The batch was filtered and purified by preparative HPLC (Method 11). 51 mg (26% of theory) of the title compound were obtained.

LC-MS (Method 5): R _t = 1.01 min; MS (ESIpos): m / z = 856.5 [M + H] ⁺ . Example 73A 4- (5-Aniinopyridin-3-yl) -Na / j / ia - [(1α-ε-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) -carbonyl 1] -N- [4 - (1 / i-tetrazol-5-yl) phenyl 1] -L-phenylalanine amide formate

A solution of 150 mg (0.24 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -N- [4- ( l / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide and 79.0 mg (0.36 mmol) of 5- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) pyridine. 3-Amine in 1.8 ml DMSO was treated with 27.7 mg (23.9 μηιοΐ) of tetrakis (triphenylphosphine) palladium (0), 76.1 mg (0.72 mmol) of sodium carbonate and 0.36 ml (20.0 mmol) of water. The mixture was microwaved for 2.5 h at 110 ° C. The batch was filtered and purified by preparative HPLC (Method 10). 11 mg (7% of theory) of the title compound were obtained.

LC-MS (Method 4): R _t = 0.89 min; MS (ESIpos): m / z = 640.4 [M + H-HCOOH] ⁺ . Example 74A

N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] - N - [4- (1-i-tetrazol-5-yl) -phenyl] -4- [2- (trifluoromethyl) pyridin-3-yl] -L-phenylalaninamide formate

A solution of 150 mg (0.24 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -N- [4- ( l / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide and 98.1 mg (0.36 mmol) of 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2- (trifluoromethyl) pyridine in 1.8 ml of dimethylformamide were mixed with 27.7 mg (23.9 μηιοΐ) of tetrakis ( triphenylphosphine) palladium (0), 76.1 mg (0.72 mmol) of sodium carbonate and 0.36 ml (20.0 mmol) of water. The mixture was microwaved for 2.5 h at 110 ° C. It became 1 eq. Added 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2- (trifluoromethyl) pyridine and microwaved at 110 ° C for 2 h. The batch was filtered and purified by preparative HPLC (Method 9). 25 mg (15% of theory) of the title compound were obtained.

LC-MS (Method 4): R _t = 1.18 min; MS (ESIpos): m / z = 693.5 [M + H-HCOOH] ⁺ . Example 75A 4- (6-Anilino-2-methylpyridin-3-yl) -Na / j / ia - [(iraM5-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl-1) -carbonyl 1] -N - [4- (1-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide formate

To a solution of 150 mg (0.24 mmol) 4-bromo-Na / j / ia - [(1α-ε-4- {[(ieri-butoxycarbonyl) -amino] -methyl} cyclohexyl) -carbonyl] -N- [4- (l / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide and 84.1 mg (0.36 mmol) of 6-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl) pyridin-2-amine in 1.8 ml of DMSO were added 27.7 mg (23.9 μηιοΐ) of tetrakis (triphenylphosphine) palladium (0), 76.1 mg (0.72 mmol) of sodium carbonate and 0.36 ml (20 mmol) of water. The mixture was microwaved for 2.5 h at 110 ° C. The batch was filtered and purified by preparative HPLC (Method 10). 19 mg (12% of theory) of the title compound were obtained. LC-MS (Method 4): R _t = 0.91 min; MS (ESIpos): m / z = 654.5 [M + H-HCOOH] Example 76A ieri-butyl-4- {[(5- {4 - [(2S) -2- {[(trans-A- {[(feri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl 1] amino} - 3 -oxo-3 - {[4- (1-i-tetrazol-5-yl) -phenyl] -amino} -propyl] -phenyl-pyridin-3-yl-sulfonyl-amino-1-piperidine-1-carboxylate

To a solution of 200 mg (0.3 mmol) of Na / j / ia - [(1α-ε-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -4- (4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) - N - [4- (1-i-tetrazol-5-yl) -phenyl] -L-phenylalanine amide and 149.8 mg (0.36 mmol) of ieri-butyl 4- {[(5-Bromopyridine-3-yl) sulfonyl] amino] piperidine-1-carboxylate in 2 ml of DMSO was added under argon 34.3 mg (29.7 μηιοΐ) of tetrakis (triphenylphosphine) palladium (0), 157.3 mg (1.48 mmol) Sodium carbonate and 0.45 ml (24.8 mmol) of water. The mixture was microwaved for 2.5 h at 110 ° C. The batch was filtered and purified by preparative HPLC (Method 11). 63 mg (24% of theory) of the title compound were obtained.

LC-MS (Method 5): R _t = 0.87 min; MS (ESIpos): m / z = 887.6 [M + H] ⁺ . Example 77A

N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [2- (4-methylpiperazin-1-yl) pyridin-4-yl] -N - [4- (l / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide formate

A solution of 150 mg (0.24 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -N- [4- ( l / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide and 108.9 mg (0.36 mmol) of 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl) pyridin-2-yl] piperazine in 1.8 ml of DMSO were treated with 27.7 mg (23.9 μηιοΐ) of tetrakis (triphenylphosphine) palladium (0), 76.1 mg (0.72 mmol) of sodium carbonate and 0.36 ml (20.0 mmol) of water. The mixture was microwaved for 2.5 h at 110 ° C. The batch was filtered and purified by preparative HPLC (Method 10). 23 mg (13% of theory) of the title compound were obtained.

LC-MS (Method 5): R _t = 0.87 min; MS (ESIpos): m / z = 887.6 [M + H-HCOOH] ⁺ . Example 78A

N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [6- (4-methylpiperazin-1-yl) pyridin-3-yl] - N- [4- (1-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide formate

A solution of 150 mg (0.24 mmol) of 4-bromo-Na / j / ia - [(1α-α-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -N- [4- ( l / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide and 108.9 mg (0.36 mmol) of l-methyl-4- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl) pyridin-2-yl] piperazine in 1.8 ml of DMSO were treated with 27.7 mg (23.9 μηιοΐ) of tetrakis (triphenylphosphine) palladium (0), 76.1 mg (0.72 mmol) of sodium carbonate and 0.36 ml (20.0 mmol) of water. The mixture was microwaved for 2.5 h at 110 ° C. The batch was filtered and purified by preparative HPLC (Method 10). 49 mg (28% of theory) of the title compound were obtained.

LC-MS (Method 4): R _t = 0.89 min; MS (ESIpos): m / z = 723.6 [M + H-HCOOH] ⁺ . Example 79A

4- (2-Aniino-4-methylpyrimidin-5-yl) -Na / j / ia - [(ira "5-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexy-1) -carbonyl 1] -N - [4- (1-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide

A solution of 200 mg (0.3 mmol) of Na / j / ia - [(1α-ε-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -4- (4,4,5,5 -tetramethyl-l, 3,2-dioxaborolan-2-yl) -N- [4- (1-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide and 67.0 mg (0.36 mmol) 5-bromo-4 -methylpyrimidin-2-amine in 2 ml DMSO were mixed with 34.3 mg (29.7 μηιοΐ) tetrakis (triphenylphosphine) palladium (0), 157.3 mg (1.48 mmol) of sodium carbonate and 0.45 ml (24.8 mmol) of water. The mixture was microwaved for 2.5 h at 110 ° C. It was 24.2 mg (26.7 μηιοΐ) 1, 1'-bis (diphenylphosphine) ferrocenpalladium (II) chloride added and treated for 60 min at 110 ° C in the microwave. The batch was filtered and purified by preparative HPLC (Method 11). 11 mg (6% of theory) of the title compound were obtained. LC-MS (Method 5): R _t = 0.73 min; MS (ESIpos): m / z = 655.5 [M + H] ⁺ .

Example 80A

N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -N- [4- (3-chloro-4-yl, 2,4-triazole-5- yl) phenyl] -4- {6- [3- (dimethylamino) propoxy] pyridin-3-yl} -L-phenylalanine amide

formate

A solution of 150 mg (0.23 mmol) 4-bromo-Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -N- [4- ( 3-chloro-4 / i-1, 2,4-triazol-5-yl) phenyl] -L-phenylalanine amide and 104.4 mg (0.34 mmol) N, N-dimethyl-3- {[5- (4.4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl] oxy} propan-1-amine in 2 ml of DMSO was treated with 26.3 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (O), 72.3 mg (0.68 mmol) of sodium carbonate and 0.34 ml (19.0 mmol) of water. The mixture was microwave-treated at 110 ° C for 90 minutes. It became 1 eq. N, N-dimethyl-3- {[5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl] oxy} propan-1-amine and 0.1 eq. Tetrakis (triphenylphosphine) palladium (0) added and treated for 1 h at 110 ° C in the microwave. The batch was filtered and purified by preparative HPLC (Method 10). 38 mg (22% of theory) of the title compound were obtained. LC-MS (Method 4): R _t = 0.99 min; MS (ESIpos): m / z = 759.5 [M + H-HCOOH] ⁺ . Example 81A

N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (4-methylpyridin-3-yl) -N- [4- (2-i) tetrazol-5-yl) phenyl] -L-phenylalaninamide

A solution of 150 mg (0.24 mmol) 4-bromo-Na / j / ia - [(1α-ε-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -N- [4- ( l / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide and 49.2 mg (0.36 mmol) of (4-methylpyridin-3-yl) boronic acid in 2.5 ml of dimethylformamide were treated with 0.36 ml (0.72 mmol) of 2M sodium carbonate solution in Added water and degassed with argon for 5 min. 17.5 mg (24 μηιοΐ) of l, r-bis (diphenylphosphine) ferrocenpalladium (II) chloride was added and the mixture was stirred for 2 h at 120 ° C in a preheated oil bath. The mixture was filtered through kieselguhr and washed with ethyl acetate. The filtrate was diluted with ethyl acetate and water, acidified with 10% citric acid, the phases separated and the aqueous phase washed with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was stirred with dichloromethane, the solid was filtered off and dried under high vacuum. 60 mg (38% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.80 min; MS (ESIpos): m / z = 639 [M + H] ⁺ . Example 82A 4- [4- (Benzyloxy) -2- (piperidin-1-yl) -pyrimidin-5-yl] -Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) -amino ] methyl} cyclohexyl) carbonyl] - N - [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate

200 mg (0.32 mmol) 4-bromo-Na / j / ia - [(1α-ε-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide and 37 mg (0.03 mmol) of tetrakis (triphenylphosphine) palladium (0) were taken up under argon in 2.9 ml of 1,2-dimethoxyethane and stirred at RT for 10 min. A solution of 300 mg (0.96 mmol) of 4-benzyloxy-2-piperidin-1-yl-pyrimidine-5-boronic acid in 1.1 ml of ethanol was added dropwise to the reaction mixture and the mixture was stirred at RT for a further 10 min. After the addition of 2.4 ml of 2N aqueous sodium carbonate solution, the mixture was stirred at RT for 5 min and under reflux for 3 h. The reaction mixture was mixed with a little methanol, filtered through a Milhspornes syringe filter and separated by preparative HPLC (eluent: acetonitrile / water gradient, 0.1% trifluoroacetic acid). This gave 194 mg of a mixture of the title compound and the partially deprotected title compound, which was used directly in the next step.

LC-MS (Method 1): R _t = 1.26 min; MS (ESfneg): m / z = 814 [MH-TFA] ^" .

Example 83A Methyl 3- {5- [4- ({4-biom-N - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -L-phenylalanyl} amino) phenyl] - IH-l, 2,4-triazol-3-yl} -2,2,3,3-tetrafluoropropanoate

1500 mg (3.1 mmol) of 4-bromo-A ^r - [(1α-ε-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) -carbonyl] -L-phenylalanine and 1185 mg (3.7 mmol) of methyl 3- [5- (4-Amino-phenyl) -l-il, 2,4-triazol-3-yl] -2,2,3,3-tetrafluoropropanoate were dissolved in 10 ml of pyridine and washed with 7.2 ml (50% in DMF , 12.4 mmol) of 2,4,6-tripropyl-l, 3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide and stirred at 85 ° C for 5 h. Water was added and the pyridine removed in vacuo. The residue was treated with dilute ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulphate and in vacuo. The residue was purified by chromatography (silica gel, eluent: dichloromethane / methanol = 10/1). 1675 mg (63% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-ife): δ = ppm 0.82 (m, 2H), 1.05-1.30 (m, 3H), 1.36 (s, 9H), 1.53-1.60 (m, 1H), 1.68 (m, 3H), 2.03-2.14 (m, 1H), 2.70-2.78 (m, 2H), 2.80-2.91 (m, 1H), 2.97-3.09 (m, 1H), 3.95 ( s, 2H), 4.57-4.72 (m, 1H), 6.72-6.82 (m, 1H), 7.26 (d, 2H), 7.48 (d, 2H), 7.73-7.81 (m, 2H ), 7.96 (d, 2H), 8.15 (d, 1H), 10.44 (s, 1H), 15.19 (br. S, 1H).

LC-MS (Method 1): R _t = 1.23 min; MS (ESIpos): m / z = 785.4 [M + H] ⁺ .

Example 84A

Methyl-2,2,3,3-tetrafluoro-3- [5- (4-nitrophenyl) -l / il, 2,4-triazol-3-yl] propanoate

30.3 g (90.8 mmol) of 2,2,3,3-tetrafluoro-3- [5- (4-nitrophenyl) -1 / il, 2,4-triazol-3-yl] propanoic acid was dissolved in 500 ml of methanol and washed with Added 3 ml of concentrated sulfuric acid. The mixture was stirred at 65 ° C. for 22 h. Then 5 ml of concentrated sulfuric acid were added and stirred again at 65 ° C for 22 h. It was added at RT sodium bicarbonate to pH = 7, filtered and the solvent removed in vacuo. The residue was stirred in pertrol ether and diethyl ether and then filtered. 31.6 g (77% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.96 min; MS (ESIpos): m / z = 349.1 [M + H] ⁺ .

Example 85A Methyl 3- [5- (4-aminophenyl) -l / i-l, 2,4-triazol-3-yl] -2,2,3,3-tetrafluoropropanoate

24.0 g (68.9 mmol) of methyl 2,2,3,3-tetrafluoro-3- [5- (4-nitrophenyl) -1 / il, 2,4-triazol-3-yl] propanoate was initially charged in 370 ml of THF and under argon atmosphere with Pd / C (10%, 50% water wet). It was hydrogenated at RT for 18 h with hydrogen (1 bar). It was filtered through kieselguhr and washed with dichloromethane / methanol 9: 1. The filtrate was concentrated and the residue was dried in vacuo. 21.7 g (99% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.78 min; MS (ESIpos): m / z = 319.1 [M + H] ⁺ . Example 86A

3- {5- [4 - ({A ^r - [(ω-γ-4- {[(ω-butoxycarbonyl) -arano] -methyl} -cyclohexyl) -carbonyl] -4- [2- (morpholin-4-yl) -pyrimidine -5-yl] -L-phenylalanyl} amino) phenyl] - IH-l, 2,4-triazol-3-yl} -2,2,3,3-tetrafluoropropanoic acid

125 mg (0.16 mmol) of methyl 3- {5- [4 - ({4-bromo-A ^r - [(ira-A-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] - L-phenylalanyl} amino) phenyl] -1 H -1, 2,4-triazol-3-yl} -2,2,3,3-tetrafluoropropanoate and 93 mg (0.32 mmol) of 4- [5- (4 , 4,5,5-Tetramethyl-l, 3,2-dioxaborolan-2-yl) pyrimidin-2-yl] morpholine were dissolved in 1.3 ml of dimethylformamide and mixed with 0.16 ml (0.32 mmol) 2 M sodium carbonate solution and degassed. After adding 12 mg (0.02 mmol) of 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) chloride, the reaction mixture was stirred at 120 ° C. for 30 min. The reaction solution was filtered through a Millipore syringe filter and purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% trifluoroacetic acid (gradient)). 72 mg (51% of theory) of the title compound were obtained. LC-MS (Method 1): R _t = 0.95 min; MS (ESIpos): m / z = 854.5 [M + H] ⁺ .

embodiments

example 1

N-alpha- [[iraws-4- (aminomethyl) cyclohexyl] carbonyl} -4- [2- (morpholin-4-yl) pyrimidin-5-yl] - N - [4- (1-i-tetrazole-5 -yl) phenyl] -L-phenylalanine amide hydrochloride

A suspension of 28 mg (0.04 mmol) Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -4- [2- (morpholine-4- yl) pyrimidin-5-yl] - N - [4- (1-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide formate in 2 ml of 1,4-dioxane was mixed with 0.07 ml (0.27 mmol) 4M hydrogen chloride in 1,4-dioxane and stirred overnight at RT. After addition of another 0.06 ml (0.24 mmol) 4M hydrogen chloride in 1,4-dioxane was stirred at 40 ° C for 20 h. The reaction mixture was mixed with 5 ml of acetonitrile and the resulting precipitate was filtered off with suction and dried under high vacuum. 19 mg (67% of theory) of the title compound were obtained.

^: H NMR (300 MHz, DMSO-d ₆ ): δ = ppm 0.78-0.97 (m, 2H), 1.05-1.33 (m, 2H), 1.34-1.49 (m, 1H), 1.51-1.61 (m, 1H), 1.65-1.78 (m, 3H), 2.05-2.17 (m, 1H), 2.56-2.64 (m, 2H), 2.82-2.93 (m, 1H), 3.02-3.11 (m, 1H), 3.64 (m, 4H), 3.67 - 3.74 (m, 4H), 4.60 - 4.73 (m, 1H), 7.37 (d, 2H), 7.53 (d, 2H) , 7.69 - 7.77 (m, 2H), 7.80 (d, 2H), 7.98 (d, 2H), 8.22 (d, 1H), 8.68 (s, 2H), 10.53 (s, 1H) ,

LC-MS (Method 4): R _t = 0.80 min; MS (ESIpos): m / z = 611 [M + H-HC1] ⁺ .

EXAMPLE 2 ^~ N-alpha- {[iraws-4- (Aminomefhyl) cyclohexyl] carbonyl} -4- {5- [(4-methylpiperazin-1-yl) - sulfonyl] pyridin-3-yl} -N- [4 - (l / f-tetrazol-5-yl) phenyl] -L-phenylalanine amide hydrochloride

A suspension of 111 mg (0.14 mmol) Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -4- {5 - [(4-methylpiperazine -l-yl) sulfonyl] pyridin-3-yl} -N- [4- (1-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide formate in 4.0 ml of 1,4-dioxane was mixed with 0.35 ml (1.4 mmol) 4M hydrogen chloride in 1,4-dioxane and stirred overnight at RT and then at 40 ° C for 1 h. Subsequently, the reaction mixture was mixed with 5 ml of acetonitrile, the resulting precipitate was filtered off with suction and dried under high vacuum. 106 mg (97% of theory) of the title compound were obtained.

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.81-0.95 (m, 2H), 1.10-1.29 (m, 2H), 1.39-1.50 (m, 1H), 1.53-1.60 (m, 1H), 1.66 - 1.78 (m, 3H), 2.07 - 2.17 (m, 1H), 2.55 - 2.62 (m, 2H), 2.71 (s, 3H), 2.75 - 2.85 (m , 2H), 2.94 (dd, 1H), 3.07 - 3.19 (m, 3H), 3.39 - 3.47 (m, 2H), 4.66 - 4.75 (m, 1H), 7.49 (d, 2H) , 7.80 (m, 8H), 7.99 (d, 2H), 8.28 (d, 1H), 8.31 (dd, 1H), 8.91 (d, 1H), 9.24 (d, 1H), 10.61 (s, 1H), 10.68 - 10.82 (m, 1H).

LC-MS (Method 4): R _t = 0.6 min; MS (ESIpos): m / z = 687 [M + H-HC1] ⁺ . Example 3

Na / ia- {[ira-Ä- 4- (aminomethyl) cyclohexyl] carbonyl} -4- (2-chloropyridin-3-yl) -N- [4- (1-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide hydrochloride

A suspension of 31 mg (0.05 mmol) of N-a / j / ia - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -4- (2-chloro)

Alaninamide formate in 1.5 ml of 1,4-dioxane was treated with 0.08 ml (0.33 mmol) of 4M hydrogen chloride in 1,4-dioxane and stirred overnight at RT. Subsequently, the reaction mixture was mixed with 5 ml of acetonitrile, the resulting precipitate was filtered off with suction and dried under high vacuum. 25 mg (87% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.76-0.96 (m, 2H), 1.07-1.27 (m, 2H), 1.36-1.49 (m, 1H), 1.50- 1.58 ( m, 1H), 1.65-1.78 (m, 3H), 2.06-2.16 (m, 1H), 2.56-2.62 (m, 2H), 2.92 (dd, 1H), 3.12 (dd, 1H) , 7.68 (m, 1H), 7.69-7.84 (m, 6H), d, 1H), 8.36 - 8.41 (m, 1H), 10.54 (s, 1H).

LC-MS (Method 4): R _t = 0.77 min; MS (ESIpos): m / z = 559.4 [M + H-HC1] ⁺ .

Example 4

^~ N-alpha- {[iraws-4- (Aminomefhyl) cyclohexyl] carbonyl} -4- [6- (dimethylamino) pyridin-3-yl] -N- [4- (l / i-tetrazol-5-yl) phenyl] -L-phenylalaninamide hydrochloride

x HCl

A suspension of 47 mg (0.11 mmol) of N-a / j / ia - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -4- [6- (dimem ^

 L-phenylalanine amide formate in 1.5 ml of dichloromethane was treated with 0.09 ml (0.35 mmol) of 4M hydrogen chloride in 1,4-dioxane and stirred at RT overnight. Subsequently, the reaction mixture was mixed with 5 ml of acetonitrile, the resulting precipitate was filtered off with suction and dried under high vacuum. The residue was purified by chromatography via HPLC (Method 7). 2 mg (5% of theory) of the title compound were obtained.

^: H NMR (500 MHz, DMSO-d ₆ ): δ = ppm 0.81-0.93 (m, 2H), 1.12-1.30 (m, 2H), 1.54-1.65 (m, 1H), 1.69-1.78 (m, 3H), 2.10-2.16 (m, 1H), 2.55-2.58 (m, 2H), 2.88 (dd, 1H), 3.04 (s, 6H), 3.07 (dd, 1H) , 4.64 - 4.72 (m, 1H), 6.69 (d, 1H), 7.33 (d, 2H), 7.51 (d, 2H), 7.59 (d, 2H), 7.77 - 7.81 (m, 1 H), 7.89 (d, 2H), 8.10 (d, 1H), 8.33-8.38 (m, 1H), 8.40 (d, 1H), 10.10 (s, 1H).

LC-MS (Method 4): R _t = 0.60 min; MS (ESIpos): m / z = 568.3 [M + H-HC1] ⁺

Example 5 NaI / ia- {[Ira «A-4- (Aminomethyl) cyclohexyl] carbonyl} -4-pyridin-3-yl-N- [4- (2-i-tetrazol-5-yl) phenyl] phenylalanine amide

A solution of 100 mg (0.16 mmol) 4-bromo-Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) -amino] -methyl} cyclohexyl) -carbonyl] -N- [4- ( l / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide in 1.4 ml of 1,2-dimethoxyethane was treated with 18.4 mg (0.02 mmol) of tetrakis (triphenylphosphine) palladium (O) and stirred at RT for 10 min A solution of 59 mg (0.48 mmol) of pyridine-3-boronic acid was added dropwise and the mixture was stirred at RT for a further 10 min After addition of 1.2 ml of a 2N aqueous sodium carbonate solution, the reaction mixture was stirred at reflux for 3 h The reaction mixture was treated with a few milliliters of 0.5N Hydrochloric acid solution, the phases were separated and the aqueous phase was extracted three times with ethyl acetate The organic phases were combined and washed with saturated aqueous sodium chloride solution The combined aqueous phases were concentrated on a rotary evaporator The residue was dissolved in a little DMSO and methanol filtered through a Millipore syringe filter and mi separated by preparative HPLC (mobile phase: acetonitrile / water gradient). The product-containing fractions were combined and the solution was concentrated on a rotary evaporator. The residue was recrystallized from acetonitrile to give 16 mg (19% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.84-1.00 (m, 2H), 1.13-1.33 (m, 2H), 1.40-1.65 (m, 2H), 1.68-1.82 (m, 3H 2.10-2.20 (m, 1H), 2.5 (d, 2H), 2.93 (dd, 1H), 3.13 (dd, 1H), 4.68-4.77 (m, 1H), 7.41-7.50 (m, 3H), 7.58-7.71 (m, 6H), 7.91 (d, 2H), 8.06 (d, 1H), 8.16 (d, 1H), 8.55 (d, 1H), 8.88 (s, 1H), 10.16 (s, 1H) , LC-MS (Method 1): R _t = 0.57 min; MS (ESIneg): m / z = 523 [MH] \

Analogously to the following general procedure (AAV 1), the compounds of Examples 6 to 36 and 40 and 41 were synthesized:

0.03-0.5 mmol of the starting compounds from Example 6A to Example 36A and Example 40A and Example 41A were initially charged in 1,4-dioxane (2.0-6.7 ml / 0.1 mmol starting compound). After the addition of 10-40 equivalents of 4M hydrogen chloride in 1,4-dioxane was 4 h to 14 d at RT touched. The precipitated solid was filtered off, washed with 1,4-dioxane or acetonitrile and then dried under high vacuum.

Example 6

N-alpha- [[iraws-4- (aminomethyl) cyclohexyl] carbonyl} -4- {6- [3- (dimethylamino) propoxy] -pyridin-3-yl} -N- [4- (2-i-tetrazole -5-yl) phenyl] -L-phenylalaninamide hydrochloride

Starting compound: Na / i / a - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- {6- [3- (dimethylamino) propoxy] pyridine-3- yl} - N - [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate (64 mg, 0.088 mmol), dioxane (2 ml), 4M hydrogen chloride in 1,4-dioxane ( 0.33 ml, 1.3 mmol), yield: 55 mg (89% of theory).

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.85-1.00 (m, 2H), 1.13-1.33 (m, 2H), 1.41-1.66 (m, 2H), 1.70-1.82 (m, 3H), 2.10-2.20 (m, 3H), 2.59-2.68 (m, 2H), 2.78 (s, 3H), 2.79 (s, 3H), 2.90-2.99 (m, IH), 3.08-3.25 (m, 3H), 4.36 (t, 2H), 4.66-4.75 (m, IH), 6.89 (d, IH), 7.40 (d, 2H), 7.59 (d, 2H), 7.79-7.92 (m, 5H), 7.98 -8.04 (m, 3H), 8.26 (d, IH), 8.46 (d, IH), 10.22 (bs, IH), 10.58 (s, IH).

LC-MS (Method 1): R _t = 0.59 min; MS (ES Ineg): m / z = 624 [MH-HC1] \

Example 7

^~ N-alpha- {[iraws-4- (Aminomefhyl) cyclohexyl] carbonyl} -4- [6- (morpholin-4-yl) pyridin-3-yl] -N- [4- (2 / i-tetrazol- 5 -yl) phenyl] -L-phenylalanine amide hydrochloride

Starting compound: Na / j / ia - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [6- (morpholin-4-yl) pyridin-3-yl ] -N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate (118 mg, 0.17 mmol), dioxane (3.5 mL), 4M hydrogen chloride in 1,4-dioxane (0.62 ml, 2.5 mmol), yield: 110 mg (94% of theory).

^: H NMR (400 MHz, DMSO-de): δ = ppm 0.86-1.00 (m, 2H), 1.13-1.34 (m, 2H), 1.42-1.65 (m, 2H), 1.70-1.82 (m, 3H ), 2.10-2.21 (m, IH), 2.57-2.70 (m, 2H), 2.95 (dd, IH), 3.14 (dd, IH), 3.60- 3.70 (m, 4H), 3.73-3.79 (m, 4H ), 4.68-4.76 (m, IH), 7.25-7.39 (m, IH), 7.44 (d, 2H), 7.63 (d, 2H), 7.80-7.99 (m, 5H), 8.03 (d, 2H), 8.17-8.32 (m, 3H), 10.63 (s, IH). LC-MS (Method 1): R _t = 0.65 min; MS (ES Ineg): m / z = 608 [MH-HC1] \

Example 8

^~ N-alpha- {[iraws-4- (Aminomefhyl) cyclohexyl] carbonyl} -N- [4- (5-oxo-4,5-dihydro-1, 2,4-oxadiazol-3-yl) phenyl] - 4-pyridin-4-yl-L-phenylalanine amide hydrochloride

Starting compound: Na / j / ia - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -N- [4- (5-oxo-4,5-dihydroxy) 1, 2,4-oxadiazol-3-yl) phenyl] -4-pyridin-4-yl-L-phenylalanine amide (36.5 mg, 0.057 mmol), dioxane (2 ml), 4M hydrogen chloride in 1,4-dioxane (0.14 ml, 0.57 mmol), yield: 40 mg (quant.). ^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.84-1.00 (m, 2H), 1.10-1.32 (m, 2H), 1.40-1.62 (m, 2H), 1.67-1.82 (m, 3H), 2.09-2.20 (m, IH), 2.57-2.68 (m, 2H), 3.01 (dd, IH), 3.21 (dd, IH), 4.71-4.80 (m, IH), 7.59 (d, 2H) , 7.75-8.05 (m, 8H), 8.25-8.39 (m, 3H), 8.83-8.96 (m, 2H), 10.70 (s, IH), 12.98 (bs, IH).

LC-MS (Method 1): R _t = 0.56 min; MS (ES Ineg): m / z = 539 [MH-HC1] \ Example 9

Ή-alpha- {[iraws-4- (aminomethyl) cyclohexyl] carbonyl} -4- {6- [(2RS, 6SR) -2,6-dimethylmorpholin-4-yl] pyridin-3-yl} -N- [ 4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide hydrochloride

Starting compound: Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- {6 - [(2R5,65R) -2,6-dimethylmorpholine -4-yl] pyridin-3-yl} -N- [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate (100 mg, 0.14 mmol), dioxane (3 ml), 4M hydrogen chloride in 1,4-dioxane (0.51 ml, 2.0 mmol), yield: 97 mg (92% of theory, 92% purity).

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.85-1.00 (m, 2H), 1.11-1.33 (m, 2H), 1.17 (s, 3H), 1.18 (s, 3H), 1.40 -1.65 (m, 2H), 1.70-1.82 (m, 3H), 2.10-2.21 (m, IH), 2.45-2.70 (m, 4H), 2.92 (dd, IH), 3.11 (dd, IH), 3.60 -3.70 (m, 2H), 4.22 (d, 2H), 4.67-4.75 (m, IH), 7.15-7.28 (m, IH), 7.40 (d, 2H), 7.51 (d, 2H), 7.75-7.89 (m, 5H), 8.02 (d, 2H), 8.03-8.17 (m, IH), 8.24 (d, IH), 8.32 (s, IH), 10.58 (s, IH).

LC-MS (Method 1): R _t = 0.73 min; MS (ES Ineg): m / z = 636 [MH-HC1] \ Example 10 NaI / ia- {[ira-i-4- (aniinomethyl) cyclohexyl] carbonyl} -4- (5-chloropyridin-3-yl ) -N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide hydrochloride

Starting compound: Na / j / ia - [(α-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (5-chloropyridin-3-yl) -N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide (90 mg, 0.14 mmol), dioxane (3 mL), 4M hydrogen chloride in 1,4-dioxane (0.51 mL, 2.0 mmol), Yield: 84 mg (96% of theory).

^: H-NMR (400 MHz, DMSO-de): δ = ppm 0.85-1.00 (m, 2H), 1.12-1.33 (m, 2H), 1.40-1.63 (m, 2H), 1.69-1.81 (m, 3H ), 2.10-2.20 (m, IH), 2.59-2.68 (m, 2H), 2.95 (dd, IH), 3.13 (dd, IH), 4.69-4.78 (m, IH), 7.44 (d, 2H), 7.70-7.87 (m, 7H), 8.02 (d, 2H), 8.20-8.30 (m, 2H), 8.60 (d, IH), 8.87 (d, IH), 10.57 (s, IH).

LC-MS (Method 1): R _t = 0.76 min; MS (ESIneg): m / z = 557 [MH-HC1] \

Example 11

NaI / ia- {[ira «A-4- (aminomethyl) cyclohexyl] carbonyl} -4-pyridin-4-yl-N- [4- (2-i-tetrazol-5-yl) phenyl] -L -phenylalaninamide hydrochloride

Starting compound: Na / j / ia - [(ω-α-4- {[(ω-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4-pyridin-4-yl-N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate (310 mg, 0.42 mmol), dioxane (15 ml), 4M hydrogen chloride in 1,4-dioxane (1.57 ml, 6.3 mmol), yield: 267 mg ( 98% of theory).

Ή-NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.85-1.00 (m, 2H), 1.12-1.32 (m, 2H), 1.42-1.65 (m, 2H), 1.69-1.82 (m, 3H ), 2.10-2.20 (m, 1H), 2.58-2.68 (m, 2H), 3.01 (dd, 1H), 3.20 (dd, 1H), 4.72-4.80 (m, 1H), 7.57 (d, 2H), 7.77-8.06 (m, 8H), 8.29-8.39 (m, 3H), 8.90 (d, 2H), 10.66 (s, 1H).

LC-MS (Method 1): R _t = 0.48 min; MS (ES Ineg): m / z = 523 [MH-HC1] \ Example 12

NaI / ia- {[ira-i-4- (aniinomethyl) cyclohexyl] carbonyl} -4- (4-chloropyridin-3-yl) -N- [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide hydrochloride

Starting compound: Na / j / ia - [(α-α-4- {[(feri-butoxycarbonyl) amino] methyl} cyclohexylcarbonyl] -4- (4-chloropyridin-3-yl) -N- [4- (4-chloropyridin-3-yl) 2 / i-tetrazol-5-yl) phenyl] -L-phenylalaninamid- Trifluoroacetate (80 mg, 0.10 mmol), dioxane (3 ml), 4M hydrogen chloride in 1,4-dioxane (0.38 ml, 1.55 mmol), yield: 64 mg (98% of theory).

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.85-1.00 (m, 2H), 1.11-1.34 (m, 2H), 1.41-1.62 (m, 2H), 1.68-1.82 (m, 3H), 2.10-2.20 (m, IH), 2.58-2.70 (m, 2H), 2.98 (dd, IH), 3.18 (dd, IH), 4.72-4.80 (m, IH), 7.45 (q, 3H) , 7.70-7.93 (m, 5H), 8.02 (d, 2H), 8.29 (d, IH), 8.55-8.61 (m, 2H), 10.60 (s, IH).

LC-MS (Method 1): R _t = 0.73 min; MS (ES Ineg): m / z = 557 [MH-HC1] \ Example 13

Na / ia- {[ira-i-4- (aniinomethyl) cyclohexyl] carbonyl} -4- (2-methylpyridin-3-yl) -N- [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide hydrochloride

Starting compound: Na / j / ia - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (2-methylpyridin-3-yl) -N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate (60mg, 0.08mmol), dioxane (2.5mL), 4M hydrogen chloride in 1,4-dioxane (0.3mL, 1.2mmol), Yield : 43 mg (88% of theory).

Ή NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.84-1.00 (m, 2H), 1.13-1.34 (m, 2H), 1.42-1.62 (m, 2H), 1.65-1.81 (m, 3H ), 2.11-2.21 (m, IH), 2.4-2.7 (m, 2H), 2.70 (s, 3H), 2.98 (dd, IH), 3.17 (dd, IH), 4.72-4.81 (m, IH), 7.39 (d, 2H), 7.48 (d, 2H), 7.75-7.90 (m, 6H), 8.02 (d, 2H), 8.16-8.26 (m, IH), 8.30 (d, IH), 8.70 (d, IH), 10.57 (s, IH). LC-MS (method 1): R _t = 0.52 min; MS (ES Ineg): m / z = 537 [MH-HC1] ^" . Example 14

N-alpha- [[iraws-4- (aminomethyl) cyclohexyl] carbonyl} - N - [4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -phenyl] -4 pyridin-3-yl-L-phenylalanine amide hydrochloride

Starting compound: N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -N- [4- (5-oxo-4,5-dihydro-l, 2,4 -oxadiazol-3-yl) phenyl] -4-pyridin-3-yl-L-phenylalanine amide trifluoroacetate (73 mg, 0.11 mmol), dioxane (3 ml), 4M hydrogen chloride in 1,4-dioxane (0.28 ml , 1.14 mmol), yield: 59 mg (82% of theory).

^: H NMR (400 MHz, DMSO-de): δ = ppm 0.85-1.00 (m, 2H), 1.13-1.33 (m, 2H), 1.40-1.65 (m, 2H), 1.70-1.82 (m, 3H ), 2.10-2.20 (m, IH), 2.58-2.69 (m, 2H), 2.97 (dd, IH), 3.16 (dd, IH), 4.70-4.78 (m, IH), 7.50 (dd, 2H), 7.75-7.94 (m, 9H), 8.31 (d, IH), 8.55-8.61 (m, IH), 8.76 (d, IH), 9.12 (s, IH), 10.71 (s, IH), 12.94 (bs, IH).

LC-MS (Method 1): R _t = 0.54 min; MS (ES Ineg): m / z = 539 [MH-HC1] \

Example 15 Na / ia- {[ira-Ä- 4- (aminomethyl) cyclohexyl] carbonyl} -4- (3-chloropyridin-4-yl) -N- [4- (2 / i-tetrazole-5 - yl) phenyl] -L-phenylalanine amide hydrochloride

Starting compound: Na / j / ia - [(α-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (3-chloropyridin-4-yl) -N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate (71mg, 0.09mmol), dioxane (3mL), 4M hydrogen chloride in 1,4-dioxane (0.32mL, 1.3mmol), Yield : 67 mg (quant.).

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.85-0.99 (m, 2H), 1.10-1.33 (m, 2H), 1.41-1.62 (m, 2H), 1.66-1.81 (m, 3H), 2.10-2.19 (m, 1H), 2.59-2.69 (m, 2H), 2.97 (dd, 1H), 3.18 (dd, 1H), 4.73-4.80 (m, 1H), 7.40-7.49 (m, 5H), 7.74-7.91 (m, 5H), 8.02 (d, 2H), 8.28 (d, 1H), 8.58 (d, 1H), 8.72 (s, 1H), 10.58 (s, 1H). LC-MS (Method 1): R _t = 0.69 min; MS (ESIneg): m / z = 557 [MH-HC1] \

Example 16

Na / ia- {[ira «-4- (aminomethyl) cyclohexyl] carbonyl} -4- (6- {[2- (morpholin-4-yl) ethyl] amino} pyridin-3-yl) - N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalaninamide hydrochloride

Starting compound: Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) -carbonyl] -4- (6- {[2- (m-holin-4-yl ) ethyl] amino} pyridin-3-yl) -N- [4- (2 / ί-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate (126.4 mg, 0.15 mmol), dioxane (4 mL), 4M hydrogen chloride in 1,4-dioxane (0.36 ml, 1.46 mmol), yield: 94 mg (83% of theory). ^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.85-0.99 (m, 2H), 1.12-1.33 (m, 2H), 1.42-1.64 (m, 2H), 1.70-1.82 (m, 3H), 2.10-2.20 (m, IH), 2.58-2.69 (m, 2H), 2.95 (dd, IH), 3.12 (dd, IH), 3.20- 3.45 (m, 6H), 3.70-4.00 (m, 7H), 4.68-4.75 (m, IH), 7.04-7.20 (m, IH), 7.41 (d, 2H), 7.62 (d, 2H), 7.80-8.00 (m, 5H), 8.02 (d, 2H) , 8.12-8.30 (m, 3H), 10.62 (s, IH).

LC-MS (method 1): R _t = 0.52 min; MS (ES Ineg): m / z = 651 [MH-HC1] \ Example 17

^~ N-alpha- {[iraws-4- (Aminomefhyl) cyclohexyl] carbonyl} -4- (6-hydroxy-pyridin-3-yl) -N- [4- (2H-tetrazol-5-yl) phenyl] -L- phenylalaninamide hydrochloride

Starting compound: Na / j / ia - [(α-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (6-hydroxypyridin-3-yl) -N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalaninamid-

Trifluoroacetate (23 mg, 0.03 mmol), dioxane (2 ml), 4M hydrogen chloride in 1,4-dioxane (0.11 ml, 0.46 mmol), yield: 16 mg (80% of theory, 93% purity).

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.85-1.00 (m, 2H), 1.11-1.32 (m, 2H), 1.40-1.64 (m, 2H), 1.67-1.82 (m, 3H), 2.10-2.20 (m, IH), 2.55-2.70 (m, 2H), 2.91 (dd, IH), 3.09 (dd, IH), 4.65-4.72 (m, IH), 6.41 (d, IH) , 7.06-7.10, 7.19-7.24 (each m, IH), 7.34 (d, 2H), 7.47 (d, 2H), 7.67 (s, IH), 7.76-7.93 (m, 5H), 8.02 (d, 2H ), 8.22 (d, IH), 10.58 (s, IH), 11.8 (bs, IH).

LC-MS (Method 1): R _t = 0.58 min; MS (ES Ineg): m / z = 539 [MH-HC1] \ Example 18

N-alpha- [[iraws-4- (aminomethyl) cyclohexyl] carbonyl} - N - [4- (2-i-tetrazol-5-yl) phenyl] -4- [6- (trifluoromethyl) pyridin-3-y 1] -L-phenylalaninamide-Hy dro chloride

Starting compound: N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -N- [4- (2-i-tetrazol-5-yl) phenyl] -4- [6- (trifluoromethyl) pyridin-3-yl] -L-phenylalanine amide trifluoroacetate (59 mg, 0.07 mmol), dioxane (2 mL), 4M hydrogen chloride in 1,4-dioxane (0.18 mL, 0.73 mmol), Yield: 48 mg (96% of theory).

^: H NMR (400 MHz, DMSO-de): δ = ppm 0.85-1.00 (m, 2H), 1.13-1.35 (m, 2H), 1.40-1.65 (m, 2H), 1.69-1.81 (m, 3H ), 2.10-2.20 (m, IH), 2.58-2.69 (m, 2H), 2.98 (dd, IH), 3.16 (dd, IH), 4.70-4.79 (m, IH), 7.49 (d, 2H), 7.66-7.91 (m, 7H), 7.96 (d, IH), 8.02 (d, 2H), 8.27 (d, IH), 8.35 (d, IH), 9.09 (s, IH), 10.60 (s, IH) ,

LC-MS (Method 1): R _t = 0.79 min; MS (ES Ineg): m / z = 591 [MH-HC1] ^" .

Example 19 ^~ N-alpha- {[iraws-4- (Aminomefhyl) cyclohexyl] carbonyl} -4- {6- [3- (dimethylamino) propoxy] pyridin-3-yl} -N- [4- (5-oxo -4,5-dihydro-l, 2,4-oxadiazol-3-yl) phenyl] -L-phenylalaninamide hydrochloride

Starting compound: Na / i / a - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- {6- [3- (dimethylamino) propoxy] pyridine-3- yl} - N - [4- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) phenyl] -L-phenylalanine amide trifluoroacetate (89 mg, 0.11 mmol), dioxane (3 ml), 4M hydrogen chloride in 1,4-dioxane (0.26 ml, 1.04 mmol), yield: 71 mg (93% of theory).

^: H NMR (400 MHz, DMSO-de): δ = ppm 0.85-1.00 (m, 2H), 1.13-1.34 (m, 2H), 1.42-1.64 (m, 2H), 1.70-1.82 (m, 3H ), 2.09-2.20 (m, 3H), 2.57-2.67 (m, 2H), 2.77 (d, 6H), 2.94 (dd, IH), 3.11 (dd, IH), 3.15-3.23 (m, 2H), 4.36 (t, 2H), 4.66-4.75 (m, IH), 6.89 (d, IH), 7.41 (d, 2H), 7.58 (d, 2H), 7.76-8.00 (m, 7H), 8.01 (dd, IH), 8.29 (d, IH), 8.45 (d, IH), 10.45 (bs, IH), 10.58 (s, IH). LC-MS (Method 1): R _t = 0.60 min; MS (ES Ineg): m / z = 640 [MH-HC1] ^" .

Example 20

Na / ia- {[ira «A-4- (aminomethyl) cyclohexyl] carbonyl} -4- (3-methoxypyridin-4-yl) -N- [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide hydrochloride

Starting compound: Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (3-methoxypyridin-4-yl) -N- [4 - (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate (75mg, 0.10mmol), dioxane (2.5mL), 4M hydrogen chloride in 1,4-dioxane (0.36mL, 1.46mmol), Yield: 60 mg (94% of theory). ^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.86-1.00 (m, 2H), 1.13-1.34 (m, 2H), 1.41-1.65 (m, 2H), 1.70-1.82 (m, 3H), 2.11-2.21 (m, 1H), 2.57-2.69 (m, 2H), 2.98 (dd, 1H), 3.17 (dd, 1H), 3.98 (s, 3H), 4.71-4.79 (m, 1H) , 7.47 (d, 2H), 7.63 (d, 2H), 7.72-7.91 (m, 6H), 8.02 (d, 2H), 8.30 (d, 1H), 8.54 (d, 1H), 8.67 (s, 1H ), 10.61 (s, 1H).

LC-MS (Method 1): R _t = 0.53 min; MS (ES Ineg): m / z = 553 [MH-HC1] \ Example 21

Na / ia- {[ira «A-4- (aminomethyl) cyclohexyl] carbonyl} -4- (6-methoxy-2-methylpyridin-3-yl) -N- [4- (2-i-tetrazole) 5 -yl) phenyl] -L-phenylalanine amide hydrochloride

Starting compound: Na / yl - [(α-ε-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (6-methoxy-2-methylpyridin-3-yl) -N - [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenyl-alaninamide trifluoroacetate (86 mg, 0.11 mmol), dioxane (3.0 ml), 4M hydrogen chloride in 1,4-dioxane (0.41 ml , 1.65 mmol), yield: 67 mg (88% of theory, 93% purity).

^: H-NMR (400 MHz, DMSO-de): δ = ppm 0.84-0.98 (m, 2H), 1.09-1.33 (m, 2H), 1.40-1.60 (m, 2H), 1.68-1.81 (m, 3H ), 2.10-2.20 (m, 1H), 2.30 (s, 3H), 2.58-2.69 (m, 2H), 2.94 (dd, 1H), 3.12 (dd, 1H), 3.85 (s, 3H), 4.70- 4.78 (m, 1H), 6.71 (d, 1H), 7.24 (d, 2H), 7.38 (d, 2H), 7.50 (d, 1H), 7.75-7.87 (m, 5H), 8.02 (d, 2H) , 8.28 (d, 1H), 10.56 (s, 1H).

LC-MS (Method 1): R _t = 0.70 min; MS (ESIneg): m / z = 567 [MH-HC1] \ Example 22

N-alpha- [[iraws-4- (aminomethyl) cyclohexyl] carbonyl} -4- [4- (benzyloxy) -2- (dimethylpyrimidin-5-yl] -N- [4- (2-i-tetrazole) 5-yl) phenyl] -L-phenylalaninamide hydrochloride

Starting compound: 4- [4- (benzyloxy) -2- (dimethylamino) pyrimidin-5-yl] -Na / j / ia - [(i-i-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] - N - [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate (50mg, 0.06mmol), dioxane (2.0mL), 4M hydrogen chloride in 1,4-dioxane ( 0.21 ml, 0.84 mmol), yield: 30 mg (70% of theory).

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.84-0.97 (m, 2H), 1.13-1.32 (m, 2H), 1.40-1.62 (m, 2H), 1.68-1.81 (m, 3H), 2.09-2.19 (m, IH), 2.58-2.69 (m, 2H), 2.91 (dd, IH), 3.08 (dd, IH), 3.20 (s, 6H), 4.65-4.72 (m, IH) , 5.46-5.54 (m, 2H), 7.29-7.47 (m, 9H), 7.76-7.90 (m, 5H), 8.02 (d, 2H), 8.17 (s, IH), 8.26 (d, IH), 10.58 (s, IH).

LC-MS (Method 1): R _t = 0.74 min; MS (ESIneg): m / z = 673 [MH-HC1] \

Example 23 NaI / ia- {[ira «A-4- (aminomethyl) cyclohexyl] carbonyl} -4- (3-methylpyridin-4-yl) -N- (3-oxo-2,3-dihydro-1H / i-indazol-6-yl) -L-phenylalaninamide hydrochloride

Starting compound: Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (3-methylpyridin-4-yl) -N- (3 oxo-2,3-dihydro-l / i-indazol-6-yl) -L-phenylalanine amide trifluoroacetate (64mg, 0.09mmol), dioxane (2.0ml), 4M hydrogen chloride in 1,4-dioxane (0.21ml, 0.86 mmol), yield: 48 mg (92% of theory).

^: H-NMR (400 MHz, DMSO-de): δ = ppm 0.84-0.99 (m, 2H), 1.10-1.33 (m, 2H), 1.42-1.60 (m, 2H), 1.67-1.82 (m, 3H 2.10-2.20 (m, 1H), 2.37 (s, 3H), 2.58-2.67 (m, 2H), 2.99 (dd, 1H), 3.16 (dd, 1H), 4.72-4.80 (m, 1H), 7.04 (d, 1H), 7.44-7.56 (m, 5H), 7.82-8.03 (m, 5H), 8.34 (d, 1H), 8.80 (d, 1H), 8.88 (s, 1H), 10.42 (s, 1H), 11.3 (bs, 1H). LC-MS (method 1): R _t = 0.39 min; MS (ESIneg): m / z = 525 [MH-HC1] \

Example 24

^~ N-alpha- {[iraws-4- (Aminomefhyl) cyclohexyl] carbonyl} -4- [6- (morpholin-4-yl) pyridin-3-yl] -N- (3-oxo-2, 3-dihydro -l / i-indazol-6-yl) -L-phenylalaninamide hydrochloride

Starting compound: N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [6- (morpholin-4-yl) pyridin-3-yl] -N- (3-oxo-2,3-dihydro-l / i-indazol-6-yl) -L- phenylalanine amide trifluoroacetate (50 mg, 0.06 mmol), dioxane (2.5 mL), 4M hydrogen chloride in 1,4-dioxane (0.23 mL, 0.92 mmol), yield: 65 mg (89% of theory).

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.85-0.99 (m, 2H), 1.12-1.33 (m, 2H), 1.41-1.63 (m, 2H), 1.70-1.82 (m, 3H), 2.10-2.20 (m, IH), 2.57-2.67 (m, 2H), 2.93 (dd, IH), 3.11 (dd, IH), 3.61-3.71 (m, 4H), 3.71-3.78 (m, 4H), 4.67-4.75 (m, IH), 7.05 (d, IH), 7.26-7.38 (m, IH), 7.41 (d, 2H), 7.56 (d, IH), 7.62 (d, 2H), 7.83 -7.98 (m, 4H), 8.18-8.32 (m, 3H), 10.42 (s, IH), 11.3 (bs, IH).

LC-MS (Method 1): R _t = 0.58 min; MS (ES Ineg): m / z = 596 [MH-HC1] \

Example 25

^~ N -alpha {[ira_A-4- (aminomethyl) cyclohexyl] carbonyl} -4- [2- (dimethylamino) pyrimidin-5-yl] - N - [4- (2-i-tetrazole-5 - yl) phenyl] -L-phenylalanine amide hydrochloride

Starting compound: Na / j / ia - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [2- (dimethylamino) pyrimidin-5-yl] -N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate (70mg, 0.09mmol), dioxane (2.5mL), 4M hydrogen chloride in 1,4-dioxane (0.55mL, 2.25 mmol), yield: 60 mg (quant.).

^: H-NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.85-1.00 (m, 2H), 1.12-1.32 (m, 2H), 1.40-1.63 (m, 2H), 1.68-1.82 (m, 3H), 2.10-2.20 (m, IH), 2.57-2.69 (m, 2H), 2.90 (dd, IH), 3.09 (dd, IH), 3.16 (s, 6H), 4.65-4.74 (m, IH) , 7.38 (d, 2H), 7.57 (d, 2H), 7.70-7.95 (m, 5H), 8.02 (d, 2H), 8.25 (d, IH), 8.69 (s, 2H), 10.58 (s, IH ). LC-MS (Method 1): R _t = 0.71 min; MS (ES Ineg): m / z = 567 [MH-HC1] ^" . Example 26

tetrazol-5-yl) phenyl] -L-phenylalanine amide hydrochloride

Starting compound: 4- (2-aminopyridin-3-yl) -Na / j / ia - [(ira "5-4- {[(ieri-butoxycarbonyl) amino] -methyl} -cyclohexyl) carbonyl] -N- [4 - (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate (60 mg, 0.08 mmol), dioxane (2.5 ml), 4M hydrogen chloride in 1,4-dioxane (0.30 ml, 1.20 mmol), Yield: 45 mg (92% of theory).

Ή-NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.86-1.01 (m, 2H), 1.16-1.33 (m, 2H), 1.43-1.66 (m, 2H), 1.70-1.83 (m, 3H ), 2.11-2.20 (m, IH), 2.59-2.69 (m, 2H), 2.98 (dd, IH), 3.14 (dd, IH), 4.68-4.76 (m, IH), 6.99 (t, IH), 7.40 (d, 2H), 7.50 (d, 2H), 7.62-7.73 (m, 2H), 7.76-7.91 (m, 6H), 8.00-8.06 (m, 3H), 8.32 (d, IH), 10.63 ( s, IH), 14.0 (bs, IH).

LC-MS (Method 1): R _t = 0.47 min; MS (ES Ineg): m / z = 538 [MH-HC1] ^" .

Example 27 NaI / ia- {[Ira'A-4- (Aminomethyl) cyclohexyl] carbonyl} -4- (2-methylpyridin-3-yl) -N- (3-oxo-2,3-dihydro-1H / i-indazol-6-yl) -L-phenylalaninamide hydrochloride

Starting compound: Na / j / ia - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (2-methylpyridin-3-yl) -N- (3 oxo-2-dihydro-l / i-indazol-6-yl) -L-phenylalanine amide trifluoroacetate (48 mg, 0.07 mmol), dioxane (2.0 mL), 4M hydrogen chloride in 1,4-dioxane (0.16 mL, 0.65 mmol Yield: 37 mg (95% of theory).

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.85-1.00 (m, 2H), 1.10-1.34 (m, 2H), 1.42-1.61 (m, 2H), 1.76-1.82 (m, 3H), 2.10-2.20 (m, 1H), 2.57-2.70 (m, 5H), 2.97 (dd, 1H), 3.16 (dd, 1H), 4.71-4.80 (m, 1H), 7.03 (d, 1H) , 7.42 (d, 2H), 7.49 (d, 2H), 7.53 (d, 1H), 7.85-8.05 (m, 5H), 8.30-8.40 (m, 2H), 8.77 (d, 1H), 10.41 (s , 1H), 11.2 (bs, 1H). LC-MS (Method 1): R _t = 0.36 min; MS (ESIneg): m / z = 525 [MH-HC1] \

Example 28

^~ N-alpha- {[iraws-4- (Aminomefhyl) cyclohexyl] carbonyl} -N-l / i-indazol-6-yl-4- (6-methoxy-2-methyl-lpyridin-3 -yl) -L- phenylalanine amide hydrochloride

Starting compound: N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -Nl / i-indazol-6-yl-4- (6-methoxy-2-methylpyridine) 3-yl) -L-phenylalaninamid- Trifluoroacetate (87 mg, 0.12 mmol), dioxane (3.0 mL), 4M hydrogen chloride in 1,4-dioxane (0.43 mL, 1.73 mmol), yield: 71 mg (quant.).

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.85-0.99 (m, 2H), 1.09-1.35 (m, 2H), 1.41-1.61 (m, 2H), 1.68-1.81 (m, 3H), 2.10-2.20 (m, 1H), 2.31 (s, 3H), 2.56-2.69 (m, 2H), 2.94 (dd, 1H), 3.12 (dd, 1H), 3.87 (s, 3H), 4.71 -4.80 (m, 1H), 6.72 (d, 1H), 7.13 (d, 1H), 7.25 (d, 2H), 7.38 (d, 2H), 7.51 (d, 1H), 7.66 (d, 1H), 7.76-7.95 (m, 3H), 7.97 (s, 1H), 8.12 (s, 1H), 8.26 (d, 1H), 10.36 (s, 1H), 12.9 (bs, 1H).

LC-MS (Method 1): R _t = 0.71 min; MS (ES Ineg): m / z = 539 [MH-HC1] \ Example 29 N-alpha- [[ira-Ä- 4- (aminomethyl) cyclohexyl] carbonyl} -4- [4-methyl-6- (morpholine) 4-yl) pyridin-3-yl] - N - [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide hydrochloride

Starting compound: Na / ia - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [4-methyl-6- (morpholin-4-yl) pyridine 3-yl] - N - [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate (42 mg, 0.05 mmol), dioxane (2.0 mL), 4M hydrogen chloride in 1 , 4-dioxane (0.19 ml, 0.75 mmol), yield: 31 mg (83% of theory).

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.85-0.99 (m, 2H), 1.01-1.35 (m, 2H), 1.40-1.60 (m, 2H), 1.70-1.84 (m, 4H), 2.10-2.23 (m, 4H), 2.59-2.69 (m, 2H), 2.95 (dd, 1H), 3.12 (dd, 1H), 3.55-3.62 (m, 4H), 3.71-3.77 (m, 2H), 4.70-4.78 (m, 1H), 7.12 (bs, 1H), 7.28 (d, 2H), 7.40 (d, 2H), 7.72-7.85 (m, 7H), 8.01 (d, 2H), 8.29 (d, 1H), 10.53 (s, 1H).

LC-MS (Method 1): R _t = 0.62 min; MS (ES Ineg): m / z = 622 [MH-HC1] \ Example 30

N-a / j / ia- {[ira «A-4- (arnomethyl) cyclohexyl] carbonyl} -4- (6-methoxy-2-me

oxo-2,3-dihydro-l / i-indazol-6-yl) -L-phenylalaninamide hydrochloride

Starting compound: N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (6-methoxy-2-methylpyridin-3-yl) -N- (3 oxo-2,3-dihydro-l / i-indazol-6-yl) -L-phenyl-alaninamide trifluoroacetate (75 mg, 0.10 mmol), dioxane (2.5 mL), 4M hydrogen chloride in 1,4-dioxane (0.25 ml, 0.98 mmol), yield: 62 mg (97% of theory).

Ή-NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.85-1.00 (m, 2H), 1.09-1.35 (m, 2H), 1.41-1.62 (m, 2H), 1.63-1.81 (m, 3H ), 2.08-2.20 (m, 1H), 2.31 (s, 3H), 2.57-2.69 (m, 2H), 2.94 (dd, 1H), 3.11 (dd, 1H), 3.88 (s, 3H), 4.68- 4.78 (m, 1H), 6.74 (d, 1H), 7.05 (d, 1H), 7.24 (d, 2H), 7.38 (d, 2H), 7.49-7.60 (m, 2H), 7.80-8.00 (m, 3H), 8.28 (d, 1H), 10.38 (s, 1H), 12.9 (bs, 1H).

LC-MS (Method 1): R _t = 0.70 min; MS (ESIneg): m / z = 555 [MH-HC1] \

Example 31 ^~ N-alpha- {[iraws-4- (Aminomefhyl) cyclohexyl] carbonyl} -4- [4-methoxy-2- (4-methylpiperazin-1 - yl) pyrimidin-5 -y 1] -N- [ 4- (2 / i-tetrazol-5-yl) phenyl 1] -L-phenylalanine amide hydrochloride

Starting compound: Na / ia - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [4-methoxy-2- (4-methylpiperazin-1-yl ) pyrirnidin-5-yl] - N - [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate (122 mg, 0.14 mmol), dioxane (3.0 ml), 4M hydrogen chloride in 1 , 4-dioxane (0.53 ml, 2.10 mmol), yield: 87 mg (85% of theory).

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.85-1.00 (m, 2H), 1.14-1.35 (m, 2H), 1.41-1.64 (m, 2H), 1.69-1.82 (m, 3H), 2.10-2.20 (m, IH), 2.57-2.69 (m, 2H), 2.80 (d, 3H), 2.92 (dd, IH), 2.99-3.13 (m, 4H), 3.31-3.52 (m, 4H), 3.91 (s, 3H), 4.65-4.69 (m, 3H), 7.34 (d, 2H), 7.40 (d, 2H), 7.74-7.97 (m, 5H), 8.02 (d, 2H), 8.22 (s, IH), 8.27 (d, IH), 10.59 (s, IH), 10.9 (bs, IH). LC-MS (Method 1): R _t = 0.58 min; MS (ES Ineg): m / z = 652 [MH-HC1] \

Example 32

NaI / ia- {[ira-i-4- (aniinomethyl) cyclohexyl] carbonyl} -4- [6- (pyridin-3-yloxy) pyridin-3-yl] -N- [4- (2 / i tetrazol-5-yl) phenyl] -L-phenylalanine amide hydrochloride

Starting compound: Na / j / ia - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [6- (pyridin-3-yloxy) -pyridine-3-one yl] - N - [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate (101 mg, 0.12 mmol), dioxane (3.0 ml), 4M hydrogen chloride in 1,4-dioxane ( 0.46 ml, 1.82 mmol), yield: 77 mg (87% of theory). ^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.83-0.98 (m, 2H), 1.11-1.33 (m, 2H), 1.40-1.64 (m, 2H), 1.67-1.81 (m, 3H), 2.09-2.20 (m, 1H), 2.57-2.68 (m, 2H), 2.93 (dd, 1H), 3.12 (dd, 1H), 4.66-4.75 (m, 1H), 7.26 (d, 1H) , 7.42 (d, 2H), 7.57-7.74 (m, 3H), 7.75-7.97 (m, 6H), 8.02 (d, 2H), 8.20 (dd, 1H), 8.27 (d, 1H), 8.45 (i.e. , 1H), 8.56 (d, 1H), 8.67 (s, 1H), 10.61 (s, 1H).

LC-MS (Method 1): R _t = 0.72 min; MS (ES Ineg): m / z = 616 [MH-HC1] \ Example 33

^~ N-alpha- {[iraws-4- (Aminomefhyl) cyclohexyl] carbonyl} -4- [2- (piperazin-1-yl) pyridin-4-yl] -N- [4- (2 / i-tetrazol- 5 -yl) phenyl] -L-phenylalanine amide hydrochloride

Starting compound: Na / j / ia - [(α-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [2- (piperazin-1-yl) pyridin-4-yl ] -N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate (72 mg, 0.08 mmol), dioxane (3.0 mL), 4M hydrogen chloride in 1,4-dioxane (0.29 ml, 1.17 mmol), yield: 64 mg (quant.).

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.87-1.00 (m, 2H), 1.13-1.34 (m, 2H), 1.43-1.65 (m, 2H), 1.69-1.82 (m, 3H), 2.10-2.20 (m, 1H), 2.56-2.69 (m, 2H), 2.98 (dd, 1H), 3.15 (dd, 1H), 3.22 (bs, 4H), 3.94 (bs, 4H), 4.70 -4.78 (m, 1H), 7.22 (bs, 1H), 7.37 (bs, 1H), 7.49 (d, 2H), 7.75-7.98 (m, 7H), 8.03 (d, 2H), 8.17 (d, 1H ), 8.31 (d, 1H), 9.4 (bs, 2H), 10.67 (s, 1H).

LC-MS (Method 1): R _t = 0.53 min; MS (ES Ineg): m / z = 607 [MH-HC1] \ Example 34

N-alpha- {[ira_A-4- (aminomethyl) cyclohexyl] carbonyl} -4- [6- (morpholin-4-yl) pyridin-3-yl] -N- [4- (5-oxo-2 , 5-dihydro-l / i-pyrazol-3-yl) phenyl] -L-phenylalaninamide hydrochloride

Starting compound: N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [6- (morpholin-4-yl) pyridin-3-yl] -N- [4- (5-oxo-2,5-dihydro-1-pyrazol-3-yl) phenyl] -L-phenylalanine amide trifluoroacetate (93 mg, 0.11 mmol), dioxane (4.0 mL), 4M hydrogen chloride in 1 , 4-dioxane (0.41 ml, 1.66 mmol), yield: 71 mg (92% of theory).

Ή NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.85-0.99 (m, 2H), 1.11-1.33 (m, 2H), 1.42-1.63 (m, 2H), 1.66-1.82 (m, 3H ), 2.09-2.19 (m, IH), 2.57-2.68 (m, 2H), 2.92 (dd, IH), 3.11 (dd, IH), 3.60-3.79 (m, 8H), 4.65-4.74 (m, IH ), 6.04 (s, IH), 7.29 (d, IH), 7.41 (d, 2H), 7.62 (d, 2H), 7.66-7.79 (m, 4H), 7.84-8.05 (m, 2H), 8.21 ( d, IH), 8.25-8.33 (m, 2H), 10.51 (s, IH).

LC-MS (Method 1): R _t = 0.64 min; MS (ES Ineg): m / z = 622 [MH-HC1] ^" .

Example 35 ^~ N -alpha {[ira_A-4- (aminomethyl) cyclohexyl] carbonyl} -4- [2- (morpholin-4-yl) pyridin-4-yl] -N- [4- (2 / i-tetrazol-5-yl) phenyl 1] -L-phenylalanine amide hydrochloride

Starting compound: Na / j / ia - [(α-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [2- (morpholin-4-yl) pyridin-4-yl ] -N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate (81 mg, 0.1 mmol), dioxane (3.0 mL), 4M hydrogen chloride in 1,4-dioxane (0.37 ml, 1.5 mmol), yield: 59 mg (88% of theory).

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.83-0.99 (m, 2H), 1.13-1.34 (m, 2H), 1.42-1.64 (m, 2H), 1.70-1.83 (m, 3H), 2.10-2.20 (m, 1H), 2.58-2.69 (m, 2H), 2.98 (dd, 1H), 3.17 (dd, 1H), 3.3-3.6 (m, 2H), 3.64-3.78 (m, 6H), 4.70-4.77 (m, 1H), 7.23 (bs, 1H), 7.41 (bs, 1H), 7.49 (d, 2H), 7.74- 7.94 (m, 7H), 8.02 (d, 2H), 8.11 (d, 1H), 8.31 (d, 1H), 10.63 (s, 1H). LC-MS (Method 1): R _t = 0.60 min; MS (ES Ineg): m / z = 608 [MH-HC1] \

Example 36

^~ N-alpha- {[iraws-4- (Aminomefhyl) cyclohexyl] carbonyl} -4- [2- (morpholin-4-yl) pyridin-4-yl] -N- (3-oxo-2, 3-dihydro -l / i-indazol-6-yl) -L-phenylalaninamide hydrochloride

Starting compound: N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [2- (morpholin-4-yl) pyridin-4-yl] -N- (3-oxo-2,3-dihydro-l / i-indazol-6-yl) -L-phenyl- alaninamide trifluoroacetate (81 mg, 0.10 mmol), dioxane (3.0 mL), 4M hydrogen chloride in 1,4-dioxane (0.37 mL, 1.50 mmol), Yield: 51 mg (74% of theory).

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.84-0.99 (m, 2H), 1.13-1.34 (m, 2H), 1.42-1.63 (m, 2H), 1.68-1.83 (m, 3H), 2.10-2.20 (m, 1H), 2.57-2.69 (m, 2H), 2.98 (dd, 1H), 3.17 (dd, 1H), 3.70-3.84 (m, 8H), 4.70-4.78 (m, 1H), 7.05 (d, 1H), 7.32 (d, 1H), 7.46-7.59 (m, 4H), 7.80-8.02 (m, 6H), 8.08 (d, 1H), 8.32 (d, 1H), 10.43 (s, 1H), 11.3 (bs, 1H).

LC-MS (Method 1): R _t = 0.60 min; MS (ES Ineg): m / z = 608 [MH-HC1] \

Example 37

^~ N -alpha {[ira_A-4- (aminomethyl) cyclohexyl] carbonyl} -4- (2-hydroxypyridin-3-yl) -N- [4- (2H-tetrazol-5-yl) -phenyl] - L-phenylalaninamide hydrochloride

A solution of 100 mg (0.15 mmol) of Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- (2-methoxypyridin-3-yl ) N- [4- (2-i-tetrazol-5-yl) phenyl] -L-phenyl-alaninamide in 2 ml of 1,4-dioxane was treated with 0.76 ml (3.05 mmol) of 4M hydrogen chloride in 1,4-dioxane mixed and stirred for 2.5 d at RT. After the addition of another 0.38 ml (1.53 mmol) of 4M hydrogen chloride in 1,4-dioxane, the reaction mixture was stirred at RT overnight. An additional 0.38 ml (1.53 mmol) of 4M hydrogen chloride in 1,4-dioxane was added and the mixture was stirred overnight at 50.degree. The resulting precipitate was filtered off, washed with 1,4-dioxane and then dried under high vacuum. 69 mg (69% of theory, 94% purity) of the title compound were obtained.

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.85-1.00 (m, 2H), 1.14-1.32 (m, 2H), 1.41-1.66 (m, 2H), 1.70-1.82 (m, 3H), 2.10-2.20 (m, 1H), 2.59-2.69 (m, 2H), 2.92 (dd, 1H), 3.10 (dd, 1H), 4.66- 4.73 (m, 1H), 6.37 (t, 1H), 7.32 (d, 2H), 7.36 (d, 1H), 7.60 (dd, 1H), 7.65 (d, 2H), 7.75-7.97 (m, 5H) , 8.02 (d, 2H), 8.22 (d, 1H), 10.57 (s, 1H), 11.85 (bs, 1H).

LC-MS (Method 1): R _t = 0.60 min; MS (ES Ineg): m / z = 539 [MH-HC1] \ Example 38 Na / j / ia- {[ira-i-4- (aniinomethyl) cyclohexyl] carbonyl} -4- (6-methoxypyridin-3-yl ) -N- [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide

A solution of 40 mg (0.06 mmol) Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) amino] -methy 1} cyclohexyl) carbonyl 1] -4- (6-methoxypyridine-3 -y1) -N- [4- (2 / i-tetrazol-5-yl) -phenyl] -L-phenylalanine amide in 1.7 ml of 1,4-dioxane was mixed with 0.15 ml (0.61 mmol) of 4M hydrogen chloride in 1.4 -Dioxane and stirred for 4 h at RT. After the addition of another 0.08 ml (0.31 mmol) of 4M hydrogen chloride in 1,4-dioxane, the reaction mixture was stirred at RT for a further 3 h. The precipitate was filtered off, washed with 1,4-dioxane and then dried under high vacuum. The crude product was taken up in methanol / DMSO, filtered through a Millipore syringe filter and separated by preparative HPLC (eluent: acetonitrile / water gradient). The product-containing fractions were combined, freed from the solvent and the residue was then dried under high vacuum. 18 mg (52% of theory) of the title compound were obtained.

^: H NMR (400 MHz, DMSO-de): δ = ppm 0.85-0.99 (m, 2H), 1.13-1.33 (m, 2H), 1.38-1.64 (m, 2H), 1.66-1.81 (m, 3H ), 2.10-2.20 (m, 1H), 2.60-2.68 (m, 2H), 2.86-2.96 (m, 1H), 3.06-3.15 (m, 1H), 3.89 (s, 3H), 4.67-4.75 (m , 1H), 6.88 (d, 1H), 7.38 (d, 2H), 7.50-7.80 (m, 6H), 7.88 (d, 2H), 7.97 (d, 1H), 8.13 (d, 1H), 8.45 ( s, 1H), 10.13 (s, 1H).

LC-MS (Method 1): R _t = 0.71 min; MS (ES Ineg): m / z = 553 Example 39

^~ N -alpha {[ira_A-4- (aminomethyl) cyclohexyl] carbonyl} -4- [5- (methylsulfonyl) pyridin-3-yl] - N - [4- (2-i-tetrazole-5 - yl) phenyl 1] -L-phenylalanine amide hydrochloride

A solution of 100 mg (0.08 mmol) Na / j / ia - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -4- [5- (methylsulfonyl) pyridine] 3-yl] - N - [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate in 3 ml of 1,4-dioxane was mixed with 0.30 ml (1.18 mmol) of 4M hydrogen chloride in 1, 4-dioxane and stirred for 38 h at RT. The reaction solution was concentrated on a rotary evaporator. The residue with 6 ml of methanol and 0.5 ml of DMSO stirred and then filtered out the solid. The residue was dissolved with methanol, the solvent was removed on a rotary evaporator and the residue was dried under high vacuum. 45 mg (83% of theory) of the title compound were obtained.

^: H-NMR (400 MHz, DMSO-de): δ = ppm 0.85-0.99 (m, 2H), 1.13-1.34 (m, 2H), 1.40-1.65 (m, 2H), 1.67-1.82 (m, 3H ), 2.11-2.20 (m, IH), 2.58-2.68 (m, 2H), 2.97 (dd, IH), 3.16 (dd, IH), 3.39 (s, 3H), 4.70-4.79 (m, IH), 7.49 (d, 2H), 7.66-7.85 (m, 4H), 8.01 (d, 2H), 8.25 (d, IH), 8.51 (s, IH), 9.02 (s, IH), 9.22 (s, IH) , 10.57 (s, IH), 16.8 (bs, IH).

LC-MS (Method 1): R _t = 0.65 min; MS (ES Ineg): m / z = 601 [MH-HC1] \

Example 40

^~ N-alpha- {[iraws-4- (Aminomefhyl) cyclohexyl] carbonyl} -4- [4-hydroxy-2- (piperidin-1-yl) pyrimidin-5-yl] -N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalaninamide hydrochloride

Starting compound: NaI / ia - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4- [4-hydroxy-2- (piperidin-1-yl) pyrimidine -5-yl] - N - [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate (49 mg, 0.06 mmol), dioxane (2.0 mL), 4M hydrogen chloride in 1.4 Dioxane (0.22 ml, 0.88 mmol), yield: 23 mg (55% of theory).

^: H NMR (400 MHz, DMSO-de): δ = ppm 0.85-0.99 (m, 2H), 1.13-1.34 (m, 2H), 1.42-1.55 (m, IH), 1.55-1.70 (m, 7H ), 1.70-1.82 (m, 3H), 2.10-2.20 (m, IH), 2.58-2.68 (m, 2H), 2.91 (dd, IH), 3.09 (dd, IH), 3.61-3.77 (m, 4H ), 4.64-4.73 (m, IH), 7.32 (d, 2H), 7.52 (d, 2H), 7.76-7.98 (m, 5H), 8.03 (d, 2H), 8.27 (d, IH), 10.61 ( s, IH). LC-MS (Method 1): R _t = 0.71 min; MS (ESIneg): m / z = 623 [MH-HC1] \

Example 41

^~ N-alpha- {[iraws-4- (Aminomefhyl) cyclohexyl] carbonyl} -4- [4-methyl-6- (piperazin-1-yl) pyridin-3-yl] -N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide hydrochloride

Starting compound: feri-butyl-4- (5- {4 - [(2S) -2- {[(trans - - {[(ieri-butoxycarbonyl) amino] - methyl} cyclohexyl) carbonyl] amino} -3-oxo -3- {[4- (2 / i-tetrazol-5-yl) -phenyl] -amino} -propyl] -phenyl} -4-methyl-pyridin-2-yl) -piperazine-1-carboxylate-trifluoroacetate (150 mg, 0.16 mmol) , Dioxane (4.0 ml), 4M hydrogen chloride in 1,4-dioxane (0.60 ml, 2.40 mmol), yield: 72 mg (58% of theory, 90% purity).

^: H NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.82-1.00 (m, 2H), 1.07-1.34 (m, 2H), 1.40-1.61 (m, 2H), 1.67-1.83 (m, 3H), 2.04-2.30 (m, 4H), 2.55-2.68 (m, 2H), 2.95 (dd, IH), 3.07-3.34 (m, 5H), 3.88 (d, 4H), 4.70-4.78 (m, IH), 7.15 (bs, IH), 7.28 (d, 2H), 7.40 (d, 2H), 7.75-7.98 (m, 6H), 8.02 (d, 2H), 8.31 (d, IH), 9.4 (bs , IH), 10.61 (s, IH).

LC-MS (Method 1): R _t = 0.47 min; MS (ESIneg): m / z = 621 [MH-HC1] \

Example 42

NaI / ia- {[ira «A-4- (aminomethyl) cyclohexyl] carbonyl} -4- (2-ethoxypyridin-3-yl) -N- [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide hydrochloride

A solution of 27 mg (0.04 mmol) Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -4- (2-ethoxypyridin-3-yl ) N- [4- (2-i-tetrazol-5-yl) phenyl] -L-phenyl-alanineamide in 2 ml of 1,4-dioxane was treated with 0.10 ml (0.41 mmol) of 4M hydrogen chloride in 1,4-dioxane mixed and stirred for 4 h at RT. After the addition of another 0.10 ml (0.41 mmol) 4M hydrogen chloride in 1,4-dioxane was stirred overnight at RT. The precipitate was filtered off, washed with a little 1,4-dioxane and dried under high vacuum. 24 mg (81% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.85-1.01 (m, 2H), 1.14-1.34 (m, 5H), 1.40-1.55 (m, 1H), 1.57-1.67 ( m, 1H), 1.70-1.83 (m, 3H), 2.11-2.22 (m, 1H), 2.59-2.69 (m, 2H), 2.89

- 2.99 (m, 1H), 3.06 - 3.17 (m, 1H), 3.06 - 3.16 (m, 1H), 4.34 (q, 2H), 4.67 - 4.77 (m, 1H), 7.02

- 7.09 (m, 1H), 7.37 (d, 2H), 7.50 (d, 2H), 7.68 - 7.73 (m, 1H), 7.74 - 7.88 (m, 5H), 8.02 (d, 2 H), 8.11-8.15 (m, 1H), 8.26 (d, 1H), 10.55 (s, 1H).

LC-MS (Method 1): R _t = 0.75 min; MS (ES Ineg): m / z = 567 [MH-HC1] ^" . Example 43

^~ N-alpha- {[iraws-4- (Aminomefhyl) cyclohexyl] carbonyl} -4- [3-chloro-2- (morpholin-4-yl) pyridin-4-yl] -N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide hydrochloride

A solution of 71 mg (0.08 mmol) Na / j / ia - [(1α-ε-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -4- [3-chloro-2 ( morpholin-4-yl) pyridin-4-yl] - N - [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate in 3 ml of 1,4-dioxane was mixed with 0.31 ml ( 1.24 mmol) of 4M hydrogen chloride in 1,4-dioxane and stirred overnight at RT. The precipitate was filtered off, washed with a little acetonitrile and dried under high vacuum. The crude product was separated by preparative HPLC (mobile phase: acetonitrile / water with 0.1% TFA (gradient)). The product-containing fractions were combined, mixed with 0.2 ml of 4M hydrogen chloride in 1,4-dioxane and the mixture was concentrated on a rotary evaporator. The aqueous residue was then lyophilized. This gave 26 mg (43% of theory) of the title compound.

^: H NMR (400 MHz, DMSO-ife): δ = 0.81-1.01 (m, 2H), 1.09-1.35 (m, 2H), 1.39-1.63 (m, 2H), 1.67-1.85 (m , 3H), 2.07 - 2.21 (m, 1H), 2.59 - 2.70 (m, 2H), 2.89 - 3.02 (m, 1H), 3.09 - 3.15 (m, 1H), 3.20 - 3.33 (m , 4H), 3.68-3.82 (m, 4H), 4.70-4.81 (m, 1H), 6.99 (d, 1H), 7.35-7.49 (m, 4H), 7.67-7.92 (d, 5 H), 8.02 (d, 2H), 8.25 (d, 1H), 8.30 (d, 1H), 10.57 (s, 1H).

LC-MS (Method 1): R _t = 0.70 min; MS (ESIneg): m / z = 642 [MH-HC1] \

Example 44

Na / ia- {[ira5-4 (aniinomethyl) cyclohexyl] carbonyl} -3-fluoro-4- [6- (morpholin-4-yl) pyridin-3-yl] -N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide hydrochloride

A solution of 80 mg (0.10 mmol) Na / j / ia - [(1α-ε-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -3-fluoro-4- [6- ( morpholin-4-yl) pyridin-3-yl] - N - [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate in 4 ml of 1,4-dioxane was mixed with 0.36 ml ( 1.42 mmol) of 4M hydrogen chloride in 1,4-dioxane and stirred overnight at RT. The precipitate was filtered off, washed with a little acetonitrile and dried under high vacuum. 51 mg (76% of theory) of the title compound were obtained.

^: H NMR (400 MHz, DMSO-ife): δ = 0.83-1.01 (m, 2H), 1.12-1.34 (m, 2H), 1.40-1.65 (m, 2H), 1.68-1.84 (m , 3H), 2.08 - 2.21 (m, 1H), 2.58 - 2.69 (m, 2H), 2.87 - 3.01 (m, 1H), 3.09 - 3.20 (m, 1H), 3.52 - 3.64 (m , 4H), 3.71 - 3.77 (m, 4H), 4.67 - 4.78 (m, 1H), 7.08 - 7.20 (m, 1H), 7.22 - 7.34 (m, 2H), 7.45 - 7.56 (m , 1H), 7.73 - 7.97 (m, 6H), 8.03 (d, 2H), 8.24 (s, 1H), 8.30 (d, 1H), 10.63 (s, 1H).

LC-MS (Method 1): R _t = 0.63 min; MS (ES Ineg): m / z = 626 [MH-HC1] \

Example 45 ^~ N-alpha- {[iraws-4- (Aminomefhyl) cyclohexyl] carbonyl} -4- {6- [3- (dimethylamino) propoxy] pyridin-3-yl} -3-fluoro-N- [4- (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide hydrochloride

A solution of 69 mg (0.08 mmol) Na / j / ia - [(1α-ε-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -4- {6- [3- (dimethylamino ) propoxy] pyridin-3-yl} -3-fluoro-N- [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate in 3 ml of 1,4-dioxane was mixed with 0.30 ml (1.20 mmol) 4M hydrogen chloride in 1,4-dioxane and stirred overnight at RT. The precipitate was filtered off, washed with a little acetonitrile and dried under high vacuum. 40 mg (70% of theory) of the title compound were obtained.

^: H NMR (400 MHz, DMSO-ife): δ = 0.85-1.01 (m, 2H), 1.12-1.35 (m, 2H), 1.42-1.66 (m, 2H), 1.70-1.84 (m , 3 H), 2.10 - 2.22 (m, 3 H), 2.59 - 2.67 (m, 2 H), 2.78 (d, 6 H), 2.90 - 3.00 (m, 1 H), 3.10 - 3.25 (m, 3 H), 4.33-4.41 (m, 2H), 4.68-4.78 (m, 1H), 6.93 (d, 1H), 7.24-7.36 (m, 2H), 7.48 (t, 1H), 7.79 - 7.96 (m, 5H), 8.04 (d, 2H), 8.28 - 8.37 (m, 2H), 10.3 (bs, 1H), 10.66 (s, 1H).

LC-MS (Method 1): R _t = 0.62 min; MS (ESIneg): m / z = 642 [MH-HC1] \

Example 46 ^~ N -alpha {[ira_A-4- (aminomethyl) cyclohexyl] carbonyl} -4- [3-fluoro-2- (morpholin-4-yl) pyridin-4-yl] -N- [4 - (2 / i-tetrazol-5-yl) phenyl] -L-phenylalanine amide hydrochloride

A solution of 57 mg (0.07 mmol) Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -4- [3-fluoro-2 ( morpholin-4-yl) pyridin-4-yl] - N - [4- (2-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide trifluoroacetate in 2 ml of 1,4-dioxane was mixed with 0.25 ml ( 1.02 mmol) of 4M hydrogen chloride in 1,4-dioxane and stirred overnight at RT. The precipitate was filtered off, washed with a little acetonitrile and dried under high vacuum. 44 mg (83% of theory, 90% purity) of the title compound were obtained.

^: H NMR (400 MHz, DMSO-ife): δ = 0.82-1.00 (m, 2H), 1.10-1.34 (m, 2H), 1.40-1.64 (m, 2H), 1.67-1.82 (m , 3H), 2.10 - 2.20 (m, 1H), 2.58 - 2.69 (m, 2H), 2.90 - 3.02 (m, 1H), 3.08 - 3.20 (m, 1H), 3.28 - 3.45 (m , 4H), 3.65 - 3.79 (m, 4H), 4.69 - 4.80 (m, 1H), 6.95 - 7.07 (m, 1H), 7.40 - 7.57 (m, 4H), 7.72 - 7.90 (m , 5H), 7.97 - 8.09 (m, 3H), 8.30 (d, 1H), 10.61 (s, 1H).

LC-MS (Method 1): R _t = 0.70 min; MS (ES Ineg): m / z = 626 [MH-HC1] \

Example 47

^~ N-alpha- {[iraws-4- (Aminomefhyl) cyclohexyl] carbonyl} -N- [3-fluoro-4- (2 / i-tetrazol-5-yl) phenyl] -4- [4-methyl-6 - (piperazine-1-yl) pyridin-3-yl] -L-phenylalanine amide hydrochloride

To a solution of 79.9 mg (0.1 mmol) of tert-butyl 4- (5- {4 - [(2S) -2- {[(trans-4- {[(tert-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl ] amino} -3- {[3-fluoro-4- (2 / i-tetrazol-5-yl) phenyl] amino} -3-oxopropyl] phenyl} -4-methylpyridin-2-yl) piperazine-1-carboxylate in 2.5 ml of dioxane was added 119 μM (0.48 mmol) of 4M hydrogen chloride in dioxane. It was stirred for 16 h at RT. It was added 23.8 μΐ (0.1 mmol) of 4M hydrogen chloride in dioxane and stirred for a further 24 h at RT. The contents of the flask were treated with acetonitrile. The precipitated product was filtered off with suction, washed with acetonitrile and dried under high vacuum. 62 mg (92% of theory) of the title compound was obtained. ^: H NMR (300 MHz, DMSO-d ₆ ): δ = ppm 0.82-1.01 (m, 2H), 1.08-1.32 (m, 2H), 1.41-1.62 (m, 2H), 1.70-1.81 (m, 3H), 2.09 - 2.15 (m, 1H), 2.17 (s, 3H), 2.58 - 2.67 (m, 2H), 2.96 (dd, 1H), 3.12 (dd, 1H) , 3.16-3.24 (m, 4H), 3.79-3.84 (m, 4H), 4.66-4.76 (m, 1H), 7.01 (s, 1H), 7.24 (d, 2H), 7.38 (i.e. , 2H), 7.54 (dd, 1H), 7.80-7.90 (m, 5H), 8.01 (t, 1H), 8.30 (d, 1H), 9.28 (br. S, 2H), 10.81 (brs s, 1 H). LC-MS (Method 4): R _t = 0.58 min; MS (ESIpos): m / z = 641.5 [M + H-HC1] ⁺ .

Example 48

N-alpha- [[iraws-4- (aminomethyl) cyclohexyl] carbonyl} - N - [4- (3-chloro-4-i-1,2,4-triazol-5-yl) phenyl] -4- [ 4-methyl-6- (piperazin-1-yl) pyridin-3-yl] -L-phenylalanine amide hydrochloride

To a solution of 48.5 mg (56.6 μηιοΐ) of tert-butyl 4- (5- {4 - [(2S) -2- {[(trans-4- {[(tert-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl ] amino} -3- {[4- (3-chloro-4 / il, 2,4-triazol-5-yl) -phenyl] -amino} -3-oxopropyl] -phenyl} -4-methyl-pyridin-2-yl) -piperazine -l-carboxylate in 1.4 ml of dioxane was added 70.8 μΐ (283.1 μηιοΐ) 4M hydrogen chloride in dioxane. It was stirred for 24 h at RT. The contents of the flask were treated with acetonitrile. The precipitated product was filtered off with suction, washed with acetonitrile and dried under high vacuum. 30 mg (69% of theory) of the title compound were obtained.

Ή-NMR (300 MHz, DMSO-de): δ = ppm 0.79-0.97 (m, 2H), 1.06-1.32 (m, 2H), 1.37-1.58 (m, 2H), 1.64-1.79 (m , 3H), 2.06 - 2.13 (m, 1H), 2.15 (s, 3H), 2.55 - 2.64 (m, 2H), 2.90 (dd, 1H), 3.07 (dd, 1H), 3.13 3.21 (m, 4H), 3.75-3.82 (m, 4H), 4.63-4.74 (m, 1H), 6.96-7.02 (m, 1H), 7.23 (d, 2H), 7.33 (i.e. , 2H), 7.75 (d, 2H), 7.77-7.84 (m, 3H), 7.86 (d, 2H), 7.89-7.92 (m, 1H), 8.26 (d, 1H), 9.20 (brs s, 2H), 10.48 (s, 1H).

LC-MS (Method 4): R _t = 0.65 min; MS (ESIpos): m / z = 656.4 [M + H-HC1] ⁺ . Example 49

NaI / ia- {[ira «A-4- (aminomethyl) cyclohexyl] carbonyl} -4- (5-aminopyridin-3-yl) -N- [4- (1-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide hydrochloride

To a solution of 11 mg (17 μηιοΐ) of 4- (5-aminopyridin-3-yl) -Na / j / ia - [(ira "5-4- {[((fer-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl 1] -N- [4- (1-i-tetrazol-5-yl) phenyl] -L-phenyl-alaninamide formate in 0.7 ml of dioxane were added 0.04 ml (172 μηιοΐ) of 4M hydrogen chloride in dioxane. It was stirred for 24 h at 30 ° C. The contents of the flask were treated with acetonitrile. The precipitated product was filtered off with suction, washed with acetonitrile and dried under high vacuum. 9 mg (84% of theory) of the title compound were obtained.

^: H NMR (300 MHz, DMSO-d ₆ ): δ = ppm 0.77-1.00 (m, 2H), 1.10-1.30 (m, 2H), 1.37-1.49 (m, 1H), 1.53-1.62 (m, 1H), 1.65 - 1.79 (m, 3H), 2.05 - 2.18 (m, 1H), 2.57 - 2.64 (m, 2H), 2.93 (dd, 1H), 3.10 (dd, 1 H), 4.63-4.75 (m, 1H), 7.43 (d, 2H), 7.61 (d, 2H), 7.66-7.82 (m, 13H), 7.89-8.01 (m, 5H), 8.17 - 8.28 (m, 2H), 10.47 (s, 1H).

LC-MS (Method 4): R _t = 0.54 min; MS (ESIpos): m / z = 540.4 [M + H-HC1] ⁺ .

Example 50

^~ N-alpha- {[iraws-4- (Aminomefhyl) cyclohexyl] carbonyl} -N- [4- (1 / i-tetrazol-5-yl) phenyl] -4- [2- (trifluormefhyl) pyridin-3 - y 1] -L-phenylalanine amide hydrochloride

To a solution of 24.6 mg (3.5 μηιοΐ) Na / j / ia - [(ira "Ä- 4- {[(ieri-butoxycarbonyl) amino] - methyl} cyclohexyl) carbonyl] -N- [4- (l / i Etrazol-5-yl) phenyl] -4- [2- (trifluoromethyl) pyridm ^ phenylalaninamide formate in 1 ml of dichloromethane were added 0.09 ml (35.5 μηιοΐ) 4M hydrogen chloride in dioxane. It was stirred for 72 h at RT. The contents of the flask were treated with acetonitrile. The precipitated product was filtered off with suction, washed with acetonitrile and dried under high vacuum. The residue was purified by preparative HPLC (Method 7). 8 mg (36% of theory) of the title compound were obtained.

Ή-NMR (500 MHz, DMSO-d ₆ ): δ = ppm 0.85-0.97 (m, 2H), 1.12-1.33 (m, 2H), 1.39-1.50 (m, 1H), 1.53-1.59 ( m, 1H), 1.67-1.80 (m, 3H), 2.09-2.17 (m, 1H), 2.62-2.65 (m, 2H), 2.94 (dd, 1H), 3.14 (dd, 1H ), 4.71 - 4.79 (m, 1H), 7.26 (d, 2H), 7.41 (d, 2H), 7.59 (d, 2H), 7.75 (dd, 1H), 7.85 (dd, 1H ), 7.90 (d, 2H), 8.15 (d, 1H), 8.70 - 8.76 (m, 1H), 10.12 (s, 1H).

LC-MS (Method 4): R _t = 0.81 min; MS (ESIpos): m / z = 593.4 [M + H-HC1] ⁺ .

Example 51 ^~ N-alpha- {[iraws-4- (Aminomefhyl) cyclohexyl] carbonyl} -4- (6-amino-2-methyl-pyridin-3-yl) -N- [4- (1 / i-tetrazol-5 -yl) phenyl] -L-phenylalanine amide hydrochloride

To a solution of 19 mg (2.9 μηιοΐ) of 4- (6-amino-2-methylpyridin-3-yl) -Na / j / ia - [(ira "5-4- {[(ieri-butoxycarbonyl) amino] methyl } cyclohexyl) carbonyl] -N- [4- (l / i-tetrazol-5-yl) phenyl] -L-phenylalaninamide formate in 1.2 ml of dioxane was added 0.07 ml (29.1 μηιοΐ) 4M hydrogen chloride in dioxane. It was stirred for 24 h at 30 ° C. The contents of the flask were treated with acetonitrile. The precipitated product was filtered off with suction, washed with acetonitrile and dried under high vacuum. 16 mg (85% of theory) of the title compound were obtained.

^: H NMR (300 MHz, DMSO-d ₆ ): δ = ppm 0.74-0.99 (m, 2H), 1.06-1.30 (m, 2H), 1.36-1.48 (m, 1H), 1.48-1.59 (m, 1H), 1.64-1.79 (m, 3H), 2.05-2.17 (m, 1H), 2.29 (s, 3H), 2.56-2.64 (m, 2H), 2.90 (dd, 1 H), 3.07 (dd, 1H), 4.63-4.74 (m, 1H), 6.85 (d, 1H), 7.25 (d, 2H), 7.38 (d, 2H), 7.70-7.84 (m , 9H), 7.97 (d, 2H), 8.26 (d, 1H), 10.49 (s, 1H).

LC-MS (Method 4): R _t = 0.58 min; MS (ESIpos): m / z = 554.4 [M + H-HC1] ⁺ .

Example 52

NaI / ia- {[ira-i-4- (aniinomethyl) cyclohexyl] carbonyl} -4- [5- (piperidin-4-ylsulfamoyl) pyridin-3-yl] -N- [4- (1 / i tetrazol-5-yl) phenyl] -L-phenylalanine amide hydrochloride

To a solution of 60.9 mg (68.7 μηιοΐ) [(5- {A - [(2S) -2- {[(trans-A- {[(tert-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl 1] amino} -3-oxo-3 - {[4 - (1 / i-tetrazol-5-yl) - phenyl] amino} propyl] phenyl} pyridin-3-yl) sulfonyl] amino} piperidine-l-carboxylate in 1.5 ml of dioxane were 120 μΐ (480.6 μηιοΐ) 4M hydrogen chloride in Dioxane added. It was stirred for 24 h at RT. The contents of the flask were treated with acetonitrile. The precipitated product was filtered off with suction, washed with acetonitrile and dried under high vacuum. The residue was purified by preparative HPLC (Method 10). 18 mg (33% of theory) of the title compound were obtained. ^: H-NMR (300 MHz, DMSO-de): δ = ppm 0.80-0.97 (m, 2H), 1.10-1.27 (m, 2H), 1.39-1.61 (m, 5H), 1.65-1.79 ( m, 6H), 2.06-2.18 (m, 1H), 2.57-2.63 (m, 2H), 2.77-2.99 (m, 4H), 3.07-3.17 (m, 4H), 4.65-4.77 ( m, 1H), 7.47 (d, 2H), 7.69-7.76 (m, 4H), 7.81 (d, 2H), 7.98 (d, 2H), 8.26 (d, 2H), 8.36 - 8.39 (m, 1H), 8.89 - 8.92 (m, 1H), 8.94 - 8.97 (m, 1H), 9.10 - 9.14 (m, 1H), 10.55 (s, 1H). LC-MS (Method 4): R _t = 0.62 min; MS (ES Ineg): m / z = 685.4 [MH-HC1] \ Example 53

N-alpha- [[iraws-4- (arnomethyl) cyclohexyl] carbonyl} -4- [2- (4-methylpiperazin-1-yl) pyridin-4-yl] - N - [4- (1-i-tetrazole -5-yl) phenyl] -L-phenylalaninamide hydrochloride

To a solution of 23.2 mg (32 μηιοΐ) Na / j / ia - [(ira "Ä- 4- {[(ieri-butoxycarbonyl) amino] - methyl} cyclohexyl) carbonyl] -4- [2- (4-methylpiperazine -l-yl) pyridin-4-yl] -N- [4- (l / i-tetrazol-5-yl) phenyl] -L-phenylalaninamide formate in 1.4 ml of dioxane were 80 μΐ (321 μηιοΐ) 4M hydrogen chloride in Dioxane added. It was stirred for 24 h at 30 ° C. The contents of the flask were treated with acetonitrile. The precipitated product was filtered off with suction, washed with acetonitrile and dried under high vacuum. The residue was purified by preparative HPLC (Method 7). 4 mg (16% of theory) of the title compound were obtained.

^: H-NMR (400 MHz, DMSO-de): δ = ppm 0.80-0.96 (m, 2H), 1.09-1.30 (m, 2H), 1.35-1.48 (m, 1H), 1.53-1.60 m, 1H), 1.65-1.78 (m, 3H), 2.07-2.15 (m, 1H), 2.19 (s, 3H), 2.35-2.40 (m, 4H), 2.60 (d, 1H , 2.90 (dd, 1H), 3.09 (dd, 1H), 3.50 - 3.54 (m, 4H), 4.63 - 4.74 (m, 1H), 6.88 - 6.91 (m, 1H), 6.97 - 7.01 (m, 1H), 7.38 (d, 2H), 7.57 (d, 2H), 7.66 (d, 2H), 7.87 (d, 2H), 8.08-8.15 (m, 3H), 10.10 (s, 1H).

LC-MS (Method 4): R _t = 0.57 min; MS (ESIpos): m / z = 623.5 [M + H-HC1] ⁺ . Example 54

N-alpha- [[iraws-4- (aminomethyl) cyclohexyl] carbonyl} -4- [6- (4-methylpiperazin-1-yl) pyridin-3-yl] - N - [4- (1-i-tetrazole -5-yl) phenyl] -L-phenylalaninamide hydrochloride

To a solution of 49 mg (67.8 μηιοΐ) Na / j / ia - [(ira "Ä- 4- {[(ieri-butoxycarbonyl) amino] - methyl} cyclohexyl) carbonyl] -4- [6- (4-methylpiperazine -l-yl) pyridin-3-yl] -N- [4- (1-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide formate in 1 ml of dichloromethane was added 169 μΐ (678 μmol) of 4M hydrogen chloride Dioxane added. It was stirred for 72 h at RT. The contents of the flask were treated with acetonitrile. The precipitated product was filtered off with suction, washed with acetonitrile and dried under high vacuum. The residue was purified by preparative HPLC (Method 6). 30 mg (60% of theory) of the title compound were obtained.

Ή-NMR (500 MHz, DMSO-d ₆ ): δ = ppm 0.85-0.96 (m, 2H), 1.13-1.31 (m, 2H), 1.38-1.49 (m, 1H), 1.56-1.62 ( m, 1H), 1.68-1.79 (m, 3H), 2.10-2.18 (m, 1H), 2.37-2.42 (m, 4H), 2.62-2.65 (m, 2H), 2.88 (dd, 1H), 3.07 (dd, 1H), 3.49- 3.52 (m, 4H), 4.65-4.72 (m, 1H), 6.88 (d, 1H), 7.35 (d, 2H), 7.52 ( d, 2H), 7.59 (d, 2H), 7.82 (dd, 1H), 7.88 (d, 2H), 8.12 (d, 1H), 8.16 (s, 1H), 8.41-8.42 ( m, 1H), 10.11 (s, 1H).

LC-MS (Method 4): R _t = 0.58 min; MS (ESIpos): m / z = 623.5 [M + H-HC1] ⁺ . Example 55

Na / ia- {[ira «A-4- (aminomethyl) cyclohexyl] carbonyl} -4- (2-amino-4-methylpyrimidin-5-yl) -N- [4- (l / i-tetrazole) 5-yl) phenyl] -L-phenylalaninamide hydrochloride

To a solution of 11.4 mg (17 μηιοΐ) of 4- (2-amino-4-methylpyrimidin-5-yl) -Na / j / ia - [(ira "5-4- {[(ieri-butoxycarbonyl) amino] methyl } cyclohexyl) carbonyl] -N- [4- (l / i-tetrazol-5-yl) phenyl] -L-phenylalaninamide in 0.7 ml of dioxane were added 43.5 μΐ (174 μηιοΐ) 4M hydrogen chloride in dioxane. The mixture was stirred for 4 h at 40 ° C. The contents of the flask were treated with acetonitrile. The precipitated product was filtered off with suction, washed with acetonitrile and dried under high vacuum. 8 mg (73% of theory) of the title compound were obtained.

Ή-NMR (300 MHz, DMSO-d ₆ ): δ = ppm 0.79-0.97 (m, 2H), 1.05-1.31 (m, 2H), 1.36-1.59 (m, 2H), 1.65-1.81 ( m, 3H), 2.04-2.17 (m, 1H), 2.24 (s, 3H), 2.54-2.66 (m, 2H), 2.92 (dd, 1H), 3.10 (dd, 1H), 4.64-4.75 (m, 1H), 7.26 (d, 2H), 7.36 (d, 2H), 7.79 (m, 4H), 7.98 (d, 2H), 8.17 (s, 1H), 8.22 (d, 1H), 10.48 (s, 1H).

LC-MS (Method 4): R _t = 0.60 min; MS (ESIpos): m / z = 555.4 [M + H-HC1] ⁺ . Example 56

^~ N-alpha- {[iraws-4- (Aminomefhyl) cyclohexyl] carbonyl} -N- [4- (3-chloro-4 / i- 1, 2,4-triazol-5-yl) - phenyl] -4 - {6- [3- (dimethylamino) propoxy] pyridin-3-yl} -L-phenylalaninamide hydrochloride

To a solution of 35.4 mg (46.6 μηιοΐ) of Na / j / ia - [(ira «A-4- {[(ieri-butoxycarbonyl) -amino] -methyl} cyclohexyl) carbonyl] -N- [4- (3-chloro 4-i-1, 2,4-triazol-5-yl) phenyl] -4- {6- [3- (dimethylamino) propoxy] pyridin-3-yl} -L-phenylalanine amide formate in 1.2 ml of dichloromethane 58.3 μΐ (233.1 μηιοΐ) 4M hydrogen chloride in dioxane was added. The mixture was stirred for 2 h at 40 ° C. The contents of the flask were treated with acetonitrile. The precipitated product was filtered off with suction, washed with acetonitrile and dried under high vacuum. 28 mg (86% of theory) of the title compound were obtained.

^: H NMR (300 MHz, DMSO-de): δ = ppm 0.77-0.97 (m, 2H), 1.06-1.31 (m, 2H), 1.36-1.49 (m, 1H), 1.51-1.61 ( m, 1H), 1.64-1.79 (m, 3H), 2.05-2.17 (m, 3H), 2.53-2.63 (m, 2H), 2.73 (s, 3H), 2.75 (s, 3H , 2.89 (dd, 1H), 3.07 (dd, 1H), 3.12-3.21 (m, 2H), 4.29-4.36 (m, 2H), 4.60-4.71 (m, 1H), 6.86 ( d, 1H), 7.38 (d, 2H), 7.55 (d, 2H), 7.75 (d, 2H), 7.79-7.86 (m, 3H), 7.89 (d, 2H), 7.97 ( dd, 1H), 8.25 (d, 1H), 8.42 (d, 1H), 10.15-10.29 (m, 1H), 10.54 (s, 1H).

LC-MS (Method 4): R _t = 0.70 min; MS (ESIpos): m / z = 659.4 [M + H-HC1] ⁺ .

Example 57 NaI / ia- {[ira «A-4- (aminomethyl) cyclohexyl] carbonyl} -4- (4-methylpyridin-3-yl) -N- [4- (2-i-tetrazol-5- yl) phenyl] -L-phenylalanine amide hydrochloride

To a solution of 40 mg (61 μηιοΐ) Na / j / ia - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] -methy 1} cyclohexyl) carbonyl 1] -4- (4-methylpyridine) 3 -y 1) -N- [4- (2-i-tetrazol-5-yl) -phenyl] -L-phenyl-alaninamide in 4.1 ml of tetrahydrofuran was added 68.4 μΐ (2.74 mmol) of 4M hydrogen chloride in dioxane. It was stirred for 4 h at RT. There were another 15 eq. 4M hydrogen chloride in dioxane was added and stirred overnight. The precipitated product was filtered off with suction, washed with tetrahydrofuran and dried under high vacuum. 36 mg (93% of theory) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.80 - 1.00 (m, 2H), 1.1 1 - 1.35 (m, 2H), 1.42 - 1.61 (m, 2H), 1.69 - 1.83 (m, 4H), 2.10-2.21 (m, 1H), 2.43 (s, 3H), 2.63 (m, 2H), 3.00 (dd, 1H), 3.18 (dd, 1H), 4.72 - 4.81 (m, 1H), 7.43 (d, 2H), 7.51 (d, 2H), 7.86 (d, 2H), 7.93 (m, 4H), 8.04 (d, 2H), 8.37 (d, 1H), 8.68 (s, 1H), 8.74 (d, 1H), 10.67 (s, 1H).

LC-MS (Method 3): R _t = 0.52 min; MS (ESIpos): m / z = 539.3 [M + H-HC1] ⁺ .

Example 58

Ethyl 5- {4- [(2S) -2- ({[ira-Ä- 4- (aminomethyl) cyclohexyl] carbonyl} amino) -3-oxo-3- {[4- (2H-tetrazole-5- yl) phenyl] amino} propyl] phenyl} -6-methylpyridine-2-carboxylate hydrochloride

To a solution of 30.3 mg (43 μηιοΐ) of ethyl 5- {4 - [(2 _l ^S) -2- {[(ira "Ä-4- {[(ieri-butoxycarbonyl) - amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2-i-tetrazol-5-yl) -phenyl] -amino-propyl] -phenyl} -6-methyl-pyridine-2-carboxylate-trifluoroacetate in 1.5 ml of dioxane became 160 μΐ (0.64 mmol) 4M hydrogen chloride in dioxane was added. It was stirred for 6 days at RT. The precipitated product was filtered off with suction, washed with a little dioxane and dried under high vacuum. 32 mg (96% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-ife): δ = ppm 0.82-0.99 (m, 2H), 1.10-1.30 (m, 2H), 1.34 (t, 3H), 1.41-1.51 (m, 1H ), 1.53 - 1.61 (m, 1H), 1.73 (d, 3H), 2.11 - 2.20 (m, 1H), 2.45 (s, 3H), 2.62 (m, 2H), 2.97 (dd, 1 H), 3.16 (dd, 1H), 4.36 (q, 2H), 4.74 - 4.81 (m, 1H), 7.36 (d, 2H), 7.45 (d, 2H), 7.76 (d, 1H), 7.84 (m, 5H), 7.95 (d, 1H), 7.99 (d, 1H), 8.03 (d, 2H), 8.27-8.33 (m, 1H), 10.58 (br. s., 1 H)

LC-MS (Method 1): R _t = 0.7 min; MS (ESIpos): m / z = 61 1 [M + H-HC1] ⁺ . Example 59

3- (5- {4 - [(A ^r - {[ira-i-4- (aminomethyl) cyclohexyl] carbonyl} -4- [2- (morpholin-4-yl) py

L-phenylalanyl) amino] phenyl} -1 /, 2,4-riazol-3-yl) -2,2,3,3-etrafluoropropene

To a solution of 64 mg (75 μηιοΐ) of 3- {5- [4 - ({A ^r - [(1α-ε-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -4- [2- (morpholin-4-yl) pyrimidin-5-yl] -L-phenylalanyl} amino) -phenyl] -l / il, 2,4-triazol-3-yl} -2,2,3,3- tetrafluoropropanoic acid in 2 ml of dioxane was added 280 μΐ (1.1 mmol) of 4M hydrogen chloride in dioxane. It was stirred for 18 h at RT. Acetonitrile was added and the resulting solid filtered, washed with acetonitrile and dried under high vacuum. 53 mg (86% of theory) of the title compound were obtained.

^: H NMR (400 MHz, DMSO-ifc): δ = ppm 0.92 (m, 2H), 1.09 - 1.33 (m, 2H), 1.37 - 1.64 (m, 2H), 1.67 - 1.82 (m, 2 H), 2.09 - 2.21 (m, 1H), 2.57 - 2.68 (m, 2H), 2.92 (m, 1H), 3.04 - 3.15 (m, 1H), 3.64 - 3.70 (m, 4H) , 3.71 - 3.78 (m, 4H), 4.70 (m, 1H), 7.40 (d, 2H), 7.59 (d, 2H), 7.81 (m, 5H), 7.99 (d, 2H) , 8.24 (d, 1H), 8.72 (s, 2H), 10.55 (br, s, 1H), 15.06-15.31 (br, s, 1H). LC-MS (Method 1): R _t = 0.67 min; MS (ESIpos): m / z = 754.5 [M + H-HC1] B) Assessment of physiological efficacy

The suitability of the compounds according to the invention for the treatment of thromboembolic or hyperfibrinolytic disorders can be demonstrated in the following assay systems: a) Test descriptions (in vitro) a.l) Measurement of FXIa inhibition

To determine the factor XIa inhibition of the substances according to the invention, a biochemical test system is used in which the reaction of a peptide factor Xla substrate is used to determine the enzymatic activity of human factor XIa. Factor XIa from the peptic factor XIa substrate cleaves the C-terminal aminomethylcoumarin (AMC) whose fluorescence is measured. The determinations are carried out in microtiter plates.

Test substances are dissolved in dimethyl sulfoxide and serially diluted in dimethylsulfoxide (3000 μΜ to 0.0078 μΜ, resulting final concentrations in the test: 50 μΜ to 0.00013 μΜ). 1 μΐ each of the diluted substance solutions are placed in the wells of white microtiter plates from Greiner (384 wells). Subsequently, 20 μΐ assay buffer (50 mmol / l Tris buffer pH 7.4, 100 mmol / l sodium chloride, 5 mmol / l calcium chloride, 0.1% bovine serum albumin) and 20 μΐ factor XIa from Kordia (0.45 nM in assay buffer) are added successively. After incubation for 15 min, the enzyme reaction is started by addition of 20 .mu.l of the factor XIa substrate Boc-Glu (OBzl) -Ala-Arg-AMC (10 .mu.l in assay buffer) from Bachem dissolved in assay buffer, for 30 min at room temperature (22.degree C) and then a fluorescence measurement carried out (excitation: 360 nM, emission: 460 nM). The measured emissions of the test mixtures with test substance are compared with those of control preparations without test substance (excluding dimethyl sulfoxide instead of test substance in dimethylsulfoxide) and calculated from the concentration-effect relationships IC 50 values. Action data from this test are listed in Table A below:

Table A

Example No., IC ₅₀ [nM] Example No., ICso [nM]

 1 5.7 2 5.3

 3 2.3 4 3.8

5 7.0 6 15 Example No., ICso [nM] Example No., ICso [nM]

7 2.2 8 9.2

9 3.6 10 6.2

11 5.2 12 5.9

13 2.1 14 8.5

15 2.8 16 13

17 10 18 2.7

19 16 20 3.8

21 1.3 22 6.1

23 3.6 24 3.1

25 8.0 26 3.7

27 5.6 28 7.8

29 1.3 30 6.7

31 15 32 2.4

33 20 34 5.4

35 5.5 36 7.2

37 5.3 38 4.8

39 15 40 2.6

41 3.2 42 3.0

43 1.8 44 2.0

45 13 46 3.7

47 1.1 48 3.5

49 3.2 50 1.3

51 3.7 52 6.9

53 11 54 7.2

55 3.0 56 9.6

57 4.4 58 0.8 Example No., ICso [nM] Example No., ICso [nM]

 2.6

a.2) Determination of selectivity

To demonstrate the selectivity of the substances with respect to FXIa inhibition, the test substances are tested for their inhibition of other human serine proteases, such as factor Xa, trypsin and plasmin. To determine the enzymatic activity of factor Xa (1.3 nmol / l of Kordia), trypsin (83 mU / ml of Sigma) and plasmin (0.1 ug / 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 for 15 min with test substance in various concentrations in dimethyl sulfoxide and with dimethyl sulfoxide incubated without test substance. The enzymatic reaction is then started by addition of the appropriate substrates (5 μηιοΐ / ΐ Boc-Ile-Glu-Gly-Arg-AMC from Bachem for factor Xa and trypsin, 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 control preparations without test substance (excluding dimethyl sulfoxide instead of test substance in dimethyl sulfoxide) and IC 50 values are calculated from the concentration-effect relationships. a.3) thrombin generation assay (thrombogram)

The effect of the test substances on the Thrombogram (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). The reactions are carried out in the presence of varying concentrations of test substance or the corresponding solvent. Reagents from the company Thrombinoscope are used to start the reaction (30 pM or 0.1 pM recombinant tissue factor, 24 μM phospholipids in HEPES). In addition, a Thrombin Calibrator from the company Thrombinoscope is used, whose amidolytic activity is required for calculating the thrombin activity in a sample with an unknown amount of thrombin. 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 measured every 20 seconds for 120 min. 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.4) Determination of the anticoagulant effect

The anticoagulant activity of the test substances is determined in vitro in human and animal plasma (eg mouse, rat, rabbit, porcine and canine 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 using 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.

The activated partial thromboplastin time (aPTT) is determined in the presence of varying concentrations of test substance or the corresponding solvent using a commercially available test kit (CK Perst from the company Diagnostica Stago). 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 addition of a 25 mM aqueous calcium chloride solution and the time of coagulation is determined. The concentration of test substance is determined which causes a 1.5-fold prolongation of the aPTT. Effect data from this test are listed in Table B below: Table B

Example No., aPTT Example No. »aPTT

 [μπιοΐ / ΐ] [pmol l]

2 0.28 3 0.24

4 0.23 5 0.35

7 0.29 8 0.15

9 0.35 11 0.24

12 0.43 13 0.13

14 0.28 15 0.14

16 0.33 18 0.33

19 0.17 20 0.22

21 0.27 22 0.27

23 0.24 24 0.18

25 0.29 26 0.19

27 0.24 29 0.21

30 0.34 31 0.22

32 0.3 33 0.29

34 0.14 35 0.48

37 0.26 39 0.38

40 0.08 41 0.06

43 0.37 44 0.22

45 0.35 46 0.45

47 0.08 48 0.11

49 0.14 50 0.16

51 0.19 52 0.21

53 0.21 54 0.21

55 0.22 56 0.25 Example No., aPTT Example No., aPTT

 [μιηοΙΛ] [moWl

 57 0.35 58 0.34

 59 0.08

a.5) Determination of the fibrinolytic effect

The anti-fibrinolytic activity in vitro is evaluated in human, platelet-free plasma. Tissue factor (TF) (1 pM) and tissue plasminogen activator (tPA) (40 nM) are pipetted together with 12.5 mM aqueous calcium chloride solution and substance in plasma. After clot formation, the subsequent clot lysis is determined photometrically over a period of 30 minutes. a.6) Measurement of plasmin inhibition

To determine the plasmin inhibition of the substances according to the invention, a biochemical test system is used in which the reaction of a peptidic plasmin substrate is used to determine the enzymatic activity of human plasmin. Plasmin separates from the peptic plasmin substrate the C-terminal aminomethylcoumarin (AMC), whose fluorescence is measured. The determinations are carried out in microtiter plates. Test substances are dissolved in dimethyl sulfoxide and serially diluted in dimethylsulfoxide (3000 μΜ to 0.0078 μΜ, resulting final concentrations in the test: 50 μΜ to 0.00013 μΜ). 1 μΐ each of the diluted substance solutions are placed in the wells of white microtiter plates from Greiner (384 wells). Subsequently, 20 μl of assay buffer (50 mmol / l Tris buffer pH 7.4, 100 mmol / l sodium chloride, 5 mmol / l calcium chloride, 0.1% bovine serum albumin) and 20 μl plasmin from Kordia (0.3 μg / ml in assay buffer) are added successively , After incubation for 15 min, the enzyme reaction is started by adding 20 μl of the plasmin substrate MeOSuc-Ala-Phe-Lys-AMC (150 μl in assay buffer) dissolved in assay buffer, incubated for 30 min at room temperature (22 ° C.) and then a fluorescence measurement was carried out (excitation: 360 nM, emission: 460 nM). The measured emissions of the test mixtures with test substance are compared with those of control preparations without test substance (excluding dimethyl sulfoxide instead of test substance in dimethylsulfoxide) and calculated from the concentration-effect relationships IC 50 values. Action data from this test are listed in Table C below: Table C

b) Determination of the antithrombotic effect (in vivo) bl) Arterial thrombosis model (iron (II) chloride-induced thrombosis) in combination with ear bleeding time in the rabbit

The antithrombotic activity of FXIa inhibitors is tested in an arterial thrombosis model. The thrombus formation is triggered by chemical damage to a portion of the carotid artery in the rabbit. Simultaneously, the ear bleeding time is determined.

Male rabbits (Crl: KBL (NZW) BR, Charles River) under a diet of 2.2-2.5 kg body weight are administered by intramuscular administration of xylazine and ketamine (Rompun, Bayer, 5 mg kg and Ketavet, Pharmacia & Upjohn GmbH, 40 mg kg body weight) anesthetized. Anesthesia is further assisted by intravenous administration of the same preparations (bolus: continuous infusion) via the right ear vein.

After free preparation of the right carotid artery, the vascular damage is produced by wrapping a piece of filter paper (10 mm x 10 mm) on a Parafilm® (25 mm x 12 mm) strip around the carotid artery without affecting the blood flow. The filter paper containing 100 μΐ _^ of a 13% solution of iron (II) chloride (Sigma) in water. After 5 minutes, the filter paper is removed and the vessel rinsed twice with aqueous 0.9% sodium chloride solution. 30 minutes after the injury, the carotid artery is dissected out in the area of the damage and any thrombotic material is removed and weighed.

The test substances are either administered intravenously via the femoral vein anesthetized or orally by gavage to the awake animals each 5 min or 2 h before damage.

The ear bleeding time is determined 2 minutes after the injury to the carotid artery. For this purpose, the left ear is shaved and a defined section of 3 mm in length (blade Art.No. 10-150-10, Martin, Tuttlingen, Germany) is set parallel to the longitudinal axis of the ear. Care is taken not to injure any visible vessel. Any escaping blood is collected at 15-second intervals with accurately weighed pieces of filter paper without touching the wound directly. The bleeding time is calculated as the time from setting the cut to the time the blood on the filter paper is no longer detectable. The leaked blood volume is calculated after weighing the pieces of filter paper. c) Determination of fibrinolytic activity (in vivo) c. l) hyper-fibrinolytic rats The determination of the antifibrinolytic action in vivo is carried out in hyper-fibrinolytic rats. Following anesthesia and catheterization of the animals, hyper-fibinolysis is initiated by infusion of tissue plasminogen activator (tPA) (8 mg / kg / h). 10 minutes after the beginning of the tPA infusion, the substances are administered as an iv bolus. After another 15 minutes, the tPA infusion is terminated and a tail transsection performed. The subaquale bleeding (37 ° C tempered physiological sodium chloride solution) is observed over 30 minutes and determines the bleeding time.

C) Exemplary embodiments of pharmaceutical preparations

The substances according to the invention can, for example, 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) 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 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.

Orally administrable solution:

Composition:

500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of the compound according to the invention correspond to 20 g of oral solution. production:

The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention. i.v. solution: The compound of the invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g., isotonic sodium chloride solution, glucose solution 5% and / or polyethylene glycol 400 / water 30% m / m). The solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

Claims

 claims

Compound of the formula

in which for a group of the formula

where # is the point of attachment to the nitrogen atom,

R is 5-membered heteroaryl, wherein heteroaryl may be substituted with one substituent selected from the group consisting of oxo, chloro, cyano, hydroxy and C ₁ -C ₃ -alkyl, wherein alkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of hydroxy, amino, hydroxycarbonyl and methoxy, or wherein alkyl may be substituted with 1 to 7 substituents fluoro, or wherein alkyl is substituted with a substituent selected from the group consisting of hydroxy, amino, hydroxycarbonyl and methoxy and wherein alkyl is additionally substituted with 1 to 6 substituents fluoro,

R ^{7 is} hydrogen, fluorine or chlorine,

R ⁸ and R ⁹ together with the carbon atoms to which they are attached form a 5-membered heterocycle, it being possible for the heterocycle to be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, chloro, cyano, hydroxy, and Ci C3-alkyl, pyrazolyl and pyridyl, wherein alkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of hydroxy, amino, hydroxycarbonyl and methoxy, or wherein alkyl may be substituted with 1 to 7 fluorine substituents, or wherein Alkyl is substituted by a substituent selected from the group consisting of hydroxy, amino, hydroxycarbonyl and methoxy and wherein alkyl is additionally substituted by 1 to 6 substituents fluorine,

R ^{10 is} hydrogen, fluorine or chlorine, is a group of the formula

stands, where * is the point of attachment to the phenyl ring,

R ^{4 is} hydrogen, hydroxy, amino, Ci-Gt-alkoxy, Ci-C3-alkylamino, Ci-C4-alkylcarbonylamino, C3-C6-cycloalkylamino or via a nitrogen atom bonded 5- or 6-membered heterocyclyl, wherein alkoxy be substituted may be substituted with 1 to 2 substituents independently selected from the group consisting of amino and C ₁ -C 3 alkylamino, and wherein heterocyclyl may be substituted with 1 to 2 substituents independently selected from the group consisting of oxo,

Fluorine, hydroxyl, amino, hydroxycarbonyl, C ₁ -C 4 -alkyl, C ₁ -C ₃ -alkylamino, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroeth-1-yl, C ₁ -C 4 -alkoxycarbonyl, aminocarbonyl and C ₁ -C 3 alkylaminocarbonyl,

R ^{5 is} hydrogen, hydroxy, C 1 -C 4 -alkyl, methoxy, trifluoromethyl or benzyloxy,

R ^{11 represents} hydrogen, amino, C 1 -C 4 -alkoxy, C 1 -C 3 -alkylamino, C 1 -C 4 -alkoxycarbonyl, C 1 -C 3 -alkylsulfonyl, -S (O) 2NR ¹³ R ¹⁴ , pyridinyloxy or 5 or 5 bonded via a nitrogen atom 6-membered heterocyclyl, where alkoxy may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of amino and C ₁ -C ₃ -alkylamino, and where alkylamino may be substituted by a 5- or 6-membered bond via a nitrogen atom. heterocyclyl, and wherein heterocyclyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, fluoro, hydroxy, amino, hydroxycarbonyl, C 1 -C 4 -alkyl, C 1 -C 3 -alkyl, Alkylamino, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroeth-l-yl, C ₁ -C ₄ - alkoxycarbonyl, aminocarbonyl and Ci-C3-alkylaminocarbonyl, and wherein

R ^{13 is} hydrogen, C ₁ -C ₃ -alkyl, C ₃ -C ₆ -cycloalkyl, benzyl or a 4 to 8-membered heterocyclyl bonded via a carbon atom,

R ^{14 is} hydrogen or C ₁ -C ₃ -alkyl, or

R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, wherein the heterocycle may be substituted with 1 to 2 substituents independently selected from the group consisting of oxo, fluoro, hydroxy, amino , Hydroxycarbonyl, C 1 -C ₄ -alkyl, C ₁ -C ₃ -alkylamino, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroeth-1-yl, C ₁ -C ₄ -alkoxycarbonyl, aminocarbonyl and C ₁ -C ₃ -alkylaminocarbonyl, for hydrogen, fluorine, chlorine, hydroxy, Ci-C ₄ alkyl, methoxy or trifluoromethyl, represents hydrogen, amino, Ci-C ₄ alkoxy, Ci-C ₃ alkylamino, C ₁ -C ₄ - alkoxycarbonyl, Ci-C _3- alkylsulfonyl, -S (O) ₂ NR ¹⁷ R ¹⁸ , pyridinyloxy or via a nitrogen atom bonded 5- or 6-membered heterocyclyl, wherein alkoxy may be substituted by 1 to 2 substituents independently selected from the group consisting of amino and C ₁ -C 3 alkylamino, and wherein alkylamino may be substituted with an over e 5- or 6-membered heterocyclyl bonded in nitrogen atom, and where heterocyclyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of oxo, fluorine, hydroxyl, amino, hydroxycarbonyl, C 1 -C 4 -alkyl, C 1 -C 3 -alkylamino, difluoromethyl, trifluoromethyl, 2,2, 2-trifluorefh-1-yl, C1-C4 alkoxycarbonyl, aminocarbonyl and Ci-C3-alkylaminocarbonyl, and wherein

R ^{17 is} hydrogen, C 1 -C 8 -alkyl, C 1 -C 6 -cycloalkyl, benzyl or a 4 to 8-membered heterocyclyl bonded via a carbon atom,

R ^{18 is} hydrogen or C ₁ -C ₃ -alkyl, or

R ¹⁷ and R ¹⁸ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, wherein the heterocycle may be substituted with 1 to 2 substituents independently selected from the group consisting of oxo, fluoro, hydroxy, amino , Hydroxycarbonyl, C 1 -C ₄ -alkyl, C 1 -C 8 -alkylamino, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroeth-1-yl, C 1 -C 4 -alkoxycarbonyl, aminocarbonyl and C 1 -C 3 -alkylaminocarbonyl,

R ^{16 is} hydrogen, fluorine, chlorine, C 1 -C ⁴ -alkyl, methoxy or trifluoromethyl,

R ^{3 represents} hydrogen, fluorine, chlorine, methyl or methoxy, or one of their salts, their solvates or the solvates of their salts.

A compound according to claim 1, characterized in that for a group of the formula where # is the point of attachment to the nitrogen atom,

R ^{6 is} 5-membered heteroaryl, where heteroaryl may be substituted by a substituent selected from the group consisting of oxo and chlorine,

R ^{7 is} hydrogen or fluorine,

R ⁸ and R ⁹ together with the carbon atoms to which they are attached form a 5-membered heterocycle, it being possible for the heterocycle to be substituted by 1 to 2 substituents oxo,

R ^{10 is} hydrogen, for a group of the formula

the point of attachment to the phenyl ring is, for amino, Ci-C3-alkylamino or via a nitrogen atom bound 5- or 6-membered heterocyclyl, wherein heterocyclyl may be substituted with 1 to 2 substituents methyl, represents hydrogen, hydroxyl, methyl, methoxy or benzyloxy, hydrogen, amino, C 1 -C 4 -alkoxy, C 1 -C 3 -alkylamino, C 1 -C 4 -alkoxycarbonyl, C 1 -C 3 -alkylsulfonyl, -S (O) 2NR ¹³ R ¹⁴ , pyridinyloxy or a nitrogen atom bonded 5- or 6-membered heterocyclyl, wherein alkoxy may be substituted with a substituent C ₁ -C 3 alkylamino, and wherein alkylamino may be substituted with a 5- or 6-membered linked via a nitrogen atom Heterocyclyl, and wherein heterocyclyl may be substituted with 1 to 2 substituents methyl, and wherein

R ^{13 is} a 4- to 8-membered heterocyclyl bonded via a carbon atom,

R ^{14 is} hydrogen, or

R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, wherein the heterocycle may be substituted by 1 to 2 substituents methyl, represents hydrogen, hydroxy, methyl or trifluoromethyl, hydrogen, C 1 -C 4 -alkoxy or a 5- or 6-membered heterocyclyl bonded via a nitrogen atom, where heterocyclyl can be substituted by 1 to 2 substituents methyl,

R is hydrogen,

R ^{3 is} hydrogen or fluorine, or one of their salts, their solvates or the solvates of their salts.

Connection according to one of claims 1 or 2, characterized in that

R ^{1 is} a group of the formula

where # is the point of attachment to the nitrogen atom,

R ^{6 is} oxadiazolyl, pyrazolyl, triazolyl or tetrazolyl, where oxadiazolyl, pyrazolyl and triazolyl may be substituted by a substituent selected from the group consisting of oxo and chlorine,

R ^{7 is} hydrogen or fluorine,

is 2,3-dihydro-l / i-indazol-6-yl or l / hndazol-6-yl, wherein 2,3-dihydro-l / i-indazol-6-yl and l / i-indazole-6 -yl may be substituted with a substituent Oxo, for a group of the formula where * is the point of attachment to the phenyl ring,

R ^{4 is} amino, C 1 -C ³ -alkylamino or heterocyclyl bonded via a nitrogen atom selected from the group consisting of morpholinyl and

Piperazinyl, where morpholinyl and piperazinyl may be substituted by 1 to 2 methyl substituents,

R ^{5 represents} hydrogen, hydroxyl, methyl, methoxy or benzyloxy, R ^{11 represents} hydrogen, amino, C ₁ -C 4 -alkoxy, C ₁ -C ₃ -alkylamino, C ₁ -C 4 -alkyl,

Alkoxycarbonyl, Ci-C3-alkylsulfonyl, -S (0) ₂ NR ¹³ R ^14, pyridinyloxy or bonded via a nitrogen atom heterocyclyl selected from the group consisting of morpholinyl and piperazinyl is, where alkoxy may be substituted with a substituent C ₁ -C3- Alkylamino, and wherein alkylamino may be substituted with a heterocyclyl bonded via a nitrogen atom selected from the group consisting of morpholinyl and piperazinyl, and wherein morpholinyl and piperazinyl may be substituted with 1 to 2 substituents methyl, and wherein R ^{13 is} piperidinyl bound via a carbon atom,

R ^{14 is} hydrogen, or

R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a morpholinyl or piperazinyl in which morpholinyl and piperazinyl may be substituted by 1 to 2 substituents methyl, hydrogen, hydroxy, methyl or trifluoromethyl, hydrogen, Ci-C t-alkoxy or heterocyclyl bonded via a nitrogen atom selected from the group consisting of morpholinyl and piperazinyl, where morpholinyl and piperazinyl may be substituted by 1 to 2 substituents methyl, represents hydrogen,

R is hydrogen or fluorine, or one of their salts, their solvates or the solvates of their salts.

Process for the preparation of a compound of the formula (I) or one of its salts, of its solvates or of the solvates of its salts according to Claim 1, characterized in that a compound of the formula

in which R ¹ , R ² and R ^{3 have} the meaning given in claim 1, is reacted with an acid.

A compound according to any one of claims 1 to 3 for the treatment and / or prophylaxis of diseases.

Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment and / or prophylaxis of diseases.

Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment and / or prophylaxis of thrombotic or thromboembolic disorders.

A medicament containing a compound according to any one of claims 1 to 3 in combination with an inert, non-toxic, pharmaceutically suitable excipient.

Medicament according to claim 8 for the treatment and / or prophylaxis of thrombotic or thromboembolic diseases.

A method for controlling thrombotic or thromboembolic disorders in humans and animals by administering a therapeutically effective amount of at least one compound according to any one of claims 1 to 3, a drug according to claim 8 or a medicament obtained according to claim 6 or 7.