EP2044031A1 - 2-(hétéroaryl)alkylindazole-6-phényl- et -thiénylméthylamide comme inhibiteurs de la thrombine - Google Patents

2-(hétéroaryl)alkylindazole-6-phényl- et -thiénylméthylamide comme inhibiteurs de la thrombine

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Publication number
EP2044031A1
EP2044031A1 EP07764989A EP07764989A EP2044031A1 EP 2044031 A1 EP2044031 A1 EP 2044031A1 EP 07764989 A EP07764989 A EP 07764989A EP 07764989 A EP07764989 A EP 07764989A EP 2044031 A1 EP2044031 A1 EP 2044031A1
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Prior art keywords
substituents
alkyl
substituted
group
phenyl
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EP07764989A
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German (de)
English (en)
Inventor
Stephan Siegel
Dirk Schneider
Anja BUCHMÜLLER
Elke Dittrich-Wengenroth
Christoph Gerdes
Mark Jean Gnoth
Stefan Heitmeier
Martin c/o Bayer Healthcare LLC HENDRIX
Ulrich Rester
Uwe Saatmann
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Bayer Pharma AG
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Bayer Healthcare AG
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    • 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
    • C07D403/06—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 carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
    • C07D231/52—Oxygen atom in position 3 and nitrogen atom in position 5, or vice versa
    • 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
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention relates to substituted indazoles and processes for their preparation and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular of cardiovascular diseases, preferably of thromboembolic diseases.
  • Blood coagulation is a protective mechanism of the organism, with the help of which defects in the vessel wall can be "sealed” quickly and reliably, thus avoiding or minimizing blood loss and organ damage after injury in the intact organism
  • thrombocytes as well as the coagulation system, in which an enzymatic cascade of complex reactions of plasma proteins is involved, involving numerous coagulation factors, each of which, once activated, converts the next inactive precursor into its active form cleaves the activated serine protease factor Xa (FXa) or the FXa-containing prothrombinase complex finally prothrombin to thrombin, which in turn cleaves the soluble fibrinogen and converted into the insoluble form of fibrin, thus forming the actual blood clot t.
  • FXa activated serine protease factor Xa
  • prothrombin prothrombin
  • thrombin is a potent trigger of platelet aggregation via the proteolytic activation of platelet receptors, which also makes a significant contribution to hemostasis.
  • Other functions of thrombin that contribute to blood coagulation are the stabilization of the fibrin clot via the activation of the factor XHI, the enhancement of the coagulation reaction via the activation of cofactors V and VIII, and the inhibition of fibrinolysis via the activation of procarboxypeptidase B (syn. TAFI ).
  • proteolytic activation of the protein C thrombin can counteract an excessive activity of the coagulation cascade and thus an excessive hemostasis (thrombosis)
  • heparins are used which are administered parenterally or subcutaneously. Due to more favorable pharmacokinetic properties, although lower molecular weight heparin is increasingly preferred today, it is also not possible hereby to avoid the known disadvantages described below which arise during the therapy with heparin. Thus, heparin is orally ineffective and has only a comparatively low half-life. Since heparin simultaneously inhibits several factors of the blood coagulation cascade, there is an unselective effect. In addition, there is a risk of bleeding, in particular cerebral hemorrhage and bleeding may occur in the gastrointestinal tract, and it can lead to thrombocytopenia, alopecia medicomentosa or osteoporosis.
  • 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 36 to 48 hours). Although the compounds can be administered orally, because of the high risk of bleeding and the narrow therapeutic index but a complex individual attitude and observation of the patient is necessary. In addition, other side effects such as gastrointestinal disturbances, hair loss and skin necrosis are described.
  • EP-A 0 574 174 describes inter alia indazoles as angiotensin II antagonists for the treatment of hypertension.
  • An object of the present invention is therefore to provide novel compounds as thrombin inhibitors for the treatment of cardiovascular diseases, in particular of thromboembolic diseases, in humans and animals, which have a large therapeutic range.
  • the invention relates to compounds of the formula
  • R 6 is C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, phenyl, 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl,
  • cycloalkyl and heterocyclyl can be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of halogen, oxo, Ci-C 4 alkyl, C) -C 4 alkoxy, C r C 4 alkylthio , Ci-C 4 alkylamino, Ci-C4-alkylcarbonyl and C 2 -C 4 - alkoxycarbonyl,
  • phenyl and heteroaryl may be substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl, Ci-C 4 alkyl 5 Ci-C 4 alkoxy, QQ alkylthio, Ci-C 4 alkylamino, Ci-C 4 alkylcarbonyl, C] -C 4 alkoxycarbonyl and CRQ-alkylaminocarbonyl,
  • R 7 is hydrogen, C r C 6 alkyl, Ci-C 4 alkylamino, Ci-C 4 alkoxycarbonyl, 5- to 7-membered heterocyclyl, 5- to 7-membered heterocyclylcarbonyl or 5- or 6- membered heteroaryl .
  • alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, QC 4 alkoxy, QC 4 - alkylamino, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylcarbonyl, QC 4 -alkoxycarbonyl, QC 4 -alkylaminocarbonyl, C 1 -C 4 -alkylcarbonylamino, C 3 -C 9 -cycloalkyl, phenyl, 5- to 7-membered heterocyclyl and 5- to 6-membered heteroaryl,
  • cycloalkyl and heterocyclyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, hydroxycarbonyl, aminocarbonyl, oxo, QC 4 alkyl, QC 4 - alkoxy, C r C 4 alkylthio, C r C 4 alkylamino, C 1 -C 4 alkylcarbonyl, QC 4 -
  • phenyl and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano,
  • heterocyclyl and heterocyclylcarbonyl may be substituted with 1 to 3
  • Substituents wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, hydroxycarbonyl, aminocarbonyl, oxo, C] -C 4 alkyl, C 1 -C 4 -alkoxy, QC 4 - alkylthio, Ci-C 4 alkylamino, Ci-C 4 alkylcarbonyl, C] -C 4 -alkoxycarbonyl and Q C 4 alkylaminocarbonyl,
  • heteroaryl may be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, C r C 4 alkyl, C r C 4 alkoxy, C, - C 4 alkylthio, QC 4 -
  • R 8 is C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, phenyl, 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl,
  • cycloalkyl and heterocyclyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, oxo, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy,
  • phenyl and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from
  • R9 is Ci-C ⁇ alkyl, Ci-C 4 alkylamino, C] -C 4 alkoxycarbonyl, 5- to 7-membered heterocyclyl, 5- to 7-membered heterocyclylcarbonyl or 5- or 6-membered
  • alkyl may be substituted with a substituent, whereby the substituent is selected from the group consisting of hydroxy, C] -C4 alkoxy, Cj-C 4 - alkylamino, Ci-C 4 alkylthio, C r C 4 alkylcarbonyl, C] -C 4 -alkoxycarbonyl, Cj-C 4 -alkylaminocarbonyl, C 1 -C 4 -alkylcarbonylamino, C 3 -C 8 -cycloalkyl, phenyl, 5-bis
  • cycloalkyl and heterocyclyl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, hydroxy, amino, hydroxycarbonyl, aminocarbonyl, oxo, C 1 -C 4 -alkyl, C 1 -C 4 -
  • phenyl and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, Trifluoromethyl, trifluoromethoxy, trifluoromethylthio, Ci-C 4 alkyl, Ci-C 4 - alkoxy, Ci-C 4 alkylthio, C] -C4 alkylamino, Ci-C4-alkylcarbonyl and Q C 4 alkoxycarbonyl,
  • heterocyclyl and heterocyclylcarbonyl may be substituted with 1 to 3
  • Substituents wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, hydroxycarbonyl, aminocarbonyl, oxo, Ci-C 4 alkyl, C] -C 4 alkoxy, QC 4 - alkylthio, Ci-C 4 Alkylamino, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl and C 1 -C 4 -alkylaminocarbonyl,
  • heteroaryl may be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoro- methylthio, C 1 -C 4 -alkyl, C r C 4 alkoxy, C r C 4 alkylthio, Ci-C 4 alkylamino, Q
  • R 2 is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, QC 3 -alkyl, C r C 3 -alkoxy, C r C 3 -alkylthio or cyclopropyl,
  • alkyl, alkoxy, alkylthio and cyclopropyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen,
  • R 3 is hydrogen or C r C 4 alkyl
  • R 4 is hydrogen or C r C 4 alkyl
  • R 3 and R 4 together with the carbon atom to which they are attached form a cyclopropyl ring or a cyclobutyl ring,
  • R 5 is phenyl, 2-thienyl or 3-thienyl, wherein phenyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, methyl, ethynyl, methoxy and 1,2,4-triazol-1-yl,
  • methoxy may be substituted with a substituent, wherein the substituent is selected from the group consisting of Ci-C 4 alkoxycarbonyl,
  • 2-thienyl and 3-thienyl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, methyl, ethynyl and methoxy,
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, as well as the compounds encompassed by formula (I), hereinafter referred to as embodiment (e) and their salts, solvates and solvates of the salts, as far as the compounds of formula (I) mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
  • the present invention encompasses all tautomeric forms.
  • Salts which are preferred 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, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoro- acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms.
  • alkali metal salts for example sodium and potassium salts
  • alkaline earth salts for example calcium and magnesium salts
  • ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms.
  • Atoms such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and choline.
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but which are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically).
  • Alkoxycarbonvh Alkylaminocarbonyl and alkylcarbonylamino are a linear or branched alkyl radical having 1 to 6, preferably having 1 to 4 carbon atoms, by way of example and preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl and n-hexyl.
  • Alkoxy is exemplary and preferably methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy and tert-butoxy.
  • Alkylamino represents an alkylamino radical having one or two (independently selected) alkyl substituents, by way of example and by way of preference methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, N, N-dimethylamino, NN- Diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-N-propylamino, N-tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl- N-methylamino.
  • C 1 -C 3 -alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms. or for a
  • Alkylthio is exemplified and preferably methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.
  • Alkylcarbonyl is exemplified and preferably methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl and tert-butylcarbonyl.
  • Alkoxycarbonyl is exemplified and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
  • Alkylaminocarbonyl is an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents, by way of example and by way of preference for methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N, N-dimethylaminocarbonyl, NN- Diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl-N-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-Nn-pentylaminocarbonyl and Nn hexyl-
  • C 1 -C 5 -alkylaminocarbonyl is, for example, a monoalkylaminocarbonyl radical having 1 to 3 carbon atoms or a dialkylamino-carbonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.
  • Alkylcarbonylamino is, by way of example and by way of preference, methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino and tert-butylcarbonylamino.
  • Cycloalkyl represents a mono- or bicyclic cycloalkyl group having generally 3 to 8, preferably 3, 5 or 6 carbon atoms, by way of example and preferably cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Cycloalkylaminocarbonyl is by way of example and preferably cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl and cyclohexylaminocarbonyl.
  • Heterocvclyl is a monocyclic, heterocyclic radical having usually 5 to 7 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series ⁇ , O, S, SO, SO 2 , wherein a nitrogen atom is also a ⁇ Oxide can form.
  • the heterocyclyl radicals may be saturated or partially unsaturated.
  • Heteroaryl is an aromatic, monocyclic radical having usually 5 or 6 ring atoms and up to 4 heteroatoms from the series S, O and N, where a nitrogen atom can also form an N-oxide, by way of example and preferably for thienyl, furyl, pyrrolyl , Thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl.
  • Halogen is fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
  • the end point of the line next to each one * is not a carbon atom or a CH 2 group but is part of the bond to the atom to which R 1 is attached is.
  • R 6 is C r C 6 alkyl, C 3 -C 8 cycloalkyl, phenyl, 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl,
  • cycloalkyl and heterocyclyl can be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, oxo, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C r C 4 alkylamino, Ci-C4-alkylcarbonyl and C, -C 4 - alkoxycarbonyl,
  • phenyl and heteroaryl may be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl, Ci-C 4 alkyl, C] -C 4 alkoxy, C 1 -C 4 -AUCyIIhIo, C] -C 4 alkylamino, C] -C 4 alkylcarbonyl, C] -C 4 alkoxycarbonyl and C] -C 4 alkylaminocarbonyl,
  • C 1 -C 6 -alkyl is hydrogen, C 1 -C 6 -alkyl, C 5 -C 4 -alkylamino, C 1 -C 4 -alkoxycarbonyl, 5- to 7-membered heterocyclyl, 5- to 7-membered heterocyclylcarbonyl or 5- or 6-membered heteroaryl .
  • alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, C] -C 4 alkoxy, C 1 -C 4 -
  • cycloalkyl and heterocyclyl can be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of halogen, oxo, C 1 -C 4 - alkyl, C 1 -C 4 -alkoxy, C r C 4 - Alkylthio, C 1 -C 4 -alkylamino, C 1 -C 4 -alkylcarbonyl and C 1 -C 4 -alkoxycarbonyl,
  • phenyl and heteroaryl may be substituted with 1 to 3
  • substituents where the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, C 1 -C 4 -alkyl, Cj-C 4 - alkoxy, C] -C4 alkylthio, C] - C 4 alkylamino, C 1 -C 4 alkylcarbonyl and Cr C 4 alkoxycarbonyl,
  • heterocyclyl and heterocyclylcarbonyl can be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, oxo, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C] -C 4 alkylthio, C r C 4 alkylamino, Cj-Q-alkylcarbonyl, and C 1 -C 4 -
  • heteroaryl may be substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, C r C 4 alkyl, Ci-C 4 alkoxy, C r C 4- alkylthio, C, -C 4 -
  • R 8 is C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, phenyl, 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl,
  • cycloalkyl and heterocyclyl can be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of halogen, oxo, Ci-C 4 -alkyl, Ci-C 4 alkoxy, C r C 4 alkylthio, Ci-C 4 alkylamino, Ci-C4-alkylcarbonyl and C r C 4 - alkoxycarbonyl,
  • phenyl and heteroaryl may be substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, aminocarbonyl, Ci-C 4 alkyl, Ci-C 4 alkoxy, C r C 4 alkylthio, Ci-C 4 alkylamino, Ci-C 4 alkylcarbonyl, C] -C 4 alkoxycarbonyl and Ci-C4-alkylaminocarbonyl,
  • R 9 is C 1 -C 6 -alkyl, C 1 -C 4 -HCyIaHUnO, C 1 -C 4 -alkoxycarbonyl, 5- to 7-membered
  • Heterocyclyl 5- to 7-membered heterocyclylcarbonyl or 5- or 6-membered heteroaryl
  • alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of hydroxy, C r C 4 alkoxy, Ci-C 4 - alkylamino, C r C 4 alkylthio ) C r C 4 alkylcarbonyl, dC 4- alkoxycarbonyl, CpC 4 -
  • Alkylaminocarbonyl C 1 -C 4 -alkylcarbonylamino, C 3 -C 8 -cycloalkyl, phenyl, 5- to 7-membered heterocyclyl and 5- to 6-membered heteroaryl,
  • cycloalkyl and heterocyclyl may be substituted with 1 to 3
  • Substituents wherein the substituents are independently selected from the group consisting of halogen, oxo, Ci-C 4 - Alkyl, C 1 -C 4 -AJkOXy, C r C 4 alkylthio, C r C 4 alkylamino, C r C 4 - alkylcarbonyl and Ci-C 4 alkoxycarbonyl,
  • phenyl and heteroaryl may be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, C r C 4 alkyl, C 1 -C 4 - alkoxy, Ci-C 4 alkylthio, Ci-C 4 alkylamino, C r C 4 alkylcarbonyl and C 1 - C 4 alkoxycarbonyl,
  • heterocyclyl can be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of halogen, oxo, Ci-C 4 alkyl, C] -C 4 alkoxy, C 4 alkylthio, C 1 -C 4 - alkylamino, Ci-C4-alkylcarbonyl and Ci-C 4 alkoxycarbonyl,
  • heteroaryl may be substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, Ci-C 4 alkyl, C r C 4 alkoxy, Ci-C 4 -alkylthio, C 1 -C 4 -alkylamino, C 1 -C 4 -alkylcarbonyl and C 1 -C 4 -alkoxycarbonyl,
  • R 2 is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C r C 3 -alkylthio or cyclopropyl,
  • alkyl, alkoxy, alkylthio and cyclopropyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen,
  • R 3 is hydrogen or C r C 4 alkyl
  • R 4 is hydrogen or C r C 4 alkyl
  • R 3 and R 4 together with the carbon atom to which they are attached form a cyclopropyl ring or a cyclobutyl ring,
  • R 5 is phenyl, 2-thienyl or 3-thienyl
  • phenyl, 2-thienyl and 3-thienyl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, methyl, ethynyl and methoxy,
  • R 6 is C 1 -C 6 -alkyl, phenyl, 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl,
  • heterocyclyl may be substituted with 1 to 3 substituents, wherein the
  • Substituents independently of one another are selected from the group consisting of halogen, oxo, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkylamino,
  • phenyl and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from
  • R 7 is hydrogen, C r C 6 alkyl, Ci-Q-AJkylamino, C r C 4 alkoxycarbonyl, 5- to 7-membered heterocyclyl or is 5- to 7-membered heterocyclylcarbonyl, wherein alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of phenyl, 5- to 7-membered heterocyclyl and 5- to 6-membered heteroaryl,
  • heterocyclyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from
  • phenyl and heteroaryl may be substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, Ci-C 4 alkyl, Ci-C 4 alkoxy, Ci -C 4 alkylamino, Ci-C4-alkylcarbonyl and Ci-C 4 alkoxycarbonyl,
  • heterocyclyl and heterocyclylcarbo ⁇ yl can be substituted by 1 to 3
  • Substituents wherein the substituents are independently selected from the group consisting of halogen, oxo, Ci-C 4 alkyl, C] -C 4 alkoxy, C r C 4 alkylamino, Ci-C 4 alkylcarbonyl and Ci-C 4- alkoxycarbonyl,
  • heterocyclyl can be substituted with 1 to 3 substituents, where the substituents are independently selected from the group consisting of halogen, oxo, Ci-C 4 alkyl, Ci-C 4 -alkoxy and C 1 -C 4 -AUCyIaTnInO,
  • phenyl and heteroaryl can be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, amino carbonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy , C] -C 4 alkylamino and Ci-C 4 alkylamino carbonyl, R9 is Ci-COE-alkyl, Ci-C 4 alkylamino, C r C 4 alkoxycarbonyl, 5- to 7-membered heterocyclyl or 5- to 7-membered heterocyclylcarbonyl,
  • alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of phenyl, 5- to 7-membered heterocyclyl and 5- to 6-membered heteroaryl,
  • heterocyclyl may be substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, oxo, Ci-Q-Alkvl, Ci-C 4 alkoxy, Ci-C 4 - alkylamino, Ci-C 4- alkylcarbonyl and C 1 -C 4 -alkoxycarbonyl,
  • phenyl and heteroaryl may be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, Ci-C 4 -alkyl, C r C 4 alkoxy, C] - C 4 alkyl amino, Ci-C4-alkylcarbonyl and C] -C 4 alkoxycarbonyl,
  • heterocyclyl and heterocyclylcarbonyl can be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of halogen, oxo, C r C 4 alkyl, C r C 4 alkoxy, Ci-C 4 alkylamino, C 1 -C 4 -alkylcarbonyl and C 1 -C 4 -alkoxycarbonyl,
  • R 2 is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, C] -C3 alkyl, Ci-C 3 alkoxy, C 1 -C 3 -AUCyItMo or cyclopropyl,
  • R 3 is hydrogen or methyl
  • R 4 is hydrogen or methyl
  • R 3 and R 4 together with the carbon atom to which they are attached form a cyclopropyl ring
  • R 5 is phenyl, 2-thienyl or 3-thienyl, where phenyl, 2-thienyl and 3-thienyl may be substituted by 1 to 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, methyl, ethynyl and methoxy,
  • R 6 is Ci-C 6 alkyl, phenyl, 5- to 7-membered heterocyclyl or 5- or 6-membered
  • heterocyclyl can be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of oxo and C 1 -C 4 -alkyl,
  • phenyl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, aminocarbonyl, C 1 -C 4 -alkyl and CpC 4 -alkoxy,
  • R 7 is hydrogen, C r C 6 alkyl, Ci-C 4 alkylamino, Q-CrAlkoxycarbonyl, 5- to 7-membered heterocyclylcarbonyl to 7-membered heterocyclyl or 5-,
  • alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of phenyl, 5- to 7-membered heterocyclyl and 5- to 6-membered heteroaryl,
  • heterocyclyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from
  • phenyl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy,
  • heterocyclyl and heterocyclylcarbonyl can be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of oxo and C 1 -C 4 -alkyl,
  • R 8 is Ci-C 6 - alkyl, phenyl, 5- to 7-membered heterocyclyl or 5- or 6-membered
  • heterocyclyl can be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of oxo and C 1 -C 4 -alkyl,
  • phenyl and heteroaryl may be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of halogen, aminocarbonyl, Ci-C 4 alkyl and C 1 -C 4 -alkoxy,
  • R 9 is C 6 alkyl, C r C 4 alkylamino, Ci-C 4 alkoxycarbonyl, 5- to 7-membered heterocyclyl or 5- to 7-membered heterocyclylcarbonyl,
  • alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of phenyl, 5- to 7-membered heterocyclyl and 5- to 6-membered heteroaryl,
  • heterocyclyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from
  • phenyl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents are independently of one another are selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy,
  • heterocyclyl and heterocyclylcarbonyl can be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of oxo and C 1 -C 4 -alkyl,
  • R 2 is hydrogen, chlorine, trifluoromethyl, methyl, ethyl or methoxy
  • R 3 is hydrogen or methyl
  • R 4 is hydrogen or methyl
  • R 5 is phenyl or 2-thienyl
  • phenyl and 2-thienyl are substituted with a substituent, wherein the substituent is selected from the group consisting of chlorine, fluorine, methyl, ethynyl and methoxy,
  • R 6 is phenyl, 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl
  • heterocyclyl may be substituted by a substituent oxo
  • phenyl and heteroaryl may be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of halogen, aminocarbonyl, C r C 4 alkyl and C 1 -C 4 -alkoxy,
  • R 7 is hydrogen, C r C 6 alkyl, Ci-C 4 alkylamino, dC 4 alkoxycarbonyl, 5- to 7-membered heterocyclyl or 5- to 7-membered heterocyclylcarbonyl,
  • alkyl may be substituted with a substituent, wherein the substituent is selected from the group consisting of phenyl, 5- to 7-membered heterocyclyl and 5- to 6-membered heteroaryl,
  • heterocyclyl may be substituted with a substituent oxo
  • phenyl and heteroaryl may be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of halogen, C] -C 4 - alkyl and Ci-C 4 alkoxy,
  • heterocyclyl and heterocyclylcarbonyl may be substituted by a substituent oxo
  • R 8 is phenyl, 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl
  • heterocyclyl may be substituted by a substituent oxo
  • phenyl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of halogen, aminocarbonyl, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy,
  • R 9 is C 6 alkyl, C r C 4 alkylamino, C r C 4 alkoxycarbonyl, 5- to 7-membered
  • heterocyclyl may be substituted with a substituent oxo
  • phenyl and heteroaryl may be substituted by 1 to 3 substituents, where the substituents are independently selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy,
  • heterocyclyl and heterocyclylcarbonyl may be substituted by a substituent oxo
  • R 2 is hydrogen or methoxy
  • R 3 is hydrogen
  • R 4 is hydrogen
  • R 5 is phenyl or 2-thienyl
  • phenyl and 2-thienyl are substituted with a substituent, wherein the substituent is selected from the group consisting of chlorine, fluorine and methyl,
  • R 2 is hydrogen, chlorine, trifluoromethyl, methyl, ethyl or methoxy.
  • the invention further provides a process for the preparation of the compounds of the formula (I), wherein the process
  • R 1 and R 2 have the abovementioned meaning
  • R 3 , R 4 and R 5 have the abovementioned meaning
  • R 2 , R 3 , R 4 and R 5 have the abovementioned meaning
  • R 1 has the meaning given above, and
  • X is halogen, preferably bromine or chlorine
  • R, R, R 4 and R have the abovementioned meaning
  • R 1 has the meaning given above
  • 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 room temperature at normal pressure.
  • Suitable dehydrating here, for example, carbodiimides are suitable, such as N 1 N'-diethyl-, N, N'-dipropyl-, N, N'-diisopropyl-, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylamino-isopropyl) -N ' ethylcarbodiimide hydrochloride (EDC) (optionally in the presence of pentafluorophenol (PFP)), N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl 5-phenyl-1, 2-oxazolium-3-sulphate or 2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compounds such as
  • 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.
  • the condensation is carried out with diisopropylethylamine or 4-dimethylaminopyridine.
  • Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, or other solvents such as omitromethane, dioxane, dimethylformamide, dimethyl sulfoxide or acetonitrile. It is likewise possible to use mixtures of the solvents. Particularly preferred is dichloromethane or dimethylformamide.
  • the reaction according to process [B] is generally carried out in inert solvents, if appropriate in the presence of a base, if appropriate in the presence of potassium iodide, preferably in a temperature range from room temperature to reflux of the solvents under normal pressure.
  • Inert solvents are, for example, halogenated hydrocarbons, such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents, such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile; preference is given to tetrahydrofuran, methylene chloride, Acetone, acetonitrile or dimethylformamide.
  • halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane
  • ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane
  • other solvents such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile
  • bases examples include alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethoxide or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or organometallic compounds such as butyllithium or phenyllithium, or other bases such as sodium hydride, DBU, preferred is potassium tert-butoxide, cesium carbonate, DBU, sodium hydride, potassium carbonate or sodium carbonate.
  • alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethoxide or potassium tert-butoxide
  • amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or organometallic compounds such as butyllithium or phenyllithium, or other bases
  • the chromatographic separation of the regioisomers is generally carried out by HPLC on a GROM-SEL ODS-4HE, 10 ⁇ M stationary phase with a mixture of acetonitrile and water as the eluent.
  • the reaction of the first stage according to process [C] is generally carried out in pure dehydration reagent without the addition of inert solvents, preferably in a temperature range from room temperature to 50 ° C. under atmospheric pressure.
  • Dehydrating reagents are, for example, trimethyl orthoformate or anhydrous alcohols, such as ethanol or methanol.
  • reaction of the second stage according to process [C] is generally carried out in pure phosphite, phosphonite or phosphorodiamidite, if appropriate with the addition of an inert solvent, preferably in a temperature range from room temperature to reflux of the solvent under atmospheric pressure.
  • phosphites, phosphonites and phosphorodiamidites are triethyl phosphite, trimethyl phosphite, triisopropyl phosphite, diethyl methyl phosphonite, ethyl diphenyl phosphite or ethyl N-tetraethyl phosphorodiamidite, triethyl phosphite being preferred.
  • Inert solvents are, for example, toluene, benzene or xylene.
  • the compounds of the formulas (in), (V) and (VE) are known or can be synthesized by known methods from the corresponding starting compounds.
  • R 1 and R 2 have the meaning given above, and
  • Y 1 is methyl or ethyl
  • the reaction is generally carried out in inert solvents, preferably in a temperature range from room temperature to the reflux of the solvent at atmospheric pressure.
  • 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, lithium hydroxide is preferred.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, aceton
  • the compounds of formula (VHI) are known or can be prepared by reacting compounds of the formula
  • R 2 and Y 1 have the abovementioned meaning
  • the compounds of formula (DC) are known or can be synthesized by known methods from the corresponding starting compounds.
  • the compounds of the formula (IV) are known or can be prepared by reacting compounds of the formula
  • R 2 has the meaning given above, and
  • Y 2 is methyl or ethyl
  • the reaction is generally carried out in inert solvents, in the presence of methylaluminoxane, preferably in a temperature range from room temperature to the reflux of the solvent at atmospheric pressure.
  • Inert solvents are, for example, toluene, benzene, xylene or dichloromethane.
  • the compounds of formula (X) are known or can be synthesized by known methods from the corresponding starting compounds.
  • the compounds of the formula (VI) are known or can be prepared by reacting compounds of the formula
  • R 2 has the meaning given above
  • the cleavage of the acetal is generally carried out in the presence of an acid, preferably in a temperature range from room temperature to 50 0 C at atmospheric pressure.
  • Acids are for example trifluoroacetic acid, hydrochloric acid or sulfuric acid, preferred is a mixture of sulfuric acid and trifluoroacetic acid.
  • the compounds of the formula (XI) are known or can be synthesized by known processes from the corresponding starting compounds.
  • the compounds of the invention show an unpredictable, valuable pharmacological and pharmacokinetic activity spectrum. These are compounds which influence the proteolytic activity of the serine protease thrombin.
  • the compounds of the invention inhibit the enzymatic cleavage of substrates that play an essential role in the activation of blood coagulation and aggregation of platelets.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, preferably of thromboembolic diseases and / or thromboembolic complications.
  • thromboembolic disorders include in particular diseases such as acute coronary syndrome (ACS), heart attack with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI), stable angina pectoris, unstable Angina pectoris, reocclusions and restenoses following coronary interventions such as angioplasty, stent or aortocoronary bypass, peripheral arterial occlusive disease, 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 heart attack with ST segment elevation
  • non-STEMI non-STEMI
  • stable angina pectoris unstable Angina pectoris
  • reocclusions and restenoses following coronary interventions such as angioplasty, stent or aortocoronary bypass, peripheral arterial occlusive disease, pulmonary embolism, venous thrombosis, especially in deep leg veins and
  • the compounds according to the invention are therefore also suitable for the prevention and treatment of cardiogenic thromboembolisms, such as, for example, brain ischemia, stroke and systemic thromboembolisms and ischaemias, in patients with acute, intermittent or persistent cardiac arrhythmias, such as atrial fibrillation, and those undergoing cardioversion, as well as patients with valvular heart disease or with artificial heart valves.
  • cardiogenic thromboembolisms such as, for example, brain ischemia, stroke and systemic thromboembolisms and ischaemias
  • acute, intermittent or persistent cardiac arrhythmias such as atrial fibrillation, and those undergoing cardioversion
  • the compounds of the invention are suitable for the treatment of disseminated intravascular coagulation (DIC).
  • 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 wound healing, for the prophylaxis and / or treatment of atherosclerotic vascular diseases and inflammatory diseases such as rheumatic diseases of the musculoskeletal system, coronary heart diseases, cardiac insufficiency, hypertension, inflammatory diseases, e.g. Asthma, inflammatory lung disease, glomerulonephritis and inflammatory bowel disease into consideration, as well as for the prophylaxis and / or treatment of Alzheimer's disease.
  • atherosclerotic vascular diseases and inflammatory diseases such as rheumatic diseases of the musculoskeletal system, coronary heart diseases, cardiac insufficiency, hypertension, inflammatory diseases, e.g. Asthma, inflammatory lung disease, glomerulonephritis and inflammatory bowel disease into consideration, as well as for the prophylaxis and / or treatment of Alzheimer's disease.
  • the compounds according to the invention can inhibit tumor growth and metastasis, in microangiopathies, age-related macular degeneration, diabetic retinopathy, diabetic nephropathy and other microvascular diseases and for the prevention and treatment of thromboembolic complications such as venous thromboembolism in tumor patients, especially those who are undergoing major surgery or chemo- or radiotherapy.
  • the compounds of the invention may also be used to prevent coagulation ex vivo, e.g. for the preservation of blood and plasma products, for the cleaning / pre-treatment of catheters and other medical aids and devices, for the coating of artificial surfaces of in vivo or ex vivo used medical aids and devices or for biological samples containing platelets.
  • 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 erf ⁇ ndungswashen compounds 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 erf ⁇ ndungswashen connection.
  • 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 containing platelets, which is characterized in that an anticoagulatory effective amount of the compound of the invention is added.
  • Another object of the present invention are combinations of
  • B) other pharmaceutical active substances in particular with platelet aggregation inhibitors, anticoagulants, fibrinolytic agents, lipid-lowering agents, coronary therapeutic agents and / or vasodilators.
  • Combinations within the meaning of the invention not only pharmaceutical forms containing all components (so-called. Fixed combinations), and combination packs containing the components separated from each other understood, but also simultaneously or temporally staggered applied components, if they are used for the prophylaxis and / Likewise, it is possible to combine two or more active substances with each other, so it is in each case to two- or Mehrfach-Kornbinationen.
  • Platelet aggregation inhibitors are, for example, acetylsalicylic acid (such as aspirin), ticlopidine (ticlid) and clopidogrel (Plavix), or integrin antagonists such as glycoprotein ⁇ b / JHIa antagonists such as abciximab, eptifibatide, tirof ⁇ ban, lamifiban, lefradafiban and fradafiban.
  • Anticoagulant substances include, for example, heparin (UFH), low molecular weight heparins (LMWH) such as tinzaparin, certoparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, danaparoid and factor Xa inhibitors.
  • UHF heparin
  • LMWH low molecular weight heparins
  • Factor Xa inhibitors are, for example: Rivaroxaban (BAY 59-7939): 5-Chloro-N - ( ⁇ (5S) -2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidin-5 yl ⁇ methyl) thiophene-2-carboxamide [WO 2001/47919]
  • Tanogitran (BBBT-986, prodrug: BIBT-1011): N - [(1 /?) - 1- ⁇ 2 - [( ⁇ 4- [amino (imino) methyl] -phenyl ⁇ amino) methyl] -1 - methyl-1H-benzimidazol-5-yl ⁇ -1-methyl-2-oxo-2-pyrrolidin-1-yl-ethyl] -glycine [American Chemical Society - 226th National Meeting, New York City, NY, USA, 2003]
  • Razaxaban (DPC-906): l ⁇ 3-amino-1,2-benzisoxazol-5-yl) -N- (4- ⁇ 2 - [(dimethylamino) -methyl] -H-irinidazol-1-yl ⁇ - 2-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazole-5-carboxamide [J.Med.Chem. 2005, 48, 1729-1744]
  • EMD-495235 5-Chloro-N - [(li?) - 1- (methoxymethyl) -2 - ⁇ [3-methyl-4- (3-oxomethyl-4-yl) -phenyl] -amino ⁇ -2-oxo-ethyl ] thiophene-2-carboxamide [Bioorg.Med.Chem.Lett. 2004, 14, 5817-5822]
  • M-55532 V-tC ⁇ -chloro-naphthylsulfonylJ- ⁇ a-methoxymethyl) -1'-pyridin-4-yl-tetrahydro-5H-spiro [1,3-oxazolo [3,2-a] pyrazine-2,4 ' -piperidine] -5-one [ ⁇ . Nishida et al. 228th ACS National Meeting, Philadelphia, August 22-26, 2004, MEDI-251; ⁇ . Nishida et al. Chem.Pharm.Bull. 2004, 52, 406-412; ditto 459-462]
  • Otamixaban (FXV-673, RPR-130673): (2i, 3R) -2- ⁇ 3- [amino (imino) methyl] benzyl ⁇ -3 - ⁇ [4- (1-oxidopyridin-4-yl) benzoyl ] amino ⁇ butanoic acid methyl ester [V. Chu et al. Thrombosis Research 2001, 103, 309-324; K. R. Guertin et al. Bioorg Med.Chem.Lett. 2002, 12, 1671-1674]
  • Plasminogen activators include tissue plasminogen activator (t-PA), streptokinase, reteplase and urokinase.
  • lipid lowering agents are HMG-CoA- (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors such as lovastatin (Mevacor, US 4,231,938), simvastatin (Zocor, US 4,444,784), pravastatin (Pravachol, US 4,346,227), fluvastatin (Lescol, US 5,354,772) and atorvastatin (Lipitor, US 5,273,995).
  • HMG-CoA- (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors such as lovastatin (Mevacor, US 4,231,938), simvastatin (Zocor, US 4,444,784), pravastatin (Pravachol, US 4,346,227), fluvastatin (Lescol, US 5,354,772) and atorvastatin (Lipitor, US 5,273,995).
  • Coronary / vasodilators are especially 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 (US 5,863,930), losartan, valsartan, irbesartan, candesartan, eprosartan and temisartan, or ⁇ -adrenoceptor antagonists such as carvedilol, alprenolol, bisoprolol, acebutolol, atenolol, betaxolol, carteolol, metoprolol, nadolol, penbutolol, pindolol, propranolol and timolol or
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the prior art is capable of rapidly and / or modifying the compounds according to the invention which release the compounds according to the invention in crystalline and / or amorphized and / or dissolved form, for example tablets (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings controlling the release of the compound of the invention), rapidly disintegrating tablets or films / wafers, foils / lyophilisates, capsules (eg hard or soft gelatin capsules), dragees, granules, pellets, powders , Emulsions, suspensions, aerosols or solutions.
  • tablets uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings controlling the release of the compound of the invention
  • rapidly disintegrating tablets or films / wafers foils / lyophilisates
  • capsules eg hard or soft gelatin capsules
  • dragees granules, pellets, powders , Emulsions, suspensions, aerosols or
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • absorption e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • the oral application is preferred.
  • Inhalation medicines including powder inhalers, nebulizers
  • nasal drops solutions, sprays
  • lingual, sublingual or buccal tablets to be applied
  • films / wafers or capsules to be applied
  • suppositories ear or eye preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (such as patches)
  • the compounds according to the invention can be converted into the mentioned administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitol oleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odoriferous 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 dode
  • compositions containing at least one compound according to the invention preferably together with one or more inert nontoxic, pharmaceutically suitable excipient, and their use for the purposes mentioned above.
  • Method 1 Device Type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A - »2.5 min 30% A -» 3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min. 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.
  • Method 2 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A - »2.5 min 30% A -> 3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C .; UV detection: 208-400 nm.
  • Method 3 Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Merck Chromolith SpeedROD RP-18e 100 mm x 4.6 mm; Eluent A: water + 0.5 ml 50% formic acid / l; Eluent B: acetonitrile + 0.5 ml 50% formic acid / L; Gradient: 0.0 min 10% B -> 7.0 min 95% B -> 9.0 min 95% B; Flow: 0.0 min 1.0 ml / min -> 7.0 min 2.0 ml / min -> 9.0 min 2.0 ml / min; Oven: 35 ° C; UV detection: 210 nm.
  • Method 4 Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A - »3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.
  • Method 5 Device Type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Gemini 3 ⁇ 30 mm x 3.00 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A -> 3.0 min 5% A - »4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min. 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.
  • Method 6 Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Thermo Hypersil GOLD 3 ⁇ 20mm x 4mm; 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 100% A -> 0.2 min 100% A -> 2.9 min 30% A - »3.1 min 10% A -> 5.5 min 10% A; Oven: 50 ° C .; Flow: 0.8 ml / min; UV detection: 210 nm.
  • Method 7 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Onyx Monolithic Cl 8, 100 mm x 3 mm.
  • Eluent A 1 l of water + 0.5 ml of 50% formic acid
  • eluent B 1 l of acetonitrile + 0.5 ml of 50% formic acid
  • Flow 2 ml / min
  • Oven 40 ° C
  • UV detection 208-400 nm.
  • Method 8 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Gemini 3 ⁇ 30 mm x 3.00 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A - »3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C .; UV detection: 208-400 nm.
  • E ⁇ antiomerentrennu ⁇ g The enantiomer separation of corresponding exemplary embodiments can be achieved using a Daicel Chiralpak AD-H, 5 ⁇ M 250 mm x 20 mm column with an eluent mixture of iso-hexane and ethanol and diethylamine additive.
  • Example IA Analogously to the instructions for the preparation of Example IA, 1 g (3.23 mmol) of the aniline from Example 10A are diazotized with 0.67 g (9.7 mmol) of sodium nitrite in hydrochloric acid and then cyclized to give the corresponding indazole derivative. After purification, prep. HPLC 640 mg (79% of theory) of product as a solid, which crystallized from acetonitrile / water.
  • Example 9A Analogously to the instructions for the preparation of Example 9A, 1.47 g (6.96 mmol) of the acid from Example 15A are reacted with 1.08 g (7.66 mmol) of 3-chlorobenzylamine to give the corresponding amide. After working up, 2.12 g (73% of theory) of product are obtained as solid.
  • Example 10A Analogously to the instructions for the preparation of Example 10A, 2.12 g (6.33 mmol) of the nitro compound from Example 16A with 4.8 g (25.3 mmol) of stannous chloride are reduced to the corresponding aniline derivative. After purification on silica gel, 1.56 g (81% of theory) of product are obtained as a resin.
  • this solution is poured into a dropping funnel cooled with ice water and slowly added dropwise to the sodium cyanide / copper cyanide solution. It is allowed to stir at RT for 4 h (evolution of gas). It is extracted several times with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution and dried with magnesium sulfate. After removal of the solvent, 1.75 g (69% of theory) of the title compound are obtained as a solid, which is used without further purification.
  • Example 9A Analogously to the instructions for the preparation of Example 9A, 1.73 g (8.392 mmol) of the acid from Example 19A are reacted with 1.31 g (9.231 mmol) of 3-chlorobenzylamine to give the corresponding amide. After working up, 2.76 g of product (76% of theory) are obtained as a solid.
  • Example 10A Analogously to the procedure for the preparation of Example 10A, 1.38 g (4.185 mmol) of the nitro compound (Example 20A) with 3.17 g (16.74 mmol) of stannous chloride are reduced to the corresponding aniline derivative. After purification over silica gel, 1.13 g (90% of theory) are obtained as a solid.
  • Example 21A Analogously to the preparation of Example 18A, 170 mg (21% of theory) of the indazole derivative are prepared starting from 0.5 g (1.668 mmol) of 3-amino-N- (3-chlorobenzyl) -5-cyano-4-methylbenzamide (Example 21A). isolated as a solid.
  • Example 6 Analogously to the instructions for the preparation of Example 6, the corresponding indazole derivative is prepared from methyl 4-formyl-3-nitrobenzoate with 2-ethylbutan-1-amine.
  • Example 4A Analogously to the procedure for the preparation of Example 4A, the ester from Example 25A is saponified. The product is obtained in a yield of 95% of theory. Th. As a solid.
  • Example 29A Analogously to the procedure for preparing Example 29A, 199 mg (0.93 mmol) of 2,3-dipyridin-2-yl-propanenitrile are obtained after reduction with sodium borohydride in the presence of cobalt (II) chloride hexahydrate 170 mg (86% of theory). Product.
  • Example 29A Analogously to the instructions for the preparation of Example 29A, 1000 mg (2.18 mmol) of 2,3- 4- (2-oxopyrrolidin-1-yl) -2-pyridin-2-ylbutanenitrile are obtained after reduction with sodium borohydride in the presence of cobalt- ( II) chloride hexahydrate 360 mg (71% of theory) product.
  • Example 2 Analogously to the instructions for the preparation of Example 1, 500 mg (1.52 mmol) of the indazole from Example 2A with 399.7 mg (2.28 mmol) of 1- (2-bromoethyl) -1H-pyrazole are stirred at RT for 16 h and reacted to give the corresponding indazole derivative. After purification, prep. HPLC 152.8 mg (25% of theory) of product as a solid.
  • Example 2 Analogously to the instructions for the preparation of Example 1, 250 mg (0.79 mmol) of the indazole from Example 2A with 179 mg (1.19 mmol) 3- (2-chloroethyl) -1,3-oxazolidin-2-one at RT for 16 h and stirred converted to the corresponding indazole derivative. After purification, prep. HPLC 72.6 mg (22% of theory) of product as a solid.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 70 mg (0.159 mmol) of the aldehyde from Example 6A are reacted with 48.7 mg (0.21 mmol) of 2- (4-methoxyphenyl) -2-morpholin-4-ylethanamine to give the corresponding indazole derivative. After purification, prep. HPLC 23.6 mg (30% of theory) of product as a solid.
  • Example 2A Analogously to the instructions for the preparation of Example 1, 150 mg (0.48 mmol) of the indazole from Example 2A are reacted with 203.6 mg (0.955 mmol) of [1- (bromo-methyl) propyl] benzene to give the corresponding indazole derivative. Obtained after purification and separation of the isomers on prep. HPLC 11 mg (6% of theory) of product as a solid.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 527 mg (1.19 mmol) of the aldehyde from Example 6A are reacted with 300 mg (1.55 mmol) of ethyl 3-amino-2-phenylpropanoate to give the corresponding indazole derivative. After purification, prep. HPLC 125 mg (23% of theory) of product as a solid.
  • Example 2A Analogously to the instructions for the preparation of Example 1, 150 mg (0.48 mmol) of the indazole from Example 2A are reacted with 113.7 mg (0.72 mmol) of 1- (2-chloroethyl) -3,5-dimethyl-1H-pyrazole to give the corresponding indazole derivative. Obtained after purification and separation of the isomers on prep. HPLC 46 mg (23% of theory) of product as an oil.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 50 mg (0.113 mmol) of the aldehyde from Example 6A are reacted with 20.49 mg (0.147 mmol) of 2- (2-fluorophenyl) ethanamine to give the corresponding indazole derivative. After purification, prep. HPLC 27.1 mg (59% of theory) of product.
  • Example 2 Analogously to the procedure for the preparation of Example 1, 150 mg (0.48 mmol) of the indazole from Example 2A with 166.8 mg (0.955 mmol) of 1- (2-chloroethyl) -1H-l, 2,4-triazole-5-carboxamide to the corresponding Indazole derivative implemented. Obtained after purification and separation of the isomers on prep. HPLC 2.29 mg (1% of theory) of product as a solid.
  • Example 2A Analogously to the instructions for the preparation of Example 1, 150 mg (0.48 mmol) of the indazole from Example 2A are reacted with 142.7 mg (0.72 mmol) of (2-bromo-1-methylethyl) benzene to give the corresponding indazole derivative. Obtained after purification and separation of the isomers on prep. HPLC 5.7 mg (3% of theory) of product as an oil.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 70 mg (0.159 mmol) of the aldehyde from Example 6A with 39.18 mg (0.21 mmol) of 2- (2,6-Dichl ⁇ henyl) ethanamine to the corresponding Indazole derivative implemented. After purification, prep. HPLC 26 mg product (33% of theory).
  • Example 2A Analogously to the instructions for the preparation of Example 1, 150 mg (0.46 mmol) of the indazole from Example 2A are reacted with 113.1 mg (0.69 mmol) of 4-chloro-1- (2-chloroethyl) -1H-pyrazole to give the corresponding indazole derivative. Obtained after purification and separation of the isomers on prep. HPLC 24 mg (13% of theory) of product as an oil.
  • Example 2 Analogously to the instructions for the preparation of Example 1, 80 mg (0.245 mmol) of the indazole from Example 1 IA are reacted with 63.9 mg (0.49 mmol) of 1- (2-chloroethyl) -1H-pyrazole to give the corresponding 4-chloro Indazole derivative implemented. Obtained after purification and separation of the isomers on prep. HPLC 25.8 mg (25% of theory) of product as crystals.
  • Example 2 Analogously to the instructions for the preparation of Example 1, 80 mg (0.245 mmol) of the indazole from Example I IA with 94.55 mg (0.49 mmol) of 4-chloro-l- (2-chloroethyl) -3,5-dimethyl-lH-pyrazole to corresponding 4-chloro-indazole derivative implemented. Obtained after purification and separation of the isomers on prep. HPLC 19.2 mg (16% of theory) of product as crystals.
  • Example 2 Analogously to the instructions for the preparation of Example 1, 80 mg (0.245 mmol) of the indazole from Example I IA with 149.58 mg (0.49 mmol) of 3- (2-chloroethyl) -1,3-oxazolidin-2-one to the corresponding 4-chloro Implemented indazole derivative. Obtained after purification and separation of the isomers on prep. HPLC 23.3 mg (22% of theory) of product as crystals.
  • Example 1 Analogously to the instructions for the preparation of Example 1, 80 mg (0.245 mmol) of the indazole from Example IA are reacted with 141.6 mg (0.49 mmol) of 2- (2-chloroethyl) pyridine to give the corresponding 4-chloroindazole derivative. Obtained after purification and separation of the isomers on prep. HPLC 14.1 mg (13% of theory) of product as an oil.
  • Example 2 Analogously to the instructions for the preparation of Example 1, 30 mg (0.092 mmol) of the indazole from Example 18A are reacted with 32.3 mg (0.184 mmol) of 1- (2-bromoethyl) -1H-pyrazole to give the corresponding 4-methoxy-indazole derivative. Obtained after purification and separation of the isomers on prep. HPLC 6 mg (14% of theory) of product as a solid.
  • Example 2 Analogously to the instructions for the preparation of Example 1, 30 mg (0.092 mmol) of the indazole from Example 18A with 35.6 mg (0.184 mmol) of 4-chloro-1- (2-chloroethyl) -3,5-dimethyl-1H-pyrazole to the corresponding 4-methoxy-indazole derivative implemented. Obtained after purification and separation of the isomers on prep. HPLC 5 mg (11% of theory) of product as a solid.
  • Example 2 Analogously to the instructions for the preparation of Example 1, 80 mg (0.257 mmol) of the indazole from Example 22A are reacted with 77 mg (0.515 mmol) of 3- (2-chloroethyl) -1,3-oxazolidin-2-one to give the corresponding indazole derivative. Obtained after purification and separation of the isomers on prep. HPLC 31 mg (27% of theory) of product as a solid.
  • Example 2 Analogously to the procedure for the preparation of Example 1, 150 mg (0.514 mmol) of the indazole from Example 2A with 149 mg (0.772 mmol) of 4-chloro-l- (2-chloroethyl) -3,5-dimethyl-lH-pyrazole to the corresponding Indazole derivative implemented. Obtained after purification and separation of the isomers on prep. HPLC 27 mg (12% of theory) of product as a solid.
  • Example 15A Analogously to the instructions for the preparation of Example 15A, 112 mg (0.242 mmol) of the ester from Example 9 are saponified to the corresponding acid. After purification by extraction, 84 mg (72% of theory) of product are obtained as solid.
  • 35 mg (0.081 mmol) of the acid from Example 27 are initially introduced in 2 ml of dichloromethane and 1 ml of DMF, 23.2 mg (0.121 mmol) EDC, 12 mg (0.09 mmol) HOBT, 20.9 mg (0.161 mmol) DIEA and then 9.8 mg ( 0.11 mmol) of morpholine are added. The solution is stirred for 16 h at RT. Add 2M hydrochloric acid and then separate over prep. HPLC. 15 mg (37% of theory) of the product are obtained as a solid.
  • Example 6 Analogously to the procedure for the preparation of Example 6, 70 mg (0.187 mmol) of the aldehyde from Example 6A with 159 mg (0.747 mmol) of 2,3-dipyridin-2-ylpropane-l-amine (prepared analogously to Example 24A) to the corresponding indazole derivative implemented. After purification, prep. HPLC 4 mg (4% of theory) of the product.
  • Example 2 Analogously to the instructions for the preparation of Example 1, 137 mg (0.481 mmol) of the indazole from Example 2A with 190.2 mg (0.962 mmol) 2- [1- (chloromethyl) -2-methylbutyl] pyridine, which from the corresponding ethyl ester by reduction and subsequent conversion of the alcohol is obtained in the chloride under standard conditions, converted to the corresponding indazole derivative. Obtained after purification and separation of the isomers on prep. HPLC 11 mg (5% of theory) of product as an oil.
  • Example 2A Analogously to the instructions for the preparation of Example 1, 150 mg (0.53 mmol) of the indazole from Example 2A are reacted with 157.6 mg (0.79 mmol) of 1- (2-chloroethyl) pyridin-2 (1H) -one to give the corresponding indazole derivative. Obtained after purification and separation of the isomers on prep. HPLC 37 mg (17% of theory) of product as a solid.
  • Example 24A Analogously to the instructions for the preparation of Example 6, 70 mg (0.187 mmol) of the aldehyde from Example 6A with 53.47 mg (0.24 mmol) of 2-pyridin-2-yl-3- (tetrahydro-2H-pyran-4-yl) propane 1-amine (Example 24A) to give the corresponding indazole derivative. After purification, prep. HPLC 14 mg (12% of theory) of product as an oil.
  • Example 2 Analogously to the procedure for the preparation of Example 1, 80 mg (0.26 mmol) of the indazole from Example 22A with 99.4 mg (0.52 mmol) of 4-chloro-l- (2-chloroethyl) -3,5-dimethyl-lH-pyrazole to the corresponding Indazole derivative implemented. Obtained after purification and separation of the isomers on prep. HPLC 23 mg (19% of theory) of product as a solid.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 50 mg (0.157 mmol) of the aldehyde from Example 6A with 35.5 mg (0.157 mmol) of 2- (3,5-dimethyl-1H-pyrazol-1-yl) propan-1-amine dihydrochloride converted to the corresponding indazole derivative. After purification, prep. HPLC 11 mg (16% of theory) of product.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 70 mg (0.158 mmol) of the aldehyde from Example 6A with 139.4 mg (0.633 mmol) of 2-pyridin-2-yl-3- (tetrahydro-2H-pyran-2-yl) propane l- amine (prepared analogously to 2x1 Example 24A) to give the corresponding indazole derivative. After purification, prep. HPLC 14 mg (12% of theory) diastereomerically pure product as an oil.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 70 mg (0.159 mmol) of the aldehyde from Example 6A with 45.22 mg (0.21 mmol) of 3- [1- (aminomethyl) butyl] -1,3-oxazolidin-2-one to the corresponding indazole derivative implemented. After purification, prep. HPLC 35 mg (50% of theory) of product.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 50 mg (0.157 mmol) of the aldehyde from Example 6A are reacted with 24.4 mg (0.157 mmol) of 2- (2-chlorophenyl) ethylamine to give the corresponding indazole derivative. After purification, prep. HPLC 13 mg (20% of theory) of product.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 50 mg (0.157 mmol) of the aldehyde from Example 6A are reacted with 24.4 mg (0.157 mmol) of 2- (4-methoxyphenyl) ethanamine to give the corresponding indazole derivative. After purification, prep. HPLC 11 mg (17% of theory) of product.
  • Example 5 Analogously to the instructions for the preparation of Example 5, 50 mg (0.195 mmol) of the carboxylic acid from Example 13A are reacted with 40.3 mg (0.273 mmol) of 1- (5-chloro-2-thienyl) methanamine to give the corresponding amide. After purification, prep. HPLC 46 mg (60% of theory) of product.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 70 mg (0.187 mmol) of the aldehyde from Example 6A with 174.2 mg (0.75 mmol) of 1- (4-amino-3-pyridinyl-2-yl-butyl) -pyrrolidin-2-one (Synthesis analogous to Example 24A) to give the corresponding indazole derivative. After purification, prep. HPLC 4 mg (4% of theory) of product.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 70 mg (0.159 mmol) of the aldehyde from Example 6A with 48.9 mg (0.206 mmol) of 3- [1- (aminomethyl) -3-methylbutyl] -1,3-oxazolidin-2-one converted to the corresponding indazole derivative. After purification, prep. HPLC 15 mg (20% of theory) of product.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 70 mg (0.159 mmol) of the aldehyde from Example 6A are reacted with 57.33 mg (0.206 mmol) of 3-cyclohexyl-2-pyridin-2-yl-propan-1-amine to give the corresponding indazole derivative. After purification, prep. HPLC 20 mg (21% of theory) of product.
  • Example 6 Analogously to the procedure for the preparation of Example 6, 60.79 mg (0.138 mmol) of the aldehyde from Example 6A with 40.59 mg (0.179 mmol) of 1- (2-chlorophenyl) -N 1 , N 1 -diethylethane-l, 2-diamine to the corresponding Indazole derivative implemented. After purification, prep. HPLC 27 mg (40% of theory) of product.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 60.79 mg (0.138 mmol) of the aldehyde from Example 6A are reacted with 41.95 mg (0.179 mmol) of 2- (4-methoxyphenyl) -2-piperidin-1-ylethanamine to give the corresponding indazole derivative. After purification, prep. HPLC 32 mg (45% of theory) of product.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 60.79 mg (0.138 mmol) of the aldehyde from Example 6A are reacted with 39.26 mg (0.179 mmol) of 2-M ⁇ holin-4-yl-2-phenylethanamine to the corresponding indazole derivative. After purification, prep. HPLC 18 mg (26% of theory) of product.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 60.79 mg (0.138 mmol) of the aldehyde from Example 6A are reacted with 40.23 mg (0.179 mmol) of 2- (2-chlorophenyl) -2-pyrrolidin-1-ylethanamine to give the corresponding indazole derivative. After purification via preparative HPLC, 29.7 mg (44% of theory) of product are obtained.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 60.79 mg (0.138 mmol) of the aldehyde from Example 6A are reacted with 40.15 mg (0.179 mmol) of 2- (4-fluorophenyl) -2-morpholin-4-ylethanamine to give the corresponding indazole derivative. After purification via preparative HPLC, 24.3 mg (35% of theory) of product are obtained.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 60.79 mg (0.138 mmol) of the aldehyde from Example 6A are reacted with 37.3 mg (0.179 mmol) of 2- (2-fluorophenyl) -2-pyrrolidin-1-ylethanamine to give the corresponding indazole derivative. After purification via preparative HPLC, 29.7 mg (44% of theory) of product are obtained.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 58.48 mg (0.172 mmol) of the aldehyde from Example 6A with 75 mg (0.224 mmol) of 2-morpholin-4-yl-2- [2- (trifluoromethyl) -phenyl] ethanamine to the corresponding indazole derivative implemented. After purification by preparative HPLC, 30 mg (29% of theory) of product are obtained as solid.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 60.79 mg (0.138 mmol) of the aldehyde from Example 6A with 34.4 mg (0.179 mmol) of N'-diethyl-1-phenylethane-1-diamine converted to the corresponding indazole derivative. After purification via preparative HPLC, 26 mg (41% of theory) of product are obtained.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 60.79 mg (0.138 mmol) of the aldehyde from Example 6A are reacted with 39.44 mg (0.179 mmol) 2- (4-methoxyphenyl) -2-pyrrolidin-1-ylethanamine to give the corresponding indazole derivative. After purification via preparative HPLC, 19 mg (27% of theory) of product are obtained.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 60.79 mg (0.138 mmol) of the aldehyde from Example 6A with 42.48 mg (0.179 mmol) of 2- (4-fluorophenyl) -2- (4-methylpiperazin-1-yl) ethanamine give the corresponding indazole derivative implemented. After purification via preparative HPLC, 10 mg (11% of theory) of product are obtained.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 70 mg (0.187 mmol) of the aldehyde from Example 6A are reacted with 159.3 mg (0.75 mmol) of 2,3-dipyridin-2-yl-propan-1-amine to give the corresponding indazole derivative. Purification by preparative HPLC gives 4 mg (4% of theory) of product.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 60.79 mg (0.138 mmol) of the aldehyde from Example 6A are reacted with 208.3 mg (0.179 mmol) of 2- (4-fluorophenyl) -2-pyrrolidin-1-ylethanamine to give the corresponding indazole derivative. After purification via preparative HPLC, 29 mg (44% of theory) of product are obtained.
  • Example 60 Analogously to the instructions for the preparation of Example 60, 23 mg (0.09 mmol) of the acid from Example 13A with 41.7 mg (0.12 mmol) of ethyl [2- (aminomethyl) -4-chlorophenoxy] acetate, which are described in WO 98/31670 Provision can be made, converted to the corresponding amide. Purification by preparative HPLC gives 8 mg (18% of theory) of product.
  • Example 36 Analogously to the instructions for the preparation of Example 36, 20 mg (0.081 mmol) of the acid from Example 26A are reacted with 15.6 mg (0.11 mmol) 1- (5-chloro-2-thienyl) methanamine to give the corresponding amide. Purification by preparative HPLC gives 21.3 mg (70% of theory) of product.
  • Example 6 Analogously to the instructions for the preparation of Example 6, 60.79 mg (0.138 mmol) of the aldehyde from Example 6A are reacted with 39.1 mg (0.179 mmol) of 2-azepan-1-yl-2-phenylethanamine to give the corresponding indazole derivative. After purification via preparative HPLC, 13 mg (19% of theory) of product are obtained.
  • Example 36 Analogously to the instructions for the preparation of Example 36, 50 mg (0.20 mmol) of the acid from Example 13A are reacted with 40.3 mg (0.27 mmol) of 1- (5-chloro-2-thienyl) methanamine to give the corresponding amide. Purification by preparative HPLC gives 45.5 mg (60% of theory) of product.
  • Example 28 Analogously to the instructions for the preparation of Example 28, 35 mg (0.08 mmol) of the acid from Example 27 are reacted with 11.3 mg (0.11 mmol) of 1-methylpiperazine to give the corresponding amide. After purification via preparative HPLC, 10 mg (23% of theory) of product are obtained.
  • Example 28 Analogously to the instructions for the preparation of Example 28, 35 mg (0.08 mmol) of the acid from Example 27 are reacted with 12.2 mg (0.12 mmol) of piperidin-4-ol to give the corresponding amide. Purification by preparative HPLC gives 15 mg (36% of theory) of product.
  • Example 28 Analogously to the instructions for the preparation of Example 28, 35 mg (0.08 mmol) of the acid from Example 27 are reacted with 19 mg (0.12 mmol) of ethyl piperidine-4-carboxylate to give the corresponding amide. After purification by preparative HPLC, 30 mg (65% of theory) of product are obtained.

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Abstract

L'invention concerne des indazoles substitués et un procédé pour leur préparation ainsi que leur utilisation dans la préparation de produits pharmaceutiques pour le traitement et/ou la prophylaxie de maladies, en particulier de maladies du système cardiovasculaire, de préférence de maladies thromboemboliques.
EP07764989A 2006-07-14 2007-07-02 2-(hétéroaryl)alkylindazole-6-phényl- et -thiénylméthylamide comme inhibiteurs de la thrombine Withdrawn EP2044031A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006032824A DE102006032824A1 (de) 2006-07-14 2006-07-14 Substituierte Indazole
PCT/EP2007/005832 WO2008006479A1 (fr) 2006-07-14 2007-07-02 2-(hétéroaryl)alkylindazole-6-phényl- et -thiénylméthylamide comme inhibiteurs de la thrombine

Publications (1)

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EP2044031A1 true EP2044031A1 (fr) 2009-04-08

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EP07764989A Withdrawn EP2044031A1 (fr) 2006-07-14 2007-07-02 2-(hétéroaryl)alkylindazole-6-phényl- et -thiénylméthylamide comme inhibiteurs de la thrombine

Country Status (6)

Country Link
US (1) US20100105663A1 (fr)
EP (1) EP2044031A1 (fr)
JP (1) JP2009543818A (fr)
CA (1) CA2657601A1 (fr)
DE (1) DE102006032824A1 (fr)
WO (1) WO2008006479A1 (fr)

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CN113474348A (zh) * 2018-12-21 2021-10-01 拜耳公司 取代的氧代吡啶衍生物

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EP2140866A1 (fr) * 2008-07-04 2010-01-06 Bayer Schering Pharma Aktiengesellschaft Oxazolidinones pour le traitement d'états inflammatoires du tractus gastro-intestinal
ES2660892T3 (es) * 2009-03-23 2018-03-26 Merck Sharp & Dohme Corp. Antagonistas del receptor P2X3 para el tratamiento del dolor
WO2011126903A2 (fr) 2010-03-30 2011-10-13 Verseon, Inc. Composés aromatiques multisubstitués utilisés comme inhibiteurs de la thrombine
CN104023540A (zh) 2011-11-02 2014-09-03 拜耳知识产权有限责任公司 具有杀线虫活性的化合物
EP2773203A1 (fr) 2011-11-02 2014-09-10 Bayer Intellectual Property GmbH Composés présentant une activité nématicide
CN110423221A (zh) * 2013-03-15 2019-11-08 维颂公司 作为凝血酶抑制剂的卤代吡唑
NZ711064A (en) 2013-03-15 2019-06-28 Verseon Corp Pyridone-substituted pyrazolyl compounds as serine protease inhibitors
PL3102576T3 (pl) 2014-02-03 2019-12-31 Vitae Pharmaceuticals, Llc Dihydropirolopirydynowe inhibitory ror-gamma
WO2016044662A1 (fr) 2014-09-17 2016-03-24 Verseon Corporation Composés de pyridone substituée par pyrazolyl en tant qu'inhibiteurs de sérine protéase
HUE060104T2 (hu) 2015-02-27 2023-01-28 Verseon Int Corporation Szubsztituált pirazol vegyületek mint szerinproteázinhibitorok
WO2017087608A1 (fr) * 2015-11-20 2017-05-26 Vitae Pharmaceuticals, Inc. Modulateurs de ror-gamma
TWI757266B (zh) 2016-01-29 2022-03-11 美商維它藥物有限責任公司 ＲＯＲ－γ調節劑
IL298639A (en) 2017-07-24 2023-01-01 Vitae Pharmaceuticals Llc Inhibitors of gamma ror
WO2019018975A1 (fr) 2017-07-24 2019-01-31 Vitae Pharmaceuticals, Inc. Inhibiteurs de ror gamma
CN111344287B (zh) 2017-11-14 2023-12-19 默沙东有限责任公司 作为吲哚胺2，3-双加氧酶(ido)抑制剂的新型取代的联芳基化合物
CR20220006A (es) * 2019-06-12 2022-06-06 Tmem16A Ltd Compuestos para tratar enfermedad respiratoria

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EP1479675A1 (fr) * 2003-05-19 2004-11-24 Aventis Pharma Deutschland GmbH Derivés d'indazole en tant qu'inhibiteurs du facteur Xa

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Publication number Priority date Publication date Assignee Title
CN113474348A (zh) * 2018-12-21 2021-10-01 拜耳公司 取代的氧代吡啶衍生物

Also Published As

Publication number Publication date
US20100105663A1 (en) 2010-04-29
CA2657601A1 (fr) 2008-01-17
JP2009543818A (ja) 2009-12-10
WO2008006479A1 (fr) 2008-01-17
DE102006032824A1 (de) 2008-01-17

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