EP1628976A1 - Novel pyridopyrazines and use thereof as kinase inhibitors - Google Patents

Novel pyridopyrazines and use thereof as kinase inhibitors

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Publication number
EP1628976A1
EP1628976A1 EP04733782A EP04733782A EP1628976A1 EP 1628976 A1 EP1628976 A1 EP 1628976A1 EP 04733782 A EP04733782 A EP 04733782A EP 04733782 A EP04733782 A EP 04733782A EP 1628976 A1 EP1628976 A1 EP 1628976A1
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EP
European Patent Office
Prior art keywords
alkyl
aryl
heteroaryl
cycloalkyl
heterocyclyl
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Withdrawn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
EP04733782A
Other languages
German (de)
French (fr)
Inventor
Eckhard Günther
Eckhard Claus
Irene Seipelt
Ulf-R. Rapp
Ludmilla Wixler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aeterna Zentaris GmbH
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Zentaris AG
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Filing date
Publication date
Application filed by Zentaris AG filed Critical Zentaris AG
Publication of EP1628976A1 publication Critical patent/EP1628976A1/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to kinase inhibitors of the pyrido [2,3-b] pyrazine type, their preparation and use as medicaments in particular for the treatment of malignant and other diseases based on pathological cell proliferation, such as, for. B. restenosis, psoriasis, arteriosclerosis and cirrhosis.
  • protein kinases The activation of protein kinases is a key event in cellular signal transduction processes. Aberrant kinase activation is observed in various disease states. The targeted inhibition of such constitutively active kinases is therefore a fundamental therapeutic goal.
  • the phosphorylation of proteins is generally initiated by extracellular signals and provides a universal mechanism for the control of various cellular events, such as. B. metabolic processes, cell growth, cell migration, cell differentiation, membrane transport and apoptosis.
  • the protein family of kinases is responsible for protein phosphorylation. These enzymes catalyze the phosphate transfer to specific substrate proteins. Based on the substrate specificity, the kinases are divided into two main classes, the tyrosine kinases and the serine / threonine kinases. Both the receptor tyrosine kinases and the cytoplasmic tyrosine and serine / threonine kinases are important proteins in the signal transduction of the cell.
  • Overexpression or degeneration of these proteins plays an important role in diseases based on pathological cell proliferation. These include metabolic diseases, diseases of the connective tissue and blood vessels, as well as malignant and benign tumor diseases. In tumor development and development, they often occur as oncogenes, ie as aberrant, constitutively active kinase proteins. The consequences of this excessive kinase activation are e.g. B. the uncontrolled. Cell growth and reduced cell death. The stimulation of tumor-induced growth factors can also be the cause of overstimulation of kinases. The development of kinase inhibitors is therefore of particular interest for all pathogenic processes that are influenced by kinases.
  • the invention is therefore aimed at creating new compounds which are suitable as inhibitors of such constitutively active kinases, in particular the receptor tyrosine kinases and also the cytoplasmic tyrosine and serine / threonine kinases.
  • Pyrido [2,3-b] pyrazine derivatives substituted in the 6-position are widely used as pharmacologically active compounds and as synthesis building blocks in pharmaceutical chemistry.
  • the patent WO99 / 17759 describes pyrido [2,3-b] pyrazines which carry, inter alia, alkyl, aryl and heteroaryl-substituted carbamates in the 6-position. These compounds are said to be used to modulate the function of serine threonine protein kinases.
  • Amide- and acrylamide-substituted pyrido [2,3-b] pyrazines are described which also contain carbamates as additional substituents and can be used as histone deacetylase inhibitors for the treatment of cell proliferation disorders.
  • Another publication (C. Temple, Jr .; J. Med. Chem. 1990, 3044-3050) describes the synthesis of a 6-ethylcarbamate-substituted pyrido [2,3-b] pyrazine derivative using an example. An anti-tumor effect is neither disclosed nor suggested.
  • R1 and R2 can independently:
  • alkyl where the alkyl radical is saturated and can consist of 1 to 8 carbon atoms
  • R3 can:
  • cycloalkyl radical having F, Cl, Br, I, NH 2 , NH alkyl, NH cycloalkyl, NH heterocyclyl, NH aryl, NH heteroaryl, NH alkyl aryl, NH Alkyl heteroaryl, N (alkyl) 2 , NHC (O) alkyl, NHC (O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHSO 2 alkyl , NHS0 2 cycloalkyl, NHSO 2 aryl, NHSO 2 heteroaryl, OH, O alkyl, O cycloalkyl, O heterocyclyl, O aryl, O heteroaryl, O alkyl aryl, O alkyl heteroaryl, OC (O) alkyl, OC (O) cycloalkyl,
  • R4 and R5 together mean cycloalkyl or heterocyclyl
  • cycloalkyl radical having F, Cl, Br, I, NH 2 , NH alkyl, NH cycloalkyl, NH heterocyclyl, NH aryl, NH heteroaryl, NH alkyl aryl, NH Alkyl heteroaryl, N (alkyl) 2 , NHC (0) alkyl, NHC (O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHSO 2 alkyl , NHSO 2 cycloalkyl, NHSO 2 aryl, NHSO 2 heteroaryl, OH, O alkyl, O cycloalkyl, O heterocyclyl, O aryl, O heteroaryl, O alkyl aryl, O alkyl heteroaryl, OC (O) alkyl, OC (0) cycloalkyl, OC (O) alkyl, OC (0) cycloalkyl, OC (O
  • heterocyclyl radical (iv) unsubstituted or substituted heterocyclyl, it being possible for the heterocyclyl radical to be substituted one or more times, identically or differently, by OH, O-alkyl, O-aryl, NH-alkyl, NH-aryl, alkyl or aryl,
  • heterocyclyl radical unsubstituted or substituted heterocyclyl, it being possible for the heterocyclyl radical to be substituted one or more times, identically or differently, by OH, O-alkyl, O-aryl, NH-alkyl, NH-aryl, alkyl or aryl,
  • alkyl for the purposes of this invention acyclic saturated or unsaturated hydrocarbon radicals which may be branched or straight chain, having 1 to 8 carbon atoms, that is, ds-alkanyls, C 2 - 8 alkenyls, and C 2 - 8 alkynyls.
  • Alkenyls have at least one CC double bond and alkynyls have at least one CC triple bond
  • cycloalkyl for the purposes of this invention means cyclic hydrocarbons with 3-12 hydrocarbons, which can be saturated or unsaturated.
  • the binding to the compounds of general structure I can take place via any and possible ring member of the cycloalkyl radical.
  • the cycloal - The kyl radical can also be part of a bi- or polycyclic system.
  • heterocyclyl stands for a 3-, 4-, 5-, 6-, 7- or 8-membered cyclic organic radical which contains at least 1, optionally 2, 3, 4 or 5 heteroatoms, the Heteroatoms are the same or different and the cyclic radical is saturated or unsaturated but not aromatic.
  • Binding to the compounds of general structure I can take place via any and possible ring member of the heterocyclic radical.
  • the heterocycle can also be part of a bi- or a polycyclic system.
  • Preferred heteroatoms are nitrogen, oxygen and sulfur. It is preferred that the heterocyclyl radical is selected from the group consisting of tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholine.
  • aryl means aromatic hydrocarbons, including phenyls, naphthyls and anthracenyls.
  • the radicals can also be condensed with further saturated, (partially) unsaturated or aromatic ring systems.
  • the bond to the compounds of the general structure I can be via any any and possible ring member of the aryl radical take place.
  • heteroaryl stands for a 5-, 6- or 7-membered cyclic aromatic radical which contains at least 1, possibly also 2, 3, 4 or 5 heteroatoms, the heteroatoms being the same or different.
  • the bond to the Compounds of the general structure I can be made via any and possible ring member of the heteroaryl radical.
  • the heterocycle can also be part of a bi- or polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulfur.
  • the Heteroaryl radical is selected from the group consisting of pyrrolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, phthalazinyl, indolyl, indazolyl, indolizinyl, quinolinyl, quinolinyl, isoxinyl Contains quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl, acridinyl.
  • alkyl-cycloalkyl means for the purposes of the present invention that alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl have the meanings defined above and that cycloalkyl, heterocyclyl, aryl and heteroaryl radical is bonded via a C ⁇ -8 alkyl group to the compounds of general structure I.
  • alkyl In connection with “alkyl”, “cycloalkyl”, “heterocyclyl”, “aryl”, “heteroaryl”, “alkylcycloalkyl”, “alkyl heterocyclyl”, “alkyl aryl” and “alkyl heteroaryl” is understood to mean the The term substituted in the sense of this invention, unless explicitly defined above, is the substitution of one or more hydrogen radicals by F, Cl, Br, I, CN, CF 3 , NH 2 , NH-alkyl, NH-aryl, N (alkyl) 2 , NO 2 , SH, S-alkyl, OH, OCF 3 , O-alkyl, O-aryl, CHO, CO 2 H, SO 3 H or alkyl
  • the substituents can be the same or different and the substitution can be any and possible Position of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl radical occur.
  • the multiple substitution can be carried out with the same or different substituents.
  • the compounds of general formula I according to the invention have at least one asymmetry center, they can be present in the form of their racemates, in the form of the pure enantiomers and / or diastereomers or in the form of mixtures of these enantiomers and / or diastereomers.
  • the mixtures can be present in any mixing ratio of the stereoisomers.
  • the compounds of general formula I according to the invention which have one or more chiral centers and which occur as racemates can be separated into their optical isomers, ie enantiomers or diastereomers, by methods known per se.
  • the separation can be carried out by column separation on chiral phases or by recrystallization from an optically active solvent or using an optically active acid or base or by derivatization with an optically active reagent, such as, for example, an optically active alcohol, and subsequent elimination of the rest.
  • the compounds according to the invention can be in the form of the tautomers.
  • the compounds of the general formula I according to the invention if they have a sufficiently basic group, such as a primary, secondary or tertiary amine, can be converted into their physiologically tolerable salts with inorganic and organic acids.
  • the pharmaceutically acceptable salts of the compounds according to the invention are preferably in accordance with general structure I with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, sulfoacetic acid, oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid, tartaric acid , Malic acid, embonic acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid.
  • the salts formed include hydrochlorides, hydrobromides, sulfates, hydrogen sulfates, phosphates, methanesulfonates, tosylates, carbonates, hydrogen carbonates, formates, acetates, triflates, sulfoacetates, oxalates, malonates, maleates, succinates, tartrates, malates, embonates , Almondates, fumarates, lactates, citrates, glutaminates and aspartates.
  • the stoichiometry of the salts formed of the compounds according to the invention can be integer or non-integer multiples of one.
  • the compounds of general formula I according to the invention if they contain a sufficiently acidic group, such as the carboxy group, can be converted into their physiologically tolerable salts with inorganic and organic bases.
  • suitable inorganic bases are sodium hydroxide, potassium hydroxide, calcium hydroxide, and organic bases are ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dibenzylethylene diamine and lysine.
  • the stoichiometry of the salts formed of the compounds according to the invention can be integer or non-integer multiples of one.
  • Solvates and in particular hydrates of the compounds according to the invention which, for. B. can be obtained by crystallization from a solvent or from aqueous solution.
  • One, two, three or any number of solvate or water molecules can combine with the compounds according to the invention to form solvates and hydrates.
  • chemical substances form solids which are in various states of order, which are referred to as polymorphic forms or modifications.
  • the different modifications of a polymorphic substance can differ greatly in their physical properties.
  • the compounds of general formula I according to the invention can exist in various polymorphic forms, certain modifications being metastable.
  • the starting compounds are either commercially available or can be prepared by processes known per se.
  • the starting materials 1 and 4 are valuable intermediates for the preparation of the pyridopyrazines of the general formula I according to the invention.
  • 2,6-diamino-3-nitropyridine is dissolved in a polar, organic solvent, such as, for example, methanol, ethanol, dimethylformamide or dioxane, alone or in combination of two of these solvents.
  • a polar, organic solvent such as, for example, methanol, ethanol, dimethylformamide or dioxane, alone or in combination of two of these solvents.
  • a catalyst for example Raney nickel, palladium on carbon or platinum (IV) dioxide
  • the reaction mixture is placed under a hydrogen atmosphere, a pressure between 1 and 5 bar being set.
  • the reaction mixture is allowed to react for several hours, for example 1-16 hours, in a temperature range between 20 ° C. and 60 ° C.
  • the insoluble residues are filtered off, the filter medium being able to consist, for example, of silica gel, Celite or commercially available glass fiber filters, and washing is carried out with the appropriate solvent.
  • the crude product, in solution, is used for the next reaction without further purification.
  • the 1,2-dione derivative is placed in an organic solvent, for example methanol, ethanol, dioxane, toluene or dimethylformamide.
  • 2,3,6-triaminopyridine is added directly after the reduction as a solution of its crude product in one of the abovementioned solvents to the 1,2-dione, optionally with the addition of an acid, such as, for. B. acetic acid or a base, for example potassium hydroxide.
  • the reaction mixture is allowed to react in a temperature range from 20 ° C. to 80 ° C. for some time, for example 20 minutes to 40 hours.
  • the filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo.
  • dimethylformamide the reaction mixture is stirred into a large amount of water and the precipitate which has precipitated is filtered off or the aqueous phase is extracted with a suitable organic solvent and the organic phases are concentrated in vacuo.
  • the remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol, or by column or flash chromatography on silica gel or aluminum oxide. A mixture of methanol and dichloromethane, for example, serves as the mobile phase.
  • the products obtained by the basic process can be converted into secondary products according to the formula I according to the invention in a procedure known to the person skilled in the art.
  • reaction product 4 with a corresponding isocyanate and optionally a suitable base, preferably sodium hydride, potassium hexamethyldisilazide, triethylamine or potassium carbonate, in a suitable, inert solvent, such as dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, 1, 2-dichloroethane or dioxane.
  • a suitable, inert solvent such as dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, 1, 2-dichloroethane or dioxane.
  • the filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo. If dimethylformamide is used, the reaction mixture is stirred into a large amount of water and the precipitate which has separated out is filtered off or the aqueous phase is extracted with a suitable organic solvent and the organic phases are concentrated in vacuo. The remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol or toluene, or by column or flash chromatography on silica gel or aluminum oxide. A mixture of methanol and dichloromethane, for example, serves as the mobile phase.
  • a suitable solvent for example ethanol or toluene
  • reaction product 4 with phosgene or carbonyldiimidazole and a corresponding amine in a suitable inert solvent, such as, for example, tetrahydrofuran, toluene, dichloromethane or acetonitrile be implemented.
  • a suitable base preferably pyridine, sodium hydrogen carbonate, triethylamine, N-methylmorpholine or sodium acetate, is used.
  • the reaction mixture is allowed to react for a time, for example 15 minutes to 24 hours, in a temperature range between 0 and 60 ° C.
  • the filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo.
  • dimethylformamide the reaction mixture is stirred into a large amount of water and the precipitate is filtered off or the aqueous phase is extracted with a suitable organic solvent and the organic phases are concentrated in vacuo.
  • the remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol or ethyl acetate, or by column or flash chromatography on silica gel or aluminum oxide. A mixture of methanol and dichloromethane, for example, serves as the mobile phase.
  • reaction product 4 with a corresponding isothiocyanate and optionally a suitable base, preferably sodium hydride, triethylamine or pyridine, in a suitable, inert solvent, such as, for example Dimethylformamide, tetrahydrofuran, acetone or toluene can be implemented.
  • a suitable, inert solvent such as, for example Dimethylformamide, tetrahydrofuran, acetone or toluene
  • the reaction mixture is allowed to react for a time, for example 30 minutes to 90 hours, in a temperature range between 0 and 115 ° C.
  • the Filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo. If dimethylformamide is used, the reaction mixture is stirred into a large amount of water and the precipitate which has separated out is filtered off or the aqueous phase is extracted with a suitable organic solvent and the organic phases are concentrated in vacuo. The remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol or ethyl acetate, or by column or flash chromatography on silica gel or aluminum oxide. A mixture of methanol and dichloromethane, for example, serves as the mobile phase.
  • a suitable solvent for example ethanol or ethyl acetate
  • reaction product 4 with thiophosgene or thiocarbonyldiimidazole and a corresponding amine in a suitable inert solvent such as, for example, tetrahydrofuran, toluene, dichloromethane
  • a suitable inert solvent such as, for example, tetrahydrofuran, toluene, dichloromethane
  • Ethanol or acetonitrile are implemented.
  • a suitable base preferably pyridine, sodium hydrogen carbonate, potassium carbonate, triethylamine or imidazole.
  • the reaction mixture is allowed to react for several hours, for example 1 to 24 hours, in a temperature range between -10 and 80 ° C.
  • the filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo. If dimethylformamide is used, the reaction mixture is stirred into a large amount of water and the precipitate which has separated out is filtered off or the aqueous phase is extracted with a suitable organic solvent and the organic phases are concentrated in vacuo. The remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol or ethyl acetate, or by column or flash chromatography on silica gel or aluminum oxide.
  • a suitable solvent for example ethanol or ethyl acetate
  • reaction product 4 can be inert with an appropriate aminonitrile and, if appropriate, a suitable base, preferably triethylamine, or a suitable acid, preferably hydrochloric acid Solvents such as acetone, toluene, chlorobenzene, ethanol, tetrahydrofuran or dimethyl sulfoxide are reacted.
  • the reaction mixture is allowed to react for several hours, for example 2 to 140 hours, in a temperature range between 20 and 135 ° C.
  • the filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo.
  • the remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol, or by column or flash chromatography on silica gel or aluminum oxide. A mixture of methanol and dichloromethane, for example, serves as the mobile phase.
  • reaction product 4 with an appropriate nitrile and optionally a suitable base, preferably sodium amide or sodium hexamethyl disilazide, or a suitable catalyst, for example aluminum trichloride, Trimethylaluminum, glacial acetic acid or sulfuric acid, in a suitable, inert solvent, such as tetrahydrofuran, toluene, or ethanol, or without a solvent.
  • a suitable base preferably sodium amide or sodium hexamethyl disilazide
  • a suitable catalyst for example aluminum trichloride, Trimethylaluminum, glacial acetic acid or sulfuric acid
  • a suitable, inert solvent such as tetrahydrofuran, toluene, or ethanol, or without a solvent.
  • the filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo.
  • the remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol, or by column or flash chromatography on silica gel or aluminum oxide.
  • a mixture of methanol and dichloromethane, for example, serves as the mobile phase.
  • OH, SH and NH 2 groups can possibly undergo undesirable side reactions. It is therefore preferred to provide them with protecting groups or, in the case of NH 2 NO 2 by replacing and subsequently remove the protecting group or to reduce the NO 2 group.
  • At least one OH group for example by a benzyloxy group and / or at least one SH group, for example by an S-benzyl group and / or at least one NH 2 group by an NO 2 - Group to be replaced.
  • at least one - preferably all - benzyloxy group / s for example with hydrogen and palladium on carbon and / or at least one - preferably all - S-benzyl group / s, for example with sodium in ammonia, and / or at least one - preferably all - NO 2 group / s can be reduced to NH 2 , for example using hydrogen and Raney nickel.
  • carboxylic acid ester and carboxamide groups can potentially undergo undesirable side reactions. It is therefore preferred to produce carboxylic acid ester and carboxamide groups from process products which contain at least one OH and / or at least one NH 2 and / or at least one COOH group.
  • process products which have at least one OH group and / or which have at least one NH 2 group can be converted into carboxylic acid ester or carboxamide groups by reaction with an activated carboxylic acid group, for example a carboxylic acid chloride group.
  • process products which have at least one COOH group can be converted into carboxylic acid ester or carboxamide groups by reaction with an activating agent, such as, for example, thionyl chloride or carbonyldiimidazole, and subsequent reaction with a suitable alcohol or amine.
  • an activating agent such as, for example, thionyl chloride or carbonyldiimidazole
  • the pyrido [2,3-b] pyrazine derivatives according to the general formula I according to the invention are active substances in medicaments, in particular in malignant and other diseases based on pathological cell proliferation, such as, for. B. restenosis, psoriasis, arteriosclerosis and cirrhosis of the liver for the treatment of people, Suitable for mammals and poultry.
  • Mammals can be pets such as horses, cows, dogs, cats, rabbits, sheep and the like.
  • the medicinal effect of the pyrido [2,3-b] pyrazine derivatives according to the invention can be based, for example, on an inhibition of signal transduction by interaction with receptor tyrosine kinases as well as with cytoplasmic tyrosine and serine / threonine kinases.
  • receptor tyrosine kinases as well as with cytoplasmic tyrosine and serine / threonine kinases.
  • other known and unknown mechanisms of action to combat malignant processes are conceivable.
  • a method for combating tumors in humans and in mammals which is characterized in that at least one pyrido [2,3-b] pyrazine derivative according to the general formula I is used in humans or in a mammal an effective amount for tumor treatment is administered.
  • the therapeutically effective dose of the respective pyrido [2,3-bpyrazine derivative according to the invention to be administered for the treatment is directed inter alia. according to the type and stage of the tumor, the age and sex of the patient, the type of administration and the duration of treatment.
  • the pharmaceuticals according to the invention can be administered as liquid, semi-solid and solid pharmaceutical forms.
  • the pharmaceutical forms optionally contain auxiliaries, such as, inter alia, solvents, solution accelerators, solubilizers, emulsifiers, wetting agents, antifoams, gelling agents, thickeners, film formers, binders, buffers, salt formers, drying agents, flow regulators, fillers, preservatives , Antioxidants, dyes, mold release agents, lubricants, disintegrants, taste and smell correctives.
  • auxiliaries such as, inter alia, solvents, solution accelerators, solubilizers, emulsifiers, wetting agents, antifoams, gelling agents, thickeners, film formers, binders, buffers, salt formers, drying agents, flow regulators, fillers, preservatives , Antioxidants, dyes, mold release agents, lubricants, disintegrants, taste and smell correctives.
  • auxiliaries such as, inter alia, solvents, solution accelerators, solubilizers, emulsifiers, wetting agents
  • the medicaments according to the invention can be applied to the skin in a suitable dosage form, epicutaneously as a solution, suspension, emulsion, foam, ointment, paste or plaster; via the oral and tongue mucosa, buccal, lingual or sublingual as a tablet, lozenge, dragees, linctus or gargle water; via the gastric and intestinal mucosa, enterally as tablets, coated tablets, capsules, solutions, suspensions or emulsions; via the rectal mucosa, rectally as a suppository, rectal capsule or ointment; through the nasal mucosa, nasally as drops, ointments or spray; via the bronchial and alveolar epithelium, pulmonally or by inhalation as aerosol or inhalation; via the conjunctiva, conjunctival as eye drops, eye ointment, eye tablets, lamellae or eyewash; via the mucous membranes of the genital organ
  • the compounds of general structure I according to the invention can be extended with regard to practical therapeutic requirements by means of suitable measures in their drug action. This goal can be achieved chemically and / or galenically. Examples of achieving an increase in activity are the use of implants and liposomes, the formation of poorly soluble salts and complexes or the use of crystal suspensions.
  • compositions which contain at least one compound from the following group of the pyrido [2,3-b] pyrazine derivatives of the general structure I and which can be present in the form of their free base or as pharmaceutically acceptable salts of physiologically acceptable acids are particularly preferred:
  • a solution of 1.22 g of 2,6-diamino-3-nitropyridine (7.92 mmol) in 210 ml of ethanol is hydrogenated with Raney nickel as a catalyst at 50 ° C. and 5 bar. After the hydrogenation has ended, the catalyst is suctioned off through a glass fiber filter. Before the filtration, 1.68 g of phenylglyoxal hydrate (11.03 mmol) in 50 ml of ethanol are placed in the receiver. The catalyst is then filtered off under nitrogen as a protective gas and the hydrogenation solution is sucked directly into the reaction flask. The green-blue reaction mixture is under nitrogen for 30 min. heated under reflux. The mixture is allowed to cool and the solvent is removed in vacuo.
  • 0.246 g of sodium hydride (6.14 mmol) are placed in 5 ml of anhydrous dimethylformamide under nitrogen as a protective gas. The mixture is cooled to 0 ° C. in an ice bath. 1.05 g of 3-phenyl-pyrido [2,3-b] pyrazin-6-ylamine (4.72 mmol) are dissolved in 5 ml of anhydrous dimethylformamide and added dropwise. The cooling bath is removed and the mixture is allowed to stir at RT for 30 minutes. The mixture is then cooled again to 0 ° C.
  • Example 5 1 - (2-methyl-allyl) -3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea
  • Example 6 1 - (2-methyl-allyl) -3- (3-naphthalen-2-yl-pyrido [2,3-b] pyrazin-6-yl) thiourea
  • Example 7 1 - [3- (4-methoxyphenyl) pyrido [2,3-b] pyrazin-6-yl] -3- (2-methyl-allyl) thiourea
  • Example 8 1 - (3-Naphthalin-2-yl-pyrido [2,3-b] pyrazin-6-yl) -3- (4-nitro-phenyl) thiourea
  • Example 9 1 - [3- (4-methoxyphenyl) pyrido [2,3-b] pyrazin-6-yl] -3- (4-nitro-phenyl) thiourea
  • Example 12 1-Methyl-3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea
  • Example 14 1 - (4-Fluoro-phenyl) -3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea M.p .: 225-226 ° C
  • Example 15 1 - (3-Phenylpyrido [2,3-b] pyrazin-6-yl) -3-p-tolylurea
  • Example 16 1 - (4-Chloro-3-trifluoromethyl-phenyl) -3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) urea
  • Example 17 1 - (2-Morpholin-4-yl-ethyl) -3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) urea
  • the inhibitory activity of the compounds according to the invention was tested on the following human serine / threonine and tyrosine kinases in classic kinase assays: PKB / Akt1, c-Raf, B-Raf, Mek, PDGFRbeta, Flt-3, c-Kit, c-Abl, KDR , FGFR1 and IGF1 R. Both full-length kinases and truncated fragments were used - but at least the cytoplasmic, constitutively active kinase domains.
  • the kinases were produced as recombinant fusion proteins with GST (glutathione S-transferase) or HIS tag in Sf9 cell culture. Depending on the type of substrate, the various kinase reactions were carried out in sandwich ELISA formats or using a simple substrate adsorption test on 96-well flashplates (Perkin Elmer).
  • a typical kinase batch was carried out in a final volume of 50 // I with 20-150ng Raf, Mek, Erk kinase protein, 1mM ATP, 10mM MgCl 2 , 150mM NaCl, 25mM beta-glycerophosphate, 25mM Hepes pH 7.5.
  • the test substances were individually preincubated with each of the three kinase proteins for 30 minutes at room temperature.
  • the kinases preincubated with the test substance were combined and incubated at 26 ° C. for 30 minutes. The reaction was stopped by a final concentration of 2% SDS and 10 minutes at 50 ° C in the heating block.
  • the reaction mixtures were transferred to anti-Erk-Ak (K-23, Santa Cruz Biotechnology) -coated 96 MTPs, incubated for 60 minutes at room temperature and washed 3 times with TBST.
  • Anti-phospho-Erk-Ak (# 9106, New England Biolabs) 1: 500 in 50 l TBST / 1% BSA was added and incubated overnight at 4 ° C.
  • secondary anti-mouse IgG POD conjugate # NA931, Pharmacia
  • OPD o-phenyldiamine dihydrochloride
  • the compounds according to the invention show an effective inhibition of Erk phosphorylation with IC-50 values up to 400 nm (see working examples 4 and 12).

Abstract

The invention relates to novel pyrido[2,3-b]pyrazine derivatives of general formula (I), the production and use thereof as medicaments, especially for the treatment of malignant and other diseases based on pathological cell proliferations.

Description

Neue Pyridopyrazine und deren Verwendung als Kinase-Inhibitoren New pyridopyrazines and their use as kinase inhibitors
Die Erfindung betrifft Kinase-Inhibitoren vom Typ der Pyrido[2,3-b]pyrazine, deren Herstellung und Verwendung als Arzneimittel insbesondere zur Behandlung von malignen und anderen, auf pathologischen Zellproliferationen beruhenden Erkrankungen, wie z. B. Restenose, Psoriasis, Arteriosklerose und Leberzirrhose.The invention relates to kinase inhibitors of the pyrido [2,3-b] pyrazine type, their preparation and use as medicaments in particular for the treatment of malignant and other diseases based on pathological cell proliferation, such as, for. B. restenosis, psoriasis, arteriosclerosis and cirrhosis.
Die Aktivierung von Proteinkinasen ist ein zentrales Ereignis bei zellulären Signaltransduktions-Prozessen. Eine aberrante Kinaseaktivierung wird bei diversen Krankheitszuständen beobachtet. Daher ist die gezielte Inhibition solcher konstitutiv aktiven Kinasen ein fundamentales therapeutisches Ziel.The activation of protein kinases is a key event in cellular signal transduction processes. Aberrant kinase activation is observed in various disease states. The targeted inhibition of such constitutively active kinases is therefore a fundamental therapeutic goal.
Die Phosphorylierung von Proteinen wird im Allgemeinen durch extrazelluläre Signale initiiert und stellt einen universellen Mechanismus für die Kontrolle von verschiedenen zellulären Ereignissen, wie z. B. metabolischen Prozessen, Zellwachstum, Zellmigration, Zelldifferenzierung, Membrantransport und Apoptose dar. Für die Pro- teinphosphorylierung ist die Proteinfamilie der Kinasen verantwortlich. Diese Enzyme katalysieren den Phosphat-Transfer zu spezifischen Substratproteinen. Basierend auf der Substratspezifität werden die Kinasen in zwei Hauptklassen, die Tyrosinkina- sen und die Serin/Threonin-Kinasen unterteilt. Sowohl die Rezeptor-Tyrosin-kinasen als auch die cytoplasmatischen Tyrosin- und Serin/Threoninkinasen sind wichtige Proteine der Signaltransduktion der Zelle. Eine Überexpression bzw. Entartung dieser Proteine spielt eine wichtige Rolle bei auf pathologischen Zellproliferationen beruhenden Erkrankungen. Dazu zählen unter anderem Stoffwechselerkrankun-gen, Erkrankung des Bindegewebes und der Blutgefäße, sowie maligne und benigne Tumorerkrankungen. Bei der Tumorentstehung und Entwicklung treten sie häufig als Onkogene d.h. als aberrante, konstitutiv aktive Kinaseproteine auf. Die Folgen dieser übermäßigen Kinaseaktivierung sind z. B. das unkontrollierte .Zellwachstum und der reduzierte Zelltod. Auch die Stimulation von tumorinduzierten Wachstumsfaktoren kann Ursache für die Überstimulation von Kinasen sein. Die Entwicklung von Kina- seinhibitoren ist daher von besonderem Interesse für alle pathogenen Prozesse, die durch Kinasen beeinflusst werden. Die Erfindung ist daher darauf ausgerichtet, neue Verbindungen zu schaffen, die als Inhibitoren von solchen konstitutiv aktiven Kinasen, insbesondere den Rezeptor- Tyrosinkinasen als auch den cytoplasmatischen Tyrosin- und Serin/Threoninkinasen geeignet sind.The phosphorylation of proteins is generally initiated by extracellular signals and provides a universal mechanism for the control of various cellular events, such as. B. metabolic processes, cell growth, cell migration, cell differentiation, membrane transport and apoptosis. The protein family of kinases is responsible for protein phosphorylation. These enzymes catalyze the phosphate transfer to specific substrate proteins. Based on the substrate specificity, the kinases are divided into two main classes, the tyrosine kinases and the serine / threonine kinases. Both the receptor tyrosine kinases and the cytoplasmic tyrosine and serine / threonine kinases are important proteins in the signal transduction of the cell. Overexpression or degeneration of these proteins plays an important role in diseases based on pathological cell proliferation. These include metabolic diseases, diseases of the connective tissue and blood vessels, as well as malignant and benign tumor diseases. In tumor development and development, they often occur as oncogenes, ie as aberrant, constitutively active kinase proteins. The consequences of this excessive kinase activation are e.g. B. the uncontrolled. Cell growth and reduced cell death. The stimulation of tumor-induced growth factors can also be the cause of overstimulation of kinases. The development of kinase inhibitors is therefore of particular interest for all pathogenic processes that are influenced by kinases. The invention is therefore aimed at creating new compounds which are suitable as inhibitors of such constitutively active kinases, in particular the receptor tyrosine kinases and also the cytoplasmic tyrosine and serine / threonine kinases.
In 6-Position substituierte Pyrido[2,3-b]pyrazin-Derivate finden als pharmakologisch aktive Verbindungen und als Synthesebausteine in der pharmazeutischen Chemie vielfältige Verwendung. Beispielsweise werden in der Patentschrift WO99/17759 Py- rido[2,3-b]pyrazine beschrieben, die in 6-Position unter anderem Alkyl-, Aryl- und He- teroarylsubstituierte Carbamate tragen. Diese Verbindungen sollen dazu verwendet werden, die Funktion von Serin-Threonin-Proteinkinasen zu modulieren. Weiterhin werden in dem Patent WO 03/024448 A2 von Delorme et al. Amid- und Acrylamid-substituierte Pyrido[2,3-b]pyrazine beschrieben, die als zusätzliche Substi- tuenten auch Carbamate enthalten und als Histon Deacetylase-Inhibitoren zur Behandlung von Zellproliferationserkrankungen verwendet werden können. In einer weiteren Publikation (C. Temple, Jr.; J. Med. Chem. 1990, 3044-3050) wird an einem Beispiel die Synthese eines 6-Ethylcarbamat-substituierten Pyrido[2,3- b]pyrazin-Derivates beschrieben. Eine Antitumorwirkung ist weder offenbart noch nahegelegt.Pyrido [2,3-b] pyrazine derivatives substituted in the 6-position are widely used as pharmacologically active compounds and as synthesis building blocks in pharmaceutical chemistry. For example, the patent WO99 / 17759 describes pyrido [2,3-b] pyrazines which carry, inter alia, alkyl, aryl and heteroaryl-substituted carbamates in the 6-position. These compounds are said to be used to modulate the function of serine threonine protein kinases. Furthermore, in the patent WO 03/024448 A2 by Delorme et al. Amide- and acrylamide-substituted pyrido [2,3-b] pyrazines are described which also contain carbamates as additional substituents and can be used as histone deacetylase inhibitors for the treatment of cell proliferation disorders. Another publication (C. Temple, Jr .; J. Med. Chem. 1990, 3044-3050) describes the synthesis of a 6-ethylcarbamate-substituted pyrido [2,3-b] pyrazine derivative using an example. An anti-tumor effect is neither disclosed nor suggested.
Die Synthese von weiteren Derivaten des 6-Ethylcarbamat-substituierten Pyrido[2,3- b]pyrazins wird in einer Veröffentlichung von R. D. Elliott beschrieben (J. Org. Chem. 1968, 2393-2397). Eine biologische Wirkung dieser Verbindungen ist weder beschrieben noch nahegelegt.The synthesis of further derivatives of 6-ethylcarbamate-substituted pyrido [2,3-b] pyrazine is described in a publication by R. D. Elliott (J. Org. Chem. 1968, 2393-2397). A biological effect of these compounds is neither described nor suggested.
In der Publikation von C.Temple, Jr. J. Med. Chem. 1968,1216-1218 wird die Synthese und Untersuchung von 6-Ethylcarbamat-substituierten Pyrido[2,3-b]pyrazinen als potentielle Antimalaria-Wirkstoffe beschrieben. Eine Antitumorwirkung ist weder offenbart noch nahegelegt.The publication by C.Temple, Jr. J. Med. Chem. 1968, 1216-1218 describes the synthesis and investigation of 6-ethylcarbamate-substituted pyrido [2,3-b] pyrazines as potential antimalarial agents. An anti-tumor effect is neither disclosed nor suggested.
Es wurde jetzt überraschend gefunden, daß neue Verbindungen aus der Reihe der Pyrido[2,3-b]pyrazine, welche in 6-Position z. B. mit Harnstoff-, Thiohamstoff-, Gua- nidin- oder Amidingruppen substituiert sind, zur Herstellung von Arzneimitteln und insbesondere zur Behandlung von malignen und anderen, auf pathologischen Zellproliferationen beruhenden Erkrankungen geeignet sind. Gemäß diesem Aspekt werden in der vorliegenden Anmeldung neue Verbindungen aus der Reihe der Pyri- do[2,3-b]pyrazine gemäß der allgemeinen Formel I beschrieben,It has now surprisingly been found that new compounds from the series of the pyrido [2,3-b] pyrazines, which in the 6-position z. B. are substituted with urea, thiourea, guanidine or amidine groups, are suitable for the production of medicaments and in particular for the treatment of malignant and other diseases based on pathological cell proliferation. According to this aspect new compounds from the series of pyrido [2,3-b] pyrazines according to general formula I are described in the present application,
II
worin die Substituenten R1 -R3 folgende Bedeutung habenwherein the substituents R1 -R3 have the following meaning
R1 und R2 können unabhängig voneinander:R1 and R2 can independently:
(i) Wasserstoff(i) hydrogen
(ii) Hydroxyl(ii) hydroxyl
(iii) Alkyl, wobei der Alkylrest gesättigt ist und aus 1 bis 8 C-Atomen bestehen kann,(iii) alkyl, where the alkyl radical is saturated and can consist of 1 to 8 carbon atoms,
(iv) unsubstituiertes oder substituiertes Aryl, wobei der Arylrest mit F, Cl, Br, I, CF3) CN, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH- Heteroaryl, NH-Alkyl-Cycloalkyl, NH-Alkyl-Heterocyclyl, NH-Alkyl-Aryl, NH- Alkyl-Heteroaryl, NH-Alkyl-NH2, NH-Alkyl-OH, N(Alkyl)2, NHC(O)-Alkyl, NHC(O)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2-Alkyl, NHSO2-Aryl, NHSO2-Heteroaryl, NO2) SH, S-Alkyl, S-Aryl, S- Heteroaryl, OH, OCF3, O-Alkyl, O-Cycloalkyl, O-Heterocyclyl, O-Aryl, O- Heteroaryl, O-Alkyl-Cycloalkyl, O-Alkyl-Heterocyclyl, O-Alkyl-Aryl, O-Alkyl- Heteroaryl, O-Alkyl-OH, OC(O)-Alkyl, OC(O)-Cycloalkyl, OC(O)-Heterocyclyl, OC(0)-Aryl, OC(0)-Heteroaryl, OS02-Alkyl, OSO2-Aryl, OSO2-Heteroaryl, C(O)-Aryl, C(O)-Heteroaryl, CO2H, C02-Alkyl, CO2-Cycloalkyl, C02- Heterocyclyl, CO2-Aryl, CO2-Heteroaryl, CO2-Alkyl-Cycloalkyl, CO -Alkyl- Heterocyclyl, CO2-AlkyI-Aryl, CO2-Alkyl-Heteroaryl, C(O)-NH2, C(0)NH-Alkyl, C(O)NH-Cycloalkyl, C(O)NH-Heterocyclyl, C(O)NH-Aryl, C(O)NH-Heteroaryl, C(O)NH-Alkyl-CycIoalkyl, C(O)NH-Alkyl-Heterocyclyl, C(O)NH-Alkyl-Aryl, C(O)NH-Alkyl-Heteroaryl, C(O)N(Alkyl)2> SO2-Alkyl, SO2-Aryl, SO2NH2, SO2NH-Alkyl, SO2NH-Aryl, SO2NH-Heteroaryl, SO3H, SO2O-Alkyl, S020-Aryl, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- oder mehrfach, gleich oder verschieden substituiert sein kann, und die Alkyl-, Cycloalkyl-, Heterocyclyl-, Aryl-, Heteroaryl-, Alkyl-Cycloalkyl-, Alkyl-Heterocyclyl-, Alkyl-Aryl- und Al- kyl-Heteroarylsubstituenten ihrerseits wiederum substituiert sein können,(iv) unsubstituted or substituted aryl, where the aryl radical with F, Cl, Br, I, CF 3) CN, NH 2 , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH- Alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH 2 , NH-alkyl-OH, N (alkyl) 2 , NHC (O) -alkyl, NHC ( O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHSO 2 alkyl, NHSO 2 aryl, NHSO 2 heteroaryl, NO 2) SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF 3 , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl heterocyclyl, O-alkyl aryl , O-alkyl heteroaryl, O-alkyl-OH, OC (O) alkyl, OC (O) cycloalkyl, OC (O) heterocyclyl, OC (0) aryl, OC (0) heteroaryl, OS0 2 Alkyl, OSO 2 aryl, OSO 2 heteroaryl, C (O) aryl, C (O) heteroaryl, CO 2 H, C0 2 alkyl, CO 2 cycloalkyl, C0 2 heterocyclyl, CO 2 aryl , CO 2 heteroaryl, CO 2 alkyl cycloalkyl, CO alkyl Heterocyclyl, CO 2 alkylI-aryl, CO 2 alkyl heteroaryl, C (O) -NH 2 , C (0) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C ( O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH- Alkyl heteroaryl, C (O) N (alkyl) 2> SO 2 alkyl, SO 2 aryl, SO 2 NH 2 , SO 2 NH alkyl, SO 2 NH aryl, SO 2 NH heteroaryl, SO3H, SO 2 O-alkyl, S0 2 0-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, can be substituted one or more times, identically or differently, and the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, In turn, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl and alkyl-heteroaryl substituents can in turn be substituted,
(v) unsubstituiertes oder substituiertes Heteroaryl, wobei der Heteroarylrest mit F, Cl, Br, I, CF3, CN, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH-Heteroaryl, N(Alkyl)2, NHC(O)-Alkyl, NHC(O)-Cycloalkyl, NHC(O)- Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2-Alkyl, NHS02-Aryl, NHSO2-Heteroaryl, NO2, SH, S-Alkyl, S-Aryl, OH, OCF3, O-Alkyl, O- Cycloalkyl, O-Aryl, O-Heteroaryl, OC(O)-Alkyl, OC(O)-Cycloalkyl, OC(O)- Heterocyclyl, OC(O)-Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OSO2-Cycloalkyl, OSO2-Aryl, OSO2-Heteroaryl, C(O)-Alkyl, C(O)-Aryl, CO2H, CO2-Alkyl, CO2- Cycloalkyl, CO2-Heterocyclyl, CO2-Aryl, C02-Heteroaryl, C(O)-NH2, C(O)NH- Alkyl, C(O)NH-Cycloalkyl, C(O)NH-Heterocyclyl, C(O)NH-Aryl, C(O)NH- Heteroaryl, C(O)N(Alkyl)2, SO2NH2, SO2NH-Alkyl, SO2NH-Aryl, SO3H, S02O- Alkyl, S02O-Aryl, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- o- der mehrfach, gleich oder verschieden substituiert sein kann, und die Alkyl-, Cycloalkyl-, Heterocyclyl-, Aryl- und Heteroarylsubstituenten ihrerseits wiederum substituiert sein können, bedeutet.(v) unsubstituted or substituted heteroaryl, the heteroaryl radical being substituted with F, Cl, Br, I, CF 3 , CN, NH 2 , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, N ( Alkyl) 2 , NHC (O) alkyl, NHC (O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHSO 2 alkyl, NHS0 2 aryl, NHSO 2- heteroaryl, NO 2 , SH, S-alkyl, S-aryl, OH, OCF 3 , O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl, OC (O) alkyl, OC (O) - Cycloalkyl, OC (O) - heterocyclyl, OC (O) aryl, OC (O) heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OSO 2 aryl, OSO 2 heteroaryl, C (O) alkyl, C (O) aryl, CO 2 H, CO 2 alkyl, CO 2 cycloalkyl, CO 2 heterocyclyl, CO 2 aryl, C0 2 heteroaryl, C (O) -NH 2 , C (O) NH- Alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) N (alkyl) 2 , SO 2 NH 2 , SO 2 NH-alkyl, SO 2 NH-aryl, SO3H, S0 2 O-alkyl, S0 2 O-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, one or more, can be substituted several times, identically or differently, and the Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituents can in turn be substituted.
R3 kann:R3 can:
-C(Y)NR4R5 bedeuten, wobei Y = O, S und R4 und R5 unabhängig voneinanderMean -C (Y) NR4R5, where Y = O, S and R4 and R5 independently of one another
(i) Wasserstoff, (ii) unsubstituiertes oder substituiertes Alkyl, wobei der Alkylrest mit F, Cl, Br, I, CF3) CN, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH- Heteroaryl, NH-Alkyl-Aryl, NH-Alkyl-Heteroaryl, N(Alkyl)2, NHC(O)-Alkyl, NHC(O)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2-Alkyl, NHSO2-Cycloalkyl, NHSO2-Aryl, NHSO2- Heteroaryl, N02, SH, S-Alkyl, S-Cycloalkyl, S-Heterocyclyl, S-Aryl, S-Heteroaryl, OH, OCF3, O-Alkyl, O-Cycloalkyl, O-Heterocyclyl, O-Aryl, O-Heteroaryl, O-Alkyl-Cycloalkyl, O- Alkyl-Aryl, O-Alkyl-Heteroaryl, OC(0)-Alkyl, OC(O)-Cycloalkyl, OC(O)- Heterocyclyl, OC(O)-Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OSO2-Cycloalkyl, OSO2-Aryl, OSO2-Heteroaryl, C(O)-Alkyl, C(O)-Aryl, CO2H, CO2-Alkyl, C02- Cycloalkyl, CO2-Heterocyclyl, CO2-Aryl, C02-Heteroaryl, CO2-Alkyl-Cycloalkyl, CO2-Alkyl-Heterocyclyl, CO2-Alkyl-Aryl, CO2-Alkyl-Heteroaryl, C(O)-NH2, C(O)NH-Alkyl, C(0)NH-Cycloalkyl, C(0)NH-Heterocyclyl, C(O)NH-Aryl, C(O)NH-Heteroaryl, C(O)NH-Alkyl-Cycloalkyl, C(0)NH-Alkyl-Heterocyclyl, C(O)NH-Alkyl-Aryl, C(O)NH-Alkyl-Heteroaryl, C(O)N(Alkyl)2,(i) hydrogen, (ii) unsubstituted or substituted alkyl, the alkyl radical having F, Cl, Br, I, CF 3) CN, NH 2 , NH alkyl, NH cycloalkyl, NH heterocyclyl, NH aryl, NH heteroaryl, NH Alkyl aryl, NH alkyl heteroaryl, N (alkyl) 2 , NHC (O) alkyl, NHC (O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl , NHSO 2 alkyl, NHSO 2 cycloalkyl, NHSO 2 aryl, NHSO 2 - heteroaryl, N0 2 , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF 3 , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC (0) -alkyl, OC (O) -Cycloalkyl, OC (O) - heterocyclyl, OC (O) aryl, OC (O) heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OSO 2 aryl, OSO 2 heteroaryl, C (O) alkyl , C (O) aryl, CO 2 H, CO 2 alkyl, C0 2 cycloalkyl, CO 2 heterocyclyl, CO 2 aryl, C0 2 heteroaryl, CO 2 alkyl cycloalkyl, CO 2 alkyl heterocyclyl , CO 2 -alkyl-aryl, CO 2 -alkyl-heteroaryl, C (O) -NH 2 , C (O) NH-alkyl, C (0) NH-cycloalkyl, C (0) NH-heterocyclyl, C (O ) NH Aryl, C (O) NH heteroaryl, C (O) NH alkyl cycloalkyl, C (0) NH alkyl heterocyclyl, C (O) NH alkyl aryl, C (O) NH alkyl heteroaryl , C (O) N (alkyl) 2 ,
C(O)N(Cycloalkyl)2j C(O)N(Aryl)2l C(0)N(Heteroaryl)2, SO-Alkyl, SO-Aryl, S02- Alkyl, S02-Aryl, SO2NH2, SO3H, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- oder mehrfach, gleich oder verschieden substituiert sein kann,C (O) N (cycloalkyl) 2j C (O) N (aryl) 2l C (0) N (heteroaryl) 2, SO-alkyl, SO-aryl, S0 2 - alkyl, S0 2 aryl, SO 2 NH 2 , SO 3 H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, can be substituted one or more times, identically or differently,
(iii) unsubstituiertes oder substituiertes Cycloalkyl, wobei der Cycloalkylrest mit F, Cl, Br, I, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH- Heteroaryl, NH-Alkyl-Aryl, NH-Alkyl-Heteroaryl, N(Alkyl)2, NHC(O)-Alkyl, NHC(O)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2-Alkyl, NHS02-Cycloalkyl, NHSO2-Aryl, NHSO2-Heteroaryl, OH, O- Alkyl, O-Cycloalkyl, O-Heterocyclyl, O-Aryl, O-Heteroaryl, O-Alkyl-Aryl, O- Alkyl-Heteroaryl, OC(O)-Alkyl, OC(O)-Cycloalkyl, OC(O)-Heterocyclyl, OC(O)- Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OSO2-Cycloalkyl, OSO2-Aryl, OSO2- Heteroaryl, CO2H, CO2-Alkyl, C02-Cycloalkyl, CO2-Heterocyclyl, CO2-Aryl, CO2-Heteroaryl, C(O)-NH2, C(O)NH-Alkyl, C(O)NH-Cycloalkyl, C(O)NH- Heterocyclyl, C(O)NH-Aryl, C(O)NH-Heteroaryl, C(O)NH-Alkyl-Aryl, C(O)NH- Alkyl-Heteroaryl, C(O)N(Alkyl)2, Alkyl, oder Aryl ein- oder mehrfach, gleich o- der verschieden substituiert sein kann, (iv) unsubstituiertes oder substituiertes Heterocyclyl, wobei der Heterocyclylrest mit OH, O-Alkyl, O-Aryl, NH-Alkyl, NH-Aryl, Alkyl, Alkyl-Aryl oder Aryl ein- oder mehrfach, gleich oder verschieden substituiert sein kann,(iii) unsubstituted or substituted cycloalkyl, the cycloalkyl radical having F, Cl, Br, I, NH 2 , NH alkyl, NH cycloalkyl, NH heterocyclyl, NH aryl, NH heteroaryl, NH alkyl aryl, NH Alkyl heteroaryl, N (alkyl) 2 , NHC (O) alkyl, NHC (O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHSO 2 alkyl , NHS0 2 cycloalkyl, NHSO 2 aryl, NHSO 2 heteroaryl, OH, O alkyl, O cycloalkyl, O heterocyclyl, O aryl, O heteroaryl, O alkyl aryl, O alkyl heteroaryl, OC (O) alkyl, OC (O) cycloalkyl, OC (O) heterocyclyl, OC (O) aryl, OC (O) heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OSO 2 aryl, OSO 2 - heteroaryl, CO 2 H, CO 2 alkyl, C0 2 cycloalkyl, CO 2 heterocyclyl, CO 2 aryl, CO 2 heteroaryl, C (O) -NH 2 , C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-aryl, C (O) NH-alkyl- Heteroaryl, C (O) N (alkyl) 2 , alkyl, or aryl, one or more times, the same or which can be substituted differently, (iv) unsubstituted or substituted heterocyclyl, where the heterocyclyl radical may be substituted one or more times, identically or differently, with OH, O-alkyl, O-aryl, NH-alkyl, NH-aryl, alkyl, alkyl-aryl or aryl,
(v) unsubstituiertes oder substituiertes Aryl, wobei der Arylrest mit F, Cl, Br, I, CF3, CN, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH- Heteroaryl, NH-Alkyl-Cycloalkyl, NH-Alkyl-Heterocyclyl, NH-Alkyl-Aryl, NH- Alkyl-Heteroaryl, NH-Alkyl-NH2, NH-Alkyl-OH, N(Alkyl)2, NHC(0)-Alkyl, NHC(O)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2-Alkyl, NHSO2-Aryl, NHSO2-Heteroaryl, NO2) SH, S-Alkyl, S-Cycloalkyl, S-Heterocyclyl, S-Aryl, S-Heteroaryl, OH, OCF3, O-Alkyl, O-Cycloalkyl, O- Heterocyclyl, O-Aryl, O-Heteroaryl, O-Alkyl-Cycloalkyl, O-Alkyl-Heterocyclyl, O-Alkyl-Aryl, O-Alkyl-Heteroaryl, O-Alkyl-OH, OC(O)-Alkyl, OC(O)-Cycloalkyl, OC(O)- Heterocyclyl, OC(O)-Aryl, OC(0)-Heteroaryl, OSO2-Alkyl, OS02- Cycloalkyl, OSO2-Aryl, OSO2-Heteroaryl, C(O)-Alkyl, C(O)-Aryl, C(O)- Heteroaryl, CO2H, CO2-Alkyl, CO2-Cycloalkyl, CO2- Heterocyclyl, C02-Aryl, C02-Heteroaryl, CO2-Alkyl-Cycloalkyl, CO2-Alkyl-Heterocyclyl, CO2-Alkyl-aryl, CO2-Alkyl-Heteroaryl, C(O)-NH2, C(O)NH-Alkyl, C(O)NH-Cycloalkyl, C(0)NH- Heterocyclyl, C(O)NH-Aryl, C(O)NH-Heteroaryl, C(O)NH-Alkyl-Cycloalkyl, C(O)NH-Alkyl-Heterocyclyl, C(O)NH-Alkyl-Aryl, C(O)NH-Alkyl-Heteroaryl, C(0)N(Alkyl)2, C(O)N(Cycloalkyl)2, C(O)N(Aryl)2, C(O)N(Heteroaryl)2, SO- Alkyl, SO-Aryl, SO2-Alkyl, SO2-Aryl, S02NH2, SO2NH-Alkyl, SO2NH-Aryl, SO2NH-Heteroaryl, SO3H, SO2O-Alkyl, SO2O-Aryl, SO2O-Heteroaryl, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- oder mehrfach, gleich oder verschieden substituiert sein kann,(v) unsubstituted or substituted aryl, where the aryl radical with F, Cl, Br, I, CF 3 , CN, NH 2 , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH- Alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH 2 , NH-alkyl-OH, N (alkyl) 2 , NHC (0) -alkyl, NHC ( O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHSO 2 alkyl, NHSO 2 aryl, NHSO 2 heteroaryl, NO 2) SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF 3 , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl -Heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) - heterocyclyl, OC (O) -aryl, OC (0) heteroaryl, OSO 2 alkyl, OS0 2 cycloalkyl, OSO 2 aryl, OSO 2 heteroaryl, C (O) alkyl, C (O) aryl, C (O) heteroaryl, CO 2 H , CO 2 -alkyl, CO 2 -cycloalkyl, CO 2 - heterocyclyl, C0 2 -aryl, C0 2 -heteroaryl, CO 2 -alkyl-cycloalkyl, CO 2 -alkyl-heterocyclyl, CO 2 -alkyl aryl, CO 2 alkyl heteroaryl, C (O) NH 2 , C (O) NH alkyl, C (O) NH cycloalkyl, C (0) NH heterocyclyl, C (O) NH aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C ( 0) N (alkyl) 2 , C (O) N (cycloalkyl) 2 , C (O) N (aryl) 2 , C (O) N (heteroaryl) 2 , SO-alkyl, SO-aryl, SO 2 -alkyl , SO 2 aryl, S0 2 NH 2 , SO 2 NH alkyl, SO 2 NH aryl, SO 2 NH heteroaryl, SO3H, SO 2 O alkyl, SO 2 O aryl, SO 2 O heteroaryl, alkyl , Cycloalkyl, heterocyclyl, aryl or heteroaryl, can be substituted one or more times, identically or differently,
(vi) unsubstituiertes oder substituiertes Heteroaryl, wobei der Heteroarylrest mit F, Cl, Br, I, CF3, CN, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH-Heteroaryl, NH-Alkyl-Aryl, NH-Alkyl-Heteroaryl, N(Alkyl)2, NHC(O)-Alkyl, NHC(O)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2-Alkyl, NHSO2-Aryl, NHSO2-Heteroaryl, NO2, SH, S-Alkyl, S-Aryl, OH, OCF3j O-Alkyl, O-Cycloalkyl, O-Heterocyclyl, O-Aryl, O-Heteroaryl, OC(O)- Alkyl, OC(O)-Cycloalkyl, OC(0)-Heterocyclyl, OC(O)-Aryl, OC(O)-Heteroaryl, OS02-Alkyl, OS02-Cycloalkyl, OS02-Aryl, OS02-Heteroaryl, C(O)-Alkyl, C(O)- Aryl, C(0)-Heteroaryl, CO2H, CO2-Alkyl, CO2-Cycloalkyl, CO2-Heterocyclyl, CO2-Aryl, C02-Heteroaryl, CO2-Alkyl-Cycloalkyl, CO2-Alkyl-Heterocyclyl, CO2- Alkyl-aryl, C02-Alkyl-Heteroaryl, C(O)-NH2, C(O)NH-Alkyl, C(O)NH-Cycloalkyl, C(O)NH-Heterocyclyl, C(O)NH-Aryl, C(O)NH-Heteroaryl, C(O)NH-Alkyl- Cycloalkyl, C(O)NH-Alkyl-Heterocyclyl, C(O)NH-Alkyl-Aryl, C(O)NH-Alkyl- Heteroaryl, C(O)N(Alkyl)2, C(0)N(Cycloalkyl)2> C(O)N(Aryl)2,(vi) unsubstituted or substituted heteroaryl, where the heteroaryl radical with F, Cl, Br, I, CF 3 , CN, NH 2 , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH- Alkyl aryl, NH alkyl heteroaryl, N (alkyl) 2 , NHC (O) alkyl, NHC (O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl , NHSO 2 alkyl, NHSO 2 aryl, NHSO 2 heteroaryl, NO 2 , SH, S-alkyl, S-aryl, OH, OCF 3j O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O Heteroaryl, OC (O) alkyl, OC (O) cycloalkyl, OC (0) heterocyclyl, OC (O) aryl, OC (O) heteroaryl, OS0 2 alkyl, OS0 2 cycloalkyl, OS0 2 Aryl, OS0 2 heteroaryl, C (O) alkyl, C (O) Aryl, C (0) heteroaryl, CO 2 H, CO 2 alkyl, CO 2 cycloalkyl, CO 2 heterocyclyl, CO 2 aryl, C0 2 heteroaryl, CO 2 alkyl cycloalkyl, CO 2 alkyl Heterocyclyl, CO 2 -alkyl-aryl, C0 2 -alkyl-heteroaryl, C (O) -NH 2 , C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C ( O) NH aryl, C (O) NH heteroaryl, C (O) NH alkyl cycloalkyl, C (O) NH alkyl heterocyclyl, C (O) NH alkyl aryl, C (O) NH Alkyl heteroaryl, C (O) N (alkyl) 2 , C (0) N (cycloalkyl) 2> C (O) N (aryl) 2 ,
C(0)N(Heteroaryl)2, SO2-Alkyl, S02-Aryl, SO2NH2) SO2NH-Alkyl, SO2NH-Aryl, SO2NH-Heteroaryl, SO3H, SO2O-Alkyl, SO20-Aryl, SO2O-Heteroaryl, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- oder mehrfach, gleich oder verschieden substituiert sein kann, bedeuten,C (0) N (heteroaryl) 2 , SO 2 alkyl, S0 2 aryl, SO 2 NH 2) SO 2 NH alkyl, SO 2 NH aryl, SO 2 NH heteroaryl, SO3H, SO 2 O alkyl , SO 2 0-aryl, SO 2 O-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, can be substituted one or more times, identically or differently,
(vii) oder R4 und R5 zusammen Cycloalkyl oder Heterocyclyl bedeuten,(vii) or R4 and R5 together mean cycloalkyl or heterocyclyl,
-C(Y)NR6R7 bedeuten, wobei Y = NH und R6 und R7 unabhängig voneinander-C (Y) NR6R7, where Y = NH and R6 and R7 independently of one another
(i) Wasserstoff,(i) hydrogen,
(ii) unsubstituiertes oder substituiertes Alkyl, wobei der Alkylrest mit F, Cl, Br, I, CF3, CN, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH- Heteroaryl, NH-Alkyl-Aryl, NH-Alkyl-Heteroaryl, N(Alkyl)2, NHC(0)-Alkyl, NHC(O)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2-Alkyl, NHS02-Cycloalkyl, NHS02-Aryl, NHSO2-Heteroaryl, N02, SH, S-Alkyl, S-Cycloalkyl, S-Heterocyclyl, S-Aryl, S-Heteroaryl, OH, OCF3, O-Alkyl, O-Cycloalkyl, O-Heterocyclyl, O-Aryl, O-Heteroaryl, O-Alkyl-Cycloalkyl, O- Alkyl-Aryl, O-Alkyl-Heteroaryl, OC(O)-Alkyl, OC(O)-Cycloalkyl, OC(O)- Heterocyclyl, OC(O)-Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OSO2-Cycloalkyl, OS02-Aryl, OSO2-Heteroaryl, C(O)-Alkyl, C(O)-Aryl, CO2H, CO2-Alkyl, CO2- Cycloalkyl, CO2-Heterocyclyl, CO2-Aryl, CO2-Heteroaryl, CO2-Alkyl-Cycloalkyl, CO2-Alkyl-Heterocyclyl, CO2-Alkyl-Aryl, CO -Alkyl-Heteroaryl, C(0)-NH2, C(O)NH-Alkyl, C(0)NH-Cycloalkyl, C(0)NH-Heterocyclyl, C(O)NH-Aryl, C(O)NH-Heteroaryl, C(0)NH-Alkyl-Cycloalkyl, C(0)NH-Alkyl-Heterocyclyl, C(O)NH-Alkyl-Aryl, C(O)NH-Alkyl-Heteroaryl, C(0)N(Alkyl)2,(ii) unsubstituted or substituted alkyl, the alkyl radical having F, Cl, Br, I, CF 3 , CN, NH 2 , NH alkyl, NH cycloalkyl, NH heterocyclyl, NH aryl, NH heteroaryl, NH Alkyl aryl, NH alkyl heteroaryl, N (alkyl) 2 , NHC (0) alkyl, NHC (O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl , NHSO 2 alkyl, NHS0 2 cycloalkyl, NHS0 2 aryl, NHSO 2 heteroaryl, N0 2 , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF 3 , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC (O) -alkyl, OC (O) -Cycloalkyl, OC (O) - heterocyclyl, OC (O) aryl, OC (O) heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OS0 2 aryl, OSO 2 heteroaryl, C (O) alkyl , C (O) aryl, CO 2 H, CO 2 alkyl, CO 2 cycloalkyl, CO 2 heterocyclyl, CO 2 aryl, CO 2 heteroaryl, CO 2 alkyl cycloalkyl, CO 2 alkyl heterocyclyl , CO 2 -alkyl-aryl, CO -alkyl-heteroaryl, C (0) -NH 2 , C (O) NH-alkyl, C (0) NH-cycloalkyl, C (0) NH-heterocyclyl, C (O) NH-A ryl, C (O) NH heteroaryl, C (0) NH alkyl cycloalkyl, C (0) NH alkyl heterocyclyl, C (O) NH alkyl aryl, C (O) NH alkyl heteroaryl, C (0) N (alkyl) 2 ,
C(O)N(Cycloalkyl)2, C(O)N(Aryl)2, C(0)N(Heteroaryl)2) SO-Alkyl, SO-Aryl, SO2- Alkyl, SO2-Aryl, SO2NH2, SO3H, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- oder mehrfach, gleich oder verschieden substituiert sein kann,C (O) N (cycloalkyl) 2 , C (O) N (aryl) 2 , C (0) N (heteroaryl) 2) SO-alkyl, SO-aryl, SO 2 - alkyl, SO 2 -aryl, SO 2 NH 2 , SO 3 H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, can be substituted one or more times, identically or differently,
(iii) unsubstituiertes oder substituiertes Cycloalkyl, wobei der Cycloalkylrest mit F, Cl, Br, I, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH- Heteroaryl, NH-Alkyl-Aryl, NH-Alkyl-Heteroaryl, N(Alkyl)2, NHC(0)-Alkyl, NHC(O)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2-Alkyl, NHSO2-Cycloalkyl, NHSO2-Aryl, NHSO2-Heteroaryl, OH, O- Alkyl, O-Cycloalkyl, O-Heterocyclyl, O-Aryl, O-Heteroaryl, O-Alkyl-Aryl, O- Alkyl-Heteroaryl, OC(O)-Alkyl, OC(0)-Cycloalkyl, OC(O)-Heterocyclyl, OC(O)- Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OSO2-Cycloalkyl, OSO2-Aryl, OSO2- Heteroaryl, CO2H, CO2-Alkyl, CO2-Cycloalkyl, CO2-Heterocyclyl, CO2-Aryl, C02-Heteroaryl, C(O)-NH2, C(O)NH-Alkyl, C(O)NH-Cycloalkyl, C(O)NH- Heterocyclyl, C(O)NH-Aryl, C(O)NH-Heteroaryl, C(O)NH-Alkyl-Aryl, C(0)NH- Alkyl-Heteroaryl, C(O)N(Alkyl)2, Alkyl, oder Aryl ein- oder mehrfach, gleich o- der verschieden substituiert sein kann,(iii) unsubstituted or substituted cycloalkyl, the cycloalkyl radical having F, Cl, Br, I, NH 2 , NH alkyl, NH cycloalkyl, NH heterocyclyl, NH aryl, NH heteroaryl, NH alkyl aryl, NH Alkyl heteroaryl, N (alkyl) 2 , NHC (0) alkyl, NHC (O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHSO 2 alkyl , NHSO 2 cycloalkyl, NHSO 2 aryl, NHSO 2 heteroaryl, OH, O alkyl, O cycloalkyl, O heterocyclyl, O aryl, O heteroaryl, O alkyl aryl, O alkyl heteroaryl, OC (O) alkyl, OC (0) cycloalkyl, OC (O) heterocyclyl, OC (O) aryl, OC (O) heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OSO 2 aryl, OSO 2 - heteroaryl, CO 2 H, CO 2 alkyl, CO 2 cycloalkyl, CO 2 heterocyclyl, CO 2 aryl, C0 2 heteroaryl, C (O) -NH 2 , C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-aryl, C (0) NH-alkyl- Heteroaryl, C (O) N (alkyl) 2 , alkyl, or aryl, one or more times, the same or which can be substituted differently,
(iv) unsubstituiertes oder substituiertes Heterocyclyl, wobei der Heterocyclylrest mit OH, O-Alkyl, O-Aryl, NH-Alkyl, NH-Aryl, Alkyl oder Aryl ein- oder mehrfach, gleich oder verschieden substituiert sein kann,(iv) unsubstituted or substituted heterocyclyl, it being possible for the heterocyclyl radical to be substituted one or more times, identically or differently, by OH, O-alkyl, O-aryl, NH-alkyl, NH-aryl, alkyl or aryl,
(v) unsubstituiertes oder substituiertes Aryl, wobei der Arylrest mit F, Cl, Br, I, CF3, CN, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH- Heteroaryl, NH-Alkyl-Cycloalkyl, NH-Alkyl-Heterocyclyl, NH-Alkyl-Aryl, NH- Alkyl-Heteroaryl, NH-Alkyl-NH2, NH-Alkyl-OH, N(Alkyl)2, NHC(0)-Alkyl, NHC(0)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2-Alkyl, NHSO2-Aryl, NHSO2-Heteroaryl, NO2, SH, S-Alkyl, S-Cycloalkyl, S-Heterocyclyl, S-Aryl, S-Heteroaryl, OH, OCF3, O-Alkyl, O-Cycloalkyl, O- Heterocyclyl, O-Aryl, O-Heteroaryl, O-Alkyl-Cycloalkyl, O-Alkyl-Heterocyclyl, O-Alkyl-Aryl, O-Alkyl-Heteroaryl, O-Alkyl-OH, OC(0)-Alkyl, OC(O)-Cycloalkyl, OC(O)-Heterocyclyl, OC(O)-Aryl, OC(0)-Heteroaryl, OSO2-Alkyl, OSO2- Cycloalkyl, OSO2-Aryl, OSO2-Heteroaryl, C(O)-Alkyl, C(O)-Aryl, C(O)- Heteroaryl, CO2H, CO2-Alkyl, CO2-Cycloalkyl, CO2-Heterocyclyl, C02-Aryl, CO2-Heteroaryl, CO2-Alkyl-Cycloalkyl, C02-Alkyl-Heterocyclyl, CO2-Alkyl-Aryl, CO2-Alkyl-Heteroaryl, C(O)-NH2, C(0)NH-Alkyl, C(O)NH-Cycloalkyl, C(0)NH- Heterocyclyl, C(O)NH-Aryl, C(O)NH-Heteroaryl, C(O)NH-Alkyl-Cycloalkyl, C(O)NH-Alkyl-Heterocyclyl, C(O)NH-Alkyl-Aryl, C(O)NH-Alkyl-Heteroaryl, C(O)N(Alkyl)2, C(O)N(Cycloalkyl)2, C(O)N(Aryl)2, C(O)N(Heteroaryl)2, SO- Alkyl, SO-Aryl, SO2-Alkyl, SO2-Aryl, SO2NH2> SO2NH-Alkyl, SO2NH-Aryl, SO2NH-Heteroaryl, SO3H, SO2O-Alkyl, SO2O-Aryl, SO2O-Heteroaryl, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- oder mehrfach, gleich oder verschieden substituiert sein kann,(v) unsubstituted or substituted aryl, where the aryl radical with F, Cl, Br, I, CF 3 , CN, NH 2 , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH- Alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH 2 , NH-alkyl-OH, N (alkyl) 2 , NHC (0) -alkyl, NHC ( 0) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHSO 2 alkyl, NHSO 2 aryl, NHSO 2 heteroaryl, NO 2 , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF 3 , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl -Heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH, OC (0) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (0) heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OSO 2 aryl, OSO 2 heteroaryl, C (O) alkyl, C (O) aryl, C (O) - Heteroaryl, CO 2 H, CO 2 alkyl, CO 2 cycloalkyl, CO 2 heterocyclyl, C0 2 aryl, CO 2 heteroaryl, CO 2 alkyl cycloalkyl, C0 2 alkyl heterocyclyl, CO 2 alkyl Aryl, CO 2 alkyl heteroaryl, C (O) -NH 2 , C (0) NH-alkyl, C (O) NH-cycloalkyl, C (0) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O ) N (alkyl) 2 , C (O) N (cycloalkyl) 2 , C (O) N (aryl) 2 , C (O) N (heteroaryl) 2 , SO-alkyl, SO-aryl, SO 2 -alkyl, SO 2 aryl, SO 2 NH 2> SO 2 NH alkyl, SO 2 NH aryl, SO 2 NH heteroaryl, SO3H, SO 2 O alkyl, SO 2 O aryl, SO 2 O heteroaryl, alkyl, Cycloalkyl, heterocyclyl, aryl or heteroaryl, can be substituted one or more times, identically or differently,
(vi) unsubstituiertes oder substituiertes Heteroaryl, wobei der Heteroarylrest mit F, Cl, Br, I, CF3, CN, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH-Heteroaryl, NH-Alkyl-Aryl, NH-Alkyl-Heteroaryl, N(Alkyl)2, NHC(0)-Alkyl, NHC(O)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHS02-Alkyl, NHSO2-Aryl, NHSO2-Heteroaryl, NO2, SH, S-Alkyl, S-Aryl, OH, OCF3, O-Alkyl, O-Cycloalkyl, O-Heterocyclyl, O-Aryl, O-Heteroaryl, OC(O)- Alkyl, OC(0)-Cycloalkyl, OC(O)-Heterocyclyl, OC(O)-Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OSO2-Cycloalkyl, OSO2-Aryl, OSO2-Heteroaryl, C(O)-Alkyl, C(O)- Aryl, C(O)-Heteroaryl, CO2H, CO2-Alkyl, CO2-Cycloalkyl, CO2-Heterocyclyl, CO2-Aryl, CO2-Heteroaryl, CO2-Alkyl-Cycloalkyl, CO2-Alkyl-Heterocyclyl, CO2- Alkyl-aryl, CO2-Alkyl-Heteroaryl, C(O)-NH2, C(O)NH-Alkyl, C(0)NH-Cycloalkyl, C(O)NH-Heterocyclyl, C(O)NH-Aryl, C(O)NH-Heteroaryl, C(O)NH-Alkyl- Cycloalkyl, C(O)NH-Alkyl-Heterocyclyl, C(O)NH-Alkyl-Aryl, C(O)NH-Alkyl- Heteroaryl, C(O)N(Alkyl)2) C(O)N(Cycloalkyl)2, C(O)N(Aryl)2) (vi) unsubstituted or substituted heteroaryl, where the heteroaryl radical with F, Cl, Br, I, CF 3 , CN, NH 2 , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH- Alkyl aryl, NH alkyl heteroaryl, N (alkyl) 2 , NHC (0) alkyl, NHC (O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl , NHS0 2 alkyl, NHSO 2 aryl, NHSO 2 heteroaryl, NO 2 , SH, S-alkyl, S-aryl, OH, OCF 3 , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, OC (O) alkyl, OC (0) cycloalkyl, OC (O) heterocyclyl, OC (O) aryl, OC (O) heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OSO 2 aryl, OSO 2 heteroaryl, C (O) alkyl, C (O) aryl, C (O) heteroaryl, CO 2 H, CO 2 alkyl, CO 2 cycloalkyl, CO 2 heterocyclyl, CO 2 aryl, CO 2 heteroaryl, CO 2 alkyl cycloalkyl, CO 2 alkyl heterocyclyl, CO 2 alkyl aryl, CO 2 alkyl heteroaryl, C (O) -NH 2 , C (O) NH -Alkyl, C (0) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH -Alkyl heterocyclyl, C (O) NH-alkyl- Aryl, C (O) NH-alkyl heteroaryl, C (O) N (alkyl) 2) C (O) N (cycloalkyl) 2 , C (O) N (aryl) 2)
C(O)N(Heteroaryl)2, SO2-Alkyl, SO2-Aryl, SO2NH2, SO2NH-Alkyl, SO2NH-Aryl, SO2NH-Heteroaryl, SO3H, SO2O-Alkyl, SO2O-Aryl, SO2O-Heteroaryl, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- oder mehrfach, gleich oder verschieden substituiert sein kann, bedeuten, (vii) oder R6 und R7 zusammen Cycloalkyl oder Heterocyclyl bedeuten, -C(NR8)R9 bedeuten, wobei R8 = H und R9C (O) N (heteroaryl) 2 , SO 2 alkyl, SO 2 aryl, SO 2 NH 2 , SO 2 NH alkyl, SO 2 NH aryl, SO 2 NH heteroaryl, SO3H, SO 2 O alkyl , SO 2 O-aryl, SO 2 O-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, can be substituted one or more times, identically or differently, (vii) or R6 and R7 together mean cycloalkyl or heterocyclyl, -C (NR8) R9 mean, where R8 = H and R9
(i) unsubstituiertes oder substituiertes Alkyl, wobei der Alkylrest mit F, Cl, Br, I, CF3, NH , NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH-Heteroaryl, NH-Alkyl-Aryl, NH-Alkyl-Heteroaryl, N(Alkyl)2l NHC(O)-Alkyl, NHC(O)- Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2- Alkyl, NHSO2-Cycloalkyl, NHSO2-Aryl, NHSO2-Heteroaryl, N02, SH, S-Alkyl, S-Cycloalkyl, S-Heterocyclyl, S-Aryl, S-Heteroaryl, OH, OCF3, O-Alkyl, O- Cycloalkyl, O-Heterocyclyl, O-Aryl, O-Heteroaryl, O-Alkyl-Cycloalkyl, O-Alkyl- Aryl, O-Alkyl-Heteroaryl, OC(O)-Alkyl, OC(O)-Cycloalkyl, OC(O)-Heterocyclyl, OC(O)-Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OSO2-Cycloalkyl, OSO2-Aryl, OSO2-Heteroaryl, C(O)-Alkyl, C(0)-Aryl, CO2H, CO2-Alkyl, CO2-Cycloalkyl, C02-Heterocyclyl, CO2-Aryl, C02-Heteroaryl, CO2-Alkyl-Cycloalkyl, CO2-Alkyl- Heterocyclyl, C02-Alkyl-Aryl, CO2-Alkyl-Heteroaryl, C(O)-NH2, C(O)NH-Alkyl, C(O)NH-Cycloalkyl, C(O)NH-Heterocyclyl, C(O)NH-Aryl, C(0)NH-Heteroaryl, C(O)NH-Alkyl-Cycloalkyl, C(O)NH-Alkyl-Heterocyclyl, C(0)NH-Alkyl-Aryl, C(O)NH-Alkyl-Heteroaryl, C(O)N(Alkyl)2, C(O)N(Cycloalkyl)2, C(O)N(Aryl)2, C(O)N(Heteroaryl)2, SO-Alkyl, SO-Aryl, SO2-Alkyl, SO2-Aryl, SO2NH2, SO3H, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- oder mehrfach, gleich oder verschieden substituiert sein kann,(i) Unsubstituted or substituted alkyl, where the alkyl radical with F, Cl, Br, I, CF 3 , NH, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl , NH-alkyl heteroaryl, N (alkyl) 2l NHC (O) alkyl, NHC (O) - cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHSO 2 - Alkyl, NHSO 2 cycloalkyl, NHSO 2 aryl, NHSO 2 heteroaryl, N0 2 , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF 3 , O-alkyl , O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC (O) alkyl, OC (O) cycloalkyl, OC (O) heterocyclyl, OC (O) aryl, OC (O) heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OSO 2 aryl, OSO 2 heteroaryl, C (O) alkyl, C (0 ) Aryl, CO 2 H, CO 2 alkyl, CO 2 cycloalkyl, C0 2 heterocyclyl, CO 2 aryl, C0 2 heteroaryl, CO 2 alkyl cycloalkyl, CO 2 alkyl heterocyclyl, C0 2 - Alkyl aryl, CO 2 alkyl heteroaryl, C (O) -NH 2 , C (O) NH alkyl, C (O) NH cycloalkyl, C (O) NH heterocyclyl, C (O) NH aryl . C (0) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heterocyclyl, C (0) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C ( O) N (alkyl) 2 , C (O) N (cycloalkyl) 2 , C (O) N (aryl) 2 , C (O) N (heteroaryl) 2 , SO-alkyl, SO-aryl, SO 2 -alkyl , SO 2 aryl, SO 2 NH 2 , SO 3 H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, can be substituted one or more times, identically or differently,
(ii) unsubstituiertes oder substituiertes Cycloalkyl, wobei der Cycloalkylrest mit F, Cl, Br, I, NH2) NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH- Heteroaryl, NH-Alkyl-Aryl, NH-Alkyl-Heteroaryl, N(Alkyl)2, NHC(O)-Alkyl, NHC(O)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(0)-Aryl, NHC(O)-Heteroaryl, NHS02-Alkyl, NHSO2-Cycloalkyl, NHSO2-Aryl, NHSO2-Heteroaryl, OH, O- Alkyl, O-Cycloalkyl, O-Heterocyclyl, O-Aryl, O-Heteroaryl, O-Alkyl-Aryl, O- Alkyl-Heteroaryl, OC(O)-Alkyl, OC(O)-Cycloalkyl, OC(O)-Heterocyclyl, OC(O)- Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OSO2-Cycloalkyl, OSO2-Aryl, OSO2- Heteroaryl, CO2H, CO2-Alkyl, C02-Cycloalkyl, CO2-Heterocyclyl, CO2-Aryl, CO2-Heteroaryl, C(O)-NH2, C(O)NH-Alkyl, C(O)NH-Cycloalkyl, C(0)NH- Heterocyclyl, C(0)NH-Aryl, C(0)NH-Heteroaryl, C(O)NH-Alkyl-Aryl, C(0)NH- Alkyl-Heteroaryl, C(O)N(Alkyl)2, Alkyl, oder Aryl ein- oder mehrfach, gleich o- der verschieden substituiert sein kann,(ii) unsubstituted or substituted cycloalkyl, the cycloalkyl radical having F, Cl, Br, I, NH 2) NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH Alkyl heteroaryl, N (alkyl) 2 , NHC (O) alkyl, NHC (O) cycloalkyl, NHC (O) heterocyclyl, NHC (0) aryl, NHC (O) heteroaryl, NHS0 2 alkyl , NHSO 2 cycloalkyl, NHSO 2 aryl, NHSO 2 heteroaryl, OH, O alkyl, O cycloalkyl, O heterocyclyl, O aryl, O heteroaryl, O alkyl aryl, O alkyl heteroaryl, OC (O) alkyl, OC (O) cycloalkyl, OC (O) heterocyclyl, OC (O) aryl, OC (O) heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OSO 2 aryl, OSO 2 - heteroaryl, CO 2 H, CO 2 alkyl, C0 2 cycloalkyl, CO 2 heterocyclyl, CO 2 aryl, CO 2 heteroaryl, C (O) -NH 2 , C (O) NH-alkyl, C (O) NH-cycloalkyl, C (0) NH-heterocyclyl, C (0) NH-aryl, C (0) NH-heteroaryl, C (O) NH-alkyl-aryl, C (0) NH- Alkyl heteroaryl, C (O) N (alkyl) 2 , alkyl, or aryl, one or more times, the same or which can be substituted differently,
(iii) unsubstituiertes oder substituiertes Heterocyclyl, wobei der Heterocyclylrest mit OH, O-Alkyl, O-Aryl, NH-Alkyl, NH-Aryl, Alkyl oder Aryl ein- oder mehrfach, gleich oder verschieden substituiert sein kann,(iii) unsubstituted or substituted heterocyclyl, it being possible for the heterocyclyl radical to be substituted one or more times, identically or differently, by OH, O-alkyl, O-aryl, NH-alkyl, NH-aryl, alkyl or aryl,
(iv) unsubstituiertes oder substituiertes Aryl, wobei der Arylrest mit F, Cl, Br, I, CF3, NH2j NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH-Heteroaryl, NH-Alkyl-Cycloalkyl, NH-Alkyl-Heterocyclyl, NH-Alkyl-Aryl, NH-Alkyl- Heteroaryl, NH-Alkyl-NH2, NH-Alkyl-OH, N(Alkyl)2, NHC(O)-Alkyl, NHC(O)- Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2- Alkyl, NHSO2-Aryl, NHSO2-Heteroaryl, NO2, SH, S-Alkyl, S-Cycloalkyl, S- Heterocyclyl, S-Aryl, S-Heteroaryl, OH, OCF3, O-Alkyl, O-Cycloalkyl, O- Heterocyclyl, O-Aryl, O-Heteroaryl, O-Alkyl-Cycloalkyl, O-Alkyl-Heterocyclyl, O-Alkyl-Aryl, O-Alkyl-Heteroaryl, O-Alkyl-OH, OC(O)-Alkyl, OC(O)-Cycloalkyl, OC(O)-Heterocyclyl, OC(O)-Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OSO2- Cycloalkyl, OSO2-Aryl, OSO2-Heteroaryl, C(O)-Alkyl, C(O)-Aryl, C(O)- Heteroaryl, CO2H, CO2-Alkyl, CO2-Cycloalkyl, CO2-Heterocyclyl, C02-Aryl, CO2-Heteroaryl, CO2-Alkyl-CycloaIkyl, CO2-Alkyl-Heterocyclyl, CO2-Alkyl-aryl, CO2-Alkyl-Heteroaryl, C(O)-NH2, C(O)NH-Alkyl, C(O)NH-Cycloalkyl5 C(0)NH- Heterocyclyl, C(O)NH-Aryl, C(O)NH-Heteroaryl, C(O)NH-Alkyl-Cycloalkyl, C(O)NH-Alkyl-Heterocyclyl, C(O)NH-Alkyl-Aryl, C(O)NH-Alkyl-Heteroaryl, C(O)N(Alkyl)2, C(O)N(Cycloalkyl)2, C(O)N(Aryl)2, C(O)N(Heteroaryl)2, SO- Alkyl, SO-Aryl, SO2-Alkyl, SO2-Aryl, SO2NH2) SO2NH-Alkyl, SO2NH-Aryl, SO2NH-Heteroaryl, SO3H, SO2O-Alkyl, SO2O-Aryl, SO2O-Heteroaryl, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- oder mehrfach, gleich oder verschieden substituiert sein kann,(iv) unsubstituted or substituted aryl, the aryl radical having F, Cl, Br, I, CF 3 , NH 2j NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl , NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH 2 , NH-alkyl-OH, N (alkyl) 2 , NHC (O) -alkyl, NHC (O) - Cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHSO 2 alkyl, NHSO 2 aryl, NHSO 2 heteroaryl, NO 2 , SH, S-alkyl, S-cycloalkyl , S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF 3 , O-alkyl, O-cycloalkyl, O- heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH, OC (O) alkyl, OC (O) cycloalkyl, OC (O) heterocyclyl, OC (O) aryl, OC (O) Heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OSO 2 aryl, OSO 2 heteroaryl, C (O) alkyl, C (O) aryl, C (O) heteroaryl, CO 2 H, CO 2 -alkyl, CO 2 -cycloalkyl, CO 2 -heterocyclyl, C0 2 -aryl, CO 2 -heteroaryl, CO 2 -alkyl-CycloaIkyl, CO 2 -alkyl-heterocyclyl, CO 2 -alkyl-ar yl, CO 2 alkyl heteroaryl, C (O) -NH 2 , C (O) NH-alkyl, C (O) NH-cycloalkyl 5 C (0) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O ) N (alkyl) 2 , C (O) N (cycloalkyl) 2 , C (O) N (aryl) 2 , C (O) N (heteroaryl) 2 , SO-alkyl, SO-aryl, SO 2 -alkyl, SO 2 aryl, SO 2 NH 2) SO 2 NH alkyl, SO 2 NH aryl, SO 2 NH heteroaryl, SO3H, SO 2 O alkyl, SO 2 O aryl, SO 2 O heteroaryl, alkyl, Cycloalkyl, heterocyclyl, aryl or heteroaryl, can be substituted one or more times, identically or differently,
(v) unsubstituiertes oder substituiertes Heteroaryl, wobei der Heteroarylrest mit F, Cl, Br, I, CF3, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH- Heteroaryl, NH-Alkyl-Aryl, NH-Alkyl-Heteroaryl, N(Alkyl)2, NHC(0)-Alkyl, NHC(0)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHS02-Alkyl, NHSO2-Aryl, NHSO2-Heteroaryl, NO2, SH, S-Alkyl, S-Aryl, OH, OCF3, O-Alkyl, O-Cycloalkyl, O-Heterocyclyl, O-Aryl, O-Heteroaryl, OC(O)- Alkyl, OC(O)-Cycloalkyl, OC(0)-Heterocyclyl, OC(0)-Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OSO2-Cycloalkyl, OSO2-Aryl, OSO2-Heteroaryl, C(O)-Alkyl, C(O)- Aryl, C(O)-Heteroaryl, CO2H, CO2-Alkyl, CO2-Cycloalkyl, CO2-Heterocyclyl, C02-Aryl, CO2-Heteroaryl, CO2-Alkyl-Cycloalkyl, CO2-Alkyl-Heterocyclyl, CO2- Alkyl-aryl, C02-Alkyl-Heteroaryl, C(0)-NH2, C(0)NH-Alkyl, C(0)NH-Cycloalkyl, C(O)NH-Heterocyclyl, C(O)NH-Aryl, C(O)NH-Heteroaryl, C(O)NH-Alkyl- Cycloalkyl, C(0)NH-Alkyl-Heterocyclyl, C(O)NH-Alkyl-Aryl, C(O)NH-Alkyl- Heteroaryl, C(O)N(Alkyl)2, C(O)N(Cycloalkyl)2, C(O)N(Aryl)2,(v) unsubstituted or substituted heteroaryl, where the heteroaryl radical with F, Cl, Br, I, CF 3 , NH 2 , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl- Aryl, NH-alkyl heteroaryl, N (alkyl) 2 , NHC (0) alkyl, NHC (0) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHS0 2 alkyl, NHSO 2 aryl, NHSO 2 heteroaryl, NO 2 , SH, S alkyl, S aryl, OH, OCF 3 , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, OC (O) alkyl, OC (O) cycloalkyl, OC (0) heterocyclyl, OC (0) aryl , OC (O) heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OSO 2 aryl, OSO 2 heteroaryl, C (O) alkyl, C (O) aryl, C (O) heteroaryl, CO 2 H, CO 2 alkyl, CO 2 cycloalkyl, CO 2 heterocyclyl, C0 2 aryl, CO 2 heteroaryl, CO 2 alkyl cycloalkyl, CO 2 alkyl heterocyclyl, CO 2 alkyl aryl, C0 2- alkyl heteroaryl, C (0) -NH 2 , C (0) NH-alkyl, C (0) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH heteroaryl, C (O) NH alkyl cycloalkyl, C (0) NH alkyl heterocyclyl, C (O) NH alkyl aryl, C (O) NH alkyl heteroaryl, C (O) N ( Alkyl) 2 , C (O) N (cycloalkyl) 2 , C (O) N (aryl) 2 ,
C(0)N(Heteroaryl)2, SO2-Alkyl, S02-Aryl, SO2NH2, SO2NH-Alkyl, SO2NH-Aryl, SO2NH-Heteroaryl, SO3H, SO2O-Alkyl, SO2O-Aryl, SO2O-Heteroaryl, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- oder mehrfach, gleich oder verschieden substituiert sein kann, bedeuten.C (0) N (heteroaryl) 2 , SO 2 alkyl, S0 2 aryl, SO 2 NH 2 , SO 2 NH alkyl, SO 2 NH aryl, SO 2 NH heteroaryl, SO3H, SO 2 O alkyl , SO 2 O-aryl, SO 2 O-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, can be substituted one or more times, identically or differently.
Der Ausdruck „Alkyl" umfasst im Sinne dieser Erfindung acyclische gesättigte oder ungesättigte Kohlenwasserstoffreste, die verzweigt oder geradkettig sein können, mit 1 bis 8 C-Atomen, d.h. d-s-Alkanyle, C2-8-Alkenyle und C2-8-Alkinyle. Dabei weisen Alkenyle mindestens eine C-C-Doppelbindung und Alkinyle mindestens eine C-C- Dreifachbindung auf. Es ist bevorzugt, dass der Alkylrest ausgewählt ist aus der Gruppe, die Methyl, Ethyl, n-Propyl, 2-Propyl, n-Butyl, sec.-Butyl, fe/τ.-Butyl, / Pentyl, /so-Pentyl, neσ-Pentyl, π-Hexyl, 2-Hexyl, n-Octyl, Ethylenyl (Vinyl), Ethinyl, Propenyl (-CH2CH=CH2; -CH=CH-CH3, -C(=CH2)-CH3), Propinyl (-CH2-C≡CH, -C≡C-CH3), Bu- tenyl, Butinyl, Pentenyl, Pentinyl, Hexenyl, Hexinyl, Heptenyl, Heptinyl, Octenyl und Octinyl enthält.The term "alkyl" for the purposes of this invention acyclic saturated or unsaturated hydrocarbon radicals which may be branched or straight chain, having 1 to 8 carbon atoms, that is, ds-alkanyls, C 2 - 8 alkenyls, and C 2 - 8 alkynyls. Alkenyls have at least one CC double bond and alkynyls have at least one CC triple bond It is preferred that the alkyl radical is selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec.- Butyl, fe / τ.-butyl, / pentyl, / so-pentyl, neσ-pentyl, π-hexyl, 2-hexyl, n-octyl, ethyleneyl (vinyl), ethynyl, propenyl (-CH 2 CH = CH 2 ; -CH = CH-CH 3 , -C (= CH 2 ) -CH 3 ), propynyl (-CH 2 -C≡CH, -C≡C-CH 3 ), butenyl, butynyl, pentenyl, pentynyl, hexenyl Contains, hexinyl, heptenyl, heptinyl, octenyl and octinyl.
Der Ausdruck „Cycloalkyl" bedeutet für die Zwecke dieser Erfindung cyclische Kohlenwasserstoffe mit 3-12 Kohlenwasserstoffen, die gesättigt oder ungesättigt sein können. Die Bindung an die Verbindungen der allgemeinen Struktur I kann über jedes beliebige und mögliche Ringglied des Cycloalkyl-Restes erfolgen. Der Cycloal- kyl-Rest kann auch Teil eines bi- oder polycyclischen Systems sein. Der Ausdruck „Heterocyclyl" steht für einen 3-, 4-, 5-, 6-, 7- oder 8-gliedrigen cycli- schen organischen Rest, der mindestens 1 , ggf. 2, 3, 4 oder 5 Heteroatome enthält, wobei die Heteroatome gleich oder verschieden sind und der cyclische Rest gesättigt oder ungesättigt, aber nicht aromatisch ist. Die Bindung an die Verbindungen der allgemeinen Struktur I kann über jedes beliebige und mögliche Ringglied des Hetero- cyclyl-Restes erfolgen. Der Heterocyclus kann auch Teil eines bi- oder polycycli- schen Systems sein. Bevorzugte Heteroatome sind Stickstoff, Sauerstoff und Schwefel. Es ist bevorzugt, dass der Heterocyclyl-Rest ausgewählt ist aus der Gruppe, die Tetrahydrofuryl, Tetrahydropyranyl, Pyrrolidinyl, Piperidinyl, Piperazinyl und Morpho- linyl enthält.The term "cycloalkyl" for the purposes of this invention means cyclic hydrocarbons with 3-12 hydrocarbons, which can be saturated or unsaturated. The binding to the compounds of general structure I can take place via any and possible ring member of the cycloalkyl radical. The cycloal - The kyl radical can also be part of a bi- or polycyclic system. The term “heterocyclyl” stands for a 3-, 4-, 5-, 6-, 7- or 8-membered cyclic organic radical which contains at least 1, optionally 2, 3, 4 or 5 heteroatoms, the Heteroatoms are the same or different and the cyclic radical is saturated or unsaturated but not aromatic. Binding to the compounds of general structure I can take place via any and possible ring member of the heterocyclic radical. The heterocycle can also be part of a bi- or a polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulfur. It is preferred that the heterocyclyl radical is selected from the group consisting of tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholine.
Der Ausdruck „Aryl" bedeutet im Sinne dieser Erfindung aromatische Kohlenwasserstoffe, u.a. Phenyle, Naphthyle und Anthracenyle. Die Reste können auch mit weiteren gesättigten, (partiell) ungesättigten oder aromatischen Ringsystemen kondensiert sein. Die Bindung an die Verbindungen der allgemeinen Struktur I kann über jedes beliebige und mögliche Ringglied des Aryl-Restes erfolgen.For the purposes of this invention, the term “aryl” means aromatic hydrocarbons, including phenyls, naphthyls and anthracenyls. The radicals can also be condensed with further saturated, (partially) unsaturated or aromatic ring systems. The bond to the compounds of the general structure I can be via any any and possible ring member of the aryl radical take place.
Der Ausdruck „Heteroaryl" steht für einen 5-, 6- oder 7-gliedrigen cyclischen aromatischen Rest, der mindestens 1 , ggf. auch 2, 3, 4 oder 5 Heteroatome enthält, wobei die Heteroatome gleich oder verschieden sind. Die Bindung an die Verbindungen der allgemeinen Struktur I kann über jedes beliebige und mögliche Ringglied des Hete- roaryl-Restes erfolgen. Der Heterocyclus kann auch Teil eines bi- oder polycycli- schen Systems sein. Bevorzugte Heteroatome sind Stickstoff, Sauerstoff und Schwefel. Es ist bevorzugt, dass der Heteroaryl-Rest ausgewählt ist aus der Gruppe, die Pyrrolyl, Furyl, Thienyl, Thiazolyl, Oxazolyl, Isoxazolyl, Pyrazolyl, Imidazolyl, Pyridi- nyl, Pyrimidinyl, Pyridazinyl, Pyrazinyl, Phthalazinyl, Indolyl, Indazolyl, Indolizinyl, Chinolinyl, Isochinolinyl, Chinoxalinyl, Chinazolinyl, Carbazolyl, Phenazinyl, Phe- nothiazinyl, Acridinyl enthält.The term "heteroaryl" stands for a 5-, 6- or 7-membered cyclic aromatic radical which contains at least 1, possibly also 2, 3, 4 or 5 heteroatoms, the heteroatoms being the same or different. The bond to the Compounds of the general structure I can be made via any and possible ring member of the heteroaryl radical. The heterocycle can also be part of a bi- or polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulfur. It is preferred that the Heteroaryl radical is selected from the group consisting of pyrrolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, phthalazinyl, indolyl, indazolyl, indolizinyl, quinolinyl, quinolinyl, isoxinyl Contains quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl, acridinyl.
Die Ausdrücke „Alkyl-Cycloalkyl", „Alkyl-Heterocyclyl", „Alkyl-Aryl" oder „Alkyl- Heteroaryl" bedeuten für die Zwecke der vorliegenden Erfindung, daß Alkyl, Cycloalkyl, Heterocyclyl, Aryl und Heteroaryl die oben definierten Bedeutungen haben und der Cycloalkyl-, Heterocyclyl-, Aryl- und Heteroaryl-Rest über eine Cι-8-Alkyl-Gruppe an die Verbindungen der allgemeinen Struktur I gebunden ist. Im Zusammenhang mit „Alkyl", „Cycloalkyl", „Heterocyclyl", „Aryl", „Heteroaryl", „Alkyl- Cycloalkyl", „Alkyl-Heterocyclyl", „Alkyl-Aryl" und „Alkyl-Heteroaryl" versteht man unter dem Begriff substituiert im Sinne dieser Erfindung, insofern oben nicht explicit definiert, die Substitution eines oder mehrerer Wasserstoffreste durch F, Cl, Br, I, CN, CF3, NH2, NH-Alkyl, NH-Aryl, N(Alkyl)2, NO2, SH, S-Alkyl, OH, OCF3, O-Alkyl, O-Aryl, CHO, C02H, SO3H oder Alkyl. Die Substituenten können gleich oder verschieden sein und die Substitution kann in jeder beliebigen und möglichen Position des Alkyl-, Cycloalkyl-, Heterocyclyl-, Aryl- und Heteroarylrestes vorkommen.The terms "alkyl-cycloalkyl", "alkyl-heterocyclyl", "alkyl-aryl" or "alkyl-heteroaryl" mean for the purposes of the present invention that alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl have the meanings defined above and that cycloalkyl, heterocyclyl, aryl and heteroaryl radical is bonded via a Cι -8 alkyl group to the compounds of general structure I. In connection with "alkyl", "cycloalkyl", "heterocyclyl", "aryl", "heteroaryl", "alkylcycloalkyl", "alkyl heterocyclyl", "alkyl aryl" and "alkyl heteroaryl" is understood to mean the The term substituted in the sense of this invention, unless explicitly defined above, is the substitution of one or more hydrogen radicals by F, Cl, Br, I, CN, CF 3 , NH 2 , NH-alkyl, NH-aryl, N (alkyl) 2 , NO 2 , SH, S-alkyl, OH, OCF 3 , O-alkyl, O-aryl, CHO, CO 2 H, SO 3 H or alkyl The substituents can be the same or different and the substitution can be any and possible Position of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl radical occur.
Unter mehrfach substituierten Resten sind solche zu verstehen, die entweder an verschiedenen oder an gleichen Atomen mehrfach, z. B. zwei- oder dreifach substituiert sind, beispielsweise dreifach am gleichen C-Atom wie im Falle von CF3, -CH2CF3 oder an verschiedenen Stellen wie im Falle von -CH(OH)-CH=CH-CHCI2. Die Mehrfachsubstitution kann mit dem gleichen oder verschiedenen Substituenten erfolgen.Multiply substituted radicals are to be understood as meaning those which are either multiply on different or on the same atoms, for. B. are substituted twice or three times, for example three times on the same carbon atom as in the case of CF 3 , -CH 2 CF 3 or at different points as in the case of -CH (OH) -CH = CH-CHCI 2 . The multiple substitution can be carried out with the same or different substituents.
Sofern die erfindungsgemäßen Verbindungen der allgemeinen Formel I mindestens ein Asymmetriezentrum aufweisen, können sie in Form ihrer Racemate, in Form der reinen Enantiomeren und/oder Diastereomeren oder in Form von Mischungen dieser Enantiomeren und/oder Diastereomeren vorliegen. Die Mischungen können in jedem beliebigen Mischungsverhältnis der Stereoisomeren vorliegen.If the compounds of general formula I according to the invention have at least one asymmetry center, they can be present in the form of their racemates, in the form of the pure enantiomers and / or diastereomers or in the form of mixtures of these enantiomers and / or diastereomers. The mixtures can be present in any mixing ratio of the stereoisomers.
So lassen sich beispielsweise die erfindungsgemäßen Verbindungen gemäß der allgemeinen Formel I, welche ein oder mehrere Chiralitätszentren aufweisen und die als Racemate auftreten, nach an sich bekannten Methoden in ihre optischen Isomeren, also Enantiomere oder Diastereomere auftrennen. Die Trennung kann durch Säulentrennung an chiralen Phasen oder durch Umkristallisation aus einem optisch aktiven Lösungsmittel oder unter Verwendung einer optisch aktiven Säure oder Base oder durch Derivatisierung mit einem optisch aktiven Reagenz, wie beispielsweise einem optisch aktiven Alkohol, und anschließender Abspaltung des Restes erfolgen.For example, the compounds of general formula I according to the invention which have one or more chiral centers and which occur as racemates can be separated into their optical isomers, ie enantiomers or diastereomers, by methods known per se. The separation can be carried out by column separation on chiral phases or by recrystallization from an optically active solvent or using an optically active acid or base or by derivatization with an optically active reagent, such as, for example, an optically active alcohol, and subsequent elimination of the rest.
Sofern möglich, können die erfindungsgemäßen Verbindungen in Form der Tautomeren vorliegen. Die erfindungsgemäßen Verbindungen der allgemeinen Formel I können, falls sie eine ausreichend basische Gruppe, wie zum Beispiel ein primäres, sekundäres oder tertiäres Amin besitzen, mit anorganischen und organischen Säuren in ihre physiologisch verträglichen Salze überführt werden. Vorzugsweise werden die pharmazeutisch annehmbaren Salze der erfindungsgemäßen Verbindungen gemäß der allgemeinen Struktur I mit Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, p-Toluolsulfonsäure, Kohlensäure, Ameisensäure, Essigsäure, Trifluoressigsäure, Sulfoessigsäure, Oxalsäure, Malonsäure, Maleinsäure, Bernsteinsäure, Weinsäure, Traubensäure, Äpfelsäure, Embonsäure, Mandelsäure, Fumarsäure, Milchsäure, Citronensäure, Glutaminsäure oder Asparaginsäure gebildet. Bei den gebildeten Salzen handelt es sich u.a. um Hydrochloride, Hydrobromide, Sulfate, Hydrogensulfate, Phosphate, Methansulfonate, Tosylate, Carbonate, Hydro- gencarbonate, Formiate, Acetate, Triflate, Sulfoacetate, Oxalate, Malonate, Maleate, Succinate, Tartrate, Malate, Embonate, Mandelate, Fumarate, Lactate, Citrate, Glu- taminate und Aspartate. Die Stöchiometrie der gebildeten Salze der erfindungsgemäßen Verbindungen kann dabei ganzzahlige oder nicht ganzzahlige Vielfache von eins betragen.If possible, the compounds according to the invention can be in the form of the tautomers. The compounds of the general formula I according to the invention, if they have a sufficiently basic group, such as a primary, secondary or tertiary amine, can be converted into their physiologically tolerable salts with inorganic and organic acids. The pharmaceutically acceptable salts of the compounds according to the invention are preferably in accordance with general structure I with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, sulfoacetic acid, oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid, tartaric acid , Malic acid, embonic acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid. The salts formed include hydrochlorides, hydrobromides, sulfates, hydrogen sulfates, phosphates, methanesulfonates, tosylates, carbonates, hydrogen carbonates, formates, acetates, triflates, sulfoacetates, oxalates, malonates, maleates, succinates, tartrates, malates, embonates , Almondates, fumarates, lactates, citrates, glutaminates and aspartates. The stoichiometry of the salts formed of the compounds according to the invention can be integer or non-integer multiples of one.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel I können, falls sie eine ausreichend saure Gruppe, wie zum Beispiel die Carboxygruppe enthalten, mit anorganischen und organischen Basen in ihre physiologisch verträglichen Salze ü- berführt werden. Als anorganische Basen kommen beispielsweise Natriumhydroxid, Kaliumhydroxid, Calciumhydroxid, als organische Basen Ethanolamin, Diethanola- min, Triethanolamin, Cyclohexylamin, Dibenzylethylendiamin und Lysin in Betracht. Die Stöchiometrie der gebildeten Salze der erfindungsgemäßen Verbindungen kann dabei ganzzahlige oder nicht ganzzahlige Vielfache von eins betragen.The compounds of general formula I according to the invention, if they contain a sufficiently acidic group, such as the carboxy group, can be converted into their physiologically tolerable salts with inorganic and organic bases. Examples of suitable inorganic bases are sodium hydroxide, potassium hydroxide, calcium hydroxide, and organic bases are ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dibenzylethylene diamine and lysine. The stoichiometry of the salts formed of the compounds according to the invention can be integer or non-integer multiples of one.
Ebenfalls bevorzugt sind Solvate und insbesondere Hydrate der erfindungsgemäßen Verbindungen, die z. B. durch Kristallisation aus einem Lösungsmittel oder aus wäss- riger Lösung erhalten werden können. Es können sich dabei ein, zwei, drei oder beliebig viele Solvat- oder Wasser-Moleküle mit den erfindungsgemäßen Verbindungen zu Solvaten und Hydraten verbinden. Es ist bekannt, dass chemische Substanzen Festkörper ausbilden, die in verschiedenen Ordnungszuständen vorliegen, die man als polymorphe Formen oder Modifikationen bezeichnet. Die verschiedenen Modifikationen einer polymorphen Substanz können sich in ihren physikalischen Eigenschaften stark unterscheiden. Die erfindungsgemäßen Verbindungen der allgemeinen Formel I können in verschiedenen polymorphen Formen vorliegen, dabei können bestimmte Modifikationen metastabil sein.Solvates and in particular hydrates of the compounds according to the invention which, for. B. can be obtained by crystallization from a solvent or from aqueous solution. One, two, three or any number of solvate or water molecules can combine with the compounds according to the invention to form solvates and hydrates. It is known that chemical substances form solids which are in various states of order, which are referred to as polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds of general formula I according to the invention can exist in various polymorphic forms, certain modifications being metastable.
Die Verfahren zur Herstellung erfindungsgemäßer substituierter Pyrido[2,3- bjpyrazine werden nachstehend erläutert.The processes for the preparation of substituted pyrido [2,3-pyrazines according to the invention are explained below.
Die Verbindungen der allgemeinen Formel I sind gemäß der folgenden Schemata (Schema 1 und 2) erhältlich:The compounds of the general formula I can be obtained according to the following schemes (schemes 1 and 2):
Schema 1Scheme 1
2.Stufe2nd stage
Schema 2 Scheme 2
3.Stufe3rd Stage
Thiophosgen o.Thiophosgene or
10 Die Ausgangsverbindungen sind entweder im Handel erhältlich oder können nach an sich bekannten Verfahrensweisen hergestellt werden. Die Edukte 1 und 4 stellen wertvolle Zwischenverbindungen für die Herstellung der erfindungsgemäßen Pyrido- pyrazine der allgemeinen Formel I dar.10 The starting compounds are either commercially available or can be prepared by processes known per se. The starting materials 1 and 4 are valuable intermediates for the preparation of the pyridopyrazines of the general formula I according to the invention.
Für die Herstellung der Ausgangs- und Zielverbindungen sei beispielsweise auf folgende Primärliteratur verwiesen, deren Inhalt hiermit Bestandteil der Offenbarung der vorliegenden Anmeldung werden soll:For the production of the starting and target compounds, reference is made, for example, to the following primary literature, the content of which is hereby intended to become part of the disclosure of the present application:
1) Houben-Weyl, Methoden der Organischen Chemie, Band 4/1 a, S. 343-3501) Houben-Weyl, Methods of Organic Chemistry, Volume 4/1 a, pp. 343-350
2) Houben-Weyl, Methoden der Organischen Chemie, 4.Aufl., Band E 7b (Teil 2), S. 579; Degussa GB 1184848 (1970); S. Seko, et al. EP 735025 (1996)2) Houben-Weyl, Methods of Organic Chemistry, 4th edition, Volume E 7b (Part 2), p. 579; Degussa GB 1184848 (1970); S. Seko, et al. EP 735025 (1996)
3) D. Catarzi, et al.; J. Med. Chem. 1996, 1330-1336; J. K. Seydel, et al.; J. Med. Chem. 1994, 3016-30223) D. Catarzi, et al .; J. Med. Chem. 1996, 1330-1336; J.K. Seydel, et al .; J. Med. Chem. 1994, 3016-3022
4) Houben-Weyl, Methods of Organic Chemistry, Volume E 9c, S.231 -2354) Houben-Weyl, Methods of Organic Chemistry, Volume E 9c, pp. 231-235
5) A. M. Thompson, et al. J. Med. Chem. 2000, 4200-42115) A. M. Thompson, et al. J. Med. Chem. 2000, 4200-4211
6) G. Heinisch, et al. Arch. Pharm. 1997, 207-2106) G. Heinisch, et al. Arch. Pharm. 1997, 207-210
7) N. A. Dales, et al. Org. Lett. 2001 , 2313-2316; G. Dannhardt, et al. Arch. Pharm. 2000, 267-2747) N.A. Dales, et al. Org. Lett. 2001, 2313-2316; G. Dannhardt, et al. Arch. Pharm. 2000, 267-274
8) M. L. Mussous, et al. Tetrahedron 1999, 4077-4094; A. Kling, et al. Bioorg. Med. Chem. Lett. 2002, 441-4468) M. L. Mussous, et al. Tetrahedron 1999, 4077-4094; A. Kling, et al. Bioorg. Med. Chem. Lett. 2002, 441-446
9) I. K. Khanna, et al.; J. Med. Chem. 2000, 3168-31859) I.K. Khanna, et al .; J. Med. Chem. 2000, 3168-3185
10) L. Younghee, et al.; Bioorg. Med. Chem. Lett. 2000, 2771 -2774; N. L. Reddy et al.; J. Med. Chem. 1998, 3298-3302 10) L. Younghee, et al .; Bioorg. Med. Chem. Lett. 2000, 2771-2774; NL Reddy et al .; J. Med. Chem. 1998, 3298-3302
Allgemeine Vorschrift zur Darstellung der Verbindungen der allgemeinen Formel I :General instructions for the preparation of the compounds of the general formula I:
1. Stufe1st stage
2,6-Diamino-3-nitropyridin wird in einem polaren, organischen Lösungsmittel, wie beispielsweise Methanol, Ethanol, Dimethylformamid oder Dioxan, allein oder in Kombination zweier dieser Lösungsmittel, gelöst. Nach Zugabe eines Katalysators, beispielsweise Raney-Nickel, Palladium auf Kohle oder Platin(IV)dioxid, setzt man das Reaktionsgemisch unter eine Wasserstoff -Atmosphäre, wobei ein Druck zwischen 1 und 5 bar eingestellt wird. Man läßt das Reaktionsgemisch mehrere Stunden, beispielsweise 1-16 Stunden, in einem Temperaturbereich zwischen 20 °C und 60 °C reagieren. Nach beendeter Umsetzung filtriert man die unlöslichen Rückstände ab, wobei das Filtermedium beispielsweise aus Kieselgel, Celite oder handelsüblichen Glasfaserfiltern bestehen kann, und wäscht mit dem entsprechenden Lösungsmittel nach. Das Rohprodukt wird, in Lösung vorliegend, ohne weitere Aufreinigung für die nächste Umsetzung verwendet.2,6-diamino-3-nitropyridine is dissolved in a polar, organic solvent, such as, for example, methanol, ethanol, dimethylformamide or dioxane, alone or in combination of two of these solvents. After adding a catalyst, for example Raney nickel, palladium on carbon or platinum (IV) dioxide, the reaction mixture is placed under a hydrogen atmosphere, a pressure between 1 and 5 bar being set. The reaction mixture is allowed to react for several hours, for example 1-16 hours, in a temperature range between 20 ° C. and 60 ° C. When the reaction has ended, the insoluble residues are filtered off, the filter medium being able to consist, for example, of silica gel, Celite or commercially available glass fiber filters, and washing is carried out with the appropriate solvent. The crude product, in solution, is used for the next reaction without further purification.
2. Stufe2nd stage
Das 1 ,2-Dion-Derivat wird in einem organischen Lösungsmittel, beispielsweise Methanol, Ethanol, Dioxan, Toluol oder Dimethylformamid, vorgelegt. 2,3,6- Triaminopyridin wird direkt nach der Reduktion als Lösung seines Rohproduktes in einem der oben genannten Lösungsmittel zum vorgelegten 1 ,2-Dion gegeben, gegebenenfalls unter Zugabe einer Säure, wie z. B. Essigsäure oder einer Base, beispielsweise Kaliumhydroxid. Das Reaktionsgemisch läßt man in einem Temperaturbereich von 20 °C bis 80 °C einige Zeit, beispielsweise 20 Minuten bis 40 Stunden, reagieren. Nach beendeter Umsetzung wird ein eventuell ausgefallener Niederschlag abfiltriert, wobei das Filtermedium beispielsweise aus handelsüblichem Filterpapier bestehen kann, mit dem entsprechenden Lösungsmittel nachgewaschen und der zurückbleibende Feststoff im Vakuum getrocknet, bzw. wird das Reaktionsgemisch im Vakuum vom Lösungsmittel befreit. Bei Verwendung von Dimethylformamid wird das Reaktionsgemisch in eine große Menge Wasser eingerührt und der ausgefallene Niederschlag abfiltriert bzw. die wässrige Phase mit einem geeigneten organischen Lösungsmittel extrahiert und die organischen Phasen im Vakuum eingeengt. Die Reinigung des zurückbleibenden Rohproduktes erfolgt durch Umkristallisieren aus einem geeigneten Lösungsmittel, beispielsweise Ethanol, oder durch Säulen- bzw. Flash-Chromatographie an Kieselgel oder Aluminiumoxid. Als Laufmittel dient beispielsweise ein Gemisch aus Methanol und Dichlormethan.The 1,2-dione derivative is placed in an organic solvent, for example methanol, ethanol, dioxane, toluene or dimethylformamide. 2,3,6-triaminopyridine is added directly after the reduction as a solution of its crude product in one of the abovementioned solvents to the 1,2-dione, optionally with the addition of an acid, such as, for. B. acetic acid or a base, for example potassium hydroxide. The reaction mixture is allowed to react in a temperature range from 20 ° C. to 80 ° C. for some time, for example 20 minutes to 40 hours. When the reaction has ended, any precipitate that has precipitated is filtered off, the filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo. When using dimethylformamide the reaction mixture is stirred into a large amount of water and the precipitate which has precipitated is filtered off or the aqueous phase is extracted with a suitable organic solvent and the organic phases are concentrated in vacuo. The remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol, or by column or flash chromatography on silica gel or aluminum oxide. A mixture of methanol and dichloromethane, for example, serves as the mobile phase.
3. Stufe3rd stage
Im Anschluß an das Grundverfahren können in Folgereaktionen die nach dem Grundverfahren entstandenen Produkte in einer dem Fachmann bekannten Vorgehensweise zu erfindungsgemässen Folgeprodukten gemäß der Formel I umgesetzt werden.Subsequent to the basic process, in subsequent reactions, the products obtained by the basic process can be converted into secondary products according to the formula I according to the invention in a procedure known to the person skilled in the art.
So kann, wenn das Produkt ein Derivat der Verbindung 5 gemäß Schema 2 sein soll, nach Ablauf der Grundreaktion das Reaktionsprodukt 4 mit einem entsprechenden Isocyanat und gegebenenfalls einer geeigneten Base, vorzugsweise Natriumhydrid, Kaliumhexamethyldisilazid, Triethylamin oder Kaliumcarbonat, in einem geeigneten, inerten Lösungsmittel, wie beispielsweise Dimethylformamid, Acetonitril, Tetrahydro- furan, Dichlormethan, Chloroform, 1 ,2-Dichlorethan oder Dioxan umgesetzt werden. Das Reaktionsgemisch läßt man mehrere Stunden, beispielsweise 1 - 24 Stunden, in einem Temperaturbereich zwischen 0 und 80 °C reagieren. Nach beendeter Umsetzung wird ein eventuell ausgefallener Niederschlag abfiltriert, wobei das Filtermedium beispielsweise aus handelsüblichem Filterpapier bestehen kann, mit dem entsprechenden Lösungsmittel nachgewaschen und der zurückbleibende Feststoff im Vakuum getrocknet, bzw. wird das Reaktionsgemisch im Vakuum vom Lösungsmittel befreit. Bei Verwendung von Dimethylformamid wird das Reaktionsgemisch in eine große Menge Wasser eingerührt und der ausgefallene Niederschlag abfiltriert bzw. die wässrige Phase mit einem geeigneten organischen Lösungsmittel extrahiert und die organischen Phasen im Vakuum eingeengt. Die Reinigung des zurückbleibenden Rohproduktes erfolgt durch Umkristallisieren aus einem geeigneten Lösungsmittel, beispielsweise Ethanol oder Toluol, oder durch Säulen- bzw. Flash-Chromatographie an Kieselgel oder Aluminiumoxid. Als Laufmittel dient beispielsweise ein Gemisch aus Methanol und Dichlormethan.Thus, if the product is to be a derivative of compound 5 according to Scheme 2, after the end of the basic reaction, reaction product 4 with a corresponding isocyanate and optionally a suitable base, preferably sodium hydride, potassium hexamethyldisilazide, triethylamine or potassium carbonate, in a suitable, inert solvent, such as dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, 1, 2-dichloroethane or dioxane. The reaction mixture is allowed to react for several hours, for example 1-24 hours, in a temperature range between 0 and 80 ° C. When the reaction has ended, any precipitate that has precipitated is filtered off, the filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo. If dimethylformamide is used, the reaction mixture is stirred into a large amount of water and the precipitate which has separated out is filtered off or the aqueous phase is extracted with a suitable organic solvent and the organic phases are concentrated in vacuo. The remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol or toluene, or by column or flash chromatography on silica gel or aluminum oxide. A mixture of methanol and dichloromethane, for example, serves as the mobile phase.
Oder es kann alternativ, wenn das Produkt ein Derivat der Verbindung 6 gemäß Schema 2 sein soll, nach Ablauf der Grundreaktion das Reaktionsprodukt 4 mit Phosgen oder Carbonyldiimidazol und einem entsprechenden Amin in einem geeigneten, inerten Lösungsmittel, wie beispielsweise Tetrahydrofuran, Toluol, Dichlormethan oder Acetonitril umgesetzt werden. Gegebenenfalls wird eine geeignete Base, vorzugsweise Pyridin, Natriumhydrogencarbonat, Triethylamin, N-Methyl- morpholin oder Natriumacetat verwendet. Das Reaktionsgemisch läßt man einige Zeit, beispielsweise 15 Minuten bis 24 Stunden, in einem Temperaturbereich zwischen 0 und 60 °C reagieren. Nach beendeter Umsetzung wird ein eventuell ausgefallener Niederschlag abfiltriert, wobei das Filtermedium beispielsweise aus handelsüblichem Filterpapier bestehen kann, mit dem entsprechenden Lösungsmittel nachgewaschen und der zurückbleibende Feststoff im Vakuum getrocknet, bzw. wird das Reaktionsgemisch im Vakuum vom Lösungsmittel befreit. Bei Verwendung von Dimethylformamid wird das Reaktionsgemisch in eine große Menge Wasser eingerührt und der ausgefallene Niederschlag abfiltriert bzw. die wässrige Phase mit einem geeigneten organischen Lösungsmittel extrahiert und die organischen Phasen im Vakuum eingeengt. Die Reinigung des zurückbleibenden Rohproduktes erfolgt durch Umkristallisieren aus einem geeigneten Lösungsmittel, beispielweise Ethanol oder Ethylacetat, oder durch Säulen- bzw. Flash-Chromatographie an Kieselgel oder Aluminiumoxid. Als Laufmittel dient beispielsweise ein Gemisch aus Methanol und Dichlormethan.Or alternatively, if the product is to be a derivative of compound 6 according to Scheme 2, after the basic reaction has ended, reaction product 4 with phosgene or carbonyldiimidazole and a corresponding amine in a suitable inert solvent, such as, for example, tetrahydrofuran, toluene, dichloromethane or acetonitrile be implemented. If necessary, a suitable base, preferably pyridine, sodium hydrogen carbonate, triethylamine, N-methylmorpholine or sodium acetate, is used. The reaction mixture is allowed to react for a time, for example 15 minutes to 24 hours, in a temperature range between 0 and 60 ° C. When the reaction has ended, any precipitate that has precipitated is filtered off, the filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo. When using dimethylformamide, the reaction mixture is stirred into a large amount of water and the precipitate is filtered off or the aqueous phase is extracted with a suitable organic solvent and the organic phases are concentrated in vacuo. The remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol or ethyl acetate, or by column or flash chromatography on silica gel or aluminum oxide. A mixture of methanol and dichloromethane, for example, serves as the mobile phase.
So kann, wenn das Produkt ein Derivat der Verbindung 7 gemäß Schema 2 sein soll, nach Ablauf der Grundreaktion das Reaktionsprodukt 4 mit einem entsprechenden Isothiocyanat und gegebenenfalls einer geeigneten Base, vorzugsweise Natriumhydrid, Triethylamin oder Pyridin, in einem geeigneten, inerten Lösungsmittel, wie beispielsweise Dimethylformamid, Tetrahydrofuran, Aceton oder Toluol umgesetzt werden. Das Reaktionsgemisch läßt man einige Zeit, beispielsweise 30 Minuten bis 90 Stunden, in einem Temperaturbereich zwischen 0 und 115 °C reagieren. Nach beendeter Umsetzung wird ein eventuell ausgefallener Niederschlag abfiltriert, wobei das Filtermedium beispielsweise aus handelsüblichem Filterpapier bestehen kann, mit dem entsprechenden Lösungsmittel nachgewaschen und der zurückbleibende Feststoff im Vakuum getrocknet, bzw. wird das Reaktionsgemisch im Vakuum vom Lösungsmittel befreit. Bei Verwendung von Dimethylformamid wird das Reaktionsgemisch in eine große Menge Wasser eingerührt und der ausgefallene Niederschlag abfiltriert bzw. die wässrige Phase mit einem geeigneten organischen Lösungsmittel extrahiert und die organischen Phasen im Vakuum eingeengt. Die Reinigung des zurückbleibenden Rohproduktes erfolgt durch Umkristallisieren aus einem geeigneten Lösungsmittel, beispielsweise Ethanol oder Ethylacetat, oder durch Säulen- bzw. Flash-Chromatographie an Kieselgel oder Aluminiumoxid. Als Laufmittel dient beispielsweise ein Gemisch aus Methanol und Dichlormethan.Thus, if the product is to be a derivative of compound 7 according to Scheme 2, after the end of the basic reaction, reaction product 4 with a corresponding isothiocyanate and optionally a suitable base, preferably sodium hydride, triethylamine or pyridine, in a suitable, inert solvent, such as, for example Dimethylformamide, tetrahydrofuran, acetone or toluene can be implemented. The reaction mixture is allowed to react for a time, for example 30 minutes to 90 hours, in a temperature range between 0 and 115 ° C. When the reaction has ended, any precipitate that has precipitated is filtered off, the Filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo. If dimethylformamide is used, the reaction mixture is stirred into a large amount of water and the precipitate which has separated out is filtered off or the aqueous phase is extracted with a suitable organic solvent and the organic phases are concentrated in vacuo. The remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol or ethyl acetate, or by column or flash chromatography on silica gel or aluminum oxide. A mixture of methanol and dichloromethane, for example, serves as the mobile phase.
Oder es kann alternativ, wenn das Produkt ein Derivat der Verbindung 8 gemäß Schema 2 sein soll, nach Ablauf der Grundreaktion das Reaktionsprodukt 4 mit Thi- ophosgen oder Thiocarbonyldiimidazol und einem entsprechenden Amin in einem geeigneten, inerten Lösungsmittel, wie beispielsweise Tetrahydrofuran, Toluol, Dichlormethan, Ethanol oder Acetonitril umgesetzt werden. Gegebenenfalls wird eine geeignete Base, vorzugsweise Pyridin, Natriumhydrogencarbonat, Kaliumcarbonat, Triethylamin oder Imidazol verwendet. Das Reaktionsgemisch läßt man mehrere Stunden, beispielsweise 1 bis 24 Stunden, in einem Temperaturbereich zwischen -10 und 80 °C reagieren. Nach beendeter Umsetzung wird ein eventuell ausgefallener Niederschlag abfiltriert, wobei das Filtermedium beispielsweise aus handelsüblichem Filterpapier bestehen kann, mit dem entsprechenden Lösungsmittel nachgewaschen und der zurückbleibende Feststoff im Vakuum getrocknet, bzw. wird das Reaktionsgemisch im Vakuum vom Lösungsmittel befreit. Bei Verwendung von Dimethylformamid wird das Reaktionsgemisch in eine große Menge Wasser eingerührt und der ausgefallene Niederschlag abfiltriert bzw. die wässrige Phase mit einem geeigneten organischen Lösungsmittel extrahiert und die organischen Phasen im Vakuum eingeengt. Die Reinigung des zurückbleibenden Rohproduktes erfolgt durch Umkristallisieren aus einem geeigneten Lösungsmittel, beispielweise Ethanol oder Ethylacetat, oder durch Säulen- bzw. Flash-Chromatographie an Kieselgel oder Aluminiumoxid. Als Laufmittel dient beispielsweise ein Gemisch aus Ethylacetat und Hexan. So kann, wenn das Produkt ein Derivat der Verbindung 9 gemäß Schema 2 sein soll, nach Ablauf der Grundreaktion das Reaktionsprodukt 4 mit einem entsprechenden Aminonitril und gegebenenfalls einer geeigneten Base, vorzugsweise Triethylamin, oder einer geeigneten Säure, vorzugsweise Salzsäure, in einem geeigneten, inerten Lösungsmittel, wie beispielsweise Aceton, Toluol, Chlorbenzol, Ethanol, Tetrahydrofuran oder Dimethylsulfoxid umgesetzt werden. Das Reaktionsgemisch läßt man mehrere Stunden, beispielsweise 2 bis 140 Stunden, in einem Temperaturbereich zwischen 20 und 135 °C reagieren. Nach beendeter Umsetzung wird ein eventuell ausgefallener Niederschlag abfiltriert, wobei das Filtermedium beispielsweise aus handelsüblichem Filterpapier bestehen kann, mit dem entsprechenden Lösungsmittel nachgewaschen und der zurückbleibende Feststoff im Vakuum getrocknet, bzw. wird das Reaktionsgemisch im Vakuum vom Lösungsmittel befreit. Die Reinigung des zurückbleibenden Rohproduktes erfolgt durch Umkristallisieren aus einem geeigneten Lösungsmittel, beispielsweise Ethanol, oder durch Säulen- bzw. Flash- Chromatographie an Kieselgel oder Aluminiumoxid. Als Laufmittel dient beispielsweise ein Gemisch aus Methanol und Dichlormethan.Or alternatively, if the product is to be a derivative of compound 8 according to Scheme 2, reaction product 4 with thiophosgene or thiocarbonyldiimidazole and a corresponding amine in a suitable inert solvent, such as, for example, tetrahydrofuran, toluene, dichloromethane, after the basic reaction has ended , Ethanol or acetonitrile are implemented. If necessary, a suitable base, preferably pyridine, sodium hydrogen carbonate, potassium carbonate, triethylamine or imidazole, is used. The reaction mixture is allowed to react for several hours, for example 1 to 24 hours, in a temperature range between -10 and 80 ° C. When the reaction has ended, any precipitate that has precipitated is filtered off, the filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo. If dimethylformamide is used, the reaction mixture is stirred into a large amount of water and the precipitate which has separated out is filtered off or the aqueous phase is extracted with a suitable organic solvent and the organic phases are concentrated in vacuo. The remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol or ethyl acetate, or by column or flash chromatography on silica gel or aluminum oxide. A mixture of ethyl acetate and hexane, for example, serves as the eluent. Thus, if the product is to be a derivative of compound 9 according to Scheme 2, after the basic reaction has ended, reaction product 4 can be inert with an appropriate aminonitrile and, if appropriate, a suitable base, preferably triethylamine, or a suitable acid, preferably hydrochloric acid Solvents such as acetone, toluene, chlorobenzene, ethanol, tetrahydrofuran or dimethyl sulfoxide are reacted. The reaction mixture is allowed to react for several hours, for example 2 to 140 hours, in a temperature range between 20 and 135 ° C. When the reaction has ended, any precipitate that has precipitated is filtered off, the filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo. The remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol, or by column or flash chromatography on silica gel or aluminum oxide. A mixture of methanol and dichloromethane, for example, serves as the mobile phase.
Oder es kann, wenn das Produkt ein Derivat der Verbindung 10 gemäß Schema 2 sein soll, nach Ablauf der Grundreaktion das Reaktionsprodukt 4 mit einem entsprechenden Nitril und gegebenenfalls einer geeigneten Base, vorzugsweise Natriuma- mid oder Natriumhexamethyldisilazid, oder einem geeigneten Katalysator, beispielsweise Aluminiumtrichlorid, Trimethylaluminium, Eisessig oder Schwefelsäure, in einem geeigneten, inerten Lösungsmittel, wie beispielsweise Tetrahydrofuran, Toluol, oder Ethanol, bzw. ohne Lösungsmittel umgesetzt werden. Das Reaktionsgemisch läßt man einige Zeit, beispielsweise 30 Minuten bis 24 Stunden, in einem Temperaturbereich zwischen 0 und 200 °C reagieren. Nach beendeter Umsetzung wird ein eventuell ausgefallener Niederschlag abfiltriert, wobei das Filtermedium beispielsweise aus handelsüblichem Filterpapier bestehen kann, mit dem entsprechenden Lösungsmittel nachgewaschen und der zurückbleibende Feststoff im Vakuum getrocknet, bzw. wird das Reaktionsgemisch im Vakuum vom Lösungsmittel befreit. Die Reinigung des zurückbleibenden Rohproduktes erfolgt durch Umkristallisieren aus einem geeigneten Lösungsmittel, beispielsweise Ethanol, oder durch Säulen- bzw. Flash-Chromatographie an Kieselgel oder Aluminiumoxid. Als Laufmittel dient beispielsweise ein Gemisch aus Methanol und Dichlormethan. Unter einigen der genannten Reaktionsbedingungen können OH-, SH- und NH2- Gruppen möglicherweise unerwünschte Nebenreaktionen eingehen. Es ist daher bevorzugt, diese mit Schutzgruppen zu versehen oder im Falle von NH2 durch NO2 zu ersetzen und nachfolgend die Schutzgruppe abzuspalten oder die NO2-Gruppe zu reduzieren. So kann in Abwandlung des oben beschriebenen Verfahrens in den Ausgangsverbindungen mindestens eine OH-Gruppe beispielsweise durch eine Benzy- loxygruppe und/oder mindestens eine SH-Gruppe beispielsweise durch eine S- Benzylgruppe und/oder mindestens eine NH2-Gruppe durch eine NO2-Gruppe ersetzt werden. Nachfolgend kann mindestens eine - vorzugsweise alle - Benzyloxygrup- pe/n beispielsweise mit Wasserstoff und Palladium auf Kohle und/oder mindestens eine - vorzugsweise alle - S-Benzylgruppe/n beispielsweise mit Natrium in Ammoniak abgespalten und/oder mindestens eine - vorzugsweise alle - NO2-Gruppe/n beispielsweise mit Wasserstoff und Raney-Nickel zu NH2 reduziert werden.Or, if the product is intended to be a derivative of compound 10 according to Scheme 2, after the end of the basic reaction, reaction product 4 with an appropriate nitrile and optionally a suitable base, preferably sodium amide or sodium hexamethyl disilazide, or a suitable catalyst, for example aluminum trichloride, Trimethylaluminum, glacial acetic acid or sulfuric acid, in a suitable, inert solvent, such as tetrahydrofuran, toluene, or ethanol, or without a solvent. The reaction mixture is allowed to react for a time, for example 30 minutes to 24 hours, in a temperature range between 0 and 200 ° C. When the reaction has ended, any precipitate that has precipitated is filtered off, the filter medium can consist, for example, of commercially available filter paper, washed with the appropriate solvent and the remaining solid dried in vacuo, or the reaction mixture is freed from the solvent in vacuo. The remaining crude product is purified by recrystallization from a suitable solvent, for example ethanol, or by column or flash chromatography on silica gel or aluminum oxide. A mixture of methanol and dichloromethane, for example, serves as the mobile phase. Under some of the reaction conditions mentioned, OH, SH and NH 2 groups can possibly undergo undesirable side reactions. It is therefore preferred to provide them with protecting groups or, in the case of NH 2 NO 2 by replacing and subsequently remove the protecting group or to reduce the NO 2 group. Thus, in a modification of the process described above, at least one OH group, for example by a benzyloxy group and / or at least one SH group, for example by an S-benzyl group and / or at least one NH 2 group by an NO 2 - Group to be replaced. Subsequently, at least one - preferably all - benzyloxy group / s, for example with hydrogen and palladium on carbon and / or at least one - preferably all - S-benzyl group / s, for example with sodium in ammonia, and / or at least one - preferably all - NO 2 group / s can be reduced to NH 2 , for example using hydrogen and Raney nickel.
Unter einigen der genannten Reaktionsbedingungen können Carbonsäureester- und Carbonsäureamidgruppen möglicherweise unerwünschte Nebenreaktionen eingehen. Es ist daher bevorzugt, Carbonsäureester- und Carbonsäureamidgruppen aus Verfahrensprodukten, welche mindestens eine OH- und/oder mindestens eine NH2- und/oder mindestens eine COOH-Gruppe enthalten, herzustellen. In Abwandlung des oben beschriebenen Verfahrens können Verfahrensprodukte, welche mindestens eine OH-Gruppe besitzen, und/oder welche mindestens eine NH2-Gruppe besitzen, durch Umsetzung mit einer aktivierten Carbonsäuregruppe, beispielsweise einer Carbonsäurechloridgruppe, in Carbonsäureester- bzw. Carbonsäureamidgruppen überführt werden. In Abwandlung des oben beschriebenen Verfahrens können Verfahrensprodukte, welche mindestens eine COOH-Gruppe besitzen, durch Umsetzung mit einem Aktivierungsmittel, wie beispielsweise Thionylchlorid oder Carbonyldiimidazol, und nachfolgender Umsetzung mit einem geeigneten Alkohol oder Amin in Carbonsäureester- bzw. Carbonsäureamidgruppen überführt werden.Under some of the reaction conditions mentioned, carboxylic acid ester and carboxamide groups can potentially undergo undesirable side reactions. It is therefore preferred to produce carboxylic acid ester and carboxamide groups from process products which contain at least one OH and / or at least one NH 2 and / or at least one COOH group. In a modification of the process described above, process products which have at least one OH group and / or which have at least one NH 2 group can be converted into carboxylic acid ester or carboxamide groups by reaction with an activated carboxylic acid group, for example a carboxylic acid chloride group. In a modification of the process described above, process products which have at least one COOH group can be converted into carboxylic acid ester or carboxamide groups by reaction with an activating agent, such as, for example, thionyl chloride or carbonyldiimidazole, and subsequent reaction with a suitable alcohol or amine.
Die erfindungsgemäßen Pyrido[2,3-b]pyrazin-Derivate gemäß der allgemeinen Formel I sind als Wirkstoffe in Arzneimitteln, insbesondere bei malignen und anderen, auf pathologischen Zellproliferationen beruhenden Erkrankungen, wie z. B. Resteno- se, Psoriasis, Arteriosklerose und Leberzirrhose zur Behandlung von Menschen, Säugetieren und Geflügel geeignet. Säugetiere können Haustiere wie Pferde, Kühe, Hunde, Katzen, Hasen, Schafe und dergleichen sein.The pyrido [2,3-b] pyrazine derivatives according to the general formula I according to the invention are active substances in medicaments, in particular in malignant and other diseases based on pathological cell proliferation, such as, for. B. restenosis, psoriasis, arteriosclerosis and cirrhosis of the liver for the treatment of people, Suitable for mammals and poultry. Mammals can be pets such as horses, cows, dogs, cats, rabbits, sheep and the like.
Die medizinische Wirkung der erfindungsgemäßen Pyrido[2,3-b]pyrazin-Derivate kann zum Beispiel auf einer Hemmung der Signaltransduktion durch Wechselwirkung mit Rezeptor-Tyrosinkinasen als auch mit cytoplasmatischen Tyrosin- und Se- rin/Threoninkinasen beruhen. Daneben sind noch weitere bekannte und unbekannte Wirkmechanismen zur Bekämpfung von malignen Prozessen denkbar.The medicinal effect of the pyrido [2,3-b] pyrazine derivatives according to the invention can be based, for example, on an inhibition of signal transduction by interaction with receptor tyrosine kinases as well as with cytoplasmic tyrosine and serine / threonine kinases. In addition, other known and unknown mechanisms of action to combat malignant processes are conceivable.
Gemäß einem weiteren Aspekt der Erfindung wird ein Verfahren zur Bekämpfung von Tumoren beim Menschen und in Säugetieren bereitgestellt, welches dadurch gekennzeichnet ist, daß mindestens ein Pyrido[2,3-b]pyrazin-Derivat gemäß der allgemeinen Formel I dem Menschen oder einem Säugetier in einer für die Tumorbehandlung wirksamen Menge verabreicht wird. Die für die Behandlung zu verabreichende therapeutisch effektive Dosis des jeweiligen erfindungsgemäßen Pyrido[2,3- bjpyrazin-Derivates richtet sich u.a. nach der Art und dem Stadium der Tumorerkrankung, dem Alter und Geschlecht des Patienten, der Art der Verabreichung und der Dauer der Behandlung. Die erfindungsgemäßen Arzneimittel können als flüssige, halbfeste und feste Arzneiformen verabreicht werden. Dies erfolgt in der jeweils geeigneten Weise in Form von Aerosolen, Pulver, Puder und Streupuder, Tabletten, Dragees, Emulsionen, Schäume, Lösungen, Suspensionen, Gele, Salben, Pasten, Pillen, Pastillen, Kapseln oder Suppositorien.According to a further aspect of the invention, there is provided a method for combating tumors in humans and in mammals, which is characterized in that at least one pyrido [2,3-b] pyrazine derivative according to the general formula I is used in humans or in a mammal an effective amount for tumor treatment is administered. The therapeutically effective dose of the respective pyrido [2,3-bpyrazine derivative according to the invention to be administered for the treatment is directed inter alia. according to the type and stage of the tumor, the age and sex of the patient, the type of administration and the duration of treatment. The pharmaceuticals according to the invention can be administered as liquid, semi-solid and solid pharmaceutical forms. This takes place in the most suitable manner in the form of aerosols, powders, powders and scattering powders, tablets, dragees, emulsions, foams, solutions, suspensions, gels, ointments, pastes, pills, lozenges, capsules or suppositories.
Die Arzneiformen enthalten neben mindestens einem erfindungsgemäßen Bestandteil je nach eingesetzter galenischer Form gegebenenfalls Hilfsstoffe, wie unter anderem Lösungsmittel, Lösungsbeschleuniger, Lösungsvermittler, Emulgatoren, Netzmittel, Antischaummittel, Gelbildner, Verdickungsmittel, Filmbildner, Bindemittel, Puffer, Salzbildner, Trocknungsmittel, Fließregulierungsmittel, Füllstoffe, Konservierungsstoffe, Antioxidatien, Farbstoffe, Formentrennmittel, Gleitmittel, Sprengmittel, Geschmacks - und Geruchskorrigentien. Die Auswahl der Hilfsstoffe sowie die einzusetzenden Mengen derselben hängt von der gewählten galenischen Form ab und orientiert sich an den dem Fachmann bekannten Rezepturen. Die erfindungsgemäßen Arzneimittel können in einer geeigneten Darreichungsform auf die Haut, epicutan als Lösung, Suspension, Emulsion, Schaum, Salbe, Paste oder Pflaster; über die Mund- und Zungenschleimhaut, buccal, lingual oder sublingu- al als Tablette, Pastille, Dragees, Linctus oder Gurgelwasser; über die Magen- und Darmschleimhaut, enteral als Tablette, Dragees, Kapsel, Lösung, Suspension oder Emulsion; über die Rectumschleimhaut, rectal als Suppositorium, Rectalkapsel oder Salbe; über die Nasenschleimhaut, nasal als Tropfen, Salben oder Spray; über das Bronchial- und Alveolarepithel, pulmonal oder per inhalationem als Aerosol oder In- halat; über die Conjunctiva, conjunctival als Augentropfen, Augensalbe, Augentabletten, Lamellae oder Augenwasser; über die Schleimhäute der Genitalorgane, intravaginal als Vaginalkugeln, Salben und Spülung, intrauterin als Uterus-Pessare; über die ableitenden Harnwege, intraurethral als Spülung, Salbe oder Arzneistäbchen; in eine Arterie, intraarteriell als Injektion; in eine Vene, intravenös als Injektion oder Infusion; in die Haut, intracutan als Injektion oder Implantat; unter die Haut, subcutan als Injektion oder Implantat; in den Muskel, intramusculär als Injektion oder Implantat; in die Bauchhöhle, intraperitoneal als Injektion oder Infusion verabreicht werden.In addition to at least one constituent according to the invention, depending on the galenical form used, the pharmaceutical forms optionally contain auxiliaries, such as, inter alia, solvents, solution accelerators, solubilizers, emulsifiers, wetting agents, antifoams, gelling agents, thickeners, film formers, binders, buffers, salt formers, drying agents, flow regulators, fillers, preservatives , Antioxidants, dyes, mold release agents, lubricants, disintegrants, taste and smell correctives. The selection of the auxiliaries and the amounts to be used depends on the galenic form chosen and is based on the recipes known to the person skilled in the art. The medicaments according to the invention can be applied to the skin in a suitable dosage form, epicutaneously as a solution, suspension, emulsion, foam, ointment, paste or plaster; via the oral and tongue mucosa, buccal, lingual or sublingual as a tablet, lozenge, dragees, linctus or gargle water; via the gastric and intestinal mucosa, enterally as tablets, coated tablets, capsules, solutions, suspensions or emulsions; via the rectal mucosa, rectally as a suppository, rectal capsule or ointment; through the nasal mucosa, nasally as drops, ointments or spray; via the bronchial and alveolar epithelium, pulmonally or by inhalation as aerosol or inhalation; via the conjunctiva, conjunctival as eye drops, eye ointment, eye tablets, lamellae or eyewash; via the mucous membranes of the genital organs, intravaginally as vaginal balls, ointments and lavage, intrauterinely as uterine pessaries; via the urinary tract, intraurethrally as a rinse, ointment or medicine stick; into an artery, intraarterially as an injection; into a vein, intravenously as an injection or infusion; into the skin, intracutaneously as an injection or implant; under the skin, subcutaneously as an injection or implant; in the muscle, intramuscularly as an injection or implant; into the abdominal cavity, intraperitoneally as an injection or infusion.
Die erfindungsgemäßen Verbindungen der allgemeinen Struktur I können in Hinblick auf praktische therapeutische Erfordernisse mittels geeigneter Maßnahmen in ihrer Arzneistoffwirkung verlängert werden. Dieses Ziel kann auf chemischem und/oder galenischem Wege erreicht werden. Beispiele für die Erzielung einer Wirkungsverlängerung sind der Einsatz von Implantaten und Liposomen, die Bildung von schwerlöslichen Salzen und Komplexen oder der Einsatz von Kristall-Suspensionen.The compounds of general structure I according to the invention can be extended with regard to practical therapeutic requirements by means of suitable measures in their drug action. This goal can be achieved chemically and / or galenically. Examples of achieving an increase in activity are the use of implants and liposomes, the formation of poorly soluble salts and complexes or the use of crystal suspensions.
Besonders bevorzugt sind dabei Arzneimittel, die mindestens eine Verbindung aus der nachfolgenden Gruppe der Pyrido[2,3-b]pyrazin-Derivate der allgemeinen Struktur I enthalten und die in Form ihrer freien Base oder auch als pharmazeutisch annehmbare Salze physiologisch verträglicher Säuren vorliegen können:Pharmaceuticals which contain at least one compound from the following group of the pyrido [2,3-b] pyrazine derivatives of the general structure I and which can be present in the form of their free base or as pharmaceutically acceptable salts of physiologically acceptable acids are particularly preferred:
1 -Allyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thioharnstoff (Beispiel 1 ) 1 -Allyl-3-(3-naphthalin-2-yl-pyrido[2,3-b]pyrazin-6-yl)-thioharnstoff (Bsp. 2) 1 -Allyl-3-[3-(4-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-thioharnstoff (Bsp. 3) 1-Allyl-3-[3-(4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-thiohamstoff-Hydrochlorid (Bsp. 4) 1 -(2-Methyl-allyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thioharnstoff (Bsp. 5)1-allyl-3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea (Example 1) 1-allyl-3- (3-naphthalen-2-yl-pyrido [2, 3-b] pyrazin-6-yl) thiourea (Ex. 2) 1-allyl-3- [3- (4-methoxyphenyl) pyrido [2,3-b] pyrazin-6-yl] thiourea (Ex. 3) 1-allyl-3- [3- (4-hydroxyphenyl) pyrido [2,3-b] pyrazin-6-yl] thiourea hydrochloride (Ex. 4) 1 - (2-methyl-allyl) -3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea (Ex. 5)
1 -(2-Methyl-allyl)-3-(3-naphthalin-2-yl-pyrido[2,3-b]pyrazin-6-yl)-thiohamstoff (Bsp. 6)1 - (2-methyl-allyl) -3- (3-naphthalen-2-yl-pyrido [2,3-b] pyrazin-6-yl) thiourea (Ex. 6)
1 -[3-(4-Methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-(2-methyl-allyl)-thioharnstoff1 - [3- (4-Methoxyphenyl) pyrido [2,3-b] pyrazin-6-yl] -3- (2-methyl-allyl) thiourea
(Bsp. 7)(Ex. 7)
1-(3-Naphthalin-2-yl-pyrido[2,3-b]pyrazin-6-yl)-3-(4-nitro-phenyl)-thiohamstoff (Bsp.1- (3-Naphthalin-2-yl-pyrido [2,3-b] pyrazin-6-yl) -3- (4-nitro-phenyl) thiourea (Ex.
8)8th)
1 -[3-(4-Methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-(4-nitro-phenyl)-thioharnstoff1 - [3- (4-Methoxyphenyl) pyrido [2,3-b] pyrazin-6-yl] -3- (4-nitrophenyl) thiourea
(Bsp. 9)(Ex. 9)
1 -te/-f-Butyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thioharnstoff (Bsp. 10)1 -te / -f-butyl-3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea (Ex. 10)
1 -Cyclopropyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thiohamstoff (Bsp. 11)1-cyclopropyl-3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea (Ex. 11)
1 -Methyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thioharnstoff (Bsp. 12)1-methyl-3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea (Ex. 12)
1 -Benzyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thiohamstoff (Bsp. 13)1-benzyl-3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea (Ex. 13)
1 -(4-Fluoro-phenyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thioharnstoff (Bsp. 14)1 - (4-Fluoro-phenyl) -3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea (Ex. 14)
1 -(3-Phenyl-pyrido[2,3-b]pyrazin-6-yl)-3-p-tolyl-hamstoff (Bsp. 15)1 - (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) -3-p-tolylurea (Ex. 15)
1-(4-Chloro-3-trifluoromethyl-phenyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-harnstoff1- (4-Chloro-3-trifluoromethyl-phenyl) -3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) -urea
(Bsp. 16)(Ex. 16)
1 -(2-Morpholin-4-yl-ethyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-harnstoff (Bsp. 17) 1 - (2-Morpholin-4-yl-ethyl) -3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) urea (Ex. 17)
Ausführungsbeispiele:EXAMPLES
Gemäß der allgemeinen Vorschriften für die Stufen 1 -3, denen die Syntheseschemata 1 und 2 zugrundeliegen, wurden folgende Verbindungen synthetisiert, die unter der Angabe der jeweiligen chemischen Bezeichnung aus der nachfolgenden Übersicht hervorgehen. Ferner sind ihre NMR-spektroskopischen Daten und Schmelzpunkte beigefügt. In der sich anschließenden Tabelle 1 sind aus der allgemeinen Formel II und den Substituenten R1 , R2, X und Y die Strukturen dieser Verbindungen zu ersehen.In accordance with the general regulations for stages 1-3, which are based on synthesis schemes 1 and 2, the following compounds were synthesized, which can be seen from the following overview by specifying the respective chemical name. Also included are their NMR spectroscopic data and melting points. The structures of these compounds can be seen in the following Table 1 from the general formula II and the substituents R1, R2, X and Y.
Die eingesetzten Chemikalien und Lösungsmittel wurden kommerziell bei den herkömmlichen Anbietern erworben (Acros, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, etc.) oder synthetisiert.The chemicals and solvents used were purchased commercially from conventional suppliers (Acros, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, etc.) or synthesized.
Die Erfindung soll anhand der nachfolgenden Beispiele näher erläutert werden, ohne darauf beschränkt zu sein.The invention is to be explained in more detail with reference to the following examples, without being restricted thereto.
Beispiel 1 :Example 1 :
Herstellung von 3-Phenyl-pyrido[2,3-b]pyrazin-6-ylamin (Umsetzung gemäß Schema 1 , 1. und 2. Stufe)Preparation of 3-phenyl-pyrido [2,3-b] pyrazin-6-ylamine (reaction according to scheme 1, 1st and 2nd stage)
Eine Lösung aus 1.22 g 2,6-Diamino-3-nitropyridin (7.92 mmol) in 210 ml Ethanol wird mit Raney-Nickel als Katalysator bei 50 °C und 5 bar hydriert. Nach beendeter Hydrierung saugt man den Katalysator über einen Glasfaserfilter ab. In die Vorlage werden vor der Filtration 1.68 g Phenylglyoxal-Hydrat (11.03 mmol) in 50 ml Ethanol vorgelegt. Dann wird der Katalysator unter Stickstoff als Schutzgas abfiltriert und die Hydrierlösung direkt in den Reaktionskolben gesaugt. Das grün-blaue Reaktionsgemisch wird unter Stickstoff 30 min. unter Rückfluß erhitzt. Das Gemisch läßt man abkühlen und entfernt das Lösungsmittel im Vakuum. Man erhält schließlich einen dunkelbraunen Feststoff. Säulenchromatographische Reinigung an Kieselgel (Laufmittelgemisch Dichlormethan / Methanol) liefert einen hellgelben kristallinen Feststoff. Herstellung von 1-Allyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thiohamstoff (Umsetzung gemäß Schema 2, 3. Stufe)A solution of 1.22 g of 2,6-diamino-3-nitropyridine (7.92 mmol) in 210 ml of ethanol is hydrogenated with Raney nickel as a catalyst at 50 ° C. and 5 bar. After the hydrogenation has ended, the catalyst is suctioned off through a glass fiber filter. Before the filtration, 1.68 g of phenylglyoxal hydrate (11.03 mmol) in 50 ml of ethanol are placed in the receiver. The catalyst is then filtered off under nitrogen as a protective gas and the hydrogenation solution is sucked directly into the reaction flask. The green-blue reaction mixture is under nitrogen for 30 min. heated under reflux. The mixture is allowed to cool and the solvent is removed in vacuo. A dark brown solid is finally obtained. Purification by column chromatography on silica gel (mobile solvent mixture dichloromethane / methanol) gives a light yellow crystalline solid. Preparation of 1-allyl-3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea (reaction according to Scheme 2, 3rd stage)
0.246 g Natriumhydrid (6.14 mmol) werden in 5 ml wasserfreiem Dimethylformamid unter Stickstoff als Schutzgas vorgelegt. Das Gemisch wird im Eisbad auf 0 °C abgekühlt. 1.05 g 3-Phenyl-pyrido[2,3-b]pyrazin-6-ylamin (4.72 mmol) werden in 5 ml wasserfreiem Dimethylformamid gelöst und tropfenweise zugegeben. Man entfernt das Kühlbad und läßt das Gemisch 30 Minuten bei RT rühren. Danach kühlt man das Gemisch im Eisbad wieder auf 0 °C ab und fügt 0.469 g Allylisothiocyanat (4.72 mmol) in 4 ml wasserfreiem Dimethylformamid gelöst, tropfenweise hinzu. Nach beendeter Zugabe entfernt man das Kühlbad und läßt das Gemisch noch 1 ,5 Stunden bei Raumtemperatur rühren. Zur Aufarbeitung gießt man das Gemisch in ca. 250 ml destilliertes Wasser und saugt den ausgefallenen orangefarbenen Feststoff ab. Mehrfache säulenchromatographische Reinigung (Laufmittelgemische Dichlormethan / Methanol) und anschließende Aufreinigung an der präparativen HPLC liefern einen gelben Feststoff.0.246 g of sodium hydride (6.14 mmol) are placed in 5 ml of anhydrous dimethylformamide under nitrogen as a protective gas. The mixture is cooled to 0 ° C. in an ice bath. 1.05 g of 3-phenyl-pyrido [2,3-b] pyrazin-6-ylamine (4.72 mmol) are dissolved in 5 ml of anhydrous dimethylformamide and added dropwise. The cooling bath is removed and the mixture is allowed to stir at RT for 30 minutes. The mixture is then cooled again to 0 ° C. in an ice bath and 0.469 g of allyl isothiocyanate (4.72 mmol) dissolved in 4 ml of anhydrous dimethylformamide are added dropwise. When the addition is complete, the cooling bath is removed and the mixture is left to stir at room temperature for a further 1.5 hours. For working up, the mixture is poured into approx. 250 ml of distilled water and the orange solid which has precipitated is filtered off with suction. Multiple column chromatographic purification (mobile solvent mixtures dichloromethane / methanol) and subsequent purification on the preparative HPLC yield a yellow solid.
Schmelzpunkt: 239-240°C (Zers.)Melting point: 239-240 ° C (decomp.)
1H-NMR (de-DMSO): δ = 4.40 (m, 2H), 5.30 (d, 1 H), 5.60 (d, 1 H), 6.07-6.17 (m, 1 H), 7.55-7.70 (m, 4H), 8.35 (d, 2H), 8.45 (d, 1 H), 9.50 (s, 1 H), 11.35 (s, 1 H), 12.55 (m, 1 H). 1 H-NMR (de-DMSO): δ = 4.40 (m, 2H), 5.30 (d, 1 H), 5.60 (d, 1 H), 6.07-6.17 (m, 1 H), 7.55-7.70 (m , 4H), 8.35 (d, 2H), 8.45 (d, 1H), 9.50 (s, 1H), 11.35 (s, 1H), 12.55 (m, 1H).
Folgende Beispiele wurden gemäß Beispiel 1 synthetisiert :The following examples were synthesized according to example 1:
Beispiel 2: 1 -Allyl-3-(3-naphthalin-2-yl-pyrido[2,3-b]pyrazin-6-yl)-thioharnstoffExample 2: 1-Allyl-3- (3-naphthalen-2-yl-pyrido [2,3-b] pyrazin-6-yl) thiourea
Smp.: 242-243°C (Zers.)M.p .: 242-243 ° C (dec.)
1H-NMR (de-DMSO): δ = 4.42 (m, 2H), 5.37 (d, 1 H), 5.65 (d, 1 H), 6.07-6.19 (m, 1 H), 7.57-7.68 (m, 3H), 7.97-8.05 (m, 1 H), 8.07-8.19 (m, 2H), 8.40-8.52 (m, 2H), 8.99 (s, 1 H), 9.70 (s, 1 H), 11.36 (s, 1 H), 12.56 (t, 1 H). Beispiel 3: 1 -Allyl-3-[3-(4-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-thiohamstoff 1 H-NMR (de-DMSO): δ = 4.42 (m, 2H), 5.37 (d, 1 H), 5.65 (d, 1 H), 6.07-6.19 (m, 1 H), 7.57-7.68 (m , 3H), 7.97-8.05 (m, 1 H), 8.07-8.19 (m, 2H), 8.40-8.52 (m, 2H), 8.99 (s, 1 H), 9.70 (s, 1 H), 11.36 ( s, 1H), 12.56 (t, 1H). Example 3: 1-Allyl-3- [3- (4-methoxyphenyl) pyrido [2,3-b] pyrazin-6-yl] thiourea
Smp.: 240-241 °C (Zers.)M.p .: 240-241 ° C (dec.)
1H-NMR (de-DMSO): δ = 3.87 (s, 3H), 4.36-4.42 (m, 2H), 5.32 (d, 1H), 5.60 (d, 1H), 6.06-6.16 (m, 1H), 7.16 (d, 2H), 7.60 (d, 1H), 8.32 (d, 2H), 8.42 (d, 1H), 9.56 (s, 1H), 11.29(s, 1H), 12.56 (m, 1H). 1 H-NMR (de-DMSO): δ = 3.87 (s, 3H), 4.36-4.42 (m, 2H), 5.32 (d, 1H), 5.60 (d, 1H), 6.06-6.16 (m, 1H) , 7.16 (d, 2H), 7.60 (d, 1H), 8.32 (d, 2H), 8.42 (d, 1H), 9.56 (s, 1H), 11.29 (s, 1H), 12.56 (m, 1H).
Beispiel 4: 1 -Allyl-3-[3-(4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-thiohamstoff- HydrochloridExample 4: 1-Allyl-3- [3- (4-hydroxyphenyl) pyrido [2,3-b] pyrazin-6-yl] thiourea hydrochloride
Smp.: 160-161 °C (Zers.)M.p .: 160-161 ° C (dec.)
1H-NMR (de-DMSO): δ = 4.36-4.43 (m, 2H), 5.31 (d, 1H), 5.59 (d, 1H), 6.05-6.16 (m, 1H), 6.97 (d, 2H), 7.57 (d, 1H), 8.20 (d, 2H), 8.40 (d, 1H), 9.41 (s, 1H), 10.17 (bs, 1H), 11.24 (s,1H), 12.56 (m, 1H). 1 H-NMR (de-DMSO): δ = 4.36-4.43 (m, 2H), 5.31 (d, 1H), 5.59 (d, 1H), 6.05-6.16 (m, 1H), 6.97 (d, 2H) , 7.57 (d, 1H), 8.20 (d, 2H), 8.40 (d, 1H), 9.41 (s, 1H), 10.17 (bs, 1H), 11.24 (s, 1H), 12.56 (m, 1H).
Beispiel 5: 1 -(2-Methyl-allyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thioharnstoffExample 5: 1 - (2-methyl-allyl) -3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea
Smp.: 225-226°C (Zers.)M.p .: 225-226 ° C (dec.)
1H-NMR (de-DMSO): δ = 1.90 (s, 3H), 4.30-4.35 (m, 2H), 5.01 (s, 1H), 5.22 (s, 1H), 7.55-7.80 (m, 4H), 8.30-8.38 (m, 2H), 8.45 (d, 1H), 9.52 (s, 1H), 11.32 (s, 1H), 12.65 (m, 1H). 1 H-NMR (de-DMSO): δ = 1.90 (s, 3H), 4.30-4.35 (m, 2H), 5.01 (s, 1H), 5.22 (s, 1H), 7.55-7.80 (m, 4H) , 8.30-8.38 (m, 2H), 8.45 (d, 1H), 9.52 (s, 1H), 11.32 (s, 1H), 12.65 (m, 1H).
Beispiel 6: 1 -(2-Methyl-allyl)-3-(3-naphthalin-2-yl-pyrido[2,3-b]pyrazin-6-yl)-thioharn- stoffExample 6: 1 - (2-methyl-allyl) -3- (3-naphthalen-2-yl-pyrido [2,3-b] pyrazin-6-yl) thiourea
Smp.: 239-240°C (Zers.) 1H-NMR (de-DMSO): δ = 1.94 (s, 3H), 4.32 (m, 2H), 5.07 (s, 1 H), 5.28 (s, 1H), 7.60- 7.69 (m, 3H), 8.00-8.05 (m, 1 H), 8.07-8.12 (m, 1 H), 8.14 (d, 1 H), 8.42-8.51 (m, 2H), 8.98 (s, 1 H), 9.68 (s, 1 H), 11.32 (s, 1 H), 12.78 (m, 1 H).M.p .: 239-240 ° C (dec.) 1 H-NMR (de-DMSO): δ = 1.94 (s, 3H), 4.32 (m, 2H), 5.07 (s, 1H), 5.28 (s, 1H), 7.60- 7.69 (m, 3H), 8.00-8.05 (m, 1 H), 8.07-8.12 (m, 1 H), 8.14 (d, 1 H), 8.42-8.51 (m, 2H), 8.98 (s, 1 H), 9.68 (s, 1 H), 11.32 (s, 1H), 12.78 (m, 1H).
Beispiel 7: 1 -[3-(4-Methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-(2-methyl-allyl)-thio- harnstoffExample 7: 1 - [3- (4-methoxyphenyl) pyrido [2,3-b] pyrazin-6-yl] -3- (2-methyl-allyl) thiourea
Smp.: 251 -252°C (Zers.)M.p .: 251 -252 ° C (dec.)
1H-NMR (de-DMSO): δ = 1.92 (s, 3H), 3.85 (s, 3H), 4.27-4.35 (m, 2H), 5.02 (s, 1 H), 5.24 (s, 1 H), 7.15 (d, 2H), 7.58 (d, 1 H), 8.31 (d, 2H), 8.41 (d, 1 H), 9.46 (s, 1 H), 11.29 (s, 1 H), 12.68 (m, 1 H). 1 H-NMR (de-DMSO): δ = 1.92 (s, 3H), 3.85 (s, 3H), 4.27-4.35 (m, 2H), 5.02 (s, 1 H), 5.24 (s, 1 H) , 7.15 (d, 2H), 7.58 (d, 1H), 8.31 (d, 2H), 8.41 (d, 1H), 9.46 (s, 1H), 11.29 (s, 1H), 12.68 (m , 1 H).
Beispiel 8: 1 -(3-Naphthalin-2-yl-pyrido[2,3-b]pyrazin-6-yl)-3-(4-nitro-phenyl)-thioharn- stoffExample 8: 1 - (3-Naphthalin-2-yl-pyrido [2,3-b] pyrazin-6-yl) -3- (4-nitro-phenyl) thiourea
Smp.: 260-261 °C (Zers.)M.p .: 260-261 ° C (dec.)
1H-NMR (de-DMSO): δ = 7.61-7.68 (m, 3H), 7.72 (d, 2H), 7.75 (d, 1 H), 8.01 -8.06 (m, 1 H), 8.16 (m, 2H), 8.26 (d, 2H), 8.53 (d, 1 H), 8.58 (d, 1 H), 9.04 (s, 1 H), 9.62 (s, 1 H), 9.76 (s, 1 H), 11.81 (s, 1 H). 1 H-NMR (de-DMSO): δ = 7.61-7.68 (m, 3H), 7.72 (d, 2H), 7.75 (d, 1 H), 8.01 -8.06 (m, 1 H), 8.16 (m, 2H), 8.26 (d, 2H), 8.53 (d, 1 H), 8.58 (d, 1 H), 9.04 (s, 1 H), 9.62 (s, 1 H), 9.76 (s, 1 H), 11.81 (s, 1H).
Beispiel 9: 1 -[3-(4-Methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-(4-nitro-phenyl)-thio- harnstoffExample 9: 1 - [3- (4-methoxyphenyl) pyrido [2,3-b] pyrazin-6-yl] -3- (4-nitro-phenyl) thiourea
Smp.: 250-251 °C (Zers.)M.p .: 250-251 ° C (dec.)
1H-NMR (de-DMSO): δ = 3.85 (s, 3H), 7.17 (d, 2H), 7.71 (d, 2H), 8.21 (d, 2H), 8.22- 8.27 (m, 1 H), 8.36-8.42 (m, 3H), 9.53 (s, 1 H), 9.65 (s, 1 H), 11.77 (s, 1 H). Beispiel 10: 1 -terf.Butyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thioharnstoff 1 H-NMR (de-DMSO): δ = 3.85 (s, 3H), 7.17 (d, 2H), 7.71 (d, 2H), 8.21 (d, 2H), 8.22-8.27 (m, 1 H), 8.36-8.42 (m, 3H), 9.53 (s, 1H), 9.65 (s, 1H), 11.77 (s, 1H). Example 10: 1-tert-Butyl-3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea
Smp.: 227°C (Zers.)M.p .: 227 ° C (dec.)
1H-NMR (de-DMSO): δ = 1.65 (s, 9H), 7.53-7.69 (m, 4H), 8.34 (d, 2H), 8.41 (d, 1 H), 1 H-NMR (de-DMSO): δ = 1.65 (s, 9H), 7.53-7.69 (m, 4H), 8.34 (d, 2H), 8.41 (d, 1 H),
9.51 (s, 1 H), 10.98 (s, 1 H), 12.75 (s, 1 H).9.51 (s, 1H), 10.98 (s, 1H), 12.75 (s, 1H).
Beispiel 11 : 1-Cyclopropyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thiohamstoffExample 11: 1-Cyclopropyl-3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea
Smp.: 233-234°CM.p .: 233-234 ° C
1H-NMR (de-DMSO): δ = 0.70-0.80 (m, 2H), 0.91 -1.00 (m, 2H), 3.20-3.28 (m, 1 H), 7.51-7.72 (m, 4H), 8.36 (d, 2H), 8.45 (d, 1 H), 9.52 (s, 1 H), 11.31 (s, 1 H), 12.45 (s, 1 H). 1 H-NMR (de-DMSO): δ = 0.70-0.80 (m, 2H), 0.91-1.00 (m, 2H), 3.20-3.28 (m, 1H), 7.51-7.72 (m, 4H), 8.36 (d, 2H), 8.45 (d, 1H), 9.52 (s, 1H), 11.31 (s, 1H), 12.45 (s, 1H).
Beispiel 12: 1 -Methyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thiohamstoffExample 12: 1-Methyl-3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea
Smp.: 253-254°CM.p .: 253-254 ° C
1H-NMR (de-DMSO): δ = 3.25 (s, 3H), 7.59-7.67 (m, 4H), 8.38 (d, 2H), 8.46 (d, 1 H), 1 H-NMR (de-DMSO): δ = 3.25 (s, 3H), 7.59-7.67 (m, 4H), 8.38 (d, 2H), 8.46 (d, 1 H),
9.52 (s, 1 H), 11.31 (s, 1 H), 12.10 (s, 1 H).9.52 (s, 1H), 11.31 (s, 1H), 12.10 (s, 1H).
Beispiel 13: 1 -Benzyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thioharnstoffExample 13: 1-Benzyl-3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea
Smp.: 232-233°CM.p .: 232-233 ° C
1H-NMR (de-DMSO): δ = 4.96 (m, 2H), 7.37-7.48 (m, 3H), 7.54-7.67 (m, 6H), 8.32 (d, 2H), 8.47 (d, 1 H), 9.52 (s, 1 H), 11.43 (s, 1 H), 12.91 (s, 1 H). 1 H-NMR (de-DMSO): δ = 4.96 (m, 2H), 7.37-7.48 (m, 3H), 7.54-7.67 (m, 6H), 8.32 (d, 2H), 8.47 (d, 1H ), 9.52 (s, 1H), 11.43 (s, 1H), 12.91 (s, 1H).
Beispiel 14: 1 -(4-Fluoro-phenyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thiohamstoff Smp.: 225-226°CExample 14: 1 - (4-Fluoro-phenyl) -3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea M.p .: 225-226 ° C
1H-NMR (de-DMSO): δ = 7.33 (m, 2H), 7.57-7.65 (m, 3H), 7.70-7.81 (m, 3H), 8.34 (d, 2H), 8.54 (d, 1 H), 9.57 (s, 1 H), 11.62 (s, 1 H). 1 H-NMR (de-DMSO): δ = 7.33 (m, 2H), 7.57-7.65 (m, 3H), 7.70-7.81 (m, 3H), 8.34 (d, 2H), 8.54 (d, 1H ), 9.57 (s, 1H), 11.62 (s, 1H).
Beispiel 15: 1 -(3-Phenyl-pyrido[2,3-b]pyrazin-6-yl)-3-p-tolyl-hamstoffExample 15: 1 - (3-Phenylpyrido [2,3-b] pyrazin-6-yl) -3-p-tolylurea
Smp.: 298-299°CM.p .: 298-299 ° C
1H-NMR (de-DMSO): δ = 2.29 (s, 3H), 7.20 (d, 2H), 7.52 (d, 2H), 7.59-7.67 (m, 3H), 7.80 (d, 1 H), 8.38 (d, 2H), 8.44 (d, 1 H), 9.59 (s, 1 H), 10.36 (s, 1 H), 11.46 (s, 1 H). 1 H-NMR (de-DMSO): δ = 2.29 (s, 3H), 7.20 (d, 2H), 7.52 (d, 2H), 7.59-7.67 (m, 3H), 7.80 (d, 1 H), 8.38 (d, 2H), 8.44 (d, 1H), 9.59 (s, 1H), 10.36 (s, 1H), 11.46 (s, 1H).
Beispiel 16: 1 -(4-Chloro-3-trif luoromethyl-phenyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6- yl)-hamstoffExample 16: 1 - (4-Chloro-3-trifluoromethyl-phenyl) -3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) urea
Smp.: 250°CM.p .: 250 ° C
1H-NMR (de-DMSO): δ = 7.58-7.67 (m, 3H), 7.74 (d, 1 H), 7.80 (d, 1 H), 7.87 (d, 1 H), 8.21 (s, 1 H), 8.39 (d, 2H), 8.48 (d, 1 H), 9.53 (s, 1 H), 10.55 (s, 1 H), 11.82 (s, 1 H). 1 H-NMR (de-DMSO): δ = 7.58-7.67 (m, 3H), 7.74 (d, 1 H), 7.80 (d, 1 H), 7.87 (d, 1 H), 8.21 (s, 1 H), 8.39 (d, 2H), 8.48 (d, 1H), 9.53 (s, 1H), 10.55 (s, 1H), 11.82 (s, 1H).
Beispiel 17: 1 -(2-Morpholin-4-yl-ethyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-harn- stoffExample 17: 1 - (2-Morpholin-4-yl-ethyl) -3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) urea
Smp.: 226°CM.p .: 226 ° C
1H-NMR (de-DMSO): δ = 2.45-2.67 (m, 6H), 3.40-3.48 (m, 2H), 3.60-3.69 (m, 4H), 7.55-7.70 (m, 4H), 8.30-8.40 (m, 3H), 9.29 (s, 1 H), 9.42 (s, 1 H), 10.18 (s, 1 H). Tabelle 1 : 1 H-NMR (de-DMSO): δ = 2.45-2.67 (m, 6H), 3.40-3.48 (m, 2H), 3.60-3.69 (m, 4H), 7.55-7.70 (m, 4H), 8.30- 8.40 (m, 3H), 9.29 (s, 1H), 9.42 (s, 1H), 10.18 (s, 1H). Table 1 :
Biologische Wirkungen der erfindungsgemäßen VerbindungenBiological effects of the compounds according to the invention
Die inhibitorische Wirkung der erfindungsgemäßen Verbindungen wurde an folgenden humanen Serin/ Threonin- und Tyrosinkinasen in klassischen Kinaseassays getestet: PKB/Akt1 , c-Raf, B-Raf, Mek, PDGFRbeta, Flt-3, c-Kit, c-Abl, KDR, FGFR1 und IGF1 R. Eingesetzt wurden sowohl die Volllängenkinasen als auch verkürzte Fragmente - mindestens aber die cytoplasmatischen, konstitutiv aktiven Kinasedo- mänen. Die Kinasen wurden als rekombinante Fusionsproteine mit GST-(Glutathion- S-Transferase) oder HIS-Tag in Sf9-Zellkultur hergestellt. Je nach Substrattyp wurden die verschiedenen Kinasereaktionen in Sandwich-ELISA-Formaten oder mittels einfacher Substratadsorptionstest auf 96-Well Flashplates (Perkin Eimer) durchgeführt.The inhibitory activity of the compounds according to the invention was tested on the following human serine / threonine and tyrosine kinases in classic kinase assays: PKB / Akt1, c-Raf, B-Raf, Mek, PDGFRbeta, Flt-3, c-Kit, c-Abl, KDR , FGFR1 and IGF1 R. Both full-length kinases and truncated fragments were used - but at least the cytoplasmic, constitutively active kinase domains. The kinases were produced as recombinant fusion proteins with GST (glutathione S-transferase) or HIS tag in Sf9 cell culture. Depending on the type of substrate, the various kinase reactions were carried out in sandwich ELISA formats or using a simple substrate adsorption test on 96-well flashplates (Perkin Elmer).
Nachfolgend wird die Substanztestung an der Raf-Mek-Erk-Kaskade genauer beschrieben. Ausgewählte Testergebnisse zu den Raf- bzw. Mek-Inhibitoren sind anschließend aufgeführt.The substance test on the Raf-Mek-Erk cascade is described in more detail below. Selected test results for the Raf or Mek inhibitors are listed below.
Prozedere: Raf- ek-Erk-ELISAProcedure: Raf-ek-Erk-ELISA
Potentielle Inhibitoren wurden zunächst bei einer Konzentration von 20μg/ml in initialen Single-Dose-Bestimmungen auf 96er Mikrotiterplatten (MTPs) untersucht. Substanzen >70% Inhibition wurden für Dosis-Wirkungsstudien eingesetzt. Die Rekonstitution der Raf-Mek-Erk-Kaskade wurde mithilfe eines zellfreien ELISAs quantifiziert. Verwendet wurden folgende rekombinant hergestellte Kinaseproteine: 1.) konstitutiv aktive GST-c-Raf-DD aus Sf9-Zellen 2.) nicht aktive GST-Mek1 aus E. coli und 3.) nicht aktive His-Erk2 aus E. coli.Potential inhibitors were initially examined at a concentration of 20μg / ml in initial single-dose determinations on 96-well microtiter plates (MTPs). Substances> 70% inhibition were used for dose-effect studies. The reconstitution of the Raf-Mek-Erk cascade was quantified using a cell-free ELISA. The following recombinantly produced kinase proteins were used: 1.) constitutively active GST-c-Raf-DD from Sf9 cells 2.) inactive GST-Mek1 from E. coli and 3.) inactive His-Erk2 from E. coli.
Ein typischer Kinaseansatz wurde in einem finalen Volumen von 50//I mit je 20-150ng Raf-, Mek-, Erk-Kinaseprotein, 1 mM ATP, 10mM MgCI2, 150mM NaCI, 25mM beta- Glycerophosphat, 25mM Hepes pH 7.5 durchgeführt. Vor der Kinasereaktion wurden die Testsubstanzen jeweils für 30 Minuten bei Raumtemperatur mit jedem der drei Kinaseproteine einzeln vorinkubiert. Für die Kinasereaktion wurden die mit Testsubstanz vorinkubierten Kinasen zusammengeführt und für 30 Minuten bei 26°C inkubiert. Durch eine finale Konzentration von 2% SDS und 10 Minuten bei 50°C im Heizblock wurde die Reaktion gestoppt. Zur Immundetektion wurden die Reaktionsansätze auf anti-Erk-Ak(K-23, Santa Cruz Biotechnology)-beschichtete 96er MTPs übertragen, 60 Minuten bei Raumtemperatur inkubiert und 3x mit TBST gewaschen. Anti-phospho-Erk-Ak (#9106, New England Biolabs) 1 :500 in 50 l TBST/1% BSA wurde zugegeben und über Nacht bei 4°C inkubiert. Nach 3x Wasch der MTPs mit TBST wurde mit sekundärem anti-Maus- lgGPOD-Konjugat (#NA931 , Pharmacia) 1 :2500 versetzt, 1 h bei Raumtemperatur inkubiert und wiederum 3x mit TBST gewaschen. Zur kolorimetrischen Detektion der Kinasereaktion wurden je 50μl OPD (o-Phenyldiamin-dihydrochlorid)-Färbepuffer auf die Kavitäten pipettiert und 30 Minuten bei 37°C inkubiert. Die Farbreaktion wurde anschließend im ELISA-Reader bei 492nm bestimmt.A typical kinase batch was carried out in a final volume of 50 // I with 20-150ng Raf, Mek, Erk kinase protein, 1mM ATP, 10mM MgCl 2 , 150mM NaCl, 25mM beta-glycerophosphate, 25mM Hepes pH 7.5. Before the kinase reaction, the test substances were individually preincubated with each of the three kinase proteins for 30 minutes at room temperature. For the kinase reaction, the kinases preincubated with the test substance were combined and incubated at 26 ° C. for 30 minutes. The reaction was stopped by a final concentration of 2% SDS and 10 minutes at 50 ° C in the heating block. For immunodetection, the reaction mixtures were transferred to anti-Erk-Ak (K-23, Santa Cruz Biotechnology) -coated 96 MTPs, incubated for 60 minutes at room temperature and washed 3 times with TBST. Anti-phospho-Erk-Ak (# 9106, New England Biolabs) 1: 500 in 50 l TBST / 1% BSA was added and incubated overnight at 4 ° C. After washing the MTPs 3 times with TBST, secondary anti-mouse IgG POD conjugate (# NA931, Pharmacia) was added 1: 2500, incubated for 1 h at room temperature and washed again 3 times with TBST. For colorimetric detection of the kinase reaction, 50 μl each of OPD (o-phenyldiamine dihydrochloride) staining buffer was pipetted onto the wells and incubated at 37 ° C. for 30 minutes. The color reaction was then determined in the ELISA reader at 492nm.
Die experimentelle Bestimmung von Dosis-Wirkungskurven erfolgte mittels des selben Versuchsaufbaus bei 10 halblogarithmisch abgestuften Konzentrationen von 31.6pM-100μM. Die IC50-Werte wurden in GraphPadPrism kalkuliert.The experimental determination of dose-response curves was carried out using the same experimental setup at 10 semilogarithmic gradations from 31.6pM-100μM. The IC 50 values were calculated in GraphPadPrism.
Die erfindungsgemäßen Verbindungen zeigen eine effektive Inhibition der Erk- Phosphorylierung mit IC-50-Werten bis zu 400nM (siehe Ausführungsbeispiele 4 und 12).The compounds according to the invention show an effective inhibition of Erk phosphorylation with IC-50 values up to 400 nm (see working examples 4 and 12).
Ausführungsbeispiel IC50 (pM)Embodiment IC 50 (pM)
1 ca. 1.0 / 3.01 approx. 1.0 / 3.0
2 162 16
3 ca. 1.03 approx. 1.0
4 0.44 0.4
5 ca. 1.05 approx. 1.0
6 ca. 1006 approx. 100
7 437 43
8 > 1008> 100
9 > 1009> 100
10 > 10010> 100
11 0.911 0.9
12 0.412 0.4
13 > 10013> 100
14 ca. 5014 about 50
15 > 10015> 100
16 > 10016> 100
17 15 17 15

Claims

Patentansprüche claims
1. Neue Pyrido[2,3-b]pyrazin-Derivate gemäß der allgemeinen Formel I1. New pyrido [2,3-b] pyrazine derivatives according to the general formula I
II
worin die Substituenten R1 -R3 folgende Bedeutung haben :where the substituents R1 -R3 have the following meaning:
R1 und R2 können unabhängig voneinander:R1 and R2 can independently:
(i) Wasserstoff(i) hydrogen
(ii) Hydroxyl(ii) hydroxyl
(iii) Alkyl, wobei der Alkylrest gesättigt ist und aus 1 bis 8 C-Atomen bestehen kann,(iii) alkyl, where the alkyl radical is saturated and can consist of 1 to 8 carbon atoms,
(iv) unsubstituiertes oder substituiertes Aryl, wobei der Arylrest mit F, Cl, Br, I, CF3, CN, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH- Heteroaryl, NH-Alkyl-Cycloalkyl, NH-Alkyl-Heterocyclyl, NH-Alkyl-Aryl, NH- Alkyl-Heteroaryl, NH-Alkyl-NH2, NH-Alkyl-OH, N(Alkyl)2, NHC(O)-Alkyl, NHC(O)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2-Alkyl, NHSO2-Aryl, NHSO2-Heteroaryl, N02, SH, S-Alkyl, S-Aryl, S- Heteroaryl, OH, OCF3, O-Alkyl, O-Cycloalkyl, O-Heterocyclyl, O-Aryl, O- Heteroaryl, O-Alkyl-Cycloalkyl, O-Alkyl-Heterocyclyl, O-Alkyl-Aryl, O-Alkyl- Heteroaryl, O-Alkyl-OH, OC(O)-Alkyl, OC(0)-Cycloalkyl, OC(O)-Heterocyclyl, OC(O)-Aryl, OC(0)-Heteroaryl, OSO2-Alkyl, OS02-Aryl, OSO2-Heteroaryl, C(0)-Aryl, C(O)-Heteroaryl, CO2H, C02-Alkyl, CO2-Cycloalkyl, CO2- Heterocyclyl, CO2-Aryl, CO2-Heteroaryl, CO2-Alkyl-Cycloalkyl, CO2-Alkyl- Heterocyclyl, CO2-Alkyl-Aryl, CO2-Alkyl-Heteroaryl, C(O)-NH2, C(O)NH-Alkyl, C(O)NH-Cycloalkyl, C(O)NH-Heterocyclyl, C(0)NH-Aryl, C(0)NH-Heteroaryl, C(O)NH-Alkyl-Cycloalkyl, C(O)NH-Alkyl-Heterocyclyl, C(O)NH-Alkyl-Aryl, C(O)NH-Alkyl-Heteroaryl, C(O)N(Alkyl)2, S02-Alkyl, SO2-Aryl, SO2NH2, SO2NH-Alkyl, SO2NH-Aryl, SO2NH-Heteroaryl, SO3H, SO2O-Alkyl, SO2O-Aryl, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- oder mehrfach, gleich oder verschieden substituiert sein kann, und die Alkyl-, Cycloalkyl-, Heterocyclyl-, Aryl-, Heteroaryl-, Alkyl-Cycloalkyl-, Alkyl-Heterocyclyl-, Alkyl-Aryl- und Al- kyl-Heteroarylsubstituenten ihrerseits wiederum substituiert sein können,(iv) unsubstituted or substituted aryl, where the aryl radical with F, Cl, Br, I, CF 3 , CN, NH 2 , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH- Alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH 2 , NH-alkyl-OH, N (alkyl) 2 , NHC (O) -alkyl, NHC ( O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHSO 2 alkyl, NHSO 2 aryl, NHSO 2 heteroaryl, N0 2 , SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF 3 , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl heterocyclyl, O-alkyl aryl , O-alkyl heteroaryl, O-alkyl-OH, OC (O) alkyl, OC (0) cycloalkyl, OC (O) heterocyclyl, OC (O) aryl, OC (0) heteroaryl, OSO 2 Alkyl, OS0 2 aryl, OSO 2 heteroaryl, C (0) aryl, C (O) heteroaryl, CO 2 H, C0 2 alkyl, CO 2 cycloalkyl, CO 2 heterocyclyl, CO 2 aryl , CO 2 heteroaryl, CO 2 alkyl cycloalkyl, CO 2 alkyl Heterocyclyl, CO 2 -alkyl-aryl, CO 2 -alkyl-heteroaryl, C (O) -NH 2 , C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C ( 0) NH-aryl, C (0) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH- alkyl-heteroaryl, C (O) N (alkyl) 2, S0 2 -alkyl, SO 2 -aryl, SO 2 NH 2, SO 2 NH-alkyl, SO 2 NH-aryl, SO 2 NH-heteroaryl, SO 3 H, SO 2 O-alkyl, SO 2 O-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, can be substituted one or more times, identically or differently, and the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, In turn, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl and alkyl-heteroaryl substituents can in turn be substituted,
(v) unsubstituiertes oder substituiertes Heteroaryl, wobei der Heteroarylrest mit F, Cl, Br, I, CF3, CN, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH-Heteroaryl, N(Alkyl)2, NHC(O)-Alkyl, NHC(O)-Cycloalkyl, NHC(O)- Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHS02-Alkyl, NHS02-Aryl, NHSO2-Heteroaryl, NO2, SH, S-Alkyl, S-Aryl, OH, OCF3, O-Alkyl, O- Cycloalkyl, O-Aryl, O-Heteroaryl, OC(O)-Alkyl, OC(O)-Cycloalkyl, OC(O)- Heterocyclyl, OC(O)-Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OSO2-Cycloalkyl, OSO2-Aryl, OS02-Heteroaryl, C(O)-Alkyl, C(0)-Aryl, CO2H, CO2-Alkyl, CO2- Cycloalkyl, C02- Heterocyclyl, CO2-Aryl, CO2-Heteroaryl, C(O)-NH2, C(O)NH- Alkyl, C(O)NH-Cycloalkyl, C(O) NH-Heterocyclyl, C(O)NH-Aryl, C(O)NH- Heteroaryl, C(O)N(Alkyl)2, SO2NH2, SO2NH-Alkyl, SO2NH-Aryl, SO3H, SO2O- Alkyl, SO2O-Aryl, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- o- der mehrfach, gleich oder verschieden substituiert sein kann, und die Alkyl-, Cycloalkyl-, Heterocyclyl-, Aryl- und Heteroarylsubstituenten ihrerseits wiederum substituiert sein können, bedeutet.(v) unsubstituted or substituted heteroaryl, the heteroaryl radical being substituted with F, Cl, Br, I, CF 3 , CN, NH 2 , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, N ( Alkyl) 2 , NHC (O) alkyl, NHC (O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHS0 2 alkyl, NHS0 2 aryl, NHSO 2- heteroaryl, NO 2 , SH, S-alkyl, S-aryl, OH, OCF 3 , O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl, OC (O) alkyl, OC (O) - Cycloalkyl, OC (O) - heterocyclyl, OC (O) aryl, OC (O) heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OSO 2 aryl, OS0 2 heteroaryl, C (O) alkyl, C (0) aryl, CO 2 H, CO 2 alkyl, CO 2 - cycloalkyl, C0 2 - heterocyclyl, CO 2 aryl, CO 2 heteroaryl, C (O) -NH 2 , C (O) NH- Alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) N (alkyl) 2 , SO 2 NH 2 , SO 2 NH-alkyl, SO 2 NH-aryl, SO3H, SO 2 O-alkyl, SO 2 O-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, which can be substituted one or more times, identically or differently, and di e Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituents can in turn be substituted.
R3 kann:R3 can:
-C(Y)NR4R5 bedeuten, wobei Y = O, S und R4 und R5 unabhängig voneinanderMean -C (Y) NR4R5, where Y = O, S and R4 and R5 independently of one another
(i) Wasserstoff, (ii) unsubstituiertes oder substituiertes Alkyl, wobei der Alkylrest mit F, Cl, Br, I, CF3, CN, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH- Heteroaryl, NH-Alkyl-Aryl, NH-Alkyl-Heteroaryl, N(Alkyl)2, NHC(0)-Alkyl, NHC(O)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2-Alkyl, NHSO2-Cycloalkyl, NHSO2-Aryl, NHSO2-Heteroaryl, NO2, SH, S-Alkyl, S-Cycloalkyl, S-Heterocyclyl, S-Aryl, S-Heteroaryl, OH, OCF3, O-Alkyl, O-Cycloalkyl, O-Heterocyclyl, O-Aryl, O-Heteroaryl, O-Alkyl-Cycloalkyl, O- Alkyl-Aryl, O-Alkyl-Heteroaryl, OC(0)-Alkyl, OC(O)-Cycloalkyl, OC(O)- Heterocyciyl, OC(O)-Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OSO2-Cycloalkyl, OSO2-Aryl, OSO2-Heteroaryl, C(O)-Alkyl, C(0)-Aryl, CO2H, CO2-Alkyl, CO2- Cycloalkyl, CO2-Heterocyclyl, CO2-Aryl, CO2-Heteroaryl, C02-Alkyl-Cycloalkyl, CO2-Alkyl-Heterocyclyl, CO2-Alkyl-Aryl, CO2-Alkyl-Heteroaryl, C(O)-NH2, C(O)NH-Alkyl, C(O)NH-Cycloalkyl, C(O)NH-Heterocyclyl, C(O)NH-Aryl, C(O)NH-Heteroaryl, C(O)NH-Alkyl-Cycloalkyl, C(O)NH-Alkyl-Heterocyclyl, C(O)NH-Alkyl-Aryl, C(O)NH-Alkyl-Heteroaryl, C(O)N(Alkyl)2,(i) hydrogen, (ii) unsubstituted or substituted alkyl, the alkyl radical having F, Cl, Br, I, CF 3 , CN, NH 2 , NH alkyl, NH cycloalkyl, NH heterocyclyl, NH aryl, NH heteroaryl, NH Alkyl aryl, NH alkyl heteroaryl, N (alkyl) 2 , NHC (0) alkyl, NHC (O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl , NHSO 2 alkyl, NHSO 2 cycloalkyl, NHSO 2 aryl, NHSO 2 heteroaryl, NO 2 , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF 3 , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC (0) -alkyl, OC (O) -Cycloalkyl, OC (O) - heterocyciyl, OC (O) aryl, OC (O) heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OSO 2 aryl, OSO 2 heteroaryl, C (O) alkyl , C (0) aryl, CO 2 H, CO 2 alkyl, CO 2 cycloalkyl, CO 2 heterocyclyl, CO 2 aryl, CO 2 heteroaryl, C0 2 alkyl cycloalkyl, CO 2 alkyl heterocyclyl , CO 2 -alkyl-aryl, CO 2 -alkyl-heteroaryl, C (O) -NH 2 , C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O ) NH Aryl, C (O) NH heteroaryl, C (O) NH alkyl cycloalkyl, C (O) NH alkyl heterocyclyl, C (O) NH alkyl aryl, C (O) NH alkyl heteroaryl , C (O) N (alkyl) 2 ,
C(O)N(Cycloalkyl)2, C(0)N(Aryl)2, C(O)N(Heteroaryl)2, SO-Alkyl, SO-Aryl, S02- Alkyl, SO2-Aryl, SO2NH2, SO3H, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- oder mehrfach, gleich oder verschieden substituiert sein kann,C (O) N (cycloalkyl) 2, C (0) N (aryl) 2, C (O) N (heteroaryl) 2, SO-alkyl, SO-aryl, S0 2 - alkyl, SO 2 -aryl, SO 2 NH 2 , SO 3 H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, can be substituted one or more times, identically or differently,
(iii) unsubstituiertes oder substituiertes Cycloalkyl, wobei der Cycloalkylrest mit F, Cl, Br, I, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH- Heteroaryl, NH-Alkyl-Aryl, NH-Alkyl-Heteroaryl, N(Alkyl)2, NHC(O)-Alkyl, NHC(O)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2-Alkyl, NHSO2-Cycloalkyl, NHSO2-Aryl, NHSO2-Heteroaryl, OH, O- Alkyl, O-Cycloalkyl, O-Heterocyclyl, O-Aryl, O-Heteroaryl, O-Alkyl-Aryl, O- Alkyl-Heteroaryl, OC(O)-Alkyl, OC(O)-Cycloalkyl, OC(O)-Heterocyclyl, OC(O)- Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OSO2-Cycloalkyl, OSO2-Aryl, OSO2- Heteroaryl, CO2H, CO2-Alkyl, CO2-Cycloalkyl, CO2-Heterocyclyl, CO2-Aryl, CO2-Heteroaryl, C(O)-NH2, C(O)NH-Alkyl, C(O)NH-Cycloalkyl, C(O)NH- Heterocyclyl, C(O)NH-Aryl, C(O)NH-Heteroaryl, C(O)NH-Alkyl-Aryl, C(O)NH- Alkyl-Heteroaryl, C(O)N(Alkyl)2, Alkyl, oder Aryl ein- oder mehrfach, gleich o- der verschieden substituiert sein kann, (iv) unsubstituiertes oder substituiertes Heterocyclyl, wobei der Heterocyclylrest mit OH, O-Alkyl, O-Aryl, NH-Alkyl, NH-Aryl, Alkyl, Alkyl-Aryl oder Aryl ein- oder mehrfach, gleich oder verschieden substituiert sein kann,(iii) unsubstituted or substituted cycloalkyl, the cycloalkyl radical having F, Cl, Br, I, NH 2 , NH alkyl, NH cycloalkyl, NH heterocyclyl, NH aryl, NH heteroaryl, NH alkyl aryl, NH Alkyl heteroaryl, N (alkyl) 2 , NHC (O) alkyl, NHC (O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHSO 2 alkyl , NHSO 2 cycloalkyl, NHSO 2 aryl, NHSO 2 heteroaryl, OH, O alkyl, O cycloalkyl, O heterocyclyl, O aryl, O heteroaryl, O alkyl aryl, O alkyl heteroaryl, OC (O) alkyl, OC (O) cycloalkyl, OC (O) heterocyclyl, OC (O) aryl, OC (O) heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OSO 2 aryl, OSO 2 - heteroaryl, CO 2 H, CO 2 alkyl, CO 2 cycloalkyl, CO 2 heterocyclyl, CO 2 aryl, CO 2 heteroaryl, C (O) -NH 2 , C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-aryl, C (O) NH-alkyl- Heteroaryl, C (O) N (alkyl) 2 , alkyl, or aryl, one or more times, the same or which can be substituted differently, (iv) unsubstituted or substituted heterocyclyl, where the heterocyclyl radical may be substituted one or more times, identically or differently, with OH, O-alkyl, O-aryl, NH-alkyl, NH-aryl, alkyl, alkyl-aryl or aryl,
(v) unsubstituiertes oder substituiertes Aryl, wobei der Arylrest mit F, Cl, Br, I, CF3, CN, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH- Heteroaryl, NH-Alkyl-Cycloalkyl, NH-Alkyl-Heterocyclyl, NH-Alkyl-Aryl, NH- Alkyl-Heteroaryl, NH-Alkyl-NH2, NH-Alkyl-OH, N(Alkyl)2, NHC(0)-Alkyl, NHC(0)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2-Alkyl, NHSO2-Aryl, NHSO2-Heteroaryl, NO2, SH, S-Alkyl, S-Cycloalkyl, S-Heterocyclyl, S-Aryl, S-Heteroaryl, OH, OCF3, O-Alkyl, O-Cycloalkyl, O- Heterocyclyl, O-Aryl, O-Heteroaryl, O-Alkyl-Cycloalkyl, O-Alkyl-Heterocyclyl, O-Alkyl-Aryl, O-Alkyl-Heteroaryl, O-Alkyl-OH, OC(O)-Alkyl, OC(O)-Cycloalkyl, OC(O)-Heterocyclyl, OC(O)-Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OSO2- Cycloalkyl, OSO2-Aryl, OSO2-Heteroaryl, C(O)-Alkyl, C(O)-Aryl, C(O)- Heteroaryl, CO2H, CO2-Alkyl, C02-Cycloalkyl, CO2-Heterocyclyl, C02-Aryl, CO2-Heteroaryl, CO2-Alkyl-Cycloalkyl, CO2-Alkyl-Heterocyclyl, CO2-Alkyl-aryl, CO2-Alkyl-Heteroaryl, C(O)-NH2, C(0)NH-Alkyl, C(O)NH-Cycloalkyl, C(0)NH- Heterocyclyl, C(O)NH-Aryl, C(O)NH-Heteroaryl, C(O)NH-Alkyl-Cycloalkyl, C(O)NH-Alkyl-Heterocyclyl, C(O)NH-Alkyl-Aryl, C(O)NH-Alkyl-Heteroaryl, C(O)N(Alkyl)2, C(O)N(Cycloalkyl)2, C(0)N(Aryl)2, C(O)N(Heteroaryl)2, SO- Alkyl, SO-Aryl, SO2-Alkyl, SO2-Aryl, SO2NH2, SO2NH-Alkyl, SO2NH-Aryl, S02NH-Heteroaryl, SO3H, SO2O-Alkyl, SO2O-Aryl, SO2O-Heteroaryl, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- oder mehrfach, gleich oder verschieden substituiert sein kann,(v) unsubstituted or substituted aryl, where the aryl radical with F, Cl, Br, I, CF 3 , CN, NH 2 , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH- Alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH 2 , NH-alkyl-OH, N (alkyl) 2 , NHC (0) -alkyl, NHC ( 0) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHSO 2 alkyl, NHSO 2 aryl, NHSO 2 heteroaryl, NO 2 , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF 3 , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl -Heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OSO 2 aryl, OSO 2 heteroaryl, C (O) alkyl, C (O) aryl, C (O) heteroaryl, CO 2 H , CO 2 alkyl, C0 2 cycloalkyl, CO 2 heterocyclyl, C0 2 aryl, CO 2 heteroaryl, CO 2 alkyl cycloalkyl, CO 2 alkyl heterocyclyl, CO 2 alkyl aryl, CO 2 alkyl heteroaryl, C (O) -NH 2 , C (0) NH-alkyl, C (O) NH-cycloalkyl, C (0) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O ) N (alkyl) 2 , C (O) N (cycloalkyl) 2 , C (0) N (aryl) 2 , C (O) N (heteroaryl) 2 , SO-alkyl, SO-aryl, SO 2 -alkyl, SO 2 aryl, SO 2 NH 2 , SO 2 NH alkyl, SO 2 NH aryl, S0 2 NH heteroaryl, SO3H, SO 2 O alkyl, SO 2 O aryl, SO 2 O heteroaryl, alkyl, Cycloalkyl, heterocyclyl, aryl or heteroaryl, can be substituted one or more times, identically or differently,
(vi) unsubstituiertes oder substituiertes Heteroaryl, wobei der Heteroarylrest mit F, Cl, Br, I, CF3, CN, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH-Heteroaryl, NH-Alkyl-Aryl, NH-Alkyl-Heteroaryl, N(Alkyl)2, NHC(O)-Alkyl, NHC(0)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2-Alkyl, NHSO2-Aryl, NHSO2-Heteroaryl, NO2, SH, S-Alkyl, S-Aryl, OH, OCF3, O-Alkyl, O-Cycloalkyl, O-Heterocyclyl, O-Aryl, O-Heteroaryl, OC(O)- Alkyl, OC(O)-Cycloalkyl, OC(O)-Heterocyclyl, OC(O)-Aryl, OC(0)-Heteroaryl, OSO2-Alkyl, OSO -Cycloalkyl, OSO2-Aryl, OSO2-Heteroaryl, C(0)-Alkyl, C(O)- Aryl, C(O)-Heteroaryl, CO2H, CO2-Alkyl, CO2-Cycloalkyl, C02-Heterocyclyl, CO2-Aryl, CO2- Heteroaryl, CO2-Alkyl-Cycloalkyl, CO2-Alkyl-Heterocyclyl, CO2- Alkyl-aryl, CO2-Alkyl-Heteroaryl, C(O)-NH2, C(O)NH-Alkyl, C(O)NH-Cycloalkyl, C(O)NH-Heterocyclyl, C(O)NH-Aryl, C(0)NH-Heteroaryl, C(0)NH-Alkyl- Cycloalkyl, C(O)NH-Alkyl-Heterocyclyl, C(O)NH-Alkyl-Aryl, C(0)NH-Alkyl- Heteroaryl, C(O)N(Alkyl)2, C(O)N(Cycloalkyl)2, C(O)N(Aryl)2,(vi) unsubstituted or substituted heteroaryl, where the heteroaryl radical with F, Cl, Br, I, CF 3 , CN, NH 2 , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH- Alkyl aryl, NH alkyl heteroaryl, N (alkyl) 2 , NHC (O) alkyl, NHC (0) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl , NHSO 2 alkyl, NHSO 2 aryl, NHSO 2 heteroaryl, NO 2 , SH, S-alkyl, S-aryl, OH, OCF 3 , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, OC (O) alkyl, OC (O) cycloalkyl, OC (O) heterocyclyl, OC (O) aryl, OC (0) heteroaryl, OSO 2 alkyl, OSO cycloalkyl, OSO 2 Aryl, OSO 2 heteroaryl, C (0) alkyl, C (O) Aryl, C (O) heteroaryl, CO 2 H, CO 2 alkyl, CO 2 cycloalkyl, C0 2 heterocyclyl, CO 2 aryl, CO 2 heteroaryl, CO 2 alkyl cycloalkyl, CO 2 alkyl Heterocyclyl, CO 2 -alkyl-aryl, CO 2 -alkyl-heteroaryl, C (O) -NH 2 , C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C ( O) NH aryl, C (0) NH heteroaryl, C (0) NH alkyl cycloalkyl, C (O) NH alkyl heterocyclyl, C (O) NH alkyl aryl, C (0) NH- Alkyl heteroaryl, C (O) N (alkyl) 2 , C (O) N (cycloalkyl) 2 , C (O) N (aryl) 2 ,
C(O)N(Heteroaryl)2, SO2-Alkyl, SO2-Aryl, S02NH2j SO2NH-Alkyl, SO2NH-Aryl, SO2NH-Heteroaryl, SO3H, SO2O-Alkyl, SO2O-Aryl, SO2O-Heteroaryl, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- oder mehrfach, gleich oder verschieden substituiert sein kann, bedeuten,C (O) N (heteroaryl) 2 , SO 2 alkyl, SO 2 aryl, S0 2 NH 2j SO 2 NH alkyl, SO 2 NH aryl, SO 2 NH heteroaryl, SO3H, SO 2 O alkyl, SO 2 O aryl, SO 2 O heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, which can be substituted one or more times, identically or differently,
(vii) oder R4 und R5 zusammen Cycloalkyl oder Heterocyclyl bedeuten,(vii) or R4 and R5 together mean cycloalkyl or heterocyclyl,
-C(Y)NR6R7 bedeuten, wobei Y = NH und R6 und R7 unabhängig voneinander-C (Y) NR6R7, where Y = NH and R6 and R7 independently of one another
(i) Wasserstoff,(i) hydrogen,
(ii) unsubstituiertes oder substituiertes Alkyl, wobei der Alkylrest mit F, Cl, Br, I, CF3, CN, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH- Heteroaryl, NH-Alkyl-Aryl, NH-Alkyl-Heteroaryl, N(Alkyl)2, NHC(O)-Alkyl, NHC(O)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2-Alkyl, NHSO2-Cycloalkyl, NHSO2-Aryl, NHSO2-Heteroaryl, NO2, SH, S-Alkyl, S-Cycloalkyl, S-Heterocyclyl, S-Aryl, S-Heteroaryl, OH, OCF3, O-Alkyl, O-Cycloalkyl, O-Heterocyclyl, O-Aryl, O-Heteroaryl, O-Alkyl-Cycloalkyl, O- Alkyl-Aryl, O-Alkyl-Heteroaryl, OC(O)-Alkyl, OC(O)-Cycloalkyl, OC(O)- Heterocyclyl, OC(O)-Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OSO2-Cycloalkyl, OSO2-Aryl, OSO2-Heteroaryl, C(O)-Alkyl, C(O)-Aryl, CO2H, CO2-Alkyl, CO2- Cycloalkyl, CO2-Heterocyclyl, CO2-Aryl, CO2-Heteroaryl, CO2-Alkyl-Cycloalkyl, CO2-Alkyl-Heterocyclyl, CO2-Alkyl-Aryl, CO2-Alkyl-Heteroaryl, C(O)-NH2, C(O)NH-Alkyl, C(O)NH-Cycloalkyl, C(O)NH-Heterocyclyl, C(0)NH-Aryl, C(O)NH-Heteroaryl, C(O)NH-Alkyl-Cycloalkyl, C(O)NH-Alkyl-Heterocyclyl, C(0)NH-Alkyl-Aryl, C(O)NH-Alkyl-Heteroaryl, C(O)N(Alkyl)2,(ii) unsubstituted or substituted alkyl, the alkyl radical having F, Cl, Br, I, CF 3 , CN, NH 2 , NH alkyl, NH cycloalkyl, NH heterocyclyl, NH aryl, NH heteroaryl, NH Alkyl aryl, NH alkyl heteroaryl, N (alkyl) 2 , NHC (O) alkyl, NHC (O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl , NHSO 2 alkyl, NHSO 2 cycloalkyl, NHSO 2 aryl, NHSO 2 heteroaryl, NO 2 , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF 3 , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC (O) -alkyl, OC (O) -Cycloalkyl, OC (O) - heterocyclyl, OC (O) aryl, OC (O) heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OSO 2 aryl, OSO 2 heteroaryl, C (O) alkyl , C (O) aryl, CO 2 H, CO 2 alkyl, CO 2 cycloalkyl, CO 2 heterocyclyl, CO 2 aryl, CO 2 heteroaryl, CO 2 alkyl cycloalkyl, CO 2 alkyl heterocyclyl , CO 2 -alkyl-aryl, CO 2 -alkyl-heteroaryl, C (O) -NH 2 , C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (0 ) NH Aryl, C (O) NH heteroaryl, C (O) NH alkyl cycloalkyl, C (O) NH alkyl heterocyclyl, C (0) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl) 2 ,
C(0)N(Cycloalkyl)2, C(0)N(Aryl)2, C(O)N(Heteroaryl)2, SO-Alkyl, SO-Aryl, SO2- Alkyl, SO2-Aryl, SO2NH2, SO3H, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- oder mehrfach, gleich oder verschieden substituiert sein kann,C (0) N (cycloalkyl) 2 , C (0) N (aryl) 2 , C (O) N (heteroaryl) 2 , SO-alkyl, SO-aryl, SO 2 - alkyl, SO 2 -aryl, SO 2 NH 2 , SO 3 H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, can be substituted one or more times, identically or differently,
(iii) unsubstituiertes oder substituiertes Cycloalkyl, wobei der Cycloalkylrest mit F, Cl, Br, I, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH- Heteroaryl, NH-Alkyl-Aryl, NH-Alkyl-Heteroaryl, N(Alkyl)2, NHC(O)-Alkyl, NHC(O)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2-Alkyl, NHS02-Cycloalkyl, NHSO2-Aryl, NHSO2-Heteroaryl, OH, O- Alkyl, O-Cycloalkyl, O-Heterocyclyl, O-Aryl, O-Heteroaryl, O-Alkyl-Aryl, O- Alkyl-Heteroaryl, OC(0)-Alkyl, OC(0)-Cycloalkyl, OC(O)-Heterocyclyl, OC(O)- Aryl, OC(O)-Heteroaryl, OS02-Alkyl, OSO2-Cycloalkyl, OSO2-Aryl, OSO2- Heteroaryl, CO2H, C02-Alkyl, CO2-Cycloalkyl, C02-Heterocyclyl, CO2-Aryl, CO2-Heteroaryl, C(O)-NH2, C(O)NH-Alkyl, C(0)NH-Cycloalkyl, C(O)NH- Heterocyclyl, C(O)NH-Aryl, C(O)NH-Heteroaryl, C(O)NH-Alkyl-Aryl, C(0)NH- Alkyl-Heteroaryl, C(0)N(Alkyl)2, Alkyl, oder Aryl ein- oder mehrfach, gleich o- der verschieden substituiert sein kann,(iii) unsubstituted or substituted cycloalkyl, the cycloalkyl radical having F, Cl, Br, I, NH 2 , NH alkyl, NH cycloalkyl, NH heterocyclyl, NH aryl, NH heteroaryl, NH alkyl aryl, NH Alkyl heteroaryl, N (alkyl) 2 , NHC (O) alkyl, NHC (O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHSO 2 alkyl , NHS0 2 cycloalkyl, NHSO 2 aryl, NHSO 2 heteroaryl, OH, O alkyl, O cycloalkyl, O heterocyclyl, O aryl, O heteroaryl, O alkyl aryl, O alkyl heteroaryl, OC (0) alkyl, OC (0) cycloalkyl, OC (O) heterocyclyl, OC (O) aryl, OC (O) heteroaryl, OS0 2 alkyl, OSO 2 cycloalkyl, OSO 2 aryl, OSO 2 - heteroaryl, CO 2 H, C0 2 alkyl, CO 2 cycloalkyl, C0 2 heterocyclyl, CO 2 aryl, CO 2 heteroaryl, C (O) -NH 2 , C (O) NH-alkyl, C (0) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-aryl, C (0) NH-alkyl- Heteroaryl, C (0) N (alkyl) 2 , alkyl, or aryl, one or more times, the same or which can be substituted differently,
(iv) unsubstituiertes oder substituiertes Heterocyclyl, wobei der Heterocyclylrest mit OH, O-Alkyl, O-Aryl, NH-Alkyl, NH-Aryl, Alkyl oder Aryl ein- oder mehrfach, gleich oder verschieden substituiert sein kann,(iv) unsubstituted or substituted heterocyclyl, it being possible for the heterocyclyl radical to be substituted one or more times, identically or differently, by OH, O-alkyl, O-aryl, NH-alkyl, NH-aryl, alkyl or aryl,
(v) unsubstituiertes oder substituiertes Aryl, wobei der Arylrest mit F, Cl, Br, I, CF3, CN, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH- Heteroaryl, NH-Alkyl-Cycloalkyl, NH-Alkyl-Heterocyclyl, NH-Alkyl-Aryl, NH- Alkyl-Heteroaryl, NH-Alkyl-NH2, NH-Alkyl-OH, N(Alkyl)2, NHC(O)-Alkyl, NHC(O)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2-Alkyl, NHSO2-Aryl, NHSO2-Heteroaryl, NO2, SH, S-Alkyl, S-Cycloalkyl, S-Heterocyclyl, S-Aryl, S-Heteroaryl, OH, OCF3, O-Alkyl, O-Cycloalkyl, O- Heterocyclyl, O-Aryl, O-Heteroaryl, O-Alkyl-Cycloalkyl, O-Alkyl-Heterocyclyl, O-Alkyl-Aryl, O-Alkyl-Heteroaryl, O-Alkyl-OH, OC(O)-Alkyl, OC(O)-Cycloalkyl, OC(O)-Heterocyclyl, OC(O)-Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OSO2- Cycloalkyl, OSO2-Aryl, OSO2-Heteroaryl, C(O)-Alkyl, C(O)-Aryl, C(O)- Heteroaryl, CO2H, CO2-Alkyl, C02-Cycloalkyl, C02-Heterocyclyl, CO2-Aryl, C02-Heteroaryl, CO2-Alkyl-Cycloalkyl, CO2-Alkyl-Heterocyclyl, CO2-Alkyl-Aryl, CO2-Alkyl-Heteroaryl, C(O)-NH2, C(O)NH-Alkyl, C(O)NH-Cycloalkyl, C(0)NH- Heterocyclyl, C(O)NH-Aryl, C(O)NH-Heteroaryl, C(O)NH-Alkyl-Cycloalkyl, C(O)NH-Alkyl-Heterocyclyl, C(O)NH-Alkyl-Aryl, C(O)NH-Alkyl-Heteroaryl, C(O)N(Alkyl)2, C(O)N(Cycloalkyl)2, C(O)N(Aryl)2, C(O)N(Heteroaryl)2, SO- Alkyl, SO-Aryl, SO2-Alkyl, SO2-Aryl, S02NH , SO2NH-Alkyl, S02NH-Aryl, SO2NH-Heteroaryl, SO3H, SO2O-Alkyl, S02O-Aryl, SO2O-Heteroaryl, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- oder mehrfach, gleich oder verschieden substituiert sein kann,(v) unsubstituted or substituted aryl, where the aryl radical with F, Cl, Br, I, CF 3 , CN, NH 2 , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH- Alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH 2 , NH-alkyl-OH, N (alkyl) 2 , NHC (O) -alkyl, NHC ( O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHSO 2 alkyl, NHSO 2 aryl, NHSO 2 heteroaryl, NO 2 , SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF 3 , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl -Heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OSO 2 aryl, OSO 2 heteroaryl, C (O) alkyl, C (O) aryl, C (O) - Heteroaryl, CO 2 H, CO 2 alkyl, C0 2 cycloalkyl, C0 2 heterocyclyl, CO 2 aryl, C0 2 heteroaryl, CO 2 alkyl cycloalkyl, CO 2 alkyl heterocyclyl, CO 2 alkyl Aryl, CO 2 alkyl heteroaryl, C (O) -NH 2 , C (O) NH alkyl, C (O) NH cycloalkyl, C (0) NH heterocyclyl, C (O) NH aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O ) N (alkyl) 2 , C (O) N (cycloalkyl) 2 , C (O) N (aryl) 2 , C (O) N (heteroaryl) 2 , SO-alkyl, SO-aryl, SO 2 -alkyl, SO 2 aryl, S0 2 NH, SO 2 NH alkyl, S0 2 NH aryl, SO 2 NH heteroaryl, SO3H, SO 2 O alkyl, S0 2 O aryl, SO 2 O heteroaryl, alkyl, cycloalkyl , Heterocyclyl, aryl or heteroaryl, can be substituted one or more times, identically or differently,
(vi) unsubstituiertes oder substituiertes Heteroaryl, wobei der Heteroarylrest mit F, Cl, Br, I, CF3, CN, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH-Heteroaryl, NH-Alkyl-Aryl, NH-Alkyl-Heteroaryl, N(Alkyl)2, NHC(O)-Alkyl, NHC(0)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSOs-Alkyl, NHSO2-Aryl, NHSO2-Heteroaryl, NO2, SH, S-Alkyl, S-Aryl, OH, OCF3, O-Alkyl, O-Cycloalkyl, O-Heterocyclyl, O-Aryl, O-Heteroaryl, OC(O)- Alkyl, OC(0)-Cycloalkyl, OC(O)-Heterocyclyl, OC(O)-Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OSO2-Cycloalkyl, OSO2-Aryl, OSO2-Heteroaryl, C(O)-Alkyl, C(O)- Aryl, C(O)-Heteroaryl, CO2H, CO2-Alkyl, CO2-Cycloalkyl, CO2-Heterocyclyl, CO2-Aryl, CO2- Heteroaryl, CO2-Alkyl-Cycloalkyl, CO2-Alkyl-Heterocyclyl, CO2- Alkyl-aryl, CO2-Alkyl-Heteroaryl, C(O)-NH2, C(O)NH-Alkyl, C(0)NH-Cycloalkyl; C(O)NH-Heterocyclyl, C(O)NH-Aryl, C(0)NH-Heteroaryl, C(O)NH-Alkyl- Cycloalkyl, C(O)NH-Alkyl-Heterocyclyl, C(O)NH-Alkyl-Aryl, C(O)NH-Alkyl- Heteroaryl, C(O)N(Alkyl)2, C(O)N(Cycloalkyl)2, C(O)N(Aryl)2,(vi) unsubstituted or substituted heteroaryl, where the heteroaryl radical with F, Cl, Br, I, CF 3 , CN, NH 2 , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH- Alkyl aryl, NH alkyl heteroaryl, N (alkyl) 2 , NHC (O) alkyl, NHC (0) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl , NHSOs alkyl, NHSO 2 aryl, NHSO 2 heteroaryl, NO 2 , SH, S alkyl, S aryl, OH, OCF 3 , O alkyl, O cycloalkyl, O heterocyclyl, O aryl, O Heteroaryl, OC (O) alkyl, OC (0) cycloalkyl, OC (O) heterocyclyl, OC (O) aryl, OC (O) heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OSO 2 Aryl, OSO 2 heteroaryl, C (O) alkyl, C (O) aryl, C (O) heteroaryl, CO 2 H, CO 2 alkyl, CO 2 cycloalkyl, CO 2 heterocyclyl, CO 2 -Aryl, CO 2 - heteroaryl, CO 2 -alkyl-cycloalkyl, CO 2 -alkyl-heterocyclyl, CO 2 - alkyl-aryl, CO 2 -alkyl-heteroaryl, C (O) -NH 2 , C (O) NH- Alkyl, C (0) NH-cycloalkyl ; C (O) NH heterocyclyl, C (O) NH aryl, C (0) NH heteroaryl, C (O) NH alkyl cycloalkyl, C (O) NH alkyl heterocyclyl, C (O) NH Alkyl-aryl, C (O) NH-alkyl heteroaryl, C (O) N (alkyl) 2 , C (O) N (cycloalkyl) 2 , C (O) N (aryl) 2 ,
C(O)N(Heteroaryl)2, SO2-Alkyl, SO2-Aryl, SO2NH2, SO2NH-Alkyl, SO2NH-Aryl, SO2NH-Heteroaryl, SO3H, SO2O-Alkyl, SO2O-Aryl, SO2O-Heteroaryl, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- oder mehrfach, gleich oder verschieden substituiert sein kann, bedeuten, (vii) oder R6 und R7 zusammen Cycloalkyl oder Heterocyclyl bedeuten,C (O) N (heteroaryl) 2 , SO 2 alkyl, SO 2 aryl, SO 2 NH 2 , SO 2 NH alkyl, SO 2 NH aryl, SO 2 NH heteroaryl, SO3H, SO 2 O alkyl , SO 2 O-aryl, SO 2 O-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, can be substituted one or more times, identically or differently, (vii) or R6 and R7 together mean cycloalkyl or heterocyclyl,
-C(NR8)R9 bedeuten, wobei R8 = H und R9Mean -C (NR8) R9, where R8 = H and R9
(i) unsubstituiertes oder substituiertes Alkyl, wobei der Alkylrest mit F, Cl, Br, I, CF3, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH-Heteroaryl, NH-Alkyl-Aryl, NH-Alkyl-Heteroaryl, N(Alkyl)2, NHC(O)-Alkyl, NHC(O)- Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2- Alkyl, NHSO2-Cycloalkyl, NHS02-Aryl, NHSO2-Heteroaryl, NO , SH, S-Alkyl, S-Cycloalkyl, S-Heterocyclyl, S-Aryl, S-Heteroaryl, OH, OCF3, O-Alkyl, O- Cycloalkyl, O-Heterocyclyl, O-Aryl, O-Heteroaryl, O-Alkyl-Cycloalkyl, O-Alkyl- Aryl, O-Alkyl-Heteroaryl, OC(O)-Alkyl, OC(0)-Cycloalkyl, OC(O)-Heterocyclyl, OC(O)-Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OSO2-Cycloalkyl, OSO2-Aryl, OSO2-Heteroaryl, C(O)-Alkyl, C(0)-Aryl, CO2H, CO2-Alkyl, CO2-Cycloalkyl, CO2-Heterocyclyl, CO2-Aryl, C02-Heteroaryl, CO2-Alkyl-Cycloalkyl, CO2-Alkyl- Heterocyclyl, CO2-Alkyl-Aryl, CO2-Alkyl-Heteroaryl, C(O)-NH2, C(O)NH-Alkyl, C(O)NH-Cycloalkyl, C(O)NH-Heterocyclyl, C(O)NH-Aryl, C(0)NH-Heteroaryl, C(0)NH-Alkyl-Cycloalkyl, C(0)NH-Alkyl-Heterocyclyl, C(O)NH-Alkyl-Aryl, C(O)NH-Alkyl-Heteroaryl, C(O)N(Alkyl)2, C(O)N(Cycloalkyl)2, C(O)N(Aryl)2, C(O)N(Heteroaryl)2, SO-Alkyl, SO-Aryl, SO2-Alkyl, SO2-Aryl, SO2NH2, SO3H, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- oder mehrfach, gleich oder verschieden substituiert sein kann,(i) unsubstituted or substituted alkyl, the alkyl radical having F, Cl, Br, I, CF 3 , NH 2 , NH alkyl, NH cycloalkyl, NH heterocyclyl, NH aryl, NH heteroaryl, NH alkyl Aryl, NH-alkyl heteroaryl, N (alkyl) 2 , NHC (O) alkyl, NHC (O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHSO 2 - alkyl, NHSO 2 cycloalkyl, NHS0 2 aryl, NHSO 2 heteroaryl, NO, SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF 3 , O- Alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC (O) -alkyl, OC (0) -cycloalkyl, OC (O) heterocyclyl, OC (O) aryl, OC (O) heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OSO 2 aryl, OSO 2 heteroaryl, C (O) alkyl, C ( 0) aryl, CO 2 H, CO 2 alkyl, CO 2 cycloalkyl, CO 2 heterocyclyl, CO 2 aryl, C0 2 heteroaryl, CO 2 alkyl cycloalkyl, CO 2 alkyl heterocyclyl, CO 2 -Alkyl-aryl, CO 2 -alkyl heteroaryl, C (O) -NH 2 , C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH- aryl, C (0) NH-heteroaryl, C (0) NH-alkyl-cycloalkyl, C (0) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C ( O) N (alkyl) 2 , C (O) N (cycloalkyl) 2 , C (O) N (aryl) 2 , C (O) N (heteroaryl) 2 , SO-alkyl, SO-aryl, SO 2 -alkyl , SO 2 aryl, SO 2 NH 2 , SO 3 H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, can be substituted one or more times, identically or differently,
(ii) unsubstituiertes oder substituiertes Cycloalkyl, wobei der Cycloalkylrest mit F, Cl, Br, I, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH- Heteroaryl, NH-Alkyl-Aryl, NH-Alkyl-Heteroaryl, N(Alkyl)2, NHC(O)-Alkyl, NHC(O)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHS02-Alkyl, NHSO2-Cycloalkyl, NHSO2-Aryl, NHSO2-Heteroaryl, OH, O- Alkyl, O-Cycloalkyl, O-Heterocyclyl, O-Aryl, O-Heteroaryl, O-Alkyl-Aryl, O- Alkyl-Heteroaryl, OC(O)-Alkyl, OC(O)-Cycloalkyl, OC(O)-Heterocyclyl, OC(O)- Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OS02-Cycloalkyl, OSO2-Aryl, OSO2- Heteroaryl, CO2H, CO2-Alkyl, CO2-Cycloalkyl, CO2-Heterocyclyl, CO2-Aryl, CO2-Heteroaryl, C(O)-NH2, C(0)NH-Alkyl, C(0)NH-Cycloalkyl, C(0)NH- Heterocyclyl, C(O)NH-Aryl, C(0)NH-Heteroaryl, C(O)NH-Alkyl-Aryl, C(0)NH- Alkyl-Heteroaryl, C(O)N(Alkyl)2, Alkyl, oder Aryl ein- oder mehrfach, gleich o- der verschieden substituiert sein kann,(ii) unsubstituted or substituted cycloalkyl, where the cycloalkyl radical with F, Cl, Br, I, NH 2 , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH Alkyl heteroaryl, N (alkyl) 2 , NHC (O) alkyl, NHC (O) cycloalkyl, NHC (O) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHS0 2 alkyl , NHSO 2 cycloalkyl, NHSO 2 aryl, NHSO 2 heteroaryl, OH, O alkyl, O cycloalkyl, O heterocyclyl, O aryl, O heteroaryl, O alkyl aryl, O alkyl heteroaryl, OC (O) alkyl, OC (O) cycloalkyl, OC (O) heterocyclyl, OC (O) aryl, OC (O) heteroaryl, OSO 2 alkyl, OS0 2 cycloalkyl, OSO 2 aryl, OSO 2 - heteroaryl, CO 2 H, CO 2 alkyl, CO 2 cycloalkyl, CO 2 heterocyclyl, CO 2 aryl, CO 2 heteroaryl, C (O) -NH 2 , C (0) NH-alkyl, C (0) NH-cycloalkyl, C (0) NH-heterocyclyl, C (O) NH-aryl, C (0) NH-heteroaryl, C (O) NH-alkyl-aryl, C (0) NH- Alkyl heteroaryl, C (O) N (alkyl) 2 , alkyl, or aryl, one or more times, the same or which can be substituted differently,
(iii) unsubstituiertes oder substituiertes Heterocyclyl, wobei der Heterocyclylrest mit OH, O-Alkyl, O-Aryl, NH-Alkyl, NH-Aryl, Alkyl oder Aryl ein- oder mehrfach, gleich oder verschieden substituiert sein kann,(iii) unsubstituted or substituted heterocyclyl, it being possible for the heterocyclyl radical to be substituted one or more times, identically or differently, by OH, O-alkyl, O-aryl, NH-alkyl, NH-aryl, alkyl or aryl,
(iv) unsubstituiertes oder substituiertes Aryl, wobei der Arylrest mit F, Cl, Br, I, CF3, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH-Heteroaryl, NH-Alkyl-Cycloalkyl, NH-Alkyl-Heterocyclyl, NH-Alkyl-Aryl, NH-Alkyl- Heteroaryl, NH-Alkyl-NH2, NH-Alkyl-OH, N(Alkyl)2, NHC(O)-Alkyl, NHC(O)- Cycloalkyl, NHC(0)-Heterocyclyl, NHC(O)-Aryl, NHC(O)-Heteroaryl, NHSO2- Alkyl, NHSO2-AryI, NHSO2-Heteroaryl, NO2, SH, S-Alkyl, S-Cycloalkyl, S- Heterocyclyl, S-Aryl, S-Heteroaryl, OH, OCF3, O-Alkyl, O-Cycloalkyl, O- Heterocyclyl, O-Aryl, O-Heteroaryl, O-Alkyl-Cycloalkyl, O-Alkyl-Heterocyclyl, O-Alkyl-Aryl, O-Alkyl-Heteroaryl, O-Alkyl-OH, OC(O)-Alkyl, OC(O)-Cycloalkyl, OC(O)-Heterocyclyl, OC(O)-Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OSO2- Cycloalkyl, OSO2-Aryl, OSO2-Heteroaryl, C(0)-Alkyl, C(O)-Aryl, C(O)- Heteroaryl, CO2H, CO2-Alkyl, CO2-Cycloalkyl, CO2-Heterocyclyl, CO2-Aryl, CO2-Heteroaryl, CO2-Alkyl-Cycloalkyl, CO2-Alkyl-Heterocyclyl, CO2-Alkyl-aryl, CO2-Alkyl-Heteroaryl, C(O)-NH2, C(O)NH-Alkyl, C(0)NH-Cycloalkyl, C(O)NH- Heterocyclyl, C(0)NH-Aryl, C(O)NH-Heteroaryl, C(O)NH-Alkyl-Cycloalkyl, C(O)NH-Alkyl-Heterocyclyl, C(O)NH-Alkyl-Aryl, C(O)NH-Alkyl-Heteroaryl, C(O)N(Alkyl)2, C(O)N(Cycloalkyl)2, C(O)N(Aryl)2, C(O)N(Heteroaryl)2, SO- Alkyl, SO-Aryl, SO2-Alkyl, SO2-Aryl, SO2NH2, SO2NH-Alkyl, SO2NH-Aryl, SO2NH-Heteroaryl, SO3H, SO2O-Alkyl, SO2O-Aryl, SO2O-Heteroaryl, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- oder mehrfach, gleich oder verschieden substituiert sein kann,(iv) unsubstituted or substituted aryl, where the aryl radical with F, Cl, Br, I, CF 3 , NH 2 , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl- Cycloalkyl, NH-alkyl heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH 2 , NH-alkyl-OH, N (alkyl) 2 , NHC (O) -alkyl, NHC (O) Cycloalkyl, NHC (0) heterocyclyl, NHC (O) aryl, NHC (O) heteroaryl, NHSO 2 alkyl, NHSO 2 aryl, NHSO 2 heteroaryl, NO 2 , SH, S alkyl, S Cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF 3 , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl , O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O ) Heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OSO 2 aryl, OSO 2 heteroaryl, C (0) alkyl, C (O) aryl, C (O) heteroaryl, CO 2 H, CO 2 alkyl, CO 2 cycloalkyl, CO 2 heterocyclyl, CO 2 aryl, CO 2 heteroaryl, CO 2 alkyl cycloalkyl, CO 2 alkyl heterocyclyl, CO 2 alkyl a ryl, CO 2 alkyl heteroaryl, C (O) -NH 2 , C (O) NH alkyl, C (0) NH cycloalkyl, C (O) NH heterocyclyl, C (0) NH aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O ) N (alkyl) 2 , C (O) N (cycloalkyl) 2 , C (O) N (aryl) 2 , C (O) N (heteroaryl) 2 , SO-alkyl, SO-aryl, SO 2 -alkyl, SO 2 aryl, SO 2 NH 2 , SO 2 NH alkyl, SO 2 NH aryl, SO 2 NH heteroaryl, SO3H, SO 2 O alkyl, SO 2 O aryl, SO 2 O heteroaryl, alkyl, Cycloalkyl, heterocyclyl, aryl or heteroaryl, can be substituted one or more times, identically or differently,
(v) unsubstituiertes oder substituiertes Heteroaryl, wobei der Heteroarylrest mit F, Cl, Br, I, CF3, NH2, NH-Alkyl, NH-Cycloalkyl, NH-Heterocyclyl, NH-Aryl, NH- Heteroaryl, NH-Alkyl-Aryl, NH-Alkyl-Heteroaryl, N(Alkyl)2, NHC(O)-Alkyl, NHC(O)-Cycloalkyl, NHC(O)-Heterocyclyl, NHC(0)-Aryl, NHC(O)-Heteroaryl, NHSO2-Alkyl, NHSO2-Aryl, NHSO2-Heteroaryl, N02, SH, S-Alkyl, S-Aryl, OH, OCF3, O-Alkyl, O-Cycloalkyl, O-Heterocyclyl, O-Aryl, O-Heteroaryl, OC(O)- Alkyl, OC(O)-Cycloalkyl, OC(O)-Heterocyclyl, OC(O)-Aryl, OC(O)-Heteroaryl, OSO2-Alkyl, OSO2-Cycloalkyl, OSO2-Aryl, OSO2-Heteroaryl, C(O)-Alkyl, C(O)- Aryl, C(O)-Heteroaryl, CO2H, CO2-Alkyl, CO2-Cycloalkyl, CO2-Heterocyclyl, CO2-Aryl, CO2-Heteroaryl, CO2-Alkyl-Cycloalkyl, CO2-Alkyl-Heterocyclyl, C02- Alkyl-aryl, CO2-Alkyl-Heteroaryl, C(O)-NH2, C(O)NH-Alkyl, C(O)NH-Cycloalkyl, C(0)NH-Heterocyclyl, C(O)NH-Aryl, C(0)NH-Heteroaryl, C(0)NH-Alkyl- Cycloalkyl, C(O)NH-Alkyl-Heterocyclyl, C(O)NH-Alkyl-Aryl, C(O)NH-Alkyl- Heteroaryl, C(O)N(Alkyl)2, C(O)N(Cycloalkyl)2, C(O)N(Aryl)2,(v) unsubstituted or substituted heteroaryl, where the heteroaryl radical with F, Cl, Br, I, CF 3 , NH 2 , NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl- Aryl, NH-alkyl heteroaryl, N (alkyl) 2 , NHC (O) alkyl, NHC (O) cycloalkyl, NHC (O) heterocyclyl, NHC (0) aryl, NHC (O) heteroaryl, NHSO 2 alkyl, NHSO 2 aryl, NHSO 2 heteroaryl, N0 2 , SH, S-alkyl, S-aryl, OH, OCF 3 , O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, OC (O) alkyl, OC (O) cycloalkyl, OC (O) heterocyclyl, OC (O) aryl , OC (O) heteroaryl, OSO 2 alkyl, OSO 2 cycloalkyl, OSO 2 aryl, OSO 2 heteroaryl, C (O) alkyl, C (O) aryl, C (O) heteroaryl, CO 2 H, CO 2 alkyl, CO 2 cycloalkyl, CO 2 heterocyclyl, CO 2 aryl, CO 2 heteroaryl, CO 2 alkyl cycloalkyl, CO 2 alkyl heterocyclyl, C0 2 alkyl aryl, CO 2 -alkyl heteroaryl, C (O) -NH 2 , C (O) NH-alkyl, C (O) NH-cycloalkyl, C (0) NH-heterocyclyl, C (O) NH-aryl, C (0) NH heteroaryl, C (0) NH alkyl cycloalkyl, C (O) NH alkyl heterocyclyl, C (O) NH alkyl aryl, C (O) NH alkyl heteroaryl, C (O) N ( Alkyl) 2 , C (O) N (cycloalkyl) 2 , C (O) N (aryl) 2 ,
C(O)N(Heteroaryl)2) SO2-Alkyl, SO2-Aryl, SO2NH2, SO2NH-Alkyl, SO2NH-Aryl, SO2NH-Heteroaryl, SO3H, SO2O-Alkyl, SO20-Aryl, SO2O-Heteroaryl, Alkyl, Cycloalkyl, Heterocyclyl, Aryl oder Heteroaryl, ein- oder mehrfach, gleich oder verschieden substituiert sein kann, bedeuten.C (O) N (heteroaryl) 2) SO 2 alkyl, SO 2 aryl, SO 2 NH 2 , SO 2 NH alkyl, SO 2 NH aryl, SO 2 NH heteroaryl, SO3H, SO 2 O alkyl , SO 2 0-aryl, SO 2 O-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, can be substituted one or more times, identically or differently.
2. Pyrido[2,3-b]pyrazin-Derivate der allgemeinen Formel I nach anspruch 1 , worin:2. Pyrido [2,3-b] pyrazine derivatives of the general formula I according to claim 1, in which:
„Alkyl" acyclische gesättigte oder ungesättigte Kohlenwasserstoffreste verzweigt oder geradkettig, mit 1 bis 8 C-Atomen sein können, wobei Alkenyle mindestens eine C-C- Doppelbindung und Alkinyle mindestens eine C-C-Dreifachbindung aufweisen,"Alkyl" acyclic saturated or unsaturated hydrocarbon radicals can be branched or straight-chain, with 1 to 8 C atoms, where alkenyls have at least one C-C double bond and alkynyls have at least one C-C triple bond,
„Cycloalkyl" cyclische Kohlenwasserstoffe mit 3-12 Kohlenwasserstoffen, gesättigt oder ungesättigt sein können, deren Bindung an die Verbindungen der allgemeinen Struktur I über jedes beliebige und mögliche Ringglied des Cycloalkyl-Restes erfolgen kann und der Cycloalkyl-Rest auch Teil eines bi- oder polycyclischen Systems sein kann,"Cycloalkyl" cyclic hydrocarbons with 3-12 hydrocarbons, saturated or unsaturated, whose binding to the compounds of general structure I can take place via any and possible ring member of the cycloalkyl radical and the cycloalkyl radical also part of a bi- or polycyclic System can be
„Heterocyclyl" für einen 3-, 4-, 5-, 6-, 7- oder 8-gliedrigen cyclischen organischen Rest, gesättigt oder ungesättigt, jedoch nicht aromatisch steht, der mindestens 1 , ggf. 2, 3, 4 oder 5 Heteroatome, bevorzugt Stickstoff, Sauerstoff und Schwefel enthält, wobei die Heteroatome gleich oder verschieden sind und dessen Bindung an die Verbindungen der allgemeinen Struktur I über jedes beliebige und mögliche Ringglied des Heterocyclyl-Restes erfolgen kann, wobei der Heterocyclus auch Teil eines bi- oder polycyclischen Systems sein kann, „Aryl" aromatische Kohlenwasserstoffe, u.a. Phenyle, Naphthyle und Anthracenyle bezeichnet, deren Reste auch mit weiteren gesättigten, (partiell) ungesättigten oder aromatischen Ringsystemen kondensiert sein können und deren Bindung an die Verbindungen der allgemeinen Struktur I über jedes beliebige und mögliche Ringglied des Aryl-Restes erfolgen kann,"Heterocyclyl" stands for a 3-, 4-, 5-, 6-, 7- or 8-membered cyclic organic radical, saturated or unsaturated, but not aromatic, which has at least 1, optionally 2, 3, 4 or 5 heteroatoms , preferably contains nitrogen, oxygen and sulfur, where the heteroatoms are the same or different and can be bound to the compounds of general structure I via any and possible ring member of the heterocyclyl radical, the heterocycle also being part of a bi- or polycyclic system can be, “Aryl” denotes aromatic hydrocarbons, including phenyls, naphthyls and anthracenyls, the residues of which can also be condensed with further saturated, (partially) unsaturated or aromatic ring systems and their binding to the compounds of the general structure I via any and possible ring member of the aryl Rest can be done
„Heteroaryl" für einen 5-, 6- oder 7-gliedrigen cyclischen aromatischen Rest steht, der mindestens 1 , gegebenenfalls auch 2, 3, 4 oder 5 Heteroatome, bevorzugt Stickstoff, Sauerstoff, Schwefel enthält, wobei die Heteroatome gleich oder verschieden sind und dessen Bindung an die Verbindungen der allgemeinen Struktur I über jedes beliebige und mögliche Ringglied des Heteroaryl-Restes erfolgen kann, wobei der Heterocyclus auch Teil eines bi- oder polycyclischen Systems sein kann,"Heteroaryl" represents a 5-, 6- or 7-membered cyclic aromatic radical which contains at least 1, optionally also 2, 3, 4 or 5 heteroatoms, preferably nitrogen, oxygen, sulfur, the heteroatoms being the same or different and whose binding to the compounds of general structure I can take place via any and possible ring member of the heteroaryl radical, where the heterocycle can also be part of a bi- or polycyclic system,
„Alkyl-Cycloalkyl", „Alkyl-Heterocyclyl", „Alkyl-Aryl" oder „Alkyl-Heteroaryl" die für Alkyl, Cycloalkyl, Heterocyclyl, Aryl und Heteroaryl definierten Bedeutungen haben und der Cycloalkyl-, Heterocyclyl-, Aryl- und Heteroaryl-Rest über eine Cι-8-Alkyl-Gruppe an die Verbindungen der allgemeinen Struktur I gebunden ist,"Alkyl-cycloalkyl", "alkyl-heterocyclyl", "alkyl-aryl" or "alkyl-heteroaryl" have the meanings defined for alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl and the cycloalkyl-, heterocyclyl-, aryl- and heteroaryl- radical is bonded via a Cι -8 alkyl group to the compounds of general structure I,
„substituiert" im Zusammenhang mit „Alkyl", „Cycloalkyl", „Heterocyclyl", „Aryl", „Heteroaryl", „Alkyl-Cycloalkyl", „Alkyl-Heterocyclyl", „Alkyl-Aryl" und „Alkyl-Heteroaryl", insofern nicht gemäß Anspruch 1 bereits explicit definiert, die Substitution eines oder mehrerer Wasserstoffreste durch F, Cl, Br, I, CN, CF3, NH2, NH-Alkyl, NH-Aryl, N(Alkyl)2, NO2, SH, S-Alkyl, OH, OCF3, O-Alkyl, O-Aryl, CO2H, SO3H oder Alkyl bedeuten kann, wobei die Substituenten gleich oder verschieden sein und in jeder beliebigen und möglichen Position des Alkyl-, Cycloalkyl-, Heterocyclyl-, Aryl- und Hete- roarylrestes vorkommen können und wobei mehrfach substituierte Reste entweder an verschiedenen oder an gleichen Atomen mehrfach, mit dem gleichen oder mit verschiedenen Substituenten erfolgen können."Substituted" in connection with "alkyl", "cycloalkyl", "heterocyclyl", "aryl", "heteroaryl", "alkyl-cycloalkyl", "alkyl-heterocyclyl", "alkyl-aryl" and "alkyl-heteroaryl", insofar as not already explicitly defined according to claim 1, the substitution of one or more hydrogen radicals by F, Cl, Br, I, CN, CF 3 , NH 2 , NH-alkyl, NH-aryl, N (alkyl) 2 , NO 2 , SH , S-alkyl, OH, OCF 3 , O-alkyl, O-aryl, CO 2 H, SO 3 H or alkyl, where the substituents may be the same or different and in any and possible position of the alkyl, cycloalkyl , Heterocyclyl, aryl and heteroaryl radicals can occur and where multiply substituted radicals can be carried out either on different or on the same atoms several times, with the same or with different substituents.
3. Pyrido[2,3-b]pyrazin-Derivate der allgemeinen Formel I nach den Ansprüchen 1 und 2, dadurch gekennzeichnet, dass der Alkylrest Methyl, Ethyl, n-Propyl, 2-Propyl, /7-Butyl, sec.-Butyl, te/t-Butyl, n-Pentyl, /so-Pentyl, neσ-Pentyl, π-Hexyl, 2-Hexyl, n- Octyl, Ethylenyl (Vinyl), Ethinyl, Propenyl (-CH2CH=CH2; -CH=CH-CH3, -C(=CH2)- CH3), Propinyl (-CH2-C≡CH, -C≡C-CH3), Butenyl, Butinyl, Pentenyl, Pentinyl, Hexenyl, Hexinyl, Heptenyl, Heptinyl, Octenyl und Octinyl sein kann.3. pyrido [2,3-b] pyrazine derivatives of the general formula I according to claims 1 and 2, characterized in that the alkyl radical is methyl, ethyl, n-propyl, 2-propyl, / 7-butyl, sec.- Butyl, te / t-butyl, n-pentyl, / so-pentyl, neσ-pentyl, π-hexyl, 2-hexyl, n-octyl, ethyleneyl (vinyl), ethynyl, propenyl (-CH 2 CH = CH 2 ; -CH = CH-CH 3 , -C (= CH 2 ) - CH 3 ), propynyl (-CH 2 -C≡CH, -C≡C-CH 3 ), butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, heptenyl, heptynyl, octenyl and octynyl.
4. Pyrido[2,3-b]pyrazin-Derivate der allgemeinen Formel I nach den Ansprüchen 1 und 2, dadurch gekennzeichnet, dass der Heterocyclyl-Rest Tetrahydrofuryl, Tetra- hydropyranyl, Pyrrolidinyl, Piperidinyl, Piperazinyl und Morpholinyl sein kann.4. pyrido [2,3-b] pyrazine derivatives of the general formula I according to claims 1 and 2, characterized in that the heterocyclyl radical can be tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.
5. Pyrido[2,3-b]pyrazin-Derivate der allgemeinen Formel I nach den Ansprüchen 1 und 2, dadurch gekennzeichnet, dass der Heteroaryl-Rest Pyrrolyl, Furyl, Thienyl, Thiazolyl, Oxazolyl, Isoxazolyl, Pyrazolyl, Imidazolyl, Pyridinyl, Pyrimidinyl, Pyridazi- nyl, Pyrazinyl, Phthalazinyl, Indolyl, Indazolyl, Indolizinyl, Chinolinyl, Isochinolinyl, Chinoxalinyl, Chinazolinyl, Carbazolyl, Phenazinyl, Phenothiazinyl, Acridinyl sein kann.5. pyrido [2,3-b] pyrazine derivatives of the general formula I according to claims 1 and 2, characterized in that the heteroaryl radical pyrrolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl, Pyrimidinyl, pyridazinyl, pyrazinyl, phthalazinyl, indolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl, acridinyl.
6. Physiologisch verträgliche Salze der Verbindungen nach Formel I gemäß Ansprüchen 1 bis 5, gekennzeichnet durch Neutralisation der basischen Verbindungen mit anorganischen und organischen Säuren bzw. Neutralisation der sauren Verbindungen mit anorganischen und organischen Basen, sowie deren Solvate und Hydrate.6. Physiologically acceptable salts of the compounds of formula I according to claims 1 to 5, characterized by neutralization of the basic compounds with inorganic and organic acids or neutralization of the acidic compounds with inorganic and organic bases, and their solvates and hydrates.
7. Pyrido[2,3-b]pyrazin-Derivate der allgemeinen Formel I gemäß den Ansprüchen 1 bis 6 mit mindestens einem asymmetrischen Kohlenstoffatom in Form ihrer Racemate, in Form der reinen Enantiomeren und/oder Diastereomeren oder in Form von Mischungen dieser Enantiomeren und/oder Diastereomeren oder in Form der Tautomeren.7. pyrido [2,3-b] pyrazine derivatives of the general formula I according to claims 1 to 6 with at least one asymmetric carbon atom in the form of their racemates, in the form of the pure enantiomers and / or diastereomers or in the form of mixtures of these enantiomers and / or diastereomers or in the form of tautomers.
8. Pyrido[2,3-b]pyrazin-Derivate der allgemeinen Formel I gemäß den Ansprüchen 1 bis 7, insbesondere eine der folgenden Verbindungen:8. pyrido [2,3-b] pyrazine derivatives of the general formula I according to claims 1 to 7, in particular one of the following compounds:
1-Allyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thioharnstoff1-allyl-3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea
1-Allyl-3-(3-naphthalin-2-yl-pyrido[2,3-b]pyrazin-6-yl)-thiohamstoff1-allyl-3- (3-naphthalen-2-yl-pyrido [2,3-b] pyrazin-6-yl) -thiohamstoff
1-Allyl-3-[3-(4-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-thioharnstoff1-allyl-3- [3- (4-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] thiourea
1-Allyl-3-[3-(4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-thioharnstoff-Hydrochlorid1-allyl-3- [3- (4-hydroxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] thiourea hydrochloride
1-(2-Methyl-allyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thioharnstoff1- (2-methyl-allyl) -3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea
1-(2-Methyl-allyl)-3-(3-naphthalin-2-yl-pyrido[2,3-b]pyrazin-6-yl)-thioharnstoff 1-[3-(4-Methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-(2-methyl-allyl)-thiohamstoff1- (2-methyl-allyl) -3- (3-naphthalen-2-yl-pyrido [2,3-b] pyrazin-6-yl) thiourea 1- [3- (4-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (2-methyl-allyl) -thiohamstoff
1-(3-Naphthalin-2-yl-pyrido[2,3-b]pyrazin-6-yl)-3-(4-nitro-phenyl)-thioharnstoff1- (3-naphthalene-2-yl-pyrido [2,3-b] pyrazin-6-yl) -3- (4-nitro-phenyl) -thiourea
1-[3-(4-Methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-(4-nitro-phenyl)-thioharnstoff1- [3- (4-methoxy-phenyl) -pyrido [2,3-b] pyrazin-6-yl] -3- (4-nitro-phenyl) -thiourea
1- erf-Butyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thioharnstoff1-erf-butyl-3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea
1-Cyclopropyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thiohamstoff1-cyclopropyl-3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) -thiohamstoff
1-Methyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thiohamstoff1-Methyl-3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) -thiohamstoff
1-Benzyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thiohamstoff1-Benzyl-3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) -thiohamstoff
1-(4-Fluoro-phenyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thioharnstoff1- (4-Fluoro-phenyl) -3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) thiourea
1-(3-Phenyl-pyrido[2,3-b]pyrazin-6-yl)-3-p-tolyl-hamstoff1- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) -3-p-tolyl-urea
1-(4-Chloro-3-trifluoromethyl-phenyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-harnstoff1- (4-Chloro-3-trifluoromethyl-phenyl) -3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) -urea
1-(2-Morpholin-4-yl-ethyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-hamstoff1- (2-morpholin-4-yl-ethyl) -3- (3-phenyl-pyrido [2,3-b] pyrazin-6-yl) -hamstoff
9. Verwendung der Pyrido[2,3-b]pyrazin-Derivate der allgemeinen Formel I nach einem der Ansprüche 1 bis 8 als therapeutische Wirkstoffe zur Herstellung von Arzneimitteln zur Behandlung von malignen Erkrankungen.9. Use of the pyrido [2,3-b] pyrazine derivatives of the general formula I according to one of claims 1 to 8 as therapeutic active substances for the manufacture of medicaments for the treatment of malignant diseases.
10. Verwendung der Pyrido[2,3-b]pyrazin-Derivate der allgemeinen Formel I nach einem der Ansprüche 1 bis 8 als therapeutische Wirkstoffe zur Herstellung von Arzneimitteln zur Behandlung von auf pathologischen Zellproliferationen beruhenden Erkrankungen.10. Use of the pyrido [2,3-b] pyrazine derivatives of the general formula I according to one of claims 1 to 8 as therapeutic active substances for the manufacture of medicaments for the treatment of diseases based on pathological cell proliferation.
11. Verwendung der Pyrido[2,3-b]pyrazin-Derivate der allgemeinen Formel I nach einem der Ansprüche 1 bis 8 und 10 als therapeutische Wirkstoffe zur Herstellung von Arzneimitteln zur Behandlung von Erkrankungen wie Restenose, Psoriasis, Arteriosklerose und Leberzirrhose.11. Use of the pyrido [2,3-b] pyrazine derivatives of the general formula I according to one of claims 1 to 8 and 10 as therapeutic active ingredients for the manufacture of medicaments for the treatment of diseases such as restenosis, psoriasis, arteriosclerosis and cirrhosis of the liver.
12. Verwendung der Pyrido[2,3-b]pyrazin-Derivate der allgemeinen Formel I nach einem der Ansprüche 1 bis 8 als therapeutische Wirkstoffe zur Herstellung von Arzneimitteln zur Behandlung von Tumoren im Menschen und in Säugetieren.12. Use of the pyrido [2,3-b] pyrazine derivatives of the general formula I according to one of claims 1 to 8 as therapeutic active substances for the manufacture of medicaments for the treatment of tumors in humans and in mammals.
13. Verwendung der Pyrido[2,3-b]pyrazin-Derivate der allgemeinen Formel I nach einem der Ansprüche 1 bis 8 als therapeutische Wirkstoffe zur Herstellung von Arzneimitteln zur Modulation von fehlgeleiteten zellulären Signaltransduktionsprozessen, insbesondere zur Beeinflussung der Aktivität von Tyrosin- und Se- rin/Threoninkinasen.13. Use of the pyrido [2,3-b] pyrazine derivatives of the general formula I according to one of claims 1 to 8 as therapeutic active substances for the production of medicaments for modulating misguided cellular signal transduction processes, in particular to influence the activity of tyrosine and serine / threonine kinases.
14. Verwendung der Pyrido[2,3-b]pyrazin-Derivate der allgemeinen Formel I nach einem der Ansprüche 1 bis 8 und 13 als therapeutische Wirkstoffe zur Herstellung von Arzneimitteln zur Modulation von fehlgeleiteten zellulären Signaltransduktionsprozessen, insbesondere zur Beeinflussung der Aktivität von Kinasen, wie c-Raf, B-Raf, Mek, PDGFRbeta, Flt-3, IGF1R, PKB/Akt1 , c-Kit, c-Abl, FGFR1 und KDR.14. Use of the pyrido [2,3-b] pyrazine derivatives of the general formula I according to one of claims 1 to 8 and 13 as therapeutic active substances for the manufacture of medicaments for modulating misguided cellular signal transduction processes, in particular for influencing the activity of kinases, such as c-Raf, B-Raf, Mek, PDGFRbeta, Flt-3, IGF1R, PKB / Akt1, c-Kit, c-Abl, FGFR1 and KDR.
15. Arzneimittel zur Verwendung bei der Behandlung von malignen Erkrankungen, enthaltend mindestens eine Verbindung der allgemeinen Formel I gemäß den Ansprüchen 1 bis 8, vorzugsweise zusammen mit gebräuchlichen pharmazeutischen Trägerstoffen und/oder Verdünnungsmitteln beziehungsweise sonstigen Hilfsstoffen.15. Medicament for use in the treatment of malignant diseases, comprising at least one compound of the general formula I according to claims 1 to 8, preferably together with customary pharmaceutical carriers and / or diluents or other auxiliaries.
16. Arzneimittel zur Verwendung bei der Behandlung von auf pathologischen Zellproliferationen beruhenden Erkrankungen, enthaltend mindestens eine Verbindung der allgemeinen Formel I gemäß den Ansprüchen 1 bis 8, vorzugsweise zusammen mit gebräuchlichen pharmazeutischen Trägerstoffen und/oder Verdünnungsmitteln beziehungsweise sonstigen Hilfsstoffen.16. Medicaments for use in the treatment of diseases based on pathological cell proliferation, comprising at least one compound of the general formula I according to claims 1 to 8, preferably together with customary pharmaceutical carriers and / or diluents or other auxiliaries.
17. Arzneimittel zur Verwendung bei der Behandlung von Tumoren im Menschen und in Säugetieren, enthaltend mindestens eine Verbindung der allgemeinen Formel I gemäß den Ansprüchen 1 bis 8, vorzugsweise zusammen mit gebräuchlichen pharmazeutischen Trägerstoffen und/oder Verdünnungsmitteln beziehungsweise sonstigen Hilfsstoffen.17. Medicaments for use in the treatment of tumors in humans and in mammals, containing at least one compound of the general formula I according to claims 1 to 8, preferably together with customary pharmaceutical carriers and / or diluents or other auxiliaries.
18. Arzneimittel zur Verwendung bei der Modulation von fehlgeleiteten zellulären Signaltransduktionsprozessen, insbesondere zur Beeinflussung der Aktivität von Tyrosin- und Serin/Threoninkinasen, enthaltend mindestens eine Verbindung der allgemeinen Formel I gemäß den Ansprüchen 1 bis 8, vorzugsweise zusammen mit gebräuchlichen pharmazeutischen Trägerstoffen und/oder Verdünnungsmitteln beziehungsweise sonstigen Hilfsstoffen. 18. Medicament for use in the modulation of misdirected cellular signal transduction processes, in particular for influencing the activity of tyrosine and serine / threonine kinases, comprising at least one compound of the general formula I according to claims 1 to 8, preferably together with customary pharmaceutical carriers and / or Diluents or other auxiliaries.
19. Arzneimittel, enthaltend eine oder mehrere Verbindungen der allgemeinen Formel I nach einem der Ansprüche 1 bis 8 neben üblichen physiologisch verträglichen Hilfs-, Zusatz- und Trägerstoffen.19. Medicament containing one or more compounds of the general formula I according to one of claims 1 to 8 in addition to customary physiologically compatible auxiliaries, additives and carriers.
20. Verfahren zur Herstellung eines Arzneimittels nach Anspruch 19, dadurch gekennzeichnet, daß ein oder mehrere Pyrido[2,3-b]pyrazin-Derivate der allgemeinen Formel I nach einem der Ansprüche 1 bis 8 mit gebräuchlichen pharmazeutischen Trägerstoffen und/oder Verdünnungsmitteln beziehungsweise sonstigen Hilfsstoffen zu pharmazeutischen Zubereitungen verarbeitet, beziehungsweise in eine therapeutisch anwendbare Form gebracht werden.20. A method for producing a medicament according to claim 19, characterized in that one or more pyrido [2,3-b] pyrazine derivatives of the general formula I according to one of claims 1 to 8 with customary pharmaceutical carriers and / or diluents or others Auxiliaries processed into pharmaceutical preparations or brought into a therapeutically usable form.
21. Verfahren zur Behandlung von Tumoren beim Menschen und in Säugetieren, dadurch gekennzeichnet, daß mindestens eine Verbindung der allgemeinen Formel I nach einem der Ansprüche 1 bis 8 dem Menschen oder einem Säugetier in einer für die Tumorbehandlung wirksamen Menge verabreicht wird. 21. A method for the treatment of tumors in humans and in mammals, characterized in that at least one compound of the general formula I according to one of claims 1 to 8 is administered to humans or a mammal in an amount effective for the treatment of tumors.
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