EP3049408A1 - 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 drugs 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 for a group of the formula where # is the point of attachment to the nitrogen atom,

R ^{5 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 is hydrogen, fluorine or chlorine, and R ⁸ together with the carbon atoms to which they are attached form a 5-membered heterocycle, which heterocycle may be substituted by 1 to 2 substituents independently selected from the group consisting of oxo, chloro , Cyano, hydroxy, C ₁ -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 fluorine, 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 ^{9 is} hydrogen, fluorine or chlorine, is hydrogen, fluorine, chlorine, methyl or methoxy, is hydrogen, fluorine, chlorine, Ci-Gt-alkyl, methoxy or trifluoromethyl, is hydrogen or methyl, amino, cyano , trifluoromethyl, Ci-C ₃ alkoxy, C ₃ alkylamino, C ₁ -C3- alkoxycarbonyl, -S (O) ₂ NR ¹⁰ R ^n, -C (0) NR ¹² R ¹³ or -NR ¹⁴ (CO ) R ¹⁵ , wherein alkoxy is substituted with 1 to 2 substituents independently selected from the group consisting of fluoro, hydroxy, amino, hydroxycarbonyl, Ci-Cs-alkylamino, difluoromethyl, trifluoromethyl, - (OCH ₂ CH ₂ ) _n -OCH ₃ , - (OCH ₂ CH ₂ ) _m -OH, morpholinyl, piperidinyl and pyrrolidinyl, wherein n is a number from 1 to 6, wherein m is a number from 1 to 6, and wherein

R ^{10 is} hydrogen, C ₁ -C ₃ -alkyl, C ₃ -C 6 -cycloalkyl, benzyl or a carbon atom-bonded 4- to 8-membered heterocyclyl,

R ^{11 is} hydrogen or C ₁ -C ₃ -alkyl, or

R ¹⁰ and R ¹¹ 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-1, for hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 3 -C 6 -cycloalkyl, benzyl or above Is carbon atom-bonded 4- to 8-membered heterocyclyl, wherein alkyl may be substituted with 1 to 2 substituents independently of one another selected from the group consisting of fluorine, hydroxyl, amino, hydroxycarbonyl, C 1 -C 3 -alkylamino, difluoromethyl, trifluoromethyl, - ( OCH ₂ CH ₂ ) n -OCH ₃ , - (OCH ₂ CH ₂ ) _m -OH, morpholinyl, piperidinyl and pyrrolidinyl, wherein n is a number from 1 to 6, wherein m is a number from 1 to 6, and wherein cycloalkyl may be substituted with 1 to 2 substituents independently selected from the group a us oxo, fluoro, hydroxy, amino, Ci-C t-alkyl and Ci-C3-alkylamino, wherein alkyl and alkylamino in turn may be substituted with 1 to 5 substituents fluorine, and wherein heterocyclyl may be substituted with 1 to 2 substituents independently selected from the group consisting of oxo, fluoro, hydroxy, amino, hydroxycarbonyl, Ci-C t-alkyl, Ci-C3-alkylamino, Ci-C t -alkoxycarbonyl, aminocarbonyl and Ci-C3-alkylaminocarbonyl, wherein alkyl and alkylamino in turn substituted may be with 1 to 5 substituents fluorine, and wherein heterocyclyl may be additionally substituted with 1 to 4 substituents independently selected from the group consisting of fluorine and methyl,

R ^{13 is} hydrogen or C ₁ -C ₃ -alkyl, or

R ¹² and R ¹³ 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, Ci-Gt-alkyl, Ci-C3-alkylamino, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroeth-1-yl, Ci-C t -alkoxycarbonyl, aminocarbonyl and C l -C3-Alky laminocarbony 1, wherein Alkyl in turn may be substituted with a hydroxy substituent,

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

R ^{15 is} C 1 -C 4 -alkyl, C ³ -C 6 -cycloalkyl, phenyl or a 5- to 7-membered heterocyclyl, 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 according to the invention may exist in different stereoisomeric forms, ie in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in the case of 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 in a known manner isolate; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.

If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms. The present invention also includes all suitable isotopic variants of the compounds of the invention. An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature. Examples of isotopes 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. Moreover, the incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.

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

Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethane sulfonic 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 may themselves be biologically active or inactive, but during their residence time in the body are converted to compounds of the invention (for example metabolically or hydrolytically).

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}. Furthermore, this also applies to the structural element of trans- - hydroxycyclohexylamine, for example in (ira "Ä- 4-hydroxycyclohexyl) carbamoyl. In the present invention, the preparation (A) is preferably used for the tranexamic acid amide. 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

and all L-phenylalanine intermediates are those marked with an * in the above formula Stereocenter described as (S) configuration, since L-phenylalanine derivatives are introduced as central building blocks in the synthesis. In the preparation of the compounds of the invention may occur in the coupling of the L-phenylalanine intermediates with the amine H2N-R ¹ for partial epimerization at the marked with a * 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 H2N-R ¹ or at a later intermediate of the synthesis or else the compounds according to the invention can be separated. 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 interchangeably in the context of the present invention and denote the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a Progression of such conditions and / or to get, experience, suffer or have the symptoms of such conditions. The treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.

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

Alkyl is a linear or branched alkyl radical having 1 to 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 feri-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 ^ .V-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.

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 ¹⁰ and R ¹² 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 SO2, where a nitrogen atom can also form an N-oxide, by way of example and preferably azetidinyl, Pyrrolidinyl, piperidinyl, tetrahydropyranyl, 3-azabicyclo [3.1.0] hex-6-yl, 8-azabicyclo [3.2.1] octane

3-yl and azepanyl, most preferably pyrrolidinyl and piperidinyl.

4- to 7-membered heterocycle in the definition of the radicals R ¹⁰ and R ¹¹ and the radicals R ¹² and R ¹³ is a saturated or partially unsaturated monocyclic or bicyclic radical having 4 to 7 ring atoms, preferably 5 or 6 ring atoms, and 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 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 ⁵ 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- Oxide, by way of example and preferably for thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl, particularly preferably triazolyl and tetrazolyl.

5-membered heterocycle in the definition of the radicals R ⁷ and R ⁸ 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 together with the phenyl ring to which it is attached is by way of example 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-indazole -5-yl, 2,3-dihydro-l / i-benzimidazol-5-yl, l, 3-dihydro-2, l-benzoxazol-5-yl, 2,3-dihydro-l, 3-benzoxazole-5 - yl, l, 3-dihydro-2, l-benzothiazol-5-yl, 2,3-dihydro-l, 3-benzothiazol-5-yl, l / i-benzimidazol-5-yl, l / i-indazole -5-yl, l, 2-benzoxazol-5-yl, indol-5-yl, isoindol-5-yl, benzofuran-5-yl, benzothiophen-5-yl, 2,3-dihydro-l-benzothiophene-6 -yl, 1,3-dihydro-2-benzothiophen-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-l / i-indazol-6-yl, 2,3-dihydro-l / i-benzimidazol-6-yl, l, 3-dihydro-2, l-benzoxazole -6-yl, 2,3-dihydro-l, 3-benzoxazol-6-yl, l, 3-dihydro-2, l-benzothiazol-6-yl, 2,3-dihydro-l, 3-benzothiazole-6 -yl, IH-benzimidaz ol-6-yl, l / i-indazol-6-yl, l, 2-benzoxazol-6-yl, indol-6-yl, isoindol-6-yl, benzofuran-6-yl and benzothiophene-6-yl, more preferably 2,3-dihydro-l / i-indazol-6-yl and IH-benzimidazol-6-yl, most preferably 2,3-dihydro-l / i-indazol-6-yl.

5- to 7-membered heterocyclyl in the definition of the radical R ¹⁵ is a saturated or partially unsaturated monocyclic or bicyclic radical having 5 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 SO2, wherein a nitrogen atom can also form an N-oxide, by way of example and preferably pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, 3-azabicyclo [3.1.0] hex-6-yl, 8-azabicyclo [3.2.1] oct-3-yl and azepanyl, most preferably tetrahydropyranyl.

In the formulas of the group which may stand for R ¹ , the end point of the line next to each of which represents a # does not represent a carbon atom or a CH ₂ group but is part of the bond to the atom to which R ^{1 is} attached is.

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 ^{5 is} 5-membered heteroaryl, where heteroaryl may be substituted by a 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 fluorine, or wherein alkyl is substituted with one substituent selected from the group consisting from hydroxy, amino, hydroxycarbonyl and methoxy and in which alkyl is additionally substituted by 1 to 6 substituents fluorine, R ^{6 is} hydrogen, fluorine or chlorine,

R ⁷ and R ⁸ 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, chlorine, cyano, hydroxyl, 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 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 ^{9 represents} hydrogen, fluorine or chlorine, represents hydrogen, fluorine, chlorine, methyl or methoxy, represents hydrogen, fluorine, chlorine, C 1 -C 4 -alkyl, methoxy or trifluoromethyl, represents hydrogen, represents amino, cyano, trifluoromethyl, Ci-C ₃ alkoxy, C ₃ alkylamino, C ₁ -C3- alkoxycarbonyl, -S (O) ₂ NR ¹⁰ R ^n, -C (0) NR ¹² R ¹³ or -NR ¹⁴ (CO) R ¹⁵ is where alkoxy is substituted with 1 to 2 substituents independently selected from the group consisting of fluoro, hydroxy, amino, hydroxycarbonyl, Ci-Cs-alkylamino, difluoromethyl, trifluoromethyl, - (OCH ₂ CH ₂ ) _n -OCH ₃ , - (OCH ₂ CH ₂ ) _m -OH, morpholinyl, piperidinyl and pyrrolidinyl, wherein n is a number from 1 to 6, wherein m is a number from 1 to 6, and wherein

R ^{10 is} hydrogen, C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl, benzyl or a carbon atom-bonded 4- to 8-membered heterocyclyl,

R ^{11 is} hydrogen or C ₁ -C ₃ -alkyl, or

R ¹⁰ and R ¹¹ 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 ¹² represents hydrogen, Ci-C ₃ alkyl, Ci-C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, benzyl, or via a carbon atom bound 4- to 8-membered heterocyclyl, wherein alkyl may be substituted with 1 to 2 substituents independently of one another selected from the group consisting of fluorine, hydroxyl, amino, hydroxycarbonyl, C ₁ -C ₃ -alkylamino, difluoromethyl, trifluoromethyl, - (OCH ₂ CH ₂ ) n -OCH ₃ , - (OCH ₂ CH ₂ ) _m - OH, morpholinyl, piperidinyl and pyrrolidinyl, wherein n is a number from 1 to 6, wherein m is a number from 1 to 6, and wherein cycloalkyl may be substituted with 1 to 2 substituents independently selected from the group consisting of oxo, fluoro , Hydroxy, amino, C 1 -C 4 -alkyl and C 1 -C 3 -alkylamino, wherein alkyl and alkylamino may in turn be substituted with 1 to 5 substituents fluorine, and wherein heterocyclyl may be substituted by 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, C 1 -C 4 -alkoxycarbonyl, aminocarbonyl and C 1 -C 3 -alkylaminocarbonyl, in which alkyl and alkylamino in turn may be substituted by 1 to 5 fluorine substituents, and heterocyclyl may additionally be substituted by 1 to 4 substituents independently of one another selected from the group consisting of fluorine and methyl,

R ^{13 is} hydrogen or C ₁ -C ₃ -alkyl, or R ¹² and R ¹³ 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, Ci-C t-alkyl, Ci-C3-alkylamino, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroeth-l-yl, Ci-C t Alkoxycarbonyl, aminocarbonyl and

C 1 -C 3 -alkylaminocarbonyl, in which alkyl in turn may be substituted by a hydroxy substituent,

R ^{14 is} hydrogen or C ₁ -C 8 -alkyl, R ^{15 is} C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, phenyl or a 5- to 7-membered one

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

Preference is also 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 ^{5 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 consisting of hydroxycarbonyl and methoxy, or wherein alkyl may be substituted with 1 to 7 fluorine substituents, or wherein alkyl is substituted with a hydroxy carbonyl substituent and wherein alkyl is additionally substituted with 1 to 6 fluorine substituents,

R ^{6 is} hydrogen or fluorine,

R ⁷ and R ⁸ 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 independently 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 ^{9 represents} hydrogen or fluorine, represents hydrogen, fluorine, methyl or methoxy, represents hydrogen, fluorine, chlorine, C 1 -C 4 -alkyl, methoxy or trifluoromethyl, represents hydrogen, represents amino, cyano, trifluoromethyl, ci C 3 alkoxy, C 1 -C 3 alkylamino, C 1 -C 3 alkoxycarbonyl, -S (O) ₂ NR ¹⁰ R ⁿ , -C (O) NR ¹² R ¹³ or -NR ¹⁴ (CO) R ¹⁵ , where alkoxy is substituted is with a substituent morpholinyl, and wherein

R ^{10 is} hydrogen, methyl, ethyl, C ₃ -C 6 -cycloalkyl or 4 to 8-membered heterocyclyl bonded via a carbon atom,

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

R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, in which 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 ^{12 is} hydrogen, C ₁ -C ₃ -alkyl, C ₃ -C 6 -cycloalkyl or a 4 to 8-membered heterocyclyl bonded via a carbon atom, wherein alkyl may be substituted with 1 to 2 substituents independently selected from the group consisting of C 1 -C 3 -alkylamino and morpholinyl, and wherein cycloalkyl may be substituted with 1 to 2 substituents independently selected from the group consisting of hydroxy, amino, C C ₁ -C 4 -alkyl and C ₁ -C ₃ -alkylamino, and in which heterocyclyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of C ₁ -C 4 -alkyl,

R ^{13 is} hydrogen, methyl or ethyl, or

R ¹² and R ¹³ 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 ^{14 is} hydrogen, methyl or ethyl,

R ^{15 is} C 1 -C 4 -alkyl or a 5- to 7-membered heterocyclyl, and their salts, their solvates and the solvates of their salts.

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

R ^{1 is} a group of the formula

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

R ^{5 is} 5-membered heteroaryl, where heteroaryl may be substituted by a substituent chlorine,

R ^{6 is} hydrogen, R ⁷ and R ⁸ together with the carbon atoms to which they are attached form a 5-membered heterocycle, where the heterocycle may be substituted by a substituent Oxo, R ^{9 is} hydrogen, R ^{2 is} hydrogen R ^{3a is} hydrogen, fluorine, C 1 -C ₄ -alkyl or methoxy, R ^{3b is} hydrogen,

R ⁴ is cyano, trifluoromethyl, Ci-C ₃ alkoxy, C ₃ alkylamino, G-C3-alkoxycarbonyl, - S (O) ₂ NR ¹⁰ R ^n, -C (0) NR ¹² R ¹³ or -NR ¹⁴ (CO) R ¹⁵ , wherein alkoxy is substituted with a substituent morpholinyl, and wherein

R ^{10 is} hydrogen or methyl, R ^{11 is} hydrogen or methyl, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle,

R ^{12 is} C 1 -C 3 -alkyl or 4 to 8-membered heterocyclyl bonded via a carbon atom, wherein alkyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of C 1 -C 3 -alkylamino and morpholinyl,

R ^{13 is} hydrogen, or

R ¹² and R ¹³ 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 ^{14 is} hydrogen,

R ^{15 is} a 5- to 7-membered heterocyclyl, and their salts, their solvates and the solvates of their salts. Preference is also given to compounds of the formula (II) in which R ^{1 is} a group of the formula

where # is the point of attachment to the nitrogen atom, R ^{5 is} triazolyl or tetrazolyl, where triazolyl may be substituted by a substituent chlorine, R ^{6 is} hydrogen, or

R ^{1 is} 2,3-dihydro-l # -indazol-6-yl, where 2,3-dihydro-l / i-indazol-6-yl may be substituted by a substituent oxo, R ^{2 is} hydrogen,

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

R ^{4 is} cyano, trifluoromethyl, C ₁ -C ₃ alkoxycarbonyl, -S (O) ₂ NR ¹⁰ R ⁿ or -C (O) NR ¹² R ¹³ , wherein

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

R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a morpholinyl or piperazinyl,

R ^{12 is} C 1 -C 3 -alkyl or heterocyclyl bonded via a carbon atom selected from the group consisting of pyrrohdinyl and piperidinyl, wherein alkyl may be substituted by 1 to 2 substituents independently selected from the group consisting of C 1 -C 3 -alkylamino and morpholinyl .

R ^{13 is} hydrogen, or

R ¹² and R ¹³ 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 methyl substituents, and their salts, solvates and 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 ^{5 is} triazolyl or tetrazolyl, where triazolyl may be substituted by a substituent chlorine,

R ^{6 is} hydrogen, or

R ^{1 is} 2,3-dihydro-l / i-indazol-6-yl or 2,3-dihydro-l / i-benzimidazol-5-yl, wherein 2,3-dihydro-l / i-indazole-6 -yl and 2,3-dihydro-l # -benzimidazol-5-yl may be substituted with a substituent oxo,

R ^{2 is} hydrogen,

R ^{3a represents} hydrogen, fluorine, C 1 -C ₄ -alkyl or methoxy,

R ^{3b is} hydrogen,

R ^{4 is} cyano, trifluoromethyl, Ci-C ₃ alkoxycarbonyl, -S (O) ₂ NR ¹⁰ R ^u or -C (O) NR ¹² R ¹³ , wherein is hydrogen or methyl, is hydrogen or methyl, or

R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a morpholinyl or piperazinyl, R ^{12 is} C ₁ -C ₃ -alkyl or heterocyclyl bonded via a carbon atom selected from the group consisting of pyrrohdinyl and piperidinyl, in which alkyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of C ₁ -C ₃ -alkylamino and morpholinyl,

R ^{13 is} hydrogen, or

R ¹² and R ¹³ 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 methyl substituents, and their salts, solvates and solvates of their salts.

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

wherein # is the point of attachment to the nitrogen atom, R ^{5 is} triazolyl or tetrazolyl, where triazolyl may be substituted by a substituent chlorine, and

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

R ^{1 is} 2,3-dihydro-l / i-indazol-6-yl or 2,3-dihydro-l / i-benzimidazol-5-yl, wherein 2,3-dihydro-l / i-indazole-6 -yl and 2,3-dihydro-l / i-benzimidazol-5-yl may be substituted with a substituent oxo.

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

Preference is also given to compounds of the formula (I) in which R ^{3 is} hydrogen, fluorine, C ₁ -C 4 -alkyl or methoxy.

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

R ^{4 is} cyano, trifluoromethyl, C ₁ -C ₃ alkoxycarbonyl, -S (O) ₂ NR ¹⁰ R ⁿ or -C (O) NR ¹² R ¹³ , wherein

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

R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a morpholinyl or piperazinyl,

R ^{12 is} C 1 -C 3 -alkyl or heterocyclyl bonded via a carbon atom selected from the group consisting of pyrrolidinyl and piperidinyl, in which alkyl may be substituted by 1 to 2 substituents independently selected from the group consisting of C 1 -C 3 -alkylamino and morpholinyl .

R ^{13 is} hydrogen, or R ¹² and R ¹³ 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 methyl substituents.

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 , R ³ , R ^3b and R ^{4 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 the formula (II) are known or can be prepared by [A] compounds of the formula

in which

R ¹ , R ² , R ³ and R ^{3b have} the abovementioned meaning, with compounds of the formula

R ¹³

 I

HN ^ ₁₂ (IV),

 R in which

R ¹² and R ¹³ are as defined above, are reacted in the presence of a dehydrating reagent, or

[B] Compounds of the formula in which

R ¹ and R ^{2 have} the meaning given above, and

X ^{1 is} bromine or iodine, with compounds of the formula

in which

R ^3a , R ^3b and R ^{4 have} the abovementioned meaning, and

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

[C] Compounds of the formula in which

R ² , R ³ , R ^3b and R ^{4 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 a dehydrating reagent.

The reaction according to process [A] 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-dicyclohexylcarbodiimide, N - ^ - dimethylamino-isopropyl ^ - are suitable as dehydrating reagents in this case, for example 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, 1, 3,3-tetramethyluronium tetrafluoroborate (TPTU), (benzotriazol-1-yloxy) bis-dimethylamino-methylium-fluoroborate (TBTU) or (^ - (T-azabenzotriazole-1-yl-1-yl) -tetramethyl-uronium-hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), or Efhyl-cyano (hydroxy-imino) 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 hexafluorophosph 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- [1,2,3] 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 (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 process [B] is generally carried out in inert solvents, in the presence of a catalyst, if appropriate 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, [l, l-bis- (diphenylphosphino) -ferrocene] -palladium (II) chloride monodichloromethane adduct, XPhos precatalyst [(2 '-Aminobiphenyl-2-yl) (chloro) palladium-dicyclohexyl (2', 4 ', 6'-triisopropyl-biphenyl-2-yl) -phosphine (1: 1)] or [2'- (azanidyl-ca) -ja- A ^r -) biphenyl-2-yl- / ca j jaC 2] [di- (3s, 5s, 7s) -adamantan-1-yl (butyl) phosphorane (memansulfonatato-fca / j / ja-0) palladium is tetrakistriphenylphosphine palladium (O), [1,1-bis (diphenylphosphino) ferrocene] palladium (II) chloride monodichloromethane adduct or XPhos precatalyst [(2'-Arninobiphenyl-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 (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 method [C] is carried out as described for method [A].

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 can be prepared by

[D] Compounds of the formula in which

R ¹ , R ² , R ³ and R ^{3b have} the abovementioned meaning, and X ^{2 is} methyl or ethyl, are reacted with a base, or

[E] Compounds of the formula (V) with compounds of the formula

in which R ³ and R ^{3b have} the abovementioned meaning, and

Q ^{2 is} -B (OH) ₂ , a boronic acid ester, preferably boronic acid pinacol ester, or -BF ₃ ^~ K ⁺ , can be reacted under Suzuki coupling conditions.

The reaction according to process [D] is generally carried out in inert solvents, preferably in a temperature range from room temperature to the reflux of the solvent Normal 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 reaction according to method [E] is carried out as described for method [B].

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

[F] Compounds of the formula (V) with compounds of the formula

in which

R ³ and R ^{3b have} the abovementioned meaning, X ^{2 is} methyl or ethyl, and

Q ^{3 is} -B (OH) ₂ , a boronic acid ester, preferably boronic acid pinacol ester, or -BF ₃ ^~ K ⁺ , can be reacted under Suzuki coupling conditions, or [G] Compounds of the formula

in which

R ² , R ³ and R ^{3b have} the abovementioned meaning, and X ^{2 is} methyl or ethyl, are reacted with compounds of formula (VIII) in the presence of a dehydrating reagent.

The reaction according to method [F] is carried out as described for method [B].

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 partially described in the example.

The reaction according to method [G] is carried out as described for method [A].

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

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

X ^{1 is} bromine or iodine, are reacted with compounds of formula (VIII) in the presence of a dehydrating reagent.

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

The compounds of the formula (XIII) 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 the formula (ΧΠ) are known or can be prepared by reacting compounds of the formula (XIII) with compounds of the formula (XI) under Suzuki coupling conditions.

The reaction is carried out as described for method [B]. The compounds of the formula (VII) are known or can be prepared by reacting compounds of the formula (XIII) with compounds of the formula (VI) under Suzuki coupling conditions.

The reaction is carried out as described for method [B].

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

Scheme 2:

The compounds of the invention show an unpredictable, valuable pharmacological spectrum of activity 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), myocardial infarction 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 the healing of wounds, for the prophylaxis and / or treatment of atherosclerotic vascular diseases and inflammatory diseases such as rheumatic diseases of the locomotor system, coronary heart diseases, cardiac insufficiency, hypertension, inflammatory diseases, such as, for example, asthma Pulmonary 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, particularly those that undergo 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), which is associated with collagenosis , congenital systemic pulmonary shunt veins, portal hypertension, HIV infections, the use of certain drugs and medications, with other diseases (thyroid disorders, glycogen storage diseases, Gaucher disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy), with diseases with a significant venous / capillary involvement, such as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, as well as persistent pulmonary hypertension of newborns.

Pulmonary hypertension in left heart disease includes left atrial or ventricular disease and mitral or aortic valve failure. Pulmonary hypertension in lung disease and / or hypoxia includes chronic obstructive pulmonary disease, interstitial lung disease, sleep apnea syndrome, alveolar hypoventilation, chronic altitude sickness, and plant-related malformations.

Pulmonary hypertension due to chronic thromboembolism (CTEPH) includes thromboembolic occlusion of proximal pulmonary arteries, thromboembolic occlusion of distal pulmonary arteries, and non-thrombotic pulmonary embolisms (tumor, parasites, foreign bodies).

Another object of the present invention is the use of the compounds of the invention for the preparation of medicaments for the treatment and / or prophylaxis of pulmonary hypertension in sarcoidosis, histiocytosis X and Lymphangiomatosis. In addition, the substances according to the invention are also suitable for the treatment of pulmonary and hepatic fibroses. In addition, the compounds according to the invention also come for the treatment and / or prophylaxis of Disseminated intravascular coagulation in the context of infectious disease and / or systemic inflammatory syndrome (SIRS), septic organ dysfunction, septic organ failure and multi-organ failure, Acute lung injury 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 aforementioned indications, it may be used perioperatively for the use of extracorporeal circulatory systems or filtration systems, e.g. Cardiopulmonary machine, hemofiltration, hemodialysis, extracorporeal membrane oxygenation or ventricular assistive system, e.g. Artificial heart, come. 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. The compounds of the invention can also be used ex vivo to prevent coagulation, eg for the preservation of blood and plasma products, for cleaning / pretreatment of catheters and other medical aids and devices, for coating artificial surfaces of in vivo or ex vivo used medical Aids and equipment or biological samples that may 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 according to the invention and one or more further 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, for example, 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, antiplatelet agents) such as acetylsalicylic acid (such as aspirin), Ticlopidine (Ticlid), Clopidogrel (Plavix), Prasugrel, Ticagrelor, Cangrelor, Elinogrel, Vorapaxar;

Fibrinogen receptor antagonists (glycoprotein IIb / iria 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 microbial condition is present) 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" in the sense 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 / or It is likewise possible to combine two or more active substances with one another, ie in each case in two or more combinations The compounds according to the invention can have a systemic and / or local action be applied in a suitable manner, such as oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

For these 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, the compounds of the invention in crystalline and / or amorphised and / or dissolved Such as tablets (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules ( hard or soft gelatin capsules, for example), 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 the other routes of administration are suitable, for example Inhalation medicines (including powder inhalants, nebulizers), nasal drops, solutions, sprays; lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), milk, Pastes, foams, scattering powders, implants or stents. The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecylsulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), Stabilizers (eg, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.

Another object of the present invention are pharmaceutical compositions containing at least one inventive compound, 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 (^ - (T-Azabenzotriazol-1-yl-^ ^ A ^^ 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% ammonia in water, eluent B: acetonitrile, gradient: A 90% / B 10% -> A 50% / B 50%; Flow: 150 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 a partial epimerization of the stereocenter occurred in the coupling of the L-phenylalanine intermediate with the amine H2N-R ¹ . 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- [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -4-iodo-L-phenylalaninate

Methyl 4-iodo-L-phenylalaninate hydrochloride (5.7 g, 16.7 mmol), 1: 1 - [[(4-i-butoxycarbonyl) -amino] -methyl} -cyclohexanecarboxylic acid (4.4 g, 16.7 mmol) 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 aqueous saturated ammonium chloride solution and once with aqueous saturated 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.

Ή-NMR (300 MHz, DMSO δ ppm 0.68-0.86 (m, 2H), 1.02-1.27 (m, 3H), 1.33 (s, 9H), 1.45- 1.55 (m, 1H), 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. The tetrahydrofuran was then stripped off and the aqueous phase was washed twice with tert-butyl methyl 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.

Ή-NMR (400 MHz, DMSO δ ppm 0.72-0.85 (m, 2H), 1.08-1.27 (m, 3H), 1.33 (s, 9H), 1.63 (m, 4H), 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

Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -N- [4- (5-chloro-4-i-l, 2,4- triazol-3-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- (5-chloro-4 /, 2,4-triazol-3-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, 3rd , 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-ife): δ ppm 0.78 (m, 2H), 1.05-1.27 (m, 4H), 1.33 (s, 9H), 1.48-15.5 (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 Methyl 4-bromo-N - [(ira "5-4- {[(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] methylcyclohexanecarboxylic 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 aqueous saturated sodium bicarbonate solution, aqueous saturated ammonium chloride solution, and aqueous saturated sodium chloride solution washed. It was dried over sodium sulfate and the solvent removed. One received

420 g (97% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-de): δ = 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 5A

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

A solution of methyl 4-bromo / V - [(1α'-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -L-phenylalaninate in tetrahydrofuran (3,000 ml) was treated with a solution of lithium hydroxide (72 g, 3015 mmol) in water (600 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 organic phase was washed with aqueous saturated sodium chloride solution, dried over sodium sulfate, and the solvent removed. This gave 284 g (97% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ = 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, 2 H), 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 6A

4-Bromo-Na / j / ia - [(ω-α-4- {[(fer-butoxycarbonyl) -amino] -methyl-cyclohexyl-carbonyl] -N- [4- (l-i-tetrazol-5-yl) phenyl] -L-phenylalanine amide

A solution of 4-bromo-N - [(α-α-4- {[(feri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -L-phenylalanine (11 g, 22 mmol) and 4- (1 i-Tetrazol-5-yl) aniline (4g, 24mmol) in dimethylformamide (161ml) was added N, N -diisopropylethylamine (9.6ml, 55mmol). 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 = 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 (ESIneg): m / z = 624 [MH] \

Example 7A

4-Bromo-Na / j / ia - [(1α'-4- {[(fer ^ butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -N- (2-oxo-2,3-dihydro-1: 1) benzimidazol-5-yl) -L-phenylalaninamide

A solution of 4-bromo-N - [(1α-ε-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -L-phenylalanine (1500 mg, 3 mmol) and 5-amino -l, 3-dihydro-2 / i-benzimidazol-2-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-1,3,2,2,4,6-trioxatriphosphinane-2,4,6-trioxide solution (50% in dimethylformamide, 2.2 ml, 3.7 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, washed twice with water and once with aqueous saturated 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: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). The crude product was stirred with methanol and filtered with suction. 202 mg (11% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ): δ = 0.69-0.89 (m, 2H), 1.04-1.29 (m, 3H), 1.37 (s, 9H), 1.67 (m, 4H) , 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), 6.96 (dd, 1H), 7.25 (d, 2H), 7.39-7.56 (m, 3H), 7.84 (s, 1H), 8.09 (d, 1H), 10.20 (s, 1H), 11.08 (brs s, 1 H).

LC-MS (Method 1): R _t = 1.00 min; MS (ESIpos): m / z = 614 [M + H] ⁺ . Example 8A

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

A solution of 4-bromo-N - [(1α'-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-1,3,2,2,4,6-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 at RT for 16 h. The reaction mixture was stirred into ethyl acetate (2500 ml), washed three times with water (300 ml) and once with aqueous saturated 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.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ = 0.68-0.98 (m, 2H), 1.05-1.31 (m, 4H), 1.39 (s, 9H), 1.46-1.76 (m, 4 H), 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, 2H) , 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 9A

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

1000 mg (1.60 mmol) 4-biome N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] - N - [4- (2-i-tetrazole-5 -yl) phenyl] -L-phenylalanine amide, 184 mg (0.16 mmol) of tetrakis (triphenylphosphine) palladium (0) and 677 mg (3.19 mmol) of [3- (ethoxycarbonyl) -2-fluorophenyl] boronic acid were dissolved in 12 ml of 1, 2-dimethoxyethane and 5 ml of ethanol. After the addition of 3 ml of 2N aqueous sodium carbonate solution, the mixture was stirred at reflux for 4 h and at RT for 16 h. The reaction mixture was filtered through kieselguhr and the solvent removed. The residue of the filtrate was separated by column chromatography on silica gel (eluent: ethyl acetate -> ethyl acetate / methanol 8: 2). 977 mg (82% of theory) of the title compound were obtained. Ή NMR (400 MHz, DMSO-d ₆ ): δ = 0.74-0.92 (m, 2H), 1.09-1.42 (m, 16H), 1.50-1.77 (m, 4H), 2.05-2.11 (m , 1H), 2.70 - 2.78 (m, 2H), 2.88 - 2.99 (m, 2H), 3.08 - 3.18 (m, 1H), 4.28 - 4.39 (m, 2H), 4.67 - 4.76 (m , 1H), 6.72 - 6.84 (m, 1H), 7.34 - 7.51 (m, 4H), 7.52 - 7.66 (m, 1H), 7.68 - 7.74 (m, 1H), 7.76 - 7.87 (m , 3H), 7.94 - 8.02 (m, 2H), 8.19 (d, 1H), 10.43 (s, 1H). LC-MS (Method 1): R _t = 1.15 min; MS (ESIneg): m / z = 712 [MH] \

Example 10A

4 '- [(2S) -2- {[(trans - - {[(i.i.-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2 / i-tetrazole -5-yl) phenyl] amino} propyl] -2-fluorobiphenyl-3-carboxylic acid

915 mg (1.28 mmol) of ethyl 4 '- [(2 _L S ^, ) -2- {[(ira-.y-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexy-1-carbonyl-1-amino } -3-oxo-3 - {[4- (2-i-tetrazol-5-yl) phenyl] amino} propyl 1] -2-fluorobiphenyl-3-carboxylate was dissolved in 22.5 ml of tetrahydrofuran and 7.5 ml of water, with 538 mg (12.82 mmol) of lithium hydroxide monohydrate and stirred for 16 h at RT. The reaction mixture was mixed with 50 ml of water and IN hydrochloric acid to pH 4. It was extracted three times with 100 ml of dichloromethane and the organic phase dried over sodium sulfate, filtered and concentrated. The residue was stirred with 10 ml of acetonitrile in an ultrasonic bath, filtered and concentrated to dryness. 604 mg (66% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ = 0.73-0.93 (m, 2H), 1.09-1.32 (m, 3H), 1.36 (s, 9H), 1.50-1.76 (m, 4 H), 2.06 - 2.18 (m, 1H), 2.69 - 2.80 (m, 2H), 2.90 - 3.00 (m, 1H), 3.07 - 3.17 (m, 1H), 4.67 - 4.79 (m, 1 H), 6.74-6.83 (m, 1H), 7.36 (t, 1H), 7.40-7.51 (m, 3H), 7.52-7.72 (m, 2H), 7.78-7.87 (m, 3H) , 8.00 (d, 2H), 8.16 - 8.25 (m, 1H), 10.48 (s, 1H), 13.3 (br, s, 1H), 16.7 (br, s, 1H). LC-MS (Method 1): R _t = 0.98 min; MS (ES Ineg): m / z = 684 [MH] \ Example IIA

Mefhyl-4 '- [(2S) -2- {[(trans-4- {[(feri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] 3-oxo-3- {[4- (2-i-tetrazole -5-yl) phenyl] amino} propyl] -6-methylbiphenyl-3-carboxylate

1000 mg (1.60 mmol) of 4-bromo-Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i tetrazol-5-yl) phenyl] -L-phenylalanine amide, 184 mg (0.16 mmol) tetrakis (triphenylphosphine) palladium (0) and 881 mg (3.19 mmol) methyl-4-methyl-3- (4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate were taken up in 12 ml of 1,2-dimethoxyethane and 5 ml of ethanol. After the addition of 3 ml of 2N aqueous sodium carbonate solution, the reaction mixture was stirred at reflux for 4 h and at RT for 16 h, then the salts were filtered through kieselguhr and the filtrate was separated by column chromatography on silica gel (mobile phase: ethyl acetate -> ethyl acetate / methanol 8 : 2) separately. 1024 mg (88% of theory) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-d ₆ ): δ = 0.73-0.92 (m, 2H), 1.09-1.31 (m, 3H), 1.36 (s, 9H), 1.48- 1.57 (m, 1 H), 1.59 - 1.73 (m, 3H), 2.06 - 2.16 (m, 1H), 2.24 (s, 3H), 2.69 - 2.79 (m, 2H), 2.89 - 3.00 (m, 1H) , 3.08-3.18 (m, 1H), 3.83 (s, 3H), 4.70-4.81 (m, 1H), 6.74-6.82 (m, 1H), 7.28 (d, 2H), 7.35-7.48 (m, 3H), 7.68-7.73 (m, 1H), 7.74-7.81 (m, 2H), 7.81-7.86 (m, 1H), 7.93-8.02 (m, 2H), 8.18 (i.e. , 1 H), 10.39 (s, 1 H), 16.7 (brs s, 1 H). LC-MS (Method 1): R _t = 1.14 min; MS (ES Ineg): m / z = 694 [MH] ^" . Example 12A

4 '- [(2S) -2- {[(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2/4) tetrazol-5-yl) phenyl] amino} propyl] -6-methylbiphenyl-3-carboxylic acid

965 mg (1.39 mmol) of methyl 4'- [(2 _L S ^, ) -2- {[(ira-.y-4- {[(ieri-butoxycarbonyl) amino] methyl} -cyclohexy-1-carbonyl-1-amino } -3-oxo-3 - {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propy 1] -6-methylbiphenyl-3-carboxylate were dissolved in 22.5 ml of tetrahydrofuran and 7.5 ml of water, with 582 mg (13.87 mmol) of lithium hydroxide monohydrate and stirred for 16 h at RT. From the reaction mixture, two-thirds of the solvent was removed. The remaining suspension was mixed with 20 ml of water and IN hydrochloric acid until pH 4. The precipitate was filtered off, washed with a little water and the crude product dried under high vacuum. 650 mg (63% of theory, 92% purity) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ = 0.72-0.92 (m, 2H), 1.04-1.30 (m, 3H), 1.36 (s, 9H), 1.47-1.57 (m, 1 H), 1.59 - 1.76 (m, 3H), 2.04 - 2.17 (m, 1H), 2.24 (s, 3H), 2.69 - 2.79 (m, 2H), 2.87 - 3.00 (m, 1H) , 3.06 - 3.18 (m, 1H), 4.68 - 4.82 (m, 1H), 6.71 - 6.84 (m, 1H), 7.28 (d, J = 8.07 Hz, 2H), 7.34 - 7.45 (m, 3H), 7.50 - 7.66 (m, 1H), 7.68 - 7.78 (m, 3H), 7.79 - 7.85 (m, 1H), 7.96 (d, J = 8.56Hz, 2H), 8.13 - 8.21 (m, 1H), 10.33 (s, 1H).

LC-MS (Method 1): R _t = 1.10 min; MS (ES Ineg): m / z = 680 [MH] ^" . Example 13A

Methyl 4 '- [(2S) -2- {[(trans - - {[(feri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} 3-oxo-3- {[4- (2 / tetrazol-5-yl) phenyl] amino} propyl] biphenyl-3-carboxylate

1000 mg (1.60 mmol) of 4-bromo-Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide, 184 mg (0.16 mmol) tetrakis (triphenylphosphine) palladium (0) and 574 mg (3.19 mmol) of [3- (mehoxycarbonyl) phenyl] boronic acid were dissolved in 12 ml of 1 , 2-dimethoxyethane and 5 ml of ethanol. After the addition of 3 ml of 2N aqueous sodium carbonate solution, the reaction mixture was stirred at reflux for a total of 8 h and at RT for 16 h, then the salts were filtered through kieselguhr and the filtrate was separated by column chromatography on silica gel (mobile phase: ethyl acetate / ethyl acetate / methanol 8: 2) separately. The product fraction was concentrated and the solid was boiled briefly with 8 ml of acetonitrile and swirled in an ultrasonic bath for 1 min. The solid was filtered off, washed with 3 ml of acetonitrile and dried under high vacuum. 466 mg (40% of theory, 94% purity) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ = 0.73-0.92 (m, 2H), 1.08-1.30 (m, 3H), 1.36 (s, 9H), 1.52-1.76 (m, 4 H), 2.06 - 2.17 (m, 1H), 2.70 - 2.78 (m, 2H), 2.88 - 2.99 (m, 1H), 3.07 - 3.15 (m, 1H), 3.88 (s, 3H) , 4.67-4.77 (m, 1H), 6.74-6.82 (m, 1H), 7.44 (d, 2H), 7.57-7.69 (m, 3H), 7.80 (d, 2H), 7.90-8.02 (m, 4H), 8.13 - 8.22 (m, 2H), 10.44 (s, 1H). LC-MS (Method 1): R _t = 1.11 min; MS (ES Ineg): m / z = 680 [MH] ^" . Example 14A

4 '- [(2S) -2- {[(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2/4) tetrazol-5-yl) phenyl] amino} propyl] biphenyl-3-carboxylic acid

465 mg (0.53 mmol, 78% purity) of methyl 4 '- [(2 _L S ^, ) -2- {[(ira "_> y-4- {[(ieri-butoxycarbonyl) amino] -methy 1} cyclohexyl) carbonyl 1] amino} -3-oxo-3 - {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propy 1] -biphenyl-3-carboxylate were dissolved in 15 ml of tetrahydrofuran and 5 ml of water , mixed with 223 mg (5.31 mmol) of lithium hydroxide monohydrate and stirred at RT for 16 h. The reaction mixture was mixed with 150 ml of water and IN hydrochloric acid until pH 4. The precipitate was filtered off, washed with a little water and the crude product dried under high vacuum. This gave 418 mg (78% of theory, 66% purity) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ = 0.72-0.92 (m, 2H), 1.09-1.31 (m, 3H), 1.36 (s, 9H), 1.53-1.7 (m, 4 H), 2.07 - 2.17 (m, 1H), 2.69 - 2.79 (m, 2H), 2.88 - 2.99 (m, 1H), 3.05 - 3.16 (m, 1H), 4.67 - 4.78 (m, 1 H), 6.72-6.82 (m, 1H), 7.43 (d, 2H), 7.55-7.68 (m, 3H), 7.82 (d, 2H), 7.87-7.94 (m, 2H), 8.00 (d, 2H), 8.13 - 8.23 (m, 2H), 10.49 (s, 1H), 13.1 (br, s, 1H), 16.8 (br, s, 1H).

LC-MS (Method 1): R _t = 0.99 min; MS (ESIneg): m / z = 666 [MH] \

Example 15A ieri-butyl - [(ira- _1- y-4- {[(2 _L S ') - 3- [5' - (dimethylsulfamoyl) -2'-methylbiphenyl-4-yl] -l-oxo-1-one {[4- (m-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate

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

tetrazol-5-yl) phenyl] -L-phenylalanine amide (150mg, 0.24mmol) and 5- (dimethylsulfamoyl) -2-methylphenyl] boronic acid (87mg, 0.36mmol) were dissolved in dimethyl sulfoxide (2mL) and extracted with tetrakis ( triphenylphosphine) palladium (0) (28 mg, 24 μηιοΐ), sodium carbonate (76 mg, 0.72 mmol) and water (0.36 ml, 20 mmol) were added. 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). 57 mg (32% of th.) Of the title compound were obtained.

LC-MS (Method 5): R _t = 0.89 min; MS (ESIpos): m / z = 745.5 [M + H] ⁺ . Example 16A tert -butyl - [(trans-A- {[(2S) -3- [2'-methyl-5 '- (morpholin-4-ylsulfonyl) biphenyl-4-yl] -1-oxo-1 - {[4- (l-i-tetrazol-5-yl) -phenyl] amino} propan-2-yl] carbamoyl}} cyclohexyl] methyl] carbamate

4-bromo-Na / j / ia - [(i5a] 5-4- {[(fer ^ butoxycarbonyl) amino] methyl} cyclohexyl) carbo ^

tetrazol-5-yl) phenyl] -L-phenylalanine amide (150mg, 0.24mmol) and [2-methyl-5- (morpholin-4-ylsulfonyl) phenyl] boronic acid (102mg, 0.36mmol) were dissolved in dimethyl sulfoxide (2mL ) 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). 100 mg (53% of th.) Of the title compound were obtained.

LC-MS (Method 5): R _t = 0.88 min; MS (ESIpos): m / z = 787.5 [M + H] ⁺ .

Example 17A ieri-butyl {[ira-.y-4 - ({(2S) -l- {[4- (5-chloro-4-yl, 2,4-triazol-3-yl) -phenyl] -amino} -3- [5 '- (dimethylsulfoamyl) -2'-methylbiphenyl-4-yl] -1-oxopropan-2-yl} carbamoyl) cyclohexyl 1] methyl} carbamate

Na / j / ia - [(1α'-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] -N- [4- (5-chloro-4-i-l, 2,4- triazol-3-yl) phenyl] -4-iodo-L-phenylalanine amide (150 mg, 0.21 mmol) and 5- (dimethylsulfamoyl) -2-methylphenyl] boronic acid (79 mg, 0.32 mmol) were dissolved in dimethylsulfoxide (2 ml) and tetrakis (triphenylphosphine) palladium (0) (24 mg, 21 μηιοΐ), sodium carbonate (67 mg, 0.64 mmol) and water (0.32 ml, 18 mmol) were added. The reaction mixture was stirred for 90 min at 110 ° C. in the microwave (Biotage Initiator), cooled, filtered and purified by chromatography via HPLC (Method 11). 34 mg (21% of Th.) Of the title compound were obtained.

LC-MS (Method 5): R _t = 0.88 min; MS (ESIpos): m / z = 778.5 [M + H] ⁺ . Example 18A

[(2 _{L of} S ^, ) -1-oxo-3- (3'-sulfamoyl-biphenyl-4-yl) -l- [[4- (m-tetrazol-5-yl) -phenyl] -amino} -propan-2-yl ] carbamoyl 1} cyclohexyl) methyl] carbamate

4-Bromo-Na / j / ia - [(1α-α-4- {[(ferric-butoxycarbonyl) -rano] -methyl} -cyclohexyl) carbonyl

tetrazol-5-yl) phenyl] -L-phenylalanine amide (150 mg, 0.24 mmol) and (3-sulfamoylphenyl) boronic acid (72 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) were added. The reaction mixture was stirred for 120 min at 110 ° C. in the microwave (Bio day initiator), cooled, filtered and purified by chromatography via HPLC (Method 11). 91 mg (54% of th.) Of the title compound were obtained.

LC-MS (Method 5): R _t = 0.76 min; MS (ESIpos): m / z = 703.4 [M + H] ⁺ .

Example 19A tert -butyl - [(trans-A- {[(2S) -3- {3'- [(4-methylpiperazin-1-yl) carbonyl] biphenyl-4-yl} -1-oxo-1 - {[4- (1-i-tetrazol-5-yl) -phenyl] amino} propan-2-yl] carbamoyl}} cyclohexyl] methyl] 1-carbamate formate

A solution of 150 mg (0.24 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 and 102.2 mg (0.36 mmol) of {3 - [(4-methylpiperazin-1-yl) carbonyl] phenyl} boronic acid hydrochloride 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 1.5 h at 110 ° C. The batch was filtered and purified by preparative HPLC (Method 10). 52 mg (29% of theory) of the title compound were obtained.

LC-MS (Method 4): R _t = 0.92 min; MS (ESIpos): m / z = 750 [M + H-HCOOH] ⁺ .

Example 20A The butyl {[iraws {(2 ^ -3 2'-memyl) ^

oxo-2,3-dihydro-l / i-benzimidazol-5-yl) amino] propan-2-yl} carbamoyl) cyclohexyl] methyl} carbamate

To a solution of 150 mg (0.24 mmol) of 4-bromo-Na / j / ia - [(1α-ε-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- (2- oxo-2,3-dihydro-l / i-benzimidazol-5-yl) -L-phenyl-alaninamide and 100.5 mg (0.37 mmol) of [2-methyl-5- (pyrrolidin-1-ylsulfonyl) -phenyl] boronic acid in 1.8 To DMSO was added 28.2 mg (24.4 μηιοΐ) of tetrakis (triphenylphosphine) palladium (0), 77.6 mg (0.7 mmol) of sodium carbonate and 0.37 ml (20.4 mmol) of water. The mixture was microwave-treated at 110 ° C for 90 minutes. The batch was filtered and purified by preparative HPLC (Method 10). 74 mg (40% of theory) of the title compound were obtained.

LC-MS (Method 4): R _t = 1.22 min; MS (ESIpos): m / z = 759 [M + H] ⁺ .

Example 21 A Butyl-4 - [({4 '- [(2 ^ -2- {[(ira-Ä4- {[(feri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} - 3-oxo-3- {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propyl] -6-methyl-biphenyl-3-yl} carbonyl (l) -amino] -piperidine-1-carboxy-lat

A solution of 100 mg (0.15 mmol) of 4 '(2 ^ -2- {[(iraay-4- {[(ieri-butoxycarbonyl) -amino] -methyl} cyclohexyl) -carbonyl] -amino} -3-oxo-3 { [4- (2 / i-tetrazol-5-yl) -phenyl] -amino-propyl] -6-methyl-biphenyl-3-carboxylic acid and 35 mg (0.18 mmol) of feri-butyl-4-aminopiperidine-1-carboxylate in 5 ml of tetrahydrofuran with 67 mg (0.18 mmol) of N - [(dimethylamino) (3 / i- [l, 23] triazolo [4,5-b] pyridin-3-yloxy) methylidene] -N-methyl-methanaminium hexafluorophosphate and 0.03 ml (0.18 mmol) Ν, Ν-diisopropylethylamine and stirred for 16 h at RT The reaction mixture was separated directly by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid) to give 69 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 = 1.18 min; MS (ES Ineg): m / z = 862 [MH] \ Example 22A tert-butyl - [(trans-4-{[(25) -3- (5'-{[2- (diethylamino) ethyl] carbamoyl} -2'-methylbiphenyl-4-yl) -1-oxo-1 - {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propan-2-yl] -carbamoyl} -cyclohexyl) -methyl] -carbamate trifluoroacetate

A solution of 100 mg (0.15 mmol) of 4 '- [(2 ^ -2- {[(iraw.y-4- {[(ieri-butoxycarbonyl) -amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo -3- {[4- (2-i-tetrazol-5-yl) -phenyl] -amino-propyl] -6-methyl-biphenyl-3-carboxylic acid and 20 mg (0.18 mmol) of diethylamino-ethylamine in 5 ml of tetrahydrofuran were mixed with 67 mg (0.18 mmol ) N - [(dimethylamino) (3 / i- [l, 2,3] triazolo [4,5-b] pyridin-3-yloxy) methylidene] -N-methyl-methanaminium hexafluorophosphate and 0.03 ml (0.18 mmol) The reaction mixture was separated directly by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid) to give 64 mg of a mixture of the title compound and the partially deprotected title compound, which used directly in the next step LC-MS (Method 1): R _t = 0.84 min, MS (ES Ineg): m / z = 778 [MH-TFA] ^" .

Example 23A ieri-butyl- (3R) -3 - [({4 '- [(2, S ^, ) -2- {[(iraM _> y-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propyl] -6-methyl-biphenyl-3-yl} carbonyl) amino] pyrrolidine 1-carboxylate

A solution of 100 mg (0.15 mmol) 4 '- [(2 _L S ^r ) -2- [[(iraws-4- {[(ieri-butoxycarbonyl) -amino] -methyl} cyclohexyl) carbonyl] amino} -3- oxo-3- {[4- (2-i-tetrazol-5-yl) -phenyl] -amino-propyl] -6-methyl-biphenyl-3-carboxylic acid and 33 mg (0.18 mmol) of (R) - (+) - l- ( ieri-butoxycarbonyl) -3-aminopyrrolidine in 5 ml of tetrahydrofuran was treated with 67 mg (0.18 mmol) of N - [(dimethylamino) (3 / i- [1,2,3] triazolo [4,5-b] pyridine-3-) yloxy) methylidene] -N-methyl-methanaminium hexafluorophosphate and 0.03 ml (0.18 mmol) of Ν, Ν-diisopropylethylamine and stirred at RT for 40 h. The reaction mixture was separated directly by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). 65 mg of a mixture of Title compound and the partially deprotected title compound, which was used directly in the next step.

LC-MS (Method 1): R _t = 1.16 min; MS (ES Ineg): m / z = 848 [MH] \ Example 24A ieri-butyl-4- ({4'- [(2S) -2- {[(trans - {[(ieri-butoxycarbonyl) amino] methyl } cyclohexyl) carbonyl] -amino} -3-oxo-3- {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propyl] -6-methylbiphenyl-3-yl} carbonyl) -piperazine 1-carboxylate

A solution of 100 mg (0.15 mmol) of 4 '- [(2 _L S ^r ) -2- [[(α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} cyclohexyl) carbonyl] amino} - 3-oxo-3- {[4- (2-i-tetrazol-5-yl) -phenyl] -amino-propyl] -6-methyl-biphenyl-3-carboxylic acid and 33 mg (0.18 mmol) of 1- (ferric-butoxycarbonyl) -piperazine 5 ml of tetrahydrofuran were mixed with 67 mg (0.18 mmol) of N - [(dimethylamino) (3 / i- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methylidene] -N-methyl- methanaminium hexafluorophosphate and 0.03 ml (0.18 mmol) of Ν, Ν-diisopropylethylamine and stirred for 16 h at RT. The reaction mixture was separated directly by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). This gave 79 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 = 1.16 min; MS (ES Ineg): m / z = 848 [MH] ^" . Example 25A Butyl 4 - [({4 '- [(2 ^ -2- {[(iraws-4- {[(fer ^ butoxycarbony

amino} -3-oxo-3- {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propyl] -biphenyl-3-yl} carbonyl) -amino] -piperidine-1-carboxylate

A solution of 100 mg (0.15 mmol) of 4 '- [(2 _L S ^r ) -2- [[(α-α-4- {[(ieri-butoxycarbonyl) -amino] -methyl} cyclohexyl) carbonyl] amino} - 3-oxo-3- {[4- (2-i-tetrazol-5-yl) -phenyl] -amino-propyl] -biphenyl-1,3-carboxylic acid and 36 mg (0.18 mmol) of iperi-butyl-4-aminopiperidine-1 L - carboxylate in 5 ml of tetrahydrofuran was treated with 68 mg (0.18 mmol) of N - [(dimethylamino) (3 / i- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methylidene] -N- methyl-methanaminium hexafluorophosphate and 0.03 ml (0.18 mmol) of Ν, Ν-diisopropylethylamine and stirred for 16 h at RT. The reaction mixture was separated directly by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). This gave 90 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 = 1.15 min; MS (ESIneg): m / z = 848 [MH] \

Example 26A tert -butyl - [(trans-A- {[(25) -3- (3'-{[2- (diethylamino) ethyl] carbamoyl} biphenyl-4-yl) -1-oxo-1 - { [4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propan-2-yl] -carbamoyl-cyclohexyl-1-methyl-1-carbamate-trifluoroacetate

A solution of 100 mg (0.15 mmol) of 4 '- [(2 ^ -2- {[(iraay-4- {[(ieri-butoxycarbonyl) -amino] -methyl} cyclohexyl) carbonyl] amino} -3-oxo-3 - {[4- (2-i-tetrazol-5-yl) -phenyl] -amino-propyl] -biphenyl-1, 3-carboxylic acid and 21 mg (0.18 mmol) of diethylaminoethylamine in 5 ml of tetrahydrofuran were mixed with 68 mg (0.18 mmol) of N- [(Dimethylamino) (3 / i- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methylidene] -N-methyl-methanaminium hexafluorophosphate and 0.03 ml (0.18 mmol) Ν, Ν The reaction mixture was separated directly by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid) to give 66 mg of a mixture of the title compound and the partially deprotected title compound, which is directly in the next stage was used.

LC-MS (Method 1): R _t = 0.83 min; MS (ES Ineg): m / z = 764 [MH-TFA] ^" .

Example 27A is Butyl 4 - [({4 '- [(2 ^ -2- {[(1α-α-4- {[(feri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3 -oxo-3- {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propyl] -2-fluorobiphenyl-3-yl} -carbonyl} amino] -piperidine-1-carboxy-lat

A solution of 100 mg (0.15 mmol) of 4 '- [(2S) -2- [[(iraws-4- {[(tert-butoxycarbonyl) amino] -methy 1} cyclohexyl) carbonyl 1] amino} -3-oxo 3 - {[4- (2-i-tetrazol-5-yl) phenyl] amino} propyl 1] -2-fluorobiphenyl-3-carboxylic acid and 35 mg (0.18 mmol) of ferric-butyl-4-aminopiperidine-1-one. carboxylate in 5 ml of tetrahydrofuran was treated with 67 mg (0.18 mmol) of N - [(dimethylamino) (3 / i- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methylidene] -N- methyl-methanaminium hexafluorophosphate and 0.03 ml (0.18 mmol) of Ν, Ν-diisopropylethylamine and stirred for 16 h at RT. The reaction mixture was separated directly by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). This gave 67 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 = 1.13 min; MS (ESIneg): m / z = 866 [MH] \

Example 28A tert -butyl - [(trans-A- {[(2S) -3- (3'-{[2- (diethylamino) ethyl] carbamoyl} -2'-fluorobiphenyl-4-yl) -1-oxo - 1- {[4- (2-i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate

trifluoroacetate

A solution of 100 mg (0.15 mmol) of 4 '- [(2S) -2- [[(iraws-4- {[(tert-butoxycarbonyl) amino] -methy 1} cyclohexyl) carbonyl 1] amino} -3-oxo 3 - {[4- (2-i-tetrazol-5-yl) phenyl] amino} propy 1] -2-fluorobiphenyl-3-carboxylic acid and 20 mg (0.18 mmol) of diethylaminoethylamine in 5 ml of tetrahydrofuran were mixed with 67 mg of 0.18 mmol) of N - [(dimethylamino) (3-i- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methylidene] -N-methyl-methanaminium hexafluorophosphate and 0.03 ml (0.18 mmol) mmol) Ν, Ν-diisopropylethylamine and stirred at RT for 16 h. The reaction mixture was separated directly by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). This gave 83 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 = 782 [MH-TFA]. ^" Example 29A The butyl (3R) -3 - [({4 '- [(2 ^ -2- {[(iraM.y-4 - {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propyl] -2- fluorobiphenyl-3-yl} carbonyl l) amino] pyrrolidine-1-carboxylate

A solution of 100 mg (0.15 mmol) of 4 '- [(2S) -2- [[(iraws-4- {[(tert-butoxycarbonyl) amino] -methy 1} cyclohexyl) carbonyl 1] amino} -3-oxo 3 - {[4- (2-i-tetrazol-5-yl) phenyl] amino} propy 1] -2-fluorobiphenyl-3-carboxylic acid and 33 mg (0.18 mmol) of (R) - (+) - l- (ieri-butoxycarbonyl) -3-aminopyrrolidine in 5 ml of tetrahydrofuran was treated with 67 mg (0.18 mmol) of N - [(dimethylamino) (3 / i- [1,2,3] triazolo [4,5-b] pyridine-3 -yloxy) methylidene] -N-methyl-methanaminium hexafluorophosphate and 0.03 ml (0.18 mmol) of Ν, Ν-diisopropylethylamine and stirred at RT for 16 h. The reaction mixture was separated directly by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). This gave 71 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 = 1.11 min; MS (ES Ineg): m / z = 852 [MH] ^" . Example 30A ieri-butyl-4- ({4'- [(2S) -2- {[(trans - {- [(irei-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3 - {[4- (2 / i-etrazol-5-yl) -phenyl] -amino} -propyl] -2-fluorobiphenyl-3-yl} -carbonyl (l) -piperazine-1-carboxy-lat

A solution of 100 mg (0.15 mmol) of 4 '- [(2 _L S ^, ) -2- [[(α-α-4- {[(ieri-butoxycarbonyl) amino] -methy 1} cyclohexyl) carbonyl 1] amino } -3-oxo-3 - {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propy 1] -2-fluorobiphenyl-3-carboxylic acid and 33 mg (0.18 mmol) of l- ( Butoxycarbonyl) piperazine in 5 ml of tetrahydrofuran was treated with 67 mg (0.18 mmol) of N - [(dimethylamino) (3 / i- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methylidene] - N-methyl-methanaminium hexafluorophosphate and 0.03 ml (0.18 mmol) of Ν, Ν-diisopropylethylamine and stirred for 16 h at RT. The reaction mixture was separated directly by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). This gave 63 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 = 1.12 min; MS (ESIneg): m / z = 852 [MH] \ Example 31 A te ^ Butyl - [(/ raws-4- {[(2S) -3- (5 '- {[3- (diethyl) ^

oxo-1 - {[4- (2-i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate trifluoroacetate

A solution of 100 mg (0.15 mmol) of 4 '- [(2S) -2- [[(iraws-4- {[(tert-butoxycarbonyl) amino] -methy 1} cyclohexyl) carbonyl 1] amino} -3-oxo 3 - {[4- (2-i-tetrazol-5-yl) phenyl] amino} propyl 1] -6-methylbiphenyl-3-carboxylic acid and 23 mg (0.18 mmol) of diethylaminopropylamine in 5 ml of tetrahydrofuran was 0.18 mmol) N - [(dimethylamino) (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methylidene] -N-methyl-methanaminium hexafluorophosphate and 0.03 ml (0.18 mmol). Added Ν, Ν-diisopropylethylamine and stirred at RT for 16 h. After addition of 0.4 ml of N, N-dimethylformamide was stirred for a further 3 d at RT. The reaction mixture was separated twice by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). This gave 77 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 (ES Ineg): m / z = 793 [MH-TFA] ^" .

Example 32A tert -butyl - [(trans-A- {[(2S) -3- [3 '- (morpholin-4-ylcarbonyl) biphenyl-4-yl] -1-oxo-1 - {[4- ( 2 / metrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate

A solution of 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 and 84 mg (0.36 mmol) of [3- (morpholin-4-ylcarbonyl) phenyl] boronic acid in 2.5 ml DMF were treated with 0.36 ml (0.72 mmol) 2M Sodium carbonate solution in water and degassed with argon for 5 min. 17.5 mg (0.02 mmol) of 1, r-bis (diphenylphosphino) ferrocenepalladium (II) chloride was added and the mixture was stirred for 30 min at 120 ° C in a preheated oil bath. The reaction solution was separated by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). The product-containing fractions were combined and concentrated on a rotary evaporator. The residue was dried under high vacuum. 109 mg (56% of theory, 91% purity) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-d ₆ ) δ = 0.83 (m, 2H), 1.05-1.44 (m, 13H), 1.68 (m, 4H), 2.03-2.20 (m, 1H), 2.75 (m, 2H), 2.87-2.99 (m, 1H), 3.04-3.16 (m, 1H), 3.25-3.45 (m, 3H), 4.62-4.77 (m, 1H), 6.78 ( m, 1H), 7.28-7.88 (m, 12H), 8.00 (d, 2H), 8.20 (d, 1H), 10.49 (s, 1H).

LC-MS (Method 1): R _t = 0.97 min; MS (ES Ineg): m / z = 735 [MH] ^" . Example 33A ieri-butyl-4- ({4'- [(2S) -2- {[(trans-4- {[(ε-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -amino} -3-oxo 3- {[4- (2-Etrazol-5-yl) -phenyl] -amino} -propyl] -4-methyl-biphenyl-3-yl} -carbamidine-1-carboxylate

A solution of 80 mg (0.12 mmol) of ieri-butyl - [(ira «A-4- {[(2 _L S ') - 3- (3'-amino-4'-methylbiphenyl-4-yl)-1-one. oxo-1- {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propan-2-yl] carbamoyl} cyclohexyl) -methyl] -carbamate and 56.2 mg (0.25 mmol) of l- (ieri-butoxycarbonyl ) piperidine-4-carboxylic acid in 1 ml DMF were treated with 64 μΐ (0.37 mmol) Ν, Ν-diisopropylethylamine and 69.9 mg (0.18 mmol) N- [(dimethylamino) (3 / i- [1,2,3] triazolo [ 4,5-b] pyridin-3-yloxy) methylidene] -N-methyl-methane-amino-hexafluorophosphate and stirred at RT for 16 h. The contents of the flask were diluted with water and acetonitrile and separated by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). The product-containing fractions were combined and concentrated on a rotary evaporator. The residue was dried under high vacuum. 18 mg (15% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.16 min; MS (ESIpos): m / z = 864 [M + H] ⁺ . Example 34A tert -butyl - [(trans-A- {[(25) -3- (5 '- {[2- (diethylamino) ethyl] carbamoyl} -2'-ethylbiphenyl-4-yl) -1-oxo - 1- {[4- (2-i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate

trifluoroacetate

A solution of 100 mg (0.14 mmol) of 4 '- [(2 _L S ^, ) -2- [[ira-E-4- {[(ieri-butoxycarbonyl) amino] -methy 1} cyclohexyl) carbonyl 1] amino } -3-oxo-3 - {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propy 1] -6-ethyl-biphenyl-3-carboxylic acid and 20 mg (0.17 mmol) of N, N-diethylethane 1-l, 2-diamine in 3 ml DMF was treated with 75 μΐ (0.43 mmol) Ν, Ν-diisopropylethylamine and 65.6 mg (0.17 mmol) N- [(dimethylamino) (3 / i- [1,2,3] triazolo [ 4,5-b] pyridin-3-yloxy) methylidene] -N-methyl-methane-amino-hexafluorophosphate and stirred at RT for 16 h. The contents of the flask were diluted with water and acetonitrile and separated by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). The product-containing fractions were combined and concentrated on a rotary evaporator. The residue was dried under high vacuum. 63 mg (50% of theory, 94% purity) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.85 min; MS (ESIpos): m / z = 794 [M + H] ⁺ . Example 35A ieri-butyl - [(ira ".y-4- {[(2 _L S ^, ) -1-oxo-3- (3'-sulfamoyl-biphenyl-4-yl) -l- {[4- (m- tetrazol-5-yl) phenyl] -amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate

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 72.2 mg (0.36 mmol) of (3-sulfamoylphenyl) boronic acid 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 h at 110 ° C. The batch was filtered and purified by preparative HPLC (basic). 91 mg (54% of theory) of the title compound were obtained. LC-MS (Method 5): R _t = 0.76 min; MS (ESIpos): m / z = 703 [M + H] ⁺ .

Example 36A tert -Butyl - [(trans-4- {[(2S) -3- {3'- [2- (morpholin-4-yl) ethoxy] biphenyl-4-yl} -1-oxo-1 - { [4- (2H-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate trifluoroacetate

A solution of 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 133.0 mg (0.4 mmol) of 4- {2- [3- (4,4,5,5-tetramethyl-1,2,2-dioxaborolane 2-yl) phenoxy] ethyl} morpholine in 1.5 ml of 1,2-dimethoxyethane and 0.5 ml of ethanol were mixed with 18.4 mg (0.016 mmol) of tetrakis (triphenylphosphine) palladium (0) and 1.2 ml of 2M sodium carbonate solution in water. The mixture was stirred at 100 ° C for 3 h. The batch was filtered through kieselguhr and the filtrate was separated by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). The product-containing fractions were combined and dried under high vacuum. 112 mg (63% of theory, 77% purity) of the title compound were obtained. LC-MS (Method 1): R _t = 0.84 min; MS (ESIpos): m / z = 753 [M + H-TFA] ⁺ .

Example 37A

ieri-butyl - [(ira "_> y-4- {[(2 _L S ^, ) -3- (3'-amino-4'-methylbiphenyl-4-yl) -l-oxo-l- {4- (2 / i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl 1} cyclohexyl) methyl] carbamate

A solution of 1000 mg (1.60 mmol) of 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 289.1 mg (1.92 mmol) of (3-amino-4-methylphenyl) boronic acid in 16 ml of 1,2-dimethoxyethane were mixed with 65.17 mg (0.08 mmol). l, l-bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex and 1.6 ml of 2M sodium carbonate solution in water. The mixture was stirred at reflux for 2 h. The reaction was filtered, concentrated and recrystallized hot from acetonitrile. The precipitate was filtered off with suction, washed with a little cold acetonitrile and dried under high vacuum. 404 mg (39% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.03 min; MS (ESIpos): m / z = 653 [M + H] ⁺ . Example 38A

Ethyl 4'- [(2S) -2- {[(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] oxo-3- {[4- (2-i-tetrazole-5 -yl) phenyl] amino} propyl] -6-ethyl-biphenyl-3-carboxylate

182.4 mg (0.48 mmol) of bis (pinacolato) diborane, 172.4 mg (0.67 mmol) of ethyl-3-bromo-4-ethylbenzoate and 140.9 mg (1.44 mmol) of potassium acetate were initially charged under argon in 4 ml of toluene, with 19.6 mg (24 μηιοΐ ) [l, l-bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex and stirred for 3 h at 110 ° C. The mixture was mixed with 300 mg (0.48 mmol) of 4-biome N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -N- [4- (2 / i -tetrazol-5-yl) phenyl] -L-phenylalanine amide, 19.6 mg (24 μηιοΐ) of 1,1-bis (diphenylphosphino) ferrocene] -dichloropalladium-dichloromethane complex, 1.5 ml of ethanol and 0.48 ml (0.96 mmol) 2M Sodium carbonate solution in water. The mixture was stirred at 110 ° C. for 6 h and then at RT overnight. The batch was separated by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). The product-containing fractions were combined and concentrated on a rotary evaporator. The residue was dried under high vacuum. 107 mg (31% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.23 min; MS (ESIpos): m / z = 724 [M + H] ⁺ .

Example 39A

4 '- [(2S) -2- {[(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2/4) tetrazol-5-yl) phenyl] amino} propyl] -6-ethyl-biphenyl-3-carboxylic acid

A solution of 105 mg (0145 μηιοΐ) of ethyl-4 '- [(2 _{l of} S ^, ) -2- {[(ira "Ä4- {[(ieri-butoxycarbonyl) amino] -methy 1} cyclohexyl) carbonyl 1 ] amino} -3-oxo-3 - {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propy 1] -6-ethyl-biphenyl-3-carboxylate, 3 ml of tetrahydrofuran, and 1 ml of water was added RT with 60.9 mg (1.45 mmol) of lithium hydroxide. The reaction mixture was stirred at RT for 4 days, then adjusted to pH 5-6 with 1M hydrochloric acid solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. 102 mg (80% of theory, 79% purity) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.05 min; MS (ES Ineg): m / z = 696 [M + H] ⁺ . Example 40A ieri-butyl - [(ira "_> y-4- {[(2 _l S ^, ) -3- (5'-cyano-2'-methylbiphenyl-4-yl) -l-oxo-l- [[ 4- (2 / i-tetrazol-5-yl) -phenyl] -amino} -propan-2-yl] carbamoyl 1} cyclohexyl) methyl] carbamate

A solution of 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-phenylalanineamide and 87.3 mg (0.36 mmol) of (5-cyano-2-methylphenyl) boronic acid in 2.5 ml of DMF 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 (0.02 mmol) of 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride was added and the mixture was stirred for 2 hours 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 and washed again with ethyl acetate. The organic phase of the filtrate was dried over magnesium sulfate and concentrated in vacuo. The residue was slurried with dichloromethane, the resulting solid was precipitated and filtered, washed with acetonitrile and dried under high vacuum. 86 mg (51% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.11 min; MS (ESIpos): m / z = 663 [M + H] ⁺ .

Example 41 A tert-Quty - [(trans-A- {[(2S) -3- [4'-methoxy-3 '- (morpholin-4-ylsulphonyl) biphenyl-4-yl] -1-oxo-1 - {[4- (1-i-tetrazol-5-yl) -phenyl] amino} propan-2-yl] carbamoyl}} cyclohexyl] methyl] carbamate

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 108.2 mg (0.36 mmol) of [4-methoxy-3- (morpholin-4-ylsulfonyl) phenyl] boronic acid in 1.8 ml of DMSO were treated with 27.7 mg (23.9 μηιοΐ) 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). 86 mg (45% of theory) of the title compound were obtained. LC-MS (Method 4): R _t = 1.20 min; MS (ESIpos): m / z = 803 [M + H] ⁺ . Example 42A The butyl-{[ira-.y-4 - ({(2 ₁ S ^, ) -3- [5 '- (dimethylsulfamoyl) -2'-methylbiphenyl-4-yl] -l-oxo-1-one [(2-oxo-2,3-dihydro-1 / i-benzimidazol-5-yl) amino] propan-2-yl} carbamoyl) cyclohexyl-1-methyl-1-carbamate

To a solution of 150 mg (0.24 mmol) of 4-bromo-Na / j / ia - [(1α-ε-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- (2- oxo-2,3-dihydro-l / i-benzimidazol-5-yl) -L-phenylalanine amide and 90.8 mg (0.37 mmol) of [5- (dimethylsulfamoyl) -2-methylphenyl] boronic acid in 1.8 ml of DMSO, 28.2 mg (24.4 μηιοΐ) tetrakis (triphenylphosphine) palladium (0), 77.6 mg (0.7 mmol) of sodium carbonate and 0.37 ml (20.4 mmol) of water. The mixture was microwave-treated at 110 ° C for 90 minutes. The batch was filtered and purified by preparative HPLC (Method 10). 68 mg (38% of theory) of the title compound were obtained.

LC-MS (Method 4): R _t = 1.18 min; MS (ESIpos): m / z = 733 [M + H] ⁺ .

Example 43A te ^ Butyl {[/ raws-4 - ({(2S) -3- [2'-methyl-5Xm

oxo-2-dihydro-l / i-benzimidazol-5-yl) amino] propan-2-yl} carbamoyl) cyclohexyl] methyl} carbamate

To a solution of 150 mg (0.24 mmol) of 4-bromo-Na / j / ia - [(1α-ε-4- {[(ieri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) -carbonyl] -N- (2- oxo-2,3-dihydro-l / i-benzimidazol-5-yl) -L-phenyl-alaninamide and 106.5 mg (0.37 mmol) of [2-methyl-5- (morpholin-4-ylsulfonyl) -phenyl] boronic acid in 1.8 To DMSO was added 28.2 mg (24.4 μηιοΐ) of tetrakis (triphenylphosphine) palladium (0), 77.6 mg (0.7 mmol) of sodium carbonate and 0.37 ml (20.4 mmol) of water. The mixture was microwave-treated at 110 ° C for 90 minutes. The batch was filtered and purified by preparative HPLC (Method 10). 79 mg (42% of theory) of the title compound were obtained.

LC-MS (Method 4): R _t = 1.17 min; MS (ESIpos): m / z = 775 [M + H] ⁺ . Example 44A tert -butyl - [(trans-A- {[(25) -3- (3'-{[2- (morpholin-4-yl) ethyl] carbamoyl} biphenyl-4-yl) -1-oxo - 1 - {[4- (l-i-tetrazol-5-yl) -phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] 1-carbamate 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 123.0 mg (0.36 mmol) of (3- {[2- (morpholin-4-yl) ethyl] carbamoyl} phenyl) boronic acid hydrochloride in 1.8 ml of DMSO were added 27.7 mg (23.9 μηιοΐ) 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). 60 mg (32% of theory) of the title compound were obtained.

LC-MS (Method 4): R _t = 0.94 min; MS (ESIpos): m / z = 780 [M + H-HCOOH] Example 45A The Butyl - [(1α-i-4- {[(25) -3- [5 '- (dimethylamino) -2'-methylbiphenyl-4-yl] -l-oxo-1

tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate 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 64.3 mg (0.36 mmol) of [5- (dimethylamino) -2-methylphenyl] boronic acid 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 1.5 h at 110 ° C. The batch was filtered and purified by preparative HPLC (Method 11). 30 mg (18% of theory) of the title compound were obtained.

LC-MS (method 5): R _t = 0.94 min; MS (ESIpos): m / z = 681 [M + H-HCOOH] ⁺ .

Example 46A tert -Butyl - [(trans-4- {[(2S) -3- {4'-methyl-3 '- [(tetrahydro-2-pyran-4-ylcarbonyl) amino] biphenyl-4-yl } - 1 -oxo-1 - {[4- (2-i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate

A solution of 83 mg (0.13 mmol) of ieri-butyl - [(ira «A-4- {[(2 _L S ') - 3- (3'-amino-4'-methylbiphenyl-4-yl)-1-one. oxo 1- {[4- (2-i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate and 33 mg (0.25 mmol) tetrahydro-2 / i Pyran-4-carboxylic acid in 1 ml DMF was treated with 66 μΐ (0.38 mmol) Ν, Ν-diisopropylethylamine and 72.5 mg (0.19 mmol) N - [(dimethylamino) (3 / i- [l, 23] triazolo [4,5 -b] pyridin-3-yloxy) methylidenes] -N-methylmethanaminium hexafluorophosphate and stirred for 16 h at RT. The contents of the flask were diluted with water and acetonitrile and separated by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). The product-containing fractions were combined and concentrated on a rotary evaporator. The residue was dried under high vacuum. 24 mg (22% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.01 min; MS (ESIpos): m / z = 765 [M + H] ⁺ .

Example 47A

4 '- [(2S) -2- {[(trans - - {[(i.i.-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2 / i-tetrazole -5-yl) phenyl] amino} propyl] -5-fluoro-6-methylbiphenyl-3-carboxylic acid

4-Bromo-A ^L a / j / ia - [(iraay-4- {[(iper ^ butoxycarb

tetrazol-5-yl) -phenyl] -L-phenylalanine amide (1.00 g, 1.60 mmol) from Example 6A, methyl-3-fluoro-4-methyl-5- (4,4,5,5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (704mg, 2.39mmol) and [2'- (azanidyl- / ca j yes-A ⁱ -) biphenyl-2-yl- / ca j jaC2] [di- (3s, 5s, 7s) -adamantan-1-yl (butyl) phosphoranyl] - (methanesulfonatato-fca j yes-0) palladium (116 mg, 0.16 mmol) were placed under argon, then 12.0 ml of methanol and 6.38 ml (6.38 mmol) Added to the aqueous potassium phosphate solution and the reaction mixture shaken overnight at 65 ° C. The mixture was then diluted at RT with 10 ml of water and filtered. The filtrate was acidified with 1M hydrochloric acid, the resulting solid was filtered off, washed with water and dried under high vacuum. The crude product thus obtained (1.07 g, mixture of title compound and corresponding methyl ester approximately 1: 4) was taken up in 5.0 ml of THF without further purification, admixed with 6.0 ml of 1M aqueous lithium hydroxide solution and stirred at RT overnight. It was then diluted with water and acidified with 1M hydrochloric acid. The resulting solid was filtered off, washed with water and dried under high vacuum. The mixture was then stirred with methyl tert-butyl ether / ethyl acetate (2: 1), filtered and dried under high vacuum. This gave 666 mg (90% purity) of the title compound, which was reacted without further purification.

LC-MS (Method 1): R _t = 1.02 min; MS (ESIpos): m / z = 700 [M + H] ⁺ . Ή-NMR (400 MHz, DMSO-ώ): δ = ppm 13.20 (br, s, 1H), 10.44 (s, 1H), 8.18 (d, 1H), 8.00 (d, 2H), 7.82 (d, 2H), 7.66-7.54 (m, 2H), 7.42 (d, 2H), 7.31 (d, 2H), 6.81-6.70 (m, 1H), 4.82-4.71 (m, 1H), 3.20-3.10 (m, 1H), 3.01-2.91 (m, 1H), 2.79-2.71 (m, 2H), 2.20-2.09 (m, 4H), 1.73-1.59 (m, 3H), 1.54 (d, 1H), 1.42-1.32 ( m, 6H), 1.25 (d, 1H), 0.82 (d, 1H). Example 48A tert -Butyl - [(trans-4- {[(2 _L S ') - 3- [3'-fluoro-5' - (isopropylcarbamoyl) -2'-methylbiphenyl-4-yl] -1-oxo 1 - {[4- (2-i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate

4 '- [(2S) -2- {[(1-methyl-4-one {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3 {[4- (2) tetrazol-5-yl) -phenyl] -amino} -propyl] -5-fluoro-6-methylbiphenyl-3-carboxylic acid (200 mg, 0.25 mmol) were initially charged in 3.5 ml of dimethylformamide and treated with isopropylamine (30 mg, 0.51 mmol), N, N-Diisopropylethylamine (0.13 mL, 0.77 mmol) and 1- [bis (dimethylamino) methylene] -1 / il, 2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (147 mg, 0.39 mmol ). The reaction mixture was stirred for 1 h at RT and allowed to stand for 3 days at RT. Subsequently, the reaction mixture was diluted with water and acidified with 1M hydrochloric acid. The resulting solid was filtered off, washed with 10 ml of water and methyl tert-butyl ether and dried under high vacuum. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid (gradient)). 71 mg (37% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.06 min; MS (ESIpos): m / z = 741 [M + H] ⁺ .

Ή NMR (400 MHz, DMSO-ώ): δ = ppm 16.67 (br, s, 1H), 10.43 (s, 1H), 8.29 (d, 1H), 8.17 (d, 1H), 7.99 (d, 2H), 7.82 (d, 2H), 7.64-7.54 (m, 2H), 7.41 (d, 2H), 7.31 (d, 2H), 6.81-6.72 (m, 1H), 4.81-4.69 (m, 1H) , 4.16-4.00 (m, 1H), 3.20-3.07 (m, 1H), 3.01-2.89 (m, 1H), 2.79-2.72 (m, 2H), 2.18-2.05 (m, 4H), 1.74-1.49 ( m, 4H), 1.37 (s, 9H), 1.29-1.20 (m, 2H), 1.15 (d, 7H), 0.91-0.74 (m, 2H). Example 49A Butyl 4 - [({4 '- [(2 ^ -2- {[(ira-i-4- {[(fer-butoxycarbonyl) -nino] -methyl} -cyclohexyl) -carbonyl 1-amino} - 3 -oxo-3 - {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propy 1] -5-fluoro-6-methyl-biphenyl-3-yl} -carbonyl) -amino] -piperidine-1-carboxylate

4'- [(2S) -2- {[(trans- - {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2 / i-tetrazole -5-yl) phenyl] amino} propyl] -5-fluoro-6-methylbiphenyl-3-carboxylic acid (200 mg, 0.25 mmol) were initially charged in 3.1 ml of dimethylformamide and treated with feri-butyl-4-aminopiperidine-l-carboxylate ( 92 mg, 0.46 mmol), N, N-diisopropylethylamine (0.12 ml, 0.69 mmol) and 1- [bis (dimethylamino) methylene] -1 / l, 2,3-triazolo [4,5-b] pyridinium-3 oxide hexafluorophosphate

(130 mg, 0.34 mmol). The reaction mixture was stirred for 1 h at RT and allowed to stand for 3 days at RT. Subsequently, the reaction mixture was diluted with water and acidified with 1M hydrochloric acid. The resulting solid was filtered off, washed with 10 ml of water and methyl tert-butyl ether and dried under high vacuum. The crude product was purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid (gradient)). 108 mg (53% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.15 min; MS (ESIpos): m / z = 882 [M + H] Ή NMR (400 MHz, DMSO-ifc): δ = ppm 16.68 (br, s, 1H), 10.42 (s, 1H), 8.33 (d, 1H), 8.17 (d, 1H), 7.99 (d, 2H), 7.82 (d, 2H), 7.65-7.55 (m, 2H), 7.41 (d, 2H), 7.30 (d, 2H), 6.79-6.72 (m, 1H), 4.81-4.70 (m, 1H) , 4.83-2.71 (m, 3H), 2.16-2.06 (m, 3H) m, 4H), 1.59-1.49 (m, 1H), 1.30-1.07 (m, 3H), 0.82 (br, s, 2H).

Example 50A

[(25) -3- {5 '- [(1α-α-4-hydroxycyclohexyl) carbamoyl] -2'-methylbiphenyl) -1-oxo-1 - {[4- (2-i-tetrazole-5 - yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate

4 '- [(2S) -2- {[(trans - - {[(i.i.-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2 / i-tetrazole -5-yl) phenyl] amino} propyl] -6-methylbiphenyl-3-carboxylic acid (120 mg, 0.18 mmol) from Example 12A and iraws-4-aminocyclohexanol (41 mg, 0.35 mmol) were introduced into 3.0 ml of dimethylformamide, with N, N-diisopropylethylamine (0.09 ml, 0.53 mmol) and 1- [bis (dimethylamino) methylene] -1 / il, 2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (100 mg, 0.26 mmol) and the mixture allowed to stand at RT overnight. The reaction mixture was diluted with acetonitrile / water, filtered and the filtrate was purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid (gradient)). 136 mg (99% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.97 min; MS (ESIpos): m / z = 779 [M + H] ⁺ . Ή-NMR (400 MHz, DMSO-ifc): δ = ppm 10.42 (s, 1H), 8.20-8.10 (m, 2H), 7.99 (d, 2H), 7.82 (d, 2H), 7.74-7.70 (m , 1H), 7.66-7.64 (m, 1H), 7.39 (d, 2H), 7.33 (d, 1H), 7.28 (d, 2H), 6.80-6.72 (m, 1H), 4.78-4.69 (m, 1H ), 4.58-4.46 (m, 1H), 3.77-3.65 (m, 1H), 3.16-3.08 (m, 1H), 2.99-2.90 (m, 1H), 2.80-2.71 (m, 2H), 2.20 (s , 3H), 2.16-2.06 (m, 1H), 1.88-1.74 (m, 4H), 1.73-1.51 (m, 4H), 1.37 (s, 9H), 1.34-1.11 (m, 6H), 0.90-0.75 (m, 2H).

Example 51 A [(25) -3- [2'-methyl-5 '- (morpholin-4-ylcarbonyl) biphenyl-4-yl]

(2 / i-tetrazol-5-yl) phenyl 1] amino} propan-2-yl] carbamoyl 1} cyclohexyl-1-methyl] carbamate

4'- [(2S) -2- {[(trans- - {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2 / i-tetrazole -5-yl) phenyl] amino} propyl] -6-methylbiphenyl-3-carboxylic acid from Example 12A (130 mg, 0.19 mmol) and morpholine (0.03 ml, 0.38 mmol) were initially charged in 3.0 ml of dimethylformamide, with N, N- Diisopropylethylamine (0.10 ml, 0.57 mmol) and 1- [bis (dimethylamino) methylene] -1 / il, 2,3-triazolo [4,5-b] pyridinium-3-oxide hexafluorophosphate (108 mg, 0.28 mmol) were added and let the mixture stand at RT overnight. The reaction mixture was diluted with acetonitrile / water, filtered and the filtrate was purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid (gradient)). 56 mg of the title compound were obtained as crude product which was reacted without further purification. LC-MS (Method 1): R _t = 0.96 min; MS (ESIpos): m / z = 752 [M + H] Example 52A

4 '- [(2S) -2- {[(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino}

{[4- (2 / i-tetrazol-5-yl) -phenyl] -amino} -propyl] -5,6-dimethylbiphenyl-3-carboxylic acid

In a mixture of 15.0 ml of DMF and 1.5 ml of water under argon, 3,4-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid (617 mg, 2.23 mmol), 4-Bmm-N-alpha- [(trans - - {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] - N - [4- (2-i-tetrazol-5-yl) -phenyl ] -L-phenylalanine amide (1.00 g, 1.60 mmol) from Example 6A and 507 mg (4.79 mmol) of sodium carbonate submitted. Subsequently, 1,1-bis (diphenylphosphino) ferrocenedichloro palladium (II) (130 mg, 0.16 mmol) was added and the mixture was stirred for 1 h at 150 ° C in the microwave. Thereafter, the reaction mixture was diluted with 50 ml of water, acidified with 1M hydrochloric acid and extracted twice with 50 ml of diethyl ether. The combined organic phases were washed once each with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid (gradient)). This gave 299 mg of the title compound as a crude product which was reacted further without further purification.

LC-MS (Method 1): R _t = 1.04 min; MS (ESIpos): m / z = 696 [M + H] ⁺ . Example 53A tert -butyl - [(trans-A- {[(2S) -3- {2 ', 3'-dimethyl-5' - [(1-methylpiperidin-4-yl) carbamoyl] biphenyl-4-yl } - 1 -oxo-1 - {[4- (2-i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate

4 '- [(2S) -2- {[(trans- - {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2-i-tetrazole) 5-yl) phenyl] amino} propyl] -5,6-dimethylbiphenyl-3-carboxylic acid (150 mg, 0.22 mmol) and 4-amino-A ^L mefhylpiperidin (49 mg, 0.43 mmol) were placed in 3.0 ml of dimethylformamide, with N, N-diisopropylethylamine (0.15 mL, 0.86 mmol) and 1- [bis (dimethylamino) -methylene] -l / il, 2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (123 mg , 0.32 mmol) and the mixture allowed to stand at RT overnight. The reaction mixture was diluted with acetonitrile / water, filtered and the filtrate was purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid (gradient)). 80 mg (46% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.85 min; MS (ESIpos): m / z = 792 [M + H] ⁺ .

Ή NMR (400 MHz, DMSO-ifc): δ = ppm 10.15 (s, IH), 8.29 (d, IH), 8.18-8.09 (m, IH), 7.92 (d, 2H), 7.68-7.59 (m , 3H), 7.49 (s, IH), 7.37 (d, 2H), 7.22 (d, 2H), 6.82-6.73 (m, IH), 4.79-4.69 (m, IH), 3.99-3.85 (m, IH ), 3.30-3.15 (m, 4H), 3.15-3.08 (m, 2H), 2.99-2.90 (m, IH), 2.82-2.70 (m, 4H), 2.59 (s, 3H), 2.33 (s, 3H , 2.18-2.12 (m, IH), 2.09 (s, 3H), 1.90 (d, 2H), 1.76-1.54 (m, 6H), 1.37 (s, 9H), 1.33-1.10 (m, 3H), 0.91-0.75 (m, 2H). Example 54A

4 '- [(2S) -2- {[(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2/4) tetrazol-5-yl) phenyl] amino} propyl] -4-fluorobiphenyl-3-carboxylic acid

In a mixture of 2.0 ml of DMF and 0.2 ml of water under argon, 2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid (64 mg, 0.24 mmol ), 4-Bmm-N-alpha - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] - N - [4- (2-i-tetrazol-5-yl) -phenyl] -L-phenylalaninamide (100 mg, 0.16 mmol) from Example 6A and 51 mg (0.48 mmol) of sodium carbonate submitted. Subsequently, 1,1-bis (diphenylphosphino) ferrocenedichloro palladium (II) (12 mg, 0.02 mmol) was added and the mixture was stirred for 1 h at 150 ° C in the microwave. Thereafter, the reaction mixture was diluted with 20 ml of water, acidified with 1M hydrochloric acid and extracted twice with 20 ml of ethyl acetate each time. The combined organic phases were washed once each with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid (gradient)). This gave 38 mg of the title compound as a crude product which was reacted further without further purification.

LC-MS (Method 1): R _t = 0.97 min; MS (ESIpos): m / z = 686 [M + H] ⁺ . Example 55A ieri-butyl-4 - [({4 '- [(2S) -2- {[(trans-4- {[(feri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo -3- {[4- (2 / i-tetrazol-5-yl) -phenyl] -amino} -propyl] -4-fluorobiphenyl-3-yl} -carbonyl} amino] -piperidine-1-carboxy-lat

4 '- [(2S) -2- {[(trans - - {[(i.i.-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2 / i-tetrazole -5-yl) phenyl] amino} propyl] -4-fluorobiphenyl-3-carboxylic acid (300 mg, 0.22 mmol, 50% purity) were initially charged in 4.0 ml of dimethylformamide and then ieri-butyl-4-aminopiperidine-l-carboxylate ( 88 mg, 0.44 mmol). Thereafter, N, N-diisopropylethylamine (0.15 ml, 0.88 mmol) and 1- [bis (dimethylamino) methylene] -1 / il, 2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (125 mg, 0.33 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was diluted with acetonitrile and purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid (gradient)). 112 mg (56% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.17 min; MS (ESIpos): m / z = 868 [M + H] ⁺ .

Ή-NMR (400 MHz, DMSO-ώ): δ = ppm 16.64 (br.s, IH), 10.45 (s, IH), 8.34 (d, IH), 8.15 (d, IH), 7.99 (d, 2H), 7.87-7.72 (m, 4H), 7.61 (d, 2H), 7.41 (d, 2H), 7.34 (t, IH), 6.80-6.70 (m, IH), 4.76-4.65 (m, IH) , 4.02-3.83 (m, 3H), 3.14-3.05 (m, IH), 2.98-2.81 (m, 3H), 2.78-2.70 (m, 2H), 2.17-2.06 (m, IH), 1.86-1.76 ( m, 2H), 1.75-1.53 (m, 4H), 1.40 (s, 8H), 1.36 (s, 9H), 1.31-1.09 (m, 3H), 0.91-0.74 (m, 2H). Example 56A tert -Butyl - [(trans-4- {[(2S) -3- {2'-methyl-5 '- [(2-oxopiperidin-4-yl) carbamoyl] biphenyl-4-yl} -1 oxo-1- {[4- (2-i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate

4 '- [(2S) -2- {[(trans - - {[(i.i.-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2 / i-tetrazole -5-yl) phenyl] amino} propyl] -6-methylbiphenyl-3-carboxylic acid (120 mg, 0.15 mmol, 88% purity) from Example 12A were initially charged in 3.0 ml of dimethylformamide and then 4-aminopiperidin-2-one (44 mg, 0.39 mmol). Thereafter, N, N-diisopropylethylamine (0.08 ml, 0.46 mmol) and 1- [bis (dimethylamino) methylene] -1 / il, 2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (88 Mg, 0.23 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was diluted with water / acetonitrile, filtered and the filtrate was purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid (gradient)). 81 mg (68% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.91 min; MS (ESIpos): m / z = 778 [M + H] ⁺ . Ή NMR (400 MHz, DMSO δ = ppm 16.73 (br, s, 1H), 10.45 (s, 1H), 8.41 (d, 1H), 8.20 (d, 1H), 7.99 (d, 2H), 7.82 (d, 2H), 7.77-7.71 (m, 1H), 7.70-7.66 (m, 1H), 7.59-7.52 (m, 1H), 7.45-7.32 (m, 3H), 7.29 (d, 2H), 6.84 -6.73 (m, 1H), 4.79-4.68 (m, 1H), 4.25-4.11 (m, 1H), 3.24-3.06 (m, 3H), 3.00-2.88 (m, 1H), 2.79-2.70 (m, 2H), 2.48-2.40 (m, 1H), 2.29-2.22 (m, 1H), 2.18-2.07 (m, 1H), 1.96-1.87 (m, 1H), 1.75-1.50 (m, 5H), 1.37 ( s, 9H), 1.31-1.08 (m, 3H), 0.91-0.75 (m, 2H). Example 57A Ethyl Butyl - [(Iraws-4- {[(2S) -3- (3 '- {[4- (dimethylam

yl) - 1 -oxo-1- {[4- (2-i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate

4 '- [(2S) -2- {[(trans - - {[(i.i.-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2 / i-tetrazole -5-yl) phenyl] amino} propyl] -5-methylbiphenyl-3-carboxylic acid (100 mg, 0.15 mmol) were initially charged in 2.0 ml of dimethylformamide and then N, N-Dimefhylcyclohexan- 1,4-diamine (42 mg, 0.29 mmol). Thereafter, N, N-diisopropylethylamine (0.10 ml, 0.59 mmol) and 1- [bis (dimethylamino) methylene] -1H-1,3,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (84 mg, 0.22 mmol) and the mixture was allowed to stand at RT overnight. The reaction mixture was diluted with acetonitrile and purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid (gradient)). 38 mg (30% of theory) of the title compound were obtained. LC-MS (Method 1): R _t = 0.83 min; MS (ESIpos): m / z = 806 [M + H] ⁺ .

Ή NMR (400 MHz, DMSO-ifc): δ = ppm 10.16 (s, IH), 8.34-8.28 (m, IH), 8.19-8.06 (m, 2H), 7.91 (d, 2H), 7.83 (i.e. , IH), 7.67-7.56 (m, 6H), 7.40 (d, 2H), 6.79-6.72 (m, IH), 4.76-4.66 (m, IH), 4.07-3.73 (m, IH), 3.50-3.30 (m, 2H), 3.15-3.06 (m, 2H), 2.99-2.88 (m, IH), 2.78-2.72 (m, 2H), 2.68 (s, 3H), 2.58 (s, 2H), 2.41 (d, 3H), 2.19-2.09 (m, 1H), 2.04-1.89 (m, 3H), 1.83-1.43 (m, 8H), 1.36 ( s, 9H), 1.29-1.12 (m, 3H), 0.91-0.75 (m, 2H).

Example 58A

4 '- [(2S) -2- {[(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2/4) tetrazol-5-yl) phenyl] amino} propyl] -5-methylbiphenyl-3-carboxylic acid

In a mixture of 10.0 mL DMF and 1.67 mL water under argon, 3- (dihydroxyboryl) -5-methylbenzoic acid (402 mg, 2.23 mmol), 4-bromo-A ⁱ -a / j / ia - [(ira Ä -4- {[(ieri-butoxycarbonyl) -amino] -methyl} cyclohexyl) -carbonyl] -N- [4- (2-i-tetrazol-5-yl) -phenyl] -L-phenyl-alanineamide (1.00 g, 1.60 mmol ) from Example 6A and 507 mg (4.79 mmol) of sodium carbonate. Then, 1,1-bis (diphenylphosphino) ferrocenedichloro-palladium (II) (117 mg, 0.16 mmol) was added and the mixture was stirred for 1 h at 140 ° C in the microwave. Thereafter, the reaction mixture was diluted with 50 ml of water, acidified with 1M hydrochloric acid and extracted twice with 50 ml of ethyl acetate each time. The combined organic phases were washed once each with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The solid formed was filtered off, washed with ethyl acetate and dried under high vacuum. This gave 268 mg of the title compound as a crude product which was reacted further without further purification.

LC-MS (Method 1): R _t = 1.00 min; MS (ESIpos): m / z = 682 [M + H] ⁺ . Ή-NMR (400 MHz, DMSO-ώ): δ = ppm 10.44 (s, 1H), 8.14 (d, 1H), 7.99 (d, 2H), 7.82 (d, 2H), 7.64-7.56 (m, 3H ), 7.49-7.43 (m, 1H), 7.38 (d, 2H), 7.34 (d, 1H), 6.79-6.71 (m, 1H), 4.74-4.66 (m, 1H), 3.75-3.59 (m, 4H 3.58-3.40 (m, 2H), 3.23-3.12 (m, 2H), 3.12-3.05 (m, 1H), 2.97-2.88 (m, 1H), 2.79-2.70 (m, 2H), 2.25 (s, 3H), 2.17-2.08 (m, 1H), 1.74-1.55 (m, 4H), 1.36 (s, 9H), 1.30-1.11 (m, 4H), 0.89-0.77 (m, 2H).

Example 59A

[(25) -3- [4'-methyl-3 '- (morpholin-4-ylcarbonyl) biphenyl-4 ^

(2 / i-tetrazol-5-yl) phenyl 1] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] 1-carbamate

4'- [(2S) -2- {[(trans- - {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2 / i-tetrazole -5-yl) phenyl] amino} propyl] -4-methylbiphenyl-3-carboxylic acid from Example 12A (100 mg, 0.15 mmol) and morpholine (26 mg, 0.29 mmol) were initially charged in 3.0 ml of dimethylformamide, with N, N- Diisopropylethylamine (0.08 mL, 0.44 mmol) and 1- [bis (dimethylamino) methylene] -1H, 1,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (84 mg, 0.22 mmol) and the mixture stirred at RT overnight. The reaction mixture was diluted with acetonitrile / water, filtered and the filtrate was purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid (gradient)). 81 mg (73% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.99 min; MS (ESIpos): m / z = 751 [M + H] ⁺ . Example 60A

Mefhyl-4 '- [(2S) -2- {[(trans-4- {[(feri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] 3-oxo-3- {[4- (2-i-tetrazole -5-yl) phenyl] amino} propyl] -4-methylbiphenyl-3-carboxylate

4-bromo-A ^r -a / j / ia - [(ira "Ä-4- {[(ier ^ butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -N- [4- (2 / i-tetrazol-5 -yl) phenyl] -L-phenylalanine amide (1.00 g, 1.60 mmol) from Example 6A, [3- (methoxycarbonyl) -4-methylphenyl] boronic acid (433 mg, 2.23 mmol) and sodium carbonate (507 mg, 4.79 mmol) were added Argon in 12 ml of DMF / water (10: 2) submitted. Then, 1,1-bis (diphenylphosphino) ferrocenedichloro-palladium (II) (117 mg, 0.16 mmol) was added and the mixture was stirred for 1 h at 140 ° C in the microwave. The reaction mixture was then diluted at RT with 50 ml of water, acidified with 1M hydrochloric acid and extracted twice with 70 ml of ethyl acetate each time. The combined organic phases were washed once each with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated. The residue obtained was taken up in ethyl acetate, the precipitate formed was filtered off, washed with ethyl acetate and dried under high vacuum. The crude product thus obtained (82% purity) was reacted further without further purification.

LC-MS (Method 1): R _t = 1.14 min; MS (ESIpos): m / z = 696 [M + H] ⁺ . Example 61 A

4 '- [(2S) -2- {[(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2/4) tetrazol-5-yl) phenyl] amino} propyl] -4-methylbiphenyl-3-carboxylic acid

Mefhyl-4 '- [(2S) -2- {[(trans - - {[(ferro-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} - 3-oxo-3- {[4- (2 / i etrazol-5-yl) -phenyl] -amino} -propyl] -4-methylbiphenyl-3-carboxylate (608 mg, 0.72 mmol, 82% purity) was charged in 6.0 mL of THF and then with lithium hydroxide (171 mg, 7.15 mmol) and 2.0 ml of water. The mixture was stirred at RT for 2 days and at 45 ° C. for 6 h. The reaction mixture was then acidified with 1M hydrochloric acid, the solid formed was filtered off, washed with water and dried under high vacuum. This gave 549 mg (84% purity) of the title compound, which was reacted further without further purification.

LC-MS (Method 1): R _t = 1.01 min; MS (ESIpos): m / z = 682 [M + H]

Example 62A tert -butyl - [(/ raws-4- {[(2S) -3- [5Xdimethyce]

 (2 / i-tetrazol-5-yl) phenyl 1] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] 1-carbamate

4 '- [(2S) -2- {[(trans - - {[(i.i.-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2 / i-tetrazole -5-yl) phenyl] amino} propyl] -4,6-dimethylbiphenyl-3-carboxylic acid (95 mg, 0.14 mmol) were initially charged in 2.0 ml of dimethylformamide and then N, N-dimethylamine (40% in water, 31 mg , 0.27 mmol) was added. Thereafter, N, N-diisopropylethylamine (0.10 ml, 0.55 mmol) and 1- [bis (dimethylamino) methylene] -1 / il, 2,3-triazolo [4,5-b] pyridinium-3-oxide hexafluorophosphate (78 mg, 0.21 mmol), the mixture was stirred for 1 h at RT and allowed to stand overnight. The reaction mixture was diluted with acetonitrile and purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid (gradient)). 80 mg (78% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-ife): δ = ppm 10.40 (s, IH), 8.14 (d, IH), 7.98 (d, 2H), 7.81 (d, 2H), 7.35 (d, 2H), 7.23 (d, 2H), 7.16 (s, IH), 6.89 (s, IH), 6.78-6.72 (m, IH), 4.78-4.69 (m, IH), 3.14- 3.06 (m, IH), 2.98 ( s, 2H), 2.97-2.90 (m, 2H), 2.78 (s, 3H), 2.77-2.72 (m, 2H), 2.18 (s, 3H), 2.14-2.06 (m, IH), 1.73-1.59 ( m, 3H), 1.58-1.51 (m, IH), 1.37 (s, 9H), 1.30-1.19 (m, 2H), 1.19-1.08 (m, IH), 0.89-0.75 (m, 2H).

LC-MS (Method 1): R _t = 1.05 min; MS (ESIpos): m / z = 723 [M + H] Example 63A

4 '- [(2S) -2- {[(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino}

{[4- (2 / i-tetrazol-5-yl) -phenyl] -amino} -propyl] -4,6-dimethylbiphenyl-3-carboxylic acid

Mefhyl-4 '- [(2S) -2- {[(trans- - {[(feri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} - 3-oxo-3- {[4- (2 / i -tetrazol-5-yl) -phenyl] -amino} -propyl] -4,6-dimethylbiphenyl-3-carboxylate (323 mg, 0.46 mmol) were placed in 2.4 ml of THF and washed with a solution of lithium hydroxide (109 mg, 4.55 mmol) in Added 1.5 ml of water. The mixture was allowed to stand overnight at RT and stirred at 60 ° C for 90 min. Subsequently, another 10 eq. Added lithium hydroxide and stirred at 60 ° C for 10 h. After that, another 10 eq. Lithium hydroxide added and stirred at 60 ° C for 2 h. The resulting suspension was diluted with water and acidified with 1M hydrochloric acid. The solid was filtered off, washed with ethyl acetate and dried under high vacuum. 204 mg (60% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-ifc): δ = ppm 12.70 (br, s, 1H), 10.44 (s, 1H), 8.17 (d, 1H), 7.99 (d, 2H), 7.81 (d, 2H), 7.63 (s, 1H), 7.37 (d, 2H), 7.27-7.19 (m, 3H), 6.82-6.74 (m, 1H), 4.80-4.69 (m, 1H), 3.16-3.06 (m, 1H), 2.98-2.88 (m, 1H), 2.78-2.71 (m, 2H), 2.54 (s, 3H), 2.18 (s, 3H), 2.16-2.06 (m, 1H), 1.73-1.58 (m, 3H), 1.58-1.48 (m, 1H), 1.37 (s, 9H), 1.31-1.06 (m, 3H), 0.89-0.73 (m, 2H).

LC-MS (Method 1): R _t = 1.04 min; MS (ESIpos): m / z = 696 [M + H] ⁺ .

Example 64A methyl 4 '- [(2 _l ^r S) -2- {[(ira "Ä-4- {[(feri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} - 3-oxo-3- {[4- (2H-tetrazol-5-yl) -phenyl] -amino} -propyl] -4,6-dimethylbiphenyl-3-carboxylate

4-Bromo-A ^L a / j / ia - [(iraay-4- {[(iper ^ butoxycarb

tetrazol-5-yl) -phenyl] -L-phenylalanine amide (1.00 g, 1.60 mmol) from Example 6A, methyl-2,4-dimethyl-5- (4,4,5,5-tetramethyl-1, 3.2- dioxaborolan-2-yl) benzoate (1.39 g, 2.39 mmol, 50% purity, synthesis described in WO2014 / 008197) and sodium carbonate (507 mg, 4.79 mmol) were placed under argon in 12 ml of DMFA water (10: 2). Subsequently, 1,1-bis (diphenylphosphino) ferrocenedichloro-palladium (II) (117 mg, 0.16 mmol) was added and the mixture was stirred for 1 h at 100 ° C in the microwave. The reaction mixture was then diluted at RT with 50 ml of water, acidified with 1M hydrochloric acid and extracted twice with 50 ml of ethyl acetate each time. The combined organic phases were washed once each with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and the filtrate was concentrated. The residue obtained was purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid (gradient)). 331 mg (28% of theory) of the title compound were obtained. Ή-NMR (400 MHz, DMSO δ = ppm 10.40 (s, 1H), 8.14 (d, 1H), 7.99 (d, 2H), 7.81 (d, 2H), 7.62 (s, 1H), 7.37 (d, 2H), 7.26-7.21 (m, 3H), 6.80-6.72 (m, 1H), 4.79-4.69 (m, 1H), 3.79 (s, 3H), 3.16-3.07 (m, 1H), 2.98-2.88 ( m, 1H), 2.78-2.72 (m, 2H), 2.54 (s, 3H), 2.19 (s, 3H), 2.16-2.07 (m, 1H), 1.73-1.58 (m, 3H), 1.57-1.49 ( m, 1H), 1.34 (br, s, 1H), 1.31-1.18 (m, 2H), 1.18-1.04 (m, 1H), 0.90-0.74 (m, 2H) LC-MS (Method 1): R _t = 1.16 min; MS (ESIpos): m / z = 696 [M + H] ⁺ . Example 65A ieri-butyl-4 - [({4'- [(2S) -2- [[(trans - {- [(ferric-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -amino} -3-oxo 3- {[4- (2 / i-tetrazol-5-yl) phenyl] amino} propyl] -5-

amino] piperidine-1-carboxy lat

4 '- [(2S) -2- {[(trans - - {[(i.i.-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2 / i-tetrazole -5-yl) phenyl] amino} propyl] -5-methylbiphenyl-3-carboxylic acid (100 mg, 0.15 mmol) were initially charged in 2.0 ml of dimethylformamide and then ieri-butyl-4-aminopiperidin-1-carboxylate (59 mg, 0.29 mmol) was added. Thereafter, N, N-diisopropylethylamine (0.10 ml, 0.59 mmol) and 1- [bis (dimethylamino) methylene] -1 / il, 2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (84 mg, 0.22 mmol) was added and the mixture was stirred at RT for 6 h and allowed to stand for 2 days at RT. The reaction mixture was diluted with acetonitrile and purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid (gradient)). 66 mg (49% of theory) of the title compound were obtained. Ή-NMR (400 MHz, DMSO δ = ppm 16.71 (br.s, IH), 10.47 (s, IH), 8.32 (d, IH), 8.18 (d, IH), 7.99 (d, 2H), 7.89 -7.78 (m, 3H), 7.69-7.57 (m, 4H), 7.42 (d, 2H), 6.81-6.71 (m, IH), 4.76-4.66 (m, IH), 4.06-3.86 (m, 3H) , 3.16-3.04 (m, IH), 2.99-2.69 (m, 5H), 2.41 (s, 3H), 2.18-2.06 (m, IH), 1.84-1.75 (m, 2H), 1.74-1.52 (m, 4H), 1.41 (s, 9H), 1.36 (s, 9H), 1.30-1.10 (m, 3H), 0.91-0.74 (m, 2H).

LC-MS (Method 1): R _t = 1.18 min; MS (ESIpos): m / z = 864 [M + H] ⁺ . Example 66A 3- {5- [4- ({(2S) -2- {[(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3- [2'-methyl -5 '- (methylcarbamoyl) biphenyl-4-yl] propanoyl} amino) phenyl] -4 / il, 2,4-triazol-3-yl} -2,2,3,3-tetrafluoropropanoic acid

3- {5- [4- ({(2S) -2- {[(trans-4- {[(aminobutoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3- [2'-methyl-5 '- (methylcarbamoyl) biphenyl-4-yl] propanoyl} amino) phenyl] -4 / il, 2,4-triazol-3-yl} -2,2,3,3-tetrafluoropropanoic acid (70 mg, 0.09 mmol) and Methylamine (0.08 ml, 0.17 mmol, 2M in THF) was placed in 1.0 ml of dimethylformamide. Thereafter, N, N-diisopropylethylamine (0.04 ml, 0.26 mmol) and 1- [bis (dimethylamino) methylene] -1 / il, 2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (48 mg, 0.13 mmol) and the mixture shaken overnight at RT. The reaction mixture was diluted with acetonitrile and purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid (gradient)). 6 mg of crude product (90% purity) were obtained, which was reacted further without further purification.

LC-MS (Method 1): R _t = 0.95 min; MS (ESIpos): m / z = 838 [M + H-HC1] ⁺ . Example 67A

(2S) -2- {[(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3- [5'- (methoxycarbonyl) -2'-methylbiphenyl-4-yl] propanoic acid

4-Biom-N - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -L-phenylalanine (43.4 g, 90 mmol) and methyl 4-methyl-3- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (33.6 g, 117 mmol) was dissolved in DMF (400 ml) and treated with a 2N aqueous sodium carbonate solution (135 ml). The reaction solution was degassed with argon for 5 minutes before the catalyst was added to 1,1'-bis (diphenylphosphino) ferrocenepalladium (II) chloride (6.6 g, 9.0 mmol). The mixture was stirred for 30 min at 120 ° C (oil bath temperature). The contents of the flask were filtered through kieselguhr and washed with ethyl acetate. The solvent was removed on a rotary evaporator and the residue was partitioned between ethyl acetate and 10% aqueous citric acid solution. The mixture was extracted with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed on a rotary evaporator. The residue was suspended in diethyl ether and the solid was filtered off with suction, washed with diethyl ether and dried under high vacuum. 38.1 g (77% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.71-0.89 (m, 2H), 1.03-1.29 (m, 3H), 1.36 (s, 9H), 1.45-1.54 (m, 1 H), 1.57 - 1.73 (m, 3 H), 1.98 - 2.10 (m, 1 H), 2.27 (s, 3 H), 2.74 (m, 2 H), 2.85 - 2.95 (m, 1 H), 3.14 (dd, 1H), 3.84 (s, 3H), 4.50 (br, s, 1H), 6.71-6.82 (m, 1H), 7.23-7.35 (m, 4H), 7.45 (i.e. , 1H), 7.71 (d, 1H), 7.85 (dd, 1H), 8.03 (d, 1H), 12.68 (br. S, 1H).

LC-MS (Method 1): R _t = 1.13 min; MS (ESIpos): m / z = 553 [M + H] ⁺ . Example 68A

3- {5- [4- ({(2S) -2- {[(trans - - {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-

[5Xmethoxycarbonyl) -2'-methylbiphenyl-4-yl] propanoy

 2,2,3,3-tetrafluoro propanoic acid

A solution of (2S) -2- {[(trans- - {[(ieri-butoxycarbonyl) amino] methyl} cy clohexyl) carbonyl] amino} -3- [5 '- (methoxycarbonyl) -2'-methylbiphenyl] 4-yl] propanoic acid (500 mg, 0.91 mmol) and 3- [5- (4-aminophenyl) -1 / il, 2,4-triazol-3-yl] -2,2,3,3-tetrafluoropropanoic acid (682 mg, 1.81 mmol) in DMF (7.4 mL) was added N, N -diisopropylamine (0.79 mL, 4.5 mmol) and HATU (516 mg, 1.36 mmol) was added. The reaction mixture was stirred at RT overnight (about 16 h), then the solvent was removed under high vacuum. The residue was dissolved in DMSO, treated with a little water and acetonitrile and filtered through a Millipore filter, then purified by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). 466 mg (25% of theory) of the title compound were obtained. LC-MS (Method 1): R _t = 1.09 min; MS (ESIpos): m / z = 839 [M + H] ⁺ .

Example 69A

4 '- [(2S) -2- {[(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3- ({4- [3- (2-carboxy-1 , 1, 2,2-tetrafluorofhyl) -1 H -1, 2,4-triazol-5-yl] phenyl} amino) -3-oxopropyl] -6-methylbiphenyl-3-carboxylic acid

3- {5- [4- ({(2S) -2- {[(trans - - {[(i.i.-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3- [5 '- (memoxycarbonyl) - 2'-methylbiph ^

 2,2,3,3-Tetrafluoropropanoic acid (463 mg, 0.49 mmol) was dissolved in tetrahydrofuran / water 3: 1 (8 ml), combined with lithium hydroxide monohydrate (62 mg, 1.48 mmol) and stirred at RT overnight. The mixture was added to ethyl acetate / water and made slightly acidic (pH 4-5) with 0.5N hydrochloric acid. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed with aqueous saturated sodium chloride solution, dried over sodium sulfate, filtered and the solvent was removed in vacuo. The residue was dissolved in DMSO, treated with a little water and acetonitrile and filtered through a Millipore filter, then purified by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). 423 mg (95% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.00 min; MS (ESIpos): m / z = 825 [M + H] ⁺ . Example 70A

3- [5- (4- {[(2 _l S ^, ) -2- {[(ira-A-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-

{2'-methyl-5 '- [(1-methylpiperidin-4-yl) carbamoyl] biphenyl-4-yl} propanoyl] amino} phenyl) -1,2,4-triazol-3-yl] -2,2,3,3-tetrafluoro propanoic acid

A solution of 4 '- [(2 _L S ^, ) -2- {[(ira-A-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3- (4- [3- (2-carboxy-1,1,2,2-tetrafluoroethyl) -HH-1, 2,4-triazol-5-yl] -phenyl} -amino) -3-oxopropyl] -6-methylbiphenyl-3- carboxylic acid (220mg, 0.27mmol) and 1-methylpiperidin-4-amine (61mg, 0.53mmol) in DMF (2.75mL) was added N, N -diisopropylamine (0.14mL, 0.80mmol) and HATU (152mg, 0.40 mmol) was added thereto. The reaction mixture was stirred at RT overnight. The mixture was diluted with water / acetonitrile and filtered through a Millipore filter, then purified by preparative HPLC (eluent: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). 87 mg (29% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.86 min; MS (ESIpos): m / z = 921 [M + H] ⁺ .

Example 71 A

benzamide / V-isopropyl-4-methyl-3- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl)

Under argon, a solution of 4-methyl-3- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) benzoic acid (1.17 g, 4.45 mmol) and isopropylamine (0.38 ml, 4.45 mmol) in DMF (45 mL) was added N, N -diisopropylamine (1.7 mL, 9.78 mmol) and a solution of HATU (2.03 g, 5.33 mmol) in DMF (15 mL) was added. The reaction mixture was stirred at RT with LC / MS control until complete reaction. The solvent was removed on a rotary evaporator and the residue was treated with water, then the solid was filtered off with suction. 1.2 g (83% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.14 min; MS (ESIpos): m / z = 304 [M + H] ⁺ . Example 72A

(2S) -2- {[(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3- [5'- (isopropylcarbamoyl) -2'-methylbiphenyl-4-yl] propanoic acid

To a solution of 4-bromo-A ^r - [(ω-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -L-phenylalanine (1.64 g, 3.39 mmol) and A ^r - Isopropyl 4-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -benzamide (1.33 g, 4.07 mmol) in DMF (34 mL) was added 2N aqueous sodium carbonate. Solution (8.7 ml) was added. The solution was degassed with argon for 25 minutes before the catalyst was added to the 1,1'-bis (diphenylphosphino) ferrocene paladium (II) chloride-dichloromethane complex (277 mg, 0.34 mmol). The reaction mixture was stirred for 30 min at 120 ° C. The mixture was filtered through kieselguhr and the residue was washed with ethyl acetate. The solvent was removed on a rotary evaporator and dried under high vacuum. The residue was dissolved in ethyl acetate, washed once with 10% aqueous citric acid solution and once with saturated aqueous sodium chloride solution, then dried with magnesium sulfate. The suspension was filtered and the solvent removed on a rotary evaporator. The residue was purified by flash chromatography (eluent: dichloromethane / methanol, gradient: 10: 0 to 10: 0.5). 1.72 g (81% of theory) of the title compound were obtained. Ή NMR (400 MHz, DMSO-d ₆ ): δ = ppm 0.65-0.93 (m, 2H), 1.14 (d, 7H), 1.19-1.31 (m, 2H), 1.36 (s, 9H ), 1.48 - 1.56 (m, 1H), 1.58 - 1.73 (m, 3H), 2.00 - 2.11 (m, 1H), 2.24 (s, 3H), 2.70 - 2.76 (m, 3H), 2.90 - 2.93 (m, 1H), 3.07 - 3.19 (m, 1H), 4.04 - 4.15 (m, 1H), 4.42 - 4.52 (m, 1H), 6.71 - 6.83 (m, 1H), 7.31 (m, 5H), 7.67 (d, 1H), 7.71-7.78 (m, 1H), 8.04 (d, 1H), 8.20 (d, 1H), 12.68 (br. S, 1H ) LC-MS (Method 1): R _t = 1.04 min; MS (ESIpos): m / z = 580 [M + H] ⁺ . Example 73A ieri-butyl-4- {2 - [(4-nitrophenyl) carbonoimidoyl] hydrazino} -4-oxobutanoate

Under argon, a solution of 4-nitrobenzenecarboximidohydrazide (1.72 g, 9.57 mmol) and 4-ieri-butoxy-4-oxobutanoic acid (1.67 g, 9.57 mmol) in THF (35 mL) was treated with HATU (2.03 g, 5.33 mmol) and stirred overnight at RT. The solvent was removed on a rotary evaporator and the residue was dried under high vacuum. The residue was dissolved in a little methanol and filtered through a Millipore filter, then purified by preparative HPLC (mobile phase: Gradient of acetonitrile / water with 0.1% trifluoroacetic acid). 1.47 g (35% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.62 min; MS (ESIpos): m / z = 337 [M + H] ⁺ . Example 74A ieri-butyl-3- [5- (4-nitrophenyl) -1 / il, 2,4-triazol-3-yl] propanoate

ieri-butyl-4- {2 - [(4-nitrophenyl) carbonoimidoyl] hydrazino} -4-oxobutanoate (1.46 g, 4.34 mmol) was dissolved in 1-methylpyrrolidine (15 ml) and stirred at 120 ° C for 3 days. The solvent was removed on a rotary evaporator and the residue was dried under high vacuum. The substance was recrystallized from methanol, the solid was filtered off with suction and washed with a little methanol, then dried under high vacuum. 657.4 mg (44% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.62 min; MS (ESIpos): m / z = 319 [M + H] ⁺ . Example 75A

Butyl-3 - [5 - (4-aminophenyl) -1 H -1,2,4-triazol-3-yl] propanoate

To a solution of iper-butyl-3- [5- (4-nitrophenyl) -1 / il, 2,4-triazol-3-yl] propanoate (622 mg, 1.95 mmol) in ethanol (20 ml) was added tin (m.p. II) chloride dihydrate and the reaction mixture was stirred at 70 ° C for 1 h. The solution was cooled to RT, then added to ice-water and adjusted to pH 8 with solid sodium carbonate. The mixture was diluted with water and extracted three times with ethyl acetate. The organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered, then the solvent was removed on a rotary evaporator. The residue was recrystallized from diethyl ether / pentane, filtered off with suction and washed with pentane, then dried under high vacuum. 537.7 mg (95% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.65 min; MS (ESIpos): m / z = 289 [M + H] ⁺ .

Example 76A ieri-butyl-3- {5- [4 - ({(2S) -2- {[(trans-A- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3- [5 '- (isopropylcarbamoyl) -2'-methylbiphenyl-4-yl] -propanoyl} -amino) -phenyl] -1 / il, 2,4-triazol-3-yl} -propanoate

A solution of (2 _{L of} S ^, ) -2- [[ira-A-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -amino} -3- [5 '- (isopropylcarbamoyl) - 2'-methylbiphenyl-4-yl] propanoic acid (100 mg, 0.17 mmol) and ieri-butyl-3- [5- (4-aminophenyl) -1 / il, 2,4-triazol-3-yl] propanoate (99 mg, 0.35 mmol) in DMF (1 mL) was added N, N -diisopropylamine (0.9 mL, 0.52 mmol) and HATU (98 mg, 0.26 mmol) was added. The reaction mixture was stirred at RT overnight (about 16 h). The residue was diluted with water / acetonitrile and filtered through a Milhporefilter, then with purified by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). 49.3 mg (34% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 1.14 min; MS (ESIpos): m / z = 850 [M + H] ⁺ .

Example 77A Methyl 3- {5- [4 - ({4-bromo / V - [(1α-α-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -L-phenylalanyl} amino ) phenyl] - IH-l, 2,4-triazol-3-yl} -2,2,3,3-tetrafluoropropanoate

4-Biom-N - [(trans-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] -L-phenylalanine (1500 mg, 3.1 mmol) and methyl 3- [5- (4-aminophenyl ) -l / il, 2,4-triazol-3-yl] -2,2,3,3-tetrafluoropropanoate (1185 mg, 3.7 mmol) were dissolved in 10 ml of pyridine and treated with 2,4,6-tripropyl-1 , 3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide (50% in DMF, 7.2 ml, 12.4 mmol) 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 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, 2 H), 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 (brs s, 1H).

LC-MS (Method 1): R _t = 1.23 min; MS (ESIpos): m / z = 785.4 [M + H] Example 78A

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

2,2,3,3-Tetrafluoro-3- [5- (4-nitrophenyl) -1 / il, 2,4-triazol-3-yl] propanoic acid (30.3 g, 90.8 mmol) was dissolved in methanol (500 ml). dissolved and treated with concentrated sulfuric acid (3 ml). The mixture was stirred at 65 ° C. for 22 h. Then, concentrated sulfuric acid (5 ml) was 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 79A

Methyl 3- [5- (4-aminophenyl) -l / i-l, 2,4-triazol-3-yl] -2,2,3,3-tetrafluorpropanoat

Methyl 2,2,3,3-tetrafluoro-3- [5- (4-nitrophenyl) -1 / il, 2,4-triazol-3-yl] propanoate (24.0 g, 68.9 mmol) was dissolved in THF (370 ml) and treated under argon atmosphere with palladium / carbon (10%, 50% pure water). 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 80A

3- {5- [4- ({(2S) -2- {[(trans-4- {[(ω-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3- [4'-methoxy-3 '- (morpholin-4-ylsulfonyl) biphenyl-4-yl] propanoyl} amino) phenyl] -l / il, 2,4-triazol-

Methyl 3- {5- [4 - ({4-bromo-A ^r - [(ira "5-4- {[(ier ^ butoxycarbonyl) amino] methyl} cyclohexyl ^

Methylene-nylanyl) arnino) -phenyl] -l-il, 2,4-triazol-3-yl-2,2,2,3,3-tetrafluoropropanoate (125 mg, 0.16 mmol) and [4-methoxy-3- (morpholine -4-ylsulfonyl) phenyl] boric acid (96 mg, 0.32 mmol) were dissolved in 1.3 ml of dimethylformamide and treated with aqueous sodium carbonate solution (2M, 0.16 ml, 0.32 mmol) 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)). 97 mg (62% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.96 min; MS (ESIpos): m / z = 946.4 [M + H] ⁺ .

Example 81A

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

A solution of 4-bromo-N - [(1α-ε-4- {[(ieri-butoxycarbonyl) -amino] methyl} -cyclohexyl) -carbonyl] -L-phenylalanine and 6-amino-1,2-dihydro- 3 / i-indazol-3-one in ethyl acetate is treated with Ν, Ν-diisopropylethylamine. The reaction mixture is admixed with a 2,4,6-tripropyl-1,3,5,4,4,6-trioxatriphosphinane-2,4,6-trioxide solution (50% in dimethylformamide) and then stirred at RT overnight , The reaction mixture is worked up by methods known to those skilled in the art and the residue is separated by preparative HPLC. You get the title compound.

Example 82A ieri-butyl {[trans-A- ({(2 ^ -3- [2'-methyl-5 '- (pyrrolidin-1-ylsulphonyl) biphenyl-4-yl] -1-oxo-1 - [ (3-oxo-2,3-dihydro-1-i-indazol-6-yl) -amino] -propan-2-yl-carbamoyl) cyclohexyl] -methyl} carbamate

To a solution of 4-bromo-Na / j / ia - [(ira «A-4- {[(feri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) carbonyl] -N- (3-oxo-2,3 -dihydro-l / i-indazol-6-yl) -L-phenylalanine amide and [2-methyl-5 - (pyrrolidin-1-ylsulfonyl) -phenyl] boronic acid in DMSO are tetrakis (triphenylphosphine) -palladium (O), sodium carbonate and Water added. The mixture is microwaved for 1 to 3 hours at 110 ° C. The batch is filtered and purified by preparative HPLC. The title compound is obtained. Example 83A The butyl {[ira-i- ({(2 ^ -3,5 '- (dimethylsulfamoyl) -2'-methylbiphenyl

2-dihydro-l / i-indazol-6-yl) -amino] -propan-2-yl} carbamoyl) cyclohexyl] methyl} carbamate

To a solution of 4-bromo-Na / j / ia - [(ira «A-4- {[(feri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) carbonyl] -N- (3-oxo-2,3 -dihydro-l / i-indazol-6-yl) -L-phenylalanine amide and [5- (dimethylsulfamoyl) -2-methylphenyl] boronic acid in DMSO are added tetrakis (triphenylphosphine) -palladium (O), sodium carbonate and water. The mixture is microwaved for 1 to 3 hours at 110 ° C. The batch is filtered and purified by preparative HPLC. You get the title compound.

Example 84A ieri-butyl {[trans-A- ({(2S) -3- [2'-methyl-5 '- (morpholin-4-ylsulfonyl) biphenyl-4-yl] -1-oxo-1 - [ (3-oxo-2-dihydro-1-i-indazol-6-yl) -amino] -propan-2-yl} -carbamoyl) cyclohexyl] -methyl} carbamate

To a solution of 4-bromo-Na / j / ia - [(ira «A-4- {[(feri-butoxycarbonyl) -amino] -methyl} -cyclohexyl) carbonyl] -N- (3-oxo-2,3 -dihydro-l / i-indazol-6-yl) -L-phenylalanine amide and [2-methyl-5- (morpholin-4-ylsulfonyl) -phenyl] boronic acid in DMSO are tetrakis (triphenylphosphine) -palladium (O), sodium carbonate and Water added. The mixture is microwaved for 1 to 3 hours at 110 ° C. The batch is filtered and purified by preparative HPLC. You get the title compound.

embodiments

example 1

/ Raws-4- (aminomethyl) -N - [(2S) -3- [5Xdim ^

 (1-i-tetrazol-5-yl) phenyl] amino} propan-2-yl] cyclohexanecarboxamide hydrochloride

A suspension of 57 mg (0.077 mmol) of ieri-butyl - [(ira «A-4- {[(2 _L S ') - 3- [5' - (dimethylsulfamoyl) -2'-methylbiphenyl-4-yl] - 1-Oxo-1 - {[4- (l-i-tetrazol-5-yl) -phenyl] -amino} -propan-2-yl] carbamoyl} -cyclohexyl) methyl] carbamate in 2.3 ml of 1,4-dioxane was treated with 0.19 ml (0.77 mmol) of 4M hydrogen chloride in 1,4-dioxane and stirred overnight at RT. After further addition of 0.06 ml (0.23 mmol) of 4M hydrogen chloride in 1,4-dioxane and stirring for 48 h at RT, the reaction mixture was treated with 5 ml of acetonitrile, the resulting precipitate was filtered off, taken up in water and lyophilized. 35 mg (63% of theory) of the title compound were obtained.

Ή NMR (300 MHz, DMSO-d ₆ ): δ ppm 0.74-1.00 (m, 2H), 1.02-1.31 (m, 2H), 1.34-1.47 (m, 1H), 1.48-1.58 (m , 1H), 1.63 - 1.80 (m, 3H), 2.04 - 2.17 (m, 1H), 2.24 (s, 3H), 2.55 - 2.64 (m, 8H), 2.92 (dd, 1H) , 3.11 (dd, 1H), 4.68 - 4.79 (m, 1H), 7.28 (d, 2H), 7.38 (m, 3H), 7.54 (d, 1H), 7.57 - 7.63 (m, 1 H), 7.70 (br s, 3H), 7.79 (d, 2H), 7.97 (d, 2H), 8.24 (d, 1H), 10.49 (br s, 1H).

LC-MS (Method 4): R _t = 0.86 min; MS (ESIpos): m / z = 645 [M + H-HC1] Example 2 iraws-4- (aminomethyl) -N- [(2S) -3- [2'-methyl-5 '- (morpholin-4-ylsulfonyl) biphenyl-4-yl] -1-oxo-1 - {[ 4- (l / i-tetrazol-5-yl) -phenyl] -amino} -propan-2-yl] cyclohexanecarboxylate-hydrochloride

A suspension of 100 mg (0.13mmol) ieri-butyl - [(ira "i-4- {[(2 _l ^r S) -3- [2'-methyl-5 '- (morpholine 4-ylsulfonyl) biphenyl 4-yl] - 1 -oxo-1 - {[4- (1-i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate in 4.0 ml of 1.4 -Dioxane was mixed with 0.3 ml (1.3 mmol) of 4M hydrogen chloride in 1,4-dioxane and stirred overnight at RT. After further addition of 0.1 ml (0.39 mmol) 4M hydrogen chloride in 1,4-dioxane and stirring for 48 h at RT, the reaction mixture was mixed with 5 ml of acetonitrile, the resulting precipitate was filtered off with suction, taken up in water and lyophilized. 70 mg (71% of theory) of the title compound were obtained.

Ή-NMR (300 MHz, DMSO-de): δ ppm 0.78-0.97 (m, 2H), 1.04-1.31 (m, 2H), 1.34-1.47 (m, 1H), 1.48-1.58 (m, 1 H), 1.63 - 1.77 (m, 3H), 2.05 - 2.18 (m, 1H), 2.24 (s, 3H), 2.56 - 2.64 (m, 2H), 2.79 - 2.86 (m, 4H ), 2.92 (dd, 1H), 3.11 (dd, 1H), 3.55 - 3.63 (m, 4H), 4.66 - 4.78 (m, 1H), 7.25 - 7.32 (m, 2H), 7.35 - 7.41 (m, 3H), 7.53-7.61 (m, 2H), 7.63-7.73 (m, 3H), 7.79 (d, 2H), 7.97 (d, 2H), 8.24 (d, 1H ), 10.47 (s, 1 H).

LC-MS (Method 4): R _t = 0.85 min; MS (ESIpos): m / z = 687 [M + H-HC1] ⁺ . Example 3

iraM.y-4- (aminomethyl) -N- {(2S) - 1- {[4- (5-chloro-4-yl-2,4-triazol-3-yl) -phenyl] -amino} -3- [5'- (Dimethylsulfamoyl) -2'-methylbiphenyl-4-yl] -1-oxopropan-2-yl} cyclohexanecarboxamide hydrochloride

A suspension of 30 mg (0.04 mmol) of tert-butyl {[trans - - ({(2S) -l- {[4- (5-chloro-Hl, 2,4-triazol-3-yl) -phenyl] -amino } -3- [5 '- (dimethylsulfamoyl) -2'-methylbiphenyl-4-yl] -1-oxopropan-2-yl} carbamoyl) cyclohexyl] methylcarbamate in 1.1 ml of 1,4-dioxane was mixed with 0.07 ml (0.3 mmol ) 4M hydrogen chloride in 1,4-dioxane and stirred overnight at RT. After further addition of 0.1 ml (0.39 mmol) of 4M hydrogen chloride in 1,4-dioxane and stirring for 24 h at RT and 2 h at 40 ° C, the reaction mixture was mixed with 5 ml of acetonitrile, the resulting precipitate was filtered off with suction and purified by chromatography via HPLC ( Method 10). 10 mg (33% of theory) of the title compound were obtained.

Ή-NMR (300 MHz, DMSO-de): 8 ppm 0.77-0.94 (m, 2H), 1.03-1.28 (m, 2H), 1.28-1.43 (m, 1H), 1.47-1.58 (m, 1H), 1.62 - 1.78 (m, 3H), 2.04 - 2.16 (m, 1H), 2.24 (s, 3H), 2.52 - 2.56 (m, 2H), 2.58 (s, 6H), 2.91 (dd, 2H), 3.10 (dd, 1H), 4.65-4.78 (m, 1H), 7.27 (d, 2H), 7.34-7.41 (m, 3H), 7.53 (d, 1H ), 7.57 - 7.67 (m, 3H), 7.82 (d, 2H), 8.16 (d, 1H), 8.32 (s, 1H), 10.23 (s, 1H).

LC-MS (Method 4): R _t = 0.95 min; MS (ESIpos): m / z = 680 [M + H-HC1] Example 4

/ Raws-4- (Aminomethyl) -N - [(2S) -l-oxo-3- (3'-sutf ^

yl) phenyl] amino} propan-2-yl] cyclohexanecarboxamide hydrochloride

A suspension of 91 mg (0.13 mmol) of ferric butyl [(1α-α-4- {[(2 _L S ') -1-oxo-3- (3'-sulfamoyl-biphenyl-4-yl) -l - {[4- (l / i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} -cyclohexyl) methyl] carbamate in 4.0 ml of 1,4-dioxane was mixed with 0.23 ml (0.9 mmol ) 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. 64 mg (76% of theory) of the title compound were obtained.

Ή-NMR (300 MHz, DMSO-d ₆ ): δ ppm 0.76-0.98 (m, 2H), 1.05-1.31 (m, 2H), 1.35-1.50 (m, 1H), 1.51-1.61 (m , 1H), 1.64 - 1.77 (m, 3H), 2.06 - 2.17 (m, 1H), 2.55 - 2.64 (m, 2H), 2.91 (dd, 1H), 3.10 (dd, 1H) , 7.37 (s, 1H), 7.43 (d, 2H), 7.56 - 7.65 (m, 3H), 7.78 (m, 7H), 7.99 (d, 2H), 8.06 (s, 1H) , 8.25 (d, 1H), 10.56 (s, 1H). LC-MS (Method 4): R _t = 0.71 min; MS (ESIpos): m / z = 603.5 [M + H-HC1] Example 5 iraws-4- (aminomethyl) -N- [(2S) -3 - {3'- [(4-methylpiperazin-1-yl) carbonyl] biphenyl-4-yl} -1-oxo-1 - {[ 4- (l / i-tetrazol-5-yl) phenyl] amino} propan-2-yl] cyclohexancarboxarrüd hydrochloride

To a solution of 51.8 mg (69 μηιοΐ) of feri-butyl - [(ira «A-4- {[(2 _L S ') - 3- {3' - [(4-methylpiperazin-1-yl) carbonyl] biphenyl -4-yl} - 1 -oxo-1 - {[4- (1-i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate formate in 3 ml Dioxane was added 173 μΐ (0.69 mmol) 4M hydrogen chloride in dioxane. It was stirred overnight at 35 ° 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. 41 mg (85% of theory) of the title compound were obtained.

LC-MS (Method 5): R _t = 0.58 min; MS (ESIpos): m / z = 650 [M + H-HC1] ⁺ .

Ή-NMR (300 MHz, DMSO-de) δ ppm 0.77-0.98 (m, 2H), 1.04-1.30 (m, 2H), 1.32-1.62 (m, 2H), 1.64-1.79 (m, 3 H), 2.05-2.19 (m, 1H), 2.58 (m, 2H), 2.73 (s, 3H), 2.84-2.97 (m, 1H), 3.04-3.14 (m, 3H), 4.62 - 4.76 (m, 1H), 7.40 (m, 3H), 7.47 - 7.55 (m, 1H), 7.60 (d, 2H), 7.66 (s, 1H), 7.70 - 7.88 (m, 5 H), 7.99 (d, 2H), 8.26 (s, 1H), 10.57 (s, 1H). Example 6 iraws-4- (aminomethyl) -A4 (2 ^ -3- {3 2- (morphoh ^

tetrazol-5-yl) phenyl] amino} propan-2-yl] cyclohexanecarboxamide hydrochloride

A solution of 108 mg (0.13 mmol) of ieri-butyl - [(ira ".y-4- {[(2 _L S ^, ) -3- {3 '- [2- (morpholin-4-yl) ethoxy] biphenyl -4-yl} - 1 -oxo-1 - {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propan-2-yl] carbamoyl} -cyclohexyl) -methyl] carbamate-trifluoroacetate in 3 ml 1,4-Dioxane was mixed with 0.47 ml (1.9 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. 76 mg (79% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-ife): δ = 0.85-0.99 (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), 2.58-2.70 (m, 2H), 2.93 (dd, IH), 3.07-3.28 (m, 3H), 3.42-4.03 (m, 8H), 4.47-4.54 (m, 2H ), 4.68-4.76 (m, IH), 6.98 (d, IH), 7.22-7.29 (m, 2H), 7.36-7.44 (m, 3H), 7.50 (d, 2H), 7.76-7.90 (m, 5H ), 8.02 (d, 2H), 8.30 (d, IH), 10.61 (s, IH), 11.1 (bs, IH). LC-MS (Method 1): R _t = 0.53 min; MS (ES Ineg): m / z = 651 [MH-HC1] ^" .

Example 7 iraws-4- (aminomethyl) -N- {(2S) -3- [2'-methyl-5 '- (pyrrolidin-1-ylsulphonyl) biphenyl-4-yl] -1-oxo-1 -

[(2-oxo-23-dihydro-l / i-benzimidazol-5-yl) amino] propan-2-yl} cyclohexancarboxamid-

hydrochloride

To a solution of 71.5 mg (94 μηιοΐ) of ieri-butyl {[ira «A-4 - ({(2 _l S ') - 3- [2'-methyl-5' - (pyrrolidin-1-ylsulfonyl) biphenyl -4-yl] - 1 -oxo-1 - [(2-oxo-2,3-dihydro-l / i-benzimidazol-5-yl) amino] propan-2-yl} carbamoyl) cyclohexyl] methyl} carbamate in To 2.5 ml of dioxane was added 118 μM (0.47 mmol) of 4M hydrogen chloride in dioxane. It was stirred for 4 days 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 11). 14 mg (21% of theory) of the title compound were obtained.

LC-MS (Method 5): R _t = 1.09 min; MS (ESIpos): m / z = 659 [M + H-HC1] ⁺ .

Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.73-0.89 (m, 2H), 1.01-1.05 (m, 1H), 1.06-1.32 (m, 3H), 1.46-1.55 (m, 1 H), 1.66 (brs., 7 H), 2.01 - 2.15 (m, 1 H), 2.26 (s, 3 H), 2.34 - 2.39 (m, 1 H), 2.85 - 2.95 (m, 1 H), 3.09-3.16 (m, 4H), 3.45-3.57 (m, 2H), 4.65-4.76 (m, 1H), 6.82 (d, 1H), 6.98 (dd, 1H), 7.28 (d, 2H), 7.37 (d, 2H), 7.41-7.43 (m, 1H), 7.44-7.48 (m, 1H), 7.54 (d, 1H), 7.67 (dd, 1H) , 8.05 (d, 1H), 9.92 (s, 1H), 10.49 (br. S, 1H). Example 8

Ethyl 4 '- [(25) -2- ({[ira-Ä4- (arnomethyl) cyclohexyl] carbonyl} amino) -3-oxo-3 {

yl) phenyl] amino} propyl] -2-fluorobiphenyl-3-carboxylate hydrochloride

A solution of 50 mg (0.07 mmol) of ethyl 4 '- [(2 _l ^S) -2- {[(ira "Ä-4- {[(ieri-butoxycarbonyl) amino] - 1 methyl} cyclohexyl) carbonyl 1 ] amino} -3-oxo-3 - {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propy 1] -2-fluorobiphenyl-3-carboxylate in 2 ml of 1,4-dioxane was washed with 0.26 ml (1.05 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. 39 mg (80% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-de) δ = 0.84-1.01 (m, 2H), 1.09-1.37 (m, 5H), 1.40-1.66 (m, 2H), 1.68-1.83 (m, 3 H), 2.10 - 2.20 (m, 1H), 2.58 - 2.68 (m, 2H), 2.90 - 3.01 (m, 1H), 3.08 - 3.21 (m,

1 H), 4.29 - 4.39 (m, 2H), 4.68 - 4.80 (m, 1H), 7.35 - 7.51 (m, 5H), 7.67 - 7.90 (m, 7H), 8.02 (d,

2H), 8.28 (d, 1H), 10.58 (s, 1H).

LC-MS (Method 1): R _t = 0.79 min; MS (ES Ineg): m / z = 612 [MH-HC1] ^"

Example 9

4 '- [(2S) -2 - ({[iraws-4- (aminomethyl) cyclohexyl] ca ^^

yl) phenyl] amino} propyl] -6-methyl-A ^r - (piperidin-4-yl) biphenyl-3-carboxamide Hydroc ^^

A solution of 66 mg (0.7 mmol) of feri-butyl-4 - [({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] -6-methyl-biphenyl-3-yl} -carbonyl) -amino] piperidine-1-carboxylate in 2.5 ml of 1,4-dioxane was treated with 0.25 ml (1.01 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. 54 mg (99% of theory, 91% purity) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-de) δ = 0.84-1.00 (m, 2H), 1.09-1.35 (m, 2H), 1.41-1.64 (m, 2H), 1.66-1.84 (m, 5H) H), 1.88 - 2.00 (m, 2H), 2.11 - 2.26 (m, 4H), 2.58 - 2.68 (m, 2H), 2.90 - 3.06 (m, 3H), 3.09 - 3.19 (m, 1 H), 3.23-3.35 (m, 2H), 3.99-4.12 (m, 1H), 4.69-4.81 (m, 1H), 7.27 (d, 2H), 7.33-7.46 (m, 3H) , 7.66-7.71 (m, 1H), 7.73-7.93 (m, 6H), 8.02 (d, 2H), 8.31 (d, 1H), 8.48 (d, 1H), 8.67-8.90 (m , 2H), 10.59 (s, 1H).

LC-MS (Method 1): R _t = 0.56 min; MS (ES Ineg): m / z = 662 [MH-HC1] ^" .

Example 10

4 '- [(2S) -2 - ({[iraws-4- (aminomethyl) cyclohexyl] ca ^^

yl) phenyl] amino} propyl] -A ^r - [2- (diethylamino) ethyl] -6-methyl-biphenyl-3-carboxamide

A solution of 60 mg (0.07 mmol) of ieri-butyl - [(ira ".y-4- {[(2 _l S ^, ) -3- (5 '- {[2- (diethylamino) ethyl] carbamoyl} - 2'-methylbiphenyl-4-yl) -1-oxo-1 - {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propan-2-yl] carbamoyl} cyclohexyl) -methyl] carbamate-trifluoroacetate in 2.5 ml of 1,4-dioxane was added 0.25 ml (1.01 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 (87% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de) δ = 0.85-1.01 (m, 2H), 1.12- 1.34 (m, 8H), 1.40-1.64 (m, 2H), 1.67-1.83 (m, 3 H), 2.10 - 2.28 (m, 4H), 2.59 - 2.69 (m, 2H), 2.89 - 3.02 (m, 1H), 3.08 - 3.26 (m, 7H), 3.59 - 3.66 (m, 2 H), 4.71-4.81 (m, 1H), 7.29 (d, 2H), 7.35-7.45 (m, 3H), 7.71 (s, 1H), 7.74-7.92 (m, 6H), 8.02 (d, 2H), 8.31 (dIH), 8.80 - 8.90 (m, 1H), 10.0 (br, s, 1H), 10.58 (s, 1H).

LC-MS (Method 1): R _t = 0.57 min; MS (ES Ineg): m / z = 678 [MH-HC1] ^" .

Example 11

4 '- [(2S) -2 - ({[iraws-4- (aminomethyl) cyd]

yl) phenyl] amino} propyl] -ö-memyl-N- [(3R ^

A solution of tert-butyl (3R) -3 - [({4 '- [(2S) -2- {[(trans-4- {[(tert-butoxycarbonyl) amino] methyl, 61 mg (0.06 mmol) } cyclohexyl) carbonyl 1] amino} -3-oxo-3 - {[4- (2-i-tetrazol-5-yl) phenyl] amino} propyl] -6-methylbiphenyl-3-yl} carbonyl) amino] pyrrolidine -l-carboxylate in 2.5 ml of 1,4-dioxane was mixed with 0.24 ml (0.95 mmol) of 4M hydrogen chloride in 1,4-dioxane and stirred overnight at RT. The precipitate was filtered off, washed with a little acetonitrile, dried under high vacuum and then separated by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). 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 residue was dried under high vacuum. 25 mg (54% of theory) of the title compound were obtained. Ή NMR (400 MHz, DMSO-ife) δ = 0.82-1.01 (m, 2H), 1.11-1.35 (m, 2H), 1.40-1.64 (m, 2H), 1.67-1.83 (m, 3 H), 1.91 - 2.03 (m, 1H), 2.09 - 2.27 (m, 5H), 2.58 - 2.69 (m, 2H), 2.90 - 3.02 (m, 1H), 3.08 - 3.43 (m, 5 H), 4.47 - 4.59 (m, 1H), 4.69 - 4.80 (m, 1H), 7.29 (d, 2H), 7.35 - 7.46 (m, 3H), 7.71 (s, 1H), 7.74 - 7.92 (m, 5H), 8.02 (d, 2H), 8.31 (d, 1H), 8.69 (d, 1H), 9.1 (br s, 1H), 9.3 (br s, 1 H), 10.59 (s, 1 H).

LC-MS (Method 1): R _t = 0.62 min; MS (ES Ineg): m / z = 648 [MH-HC1] ^" Example 12 ira "Ä-4- (aminomethyl) -A ^r - [(2 _l ^r S) -3- [2'-methyl-5 '- (piperazin-1 -ylcarbonyl) biphenyl-4-yl] -1 - oxo-1 - {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propan-2-yl] -cyclohexanecarboxylate-hydrochloride

A solution of 75 mg (0.08 mmol) tert-butyl 4 - ({4 '- [(2S) -2- [[(trans-4- {[(tert-butoxycarbonyl) -amino] -methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2-i-tetrazol-5-yl) -phenyl] -amino-propyl] -6-methyl-biphenyl-3-yl} -carbonyl) -piperazine-1-carboxylate in 2.5 ml of 1, 4-dioxane was mixed with 0.29 ml (1.17 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. 57 mg (93% of theory, 92% purity) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de) δ = 0.83-1.01 (m, 2H), 1.11-1.35 (m, 2H), 1.42-1.65 (m, 2H), 1.67-1.83 (m, 3 H), 2.10 - 2.28 (m, 4H), 2.59 - 2.69 (m, 2H), 2.90 - 3.02 (m, 1H), 3.06 - 3.21 (m, 5H), 3.63 - 3.82 (m, 4 H), 4.70-4.81 (m, 1H), 7.20-7.32 (m, 3H), 7.32-7.47 (m, 4H), 7.71-7.92 (m, 5H), 8.02 (d, 2H) , 8.27 (d, 1H), 9.14 - 9.31 (m, 2H), 10.53 (s, 1H).

LC-MS (Method 1): R _t = 0.56 min; MS (ES Ineg): m / z = 648 [MH-HC1] ^" .

Example 13

4 '- [(2S) -2 - ({[iraws-4- (aminomethyl) cyd]

yl) phenyl] amino} propyl] -A ^r - (piperidin-4-yl) biphenyl-3-carboxamide Hydrochlori

A solution of 86 mg (0.09 mmol) of tert-butyl 4 - [({4 '- [(2S) -2- [[(trans-4- {[(tert-butoxycarbonyl) -amino] -methyl} cyclohexyl) - carbonyl] amino} -3-oxo-3 - {[4- (2-i-tetrazol-5-yl) phenyl] amino} propyl] -biphenyl-3-yl} carbonyl) -amino] -piperidine-1-carboxylate in 3 ml of 1,4-dioxane was mixed with 0.34 ml (1.34 mmol) of 4M hydrogen chloride in 1,4-dioxane and stirred overnight at RT. The precipitate was filtered off, washed with a little acetonitrile, dried under high vacuum and then separated by preparative HPLC (mobile phase: gradient of acetonitrile / water with 0.1% trifluoroacetic acid). 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 residue was dried under high vacuum. 38 mg (58% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-ife) δ = 0.82 - 1.02 (m, 2H), 1.10 - 1.35 (m, 2H), 1.41 - 1.66 (m, 2H), 1.68 - 1.88 (m, 5 H), 1.91 - 2.04 (m, 2H), 2.10 - 2.21 (m, 1H), 2.58 - 2.68 (m, 2H), 2.89 - 3.19 (m, 4H), 3.26 - 3.37 (m, 2 H), 4.03 - 4.14 (m, 1H), 4.67 - 4.78 (m, 1H), 7.45 (d, 2H), 7.50 - 7.58 (m, 1H), 7.66 (d, 2H), 7.74 - 7.97 (m, 6H), 8.03 (d, 2H), 8.10 (s, 1H), 8.25 - 8.36 (m, 1H), 8.62 (d, 1H), 8.79 - 8.99 (m, 2 H), 10.63 (s, 1 H).

LC-MS (Method 1): R _t = 0.60 min; MS (ES Ineg): m / z = 648 [MH-HC1] ^" . Example 14

4 '- [(2S) -2 - ({[iraws-4- (aminomethyl) cyclohexyl] ca ^^

yl) phenyl] amino} propyl] - N - [2- (diethylamino) ethyl] biphenyl-3-carboxamide hydrochloride

A solution of 62 mg (0.07 mmol) of tert-butyl - [(ira-.y-4- {[(2 _l S ^, ) -3- (3 '- {[2- (diethylamino) ethyl] carbamoyl} biphenyl -4-yl) - 1-oxo-1- {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propan-2-yl] carbamoyl} -cyclohexyl) methyl] carbamate trifluoroacetate in 2.5 ml of 1,4-dioxane was mixed with 0.26 ml (1.06 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. 42 mg (77% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-ife) δ = 0.83 - 1.02 (m, 2H), 1.11 - 1.35 (m, 8H), 1.41 - 1.67 (m, 2H), 1.68 - 1.83 (m, 3 H), 2.10 - 2.22 (m, 1H), 2.58 - 2.69 (m, 2H), 2.88 - 3.01 (m, 1H), 3.07 - 3.30 (m, 7H), 3.63 - 3.72 (m, 2 H), 4.67 - 4.79 (m, 1H), 7.44 (d2H), 7.56 (t, 1H), 7.70 (d, 2H), 7.74 - 7.92 (m, 7H), 8.02 (d, 2 H), 8.19 (s, 1H), 8.24 - 8.35 (m, 1H), 9.00 - 9.09 (m, 1H), 10.1 (brs s, 1H), 10.60 (s, 1H).

LC-MS (Method 1): R _t = 0.56 min; MS (ESIneg): m / z = 664 [MH-HC1] \

Example 15

4 '- [(2S) -2 - ({[iraws-4- (aminomethyl) cyclohexyl] ca ^^

yl) phenyl] amino} propyl] -2-fluoro-A ^r - (piperidin-4-yl) biphenyl-3-carboxamide Hydroch

A solution of 63 mg (0.06 mmol) of tert-butyl 4 - [({4 '- [(2S) -2- [[(trans-4- {[(tert-butoxycarbonyl) -amino] -methyl} cyclohexyl) - carbonyl] amino} -3-oxo-3 - {[4- (2-i-tetrazol-5-yl) phenyl] amino} propyl] -2-fluorobiphenyl-3-yl} carbonyl) amino] piperidine-1-carboxylate in 2.5 ml of 1,4-dioxane was added 0.24 ml (0.96 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. 56 mg (77% of theory, 92% purity) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-ife) δ = 0.83-1.01 (m, 2H), 1.11-1.34 (m, 2H), 1.42-1.65 (m, 2H), 1.66-1.85 (m, 2H) H), 1.92 - 2.04 (m, 2H), 2.09 - 2.21 (m, 1H), 2.58 - 2.69 (m, 2H), 2.90 - 3.08 (m, 3H), 3.09 - 3.19 (m, 1 H), 3.20-3.32 (m, 2H), 3.98-4.12 (m, 1H), 4.66-4.79 (m, 1H), 7.33 (t, 1H), 7.46 (d, 5H), 7.72 - 7.94 (m, 5H), 8.02 (d, 2H), 8.31 (d, Hz, 1H), 8.58 (d, 1H), 8.64 - 8.89 (m, 2H), 10.60 (s, 1 H), 16.8 (brs s, 1 H).

LC-MS (Method 1): R _t = 0.53 min; MS (ES Ineg): m / z = 666 [MH-HC1] ^" .

Example 16

4 '- [(2S) -2 - ({[iraws-4- (aminomethyl) cyclohexyl] ca ^^

yl) phenyl] amino} propyl] -A ^r - [2- (diethylamino) ethyl] -2-fluoro-biphenyl-3-carboxamide

A solution of 79 mg (0.09 mmol) of ieri-butyl - [(ira ".y-4- {[(2 _l S ^, ) -3- (3 '- {[2- (diethylamino) ethyl] carbamoyl} - 2'-fluorobiphenyl-4-yl) -1-oxo-1 - {[4- (2-i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate trifluoroacetate in 3 ml of 1,4-dioxane was added 0.33 ml (1.32 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. 64 mg (88% of theory, 92% purity) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-ife) δ = 0.84-1.01 (m, 2H), 1.12-1.35 (m, 8H), 1.42- 1.55 (m, 1H), 1.56- 1.66 (m, 1 H), 1.69 - 1.83 (m, 3H), 2.11 - 2.21 (m, 1H), 2.59 - 2.68 (m, 2H), 2.92 - 3.02 (m, 1H), 3.09 - 3.29 (m, 7 H), 3.61 - 3.70 (m, 2H), 4.68 - 4.79 (m, 1H), 7.36 (t, 1H), 7.41 - 7.53 (m, 4H), 7.56 - 7.69 (m, 2H) , 7.75 - 7.95 (m, 5H), 8.03 (d, 2H), 8.31 (d, 1H), 8.68 - 8.80 (m, 1H), 10.2 (br, s, 1H), 10.61 (s , 1 H).

LC-MS (Method 1): R _t = 0.54 min; MS (ES Ineg): m / z = 682 [MH-HC1] ^" .

Example 17

4 '- [(2S) -2 - ({[iraws-4- (aminomethyl) cyclohexyl] ca ^^

yl) phenyl] amino} propyl] -2-fluoro-A - [(3 ^R ) -pyrrolidin-3-yl] biphenyl-3-carboxy-urethane-H

A solution of 67 mg (0.07 mmol) of ieri-butyl- (3R) -3 - [({4 '- [(2 _l S ^, ) -2- {[(ira "_> y-4- {[(ethyl) butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propyl] -2-fluorobiphenyl-3 -yl} carbonyl) amino] pyrrolidine-l-carboxylate trifluoroacetate in 2 ml of 1,4-dioxane was treated with 0.26 ml (1.04 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. 48 mg (91% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-ife) δ = 0.84-1.00 (m, 2H), 1.12-1.34 (m, 2H), 1.41-1.54 (m, 1H), 1.55-1.66 (m, 1 H), 1.68 - 1.83 (m, 3H), 1.88 - 2.00 (m, 1H), 2.10 - 2.26 (m, 2H), 2.59 - 2.68 (m, 2H), 2.90 - 3.01 (m, 1 H), 3.07 - 3.18 (m, 2H), 3.19 - 3.49 (m, 3H), 4.47 - 4.57 (m, 1H), 4.68 - 4.79 (m, 1H), 7.35 (t, 1H) , 7.40-7.52 (m, 4H), 7.54-7.64 (m, 2H), 7.72-7.90 (m, 5H), 8.02 (d, 2H), 8.30 (d, 1H), 8.76 (i.e. , 1 H), 9.02 - 9.29 (m, 2 H), 10.59 (s, 1 H), 16.8 (brs s, 1 H).

LC-MS (method 1): R _t = 0.52 min; MS (ES Ineg): m / z = 652 [MH-HC1] ^" .

Example 18

ira "i-4- (aminomethyl) -A ^r - [(2 ^ -3- [2-fluoro-3 '- (piperazin-l-ylcarbonyl) biphenyl

(2 / i-tetrazol-5-yl) phenyl 1] amino} propan-2-yl] cyclohexanecarboxamide hydrochloride

A solution of 59 mg (0.06 mmol) tert-butyl 4 - ({4 '- [(2S) -2- [[(trans-4- {[(tert-butoxycarbonyl) -amino] -methyl} cyclohexyl) -carbonyl ] amino} -3-oxo-3 - {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propyl] -2-fluorobiphenyl-3-yl} carbonyl) -piperazine-1-carboxylate trifluoroacetate 2 ml of 1,4-dioxane were mixed with 0.23 ml (0.91 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. 42 mg (85% of theory, 90% purity) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-ife) δ = 0.83-1.01 (m, 2H), 1.10-1.34 (m, 2H), 1.42-1.66 (m, 2H), 1.67-1.84 (m, 3 H), 2.10 - 2.21 (m, 1H), 2.59 - 2.69 (m, 2H), 2.90 - 3.00 (m, 1H), 3.01 - 3.26 (m, 5H), 3.49 - 3.56 (m, 2 H), 3.76 - 4.01 (m, 2H), 4.68 - 4.80 (m, 1H), 7.33 - 7.54 (m, 6H), 7.56 - 7.64 (m, 1H), 7.74 - 7.93 (m, 5 H), 8.03 (d, 2H), 8.30 (d, 1H), 9.3 (br, s, 2H), 10.60 (s, 1H), 16.8 (br, s, 1H).

LC-MS (Method 1): R _t = 0.51 min; MS (ES Ineg): m / z = 652 [MH-HC1] ^" .

Example 19

4 '- [(2S) -2 - ({[iraws-4- (aminomethyl) cyclohexyl] ca ^^

yl) phenyl] amino} propyl] -A ^r - [3- (diethylamino) propyl] -6-methyl-biphenyl-3-carboxamide ^

hydrochloride

A solution of 73 mg (0.08 mmol) of ieri-butyl - [(ira ".y-4- {[(2 _l S ^, ) -3- (5 '- {[3- (diethylamino) -propyl] carbamoyl} - 2'-methylbiphenyl-4-yl) -1-oxo-1 - {[4- (2-i-tetrazol-5-yl) -phenyl] -amino-jpropan-2-yl] -carbamoyl} -cyclohexyl) -methyl] -carbamate trifluoroacetate 2.5 ml of 1,4-dioxane were mixed with 0.30 ml (1.21 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 (83% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de) δ = 0.85-1.00 (m, 2H), 1.11-1.34 (m, 8H), 1.41-1.63 (m, 2H), 1.69-1.82 (m, 3 H), 1.83 - 1.94 (m, 2H), 2.10 - 2.27 (m, 4H), 2.60 - 2.67 (m, 2H), 2.90 - 3.01 (m, 1H), 3.02 - 3.19 (m, 7 H), 3.26-3.338 (m, 2H), 4.71-4.81 (m, 1H), 7.29 (d, 2H), 7.35-7.44 (m, 3H), 7.66-7.70 (m, 1H) , 7.72 - 7.90 (m, 6H), 7.99 - 8.06 (m, 2H), 8.31 (d, 1H), 8.62 - 8.70 (m, 1H), 9.9 (br, s, 1H), 10.58 (s, 1H).

LC-MS (Method 1): R _t = 0.65 min; MS (ES Ineg): m / z = 692 [MH-HC1] ^" . Example 20

/ raws-4- (aminomethyl) - N - [(2S) -3- [3 '- (morpholin-4-ylcarbonyl) biphenyl-4-yl] -1-oxo-1 - {[4- (2H-tetrazole -5-yl) phenyl] amino} propan-2-yl] cyclohexanecarboxamide hydrochloride

A solution of 91 mg (0.12 mmol) of tert-butyl - [(ira-i-4- {[(2 _L ^Sr ) -3- [3 '- (morpholin-4-ylcarbonyl) biphenyl-4-yl] - 1-Oxo-1 - {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propan-2-yl] carbamoyl} -cyclohexyl) methyl] carbamate in 5 ml of tetrahydrofuran was mixed with 1.00 ml (4.00 mmol ) 4M hydrogen chloride in 1,4-dioxane and stirred for 16 h at RT. The solvent was removed on a rotary evaporator and dried under high vacuum. The residue was stirred in acetonitrile, filtered, washed with acetonitrile and dried under high vacuum. 75 mg (84% of theory, 93% purity) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO δ = 0.80-1.00 (m, 2H), 1.12- 1.34 (m, 2H), 1.39-1.83 (m, 6H), 2.08-2.23 (m, 1H), 2.63 (m, 2H), 2.87 - 3.02 (m, 1H), 3.07 - 3.20 (m, 1H), 3.38 (d, 2H), 3.55 - 3.58 (m, 3H), 4.66 - 4.79 ( m, 1H), 7.29-7.97 (m, 14H), 8.04 (d, 2H), 8.30 (d, 1H), 10.63 (br, s, 1H).

LC-MS (Method 1): R _t = 0.64 min; MS (ES Ineg): m / z = 635 [MH-HC1] ^" . Example 21

/ Raws-4- (Aminomethyl) -N - [(2S) -3- (5'-cyano ^

yl) phenyl] amino} propan-2-yl] cyclohexanecarboxamide hydrochloride

A solution of 70 mg (0.1 mmol) ieri-butyl - [(ira "i-4- {[(2 S _l ^r) -3- (5'-cyano-2'-methylbiphenyl-4-yl) - 1 - oxo-1- {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propan-2-yl] carbamoyl} cyclohexyl) -methyl] -carbamate in 4 mL of tetrahydrofuran was mixed with 1.25 mL (5 mmol) 4M Hydrogen chloride in 1,4-dioxane and stirred for 4 h at RT. Another 0.2 ml (1 mmol) of 4M hydrogen chloride in 1,4-dioxane were added and the mixture was stirred at RT for 16 h. The resulting solid was filtered and washed with tetrahydrofuran and acetonitrile and dried under high vacuum. 55.5 mg (85% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de) δ = 0.82 - 1.03 (m, 2H), 1.10 - 1.33 (m, 2H), 1.41 - 1.63 (m, 2H), 1.67 - 1.85 (m, 3 H), 2.12 - 2.19 (m, 1H), 2.25 (s, 3H), 2.63 (t, 1H), 2.87 - 3.02 (m, 2H), 3.07 - 3.23 (m, 1H), 4.67 - 4.80 (m, 1H), 7.30 (d, 2H), 7.42 (d, 2H), 7.51 (d, 1H), 7.60 (d, 1H), 7.68 - 7.91 (m, 6H) , 8.02 (d, 1H), 8.31 (d, 1H), 10.58 (br, s, 1H).

LC-MS (Method 1): R _t = 0.74 min; MS (ES Ineg): m / z = 561 [MH-HC1] ^" .

Example 22

N- {4 (2S) -2 - ({[/ raws-4- (armnomethyl) cy ^

yl) phenyl] amino} propyl] -4-methylbiphenyl 1-3-yl} piperidine-4-carboxamide hydrochloride

To a solution of 17.2 mg (0.018 mmol) of tert-butyl 4 - ({4 '- [(2S) -2- [[(trans-4- {[(tert-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propyl] -4-methyl-biphenyl-1-yl-1-carbamoyl) -piperidine-1-carboxylate Trifluoroacetate in 1 ml of dioxane was added 0.07 ml (0.26 mmol) of 4M hydrogen chloride in dioxane. It was stirred for 7 d at RT. The precipitated product was filtered off with suction, washed with dioxane and dried under high vacuum. 14 mg (100% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.60 min; MS (ESIpos): m / z = 664 [M + H-HC1] ⁺ .

Ή-NMR (400 MHz, DMSO-d ₆ ) δ = 0.85-0.98 (m, 2H), 1.11-1.32 (m, 2H), 1.44-1.53 (m, 1H), 1.60 (d, 1H ), 1.70 - 1.92 (m, 5 H), 1.96 - 2.04 (m, 2 H), 2.15 (br, s, 1 H), 2.21 (s, 3 H), 2.63 (t, 2 H), 2.75 (brs, 1H), 2.87-2.99 (m, 3H), 3.06-3.15 (m, 1H), 4.72 (m, 1H), 7.28 (d, 1H), 7.39 (d, 3 H), 7.53 (d, 2H), 7.63 (s, 1H), 7.84 (d, 4H), 8.02 (d, 2H), 8.26 (d, 1H), 8.56 - 8.72 (m, 1 H), 8.80 - 9.04 (m, 1 H), 9.54 (s, 1 H), 10.57 (brs., 1 H). Example 23

4 '- [(2S) -2 - ({[iraws-4- (aminomethyl) c]

yl) phenyl] amino} propyl] - N - [2- (diethylamino) ethyl] -6-ethylbiphenyl-3-carboxamide-H

To a solution of 60 mg (0.07 mmol) of ieri-butyl - [(ira s-4- {[(2 _L S ') - 3- (5' - {[2- (diethylamino) ethyl] carbamoyl} 2'-ethylbiphenyl-4-yl) -1-oxo-1 - {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propan-2-yl] carbamoyl} cyclohexyl) -methyl] carbamate-trifluoroacetate in 2.5 ml of dioxane was added 0.25 ml (0.99 mmol) of 4M hydrogen chloride in dioxane. It was stirred for 16 h at RT. The precipitated product was filtered off with suction, washed with acetonitrile and dried under high vacuum. 48 mg (91% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.61 min; MS (ES Ineg): m / z = 694 [M + H-HC1] ⁺ .

Ή-NMR (400 MHz, DMSO-de) δ ppm 0.86 - 1.05 (m, 6H), 1.22 (m, 9H), 1.40 - 1.54 (m, 1H), 1.55 - 1.63 (m, 1H) , 1.67 - 1.82 (m, 3H), 2.10 - 2.21 (m, 1H), 2.63 (t, 2H), 2.91 - 3.02 (m, 1H), 3.11 - 3.26 (m, 7H), 3.59 - 3.66 (m, 2H), 4.70 - 4.82 (m, 1H), 7.25 (d, 2H), 7.42 (dd, 3H), 7.67 (d, 1H), 7.85 (m, 6H) , 8.03 (d, 2H), 8.32 (d, 1H), 8.86 (t, 1H), 10.14 (s, 1H), 10.60 (s, 1H). Example 24

ira "i-4- (aminomethyl) -N - [(25) -3- [4'-methoxy-3 '- (morpholin-4-ylsulfonyl) bi ^^

{[4- (1-i-tetrazol-5-yl) phenyl] amino} propan-2-yl] cyclohexanecarboxamide hydrochloride

To a solution of 86 mg (107 μηιοΐ) of ieri-butyl - [(ira «A-4- {[(2 _L S ') - 3- [4'-methoxy-3' - (morpholin-4-ylsulfonyl) biphenyl -4-yl] - 1 -oxo-1 - {[4- (1-i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate in 1 ml of dichloromethane 268 μΐ (1.1 mmol) of 4M hydrogen chloride in dioxane was added. It was stirred at RT 3d. 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 8). 43 mg (53% of theory) of the title compound were obtained.

LC-MS (Method 4) R _t = 0.83 min; MS (ESIpos): m / z = 703 [M + H-HC1] ⁺ .

Ή-NMR (500 MHz, DMSO-d ₆ ) δ ppm 0.84-0.98 (m, 2H), 1.13-1.32 (m, 2H), 1.39-1.49 (m, 1H), 1.56- 1.64 (m, 1 H), 1.68-1.79 (m, 3H), 2.10-2.29 (m, 1H), 2.63 (d, 2H), 2.85-2.94 (m, 1H), 3.05-3.13 (m, 5H ), 3.56 - 3.61 (m, 4H), 3.93 (s, 3H), 4.66 - 4.75 (m, 1H), 7.34 (d, 1H), 7.40 (d, 2H), 7.56 (d, 2H), 7.60 (d, 2H), 7.84-7.94 (m, 4H), 8.13 (d, 1H), 10.14 (s, 1H).

Example 25

/ raws-4- (aminomethyl) -N- {(2S) -3- [5 '- (dimethylsulfamoyl) -2'-methylbiphenyl-4-yl] -1-oxo-1 - [(2-oxo-2, 3-dihydro-l / i-benzimidazol-5-yl) amino] propan-2-yl} cyclohexancarboxam

₃ To a solution of 66.7 mg (91 μηιοΐ) of ferric butyl {[ira «A-4 - ({(2 _l S ') - 3- [5' - (dimethylsulfamoyl) -2'-methylbiphenyl-4-yl ] - 1-oxo-l - [(2-0X0-2,3-dihydro-l / i-benzimidazol-5-yl) amino] propan-2-yl} carbamoyl) cyclohexyl] methyl} carbamate in 2 ml of dichloromethane were added 114 μΐ (0.45 mmol) of 4M hydrogen chloride in dioxane. It was stirred for 4 days at RT and 2.5 eq again. Added 4M hydrogen chloride in dioxane. The mixture was stirred at RT overnight. 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 11). 14 mg (23% of theory) of the title compound were obtained.

LC-MS (Method 5) R _t = 1.05 min; MS (ESIpos): m / z = 633 [M + H-HC1] ⁺ .

Ή-NMR (400 MHz, DMSO-de) δ ppm 0.66-0.90 (m, 2H), 1.02-1.31 (m, 3H), 1.45- 1.56 (m, 1H), 1.61-1.78 (m, 3 H), 2.02 - 2.14 (m, 1H), 2.27 (s, 3H), 2.30 - 2.37 (m, 2H), 2.60 (s, 6H), 2.91 (dd, 1H), 3.08 (dd , 1H), 4.64-4.76 (m, 1H), 6.82 (d, 1H), 6.97 (dd, 1H), 7.29 (d, 2H), 7.37 (d, 2H), 7.40-7.44 (m, 2H), 7.55 (d, 1H), 7.63 (dd, 1H), 8.04 (d, 1H), 9.88 - 9.96 (m, 1H), 10.45 (br, s, 1H) , Example 26 iraws-4- (aminomethyl) -N- {(2S) -3- [2'-methyl-5 '- (morpholin-4-ylsulfonyl) -biphenyl-4-yl]-1-oxo-1 -

[(2-oxo-23-dihydro-l / i-benzimidazol-5-yl) amino] propan-2-yl} cyclohexancarboxamid-

hydrochloride

To a solution of 77 mg (99 μηιοΐ) of ferric butyl {[ira «A-4 - ({(2 _l S ') - 3- [2'-methyl-5' - (morpholin-4-ylsulfonyl) biphenyl 4-yl] - 1 -oxo-1 - [(2-oxo-2,3-dihydro-l / i-benzimidazol-5-yl) -amino] -propan-2-yl} -carbamoyl) -cyclohexyl] -methyl} carbamate in 2.5 ml of dichloromethane was added 124 μM (0.50 mmol) of 4M hydrogen chloride in dioxane. It was stirred for 4 days 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 11). 14 mg (20% of theory) of the title compound were obtained.

LC-MS (Method 5) R _t = 1.02 min; MS (ESIpos): m / z = 675 [M + H-HC1] ⁺ .

Ή-NMR (400 MHz, DMSO-de) δ ppm 0.71-0.89 (m, 2H), 1.04-1.32 (m, 2H), 1.46-1.55 (m, 1H), 1.60-1.78 (m, 3 H), 2.02 - 2.14 (m, 1H), 2.28 (s, 3H), 2.30 - 2.36 (m, 3H), 2.63 - 2.68 (m, 1H), 2.82 - 2.89 (m, 4H) , 3.04 - 3.13 (m, 1H), 3.57 - 3.67 (m, 4H), 4.65 - 4.75 (m, 1H), 6.82 (d, 1H), 6.99 (dd, 1H), 7.29 (i.e. , 2H), 7.35 - 7.45 (m, 4H), 7.54 - 7.65 (m, 2H), 8.04 (d, 1H), 9.91 (s, 1H), 10.47 (br. S, 1H) , Example 27

4 '- [(2S) -2 - ({[iraws-4- (aminomethyl) cyclohexyl] ca ^^

yl) phenyl] amino} propyl] - N - [2- (morpholin-4-yl) ethyl] biphenyl-3-carboxamide HydrocM

To a solution of 60.5 mg (78 μηιοΐ) of ieri-butyl - [(ira «A-4- {[(2S) -3- (3 '- {[2- (morpholin-4-yl) ethyl] carbamoyl} biphenyl -4-yl) - 1-oxo-1- {[4- (l-i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate formate in 3.3 ml Dioxane was added 194 μΐ (0.78 mmol) of 4M hydrogen chloride in dioxane. It was stirred overnight at 35 ° 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. 45 mg (80% of theory) of the title compound were obtained.

LC-MS (Method 4) R _t = 0.69 min; MS (ESIpos): m / z = 680 [M + H-HC1] ⁺ .

Ή-NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.81-0.98 (m, 2H), 1.09-1.33 (m, 2H), 1.38-1.51 (m, 1H), 1.54-1.63 (m, 1 H), 1.66 - 1.81 (m, 3H), 2.07 - 2.17 (m, 1H), 2.55 - 2.62 (m, 2H), 2.88 - 2.98 (m, 1H), 3.06 - 3.14 (m, 2 H), 3.52 (brs s, 2 H), 3.66 - 3.73 (m, 2 H), 3.80 (brs s, 2 H), 3.94 (brs s, 2 H), 4.65 - 4.74 (m, 1 H), 7.41 (d, 2 H), 7.52 (t, 1 H), 7.67 (d, 2 H), 7.74 - 7.88 (m, 7 H), 7.99 (d, 2 H), 8.18 (s, 1H), 8.24 (d, 1H), 8.96-9.05 (m, 1H), 10.55 (s, 1H). Example 28 ira «-4- (aminomethyl) -N - [(25) -3- [5 '- (dimethylarrino) -2'-me

tetrazol-5-yl) phenyl] amino} propan-2-yl] cyclohexanecarboxamide hydrochloride

To a solution of 30 mg (44 μηιοΐ) of ieri-butyl - [(ira «A-4- {[(2S) -3- [5 '- (dimethylamino) -2'-methylbiphenyl-4-yl] - 1 - oxo-1 - {[4- (l-i-tetrazol-5-yl) -phenyl] -amino} -propan-2-yl] carbamoyl} -cyclohexyl) -methyl] -carbamate Formate in 1.8 ml of dioxane was added 110 μΐ (0.44 mmol) Added 4M hydrogen chloride in dioxane. It was stirred overnight at 35 ° 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. 23 mg (78% of theory) of the title compound were obtained.

LC-MS (Method 4) R _t = 0.74 min; MS (ESIpos): m / z = 581 [M + H-HC1] ⁺ .

Ή-NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.80-0.96 (m, 2H), 1.07-1.31 (m, 2H), 1.38-1.59 (m, 2H), 1.65-1.80 (m, 3H), 2.08 - 2.18 (m, 4H), 2.54 - 2.66 (m, 2H), 2.89 - 2.97 (m, 1H), 3.02 (br, s, 6H), 3.08 - 3.16 (m , 1H), 4.66 - 4.79 (m, 1H), 7.19 - 7.43 (m, 6H), 7.74 - 7.91 (m, 5H), 8.00 (d, 2H), 8.25 (d, 1H) , 10.54 (s, 1H).

Example 29

N- {4 '(25) -2 - ({[ira-i- (armnomethyl) cyclohexyl] carbonyl} amino) -3-oxo ^

yl) phenyl] amino} propyl] -4-methylbiphenyl 1-3-yl] tetrahydro-2 / i-pyran-4-carboxamide hydrochloride

To a solution of 22.6 mg (26 μηιοΐ) of ieri-butyl - [(ira ".y-4- {[(2 _L s ^, ) -3- {4'-methyl-3 '- [(tetrahydro-2 / i -pyran-4-ylcarbonyl) amino] biphenyl-4-yl} - 1 -oxo-1 - {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate in 1 ml of dioxane was added 96 μΐ (0.39 mmol) of 4M hydrogen chloride in dioxane. It was stirred for 5 days at RT. The precipitated product was filtered off with suction, washed with dioxane and dried under high vacuum. 18 mg (95% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.69 min; MS (ESIpos): m / z = 665 [M + H-HC1] ⁺ .

Ή-NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.84-0.99 (m, 2H), 1.09-1.34 (m, 2H), 1.38-1.53 (m, 1H), 1.56-1.82 (m, 7H), 2.10 - 2.18 (m, 1H), 2.21 (s, 3H), 2.58 - 2.76 (m, 3H), 2.88 - 2.99 (m, 1H), 3.06 - 3.14 (m, 1H ), 3.32 - 3.42 (m, 2H), 3.57 (s, 3H), 3.92 (m, 2H), 4.72 (m, 1H), 7.27 (d, 1H), 7.34 - 7.42 (m, 3 H), 7.53 (d, 2H), 7.65 (s, 1H), 7.76 (br, s, 3H), 7.83 (d, 2H), 8.02 (d, 2H), 8.24 (i.e. , 1H), 9.34 (s, 1H), 10.55 (s, 1H). Example 30

4 '- [(2S) -2 - ({[iraws-4- (aminomethyl) cyd]

yl) phenyl] amino} propyl] -5-fluoro-N-isopropyl-6-methylbiphenyl-3-carboxamide Hydrochlo

To a suspension of 63 mg (0.085 mmol) of tert-butyl - [(ira "5-4- {[(2 _L S ^r ) -3- [3'-fluoro-5'- (isopropylcarbamoyl) -2'-methylbiphenyl 4-yl] - 1 -oxo-1 - {[4- (2-i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate in 1.0 ml of dioxane Add 0.45 ml (1.70 mmol) 4M hydrogen chloride in dioxane. The reaction mixture was stirred for 1 h at RT and allowed to stand at RT overnight. The mixture was then concentrated to dryness, the residue was treated with a further 1.0 ml of 4M hydrogen chloride in dioxane and stirred at RT for 3 h. The mixture was then concentrated to dryness and the residue taken up in 3.0 ml of dioxane. The resulting suspension was filtered, the solid washed three times with diethyl ether and dried under high vacuum. 51 mg (85% of theory) of the title compound were obtained. Ή-NMR (400 MHz, DMSO-ife): δ = ppm 10.54 (br.s .., 1H), 8.34-8.21 (m, 2H), 8.02 (d, 2H), 7.87-7.69 (m, 5H), 7.66-7.55 (m, 2H), 7.43 (d, 2H), 7.30 (d, 2H), 4.82-4.72 (m, 1H), 4.16-4.02 (m, 1H), 3.21-3.10 (m, 1H), 3.02-2.91 (m, 1H), 2.69-2.59 (m, 2H), 2.21-2.07 (m, 4H), 1.84-1.67 (m, 3H), 1.63-1.54 (m, 1H), 1.53-1.41 (m , 1H), 1.35-1.21 (m, 1H), 1.15 (d, 7H), 0.91 (d, 2H).

LC-MS (Method 1): R _t = 0.76 min; MS (ESIpos): m / z = 641 [M + H-HC1] ⁺ . Example 31

4 '- [(2S) -2 - ({[iraws-4- (aminomethyl) cyclohexyl] ca ^^

yl) phenyl] amino} propyl] -5-fluoro-6-methyl-N- (piperidin-4-yl) biphenyl-3-carboxamide-Hyd ^

To a suspension of 95 mg (0.108 mmol) of tert-butyl 4 - [({4 '- [(2S) -2- [[trans-4- {[(tert-butoxycarbonyl) amino] methyl}} cyclohexyl) carbonyl 1] amino} -3-oxo-3 - {[4- (2-i-tetrazol-5-yl) phenyl] amino} propyl] -5-fluoro-6-methylbiphenyl-3-yl} carbonyl) amino] piperidine-1-carboxylate in 1.0 ml of dioxane, 1.08 ml (4.31 mmol) of 4M hydrogen chloride in dioxane were added and the reaction mixture was stirred at RT for 45 min. Subsequently, the reaction mixture was diluted with 3 ml of dioxane and filtered. The filter residue was washed three times with 2 ml of diethyl ether and the solid dried under high vacuum. 75 mg (87% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-ife): δ = ppm 16.79 (br, s, 1H), 10.54 (br, s, 1H), 8.75 (br, s, 2H), 8.55 (d, 1H ), 8.28 (d, 1H), 8.02 (d, 2H), 7.88-7.74 (m, 5H), 7.66 (d, 1H), 7.59 (s, 1H), 7.43 (d, 2H), 7.30 (d, 2H), 4.82-4.71 (m, 1H), 4.11-3.99 (m, 1H), 3.20-3.10 (m, 1H), 3.06-2.91 (m, 3H), 2.69- 2.59 (m, 2H), 2.21- 2.06 (m, 4H), 2.00-1.89 (m, 2H), 1.82-1.67 (m, 6H), 1.63-1.54 (m, 1H), 1.53-1.41 (m, 1H), 1.41-1.05 (m, 3H ), 1.01-0.84 (m, 2H).

LC-MS (Method 1): R _t = 0.53 min; MS (ESIpos): m / z = 682 [M + H-HC1] ⁺ . Example 32

4 '- [(2S) -2 - ({[iraws-4- (aminomethyl) cyclohexyl] ca ^^

yl) phenyl] amino} propyl] -N- (1α-α-4-hydroxycyclohexyl) -6-methylbiphenyl-3-carboxamide hydrochloride

To a suspension of 50 mg (0.064 mmol) of tert-butyl - [(trans-4- {[(2S) -3- {5 '- [(trans-4-hydroxycyclohexyl) carbamoyl] -2'-methylbiphenyl-4- yl} - 1 -oxo-1 - {[4- (2-i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate in 2.0 ml of dioxane were added 0.32 ml (1.28 mmol) 4M hydrogen chloride in dioxane and the reaction mixture left for 1 h at RT in an ultrasonic bath. The reaction mixture was then concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% formic acid (gradient)). 18 mg (36% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-ife): δ = ppm 10.46 (s, 1H), 8.22 (d, 1H), 8.14 (d, 1H), 8.00 (d, 2H), 7.82 (d, 2H), 7.75-7.71 (m, 1H), 7.68-7.59 (m, 4H), 7.39 (d, 2H), 7.34 (d, 1H), 7.28 (d, 2H), 4.80-4.72 (m, 1H), 3.75- 3.65 (m, 2H), 3.00-2.91 (m, 1H), 2.69-2.61 (m, 3H), 2.20 (s, 3H), 1.88-1.69 (m, 7H), 1.63-1.56 (m, 1H), 1.48-1.42 (m, 1H), 1.38-1.15 (m, 7H), 0.97-0.86 (m, 2H).

LC-MS (Method 1): R _t = 0.69 min; MS (ESIpos): m / z = 679 [M + H-HC1] ⁺ . Example 33 iraws-4- (aminomethyl) -N- [(2S) -3- [2'-methyl-5 '- (morpholin-4-ylcarbonyl) biphenyl-4-yl] -1-oxo-1 - {[ 4- (2 / i-tetrazol-5-yl) phenyl] amino} propan-2-yl] cyclohexancarboxarrüd hydrochloride

To a suspension of 54 mg (0.072 mmol) ieri-butyl - [(ira ".y-4- {[(2 _l ^S,) -3- [2'-methyl-5'- (morpholin-4-ylcarbonyl) biphenyl-4-yl] -1-oxo-1- {[4- (2-i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate in 2.6 ml of dioxane 0.36 ml (1.43 mmol) of 4M hydrogen chloride in dioxane and the reaction mixture left for 1 h at RT in an ultrasonic bath. The reaction mixture was then concentrated and the residue was dried under high vacuum. 45 mg (88% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-ife): δ = ppm 10.47 (s, 1H), 8.23 (d, 1H), 8.00 (d, 2H), 7.82 (d, 2H), 7.74-7.61 (m, 2H ), 7.41-7.23 (m, 6H), 7.18-7.14 (m, 1H), 4.80-4.71 (m, 1H), 3.65-3.20 (m, 8H), 3.16-3.09 (m, 1H), 3.00-2.91 (m, 1H), 2.68-2.60 (m, 2H), 2.21 (s, 3H), 2.17-2.11 (m, 1H), 1.81- 1.69 (m, 3H), 1.63-1.55 (m, 1H), 1.50 -1.41 (m, 1H), 1.38-1.12 (m, 3H), 1.00-0.84 (m, 2H). LC-MS (Method 1): R _t = 0.68 min; MS (ESIpos): m / z = 651 [M + H-HC1] Example 34

4 '- [(2S) -2 - ({[iraws-4- (aminomethyl) cyclohexyl] ca ^^

yl) phenyl] amino} propyl] -5,6-dimethyl-N- (1-methylpiperidin-4-yl) biphenyl-3-carboxamide

hydrochloride

To a suspension of 75 mg (0.094 mmol) of ieri-butyl - [(ira "_> y-4- {[(2 _l S ^, ) -3- {2 ', 3'-dimethyl-5' - [(l- methylpiperidin-4-yl) carbamoyl] biphenyl-4-yl} - 1 -oxo-1 - {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propan-2-yl] carbamoyl} cyclohexyl ) methyl] carbamate in 2.0 ml of dioxane were added 0.35 ml (1.41 mmol) of 4M hydrogen chloride in dioxane and the reaction mixture was stirred overnight at RT. The reaction mixture was then concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% trifluoroacetic acid (gradient)). There were obtained 34 mg (42% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-ife): δ = ppm 16.73 (br.s .., IH), 10.48 (brs., IH), 9.87-9.71 (m, IH), 8.44-8.37 (m, IH), 8.28-8.22 (m, IH), 8.01 (d, 2H), 7.82 (d, 2H), 7.79-7.63 (m, 3H), 7.51 (s, IH), 7.39 (d, 2H), 7.22 (d, 2H), 4.80-4.70 (m, IH), 4.05-3.93 (m, IH), 3.49-3.38 (m, 2H), 3.18-3.02 (m, 3H), 3.00-2.90 (m, IH) , 2.74 (s, 3H), 2.68-2.61 (m, 2H), 2.33 (s, 3H), 2.21-2.13 (m, IH), 2.08 (s, 3H), 2.02-1.93 (m, 2H), 1.87 -1.69 (m, 5H), 1.65-1.56 (m, IH), 1.53-1.42 (m, IH), 1.33-1.13 (m, 2H), 0.99-0.85 (m, 2H).

LC-MS (Method 1): R _t = 0.59 min; MS (ESIpos): m / z = 692 [M + H-HC1] ⁺ . Example 35

4 '- [(2S) -2 - ({[iraws-4- (aminomethyl) cyclohexyl] ca ^^

yl) phenyl] amino} propyl] -4-fluoro-N- (piperidin-4-yl) biphenyl-3-carboxamide Hydrochlori

To a suspension of 104 mg (0.119 mmol) ieri-butyl 4 - [({4 '- [(2 _l ^S) -2- {[(ira _"> y-4- {[(ieri- butoxycarbonyl) amino ] methyl} cyclohexyl) carbonyl] amino} -3-oxo-3- {[4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propyl] -4-fluorobiphenyl-3-yl} carbonyl) -amino ] piperidine-1-carboxylate in 2.0 ml of dioxane was added 0.45 ml (1.79 mmol) of 4M hydrogen chloride in dioxane and the reaction mixture allowed to stand at RT overnight. The reaction mixture was then concentrated and the residue was stirred with diethyl ether. The solid present was filtered off and dried under high vacuum. 93 mg (94% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-ife): δ = ppm 16.78 (br.s .., IH), 10.55 (br.s .., IH), 8.82-8.73 (m, IH), 8.70-8.61 (m, IH), 8.58 (d, IH), 8.26 (d, IH), 8.02 (d, 2H), 7.88-7.71 (m, 6H), 7.62 (d, 2H), 7.42 (d, 2H), 7.39-7.32 (m, IH), 4.78-4.67 (m, IH), 4.10-4.00 (m, IH), 3.41-3.31 (m, 2H), 3.17-3.07 (m, IH), 3.07-2.90 (m, 3H) , 2.68-2.58 (m, 2H), 2.21-2.10 (m, IH), 2.05-1.95 (m, 2H), 1.83-1.68 (m, 5H), 1.67-1.58 (m, IH), 1.54-1.42 ( m, IH), 1.33-1.14 (m, 2H), 1.01-0.84 (m, 2H).

LC-MS (Method 1): R _t = 0.51 min; MS (ESIpos): m / z = 668 [M + H-HC1] ⁺ . Example 36

4 '- [(25) -2- ({[ira-i-4- (aminomethyl) cyclohexyl] carbonyl} amino) -3-oxo-3- {[4- (2-i-etrazol-5-yl) -phenyl ] amino} propyl] -6-methyl-N- (2-oxo-piperidin-4-yl) biphenyl-3-carboxamide Hydroch

To a suspension of 467 mg (0.60 mmol) of tert-butyl [(iraws-4- {[(2S) -3- {2'-methyl-5 '- [(2-oxopiperidin-4-yl) carbamoyl] biphenyl -4-yl} - 1 -oxo-1 - {[4- (2-i-tetrazol-5-yl) -phenyl] -amino-jpropan-2-yl] -carbamoyl} -cyclohexyl) -methyl] carbamate in 24.4 ml of dioxane was added 1.5 ml (6.00 mmol) 4M hydrogen chloride in dioxane and the reaction mixture stirred overnight at RT. The reaction mixture was then concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% trifluoroacetic acid (gradient)). There was obtained 26 mg (5% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO-ife): δ = ppm 10.51 (br.s, IH), 8.45-8.37 (m, IH), 8.24 (d, IH), 8.01 (d, 2H), 7.88- 7.63 (m, 8H), 7.60-7.52 (m, IH), 7.45-7.33 (m, 3H), 7.28 (d, 2H), 4.82-4.70 (m, IH), 4.26-4.12 (m, IH), 3.56-3.29 (m, 2H), 3.21-3.09 (m, 3H), 3.02-2.89 (m, IH), 2.70-2.59 (m, 2H), 2.22 (s, 4H), 1.98-1.88 (m, IH ), 1.83-1.64 (m, 4H), 1.63-1.55 (m, IH), 1.53-1.40 (m, IH), 1.36-1.10 (m, 2H), 1.02-0.82 (m, 2H).

LC-MS (Method 1): R _t = 0.67 min; MS (ESIpos): m / z = 678 [M + H-HC1] ⁺ . Example 37

4 '- [(2S) -2 - ({[iraws-4- (aminomethyl) cyd]

yl) phenyl] amino} propyl] - N - [4- (dimethylamino) cyclohexyl] -5-methylbiphenyl-3-carbox

hydrochloride

To a suspension of 28 mg (0.04 mmol) of tert-butyl - [(trans-4- {[(2S) -3- 3 '- {[4- (dimethylamino) cyclohexyl] carbamoyl} -5'-methylbiphenyl-4- yl) -1-oxo-1- {[4- (2-i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate in 1.0 ml of dioxane were added 0.18 ml (0.71 ml) mmol) 4M hydrogen chloride in dioxane and the reaction mixture stirred for 6 h at RT and allowed to stand overnight. The mixture was then concentrated, the residue was suspended in dioxane and added again 1.0 ml of 4M hydrogen chloride in dioxane. The mixture was allowed to stand overnight. It was then concentrated again, mixed with 1.0 ml of 4M hydrogen chloride in dioxane and stirred for 1 h in an ultrasonic bath. The reaction mixture was concentrated, the residue was stirred with diethyl ether and filtered. The filter residue was washed with diethyl ether and the solid was purified by preparative HPLC (mobile phase: acetonitrile / water with 0.1% trifluoroacetic acid (gradient)). 4 mg (14% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-ifc): δ = ppm 10.55-10.49 (m, 1H), 10.00-9.85 (m, 1H), 8.28-8.21 (m, 1H), 8.01 (d, 1H), 7.87 -7.79 (m, 2H), 7.78-7.69 (m, 2H), 7.67-7.58 (m, 3H), 7.45-7.39 (m, 1H), 4.77-4.65 (m, IH), 3.84-3.77 (m, IH), 3.70-3.40 (m, 4H), 3.22-3.07 (m, 2H), 2.99-2.90 (m, IH), 2.76-2.70 (m , 6H), 2.69-2.59 (m, 2H), 2.44-2.38 (m, 3H), 2.22-2.11 (m, IH), 2.10-1.94 (m, 3H), 1.89-1.69 (m, 4H), 1.68 -1.55 (m, 3H), 1.51-1.36 (m, 2H), 1.33-1.17 (m, 2H), 1.00-0.86 (m, 2H).

LC-MS (Method 1): R _t = 0.57 min; MS (ESIpos): m / z = 706 [M + H-HC1] ⁺ . Example 38 iraws-4- (aminomethyl) -N- [(2S) -3 - [4'-methyl-3 '- (morpholin-4-ylcarbonyl) biphenyl-4-yl] -1-oxo-1 - {[ 4- (2 / i-tetrazol-5-yl) -phenyl] -amino} -propan-2-yl] cyclohexanecarboxamide hydrochloride

ieri-butyl - [(ira "_> y-4- {[(2 _L S ^, ) -3- [4'-methyl-3 '- (morpholin-4-ylcarbonyl) biphenyl-4-yl] -l-oxo -l- {[4- (2 / i-tetrazol-5-yl) phenyl] amino} propan-2-yl] carbamoyl} cyclohexyl) methyl] carbamate (55 mg, 0.07 mmol) was placed in 2.0 ml of dioxane, with 0.18 ml (0.73 mmol) of 4M hydrogen chloride in dioxane were added and the mixture was stirred for 3 days. The mixture was then stirred in an ultrasonic bath for 2 h. The resulting suspension was filtered, the filter residue washed with dioxane and dried under high vacuum. 31 mg (60% of theory) of the title compound were obtained. Ή NMR (400 MHz, DMSO-ifc): δ = ppm 10.52 (s, IH), 8.22 (d, IH), 8.01 (d, 2H), 7.83 (d, 2H), 7.72 (br. 3H), 7.64-7.57 (m, 3H), 7.48-7.44 (m, IH), 7.39 (d, 2H), 7.34 (d, IH), 4.77-4.66 (m, IH), 3.75-3.59 (m, 4H), 3.56-3.51 (m, IH), 3.50-3.45 (m, IH), 3.22-3.06 (m, 4H), 2.98-2.88 (m, IH), 2.63 (d, 2H), 2.25 (s, 3H), 2.20-2.10 (m, IH), 1.81-1.68 (m, 3H), 1.66-1.57 (m, IH), 1.51-1.40 (m, IH), 1.31-1.13 (m, 2H), 0.99- 0.84 (m, 2H). LC-MS (Method 1): R _t = 0.70 min; MS (ESIpos): m / z = 651 [M + H-HC1] ⁺ . Example 39

4 '- [(2S) -2 - ({[iraws-4- (aminomethyl) cyclohexyl] ca ^^

yl) phenyl] amino} propyl] -N, N, 4,6-tetramethylbiphenyl-3-carboxamide hydrochloride

 (2 / i-Tetrazol-5-yl) -phenyl] -amino} -propan-2-yl] -carbamoyl-cyclohexyl-methyl] -carbamate (73 mg, 0.10 mmol) was initially charged in 2.2 ml dioxane with 0.50 ml (2.01 mmol) 4M Hydrogen chloride in dioxane and the mixture allowed to stand overnight. Subsequently, the reaction mixture was completely concentrated, the residue was stirred with diethyl ether, filtered and the filter residue dried under high vacuum. There were obtained 61 mg (83% of theory) of the title compound.

Ή NMR (400 MHz, DMSO-ifc): δ = ppm 10.45 (s, IH), 8.21 (d, IH), 7.99 (d, 2H), 7.81 (d, 2H), 7.73-7.62 (m, 3H ), 7.36 (d, 2H), 7.23 (d, 2H), 7.16 (s, IH), 6.89 (s, IH), 4.80-4.69 (m, IH), 3.16- 3.07 (m, IH), 2.98 ( s, 3H), 2.95-2.90 (m, IH), 2.78 (s, 3H), 2.69-2.60 (m, 2H), 2.23-2.08 (m, 7H), 1.82-1.67 (m, 2H), 1.63- 1.54 (m, IH), 1.53-1.38 (m, IH), 1.32-1.21 (m, 2H), 1.20-1.13 (m, IH), 1.00-0.83 (m, 2H).

LC-MS (Method 1): R _t = 1.17 min; MS (ESIpos): m / z = 868 [M + H-HC1] ⁺ . Example 40

4 '- [(2S) -2 - ({[iraws-4- (aminomethyl) cyclohexyl] ca ^^

yl) phenyl] amino} propyl] -5-methyl-N- (piperidin-4-yl) bip

tert-Qutyl - [(trans-A- {[(2S) -3- [3'-methyl-5 '- (piperidin-4-ylcarbamoyl) biphenyl-4-yl] -1-oxo-1 - {[ 4- (2-i-tetrazol-5-yl) -phenyl] -amino} -propan-2-yl] -carbamoyl-cyclohexyl-methyl] -carbamate (54 mg, 0.06 mmol) was dissolved in methanol / dioxane with 0.31 ml of 4M hydrogen chloride in Dioxane added, the mixture stirred for 30 min in an ultrasonic bath and allowed to stand for 1 h at RT. Subsequently, the reaction mixture was completely concentrated and the residue dried under high vacuum. 45 mg (92% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-ife): δ = ppm 16.87 (br. S., 1H), 10.58 (br. S., 1H), 8.85-8.68 (m, 2H), 8.54 (d, 1H) , 8.29 (d, 1H), 8.02 (d, 2H), 7.91-7.74 (m, 6H), 7.69-7.58 (m, 4H), 7.43 (d, 2H), 4.76-4.68 (m, 1H), 4.14 -4.01 (m, 1H), 3.17-3.09 (m, 1H), 3.08-2.90 (m, 3H), 2.69-2.57 (m, 2H), 2.41 (s, 3H), 2.22-2.11 (m, 1H) , 2.02-1.92 (m, 2H), 1.84-1.70 (m, 6H), 1.67-1.57 (m, 1H), 1.53-1.42 (m, 1H), 1.34-1.12 (m, 3H), 1.00-0.83 ( m, 2H).

LC-MS (Method 1): R _t = 0.58 min; MS (ESIpos): m / z = 664 [M + H-HC1] ⁺ . Example 41

3- {5- [4- ({(2S) -2- ({[trans-A- (aminomethyl) cyclohexyl] carbonyl} amino) -3- [2'-methyl-5'-

(methylcarbamoyl) biphenyl-4-yl] propanoyl} amino) phenyl] -4 / i-l, 2,4-riazol-3-yl} -2,23,3-tetrafluoropropanoic acid hydrochloride

3- {5- [4- ({(2S) -2- {[(trans - - {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} -3- [2'-methyl-5 ' - (methylcarbamoyl ^

 2,2,3,3-Tetrafluoropropanoic acid (9.2 mg, 0.01 mmol) were placed in 1.0 ml of dioxane and mixed with 14 xL 4M hydrogen chloride in dioxane. Subsequently, 0.25 ml of methanol were added and the mixture was stirred for 30 min at RT in an ultrasound bath. The reaction mixture was allowed to stand overnight at RT, concentrated with 0.5 ml of 4M hydrogen chloride in dioxane and stirred for a further 30 min at RT in an ultrasonic bath. The reaction mixture was then concentrated, the residue taken up in water / acetonitrile and purified by double preparative HPLC (mobile phase: acetonitrile / water with 0.1% trifluoroacetic acid (gradient) and acetonitrile / water with 0.1% aqueous ammonia solution (gradient)). 1.1 mg (13% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-ife): δ = ppm 10.40 (br.s .., 1H), 8.44-8.38 (m, 1H), 8.28-8.21 (m, 1H), 7.95 (d, 2H), 7.81-7.63 (m, 5H), 7.43-7.32 (m, 3H), 7.28 (d, 2H), 4.79-4.69 (m, 1H), 3.50-3.30 (m, .19-3.10 (m, 1H), 2.99-2.91 (m, 1H), 2.76 (d, 3H), 2.67-2.60 (m, 2H), 2.22 (s, 3H), 2.20-2.12 (m, 1H), 1.80-1.69 (m, 3H), 1.63-1.55 (m, 1H), 1.51-1.41 (m, 1H), 1.33-1.12 (m, 3H), 0.98-0.85 (m, 2H) LC-MS (Method 1): R _t = 0.99 min; MS (ESIpos): m / z = 751 [M + H-HC1] ⁺ . Example 42

3- [5- (4- {[(2S) -2- ({[iraws-4- (aminomethyl) cyclohexyl] carbonyl} amino) -3- {2'-methyl-5'- [(1-methylpiperidine) 4-yl) carbamoyl] biphenyl-4-yl} propanoyl] amino} phenyl) -1 / il, 2,4-triazol-3-yl] -2,2,3,3-tetrafluoropropanoic acid hydrochloride

CH _Q

A solution of 3- [5- (4- {[(2 _L S ^, ) -2- {[(ira-A-4- {[(ieri-butoxycarbonyl) amino] methyl} cyclohexyl) carbonyl] amino} - 3- {2'-methyl-5 '- [(1-methylpiperidin-4-yl) carbamoyl] biphenyl-4-ylpropanoyl] -amino} phenyl) -l / il, 2,4-triazol-3-yl] -2,2,3,3-Tetrafluoropropanoic acid (117 mg, 0.13 mmol) in dioxane (4 ml) was combined with 4M hydrogen chloride in 1,4-dioxane (0.48 ml, 1.91 mmol) and stirred at RT overnight. The solid was filtered off, washed with dioxane, then dried under high vacuum. 113 mg (99% of theory) of the title compound were obtained.

Ή-NMR (400 MHz, DMSO-de): 8 = ppm 0.81 - 1.01 (m, 2H), 1.12 - 1.35 (m, 2H), 1.41 - 1.52 (m,

1H), 1.54 - 1.64 (m, 1H), 1.66 - 1.91 (m, 4H), 1.92 - 2.02 (m, 2H), 2.09 - 2.18 (m, 1H), 2.21 (s, 3H ), 2.49 - 3.00 (m, 1 H), 3.01 - 3.19 (m, 3 H), 3.34 - 3.47 (m, 3 H), 3.94 - 4.07 (m, 1H), 4.68 - 4.82 (m, 1H), 7.28 (d, 2H), 7.33 - 7.38 (m, 1H), 7.39 - 7.45 (m,

2 H), 7.68 (s, 1H), 7.72-7.88 (m, 5H), 7.98 (d, 2H), 8.29 (d, 1H), 8.50 (d, 1H), 9.91 - 10.27 ( m, 1H), 10.42-10.64 (m, 1H), 14.96-15.33 (m, 1H). LC-MS (Method 1): R _t = 0.56 min; MS (ES Ineg): m / z = 819 [M-HC1] ^" . Example 43

3- {5- [4- ({(2S) -2- ({[irani-4- (aminomethyl) cyclohexyl] carbonyl} amino) -3- [5'- (isopropylcarbamoyl) -2'-methylbiphenyl-4- yl] propanoyl} amino) phenyl] -l / il, 2,4-triazol-3-yl} propanoic acid hydrochloride H

A solution of ieri-butyl-3- {5- [4 - ({(2 _L S ^, ) -2- {[(ira-A-4- {[(ieri-butoxycarbonyl) amino] methyl} -cyclohexyl) carbonyl ] amino} -3- [5 '- (isopropylcarbamoyl) -2'-methylbiphenyl-4-yl] -propanoyl} -amino) -phenyl] -l-il, 2,4-triazol-3-yl} -propanoate (42.2 mg, 0.05 mmol) in dioxane (1.5 ml) was combined with 4M hydrogen chloride in 1,4-dioxane (0.19 ml, 0.75 mmol) and stirred at RT for three days. The solid was filtered off, washed with dioxane, then dried under high vacuum. 37.4 mg (96% of theory) of the title compound were obtained.

Ή NMR (400 MHz, DMSO-ife): δ = ppm 0.84-1.01 (m, 2H), 1.14 (s, 3H), 1.15 (s, 3H), 1.17-1.34 (m, 2H) , 1.41 - 1.53 (m, 1H), 1.53 - 1.63 (m, 1H), 1.74 (d, 3H), 2.10 - 2.19 (m, 1H), 2.22 (s, 3H), 2.63 (m , 2H), 2.74 - 2.83 (m, 2H), 2.91 - 3.04 (m, 3H), 3.10 - 3.19 (m, 1H), 4.08 (m, 1H), 4.70 - 4.79 (m, 1 H), 7.29 (d, 2H), 7.35 (d, 1H), 7.41 (d, 2H), 7.68 (d, 1H), 7.71-7.79 (m, 3H), 7.84 (br ., 3H), 7.97 (d, 2H), 8.22 (d, 1H), 8.28 (d, 1H), 10.48 (br, s, 1H).

LC-MS (Method 1): R _t = 0.73 min; MS (ES Ineg): m / z = 692 [M-HC1] ^" . Example 44

3- {5- [4- ({(2S) -2- ({\ trans- (aminomethyl) cyclohexyl] carbonyl} amino) -3- [4'-methoxy-3'- (morpholin-4-ylsulfonyl) biphenyl-4-yl] propanoyl} amino) phenyl] - IH-1, 2,4-triazol-3-yl} -2,2,3,3-tetrafluoropropanoic acid hydrochloride

To a solution of 92 mg (97 μηιοΐ) of 3- {5- [4 - ({(2 _l S ^, ) -2- {[(ira-A-4- {[(ieri-butoxycarbonyl) amino] -methyl} cyclohexyl) carbonyl] amino} -3- [4'-methoxy-3 '- (morpholin-4-ylsulphonyl) biphenyl-4-yl] propanoyl} amino) phenyl] -1 / l, 2,4-triazole-3 yl} -2,2,3,3-tetrafluoropropanoic acid in 2 ml of dioxane was added 364 μΐ (1.5 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. There were obtained 76 mg (86% of theory) of the title compound.

Ή-NMR (400 MHz, DMSO δ = ppm 0.78-1.01 (m, 2H), 1.12-1.36 (m, 2H), 1.41-1.65 (m, 2H), 1.75 (m, 3H), 2.08 - 2.22 (m, 1H), 2.63 (m, 2H), 2.87 - 3.02 (m, 1H), 3.06 - 3.16 (m, 5H), 3.53 - 3.64 (m, 4H), 3.94 (s , 3H), 4.65-4.79 (m, 1H), 7.36 (d, 1H), 7.42 (d, 2H), 7.58 (d, 2H), 7.82 (m, 4H), 7.90-7.96 (m, 2H), 8.00 (d, 2H), 8.26 (d, 1H), 10.58 (br, s, 1H), 15.20 (br, s, 1H).

LC-MS (Method 1): R _t = 0.69 min; MS (ESIpos): m / z = 846.4 [M + H-HC1] ⁺ . Example 45 / raws-4- (aminomethyl) - N - {(2S) -3- [2'-methyl-5 '- (pyrrolidin-1-ylsulphonyl) biphenyl-4-yl] -1-oxo-1 - [ (3-oxo-2,3-dihydro-l / i-indazol-6-yl) amino] propan-2-yl} cyclohexanecarboxamide hydrochloride

To a solution [ίΓα «5-4 - ({(25) -3- [2'-ηιε11ιγ1-5 '- (ργΓΓθ1ϊ (1ϊη-1-γΐ8υ1ίοηγ1) 1ριιηγ1-4-yl] -l-oxo-l - [(3 oxo-23-dihydro-l / i-indazol-6-yl) -amino] -propan-2-yl} carbamoyl) cyclohexyl] -methyl-carbamate in dioxane is added 4M hydrogen chloride in dioxane and the mixture is stirred for 3 to 4 days at RT The reaction mixture is worked up by methods known to those skilled in the art and the residue is separated by preparative HPLC to give the title compound.

Example 46 ira "Ä-4- (Aminomethyl) -N - _{(l S 2 ') - 3- [5' - (dimethylsulfamoyl) -2'-methylbiphenyl-4-yl] -l-oxo-l - [( 3-oxo-2,3-dihydro-1-i-indazol-6-yl) -amino] -propan-2-yl} cyclohexanecarboxamide hydrochloride

To a solution of ethyl-butyl [[ira] A-4 - ({(2 ^ -3- [5 '- (dimethylsulfamoyl) -2'-methylbiphenyl-4-yl] -1-oxo-1 - [( 3-0X0-2, 3-dihydro-l / i-indazol-6-yl) -amino] -propan-2-yl} -carbamoyl) cyclohexyl] -methyl-carbamate In 2 ml of dichloromethane is added 4M hydrogen chloride in dioxane The reaction mixture is worked up by methods known to the person skilled in the art and the residue is separated by preparative HPLC to give the title compound.

Example 47 iraws-4- (aminomethyl) -N- {(2S) -3- [2'-methyl-5 '- (morpholin-4-ylsulphonyl) biphenyl-4-yl] -1-oxo-1 - [( 3-oxo-2,3-dihydro-l / i-indazol-6-yl) amino] propan-2-yl} cyclohexanecarboxamide hydrochloride

To a solution of ieri-butyl {[ira "i-4 - ({(2 _l ^r S) -3- [2'-methyl-5 '- (morpholin-4-ylsulfonyl) biphenyl-4-yl] - 1-Oxo-1 - [(3-0X0-2,3-dihydro-l / i-indazol-6-yl) -amino] -propan-2-yl} -carbamoyl) cyclohexyl] -methyl-carbamate in dichloromethane becomes 4M hydrogen chloride in dioxane added. It is stirred for 3 to 4 days at RT. The reaction mixture is worked up by methods known to those skilled in the art and the residue is separated by preparative HPLC. You get the title compound. 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 ICso values are calculated from the concentration-effect relationships. Action data from this test are listed in Table A below:

Table A

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

 1 0.5 2 0.1

 3 2.8 4 3.1

5 11.0 6 14.0 Example No., ICso [n] Example No., ICso [nM]

 7 11.0 8 6.9

 9 7.4 10 8.0

 11 6.9 12 8.1

 13 17.0 14 15.0

 15 10.0 16 9.0

 17 9.3 18 16.0

 19 6.4 20 2.7

 21 8.3 22 25.0

 23 13.0 24 2.0

 25 6.1 26 6.1

 27 6.0 28 1.5

 29 11.0 30 2.7

 31 4.5 32 4.7

 33 5.4 34 4.1

 35 10 36 1.9

 37 7.5 38 4.1

 39 3.3 40 4.1

 41 2.8 42 6.8

 43 9.7 44 2.2

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 without test substance incubated. 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 test mixtures without test substance (excluding dimethylsulfoxide instead of test substance in dimethyl sulfoxide) and ICso values are calculated from the concentration-activity relationships. a.3) 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). This is under the blood Using a 0.11 molar sodium citrate solution as a template in a mixing ratio of sodium citrate / blood 1/9 removed. 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 with a commercially available test kit (C.K. 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. Action data from this test are listed in Table B below: Table B

Example No., aPTT Example No. »aPTT

 [μπιοΐ / ΐ] [pmol l]

 1 0.16 2 0.22

 3 0.19 4 0.16

 5 0.37 6 0.54

 7 0.39 8 0.51

 9 0.08 10 0.38

 11 0.26 12 0.49

 13 0.28 14 0.35

15 0.52 16 0.2 Example No., aPTT Example No., aPTT

 [μιηοΙΛ] [moWl

 17 0.58 18 0.35

 19 0.26 20 0.39

 21 0.22 22 0.34

 23 0.36 24 0.09

 25 0.15 26 0.18

 27 0.19 28 0.26

 29 0.3 30 0.2

 31 0.16 32 0.15

 33 0.18 34 0.06

 35 0.2 36 0.14

 37 0.14 38 0.22

 39 0.17 40 0.06

 41 0.31 42 0.16

 43 0.38 44 0.2

a.5) Determination of fibrinolvtischen 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. b) Determination of the antithrombotic effect (in vivo) b.l) Arterial thrombosis model (iron (II) chloride-induced thrombosis) in combination with rabbit ear bleeding time

The antithrombotic activity of FXIa inhibitors is tested in an arterial thrombosis model. The thrombus formation is due to chemical damage of a range of Arteria carotis raised 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 placement of the incision to the time when no more blood is detectable on the filter paper. 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. Subaquale bleeding (In 37 ° C tempered physiological sodium chloride solution) is observed over 30 minutes and determines the bleeding time.

C) Exemplary Embodiments for Pharmaceutical Preparations The substances according to the invention can be converted, for example, 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 tearat.

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 ^{5 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 ^{6 is} hydrogen, fluorine or chlorine,

R ⁷ and R ⁸ 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, chlorine, cyano, hydroxyl, 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 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 ^{9 represents} hydrogen, fluorine or chlorine, represents hydrogen, fluorine, chlorine, methyl or methoxy, represents hydrogen, fluorine, chlorine, C 1 -C 4 -alkyl, methoxy or trifluoromethyl, represents hydrogen or methyl, represents amino, cyano, trifluoromethyl, Ci-C ₃ alkoxy, C ₃ alkylamino, C ₁ -C3- alkoxycarbonyl, -S (O) ₂ NR ¹⁰ R ^n, -C (0) NR ¹² R ¹³ or -NR ¹⁴ ( CO) R ¹⁵ stands, wherein alkoxy is substituted with 1 to 2 substituents independently selected from the group consisting of fluoro, hydroxy, amino, hydroxycarbonyl, Ci-C3-alkylamino, difluoromethyl, trifluoromethyl, - (OCH ₂ CH ₂ ) n-OCH ₃ , - (OCH ₂ CH ₂ ) _m -OH, morpholinyl, piperidinyl and pyrrolidinyl, wherein n is a number from 1 to 6, wherein m is a number from 1 to 6, and wherein

R ^{10 is} hydrogen, C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl, benzyl or 4 to 8-membered heterocyclyl bonded via a carbon atom,

R ^{11 is} hydrogen or C ₁ -C ₃ -alkyl, or

R ¹⁰ and R ¹¹ 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 ¹² represents hydrogen, Ci-C ₃ alkyl, Ci-C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, benzyl, or bonded via a carbon atom 4- to 8-membered heterocyclyl, wherein alkyl may be substituted with 1 to 2 substituents independently selected from the group consisting of fluoro, hydroxy, amino, hydroxycarbonyl, Ci-C3-alkylamino, difluoromethyl, trifluoromethyl, - (OCH ₂ CH ₂ ) _n -OCH ₃ , - (OCH ₂ CH ₂ ) _m -OH , Morpholinyl, piperidinyl and pyrrolidinyl, wherein n is a number from 1 to 6, wherein m is a number from 1 to 6, and wherein cycloalkyl may be substituted with 1 to 2 substituents independently selected from the group consisting of oxo, fluoro, hydroxy, amino, Ci-C t-alkyl and Ci-C3-alkylamino, wherein alkyl and alkylamino in turn may be substituted with 1 to 5 fluorine substituents, and wherein heterocyclyl may be substituted with 1 to 2 substituents independently selected from the group consisting of oxo, fluoro, hydroxy, amino, hydroxycarbonyl, Ci-C t-alkyl , C ₁ -C ₃ -alkylamino, C ₁ -C 4 -alkoxycarbonyl, aminocarbonyl and C ₁ -C ₃ -alkylaminocarbonyl, in which alkyl and alkylamino in turn may be substituted by 1 to 5 fluorine substituents, and wherein heterocyclyl may additionally be substituted by 1 to 4 Substituents independently selected from the group consisting of fluorine and methyl,

R ^{13 is} hydrogen or C ₁ -C ₃ -alkyl, or

R ¹² and R ¹³ 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, wherein alkyl in turn may be substituted with a hydroxy substituent, is hydrogen or C ₁ -C ₃ -alkyl, C ₁ -C 4 -alkyl, C ₃ -C 6 -cycloalkyl, phenyl or a 5- to 7-membered heterocyclyl, or one of its salts, its solvates or the solvates of its 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 ^{5 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 consisting of hydroxycarbonyl and methoxy, or in which alkyl may be substituted by 1 to 7 fluorine substituents, or in which alkyl is substituted by one substituent hydroxycarbonyl and in which alkyl is additionally substituted by 1 to 6 fluorine substituents, represents hydrogen or fluorine, R ⁷ and R ⁸ 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 independently 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 fluorine substituents, or wherein alkyl is substituted with a substituent Hydroxycarbonyl and in which alkyl is additionally substituted by 1 to 6 substituents fluorine,

R ^{9 represents} hydrogen or fluorine, represents hydrogen, fluorine, methyl or methoxy, represents hydrogen, fluorine, chlorine, C 1 -C 4 -alkyl, methoxy or trifluoromethyl, represents hydrogen, represents amino, cyano, trifluoromethyl, ci C ₃ alkoxy, C ₃ alkylamino, C ₁ -C3- alkoxycarbonyl, -S (O) ₂ NR ¹⁰ R ^n, -C (0) NR ¹² R ¹³ or -NR ¹⁴ (CO) R ^15, wherein alkoxy is substituted with a substituent morpholinyl, and wherein

R ^{10 is} hydrogen, methyl, ethyl, C 3 -C 6 -cycloalkyl or 4 to 8-membered heterocyclyl bonded via a carbon atom,

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

R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle in which 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 ^{12 is} hydrogen, C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl or a 4 to 8-membered heterocyclyl bonded via a carbon atom, in which alkyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of C3-alkylamino, and morpholinyl, and wherein cycloalkyl may be substituted with 1 to 2 substituents independently selected from the group consisting of hydroxy, amino, Ci-C t-alkyl and _{Ci-C3-alkylamino,} and wherein heterocyclyl can be substituted with 1 to 2 substituents independently selected from the group consisting of C ₁ -C 4 alkyl, R ^{13 is} hydrogen, methyl or ethyl, or

R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle in which 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 ^{14 is} hydrogen, methyl or ethyl,

R ^{15 is} C 1 -C 4 -alkyl or a 5- to 7-membered heterocyclyl, or one of its salts, its solvates or the solvates of its salts.

3. A compound according to any one of claims 1 or 2, characterized in that for a group of the formula

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

R ^{5 is} 5-membered heteroaryl, where heteroaryl may be substituted by a substituent chlorine,

R is hydrogen,

R ⁷ and R ⁸ 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 a substituent oxo, represents hydrogen,

R ^{2 is} hydrogen,

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

R is hydrogen,

R ⁴ represents cyano, Trifluormefhyl, Ci-C ₃ alkoxy, C ₃ alkylamino, GC ₃ alkoxycarbonyl, -S (O) ₂ NR ¹⁰ R ^n, -C (0) NR ¹² R ¹³ or -NR ¹⁴ ( CO) R ¹⁵ , wherein alkoxy is substituted with a substituent morpholinyl, and wherein R ^{10 is} hydrogen or methyl, R ^{11 is} hydrogen or methyl, or

R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle,

R ^{12 is} C 4 -C 8 -alkyl or 4 to 8-membered heterocyclyl bonded via a carbon atom, in which alkyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of C 1 -C 3 -alkylamino and morpholinyl,

R ^{13 is} hydrogen, or

R ¹² and R ¹³ 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 ^{14 is} hydrogen,

R ^{15 is} a 5- to 7-membered heterocyclyl, or one of their salts, their solvates or the solvates of their salts. Compound according to one of claims 1 to 3, characterized in that R ^{1 represents} a group of formula

stands, where # is the point of attachment to the nitrogen atom, R ^{5 is} triazolyl or tetrazolyl, where triazolyl may be substituted by a substituent chlorine, R ^{6 is} hydrogen,

is 2,3-dihydro-l / i-indazol-6-yl or 2,3-dihydro-l / i-benzimidazol-5-yl, wherein 2,3-dihydro-l / i-indazol-6-yl and 2,3-dihydro-l / i-benzimidazol-5-yl may be substituted with a substituent Oxo, is hydrogen, is hydrogen, fluorine, Ci-Gt-alkyl or methoxy, is hydrogen, cyano, trifluoromethyl , C ₁ -C ₃ alkoxycarbonyl, -S (O) ₂ NR ¹⁰ R ⁿ or -C (O) NR ¹² R ¹³ , where

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

R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a morpholinyl or piperazinyl,

R ^{12 is} C 1 -C 3 -alkyl or heterocyclyl bonded via a carbon atom selected from the group consisting of pyrrolidinyl and piperidinyl, in which alkyl may be substituted by 1 to 2 substituents independently selected from the group consisting of C 1 -C 3 -alkylamino and morpholinyl . R ^{13 is} hydrogen, or

R ¹² and R ¹³ 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 methyl substituents, or one of their salts, solvates or solvates of their salts.

5. A process for the preparation of a compound of formula (I) or one of its salts, its solvates or the solvates of their salts according to claim 1, characterized in that a compound of formula

in which

R ¹ , R ² , R ³ , R ^3b and R ^{4 have} the meaning given in claim 1, is reacted with an acid. 6. A compound according to any one of claims 1 to 4 for the treatment and / or prophylaxis of diseases.

Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment and / or prophylaxis of diseases.

8. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment and / or prophylaxis of thrombotic or thromboembolic diseases.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 in combination with an inert, non-toxic, pharmaceutically suitable excipient.

10. Medicament according to claim 9 for the treatment and / or prophylaxis of thrombotic or thromboembolic diseases.

11. A method for controlling thrombotic or thromboembolic diseases in humans and animals by administering a therapeutically effective amount of at least one compound according to any one of claims 1 to 4, a

A medicament according to claim 9 or a medicament obtained according to claim 7 or 8.