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WO2009071691A2 - Dérivés oxindoliques et leur utilisation comme médicament - Google Patents

Dérivés oxindoliques et leur utilisation comme médicament Download PDF

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WO2009071691A2
WO2009071691A2 PCT/EP2008/066937 EP2008066937W WO2009071691A2 WO 2009071691 A2 WO2009071691 A2 WO 2009071691A2 EP 2008066937 W EP2008066937 W EP 2008066937W WO 2009071691 A2 WO2009071691 A2 WO 2009071691A2
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alkyl
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WO2009071691A3 (fr
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Astrid Netz
Thorsten Oost
Hervé Geneste
Wilfried Braje
Wolfgang Wernet
Liliane Unger
Wilfried Hornberger
Wilfried Lubisch
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Abbott GmbH and Co KG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to novel substituted oxindole derivatives, pharmaceutical compositions containing them and their use as medicaments and in particular for the treatment of vasopressin-dependent diseases.
  • Vasopressin is an endogenous hormone that has a variety of effects on organs and tissues. In various disease states, such as heart failure and hypertension, it is believed that the vasopressin system plays a role.
  • three receptors V1a, V1b and V3 and V2 are known, through which vasopressin mediates its numerous effects. Therefore, antagonists of these receptors are being investigated as potential new therapeutic approaches to the treatment of disease (M. Thibonnier, Exp. Olpin Invest. Drugs 1998, 7 (5), 729-740).
  • novel substituted oxindoles which carry a (het) arylsulfonyl group in the 1-position.
  • 1-phenylsulfonyl-1,3-dihydro-2 / - / - indole-2-ones have already been described as ligands of vasopressin receptors.
  • WO 93/15051, WO 95/18105, WO 98/25901, WO 01/55130, WO 01/55134, WO 01/164668 and WO 01/98295 also describe derivatives which, in the 1-position of the oxindole skeleton, arylsulfonyl groups wear. These compounds differ significantly from the compounds of the invention by the substituents in the 3-position.
  • WO 93/15051 and WO 98/25901 describe 1-phenylsulfonyl-1,3-dihydro-2H-indole-2-ones as ligands of vasopressin receptors in which the oxindole skeleton in the 3-position is represented by two alkyl radicals is substituted, which together can also form a cycloalkyl radical (spiro linkage).
  • the spiro ring may contain heteroatoms such as oxygen and nitrogen (optionally with substituents).
  • WO 95/18105 describes 1-phenylsulfonyl-1,3-dihydro-2 / - / - indole-2-ones as ligands of vasopressin receptors having a nitrogen atom in the 3-position.
  • residues are attached in the 3-position, which are selected from optionally substituted alkyl, cycloalkyl, phenyl or benzyl radicals.
  • WO 2005/030755 relates to 1-phenylsulfonyloxindoles in which piperidylpiperazines or piperazinylpiperidines are bonded to the oxindole via a urea, carbamate or 2-oxoethyl group in the 3-position.
  • WO 2006/005609 describes 1-phenylsulfonyloxindoles which carry a phenyl group in the 3-position and also a piperidylpiperazine group or piperazinylpiperidine group bonded via a urea, carbamate or 2-oxoethyl group.
  • vasopressin V1 b receptor binding affinity for the vasopressin V1 b receptor
  • further properties may be advantageous for the treatment and / or prophylaxis of vasopressin-dependent diseases, such as, for example:
  • a selectivity to the vasopressin V1 b receptor compared to the vasopressin V1a receptor i. the ratio of the binding affinity to the V1a receptor (Ki (VIa) (determined in the unit “nanomolar (nM)") and the binding affinity to the V1 b receptor (Ki (VI b)) (determined in the unit "nanomolar (nM)"
  • Ki (VIa) determined in the unit "nanomolar (nM)
  • Ki (VI b) the binding affinity to the V1 b receptor
  • a selectivity to the vasopressin V1 b receptor compared to the vasopressin V2 receptor i. the quotient of the binding affinity for the V2 receptor (Ki (V2) (determined in the unit “nanomolar (nM)") and the binding affinity for the V1 b receptor (Ki (VI b)) (determined in the unit "nanomolar (nM)"
  • a selectivity to the vasopressin V1 b receptor compared to the oxytocin OT receptor i. the quotient of the binding affinity for the OT receptor (Ki (OT) (determined in the unit “nanomolar (nM)") and the binding affinity for the V1 b receptor (Ki (VI b)) (determined in the unit "nanomolar (nM)”
  • Ki (OT) determined in the unit "nanomolar (nM)
  • V1 b binding affinity for the V1 b receptor
  • the metabolic stability for example determined on the basis of in-vitro determined half-lives in liver microsomes of different species (eg rat or Human);
  • Cytochrome P450 is the name of a superfamily of heme proteins with enzymatic activity (oxidase). They also have special significance for the degradation (metabolism) of foreign substances such as drugs or xenobiotics in mammalian organisms. The most important representatives of the types and subtypes of CYP in the human organism are: CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4.
  • CYP3A4 inhibitors eg, grapefruit juice, cimetidine, erythromycin
  • drugs degraded by this enzyme system and thus compete for the same binding site on the enzyme may slow their degradation, thereby undesirably enhancing the effects and side effects of the drug being administered ;
  • a suitable pharmacokinetics time course of the concentration of the compound according to the invention in the plasma or in tissues, for example brain.
  • Pharmacokinetics can be described by the following parameters: half-life (in h), volume of distribution (in l-kg “1 ), plasma clearance (in lh “ 1- kg “1 ), AUC (" area under the curve "). , Area under the concentration-time curve, in ng-hl "1 ), oral bioavailability (the dose-normalized ratio of AUC after oral administration and AUC after intravenous administration), the so-called brain plasma ratio (the ratio of AUC in brain tissue and AUC in plasma);
  • the blockade of the hERG channel can be measured by means of electrophysiological experiments on cells transfected with the hERG channel by means of so-called “whole-cell patch clamping" (GJ Diaz et al., Journal of Pharmacological and Toxicological Methods , 50 (2004), 187-199).
  • the object of the present invention was to provide compounds for the treatment or prophylaxis of various vasopressin-dependent diseases.
  • the compounds should have high activity and selectivity, especially high affinity and selectivity over the vasopressin V1 b receptor, in particular sufficient selectivity for the V1 b receptor compared to the V1 a receptor.
  • the substance according to the invention should possess one or more of the abovementioned advantages 1) to 8).
  • X 1 is O, NR 9 or CH 2 ;
  • X 2 is N or CH;
  • R 1, R 2 and R 3 are each independently hydrogen, -C 4 -alkyl, dC 4 fluoroalkyl, dC 4 alkoxy, dC 4 fluoroalkoxy, Ci-C4-alkoxy-Ci-C 4 alkyl, halogen or CN stand;
  • R 4 is NR 10 R 11 , OR 11 or a saturated 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heteromonocyclic or heterobicyclic radical having 1 or 2 nitrogen atoms as ring members, wherein the heteromonocyclic or heterobicyclic radical is bonded via a nitrogen atom to the carbonyl group of the radical -X 1 -CO- and carries a substituent R 12 and optionally 1 or 2 further substituents R 13 ;
  • R 5 is ethoxy, fluorinated ethoxy, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, isopropoxy or halogen;
  • R 6 is hydrogen or methyl
  • R 7 and R 8 are independently hydrogen, I, Br, Cl, F, CN, C r C 4 alkyl, Ci-C 4 - fluoroalkyl, Ci-C 4 alkoxy or Ci-C are 4 fluoroalkoxy;
  • R 9 and R 10 are each independently hydrogen, CrC 4 alkyl, Ci-C4-fluoroalkyl, -C 4 - alkoxy or CrC are 4 fluoroalkoxy;
  • R 11 is a saturated 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heteromonocyclic or heterobicyclic radical having 1 or 2 nitrogen atoms as ring members, which also has a group A to the nitrogen or Oxygen atom of the group OR 11 or NR 10 R 11 may be bonded and may carry 1 or 2 substituents R 14 ; with the proviso that R 11 is not bonded via a ring nitrogen atom to the oxygen atom of the group OR 11 or to the nitrogen atom of the group NR 10 R 11 , if it is not bound via a group A,
  • R 12 is C 1 -C 6 -alkyl which may be substituted by C 1 -C 4 -alkoxy, cyano, amino, C 1 -C 4 -alkylamino or di- (C 1 -C 4 -alkyl) -amino, NR 15 R 16 , or for a saturated 4, 5-, 6-, 7-, 8-, 9- or 10-membered heteromonocyclic or heterobicyclic radical having 1 or 2 nitrogen atoms as ring members, which may also be bonded via a group B and the radical R 17 and optionally 1 or two further substituents R 18 bears; with the proviso that NR 15 R 16 is not linked to a ring nitrogen atom of the heterocycle R is bound, and with the proviso that the heteromo- nocylic or heterobicyclic radical R 1 12 2 is not bound via a ring nitrogen atom to a ring nitrogen atom of the heterocycle R 4 ;
  • each R 13 and each R 18 each independently dC 4 alkyl, -C 4 fluoroalkyl, dC 4 - alkoxy, dC 4 fluoroalkoxy or halogen;
  • each R 14 is independently C r C 4 alkyl, C r C 4 fluoroalkyl, C 1 -C 4 alkoxyC r C 4 alkyl, C r C 4 cyanoalkyl, C r C 4 alkoxy, C r C 4 -fluoroalkoxy, C 3 -C 6 -cycloalkyl, C 3 -C 6 -fluoro-cycloalkyl, -CH 2 - (C 3 -C 6 -cycloalkyl), -CH 2 - (C 3 -C 6 -fluorocycloalkyl), where cyclo - alkyl in the four aforementioned radicals may also be substituted by one or two dC 4 - alkyl groups, or a saturated 4-, 5- or 6-membered heterocyclic radical having 1 or 2 nitrogen atoms as ring members, the 1 or two radicals R 19 can wear; the proviso is that in the event that the radical R 14 is bonded to a
  • R 15 is hydrogen, C r C 4 alkyl, C r C 4 fluoroalkyl, C r C 4 alkoxy or C r C 4 fluoroalkoxy;
  • R 16 is hydrogen or C 4 alkyl optionally substituted by cyano, dC 4-4 alkylamino or di- (Ci-C 4 alkyl) amino is substituted alkoxy, amino, Ci-C;
  • R 17 is hydrogen, dC 4 alkyl, C r C 4 fluoroalkyl, dd-dd-alkoxy-alkyl, C r C 4 -
  • Cyanoalkyl C 2 -C 6 alkenyl, C 2 -C 6 fluoroalkenyl, C 2 -C 6 alkynyl, C 2 -C 6 fluoroalkynyl, C 3 -Ce cycloalkyl, C 3 -C 6 fluorocycloalkyl, CH 2 - (C 3 -C 6 -cycloalkyl), -CH 2 - (C 3 -C 6 -fluorocycloalkyl), where cycloalkyl in the four abovementioned radicals may also be substituted by one or two C 1 -C 4 -alkyl groups, C 4 -alkylcarbonyl, C 1 -C 4 -fluoroalkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -fluoroalkoxycarbonyl, amino, d-
  • each R 19 is independently defined as R 17 ; wherein the proviso applies that in the event that the radical R 19 is bonded to a ring nitrogen atom of the heterocyclic radical R 14 , R 19 does not represent amino, C 1 -C 4 -alkylamino, C 1 -C 4 -fluoroalkylamino, di- ( C 1 -C 4 -alkyl) amino or di- (C 1 -C 4 -fluoroalkyl) amino;
  • R 20, R 21, R 4 -alkyl, Ci-C 4 22 and R 23 are independently hydrogen, C r C - fluoroalkyl, Ci-C 4 -alkoxy or C are 4 fluoroalkoxy;
  • A is C 1 -C 6 -alkylene, where a CH 2 group of the alkylene bridge may also be replaced by a group selected from CO, NR 20 , CONR 20 , NR 20 CO, NR 20 CONR 21 , SO, SO 2 , NR 20 SO 2 and SO 2 NR 20 ; and
  • B is CO, CH 2 , NR 22 , CONR 22 , NR 22 CO, NR 22 CONR 23 , SO, SO 2 , NR 22 SO 2 or SO 2 NR 22 , with the proviso that NR 22 and NR 23 in the groups are not bound to a nitrogen atom of the radical R 4 or R 12 ;
  • Ar is phenyl wherein R 1 , R 2 and R 3 are independently hydrogen, C 1 -C 4 alkyl, trifluoromethyl, methoxy, trifluoromethoxy, F, Cl, Br or CN; or is thienyl, wherein R 3 is H and R 1 and R 2 are independently H, methoxy, methyl or Cl; or is thiazolyl, wherein R 1 and R 2 are independently H or methyl; or isoxazolyl, wherein R 1 and R 2 are independently H or methyl; or imidazolyl, wherein R 3 is H and R 1 and R 2 are independently H or methyl; or is pyridyl, wherein R 3 is H and R 1 and R 2 are independently H or methyl; or is benzothien-2-yl or benzothien-3-yl, wherein R 1 , R 2 and R 3 are H; or is quinolin-8-yl, wherein R 1 , R 2 and R 3 are H; and at the same time R 4 is
  • R A is hydrogen, C 1 -C 4 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl; and Y 1 , Y 2 and Y 3 are N or CH, with the proviso that Y 1 and Y 2 are not simultaneously N and that at least one of Y 2 and Y 3 is N; and at the same time
  • R 6 is hydrogen
  • R 7 is hydrogen, C r C 4 -alkyl, trifluoromethyl, methoxy, Cl, F or CN; and at the same time
  • R 8 is hydrogen; and their pharmaceutically acceptable salts and prodrugs thereof.
  • the present invention relates to compounds of the formula I (hereinafter also referred to as "compounds I”) and to the pharmaceutically acceptable salts of the compounds I and to the prodrugs of the compounds I.
  • the pharmaceutically acceptable salts of compounds of the formula I are generally obtainable by reacting the free base of the compounds I according to the invention (ie the compounds I according to structural formula I) with suitable acids.
  • suitable acids are listed, for example, in "Fort Whitney der Arzneistoffforschung", 1966, Birkhäuser Verlag, Vol.10, p.224-285, which include, for example, hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid and fumaric acid.
  • prodrugs is understood as meaning those compounds which are metabolized in vivo to the compounds I according to the invention.
  • prodrugs are described in CG. Wermeth (ed.): The Practice of Medicinal Chemistry, Academic Press, San Diego, 1996, pp. 671-715. These include, for example, phosphates, carbamates, amino acids, esters, amides, peptides, ureas and the like.
  • suitable prodrugs may be, for example, those compounds I in which an outer ring nitrogen atom (ie, a nitrogen atom not bonded to R 4 or B) of the nitrogen-containing heterocycle R 12 forms an amide / peptide bond by replacing this nitrogen atom with a CrC 4 Alkylcarbonyl group, for example, by acetyl, propionyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl or tert-butylcarbonyl (pivaloyl), by benzoyl, or by an amino acid residue bonded via CO, eg glycine bound via CO, alanine, serine, phenylalanine and the like is substituted for example in the position of the radical R 17 .
  • alkylcarbonyloxyalkyl carbamates in which such a nitrogen atom, for example in the position of the radical R 17, carries a group of the formula -C (OO) -O-CHR a -OC (OO) -R b , where R a and R b independently represent dC 4 alkyl.
  • Such carbamates are described, for example, in J. Alexander, R. Cargill, SR Michelson, H. Schwam, J. Medicinal Chem. 1988, 31 (2), 318-322. These groups can then be cleaved under metabolic conditions and result in compounds I where R 17 is H.
  • C 1 -C 3 -alkyl in the context of the present invention is a linear or branched alkyl radical having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl or isopropyl.
  • C 1 -C 4 -alkyl in the context of the present invention represents a linear or branched alkyl radical having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert butyl.
  • C 2 -C 4 -alkyl in the context of the present invention is a linear or branched alkyl radical having 2 to 4 carbon atoms, such as ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
  • C 1 -C 6 -alkyl is a linear or branched alkyl radical having 1 to 6 carbon atoms. Examples of these are, in addition to the radicals mentioned above for C 1 -C 4 -alkyl, n-pentyl, n-hexyl and the positional isomers thereof.
  • C 1 -C 3 -fluoroalkyl in the context of the present invention represents a linear or branched alkyl radical having 1 to 3 carbon atoms, as defined above, in which at least one hydrogen atom, for example 1, 2, 3, 4 or 5 hydrogen atoms, is replaced by fluorine atoms are.
  • C 1 -C 4 -fluoroalkyl in the context of the present invention represents a linear or branched alkyl radical having 1 to 4 carbon atoms, as defined above, in which at least one hydrogen atom, for example 1, 2, 3, 4 or 5 hydrogen atoms, is replaced by fluorine atoms are.
  • Examples include, in addition to the previously mentioned in CrC 3 -Fluoralkyl radicals 1-, 2-, 3- or 4-fluoro-n-butyl, 1,1-, 1,2-, 1,3-, 1,4-, 2 , 2-, 2,3-, 2,4-, 3,3-, 3,4- or 4,4-
  • C 2 -C 4 -Fluoralkyl in the context of the present invention represents a linear or branched alkyl radical having 2 to 4 carbon atoms, as defined above, in which at least one hydrogen atom, for example 1, 2, 3, 4 or 5 hydrogen atoms, are replaced by fluorine atoms , Examples of these are 1- and 2-fluoroethyl, 1,1-, 1,2- and 2,2-difluoroethyl, 1,1,2-, 1,2,2 and 2,2,2-trifluoroethyl, 1,1 , 2,2-tetrafluoroethyl, 1,2,2,2-tetrafluoroethyl, pentafluoroethyl, 1-, 2- and 3-fluoroprop-1-yl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- and 3,3-difluoroprop-1-yl,
  • C 1 -C 3 -alkoxy in the context of the present invention is a linear or branched alkyl radical having 1 to 3 carbon atoms bound via an oxygen atom. Examples are methoxy, ethoxy, n-propoxy and isopropoxy.
  • C 1 -C 4 -alkoxy is a linear or branched alkyl radical having 1 to 4 carbon atoms bound via an oxygen atom. Examples of these are n-butoxy, sec-butoxy, isobutoxy and tert-butoxy, in addition to the radicals mentioned above for CrC 3 -alkoxy.
  • Fluorinated ethoxy in the context of the present invention represents ethoxy, in which 1, 2, 3, 4 or 5 of the hydrogen atoms are substituted by fluorine atoms.
  • Examples are 1-fluoroethoxy, 2-fluoroethoxy, 1, 1-difluoroethoxy, 1, 2-difluoroethoxy, 2,2-difluoroethoxy, 1, 1, 2-trifluoroethoxy, 1, 2,2-trifluoroethoxy, 2,2,2- Trifluoroethoxy, 1, 1, 2,2-tetrafluoroethoxy, 1, 2,2,2-tetrafluoroethoxy and 1, 1, 2,2,2-pentafluoroethoxy.
  • dC 3 -fluoroalkoxy is a linear or branched alkyl radical having 1 to 3 carbon atoms, as defined above, in which at least one hydrogen atom, for example 1, 2, 3, 4 or 5 hydrogen atoms, is bonded by fluorine atoms are replaced.
  • C 1 -C 4 -fluoroalkoxy is a linear or branched alkyl radical having 1 to 4 carbon atoms, as defined above, in which at least one hydrogen atom, for example 1, 2, 3, 4 or 5 hydrogen atoms, is bonded by fluorine atoms are replaced.
  • Examples of these are, in addition to the radicals mentioned above for dC 3 -fluoroalkoxy, 1-, 2-, 3- or 4-fluoro-n-butoxy, 1, 1-, 1, 2-, 1, 3-, 1, 4-, 2,2-, 2,3-, 2,4-, 3,3-, 3,4- or 4,4-difluoro-n-butoxy, 4,4,4-trifluoro-n-butoxy, 2-fluoro -2-methyl-1-propoxy, 1,1-difluoro-2-methyl-1-propoxy, 2- (trifluoromethyl) -1-propoxy, 3,3,3-trifluoro-2- (trifluoromethyl) -1-propoxy and the same.
  • C 1 -C 4 -aryanoalkyl in the context of the present invention represents a linear or branched alkyl radical having 1 to 4 carbon atoms, as defined above, in which a hydrogen atom is replaced by a cyano group CN.
  • C 1 -C 4 cyanoalkyl is a linear alkyl radical having 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl or n-butyl) in which a hydrogen atom is replaced by a cyano group CN.
  • Examples of these are cyanomethyl, 1- and 2-cyanoethyl, 1-, 2- and 3-cyanoprop-1-yl and 1-, 2-, 3- and 4-cyanobut-1-yl.
  • C 2 -C 4 -Cyanoalkyl in the context of the present invention represents a linear or branched alkyl radical having 2 to 4 carbon atoms, as defined above, in which a hydrogen atom is replaced by a cyano group CN.
  • Examples of these are 1- and 2-cyanoethyl, 1-, 2- and 3-cyanoprop-1-yl, 1- and 2-cyanoprop-2-yl, 1-, 2-, 3- and 4-cyanobut-1 yl, 1-, 2-, 3- and 4-cyanobut-2-yl, 1-cyano-2-methylpropyl, 2-cyano-2-methylpropyl, 3-cyano-2-methylpropyl and cyano-tert-butyl.
  • C 2 -C 4 cyanoalkyl is a linear alkyl radical having 2 to 4 carbon atoms (ie, ethyl, n-propyl or n-butyl) in which a hydrogen atom is replaced by a cyano group CN.
  • examples of these are cyanomethyl, 1- and 2-cyanoethyl, 1-, 2- and 3-cyanoprop-1-yl and 1-, 2-, 3- and 4-cyanobut-1-yl.
  • C 2 -C 4 -cyanoalkyl is preferably a linear alkyl radical having 2 to 4 carbon atoms (ie ethyl, n-propyl or n-butyl) in which a hydrogen atom is replaced by a cyano group CN, where the cyano radical is preferably not in the 1 position.
  • Examples of these are 2-cyanoethyl, 2- and especially 3-cyanoprop-1-yl and 2-, 3- and in particular 4-cyanobut-1-yl.
  • C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl in the context of the present invention represents a linear or branched alkyl radical having 1 to 4 carbon atoms, as defined above, in which a hydrogen atom is represented by a C 1 -C 4 -alkoxy group, as defined above, Examples of these are methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butyloxymethyl, sec-butoxymethyl, isobutoxymethyl, tert-butoxymethyl, methoxy-1-ethyl, methoxy-2-ethyl, ethoxy-1-ethyl, ethoxy 2-ethyl, propoxy-1-ethyl, propoxy-2-ethyl, isopropoxy-1-ethyl, isopropoxy-2-ethyl, butoxy-1-ethyl, butoxy-2-ethyl, sec-butoxy-1-ethyl, sec-butoxy-2-ethy
  • Ci-C 4 -alkoxy-C 2 -C 4 -alkyl in the context of the present invention is a linear or branched alkyl radical having 2 to 4 carbon atoms, as defined above in which a hydrogen atom by a DC 4 alkoxy group, as defined above, , is replaced.
  • Examples of these are methoxy-1-ethyl, methoxy-2-ethyl, ethoxy-1-ethyl, ethoxy-2-ethyl, propoxy-1-ethyl, propoxy-2-ethyl, isopropoxy-1-ethyl, isopropoxy-2 -ethyl, butoxy-1-ethyl, butoxy-2-ethyl, sec-butoxy-1-ethyl, sec-butoxy-2-ethyl, isobutoxy-1-ethyl, isobutoxy-2-ethyl, tert-butoxy-1-ethyl , tert-butoxy-1-ethyl, methoxy-3-propyl, ethoxy-3-propyl, propoxy-3-propyl, butoxy-3-propyl, methoxy-4-butyl, ethoxy-4-butyl, propoxy-4 butyl, butoxy-4-butyl and the like.
  • these are ethoxy-2-ethyl, propoxy-2-ethyl, isopropoxy-2-ethyl, butoxy-2-ethyl, sec-butoxy-2-ethyl, isobutoxy-2-ethyl, tert-butoxy-2-ethyl, metho xy-3-propyl, ethoxy-3-propyl, propoxy-3-propyl, butoxy-3-propyl, methoxy-4-butyl, ethoxy-4-butyl, propoxy-4-butyl, butoxy-4-butyl and the same.
  • C 2 -C 6 -alkenyl in the context of the present invention represents a linear or branched alkenyl radical, ie an olefinically unsaturated aliphatic hydrocarbon radical having 2 to 6 carbon atoms with one or two, preferably one, double bonds in any position.
  • Examples of these are ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2 -propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl , 1-
  • C 2 -C 6 -fluoroalkenyl in the context of the present invention represents a linear or branched alkenyl radical having 2 to 6 carbon atoms, as defined above, in which at least one hydrogen atom, for example 1, 2, 3, 4 or 5 hydrogen atoms, is replaced by fluorine atoms are.
  • Examples of these are 1-fluorovinyl, 2-fluorovinyl, 2,2-difluorovinyl, 3-fluoropropen-1-yl, 3,3-difluoropropen-1-yl, 3,3,3-trifluoropropen-1-yl, 1, 1 Difluoro-2-propenyl, 1-fluoro-2-propenyl and the like.
  • C 2 -C 6 -alkynyl in the context of the present invention represents a linear or branched alkynyl radical, ie an aliphatic hydrocarbon radical having a triple bond in any position, having 2 to 6 carbon atoms.
  • Examples of these are ethynyl, 1-propynyl, 2-propynyl, 1-methylethynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-1-propynyl, 2-methyl-1-propynyl, 1-methyl-2 -propynyl, 2-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 3-methyl-1-butynyl , 1-methyl-2-butynyl, 2-methyl-2-butynyl, 3-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-3-butynyl, 1 , 1-dimethyl-2-propynyl, 1, 2-dimethyl-1-propynyl, 1, 2-dimethyl-2
  • C 2 -C 6 -fluoroalkynyl in the context of the present invention represents a linear or branched alkynyl radical having 2 to 6 carbon atoms, as defined above, in which at least one hydrogen atom, for example 1, 2, 3, 4 or 5 hydrogen atoms, are replaced by fluorine atoms.
  • Examples of these are 3-fluoropropyne-1-yl, 3,3-difluoropropyne-1-yl, 3,3,3-trifluoropropyne-1-yl, 1, 1-difluoro-2-propynyl, 1-fluoro-2-propynyl and the same.
  • C ß -Ce-cycloalkyl is a saturated cycloaliphatic radical having 3 to 6 carbon ring members. Examples of these are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C 3 -C 6 -fluorocycloalkyl is a saturated cycloaliphatic radical having 3 to 6 carbon ring members, as defined above, in which at least one hydrogen atom, for example 1, 2, 3, 4 or 5 hydrogen atoms, are replaced by fluorine atoms.
  • Examples of these are 1- or 2-fluorocyclopropyl, 1, 2, 2,2 and 2,3-difluorocyclopropyl, 2,2,3-trifluorocyclopropyl, 2,2,3,3-trifluorocyclopropyl, 1-, 2- or 3 Fluorocyclobutyl, 1, 2, 1, 3, 2,2, 2,3 and 2,4-difluorocyclobutyl, 1, 2,2, 1,2,3, 1,3,3, 1, 2,4-, 2,2,3-, 2,2,4-, 2,3,4- and 2,3,3-trifluorobutylcyclopropyl, 1-, 2- and 3-fluorocyclopentyl, 1, 2- , 1, 3, 2,2, 2,3, 2,4, 2,5, 3,3 and 3,4-difluorocyclopentyl, 1-, 2-, 3- and 4-fluorocyclohexyl, 1, 2-, 1, 3-, 1, 4-, 2,2-, 2,3-, 2,4-, 2,5-, 2,6-, 3,3-, 3,4- and 3,5-difluorocyclo
  • dC 4 alkylcarbonyl is a radical R-CO- wherein R is as defined above dC 4 -, alkyl.
  • C 1 -C 4 -fluoroalkylcarbonyl is a radical R-CO- in which R is C 1 -C 4 -fluoroalkyl as defined above.
  • C 1 -C 4 alkoxycarbonyl is a radical R-CO- in which R is dC 4 -alkoxy as defined above.
  • C 1 -C 4 -fluoroalkoxycarbonyl is a radical R-CO- in which R is dC 4 -fluoroalkoxy as defined above.
  • C 1 -C 4 -alkylamino is a radical R - H - -, in which R is as defined above for C 1 -C 4 -alkyl.
  • Di- (C 1 -C 4 -alkyl) -amino represents a group RR'N- in which R and R 'independently of one another are C 1 -C 4 -alkyl as defined above.
  • Ci-C 4 -Fluoralkylamino represents a radical RHN-, wherein R is as defined above CrC 4 - fluoroalkyl.
  • Di (C 1 -C 4 -fluoroalkyl) -amino represents a group RR'N- in which R and R 'independently of one another are dC 4 -fluoroalkyl as defined above.
  • C 1 -C 4 -alkylaminocarbonyl is a radical RHN-CO- in which R is C r C 4 -alkyl as defined above.
  • Di (C 1 -C 4 alkyl) aminocarbonyl is a group RR'N-CO- wherein R and R 'are independently dC 4 alkyl as defined above.
  • C 1 -C 4 -fluoroalkylaminocarbonyl is a radical RHN-CO- in which R is dC 4 -fluoroalkyl as defined above.
  • Di- (C 1 -C 4 -fluoroalkyl) aminocarbonyl is a radical R-R'N-CO- wherein R and R 'are independently C 1 -C 4 fluoroalkyl as defined above.
  • Ci-C 4 alkylsulfonyl is a radical R-SO 2 -, wherein R is as defined above Ci-C 4 -, alkyl.
  • C 1 -C 4 -fluoroalkylsulfonyl is a radical R-SO 2 -, in which R is d-C 4 -fluoroalkyl as defined above.
  • -C 4 alkoxysulfonyl stands for a group R-SO2 - wherein R is as defined above -C 4 - alkoxy stands.
  • dC 4 -Fluoralkoxysulfonyl is a radical R-SO 2 -, wherein R is as defined above d-C 4 -Fluoralkoxy.
  • C 1 -C 4 -alkylaminosulfonyl is a radical RHN-SO 2 -, in which R is C r C 4 -alkyl as defined above.
  • Di- (C 1 -C 4 -alkyl) -aminosulfonyl is a radical RR 1 N-SO 2 -, where R and R 'are independently gigeineiner for as defined above Ci-C 4 alkyl.
  • C 1 -C 4 -fluoroalkylaminosulfonyl represents a radical RHN-SC> 2 -, in which R is dC 4 -fluoroalkyl as defined above.
  • Di- (C 1 -C 4 -fluoroalkyl) -aminosulfonyl is a radical R R 1 N-SO 2 -, wherein R and R 'are independently C 1 -C 4 -fluoroalkyl as defined above.
  • C 1 -C 4 -alkylene is a linear or branched divalent alkyl radical ("alkylene bridge") having 1, 2, 3 or 4 carbon atoms
  • alkylene bridge divalent alkyl radical
  • Examples are -CH 2 -, -CH 2 CH 2 -, -CH (CH 3 ) -, -CH 2 CH 2 CH 2 -, -CH (CHs) CH 2 -, -CH 2 CH (CHs) -, -C (CHs) 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH (CH 3 ) CH 2 CH 2 -, -CH 2 CH (CH 3 ) CH 2 -, -CH 2 CH 2 CH (CH 3 ) -, -C (CH 3 ) 2 CH 2 -, -CH 2 C (CH 3 ) 2 - and the same.
  • C 1 -C 6 -alkylene is a linear or branched divalent alkyl radical ("alkylene bridge") having 1, 2, 3, 4, 5 or 6 carbon atoms
  • alkylene bridge divalent alkyl radical
  • Examples are, in addition to the groups mentioned above for C 1 -C 4 -alkylene, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH (CH 3 ) CH 2 CH 2 CH 2 -,
  • Examples of C 1 -C 6 -alkylene in which one CH 2 group is represented by a group Z selected from CO, NR 20 , CONR 20 , NR 20 CO, NR 20 CONR 21 , SO, SO 2 , NR 20 SO 2 and SO 2 NR 20 , are -Z-, -Z-CH 2 -, -CH 2 -Z-, -Z-CH 2 CH 2 -, -CH 2 -Z-CH 2 -, -CH 2 CH 2 -Z-
  • C 1 -C 4 -alkylene in which a CH 2 group in is replaced by a carbonyl group are -CO-, -CH 2 -CO-, -CO-CH 2 -, -CO-CH 2 CH 2 -, -CH 2 -CO-CH 2 -, -CH 2 CH 2 -CO-, -CH (CH 3 ) -CO-, -CO-CH (CH 3 ) -, -CO-CH 2 CH 2 CH 2 -, -CH 2 -CO-CH 2 CH 2 -, -CH 2 CH 2 CH 2 -CO-, -CH (CH 3 ) -CO-CH 2 -, -CH (CH 3 ) CH 2 -CO-, -CO-CH 2 CH (CH 3 ) -, -CH 2 -CO-CH (CH 3 ) -, -CH 2 ) CH 2 -CO-, -CO-CH 2 CH (CH 3 ) -, -CH 2 -CO-
  • C 6 -C 4 -Aryl represents a carboaromatic radical having 6 to 14 carbon atoms. Examples are phenyl, naphthyl, anthracenyl and phenanthrenyl. Aryl is preferably phenyl or naphthyl and in particular phenyl.
  • the 5-membered hetaryl having 1, 2 or 3 heteroatoms as ring members selected from N, O and S contains, in the case where it has two heteroatoms as ring members, a nitrogen atom and another heteroatom which is selected under N, O and S.
  • the 5-membered hetaryl has three heteroatoms as ring members, it contains two nitrogen atoms and another heteroatom selected from N, O and S.
  • Examples of 5-membered hetaryl having 1, 2 or 3 Heteroatoms as ring members selected from N, O and S are pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl and thiadiazolyl.
  • the 6-membered hetaryl contains 1, 2 or 3 nitrogen atoms as ring members. Examples are pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl.
  • Examples of 5- or 6-membered hetaryl having 1, 2 or 3 heteroatoms as ring members, which are selected from N, O and S, which is fused to phenyl, are indolyl, isoindolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, Benzoxazolyl, benzothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl and phthalazinyl.
  • the binding to the rest of the molecule can take place both via the hetaryl ring and via the benzene ring.
  • saturated A-, 5- or 6-membered heterocycles also referred to as A-, 5- or 6-membered heteromonocyclic radicals
  • A-, 5- or 6-membered heteromonocyclic radicals having one or two nitrogen atoms as ring members are azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, hexahydropyrimidinyl and piperazinyl.
  • saturated A-, 5- or 6-membered heterocycles having one or two nitrogen atoms as ring members bonded via N are 1-azidinyl, 1-pyrrolidinyl, 1- or 2-pyrazolidinyl, 1- or 3-imidazolidinyl, 1-piperidinyl, 1- or 3-hexahydropyrimidinyl and 1- or 4-piperazinyl.
  • saturated A, 5-, 6-, 7-, 8-, 9- or 10-membered heteromonocyclic radicals having one or two nitrogen atoms as ring members are, in addition to the radicals mentioned above in the A- to 6-membered heterocycles, azepanyl, Diazepanyl, azacyclooctanyl, diacacyclooctanyl and the like.
  • the saturated A-, 5-, 6-, 7-, 8-, 9- or 10-membered heterobicyclic radicals having one or two nitrogen atoms as ring members are in particular 7-, 8-, 9- or 10-membered heterobicyclic radicals. Examples of these are radicals of the following formulas:
  • Halogen in the context of the present invention is fluorine, chlorine, bromine or iodine and in particular fluorine, chlorine or bromine.
  • solvates are crystalline forms of the compounds I or of their pharmaceutically acceptable salts or prodrugs thereof, which contain solvent molecules incorporated in the crystal lattice.
  • solvent molecules are incorporated in stoichiometric proportions.
  • Hydrate is a special form of solvate; the solvent is water here.
  • the invention provides compounds of the formula I, but with the exception of compounds wherein
  • Ar is phenyl, wherein R 1, R 2 and R 3 are independently hydrogen, C d- 4 -alkyl, C r C 4 fluoroalkyl, C r C 4 alkoxy, C r C 4 -fluoroalkoxy, F, Cl , Br or CN stand; or is thienyl, where R 3 is H and R 1 and R 2 are each independently H,
  • R 4 is a radical of the formula
  • R A is hydrogen, C 1 -C 4 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl; and Y 1 , Y 2 and Y 3 are N or CH, with the proviso that Y 1 and Y 2 are not simultaneously N and that at least one of Y 2 and Y 3 is N; and at the same time
  • R 6 is hydrogen
  • R 7 is hydrogen, C r C 4 -alkyl, trifluoromethyl, methoxy, Br, Cl, F or CN; and at the same time
  • R 8 is hydrogen; and their pharmaceutically acceptable salts and prodrugs thereof.
  • the invention provides compounds of the formula I, but with the exception of compounds wherein
  • Ar is phenyl, in which R 1 , R 2 and R 3 are each independently hydrogen,
  • R 4 is a radical of the formula
  • R A is hydrogen, C 1 -C 4 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl;
  • Y 1 , Y 2 and Y 3 are N or CH, with the proviso that Y 1 and Y 2 are not simultaneously N and that at least one of Y 2 and Y 3 is N;
  • R B and R c independently of one another are C 1 -C 3 -alkyl or C 1 -C 3 -fluoroalkyl;
  • u, v, w and x are independently 1, 2 or 3; and
  • y and z are independently 0, 1 or 2; and at the same time
  • R 6 is hydrogen; while R 7 is hydrogen, C r C 4 alkyl, trifluoromethyl, methoxy, Br, Cl, F or CN; and at the same time
  • R 8 is hydrogen; and their pharmaceutically acceptable salts and prodrugs thereof.
  • the invention provides compounds of the formula I, but with the exception of compounds in which
  • Ar is phenyl, wherein R 1, R 2 and R 3 are independently hydrogen, C d- 4 alkyl, C r C 4 fluoroalkyl, C r C 4 alkoxy, C r C 4 -fluoroalkoxy, F, Cl , Br or CN stand; or is thienyl, wherein R 3 is H and R 1 and R 2 are independently H, methoxy, methyl or Cl; or represents thiazolyl, wherein R 1 and R 2 independently of one another are H or methyl; or isoxazolyl, wherein R 1 and R 2 are independently H or methyl; or imidazolyl, wherein R 3 is H and R 1 and R 2 are independently H or methyl; or is pyridyl, wherein R 3 is H and R 1 and R 2 are independently H or methyl; or is benzothien-2-yl or benzothien-3-yl, wherein R 1 , R 2 and R 3 are H; or is quinolin-8-yl, where
  • R 4 is a radical of the formula
  • R A is hydrogen, C 1 -C 4 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl; and Y 1 , Y 2 and Y 3 are N or CH, with the proviso that Y 1 and Y 2 are not simultaneously N and that at least one of Y 2 and Y 3 is N; and at the same time R 6 is hydrogen; and at the same time
  • R 7 is hydrogen, C r C 4 alkyl, CF 3 , methoxy, Cl, F, Br or CN; and at the same time
  • R 8 is hydrogen; and their pharmaceutically acceptable salts and prodrugs thereof.
  • the invention provides compounds of the formula I, but with the exception of compounds in which
  • Ar is phenyl, wherein R 1, R 2 and R 3 independently of one another are hydrogen, Cr C4 alkyl, C r C 4 fluoroalkyl, C r C 4 alkoxy, C r C 4 -fluoroalkoxy, F, Cl, Br or CN stand; or is thienyl, wherein R 3 is H and R 1 and R 2 are independently H, methoxy, methyl or Cl; or is thiazolyl, wherein R 1 and R 2 are independently H or methyl; or isoxazolyl, wherein R 1 and R 2 are independently H or methyl; or imidazolyl, wherein R 3 is H and R 1 and R 2 are independently H or methyl; or is pyridyl, wherein R 3 is H and R 1 and R 2 are independently H or methyl; or is benzothien-2-yl or benzothien-3-yl, wherein R 1 , R 2 and R 3 are H; or is quinolin-8-yl, wherein R 1
  • R A is hydrogen, C 1 -C 4 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl;
  • Y 1 , Y 2 and Y 3 are N or CH, with the proviso that Y 1 and Y 2 are not simultaneously N and that at least one of Y 2 and Y 3 is N;
  • R B and R c independently of one another are C 1 -C 3 -alkyl or C 1 -C 3 -fluoroalkyl; u, v, w and x are independently 1, 2 or 3; and y and z are independently 0, 1 or 2; and at the same time R 6 is hydrogen; and at the same time
  • R 7 is hydrogen, C r C 4 alkyl, CF 3 , methoxy, Cl, F, Br or CN; and at the same time
  • R 8 is hydrogen; and their pharmaceutically acceptable salts and prodrugs thereof.
  • the invention provides compounds of the formula I, but with the exception of compounds in which
  • Ar is phenyl, wherein R 1, R 2 and R 3 are independently hydrogen, C d- 4 alkyl, C r C 4 fluoroalkyl, C r C 4 alkoxy, C r C 4 -fluoroalkoxy, F, Cl , Br or CN stand; or is thienyl, wherein R 3 is H and R 1 and R 2 are independently H, methoxy, methyl or Cl; or represents thiazolyl, wherein R 1 and R 2 independently of one another are H or methyl; or isoxazolyl, wherein R 1 and R 2 are independently H or methyl; or imidazolyl, wherein R 3 is H and R 1 and R 2 are independently H or methyl; or is pyridyl, wherein R 3 is H and R 1 and R 2 are independently H or methyl; or is benzothien-2-yl or benzothien-3-yl, wherein R 1 , R 2 and R 3 are H; or is quinolin-8-yl, where
  • R 4 is a radical of the formula
  • R A is hydrogen, C 1 -C 4 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl;
  • Y 1 , Y 2 and Y 3 are N or CH, with the proviso that Y 1 and Y 2 are not simultaneously N and that at least one of Y 2 and Y 3 is N;
  • R B and R c independently of one another are C 1 -C 3 -alkyl or C 1 -C 3 -fluoroalkyl; u, v, w and x are independently 1, 2 or 3; and y and z are independently 0, 1 or 2; and at the same time
  • R 6 is hydrogen
  • R 7 and R 8 are independently hydrogen, C 1 -C 4 alkyl, CF 3 , methoxy, Cl, F, Br or CN; and their pharmaceutically acceptable salts and prodrugs thereof.
  • the subject of the invention are compounds of
  • Ar is phenyl, thienyl, thiazolyl, isoxazolyl, imidazolyl, pyridyl, benzothien-2-yl or benzothien-3-yl, wherein R 1 , R 2 and R 3 have one of the meanings given above; and at the same time
  • R 4 is a radical of the formula
  • R A is hydrogen, C 1 -C 4 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl;
  • Y 1 , Y 2 and Y 3 are N or CH, with the proviso that Y 1 and Y 2 are not simultaneously N and that at least one of Y 2 and Y 3 is N;
  • R B and R c independently of one another are C 1 -C 3 -alkyl or C 1 -C 3 -fluoroalkyl;
  • u, v, w and x are independently 1, 2 or 3; and
  • y and z are independently 0, 1 or 2; and at the same time
  • R 6 is hydrogen; and at the same time R 7 and R 8 independently of one another are hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -fluoroalkyl, methoxy, Cl, F, Br or CN; and their pharmaceutically acceptable salts and prodrugs thereof.
  • the invention provides compounds of the formula I, but with the exception of compounds in which R 4 is a radical of the formula
  • R A is hydrogen, C r C 4 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl; and Y 1 , Y 2 and Y 3 are N or CH, with the proviso that Y 1 and Y 2 are not simultaneously N and that at least one of Y 2 and Y 3 stands for N and their pharmaceutically acceptable salts and prodrugs from that.
  • the invention provides compounds of the formula I, but with the exception of compounds in which R 4 is a radical of the formula
  • R A is hydrogen, C 1 -C 4 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl;
  • Y 1 , Y 2 and Y 3 are N or CH, with the proviso that Y 1 and Y 2 are not simultaneously N and that at least one of Y 2 and Y 3 is N;
  • R B and R c independently of one another are C 1 -C 3 -alkyl or C 1 -C 3 -fluoroalkyl; u, v, w and x are independently 1, 2 or 3; and y and z independently represent 0, 1 or 2.
  • the compounds I are preferably provided in the form of the free base (i.e. according to structural formula I) or in the form of their acid addition salts.
  • Suitable radicals Ar are, for example, phenyl, naphthyl, anthraceny and phenanthrenyl (C 6 -C 4 -aryl), pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl and thiadiazolyl (5 hetaryl), pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and triazinyl (6-membered hetaryl) and indolyl, isoindolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, cinn
  • the bond to the remainder of the molecule can take place both via the hetaryl ring and via the benzene ring.
  • the bond to the rest of the molecule can take place both via a nitrogen atom and via a carbon atom.
  • radicals R 1 , R 2 and R 3 which the rest of Ar can carry, depending on the nature of Ar.
  • a 5-membered hetaryl with two heteroatoms as ring members, wherein a heteroatom of N is different and a 5-membered hetaryl with three nitrogen atoms as ring members carry a maximum of two radicals (eg R 1 and R 2 ), while a 5- membered hetaryl having three heteroatoms as ring members, wherein a heteroatom of N is different, even only a radical (eg R 1 ) can carry.
  • Ar is preferably selected from phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, quinolinyl and isoquinolinyl.
  • Ar is more preferably selected from phenyl, naphthyl, pyridyl, quinolinyl and isoquinolinyl. In particular, Ar is phenyl.
  • R 1 , R 2 and R 3 independently of one another are hydrogen, C 1 -C 4 -alkoxy or C 1 -C 4 -alkyl, particularly preferably hydrogen, C 1 -C 3 -alkoxy or C 1 -C 6 -alkyl and in particular hydrogen or d-C3-alkoxy.
  • R 1 , R 2 and R 3 are independently hydrogen or methoxy.
  • C 1 -C 3 -alkoxy is preferably ethoxy or methoxy and especially methoxy.
  • C 1 -C 3 -fluoroalkoxy is preferably C 1 -C 2 -fluoroalkoxy, ie fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1- and 2-fluoroethoxy, 1, 1, 1, 2 and 2,2-difluoroethoxy, 1, 1, 2, 1 , 2,2 and 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 1,2,2,2-tetrafluoroethoxy or pentafluoroethoxy, preferred for fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy or 2 , 2,2-trifluoroethoxy, and especially for 2,2-difluoroethoxy or trifluoroethoxy.
  • At least one of R 1 , R 2 , R 3 is hydrogen.
  • Ar is phenyl
  • R 1 be attached at the 2-position, R 2 at the 2-position and R 3 at the 4-position relative to the 1-position of the sulfonyl group, ie Ar is the following radical:
  • R 1 , R 2 and R 3 independently of one another, preferably represent hydrogen, C 1 -C 4 -alkoxy or C 1 -C 4 -alkyl, particularly preferably hydrogen, C 1 -C 4 -alkyl. Alkoxy or C 1 -C 3 -alkyl and in particular hydrogen or C 1 -C 3 -alkoxy. Specifically, R 1 , R 2 and R 3 are independently hydrogen or methoxy.
  • At least one of the radicals R 1 , R 2 , R 3 is hydrogen.
  • R 1 and R 3 independently of one another preferably represent hydrogen, C 1 -C 3 -alkoxy or C 1 -C 3 -alkyl and particularly preferably hydrogen or C 1 -C 3 -alkoxy.
  • dC 3 -alkoxy preferably stands for ethoxy or methoxy and especially for methoxy.
  • R 1 is hydrogen, methoxy or ethoxy, and in particular hydrogen or methoxy.
  • R 3 is hydrogen, methoxy or ethoxy, in particular hydrogen or methoxy and especially methoxy.
  • radical Ar.a at least one of the radicals R 1 and R 3 is methoxy.
  • R 1 and R 3 are methoxy and R 2 is hydrogen.
  • R 5 is preferably ethoxy, fluorinated ethoxy, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy or isopropoxy, particularly preferably ethoxy or fluorinated ethoxy, more preferably ethoxy, 2,2-difluoroethoxy or 2,2, 2-trifluoroethoxy and especially ethoxy.
  • R 6 is preferably H.
  • X 2 is N. In an alternatively preferred embodiment, X 2 is CH.
  • X 2 is N.
  • R 5 is ethoxy
  • R 6 is H
  • X 2 is N.
  • R 5 is ethoxy
  • R 6 is H
  • X 2 is CH.
  • R 7 and R 8 in compounds I are independently hydrogen, I, Br, Cl, F, CN, dC 4 alkyl, -C 4 fluoroalkyl, dC dC 4 alkoxy or fluoroalkoxy 4.
  • R 7 and R 8 independently of one another preferably represent hydrogen, I, Br, Cl, F, CN, C 1 -C 4 -alkoxy or C 1 -C 4 -fluoroalkoxy and particularly preferably hydrogen, I, Br, Cl, F or CN , dC 4 alkyl in the above definition is preferably methyl or ethyl and in particular methyl, dC 4 fluoroalkyl is preferably fluoromethyl, difluoromethyl or trifluoromethyl, dC 4 alkoxy is preferably methoxy or ethoxy and especially methoxy and dC 4 -Fluoralkoxy is preferably fluoromethoxy, difluoromethoxy or trifluoromethoxy.
  • R 7 and R 8 are not simultaneously CN.
  • one of R 7 or R 8 is CN.
  • one of R 7 and R 8 is CN and the other is H or F or one of R 7 and R 8 is Cl and the other is H or F.
  • R 7 is attached in the 5-position and R 8 in the 6-position of the 2,3-dihydroindol-2-one ring:
  • R 9 in the radical X 1 is preferably H or methyl and in particular H.
  • X 1 is preferably NR 9 or O.
  • R 9 is preferably H or methyl and in particular H.
  • X 1 is NR 9 .
  • R 9 is preferably H or methyl and in particular H.
  • X 1 is O.
  • X 1 is NR 9 .
  • R 9 is preferably H or methyl and in particular H.
  • R 4 is NR 10 R 11 .
  • R 10 is preferably hydrogen or C 1 -C 4 -alkyl, particularly preferably hydrogen, methyl or ethyl, in particular hydrogen or methyl and especially hydrogen.
  • the ring is preferably not linked via a ring nitrogen atom.
  • R 11 in the radical NR 10 R 11 preferably represents a saturated 4-, 5- or 6-membered heteromonocyclic radical having 1 or 2 nitrogen atoms as ring members, which is also bonded via a group A to the nitrogen atom of the group NR 10 R 11 and which may carry 1 or 2 substituents R 14 , as defined above.
  • the heteromonocyclic radical is preferably selected from azetidinyl, in particular azetidin-1-yl or azetidin-3-yl, pyrrolidinyl, in particular pyrrolidin-1-yl or pyrrolidin-3-yl, piperdiniyl, in particular piperidin-1-yl or piperidine -4-yl, and piperazinyl, especially piperazin-4-yl.
  • the heteromonocyclic radical is azetidinyl, in particular azetidin-3-yl, or piperazinyl, in particular piperazin-4-yl and, more particularly, azetidinyl, in particular azetidin-3-yl.
  • R 11 is piperazin-4-yl or another, via a ring nitrogen atom bonded heterocyclic radical, such as azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl, it is preferably bonded via a group A.
  • the heteromonocyclic or heterobicyclic ring in the radical R 11 preferably carries one or no radical R 14 .
  • the heteromonocyclic or heterobicyclic ring R 11 is not bound via a group A, it preferably carries a radical R 14 .
  • the heteromonocyclic or heterobicylic ring R 11 bears a substituent R 14 , it is preferably attached to a nitrogen atom of the ring, for example in the case of heteromonocycles at the 1-position of azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl. It goes without saying that in this position otherwise a hydrogen atom is bonded.
  • R 14 is preferably selected from dC 4 alkyl, -C 4 fluoroalkyl, Ci-C4-alkoxy-Ci-C4 - alkyl, C r C 4 cyanoalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 -Fluorcycloalkyl, -CH 2 - (C 3 -C 6 cycloalkyl), -CH 2 - (C 3 -C 6 fluorocycloalkyl), wherein cycloalkyl in the four aforementioned radicals also be substituted by one or two dC 4 alkyl groups can, and a saturated 4-, 5- or 6-membered heterocycle having 1 or 2 nitrogen atoms as ring members, which in turn can carry a radical R 19 , which is as defined above.
  • R 14 is selected from C r C 4 alkyl, C r C 4 fluoroalkyl, C r C 4 alkoxy-C 2 -C 4 alkyl, C 2 -C 4 cyanoalkyl, C 3 -C 6 -Cycloalkyl, C 3 -C 6 fluorocycloalkyl and a saturated 4-, 5- or 6-membered heterocycle having 1 or 2 nitrogen atoms as ring members, which in turn can carry a radical R 19 , which is as defined above.
  • R 19 is preferably dC 4 -alkyl and especially methyl.
  • the heterocycle is of course a heteromonocycle.
  • heterocycles examples include azetidinyl, in particular azetidin-3-yl, pyrrolidinyl, in particular pyrrolidin-3-yl, piperdiniyl, in particular piperidin-4-yl, and piperazinyl, in particular piperazin-4-yl.
  • R 14 is selected from dC 4 alkyl and a saturated 4-, 5- or ⁇ -membered heterocycle having 1 or 2 nitrogen atoms as ring members, which is as defined above.
  • the heterocycle is preferably selected from piperidinyl and piperazinyl.
  • this heterocycle is preferably not bound via a ring nitrogen atom.
  • the group A is preferably C 1 -C 4 -alkylene, where a CH 2 group of the alkylene bridge may also be replaced by CO.
  • A is - (CH 2 ) 3 -, - (CHz) 4 -, - (CHz) 2 -CO-, - (CHz) 3 -CO-, -CO- (CHz) 2 -, -CO- (CHz) 3 - or -CH 2 -CO-CH 2 - and especially for - (CH 2 ) 3 -, - (CH 2 ) 4 -, - (CH 2 ) 2 -CO- or - (CH 2 ) 3 -CO-.
  • A is - (CH 2 ) 3 - or - (CH 2 ) 2 -CO-, and more particularly, - (CH 2 ) 2 -CO-.
  • the heteromonocyclic or heterobicyclic ring R 11 is directly attached to the nitrogen atom of the group NR 10 R 11 , ie not bound via a group A, if it is not bonded via a ring nitrogen atom. However, it is then preferably attached via a group A when the binding site is a ring nitrogen atom (such as when R 11 is azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl or Piperazin-4-yl).
  • R 4 is OR 11 .
  • the ring is preferably not linked via a ring nitrogen atom.
  • the heterocyclic ring R 11 is bonded via a group A to the oxygen atom of the group OR 11 .
  • the group A is preferably C 1 -C 4 -alkylene, where a CH 2 group of the alkylene bridge may also be replaced by CO.
  • A is - (CH 2 ) S-, - (CHz) 4 -, - (CH 2 ) Z-CO-, - (CHz) 3 -CO-, -CO- (CHz) 2 -, -CO - (CHz) 3 - or -CH 2 -CO-CH 2 - and especially for - (CHz) 3 -, - (CHz) 4 -, - (CHz) 2 -CO- or - (CHz) 3 -CO- , Specifically, A is - (CH 2 ) 3 - or - (CH 2 ) 2 -CO- and more particularly - (CH 2 ) 3 -.
  • R 11 in the radical OR 11 is preferably a saturated 4-, 5- or 6-membered hetero-cyclonocyclic radical having 1 or 2 nitrogen atoms as ring members which is bonded via a group A to the oxygen atom of the group OR 11 and 1 or 2 substituents can carry R 14 , which is as defined above.
  • A has the general or preferred meaning given above.
  • the heteromonocylic radical is preferably selected from azetidinyl, in particular azetidin-1-yl or azetidin-3-yl, pyrrolidinyl, in particular pyrrolidin-1-yl or pyrrolidin-3-yl, piperdiniyl, in particular piperidin-1-yl or piperidine 4-yl, and piperazinyl, especially piperazin-4-yl.
  • the heteromonocylic radical is azetidinyl, in particular azetidin-3-yl, or pi perazinyl, especially piperazin-4-yl, and more particularly piperazinyl, especially piperazin-4-yl.
  • R 11 in the radical OR 11 is preferably a saturated 4-, 5- or 6-membered heteromonocyclic radical having 1 or 2 nitrogen atoms as ring members which is not bound via a group A but directly to the oxygen atom of the group OR 11 and which may carry 1 or 2 substituents R 14 , which is as defined above.
  • R 11 When the heteromonocyclic or heterobicyclic ring R 11 is not bound via a group A, it preferably carries a radical R 14 .
  • the heteromonocyclic see residue is not bound via a ring nitrogen atom to the oxygen atom of the group OR 11 .
  • R 11 is preferably selected from azetidinyl, in particular azetidin-3-yl, pyrrolidinyl, in particular pyrrolidin-3-yl, and piperdiniyl, in particular piperidin-4-yl.
  • R 11 in the radical OR 11 is particularly preferably a saturated 4-, 5- or 6-membered heteromonocyclic radical having 1 or 2 nitrogen atoms as ring members, via a group A to the oxygen atom the group OR 11 is bound.
  • the heteromonocyclic or heterobicyclic ring in the radical R 11 preferably carries one or no radical R 14 .
  • the heteromonocyclic or heterobicyclic ring R 11 is not bound via a group A, it preferably carries a radical R 14 .
  • the heteromonocyclic or heterobicylic ring carries a substituent R 14 , it is preferably attached to a nitrogen atom of the ring, for example in the case of heteromonocycles at the 1-position of azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl. It goes without saying that in this position otherwise a hydrogen atom is bonded.
  • R 14 is preferably selected from dC 4 alkyl, -C 4 fluoroalkyl, dC dC 4 -alkoxy 4 alkyl, C r C 4 cyanoalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 -Fluorcycloalkyl, -CH 2 - (C 3 -C 6 -cycloalkyl), -CH 2 - (C 3 -C 6 -fluorocycloalkyl), where cycloalkyl in the four aforementioned radicals may also be substituted by one or two C 1 -C 4 -alkyl groups, and a saturated 4-, 5- or 6-membered heterocycle having 1 or 2 nitrogen atoms as ring members, which in turn may carry a radical R 19 , which is as defined above.
  • R 14 is selected from dC 4 alkyl, dC 4 fluoroalkyl, -C 4 -alkoxy-C 2 -C 4 - alkyl, C 2 -C 4 cyanoalkyl, C 3 -C 6 cycloalkyl, C 3 - C 6 -fluorocycloalkyl and a saturated 4-, 5- or 6-membered heterocycle having 1 or 2 nitrogen atoms as ring members, the ne note can carry a residue R 19 , which is as defined above. However, R 19 is preferably dC 4 -alkyl and especially methyl.
  • the heterocycle is of course a heteromonocycle.
  • heterocycles examples include azetidinyl, in particular azetidin-3-yl, pyrrolidinyl, in particular pyrrolidin-3-yl, piperdiniyl, in particular piperidin-4-yl, and piperazinyl, in particular piperazin-4-yl.
  • R 14 is selected from dC 4 alkyl and a saturated 4-, 5- or 6-membered heterocycle having 1 or 2 nitrogen atoms as ring members, which is as defined above.
  • the heterocycle is preferably selected from piperidinyl and piperazinyl.
  • R 14 is selected from C 1 -C 4 alkyl and is especially methyl.
  • this heterocycle is preferably not bound via a ring nitrogen atom.
  • R 4 is a saturated 4-, 5- or 6-membered heteromonocyclic radical having 1 or 2 nitrogen atoms as ring members, wherein the heterocycle via a nitrogen atom to the carbonyl group of the radical -X 1 -CO- and bears a substituent R 12 and optionally 1 or 2 further substituents R 13 , where R 12 and R 13 are as defined above or below.
  • the heteromonocyclic radical R 4 carries no substituents R 13 .
  • Preferred heterocycles R 4 are azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl and piperazin-1-yl. Particularly preferred among these are piperidin-1-yl and piperazin-1-yl.
  • the heteromonocyclic radical R 4 is piperidin-1-yl or piperazin-1-yl which carry the substituent R 12 in the 4-position.
  • R 12 has one of the abovementioned general or preferably one of the preferred meanings given below.
  • R 12 is selected from a 4-, 5- or ⁇ -membered heteromonocyclic radical having 1 or 2 nitrogen atoms as ring members, which may also be bonded via a group B and the radical R 17 and optionally 1 or two further substituents R 18 bears; with the proviso that the heteromonocylic radical R 12 does not react via a nitrogen atom to an atom of the heterocycle R 4 is bonded
  • R 12 is selected in accordance with the abovementioned proviso under piperidinyl and piperazinyl bound directly (ie not via a group B), the radical R 17 and optionally 1 or two further substituents R 18 where R 17 and R 18 have one of the general meanings given above or preferably one of the abovementioned preferred meanings.
  • R 18 is preferably C 1 -C 4 -alkyl and in particular methyl.
  • piperidinyl or piperazinyl radical R 12 does preferably bear no substituent R 18 .
  • R 4 is piperidin-1-yl, which carries R 12 in the 4-position, wherein R 12 is piperidin-1-yl, piperidin-4-yl or piperazin-4-yl or R 4 is piperazin-1-yl bearing R 12 in the 4-position wherein R 12 is piperidin-4. More preferably R 4 is piperidin-1-yl bearing R 12 in the 4-position, wherein
  • R 12 is piperidin-4-yl or piperazin-4-yl, or R 4 is piperazin-1-yl bearing R 12 in the 4-position wherein R 12 is piperidin-4-yl.
  • the piperidin-4-yl ring or the piperazin-4-yl ring R 12 in the 1-position carry a radical R 17 which has one of the meanings given above or preferably as below has.
  • R 17 is preferably different from hydrogen and C 1 -C 4 -alkyl.
  • R 17 is hydrogen, C r C 4 alkyl, CH 2 F, CHF 2 and CF 3 different.
  • R 17 is preferably selected out of dC 4 fluoroalkyl (preferably C 2 -C 4 fluoroalkyl), dC 4 cyanoalkyl (preferably C 2 -C 4 cyanoalkyl), Ci-C4-alkoxy-Ci-C 4 alkyl (preferably C C 4 -alkoxy-C 2 -C 4 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 -Fluorcycloalkyl, C r C 4 alkylcarbonyl, aminocarbonyl amino, Ci-C 4 - alkylaminocarbonyl, CrC 4 -Fluoralkylaminocarbonyl, di- (dC 4 alkyl) - aminocarbonyl, di- (Ci-C4 fluoroalkyl) aminocarbonyl, aminosulfonyl, CrC 4 - alkylaminosulfonyl, 4 dC -Fluoralkylaminosulf
  • R 17 is particularly preferably selected from CrC 4 - Fluoroalkyl (preferably C 2 -C 4 fluoroalkyl), dC 4 cyanoalkyl (preferably C 2 -C 4 cyanoalkyl), Ci-C 4 alkoxy-dC 4 alkyl (preferably Ci-C 4 -alkoxy-C 2 - C 4 alkyl), C 3 -C 6 cycloalkyl, C 3 -C 6 - fluorocycloalkyl, Ci-C4-alkylcarbonyl, aminocarbonyl, Ci-C4-alkylaminocarbonyl, CrC 4 - Fluoralkylaminocarbonyl, di- (Ci-C 4 -alkyl) -aminocarbonyl, di (dC 4 -fluoroalkyl) aminocarbonyl, aminosulfonyl, C 1 -C 4 -alkylaminosulfonyl, C 1 -C 4 -fluoroalkyl
  • R 17 is C 1 -C 4 -fluoroalkyl (preferably C 2 -C 4 -fluoroalkyl), especially fluoroethyl, in particular 2-fluoroethyl, 2,2-difluoroethyl or 2,2,2-trifluoroethyl, C 4 cyanoalkyl (preferably C 2 -C 4 cyanoalkyl), especially for 2- cyanoethyl, Ci-C 4 -alkoxy-CrC 4 alkyl (preferably C 4 -alkoxy-C 2 -C 4 alkyl), before all for 2-methoxyethyl or 2-ethoxyethyl, or for C 3 -C 6 -cycloalkyl, especially for cyclopropyl.
  • C 4 cyanoalkyl preferably C 2 -C 4 -fluoroalkyl
  • C 4 cyanoalkyl especially for 2- cyanoethyl
  • a particularly preferred embodiment of embodiment C.1.1 relates to compounds I. C
  • Ar, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , X 1 , and X 2 has one of the general meanings given above or preferably one of the abovementioned preferred meanings;
  • X 3 and X 4 are N or CH, with the proviso that they do not simultaneously represent N;
  • R 17 is selected from dC 4 -fluoroalkyl (preferably C 2 -C 4 -fluoroalkyl), CrC 4 -
  • Cyanoalkyl Ci-C4-alkoxy-Ci-C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 -Fluorcycloalkyl, d- C 4 alkylcarbonyl, aminocarbonyl, Ci-C4-alkylaminocarbonyl, CrC 4 -
  • Fluoralkylaminocarbonyl di- (Ci-C 4 alkyl) aminocarbonyl, di- (dC 4 fluoroalkyl) - aminocarbonyl, aminosulfonyl, Ci-C4-alkylaminosulfonyl, Ci-C 4 - Fluoralkylaminosulfonyl, di- (Ci-C 4 - alkyl) -aminosulfonyl and di- (dC 4 -fluoroalkyl) -aminosulfonyl.
  • R 17 is selected in formula I.
  • C under dC 4 fluoroalkyl preferably C 2 -C 4 fluoroalkyl
  • C r C 4 cyanoalkyl preferably C 2 -C 4 cyanoalkyl
  • dC 4 -alkoxy-dC 4 - alkyl preferably Ci-C 4 -alkoxy-C 2 -C 4 alkyl
  • C 3 -C 6 cycloalkyl C 3 -C 6 -Fluorcycloalkyl
  • dd fluoroalkyl preferably C 2 -C 4 fluoroalkyl
  • dC 4 cyanoalkyl preferably C 2 -C 4 - cyanoalkyl
  • Ci-C 4 alkoxy-Ci-C4-alkyl
  • R 17 in formula I C is C 1 -C 4 -fluoroalkyl (preferably C 2 -C 4 -fluoroalkyl), especially fluoroethyl, in particular 2-fluoroethyl, 2,2-difluoroethyl or 2,2, 2-trifluoroethyl, for dC 4 cyanoalkyl (preferably C 2 -C 4 cyanoalkyl), especially 2-cyanoethyl, 4 alkoxy dC dC-4 alkyl (preferably C 4 -alkoxy-C 2 - C 4 alkyl), especially for 2-methoxyethyl or 2-ethoxyethyl, or for C 3 -C 6 cycloalkyl, especially for cyclopropyl.
  • fluoroethyl in particular 2-fluoroethyl, 2,2-difluoroethyl or 2,2, 2-trifluoroethyl
  • dC 4 cyanoalkyl preferably C 2
  • C is one of the variables X 3 , X 4 is N and the other is CH.
  • X 3 is N and X 4 is CH. In an alternative particularly preferred embodiment, X 3 is CH and X 4 stands for N.
  • both variables X 3 , X 4 stand for CH.
  • Ar has one of the meanings given above as being preferred or particularly preferred.
  • Ar is phenyl.
  • R 1 , R 2 and R 3 reference is made to the preceding statements.
  • R 1 is H or methoxy
  • R 2 is H and R 3 is H or methoxy. More particularly, R 1 is methoxy, R 2 is H and R 3 is methoxy.
  • R 5 and R 6 have one of the meanings given above as being preferred or particularly preferred.
  • R 5 is ethoxy and R 6 is H.
  • X 2 is N or CH and especially N.
  • R 7 is in the 5-position and R 8 is attached in the 6-position of the 2,3-dihydroindol-2-one ring.
  • R 7 and R 8 have one of the meanings given above as being preferred or particularly preferred.
  • R 7 is CN and R 8 is H or F, or R 7 is Cl and R 8 is H or F.
  • X 1 is NR 9 or O.
  • R 9 is preferably H or methyl and especially H.
  • X 1 is NR 9 , where R 9 is preferably H or methyl and stands specifically for H.
  • R 12 is selected from piperidinyl and piperazinyl, which are attached via a group B and one radical R 17 and optionally one or two or more Substituents carry R 18 , wherein B, R 17 and R 18 have one of the above general or preferably one of the above or below specified preferred meanings.
  • R 18 is preferably C 1 -C 4 -alkyl and in particular methyl.
  • piperidinyl or piperazinyl radical R 12 does preferably bear no substituent R 18 .
  • R 12 is piperidin-1-yl, piperidin-4-yl, in the embodiment C.1.2
  • R 4 is piperidin-1-yl which bears R 12 linked via a group B in the 4-position, or piperazin-4-yl, or R4 is piperazin-1-yl which bears R 12 linked via a group B in the 4-position, wherein R 12 is piperidin-4-yl.
  • R 4 is piperidin-1-yl which bears R 12 linked via a group B in the 4-position, wherein R 12 is piperidin-4-yl or piperazin-4-yl, or R 4 is piperazine -1- yl which R 12 is bonded via a group B in the 4-position bears, wherein R 12 is piperidin-4-yl.
  • piperidin-4-yl ring or the piperazin-4-yl ring R 12 in the 1-position carry a radical R 17 which has one of the meanings given above or preferably as below has.
  • R 17 is preferred in this case selected from hydrogen, Ci-C 4 alkyl, dC 4 fluoroalkyl, dC 4 cyanoalkyl, Ci-C 4 -alkoxy-C r C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 -Fluorcycloalkyl, C r C 4 - alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl 4 dC, dC ⁇ Fluoralkylaminocarbonyl, di- (Ci-C 4 alkyl) aminocarbonyl, di- (dC 4 fluoroalkyl) aminocarbonyl, aminosulfonyl, -C 4 - alkylaminosulfonyl, -C ⁇ Fluoralkylaminosulfonyl, di (-C 4 alkyl) aminosulfonyl and di- (-C 4 fluoroalkyl) aminosulfonyl.
  • R 17 is selected from hydrogen, dC 4 alkyl, dC 4 fluoroalkyl (preferably C 2 -C 4 fluoroalkyl), and C 3 -C 6 cycloalkyl, more preferably hydrogen, -C 3 alkyl, such as methyl, Ethyl, n-propyl or isopropyl, C 1 -C 3 -fluoroalkyl, such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1, 1-difluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl ( preferably C 2 -C 4 -fluoroalkyl, such as 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl
  • B in the embodiment C.1.2 is preferably selected from CO and CH 2 and stands in particular for CO.
  • R 12 is a saturated heteromonocyclic 4- or 5-membered radical having 1 or 2 nitrogen atoms as ring members, the radical R 17 and optionally 1 or two further Substituents R 18 carries and which may also be bound via a group B, wherein B, R 17 and R 18 have one of the above general or preferably one of the above or below specified preferred meanings.
  • R 18 is preferably C 1 -C 4 -alkyl and in particular methyl.
  • heteromonocyclic radical in R 12 bears no substituent R 18 .
  • the heteromonocyclic radical R 12 is preferably selected from azetidinyl, in particular azetidin-3-yl or azetidin-1-yl, and pyrrolidinyl, in particular pyrrolidin-3-yl or pyrrolidin-1-yl, and is particularly preferably azetidinyl and in particular azetidine 3-yl or azetidin-1-yl.
  • heteromonocyclic 4- or 5-membered radical R 12 carries the substituent
  • R 17 in the 1-position if he has the 3-position at the remainder R 4 or the group B gebudendndenn , odedeerr iinn ddeerr 33-position, if he over the 1-position to the remainder R 4 or the group B is bound.
  • R C is preferably 17 thereby selected from hydrogen, -C 4 alkyl, dC 4 fluoroalkyl, dC 4 cyanoalkyl, Ci-C4-alkoxy-Ci-C 4 alkyl, C 3 -C 6 cycloalkyl, 3 -C 6 -Fluorcycloalkyl, Ci-C 4 - alkylcarbonyl, CrC 4 -Fluoralkylcarbonyl, dC 4 alkoxycarbonyl, dC 4 -Fluoralkoxy- carbonyl, aminocarbonyl, Ci-C4-alkylaminocarbonyl, Ci-C (4 -Fluoralkylaminocarbonyl, di- Ci -C 4 alkyl) aminocarbonyl, di- (Ci-C4 fluoroalkyl) aminocarbonyl, aminosulfonyl, dC 4 - alkylaminosulfonyl, dd-Fluoralkyl
  • R 17 is particularly preferably selected from hydrogen, dd-alkyl, amino, dd-alkylamino, di (dC 4 -alkyl) amino, dC 4 -alkoxycarbonyl, Aminocarbonyl, C 1 -C 4 alkylaminocarbonyl, di (C 1 -C 4 alkyl) aminocarbonyl, aminosulfonyl, C 1 -C 4 alkylaminosulfonyl and di (C 1 -C 4 alkyl) aminosulfonyl, and more preferably under hydrogen, C 1 -C 4 alkyl , Amino, C 1 -C 4 -alkylamino and di- (C 1 -C 4 -alkyl) -amino.
  • B is preferably selected from NR 22 , CO and CH 2 , more preferably from NR 22 and CO and is in particular NR 22 .
  • R 22 is preferably H or C 1 -C 4 -alkyl and in particular H or methyl.
  • R 12 is a saturated heterobicyclic 7-, 8-, 9- or 10-membered radical having 1 or 2 nitrogen atoms as ring members, the radical R 17 and optionally 1 or two further Substituents R 18 bears and which may also be bound via a group B, wherein B, R 17 and R 18 have one of the above general or preferably one of the above or below given preferred meanings.
  • R -> 18 is preferably C 1 -C 4 -alkyl and in particular methyl.
  • heterobicyclic radical R 12 bears no substituent R 18 .
  • the heterobicyclic radical R 12 is preferably selected from radicals of the following formulas
  • R 17 and the binding site to R 4 and to group B may also be on a nitrogen atom (and replace H in the above formulas);
  • R 17 is as defined above.
  • R 17 is preferred in this case selected from hydrogen, -C 4 alkyl, -C 4 fluoroalkyl, C 4 d- cyanoalkyl, Ci-C 4 -alkoxy-CrC 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 -Fluorcycloalkyl, Ci-C 4 - alkylcarbonyl, dC 4 -Fluoralkylcarbonyl, dC 4 alkoxycarbonyl, dC 4 -Fluoralkoxy- carbonyl, aminocarbonyl, alkylaminocarbonyl 4 dC, dC 4 -Fluoralkylaminocarbonyl, di- (Ci-C 4 alkyl) aminocarbonyl, di- (Ci-C4 fluoroalkyl) aminocarbonyl, aminosulfonyl, CrC 4 - alkylaminosulfonyl, Ci-C 4 -Flu
  • R 17 is particularly preferably selected from hydrogen, C 1 -C 4 -alkyl, amino, C 1 -C 4 -alkylamino, di- (C 1 -C 4 -alkyl) amino, C 1 -C 4 -alkoxycarbonyl, aminocarbonyl, C 1 -C 4 -alkylaminocarbonyl, Di- (C 1 -C 4 -alkyl) aminocarbonyl, aminosulfonyl, C 1 -C 4 -alkylaminosulfonyl and di- (C 1 -C 4 -alkyl) -aminosulfonyl, and more preferably under hydrogen, C 1 -C 4 -alkyl, amino, C 1 -C 4 Alkylamino and di (Ci-C 4 alkyl) amino.
  • R 17 is hydrogen, C r C 4 alkyl, C r C 4 fluoroalkyl, or C 3 -C 6 - cycloalkyl, and in particular hydrogen, -C 4 alkyl, such as methyl, ethyl, n-propyl or isopropyl , C 1 -C 3 -fluoroalkyl, such as fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl, or cyclopropyl.
  • R 17 is hydrogen or C 1 -C 4 alkyl, such as methyl, ethyl, n-propyl or isopropyl, and more particularly for Hydrogen or methyl.
  • the radical R 12 is bonded via a group B, then B is preferably selected from NR 22 , CO and CH 2 , more preferably from NR 22 and CO and is in particular CO.
  • R 22 is preferably H or C 1 -C 4 -alkyl and in particular H or methyl.
  • the heterobicyclic radical R 12 is bonded directly to R 4 , ie not via the group B.
  • R 12 is a saturated heteromonocyclic or heterobicyclic 4-, 5-, 6-, 7-, 8-, 9- or 10-membered radical having 1 or 2 nitrogen atoms as ring members, which bears a radical R 17 and optionally 1 or two further substituents R 18 and which is bonded via a group B, where B, R 17 and R 18 have one of the abovementioned general or preferably one of the above or below given preferred meanings.
  • R 18 is preferably C 1 -C 4 -alkyl and in particular methyl.
  • heteromonocyclic or heterobicyclic radical R 12 does not bear any substituent R 18 .
  • the heteromonocyclic radical R 12 is preferably 4-, 5- or 6-membered.
  • the heteromonocyclic radical is particularly preferably selected from azetidinyl, pyrrolidinyl, piperidinyl and piperazinyl, and more preferably from azetidin-3-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-4-yl and piperazine-1 yl.
  • the heterobicyclic radical R 12 is preferably 7-, 8-, 9- or 10-membered. Particularly preferably, the heterobicylic radical is selected from among the radicals described in C.2.
  • B is preferably selected from NR 22 , CO and CH 2 and more preferably from NR 22 and CO.
  • R 22 is preferably H or C 1 -C 4 -alkyl and in particular H or methyl.
  • R 12 is NR 15 R 16 , wherein R 15 and R 16 have one of the abovementioned general or preferably one of the preferred meanings given above or below.
  • R 15 is preferably H or C 1 -C 4 -alkyl and in particular H or methyl.
  • R 16 stands for -C 4 -alkyl which is optionally substituted by cyano, dC 4 alkoxy, amino, dC 4 alkylamino or di- (dC 4 alkyl) amino is substituted, more preferably C 2 -C 4 - alkyl substituted by cyano, dC 4 alkoxy, amino, Ci-C 4 alkylamino or di (CrC 4 - alkyl) amino is substituted, and in particular C 2 -C 4 alkyl substituted by 4-amino dC , C 1 -C 4 -alkylamino or di- (C 1 -C 4 -alkyl) -amino.
  • R 12 is C 1 -C 6 -alkyl which may be substituted by cyano, C 1 -C 4 -alkoxy, amino, C 1 -C 4 -alkylamino or di- (C 1 -C 4 -alkyl) -amino can, particularly preferably for C 1 -C 6 -alkyl which is substituted by cyano, C 1 -C 4 -alkoxy, amino, C 1 -C 4 -alkylamino or di- (C 1 -C 4 -alkyl) -amino and in particular for C 1 -C 4 -alkyl, by Amino, C 1 -C 4 -alkylamino or di- (C 1 -C 4 -alkyl) -amino.
  • R 4 is a saturated 7-, 8-, 9- or 10-membered heterobicyl radical having 1 or 2 nitrogen atoms as ring members, which via a nitrogen atom to the carbonyl group of the radical -X 1 - CO- and having a radical R 12 and optionally 1 or 2 further substituents R 13 bears, wherein R 12 and R 13 have one of the above general or preferably one of the above or below given preferred meanings.
  • the heterobicyclic radical R 4 bears no substituent R 13 .
  • the heterobicyclic radical R 4 is preferably selected from radicals of the following formulas
  • R 12 may also be on a nitrogen atom when the bicyclic ring contains two ring nitrogen atoms (and replaces H at these nitrogens) and where R 12 may also be attached via a group B;
  • B and R s12 have one of the general meanings given above, or preferably one of the meanings given below.
  • R 12 is an A-, 5- or ⁇ -membered saturated heteromonocyclic radical which may also be bonded via a group B and which carries a radical R 17 .
  • R 12 is azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl.
  • R 12 is bonded via a group B, this is preferably selected from CH 2 , CO and NR 22 and more preferably from CO and NR 22 .
  • R 22 is preferably H or methyl.
  • R 17 is preferably selected from hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 - Fluoroalkyl, Ci-C4-alkoxy-Ci-C 4 alkyl, C r C 4 cyanoalkyl, C 3 -C 6 cycloalkyl, and C 3 -C 6 - fluorocycloalkyl, particularly preferably from hydrogen, dC 4 alkyl, and C 3 -C 6 cycloalkyl, more preferably hydrogen, dC 4 alkyl and cyclopropyl, and in particular from hydrogen and C r C 4 alkyl.
  • Examples of preferred embodiment of the present invention are compounds of formulas 1.1 to 1.22 and the pharmaceutically acceptable salts and prodrugs thereof, wherein the radicals X 1, X 2, A, R 1, R 3, R 7, R 8, R 11, R 12 , R 15 , R 16 and R 17 have the general or particularly preferred meanings given above, and wherein R 12 'has one of the meanings given in Tables 3999 to 4030 below and in which X 3 and X 4 are CH or N, with provided that they are not simultaneously N in compounds 1.6 and 1.14.
  • the radicals are particularly preferred X 1, X 2, A, R 1, R 3, R 7, R 8, R 11, R 12, R 12 ', R 15, R 16 and R 17 which (in Tables 1-4166 A, R 11 , R 12 , R 12 ', R 15 , R 16 and R 17 ) and in Table A (X 1 , X 2 , R 1 , R 3 , R 7 , R 8 ) given meanings.
  • Table 33 Compounds of the formula 1.1, in which R 11 is 1-ethoxycarbonylpyrrolidin-3-yl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A.
  • Table 50 Compounds of the formula 1.1, in which R 11 is 1-methylpiperidin-4-yl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A.
  • Table 71 Compounds of the formula 1.1, wherein R 11 is 1- (piperidin-4-yl) -piperidin-4-yl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 is in each case one Line in Table A corresponds
  • Tables 361 to 432 Compounds of the formula 1.3, in which R 11 is as defined in one of Tables 1 to 72, the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A. and A stands for CO
  • Tables 721 to 792 Compounds of the formula 1.3, wherein R 11 is as defined in one of Tables 1 to 72, the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A. and A is -CH 2 CH 2 CH 2 -CO-
  • Table 872 Compounds of the formula 1.3, in which R 11 is azetidin-1-yl, A is -CO-CH 2 CH 2 - and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds to one row in Table A.
  • Tables 895 to 904 Compounds of the formula 1.3, wherein A is as defined in one of Tables 865 to 874, the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A and R 11 is piperazin-1-yl
  • Tables 945 to 954 Compounds of the formula 1.3, wherein A is as defined in one of Tables 865 to 874, the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A and R 11 is 4-butylpiperazin-1-yl
  • Tables 995 to 1004 Compounds of the formula 1.3, wherein A is as defined in one of Tables 865 to 874, the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A and R 11 is 4-methoxycarbonylpiperazin-1-yl
  • Tables 1005 to 1014 Compounds of formula 1.3, wherein A is as defined in any one of Tables 865 to 874, the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A and R 11 to 4 -Ethoxycarbonylpiperazin-1-yl is Table 1015 to 1024 Compounds of Formula 1.3 wherein A is as defined in any one of Tables 865 to 874, the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 each corresponds to one line in Table A, and R 11 is 4-propoxycarbonylpiperazin-1-yl, Table 1025-1034
  • Tables 1 115 to 1124 Compounds of the formula 1.3, wherein A is as defined in one of Tables 865 to 874, the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A. and R 11 is 4- (piperidin-4-yl) piperazin-1-yl
  • Tables 2269 to 2340 Compounds of the formula 1.6, wherein R 11 is as defined in one of Tables 1 to 72, the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A. and A is 1, 3-propylene
  • Tables 2341 to 2412 Compounds of the formula 1.6 in which R 11 is as defined in one of Tables 1 to 72, the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A and A for 1 , 4-Butylene stands
  • Tables 2413 to 2484 Compounds of the formula 1.6, in which R 11 is as defined in one of Tables 1 to 72, the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A. and A stands for CO
  • Tables 2773 to 2844 Compounds of the formula 1.6, in which R 11 is as defined in one of Tables 1 to 72, the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 is in each case one
  • Tables 2937 to 2946 Compounds of the formula 1.6, wherein A is as defined in one of the Tables 2917 to 2926, the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A and R 11 is piperidin-1-yl
  • Tables 2987 to 2996 Compounds of the formula 1.6, wherein A is as defined in one of the tables 2917 to 2926, the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A and R 11 is 4-isopropylpiperazin-1-yl
  • Tables 3037 to 3046 Compounds of the formula 1.6, wherein A is as defined in one of the Tables 2917 to 2926, the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A and R 11 is 4-cyclopropylpiperazin-1-yl
  • Tables 3087 to 3096 Compounds of the formula 1.6, wherein A is as defined in one of the tables 2917 to 2926, the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A and R 11 is 4-butoxycarbonylpiperazin-1-yl
  • Tables 3097 to 3106 Compounds of formula 1.6, wherein A is as defined in any one of Tables 2917 to 2926, the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A and R 11 to 4 sec-butoxycarbonyl-piperazin-i-yl
  • Tables 3107 to 31 16 Compounds of the formula 1.6, in which A is as defined in one of the Tables 2917 to 2926, the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A. and R 11 is 4-isobutoxycarbonylpiperazin-1-yl
  • Tables 3157 to 3166 Compounds of the formula 1.6, wherein A is as defined in one of the Tables 2917 to 2926, the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A and R 11 is 4- (1-methylpyrrolidin-3-yl) piperazin-1-yl
  • Table 3195 Compounds of formula 1.7, wherein R 17 is 3-cyanopropyl, X 3 is N, X 4 is CH and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 is in each case one line in Table A corresponds
  • Table 3206 Compounds of formula 1.7 wherein R 17 is 2-fluorocyclopropyl, X 3 is N, X 4 is CH and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 is one each Line in Table A corresponds
  • Table 3212 Compounds of formula 1.7, wherein R 17 is aminosulfonyl, X 3 is N, X 4 is CH and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 is in each case one line in Table A. corresponds to
  • X 4 is CH and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one row in Table A.
  • Table 3301 Compounds of the formula 1.8, wherein R 17 is carboxy, X 3 is N, X 4 is CH and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 is in each case one line in Table A corresponds
  • X 4 is CH and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one row in Table A.
  • Tables 3419 to 3455 Compounds of the formula 1.9, wherein R 17 is as defined in one of the Tables 3271 to 3307 and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A.
  • Tables 3604 to 3640 Compounds of the formula 1.13 in which R 17 is as defined in one of Tables 3271 to 3307 and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A.
  • Tables 3641 to 3677 Compounds of formula 1.14 in which R 17 is as defined in one of Tables 3271 to 3307 and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A.
  • Tables 3678 to 3714 Compounds of the formula 1.15 in which R 17 is as defined in one of Tables 3271 to 3307, X 3 is N, X 4 is CH and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one row in Table A.
  • X 2 corresponds in each case to one row in Table A.
  • Tables 3863 to 3899 Compounds of the formula 1.18 in which R 17 is as defined in one of Tables 3271 to 3307 and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A.
  • Table 3902 Compounds of the formula 1.19 in which R 15 is H, R 16 is ethyl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A.
  • Table 3911 Compounds of the formula 1.19 in which R 15 is H, R 16 is 3-methoxypropyl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A.
  • Table 3912 Compounds of the formula 1.19 in which R 15 is H, R 16 is ethoxymethyl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A.
  • Table 3918 Compounds of the formula 1.19 in which R 15 is H, R 16 is 2-aminoethyl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A.
  • Table 3929 Compounds of the formula 1.19 in which R 15 is H, R 16 is 4- (methylamino) -butyl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 is in each case one row in Table A
  • Table 3930 corresponds to compounds of the formula 1.19 in which R 15 is H, R 16 is 4- (dimethylamino) -butyl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 is in each case one line Table A corresponds to Table 3931
  • R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one row in Table A.
  • Table 4009 Compounds of the formula 1.20 in which R 12 'is 3-methoxypropyl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A.
  • Table 4014 Compounds of the formula 1.20 in which R 12 'is 2-cyanoethyl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A.
  • Table 4037 Compounds of the formula 1.21 in which R 12 is 1-isopropylazetidin-3-yl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A.
  • Table 4046 Compounds of the formula 1.21 in which R 12 is 1-ethylpyrrolidin-3-yl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A.
  • Table 4055 Compounds of the formula 1.21 in which R 12 is piperidin-3-yl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A.
  • Table 4069 Compounds of the formula 1.21 in which R 12 is 4- (2-fluoroethyl) -piperazin-1-yl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 is in each case one row in Table A corresponds to
  • R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one row in Table A.
  • Table 4081 Compounds of the formula 1.21, in which R 12 is methoxymethyl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A.
  • Table 4086 Compounds of the formula 1.21 in which R 12 is 2-ethoxypropyl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A.
  • Table 4109 Compounds of the formula I.22, in which R 12 is 1-propylazetidin-3-yl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A.
  • Table 4124 Compounds of the formula 1.22 in which R 12 is 1-cyclopropylpyrrolidin-3-yl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A.
  • Table 4132 Compounds of the formula 1.22, wherein R 12 is 1- (2-fluoroethyl) -piperidin-4-yl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 is in each case one line in Table A corresponds
  • R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one row in Table A.
  • R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one row in Table A.
  • Table 4146 Compounds of the formula 1.22 in which R 12 is ethoxymethyl and the combination of R 1 , R 3 , R 7 , R 8 , X 1 and X 2 corresponds in each case to one line in Table A.

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Abstract

La présente invention concerne de nouveaux dérivés oxindoliques substitués, des produits pharmaceutiques contenant ces dérivés et leur utilisation dans le traitement de maladies vasopressine-dépendantes.
PCT/EP2008/066937 2007-12-07 2008-12-05 Dérivés oxindoliques et leur utilisation comme médicament Ceased WO2009071691A2 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010142739A1 (fr) * 2009-06-10 2010-12-16 Abbott Gmbh & Co. Kg Utilisation de dérivés substitués de l’oxindole pour le traitement et la prophylaxie de la douleur
WO2014140186A1 (fr) 2013-03-14 2014-09-18 AbbVie Deutschland GmbH & Co. KG Dérivés d'oxindole à substituant oxétane et leur utilisation pour le traitement de maladies liées à la vasopressine
WO2015091934A1 (fr) * 2013-12-20 2015-06-25 AbbVie Deutschland GmbH & Co. KG Dérivés d'oxindole à substituant piperidyl-azétidinyl à substitution amine et leur utilisation pour traiter les maladies liées à la vasopressine
WO2015091931A1 (fr) 2013-12-20 2015-06-25 AbbVie Deutschland GmbH & Co. KG Dérivés d'oxindole à substituant azétidinyl substitué par pipéridyl, et leur utilisation pour le traitement de maladies liées à la vasopressine
WO2015173392A1 (fr) 2014-05-15 2015-11-19 AbbVie Deutschland GmbH & Co. KG Dérivés d'oxindole à substituant spiro à liaison co, et leur utilisation pour le traitement de maladies liées à la vasopressine

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FR2714378B1 (fr) * 1993-12-24 1996-03-15 Sanofi Sa Dérivés de l'indol-2-one substitués en 3 par un groupe azoté, leur préparation, les compositions pharmaceutiques en contenant.
FR2827604B1 (fr) * 2001-07-17 2003-09-19 Sanofi Synthelabo Nouveaux derives de 1-phenylsulfonyl-1,3-dihydro-2h-indol-2- one, un procede pour leur preparation et les compositions pharmaceutiques en contenant
US20050070718A1 (en) * 2003-09-30 2005-03-31 Abbott Gmbh & Co. Kg Heteroaryl-substituted 1,3-dihydroindol-2-one derivatives and medicaments containing them
DE102004033834A1 (de) * 2004-07-13 2006-02-02 Abbott Gmbh & Co. Kg Substituierte Oxindol-Derivate und diese enthaltende Arzneimittel
DE102005014904A1 (de) * 2005-03-26 2007-02-01 Abbott Gmbh & Co. Kg Substituierte Oxindol-Derivate, diese enthaltende Arzneimittel und deren Verwendung
DE102005014936A1 (de) * 2005-03-24 2006-12-14 Abbott Gmbh & Co. Kg Substituierte Oxindol-Derivate, diese enthaltende Arzneimittel und deren Verwendung
PT2114921E (pt) * 2006-12-30 2013-03-26 Abbott Gmbh & Co Kg Derivado de oxindol substituído e sua utilização como ligante do recetor de vasopressina
UY30846A1 (es) * 2006-12-30 2008-07-31 Abbott Gmbh & Amp Derivados de oxindol sustituidos, medicamentos que los comprenden y uso de los mismos
WO2008080971A1 (fr) * 2006-12-30 2008-07-10 Abbott Gmbh & Co. Kg Dérivé d'oxindole substitué et son utilisation comme ligand du récepteur de la vasopressine
EP2114922B1 (fr) * 2006-12-30 2013-04-24 Abbott GmbH & Co. KG Dérivé d'oxindole substitué et son utilisation comme modulateur du récepteur de la vasopressine

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010142739A1 (fr) * 2009-06-10 2010-12-16 Abbott Gmbh & Co. Kg Utilisation de dérivés substitués de l’oxindole pour le traitement et la prophylaxie de la douleur
WO2014140186A1 (fr) 2013-03-14 2014-09-18 AbbVie Deutschland GmbH & Co. KG Dérivés d'oxindole à substituant oxétane et leur utilisation pour le traitement de maladies liées à la vasopressine
CN105339366A (zh) * 2013-03-14 2016-02-17 艾伯维德国有限责任两合公司 带有取代的氧杂环丁烷的2-吲哚酮衍生物及其治疗血管加压素相关疾病的用途
US9657002B2 (en) 2013-03-14 2017-05-23 AbbVie Deutschland GmbH & Co. KG Oxindole derivatives carrying an oxetane substituent and use thereof for treating vassopressin-related diseases
WO2015091934A1 (fr) * 2013-12-20 2015-06-25 AbbVie Deutschland GmbH & Co. KG Dérivés d'oxindole à substituant piperidyl-azétidinyl à substitution amine et leur utilisation pour traiter les maladies liées à la vasopressine
WO2015091931A1 (fr) 2013-12-20 2015-06-25 AbbVie Deutschland GmbH & Co. KG Dérivés d'oxindole à substituant azétidinyl substitué par pipéridyl, et leur utilisation pour le traitement de maladies liées à la vasopressine
US9840495B2 (en) 2013-12-20 2017-12-12 AbbVie Deutschland GmbH & Co. KG Oxindole derivatives carrying a piperidyl-substituted azetidinyl substituent and use thereof for treating vasopressine-related diseases
US9862704B2 (en) 2013-12-20 2018-01-09 AbbVie Deutschland GmbH & Co. KG Oxindole derivatives carrying an amine-substituted piperidyl-acetidinyl substituent and use thereof for treating vasopressine-related diseases
WO2015173392A1 (fr) 2014-05-15 2015-11-19 AbbVie Deutschland GmbH & Co. KG Dérivés d'oxindole à substituant spiro à liaison co, et leur utilisation pour le traitement de maladies liées à la vasopressine

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