EP3049408A1 - Dérivés de phénylalanine substitués - Google Patents

Dérivés de phénylalanine substitués

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Publication number
EP3049408A1
EP3049408A1 EP14772147.6A EP14772147A EP3049408A1 EP 3049408 A1 EP3049408 A1 EP 3049408A1 EP 14772147 A EP14772147 A EP 14772147A EP 3049408 A1 EP3049408 A1 EP 3049408A1
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EP
European Patent Office
Prior art keywords
amino
alkyl
substituted
methyl
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP14772147.6A
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German (de)
English (en)
Inventor
Ulrike RÖHN
Manuel ELLERMANN
Julia Strassburger
Astrid WENDT
Susanne Röhrig
Robert Alan WEBSTER
Martina Victoria Schmidt
Adrian Tersteegen
Kristin BEYER
Martina SCHÄFER
Anja BUCHMÜLLER
Christoph Gerdes
Michael Sperzel
Steffen SANDMANN
Stefan Heitmeier
Alexander Hillisch
Jens Ackerstaff
Carsten TERJUNG
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Bayer Pharma AG
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Bayer Pharma AG
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Priority to EP14772147.6A priority Critical patent/EP3049408A1/fr
Publication of EP3049408A1 publication Critical patent/EP3049408A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • 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
  • coagulation is initiated by binding of activated factor VIIa to tissue factor (TF).
  • TF tissue factor
  • 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.
  • PAR-1 tissue factor
  • 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.
  • 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.
  • tissue plasminogen activator tPA
  • 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.
  • systemic hypercoagulability can lead to consumption coagulopathy in the context of disseminated intravascular coagulation.
  • 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].
  • heparin 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.
  • 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.
  • 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.
  • 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
  • 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 pyrrolidin
  • 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
  • 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 fluor
  • R 13 is hydrogen or C 1 -C 3 -alkyl
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 am
  • 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.
  • the present invention also includes prodrugs of the compounds of the invention.
  • 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 structural element of the tranexamic acid amide for example N - [(trans-4- ⁇ [(ieri-butoxycarbonyl) amino] methyl ⁇ cyclohexyl) carbonyl and iraws-4- (aminomethyl) cyclohexyl] carbonyl ⁇ .
  • this also applies to the structural element of trans- - hydroxycyclohexylamine, for example in (ira " ⁇ - 4-hydroxycyclohexyl) carbamoyl.
  • 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.
  • 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.
  • L-phenylalanine derivatives are introduced as central building blocks in the synthesis.
  • 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.
  • the separation of the enantiomers is directly after the coupling of the L-phenylalanine intermediates with the amine H 2 NR 1 .
  • treatment 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.
  • therapy is understood to be synonymous with the term “treatment”.
  • prevention means 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.
  • 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.
  • 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-benzothi
  • 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.
  • 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,
  • 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
  • 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 -
  • 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
  • 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 are heterocyclyl, and their salts, their solvates and the solvates of their salts.
  • 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.
  • R 1 is a group of the formula
  • 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
  • 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
  • R 5 is triazolyl or tetrazolyl, where triazolyl may be substituted by a substituent chlorine
  • R 6 is hydrogen
  • 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
  • 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.
  • 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.
  • R 5 is triazolyl or tetrazolyl, where triazolyl may be substituted by a substituent chlorine, and
  • R 6 is hydrogen.
  • 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.
  • 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.
  • 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.
  • R 3 is hydrogen, fluorine, C 1 -C 4 -alkyl or methoxy.
  • 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
  • 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 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
  • 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.
  • R 1 , R 2 , R 3 and R 3b have the abovementioned meaning, with compounds of the formula
  • R 12 and R 13 are as defined above, are reacted in the presence of a dehydrating reagent, or
  • R 1 and R 2 have the meaning given above, and
  • X 1 is bromine or iodine, with compounds of the formula
  • R 3a , R 3b and R 4 have the abovementioned meaning
  • Q 1 is -B (OH) 2, a boronic acid ester, preferably boronic acid pinacol ester, or is reacted under Suzuki coupling conditions, or
  • 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.
  • 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 ⁇ , ⁇ '-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 perch
  • 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.
  • alkali carbonates e.g. Sodium or potassium carbonate
  • hydrogen carbonate e.g. Sodium or potassium carbonate
  • 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.
  • halogenated hydrocarbons such as dichloromethane or trichloromethane
  • hydrocarbons such as benzene
  • 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.
  • 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 ',
  • 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.
  • ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane
  • hydrocarbons such as benzene, xylene or toluene
  • carboxamides such as dimethylformamide or dimethylacetamide
  • alkylsulfoxides such as dimethylsulfoxide, or N-
  • 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.
  • 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
  • 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
  • R 3 and R 3b have the abovementioned meaning
  • 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.
  • 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.
  • 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,
  • 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.
  • 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:
  • 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
  • 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.
  • 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.
  • 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.
  • 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 ( ⁇ ) 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 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.
  • 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.
  • 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.
  • ACS acute coronary syndrome
  • STEMI myocardial infarction with ST segment elevation
  • non-STEMI 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 such as angioplasty,
  • 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.
  • cardiogenic thromboembolism such as brain ischemia, stroke and systemic thromboembolism and ischaemia
  • 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.
  • DIC disseminated intravascular coagulation
  • Thromboembolic complications also occur in microangiopathic hemolytic anemias, extracorporeal blood circuits such as hemodialysis, and heart valve prostheses.
  • 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.
  • 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
  • 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.
  • the compounds according to the invention are also suitable for the prophylaxis and / or treatment of pulmonary hypertension.
  • 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).
  • WHO World Health Organization
  • CTEPH chronic thromboembolism
  • 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.
  • Idiopathic Pulmonary Arterial Hypertension Idiopathic Pulmonary Arterial Hypertension (IPAH, formerly referred to as Primary Pulmonary Hypertension), Fa
  • 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 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.
  • the substances according to the invention are also suitable for the treatment of pulmonary and hepatic fibroses.
  • 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.
  • SIRS infectious disease and / or systemic inflammatory syndrome
  • ARDS septic organ dysfunction
  • ALI Acute lung Injury
  • septic shock and / or septic organ failure Acute lung injury syndrome
  • DIC Dispersed Intravascular Coagulation
  • Consumption Coagulopathy hereinafter referred to as "DIC”
  • endothelial damage can result in increased vascular permeability and leakage of fluid and proteins into the extravasal space.
  • organ failure e.g., renal failure, liver failure, respiratory failure, CNS deficits and cardiovascular failure
  • multiple organ failure may occur.
  • DIC DIC
  • the surface of damaged endothelial cells, foreign body surfaces or extravasated extravascular tissue causes massive activation of the coagulation system.
  • coagulation occurs in small vessels of various organs with hypoxia and subsequent organ dysfunction. This can be prevented by the compounds of the invention.
  • coagulation factors e.g., Factor X, prothrombin, and fibrinogen
  • platelets are consumed, which lowers the blood's ability to coagulate and cause severe bleeding.
  • 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.
  • 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.
  • 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
  • HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors
  • lovastatin Mevacor
  • simvastatin Zocor
  • 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, pind
  • Plasminogen activators thrombolytics / fibrinolytics
  • 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
  • UH tissue plasminogen activator
  • LMWH low molecular weight heparin
  • tinzaparin certoparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, danaparoid, semuloparin (AVE 5026), adomiparin (Ml 18) and EP-42675 / ORG42675
  • DTI direct thrombin inhibitors
  • Fibrinogen receptor antagonists such as abciximab, eptifibatide, tirofiban, lamifiban, lefradafiban and fradafiban; ⁇ As well as antiarrhythmics;
  • 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,
  • 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.
  • the compounds according to the invention can be administered in suitable administration 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
  • 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).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • 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.
  • 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.
  • 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
  • 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.
  • inventive compound preferably together with one or more inert non-toxic, pharmaceutically suitable excipient, as well as their use for the purposes mentioned above.
  • Method 1 Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 ⁇ 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 Instrument: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 ⁇ 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 Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 ⁇ 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 Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 ⁇ 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 ⁇ ; DAD scan: 210-400 nm; ELSD.
  • Method 5 Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH Cl 8 1.7 ⁇ 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 ⁇ ; DAD scan: 210-400 nm; ELSD.
  • Method 6 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 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 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 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 Instrument: Waters autopurification system SQD; Column: Waters XBrigde C18 5 ⁇ 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 ⁇ ; DAD scan: 210-400 nm.
  • Method 11 Instrument: Waters autopurification system SQD; Column: Waters XBrigde C18 5 ⁇ 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 ⁇ ; DAD scan: 210-400 nm.
  • Method 12 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 Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 ⁇ 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 Instrument MS: Waters (Micromass) Quattro Micro; Instrument HPLC: Agilent 1100 series; Column: YMC-Triart C18 3 ⁇ 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 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 TM initiator.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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
  • Example 20A The butyl ⁇ [iraws ⁇ (2 ⁇ -3 2'-memyl) ⁇
  • 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
  • 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.
  • 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.
  • 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
  • Example 27A is Butyl 4 - [( ⁇ 4 '- [(2 ⁇ -2- ⁇ [(1 ⁇ - ⁇ -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
  • 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
  • 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.
  • 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 ⁇ ) 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.
  • 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.
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Example 64A methyl 4 '- [(2 l r S) -2- ⁇ [(ira " ⁇ -4- ⁇ [(feri-butoxycarbonyl) amino] methyl ⁇ cyclohexyl) carbonyl] amino ⁇ - 3-oxo-3- ⁇ [4- (2H-tetrazol-5-yl) -phenyl] -amino ⁇ -propyl] -4,6-dimethylbiphenyl-3-carboxylate
  • 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-
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Example 77A Methyl 3- ⁇ 5- [4 - ( ⁇ 4-bromo / V - [(1 ⁇ - ⁇ -4- ⁇ [(ieri-butoxycarbonyl) amino] methyl ⁇ cyclohexyl) carbonyl] -L-phenylalanyl ⁇ amino ) phenyl] - IH-l, 2,4-triazol-3-yl ⁇ -2,2,3,3-tetrafluoropropanoate
  • 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
  • Example 83A The butyl ⁇ [ira-i- ( ⁇ (2 ⁇ -3,5 '- (dimethylsulfamoyl) -2'-methylbiphenyl
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • Example 46 ira " ⁇ -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
  • 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 ⁇ to 0.0078 ⁇ , resulting final concentrations in the test: 50 ⁇ to 0.00013 ⁇ ). 1 ⁇ each of the diluted substance solutions are placed in the wells of white microtiter plates from Greiner (384 wells). Subsequently, 20 ⁇ 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 ⁇ factor XIa from Kordia (0.45 nM in assay buffer) are added successively.
  • 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
  • 20 ⁇ factor XIa from Kordia (0.45 nM in assay buffer
  • test substances are tested for their inhibition of other human serine proteases, such as factor Xa, trypsin and plasmin.
  • factor Xa 1.3 nmol / l of Kordia
  • trypsin 83 mU / ml of Sigma
  • 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 ⁇ / ⁇ Boc-Ile-Glu-Gly-Arg-AMC from Bachem for factor Xa and trypsin, 50 ⁇ / ⁇ 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)
  • Thrombogram thrombin generation assay according to Hemker
  • Octaplas® from Octapharma
  • 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 ⁇ M 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 ⁇ of the test substance or the solvent, 76 ⁇ plasma and 20 ⁇ PPP reagent or thrombin calibrator are incubated for 5 min at 37 ° C. After addition of 20 ⁇ M 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.
  • a fluorometer Fluoroskan Ascent
  • 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.
  • human and animal plasma eg mouse, rat, rabbit, porcine and canine plasma.
  • 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 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
  • 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.
  • TF tissue factor
  • tPA tissue plasminogen activator
  • 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.
  • the ear bleeding time is determined.
  • 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 ⁇ ⁇ 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.
  • 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.
  • 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.
  • 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.
  • tissue plasminogen activator tPA

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Abstract

L'invention concerne des dérivés de phénylalanine substitués et des procédés pour leur préparation, ainsi que leur utilisation pour la préparation de médicaments pour le traitement et/ou la prophylaxie de maladies, notamment de maladies cardiovasculaires et/ou de fortes pertes sanguines péri-opératoires.
EP14772147.6A 2013-09-26 2014-09-24 Dérivés de phénylalanine substitués Withdrawn EP3049408A1 (fr)

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EP13186058 2013-09-26
PCT/EP2014/070315 WO2015044169A1 (fr) 2013-09-26 2014-09-24 Dérivés de phénylalanine substitués
EP14772147.6A EP3049408A1 (fr) 2013-09-26 2014-09-24 Dérivés de phénylalanine substitués

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JP6479763B2 (ja) 2013-03-25 2019-03-06 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ 第ｘｉａ因子阻害剤としての置換アゾール含有のテトラヒドロイソキノリン
NO2760821T3 (fr) 2014-01-31 2018-03-10
WO2015116886A1 (fr) 2014-01-31 2015-08-06 Bristol-Myers Squibb Company Macrocycles à groupes hétérocycliques p2' servant d'inhibiteurs du facteur xia
ES2714283T3 (es) 2014-09-04 2019-05-28 Bristol Myers Squibb Co Macrociclos de diamida que son inhibidores de FXIa
US9453018B2 (en) 2014-10-01 2016-09-27 Bristol-Myers Squibb Company Pyrimidinones as factor XIa inhibitors
US10344039B2 (en) 2015-10-29 2019-07-09 Merck Sharp & Dohme Corp. Macrocyclic spirocarbamate derivatives as factor XIa inhibitors, pharmaceutically acceptable compositions and their use
EP3500556B1 (fr) 2016-08-22 2023-08-02 Merck Sharp & Dohme LLC Dérivés pyridine-1-oxyde et leur utilisation en tant qu'inhbiteurs du facteur xia

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US8466295B2 (en) * 2005-12-14 2013-06-18 Bristol-Myers Squibb Company Thiophene derivatives as factor XIa inhibitors

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